Benzotriazine compound with PAR4 antagonistic activity and application thereof
阅读说明：本技术 一种具有par4拮抗活性的苯并三嗪类化合物及其应用 (Benzotriazine compound with PAR4 antagonistic activity and application thereof ) 是由 朱雄 刘尚德 孔毅 张玮琪 袁铎 张韬 郑毅政 张纵硕 于 2020-05-15 设计创作，主要内容包括：本发明公开了一种具有PAR4拮抗活性的苯并三嗪类化合物及其应用。本发明涉及式(I)化合物或其立体异构体、互变异构体、药学上可接受的盐、酯、溶剂化物或前药,本发明化合物对PAR4具有显著的拮抗活性,从而有效抑制血小板聚集,因而可用于制备预防或治疗多种血栓栓塞性疾病的药物。<Image he="335" wi="384" file="DDA0002494108410000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a phentriazine compound with PAR4 antagonistic activity and application thereof. The invention relates to compounds of formula (I)Or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, an ester, a solvate or a prodrug thereof, has remarkable antagonistic activity on PAR4, so that the compound can effectively inhibit platelet aggregation, and can be used for preparing medicaments for preventing or treating various thromboembolic diseases.)
1. A compound of formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof,
wherein:
R1selected from: substituted or unsubstituted C1-4Alkyl, said substituents being selected from hydroxy, C1-3Alkoxy, heterocycle; - (CH)2)1- 3Osi(Rb) Wherein R isbIs selected from C1-4An alkyl group; -C (O) NRaRa，-C(O)O(C1-6Alkyl), -NH (C)1-6Alkyl), H, halogen, -OH, C1-4Fluoroalkyl radical, C3-7Cycloalkyl radical, C1-3Alkoxy radical, C2-4Hydroxyalkoxy, C3-6Cycloalkoxy, -NH2、N(C1-6Alkyl radical)2Azetidin-1-yl, pyrrolidin-1-yl, furanyl, pyranyl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, -S (O)2(C1-3Alkyl), -S (O)2NRaRaOr C1-3An alkylthio group; raIndependently selected from H or-CH3；
R2Selected from: H. halogen, -OH, -CN, C1-4Alkyl radical, C1-4Fluoroalkyl radical, C1-4Hydroxy alkaneBase, C1-6Alkoxy radical, C1-3Fluoroalkoxy radical, C1-3An alkylthio group;
R3is a bicyclic group selected from indolyl, benzofuranyl, benzothienyl, quinolinyl, benzoxazolyl, benzothiazolyl, imidazopyridinyl, thiazolopyridyl, tetrahydrobenzothiazolyl, tetrahydrobenzofuranyl, tetrahydrobenzopyridyl, 5,6,7, 8-tetrahydro-4H-cyclohepta [5,4-c ] o]Thiazolyl, 5, 6-dihydro-4H-cyclopenta [ d ]]Thiazolyl, indolizinyl, pyrrolo [1,2-a ]]Pyrimidinyl, 6, 7-dihydrothiazolo [5,4-c]Pyridyl, 6, 7-dihydro-5H-imidazo [2,1-b ]][1,3]Oxazinyl, furo [3,2-b ]]Pyridyl, phenylpyridin-2-yl, or 1H-pyrrolo [2,3-b ] s]Pyridin-6-yl substituted with 0-3R per bicyclic group3a；
R3aIndependently selected from: H. halogen, -CN, -OH, C1-3Alkyl radical, C1-3Fluoroalkyl radical, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, 3-to 6-membered heterocyclyl, -C (O) OH, -C (O) O (C)1-6Alkyl), wherein each of said heterocyclyl groups is substituted with 0-5 substituents independently selected from: halogen, -CN, C1-3Alkyl radical, C1-4Hydroxyalkyl radical, C1-3Alkoxy, -OCF3、-OCHF2Or C1-3A hydroxyalkoxy group.
2. A compound of formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof according to claim 1, characterized in that:
R1selected from substituted or unsubstituted C1-4Alkyl, said substituents being selected from hydroxy, C1-3Alkoxy, morpholinyl; - (CH)2)1- 3Osi(Rb) Wherein R isbIs selected from-CH3、-CH2CH3、-(CH2)3CH3、-C(CH3)3；-C(O)NHCH3，-C(O)NRaRa，-C(O)O(C1-3Alkyl), -NH (C)1-3Alkyl groups);
R2selected from H, Cl, -CH3、-CH2CH3、-(CH2)3CH3；
R3Selected from substitution with 0 to 2R3aBenzo [ d ] o]Thiazolyl, 4-phenylpyridin-2-yl, 5-phenylpyridin-2-yl, 6-phenylpyridin-2-yl, quinolinyl, 4,5,6, 7-tetrahydrobenzo [ d ]]Thiazolyl, 6-phenylpyridin-2-yl and 1H-pyrrolo [2,3-b ]]Pyridin-6-yl; and is
R3aIndependently selected from F, Cl, C1-3An alkoxy group.
3. A compound of formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof according to claim 1, characterized in that:
R1is selected from
R2Selected from H, Cl or-CH3；
R3Is selected fromWherein X is Cl or F.
4. The compound of formula (I), or a pharmaceutically acceptable salt, ester or solvate thereof, according to claim 1, characterized by being selected from any one of the following compounds, or a pharmaceutically acceptable salt, ester or solvate thereof:
5. the compound of formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof according to any one of claims 1 to 4, wherein the pharmaceutically acceptable salt is prepared by salifying the compound of formula (I) according to any one of claims 1 to 4 with a relatively non-toxic acid or base, wherein the compound of formula (I) and the pharmaceutically acceptable acid addition salt are selected from inorganic acid salts, organic acid salts or amino acid salts, and the inorganic acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid; the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, glucuronic acid or methanesulfonic acid; the amino acid is selected from arginine; pharmaceutically acceptable base addition salts of the compounds of formula (I) include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts.
6. Use of a compound of formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof as claimed in any one of claims 1 to 4 in the manufacture of a medicament for the prevention and/or treatment of a thromboembolic disorder.
7. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable salt or ester or solvate thereof as an active ingredient and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is in the form of capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository, or patch.
9. A process for the preparation of a compound of formula (I) according to claim 1, characterized by being selected from any one of the following schemes:
scheme 1 compounds of formula (I) can be obtained by palladium catalyzed cross-coupling of aryl halides of formula Ia with organometallic species R3-M, the reaction scheme being:
scheme 2 compounds of formula I are prepared by palladium catalyzed cross-coupling of arylboronic acids or boronic esters of formula Ib with halides R3-X, the reaction scheme being:
Technical Field
The invention belongs to the technical field of chemical drugs, and particularly provides a compound serving as a PAR4 antagonist for resisting platelet aggregation.
Background
Thromboembolic diseases are one of the most causes of death in the world at present, and the existing antiplatelet medicaments have the defects of limiting the clinical safety and/or the practicability. Thrombin protease receptor-4 (PAR4), one of the three platelet G protein-coupled receptors (GPCRs) that binds thrombin (the other two are PAR1 and PAR3), mediates relatively slow, but highly robust, sustained calcium mobilization that is critical in the diffusion phase late in platelet activation (Wong, Seiffert et al 2017). Targeted antagonism of PAR4 may be safer and more effective, blocking sustained calcium signaling from PAR4 may prevent the growth of harmful stable thrombi while retaining PAR1 transient signaling to retain initial thrombus formation (angioillo 2017). Indazoles, indoles and imidazo [2,1-b ] [1,3,4] thiadiazole PAR4 antagonists are in preclinical or clinical research phase. Among them, oral PAR4 antagonists BMS-986120 and BMS-986141, developed by Bethes-Messajou-Guibao, were in second and third clinical studies, respectively. To date, no oral small molecule PAR4 antagonist has been marketed. Quinoxaline and quinoline PAR4 antagonists have recently been reported in patents published by the centuries meissnobao company. Therefore, there is a clinical need to develop a highly potent PAR4 receptor antagonist of a novel structure for prophylactic and therapeutic use in the patient population suffering from a disease associated with thrombosis, embolism, hypercoagulation or fibrotic changes.
There are several PAR4 antagonist patent applications published, e.g. CN104583218A disclosing a series of PAR4 antagonists of the formula for use in medicaments for inhibiting or preventing platelet aggregation.
EP1166785a1 and EP0667345 disclose various pyrazole derivatives useful as inhibitors of platelet aggregation.
PCT publications WO 2013/163279, WO 2013/163244 and WO 2013/163241 disclose various PAR4 antagonists useful as inhibitors of platelet aggregation.
There remains a need for compounds that can be used as inhibitors of platelet aggregation.
Disclosure of Invention
The invention aims to provide a phentriazine compound with PAR4 antagonistic activity.
Another object of the invention is to provide a pharmaceutical use of said bicyclic heteroaryl class of compounds as PAR4 antagonists. The compounds show remarkable antagonistic activity on PAR4 in vitro anti-platelet aggregation experiments, so that the compounds can effectively inhibit platelet aggregation, and can be used for preparing medicines for preventing or treating various thromboembolic diseases.
The invention relates to a compound as shown in the following formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof:
wherein:
R1selected from: substituted or unsubstituted C1-4Alkyl, said substituents being selected from hydroxy, C1-3Alkoxy, heterocycle; - (CH)2)1-3Osi(Rb) Wherein R isbIs selected from C1-4An alkyl group;-C(O)NRaRa，-C(O)O(C1-6alkyl), -NH (C)1-6Alkyl), H, halogen, -OH, C1-4Fluoroalkyl, -NH2、N(C1-6Alkyl radical)2Azetidin-1-yl, pyrrolidin-1-yl, furanyl, pyranyl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, -S (O)2(C1-3Alkyl), -S (O)2NRaRaOr C1-3An alkylthio group; raIndependently selected from H or-CH3；
R2Selected from: H. halogen, -OH, -CN, C1-4Alkyl radical, C1-4Fluoroalkyl radical, C1-4Hydroxyalkyl radical, C1-6Alkoxy radical, C1-3Fluoroalkoxy radical, C1-3An alkylthio group;
R3is a bicyclic group selected from indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, aryl substituted pyridyl, quinolinyl, imidazo [1,2-a]Pyridyl, thiazolopyridyl, 4,5,6, 7-tetrahydrobenzo [ d]Thiazolyl, 4,5,6, 7-tetrahydrobenzofuranyl, 4,5,6, 7-tetrahydrobenzo [5,4-c ]]Pyridyl, 4,5,6, 7-tetrahydrobenzothienyl, furopyridyl, and 1H-pyrrolo [2,3-b ] o]Pyridyl substituted with 0-3R per bicyclic group3a；
R3aIndependently selected from: H. halogen, -CN, -OH, C1-3Alkyl radical, C1-3Fluoroalkyl radical, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl, 3-to 6-membered heterocyclyl, -C (O) OH, -C (O) O (C)1-6Alkyl), wherein each of said heterocyclyl groups is substituted with 0-5 substituents independently selected from: halogen, -CN, C1-3Alkyl radical, C1-4Hydroxyalkyl radical, C1-3Alkoxy, -OCF3、-OCHF2Or C1-3A hydroxyalkoxy group;
as a preferred embodiment of the present invention, a compound of formula (I) or formula (II):
R1selected from substituted or unsubstituted C1-4Alkyl, said substituent being selected from the group consisting of hydroxy,C1-3Alkoxy, morpholinyl; - (CH)2)1-3Osi(Rb) Wherein R isbIs selected from-CH3、-CH2CH3、-(CH2)3CH3、-C(CH3)3；-C(O)NHCH3，-C(O)NRaRa，-C(O)O(C1-3Alkyl), -NH (C)1-3Alkyl groups);
R2selected from H, -CH3、-CH2CH3、-(CH2)3CH3；
R3Selected from substitution with 0 to 2R3aBenzo [ d ] o]Thiazolyl, 4-phenylpyridin-2-yl, 5-phenylpyridin-2-yl, 6-phenylpyridin-2-yl, quinolinyl, 4,5,6, 7-tetrahydrobenzo [ d ]]Thiazolyl, 6-phenylpyridin-2-yl and 1H-pyrrolo [2,3-b ]]Pyridin-6-yl; and is
R3aIndependently selected from F, Cl, C1-3An alkoxy group.
As a further preferred embodiment of the invention, a compound of formula (I) or formula (II):
R1is selected from
R2Is selected from H or-CH3；
R3Is selected fromWherein X is Cl or F.
As a further preferred embodiment of the present invention, the compound represented by formula (I), or a pharmaceutically acceptable salt, ester or solvate thereof, is selected from any one of the following compounds, or a pharmaceutically acceptable salt, ester or solvate thereof:
as a preferred embodiment of the present invention, the pharmaceutically acceptable salt is selected from salts of inorganic acids or organic acids, the inorganic or organic acid is selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, formic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, ethanic acid, ethanedisulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, trifluoroacetic acid, tannic acid, tartaric acid, and p-toluenesulfonic acid.
Another object of the present invention is to provide a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
The invention also aims to provide a pharmaceutical application, and the application refers to the application of the compound or the pharmaceutically acceptable salt thereof in preparing medicines for treating diseases related to thrombus.
Preferably, the thrombosis related disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, cerebrovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart or in the peripheral circulation.
The compounds of the invention can be prepared in a number of ways known to those skilled in the art of organic synthesis. The compounds of the invention can be synthesized using the methods described below, as well as synthetic methods known in the art 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 is carried out in a solvent or solvent mixture suitable for the kit materials used and for the conversion. Those skilled in the art of organic synthesis will appreciate that the functional groups present on the molecule should be consistent with the proposed transformations. This sometimes requires judgment to modify the order of the synthetic steps or to select one particular process scheme over another to obtain the desired compounds of the invention.
It will also be appreciated that another major consideration in planning any synthetic route in the art is the judicious choice of protecting groups for protecting reactive functional groups present in the compounds of the present invention.
As shown in scheme I, the compounds of formula (I) can be obtained by palladium catalyzed cross-coupling of aryl halides of formula Ia with an organometallic species R3-M.
Scheme 1
Alternatively, compounds of formula I may also be prepared by palladium catalyzed cross-coupling of arylboronic acids or boronic esters of formula Ib, as shown in scheme 2, with halides R3-X.
Scheme 2
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including such acids as formic acid, acetic acid, trifluoroacetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like; also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid and the like. Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.
Preferably, the neutral form of the compound is regenerated by contacting the salt or base or acid in a conventional manner and isolating the parent compound. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.
As used herein, "pharmaceutically acceptable salts" belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, for example, salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic or organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, formic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, hydrocarbonic acid, carbonic acid, citric acid, ethandisulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, trifluoroacetic acid, tannic acid, tartaric acid, and p-toluenesulfonic acid.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.
Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The present invention contemplates all such compounds, including the cis and trans isomers, the (-) -and (+) -enantiomers, the (R) -and (S) -enantiomers, the diastereomers, (D) -isomers, the (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
Optically active (R) -and (S) -isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents, or other conventional techniques, if one wishes to obtain one enantiomer of a compound of the invention, either by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, a compound such as tritium (3H), iodine-125 (125I) or C-14(14C) may be labeled with a radioisotope. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "pharmaceutically acceptable carrier" refers to any formulation vehicle or medium capable of delivering an effective amount of an active agent of the present invention, without interfering with the biological activity of the active agent and without toxic side effects to the host or patient, and representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. These include suspending agents, viscosity enhancers, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.
Has the advantages that:
the invention provides a series of compounds serving as protease activated receptor 4(PAR4) inhibitors for treating platelet aggregation and medical application thereof, and results show that the compounds have remarkable antagonistic activity on PAR4, so that the compounds can effectively inhibit the platelet aggregation, and can be used for preparing medicines for preventing or treating various thromboembolic diseases.
Detailed Description
The present invention will be described in detail with reference to examples. In the present invention, the following examples are given to better illustrate the present invention and are not intended to limit the scope of the present invention. Various changes and modifications may be made to the invention without departing from the spirit and scope of the invention.