WO2022218379A1

WO2022218379A1 - Small-molecule compound having substituted phenyl spiro[indoline-3,3'-pyrrolidine] structure

Info

Publication number: WO2022218379A1
Application number: PCT/CN2022/086834
Authority: WO
Inventors: 赵玉军; 张世言; 严子琴; 吕细林; 程靖; 周飞龙; 巩洋
Original assignee: 中国科学院上海药物研究所
Priority date: 2021-04-15
Filing date: 2022-04-14
Publication date: 2022-10-20
Also published as: CN117120416A; CN115215872A

Abstract

A small-molecule compound having a substituted phenyl spiro[indoline-3,3'-pyrrolidine] structure. The structure is represented by general formula I, and the definition of each substituent is as described in the description and the claims. The compound of the present invention can inhibit MDM2-p53 and MDMX-p53 protein-protein interactions, serves as a small-molecule inhibitor for MDM2-p53 and MDMX-p53 protein-protein interactions, and is used for preparation of a medicament for preventing and/or treating MDM2 and MDMX-related diseases, in particular tumors.

Description

Small Molecular Compounds with Substituted Phenyl Spiro[Indoline-3,3'-Pyrrolidine] Structure

technical field

The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a class of compounds having a substituted phenyl spiro[indoline-3,3'-pyrrolidine] structure, its stereoisomers, enantiomers or pharmaceutically acceptable salts thereof , its preparation method and use.

technical background

The tumor suppressor p53 exerts antiproliferative effects in response to various stresses, including cell growth arrest, DNA repair, and apoptosis. Mice lacking p53 develop normally but are prone to a variety of tumors. The TP53 gene, which encodes the p53 protein, is mutated or deleted in nearly 50 percent of human cancers, rendering the cells unable to function as a p53 tumor suppressor. Although p53 remains wild-type in the remaining 50% of human cancers, its function is inhibited by multiple inhibitors. Studies have shown that there are two proteins that are critical for the regulation of p53 - MDM2 and MDMX (also known as MDM4). Embryonic lethality caused by knockout of MDM2 and MDMX genes was rescued by simultaneous knockout of TP53 in mice, elucidating the roles of MDM2 and MDMX as major negative endogenous regulators of p53. In vitro studies have shown that MDM2 and MDMX inhibit the gene transcription function of p53 protein through the interaction of their amino-terminal p53 binding domain with the transcriptional activation domain (TAD) of p53 protein. In addition, MDM2 can promote MDM2 itself, MDMX and p53 protein ubiquitination and proteasomal degradation. Conversely, p53 specifically binds to the MDM2P2 promoter and activates its transcription, thereby forming an autoregulatory feedback loop—the MDM2-p53 feedback loop. MDM2 also promotes the translocation of p53 protein out of the nucleus, making p53 unable to access its target DNA, thereby reducing its transcriptional capacity. For MDMX, although it cannot degrade as E3 ubiquitin ligase like MDM2, it can form a stable heterodimer through the interaction of the carboxy-terminal RING domain with the carboxy-terminal RING domain of MDM2 to promote MDM2 mediation. induced ubiquitination of p53.

Studies have shown that compared with normal cells, the levels of MDM2 and MDMX oncogenic factors in cancer cells are abnormally elevated, the gene transcription function mediated by p53 is inhibited, and the level of p53 is reduced. These characteristics are closely related to the overgrowth of tumor cells.

RG7112(NCT00559533,NCT00623870,NCT01677780,NCT01164033,NCT01605526,NCT01143740和NCT01635296)，RG7388(Ding et al.,J Med Chem 2013,56(14),5979-83)，MI-77301(NCT01636479和NCT01985191)和AMG 232 Compounds reported in literature such as (NCT01723020 and NCT02016729) can selectively block the MDM2/p53 interaction. SJ-172550 (Reed et al., J Biol Chem 2010, 285(14), 10786-96; Bista et al., PLoS One 2012, 7(6), e37518), CTX-1 (Karan et al., Mol Compounds reported in literature such as Cancer Ther 2016, 15(4), 574-582) and K-178 (Uesato et al., Bioorg Med Chem 2016, 24(8), 1919-26) can selectively block MDMX/ p53 interaction. WK298 (Popowicz et al., Cell Cycle 2010, 9(6), 1104-11), ATSP-7041 (Chang et al., Proc Natl Acad Sci U S A 2013, 110(36), E3445-54), RO -5963 (Graves et al., Proc Natl Acad Sci U S A 2012, 109(29), 11788-93) and ALRN-6924 (Carvajal et al., Sci Transl Med 2018, 10(436)) and other literature reports Compounds can inhibit both MDM2/p53 and MDMX/p53 interactions. Small molecule inhibitors block MDM2/p53 and MDMX/p53 interactions and have the potential to treat related diseases.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a small molecule inhibitor that blocks the interaction of MDM2/p53 and/or MDMX/p53.

The first aspect of the present invention provides a compound of formula (I), its enantiomer, diastereomer, racemate or a pharmaceutically acceptable salt thereof,

In the formula, Ar is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group, wherein the substitution refers to a group in which one or more hydrogen atoms on the phenyl group or naphthyl group are selected from the group consisting of Group substitution: halogen, deuterium, cyano, hydroxyl, amino, nitro, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl , substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C1-C4 alkylcarbonyl;

R ₁ and R ₂ are each independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C8 cycloalkane radical, substituted or unsubstituted C1-C4 alkoxy;

_R3 is

Y and Z are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, -(CH ₂ ) _m -substituted or unsubstituted C3-C8 cycloalkyl, -(CH ₂ ) _m -substituted or unsubstituted 5-13 membered heterocyclyl, -(CH ₂ ) _m -substituted or unsubstituted 5-12 membered heteroaryl, -(CH ₂ ) _m -substituted or unsubstituted 6-10 membered aryl; or Y , Z and N form a substituted or unsubstituted 5-13-membered heterocyclic group;

R ₄ is hydrogen, substituted or unsubstituted C1-C6 alkyl, -(CH ₂ ) _m -substituted or unsubstituted 6-10-membered aryl, -(CH ₂ ) _m -substituted or unsubstituted C3-C8 Cycloalkyl, -(CH ₂ ) _m -substituted or unsubstituted 5-12 membered heteroaryl, -(CH ₂ ) _m -substituted or unsubstituted 5-13 membered heterocyclyl, -CO-substituted or unsubstituted Substituted 6-10-membered aryl, -CO-substituted or unsubstituted 3-10-membered cycloalkyl, -SO ₂ -substituted or unsubstituted 6-10-membered aryl;

m is independently 0, 1, 2, 3, or 4 at each occurrence;

R ₅ is substituted or unsubstituted C1-C6 alkyl, -(CH ₂ ) _m -substituted or unsubstituted C3-C8 cycloalkyl, -(CH ₂ ) _m -substituted or unsubstituted 5-12-membered heterocyclic ring base;

Unless otherwise defined, each of the substitutions described above independently means that one or more hydrogen atoms on the group are replaced by a group selected from the group consisting of halogen, deuterium, cyano, hydroxy, amino, nitro, C2-C4 alkynyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonamidocarbonyl (C1-C4 alkylSO ₂ NHCO-), carboxyl, -CONH ₂ , C1-C4 alkyl, C3-C6 Cycloalkyl, C1-C4alkoxy, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkylethynyl, mono(C1-C4alkyl)amino, di(C1-C4alkyl)amino , C1-C4 alkylcarbonylamino, C1-C4 alkoxycarbonylamino, C1-C4 alkylSO ₂ -, C1-C4 alkyl-S(O ₂ )-C1-C4 alkylene-, carboxyl substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, C1-C4 alkyl-S-, C2-C10 acyl, C1-C4 alkylcarbonyl, C1-C4 alkylaminocarbonyl, 5-12-membered heteroaryl base, 5-12-membered heteroarylcarbonyl, C1-C4 alkyl 5-12-membered heteroarylcarbonyl.

In another preferred example, R ₄ is hydrogen, substituted or unsubstituted C1-C8 alkyl, -(CH ₂ ) _m -substituted or unsubstituted 6-10-membered aryl, -(CH ₂ ) _m -substituted or unsubstituted C3-C8 cycloalkyl, -(CH ₂ ) _m -substituted or unsubstituted 5-12 membered heteroaryl, -(CH ₂ ) _m -substituted or unsubstituted 5-13 membered heterocyclyl , -CO-substituted or unsubstituted 6-10-membered aryl, -CO-substituted or unsubstituted 3-10-membered cycloalkyl (3-6- or 6-10-membered cycloalkyl), -SO ₂ - Substituted or unsubstituted 6-10 membered aryl;

Other groups are defined as before;

Unless otherwise defined, each of the substitutions described above independently means that one or more hydrogen atoms on the group are replaced by a group selected from the group consisting of halogen, deuterium, cyano, hydroxy, amino, nitro, C2-C4 alkynyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonamidocarbonyl (C1-C4 alkylSO ₂ NHCO-), carboxyl, -CONH ₂ , C1-C4 alkyl, C3-C6 Cycloalkyl, C1-C4alkoxy, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkylethynyl, mono(C1-C4alkyl)amino, di(C1-C4alkyl)amino , C1-C4 alkylcarbonylamino, C1-C4 alkoxycarbonylamino, C1-C4 alkylSO ₂ -, C1-C4 alkyl-S(O ₂ )-C1-C4 alkylene-, carboxyl substituted C1-C4 alkyl, hydroxy substituted C1-C4 alkyl, C1-C4 alkyl-S-, C2-C10 acyl, C1-C4 alkylcarbonyl, C1-C4 alkylaminocarbonyl, C1-C4 haloalkylamino Carbonyl, 5-12-membered heteroaryl, 5-12-membered heteroarylcarbonyl, C1-C4 alkyl 5-12-membered heteroarylcarbonyl.

In another preferred example, the compound has the structure shown in formula (II):

In the formula, Ar, R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

In another preferred example, Ar is a substituted or unsubstituted phenyl group, and the substitution means that one or more hydrogen atoms on the phenyl group are replaced by a group selected from the group consisting of halogen, deuterium, cyano, Hydroxyl, carboxyl, amino, nitro, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl; the above C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4alkoxy, C1-C4alkylcarbonyl are optionally further substituted with one or more groups selected from the group consisting of halogen, deuterium, cyano, hydroxy, amino, nitro, carboxyl, C1-C4alkane group, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino.

In another preferred example, Ar is a substituted or unsubstituted phenyl group, and the substitution means that one or more hydrogen atoms on the phenyl group are replaced by a group selected from the group consisting of fluorine, chlorine, bromine, C1- C4 alkyl, halogenated C1-C4 alkyl (eg trifluoromethyl).

In another preferred embodiment, R ₁ and R ₂ are each independently hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy.

In another preferred embodiment, Y is H or substituted or unsubstituted C1-C4 alkyl; Z is H, -(CH ₂ ) _m -substituted or unsubstituted phenyl, -(CH ₂ ) _m -substituted or Unsubstituted 5-7 membered heteroaryl, -(CH ₂ ) _m -substituted or unsubstituted C3-C6 cycloalkyl, -(CH ₂ ) _m -substituted or unsubstituted 5-7 membered heterocyclyl; Or Y, Z and N form a substituted or unsubstituted 5-13-membered heterocyclic group;

where m is independently 0, 1, 2, or 3 at each occurrence;

The substitution refers to substitution with one or more groups selected from the group consisting of amino, hydroxyl, carboxyl, C1-C4alkoxy, _-CONH2 , C1-C4alkyl-CONH-, C1-C4alkyl -NHCO-, C1-C4 alkyl, C1-C4 alkyl-S(O ₂ )-C1-C4 alkylene-, C1-C4 alkyl SO ₂ NHCO-, carboxy-substituted C1-C4 alkyl, di- (C1-C4 alkyl)amino, mono(C1-C4 alkyl)amino, hydroxy substituted C1-C4 alkyl, deuterium, fluorine, chlorine, bromine, cyano, nitro.

In another preferred example, Y is H or a substituted or unsubstituted C1-C4 alkyl group, and the substitution refers to being substituted by one or more groups selected from the group consisting of: carboxyl group, bis(C1-C4 alkyl group) ) amino, C1-C4 alkyl-CONH-, mono(C1-C4 alkyl)amino, hydroxyl, C1-C4 alkyl-NHCO-.

In another preferred embodiment, R ₃ is OH or

Y is H; Z is H, substituted or unsubstituted C1-C4 alkyl, -(CH ₂ ) _m -substituted or unsubstituted phenyl, -(CH ₂ ) _m -substituted or unsubstituted 5-7 membered Heteroaryl, -(CH ₂ ) _m -substituted or unsubstituted C3-C6 cycloalkyl, or -(CH ₂ ) _m -substituted or unsubstituted 5-7 membered heterocyclyl; or Y, Z and N Forms a substituted or unsubstituted 5-13 membered heterocyclyl; the substitution refers to substitution with one or more groups selected from the group consisting of fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1-C4 alkoxy base, -CONH ₂ , C1-C4 alkyl-CONH-, C1-C4 alkyl-NHCO-, C1-C4 alkyl, C1-C4 alkyl-S(O ₂ )-C1-C4 alkylene-, Mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkyl SO ₂ NHCO-, carboxy-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl; each m independently 0, 1 or 2.

In another preferred example, R ₄ is hydrogen, substituted or unsubstituted C1-C4 alkyl, -(CH ₂ ) _m -substituted or unsubstituted phenyl, -(CH ₂ ) _m -substituted or unsubstituted C3-C6 cycloalkyl, -(CH ₂ ) _m -substituted or unsubstituted 5-7 membered heteroaryl, -(CH ₂ ) _m -substituted or unsubstituted 5-7 membered heterocyclyl, -CO- Substituted or unsubstituted phenyl, -CO-substituted or unsubstituted 3-6 membered cycloalkyl, -SO ₂ -substituted or unsubstituted phenyl;

The substitution refers to substitution with one or more groups selected from the group consisting of halogen, cyano, amino, hydroxyl, nitro, carboxyl, C1-C4alkoxy, _-CONH2 , C1-C4alkyl- CONH-, C1-C4 alkyl-NHCO-, C1-C4 alkyl, C1-C4 alkyl-S(O ₂ )-C1-C4 alkylene-, C1-C4 alkyl SO ₂ -, 6-10 Aryl, C3-C6 cycloalkyl, 5-7-membered heteroaryl, 5-7-membered heterocyclic, carboxyl-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, C1-C4 alkyl SO ₂ NHCO-, (C1-C4 alkyl) amino, two (C1-C4 alkyl) amino, C1-C4 alkyl carbonyl, C1-C4 alkyl amino carbonyl, 5-7 membered heteroaryl carbonyl, C1- C4 alkyl 5-7 membered heteroarylcarbonyl.

In another preferred example, R ₅ is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 5-7 membered heterocyclic group; the substitution is means substituted with one or more groups selected from the group consisting of C1-C4 alkyl, C1-C4 alkylcarbonyl.

In another preferred example, R ₅ is tert-butyl, C3-C6 cycloalkyl, C1-C4 alkyl substituted C3-C6 cycloalkyl,

In another preferred embodiment, each substituent is a corresponding group in a specific compound.

In another preferred example, the above heterocyclic group and heteroaryl group each independently contain 1, 2, 3 or 4 heteroatoms selected from N and O.

In another preferred embodiment, the compound is selected from the compounds of any of the sequence numbers 1-148.

The compound provided by the present invention can be used as a small molecule inhibitor for inhibiting the protein-protein interaction of MDM2-p53 and MDMX-p53.

The second aspect of the present invention provides a pharmaceutical composition, comprising the compound according to the first aspect, the enantiomer, diastereomer, racemate or pharmaceutically acceptable salt of the compound one or more; and

A pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition optionally further comprises pharmaceutically acceptable adjuvants selected from the group consisting of binders, fillers, diluents, disintegrants, suspensions, Suspending agent, slow (controlled) release agent, freeze-drying protective agent, coating agent, enteric material, lubricant, glidant, anti-sticking agent, sweetener, flavoring agent, plasticizer, opacifier, enhancer Solvents, humectants, solvents, osmotic pressure regulators, colorants, pigments, surfactants, emulsifiers, water-soluble bases, fat-soluble bases, oleaginous bases, porogens, gelling agents, preservatives, buffers, Chelating agents, antioxidants, or combinations thereof.

The third aspect of the present invention provides the use of the compound described in the first aspect, its enantiomers, diastereomers, racemates or pharmaceutically acceptable salts thereof, for the preparation of blocking MDM2 A small molecule inhibitor of /p53 and/or MDMX/p53 interaction; or a medicament for treating diseases related to the activity or expression of MDM2 or MDMX protein.

In another preferred embodiment, the disease related to the activity or expression level of MDM2 or MDMX protein is selected from the group consisting of: glioma, liposarcoma, skin melanoma, squamous cell carcinoma, retinoblastoma, Breast, esophagus, lung, ovarian, gastric, bladder, liver, soft tissue sarcoma, chronic lymphocytic leukemia, acute myeloid leukemia, lymphoma, osteosarcoma and colon cancer.

Compared with the prior art, the main advantages of the present invention include:

(1) A class of small molecular compounds with novel structures of substituted phenyl spiro[indoline-3,3'-pyrrolidine] structures and similar structures are provided. The preparation method has the advantages of mild reaction conditions, abundant raw materials and easy availability. , simple operation and post-processing, good corresponding selectivity and so on. The compound has good activity of inhibiting MDM2-p53 and MDMX-p53 protein-protein interaction.

(2) A small molecule inhibitor of MDM2-p53, MDMX-p53 protein-protein interaction is provided, which has strong MDM2-p53, MDMX-p53 protein-protein interaction inhibitory activity at the same time, is a kind of potential of antitumor drugs.

Description of drawings

Figure 1 shows the relative steric configuration of YK094-Me.

Figure 2 shows a graph of compound purity over time.

Detailed ways

After long-term and in-depth research, the inventors of the present invention have unexpectedly developed small molecular compounds with a substituted phenyl spiro[indoline-3,3'-pyrrolidine] structure and similar structures, which can inhibit MDM2-p53 , MDMX-p53 protein-protein interaction, regulates p53-mediated gene expression in tumor cells, so it can be used to inhibit MDM2-p53, MDMX-p53 interaction-related diseases, such as cancer prevention and treatment. Based on the above findings, the inventors have completed the present invention.

compound

The compound of the present invention, the structure is shown in general formula I:

In another preferred example, the compound has the structure shown in the following formula I-1 or I-2:

In another preferred example, Ar is a substituted or unsubstituted phenyl group, and the substitution means that 1, 2, 3 or 4 hydrogen atoms on the phenyl group are replaced by a group selected from the group consisting of fluorine, chlorine, bromo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, halogenated C1-C4 alkyl (such as trifluoromethyl);

R ₁ and R ₂ are each independently hydrogen, deuterium, fluorine, chlorine or bromine;

R ₃ is OH or

Y is H; Z is H, substituted or unsubstituted C1-C4 alkyl, -(CH ₂ ) _m -substituted or unsubstituted phenyl, -(CH ₂ ) _m -substituted or unsubstituted 5-7 membered Heteroaryl, -(CH ₂ ) _m -substituted or unsubstituted C3-C6 cycloalkyl, or -(CH ₂ ) _m -substituted or unsubstituted 5-7 membered heterocyclyl; or Y, Z and N Forms a substituted or unsubstituted 5-7 membered heterocyclyl; the substitution refers to substitution with 1, 2, 3 or 4 groups selected from the group consisting of fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, C1 -C4 alkoxy, -CONH ₂ , C1-C4 alkyl-CONH-, C1-C4 alkyl-NHCO-, C1-C4 alkyl, C1-C4 alkyl-S(O ₂ )-C1-C4 alkylene Alkyl-, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkyl SO ₂ NHCO-, carboxy substituted C1-C4 alkyl, hydroxy substituted C1-C4 alkane base; each m is independently 0, 1, or 2;

R ₄ is hydrogen, substituted or unsubstituted C1-C4 alkyl, -(CH ₂ ) _m -substituted or unsubstituted phenyl, -(CH ₂ ) _m -substituted or unsubstituted C3-C6 cycloalkyl, or -CO-substituted or unsubstituted phenyl; each m is independently 0, 1 or 2; the substitution means substitution with 1, 2, 4 or 3 groups selected from the group consisting of fluorine, chlorine, Bromine, cyano, amino, hydroxyl, nitro, carboxyl, C1-C4 alkoxy, -CONH ₂ , C1-C4 alkyl-CONH-, C1-C4 alkyl-NHCO-, C1-C4 alkyl, C1 -C4 alkyl-S(O ₂ )-C1-C4 alkylene-, C1-C4 alkyl SO ₂ -, 5-7-membered heteroaryl, carboxy-substituted C1-C4 alkyl, hydroxy-substituted C1- C4 alkyl, C1-C4 alkyl SO ₂ NHCO-;

R ₅ is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted 5-7-membered heterocyclic group; the substitution refers to a group selected from the group consisting of One or more group substitutions: C1-C4 alkyl, C1-C4 alkylcarbonyl.

In another preferred example, the heteroaryl group in the present invention is selected from: tetrazolyl, isoxazolyl, oxazolyl, pyridyl, imidazolyl, and pyrazolyl. In another preferred embodiment, the heteroaryl group in the present invention is selected from:

),

In another preferred embodiment, the heterocyclic group in the present invention is selected from: oxetanyl, tetrahydropyranyl, and piperidinyl.

Preparation

The compounds of the present invention can be prepared by the following reaction schemes.

route one

Step 1: Aldehyde S1 and substituted 2-fluorobenzeneacetonitrile S2 are mixed in a suitable solvent (eg methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or N,N-dimethylformamide, etc.) . Appropriate base (sodium methoxide, sodium ethoxide, etc.) is added, and the intermediate S3 is obtained by the reaction at room temperature or under appropriately elevated temperature conditions (eg, 40-60° C.). Step 2: Mix S3 and corresponding raw material S4 in a suitable solvent (for example: tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or acetonitrile, etc.), add silver fluoride and alkali (triethylamine, N,N-diisopropyl) ethylamine and DBU, etc.), at room temperature, the reaction obtains the intermediate S5. Step 3: S5 is subjected to a hydrogenation reduction reaction to obtain an intermediate S6 (eg, Pd/C hydrogen hydrogenation reduction, Raney nickel hydrogen hydrogenation reduction, Raney nickel hydrazine hydrate hydrogenation reduction, etc.). Step 4: Mix S6 and FmocCl in a suitable solvent (for example: tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or acetonitrile, etc.), add a base (triethylamine, N,N-diisopropylethylamine and DBU etc.), at room temperature, the reaction obtains intermediate S7. Step 5: S7 is dissolved in dichloromethane, trifluoroacetic acid is added, and the reaction is carried out at room temperature to obtain intermediate S8. Step 6: Dissolve S8 in a suitable solvent (for example: tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, N,N-dimethylformamide or acetonitrile, etc.), add a base (triethylamine, N,N-dichloromethane, etc.) Isopropylethylamine and DBU, etc.) and condensation reagents (diphenylphosphine chloride, CDI, HATU and EDCI, etc.), add alcohol or amine after half an hour of reaction, and react at room temperature to obtain intermediate S9. Step 7: S9 is dissolved in a suitable solvent (eg: N,N-dimethylformamide, etc.), piperidine is added, and the intermediate S10 is obtained by the reaction at room temperature. Step 8: S10 and halogenated hydrocarbon R ₄ X (R ₄ is arylmethyl or aliphatic alkyl) in appropriate solvent (for example: acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, toluene and benzene etc.), add alkali (for example: potassium carbonate, cesium carbonate and sodium carbonate, etc.), under the condition of elevated temperature (for example, 80-120 ° C), the reaction obtains the final product II.

route two

Step 1: Dissolve S10 and R ₄ CHO in a suitable solvent (for example: methanol, tetrahydrofuran, ethanol, 1,2-dichloroethane and N,N-dimethylformamide, etc.), add a reducing agent (hydroboration, etc.) Sodium, sodium acetate borohydride, sodium cyanoborohydride, etc.), intermediate S11 is obtained by reductive amination reaction.

Step 2: Mix S11 and a base (eg, potassium carbonate, cesium carbonate, sodium carbonate, etc.) in a suitable solvent (eg, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, toluene, and benzene, etc.) , under elevated temperature conditions (eg, 80-120° C.), the reaction yields the final product II.

route three

Route 3: Step 1: S10 and base (eg: potassium carbonate, cesium carbonate and sodium carbonate, etc.) in appropriate solvent (eg: acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, toluene and benzene, etc.) ) and mixed, under the condition of elevated temperature (for example, 80-120 ° C), the reaction obtains S12;

Step 2: S12 and halogenated hydrocarbons, bases (eg: potassium carbonate, cesium carbonate and sodium carbonate, etc.) in appropriate solvents (eg: acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, toluene and benzene) etc.), under elevated temperature conditions (eg 80-120 ° C), the reaction to obtain the final product II; or S12 and an aromatic halide, Pd or copper catalyst, a suitable ligand, in a suitable solvent (benzene, toluene, etc.) , tetrahydrofuran and ethylene glycol dimethyl ether, etc.), under elevated temperature conditions (for example, 80-120 ° C), the reaction obtains the final product II; or S12, acid halide such as acid chloride, acid bromide and base (for example: triethyl ether amine, diisopropylethylamine DIEA and DBU, etc.), mixed in a suitable solvent (tetrahydrofuran, dichloromethane, dichloroethane and toluene, etc.), at a suitable temperature (-10℃-50℃), The reaction yields the final product II.

I, I-1 and I-2 can be synthesized synthetically using the three synthetic strategies described above.

Example 1: Synthesis of Compounds

Final product 1: 4-((2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2,3- Dichlorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK114)

Step 1: Synthesis of (Z)-2-(5-chloro-2-fluorophenyl)-3-(2,3-dichlorophenyl)acrylonitrile (YK090)

5-Chloro-2-fluorobenzeneacetonitrile (3.4g, 20mmol) and 2,3-dichlorobenzaldehyde (3.5g, 20mmol) were weighed into a 250mL round bottom flask, 150mL methanol was added to dissolve the reactant, and 5N methanol was added dropwise The methanol solution of sodium was 4.8 mL, and the reaction system was stirred at 50 °C overnight. After the reaction was completed, it was cooled to room temperature and filtered to obtain 6.1 g of crude product with a yield of 93%. ¹ H NMR(500MHz, Chloroform-d)δ7.98-7.89(m,2H),7.59(ddd,J=14.3,7.4,2.0Hz,2H),7.42-7.32(m,2H),7.15(dd, J=10.5,8.8Hz,1H).

Step 2: Synthesis of (2R, 3S, 4R, 5S)-4-(5-chloro-2-fluorophenyl)-4-cyano-3-(2,3-dichlorophenyl)-5-neopentyl tert-butyl pyrrolidine-2-carboxylate (YK093)

(Z)-2-(5-Chloro-2-fluorophenyl)-3-(2,3-dichlorophenyl)acrylonitrile (6.1 g, 18.65 mmol) and AgF (2.37 g, 18.65 mmol) were weighed Put it into a 100mL round-bottomed flask, add 30mL of ultra-dry dichloromethane to dissolve it, and dropwise add 4.15mL of triethylamine and (E)-2-(((3,3-dimethylbutylene)amino)acetic acid tert-butyl ester ( 3.97g, 19mmol), react at room temperature for 24h. After the reaction, add saturated ammonium chloride to the reaction solution, extract with dichloromethane (30mL×3 times), combine the organic phases, wash twice with saturated sodium chloride, use Dry over anhydrous sodium sulfate, spin dry the organic phase and purify through column to obtain 3.72 g of crude product with a yield of 37%. ¹ H NMR (500 MHz, Chloroform-d) δ7.72 (dd, J=8.0, 1.6 Hz, 1H), 7.45 –7.38(m,2H),7.36–7.28(m,2H),7.05(dd,J=12.0,8.8Hz,1H),5.05(dd,J=6.3,1.0Hz,1H),4.08(d,J ＝8.8Hz,1H),4.02(d,J＝6.3Hz,1H),1.65(ddd,J＝14.5,9.0,1.2Hz,1H),1.42(s,9H),1.31(dd,J＝14.5, 1.1Hz, 1H), 0.90(s, 9H).

Step 3: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-4-(5-chloro-2-fluorophenyl)-3-(2,3-dichlorophenyl)-5 - Neopentylpyrrolidine-2-carboxylate tert-butyl ester (YK108)

YK093 (3.72g, 6.8mmol) was weighed into a 100mL round-bottomed flask, dissolved in tetrahydrofuran/ethanol (THF/EtOH) (30mL/10mL), heated to 55°C, added Raney nickel 3g, hydrazine hydrate 10mL, and reacted for 2h , filtered, turned to dryness, and purified by normal phase column to obtain 1.23 g of crude product with a yield of 32%.

Step 4: Synthesis of (2R,3S,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-4-(5-chloro-2 -Fluorophenyl)-3-(2,3-dichlorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YK109)

YK108 (1200 mg, 2.2 mmol) was weighed into a 50 mL single-necked flask, dissolved in dry tetrahydrofuran, added diisopropylethylamine (1200 mg, 8.8 mmol) and FmocCl (854 mg, 3.3 mmol), and reacted at room temperature overnight. The reactant was spin-dried under reduced pressure, dissolved in 5 mL of dichloromethane, added with 3 mL of trifluoroacetic acid, and kept at room temperature overnight. The reaction solution was turned to dryness, saturated sodium bicarbonate solution was added, extracted three times with dichloromethane, the organic phases were combined, and after drying, normal phase column purification was performed to obtain 1080 mg of crude product with a yield of 69%.

Step 5: Synthesis of methyl 4-((2R,3S,4S,5S)-4-(aminomethyl)-4-(5-chloro-2-fluorophenyl)-3-(2,3-dichloro Phenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YK113)

Weigh YK109 (100mg, 0.14mmol) into a 50mL single-necked flask, dissolve with dry tetrahydrofuran, add diisopropylethylamine (90mg, 0.7mmol), stir for 5 minutes, add diphenylphosphine chloride (99mg, 0.42 mmol), stir for half an hour, add methyl 4-amino-3-methoxybenzoate (102 mg, 0.56 mmol), and react at room temperature overnight. Saturated sodium bicarbonate solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried by normal phase column purification, the obtained crude product was dissolved in DMF (2 mL), piperidine (0.2 mL) was added, the reaction was performed at room temperature for 15 minutes, and water was added. , extracted with ethyl acetate, the organic phase was spin-dried 24 mg of the target product, and the yield was 26%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.30-8.21(m,1H),7.66-7.52(m,4H),7.50-7.42(m,2H),7.39(dd,J=7.0,2.5Hz ,1H),7.08(dd,J＝12.6,8.8Hz,1H),4.64–4.51(m,2H),4.46(d,J＝10.5Hz,1H),3.92(s,3H),3.87(s, 3H), 3.82–3.75 (m, 1H), 3.66 (d, J=14.0Hz, 1H), 1.87–1.76 (m, 1H), 1.68 (dd, J=14.0, 11.3Hz, 1H), 1.27 (s ,9H).

Step 6: Synthesis of 4-((2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2,3- Dichlorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK114)

Weigh YK113 (24 mg, 0.037 mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (10 mg, 0.055 mmol), sodium borohydride acetate (16 mg, 0.074 mmol) and 0.1 mL of acetic acid into a 50 mL round bottom In a flask, dissolve with 1,2-dichloroethane overnight at room temperature. Add water, extract with ethyl acetate, spin dry the organic phase, add potassium carbonate (15 mg, 0.11 mmol), dissolve in DMF, heat at 110 °C overnight, add water, extract with ethyl acetate, spin dry the organic phase, add lithium hydroxide- The hydrate (8 mg, 0.2 mmol) was dissolved in tetrahydrofuran/H ₂ O (v/v=2 mL/mL), stirred at room temperature overnight, and purified by HPLC to obtain 19.6 mg of the target compound with a yield of 68%. ESI-MS theoretical calculation value C ₃₉ H ₃₉ ³⁵ Cl ₃ N ₇ O ₄ [M+H] ⁺ =744.21, experimentally found: 744.3.

Final product 2: 4-((2'S,3S,4'S,5'R)-1-(4-carboxybenzoyl)-5-chloro-4'-(2-chlorophenyl)-2'-neopenta Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK119)

Step 1: Synthesis of methyl 4-((((2'S,3S,4'S,5'R)-5-chloro-4'-(2-chlorophenyl)-2'-neopentylspiro[indoline-3 ,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoate (YK117)

YK017 (see step 5 of final product 56, 140 mg, 0.23 mol) and potassium carbonate (94 mg, 0.68 mmol) were weighed into a bottle, dissolved in DMF, stirred at 110 °C overnight, added with water, extracted with ethyl acetate, and the organic phase was spin-dried, Purified by normal phase column to obtain 87 mg of crude product, yield: 64%.

Step 2: Synthesis of 4-((2'S,3S,4'S,5'R)-1-(4-carboxybenzoyl)-5-chloro-4'-(2-chlorophenyl)-2'-neopenta Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK119)

YK117 (46 mg, 0.077 mmol) was weighed into a bottle, dissolved in dichloromethane, methyl p-formate benzoyl chloride (23 mg, 0.12 mmol) and diisopropylethylamine (30 mg, 0.23 mmol) were added, and the reaction was carried out at room temperature. Overnight, the reaction solution was spin-dried, and lithium hydroxide monohydrate (11 mg, 0.27 mmol) was added, dissolved in tetrahydrofuran/H ₂ O (v/v=2 mL/2 mL), stirred at room temperature overnight, and purified by HPLC to obtain 40 mg of the target compound. rate 71%. ESI-MS theoretical calculation value C ₃₉ H ₃₈ ³⁵ Cl ₂ N ₃ O ₇ [M+H] ⁺ =730.21, experimentally found: 730.3.

Final product 3: 4-((2'S,3S,4'S,5'R)-5-chloro-4'-(2-chlorophenyl)-2'-neopentyl-1-(3-nitrobenzyl) ) Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK094)

Step 1: Synthesis of 4-((2'S,3S,4'S,5'R)-5-chloro-4'-(2-chlorophenyl)-2'-neopentyl-1-(3-nitrobenzyl) ) Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK094)

YK017 (see step 5 of final product 56, 126 mg, 0.2 mmol), potassium carbonate (83 mg, 0.6 mmol) and m-nitrobenzyl bromide (66 mg, 0.3 mmol) were weighed into a bottle, dissolved in DMF, and stirred at 110 °C overnight, Add water, extract with ethyl acetate, spin dry the organic phase, add lithium hydroxide monohydrate (42 mg, 1 mmol), dissolve with tetrahydrofuran/H ₂ O (v/v=2 mL/2 mL), stir at room temperature overnight, and obtain pure HPLC The target compound was 22 mg, and the yield was 15%. ESI-MS theoretical calculation value C ₃₈ H ₃₉ ³⁵ Cl ₂ N ₄ O ₆ [M+H] ⁺ =717.22, experimentally found: 717.1.

Final product 4: (1R,4r)-4-((2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4' -(2-Chlorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)cyclohexane-1-carboxylic acid (YK121)

Step 1: Synthesis of methyl (1R,4r)-4-((2R,3S,4S,5S)-4-(aminomethyl)-4-(5-chloro-2-fluorophenyl)-3-( 2-Chlorophenyl)-5-neopentylpyrrolidine-2-carboxamido)cyclohexane-1-carboxylic acid (YK115)

YK013 (see step 4 of final product 56, 100 mg, 0.15 mmol), methyl trans-4-aminocyclohexanecarboxylate hydrochloride (114 mg, 0.59 mmol), diphenylphosphine chloride (104 mg, 0.44 mmol), diphenylphosphine chloride (104 mg, 0.44 mmol), two Isopropylethylamine (95 mg, 0.74 mmol) and piperazine 0.2 mL, see the final product 1 step 5 for the reaction steps, to obtain 68 mg of crude product, yield: 77%. ¹ H NMR (500MHz, Methanol-d ₄ )δ7.68 (d, J=7.8Hz, 1H), 7.51 (ddt, J=9.4, 5.2, 2.3Hz, 2H), 7.40 (qd, J=8.1, 1.7 Hz, 2H), 7.32(dd, J＝6.9, 2.5Hz, 1H), 7.13(dd, J＝12.8, 8.8Hz, 1H), 5.10(d, J＝11.3Hz, 1H), 4.76(d, J =11.0Hz,1H),4.54(d,J=11.1Hz,1H),3.92(dd,J=14.8,2.9Hz,1H),3.82(d,J=14.9Hz,1H),3.69–3.51(m ,4H),2.18(tt,J＝12.1,3.5Hz,1H),2.09(dd,J＝14.8,11.4Hz,1H),2.00–1.87(m,2H),1.87–1.78(m,1H), 1.63–1.52 (m, 1H), 1.51–1.31 (m, 2H), 1.27–1.10 (m, 11H), 0.94–0.79 (m, 1H).

Step 2: Synthesis of (1R,4r)-4-((2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4' -(2-Chlorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)cyclohexane-1-carboxylic acid (YK121)

YK115 (30mg, 0.05mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (17mg, 0.1mmol), sodium borohydride acetate (21mg, 0.1mmol), 0.1mL acetic acid, potassium carbonate (21mg, 0.15 mmol) and lithium hydroxide monohydrate (11 mg, 0.25 mmol). For the reaction steps, refer to the final product 1, step 6, to obtain 18.6 mg of the target compound, yield: 52%. ¹ H NMR(500MHz,Methanol-d ₄ )δ7.90-7.84(m,2H),7.54-7.47(m,1H),7.41(d,J=2.1Hz,1H),7.36(dt,J=8.0 ,3.2Hz,1H),7.34–7.28(m,2H),7.07(dd,J=8.3,2.7Hz,3H),6.39(d,J=8.5Hz,1H),4.60(d,J=9.6Hz ,1H),4.54(d,J＝9.6Hz,1H),4.36(t,J＝5.0Hz,1H),4.24(d,J＝15.6Hz,1H),4.11(d,J＝15.6Hz,1H) ),3.66(tt,J＝11.2,4.0Hz,1H),3.56(d,J＝10.8Hz,1H),3.49(d,J＝10.8Hz,1H),2.14(tq,J＝10.7,3.6Hz , 1H), 2.03–1.85 (m, 2H), 1.76–1.63 (m, 3H), 1.46 (pd, J=13.4, 3.6Hz, 3H), 1.20 (qd, J=12.5, 3.5Hz, 1H), 1.02-0.87 (m, 9H). ESI-MS calcd. C ₃₉ H ₄₄ ³⁵ Cl ₂ N ₇ O ₃ [M+H] ⁺ =716.29, found: 716.0.

Final product 5: (1S,4s)-4-((2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4' -(2-Chlorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)cyclohexane-1-carboxylic acid (YK122)

Step 1: Synthesis of methyl (1S,4s)-4-((2R,3S,4S,5S)-4-(aminomethyl)-4-(5-chloro-2-fluorophenyl)-3-( 2-Chlorophenyl)-5-neopentylpyrrolidine-2-carboxamido)cyclohexane-1-carboxylic acid (YK118)

YK013 (see step 4 of final product 56, 100 mg, 0.15 mmol), methyl cis-4-aminocyclohexanecarboxylate hydrochloride (114 mg, 0.59 mmol), diphenylphosphine chloride (104 mg, 0.44 mmol), Diisopropylethylamine (95 mg, 0.74 mmol) and piperazine 0.2 mL, refer to the final product 1 step 5 for the reaction procedure, to obtain 85 mg of crude product, yield: 97%. ¹ H NMR(500MHz,Methanol-d ₄ )δ7.74-7.64(m,1H),7.51(ddt,J=9.2,6.6,2.0Hz,2H),7.44-7.30(m,3H),7.12(ddt ,J=12.8,8.9Hz,1H),5.09(d,J=11.3Hz,1H),4.82(d,J=11.3Hz,1H),4.51(d,J=11.2Hz,1H),3.92(dd , J=14.7, 3.0Hz, 1H), 3.85–3.72 (m, 2H), 3.61 (s, 3H), 2.37 (dq, J=7.7, 3.8, 3.2Hz, 1H), 2.09 (dd, J=14.8 ,11.4Hz,1H),1.87(d,J=14.7Hz,1H),1.82–1.41(m,5H),1.20(s,12H).

Step 2: Synthesis of (1S,4s)-4-((2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4' -(2-Chlorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)cyclohexane-1-carboxylic acid (YK122)

YK118 (45mg, 0.076mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (26mg, 0.15mmol), sodium borohydride acetate (32mg, 0.15mmol), 0.1mL acetic acid, potassium carbonate (31mg, 0.23 mmol) and lithium hydroxide monohydrate (16 mg, 0.38 mmol). For the reaction steps, see Step 6 of Final Product 1 to obtain 11.4 mg of the target compound, yield: 21%. ¹ H NMR(500MHz, Methanol-d ₄ )δ7.89-7.82(m,2H),7.52(dd,J=6.8,2.5Hz,1H),7.43(d,J=2.1Hz,1H),7.39- 7.34 (m, 1H), 7.33–7.27 (m, 2H), 7.13–7.01 (m, 3H), 6.38 (d, J=8.5Hz, 1H), 4.67–4.56 (m, 2H), 4.38 (dd, J=6.5, 3.6Hz, 1H), 4.25 (d, J=15.6Hz, 1H), 4.11 (d, J=15.6Hz, 1H), 3.83 (s, 1H), 3.59 (d, J=10.7Hz, ESI-MS Theoretical calculated value C ₃₉ H ₄₄ ³⁵ Cl ₂ N ₇ O ₃ [M+H] ⁺ =716.29, experimentally found: 716.7.

Final product 6: 4-((2'S,3S,4'S,5'R)-1-(4-carboxyphenyl)-5-chloro-4'-(2-chlorophenyl)-2'-neopentyl Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK124)

Step 1: Synthesis of 4-((2'S,3S,4'S,5'R)-1-(4-carboxyphenyl)-5-chloro-4'-(2-chlorophenyl)-2'-neopentyl Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK124)

Add Pd ₂ (dba) ₃ (20mg, 0.022mmol), BINAP (40mg, 0.065mmol) in the two-necked flask of drying, dissolve with toluene, nitrogen protection after deoxygenation, naturally cool to room temperature after stirring at 80 ℃ for 5 minutes for subsequent use . Take another two-necked bottle, add YK117 (end product 2 step 1, 43mg, 0.072mmol), p-iodobenzoate (57mg, 0.22mmol) and sodium tert-butoxide (28mg, 0.288mmol), dissolve with toluene, remove After oxygen and nitrogen protection, the prepared catalyst was added to the above system, deoxygenated and nitrogen protection again, reacted at 80 ° C for 16 h, added water, extracted with ethyl acetate, the organic phase was spin-dried and purified by a normal phase column, and the crude product was purified with tetrahydrofuran/H ₂ O ( v/v=2mL/2mL) was dissolved, lithium hydroxide monohydrate (15mg, 0.36mmol) was added, and the mixture was stirred at room temperature overnight. The target compound was purified by HPLC to obtain 4.2mg of the target compound with a yield of 8%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.25(d,J=8.6Hz,1H),7.85(d,J=7.8Hz,2H),7.70-7.58(m,2H),7.54(d, J=5.5Hz, 2H), 7.31 (d, J=7.9Hz, 1H), 7.24–7.15 (m, 1H), 7.07 (dt, J=36.1, 7.6Hz, 3H), 6.87 (d, J=8.1 Hz, 2H), 5.11(s, 1H), 4.68–4.39(m, 2H), 4.26(d, J=11.0Hz, 1H), 4.10(d, J=11.3Hz, 1H), 3.69(s, 3H) ), 1.75(dd, J=35.5, 12.6Hz, 2H), 1.08(s, 9H). ESI-MS theoretical calculated value C ₃₈ H ₃₈ ³⁵ Cl ₂ N ₃ O ₆ [M+H] ⁺ =702.21, experimental Measured: 702.4.

Final product 7: 4-((((2'S,3S,4'S,5'R)-5'-(((4-carboxyphenyl)carbamoyl)-5-chloro-4'-(2-chlorobenzene (YK125)

Step 1: Synthesis of 4-((((2'S,3S,4'S,5'R)-5'-(((4-carboxyphenyl)carbamoyl)-5-chloro-4'-(2-chlorobenzene (YK125)

YK100 (see final product 72, step 1, 35 mg, 0.0596 mmol), 2-methoxy, methyl 4-carboxylate benzyl bromide (23 mg, 0.089 mmol), potassium carbonate (25 mg, 0.179 mmol) and lithium hydroxide monohydrate (13 mg, 0.3 mmol), refer to the synthesis method of the final product 3 for the reaction steps to obtain 10 mg of the target compound, yield: 23%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.03-7.93(m,2H),7.69-7.60(m,2H),7.51(d,J=1.5Hz,1H),7.48(dd,J=7.6 ,1.9Hz,1H),7.44(dd,J＝7.7,1.5Hz,1H),7.41(d,J＝2.1Hz,1H),7.34(dd,J＝7.7,1.7Hz,1H),7.27(dtd , J＝16.6,7.4,1.7Hz,2H),7.07(dd,J＝8.5,2.1Hz,1H),6.72(d,J＝7.8Hz,1H),6.38(d,J＝8.5Hz,1H) ,4.75(s,2H),4.31(d,J＝7.7Hz,1H),4.18(d,J＝15.8Hz,1H),4.11(d,J＝15.9Hz,1H),3.80(s,3H) , 3.53(s, 2H), 1.80–1.58(m, 2H), 0.95(s, 9H). ESI-MS calculated value for C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₃ O ₆ [M+H] ⁺ =716.23, Experimentally measured: 716.5.

Final product 8: 4-((2'S,3S,4'R,5'R)-1-(3-carboxybenzyl)-6-chloro-2'-neopentyl-4'-phenylspiro[indium Doline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI007)

Step 1: Synthesis of (Z)-2-(4-chloro-2-fluorophenyl)-3-phenylacrylonitrile (YG152)

4-Chloro-2-fluorobenzeneacetonitrile (3.19g, 18.9mmol) and benzaldehyde (2g, 18.9mmol) were weighed into a 250mL round bottom flask, 150mL methanol was added to dissolve the reactant, and 5N sodium methoxide methanol solution was added dropwise 5.7 mL, and the reaction system was stirred at 50 °C overnight. After the reaction was completed, it was cooled to room temperature and filtered to obtain 4.37 g of crude product with a yield of 90%. ¹ H NMR (500MHz, Chloroform-d) δ7.92-7.84(m, 2H), 7.57(s, 1H), 7.54(t, J=8.3Hz, 1H), 7.51-7.44(m, 3H), 7.26 –7.18(m,2H).

Step 2: Synthesis of (2R,3R,4R,5S)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentyl-3-phenylpyrrolidine-2-carboxylic acid Tert-Butyl Ester (YG157)

(Z)-2-(4-Chloro-2-fluorophenyl)-3-phenylacrylonitrile (4.37 g, 17 mmol) and AgF (2.16 g, 17 mmol) were weighed into a 100 mL round-bottomed flask, and 30 mL supernatant was added. Dry dichloromethane was dissolved, 2.75 mL of triethylamine and (E)-2-(((3,3-dimethylbutylene)amino)acetic acid tert-butyl ester (3.6 g, 17 mmol) were added dropwise, and the reaction was carried out at room temperature for 24 h. After the reaction, saturated ammonium chloride was added to the reaction solution, extracted with dichloromethane (30 mL×3 times), the organic phases were combined, washed twice with saturated sodium chloride, dried with anhydrous sodium sulfate, and the organic phase was spin-dried. After column purification, 2.12 g of crude product was obtained, with a yield of 29%. ¹ H NMR (500 MHz, Chloroform-d) δ 7.32 (t, J=8.5 Hz, 1H), 7.26 (dd, J=5.1, 1.9 Hz, 3H) ,7.18(dt,J＝8.4,2.3Hz,3H),7.09(dd,J＝8.4,2.1Hz,1H),4.30(d,J＝7.9Hz,1H),4.20–4.14(m,1H), 4.08(dd,J=9.1,1.2Hz,1H),1.61(ddd,J=14.3,9.2,1.1Hz,1H),1.36(s,9H),1.30(dd,J=14.2,1.2Hz,1H) ,0.90(s,9H).

Step 3: Synthesis of (2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-3-phenylpyrrolidine-2 - tert-butyl carboxylate (YH153)

YG157 (1.8g, 3.8mmol) was weighed into a 100mL round-bottomed flask, dissolved in tetrahydrofuran/EtOH (30mL/10mL), heated to 55°C, added with Raney nickel 1.8g, hydrazine hydrate 10mL, reacted for 2h, filtered, transferred The dry solvent was purified by normal phase column to obtain 293 mg of crude product with a yield of 16%.

Step 4: Synthesis of (2R,3R,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-4-(4-chloro-2 -Fluorophenyl)-5-neopentyl-3-phenylpyrrolidine-2-carboxylic acid (YH157)

YH153 (293 mg, 0.62 mmol) was weighed into a 50 mL single-necked flask, dissolved in dry tetrahydrofuran, added diisopropylethylamine (320 mg, 2.48 mmol) and FmocCl (239 mg, 0.93 mmol), and reacted at room temperature overnight. The reactant was spin-dried under reduced pressure, dissolved in 5 mL of dichloromethane, added with 3 mL of trifluoroacetic acid, and kept at room temperature overnight. The reaction solution was turned to dryness, saturated sodium bicarbonate solution was added, extracted three times with dichloromethane, the organic phases were combined, and after being turned to dryness, normal phase column purification was performed to obtain 312 mg of crude product with a yield of 79%.

Step 5: Synthesis of 4-((2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-3-phenylpyrrole Alkyl-2-carboxamido)-3-methoxybenzoic acid methyl ester (YI003)

Weighing YH157 (312mg, 0.487mmol) was added in a 50mL single-neck flask, dissolved in dry tetrahydrofuran, added diisopropylethylamine (314mg, 2.44mmol), stirred for 5 minutes, added diphenylphosphine chloride (345mg, 1.46 mmol), stir for half an hour, add methyl 4-amino-3-methoxybenzoate (352 mg, 1.95 mmol), and react at room temperature overnight. Saturated sodium bicarbonate solution was added to the reaction solution, extracted with dichloromethane, the organic phase was dried by normal phase column purification, the obtained crude product was dissolved in DMF (2 mL), piperidine (0.2 mL) was added, the reaction was performed at room temperature for 15 minutes, and water was added. , extracted with ethyl acetate, the organic phase was spin-dried 42 mg of the target product, the yield was 15%.

Step 6: Synthesis of 4-((2'S,3S,4'R,5'R)-1-(3-carboxybenzyl)-6-chloro-2'-neopentyl-4'-phenylspiro[indium Doline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI007)

YI003 (22 mg, 0.038 mmol) was weighed into a bottle, dissolved in 2 mL of DMF, methyl 3-(bromomethyl)benzoate (10 mg, 0.045 mmol) and potassium carbonate (16 mg, 0.11 mmol) were added, and the mixture was stirred at 110 °C overnight , cooled to room temperature after the reaction, added water, extracted with ethyl acetate, after the organic phase was spin-dried, the crude product was dissolved in 10 mL of water/tetrahydrofuran/MeOH (V/V/V=1/1/1) mixed solvent, added Lithium hydroxide monohydrate (10 mg, 0.23 mmol) overnight at room temperature. The reaction solution was spin-dried and purified by HPLC to obtain 11.7 mg of the product with a yield of 45%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.28(d,J=8.4Hz,1H),7.91(dt,J=7.8,1.4Hz,1H),7.79(s,1H),7.62(dd, J＝8.4,1.8Hz,1H),7.50(d,J＝1.8Hz,1H),7.35(dq,J＝22.3,7.8Hz,5H),7.18(d,J＝7.2Hz,2H),7.02( d, J=7.6Hz, 1H), 6.76 (dd, J=8.0, 1.8Hz, 1H), 6.48 (s, 1H), 5.11 (d, J=11.3Hz, 1H), 4.27–3.97 (m, 4H) ),3.64(s,3H),3.49(d,J=10.5Hz,1H),3.37(d,J=10.6Hz,1H),1.78–1.60(m,2H),0.95(s,9H).ESI -MS theoretical calculated value C ₃₉ H ₄₁ ³⁵ ClN ₃ O ₆ [M+H] ⁺ =682.27, experimentally found: 682.3.

Final product 9: 4-((2'S,3S,4'R,5'R)-1-(4-carboxybenzyl)-6-chloro-2'-neopentyl-4'-phenylspiro[indium Doline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI008)

YI003 (final product 8, step five, 22mg, 0.038mmol), methyl 4-(bromomethyl)benzoate (10mg, 0.045mmol), potassium carbonate (16mg, 0.11mmol) and lithium hydroxide monohydrate (10mg, 0.23 mmol), refer to step 6 of final product 8 for the reaction steps to obtain 12 mg of the target product with a yield of 45%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.28(d,J=8.5Hz,1H),7.85(d,J=8.0Hz,2H),7.62(dd,J=8.4,1.8Hz,1H) ,7.56–7.30(m,5H),7.21(d,J＝7.6Hz,2H),6.88(d,J＝7.9Hz,2H),6.76(dd,J＝8.0,1.8Hz,1H),6.39( d, J=1.8Hz, 1H), 5.15 (d, J=11.4Hz, 1H), 4.30–4.01 (m, 4H), 3.64 (s, 3H), 3.48 (q, J=10.7Hz, 2H), 1.82-1.53 (m, 2H), 0.96 (s, 9H). ESI-MS calculated for C ₃₉ H ₄₁ ³⁵ ClN ₃ O ₆ [M+H] ⁺ = 682.27, found by experiment: 682.3.

Final product 10: 4-((2'S,3S,4'R,5'R)-1-(3-carboxybenzyl)-6-chloro4'-(3-chlorophenyl)-2'-neopenta Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI014)

Step 1: Synthesis of (Z)-2-(4-chloro-2-fluorophenyl)-3-(3-chlorophenyl)acrylonitrile (YH132)

m-chlorobenzaldehyde (1.4g, 10mmol), 4-chloro-2-fluorobenzeneacetonitrile (1.7g, 10mmol), 3mL of 5N methanol solution of sodium methoxide, see step 1 of final product 8 for the reaction steps to obtain the target product 2.7g , the yield is 92%. ¹ H NMR(500MHz, Chloroform-d)δ7.84-7.80(m,1H),7.78(dt,J=2.6,1.3Hz,1H),7.58-7.49(m,2H),7.46-7.38(m, 2H), 7.24(dd, J＝2.0, 0.7Hz, 1H), 7.22(dd, J＝10.9, 2.1Hz, 1H).

Step 2: Synthesis of (2R,3R,4R,5S)-4-(4-chloro-2-fluorophenyl)-3-(3-chlorophenyl)-4-cyano-5-neopentylpyrrolidine -2-Carboxylic acid tert-butyl ester (YH156)

YH132 (2.7 g, 9.3 mmol), AgF (1.17 g, 9.3 mmol), triethylamine 2.1 mL and (E)-tert-butyl 2-(((3,3-dimethylbutylene)amino)acetate ( 1.97 g, 9.3 mmol), refer to step 2 of final product 8 for the reaction steps to obtain 1.42 g of the target product with a yield of 30%.

Step 3: Synthesis of (2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(3-chlorophenyl)-5-neopentyl Pyrrolidine-2-carboxylate tert-butyl ester (YH160)

YH156 (1.42 g, 2.8 mmol) Raney nickel 1.4 g, hydrazine hydrate 10 mL, see step 3 of final product 8 for the reaction steps to obtain 117 mg of the target product with a yield of 8%. ¹ H NMR (500MHz, Chloroform-d) δ 7.25-7.01 (m, 6H), 6.97 (dd, J=7.5, 1.7Hz, 1H), 4.28 (d, J=8.7Hz, 1H), 4.11 (d , J＝9.1Hz, 1H), 3.87(dd, J＝8.8, 2.1 Hz, 1H), 3.25(d, J＝13.3Hz, 1H), 3.07(d, J＝13.3Hz, 1H), 1.56–1.35 (m,2H),1.30(s,9H),0.91(s,9H).

Step 4: Synthesis of (2R,3R,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-4-(4-chloro-2 -Fluorophenyl)-3-(3-chlorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YI005)

YH160 (236 mg, 0.46 mmol), FmocCl (180 mg, 0.7 mmol), diisopropylethylamine (239 mg, 1.8 mmol) and 2 mL of trifluoroacetic acid, refer to step 4 of final product 8 for the reaction steps to obtain 219 mg of the target product, Yield 70%.

Step 5: Synthesis of methyl 4-((2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(3-chlorophenyl) -5-Neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YI009)

YI005 (219mg, 0.32mmol), methyl 4-amino-3-methoxybenzoate (235mg, 1.295mmol), diphenylphosphine chloride (229mg, 0.97mmol), diisopropylethylamine (209mg , 1.62 mmol) and piperidine 0.4 mL, see step 5 of final product 8 for the reaction steps to obtain 62 mg of the target product with a yield of 31%.

Step 6: Synthesis of 4-((2'S,3S,4'R,5'R)-1-(3-carboxybenzyl)-6-chloro-4'-(3-chlorophenyl)-2'-neopenta Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI014)

YI009 (30mg, 0.049mmol), methyl 3-(bromomethyl)benzoate (13.4mg, 0.058mmol), potassium carbonate (20mg, 0.15mmol) and lithium hydroxide monohydrate (10mg, 0.25mmol), reacted For the steps, refer to step 6 of final product 8 to obtain 19.7 mg of the target product with a yield of 56%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.26(d,J=8.4Hz,1H),7.92(dt,J=7.7,1.4Hz,1H),7.78(d,J=1.8Hz,1H) ,7.62(dd,J=8.4,1.8Hz,1H),7.52(d,J=1.8Hz,1H),7.42–7.32(m,3H),7.28(t,J=7.9Hz,1H),7.21( d, J=2.0Hz, 1H), 7.10–6.98(m, 2H), 6.78(dd, J=8.0, 1.8Hz, 1H), 6.54(d, J=1.8Hz, 1H), 5.10(d, J = 11.2Hz, 1H), 4.24–4.09 (m, 3H), 4.05 (d, J=11.3Hz, 1H), 3.72 (s, 3H), 3.49 (d, J=10.7Hz, 1H), 3.30–3.27 (m, 1H), 1.81–1.60 (m, 2H), 0.95 (s, 9H). ESI-MS calculated value C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₃ O ₆ [M+H] ⁺ =716.23, experimentally determined Got: 716.3.

Final product 11: 4-((2'S,3S,4'R,5'R)-1-(4-carboxybenzyl)-6-chloro4'-(3-chlorophenyl)-2'-neopenta Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI015)

YI009 (final product 10, step five, 30 mg, 0.049 mmol), methyl 4-(bromomethyl)benzoate (13.4 mg, 0.058 mmol), potassium carbonate (20 mg, 0.15 mmol) and lithium hydroxide monohydrate (10 mg , 0.25mmol), refer to step 6 of final product 8 for the reaction steps to obtain 15.4 mg of the target product with a yield of 44%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.27(d,J=8.4Hz,1H),7.92-7.83(m,2H),7.62(dd,J=8.4,1.8Hz,1H),7.53( d, J=1.8Hz, 1H), 7.43 (dd, J=7.9, 1.9Hz, 1H), 7.37 (d, J=8.0Hz, 1H), 7.33–7.22 (m, 2H), 7.04 (d, J ＝7.8Hz,1H), 6.92(d,J＝8.0Hz,2H),6.78(dd,J＝8.0,1.8Hz,1H),6.47(d,J＝1.8Hz,1H),5.12(d,J ＝11.2Hz, 1H), 4.31(d, J＝15.8Hz, 1H), 4.19(d, J＝8.1Hz, 1H), 4.14–3.99(m, 2H), 3.73(s, 3H), 3.49(d , J=10.7Hz, 1H), 3.37 (d, J=10.7Hz, 1H), 1.74 (dd, J=15.3, 8.4Hz, 1H), 1.65 (dd, J=15.2, 1.8Hz, 1H), 0.97 (s, 9H). ESI-MS theoretical calculation value C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₃ O ₆ [M+H] ⁺ =716.23, experimentally found: 716.3.

Final product 12: 4-((2'S,3S,4'S,5'R)-1-(4-(carboxymethyl)benzyl)-6-chloro-4'-(3-chloro-2-fluorophenyl) )-2'-neopentylspiro[indoline]-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI026)

Step 1: Synthesis of methyl 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- Fluorophenyl)-5-neopentylpyrrolidine-2-carboxamide)-3-methoxybenzoate (YI045)

Methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5 -Neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (2.5g, 3.96mmol) was dissolved in tetrahydrofuran/ethanol (10/10mL), added Raney nickel 2.5g, raised to At 55°C, 10 mL of hydrazine hydrate was added, and the reaction was performed until no gas was generated. After filtration, the filtrate was evaporated to dryness under reduced pressure and purified by normal phase column to obtain 637 mg of the target compound, yield: 25%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.24(d,J=8.2Hz,1H),7.59-7.50(m,2H),7.50-7.43(m,1H),7.40(t,J=8.6 Hz, 1H), 7.36–7.26 (m, 2H), 7.26–7.13 (m, 2H), 4.59 (d, J=10.2Hz, 1H), 4.41 (d, J=11.1Hz, 1H), 3.97 (d , J＝10.3Hz, 1H), 3.91(s, 3H), 3.85(s, 3H), 3.78(dd, J＝14.4, 3.2Hz, 1H), 3.52(d, J＝14.4Hz, 1H), 1.72 (d, J=13.6Hz, 1H), 1.60 (dd, J=13.8, 11.3Hz, 1H), 1.23(s, 9H). ¹³ C NMR (126MHz, Methanol-d ₄ )δ172.68, 168.02, 163.96(d , _JCF = 249.5Hz), 161.84 (TFA, q, _JCF = 36.5Hz), 158.22 (d, _JCF = 248.2Hz), 149.58, 136.71 (d, _JCF = 11.3Hz), 132.46, 131.36, 130.89 (d, J _CF = 5.0 Hz), 130.48, 127.23 (d, J _CF = 1.3 Hz), 126.76, 126.01 (d, J _CF = 10.1 Hz), 125.95, 123.89, 123.12 (d, J _CF = 11.3 Hz) , 122.73 (d, J _CF = 20.2 Hz), 119.34, 118.88 (d, J _CF = 29.0 Hz), 117.50 (TFA, q, J _CF = 289.8 Hz), 111.83, 63.89, 63.55, 58.24 (d, J _CF = 3.8 Hz), 56.34, 52.62, 43.20, 38.24 (d, J _CF =7.6 Hz), 32.14, 30.68. ESI-MS theoretical calculated value for C ₃₂ H ₃₆ ³⁵ Cl ₂ F ₂ N ₃ O ₄ [M+H] ⁺ = 634.2, experimentally measured: 634.1.

Step 2: Synthesis of 4-((2'S,3S,4'S,5'R)-1-(4-(carboxymethyl)benzyl)-6-chloro-4'-(3-chloro-2-fluorophenyl) )-2'-neopentylspiro[indoline]-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI026)

YI045 (25mg, 0.04mmol), methyl 4-(bromomethyl)phenylacetate (12mg, 0.047mmol), potassium carbonate (16mg, 0.12mmol) and lithium hydroxide monohydrate (10mg, 0.25mmol), reaction procedure Referring to step 6 of final product 8, 7 mg of the target product was obtained with a yield of 23%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.23(d,J=8.4Hz,1H),7.64(dd,J=8.4,1.8Hz,1H),7.57(d,J=1.8Hz,1H) ,7.49(t,J＝7.5Hz,1H),7.31(d,J＝8.0Hz,1H),7.25(t,J＝7.0Hz,1H),7.18(d,J＝7.8Hz,2H),7.14 (t, J=8.0Hz, 1H), 6.94 (d, J=7.9Hz, 2H), 6.72 (dd, J=8.0, 1.8Hz, 1H), 6.51 (d, J=2.0Hz, 1H), 4.97 (s,1H),4.29(d,J＝10.3Hz,1H), 4.17(d,J＝15.1Hz,1H),4.09(d,J＝15.0Hz,1H),4.07–3.95(m,1H) ,3.77(s,3H),3.60(s,2H),3.50(d,J=10.7Hz,1H),3.34(d,J=10.7Hz,1H),1.74–1.56(m,2H),0.95( s, 9H). ESI-MS theoretical calculation value C ₄₀ H ₄₁ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =748.24, experimentally found: 748.4.

Final product 13: 4-((2'S,3S,4'S,5'R)-1-(3-(carboxymethyl)benzyl)-6-chloro-4'-(3-chloro-2-fluorophenyl) )-2'-neopentylspiro[indoline]-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI027)

YI045 (25mg, 0.04mmol), methyl 3-(bromomethyl)phenylacetate (12mg, 0.047mmol), potassium carbonate (16mg, 0.12mmol) and lithium hydroxide monohydrate (10mg, 0.25mmol), reaction procedure Referring to step 6 of final product 8, 4.5 mg of the target product was obtained with a yield of 15%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.22(d,J=8.3Hz,1H),7.64(dd,J=8.4,1.8Hz,1H),7.56(d,J=1.8Hz,1H) ,7.52(t,J＝7.5Hz,1H),7.40-7.26(m,2H),7.20(h,J＝7.8Hz,3H),7.05(s,1H),6.91-6.82(m,1H), 6.74(dd,J＝8.1,1.8Hz,1H),6.53(d,J＝1.8Hz,1H),5.03(d,J＝10.3Hz,1H),4.34(d,J＝10.4Hz,1H), 4.21–4.03 (m, 3H), 3.75 (s, 3H), 3.65–3.48 (m, 3H), 3.37–3.32 (m, 1H), 1.76–1.69 (m, 1H), 1.65 (dd, J=15.4 , 8.2Hz, 1H), 0.94 (s, 9H). ESI-MS theoretical calculation value C ₄₀ H ₄₁ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =748.24, experimentally measured: 748.7.

Final product 14: 4-((2'S,3S,4'S,5'R)-1-(4-carboxybenzyl)-6-chloro4'-(3-chloro-2-fluorophenyl)-2'- Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI031)

Step 1: Synthesis of 4-((2'S,3S,4'S,5'R)-1-(4-carboxybenzyl)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'- Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI031)

YI045 (20 mg, 0.03 mmol), methyl 4-(bromomethyl)benzoate (9 mg, 0.038 mmol), potassium carbonate (13 mg, 0.094 mmol) and lithium hydroxide monohydrate (10 mg, 0.25 mmol), reaction procedure Referring to step 6 of final product 8, 8 mg of the target product was obtained with a yield of 35%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.22(d,J=8.4Hz,1H),7.89(d,J=8.1Hz,2H),7.64(dd,J=8.4,1.8Hz,1H) ,7.56(d,J＝1.8Hz,1H),7.50(t,J＝7.4Hz,1H),7.35(d,J＝8.0Hz,1H),7.26(t,J＝7.0Hz,1H),7.14 (t, J=7.9Hz, 1H), 7.04 (d, J=8.0Hz, 2H), 6.76 (dd, J=8.1, 1.8Hz, 1H), 6.53 (d, J=1.8Hz, 1H), 5.06 (d, J=10.3Hz, 1H), 4.39–4.25 (m, 2H), 4.21–4.05 (m, 2H), 3.76 (s, 3H), 3.54 (d, J=10.8Hz, 1H), 3.36 ( d, J=10.8Hz, 1H), 1.68 (d, J=5.0Hz, 2H), 0.95 (s, 9H). ESI-MS calculated value C ₃₉ H ₃₉ ³⁵ Cl ₂ FN ₃ O ₆ [M+H ] ⁺ =734.22, experimentally measured: 734.3.

Final product 15: 4-((2'S,3S,4'S,5'R)-1-(2-carboxybenzyl)-6-chloro4'-(3-chloro-2-fluorophenyl)-2'- Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI032)

YI045 (20 mg, 0.03 mmol), methyl 2-(bromomethyl)benzoate (9 mg, 0.038 mmol), potassium carbonate (13 mg, 0.094 mmol) and lithium hydroxide monohydrate (10 mg, 0.25 mmol), reaction procedure Referring to step 6 of final product 8, 9.6 mg of the target product was obtained with a yield of 44%. ¹ H NMR(500MHz, Methanol-d ₄ )δ8.23(d,J=8.4Hz,1H),8.01-7.93(m,1H),7.64(dd,J=8.4,1.8Hz,1H),7.59- 7.48 (m, 2H), 7.43–7.28 (m, 4H), 7.18 (t, J=8.0Hz, 1H), 6.87–6.79 (m, 1H), 6.73 (dd, J=8.1, 1.8Hz, 1H) ,6.39(d,J＝1.8Hz,1H),4.99(d,J＝10.3Hz,1H),4.67(d,J＝15.7Hz,1H),4.37–4.26(m,2H),4.06(d, J＝7.3Hz, 1H), 3.77(s, 3H), 3.55(d, J＝10.7Hz, 1H), 3.40(d, J＝10.8Hz, 1H), 1.68(d, J＝15.1Hz, 1H) , 1.60(dd, J=15.2, 8.3Hz, 1H), 0.95(s, 9H). ESI-MS theoretical calculation value C ₃₉ H ₃₉ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =734.22, experimentally determined Got: 734.8.

Final product 16: 4-((2'S,3S,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-neopentyl-1-(pyridine- 4-ylmethyl)spiro[indoline]-3,3'-pyrrolidone]-5'-carboxamido)-3-methoxybenzoic acid (YI035)

YI045 (20 mg, 0.03 mmol), 4-(bromomethyl)pyridine hydrobromide (12 mg, 0.047 mmol), potassium carbonate (13 mg, 0.094 mmol) and lithium hydroxide monohydrate (10 mg, 0.25 mmol), reacted For the steps, refer to step 6 of final product 8 to obtain 9.6 mg of the target product with a yield of 46%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.71(d,J=6.1Hz,2H),8.22(d,J=8.4Hz,1H),7.64(dd,J=8.4,1.7Hz,1H) ,7.61–7.53(m,2H),7.46(dt,J＝17.3,8.3Hz,4H),7.24(t,J＝7.9Hz,1H),6.85(dd,J＝8.1,1.8Hz,1H), 6.45(d,J＝1.8Hz,1H),5.16(d,J＝10.5Hz,1H),4.52(d,J＝17.7Hz,1H),4.42(d,J＝17.7Hz,1H),4.35( d,J＝10.5Hz,1H),4.23(d,J＝8.7Hz,1H),3.78(s,3H),3.69(d,J＝10.8Hz,1H),3.56(d,J＝10.8Hz, 1H), 1.89–1.76(m, 1H), 1.65(d, J=14.9Hz, 1H), 1.00(s, 9H). ESI-MS calculated for C ₃₇ H ₃₈ ³⁵ Cl ₂ FN ₄ O ₄ [M +H] ⁺ =691.22, experimentally measured: 691.0.

Final product 17: 4-((2'S,3S,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-neopentyl-1-(pyridine- 3-ylmethyl)spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI036)

YI045 (20 mg, 0.03 mmol), 3-(bromomethyl)pyridine hydrobromide (12 mg, 0.047 mmol), potassium carbonate (13 mg, 0.094 mmol) and lithium hydroxide monohydrate (10 mg, 0.25 mmol), reacted For the steps, refer to step 6 of final product 8 to obtain 11.8 mg of the target product with a yield of 56%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.77(d,J=5.1Hz,1H),8.51(s,1H),8.20(d,J=8.4Hz,1H),7.99-7.86(m, 2H), 7.63 (dd, J=8.4, 1.8Hz, 1H), 7.60–7.49 (m, 2H), 7.42 (dd, J=12.1, 7.5Hz, 2H), 7.18 (t, J=7.9Hz, 1H) ), 6.84(dd, J＝8.1, 1.8Hz, 1H), 6.61(d, J＝1.8Hz, 1H), 5.14(d, J＝10.5Hz, 1H), 4.42(d, J＝15.9Hz, 1H) ), 4.36–4.25(m, 2H), 4.21(d, J=8.7Hz, 1H), 3.77(s, 3H), 3.61(d, J=10.8Hz, 1H), 3.45(d, J=10.8Hz) , 1H), 1.80(dd, J＝15.2, 8.8Hz, 1H), 1.69–1.57(m, 1H), 0.99(s, 9H). ESI-MS calculated value for C ₃₇ H ₃₈ ³⁵ Cl ₂ FN ₄ O ₄ [M+H] ⁺ =691.22, experimentally measured: 691.5.

Final product 18: 4-((2'S,3S,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-neopentyl-1-(pyridine- 2-ylmethyl)spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI046)

YI045 (20mg, 0.03mmol), 2-(bromomethyl)pyridine hydrobromide (12mg, 0.047mmol), potassium carbonate (13mg, 0.094mmol) and lithium hydroxide monohydrate (10mg, 0.25mmol), reacted For the steps, refer to step 6 of final product 8 to obtain 13.3 mg of the target product with a yield of 63%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.54(d,J=5.1Hz,1H),8.25(d,J=8.4Hz,1H),7.87(td,J=7.7,1.7Hz,1H) ,7.64(dd,J＝8.4,1.8Hz,1H),7.58(d,J＝1.8Hz,1H),7.48(t,J＝6.6Hz,2H),7.33(dd,J＝11.1,7.2Hz, 2H), 7.14(t, J＝7.9Hz, 1H), 6.88(d, J＝7.9Hz, 1H), 6.76(dd, J＝8.1, 1.8Hz, 1H), 6.47(d, J＝1.8Hz, 1H), 5.03–4.92(m, 1H), 4.38 (d, J=16.2Hz, 1H), 4.33–4.21(m, 2H), 3.99(s, 1H), 3.81(s, 3H), 3.65(d , J＝10.7Hz, 1H), 3.48(d, J＝10.7Hz, 1H), 1.73–1.56(m, 2H), 0.98(s, 9H). ESI-MS theoretical calculated value for C ₃₇ H ₃₈ ³⁵ Cl ₂ FN ₄ O ₄ [M+H] ⁺ =691.22, found experimentally: 691.0.

Final product 19: 4-((2'S,3S,4'S,5'R)-1-(3-carboxybenzyl)-6-chloro4'-(3-chloro-2-fluorophenyl)-2'- Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI052)

YI045 (30 mg, 0.047 mmol), methyl 3-(bromomethyl)benzoate (13 mg, 0.057 mmol), potassium carbonate (20 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.25 mmol), reaction procedure Referring to step 6 of final product 8, 12.7 mg of the target product was obtained with a yield of 36%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.22(d,J=8.4Hz,1H),7.93(d,J=8.0Hz,1H),7.82(d,J=1.8Hz,1H),7.63 (dd, J=8.4, 1.8Hz, 1H), 7.56(d, J=1.8Hz, 1H), 7.45(t, J=7.5Hz, 1H), 7.40–7.31(m, 2H), 7.27(t, J=7.0Hz, 1H), 7.19(d, J=7.6Hz, 1H), 7.12(t, J=7.9Hz, 1H), 6.74(dd, J=8.0, 1.8Hz, 1H), 6.57(d, J=1.8Hz, 1H), 4.97(d, J=10.2Hz, 1H), 4.31(d, J=10.3Hz, 1H), 4.20(s, 2H), 4.03(s, 1H), 3.77(s, 3H), 3.53(d, J＝10.8Hz, 1H), 3.29-3.26(m, 1H), 1.75-1.56(m, 2H), 0.94(s, 9H). ESI-MS calculated value C ₃₉ H ₃₉ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =734.22, found by experiment: 734.8.

Final product 20: 4-((2'S,3S,4'S,5'R)-1-(3-(1H-imidazol-4-yl)propyl)-6-chloro-4'-(3-chloro-2 -Fluorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI055)

Dry a 50mL single-necked bottle, add YI045 (84mg, 0.13mmol) and 3-(1H-imidazol-4-yl) propanal (44mg, 0.13mmol), dissolve the reactant with 10mL 1,2-dichloroethane, Sodium borohydride acetate (51 mg, 0.24 mmol) and 0.1 mL of acetic acid were added, reacted at room temperature overnight, the reactant was spin-dried, water was added, extracted with ethyl acetate, the organic phase was spin-dried to obtain a crude product, the crude product was weighed into a bottle, and potassium carbonate ( 36 mg, 0.26 mmol), dissolved in 2 mL of DMF, reacted at 110 °C overnight, added water, extracted with ethyl acetate, the organic phase was spin-dried, dissolved in 10 mL of water/tetrahydrofuran/MeOH (V/V/V=1/1/1) and mixed Lithium hydroxide monohydrate (27 mg, 0.65 mmol) was added to the solvent, stirred at room temperature overnight, the reaction solution was spin-dried, and purified by HPLC to obtain 5 mg of the target compound with a yield of 5%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.89-8.76(m,1H),8.22(d,J=8.4Hz,1H),7.65(dd,J=8.5,1.8Hz,1H),7.57( d, J＝1.8Hz, 1H), 7.49(t, J＝7.1Hz, 1H), 7.40(t, J＝7.5Hz, 1H), 7.33(d, J＝8.0Hz, 1H), 7.26–7.13( m, 2H), 6.72 (dd, J=8.0, 1.8Hz, 1H), 6.37 (d, J=1.9Hz, 1H), 5.19 (d, J=10.3Hz, 1H), 4.33 (d, J=10.5 Hz,1H),4.14(d,J=7.9Hz,1H),3.78(s,3H),3.65(d,J=10.7Hz,1H),3.53–3.42(m,1H),2.98(dp,J =27.7,7.0Hz,2H),2.51(dtd,J=25.8,13.5,11.3,5.9Hz,2H),1.95–1.68(m,3H),1.63(d,J=15.1Hz,1H),0.95( s, 9H). ESI-MS theoretical calculation value C ₃₇ H ₄₁ ³⁵ Cl ₂ FN ₅ O ₄ [M+H] ⁺ =708.25, experimentally found: 708.2.

Final product 21: 4-((2'S,3S,4'S,5'R)-1-(carboxymethyl)-6-chloro4'-(3-chloro-2-fluorophenyl)-2'-neopenta Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI056)

YI045 (30 mg, 0.047 mmol), ethyl bromoacetate (9.5 mg, 0.057 mmol), potassium carbonate (20 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.25 mmol), see the step of final product 8 for the reaction procedure Sixth, 12 mg of the target product was obtained, and the yield was 39%. ¹ H NMR(500MHz, Methanol-d ₄ )δ8.23(d,J=8.4Hz,1H),7.65(dd,J=8.4,1.8Hz,1H),7.57(d,J=1.8Hz,1H) ,7.46(dt,J＝16.9,6.9Hz,2H),7.33(d,J＝8.2Hz,1H),7.22(t,J＝7.9Hz,1H),6.71(dd,J＝8.1,1.8Hz, 1H), 6.36 (d, J=1.8Hz, 1H), 5.13 (d, J=10.5Hz, 1H), 4.37 (d, J=10.5Hz, 1H), 4.12 (d, J=8.2Hz, 1H) ,3.88–3.79(m,2H),3.77(s,3H),3.72(d,J=18.2Hz,1H),3.62(d,J=10.4Hz,1H),1.91–1.82(m,1H), 1.74(dd, J=15.5, 8.3Hz, 1H), 0.94(s, 9H). ESI-MS theoretical calculation value C ₃₃ H ₃₅ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =658.19, experimentally measured : 657.7.

Final product 22: 4-((2'S,3S,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-1-methyl-2'-neopentylspiro [Indoline-3,3'-pyrrolidone]-5'-carboxamido)-3-methoxybenzoic acid (YI057)

YI045 (30 mg, 0.047 mmol), methyl iodide (8 mg, 0.057 mmol), potassium carbonate (20 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.25 mmol). For the reaction procedure, refer to step 6 of final product 8, to obtain The target product was 5 mg, and the yield was 17%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.24(d,J=8.4Hz,1H),7.65(dd,J=8.4,1.7Hz,1H),7.58(d,J=1.8Hz,1H) ,7.49(t,J＝7.5Hz,1H),7.40(t,J＝6.9Hz,1H),7.30(d,J＝8.0Hz,1H),7.22(t,J＝8.0Hz,1H),6.71 (dd,J＝8.0,1.9Hz,1H),6.41(d,J＝1.8Hz,1H),5.08(d,J＝10.3Hz,1H),4.33(d,J＝10.3Hz,1H),4.07 (d, J＝9.4Hz, 1H), 3.78(s, 3H), 3.60(d, J＝10.6Hz, 1H), 3.28(d, J＝10.9Hz, 1H), 2.57(s, 3H), 1.80 -1.63 (m, 2H), 0.93 (s, 9H). ESI-MS theoretical calculation for C ₃₂ H ₃₅ ³⁵ Cl ₂ FN ₃ O ₄ [M+H] ⁺ =614.20, experimentally found: 614.1.

Final product 23: 4-((2'S,3S,4'S,5'R)-1-(((1H-imidazol-4-yl)methyl)-6-chloro-4'-(3-chloro-2- Fluorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidone]-5'-carboxamido)-3-methoxybenzoic acid (YI058)

YI045 (30 mg, 0.047 mmol), 4-aldehyde-1H-imidazole (5.4 mg, 0.057 mmol), sodium borohydride acetate (20 mg, 0.094 mmol), 0.1 mL of acetic acid, potassium carbonate (13 mg, 0.094 mmol) and hydroxide Lithium monohydrate (10 mg, 0.24 mmol), see the synthesis method of the final product 20 for the reaction steps, to obtain 9.8 mg of the target compound with a yield of 31%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.86(d,J=1.4Hz,1H),8.22(d,J=8.4Hz,1H),7.64(dd,J=8.4,1.8Hz,1H) ,7.57(d,J＝1.8Hz,1H),7.46(t,J＝7.5Hz,1H),7.39(d,J＝7.8Hz,2H),7.15(t,J＝7.9Hz,1H),7.10 (s, 1H), 6.82 (dd, J=8.1, 1.8Hz, 1H), 6.70 (d, J=1.9Hz, 1H), 5.10 (d, J=10.5Hz, 1H), 4.42–4.27 (m, 2H), 4.22(d, J＝15.9Hz, 1H), 4.08(d, J＝6.7Hz, 1H), 3.79(s, 3H), 3.63(d, J＝10.8Hz, 1H), 3.42–3.33( m, 1H), 1.76(dd, J=15.2, 8.7Hz, 1H), 1.56(d, J=15.1Hz, 1H), 0.95(s, 9H). ESI-MS theoretical calculated value for C ₃₅ H ₃₇ ³⁵ Cl ₂ FN ₅ O ₄ [M+H] ⁺ =680.22, experimentally found: 679.5.

Final product 24: 4-((2'S,3S,4'S,5'R)-1-(2-(carboxymethyl)benzyl)-6-chloro-4'-(3-chloro-2-fluorophenyl) )-2'-neopentylspiro[indoline]-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI067)

YI045 (30 mg, 0.047 mmol), methyl 2-(bromomethyl)phenylacetate (16 mg, 0.066 mmol), potassium carbonate (20 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.25 mmol), reaction procedure Referring to step 6 of final product 8, 14.1 mg of the target product was obtained with a yield of 40%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.21(d,J=8.4Hz,1H),7.64(dd,J=8.4,1.8Hz,1H),7.60-7.47(m,2H),7.35( d, J=8.1Hz, 1H), 7.30–7.20 (m, 3H), 7.15 (td, J=7.8, 3.4Hz, 2H), 6.84 (d, J=7.6Hz, 1H), 6.76 (dd, J ＝8.0,1.8Hz,1H),6.46(d,J＝1.8Hz,1H),5.03(d,J＝10.3Hz,1H),4.30(d,J＝10.4Hz,1H),4.16(s,3H) ),3.75(s,3H),3.56-3.39(m,3H),3.36(d,J=10.8Hz,1H),1.78-1.56(m,2H),0.97(s,9H).ESI-MS theory Calculated for _{C40H4135Cl2FN3O6} _[ _M ₊ H] ⁺ = _748.24 , found: ^748.0 .

Final product 25: 4-((2'S,3S,4'S,5'R)-1-(3-carboxypropyl)-6-chloro4'-(3-chloro-2-fluorophenyl)-2'- Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI069)

YI045 (30 mg, 0.047 mmol), methyl 4-(toluenesulfonyloxy)butyrate (19 mg, 0.071 mmol), potassium carbonate (20 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.25 mmol), For the reaction steps, refer to step 6 of final product 8 to obtain 12 mg of the target product with a yield of 38%. ¹ H NMR(500MHz, Methanol-d ₄ )δ8.23(d,J=8.4Hz,1H),7.65(dd,J=8.4,1.8Hz,1H),7.57(d,J=1.8Hz,1H) ,7.46(dt,J＝26.5,7.3Hz,2H),7.30(d,J＝8.0Hz,1H),7.23(t,J＝7.9Hz,1H),6.69(dd,J＝8.0,1.8Hz, 1H), 6.40(d, J＝1.9Hz, 1H), 5.14(d, J＝10.4Hz, 1H), 4.30(d, J＝10.4Hz, 1H), 4.14(d, J＝7.7Hz, 1H) ,3.77(s,3H),3.59(d,J＝10.8Hz,1H),3.44(d,J＝10.7Hz,1H),2.95(ddt,J＝36.5,13.9,6.9Hz,2H),2.12( q, J=7.3Hz, 2H), 1.83–1.52 (m, 4H), 0.95 (s, 9H). ESI-MS theoretical calculated value for C ₃₅ H ₃₉ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ = 686.22, experimentally measured: 685.6.

Final product 26: 4-((2'S,3S,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-1-(3-hydroxybenzyl)-2' -Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI070)

YI045 (30 mg, 0.047 mmol), 3-aldehyde phenol (5 mg, 0.038 mmol), sodium borohydride acetate (20 mg, 0.094 mmol), 0.1 mL of acetic acid, potassium carbonate (13 mg, 0.094 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), refer to the synthesis method of the final product 20 for the reaction steps to obtain 12.1 mg of the target compound with a yield of 37%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.22(d,J=8.4Hz,1H),7.64(dd,J=8.4,1.8Hz,1H),7.56(d,J=1.8Hz,1H) ,7.53–7.44(m,1H),7.30(dd,J＝18.0,7.5Hz,2H),7.16(t,J＝7.9Hz,1H),7.06(t,J＝7.8Hz,1H),6.69( ddd,J＝20.0,8.1,2.1Hz,2H),6.52(dd,J＝13.4,2.0Hz,2H),6.45(d,J＝7.5Hz,1H),5.03(d,J＝10.4Hz,1H) ), 4.33(d, J＝10.4Hz, 1H), 4.06(s, 3H), 3.76(s, 3H), 3.52(d, J＝10.8Hz, 1H), 3.34(d, J＝10.6Hz, 1H) ), 1.76-1.50 (m, 2H), 0.93 (s, 9H). ESI-MS theoretical calculation value C ₃₈ H ₃₉ ³⁵ Cl ₂ FN ₃ O ₅ [M+H] ⁺ =706.22, experimentally found: 706.0.

Final product 27: 4-((2'S,3S,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-1-(4-hydroxybenzyl)-2' -Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI073)

YI045 (30 mg, 0.047 mmol), 4-aldehyde phenol (5 mg, 0.038 mmol), sodium borohydride acetate (20 mg, 0.094 mmol), 0.1 mL of acetic acid, potassium carbonate (13 mg, 0.094 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), refer to the synthesis method of the final product 20 for the reaction steps to obtain 12.1 mg of the target compound with a yield of 37%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.22(d,J=8.4Hz,1H),7.64(dd,J=8.4,1.8Hz,1H),7.56(d,J=1.8Hz,1H) ,7.49(t,J＝7.4Hz,1H),7.30(d,J＝8.1Hz,1H),7.28-7.20(m,1H),7.14(t,J＝7.9Hz,1H),6.89-6.79( m, 2H), 6.74–6.61 (m, 3H), 6.53 (d, J=1.9Hz, 1H), 5.02 (d, J=10.3Hz, 1H), 4.29 (d, J=10.3Hz, 1H), 4.04(q,J=14.6Hz,3H),3.76(s,3H),3.46(d,J=11.0Hz,1H),1.75-1.55(m,2H),0.93(s,9H).ESI-MS Theoretical calculated value C ₃₈ H ₃₉ ³⁵ Cl ₂ FN ₃ O ₅ [M+H] ⁺ =706.22, experimentally found: 706.3.

Final product 28: 4-((2'S,3S,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-neopentylspiro[indoline- 3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI075-1)

YI045 (40 mg, 0.068 mmol), potassium carbonate (29 mg, 0.21 mmol) and lithium hydroxide monohydrate (10 mg, 0.25 mmol), refer to step 6 of final product 8 for the reaction procedure, to obtain YI075-1 13 mg, yield 32% . ¹ H NMR(500MHz,Methanol-d ₄ )δ8.22(d,J=8.4Hz,1H),7.65(dd,J=8.4,1.8Hz,1H),7.57(d,J=1.8Hz,1H) ,7.50(t,J＝7.5Hz,1H),7.42(t,J＝7.1Hz,1H),7.34(d,J＝8.1Hz,1H),7.24(t,J＝7.9Hz,1H),6.71 (dd, J＝8.1, 1.9Hz, 1H), 6.49 (d, J＝1.9Hz, 1H), 5.18 (d, J＝10.4Hz, 1H), 4.41 (d, J＝10.5Hz, 1H), 4.11 (t, J＝5.0Hz, 1H), 3.76(s, 3H), 3.73(d, J＝11.1Hz, 1H), 3.56(d, J＝11.0Hz, 1H), 1.85–1.64(m, 2H) , 0.91(s, 9H). ESI-MS theoretical calculation value C ₃₁ H ₃₂ ³⁵ Cl ₂ FN ₃ O ₄ [M+H] ⁺ =600.18, experimentally measured: 600.2.

Final Product 30: 4-((2'S,3S,4'S,5'R)-1-((1r,4R)-4-carboxycyclohexyl)-6-chloro-4'-(3-chloro-2-fluoro Phenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI078-1)

Final Product 31: 4-((2'S,3S,4'S,5'R)-1-((1s,4S)-4-carboxycyclohexyl)-6-chloro-4'-(3-chloro-2-fluoro Phenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI078-2)

YI045 (30 mg, 0.047 mmol), methyl 4-oxocyclohexane-1-carboxylate (9 mg, 0.052 mmol), sodium borohydride acetate (20 mg, 0.094 mmol), 0.1 mL acetic acid, potassium carbonate (13 mg, 0.094 mmol) ) and lithium hydroxide monohydrate (10 mg, 0.24 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain the target compound YI078-1 7.2 mg with a yield of 21% and YI078-2 6.4 mg with a yield of 19%.

YI078-1: ¹ H NMR (500 MHz, Methanol-d ₄ ) δ 8.25 (d, J=8.4 Hz, 1H), 7.65 (dd, J=8.4, 1.8 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.48 (t, J=7.4Hz, 1H), 7.35 (t, J=7.0Hz, 1H), 7.28–7.16 (m, 2H), 6.63 (dd, J=8.0, 1.8Hz, 1H) ), 6.35(d, J=1.9Hz, 1H), 5.06(s, 1H), 4.21(d, J=10.3Hz, 1H), 4.17–3.95(m, 1H), 3.78(s, 3H), 3.56 (d, J=10.6Hz, 1H), 3.51–3.39 (m, 1H), 3.26–3.13 (m, 1H), 2.61 (s, 1H), 2.20 (d, J=7.0Hz, 1H), 2.10 ( d, J=13.8Hz, 1H), 1.73–1.43 (m, 6H), 1.27–1.20 (m, 1H), 1.15 (d, J=12.3Hz, 1H), 0.96 (s, 9H). ESI-MS Theoretical calculated value C ₃₈ H ₄₃ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =726.25, experimentally found: 726.1.

YI078-2: ¹ H NMR (500 MHz, Methanol-d ₄ ) δ 8.26 (d, J=8.4 Hz, 1H), 7.65 (dd, J=8.4, 1.8 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.47 (t, J=7.4Hz, 1H), 7.35 (t, J=7.1Hz, 1H), 7.28–7.15 (m, 2H), 6.63 (dd, J=7.9, 1.8Hz, 1H) ),6.35(d,J=1.8Hz,1H),5.11-4.96(m,1H),4.19(d,J=10.2Hz,1H),4.12-3.90(m,1H),3.80(s,3H) ,3.57(d,J＝10.7Hz,1H),3.50-3.39(m,1H),3.26-3.11(m,1H),2.24-2.13(m,1H),2.12-2.02(m,1H),2.01 –1.90(m,1H),1.84–1.74(m,1H),1.71–1.39(m,5H),1.38–1.31(m,1H),1.18–1.04(m,1H),0.97(s,9H) .ESI-MS theoretical calculation value C ₃₈ H ₄₃ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =726.25, experimentally found: 725.6.

Final product 32: 4-((2'S,3S,4'S,5'R)-1-((1r,3S)-3-carboxybicyclobutyl)-6-chloro-4'-(3-chloro-2- Fluorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI079-1)

Final product 33: 4-((2'S,3S,4'S,5'R)-1-((1s,3R)-3-carboxycyclobutyl)-6-chloro-4'-(3-chloro-2- Fluorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI079-2)

YI045 (30mg, 0.047mmol), methyl 3-oxocyclobutane-1-carboxylate (7mg, 0.052mmol), sodium borohydride acetate (20mg, 0.094mmol), 0.1mL acetic acid, potassium carbonate (13mg, 0.094mmol) ) and lithium hydroxide monohydrate (10 mg, 0.24 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain the target compound YI079-1 7.3 mg, yield 22%, YI079-2 9.4 mg, yield 28%. YI079-1: ¹ H NMR (500 MHz, Methanol-d ₄ ) δ 8.26 (d, J=8.4 Hz, 1H), 7.65 (dd, J=8.4, 1.8 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.51(t, J＝7.5Hz, 1H), 7.37(t, J＝7.0Hz, 1H), 7.27(d, J＝8.0Hz, 1H), 7.22(t, J＝8.0Hz, 1H), 6.71(dd, J=8.0, 1.8Hz, 1H), 6.28(d, J=1.8Hz, 1H), 5.11(s, 1H), 4.25–4.02(m, 2H), 3.96–3.84(m ,1H),3.79(s,3H),3.54(q,J=10.5Hz,2H),2.98–2.85(m,1H),2.49–2.32(m,2H),2.28(td,J=7.9,4.0 Hz, 1H), 2.05–1.92(m, 1H), 1.67(s, 2H), 0.99(s, 9H). ESI-MS calculated for C ₃₆ H ₃₉ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ = 698.22, experimentally measured: 697.9. YI079-2: ¹ H NMR (500 MHz, Methanol-d ₄ ) δ 8.24 (d, J=8.4 Hz, 1H), 7.65 (dd, J=8.4, 1.8 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.46(dt, J＝23.9, 6.9Hz, 2H), 7.28(d, J＝8.0Hz, 1H), 7.23(t, J＝8.0Hz, 1H), 6.71(dd, J＝7.9 ,1.8Hz,1H),6.37(d,J＝1.9Hz,1H),5.16(d,J＝10.5Hz,1H),4.21(dd,J＝32.8,8.7Hz,2H),3.83–3.67(m ,4H),3.66–3.50(m,2H),2.82(tt,J=9.8,8.0Hz,1H),2.48–2.35(m,1H),2.35–2.17(m,2H),1.91(dd,J = 20.3, 10.3 Hz, 1H), 1.80–1.62 (m, 2H), 0.97 (s, 9H). ESI-MS theoretical calculated value for C ₃₆ H ₃₉ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =698.22 , experimentally measured: 697.8.

Final product 34: 4-((2'S,3S,4'S,5'R)-1-((((1r,4S)-4-carboxycyclohexyl)methyl)-6-chloro-4'-(3- Chloro-2-fluorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI084)

YI045 (30 mg, 0.047 mmol), methyl trans-4-formylcyclohexane-1-carboxylate (9 mg, 0.052 mmol), sodium borohydride acetate (20 mg, 0.094 mmol), 0.1 mL of acetic acid, potassium carbonate (13 mg , 0.094 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 9.3 mg of the target compound with a yield of 27%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.24(d,J=8.4Hz,1H),7.65(dd,J=8.4,1.7Hz,1H),7.57(d,J=1.8Hz,1H) ,7.50(t,J＝7.3Hz,1H),7.40(t,J＝7.1Hz,1H),7.33–7.18(m,2H),6.65(dd,J＝8.0,1.8Hz,1H),6.33( d, J＝1.9Hz, 1H), 5.13(d, J＝10.2Hz, 1H), 4.27(d, J＝10.3Hz, 1H), 4.10(s, 1H), 3.78(s, 3H), 3.57( d, J=10.8Hz, 1H), 3.47 (d, J=10.8Hz, 1H), 2.75 (h, J=7.5Hz, 2H), 2.24–2.11 (m, 1H), 2.03–1.84 (m, 2H) ), 1.81–1.54 (m, 3H), 1.46–1.22 (m, 3H), 1.02–0.87 (m, 11H), 0.87–0.75 (m, 1H). ESI-MS calculated value for C ₃₉ H ₄₅ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =740.27, experimentally found: 740.6.

Final product 35: 4-((((2'S,3S,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-neopentyl-5'- (Pyridin-3-ylcarbamoyl)spiro[indoline-3,3'-pyrrolidin]-1-yl)methyl)benzoic acid (YI085)

YI082 (refer to the synthesis of final product 8, step 5, YI003 for the synthesis procedure, 29 mg, 0.053 mmol), methyl 4-(bromomethyl)benzoate (15 mg, 0.064 mmol), potassium carbonate (22 mg, 0.16 mmol) and lithium hydroxide Monohydrate (11 mg, 0.27 mmol), see the synthesis method of the final product 8 for the reaction steps to obtain 15.6 mg of the target product with a yield of 45%. ¹ H NMR(500MHz,Methanol-d ₄ )δ9.06(d,J=2.4Hz,1H),8.47(dd,J=5.2,1.3Hz,1H),8.32(dt,J=8.7,1.6Hz, 1H), 7.96–7.81 (m, 2H), 7.74 (dd, J=8.5, 5.2Hz, 1H), 7.50–7.41 (m, 1H), 7.39 (d, J=8.1Hz, 1H), 7.20 (t ,J=7.0Hz,1H),7.08(t,J=7.9Hz,1H),7.01(d,J=8.1Hz,2H),6.78(dd,J=8.0,1.8Hz,1H),6.55(d ,J=1.8Hz,1H),4.99(d,J=9.7Hz,1H),4.41(d,J=9.7Hz,1H),4.33(d,J=15.6Hz,1H),4.20(dd,J =8.1,1.8Hz,1H),4.14(d,J=15.6Hz,1H),3.56(d,J=11.0Hz,1H),1.90–1.62(m,2H),0.94(s,9H).ESI -MS theoretical calculated value C ₃₆ H ₃₆ ³⁵ Cl ₂ FN ₄ O ₃ [M+H] ⁺ =661.21, experimentally found: 661.5.

Final product 36: 4-((2'S,3S,4'S,5'R)-1-((S)-1-(4-carboxyphenyl)ethyl)-6-chloro-4'-(3-chloro) -2-Fluorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI094-1)

Final product 37: 4-((2'S,3S,4'S,5'R)-1-((R)-1-(4-carboxyphenyl)ethyl)-6-chloro-4'-(3-chloro) -2-Fluorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI094-2)

YI045 (30mg, 0.047mmol) was weighed into a dry 50mL round-bottomed flask, dissolved in acetonitrile, methyl 4-(1-bromoethyl)benzoate (17mg, 0.071mmol), potassium carbonate (13mg, 0.094mmol) were added ) and potassium iodide (8 mg, 0.047 mmol), react at 60 °C overnight, spin dry, add water, extract with dichloromethane, spin dry the organic phase, add potassium carbonate (13 mg, 0.094 mmol) and potassium iodide (8 mg, 0.047 mmol) after vacuum drying ), dissolved in DMF, reacted at 110 °C overnight, added water, extracted with ethyl acetate, the organic phase was spin-dried and dissolved in 10 mL of mixed solvent of water/tetrahydrofuran/MeOH (V/V/V=1/1/1), and added hydroxide Lithium monohydrate (10 mg, 0.24 mmol), overnight at room temperature, spin-dried the reaction solution, and purified by reverse-phase HPLC to obtain the target product YI094-1: 4.9 mg, yield 14%; YI094-2: 5.2 mg, yield 15% . YI094-1: ¹ H NMR (500 MHz, Methanol-d ₄ ) δ 8.26 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.64 (dd, J=8.4, 1.8 Hz, 1H), 7.58(d, J＝1.8Hz, 1H), 7.45(t, J＝7.3Hz, 1H), 7.26(d, J＝8.0Hz, 1H), 7.19(t, J＝7.0Hz, 1H), 7.08(t, J=7.9Hz, 1H), 6.91(d, J=8.1Hz, 2H), 6.67(dd, J=7.9, 1.8Hz, 1H), 6.34(s, 1H), 4.74( q, J=7.0Hz, 1H), 4.19 (d, J=9.9Hz, 1H), 4.02–3.71 (m, 4H), 3.63 (d, J=10.7Hz, 1H), 3.25 (d, J=10.7 Hz, 1H), 1.61 (t, J=15.1 Hz, 2H), 1.52 (d, J=7.0 Hz, 3H), 0.97 (s, 9H). ESI-MS calculated value C ₄₀ H ₄₁ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =748.24, experimentally found: 747.3; YI094-2: ¹ H NMR (500MHz, Methanol-d ₄ )δ8.26(d, J=8.4Hz, 1H), 8.00(d , J＝8.2Hz, 2H), 7.64(dd, J＝8.4, 1.8Hz, 1H), 7.58(d, J＝1.8Hz, 1H), 7.53(d, J＝7.8Hz, 1H), 7.36(t , J=8.6Hz, 3H), 7.31–7.20 (m, 2H), 6.68 (dd, J=8.0, 1.8Hz, 1H), 6.44 (s, 1H), 4.76 (q, J=6.8Hz, 1H) ,4.27(d,J＝10.2Hz,1H),4.08-3.72(m,4H),3.48-3.40(m,1H),3.36(d,J＝10.7Hz,1H),1.50(d,J＝14.9 Hz, 1H), 1.41(t, J=11.7Hz, 1H), 1.28(d, J=5.3Hz, 2H), 0.91(s, 9H). ESI-MS calculated value C ₄₀ H ₄₁ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =748.24, experimentally found: 748.1.

Final product 38: 4-((2'S,3S,4'S,5'R)-1-((R)-1-((1r,4R)-4-carboxycyclohexyl)methyl)-6-chloro-4 '-(3-Chloro-2-fluorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI103-1)

Final product 39: 4-((2'S,3S,4'S,5'R)-1-((S)-1-(((1r,4S)-4-carboxycyclohexyl)methyl)-6-chloro- 4'-(3-Chloro-2-fluorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzene Formic acid (YI103-2)

YI045 (60 mg, 0.09 mmol), methyl trans-4-acetyl-cyclohexane-1-carboxylate (21 mg, 0.11 mmol), sodium borohydride acetate (40 mg, 0.19 mmol), 0.1 mL of acetic acid, potassium carbonate ( 55mg, 0.33mmol) and lithium hydroxide monohydrate (23mg, 0.55mmol), see the synthesis method of the final product 20 for the reaction steps to obtain the target product YI103-1: 19mg, yield 23%; YI103-2: 6.1mg, Yield 7%.

YI103-1: ¹ H NMR (500 MHz, Methanol-d ₄ ) δ 8.22 (d, J=8.4 Hz, 1H), 7.65 (dd, J=8.4, 1.8 Hz, 1H), 7.57 (d, J=1.8 Hz,1H),7.49(dt,J=12.1,7.0Hz,2H),7.26(t,J=7.9Hz,2H),6.58(dd,J=7.9,1.8Hz,1H),6.32(d,J ＝1.8Hz, 1H), 5.22(d, J＝10.4Hz, 1H), 4.37(d, J＝10.4Hz, 1H), 4.11(d, J＝8.2Hz, 1H), 3.77(s, 3H), 3.65(d,J＝11.2Hz,1H),3.40(d,J＝11.2Hz,1H),3.20-3.07(m,1H),2.17-2.04(m,1H),1.98(d,J＝13.2Hz ,1H),1.85–1.71(m,2H),1.67(d,J=13.2Hz,1H),1.53(d,J=15.1Hz,1H),1.38–1.13(m,2H),1.13–1.00( m, 4H), 0.99–0.81 (m, 10H), 0.74 (d, J=13.3Hz, 1H), 0.56 (dd, J=12.6, 3.3Hz, 1H). ESI-MS Theoretical calcd for C ₄₀ H ₄₇ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =754.28, experimentally measured: 753.8.

YI103-2: ¹ H NMR (500 MHz, Methanol-d ₄ ) δ 8.25 (d, J=8.4 Hz, 1H), 7.66 (dd, J=8.4, 1.8 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.50(t, J＝7.5Hz, 1H), 7.38(t, J＝7.0Hz, 1H), 7.28(d, J＝8.0Hz, 1H), 7.23(t, J＝7.9Hz, 1H), 6.63(dd, J＝8.0, 1.8Hz, 1H), 6.37(d, J＝1.9Hz, 1H), 5.09(s, 1H), 4.37(d, J＝10.3Hz, 1H), 3.99( s, 1H), 3.79 (s, 3H), 3.54 (d, J=10.9Hz, 1H), 3.39 (d, J=10.9Hz, 1H), 3.12 (dd, J=9.8, 6.4Hz, 1H), 2.30–2.16(m,1H), 2.03(t,J=11.7Hz,1H), 2.00–1.91(m,1H), 1.85(d,J=13.0Hz,2H), 1.79–1.54(m,2H) ,1.49–1.33(m,3H),1.09–0.97(m,1H),0.97–0.81(m,10H),0.69(d,J=6.6Hz,3H).ESI-MS calculated value C ₄₀ H ₄₇ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =754.28, found by experiment: 753.5.

Final product 40: 4-((2'S,3S,4'S,5'R)-1-(3-(1-carboxyethyl)benzyl)-6-chloro-4'-(3-chloro-2-fluoro Phenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI113)

YI045 (40 mg, 0.063 mmol), methyl 2-(3-(bromomethyl)phenyl)propanoate (24 mg, 0.094 mmol), potassium carbonate (18 mg, 0.13 mmol) and lithium hydroxide monohydrate (13 mg, 0.3 mmol), refer to step 6 of final product 8 for the reaction steps to obtain 12.4 mg of the target product with a yield of 26%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.21(d,J=8.4Hz,1H),7.64(dd,J=8.4,1.8Hz,1H),7.55(d,J=1.7Hz,1H) ,7.51(t,J＝7.4Hz,1H),7.33(td,J＝8.0,2.9Hz,2H),7.20(ddd,J＝15.9,7.4,4.8Hz,3H),7.12(d,J＝12.4 Hz,1H),6.86–6.77(m,1H),6.74(dd,J=8.0,1.8Hz,1H),6.52(s,1H),5.08(d,J=10.4Hz,1H),4.36(d , J=10.5Hz, 1H), 4.23–4.02 (m, 3H), 3.75 (s, 3H), 3.68 (q, J=7.2Hz, 1H), 3.55 (dd, J=10.9, 1.6Hz, 1H) ,3.41–3.33(m,1H),1.80–1.63(m,2H),1.50–1.36(m,3H),0.93(s,9H).ESI-MS calculated value for C ₄₁ H ₄₃ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =762.25, experimentally measured: 762.0.

Final product 41: 4-((2'S,3S,4'S,5'R)-1-(4-carbamoylbenzyl)-6-chloro4'-(3-chloro-2-fluorophenyl)-2 '-Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI122)

YI045 (40mg, 0.063mmol), 4-bromomethylbenzamide (20mg, 0.094mmol), potassium carbonate (17mg, 0.13mmol) and lithium hydroxide monohydrate (13mg, 0.3mmol), see the final product for the reaction procedure In step 6 of 8, 21.6 mg of the target product was obtained with a yield of 47%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.19(d,J=8.4Hz,1H),7.76(d,J=7.9Hz,2H),7.63(dd,J=8.4,1.7Hz,1H) ,7.58–7.45(m,2H),7.34(dd,J＝17.5,7.5Hz,2H),7.16(t,J＝8.0Hz,1H),7.02(d,J＝7.9Hz,2H),6.75( dd,J＝8.0,1.9Hz,1H),6.50(d,J＝1.8Hz,1H),5.15(d,J＝10.5Hz,1H),4.35(d,J＝10.5Hz,1H),4.29( d, J=15.5Hz, 1H), 4.19 (d, J=8.0Hz, 1H), 4.14 (d, J=15.6Hz, 1H), 3.74 (s, 3H), 3.57 (d, J=10.9Hz, 1H), 3.41(d, J=10.9Hz, 1H), 1.85–1.58(m, 2H), 0.94(s, 9H). ESI-MS calculated value for C ₃₉ H ₄₀ ³⁵ Cl ₂ FN ₄ O ₅ [M +H] ⁺ =733.24, experimentally measured: 733.2.

Final product 42: 4-((((2'S,3S,4'S,5'R)-5)-(((4-carbamoylphenyl)carbamoyl)-6-chloro-4'-(3- Chloro-2-fluorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidin]-1-yl)methyl)benzoic acid (YI123)

YI121 (see YI003 for the synthesis procedure, 23 mg, 0.039 mmol), methyl 4-bromomethylbenzoate (14 mg, 0.058 mmol), potassium carbonate (11 mg, 0.078 mmol) and lithium hydroxide monohydrate (8 mg, 0.2 mmol) , see step 6 of final product 8 for the reaction steps to obtain 8.7 mg of the target product with a yield of 32%. ¹ H NMR(500MHz,Methanol-d ₄ )δ7.93-7.79(m,4H),7.71-7.62(m,2H),7.53-7.42(m,1H),7.39(d,J=8.1Hz,1H ),7.15(t,J＝6.6Hz,1H),7.09(t,J＝7.9Hz,1H),7.02(d,J＝8.0Hz,2H),6.79(dd,J＝8.0,1.8Hz,1H) ),6.57(d,J＝1.8Hz,1H),4.40–4.29(m,2H),4.23(dd,J＝6.8,2.9Hz,1H),4.15(d,J＝15.6Hz,1H),3.54 (d, J=10.9Hz, 1H), 3.30–3.27 (m, 2H), 1.79–1.61 (m, 2H), 0.94 (s, 9H). ESI-MS Theoretical calcd for C ₃₈ H ₃₈ ³⁵ Cl ₂ FN ₄ O ₄ [M+H] ⁺ =703.22, experimentally measured: 703.3.

Final product 43: 4-((2'S,3S,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-1-(4-(hydroxymethyl)benzyl) )-2'-neopentylspiro[indoline]-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI131)

YI045 (30 mg, 0.047 mmol), 4-bromomethylbenzyl alcohol (12 mg, 0.057 mmol), potassium carbonate (20 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), see final product 8 for the reaction procedure In the sixth step, 12 mg of the target product was obtained with a yield of 35%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.21(d,J=8.4Hz,1H),7.64(dd,J=8.4,1.8Hz,1H),7.59-7.46(m,2H),7.31( dd,J＝18.4,7.4Hz,2H),7.24(d,J＝7.7Hz,2H),7.17(t,J＝8.0Hz,1H),6.94(d,J＝7.7Hz,2H),6.72( dd,J＝8.0,1.8Hz,1H),6.48(d,J＝1.9Hz,1H),5.11(d,J＝10.4Hz,1H),4.60(s,2H),4.33(d,J＝10.4 Hz,1H),4.23–4.04(m,3H),3.75(s,3H),3.54(d,J=11.0Hz,1H),3.40(d,J=10.9Hz,1H),1.70(d,J =5.0Hz, 2H), 0.94 (s, 9H). ESI-MS theoretical calculation value C ₃₉ H ₄₁ ³⁵ Cl ₂ FN ₃ O ₅ [M+H] ⁺ =720.24, experimentally found: 720.1.

Final product 44: 4-((2'S,3S,4'S,5'R)-1-(4-carboxyphenyl)-6-chloro4'-(3-chloro-2-fluorophenyl)-2'- Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI136)

YI045 (40 mg, 0.063 mmol), methyl 4-carboxylate phenylacetaldehyde (13 mg, 0.076 mmol), sodium borohydride acetate (27 mg, 0.13 mmol), 0.1 mL of acetic acid, potassium carbonate (17 mg, 0.13 mmol) and lithium hydroxide Monohydrate (13 mg, 0.32 mmol), refer to the synthesis method of the final product 20 for the reaction steps to obtain 5.6 mg of the target compound with a yield of 12%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.23(d,J=8.4Hz,1H),7.96-7.84(m,2H),7.65(dd,J=8.5,1.8Hz,1H),7.57( d, J=1.8Hz, 1H), 7.51 (t, J=7.3Hz, 1H), 7.42 (t, J=7.1Hz, 1H), 7.31–7.11 (m, 4H), 6.65 (dd, J=8.0 ,1.8Hz,1H),6.27(d,J＝1.9Hz,1H),5.09(d,J＝10.3Hz,1H),4.35(d,J＝10.4Hz,1H),4.08–3.90(m,1H ),3.78(s,3H),3.62(d,J=10.7Hz,1H),3.47-3.34(m,2H),3.23-3.06(m,1H),2.76(dt,J=7.1,4.1Hz, 2H), 1.62-1.41(m, 2H), 0.86(s, 9H). ESI-MS calculated value for C ₄₀ H ₄₁ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =748.24, found by experiment: 748.8 .

Final product 45: 4-((2'S,3S,4'S,5'R)-1-(4-aminobenzyl)-6-chloro4'-(3-chloro-2-fluorophenyl)-2'- Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI140)

YI045 (30 mg, 0.047 mmol), 4-((tert-butoxycarbonyl)amino)benzyl bromide (16 mg, 0.057 mmol), potassium carbonate (20 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol) , the reaction steps refer to step 6 of final product 8 to obtain crude product. The obtained crude product was dissolved in 5 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, stirred at room temperature for 2 h, the reaction solution was spin-dried, and purified by reverse-phase HPLC to obtain 9 mg of the target compound with a yield of 27%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.23(d,J=8.4Hz,1H),7.64(dd,J=8.4,1.8Hz,1H),7.57(d,J=1.8Hz,1H) ,7.50(t,J＝7.3Hz,1H),7.43-7.28(m,2H),7.28-7.20(m,2H),7.17(t,J＝8.0Hz,1H),7.05(d,J＝8.1 Hz, 2H), 6.73(dd, J＝8.0, 1.8Hz, 1H), 6.38(d, J＝1.8Hz, 1H), 5.08(d, J＝10.4Hz, 1H), 4.30(d, J＝10.4 Hz, 1H), 4.22(d, J＝15.7Hz, 1H), 4.14(d, J＝15.7Hz, 1H), 4.07(d, J＝8.3Hz, 1H), 3.79(s, 3H), 3.59( d, J=10.8Hz, 1H), 3.46 (d, J=10.8Hz, 1H), 1.78–1.68 (m, 1H), 1.65–1.56 (m, 1H), 0.97 (s, 9H). ESI-MS Theoretical calculated value C ₃₈ H ₄₀ ³⁵ Cl ₂ FN ₄ O ₄ [M+H] ⁺ =705.24, experimentally found: 705.1.

Final product 46: 4-((2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-6-chloro-4'-(3-chloro- 2-Fluorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI159)

YI045 (30mg, 0.047mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (12mg, 0.066mmol), sodium borohydride acetate (20mg, 0.094mmol), 0.1mL acetic acid, potassium carbonate (19mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 6.4 mg of the target compound with a yield of 18%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.22(d,J=8.4Hz,1H),7.90(d,J=8.1Hz,2H),7.64(dd,J=8.4,1.7Hz,1H) ,7.56(d,J=1.7Hz,1H),7.46(t,J=7.5Hz,1H),7.36(d,J=8.0Hz,1H),7.28(s,1H),7.15(dd,J= 8.0, 5.6Hz, 3H), 6.77(dd, J=8.1, 1.8Hz, 1H), 6.55(d, J=1.9Hz, 1H), 5.07(d, J=10.3Hz, 1H), 4.37(d, J＝15.6Hz, 1H), 4.30(d, J＝10.3Hz, 1H), 4.22–4.04(m, 2H), 3.75(s, 3H), 3.57(d, J＝10.8Hz, 1H), 3.40( d, J=10.8Hz, 1H), 1.70 (d, J=5.0Hz, 2H), 0.96 (s, 9H). ESI-MS calculated value for C ₃₉ H ₃₉ ³⁵ Cl ₂ FN ₇ O ₄ [M+H ] ⁺ =758.24, experimentally measured: 758.1.

Final product 47: 4-((2'S,3S,4'R,5'R)-1-(4-carboxybenzyl)-6-chloro4'-(4-chlorophenyl)-2'-neopenta Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI065)

Step 1: Synthesis of (Z)-2-(4-chloro-2-fluorophenyl)-3-(4-chlorophenyl)acrylonitrile (YI037)

p-Chlorobenzaldehyde (1.4g, 10mmol), 4-chloro-2-fluorobenzeneacetonitrile (1.7g, 10mmol), 3mL of methanol solution of 5N sodium methoxide, refer to step 1 of final product 8 for the reaction steps to obtain the target product 2.78g , the yield is 95%. ¹ H NMR (500MHz, Chloroform-d)δ7.85–7.78(m,2H),7.57–7.50(m,2H),7.48–7.42(m,2H),7.25–7.18(m,2H).

Step 2: Synthesis of (2R,3R,4R,5S)-4-(4-chloro-2-fluorophenyl)-3-(4-chlorophenyl)-4-cyano-5-neopentylpyrrolidine -2-Carboxylic acid tert-butyl ester (YI040)

YI037 (2.7 g, 9.1 mmol), AgF (1.16 g, 9.1 mmol), triethylamine 2.1 mL and (E)-tert-butyl 2-(((3,3-dimethylbutylene)amino)acetate ( 1.94g, 9.1mmol), refer to step 2 of final product 8 for the reaction steps to obtain the target product 1.57g, yield 34%. ¹ H NMR (500MHz, Chloroform-d) δ7.32 (t, J=8.5Hz, 1H ), 7.26–7.21 (m, 2H), 7.18 (dd, J=12.3, 2.1Hz, 1H), 7.11 (dd, J=8.7, 2.4Hz, 3H), 4.23 (d, J=7.9Hz, 1H) ,4.13(d,J＝7.8Hz,1H),4.06(dd,J＝9.2,1.2Hz,1H),1.60(ddd,J＝14.4,9.2,1.1Hz,1H),1.37(s,9H), 1.29(dd,J=14.3,1.2Hz,1H),0.89(s,9H).

Step 3: Synthesis of (2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(4-chlorophenyl)-5-neopenta Pyrrolidine-2-carboxylate tert-butyl ester (YI051)

YI040 (1.57 g, 3.1 mmol), Raney nickel 1.57 g, hydrazine hydrate 10 mL, see step 3 of final product 8 for the reaction steps to obtain 584 mg of the target product with a yield of 37%.

Step 4: Synthesis of (2R,3R,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-4-(4-chloro-2 -Fluorophenyl)-3-(4-chlorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YI054)

YI051 (584 mg, 1.15 mmol), FmocCl (385 mg, 1.49 mmol), diisopropylethylamine (592 mg, 4.6 mmol) and 4 mL of trifluoroacetic acid, see step 4 of final product 8 for the reaction steps to obtain 722 mg of the target product, Yield 95%.

Step 5: Synthesis of methyl 4-((2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(4-chlorophenyl) -5-Neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YI059)

YI054 (271 mg, 0.4 mmol), methyl 4-amino-3-methoxybenzoate (290 mg, 1.6 mmol), diphenylphosphine chloride (283 mg, 1.2 mmol), diisopropylethylamine (259 mg) , 2mmol) and piperidine 0.4mL, see step 5 of final product 8 for the reaction steps to obtain 80mg of the target product with a yield of 32%.

Step 6: Synthesis of 4-((2'S,3S,4'R,5'R)-1-(4-carboxybenzyl)-6-chloro-4'-(4-chlorophenyl)-2'-neopenta Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI065)

YI059 (24mg, 0.039mmol), methyl 4-bromomethylbenzoate (13mg, 0.054mmol), potassium carbonate (16mg, 0.117mmol) and lithium hydroxide monohydrate (8mg, 0.2mmol), see the end of the reaction procedure In the sixth step of product 8, 14.2 mg of the target product was obtained with a yield of 51%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.27(d,J=8.5Hz,1H),7.95-7.81(m,2H),7.62(dd,J=8.4,1.8Hz,1H),7.53( d,J＝1.7Hz,1H),7.35(dd,J＝8.2,3.2Hz,3H),7.16(d,J＝8.4Hz,2H),6.90(d,J＝8.0Hz,2H),6.75( dd,J＝7.9,1.8Hz,1H),6.40(d,J＝1.8Hz,1H),5.09(d,J＝11.2Hz,1H),4.26(d,J＝15.9Hz,1H),4.17( d, J=8.2Hz, 1H), 4.11 (d, J=15.9Hz, 1H), 4.01 (d, J=11.2Hz, 1H), 3.71 (s, 3H), 3.50 (d, J=10.7Hz, 1H), 3.41(d, J＝10.7Hz, 1H), 1.77-1.59(m, 2H), 0.97(s, 9H). ESI-MS calculated value for C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₃ O ₆ [M +H] ⁺ =716.23, experimentally measured: 716.5.

Final product 48: 4-((2'S,3S,4'S,5'R)-1-(4-carboxybenzyl)-6-chloro4'-(2,4-dichlorophenyl)-2'-neo Amylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI108)

Step 1: Synthesis of ((Z)-2-(4-chloro-2-fluorophenyl)-3-(2,4-dichlorophenyl)acrylonitrile (YI090)

2,4-Dichlorobenzaldehyde (3.5g, 20mmol), 4-chloro-2-fluorophenylacetonitrile (3.4g, 20mmol), 4.8mL of 5N methanol solution of sodium methoxide, see step 1 of final product 8 for reaction steps, The target product was obtained in 6.2 g with a yield of 95%. ¹ H NMR (500MHz, Chloroform-d) δ8.06 (dd, J=8.6, 0.6Hz, 1H), 7.87 (d, J=0.7Hz, 1H), 7.56 (t, J=8.3Hz, 1H), 7.51(d,J=2.1Hz,1H),7.39(dd,J=8.5,2.1Hz,1H),7.30–7.18(m,2H).

Step 2: Synthesis of (2R,3R,4R,5S)-4-(4-chloro-2-fluorophenyl)-3-(2,4-dichlorophenyl)-4-cyano-5-neopenta tert-butyl pyrrolidine-2-carboxylate (YI095-1)

YI090 (6.2g, 19mmol), AgF (2.54g, 20mmol), triethylamine 4.5mL and (E)-tert-butyl 2-(((3,3-dimethylbutylene)amino)acetate (4.26g) , 20mmol), refer to step 2 of final product 8 for the reaction steps to obtain the target product 3.64g with a yield of 35%. ¹ H NMR (500MHz, Chloroform-d) δ7.73 (d, J=8.5Hz, 1H), 7.38 –7.30(m, 2H), 7.25(d, J=2.2Hz, 1H), 7.16–7.05(m, 2H), 4.87(d, J=6.5Hz, 1H), 4.10(d, J=8.9Hz, 1H), 4.01(d, J＝6.5Hz, 1H), 1.64(ddd, J＝14.4, 9.0, 1.2Hz, 1H), 1.42(s, 9H), 1.29(dd, J＝14.4, 1.1Hz, 1H) ),0.91(s,9H).

Step 3: Synthesis of (2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(2,4-dichlorophenyl)-5 - Neopentylpyrrolidine-2-carboxylate tert-butyl ester (YI095-2)

YI095-1 (3.64 g, 6.7 mmol), Raney nickel 6 g, hydrazine hydrate 10 mL, see step 3 of final product 8 for the reaction steps to obtain 470 mg of the target product with a yield of 13%. ¹ H NMR(500MHz, Chloroform-d)δ7.98-7.86(m,1H),7.28-7.23(m,2H),7.12-7.01(m,2H),6.96(dd,J=12.9,2.2Hz, 1H), 4.29(d, J＝9.1Hz, 1H), 4.23(dd, J＝8.4, 2.4Hz, 1H), 4.01(d, J＝9.1Hz, 1H), 3.29(d, J＝1.4Hz, 2H), 1.59–1.46(m, 2H), 1.27(s, 9H), 0.99(s, 9H).

Step 4: Synthesis of (2R,3R,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-4-(4-chloro-2 -Fluorophenyl)-3-(2,4-dichlorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YI099)

YI095-2 (470 mg, 0.86 mmol), FmocCl (334 mg, 1.39 mmol), diisopropylethylamine (444 mg, 3.4 mmol) and trifluoroacetic acid 4 mL, refer to step 4 of final product 8 for the reaction steps to obtain the target product 496 mg, 81% yield.

Step 5: Synthesis of methyl 4-((2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(2,4-dichloro Phenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YI104)

YI099 (284mg, 0.4mmol), methyl 4-amino-3-methoxybenzoate (290mg, 1.6mmol), diphenylphosphine chloride (283mg, 1.2mmol), diisopropylethylamine (259mg , 2mmol) and piperidine 0.4mL, see step 5 of final product 8 for the reaction steps to obtain 50mg of the target product with a yield of 19%.

Step 6: Synthesis of 4-((2'S,3S,4'S,5'R)-1-(4-carboxybenzyl)-6-chloro-4'-(2,4-dichlorophenyl)-2'-new Amylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI108)

YI104 (50mg, 0.077mmol), methyl 4-bromomethylbenzoate (21mg, 0.092mmol), potassium carbonate (21mg, 0.154mmol) and lithium hydroxide monohydrate (16mg, 0.39mmol), see the end of the reaction procedure In the sixth step of product 8, 19.2 mg of the target product was obtained with a yield of 33%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.18(d,J=8.4Hz,1H),7.94(d,J=8.1Hz,2H),7.69-7.59(m,2H),7.54(d, J=1.8Hz, 1H), 7.47 (d, J=2.2Hz, 1H), 7.37–7.23 (m, 2H), 6.99 (d, J=8.0Hz, 2H), 6.72 (dd, J=8.0, 1.8 Hz,1H),6.42(d,J＝1.8Hz,1H),5.05(d,J＝10.2Hz,1H),4.59(d,J＝10.2Hz,1H),4.34(d,J＝8.5Hz, 1H), 4.27(d, J＝15.6Hz, 1H), 4.06(d, J＝15.5Hz, 1H), 3.73(s, 3H), 3.59(d, J＝10.9Hz, 1H), 3.51(d, J=10.9Hz, 1H), 1.81-1.57(m, 2H), 0.99(s, 9H). ESI-MS calculated value C ₃₉ H ₃₉ ³⁵ Cl ₃ N ₃ O ₆ [M+H] ⁺ =750.19, Experimentally measured: 749.7.

Final product 49: 4-((2'S,3S,4'S,5'R)-1-(4-carboxybenzyl)-6-chloro-4'-(2-chlorophenyl)-2'-neopentyl Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI109)

Step 1: Synthesis of (Z)-2-(4-chloro-2-fluorophenyl)-3-(2-chlorophenyl)acrylonitrile (YI091)

2-Chlorobenzaldehyde (2.82g, 20mmol), 4-chloro-2-fluorophenylacetonitrile (3.4g, 20mmol), 4.8mL of 5N methanol solution of sodium methoxide, refer to step 1 of final product 8 for reaction steps to obtain the target product 5.46 g, 93% yield. ¹ H NMR(500MHz, Chloroform-d)δ8.11(dd,J=5.5,3.8Hz,1H),7.94(s,1H),7.57(t,J=8.3Hz,1H),7.52-7.46(m ,1H),7.44–7.37(m,2H),7.29–7.20(m,2H).

Step 2: Synthesis of (2R,3R,4R,5S)-4-(4-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-4-cyano-5-neopentylpyrrolidine -2-Carboxylic acid tert-butyl ester (YI097-1)

YI091 (5.46 g, 18.6 mmol), AgF (2.36 g, 18.6 mmol), triethylamine 4 mL and (E)-tert-butyl 2-(((3,3-dimethylbutylene)amino)acetate (3.97 g g, 18.6 mmol), refer to step 2 of final product 8 for the reaction steps to obtain the target product 4 g with a yield of 43%. ¹ H NMR (500 MHz, Chloroform-d) δ7.80 (dd, J=8.1, 1.4 Hz, 1H ),7.37(ddd,J=8.2,6.8,1.8Hz,1H),7.32(t,J=8.5Hz,1H),7.25–7.16(m,2H),7.12(dd,J=12.2,2.1Hz, 1H), 7.09–7.03 (m, 1H), 4.92 (d, J=6.7Hz, 1H), 4.18–4.10 (m, 1H), 4.08 (d, J=6.7Hz, 1H), 1.72–1.57 (m ,1H),1.40(s,9H),1.30(dd,J=14.4,1.1Hz,1H),0.92(s,9H).

Step 3: Synthesis of (2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopenta Pyrrolidine-2-carboxylate tert-butyl ester (YI097-2)

YI097-1 (4 g, 7.91 mmol), Raney nickel 4 g, hydrazine hydrate 10 mL, refer to step 3 of final product 8 for the reaction steps to obtain 1 g of the target product with a yield of 24%. ¹ H NMR (500MHz, Chloroform-d) δ 7.80 (dd, J=7.9, 1.6 Hz, 1H), 7.31-7.20 (m, 2H), 7.17-7.10 (m, 2H), 7.05 (dd, J= 8.6,2.3Hz,1H),6.95(dd,J＝12.8,2.2Hz,1H),4.33(d,J＝8.9Hz,1H),4.19(dd,J＝9.6,1.2Hz,1H),4.03( d,J＝8.9Hz,1H),3.35(dd,J＝9.7,1.6Hz,2H),1.57(dd,J＝13.8,1.3Hz,1H),1.51(d,J＝9.7Hz,1H), 1.25(s, 9H), 1.01(s, 9H).

Step 4: Synthesis of (2R,3R,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-4-(4-chloro-2 -Fluorophenyl)-3-(2-chlorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YI100)

YI097-2 (980 mg, 1.93 mmol), FmocCl (745 mg, 2.89 mmol), diisopropylethylamine (996 mg, 7.72 mmol) and trifluoroacetic acid 4 mL, refer to step 4 of final product 8 for the reaction steps to obtain the target product 1.12 g, 86% yield.

Step 5: Synthesis of methyl 4-((2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(2-chlorophenyl) -5-Neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YI105)

YI100 (270mg, 0.4mmol), methyl 4-amino-3-methoxybenzoate (290mg, 1.6mmol), diphenylphosphine chloride (283mg, 1.2mmol), diisopropylethylamine (259mg , 2mmol) and piperidine 0.4mL, the reaction steps refer to step 5 of the final product 8, to obtain 67mg of the target product with a yield of 27%.

Step 6: Synthesis of 4-((2'S,3S,4'S,5'R)-1-(4-carboxybenzyl)-6-chloro-4'-(2-chlorophenyl)-2'-neopentyl Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI109)

YI105 (67mg, 0.11mmol), methyl 4-bromomethylbenzoate (29mg, 0.13mmol), potassium carbonate (30mg, 0.22mmol) and lithium hydroxide monohydrate (23mg, 0.55mmol), see the end of the reaction procedure The sixth step of product 8, 43 mg of the target product was obtained, and the yield was 54%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.19(d,J=8.4Hz,1H),7.87(d,J=8.2Hz,2H),7.67(dd,J=7.0,2.1Hz,1H) ,7.62(dd,J=8.4,1.7Hz,1H),7.51(d,J=1.8Hz,1H),7.45–7.32(m,4H),6.96(d,J=8.0Hz,2H),6.71( dd,J＝8.1,1.9Hz,1H),6.38(d,J＝1.8Hz,1H),5.15(d,J＝10.4Hz,1H),4.71(d,J＝10.4Hz,1H),4.33( d, J=8.5Hz, 1H), 4.22 (d, J=15.6Hz, 1H), 4.09 (d, J=15.6Hz, 1H), 3.70–3.61 (m, 5H), 3.54 (d, J=10.9 Hz, 1H), 1.78 (d, J=8.7 Hz, 1H), 1.66 (d, J=15.2 Hz, 1H), 0.97 (s, 9H). ESI-MS calculated value for C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₃ O ₆ [M+H] ⁺ =716.23, experimentally found: 716.2.

Final product 50: 4-((2'S,3S,4'R,5'R)-1-(4-carboxybenzyl)-6-chloro4'-(3,4-dichlorophenyl)-2' -Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI132)

Step 1: Synthesis of (Z)-2-(4-chloro-2-fluorophenyl)-3-(3,4-dichlorophenyl)acrylonitrile (YI115)

3,4-Dichlorobenzaldehyde (3.5g, 20mmol), 4-chloro-2-fluorophenylacetonitrile (3.4g, 20mmol), 4.8mL of 5N methanol solution of sodium methoxide, see step 1 of final product 8 for reaction steps, The target product 6g was obtained with a yield of 92%. ¹ H NMR (500MHz, Chloroform-d)δ7.89(d,J=2.1Hz,1H),7.82-7.77(m,1H),7.60-7.51(m,2H),7.49(s,1H),7.28 –7.19(m,2H).

Step 2: Synthesis of (2R,3R,4R,5S)-4-(4-chloro-2-fluorophenyl)-3-(3,4-dichlorophenyl)-4-cyano-5-neopenta tert-butyl pyrrolidine-2-carboxylate (YI120-1)

YI115 (6g, 18.4mmol), AgF (2.34g, 18.4mmol), triethylamine 4mL and (E)-tert-butyl 2-(((3,3-dimethylbutylene)amino)acetate (3.92g) , 18.4mmol), refer to step 2 of final product 8 for the reaction steps to obtain the target product 3.4g with a yield of 34%. ¹ H NMR (500MHz, Chloroform-d) δ7.35 (d, J=3.4Hz, 1H), 7.34(d,J＝3.5Hz,1H),7.27(d,J＝2.3Hz,1H),7.19(dd,J＝12.3,2.1Hz,1H),7.17–7.11(m,1H),7.04(dd , J=8.4, 2.2Hz, 1H), 4.18 (d, J=7.5Hz, 1H), 4.12 (dd, J=7.6, 1.2Hz, 1H), 4.02 (dd, J=9.2, 1.2Hz, 1H) ,1.60(ddd,J＝14.4,9.1,1.1Hz,1H),1.40(s,9H),1.28(dd,J＝14.3,1.3Hz,1H),0.89(s,9H).

Step 3: Synthesis of (2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(3,4-dichlorophenyl)-5 - Neopentylpyrrolidine-2-carboxylate tert-butyl ester (YI120-2)

YI120-1 (3.4 g, 6,3 mmol), Raney nickel 3.4 g, hydrazine hydrate 10 mL, see step 3 of final product 8 for the reaction steps to obtain 720 mg of the target product with a yield of 21%. ¹ H NMR(500MHz, Chloroform-d)δ7.39(d,J=2.1Hz,1H),7.27(d,J=7.4Hz,1H),7.13-7.02(m,3H),6.98-6.91(m ,1H),4.26(d,J＝8.9Hz,1H),4.17–4.08(m,1H),3.83(dd,J＝8.8,2.2Hz,1H),3.24(d,J＝12.9Hz,1H) ,3.01(d,J=13.0Hz,1H),1.52–1.35(m,2H),1.31(s,9H),0.91(s,9H).

Step 4: Synthesis of (2R,3R,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-4-(4-chloro-2 -Fluorophenyl)-3-(3,4-dichlorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YI125)

YI120-2 (720 mg, 1.32 mmol), FmocCl (512 mg, 1.98 mmol), diisopropylethylamine (681 mg, 5.28 mmol) and 4 mL of trifluoroacetic acid, see step 4 of final product 8 for the reaction steps to obtain the target product 838 g, 89% yield.

Step 5: Synthesis of methyl 4-((2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(3,4-dichloro Phenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YI128)

YI125 (284mg, 0.4mmol), methyl 4-amino-3-methoxybenzoate (290mg, 1.6mmol), diphenylphosphine chloride (283mg, 1.2mmol), diisopropylethylamine (259mg , 2mmol) and piperidine 0.4mL, see step 5 of final product 8 for the reaction steps to obtain 26mg of the target product with a yield of 10%.

Step 6: Synthesis of 4-((2'S,3S,4'R,5'R)-1-(4-carboxybenzyl)-6-chloro-4'-(3,4-dichlorophenyl)-2' -Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI132)

YI128 (see YI003 for synthesis procedure, 26 mg, 0.04 mmol), methyl 4-bromomethylbenzoate (11 mg, 0.048 mmol), potassium carbonate (11 mg, 0.08 mmol) and lithium hydroxide monohydrate (9 mg, 0.2 mmol) , and the reaction steps refer to step 6 of final product 8 to obtain 9.3 mg of the target product with a yield of 31%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.28(d,J=8.4Hz,1H),7.97-7.84(m,2H),7.62(dd,J=8.5,1.8Hz,1H),7.55( d, J=1.8Hz, 1H), 7.42 (d, J=8.4Hz, 1H), 7.39–7.26 (m, 2H), 7.00 (dd, J=8.4, 2.2Hz, 1H), 6.93 (d, J =8.1Hz,2H),6.77(dd,J=8.0,1.8Hz,1H),6.46(d,J=1.8Hz,1H),4.97(d,J=10.7Hz,1H),4.31(d,J =15.7Hz,1H),4.16–4.02(m,2H),3.96(d,J=10.9Hz,1H),3.77(s,3H),3.47(d,J=10.7Hz,1H),3.34(d , 1H), 1.80–1.50(m, 2H), 0.99(s, 9H). ESI-MS theoretical calculation value C ₃₉ H ₃₉ ³⁵ Cl ₃ N ₃ O ₆ [M+H] ⁺ =750.19, experimentally measured: 749.7.

Final product 51: 4-((2'S,3S,4'S,5'R)-1-(4-carboxybenzyl)-6-chloro4'-(2,3-dichlorophenyl)-2'-neo Amylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI133)

Step 1: Synthesis of (Z)-2-(4-chloro-2-fluorophenyl)-3-(2,3-dichlorophenyl)acrylonitrile (YI116)

2,3-Dichlorobenzaldehyde (3.5g, 20mmol), 4-chloro-2-fluorophenylacetonitrile (3.4g, 20mmol), 4.8mL of 5N methanol solution of sodium methoxide, see step 1 of final product 8 for reaction steps, The target product 6.23g was obtained with a yield of 95%. ¹ H NMR (500MHz, Chloroform-d)δ7.98-7.89(m,2H),7.62-7.54(m,2H),7.39-7.32(m,1H),7.28(dd,J=2.1,0.9Hz, 1H), 7.23(d, J=2.1Hz, 1H).

Step 2: Synthesis of (2R,3R,4R,5S)-4-(4-chloro-2-fluorophenyl)-3-(2,3-dichlorophenyl)-4-cyano-5-neopenta tert-butyl pyrrolidine-2-carboxylate (YI124-1)

YI116 (6.23 g, 19 mmol), AgF (2.41 g, 19 mmol), triethylamine 4.24 mL and (E)-tert-butyl 2-(((3,3-dimethylbutylene)amino)acetate (4 g, 19mmol), refer to step 2 of the final product 8 for the reaction steps to obtain the target product 4.57g with a yield of 45%. ¹ H NMR (500MHz, Chloroform-d) δ7.72 (dd, J=7.9, 1.6Hz, 1H), 7.39 (dd, J=8.0, 1.6Hz, 1H), 7.38–7.29 (m, 2H), 7.14 (dd, J=12.3, 2.1Hz, 1H), 7.12–7.08 (m, 1H), 5.02 (d, J=6.4Hz, 1H), 4.09(d, J=8.9Hz, 1H), 4.03(d, J=6.3Hz, 1H), 1.74–1.61(m, 1H), 1.42(s, 9H), 1.29( dd,J=14.3,1.0Hz,1H),0.91(s,9H).

Step 3: Synthesis of (2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(2,3-dichlorophenyl)-5 - Neopentylpyrrolidine-2-carboxylate tert-butyl ester (YI124-2)

YI124-1 (4.57 g, 8.5 mmol), Raney nickel 4.5 g, hydrazine hydrate 10 mL, see step 3 of final product 8 for the reaction steps to obtain the target product 1.04 g with a yield of 23%. ¹ H NMR (500MHz, Chloroform-d) δ 7.87 (dd, J=7.9, 1.6 Hz, 1H), 7.34 (dd, J=7.9, 1.4 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H) ),7.11(t,J＝8.6Hz,1H),7.05(dd,J＝8.7,2.2Hz,1H),6.97(dd,J＝12.9,2.2Hz,1H),4.44(d,J＝8.9Hz ,1H),4.20(dd,J＝9.1,1.8Hz,1H),4.01(d,J＝8.9Hz,1H),3.32(d,J＝1.5Hz,2H),1.60–1.47(m,2H) ,1.26(s,9H),1.00(s,9H).

Step 4: Synthesis of (2R,3R,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-4-(4-chloro-2 -Fluorophenyl)-3-(2,3-dichlorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YI126)

YI124-2 (1.04g, 1.91mmol), FmocCl (740mg, 2.87mmol), diisopropylethylamine (986mg, 7.62mmol) and trifluoroacetic acid 4mL, see step 4 of final product 8 for the reaction steps to obtain the target Product 1.08 g, 80% yield.

Step 5: Synthesis of methyl 4-((2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(2,3-dichloro Phenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YI129)

YI126 (284mg, 0.4mmol), methyl 4-amino-3-methoxybenzoate (290mg, 1.6mmol), diphenylphosphine chloride (283mg, 1.2mmol), diisopropylethylamine (259mg , 2mmol) and piperidine 0.4mL, see step 5 of final product 8 for the reaction steps, to obtain 46mg of the target product with a yield of 18%.

Step 6: Synthesis of 4-((2'S,3S,4'S,5'R)-1-(4-carboxybenzyl)-6-chloro-4'-(2,3-dichlorophenyl)-2'-new Amylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI133)

YI129 (46mg, 0.07mmol), methyl 4-bromomethylbenzoate (19mg, 0.085mmol), potassium carbonate (19mg, 0.14mmol) and lithium hydroxide monohydrate (15mg, 0.35mmol), see the end of the reaction procedure The sixth step of product 8, 18 mg of the target product was obtained, and the yield was 34%. ¹ H NMR(500MHz, Methanol-d ₄ )δ8.20(d,J=8.4Hz,1H),7.99-7.84(m,2H),7.64(dd,J=8.4,1.7Hz,1H),7.59- 7.47 (m, 3H), 7.40–7.25 (m, 2H), 6.99 (d, J=8.0Hz, 2H), 6.72 (dd, J=8.1, 1.8Hz, 1H), 6.43 (d, J=1.8Hz) ,1H),4.98–4.92(m,1H),4.72(d,J=9.6Hz,1H),4.25(d,J=15.6Hz,1H),4.19(s,1H),4.08(d,J= 15.5Hz, 1H), 3.75(s, 3H), 3.50(d, J=5.2Hz, 2H), 1.77–1.54(m, 2H), 0.98(s, 9H). ESI-MS calculated value C ₃₉ H ₃₉ ³⁵ Cl ₃ N ₃ O ₆ [M+H] ⁺ =750.19, found by experiment: 749.8.

Final product 52: 4-((2'S,3S,4'S,5'R)-1-(4-carboxybenzyl)-5-chloro-4'-(3-chloro-2-fluorophenyl)-2' -Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI138)

Step 1: Synthesis of ((Z)-3-(3-chloro-2-fluorophenyl)-2-(5-chloro-2-fluorophenyl)acrylonitrile (YI127)

3-Chloro-2-fluorobenzaldehyde (3.16g, 20mmol), 5-chloro-2-fluorobenzeneacetonitrile (3.4g, 20mmol), 4.8mL of 5N methanol solution of sodium methoxide, see step 1 of final product 8 for reaction steps , the target product 5.66g was obtained with a yield of 92%. ¹ H NMR (500MHz, Chloroform-d)δ8.18-8.10(m,1H),7.80(s,1H),7.59(dd,J=6.6,2.6Hz,1H),7.56-7.48(m,1H) ,7.42–7.34(m,1H),7.23(dd,J=8.1,1.3Hz,1H),7.15(dd,J=10.5,8.8Hz,1H).

Step 2: Synthesis of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(5-chloro-2-fluorophenyl)-4-cyano-5-new Amylpyrrolidine-2-carboxylate tert-butyl ester (YI130-1)

YI127 (5.66 g, 18.3 mmol), AgF (2.3 g, 18.3 mmol), triethylamine 4 mL and (E)-tert-butyl 2-(((3,3-dimethylbutylene)amino)acetate (3.9 g, 18.3 mmol), refer to step 2 of final product 8 for the reaction steps, to obtain the target product 4.48 g with a yield of 47%. ¹ H NMR (500 MHz, Chloroform-d) δ 7.66–7.58 (m, 1H), 7.42 ( dd, J=6.7, 2.6Hz, 1H), 7.37–7.27 (m, 2H), 7.20–7.12 (m, 1H), 7.07 (dt, J=12.1, 8.8Hz, 1H), 4.73 (dd, J= 7.4, 2.1Hz, 1H), 4.14 (d, J=7.4Hz, 1H), 4.11–4.02 (m, 1H), 1.63 (ddd, J=14.4, 9.1, 1.3Hz, 1H), 1.39 (s, 9H) ),1.31(dd,J=14.4,1.3Hz,1H),0.90(s,9H).

Step 3: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(5-chloro-2-fluorophenyl)- 5-Nopentylpyrrolidine-2-carboxylate tert-butyl ester (YI130-2)

YI130-1 (4.48 g, 8.57 mmol), Raney nickel 4.5 g, hydrazine hydrate 10 mL, see step 3 of final product 8 for the reaction steps to obtain 1.42 g of the target product with a yield of 32%. ¹ H NMR (500MHz, Chloroform-d) δ 7.71 (ddd, J=7.9, 6.2, 1.6 Hz, 1H), 7.29-7.21 (m, 1H), 7.22-7.11 (m, 2H), 7.06 (td, J=7.9, 1.1Hz, 1H), 6.92 (dd, J=12.7, 8.7Hz, 1H), 4.21–4.13 (m, 3H), 3.32 (dd, J=13.1, 1.6Hz, 1H), 3.21 (d , J=13.1Hz, 1H), 1.58–1.43(m, 2H), 1.27(s, 9H), 0.98(s, 9H).

Step 4: Synthesis of (2R,3S,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-3-(3-chloro-2 -Fluorophenyl)-4-(5-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YI134)

YI130-2 (1.4g, 2.66mmol), FmocCl (1.03g, 4mmol), diisopropylethylamine (1.37g, 10.67mmol) and trifluoroacetic acid 4mL, see step 4 of final product 8 for the reaction steps, to obtain The target product was 1.24 g, and the yield was 67%.

Step 5: Synthesis of methyl 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(5-chloro-2- Fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YI137)

YI134 (280mg, 0.4mmol), methyl 4-amino-3-methoxybenzoate (290mg, 1.6mmol), diphenylphosphine chloride (283mg, 1.2mmol), diisopropylethylamine (259mg , 2mmol) and piperidine 0.4mL, see step 5 of final product 8 for the reaction steps to obtain 41mg of the target product with a yield of 16%.

Step 6: Synthesis of 4-((2'S,3S,4'S,5'R)-1-(4-carboxybenzyl)-5-chloro-4'-(3-chloro-2-fluorophenyl)-2' -Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI138)

YI137 (41 mg, 0.065 mmol), methyl 4-bromomethylbenzoate (18 mg, 0.077 mmol), potassium carbonate (18 mg, 0.13 mmol) and lithium hydroxide monohydrate (14 mg, 0.33 mmol), see the end of the reaction procedure The sixth step of product 8, 21 mg of the target product was obtained, and the yield was 44%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.22(d,J=8.4Hz,1H),7.88(d,J=8.0Hz,2H),7.64(dd,J=8.4,1.8Hz,1H) ,7.56(d,J＝1.8Hz,1H),7.50(t,J＝7.5Hz,1H),7.44(d,J＝2.0Hz,1H),7.30(t,J＝7.1Hz,1H),7.21 –7.08(m, 2H), 7.03(d, J=8.0Hz, 2H), 6.49(d, J=8.5Hz, 1H), 5.08(d, J=10.4Hz, 1H), 4.42–4.22(m, 2H), 4.13(d, J＝15.5Hz, 2H), 3.76(s, 3H), 3.52(d, J＝10.8Hz, 1H), 3.35(d, J＝10.8Hz, 1H), 1.70(d, J=5.0Hz, 2H), 0.95 (s, 9H). ESI-MS theoretical calculation value C ₃₉ H ₃₉ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =734.22, experimentally found: 734.7.

Final product 53: 4-((2'S,3S,4'S,5'R)-1-((((1r,4S)-4-carboxycyclohexyl)methyl)-5-chloro-4'-(3- Chloro-2-fluorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI154)

YI137 (22 mg, 0.035 mmol), methyl trans-4-formylcyclohexane-1-carboxylate (8 mg, 0.049 mmol), sodium borohydride acetate (15 mg, 0.07 mmol), 0.1 mL of acetic acid, potassium carbonate (15 mg , 0.11 mmol) and lithium hydroxide monohydrate (8 mg, 0.18 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 6.5 mg of the target compound with a yield of 25%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.25(d,J=8.4Hz,1H),7.65(dd,J=8.4,1.8Hz,1H),7.59(d,J=1.8Hz,1H) ,7.47(t,J＝7.6Hz,1H),7.40(t,J＝7.0Hz,1H),7.33(d,J＝2.1Hz,1H),7.22(t,J＝7.9Hz,1H),7.05 (dd,J＝8.4,2.1Hz,1H),6.32(d,J＝8.5Hz,1H),5.06(s,1H),4.26(d,J＝10.2Hz,1H),4.04(s,1H) ,3.81(s,3H),3.53(d,J＝10.7Hz,1H),3.42(d,J＝10.7Hz,1H),2.72(tt,J＝13.8,7.3Hz,2H),2.17(td, J=11.9, 5.9Hz, 1H), 2.01–1.78 (m, 2H), 1.67 (d, J=9.8Hz, 3H), 1.46–1.10 (m, 4H), 1.05–0.67 (m, 11H).ESI -MS calculated value for C ₃₉ H ₄₅ ³⁵ Cl ₂ FN ₃ O ₆ [M+H] ⁺ =740.27, experimentally found: 740.0.

Final product 54: 4-((2'S,3S,4'R,5'R)-1-(4-carboxybenzyl)-5-chloro-4'-(3-chlorophenyl)-2'-neo Amylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK011)

Step 1: Synthesis of ((Z)-3-(3-chlorophenyl)-2-(5-chloro-2-fluorophenyl)acrylonitrile (YI153)

m-chlorobenzaldehyde (2.81g, 20mmol), 5-chloro-2-fluorobenzeneacetonitrile (3.4g, 20mmol), 4.8mL of 5N methanol solution of sodium methoxide, refer to step 1 of final product 8 for reaction steps to obtain target product 5.5 g, 94% yield. ¹ H NMR (500MHz, Chloroform-d)δ7.87-7.81(m,1H),7.81-7.74(m,1H),7.57(dd,J=6.7,2.6Hz,1H),7.53(s,1H) ,7.49–7.39(m,2H),7.35(ddd,J=8.8,4.2,2.6Hz,1H),7.13(dd,J=10.5,8.8Hz,1H).

Step 2: Synthesis of (2R,3S,4R,5S)-3-(3-chlorophenyl)-4-(5-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine -2-Carboxylic acid tert-butyl ester (YI155)

YI153 (4.72g, 16mmol), AgF (2g, 16mmol), triethylamine 3.5mL and (E)-tert-butyl 2-(((3,3-dimethylbutylene)amino)acetate (3.4g, 16mmol), refer to step 2 of final product 8 for the reaction steps to obtain the target product 1.79g with a yield of 22%. ¹ H NMR (500MHz, Chloroform-d) δ 7.41 (dd, J=6.7, 2.6Hz, 1H), 7.33 (ddd, J=8.7, 4.2, 2.6Hz, 1H), 7.28–7.19 (m, 2H), 7.16 (d, J=2.0Hz, 1H), 7.14–7.05 (m, 2H), 4.23 (d, J=7.7Hz, 1H), 4.17 (dd, J=7.7, 1.3Hz, 1H), 4.08–3.97 (m, 1H), 1.67–1.55 (m, 1H), 1.38 (s, 9H), 1.31 (dd ,J=14.4,1.2Hz,1H),0.89(s,9H).

Step 3: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chlorophenyl)-4-(5-chloro-2-fluorophenyl)-5-neopenta Pyrrolidine-2-carboxylate tert-butyl ester (YK001)

YI155 (1.79 g, 3.5 mmol), Raney nickel 1.8 g, hydrazine hydrate 10 mL, see step 3 of final product 8 for the reaction steps to obtain 372 mg of the target product with a yield of 21%. ¹ H NMR(500MHz, Chloroform-d)δ7.24-7.05(m,5H),6.99-6.88(m,2H),4.24(d,J=8.9Hz,1H),4.15-4.03(m,1H) ,3.80(dd,J＝8.9,2.0Hz,1H),3.24(d,J＝13.2Hz,1H),3.06(d,J＝13.2Hz,1H),1.51–1.39(m,2H),1.26( s,9H),0.91(s,9H).

Step 4: Synthesis of (2R,3S,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-3-(3-chlorophenyl )-4-(5-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YK002)

YK001 (372 mg, 0.73 mmol), FmocCl (283 mg, 1.1 mmol), diisopropylethylamine (377 mg, 2.9 mmol) and 4 mL of trifluoroacetic acid, refer to step 4 of final product 8 for the reaction steps to obtain 383 mg of the target product, Yield 78%.

Step 5: Synthesis of methyl 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chlorophenyl)-4-(5-chloro-2-fluorophenyl) -5-Neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YK009)

YK002 (383mg, 0.57mmol), methyl 4-amino-3-methoxybenzoate (410mg, 2.3mmol), diphenylphosphine chloride (404mg, 1.7mmol), diisopropylethylamine (368mg , 2.85 mmol) and piperidine 0.4 mL, see step 5 of final product 8 for the reaction steps to obtain 49 mg of the target product with a yield of 14%.

Step 6: Synthesis of 4-((2'S,3S,4'R,5'R)-1-(4-carboxybenzyl)-5-chloro-4'-(3-chlorophenyl)-2'-new Amylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK011)

YK009 (49mg, 0.079mmol), methyl 4-bromomethylbenzoate (22mg, 0.095mmol), potassium carbonate (33mg, 0.24mmol) and lithium hydroxide monohydrate (17mg, 0.4mmol), see the end of the reaction procedure The sixth step of product 8, 14 mg of the target product was obtained, and the yield was 25%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.28(d,J=8.4Hz,1H),7.88(d,J=8.1Hz,2H),7.63(dd,J=8.4,1.8Hz,1H) ,7.54(d,J＝1.8Hz,1H),7.46(d,J＝2.1Hz,1H),7.42(dd,J＝7.9,2.0Hz,1H),7.33–7.21(m,2H),7.12( dd,J＝8.4,2.1Hz,1H),7.04(d,J＝7.7Hz,1H),6.93(d,J＝7.9Hz,2H),6.43(d,J＝8.5Hz,1H),5.07( d, J=11.1Hz, 1H), 4.28 (d, J=15.7Hz, 1H), 4.16 (d, J=7.8Hz, 1H), 4.11–3.96 (m, 2H), 3.75 (s, 3H), 3.45(d,J＝10.6Hz,1H),3.35(d,J＝10.7Hz,1H),1.80–1.53(m,2H),0.98(s,9H).ESI-MS calculated value C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₃ O ₆ [M+H] ⁺ =716.23, found by experiment: 715.3.

Final product 55: 4-((2'S,3S,4'R,5'R)-1-(4-carboxybenzyl)-5-chloro-4'-(4-chlorophenyl)-2'-neo Amylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK018)

Step 1: Synthesis of ((Z)-3-(4-chlorophenyl)-2-(5-chloro-2-fluorophenyl)acrylonitrile (YK003)

4-Chlorobenzaldehyde (2.81g, 20mmol), 5-chloro-2-fluorobenzeneacetonitrile (3.4g, 20mmol), 4.8mL of 5N methanol solution of sodium methoxide, see step 1 of final product 8 for the reaction steps to obtain the target product 5.5g, 95% yield. ¹ H NMR(500MHz, Chloroform-d)δ7.87-7.78(m,2H),7.61-7.49(m,2H),7.49-7.41(m,2H),7.34(ddd,J=8.9,4.2,2.6 Hz,1H),7.12(dd,J=10.5,8.7Hz,1H).

Step 2: Synthesis of (2R,3S,4R,5S)-3-(4-chlorophenyl)-4-(5-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine -2-Carboxylic acid tert-butyl ester (YK007-1)

YK003 (5.5 g, 18.8 mmol), AgF (2.4 g, 18.8 mmol), triethylamine 4 mL and (E)-tert-butyl 2-(((3,3-dimethylbutylene)amino)acetate (4.14 g, 18.8 mmol), refer to step 2 of final product 8 for the reaction steps to obtain the target product 3.36 g with a yield of 35%. ¹ H NMR (500 MHz, Chloroform-d) δ 7.39 (dd, J=6.7, 2.6 Hz, 1H), 7.32 (ddd, J=8.8, 4.2, 2.6Hz, 1H), 7.25–7.20 (m, 2H), 7.16–7.04 (m, 3H), 4.22 (d, J=7.8Hz, 1H), 4.18 (dd,J＝7.8,1.2Hz,1H),4.05(dd,J＝9.2,1.2Hz,1H),1.61(ddd,J＝14.4,9.1,1.1Hz,1H),1.37(s,9H), 1.30(dd,J＝14.3,1.2Hz,1H),0.89(d,J＝2.0Hz,9H).

Step 3: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-3-(4-chlorophenyl)-4-(5-chloro-2-fluorophenyl)-5-neopenta Pyrrolidine-2-carboxylate tert-butyl ester (YK007-2)

YK007-1 (3.36 g, 6.7 mmol), Raney nickel 3 g, hydrazine hydrate 10 mL, see step 3 of final product 8 for the reaction steps to obtain 1.19 g of the target product with a yield of 35%. ¹ H NMR (500MHz, Chloroform-d) δ 7.24-7.18 (m, 3H), 7.16 (dd, J=7.0, 2.6Hz, 1H), 7.13-7.05 (m, 2H), 6.95 (dd, J= 12.7, 8.7Hz, 1H), 4.26 (d, J=9.0Hz, 1H), 4.11 (dd, J=6.1, 4.5Hz, 1H), 3.82 (dd, J=9.1, 1.9Hz, 1H), 3.24 ( dd,J=13.1,1.3Hz,1H),3.07(d,J=13.1Hz,1H),1.51–1.38(m,2H),1.29(s,9H),0.94(s,9H).

Step 4: Synthesis of (2R,3S,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-3-(4-chlorophenyl )-4-(5-Chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YK012)

YK007-2 (1.19 g, 2.34 mmol), FmocCl (900 mg, 3.5 mmol), diisopropylethylamine (1.2 g, 9.4 mmol) and 4 mL of trifluoroacetic acid, refer to step 4 of final product 8 for the reaction steps, to obtain The target product was 1.11 g, and the yield was 70%.

Step 5: Synthesis of methyl 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(4-chlorophenyl)-4-(5-chloro-2-fluorophenyl) -5-Neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YK016)

YK012 (383 mg, 0.57 mmol), methyl 4-amino-3-methoxybenzoate (410 mg, 2.3 mmol), diphenylphosphine chloride (404 mg, 1.7 mmol), diisopropylethylamine (368 mg) , 2.85mmol) and piperidine 0.4mL, see step 5 of final product 8 for the reaction steps to obtain 96mg of the target product with a yield of 27%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.25(d,J=8.4Hz,1H),7.59-7.50(m,2H),7.50-7.42(m,2H),7.36(d,J=8.5 Hz, 2H), 7.17–6.99 (m, 3H), 4.72 (d, J=10.7Hz, 1H), 4.47 (dd, J=9.8, 2.7Hz, 1H), 3.89–3.80 (m, 6H), 3.78 –3.59(m,2H),3.56–3.45(m,1H),1.77–1.63(m,2H),1.22(s,9H).

Step 6: Synthesis of 4-((2'S,3S,4'R,5'R)-1-(4-carboxybenzyl)-5-chloro-4'-(4-chlorophenyl)-2'-new Amylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK018)

YK016 (see YI003 for the synthesis procedure, 48 mg, 0.078 mmol), methyl 4-bromomethylbenzoate (21 mg, 0.093 mmol), potassium carbonate (32 mg, 0.23 mmol) and lithium hydroxide monohydrate (16 mg, 0.39 mmol) , the reaction steps refer to step 6 of the final product 8 to obtain 22 mg of the target product with a yield of 39%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.26(d,J=8.4Hz,1H),7.96-7.82(m,2H),7.62(dd,J=8.4,1.8Hz,1H),7.54- 7.42 (m, 2H), 7.38–7.26 (m, 2H), 7.23–7.14 (m, 2H), 7.10 (dd, J=8.5, 2.1Hz, 1H), 6.90 (d, J=8.0Hz, 2H) ,6.37(d,J＝8.5Hz,1H),5.20(d,J＝11.3Hz,1H),4.33-4.17(m,2H),4.14-3.95(m,2H),3.69(s,3H), 3.51(d,J＝10.7Hz,1H),3.43(d,J＝10.7Hz,1H),1.79(dd,J＝15.4,8.5Hz,1H),1.67(dd,J＝15.4,1.7Hz,1H) ), 0.97 (s, 9H). ESI-MS theoretical calculation value C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₃ O ₆ [M+H] ⁺ =716.23, experimentally found: 716.7.

Final product 56: 4-((2'S,3S,4'R,5'R)-1-(4-carboxybenzyl)-5-chloro-4'-(2-chlorophenyl)-2'-neo Amylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK019)

Step 1: Synthesis of ((Z)-3-(2-chlorophenyl)-2-(5-chloro-2-fluorophenyl)acrylonitrile (YK008)

2-Chlorobenzaldehyde (2.81g, 20mmol), 5-chloro-2-fluorophenylacetonitrile (3.4g, 20mmol), 4.8mL of 5N methanol solution of sodium methoxide, see step 1 of final product 8 for the reaction steps to obtain the target product 5.5g, 95% yield. ¹ H NMR (500MHz, Chloroform-d) δ 8.11 (dq, J=6.6, 3.8Hz, 1H), 7.96 (s, 1H), 7.60 (dd, J=6.6, 2.6Hz, 1H), 7.55-7.46 (m, 1H), 7.41 (dd, J=6.0, 3.5Hz, 2H), 7.37 (ddd, J=8.7, 4.2, 2.6Hz, 1H), 7.14 (dd, J=10.4, 8.8Hz, 1H).

Step 2: Synthesis of (2R,3S,4R,5S)-3-(2-chlorophenyl)-4-(5-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine -2-Carboxylic acid tert-butyl ester (YK010-1)

YK008 (5.5 g, 18.8 mmol), AgF (2.4 g, 18.8 mmol), triethylamine 4 mL and (E)-tert-butyl 2-(((3,3-dimethylbutylene)amino)acetate (4.14 g, 18.8 mmol), refer to step 2 of final product 8 for the reaction steps, to obtain the target product 2.7 g with a yield of 28%. ¹ H NMR (500 MHz, Chloroform-d) δ 7.80 (dd, J=8.0, 1.4 Hz, 1H),7.38(ddd,J=9.4,7.4,2.2Hz,2H),7.30(ddd,J=8.7,4.1,2.6Hz,1H),7.25-7.17(m,2H),7.03(dd,J= 12.0, 8.7Hz, 1H), 4.97 (d, J=6.6Hz, 1H), 4.13 (d, J=8.9Hz, 1H), 4.08 (d, J=6.6Hz, 1H), 1.66 (ddd, J= 14.4,9.0,1.2Hz,1H),1.41(s,9H),1.33(dd,J=14.4,1.1Hz,1H),0.92(s,9H).

Step 3: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-3-(2-chlorophenyl)-4-(5-chloro-2-fluorophenyl)-5-neopenta Pyrrolidine-2-carboxylate tert-butyl ester (YK010-2)

YK010-1 (2.7 g, 5.3 mmol), Raney nickel 2.7 g, hydrazine hydrate 10 mL, see step 3 of final product 8 for the reaction steps to obtain 553 mg of the target product with a yield of 20%. ¹ H NMR (500MHz, Chloroform-d) δ 7.81 (dd, J=8.0, 1.6Hz, 1H), 7.29 (td, J=7.6, 1.4Hz, 1H), 7.24 (dd, J=8.0, 1.4Hz) ,1H),7.22–7.10(m,3H),6.85(dd,J=12.4,8.6Hz,1H),4.32(d,J=9.0Hz,1H),4.19(d,J=9.7Hz,1H) ,4.04(d,J＝9.0Hz,1H),3.37(dd,J＝4.4,1.7Hz,2H),1.63(d,J＝13.8Hz,1H),1.52(dd,J＝13.9,9.8Hz, 1H), 1.25(s, 9H), 1.03(s, 9H).

Step 4: Synthesis of (2R,3S,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-3-(2-chlorophenyl )-4-(5-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YK013)

YK010-2 (550mg, 1.08mmol), FmocCl (418mg, 1.62mmol), diisopropylethylamine (558mg, 4.32mmol) and trifluoroacetic acid 4mL, see step 4 of final product 8 for the reaction steps to obtain the target product 469 mg, 62% yield.

Step 5: Synthesis of methyl 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(2-chlorophenyl)-4-(5-chloro-2-fluorophenyl) -5-Neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YK017)

YK013 (469mg, 0.69mmol), methyl 4-amino-3-methoxybenzoate (502mg, 2.78mmol), diphenylphosphine chloride (489mg, 2.07mmol), diisopropylethylamine (445mg , 3.45mmol) and piperidine 0.4mL, see step 5 of final product 8 for the reaction steps to obtain 93mg of the target product with a yield of 22%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.25(d,J=8.3Hz,1H),7.70-7.52(m,3H),7.50-7.39(m,2H),7.39-7.27(m,3H) ),7.05(dd,J＝12.6,8.8Hz,1H),4.59(d,J＝10.5Hz,1H),4.52(d,J＝11.1Hz,1H),4.37(d,J＝10.5Hz,1H) ), 3.90(s, 3H), 3.86(s, 3H), 3.80(dd, J=14.3, 3.3Hz, 1H), 3.67(d, J=14.4Hz, 1H), 1.86–1.73(m, 1H) ,1.69(d,J=11.3Hz,1H),1.26(s,9H).

Step 6: Synthesis of 4-((2'S,3S,4'R,5'R)-1-(4-carboxybenzyl)-5-chloro-4'-(2-chlorophenyl)-2'-new Amylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK019)

YK017 (47mg, 0.076mmol), methyl 4-bromomethylbenzoate (21mg, 0.093mmol), potassium carbonate (32mg, 0.23mmol) and lithium hydroxide monohydrate (16mg, 0.39mmol), see the end of the reaction procedure The sixth step of product 8, 21 mg of the target product was obtained with a yield of 39%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.20(d,J=8.4Hz,1H),7.92-7.80(m,2H),7.65(ddd,J=12.1,7.3,2.3Hz,2H), 7.53(d,J＝1.8Hz,1H),7.45(d,J＝2.2Hz,1H),7.39(pq,J＝6.3,3.1Hz,3H),7.06(dd,J＝8.4,2.1Hz,1H) ), 6.98(d, J＝8.1Hz, 2H), 6.36(d, J＝8.5Hz, 1H), 5.13(d, J＝10.4Hz, 1H), 4.72(d, J＝10.4Hz, 1H), 4.35(dd,J＝8.5,1.7Hz,1H),4.22(d,J＝15.5Hz,1H),4.09(d,J＝15.5Hz,1H),3.69(s,3H),3.61(d,J =10.7Hz,1H),3.51(d,J=10.8Hz,1H),1.86-1.59(m,2H),0.98(s,9H).ESI-MS theoretical calculated value for C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₃ O ₆ [M+H] ⁺ =716.23, experimentally measured: 716.6.

Final product 57: 4-((2'S,3S,4'R,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(4- Chlorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK020)

YK016 (48mg, 0.078mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (27mg, 0.16mmol), sodium borohydride acetate (34mg, 0.16mmol), 0.1mL acetic acid, potassium carbonate (32mg, 0.23 mmol) and lithium hydroxide monohydrate (16 mg, 0.4 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 13 mg of the target compound with a yield of 22%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.28(d,J=8.5Hz,1H),7.95-7.81(m,2H),7.62(dd,J=8.5,1.7Hz,1H),7.52( d, J=1.8Hz, 1H), 7.47 (d, J=2.1Hz, 1H), 7.34–7.26 (m, 2H), 7.21–7.14 (m, 2H), 7.11 (dd, J=8.5, 2.1Hz) ,1H),7.06(d,J＝8.1Hz,2H),6.46(d,J＝8.5Hz,1H),5.09(d,J＝11.1Hz,1H),4.31(d,J＝15.7Hz,1H) ),4.17(d,J＝8.0Hz,1H),4.10(d,J＝15.7Hz,1H),4.04(d,J＝11.2Hz,1H),3.71(s,3H),3.50(d,J =10.6Hz, 1H), 3.39(d, J=10.6Hz, 1H), 1.81–1.60(m, 2H), 0.98(s, 9H). ESI-MS theoretical calculated value for C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₇ O ₄ [M+H] ⁺ =740.25, experimentally measured: 740.8.

Final product 58: 4-((2'S,3S,4'R,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2- Chlorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK021)

YK017 (48mg, 0.078mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (27mg, 0.16mmol), sodium borohydride acetate (34mg, 0.16mmol), 0.1mL acetic acid, potassium carbonate (32mg, 0.23 mmol) and lithium hydroxide monohydrate (16 mg, 0.4 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 14 mg of the target compound with a yield of 24%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.21(d,J=8.4Hz,1H),7.92-7.83(m,2H),7.65(ddd,J=16.7,7.9,2.5Hz,2H), 7.53(d,J＝1.7Hz,1H),7.48-7.33(m,4H),7.12-7.01(m,3H),6.39(d,J＝8.5Hz,1H),5.11(d,J＝10.3Hz ,1H),4.72(d,J＝10.3Hz,1H),4.35(dd,J＝8.1,2.1Hz,1H),4.26(d,J＝15.6Hz,1H),4.12(d,J＝15.6Hz ESI- MS theoretical calculated value C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₇ O ₄ [M+H] ⁺ =740.25, experimentally found: 740.9.

Final product 59: 4-((2'S,3S,4'R,5'R)-1-(3-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2- Chlorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK052)

YK017 (30mg, 0.049mmol), 3-(1H-tetrazol-5-yl)benzaldehyde (17mg, 0.097mmol), sodium borohydride acetate (21mg, 0.097mmol), 0.1mL acetic acid, potassium carbonate (15mg, 0.1 mmol) and lithium hydroxide monohydrate (6 mg, 0.13 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 2.8 mg of the target compound with a yield of 8%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.24(d,J=8.4Hz,1H),7.90(d,J=7.7Hz,1H),7.79(d,J=2.1Hz,1H),7.64 (dd, J=8.4, 1.7Hz, 1H), 7.59–7.39 (m, 4H), 7.38–7.29 (m, 1H), 7.30–7.18 (m, 2H), 7.16 (d, J=7.7Hz, 1H) ), 7.10(dd, J＝8.5, 2.1Hz, 1H), 6.51(d, J＝8.5Hz, 1H), 4.98–4.90(m, 1H), 4.69(d, J＝10.1Hz, 1H), 4.33 –4.09(m, 3H), 3.72(s, 3H), 3.58–3.41(m, 2H), 1.79–1.53(m, 2H), 0.97(s, 9H). ESI-MS calculated value for C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₇ O ₄ [M+H] ⁺ =740.25, found experimentally: 740.5.

Final product 60: 4-((2'S,3S,4'R,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(3- Chlorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK059)

YK009 (32mg, 0.052mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (20mg, 0.11mmol), sodium borohydride acetate (25mg, 0.12mmol), 0.1mL acetic acid, potassium carbonate (22mg, 0.16 mmol) and lithium hydroxide monohydrate (11 mg, 0.26 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 8 mg of the target compound with a yield of 21%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.28(d,J=8.4Hz,1H),7.94-7.82(m,2H),7.62(dd,J=8.5,1.8Hz,1H),7.53( d, J=1.8Hz, 1H), 7.49 (d, J=2.1Hz, 1H), 7.40 (dd, J=7.8, 1.8Hz, 1H), 7.34–7.24 (m, 2H), 7.13 (dd, J =8.4,2.1Hz,1H),7.04(t,J=7.8Hz,3H),6.46(d,J=8.5Hz,1H),5.11(d,J=11.2Hz,1H),4.34(d,J =15.7Hz,1H),4.21(d,J=8.0Hz,1H),4.15-3.99(m,2H),3.73(s,3H),3.49(d,J=10.7Hz,1H),3.40(d , J=10.7Hz, 1H), 1.83-1.58(m, 2H), 0.98(s, 9H). ESI-MS calculated value C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₇ O ₄ [M+H] ⁺ =740.25 , experimentally measured: 740.7.

Final product 61: 4-((2'S,3S,4'S,5'R)-1-(4-(1H-pyrazol-4-yl)benzyl)-5-chloro-4'-(2-chlorobenzene (YK060)

YK017 (32 mg, 0.052 mmol), 4-(1H-pyrazol-4-yl)benzaldehyde (18 mg, 0.1 mmol), sodium borohydride acetate (22 mg, 0.1 mmol), 0.1 mL acetic acid, potassium carbonate (16 mg, 0.11 mmol) mmol) and lithium hydroxide monohydrate (8 mg, 0.19 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 10 mg of the target compound with a yield of 26%. ESI-MS theoretical calculation value C ₄₁ H ₄₂ ³⁵ Cl ₂ N ₅ O ₄ [M+H] ⁺ =738.26, experimentally found: 738.3.

Final product 62: 4-((2'S,3S,4'R,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2- Methylphenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK062)

Step 1: Synthesis of ((Z)-3-(2-methylphenyl)-2-(5-chloro-2-fluorophenyl)acrylonitrile (YK043)

2-methylbenzaldehyde (2.4g, 20mmol), 5-chloro-2-fluorophenylacetonitrile (3.4g, 20mmol), 4.8mL of 5N methanol solution of sodium methoxide, see step 1 of final product 8 for the reaction steps to obtain the target The product was 5 g, and the yield was 92%. ¹ H NMR (500MHz, Chloroform-d) δ 7.96 (dd, J=7.5, 1.5Hz, 1H), 7.85 (s, 1H), 7.60 (dd, J=6.7, 2.6Hz, 1H), 7.40–7.30 (m, 3H), 7.27 (dd, J=7.1, 1.4Hz, 1H), 7.13 (dd, J=10.5, 8.8Hz, 1H), 2.39 (s, 3H).

Step 2: Synthesis of (2R,3S,4R,5S)-3-(2-methylphenyl)-4-(5-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrole Alkane-2-carboxylate tert-butyl ester (YK051-1)

YK043 (5g, 18.5mmol), AgF (2.35g, 18.5mmol), triethylamine 4mL and (E)-tert-butyl 2-(((3,3-dimethylbutylene)amino)acetate (3.9g) , 18.5mmol), refer to step 2 of final product 8 for the reaction steps, to obtain the target product 2.78g, yield 31%. ¹ H NMR (500MHz, Chloroform-d) δ7.71 (dd, J=7.9, 1.4Hz, 1H ), 7.44 (dd, J=6.7, 2.6Hz, 1H), 7.36–7.28 (m, 2H), 7.16 (td, J=7.5, 1.4Hz, 1H), 7.11–6.99 (m, 2H), 4.63 ( d,J＝6.0Hz,1H),4.10(d,J＝5.9Hz,1H),4.06(d,J＝8.9Hz,1H),1.83(s,3H),1.67(ddd,J＝14.5,9.0 ,1.3Hz,1H),1.43(s,9H),1.31(dd,J=14.4,1.1Hz,1H),0.91(s,9H).

Step 3: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-3-(2-methylphenyl)-4-(5-chloro-2-fluorophenyl)-5-new Pentapyrrolidine-2-carboxylate tert-butyl ester (YK051-2)

YK051-1 (2.78 g, 5.7 mmol), Raney nickel 2.8 g, hydrazine hydrate 10 mL, see step 3 of final product 8 for the reaction steps to obtain 234 mg of the target product with a yield of 8%. ¹ H NMR (500MHz, Chloroform-d)δ7.56(d,J=7.9Hz,1H),7.32-6.80(m,6H),4.05(q,J=7.7Hz,3H),3.37(q,J = 13.8, 13.4Hz, 2H), 1.67(s, 3H), 1.61–1.44(m, 2H), 1.27(s, 9H), 0.98(s, 9H).

Step 4: Synthesis of (2R,3S,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-3-(2-methylbenzene yl)-4-(5-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YK055)

YK051-2 (356 mg, 0.73 mmol), FmocCl (282 mg, 1.09 mmol), diisopropylethylamine (377 mg, 2.92 mmol) and 4 mL of trifluoroacetic acid, see step 4 of final product 8 for reaction steps to obtain the target product 287 mg, 60% yield.

Step 5: Synthesis of methyl 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(2-methylphenyl)-4-(5-chloro-2-fluorophenyl) )-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YK061)

YK055 (287mg, 0.44mmol), methyl 4-amino-3-methoxybenzoate (318mg, 1.75mmol), diphenylphosphine chloride (314mg, 1.32mmol), diisopropylethylamine (284mg , 2.2 mmol) and piperidine 0.4 mL, see step 5 of final product 8 for the reaction steps to obtain 156 mg of the target product with a yield of 59%.

Step 6: Synthesis of 4-((2'S,3S,4'R,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2- Methylphenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK062)

YK061 (30mg, 0.05mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (17mg, 0.1mmol), sodium borohydride acetate (22mg, 0.1mmol), 0.1mL acetic acid, potassium carbonate (21mg, 0.15 mmol) and lithium hydroxide monohydrate (11 mg, 0.25 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 7 mg of the target compound with a yield of 19%. ESI-MS theoretical calculation value C ₄₀ H ₄₃ ³⁵ ClN ₇ O ₄ [M+H] ⁺ =720.31, experimentally found: 720.7.

Final product 63: 4-((2'S,3S,4'S,5'R)-5-chloro-4'-(2-chlorophenyl)-1-(4-(isoxazol-4-yl)benzyl )-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK067)

YK017 (32mg, 0.052mmol), 4-(isoxazol-4-yl)benzaldehyde (18mg, 0.1mmol), sodium borohydride acetate (22mg, 0.1mmol), 0.1mL acetic acid, potassium carbonate (16mg, 0.11mmol) ) and lithium hydroxide monohydrate (8 mg, 0.19 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 2.7 mg of the target compound with a yield of 7%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.27-8.19(m,1H),7.70-7.59(m,2H),7.55(t,J=5.5Hz,2H),7.47-7.34(m,4H) ), 7.32–7.23 (m, 1H), 7.08 (ddd, J=8.2, 5.9, 2.1Hz, 1H), 6.96 (dd, J=14.9, 8.2Hz, 2H), 6.45 (dd, J=10.2, 8.5 Hz, 1H), 5.00(d, J＝10.7Hz, 1H), 4.71(d, J＝10.2Hz, 1H), 4.27(s, 1H), 4.15(dd, J＝15.1, 5.7Hz, 1H), 4.04 (dd, J=14.9, 7.2Hz, 1H), 3.71 (d, J=1.8Hz, 3H), 3.56–3.49 (m, 1H), 3.47–3.37 (m, 1H), 1.81–1.50 (m, 2H), 0.98(d, J=7.2Hz, 9H). ESI-MS theoretical calculation value C ₄₁ H ₄₁ ³⁵ Cl ₂ N ₄ O ₅ [M+H] ⁺ =739.24, experimentally measured: 739.6

Final product 64: 4-(((2'S,3S,4'S,5'R)-5-chloro-4'-(2-chlorophenyl)-2'-neopentylspiro[indoline-3,3 '-Pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK068)

YK017 (30 mg, 0.049 mmol), potassium carbonate (20 mg, 0.15 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol). For the reaction steps, refer to step 6 of final product 8 to obtain the target product 5 mg with a yield of 18%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.24(d,J=8.4Hz,1H),7.73(dd,J=7.9,1.5Hz,1H),7.66(dd,J=8.4,1.8Hz, 1H), 7.55(d, J＝1.8Hz, 1H), 7.49(td, J＝7.4, 1.7Hz, 1H), 7.45(d, J＝2.1Hz, 1H), 7.42–7.33(m, 2H), 7.02(dd,J＝8.4,2.1Hz,1H),6.45(d,J＝8.4Hz,1H),5.11(d,J＝10.3Hz,1H),4.81(d,J＝10.4Hz,1H), 4.22(t, J=4.9Hz, 1H), 3.79–3.66(m, 5H), 1.77(d, J=5.0Hz, 2H), 0.94(s, 9H). ESI-MS calculated value C ₃₁ H ₃₄ ³⁵ Cl ₂ N ₃ O ₄ [M+H] ⁺ =582.19, found by experiment: 583.1.

Final product 65: 4-((2'S,3S,4'S,5'R)-1-((((1r,4S)-4-carboxycyclohexyl)methyl)-5-chloro-4'-(2- Chlorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK071)

YK017 (26mg, 0.042mmol), methyl trans-4-formylcyclohexane-1-carboxylate (14mg, 0.084mmol), sodium borohydride acetate (18mg, 0.084mmol), 0.1mL acetic acid, potassium carbonate (18mg , 0.13 mmol) and lithium hydroxide monohydrate (9 mg, 0.2 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 12 mg of the target compound with a yield of 40%. ESI-MS theoretical calculation value C ₃₉ H ₄₆ ³⁵ Cl ₂ N ₃ O ₆ [M+H] ⁺ =722.28, experimentally found: 722.0.

Final product 66: 4-((2'S,3S,4'R,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-2'-neopentyl -4'-(2-(trifluoromethyl)phenyl)spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK077)

Step 1: Synthesis of ((Z)-3-(2-trifluoromethylphenyl)-2-(5-chloro-2-fluorophenyl)acrylonitrile (YK063)

2-Trifluoromethylbenzaldehyde (3.48g, 20mmol), 5-chloro-2-fluorobenzeneacetonitrile (3.4g, 20mmol), 4.8mL of 5N methanol solution of sodium methoxide, see step 1 of final product 8 for reaction steps, The target product 5.9g was obtained, and the yield was 91%. ¹ H NMR (500MHz, Chloroform-d) δ8.11-7.97 (m, 2H), 7.83-7.75 (m, 1H), 7.70 (td, J=7.7, 1.4Hz, 1H), 7.67-7.50 (m, 2H),7.38(ddd,J=8.8,4.2,2.6Hz,1H),7.15(dd,J=10.5,8.8Hz,1H).

Step 2: Synthesis of (2R,3S,4R,5S)-3-(2-trifluoromethylphenyl)-4-(5-chloro-2-fluorophenyl)-4-cyano-5-neopenta tert-butyl pyrrolidine-2-carboxylate (YK064)

YK063 (5.9g, 18mmol), AgF (2.3g, 18mmol), triethylamine 4mL and (E)-tert-butyl 2-(((3,3-dimethylbutylidene)amino)acetate (4.3g, 18mmol), refer to step 2 of final product 8 for the reaction steps to obtain 3.5g of the target product with a yield of 36%. ¹ H NMR (500MHz, Chloroform-d) δ8.03(d, J=8.0Hz, 1H), 7.69( td, J=7.8, 1.4Hz, 1H), 7.56 (dd, J=8.0, 1.4Hz, 1H), 7.48–7.36 (m, 2H), 7.30 (ddd, J=8.7, 4.1, 2.5Hz, 1H) ,7.05(dd,J＝12.0,8.7Hz,1H),4.71(d,J＝4.3Hz,1H),4.01(d,J＝4.3Hz,1H),3.97(d,J＝8.7Hz,1H) ,1.69(ddd,J=14.5,8.9,1.4Hz,1H),1.45(s,9H),1.37–1.28(m,1H),0.90(s,9H).

Step 3: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-3-(2-trifluoromethylphenyl)-4-(5-chloro-2-fluorophenyl)-5 - Neopentylpyrrolidine-2-carboxylate tert-butyl ester (YK069)

YK064 (3.5g, 6.5mmol), Raney nickel 3.5g, hydrazine hydrate 10mL, refer to step 3 of final product 8 for the reaction steps to obtain 148mg of the target product with a yield of 4%. ¹ H NMR(500MHz, Chloroform-d)δ8.02(d,J=8.0Hz,1H),7.69-7.48(m,2H),7.33(t,J=7.6Hz,1H),7.29-7.18(m ,1H),7.13(dt,J＝6.4,3.1Hz,1H),6.84(dd,J＝12.5,8.6Hz,1H),4.29(d,J＝6.9Hz,1H),4.11–3.82(m, 2H), 3.51–3.30 (m, 2H), 1.56–1.41 (m, 2H), 1.29 (s, 9H), 0.96 (s, 9H).

Step 4: Synthesis of (2R,3S,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-3-(2-trifluoromethyl) phenyl)-4-(5-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YK073)

YK069 (320 mg, 0.59 mmol), FmocCl (228 mg, 0.89 mmol), diisopropylethylamine (305 mg, 2.36 mmol) and trifluoroacetic acid 4 mL, refer to step 4 of final product 8 for the reaction steps to obtain 248 mg of the target product, Yield 59%.

Step 5: Synthesis of methyl 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(2-trifluoromethylphenyl)-4-(5-chloro-2-fluoro Phenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YK075)

YK073 (248mg, 0.35mmol), methyl 4-amino-3-methoxybenzoate (253mg, 1.4mmol), diphenylphosphine chloride (248mg, 1.05mmol), diisopropylethylamine (226mg , 1.75mmol) and piperidine 0.4mL, see step 5 of final product 8 for the reaction steps to obtain 133mg of the target product with a yield of 58%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.21(d,J=8.5Hz,1H),7.85(d,J=8.0Hz,1H),7.80(t,J=7.6Hz,1H),7.71 –7.62(m,1H), 7.60–7.50(m,3H),7.38(ddd,J=8.8,4.0,2.4Hz,1H),7.30(d,J=6.3Hz,1H),6.98(dd,J =12.3,8.8Hz,1H),4.66(d,J=10.6Hz,1H),4.54(d,J=11.1Hz,1H),3.95(dd,J=6.4,4.1Hz,3H),3.89–3.75 (m,6H),1.87(d,J=13.8Hz,1H),1.75(dd,J=14.0,11.3Hz,1H),1.28(s,9H).

Step 6: Synthesis of 4-((2'S,3S,4'R,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-2'-neopentyl -4'-(2-(trifluoromethyl)phenyl)spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK077)

YK075 (34mg, 0.052mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (17mg, 0.1mmol), sodium borohydride acetate (22mg, 0.1mmol), 0.1mL acetic acid, potassium carbonate (21mg, 0.15 mmol) and lithium hydroxide monohydrate (11 mg, 0.25 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 24 mg of the target compound with a yield of 60%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.24(d,J=8.4Hz,1H),7.94-7.85(m,2H),7.81(d,J=7.9Hz,1H),7.74-7.62( m, 3H), 7.59–7.47 (m, 2H), 7.25 (d, J=2.0Hz, 1H), 7.13 (d, J=8.1Hz, 2H), 7.06 (dd, J=8.4, 2.1Hz, 1H) ), 6.42(d, J＝8.5Hz, 1H), 5.02(d, J＝8.6Hz, 1H), 4.36(d, J＝8.5Hz, 1H), 4.32–4.19(m, 2H), 4.12(d , J＝15.3Hz, 1H), 3.72(s, 3H), 3.62(d, J＝10.9Hz, 1H), 3.53(d, J＝10.9Hz, 1H), 1.84–1.67(m, 2H), 0.99 (s, 9H). ESI-MS theoretical calculated value for C ₄₀ H ₄₀ ³⁵ ClF ₃ N ₇ O ₄ [M+H] ⁺ =774.28, experimentally found: 774.2.

Final product 67: 4-((2'S,3S,4'S,5'R)-5-chloro-4'-(2-chlorophenyl)-1-(4-(methylsulfonyl)benzyl)-2 '-Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK082)

YK017 (42 mg, 0.068 mmol), 1-(bromomethyl)-4-(methylsulfonyl)benzene (20 mg, 0.08 mmol), potassium carbonate (28 mg, 0.2 mmol) and lithium hydroxide monohydrate (14 mg, 0.34 mmol), refer to step 6 of final product 8 for the reaction steps to obtain 5.6 mg of the target product with a yield of 11%. ESI-MS theoretical calculation value C ₃₉ H ₄₂ ³⁵ Cl ₂ N ₃ O ₆ S[M+H] ⁺ =750.22, experimentally found: 750.0.

Final product 68: 4-((2'S,3S,4'S,5'R)-5-chloro-4'-(2-chlorophenyl)-1-(4-cyanobenzyl)-2'-neopenta Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK083)

YK017 (42 mg, 0.068 mmol), 4-cyanobenzyl bromide (16 mg, 0.08 mmol), potassium carbonate (28 mg, 0.2 mmol) and lithium hydroxide monohydrate (14 mg, 0.34 mmol), see the final product 8 for the reaction procedure In the sixth step, 10.3 mg of the target product was obtained with a yield of 22%. ESI-MS theoretical calculation value C ₃₉ H ₃₉ ³⁵ Cl ₂ N ₄ O ₄ [M+H] ⁺ =697.23, experimentally found: 697.4.

Final product 69: 4-((((2'S,3S,4'S,5'R)-5'-(((4-carboxyphenyl)carbamoyl)-5-chloro-4'-(2-chlorobenzene (YK126)

YK100 (see final product 72, step one, 35 mg, 0.0596 mmol), 3-methoxy, methyl 4-carboxylate benzyl bromide (23 mg, 0.089 mmol), potassium carbonate (25 mg, 0.179 mmol) and lithium hydroxide monohydrate (13 mg, 0.3 mmol), refer to the synthesis method of the final product 3 for the reaction steps to obtain 15 mg of the target compound, yield: 35%. ¹ H NMR(500MHz,Methanol-d ₄ )δ7.98(d,J=8.3Hz,2H),7.75-7.56(m,3H),7.46(s,2H),7.39-7.21(m,3H), 7.12(d,J＝8.8Hz,1H),6.81(s,1H),6.52(dd,J＝8.3,4.5Hz,2H),4.78(d,J＝4.9Hz,2H),4.35(t,J ＝4.7Hz, 1H), 4.23(d, J＝15.4Hz, 1H), 4.11(d, J＝15.4Hz, 1H), 3.78(s, 3H), 3.57–3.41(m, 2H), 1.75(d , J=6.4Hz, 2H), 0.95 (s, 9H). ESI-MS theoretical calculation value C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₃ O ₆ [M+H] ⁺ =716.23, experimentally measured: 716.6.

Final product 70: 2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2-chlorophenyl)-N -Methyl-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (YK101)

Step 1: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-N-methyl -5-Neopentylpyrrolidine-2-carboxamide (YK097)

YK013 (100 mg, 0.15 mmol), methylamine hydrochloride (40 mg, 0.59 mmol), diphenylphosphine chloride (104 mg, 0.44 mmol), diisopropylethylamine (129 mg, 1 mmol) and piperidine 0.4 mL , see step 5 of final product 1 for the reaction steps to obtain 56 mg of the target product with a yield of 81%.

Step 2: Synthesis of 2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2-chlorophenyl)-N -Methyl-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (YK101)

YK097 (56 mg, 0.12 mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (31 mg, 0.18 mmol), sodium borohydride acetate (51 mg, 0.24 mmol), 0.1 mL of acetic acid and potassium carbonate (50 mg, 0.36 mmol) For the reaction steps, refer to the synthesis method of the final product 20 to obtain 21 mg of the target compound with a yield of 29%. ¹ H NMR(500MHz,Methanol-d ₄ )δ7.86(d,J=8.3Hz,2H),7.52(dt,J=7.5,3.7Hz,1H),7.43(d,J=2.1Hz,1H) ,7.39-7.34(m,1H),7.32-7.26(m,2H),7.11-6.99(m,3H),6.37(d,J=8.5Hz,1H),4.69-4.54(m,2H),4.36 (dd, J＝7.6, 2.4Hz, 1H), 4.23 (d, J＝15.6Hz, 1H), 4.08 (d, J＝15.6Hz, 1H), 3.54 (d, J＝10.8Hz, 1H), 3.47 (d, J = 10.8 Hz, 1H), 2.73 (s, 3H), 1.77–1.67 (m, 2H), 0.96 (s, 9H). ESI-MS calculated for C ₃₂ H ₃₆ ³⁵ Cl ₂ N ₇ O [M+H] ⁺ =604.24, experimentally measured: 603.7.

Final product 71: (2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2-chlorophenyl)- N-(6-Hydroxypyridin-3-yl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (YK102)

Step 1: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-N-(6 -Hydroxypyridin-3-yl)-5-neopentylpyrrolidine-2-carboxamide (YK098)

YK013 (100 mg, 0.15 mmol), 2-hydroxy-5aminopyridine (65 mg, 0.59 mmol), diphenylphosphine chloride (104 mg, 0.44 mmol), diisopropylethylamine (129 mg, 1 mmol) and piperidine 0.4 mL, see step 5 of final product 1 for the reaction steps, to obtain 90 mg of the target product with a yield of 99%.

Step 2: Synthesis of (2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2-chlorophenyl)- N-(6-Hydroxypyridin-3-yl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (YK102)

YK098 (90 mg, 0.165 mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (42 mg, 0.248 mmol), sodium borohydride acetate (70 mg, 0.33 mmol), 0.1 mL of acetic acid and potassium carbonate (68 mg, 0.495 mmol) For the reaction steps, refer to the synthesis method of the final product 20 to obtain 28 mg of the target compound with a yield of 25%. ¹ H NMR(500MHz,Methanol-d ₄ )δ7.98(d,J=3.0Hz,1H),7.88(d,J=7.9Hz,2H),7.54-7.43(m,3H),7.42-7.29( m, 3H), 7.14–7.04 (m, 3H), 6.53 (d, J=9.7Hz, 1H), 6.43 (d, J=8.4Hz, 1H), 4.75–4.65 (m, 2H), 4.39 (d , J=7.8Hz, 1H), 4.27 (d, J=15.6Hz, 1H), 4.13 (d, J=15.6Hz, 1H), 3.51 (q, J=10.7Hz, 2H), 1.83–1.63 (m , 2H), 0.97 (s, 9H). ESI-MS theoretical calculation value C ₃₆ H ₃₇ ³⁵ Cl ₂ N ₈ O ₂ [M+H] ⁺ =683.24, experimentally found: 683.1.

Final Product 72: 4-((2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2-chlorobenzene yl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)benzoic acid (YK103)

Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(aminomethyl)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5 -Neopentylpyrrolidine-2-carboxamido)benzoic acid (YK100)

YK013 (100 mg, 0.15 mmol), methyl para-aminobenzoate (89 mg, 0.59 mmol), diphenylphosphine chloride (104 mg, 0.44 mmol), diisopropylethylamine (129 mg, 1 mmol) and piperidine 0.4 mL, see step 5 of final product 1 for reaction steps, to obtain 85 mg of the target product with a yield of 98%.

Step 2: Synthesis of 4-((2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2-chlorobenzene yl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)benzoic acid (YK103)

YK100 (85mg, 0.145mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (50mg, 0.29mmol), sodium borohydride acetate (61mg, 0.29mmol), 0.1mL acetic acid, potassium carbonate (60mg, 0.44 mmol) and lithium hydroxide monohydrate (31 mg, 0.73 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 24 mg of the target compound with a yield of 23%. ESI-MS theoretical calculation value C ₃₈ H ₃₈ ³⁵ Cl ₂ N ₇ O ₃ [M+H] ⁺ =710.24, experimentally found: 709.6.

Final Product 73: 3-((2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2-chlorobenzene yl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)benzoic acid (YK106)

Step 1: Synthesis of 3-((2R,3S,4S,5S)-4-(aminomethyl)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5 -Neopentylpyrrolidine-2-carboxamido)benzoic acid (YK104)

YK013 (100 mg, 0.15 mmol), methyl m-aminobenzoate (89 mg, 0.59 mmol), diphenylphosphine chloride (104 mg, 0.44 mmol), diisopropylethylamine (129 mg, 1 mmol) and piperidine 0.4 For the reaction steps, refer to step 5 of final product 1 to obtain 94 mg of the target product with a yield of 100%.

Step 2: Synthesis of 3-((2'S,3S,4'S,5'R)-1-(4-(1H-tetrazol-5-yl)benzyl)-5-chloro-4'-(2-chlorobenzene yl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)benzoic acid (YK106)

YK104 (94mg, 0.16mmol), 4-(1H-tetrazol-5-yl)benzaldehyde (42mg, 0.24mmol), sodium borohydride acetate (68mg, 0.32mmol), 0.1mL acetic acid, potassium carbonate (66mg, 0.48 mmol) and lithium hydroxide monohydrate (34 mg, 0.8 mmol). For the reaction steps, refer to the synthesis method of the final product 20 to obtain 25.7 mg of the target compound with a yield of 23%. ESI-MS theoretical calculation value C ₃₈ H ₃₈ ³⁵ Cl ₂ N ₇ O ₃ [M+H] ⁺ =710.24, experimentally found: 710.7.

Final product 74: 4-((2'S,3S,4'S,5'R)-5-chloro-4'-(2-chlorophenyl)-1-(4-((methylsulfonyl)carbamoyl) Benzyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK107)

Step 1: Synthesis of 4-((2'S,3S,4'S,5'R)-5-chloro-4'-(2-chlorophenyl)-1-(4-((methylsulfonyl)carbamoyl) Benzyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YK107)

YK017 (35 mg, 0.057 mmol), 4-(bromomethyl)-N-(methylsulfonyl)benzamide (25 mg, 0.085 mmol), potassium carbonate (24 mg, 0.17 mmol) and lithium hydroxide monohydrate ( 12 mg, 0.29 mmol), refer to step 6 of final product 8 for the reaction steps to obtain 16.4 mg of the target product with a yield of 36%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.21(d,J=8.4Hz,1H),7.77(d,J=8.1Hz,2H),7.72-7.59(m,2H),7.53(d, J=1.8Hz, 1H), 7.49–7.36 (m, 4H), 7.06 (dd, J=8.5, 2.1Hz, 1H), 7.00 (d, J=8.0Hz, 2H), 6.33 (d, J=8.5 Hz, 1H), 5.14 (d, J=10.4Hz, 1H), 4.72 (d, J=10.4Hz, 1H), 4.43–4.35 (m, 1H), 4.25 (d, J=15.7Hz, 1H), 4.09(d,J＝15.7Hz,1H),3.69(s,3H),3.63(d,J＝10.8Hz,1H),3.52(d,J＝10.8Hz,1H),3.38(s,3H), 1.88-1.61 (m, 2H), 0.99 (s, 9H). ESI-MS calculated value for C ₄₀ H ₄₃ ³⁵ Cl ₂ N ₄ O ₇ S[M+H] ⁺ =793.22, found by experiment: 793.7.

Final product 118: 4-((((2'S,3S,4'S,5'R)-5)-(((4-(carboxymethyl)phenyl)carbamoyl)-5-chloro-4'-( 2-Chlorophenyl)-2'-neopentylspiro[indoline]-3,3'-pyrrolidinyl]-1-yl)methyl)benzoic acid (YK133)

Step 1: Synthesis of methyl 2-(4-((2R,3S,4S,5S)-4-(aminomethyl)-4-(5-chloro-2-fluorophenyl)-3-(2-chloro Phenyl)-5-neopentylpyrrolidine-2-carboxamido)phenyl)acetate (YK128)

YK013 (100 mg, 0.15 mmol), methyl p-aminophenylacetate (98 mg, 0.59 mmol), diphenylphosphine chloride (104 mg, 0.44 mmol), diisopropylethylamine (95 mg, 0.74 mmol) and piperazine 0.2 mL, see step 5 of final product 1 for reaction steps, to obtain 81 mg of crude product, yield: 91%. ¹ H NMR(500MHz,Methanol-d ₄ )δ7.73(d,J=7.8Hz,1H),7.51(ddd,J=8.4,6.4,2.5Hz,2H),7.46-7.27(m,5H), 7.18(d, J＝8.4Hz, 2H), 7.13(dd, J＝12.8, 8.8Hz, 1H), 5.18–5.10(m, 1H), 4.96(d, J＝11.2Hz, 1H), 4.72(d , J＝11.1Hz, 1H), 3.93(dd, J＝14.7, 2.8Hz, 1H), 3.85(d, J＝14.8Hz, 1H), 3.63(s, 3H), 3.57(s, 2H), 2.10 (dd,J=14.8,11.4Hz,1H),1.91(d,J=14.7Hz,1H),1.21(s,9H).

Step 2: Synthesis of 4-((((2'S,3S,4'S,5'R)-5)-(((4-(carboxymethyl)phenyl)carbamoyl)-5-chloro-4'-( 2-Chlorophenyl)-2'-neopentylspiro[indoline]-3,3'-pyrrolidinyl]-1-yl)methyl)benzoic acid (YK133)

YK128 (78 mg, 0.13 mmol), methyl p-formate benzyl bromide (45 mg, 0.19 mmol), potassium carbonate (54 mg, 0.39 mmol) and lithium hydroxide monohydrate (27 mg, 0.65 mmol), see the final product 8 for the reaction procedure step to obtain the target compound. ¹ H NMR(500MHz,Methanol-d ₄ )δ7.92-7.84(m,2H),7.62-7.55(m,1H),7.49-7.41(m,3H),7.38-7.28(m,3H),7.27 –7.19(m,2H),7.07(dd,J=8.4,2.1Hz,1H),6.98(d,J=8.2Hz,2H),6.37(d,J=8.5Hz,1H),4.84–4.73( m, 2H), 4.39 (dd, J=7.9, 2.1Hz, 1H), 4.21 (d, J=15.5Hz, 1H), 4.09 (d, J=15.6Hz, 1H), 3.64–3.47 (m, 4H) ), 1.88-1.62 (m, 2H), 0.96 (s, 9H). ESI-MS theoretical calculation value C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₃ O ₅ [M+H] ⁺ =700.23, experimentally found: 700.8.

Final product 119: 4-((((2'S,3S,4'S,5'R)-5)-(((3-(carboxymethyl)phenyl)carbamoyl)-5-chloro-4'-( 2-Chlorophenyl)-2'-neopentylspiro[indoline]-3,3'-pyrrolidinyl]-1-yl)methyl)benzoic acid (YK134)

Step 1: Synthesis of 2-(3-((2R,3S,4S,5S)-4-(aminomethyl)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl) )-5-neopentylpyrrolidine-2-carboxamido)phenylacetate methyl ester (YK129)

YK013 (100 mg, 0.15 mmol), methyl m-aminophenylacetate (98 mg, 0.59 mmol), diphenylphosphine chloride (104 mg, 0.44 mmol), diisopropylethylamine (95 mg, 0.74 mmol) and piperazine 0.2 mL, refer to the final product 1, step 5 for the reaction steps to obtain 86 mg of crude product, yield: 97%. ¹ H NMR(500MHz,Methanol-d ₄ )δ7.73(d,J=7.9Hz,1H),7.51(ddd,J=8.5,6.2,2.2Hz,2H),7.43(d,J=2.1Hz, 1H), 7.41–7.28 (m, 4H), 7.23 (t, J=7.9Hz, 1H), 7.14 (dd, J=12.8, 8.8Hz, 1H), 7.02 (d, J=7.6Hz, 1H), 5.11(d,J＝11.4Hz,1H),4.97(d,J＝11.1Hz,1H),4.73(d,J＝11.1Hz,1H),3.93(dd,J＝14.8,2.8Hz,1H), 3.85(d,J＝14.8Hz,1H),3.64(s,3H),3.59(s,2H),2.10(dd,J＝14.8,11.4Hz,1H),1.90(d,J＝14.7Hz,1H ),1.21(s,9H).

Step 2: Synthesis of 4-((((2'S,3S,4'S,5'R)-5)-(((3-(carboxymethyl)phenyl)carbamoyl)-5-chloro-4'-( 2-Chlorophenyl)-2'-neopentylspiro[indoline]-3,3'-pyrrolidinyl]-1-yl)methyl)benzoic acid (YK134)

YK129 (78 mg, 0.13 mmol), methyl p-formate benzyl bromide (45 mg, 0.19 mmol), potassium carbonate (54 mg, 0.39 mmol) and lithium hydroxide monohydrate (27 mg, 0.65 mmol), see the final product 8 for the reaction procedure In the sixth step, the target compound is obtained. ¹ H NMR (500MHz, Methanol-d ₄ )δ7.89-7.84(m,2H),7.60-7.53(m,1H),7.50-7.43(m,2H),7.43-7.37(m,1H),7.37 –7.28(m,3H),7.26(t,J=7.9Hz,1H),7.07(ddd,J=7.5,3.9,2.0Hz,2H),6.98(d,J=8.1Hz,2H),6.37( d, J=8.4Hz, 1H), 4.84–4.70 (m, 2H), 4.40 (dd, J=7.8, 2.1Hz, 1H), 4.21 (d, J=15.6Hz, 1H), 4.09 (d, J =15.6Hz,1H),3.56(d,J=10.6Hz,3H),3.50(d,J=10.8Hz,1H),1.81–1.64(m,2H),0.96(s,9H).ESI-MS Theoretical calculated value C ₃₉ H ₄₀ ³⁵ Cl ₂ N ₃ O ₅ [M+H] ⁺ =700.23, experimentally found: 700.6.

Final product 125: 4-((2'S,3S,4'S,5'R)-6-chloro-4'-(2-chlorophenyl)-2'-neopentylspiro[indoline-3,3 '-Pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YM147)

YI105 (30 mg, 0.049 mmol), potassium carbonate (21 mg, 0.146 mmol) and lithium hydroxide monohydrate (10 mg, 0.25 mmol). For the reaction procedure, refer to the synthesis method of the final product 28 to obtain 16.4 mg of YM147 with a yield of 48%. ¹ H NMR(400MHz,Methanol-d ₄ )δ8.24(d,J=8.4Hz,1H),7.72(d,J=7.8Hz,1H),7.65(dd,J=8.4,1.8Hz,1H) ,7.55(d,J＝1.8Hz,1H),7.48(td,J＝7.4,1.8Hz,1H),7.44–7.23(m,3H),6.66(dd,J＝8.1,1.9Hz,1H), 6.43(d,J＝1.9Hz,1H),5.09(d,J＝10.2Hz,1H),4.77(d,J＝10.2Hz,1H),4.17(t,J＝5.0Hz,1H),3.79– 3.62(m, 5H), 1.76(d, J=5.0Hz, 2H), 0.94(s, 9H). ESI-MS calculated value C ₃₁ H ₃₄ ³⁵ Cl ₂ N ₃ O ₄ [M+H] ⁺ = 582.2, experimentally measured: 582.9.

Final product 126: 4-((2'S,3S,4'R,5'R)-6-chloro-4'-(3-chlorophenyl)-2'-neopentylspiro[indoline-3 ,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YM85)

YI009 (10 mg, 0.016 mmol), potassium carbonate (10 mg, 0.063 mmol) and lithium hydroxide monohydrate (4 mg, 0.08 mmol). For the reaction steps, refer to the synthesis method of the final product 28 to obtain 3.6 mg of YM85 with a yield of 33%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.31(d,J=8.4Hz,1H),7.64(dd,J=8.5,1.8Hz,1H),7.55(d,J=1.8Hz,1H) ,7.41–7.27(m,4H),7.15(d,J＝7.8Hz,1H),6.72(dd,J＝8.0,1.9Hz,1H),6.45(d,J＝1.9Hz,1H),5.08( s, 1H), 4.19–3.94 (m, 2H), 3.76 (s, 3H), 3.63 (d, J=10.7Hz, 1H), 3.49 (d, J=10.8Hz, 1H), 1.82–1.59 (m , 2H), 0.94 (s, 9H). ESI-MS theoretical calculation value C ₃₁ H ₃₄ ³⁵ Cl ₂ N ₃ O ₄ [M+H] ⁺ =582.2, experimentally found: 581.7.

Final product 127: 4-((2'S,3S,4'R,5'R)-6-chloro-4'-(4-chlorophenyl)-2'-neopentylspiro[indoline-3 ,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YM126)

YI059 (9.3 mg, 0.015 mmol), potassium carbonate (6 mg, 0.045 mmol) and lithium hydroxide monohydrate (4 mg, 0.08 mmol). For the reaction procedure, see the synthesis method of the final product 28, to obtain 5 mg of YM126 with a yield of 48%. ¹ H NMR(400MHz,Methanol-d ₄ )δ8.29(d,J=8.4Hz,1H),7.64(dd,J=8.4,1.8Hz,1H),7.54(d,J=1.8Hz,1H) ,7.38(d,J＝8.2Hz,2H),7.33(d,J＝8.0Hz,1H),7.25(d,J＝8.2Hz,2H),6.71(dd,J＝8.0,1.9Hz,1H) ,6.45(d,J＝1.9Hz,1H),5.11(d,J＝11.3Hz,1H),4.08(d,J＝10.8Hz,2H),3.72(s,3H),3.64(d,J＝ 10.8Hz, 1H), 3.51 (d, J=10.8Hz, 1H), 1.82–1.68 (m, 2H), 0.94 (s, 9H). ESI-MS calculated value for C ₃₁ H ₃₄ ³⁵ Cl ₂ N ₃ O ₄ [M+H] ⁺ =582.2, experimentally measured: 583.1.

Final product 128: 4-((2'S,3S,4'R,5'R)-6-chloro-4'-(2,3-dichlorophenyl)-2'-neopentylspiro[indoline] Indol-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YM135)

YI129 (39 mg, 0.06 mmol), potassium carbonate (25 mg, 0.18 mmol) and lithium hydroxide monohydrate (13 mg, 0.3 mmol). For the reaction steps, refer to the synthesis method of the final product 28 to obtain 19.6 mg of YM135 with a yield of 45%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.21(d,J=8.4Hz,1H),7.70(dd,J=8.0,1.4Hz,1H),7.65(dd,J=8.4,1.7Hz, 1H), 7.62–7.53 (m, 2H), 7.45 (t, J=8.0Hz, 1H), 7.33 (d, J=8.1Hz, 1H), 6.67 (dd, J=8.1, 1.9Hz, 1H), 6.45(d,J＝1.9Hz,1H),5.06(d,J＝9.9Hz,1H),4.82(d,J＝10.0Hz,1H),4.18(d,J＝7.6Hz,1H),3.74( s, 3H), 3.69(s, 2H), 1.80–1.66(m, 2H), 0.95(s, 9H). ESI-MS calculated for C ₃₁ H ₃₃ ³⁵ Cl ₃ N ₃ O ₄ [M+H] ⁺ = 616.2, experimentally measured: 616.3.

Final product 129: 4-((2'S,3S,4'R,5'R)-5-chloro-4'-(3-chlorophenyl)-2'-neopentylspiro[indoline-3 ,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YM35)

YK009 (44.8 mg, 0.073 mmol), potassium carbonate (30 mg, 0.22 mmol) and lithium hydroxide monohydrate (15 mg, 0.37 mmol), refer to the synthesis method of final product 28 for the reaction steps, to obtain 16.8 mg of YM135, yield 33% . ¹ H NMR(500MHz,Methanol-d ₄ )δ8.30(d,J=8.4Hz,1H),7.64(dd,J=8.4,1.8Hz,1H),7.55(d,J=1.8Hz,1H) ,7.47(d,J＝2.1Hz,1H),7.41–7.27(m,3H),7.17(d,J＝7.5Hz,1H),7.05(dd,J＝8.4,2.1Hz,1H),6.47( d, J=8.4Hz, 1H), 5.16 (d, J=11.3Hz, 1H), 4.13 (d, J=11.3Hz, 1H), 4.10 (d, J=8.0Hz, 1H), 3.75 (s, 3H),3.65(d,J＝10.9Hz,1H),3.52(d,J＝10.9Hz,1H),1.79(dd,J＝15.4,8.0Hz,1H),1.72(dd,J＝15.5,2.0 Hz, 1H), 0.94 (s, 9H). ESI-MS theoretical calculation value C ₃₁ H ₃₄ ³⁵ Cl ₂ N ₃ O ₄ [M+H] ⁺ =582.2, experimentally found: 582.7.

Final product 130: 4-((2'S,3S,4'R,5'R)-5-chloro-4'-(2,3-dichlorophenyl)-2'-neopentylspiro[indoline] Indol-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YM43)

YK113 (18 mg, 0.028 mmol), potassium carbonate (11 mg, 0.08 mmol) and lithium hydroxide monohydrate (6 mg, 0.14 mmol). For the reaction steps, refer to the synthesis method of the final product 28 to obtain 3 mg of the target product with a yield of 15%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.22(d,J=8.4Hz,1H),7.77-7.64(m,2H),7.61-7.52(m,2H),7.52-7.38(m,2H) ), 7.03(dd, J＝8.4, 2.1Hz, 1H), 6.47(d, J＝8.4Hz, 1H), 5.05(d, J＝10.0Hz, 1H), 4.83(d, J＝10.0Hz, 1H) ),4.22(d,J＝6.2Hz,1H),3.76(s,3H),3.69(s,2H),1.75(d,J＝5.0Hz,2H),0.95(s,9H).ESI-MS Theoretical calculated value C ₃₁ H ₃₃ ³⁵ Cl ₃ N ₃ O ₄ [M+H] ⁺ =616.2, experimentally found: 616.0.

Final product 131: 6-(((2'S,3S,4'S,5'R)-5'-((4-carboxy-2-methoxyphenyl)carbamoyl)-5-chloro-4'-( 2-Chlorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidin]-1-yl)methyl)nicotinic acid (YL53)

YK017 (47 mg, 0.076 mmol), methyl 6-(bromomethyl)nicotinate (26 mg, 0.114 mmol), potassium carbonate (32 mg, 0.228 mmol) and lithium hydroxide monohydrate (32 mg, 0.23 mmol), reaction procedure Refer to step 6 of final product 8 to obtain 6.2 mg of the target compound, yield: 10%. ¹ H NMR(500MHz,Methanol-d ₄ )δ9.00(d,J=2.1Hz,1H),8.25(d,J=8.4Hz,1H),8.14(dd,J=8.1,2.2Hz,1H) ,7.69–7.60(m,2H),7.56(d,J=1.8Hz,1H),7.47–7.30(m,4H),7.07(dd,J=8.5,2.1Hz,1H),6.73(d,J ＝8.1Hz,1H),6.34(d,J＝8.5Hz,1H),5.02-4.96(m,1H),4.69(d,J＝10.1Hz,1H),4.35(d,J＝16.4Hz,1H) ), 4.31–4.16 (m, 2H), 3.74 (s, 3H), 3.70 (d, J=10.7Hz, 1H), 3.63 (d, J=10.6Hz, 1H), 1.77–1.61 (m, 2H) , 1.00 (s, 9H). ESI-MS calculated value C ₃₈ H ₃₉ ³⁵ Cl ₂ N ₄ O ₆ [M+H] ⁺ =717.2, experimentally found: 717.5.

Final product 132: 4-((2'S,3S,4'S,5'R)-6-chloro-4'-(2-fluorophenyl)-2'-neopentylspiro[indoline-3,3 '-Pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YM154-6)

YI075-1 (100 mg, 0.17 mmol) was dissolved in MeOH, added with Pd/C (10 mg), reacted under hydrogen overnight, and filtered. The filtrate was spin-dried and purified by HPLC to obtain 9.2 mg of the target compound as a trifluoroacetic acid salt, yield: 8%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.26(d,J=8.4Hz,1H),7.65(dd,J=8.4,1.8Hz,1H),7.55(d,J=1.8Hz,1H) ,7.46(td,J=7.6,1.7Hz,1H),7.45-7.38(m,1H),7.34(dd,J=8.1,1.6Hz,1H),7.26(td,J=7.6,1.2Hz,1H) ), 7.14 (ddd, J=11.2, 8.3, 1.2Hz, 1H), 6.69 (dd, J=8.1, 1.8Hz, 1H), 6.46 (d, J=1.9Hz, 1H), 5.19 (d, J= 10.7Hz, 1H), 4.41 (d, J=10.7Hz, 1H), 4.07 (dd, J=6.5, 3.4Hz, 1H), 3.79–3.68 (m, 4H), 3.60 (d, J=10.9Hz, 1H), 1.86-1.70 (m, 2H), 0.91 (s, 9H). ESI-MS calculated for C ₃₁ H ₃₄ ³⁵ ClFN ₃ O ₄ [M+H] ⁺ =566.2, found: 566.8.

Final product 133: (2'S,3S,4'S,5'R)-N-(4-carbamoyl-2-methoxyphenyl)-6-chloro-4'-(3-chloro-2-fluorobenzene yl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (YN34)

YI075-1 (30 mg, 0.05 mmol) and HATU (38 mg, 0.1 mmol) were dissolved in DMF (2 mL), ammonium chloride (11 mg, 0.2 mmol) and diisopropylethylamine (52 mg, 0.4 mmol) were added at room temperature Stir overnight. Water was added and purified by HPLC to obtain 25 mg of trifluoroacetic acid salt of the target compound, yield: 70%. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.20(d,J=8.2Hz,1H),7.54-7.45(m,3H),7.42(t,J=7.1Hz,1H),7.33(dd, J=8.1, 1.4Hz, 1H), 7.23(t, J=8.0Hz, 1H), 6.71(dd, J=8.1, 1.9Hz, 1H), 6.48(d, J=1.9Hz, 1H), 5.13( d, J＝10.5Hz, 1H), 4.39(d, J＝10.5Hz, 1H), 4.07(d, J＝5.2Hz, 1H), 3.77(s, 3H), 3.73(d, J＝10.9Hz, 1H), 3.56(d, J=11.0Hz, 1H), 1.76(d, J=4.9Hz, 2H), 0.91(s, 9H). ESI-MS calculated value C ₃₁ H ₃₄ ³⁵ Cl ₂ FN ₄ O ₃ [M+H] ⁺ =599.2, found experimentally: 599.7.

Final product 134: 4-((2'S,3S,4'S,5'R)-1-(7-aminoheptyl)-5-chloro-4'-(2-chlorophenyl)-2'-neopentyl Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (GC062)

Step 1: Synthesis of methyl 4-((2'S,3S,4'S,5'R)-1-(7-aminoheptyl)-5-chloro-4'-(2-chlorophenyl)-2'-new Amylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoate (GC058)

Weigh (7-oxoheptyl) tert-butyl carbamate (29.7 mg, 0.13 mmol) and YK017 (40.0 mg, 0.06 mmol) into a 50 ml round-bottom flask, add 10 ml of dichloroethane to dissolve the reactants, and stir at room temperature After 1 hour, 0.1 ml of acetic acid and sodium borohydride acetate (54.8 mg, 0.26 mmol) were added, and the reaction system was stirred at room temperature overnight. After the reaction, water was added to the reaction solution, the aqueous phase was extracted three times with dichloromethane, and the organic layers were combined. It was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator to obtain 75.4 mg of crude product. 75.4 mg of the crude product obtained by the reaction and potassium carbonate (37.6 mg. 0.27 mmol) were placed in a 50 ml round-bottomed flask, 5 ml of N,N-dimethylformamide was added, and the reaction system was stirred at 110° C. overnight. After the reaction was completed, it was cooled to room temperature. Water was added to the reaction solution, the aqueous phase was extracted three times with ethyl acetate, and the organic layers were combined. It was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator to obtain 69.0 mg of crude product. The crude product (69 mg, 0.08 mmol) obtained from the above reaction was weighed in a 50 ml round-bottomed flask, 1 ml of trifluoroacetic acid and 3 ml of dichloromethane were added, and the reaction system was stirred at room temperature for 2 hours. After the reaction, HPLC was purified to obtain the target compound. Trifluoroacetate 21 mg. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.22(d,J=8.4Hz,1H),7.85(d,J=7.9Hz,1H),7.64(dd,J=8.4,1.7Hz,1H) ,7.53(d,J＝1.7Hz,1H),7.48(td,J＝8.0,7.2,2.1Hz,1H),7.41–7.33(m,3H), 7.04(dd,J＝8.5,2.1Hz,1H) ),6.31(d,J＝8.5Hz,1H),5.22(d,J＝10.3Hz,1H),4.74(d,J＝10.3Hz,1H),4.29(d,J＝8.3Hz,1H), 3.88(s,3H), 3.71(s,3H), 3.62–3.53(m,2H), 2.95–2.75(m,4H), 1.69–1.60(m,2H), 1.53–1.25(m,10H), 0.95(s,9H).

Step 2: Synthesis of GC062

GC058 (16.0 mg, 0.02 mmol) was weighed into a 50 ml round-bottomed flask, lithium hydroxide (21.6 mg.0, 40 mmol) was added, 1 ml of water and 1 ml of tetrahydrofuran were added, and the reaction system was stirred at room temperature overnight, and purified by HPLC to obtain the target Compound trifluoroacetate 4 mg. ¹ H NMR(500MHz,Methanol-d4)δ8.26(d,J=8.4Hz,1H),7.75(d,J=7.6Hz,1H),7.65(dd,J=8.4,1.8Hz,1H), 7.58(d, J=1.8Hz, 1H), 7.44(t, J=7.6Hz, 1H), 7.38–7.29(m, 3H), 7.02(dd, J=8.4, 2.1Hz, 1H), 6.29(d , J=8.5Hz, 1H), 4.68(d, J=9.8Hz, 1H), 3.78(s, 3H), 3.51(s, 2H), 2.94–2.79(m, 4H), 1.67–1.60(m, 4H), 1.41–1.07(m, 10H), 0.97(s, 9H). ESI-MS calculated value for C ₃₈ H ₄₉ ³⁵ Cl ₂ N ₄ O ₄ [M+H] ⁺ =695.3; actual value: 695.3.

Final product 135: 4-((2'S,3S,4'S,5'R)-1-(6-aminohexyl)-5-chloro-4'-(2-chlorophenyl)-2'-neopentylspiro [Indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (GB142)

Step 1: Synthesis of methyl 4-((2'S,3S,4'S,5'R)-1-(6-aminohexyl)-5-chloro-4'-(2-chlorophenyl)-2'-neopentyl Base spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoate (GB140)

Weigh (6-oxohexyl) tert-butyl carbamate (40.0 mg, 0.18 mmol) and YK017 (229.0 mg, 0.27 mmol) into a 50 ml round-bottom flask, add 10 ml of dichloroethane to dissolve the reactants, and stir at room temperature for 1 After 1 hour, 0.1 ml of acetic acid and sodium borohydride acetate (156.8 mg, 0.72 mmol) were added, and the reaction system was stirred at room temperature overnight. After the reaction, water was added to the reaction solution, the aqueous phase was extracted three times with dichloromethane, and the organic layers were combined. It was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator to obtain 137.1 mg of crude product. 137.1 mg of the crude product obtained by the reaction and potassium carbonate (70.0 mg. 0.51 mmol) were placed in a 50 ml round-bottomed flask, 5 ml of N,N-dimethylformamide was added, and the reaction system was stirred at 110° C. overnight. After the reaction was completed, it was cooled to room temperature. Water was added to the reaction solution, the aqueous phase was extracted three times with ethyl acetate, and the organic layers were combined. It was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator to obtain 130.0 mg of crude product. The crude product (130.0 mg, 0.21 mmol) obtained from the above reaction was weighed into a 50 ml round-bottomed flask, 2 ml of trifluoroacetic acid and 6 ml of dichloromethane were added, and the reaction system was stirred at room temperature for 2 hours. After the reaction, HPLC was purified to obtain the target compound. of trifluoroacetate 150.0 mg. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.21(d,J=8.4Hz,1H),7.87(d,J=7.9Hz,1H),7.63(dd,J=8.4,1.8Hz,1H) ,7.55–7.45(m,2H),7.42–7.30(m,3H),7.04(dd,J=8.5,2.1Hz,1H),6.31(d,J=8.5Hz,1H),5.25(d,J =10.3Hz,1H),4.74(d,J=10.2Hz,1H),4.30(d,J=8.4Hz,1H),3.87(s,3H),3.70(s,3H),3.58(q,J = 10.8Hz, 2H), 2.96–2.70 (m, 4H), 1.89 (dd, J=15.4, 8.5Hz, 1H), 1.73–1.52 (m, 3H), 1.48–1.10 (m, 6H), 0.96 ( s, 9H).

Step 2: Synthesize GB142

GB140 (150mg, 0.21mmol) was weighed into a 50ml round-bottomed flask, lithium hydroxide (206.0mg, 4.3 mmol) was added, 1ml of water and 1ml of tetrahydrofuran were added, the reaction system was stirred at room temperature overnight, and purified by HPLC to obtain the target compound. Trifluoroacetate 13 mg. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.25(d,J=8.4Hz,1H),7.78(d,J=8.0Hz,1H),7.65(dd,J=8.4,1.7Hz,1H) ,7.60-7.53(m,1H),7.50-7.41(m,1H),7.39-7.30(m,3H),7.02(dd,J=8.4,2.1Hz,1H),6.30(d,J=8.4Hz ,1H),5.00(d,1H),4.69(d,J=9.9Hz,1H),4.09(s,1H),3.77(s,3H),3.53(s,2H),2.96–2.74(m, 4H), 1.74(t, J＝12.1Hz, 1H), 1.68-1.56(m, 3H), 1.45-1.14(m, 6H), 0.97(s, 9H). ESI-MS calculated value C ₃₇ H ₄₇ ^35Cl2N4O4 [M ₊ H] ₊ ⁼ _681.3 found experimentally: 681.3.

Final product 136: 4-((2'S,3S,4'S,5'R)-1-(4-aminobutyl)-5-chloro-4'-(2-chlorophenyl)-2'-neopentyl Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (GC104)

Step 1: Synthesized methyl 4-((2'S,3S,4'S,5'R)-1-(4-aminobutyl)-5-chloro-4'-(2-chlorophenyl)-2'-new Amylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoate (GC098)

Weigh (4-oxobutyl) tert-butyl carbamate (75.0 mg, 0.40 mmol) and YK017 (123.5 mg, 0.2 mmol) into a 50 ml round bottom flask, add 10 ml of dichloroethane to dissolve the reactants, and stir at room temperature After 1 hour, 0.1 ml of acetic acid and sodium borohydride acetate (169.3 mg, 0.80 mmol) were added, and the reaction system was stirred at room temperature overnight. After the reaction, water was added to the reaction solution, the aqueous phase was extracted three times with dichloromethane, and the organic layers were combined. Washed with saturated brine, dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, the crude product obtained from the reaction (148.0 mg, 0.18 mmol) and potassium carbonate (78.4 mg, 0.56 mmol) were placed in a 50 ml round-bottomed flask, and 5 ml of N was added. N-dimethylformamide, the reaction system was stirred at 110 °C overnight. After the reaction was completed, it was cooled to room temperature. Water was added to the reaction solution, the aqueous phase was extracted three times with ethyl acetate, and the organic layers were combined. Washed with saturated brine, dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, the obtained crude product was weighed into a 50ml round-bottomed flask, 2ml of trifluoroacetic acid and 6ml of dichloromethane were added, and the reaction system was stirred at room temperature for 2 hours. After completion, HPLC purification to obtain the target compound trifluoroacetate 74.6mg. ¹ H NMR (500MHz, Methanol-d ₄ ) δ8.21 (d, J=8.5Hz, 1H), 7.88 (d, J=7.9Hz ,1H),7.64(dd,J＝8.5,1.8Hz,1H),7.53(d,J＝1.8Hz,1H),7.51–7.47(m,1H),7.41(d,J＝2.2Hz,1H) ,7.38–7.34(m,2H),7.06(dd,J＝8.5,2.1Hz,1H),6.35(d,J＝8.5Hz,1H),5.24(d,J＝10.2Hz,1H),4.74( d, J=10.3Hz, 1H), 4.31 (dd, J=8.7, 1.4Hz, 1H), 3.88 (s, 3H), 3.71 (s, 3H), 3.64–3.53 (m, 2H), 2.99–2.74 (m, 4H), 1.90 (dd, J=15.4, 8.6Hz, 1H), 1.67 (dd, J=15.5, 1.5Hz, 1H), 1.58–1.32 (m, 4H), 0.96 (s, 9H).

Step 2: Synthesis of GC104

GC098 (74.6mg, 0.11mmol) was weighed into a 50ml round-bottomed flask, lithium hydroxide (107.4mg, 2.2mmol) was added, 1ml water and 1ml tetrahydrofuran were added, the reaction system was stirred at room temperature overnight, and the target was obtained by HPLC purification Compound trifluoroacetate 5.9 mg. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.24(d,J=8.4Hz,1H),7.81(d,J=7.9Hz,1H),7.65(dd,J=8.4,1.8Hz,1H) ,7.57(d,J＝1.8Hz,1H),7.51-7.43(m,1H),7.40-7.28(m,3H),7.05(dd,J＝8.5,2.1Hz,1H),6.34(d,J =8.5Hz,1H),5.09-5.04(m,1H),4.70(d,J=10.1Hz,1H),4.21-4.14(m,1H),3.75(s,3H),3.56(d,J= 2.2Hz, 2H), 2.96–2.81 (m, 4H), 1.78 (dd, J=15.3, 8.7Hz, 1H), 1.63 (d, J=15.1Hz, 1H), 1.57–1.36 (m, 4H), 0.98 (s, 9H). ESI _- MS theoretical calculated for _{C35H4335Cl2N4O4} ₊ [M ₊ H] ⁼ _653.3 found: ^653.3 .

Final product 137: 4-((2'S,3S,4'S,5'R)-1-(5-aminopentyl)-5-chloro-4'-(2-chlorophenyl)-2'-neopentyl Spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (GC128)

Step 1: Synthesis of methyl 4-((2'S,3S,4'S,5'R)-1-(5-aminopentyl)-5-chloro-4'-(2-chlorophenyl)-2'-new Amylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoate (GC126)

Weigh ((5-oxopentyl)carbamate tert-butyl ester (65.3mg, 0.32mmol) and YK017 (100.0mg, 0.16mmol) into a 50ml round-bottom flask, add 10ml of dichloroethane to dissolve the reactants, room temperature Stir for 1 hour, add 0.1 ml of acetic acid, sodium borohydride (137.0 mg, 0.64 mmol), and the reaction system is stirred at room temperature overnight. After the reaction is completed, water is added to the reaction solution, and the aqueous phase is extracted 3 times with dichloromethane and combined The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and the crude product (199.6 mg, 0.25 mmol) obtained from the reaction and potassium carbonate (103.0 mg, 0.75 mmol) were placed in a 50 ml round-bottomed flask, and added 5ml N,N-dimethylformamide, the reaction system was stirred overnight at 110 ° C. After the reaction was completed, it was cooled to room temperature. Water was added to the reaction solution, and the aqueous phase was extracted 3 times with ethyl acetate, and the organic layers were combined. Saturated common salt Washed with water, dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, weighed the obtained crude product in a 50ml round-bottomed flask, added 2ml of trifluoroacetic acid and 6ml of dichloromethane, and the reaction system was stirred at room temperature for 2 hours. , HPLC purification to obtain the target compound trifluoroacetate 63.4mg.

Step 2: Synthesis of GC128

GC126 (63.4 mg, 0.09 mmol) was weighed into a 50 ml round-bottomed flask, lithium hydroxide (89.0 mg, 1.86 mmol) was added, 1 ml of water and 1 ml of tetrahydrofuran were added, the reaction system was stirred at room temperature overnight, and purified by HPLC to obtain the target compound of trifluoroacetate 1.4mg. ESI-MS theoretical calculated for _{C36H45Cl2N4O4} [M ₊ H] ₊ ⁼ _667.28 ; found: _667.3 .

Final product 138: Synthesis of 4-((2'R,3R,4'R,5'S)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-neopentylspiro[di Indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YN21-CF1)

Step 1: Synthesis of the enantiomer (2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorobenzene yl)-5-neopentylpyrrolidine-2-carboxylate tert-butyl ester and enantiomer (2S,3R,4R,5R)-4-(aminomethyl)-3-(3-chloro-2-fluoro Phenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxylate tert-butyl ester (YM159)

SM1 (5.45g, 1.04mmol) was weighed into a 100mL round-bottomed flask, 2g of Raney Nickel was added, dissolved in tetrahydrofuran/ethanol, raised to 55°C, 10mL of hydrazine hydrate was added, the reaction was performed until no bubbling occurred, and the solution was filtered and vortexed. The filtrate was dried and purified by normal phase column to obtain 1.9 g of the target compound, yield: 36%. ¹ H NMR(500MHz,Methanol-d ₄ )δ7.54-7.42(m,2H),7.34(dd,J=8.7,2.2Hz,1H),7.31-7.22(m,3H),4.72(d,J =10.3Hz,1H),4.67(d,J=9.9Hz,1H),4.30(d,J=9.9Hz,1H),3.66-3.60(m,1H),3.60-3.52(m,1H),1.77 (dd, J=14.4, 10.4 Hz, 1H), 1.67–1.54(m, 1H), 1.31(s, 9H), 1.08(s, 9H). ¹³ C NMR(126MHz, Methanol-d ₄ )δ170.86,163.01 (TFA, q, J _CF = 35.3 Hz), 162.47 (d, J _CF = 250.7 Hz), 157.99 (d, J _CF = 248.2 Hz), 137.10 (d, J _CF = 11.3 Hz), 131.82, 130.70 (d , _JCF = 5.0Hz), 129.59, 127.05 (d, _JCF = 3.8Hz), 126.50 (d, _JCF = 3.8Hz), 124.95 (d, _JCF = 13.9Hz), 123.09 (d, _JCF = 3.8Hz) 10.1 Hz), 122.71 (d, J _CF = 18.9 Hz), 119.01 (d, J _CF = 30.2 Hz), 118.00 (TFA, q, J _CF = 292.3 Hz), 84.70, 63.16 (d, J _CF = 3.8 Hz) ), 61.59, 55.58 (d, J _CF = 5.0Hz), 51.79, 42.42, 39.29 (d, J _CF = 6.3 Hz), 31.83, 30.01, 27.88. LRMS(ESI) calculated for C ₂₇ H ₃₅ ³⁵ Cl ₂ F ₂ N ₂ O ₂ [M+H] ⁺ =527.2, obtained: 527.2.

Step 2: Synthesis of Epimer (2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-( ((R)-2-Methoxy-2-phenylacetamide)methyl)-5-neopentylpyrrolidine-2-carboxylic acid and the epimer (2S,3R,4R,5R)- 3-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-(((R)-2-methoxy-2-phenylacetamide)methane yl)-5-neopentylpyrrolidine-2-carboxylic acid (YN003)

Dissolve YM159 (210mg, 0.4mmol) in dichloromethane, add (R)-(-)-alpha-methoxyphenylacetyl chloride (110mg, 0.6mmol) and triethylamine (162mg, 1.6mmol), stir at room temperature overnight. After the reaction was completed, water was added, extracted with dichloromethane, the organic phase was spin-dried and purified with a normal phase column to obtain the crude product. The crude product was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added, overnight at room temperature. After the reaction, water was added, extracted with dichloromethane, the organic phase was spin-dried and purified by a normal phase column to obtain 226 mg of the target compound, yield: 91%.

Step 3: Synthesis of (2S,3R,4R,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-(((R)- 2-Methoxy-2-phenylacetamide)methyl)-5-neopentyl-N-((S)-1-phenethyl)pyrrolidine-2-carboxamide (YN015-CF1) and ( 2R,3S,4S,5S)-3-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-(((R)-2-methoxy -2-Phenylacetamide)methyl)-5-neopentyl-N-((S)-1-phenethyl)pyrrolidine-2-carboxamide (YN015-CF2)

YN003 (226 mg, 0.36 mmol) was weighed into a bottle, dissolved in tetrahydrofuran, diisopropylethylamine (232 mg, 1.8 mmol) and diphenylphosphine chloride (255 mg, 1.08 mmol) were added, and the mixture was stirred at room temperature for 30 min. (S)-1-Phenethylamine (176 mg, 1.46 mmol) was reacted at room temperature overnight. Water was added, extracted with dichloromethane, the organic phase was spin-dried and purified with a normal phase column to obtain 200 mg of the target compound mixture, yield: 77%. The above operation was repeated to accumulate 400 mg of the mixture. The mixture was purified by reverse-phase HPLC to isolate YN015-CF1, 172 mg, ¹ H NMR (500 MHz, Methanol-d ₄ ) δ 7.73 (t, J=7.0 Hz, 1H), 7.67-7.54 (m, 1H), 7.38(t,J=8.0Hz,1H),7.31-7.19(m,5H),7.17-7.08(m,3H),7.04-6.97(m,2H),6.94(t,J=8.8Hz,1H) ,6.89–6.82(m,2H),6.75(dd,J=8.5,2.6Hz,1H),5.22–4.96(m,2H),4.88(dd,J=10.4,5.7Hz,1H),4.52(d , J=9.4Hz, 1H), 4.45(s, 1H), 4.18(d, J=15.3Hz, 1H), 3.74(dd, J=15.2, 2.5Hz, 1H), 3.06(s, 3H), 1.82 (dd, J=15.3, 9.5Hz, 1H), 1.46-1.35(m, 4H), 0.82(s, 9H). YN015-CF2, 172mg, ¹ H NMR (500MHz, Methanol-d ₄ )δ7.65( t, J=7.2Hz, 1H), 7.56 (t, J=7.5Hz, 1H), 7.40–7.18 (m, 10H), 7.17–6.97 (m, 4H), 5.03 (d, J=10.0Hz, 1H) ), 4.97 (q, J=6.8Hz, 1H), 4.85–4.62 (m, 2H), 4.52 (s, 1H), 4.17–3.95 (m, 1H), 3.85 (d, J=15.3Hz, 1H) ,3.10(s,3H),1.97(dd,J＝15.2,9.9Hz,1H),1.60(d,J＝15.0Hz,1H),1.23(d,J＝7.0Hz,3H),0.95(s, 9H). Repeat the above operation, accumulative mixture YN05-CF1 383mg, YN05-CF2 383mg.

Step 4: Synthesis of (2S,3R,4R,5R)-4-(aminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)- 5-Neopentylpyrrolidine-2-carboxylic acid (YN16-CF1)

YN015-CF1 (383 mg, 0.5 mmol) was dissolved in 10 mL of concentrated hydrochloric acid, ethanol was added, and refluxed for 18 h. After the reaction was completed, 187 mg of YN16-CF1 trifluoroacetate was purified by HPLC, and the yield was 75%. ¹ H NMR(500MHz, Methanol-d ₄ )δ7.55-7.48(m,1H),7.47-7.41(m,1H),7.40-7.36(m,1H),7.36-7.20(m,3H),5.07 (d, J＝11.1Hz, 1H), 4.97 (d, J＝10.9Hz, 1H), 4.29 (d, J＝11.1Hz, 1H), 3.82 (d, J＝14.2Hz, 1H), 3.72–3.63 (m, 1H), 2.09–1.94 (m, 1H), 1.84–1.70 (m, 1H), 1.13 (s, 9H).

Step 5: Synthesis of (2S,3R,4R,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-(((4-methyl Oxybenzyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxylic acid (YN18-CF1)

YN16-CF1 (187 mg, 0.4 mmol) was dissolved in methanol, p-methoxybenzaldehyde (109 mg, 0.8 mmol), sodium cyanoborohydride (101 mg, 1.6 mmol) and 1 mL of acetic acid were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, 133 mg of trifluoroacetic acid salt of the target compound was obtained by HPLC purification, yield: 47%.

Step 6: Synthesis of methyl 4-((2S,3R,4R,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-( ((4-Methoxybenzyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YN20-CF1)

YN18-CF1 (133 mg, 0.22 mmol) was weighed into a bottle, dissolved in tetrahydrofuran, diisopropylethylamine (144 mg, 1.12 mmol) and diphenylphosphine chloride (156 mg, 0.66 mmol) were added, and the mixture was stirred at room temperature for 30 min Then, methyl 3-methoxy-4-aminobenzoate (163 mg, 0.9 mmol) was added, and the reaction was carried out at room temperature overnight. Water was added, extracted with dichloromethane, the organic phase was spin-dried and purified with a normal phase column to obtain the crude product of the target compound YN20-CF1, which was directly used in the next step.

Step 7: Synthesis of 4-((2'R,3R,4'R,5'S)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-neopentylspiro[dihydro Indole-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YN21-CF1)

The crude product of YN20-CF1 was dissolved in N,N-dimethylformamide, potassium carbonate (36 mg, 0.26 mmol) was added, and the mixture was stirred at 100° C. overnight. After the reaction, water was added, extracted with ethyl acetate, the organic phase was spin-dried, dissolved in TFA, and reacted at 50 °C for 1 h. After the reaction, it was directly dried, dissolved in ethyl acetate, washed with saturated sodium bicarbonate three times, the organic phase was spin-dried, dissolved in tetrahydrofuran/water (5/5 mL), and lithium hydroxide monohydrate (18 mg, 0.43 mmol) was added. , and stirred overnight at room temperature. After the reaction was completed, 6.5 mg of the trifluoroacetate salt of the target compound YN21-CF1 was obtained by HPLC purification. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.25(d,J=8.4Hz,1H),7.65(dd,J=8.4,1.8Hz,1H),7.58(d,J=1.8Hz,1H) ,7.48(t,J＝7.6Hz,1H),7.39(t,J＝7.1Hz,1H),7.34–7.28(m,1H),7.22(t,J＝7.9Hz,1H),6.70(dd, J=8.1, 2.0Hz, 1H), 6.47(d, J=1.9Hz, 1H), 5.06(d, J=9.8Hz, 1H), 4.36(d, J=10.3Hz, 1H), 3.99(s, 1H), 3.79(s, 3H), 3.71(d, J=10.8Hz, 1H), 3.53(d, J=10.9Hz, 1H), 1.72(d, J=6.3Hz, 2H), 0.92(s, 9H). ESI-MS theoretical calculation value C ₃₁ H ₃₂ ³⁵ Cl ₂ FN ₃ O ₄ [M+H] ⁺ =600.18, experimentally measured: 600.6.

Final Product 139: Synthesis of 4-((2'S,3S,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-neopentylspiro[indoline] Indol-3,3'-pyrrolidine]-5'-carboxamide)-3-methoxybenzoic acid (YN24-CF2)

Step 1: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)- 5-Neopentylpyrrolidine-2-carboxylic acid (YN17-CF2)

Referring to the synthesis method of YN16-CF1 in Step 4 of Example 138, using YN015-CF2 as a raw material, 203 mg of trifluoroacetate of YN17-CF2 was obtained with a yield of 81%. ¹ H NMR (500MHz, Methanol-d ₄ )δ7.55-7.48(m,1H),7.47-7.41(m,1H),7.40-7.36(m,1H),7.36-7.20(m,3H),5.01 (d, J＝11.1Hz, 1H), 4.95 (d, J＝10.9Hz, 1H), 4.28 (d, J＝11.1Hz, 1H), 3.81 (d, J＝14.2Hz, 1H), 3.71–3.61 (m, 1H), 2.09–1.94 (m, 1H), 1.84–1.70 (m, 1H), 1.12 (s, 9H).

Step 2: Synthesis of (2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-(((4-methyl Oxybenzyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxylic acid (YN19-CF2)

Referring to the synthesis method of YN18-CF1 in Step 5 of Example 138, using YN17-CF2 as a raw material, 181 mg of trifluoroacetic acid salt of YN19-CF2 was obtained with a yield of 60%.

Step 3: Synthesis of methyl 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-( ((4-Methoxybenzyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YN22-CF2)

Referring to the synthesis method of YN20-CF1 in Step 6 of Example 138, using YN19-CF2 as a raw material, a crude product of YN22-CF2 was obtained.

Step 4: Synthesis of 4-((2'S,3S,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-neopentylspiro[indoline -3,3'-pyrrolidine]-5'-carboxamide)-3-methoxybenzoic acid (YN24-CF2)

Referring to the synthesis method of YN21-CF1 in Step 7 of Example 138, using YN22-CF2 as a raw material, 21.8 mg of the trifluoroacetate salt of YN24-CF2 was obtained. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.25(d,J=8.4Hz,1H),7.65(dd,J=8.4,1.8Hz,1H),7.58(d,J=1.8Hz,1H) ,7.48(t,J＝7.6Hz,1H),7.39(t,J＝7.1Hz,1H),7.34–7.28(m,1H),7.22(t,J＝7.9Hz,1H),6.70(dd, J=8.1, 2.0Hz, 1H), 6.47(d, J=1.9Hz, 1H), 5.06(d, J=9.8Hz, 1H), 4.36(d, J=10.3Hz, 1H), 3.99(s, 1H), 3.79(s, 3H), 3.71(d, J=10.8Hz, 1H), 3.53(d, J=10.9Hz, 1H), 1.72(d, J=6.3Hz, 2H), 0.92(s, 9H). ESI-MS theoretical calculation value C ₃₁ H ₃₂ ³⁵ Cl ₂ FN ₃ O ₄ [M+H] ⁺ =600.18, experimentally measured: 600.6. Optical rotation α=7.95 (T=20°C, concentration=0.87g/100mL).

Final product 140: (2'S,3S,4'R,5'R)-N-(4-carbamoyl-2-methoxyphenyl)-6-chloro-4'-(3-chlorophenyl) -2'-Neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (YN56)

YM85 (30 mg, 0.05 mmol) and HATU (38 mg, 0.1 mmol) were dissolved in DMF (2 mL), ammonium chloride (11 mg, 0.2 mmol) and diisopropylethylamine (52 mg, 0.4 mmol) were added and stirred at room temperature overnight . Water was added and purified by HPLC to obtain 19 mg of trifluoroacetic acid salt of the target compound, yield: 55%. ESI-MS theoretical calculated value for C ₃₁ H ₃₅ ³⁵ Cl ₂ N ₄ O ₃ [M+H] ⁺ =581.2, experimentally found: 581.4.

Selecting corresponding raw materials, each compound in the following table 1 can be synthesized:

Table 1

Example 2: Ki value of FP detection compound and MDMX protein

His-tagged MDMX (14-111, C17S) was expressed in E. coli, purified by Ni affinity column and then purified by Superdex75 molecular sieve. The obtained MDMX protein was more than 95% pure, and the protein concentration was 12.5 μM. FAM-labeled PDI polypeptide (FAM-PDI) [Cancer Res 2007, 67, 8810-8817] was used as a fluorescently labeled molecular probe, wherein the dissociation constant K _d of the MDMX/FAM-PDI interaction was 2.1 nM.

96-well plates were purchased from Corning Corporation (black, #3694). The multi-function microplate reader is a product of TECAN company, model: SPARK 10M. Detection buffer: 10 mM Tris (pH 7.5), 200 mM NaCl (Sigma), 0.01% Tween-20 and 0.01% Trition X-100 (Sigma), and the experimental water was Millipore-Q pure water.

The compounds to be tested were firstly dissolved in DMSO into 20 mM stock standard solutions. Subsequently, the standard stock solution of the test compound was diluted into a working sample solution with DMSO in an EP tube, and the concentration of the prepared working sample solution = 25 times the maximum sample concentration required on the test plate (25 × test compound solution), in the EP tube 3-fold serial dilution of compounds in medium and set aside.

Add 4 μL of 25× test compound solution of compound A to be tested in gradient dilutions in wells B1-D1 to B12-D12 of the 96-well plate, and add 25× of compound B to be tested in gradient dilutions in wells E1-G1 to E12-G12. Test compound solution 4 μL. Finally, 96 μL of detection buffer containing 5.2 nM FAM-PDI and 62.5 nM MDMX protein was added to each well above.

Wells A1-A3 were used as blank control group: add 100uL detection buffer. Wells A4-A6 were used as negative signal reference group: 100 μL of buffer containing only 5nM fluorescently labeled molecular probe was added. Wells A7-A9 are used as positive reference group: add 100 μL of mixed solution containing 5nM fluorescently labeled molecular probe and 60nM MDMX protein.

The above reaction plate was covered with aluminum foil, and the 96-well plate was placed on a 96-well plate shaker and incubated at room temperature for 1 h, and the fluorescence polarization mP value at Ex485nm/Em530nm was read with a microplate reader. The measured mP value is plotted against the compound concentration gradient, and the sample compound concentration corresponding to the median value of the mP maximum value and minimum value is the IC ₅₀ value ([I] ₅₀ ) of the binding of the compound to the protein.

According to this IC ₅₀ value ([I] ₅₀ ), use the formula to calculate the binding rate constant of the compound to the protein

K _i : K _i =[I] ₅₀ /([L] ₅₀ /K _d +[P] ₀ /K _d +1).

Wherein [L] ₅₀ represents 50% of the concentration of fluorescently labeled molecular probe in the above test system; [P] ₀ represents the concentration of MDMX protein in the above test system, and K _d is the dissociation constant of protein and fluorescently labeled molecular probe.

Using the above method, the K _i values of the compounds of the examples for inhibiting the MDMX/p53 interaction were determined as shown in Table 2 below. Experimental data show that the compound has activity as an inhibitor of the MDMX/p53 interaction.

Table 2: Example compounds inhibit MDMX/p53 and MDM2/p53 interaction activities

*indicates K _i between 100,000 nM and 10,000 nM; **indicates K _i between 10,000 nM and 100 nM; *** indicates K _i between 100 nM and 10 nM; **** indicates K _i < 10 nM.

Example 3: Ki value of FP detection compound and MDX2 protein

His-tagged MDM2 (1-118) was expressed in E.coli, purified by Ni affinity column and then purified by Superdex75 molecular sieve. The purity of the obtained MDMX protein was more than 95%, and the protein concentration was 151 μM. FAM-labeled PDI polypeptide (FAM-PDI) [Cancer Res 2007, 67, 8810-8817] was used as a fluorescently labeled molecular probe, wherein the dissociation constant K _d of the MDM2/FAM-PDI interaction was 0.7 nM.

96-well plates were purchased from Corning Corporation (black, #3694). The multi-function microplate reader is a product of TECAN company, model: SPARK 10M. Detection buffer: 100mM potassium phosphate (pH 8.0), 100ug/mL Bovine-r-globulin (Sigma) and 0.01% Triition X-100 (Sigma), and the experimental water was Millipore-Q pure water.

Add 4 μL of 25× test compound solution of compound A to be tested in gradient dilutions in wells B1-D1 to B12-D12 of the 96-well plate, and add 25× of compound B to be tested in gradient dilutions in wells E1-G1 to E12-G12. Test compound solution 4 μL. Finally, 96 μL of detection buffer containing 2.08 nM FAM-PDI and 20.8 nM MDM2 protein was added to each well above.

Wells A1-A3 were used as blank control group: add 100 μL detection buffer. Wells A4-A6 are used as negative signal reference group: add 100 μL of buffer containing only 2nM fluorescently labeled molecular probe. Wells A7-A9 were used as a positive reference group: add 100 μL of a mixed solution containing 2nM fluorescently labeled molecular probes and 20nM MDM2 protein.

K _i : K _i =[I] ₅₀ /([L] ₅₀ /K _d +[P] ₀ /K _d +1).

Wherein [L] ₅₀ represents 50% of the concentration of fluorescently labeled molecular probe in the above test system; [P] ₀ represents the concentration of MDM2 protein in the above test system, K _d is the dissociation constant of protein and fluorescently labeled molecular probe.

Using the above method, the K _i values of the compounds of the examples for inhibiting the MDM2/p53 interaction were determined as shown in Table 2. The experimental data show that the compounds are very active in inhibiting the MDM2/p53 interaction.

Example 4: Determination of relative stereoconfiguration of compounds

The pre-hydrolysis compound of the final product 3 (YK094-Me, 4-((2'S,3S,4'S,5'R)-5-chloro-4'-(2-chlorophenyl)-2'-neopentyl- 1-(3-Nitrobenzyl)spiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid methyl ester) 80mg was weighed into a 10mL glass vial Add 1.5 mL of chloroform, add 1 mL of ethyl acetate, heat to dissolve the compound completely, seal with aluminum foil and prick 3 small holes with a needle, stand at room temperature for 4 days to grow a single crystal, X-ray single crystal diffraction test The compound diffraction data and results are shown in Table 3 below: The crystal data indicate that the relative stereo configuration of YK094-Me is shown in Figure 1 .

Table 3 X-ray single crystal diffraction test compound diffraction data

Example 5 Cell Growth Inhibitory Activity Experiment

Cell growth inhibition assay: dissolve the sample to be tested with 100% dimethyl sulfoxide, and prepare a 20 mM compound stock solution. Compounds were diluted in 100% dimethyl sulfoxide to the highest concentration (1 mM or 10 mM) required for the experiment.

First, add 145 μL of cell complete medium to wells B1-G1 of a 96-well flat-bottomed clear cell culture plate, and add 100 μL of complete medium to wells B2-G12, respectively. Then, 5 μL of 1 mM or 10 mM compound solution was added to the B1-D1 and E1-G1 wells of the 96-well flat-bottom clear cell culture plate, respectively, and sequentially diluted 3-fold to B12-D12 and E12- of the 96-well flat-bottom clear cell culture plate. G12. Finally, add 50 μL of the cell solution to be tested to each well. The cell density of each well is: about 3000 per well for HCT116 and RKO, about 5000 per well for U2-OS, about 8000 per well for JEG-3, and about 8000 per well per well. The total volume is 150 μL. In the experiment, in addition to the tested compounds, two control groups were set up: (1) control group with cells and medium, but no compound added; (2) group with complete medium only, no cells and no compound. After incubating the 96-well plate in a 37°C cell incubator with 5% carbon dioxide for 4 days, add 15 μL of CCK-8 reagent to each well, and then incubate at 37°C for 2-3 hours. The absorbance at 450 nm was read with a TECAN microplate reader.

The effect of different concentrations of compounds on cell viability was calculated by the following formula: cell growth inhibition rate=[absorption value of experimental group-absorption value of complete medium only (no cells and no compound group)]/[absorption value of cells added without compound group- Add only complete medium (no cell and no compound group) absorption value] × 100%. The above data were processed by GraphPad Prism 7.0 software, and the IC ₅₀ value was taken as the compound concentration corresponding to the cell growth inhibition rate of 50%.

Using the above method, the cellular activities of compound 28 (YI075-1)/126 (YM85) and literature compounds YM30 and RG7388 were tested, and the data are shown in the following table.

化合物compound	HCT-116HCT-116	RKO(nM)RKO(nM)	U-2OS(nM)U-2OS(nM)	JEG-3(nM)JEG-3(nM)
	IC ₅₀(nM) _IC50 (nM)	IC ₅₀(nM) _IC50 (nM)	IC ₅₀(nM) _IC50 (nM)	IC ₅₀(nM) _IC50 (nM)
RG7388RG7388	28.84±2.4728.84±2.47	212.36±84.47212.36±84.47	181.80±29.41181.80±29.41	1700±5651700±565
YM30YM30	1.59±0.681.59±0.68	35.09±27.3535.09±27.35	42.34±10.0142.34±10.01	17.00±19.7917.00±19.79
28(YI075-1)28(YI075-1)	0.006±0.0040.006±0.004	0.012±0.0020.012±0.002	0.237±0.1430.237±0.143	0.30.3
126(YM85)126 (YM85)	<0.001<0.001	<0.01<0.01	<0.01<0.01	0.50.5

The above experimental results showed that in HCT-116, RKO, U-2OS, JEG-3 and other tumor cell models, the cell proliferation inhibitory activity of compounds 28 (YI075-1) and 126 (YM85) was higher than that of RG7388 and YM30. The inhibitory activity is increased by more than 100 times, which has a significant activity advantage.

Example 6: Comparison of the stability of compound 28 (YI075-1) and literature compound YM30

YM30 was dissolved in 0.4mL acetonitrile:water mixed solution (volume ratio=1:1), and ammonia water was added dropwise to pH=9-10, placed at room temperature, and then 5 microliters were sampled at regular intervals, and the purity was tested on UPLC. The purity (%) of the compound was plotted against the corresponding sampling time, and the curve of the purity of compound YM30 changing with time was obtained. In the same way, the curve of the purity of 28 (YI075-1) in acetonitrile/water solution, pH=9-10, as a function of time can be tested (Fig. 2).

The results in Figure 2 show that, under the same experimental conditions, after 3 days, the purity of compound 28 (YI075-1) in solution is higher than that of YM30, indicating that compound 28 has higher stability.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

A compound of formula (I), its enantiomer, diastereomer, racemate or a pharmaceutically acceptable salt thereof,

In the formula, Ar is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group, wherein the substitution refers to a group in which one or more hydrogen atoms on the phenyl group or naphthyl group are selected from the group consisting of Group substitution: halogen, deuterium, cyano, hydroxyl, amino, nitro, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl , substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C1-C4 alkylcarbonyl;

R 1 and R 2 are each independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C8 cycloalkane radical, substituted or unsubstituted C1-C4 alkoxy;

R3 is

Y and Z are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, -(CH 2 ) m -substituted or unsubstituted C3-C8 cycloalkyl, -(CH 2 ) m -substituted or unsubstituted 5-13 membered heterocyclyl, -(CH 2 ) m -substituted or unsubstituted 5-12 membered heteroaryl, -(CH 2 ) m -substituted or unsubstituted 6-10 membered aryl; or Y , Z and N form a substituted or unsubstituted 5-13-membered heterocyclic group;

R 4 is hydrogen, substituted or unsubstituted C1-C6 alkyl, -(CH 2 ) m -substituted or unsubstituted 6-10-membered aryl, -(CH 2 ) m -substituted or unsubstituted C3-C8 Cycloalkyl, -(CH 2 ) m -substituted or unsubstituted 5-12 membered heteroaryl, -(CH 2 ) m -substituted or unsubstituted 5-13 membered heterocyclyl, -CO-substituted or unsubstituted Substituted 6-10-membered aryl, -CO-substituted or unsubstituted 3-10-membered cycloalkyl, -SO 2 -substituted or unsubstituted 6-10-membered aryl;

m is independently 0, 1, 2, 3, or 4 at each occurrence;

R 5 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12-membered heterocyclic group;

Unless otherwise defined, each of the substitutions described above independently means that one or more hydrogen atoms on the group are replaced by a group selected from the group consisting of halogen, deuterium, cyano, hydroxy, amino, nitro, C2-C4 alkynyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonamidocarbonyl (C1-C4 alkylSO 2 NHCO-), carboxyl, -CONH 2 , C1-C4 alkyl, C3-C6 Cycloalkyl, C1-C4alkoxy, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkylethynyl, mono(C1-C4alkyl)amino, di(C1-C4alkyl)amino , C1-C4 alkylcarbonylamino, C1-C4 alkoxycarbonylamino, C1-C4 alkylSO 2 -, C1-C4 alkyl-S(O 2 )-C1-C4 alkylene-, carboxyl substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, C1-C4 alkyl-S-, C2-C10 acyl, C1-C4 alkylcarbonyl, C1-C4 alkylaminocarbonyl, 5-12-membered heteroaryl base, 5-12-membered heteroarylcarbonyl, C1-C4 alkyl 5-12-membered heteroarylcarbonyl.
A compound of formula (I), its enantiomer, diastereomer, racemate or a pharmaceutically acceptable salt thereof,

In the formula, Ar is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group, wherein the substitution refers to a group in which one or more hydrogen atoms on the phenyl group or naphthyl group are selected from the group consisting of Group substitution: halogen, deuterium, cyano, hydroxyl, amino, nitro, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl , substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C1-C4 alkylcarbonyl;

R 1 and R 2 are each independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C8 cycloalkane radical, substituted or unsubstituted C1-C4 alkoxy;

R3 is

Y and Z are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, -(CH 2 ) m -substituted or unsubstituted C3-C8 cycloalkyl, -(CH 2 ) m -substituted or unsubstituted 5-13 membered heterocyclyl, -(CH 2 ) m -substituted or unsubstituted 5-12 membered heteroaryl, -(CH 2 ) m -substituted or unsubstituted 6-10 membered aryl; or Y , Z and N form a substituted or unsubstituted 5-13-membered heterocyclic group;

R 4 is hydrogen, substituted or unsubstituted C1-C8 alkyl, -(CH 2 ) m -substituted or unsubstituted 6-10-membered aryl, -(CH 2 ) m -substituted or unsubstituted C3-C8 Cycloalkyl, -(CH 2 ) m -substituted or unsubstituted 5-12 membered heteroaryl, -(CH 2 ) m -substituted or unsubstituted 5-13 membered heterocyclyl, -CO-substituted or unsubstituted Substituted 6-10-membered aryl, -CO-substituted or unsubstituted 3-10-membered cycloalkyl, -SO 2 -substituted or unsubstituted 6-10-membered aryl;

m is independently 0, 1, 2, 3, or 4 at each occurrence;

R 5 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12-membered heterocyclic group;

Unless otherwise defined, each of the substitutions described above independently means that one or more hydrogen atoms on the group are replaced by a group selected from the group consisting of halogen, deuterium, cyano, hydroxy, amino, nitro, C2-C4 alkynyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonamidocarbonyl (C1-C4 alkylSO 2 NHCO-), carboxyl, -CONH 2 , C1-C4 alkyl, C3-C6 Cycloalkyl, C1-C4alkoxy, C2-C4alkenyl, C2-C4alkynyl, C1-C4alkylethynyl, mono(C1-C4alkyl)amino, di(C1-C4alkyl)amino , C1-C4 alkylcarbonylamino, C1-C4 alkoxycarbonylamino, C1-C4 alkylSO 2 -, C1-C4 alkyl-S(O 2 )-C1-C4 alkylene-, carboxyl substituted C1-C4 alkyl, hydroxy substituted C1-C4 alkyl, C1-C4 alkyl-S-, C2-C10 acyl, C1-C4 alkylcarbonyl, C1-C4 alkylaminocarbonyl, C1-C4 haloalkylamino Carbonyl, 5-12-membered heteroaryl, 5-12-membered heteroarylcarbonyl, C1-C4 alkyl 5-12-membered heteroarylcarbonyl.
The compound of claim 1 or 2, wherein the compound has a structure as shown in formula (II):

In the formula, the definitions of Ar, R 1 , R 2 , R 3 and R 4 are as described in claim 1 .
The compound of claim 1 or 2, wherein Ar is a substituted or unsubstituted phenyl group, and the substitution means that one or more hydrogen atoms on the phenyl group are replaced by a group selected from the group consisting of : halogen, deuterium, cyano, hydroxyl, carboxyl, amino, nitro, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl; above C1-C4 alkyl , C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl optionally further substituted with one or more groups selected from the group consisting of halogen, deuterium, cyano, hydroxyl, amino, nitro group, carboxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino.
The compound of claim 1 or 2, wherein R 1 and R 2 are each independently hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4alkoxy.
The compound of claim 1 or 2, wherein Y is H or substituted or unsubstituted C1-C4 alkyl; Z is H, -(CH 2 ) m -substituted or unsubstituted phenyl, - (CH 2 ) m -substituted or unsubstituted 5-7 membered heteroaryl, -(CH 2 ) m -substituted or unsubstituted C3-C6 cycloalkyl, -(CH 2 ) m -substituted or unsubstituted 5-7 membered heterocyclyl; or Y, Z and N form a substituted or unsubstituted 5-13 membered heterocyclyl;

where m is independently 0, 1, 2, or 3 at each occurrence;

The substitution refers to substitution with one or more groups selected from the group consisting of amino, hydroxyl, carboxyl, C1-C4alkoxy, -CONH2 , C1-C4alkyl-CONH-, C1-C4alkyl -NHCO-, C1-C4 alkyl, C1-C4 alkyl-S(O 2 )-C1-C4 alkylene-, C1-C4 alkyl SO 2 NHCO-, carboxy-substituted C1-C4 alkyl, di- (C1-C4 alkyl)amino, mono(C1-C4 alkyl)amino, hydroxy substituted C1-C4 alkyl, deuterium, fluorine, chlorine, bromine, cyano, nitro.
The compound of claim 1 or 2, wherein R 4 is hydrogen, substituted or unsubstituted C1-C6 alkyl, -(CH 2 ) m -substituted or unsubstituted phenyl, -(CH 2 ) m -substituted or unsubstituted C3-C6 cycloalkyl, -(CH 2 ) m -substituted or unsubstituted 5-7 membered heteroaryl, -(CH 2 ) m -substituted or unsubstituted 5-7 membered heterocyclyl, -CO-substituted or unsubstituted phenyl, -CO-substituted or unsubstituted 6-10 membered cycloalkyl, -SO 2 -substituted or unsubstituted 6-10 membered aryl;

The substitution refers to substitution with one or more groups selected from the group consisting of halogen, cyano, amino, hydroxyl, nitro, carboxyl, C1-C4alkoxy, -CONH2 , C1-C4alkyl- CONH-, C1-C4 alkyl-NHCO-, C1-C4 alkyl, C1-C4 alkyl-S(O 2 )-C1-C4 alkylene-, C1-C4 alkyl SO 2 -, 6-10 Aryl, C3-C6 cycloalkyl, 5-7-membered heteroaryl, 5-7-membered heterocyclic, carboxyl-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, C1-C4 alkyl SO 2 NHCO-, (C1-C4 alkyl) amino, two (C1-C4 alkyl) amino, C1-C4 alkyl carbonyl, C1-C4 alkyl amino carbonyl, 5-7 membered heteroaryl carbonyl, C1- C4 alkyl 5-7 membered heteroarylcarbonyl.
The compound of claim 1 or 2, wherein the compound is selected from the group consisting of:
A pharmaceutical composition, characterized in that, comprising: the compound according to any one of claims 1-8, its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt one or more of; and

A pharmaceutically acceptable carrier.
The compound of any one of claims 1-8, its enantiomer, diastereomer, racemate or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 9 The use is characterized in that it is used to prepare a small molecule inhibitor for blocking the interaction of MDM2/p53 and/or MDMX/p53; or to prepare a medicine for treating diseases related to the activity or expression of MDM2 or MDMX protein.
The use according to claim 10, wherein the disease related to the activity or expression level of MDM2 or MDMX protein is selected from the group consisting of: glioma, liposarcoma, skin melanoma, squamous cell carcinoma , retinoblastoma, breast, esophagus, lung, ovarian, gastric, bladder, liver, soft tissue sarcoma, chronic lymphocytic leukemia, acute myeloid leukemia, lymphoma, osteosarcoma and colon cancer.