Sulfonamide compound as well as preparation method and medical application thereof

Abstract

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

Description

A sulfonamide compound and its preparation method and medical use Technical Field

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

[0002] LPA is the name of the gene encoding apolipoprotein (a) (apo(a)). It is primarily expressed in the liver, with expression restricted to humans and non-primates. Apolipoprotein (a) is attached to apo(B)-100 via a disulfide bond, forming a lipid core that forms the lipoprotein (a) (Lp(a)) particle. Lp(a) particles are specialized, large cholesterol-rich lipoproteins with a surface coated with cholesterol and phospholipids and embedded with the hydrophilic apolipoprotein components apolipoprotein (a) and apo(B)-100. Lp(a) can enter and deposit on blood vessel walls, promoting atherosclerosis. Lp(a) shares structural homology with plasminogen (PLG) and can compete with plasminogen for binding sites on fibrin, thereby inhibiting fibrinogen hydrolysis and promoting thrombosis. Therefore, Lp(a) is closely associated with atherosclerosis and thrombosis. Studies have shown that Lp(a) levels in the blood 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 diet, exercise, or other lifestyle changes.

[0003] Currently reported LP(a) inhibitors are primarily macromolecular or small nucleic acid drugs. For example, WO2023046093A1 discloses a bispecific fusion polypeptide; CN111465694A discloses a nucleic acid for inhibiting LPA expression in cells; CN108368506A also discloses compositions and methods for inhibiting LPA gene expression; and CN113166759A discloses a chemically modified RNAi construct and its use. Currently, there are no marketed small-molecule LP(a) drugs. Among the projects under development, the only one, 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.

[0004] Summary of the Invention

[0005] In view of the problems existing in the prior art, the present invention provides a small molecule LP(a) drug to solve the problem of the shortage of small molecule LP(a) drugs in the prior art.

[0006] The present invention is achieved through the following technical solutions:

[0007] The present invention provides a sulfonamide compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that the structure of the sulfonamide compound is as shown in general formula I:

[0008] Among them, X1~X 15 Each is independently selected from -N- or -CR1, wherein R1 is selected from H, halogen, -OH, -NH2, -CN, -NO2, -COOH, -SO3H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or X1~X 15 At least one of them is -N-;

[0009] Or when X1~X 15 When all are independently selected from -CR1, at least one R1 is not hydrogen, and at least one R1 among X1 to X5 is independently selected from And the X6~X 10 At least one R1 is independently selected from

[0010] Or when X1~X 15 When all of X1 to X 15 Any two adjacent R1 and the connected carbon atom together form a substituted or unsubstituted C6-C 10 Aryl or 5-10 membered heteroaryl;

[0011] Said R2 is selected from -H, halogen, substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C1-C6 alkoxy;

[0012] Said R3 is selected from -(CH2) q -(5-8 membered heterocyclyl);

[0013] The substituted C1-C6 alkyl, substituted C1-C6 alkoxy, substituted C3-C 10 Cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C6-C 10 The substituents in the aryl or substituted 5-10 membered heteroaryl are independently selected from halogen, hydroxy, carboxyl, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C3-C6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C3-C6 cycloalkoxy, C6-C6 alkyl, C1 ... 10one or more of aryl or 5-10 membered heteroaryl;

[0014] n, p, and r are independently selected from integers of 1, 2, or 3; m and q are independently selected from integers of 0, 1, 2, or 3.

[0015] As a preferred technical solution of the present invention, the R1 is selected from H, halogen, -OH, -NH2, -CN, -NO2, -COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or The R2 is selected from -H, substituted or unsubstituted C1-C6 alkyl; the R3 is selected from 5-8 membered heterocyclic group; the substituted C3-C 10 Cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C6-C 10 The substituents in the aryl or substituted 5-10 membered heteroaryl are independently selected from halogen, hydroxy, carboxyl, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C3-C6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C3-C6 cycloalkoxy, C6-C6 alkyl, C1 ... 10 one or more of aryl or 5-10 membered heteroaryl.

[0016] As a preferred technical solution of the present invention, the Selected from quinolinyl; More preferably:

[0017] As a preferred technical solution of the present invention, one of X4 or X5 is selected from The X9 or X 10 One of the The X 11 or X 12 One of the

[0018] As a preferred technical solution of the present invention, X4 or X5 is selected from One of the X9 or X 10 Selected from One of the X 11 or X 12 Selected from one of the.

[0019] As a preferred technical solution of the present invention, the structure of the sulfonamide compound is shown in general formula II or III:

[0020] 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 The R2 is selected from H, substituted or unsubstituted C1-C6 alkyl; the R3 is selected from 5-8 membered heterocyclic group; the substituents in the substituted C1-C6 alkyl and substituted C1-C6 alkoxy are independently selected from halogen, hydroxyl, carboxyl, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C3-C6 cycloalkoxy, C6-C 10 one or more of aryl or 5-10 membered heteroaryl.

[0021] As a preferred technical solution of the present invention, the structure of the sulfonamide compound is shown in Formula IV or V:

[0022] 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 The R2 is selected from H, substituted or unsubstituted C1-C6 alkyl; the R3 is selected from 5-8 membered heterocyclic group; the substituents in the substituted C1-C6 alkyl and substituted C1-C6 alkoxy are independently selected from halogen, hydroxyl, carboxyl, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C3-C6 cycloalkoxy, C6-C 10 one or more of aryl or 5-10 membered heteroaryl.

[0023] As a preferred technical solution of the present invention, the X 11 、X 12 、X 13 、X 14 or X 15 Any one of which is independently selected from -CR1, wherein R1 is selected from Preferably, the R1 is selected from Any one of .

[0024] As a preferred technical solution of the present invention, the R1 is selected from H, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, piperazinyl, -CH2COOH, -CH2CH2COOH, -CH2CH(CH3)COOH, The R3 is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl or pyrazinyl.

[0025] As a preferred technical solution of the present invention, the Selected from:

[0026] As a preferred technical solution of the present invention, the Selected from:

[0027] As a preferred technical solution of the present invention, the Selected from:

[0028] In the chemical structure of the compound of the present invention, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or colleagues include Two configurations;

[0029] In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations;

[0030] The compounds of the present invention and intermediates can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. The lactam-lactim equilibrium example is between A and B as shown below.

[0031] All compounds in the present invention can be drawn as either Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of the compounds does not exclude any tautomers.

[0032] As a preferred technical solution of the present invention, the C1-C6 alkyl group is preferably a 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.

[0033] As a preferred technical solution of the present invention, the C1-C6 alkoxy group is preferably a C1-C2, C1-C3, C1-C4 or C1-C5 alkoxy group. Furthermore, the alkoxy group is specifically selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

[0034] 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, preferably C3-C8 cycloalkyl, and the cycloalkyl group is specifically selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0035] As a preferred technical solution of the present invention, in some embodiments, the "heterocyclyl" is a 5-10-membered heterocyclyl composed of 5-10 ring atoms; in other embodiments, the "heterocyclyl" is a 5-8-membered heterocyclyl composed of 5-8 ring atoms; in other embodiments, the "heterocyclyl" is a 6-8-membered heterocyclyl composed of 6-8 ring atoms; in other embodiments, the "heterocyclyl" is a 5-6-membered heterocyclyl composed of 5-6 ring atoms. Examples of heterocyclic groups include, but are not limited to, pyranyl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl, tetrahydro-thiopyran 1,1-dioxide, 1,4-diazepanyl.

[0036] As a preferred technical solution of the present invention, in some embodiments, "heterocycloalkyl" is preferably 3-12 membered heterocycloalkyl; more preferably 3-10 membered heterocycloalkyl; more preferably 5-8 membered heterocycloalkyl; most preferably 5-6 membered heterocycloalkyl; examples of the heterocycloalkyl are but not limited to: aziridine, oxirane, azetidine, oxetane, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazine ]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, 3-thia-9-aza-bicyclo[3.3.1]nonyl, 2,6-diaza-spiro[3.3]heptanyl. More particular examples of heterocycloalkyl are pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazinyl and 2,6-diaza-spiro[3.3]heptanyl.

[0037] As a preferred embodiment of the present invention, the substituted or unsubstituted C6-C 10 The aryl group is preferably a substituted or unsubstituted C6-C8 aryl group, a substituted or unsubstituted C6-C7 aryl group; when the aryl group is substituted, the substituent is preferably selected from H, halogen, -OH, -NH2, -CN, -NO2, -COOH, -SO3H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 10 Cycloalkyl, C6-C 10 Substituted or unsubstituted aryl, C5-C 10 a substituted or unsubstituted heteroaryl group, wherein the aryl group is specifically selected from phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like;

[0038] The substituted or unsubstituted 5-10 membered heteroaryl group is preferably a substituted or unsubstituted 5-8 membered aromatic heteroyl group, a substituted or unsubstituted 5-7 membered heteroaryl group or a substituted or unsubstituted 5-6 membered heteroaryl group; when the heteroaryl group is substituted, the substituent is preferably selected from H, halogen, -OH, -NH2, -CN, -NO2, -COOH, -SO3H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 10Cycloalkyl, substituted or unsubstituted C5-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroatom in the heteroaryl is one or more of N, O, and S. The heteroaryl is preferably selected from: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, pyrazolyl, isoxazolyl, thiazolyl, pyrazolyl, tetrazolyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, tetrazolyl and the like.

[0039] As a preferred technical solution of the present invention, the sulfonamide compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt is selected from the compounds shown in Table 1A or Table 1B:

[0040] Table 1A

[0041] Table 1B

[0042] The present invention further provides a method for preparing a sulfonamide compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, which is prepared by referring to the method of patent CN114008021A and methods known in the art.

[0043] The present invention further provides a pharmaceutical composition, characterized in that it comprises a sulfonamide compound described in general formula I, general formula II, general formula III, general formula IV or general formula V, or its isomer, or its racemate or pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients and / or carriers.

[0044] The present invention further provides a use of a sulfonamide compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt in the preparation of a drug for preventing or treating diseases associated with LP(a).

[0045] Furthermore, the Lp(a)-related disease is selected from cardiovascular disease;

[0046] Furthermore, the cardiovascular disease is selected from stroke, atherosclerosis, thrombosis, coronary heart disease or aortic valve stenosis and any other disease associated with elevated Lp(a) levels.

[0047] The beneficial effects of the present invention over the prior art include but are not limited to:

[0048] Compared with the prior art, the sulfonamide compounds of the present invention have lower IC 90value.

[0049] For the sake of clarity, general terms used in the description of the compounds are defined herein.

[0050] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered as undefined or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0051] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared by reacting a compound having a specific substituent discovered in the present invention with a pharmaceutically acceptable acid or base.

[0052] In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0053] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrates. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0054] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0055] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, separation of enantiomers and diastereomers is typically accomplished by using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., formation of carbamates from amines).

[0056] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms are preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched chain isomers thereof. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, C1-C6 alkyl, C 1- C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C5-C8 cycloalkenyl, C3-C6 cycloalkyloxy, 3- to 6-membered heterocycloalkoxy, C5-C8 cycloalkenyloxy, C6-C 10 aryl or 5 to 6 membered heteroaryl, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C3-C6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C5-C8 cycloalkenyl, C3-C6 cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C5-C8 cycloalkenyloxy, C6-C 10 The aryl or 5- to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, and cyano.

[0057] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

[0058] The term "haloalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atoms. The term "perhaloalkoxy" refers to an alkoxy group in which all of the hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy, and pentafluoroethoxy. Particular haloalkoxy groups are trifluoromethoxy and 2,2-difluoroethoxy.

[0059] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0060] The term "cycloalkyl" or "carbocycle" refers to a saturated monocyclic or polycyclic 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 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0061] The term "aryl" or "aromatic ring" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6- to 8-membered, such as phenyl and naphthyl.

[0062] The term "heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 3 heteroatoms, 5 to 12 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably a 5- to 10-membered, 5- to 8-membered heteroaryl group, and more preferably a 5- or 6-membered heteroaryl group. Pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl. Particular heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl and isothiazolyl. More particular heteroaryl groups include imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl, isothiazolyl, 2-fluoropyridinyl, 3-fluoropyridinyl, 4-fluoropyridinyl, 2-chloropyridinyl, 3-chloropyridinyl, 4-chloropyridinyl, 2,3-difluoropyridinyl, 3,4-difluoropyridinyl, 4,5-difluoropyridinyl, 3,5-difluoropyridinyl, 2-chloro-3-fluoro-pyridinyl, 3-fluoro-4-chloro-pyridinyl, 3-fluoro-5-chloro-pyridinyl, 4-fluoropyrimidinyl, 5-fluoropyrimidinyl, 4-chloropyrimidinyl, 5-chloropyrimidinyl, 4-chloro-5-fluoropyrimidinyl, 4-cyanopyrimidinyl, 5-cyanopyrimidinyl, 4,5-dicyanopyrimidinyl, 4-methylpyrimidinyl, 5-methylpyrimidinyl or 4,5-dimethylpyrimidinyl.

[0063] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl), a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) or a heteroaromatic ring system, which contains at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxoed, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS- or -SS-) in the ring, and has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3-12-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3-8-membered heterocyclic group); more preferably a heterocyclic group having 5 to 8 ring atoms (i.e., a 5-8-membered heterocyclic group); most preferably a heterocyclic group having 5 to 6 ring atoms (i.e., a 5-6-membered heterocyclic group). In some embodiments, the 5-8-membered heterocyclic group is selected from: 5-8-membered heterocycloalkyl, 5-8-membered heteroaryl. In some embodiments, the 5-6-membered heterocyclic group is selected from: 5-6-membered heterocycloalkyl, 5-6-membered heteroaryl.

[0064] The term "heterocycloalkyl" refers to a cycloalkyl group whose carbon atoms are substituted by 1-4 heteroatoms, wherein the heteroatoms are selected from one or more of N, O or S; preferably a 3-12 membered heterocycloalkyl group; more preferably a 3-10 membered heterocycloalkyl group; more preferably a 5-8 membered heterocycloalkyl group; most preferably a 5-6 membered heterocycloalkyl group; examples of the heterocycloalkyl group include, but are not limited to, aziridine, oxirane, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl , tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazinyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, 3-thia-9-aza-bicyclo[3.3.1]nonyl, 2,6-diaza-spiro[3.3]heptanyl. More particular examples of heterocycloalkyl are pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazinyl and 2,6-diaza-spiro[3.3]heptanyl.

[0065] The atoms of the molecules of the compounds of the present invention are isotopes, and isotope derivatization can generally extend half-life, reduce clearance, stabilize metabolism, and increase in vivo activity. In addition, an embodiment is included in which at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (protons and neutrons). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, which respectively include 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomy testing of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with their amount nor are they radioactive, so they can be used safely. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0066] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen, such as trifluoromethyl, trifluoroethyl, etc.;

[0067] The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen, for example, trifluoromethyloxy, trifluoroethyloxy, and the like.

[0068] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0069] Furthermore, one or more hydrogen atoms of the compounds of the present invention are replaced by the isotope deuterium (2H). After deuteration, the compounds of the present invention have the effects of extending half-life, reducing clearance rate, metabolic stability and improving in vivo activity.

[0070] The preparation method of the isotopic derivative generally includes a phase transfer catalytic method. For example, a preferred deuteration method uses a phase transfer catalyst (e.g., a tetraalkylammonium salt, NBu4HSO4). The use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in a higher deuterium incorporation than reduction with a deuterated silane (e.g., triethyldeuterated monosilane) in the presence of an acid (e.g., methanesulfonic acid) or with a Lewis acid such as aluminum trichloride using sodium deuterated borate.

[0071] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical medicine. For additional information about carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0072] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0073] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0074] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0075] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. DETAILED DESCRIPTION

[0076] The present invention is further described in detail below with reference to the embodiments, but the content of the invention is not limited to the embodiments.

[0077] Example 1

[0078] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)azepinediyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propionic acid)

[0079] The specific synthetic route is as follows:

[0080] Step A: Synthesis of (R)-3-(S)-1-tert-butyl-3-(3-chlorosulfonyl)phenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0081] 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, isopropylmagnesium chloride and lithium chloride liquid (1.1 ml, 2.5 mol / L) were added. After reacting for two hours, sulfuryl chloride (101 mg, 0.53 mmol) was added and the temperature was slowly raised to room temperature. After continued stirring for 14 hours, TLC plate analysis indicated that the starting material had reacted completely. The mixture was quenched by the addition of aqueous ammonium chloride (10 mL) at -30°C and extracted with EA (20 mL x 3). The collected organic phases were dried over colorless sodium sulfate and evaporated. The crude product was purified by column chromatography using n-hexane:ethyl acetate = 3:1 to obtain 113 mg of tert-butyl (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.17 min, [M+H] + =474.17.

[0082] Step B: Synthesis of 3,3'-((2S,2'S)-di-tert-butyl(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)sulfonyl)azepinediyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate)

[0083] At room temperature, tert-butyl (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (55 mg, 0.12 mmol) was dissolved in acetonitrile (2.5 ml) and stirred. Di-tert-butyl 3,3'-((2S,2'S)-((nitrogendiylbis(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. ), stirred at 80°C for 14 hours, and then detected by TLC. The reaction of the raw materials was completed, the reaction was terminated, and water (6 ml) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 ml × 3 times), and the collected organic phases were dried over colorless sodium sulfate. The crude product was purified by column chromatography using n-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)pyrrolidin-3-yl)-3-oxopropyl)phenyl)sulfonyl)azepinediyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0084] Step C: Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)azepinediyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propanoic acid)

[0085] 3,3'-((2S,2'S)-di-tert-butyl(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)sulfonyl)azepinediyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.081 mmol) was dissolved in 1,4-dioxane (3.0 ml), concentrated hydrochloric acid (1.0 ml) was added and the mixture was reacted at room temperature for 10 hours. The reaction was completed after LCMS monitoring. The residue was concentrated under reduced pressure to afford the crude target product, which was then purified by preparative HPLC to yield 5.2 mg of (S)-3-(3-((3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)(3-fluoro-5-methoxybenzyl)amino)methyl)phenyl)-2-(pyridin-3-yl)propanoic acid. LCMS: RT = 1.49 min, [MH] -=759.43, HPLC: 90.22%.

[0086] Example 2

[0087] Synthesis of (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)azadiyl)bis(methylene)bis(6-fluoro-3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0088] The specific synthetic route is as follows:

[0089] Step A: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0090] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-5-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (200 mg, 0.47 mmol), tert-butyl (R)-3-((S)-3-(3-(aminomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (192 mg, 0.47 mmol) and anhydrous isopropanol (5 ml) were added sequentially. The temperature was raised to 45° C., and sodium triacetoxyborohydride (201 mg, 0.94 mmol) was then added in three batches. The reaction was carried out at 45° C. for 18 hours.

[0091] After the reaction was completed, saturated aqueous ammonium chloride solution (10 ml) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 ml x 2 times) and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1) to obtain 210 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.03 min, [M+H] + =810.08.

[0092] Step B: Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorobenzyl)phenyl)sulfonamido)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0093] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (172 mg, 0.21 mmol) was added. , (R)-3-((S)-1-(tert-butoxy)-3-(3-(chlorosulfonyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.2 mmol), acetonitrile (3 ml), triethylamine (32 mg, 0.32 mmol), 4-dimethylaminopyridine (9 mg, 0.07 mmol), nitrogen replacement, heated to 80°C for 2 hours.

[0094] After the reaction was completed, tap water (10 ml) and ethyl acetate (10 ml) were added for extraction, and the mixture was concentrated to dryness to obtain a crude product, which was used directly in the next step.

[0095] Step C: (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)azepinediyl)bis(methylene)bis(6-fluoro-3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0096] The crude product from the previous step, dioxane (2.5 ml) and concentrated hydrochloric acid (0.5 ml) were added at room temperature and the mixture was reacted at 45°C for 18 hours.

[0097] After the reaction was completed, the product was concentrated to dryness, and the residue was purified by preparative high performance liquid chromatography to give 18 mg of (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)azepinediyl)bis(methylene)bis(6-fluoro-3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid). LCMS: RT = 1.58 min, [MH] - =777.30.

[0098] Example 3

[0099] Synthesis of (S)-3-(3-(((3-(S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-N-(2-((S)2-carboxy-2-(R)pyrrolidin-3-ylethyl)phenethyl)phenyl)sulfonamido)methyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0100] The specific synthetic route is as follows:

[0101] Prepared according to the method of compound 2. LCMS: RT = 1.45 min, [MH] - =773.31.

[0102] Example 4

[0103] Synthesis of (S)-3-(3-(N-(5-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-2-fluorobenzyl)-N-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropanoic acid

[0104] Prepared according to the method of compound 2. LCMS: RT = 1.52 min, [M+H] + =779.16.1H NMR(400MHz,D2O)δ7.61(d,J=6.2Hz,1H),7.53(s,1H),7.47(d,J=6.2Hz,2H),7.12(t,J=7.6Hz,1H),7.01-6.96(m,2H),6.93(d,J=7.6Hz,1H),6. 84-6.78(m,3H),4.31(s,4H),3.51-3.28(m,6H),3.21-3.12(m,3H),2.9 8-2.73(m,6H),2.72-2.24(m,9H),2.10-2.03(m,3H),1.74-1.61(m,3H).

[0105] Example 5

[0106] Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-ethyl)-2-fluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropionic acid

[0107] Prepared according to the method of compound 2. LCMS: RT = 1.51 min, [M+H] +=779.21.

[0108] Example 6

[0109] Synthesis of (2S,2'S)-3,3'-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-4-fluorophenylsulfonyl)azepinediyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propionic acid)

[0110] The specific synthetic route is as follows:

[0111] Step A: Synthesis of tert-butyl (R)-3-(S)-3-(5-(benzylthio)-2-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0112] At room temperature, tert-butyl (R)-3-(S)-3-(5-bromo-2-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (2.0 g, 4.23 mmol), benzyl mercaptan (630 mg, 5.08 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (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 the temperature was raised to 100° C. for reaction for 5 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 2.0 g of tert-butyl (R)-3-(S)-3-(5-(benzylthio)-2-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.52 min, [M+H-Boc] + =416.13.

[0113] Step B: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(5-chlorosulfonyl)-2-fluorophenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0114] To tert-butyl (R)-3-(S)-3-(5-(Benzylthio)-2-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.0 g, 1.94 mmol) was dissolved in acetic acid / water / acetonitrile (1.1 / 0.7 / 30 ml). To the solution was added dropwise a solution of 1,3-dichloro-5,5-dimethylhydantoin (760 mg, 3.88 mmol) in acetonitrile (2 ml) under ice-cooling. The mixture was stirred until the solution turned red. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate (30 ml x 2). The combined organic phases were washed with saturated brine (20 ml x 2), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to give 0.8 g of (R)-3-(S)-1-tert-butoxy-3-(5-chlorosulfonyl)-2-fluorophenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS: RT = 2.29 min, [M+H-Boc-tert-butyl] + =336.01.

[0115] Step C and step D were prepared according to the method of compound 2. LCMS: RT = 1.52 min, [M+H] + =779.16. 1 H NMR(400MHz,D2O)δ7.66(t,J=6.8Hz,1H),7.62(d,J=7.2Hz,1H),7.26(t,J=9.2 Hz,1H),7.13(t,J=7.2Hz,2H),7.05(d,J=7.2Hz,2H),6.88(d,J=7.6Hz,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).

[0116] Example 7

[0117] Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-5-fluorophenylsulfonyl)azepinediyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propionic acid)

[0118] Prepared by referring to the method of compound 2. LCMS: RT=1.51 min, [M+H]+=779.21.

[0119] Example 8

[0120] Synthesis of (2S,2'S)-3,3'(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-2-fluorophenylsulfonyl)azepinediyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propionic acid)

[0121] The specific synthetic route is as follows:

[0122] 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-carboxylate)

[0123] At room temperature, tert-butyl (R)-3-(S)-3-(3-aminomethyl)phenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (300 mg, 0.74 mmol) and tert-butyl (R)-3-(S)-1-tert-butoxy-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (300 mg, 0.74 mmol) were dissolved in DCE (6 ml). Sodium triacetoxyborohydride (551 mg, 2.6 mmol) was added portionwise. The temperature was raised to 45°C and stirring was continued for 16 hours.

[0124] The reaction was monitored by TLC until completion, after which an aqueous solution (1 ml) was added to quench the reaction. The resulting 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-carboxylate) was obtained. LC-MS: RT = 2.02 min, [M+H] + =792.61.

[0125] Step B: Synthesis of 3,3'-(((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2-fluorophenyl)sulfonyl)azepinediyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate)

[0126] 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-oxopropan-2-yl)pyrrolidine-1-carboxylic acid 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 hour.

[0127] After the reaction was completed, as determined by TLC, the product was extracted with ethyl acetate (10 ml x 2 times). The combined organic phases were washed with saturated brine (5 ml x 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)pyrrolidin-3-yl)-3-oxopropyl)-2-fluorophenyl)sulfonyl)azepinediyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0128] Step C: Synthesis of (2S,2'S)-3,3'(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-2-fluorophenylsulfonyl)azepinediyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propanoic acid)

[0129] At room temperature, 3,3'-(((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2-fluorophenyl)sulfonyl)azepinediyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (60 mg, 0.05 mmol) was dissolved in 1,4-dioxane solution (2 ml), concentrated hydrochloric acid (0.1 ml) was added, and the temperature was raised to 45 degrees Celsius for 4 hours.

[0130] The reaction was monitored by LC-MS until completion, and the product was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 16 mg of (2S,2'S)-3,3'-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-2-fluorophenylsulfonyl)azepinediyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propionic acid. LCMS: RT = 1.51 min, [MH] -=777.1.

[0131] Example 9

[0132] Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)azadiyl)bismethylene)bis(6-fluoro-3,1-phenylene)bis(2-(R)-pyrrolidin-3-ylpropionic acid)

[0133] The specific synthetic route is as follows:

[0134] 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(tert-butyl pyrrolidine-1-carboxylate)

[0135] 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 temperature was raised to 45° C. for 3 hours. Subsequently, sodium triacetoxyborohydride (528 mg, 2.49 mmol) was added portionwise. The mixture was reacted at 45°C for 4 hours. After completion of the reaction, it was diluted with water and extracted with ethyl acetate (20 ml x 2). The combined organic phases were washed with saturated brine (20 ml x 2) and then dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 350 mg 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-carboxylate). LCMS: RT = 2.11 min, [M+H] + =828.29.

[0136] Step B: Synthesis of 3,3'-(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)sulfonyl)azepinediyl)bismethylene)bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(tert-butyl pyrrolidine-1-carboxylate)

[0137] 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-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (116 mg, 0.25 mmol) in acetonitrile (1.2 ml) was added, and the mixture was reacted at room temperature for 18 hours. After completion of the reaction, the product was concentrated under reduced pressure to obtain a residue which was 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)pyrrolidin-3-yl)-3-oxopropyl)phenyl)sulfonyl)azepinediyl)bismethylene)bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(tert-butyl pyrrolidine-1-carboxylate).

[0138] Step C: Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)azepinediyl)bismethylene)bis(6-fluoro-3,1-phenylene)bis(2-(R)-pyrrolidin-3-ylpropionic acid)

[0139] 3,3'-(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)sulfonyl)azepinediyl)bismethylene)bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(tert-butyl pyrrolidine-1-carboxylate) (50 mg, 0.040 mmol) was dissolved in 1,4-dioxane (3.0 ml), concentrated hydrochloric acid (0.3 ml) was added and the mixture was reacted at 45°C for 6 hours. After the reaction, the mixture was concentrated under reduced pressure to obtain a residue which was separated and purified by high performance liquid chromatography to obtain 26.2 mg of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)azepinediyl)bismethylene)bis(6-fluoro-3,1-phenylene)bis(2-(R)-pyrrolidin-3-ylpropionic acid).

[0140] LCMS: RT = 1.53 min, [MH] - =795.12. 1H NMR(400MHz,D2O)δ7.70-7.62(m,1H),7.58(s,1H),7.51(d,J=6.6Hz,2H),6.92-6.80(m,4H),6.77(d,J=7.2Hz,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).

[0141] Example 10

[0142] Synthesis of (S)-3-(3-(N-(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-ethyl)-4-chlorobenzyl)-N-(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0143] Prepared according to the method of compound 9. LCMS: RT = 1.54 min, [M+H] + =795.11. 1 H NMR(400MHz,D2O)δ7.62(s,1H),7.51(s,1H),7.47(d,J=4.8Hz,2H),7.16(d,J=8.2Hz,1H) ,7.11(t,J=7.6Hz,1H),7.00(d,J=7.6Hz,1H),6.93(d,J=7.6Hz,1H),6.87(d,J=8.2Hz,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).

[0144] Example 11

[0145] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)nitrogendiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis((2-(R)pyrrolidin-3-ylpropionic acid)

[0146] The specific synthetic route is as follows:

[0147] Step A: (R)-tert-Butyl 3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(hydroxymethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0148] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (320 mg, 0.76 mmol) and anhydrous isopropanol (5 ml) were added. The mixture was cooled with ice water, and then sodium borohydride (28 mg, 0.76 mmol) was added in three batches. The mixture was reacted in an ice-water bath for 1 hour.

[0149] After the reaction was complete, saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction, followed by extraction with ethyl acetate (10 mL x 2), washing with saturated aqueous sodium chloride solution (10 mL x 1), drying over sodium sulfate, and concentration to dryness to yield 350 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(hydroxymethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.13 min, [M-Boc+H] + =324.17.

[0150] Step B: (R)-tert-Butyl 3-((S)-1-(tert-butoxy)-3-(3-((1,3-dioxoisoindolin-2-yl)methyl)-2-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0151] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(hydroxymethyl)phenyl)-1-oxopropan-2-yl)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 in sequence, followed by the slow dropwise addition of diisopropyl azodicarboxylate (333 mg, 1.65 mmol), and the reaction was carried out at room temperature for 2 hours.

[0152] 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 obtain 630 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((1,3-dioxoisoindolin-2-yl)methyl)-2-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0153] Step C: (R)-tert-Butyl 3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(aminomethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0154] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((1,3-dioxoisoindolin-2-yl)methyl)-2-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (630 mg, 1.14 mmol) was added and dissolved in ethanol (10 ml). Hydrazine hydrate (80%, 178 mg, 2.84 mmol) was then added, and the temperature was raised to 85°C for 3 hours.

[0155] After the reaction was complete, the white solid was removed by filtration. The filter cake was washed with ethyl acetate (20 ml x 2). The combined filtrates were 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 obtain 264 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(aminomethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 1.82 min, [M+H] + =423.16.

[0156] Step D: tert-Butyl 3,3'-di-tert-butyl((2S,2'S)-((nitrogendiylbis(methylene))bis(2-fluoro-3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bispyrrolidine-1-carboxylate

[0157] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (216 mg, 0.51 mmol), tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(aminomethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (260 mg, 0.61 mmol), and 1,2-dichloroethane (6 ml) were added sequentially. The temperature was raised to 45°C, and sodium triacetoxyborohydride (326 mg, 1.54 mmol) was then added in three batches. The reaction was carried out at 45°C for 18 hours.

[0158] After the reaction was completed, saturated aqueous ammonium chloride solution (10 ml) was added to quench the reaction. The mixture was extracted with dichloromethane (10 ml x 2) and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 1) to obtain 405 mg of tert-butyl 3,3'-di-tert-butyl ((2S,2'S)-((nitrogendiylbis(methylene))bis(2-fluoro-3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bispyrrolidine-1-carboxylate. LCMS: RT = 2.04 min, [M+H] + =828.31.

[0159] Step E: 3,3'-di-tert-butyl((2S,2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)sulfonyl)nitrogendiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate)

[0160] At room temperature, tert-butyl 3,3'-di-tert-butyl((2S,2'S)-((nitrogendiylbis(methylene))bis(2-fluoro-3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bispyrrolidine-1-carboxylate (300 mg, 0.36 mmol) and pyridine (3 ml) were added. After complete dissolution, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(chlorosulfonyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (2.1 ml, 100 mg / ml, acetonitrile solution, 0.43 mmol) was added dropwise, and the mixture was reacted at room temperature for 2 hours.

[0161] After the reaction was completed, the product was concentrated to dryness and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 226 mg of 3,3'-di-tert-butyl((2S,2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)sulfonyl)nitrogendiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0162] Step F: (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)nitrogendiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis((2-(R)pyrrolidin-3-ylpropionic acid)

[0163] 3,3'-di-tert-butyl((2S,2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)sulfonyl)nitrogendiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis(3-(tert-butoxy)-3-oxypropane-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 mixture was reacted at 45°C for 4 hours.

[0164] After the reaction was completed, the product was concentrated to dryness, and the residue was purified by preparative high performance liquid chromatography to give 104 mg of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)nitrogendiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis((2-(R)pyrrolidin-3-ylpropionic acid). LCMS: RT = 1.48 min, [MH] - =795.12. 1 H NMR(400MHz,DeuteRium Oxide)δ7.60–7.52(m,1H),7.44(t,J=7.7Hz,3H),6.99(dt,J=16.0,7.1Hz, 4H),6.88(t,J=7.6Hz,2H),4.45–4.28(m,4H),3.50–3.27(m,6H),3.16(ddd, J=17.0,12.6,7.2Hz,3H),2.97–2.69(m,5H),2.57(d,J=6.0Hz,4H),2.48–2. 29(m,6H),2.03(dd,J=6.4,3.4Hz,3H),1.65(ddt,J=22.2,13.1,9.2Hz,3H).

[0165] Example 12

[0166] Synthesis of (S)-3-(3-(N-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2-chlorobenzyl)-N-(3-((S)-2-carboxy-2-((R)pyrrolidin-3-yl)ethyl)benzyl)sulfamoyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0167] Prepared by referring to the method of compound 9. LCMS: RT = 1.49 min, [MH] - =793.07. 1H NMR(400MHz,DeuteRium Oxide)δ7.60(dt,J=6.3,2.3Hz,1H),7.52(S,1H),7.46(d,J=6.4Hz,2H),7.11–7.00(m,4H) ,6.96(d,J=7.6Hz,1H),6.90(d,J=7.6Hz,1H),6.79(S,1H),4.51–4.24(m,4H),3.42(dt,J=1 1.5,7.3Hz,2H),3.32(ddt,J=11.6,7.7,3.1Hz,4H),3.22–3.08(m,3H),2.94–2.59(m,8H), 2.50(dd,J=13.4,4.4Hz,1H),2.46–2.24(m,6H),2.05(d,J=16.2Hz,3H),1.75–1.57(m,3H).

[0168] Example 13

[0169] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)phenylsulfonyl)azepinediyl)bismethylene)bis(4-fluoro-3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propionic acid)

[0170] The specific synthetic route is as follows:

[0171] Prepared by referring to the method of compound 11. LCMS: RT = 1.51 min, [MH] - =795.09.

[0172] Example 14

[0173] Synthesis of (S)-3-(3-(5-(S)-2-carboxy-2-(R)-pyrrolidin-3-ethyl)-2-fluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-4-fluorobenzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropionic acid

[0174] Prepared by referring to the method of compound 9. LCMS: RT = 1.49 min, [MH] - =795.24. 1H NMR(400MHz,D2O)δ7.60(d,J=6.6Hz,1H),7.54(s,1H),7.47(d,J=6.6Hz,2H),6.97(d,J=2.9 Hz,1H),6.90(d,J=5.6Hz,1H),6.86(d,J=9.5Hz,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=4.1Hz,3H),3.18(td,J=11.4,10.1,5.1Hz,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).

[0175] Example 15

[0176] Synthesis of (S)-3-(3-(N-(5-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2,4-difluorobenzyl)-N-(3-(S)2-carboxy-2-(R)pyrrolidin-3-ylethyl)benzyl)sulfamoyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0177] Prepared by referring to the method of compound 9. LCMS: RT = 1.50 min, [MH] - =795.20. 1 H NMR(400MHz,DeuteRium Oxide)δ7.65–7.55(m,2H),7.55–7.45(m,2H),7.11(t,J=7.6Hz,1H),7.03(d,J=7.6Hz,1H),6.91 –6.80(m,3H),6.66(t,J=10.0Hz,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=11.8,9.7,7.3Hz,3H),3.07–2.85(m,5H),2.74(dt,J=16.5,6.4Hz,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=13.2,9.7Hz,3H).

[0178] Example 16

[0179] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)nitrogendiyl)bis(methylene))bis(4,6-difluoro-3,1-phenylene)bis(2-(R)pyrrolidin-3-yl)propionic acid)

[0180] The specific synthetic route is as follows:

[0181] Prepared by referring to the method of compound 11. LCMS: RT = 1.51 min, [MH] - =831.06. 1 H NMR(400MHz,DeuteRium Oxide)δ7.60(d,J=11.6Hz,2H),7.55–7.46(m,2H),6.92(t,J=8.3Hz,2H),6.69(t,J =10.0Hz,2H),4.38–4.23(m,4H),3.54(dd,J=11.9,8.1Hz,3H),3.37(ddd,J=12.0,8. 4,3.7Hz,3H),3.26–3.15(m,3H),3.01(q,J=10.6Hz,3H),2.95–2.84(m,2H),2.78–2. 64(m,5H),2.62–2.42(m,5H),2.12(ddt,J=13.7,7.2,3.8Hz,3H),1.77–1.63(m,3H).

[0182] Example 17

[0183] Synthesis of (2S,2'S)-3,3'-((3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)azepinediyl)bis(ethane-2,1-diyl)bis(2,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propanoic acid)

[0184] The specific synthetic route is as follows:

[0185] Prepared by referring to the method of compound 9. LCMS: RT = 1.51 min, [M+H] - =787.06.

[0186] Example 18

[0187] Synthesis of (S)-3-(2-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-N-(2-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)phenyl)sulfonamido)ethyl)phenyl)-2-(R)-pyrrolidin-3-yl)propanoic acid

[0188] The specific synthetic route is as follows:

[0189] Prepared by referring to the method of compound 9. LCMS: RT = 1.54 min, [MH] - =773.12. 1 H NMR(400MHz,D2O)δ7.69(s,1H),7.63(s,1H),7.51(d,J=4.6Hz,2H),7.25(t,J=7.4 Hz,1H),7.21-7.11(m,2H),7.12-6.99(m,4H),6.76(d,J=7.4Hz,1H),4.24(s,2H),3 .47(dd,J=11.8,7.2Hz,2H),3.40-3.30(m,3H),3.29-3.03(m,6H),2.95(dd,J=11.8 ,7.2Hz,2H),2.86-2.66(m,6H),2.68-2.24(m,9H),2.05(s,3H),1.84-1.39(m,3H).

[0190] Example 19

[0191] Synthesis of (S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-N-(2-(S)2-carboxy-2-(R)pyrrolidin-3-ylethyl)phenethyl)phenyl)sulfonamido)ethylphenyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0192] The specific synthetic route is as follows:

[0193] Prepared by referring to the method of compound 9. LCMS: RT = 1.51 min, [MH] - =787.20. 1H NMR(400MHz,DeuteRium Oxide)δ7.57–7.50(m,2H),7.50–7.39(m,2H),7.19–7.10(m,4H),7.01(d,J=7.4Hz,2H),6.93(d, J=7.6Hz,1H),6.83(S,1H),3.54–3.42(m,3H),3.35(tq,J=8.9,5.7,5.2Hz,5H),3.25–3.09(m,5H) ,2.98(td,J=10.7,6.7Hz,3H),2.93–2.84(m,2H),2.81(d,J=7.0Hz,2H),2.68(ddt,J=28.8,15.1, 7.2Hz, 9H), 2.48 (dp, J=25.0, 8.5Hz, 3H), 2.09 (ddt, J=14.1, 10.7, 7.1Hz, 3H), 1.78–1.60 (m, 3H).

[0194] Example 20

[0195] Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)phenyl)sulfonamido)ethyl)phenyl)-2-(R)-pyrrolidin-3-yl)propanoic acid

[0196] The specific synthetic route is as follows:

[0197] Prepared by referring to the method of compound 9. LCMS: RT = 1.49 min, [MH] - =773.26.

[0198] Example 21

[0199] Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)azepinediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propanoic acid)

[0200] The specific synthetic route is as follows:

[0201] 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

[0202] At room temperature, to the reaction flask were added tert-butyl (R)-3-(S)-3-(3-bromophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (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 ethylene trifluoroborate (7.57 g, 49.5 mmol), and the atmosphere was replaced with nitrogen three times. Then, tetrahydrofuran (150 ml) and purified water (30 ml) were added. ), heated to 70°C and reacted overnight. After completion of the reaction, monitored by TLC, the mixture 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 x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 8) to obtain 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.

[0203] Step B: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(3-(2-hydroxyethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0204] To a solution of tert-butyl (R)-3-(S)-1-tert-butoxy-1-oxo-3-(2-vinylphenyl)propyl-2-ylpyrrolidine-1-carboxylate (13.2 g, 32.87 mmol) in tetrahydrofuran (130 ml) was added dropwise a solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (132 ml, 0.5 mol) under ice-water bath. After stirring at room temperature for 18 hours, methanol (50 ml), aqueous sodium hydroxide solution (104 ml, 3 mol) and 30% hydrogen peroxide (22.4 g) were added to the reaction solution under ice-water bath, and the reaction was allowed to react at room temperature for 3 hours. After the reaction was completed, as monitored by TLC, an excess of a saturated sodium bisulfate solution was added to quench the reaction, followed by stirring for 10 minutes, dilution with water (100 ml), and extraction with ethyl acetate (200 ml x 2). The combined organic phases were washed with saturated brine (150 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford a residue which was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2) to yield 9.6 g of tert-butyl (R)-3-(S)-1-tert-butoxy-3-(2-hydroxyethyl)phenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.14 min, [M+H-tert-butyl-tert-butoxycarbonyl] + =320.22.

[0205] Step C: Synthesis of (R)-3-(S)-1-tert-butoxy-1-oxo-3-(3-(2-oxoethyl)phenyl)propan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0206] To a solution of tert-butyl (R)-3-(S)-1-tert-butoxy-3-(2-hydroxyethyl)phenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (5.3 g, 12.63 mmol) in ethyl acetate (100 ml) was added 2-iodobenzoic acid (3.9 g, 13.90 mmol) at room temperature. The reaction temperature was raised to 70°C and the mixture was allowed to react for 8 hours. After completion of the reaction, the mixture was filtered with suction, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 2.6 g of tert-butyl (R)-3-(S)-1-tert-butoxy-1-oxo-3-(2-oxoethyl)phenyl)propan-2-ylpyrrolidine-1-carboxylate. LCMS: RT = 2.21 min, [M+H] + =418.25.

[0207] 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-carboxylate)

[0208] (R)-3-(S)-1-tert-butoxy-1-oxo-3-(3-(2-oxoethyl)phenyl)propan-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-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (251 mg, 0.60 mmol) were dissolved in 1,2-dichloroethane, and sodium triacetoxyborohydride (444 mg, 2.1 mmol) was added portionwise and the reaction was carried out at 45°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to obtain 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-carboxylate). LCMS: RT = 2.07 min, [M+H] + =820.39.

[0209] Step E: Synthesis of 3,3'-(3-(S)-3-tert-butoxy-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)sulfonyl)azepinediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate)

[0210] 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-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester in acetonitrile (174 mg, 0.37 mmol) was slowly added dropwise. mol, 2 ml), TLC detection, after the reaction of the raw material, rotary evaporation, pyridine was removed, and the crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to obtain 100 mg of 3,3'-(3-(S)-3-tert-butoxy-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)sulfonyl)azepinediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0211] Step F: Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)azepinediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propanoic acid)

[0212] (3,3'-(3-(S)-3-tert-butoxy-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)sulfonyl)azepinediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.079 mmol) was dissolved in 1,4-dioxane (1.5 ml), concentrated hydrochloric acid (0.5 ml) was added, and the reaction was carried out at 45°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to yield 20 mg of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)azepinediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propanoic acid). LCMS: RT = 1.51 min, [MH] - =787.15. 1 H NMR (400MHz, D2O) δ7.46 (dd, J=18.4, 10.8Hz, 4H), 7.15 (t, J=7.6Hz, 2H), 7.01 (d, J= 7.7Hz,2H),6.91(d,J=7.6Hz,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=17.2,8.6Hz,3H),2.16–2.04(m,3H),1.68(p,J=10.1Hz,3H).

[0213] Example 22

[0214] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)azepinediyl)bis(methylene)bis(2,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propionic acid)

[0215] Prepared by referring to the method of compound 9. LCMS: RT=1.51min, [MH] - =759.15.

[0216] Example 23

[0217] Synthesis of (S)-3-(3-(((3-(S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-N-(2-((S)2-carboxy-2-(R)pyrrolidin-3-ylethyl)benzyl)phenyl)sulfonamido)methyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0218] The specific synthetic route is as follows:

[0219] Step A: tert-Butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-(((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0220] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.0 g, 2.48 mmol), tert-butyl ((R)-3-((S)-3-(2-(aminomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.2 g, 2.97 mmol), and 1,2-dichloroethane (20 ml) were added sequentially. The temperature was raised to 45°C, and sodium triacetoxyborohydride (1.8 mg, 8.68 mmol) was then added in three batches. The reaction was carried out at 45°C for 18 hours.

[0221] After the reaction was completed, saturated aqueous ammonium chloride solution (30 ml) was added to quench the reaction, followed by extraction with dichloromethane (20 ml x 2 times) and concentration 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)pyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.03 min, [M+H] + =792.08.

[0222] Step B: tert-Butyl-(R)-3-((S)-1-(tert-butoxy)-3-(2-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl))phenyl)sulfonamido)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate

[0223] At room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-(((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (130 mg, 0.16 mmol), tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(chlorosulfonyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (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 atmosphere was replaced with nitrogen, and the temperature was raised to 80°C for 2 hours.

[0224] After the reaction was completed, 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)pyrrolidin-3-yl)-3-oxopropyl)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl))phenyl)sulfonamido)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate.

[0225] Step C: (S)-3-(3-(((3-(S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-N-(2-((S)2-carboxy-2-(R)pyrrolidin-3-ylethyl)benzyl)phenyl)sulfonamido)methyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0226] To the mixture were added tert-butyl-(R)-3-((S)-1-(tert-butoxy)-3-(2-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl))phenyl)sulfonamido)methyl)phenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (110 mg, 0.09 mmol), dioxane (2.5 ml) and concentrated hydrochloric acid (0.5 ml) at room temperature, and the mixture was reacted at 45°C for 4 hours.

[0227] After the reaction was completed, the product was concentrated to dryness, and the residue was purified by preparative high performance liquid chromatography to give 44 mg of (S)-3-(3-(((3-(S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-N-(2-((S)2-carboxy-2-(R)pyrrolidin-3-ylethyl)benzyl)phenyl)sulfonamido)methyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid. LCMS: RT = 1.49 min, [MH] - =759.19. 1 H NMR(400MHz,DeuteRium Oxide)δ7.71(dq,J=6.7,4.5,3.4Hz,1H),7.63(S,1H),7.54(d,J=6.0Hz,2H),7.19–7 .10(m,1H),7.10–7.02(m,2H),7.02–6.92(m,3H),6.77(d,J=7.6Hz,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).

[0228] Example 24

[0229] Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-ethyl)-4-fluorobenzyl)-N-(2-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)phenethyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropionic acid

[0230] Prepared according to the method of compound 9. LCMS: RT = 1.50 min, [MH] - =791.16. NMR data: 1H-NMR(400MHz,Deuterium Oxide)δ7.64(d,J=6.6Hz,1H),7.58(s,1H),7.49(d,J=6.7Hz,2H),7.09(m,3H),7.01 (d,J=6.1Hz,1H),6.96(t,J=9.1Hz,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=16.1Hz,3H),2.10(d,J=9.6Hz,3H),1.69(t,J=10.5Hz,3H).

[0231] Example 25

[0232] Synthesis of (S)-3-(3-(N-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2-fluorobenzyl)-N-(2-(S)2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenethyl)sulfamoyl)phenyl)-2-(((R)-pyrrolidin-3-yl)propanoic acid

[0233] Prepared by referring to the method of compound 9. LCMS: RT = 1.49 min, [MH] - =791.19. 1 H NMR (400 MHz, DeuteRium Oxide)δ7.55(d,J=7.0Hz,1H),7.51–7.38(m,3H),7.16–7.03(m,5H),6.99(t,J =7.5Hz,1H),6.92(d,J=6.2Hz,1H),4.33(S,2H),3.50–3.39(m,3H),3.39–3.24 (m,5H),3.16(dd,J=17.2,10.8Hz,3H),2.95–2.81(m,3H),2.80–2.74(m,2H),2 .67(dd,J=17.2,6.9Hz,6H),2.49–2.32(m,6H),2.04(S,3H),1.73–1.59(m,3H).

[0234] Example 26

[0235] Synthesis of (S)-3-(3-(5-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-2-fluorobenzyl)-N-(2-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenethyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-yl)propanoic acid

[0236] Prepared according to the method of compound 9. LCMS: RT = 1.54 min, [M+H] + =793.16. 1 H NMR(400MHz,D2O)7.55(dd,J=5.6,3.6Hz,1H),7.49(s,1H),7.47-7.38(m,2H),7.05(h,J=4.8Hz,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).

[0237] Example 27

[0238] Synthesis of (S)-3-(3-(N-(5-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-2,4-difluorobenzyl)-N-(2-(S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenethyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropionic acid

[0239] Prepared by referring to the method of compound 9. LCMS: RT=1.55min, [MH] - =809.12. NMR data: 1H-NMR (400 MHz, Deuterium Oxide)δ8.27(s,2H),7.57(d,J=7.0Hz,1H),7.52(s,1H),7.45(d,J=7.5Hz,2H), 7.11-7.02(m,3H),6.97-6.88(m,2H),6.75(t,J=10.0Hz,1H),4.24(d,J=3.1Hz,2 H),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 .4Hz,2H),2.68(m,6H),2.55-2.33(m,6H),2.16-1.97(m,3H),1.76-1.56(m,3H).

[0240] Example 28

[0241] Synthesis of (S)-3-(3-(2-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-5-fluorophenethyl)-N-(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropanoic acid

[0242] The specific synthetic route is as follows:

[0243] Step A: Synthesis of (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(2-bromo-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0244] To a solution of tert-butyl (R)-3-(2-(S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (20 g, 51.48 mmol) in tetrahydrofuran (200 ml) was slowly added dropwise a solution of lithium bistrimethylsilylamide in tetrahydrofuran (67 ml, 1.0 mol / L) at −78° C. After reacting for 0.5 hour, a solution of 2-bromo-1-bromomethyl-4-fluorobenzene (15 g, 55.99 mmol) in tetrahydrofuran (30 ml) was slowly added, and the mixture was then allowed to warm to room temperature and react overnight.

[0245] After completion of the reaction, as monitored by LC-MS, saturated aqueous ammonium chloride was added to quench the reaction, followed by extraction with ethyl acetate (200 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), then 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 yield 17 g of tert-butyl (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(2-bromo-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LC-MS: RT = 2.29 min, [M+H-Boc] + =475.02.

[0246] Step B: Synthesis of (S)-3-(2-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidin-3-yl)propanoic acid

[0247] Under ice-water bath, tert-butyl (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(2-bromo-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (15 g, 26.13 mmol) was dissolved in tetrahydrofuran (150 ml), 30% hydrogen peroxide (6 g, 52.26 mmol) was added, and after 0.5 hour, an aqueous solution (15 ml) of lithium hydroxide monohydrate (2.2 g, 52.26 mmol) was added, and the mixture was heated to room temperature for 3 hours.

[0248] After the reaction was completed, as monitored by LC-MS, an excess of a saturated sodium bisulfate solution was slowly added to the reaction solution to quench the reaction. The mixture was stirred for 10 minutes, and then a saturated aqueous solution of citric acid was added to adjust the pH to 5. The mixture was extracted with ethyl acetate (100 ml x 2). The combined organic phases were washed with saturated brine (50 ml x 2), then 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 obtain 7.8 g of (S)-3-(2-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidin-3-yl)propanoic acid. LC-MS: RT = 2.29 min, [MH] - =414.04.

[0249] Step C: Synthesis of (R)-3-(S)-3-(2-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0250] At room temperature, (S)-3-(2-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidin-3-yl)propanoic acid (7.8 g, 18.8 mmol) and (Z)-tert-butyl N,N'-diisopropylcarbamate (11.3 g, 56.4 mmol) were dissolved in 2-methyltetrahydrofuran (80 ml), the atmosphere was replaced with nitrogen three times, and the temperature was raised to 65°C for reaction overnight.

[0251] After completion of the reaction, monitored by LC-MS, the mixture was filtered, the filter cake washed with ethyl acetate, and the filtrate diluted with ethyl acetate. The combined organic phases were washed with saturated brine (100 ml x 2), then 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 obtain 6.7 g of tert-butyl (R)-3-(S)-3-(2-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LC-MS: RT = 2.29 min, [M+H-Boc] + =372.10.

[0252] Step D: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0253] At room temperature, tert-butyl (R)-3-(S)-3-(2-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (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). The atmosphere was replaced with N2 three times and then the temperature was raised to 75°C and the reaction was carried out overnight.

[0254] After completion of the reaction, as monitored by TLC, the reaction 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), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 4.9 g of tert-butyl (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0255] Step E: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-hydroxyethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0256] Under ice-water bath, tert-butyl (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (3 g, 7.15 mmol) was dissolved in tetrahydrofuran (30 ml). A solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (28.6 ml, 0.5 mol / L) was added, and the mixture was warmed to room temperature and stirred overnight. Methanol (10 ml) was added and stirred for 10 minutes. Then, a 30% aqueous solution of hydrogen peroxide (4.87 g, 42.9 mmol) and an aqueous solution (10 ml) of sodium hydroxide (2.72 g, 67.9 mmol) were added and the reaction was continued for 1 hour.

[0257] After the reaction was completed, as monitored by LC-MS, an excess of aqueous sodium bisulfate was slowly poured into the system to quench the reaction. The mixture was stirred for 30 minutes, and then extracted with ethyl acetate (80 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), then 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 obtain 1.2 g of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-hydroxyethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. LC-MS: RT = 2.216 min, [M+H-Boc-tert-butyl] + =282.05.

[0258] Step F: Synthesis 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

[0259] (R)-3-(S)-1-tert-Butoxy-3-(4-fluoro-2-(2-hydroxyethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.75 mmol) was dissolved in ethyl acetate (50 ml), 2-iodoacylbenzoic acid (0.85 g, 3.0 mmol) was added, and the mixture was heated to 70°C and stirred for 6 hours.

[0260] After the reaction was completed, the filter cake was removed by filtration and rinsed with ethyl acetate. The combined organic phases were concentrated under reduced pressure to obtain a residue, which was then purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to yield 490 mg of tert-butyl (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-oxoethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LC-MS: RT = 2.15 min, [M+H-Boc-tert-butyl] + =280.08.

[0261] Step G: Synthesis of tert-butyl-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)ethyl)-4-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate

[0262] To the mixture of tert-butyl (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-oxoethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (390 mg, 0.9 mmol) and tert-butyl (R)-3-(S)-3-(3-aminomethyl)phenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (362 mg, 0.9 mmol) were dissolved in DCE (8 ml) at room temperature. Sodium triacetoxyborohydride (665 mg, 3.15 mmol) was added portionwise. The mixture was heated to 45°C and stirring was continued for 16 hours.

[0263] After the reaction was complete, as monitored by LC-MS, an aqueous solution (1 ml) was added to quench the reaction. The resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). This yielded 250 mg of tert-butyl-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)ethyl)-4-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate. LC-MS: RT = 2.02 min, [M+H] + =824.51.

[0264] Step H: Synthesis of (R)-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)phenyl)sulfonamido)ethyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0265] At room temperature, tert-butyl-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)ethyl)-4-fluorophenyl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (250 mg, 0.30 mmol) was dissolved in pyridine (5 ml), and a solution of tert-butyl (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (172 mg, 0.36 mmol) in acetonitrile (2 ml) was slowly added, and the reaction was carried out at room temperature for 0.5 hour.

[0266] After completion of the reaction, as determined by TLC, the mixture was extracted with ethyl acetate (10 ml x 2 times). The combined organic phases were washed with saturated brine (5 ml x 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)pyrrolidin-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)phenyl)sulfonamido)ethyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0267] Step I: Synthesis of (S)-3-(3-(2-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-5-fluorophenethyl)-N-(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropanoic acid

[0268] At room temperature, (R)-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)phenyl)sulfonamido)ethyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (150 mg, 0.12 mmol) was dissolved in 1,4-dioxane solution (3 ml), concentrated hydrochloric acid (0.2 ml) was added, and the temperature was raised to 45°C for 4 hours.

[0269] The reaction was monitored by LC-MS until completion, then concentrated under reduced pressure. The residue was purified by preparative HPLC to yield 34 mg of (S)-3-(3-(2-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-5-fluorophenethyl)-N-(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropanoic acid. LCMS: RT = 1.56 min, [MH] - =791.12. NMR data: 1 H-NMR(400MHz,Deuterium Oxide)δ7.68-7.59(m,1H),7.55(s,1H),7.46(d,J=6.3Hz,2H),7.17(t,J=7.6Hz,1 H),7.07(d,J=7.7Hz,1H),6.99(t,J=7.6Hz,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),2.7 5-2.62(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).

[0270] Example 29

[0271] Synthesis of (2S,2'S)-3,3'(5-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-2-fluorophenylsulfonyl)azepinediyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propionic acid)

[0272] The specific synthetic route is as follows:

[0273] Step A: Synthesis of (3R)-3-(2S)-1-(4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromo-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0274] To a solution of tert-butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (6.0 g, 15.45 mmol) in tetrahydrofuran (60 ml) was slowly added dropwise lithium bis(trimethylsilyl)amide (19 ml, 19 mmol) at -78°C. After stirring at -78°C for 30 minutes, a solution of 2-bromo-4-bromomethyl-1-fluorobenzene (4.97 g, 19 mmol) in tetrahydrofuran (20 ml) was slowly added to the system, and the temperature was then naturally raised to room temperature for reaction overnight. After completion of the reaction, the reaction was quenched by addition of saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate (100 ml x 2). The combined organic phases were washed with saturated brine (100 ml x 2), 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 obtain 3.1 g of tert-butyl (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromo-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.25 min, [M+H-Boc] + =475.01.

[0275] Step B: Synthesis of (3-(3-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidin-3-ylpropionic acid

[0276] To a solution of tert-butyl (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromo-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (3.8 g, 6.60 mmol) in tetrahydrofuran (40 ml) was added hydrogen peroxide (1.1 g, 30%, 9.90 mmol) under ice-water bath, and the mixture was reacted for 30 minutes. Subsequently, an aqueous solution (10 ml) of lithium hydroxide monohydrate (237 mg, 9.90 mmol) was added, and the mixture was warmed to room temperature and reacted for 3 hours. After the reaction was completed, an excess of saturated sodium bisulfate solution was slowly added to the reaction mixture to quench the reaction. The mixture was stirred for 10 minutes, and then a saturated aqueous solution of citric acid was added to adjust the pH to 3. The mixture was extracted with ethyl acetate (50 ml x 2). The combined organic phases were washed with saturated brine (200 ml x 2), 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 / 3) to obtain 2.2 g of (S)-3-(3-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid. LCMS: RT = 2.06 min, [MH] - =416.00.

[0277] Step C: Synthesis of (R)-3-(S)-3-(3-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0278] To a solution of (S)-3-(3-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (2.2 g, 5.28 mmol) in 2-methyltetrahydrofuran (20 ml) was added O-tert-butyl-N,N'-diisopropylisourea (3.18 g, 15.85 mmol) at room temperature. The atmosphere was replaced with nitrogen three times and the temperature was raised to 65°C for reaction overnight. After the reaction was completed, 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 (70 ml x 2), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 7) to obtain 2.1 g of tert-butyl (R)-3-(S)-3-(3-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.36 min, [M+H-Boc] + =371.98.

[0279] Step D: Synthesis of (R)-3-(S)-3-(3-benzylthio)-5-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0280] At room temperature, tert-butyl (R)-3-(S)-3-(3-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (2.10 g, 4.62 mmol), benzyl mercaptan (689 mg, 5.55 mmol), N,N-diisopropylethylamine (1.19 g, 9.24 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (267 mg, 0.46 mmol) and tris(dibenzylideneinacetone)dipalladium (211 mg, 0.23 mmol) were dissolved in dioxane, purged with nitrogen and reacted at 100°C under nitrogen protection overnight. After the reaction, the temperature was lowered, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 7) to obtain 2.1 g of tert-butyl (R)-3-(S)-3-(3-benzylthio)-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.43 min, [M+H-Boc] + =398.15.

[0281] Step E: Synthesis of (R)-3-(S)-1-tert-butyl-3-(3-chlorosulfonyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0282] Under ice bath, tert-butyl (R)-3-(S)-3-(3-benzylthio)-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (2.10 g, 4.22 mmol) was dissolved in acetonitrile (30 ml), and then acetic acid (1.5 ml) and water (1.5 ml) were added, and then 1,3-dichloro-5,5-dimethylhydantoin acetonitrile solution (1.66 g, 8.44 mmol, 10 ml) was added dropwise and monitored by TLC. After the reaction, water was added to the system, followed by extraction with ethyl acetate (100 ml x 2 times). The organic phases were combined and concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to obtain 1.6 g of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0283] Step F: Synthesis of 3,3'-((2S,2'S)-(3-((S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorophenyl)sulfonyl)azepinediyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate)

[0284] 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 tert-butyl (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate in acetonitrile (187 mg, 0.38 mmol, 2 ml) was slowly added dropwise. ml), TLC detection, after the reaction of the starting material was completed, the pyridine was removed by rotary evaporation, and the crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to obtain 60 mg of 3,3'-((2S,2'S)-(3-((S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorophenyl)sulfonyl)azepinediyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0285] Step G: Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-4-fluorophenylsulfonyl)azepinediyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propanoic acid)

[0286] 3,3'-((2S,2'S)-(3-((S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-4-fluorophenyl)sulfonyl)azepinediyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (60 mg, 0.048 mmol) was dissolved in 1,4-dioxane (1.5 ml), concentrated hydrochloric acid (0.5 ml) was added, and the reaction was carried out at 45°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography to yield 18 mg of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-4-fluorophenylsulfonyl)azepinediyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propionic acid. LCMS: RT = 1.53 min, [MH] - =777.12. 1 H NMR(400MHz,D2O)δ7.55–7.50(m,1H),7.47–7.41(m,1H),7.22–7.09(m,3H),7.02(d,J=7.6Hz,2H),6.90(d, J=7.6Hz,2H),6.80(s,2H),4.33(s,4H),3.44(dd,J=11.7,6.9Hz,1H),3.32(ddd,J=17.0,10.1,5.1Hz,5H),3 .13(td,J=10.7,7.3Hz,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 .9Hz,2H),2.56(dd,J=13.5,4.3Hz,2H),2.45–2.26(m,6H),2.08–1.97(m,3H),1.64(dq,J=12.4,8.9Hz,3H).

[0287] Example 30

[0288] Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-2,4-difluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0289] Prepared by referring to the method of compound 9. LCMS: RT = 1.53 min, [MH] - =795.12.

[0290] Example 31

[0291] Synthesis of (2S,2'S)-3,3'-((3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)azepinediyl)bis(methylene))bis(2,6-difluoro-3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propanoic acid)

[0292] Prepared by referring to the method of compound 9. LCMS: RT = 1.53 min, [MH] - =831.12.

[0293] Example 32

[0294] Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-2,6-difluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropionic acid

[0295] The specific synthetic route is as follows:

[0296] Step A: Synthesis of methyl 3-bromo-2,4-difluorobenzoate

[0297] 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, and the temperature was cooled to 0 degrees Celsius. Methyl iodide (3.59 g, 25.3 mmol) was slowly added, and the reaction was returned to room temperature for 1 hour.

[0298] After TLC detection of the reaction completion, 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), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 5.1 g of methyl 3-bromo-2,4-difluorobenzoate as a white solid (yield: 96.7%).

[0299] Step B: Synthesis of 3-bromo-2,4-difluorophenylmethanol

[0300] To a solution of methyl 3-bromo-2,4-difluorobenzoate (5.1 g, 20.4 mmol) in dichloromethane (50 ml) was slowly added dropwise a solution of diisobutylaluminum hydride in n-hexane (41 ml, 1.0 mol / L) under ice-water bath, and the mixture was returned to room temperature and reacted for 2 hours.

[0301] After the reaction was completed, as 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), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 4 g of 3-bromo-2,4-difluorophenylmethanol.

[0302] Step C: Synthesis of 2-bromo-4-bromomethyl-1,3-difluorobenzene

[0303] To a solution of 3-bromo-2,4-difluorophenylmethanol (4 g, 18.1 mmol) in dichloromethane (40 ml) were added carbon tetrabromide (6.24 g, 27 mmol) and triphenylphosphine (7.08 g, 27 mmol) at room temperature and the mixture was reacted for 2 hours.

[0304] After the reaction was completed, the product was extracted with ethyl acetate (100 ml x 2 times) and the combined organic phases were washed with saturated brine (50 ml x 2 times), then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane) to obtain 3.3 g of 2-bromo-4-bromomethyl-1,3-difluorobenzene.

[0305] Step D: Synthesis of (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromo-2,4-difluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0306] To a solution of tert-butyl (R)-3-(2-(S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (4.06 g, 10.5 mmol) in tetrahydrofuran (40 ml) was slowly added dropwise a solution of lithium bistrimethylsilylamide in tetrahydrofuran (14 ml, 1.0 mol / L) at −78° C. After reacting for 0.5 hour, a solution of 2-bromo-4-bromomethyl-1,3-difluorobenzene (3.3 g, 11.5 mmol) in tetrahydrofuran (30 ml) was slowly added, and the mixture was then allowed to warm to room temperature and react overnight.

[0307] After completion of the reaction, as monitored by LC-MS, the reaction was quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), 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 yield 2 g of tert-butyl (R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromo-2,4-difluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LC-MS: RT = 2.09 min, [M+H-Boc]+ = 493.02.

[0308] Step E: Synthesis of (S)-3-(3-bromo-2,4-difluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidin-3-ylpropionic acid

[0309] Under ice-water bath, tert-butyl ((R)-3-(S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromo-2,4-difluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (2 g, 3.4 mmol) was dissolved in tetrahydrofuran (20 ml), 30% hydrogen peroxide (0.77 g, 6.8 mmol) was added, and after 0.5 hour, an aqueous solution (5 ml) of lithium hydroxide monohydrate (0.29 g, 6.8 mmol) was added, and the mixture was warmed to room temperature for 3 hours.

[0310] After the reaction was completed, as monitored by LC-MS, an excess of saturated sodium bisulfate solution was slowly added to the reaction mixture to quench the reaction. The mixture was stirred for 10 minutes, and then a saturated aqueous solution of citric acid was added to adjust the pH to 5. The mixture was extracted with ethyl acetate (50 ml x 2). The combined organic phases were washed with saturated brine (20 ml x 2), then 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 obtain 850 mg of (S)-3-(3-bromo-2,4-difluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidin-3-ylpropionic acid. LC-MS: RT = 2.07 min, [MH] - =431.95.

[0311] Step F: Synthesis of tert-butyl (R)-3-(S)-3-(3-bromo-2,4-difluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0312] At room temperature, (S)-3-(3-bromo-2,4-difluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidin-3-ylpropionic acid (850 mg, 1.96 mmol) and (Z)-tert-butyl N,N'-diisopropylcarbamate (1.18 g, 5.88 mmol) were dissolved in 2-methyltetrahydrofuran (10 ml). The atmosphere was replaced with nitrogen three times and the temperature was raised to 65°C for reaction overnight.

[0313] After completion of the reaction, monitored by LC-MS, the mixture was filtered, the filter cake washed with ethyl acetate, and the filtrate diluted with ethyl acetate. The combined organic phases were washed with saturated brine (10 ml x 2), then 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 obtain 680 mg of tert-butyl (R)-3-(S)-3-(3-bromo-2,4-difluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LC-MS: RT = 2.34 min, [M+H-Boc] + =390.01.

[0314] Step G: Synthesis of (R)-3-(S)-1-tert-butyl-3-(2,4-difluoro-3-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0315] At room temperature, tert-butyl (R)-3-(S)-3-(3-bromo-2,4-difluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (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). The atmosphere was replaced with N2 three times and then the temperature was raised to 75°C and the reaction was carried out overnight.

[0316] After the reaction was completed as 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), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 510 mg of tert-butyl (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0317] Step E: Synthesis of (R)-3-(S)-1-tert-butyl-3-(2,4-difluoro-3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0318] Under ice-water bath, tert-butyl (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (510 mg, 1.17 mmol) was dissolved in tetrahydrofuran / water (8 ml / 2 ml), potassium osmate dihydrate (4.29 mg, 0.012 mmol) was added, and after stirring for 0.5 hour, sodium periodate (548 mg, 2.56 mmol) was added and the reaction was continued for 1 hour. The reaction was allowed to warm to room temperature. After completion of the reaction, monitored by LC-MS, an excess of aqueous sodium bisulfate solution was slowly poured into the system to quench the reaction. The mixture was stirred for 30 minutes, and then extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 2), then 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 obtain 220 mg of tert-butyl (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LC-MS: RT = 2.26 min, [M+H-Boc-tert-butyl] + =284.07.

[0319] Step G: Synthesis of (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0320] At room temperature, tert-butyl (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (220 mg, 0.5 mmol) and tert-butyl (R)-3-(S)-3-(3-aminomethyl)phenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (202 mg, 0.5 mmol) were dissolved in DCE (5 ml). Sodium triacetoxyborohydride (371 mg, 1.75 mmol) was added portionwise. The temperature was raised to 45°C and stirring was continued for 16 hours.

[0321] After the reaction was complete, as monitored by LC-MS, an aqueous solution (1 ml) was added to quench the reaction. The resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). This yielded 160 mg of (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LC-MS: RT = 2.05 min, [M+H] + =828.51.

[0322] Step H: Synthesis of (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)phenyl)sulfonamido)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0323] At room temperature, (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (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-oxopropan-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 hour.

[0324] After completion of the reaction, as determined by TLC, the mixture was extracted with ethyl acetate (10 ml x 2 times). The combined organic phases were washed with saturated brine (5 ml x 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)pyrrolidin-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)phenyl)sulfonamido)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0325] Step I: Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-2,6-difluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropanoic acid

[0326] At room temperature, (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)phenyl)sulfonamido)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (170 mg, 0.13 mmol) was dissolved in 1,4-dioxane solution (4 ml), concentrated hydrochloric acid (0.2 ml) was added, and the temperature was raised to 45°C for 4 hours.

[0327] The reaction was monitored by LC-MS until completion, then concentrated under reduced pressure. The residue was purified by preparative HPLC to yield 53 mg of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-2,6-difluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropanoic acid. LCMS: RT = 1.51 min, [MH] - =795.05. NMR data: 1H NMR (400MHz, Deuterium Oxide) δ8.25(s,1H),7.59-7.38(m,4H),7.09(t,J=7.6Hz,1H),6.96(m,3H),6.85(s,1H),6.64(t,J=8.9Hz,1H),4.34(d,J=23.8Hz, 4H),3.44(m,3H),3.33(m,3H),3.16(m,3H),2.90(m,3H),2.80(d,J=9.2Hz,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).

[0328] Example 34

[0329] Synthesis of (2S,2'S)-3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-4-fluorophenyl)sulfonyl)azepinediyl)bis(methylene))bis(6-fluoro-3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0330] Prepared by referring to the method of compound 9. LCMS: RT=1.55min, [MH] - =813.13.

[0331] Example 35

[0332] Synthesis of (2S,2'S)-3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-4-chlorophenyl)sulfonyl)azepinediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0333] Prepared by referring to the method of compound 9. LCMS: RT = 1.53 min, [MH] - =793.09.

[0334] Example 36

[0335] Synthesis of (2S,2'S)-3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-4-chlorophenyl)sulfonyl)azepinediyl)bis(methylene))bis(6-fluoro-3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0336] Prepared by referring to the method of compound 9. LCMS: RT = 1.53 min, [MH] - =829.02.

[0337] Example 37

[0338] Synthesis of (S)-3-(3-(2-((3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-N-(2-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)phenyl)sulfonamido)ethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0339] Prepared by referring to the method of compound 9. LCMS: RT=1.51min, [MH] - =773.12. 1 H NMR(400MHz,D2O)δ7.67(dt,J=5.0,2.4Hz,1H),7.62(s,1H),7.52(d,J=6.0Hz,2H), 7.34-7.21(m,1H),7.20-7.04(m,4H),6.98(d,J=7.6Hz,1H),6.73(d,J=7.6Hz,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).

[0340] Example 38

[0341] Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-4-chlorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)phenethyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropionic acid

[0342] The specific synthetic route is as follows:

[0343] Prepared by referring to the method of compound 9. LCMS: RT = 1.54 min, [MH] - =807.11.

[0344] Example 39

[0345] Synthesis of (S)-3-(5-(N-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-4-chlorobenzyl)-N-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)aminosulfonyl)-2-fluorophenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0346] Prepared by referring to the method of compound 9. LCMS: RT=1.55min, [MH] - =811.03. 1 H NMR(400MHz,D2O)δ7.69-7.58(m,1H),7.57(dd,J=6.6,2.4Hz,1H),7.23(t,J=9.2Hz,1H),7.17(d,J= 8.2Hz,1H),7.12(t,J=7.6Hz,1H),7.02(d,J=7.6Hz,1H),6.94(d,J=7.7Hz,1H),6.92-6.85(m,1H),6 .84-6.80(m,2H),4.44-4.01(m,4H),3.51(dd,J=11.6,7.4Hz,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).

[0347] Example 40

[0348] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)azepinediyl)bismethylene)bis(6-chloro-3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propionic acid)

[0349] Prepared by referring to the method of compound 9. LCMS: RT = 1.52 min, [MH] - =829.21.

[0350] Example 41

[0351] Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)sulfonyl)azepinediyl)bismethylene)bis(6-chloro-3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propionic acid)

[0352] Prepared by referring to the method of compound 9. LCMS: RT = 1.58 min, [MH] - =827.07.

[0353] Example 42

[0354] Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-4-fluorophenylsulfonyl)azepinediyl)bismethylene)bis(6-chloro-3,1-phenylene)bis(2-(R)-pyrrolidin-3-yl)propionic acid)

[0355] Prepared by referring to the method of compound 9. LCMS: RT = 1.58 min, [MH] - =845.07.

[0356] Examples 33, 43-47

[0357] Referring to the preparation methods of the aforementioned example compounds (e.g., Example 30 or Example 9), compounds 33, 43-47 were prepared:

[0358] Example 48 In vitro Lp(a) assembly assay

[0359] Experimental procedures

[0360] The ability of the example compounds to inhibit Lp(a) particle formation in vitro was evaluated using a cell-free assembly assay. Conditioned medium (DMEM supplemented with 10% FBS, 20 mM HEPES, and 1× penicillin / streptomycin) was collected from confluent wild-type HepG2 cells (a source of endogenously expressed ApoB) and from a HEK293 stable cell line expressing a human Apo(a) protein containing 17 Kringle repeats (selected on 1 μg / ml puromycin) after 96 hours of incubation at 37°C and 5% CO2. The in vitro assembly assay was performed by combining equal aliquots of HepG2 and HEK293 conditioned medium with the test compounds added in a dilution series (final concentrations 0.03 to 1000 nM). The reaction was incubated at 37°C for 2 hours and terminated by the addition of 6-aminoacetic acid (EACA) to a final concentration of 150 mM. Lp(a) was detected using a sandwich ELISA with an anti-Apo(a) capture antibody (ab242565) and an HRP-conjugated anti-ApoB detection antibody (ab27622). The ELISA was developed using TMB, terminated with 1N sulfuric acid, and read at 450 nm on an Envision 2104 plate reader. The % inhibition of Lp(a) formed under each test condition was determined by setting the assembly reaction in the absence of inhibitor to 0% inhibition and the assembly reaction in the presence of minimal HepG2 conditioned medium (50-fold dilution) to 100% inhibition. The data were fitted to a 4-parameter curve to determine the IC 90 The results are shown in Table 1.

[0361] Table 1 IC of sulfonamide compounds 90 value

[0362] According to the results in Table 1, it can be seen that the sulfonamide compounds of the present invention all have good LP(a) inhibitory activity.

[0363] Example 49

[0364] Pharmacokinetic experiments in SD rats

[0365] (1) Experimental materials

[0366] SD rats: male, 180-250 g, purchased from Guangdong Weitonglihua Experimental Animal Technology Co., Ltd.

[0367] Reagents: Normal saline, EDTA-K2 (anticoagulant), TCA (trichloroacetic acid), and propranolol (internal standard) are all commercially available.

[0368] Instruments: Nexera LC-40; AB SCIEX QTRAP 5500+.

[0369] (2) Experimental methods

[0370] Weigh the compound and dissolve it in saline. After oral administration to rats, collect 200 μL of venous blood at 15, 30, 1, 2, 5, 7, and 24 hours (5 minutes additionally for the IV group) into EDTA-K2 anticoagulant EP tubes. Centrifuge at 12,000 rpm for 2 minutes, and freeze the plasma at -80°C for testing. Accurately weigh a certain amount of the test compound and dissolve it in ultrapure water to 2 mg / mL to prepare a stock solution. Accurately pipette an appropriate amount of the compound stock solution and dilute it with 50% acetonitrile-water to prepare a series of standard solutions. Accurately pipette 10 μL of each standard solution and add 90 μL of blank plasma. Vortex to mix thoroughly. Prepare plasma samples equivalent to plasma concentrations of 1, 3, 5, 10, 30, 100, 300, 1000, and 3000 ng / mL. Quality control samples were prepared at concentrations of 9, 240, and 2400 ng / mL. Duplicate samples were analyzed at each concentration to construct a standard curve. 30 μL of plasma (5, 15, and 30 minutes after intravenous administration, diluted 5-fold) was collected and 200 μL of a 5% trichloroacetic acid-water solution containing the internal standard propranolol (50 ng / mL) was added. After vortex mixing, the mixture was centrifuged at 4000 rpm for 10 minutes. The supernatant was collected, 150 μL of purified water was added, and the mixture was vortexed again for LC-MS / MS analysis. LC-MS / MS detection conditions were as follows:

[0371] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0372] Mobile phase: water (0.1% formic acid)-acetonitrile with gradient elution as shown in the table below.

[0373] Table 2 Gradient elution table

[0374] (3) Data processing

[0375] After LC-MS / MS detection of blood drug concentrations, pharmacokinetic parameters were calculated using WinNonlin 6.1 software and the non-compartmental model method. The results are shown in Table 3.

[0376] Table 3: Pharmacokinetic parameters of the compounds of the present invention in SD rats

[0377] According to the results in Table 3, it can be seen that the compound of the present invention has a higher exposure amount. In addition, the compound of the present invention also shows a longer half-life and higher bioavailability.

[0378] Example 50

[0379] Monkey pharmacokinetic experiments

[0380] (1) Experimental materials

[0381] Beagle dogs: male, 8-10 kg, purchased from Beijing Mas Biotechnology Co., Ltd.

[0382] Cynomolgus macaques: male, 3-6 kg, purchased from Guangzhou Huazhen Biotechnology Co., Ltd. and Hainan Jingang Biotechnology Co., Ltd.

[0383] Reagents: Normal saline, EDTA-K2 (anticoagulant), TCA (trichloroacetic acid), and propranolol (internal standard) are all commercially available.

[0384] Instruments: Nexera LC-40; AB SCIEX QTRAP 5500+.

[0385] (2) Experimental methods

[0386] Weigh the compound and dissolve it in normal saline. After oral or intravenous administration, collect 200 μL of venous blood into EDTA-K2 anticoagulant EP tubes at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours (5 minutes and 48 hours for the IV group). Centrifuge at 12,000 rpm for 2 minutes, and freeze the plasma at -80°C for testing. Accurately weigh a certain amount of the test compound and dissolve it in ultrapure water to 2 mg / mL to prepare a stock solution. Accurately pipette an appropriate amount of the compound stock solution and dilute it with 50% acetonitrile-water to prepare a series of standard solutions. Accurately pipette 10 μL of each standard solution and add 90 μL of blank plasma. Vortex to mix thoroughly. Prepare plasma samples equivalent to plasma concentrations of 1, 3, 5, 10, 30, 100, 300, 1000, and 3000 ng / mL. Quality control samples were prepared at concentrations of 9, 240, and 2400 ng / mL. Duplicate samples were analyzed at each concentration to construct a standard curve. 30 μL of plasma (5, 15, and 30 minutes after intravenous administration, diluted 5-fold) was collected and 200 μL of a 5% trichloroacetic acid-water solution containing the internal standard propranolol (50 ng / mL) was added. After vortex mixing, the mixture was centrifuged at 4000 rpm for 10 minutes. The supernatant was collected, 150 μL of purified water was added, and the mixture was vortexed again for LC-MS / MS analysis. LC-MS / MS detection conditions were as follows:

[0387] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0388] Mobile phase: water (0.1% formic acid)-acetonitrile with gradient elution as shown in the table below.

[0389] Table 4 Gradient elution table

[0390] (3) Data processing

[0391] After LC-MS / MS detection of blood drug concentrations, WinNonlin 6.1 software was used to calculate the pharmacokinetic parameters using the non-compartmental model method. The results are shown in Tables 5 and 6.

[0392] Table 5: Pharmacokinetic parameters of the compounds of the present invention in cynomolgus monkeys

[0393] Table 6: Pharmacokinetic parameters of the compounds of the present invention in cynomolgus monkeys

[0394] According to the results in Table 5 and Table 6, it can be seen that the compound of the present invention has a higher exposure, higher bioavailability and longer half-life.

[0395] It should be understood that the above embodiments are preferred implementations of the present invention, but the implementation of the present invention is not limited to the above embodiments. For ordinary technicians in this field, they can be improved or transformed according to the above description, and all these improvements and transformations should fall within the scope of protection of the claims attached to the present invention.

Claims

1. A sulfonamide compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The structure of the sulfonamide compound is shown in general formula I: Among them, X1~X 15 Each is independently selected from -N- or -CR1, wherein R1 is selected from H, halogen, -OH, -NH2, -CN, -NO2, -COOH, -SO3H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or X1~X 15 At least one of them is -N-; Or when X1~X 15 When all are independently selected from -CR1, at least one R1 is not hydrogen, and at least one R1 among X1 to X5 is independently selected from And the X6~X 10 At least one R1 is independently selected from Or when X1~X 15 When all of X1 to X 15 Any two adjacent R1 and the connected carbon atom together form a substituted or unsubstituted C6-C 10 Aryl or substituted or unsubstituted 5-10 membered heteroaryl; 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 heterocyclyl); The substituted C1-C6 alkyl, substituted C1-C6 alkoxy, substituted C3-C 10 Cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C6-C 10 The substituents in the aryl or substituted 5-10 membered heterocyclic group are independently selected from halogen, hydroxy, carboxyl, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C3-C6 cycloalkoxy, C6-C 10 one or more of aryl or 5-10 membered heteroaryl; n, p, r are independently selected from integers of 1, 2 or 3, and m, q are independently selected from integers of 0, 1, 2 or 3.

2. The sulfonamide compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt according to claim 1, characterized in that: R1 is selected from H, halogen, -OH, -NH2, -CN, -NO2, -COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or The R2 is selected from -H, substituted or unsubstituted C1-C6 alkyl; the R3 is selected from 5-8 membered heterocyclic group; the substituted C3-C 10 Cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C6-C 10 The substituents in the aryl or substituted 5-10 membered heteroaryl are independently selected from halogen, hydroxy, carboxyl, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C3-C6 cycloalkoxy, C6-C 10 aryl or one or more of 5-10 membered heteroaryl.

3. The sulfonamide compound according to claim 1 or 2, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: One of X4 or X5 is selected from The X9 or X 10 One of the The X 11 or X 12 One of the 4. The sulfonamide compound according to any one of claims 1 to 3, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The structure of sulfonamide compounds is shown in general formula II or III: 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; the R3 is selected from 5-8 membered heterocyclic group; the substituents in the substituted C1-C6 alkyl and substituted C1-C6 alkoxy are independently selected from halogen, hydroxyl, carboxyl, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C3-C6 cycloalkoxy, C6-C 10 aryl or one or more of 5-10 membered heteroaryl.

5. The sulfonamide compound according to any one of claims 1 to 4, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The structure of the sulfonamide compound is shown in general formula IV or V: 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; the R3 is selected from 5-8 membered heterocyclic group; the substituents in the substituted C1-C6 alkyl and substituted C1-C6 alkoxy are independently selected from halogen, hydroxyl, carboxyl, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C3-C6 cycloalkoxy, C6-C 10 Aryl or 5-10 membered heteroaryl; preferably, the X 11 , X 12 , X 13 , X 14 or X 15 Any one of which is independently selected from -CR1, wherein R1 is selected from More preferably, the R1 is selected from Any one of .

6. The sulfonamide compound according to any one of claims 1 to 5, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The R1 is selected from H, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, ethyl, propyl, methoxy, ethoxy, piperazinyl, -CH2COOH, -CH2CH2COOH, -CH2CH(CH3)COOH, The R3 is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl or pyrazinyl.

7. The sulfonamide compound according to any one of claims 1 to 6, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: Said Selected from quinolinyl.

8. The sulfonamide compound according to any one of claims 1 to 7, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: Said Selected from:

9. The sulfonamide compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt according to claim 8, characterized in that: Said Selected from:

10. The sulfonamide compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt according to claim 9, characterized in that: Said Selected from:

11. The sulfonamide compound according to any one of claims 1 to 10, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The sulfonamide compound is selected from the compounds shown in Table 1A or Table 1B.

12. A pharmaceutical composition, characterized in that The invention comprises the sulfonamide compound according to any one of claims 1 to 11, or its isomer, or its racemate, or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients and / or carriers.

13. Use of the sulfonamide compound according to any one of claims 1 to 11, or its isomer, or its racemate, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for preventing or treating diseases associated with LP(a).

14. The use according to claim 13, characterized in that The Lp(a)-related disease is selected from cardiovascular disease.

15. The use according to claim 14, characterized in that The cardiovascular disease is selected from the group consisting of stroke, atherosclerosis, thrombosis, coronary heart disease or aortic valve stenosis and any other disease associated with elevated Lp(a) levels.

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