An acyl compound, a preparation method thereof and medical use thereof

Abstract

The application belongs to the technical field of chemical medicines, and provides an acyl compound, a preparation method and medical use thereof.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, and provides an acyl compound, its preparation method, and its pharmaceutical uses. Background Technology

[0002] LPA is the name of the gene encoding apolipoprotein(a) (apo(a)), which is primarily expressed in the liver, and its expression is limited to humans and non-primates. Apolipoprotein(a) is attached to apo(B)-100 via disulfide bonds, combining with a lipid core to form lipoprotein(a) (Lp(a)) particles. Lp(a) particles are specialized large lipoprotein molecules rich in cholesterol, 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, promoting atherosclerosis. Lp(a) is structurally homologous to plasminogen (PLG) and can compete with plasminogen for fibrin binding sites, thereby inhibiting fibrinogen hydrolysis and promoting thrombus formation. Therefore, Lp(a) is closely related to atherosclerosis and thrombosis. Studies have shown that blood Lp(a) levels are an independent risk factor for cardiovascular disease, stroke, and atherosclerotic stenosis. Human Lp(a) levels are genetically determined and do not change significantly with changes in diet, exercise, or other lifestyle factors.

[0003] Currently reported LP(a) inhibitors are mainly macromolecules or small nucleic acid drugs. For example, WO2023046093A1 discloses a bispecific fusion peptide; CN111465694A discloses a nucleic acid for inhibiting LPA expression in cells; CN108368506A also discloses a composition and method for inhibiting LPA gene expression; and CN113166759A discloses a chemically modified RNAi construct and its uses. However, there are currently no marketed small molecule LP(a) drugs. 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 scarcity of small molecule LP(a) drugs in the prior art.

[0005] This invention is achieved through the following technical solution:

[0006] This invention provides an acyl compound, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the structure of the acyl compound is shown in general formula I:

[0007]

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

[0009] The X 1～ X 15 Each is independently selected from -N- or -CR1, where 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 heteroaryl groups or And the X 1～ In X5, at least one R1 is independently selected. And the X 6～ X 10 At least one R1 is independently selected 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 heterocyclic group);

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

[0012] As a preferred embodiment of the present invention, Y is selected from -N- or -CH-; Z is selected from -NH-, -CH2-, or a linker bond; and X 1～ In X5, at least one R1 is independently selected. And the X 6～ X 10 At least one R1 is independently selected R1 is selected from H, halogens, -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 heteroaryl groups or R2 is selected from -H, substituted or unsubstituted C1-C6 alkyl groups; R3 is selected from 5-8 membered heterocyclic groups; substituted C1-C6 alkyl groups, substituted C3-C6 alkyl groups, and substituted C3-C6 alkyl groups are selected from -H ... 10 Cycloalkyl, substituted 3-10 membered heterocyclic alkyl, substituted C6-C 10 The substituents in the aryl or substituted 5-10-membered heteroaryl groups are independently selected from halogens, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, C1-C6 alkyl groups, C ... 1- C6 haloalkyl, C 1- C6 haloalkoxy group, 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 heteroaryl groups.

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

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

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

[0016]

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

[0018] The 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 R2 is selected from H, substituted or unsubstituted C1-C6 alkyl groups; R3 is selected from 5-8 membered heterocyclic groups; the substituents in the substituted C1-C6 alkyl groups and substituted C1-C6 alkoxy groups are independently selected from halogens, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, C1-C6 alkyl groups, C 1- C6 haloalkyl, C 1- C6 haloalkoxy group, 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 heteroaryl groups; wherein m, n, p, q or r are independently selected from integers of 1, 2 or 3.

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

[0020]

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

[0022] The 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 R2 is selected from H, substituted or unsubstituted C1-C6 alkyl groups; R3 is selected from 5-8 membered heterocyclic groups; the substituents in the substituted C1-C6 alkyl groups and substituted C1-C6 alkoxy groups are independently selected from halogens, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, C1-C6 alkyl groups, C 1- C6 haloalkyl, C 1- C6 haloalkoxy group, 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 heteroaryl groups; wherein m, n, p, q or r are independently selected from integers of 1, 2 or 3.

[0023] As a preferred technical solution of the present invention, the C 1- C6 alkyl group is preferred. 1- C2, C 1- C3, C 1- C4 or C 1- C5 alkyl; examples of said 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 group is preferred. 1- C2, C 1- C3, C 1- C4 or C 1- C5 haloalkyl groups; examples of said haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl, and pentafluoroethyl. Particularly noteworthy haloalkyl groups are trifluoromethyl and trifluoroethyl.

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

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

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

[0028] As a preferred embodiment of the present invention, in some embodiments, the "heterocyclic group" is a 5-10 membered heterocyclic group composed of 5-10 ring atoms; in other embodiments, the "heterocyclic group" is a 5-8 membered heterocyclic group composed of 5-8 ring atoms; in other embodiments, the "heterocyclic group" is a 6-8 membered heterocyclic group composed of 6-8 ring atoms; and in other embodiments, the "heterocyclic group" is a 5-6 membered heterocyclic group composed of 5-6 ring atoms. Examples of heterocyclic groups include, but are not limited to: pyranyl, tetrahydropyranyl, oxetane, tetrahydrofuranyl, dihydrofuranyl, 1,4-dioxane, morpholinyl, 1,4-dithiaalkyl, piperazine, piperidinyl, 1,3-dioxolanecycloyl, imidazolinyl, imidazolinyl, pyrrololinyl, pyrrolyl, tetrahydropyranyl, dihydropyranyl, oxetanepentane, dithiopentane, 1,3-dioxane, 1,4-dioxane, 1,3-dithiaalkyl, oxetanehexane, thiomorpholinyl, tetrahydro-thiaran 1,1-dioxide, and 1,4-diazaneheptanyl.

[0029] As a preferred embodiment of the present invention, in some embodiments, "heterocyclic alkyl" is preferably a 3-12 membered heterocyclic alkyl; more preferably a 3-10 membered heterocyclic alkyl; even more preferably a 5-8 membered heterocyclic alkyl; and most preferably a 5-6 membered heterocyclic alkyl. Examples of the heterocyclic alkyl include, but are not limited to: aziridine, ethylene oxide, aziridine, oxadiazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, and piperazine. yl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, aziridine-heptyl, diazacyclic-heptyl, high piperazineyl, oxaziridine-heptyl, thiazine-alkyl, 8-aza-bicyclo[3.2.1]octyl, quinine-cycloyl, 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]heptyl. More specific examples of heterocyclic alkyl groups are pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azirheptanyl, diazaheptanyl, high-piperazinyl, oxazheptanyl, thiazolyl and 2,6-diaza-spiro[3.3]heptyl.

[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, or a substituted or unsubstituted C6-C7 aryl group; when the aryl group is substituted, the substituent is preferably 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 groups, C5-C 10 Substituted or unsubstituted heteroaryl groups, wherein the aryl group is specifically selected from phenyl, naphthyl, anthracene, phenanthrene, 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 heteroaryl 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 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 The heteroaryl group is an aryl, substituted, or unsubstituted 5-10 membered heteroaryl group, wherein the heteroatom in the heteroaryl group is one or more of N, O, and S. The heteroaryl group is preferably selected from: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrrololyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, pyrazolyl, isoxazolyl, thiazolyl, pyrazolyl, tetrazolyl, pyridazinyl, quinolinyl, isoquinolinyl, indazole, triazolyl, tetrazolyl, etc.

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

[0033] As a preferred technical solution of the present invention, the Selected from quinolinyl; the Further preferred options are:

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

[0035] As a preferred embodiment of the present invention, the following features are provided: Selected from:

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

[0037]

[0038] Furthermore, as a preferred embodiment of the present invention, the chemical structure of the acyl compound is selected from:

[0039]

[0040]

[0041]

[0042] Furthermore, as a preferred embodiment 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 an acyl compound of general formula I, general formula IIa, general formula IIb, general formula IIIa or general formula IIIb, or an isomer thereof, or a racemic mixture thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and / or carriers.

[0046] The present invention further provides the use of the acyl compounds of the present invention, or isomers thereof, or racemates thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases related to LP(a).

[0047] Furthermore, 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 stenosis, and any other disease associated with elevated Lp(a) levels.

[0049] In the chemical structure of the compound described in this invention, the bond... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or colleagues include Two configurations;

[0050] In the chemical structure of the compounds described in this disclosure, the bonds are... The configuration is not specified, meaning it can be either Z configuration or E configuration, or both configurations can be included simultaneously;

[0051] The compounds and intermediates of the present invention may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also called proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization. Examples of lactam-lactamimide equilibrium are between A and B as shown below.

[0052]

[0053] All compounds in this invention may be designated as type A or type B. All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

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

[0055] The advantages of this invention over the prior art include, but are not limited to:

[0056] The acyl compounds of the present invention have a lower IC value compared with the prior art. 90 value.

[0057] For clarity, this article defines the general terminology used in the description of compounds.

[0058] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0059] The term "medicinal salt" refers to a salt of the compound of the present invention, prepared by reacting a compound having specific substituents discovered in the present invention with a medicinal acid or base.

[0060] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0061] Some compounds of this invention may exist in non-solventized or solvated forms, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of this invention.

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

[0063] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, 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 desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0064] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 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 their various branched isomers. The alkyl group may be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably one or more of the following groups, independently selected from halogens, deuterium, hydroxyl, oxo, nitro, cyano, C 1- C6 alkyl, C 1- C6 alkoxy, C 2- C6-olefin, C 2- C6 acetylacetyl group, 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 group, C 6- C 10 Aryl or 5- to 6-membered heteroaryl, wherein C 1- C6 alkyl, C1- C6 alkoxy, C 2- C6-olefin, C 2- C6 acetylacetyl group, 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 group, C 6- C 10 The aryl or 5- to 6-membered heteroaryl group may be optionally substituted by one or more groups selected from halogen, deuterium, hydroxyl, oxo, nitro, and cyano.

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

[0066] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy. Specific alkoxy groups include 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 a different halogen atom. The term "per-haloalkoxy" refers to an alkoxy group in which all the hydrogen atoms of the alkoxy group have been replaced by the same or a different halogen atom. 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 terms "cycloalkyl" or "carbocyclic" refer to a saturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; polycyclic cycloalkyl includes spirocyclic, fused-ring, and bridged-ring cycloalkyl.

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

[0071] The term "heteroaryl" or "heteroary ring" refers to a heteroaryl system containing 1 to 3 heteroatoms and 5 to 12 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 10-membered, 5 to 8-membered, and more preferably 5-membered or 6-membered heteroaryl groups. Pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, triazinyl, aziridineyl, and aziridineyl.

[0072] Diazazolyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothiophenyl, indolyl, isindolyl, isobenzofuranyl, benzoimidazolyl, benzooxazolyl, benzoisooxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalolinyl. Specific heteroaryl groups include pyrroleyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, isoxazolyl, and isothiazolyl. More specific heteroaryl groups include imidazole, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl, isothiazolyl, 2-fluoropyridyl, 3-fluoropyridyl, 4-fluoropyridyl, 2-chloropyridyl, 3-chloropyridyl, 4-chloropyridyl, 2,3-difluoropyridyl, 3,4-difluoropyridyl, 4,5-difluoropyridyl. 3,5-Difluoropyridyl, 2-chloro-3-fluoropyridyl, 3-fluoro-4-chloropyridyl, 3-fluoro-5-chloropyridyl, 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 "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group), polycyclic heterocyclic system (i.e., polycyclic heterocyclic group), or heteroaromatic ring system containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), and having 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., 3 to 20 membered heterocyclic groups). 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); even more 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 heterocyclic alkyl groups and 5-10 membered heteroaryl groups. In some embodiments, the heterocyclic group is selected from: 5-8 membered heterocyclic alkyl groups and 5-8 membered heteroaryl groups. In some embodiments, the 5-6 membered heterocyclic group is selected from: 5-6 membered heterocyclic alkyl groups and 5-6 membered heteroaryl groups.

[0074] The term "heterocyclic alkyl" refers to a cycloalkyl group in which one to four heteroatoms are substituted for carbon atoms, said heteroatoms being selected from one or more of N, O, or S; preferably 3-12-membered heterocyclic alkyl; more preferably 3-10-membered heterocyclic alkyl; even more preferably 5-8-membered heterocyclic alkyl; most preferably 5-6-membered heterocyclic alkyl; examples of said heterocyclic alkyl include, but are not limited to: aziridine, ethylene oxide, aziridine, oxadiazine, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thiophenyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, piperidinyl, tetrahydropyranyl Tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, aziridine heptyl, diazacyclic heptyl, high piperazinyl, oxaziridine heptyl, thiazinyl, 8-aza-bicyclo[3.2.1]octyl, quininecycloyl, 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]heptyl. More specific examples of heterocyclic alkyl groups are pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azirheptanyl, diazaheptanyl, high-piperazinyl, oxazheptanyl, thiazolyl and 2,6-diaza-spiro[3.3]heptyl.

[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... This refers to one, two, or more (e.g., three) R1s independently selected.

[0076] The atoms in the compounds of this invention are isotopes. Isotope derivatization can typically prolong half-life, reduce clearance rate, stabilize metabolism, and enhance in vivo activity. Furthermore, one embodiment is included, wherein at least one atom is replaced by an atom having the same number of atoms (protons) but different mass numbers (protons and neutrons). Examples of isotopes included in the compounds of this invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each comprising... 2 H, 3 H, 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S, 18F, 36 Cl. In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomical examination of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with quantity and are not radioactive, therefore they can be used safely. When the atoms constituting the compounds of this invention are isotopes, the isotopes can be converted according to common methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0077] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting 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, regardless of radioactivity, are included within the scope of the present invention.

[0078] Furthermore, one or more hydrogen atoms in the compound of the present invention are replaced by the isotope deuterium (2H). After deuteration, the compound of the present invention has the effects of prolonging the half-life, reducing the clearance rate, stabilizing metabolism, and improving in vivo activity.

[0079] The preparation methods of the isotope derivatives typically include phase-transfer catalysis. For example, a preferred deuteration method employs a phase-transfer catalyst (e.g., tetraalkylammonium salt, NBu4HSO4). Using a phase-transfer catalyst to exchange the methylene protons of a diphenylmethane compound results in the introduction of higher levels of deuterium than reduction with deuterated silanes (e.g., triethyldeuterated silane) in the presence of an acid (e.g., methanesulfonic acid) or with Lewis acids such as aluminum trichloride using sodium deuterated borate.

[0080] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals. For further information on carriers, see 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 the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0082] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity 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 recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0083] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0084] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur. Detailed Implementation

[0085] The present invention will be further described in detail below with reference to the 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)-pyrrolidine-3-yl)ethyl)pyridin-2-yl)methyl)azadiyl)bis(methylene)bis(3,1-phenylene))bis(2-(R)-pyrrolidine-3-yl)propionic acid)

[0088]

[0089] The specific synthesis route is as follows:

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

[0091]

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

[0093] After the reaction was complete, the mixture was quenched with 10 mL of sodium sulfite aqueous solution, extracted with ethyl acetate (20 mL × 2 times), concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 205 mg of pale yellow solid 3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)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)pyrrolidine-3-yl)-3-oxopropyl)benzoyl)azadiyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butanol)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate)

[0095]

[0096] 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)-di(pyrrolidine-1-carboxylate) (80 mg, 0.1 mmol), 3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzoic acid (42 mg, 0.1 mmol) were dissolved in acetonitrile (2 mL), followed by the addition of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (42 mL, 0.15 mmol), and N-methylimidazolium (21 mg, 0.1 mmol). The reaction was carried out at room temperature for 8 hours with 1.5 mmol of water. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2 times). The mixture was concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10) to give 63 mg of di-3,3'-di-tert-butyl((2S,2'S)-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzoyl)azonyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butanol)-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)-pyrrolidine-3-yl)ethyl)benzoyl)azidine)bis(methylene)bis(3,1-phenylene))bis(2-(R)pyrrolyl-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)pyrrolidine-3-yl)-3-oxopropyl)benzoyl)azonyl)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 reaction was carried out at 45 °C for 5 hours.

[0100] After the reaction was completed, the mixture was concentrated to dryness, and the residue was purified to yield 13 mg of ((2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzoyl)azadiyl)bis(methylene)bis(3,1-phenylene))bis(2-(R)pyrrolyl-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)-pyrrolidine-3-yl)ethyl)phenyl)carbamoyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidine-3-acyl)propionic acid)

[0103]

[0104] The specific synthesis route is as follows:

[0105] Step A: Synthesis of (R)-3-((S)-3-(3-(benzylamino)phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0106]

[0107] (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (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), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (933 mg, 1.5 mg) were dissolved in toluene (25 mL), purged with nitrogen three times, and then heated to 80 °C and reacted overnight.

[0108] After the reaction was complete, the diatomaceous earth was filtered, and the filtrate was extracted with water (30 mL) and ethyl acetate (50 mL × 2 times). The extract was concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 865 mg of a pale yellow oily liquid (R)-3-((S)-3-(3-(benzylamino)phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.05 min, [M+H] = 481.33.

[0109] Step B: Synthesis of (R)-3-((S)-3-(3-aminophenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0110]

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

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

[0113]

[0114] (R)-3-((S)-3-(3-aminophenyl)-1-(tert-butoxy)-1-oxopropyl-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 mixture of tetrahydrofuran (4 mL) and water (1 mL). Phenyl chloroformate (37 mg, 1.2 mmol) was slowly added under ice bath conditions, and the reaction was carried out at room temperature 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). The extract was concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2) to give 82 mg of (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-((phenoxycarbonyl)amino)phenyl)propyl-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-butyl3,3'-((2S,2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)carbamoyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-propane-1,2-

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

[0117]

[0118] (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-((phenoxycarbonyl)amino)phenyl)prop-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)-di(pyrrolidine-1-carboxylic acid ester) (80 mg, 0.1 mmol), and triethylamine (10 mg, 0.1 mmol) were dissolved in dimethyl sulfoxide (5 mL) at room temperature and reacted for 8 hours at room temperature. After the reaction was complete, water (5 mL) was added to quench the reaction, followed by extraction with ethyl acetate (20 mL × 2 times), and concentration to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10) to give 191 mg of di-tert-butyl 3,3'-((2S, 2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenyl)carbamoyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-propane-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)-pyrrolidine-3-yl)ethyl)phenyl)carbamoyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidine-3-acyl)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)pyrrolidine-3-yl)-3-oxopropyl)phenyl)carbamoyl)nidiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-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 yield 13 mg of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)carbamoyl)azadiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidine-3-yl)propionic acid) and 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)-pyrrolidine-3-yl)ethyl)phenyl)acetyl)azadiyl)bis(methylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid)

[0124]

[0125] The specific synthesis route is as follows:

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

[0127]

[0128] At room temperature, tert-butyl pyrrolidine-1-carboxylate (100 mg, 0.24 mmol), tert-butanol (5 mL), and water (2 mL) were added sequentially. The mixture was cooled with ice water, and then 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 sequentially. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 18 hours.

[0129] After the reaction was complete, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2 times), washed with saturated brine (10 mL), dried over sodium sulfate, and concentrated to dryness to give 110 mg of 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)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)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetyl)azadiyl)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, 202 mg (0.25 mmol) of 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)-2-((R)-1-(tert-butoxy)-2-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxy)-2-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxy)-2-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxy)-2-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxy)-2-((S)-3-(tert-butoxy)-2-((R)-3-(tert-butoxy)-2-((R)-3-(T-butoxy)-2 ... 110 mg (0.25 mmol) pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetic acid, N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (98 mg, 0.76 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (145 mg, 0.38 mmol), reacted at room temperature for 3 h.

[0133] After the reaction was completed, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2 times), washed with saturated brine (10 mL), dried over sodium sulfate, concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to give 60 mg of 3,3'-((2S,2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetyl)azadiyl)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)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis((2-(R)pyrrolidine-3-ylpropionic acid)

[0135]

[0136] Add 3,3'-((2S,2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetyl)azadiyl)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) at room temperature, and react 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)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis((2-(R)pyrrolidine-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)-pyrrolidine-3-yl)ethyl)-2-fluorobenzyl)(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid

[0140]

[0141] The specific synthesis 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)pyrrolidine-3-yl)--3-oxopropyl)benzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetamyl)methyl)-4-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate

[0143]

[0144] At room temperature, 188 mg (0.23 mmol) of tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)amino)methyl)-4-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate was added. -2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-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)hexafluorophosphate urea (133 mg, 0.35 mmol), reacted at room temperature for 3 h.

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

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

[0147]

[0148] At room temperature, tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)--3-oxopropyl)benzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetamyl)methyl)-4-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (152 mg, 0.12 mmol), dioxane (2.5 mL), and concentrated hydrochloric acid (0.5 mL) were added, and the reaction was carried out at 45 °C for 4 hours.

[0149] After the reaction was completed, the mixture was concentrated to dryness. The residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain 53 mg of (S)-3-(3-(2-((5-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-2-fluorobenzyl)(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic 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)-pyrrolidine-3-yl)ethyl)-4-fluorobenzyl)(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid

[0152]

[0153] The specific synthesis 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)pyrrolidine-3-yl)--3-oxopropyl)benzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetamyl)methyl)-4-fluorophenyl)-1-oxopropyl-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)pyrrolidine-3-yl)-3-oxopropyl)benzyl)amino)methyl)-2-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (130 mg, 0.16 mmol), 2-(3-((S)-3-(tert-butoxy) 2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-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)hexafluorophosphate urea (93 mg, 0.25 mmol), reacted at room temperature for 3 hours.

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

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

[0159]

[0160] At room temperature, tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)--3-oxopropyl)benzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetamoxy)methyl)-4-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (110 mg, 0.09 mmol), dioxane (2.5 mL), and concentrated hydrochloric acid (0.5 mL) were added, and the reaction was carried out at 45 °C for 4 hours.

[0161] After the reaction was completed, the mixture 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)-pyrrolidine-3-yl)ethyl)-4-fluorobenzyl)(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic 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)-pyrrolidine-3-yl)ethyl)-2-fluorobenzyl)(3-(S)2-carboxy-2-(R)pyrrolidine-3-alkyl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid

[0164]

[0165] The specific synthesis 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)pyrrolidine-3-yl)-3-oxopropyl)-2-fluorobenzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)phenyl)-1-oxopropyl-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)pyrrolidine-3-yl)-3-oxopropyl)-2-fluorobenzyl)amino)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (150 mg, 0.18 mmol), 2-(3-((S)-3-(tert-butoxy) 2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-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)hexafluorophosphate urea (103 mg, 0.27 mmol), reacted at room temperature for 3 hours.

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

[0170]

[0171] At room temperature, tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2-fluorobenzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (140 mg, 0.11 mmol), dioxane (2.5 mL), and concentrated hydrochloric acid (0.5 mL) were added, and the reaction was carried out 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 (HPLC) to obtain 52 mg of (S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-2-fluorobenzyl)(3-(S)2-carboxy-2-(R)pyrrolidine-3-alkyl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic 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)-pyrrolidine-3-yl)ethyl)-4-fluorophenyl)acetyl)azadiyl)bis(methylene)bis(3,1-phenylene))bis(2-((((R)-pyrrolyl-3-yl)propionic acid)

[0175]

[0176] The specific synthesis route is as follows:

[0177] Step A: 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-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-oxopropyl-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-tetramethylpiperidine oxide (43 mg, 0.27 mmol), and iodobenzene acetate (1.77 g, 5.50 mmol) were added sequentially, and the reaction was carried out at room temperature for 3 hours.

[0180] After the reaction was complete, the mixture was diluted with water (20 mL), quenched with sodium sulfite, and extracted with ethyl acetate (30 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 / 3) to give 530 mg of 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-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)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorophenyl)acetyl)nidiyl)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, 167 mg (0.21 mmol) of 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) (2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxy)) was added. Carbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorophenyl)acetic acid (95 mg, 0.21 mmol), N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (41 mg, 0.32 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (122 mg, 0.32 mmol), reacted at room temperature for 3 hours.

[0184] After the reaction was completed, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2 times), washed with saturated brine (10 mL), dried over sodium sulfate, concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to give 150 mg of 3,3'-((2S,2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorophenyl)acetyl)nidi)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)-pyrrolidine-3-yl)ethyl)-4-fluorophenyl)acetyl)azadiyl)bis(methylene)bis(3,1-phenylene))bis(2-((((R)-pyrrolyl-3-yl)propionic acid)

[0186]

[0187] 3,3'-((2S,2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorophenyl)acetyl)nidiyl)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 the reaction was carried out at 45 °C for 4 hours.

[0188] After the reaction was completed, the mixture 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)-pyrrolidine-3-yl)ethyl)-4-fluorophenyl)acetyl)azadiyl)bis(methylene)bis(3,1-phenylene))bis(2-((((R)-pyrrolyl-3-yl)propionic 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)-pyrrolidine-3-yl)ethyl)-4-fluorobenzyl)(3-(S)2-carboxy-2-(R)pyrrolidine-3-ylethyl)benzyl)amino)-2-oxoethyl)-2-fluorophenyl)-2-((R)-pyrrolyl-3-yl)propionic acid

[0191] The specific synthesis 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)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorobenzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorophenyl)acetamido)methyl)phenyl)-1-oxopropyl-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)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorobenzyl)amino)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (179 mg, 0.22 mmol), 2-(3-((S)-3-(tert-butoxy)-2 -((R)-1-(tert-butoxycarbonyl)pyrrolidine-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)hexafluorophosphate urea (125 mg, 0.33 mmol), reacted at room temperature for 3 h.

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

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

[0198]

[0199] At room temperature, add tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorobenzyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorophenyl)acetamimide)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (200 mg, 0.16 mmol), dioxane (2.5 mL), and concentrated hydrochloric acid (0.5 mL), and react at 45 °C for 4 hours.

[0200] After the reaction was completed, the mixture 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)-pyrrolidine-3-yl)ethyl)-4-fluorobenzyl)(3-(S)2-carboxy-2-(R)pyrrolidine-3-ylethyl)benzyl)amino)-2-oxoethyl)-2-fluorophenyl)-2-((R)-pyrrolyl-3-yl)propionic 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)-pyrrolidine-3-yl)ethyl)-4-chlorobenzyl)(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid

[0203]

[0204] The specific synthesis route is as follows:

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

[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 and reacted 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 complete, 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), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 360 ​​mg of (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-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-butoxycarbonylpyrrolidine-3-yl)-3-oxopropyl)-4-chlorobenzyl)-2-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0209]

[0210] 100 mg (0.23 mmol) of (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-chlorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (2-(3-(S)-3-tert-butoxy-2-(R)- ...(S)-3-tert-butoxy-2-(R)-3-(S)-3- 1-tert-Butoxycarbonylpyrrolidine-3-yl)-3-oxopropyl)phenyl)acetic acid (150 mg, 0.23 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea 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 overnight at room temperature. After the reaction was completed, 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 with anhydrous sodium sulfate. After reduced evaporation, the crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 170 mg of (R)-3-(S)-1-tert-butoxy-3-(3-(N-(3-(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)-3-oxopropyl)-4-chlorobenzyl)-2-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

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

[0212]

[0213] (R)-3-(S)-1-tert-butoxy-3-(3-(N-(3-(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)-3-oxopropyl)-4-chlorobenzyl)-2-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetamido)methyl)phenyl)-1-oxopropane-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 overnight at 45 °C. After the reaction was complete, the solvent was removed under reduced pressure, and the crude product was purified by preparative high-performance liquid chromatography (HPLC) to obtain 53.5 mg of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-4-chlorobenzyl)(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic 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)-pyrrolidine-3-yl)ethyl)phenyl)acetyl)azadiyl)bis(methylene)bis(2,1-phenylene))bis(2-(((R)-pyrrolyl-3-yl)propionic acid)

[0216]

[0217] The specific synthesis route is as follows:

[0218] Step A: 3,3'-((2S, 2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetyl)azadiyl)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-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (98 mg, 0.12 mmol), 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxy) The reaction mixture consisted of pyrrolidone-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), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (72 mg, 0.19 mmol), reacted at room temperature for 3 hours.

[0221] After the reaction was completed, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2 times), washed with saturated brine (10 mL), dried over sodium sulfate, concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to give 20 mg of foamy solid 3,3'-((2S, 2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetyl)azadiyl)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)-pyrrolidine-3-yl)ethyl)phenyl)acetyl)azadiyl)bis(methylene)bis(2,1-phenylene))bis(2-(((R)-pyrrolyl-3-yl)propionic acid)

[0223]

[0224] 3,3'-((2S,2'S)-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetyl)azadiyl)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 reaction was carried out at 45 °C for 4 hours.

[0225] After the reaction was completed, the mixture 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)-pyrrolidine-3-yl)ethyl)phenyl)acetyl)azadiyl)bis(methylene)bis(2,1-phenylene))bis(2-(((R)-pyrrolyl-3-yl)propionic acid). LCMS: RT = 1.47 min, [MH] - =737.47.

[0226] Example 11

[0227] Synthesis of (S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)(2-(S)2-carboxy-2-(R)pyrrolidine-3-ylethyl)phenethyl)amino)-2-oxoethyl)phenyl)-2-((right)-pyrrolyl-3-yl)propionic acid

[0228]

[0229] The specific synthesis 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)pyrrolidine-3-yl)-3-oxopropyl)benzyl)-2-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)acetamyl)ethyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate

[0231]

[0232] At room temperature, 100 mg (0.12 mmol) of tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(2-(((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)amino)ethyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate was added. -2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-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)hexafluorophosphate urea (72 mg, 0.19 mmol), reacted at room temperature for 3 h.

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

[0234] Step B: (S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)(2-(S)2-carboxy-2-(R)pyrrolidine-3-ylethyl)phenethyl)amino)-2-oxoethyl)phenyl)-2-((right)-pyrrolyl-3-yl)propionic acid

[0235]

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

[0237] After the reaction was completed, the mixture 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)-pyrrolidine-3-yl)ethyl)benzyl)(2-(S)2-carboxy-2-(R)pyrrolidine-3-ylethyl)phenethyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolyl-3-yl)propionic acid. LCMS: RT = 1.55 min, [MH] - =751.48.

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

[0239] Experimental steps

[0240] The ability of the compound to inhibit Lp(a) particle formation in vitro was evaluated using a cell-free assembly assay. Conditioned medium (supplemented with 10% FBS, 20 mM HEPES, and 1× penicillin / streptomycin in DMEM) was collected from confluent wild-type HepG2 cells (the source of endogenously expressed ApoB) and from a stable HEK293 cell line expressing human Apo(a) protein with 17 Kringle repeats (selected on 1 μg / ml puromycin) after 96 h of incubation at 37 °C and 5% CO2. In vitro assembly assays were performed by combining equal fractions of HepG2 and HEK293 conditioned medium with the test compound (final concentration 0.03–1000 nM) added in a dilution series. The assay was terminated by incubation at 37 °C for 2 h with the addition of 6-aminoacetic acid (EACA) to a final concentration of 150 mM. Lp(a) was detected using a sandwich ELISA with anti-Apo(a) capture antibody (ab242565) and HRP-conjugated anti-ApoB detection antibody (ab27622). The ELISA was performed using TMB colorimetry, terminated with 1N sulfuric acid, and read at 450 nm on an Envision 2104 plate reader. The percentage inhibition of Lp(a) formed under each test condition was determined by setting the assembly reaction without inhibitors as 0% inhibition and the assembly reaction with minimal HepG2 conditioned medium (50-fold dilution) as 100% inhibition. Data were fitted to a 4-parameter curve to determine IC50. 90 The values ​​are shown in Table 1.

[0241] Table 1 IC50 of acyl compounds 90 value

[0242]

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

[0244] Example 13

[0245] Pharmacokinetics of SD Rats

[0246] (1) Experimental materials

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

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

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

[0250] (2) Experimental methods

[0251] The compound was dissolved in physiological saline. After oral administration to rats, 200 μL of venous blood was collected at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h (an additional 5 min for the IV group) into EDTA-K2 anticoagulant EP tubes. The tubes were centrifuged at 12000 rpm for 2 min, and the plasma was stored at -80℃ for later analysis. A precise amount of the test sample was dissolved in ultrapure water to a concentration of 2 mg / mL to prepare a stock solution. An appropriate amount of the stock solution was accurately pipetted and diluted with 50% acetonitrile-water to prepare a series of standard solutions. 10 μL of each of the above standard solutions was accurately pipetted and added to 90 μL of blank plasma. The mixture was vortexed to prepare plasma samples with concentrations equivalent to 1, 3, 5, 10, 30, 100, 300, 1000, and 3000 ng / mL. Quality control sample concentrations were 9, 240, and 2400 ng / mL. Two-sample analysis was performed for each concentration to establish a standard curve. Take 30 μL of plasma (diluted 5-fold at 5 min, 15 min, and 30 min after intravenous administration), add 200 μL of 5% trichloroacetic acid-water solution containing propranolol (50 ng / mL) as internal standard, vortex to mix, centrifuge at 4000 rpm for 10 min, collect the supernatant, add 150 μL of purified water, vortex again to mix, and perform LC-MS / MS analysis. The LC-MS / MS detection conditions are as follows:

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

[0253] Mobile phase: water (0.1% formic acid) - acetonitrile. Gradient elution is performed according to the table below.

[0254] Table 2 Gradient Elution Table

[0255] 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 detecting blood drug concentrations by LC-MS / MS, pharmacokinetic parameters were calculated using 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 this invention in SD rats

[0259]

[0260] As can be seen from the results in Table 3, the compounds of the present invention have higher exposure levels. Furthermore, the exposure levels of compounds 3-8 are significantly better than those of compound 2 in Example 2. This indicates that when Z in general formulas I-IIIa / IIIb is selected from -CH2-, the exposure level is better than that of compounds 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. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims of the present invention.

Claims

1. An acyl compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, The structure of the acyl compound is shown in general formula I: ； Wherein, Y is selected from -N-; Z is selected from -CH2-; 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, or ; And one of X4 or X5 is selected from -CR1, and R1 is selected from... The X9 or X 10 One of them is selected from -CR1, wherein R1 is selected from... The X 11 or X 12 One of them is selected from -CR1, wherein R1 is selected from... ; The R2 is selected from -H, halogen, substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C1-C6 alkoxy; The substituted C1-C6 alkyl group and the substituted C1-C6 alkoxy group are independently selected from: halogen, hydroxyl, carboxyl, nitro, cyano, C1-C6 alkyl, C 1- C6 haloalkyl, C 1- C6 haloalkoxy group, C 1- One or more of the C6 alkoxy groups; m, n, or r are integers independently selected from 1, 2, or 3.

2. The acyl compound, its stereoisomer, or its pharmaceutically usable salt according to claim 1, characterized in that, The structures of acyl compounds are shown in general formula IIa or IIb: or , Wherein, Y is selected from -N-; Z is selected from -CH2-; The 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 X 11 or X 12 One of them is selected from -CR1, wherein R1 is selected from... The R2 is selected from H, substituted or unsubstituted C1-C6 alkyl groups; the substituents in the substituted C1-C6 alkyl groups and substituted C1-C6 alkoxy groups are independently selected from halogens, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, C1-C6 alkyl groups, C... 1- C6 haloalkyl, C 1- C6 haloalkoxy group, C 1- One or more of the C6 alkoxy groups; The m, n, p, q, or r are independently selected from integers of 1, 2, or 3.

3. The acyl compound, its stereoisomer, or its pharmaceutically usable salt according to claim 1, characterized in that, The structures of the acyl compounds are shown as general formula IIIa or IIIb: or , Wherein, Y is selected from -N-; Z is selected from -CH2-; The 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 X 11 or X 12 One of them is selected from -CR1, wherein R1 is selected from... The R2 is selected from H, substituted or unsubstituted C1-C6 alkyl groups; the substituents in the substituted C1-C6 alkyl groups and substituted C1-C6 alkoxy groups are independently selected from halogens, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, C1-C6 alkyl groups, C... 1- C6 haloalkyl, C 1- C6 haloalkoxy group, C 1- One or more of the C6 alkoxy groups; The m, n, p, q, or r are independently selected from integers of 1, 2, or 3.

4. The acyl compound, its stereoisomer, or its pharmaceutically usable salt according to claim 1, characterized in that, R1 is selected from H, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, -CH2COOH, -CH2CH2COOH, -CH2CH(CH3)COOH or .

5. The acyl compound, its stereoisomer, or its pharmaceutically usable salt according to claim 4, characterized in that, The Selected from: .

6. The acyl compound, its stereoisomer, or its pharmaceutically usable salt according to claim 5, characterized in that, The Selected from: 。 7. An acyl compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, The chemical structures of the acyl compounds are selected from: 。 8. An acyl compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, The chemical structures of the acyl compounds are selected from: 。 9. A pharmaceutical composition, characterized in that, It comprises an acyl compound as described in any one of claims 1-8, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients and / or carriers.

10. Use of the acyl compound of any one of claims 1-8, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9 in the preparation of a medicament for the prevention or treatment of diseases related to Lp(a).

11. The use according to claim 10, characterized in that, The Lp(a)-related diseases are selected from cardiovascular diseases.

12. The use according to claim 11, characterized in that, The cardiovascular diseases mentioned are selected from stroke, atherosclerosis, thrombosis, coronary heart disease, or aortic stenosis.

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