Polysubstituted uracil derivatives and their preparation and application

Abstract

The present invention relates to a polysubstituted uracil derivative, and its preparation method and application.Specifically, the compound of the present invention has the structure shown in formula I, where the definition of each group and substituent is as described in the specification.The present invention further discloses the preparation method of said compound and its use in antithrombotic, cardiovascular disease and cerebrovascular disease treatment, etc.

Description

[Technical field]

[0001] The present invention relates to the field of medicine, specifically to polysubstituted uracil derivatives, and their preparation methods and applications. [Background technology]

[0002] Thrombosis can occur at any age and at any time, and has a high disability and mortality rate, seriously threatening human life and health. According to statistics, about 18 million people die from various thrombotic diseases around the world every year, and deaths from thrombotic diseases account for 51% of the total number of deaths in the world, ranking first in the total mortality rate in the world. In China, there are 1.5 million new thrombosis patients every year, and 2.5 million people suffer from thrombotic diseases every year, of which 70% of patients suffer from sequelae.

[0003] Currently, drugs commonly used in the prevention and treatment of thrombosis can achieve the purpose of inhibiting or reversing the formation of thrombus by intervening in various stages of the blood coagulation process (e.g., inhibiting the activity of blood coagulation factors, inhibiting platelet aggregation, etc.). For a long time, antithrombotic drugs have made great progress in terms of efficacy, etc. However, all antithrombotic drugs in clinical practice, whether they are old drugs that have been used for decades or new antithrombotic drugs released in recent years, are accompanied by various degrees of side effects, among which the risk of bleeding is a common drawback of all kinds of antithrombotic drugs, and may even become a life-threatening malignant risk. This defect limits the clinical application of such drugs and seriously threatens the drug safety of patients. There is currently no satisfactory clinical solution to this defect. Currently, most drugs (e.g., clopidogrel) do not have specific rescue drugs, and when severe bleeding occurs, only platelet replacement, fresh blood coagulation factors, etc. can be used as first aid. Therefore, clinically, there is an increasing market demand for mild antithrombotic drugs, and they are expected to be widely applied to the prevention and treatment of heart, brain and other arterial circulatory disorders caused by high platelet aggregation, such as recently diagnosed cerebral stroke, myocardial infarction, and confirmed peripheral arterial disease. Summary of the Invention [Problem to be solved by the invention]

[0004] The object of the present invention is to provide compounds according to formula I, their preparation process and their use in antithrombotic disorders. [Means for solving the problem]

[0005] A first aspect of the present invention provides a compound, the compound being represented by formula I, or a pharma- ceutically acceptable salt, solvate, hydrate, isomer or prodrug thereof: [ka] During the ceremony, R1 and R2 each independently represent H, a substituted or unsubstituted C1-C10 alkyl group, a halo C1-C10 alkyl group, a C3-C10 cycloalkyl group, a halo C3-C10 cycloalkyl group, a C1-C10 alkoxy group, a halo C1-C10 alkoxy group, -(C=O)-(C1-C10 alkyl), a C2-C10 alkenyl group, a C2-C10 alkynyl group, a halogen, a substituted or unsubstituted 5- to 6-membered alkyl group containing 1, 2, or 3 heteroatoms selected from N, O, or S. selected from the group consisting of a 10-membered heterocycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, -(C1-C6 alkylene)-(substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S), and -(C1-C6 alkylene)-(substituted or unsubstituted C6-C10 aryl); X is selected from the group consisting of O, S, and NH; Y is O, R3 is selected from the group consisting of H and a C1-C10 alkyl group; R4 is selected from the group consisting of H and a C1-C10 alkyl group; R5 is selected from the group consisting of H, a C1-C10 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and a substituted or unsubstituted C5-C12 bridged cycloalkyl group; each R6 is independently selected from the group consisting of H, a C1-C10 alkyl group, and -(C1-C6 alkylene)-(substituted or unsubstituted C6-C10 aryl); each m is independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; n is selected from the group consisting of 1, 2, 3 and 4; "Substituted" refers to, independently, a C1-C10 alkyl group, a -(C1-C6 alkylene)-piperazinyl group, a -(C1-C6 alkylene)-N, a 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from O or S, a halo C1-C10 alkyl group, a C1-C10 alkoxy group, a C1-C10 alkylthio group, CN, a nitro group, -NR a R b , -(C=O)-NR a R b , halogen, hydroxyl, and oxo; R a and R b are each independently selected from the group consisting of H, a C1-C10 alkyl group, and a haloC1-C10 alkyl group; Optionally, the alkylene group within the brackets is substituted by 1, 2 or 3 OH.

[0006] In another preferred embodiment, R1 and R2 are each independently selected from H, a substituted or unsubstituted C1-C6 alkyl group, a haloC1-C6 alkyl group, a C3-C8 cycloalkyl group, a haloC3-C8 cycloalkyl group, a C1-C6 alkoxy group, a haloC1-C6 alkoxy group, -(C=O)-(C1-C6 alkyl), a C2-C6 alkenyl group, a C2-C6 alkynyl group, a halogen, a substituted or unsubstituted alkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S. selected from the group consisting of a 5-10 membered heterocycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, -(C1-C6 alkylene)-(substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S), and -(C1-C6 alkylene)-(substituted or unsubstituted C6-C10 aryl); X is selected from the group consisting of O, S, and NH; Y is O, R3 is selected from the group consisting of H and C1-C6 alkyl groups; R4 is selected from the group consisting of H and C1-C6 alkyl groups; R5 is selected from the group consisting of H, a C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and a substituted or unsubstituted C5-C12 bridged cycloalkyl group; each R6 is independently selected from the group consisting of H, a C1-C6 alkyl group, and -(C1-C6 alkylene)-(substituted or unsubstituted C6-C10 aryl); each m is independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; n is selected from the group consisting of 1, 2, 3 and 4; "Substituted" refers to, independently, a C1-C6 alkyl group, a -(C1-C6 alkylene)-piperazinyl group, a -(C1-C6 alkylene)-N, a 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from O or S, a halo C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, CN, a nitro group, -NR a R b , -(C=O)-NR a R b , halogen, hydroxyl, and oxo; R a and R b are each independently selected from the group consisting of H, a C1-C6 alkyl group, and a halo C1-C6 alkyl group; Optionally, the alkylene group within the brackets is substituted with one OH.

[0007] In another preferred embodiment, R1 and R2 are each independently selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl group, -(C1-C6 alkylene)-(substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S), and -(C1-C6 alkylene)-(substituted or unsubstituted C6-C10 aryl); X is selected from the group consisting of O, S, and NH; Y is O, R3 is selected from the group consisting of H and C1-C6 alkyl groups; R4 is H; R5 is selected from the group consisting of H, a C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, and a substituted or unsubstituted C5-C12 bridged cycloalkyl group; each R6 is independently selected from the group consisting of H, a C1-C6 alkyl group, and -(C1-C6 alkylene)-(substituted or unsubstituted C6-C10 aryl); each m is independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; n is selected from the group consisting of 1, 2, 3 and 4; "Substituted" refers to being substituted with one or more substituents each independently selected from the group consisting of a C1-C6 alkyl group, a halo C1-C6 alkyl group, CN, and halogen.

[0008] In another preferred embodiment, R1 and R2 are each independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, -CH2- (1-6 R'-substituted or unsubstituted phenyl groups), and -CH2-pyridyl; Each R' is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, F, Cl, Br, I, and CN.

[0009] In another preferred example, the -CH2-pyridyl group is selected from the group consisting of a pyridyl group in which -CH2-N is in the ortho position, a pyridyl group in which -CH2-N is in the meta position, and a pyridyl group in which -CH2-N is in the para position. In another preferred embodiment, X is O or S. In another preferred embodiment, R3 is H, R4 is H; R5 is H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl, tert-pentyl, and [ka] is selected from the group consisting of Where: [ka] is the connecting bond to Y.

[0010] In another preferred embodiment, the compound is selected from the group consisting of:

number

number

number

[0011] In another preferred embodiment, in the above table, R6 and m are all defined by the groups in formula I from left to right.

[0012] A second aspect of the invention provides a method for preparing a compound according to the first aspect of the invention, comprising the steps of: [ka] [ka] to obtain a compound of formula I, Where: R″ is a halogen; R1, R2, R3, R4, R5, R6, X, Y, m and n are as defined in the first aspect of the invention.

[0013] A third aspect of the present invention provides a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a safe and effective amount of one or more compounds according to the first aspect of the present invention. In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of tablets, capsules, granules, oral liquids, lyophilized powders, and injections. In another preferred embodiment, the dosage form is slow release and / or controlled release and / or enteric coated.

[0014] A fourth aspect of the present invention is 1) Preparation of a drug for use in treating an infarction-related disease; 2) Preparation of drugs for use in thromboprophylaxis and / or thrombolytic, anti-edema and / or immuno-inflammatory treatment of thrombotic diseases; and 3) preparation of a medicament for use in improving neuronal damage caused by brain trauma, cerebral hemorrhage and / or brain tumor surgery.

[0015] In another preferred embodiment, the infarction-related disease is selected from the group consisting of neuronal damage of nervous tissue due to acute ischemic stroke (cerebral infarction), myocardial infarction, and pulmonary embolism, and / or The thrombotic disease is selected from the group consisting of cardiovascular disease, cerebrovascular disease, and peripheral vascular disease. Effect of the Invention

[0016] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] As a result of long and thorough research, the present inventors have unexpectedly prepared a compound having excellent antithrombotic effects and high safety, and have completed the present invention based on this compound.

[0018] term In the present invention, unless otherwise specified, the terms used have their ordinary meanings known to those skilled in the art. In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0019] In the present invention, the term "C1-C6 alkyl group" refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like. The term "C1-C10 alkyl group" has an analogous meaning.

[0020] In the present invention, the term "C2-C6 alkenyl group" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, and includes, but is not limited to, a vinyl group, a propenyl group, a butenyl group, an isobutenyl group, a pentenyl group, and a hexenyl group.

[0021] In the present invention, the term "C2-C6 alkynyl group" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, and includes, but is not limited to, an ethynyl group, a propynyl group, a butynyl group, an isobutynyl group, a pentynyl group, and a hexynyl group.

[0022] In the present invention, the term "C3-C8 cycloalkyl group" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The term "C3-C10 cycloalkyl group" has an analogous meaning.

[0023] In the present invention, the term "C1-C6 alkoxy group" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. C1-C4 alkoxy groups are preferred. "C1-C10 alkoxy group" has the same meaning. The "C1-C10 alkylthio group" is -S-(C1-C10 alkyl).

[0024] In the present invention, a "heterocyclyl group" is [ka] and 4-8 membered heterocyclyl groups containing 1, 2 or 3 heteroatoms selected from N, O and S, including but not limited to:

[0025] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning, and are preferably "C6-C10 aryl group". The term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms and no heteroatoms in the ring, such as phenyl and naphthyl.

[0026] In the present invention, the terms "aromatic heterocycle" or "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one to several heteroatoms. For example, a "C3-C10 heteroaryl group" refers to an aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen and 3-10 carbon atoms. Non-limiting examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0027] In the present invention, the term "halogenated (halo)" refers to substitution by halogen. In the present invention, the term "deuterated" refers to substitution with deuterium.

[0028] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is a substituent as described in the above specification as appropriate, or a substituent as described in each example. Unless otherwise specified, a certain substituent may have a substituent selected from a specific group at any substitutable position of the group, and the substituent at each position may be the same or different. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is stable or scientifically achievable. The substituents include, but are not limited to, halogen, hydroxyl, carbonyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.

[0029] In the present invention, the term 1 to 6 means 1, 2, 3, 4, 5 or 6. Other similar terms each independently have the same meaning. The term "multiple" refers to 2 to 6, such as 2, 3, 4, 5 or 6.

[0030] The term "carbonyl group" means [ka] wherein R and R' can independently represent hydrogen, an alkyl group or substituted alkyl group, a cycloalkyl group or substituted cycloalkyl group, an aryl group or substituted aryl group, a heterocycle or substituted heterocycle, as defined above.

[0031] It is to be understood that when a group is simultaneously present in several different positions on a compound, its definition at each position is independent of each other and may be the same or different, i.e., the term "selected from the group consisting of" has the same meaning as the term "each independently selected from the group consisting of."

[0032] Compounds and methods for their preparation The present invention provides a compound according to formula I: [ka] Here, each group is as defined above.

[0033] In another preferred embodiment, in the compound, any one of R1, R2, R3, R4, R5, R6, X, Y, m, and n is each independently a corresponding group in a specific compound described in the present invention.

[0034] As used herein, the term "pharmaceutical acceptable salt" refers to a medicament-compatible salt formed by the compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salt formed by the compound of the present invention and an acid. Acids compatible with salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, etc., and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, etc.

[0035] Further preferred salts are salts formed between the compounds of the present invention and bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanol ammonium salts and other pharma- ceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, lysine, respectively.

[0036] The term "solvate" refers to a complex formed when a compound of the present invention is coordinated with a solvent molecule in a specific ratio. The term "hydrate" refers to a complex formed when a compound of the present invention is coordinated with water.

[0037] Furthermore, the compounds of the present invention further include prodrugs of the compounds shown in formula I. The term "prodrug" includes compounds that may be biologically active or inactive themselves, and that are converted into the compounds of formula I, or salts or solutions of the compounds of formula I, by metabolism or chemical reaction in the human body after administration in an appropriate manner. The prodrugs include, but are not limited to, carboxylates, carbonates, phosphates, nitrates, sulfates, sulfonates, sulfoxides, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and the like of the compounds.

[0038] As an example, the compound has the structure shown in formula (I): [ka] wherein R1 and R2 are one of the following: hydrogen, linear and cyclic alkyl groups of various structures including short carbon chains of 1 to 10 carbon atoms, alkyl ketones, alkenyl groups, alkynyl groups, fluorine, chlorine, bromine atoms, various heterocycles, benzene rings, phenyl or benzyl groups mono- or polysubstituted with small molecule groups at various positions on the benzene ring (the substituted small molecule groups include hydrogen, methyl, methylpiperazinyl, ethyl, isopropyl, trifluoromethyl, methoxy, nitrile, methylthio, nitro, dimethylamino, methylamino, amino, fluorine, chlorine or bromine), or ethylpyridyl groups in the ortho, meta or para positions, glucosyl groups, 1,2-propanediol groups, ((S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl groups, ((R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methylamine)methyl groups; Specifically, R1 is [ka] If R2 is one of [ka] where R0 represents H, CH3, or F.

[0039] R3, R4 = H, CH3, Et, R5 = H, CH3, Et, Pr, i-Pr, Bu, I-Bu, and the following groups: [ka] R6 represents any one of H, L- or D-type linear alkyl groups of various structures having a short carbon chain of 1 to 6 carbon atoms, hydroxyalkyl groups, benzyl groups, p-hydroxybenzyl groups, and carboxylic acid esters.

[0040] X=O, S, NH, Y=O, NH, NR0 R0=H, CH3, Et, m=0, 1, 2, 3 or 4, n=1, 2, 3 or 4,

[0041] The new polysubstituted uracil derivatives further include the following specific structures: [ka] In the formula, each group is as defined above.

[0042] Typically, in the present invention, formula (I) can be realized by the following synthetic methods. Bis(p-nitrobenzene) derivative (1) is reacted with a primary amine derivative to obtain a urea derivative (2), and compound (2) is reacted with triphosgene to obtain a diimine derivative (3), which is then reacted with malonic acid to obtain a barbituric acid derivative (4), or compound (2) is directly reacted with dichloromalonyl to obtain a barbituric acid derivative (4). Compound (4) is halogenated to obtain a 6-halogenated uracil derivative (5), which is reacted with a series of polysubstituted amino acid ester derivatives (5-A) in the presence of a solvent and a base to obtain a polysubstituted uracil derivative (I), which is further hydrolyzed to obtain compound (6). Compound (6) is reacted with a phenol or alcohol to obtain a polysubstituted uracil derivative (I).

[0043] The reaction scheme for synthesizing (I) is as follows: [ka] R1, R2, R3, R4, R5, R6, m, n, X, and Y are as defined above.

[0044] Here, when R1 and R2 are the same group, R=R1=R2, and R-NH2 can include any of the following structural formulas, but is not limited to the following structures: [ka] [ka]

[0045] The synthesis of 6-halogenated uracil derivatives (5) can also be achieved by the following route: [ka] wherein X0=O or S, Y0=Cl, Br, OCCl3, and R1, R2, M, X, and Y are as defined above.

[0046] (1) When R1 and R2 are the same group, compound (5) can be obtained by directly synthesizing compound (11) with a halomethyl aromatic heterocyclic derivative in the presence of a solvent and a base.

[0047] (2) When R1 and R2 are different groups, the malonic acid ester derivative (7) is reacted with a monosubstituted urea derivative (8) to give compound (9), which is then subjected to a chlorination reaction to give compound (10), and finally to a substitution reaction to give compound (5).

[0048] (3) When R1 and R2 are different groups, the primary amine analog (12) is reacted with the phosgene analog (13) to give compound (14), which is then reacted with the primary amine analog (15) to give the urea derivative (16), which is then reacted with the malonate derivative (7) to give the barbituric acid derivative (17), which is then chlorinated to give compound (5).

[0049] The synthesis of the polysubstituted amino acid ester derivative (5-A) can also be achieved by the following route: [ka] R4, R5, R6, m, and Y are as defined above.

[0050] N-Boc-L or D-amino acid or N-Boc alanine derivative compound (18) is reacted with an alanine ester derivative or an L or D-amino acid ester derivative compound (19) to obtain compound (20), and then Boc is removed to obtain compound multi-substituted amino acid ester derivative (5-A).

[0051] Typically, the molar ratio of the 6-halogenated uracil derivative (5) to a series of alanine ester derivatives having different structures in the above step is 0.9-1.1:1, preferably 1:1, and the molar ratio of the base to the 6-halopyrimidine derivative (5) is 2-4:1, preferably 3:1. Typically, the molar ratio of the compound (11) to the halomethyl aromatic heterocyclic derivative in the reaction in the above step is 1:1-1.5.

[0052] Typically, the solvent in said step is selected from any of isopropanol, tert-butanol, DMF, and DMSO. Typically the base in said step is selected from either diisopropylethylamine, triethylamine, diethylamine, 4-dimethylaminopyridine, potassium carbonate or sodium carbonate. Typically, the L- or D-amino acids in said step include, but are not limited to, any of L-alanine, D-alanine, L-serine, D-serine, L-threonine, D-threonine, L-aspartic acid, D-aspartic acid, L-glutamic acid, D-glutamic acid, L-histidine, D-histidine, L-valine, D-valine, L-leucine, D-leucine, L-isoleucine, D-isoleucine, L-aloleucine, D-aloleucine, L-tryptophan, D-tryptophan, S-methyl-L-cysteine, S-methyl-D-cysteine, L-tyrosine, D-tyrosine, L-phenylalanine or D-phenylalanine.

[0053] Typically, the derivatives are capable of (a) treating infarction-related diseases, particularly neuronal damage to nervous tissue due to acute ischemic stroke (cerebral infarction), myocardial infarction, pulmonary embolism and other related diseases, and / or (b) providing thromboprophylaxis and thrombolytic therapy, anti-edema therapy, immuno-anti-inflammatory therapy for thrombotic diseases, and / or (c) ameliorating neuronal damage caused by brain trauma, cerebral hemorrhage, brain tumor surgery.

[0054] Typically, the derivatives are used after thrombolytic treatment following cardiovascular and cerebrovascular infarction to achieve an antithrombotic effect and prevent the recurrence of infarction, while simultaneously reducing the risk of bleeding. Typically, the compounds can be formulated into sustained release, controlled release, enteric coated tablets or capsules, granules, oral liquids, lyophilized powders, injections, and the like, by adding common pharma- ceutically acceptable excipients.

[0055] It will be appreciated that the compounds of the present invention can be readily prepared by any combination of the various synthetic methods described herein or known in the art, and that such combinations can be readily performed by one of ordinary skill in the art. It is understood that all materials and reagents used are available through commercial channels unless otherwise stated.

[0056] The present invention provides a polysubstituted uracil derivative as shown in formula I, and its preparation method and application. The compound of formula I can (a) treat infarction-related diseases, especially neuronal damage of nervous tissue due to acute ischemic stroke (cerebral infarction), myocardial infarction, pulmonary embolism and other related diseases, and / or (b) perform thromboprophylaxis and thrombolytic treatment of thrombotic diseases, anti-edema treatment, immunological anti-inflammatory treatment, and / or (c) improve neuronal damage caused by brain trauma, cerebral hemorrhage, and brain tumor surgery. In addition, the polysubstituted uracil derivative (I) can be used after thrombolytic treatment after cardiovascular infarction and cerebrovascular infarction to achieve antithrombotic effect, prevent recurrence of infarction, and at the same time reduce the risk of hemorrhage, which has important clinical significance. The synthesis method of the polysubstituted uracil derivative of the present invention, such as general formula (I), is simple to operate, has mild conditions, is easy to obtain raw materials, has high yield, and has high purity of the product.

[0057] The series of target pharmaceutical compounds synthesized by the above reactions are all novel compounds, and their structures are as follows: 1 Characterized by H NMR and ESI-MS. Through animal model testing, the results strongly demonstrate that the polysubstituted uracil derivatives have a certain antiplatelet aggregation activity, and the activity is equivalent to or superior to the corresponding positive control clopidogrel. At the same time, it was surprising to discover in mouse model experiments that the compounds can greatly reduce or overcome the bleeding risk of clopidogrel, and therefore it is possible to develop clinical drugs that can control the bleeding risk in the antithrombotic process.

[0058] Pharmaceutical Compositions and Methods of Administration The present invention further provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and a safe and effective amount of one or more compounds according to the present invention. Since the compound of the present invention has excellent antithrombotic activity, the compound of the present invention and various crystal forms thereof, pharma- ceutically acceptable inorganic or organic salts, hydrates or solvates, as well as pharmaceutical compositions containing the compound of the present invention as an active ingredient, can be used for the treatment, prevention and alleviation of thrombosis-related diseases.

[0059] The pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Here, "safe and effective amount" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound / agent of the present invention, more preferably 10-1000 mg of the compound / agent of the present invention. Preferably, the "one agent" is one capsule or tablet.

[0060] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be suitable for human use, have sufficient purity and sufficiently low toxicity. "Compatibility" refers to the ability of the components of the composition to be blended with each other without significantly reducing the efficacy of the compounds of the present invention and between them. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc. The pharmaceutical composition is in the form of an injection, a capsule, a tablet, a pill, a powder or a granule.

[0061] The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as, for example, sodium citrate or dicalcium phosphate, or with (a) a filler or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) a binder, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, (c) a humectant, such as glycerin, (d) agar, calcium carbonate, potato starch, or (e) a sorbent, such as sorbitol, ... It is mixed with ingredients such as disintegrating agents such as potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) retarders such as paraffin, (f) absorption promoters such as quaternary amine compounds, (g) wetting agents such as cetyl alcohol and glyceryl monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form can also include buffering agents.

[0062] Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coating and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0063] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms can contain inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances. Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

[0064] In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar-agar, or mixtures of these substances. Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0065] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required.

[0066] The compounds of the present invention may be administered alone or in combination with other pharma- ceutically acceptable compounds (eg, antithrombotic agents).

[0067] The treatment methods of the present invention can be used alone or in combination with other treatment methods or therapeutic agents.

[0068] When a pharmaceutical composition is used, a safe and popular amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, where the dosage at the time of administration is the effective dosage considered, and for a person weighing 60 kg, the daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the health status of the patient, all of which are within the skill of a skilled physician.

[0069] Compared with the prior art, the present invention has the following main advantages: (1) the compound can significantly prolong the blood clotting time and shorten the bleeding time in mice injected with ellagic acid via the tail vein; (2) the compound has the effect of improving brain nerve function, and can reduce the cerebral infarction rate and brain water content in rats suffering from cerebral ischemia-reperfusion injury or permanent cerebral ischemia injury, and can improve the neuromotor function of rats; (3) the compound can improve the degree of myocardial lesion and inhibit the rate of myocardial infarction; (4) The compound can reduce the cerebral infarction rate, cerebral water content and pathological damage in rats with ischemic brain injury caused by autologous thrombus and thrombin, improve the neuromotor function of rats, and show excellent anti-ischemic brain injury effect. After combined with urokinase, the efficacy is more obvious. (5) the compound has immune and anti-inflammatory effects; (6) The compound has excellent safety and efficacy.

[0070] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, the experimental methods that do not show specific conditions usually follow conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or those suggested by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can all be applied to the method of the present invention. The preferred implementation methods and materials described herein are used for demonstration purposes only.

[0072] Example 1. Preparation of Compound 1-1 [ka] Under argon gas protection, β-alanine-β-alanine ethyl ester (β-alanine-β-alanine ethyl ester, CAS: 754933-31-8) 8.39g (47.76mmol, 1.0eq), 1,3-dimethyl-6-chlorouracil 7.0g (47.77mmol, 1.0eq), N,N-diisopropylethylamine 18.52g (143.29mmol, 3.0eq), 42ml of isopropanol are added to the reaction bottle, heated to 85 ° C, stirred until the reaction is completed, then stopped heating, suction filtered, the filter cake is slurried with 100ml of ethanol at room temperature, suction filtered, and the filter cake is vacuum dried at 60 ° C until a constant weight is obtained as a white powder compound 1-1, the yield is 78%, and the purity is 99.98%. 1H NMR(600MHz,DMSO-d6)δ1.29(CH3,t,3H), 2.65(CH2,m,2H), 2.66(CH2,m,2H), 3.01(CH3,s,3H ), 3.13(CH3,m,3H), 3.16(CH3,q,3H), 3.79(CH2,t,2H), 4.13(CH2,q,2H), 4.50(CH,s,H)ppm. MS:m / z:327.16(M+1).

[0073] Example 2. Preparation of Compound 1-2 [ka] Referring to the synthesis method of compound 1-1 in Example 1, 1,3-dimethyl-6-chlorouracil, compound (CAS: 1582394-73-7) is used as raw material to obtain beige powdery compound 1-2, the yield is 56.30%, and the purity is 97.92%. 1 H NMR(600MHz,DMSO-d6)δ1.32(2CH3,d,6H), 2.65(CH2,m,2H), 2.66(CH2,m,2H), 3.01(CH3,s, 3H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3.79(CH2,t,2H), 4.50(CH,s,H), 4.93(CH,s,H)ppm. MS:m / z:341.17(M+1).

[0074] Example 3. Preparation of Compounds 1-3 [ka] Compound 1-1 (3.8 mmol) is weighed and added to a 100 mL single-mouth bottle, then 0.23 g NaOH, 30 mL ethanol, and 3 mL water are added, and after the addition is complete, the reaction mixture is stirred at room temperature. After 2 hours of stirring, the reaction mixture is sampled and spotted, and the reaction mixture is monitored. After 2 hours of stirring, the raw materials in the reaction mixture are completely reacted, and the pH of the reaction mixture is adjusted to neutral with concentrated hydrochloric acid, and the reaction mixture is directly concentrated to dryness, and then concentrated with ethanol several times to obtain off-white powdery compound 1-3, with a yield of 90% and a purity of 99.16%. 1 H NMR (600MHz, DMSO-d6) δ2.49(CH2,t,2H), 2.66(CH2,t,2H), 3.01(CH3,s,3H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3.67(CH2,t,2H), 4.50(CH,s,H)ppm. MS:m / z:299.13(M+1).

[0075] Example 4. Preparation of Compounds 1-4 [ka] Weigh out 2g of compound 1-3 and add it to a 100mL three-necked bottle, then add 20mL of DCM, 1.93g of EDCI, 1.03g of borneol, and 0.08g of DMAP, then react at room temperature overnight with stirring. Since the raw materials are still remaining in the reaction liquid, the reaction is continued to react with stirring, and after stirring, the reaction is completed, water is added to the reaction to dilute it, and then it is extracted, and the organic phase is washed with water, and after washing, the reaction is dried with anhydrous sodium sulfate, and after drying, the reaction is concentrated to dryness to obtain white powder compound 1-4, with a yield of 44.36% and a purity of 98.88%. 1 H NMR(600MHz,DMSO-d6)δ0.99(2CH3,s,6H), 1.04(CH3,s,3H), 1.11,1.33(CH2,m,2H), 1.14,1.67(CH2,m,2H), 1.38,1.91(CH2,m,2H), 1.87(CH,m,H ), 2.51(CH2,t,2H), 2.66(CH2,t,2H), 3.01(CH3,s,3H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3.79(CH2,t,2H), 4.50(CH,s,H), 7.13(CH,t,H), ppm. MS:m / z:435.25(M+1).

[0076] Example 5. Preparation of Compounds 1-5 [ka] Referring to the synthesis method of compound 1-4 in Example 4, 4 g of compound 1-3 and 0.93 g of cyclopropanol were used as raw materials to obtain yellow powdery compound 1-5, with a yield of 42.91% and a purity of 98.43%. 1 H NMR(600MHz,DMSO-d6)δ0.58;0.34(2CH2,d,4H), 2.65(CH2,m,2H), 2.66(CH2,m,2H), 2.69(CH,m ,H), 3.01(CH3,s,3H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3.79(CH2,t,2H), 4.50(CH,s,H)ppm. MS:m / z:339.16(M+1).

[0077] Example 6. Preparation of Compounds 1-6 [ka] Referring to the synthesis method of compound 1-4 in Example 4, 4 g of compound 1-3 and 2.01 g of cyclohexanol were used as raw materials to obtain white powder compound 1-6, with a yield of 49.40% and a purity of 99.61%. 1 H NMR(600MHz,DMSO-d6)δ1.53;1.43(2CH2,m,4H), 1.49;1.47(CH2,m,2H), 1.80;1.55(2CH2,m,4H), 2.65(CH2,m,2H), 2.6 6(CH2,m,2H), 3.01(CH3,s,3H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3.79(CH2,t,2H), 3.91(CH,m,H), 4.50(CH,s,H)ppm. MS:m / z:381.21(M+1).

[0078] Example 7. Preparation of Compounds 1-7 [ka] Referring to the synthesis method of compound 1-4 in Example 4, 4 g of compound 1-3 and 1.89 g of phenol were used as raw materials to obtain white powdery compound 1-7, with a yield of 43.02% and a purity of 99.54%. 1 H NMR(600MHz,DMSO-d6)δ2.63(CH2,m,2H), 2.66(CH2,m,2H), 3.01(CH3,s,3H), 3.13(CH2,m,2H), 3.16 (CH3,m,3H), 3.67(CH2,t,2H), 4.50(CH,s,H), 7.26(CH,m,H), 7.29(2CH,m,2H), 7.42(2CH,m,2H)ppm. MS:m / z:375.16(M+1).

[0079] Example 8. Preparation of Compounds 1-8 [ka] Referring to the synthesis method of compound 1-4 in Example 4, 4 g of compound 1-3 and 2.46 g of 1,3-dimethylphenol were used as raw materials to obtain white powdery compound 1-8, with a yield of 45.74% and a purity of 99.14%. 1 H NMR(600MHz,DMSO-d6)δ2.15(2CH3,s,6H), 2.63(CH2,m,2H), 2.66(CH2,m,2H), 3.01(CH3,s,3H), 3.13 (CH2,m,2H), 3.16(CH3,m,3H), 3.67(CH2,t,2H), 4.50(CH,s,H), 7.01(2CH,d,2H), 7.24(CH,m,H)ppm. MS:m / z:403.19(M+1).

[0080] Example 9. Preparation of Compounds 1-9 [ka] Weigh out 3g of 1,3-dimethyl-6-chloro-2-sulfoxy-4(1H)-pyrimidinone (CAS: 6972-27-6) and add it to a 100mL single-mouth bottle, then add 3.18g of DIEA, 30mL of isopropanol, and 2.95g of β-alanine-β-alanine ethyl ester (CAS: 754933-31-8). After the addition is complete, the reaction mixture is heated to reflux and reacted with stirring. After 8 hours of reaction with stirring, the stirring is stopped and the mixture is separated by sand column chromatography. After separation, white powdery compound 1-9 is obtained, with a yield of 49.35% and a purity of 95.6%. 1 H NMR(600MHz,DMSO-d6)δ1.29(CH3,t,3H), 2.65(CH2,m,2H), 2.66(CH2,m,2H), 3.07(CH3,s,3H ), 3.13(CH2,m,2H), 3.34(CH3,s,3H), 3.79(CH2,t,2H), 4.13(CH2,q,2H), 6.09(CH,s,H)ppm. MS:m / z:343.14(M+1).

[0081] Example 10. Preparation of Compounds 1-10 [ka] Weigh out 1.3g of compound 1-9 and add it to a 100mL single-mouth bottle, then add 0.23g NaOH, 30mL ethanol, and 3mL water, and after the addition is complete, the reactant is reacted under room temperature with stirring. After 2 hours of reaction with stirring, sample and spot to monitor the reaction, after 2 hours of reaction with stirring, the raw materials in the reaction solution are completely reacted, and the pH of the reactant is adjusted to neutral with concentrated hydrochloric acid, the reactant is directly concentrated to dryness, and then concentrated with ethanol several times to obtain off-white powdery compound 1-10, with a yield of 77.26% and a purity of 99.12%. 1H NMR (600MHz, DMSO-d6) δ2.49(CH2,t,2H), 2.66(CH2,t,2H), 3.07(CH3,m,3H), 3.13(CH2,m,2H), 3.34(CH3,s,3H), 3.67(CH2,t,2H), 6.09(CH,s,H)ppm. MS:m / z:315.10(M+1).

[0082] Example 11. Preparation of Compounds 1-11 [ka] Referring to the synthesis method of compound 1-4 in Example 4, 1.19 g of compound 1-10 and 0.69 g of 1,3-dimethylphenol were used as raw materials to obtain off-white powdery compound 1-11, with a yield of 47.47% and a purity of 98.13%. 1 H NMR(600MHz,DMSO-d6)δ2.15(2CH3,s,6H), 2.63(CH2,m,2H), 2.66(CH2,m,2H), 3.07(CH3,s,3H), 3.13 (CH2,m,2H), 3.34(CH3,m,3H), 3.67(CH2,t,2H), 6.09(CH,s,H), 7.01(2CH,d,2H), 7.24(CH,m,H)ppm. MS:m / z:419.17(M+1).

[0083] Example 12. Preparation of Compounds 1-12 [ka] Referring to the synthesis method of compound 1-4 in Example 4, 4 g of compound 1-3 and 3.14 g of menthol were used as raw materials to obtain white powdery compound 1-12, with a yield of 40.85% and a purity of 98.73%. 1H NMR(600MHz,DMSO-d6)δ0.91(2CH3,m,6H), 0.96(CH3,m,3H), 1.52;1.27(2CH2,m,4H), 1.61(CH,m,H), 1.76;1.51(CH2,m,2H), 1.82(CH,m,H), 2.01(CH ,m,H), 3.90(CH,s,H), 2.51(CH2,t,2H), 2.66(CH2,t,2H), 3.01(CH3,s,3H ), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3.79(CH2,m,2H), 4.50(CH,s,H)ppm. MS: m / z: 437.27 (M+1).

[0084] Example 13. Preparation of Compounds 1-13 [ka] Refer to the synthesis method of compound 1-1 in Example 1, use 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]-4-fluorobenzonitrile (produced by the reaction of 6-chloro-3-methyluracil and 2-cyano-5-fluorobenzyl bromide), compound (CAS:1582394-73-7) as raw material to obtain white powdery compound 1-13, with a yield of 47.36% and a purity of 99.48%. 1 H NMR(600MHz,DMSO-d6)δ1.32(2CH3,d,6H), 2.65(CH2,m,2H), 2.66(CH2,m,2H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3 .79(CH2,t,2H), 4.50(CH,s,H), 4.93(CH,m,H), 5.18(CH2,s,2H), 6.95(CH,m,H), 7.23(CH,m,H), 7.50(CH,m,H)ppm. MS:m / z:460.19(M+1).

[0085] Example 14. Preparation of Compounds 1-14 [ka] 7g of compound 1-13, 0.69g of sodium hydroxide and 70ml of anhydrous ethanol are weighed into a 100mL single-mouth bottle, and reacted at room temperature for 3 hours with stirring. After the reaction is complete, concentrate to a small amount of ethanol, add water, then adjust to PH=5 with citric acid water, stir for 30 minutes, suction filter, slurry with water, and suction filter. Dry in vacuum at 60°C to obtain 3.5g of off-white powdery compound 1-14, with a yield of 90.26% and a purity of 99.31%. 1 H NMR(600MHz,DMSO-d6)δ2.49(CH2,m,2H), 2.66(CH2,m,2H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3. 67(CH2,t,2H), 4.50(CH,s,H), 5.18(CH2,s,2H), 6.95(CH,m,H), 7.23(CH,m,H), 7.50(CH,m,H)ppm. MS:m / z:418.14(M+1).

[0086] Example 15. Preparation of Compounds 1-15 [ka] Referring to the synthesis method of compound 1-4 in Example 4, 2 g of compound 1-14 and 0.5 g of phenol were used as raw materials to obtain off-white powdery compound 1-15, with a yield of 67.80% and a purity of 95.81%. 1 H NMR(600MHz,DMSO-d6)δ2.63(CH2,m,2H), 2.66(CH2,m,2H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3.67(CH2,t,2H), 4.50(CH,s ,H), 5.18(CH2,s,2H), 6.95(CH,m,H), 7.23(CH,m,H), 7.26(CH,m,H), 7.29(2CH,m,2H), 7.42(2CH,m,2H), 7.50(CH,m,H)ppm. MS:m / z:494.18(M+1).

[0087] Example 16. Preparation of Compounds 1-16 [ka] Referring to the synthesis method of compound 1-4 in Example 4, 2 g of compound 1-14 and 0.82 g of menthol were used as raw materials to obtain white powder compound 1-16, with a yield of 56.39% and a purity of 98.82%. 1 H NMR(600MHz,DMSO-d6)δ0.91(2CH3,m,6H), 0.96(CH3,m,3H), 1.52;1.27(2CH2,m,4H) , 1.61(CH,m,H), 1.76;1.51(CH2,m,2H), 1.82(CH,m,H), 2.01(CH,m,H), 2.51(CH2,t, 2H), 2.66(CH2,t,2H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3.79(CH2,m,2H), 3.90(CH ,s,H), 4.50(CH,s,H), 5.18(CH2,s,2H), 6.95(CH,m,H), 7.23(CH,m,H), 7.50(CH,m,H) ppm. MS:m / z:556.29(M+1).

[0088] Example 17. Preparation of Compounds 1-17 [ka] Refer to the synthesis method of compound 1-1 in Example 1, and use 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]benzonitrile (produced by the reaction of 6-chloro-3-methyluracil with o-cyanobenzyl chloride), β-alanine-β-alanine ethyl ester (CAS: 754933-31-8) as raw materials to obtain white powdery compound 1-17, with a yield of 49.36% and a purity of 98.89%. 1H NMR(600MHz,DMSO-d6)δ1.29(CH3,t,3H), 2.65(CH2,m,2H), 2.66(CH2,m,2H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3.79(CH2, ppm. MS:m / z:428.19(M+1).

[0089] Example 18. Preparation of Compounds 1-18 [ka] Refer to the synthesis method of compound 1-1 in Example 1, and use 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]-4-fluorobenzonitrile, β-alanine-β-alanine ethyl ester (CAS: 754933-31-8) as raw materials to obtain white powdery compound 1-18, with a yield of 48.08% and a purity of 99.46%. 1 H NMR(600MHz,DMSO-d6)δ1.29(CH3,t,3H), 2.65(CH2,m,2H), 2.66(CH2,m,2H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3. 79(CH2,t,2H), 4.13(CH2,q,2H), 4.50(CH,s,H), 5.18(CH2,s,2H), 6.95(CH,m,H), 7.23(CH,m,H), 7.50(CH,m,H)ppm. MS:m / z:446.18(M+1).

[0090] Example 19. Preparation of Compounds 1-19 [ka] Referring to the synthesis method of compound 1-4 in Example 4, 2 g of compound 1-14 and 0.64 g of 2,6-dimethylphenol were used as raw materials to obtain white powdery compound 1-19, with a yield of 52.00% and a purity of 99.23%. 1 H NMR(600MHz,DMSO-d6)δ2.15(2CH3,s,6H), 2.63(CH2,m,2H), 2.66(CH2,m,2H), 3.01(CH3,s,3H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3 .67(CH2,t,2H), 4.50(CH,s,H), 5.18(CH2,s,2H), 6.95(CH,m,H), 7.01(2CH,m,2H), 7.23(CH,m,H), 7.24(CH,m,H), 7.50(CH,m,H)ppm. MS:m / z:522.21(M+1).

[0091] Example 20. Preparation of Compounds 1-20 [ka] Weigh 31.1g of N-tert-butoxycarbonyl-L-isoleucine and 27.2g of HOBT into a 1L single-mouth bottle, dissolve in 300mL of DCM, add 20.4g of triethylamine and 38.6g of EDCI, and after the addition is complete, replace with AR gas three times and stir at 25°C for 1 hour. Add 22.7g of β-alanine ethyl ester hydrochloride and stir at 25°C. Sampling and spotting showed that the raw material reacted completely. The reaction solution was washed with water three times, washed with 5% citric acid four times (200mL x 4), washed with water and saturated sodium chloride, dried with anhydrous sodium sulfate, and concentrated to dryness to obtain 42.6g of oily compound 1-20, the yield is 99.5%, and directly put into the next step. 1 H NMR(600MHz,DMSO-d6)δ0.90(CH3,t,3H), 1.11(CH3,d,3H), 1.29(CH3,t,3H), 1.38(3CH3,s,9H), 1.55 (CH2,m,2H), 2.12(CH,m,H), 3.59(CH2,t,2H), 3.65(CH2,t,2H), 4.13(CH2,m,2H), 4.52(CH,d,H)ppm. MS:m / z:331.22(M+1).

[0092] Example 21. Preparation of Compounds 1-21 [ka] 42.5g of compound 1-20 was weighed into a 500mL single-mouth bottle, 150mL of 3M hydrochloric acid ethanol was slowly added to dissolve, and the mixture was reacted at 30°C with stirring. Sampling and spotting showed that the raw material had reacted completely. The reaction solution was cooled to room temperature, the pH was adjusted to about 5.0 with sodium bicarbonate, filtered, the filtrate was dried with anhydrous sodium sulfate, and concentrated to dryness to obtain 33g of oily compound 1-21, the yield was nearly 100%, and the purity was 99.34%. 1 H NMR(600MHz,DMSO-d6)δ0.90(CH3,t,3H), 1.11(CH3,d,3H), 1.29(CH3,t,3H), 1.55(CH2,m,2 H), 1.73(CH,m,H), 2.63(CH2,t,2H), 3.55(CH,m,H), 3.59(CH2,m,2H), 4.13(CH2,m,2H)ppm. MS:m / z:231.16(M+1).

[0093] Example 22. Preparation of Compounds 1-22 [ka] Referring to the synthesis method of compound 1-1 in Example 1, 1,3-dimethyl-6-chlorouracil, compound 1-21, was used as raw materials to obtain white powder compound 1-22, with a yield of 62% and a purity of 99.97%. 1 H NMR(600MHz,DMSO-d6)δ0.90(CH3,t,3H), 1.11(CH3,d,3H), 1.29(CH3,t,3H), 1.55(CH2,m,2H), 1.73(CH,m,H) , 2.65(CH2,t,2H), 3.01(CH3,s,3H), 3.16(CH3,s,3H), 3.55(CH,m,H), 3.59(CH2,m,2H), 4.13(CH2,m,2H)ppm. MS:m / z:369.21(M+1).

[0094] Example 23. Preparation of Compounds 1-23 [ka] Referring to the synthesis method of compound 1-1 in Example 1, 1,3-dimethyl-6-chlorouracil, CAS: 16625-95-9, was used as raw material to obtain white powder compound 1-23, with a yield of 85.59% and a purity of 99.23%. 1 H NMR(600MHz,DMSO-d6)δ1.28(CH2,m,2H), 1.29(2CH2,m,4H), 1.29(CH3,m,3H), 1.52(2CH2,m,4H), 1.64(CH2,m,2H), 2.13(CH2,m,2 H), 2.32(CH2,t,2H), 2.87(CH2,t,2H), 3.01(CH3,m,3H), 3.02(CH2,m,2H), 3.16(CH3,s,3H), 4.13(CH2,q,2H), 4.50(CH,s,H)ppm. MS:m / z:411.25(M+1).

[0095] Example 24. Preparation of Compounds 1-24 [ka] Compound 1-24 was synthesized according to the synthesis method of compound 1-3 in Example 3 to obtain a white powder, with a yield of 81.39% and a purity of 99.64%. 1 H NMR(600MHz,DMSO-d6)δ1.28(CH2,m,2H), 1.29(2CH2,m,4H), 1.52(3CH2,m,6H), 2.13(CH2,m,2H), 2.30 (CH2,t,2H), 2.87(CH2,t,2H), 3.01(CH3,m,3H), 3.02(CH2,m,2H), 3.16(CH3,s,3H), 4.50(CH,s,H)ppm. MS:m / z:383.22(M+1).

[0096] Example 25. Preparation of Compounds 1-25 [ka] Add 10.0g of 6-chlorouracil, 100.0g of DMSO, 23.8g of potassium carbonate, and 10.4g of benzyl chloride to a 250ml single-mouth bottle, react at 20 ℃ until the raw material is completely reacted, leave it overnight, add 100ml of water to dilute the reaction liquid, add EA to extract twice, each time 200ml, after extraction is completed, combine the extraction phase, add 100ml of saturated saline to wash, separate the organic phase, and concentrate under reduced pressure (50 ℃, -0.09MPa), after reducing pressure is completed, obtain yellow oily product, separate by sand column chromatography, elute with P:E=10:1, concentrate product-containing raw material liquid (50 ℃, -0.09MPa), obtain white powder compound 1-25, yield is 72%, purity is 99.12%. 1 H NMR (600MHz, DMSO-d6) δ5.18(2CH2,s,4H), 5.94(CH,s,H), 7.23(4CH,m,4H), 7.26(2CH,m,2H), 7.33(4CH,t,4H)ppm. MS:m / z:327.08(M+1).

[0097] Example 26. Preparation of Compounds 1-26 [ka] Add 3.60g of compound 1-25, 40.0g of isopropanol, 4.63g of triethylamine, 4.62g of compound (CAS: 1582394-73-7) into a 100ml single-mouth bottle, react at 85℃, concentrate under reduced pressure (55℃, -0.09MPa), after completion of pressure reduction, add 50ml of saturated sodium bicarbonate to dissolve, extract twice with dichloromethane, each time 50ml, combine the extraction phase, concentrate under reduced pressure (50℃, -0.09MPa), after completion of concentration, obtain 6.8g of white solid, separate by sand column chromatography, pass the mixed solvent of dichloromethane:isopropanol=20:1 through the column, concentrate the product-containing raw liquid (50℃, -0.09MPa), obtain white powder compound 1-26, yield is 68%, purity is 99.88%. 1H NMR(600MHz,DMSO-d6)δ1.32(2CH3,d,6H), 2.65(CH2,m,2H), 2.66(CH2,m,2H), 3.13(CH2,t,2H), 3.79(CH2,t,2 H), 4.50(CH,s,H), 4.93(CH,m,H), 5.18(2CH2,s,4H), 7.23(4CH,m,4H), 7.26(2CH,m,2H), 7.33(4CH,t,4H)ppm. MS:m / z:493.24(M+1).

[0098] Example 27. Preparation of Compounds 1-27 [ka] Refer to the synthesis method of compound 1-1 in Example 1, use the indicated raw material (produced by the reaction of 6-chloro-3-methyluracil and 3-(chloromethyl)pyridine hydrochloride), compound (CAS: 1582394-73-7) as raw material to obtain white powdery compound 1-27, with a yield of 57% and a purity of 99.28%. 1 H NMR(600MHz,DMSO-d6)δ1.32(2CH3,d,6H), 2.65(CH2,m,2H), 2.66(CH2,m,2H), 3.13(CH2,t,2H), 3.16(CH3,m,3H), 3.79(CH ppm. MS:m / z:418.20(M+1).

[0099] Example 28. Preparation of Compounds 1-28 [ka] Refer to the synthesis method of compound 1-1 in Example 1, use 1-benzyl-6-chloro-3-methyl-1H-pyrimidine-2,4-dione (produced by reacting with 6-chloro-3-methyluracil and benzyl chloride), compound (CAS: 754933-31-8) as raw material to obtain off-white powdery compound 1-28, with a yield of 55.3% and a purity of 98.75%. 1 H NMR(600MHz,DMSO-d6)δ1.29(CH3,d,3H), 2.65(CH2,m,2H), 2.66(CH2,m,2H), 3.13(CH2,t,2H), 3.16(CH3,m,3H), 3.79 (CH2,t,2H), 4.13(CH2,t,2H), 4.50(CH,s,H), 5.18(CH2,s,2H), 7.23(2CH,m,2H), 7.26(CH,m,H), 7.33(2CH,m,2H)ppm. MS:m / z:403.19(M+1).

[0100] Example 29. Preparation of Compounds 1-29 [ka] Referring to the synthesis method of compound 1-3 in Example 3, compound 1-28 was used as raw material to synthesize compound 1-29 as off-white powder, with a yield of 73.5% and a purity of 99.32%. 1 H NMR(600MHz,DMSO-d6)δ2.49(CH2,t,2H), 2.66(CH2,t,2H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3.67 (CH2,t,2H), 4.50(CH,s,H), 5.18(CH2,s,2H), 7.23(2CH,m,2H), 7.26(CH,m,H), 7.33(2CH,m,2H)ppm. MS:m / z:375.16(M+1).

[0101] Example 30. Preparation of Compounds 1-30 [ka] Referring to the synthesis method of compound 1-4 in Example 4, 8.2 g of compound 1-29 and 2.3 g of phenol were used as raw materials to obtain off-white powdery compound 1-30, with a yield of 59.3% and a purity of 98.98%. 1 H NMR(600MHz,DMSO-d6)δ2.63(CH2,m,2H), 2.66(CH2,m,2H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3.67(CH2,t,2H), 4.50( CH,s,H), 5.18(CH2,s,2H), 7.23(2CH,m,2H), 7.26(2CH,m,2H), 7.29(2CH,m,2H), 7.33(2CH,m,2H), 7.42(2CH,m,2H)ppm. MS:m / z:451.19(M+1).

[0102] Example 31. Preparation of Compounds 1-31 [ka] Referring to the synthesis method of compound 1-3 in Example 3, compound 1-27 was used as raw material to synthesize compound 1-31 as off-white powder, with a yield of 76.8% and a purity of 98.67%. 1 H NMR(600MHz,DMSO-d6)δ2.49(CH2,t,2H), 2.66(CH2,t,2H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3.67(CH2, t,2H), 4.50(CH,s,H), 5.18(CH2,s,2H), 7.38(CH,t,H), 7.86(CH,m,H), 8.45(CH,m,H), 8.59(CH,m,H)ppm. MS:m / z:376.15(M+1).

[0103] Example 32. Preparation of Compounds 1-32 [ka] Referring to the synthesis method of compound 1-4 in Example 4, 1 g of compound 1-31 and 1 g of menthol were used as raw materials to obtain off-white powdery compound 1-32, with a yield of 51% and a purity of 98.27%. 1 H NMR(600MHz,DMSO-d6)δ0.91(2CH3,m,6H), 0.96(CH3,m,3H), 1.52;1.27(2CH2,m,4H), 1.6 1(CH,m,H), 1.76;1.51(CH2,m,2H), 1.82(CH,m,H), 2.01(CH,m,H), 2.51(CH2,t,2H), 2.66( CH2,t,2H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 3.79(CH2,m,2H), 3.90(CH,m,H), 4.50(CH ,s,H), 5.18(CH2,s,2H), 7.38(CH,t,H), 7.86(CH,m,H), 8.45(CH,m,H), 8.59(CH,m,H)ppm. MS:m / z:514.30(M+1).

[0104] Example 33. Preparation of Compounds 1-33 [ka] In a 250ml single-mouth bottle, add 6g of 6-chlorouracil, 60g of DMSO, 6.7g of chloromethylpyridine hydrochloride, and 11.6g of potassium carbonate, react at 15℃, and stir overnight. Stop the reaction, add 100ml of water to dilute the reaction solution, add EA to extract twice, each time 100ml, after extraction is completed, combine the extraction phase, add 100ml of saturated saline to wash, separate the organic phase, and concentrate under reduced pressure (50℃, -0.09MPa). After reducing pressure is completed, the yellow oily compound 1-33 is directly put into the next step, the yield is 62%, and the purity is 98.35%. 1 H NMR (600MHz, DMSO-d6) δ5.18(2CH2,s,4H), 5.94(CH,s,H), 7.38(2CH,m,2H), 7.86(2CH,m,2H), 8.45(2CH,t,2H), 8.592CH,t,2H)ppm. MS:m / z:329.07(M+1).

[0105] Example 34. Preparation of Compounds 1-34 [ka] Refer to the synthesis method of compound 1-26 in Example 26, use 2.3g of compound 1-33 and 2.94g of compound (CAS: 1582394-73-7) as raw materials to obtain pale yellow powdery compound 1-34, the yield is 46%, and the purity is 99.75%. 1 H NMR(600MHz,DMSO-d6)δ1.32(2CH3,d,6H), 2.65(CH2,m,2H), 2.66(CH2,m,2H), 3.13(CH2,t,2H), 3.79(CH2,t,2H), 4.50 (CH,s,H), 4.93(CH,m,H), 5.18(2CH2,s,4H), 7.38(2CH,m,2H), 7.86(2CH,m,2H), 8.45(2CH,t,2H), 8.59(2CH,t,2H)ppm. MS:m / z:495.23(M+1).

[0106] Example 35. Preparation of Compounds 1-35 [ka] Refer to the synthesis method of compound 1-20 in Example 20, use 5.3g N-tert-butoxycarbonyl-D-isoleucine, 3.9g β-alanine ethyl ester hydrochloride, 3.5g triethylamine, 4.7g HOBT and 6.6g EDCI as raw materials to obtain pale yellow oily compound 1-34, with a yield of 95% and a purity of 99.36%. 1 H NMR(600MHz,DMSO-d6)δ0.90(CH3,t,3H), 1.11(CH3,d,3H), 1.29(CH3,t,3H), 1.38(3CH3,s,9H), 1.55 (CH2,m,2H), 2.12(CH,m,H), 3.59(CH2,t,2H), 3.65(CH2,t,2H), 4.13(CH2,m,2H), 4.52(CH,d,H)ppm. MS:m / z:331.22(M+1).

[0107] Example 36. Preparation of Compounds 1-36 [ka] Referring to the synthesis method of compound 1-21 in Example 21, 6.9g of compound 1-35 was reacted with 2mL of 3M hydrochloric acid ethanol solution to obtain pale yellow oily compound 1-36, the yield was 100%, and the purity was 99.40%. 1 H NMR(600MHz,DMSO-d6)δ0.90(CH3,t,3H), 1.11(CH3,d,3H), 1.29(CH3,t,3H), 1.55(CH2,m,2 H), 1.73(CH,m,H), 2.63(CH2,t,2H), 3.55(CH,m,H), 3.59(CH2,m,2H), 4.13(CH2,m,2H)ppm. MS:m / z:231.16(M+1).

[0108] Example 37. Preparation of Compounds 1-37 [ka] Referring to the synthesis method of compound 1-1 in Example 1, 3.8 g of 1,3-dimethyl-6-chlorouracil and 5 g of compound 1-36 were used as raw materials to obtain pale yellow powdery compound 1-37, with a yield of 55% and a purity of 99.62%. 1 H NMR(600MHz,DMSO-d6)δ0.90(CH3,t,3H), 1.11(CH3,d,3H), 1.29(CH3,t,3H), 1.55(CH2,m,2H), 1.73(CH,m,H) , 2.65(CH2,t,2H), 3.01(CH3,s,3H), 3.16(CH3,s,3H), 3.55(CH,m,H), 3.59(CH2,m,2H), 4.13(CH2,m,2H)ppm. MS:m / z:369.21(M+1).

[0109] Example 38. Preparation of Compounds 1-38 [ka] Referring to the synthesis method of compound 1-1 in Example 1, 6-chlorouracil, CAS: 16625-95-9, was used as raw material to obtain off-white powdery compound 1-38, with a yield of 65% and a purity of 98.37%. 1 H NMR(600MHz,DMSO-d6)δ1.28(CH2,m,2H), 1.29(2CH2,m,4H), 1.29(CH3,m,3H), 1.52(2CH2,m,4H), 1.64(CH2,m,2 H), 2.13(CH2,m,2H), 2.32(CH2,t,2H), 2.87(CH2,t,2H), 3.02(CH2,t,2H), 4.13(CH2,q,2H), 4.50(CH,s,H)ppm. MS:m / z:383.22(M+1).

[0110] Example 39. Preparation of Compounds 1-39 [ka] Refer to the synthesis method of compound 1-1 in Example 1, and use 2-amino-6-chloro-4-hydroxypyrimidine, β-alanine-β-alanine ethyl ester (CAS: 754933-31-8) as raw materials to obtain off-white powdery compound 1-2, with a yield of 47.8% and a purity of 98.6%. 1 H NMR (600MHz, DMSO-d6) δ1.29(CH3,t,3H), 2.65(CH2,m,2H), 2.66(CH2,m,2H), 3.13(CH2,t,2H), 3.79(CH2,t,2H), 4.13(CH2,q,2H), 6.09(CH,s,H)ppm. MS:m / z:298.14(M+1).

[0111] Example 40. Preparation of Compounds 1-40 [ka] Weigh out 12g of L-valine ethyl ester hydrochloride and add it to a 250mL single-mouth bottle, then add 15g of N-BOC-alanine, 17g of EDCI, 30g of triethylamine, 15g of Hobt, then add 150mL of DCM, and after the addition is complete, the reaction is reacted overnight under room temperature with stirring. After sampling and spotting to monitor the reaction completion, the reaction is stopped, then the reaction is washed with water, washed with saturated sodium bicarbonate solution, washed with saturated citric acid, then washed with saturated sodium chloride solution, then the reaction is dried over anhydrous sodium sulfate, and the organic phase is concentrated to dryness to obtain colorless oily compound 1-40, the yield is 76.49% and the purity is 98.6%. 1 H NMR(600MHz,DMSO-d6)δ0.91(2CH3,d,6H), 1.29(CH3,t,3H), 1.38(3CH3,s,9H), 2.2 1(CH,m,H), 2.44(CH2,t,2H), 3.44(CH2,t,2H), 4.21(CH2,m,2H), 4.21(CH,m,H)ppm. MS:m / z:317.20(M+1).

[0112] Example 41. Preparation of Compounds 1-41 [ka] Weigh out 15g of compound 1-40 into a 250mL single-mouth bottle, then add 100mL of anhydrous ethanol. Add 25mL of 11M ethanolic hydrochloric acid, then allow the reaction to react under stirring at room temperature. Monitor the reaction completion after overnight reaction, then adjust pH to about 5.0 with sodium bicarbonate, filter, dry the filtrate with anhydrous sodium sulfate, and concentrate to dryness to obtain colorless oily compound 1-41, with a yield of 97.53% and a purity of 98.49%. 1H NMR (600MHz, DMSO-d6) δ0.91(2CH3,d,6H), 1.29(CH3,t,3H), 2.21(CH,m,H), 2.44(CH2,m,2H), 2.93(CH2,t,2H), 4.21(CH2,m,2H), 4.21(CH,m,H)ppm. MS:m / z:217.15(M+1).

[0113] Example 42. Preparation of Compounds 1-42 [ka] Referring to the synthesis method of compound 1-1 in Example 1, 8.07 g of 1,3-dimethyl-6-chlorouracil and 10 g of compound 1-41 were used as raw materials to obtain white powdery compound 1-42, with a yield of 42.7% and a purity of 98.04%. 1 H NMR(600MHz,DMSO-d6)δ0.91(2CH3,d,6H), 1.29(CH3,t,3H), 2.21(CH,m,H), 2.44(CH2,t,2H), 3.01( CH3,s,3H), 3.13(CH2,m,2H), 3.16(CH3,m,3H), 4.21(CH2,m,2H), 4.21(CH,m,H), 4.50(CH,s,H)ppm. MS:m / z:355.19(M+1).

[0114] Example 43. Preparation of Compounds 1-43 [ka] Weigh 8.92g of 3-[(tert-butoxycarbonyl)(methyl)amino]propionic acid, 8.8g of β-alanine isopropyl ester hydrochloride into a 250mL round-bottomed bottle, add 100mL of dichloromethane, and dissolve by stirring until clear and cooled to 0℃. Weigh 23mL of triethylamine and slowly drip into the round-bottomed bottle. After dripping is complete, add 15.15g of EDCI to the reaction system, warm to 40℃, and react overnight with stirring. After reaction is complete, add 30ml of water to the reaction solution, stir, separate the layers, and take out the organic layer. Wash the organic layer twice with 30ml of water, then dry over anhydrous sodium sulfate. Filtrate, collect the filtrate, and concentrate to dryness under reduced pressure to obtain colorless oily compound 1-43, with a yield of 67.9% and a purity of 98.43%. 1 H NMR(600MHz,DMSO-d6)δ1.32(2CH3,d,6H), 1.38(3CH3,s,9H), 2.65(CH2,m,2H), 2.66 (CH2,m,2H), 3.24(CH2,t,2H), 3.47(CH3,s,3H), 3.79(CH2,t,2H), 4.93(CH,m,H)ppm. MS:m / z:317.20(M+1).

[0115] Example 44. Preparation of Compounds 1-44 [ka] Add 40mL DCM, 11.1g compound 1-43 to a reaction bottle, add 20mL trifluoroacetic acid, and react under room temperature with stirring. Concentrate the reaction solution to dryness to obtain an oily substance, add 30mL dichloromethane to dissolve, continue to concentrate to dryness, add 50mL ethyl acetate to the concentrate after completion of concentration to make a slurry, concentrate to dryness under reduced pressure to obtain colorless oily substance compound 1-44, yield is 91.6%, purity is 98.74%. 1H NMR (600MHz, DMSO-d6) δ1.32(2CH3,d,6H), 2.52(CH2,t,2H), 2.65(CH2,t,2H), 2.83(CH2,t,2H), 3.26(CH3,s,3H), 3.79(CH2,t,2H), 4.93(CH,m,H)ppm. MS:m / z:217.15(M+1).

[0116] Example 45. Preparation of Compounds 1-45 [ka] Refer to the synthesis method of compound 1-1 in Example 1, use 6g of 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]-4-fluorobenzonitrile (produced by the reaction of 6-chloro-3-methyluracil with 2-cyano-5-fluorobenzyl bromide), 6.07g of compound 1-44 as raw materials to obtain white powdery compound 1-13, with a yield of 48.45% and a purity of 98.76%. 1 H NMR(600MHz,DMSO-d6)δ1.32(2CH3,d,6H), 2.52(CH2,t,2H), 2.65(CH2,t,2H), 2.83(CH2,t,2H), 3.04(CH3,s,3H), 3.16(CH3 ,s,3H), 3.79(CH2,t,2H), 4.50(CH,s,H), 4.93(CH,m,H), 5.18(CH2,s,2H), 6.95(CH,m,H), 7.23(CH,m,H), 7.50(CH,m,H)ppm. MS:m / z:474.21(M+1).

[0117] Example 46. Preparation of Compounds 1-46 [ka] 21g of 5-(6-(tert-butoxycarbonylamino)hexylaminovaleric acid, 13.4g of triethylamine are weighed into a 500mL single-mouth bottle, 300mL of DCM is added, the mixture is stirred, and the mixture is replaced with AR gas three times. At 10°C, 19.0g of EDCI is added. After the addition is complete, the mixture is reacted at room temperature with stirring for 1 hour. 15.3g of 5-aminovaleric acid ethyl ester hydrochloride is added. After the addition is complete, the mixture is reacted at room temperature with stirring overnight. After the reaction is complete, the reaction solution is washed with water (50mL x 2), washed with 5% citric acid solution (50mL x 2), the aqueous phase is combined, extracted with 200mL of DCM once, the organic phase is combined, the organic phase is washed with water and saturated sodium chloride once each, dried with anhydrous sodium sulfate, and concentrated to dryness to obtain colorless oily compound 1-46, the yield is 70%, and the purity is 98.43%. 1 H NMR(600MHz,DMSO-d6)δ1.29(CH3,t,3H), 1.38(3CH3,s,9H), 1.52(3CH2,m,6H), 1.53(2CH2,m,4H), 1.64(C H2,m,2H), 2.13(2CH2,m,4H), 2.32(CH2,t,2H), 3.02(2CH2,t,4H), 3.18(CH2,m,2H), 4.13(CH2,m,2H)ppm. MS:m / z:444.30(M+1).

[0118] Example 47. Preparation of Compounds 1-47 [ka] 20.0g of compound 1-46 was weighed into a 250mL single-mouth bottle, 50mL of hydrochloric acid ethanol (3M) was added, and the mixture was stirred and reacted at room temperature. After sampling and spotting, it was found that the raw material was completely reacted, and the pH was adjusted to about 5.0 with sodium bicarbonate, filtered, and the filtrate was dried with anhydrous sodium sulfate and concentrated to dryness to obtain colorless oily compound 1-47, with a yield of nearly 100% and a purity of 98.23%. 1H NMR(600MHz,DMSO-d6)δ1.29(CH3,t,3H), 1.52(3CH2,m,6H), 1.53(2CH2,m,4H), 1.64(CH2,m,2H) , 2.13(2CH2,m,4H), 2.32(CH2,t,2H), 2.65(CH2,m,2H), 3.02(2CH2,t,4H), 4.13(CH2,m,2H)ppm. MS:m / z:344.25(M+1).

[0119] Example 48. Preparation of Compounds 1-48 [ka] Referring to the synthesis method of compound 1-1 in Example 1, 2.7 g of 1,3-dimethyl-6-chlorouracil and 6.2 g of compound 1-47 were used as raw materials to obtain pink powdery compound 1-48, with a yield of 41.42% and a purity of 99.38%. 1 H NMR(600MHz,DMSO-d6)δ1.29(CH3,t,3H), 1.52(3CH2,m,6H), 1.53(2CH2,m,4H), 1.64(CH2,m,2H), 2.13(2CH2,m,4H), 2.32 (CH2,t,2H), 2.87(CH2,m,2H), 3.01(CH3,m,3H), 3.02(2CH2,m,4H), 3.16(CH3,s,3H), 4.13(CH2,m,2H), 4.50(CH,s,H)ppm. MS:m / z:482.29(M+1).

[0120] Example 49. Preparation of Compounds 1-49 [ka] Referring to the synthesis method of compound 1-1 in Example 1, 1,3-dimethyl-6-chlorouracil and ubenimex (CAS: 58970-76-6) were used as raw materials to obtain white powder compound 1-49, with a yield of 51.63% and a purity of 98.46%. 1H NMR(600MHz,DMSO-d6)δ0.91(2CH3,d,6H), 1.49(CH,m,H), 1.75(CH2,t,2H), 2.92;2.67(CH2,m,2H), 3.01(CH3,s,3H), 3.16(CH ppm. MS:m / z:447.22(M+1).

[0121] Example 50. Preparation of Compounds 1-50 [ka] Weigh out 20g of 4-nitrophenol and dissolve it in 200mL of DCM, add 21g of DIPEA, transfer the reaction to an ice-water bath, cool it to 0℃, and flush with N2 three times. Cool the temperature to 0℃, and add 25g of triphosgene dropwise to the reaction (dissolved in 100mL of DCM). After the addition is complete, the reaction is stirred at room temperature and stopped when the raw materials are almost completely reacted as monitored by TLC. Wash the reaction repeatedly with 40mL of water until it becomes almost neutral, then wash with 50mL of saturated saline, dry over anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure at 45℃ and concentrate to dryness to obtain 22g of off-white powder compound 1-50, the yield is 100%. 1 H NMR (600MHz, DMSO-d6) δ7.52(4CH,m,4H), 8.3(4CH,m,4H)ppm. MS:m / z:305.03(M+1).

[0122] Example 51. Preparation of Compounds 1-51 [ka] Weigh out 22g of compound 1-50 and dissolve it in 250mL of DCM, add 13g of cyclopentylamine, flush with N2 three times, transfer the reaction to an oil bath and heat to 40℃ and react with stirring. Heat the temperature to 40℃ and drop 25g of triphosgene into the reaction solution (dissolved in 100mL of DCM). When the raw materials are almost completely reacted as monitored by TLC, the reaction is stopped. Concentrate the reaction solution under reduced pressure at 45℃. Concentrate to dryness, add 150mL of methanol to the concentrate, heat and dissolve, add 100mL of water after dissolution, and stir at room temperature. Filter, put the filter cake in an oven and vacuum dry at 60℃ to obtain 8g of gray-brown powder compound 1-51, the yield is 56.4%. 1 H NMR (600MHz, DMSO-d6) δ 1.73;1.63(4CH2,m,8H), 1.85;1.60(4CH2,m,8H), 3.61(2CH,m,2H)ppm. MS:m / z:197.16(M+1).

[0123] Example 52. Preparation of Compounds 1-52 [ka] Weigh out 8g of compound 1-51 and dissolve it in 80mL of DCM, replace with N2 three times, and add 5.6g of malonyl chloride dropwise. After the addition is complete, transfer the reaction mixture to an oil bath and heat it to 45°C, and react with stirring. The temperature is raised to 45°C, and the reaction is continued while keeping the temperature and stirring. When the raw material is almost completely reacted as tracked by TLC, the reaction is stopped. Concentrate the reaction solution under reduced pressure at 45°C and concentrate to dryness to obtain a dark green solid. Prepare a sample and subject it to column purification (PE:EA=15:1 to 8:1 gradient), collect the main component after elution, and concentrate to dryness to obtain 7g of yellow powder compound 1-52, the yield is 65%. 1 H NMR (600MHz, DMSO-d6) δ 1.73;1.63(4CH2,m,8H), 1.85;1.60(4CH2,m,8H), 3.07(CH2,s,2H), 3.61(2CH,m,2H)ppm. MS:m / z:265.15(M+1).

[0124] Example 53. Preparation of Compounds 1-53 [ka] Weigh out 7.0g of compound 1-52 and 3.9g of N,N-diethylaniline, add 35mL of phosphorus oxychloride, replace with N2 three times, transfer the reaction to an oil bath and heat to 100℃ and react with stirring. The temperature is raised to 100℃ and the reaction is carried out while keeping warm and stirring. When the raw materials are almost completely reacted as tracked by TLC, the reaction is stopped. The reaction liquid is slowly added to 300mL of ice water and stirred thoroughly, then extracted with 300mL of DCM three times, the organic phase is washed successively with 100mL of water and 100mL of saturated saline twice, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure at 45℃. Concentrate to dryness to obtain a brown oil. A sample was prepared and subjected to column purification (PE:EA=50:1 to 20:1 gradient), and the main component was collected after elution and concentrated to dryness to obtain 5.3 g of yellow oily compound 1-53, the yield was 70.09%. 1 H NMR(600MHz,DMSO-d6)δ 1.73;1.63(4CH2,m,8H), 1.85;1.60(4CH2,m,8H), 3.61(2CH,m,2H), 5.65(CH,s,H)ppm. MS:m / z:283.11(M+1).

[0125] Example 54. Preparation of Compounds 1-54 [ka] Weigh out 1.0g of compound 1-53 and 0.7g of β-alanine-β-alanine ethyl ester (CAS: 754933-31-8), add 10mL of isopropanol, dissolve with stirring, add 1.4g of DIPEA, heat to 85℃, react for 4 hours while keeping warm and stirring, then stir at room temperature overnight. When the raw materials are completely reacted as monitored by TLC, the reaction is stopped. The reaction solution was concentrated at 55°C, concentrated to dryness, the reaction solution was added to 200mL of DCM to dissolve, then washed successively with 40mL of water and 40mL of saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain an oily substance, a sample was prepared and subjected to column purification (methanol:DCM=1:100 to 4:100 gradient), the main component was collected after elution, concentrated to dryness to obtain 0.73g of pale yellow powder compound 1-54, the yield was 47.4%, and the purity was 98.77%. 1 H NMR(600MHz,DMSO-d6)δ1.07(CH3,t,3H), 1.73;1.63(4CH2,m,8H), 1.85;1.60(4CH2,m,8H), 2.64(CH2,m,2H) , 2.65(CH2,m,2H), 3.61(2CH,m,2H), 3.61(CH2,m,2H), 3.79(CH2,t,2H), 4.01(CH2,m,2H), 4.21(CH,s,H)ppm. MS:m / z:435.25(M+1).

[0126] Example 55. Preparation of Compounds 1-55 [ka] Weigh out 10.0g of compound 1-33, 5.7g of β-alanine-β-alanine ethyl ester (CAS: 754933-31-8), and 9.1g of triethylamine, and dissolve them in 100mL of ethanol, and react them under stirring at 80°C. Then stir at room temperature overnight, and stop the reaction when the raw material is completely reacted as tracked by TLC. Concentrate the reaction solution to dryness at 50°C, extract with DCM, wash the organic phase with water and saturated sodium chloride, dry with anhydrous sodium sulfate, and concentrate to dryness, prepare a sample, and subject it to column purification (DCM:EtOH=100:1+2% ammonia water), collect the main component after elution, and concentrate to dryness to obtain 8.2g of yellow solid, add 30mL of anhydrous ethanol to recrystallize, filter, and dry the filter cake to obtain 7.6g of white powder compound 1-55, the yield is 52%, and the purity is 98.55%. 1 H NMR(600MHz,DMSO-d6)δ1.07(CH3,t,3H), 2.64(CH2,m,2H), 2.65(CH2,m,2H), 3.61(CH2,t,2H), 3.79(CH2,t,2H), 4.01(C H2,m,2H), 4.21(CH,s,H), 4.48(2CH2,s,4H), 7.37(2CH,t,2H), 7.86(2CH,m,2H), 8.37(2CH,m,2H), 8.59(2CH,m,2H)ppm. MS:m / z:481.21(M+1).

[0127] Example 56. Effect of compounds on in vivo blood clotting time experiments in animals Testing Method: The control group and model group were given distilled water and positive clopidogrel by forced oral administration, and the test group was given a drug solution of 0.1mL / 10g by forced oral administration (ig) for 4 consecutive days. Finally, 1 hour after administration, the blank group was given 0.1mL / 10g of saline, and the remaining groups were given 0.15mL / 10g of 0.3% ellagic acid solution by tail vein injection. After 5 minutes, blood was collected from the glass capillary through the retroorbital venous plexus, and blood was collected through the glass tube every 10 seconds, and the time when blood coagulation filaments appeared was recorded. The experimental results are shown in Table 1. Calculation formula for blood clotting time prolongation: Blood clotting time prolongation rate (%) = [(mean blood clotting time of blank group or administration group / mean blood clotting time of model group) - 1] x 100%

[0128] [Table 1] As can be seen from Table 1, compared with the model group, the compounds of the present invention have the effect of extending the blood clotting time of mice to various degrees. Compared with the positive drug clopidogrel group, the compounds of the present invention all show stronger anticoagulant effect.

[0129] Example 57. Effect of compounds on in vivo bleeding time experiments in animals Testing Method: The experiment consisted of a normal control group (blank), a positive control group (clopidogrel) and an experimental group, with 10 ICR mice (male, weighing approximately 25g) in each group. The animals in each group were administered 0.1ml / 10g body weight of drug solution by gavage (ig), and the blank control group was administered distilled water once a day for 4 consecutive days. On the 4th day, 1 hour after administration, the animals were anesthetized by intraperitoneal injection of sodium barbiturate at a dose of approximately 50mg / kg, and after 20 minutes, the tails of the mice were cut 3mm from the tip of the tail, and the blood of the cut tail was periodically collected with absorbent paper until no blood leaked out, and the bleeding time was recorded, and the experimental results are shown in Table 2. Formula for calculating bleeding time prolongation rate: Bleeding time prolongation rate (%) = [mean bleeding time of treatment group / mean bleeding time of blank group-1] x 100%

[0130] [Table 2] As can be seen from Table 2, the positive control drug clopidogrel significantly prolongs the bleeding time of mice at 15 mg / kg, but the bleeding time of the compound of the present invention at 100 mg / kg is still similar to the clopidogrel group and similar to the normal control group.

[0131] Example 58. Effects of prophylactic administration of compounds on cerebral ischemia-reperfusion injury in rats Experimental method: SD rats were randomly divided into 6 groups, including a sham operation group, a model control group, a positive control drug ozagrel (6 mg / kg) group, and groups receiving high (9 mg / kg), medium (3 mg / kg), and low (1 mg / kg) doses of the test compound 1-1. The treatment group was administered in advance by tail vein injection, and the sham operation group and model control group were administered an equal amount of saline once a day for three consecutive days. 10 minutes after the last administration, a rat MCAO / R model was established, and reperfusion was performed after 2 hours of ischemia. 24 hours after MCAO reperfusion, neurobehavioral scores were performed to measure the neurological function of the rats, and the cerebral infarction rate and brain water content of the rats were measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining method.

[0132] The results are as follows: [Table 3] As can be seen from Table 3, the cerebral infarction rate of rats in the model group reached 33.61±3.56%, indicating that the modeling was successful. Compared with the model group, the white infarction area of ​​the surgical side of rats in each administration group was reduced to various degrees, where the positive drug ozagrel (6mg / kg) group and the test drug compound 1-1 high dose (9mg / kg) group can significantly reduce the cerebral infarction rate of rats with focal cerebral ischemia-reperfusion injury (P<0.01).

[0133] [Table 4] As can be seen from Table 4, compared with the sham operation group, the brain water content of rats with focal cerebral ischemia-reperfusion in the model group was significantly higher than that in the sham operation group, indicating that the modeling was successful; compared with the model group, the positive drug ozagrel (6 mg / kg) group and the test drug compound 1-1 high dose (9 mg / kg) group can significantly reduce the brain water content of rats with focal cerebral ischemia-reperfusion injury (P<0.01).

[0134] [Table 5] As can be seen from Table 5, after MCAO / R, the rats in the model group have higher neurobehavioral scores, which indicates that the rats in the model group have severe neurological dysfunction.Compared with the model group, the positive drug ozagrel (6mg / kg) group and the test compound 1-1 high dose (9mg / kg) group can significantly reduce the neurological function score of rats with focal cerebral ischemia-reperfusion injury (P<0.01). Conclusion: Prophylactic administration of compound 1-1 can reduce the cerebral infarction rate and brain water content in rats with cerebral ischemia-reperfusion injury, and improve the neuromotor function of rats.

[0135] Example 59. Inhibitory effect of compounds on myocardial ischemia-reperfusion injury induced by coronary artery ligation in rats Experimental method: Establish a myocardial ischemia-reperfusion (MI / R) injury model by coronary artery ligation in rats, and group the animals into high dose (20mg / kg), medium dose (10mg / kg), low dose (5mg / kg), clopidogrel (7.5mg / kg), sham operation, and model groups. The sham operation and model groups are administered with equal amounts of 0.5% CMC-Na, with the dose being 0.5ml / 100g body weight. The rats are given by gavage (ig) once a day for 5 consecutive days. Modeling is performed 30 minutes after the last administration, and 8 rats that have been successfully modeled after modeling are selected from each group for the next experiment. The sham operation group is left without ligation of the left anterior descending coronary artery according to the model preparation method, and the other groups are modeled according to the model preparation method. The effects of the test drugs on the myocardial infarction rate of rats and the biochemical indicators in plasma, such as creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA), and superoxide dismutase (SOD), were detected, and cardiac TTC staining was performed to detect the effects of the test drugs on the myocardial infarction area in MI / R rats.

[0136] The results are as follows: [Table 6]

[0137] [Table 7]

[0138] [Table 8] Conclusion: Compound 1-1 can affect the plasma biochemical indicators of rats with myocardial ischemia-reperfusion injury induced by coronary artery ligation, improve the degree of myocardial lesions, and inhibit the myocardial infarction rate, where the overall effect of the high-dose compound 1-1 group is slightly better than that of the positive drug clopidogrel group.

[0139] Example 60. Effect of combined administration of compound and urokinase (iv) on autologous thrombus and thrombin-induced ischemic brain injury in rats Experimental method: Prepare SD rat cerebral ischemia injury model by injecting autologous thrombus and thrombin from external carotid artery to internal carotid artery to embolize cerebral artery in rats. According to behavioral score, randomly divide into 5 groups, including sham operation group (only external carotid artery is isolated), model control group (two groups are given equal amount of saline), urokinase (5000U / kg) group, compound 1-1 (22.5mg / kg) group, etc. Each group has 20 rats (10 rats are used for detecting cerebral infarction rate, and 10 rats are referred to pathological detection). After 2 hours of modeling, administer once slowly into tail vein (1mL every minute), and monitor the reduction of blood flow after 120 minutes of administration after thrombin injection. After 24 hours, perform neurobehavioral scores on the rats to measure the neurological functions of the rats, measure the cerebral infarction rate and cerebral water content of the rats by 2,3,5-triphenyltetrazolium chloride (TTC) staining method, and use hematoxylin-eosin (HE) staining method to observe the cerebral pathological damage of the administered rats 2 hours after cerebral ischemia.

[0140] [Table 9]

[0141] [Table 10]

[0142] [Table 11]

[0143] [Table 12]

[0144] Experimental results: Intravenous administration of compound 1-1, urokinase and compound 1-1 + urokinase after cerebral ischemic injury model caused by autologous thrombosis and thrombin can significantly reduce the reduction rate of cerebral blood flow in the model rats, the cerebral infarction area and cerebral water content in rats, and improve pathological damage and behavioral changes, where compound 1-1 + urokinase has the most obvious improvement level on cerebral ischemic injury caused by autologous thrombosis and thrombin. Experimental conclusion: Compound 1-1(iv) and the combined administration of compound 1-1(iv) with urokinase can reduce the cerebral infarction rate, cerebral water content and pathological damage in rats with autologous thrombus and thrombin-induced ischemic brain injury, and improve the neuromotor function of rats, indicating an excellent anti-ischemic brain injury effect.

[0145] Example 61. Improvement of focal permanent cerebral ischemic damage by administration 3 hours after ischemia Experimental method: Using the internal carotid artery suture embolization method, a cerebral artery occlusion (MCAO) model in rats was created. Forty-eight clean grade male SD rats weighing 250-300g were randomly divided into six groups according to body weight and sex, with eight rats in each group, which were the high dose group of compound 1-1, the medium dose group of compound 1-1, the low dose group of compound 1-1, the positive control butyrolide soft capsule group 60mg / kg, the sham operation group, and the ischemia model control group (all administered with an equal amount of 0.5% CMC-Na). Administration began 3 hours after MCAO surgery, and was given orally once a day by force, with a dose of 0.5ml / 100g body weight, for 14 consecutive days. One hour after the last administration, the animals were scored for neurological dysfunction according to the Bederson method, and then the rats were killed by decapitation, the whole brains were removed and weighed, the sections were stained with ttc, and photographed to calculate the infarction rate and water content of the brain tissue.

[0146] 48 clean grade male SD rats weighing 250-300g (100 rats are actually needed because the molding rate is about 50%) were randomly divided into 6 groups according to body weight, with 8 rats in each group. The grouping, administration and operation methods were the same as before. One hour after the last administration, the rats were killed by decapitation, the whole brain was removed and fixed in 10% formaldehyde solution, and coronal sections of the brain were taken, dehydrated, embedded in paraffin, and after sectioning and HE staining, the histopathological changes were observed under a light microscope, and the degree of pathological damage was scored.

[0147] Test Results: [Table 13] Results: Compound 1-1 in the medium and high dose groups can obviously reduce the mortality rate of rats.

[0148] [Table 14] Results: The body weight of rats in the sham operation group increased steadily for 15 days, while the body weight of rats in the model group showed an overall decreasing trend within 15 days. All the treatment groups had different degrees of effect on the weight maintenance of rats, which indicates that the average body weight within the group was significantly higher than that of the model group after 15 days. Here, the weight gain of the high dose group of compound 1-1 was significantly superior to that of the other treatment groups.

[0149] [Table 15] Results: The treatment group can significantly reduce the neurological function score of rats after 15 days, which appears as mild hooking and limb asymmetry, some rats fully recover and the neurological function score is 0, but the neurological function score of the model group is significantly higher than that of the treatment group, and in severe cases, it can reach 3 points, which appears as unable to walk straight and walking in circles all the time.

[0150] Conclusion: Compound 1-1 has the effect of improving brain nerve function. Furthermore, TTC staining revealed that the infarction rate and water content of the medium and high dose groups of Compound 1-1 were significantly reduced compared with the model group. Pathological examination showed that compared with the normal control group, the brain tissue of the model group showed obvious neuronal degeneration, necrosis, microglial proliferation, neuronal and interstitial edema, interstitial congestion, hemorrhage and other pathological changes. Compared with the model group, the pathological changes of each test group were alleviated, where the high dose group was most obviously reduced, and the pathological changes of the positive control group, especially the degeneration and necrosis of cortical neurons, were aggravated. This indicates that the test product has a certain improving effect on the pathological damage of permanent cerebral ischemia.

[0151] Example 62. Detection of compound antibody chip Experimental method: ICR male mice weighing about 25g were randomly divided into four groups: normal group, ellagic acid model group, 1-1 group, and 1-22 group, each group had 4 mice. Mice in groups 1-1 and 1-22 were given 1-1, 100mg / kg and 1-22, 100mg / kg, respectively, once a day by force. One hour after the third administration, mice in the other three groups, except for the normal control group, were given 0.10ml / 10g of 0.3% fentanyl saline solution via tail vein injection. One hour after injection, whole blood from each animal was collected, left for 30 minutes, then centrifuged (3000rpm / min) for 10 minutes, and centrifuged to obtain serum. The serum from each group of animals was mixed in EP tubes, transported at -80℃, and the antibody chip was detected.

[0152] Test Results: [Table 16]

[0153] The results showed that the expression levels of IL-1b, TNFa, IL-6 and RANTES / ccl5 in the ellagic acid model group increased obviously, indicating that ellagic acid could induce acute inflammatory responses in vivo. Compound 1-1 could obviously down-regulate the expression levels of IL-6 and RANTES / ccl5, and compound 1-22 could obviously down-regulate the expression levels of IL-6 and RANTES / ccl5, indicating that compound 1-1 and compound 1-22 could alleviate the acute inflammatory responses caused by ellagic acid, but compound 1-22 could down-regulate more different protein factors. [Table 17] The results show that the model groups can all obviously up-regulate the expression levels of IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6 and IL-13, the 1-1 compound can down-regulate the expression levels of IL-1α, IL-5, IL-6 and IL-13, and the 1-22 compound can down-regulate the expression levels of IL-1α, IL-1β, IL-3, IL-4, IL-5, IL-6 and IL-13. Compared with the model group, the number of down-regulated different proteins in the 1-1 group is 4, and the number of down-regulated different proteins in the 1-22 group is 7. The different protein interleukin factors mainly down-regulated in the I-1 group and the 1-22 group are Th2 cytokines.

[0154] [Table 18] The results showed that the ellagic acid models could all significantly up-regulate the expression levels of these four inflammatory chemokines, the 1-1 compound could significantly down-regulate the expression levels of MIP-3a / CCL20 and RANTES / CCL5, and the 1-22 compounds could all significantly down-regulate the expression levels of the four inflammatory chemokines, indicating that the 1-1 compound and the 1-22 compounds could all inhibit the chemotaxis of inflammatory cells and the release of inflammatory factors.

[0155] [Table 19] The results showed that the expression levels of IFNg and CD40 in the ellagic acid model group were significantly increased compared to the normal group, indicating that 1-1 compound can significantly downregulate IFNg, and 1-22 compound can significantly downregulate the expression levels of IFNg and CD40 at the same time, suggesting that 1-1 and 1-22 can inhibit antigen presentation and inhibit the activation of immune cells.

[0156] Conclusion: Compared with the normal group, after ellagic acid injection, the content of each detected cytokine was significantly increased, and the related biological functions mentioned included positive control of leukocyte proliferation, differentiation, migration, positive control of immune effects, positive control of cell adhesion, positive control of acute inflammatory response, etc., which causes acute inflammatory response in the body. Compared with the model group, all different proteins were significantly down-regulated in the 1-1 and 1-22 groups, and 1-1 and 1-22 showed obvious anti-cytokine production effects, anti-acute inflammatory response effects, etc.

[0157] Example 63. Preparation of Compound 1-1 Tablets [Table 20] According to the above formula, compound 1-1, microcrystalline cellulose, croscarmellose sodium are mixed uniformly, and granulated with hydroxypropylcellulose aqueous solution, dried, and after granulation, microcrystalline cellulose and magnesium stearate are added to the granules, and mixed uniformly, and the above granules are compressed into tablets to obtain plain tablets. The thin-film coating solution, which is composed of titanium oxide, ferric oxide, talc, and hydroxypropylmethylcellulose aqueous solution, is thin-film coated by a coating machine to obtain thin-film coated tablets, each of which contains 100mg of compound 1-1.

[0158] Example 64. Preparation of enteric capsules of compound 1-1 [Table 21] Compound 1-1, microcrystalline cellulose SH101, and lactose monohydrate are weighed according to the prescribed amount and stored. Compound 1-1, microcrystalline cellulose SH101, and lactose monohydrate are added to the pot of the wet mixer granulator, stirring is started, and the mixture is mixed for 5 minutes and granulated. (1) Preparation of adhesive: Hypromellose E5 is weighed in an appropriate amount, and water is added to make a 5% solution and stored. (2) Granulation: Stirring is started, and adhesive solution is added by peristaltic pump. The granulation time is 3 minutes. (3) Sizing and drying: The prepared wet granules are sieved through a swing granulator and dried in an electric thermostatic drying oven at 70°C (rotating once every 15 minutes), so that the moisture is ≦3%. The dried material is sieved through a swing granulator, and the dosage of magnesium stearate is calculated based on the granule yield. After weighing, it is added to a laboratory hopper mixer together with the materials after granulation, stirred, and the mixing time is 5 minutes. It is filled into No. 1 enteric capsules and packaged in aluminum plastic packaging.

[0159] Example 65. Preparation of freeze-dried powder of compound 1-1 [Table 22] Weigh out the main drug compound 1-1 and mannitol according to the prescribed amount, add 80% prescribed amount of water for injection, stir until dissolved, measure the pH value of the solution, if the pH value is between pH6-7, do not adjust the pH value, if it exceeds, adjust the pH value of the drug solution with sodium hydroxide solution (or hydrochloric acid solution), and add water for injection up to the prescribed amount. Filter the solution first through a 0.45um microporous filter membrane, then through a 0.22um microporous filter membrane, and fill. Freeze-dry according to the set freeze-drying parameters, and perform uncorking, capping, and packaging.

[0160] Example 66. Preparation of injections of compounds 1-24 [Table 23] Take 80% of the total volume of water for injection, add the prescribed amount of sodium chloride, sodium citrate dihydrate, glycerol, and compound 1-24 in order, stir to dissolve, and adjust the pH value of the solution to 5.0-6.5 with 0.1M hydrochloric acid or sodium hydroxide. Adjust the volume to the required amount with water for injection. Dispense into 10ml glass bottles and sterilize in an autoclave to obtain an injection solution of the compound. Each bottle contains 20mg of compound 1-24.

[0161] All documents mentioned in the present invention are incorporated by reference in this application as if each document was incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalents are also included in the scope defined by the appended claims of this application.

Claims

1. A compound comprising: The compound is a compound according to formula I, or a pharma- ceutically acceptable salt, solvate, hydrate, isomer, or prodrug thereof, 【Chemistry 1】 During the ceremony, R １ and R ２ are each independently H, a substituted or unsubstituted 5-10 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from C1-C10 alkyl group, halo C1-C10 alkyl group, C3-C10 cycloalkyl group, halo C3-C10 cycloalkyl group, C1-C10 alkoxy group, halo C1-C10 alkoxy group, -(C=O)-(C1-C10 alkyl), C2-C10 alkenyl group, C2-C10 alkynyl group, halogen, N, O or S. selected from the group consisting of a heterocycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, -(C1-C6 alkylene)-(substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S), and -(C1-C6 alkylene)-(substituted or unsubstituted C6-C10 aryl); X is selected from the group consisting of O, S, and NH; Y is O; R ３ is selected from the group consisting of H and a C1-C10 alkyl group; R ４ is selected from the group consisting of H and a C1-C10 alkyl group; R ５ is selected from the group consisting of H, a C1-C10 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, a substituted or unsubstituted C5-C12 bridged cycloalkyl group; Each R ６ is independently selected from the group consisting of H, a C1-C10 alkyl group, -(C1-C6 alkylene)-(substituted or unsubstituted C6-C10 aryl); each m is independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; n is selected from the group consisting of 1, 2, 3 and 4; "Substituted" refers to, independently of one another, a C1-C10 alkyl group, a -(C1-C6 alkylene)-piperazinyl group, a -(C1-C6 alkylene)-N, a 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from O or S, a halo C1-C10 alkyl group, a C1-C10 alkoxy group, a C1-C10 alkylthio group, CN, a nitro group, -NR ａ R ｂ , -(C=O)-NR ａ R ｂ , halogen, hydroxyl, and oxo; R ａ and R ｂ are each independently selected from the group consisting of H, a C1-C10 alkyl group, and a halo C1-C10 alkyl group; Optionally, the alkylene group within the brackets is substituted with 1, 2 or 3 OH.

2. R １ and R ２ are each independently selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl group, -(C1-C6 alkylene)-(substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S), and -(C1-C6 alkylene)-(substituted or unsubstituted C6-C10 aryl); X is selected from the group consisting of O, S, and NH; Y is O; R ３ is selected from the group consisting of H and C1-C6 alkyl groups; R ４ is H, R ５ is selected from the group consisting of H, a C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, and a substituted or unsubstituted C5-C12 bridged cycloalkyl group; Each R ６ is independently selected from the group consisting of H, a C1-C6 alkyl group, -(C1-C6 alkylene)-(substituted or unsubstituted C6-C10 aryl); each m is independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; n is selected from the group consisting of 1, 2, 3 and 4; "Substituted" refers to being substituted with one or more substituents, each independently selected from the group consisting of a C1-C6 alkyl group, a halo C1-C6 alkyl group, CN, and halogen; The compound of claim 1.

3. R １ and R ２ each independently represents H, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a neopentyl group, a tert-pentyl group, or —CH ２ -(1 to 6 R' substituted or unsubstituted phenyl groups), and -CH ２ - pyridyl groups, each R' is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, F, Cl, Br, I, and CN; The compound of claim 1.

4. 2. The compound of claim 1, wherein X is O or S.

5. R ３ is H, R ４ is H, R ５ is H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl, tert-pentyl, and 【Chemistry 2】 is selected from the group consisting of Where: 【Chemistry 3】 is the connecting bond with Y, The compound of claim 1.

6. The compound is selected from the group consisting of: 【Table 1-1】 【Table 1-2】 【Table 1-3】 The compound of claim 1.

7. A process for preparing the compound of claim 1, comprising the steps of: 【Chemistry 4】 【Chemistry 5】 to obtain a compound of formula I, Where: R″ is a halogen; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , X, Y, m and n are as defined in claim 1.

8. 1. A pharmaceutical composition comprising: The pharmaceutical composition comprises a pharma- ceutically acceptable carrier and a safe and effective amount of one or more compounds according to claim 1.

9. Use of the compound according to claim 1, 1) Preparation of a drug for use in the treatment of infarction-related diseases; 2) Preparation of drugs for use in the thromboprophylactic and / or thrombolytic, anti-edematous and / or immuno-inflammatory treatment of thrombotic diseases; 3) preparation of a drug used for improving neuronal damage caused by brain trauma, cerebral hemorrhage and / or brain tumor surgery.

10. The infarction-related disease is selected from the group consisting of neuronal damage to nervous tissue due to acute ischemic stroke (cerebral infarction), myocardial infarction, and pulmonary embolism; and / or The thrombotic disease is selected from the group consisting of cardiovascular disease, cerebrovascular disease, and peripheral vascular disease; 10. The use according to claim 9.

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