Cinnolines as par4 antagonists and medical applications thereof

Abstract

The application discloses a cinnoline PAR4 antagonist and medical application thereof. The application relates to a compound of formula (I), stereoisomers, tautomers, pharmaceutically acceptable salts, esters, solvates or prodrugs thereof. The compound of the application can inhibit and prevent platelet aggregation induced by PAR4, can be used for treating and preventing thromboembolic diseases, and thus can be used as an anti-platelet drug.

Description

Technical Field

[0001] This invention belongs to the field of chemical drug technology, and specifically provides compounds of phenobarbital PAR4 antagonists for antiplatelet aggregation. Technical Background

[0002] Thromboembolic diseases have become the leading cause of death worldwide, but currently available antiplatelet drugs still have various side effects, such as low efficacy, high bleeding risk, and significant individual variability. Thrombin plays a central role in the coagulation process and is a strong platelet inducer. Its activation of human platelets is mainly mediated by two PARs (PAR1 and PAR4) receptors. PAR1 receptors have a stronger affinity for thrombin, while PAR4 receptors have a relatively weaker affinity. Inhibitors of the PAR1 receptor have been extensively studied, with Vorapaxar reaching late-stage clinical trials, but its clinical trials were terminated due to a significantly increased bleeding risk. Therefore, research has focused on the PAR4 receptor.

[0003] In recent years, several small molecule PAR4 antagonists have been published, but overall research is still in its early stages. Based on their structural core, PAR4 small molecule antagonists can be classified into indazoles, indoles, imidazole [2,1-b][1,3,4]thiadiazoles, and quinoline and quinoxaline structural types. Among them, Bristol-Myers Squibb's oral PAR4 antagonists BMS-986120 and BM-S986141 are in phase II and phase III clinical trials, respectively. To date, no oral small molecule PAR4 antagonists have been marketed. Recently, Bristol-Myers Squibb has published patents reporting quinoxaline and quinoline-based PAR4 antagonists. Therefore, there is an urgent clinical need to develop a novel PAR4 receptor antagonist with a low bleeding risk.

[0004] The patents WO2013 / 163244, WO2013 / 163279, WO2013 / 163241, WO2016 / 134450, WO2016 / 138199 and WO2017 / 066863 disclose imidazole[2,1-b][1,3,4]thiadiazole PAR4 small molecule antagonists.

[0005]

[0006] Quinoxaline-based PAR4 small molecule antagonists are disclosed in patents WO2018 / 013772, WO2017 / 019828, WO2018 / 013770, WO2018 / 013774 and WO2018 / 013776.

[0007]

[0008] There is still a need for compounds that can be used to inhibit platelet aggregation. Summary of the Invention

[0009] One of the objectives of this invention is to provide a morpholino compound with PAR4 antagonistic activity.

[0010] The morphine compounds provided by this invention include their stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs, and have PAR4 antagonistic activity that can selectively inhibit platelet aggregation activity.

[0011] A second objective of this invention is to provide the use of the compound of the invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs in the preparation of medicaments for the treatment or prevention of thromboembolic diseases.

[0012] The specific technical solution of the present invention is as follows:

[0013] The present invention comprises compounds of formula (Ⅰ) or pharmaceutically acceptable salts, esters or solvates thereof:

[0014]

[0015] in:

[0016] R1 is C that is substituted or unsubstituted. 1-4 alkoxy groups, wherein the substituents are selected from hydroxyl, halogen, C 1-2 Alkyl, C 1-2 Alkoxy, heterocyclic; substituted or unsubstituted C 1-4 Alkyl groups, wherein the substituents are selected from hydroxyl, halogen, C 1-2 Alkoxy groups, heterocycles; C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-3 fluoroalkoxy, C 1-4 Fluoroalkylthio group, -(CH2) 1-3 O(C 1-4 Alkyl), -COO(C 1-5 Alkyl), -CONR a R a pyrrolidone-1-yl, furanyl, pyranyl, piperidin-1-yl, C 3-7 Fluorocycloalkyl, -S(O)2(C 1-3 Alkyl group), -S(O)2NR a R a morpholino-4-yl, piperazine-1-yl, C 1-3Alkylthio, fluorine, chlorine, hydroxyl, hydrogen; R a Independently selected from H or -CH3;

[0017] R2 is selected from H, halogens, -OH, -CN, and C. 1-4 Alkyl, C 1-4 fluoroalkyl, C 1-4 fluoroalkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkoxy, C 1-6 Alkoxy, C 1-3 Alkyl mercapto;

[0018] R3 is selected from C 6-20 The aryl group or heterocycle having 1 to 3 heteroatoms selected from N, O or S is surrounded by 0 to 3 R atoms. 3a replace;

[0019] R 3a Independently selected from H, halogens, -CN, -OH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Alkylthio group, -COO(CH2) 1-3 -CONH(CH2) 1-3 -O(CH2) m -C 6-10 Aryl, -O(CH2) m -5-10 aromatic heterol groups, -O(CH2) m -5-10 membered heterocyclic group; m is 0, 1, 2, 3 or 4;

[0020] In a preferred embodiment of the present invention, the compound of formula (I) or its pharmaceutically acceptable salt, ester or solvation: R1 is selected from H, halogen, -OH, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2, -(CH2) 1-3 O(CH2) 1-4 Preferably, R1 is selected from H, -OH, -Cl, -OCH3, -OCHF2, -OCH2F, -OCH2CH3, -CH3, -NH2, -NHCH3, -N(CH3)2, -CH2OCH3; more preferably, R1 is selected from -H, -Cl, -OH, -OCH3, -OCHF2; in a specific example, R1 is -OCH3.

[0021] As a preferred embodiment of the present invention, the compound of formula (I) or its pharmaceutically acceptable salt, ester or solvate: R2 is selected from H, -Cl, -CH3, -CH2CH3, -OCH3, -OCHF2; preferably R2 is selected from H, -CH3, -OCH3; in a specific example, R2 is -CH3.

[0022] In a preferred embodiment of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt, ester or solvation thereof: R3 is selected from compounds consisting of 0 to 3 R's. 3a The following groups are substituted: phenyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, imidazoleyl, furanyl, oxazolyl, pyrrolidinyl, pyridinyl, pyrazinyl, isoxazolyl, benzo[d]imidazolyl, benzo[b]thiophenyl, benzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzofuranyl, indolyl, 1-naphthylcyclol, thiazo[4,5-b]pyridinyl, quinolinyl, isoquinolinyl, fluorenyl, diphenylcarbazyl, carbazolyl, anthraceneyl, indole.

[0023] In some more specific instances, R3 is selected from 0 to 3 R... 3a The following groups are substituted: phenyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, imidazoleyl, furanyl, oxazolyl, pyrroloyl, pyrimidinyl, pyrazinyl, isoxazolyl, benzo[d]imidazolyl, benzo[b]thiophene, benzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzofuranyl, indolyl, 1-naphthylcycloyl, thiazo[4,5-b]pyridyl.

[0024] Preferably, R3 is selected from:

[0025]

[0026] Where n is 0, 1, 2 or 3.

[0027] The R of the present invention 3a The substitution position can be any position that R3 is allowed from a chemical structure perspective, and each can be independently selected from H, halogen, -CN, -OH, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 fluoroalkyl, C 1-3 fluoroalkoxy, C 1-3 Alkylthio, -OC 6-10 Aryl, -O-5-10 aryl; in some preferred embodiments, R 3a Each is independently selected from H, halogen, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, trifluoromethyl, trifluoromethoxy, and phenoxy.

[0028] As a further preferred embodiment of the present invention, the compound of formula (I) or its pharmaceutically acceptable salt, ester or solvation is selected from any one of the following compounds or their pharmaceutically acceptable salt, ester or solvation:

[0029]

[0030]

[0031] The compound shown in (I) of this invention, or its pharmaceutically acceptable salt, ester, or solvate, is characterized in that the pharmaceutically acceptable salt refers to the compound forming a salt with an organic or inorganic acid, wherein the organic or inorganic acid may be selected from: acetylsalicylic acid, fumaric acid, methanesulfonic acid, ethanesulfonic acid, sulfuric acid, hydrochloric acid, formic acid, acetic acid, benzenesulfonic acid, hydrobromic acid, lactic acid, phosphoric acid, oxalic acid, 2-hydroxyethanesulfonic acid, gentian acid, tartaric acid, succinic acid, maleic acid, lauric acid, citric acid, camphoric acid, n-dodecyl sulfonic acid, adipic acid, ascorbic acid, trifluoroacetic acid, formic acid, tannic acid, and picric acid.

[0032] The present invention also provides a pharmaceutical composition comprising the compounds mentioned herein, pharmaceutically acceptable salts, esters or solvates thereof as active ingredients and pharmaceutically acceptable carriers.

[0033] Pharmaceutical compositions formed from the compounds mentioned in this invention, their pharmaceutically acceptable salts, esters, or solvates, can be prepared in pharmaceutically permissible dosage forms, such as capsules, tablets, granules, pills, injections, powders, syrups, oral liquids, inhalers, ointments, suppositories, and patches.

[0034] The present invention also provides the use of compound of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof in the preparation of PAR4 antagonists.

[0035] The present invention also provides the use of compound (I) or a pharmaceutically acceptable salt, ester or solvate thereof in the preparation of medicaments for the prevention and / or treatment of thromboembolic diseases.

[0036] The compound of formula (I) of the present invention or its pharmaceutically acceptable salt, ester or solvate can inhibit platelet aggregation by antagonizing PAR4 expression on platelets, and therefore can be used for the prevention and treatment of thromboembolic diseases.

[0037] The compounds of this invention can be prepared in many ways known to those skilled in the art of organic synthesis. The compounds of this invention can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry, or by variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction mixture is carried out in a solvent or solvent mixture suitable for the reagents and materials used and adapted to the transformation. Those skilled in the art of organic synthesis will understand that the functional groups present on the molecule should be consistent with the proposed transformation. This sometimes requires judgment to modify the order of synthetic steps or to choose a particular process scheme instead of another to obtain the desired compound of this invention.

[0038] It will also be recognized that another key consideration in planning any synthetic route in the art is the prudent selection of protecting groups for protecting the reactive functional groups present in the compounds described in this invention.

[0039] In some embodiments, the present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt, ester, or solvation thereof, said method being selected from Scheme 1, Scheme 2, or Scheme 3:

[0040] Scheme 1: Compound (I) can be prepared by palladium-catalyzed cross-coupling of aryl halides of formula Ia with organometallic substance R3-M:

[0041]

[0042] Scheme 2: Compounds of formula (I) can be prepared by palladium-catalyzed cross-coupling of arylboronic acid or boronic ester of formula Ib with halide R3-X:

[0043]

[0044] Scheme 3: Oxidate the amino group of compound Ic to obtain compound Id; react compound Id with dimethyl malonate to obtain Ie; hydrolyze and decarboxylate compound Ie to obtain compound If; esterify compound If to obtain compound Ig; reduce the nitro group of compound Ig to obtain compound Ih; react compound Ih with NOBF4 to obtain compound Ii; react compound Ii with Pb(OAc)4 to obtain Ij; methylate compound Ij to obtain Ia; and boronize compound Ia to obtain compound Ib via the Miyaura reaction.

[0045]

[0046] Unless otherwise stated, the terms and phrases used in this invention shall be understood in their ordinary sense unless otherwise specified.

[0047] The present invention is defined as follows:

[0048] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0049] "Aryl" refers to an all-carbon monocyclic or fused polycyclic group with 1 to 14 carbon atoms, possessing a fully conjugated π-electron system. Non-limiting examples of aryl groups include phenyl, naphthyl, and anthracene.

[0050] "Heterocycle" refers to a 3-14 membered aromatic or non-aromatic heterocycle containing 1-4 heteroatoms selected from O, N and S, including bicyclic or tricyclic groups; "heterocyclic group" includes heteroaryl groups, as well as their dihydrogenated and tetrahydrogenated analogs. Detailed Implementation

[0051] The present invention will be specifically illustrated below through embodiments. In this invention, the embodiments described below are for better explanation and are not intended to limit the scope of the invention. Various changes and modifications can be made to the present invention without departing from its spirit and scope.

[0052] Example 1

[0053] 8-(4-chloro-6-methoxybenzo[d]thiazo-2-yl)-3-methoxy-6-methyl-cenline (compound 1)

[0054]

[0055] Compound 1-1 (30.00 g, 147.03 mmol) was dissolved in 1,2-dichloroethane (350 mL). 85% m-CPBA (119.40 g, 588.12 mmol) was slowly and gradually added in portions under ice-water bath conditions. After the addition was complete, the mixture was stirred at room temperature for 20 min, then heated to 70 °C and reacted in the dark for 4 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed three times with a small amount of dichloromethane. The filtrate was washed once with 2 M NaOH, followed by washing with 10% sodium sulfite solution. The results were confirmed by starch-potassium iodide test paper. The filtrate was then concentrated under reduced pressure to obtain 38.5 g of a reddish-brown liquid. ESI-MS: m / z 235.23 [M+H] + 257.34 [M+Na] + .

[0056] Compounds 1-2 (38.5 g, 164.52 mmol) were dissolved in N,N-dimethylformamide (250 mL), and cesium carbonate (107.21 g, 329.03 mmol) was added, followed by the slow dropwise addition of dimethyl malonate (65.20 g, 493.55 mmol) under stirring at room temperature for 8 h. The reaction mixture was partitioned between aqueous 1 M HCl and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 6:1) to give a white solid. 1H NMR (500MHz, CDCl3) δ7.52(s,1H),7.44(s,1H),4.64(s,1H),3.82(s,6H),2.45(s,3H).

[0057] Compounds 1-3 were mixed with glacial acetic acid (100 mL) and concentrated HCl (100 mL) and stirred at room temperature for 30 min, followed by heating at 110 °C for 8 h. After the reaction was completed by TLC, the reaction solution was cooled to room temperature, and water (150 mL) and ethyl acetate (150 mL) were added. The mixture was stirred and separated. The aqueous phase was washed twice with ethyl acetate (60 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1) to give 23.57 g of a brownish-yellow solid. 1 HNMR(500MHz,DMSO-d6)δ12.71(s,1H),7.68(s,1H),7.38(s,1H),3.68(s,2H),2.38(s,3H).

[0058] Compounds 1-4 (23.57 g, 86.00 mmol) were dissolved in dichloromethane (100 mL). Oxaloyl chloride (21.83 g, 172.00 mmol) was added to the mixture under ice-water bath conditions, followed by approximately 15 drops of DMF. The mixture was stirred at room temperature for 1 h, and the reaction was monitored by TLC until completion. Methanol was then added dropwise at 0 °C until no more bubbles were observed. The mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 6:1) to give 15.70 g of a yellow oil. 1 H NMR (500MHz, DMSO-d6) δ7.69(s,1H),7.40(s,1H),3.78(s,2H),3.63(s,3H),2.38(s,3H).

[0059] Compounds 1-5 (15.00 g, 52.07 mmol) were dissolved in methanol (150 mL), followed by the addition of ammonium chloride (55.70 g, 1041.31 mmol) and mixed thoroughly. Zinc powder (34.04 g, 520.65 mmol) was then added, and the mixture was reacted at room temperature for 15 h under nitrogen protection. The reaction was monitored by TLC until it was complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 6:1) to obtain 14.28 g of a pale yellow oily liquid. 1 H NMR (500MHz, DMSO-d6) δ7.17(s,1H),6.84(s,1H),4.83(s,2H),3.64(s,2H),3.63(s,3H),3.34(s,2H).

[0060] Compounds 1-6 (14.28 g, 55.32 mmol) were suspended in dichloromethane (80 mL) at 0 °C. NOBF4 (6.46 g, 55.32 mmol) was then added to the system in portions. The mixture was stirred at 0 °C for 1 h under nitrogen protection, and the reaction was monitored by TLC until completion. At 0 °C, the mixture was added directly to a vigorously stirred solution of stannous chloride (41.96 g, 221.29 mmol) in concentrated hydrochloric acid (80 mL). The reaction solution was gradually heated to room temperature and reacted at room temperature for 24 h. The reaction was monitored by TLC until completion. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the mixture was stirred and separated. The aqueous phase was washed twice with ethyl acetate (60 mL × 2). The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 5:1) to give 6.28 g of a white solid. 1 H NMR (500MHz, DMSO-d6) δ7.24(s,1H),7.06(s,1H),5.02(s,2H),3.54(s,2H),2.26(s,3H).

[0061] Compounds 1-7 (6.28 g, 26.05 mmol) were suspended in 50 mL of dichloromethane at 0 °C. Pb(OAc)4 (23.10 g, 52.10 mmol) was added to the reaction mixture, and the reaction was carried out at room temperature for 8 h under nitrogen protection. After the reaction was complete as monitored by TLC, the reaction solution was filtered through a silica gel pad, the filtrate was concentrated under reduced pressure, and purified by column chromatography (EA:CH3OH = 2:1) to give 5.60 g of a yellow solid. 1 HNMR(500MHz,DMSO-d6)δ7.58(s,1H),7.26(s,1H),7.16(s,1H),2.33(s,3H).

[0062] Compounds 1-8 (5.60 g, 23.42 mmol) were dissolved in N,N-dimethylformamide (70 mL), stirred until homogeneous, and then cesium carbonate (15.26 g, 46.85 mmol) was added. After stirring at room temperature for 30 min, iodomethane (6.65 g, 46.85 mmol) was added, and the reaction was carried out at room temperature for 20 min. The reaction was monitored by TLC until it was complete. The reaction solution was added dropwise to ice water (150 mL), extracted with ethyl acetate (60 mL × 3), the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 3:1) to give 5.00 g of yellow solid. 1 H NMR (500MHz, DMSO-d6) δ7.57(s,1H),7.24(s,1H),7.20(s,1H),3.96(s,3H),2.33(s,3H).

[0063] Compounds 1-9 (200 mg, 0.79 mmol) were dissolved in ultradry 1,4-dioxane (20 mL), and pinacol diboronate (530 mg, 2.07 mmol), potassium acetate (260 mg, 2.69 mmol), and XPhos Pd G2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection, heated to 85 °C for 3 h, and the reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and ice water (20 mL) and ethyl acetate (20 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (20 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 240 mg of a brown solid. ESI-MS: m / z 300.36 [M+H] + .

[0064] Compound 1-10 (240 mg, 0.79 mmol) was dissolved in toluene (15 mL) and water (3 mL). 2-Bromo-4-chloro-6-methoxybenzo[d]thiazole (270 mg, 0.96 mmol), sodium carbonate (250 mg, 2.40 mmol), and XPhos Pd G2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 4 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 6:1) to give 20 mg of a brownish-yellow solid. 1 H NMR(500MHz, CDCl3)δ8.43(s,1H),7.36-7.32(m,1H),7.23-7.20(m,1H),7. 18(s,1H),7.16(s,1H),4.22(s,3H),3.94(s,3H),2.52(s,3H).ESI-MS:m / z 372.06[M+H] + 394.04 [M+Na] + .

[0065] Example 2

[0066] 8-(benzofuran-2-yl)-3-methoxy-6-methyl-zonoline (compound 2)

[0067]

[0068] Compounds 1-9 (200 mg, 0.79 mmol) were dissolved in toluene (15 mL) and water (3 mL). Benzofuran-2-boronic acid (150 mg, 0.95 mmol), sodium carbonate (250 mg, 2.37 mmol), and XPhos Pd G2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 3 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 10:1) to give 90 mg of a brownish-yellow solid. 1H NMR (500MHz, DMSO-d6) δ7.96 (s, 1H), 7.77 (d, J = 8.5Hz, 2H), 7.66 (d, J = 8.2Hz, 1H), 7.41 (t, J = 7. 6Hz,1H),7.32(t,J=7.4Hz,1H),7.25(s,1H),7.22(s,1H),4.06(s,3H),2.41(s,3H).ESI-MS:m / z 291.11[M+H]+,313.09[M+Na]+.

[0069] Example 3

[0070] 8-(4-Methoxybenzo[d]thiazo-6-yl)-3-methoxy-6-methyl-cenline (Compound 3)

[0071]

[0072] Compound 1-10 (200 mg, 0.79 mmol) was dissolved in toluene (15 mL) and water (3 mL). 6-bromo-4-methoxybenzo[d]thiazole (230 mg, 0.94 mmol), sodium carbonate (250 mg, 2.37 mmol), and XPhosPd G2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 4 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 10:1) to give 20 mg of a brownish-yellow solid. 1H NMR(500MHz, CDCl3)δ9.00(s,1H),7.77(s,1H),7.22(s,1H),7.18(s,1H),7.16( d,J=6.2Hz,2H),4.14(s,3H),4.05(s,3H),2.47(s,3H).ESI-MS:m / z338.09[M+H] + 360.08 [M+Na] + .

[0073] Example 4

[0074] 8-(3a,4,5,6,7,7a-hexahydrobenzo[d]thiazo-2-yl)-3-methoxy-6-methyl-cenline (compound 4)

[0075]

[0076] Compound 1-10 (200 mg, 0.79 mmol) was dissolved in toluene (15 mL) and water (3 mL). 2-Bromo-3a,4,5,6,7,7a-hexahydrobenzo[d]thiazole (210 mg, 0.94 mmol), sodium carbonate (250 mg, 2.37 mmol), and XPhos Pd G2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 4 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 10:1) to give 20 mg of brown solid. 1 H NMR (500MHz, CDCl3) δ8.17(d,J=6.3Hz,1H),7.14(s,1H),7.11(s,1H),4.19(s,3H),2.93(dd,J=6.2Hz,4H),2.46(s,3H),1.96(dd,4H).ESI-MS: m / z 312.12[M+H] + 334.10[M+Na] + .

[0077] Example 5

[0078] 8-(4-Trifluoromethylphenyl)-3-methoxy-6-methyl-zonoline (Compound 5)

[0079]

[0080] Compounds 1-9 (200 mg, 0.79 mmol) were dissolved in toluene (15 mL) and water (3 mL). 4-(trifluoromethyl)phenylboronic acid (180 mg, 0.94 mmol), sodium carbonate (250 mg, 2.37 mmol), and XPhos PdG2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 3 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 10:1) to give 100 mg of a bright yellow solid. 1 H NMR (500MHz, CDCl3) δ7.77-7.72(m,4H),7.14(s,2H),7.08(d,J=1.5Hz,1H),4.04(s,3H),2.45(s,3H).ESI-MS:m / z 319.10[M+H] + 341.09 [M+Na] + .

[0081] Example 6

[0082] 8-(2-Methylpyridin-4-yl)-3-methoxy-6-methyl-cenline (Compound 6)

[0083]

[0084] Compounds 1-9 (200 mg, 0.79 mmol) were dissolved in toluene (15 mL) and water (3 mL). (2-methylpyridin-4-yl)boronic acid (130 mg, 0.94 mmol), sodium carbonate (250 mg, 2.37 mmol), and XPhos PdG2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 3 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 10:1) to give 90 mg of yellow solid. 1H NMR(500MHz, CDCl3)δ8.60(d,J=5.1Hz,1H),7.39(s,1H),7.35(d,J=5.2Hz,1H),7.14 (s,1H),7.13(s,1H),7.08(s,1H),4.04(s,3H),2.67(s,3H),2.45(s,3H).ESI-MS:m / z 266.13[M+H] + 288.11[M+Na] + .

[0085] Example 7

[0086] 8-(2-Chloro-4-methoxyphenyl)-3-methoxy-6-methyl-cenline (Compound 7)

[0087]

[0088] Compounds 1-9 (200 mg, 0.79 mmol) were dissolved in toluene (15 mL) and water (3 mL). 2-chloro-4-methoxyphenylboronic acid (180 mg, 0.94 mmol), sodium carbonate (250 mg, 2.37 mmol), and XPhos PdG2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 3 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 8:1) to give 110 mg of a bright yellow solid. 1 H NMR (500MHz, CDCl3) δ7.27(d,J=8.5Hz,1H),7.12(s,1H),7.11(s,1H),7.08(d,J=2.6Hz,1H), 6.97(s,1H),6.93(dd,J=8.5,2.6Hz,1H),3.98(s,3H),3.90(s,3H),2.43(s,3H).ESI-MS:m / z 315.08[M+H] + 337.07 [M+Na] + .

[0089] Example 8

[0090] 8-(2,4-Dichlorophenyl)-3-methoxy-6-methyl-zonoline (Compound 8)

[0091]

[0092] Compounds 1-9 (200 mg, 0.79 mmol) were dissolved in toluene (15 mL) and water (3 mL). 2,4-Dichlorophenylboronic acid (180 mg, 0.94 mmol), sodium carbonate (250 mg, 2.37 mmol), and XPhos Pd G2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 3 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 8:1) to give 60 mg of a bright yellow solid. 1 H NMR (500MHz, CDCl3) δ7.54 (d, J = 2.0Hz, 1H), 7.37 (dd, J = 8.2, 2.1Hz, 1H), 7.30 (d, J = 4. 6Hz,1H),7.15(s,1H),7.12(s,1H),6.97(s,1H),3.97(s,3H),2.44(s,3H).ESI-MS:m / z 319.04[M] + 341.02 [M+Na] + .

[0093] Example 9

[0094] 3-Methoxy-6-methyl-8-(4-phenoxyphenyl)zoline (compound 9)

[0095]

[0096] Compounds 1-9 (200 mg, 0.79 mmol) were dissolved in toluene (15 mL) and water (3 mL). (4-phenoxyphenyl)boronic acid (210 mg, 0.94 mmol), sodium carbonate (250 mg, 2.37 mmol), and XPhos PdG2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 3 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 8:1) to give 90 mg of bright yellow solid. 1H NMR (500MHz, CDCl3) δ7.61(d,J=8.2Hz,2H),7.42(t,J=7.9Hz,2H),7.19(t,J=7.4Hz,1H),7.15(s,1H), 7.13(s,2H),7.12(s,1H),7.11(s,1H),7.08(s,1H),7.07(s,1H),4.06(s,3H),2.44(s,3H).ESI-MS:m / z 343.14[M+H] + 365.13 [M+Na] + .

[0097] Example 10

[0098] 8-(5-Methoxybenzo[d]thiazo-2-yl)-3-methoxy-6-methyl-cenline (Compound 10)

[0099]

[0100] Compound 1-10 (200 mg, 0.79 mmol) was dissolved in toluene (15 mL) and water (3 mL). 2-Bromo-5-methoxybenzo[d]thiazole (230 mg, 0.94 mmol), sodium carbonate (250 mg, 2.37 mmol), and XPhosPd G2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 4 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 10:1) to give 10 mg of red solid. 1 H NMR (500MHz, CDCl3) δ8.38(s,1H),8.06(d,J=8.9Hz,1H),7.45(d,J=2.5Hz,1 H),7.19(d,J=7.2Hz,3H),4.24(s,3H),3.96(s,3H),2.51(s,3H).ESI-MS:m / z 338.09[M+H] + 360.08 [M+Na] + .

[0101] Example 11

[0102] 8-(9,9-dimethyl-9H-fluorene-2-yl)-3-methoxy-6-methylcenline (Compound 11)

[0103]

[0104] Compound 1-10 (200 mg, 0.79 mmol) was dissolved in toluene (15 mL) and water (3 mL). 9,9-Dimethyl-9H-fluorene-2-boronic acid (230 mg, 0.94 mmol), sodium carbonate (250 mg, 2.37 mmol), and XPhos PdG2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 3 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 8:1) to give 110 mg of a yellow solid. 1 H NMR (500MHz, CDCl3) δ7.84(d,J=7.8Hz,1H),7.81(d,J=6.6Hz,1H),7.74(s,1H),7.62(d,J=7.8Hz,1H),7.51(d,J=6.4 Hz,1H),7.40(d,J=6.5Hz,2H),7.17(d,J=3.3Hz,2H),7.11(s,1H),4.07(s,3H),2.47(s,3H),1.59(s,6H).ESI-MS:m / z 367.18[M+H] + 389.16 [M+Na] + .

[0105] Example 12

[0106] 8-(benzo[b]thiophene-2-yl)-3-methoxy-6-methylzoline (compound 12)

[0107]

[0108] Compound 1-10 (200 mg, 0.79 mmol) was dissolved in toluene (15 mL) and water (3 mL). Benzo[b]thiophene-2-boronic acid (170 mg, 0.94 mmol), sodium carbonate (250 mg, 2.37 mmol), and XPhos Pd G2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 3 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 8:1) to give 90 mg of a reddish-brown solid.1 H NMR(500MHz, CDCl3)δ8.01(s,1H),7.93-7.85(m,2H),7.47(s,1H),7.41(tt,J=7 .2,5.5Hz,2H),7.13(s,1H),7.08(s,1H),4.19(s,3H),2.45(s,3H).ESI-MS:m / z 307.09[M+H] + 329.07 [M+Na] + .

[0109] Example 13

[0110] 3-Methoxy-6-methyl-8-(quinolin-8-yl)zoline (Compound 13)

[0111]

[0112] Compound 1-10 (200 mg, 0.79 mmol) was dissolved in toluene (15 mL) and water (3 mL). Quinoline-8-boronic acid (160 mg, 0.94 mmol), sodium carbonate (250 mg, 2.37 mmol), and XPhos Pd G2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 3 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 8:1) to give 90 mg of yellow solid. 1 H NMR (500MHz, CDCl3) δ8.85(s,1H),8.27(d,J=8.3Hz,1H),7.95(d,J=8.1Hz,1H),7.75(d,J=7.0Hz,1H),7.67(t,J= 7.6Hz, 1H), 7.44 (dd, J=8.3, 4.2Hz, 1H), 7.17 (d, J=6.9Hz, 2H), 7.13 (s, 1H), 3.78 (s, 3H), 2.46 (s, 3H). ESI-MS: m / z 302.13[M+H] + 324.11[M+Na] + .

[0113] Example 14

[0114] 3-Methoxy-6-methyl-8-(4-methylnaphth-1-yl)zoline (Compound 14)

[0115]

[0116] Compound 1-10 (200 mg, 0.79 mmol) was dissolved in toluene (15 mL) and water (3 mL). 4-methylnaphthalene-1-boronic acid (180 mg, 0.94 mmol), sodium carbonate (250 mg, 2.37 mmol), and XPhos Pd G2 (20 mg, 0.027 mmol) were added. The mixture was purged three times under nitrogen protection and heated to 85 °C for 3 h. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:EA = 8:1) to give 100 mg of yellow solid. 1 H NMR (500MHz, CDCl3) δ8.11(d,J=8.5Hz,1H),7.57-7.52(m,2H),7.44(d,J=7.1Hz,1H),7.42-7.36( m,2H),7.19(s,1H),7.17(s,1H),7.09(s,1H),3.81(s,3H),2.82(s,3H),2.45(s,3H).ESI-MS:m / z 315.15[M+H] + 337.13[M+Na] + .

[0117] Evaluation of in vitro antiplatelet aggregation activity

[0118] Assay Principle: AYPGKF-NH2 is a PAR4-specific agonist peptide that selectively activates PAR4 expression, thereby inducing platelet aggregation. The compound of this invention antagonizes platelet PAR4, thereby inhibiting platelet aggregation. The assay used washed platelets derived from mouse arterial plasma.

[0119] Pipette 300 μL of Tyrode's buffer into a clean test cup, place it in the platelet aggregation test area, and zero the instrument. The instrument reading panel should display "PRP" mode. Then, accurately pipette 270 μL of washed platelet suspension into the preheating bath. Add 20 μL of physiological saline or different concentrations of the test sample, incubate at 37°C for 5 min, and then place it in the test area. Add magnetic beads to the test cup sequentially, and immediately press the buttons for each channel to display "DP" mode. Then, add 10 μL of AYPGKF-NH2 inducer, and immediately press the buttons for each channel to display "RP" mode to start testing the aggregation rate. Finally, the aggregator displays the maximum platelet aggregation rate within 5 min. Calculate the platelet aggregation inhibition rate using the following formula: Platelet aggregation inhibition rate = [(XY) / X]*100%, where X is the maximum platelet aggregation rate in the physiological saline group, and Y is the maximum platelet aggregation rate of the compound. BMS-986120 is a PAR4 antagonist developed by BMS and is currently in Phase II clinical trials. The IC50 measured in this study... 50 =9.7 nM, which is basically consistent with the experimental data in the literature (9.5 nM). Experimental results for some compounds are as follows:

[0120]

[0121] (Note: A: 0.1-20 nM; B: 20-100 nM; C: 100 nM-1000 nM)

[0122] The results show that the compounds of the present invention have significant antiplatelet aggregation activity.

Claims

1. A compound of formula (Ⅰ) or a pharmaceutically acceptable salt thereof: ; in: R1 is -OCH3; R2 is -CH3; R3 is selected from phenyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, imidazoleyl, furanyl, oxazolyl, pyrroloyl, pyridinyl, pyridazinyl, isoxazolyl, benzo[d]imidazolyl, benzo[b]thiophene, benzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzofuranyl, indolyl, 1-naphthylcyclol, thiazo[4,5-b]pyridinyl, quinolinyl, isoquinolinyl, fluorenyl, diphenylcarbazyl, carbazolyl, anthraceneyl, indole; R3 is separated by 0 to 3 R 3a replace; R 3a Independently selected from H, halogens, -CN, -OH, C 1-3 Alkyl, C 1-3 Alkoxy, -OC 6-10 Aryl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R3 is selected from 0 to 3 R3. 3a The following groups are substituted: phenyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, imidazoleyl, furanyl, oxazolyl, pyrroloyl, pyrimidinyl, pyrazinyl, isoxazolyl, benzo[d]imidazolyl, benzo[b]thiophene, benzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzofuranyl, indolyl, 1-naphthylcyclol, thiazo[4,5-b]pyridinyl.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R3 is selected from: ； Where n is 0, 1, 2 or 3.

4. The compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, characterized in that: R in the same compound 3a Same or different, R 3a Each is independently selected from H, halogen, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and phenoxy.

5. Any of the following compounds or their pharmaceutically acceptable salts: 。 6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that, The pharmaceutically acceptable salt refers to a compound that forms a salt with an organic or inorganic acid, wherein the organic or inorganic acid is selected from: acetylsalicylic acid, fumaric acid, methanesulfonic acid, ethanesulfonic acid, sulfuric acid, hydrochloric acid, formic acid, acetic acid, benzenesulfonic acid, hydrobromic acid, lactic acid, phosphoric acid, oxalic acid, 2-hydroxyethanesulfonic acid, gentian acid, tartaric acid, succinic acid, maleic acid, lauric acid, citric acid, camphoric acid, n-dodecyl sulfonic acid, adipic acid, ascorbic acid, trifluoroacetic acid, formic acid, tannic acid, and picric acid.

7. A method for preparing the compound of formula (I) according to claim 1, wherein the method is selected from scheme 1 or scheme 2: Scheme 1: Compound (I) can be prepared by palladium-catalyzed cross-coupling of aryl halides of formula Ia with organometallic substance R3-M: ； Scheme 2: Compounds of formula (I) can be prepared by palladium-catalyzed cross-coupling of arylboronic acid or boronic ester of formula Ib with halide R3-X: ； in, R1, R2, and R3 are as described in claim 1.

8. A pharmaceutical composition comprising the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

9. The use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or the composition of claim 8 in the preparation of a PAR4 antagonist.

10. The use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or the composition of claim 8 in the preparation of a medicament for the prevention and / or treatment of PAR4-mediated thromboembolic diseases.

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