Compounds having the structure of 4-(substituted aminomethyl)-5-neopentyl-N-substituted pyrrolidine-2-carboxamide

Abstract

The present invention relates to a class of MDM2-p53 and MDMX-p53 protein-protein interaction small molecule inhibitors, and specifically to a class of small molecule compounds having a 4-(substituted aminomethyl)-5-neopentyl-N-substituted pyrrolidine-2-carboxamide structure and similar structures thereof, a preparation method thereof, a pharmaceutical composition thereof, and use thereof in preparing MDM2-p53 and MDMX-p53 protein-protein interaction small molecule inhibitors, or preventing and / or treating diseases related to MDM2 and MDMX, especially anti-tumor drugs.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and specifically relates to a compound having a 4-(substituted aminomethyl)-5-neopentyl-N-substituted pyrrolidine-2-carboxamide structure, a stereoisomer, an enantiomer or a pharmaceutically acceptable salt thereof, and a preparation method and use thereof. Technical Background

[0002] 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 susceptible to a variety of tumors. The TP53 gene encoding the p53 protein is mutated or deleted in nearly 50% 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 a variety of inhibitors. Studies have shown that two proteins are essential for the regulation of p53—MDM2 and MDMX (also known as MDM4). The embryonic lethality caused by knocking out the MDM2 and MDMX genes can be rescued by knocking out the TP53 gene in mice at the same time, clarifying the role 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 the p53 protein by interacting with the transcription activation domain (TAD) of the p53 protein through their amino-terminal p53 binding domains. In addition, MDM2 can promote the ubiquitination and proteasomal degradation of MDM2 itself, MDMX, and p53 proteins. Conversely, p53 specifically binds to the MDM2 P2 promoter and activates its transcription, thus forming an autoregulatory feedback loop—the MDM2-p53 feedback loop. MDM2 can also promote the translocation of p53 protein out of the nucleus, making it impossible for p53 to access its target DNA, thereby reducing its transcriptional capacity. As for MDMX, although it cannot act as an E3 ubiquitin ligase to degrade like MDM2, it can form a stable heterodimer with the carboxyl-terminal RING domain of MDM2 through its carboxyl-terminal RING domain to promote MDM2-mediated p53 ubiquitination.

[0003] Studies have shown that compared with normal cells, the levels of MDM2 and MDMX oncogenic factors in cancer cells are abnormally elevated, p53-mediated gene transcription function is inhibited, and p53 levels are reduced. These characteristics are closely related to the excessive growth of tumor cells.

[0004] Compounds reported in the literature, such as RG7112 (NCT00559533, NCT00623870, NCT01677780, NCT01164033, NCT01605526, NCT01143740 and NCT01635296), RG7388 (Ding et al., J Med Chem 2013, 56(14), 5979-83), MI-77301 (NCT01636479 and NCT01985191) and AMG 232 (NCT01723020 and NCT02016729), can selectively block the MDM2 / p53 interaction. Compounds reported in the literature such as 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 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 USA 2013, 110 (36), E3445-54), RO-5963 (Graves et al., Proc Natl Acad Sci USA 2012, 109 (29), 11788-93) and ALRN-6924 (Carvajal et al., Sci Transl Med 2018, 10 (436)) and other compounds reported in the literature can simultaneously inhibit 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

[0005] The object of the present invention is to provide a small molecule inhibitor that blocks the MDM2 / p53 and / or MDMX / p53 interaction.

[0006] In a first aspect of the present invention, there is provided a compound as described in formula (I), its enantiomer, diastereomer or a pharmaceutically acceptable salt thereof,

[0007]

[0008] In the formula, Ar is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group, wherein the substitution means that one or more hydrogen atoms on the phenyl group or naphthyl group are replaced by a group selected from the group consisting of halogen, deuterium, cyano, hydroxyl, amino, nitro, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 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;

[0009] R6 is hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl;

[0010] R1 is hydrogen, -COCOOH, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted -(CH2) m -6-10 membered aryl, substituted or unsubstituted -(CH2) m -C3-C8 cycloalkyl, substituted or unsubstituted -(CH2) m -5-12 membered heteroaryl, substituted or unsubstituted -(CH2) m -5-13 membered heterocyclyl, -CO-substituted or unsubstituted 6-10 membered aryl, -CO-substituted or unsubstituted 3-10 membered cycloalkyl, -SO2-substituted or unsubstituted 6-10 membered aryl, -CO-substituted or unsubstituted C1-C6 alkyl, -CO-substituted or unsubstituted 5-12 membered heteroaryl, -SO2-substituted or unsubstituted C1-C6 alkyl;

[0011] R2 is substituted or unsubstituted -(CH2) m -phenyl, substituted or unsubstituted -(CH2) m -C3-C8 cycloalkyl, substituted or unsubstituted -(CH2) m -5-12 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl;

[0012] R3 and R5 are each independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy;

[0013] m is independently 0, 1, 2, 3 or 4 at each occurrence;

[0014] R4 is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, or a substituted or unsubstituted 4-8 membered heterocyclyl group;

[0015] Unless otherwise defined, each of the above substitutions independently refers to that one or more hydrogen atoms on the group are substituted by a group selected from the group consisting of halogen, deuterium, cyano, hydroxyl, amino, nitro, C2-C4 alkynyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonamidocarbonyl (C1-C4 alkylSO2NHCO-), carboxyl, -CONH2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylethynyl, mono(C1-C4 alkyl) )amino, di(C1-C4 alkyl)amino, C1-C4 alkylcarbonylamino, C1-C4 alkoxycarbonylamino, C1-C4 alkylSO2-, C1-C4 alkyl-S(O2)-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, 5-12 membered heteroarylcarbonyl, C1-C4 alkyl 5-12 membered heteroarylcarbonyl.

[0016] In another preferred embodiment, the compound has a structure as shown in formula (II):

[0017]

[0018] In the formula, Ar, R1, R2, R3, R5 and R6 are as defined above.

[0019] In another preferred embodiment, Ar is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group, wherein the substitution refers to that one or more hydrogen atoms on the phenyl group or the naphthyl group are replaced by a group selected from the group consisting of halogen, deuterium, cyano, hydroxyl, amino, nitro, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 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.

[0020] In another preferred embodiment, Ar is a substituted or unsubstituted phenyl group, and the substitution refers to 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, and C1-C4 alkylcarbonyl; the above-mentioned C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 alkylcarbonyl are optionally further replaced by one or more groups selected from the group consisting of halogen, deuterium, cyano, hydroxyl, amino, nitro, carboxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl, and C1-C4 alkylcarbonylamino.

[0021] In another preferred embodiment, Ar is a substituted or unsubstituted phenyl group, wherein 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 (such as trifluoromethyl).

[0022] In another preferred embodiment, Ar is a substituted or unsubstituted phenyl group, wherein 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 F and Cl. In another preferred embodiment, the substituent is located at the ortho position or the meta position.

[0023] In another preferred embodiment, R1 is hydrogen, -COCOOH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted -(CH2) m -phenyl, substituted or unsubstituted -(CH2) m -C3-C6 cycloalkyl, substituted or unsubstituted -(CH2) m -5-12 membered heteroaryl, substituted or unsubstituted -(CH2) m -5-8 membered heterocyclyl, -CO-substituted or unsubstituted phenyl, -CO-substituted or unsubstituted 3-8 membered cycloalkyl, -SO2-substituted or unsubstituted phenyl, -CO-substituted or unsubstituted C1-C4 alkyl, -CO-substituted or unsubstituted 5-12 membered heteroaryl, -SO2-substituted or unsubstituted C1-C4 alkyl;

[0024] m is independently 0, 1, 2 or 3 at each occurrence;

[0025] The substitution refers to substitution by one or more groups selected from the following groups: halogen, cyano, amino, hydroxyl, nitro, carboxyl, C1-C4 alkoxy, -CONH2, C1-C4 alkyl-CONH-, C1-C4 alkyl-NHCO-, C1-C4 alkyl, C1-C4 alkyl-S(O2)-C1-C4 alkylene-, C1-C4 alkylSO2-, 6-10 membered aryl, C3-C6 cycloalkyl, 5-7 membered heteroaryl, 5-7 membered heterocyclyl, C1-C4 alkyl substituted with carboxyl, C1-C4 alkyl substituted with hydroxyl, C1-C4 alkylSO2NHCO-, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkylcarbonyl, C1-C4 alkylaminocarbonyl, 5-7 membered heteroarylcarbonyl, C1-C4 alkyl 5-7 membered heteroarylcarbonyl.

[0026] In another preferred embodiment, R1 is selected from: H, -COCOOH, substituted or unsubstituted C1-C6 alkyl, -CO-substituted or unsubstituted C1-C6 alkyl, -SO2-substituted or unsubstituted C1-C6 alkyl, -CO-substituted or unsubstituted 3-6 membered cycloalkyl, -CO-substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted -(CH2) m -6-10 membered aryl, -SO2- substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted -(CH2) m -5-12 membered heteroaryl, -CO- substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted -(CH2) m -5-13 membered heterocyclic group;

[0027] The substitution refers to that 1, 2, 3 or 4 hydrogen atoms on the group are replaced by a group selected from the following groups: F, Br, Cl, C1-C4 alkyl, C1-C4 alkoxy, carboxyl, nitro, amino, hydroxyl, CN, 5-6 membered heteroaryl.

[0028] In another preferred embodiment, R2 is substituted or unsubstituted -(CH2) m -phenyl, substituted or unsubstituted -(CH2) m -C3-C6 cycloalkyl, substituted or unsubstituted -(CH2) m -5-8 membered heteroaryl, substituted or unsubstituted C1-C4 alkyl;

[0029] wherein m is independently 0, 1, 2 or 3 at each occurrence;

[0030] The substitution refers to substitution by one or more groups selected from the following groups: amino, hydroxyl, carboxyl, C1-C4 alkoxy, -CONH2, C1-C4 alkyl-CONH-, C1-C4 alkyl-NHCO-, C1-C4 alkyl, C1-C4 alkyl-S(O2)-C1-C4 alkylene-, C1-C4 alkylSO2NHCO-, carboxyl substituted C1-C4 alkyl, di(C1-C4 alkyl)amino, mono(C1-C4 alkyl)amino, hydroxyl substituted C1-C4 alkyl, deuterium, fluorine, chlorine, bromine, cyano, nitro.

[0031] In another preferred embodiment, R2 is selected from substituted or unsubstituted -(CH2) m -phenyl, substituted or unsubstituted -(CH2) m -C3-C8 cycloalkyl, substituted or unsubstituted -(CH2) m -5-12 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl; the substitution means that 1, 2, 3 or 4 hydrogen atoms on the group are replaced by a group selected from the following groups: carboxyl, C1-C4 alkoxy, hydroxyl, carboxyl substituted C1-C4 alkyl.

[0032] In another preferred embodiment, R3 and R5 are each independently hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, or C1-C4 alkoxy.

[0033] In another preferred embodiment, R3 and R5 are independently selected from: F, Cl, C1-C4 alkoxy.

[0034] In another preferred embodiment, R4 is selected from: substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-8 membered heterocyclyl; the substitution means that 1, 2, 3 or 4 hydrogen atoms on the group are replaced by a group selected from the following group: C1-C4 alkyl.

[0035] In another preferred embodiment, R4 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C6 cycloalkyl, or a substituted or unsubstituted 5-7 membered heterocyclyl; the substitution refers to substitution by one or more groups selected from the following group: C1-C4 alkyl, C1-C4 alkylcarbonyl.

[0036] In another preferred embodiment, R4 is tert-butyl,

[0037] In another preferred embodiment, R6 is hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl.

[0038] In another preferred embodiment, R6 is selected from: H, C1-C4 alkyl, cyclopropyl.

[0039] In another preferred embodiment, each substituent is a corresponding group in a specific compound.

[0040] In another preferred embodiment, the above heterocyclic group and heteroaryl group each independently contain 1, 2, 3 or 4 heteroatoms selected from N and O.

[0041] In another preferred embodiment, the compound is selected from any one of compounds Nos. 1-122.

[0042] 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 proteins.

[0043] The second aspect of the present invention provides a pharmaceutical composition comprising the compound as described in the first aspect, or one or more of its enantiomers, diastereomers or pharmaceutically acceptable salts; and

[0044] A pharmaceutically acceptable carrier.

[0045] In another preferred embodiment, the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, and the excipient is selected from the following group: an adhesive, a filler, a diluent, a disintegrant, a suspending agent, a suspending aid, a sustained (controlled) release agent, a lyoprotectant, a coating agent, an enteric material, a lubricant, a glidant, an anti-adherent, a sweetener, a flavoring agent, a plasticizer, a sunscreen, a solubilizer, a humectant, a solvent, an osmotic pressure regulator, a colorant, a pigment, a surfactant, an emulsifier, a water-soluble matrix, a fat-soluble matrix, an oily matrix, a pore-forming agent, a gelling agent, a preservative, a buffer, a chelating agent, an antioxidant, or a combination thereof.

[0046] The third aspect of the present invention provides the use of the compound described in the first aspect, its enantiomers, diastereomers or pharmaceutically acceptable salts thereof, for preparing small molecule inhibitors that block the MDM2 / p53 and / or MDMX / p53 interaction; or for preparing drugs for treating diseases related to the activity or expression of MDM2 or MDMX protein.

[0047] In another preferred embodiment, the disease associated with the activity or expression of MDM2 or MDMX protein is selected from the group consisting of glioma, liposarcoma, skin melanoma, squamous cell carcinoma, retinoblastoma, breast cancer, esophageal cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, liver cancer, soft tissue sarcoma, chronic lymphocytic leukemia, acute myeloid leukemia, lymphoma, osteosarcoma and colon cancer.

[0048] Compared with the prior art, the main advantages of the present invention include:

[0049] (1) A novel small molecule compound having a 4-(substituted aminomethyl)-5-neopentyl-N-substituted pyrrolidine-2-carboxamide structure is provided, and the preparation method thereof has the advantages of mild reaction conditions, abundant and readily available raw materials, simple operation and post-treatment, and good corresponding selectivity. The compound has good activity in inhibiting MDM2-p53 and MDMX-p53 protein-protein interactions.

[0050] (2) Provided is a small molecule inhibitor of MDM2-p53 and MDMX-p53 protein-protein interaction. This type of inhibitor also has strong MDM2-p53 and MDMX-p53 protein-protein interaction inhibitory activity and is a potential anti-tumor drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 The figure shows the effect of compound YL093 and positive compound Nutlin-3a on the expression levels of some intracellular proteins after treating HCT116 cells.

[0052] Figure 2 The relative stereo configuration of FE071 is shown.

[0053] Figure 3 The relative stereo configuration of FE098 is shown.

[0054] Figure 4 The relative stereo configuration of YL141 is shown. DETAILED DESCRIPTION

[0055] After long-term and in-depth research, the inventors of the present invention unexpectedly developed a small molecule compound having a 4-(substituted aminomethyl)-5-neopentyl-N-substituted pyrrolidine-2-carboxamide structure and a similar structure thereof, which can inhibit the MDM2-p53 and MDMX-p53 protein-protein interaction and regulate p53-mediated gene expression in tumor cells, and can therefore be used to inhibit diseases related to the MDM2-p53 and MDMX-p53 interaction, such as the prevention and treatment of cancer. Based on the above findings, the inventors completed the present invention.

[0056] Compound

[0057] The compound of the present invention has a structure as shown in the general formula I, and the definitions of each substituent are as described above.

[0058]

[0059] Preparation method

[0060] The compounds of the present invention can be prepared through the following reaction routes.

[0061] Route 1

[0062] Route 1

[0063]

[0064] Step 1: Aldehyde S1 is mixed with substituted benzyl cyanide S2 in a suitable solvent (e.g., methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or N, N-dimethylformamide, etc.). A suitable base (sodium methoxide, sodium ethoxide, etc.) is added, and the intermediate S3 is obtained by reaction at room temperature or at a suitable elevated temperature (e.g., 40-60°C). Step 2: S3 is mixed with the corresponding raw material S4 in a suitable solvent (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,2-dichloroethane, or acetonitrile, etc.), and silver fluoride and a base (triethylamine, N, N-diisopropylethylamine and DBU, etc.) are added, and the intermediate S5 is obtained by reaction at room temperature. Step 3: S5 is subjected to a hydrogenation reduction reaction to obtain the intermediate S6 (e.g., Pd / C hydrogenation reduction, Raney nickel hydrogenation reduction, and Raney nickel hydrazine hydrate hydrogenation reduction, etc.). Step 4: S6 and FmocCl are mixed in an appropriate solvent (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or acetonitrile), a base (e.g., triethylamine, N,N-diisopropylethylamine, and DBU) is added, and the reaction is carried out at room temperature to obtain the intermediate S7. Step 5: S7 is dissolved in dichloromethane, trifluoroacetic acid is added, and the reaction is carried out at room temperature to obtain the intermediate S8. Step 6: S8 is dissolved in an appropriate solvent (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, N,N-dimethylformamide, or acetonitrile), a base (e.g., triethylamine, N,N-diisopropylethylamine, and DBU) and a condensation reagent (e.g., diphenylphosphinoyl chloride, CDI, HATU, and EDCI) are added, and the reaction is carried out for half an hour, and an alcohol or amine is added, and the reaction is carried out at room temperature to obtain the intermediate S9. Step 7: S9 is dissolved in a suitable solvent (e.g., N,N-dimethylformamide, etc.), piperidine is added, and the reaction is carried out at room temperature to obtain the intermediate S10. Step 8: S10 and halogenated hydrocarbon R1X (R1 is aromatic methyl, aromatic or fatty alkyl) are mixed in a suitable solvent (e.g., acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, toluene and benzene, etc.), a base (e.g., potassium carbonate, cesium carbonate and sodium carbonate, etc.) is added, and the reaction is carried out at room temperature or at a suitable elevated temperature (e.g., 30-50°C) to obtain the final product II.

[0065] Route 2

[0066] Route 2

[0067]

[0068] Step 1: S10 and R1'CHO are dissolved in a suitable solvent (eg, methanol, tetrahydrofuran, ethanol, 1,2-dichloroethane and N,N-dimethylformamide, etc.), a reducing agent (sodium borohydride, sodium acetate borohydride, sodium cyanoborohydride, etc.) is added, and the final product II is obtained by reductive amination reaction.

[0069] Route 3

[0070] Route 3

[0071]

[0072] Step 1: S10 and R1'COX (acyl halide) are dissolved in a suitable solvent (for example, tetrahydrofuran, dichloromethane, chloroform, 1,2-dichloroethane and N,N-dimethylformamide, etc.), and a suitable base (triethylamine, DIEA, DBU, potassium carbonate, cesium carbonate, sodium carbonate and sodium bicarbonate, etc.) is added to obtain the final product II through acylation reaction.

[0073] I can be synthesized using the three synthetic strategies mentioned above.

[0074] Example 1: Synthesis of compounds

[0075] Final product 1: 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YH018)

[0076]

[0077] Step 1: Synthesis of (Z)-2-(4-chloro-2-fluorophenyl)-3-(3-chloro-2-fluorophenyl) acrylonitrile (YG019)

[0078] Weigh 4-chloro-2-fluorobenzyl acetonitrile (5 g, 29.58 mmol) and 3-chloro-2-fluorobenzaldehyde (4.54 g, 28.7 mmol), add to a 250 mL round-bottom flask, dissolve with 100 mL of methanol, add 8.6 mL of 5N sodium methoxide solution, react at 50 ° C overnight, cool to room temperature, filter, wash the filter cake with water, dry, weigh 7.5 g, and the yield is 84%. 1 H NMR (400MHz, Chloroform-d) δ8.17–8.08(m,1H),7.79(s,1H),7.62–7.46(m,2H),7.32–7.18(m,3H).

[0079] Step 2: Synthesis of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YG035)

[0080] Weigh YG019 (3.72 g, 12 mmol) and add it to a 100 mL reaction bottle, dissolve it with 50 mL of dichloromethane, add silver fluoride (1.53 g, 12 mmol) and triethylamine (5 mL, 19.2 mmol), and then add tert-butyl 2-((3,3-dimethylbutylidene)amino)acetate (2.5 g, 12.56 mmol), react at room temperature in the dark overnight, pour into saturated ammonium chloride solution, filter, extract the filtrate three times with dichloromethane, combine the filtrates, distill under reduced pressure to remove the solvent, and purify on a normal phase silica gel column to obtain 2.15 g of the target compound with a yield of 34%. 1 H NMR(400MHz,Chloroform-d)δ7.61(ddd,J=8.0,6.2,1.6Hz,1H),7.40–7.27(m,2H),7.21–7.07(m,3H),4.69(dd,J=7.4,1 .9Hz,1H),4.14(d,J=7.4Hz,1H),4.07(d,J=8.9Hz,1H),1.66–1.60(m,1H),1.39(s,9H),1.30–1.23(m,1H),0.89(s,9H).

[0081] Step 3: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YG155)

[0082] Weigh YG035 (3 g, 5.7 mmol) and add it to a 100 mL reaction bottle, dissolve it with a mixed solvent of ethanol and tetrahydrofuran, add 3 g of Raney nickel, raise the temperature to 55 ° C, add 5 mL of hydrazine hydrate dropwise, stir and react for 1 h, cool, filter, and distill under reduced pressure to remove the filtrate. Purify it on a normal phase silica gel column to obtain 875 mg of the target compound with a conversion rate of 29%. 1 H NMR(500MHz, Methanol-d4)δ7.60(ddd,J=8.0,6.4,1.6Hz,1H),7.35(ddd,J=8.4,7.0,1.6Hz,1H),7.24(t,J=8.7Hz,1H),7.20–7.11(m,3H),4.30–4 .13(m,3H),3.24(dd,J=13.9,1.7Hz,1H),3.20–3.13(m,1H),1.56(dd,J= 14.1,1.4Hz,1H),1.48(dd,J=14.2,9.7Hz,1H),1.28(s,9H),0.98(s,9H).

[0083] Step 4: Synthesis of (2R,3S,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YG156)

[0084] Weigh YG155 (280 mg, 0.53 mmol) into a 50 mL round-bottom flask, dissolve it in 10 mL of dichloromethane, add FmocCl (180 mg, 0.69 mmol) and triethylamine (161 mg, 1.59 mmol), react at room temperature overnight, remove the solvent under reduced pressure, add 5 mL of dichloromethane and 4 mL of trifluoroacetic acid, react at room temperature overnight, spin dry the solvent, extract three times with dichloromethane, spin dry the organic phase, and purify with a normal phase column to obtain 404 mg of the product with a yield of 99%.

[0085] Step 5: Synthesis of methyl 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YL090)

[0086] Weigh YG156 (114 mg, 0.164 mol) and dissolve it in THF. Add DIEA (169 mg, 1.312 mmol) and react for 5 min. Add diphenylphosphinoyl chloride (232 mg, 0.984 mmol) and react for 30 min. Add methyl 4-amino-3-methoxybenzoate (149 mg, 0.82 mmol) and react overnight. Remove the solvent under reduced pressure, add water, extract with dichloromethane 3 times, and purify the organic phase with a normal phase silica gel column after drying. Add 2 mL of DMF solution containing 20% ​​piperidine to obtain the crude product. After reacting at room temperature for 30 min, extract with ethyl acetate, dry the organic phase, and purify with a normal phase column to obtain 40 mg of the target compound with a yield of 38%. 1H NMR(500MHz, Methanol-d4)δ8.28(d,J=8.4Hz,1H),7.64–7.54(m,2H),7.50–7.44(m,1H),7.41( t,J=8.6Hz,1H),7.35(dd,J=8.7,2.2Hz,1H),7.31–7.14(m,3H),4.54(d,J=10.3Hz,1H),4.38(d, J=11.2Hz,1H),3.96(s,3H),3.92(d,J=10.6Hz,1H),3.88(s,3H),3.73(dd,J=14.3,3.4Hz,1H),3 .51(d,J=14.1Hz,1H),1.71(dd,J=13.8,1.3Hz,1H),1.54(dd,J=13.7,11.4Hz,1H),1.24(s,9H).

[0087] Step 6: Synthesis of 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YH018)

[0088] YL090 (20 mg, 0.032 mmol) was weighed into a 50 mL round-bottom flask, and lithium hydroxide monohydrate (7 mg, 0.16 mmol) was added and dissolved in THF / H2O (v / v = 2 mL / 2 mL). The mixture was stirred at room temperature overnight and the solvent was removed by distillation under reduced pressure. 17 mg of the trifluoroacetate salt of the target compound was obtained by HPLC with a yield of 74%. 1 H NMR(500MHz,Methanol-d4)δ8.28(d,J=8.4Hz,1H),7.65–7.58(m,2H),7.46(td,J=7.3,1.7Hz, 1H),7.41(t,J=8.6Hz,1H),7.35(dd,J=8.8,2.2Hz,1H),7.30–7.14(m,3H),4.52(d,J=10.3Hz,1 H), 4.36 (d, J = 11.3 Hz, 1H), 3.97 (s, 3H), 3.91 (d, J = 10.2 Hz, 1H), 3.73 (dd, J = 14.2, 3.3 Hz, 1H), 3.55–3.46 (m, 1H), 1.74–1.66 (m, 1H), 1.52 (dd, J = 13.7, 11.4 Hz, 1H), 1.25 (s, 9H). ESI-MS theoretical calculated value C 31 H 34 35 Cl2F2N3O4[M+H] +=620.19, experimentally measured: 620.2.

[0089] Final product 2: 4-((2R,3S,4S,5S)-4-((4-bromobenzamide)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM011)

[0090]

[0091] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-((4-bromobenzamide)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM011)

[0092] YL090 (50 mg, 0.079 mmol) was weighed into a dried 50 mL round-bottom flask, dissolved in 10 mL of dichloromethane, triethylamine (24 mg, 0.236 mmol) and 4-bromobenzoyl chloride (26 mg, 0.12 mmol) were added, stirred at room temperature overnight, and dried by normal phase column purification to obtain 51 mg of crude YL141. A portion of YL141 (20 mg, 0.024 mmol) was dissolved in THF / H2O (v / v=2 mL / 2 mL), lithium hydroxide monohydrate (5 mg, 0.12 mmol) was added, stirred at room temperature overnight, the solvent was dried by spin drying, and HPLC purification was performed to obtain 9.5 mg of trifluoroacetate of the target compound with a two-step yield of 34%. 1 H NMR (500 MHz, Methanol-d4) δ8.24 (d, J = 8.4 Hz, 1H), 7.68–7.52 (m, 5H), 7.41 (h, J = 8.7, 8.1 Hz, 4H), 7.33–7.17 (m, 3H), 5.11 (s, 1H), 4.73–4.61 (m, 1H), 4.47 (s, 1H), 4.24 (d, J = 15.2 Hz, 1H), 3.90–3.71 (m, 4H), 1.75–1.54 (m, 2H), 0.99 (s, 9H). ESI-MS calculated value C 38 H 37 79 Br 35 Cl2F2N3O5[M+H] + =802.13, experimentally measured: 801.5.

[0093] Final product 3: 4-((2R,3S,4S,5S)-4-(acetylaminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YI049)

[0094]

[0095] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(acetylaminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YI049)

[0096] Take YL090 (30 mg, 0.047 mmol), acetyl chloride (4 mg, 0.052 mmol), triethylamine (14 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.235 mmol), and follow the steps of final product 2 to obtain 29 mg of trifluoroacetate of the target compound with a yield of 79%. 1 H NMR (500 MHz, Methanol-d4) δ8.21 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.4, 1.8 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.49 (dt, J = 19.6, 7.0 Hz, 2H), 7.32–7.20 (m, 4H), 5.09 (d, J = 10.2 Hz, 1H), 4.60–4.42 (m, 2H), 3.98 (d, J = 15.3 Hz, 1H), 3.82 (s, 3H), 3.74 (d, J = 15.2 Hz, 1H), 1.80 (s, 3H), 1.70–1.61 (m, 2H), 1.03 (s, 9H). ESI-MS calculated value C 33 H 36 35 Cl2F2N3O5[M+H] + =662.20, experimentally measured: 662.2.

[0097] Final product 4: 4-((2R,3S,4S,5S)-4-(propionylaminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL102)

[0098]

[0099] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(propionylaminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL102)

[0100] Take YL090 (20 mg, 0.03 mmol), propionyl chloride (4.4 mg, 0.047 mmol), triethylamine (9 mg, 0.1 mmol) and lithium hydroxide monohydrate (6 mg, 0.15 mmol), and follow the steps of final product 2 to obtain 13 mg of trifluoroacetate of the target compound with a yield of 55%. 1 H NMR (500 MHz, Methanol-d4) δ8.24 (d, J = 8.4 Hz, 1H), 7.67–7.55 (m, 2H), 7.52–7.41 (m, 2H), 7.34–7.16 (m, 4H), 4.41 (d, J = 9.9 Hz, 2H), 4.03 (d, J = 15.1 Hz, 1H), 3.86 (s, 3H), 3.64 (d, J = 15.1 Hz, 1H), 2.17–1.93 (m, 2H), 1.73–1.46 (m, 2H), 1.10–0.92 (m, 12H). ESI-MS calculated value C 34 H 38 35 Cl2F2N3O5[M+H] + =676.22, experimentally measured: 676.2.

[0101] Final product 5: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-(cyclopropanecarboxamidoethyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL103)

[0102]

[0103] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-(cyclopropanecarboxamidoethyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL103)

[0104] Take YL090 (20 mg, 0.03 mmol), cyclopropylcarbonyl chloride (5 mg, 0.047 mmol), triethylamine (9 mg, 0.1 mmol) and lithium hydroxide monohydrate (6 mg, 0.15 mmol), and follow the steps of final product 2 to obtain 14.8 mg of trifluoroacetate of the target compound with a yield of 61%. 1H NMR(500MHz,Methanol-d4)δ8.23(d,J=8.4Hz,1H),7.63(dd,J=8.4,1.8Hz,1H),7.6 0(d,J=1.8Hz,1H),7.47(dt,J=15.4,7.3Hz,2H),7.36–7.16(m,4H),5.06–4.95(m,1 H), 4.53–4.34 (m, 2H), 4.07 (d, J = 15.2 Hz, 1H), 3.85 (s, 3H), 3.62 (d, J = 15.2 Hz, 1H), 1.73–1.44 (m, 3H), 1.03 (s, 9H), 0.93–0.78 (m, 2H), 0.77–0.64 (m, 2H). ESI-MS theoretical calculated value C 35 H 38 35 Cl2F2N3O5[M+H] + =688.22, experimentally measured: 688.2.

[0105] Final product 6: 4-((2R,3S,4S,5S)-4-((benzamide)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL104)

[0106]

[0107] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-((benzamide)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL104)

[0108] Take YL090 (20 mg, 0.03 mmol), benzoyl chloride (6.6 mg, 0.047 mmol), triethylamine (9 mg, 0.1 mmol) and lithium hydroxide monohydrate (6 mg, 0.15 mmol), and follow the steps of final product 2 to obtain 13 mg of trifluoroacetate of the target compound with a yield of 52%. 1H NMR (500 MHz, Methanol-d4) δ8.29 (d, J = 8.4 Hz, 1H), 7.69–7.54 (m, 3H), 7.51 (t, J = 7.3 Hz, 1H), 7.48–7.31 (m, 6H), 7.30–7.13 (m, 3H), 4.63 (d, J = 9.2 Hz, 1H), 4.42–4.16 (m, 2H), 3.89 (s, 3H), 3.76 (d, J = 15.1 Hz, 1H), 1.73–1.47 (m, 2H), 1.00 (s, 9H). ESI-MS calculated value C 38 H 38 35 Cl2F2N3O5[M+H] + =724.22, experimentally measured: 724.2.

[0109] Final product 7: 4-((2R,3S,4S,5S)-4-((carboxycarbonylamino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YH022)

[0110]

[0111] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-((carboxycarboxamido)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YH022)

[0112] Take YL090 (30 mg, 0.047 mmol), monomethyl oxalyl chloride (8.7 mg, 0.07 mmol), triethylamine (14 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of final product 2 to obtain 27.9 mg of trifluoroacetate of the target compound with a yield of 74%. 1H NMR (500 MHz, Methanol-d4) δ8.25 (d, J = 8.4 Hz, 1H), 7.66–7.55 (m, 2H), 7.54–7.39 (m, 2H), 7.34–7.16 (m, 4H), 5.03–4.97 (m, 1H), 4.65 (dd, J = 9.8, 2.9 Hz, 1H), 4.35 (d, J = 9.9 Hz, 1H), 4.03 (d, J = 15.0 Hz, 1H), 3.91–3.79 (m, 4H), 1.65 (dd, J = 14.6, 10.1 Hz, 1H), 1.53 (d, J = 14.4 Hz, 1H), 1.02 (s, 9H). ESI-MS calculated value C 33 H 34 35 Cl2F2N3O7[M+H] + =692.17, experimentally measured: 692.1.

[0113] Final product 8: 4-((2R,3S,4S,5S)-4-((4-carboxybenzamido)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YG117)

[0114]

[0115] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-((4-carboxybenzamido)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YG117)

[0116] Take YL090 (30 mg, 0.047 mmol), methyl 4-chloroformylbenzoate (14 mg, 0.07 mmol), triethylamine (14 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of final product 2 to obtain 23.9 mg of trifluoroacetate of the target compound with a yield of 58%. 1H NMR (400 MHz, Methanol-d4) δ8.27 (d, J = 8.3 Hz, 1H), 8.05–7.96 (m, 2H), 7.69–7.57 (m, 3H), 7.53 (d, J = 8.3 Hz, 2H), 7.45–7.31 (m, 2H), 7.31–7.15 (m, 3H), 4.63 (d, J = 9.7 Hz, 1H), 4.39 (d, J = 9.3 Hz, 1H), 4.25 (d, J = 15.1 Hz, 1H), 3.92–3.80 (m, 4H), 1.79–1.58 (m, 2H), 1.02 (s, 9H). ESI-MS calculated value C 39 H 38 35 Cl2F2N3O7[M+H] + =768.20, experimentally measured: 768.2.

[0117] Final product 9: 4-((2R,3S,4S,5S)-4-((carboxymethylsulfonylamino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YI001)

[0118]

[0119] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-((carboxymethylsulfonylamino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YI001)

[0120] Take YL090 (36 mg, 0.048 mmol), methyl chlorosulfonylacetate (9 mg, 0.052 mmol), triethylamine (14 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of final product 2 to obtain 10.4 mg of trifluoroacetate of the target compound with a yield of 25%. 1H NMR (500 MHz, Methanol-d4) δ8.25 (d, J = 8.3 Hz, 1H), 7.66–7.51 (m, 3H), 7.49–7.40 (m, 1H), 7.30–7.16 (m, 4H), 4.53 (d, J = 10.3 Hz, 1H), 4.39 (d, J = 10.5 Hz, 1H), 4.17 (s, 2H), 3.86 (s, 3H), 3.76 (d, J = 4.0 Hz, 2H), 2.00–1.87 (m, 1H), 1.74 (d, J = 14.9 Hz, 1H), 1.10 (s, 9H). ESI-MS calculated value C 33 H 36 35 Cl2F2N3O8S[M+H] + =742.16, experimentally measured: 742.1.

[0121] Final product 10: 4-((2R,3S,4S,5S)-4-((3-carboxybenzenesulfonylamino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YI004)

[0122]

[0123] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-((3-carboxybenzenesulfonylamino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YI004)

[0124] Take YL090 (36 mg, 0.048 mmol), methyl 3-chlorosulfonylbenzoate (13 mg, 0.058 mmol), triethylamine (14 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of final product 2 to obtain 6 mg of trifluoroacetate of the target compound with a yield of 14%. 1H NMR(500MHz,Methanol-d4)δ8.44(t,J=1.7Hz,1H),8.31–8.20(m,2H),8.02(dt,J=7.9,1.3Hz,1H),7 .70(t,J=7.8Hz,1H),7.61(d,J=7.6Hz,2H),7.38(t,J=7.4Hz,1H),7.27(s,1H),7.19–7.06(m,2H),7. 03 (dd, J = 13.0, 2.2 Hz, 1H), 6.91 (t, J = 8.6 Hz, 1H), 4.68 (s, 1H), 4.41 (s, 1H), 4.00 (d, J = 10.0 Hz, 1H), 3.89 (s, 3H), 3.67–3.58 (m, 1H), 3.23 (d, J = 12.9 Hz, 1H), 1.89–1.69 (m, 2H), 1.15 (s, 9H). ESI-MS theoretical calculated value C 38 H 38 35 Cl2F2N3O8S[M+H] + =804.17, experimentally measured: 804.2.

[0125] Final product 11: 4-((2R,3S,4S,5S)-4-((2-carboxybenzenesulfonylamino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YI010)

[0126]

[0127] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-((2-carboxybenzenesulfonylamino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YI010)

[0128] Take YL090 (20 mg, 0.032 mmol), methyl 2-chlorosulfonylbenzoate (9 mg, 0.038 mmol), triethylamine (10 mg, 0.096 mmol) and lithium hydroxide monohydrate (7 mg, 0.16 mmol), and follow the steps of final product 2 to obtain 11.9 mg of trifluoroacetate of the target compound with a yield of 40%. 1H NMR(500MHz, Methanol-d4)δ8.22(d,J=8.4Hz,1H),8.09–8.01(m,1H),7.96–7.87(m,1H),7.78 –7.69(m,2H),7.63–7.53(m,2H),7.46–7.37(m,1H),7.31–7.22(m,1H),7.20–7.06(m,3H),7.00 (dd, J = 13.0, 2.2 Hz, 1H), 4.78–4.68 (m, 1H), 4.51 (s, 1H), 4.07 (d, J = 10.2 Hz, 1H), 3.85 (s, 3H), 3.63 (dd, J = 13.1, 1.9 Hz, 1H), 3.50–3.38 (m, 1H), 1.89–1.69 (m, 2H), 1.15 (s, 9H). ESI-MS theoretical calculated value C 38 H 38 35 Cl2F2N3O8S[M+H] + =804.17, experimentally measured: 804.2.

[0129] Final product 12: 4-((2R,3S,4S,5S)-4-((4-carboxybenzenesulfonylamino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YI011)

[0130]

[0131] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-((4-carboxybenzenesulfonylamino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YI011)

[0132] Take YL090 (20 mg, 0.032 mmol), methyl 4-chlorosulfonylbenzoate (9 mg, 0.038 mmol), triethylamine (10 mg, 0.096 mmol) and lithium hydroxide monohydrate (7 mg, 0.16 mmol), and follow the steps of final product 2 to obtain 9.5 mg of trifluoroacetate of the target compound with a yield of 32%. 1H NMR(500MHz, Methanol-d4)δ8.21(dd,J=11.6,8.4Hz,3H),7.96–7.88(m,2H),7.64–7.55(m, 2H),7.43(t,J=7.4Hz,1H),7.30–7.19(m,1H),7.18–7.10(m,2H),7.06(dd,J=13.0,2.3Hz,1 H), 6.95 (t, J = 8.6 Hz, 1H), 4.82–4.66 (m, 1H), 4.48 (s, 1H), 4.03 (d, J = 10.2 Hz, 1H), 3.86 (s, 3H), 3.66–3.56 (m, 1H), 3.27 (d, J = 13.2 Hz, 1H), 1.86–1.69 (m, 2H), 1.13 (s, 9H). ESI-MS theoretical calculated value C 38 H 38 35 Cl2F2N3O8S[M+H] + =804.17, experimentally measured: 804.2.

[0133] Final product 13: 4-((((2S,3S,4S,5R)-5-((4-carboxy-2-methoxyphenyl)carbamoyl)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2)-fluorophenyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)-3-nitrobenzoic acid (YH020)

[0134]

[0135] Step 1: 4-((((2S,3S,4S,5R)-5-((4-carboxy-2-methoxyphenyl)carbamoyl)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2)-fluorophenyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)-3-nitrobenzoic acid (YH020)

[0136] YL090 (20 mg, 0.032 mmol) was weighed into a bottle, dissolved in 5 mL of acetonitrile, methyl 4-fluoro-3-nitrobenzoate (8 mg, 0.038 mmol) and potassium carbonate (9 mg, 0.064 mmol) were added, stirred at room temperature overnight, water was added, extracted three times with dichloromethane, the organic phase was spin-dried and purified to obtain a crude product, the crude product was dissolved in a THF / H2O mixed solution, lithium hydroxide monohydrate (7 mg, 0.16 mmol) was added, stirred at room temperature overnight, spin-dried and purified by HPLC to obtain 14.7 mg of trifluoroacetate of the target compound with a yield of 51%. 1HNMR (500 MHz, Methanol-d4) δ8.65 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.11 (dd, J = 9.0, 2.1 Hz, 1H), 7.69–7.57 (m, 2H), 7.46 (t, J = 8.7 Hz, 1H), 7.37–7.16 (m, 4H), 7.07 (d, J = 9.0 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 4.99–4.76 (m, 2H), 4.17 (s, 1H), 3.99 (d, J = 5.5 Hz, 2H), 3.89 (s, 3H), 1.68–1.47 (m, 2H), 1.00 (s, 9H). ESI-MS calculated value C 38 H 37 35 Cl2F2N4O8[M+H] + =785.20, experimentally measured: 785.4.

[0137] Final product 14: 4-((2R,3S,4S,5S)-4-(((carboxymethyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YH017)

[0138]

[0139] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((carboxymethyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YH017)

[0140] YL090 (20 mg, 0.032 mmol) was weighed into a bottle, dissolved in 5 mL of acetonitrile, ethyl bromoacetate (6.3 mg, 0.038 mmol) and potassium carbonate (9 mg, 0.064 mmol) were added, stirred at room temperature overnight, water was added, extracted three times with dichloromethane, the organic phase was spin-dried and purified to obtain a crude product, the crude product was dissolved in a THF / H2O mixed solution, lithium hydroxide monohydrate (7 mg, 0.16 mmol) was added, stirred at room temperature overnight, spin-dried and purified by HPLC to obtain 16 mg of trifluoroacetate of the target compound with a yield of 63%. 1H NMR (500 MHz, Methanol-d4) δ8.23 (d, J = 8.3 Hz, 1H), 7.66–7.56 (m, 2H), 7.54–7.43 (m, 2H), 7.34–7.20 (m, 4H), 4.89–4.83 (m, 1H), 4.56 (d, J = 9.7 Hz, 1H), 4.35 (d, J = 10.0 Hz, 1H), 3.89 (s, 3H), 3.85 (d, J = 17.4 Hz, 1H), 3.77 (d, J = 17.4 Hz, 1H), 3.66 (d, J = 14.1 Hz, 1H), 3.56 (d, J = 14.1 Hz, 1H), 1.88–1.67 (m, 2H), 1.14 (s, 9H). ESI-MS calculated value C 33 H 36 35 Cl2F2N3O6[M+H] + =678.19, experimentally measured: 678.2.

[0141] Final product 15: 4-((2R,3S,4S,5S)-4-(((3-nitrobenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL139)

[0142]

[0143] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((3-nitrobenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL139)

[0144] YL090 (38 mg, 0.059 mmol), 3-nitrobenzyl bromide (17 mg, 0.08 mmol), potassium carbonate (24 mg, 0.18 mmol) and lithium hydroxide monohydrate (12 mg, 0.3 mmol) were taken, and the steps were referred to the final product 14 to obtain 17.4 mg of the trifluoroacetate salt of the target compound with a yield of 34%. 1H NMR(500MHz,Methanol-d4)δ8.36(dd,J=5.9,2.7Hz,2H),8.26(d,J=8.4Hz,1H),7.83(d,J=7.7Hz,1H),7 .75(t,J=8.2Hz,1H),7.66–7.56(m,2H),7.41(td,J=7.0,3.7Hz,1H),7.33–7.21(m,2H),7.20–7.06(m,3 H), 4.47 (d, J = 10.0 Hz, 1H), 4.33 (d, J = 10.0 Hz, 3H), 3.96 (s, 3H), 3.92–3.83 (m, 1H), 3.68–3.60 (m, 1H), 3.35 (d, J = 14.2 Hz, 1H), 1.73 (d, J = 13.6 Hz, 1H), 1.57 (dd, J = 13.7, 11.2 Hz, 1H), 1.24 (s, 9H). ESI-MS theoretical calculated value C 38 H 39 35 Cl2F2N4O6[M+H] + =755.22, experimentally measured: 755.6.

[0145] Final product 16: 4-((2R,3S,4S,5S)-4-(((4-bromobenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM001)

[0146]

[0147] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((4-bromobenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM001)

[0148] YL090 (30 mg, 0.047 mmol) was weighed into a reaction flask, dissolved in 10 mL of 1,2-dichloroethane, and sodium acetate borohydride (30 mg, 0.14 mmol), p-bromobenzaldehyde (13 mg, 0.07 mmol) and 0.1 mL of acetic acid were added. After reacting at room temperature overnight, a saturated sodium bicarbonate solution was added, and the mixture was extracted three times with dichloromethane. The organic phase was spin-dried and purified by a normal phase column to obtain a crude product FE098. The crude product was dissolved in a THF / H2O mixed solution, and lithium hydroxide monohydrate (10 mg, 0.24 mmol) was added. The mixture was stirred at room temperature overnight, and then spin-dried and purified by HPLC to obtain 19.7 mg of the trifluoroacetate of the target compound with a yield of 46%. 1H NMR(500MHz, Methanol-d4)δ8.26(d,J=8.4Hz,1H),7.69–7.54(m,4H),7.48–7.41(m,1H),7.37–7.30(m ,2H),7.27(dd,J=8.6,2.2Hz,1H),7.19–7.08(m,3H),7.09–6.95(m,1H),4.41(d,J=10.1Hz,1H),4.28(d , J = 11.4 Hz, 1H), 4.20 (d, J = 2.3 Hz, 2H), 3.96 (s, 3H), 3.79 (d, J = 10.1 Hz, 1H), 3.67 (dd, J = 14.1, 2.8 Hz, 1H), 3.36–3.32 (m, 1H), 1.71 (d, J = 13.4 Hz, 1H), 1.51 (dd, J = 13.6, 11.5 Hz, 1H), 1.24 (s, 9H). ESI-MS theoretical calculated value C 38 H 39 79 Br 35 Cl2F2N3O4[M+H] + =788.15, experimentally measured: 787.9.

[0149] Final product 17: 4-((2R,3S,4S,5S)-4-(((2-carboxybenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL094)

[0150]

[0151] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((2-carboxybenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL094)

[0152] Take YL090 (30 mg, 0.047 mmol), methyl 2-bromomethylbenzoate (16 mg, 0.07 mmol), potassium carbonate (19 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of final product 14 to obtain 17 mg of trifluoroacetate of the target compound with a yield of 42%. 1H NMR (500MHz, Methanol-d4) δ8.27(d,J=8.4Hz,1H),8.15(dd,J=7.8,1.4Hz,1H),7.75(td,J=7.6,1.5Hz,1H),7. 69–7.62(m,2H),7.61–7.55(m,2H),7.45–7.39(m,1H),7.38–7.27(m,2H),7.16–7.08(m,2H),7.07–6.99(m,1H) ,4.48(d,J=13.0Hz,1H),4.44–4.30(m,2H),4.26(d,J=11.3Hz,1H),3.98(s,3H),3.81(ddd,J=13.8,9.5,3.2Hz,2H),3.42(d,J=13.9Hz,1H),1.74(d,J=13.2Hz,1H),1.54(dd,J=13.3,11.5Hz,1H),1.27(s,9H).ESI-MS theoretical calculated value C 39 H 40 35 Cl2F2N3O6[M+H] + =754.23, experimentally measured: 754.1.

[0153] Final product 18: 4-((2R,3S,4S,5S)-4-(((3-carboxybenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YH015)

[0154]

[0155] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((3-carboxybenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YH015)

[0156] Take YL090 (30 mg, 0.047 mmol), methyl 3-bromomethylbenzoate (16.6 mg, 0.07 mmol), potassium carbonate (19 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of final product 14 to obtain 26 mg of trifluoroacetate of the target compound with a yield of 64%. 1H NMR(500MHz, Methanol-d4)δ8.24(dd,J=8.4,1.7Hz,1H),8.17–8.02(m,2H),7.70–7.49(m, 4H),7.41(t,J=7.2Hz,1H),7.24(d,J=8.5Hz,1H),7.19–6.92(m,4H),4.47(d,J=10.1Hz,1H ),4.36(d,J=11.1Hz,1H),4.29(s,2H),3.99–3.82(m,4H),3.75(d,J=14.2Hz,1H),3.36(d,J=14.4Hz,1H),1.74(d,J=13.6Hz,1H),1.65(t,J=12.5Hz,1H),1.23(s,9H).ESI-MS theoretical calculated value C 39 H 40 35 Cl2F2N3O6[M+H] + =754.23, experimentally measured: 754.1.

[0157] Final product 19: 4-((2R,3S,4S,5S)-4-(((4-carboxybenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YH014)

[0158]

[0159] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((4-carboxybenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YH014)

[0160] Take YL090 (30 mg, 0.047 mmol), methyl 4-bromomethylbenzoate (16.6 mg, 0.07 mmol), potassium carbonate (19 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of final product 14 to obtain 22.8 mg of trifluoroacetate of the target compound with a yield of 56%. 1H NMR(500MHz, Methanol-d4)δ8.24(d,J=8.4Hz,1H),8.14–8.08(m,2H),7.63–7.56(m,2H),7.56–7.51(m ,2H),7.46–7.39(m,1H),7.27(dd,J=8.7,2.2Hz,1H),7.20–7.09(m,3H),7.07–7.00(m,1H),4.49(d,J= 10.2Hz,1H),4.38–4.24(m,3H),3.93(s,3H),3.83(d,J=10.1Hz,1H),3.72(dd,J=14.2,2.7Hz,1H),3.34(d,J=14.4Hz,1H),1.74(d,J=13.5Hz,1H),1.61(dd,J=13.7,11.4Hz,1H),1.23(s,9H).ESI-MS theoretical calculated value C 39 H 40 35 Cl2F2N3O6[M+H] + =754.23, experimentally measured: 754.1.

[0161] Final product 20: 4-((2R,3S,4S,5S)-4-(((phenylmethyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL115)

[0162]

[0163] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((phenylmethyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL115)

[0164] Take YL090 (30 mg, 0.047 mmol), benzyl bromide (12 mg, 0.07 mmol), potassium carbonate (19 mg, 0.14 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of final product 14 to obtain 16.9 mg of trifluoroacetate of the target compound with a yield of 44%. 1H NMR(500MHz, Methanol-d4)δ8.27(d,J=8.4Hz,1H),7.68–7.55(m,2H),7.54–7.37(m,6 H),7.25–7.10(m,3H),7.09–6.90(m,2H),4.38(d,J=10.1Hz,1H),4.30–4.14(m,3H),3 .97 (s, 3H), 3.77 (d, J = 10.0 Hz, 1H), 3.69 (dd, J = 14.2, 2.6 Hz, 1H), 3.38 (d, J = 14.3 Hz, 1H), 1.72 (d, J = 13.3 Hz, 1H), 1.51 (dd, J = 13.6, 11.5 Hz, 1H), 1.24 (s, 9H). ESI-MS theoretical calculated value C 38 H 40 35 Cl2F2N3O4[M+H] + =710.24, experimentally measured: 710.1.

[0165] Final product 21: 4-((2R,3S,4S,5S)-4-(((2-pyridylmethyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL091)

[0166]

[0167] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((2-pyridylmethyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL091)

[0168] Take YL090 (30 mg, 0.047 mmol), 2-bromomethylpyridine hydrobromide (18 mg, 0.07 mmol), potassium carbonate (33 mg, 0.24 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of final product 14 to obtain 22 mg of trifluoroacetate of the target compound with a yield of 57%. 1H NMR (500MHz, Methanol-d4) δ8.66–8.59(m,1H),8.27(d,J=8.3Hz,1H),7.96(td,J=7.7,1.7Hz,1H),7. 68–7.57(m,2H),7.54–7.43(m,3H),7.41–7.25(m,3H),7.23–7.16(m,2H),4.57(d,J=10.1Hz,1H),4.40 (s, 2H), 4.36 (d, J = 10.6 Hz, 1H), 4.06 (d, J = 10.1 Hz, 1H), 3.95 (s, 3H), 3.81 (dd, J = 14.0, 2.5 Hz, 1H), 3.67 (d, J = 14.1 Hz, 1H), 1.83 (d, J = 12.8 Hz, 1H), 1.76 (dd, J = 13.7, 10.7 Hz, 1H), 1.23 (s, 9H). ESI-MS theoretical calculated value C 37 H 39 35 Cl2F2N4O4[M+H] + =711.23, experimentally measured: 711.3.

[0169] Final product 22: 4-((2R,3S,4S,5S)-4-(((3-pyridylmethyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL092)

[0170]

[0171] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((3-pyridylmethyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL092)

[0172] Take YL090 (30 mg, 0.047 mmol), 3-bromomethylpyridine hydrobromide (18 mg, 0.07 mmol), potassium carbonate (33 mg, 0.24 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of final product 14 to obtain 12 mg of trifluoroacetate of the target compound with a yield of 31%. 1H NMR (500 MHz, Methanol-d4) δ8.73 (t, J = 4.0 Hz, 2H), 8.26 (dd, J = 10.9, 8.4 Hz, 2H), 7.80 (dd, J = 8.1, 5.3 Hz, 1H), 7.62 (dd, J = 6.9, 2.0 Hz, 2H), 7.49–7.30 (m, 2H), 7.28–7.15 (m, 4H), 4.46 (d, J = 9.9 Hz, 1H), 4.30–4.08 (m, 3H), 3.90 (s, 3H), 3.46 (d, J = 13.8 Hz, 1H), 3.36–3.33 (m, 1H), 1.83–1.63 (m, 2H), 1.14 (s, 9H). ESI-MS calculated value C 37 H 39 35 Cl2F2N4O4[M+H] + =711.23, experimentally measured: 711.3.

[0173] Final product 23: 4-((2R,3S,4S,5S)-4-(((4-pyridylmethyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL093)

[0174]

[0175] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((4-pyridylmethyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL093)

[0176] Take YL090 (30 mg, 0.047 mmol), 4-bromomethylpyridine hydrobromide (18 mg, 0.07 mmol), potassium carbonate (33 mg, 0.24 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of final product 14 to obtain 16 mg of trifluoroacetate of the target compound with a yield of 41%. 1H NMR(500MHz,Methanol-d4)δ8.75(d,J=5.9Hz,2H),8.23(d,J=8.4Hz,1H),7.93(d,J=5.9Hz,2H), 7.70–7.51(m,3H),7.46(t,J=7.5Hz,1H),7.30–7.15(m,4H),5.22(d,J=10.1Hz,1H),4.59(d,J=9 .7Hz,1H),4.53(d,J=10.3Hz,1H),4.11(d,J=2.6Hz,2H),3.85(s,3H),3.35–3.32(m,1H),3.20(d,J=13.4Hz,1H),1.91(dd,J=15.0,9.9Hz,1H),1.73(d,J=14.8Hz,1H),1.06(s,9H).ESI-MS theoretical calculated value C 37 H 39 35 Cl2F2N4O4[M+H] + =711.23, experimentally measured: 711.2.

[0177] Final product 24: 4-((2R,3S,4S,5S)-4-(((2-hydroxybenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL095)

[0178]

[0179] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((2-hydroxybenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL095)

[0180] Take YL090 (30 mg, 0.047 mmol), 2-hydroxybenzaldehyde (12 mg, 0.094 mmol), sodium acetate borohydride (30 mg, 0.14 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of the final product 16 to obtain 17.6 mg of the trifluoroacetate of the target compound with a yield of 45%. 1H NMR(500MHz, Methanol-d4)δ8.27(d,J=8.4Hz,1H),7.67–7.56(m,2H),7.48–7.38(m,1H),7.33 –7.22(m,3H),7.21–7.06(m,4H),6.95–6.83(m,2H),4.40(d,J=10.1Hz,1H),4.35(d,J=13.1Hz, 1H), 4.30 (d, J = 11.3 Hz, 1H), 4.23 (d, J = 13.1 Hz, 1H), 3.97 (s, 3H), 3.90–3.80 (m, 2H), 3.53 (d, J = 14.2 Hz, 1H), 1.76 (d, J = 13.2 Hz, 1H), 1.57 (dd, J = 13.4, 11.5 Hz, 1H), 1.25 (s, 9H). ESI-MS theoretical calculated value C 38 H 40 35 Cl2F2N3O5[M+H] + =726.23, experimentally measured: 726.2.

[0181] Final product 25: 4-((2R,3S,4S,5S)-4-(((3-hydroxybenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL096)

[0182]

[0183] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((3-hydroxybenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL096)

[0184] Take YL090 (30 mg, 0.047 mmol), 3-hydroxybenzaldehyde (12 mg, 0.094 mmol), sodium acetate borohydride (30 mg, 0.14 mmol), acetic acid 0.1 mL and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of the final product 16 to obtain 17.4 mg of the trifluoroacetate of the target compound with a yield of 44%. 1H NMR(500MHz, Methanol-d4)δ8.27(d,J=8.3Hz,1H),7.66–7.54(m,2H),7.43(t,J=7.5Hz,1H),7. 27(t,J=7.8Hz,1H),7.23–7.04(m,4H),6.96–6.76(m,4H),4.38(d,J=10.0Hz,1H),4.30(d,J=11 .4Hz,1H),4.19–4.05(m,2H),3.96(s,3H),3.81(d,J=10.1Hz,1H),3.68(dd,J=14.3,2.4Hz,1H),3.41(t,J=17.2Hz,1H),1.71(d,J=13.5Hz,1H),1.56–1.38(m,1H),1.24(s,9H).ESI-MS theoretical calculated value C 38 H 40 35 Cl2F2N3O5[M+H] + =726.23, experimentally measured: 726.1.

[0185] Final product 26: 4-((2R,3S,4S,5S)-4-(((4-hydroxybenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL097)

[0186]

[0187] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((4-hydroxybenzyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL097)

[0188] YL090 (30 mg, 0.047 mmol), 4-hydroxybenzaldehyde (12 mg, 0.094 mmol), sodium acetate borohydride (30 mg, 0.14 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (10 mg, 0.24 mmol) were taken, and the steps were referred to the final product 16 to obtain 21 mg of the trifluoroacetate salt of the target compound with a yield of 53%. 1H NMR(500MHz, Methanol-d4)δ8.27(d,J=8.5Hz,1H),7.66–7.54(m,2H),7.49–7.41(m,1H),7.29–6.9 9(m,6H),6.97–6.79(m,3H),4.40(d,J=10.1Hz,1H),4.29(d,J=11.4Hz,1H),4.14(d,J=13.3Hz,1H) ,4.09(d,J=13.2Hz,1H),3.97(s,3H),3.77(d,J=10.1Hz,1H),3.64(dd,J=14.1,2.5Hz,1H),3.38(d,J=14.3Hz,1H),1.70(d,J=13.4Hz,1H),1.46(dd,J=13.5,11.6Hz,1H),1.24(s,9H).ESI-MS theoretical calculated value C 38 H 40 35 Cl2F2N3O5[M+H] + =726.23, experimentally measured: 726.3.

[0189] Final product 27: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((1-methyl-1H-pyrazol-4-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL099)

[0190]

[0191] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((1-methyl-1H-pyrazol-4-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL099)

[0192] Take YL090 (30 mg, 0.047 mmol), 1-methyl-1H-pyrazole-4-carbaldehyde (10 mg, 0.094 mmol), sodium acetate borohydride (30 mg, 0.14 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of the final product 16 to obtain 22.8 mg of the trifluoroacetate of the target compound with a yield of 59%. 1H NMR(500MHz, Methanol-d4)δ8.27(d,J=8.4Hz,1H),7.71(s,1H),7.65–7.56(m,2H),7.53(s,1H),7.48(td,J =7.4,1.6Hz,1H),7.29(dd,J=8.6,2.2Hz,1H),7.25–7.11(m,4H),4.44(d,J=10.1Hz,1H),4.30(d,J=11.4Hz , 1H), 4.14 (d, J = 2.3 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.82 (d, J = 10.0 Hz, 1H), 3.70 (dd, J = 14.1, 2.8 Hz, 1H), 3.41 (d, J = 14.2 Hz, 1H), 1.71 (d, J = 13.5 Hz, 1H), 1.48 (dd, J = 13.6, 11.6 Hz, 1H), 1.25 (s, 9H). ESI-MS theoretical calculated value C 36 H 40 35 Cl2F2N5O4[M+H] + =714.24, experimentally measured: 714.3.

[0193] Final product 28: 4-((2R,3S,4S,5S)-4-(((((1H-imidazol-4-yl)methyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL100)

[0194]

[0195] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((((1H-imidazol-4-yl)methyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL100)

[0196] YL090 (30 mg, 0.047 mmol), 1H-imidazole-4-carboxaldehyde (9 mg, 0.094 mmol), sodium acetate borohydride (30 mg, 0.14 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (10 mg, 0.24 mmol) were taken, and the steps were referred to the final product 16 to obtain 17.6 mg of the trifluoroacetate salt of the target compound with a yield of 46%. 1H NMR (500 MHz, Methanol-d4) δ8.83 (d, J = 1.3 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.65–7.40 (m, 5H), 7.29–7.13 (m, 4H), 5.12 (d, J = 10.3 Hz, 1H), 4.55 (d, J = 9.8 Hz, 1H), 4.45 (d, J = 10.1 Hz, 1H), 4.08 (s, 2H), 3.87 (s, 3H), 1.78 (dd, J = 14.7, 9.9 Hz, 1H), 1.64 (d, J = 14.4 Hz, 1H), 1.07 (s, 9H). ESI-MS calculated value C 35 H 38 35 Cl2F2N5O4[M+H] + =700.23, experimentally measured: 700.3.

[0197] Final product 29: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((ethylamino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL106)

[0198]

[0199] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((ethylamino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL106)

[0200] Take YL090 (20 mg, 0.03 mmol), acetaldehyde (13 mg, 0.3 mmol), sodium acetate borohydride (64 mg, 0.3 mmol), acetic acid 0.1 mL and lithium hydroxide monohydrate (6 mg, 0.15 mmol), and follow the steps of the final product 16 to obtain 13 mg of the trifluoroacetate salt of the target compound with a yield of 57%. 1H NMR(500MHz,Methanol-d4)δ8.29(d,J=8.4Hz,1H),7.69–7.57(m,2H),7.47(td,J=7.4,1.7Hz,1H), 7.41(t,J=8.6Hz,1H),7.36(dd,J=8.7,2.2Hz,1H),7.32–7.16(m,3H),4.44(d,J=10.3Hz,1H),4.32 (d, J = 11.3 Hz, 1H), 3.99 (s, 3H), 3.93–3.78 (m, 2H), 3.49 (t, J = 15.4 Hz, 1H), 3.21–3.07 (m, 2H), 1.77 (d, J = 13.3 Hz, 1H), 1.54 (dd, J = 13.5, 11.5 Hz, 1H), 1.32 (t, J = 7.3 Hz, 3H), 1.28 (s, 9H). ESI-MS theoretical calculated value C 33 H 38 35 Cl2F2N3O4[M+H] + =648.22, experimentally measured: 648.1.

[0201] Final product 30: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((propylamino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL121)

[0202]

[0203] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((propylamino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL121)

[0204] YL090 (20 mg, 0.03 mmol), propionaldehyde (9 mg, 0.15 mmol), sodium acetate borohydride (32 mg, 0.15 mmol), acetic acid 0.1 mL and lithium hydroxide monohydrate (6 mg, 0.15 mmol) were taken, and the steps were referred to the final product 16 to obtain 12.4 mg of the trifluoroacetate salt of the target compound with a yield of 53%. 1H NMR(500MHz, Methanol-d4)δ8.29(d,J=8.4Hz,1H),7.68–7.56(m,2H),7.51–7.44(m,1H),7.40( t,J=8.6Hz,1H),7.35(dd,J=8.7,2.1Hz,1H),7.32–7.15(m,3H),4.44(d,J=10.2Hz,1H),4.31(d , J=11.4Hz,1H),3.98(s,3H),3.93–3.82(m,2H),3.49(t,J=14.3Hz,1H),3.08–2.91(m,2H),1.82–1.65(m,3H),1.54(dd,J=13.5,11.5Hz,1H),1.27(s,9H),0.99(t,J=7.4Hz,3H).ESI-MS theoretical calculated value C 34 H 40 35 Cl2F2N3O4[M+H] + =662.24, experimentally measured: 662.1.

[0205] Final product 31: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-((((tetrahydro-2H-pyran-4-yl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL107)

[0206]

[0207] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-((((tetrahydro-2H-pyran-4-yl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL107)

[0208] Take YL090 (20 mg, 0.03 mmol), tetrahydro-4H-pyran-4-one (4.4 mg, 0.044 mmol), sodium acetate borohydride (19 mg, 0.09 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (6 mg, 0.15 mmol), and follow the steps of the final product 16 to obtain 17.8 mg of the trifluoroacetate of the target compound with a yield of 72%. 1H NMR(500MHz,Methanol-d4)δ8.29(d,J=8.4Hz,1H),7.67–7.57(m,2H),7.52–7.44(m,1H) ),7.43–7.15(m,5H),4.49(d,J=10.2Hz,1H),4.34(d,J=11.3Hz,1H),4.04(dt,J=10.6,4 .7Hz,2H),3.98(s,3H),3.95–3.83(m,2H),3.60–3.37(m,4H),1.93(dd,J=13.0,4.1Hz,2H),1.89–1.72(m,2H),1.56(dd,J=13.6,11.5Hz,1H),1.36–1.21(m,10H).ESI-MS theoretical calculated value C 36 H 42 35 Cl2F2N3O5[M+H] + =704.25, experimentally measured: 704.2.

[0209] Final product 32: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-(((1-methylpiperidin-4-yl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL108)

[0210]

[0211] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-(((1-methylpiperidin-4-yl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL108)

[0212] YL090 (20 mg, 0.03 mmol), 1-methylpiperidin-4-one (5 mg, 0.045 mmol), sodium acetate borohydride (19 mg, 0.09 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (6 mg, 0.15 mmol) were taken, and the steps were referred to the final product 16 to obtain 17.6 mg of the trifluoroacetate salt of the target compound with a yield of 71%. 1H NMR(500MHz, Methanol-d4)δ8.25(d,J=8.4Hz,1H),7.67–7.51(m,3H),7.47(t,J=7. 4Hz,1H),7.36–7.19(m,4H),5.11–4.99(m,1H),4.51(d,J=9.9Hz,1H),4.41(d,J=10. 2Hz,1H),3.89(s,3H),3.67–3.35(m,4H),3.18–2.96(m,3H),2.87(s,3H),2.30(t,J=15.2Hz,2H),1.96–1.75(m,3H),1.70(d,J=14.3Hz,1H),1.09(s,9H).ESI-MS theoretical calculated value C 37 H 45 35 Cl2F2N4O4[M+H] + =717.28, experimentally measured: 717.3.

[0213] Final product 33: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-(((piperidin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL109)

[0214]

[0215] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-(((piperidin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL109)

[0216] YL090 (25 mg, 0.039 mmol) was weighed into a reaction bottle, tert-butyl 4-formylpiperidine-1-carboxylate (13 mg, 0.059 mmol) and sodium borohydride acetate (25 mg, 0.12 mmol) were added, dissolved in 1,2-dichloroethane, 0.1 mL of acetic acid was added, and the reaction was allowed to react at room temperature overnight. After being spun dry, the mixture was dissolved in 5 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 6 h. After being spun dry, water was added, and the mixture was extracted with dichloromethane. The organic phase was spun dry and dissolved in a tetrahydrofuran / water mixed solvent. Lithium hydroxide monohydrate (8 mg, 0.2 mmol) was added, and the mixture was allowed to react at room temperature overnight. After the solvent was spun dry, the mixture was purified by HPLC to obtain 17.5 mg of the trifluoroacetate of the target compound with a yield of 54%. 1H NMR(500MHz, Methanol-d4)δ8.28(d,J=8.4Hz,1H),7.66–7.58(m,2H),7.51–7.44(m,1H),7.42–7.35(m,2 H),7.33(dd,J=8.7,2.2Hz,1H),7.27–7.18(m,2H),4.64(d,J=10.2Hz,1H),4.39(d,J=10.8Hz,1H),4.02(d , J=10.2Hz,1H),3.96(s,3H),3.92(d,J=14.5Hz,1H),3.49–3.37(m,3H),3.06–2.90(m,4H),2.15–1.92(m,3H),1.77(d,J=13.5Hz,1H),1.67(dd,J=13.7,11.0Hz,1H),1.59–1.40(m,2H),1.21(s,9H).ESI-MS theoretical calculated value C 37 H 45 35 Cl2F2N4O4[M+H] + =717.28, experimentally measured: 717.3.

[0217] Final product 34: 4-(((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-(((((R / S)-piperidin-3-yl)methyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL110)

[0218]

[0219] Step 1: Synthesis of 4-(((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-(((((R / S)-piperidin-3-yl)methyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL110)

[0220] Take YL090 (25 mg, 0.039 mmol), tert-butyl 3-formylpiperidine-1-carboxylate (13 mg, 0.059 mmol), sodium acetate borohydride (25 mg, 0.12 mmol), 0.1 mL acetic acid, 3 mL trifluoroacetic acid and lithium hydroxide monohydrate (8 mg, 0.2 mmol), and refer to the final product 33 for the reaction steps to obtain 10.9 mg of the trifluoroacetate salt of the target compound with a yield of 34%. 1H NMR(500MHz, Methanol-d4)δ8.27(d,J=8.2Hz,1H),7.62(d,J=8.2Hz,2H),7.57–7.14(m,6H ),4.72(dd,J=10.2,5.5Hz,1H),4.40(d,J=10.4Hz,1H),4.13(d,J=9.5Hz,1H),3.94(s,3H), 3.74 (q, J = 16.1 Hz, 1H), 3.56–3.34 (m, 3H), 3.01–2.81 (m, 3H), 2.73 (q, J = 12.8 Hz, 1H), 2.17 (s, 1H), 2.02–1.85 (m, 2H), 1.83–1.55 (m, 3H), 1.41–1.27 (m, 1H), 1.18 (s, 9H). ESI-MS theoretical calculated value C 37 H 45 35 Cl2F2N4O4[M+H] + =717.28, experimentally measured: 717.6.

[0221] Final product 35: 4-(((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-(((((S)-piperidin-2-yl)methyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL111-1)

[0222] Final product 36: 4-(((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-(((((R)-piperidin-2-yl)methyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL111-2)

[0223]

[0224] Step 1: Synthesis of 4-(((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-(((((S)-piperidin-2-yl)methyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL111-1) and 4-(((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-(((((R)-piperidin-2-yl)methyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL111-2)

[0225] YL090 (25 mg, 0.039 mmol), tert-butyl 2-formylpiperidine-1-carboxylate (13 mg, 0.059 mmol), sodium acetate borohydride (25 mg, 0.12 mmol), 0.1 mL acetic acid, 3 mL trifluoroacetic acid and lithium hydroxide monohydrate (8 mg, 0.2 mmol) were taken. The reaction steps refer to the final product 33 to obtain the trifluoroacetate of the target compound YL111-1 12.4 mg and YL111-2 4.3 mg, with a yield of 51%. The chirality of the piperidine on YL111-1 and YL111-2 is a relative concept. For the convenience of expression, YL111-1 is named S configuration, and YL111-2 is named R configuration. YL111-1 1 H NMR(500MHz, Methanol-d4)δ8.23(d,J=8.4Hz,1H),7.68–7.55(m,3H),7.48(t,J=7.5Hz,1H),7.33–7.1 8(m,4H),5.34–5.20(m,1H),4.71–4.53(m,2H),3.83(s,3H),3.47–3.36(m,1H),3.29–3.23(m,1H),3.1 9 (d, J = 13.3 Hz, 1H), 3.09 (d, J = 13.3 Hz, 1H), 2.97 (td, J = 12.6, 2.9 Hz, 1H), 2.88–2.70 (m, 2H), 2.02 (d, J = 13.9 Hz, 1H), 1.98–1.79 (m, 3H), 1.77–1.52 (m, 3H), 1.44 (q, J = 12.6 Hz, 1H), 1.02 (s, 9H). ESI-MS theoretical calculated value C 37 H 45 35 Cl2F2N4O4[M+H] + =717.28, experimentally measured: 718.0; YL111-2 1HNMR(500MHz,Methanol-d4)δ8.30(d,J=8.4Hz,1H),7.71–7.52(m,3H),7.49(t,J=7.4Hz,1H),7.35–7.1 9(m,4H),4.47(s,1H),3.91(s,3H),3.39(d,J=13.6Hz,1H),3.25(d,J=12.9Hz,1H),3.18–3.01(m,2H),2. 96 (t, J = 12.6 Hz, 1H), 2.82 (dd, J = 12.9, 4.8 Hz, 1H), 2.78–2.68 (m, 1H), 2.02–1.86 (m, 3H), 1.83–1.64 (m, 2H), 1.58 (d, J = 12.7 Hz, 1H), 1.47 (q, J = 11.9, 11.3 Hz, 1H), 1.39–1.24 (m, 1H), 1.09 (s, 9H). ESI-MS theoretical calculated value C 37 H 45 35 Cl2F2N4O4[M+H] + =717.28, experimentally measured: 718.1.

[0226] Final product 37: 4-(((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-((((R)-pyrrolidin-3-yl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL112-1)

[0227] Final product 38: 4-(((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-((((S)-pyrrolidin-3-yl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL112-2)

[0228]

[0229] YL090 (25 mg, 0.039 mmol), tert-butyl 3-oxopyrrolidine-1-carboxylate (11 mg, 0.059 mmol), sodium acetate borohydride (25 mg, 0.12 mmol), 0.1 mL acetic acid, 3 mL trifluoroacetic acid and lithium hydroxide monohydrate (8 mg, 0.2 mmol) were taken. The reaction steps refer to the final product 33 to obtain the trifluoroacetate of the target compound YL112-1 10.6 mg and YL112-2 10.9 mg, with a yield of 69%. The chirality on the pyrrole of YL112-1 and YL1122-2 is a relative concept. For the convenience of expression, YL112-1 is named R configuration, and YL111-2 is named S configuration. YL112-1 1 H NMR(500MHz, Methanol-d4)δ8.25(d,J=8.4Hz,1H),7.73–7.55(m,3H),7.47(t,J=7.4 Hz,1H),7.34–7.17(m,4H),5.34–5.12(m,1H),4.72–4.39(m,2H),3.86(s,3H),3.53– 3.34 (m, 4H), 3.23 (d, J = 12.9 Hz, 1H), 3.16–3.01 (m, 2H), 2.25 (dd, J = 13.9, 7.0 Hz, 1H), 2.10–1.96 (m, 1H), 1.83 (s, 1H), 1.64 (d, J = 14.8 Hz, 1H), 1.03 (s, 9H). ESI-MS theoretical calculated value C 35 H 41 35 Cl2F2N4O4[M+H] + =689.25, experimentally measured: 689.2; YL112-2 1 H NMR(500MHz,Methanol-d4)δ8.26(d,J=8.4Hz,1H),7.64(dd,J=8.4,1.8Hz,2H),7.60( d,J=1.8Hz,1H),7.47(t,J=7.4Hz,1H),7.33–7.18(m,4H),5.32–5.08(m,1H),4.70–4.3 8 (m, 2H), 3.86 (s, 3H), 3.53–3.34 (m, 4H), 3.28–3.14 (m, 2H), 3.01 (d, J = 13.0 Hz, 1H), 2.26–2.10 (m, 1H), 1.92–1.72 (m, 2H), 1.63 (d, J = 14.7 Hz, 1H), 1.03 (s, 9H). ESI-MS theoretical calculated value C 35 H 41 35 Cl2F2N4O4[M+H]+ =689.25, experimentally measured: 689.0.

[0230] Final product 39: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-((((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL113)

[0231]

[0232] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-((((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YL113)

[0233] YL090 (23 mg, 0.036 mmol), 4-formyl-tetrahydro-2H-pyran (6 mg, 0.054 mmol), sodium acetate borohydride (23 mg, 0.11 mmol), 0.1 mL acetic acid, 3 mL trifluoroacetic acid and lithium hydroxide monohydrate (8 mg, 0.2 mmol) were taken. The reaction steps were referred to the final product 33 to obtain 14 mg of the trifluoroacetate salt of the target compound with a yield of 47%. 1 H NMR(500MHz,Methanol-d4)δ8.29(d,J=8.4Hz,1H),7.67–7.57(m,2H),7.49(td,J=7.3,2.0Hz,1H),7.44–7.33(m,2H) ,7.31–7.17(m,3H),4.48(d,J=10.1Hz,1H),4.33(d,J=11.3Hz,1H),4.02–3.92(m,5H),3.92–3.84(m,2H),3.55(t,J= 13.3Hz,1H),3.42(tdd,J=11.8,7.2,2.2Hz,2H),3.00(dd,J=6.8,2.8Hz,2H),2.02(ttd,J=11.0,7.1,3.3Hz,1H),1.82(d,J=13.4Hz,1H),1.69–1.57(m,2H),1.51(dd,J=13.5,11.4Hz,1H),1.42–1.30(m,2H),1.27(s,9H).ESI-MS theoretical calculated value C 37 H 44 35 Cl2F2N3O5[M+H] +=718.26, experimentally measured: 718.0.

[0234] Final product 40: 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(((1r,4R))-4-hydroxycyclohexyl)carbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (YH107)

[0235]

[0236] Step 1: Synthesis of (2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((3-(methoxycarbonyl)benzyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxylic acid (YH101)

[0237] YG155 (460 mg, 0.87 mmol) was weighed into a reaction bottle, dissolved with an appropriate amount of acetonitrile, methyl 3-bromomethylbenzoate (240 mg, 1.05 mmol) and potassium carbonate (241 mg, 1.75 mmol) were added, stirred at room temperature overnight, water was added, extracted with dichloromethane, the organic phase was dried by spin drying, dissolved in 5 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, stirred at room temperature overnight, the solvent was dried by spin drying, and purified by normal phase column to obtain 359 mg of trifluoroacetate of the target compound with a yield of 66%. 1 H NMR(500MHz,Methanol-d4)δ7.98(t,J=1.8Hz,1H),7.93–7.86(m,1H),7.78(t,J=7.2Hz,1H),7.56(d ,J=7.5Hz,1H),7.43(t,J=7.7Hz,1H),7.37(t,J=7.4Hz,1H),7.28–7.19(m,2H),7.14(dd,J=8.7,2.2 Hz,1H),6.97(t,J=8.9Hz,1H),5.00(d,J=8.5Hz,1H),4.77(d,J=9.0Hz,1H),4.62–4.49(m,1H),3.90 (s,3H),3.84(s,2H),2.98(d,J=13.3Hz,1H),2.78(d,J=13.2Hz,1H),1.32–1.25(m,2H),0.87(s,9H).

[0238] Step 2: Synthesis of 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(((1r,4R))-4-hydroxycyclohexyl)carbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (YH107)

[0239] YH101 (62 mg, 0.1 mmol) was weighed into a reaction flask, dissolved in dry THF, DIEA (65 mg, 0.5 mmol) was added and stirred for 5 minutes, diphenylphosphinoyl chloride (71 mg, 0.3 mmol) was added and stirred for half an hour, trans-4-hydroxycyclohexylamine (46 mg, 0.4 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and purified with a normal phase column to obtain a crude carboxylate precursor. The crude product was dissolved in a tetrahydrofuran / water mixture, and lithium hydroxide monohydrate (21 mg, 0.5 mmol) was added. The mixture was stirred at room temperature overnight, the solvent was dried and purified by HPLC to obtain 18.8 mg of trifluoroacetate of the target compound with a yield of 23%. 1 H NMR (500MHz, Methanol-d4) δ8.06(dd,J=4.6,2.6Hz,2H),7.62(d,J=7.6Hz,1H),7.54(t,J=7.9Hz,1H),7.44(t,J=7.2Hz ,1H),7.35(t,J=7.1Hz,1H),7.30–7.15(m,3H),7.01(t,J=8.7Hz,1H),4.67–4.51(m,2H),4.27(d,J=9.2Hz,1H),4.21–4. 05(m,2H),3.59(tt,J=11.3,3.9Hz,1H),3.46(tt,J=10.0,3.8Hz,1H),3.38–3.32(m,1H),3.24(d,J=14.0Hz,1H),2.10–1.76(m,3H),1.70(dd,J=14.5,9.8Hz,2H),1.59(d,J=14.4Hz,1H),1.37–1.21(m,3H),1.19–0.77(m,10H).ESI-MS theoretical calculated value C 37 H 44 35 Cl2F2N3O4[M+H] + =702.27, experimentally measured: 702.2.

[0240] Final product 41: 3-((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-((6-hydroxypyridin-3-yl)carbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (YH120)

[0241]

[0242] Step 1: Synthesis of 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-((6-hydroxypyridin-3-yl)carbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (YH120)

[0243] YH101 (62 mg, 0.1 mmol) was weighed into a reaction flask, dissolved in dry THF, DIEA (65 mg, 0.5 mmol) was added and stirred for 5 minutes, diphenylphosphinoyl chloride (71 mg, 0.3 mmol) was added and stirred for half an hour, 2-hydroxypyridine-5-amine (44 mg, 0.4 mmol) was added, stirred at room temperature overnight, water was added, extracted with ethyl acetate, the organic phase was spin-dried and purified with a normal phase column to obtain a crude carboxylate precursor, the crude product was dissolved in a tetrahydrofuran / water mixture, lithium hydroxide monohydrate (21 mg, 0.5 mmol) was added, stirred at room temperature overnight, the solvent was spin-dried, and HPLC was used to purify the trifluoroacetate of the target compound 22.9 mg, with a yield of 28%. 1 H NMR(500MHz,Methanol-d4)δ8.15–8.06(m,2H),7.96(d,J=2.9Hz,1H),7.65(dt,J=7.7,1.5Hz,1H),7.57 (t,J=7.7Hz,1H),7.52(dd,J=9.7,2.9Hz,1H),7.46(td,J=7.7,7.1,1.6Hz,1H),7.30–7.14(m,4H),7.04( t, J = 8.9 Hz, 1H), 6.54 (d, J = 9.7 Hz, 1H), 4.77–4.63 (m, 2H), 4.33–4.15 (m, 3H), 3.62 (dd, J = 14.1, 2.0 Hz, 1H), 3.35 (d, J = 14.3 Hz, 1H), 1.83 (dd, J = 14.5, 10.6 Hz, 1H), 1.73–1.65 (m, 1H), 1.10 (s, 9H). ESI-MS theoretical calculated value C 36 H 37 35 Cl2F2N4O4[M+H] + =697.22, experimentally measured: 697.1.

[0244] Final product 42: 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(methylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (YH122)

[0245]

[0246] Step 1: Synthesis of 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(methylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (YH122)

[0247] Take YH101 (62 mg, 0.1 mmol), DIEA (77 mg, 0.6 mmol), diphenylphosphinoyl chloride (71 mg, 0.3 mmol), methylamine hydrochloride (27.2 mg, 0.4 mmol) and lithium hydroxide monohydrate (21 mg, 0.5 mmol), and refer to the final product 41 for the reaction steps to obtain 13.7 mg of the trifluoroacetate salt of the target compound with a yield of 19%. 1 H NMR (500MHz, Methanol-d4) δ8.10–8.04(m,2H),7.62(dt,J=7.6,1.6Hz,1H),7.55(t,J=7.6Hz,1 H),7.49–7.42(m,1H),7.34(t,J=7.0Hz,1H),7.29–7.18(m,3H),7.00(t,J=8.8Hz,1H),4.74–4. 62 (m, 2H), 4.27 (d, J = 9.6 Hz, 1H), 4.21–4.02 (m, 2H), 3.42 (d, J = 14.1 Hz, 1H), 3.27 (d, J = 14.1 Hz, 1H), 2.71 (s, 3H), 1.77 (dd, J = 14.7, 10.1 Hz, 1H), 1.67–1.53 (m, 1H), 1.04 (s, 9H). ESI-MS theoretical calculated value C 32 H 36 35 Cl2F2N3O3[M+H] + =618.21, experimentally measured: 618.1.

[0248] Final product 43: 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(hydroxyethylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (YH128)

[0249]

[0250] Step 1: Synthesis of 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(hydroxyethylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (YH128)

[0251] Take YH101 (62 mg, 0.1 mmol), DIEA (65 mg, 0.5 mmol), diphenylphosphinoyl chloride (71 mg, 0.3 mmol), 2-aminoethanol (24.4 mg, 0.4 mmol) and lithium hydroxide monohydrate (21 mg, 0.5 mmol), and refer to the final product 41 for the reaction steps to obtain 29.9 mg of the trifluoroacetate salt of the target compound with a yield of 39%. 1 H NMR (500MHz, Methanol-d4) δ8.09(dt,J=7.7,1.4Hz,1H),8.06(d,J=1.8Hz,1H),7.64(dt,J=7.7,1.5Hz,1H),7. 55(t,J=7.7Hz,1H),7.45(td,J=7.6,7.2,1.6Hz,1H),7.31–7.14(m,4H),6.97(t,J=8.6Hz,1H),4.74(d,J=10.6H z, 1H), 4.68 (d, J = 9.9 Hz, 1H), 4.29–4.12 (m, 3H), 3.66–3.58 (m, 1H), 3.57–3.42 (m, 2H), 3.36–3.31 (m, 2H), 3.21 (ddd, J = 13.8, 6.2, 4.7 Hz, 1H), 1.89 (dd, J = 14.6, 10.7 Hz, 1H), 1.70 (d, J = 14.4 Hz, 1H), 1.09 (s, 9H). ESI-MS theoretical calculated value C 33 H 38 35 Cl2F2N3O4[M+H] + =648.22, experimentally measured: 648.2.

[0252] Final product 44: 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(3-pyridylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (YH129)

[0253]

[0254] Step 1: Synthesis of 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(3-pyridylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (YH129)

[0255] Take YH101 (62 mg, 0.1 mmol), DIEA (65 mg, 0.5 mmol), diphenylphosphinoyl chloride (71 mg, 0.3 mmol), 3-aminopyridine (37.6 mg, 0.4 mmol) and lithium hydroxide monohydrate (21 mg, 0.5 mmol), and refer to the final product 41 for the reaction steps to obtain 24.2 mg of the trifluoroacetate salt of the target compound with a yield of 30%. 1 H NMR (500MHz, Methanol-d4) δ9.28(d,J=2.4Hz,1H),8.54(dd,J=5.7,1.2Hz,1H),8.47(ddd,J=8.7,2.5,1.3Hz,1H),8.18 –8.06(m,2H),7.95(dd,J=8.7,5.6Hz,1H),7.67(dt,J=7.6,1.5Hz,1H),7.57(t,J=7.7Hz,1H),7.47–7.37(m,1H),7.30– 7.13 (m, 4H), 7.07 (t, J = 8.7 Hz, 1H), 4.74 (d, J = 10.0 Hz, 1H), 4.63 (d, J = 10.5 Hz, 1H), 4.34–4.20 (m, 3H), 3.72 (dd, J = 14.2, 2.3 Hz, 1H), 3.41–3.34 (m, 1H), 1.79 (dd, J = 14.2, 10.7 Hz, 1H), 1.72 (dd, J = 14.1, 1.6 Hz, 1H), 1.13 (s, 9H). ESI-MS theoretical calculated value C 36 H 37 35 Cl2F2N4O3[M+H] + =681.22, experimentally measured: 681.2.

[0256] Final product 45: 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(4-carboxyphenylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (FE028)

[0257]

[0258] Step 1: Synthesis of 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(4-carboxyphenylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (FE028)

[0259] Take YH101 (62 mg, 0.1 mmol), DIEA (65 mg, 0.5 mmol), diphenylphosphinoyl chloride (71 mg, 0.3 mmol), methyl 4-aminobenzoate (60 mg, 0.4 mmol) and lithium hydroxide monohydrate (21 mg, 0.5 mmol), and follow the reaction steps of the final product 41 to obtain 11.8 mg of the trifluoroacetate salt of the target compound with a yield of 14%. 1 H NMR (500 MHz, Methanol-d4) δ 8.15–8.07 (m, 2H), 7.97 (d, J = 8.6 Hz, 2H), 7.61 (tt, J = 15.3, 7.6 Hz, 4H), 7.44 (t, J = 7.4 Hz, 1H), 7.29–7.16 (m, 4H), 7.09 (t, J = 8.7 Hz, 1H), 4.67 (d, J = 9.6 Hz, 1H), 4.62 (d, J = 9.8 Hz, 1H), 4.29–4.20 (m, 3H), 3.58 (d, J = 14.0 Hz, 1H), 3.34 (d, J = 14.2 Hz, 1H), 1.82–1.63 (m, 2H), 1.13 (s, 9H). ESI-MS calculated value C 38 H 38 35 Cl2F2N3O5[M+H] + =724.22, experimentally measured: 724.2.

[0260] Final product 46: 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(3-carboxyphenylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (FE037)

[0261]

[0262] Step 1: Synthesis of 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(3-carboxyphenylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (FE037)

[0263] Take YH101 (62 mg, 0.1 mmol), DIEA (65 mg, 0.5 mmol), diphenylphosphinoyl chloride (71 mg, 0.3 mmol), methyl 3-aminobenzoate (60 mg, 0.4 mmol) and lithium hydroxide monohydrate (21 mg, 0.5 mmol), and follow the reaction steps of the final product 41 to obtain 9.1 mg of the trifluoroacetate salt of the target compound with a yield of 11%. 1 H NMR(500MHz, Methanol-d4)δ8.16(d,J=1.9Hz,1H),8.09(dt,J=3.9,1.8Hz,2H),7.81–7.73(m,2H),7.64( d,J=7.6Hz,1H),7.56(t,J=7.9Hz,1H),7.42(td,J=7.8,4.0Hz,2H),7.31(t,J=7.1Hz,1H),7.28–7.16(m, 3H), 7.12 (t, J = 8.7 Hz, 1H), 4.66 (d, J = 9.3 Hz, 1H), 4.56 (t, J = 5.9 Hz, 1H), 4.28 (d, J = 9.4 Hz, 1H), 4.19 (d, J = 2.1 Hz, 2H), 3.46 (d, J = 14.0 Hz, 1H), 3.31–3.25 (m, 1H), 1.64 (d, J = 5.8 Hz, 2H), 1.10 (s, 9H). ESI-MS theoretical calculated value C 38 H 38 35 Cl2F2N3O5[M+H] + =724.22, experimentally measured: 724.2.

[0264] Final product 47: 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(4-carboxybenzylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (FE040)

[0265]

[0266] Step 1: Synthesis of 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(4-carboxybenzylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (FE040)

[0267] Take YH101 (62 mg, 0.1 mmol), DIEA (65 mg, 0.5 mmol), diphenylphosphinoyl chloride (71 mg, 0.3 mmol), methyl 4-aminomethylbenzoate hydrochloride (80 mg, 0.4 mmol) and lithium hydroxide monohydrate (21 mg, 0.5 mmol), and refer to the final product 41 for the reaction steps to obtain 6.3 mg of the trifluoroacetate salt of the target compound with a yield of 7%. 1 H NMR (500MHz, Methanol-d4) δ8.14–8.06(m,2H),7.86(d,J=8.0Hz,2H),7.65(d,J=7.6Hz,1H),7.56(t,J=7 .7Hz,1H),7.48(t,J=7.4Hz,1H),7.36–7.19(m,4H),7.10(d,J=8.0Hz,2H),7.00(d,J=9.0Hz,1H),4.80(d, J=10.5Hz,1H),4.76(d,J=10.1Hz,1H),4.54(d,J=15.4Hz,1H),4.29–4.18(m,4H),3.60(d,J=14.3Hz,1H),3.37(d,J=14.3Hz,1H),1.90(dd,J=14.7,10.5Hz,1H),1.70(d,J=14.6Hz,1H),1.07(s,9H). ESI-MS theoretical calculated value C 39 H 40 35 Cl2F2N3O5[M+H] + =738.23, experimentally measured: 738.2.

[0268] Final product 48: 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(4-carboxylic acid methylphenylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (FE041)

[0269]

[0270] Step 1: Synthesis of 3-(((((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-5-(4-carboxylic acid methylphenylcarbamoyl)-2-neopentylpyrrolidin-3-yl)methyl)amino)methyl)benzoic acid (FE041)

[0271] Take YH101 (62 mg, 0.1 mmol), DIEA (65 mg, 0.5 mmol), diphenylphosphinoyl chloride (71 mg, 0.3 mmol), methyl 4-aminophenylacetate hydrochloride (80 mg, 0.4 mmol) and lithium hydroxide monohydrate (21 mg, 0.5 mmol), and refer to the final product 41 for the reaction steps to obtain 4.7 mg of the trifluoroacetate salt of the target compound with a yield of 6%. 1 H NMR (500MHz, Methanol-d4) δ8.16–8.05(m,2H),7.65(d,J=7.6Hz,1H),7.58(t,J=7.7Hz ,1H),7.45(dd,J=22.3,8.0Hz,3H),7.30–7.16(m,6H),7.05(s,1H),4.74(dd,J=14.6,1 0.0Hz,2H),4.32–4.20(m,3H),3.63(d,J=14.1Hz,1H),3.55(s,2H),3.37(d,J=14.4Hz,1H),1.84(dd,J=14.5,10.6Hz,1H),1.72(d,J=14.3Hz,1H),1.13(s,9H).ESI-MS theoretical calculated value C 39 H 40 35 Cl2F2N3O5[M+H] + =738.23, experimentally measured: 738.2.

[0272] Final product 49: 4-((2R,3S,4S,5S)-4-(aminomethyl)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM031)

[0273]

[0274] Step 1: Synthesis of (Z)-2-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)acrylonitrile (YK008)

[0275] Weigh 5-chloro-2-fluorobenzyl acetonitrile (2.81 g, 20 mmol) and 2-chlorobenzaldehyde (3.39 g, 20 mmol), add into a 250 mL round-bottom flask, dissolve with 100 mL methanol, add 4.8 mL of 5N sodium methoxide solution, react at 50 ° C overnight, cool to room temperature, filter, wash the filter cake with water, dry, weigh 5.5 g, and the yield is 95%. 1 H NMR(500MHz,Chloroform-d)δ8.11(dq,J=6.6,3.8Hz,1H),7.96(s,1H),7.60(dd,J=6.6,2.6Hz,1H),7.52– 7.46(m,1H),7.41(dd,J=5.9,3.5Hz,2H),7.37(ddd,J=8.7,4.2,2.6Hz,1H),7.14(dd,J=10.4,8.8Hz,1H).

[0276] 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)

[0277] Weigh YK008 (5.5 g, 18.8 mmol) and add it to a 100 mL reaction bottle, dissolve it with 50 mL of dichloromethane, add silver fluoride (2.4 g, 18.8 mmol) and triethylamine (4.2 mL, 30 mmol), and then add tert-butyl 2-((3,3-dimethylbutylidene)amino)acetate (4.1 g, 19 mmol). React at room temperature overnight in the dark, pour into saturated ammonium chloride solution, filter, and extract the filtrate three times with dichloromethane. Combine the filtrates, distill under reduced pressure to remove the solvent, and purify on a normal phase silica gel column to obtain 2.7 g of the target compound with a yield of 28%. 1 HNMR(500MHz,Chloroform-d)δ7.80(dd,J=8.0,1.5Hz,1H),7.38(ddd,J=9.4,7.3 ,2.2Hz,2H),7.30(ddd,J=8.8,4.1,2.6Hz,1H),7.25–7.18(m,2H),7.03(dd,J=11. 9,8.7Hz,1H),4.96(d,J=6.6Hz,1H),4.13(d,J=8.9Hz,1H),4.08(d,J=6.6Hz,1H) ,1.66(ddd,J=14.4,9.1,1.3Hz,1H),1.41(s,9H),1.35–1.29(m,1H),0.92(s,9H).

[0278] Step 3: Synthesis of (2R, 3S, 4S, 5S)-4-(aminomethyl)-3-(2-chlorophenyl)-4-(5-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YK010-2)

[0279] Weigh YK010 (2.7 g, 5.3 mmol) and add it to a 100 mL reaction bottle, dissolve it with a mixed solvent of ethanol and tetrahydrofuran, add 2.5 g of Raney nickel, raise the temperature to 55 ° C, add 5 mL of hydrazine hydrate dropwise, stir and react for 1 h, cool, filter, and distill under reduced pressure to remove the filtrate. Purify it on a normal phase silica gel column to obtain 553 mg of the target compound with a conversion rate of 20%. 1 H NMR(500MHz,Chloroform-d)δ7.81(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),7.22–7.12(m,3H),6.85(dd,J=12.4,8.6Hz,1H),4 .32(d,J=9.1Hz,1H),4.19(d,J=9.6Hz,1H),4.04(d,J=9.1Hz,1H),3.42–3.32(m,2 H),1.63(d,J=13.8Hz,1H),1.52(dd,J=13.9,9.8Hz,1H),1.25(s,9H),1.03(s,9H).

[0280] 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)

[0281] Weigh YK010-2 (550 mg, 1.08 mmol) into a 50 mL round-bottom flask, dissolve it in 10 mL of dichloromethane, add FmocCl (418 mg, 1.62 mmol) and triethylamine (558 mg, 4.32 mmol), react at room temperature overnight, remove the solvent under reduced pressure, add 5 mL of dichloromethane and 4 mL of trifluoroacetic acid, react at room temperature overnight, spin dry the solvent, extract three times with dichloromethane, spin dry the organic phase, and purify with a normal phase column to obtain 469 mg of the product with a yield of 64%.

[0282] 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)

[0283] Weigh YK013 (469 mg, 0.69 mol) and dissolve it in THF. Add DIEA (445 mg, 3.45 mmol) and react for 5 min. Add diphenylphosphinoyl chloride (489 mg, 2.07 mmol) and react for 30 min. Add methyl 4-amino-3-methoxybenzoate (502 mg, 2.78 mmol) and react overnight. Remove the solvent under reduced pressure, add water, extract with dichloromethane 3 times, and purify the organic phase with a normal phase silica gel column after drying. Add 2 mL of DMF solution containing 20% ​​piperidine to obtain the crude product. After reacting at room temperature for 30 min, extract with ethyl acetate, dry the organic phase, and purify with a normal phase column to obtain 93 mg of the target compound with a yield of 22%. 1 H NMR(500MHz,Methanol-d4)δ8.25(d,J=8.3Hz,1H),7.62(d,J=7.9Hz,1H),7.59–7.51(m,2H), 7.49–7.39(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=14.3,3.3H z,1H),3.67(d,J=14.3Hz,1H),1.83–1.73(m,1H),1.67(dd,J=13.9,11.3Hz,1H),1.26(s,9H).

[0284] Step 6: Synthesis of 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(2-chlorophenyl)-4-(5-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM031)

[0285] YK017 (28 mg, 0.045 mmol) was weighed into a 50 mL round-bottom flask, and lithium hydroxide monohydrate (10 mg, 0.24 mmol) was added and dissolved with THF / H2O (v / v = 2 mL / 2 mL). The mixture was stirred at room temperature overnight and the solvent was removed by distillation under reduced pressure. 25 mg of the trifluoroacetate of the target compound was obtained by HPLC with a yield of 77%. 1H NMR (400MHz, Methanol-d4) δ8.27 (d, J=8.3Hz, 1H), 7.67–7.52 (m, 3H), 7.42 (dddd, J=11. 0,8.7,5.5,2.2Hz,2H),7.38–7.26(m,3H),7.04(dd,J=12.6,8.8Hz,1H),4.58–4.37(m,2 H), 4.31 (d, J = 10.3 Hz, 1H), 3.96 (s, 3H), 3.76 (dd, J = 14.2, 3.3 Hz, 1H), 3.64 (d, J = 14.2 Hz, 1H), 1.76 (d, J = 13.6 Hz, 1H), 1.58 (dd, J = 13.8, 11.4 Hz, 1H), 1.27 (s, 9H). ESI-MS theoretical calculated value C 31 H 35 35 Cl2FN3O4[M+H] + =602.20, experimentally measured: 602.4.

[0286] Final product 50: 4-((2R,3R,4S,5S)-4-(aminomethyl)-4-(5-chloro-2-fluorophenyl)-3-(3-chlorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM036)

[0287]

[0288] Step 1: Synthesis of (Z)-2-(5-chloro-2-fluorophenyl)-3-(3-chlorophenyl)acrylonitrile (YK028)

[0289] Weigh 5-chloro-2-fluorobenzyl acetonitrile (8.48 g, 50 mmol) and 3-chlorobenzaldehyde (7 g, 50 mmol), add into a 250 mL round-bottom flask, dissolve with 100 mL methanol, add 4.8 mL of 5N sodium methoxide solution, react at 50 ° C overnight, cool to room temperature, filter, wash the filter cake with water, dry, weigh 13.6 g, and the yield is 93%. 1 H NMR(500MHz,Chloroform-d)δ7.83(dt,J=6.7,1.9Hz,1H),7.79(d,J=2.0Hz,1H),7.57(dd,J=6.7,2.6H z,1H),7.53(s,1H),7.48–7.39(m,2H),7.35(ddd,J=8.9,4.3,2.6Hz,1H),7.13(dd,J=10.5,8.8Hz,1H).

[0290] 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 (YK031)

[0291] Weigh YK028 (5.84 g, 20 mmol) and add it to a 100 mL reaction bottle, dissolve it with 50 mL of dichloromethane, add silver fluoride (2.54 g, 20 mmol) and triethylamine (4.5 mL, 32 mmol), and then add tert-butyl 2-((3,3-dimethylbutylidene)amino)acetate (4.26 g, 20 mmol). React at room temperature overnight in the dark, pour into saturated ammonium chloride solution, filter, and extract the filtrate three times with dichloromethane. The filtrates are combined and the solvent is distilled off under reduced pressure. Purify on a normal phase silica gel column to obtain 2.5 g of the target compound with a yield of 25%. 1 HNMR (500MHz, Chloroform-d) δ7.41 (dd, J=6.7, 2.6Hz, 1H), 7.33 (ddd, J=8.7, 4. 2,2.6Hz,1H),7.28–7.24(m,1H),7.22(t,J=7.7Hz,1H),7.16(d,J=2.0Hz,1H),7. 13–7.06(m,2H),4.23(d,J=7.7Hz,1H),4.17(dd,J=7.7,1.3Hz,1H),4.07–3.98(m ,1H),1.69–1.54(m,1H),1.38(s,9H),1.31(dd,J=14.4,1.2Hz,1H),0.89(s,9H).

[0292] Step 3: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chlorophenyl)-4-(5-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YK035)

[0293] Weigh YK031 (3.5 g, 6.9 mmol) and add it to a 100 mL reaction bottle, dissolve it with a mixed solvent of ethanol and tetrahydrofuran, add 3.5 g of Raney nickel, raise the temperature to 55 ° C, add 5 mL of hydrazine hydrate dropwise, stir and react for 1 h, cool, filter, and distill under reduced pressure to remove the filtrate. Purify it on a normal phase silica gel column to obtain 490 mg of the target compound with a conversion rate of 14%. 1H NMR(500MHz,Chloroform-d)δ7.24–7.05(m,5H),7.00–6.88(m,2H),4.24(d,J=8.9Hz,1H),4.14–4.04(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),1.48–1.39(m,2H),1.26(s,9H),0.91(s,9H).

[0294] 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 (YK039)

[0295] Weigh YK035 (692 mg, 1.36 mmol) into a 50 mL round-bottom flask, dissolve it in 10 mL of dichloromethane, add FmocCl (526 mg, 2.04 mmol) and triethylamine (702 mg, 5.44 mmol), react at room temperature overnight, remove the solvent under reduced pressure, add 5 mL of dichloromethane and 4 mL of trifluoroacetic acid, react at room temperature overnight, spin dry the solvent, extract three times with dichloromethane, spin dry the organic phase, and purify with a normal phase column to obtain 710 mg of the product with a yield of 77%.

[0296] 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 (YK045)

[0297] Weigh YK039 (383 mg, 0.57 mol) and dissolve it in THF. Add DIEA (368 mg, 2.85 mmol) and react for 5 min. Add diphenylphosphinoyl chloride (404 mg, 1.71 mmol) and react for 30 min. Add methyl 4-amino-3-methoxybenzoate (410 mg, 2.27 mmol) and react overnight. Remove the solvent under reduced pressure, add water, extract with dichloromethane 3 times, and purify the organic phase with a normal phase silica gel column after drying. Add 2 mL of DMF solution containing 20% ​​piperidine to obtain the crude product. After reacting at room temperature for 30 min, extract with ethyl acetate, dry the organic phase, and purify by HPLC to obtain 184 mg of trifluoroacetate of the target compound with a yield of 44%. 1H NMR(500MHz, Methanol-d4)δ8.21(d,J=8.5Hz,1H),7.54–7.42(m,4H),7.41–7.29(m,2H),7.17–7.00(m,3H),4.79(d,J=10.8Hz, 1H),4.52(t,J=6.2Hz,1H),3.84(s,3H),3.82(s,3H),3.79–3.68(m,2H),3.55–3.46(m,1H),1.75(d,J=6.2Hz,2H),1.22(s,9H).

[0298] Step 6: Synthesis of 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chlorophenyl)-4-(5-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM036)

[0299] YK045 (33 mg, 0.05 mmol) was weighed into a 50 mL round-bottom flask, and lithium hydroxide monohydrate (10 mg, 0.24 mmol) was added and dissolved in THF / H2O (v / v = 2 mL / 2 mL). The mixture was stirred at room temperature overnight and the solvent was removed by distillation under reduced pressure. 18.4 mg of the trifluoroacetate of the target compound was obtained by HPLC with a yield of 51%. 1 H NMR(500MHz,Methanol-d4)δ8.29(d,J=8.4Hz,1H),7.65–7.56(m,2H),7.46(dd,J=8.0,4.7Hz ,2H),7.39–7.28(m,2H),7.15–7.03(m,2H),6.99(d,J=7.4Hz,1H),4.55(d,J=10.5Hz,1H),4.3 6 (d, J = 11.1 Hz, 1H), 3.95 (s, 3H), 3.68 (dd, J = 14.3, 3.5 Hz, 1H), 3.61 (d, J = 10.5 Hz, 1H), 3.53–3.41 (m, 1H), 1.70 (d, J = 13.6 Hz, 1H), 1.57 (dd, J = 13.8, 11.2 Hz, 1H), 1.24 (s, 9H). ESI-MS theoretical calculated value C 31 H 35 35 Cl2FN3O4[M+H] + =602.20, experimentally measured: 602.3.

[0300] Final product 51: 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentyl-4-(((pyridin-2-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YL134)

[0301]

[0302] Step 1: Synthesis of methyl 4-((2R,3S,4S,5S)-4-(aminomethyl)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentylpyrrolidine-2-carboxamide)benzoate (YL130)

[0303] Weigh YK013 (280 mg, 0.41 mol) and dissolve it in THF. Add DIEA (271 mg, 2.1 mmol) and react for 5 min. Add diphenylphosphinoyl chloride (298 mg, 1.26 mmol) and react for 30 min. Add methyl 4-aminobenzoate (250 mg, 1.66 mmol) and react overnight. Remove the solvent under reduced pressure. Add water. Extract with dichloromethane 3 times. The organic phase is spin-dried and purified with a normal phase silica gel column. After obtaining the crude product, add 2 mL of DMF solution containing 20% ​​piperidine. After reacting at room temperature for 30 min, extract with ethyl acetate. The organic phase is spin-dried and purified by HPLC to obtain 173 mg of the target compound trifluoroacetate with a yield of 60%. 1 H NMR(500MHz,Methanol-d4)δ8.83(d,J=1.3Hz,1H),8.24(d,J=8.4Hz,1H),7.65 –7.58(m,2H),7.58–7.49(m,2H),7.46(t,J=7.4Hz,1H),7.28–7.15(m,4H),5.12 (d,J=10.3Hz,1H),4.55(d,J=9.8Hz,1H),4.45(d,J=10.1Hz,1H),4.08(s,2H), 3.87(s,3H),1.78(dd,J=14.7,9.9Hz,1H),1.64(d,J=14.4Hz,1H),1.07(s,9H).

[0304] Step 2: Synthesis of 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentyl-4-(((pyridin-2-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YL134)

[0305] YL130 (20 mg, 0.034 mmol), 2-bromomethylpyridine hydrobromide (13 mg, 0.05 mmol), potassium carbonate (23 mg, 0.17 mmol) and lithium hydroxide monohydrate (8 mg, 0.17 mmol) were taken, and the steps were referred to the final product 14 to obtain 19.5 mg of the trifluoroacetate salt of the target compound with a yield of 74%. 1 H NMR(500MHz, Methanol-d4)δ8.65(dd,J=5.3,1.7Hz,1H),8.02(td,J=7.8,1.7Hz,1H),7.99–7.93(m,2H),7.72(d,J=7.8H z,1H),7.64–7.59(m,2H),7.57(d,J=7.9Hz,1H),7.53(dd,J=7.6,5.2Hz,1H),7.48–7.40(m,2H),7.37–7.31(m,2H),7.23( dd, J = 6.9, 2.6 Hz, 1H), 7.11 (dd, J = 13.0, 8.8 Hz, 1H), 4.86–4.82 (m, 2H), 4.78 (d, J = 9.7 Hz, 1H), 4.35 (d, J = 15.3 Hz, 1H), 4.28 (d, J = 15.3 Hz, 1H), 3.74–3.53 (m, 2H), 1.95 (dd, J = 14.6, 9.9 Hz, 1H), 1.82 (d, J = 14.5 Hz, 1H), 1.11 (s, 9H). ESI-MS theoretical calculated value C 36 H 38 35 Cl2FN4O3[M+H] + =663.23, experimentally measured: 663.0.

[0306] Final product 52: 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentyl-4-(((pyridin-3-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YL135)

[0307]

[0308] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentyl-4-(((pyridin-3-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YL135)

[0309] Take YL130 (20 mg, 0.034 mmol), 3-bromomethylpyridine hydrobromide (13 mg, 0.05 mmol), potassium carbonate (23 mg, 0.17 mmol) and lithium hydroxide monohydrate (8 mg, 0.17 mmol), and follow the steps of final product 14 to obtain 16 mg of trifluoroacetate of the target compound with a yield of 60%. 1 H NMR(500MHz, Methanol-d4)δ8.78–8.69(m,2H),8.44–8.38(m,1H),8.01–7.93(m,2H),7.89(dd,J=8.0,5.5H z,1H),7.83(d,J=7.9Hz,1H),7.64–7.58(m,2H),7.46(ddd,J=8.2,5.9,2.8Hz,1H),7.43–7.38(m,1H),7.36– 7.28 (m, 2H), 7.19–7.07 (m, 2H), 5.08 (d, J = 10.0 Hz, 1H), 5.03–4.93 (m, 2H), 4.08 (s, 2H), 3.37 (d, J = 13.4 Hz, 1H), 3.28 (d, J = 13.5 Hz, 1H), 1.99 (dd, J = 15.2, 9.6 Hz, 1H), 1.80 (d, J = 15.1 Hz, 1H), 1.06 (s, 9H). ESI-MS theoretical calculated value C 36 H 38 35 Cl2FN4O3[M+H] + =663.23, experimentally measured: 663.0.

[0310] Final product 53: 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YL136)

[0311]

[0312] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YL136)

[0313] Take YL130 (20 mg, 0.034 mmol), 4-bromomethylpyridine hydrobromide (13 mg, 0.05 mmol), potassium carbonate (23 mg, 0.17 mmol) and lithium hydroxide monohydrate (8 mg, 0.17 mmol), and follow the steps of final product 14 to obtain 14.6 mg of trifluoroacetate of the target compound with a yield of 55%. 1 H NMR(500MHz, Methanol-d4)δ8.77–8.70(m,2H),8.01–7.91(m,4H),7.88(d,J=7.9Hz,1H),7.65–7.58(m, 2H),7.45(dt,J=8.3,4.2Hz,1H),7.40(dt,J=8.7,3.2Hz,1H),7.32(d,J=4.2Hz,2H),7.18–7.05(m,2H), 5.18 (d, J = 10.1 Hz, 1H), 5.02 (d, J = 10.1 Hz, 1H), 5.00–4.95 (m, 1H), 4.10 (d, J = 3.4 Hz, 2H), 3.37 (d, J = 13.3 Hz, 1H), 3.20 (d, J = 13.3 Hz, 1H), 2.13–2.00 (m, 1H), 1.86 (d, J = 15.3 Hz, 1H), 1.05 (s, 9H). ESI-MS theoretical calculated value C 36 H 38 35 Cl2FN4O3[M+H] + =663.23, experimentally measured: 663.0.

[0314] Final product 54: 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-4-(((2-hydroxybenzoyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamide)benzoic acid (YL148)

[0315]

[0316] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-4-(((2-hydroxybenzoyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamide)benzoic acid (YL148)

[0317] YL130 (58 mg, 0.1 mmol), 2-hydroxybenzaldehyde (24 mg, 0.2 mmol), sodium acetate borohydride (64 mg, 0.3 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (10 mg, 0.24 mmol) were taken, and the steps were referred to the final product 16 to obtain 26 mg of the trifluoroacetate salt of the target compound with a yield of 33%. 1 H NMR (500MHz, Methanol-d4) δ7.95(d,J=8.7Hz,2H),7.58(d,J=8.7Hz,2H),7.53(d,J=7.8Hz ,1H),7.47–7.38(m,2H),7.34–7.23(m,4H),7.14–7.03(m,2H),6.95–6.85(m,2H),4.73(d, J=10.2Hz,1H),4.59–4.47(m,2H),4.34(d,J=13.0Hz,1H),4.25(d,J=13.0Hz,1H),3.93(dd,J=14.1,2.0Hz,1H),3.66(d,J=14.2Hz,1H),1.94–1.76(m,2H),1.20(s,9H).ESI-MS theoretical calculated value C 37 H 39 35 Cl2FN3O4[M+H] + =678.23, experimentally measured: 678.2.

[0318] Final product 55: 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-4-(((3-hydroxybenzoyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamide)benzoic acid (YL150)

[0319]

[0320] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-4-(((3-hydroxybenzoyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamide)benzoic acid (YL150)

[0321] YL130 (58 mg, 0.1 mmol), 3-hydroxybenzaldehyde (24 mg, 0.2 mmol), sodium acetate borohydride (64 mg, 0.3 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (10 mg, 0.24 mmol) were taken, and the steps were referred to the final product 16 to obtain 12.4 mg of the trifluoroacetate of the target compound with a yield of 16%. 1H NMR (500 MHz, Methanol-d4) δ7.95 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.47–7.38 (m, 3H), 7.35–7.23 (m, 3H), 7.13–6.99 (m, 2H), 6.96–6.82 (m, 3H), 4.67 (d, J = 10.2 Hz, 1H), 4.49 (s, 2H), 4.13 (d, J = 2.5 Hz, 2H), 3.80–3.69 (m, 1H), 3.58 (d, J = 14.2 Hz, 1H), 1.84–1.62 (m, 2H), 1.19 (s, 9H). ESI-MS calculated value C 37 H 39 35 Cl2FN3O4[M+H] + =678.23, experimentally measured: 677.5.

[0322] Final product 56: 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-4-(((4-hydroxybenzoyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamide)benzoic acid (YL143)

[0323]

[0324] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-4-(((4-hydroxybenzoyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamide)benzoic acid (YL143)

[0325] YL130 (58 mg, 0.1 mmol), 4-hydroxybenzaldehyde (24 mg, 0.2 mmol), sodium acetate borohydride (64 mg, 0.3 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (10 mg, 0.24 mmol) were taken, and the steps were referred to the final product 16 to obtain 14.4 mg of the trifluoroacetate salt of the target compound with a yield of 18%. 1H NMR (500MHz, Methanol-d4) δ7.97(d,J=8.5Hz,2H),7.59(d,J=8.5Hz,2H),7.48(dt,J=13.4,3.8Hz,3 H),7.43–7.32(m,2H),7.26(d,J=8.2Hz,2H),7.13(dd,J=12.7,8.8Hz,1H),7.06–6.57(m,3H),4.71(d , J = 10.5 Hz, 1H), 4.58 (d, J = 10.5 Hz, 1H), 4.24 (d, J = 13.2 Hz, 1H), 4.16 (d, J = 13.3 Hz, 1H), 3.98–3.79 (m, 1H), 3.62 (d, J = 14.4 Hz, 1H), 2.09–1.97 (m, 1H), 1.87 (d, J = 14.3 Hz, 1H), 1.24 (s, 9H). ESI-MS theoretical calculated value C 37 H 39 35 Cl2FN3O4[M+H] + =678.23, experimentally measured: 678.5.

[0326] Final product 57: 4-(((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentyl-4-(((((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YM003)

[0327]

[0328] Step 1: Synthesis of 4-(((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentyl-4-(((((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YM003)

[0329] Take YL130 (58 mg, 0.1 mmol), 4-formyltetrahydropyran (17 mg, 0.15 mmol), sodium acetate borohydride (64 mg, 0.3 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of the final product 16 to obtain 15.8 mg of the trifluoroacetate of the target compound with a yield of 20%. 1H NMR(500MHz, Methanol-d4)δ8.01–7.93(m,2H),7.75(d,J=7.9Hz,1H),7.67–7.56(m,2H),7.53–7.41(m,2H),7.39–7.30(m,3 H),7.11(dd,J=12.8,8.8Hz,1H),4.76(d,J=10.4Hz,1H),4.66(s,2H),3.95(ddd,J=11.6,4.8,1.9Hz,2H),3.88(dd,J=14.1,2 .2Hz,1H),3.63(d,J=14.1Hz,1H),3.42(tt,J=11.8,1.9Hz,2H),2.97(qd,J=12.8,6.8Hz,2H),2.01(ddd,J=15.3,8.1,4.3Hz,1H),1.88(d,J=14.1Hz,1H),1.77(dd,J=14.2,10.5Hz,1H),1.71–1.58(m,2H),1.43–1.27(m,2H),1.18(s,9H).ESI-MS theoretical calculated value C 36 H 43 35 Cl2FN3O4[M+H] + =670.26, experimentally measured: 670.5.

[0330] Final product 58: 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentyl-4-(((piperidin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YM006)

[0331]

[0332] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentyl-4-(((piperidin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YM006)

[0333] Take YL130 (58 mg, 0.1 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (32 mg, 0.15 mmol), sodium acetate borohydride (64 mg, 0.3 mmol), 0.1 mL acetic acid, 3 mL trifluoroacetic acid and lithium hydroxide monohydrate (8 mg, 0.2 mmol), and refer to the final product 33 for the reaction steps to obtain 20.4 mg of the trifluoroacetate of the target compound with a yield of 30%. 1H NMR (500MHz, Methanol-d4) δ7.97(d,J=8.7Hz,2H),7.85(d,J=7.9Hz,1H),7.62(d,J=8.7Hz,2H),7.51–7.45(m ,1H),7.45–7.39(m,1H),7.34(d,J=4.3Hz,2H),7.26(dd,J=7.1,2.6Hz,1H),7.12(dd,J=13.1,8.8Hz,1H),4.98 (d, J = 9.9 Hz, 1H), 4.88–4.85 (m, 2H), 3.56 (d, J = 13.9 Hz, 1H), 3.51–3.38 (m, 3H), 2.97 (td, J = 13.0, 2.9 Hz, 2H), 2.86 (d, J = 6.2 Hz, 2H), 2.11–1.88 (m, 4H), 1.84 (d, J = 14.6 Hz, 1H), 1.58–1.36 (m, 2H), 1.10 (s, 9H). ESI-MS theoretical calculated value C 36 H 44 35 Cl2FN4O3[M+H] + =669.28, experimentally measured: 669.0.

[0334] Final product 59: 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-4-((((1-methyl-1H-pyrazol-4-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamide)benzoic acid (YM004)

[0335]

[0336] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(5-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-4-((((1-methyl-1H-pyrazol-4-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamide)benzoic acid (YM004)

[0337] YL130 (58 mg, 0.1 mmol), 1-methyl-4-formylpyrazole (17 mg, 0.15 mmol), sodium acetate borohydride (64 mg, 0.3 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (10 mg, 0.24 mmol) were taken, and the steps were referred to the final product 16 to obtain 21.8 mg of the trifluoroacetate salt of the target compound with a yield of 28%. 1H NMR(500MHz,Methanol-d4)δ8.00–7.90(m,2H),7.72(s,1H),7.65–7.55(m,3H),7.54–7.49(m,2H),7.4 6(ddd,J=8.8,4.0,2.4Hz,1H),7.42–7.32(m,2H),7.09(dd,J=12.7,8.8Hz,1H),6.97(s,1H),4.81(d,J =11.0 Hz, 1H), 4.67 (d, J = 10.4 Hz, 1H), 4.57 (d, J = 10.4 Hz, 1H), 4.26–4.10 (m, 2H), 3.96–3.84 (m, 4H), 3.62 (d, J = 14.3 Hz, 1H), 1.89 (dd, J = 14.2, 11.2 Hz, 1H), 1.80 (d, J = 14.1 Hz, 1H), 1.21 (s, 9H). ESI-MS calculated value C 35 H 39 35 Cl2FN5O3[M+H] + =666.24, experimentally measured: 666.3.

[0338] Final product 60: 4-((2R,3S,4S,5S)-4-((((4-(1H-tetrazol-5-yl)benzyl)amino)methyl)-3-(2-chlorophenyl)-4-(2-fluoro-5-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamido)benzoic acid (YL151)

[0339]

[0340] Step 1: Synthesis of (Z)-2-(5-methoxy-2-fluorophenyl)-3-(2-chlorophenyl)acrylonitrile (YL036)

[0341] Weigh 5-methoxy-2-fluorobenzyl acetonitrile (825 mg, 5 mmol) and 2-chlorobenzaldehyde (705 mg, 5 mmol), add to a 250 mL round-bottom flask, dissolve with 100 mL of methanol, add 1.5 mL of 5N sodium methoxide solution, react at 50°C overnight, cool to room temperature, filter, wash the filter cake with water, dry, weigh 1.36 g, and the yield is 94%. 1 H NMR(500MHz,Chloroform-d)δ8.14–8.08(m,1H),7.96(s,1H),7.51–7.44(m,1H) ,7.44–7.36(m,2H),7.13–7.06(m,2H),6.91(dt,J=9.0,3.5Hz,1H),3.84(s,3H).

[0342] Step 2: Synthesis of (2R,3S,4R,5S)-3-(2-chlorophenyl)-4-(5-methoxy-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YL041)

[0343] Weigh YL036 (1.36 g, 4.7 mmol) and add it to a 100 mL reaction bottle. Dissolve it with 50 mL of dichloromethane. Add silver fluoride (0.6 g, 4.7 mmol) and triethylamine (1.05 mL, 7.56 mmol). Add tert-butyl 2-((3,3-dimethylbutylidene)amino)acetate (1 g, 4.7 mmol). React at room temperature overnight in the dark. Pour in saturated ammonium chloride solution, filter, and extract the filtrate three times with dichloromethane. Combine the filtrates, remove the solvent by distillation under reduced pressure, and purify on a normal phase silica gel column to obtain 0.53 g of the target compound with a yield of 22%. 1 H NMR(500MHz,Chloroform-d)δ7.81(dd,J=7.9,1.5Hz,1H),7.36(ddd,J=8.1,7.0,1.7Hz,1H),7 .24–7.15(m,2H),6.99(dd,J=12.0,8.9Hz,1H),6.90(dd,J=6.2,3.1Hz,1H),6.81(dt,J=8.9,3 .4Hz,1H),4.98(dd,J=6.7,0.9Hz,1H),4.15(d,J=8.8Hz,1H),4.07(d,J=6.7Hz,1H),3.70(s,3 H),1.65(ddd,J=14.4,9.0,1.3Hz,1H),1.41(s,9H),1.36(dd,J=14.4,1.1Hz,1H),0.91(s,9H).

[0344] Step 3: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-3-(2-chlorophenyl)-4-(5-methoxy-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YL058)

[0345] Weigh YL041 (2.86 g, 5.7 mmol) and add it to a 100 mL reaction bottle, dissolve it with a mixed solvent of ethanol and tetrahydrofuran, add 2 g of Raney nickel, raise the temperature to 55 ° C, add 5 mL of hydrazine hydrate dropwise, stir and react for 1 h, cool, filter, and distill under reduced pressure to remove the filtrate. Purify it on a normal phase silica gel column to obtain 537 mg of the target compound with a conversion rate of 19%. 1H NMR(500MHz,Chloroform-d)δ7.77(dd,J=7.9,1.6Hz,1H),7.29(dd,J=7.5,1.4Hz,1H),7. 23(dd,J=8.0,1.4Hz,1H),7.16–7.11(m,1H),6.88–6.78(m,1H),6.70(dd,J=7.6,4.1Hz,2 H),4.31(d,J=9.1Hz,1H),4.22(d,J=9.9Hz,1H),4.02(d,J=9.1Hz,1H),3.72(s,3H),3.37 (s,2H),1.66(d,J=13.8Hz,1H),1.53(dd,J=13.8,10.0Hz,1H),1.24(s,9H),1.03(s,9H).

[0346] Step 4: Synthesis of (2R,3S,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-3-(2-chlorophenyl)-4-(5-methoxy-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YL061)

[0347] Weigh YL058 (520 mg, 1.03 mmol) into a 50 mL round-bottom flask, dissolve it in 10 mL of dichloromethane, add FmocCl (398 mg, 1.54 mmol) and triethylamine (531 mg, 4.12 mmol), react at room temperature overnight, remove the solvent under reduced pressure, add 5 mL of dichloromethane and 4 mL of trifluoroacetic acid, react at room temperature overnight, spin dry the solvent, extract three times with dichloromethane, spin dry the organic phase, and purify with a normal phase column to obtain 607 mg of the product with a yield of 88%.

[0348] Step 5: Synthesis of methyl 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(2-chlorophenyl)-4-(5-methoxy-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YL066)

[0349] Weigh YL061 (607 mg, 0.9 mmol) and dissolve it in THF. Add DIEA (583 mg, 4.5 mmol) and react for 5 min. Add diphenylphosphinoyl chloride (640 mg, 2.7 mmol) and react for 30 min. Add methyl 4-aminobenzoate (546 mg, 3.6 mmol) and react overnight. Remove the solvent under reduced pressure. Add water. Extract with dichloromethane 3 times. The organic phase is spin-dried and purified with a normal phase silica gel column. After obtaining the crude product, add 2 mL of DMF solution containing 20% ​​piperidine. After reacting at room temperature for 30 min, extract with ethyl acetate. The organic phase is spin-dried and purified by HPLC to obtain 73 mg of the target compound trifluoroacetate with a yield of 12%.1 H NMR(500MHz,Methanol-d4)δ7.98–7.89(m,2H),7.70(d,J=7.9Hz,1H),7.63–7.58(m,2H ),7.49(td,J=7.9,7.3,2.1Hz,1H),7.40–7.30(m,2H),7.10–6.96(m,2H),6.78–6.67(m, 1H),5.04(d,J=11.2Hz,1H),4.90(d,J=11.3Hz,1H),4.70(d,J=11.0Hz,1H),3.93–3.78( m,5H),3.77(s,3H),2.01(dd,J=14.6,11.3Hz,1H),1.91(d,J=14.4Hz,1H),1.21(s,9H).

[0350] Step 6: Synthesis of 4-((2R,3S,4S,5S)-4-((((4-(1H-tetrazolyl-5-yl)benzyl)amino)methyl)-3-(2-chlorophenyl)-4-(2-fluoro-5-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamido)benzoic acid (YL151)

[0351] Take YL066 (32 mg, 0.055 mmol), 4-(1H-tetrazolyl-5-yl)benzaldehyde (29 mg, 0.16 mmol), sodium acetate borohydride (47 mg, 0.22 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (12 mg, 0.28 mmol), and follow the steps of the final product 16 to obtain 26.6 mg of the trifluoroacetate of the target compound with a yield of 58%. 1 H NMR(500MHz, Methanol-d4)δ8.14(d,J=8.0Hz,2H),7.99–7.89(m,2H),7.65(d,J=8.1Hz,2H),7.61–7.5 3(m,2H),7.48(d,J=7.8Hz,1H),7.37(ddd,J=8.1,5.4,3.2Hz,1H),7.32–7.22(m,2H),7.08–6.96(m,2H) ,6.46(s,1H),4.78(d,J=10.5Hz,1H),4.64(d,J=10.5Hz,1H),4.41–4.24(m,2H),3.90–3.77(m,1H),3.72(s,3H),3.60(d,J=14.2Hz,1H),2.12–1.96(m,1H),1.91(d,J=14.4Hz,1H),1.19(s,9H).ESI-MS theoretical calculated value C 39 H 4235 ClFN7O4[M+H] + =726.30, experimentally measured: 725.8.

[0352] Final product 61: 4-((2R,3S,4S,5S)-4-(benzamidomethyl)-3-(2-chlorophenyl)-4-(2-fluoro-5-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamido)benzoic acid (YL154)

[0353]

[0354] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(benzamidomethyl)-3-(2-chlorophenyl)-4-(2-fluoro-5-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamido)benzoic acid (YL154)

[0355] Take YL066 (20 mg, 0.034 mmol), benzoyl chloride (7 mg, 0.05 mmol), triethylamine (10 mg, 0.096 mmol) and lithium hydroxide monohydrate (7 mg, 0.16 mmol), and follow the steps of final product 2 to obtain 13.3 mg of trifluoroacetate of the target compound with a yield of 50%. 1 H NMR(500MHz, Methanol-d4)δ8.04–7.95(m,2H),7.83(d,J=7.9Hz,1H),7.67–7.59(m,2H ),7.55–7.44(m,4H),7.43–7.28(m,4H),7.07(dd,J=13.1,9.0Hz,1H),6.94(dt,J=9.0,3 .2Hz,1H),6.74(dd,J=6.7,3.0Hz,1H),5.13(dd,J=8.9,2.2Hz,1H),4.26(d,J=15.0Hz,1H),3.95(d,J=15.0Hz,1H),3.65(s,3H),1.95–1.73(m,2H),1.02(s,9H).ESI-MS theoretical calculated value C 38 H 40 35 ClFN3O5[M+H] + =672.26, experimentally measured: 672.4.

[0356] Final product 62: 4-((2R,3S,4S,5S)-4-((benzylamino)methyl)-3-(2-chlorophenyl)-4-(2-fluoro-5-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide)benzoic acid (YL155)

[0357]

[0358] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-((benzylamino)methyl)-3-(2-chlorophenyl)-4-(2-fluoro-5-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide)benzoic acid (YL155)

[0359] Take YL066 (20 mg, 0.034 mmol), benzyl bromide (9 mg, 0.05 mmol), potassium carbonate (23 mg, 0.17 mmol) and lithium hydroxide monohydrate (8 mg, 0.17 mmol), and follow the steps of final product 14 to obtain 13.9 mg of trifluoroacetate of the target compound with a yield of 53%. 1 H NMR (500 MHz, Methanol-d4) δ7.95 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.54–7.41 (m, 5H), 7.41–7.25 (m, 4H), 7.04–6.93 (m, 2H), 6.56 (s, 1H), 4.74 (d, J = 10.2 Hz, 1H), 4.61–4.48 (m, 2H), 4.23 (s, 2H), 3.78–3.68 (m, 4H), 3.58 (d, J = 14.0 Hz, 1H), 1.94–1.72 (m, 2H), 1.19 (s, 9H). ESI-MS calculated value C 38 H 42 35 ClFN3O4[M+H] + =658.28, experimentally measured: 657.9.

[0360] Final product 63: 4-((2R,3S,4S,5S)-3-(2-chlorophenyl)-4-(2-fluoro-5-methoxyphenyl)-5-neopentyl-4-(((pyridin-2-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YL156)

[0361]

[0362] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(2-chlorophenyl)-4-(2-fluoro-5-methoxyphenyl)-5-neopentyl-4-(((pyridin-2-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YL156)

[0363] Take YL066 (20 mg, 0.034 mmol), 2-bromomethylpyridine hydrochloride (13 mg, 0.05 mmol), potassium carbonate (23 mg, 0.17 mmol) and lithium hydroxide monohydrate (7 mg, 0.17 mmol), and follow the steps of final product 14 to obtain 19.5 mg of trifluoroacetate of the target compound with a yield of 75%. 1 H NMR (500MHz, Methanol-d4) δ8.63(d,J=4.9Hz,1H),8.04(td,J=7.8,1.7Hz,1H),7.95(d,J=8.5Hz ,2H),7.69(d,J=7.9Hz,1H),7.64–7.52(m,4H),7.44(ddd,J=8.2,5.6,3.2Hz,1H),7.37–7.29(m,2 H), 7.07–6.92 (m, 2H), 6.66 (dd, J = 6.6, 2.9 Hz, 1H), 4.87–4.78 (m, 3H), 4.39–4.24 (m, 2H), 3.73 (d, J = 12.0 Hz, 5H), 2.05 (dd, J = 14.7, 10.4 Hz, 1H), 1.93 (d, J = 14.5 Hz, 1H), 1.14 (s, 9H). ESI-MS theoretical calculated value C 37 H 41 35 ClFN4O4[M+H] + =659.28, experimentally measured: 658.5.

[0364] Final product 64: 4-((2R,3S,4S,5S)-3-(2-chlorophenyl)-4-(2-fluoro-5-methoxyphenyl)-5-neopentyl-4-(((pyridin-3-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YL157)

[0365]

[0366] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(2-chlorophenyl)-4-(2-fluoro-5-methoxyphenyl)-5-neopentyl-4-(((pyridin-3-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YL157)

[0367] Take YL066 (20 mg, 0.034 mmol), 3-bromomethylpyridine hydrochloride (13 mg, 0.05 mmol), potassium carbonate (23 mg, 0.17 mmol) and lithium hydroxide monohydrate (7 mg, 0.17 mmol), and follow the steps of final product 14 to obtain 12.1 mg of trifluoroacetate of the target compound with a yield of 46%. 1H NMR (500MHz, Methanol-d4) δ8.74(d,J=2.0Hz,1H),8.71(dd,J=5.4,1.4Hz,1H),8.35(d,J=8.0Hz,1H),8.00–7.92(m,2H),7.84(dd, J=8.0,5.4Hz,1H),7.78(d,J=7.9Hz,1H),7.64–7.54(m,2H),7.44(ddd,J=8.2,6.3,2.4Hz,1H),7.35–7.24(m,2H),7.01(dd,J=13.1 ,9.0Hz,1H),6.93(dt,J=8.9,3.2Hz,1H),6.60(dd,J=6.8,3.0Hz,1H),5.02(d,J=10.0Hz,1H),4.97–4.92(m,2H),4.10(s,2H),3.72(s,3H),3.39(d,J=13.4Hz,1H),3.30–3.26(m,1H),1.96(dd,J=15.1,9.8Hz,1H),1.81(d,J=14.9Hz,1H),1.07(s,9H).ESI-MS theoretical calculated value C 37 H 41 35 ClFN4O4[M+H] + =659.28, experimentally measured: 658.6.

[0368] Final product 65: 4-((2R,3S,4S,5S)-3-(2-chlorophenyl)-4-(2-fluoro-5-methoxyphenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YL158)

[0369]

[0370] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(2-chlorophenyl)-4-(2-fluoro-5-methoxyphenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)benzoic acid (YL158)

[0371] Take YL066 (20 mg, 0.034 mmol), 4-bromomethylpyridine hydrochloride (13 mg, 0.05 mmol), potassium carbonate (23 mg, 0.17 mmol) and lithium hydroxide monohydrate (7 mg, 0.17 mmol), and follow the steps of final product 14 to obtain 18.6 mg of trifluoroacetate of the target compound with a yield of 72%. 1H NMR (500MHz, Methanol-d4) δ8.80–8.71(m,2H),8.00(d,J=6.1Hz,2H),7.98–7.92(m,2H),7.88(d,J=7.9Hz,1H),7.64–7.57(m ,2H),7.43(ddd,J=8.3,6.0,2.6Hz,1H),7.35–7.25(m,2H),7.03(dd,J=13.3,9.0Hz,1H),6.92(dt,J=9.0,3.2Hz,1H),6.57(dd , J=6.8,3.0Hz,1H),5.23(d,J=10.2Hz,1H),5.09–4.99(m,2H),4.16(d,J=16.1Hz,1H),4.09(d,J=16.1Hz,1H),3.70(s,3H),3.39(d,J=13.2Hz,1H),3.18(d,J=13.2Hz,1H),2.11(dd,J=15.5,9.6Hz,1H),1.89(d,J=15.3Hz,1H),1.04(s,9H).ESI-MS theoretical calculated value C 37 H 41 35 ClFN4O4[M+H] + =659.28, experimentally measured: 658.5.

[0372] Final product 66: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((1-methyl-1H-indol-3-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM048)

[0373]

[0374] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((1-methyl-1H-indol-3-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM048)

[0375] Take YL090 (20 mg, 0.03 mmol), 1-methylindole-3-carbaldehyde (8 mg, 0.047 mmol), sodium acetate borohydride (20 mg, 0.09 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (6 mg, 0.15 mmol), and follow the steps of the final product 16 to obtain 7.9 mg of the trifluoroacetate salt of the target compound with a yield of 30%. 1H NMR (500MHz, Methanol-d4) δ8.25(d,J=8.5Hz,1H),7.66(d,J=8.0Hz,1H),7.62(d,J=1.8Hz,1H),7.59(dd,J=8.5,1. 8Hz,1H),7.52(d,J=8.3Hz,1H),7.40–7.30(m,3H),7.25(t,J=7.5Hz,1H),7.07(dd,J=12.8,2.2Hz,1H),6.99–6.88( m, 3H), 6.78 (s, 1H), 4.48 (d, J = 13.9 Hz, 1H), 4.40 (d, J = 13.9 Hz, 1H), 4.27 (t, J = 11.9 Hz, 2H), 3.96 (s, 3H), 3.85 (s, 3H), 3.81–3.67 (m, 2H), 3.55–3.44 (m, 1H), 1.69 (d, J = 13.4 Hz, 1H), 1.35 (t, J = 12.6 Hz, 1H), 1.18 (s, 9H). ESI-MS theoretical calculated value C 41 H 43 35 Cl2F2N4O4[M+H] + =763.26, experimentally measured: 762.9.

[0376] Final product 67: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-(((quinolin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM050)

[0377]

[0378] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-(((quinolin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM050)

[0379] Take YL090 (20 mg, 0.03 mmol), quinoline-4-carboxaldehyde (7.4 mg, 0.047 mmol), sodium acetate borohydride (20 mg, 0.09 mmol), acetic acid 0.1 mL and lithium hydroxide monohydrate (6 mg, 0.15 mmol), and follow the steps of the final product 16 to obtain 10 mg of the trifluoroacetate salt of the target compound with a yield of 38%. 1H NMR(500MHz,Methanol-d4)δ9.07(d,J=5.4Hz,1H),8.49(d,J=8.5Hz,1H),8.23(t,J=8.5Hz,2H), 8.16–8.10(m,1H),8.04–7.91(m,2H),7.66–7.49(m,3H),7.41(q,J=7.9,7.4Hz,1H),7.25–7.15( m, 3H), 7.10 (t, J = 8.0 Hz, 1H), 5.23 (s, 1H), 4.65–4.48 (m, 4H), 3.84 (s, 3H), 3.40–3.34 (m, 1H), 3.28 (d, J = 13.8 Hz, 1H), 1.83 (t, J = 12.5 Hz, 1H), 1.70 (d, J = 14.8 Hz, 1H), 1.00 (s, 9H). ESI-MS theoretical calculated value C 41 H 41 35 Cl2F2N4O4[M+H] + =761.25, experimentally measured: 761.2.

[0380] Final product 95: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-(nicotinamidomethyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM061)

[0381]

[0382] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentyl-4-(nicotinamidomethyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM061)

[0383] Take YL090 (20 mg, 0.03 mmol), nicotinoyl chloride (8 mg, 0.047 mmol), triethylamine (12 mg, 0.12 mmol) and lithium hydroxide monohydrate (6 mg, 0.15 mmol), and follow the steps of final product 2 to obtain 20 mg of trifluoroacetate of the target compound with a yield of 79%. 1H NMR(500MHz, Methanol-d4)δ8.72(dd,J=5.2,1.6Hz,1H),8.68(d,J=2.1Hz,1H),8.26(d,J=8.4Hz,1H), 8.10(dt,J=8.0,1.9Hz,1H),7.68–7.59(m,3H),7.55(t,J=7.2Hz,1H),7.45–7.40(m,1H),7.37(t,J=8.6 Hz, 1H), 7.31–7.23 (m, 2H), 7.21 (t, J = 8.0 Hz, 1H), 4.99 (s, 1H), 4.52 (d, J = 9.9 Hz, 1H), 4.43 (s, 1H), 4.24 (d, J = 15.1 Hz, 1H), 3.94 (d, J = 15.1 Hz, 1H), 3.87 (s, 3H), 1.80–1.59 (m, 2H), 1.04 (s, 9H). ESI-MS theoretical calculated value C 37 H 37 35 Cl2F2N4O5[M+H] + =725.21, experimentally measured: 725.3.

[0384] Final product 96: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-(isonicotinamidomethyl)-5-neopentylpyrrolidine-2-carboxamide)-3-methoxybenzoic acid (YM062)

[0385]

[0386] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-(isonicotinamidomethyl)-5-neopentylpyrrolidine-2-carboxamide)-3-methoxybenzoic acid (YM062)

[0387] Take YL090 (20 mg, 0.03 mmol), isonicotinoyl chloride (8 mg, 0.047 mmol), triethylamine (12 mg, 0.12 mmol) and lithium hydroxide monohydrate (6 mg, 0.15 mmol), and follow the steps of final product 2 to obtain 17.3 mg of trifluoroacetate of the target compound with a yield of 69%. 1H NMR (500 MHz, Methanol-d4) δ 8.79–8.67 (m, 2H), 8.28 (d, J = 8.3 Hz, 1H), 7.63 (ddd, J = 10.8, 5.4, 1.7 Hz, 4H), 7.53 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.29–7.15 (m, 3H), 4.46 (d, J = 9.7 Hz, 1H), 4.37 (d, J = 8.5 Hz, 1H), 4.25 (d, J = 15.1 Hz, 1H), 3.97–3.83 (m, 4H), 1.79–1.58 (m, 2H), 1.06 (s, 9H). ESI-MS calculated value C 37 H 37 35 Cl2F2N4O5[M+H] + =725.21, experimentally measured: 725.1.

[0388] Final product 100: 4-((2R,3R,4S,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-((ethyl(pyridin-4-ylmethyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid

[0389]

[0390] Step 1: Synthesis of (Z)-3-(3-chlorophenyl)-2-(4-chlorophenyl)acrylonitrile (YM068)

[0391] Weigh 4-chlorobenzyl acetonitrile (3.02 g, 20 mmol) and 3-chlorobenzaldehyde (2.8 g, 20 mmol), add into a 250 mL round-bottom flask, dissolve with 100 mL methanol, add 6 mL of 5N sodium methoxide solution, react at 50 ° C overnight, cool to room temperature, filter, wash the filter cake with water, dry, weigh 4.5 g, and the yield is 82%. 1 H NMR (500MHz, Chloroform-d) δ7.85–7.75(m,2H),7.63–7.56(m,2H),7.48–7.35(m,5H).

[0392] Step 2: Synthesis of (2R,3S,4R,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YM070)

[0393] Weigh YM068 (4.48 g, 16 mmol) and add it to a 100 mL reaction bottle, dissolve it with 50 mL of dichloromethane, add silver fluoride (2 g, 16 mmol) and triethylamine (3.6 mL, 26 mmol), and then add tert-butyl 2-((3,3-dimethylbutylidene)amino)acetate (4.13 g, 16 mmol). React at room temperature overnight in the dark, pour into saturated ammonium chloride solution, filter, and extract the filtrate three times with dichloromethane. The filtrates are combined and the solvent is removed by distillation under reduced pressure. Purification on a normal phase silica gel column gives 4.56 g of the target compound with a yield of 59%. 1 HNMR(500MHz,Chloroform-d)δ7.38–7.33(m,2H),7.30–7.26(m,2H),7.24(ddd,J =8.0,2.0,1.1Hz,1H),7.19(t,J=7.8Hz,1H),7.10(t,J=1.9Hz,1H),7.02(dt,J=7. 7,1.5Hz,1H),4.26(d,J=8.4Hz,1H),3.75(dd,J=9.4,1.2Hz,1H),3.69(d,J=8.4H z,1H),1.58(dd,J=14.3,9.4Hz,1H),1.36(s,9H),1.35–1.31(m,1H),0.89(s,9H).

[0394] Step 3: Synthesis of (2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YM073)

[0395] Weigh YM070 (4.56 g, 9.4 mmol) and add it to a 100 mL reaction bottle, dissolve it with a mixed solvent of ethanol and tetrahydrofuran, add 3 g of Raney nickel, raise the temperature to 55 ° C, add 5 mL of hydrazine hydrate dropwise, stir and react for 1 h, cool, filter, and distill under reduced pressure to remove the filtrate. Purify it on a normal phase silica gel column to obtain 1.03 g of the target compound with a conversion rate of 22%. 1 H NMR(500MHz,Chloroform-d)δ7.29–7.22(m,3H),7.19(ddd,J=8.0,2.1,1.1Hz,1H),7.14(t,J=7.8Hz,1H),7.09–7.02(m,2H),6.93(d,J=7.7 Hz,1H),4.30(d,J=9.5Hz,1H),3.97(dd,J=8.7,2.0Hz,1H),3.36(d,J=9.5Hz,1H),3.15(s,2H),1.55–1.43(m,2H),1.27(s,9H),0.95(s,9H).

[0396] Step 4: Synthesis of (2R,3S,4S,5S)-4-((((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid (YM075)

[0397] Weigh YM073 (1030 mg, 2.1 mmol) into a 50 mL round-bottom flask, dissolve it in 10 mL of dichloromethane, add FmocCl (812 mg, 3.15 mmol) and triethylamine (1.08 g, 8.4 mmol), react at room temperature overnight, remove the solvent under reduced pressure, add 5 mL of dichloromethane and 4 mL of trifluoroacetic acid, react at room temperature overnight, spin dry the solvent, extract three times with dichloromethane, spin dry the organic phase, and purify with a normal phase column to obtain 1.3 g of the product with a yield of 93%.

[0398] Step 5: Synthesis of methyl 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YM078)

[0399] Weigh YM075 (264 mg, 0.4 mol) and dissolve it in DCM. Add DIEA (258 mg, 2 mmol) and react for 5 min. Add diphenylphosphinoyl chloride (284 mg, 1.2 mmol) and react for 30 min. Add methyl 4-amino-3-methoxybenzoate (290 mg, 1.6 mmol) and react overnight. Remove the solvent under reduced pressure, add water, extract with dichloromethane 3 times, and purify the organic phase with a normal phase silica gel column after drying. Add 2 mL of DMF solution containing 20% ​​piperidine to obtain the crude product. After reacting at room temperature for 30 min, extract with ethyl acetate, dry the organic phase, and purify with a normal phase column to obtain 20 mg of the target compound with a yield of 7%.

[0400] Step 6: Synthesis of methyl 4-((2R,3R,4S,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-((ethylamino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YM080)

[0401] YM078 (20 mg, 0.033 mmol) was dissolved in 1,2-dichloroethane (5 mL), and acetaldehyde (15 mg, 0.3 mmol), sodium acetate borohydride (64 mg, 0.3 mmol) and acetic acid (0.1 mL) were added. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the mixture was evaporated under reduced pressure and purified by normal phase column to obtain 11 mg of the target compound, 52%. 1H NMR (500MHz, Methanol-d4) δ8.28 (dd, J=8.4, 3.3Hz, 1H), 7.59 (ddd, J=14.6, 7.1, 1. 8Hz,2H),7.52–7.33(m,3H),7.14–6.95(m,3H),4.83(d,J=10.6Hz,1H),4.41(d,J=2 9.2Hz,1H),3.97(d,J=5.6Hz,1H),3.94–3.80(m,6H),3.62(d,J=10.6Hz,1H),3.25( d,J=14.5Hz,1H),3.14(q,J=7.1Hz,2H),1.78(d,J=5.6Hz,2H),1.30–1.13(m,12H).

[0402] Step 7: Synthesis of 4-((2R,3R,4S,5S)-3-(3-chlorophenyl)-4-(4-chlorophenyl)-4-((ethyl(pyridin-4-ylmethyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM081)

[0403] YM080 (8.2 mg, 0.013 mmol), 4-bromomethylpyridine hydrochloride (7 mg, 0.026 mmol), potassium carbonate (7 mg, 0.052 mmol) and lithium hydroxide monohydrate (3 mg, 0.065 mmol) were taken, and the steps were similar to those of the final product 14 to obtain 1.6 mg of the trifluoroacetate of the target compound with a yield of 18%. ESI-MS theoretical calculated value C 39 H 45 35 Cl2N4O4[M+H] + =703.28, experimentally measured: 703.4.

[0404] Final product 112: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(5-chloro-2-fluorophenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM091)

[0405]

[0406] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(5-chloro-2-fluorophenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM091)

[0407] Take YM89 (synthesis see YL090, 25 mg, 0.039 mmol), 4-bromomethylpyridine hydrochloride (15 mg, 0.059 mmol), potassium carbonate (23 mg, 0.17 mmol) and lithium hydroxide monohydrate (8 mg, 0.19 mmol), and follow the steps of final product 14 to obtain 12.6 mg of trifluoroacetate of the target compound with a yield of 39%. 1 H NMR (500 MHz, Methanol-d4) δ 8.81–8.66 (m, 2H), 8.26 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 5.8 Hz, 2H), 7.67–7.56 (m, 2H), 7.53–7.33 (m, 3H), 7.29–7.15 (m, 2H), 7.10 (dd, J = 13.0, 8.7 Hz, 1H), 5.03–4.95 (m, 1H), 4.53–4.30 (m, 2H), 4.09 (s, 2H), 3.89 (s, 3H), 3.28–3.18 (m, 2H), 1.88–1.67 (m, 2H), 1.11 (s, 9H). ESI-MS calculated value C 37 H 39 35 Cl2F2N4O4[M+H] + =711.2, experimentally measured: 711.1.

[0408] Final product 113: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((2-methoxypyridin-4-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM092)

[0409]

[0410] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((2-methoxypyridin-4-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM092)

[0411] YL090 (30 mg, 0.047 mmol), 2-methoxypyridine-4-carboxaldehyde (10 mg, 0.07 mmol), sodium cyanoborohydride (9 mg, 0.14 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (6 mg, 0.15 mmol) were taken, and the steps were referred to the final product 16 to obtain 18.6 mg of the trifluoroacetate salt of the target compound with a yield of 47%. 1H NMR (400MHz, Methanol-d4) δ8.24 (dd, J=12.2, 6.8Hz, 2H), 7.60 (d, J=10.0Hz, 2H), 7.45 (q, J=5. 8Hz,1H),7.28(d,J=8.7Hz,1H),7.18(t,J=8.5Hz,4H),7.00(d,J=5.4Hz,1H),6.89(s,1H),4.57( d, J = 10.0 Hz, 1H), 4.36 (d, J = 10.7 Hz, 1H), 4.14 (s, 2H), 4.02–3.83 (m, 7H), 3.61 (d, J = 14.0 Hz, 1H), 3.39–3.34 (m, 1H), 1.72 (d, J = 13.7 Hz, 1H), 1.63 (d, J = 11.7 Hz, 1H), 1.21 (s, 9H). ESI-MS theoretical calculated value C 38 H 41 35 Cl2F2N4O5[M+H] + =741.24, experimentally measured: 741.3.

[0412] Final product 114: 4-((2R,3S,4S,5S)-4-(((((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM094)

[0413]

[0414] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(((((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)methyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM094)

[0415] Take YL090 (30 mg, 0.047 mmol), 1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (8 mg, 0.06 mmol), sodium cyanoborohydride (9 mg, 0.14 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (6 mg, 0.15 mmol), and follow the steps of the final product 16 to obtain 12.5 mg of the trifluoroacetate salt of the target compound with a yield of 30%. 1H NMR (400MHz, Methanol-d4) δ8.31(d,J=5.3Hz,1H),8.23(d,J=8.5Hz,1H),7.66(d,J=3.5H z,1H),7.60(d,J=7.7Hz,2H),7.37(t,J=7.5Hz,1H),7.31(d,J=5.4Hz,1H),7.23–6.93(m,5 H), 6.80 (d, J = 3.6 Hz, 1H), 4.68 (d, J = 10.1 Hz, 1H), 4.56–4.30 (m, 3H), 4.10 (d, J = 10.0 Hz, 1H), 3.91 (s, 3H), 3.55 (d, J = 13.8 Hz, 1H), 1.65 (d, J = 10.0 Hz, 2H), 1.14 (s, 9H). ESI-MS theoretical calculated value C 39 H 40 35 Cl2F2N5O4[M+H] + =750.24, experimentally measured: 750.1.

[0416] Final product 115: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((3-fluoropyridin-4-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM099)

[0417]

[0418] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((3-fluoropyridin-4-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM099)

[0419] YL090 (30 mg, 0.047 mmol), 3-fluoropyridine-4-carboxaldehyde (19 mg, 0.14 mmol), sodium cyanoborohydride (18 mg, 0.28 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (10 mg, 0.24 mmol) were taken, and the steps were referred to the final product 16 to obtain 15.3 mg of the trifluoroacetate of the target compound with a yield of 38.5%. 1H NMR (500MHz, Methanol-d4) δ8.57(d,J=1.7Hz,1H),8.46(d,J=5.0Hz,1H),8.23(d,J=8.3Hz,1H),7. 65–7.54(m,3H),7.47(td,J=8.3,4.1Hz,2H),7.33–7.12(m,4H),5.02(d,J=10.1Hz,1H),4.57(d,J=9 .8Hz,1H),4.37(d,J=10.1Hz,1H),4.17(d,J=2.6Hz,2H),3.87(s,3H),3.42(d,J=13.8Hz,1H),3.35(d,J=13.7Hz,1H),1.80(dd,J=14.5,9.9Hz,1H),1.69(d,J=14.4Hz,1H),1.10(s,9H).ESI-MS theoretical calculated value C 37 H 38 35 Cl2F3N4O4[M+H] + =729.22, experimentally measured: 729.4.

[0420] Final product 116: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((3-hydroxypyridin-4-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM100)

[0421]

[0422] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((3-hydroxypyridin-4-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM100)

[0423] Take YL090 (30 mg, 0.047 mmol), 3-hydroxypyridine-4-carboxaldehyde (12 mg, 0.094 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of the final product 16 to obtain 21.7 mg of the trifluoroacetate of the target compound with a yield of 55%. 1H NMR (500MHz, Methanol-d4) δ8.32–8.24(m,2H),8.22(d,J=8.4Hz,1H),7.85(d,J=5.6Hz,1 H),7.69–7.52(m,3H),7.47(t,J=7.5Hz,1H),7.25(td,J=14.1,13.1,7.7Hz,4H),5.19(d,J =10.4 Hz, 1H), 4.64 (d, J = 9.8 Hz, 1H), 4.51 (d, J = 10.3 Hz, 1H), 4.19 (s, 2H), 3.85 (s, 3H), 3.40 (s, 2H), 1.94 (dd, J = 14.7, 9.9 Hz, 1H), 1.72 (d, J = 14.6 Hz, 1H), 1.08 (s, 9H). ESI-MS theoretical calculated value C 37 H 39 35 Cl2F2N4O5[M+H] + =727.23, experimentally measured: 727.2.

[0424] Final product 117: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((2-hydroxypyridin-4-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM105)

[0425]

[0426] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((2-hydroxypyridin-4-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM105)

[0427] Take YL090 (30 mg, 0.047 mmol), 2-hydroxypyridine-4-carboxaldehyde (12 mg, 0.094 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of the final product 16 to obtain 19.3 mg of the trifluoroacetate salt of the target compound with a yield of 49%. 1H NMR(500MHz,Methanol-d4)δ8.24(d,J=8.8Hz,1H),7.67–7.58(m,2H),7.51(d,J=6.7Hz,1H), 7.49–7.43(m,1H),7.42–7.13(m,5H),6.58(d,J=1.7Hz,1H),6.43(dd,J=6.7,1.8Hz,1H),4.7 5 (d, J = 10.2 Hz, 1H), 4.46 (d, J = 9.8 Hz, 1H), 4.14 (d, J = 10.1 Hz, 1H), 4.00 (s, 2H), 3.91 (s, 3H), 3.54 (d, J = 13.8 Hz, 1H), 3.37 (d, J = 14.0 Hz, 1H), 1.81–1.62 (m, 2H), 1.18 (s, 9H). ESI-MS theoretical calculated value C 37 H 39 35 Cl2F2N4O5[M+H] + =727.23, experimentally measured: 727.4.

[0428] Final product 118: 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((2-hydroxypyridin-5-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM106)

[0429]

[0430] Step 1: Synthesis of 4-((2R,3S,4S,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-((((2-hydroxypyridin-5-yl)methyl)amino)methyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM106)

[0431] Take YL090 (30 mg, 0.047 mmol), 2-hydroxypyridine-5-carboxaldehyde (12 mg, 0.094 mmol), sodium cyanoborohydride (12 mg, 0.19 mmol), 0.1 mL of acetic acid and lithium hydroxide monohydrate (10 mg, 0.24 mmol), and follow the steps of the final product 16 to obtain 14 mg of the trifluoroacetate salt of the target compound with a yield of 35%. 1H NMR(500MHz,Methanol-d4)δ8.28(d,J=8.5Hz,1H),7.67–7.51(m,4H),7.46(td,J=7.2,2.1Hz,1H) ,7.37–7.26(m,2H),7.23–7.14(m,3H),6.57(d,J=9.3Hz,1H),4.47(d,J=10.1Hz,1H),4.32(d,J=11 .2Hz,1H),4.07(s,2H),3.97(s,3H),3.85(d,J=10.1Hz,1H),3.74(dd,J=14.0,2.9Hz,1H),3.38(d,J=14.2Hz,1H),1.72(d,J=13.4Hz,1H),1.59(dd,J=13.6,11.4Hz,1H),1.25(s,9H).ESI-MS theoretical calculated value C 37 H 39 35 Cl2F2N4O5[M+H] + =727.23, experimentally measured: 727.4.

[0432] Final product 119: 4-((2R,3S,4S,5S)-4-(4-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM117)

[0433]

[0434] Step 1: Synthesis of (Z)-2-(4-chloro-2-fluorophenyl)-3-(2-chlorophenyl)acrylonitrile (YI091)

[0435] 2-Chlorobenzaldehyde (2.82 g, 20 mmol), 4-chloro-2-fluorobenzeneacetonitrile (3.4 g, 20 mmol), 4.8 mL of 5N sodium methoxide methanol solution, the reaction steps refer to step 1 of the final product 1, and 5.46 g of the target product is obtained with a yield of 93%. 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).

[0436] 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)

[0437] YI091 (5.46 g, 18.6 mmol), AgF (2.36 g, 18.6 mmol), triethylamine 4 mL and (E)-2-(((3,3-dimethylbutylene)amino)acetic acid tert-butyl ester (3.97 g, 18.6 mmol), the reaction steps refer to step 2 of the final product 1, and the target product 4 g is obtained with a yield of 43%. 1 H NMR(500MHz,Chloroform-d)δ7.80(dd,J=8.1,1.4Hz,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,1 H),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).

[0438] Step 3: Synthesis of (2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YI097-2)

[0439] YI097-1 (4 g, 7.91 mmol), nickel powder 4 g, hydrazine hydrate 10 mL, reaction steps refer to step 3 of final product 1, to obtain 1 g of the target product, with a yield of 24%. 1 H NMR(500MHz,Chloroform-d)δ7.80(dd,J=7.9,1.6Hz,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).

[0440] 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)

[0441] YI097-2 (980 mg, 1.93 mmol), FmocCl (745 mg, 2.89 mmol), DIEA (996 mg, 7.72 mmol) and 4 mL of trifluoroacetic acid. The reaction steps refer to step 4 of the final product 1 to obtain 1.12 g of the target product with a yield of 86%.

[0442] 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)

[0443] YI100 (270 mg, 0.4 mmol), methyl 4-amino-3-methoxybenzoate (290 mg, 1.6 mmol), diphenylphosphinoyl chloride (283 mg, 1.2 mmol), DIEA (259 mg, 2 mmol) and piperidine 0.4 mL. The reaction steps refer to step 5 of the final product 1 to obtain 67 mg of the target product with a yield of 27%. 1 H NMR(500MHz, Methanol-d4)δ8.25(d,J=8.9Hz,1H),7.66–7.53(m,3H),7.48–7.41(m ,1H),7.38–7.27(m,4H),7.15(dd,J=13.0,1.9Hz,1H),4.55(dd,J=20.7,10.8Hz,2H) ,4.33(d,J=10.5Hz,1H),3.91(s,3H),3.87(s,3H),3.79(dd,J=14.3,3.3Hz,1H),3. 66(d,J=14.3Hz,1H),1.80–1.72(m,1H),1.64(dd,J=13.9,11.4Hz,1H),1.25(s,9H).

[0444] Step 6: Synthesis of 4-((2R,3S,4S,5S)-4-(4-chloro-2-fluorophenyl)-3-(2-chlorophenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM117)

[0445] Take YI105 (27 mg, 0.044 mmol), 4-(bromomethyl)pyridine hydrobromide (17 mg, 0.066 mmol), potassium carbonate (24 mg, 0.18 mmol) and lithium hydroxide monohydrate (9 mg, 0.22 mmol), and follow the steps of final product 14 to obtain 12.3 mg of trifluoroacetate of the target compound with a yield of 34.6%. 1 H NMR (500MHz, Methanol-d4) δ8.80–8.68(m,2H),8.23(d,J=8.5Hz,1H),7.90(d,J=6.0Hz,2H),7.79(d,J =7.9Hz,1H),7.62(dd,J=8.4,1.8Hz,1H),7.57(d,J=1.8Hz,1H),7.44(ddd,J=8.2,5.9,2.7Hz,1H),7.3 8–7.29 (m, 2H), 7.23–7.10 (m, 3H), 5.10 (d, J = 10.5 Hz, 1H), 4.78–4.62 (m, 2H), 4.14 (s, 2H), 3.79 (s, 3H), 3.43–3.34 (m, 2H), 1.96 (dd, J = 14.9, 10.2 Hz, 1H), 1.83 (d, J = 14.7 Hz, 1H), 1.11 (s, 9H). ESI-MS theoretical calculated value C 37 H 39 35 Cl2FN4O4[M+H] + =693.2, experimentally measured: 693.4.

[0446] Final product 120: 4-((2R,3S,4S,5S)-4-(4-chloro-2-fluorophenyl)-3-(4-chlorophenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM123)

[0447]

[0448] Step 1: Synthesis of (Z)-2-(4-chloro-2-fluorophenyl)-3-(4-chlorophenyl)acrylonitrile (YI037)

[0449] p-Chlorobenzaldehyde (1.4 g, 10 mmol), 4-chloro-2-fluorobenzeneacetonitrile (1.7 g, 10 mmol), 3 mL of 5N sodium methoxide methanol solution, the reaction steps refer to step 1 of the final product 1, and 2.78 g of the target product is obtained with a yield of 95%. 1H 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).

[0450] 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)

[0451] 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 (1.94 g, 9.1 mmol), the reaction steps refer to step 2 of the final product 1, and the target product 1.57 g is obtained with a yield of 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).

[0452] Step 3: Synthesis of (2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(4-chlorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YI051)

[0453] YI040 (1.57 g, 3.1 mmol), nickel powder 1.57 g, hydrazine hydrate 10 mL, reaction steps refer to step 3 of final product 1, and the target product 584 mg is obtained with a yield of 37%.

[0454] 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)

[0455] YI051 (584 mg, 1.15 mmol), FmocCl (385 mg, 1.49 mmol), DIEA (592 mg, 4.6 mmol) and trifluoroacetic acid 4 mL, the reaction steps refer to step 4 of the final product 1, and the target product 722 mg is obtained with a yield of 95%.

[0456] 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)

[0457] YI054 (271 mg, 0.4 mmol), methyl 4-amino-3-methoxybenzoate (290 mg, 1.6 mmol), diphenylphosphinoyl chloride (283 mg, 1.2 mmol), DIEA (259 mg, 2 mmol) and piperidine 0.4 mL. The reaction steps refer to step 5 of the final product 1 to obtain 80 mg of the target product with a yield of 32%. 1 H NMR (400MHz, Methanol-d4) δ8.25(d,J=8.3Hz,1H),7.63–7.50(m,2H),7.44–7.31(m,4H),7.22(dd,J=13.1,2.1Hz,1H),7.07(d,J=8.0Hz,2H ),4.79(d,J=10.8Hz,1H),4.56–4.44(m,1H),3.92–3.82(m,6H),3.78–3.64(m,2H),3.52(d,J=14.5Hz,1H),1.80–1.60(m,2H),1.19(s,9H).

[0458] Step 6: Synthesis of 4-((2R,3S,4S,5S)-4-(4-chloro-2-fluorophenyl)-3-(4-chlorophenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM123)

[0459] YI059 (41 mg, 0.066 mmol), 4-(bromomethyl)pyridine hydrobromide (25 mg, 0.0997 mmol), potassium carbonate (36 mg, 0.27 mmol) and lithium hydroxide monohydrate (14 mg, 0.33 mmol). The reaction steps refer to the final product 14. The target product 17 mg was obtained with a yield of 32%. 1H NMR (400MHz, Methanol-d4) δ8.75(d,J=6.0Hz,2H),8.26(d,J=8.4Hz,1H),7.95(d,J=6.2Hz,2H),7. 63(dd,J=8.4,1.8Hz,1H),7.56(d,J=1.8Hz,1H),7.41–7.28(m,3H),7.28–7.04(m,4H),5.52(d,J=1 0.6Hz,1H),4.67(d,J=9.2Hz,1H),4.34(d,J=10.6Hz,1H),4.16–3.89(m,2H),3.77(s,3H),3.28(s,1H),3.01(d,J=13.3Hz,1H),2.08–1.90(m,1H),1.70(d,J=15.1Hz,1H),1.00(s,9H).ESI-MS theoretical calculated value C 37 H 39 35 Cl2FN4O4[M+H] + =693.2, experimentally measured: 693.3.

[0460] Final product 121: 4-((2R,3S,4S,5S)-4-(4-chlorophenyl)-3-(3-chlorophenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM125)

[0461]

[0462] Step 1: Synthesis of 4-((2R,3S,4S,5S)-4-(4-chlorophenyl)-3-(3-chlorophenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM125)

[0463] YM078 (24 mg, 0.04 mmol), 4-(bromomethyl)pyridine hydrobromide (20 mg, 0.08 mmol), potassium carbonate (22 mg, 0.16 mmol) and lithium hydroxide monohydrate (8.4 mg, 0.2 mmol), reaction steps refer to the final product 14, and the target product 6 mg was obtained with a yield of 19%. 1H NMR (400MHz, Methanol-d4) δ8.73(d,J=6.0Hz,2H),8.30(d,J=8.4Hz,1H),7.92(d,J=5.8Hz,2H),7.64(dd,J =8.4,1.8Hz,1H),7.60–7.52(m,1H),7.40(t,J=9.4Hz,3H),7.34–7.20(m,4H),6.96(d,J=7.7Hz,1H),5.47( d, J = 10.7 Hz, 1H), 4.40 (d, J = 9.5 Hz, 1H), 4.12 (d, J = 15.8 Hz, 1H), 4.08–3.90 (m, 2H), 3.78 (s, 3H), 3.25 (d, J = 13.5 Hz, 1H), 3.04 (d, J = 13.4 Hz, 1H), 2.12–1.85 (m, 1H), 1.68 (d, J = 15.0 Hz, 1H), 1.00 (s, 9H). ESI-MS theoretical calculated value C 37 H 41 35 Cl2N4O4[M+H] + =675.2, experimentally measured: 675.3.

[0464] Final product 122: 4-((2R,3S,4S,5S)-4-(4-chloro-2-fluorophenyl)-3-(2,3-dichlorophenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM129)

[0465]

[0466] Step 1: Synthesis of (Z)-2-(4-chloro-2-fluorophenyl)-3-(2,3-dichlorophenyl)acrylonitrile (YI116)

[0467] 2,3-Dichlorobenzaldehyde (3.5 g, 20 mmol), 4-chloro-2-fluorobenzeneacetonitrile (3.4 g, 20 mmol), 4.8 mL of 5N sodium methoxide methanol solution, the reaction steps refer to step 1 of the final product 1, and 6.23 g of the target product is 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).

[0468] Step 2: Synthesis of (2R,3R,4R,5S)-4-(4-chloro-2-fluorophenyl)-3-(2,3-dichlorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YI124-1)

[0469] YI116 (6.23 g, 19 mmol), AgF (2.41 g, 19 mmol), triethylamine 4.24 mL and (E)-tert-butyl 2-(((3,3-dimethylbutylidene)amino)acetate (4 g, 19 mmol). The reaction steps refer to step 2 of the final product 1 to obtain 4.57 g of the target product 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).

[0470] Step 3: Synthesis of (2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(2,3-dichlorophenyl)-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YI124-2)

[0471] YI124-1 (4.57 g, 8.5 mmol), nickel powder 4.5 g, hydrazine hydrate 10 mL, reaction steps refer to step 3 of final product 1, and the target product 1.04 g is obtained with a yield of 23%. 1 H NMR(500MHz,Chloroform-d)δ7.87(dd,J=7.9,1.6Hz,1H),7.34(dd,J=7.9,1.4Hz, 1H),7.22(t,J=7.9Hz,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).

[0472] 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)

[0473] YI124-2 (1.04 g, 1.91 mmol), FmocCl (740 mg, 2.87 mmol), DIEA (986 mg, 7.62 mmol) and 4 mL of trifluoroacetic acid. The reaction steps refer to step 4 of the final product 1 to obtain 1.08 g of the target product with a yield of 80%.

[0474] Step 5: Synthesis of methyl 4-((2R,3R,4S,5S)-4-(aminomethyl)-4-(4-chloro-2-fluorophenyl)-3-(2,3-dichlorophenyl)-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (YI129)

[0475] YI126 (284 mg, 0.4 mmol), methyl 4-amino-3-methoxybenzoate (290 mg, 1.6 mmol), diphenylphosphinoyl chloride (283 mg, 1.2 mmol), DIEA (259 mg, 2 mmol) and piperidine 0.4 mL. The reaction steps refer to step 5 of the final product 1 to obtain 46 mg of the target product with a yield of 18%.

[0476] Step 6: Synthesis of 4-((2R,3S,4S,5S)-4-(4-chloro-2-fluorophenyl)-3-(2,3-dichlorophenyl)-5-neopentyl-4-(((pyridin-4-ylmethyl)amino)methyl)pyrrolidine-2-carboxamido)-3-methoxybenzoic acid (YM129)

[0477] YI129 (15 mg, 0.023 mmol), 4-(bromomethyl)pyridine hydrobromide (12 mg, 0.046 mmol), potassium carbonate (19 mg, 0.14 mmol) and lithium hydroxide monohydrate (5 mg, 0.12 mmol). The reaction steps refer to the final product 14 to obtain 5.2 mg of the target product with a yield of 34%. 1H NMR (500MHz, Methanol-d4) δ8.79–8.64(m,2H),8.24(d,J=8.4Hz,1H),7.88(d,J=5.8Hz,2H),7.70 (d,J=7.9Hz,1H),7.66–7.56(m,2H),7.53(dd,J=8.1,1.4Hz,1H),7.40(t,J=8.0Hz,1H),7.27–7.1 8 (m, 2H), 7.18–7.07 (m, 1H), 4.69 (d, J = 10.1 Hz, 1H), 4.61 (s, 1H), 4.14 (d, J = 15.9 Hz, 1H), 4.10 (d, J = 15.9 Hz, 1H), 3.85 (s, 3H), 3.39–3.34 (m, 2H), 1.84 (d, J = 5.2 Hz, 2H), 1.14 (s, 9H). ESI-MS theoretical calculated value C 37 H 39 35 Cl3FN4O4[M+H] + =727.2, experimentally measured: 727.2.

[0478] By selecting the corresponding raw materials, the compounds in Table 1 below can be synthesized:

[0479] Table 1 Basic information of compounds

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508] Example 2: FP detection of the binding constant Ki value of the compound and MDMX protein

[0509] His-tagged MDMX (14-111, C17S) was expressed in E. coli and purified by Ni affinity column and then by Superdex75 molecular sieve. The purity of the obtained MDMX protein was greater than 95% and the protein concentration was 12.5 μM. FAM-tagged PDI polypeptide (FAM-PDI) [Cancer Res 2007, 67, 8810-8817] was used as a fluorescent labeled molecular probe. The dissociation constant K of the MDMX / FAM-PDI interaction was d is 2.1nM.

[0510] 96-well plate was purchased from Corning (black, #3694). Multifunctional microplate reader was a product of TECAN, model: SPARK 10M. Detection buffer: 10mM Tris (pH 7.5), 200mM NaCl (Sigma), 0.01% Tween-20 and 0.01% Trition X-100 (Sigma), and the experimental water was Millipore-Q pure water.

[0511] First, the test compound was dissolved in DMSO to form a 20 mM standard stock solution. Subsequently, the standard stock solution of the test compound was diluted with DMSO in an EP tube to form a working sample solution. The concentration of the prepared working sample solution = 25 times the highest sample concentration required on the test plate (25×test compound solution). The compound was diluted 3 times in an EP tube for later use.

[0512] 4 μL of the 25× test compound solution of the test compound A was added to the wells B1-D1 to B12-D12 of the 96-well plate, and 4 μL of the 25× test compound solution of the test compound B was added to the wells E1-G1 to E12-G12. Finally, 96 μL of the detection buffer containing 5.2 nM FAM-PDI and 62.5 nM MDMX protein was added to each well.

[0513] Wells A1-A3 were used as blank control groups: 100uL detection buffer was added. Wells A4-A6 were used as negative signal reference groups: 100μL buffer containing only 5nM fluorescently labeled molecular probe was added. Wells A7-A9 were used as positive reference groups: 100μL mixed solution containing 5nM fluorescently labeled molecular probe and 60nM MDMX protein was added.

[0514] Cover the reaction plate with aluminum foil, place the 96-well plate on a 96-well plate shaker and incubate at room temperature for 1 hour, then read the fluorescence polarization mP value at Ex485nm / Em530nm using an ELISA reader. The measured mP value is plotted against the compound concentration gradient, and the sample compound concentration corresponding to the median of the maximum and minimum mP values ​​is the IC value of the compound binding to the protein. 50 value([I] 50 ).

[0515] According to this IC 50 value([I] 50 ), the binding rate constant between the compound and the protein was calculated using the formula

[0516] K i :K i =[I] 50 / ([L] 50 / K d +[P]0 / Kd +1).

[0517] Where [L] 50 represents 50% of the concentration of the fluorescent labeled molecular probe in the above test system; [P]0 represents the concentration of MDMX protein in the above test system, K d is the dissociation constant between the protein and the fluorescent labeled molecular probe.

[0518] Using the above method, the K of the example compounds for inhibiting MDMX / p53 interaction was measured. i The values ​​are shown in Table 2. The experimental data show that the compound has the activity of an inhibitor of MDMX / p53 interaction.

[0519] Table 2: Inhibitory activity of the example compounds on MDMX / p53 interaction

[0520]

[0521]

[0522] * indicates K i Between 100,000nM and 10,000nM; ** indicates K i Between 10,000nM and 100nM;

[0523] Experimental data showed that the activity of the new synthesized compound in binding to MDMX was similar to or significantly improved than that of the positive compound RG7388 (CAS: 1229705-06-9).

[0524]

[0525] Example 3

[0526] FP detection of the binding constant Ki value of the compound and MDM2 protein

[0527] His-tagged MDM2 (1-118) was expressed in E. coli and purified by Ni affinity column and then by Superdex75 molecular sieve. The purity of the obtained MDMX protein was greater than 95% and the protein concentration was 151 μM. FAM-tagged PDI polypeptide (FAM-PDI) [Cancer Res 2007, 67, 8810-8817] was used as a fluorescent labeled molecular probe. The dissociation constant K of the MDM2 / FAM-PDI interaction was d is 0.7nM.

[0528] The 96-well plate was purchased from Corning (black, #3694). The multifunctional microplate reader was a product of TECAN, model: SPARK 10M. The detection buffer: 100mM potassium phosphate (pH 8.0), 100ug / mL Bovine-r-globulin (Sigma) and 0.01% Trition X-100 (Sigma), and the experimental water was Millipore-Q pure water.

[0529] First, the test compound was dissolved in DMSO to form a 20 mM standard stock solution. Subsequently, the standard stock solution of the test compound was diluted with DMSO in an EP tube to form a working sample solution. The concentration of the prepared working sample solution = 25 times the highest sample concentration required on the test plate (25×test compound solution). The compound was diluted 3 times in an EP tube for later use.

[0530] 4 μL of the 25× test compound solution of the test compound A was added to the B1-D1 to B12-D12 wells of the 96-well plate, and 4 μL of the 25× test compound solution of the test compound B was added to the E1-G1 to E12-G12 wells. Finally, 96 μL of the detection buffer containing 2.08 nM FAM-PDI and 20.8 nM MDM2 protein was added to each well.

[0531] Wells A1-A3 were used as blank control groups: 100 μL of detection buffer was added. Wells A4-A6 were used as negative signal reference groups: 100 μL of buffer containing only 2 nM fluorescently labeled molecular probe was added. Wells A7-A9 were used as positive reference groups: 100 μL of a mixed solution containing 2 nM fluorescently labeled molecular probe and 20 nM MDM2 protein was added.

[0532] Cover the reaction plate with aluminum foil, place the 96-well plate on a 96-well plate shaker and incubate at room temperature for 1 hour, then read the fluorescence polarization mP value at Ex485nm / Em530nm using an ELISA reader. The measured mP value is plotted against the compound concentration gradient, and the sample compound concentration corresponding to the median of the maximum and minimum mP values ​​is the IC value of the compound binding to the protein. 50 value([I] 50 ).

[0533] According to this IC 50 value([I] 50 ), the binding rate constant between the compound and the protein was calculated using the formula

[0534] K i :K i =[I] 50 / ([L] 50 / K d+[P]0 / K d +1).

[0535] Where [L] 50 represents 50% of the concentration of the fluorescent 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 between the protein and the fluorescent labeled molecular probe.

[0536] Using the above method, the K of the example compounds for inhibiting the MDM2 / p53 interaction was measured. i The values ​​are shown in Table 3. The experimental data showed that the compounds had very good activity in inhibiting the MDM2 / p53 interaction, and the Ki values ​​of compounds 1-15, 17-39, 41, 44-46 and 48 were all below 10 nM, significantly better than Nutlin-3a.

[0537] Table 3: Inhibitory activity of the compounds in the examples on the interaction of MDM2 / p53

[0538]

[0539]

[0540] * indicates K i Between 100,000nM and 10,000nM; ** indicates K i Between 10,000nM and 100nM; *** indicates K i Between 100nM and 10nM; **** indicates K i <10nM.

[0541]

[0542] Experimental data showed that the activity of the new synthesized compounds in binding to MDM2 was similar to or significantly improved over that of the positive compound Nutlin-3a.

[0543] Example 4: Testing the cell growth inhibition ability of compounds in various human tumor cells

[0544] Dissolve the sample to be tested in 100% dimethyl sulfoxide to prepare a 20 mM stock solution of the compound. Dilute the compound with 100% dimethyl sulfoxide to the highest concentration required for the experiment (1 mM or 10 mM).

[0545] First, add 145 μL of complete cell culture medium to the B1-G1 wells of a 96-well flat-bottom transparent cell culture plate, and add 100 μL of complete culture medium to the B2-G12 wells. Then, add 5 μL of 1mM or 10mM compound solution to the B1-D1 and E1-G1 wells, respectively, and dilute to B12-D12 and E12-G12 in a 3-fold gradient. Finally, add 50 μL of the cell solution to be tested to each well, and the cell density of each well is about 3000 for HCT116, RKO and Hela, about 5000 for H460 and U2-OS, and about 8000 for SW480 and MCF-7, and the total volume of each well is 150 μL. In the experiment, in addition to the tested compounds, two control groups were set up: 1) a control group with cells and culture medium, but no compound; 2) a control group with only complete culture medium, no cells and no compound. After incubating the 96-well plate in a 37°C cell culture incubator containing 5% carbon dioxide for 4 days, 15uL of CCK-8 reagent was added to each well and then incubated at 37°C for 2-3 hours. The absorbance value at a wavelength of 450nm was read using a TECAN microplate reader.

[0546] The effects of different concentrations of compounds on cell activity were calculated using the following formula: [absorption value of the experimental group - absorption value of only adding complete culture medium (no cells and no compound group)] / [absorption value of the group with cells but no compound - absorption value of only adding complete culture medium (no cells and no compound group)]×100%.

[0547] The above data were processed using GraphPad Prism 6 software, and the IC 50 The value is the concentration of compound corresponding to 50% inhibition of cell growth.

[0548] Table 4: Activity of Example Compounds in Inhibiting Cell Growth

[0549]

[0550] # indicates IC 50 Between 100,000nM and 10,000nM; ## indicates IC 50 Between 10,000nM and 1000nM; ### indicates IC 50 Between 1,000 nM and 100 nM, #### indicates IC 50 Less than 100nM.

[0551] \ indicates that the result has not been tested.

[0552] Experimental data show that in p53 wild-type cell lines (HCT116, H460, Hela, US-OS, MCF-7 and RKO), the cell growth inhibition ability of the tested compounds in the table is stronger than that of Nutlin3a. In the p53 mutant SW480 cell line, the cell growth inhibition ability of the tested compounds is also stronger than that of Nutlin3a.

[0553] Example 5: Western Blot detection of the effects of Nutlin-3a and YL93 on biomarker proteins p53, p21, MDM2, MDM4, Caspase-3 and PARP in HCT116 cells

[0554] After trypsin digestion, HCT116 cells were evenly plated on a 6-well plate and placed in a 37°C cell culture incubator containing 5% carbon dioxide for 24 hours. After complete attachment, the original culture medium was removed, and fresh culture medium containing different concentrations of compounds was added to each well of the 6-well plate. The DMSO group was used as a blank control and placed in a 37°C cell culture incubator for 24 hours. After the incubation, the 6-well plate was removed, and after removing the culture medium containing the compound, 1 mL of ice-cooked 1X PBS was added to each well to wash once. 100uLRIPA cell lysis buffer was added to each well, and the cells were lysed on ice for 30 minutes. After centrifugation at 14,000 rpm at 4°C for 30 minutes, the cell lysis supernatant was taken. The concentration of each protein sample was determined using the BCA protein concentration detection kit. SDS-PAGE was performed first by loading 20ug protein per well, and then the protein was transferred to a nitrocellulose membrane. The nitrocellulose membrane was blocked with 5% skim milk powder 1×TBST (20mM Tris, 150mM NaCl, pH 7.6, 0.1% Tween-20) solution at room temperature for 2 hours, and then washed with 1XTBST for 5×5 minutes. Subsequently, the primary antibody of the corresponding protein (p53, p21, MDM2, MDM4, Caspase-3, PARP, GAPDH) was added and incubated overnight at 4°C. The next day, after removing the primary antibody, the membrane was washed with 1×TBST for 5×5 minutes, the corresponding secondary antibody was added, and the membrane was washed with 1×TBST for 5×5 minutes after incubation at room temperature for 2 hours. Finally, the ECL luminescence kit (Thermo Scientific) was used to detect and analyze the bands of the corresponding proteins. The read images were processed with photoshop and power point to obtain the corresponding image data.

[0555] Figure 1 The figure shows the effect of compound YL093 and positive compound Nutlin-3a on the expression levels of some intracellular proteins after treating HCT116 cells.

[0556] Experimental data show that compound YL093 can increase the expression levels of p53, p21, MDM2, and MDMX proteins in cells, and promote the conversion of intracellular Caspase-3 and PARP to spliced ​​Caspase-3 and spliced ​​PARP. Since the increase of p21 can lead to cell cycle arrest, the production of spliced ​​Caspase-3 and spliced ​​PARP indicates that the cells enter apoptosis.

[0557] In addition, compound YL093 can significantly increase the expression of MDM2 and p21 proteins at 0.3125 μM, while the positive compound Nutlin3a has a similar cell function to YL093 at 5 μM. In terms of the ability to affect p21 and MDM2 proteins in cells, the activity of YL093 is more than 10 times that of Nutlin3a.

[0558] The above data show that YL093 can promote cell cycle arrest and apoptosis of HCT-116 colorectal cancer cells. The activity of YL093 is significantly stronger than that of Nutlin3a, an MDM2 inhibitor widely reported in the literature.

[0559] Example 6: Determination of relative stereo configuration of compounds

[0560]

[0561] FE071 (10 mg) was weighed into a 10 mL glass sample bottle, added to 1.5 mL of ether, and then slowly added to 2 mL of n-hexane. After sealing with aluminum foil, 3 small holes were pierced with a needle. The sample was allowed to stand at room temperature for 2 days to grow a single crystal. The X-ray single crystal diffraction test compound diffraction data and results are shown in Table 5 below: The crystal data showed that the relative stereo configuration of FE71 was as follows: Figure 2 shown.

[0562] Table 5 X-ray single crystal diffraction test compound diffraction data

[0563]

[0564]

[0565] FE098 (10 mg) was weighed into a 10 mL glass sample bottle, added to 1.5 mL of ether, and then slowly added to 2 mL of n-hexane. After sealing with aluminum foil, 3 small holes were pierced with a needle. The sample was allowed to stand at room temperature for 2 days to grow a single crystal. The X-ray single crystal diffraction test compound diffraction data and results are shown in Table 6 below: The crystal data show that the relative stereo configuration of FE098 is as follows: Figure 3 shown.

[0566] Table 6 X-ray single crystal diffraction test compound diffraction data

[0567]

[0568]

[0569] YL141 (10 mg) was weighed into a 10 mL glass sample bottle, added to 1.5 mL of ether, and then slowly added to 2 mL of n-hexane. After sealing with aluminum foil, 3 small holes were pierced with a needle. The solution was left to stand at room temperature for 2 days to grow a single crystal. The X-ray single crystal diffraction test compound diffraction data and results are shown in Table 7 below: The crystal data showed that the relative stereo configuration of YL141 was as follows: Figure 4 shown.

[0570] Table 7 X-ray single crystal diffraction test compound diffraction data

[0571]

[0572] The above experimental data show that FE071, FE098 and YL141 are the compounds containing methyl ester before hydrolysis of final product 15 (YL139), final product 16 (YM001) and final product 2 (YM011), respectively. The three crystal structure data show that the site of SN2 substitution reaction between m-nitrobenzyl bromide and YL090, the site of reductive amination reaction between p-bromobenzaldehyde and YL090, and the site of acylation reaction between p-bromobenzoyl chloride and YL090 are all at the primary amine position. It is inferred that the substitution, reductive amination and acylation reaction sites of YL090 and its analogues are all at the fatty primary amine position.

[0573] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings 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 claims attached to this application.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, In the formula, Ar is a substituted or unsubstituted phenyl group, wherein, The substitution refers to the substitution of one or more hydrogen atoms on the phenyl group by a group selected from the group consisting of: halogen; R6 is hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl; R1 is -COCOOH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted -(CH2) m -phenyl, substituted or unsubstituted -(CH2) m -5-12 membered heteroaryl, substituted or unsubstituted -(CH2) m -5-8 membered heterocyclic group, -CO-substituted or unsubstituted phenyl, -CO-substituted or unsubstituted 3-8 membered cycloalkyl, -SO2-substituted or unsubstituted phenyl, -CO-substituted or unsubstituted C1-C4 alkyl, -CO-substituted or unsubstituted 5-12 membered heteroaryl, -SO2-substituted or unsubstituted C1-C4 alkyl; the substitutions independently refer to that one or more hydrogen atoms on the group are replaced by a group selected from the group consisting of halogen, cyano, hydroxyl, amino, nitro, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, 5-7 membered heteroaryl; R2 is selected from: substituted or unsubstituted -(CH2) m -phenyl, substituted or unsubstituted -(CH2) m -C3-C6 cycloalkyl, substituted or unsubstituted -(CH2) m -5-8 membered heteroaryl, substituted or unsubstituted C1-C4 alkyl; the substitution refers to substitution by one or more groups selected from the following group: hydroxyl, carboxyl, C1-C4 alkoxy; R3 and R5 are each independently hydrogen, halogen, or C1-C4 alkoxy; m is independently 0, 1, 2 or 3 at each occurrence; R4 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C8 cycloalkyl, or a substituted or unsubstituted 4-8 membered heterocyclic group; the substitution means that one or more hydrogen atoms on the group are replaced by a group selected from the following group: C1-C4 alkyl.

2. The compound according to claim 1, characterized in that The compound has a structure as shown in formula (II): In the formula, Ar, R1, R2, R3, R5 and R6 are as defined in claim 1.

3. The compound according to claim 1, characterized in that Ar is a substituted or unsubstituted phenyl group, wherein 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 and bromine.

4. The compound according to claim 1, characterized in that Ar is a substituted or unsubstituted phenyl group, wherein 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 F and Cl.

5. The compound according to any one of claims 1 to 4, characterized in that Ar is a substituted phenyl group, and the substituent is at the ortho position or the meta position.

6. The compound according to claim 1, characterized in that R1 is selected from: -COCOOH, substituted or unsubstituted C1-C4 alkyl, -CO-substituted or unsubstituted C1-C4 alkyl, -SO2-substituted or unsubstituted C1-C4 alkyl, -CO-substituted or unsubstituted 3-6 membered cycloalkyl, -CO-substituted or unsubstituted phenyl, substituted or unsubstituted -(CH2) m -phenyl, -SO2-substituted or unsubstituted phenyl, substituted or unsubstituted -(CH2) m -5-12 membered heteroaryl, -CO- substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted -(CH2) m -5-8 membered heterocyclic group; The substitution refers to that 1, 2, 3 or 4 hydrogen atoms on the group are replaced by a group selected from the following groups: F, Br, Cl, C1-C4 alkyl, C1-C4 alkoxy, carboxyl, nitro, amino, hydroxyl, CN, 5-6 membered heteroaryl.

7. The compound according to claim 1, characterized in that R2 is selected from substituted or unsubstituted -(CH2) m -phenyl, substituted or unsubstituted -(CH2) m -C3-C6 cycloalkyl, substituted or unsubstituted -(CH2) m -5-8 membered heteroaryl, substituted or unsubstituted C1-C4 alkyl; the substitution means that 1, 2, 3 or 4 hydrogen atoms on the group are replaced by a group selected from the following group: carboxyl, C1-C4 alkoxy, hydroxyl.

8. The compound according to claim 1, characterized in that R3 and R5 are each independently hydrogen, fluorine, chlorine, bromine or C1-C4 alkoxy.

9. The compound according to claim 1, characterized in that R3 and R5 are each independently selected from: F, Cl, C1-C4 alkoxy.

10. The compound according to claim 1, characterized in that R4 is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, or a substituted or unsubstituted 5-7 membered heterocyclyl group; the substitution refers to substitution with one or more groups selected from the following group: C1-C4 alkyl group.

11. The compound according to claim 1, characterized in that R4 is tert-butyl, 12. The compound according to claim 1, characterized in that R6 is selected from: H, C1-C4 alkyl, cyclopropyl.

13. The compound according to claim 1, characterized in that The compound is selected from the group consisting of:

14. A pharmaceutical composition, characterized in that include: One or more of the compounds according to any one of claims 1 to 13 or their pharmaceutically acceptable salts; and a pharmaceutically acceptable carrier.

15. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, characterized in that: Used to prepare small molecule inhibitors that block MDM2 / p53 and / or MDMX / p53 interactions; or used to prepare drugs for treating diseases related to the activity or expression level of MDM2 or MDMX proteins.

16. The use according to claim 15, characterized in that The disease associated with the activity or expression of MDM2 or MDMX protein is selected from the following group: glioma, liposarcoma, skin melanoma, squamous cell carcinoma, retinoblastoma, breast cancer, esophageal cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, liver cancer, soft tissue sarcoma, chronic lymphocytic leukemia, acute myeloid leukemia, lymphoma, osteosarcoma and colon cancer.

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