Polysubstituted uracil derivatives and their preparation method and applications

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, in particular 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 rate of disability and mortality, posing a serious threat to human life and health. Statistics show that approximately 18 million people die from various thrombotic diseases worldwide each year, accounting for 51% of the total number of deaths worldwide and making it the leading cause of total mortality in the world. In China, there are 1.5 million new cases of thrombosis each year, and 2.5 million people suffer from thrombotic diseases each year, with 70% of these patients suffering from sequelae.

[0003] Currently, drugs commonly used to prevent and treat thrombosis can achieve the goal of inhibiting or reversing thrombus formation by intervening in various stages of the blood coagulation process (e.g., inhibiting the activity of blood coagulation factors, inhibiting platelet aggregation, etc.). Over the years, antithrombotic drugs have made great progress in terms of efficacy. However, all antithrombotic drugs in clinical use, whether they are old drugs that have been used for decades or newer 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 antithrombotic drugs and can even become a life-threatening risk. This drawback limits the clinical application of such drugs and significantly threatens patient safety. There is currently no satisfactory clinical solution to this drawback. Currently, most drugs (e.g., clopidogrel) do not have specific rescue medications, and when severe bleeding occurs, the only emergency treatment available is platelet replacement, fresh blood coagulation factors, etc. 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 cardiac, cerebral, and other arterial circulatory disorders caused by high platelet aggregation, such as recently diagnosed 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 pharmaceutically 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 haloC1-C10 alkyl group, a C3-C10 cycloalkyl group, a haloC3-C10 cycloalkyl group, a C1-C10 alkoxy group, a haloC1-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 a 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from a C1-C10 alkyl group, a -(C1-C6 alkylene)-piperazinyl group, a -(C1-C6 alkylene)-N, O, or S, a haloC1-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 substituted by one or more substituents selected from the group consisting of 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 with 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 a C1-C6 alkyl group; R4 is selected from the group consisting of H and a C1-C6 alkyl group; 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 a 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from a C1-C6 alkyl group, a -(C1-C6 alkylene)-piperazinyl group, a -(C1-C6 alkylene)-N, O, or S, a haloC1-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 substituted by one or more substituents selected from the group consisting of 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 haloC1-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 a C1-C6 alkyl group; 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 haloC1-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 to 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 with 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 present invention provides a method for preparing a compound according to the first aspect of the present 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 pharmaceutically 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 drugs used in the treatment of infarction-related diseases; 2) Preparation of drugs used in thromboprophylaxis and / or thrombolytic treatment of thrombotic diseases, anti-edema treatment and / or immuno-anti-inflammatory treatment; 3) preparation of a medicament for use in ameliorating 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 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. [Effects of the Invention]

[0016] It should be understood that within the scope of the present invention, the above-mentioned 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 INVENTION

[0017] As a result of extensive 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.

[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-chain or branched-chain alkenyl group containing one double bond and having 2 to 6 carbon atoms, including, but 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-chain or branched-chain alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including, but 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 a similar meaning.

[0023] In the present invention, the term "C1-C6 alkoxy group" refers to a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. A C1-C4 alkoxy group is preferred. A "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, 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 containing no heteroatoms in the ring, such as a phenyl group and naphthyl group.

[0026] As used herein, the terms "heteroaromatic ring" and "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one to multiple heteroatoms. For example, a "C3-C10 heteroaryl group" refers to an aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen and 3 to 10 carbon atoms. Non-limiting examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. A heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring. A 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] As used herein, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituents are those described in the preceding specification, as appropriate, or in each example. Unless otherwise specified, a substituent may have a substituent selected from the specified group at any substitutable position of the group, and the substituents at each position may be the same or different. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are stable or chemically achievable. Examples of substituents include, but are not limited to, halogen, hydroxyl, carbonyl (—COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, and C1-C10 sulfonyl.

[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 "plurality" 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, and are as defined above.

[0031] It is understood that when a group is present simultaneously 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 compounds according to formula I: [ka] wherein 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 "pharmaceutically acceptable salt" refers to a medicament-compatible salt formed between 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 between the compound of the present invention and an acid. Acids suitable for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; 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, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0035] Other 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 alkanolammonium salts and other pharmaceutically 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, and lysine, respectively.

[0036] The term "solvate" refers to a complex formed when a compound of the present invention is coordinated with solvent molecules in a specific ratio. "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 represented by Formula I. The term "prodrug" includes compounds that may be biologically active or inactive themselves, and that, after being administered in an appropriate manner, are converted into the compounds of Formula I or salts or solutions consisting of the compounds of Formula I through metabolism or chemical reaction in the human body. The prodrugs include, but are not limited to, carboxylic esters, carbonate esters, phosphate esters, nitrates, sulfates, sulfonates, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and other forms of the compounds.

[0038] As an example, the compound may have the structure shown in formula (I): [ka] wherein R1 and R2 represent one of the following: hydrogen atoms, linear and cyclic alkyl groups of various structures containing 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 at the ortho, meta, or para positions, glucosyl groups, 1,2-propanediol groups, ((S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl groups, and ((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 short carbon chain alkyl groups of various structures having 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] wherein each group is as defined above.

[0042] Typically, in the present invention, formula (I) can be realized by the following synthesis methods. Bis(p-nitrobenzene) derivative (1) is reacted with a primary amine derivative to give urea derivative (2), which is then reacted with triphosgene to give diimine derivative (3), which is then reacted with malonic acid to give barbituric acid derivative (4). Alternatively, compound (2) is directly reacted with dichloromalonyl to give barbituric acid derivative (4). Compound (4) is halogenated to give 6-halogenated uracil derivative (5). Compound (5) is reacted with a series of polysubstituted amino acid ester derivatives (5-A) in the presence of a solvent and base to give polysubstituted uracil derivative (I), which is then hydrolyzed to give compound (6). Compound (6) is reacted with phenol or alcohol to give 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 = either O or S, Y0 = either Cl, Br, or 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 chlorinated to give compound (10), and finally substituted 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 malonic acid ester 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), which is then deprotected to obtain multi-substituted amino acid ester derivative compound (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 to 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 the above steps 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-alloleucine, D-alloleucine, 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 treatment for thrombotic diseases, anti-edema treatment, immuno-anti-inflammatory treatment, and / or (c) ameliorating neuronal damage caused by brain trauma, cerebral hemorrhage, and brain tumor surgery.

[0054] Typically, the derivatives are used after thrombolytic treatment following cardiovascular and cerebrovascular infarction to achieve antithrombotic effects and prevent recurrence of infarction, while 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 pharmaceutically 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 commercially available unless otherwise specified.

[0056] The present invention provides polysubstituted uracil derivatives represented by Formula I, as well as their preparation and application. The compounds of Formula I can (a) treat infarction-related diseases, particularly neuronal damage to nervous tissue due to acute ischemic stroke (cerebral infarction), myocardial infarction, pulmonary embolism, and other related diseases; (b) provide thromboprophylaxis and thrombolytic treatment for thrombotic diseases, anti-edema treatment, and immuno-inflammatory treatment; and (c) ameliorate neuronal damage caused by brain trauma, cerebral hemorrhage, and brain tumor surgery. Furthermore, polysubstituted uracil derivatives (I) can be used after thrombolytic treatment following cardiovascular and cerebrovascular infarction to achieve antithrombotic effects, prevent infarction recurrence, and simultaneously reduce the risk of bleeding, which has important clinical significance. The synthetic method for the polysubstituted uracil derivatives of the present invention, such as those represented by Formula (I), is simple, requires mild conditions, has easy access to raw materials, and produces high yields and high product purity.

[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 demonstrated that the polysubstituted uracil derivatives have a certain antiplatelet aggregation activity, and that this activity is equivalent to or superior to that of the corresponding positive control, clopidogrel. At the same time, it was surprising to find in mouse model experiments that the compounds can significantly 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 pharmaceutically 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 its various crystal forms, pharmaceutically 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. Typically, the pharmaceutical composition contains 1 to 2000 mg of the compound / agent of the present invention, more preferably 10 to 1000 mg of the compound / agent of the present invention. Preferably, the "single 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 of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatibility" refers to the ability of the components of the composition to blend with each other without significantly reducing the efficacy of the compounds of the present invention and with each other. 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, capsule, tablet, pill, powder or 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 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, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) a humectant, such as glycerin; or (d) agar, calcium carbonate, potato starch. 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 accelerators 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 may also contain buffering agents.

[0062] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared with coatings and shells, 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 specific part of the digestive tract. Examples of embedding materials that can be used include 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 pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor seed 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 agents, and 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 used 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 that may be required.

[0066] The compounds of the present invention can be administered alone or in combination with other pharmaceutically 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 prevalent amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, where the dosage at the time of administration is a considered effective dose, and for a person weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the patient's health condition, 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 cranial 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 reduces the cerebral infarction rate, cerebral water content and pathological damage in rats with ischemic brain injury caused by autologous thrombus and thrombin, and improves the rats' neuromotor function, showing excellent anti-ischemic brain injury effects. When used in combination 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 used only to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods without specific conditions are generally in accordance with conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or conditions 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 methods 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, 8.39 g (47.76 mmol, 1.0 eq) of β-alanine-β-alanine ethyl ester (CAS: 754933-31-8), 7.0 g (47.77 mmol, 1.0 eq) of 1,3-dimethyl-6-chlorouracil, 18.52 g (143.29 mmol, 3.0 eq) of N,N-diisopropylethylamine, and 42 ml of isopropanol were added to a reaction vessel, heated to 85 °C, and stirred until the reaction was complete. After heating, the mixture was suction filtered, and the filter cake was slurried in 100 ml of ethanol at room temperature, suction filtered, and dried under vacuum at 60 °C to a constant weight to obtain white powdery compound 1-1. The yield was 78% and the purity was 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) was used as raw material to obtain beige powder compound 1-2, with a yield of 56.30% and a purity of 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) was weighed and added to a 100 mL single-neck bottle, followed by 0.23 g of NaOH, 30 mL of ethanol, and 3 mL of water. After the addition was complete, the reaction mixture was stirred at room temperature. After stirring for 2 hours, the mixture was sampled and spotted to monitor the reaction mixture. After stirring for 2 hours, the raw materials in the reaction mixture were completely reacted. The pH of the mixture was adjusted to neutral with concentrated hydrochloric acid, and the mixture was directly concentrated to dryness and then concentrated with ethanol several times to obtain compound 1-3 as an off-white powder. The yield was 90% and the purity was 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] 2g of compound 1-3 was weighed and added to a 100mL three-neck bottle, followed by 20mL of DCM, 1.93g of EDCI, 1.03g of borneol, and 0.08g of DMAP. The reaction mixture was then stirred overnight at room temperature. Since the raw materials were still present in the reaction mixture, the reaction mixture was stirred continuously. After stirring, the reaction mixture was diluted with water and extracted. The organic phase was then washed with water. After washing, the reaction mixture was dried over anhydrous sodium sulfate. After drying, the reaction mixture was concentrated to dryness to obtain white powder compound 1-4. The yield was 44.36% and the purity was 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 powder 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 powder 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] 3g of 1,3-dimethyl-6-chloro-2-sulfoxy-4(1H)-pyrimidinone (CAS: 6972-27-6) was weighed and added to a 100mL single-neck bottle, followed by 3.18g of DIEA, 30mL of isopropanol, and 2.95g of β-alanine-β-alanine ethyl ester (CAS: 754933-31-8). After the addition was complete, the reaction mixture was heated to reflux and stirred. After 8 hours of stirring, the mixture was stopped and separated by sand column chromatography to obtain white powder compound 1-9. The yield was 49.35% and the purity was 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-neck bottle. Then add 0.23g of NaOH, 30mL of ethanol, and 3mL of water. After the addition is complete, the reaction mixture is stirred at room temperature. After stirring for 2 hours, the mixture is sampled and spotted to monitor the reaction. After stirring for 2 hours, the raw materials in the reaction mixture are completely reacted. The pH of the mixture is adjusted to neutral with concentrated hydrochloric acid, and the mixture is directly concentrated to dryness. Then, the mixture is concentrated with ethanol several times to obtain off-white powder compound 1-10. The yield is 77.26% and the purity is 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 powder 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] Referring to the synthesis method of compound 1-1 in Example 1, 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]-4-fluorobenzonitrile (produced by reacting 6-chloro-3-methyluracil with 2-cyano-5-fluorobenzyl bromide), compound (CAS: 1582394-73-7) was used as raw material to obtain white powder 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] 7 g of compound 1-13, 0.69 g of sodium hydroxide, and 70 ml of absolute ethanol were weighed into a 100 mL single-neck bottle and reacted at room temperature with stirring for 3 hours. After the reaction was completed, the mixture was concentrated to a small amount of ethanol, water was added, and the pH was adjusted to 5 with citric acid water. The mixture was stirred for 30 minutes, suction filtered, and the resulting mixture was slurried in water and suction filtered. The mixture was dried under vacuum at 60 °C to obtain 3.5 g of off-white powdered 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] Referring to the synthesis method of compound 1-1 in Example 1, 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) and β-alanine-β-alanine ethyl ester (CAS: 754933-31-8) were used as raw materials to obtain white powder 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] Referring to the synthesis method of compound 1-1 in Example 1, 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) was used as raw materials to obtain white powder 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 powder 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] 31.1 g of N-tert-butoxycarbonyl-L-isoleucine and 27.2 g of HOBT were weighed into a 1 L single-neck bottle and dissolved in 300 mL of DCM. 20.4 g of triethylamine and 38.6 g of EDCI were added. After the addition was complete, the atmosphere was purged with AR gas three times and the mixture was stirred at 25 °C for 1 hour. 22.7 g of β-alanine ethyl ester hydrochloride was added and the mixture was stirred at 25 °C. Samples were spotted and the raw material was found to have reacted completely. The reaction mixture was washed three times with water, four times with 5% citric acid (200 mL x 4), washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 42.6 g of oily compound 1-20 (99.5% yield), which was directly used in 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] 42.5 g of compound 1-20 was weighed into a 500 mL single-neck bottle, and 150 mL of 3 M hydrochloric acid in ethanol was slowly added to dissolve the compound. The mixture was then stirred at 30°C. Sampling and spotting revealed that the starting material had completely reacted. The reaction mixture was cooled to room temperature, the pH adjusted to approximately 5.0 with sodium bicarbonate, filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated to dryness to give 33 g 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] Following the synthesis method of compound 1-3 in Example 3, white powder compound 1-24 was obtained 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-neck bottle and react at 20°C until the raw materials are completely reacted. Allow to stand overnight. Add 100ml of water to dilute the reaction solution. Add EA to extract twice, each time with 200ml. After extraction is complete, the extracted phases are combined and washed with 100ml of saturated brine. The organic phase is separated and concentrated under reduced pressure (50°C, -0.09MPa). After the reduction in pressure, a yellow oily product is obtained. This is separated by sand column chromatography and eluted with P:E=10:1. The product-containing raw material solution (50°C, -0.09MPa) is concentrated to obtain white powder compound 1-25. The yield is 72% and the 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] In a 100ml single-neck bottle, 3.60g of compound 1-25, 40.0g of isopropanol, 4.63g of triethylamine, and 4.62g of compound (CAS: 1582394-73-7) were added and reacted at 85°C. The mixture was concentrated under reduced pressure (55°C, -0.09MPa). After the reduction in pressure, 50ml of saturated sodium bicarbonate was added to dissolve the mixture. The mixture was extracted twice with dichloromethane, each time with 50ml of dichloromethane. The combined extracts were concentrated under reduced pressure (50°C, -0.09MPa). After the reduction in pressure, 6.8g of white solid was obtained. This was separated by sand column chromatography. A mixed solvent of dichloromethane: isopropanol = 20:1 was passed through the column. The product-containing raw liquid (50°C, -0.09MPa) was concentrated to obtain white powder compound 1-26. The yield was 68% and the purity was 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] Referring to the synthesis method of compound 1-1 in Example 1, the compound (CAS: 1582394-73-7) shown in the table (produced by the reaction of 6-chloro-3-methyluracil with 3-(chloromethyl)pyridine hydrochloride) was used as the raw material to obtain white powder 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] Referring to the synthesis method of compound 1-1 in Example 1, 1-benzyl-6-chloro-3-methyl-1H-pyrimidine-2,4-dione (produced by reacting 6-chloro-3-methyluracil with benzyl chloride), compound (CAS: 754933-31-8) was used 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] Compound 1-29 was synthesized as an off-white powder using compound 1-28 as the raw material, following the synthesis method of compound 1-3 in Example 3. The yield was 73.5% and the purity was 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] Following the synthesis method of compound 1-3 in Example 3, compound 1-27 was used as the raw material to synthesize compound 1-31 as an 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] Add 6g of 6-chlorouracil, 60g of DMSO, 6.7g of chloromethylpyridine hydrochloride, and 11.6g of potassium carbonate to a 250ml single-neck bottle and react at 15°C. Stir overnight. The reaction is stopped, and 100ml of water is added to dilute the reaction solution. EA is added to extract twice, each time with 100ml. After extraction is complete, the combined extracts are washed with 100ml of saturated brine. The organic phase is separated and concentrated under reduced pressure (50°C, -0.09MPa). After decompression, the yellow oily compound 1-33 is directly introduced into the next step with a yield of 62% and a purity of 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] Referring to the synthesis method of compound 1-26 in Example 26, 2.3 g of compound 1-33 and 2.94 g of compound (CAS: 1582394-73-7) were used as raw materials to obtain pale yellow powdery compound 1-34, with a yield of 46% and a purity of 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] Referring to the synthesis method of compound 1-20 in Example 20, 5.3 g of N-tert-butoxycarbonyl-D-isoleucine, 3.9 g of B-alanine ethyl ester hydrochloride, 3.5 g of triethylamine, 4.7 g of HOBT and 6.6 g of EDCI were used 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, 6.9 g of compound 1-35 was reacted with 2 mL of 3 M hydrochloric acid ethanol solution to obtain pale yellow oily compound 1-36, with a yield of 100% and a purity of 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] Referring to the synthesis method of compound 1-1 in Example 1, 2-amino-6-chloro-4-hydroxypyrimidine, β-alanine-β-alanine ethyl ester (CAS: 754933-31-8) was used 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] 12g of L-valine ethyl ester hydrochloride was weighed and added to a 250mL single-neck bottle, followed by 15g of N-BOC-alanine, 17g of EDCI, 30g of triethylamine, and 15g of Hobt, followed by 150mL of DCM. After the addition was complete, the reaction mixture was stirred overnight at room temperature. After sampling and spotting to monitor the completion of the reaction, the reaction mixture was stopped and washed with water, saturated sodium bicarbonate solution, saturated citric acid, and saturated sodium chloride solution. The reaction mixture was then dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness to obtain colorless oily compound 1-40. The yield was 76.49% and the purity was 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] 15 g of compound 1-40 was weighed and added to a 250 mL single-neck bottle, followed by 100 mL of absolute ethanol. 25 mL of 11 M ethanolic hydrochloric acid was added, and the reaction mixture was stirred at room temperature. After overnight reaction, the reaction was monitored for completion, and the pH was adjusted to approximately 5.0 with sodium bicarbonate, filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated to dryness to give compound 1-41 as a colorless oil 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 powder 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 8.92 g of 3-[(tert-butoxycarbonyl)(methyl)amino]propionic acid and 8.8 g of β-alanine isopropyl ester hydrochloride into a 250 mL round-bottom bottle, add 100 mL of dichloromethane, and dissolve by stirring until clear and cooled to 0 °C. Weigh 23 mL of triethylamine and slowly add dropwise to the round-bottom bottle. After the addition is complete, add 15.15 g of EDCI to the reaction mixture, warm to 40 °C, and react overnight with stirring. After the reaction is complete, add 30 mL of water to the reaction mixture, stir, separate the layers, and remove the organic layer. Wash the organic layer twice with 30 mL of water and then dry over anhydrous sodium sulfate. After filtration, the filtrate was collected and concentrated to dryness under reduced pressure to give compound 1-43 as a colorless oil in 67.9% yield and 98.43% purity. 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 40 mL of DCM and 11.1 g of compound 1-43 to a reaction bottle, add 20 mL of trifluoroacetic acid, and react at room temperature with stirring. The reaction solution is concentrated to dryness to obtain an oil, add 30 mL of dichloromethane to dissolve, and continue to concentrate to dryness. After concentration is complete, add 50 mL of ethyl acetate to the concentrate to form a slurry, and concentrate to dryness under reduced pressure to obtain colorless oily compound 1-44. The yield is 91.6% and the 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] Referring to the synthesis method of compound 1-1 in Example 1, 6 g 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) and 6.07 g of compound 1-44 were used as raw materials to obtain white powder 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] 21 g of 5-(6-(tert-butoxycarbonylamino)hexylaminovaleric acid) and 13.4 g of triethylamine were weighed into a 500 mL single-neck bottle, 300 mL of DCM was added, and the mixture was stirred and purged with AR gas three times. 19.0 g of EDCI was added at 10 °C. After the addition was complete, the mixture was stirred at room temperature for 1 hour. 15.3 g of 5-aminovaleric acid ethyl ester hydrochloride was added. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction mixture was washed with water (50 mL x 2) and 5% citric acid solution (50 mL x 2). The aqueous phases were combined and extracted once with 200 mL of DCM. The organic phases were combined, washed once with water and once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness to give colorless oily compound 1-46 in a 70% yield and 98.43% purity. 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] 20.0 g of compound 1-46 was weighed into a 250 mL single-neck bottle, and 50 mL of 3 M hydrochloric acid in ethanol was added. The mixture was stirred and reacted at room temperature. After sampling and spotting, it was confirmed that the raw materials had completely reacted. The pH was adjusted to approximately 5.0 with sodium bicarbonate, filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated to dryness to obtain colorless oily compound 1-47. The yield was nearly 100% and the purity was 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] 20 g of 4-nitrophenol was weighed and dissolved in 200 mL of DCM, and 21 g of DIPEA was added. The reaction mixture was transferred to an ice-water bath, cooled to 0 °C, and purged with N2 three times. The temperature was then cooled to 0 °C, and 25 g of triphosgene (dissolved in 100 mL of DCM) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred at room temperature and stopped when the starting materials were almost completely reacted, as monitored by TLC. The reaction mixture was washed repeatedly with 40 mL of water until nearly neutral, then washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 45 °C to dryness, yielding 22 g of off-white powder compound 1-50 (100% yield). 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] 22 g of compound 1-50 was weighed and dissolved in 250 mL of DCM. 13 g of cyclopentylamine was added. The mixture was flushed with N2 three times, transferred to an oil bath, and heated to 40 °C with stirring. The temperature was raised to 40 °C, and 25 g of triphosgene (dissolved in 100 mL of DCM) was added dropwise to the reaction mixture. The reaction was stopped when the starting materials were almost completely reacted, as monitored by TLC. The reaction mixture was concentrated under reduced pressure at 45 °C. The concentrate was concentrated to dryness, and 150 mL of methanol was added to the concentrate, heated, and dissolved. After dissolution, 100 mL of water was added and stirred at room temperature. The filter cake was filtered and dried in an oven at 60 °C under vacuum to obtain 8 g of gray-brown powder compound 1-51, a yield of 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] 8 g of compound 1-51 was weighed and dissolved in 80 mL of DCM. The mixture was purged with N2 three times, and 5.6 g of malonyl chloride was added dropwise. After the addition was complete, the reaction mixture was transferred to an oil bath and heated to 45 °C, with stirring. The temperature was then raised to 45 °C and the reaction was continued while maintaining the temperature and stirring. The reaction was stopped when the starting materials were almost completely reacted, as monitored by TLC. The reaction mixture was concentrated under reduced pressure at 45 °C and dried to obtain a dark green solid. A sample was prepared and subjected to column purification (PE:EA = 15:1 to 8:1 gradient). The major component was collected after elution and concentrated to dryness to obtain 7 g of yellow powder compound 1-52, with a yield of 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 7.0 g of compound 1-52 and 3.9 g of N,N-diethylaniline, add 35 mL of phosphorus oxychloride, and flush with N2 three times. Transfer the reaction mixture to an oil bath, heat to 100 °C, and continue the reaction with stirring. The temperature is raised to 100 °C and the reaction is continued while maintaining the temperature and stirring. When the starting materials are almost completely reacted as monitored by TLC, the reaction is stopped. The reaction mixture is slowly added to 300 mL of ice water and stirred thoroughly. The mixture is then extracted three times with 300 mL of DCM. The organic phase is washed successively with 100 mL of water and 100 mL of saturated brine twice, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure at 45 °C. Concentration to dryness gives a brown oil. The sample was prepared and subjected to column purification (PE:EA=50:1 to 20:1 gradient). After elution, the main component was collected 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 1.0 g of compound 1-53 and 0.7 g of β-alanine-β-alanine ethyl ester (CAS: 754933-31-8), add 10 mL of isopropanol, dissolve with stirring, add 1.4 g of DIPEA, heat to 85 ° C, and 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 mixture was concentrated at 55°C and dried. The reaction mixture was dissolved in 200 mL of DCM, washed with 40 mL of water and 40 mL of saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain an oil. A sample was then purified by column chromatography (methanol:DCM = 1:100 to 4:100 gradient). The main component was collected after elution and concentrated to dryness to obtain 0.73 g of pale yellow powder compound 1-54, with a yield of 47.4% and a purity of 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] 10.0 g of compound 1-33, 5.7 g of β-alanine-β-alanine ethyl ester (CAS: 754933-31-8), and 9.1 g of triethylamine were dissolved in 100 mL of ethanol and stirred at 80 °C. The mixture was then stirred overnight at room temperature. The reaction was stopped when the starting materials were completely reacted, as monitored by TLC. The reaction mixture was concentrated to dryness at 50 °C, extracted with DCM, and the organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness. A sample was then purified by column chromatography (DCM:EtOH = 100:1 + 2% aqueous ammonia). The major component was collected after elution and concentrated to dryness to give 8.2 g of a yellow solid. The solid was recrystallized from 30 mL of absolute ethanol, filtered, and the filter cake was dried to give 7.6 g of white powder compound 1-55. The yield was 52% and the purity was 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 Experimental Method: The control and model groups were given distilled water and clopidogrel by oral gavage. The test group was given 0.1 mL / 10 g of drug solution by oral gavage (ig) for four consecutive days. One hour after the final administration, the blank group was given 0.1 mL / 10 g of saline, and the remaining groups were given 0.15 mL / 10 g of 0.3% ellagic acid solution via tail vein. After five minutes, blood was collected from a glass capillary via the retroorbital venous plexus. Blood was collected every 10 seconds through a glass tube, and the time when blood clots 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] × 100%

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

[0129] Example 57. Effect of compounds on in vivo bleeding time experiments in animals Experimental Method: The experiment consisted of a normal control group (blank), a positive control group (clopidogrel), and an experimental group, each containing 10 ICR mice (male, weighing approximately 25g). Each group received 0.1ml / 10g body weight of drug solution by oral gavage (i.g.), while the blank control group received distilled water once daily for four consecutive days. On the fourth day, one hour after administration, the animals were anesthetized with an intraperitoneal injection of approximately 50mg / kg sodium barbiturate. After 20 minutes, the mice's tails were cut 3mm from the tip. Blood was periodically collected from the cut tail using absorbent paper until no more blood was leaking. The bleeding time was recorded, and the experimental results are shown in Table 2. Bleeding time prolongation calculation formula: 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 that of the clopidogrel group and the normal control group.

[0131] Example 58. Effect of prophylactic administration of compounds on cerebral ischemia-reperfusion injury in rats Experimental Method: SD rats were randomly divided into six groups: a sham-operated group, a model control group, a positive control drug ozagrel (6 mg / kg) group, and high (9 mg / kg), medium (3 mg / kg), and low (1 mg / kg) dose groups of the test drug compound 1-1. The treatment groups received a tail vein injection of ozagrel in advance, while the sham-operated and model control groups received an equal volume of saline once daily for three consecutive days. Ten minutes after the final administration, a rat MCAO / R model was established, followed by 2 hours of ischemia and reperfusion. Twenty-four hours after MCAO / reperfusion, neurobehavioral scores were performed to assess neurological function, and cerebral infarction rates and brain water content were measured using 2,3,5-triphenyltetrazolium chloride (TTC) staining.

[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 successful modeling. Compared with the model group, the white infarct area on the surgical side of rats in each treatment group was reduced to various degrees. Here, the positive drug ozagrel (6 mg / kg) group and the high-dose test compound 1-1 (9 mg / 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-operated group, the brain water content of rats with focal cerebral ischemia-reperfusion in the model group was significantly higher than that in the sham-operated group, indicating that the modeling was successful. Compared with the model group, the positive drug ozagrel (6 mg / kg) group and the high-dose test compound 1-1 (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 had higher neurobehavioral scores, indicating that the rats in the model group had severe neurological dysfunction.Compared with the model group, the positive drug ozagrel (6 mg / kg) group and the high-dose test compound 1-1 (9 mg / kg) group can significantly reduce the neurological function scores 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 cerebral 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: A myocardial ischemia-reperfusion (MI / R) injury model was established in rats by coronary artery ligation. Animals were divided into groups: high-dose (20 mg / kg), medium-dose (10 mg / kg), low-dose (5 mg / kg), clopidogrel (7.5 mg / kg), sham-operated, and model groups. The sham-operated and model groups received equal doses of 0.5% CMC-Na at a dose of 0.5 ml per 100 g body weight. The drug was administered by oral gavage (ig) once daily for five consecutive days. Modeling was performed 30 minutes after the last administration, and eight rats that successfully modeled after modeling were selected from each group for further experiments. The sham-operated group underwent modeling without ligation of the left anterior descending coronary artery according to the modeling method, while the other groups underwent modeling according to the modeling method. The effects of the test drug on the myocardial infarction rate and plasma biochemical indicators creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA), and superoxide dismutase (SOD) in rats were detected, and cardiac TTC staining was performed to detect the effects of the test drug on 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 plasma biochemical indicators in rats with coronary artery ligation-induced myocardial ischemia-reperfusion injury, improve the degree of myocardial lesions, and inhibit the rate of myocardial infarction. The overall effect of the high-dose compound 1-1 group was slightly better than that of the active 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: Sprague-Dawley rats were prepared using a method of injecting autologous thrombus and thrombin into the external carotid artery and then into the internal carotid artery to embolize the cerebral arteries. Based on behavioral scores, the rats were randomly divided into five groups: a sham-operated group (only the external carotid artery was isolated), a model control group (two groups given equal amounts of saline), a urokinase (5000 U / kg) group, and a compound 1-1 (22.5 mg / kg) group. Each group contained 20 rats (10 rats for cerebral infarction detection and 10 rats for pathological detection). Two hours after modeling, thrombin was slowly injected once (1 mL every minute) into the tail vein. The blood flow reduction was monitored 120 minutes after thrombin injection. After 24 hours, perform neurobehavioral scoring on the rats to measure the rats' neurological function, 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 a cerebral ischemic injury model induced by autologous thrombosis and thrombin significantly reduced the rate of cerebral blood flow reduction, cerebral infarction area, and cerebral water content in the model rats, and improved pathological damage and behavioral changes. Compound 1-1 + urokinase showed the most obvious improvement in cerebral ischemic injury induced 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 ischemic brain injury caused by autologous thrombus and thrombin, and improve the neuromotor function of the rats, demonstrating excellent anti-ischemic brain injury effects.

[0145] Example 61. Amelioration of focal permanent cerebral ischemic damage by administration 3 hours after ischemia Experimental Method: A cerebral artery occlusion (MCAO) model was established in rats using the internal carotid artery suture embolization technique. Forty-eight clean-grade male SD rats weighing 250-300 g were randomly divided into six groups according to weight and sex. Each group consisted of eight rats. They were assigned to the high-dose, medium-dose, and low-dose Compound 1-1 groups, a 60 mg / kg butyrolide soft capsule positive control group, a sham-operated group, and an ischemic model control group (all administered an equal volume of 0.5% CMC-Na). Administration began 3 hours after MCAO surgery and was administered by oral gavage once daily at a dose of 0.5 ml per 100 g body weight for 14 consecutive days. One hour after the last administration, the animals were scored for neurological dysfunction according to the Bederson method. The rats were then decapitated and sacrificed. The entire brains were removed, weighed, and sections were stained with TTC and photographed to calculate the infarction rate and brain tissue water content.

[0146] Forty-eight clean-grade male SD rats weighing 250-300 g (100 rats were actually needed because the maturation rate was approximately 50%) were randomly divided into six groups of eight rats each based on their weight. The grouping, administration, and surgical procedures were the same as previously described. One hour after the final administration, the rats were killed by decapitation, and the entire brains were removed and fixed in 10% formaldehyde solution. Coronal sections of the brains were then taken, dehydrated, embedded in paraffin, and sectioned and stained with HE. Histopathological changes were observed under a light microscope, and the degree of pathological damage was scored.

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

[0148] [Table 14] Results: The weight of rats in the sham-operated group steadily increased over 15 days, while the weight of rats in the model group showed an overall tendency to decrease within 15 days. All treatment groups had varying degrees of effect on the weight maintenance of rats, indicating that the average 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 manifests 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 manifests as being unable to walk straight and constantly walking in circles.

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

[0151] Example 62. Detection of compound antibody chip Experimental Method: ICR male mice weighing approximately 25g were randomly divided into four groups: normal, ellagic acid model, 1-1, and 1-22. Each group consisted of four mice. Mice in groups 1-1 and 1-22 were given 100mg / kg 1-1 and 100mg / kg 1-22, respectively, by oral gavage once daily. One hour after the third dose, mice in the other three groups, except for the normal control group, were given a tail vein injection of 0.10ml / 10g of 0.3% fentanyl saline solution. One hour after injection, whole blood was collected from each animal and allowed to stand for 30 minutes. After 10 minutes of centrifugation (3000 rpm / min), serum was obtained. The serum from each group was mixed in EP tubes and transported at -80°C for antibody chip detection.

[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 were significantly increased, indicating that ellagic acid can induce acute inflammatory responses in vivo. Compound 1-1 significantly down-regulated the expression levels of IL-6 and RANTES / ccl5, while compound 1-22 significantly down-regulated the expression levels of IL-6 and RANTES / ccl5. This indicates that while both 1-1 and 1-22 can alleviate the acute inflammatory response induced by ellagic acid, compound 1-22 down-regulated a greater number of different protein factors. [Table 17] The results showed that the model groups all significantly upregulated the expression levels of IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, and IL-13, while compound 1-1 downregulated the expression levels of IL-1α, IL-5, IL-6, and IL-13, and compound 1-22 downregulated 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 downregulated proteins in group 1-1 was four, while the number of downregulated proteins in group 1-22 was seven. The predominant downregulated proteins in groups 1-1 and 1-22 were Th2 cytokines.

[0154] [Table 18] The results showed that the ellagic acid model could significantly upregulate the expression levels of these four inflammatory chemokines, compound 1-1 could significantly downregulate the expression levels of MIP-3a / CCL20 and RANTES / CCL5, and compound 1-22 could significantly downregulate the expression levels of the four inflammatory chemokines, indicating that compound 1-1 and compound 1-22 could both 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 higher than those in the normal group, indicating that compound 1-1 can significantly downregulate IFNg and compound 1-22 can simultaneously downregulate the expression levels of IFNg and CD40, suggesting that 1-1 and 1-22 can inhibit antigen presentation and immune cell activation.

[0156] Conclusion: Compared with the normal group, the content of each detected cytokine after ellagic acid injection was significantly increased, and the related biological functions mentioned included positive regulation of leukocyte proliferation, differentiation, and migration, positive regulation of immune effects, positive regulation of cell adhesion, and positive regulation of acute inflammatory responses, etc., causing acute inflammatory responses 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 and anti-acute inflammatory response effects.

[0157] Example 63. Preparation of Compound 1-1 Tablets [Table 20] According to the above formula, compound 1-1, microcrystalline cellulose, and croscarmellose sodium are mixed uniformly and granulated with aqueous hydroxypropyl cellulose solution, dried, and after granulation, microcrystalline cellulose and magnesium stearate are added to the granules and mixed uniformly. The granules are compressed into uncoated tablets. A thin film coating solution consisting of titanium oxide, ferric oxide, talc, and aqueous hydroxypropyl methylcellulose solution is thin-coated in a coating machine to obtain thin-film-coated tablets containing 100 mg of compound 1-1 per tablet.

[0158] Example 64. Preparation of enteric capsules of compound 1-1 [Table 21] Compound 1-1, microcrystalline cellulose SH101, and lactose monohydrate were weighed according to the prescribed amounts and stored. Compound 1-1, microcrystalline cellulose SH101, and lactose monohydrate were added to the pot of the wet mixer granulator, and the mixture was stirred and mixed for 5 minutes to granulate. (1) Preparation of adhesive: Hypromellose E5 was weighed in an appropriate amount, and water was added to make a 5% solution, which was stored. (2) Granulation: The mixture was stirred, and the adhesive solution was added using a peristaltic pump. The granulation time was 3 minutes. (3) Sizing and drying: The prepared wet granules are sieved using a swing granulator and dried in an electric constant temperature drying oven at 70°C (rotating once every 15 minutes) until the moisture content 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 and sieving, the granules are added to a laboratory hopper mixer together with the ingredients, stirred, and mixed for 5 minutes. The mixture is then filled into No. 1 enteric capsules and packaged in aluminum plastic packaging.

[0159] Example 65. Preparation of lyophilized powder of compound 1-1 [Table 22] Weigh out the prescribed amounts of active ingredient 1-1 and mannitol, add 80% of the prescribed amount of water for injection, and stir until dissolved. Measure the pH of the solution. If the pH is between 6 and 7, do not adjust the pH. If it exceeds this value, adjust the pH of the drug solution with sodium hydroxide solution (or hydrochloric acid solution) and add water for injection to the prescribed amount. Filter the solution first through a 0.45 μm microporous filter membrane, then through a 0.22 μm microporous filter membrane, and fill. Freeze-dry according to the specified freeze-drying parameters, then uncork, cap, and package.

[0160] Example 66. Preparation of injection of Compound 1-24 [Table 23] Take 80% of the total volume of water for injection, add the prescribed amounts of sodium chloride, sodium citrate dihydrate, glycerol, and Compound 1-24 in order, stir to dissolve, and adjust the pH 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 vials and sterilize in an autoclave to obtain the compound injectable solution. Each vial contains 20mg of Compound 1-24.

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

Claims

1. A compound comprising: The compound is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof: 【Chemistry 1】 During the ceremony, R １ and R ２ are each independently H, a substituted or unsubstituted C1-C10 alkyl group, a haloC1-C10 alkyl group, a C3-C10 cycloalkyl group, a haloC3-C10 cycloalkyl group, a C1-C10 alkoxy group, a haloC1-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 10-membered heteroatom containing 1, 2, or 3 heteroatoms selected from N, O, and S. selected from the group consisting of a heterocycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, or S, -(C1-C6 alkylene)-(substituted or unsubstituted 5- to 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- to 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 R ６ 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 a 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from a C1-C10 alkyl group, a -(C1-C6 alkylene)-piperazinyl group, a -(C1-C6 alkylene)-N, O, or S, a haloC1-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 substituted by one or more substituents selected from the group consisting of 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 in 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- to 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, 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 haloC1-C6 alkyl group, CN, and halogen; The compound of claim 1.

3. R １ and R ２ are each independently H, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-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: 【Transformation 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: 【Chemistry 4】 【Transformation 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:

10. The pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds of claim 1.

9. Use of the compound of claim 1, 1) drugs used in the treatment of infarction-related diseases; 2) Drugs used in thromboprophylaxis and / or thrombolytic therapy of thrombotic disorders, anti-edema therapy and / or immuno-anti-inflammatory therapy, or 3) Drugs used to improve neuronal damage caused by brain trauma, cerebral hemorrhage, and / or brain tumor surgery The use in the preparation of

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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