Acyl compound as well as preparation method and medical application thereof

Abstract

The invention belongs to the technical field of chemical medicines, and provides an acyl compound as well as a preparation method and medical application thereof. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of chemical medicines and provides an acyl compound and a preparation method and medical use thereof. Background Art

[0002] LPA is the name of the gene encoding apolipoprotein (a) (apo(a)), which is mainly expressed in the liver, and its expression is limited to humans and non-primates. Apolipoprotein (a) is attached to apo(B)-100 through a disulfide bond and is combined with a lipid core to form lipoprotein (a) (Lp(a)) particles. Lp(a) particles are a special type of cholesterol-rich macromolecular lipoprotein, with a surface coated with cholesterol and phospholipids, and embedded with hydrophilic apolipoprotein components apolipoprotein (a) and apo(B)-100. Lp(a) can enter and deposit on the blood vessel wall, which has the effect of promoting atherosclerosis. Lp(a) is structurally homologous to plasminogen (PLG), and can compete with plasminogen for binding to fibrin sites, thereby inhibiting fibrinogen hydrolysis and promoting thrombosis. Therefore, LP(a) is closely related to atherosclerosis and thrombosis. Studies have shown that the level of Lp(a) in the blood is an independent risk factor for cardiovascular disease, stroke and atherosclerotic stenosis. Human Lp(a) levels are genetically determined and do not change significantly with diet, exercise, or other lifestyle changes.

[0003] Currently reported LP(a) inhibitors are mainly macromolecular or small nucleic acid drugs, for example: WO2023046093A1 discloses a bispecific fusion polypeptide; CN111465694A discloses a nucleic acid for inhibiting the expression of LPA in cells; CN108368506A also discloses a composition and method for inhibiting the gene expression of LPA; CN113166759A discloses a chemically modified RNAi construct and its use. However, there are currently no small molecule LP(a) drugs on the market. Among the projects under development, only patent CN114008021A reports a pyrrolidine compound as a small molecule LP(a) drug. Therefore, there is an urgent need to provide more small molecule LP(a) drugs. Summary of the invention

[0004] In view of the problems existing in the prior art, the present invention provides a small molecule LP(a) drug to solve the problem of the shortage of small molecule LP(a) drugs in the prior art.

[0005] The present invention is achieved through the following technical solutions:

[0006] The present invention provides an acyl compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the acyl compound is as shown in general formula I:

[0007]

[0008] Wherein, the Y is selected from -N- or -CH-; the Z is selected from: -NH-, -CH2- or a connecting bond;

[0009] The X 1～ X 15 Each is independently selected from -N- or -CR1, wherein R1 is selected from H, halogen, -OH, -NH2, -CN, -NO2, -COOH, -SO3H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or And the X 1～ At least one R1 in X5 is independently selected from And the X 6～ X 10 At least one R1 is independently selected from The R2 is selected from -H, halogen, substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C1-C6 alkoxy;

[0010] The R3 is selected from -(CH2) s -(5-8 membered heterocyclyl);

[0011] The substituted C1-C6 alkyl, substituted C1-C6 alkoxy, substituted C3-C 10 Cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C6-C 10 The substituents in the aryl or substituted 5-10 membered heterocyclic group are independently selected from halogen, hydroxyl, carboxyl, nitro, cyano, C1-C6 alkyl, C 1- C6 haloalkyl, C 1- C6 haloalkoxy, C 1- C6 alkoxy, C 3- C8 cycloalkyl, 3-10 membered heterocycloalkyl, C 3- C6 cycloalkoxy, C 6- C 10 m, n or r is independently selected from an integer of 1, 2 or 3; s is independently selected from an integer of 0, 1, 2 or 3.

[0012] As a preferred technical solution of the present invention, the Y is selected from -N- or -CH-; the Z is selected from: -NH-, -CH2- or a connecting bond; and the X 1～ At least one R1 in X5 is independently selected from And the X 6～ X 10 At least one R1 is independently selected from R1 is selected from H, halogen, -OH, -NH2, -CN, -NO2, -COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or The R2 is selected from -H, substituted or unsubstituted C1-C6 alkyl; the R3 is selected from 5-8 membered heterocyclic group; the substituted C1-C6 alkyl, substituted C3-C 10 Cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C6-C 10 The substituents in the aryl or substituted 5-10 membered heteroaryl are independently selected from halogen, hydroxyl, carboxyl, nitro, cyano, C1-C6 alkyl, C 1- C6 haloalkyl, C 1- C6 haloalkoxy, C 1- C6 alkoxy, C 3- C8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3- C8 cycloalkoxy, C 6- C 10 aryl or one or more of 5-10 membered heteroaryl.

[0013] As a preferred technical solution of the present invention, one of X4 or X5 is selected from The X9 or X 10 One of the The X 11 or X 12 One of the

[0014] As a preferred technical solution of the present invention, X4 or X5 is selected from One of the X9 or X 10 Selected from one of the following; the X 11 or X 12 Selected from one of the.

[0015] As a preferred technical solution of the present invention, the structure of the acyl compound is shown in the general formula IIa or IIb:

[0016]

[0017] Wherein, the Y is selected from -N- or -CH-; the Z is selected from: -NH-, -CH2- or a connecting bond;

[0018] X1-X3 and X 5～ X 15 Each is independently selected from -N- or -CR1, wherein R1 is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy or The R2 is selected from H, substituted or unsubstituted C1-C6 alkyl; the R3 is selected from 5-8 membered heterocyclic group; the substituents in the substituted C1-C6 alkyl and substituted C1-C6 alkoxy are independently selected from halogen, hydroxyl, carboxyl, nitro, cyano, C1-C6 alkyl, C 1- C6 haloalkyl, C 1- C6 haloalkoxy, C 1- C6 alkoxy, C 3- C8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3- C8 cycloalkoxy, C 6- C 10 one or more of aryl or 5-10 membered heteroaryl; said m, n, p, q or r is independently selected from an integer of 1, 2 or 3.

[0019] As a preferred technical solution of the present invention, the structure of the acyl compound is shown in the general formula IIIa or IIIb:

[0020]

[0021] Wherein, the Y is selected from -N- or -CH-; the Z is selected from: -NH-, -CH2- or a connecting bond;

[0022] X1-X3 and X 5～ X 15 Each is independently selected from -N- or -CR1, wherein R1 is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy or The R2 is selected from H, substituted or unsubstituted C1-C6 alkyl; the R3 is selected from 5-8 membered heterocyclic group; the substituents in the substituted C1-C6 alkyl and substituted C1-C6 alkoxy are independently selected from halogen, hydroxyl, carboxyl, nitro, cyano, C1-C6 alkyl, C 1- C6 haloalkyl, C 1- C6 haloalkoxy, C 1- C6 alkoxy, C 3- C8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3- C8 cycloalkoxy, C 6- C 10one or more of aryl or 5-10 membered heteroaryl; said m, n, p, q or r is independently selected from an integer of 1, 2 or 3.

[0023] As a preferred technical solution of the present invention, the C 1- C6 alkyl is preferably C 1- C2, C 1- C3, C 1- C4 or C 1- C5 alkyl; examples of the alkyl include: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, 1-ethylbutyl.

[0024] As a preferred technical solution of the present invention, the C 1- C6 haloalkyl preferably C 1- C2, C 1- C3, C 1- C4 or C 1- C5 haloalkyl; Examples of the haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl. Particular haloalkyl are trifluoromethyl and trifluoroethyl.

[0025] As a preferred technical solution of the present invention, the C 1- C6 alkoxy is preferably C 1- C2, C 1- C3, C 1- C4 or C 1- C5 alkoxy, further, the alkoxy is specifically selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

[0026] As a preferred technical solution of the present invention, the C 1- C6 haloalkoxy is preferably C 1- C2, C 1- C3, C 1- C4 or C 1- C5 haloalkoxy, examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy. Particular haloalkoxy are trifluoromethoxy and 2,2-difluoroethoxy.

[0027] As a preferred technical solution of the present invention, the C 3- C 10 The cycloalkyl group is preferably selected from: C 3-C8 cycloalkyl, C 3- C6 cycloalkyl or C 3- C5 cycloalkyl, preferably C 3- C8 cycloalkyl, wherein the cycloalkyl is specifically selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0028] As a preferred technical solution of the present invention, in some embodiments, the "heterocyclyl" is a 5-10-membered heterocyclyl composed of 5-10 ring atoms; in other embodiments, the "heterocyclyl" is a 5-8-membered heterocyclyl composed of 5-8 ring atoms; in other embodiments, the "heterocyclyl" is a 6-8-membered heterocyclyl composed of 6-8 ring atoms; in other embodiments, the "heterocyclyl" is a 5-6-membered heterocyclyl composed of 5-6 ring atoms. Examples of heterocyclic groups include, but are not limited to, pyranyl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dithianyl, oxathiolanyl, thiomorpholinyl, tetrahydro-thiopyran 1,1-dioxide, 1,4-diazepanyl.

[0029] As a preferred technical solution of the present invention, in some embodiments, "heterocycloalkyl" is preferably 3-12 membered heterocycloalkyl; more preferably 3-10 membered heterocycloalkyl; more preferably 5-8 membered heterocycloalkyl; most preferably 5-6 membered heterocycloalkyl; examples of the heterocycloalkyl are but not limited to: aziridine, oxirane, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazine 1 ,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazinyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, 3-thia-9-aza-bicyclo[3.3.1]nonyl, 2,6-diaza-spiro[3.3]heptanyl. More particular examples of heterocycloalkyl are pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazinyl and 2,6-diaza-spiro[3.3]heptanyl.

[0030] As a preferred embodiment of the present invention, the substituted or unsubstituted C6-C 10 The aryl group is preferably a substituted or unsubstituted C6-C8 aryl group, a substituted or unsubstituted C6-C7 aryl group; when the aryl group is substituted, the substituent is preferably selected from H, halogen, -OH, -NH2, -CN, -NO2, -COOH, -SO3H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 10 Cycloalkyl, C6-C 10 Substituted or unsubstituted aryl, C5-C 10 A substituted or unsubstituted heteroaryl group, wherein the aryl group is specifically selected from phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.;

[0031] As a preferred embodiment of the present invention, the substituted or unsubstituted 5-10 membered heteroaryl group is preferably a substituted or unsubstituted 5-8 membered aromatic heteroyl group, a substituted or unsubstituted 5-7 membered heteroaryl group or a substituted or unsubstituted 5-6 membered heteroaryl group; when the heteroaryl group is substituted, the substituent is preferably selected from H, halogen, -OH, -NH2, -CN, -NO2, -COOH, -SO3H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 10Cycloalkyl, substituted or unsubstituted C5-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroatom in the heteroaryl is one or more of N, O and S. The heteroaryl is preferably selected from the group consisting of imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, pyrazolyl, isoxazolyl, thiazolyl, pyrazolyl, tetrazolyl, pyridazinyl, quinolyl, isoquinolyl, indazolyl, triazolyl, tetrazolyl and the like.

[0032] Further, as a preferred technical solution of the present invention, the R1 is selected from H, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, piperazinyl, -CH2COOH, -CH2CH2COOH, -CH2CH(CH3)COOH, The R3 is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl.

[0033] As a preferred technical solution of the present invention, is selected from quinolinyl; More preferably:

[0034] As a preferred technical solution of the present invention, Selected from:

[0035] As a preferred technical solution of the present invention, it is characterized in that Selected from:

[0036] As a preferred technical solution of the present invention, Selected from:

[0037]

[0038] Further, as a preferred technical solution of the present invention, the chemical structure of the acyl compound is selected from:

[0039]

[0040]

[0041]

[0042] Further, as a preferred technical solution of the present invention, the chemical structure of the acyl compound is selected from:

[0043]

[0044]

[0045] The present invention further provides a pharmaceutical composition, characterized in that it comprises the acyl compound described in general formula I, general formula IIa, general formula IIb, general formula IIIa or general formula IIIb, or its isomer, or its racemate or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients and / or carriers.

[0046] The present invention further provides a use of the acyl compound of the present invention, or its isomer, or its racemate, or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention in the preparation of a drug for preventing or treating diseases associated with LP(a).

[0047] Further, the Lp(a)-related diseases are selected from cardiovascular diseases;

[0048] Furthermore, the cardiovascular disease is selected from stroke, atherosclerosis, thrombosis, coronary heart disease or aortic valve stenosis and any other disease associated with elevated Lp(a) levels.

[0049] In the chemical structure of the compound described in the present invention, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be Or colleagues include Two configurations;

[0050] In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or both configurations;

[0051] Compounds and intermediates of the present invention can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. Lactam-lactim equilibrium examples are between A and B as shown below.

[0052]

[0053] All compounds in the present invention can be drawn as either Form A or Form B. All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomers.

[0054] The present invention further provides a method for preparing an acyl compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, which is prepared by referring to the method of patent CN114008021A and methods known in the art.

[0055] The beneficial effects of the present invention compared with the prior art include but are not limited to:

[0056] Compared with the prior art, the acyl compounds of the present invention have lower IC 90 value.

[0057] For the sake of clarity, general terms used in the description of the compounds are defined herein.

[0058] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood in accordance with the ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" used here refers to those compounds, materials, compositions and / or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0059] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are prepared by reacting the compounds discovered in the present invention with specified substituents and a pharmaceutically acceptable acid or base.

[0060] In addition to the form of salts, compounds provided by the present invention also exist in prodrug forms. Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention. In addition, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0061] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0062] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0063] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (e.g., carbamate formation from an amine).

[0064] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms are preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched isomers thereof. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C 1- C6 alkyl, C 1- C6 alkoxy, C 2- C6 alkenyloxy, C 2- C6 alkynyloxy, C 3- C6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 5- C8 cycloalkenyl, C 3- C6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 5- C8 cycloalkenyloxy, C 6- C 10 aryl or 5- to 6-membered heteroaryl, the C 1- C6 alkyl, C1- C6 alkoxy, C 2- C6 alkenyloxy, C 2- C6 alkynyloxy, C 3- C6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 5- C8 cycloalkenyl, C 3- C6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 5- C8 cycloalkenyloxy, C 6- C 10 The aryl or 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, and cyano.

[0065] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen, wherein the definition of alkyl is the same as above. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl. Particular haloalkyl groups are trifluoromethyl and trifluoroethyl.

[0066] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy. Particular alkoxy includes methoxy, ethoxy and tert-butoxy.

[0067] The term "haloalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atoms. The term "perhaloalkoxy" refers to an alkoxy group in which all of the hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy. Particular haloalkoxy groups are trifluoromethoxy and 2,2-difluoroethoxy.

[0068] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0069] The term "cycloalkyl" or "carbocycle" refers to a saturated monocyclic or polycyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls.

[0070] The term "aryl" or "aromatic ring" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 8-membered, such as phenyl and naphthyl.

[0071] The term "heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 3 heteroatoms, 5 to 12 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably a 5- to 10-membered, 5- to 8-membered heteroaryl, more preferably a 5- or 6-membered heteroaryl. Pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepine,

[0072] The heteroaryl groups include benzodiazepine, isoxazolyl, benzofuranyl, isothiazolyl, benzothiophenyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl and quinoxalinyl. Particular heteroaryl groups include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl and isothiazolyl. More specific heteroaryl groups include imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl, isothiazolyl, 2-fluoropyridinyl, 3-fluoropyridinyl, 4-fluoropyridinyl, 2-chloropyridinyl, 3-chloropyridinyl, 4-chloropyridinyl, 2,3-difluoropyridinyl, 3,4-difluoropyridinyl, 4,5-difluoropyridinyl, 3,5-difluoropyridinyl, 2-chloro-3-fluoro-pyridinyl, 3-fluoro-4-chloro-pyridinyl, 3-fluoro-5-chloro-pyridinyl, 4-fluoropyrimidinyl, 5-fluoropyrimidinyl, 4-chloropyrimidinyl, 5-chloropyrimidinyl, 4-chloro-5-fluoropyrimidinyl, 4-cyanopyrimidinyl, 5-cyanopyrimidinyl, 4,5-dicyanopyrimidinyl, 4-methylpyrimidinyl, 5-methylpyrimidinyl or 4,5-dimethylpyrimidinyl.

[0073] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl), a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) or a heteroaromatic ring system, which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-) in the ring, and has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3-12-membered heterocyclic group); more preferably a heterocyclic group having 3 to 10 ring atoms (i.e., a 3-10-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3-8-membered heterocyclic group); more preferably a heterocyclic group having 5 to 8 ring atoms (i.e., a 5-8-membered heterocyclic group); most preferably a heterocyclic group having 5 to 6 ring atoms (i.e., a 5-6-membered heterocyclic group). In some embodiments, the heterocyclic group is selected from: 5-10-membered heterocycloalkyl, 5-10-membered heteroaryl, in some embodiments, the heterocyclic group is selected from: 5-8-membered heterocycloalkyl, 5-8-membered heteroaryl, in some embodiments, the 5-6-membered heterocyclic group is selected from: 5-6-membered heterocycloalkyl, 5-6-membered heteroaryl.

[0074] The term "heterocycloalkyl" refers to a cycloalkyl group with 1-4 carbon atoms substituted by one or more heteroatoms selected from N, O or S; preferably a 3-12-membered heterocycloalkyl group; more preferably a 3-10-membered heterocycloalkyl group; more preferably a 5-8-membered heterocycloalkyl group; most preferably a 5-6-membered heterocycloalkyl group; examples of the heterocycloalkyl group include, but are not limited to, aziridine, oxirane, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl , tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazinyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, 3-thia-9-aza-bicyclo[3.3.1]nonyl, 2,6-diaza-spiro[3.3]heptanyl. More particular examples of heterocycloalkyl are pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazinyl and 2,6-diaza-spiro[3.3]heptanyl.

[0075] The term "at least one" or "at least one" refers to a combination of one, two or more, for example: at least one R1 is independently selected from It means that there is one, two or more (such as 3) R1 independently selected from

[0076] The atoms of the molecules of the compounds of the present invention are isotopes, and isotope derivatization can generally extend the half-life, reduce the clearance rate, stabilize metabolism, and improve the in vivo activity. In addition, an embodiment is included in which at least one atom is replaced by an atom with the same atomic number (proton number) and a different mass number (proton and neutron sum). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, which respectively include 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18F. 36 In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomy inspection of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay or change with their amount nor have radioactivity, so they can be used safely. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0077] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0078] Furthermore, one or more hydrogen atoms of the compounds of the present invention are replaced by the isotope deuterium (2H). After deuteration, the compounds of the present invention have the effects of extending half-life, reducing clearance rate, metabolic stability and improving in vivo activity.

[0079] The preparation method of the isotopic derivative generally includes: a phase transfer catalytic method. For example, a preferred deuteration method uses a phase transfer catalyst (e.g., a tetraalkylammonium salt, NBu4HSO4). The use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in a higher deuterium introduction than reduction with deuterated silane (e.g., triethyldeuterated monosilane) or with a Lewis acid such as aluminum trichloride using sodium deuterated borate in the presence of an acid (e.g., methanesulfonic acid).

[0080] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical drugs. For other information about the carrier, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0081] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0082] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0083] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0084] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. DETAILED DESCRIPTION

[0085] The present invention is further described in detail below in conjunction with embodiments, but the content of the invention is not limited to the embodiments.

[0086] Example 1

[0087] Synthesis of (2S,2'S)-3,3'-((6-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)pyridin-2-yl)methyl)azepinediyl)bis(methylene)bis(methylene)bis(3,1-phenylene))bis(2-(R)-pyrrolidin-3-yl)propionic acid)

[0088]

[0089] The specific synthetic route is as follows:

[0090] Step A: Synthesis of 3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxypropyl)benzoic acid

[0091]

[0092] (R)-tert-butyl 3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (200 mg, 0.5 mmol), sodium chlorite (89 mg, 1 mmol), 2-methyl-2-butene (105 mg, 1.5 mmol), potassium dihydrogen phosphate (178 mg, 1.5 mmol) were dissolved in a mixed solution of tert-butanol (3 ml) / tetrahydrofuran (3 ml) / water (1 ml), and sodium hypochlorite (89 mg, 1 mmol) was finally added, and the reaction was carried out at room temperature for 2 hours.

[0093] After the reaction was completed, sodium sulfite aqueous solution (10 ml) was added to quench, extracted with ethyl acetate (20 ml x 2 times), concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 205 mg of light yellow solid 3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxypropyl)benzoic acid. LCMS: RT = .2.01 min, [MH] - =419.

[0094] Step B: Synthesis of 3,3'-di-tert-butyl((2S,2'S)-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzoyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butanol)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate)

[0095]

[0096] 3,3'-((2S,2'S)-((azadiylbis(methylene))bis(3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (80 mg, 0.1 mmol), 3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzoic acid (42 mg, 0.1 mmol) were dissolved in acetonitrile (2 ml) at room temperature, followed by the addition of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (42 ml, 0.15 mmol), N-methylimidazole (21 mg, After the reaction was completed, water (5 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (20 ml x 2 times), concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10) to obtain 63 mg of 3,3'-di-tert-butyl((2S, 2'S)-(((3-((S)-3-(tert-butyloxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzoyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butyl)-3-oxopropane-1,2-diyl))(3R, 3'R)-bis(pyrrolidine-1-carboxylate).

[0097] Step C: Synthesis of ((2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzoyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(2-(R)pyrrolidin-3-yl)propionic acid)

[0098]

[0099] At room temperature, 3,3'-di-tert-butyl((2S,2'S)-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzoyl)azinediyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butanol)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (63 mg, 0.053 mmol), dioxane (2.5 ml) and concentrated hydrochloric acid (0.5 ml) were added and the mixture was reacted at 45°C for 5 hours.

[0100] After the reaction was completed, the mixture was concentrated to dryness, and the residue was purified to obtain 13 mg of ((2S, 2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzoyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(2-(R)pyrrolidin-3-yl)propionic acid). LCMS: RT = 1.49 min, [MH] - =723.23.

[0101] Example 2

[0102] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)carbamoyl)nitrogendiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidin-3-yl)propionic acid)

[0103]

[0104] The specific synthetic route is as follows:

[0105] Step A: Synthesis of tert-butyl (R)-3-((S)-3-(3-(benzylamino)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0106]

[0107] Tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (900 mg, 2 mmol), benzylamine (321 mg, 3 mmol), tris(dibenzylideneacetone)dipalladium (457 mg, 0.25 mmol), potassium tert-butoxide (268 mg, 2.8 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (933 mg, 1.5 mg) were dissolved in toluene (25 ml), the atmosphere was replaced with nitrogen three times, and the temperature was raised to 80°C for reaction overnight.

[0108] After the reaction was completed, the filtrate was filtered through celite, water (30 ml) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 ml x 2 times), concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 865 mg of light yellow oily liquid (R)-tert-butyl 3-((S)-3-(3-(benzylamino)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.05 min, [M+H] = 481.33.

[0109] Step B: Synthesis of (R)-tert-butyl 3-((S)-3-(3-aminophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0110]

[0111] (R)-3-((S)-3-(3-(benzylamino)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (865 mg, 1.8 mmol) and palladium carbon (100 mg) were dissolved in methanol (20 ml), replaced with hydrogen three times, and reacted at room temperature for 10 hours. After the reaction was completed, the filtrate was filtered and concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2) to obtain 610 mg of (R)-3-((S)-3-(3-aminophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.01 min, [M+H-Boc] = 291.27.

[0112] Step C: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-((phenoxycarbonyl)amino)phenyl)propan-2-yl)pyrrolidine-1-carboxylate

[0113]

[0114] (R)-3-((S)-3-(3-aminophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (80 mg, 0.2 mmol) and sodium bicarbonate (20 mg, 1.2 mmol) were dissolved in a tetrahydrofuran (4 ml) / water (1 ml) mixed solution, phenyl chloroformate (37 mg, 1.2 mmol) was slowly added under ice bath, and the mixture was heated to room temperature for reaction for 3 hours. After the reaction was completed, water (5 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 ml × 2 times), concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2) to obtain 82 mg of (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-((phenoxycarbonyl)amino)phenyl)propan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT=2.23min, [M+H-Boc]=411.17.

[0115] Step D: Synthesis of di-tert-butyl 3,3'-((2S,2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxypropyl)phenyl)carbamoyl)nitrogendiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxypropane-1,2-

[0116] dimethyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate)

[0117]

[0118] (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-((phenoxycarbonyl)amino)phenyl)propan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (82 mg, 0.16 mmol), 3,3'-((2S,2'S)-((azadiylbis(methylene))bis(3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (80 mg, 0.1 mmol), and triethylamine (10 mg, 0.1 mmol) were dissolved in dimethyl sulfoxide (5 ml) at room temperature and reacted at room temperature for 8 hours; After the reaction was completed, water (5 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (20 ml × 2 times) and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10) to obtain 191 mg of di-tert-butyl 3,3'-((2S, 2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxypropyl)phenyl)carbamoyl)nitrogendiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))(3R, 3'R)-bis(pyrrolidine-1-carboxylate). Step E: Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)carbamoyl)nitrogendiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidin-3-yl)propionic acid)

[0119]

[0120] At room temperature, di-tert-butyl 3,3'-((2S,2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxypropyl)phenyl)carbamoyl)nitrogendiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (191 mg, 0.16 mmol), dioxane (2.5 ml) and concentrated hydrochloric acid (0.5 ml) were added and the mixture was reacted at 45°C for 5 hours.

[0121] After the reaction was completed, the mixture was concentrated to dryness, and the residue was purified to obtain 13 mg of (2S, 2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)carbamoyl)nitrogendiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidin-3-yl)propionic acid) 48.6 mg. LCMS: RT = 1.46 min, [MH] - =738.47.

[0122] Example 3

[0123] Synthesis of (2S,2'S)-3,3'-(((2-(2-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)acetyl)azepinediyl)bis(methylene))bis(2-((R)-pyrrolidin-3-yl)propionic acid)

[0124]

[0125] The specific synthetic route is as follows:

[0126] Step A: 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetic acid

[0127]

[0128] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxoethyl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.24 mmol), tert-butanol (5 ml), and water (2 ml) were added in sequence. The mixture was cooled with ice water, and 2-methyl-2-butene (337 mg, 4.82 mmol), sodium dihydrogen phosphate (58 mg, 0.48 mmol), and sodium chlorite (43 mg, 0.48 mmol) were added in sequence. After the addition was completed, the mixture was naturally warmed to room temperature and reacted for 18 hours.

[0129] After the reaction was completed, water (10 ml) was added to dilute, and ethyl acetate (10 ml x 2 times) was used for extraction. The organic phase was washed with saturated brine (10 ml), dried over sodium sulfate, and concentrated to dryness to obtain 110 mg of 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxypropyl)phenyl)acetic acid. LCMS: RT = 2.11 min, [M+H-tert-butoxycarbonyl] + =334.21.

[0130] Step B: 3,3'-((2S,2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetyl)azepinediyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate)

[0131]

[0132] At room temperature, 3,3'-((2S,2'S)-((azadiylbis(methylene))bis(3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (202 mg, 0.25 mmol), 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxy)-3-oxopropane-1,2-diyl))-bis(3,1-phenylene))-bis(3 ... 4-(4-(4-(4-(4-nitro-2-yl)-3-oxopropyl)phenyl)acetic acid (110 mg, 0.25 mmol), N,N-dimethylformamide (2 ml), N,N-diisopropylethylamine (98 mg, 0.76 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (145 mg, 0.38 mmol), react at room temperature for 3 hours.

[0133] After the reaction was completed, water (10 ml) was added to dilute, and the mixture was extracted with ethyl acetate (10 ml × 2 times). The organic phase was washed with saturated brine (10 ml), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 60 mg of 3,3'-((2S, 2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetyl)azepinediyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R, 3'R)-bis(pyrrolidine-1-carboxylate).

[0134] Step C: (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)nitrogendiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis((2-(R)pyrrolidin-3-ylpropionic acid)

[0135]

[0136] 3,3'-((2S,2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetyl)azepinediyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (60 mg, 0.05 mmol), dioxane (2.5 ml) and concentrated hydrochloric acid (0.5 ml) were added at room temperature and reacted at 45°C for 4 hours.

[0137] After the reaction was completed, the mixture was concentrated to dryness and the residue was purified by preparative high performance liquid chromatography to obtain 10.7 mg of (2S, 2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)nitrogendiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis((2-(R)pyrrolidin-3-ylpropionic acid). LCMS: RT = 1.48 min, [MH] + =737.49. 1 H NMR(400MHz, Deuterium Oxide)δ7.28–7.17(m,3H),7.14–7.01(m,4H),6.99–6.87(m,4H),6.81(s,1H),4.61–4.38(m,4H),3.80(s,2H),3.38–3.24(m, 6H),3.22–3.03(m,3H),2.83–2.66(m,6H),2.61(d,J=13.6Hz,3H),2.33(d,m,6H),2.02(s,3H),1.64(q,J=11.8,10.2Hz,3H).

[0138] Example 4

[0139] Synthesis of (S)-3-(3-(2-((5-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2-fluorobenzyl)(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0140]

[0141] The specific synthetic route is as follows:

[0142] Step A: Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0143]

[0144] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)methyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (188 mg, 0.23 mmol), 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)methyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (188 mg, 0.23 mmol) were added. -2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetic acid (100 mg, 0.23 mmol), N,N-dimethylformamide (3 ml), N,N-diisopropylethylamine (60 mg, 0.46 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (133 mg, 0.35 mmol), react at room temperature for 3 hours.

[0145] After the reaction was completed, water (10 ml) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (10 ml x 2 times). The organic phase was washed with saturated brine (10 ml), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 152 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0146] Step B: (S)-3-(3-(2-((5-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2-fluorobenzyl)(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0147]

[0148] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (152 mg, 0.12 mmol), dioxane (2.5 ml) and concentrated hydrochloric acid (0.5 ml) were added at room temperature and the mixture was reacted at 45°C for 4 hours.

[0149] After the reaction was completed, the mixture was concentrated to dryness and the residue was purified by preparative high performance liquid chromatography to obtain 53 mg of (S)-3-(3-(2-((5-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2-fluorobenzyl)(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid. LCMS: RT = 1.51 min, [MH] - =755.28.

[0150] Example 5

[0151] Synthesis of (S)-3-(3-(2-((5-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-4-fluorobenzyl)(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0152]

[0153] The specific synthetic route is as follows:

[0154] Step A: Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0155]

[0156] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)methyl)-2-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (130 mg, 0.16 mmol), 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)methyl)-2-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (130 mg, 0.16 mmol) were added. )-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetic acid (70 mg, 0.16 mmol), N,N-dimethylformamide (3 ml), N,N-diisopropylethylamine (42 mg, 0.32 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (93 mg, 0.25 mmol), react at room temperature for 3 hours.

[0157] After the reaction was completed, water (10 ml) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (10 ml x 2 times). The organic phase was washed with saturated brine (10 ml), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 110 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)-2-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0158] Step B: (S)-3-(3-(2-((5-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-4-fluorobenzyl)(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0159]

[0160] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (110 mg, 0.09 mmol), dioxane (2.5 ml) and concentrated hydrochloric acid (0.5 ml) were added at room temperature and the mixture was reacted at 45°C for 4 hours.

[0161] After the reaction was completed, the product was concentrated to dryness and the residue was purified by preparative high performance liquid chromatography to obtain 23 mg of (S)-3-(3-(2-((5-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-4-fluorobenzyl)(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid. LCMS: RT=1.49 min, [MH]-=755.38

[0162] Example 6

[0163] Synthesis of (S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2-fluorobenzyl)(3-(S)2-carboxy-2-(R)pyrrolidin-3-alkyl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0164]

[0165] The specific synthetic route is as follows:

[0166] Step A: tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2-fluorobenzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0167]

[0168] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2-fluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (150 mg, 0.18 mmol), 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2-fluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (150 mg, 0.18 mmol) were added. )-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetic acid (80 mg, 0.18 mmol), N,N-dimethylformamide (3 ml), N,N-diisopropylethylamine (46 mg, 0.36 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (103 mg, 0.27 mmol), react at room temperature for 3 hours.

[0169] After the reaction was completed, water (10 ml) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (10 ml x 2 times). The organic phase was washed with saturated brine (10 ml), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 140 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2-fluorobenzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. Step B: ((S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2-fluorobenzyl)(3-(S)2-carboxy-2-(R)pyrrolidin-3-alkyl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0170]

[0171] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2-fluorobenzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (140 mg, 0.11 mmol), dioxane (2.5 ml) and concentrated hydrochloric acid (0.5 ml) were added at room temperature and the mixture was reacted at 45°C for 4 hours.

[0172] After the reaction was completed, the mixture was concentrated to dryness and the residue was purified by preparative high performance liquid chromatography to obtain 52 mg of (S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2-fluorobenzyl)(3-(S)2-carboxy-2-(R)pyrrolidin-3-alkyl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid. LCMS: RT = 1.46 min, [MH] - =755.26. 1 H NMR(400MHz, Deuterium Oxide)δ7.24–7.12(m,2H),7.11–6.86(m,8H),6.80(d,J=27.8Hz,1H),4.63–4.37(m,4H),3.79(d,J=25.0Hz,2H ),3.47–3.23(m,6H),3.18–3.05(m,3H),2.91–2.52(m,9H),2.43–2.25(m,6H),2.00(s,3H),1.69–1.54(m,3H).

[0173] Example 7

[0174] Synthesis of (2S,2'S)-3,3'-(((2-(3-((S)-2-carboxy-2-(((R)-pyrrolidin-3-yl)ethyl)-4-fluorophenyl)acetyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propionic acid)

[0175]

[0176] The specific synthetic route is as follows:

[0177] Step A: 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorophenyl)acetic acid

[0178]

[0179] At room temperature, (tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-5-(2-hydroxyethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (800 mg, 1.83 mmol), acetonitrile (10 ml), water (10 ml), disodium hydrogen phosphate dodecahydrate (3.80 g, 10.61 mmol), 2,2,6,6-tetramethylpiperidinoxide (43 mg, 0.27 mmol), and iodobenzene acetate (1.77 g, 5.50 mmol) were added in sequence and reacted at room temperature for 3 hours.

[0180] After the reaction was completed, water (20 ml) was added for dilution, sodium sulfite was quenched, and ethyl acetate (30 ml x 2 times) was used for extraction. The organic phase was washed with saturated brine (10 ml), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 530 mg of 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxypropyl)-4-fluorophenyl)acetic acid. LCMS: RT = 2.13 min, [M+H-tert-butoxycarbonyl] + =352.23.

[0181] Step B: 3,3'-((2S,2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorophenyl)acetyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate)

[0182]

[0183] At room temperature, 3,3'-((2S,2'S)-((azadiylbis(methylene))bis(3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (167 mg, 0.21 mmol), 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxy)-3-oxopropane-1,2-diyl))-bis(3,1-phenylene))-bis(3 ...-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))-bis(3,1-phenylene)-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))-bis(3,1-phenylene)-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))-bis(3,1-phenylene)-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))- To the mixture was added 1,2-dimethyl-2-nitropropylidene-1-yl)-4-fluorophenyl-3-yl)-2-nitropropylidene-1 ...

[0184] After the reaction was completed, water (10 ml) was added to dilute, and the mixture was extracted with ethyl acetate (10 ml × 2 times). The organic phase was washed with saturated brine (10 ml), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 150 mg of 3,3'-((2S, 2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorophenyl)acetyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R, 3'R)-bis(pyrrolidine-1-carboxylate).

[0185] Step C: (2S,2'S)-3,3'-(((2-(3-((S)-2-carboxy-2-(((R)-pyrrolidin-3-yl)ethyl)-4-fluorophenyl)acetyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0186]

[0187] 3,3'-((2S,2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorophenyl)acetyl)azinediyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (150 mg, 0.12 mmol), dioxane (2.5 ml) and concentrated hydrochloric acid (0.5 ml) were added at room temperature and reacted at 45°C for 4 hours.

[0188] After the reaction was completed, the product was concentrated to dryness and the residue was purified by preparative high performance liquid chromatography to obtain 50 mg of (2S,2'S)-3,3'-(((2-(3-((S)-2-carboxy-2-(((R)-pyrrolidin-3-yl)ethyl)-4-fluorophenyl)acetyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid). (LCMS: RT=1.49 min, [MH]-=755.41. 1 HNMR(400MHz,DeuteriumOxide)δ7.21(td,J=7.6,5.6Hz,2H),7.13–7.05(m,2H) ,7.05–6.94(m,4H),6.91(d,J=7.3Hz,2H),6.80(s,1H),4.58(s,2H),4.48(d,J= 5.0Hz,2H),3.76(s,2H),3.44–3.26(m,6H),3.21–3.08(m,3H),2.90–2.57(m,9H ), 2.36(tt,J=10.7,5.7Hz,6H),2.03(s,3H),1.65(dtt,J=14.3,9.2,4.5Hz,3H).

[0189] Example 8

[0190] Synthesis of (S)-3-(5-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-4-fluorobenzyl)(3-(S)2-carboxy-2-(R)pyrrolidin-3-ylethyl)benzyl)amino)-2-oxoethyl)-2-fluorophenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0191] The specific synthetic route is as follows:

[0192]

[0193] Step A: Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorobenzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorophenyl)acetamido)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0194]

[0195] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (179 mg, 0.22 mmol), 2-(3-((S)-3-(tert-butoxy)-2 -((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorophenyl)acetic acid (100 mg, 0.22 mmol), N,N-dimethylformamide (3 ml), N,N-diisopropylethylamine (58 mg, 0.44 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (125 mg, 0.33 mmol), react at room temperature for 3 hours.

[0196] After the reaction was completed, water (10 ml) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (10 ml x 2 times). The organic phase was washed with saturated brine (10 ml), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 200 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorobenzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorophenyl)acetamido)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0197] Step B: (S)-3-(5-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-4-fluorobenzyl)(3-(S)2-carboxy-2-(R)pyrrolidin-3-ylethyl)benzyl)amino)-2-oxoethyl)-2-fluorophenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0198]

[0199] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorobenzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorophenyl)acetamido)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (200 mg, 0.16 mmol), dioxane (2.5 ml) and concentrated hydrochloric acid (0.5 ml) were added at room temperature and the reaction was carried out at 45°C for 4 hours.

[0200] After the reaction was completed, the product was concentrated to dryness and the residue was purified by preparative high performance liquid chromatography to obtain 48 mg of (S)-3-(5-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-4-fluorobenzyl)(3-(S)2-carboxy-2-(R)pyrrolidin-3-ylethyl)benzyl)amino)-2-oxoethyl)-2-fluorophenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid. LCMS: RT=1.49 min, [MH]-=773.29. 1 H NMR(400MHz, Deuterium Oxide)δ7.21(td,J=7.6,4.2Hz,1H),7.08(d,J=7.7Hz,1H),7.05–6.85(m,7H),6.85–6.76(m,1H),4.58(d,J=12.0Hz,2H),4.47(d,J=11.8 Hz,2H),3.78(d,J=6.7Hz,2H),3.48–3.28(m,6H),3.23–3.09(m,3H),2.93–2.56(m,9H),2.36(d,J=14.1Hz,6H),2.04(s,3H),1.66(s,3H).

[0201] Example 9

[0202] Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-4-chlorobenzyl)(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0203]

[0204] The specific synthetic route is as follows:

[0205] Step A: Synthesis of tert-butyl (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-chlorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0206]

[0207] At room temperature, (R)-3-(S)-1-tert-butoxy-3-(2-chloro-5-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.74 mmol) and (R)-3-(S)-3-(3-aminomethyl)phenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (324 mg, 0.74 mmol) were dissolved in dry 1,2-dichloroethane (3 ml), and the mixture was heated to 45° C. for 3 hours. Subsequently, sodium triacetoxyborohydride (451 mg, 2.13 mmol) was added in portions and the mixture was reacted at 45° C. for 4 hours. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate (20 ml × 2 times). The combined organic phases were washed with saturated brine (20 ml × 2 times), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 360 mg of (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-chlorobenzyl)amino)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.04 min, [M+H] + =826.32.

[0208] Step B: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(3-(N-(3-(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidin-3-yl)-3-oxopropyl)-4-chlorobenzyl)-2-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0209]

[0210] (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-chlorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol), 2-(3-(S)-3-tert-butoxy-2-(R) -1-tert-Butyloxycarbonylpyrrolidin-3-yl)-3-oxopropyl)phenyl)acetic acid (150 mg, 0.23 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (130 mg, 0.33 mmol) and N,N-diisopropylethylamine (60 mg, 0.46 mmol) were dissolved in N,N-dimethylformamide (3 ml) and stirred at room temperature overnight. After the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and then dried over anhydrous sodium sulfate. After distillation, the crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to obtain 170 mg of (R)-3-(S)-1-tert-butoxy-3-(3-(N-(3-(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidin-3-yl)-3-oxopropyl)-4-chlorobenzyl)-2-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0211] Step C: Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-4-chlorobenzyl)(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0212]

[0213] (R)-3-(S)-1-tert-butoxy-3-(3-(N-(3-(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidin-3-yl)-3-oxopropyl)-4-chlorobenzyl)-2-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetylamino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (170 mg, 0.14 mmol) was dissolved in dioxane / concentrated hydrochloric acid (3 ml / 0.3 ml) and reacted at 45°C overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to obtain 53.5 mg of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-4-chlorobenzyl)(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid. LCMS: RT = 1.51 min, [MH] - =771.21. 1 H NMR(400MHz,D2O)δ7.21(dd,J=8.0,2.0Hz,1H),7.15(td,J=7.6,3.8Hz,2H),7.07-6.94(m,3H),6.93-6.65(m,5H),4.61-4.32(m,4H),3 .74(d,J=6.0Hz,2H),3.52-3.20(m,6H),3.20-2.91(m,3H),2.93-2.46(m,9H),2.46-2.19(m,6H),2.15-1.92(m,3H),1.75-1.44(m,3H).

[0214] Example 10

[0215] Synthesis of (2S,2'S)-3,3'-(((2-(3-((S)-2-carboxy-2-(((R)-pyrrolidin-3-yl)ethyl)phenyl)acetyl)nitrogendiyl)bis(methylene)bis(2,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propionic acid)

[0216]

[0217] The specific synthetic route is as follows:

[0218] Step A: 3,3'-((2S,2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetyl)azepinediyl)bis(methylene))bis(2,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate)

[0219]

[0220] At room temperature, 3,3'-((2S,2'S)-((azadiylbis(methylene))bis(2,1-phenylene))-(3-(tert-butyloxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (98 mg, 0.12 mmol), 2-(3-((S)-3-(tert-butyloxy)-2-((R)-1-(tert-butyloxy)-3-oxopropane-1,2-diyl)-1,2-diyl)-3R,3'R)-bis(pyrrolidine-1-carboxylate) were added. 1-(4-(4-(4-nitro-1-yl)-2-nitro-2-yl)-4-nitro-2-yl)-6-nitro-3-ol)-1,2-dinitro-4-nitro-2-ol ...

[0221] After the reaction was completed, water (10 ml) was added to dilute, and the mixture was extracted with ethyl acetate (10 ml × 2 times). The organic phase was washed with saturated brine (10 ml), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 20 mg of foamy solid 3,3'-((2S, 2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetyl)azepinediyl)bis(methylene))bis(2,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R, 3'R)-bis(pyrrolidine-1-carboxylate).

[0222] Step B: (2S,2'S)-3,3'-(((2-(3-((S)-2-carboxy-2-(((R)-pyrrolidin-3-yl)ethyl)phenyl)acetyl)nitrogendiyl)bis(methylene)bis(2,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0223]

[0224] 3,3'-((2S,2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetyl)azepinediyl)bis(methylene))bis(2,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (20 mg, 0.02 mmol), dioxane (2.5 ml) and concentrated hydrochloric acid (0.5 ml) were added at room temperature and the mixture was reacted at 45°C for 4 hours.

[0225] After the reaction was completed, the product was concentrated to dryness and the residue was purified by preparative high performance liquid chromatography to obtain 1.9 mg of (2S, 2'S)-3,3'-(((2-(3-((S)-2-carboxy-2-(((R)-pyrrolidin-3-yl)ethyl)phenyl)acetyl)nitrogendiyl)bis(methylene)bis(2,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propionic acid). LCMS: RT = 1.47 min, [MH] - =737.47.

[0226] Embodiment 11

[0227] Synthesis of (S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)(2-(S)2-carboxy-2-(R)pyrrolidin-3-ylethyl)phenethyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0228]

[0229] The specific synthetic route is as follows:

[0230] Step A: tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-(N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-2-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)ethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0231]

[0232] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-(((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)ethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.12 mmol), 2-(3-((S)-3-(tert-butoxy)-3-(2-(((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)ethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.12 mmol) were added. -2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetic acid (53 mg, 0.12 mmol), N,N-dimethylformamide (2 ml), N,N-diisopropylethylamine (49 mg, 0.38 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (72 mg, 0.19 mmol), react at room temperature for 3 hours.

[0233] After the reaction was completed, water (10 ml) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (10 ml x 2 times). The organic phase was washed with saturated brine (10 ml), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 32 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-(N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-2-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)ethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0234] Step B: (S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)(2-(S)2-carboxy-2-(R)pyrrolidin-3-ylethyl)phenethyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0235]

[0236] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-(N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-2-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)acetamido)ethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (32 mg, 0.03 mmol), dioxane (2.5 ml) and concentrated hydrochloric acid (0.5 ml) were added at room temperature and the reaction was carried out at 45°C for 4 hours.

[0237] After the reaction was completed, the product was concentrated to dryness and the residue was purified by preparative high performance liquid chromatography to obtain 5.1 mg of (S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)(2-(S)2-carboxy-2-(R)pyrrolidin-3-ylethyl)phenethyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid. LCMS: RT = 1.55 min, [MH] - =751.48.

[0238] Example 12 In vitro Lp(a) assembly assay

[0239] Experimental procedures

[0240] The ability of the example compounds to inhibit Lp(a) particle formation in vitro was evaluated by a cell-free assembly assay. Conditioned media (DMEM supplemented with 10% FBS, 20 mM HEPES and 1× penicillin / streptomycin) were collected from confluent wild-type HepG2 cells (source of endogenously expressed ApoB) and from a HEK293 stable cell line expressing a human Apo(a) protein containing 17 Kringle repeats (selected on 1 ug / ml puromycin) after 96 h of incubation at 37°C and 5% CO2. In vitro assembly assays were performed by combining equal parts of HepG2 and HEK293 conditioned media with test compounds added in a dilution series (final concentration 0.03-1000 nM). The reactions were incubated at 37°C for 2 hours and terminated by the addition of 6-aminoacetic acid (EACA) to a final concentration of 150 mM. Lp(a) was detected using a sandwich ELISA with an anti-Apo(a) capture antibody (ab242565) and an HRP-conjugated anti-ApoB detection antibody (ab27622). The ELISA was developed using TMB, terminated with 1N sulfuric acid and read at 450 nm on an Envision 2104 plate reader. The % inhibition of Lp(a) formed under each tested condition was determined by setting the assembly reaction in the absence of inhibitor to 0% inhibition and the assembly reaction in the presence of minimal HepG2 conditioned medium (50-fold dilution) to 100% inhibition. The data were fit to a 4-parameter curve to determine the IC 90 The results are shown in Table 1.

[0241] Table 1 IC of acyl compounds 90 value

[0242]

[0243] It can be seen from the results in Table 1 that the acyl compounds of the present invention all have good LP(a) inhibitory activity.

[0244] Embodiment 13

[0245] Pharmacokinetics experiment in SD rats

[0246] (1) Experimental Materials

[0247] SD rats: male, 180-250 g, purchased from Guangdong Weitonglihua Experimental Animal Technology Co., Ltd.

[0248] Reagents: physiological saline, EDTA-K2 (anticoagulant), TCA (trichloroacetic acid), and propranolol (internal standard) are all commercially available.

[0249] Instrument: Nexera LC-40; AB SCIEX QTRAP 5500+.

[0250] (2) Experimental methods

[0251] Weigh the compound and dissolve it in the physiological saline system. After oral administration to rats, collect 200 μL of venous blood in EDTA-K2 anticoagulation EP tubes at 15min, 30min, 1h, 2h, 5h, 7h, and 24h (5min for the iv group), centrifuge at 12000rpm for 2min, and freeze the plasma at -80℃ for testing. Accurately weigh a certain amount of the test sample and dissolve it in ultrapure water to 2mg / mL as a stock solution. Accurately draw an appropriate amount of the compound stock solution and add 50% acetonitrile-water to dilute it to prepare a standard series of solutions. Accurately draw 10μL of each of the above standard series solutions, add 90μL of blank plasma, vortex and mix, and prepare plasma samples equivalent to plasma concentrations of 1, 3, 5, 10, 30, 100, 300, 1000, and 3000ng / mL. The concentrations of the quality control samples are 9, 240, and 2400ng / ml. Double sample analysis is performed at each concentration to establish a standard curve. Take 30 μL of plasma (5 minutes, 15 minutes, and 30 minutes of intravenous administration, the plasma was diluted 5 times), add 200 μL of 5% trichloroacetic acid-water solution of internal standard propranolol (50 ng / mL), vortex mix, centrifuge at 4000 rpm for 10 minutes, take the supernatant, add 150 μL of purified water, vortex mix again, and perform LC-MS / MS analysis. LC-MS / MS detection conditions are as follows:

[0252] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0253] Mobile phase: water (0.1% formic acid)-acetonitrile with gradient elution as shown in the table below.

[0254] Table 2 Gradient elution table

[0255] Time (min) Water (containing 0.1% formic acid) Acetonitrile 0 95％ 5％ 0.60 95％ 5％ 1.50 30％ 70％ 3.00 30％ 70％ 3.01 95％ 5％ 3.50 95％ 5％

[0256] (3) Data processing

[0257] After LC-MS / MS was used to detect the blood drug concentration, the pharmacokinetic parameters were calculated using the WinNonlin 6.1 software and the non-compartmental model method. The results are shown in Table 3.

[0258] Table 3: Pharmacokinetic parameters of the compounds of the present invention in SD rats

[0259]

[0260] According to the results in Table 3, it can be seen that the compounds of the present invention have a higher exposure amount. In addition, the exposure amount of compound 3-8 is significantly better than that of compound 2 in Example 2, which indicates that when Z in general formula I-IIIa / IIIb is selected from -CH2-, its exposure amount is better than that of the compound when Z is selected from -NH-.

[0261] It should be understood that the above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. For ordinary technicians in this field, they can be improved or transformed according to the above description, and all these improvements and transformations should fall within the scope of protection of the claims attached to the present invention.

Claims

1. An acyl compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the acyl compound is shown in general formula I: Wherein, the Y is selected from -N- or -CH-; the Z is selected from: -NH-, -CH2- or a connecting bond; The X 1～ X 15 Each is independently selected from -N- or -CR1, wherein R1 is selected from H, halogen, -OH, -NH2, -CN, -NO2, -COOH, -SO3H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or And the X 1～ At least one R1 in X5 is independently selected from And the X 6～ X 10 At least one R1 is independently selected from The R2 is selected from -H, halogen, substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C1-C6 alkoxy; The R3 is selected from -(CH2) s -(5-8 membered heterocyclyl); The substituted C1-C6 alkyl, substituted C1-C6 alkoxy, substituted C3-C 10 Cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C6-C 10 The substituents in the aryl or substituted 5-10 membered heterocyclic group are independently selected from halogen, hydroxyl, carboxyl, nitro, cyano, C1-C6 alkyl, C 1- C6 haloalkyl, C 1- C6 haloalkoxy, C 1- C6 alkoxy, C 3- C8 cycloalkyl, 3-10 membered heterocycloalkyl, C 3- C6 cycloalkoxy, C 6- C 10 one or more of aryl or 5-10 membered heteroaryl; m, n or r are independently selected from an integer of 1, 2 or 3; s is independently selected from an integer of 0, 1, 2 or 3; Preferably, the Y is selected from -N- or -CH-; the Z is selected from: -NH-, -CH2- or a connecting bond; and the X 1～ At least one R1 in X5 is independently selected from And the X 6～ X 10 At least one R1 is independently selected from R1 is selected from H, halogen, -OH, -NH2, -CN, -NO2, -COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or The R2 is selected from -H, substituted or unsubstituted C1-C6 alkyl; the R3 is selected from 5-8 membered heterocyclic group; the substituted C1-C6 alkyl, substituted C3-C 10 Cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C6-C 10 The substituents in the aryl or substituted 5-10 membered heteroaryl are independently selected from halogen, hydroxyl, carboxyl, nitro, cyano, C1-C6 alkyl, C 1- C6 haloalkyl, C 1- C6 haloalkoxy, C 1- C6 alkoxy, C 3- C8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3- C8 cycloalkoxy, C 6- C 10 one or more of aryl or 5-10 membered heteroaryl; More preferably, one of X4 or X5 is selected from The X9 or X 10 One of the The X 11 or X 12 One of the 2. The acyl compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt according to claim 1, characterized in that: The structure of the acyl compound is shown in the general formula IIa or IIb: Wherein, the Y is selected from -N- or -CH-; the Z is selected from: -NH-, -CH2- or a connecting bond; X1-X3 and X 5～ X 15 Each is independently selected from -N- or -CR1, wherein R1 is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy or The R2 is selected from H, substituted or unsubstituted C1-C6 alkyl; the R3 is selected from 5-8 membered heterocyclic group; the substituents in the substituted C1-C6 alkyl and substituted C1-C6 alkoxy are independently selected from halogen, hydroxyl, carboxyl, nitro, cyano, C1-C6 alkyl, C 1- C6 haloalkyl, C 1- C6 haloalkoxy, C 1- C6 alkoxy, C 3- C8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3- C8 cycloalkoxy, C 6- C 10 one or more of aryl or 5-10 membered heteroaryl; The m, n, p, q or r is independently selected from an integer of 1, 2 or 3.

3. The acyl compound according to any one of claims 1 to 2, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The structure of the acyl compound is shown in the general formula IIIa or IIIb: Wherein, the Y is selected from -N- or -CH-; the Z is selected from: -NH-, -CH2- or a connecting bond; X1-X3 and X 5～ X 15 Each is independently selected from -N- or -CR1, wherein R1 is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy or The R2 is selected from H, substituted or unsubstituted C1-C6 alkyl; the R3 is selected from 5-8 membered heterocyclic group; the substituents in the substituted C1-C6 alkyl and substituted C1-C6 alkoxy are independently selected from halogen, hydroxyl, carboxyl, nitro, cyano, C1-C6 alkyl, C 1- C6 haloalkyl, C 1- C6 haloalkoxy, C 1- C6 alkoxy, C 3- C8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3- C8 cycloalkoxy, C 6- C 10 one or more of aryl or 5-10 membered heteroaryl; The m, n, p, q or r is independently selected from an integer of 1, 2 or 3.

4. The acyl compound according to any one of claims 1 to 3, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The R1 is selected from H, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, piperazinyl, -CH2COOH, -CH2CH2COOH, -CH2CH(CH3)COOH, The R3 is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl; Preferably, the is selected from quinolinyl; More preferably, the Selected from:

5. The acyl compound according to claim 4, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: Said Selected from:

6. The acyl compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt according to claim 5, characterized in that: Said Selected from:

7. The acyl compound according to any one of claims 1 to 6, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The chemical structure of the acyl compound is selected from:

8. The acyl compound according to any one of claims 1 to 7, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The chemical structure of the acyl compound is selected from:

9. A pharmaceutical composition, characterized in that The invention comprises the acyl compound according to any one of claims 1 to 8, or its isomer, or its racemate, or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients and / or carriers.

10. Use of the acyl compound according to any one of claims 1 to 8, or its isomer, or its racemate, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing or treating diseases associated with LP (a); Preferably, the Lp(a)-related disease is selected from cardiovascular disease; Further preferably, the cardiovascular disease is selected from stroke, atherosclerosis, thrombosis, coronary heart disease or aortic valve stenosis and any other disease associated with elevated Lp(a) levels.

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