A sulfonamide compound, a preparation method and medical use thereof

Abstract

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

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, and provides a sulfonamide 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 a sulfonamide compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that the structure of the sulfonamide compound is shown in general formula I: ,

[0007] Among them, X1~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 ; The X1~X 15 At least one of them is -N-; Or when X1~X 15 When each of the X1 to X5 is independently selected from -CR1, at least one of the R1s is not hydrogen, and at least one of the R1s is independently selected from... And the X6~X 10 At least one R1 is independently selected ; Or when X1~X 15 When each is independently selected from -CR1, the X1~X 15 Any two adjacent R1 atoms and the attached carbon atom together form a substituted or unsubstituted C6-C bond. 10 Aryl or 5-10 heteroaryl groups; 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). q -(5-8 membered heterocyclic group); 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 heteroaryl groups are independently selected from halogens, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 haloalkoxy groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, 3- to 6-membered heterocyclic alkyl groups, C3-C6 cycloalkoxy groups, C6-C 10 One or more of aryl or 5-10 heteroaryl groups; n, p, r are independently selected from integers of 1, 2, or 3, and m, q are selected from integers of 0, 1, 2, or 3.

[0008] As a preferred embodiment of the present invention, 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; the 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 heteroaryl groups are independently selected from halogens, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 haloalkoxy groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, 3- to 6-membered heterocyclic alkyl groups, C3-C6 cycloalkoxy groups, C6-C 10 One or more of aryl or 5-10 heteroaryl groups.

[0009] As a preferred technical solution of the present invention, the Selected from quinolinyl; the Further preferred options are: ;

[0010] 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 .

[0011] 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.

[0012] As a preferred embodiment of the present invention, the structure of the sulfonamide compound is shown in general formula II or III: or , Among them, X 1~ X 15Each 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 and substituted C1-C6 alkoxy groups are independently selected from halogens, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 haloalkoxy groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic alkyl groups, C3-C6 cycloalkoxy groups, C6-C 10 One or more of aryl or 5-10 heteroaryl groups.

[0013] As a preferred embodiment of the present invention, the structure of the sulfonamide compound is shown in general formula IV or V: or ,

[0014] Among them, X 1~ 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 and substituted C1-C6 alkoxy groups are independently selected from halogens, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 haloalkoxy groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic alkyl groups, C3-C6 cycloalkoxy groups, C6-C 10 One or more of aryl or 5-10 heteroaryl groups.

[0015] As a preferred technical solution of the present invention, the X 11 X 12 X 13 X 14 or X 15 Each of them is independently selected from -CR1, wherein R1 is selected from Preferably, R1 is selected from... Any one of them.

[0016] 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. , or R3 is selected from pyrrolidinyl, piperidinyl, piperazine, morpholinyl, pyridinyl, pyrimidinyl, or pyrazine.

[0017] As a preferred technical solution of the present invention, the Selected from: , , , , , , , , , or .

[0018] As a preferred technical solution of the present invention, the Selected from: .

[0019] As a preferred technical solution of the present invention, the Selected from: .

[0020] In the chemical structure of the compound described in this invention, the bond " "" indicates that the configuration is not specified, meaning that if a chiral isomer exists in the chemical structure, the bond " "can be " "or" , or colleagues containing " "and" Two configurations;

[0021] In the chemical structure of the compounds described in this disclosure, the bond " "No configuration is specified, meaning it can be Z configuration or E configuration, or both configurations can be included simultaneously;"

[0022] 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.

[0023]

[0024] 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.

[0025] As a preferred embodiment of the present invention, the C1-C6 alkyl group is preferably C1-C2, C1-C3, C1-C4, or C1-C5 alkyl group; examples of the alkyl group 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, and 1-ethylbutyl.

[0026] As a preferred embodiment of the present invention, the C1-C6 alkoxy group is preferably C1-C2, C1-C3, C1-C4 or C1-C5 alkoxy group. Further, the alkoxy group is specifically selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0027] As a preferred technical solution of the present invention, the C3-C 10 The cycloalkyl group is preferably selected from C3-C8 cycloalkyl, C3-C6 cycloalkyl or C3-C5 cycloalkyl, with C3-C8 cycloalkyl being the most preferred. Specifically, the cycloalkyl group is 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] The substituted or unsubstituted 5-10-membered heteroaryl groups are preferably substituted or unsubstituted 5-8-membered heteroaryl groups, substituted or unsubstituted 5-7-membered heteroaryl groups, or substituted or unsubstituted 5-6-membered heteroaryl groups; 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, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and pyrazine. Pyrazolyl, isoxazolyl, thiazolyl, pyrazolyl, tetrazolyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, tetrazolyl, etc.

[0032] As a preferred embodiment of the present invention, the sulfonamide compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is selected from the compounds shown in Table 1A or Table 1B:

[0033] Table 1A

[0034]

[0035]

[0036]

[0037] Table 1B

[0038]

[0039]

[0040]

[0041] The present invention further provides a method for preparing sulfonamide compounds, or isomers thereof, racemates thereof, or pharmaceutically acceptable salts thereof, by referring to the method of patent CN114008021A and methods known in the art.

[0042] The present invention further provides a pharmaceutical composition characterized in that it comprises a sulfonamide compound of formula I, formula II, formula III, formula IV or formula V, or an isomer thereof, a racemic mixture thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and / or carriers.

[0043] The present invention further provides the use of sulfonamide compounds, or isomers thereof, or racemates thereof, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the prevention or treatment of diseases related to LP(a).

[0044] Furthermore, the Lp(a)-related diseases are selected from cardiovascular diseases;

[0045] 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.

[0046] The advantages of this invention over the prior art include, but are not limited to:

[0047] The sulfonamide compounds of this invention have a lower IC value compared to existing technologies. 90 value.

[0048] For clarity, this article defines the general terminology used in the description of compounds.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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).

[0055] "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. Alkyl groups can 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, C1-C6 alkyl, C 1- C6 alkoxy, C2-C6 alkenoxy, C2-C6 alkynoxy, C3-C6 cycloalkyl, 3- to 6-membered heterocyclic alkyl, C5-C8 cycloalkenyl, C3-C6 cycloalkoxy, 3- to 6-membered heterocyclic alkoxy, C5-C8 cycloalkenoxy, C6-C 10 aryl or 5- to 6-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenoxy, C2-C6 alkynoxy, C3-C6 cycloalkyl, 3- to 6-membered heterocyclic alkyl, C5-C8 cycloalkenyl, C3-C6 cycloalkoxy, 3- to 6-membered heterocyclic alkoxy, C5-C8 cycloalkenoxy, C6-C 10The 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.

[0056] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0057] 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.

[0058] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0059] 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.

[0060] 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.

[0061] 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. The heteroaryl is preferably a 5- to 10-membered or 5- to 8-membered heteroaryl, and more preferably a 5-membered or 6-membered heteroaryl. Pyrrole, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azazolyl, diazazolyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothiophene, indolyl, isindolyl, isobenzofuranyl, benzoimidazolyl, benzooxazolyl, benzoisooxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxolinyl. Specific heteroaryl groups include pyrrolyl, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, isoxazolyl, and isothiazolyl. More specific heteroaryl groups include imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, 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.

[0062] 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 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 5-8 membered 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.

[0063] 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.

[0064] 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, 18 F, 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.

[0065] The term "halogenated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogens, such as trifluoromethyl, trifluoroethyl, etc.

[0066] The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogens, such as trifluoromethyloxy and trifluoroethyloxy.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] The term "excipient" generally refers to the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0072] 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.

[0073] 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.

[0074] "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

[0075] 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.

[0076] Example 1

[0077] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid)

[0078] The specific synthesis route is as follows:

[0079] Step A: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0080] At room temperature, (R)-3-(S)-3-(3-bromophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.44 mmol) was dissolved in anhydrous THF (3 mL) under nitrogen protection and stirred at -40 °C. Then, isopropyl magnesium chloride and lithium chloride liquid (1.1 mL, 2.5 mol / L) were added and reacted for two hours. Then, sulfonyl chloride (101 mg, 0.53 mmol) was added, and the mixture was slowly heated to room temperature and stirred for another 14 hours. After TLC detection, the reaction was complete. Quenching was performed at ℃ with 10 mL of ammonium chloride aqueous solution, followed by extraction with EA (20 mL × 3 times). The collected organic phase was dried over colorless sodium sulfate, subjected to reduced evaporation, and the crude product was subjected to column chromatography with hexane:ethyl acetate = 3:1 to give 113 mg of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.17 min, [M+H] + = 474.17.

[0081] Step B: Synthesis of 3,3'-((2S,2'S)-di-tert-butyl(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azadiyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester)

[0082] At room temperature, (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (55 mg, 0.12 mmol) was dissolved in acetonitrile (2.5 mL) and stirred. Then, di-tert-butyl 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) (101 mg, 0.13 mmol), 4-dimethylaminopyridine (4.0 mg, 0.036 mmol), and triethylamine (15.4 mg, 0.15 mmol) were added. After stirring at 80℃ for 14 hours, the reaction was detected by TLC. Once the reactants had reacted completely, the reaction was stopped. Water (6 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3 times). The collected organic phase was dried with colorless sodium sulfate and evaporated by distillation to obtain the crude product. The crude product was then subjected to column chromatography with hexane:ethyl acetate = 3:1 to obtain 100 mg of 3,3'-((2S,2'S)-di-tert-butyl(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azadiyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester).

[0083] Step C: Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid)

[0084] 3,3'-((2S,2'S)-di-tert-butyl(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azadiyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) (100 mg, 0.081 mmol) was dissolved in 1,4-dioxane (3.0 mL), and concentrated hydrochloric acid (1.0 mL) was added. The reaction was carried out at room temperature for 10 hours. The reaction was monitored by LCMS until it was complete. The target product was concentrated under reduced pressure to obtain a crude product, which was then purified by preparative high-performance liquid chromatography (HPLC) to yield 5.2 mg of (S)-3-(3-((3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)(3-fluoro-5-methoxybenzyl)amino)methyl)phenyl)-2-(pyridin-3-yl)propionic acid. LCMS: RT = 1.49 min, [MH] -= 759.43, HPLC: 90.22%.

[0085] Example 2

[0086] Synthesis of (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)azadiyl)bis(methylene)bis(6-fluoro-3,1-phenylene))bis(2-((((R)-pyrrolyl-3-yl)propionic acid))

[0087] The specific synthesis route is as follows:

[0088] Step A: Synthesis 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)-4-fluorobenzyl)amino)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate

[0089] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-5-carboxyphenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (200 mg, 0.47 mmol), tert-butyl (R)-3-((S)-3-(3-(aminomethyl)phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (192 mg, 0.47 mmol), and anhydrous isopropanol (5 mL) were added sequentially. The mixture was heated to 45 °C, and then sodium triacetoxyborohydride (201 mg, 0.94 mmol) was added in three batches. The mixture was reacted at 45 °C for 18 hours.

[0090] After the reaction was complete, 10 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. Extraction was performed with ethyl acetate (20 mL × 2 times), and the mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1) to give 210 mg 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)-4-fluorobenzyl)amino)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.03 min, [M+H] + =810.08.

[0091] Step B: 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)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorobenzyl)phenyl)sulfonylamino)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester

[0092] 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 (172 mg, 0.21 mmol), (R)-3-((S)-1-(tert-butoxy)-3-(3-(chlorosulfonyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate tert-butyl ester (100 mg, 0.2 mmol), acetonitrile (3 mL), triethylamine (32 mg, 0.32 mmol), and 4-dimethylaminopyridine (9 mg, 0.07 mmol) were added, the mixture was purged with nitrogen, and the temperature was raised to 80 °C for 2 hours.

[0093] After the reaction is complete, add tap water (10 ml) and ethyl acetate (10 ml) for extraction, concentrate to dryness to obtain crude product, which can be used directly in the next step.

[0094] Step C: (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)azadiyl)bis(methylene)bis(6-fluoro-3,1-phenylene))bis(2-((((R)-pyrrolyl-3-yl)propionic acid))

[0095] Add the crude product from the previous step, dioxane (2.5 mL), and concentrated hydrochloric acid (0.5 mL) at room temperature, and react at 45°C for 18 hours.

[0096] After the reaction was completed, the mixture was concentrated to dryness, and the residue was purified by preparative high-performance liquid chromatography to obtain 18 mg of (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)azadiyl)bis(methylene)bis(6-fluoro-3,1-phenylene))bis(2-((((R)-pyrrolyl-3-yl)propionic acid). LCMS: RT = 1.58 min, [MH] - =777.30.

[0097] Example 3

[0098] Synthesis of (S)-3-(3-(((3-(S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-N-(2-((S)2-carboxy-2-(R)pyrrolidine-3-ylethyl)phenethyl)phenyl)sulfonamido)methyl)phenyl)-2-((R)-pyrrolyl-3-yl)propionic acid

[0099] The specific synthesis route is as follows:

[0100] The compound was prepared according to the method used for compound 2. LCMS: RT = 1.45 min, [MH] - = 773.31.

[0101] Example 4

[0102] Synthesis of (S)-3-(3-(N-(5-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2-fluorobenzyl)-N-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid (Compound 4)

[0103] The compound was prepared according to the method used for compound 2. LCMS: RT = 1.52 min, [M+H] + 779.16 (m, 2H), 6.93 (d, J = 7.6 Hz, 1H),6.84 - 6.78 (m, 3H), 4.31 (s, 4H), 3.51 - 3.28 (m, 6H), 3.21 - 3.12 (m, 3H),2.98 - 2.73 (m, 6H), 2.72 - 2.24 (m, 9H), 2.10 - 2.03 (m, 3H), 1.74 - 1.61 (m, 3H).

[0104] Example 5

[0105] Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-ethyl)-2-fluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid (Compound 5)

[0106] The compound was prepared according to the method used for compound 2. LCMS: RT = 1.51 min, [M+H] + = 779.21.

[0107] Example 6

[0108] Synthesis of (2S,2'S)-3,3'(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-4-fluorophenylsulfonyl)azadiyl)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid)

[0109] The specific synthesis route is as follows:

[0110] Step A: Synthesis of (R)-3-(S)-3-(5-(benzylthio)-2-fluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0111] At room temperature, (R)-3-(S)-3-(5-bromo-2-fluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.0 g, 4.23 mmol), benzyl mercaptan (630 mg, 5.08 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (245 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (194 mg, 0.21 mmol) and N,N-diisopropylethylamine (1.1 g, 8.46 mmol) were dissolved in dioxane (40 mL) and reacted at 100 °C for 5 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to give 2.0 g of (R)-3-(S)-3-(5-(benzylthio)-2-fluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.52 min, [M+H-Boc] + = 416.13.

[0112] Step B: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(5-chlorosulfonyl)-2-fluorophenyl-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0113] Dissolve (R)-3-(S)-3-(5-(benzylthio)-2-fluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 1.94 mmol) in acetic acid / water / acetonitrile (1.1 / 0.7 / 30 mL), and add dropwise a solution (2 mL) of 1,3-dichloro-5,5-dimethylhydantoin (760 mg, 3.88 mmol) in acetonitrile under ice bath conditions. Stir until the solution turns red. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate (30 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 / 4) to give 0.8 g of (R)-3-(S)-1-tert-butoxy-3-(5-chlorosulfonyl)-2-fluorophenyl-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.29 min, [M+H-Boc-tert-butyl] + = 336.01.

[0114] Steps C and D were prepared according to the method for compound 2. LCMS: RT = 1.52 min, [M+H] + =779.16. 1 H NMR (400 MHz, D2O) δ 7.66 (t, J = 6.8 Hz, 1H), 7.62 (d, J = 7.2 Hz,1H), 7.26 (t, J = 9.2 Hz, 1H), 7.13 (t, J = 7.2 Hz, 2H), 7.05 (d, J = 7.2 Hz,2H), 6.88 (d, J = 7.6 Hz, 2H), 6.79 (s, 2H), 4.26 (q, 4H) , 3.53 - 3.47 (m,3H), 3.40 - 3.34 (m, 3H), 3.27 - 3.12 (m, 3H), 3.11 - 2.84 (m, 6H), 2.78 -2.36 (m, 9H), 2.14 - 2.09 (m, 3H), 1.77 - 1.64 (m, 3H).

[0115] Example 7

[0116] Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-5-fluorophenylsulfonyl)azadiyl)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) (Compound 7)

[0117] The compound was prepared according to the method for compound 2. LCMS: RT = 1.51 min, [M+H]+ = 779.21.

[0118] Example 8

[0119] Synthesis of (2S,2'S)-3,3'(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2-fluorophenylsulfonyl)azadiyl)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid)

[0120] The specific synthesis route is as follows:

[0121] Step A: Synthesis of 3,3'-((2S,2'S)-(azadiylbismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester)

[0122] At room temperature, (R)-3-(S)-3-(3-aminomethyl)phenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.74 mmol) and (R)-3-(S)-1-tert-butoxy-3-(3-formylphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.74 mmol) were dissolved in DCE (6 mL), and sodium triacetoxyborohydride (551 mg, 2.6 mmol) was added in portions. The mixture was heated to 45°C and stirred for 16 hours.

[0123] The reaction was monitored by TLC until complete, and then quenched by adding 1 mL of aqueous solution. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). 450 mg of 3,3'-((2S,2'S)-(azadiylbismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) was obtained. LC-MS: RT = 2.02 min, [M+H] + =792.61.

[0124] Step B: Synthesis of 3,3'-(((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2-fluorophenyl)sulfonyl)azadiyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester)

[0125] At room temperature, 3,3'-((2S,2'S)-(azadiylbismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (200 mg, 0.25 mmol) was dissolved in pyridine (4 mL), and a solution of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)-2-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylate tert-butyl ester (149 mg, 0.30 mmol) in acetonitrile (2 mL) was slowly added, and the reaction was carried out at room temperature for 0.5 h.

[0126] After the reaction was detected by TLC, the mixture was extracted with ethyl acetate (10 mL × 2 times). The combined organic phases were washed with saturated brine (5 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 60 mg of 3,3'-(((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2-fluorophenyl)sulfonyl)azadiyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester).

[0127] Step C: Synthesis of (2S,2'S)-3,3'(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2-fluorophenylsulfonyl)azadiyl)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid)

[0128] At room temperature, 60 mg (0.05 mmol) of 3,3'-(((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2-fluorophenyl)sulfonyl)azadiyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) was dissolved in 2 mL of 1,4-dioxane solution, and concentrated hydrochloric acid (0.1 mL) was added. The mixture was heated to 45°C and reacted for 4 hours.

[0129] The reaction was monitored by LC-MS until complete, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain 16 mg of (2S,2'S)-3,3'-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2-fluorophenylsulfonyl)azadiyl)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid. LC-MS: RT = 1.51 min, [MH] - =777.1.

[0130] Example 9

[0131] Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(6-fluoro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-ylpropionic acid)

[0132] The specific synthesis route is as follows:

[0133] Step A: Synthesis of 3,3'-((2S, 2'S)-(azadiylbismethylene)bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R, 3'R)-bis(pyrrolidine-1-carboxylic acid tert-butyl ester)

[0134] At room temperature, (R)-3-(S)-1-tert-butoxy-3-(2-fluoro-5-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (350 mg, 0.83 mmol) and (R)-3-(S)-3-(5-aminomethyl)-2-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (420 mg, 1.00 mmol) were dissolved in dry 1,2-dichloroethane (5 mL), and the mixture was heated to 45 °C and reacted for 3 hours. Subsequently, sodium triacetoxyborohydride (528 mg, 2.49 mmol) was added in portions, and the mixture was reacted at 45 °C. The reaction was carried out at ℃ for 4 hours. After the reaction, 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 350 mg of 3,3'-((2S,2'S)-(azadiylbis(methylene))bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester). LCMS: RT = 2.11 min, [M+H] + = 828.29.

[0135] Step B: Synthesis of 3,3'-(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azadiyl)bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R, 3'R)-bis(pyrrolidine-1-carboxylic acid tert-butyl ester)

[0136] At room temperature, 3,3'-((2S, 2'S)-(azadiylbismethylene)bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R, 3'R)-bis(pyrrolidine-1-carboxylate) (170 mg, 0.20 mmol) was dissolved in pyridine (2 mL), and a solution of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropane-2-yl)pyrrolidine-1-carboxylate tert-butyl ester (116 mg, 0.25 mmol) in acetonitrile (1.2 mL) was added, and the reaction was carried out at room temperature for 18 hours. After the reaction was completed, the residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 50 mg of 3,3'-(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azadiyl)bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R, 3'R)-bis(pyrrolidine-1-carboxylic acid tert-butyl ester).

[0137] Step C: Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(6-fluoro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-ylpropionic acid)

[0138] 3,3'-(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azadiyl)bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid tert-butyl ester) (50 mg, 0.040 mmol) was dissolved in 1,4-dioxane (3.0 mL), and concentrated hydrochloric acid (0.3 mL) was added. The mixture was reacted at 45 °C for 6 hours. After the reaction was completed, the residue was concentrated under reduced pressure and purified by high performance liquid chromatography to obtain 26.2 mg of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bismethylene)bis(6-fluoro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-ylpropionic acid).

[0139] LCMS: RT = 1.53 min, [MH] - = 795.12. 1 H NMR (400 MHz, D2O) δ 7.70 -7.62 (m, 1H), 7.58 (s, 1H), 7.51 (d, J = 6.6 Hz, 2H), 6.92 - 6.80 (m, 4H), 6.77 (d, J = 7.2 Hz, 2H), 4.23 (s, 2H), 4.20 (s, 2H), 3.54 (dd, J = 11.8, 7.8Hz, 3H), 3.40 - 3.35 (m, 3H), 3.31 - 3.14 (m, 3H), 3.09 - 2.81 (m, 6H), 2.81- 2.30 (m, 9H), 2.15 - 2.08 (m, 3H), 1.77 - 1.64 (m, 3H).

[0140] Example 10

[0141] Synthesis of (S)-3-(3-(N-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-ethyl)-4-chlorobenzyl)-N-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid (Compound 10)

[0142] The compound was prepared according to the method used for compound 9. LCMS: RT = 1.54 min, [M+H] += 795.11. 1 H NMR(400 MHz, D2O) δ 7.62 (s, 1H), 7.51 (s, 1H), 7.47 (d, J = 4.8 Hz, 2H), 7.16(d, J = 8.2 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.93(d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.84 - 6.76 (m, 2H), 4.29 (s,2H), 4.23 (s, 2H), 3.53 - 3.27 (m, 6H), 3.23 - 3.06 (m, 3H), 2.98 - 2.73 (m,6H), 2.72 - 2.56 (m, 3H), 2.55 - 2.16 (m, 6H), 2.09 - 2.06 (m, 3H), 1.73 -1.59 (m, 3H).

[0143] Example 11

[0144] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolid-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis((2-(R)pyrrolid-3-ylpropionic acid)

[0145] The specific synthesis route is as follows:

[0146] Step A: (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(hydroxymethyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0147] At room temperature, (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-carboxyphenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (320 mg, 0.76 mmol) and anhydrous isopropanol (5 mL) were added, and the mixture was cooled in an ice water bath. Then, sodium borohydride (28 mg, 0.76 mmol) was added in three batches, and the mixture was reacted in an ice water bath for 1 hour.

[0148] After the reaction was complete, 10 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 2 times), washed with 10 mL of saturated sodium chloride aqueous solution (1 time), dried over sodium sulfate, and concentrated to dryness to obtain 350 mg of (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(hydroxymethyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.13 min, [M-Boc+H] + =324.17.

[0149] Step B: (R)-3-((S)-1-(tert-butoxy)-3-(3-((1,3-dioxoisoindoline-2-yl)methyl)-2-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0150] At room temperature, tert-butyl pyrrolidine-1-carboxylate (350 mg, 0.83 mmol), phthalimide (157 mg, 1.07 mmol), triphenylphosphine (434 mg, 1.65 mmol), and tetrahydrofuran (5 mL) were added sequentially, followed by the slow addition of diisopropyl azodicarbonate (333 mg, 1.65 mmol), and the reaction was carried out at room temperature for 2 hours.

[0151] After the reaction was completed, the mixture was concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to give 630 mg of (R)-3-((S)-1-(tert-butoxy)-3-(3-((1,3-dioxoisoindoline-2-yl)methyl)-2-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0152] Step C: (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(aminomethyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0153] At room temperature, (R)-3-((S)-1-(tert-butoxy)-3-(3-((1,3-dioxoisoindoline-2-yl)methyl)-2-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (630 mg, 1.14 mmol) was added, dissolved in ethanol (10 mL), and then hydrazine hydrate (80%, 178 mg, 2.84 mmol) was added. The mixture was heated to 85 °C and reacted for 3 hours.

[0154] After the reaction was complete, the white solid was removed by filtration. The filter cake was washed with ethyl acetate (20 mL × 2 times), the filtrates were combined, concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate (containing 0.5% V / V triethylamine) / n-hexane = 9 / 1) to give 264 mg of (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(aminomethyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 1.82 min, [M + H] + =423.16.

[0155] Step D: 3,3'-Di-tert-butyl((2S,2'S)-((N-dimethylbis(methylene))bis(2-fluoro-3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bispyrrolidine-1-carboxylic acid tert-butyl ester

[0156] At room temperature, (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-carboxyphenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (216 mg, 0.51 mmol), (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(aminomethyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (260 mg, 0.61 mmol), and 1,2-dichloroethane (6 mL) were added sequentially. The temperature was raised to 45 °C, and then sodium triacetoxyborohydride (326 mg, 1.54 mmol) was added in three batches. The reaction was carried out at 45 °C for 18 hours.

[0157] After the reaction was complete, 10 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. Extraction was performed with dichloromethane (10 mL × 2 times), and the mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 1) to give 405 mg of 3,3'-di-tert-butyl((2S,2'S)-((azadiylbis(methylene))bis(2-fluoro-3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bispyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.04 min, [M+H] + =828.31.

[0158] Step E: 3,3'-Di-tert-butyl((2S,2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenyl)sulfonyl)azadiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis(3-(tert-butoxy)-3-propane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate)

[0159] At room temperature, 3,3'-di-tert-butyl((2S,2'S)-((nitrobis(methylene))bis(2-fluoro-3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bispyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.36 mmol) and pyridine (3 mL) were added. After complete dissolution, (R)-3-((S)-1-(tert-butoxy)-3-(3-(chlorosulfonyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.1 mL, 100 mg / mL, acetonitrile solution, 0.43 mmol) was added dropwise, and the reaction was carried out at room temperature for 2 hours.

[0160] After the reaction was completed, the mixture was concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 226 mg of 3,3'-di-tert-butyl((2S,2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenyl)sulfonyl)azadiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis(3-(tert-butoxy)-3-propane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0161] Step F: (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)

[0162] 3,3'-di-tert-butyl((2S,2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azonyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (220 mg, 0.17 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.

[0163] 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 104 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] -=795.12. 1 H NMR (400 MHz, DeuteRium Oxide) δ 7.60 – 7.52 (m, 1H), 7.44 (t, J = 7.7 Hz, 3H), 6.99 (dt, J = 16.0, 7.1 Hz, 4H), 6.88 (t, J = 7.6 Hz, 2H), 4.45 – 4.28 (m, 4H), 3.50 – 3.27 (m, 6H), 3.16 (ddd, J = 17.0, 12.6, 7.2 Hz, 3H), 2.97 – 2.69 (m, 5H), 2.57 (d, J = 6.0 Hz, 4H), 2.48 – 2.29 (m, 6H), 2.03 (dd, J = 6.4, 3.4 Hz, 3H), 1.65 (ddt, J = 22.2, 13.1, 9.2 Hz, 3H).

[0164] Example 12

[0165] Synthesis of (S)-3-(3-(N-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-2-chlorobenzyl)-N-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-((R)-pyrrolyl-3-yl)propionic acid (Compound 12)

[0166] Prepared according to the method for compound 9. LCMS: RT = 1.49 min, [MH] - = 793.07. 1H NMR (400 MHz, DeuteRium Oxide) δ 7.60 (dt, J = 6.3, 2.3 Hz, 1H), 7.52 (S, 1H), 7.46 (d, J = 6.4 Hz, 2H), 7.11 – 7.00 (m, 4H), 6.96 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.79 (S, 1H), 4.51 – 4.24 (m, 4H), 3.42 (dt, J = 11.5,7.3 Hz, 2H), 3.32 (ddt, J = 11.6, 7.7, 3.1 Hz, 4H), 3.22 – 3.08 (m, 3H), 2.94 – 2.59 (m, 8H), 2.50 (dd, J = 13.4, 4.4 Hz, 1H), 2.46 – 2.24 (m, 6H), 2.05 (d, J = 16.2 Hz, 3H), 1.75 – 1.57 (m, 3H).

[0167] Example 13

[0168] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenylsulfonyl)azadiyl)bis(4-fluoro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) (Compound 13)

[0169] The specific synthesis route is as follows:

[0170] Prepared according to the method for compound 11. LCMS: RT = 1.51 min, [MH] - = 795.09.

[0171] Example 14

[0172] Synthesis of (S)-3-(3-(5-(S)-2-carboxy-2-(R)-pyrrolidine-3-ethyl)-2-fluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-4-fluorobenzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid (Compound 14)

[0173] Prepared according to the method for compound 9. LCMS: RT = 1.49 min, [MH]- = 795.24. 1 H NMR(400 MHz, D2O)δ 7.60 (d, J = 6.6 Hz, 1H), 7.54 (s, 1H), 7.47 (d, J = 6.6 Hz, 2H), 6.97 (d, J = 2.9 Hz, 1H), 6.90 (d, J = 5.6 Hz, 1H), 6.86 (d, J = 9.5 Hz, 1H), 6.84 – 6.76 (m, 3H), 4.37 – 4.21 (m, 4H), 3.46 (td, J = 13.1, 12.5, 7.4Hz, 3H), 3.34 (t, J = 4.1 Hz, 3H), 3.18 (td, J = 11.4, 10.1, 5.1 Hz, 3H),2.98 – 2.79 (m, 5H), 2.69 – 2.56 (m, 4H), 2.54 – 2.33 (m, 6H), 2.06 (s, 3H),1.77 – 1.60 (m, 3H).

[0174] Example 15

[0175] Synthesis of (S)-3-(3-(N-(5-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-2,4-difluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)pyrrolidine-3-ylethyl)benzyl)aminosulfonyl)phenyl)-2-((R)-pyrrolyl-3-yl)propionic acid (Compound 15)

[0176] Prepared according to the method for compound 9. LCMS: RT = 1.50 min, [MH] - =795.20. 1H NMR (400MHz, DeuteRium Oxide) δ 7.65 – 7.55 (m, 2H), 7.55 – 7.45 (m, 2H), 7.11 (t, J= 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.91 – 6.80 (m, 3H), 6.66 (t, J =10.0 Hz, 1H), 4.38 – 4.20 (m, 4H), 3.60 – 3.46 (m, 3H), 3.37 (dd, J = 11.7,8.6 Hz, 3H), 3.20 (ddd, J = 11.8, 9.7, 7.3 Hz, 3H), 3.07 – 2.85 (m, 5H), 2.74 (dt, J = 16.5, 6.4 Hz, 4H), 2.69 – 2.57 (m, 3H), 2.50 (dq, J = 19.1, 9.4, 9.0Hz, 3H), 2.18 – 2.06 (m, 3H), 1.70 (dq, J = 13.2, 9.7 Hz, 3H).

[0177] Example 16

[0178] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(methylene))bis(4,6-difluoro-3,1-phenylene)bis(2-(R)pyrrolyl-3-yl)propionic acid)

[0179] The specific synthesis route is as follows:

[0180] Prepared according to the method for compound 11. LCMS: RT = 1.51 min, [MH] - =831.06. 1H NMR (400MHz, DeuteRium Oxide) δ 7.60 (d, J = 11.6 Hz, 2H), 7.55 – 7.46 (m, 2H), 6.92 (t, J = 8.3 Hz, 2H), 6.69 (t, J = 10.0 Hz, 2H), 4.38 – 4.23 (m, 4H), 3.54 (dd, J = 11.9, 8.1 Hz, 3H), 3.37 (ddd, J = 12.0, 8.4, 3.7 Hz, 3H), 3.26 –3.15 (m, 3H), 3.01 (q, J = 10.6 Hz, 3H), 2.95 – 2.84 (m, 2H), 2.78 – 2.64 (m, 5H), 2.62 – 2.42 (m, 5H), 2.12 (ddt, J = 13.7, 7.2, 3.8 Hz, 3H), 1.77 – 1.63 (m, 3H).

[0181] Example 17

[0182] Synthesis of (2S,2'S)-3,3'-((3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(ethane-2,1-diyl)bis(2,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid)

[0183] The specific synthesis route is as follows:

[0184] Prepared according to the method for compound 9. LCMS: RT = 1.51 min, [M+H] - = 787.06.

[0185] Example 18

[0186] Synthesis of (S)-3-(2-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-N-(2-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)phenyl)sulfonamido)ethyl)phenyl)-2-(R)-pyrrolidine-3-yl)propionic acid

[0187] The specific synthesis route is as follows: Prepared according to the method for compound 9. LCMS: RT = 1.54 min, [MH] - = 773.12. 1H NMR (400 MHz, D2O) δ 7.69 (s, 1H), 7.63 (s, 1H), 7.51 (d, J = 4.6 Hz, 2H), 7.25 (t, J = 7.4Hz, 1H), 7.21 - 7.11 (m, 2H), 7.12 - 6.99 (m, 4H), 6.76 (d, J = 7.4 Hz, 1H), 4.24 (s, 2H), 3.47 (dd, J = 11.8, 7.2 Hz, 2H), 3.40 - 3.30 (m, 3H), 3.29 -3.03 (m, 6H), 2.95 (dd, J = 11.8, 7.2 Hz, 2H), 2.86 - 2.66 (m, 6H), 2.68 -2.24 (m, 9H), 2.05 (s, 3H), 1.84 - 1.39 (m, 3H).

[0188] Example 19

[0189] Synthesis of (S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-N-(2-(S)2-carboxy-2-(R)pyrrolidine-3-ylethyl)phenethyl)phenyl)sulfonamide)ethylphenyl)phenyl)-2-((R)-pyrrolyl-3-yl)propionic acid

[0190] The specific synthesis route is as follows:

[0191] Prepared according to the method for compound 9. LCMS: RT = 1.51 min, [MH] - =787.20. 1H NMR (400MHz, DeuteRium Oxide) δ 7.57 – 7.50 (m, 2H), 7.50 – 7.39 (m, 2H), 7.19 – 7.10 (m, 4H), 7.01 (d, J = 7.4 Hz, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.83 (S, 1H), 3.54 – 3.42 (m, 3H), 3.35 (tq, J = 8.9, 5.7, 5.2 Hz, 5H), 3.25 – 3.09 (m, 5H), 2.98 (td, J = 10.7, 6.7 Hz, 3H), 2.93 – 2.84 (m, 2H), 2.81 (d, J = 7.0Hz, 2H), 2.68 (ddt, J = 28.8, 15.1, 7.2 Hz, 9H), 2.48 (dp, J = 25.0, 8.5 Hz, 3H), 2.09 (ddt, J = 14.1, 10.7, 7.1 Hz, 3H), 1.78 – 1.60 (m, 3H).

[0192] Example 20

[0193] Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)phenyl)sulfonamido)ethyl)phenyl)-2-(R)-pyrrolidine-3-yl)propionic acid

[0194] The specific synthesis route is as follows:

[0195] Prepared according to the method for compound 9. LCMS: RT = 1.49 min, [MH] - = 773.26.

[0196] Example 21

[0197] Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(ethane-2,1-diyl)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid)

[0198] The specific synthesis route is as follows:

[0199] Step A: Synthesis of (R)-3-(S)-1-tert-butoxy-1-oxo-3-(3-vinylphenyl)propyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0200] At room temperature, tert-butyl (R)-3-(S)-3-(3-bromophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid (15 g, 33.0 mmol), triphenylphosphine (866 mg, 3.30 mmol), cesium carbonate (32.3 g, 99 mmol), palladium dichloride (292 mg, 1.65 mmol), and potassium trifluoroborate (7.57 g, 49.5 mmol) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times, followed by the addition of tetrahydrofuran (150 mL) and purified water (30 mL). The mixture was heated to 70°C and reacted overnight. After the reaction was completed by TLC monitoring, it was cooled to room temperature, diluted with water (150 mL), and then extracted with ethyl acetate (150 mL twice). The combined organic phases were washed with saturated brine (150 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 / 8) to give 13.2 g of (R)-3-(S)-1-tert-butoxy-1-oxo-3-(2-vinylphenyl)propyl-2-ylpyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.35 min, [M+H] + = 402.23.

[0201] Step B: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(3-(2-hydroxyethyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0202] Under ice-water bath conditions, a tetrahydrofuran solution (132 mL, 0.5 mol / L) of 9-boronbicyclo[3.3.1]nonane was added dropwise to a tetrahydrofuran solution (130 mL, 32.87 mmol) of (R)-3-(S)-1-tert-butoxy-1-oxo-3-(2-vinylphenyl)propyl-2-ylpyrrolidine-1-carboxylic acid tert-butyl ester (13.2 g, 32.87 mmol) containing tetrahydrofuran. After stirring at room temperature for 18 hours, methanol (50 mL), sodium hydroxide aqueous solution (104 mL, 3 mol / L), and 30% hydrogen peroxide (22.4 g) were added to the reaction solution under ice-water bath conditions. The reaction was allowed to proceed for 3 hours at room temperature. After the reaction was monitored by TLC, excess saturated sodium bisulfate solution was added to quench the reaction. The mixture was stirred for 10 minutes, diluted with water (100 mL), and then extracted with ethyl acetate (200 mL × 2 times). The combined organic phases were washed with saturated brine (150 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 / 2) to give 9.6 g of (R)-3-(S)-1-tert-butoxy-3-(2-hydroxyethyl)phenyl-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.14 min, [M+H-tert-butyl-tert-butoxycarbonyl] + = 320.22.

[0203] Step C: Synthesis of (R)-3-(S)-1-tert-butoxy-1-oxo-3-(3-(2-oxoethyl)phenyl)prop-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0204] At room temperature, 2-iodobenzoic acid (3.9 g, 13.90 mmol) was added to a 100 mL solution of (R)-3-(S)-1-tert-butoxy-3-(2-hydroxyethyl)phenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (5.3 g, 12.63 mmol) in ethyl acetate. The reaction was carried out at 70 °C for 8 hours. After the reaction was completed by TLC monitoring, the mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 2.6 g of (R)-3-(S)-1-tert-butoxy-1-oxo-3-(2-oxoethyl)phenyl)propan-2-ylpyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.21 min, [M+H] + = 418.25.

[0205] Step D: Synthesis of 3,3'-((2S,2'S)-(azadiylbisethane-2,1-diyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester)

[0206] (R)-3-(S)-1-tert-butoxy-1-oxo-3-(3-(2-oxoethyl)phenyl)prop-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 0.60 mmol) and (R)-3-(S)-3-(3-(2-aminoethyl)phenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (251 mg, 0.60 mmol) were dissolved in 1,2-dichloroethane, and then sodium triacetoxyborohydride (444 mg, 2.1 mmol) was added in portions. The reaction was carried out overnight at 45°C. After the reaction was complete, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to give 150 mg of 3,3'-((2S,2'S)-(azadiylbisethane-2,1-diyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester). LCMS: RT = 2.07 min, [M+H] + = 820.39.

[0207] Step E: Synthesis of 3,3'-(3-(S)-3-tert-butoxy-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azadiyl)bis(ethane-2,1-diyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester)

[0208] At room temperature, 3,3'-((2S,2'S)-(azadiylbisethane-2,1-diyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (250 mg, 0.30 mmol) was dissolved in anhydrous pyridine (2 mL), and then a solution of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropane-2-yl)pyrrolidine-1-carboxylate tert-butyl acetonitrile (174 mg, 0.37 mmol) was slowly added dropwise. (2 mL), TLC detection, after the reactants were completely reacted, rotary evaporated to remove pyridine, the crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 100 mg of 3,3'-(3-(S)-3-tert-butoxy-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azadiyl)bis(ethane-2,1-diyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester).

[0209] Step F: Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(ethane-2,1-diyl)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid)

[0210] Dissolve (3,3'-(3-(S)-3-tert-butoxy-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azadiyl)bis(ethane-2,1-diyl))bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) (100 mg, 0.079 mmol) in 1,4-dioxane (1.5 mL), add concentrated hydrochloric acid (0.5 mL), and react overnight at 45 °C. After the reaction was complete, the solvent was removed by vacuum distillation, and the crude product was purified by preparative high-performance liquid chromatography to obtain 20 mg of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(ethane-2,1-diyl))bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid). LCMS: RT = 1.51 min, [MH] - = 787.15. 1 H NMR (400 MHz, D2O) δ 7.46(dd, J = 18.4, 10.8 Hz, 4H), 7.15 (t, J = 7.6 Hz, 2H), 7.01 (d, J = 7.7 Hz,2H), 6.91 (d, J = 7.6 Hz, 2H), 6.83 (s, 2H), 3.49 (ddd, J = 19.2, 11.8, 7.9Hz, 3H), 3.40 – 3.25 (m, 7H), 3.22 – 3.11 (m, 3H), 3.04 – 2.87 (m, 4H), 2.80– 2.74 (m, 4H), 2.73 – 2.57 (m, 8H), 2.45 (dd, J = 17.2, 8.6 Hz, 3H), 2.16 –2.04 (m, 3H), 1.68 (p, J = 10.1 Hz, 3H).

[0211] Example 22

[0212] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(methylene)bis(2,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) (Compound 22)

[0213] Prepared according to the method for compound 9. LCMS: RT = 1.51 min, [MH] - = 759.15.

[0214] Example 23

[0215] Synthesis of (S)-3-(3-(((3-(S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-N-(2-((S)2-carboxy-2-(R)pyrrolidine-3-ylethyl)benzyl)phenyl)sulfonamido)methyl)phenyl)-2-((R)-pyrrolyl-3-yl)propionic acid

[0216] The specific synthesis route is as follows:

[0217] Step A: 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)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate

[0218] At room temperature, (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.48 mmol), ((R)-3-((S)-3-(2-(aminomethyl)phenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.97 mmol), and 1,2-dichloroethane (20 mL) were added sequentially. The mixture was heated to 45 °C, and then sodium triacetoxyborohydride (1.8 mg, 8.68 mmol) was added in three batches. The mixture was reacted at 45 °C for 18 hours.

[0219] After the reaction was complete, saturated ammonium chloride aqueous solution (30 mL) was added to quench the reaction. Extraction was performed with dichloromethane (20 mL × 2 times), and the mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 1) to give 1.3 g 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)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.03 min, [M+H] + =792.08.

[0220] Step B: 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)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl))phenyl) sulfonylamino) methyl) phenyl)-1-oxopropyl-2-yl) pyrrolidine-1-carboxylate

[0221] At room temperature, 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)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (130 mg, 0.16 mmol), (R)-3-((S)-1-(tert-butoxy)-3-(3-(chlorosulfonyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate tert-butyl ester (95 mg, 0.20 mmol), acetonitrile (3 mL), triethylamine (32 mg, 0.32 mmol), and 4-dimethylaminopyridine (9 mg, 0.07 mmol) were added, the mixture was purged with nitrogen, and the temperature was raised to 80 °C for 2 hours.

[0222] After the reaction was complete, tap water (10 mL) and ethyl acetate (10 mL) were added for extraction, and the mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 110 mg 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)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl))phenyl)sulfonamide)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate.

[0223] Step C: (S)-3-(3-(((3-(S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-N-(2-((S)-2-carboxy-2-(R)-pyrrolidine-3-ylethyl)benzyl)phenyl)sulfonamido)methyl)phenyl)-2-((R)-pyrrolyl-3-yl)propionic acid

[0224] At room temperature, add 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)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl))phenyl)sulfonamide)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (110 mg, 0.09 mmol), dioxane (2.5 mL), concentrated hydrochloric acid (0.5 mL), and react 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 44 mg of (S)-3-(3-(((3-(S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-N-(2-(((S)2-carboxy-2-(R)-pyrrolidine-3-ylethyl)benzyl)phenyl)sulfonamide)methyl)phenyl)-2-((R)-pyrrolyl-3-yl)propionic acid. LCMS: RT = 1.49 min, [MH] - =759.19. 1 H NMR (400 MHz, DeuteRium Oxide) δ 7.71 (dq, J = 6.7, 4.5, 3.4Hz, 1H), 7.63 (S, 1H), 7.54 (d, J = 6.0 Hz, 2H), 7.19 – 7.10 (m, 1H), 7.10 –7.02 (m, 2H), 7.02 – 6.92 (m, 3H), 6.77 (d, J = 7.6 Hz, 1H), 6.50 (S, 1H), 4.40 – 4.24 (m, 2H), 4.14 (S, 2H), 3.60 – 3.29 (m, 6H), 3.26 – 3.12 (m, 3H), 3.09 – 2.86 (m, 5H), 2.82 – 2.36 (m, 10H), 2.11 (ttd, J = 12.4, 6.4, 5.7, 3.2Hz, 3H), 1.80 – 1.58 (m, 3H).

[0226] Example 24

[0227] Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-ethyl)-4-fluorobenzyl)-N-(2-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenethyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid (Compound 24)

[0228] Prepared according to the method for compound 9. LCMS: RT = 1.50 min, [MH] - =791.16. NMR data: 1 H-NMR(400 MHz, Deuterium Oxide) δ 7.64 (d, J = 6.6 Hz, 1H), 7.58 (s, 1H), 7.49 (d,J = 6.7 Hz, 2H), 7.09 (m, 3H), 7.01 (d, J = 6.1 Hz, 1H), 6.96 (t, J = 9.1 Hz,1H), 6.93 - 6.87 (m, 2H), 4.22 (m, 2H), 3.60 - 3.42 (m, 3H), 3.36 (t, J = 9.6Hz, 3H), 3.30 - 3.13 (m, 5H), 3.07 - 2.86 (m, 5H), 2.85 - 2.72 (m, 2H), 2.67(m, 7H), 2.47 (d, J = 16.1 Hz, 3H), 2.10 (d, J = 9.6 Hz, 3H), 1.69 (t, J =10.5 Hz, 3H).

[0229] Example 25

[0230] Synthesis of (S)-3-(3-(N-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-2-fluorobenzyl)-N-(2-(S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenethyl)aminosulfonyl)phenyl)-2-(((R)-pyrrolyl-3-yl)propionic acid) (Compound 25)

[0231] The compound was prepared according to the method described for compound 9. LCMS: RT = 1.49 min, [MH] - =791.19. 1H NMR (400MHz, DeuteRium Oxide) δ 7.55 (d, J = 7.0 Hz, 1H), 7.51 – 7.38 (m, 3H), 7.16 –7.03 (m, 5H), 6.99 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 4.33 (S, 2H), 3.50 – 3.39 (m, 3H), 3.39 – 3.24 (m, 5H), 3.16 (dd, J = 17.2, 10.8 Hz, 3H), 2.95 – 2.81 (m, 3H), 2.80 – 2.74 (m, 2H), 2.67 (dd, J = 17.2, 6.9 Hz, 6H), 2.49 – 2.32 (m, 6H), 2.04 (S, 3H), 1.73 – 1.59 (m, 3H).

[0232] Example 26

[0233] Synthesis of (S)-3-(3-(5-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2-fluorobenzyl)-N-(2-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenethyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-yl)propionic acid (Compound 26)

[0234] The compound was prepared according to the method used for compound 9. LCMS: RT = 1.54 min, [M+H] + = 793.16. 1 H NMR(400 MHz, D2O) 7.55 (dd, J = 5.6, 3.6 Hz, 1H), 7.49 (s, 1H), 7.47 - 7.38 (m,2H), 7.05 (h, J = 4.8 Hz, 4H), 6.99 - 6.94 (m, 1H), 6.93 - 6.85 (m, 2H), 4.30 (s, 2H), 3.62 - 3.22 (m, 8H), 3.22 - 3.08 (m, 3H), 2.96 - 2.48 (m, 11H), 2.44- 2.23 (m, 6H), 2.10 - 1.93 (m, 3H), 1.68 - 1.57 (m, 3H).

[0235] Example 27

[0236] Synthesis of (S)-3-(3-(N-(5-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2,4-difluorobenzyl)-N-(2-(S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenethyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid (Compound 27)

[0237] Prepared according to the method for compound 9. LCMS: RT = 1.55 min, [MH] - =809.12. NMR data: 1 H-NMR (400 MHz, Deuterium Oxide) δ 8.27 (s, 2H), 7.57 (d, J = 7.0 Hz, 1H), 7.52(s, 1H), 7.45 (d, J = 7.5 Hz, 2H), 7.11 - 7.02 (m, 3H), 6.97 - 6.88 (m, 2H),6.75 (t, J = 10.0 Hz, 1H), 4.24 (d, J = 3.1 Hz, 2H), 3.48 (m, 3H), 3.33 (m,5H), 3.25 – 3.10 (m, 3H), 3.01 – 2.88 (m, 3H), 2.81 (d, J = 7.4 Hz, 2H), 2.68(m, 6H), 2.55 - 2.33 (m, 6H), 2.16 - 1.97 (m, 3H), 1.76 - 1.56 (m, 3H).

[0238] Example 28

[0239] Synthesis of (S)-3-(3-(2-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-5-fluorophenylethyl)-N-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid

[0240] The specific synthesis route is as follows:

[0241] Step A: Synthesis of (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidine-3-yl)-3-(2-bromo-4-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0242] At -78 °C, a tetrahydrofuran solution (67 mL, 1.0 mol / L) of lithium bis(trimethylsilylamino)amine was slowly added dropwise to a tetrahydrofuran solution (20 g, 51.48 mmol) of (R)-3-(2-(S)-4-benzyl-2-oxooxazolidine-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (20 g, 51.48 mmol). After reacting for 0.5 hours, a tetrahydrofuran solution (30 mL) of 2-bromo-1-bromomethyl-4-fluorobenzene (15 g, 55.99 mmol) was slowly added, followed by allowing the mixture to rise naturally to room temperature and react overnight.

[0243] After the reaction was monitored by LC-MS, saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL × 2 times). The combined organic phases were washed with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to give 17 g of (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidine-3-yl)-3-(2-bromo-4-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LC-MS: RT = 2.29 min, [M+H-Boc] + = 475.02.

[0244] Step B: Synthesis of (S)-3-(2-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)propionic acid

[0245] Under ice-water bath conditions, (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidine-3-yl)-3-(2-bromo-4-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (15 g, 26.13 mmol) was dissolved in tetrahydrofuran (150 mL), followed by the addition of 30% hydrogen peroxide (6 g, 52.26 mmol). After 0.5 hours, an aqueous solution of lithium hydroxide monohydrate (2.2 g, 52.26 mmol) (15 mL) was added, and the reaction was brought to room temperature for 3 hours.

[0246] After the reaction was monitored by LC-MS, excess saturated sodium bisulfate solution was slowly added to the reaction solution to quench the reaction. The mixture was stirred for 10 minutes, then saturated citric acid solution was added to adjust the pH to 5. Extraction was performed with ethyl acetate (100 mL × 2 times). The combined organic phases were washed with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to give 7.8 g of (S)-3-(2-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)propionic acid. LC-MS: RT = 2.29 min, [MH] - = 414.04.

[0247] Step C: Synthesis of (R)-3-(S)-3-(2-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0248] At room temperature, (S)-3-(2-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)propionic acid (7.8 g, 18.8 mmol) and (Z)-N,N'-diisopropylcarbamate tert-butyl ester (11.3 g, 56.4 mmol) were dissolved in 2-methyltetrahydrofuran (80 mL), nitrogen was purged three times, and the mixture was heated to 65 °C and reacted overnight.

[0249] After the reaction was completed as monitored by LC-MS, the mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was diluted with ethyl acetate, and the combined organic phases were washed with saturated brine (100 mL × 2 times), then dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 9 / 1) to give 6.7 g of (R)-3-(S)-3-(2-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LC-MS: RT = 2.29 min, [M+H-Boc] + = 372.10.

[0250] Step D: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-vinylphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0251] At room temperature, (R)-3-(S)-3-(2-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (6.7 g, 14.2 mmol), potassium ethylene trifluoroborate (2.86 g, 21.3 mmol), palladium chloride (83 mg, 0.71 mmol), triphenylphosphine (370 mg, 1.4 mmol), and cesium carbonate (13.87 g, 42.67 mmol) were dissolved in tetrahydrofuran / water (60 mL / 7 mL), and after three N2 displacements, the mixture was heated to 75 °C and reacted overnight.

[0252] After the reaction was monitored by TLC, the mixture was cooled to room temperature, diluted with water (10 mL), and then extracted with ethyl acetate (100 mL twice). The combined organic phases were washed with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to give 4.9 g of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-vinylphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0253] Step E: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-hydroxyethyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0254] Under ice-water bath conditions, (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-vinylphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 7.15 mmol) was dissolved in tetrahydrofuran (30 mL), and 9-boronbicyclo[3.3.1]nonanetetrahydrofuran solution (28.6 mL, 0.5 mol / L) was added. The mixture was heated to room temperature and stirred overnight. Methanol (10 mL) was added and stirred for 10 minutes. Then, 30% hydrogen peroxide aqueous solution (4.87 g, 42.9 mmol) and sodium hydroxide (2.72 g, 67.9 mmol) aqueous solution (10 mL) were added and the reaction was continued for 1 hour.

[0255] After the reaction was monitored by LC-MS, excess sodium bisulfate solution was slowly added to quench the reaction. The mixture was stirred for 30 minutes, and the solution was extracted with ethyl acetate (80 mL × 2 times). The combined organic phases were washed with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 1.2 g of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-hydroxyethyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LC-MS: RT = 2.216 min, [M+H-Boc-tert-butyl]+ =282.05.

[0256] Step F: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-oxoethyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0257] (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-hydroxyethyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.75 mmol) was dissolved in ethyl acetate (50 mL), and 2-iodobenzoic acid (0.85 g, 3.0 mmol) was added. The mixture was heated to 70 °C and stirred for 6 hours.

[0258] After the reaction was completed as monitored by LC-MS, the filter cake was removed by filtration, washed with ethyl acetate, and the organic phases were combined. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 490 mg of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-oxoethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LC-MS: RT = 2.15 min, [M+H-Boc-tert-butyl] + = 280.08.

[0259] Step G: Synthesis of tert-butyl-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)-3-oxopropyl)benzyl)amino)ethyl)-4-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid ester

[0260] At room temperature, (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-oxoethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (390 mg, 0.9 mmol) and (R)-3-(S)-3-(3-aminomethyl)phenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (362 mg, 0.9 mmol) were dissolved in DCE (8 mL), and sodium triacetoxyborohydride (665 mg, 3.15 mmol) was added in portions. The mixture was heated to 45°C and stirred for 16 hours.

[0261] After the reaction was monitored to be complete by LC-MS, the reaction was quenched by adding an aqueous solution (1 mL). The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). 250 mg of tert-butyl-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)-3-oxopropyl)benzyl)amino)ethyl)-4-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid ester was obtained. LC-MS: RT = 2.02 min, [M+H] + =824.51.

[0262] Step H: Synthesis of (R)-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)phenyl)sulfonamido)ethyl)-4-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester

[0263] At room temperature, tert-butyl-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)-3-oxopropyl)benzyl)amino)ethyl)-4-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid ester (250 mg, 0.30 mmol) was dissolved in pyridine (5 mL), and (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropyl-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (172 mg, 0.36 mmol) in acetonitrile solution (2 mL) was slowly added, and the reaction was carried out at room temperature for 0.5 h.

[0264] After the reaction was detected by TLC, the mixture was extracted with ethyl acetate (10 mL × 2 times). The combined organic phases were washed with saturated brine (5 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 150 mg of (R)-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)phenyl)sulfonamide)ethyl)-4-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester.

[0265] Step I: Synthesis of (S)-3-(3-(2-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-5-fluorophenylethyl)-N-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid

[0266] At room temperature, (R)-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)phenyl)sulfonamide)ethyl)-4-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (150 mg, 0.12 mmol) was dissolved in 1,4-dioxane solution (3 mL), concentrated hydrochloric acid (0.2 mL) was added, and the mixture was heated to 45°C and reacted for 4 hours.

[0267] The reaction was monitored by LC-MS until complete, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain 34 mg of (S)-3-(3-(2-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-5-fluorophenylethyl)-N-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid. LC-MS: RT = 1.56 min, [MH] - =791.12. NMR data: 1H-NMR (400 MHz, Deuterium Oxide) δ 7.68 - 7.59(m, 1H), 7.55 (s, 1H), 7.46 (d, J = 6.3 Hz, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 6.99 (t, J = 7.6 Hz, 2H), 6.89 (s, 1H), 6.79 (m,1H), 6.66 (m 1H), 4.24 (s, 2H), 3.49 - 3.26 (m, 8H), 3.23 - 3.09 (m, 3H),2.95 - 2.87 (m, 1H), 2.80 (m, 4H), 2.75 - 2.62 (m, 3H), 2.53 (m, 2H), 2.48 -2.28 (m, 6H), 2.22 (m, 1H), 2.03 (m, 3H), 1.76 - 1.53 (m, 3H).

[0268] Example 29

[0269] Synthesis of (2S,2'S)-3,3'(5-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2-fluorophenylsulfonyl)azadiyl)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid)

[0270] The specific synthesis route is as follows:

[0271] Step A: Synthesis of (3R)-3-(2S)-1-(4-benzyl-2-oxooxazolidine-3-yl)-3-(3-bromo-4-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0272] At -78 °C, lithium bis(trimethylsilylamino)amine (19 mL, 19 mmol) was slowly added dropwise to a tetrahydrofuran (60 mL) solution of (R)-3-(2-((S)-4-benzyl-2-oxooxazolidine-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (6.0 g, 15.45 mmol). After stirring at -78 °C for 30 minutes, a tetrahydrofuran (20 mL) solution of 2-bromo-4-bromomethyl-1-fluorobenzene (4.97 g, 19 mmol) was slowly added to the system, and then allowed to rise naturally to room temperature overnight. After the reaction was monitored by TLC, saturated ammonium chloride aqueous solution was added for quenching. Extraction was performed with ethyl acetate (100 mL × 2 times). The combined organic phases were washed with saturated brine (100 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 3.1 g of (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidine-3-yl)-3-(3-bromo-4-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.25 min, [M+H-Boc] + = 475.01.

[0273] Step B: Synthesis of (3-(3-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-ylpropionic acid

[0274] Under ice-water bath conditions, hydrogen peroxide (1.1 g, 30%, 9.90 mmol) was added to a tetrahydrofuran (40 mL) solution of (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidine-3-yl)-3-(3-bromo-4-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.8 g, 6.60 mmol) and reacted for 30 min. Then, an aqueous solution of lithium hydroxide monohydrate (237 mg, 9.90 mmol) (10 mL) was added, and the mixture was allowed to rise to room temperature for 3 h. After the reaction was complete, excess saturated sodium bisulfate solution was slowly added to the reaction solution to quench the reaction. The mixture was stirred for 10 minutes, then saturated citric acid solution was added to adjust the pH to 3. Extraction was performed with ethyl acetate (50 mL × 2 times). The combined organic phases were washed with saturated brine (200 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 2.2 g of (S)-3-(3-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonyl)pyrrolidine-3-yl)propionic acid. LCMS: RT = 2.06 min, [MH] - = 416.00.

[0275] Step C: Synthesis of (R)-3-(S)-3-(3-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0276] At room temperature, O-tert-butyl-N,N'-diisopropylisourea (3.18 g, 15.85 mmol) was added to a solution of (S)-3-(3-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonyl)pyrrolidine-3-yl)propionic acid (2.2 g, 5.28 mmol) in 2-methyltetrahydrofuran (20 mL), purged with nitrogen three times, and the mixture was heated to 65 °C and reacted overnight. After the reaction was completed as monitored by TLC, the filter cake was washed with ethyl acetate, and the filtrate was diluted with ethyl acetate. The combined organic phases were first washed with saturated brine (70 mL × 2 times), then 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 / 7) to give 2.1 g of (R)-3-(S)-3-(3-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.36 min, [M+H-Boc] + = 371.98.

[0277] Step D: Synthesis of (R)-3-(S)-3-(3-benzylthio)-5-fluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0278] At room temperature, (R)-3-(S)-3-(3-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.10 g, 4.62 mmol), benzyl thiol N,N-Diisopropylethylamine 4,5-Bisdiphenylphosphine-9,9-dimethyloxanthracene Tris(dibenzylidene indacetone)dipalladium Dissolved in dioxane, the mixture was purged with nitrogen and reacted overnight at 100°C under nitrogen protection. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 7) to give 2.1 g of (R)-3-(S)-3-3-(3-benzylthio)-4-fluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.43 min, [M+H-Boc] + = 398.15.

[0279] Step E: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)-4-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0280] (R)-3-(S)-3-(3-benzylthio)-4-fluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.10 g, 4.22 mmol) was dissolved in acetonitrile (30 mL) under ice bath conditions, followed by the addition of acetic acid (1.5 mL), water (1.5 mL), and then dropwise the addition of 1,3-dichloro-5,5-dimethylhydantoin acetonitrile solution (1.66 g, 8.44 mmol, 10 mL). The mixture was monitored by TLC. After the reaction was complete, water was added to the system, and then the mixture was extracted with ethyl acetate (100 mL × 2 times). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to give 1.6 g of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)-4-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0281] Step F: Synthesis of 3,3'-((2S,2'S)-(3-((S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorophenyl)sulfonyl)azadiyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester)

[0282] At room temperature, 3,3'-((2S,2'S)-(azadiylbismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (250 mg, 0.32 mmol) was dissolved in anhydrous pyridine (2 mL), and then a solution of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)-4-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylate tert-butyl acetonitrile (187 mg, 0.38 mmol, 2 mL) was slowly added dropwise. (mL), TLC detection, after the reactant was completely reacted, rotary evaporated, and after removing pyridine, the crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 60 mg of 3,3'-((2S,2'S)-(3-((S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorophenyl)sulfonyl)azadiyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester).

[0283] Step G: Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-4-fluorophenylsulfonyl)azadiyl)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid)

[0284] 3,3'-((2S,2'S)-(3-((S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorophenyl)sulfonyl)azadiyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) (60 mg, 0.048 mmol) was dissolved in 1,4-dioxane (1.5 mL), and concentrated hydrochloric acid (0.5 mL) was added. The reaction was carried out 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 18 mg of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-4-fluorophenylsulfonyl)azadiyl)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid). LCMS: RT = 1.53 min, [MH] - = 777.12. 1 H NMR (400 MHz, D2O) δ7.55 – 7.50 (m, 1H), 7.47 – 7.41 (m, 1H), 7.22 – 7.09 (m, 3H), 7.02 (d, J =7.6 Hz, 2H), 6.90 (d, J = 7.6 Hz, 2H), 6.80 (s, 2H), 4.33 (s, 4H), 3.44 (dd,J = 11.7, 6.9 Hz, 1H), 3.32 (ddd, J = 17.0, 10.1, 5.1 Hz, 5H), 3.13 (td, J =10.7, 7.3 Hz, 3H), 2.95 – 2.87 (m, 1H), 2.84 – 2.76 (m, 2H), 2.73 (d, J = 8.9Hz, 2H), 2.65 (dd, J = 13.6, 8.9 Hz, 2H), 2.56 (dd, J = 13.5, 4.3 Hz, 2H), 2.45 – 2.26 (m, 6H), 2.08 – 1.97 (m, 3H), 1.64 (dq, J = 12.4, 8.9 Hz, 3H).

[0285] Example 30

[0286] Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2,4-difluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid (Compound 30)

[0287] Prepared according to the method for compound 9. LCMS: RT = 1.53 min, [MH] - = 795.12.

[0288] Example 31

[0289] Synthesis of (2S,2'S)-3,3'-((3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(methylene))bis(2,6-difluoro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) (Compound 31)

[0290] Prepared according to the method for compound 9. LCMS: RT = 1.53 min, [MH] - = 831.12.

[0291] Example 32

[0292] Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2,6-difluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid

[0293] The specific synthesis route is as follows:

[0294] Step A: Synthesis of methyl 3-bromo-2,4-difluorobenzoate

[0295] At room temperature, 3-bromo-2,4-difluorobenzoic acid (5 g, 21.19 mmol) was dissolved in N,N-dimethylformamide solution (50 mL), potassium carbonate (5.86 g, 42.4 mmol) was added, the temperature was lowered to 0°C, and iodomethane (3.59 g, 25.3 mmol) was slowly added. The reaction was allowed to return to room temperature for 1 hour.

[0296] After the reaction was confirmed to be complete by TLC, the mixture was diluted with water and extracted with ethyl acetate (100 mL × 2 times). The combined organic phases were washed with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to give 5.1 g of white solid methyl 3-bromo-2,4-difluorobenzoate (yield: 96.7%).

[0297] Step B: Synthesis of 3-bromo-2,4-difluorophenylmethanol

[0298] Under ice-water bath conditions, a solution of diisobutylaluminum hydride in n-hexane (41 mL, 1.0 mol / L) was slowly added dropwise to a solution of methyl 3-bromo-2,4-difluorobenzoate (5.1 g, 20.4 mmol) in dichloromethane (50 mL), and the reaction was allowed to proceed for 2 hours at room temperature.

[0299] After the reaction was monitored by LC-MS, 1 M / L hydrochloric acid solution (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL × 2 times). The combined organic phases were washed with saturated brine (50 mL × 2 times), dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 4 g of 3-bromo-2,4-difluorophenylmethanol.

[0300] Step C: Synthesis of 2-bromo-4-bromomethyl-1,3-difluorobenzene

[0301] At room temperature, carbon tetrabromide (6.24 g, 27 mmol) and triphenylphosphine (7.08 g, 27 mmol) were added to a solution of 3-bromo-2,4-difluorophenylmethanol (4 g, 18.1 mmol) in dichloromethane (40 mL) and reacted for 2 hours.

[0302] After the reaction was monitored by LC-MS, the mixture was extracted with ethyl acetate (100 mL × 2 times). The combined organic phases were washed with saturated brine (50 mL × 2 times), dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane) to give 3.3 g of 2-bromo-4-bromomethyl-1,3-difluorobenzene.

[0303] Step D: Synthesis of (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidine-3-yl)-3-(3-bromo-2,4-difluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0304] At -78 °C, a tetrahydrofuran solution (14 mL, 1.0 mol / L) of lithium bis(trimethylsilylamino)carboxylate tert-butyl ester (4.06 g, 10.5 mmol) was slowly added dropwise to a tetrahydrofuran solution (40 mL) of (R)-3-(2-(S)-4-benzyl-2-oxooxazolidine-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (4.06 g, 10.5 mmol). After reacting for 0.5 hours, a tetrahydrofuran solution (30 mL) of 2-bromo-4-bromomethyl-1,3-difluorobenzene (3.3 g, 11.5 mmol) was slowly added, followed by allowing the mixture to rise naturally to room temperature and react overnight.

[0305] After the reaction was monitored by LC-MS, saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL × 2 times). The combined organic phases were washed with saturated brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to give 2 g of (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidine-3-yl)-3-(3-bromo-2,4-difluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LC-MS: RT = 2.09 min, [M+H-Boc]+ = 493.02.

[0306] Step E: Synthesis of (S)-3-(3-bromo-2,4-difluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-ylpropionic acid

[0307] Under ice-water bath conditions, tert-butyl pyrrolidine-1-carboxylic acid (2 g, 3.4 mmol) was dissolved in tetrahydrofuran (20 mL), followed by the addition of 30% hydrogen peroxide (0.77 g, 6.8 mmol). After 0.5 hours, an aqueous solution of lithium hydroxide monohydrate (0.29 g, 6.8 mmol) (5 mL) was added, and the reaction was brought to room temperature for 3 hours.

[0308] After the reaction was monitored by LC-MS, excess saturated sodium bisulfate solution was slowly added to the reaction solution to quench the reaction. The mixture was stirred for 10 minutes, then saturated citric acid aqueous solution was added to adjust the pH to 5. Extraction was performed with ethyl acetate (50 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: n-hexane / ethyl acetate = 2 / 1) to give 850 mg of (S)-3-(3-bromo-2,4-difluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-ylpropionic acid. LC-MS: RT = 2.07 min, [MH] -= 431.95.

[0309] Step F: Synthesis of (R)-3-(S)-3-(3-bromo-2,4-difluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0310] At room temperature, (S)-3-(3-bromo-2,4-difluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-ylpropionic acid (850 mg, 1.96 mmol) and (Z)-N,N'-diisopropylcarbamate tert-butyl ester (1.18 g, 5.88 mmol) were dissolved in 10 mL of 2-methyltetrahydrofuran, purged with nitrogen three times, and the mixture was heated to 65 °C and reacted overnight.

[0311] After the reaction was completed as monitored by LC-MS, the mixture was filtered. The filter cake was washed with ethyl acetate, and the filtrate was diluted with ethyl acetate. The combined organic phases were washed with saturated brine (10 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 9 / 1) to give 680 mg of (R)-3-(S)-3-(3-bromo-2,4-difluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LC-MS: RT = 2.34 min, [M+H-Boc] + = 390.01.

[0312] Step G: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-vinylphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0313] At room temperature, (R)-3-(S)-3-(3-bromo-2,4-difluorophenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (680 mg, 1.39 mmol), potassium ethylene trifluoroborate (279 mg, 2.09 mmol), palladium chloride (8.12 mg, 0.07 mmol), triphenylphosphine (36.4 mg, 0.14 mmol), and cesium carbonate (1.35 g, 4.17 mmol) were dissolved in tetrahydrofuran / water (10 mL / 4 mL), and after three N2 displacements, the mixture was heated to 75 °C and reacted overnight.

[0314] After the reaction was monitored by TLC, the mixture was cooled to room temperature, diluted with water (10 mL), and then extracted with ethyl acetate (50 mL twice). 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: n-hexane / ethyl acetate = 4 / 1) to give 510 mg of (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-vinylphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0315] Step E: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-formylphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0316] Under ice-water bath conditions, (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-vinylphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (510 mg, 1.17 mmol) was dissolved in tetrahydrofuran / water (8 mL / 2 mL), potassium osmium tetroxide dihydrate (4.29 mg, 0.012 mmol) was added, and the mixture was stirred for 0.5 hours. Then, sodium periodate (548 mg, 2.56 mmol) was added, and the reaction was continued for 1 hour. The reaction was brought to room temperature. After the reaction was completed as monitored by LC-MS, excess sodium bisulfate aqueous solution was slowly added to quench the reaction. The mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate (50 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: n-hexane / ethyl acetate = 2 / 1) to give 220 mg of (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-formylphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LC-MS: RT = 2.26 min, [M+H-Boc-tert-butyl] + = 284.07.

[0317] Step G: 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)-2,6-difluorobenzyl)amino)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester

[0318] At room temperature, (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-carboxylphenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (220 mg, 0.5 mmol) and (R)-3-(S)-3-(3-aminomethyl)phenyl)-1-tert-butoxy-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (202 mg, 0.5 mmol) were dissolved in DCE (5 mL), and sodium triacetoxyborohydride (371 mg, 1.75 mmol) was added in portions. The mixture was heated to 45 °C and stirred for 16 hours.

[0319] After the reaction was monitored to be complete by LC-MS, the reaction was quenched by adding an aqueous solution (1 mL). The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). 160 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)-2,6-difluorobenzyl)amino)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester was obtained. LC-MS: RT = 2.05 min, [M+H] + =828.51.

[0320] Step H: 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)-N-(3-(S)-3-tert-butoxy-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)phenyl)sulfonamido)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester

[0321] At room temperature, (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)amino)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (160 mg, 0.19 mmol) was dissolved in pyridine (4 mL), and a solution of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (110 mg, 0.23 mmol) in acetonitrile (2 mL) was slowly added, and the reaction was carried out at room temperature for 0.5 h.

[0322] After the reaction was detected by TLC, the mixture was extracted with ethyl acetate (10 mL × 2 times). The combined organic phases were washed with saturated brine (5 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue 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-((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)phenyl)sulfonamide)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester.

[0323] Step I: Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2,6-difluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid

[0324] At room temperature, (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)phenyl)sulfonamide)methyl)phenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid ester (170 mg, 0.13 mmol) was dissolved in 1,4-dioxane solution (4 mL), concentrated hydrochloric acid (0.2 mL) was added, and the mixture was heated to 45°C and reacted for 4 hours.

[0325] The reaction was monitored by LC-MS until complete, concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain 53 mg of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2,6-difluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid. LC-MS: RT = 1.51 min, [MH - =795.05. NMR data: 1H NMR (400 MHz, Deuterium Oxide) δ 8.25 (s,1H), 7.59 - 7.38 (m, 4H), 7.09 (t, J = 7.6 Hz, 1H), 6.96 (m, 3H), 6.85 (s,1H), 6.64 (t, J = 8.9 Hz, 1H), 4.34 (d, J = 23.8 Hz, 4H), 3.44 (m, 3H), 3.33(m, 3H), 3.16 (m, 3H), 2.90 (m, 3H), 2.80 (d, J = 9.2 Hz, 2H), 2.73 - 2.61(m, 2H), 2.57 (m, 2H), 2.53 - 2.47 (m, 1H), 2.47 - 2.30 (m, 5H), 2.06 (m, 3H), 1.67 (m, 3H).

[0326] Example 34

[0327] Synthesis of (2S,2'S)-3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolid-3-yl)ethyl)-4-fluorophenyl)sulfonyl)azadiyl)bis(methylene))bis(6-fluoro-3,1-phenylene))bis(2-((R)-pyrrolid-3-yl)propionic acid) (Compound 34)

[0328] Prepared according to the method for compound 9. LCMS: RT = 1.55 min, [MH] - = 813.13.

[0329] Example 35

[0330] Synthesis of (2S,2'S)-3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-4-chlorophenyl)sulfonyl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) (Compound 35)

[0331] Prepared according to the method for compound 9. LCMS: RT = 1.53 min, [MH] - = 793.09.

[0332] Example 36

[0333] Synthesis of (2S,2'S)-3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolid-3-yl)ethyl)-4-chlorophenyl)sulfonyl)azadiyl)bis(methylene))bis(6-fluoro-3,1-phenylene))bis(2-((R)-pyrrolid-3-yl)propionic acid) (Compound 36)

[0334] Prepared according to the method for compound 9. LCMS: RT = 1.53 min, [MH] - = 829.02.

[0335] Example 37

[0336] Synthesis of (S)-3-(3-(2-((3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-N-(2-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)phenyl)sulfonamido)ethyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid (Compound 37)

[0337] Prepared according to the method for compound 9. LCMS: RT = 1.51 min, [MH] - = 773.12. 1 H NMR(400 MHz, D2O) δ 7.67 (dt, J = 5.0, 2.4 Hz, 1H), 7.62 (s, 1H), 7.52 (d, J =6.0 Hz, 2H), 7.34 - 7.21 (m, 1H), 7.20 - 7.04 (m, 4H), 6.98 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 4.33 - 4.13 (m, 2H), 3.56 - 3.45(m, 3H), 3.42 - 3.31 (m, 3H), 3.23 - 3.15 (m, 5H), 3.12 - 2.83 (m, 5H), 2.78- 2.35 (m, 12H), 2.14 - 2.07 (m, 3H), 1.74 - 1.65 (m, 3H).

[0338] Example 38

[0339] Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-4-chlorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenethyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid (Compound 38)

[0340] The specific synthesis route is as follows:

[0341] Prepared according to the method for compound 9. LCMS: RT = 1.54 min, [MH] - = 807.11.

[0342] Example 39

[0343] Synthesis of (S)-3-(5-(N-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-4-chlorobenzyl)-N-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)-2-fluorophenyl)-2-((R)-pyrrolidine-3-yl)propionic acid (Compound 39)

[0344] Prepared according to the method for compound 9. LCMS: RT = 1.55 min, [MH] - = 811.03. 1H NMR(400 MHz, D2O) δ 7.69 - 7.58 (m, 1H), 7.57 (dd, J = 6.6, 2.4 Hz, 1H), 7.23(t, J = 9.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.02(d, J = 7.6 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.92 - 6.85 (m, 1H), 6.84-6.80 (m, 2H), 4.44 - 4.01 (m, 4H), 3.51 (dd, J = 11.6, 7.4 Hz, 1H), 3.48 -3.29 (m, 5H), 3.28 - 3.10 (m, 3H), 3.04 - 2.92 (m, 1H), 2.93 - 2.53 (m, 8H), 2.55 - 2.28 (m, 6H), 2.17 - 1.93 (m, 3H), 1.80 - 1.49 (m, 3H).

[0345] Example 40

[0346] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(6-chloro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) (Compound 40)

[0347] Prepared according to the method for compound 9. LCMS: RT = 1.52 min, [MH] - = 829.21.

[0348] Example 41

[0349] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bis(6-chloro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) (Compound 41)

[0350] Prepared according to the method for compound 9. LCMS: RT = 1.58 min, [MH] - =827.07.

[0351] Example 42

[0352] Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-4-fluorophenylsulfonyl)azadiyl)bis(6-chloro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) (Compound 42)

[0353] Prepared according to the method for compound 9. LCMS: RT = 1.58 min, [MH] - =845.07.

[0354] Examples 33, 43-47

[0355] Compounds 33 and 43-47 were prepared by referring to the preparation methods of the compounds in the foregoing examples (e.g., Example 30 or Example 9):

[0356]

[0357] Example 48 In vitro Lp(a) assembly detection

[0358] Experimental steps

[0359] 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 the IC50. 90 The values ​​are shown in Table 1.

[0360] Table 1 IC50 of sulfonamide compounds 90 value

[0361]

[0362]

[0363] As can be seen from the results in Table 1, the sulfonamide compounds of the present invention all have good LP(a) inhibitory activity.

[0364] Example 49

[0365] Pharmacokinetics of SD rats

[0366] (1) Experimental materials

[0367] SD rats: male, 180-250g, purchased from Guangdong Vital River Laboratory Animal Technology Co., Ltd.

[0368] Reagents: physiological saline, EDTA-K2 (anticoagulant), TCA (trichloroacetic acid), and propranolol (internal standard) are all commercially available.

[0369] Instruments: Nexera LC-40; AB SCIEX QTRAP 5500+.

[0370] (2) Experimental methods

[0371] The compound was dissolved in physiological saline. After administration to rats via gavage, 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 compound 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 equivalent to concentrations of 1, 3, 5, 10, 30, 100, 300, 1000, and 3000 ng / mL. Quality control sample concentrations were 9, 240, and 2400 ng / mL. Two samples were analyzed 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:

[0372] Column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0373] Mobile phase: water (0.1% formic acid) - acetonitrile. Gradient elution is performed according to the table below.

[0374] Table 2 Gradient Elution Table

[0375]

[0376] (3) Data processing

[0377] 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.

[0378] Table 3: Pharmacokinetic parameters of the compounds of this invention in SD rats

[0379]

[0380] As can be seen from the results in Table 3, the compounds of the present invention have higher exposure levels. In addition, the compounds of the present invention also exhibit longer half-lives and higher bioavailability.

[0381] Example 50

[0382] Monkey pharmacokinetics experiment

[0383] (1) Experimental materials

[0384] Beagle: Male, 8-10 kg, purchased from Beijing Mars Biotechnology Co., Ltd.

[0385] Crab-eating macaques: Male, 3-6 kg, purchased from Guangzhou Huazhen Biotechnology Co., Ltd. and Hainan Jingang Biotechnology Co., Ltd.

[0386] Reagents: physiological saline, EDTA-K2 (anticoagulant), TCA (trichloroacetic acid), and propranolol (internal standard) are all commercially available.

[0387] Instruments: Nexera LC-40; AB SCIEX QTRAP 5500+.

[0388] (2) Experimental methods

[0389] The compound was dissolved in physiological saline. After administration by gavage or intravenous injection to experimental animals, 200 μL of venous blood was collected at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h (5 min and 48 h 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 compound 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. The quality control sample concentrations were 9, 240, and 2400 ng / mL. Two samples were analyzed 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:

[0390] Column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0391] Mobile phase: water (0.1% formic acid) - acetonitrile. Gradient elution is performed according to the table below.

[0392] Table 4 Gradient Elution Table

[0393]

[0394] (3) Data processing

[0395] After LC-MS / MS was used to detect blood drug concentrations, pharmacokinetic parameters were calculated using WinNonlin 6.1 software and the non-compartmental model method. The results are shown in Tables 5 and 6.

[0396] Table 5: Pharmacokinetic parameters of the compounds of this invention in cynomolgus monkeys

[0397]

[0398] Table 6: Pharmacokinetic parameters of the compounds of this invention in cynomolgus monkeys

[0399]

[0400] As can be seen from the results in Tables 5 and 6, the compounds of the present invention have higher exposure levels, higher bioavailability, and longer half-lives.

[0401] 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. A sulfonamide compound, or its stereoisomer, its racemate, or its pharmaceutically acceptable salt, characterized in that, The structure of the sulfonamide compounds is shown in general formula I: Among them, X1~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 ; The X1~X 15 At least one of them is -N-; Or when X1~X 15 When each of the X1 to X5 is independently selected from -CR1, at least one of the R1s is not hydrogen, and at least one of the R1s is independently selected from... And the X6~X 10 At least one R1 is independently selected ; The Selected from: , , , , , , , , , or ; 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, 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 heteroaryl groups are independently selected from halogens, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 haloalkoxy groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, 3-6-membered heterocyclic alkyl groups, C3-C6 cycloalkoxy groups, C6-C 10 One or more of aryl or 5-10 heteroaryl groups; n, p, r are integers independently selected from 1, 2, or 3, and m is an integer selected from 0, 1, 2, or 3.

2. The sulfonamide compound, or its stereoisomer, racemate, or pharmaceutically acceptable salt according to claim 1, characterized in that, 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 The R2 is selected from -H, substituted or unsubstituted C1-C6 alkyl groups; the substituted C1-C6 alkyl groups, substituted C3-C6 alkyl groups... 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, C1-C6 haloalkyl groups, C1-C6 haloalkoxy groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, 3-6-membered heterocyclic alkyl groups, C3-C6 cycloalkoxy groups, C6-C 10 One or more of aryl or 5-10 heteroaryl groups.

3. The sulfonamide compound, or its isomer, racemate, or pharmaceutically acceptable salt according to claim 1 or 2, characterized in that, 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, and R1 is selected from: The X 11 or X 12 One of them is selected from CR1, and R1 is selected from: .

4. The sulfonamide compound, or its stereoisomer, racemate, or pharmaceutically acceptable salt according to any one of claims 1-3, characterized in that, The structures of sulfonamide compounds are shown in general formula II or III: or , Among them, X1~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 groups; Selected from: , , , , , , , , , or The substituents in the substituted C1-C6 alkyl and substituted C1-C6 alkoxy groups are independently selected from halogens, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 haloalkoxy groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic alkyl groups, C3-C6 cycloalkoxy groups, and C6-C6 cycloalkoxy groups. 10 One or more of aryl or 5-10 heteroaryl groups.

5. The sulfonamide compound, or its stereoisomer, racemate, or pharmaceutically acceptable salt according to any one of claims 1-4, characterized in that, The structures of the sulfonamide compounds are shown in general formula IV or V: or , Wherein, X1~X3 and X5~X9 are each independently selected from -N- or -CR1, and R1 is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, or The X 11 X 12 X 13 X 14 or X 15 Each of them is independently selected from -CR1, wherein R1 is selected from The Selected from: , , , , , , , , , or 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, C1-C6 haloalkyl groups, C1-C6 haloalkoxy groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic alkyl groups, C3-C6 cycloalkoxy groups, C6-C 10 One or more of aryl or 5-10 heteroaryl groups; preferably, R1 is selected from... Any one of them.

6. The sulfonamide compound, or its stereoisomer, racemate, or pharmaceutically acceptable salt according to any one of claims 1-5, characterized in that, R1 is selected from H, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, piperazine, -CH2COOH, -CH2CH2COOH, -CH2CH(CH3)COOH, , or The Selected from: , , , , , , , , , or ; .

7. The sulfonamide compound, or its stereoisomer, racemate, or pharmaceutically acceptable salt according to claim 6, characterized in that, The Selected from: .

8. The sulfonamide compound, or its stereoisomer, racemate, or pharmaceutically acceptable salt according to claim 7, characterized in that, The Selected from: 。 9. The sulfonamide compound, or its stereoisomer, racemate, or pharmaceutically acceptable salt according to any one of claims 1-8, characterized in that, One or more hydrogen atoms of the sulfonamide compound are coated with the isotope deuterium ( 2 H) substitution.

10. A pharmaceutical composition, characterized in that, The compound comprises a sulfonamide compound as described in any one of claims 1-9, or a stereoisomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and / or carriers; preferably, the sulfonamide compound is selected from: .

11. Use of the sulfonamide compound of any one of claims 1-9, or its stereoisomer, racemate, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 10, in the preparation of a medicament for the prevention or treatment of diseases related to LP(a); preferably, the sulfonamide compound is selected from: .

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

13. The use according to claim 12, characterized in that, 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.

14. A method for preparing compound 9, characterized in that, The synthetic route for preparing compound 9 is as follows: 。 15. An intermediate 1, characterized in that, The structural formula of intermediate 1 is: .

16. An intermediate 2, characterized in that, The structural formula of intermediate 2 is as follows: .

17. An intermediate 3, characterized in that, The structural formula of the intermediate 3 is as follows: .

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