Sulfonamide compounds, as well as methods for preparing them and their pharmaceutical uses.

Abstract

The present invention belongs to the field of chemical pharmaceutical technology and provides a sulfonamide compound (I), as well as a method for preparing the same and its pharmaceutical applications. [Formula 1] JPEG2026518734000112.jpg86170

Description

[Technical Field]

[0001] This invention belongs to the field of chemical pharmaceutical technology and provides sulfonamide compounds, as well as methods for preparing them and their pharmaceutical applications. [Background technology]

[0002] LPA is the name of the gene encoding apolipoprotein (a) (apo(a)), which is primarily expressed in the liver, and its expression is limited to humans and non-primate animals. Apolipoprotein (a) binds to apo(B)-100 via a disulfide bond, forming lipoprotein (a) (Lp(a)) particles together with a lipid core. Lp(a) particles are special high molecular weight lipoproteins rich in cholesterol, with their surface coated in cholesterol and phospholipids, and embedded with the hydrophilic apolipoprotein components apolipoprotein (a) and apo(B)-100. Lp(a) can penetrate and accumulate in the blood vessel walls, promoting atherosclerosis. Lp(a) is structurally cognate with plasminogen (PLG) and competes with plasminogen to bind to the fibrin site, thereby inhibiting the hydrolysis of fibrinogen and promoting thrombus formation. 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 are not significantly altered by diet, exercise, or other lifestyle changes.

[0003] Currently reported LP(a) inhibitors are mainly high-molecular-weight or low-molecular-weight nucleic acid-based drugs. For example, WO2023 / 046093A1 discloses a bispecific fusion polypeptide, CN111465694A discloses nucleic acids for inhibiting LPA expression in cells, CN108368506A also discloses compositions and methods for inhibiting LPA gene expression, and CN113166759A discloses chemically modified RNAi constructs and their use. However, regarding low-molecular-weight LP(a) drugs that are not currently commercially available, among the projects under development, only Chinese patent CN114008021A reports a pyrrolidine compound as a low-molecular-weight LP(a) drug. Therefore, there is an urgent need to provide more low-molecular-weight LP(a) drugs. [Overview of the project]

[0004] In view of the problems existing in the prior art, the present invention provides a low-molecular-weight LP(a) drug to solve the problem of the deficiency of low-molecular-weight LP(a) drugs in the prior art.

[0005] This invention is achieved by the following technical solution.

[0006] The present invention relates to a sulfonamide compound, its isomer, its racemate, or a pharmaceutically acceptable salt thereof, wherein the structure of the sulfonamide compound is represented by general formula I. [ka] Here, X1~X 15 Each is independently selected from -N- or -CR1, where R1 is H, halogen, -OH, -NH2, -CN, -NO2, -COOH, -SO3H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C3-C 10 Cycloalkyl groups, substituted or unsubstituted 3-10 member heterocycloalkyl groups, substituted or unsubstituted C6-C 10 Aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, or [Chemistry] selected from, where at least one of the aforementioned X1 to X 15 is -N-, or when X1 to X 15 are each independently selected from -CR1, at least one of the R1s is not hydrogen, and at least one of the R1s of the aforementioned X1 to X5 is independently [Chemistry] selected from, and at least one of the R1s of the aforementioned X6 to X 10 is independently [Chemistry] selected from, or when X1 to X 15 are each independently selected from -CR1, any two adjacent R1s of the aforementioned X1 to X 15 form a substituted or unsubstituted C6-C 10 aryl group or a substituted or unsubstituted 5- to 10-membered heteroaryl group together with the carbon atom to which they are attached, the aforementioned R2 is selected from -H, halogen, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted C1-C6 alkoxy group, the aforementioned R3 is selected from -(CH2) q -(a 5- to 8-membered heterocyclic group), the substituted C1-C6 alkyl group, the substituted C1-C6 alkoxy group, the substituted C3-C 10 cycloalkyl group, the substituted 3- to 10-membered heterocycloalkyl group, the substituted C6-C 10The substituents on the aryl group or substituted 5-10 membered heteroaryl group are, independently, 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, and C6-C 10 One or more selected from aryl groups and 5-10 membered heteroaryl groups, The present invention provides a sulfonamide compound, its isomer, its racemic mixture, or its pharmaceutically acceptable salt, characterized in that n, p, and r are independently selected from integers 1, 2, or 3, and m and q are selected from integers 0, 1, 2, or 3.

[0007] As one preferred technical application of the present invention, R1 may be H, halogen, -OH, -NH2, -CN, -NO2, -COOH, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, substituted or unsubstituted C3-C 10 Cycloalkyl groups, substituted or unsubstituted 3-10 member heterocycloalkyl groups, substituted or unsubstituted C6-C 10 Aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, or [ka] R2 is selected from -H, substituted or unsubstituted C1-C6 alkyl groups, and R3 is selected from 5-8 member heterocyclic groups, and the substituted C3-C 10 Cycloalkyl groups, substituted 3-10 member heterocycloalkyl groups, substituted C6-C 10 The substituents on the aryl group or substituted 5-10 membered heteroaryl group are, independently, 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, and C6-C 10It is one or more selected from aryl groups and 5-10 membered heteroaryl groups.

[0008] As one preferred technical example of the present invention, [ka] This is a quinolinyl group, The aforementioned [ka] More preferably, [ka] That is the case.

[0009] As one preferred technical example of the present invention, one of X4 and X5 is [ka] Selected from, the above X9 and X 10 One of them is, [ka] Selected from, the X 11 and X 12 One of them is, [ka] Selected from. As one preferred technical application of the present invention, X4 or X5 is [ka] It is one selected from the above, and the above X9 or X 10 teeth, [ka] It is one selected from the above X 11 or X 12 teeth, [ka] It is one of the options selected from the others.

[0010] As one preferred technical example of the present invention, the structure of the sulfonamide compound is represented by general formula II or general formula III, [ka] Here, X1~X 15 Each is independently selected from -N- or -CR1, wherein R1 is H, halogen, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, or [ka] R2 is selected from H, substituted or unsubstituted C1-C6 alkyl groups, R3 is selected from 5-8 membered heterocyclic groups, and the substituents in the substituted C1-C6 alkyl group and substituted C1-C6 alkoxy group are independently halogen, hydroxyl group, carboxyl group, nitro group, cyano group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 haloalkoxy group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C3-C6 cycloalkoxy group, and C6-C 10 It is one or more selected from aryl groups and 5-10 membered heteroaryl groups.

[0011] As one preferred technical example of the present invention, the structure of the sulfonamide compound is represented by general formula IV or general formula V, [ka] Here, X1~X 15 Each is independently selected from -N- or -CR1, wherein R1 is H, halogen, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, or [ka] R2 is selected from H, substituted or unsubstituted C1-C6 alkyl groups, R3 is selected from 5-8 membered heterocyclic groups, and the substituents in the substituted C1-C6 alkyl group and substituted C1-C6 alkoxy group are independently halogen, hydroxyl group, carboxyl group, nitro group, cyano group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 haloalkoxy group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C3-C6 cycloalkoxy group, and C6-C 10 It is one or more selected from aryl groups and 5-10 membered heteroaryl groups.

[0012] As one preferred technical example of the present invention, X 11 , X 12 , X 13 , X 14 and X 15 One of the following is independently selected from -CR1, and R1 is [ka] Selected from, preferably, R1 is [ka] It is one of the following that can be selected.

[0013] As one preferred technical application of the present invention, R1 is H, fluorine, chlorine, bromine, iodine, trifluoromethyl group, methyl group, ethyl group, propyl group, methoxy group, ethoxy group, piperazinyl group, -CH2COOH, -CH2CH2COOH, -CH2CH(CH3)COOH, [ka] R3 is selected from a pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, pyridyl group, pyrimidinyl group, or pyrazinyl group.

[0014] As one preferred technical example of the present invention, [ka] teeth, [ka] Selected from.

[0015] As one preferred technical example of the present invention, [ka] teeth, [ka] Selected from.

[0016] As one preferred technical example of the present invention, [ka] teeth, [ka] Selected from.

[0017] In the chemical structure of the compound described in the present invention, [ka] This indicates an unspecified stereoconfiguration, i.e., when chiral isomers exist in the chemical structure. join [ka] teeth [ka] is, or [ka] Both three-dimensional configurations may be included simultaneously.

[0018] In the chemical structure of the compound described in the present invention, [ka] This does not specify a configuration, meaning it may be either a Z configuration or an E configuration, or it may include both configurations simultaneously.

[0019] Furthermore, the compounds and intermediates of the present invention may exist in different tautomer forms, and all such forms are included within the scope of the present invention. The term “tautomer” or “tautomer form” refers to structural isomers of different energies that can be interconverted over a low energy barrier. For example, proton tautomers (also called proton-transfer tautomers) include tautomerization via proton transfer, such as keto-enols, imine-enamines, and lactam-lactim isomerization. A specific example of lactam-lactim equilibrium lies between A and B shown below. [ka]

[0020] All compounds in this invention can be described as either type A or type B. All tautomer forms are within the scope of this invention. The naming of the compounds does not exclude any tautomer.

[0021] As one preferred technical application of the present invention, the C1-C6 alkyl group is preferably a C1-C2, C1-C3, C1-C4, or C1-C5 alkyl group. Specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a sec-pentyl group, a 1-ethylpropyl group, a 2-methylbutyl group, a tert-pentyl group, a 1,2-dimethylpropyl group, an isopentyl group, a neopentyl group, an n-hexyl group, an isohexyl group, a sec-hexyl group, a tert-hexyl group, a neohexyl group, a 2-methylpentyl group, a 1,2-dimethylbutyl group, and a 1-ethylbutyl group.

[0022] In one preferred technical application 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 a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group.

[0023] As one preferred technical example of the present invention, C3-C 10 The cycloalkyl group is preferably selected from C3-C8 cycloalkyl groups, C3-C6 cycloalkyl groups, or C3-C5 cycloalkyl groups, and is preferably a C3-C8 cycloalkyl group. Specifically, the cycloalkyl group is selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group.

[0024] In one preferred technical application of the present invention, in some embodiments, the "heterocyclic group" is a 5-10 membered heterocyclic group consisting of 5-10 ring atoms. In some other embodiments, the "heterocyclic group" is a 5-8 membered heterocyclic group consisting of 5-8 ring atoms. In some other embodiments, the "heterocyclic group" is a 6-8 membered heterocyclic group consisting of 6-8 ring atoms. In some other embodiments, the "heterocyclic group" is a 5-6 membered heterocyclic group consisting of 5-6 ring atoms. Specific examples of heterocyclic groups include, but are not limited to, pyranyl group, tetrahydropyranyl group, oxetanyl group, tetrahydrofuranyl group, dihydrofuranyl group, 1,4-dioxanyl group, morpholinyl group, 1,4-dithianyl group, piperazinyl group, piperidinyl group, 1,3-dioxolanyl group, imidazolidinyl group, imidazolinyl group, pyrrolinyl group, pyrrolidinyl group, tetrahydropyranyl group, dihydropyranyl group, oxathiolanyl group, dithiolanyl group, 1,3-dioxanyl group, 1,4-dioxanyl group, 1,3-dithianyl group, oxathianyl group, thiomorpholinyl group, tetrahydrothiopyran-1,1-dioxide, and 1,4-diazepanyl group.

[0025] In one preferred technical application of the present invention, in some embodiments, the "heterocycloalkyl group" is preferably a 3-12 member heterocycloalkyl group, more preferably a 3-10 member heterocycloalkyl group, more preferably a 5-8 member heterocycloalkyl group, and most preferably a 5-6 member heterocycloalkyl group. Specific examples of the heterocycloalkyl group include azilidinyl group, oxyranyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, pyrazolidinyl group, imidazolidinyl group, oxazolidinyl group, isoxazolidinyl group, thiazolidinyl group, piperidinyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, and 1,1-dioxo-thiomorpholinyl-4-yl This includes, but is not limited to, the group, azepanyl group, diazepanyl group, homopiperazinyl group, oxazepanyl group, thiadinyl group, 8-aza-bicyclo[3.2.1]octyl group, quinuclidinyl group, 8-oxa-3-aza-bicyclo[3.2.1]octyl group, 9-aza-bicyclo[3.3.1]nonyl group, 3-oxa-9-aza-bicyclo[3.3.1]nonyl group, 3-thia-9-aza-bicyclo[3.3.1]nonyl group, and 2,6-diaza-spiro[3.3]heptanyl group. More specific examples of heterocycloalkyl groups include pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiadinyl, and 2,6-diaza-spiro[3.3]heptanyl.

[0026] One preferred technical example of the present invention is the substituted or unsubstituted C6-C 10The aryl group is preferably a substituted or unsubstituted C6-C8 aryl group or a substituted or unsubstituted C6-C7 aryl group. If the aryl group is substituted, the substituent is preferably H, halogen, -OH, -NH2, -CN, -NO2, -COOH, -SO3H, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, or C3-C 10 Cycloalkyl groups, C6-C 10 Substituted or unsubstituted aryl group, C5-C 10 The group is selected from substituted or unsubstituted heteroaryl groups. Specifically, the aryl group is selected from phenyl, naphthyl, anthryl, and phenanthryl groups.

[0027] The substituted or unsubstituted 5-10 membered heteroaryl group is preferably a substituted or unsubstituted 5-8 membered heteroaryl group, a substituted or unsubstituted 5-7 membered heteroaryl group, or a substituted or unsubstituted 5-6 membered heteroaryl group. When the heteroaryl group is substituted, the substituent is preferably H, halogen, -OH, -NH2, -CN, -NO2, -COOH, -SO3H, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C 10 Cycloalkyl groups, substituted or unsubstituted C5-C 10 The heteroaryl group is selected from an aryl group and a substituted or unsubstituted 5-10 membered heteroaryl group. The heteroatom in the heteroaryl group is one or more of N, O, and S. The heteroaryl group is preferably an imidazolyl group, a furanyl group, a thienyl group, a thiazolyl group, a pyrazolyl group, an oxazolyl group, a pyrrolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a thiadiazolyl group, a pyrazinyl group, [ka] The group can be selected from pyrazolyl, isoxazolyl, thiazolyl, pyrazolyl, tetrazolyl, pyridadinyl, quinolyl, isoquinolyl, triazolyl, and tetrazolyl groups.

[0028] As one preferred technical application of the present invention, the sulfonamide compound, its isomer, its racemate, or its pharmaceutically acceptable salt is selected from the compounds shown in Table 1A or Table 1B.

[0029] [Table 1A-1]

[0030] [Table 1A-2]

[0031] [Table 1A-3]

[0032] [Table 1B-1]

[0033] [Table 1B-2]

[0034] [Table 1B-3]

[0035] The present invention further provides a method for preparing sulfonamide compounds, their isomers, their racemates, or pharmaceutically acceptable salts thereof. This preparation method is based on the method of Chinese Patent CN114008021A and methods known in the art.

[0036] The present invention further provides a pharmaceutical composition characterized by comprising a sulfonamide compound described in general formula I, general formula II, general formula III, general formula IV, or general formula V, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and / or carriers.

[0037] The present invention further provides the use of sulfonamide compounds, their isomers, their racemates, or pharmaceutically acceptable salts thereof in the preparation of pharmaceuticals for the prevention or treatment of LP(a)-related diseases.

[0038] Furthermore, the aforementioned Lp(a)-related diseases are cardiovascular diseases.

[0039] Furthermore, the cardiovascular disease is selected from stroke, atherosclerosis, thrombosis, coronary artery disease or aortic stenosis, and any other disease associated with elevated Lp(a) levels.

[0040] Compared to the prior art, the beneficial effects of the present invention include, but are not limited to, the following: The sulfonamide compounds of the present invention have a lower IC50 than those of the prior art. 90 It has a value.

[0041] For clarity, common terms used in describing compounds are defined herein.

[0042] Unless otherwise specified, the following terms and phrases used herein are intended to have the meanings set forth below. Certain terms or phrases, in the absence of a specific definition, should not be considered uncertain or ambiguous, but should be understood according to their ordinary meaning. Trademarks used herein are intended to refer to the corresponding product or its active ingredient. The term “pharmaceutically acceptable” as used herein means that, within the bounds of sound medical judgment, a compound, material, composition, and / or dosage form is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and that the benefit / risk ratio is reasonable.

[0043] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention prepared from a compound having a specific substituent discovered in the present invention, and from a pharmaceutically acceptable acid or alkali.

[0044] In addition to salt forms, the compounds provided in this invention may also exist in prodrug forms. Prodrugs of the compounds described herein can readily undergo chemical changes under physiological conditions, thereby being converted into the compounds of the present invention. In addition, prodrugs can be chemically or biologically converted into the compounds of the present invention in vivo.

[0045] Some of the compounds of the present invention may exist in non-solvated or solvated forms (including hydrate forms). In general, the solvated and non-solvated forms are equivalent and both fall within the scope of the present invention.

[0046] The compounds of the present invention may exist in the form of specific geometric isomers or stereoisomers. The present invention assumes that all cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and other mixtures thereof, such as racemic mixtures and mixtures enriched with enantiomers or diastereomers, are included within the scope of the invention. Substituents such as alkyl groups may have additional asymmetric carbon atoms. All of these isomers and mixtures thereof are included within the scope of the invention.

[0047] Optically active (R)- and (S)-isomers, as well as D and L isomers, may be prepared by chiral synthesis, chiral reagents, or other prior art. To obtain one enantiomer of a particular compound disclosed herein, preparation may be carried out by asymmetric synthesis or derivatization using chiral auxiliaries. In this case, the resulting diastereomer mixture is separated, and the auxiliaries are cleaved to obtain the desired pure enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), the compound forms a salt of the diastereomer with a suitable optically active acid or base, and then the diastereomer is divided by conventional methods in the art to recover the pure enantiomer. Furthermore, the separation of enantiomers and diastereomers is typically carried out by chromatography using a chiral stationary phase, and, if necessary, combined with chemical derivatization (e.g., producing a carbamate from an amine).

[0048] "Alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms. Preferably, it is an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, and various branched isomers thereof. Alkyl groups may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linking site, independently including halogens, deuterium, hydroxyl groups, oxo, nitro groups, cyano groups, C1-C6 alkyl groups, C 1- C6 alkoxy group, C2-C6 alkenyloxy group, C2-C6 alkynyloxy group, C3-C6 cycloalkyl group, 3-6 member heterocycloalkyl group, C5-C8 cycloalkenyl group, C3-C6 cycloalkoxy group, 3-6 member heterocycloalkyloxy group, C5-C8 cycloalkenyloxy group, C6-C 10 One or more selected from aryl groups and 5-6 membered heteroaryl groups. The C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyloxy group, C2-C6 alkynyloxy group, C3-C6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C5-C8 cycloalkenyl group, C3-C6 cycloalkoxy group, 3-6 membered heterocycloalkyloxy group, C5-C8 cycloalkenyloxy group, C6-C 10 The aryl group or the 5-6 membered heteroaryl group may optionally be substituted with one or more substituents selected from halogens, deuterium, hydroxyl groups, oxo groups, nitro groups, and cyano groups.

[0049] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), and the definition of alkyl group here is as described above. Non-exclusive specific examples of alkoxy groups include methoxy group, ethoxy group, propoxy group, butoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, and cyclohexyloxy group.

[0050] The term "haloalkoxy group" refers to an alkoxy group in which at least one of its hydrogen atoms is substituted with the same or a different halogen atom. The term "total haloalkoxy group" refers to an alkoxy group in which all of its hydrogen atoms are substituted with the same or a different halogen atom. Specific examples of haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy, and pentafluoroethoxy. Specific haloalkoxy groups are trifluoromethoxy and 2,2-difluoroethoxy.

[0051] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0052] The term "cycloalkyl group" or "carbocyclic group" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the ring of a cycloalkyl group contains 3-10 carbon atoms, preferably 3-8 carbon atoms, and more preferably 3-6 carbon atoms. Non-limiting specific examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings, and crosslinked rings.

[0053] The terms "aryl group" or "aromatic ring" refer to a 6-10 member all-carbon monocycle or fused polycycle (i.e., a ring sharing adjacent carbon atom pairs) having a conjugated π-electron system, preferably a 6-8 member, such as a phenyl group or a naphthyl group.

[0054] The term "heteroaryl group" or "heteroaryl ring" refers to a heteroaryl system containing 1-3 heteroatoms and 5-12 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably a 5-10 membered or 5-8 membered heteroaryl group, and more preferably a 5- or 6-membered heteroaryl group. Specific examples of the heteroaryl group include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridadinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, prinyl, quinolyl, isoquinolyl, quinazolinyl, and quinoxalinyl groups. Certain heteroaryl groups include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridadinyl, pyrimidinyl, isoxazolyl, and isothiazolyl.More specific heteroaryl groups include imidazolyl group, oxazolyl group, thiazolyl group, oxadiazolyl group, thiadiazolyl group, tetrazolyl group, pyridyl group, pyrazinyl group, pyrazolyl group, pyridadinyl group, pyrimidinyl group, isoxazolyl group, isothiazolyl group, 2-fluoropyridyl group, 3-fluoropyridine group, 4-fluoropyridyl group, 2-chloropyridyl group, 3-chloropyridine group, 4-chloropyridyl group, 2,3-difluoropyridyl group, 3,4-difluoropyridyl group, 4,5-difluoropyridyl group, 3 It contains a 5-difluoropyridyl group, a 2-chloro-3-fluoropyridyl group, a 3-fluoro-4-chloropyridyl group, a 3-fluoro-5-chloropyridinyl group, a 4-fluoropyrimidinyl group, a 5-fluoropyrimidinyl group, a 4-chloropyrimidinyl group, a 5-chloropyrimidinyl group, a 4-chloro-5-fluoropyrimidinyl group, a 4-cyanopyrimidinyl group, a 5-cyanopyrimidinyl group, a 4,5-dicyanopyrimidinyl group, a 4-methylpyrimidinyl group, a 5-methylpyrimidinyl group, or a 4,5-dimethylpyrimidinyl group.

[0055] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocyclic system (i.e., monocyclic heterocyclic group), a polycyclic heterocyclic system (i.e., polycyclic heterocyclic group), or a heteroaryl ring system, wherein the ring contains at least one heteroatom (e.g., 1, 2, 3, or 4) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., to form a nitrogen oxide, and the sulfur may optionally be substituted with oxygen, i.e., to form a sulfoxide or sulfone, but without -OO-, -OS-, or -SS-), and has 3 to 20 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., a 3-20 membered heterocyclic group). The heterocyclic group is preferably a heterocyclic group having 3-12 ring atoms (i.e., a 3-12 membered heterocyclic group), more preferably a heterocyclic group having 3-8 ring atoms (i.e., a 3-8 membered heterocyclic group), even more preferably a heterocyclic group having 5-8 ring atoms (i.e., a 5-8 membered heterocyclic group), and most preferably a heterocyclic group having 5-6 ring atoms (i.e., a 5-6 membered heterocyclic group). In some examples, the 5-8 membered heterocyclic group is selected from a 5-8 membered heterocycloalkyl group and a 5-8 membered heteroaryl group. In some examples, the 5-6 membered heterocyclic group is selected from a 5-6 membered heterocycloalkyl group and a 5-6 membered heteroaryl group.

[0056] The term "heterocycloalkyl group" refers to a cycloalkyl group in which one to four carbon atoms are substituted with heteroatoms, where the heteroatoms are one or more selected from N, O, and S, and are preferably 3-12 member heterocycloalkyl groups, more preferably 3-10 member heterocycloalkyl groups, more preferably 5-8 member heterocycloalkyl groups, and most preferably 5-6 member heterocycloalkyl groups. Specific examples of the heterocycloalkyl groups include azilidinyl group, oxyranyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, pyrazolidinyl group, imidazolidinyl group, oxazolidinyl group, isoxazolidinyl group, thiazolidinyl group, piperidinyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, and 1,1-dioxo-thiomorpholinyl-4-yl This includes, but is not limited to, the group, azepanyl group, diazepanyl group, homopiperazinyl group, oxazepanyl group, thiadinyl group, 8-aza-bicyclo[3.2.1]octyl group, quinuclidinyl group, 8-oxa-3-aza-bicyclo[3.2.1]octyl group, 9-aza-bicyclo[3.3.1]nonyl group, 3-oxa-9-aza-bicyclo[3.3.1]nonyl group, 3-thia-9-aza-bicyclo[3.3.1]nonyl group, and 2,6-diaza-spiro[3.3]heptanyl group. More specific examples of heterocycloalkyl groups include pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiadinyl, and 2,6-diaza-spiro[3.3]heptanyl.

[0057] The atoms of the compound molecules of the present invention are isotopes, and isotopic derivatization typically has effects such as extension of half-life, reduction of clearance, stabilization of metabolism, and improvement of in vivo activity. Furthermore, embodiments include those in which at least one atom is substituted with an atom having the same number of atoms (number of protons) and a different mass number (sum of the number of protons and neutrons). Specific examples of isotopes contained in the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine atoms, each of which is an isotope. 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Contains Cl. In particular, radioactive isotopes that emit radiation as Cl decays, for example, 3 H or 14 C can be used for local anatomical examination of pharmaceutical formulations or in vivo compounds. Stable isotopes do not decay or change depending on their quantity and are not radioactive, so they can be used safely. When the atoms constituting the compound molecule of the present invention are isotopes, the isotopes can be converted by conventional methods by using reagents containing the corresponding isotopes instead of the reagents used in synthesis.

[0058] The term "haloalkyl group" refers to an alkyl group, such as a trifluoromethyl group or a trifluoroethyl group, in which one or more hydrogen atoms are substituted with halogens.

[0059] The term "haloalkoxy group" refers to an alkoxy group in which one or more hydrogen atoms are substituted with halogens, such as the trifluoromethyloxy group and the trifluoroethyloxy group.

[0060] The compounds of the present invention may contain atomic isotopes in unnatural proportions in one or more atoms constituting the compound. Deuterium ( 2 H), Iodine-125(125 I) or C-14 ( 14 The compounds may be labeled using radioactive isotopes such as C). All isotopic transformations of the compounds of the present invention, regardless of their radioactivity, are included within the scope of the present invention.

[0061] Furthermore, one or more hydrogen atoms in the compound of the present invention are isotopes of deuterium ( 2 When substituted with H, the compound of the present invention exhibits effects such as extended half-life, reduced clearance, stabilization of metabolism, and improved in vivo activity.

[0062] The method for preparing the isotope derivatives typically involves a phase-transfer catalytic method. For example, a preferred deuterating method uses a phase-transfer catalyst (e.g., tetraalkylammonium salt, NBu4HSO4). By exchanging the methylene protons of the diphenylmethane compound using a phase-transfer catalyst, a higher level of deuterium is introduced compared to reduction using sodium deuterated borate with a deuterated silane (e.g., triethyl deuterated silane) or a Lewis acid (e.g., aluminum chloride) in the presence of an acid (e.g., methanesulfonic acid).

[0063] The term “pharmaceutically acceptable carrier” refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of the present invention without inhibiting the biological activity of the active substance and without causing toxic side effects to the host or patient. Typical carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, thickeners, transdermal absorption enhancers, etc. These formulations are well known to those skilled in the art in the fields of cosmetics or topical pharmaceuticals. Further information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0064] The term "excipient" typically refers to a carrier, diluent, and / or medium necessary for the preparation of an effective pharmaceutical composition.

[0065] For pharmaceuticals or pharmacological activators, the term “effective dose” or “therapeutic dose” refers to a sufficient amount of the pharmaceutical or drug that is non-toxic but capable of achieving the desired effect. For oral dosage forms in this invention, the “effective dose” of one active substance in the composition refers to the dose required to achieve the desired effect when used in combination with another active substance in the composition. Determining the effective dose varies from person to person, depends on the person’s age and general condition, and also depends on the specific active substance. In individual cases, an appropriate effective dose may be determined by those skilled in the art based on conventional testing.

[0066] The terms "active ingredient," "therapeutic agent," "active substance," or "activator" refer to a single chemical substance that can effectively treat a target disorder, disease, or condition.

[0067] "Optional" or "at will" means that the matters or circumstances described below may or may not occur, and this expression includes both cases in which the aforementioned matters or circumstances occur and cases in which they do not occur. [Modes for carrying out the invention]

[0068] The present invention will be described in more detail below based on examples, but the content of the present invention is not limited to these examples.

[0069] Example 1 Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid The specific synthesis route is as follows: [ka]

[0070] Step A: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl At room temperature, dissolve (R)-3-(S)-3-(3-bromophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (200 mg, 0.44 mmol) in anhydrous THF (3 ml), stir under a nitrogen atmosphere at -40°C, then add isopropyl magnesium chloride and lithium chloride liquid (1.1 ml, 2.5 mol / liter) and react for 2 hours. After that, add sulfonyl chloride (101 mg, 0.53 mmol), gradually raise the temperature to room temperature and continue stirring for 14.0 hours. After confirming that the starting materials had reacted completely by TLC spot plate detection, the mixture was quenched with an aqueous solution of ammonium chloride (10 ml) at -30°C, extracted with EA (20 ml x 3 times), the collected organic phase was dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was subjected to column chromatography with n-hexane:ethyl acetate = 3:1 to obtain 113 mg of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl. LCMS:RT=2.17min, [M+H] + = 474.17.

[0071] Step B: Synthesis of 3,3'-((2S,2'S)-di-tert-butyl(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) At room temperature, dissolve (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (55 mg, 0.12 mmol) in acetonitrile (2.5 ml) and begin stirring. Then, di-tert-butyl-3,3'-((2S,2'S)-((azandiylbis(methylene))bis( Add 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), and stir at 80°C for 14 hours, After confirming that the starting materials had reacted completely by TLC spot plate detection, the reaction was terminated, water (6 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 ml x 3 times). The collected organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure. The resulting crude product was subjected to column chromatography in n-hexane:ethyl acetate = 3:1 to obtain 100 ml of 3,3'-((2S,2'S)-di-tert-butyl(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0072] Step C: Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) 3,3'-((2S,2'S)-di-tert-butyl(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azandiyl)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. After confirming that the starting material had reacted completely by LC-MS monitoring, the reaction was terminated. The solution was concentrated under reduced pressure to obtain the crude product of the target product. The crude product was purified by preparative high-performance liquid chromatography to obtain 5.2 milligrams of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bis(methylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid). LCMS: RT=1.49 min, [MH] - =759.43, HPLC: 90.22%.

[0073] Example 2 Synthesis of (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)azandiyl)bis(methylene)bis(6-fluoro-3,1-phenylene))bis(2-(((R)-pyrrolidine-3-yl)propionic acid) The specific synthesis route is as follows: [ka]

[0074] Step A: Synthesis of tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-(((3(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate At room temperature, (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-5-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (200 mg, 0.47 mmol), (R)-3-((S)-3-(3-(aminomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (192 mg, 0.47 mmol), and anhydrous isopropanol (5 ml) were added in that order. After raising the temperature to 45°C, sodium triacetyloxyhydride (201 mg, 0.94 mmol) was added in three portions, and the mixture was reacted at 45°C for 18 hours. After the reaction was complete, an aqueous solution of saturated ammonium chloride (10 ml) was added to quench the mixture, and it was extracted with ethyl acetate (20 ml x 2 times). The mixture was concentrated until dry, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1) to obtain 210 ml of tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-(((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.03 min, [M + H] + = 810.08.

[0075] Step B: Synthesis of tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-(((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorobenzyl)phenyl)sulfonamide)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate At room temperature, tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(3-(((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (172 mg, 0.21 mmol), (R)-3-( (S)-1-(tert-butoxy)-3-(3-(chlorosulfonyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (100 mg, 0.2 mmol), acetonitrile (3 ml), triethylamine (32 mg, 0.32 mmol), and 4-dimethylaminopyridine (9 mg, 0.07 mmol) were added, the mixture was purged with nitrogen gas, and the temperature was raised to 80°C and the mixture was reacted for 2 hours. After the reaction was complete, tap water (10 ml) and ethyl acetate (10 ml) were added for extraction, and the mixture was concentrated until dry to obtain the crude product, which was then directly used for the next step.

[0076] Step C: Synthesis of (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)azandiyl)bis(methylene)bis(6-fluoro-3,1-phenylene))bis(2-(((R)-pyrrolidine-3-yl)propionic acid) At room temperature, the crude product from the previous step, dioxane (2.5 ml), and concentrated hydrochloric acid (0.5 ml) were added and the mixture was reacted at 45°C for 18 hours. After the reaction was complete, the mixture was concentrated until dry, and the resulting residue was purified by preparative high-performance liquid chromatography to obtain 18 milligrams of (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)azandiyl)bis(methylene)bis(6-fluoro-3,1-phenylene))bis(2-(((R)-pyrrolidine-3-yl)propionic acid). LCMS:RT=1.58min,[MH] - = 777.30.

[0077] Example 3 Synthesis of (S)-3-(3-(((3-(S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-N-(2-((S)2-carboxy-2-(R)pyrrolidine-3-ylethyl)phenylethyl)phenyl)sulfonamide)methyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid The specific synthesis route is as follows: [ka] Prepared according to the method for Compound 2. LC-MS: RT = 1.45 min, [MH] - = 773.31.

[0078] Example 4 Synthesis of (S)-3-(3-(N-(5-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2-fluorobenzyl)-N-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid [ka] Prepared according to the method for Compound 2. LC-MS: 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).

[0079] Example 5 Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-ethyl)-2-fluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid [ka] Prepared according to the method for Compound 2. LC-MS: RT=1.51 min, [M+H] + = 779.21.

[0080] Example 6 Synthesis of (2S,2'S)-3,3'(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-4-fluorophenylsulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) The specific synthesis route is as follows: [ka]

[0081] Step A: Synthesis of (R)-3-(S)-3-(5-(benzylthio)-2-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl At room temperature, (R)-3-(S)-3-(5-bromo-2-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (2.0 g, 4.23 mmol), benzyl mercaptan (630 mg, 5.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxyheteroanthracene (245 mg, 0.42 mmol), tri(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 mixture was heated to 100°C and reacted for 5 hours. After the reaction was complete, the filtrate was filtered by suction, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 2.0 grams of (R)-3-(S)-3-(5-(benzylthio)-2-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl. LCMS: RT = 2.52 min, [M + H-Boc] + = 416.13.

[0082] Step B: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(5-chlorosulfonyl)-2-fluorophenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (R)-3-(S)-3-(5-(benzylthio)-2-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (1.0 g, 1.94 mmol) was dissolved in acetic acid / water / acetonitrile (1.1 / 0.7 / 30 ml), and a solution of 1,3-dichloro-5,5-dimethylhydantoin (760 mg, 3.88 mmol) in acetonitrile (2 ml) was added dropwise in an ice bath, and the mixture was stirred until the solution turned red. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate (30 ml x 2 times). The organic phases were combined, washed first with saturated brine (20 ml x 2 times), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 0.8 g of (R)-3-(S)-1-tert-butoxy-3-(5-chlorosulfonyl)-2-fluorophenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl. LCMS: RT = 2.29 min, [M+H-Boc-tert-butyl] + =336.01.

[0083] Steps C and D were prepared according to the method for Compound 2. LCMS: RT = 1.52 min, [M + H] + = 779.16. 1 H NMR(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).

[0084] Example 7 Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-5-fluorophenylsulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) [ka] Prepared according to the method for Compound 2. LCMS: RT = 1.51 min, [M + H] + = 779.21.

[0085] Example 8 Synthesis of (2S,2'S)-3,3'(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2-fluorophenylsulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) The specific synthesis route is as follows: [ka]

[0086] Step A: Synthesis of 3,3'-((2S,2'S)-(azandiylbismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) At room temperature, (R)-3-(S)-3-(3-aminomethyl)phenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (300 mg, 0.74 mmol) and (R)-3-(S)-1-tert-butoxy-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (300 mg, 0.74 mmol) were dissolved in DCE (6 ml), sodium triacetyloxyhydride (551 mg, 2.6 mmol) was added in several batches, the temperature was raised to 45 degrees Celsius, and the mixture was stirred for 16 hours. After confirming the completion of the reaction by TLC monitoring, the reaction was quenched by adding an aqueous solution (1 ml). The resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to obtain 450 ml of 3,3'-((2S,2'S)-(azandiylbismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate). LC-MS: RT = 2.02 min, [M+H] + = 792.61.

[0087] Step B: Synthesis of 3,3'-(((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2-fluorophenyl)sulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) At room temperature, 3,3'-((2S,2'S)-(azandiylbismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (200 mg, 0.25 mmol) was dissolved in pyridine (4 ml), and a solution of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)-2-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylate tert-butyl (149 mg, 0.30 mmol) in acetonitrile (2 ml) was gradually added, and the mixture was reacted at room temperature for 0.5 hours. After confirming the completion of the reaction by TLC monitoring, the mixture was extracted with ethyl acetate (10 ml x 2 times), the combined organic phase was first washed with saturated saline solution (5 ml x 2 times), then dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to obtain 60 ml of 3,3'-(((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2-fluorophenyl)sulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0088] Step C: Synthesis of (2S,2'S)-3,3'(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2-fluorophenylsulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) At room temperature, 3,3'-(((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2-fluorophenyl)sulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (60 milligrams, 0.05 mmol) was dissolved in a solution of 1,4-dioxane (2 ml), concentrated hydrochloric acid (0.1 ml) was added, and the mixture was heated to 45 degrees Celsius and reacted for 4 hours. After confirming the completion of the reaction by LC-MS monitoring, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain 16 milligrams of (2S,2'S)-3,3'(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2-fluorophenylsulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid). LCMS: RT=1.51 min, [MH] - = 777.1.

[0089] Example 9 Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bismethylene)bis(6-fluoro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-ylpropionic acid) The specific synthesis route is as follows: [ka]

[0090] Step A: Synthesis of 3,3'-((2S,2'S)-(azandiylbismethylene)bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(tert-butyl pyrrolidine-1-carboxylate) At room temperature, (R)-3-(S)-1-tert-butoxy-3-(2-fluoro-5-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (350 mg, 0.83 mmol) and (R)-3-(S)-3-(5-aminomethyl)-2-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (420 mg, 1.00 mmol) are dissolved in dry 1,2-dichloroethane (5 ml), the mixture is heated to 45°C and reacted for 3 hours, after which sodium triacetyloxyhydride (528 mg, 2.49 mmol) is added. The mixture was added in several batches and reacted at 45°C for 4 hours. After the reaction was complete, water was added to dilute the mixture, and the mixture was extracted with ethyl acetate (20 ml x 2 times). The organic phases were combined, washed first with saturated brine (20 ml x 2 times), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 350 mg of 3,3'-((2S,2'S)-(azandiylbismethylene)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.

[0091] Step B: Synthesis of 3,3'-(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azandiyl)bismethylene)bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate tert-butyl) At room temperature, 3,3'-((2S,2'S)-(azandiylbismethylene)bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropan-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-carboxylate tert-butyl (116 mg, 0.25 mmol) in acetonitrile (1.2 ml) was added, and the mixture was reacted at room temperature for 18 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 50 milligrams of 3,3'-(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azandiyl)bismethylene)bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid tert-butyl).

[0092] Step C: Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bismethylene)bis(6-fluoro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-ylpropionic acid) 3,3'-(3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azandiyl)bismethylene)bis(6-fluoro-3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate tert-butyl) (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 was complete, the mixture was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography to obtain 26.2 milligrams of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bismethylene)bis(6-fluoro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-ylpropionic acid). LCMS:RT=1.53min, [MH] - = 795.12. 1 H 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).

[0093] Example 10 Synthesis of (S)-3-(3-(N-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-ethyl)-4-chlorobenzyl)-N-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)2-((R)-pyrrolidine-3-yl)propionic acid [ka] Prepared according to the method for compound 9. LCMS: RT=1.54min, [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).

[0094] Example 11 Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis((2-(R)pyrrolidine-3-ylpropionic acid) The specific synthesis route is as follows: [ka]

[0095] Step A: Synthesis of (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(hydroxymethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl At room temperature, (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (320 mg, 0.76 mmol) and anhydrous isopropanol (5 ml) were added, the mixture was cooled in ice water, and then sodium borohydride (28 mg, 0.76 mmol) was added in three portions. The mixture was reacted in an ice water bath for 1 hour. After the reaction was complete, an aqueous solution of saturated ammonium chloride (10 ml) was added to quench the reaction, and the solution was extracted with ethyl acetate (10 ml twice). The mixture was washed with an aqueous solution of saturated sodium chloride (10 ml once), dried over sodium sulfate, and concentrated until dry to obtain 350 ml of (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(hydroxymethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl. LCMS: RT = 2.13 min, [M-Boc+H] + = 324.17.

[0096] Step B: Synthesis of (R)-3-((S)-1-(tert-butoxy)-3-(3-((1,3-dioxoisoindolin-2-yl)methyl)-2-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl At room temperature, (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(hydroxymethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (350 mg, 0.83 mmol), phthalimide (157 mg, 1.07 mmol), triphenylphosphine (434 mg, 1.65 mmol), and tetrahydrofuran (5 ml) were added in that order, followed by the dropwise addition of diisopropyl azodicarboxylate (333 mg, 1.65 mmol), and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated until dry, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 630 milligrams of (R)-3-((S)-1-(tert-butoxy)-3-(3-((1,3-dioxoisoindolin-2-yl)methyl)-2-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl.

[0097] Step C: Synthesis of (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(aminomethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl At room temperature, (R)-3-((S)-1-(tert-butoxy)-3-(3-((1,3-dioxoisoindolin-2-yl)methyl)-2-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (630 mg, 1.14 mmol) was dissolved in ethanol (10 ml), and hydrazine monohydrate (80%, 178 mg, 2.84 mmol) was added. The mixture was then heated to 85°C and reacted for 3 hours. After the reaction was complete, the mixture was filtered to remove the white solid. The filtered cake was washed with ethyl acetate (20 ml x 2 times), the filtrates were combined, concentrated until dry, 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 (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(aminomethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl. LCMS: RT=1.82 min, [M+H] + = 423.16.

[0098] Step D: Synthesis of 3,3'-di-tert-butyl((2S,2'S)-((azandiylbis(methylene))bis(2-fluoro-3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bispyrrolidine-1-carboxylate t-butyl At room temperature, (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (216 mg, 0.51 mmol), (R)-3-((S)-1-(tert-butoxy)-3-(2-fluoro-3-(aminomethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (260 mg, 0.61 mmol), and 1,2-dichloroethane (6 ml) were added in that order. After raising the temperature to 45°C, sodium borotriacetyloxyhydride (326 mg, 1.54 mmol) was added in three portions, and the mixture was reacted at 45°C for 18 hours. After the reaction was complete, an aqueous solution of saturated ammonium chloride (10 ml) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 ml x 2 times). The mixture was concentrated until dry, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 1) to obtain 405 ml of 3,3'-di-tert-butyl((2S,2'S)-((azandiylbis(methylene))bis(2-fluoro-3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bispyrrolidine-1-carboxylate t-butyl. LCMS: RT = 2.04 min, [M + H] + = 828.31.

[0099] Step E: Synthesis of 3,3'-di-tert-butyl((2S,2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenyl)sulfonyl)azandiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) At room temperature, 3,3'-di-tert-butyl((2S,2'S)-((azandiylbis(methylene))bis(2-fluoro-3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropan-1,2-diyl))(3R,3'R)-bispyrrolidine-1-carboxylate t-butyl (300 mg, 0.36 mmol) and pyridine (3 ml) were added and completely dissolved. Then, (R)-3-((S)-1-(tert-butoxy)-3-(3-(chlorosulfonyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (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. After the reaction was complete, the mixture was concentrated until dry, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 226 milligrams of 3,3'-di-tert-butyl((2S,2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenyl)sulfonyl)azandiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0100] Step F: Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis((2-(R)pyrrolidine-3-ylpropionic acid) At room temperature, 3,3'-di-tert-butyl((2S,2'S)-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxypropyl)phenyl)sulfonyl)azandiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (220 mg, 0.17 mmol), dioxane (2.5 ml), and concentrated hydrochloric acid (0.5 ml) were added and reacted at 45°C for 4 hours. After the reaction was complete, the mixture was concentrated until dry, and the residue was purified by preparative high-performance liquid chromatography to obtain 104 milligrams of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bis(methylene))bis(2-fluoro-3,1-phenylene)bis((2-(R)pyrrolidine-3-ylpropionic acid). LCMS:RT=1.48min, [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).

[0101] Example 12 Synthesis of (S)-3-(3-(N-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-2-chlorobenzyl)-N-(3-((S)-2-carboxy-2-((R)pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)2-((R)-pyrrolidine-3-yl)propionic acid [ka] Prepared according to the method for compound 9. LCMS: RT = 1.49 min, [MH] - = 793.07. 1 H 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).

[0102] Example 13 Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenylsulfonyl)azandiyl)bismethylene)bis(4-fluoro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) [ka] The specific synthesis route is as follows: Prepared according to the method for compound 11. LCMS: RT = 1.51 min, [MH] - = 795.09.

[0103] Example 14 (S)-3-(3-(5-(S)-2-Carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-2-fluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-4-fluorobenzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropionic acid synthesis

Chemical Structure

[0104] Example 15 (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-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-((R)-pyrrolidin-3-yl)propionic acid synthesis

Chemical Structure

[0105] Example 16 Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bis(methylene))bis(4,6-difluoro-3,1-phenylene)bis(2-(R)pyrrolidine-3-yl)propionic acid The specific synthesis route is as follows: [ka] Prepared according to the method for compound 11. LCMS: RT = 1.51 min, [MH] - = 831.06. 1H 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).

[0106] Example 17 Synthesis of (2S,2'S)-3,3'-((3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bis(ethane-2,1-diyl)bis(2,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid The specific synthesis route is as follows: [ka] Prepared according to the method for compound 9. LC-MS: RT=1.51 min, [M+H] - = 787.06.

[0107] Example 18 Synthesis of (S)-3-(2-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-N-(2-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)phenyl)sulfonamide)ethyl)phenyl)-2-(R)-pyrrolidine-3-yl)propionic acid The specific synthesis route is as follows: [ka] Prepared according to the method for compound 9. LCMS: RT = 1.54 min, [MH] -=773.12。 1 H NMR(400 MHz, D2O) δ 7.69 (S, 1H), 7.63 (S, 1H), 7.51 (d, J = 4.6 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1H), 7.21 - 7.11 (m, 2H), 7.12 - 6.99 (m, 4H), 6.76 (d, J = 7.4 Hz, 1H), 4.24 (S, 2H), 3.47 (dd, J = 11.8, 7.2 Hz, 2H), 3.40 - 3.30 (m, 3H), 3.29 - 3.03 (m, 6H), 2.95 (dd, J = 11.8, 7.2 Hz, 2H), 2.86 - 2.66 (m, 6H), 2.68 - 2.24 (m, 9H), 2.05 (S, 3H), 1.84 - 1.39 (m, 3H).

[0108] Example 19 (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)phenyl)ethyl)phenyl)sulfonamido)ethyl)phenyl)phenyl)-2-((R)-pyrrolidin-3-yl)propionic acid synthesis The specific synthetic route is as follows.

Chemical Structure

[0109] Example 20 Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)phenyl)sulfonamide)ethyl)phenyl)-2-(R)-pyrrolidine-3-yl)propionic acid The specific synthesis route is as follows: [ka] Prepared according to the method for compound 9. LCMS: RT = 1.49 min, [MH] - = 773.26.

[0110] Example 21 Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bis(ethane-2,1-diyl))bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) The specific synthesis route is as follows: [ka]

[0111] Step A: Synthesis of (R)-3-(S)-1-tert-butoxy-1-oxo-3-(3-vinylphenyl)propan-2-yl)pyrrolidine-1-carboxylate tert-butyl At room temperature, add (R)-3-(S)-3-(3-bromophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (15 g, 33.0 mmol), triphenylphosphine (866 mg, 3.30 mmol), cesium carbonate (32.3 g, 99 mmol), palladium chloride (292 mg, 1.65 mmol), and potassium vinyltrifluoroborate (7.57 g, 49.5 mmol) in that order to a reaction flask, purging three times with nitrogen gas, then add tetrahydrofuran (150 ml) and purified water (30 ml), and heat to 70°C. The reaction was incubated overnight at a raised temperature, and after confirming completion of the reaction by TLC monitoring, it was cooled to room temperature, diluted with water (150 ml), extracted with ethyl acetate (150 ml x 2 times), washed the combined organic phase with saturated brine (150 ml x 2 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 8) to obtain 13.2 grams of (R)-3-(S)-1-tert-butoxy-1-oxo-3-(2-vinylphenyl)propan-2-ylpyrrolidine-1-carboxylate tert-butyl. LCMS: RT = 2.35 min, [M + H] + = 402.23.

[0112] Step B: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(3-(2-hydroxyethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl In an ice bath, a solution of (R)-3-(S)-1-tert-butoxy-1-oxo-3-(2-vinylphenyl)propan-2-ylpyrrolidine-1-carboxylate tert-butyl (13.2 g, 32.87 mmol) in tetrahydrofuran (130 ml) was added dropwise with a solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (132 ml, 0.5 mol / L), and the mixture was stirred at room temperature for 18 hours. Then, in an ice bath, methanol (50 ml), an aqueous solution of sodium hydroxide (104 ml, 3 mol / L), and 30% hydrogen peroxide (22.4 g) were added to the reaction mixture, and the mixture was reacted at room temperature for 3 hours. After confirming the completion of the reaction by TLC monitoring, an excess saturated sodium bisulfate solution was added to quench the reaction, stirred for 10 minutes, diluted with water (100 ml), extracted with ethyl acetate (200 ml x 2 times), washed the combined organic phase with saturated brine (150 ml x 2 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2) to obtain 9.6 g of (R)-3-(S)-1-tert-butoxy-3-(2-hydroxyethyl)phenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl. LCMS: RT = 2.14 min, [M + H-tert-butyl-tert-butoxycarbonyl] + = 320.22.

[0113] Step C: Synthesis of (R)-3-(S)-1-tert-butoxy-1-oxo-3-(3-(2-oxoethyl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate tert-butyl At room temperature, 5.3 grams (12.63 mmol) of (R)-3-(S)-1-tert-butoxy-3-(2-hydroxyethyl)phenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl was dissolved in 100 ml of ethyl acetate, and 3.9 grams (13.90 mmol) of 2-iodoxybenzoic acid was added. The mixture was heated to 70°C and reacted for 8 hours. After confirming that the reaction was complete by TLC monitoring, the mixture was filtered by suction, the filtered cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 2.6 grams of (R)-3-(S)-1-tert-butoxy-1-oxo-3-(2-oxoethyl)phenyl)propan-2-ylpyrrolidine-1-carboxylate tert-butyl. LCMS:RT=2.21min, [M+H] + = 418.25.

[0114] Step D: Synthesis of 3,3'-((2S,2'S)-(azandiylbisethane-2,1-diyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (R)-3-(S)-1-tert-butoxy-1-oxo-3-(3-(2-oxoethyl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate tert-butyl (250 mg, 0.60 mmol) and (R)-3-(S)-3-(3-(2-aminoethyl)phenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (251 mg, 0.60 mmol) were dissolved in 1,2-dichloroethane, and then sodium triacetyloxyhydride (444 mg, 2.1 mmol) was added in several batches, and the mixture was reacted overnight at 45°C. After the reaction was complete, the solvent was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to obtain 150 milligrams of 3,3'-((2S,2'S)-(azandiylbisethane-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.

[0115] Step E: Synthesis of 3,3'-(3-(S)-3-tert-butoxy-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azandiyl)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) At room temperature, 3,3'-((2S,2'S)-(azandiylbisethane-2,1-diyl)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (250 mg, 0.30 mmol) was dissolved in anhydrous pyridine (2 ml), and then a solution of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropane-2-yl)pyrrolidine-1-carboxylate tert-butyl in acetonitrile (174 mg, 0.37 mmol, 2 ml) was gradually added dropwise, and the TLC spot was used. After confirming that the starting materials had reacted completely by plate detection, the mixture was rotated and evaporated to remove pyridine. The crude product was then purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to obtain 100 milligrams of 3,3'-(3-(S)-3-tert-butoxy-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azandiyl)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).

[0116] Step F: Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bis(ethane-2,1-diyl))bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) (3,3'-(3-(S)-3-tert-butoxy-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)phenyl)sulfonyl)azandiyl)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 milligrams, 0.079 mmol) was dissolved in 1,4-dioxane (1.5 ml), concentrated hydrochloric acid (0.5 ml) was added, and the mixture was reacted overnight at 45°C. After the reaction was complete, the solvent was removed by vacuum distillation, and the crude product was purified by preparative high-performance liquid chromatography to obtain 20 milligrams of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bis(ethane-2,1-diyl))bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid). LCMS: RT=1.51 min, [MH] - = 787.15. 1 H NMR(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).

[0117] Example 22 Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bis(methylene)bis(2,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid [ka] It was prepared by referring to the method of Compound 9. LCMS: RT = 1.51 min, [M-H] - = 759.15.

[0118] Example 23 (S)-3-(3-(((3-(S)-2-Carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-N-(2-((S)2-carboxy-2-(R)pyrrolidin-3-yl)ethyl)benzyl)phenyl)sulfonamide)methyl)phenyl)-2-((R)-pyrrolidin-3-yl)propionic acid synthesis The specific synthetic route is as follows. [Chemical formula]

[0119] Step A: Synthesis 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 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 in this order. After heating to 45 °C, sodium triacetoxyborohydride (1.8 mg, 8.68 mmol) was added in three portions, and the reaction was carried out at 45 °C for 18 hours. After the reaction was complete, an aqueous solution of saturated ammonium chloride (30 ml) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 ml x 2 times). The mixture was concentrated until dry, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 1) to obtain 1.3 grams of tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(2-(((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LCMS: RT = 2.03 min, [M + H] + = 792.08.

[0120] Step B: Synthesis of tert-butyl-(R)-3-((S)-1-(tert-butoxy)-3-(2-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl))phenyl)sulfonamide)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate At room temperature, tert-butyl(R)-3-((S)-1-(tert-butoxy)-3-(2-(((3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (130 mg, 0.16 mmol), (R)-3-((S)- 1-(tert-butoxy)-3-(3-(chlorosulfonyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate t-butyl (95 mg, 0.20 mmol), acetonitrile (3 ml), triethylamine (32 mg, 0.32 mmol), and 4-dimethylaminopyridine (9 mg, 0.07 mmol) were added, the mixture was purged with nitrogen gas, and the temperature was raised to 80°C for 2 hours. After the reaction was complete, tap water (10 ml) and ethyl acetate (10 ml) were added for extraction, and the mixture was concentrated until dry. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 110 ml of tert-butyl-(R)-3-((S)-1-(tert-butoxy)-3-(2-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl))phenyl)sulfonamide)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0121] Step C: Synthesis of (S)-3-(3-(((3-(S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-N-(2-((S)2-carboxy-2-(R)pyrrolidine-3-ylethyl)benzyl)phenyl)sulfonamide)methyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid At room temperature, tert-butyl-(R)-3-((S)-1-(tert-butoxy)-3-(2-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl))phenyl)sulfonamide)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (110 mg, 0.09 mmol), dioxane (2.5 ml), and concentrated hydrochloric acid (0.5 ml) were added and reacted at 45°C for 4 hours. After the reaction was complete, the mixture was concentrated until dry, and the residue was purified by preparative high-performance liquid chromatography to obtain 44 milligrams of (S)-3-(3-(((3-(S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-N-(2-((S)2-carboxy-2-(R)pyrrolidine-3-ylethyl)benzyl)phenyl)sulfonamide)methyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid. LCMS:RT=1.49min,[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).

[0122] Example 24 Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-ethyl)-4-fluorobenzyl)-N-(2-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenylethyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid [ka] Prepared according to the method for compound 9. LC-MS: RT = 1.50 min, [MH] - =791.16. Nuclear magnetic resonance data: 1 H-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).

[0123] Example 25 Synthesis of (S)-3-(3-(N-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-2-fluorobenzyl)-N-(2-(S)2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenylethyl)aminosulfonyl)phenyl)-2-(((R)-pyrrolidine-3-yl)propionic acid [ka] Prepared according to the method for compound 9. LCMS: RT = 1.49 min, [MH] - = 791.19. 11H NMR (400MHz, 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).

[0124] Example 26 Synthesis of (S)-3-(3-(5-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2-fluorobenzyl)-N-(2-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenylethyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-yl)propionic acid [ka] Prepared according to the method for compound 9. LCMS: RT=1.54min, [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).

[0125] Example 27 (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)phenyl)ethyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropionic acid synthesis

Chem.

[0126] Example 28 (S)-3-(3-(2-(S)-2-Carboxy-2-(R)-pyrrolidin-3-yl)ethyl)-5-fluorophenyl)ethyl)-N-(3-((S)-2-carboxy-2-(R)-pyrrolidin-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidin-3-ylpropionic acid synthesis The specific synthetic route is as follows.

Chem.

[0127] Step A: Synthesis of (R)-3-(S)-1-(S)-4-benzyl-2-oxoxazolidine-3-yl)-3-(2-bromo-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl At -78°C, a solution of (R)-3-(2-(S)-4-benzyl-2-oxoxazolidine-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate tert-butyl (20 g, 51.48 mmol) in tetrahydrofuran (200 ml) was gradually added dropwise to a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (67 ml, 1.0 mol / L). After reacting for 0.5 hours, a solution of 2-bromo-1-bromomethyl-4-fluorophenyl (15 g, 55.99 mmol) in tetrahydrofuran (30 ml) was gradually added, and the mixture was allowed to react overnight after being allowed to rise naturally to room temperature. After confirming the completion of the reaction by LC-MS monitoring, the reaction was quenched with an aqueous solution of saturated ammonium chloride, extracted with ethyl acetate (200 ml x 2 times), washed with saturated brine (50 ml x 2 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 17 grams of (R)-3-(S)-1-(S)-4-benzyl-2-oxoxazolidine-3-yl)-3-(2-bromo-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl. LC-MS: RT = 2.29 min, [M + H-Boc] + = 475.02.

[0128] Step B: Synthesis of (S)-3-(2-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)propionic acid In an ice bath, (R)-3-(S)-1-(S)-4-benzyl-2-oxoxazolidine-3-yl)-3-(2-bromo-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (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 hours, an aqueous solution of lithium hydroxide monohydrate (2.2 g, 52.26 mmol) (15 ml) was added, and the mixture was heated to room temperature and reacted for 3 hours. After confirming the completion of the reaction by LC-MS monitoring, the reaction was quenched by gradually adding an excess saturated sodium bisulfate solution to the reaction mixture, and the mixture was stirred for 10 minutes. Saturated aqueous citrate solution was then added to adjust the pH to 5, and the mixture was extracted with ethyl acetate (100 ml x 2 times). The combined organic phase was first washed with saturated brine (50 ml x 2 times), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to obtain 7.8 grams of (S)-3-(2-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)propionic acid. LC-MS: RT = 2.29 min, [MH] - = 414.04.

[0129] Step C: Synthesis of (R)-3-(S)-3-(2-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl At room temperature, (S)-3-(2-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)propionic acid (7.8 g, 18.8 mmol) and (Z)-N,N'-diisopropylaminocarboxylic acid t-butyl (11.3 g, 56.4 mmol) were dissolved in 2-methyltetrahydrofuran (80 ml), the mixture was purged three times with nitrogen gas, and the temperature was raised to 65°C and the mixture was reacted overnight. After confirming the completion of the reaction by LC-MS monitoring, the filtrate was filtered and the filter cake was washed with ethyl acetate. The filtrate was diluted with ethyl acetate, and the combined organic phase was first washed with saturated brine (100 ml x 2 times), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 9 / 1) to obtain 6.7 grams of (R)-3-(S)-3-(2-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl. LC-MS: RT = 2.29 min, [M + H-Boc] + = 372.10.

[0130] Step D: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl At room temperature, (R)-3-(S)-3-(2-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (6.7 g, 14.2 mmol), potassium vinyltrifluoroborate (2.86 g, 21.3 mmol), palladium chloride (83 mg, 0.71 mmol), triphenylphosphin (370 mg, 1.4 mmol), and cesium carbonate (13.87 g, 42.67 mmol) were dissolved in tetrahydrofuran / water (60 ml / 7 ml), substituted three times with N2, and then heated to 75°C and reacted overnight. After confirming the completion of the reaction by TLC monitoring, the mixture was cooled to room temperature, diluted with water (10 ml), extracted with ethyl acetate (100 ml x 2 times), washed with saturated brine (50 ml x 2 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 4.9 grams of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl.

[0131] Step E: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-hydroxyethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl In an ice bath, (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (3 g, 7.15 mmol) was dissolved in tetrahydrofuran (30 ml), and a solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (28.6 ml, 0.5 mol / liter) was added. The mixture was heated 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 of sodium hydroxide (2.72 g, 67.9 mmol) (10 ml) were added, and the reaction was continued for 1 hour. After confirming the completion of the reaction by LC-MS monitoring, the reaction was quenched by gradually adding an excess aqueous solution of sodium bisulfate to the reaction system, and the mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate (80 ml x 2 times), the combined organic phase was washed first with saturated brine (50 ml x 2 times), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to obtain 1.2 grams of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-hydroxyethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl. LC-MS: RT = 2.216 min, [M+H-Boc-tert-butyl] + = 282.05.

[0132] Step F: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-oxoethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-hydroxyethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (1.2 g, 2.75 mmol) was dissolved in ethyl acetate (50 ml), 2-iodoxybenzoic acid (0.85 g, 3.0 mmol) was added, and the mixture was heated to 70 degrees Celsius and stirred for 6 hours. After confirming the completion of the reaction by LC-MS monitoring, the filtration cake was removed by filtration, washed with ethyl acetate, and the organic phase was combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to obtain 490 milligrams of (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-oxoethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl. LC-MS: RT = 2.15 min, [M+H-Boc-tert-butyl] + = 280.08.

[0133] Step G: Synthesis of tert-butyl-3-(S)-1-tert-butoxy)-3-(2-(3(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)-3-oxopropyl)benzyl)amino)ethyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate At room temperature, (R)-3-(S)-1-tert-butoxy-3-(4-fluoro-2-(2-oxoethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (390 mg, 0.9 mmol) and (R)-3-(S)-3-(3-aminomethyl)phenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (362 mg, 0.9 mmol) were dissolved in DCE (8 ml), sodium triacetyloxyhydride (665 mg, 3.15 mmol) was added in several batches, the temperature was raised to 45 degrees Celsius, and the mixture was stirred for 16 hours. After confirming the completion of the reaction by LC-MS monitoring, the reaction was quenched by adding an aqueous solution (1 ml), and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to obtain 250 ml of tert-butyl-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)-3-oxopropyl)benzyl)amino)ethyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LC-MS: RT = 2.02 min, [M + H] + = 824.51.

[0134] Step H: Synthesis of (R)-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)phenyl)sulfonamide)ethyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate At room temperature, tert-butyl-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-yl)-3-oxopropyl)benzyl)amino)ethyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (250 mg, 0.30 mmol) was dissolved in pyridine (5 ml), and a solution of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)phenyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (172 mg, 0.36 mmol) in acetonitrile (2 ml) was gradually added, and the mixture was reacted at room temperature for 0.5 hours. After detecting the end of the reaction by TLC, the reaction was extracted with ethyl acetate (10 ml x 2 times), the combined organic phase was first washed with saturated saline solution (5 ml x 2 times), then dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1), yielding 150 ml of (R)-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-ter t-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)phenyl)sulfonamide)ethyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate was obtained.

[0135] Step I: Synthesis of (S)-3-(3-(2-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-5-fluorophenylethyl)-N-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid At room temperature, (R)-3-(S)-1-tert-butoxy)-3-(2-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)benzyl)phenyl)sulfonamide)ethyl)-4-fluorophenyl)-1-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 mixture was heated to 45 degrees Celsius and reacted for 4 hours. After confirming the completion of the reaction by LC-MS monitoring, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain 34 milligrams of (S)-3-(3-(2-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-5-fluorophenylethyl)-N-(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid. LCMS: RT=1.56min, [MH] - =791.12. Nuclear magnetic resonance data: 1H-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).

[0136] Example 29 Synthesis of (2S,2'S)-3,3'(5-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2-fluorophenylsulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) The specific synthesis route is as follows: [ka]

[0137] Step A: Synthesis of (3R)-3-(2S)-1-(4-benzyl-2-oxoxazolidine-3-yl)-3-(3-bromo-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl At -78°C, bistrimethylsilylaminolithium (19 ml, 19 mmol) was gradually added dropwise to a solution of (R)-3-(2-((S)-4-benzyl-2-oxoxazolidine-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate t-butyl (6.0 g, 15.45 mmol) in tetrahydrofuran (60 ml), and the mixture was stirred at -78°C for 30 minutes. Then, a solution of 2-bromo-4-bromomethyl-1-fluorophenyl (4.97 g, 19 mmol) in tetrahydrofuran (20 ml) was gradually added to the reaction system, and the temperature was allowed to rise naturally to room temperature and the reaction was allowed to proceed overnight. After confirming the completion of the reaction by TLC monitoring, the reaction was quenched with an aqueous solution of saturated ammonium chloride, extracted with ethyl acetate (100 ml x 2 times), washed with saturated brine (100 ml x 2 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 3.1 grams of (R)-3-(S)-1-(S)-4-benzyl-2-oxoxazolidine-3-yl)-3-(3-bromo-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl. LCMS: RT = 2.25 min, [M + H-Boc] + = 475.01.

[0138] Step B: Synthesis of (3-(3-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-ylpropionic acid) In an ice bath, a solution of (R)-3-(S)-1-(S)-4-benzyl-2-oxoxazolidine-3-yl)-3-(3-bromo-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (3.8 g, 6.60 mmol) in tetrahydrofuran (40 ml) was added and reacted for 30 minutes with hydrogen peroxide (1.1 g, 30%, 9.90 mmol). Then, an aqueous solution of lithium hydroxide monohydrate (237 mg, 9.90 mmol) (10 ml) was added, and the mixture was heated to room temperature and reacted for 3 hours. After the reaction was complete, an excess saturated sodium bisulfate solution was gradually added to the reaction mixture to quench the reaction, and the mixture was stirred for 10 minutes. A saturated aqueous citrate solution was then added to adjust the pH to 3, and the mixture was extracted with ethyl acetate (50 ml x 2 times). The combined organic phase was first washed with saturated brine (200 ml x 2 times), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 2.2 grams of (S)-3-(3-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonyl)pyrrolidine-3-yl)propionic acid. LCMS: RT = 2.06 min, [MH] - = 416.00.

[0139] Step C: Synthesis of (R)-3-(S)-3-(3-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl At room temperature, (S)-3-(3-bromo-4-fluorophenyl)-2-(R)-1-tert-butoxycarbonyl)pyrrolidine-3-yl)propionic acid (2.2 g, 5.28 mmol) was dissolved in 20 ml of 2-methyltetrahydrofuran, to which 3.18 g, 15.85 mmol of o-tert-butyl-N,N'-diisopropylisourea was added. The mixture was purged with nitrogen gas three times, and the temperature was raised to 65°C and the reaction was allowed to proceed overnight. After confirming the completion of the reaction by TLC monitoring, the filtration cake was washed with ethyl acetate, the filtrate was diluted with ethyl acetate, the combined organic phase was first washed with saturated brine (70 ml x 2 times), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 7) to obtain 2.1 grams of (R)-3-(S)-3-(3-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl. LCMS: RT = 2.36 min, [M + H-Boc] + = 371.98.

[0140] Step D: Synthesis of (R)-3-(S)-3-(3-benzylthio)-5-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl At room temperature, (R)-3-(S)-3-(3-bromo-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (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-dimethyloxyheteroanthracene (267 mg, 0.46 mmol), and tri(dibenzylideneindenacetone)dipalladium (211 mg, 0.23 mmol) were dissolved in dioxane, purged with nitrogen gas, and reacted overnight at 100°C under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled and filtered by suction. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 7) to obtain 2.1 grams of (R)-3-(S)-3-(3-benzylthio)-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl. LCMS: RT = 2.43 min, [M + H-Boc] + = 398.15.

[0141] Step E: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl After dissolving (R)-3-(S)-3-(3-benzylthio)-4-fluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (2.10 g, 4.22 mmol) in acetonitrile (30 ml) in an ice bath, acetic acid (1.5 ml) and water (1.5 ml) were added, followed by acetonitrile solution of 1,3-dichloro-5,5-dimethylhydantoin (1.66 g, 8.44 mmol, 10 ml). After adding the solution dropwise and confirming the completion of the reaction by TLC monitoring, water was added to the reaction 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 grams of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)-4-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl.

[0142] Step F: Synthesis of 3,3'-((2S,2'S)-(3-((S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorophenyl)sulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) At room temperature, 3,3'-((2S,2'S)-(azandiylbismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (250 mg, 0.32 mmol) was dissolved in anhydrous pyridine (2 ml), and then a solution of (R)-3-(S)-1-tert-butoxy-3-(3-chlorosulfonyl)-4-fluorophenyl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylate tert-butyl in acetonitrile (187 mg, 0.38 mmol, 2 ml) was gradually added dropwise, and the solution was applied using a TLC spot spray. After confirming that the starting materials had reacted completely by detection, 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 milligrams of 3,3'-((2S,2'S)-(3-((S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorophenyl)sulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(3-tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0143] Step G: Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-4-fluorophenylsulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) 3,3'-((2S,2'S)-(3-((S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-4-fluorophenyl)sulfonyl)azandiyl)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 mixture was reacted overnight at 45°C. After the reaction was complete, the solvent was removed by vacuum distillation, and the crude product was purified by preparative high-performance liquid chromatography to obtain 18 milligrams of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-4-fluorophenylsulfonyl)azandiyl)bismethylene)bis(3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid). LCMS:RT=1.53min,[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).

[0144] Example 30 Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2,4-difluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid [ka] Prepared according to the method for compound 9. LCMS: RT = 1.53 min, [MH] - = 795.12.

[0145] Example 31 Synthesis of (2S,2'S)-3,3'-((3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bis(methylene))bis(2,6-difluoro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid [ka] Prepared according to the method for compound 9. LCMS: RT = 1.53 min, [MH] - = 831.12.

[0146] Example 32 Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2,6-difluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid The specific synthesis route is as follows: [ka]

[0147] Step A: Synthesis of methyl 3-bromo-2,4-difluorobenzoate 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 after cooling to 0 degrees Celsius, iodine methane (3.59 g, 25.3 mmol) was gradually added, and the mixture was allowed to react for 1 hour after returning to room temperature. After detecting the completion of the reaction by TLC, the mixture was diluted with water and extracted with ethyl acetate (100 ml twice). The combined organic phase was first washed with saturated brine (50 ml twice), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 5.1 grams of methyl 3-bromo-2,4-difluorobenzoate (yield: 96.7%), which is a white solid.

[0148] Step B: Synthesis of 3-bromo-2,4-difluorophenylmethanol In an ice bath, a solution of methyl 3-bromo-2,4-difluorobenzoate (5.1 g, 20.4 mmol) in dichloromethane (50 ml) was gradually added dropwise to an n-hexane solution of aluminum diisobutylhydride (41 ml, 1.0 mol / liter), and the mixture was allowed to react for 2 hours at room temperature. After confirming the completion of the reaction by LC-MS monitoring, the mixture was quenched with 1 M / L hydrochloric acid solution (5 ml), extracted with ethyl acetate (200 ml x 2 times), washed with saturated brine (50 ml x 2 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to obtain 4 grams of 3-bromo-2,4-difluorophenylmethanol.

[0149] Step C: Synthesis of 2-bromo-4-bromomethyl-1,3-difluorophenyl At room temperature, 3-bromo-2,4-difluorophenylmethanol (4 g, 18.1 mmol) was dissolved in dichloromethane (40 ml), carbon tetrabromide (6.24 g, 27 mmol) was added, and triphenylphosphine (7.08 g, 27 mmol) was added and the mixture was reacted for 2 hours. After confirming the completion of the reaction by LC-MS monitoring, the mixture was extracted with ethyl acetate (100 ml x 2 times), the combined organic phase was first washed with saturated brine (50 ml x 2 times), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane) to obtain 3.3 grams of 2-bromo-4-bromomethyl-1,3-difluorobenzene.

[0150] Step D: Synthesis of (R)-3-(S)-1-(S)-4-benzyl-2-oxoxazolidine-3-yl)-3-(3-bromo-2,4-difluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl At -78°C, a solution of (R)-3-(2-(S)-4-benzyl-2-oxoxazolidine-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate tert-butyl (4.06 g, 10.5 mmol) in tetrahydrofuran (40 ml) was gradually added dropwise to a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (14 ml, 1.0 mol / L). After reacting for 0.5 hours, a solution of 2-bromo-4-bromomethyl-1,3-difluorobenzene (3.3 g, 11.5 mmol) in tetrahydrofuran (30 ml) was gradually added, and the mixture was allowed to react overnight after being allowed to rise naturally to room temperature. After confirming the completion of the reaction by LC-MS monitoring, the reaction was quenched with an aqueous solution of saturated ammonium chloride, extracted with ethyl acetate (100 ml x 2 times), washed with saturated brine (50 ml x 2 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 2 grams of (R)-3-(S)-1-(S)-4-benzyl-2-oxoxazolidine-3-yl)-3-(3-bromo-2,4-difluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl. LC-MS: RT = 2.09 min, [M + H-Boc] + = 493.02.

[0151] Step E: Synthesis of (S)-3-(3-bromo-2,4-difluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-ylpropionic acid In an ice bath, ((R)-3-(S)-1-(S)-4-benzyl-2-oxoxazolidine-3-yl)-3-(3-bromo-2,4-difluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (2 grams, 3.4 mmol) was dissolved in tetrahydrofuran (20 ml), 30% hydrogen peroxide (0.77 grams, 6.8 mmol) was added, and after 0.5 hours, an aqueous solution of lithium hydroxide monohydrate (0.29 grams, 6.8 mmol) (5 ml) was added, and the mixture was heated to room temperature and reacted for 3 hours. After confirming the completion of the reaction by LC-MS monitoring, the reaction was quenched by gradually adding an excess saturated sodium bisulfate solution to the reaction mixture, and the mixture was stirred for 10 minutes. A saturated aqueous solution of citric acid was then added to adjust the pH to 5, and the mixture was extracted with ethyl acetate (50 ml x 2 times). The combined organic phase was first washed with saturated brine (20 ml x 2 times), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting 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-butoxycarbonylpyrrolidine-3-ylpropionic acid. LC-MS: RT = 2.07 min, [MH] - = 431.95.

[0152] Step F: Synthesis of (R)-3-(S)-3-(3-bromo-2,4-difluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl At room temperature, (S)-3-(3-bromo-2,4-difluorophenyl)-2-(R)-1-tert-butoxycarbonylpyrrolidine-3-ylpropionic acid (850 mg, 1.96 mmol) and (Z)-N,N'-diisopropylaminocarboxylic acid t-butyl (1.18 g, 5.88 mmol) were dissolved in 2-methyltetrahydrofuran (10 ml), the mixture was purged three times with nitrogen gas, and the temperature was raised to 65°C and the mixture was reacted overnight. After confirming the completion of the reaction by LC-MS monitoring, the filtrate was filtered and the filter cake was washed with ethyl acetate. The filtrate was diluted with ethyl acetate, and the combined organic phase was first washed with saturated brine (10 ml x 2 times), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 9 / 1) to obtain 680 mg of (R)-3-(S)-3-(3-bromo-2,4-difluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl. LC-MS: RT = 2.34 min, [M + H-Boc]+ =390.01.

[0153] Step G: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl At room temperature, (R)-3-(S)-3-(3-bromo-2,4-difluorophenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (680 mg, 1.39 mmol), potassium vinyltrifluoroborate (279 mg, 2.09 mmol), palladium chloride (8.12 mg, 0.07 mmol), triphenylphosphin (36.4 mg, 0.14 mmol), and cesium carbonate (1.35 g, 4.17 mmol) were dissolved in tetrahydrofuran / water (10 ml / 4 ml), substituted three times with N2, and then heated to 75°C and reacted overnight. After confirming the completion of the reaction by TLC monitoring, the mixture was cooled to room temperature, diluted with water (10 ml), extracted with ethyl acetate (50 ml x 2 times), washed with saturated brine (20 ml x 2 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 510 ml of (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl.

[0154] Step E: Synthesis of (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl In an ice bath, (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (510 mg, 1.17 mmol) was dissolved in tetrahydrofuran / water (8 ml / 2 ml), potassium osmite dihydrate (4.29 mg, 0.012 mmol) was added, and the mixture was stirred for 0.5 hours. Then sodium periodate (548 mg, 2.56 mmol) was added, and the reaction was continued for 1 hour. The reaction was allowed to proceed after raising the temperature to room temperature. After confirming the completion of the reaction by LC-MS monitoring, an excess aqueous solution of sodium bisulfate was gradually added to the reaction system to quench it. The mixture was stirred for 30 minutes, and the mixture was extracted with ethyl acetate (50 ml x 2 times). The combined organic phase was first washed with saturated brine (20 ml x 2 times), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to obtain 220 mg of (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl. LC-MS: RT = 2.26 min, [M+H-Boc-tert-butyl] + =284.07.

[0155] Step G: Synthesis of (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate At room temperature, (R)-3-(S)-1-tert-butoxy-3-(2,4-difluoro-3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (220 mg, 0.5 mmol) and (R)-3-(S)-3-(3-aminomethyl)phenyl)-1-tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl (202 mg, 0.5 mmol) were dissolved in DCE (5 ml), sodium triacetyloxyhydride (371 mg, 1.75 mmol) was added in several batches, the temperature was raised to 45 degrees Celsius, and the mixture was stirred for 16 hours. After confirming the completion of the reaction by LC-MS monitoring, the reaction was quenched by adding an aqueous solution (1 ml), and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to obtain 160 ml of (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate. LC-MS: RT = 2.05 min, [M + H] + = 828.51.

[0156] Step H: Synthesis of (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)phenyl)sulfonamide)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate At room temperature, (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)amino)methyl)phenyl)-1-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-carboxylate tert-butyl (110 mg, 0.23 mmol) in acetonitrile (2 ml) was gradually added, and the mixture was reacted at room temperature for 0.5 hours. After detecting the end of the reaction by TLC, the reaction was extracted with ethyl acetate (10 ml x 2 times), the combined organic phase was first washed with saturated saline solution (5 ml x 2 times), then dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to obtain 170 mg of (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-ter t-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)phenyl)sulfonamide)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate was obtained.

[0157] Step I: Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2,6-difluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid At room temperature, (R)-3-(S)-1-tert-butoxy)-3-(3-((3-(S)-3-tert-butoxy)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-N-(3-(S)-3-tert-butoxy-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-oxopropyl)-2,6-difluorobenzyl)phenyl)sulfonamide)methyl)phenyl)-1-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 mixture was heated to 45 degrees Celsius and reacted for 4 hours. After confirming the completion of the reaction by LC-MS monitoring, the mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain 53 milligrams of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-2,6-difluorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid. LCMS: RT=1.51 min, [MH] - =795.05. Nuclear magnetic resonance data: 1 H 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).

[0158] Example 34 Synthesis of (2S,2'S)-3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-4-fluorophenyl)sulfonyl)azandiyl)bis(methylene))bis(6-fluoro-3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) [ka] Prepared according to the method for compound 9. LCMS: RT=1.55min, [MH] - = 813.13.

[0159] Example 35 Synthesis of (2S,2'S)-3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-4-chlorophenyl)sulfonyl)azandiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid [ka] Prepared according to the method for compound 9. LCMS: RT = 1.53 min, [MH] - = 793.09.

[0160] Example 36 Synthesis of (2S,2'S)-3,3'-(((((3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-4-chlorophenyl)sulfonyl)azandiyl)bis(methylene))bis(6-fluoro-3,1-phenylene))bis(2-((R)-pyrrolidine-3-yl)propionic acid) [ka] Prepared according to the method for compound 9. LCMS: RT = 1.53 min, [MH] - = 829.02.

[0161] Example 37 Synthesis of (S)-3-(3-(2-((3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-N-(2-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)benzyl)phenyl)sulfonamide)ethyl)phenyl)-2-((R)-pyrrolidine-3-yl)propionic acid [ka] Prepared according to the method for compound 9. LCMS: RT = 1.51 min, [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).

[0162] Example 38 Synthesis of (S)-3-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-4-chlorobenzyl)-N-(3-(S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)phenylethyl)aminosulfonyl)phenyl)-2-(R)-pyrrolidine-3-ylpropionic acid [ka] The specific synthesis route is as follows: Prepared according to the method for compound 9. LCMS: RT = 1.54 min, [MH] - = 807.11.

[0163] Example 39 Synthesis of (S)-3-(5-(N-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)-4-chlorobenzyl)-N-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)benzyl)aminosulfonyl)-2-fluorophenyl)-2-((R)-pyrrolidine-3-yl)propionic acid [ka] Prepared according to the method for 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).

[0164] Example 40 Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bismethylene)bis(6-chloro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) [ka] Prepared according to the method for compound 9. LC-MS: RT = 1.52 min, [MH] - = 829.21.

[0165] Example 41 Synthesis of (2S,2'S)-3,3'-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenyl)sulfonyl)azandiyl)bismethylene)bis(6-chloro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) [ka] Prepared according to the method for compound 9. LCMS: RT = 1.58 min, [MH] - = 827.07.

[0166] Example 42 Synthesis of (2S,2'S)-3,3'(3-((S)-2-carboxy-2-(R)-pyrrolidine-3-yl)ethyl)-4-fluorophenylsulfonyl)azandiyl)bismethylene)bis(6-chloro-3,1-phenylene)bis(2-(R)-pyrrolidine-3-yl)propionic acid) [ka] Prepared according to the method for compound 9. LCMS: RT = 1.58 min, [MH] - = 845.07.

[0167] Examples 33, 43-47 Compounds 33 and 43-47 were prepared by referring to the preparation methods of the compounds in the above examples (for example, Example 30 or Example 9). [Table 1C]

[0168] Example 48: In vitro Lp(a) assembly assay

[0169] Experimental Steps The ability of the compounds in the examples to inhibit Lp(a) particle formation in vitro was evaluated by a cell-free assembly assay. Conditioning media (DMEM supplemented with 10% FBS, 20 mM HEPES, and 1x penicillin / streptomycin) were incubated at 37°C and 5% CO2 for 96 hours, and then collected from confluent wild-type HepG2 cells (source of endogenously expressed ApoB) and from HEK293 stable cell lines expressing human Apo(a) containing 17 kringle repeats (selected with 1 μg / ml puromycin). In vitro assembly assays were performed by combining the test compounds (final concentrations 0.03–1000 nM) with equal volumes of HepG2 and HEK293 conditioning media in a dilution series. The reaction was incubated at 37°C for 2 hours, then stopped by adding 6-aminoacetic acid (EACA) to a final concentration of 150 mM. Lp(a) was detected using a sandwich ELISA with anti-Lp(a) capture antibody (ab242565) and HRP-conjugated anti-ApoB detection antibody (ab27622). The ELISA was colorimetrically developed using TMB and stopped using 1N sulfuric acid, and the signal was read at 450 nm using an Envision 2104 plate reader. The inhibition rate of Lp(a) formed under each test condition was measured with the assembly reaction in the absence of an inhibitor set to 0% inhibition and the assembly reaction in the presence of a minimum amount of HepG2 conditioned medium (50-fold dilution) set to 100% inhibition. The data were fitted to a 4-parameter curve for IC50. 90 The values ​​were measured, and the results are shown in Table 1.

[0170] [Table 1] The results in Table 1 show that all of the sulfonamide compounds of the present invention have good LP(a) inhibitory activity.

[0171] Example 49 SD rat pharmacokinetic experiment

[0172] (1) Experimental materials SD rat: Male, 180-250g, purchased from Guangdong Weitong Lihua Laboratory Animal Technology Co., Ltd. Reagents: Physiological saline, EDTA-K2 (anticoagulant), TCA (trichloroacetic acid), and propranolol (internal standard) are all commercially available. Equipment: Nexera LC-40; AB SCIEX QTRAP 5500+.

[0173] (2) Experimental method The compounds were weighed and dissolved in physiological saline solution. After oral administration to rats, 200 μL of venous blood was collected in EDTA-K2 anticoagulant EP tubes at 15 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 7 hours, and 24 hours (an additional 5 minutes for group iv). The blood was centrifuged at 12000 rpm for 2 minutes, and the plasma was collected and stored frozen at -80°C. A fixed amount of the test substance was accurately weighed and dissolved in ultrapure water to 2 mg / mL, which was used as the stock solution. An appropriate amount of the compound stock solution was accurately pipettered and diluted with 50% acetonitrile-water to prepare a series of standard solutions. 10 μL of each of the above standard solutions was accurately pipettered, 90 μL of blank plasma was added, and the mixture was vortex-mixed to prepare plasma samples corresponding to plasma concentrations of 1, 3, 5, 10, 30, 100, 300, 1000, and 3000 ng / mL. The concentrations of the quality control samples were set to 9, 240, and 2400 ng / mL. Two samples were analyzed for each concentration to create a standard curve. 30 μL of plasma (diluted 5-fold 5 minutes, 15 minutes, and 30 minutes after intravenous administration) was taken, 200 μL of 5% trichloroacetic acid aqueous solution of the internal standard propranolol (50 ng / mL) was added, and the mixture was mixed using a vortex mixer. The mixture was then centrifuged at 4000 rpm for 10 minutes, the supernatant was taken, 150 μL of purified water was added, and the mixture was mixed again using a vortex mixer. The mixture was then analyzed by LC-MS / MS. The detection conditions for LC-MS / MS were as follows. Column: YMC Triart C18, 50 × 3.0 mm, 2.1 μm. Mobile phase: Water (0.1% formic acid)-acetonitrile. Gradient elution was performed as shown in the table below.

[0174] [Table 2]

[0175] (3) Data processing After detecting blood drug concentrations using LC-MS / MS, pharmacokinetic parameters were calculated using a non-compartmental model analysis with WinNonlin 6.1 software, and the results are shown in Table 3.

[0176] [Table 3] The results in Table 3 show that the compounds of the present invention exhibit higher exposure levels, longer half-lives, and higher bioavailability.

[0177] Example 50 Pharmacokinetic experiments in monkeys

[0178] (1) Experimental materials Beagle: Male, 8-10kg, purchased from Beijing Mas Biotechnology Co., Ltd. Crab-eating macaque: Male, 3-6 kg, purchased from Guangzhou Huazhen Biotechnology Co., Ltd. and Hainan Jingang Biotechnology Co., Ltd. Reagents: Physiological saline, EDTA-K2 (anticoagulant), TCA (trichloroacetic acid), and propranolol (internal standard) are all commercially available. Equipment: Nexera LC-40, AB SCIEX QTRAP 5500+.

[0179] (2) Experimental method The compounds were weighed and dissolved in physiological saline. After oral or intravenous administration to experimental animals, 200 μL of venous blood was collected in EDTA-K2 anticoagulant EP tubes at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours (additional 5 minutes and 48 hours for group iv). The blood was centrifuged at 12000 rpm for 2 minutes, and the plasma was collected and stored frozen at -80°C. A fixed amount of the test substance was accurately weighed and dissolved in ultrapure water to 2 mg / mL, which was used as the stock solution. An appropriate amount of the compound stock solution was accurately pipetteed and diluted with 50% acetonitrile-water to prepare a series of standard solutions. Accurately pipette 10 μL of each of the above standard solutions, add 90 μL of blank plasma, and mix with a vortex mixer to prepare plasma samples corresponding to plasma concentrations of 1, 3, 5, 10, 30, 100, 300, 1000, and 3000 ng / mL. Quality control sample concentrations were set to 9, 240, and 2400 ng / mL. Two samples were analyzed for each concentration to create standard curves. 30 μL of plasma (diluted 5-fold after intravenous administration at 5, 15, and 30 minutes) was taken, 200 μL of 5% trichloroacetic acid aqueous solution of the internal standard substance propranolol (50 ng / mL) was added, and after mixing with a vortex mixer, the mixture was centrifuged at 4000 rpm for 10 minutes, the supernatant was taken, 150 μL of purified water was added, and the mixture was mixed again with a vortex mixer and analyzed by LC-MS / MS. The detection conditions for LC-MS / MS were as follows. Column: YMC Triart C18, 50 × 3.0 mm, 2.1 μm. Mobile phase: Water (0.1% formic acid)-acetonitrile. Gradient elution was performed as shown in the table below.

[0180] [Table 4]

[0181] (3) Data processing After detecting blood drug concentrations using LC-MS / MS, pharmacokinetic parameters were calculated using a non-compartmental model analysis with WinNonlin 6.1 software, and the results are shown in Tables 5 and 6.

[0182] [Table 5]

[0183] [Table 6] The results in Tables 5 and 6 show that the compounds of the present invention have higher exposure levels, higher bioavailability, and longer half-lives.

[0184] While the above embodiments represent preferred embodiments of the present invention, the embodiments of the present invention are not limited thereto and those skilled in the art should understand that improvements or modifications can be made in accordance with the above description, and all such improvements and modifications fall within the scope of protection of the appended claims of the present invention.

Claims

1. A sulfonamide compound, its isomer, its racemic mixture, or a pharmaceutically acceptable salt thereof, The structure of the aforementioned sulfonamide compound is represented by general formula I, 【Chemistry 1】 Here, X １ ~X １５ are each independently selected from -N- or -CR １ and the R １ is H, halogen, -OH, -NH ２ , -CN, -NO ２ , -COOH, -SO ３ H, substituted or unsubstituted C １ -C ６ alkyl group, substituted or unsubstituted C １ -C ６ alkoxy group, substituted or unsubstituted C ３ -C １０ cycloalkyl group, substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, substituted or unsubstituted C ６ -C １０ aryl group, substituted or unsubstituted 5- to 10-membered heteroaryl group, or 【Chemistry 2】 Selected from, The aforementioned X １ ~X １５ At least one of them is -N-, or X １ ~X １５ Each of these is independently -CR １ If selected from, at least one of R １ is not hydrogen, and the aforementioned X １ ~X ５ at least one of R １ Independently 【Transformation 3】 Selected from, and the X ６ ~X １０ at least one of R １ Independently, 【Chemistry 4】 Selected from, or, X １ ~X １５ Each of these is independently -CR １ If selected from, the X １ ~X １５ Any two adjacent R １ This includes substituted or unsubstituted carbon atoms bonded to it. ６ -C １０ Forming an aryl group, or a substituted or unsubstituted 5-10 membered heteroaryl group, The aforementioned R ２ -H, halogen, substituted or unsubstituted C １ -C ６ Alkyl alkyl groups, or substituted or unsubstituted C １ -C ６ Selected from alkoxy groups, The aforementioned R ３ is, -(CH ２ ) ｑ - Selected from (a 5-8 member heterocyclic group), The substitution C １ -C ６ alkyl group, substituted C １ -C ６ Alkoxy group, substituted C ３ -C １０ Cycloalkyl groups, substituted 3-10 member heterocycloalkyl groups, substituted C ６ -C １０ The substituents on an aryl group or a substituted 5-10 membered heteroaryl group can independently be halogen, hydroxyl, carboxyl, nitro, cyano, or C. １ -C ６ alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Haloalkoxy group, C １ -C ６ Alkoxy group, C ３ -C ６ Cycloalkyl groups, 3-6 member heterocycloalkyl groups, C ３ -C ６ Cycloalkoxy group, C ６ -C １０ One or more selected from aryl groups and 5-10 membered heteroaryl groups, A sulfonamide compound, its isomer, its racemic mixture, or its pharmaceutically acceptable salt, characterized in that n, p, and r are independently selected from integers 1, 2, or 3, and m and q are selected from integers 0, 1, 2, or 3.

2. The aforementioned R １ H, halogen, -OH, -NH ２ -CN, -NO ２ , -COOH, C １ -C ６ alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Haloalkoxy group, substituted or unsubstituted C ３ -C １０ Cycloalkyl groups, substituted or unsubstituted 3-10 member heterocycloalkyl groups, substituted or unsubstituted C ６ -C １０ Aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, 【Transformation 5】 Selected from, Said R ２ is selected from -H, a substituted or unsubstituted C １ -C ６ alkyl group, said R ３ is selected from a 5- to 8-membered heterocyclic group, and the substituent in said substituted C ３ -C １０ cycloalkyl group, substituted 3- to 10-membered heterocycloalkyl group, substituted C ６ -C １０ aryl group or substituted 5- to 10-membered heteroaryl group is independently halogen, hydroxy group, carboxy group, nitro group, cyano group, C １ -C ６ alkyl group, C １ -C ６ haloalkyl group, C １ -C ６ haloalkoxy group, C １ -C ６ alkoxy group, C ３ -C ６ cycloalkyl group, 3- to 6-membered heterocycloalkyl group, C ３ -C ６ cycloalkoxy group, C ６ -C １０ aryl group and 5- to 10-membered heteroaryl group, and is characterized in that it is one or more selected therefrom, the sulfonamide compound according to claim 1, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof.

3. The aforementioned X ４ and X ５ One of them is, 【Transformation 6】 Selected from, The aforementioned X ９ and X １０ One of them is, 【Transformation 7】 Selected from, The aforementioned X １１ and X １２ One of them is, 【Transformation 8】 A sulfonamide compound according to claim 1 or 2, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from the above.

4. The structure of sulfonamide compounds is represented by general formula II or general formula III. 【Chemistry 9】 Here, X １ ~X １５ These are independently -N- or -CR １ Selected from, the R １ H, halogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Alkoxy group, or 【Chemistry 10】 Selected from, The aforementioned R ２ H, substituted or unsubstituted C １ -C ６ Selected from alkyl groups, the R ３ The C is selected from 5-8 member heterocyclic groups, and the substitution C is １ -C ６ alkyl group, substituted C １ -C ６ The substituents on the alkoxy group can be, independently, halogen, hydroxyl, carboxyl, nitro, cyano, or C. １ -C ６ alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Haloalkoxy group, C １ -C ６ Alkoxy group, C ３ -C ６ Cycloalkyl groups, 3-6 member heterocycloalkyl groups, C ３ -C ６ Cycloalkoxy group, C ６ -C １０ A sulfonamide compound according to any one of claims 1 to 3, characterized by comprising one or more selected from an aryl group and a 5-10 membered heteroaryl group, an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.

5. The structure of the aforementioned sulfonamide compound is represented by general formula IV or general formula V, 【Chemistry 11】 Here, X １ ~X １５ These are independently -N- or -CR １ Selected from, the R １ H, halogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Alkoxy group, or 【Chemistry 12】 Selected from, The aforementioned R ２ H, substituted or unsubstituted C １ -C ６ Selected from alkyl groups, the R ３ The C is selected from 5-8 member heterocyclic groups, and the substitution C is １ -C ６ alkyl group, substituted C １ -C ６ The substituents on the alkoxy group can be, independently, halogen, hydroxyl, carboxyl, nitro, cyano, or C. １ -C ６ alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Haloalkoxy group, C １ -C ６ Alkoxy group, C ３ -C ６ Cycloalkyl groups, 3-6 member heterocycloalkyl groups, C ３ -C ６ Cycloalkoxy group, C ６ -C １０ One or more selected from aryl groups and 5-10 membered heteroaryl groups, preferably the X １１ , X １２ , X １３ , X １４ and X １５ One of the following is independently -CR １ Selected from, the R １ teeth, 【Chemistry 13】 Selected from, More preferably, the R １ teeth, 【Chemistry 14】 A sulfonamide compound according to any one of claims 1 to 4, characterized by being one selected from the above, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.

6. The aforementioned R １ H, fluorine, chlorine, bromine, iodine, trifluoromethyl group, methyl group, ethyl group, propyl group, methoxy group, ethoxy group, piperazinyl group, -CH ２ COOH, -CH ２ CH ２ COOH, -CH ２ CH (CH ３ ) COOH, 【Chemistry 15】 Selected from, the R ３ The sulfonamide compound according to any one of claims 1 to 5, characterized in that the group is selected from a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a pyridyl group, a pyrimidinyl group, or a pyrazinyl group, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.

7. The aforementioned 【Chemistry 16】 The sulfonamide compound according to any one of claims 1 to 6, characterized in that it is a quinolinyl group, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.

8. The aforementioned 【Chemistry 17】 teeth, [Chemistry 18] A sulfonamide compound according to any one of claims 1 to 7, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from among.

9. The aforementioned 【Chemistry 19】 teeth, 【Chemistry 20】 A sulfonamide compound according to claim 8, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from among.

10. The aforementioned 【Chemistry 21】 teeth, 【Chemistry 22】 A sulfonamide compound according to claim 9, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from among.

11. The sulfonamide compound is selected from the compounds shown in Table 1A or Table 1B, as described in any one of claims 1 to 10, and is an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a sulfonamide compound according to any one of claims 1 to 11, an isomer thereof, a racemic mixture thereof, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and / or carriers.

13. Use of a sulfonamide compound according to any one of claims 1-11, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, in the preparation of a pharmaceutical for the prevention or treatment of LP(a)-related diseases.

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

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

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