CN116283701A

CN116283701A - Compounds having the structure 4- (substituted aminomethyl) -5-neopentyl-N-substituted pyrrolidine-2-carboxamide

Info

Publication number: CN116283701A
Application number: CN202111571938.5A
Authority: CN
Inventors: 赵玉军; 张世言; 严子琴; 吕细林; 周飞龙
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2021-12-21
Filing date: 2021-12-21
Publication date: 2023-06-23

Abstract

The invention relates to a small molecule inhibitor for MDM2-p53 and MDMX-p53 protein interaction, in particular to a small molecule compound with a 4- (substituted aminomethyl) -5-neopentyl-N-substituent pyrrolidine-2-carboxamide structure and a similar structure, a preparation method and a pharmaceutical composition thereof, and application of the small molecule inhibitor for MDM2-p53 and MDMX-p53 protein interaction in preparation of MDM2-p53 and MDMX-p53 protein interaction or prevention and/or treatment of diseases related to MDM2 and MDMX, in particular to an antitumor drug.

Description

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

Technical Field

The invention belongs to the field of medicine synthesis, and in particular relates to a compound with a 4- (substituted aminomethyl) -5-neopentyl-N-substituent pyrrolidine-2-carboxamide structure, a stereoisomer, an enantiomer or pharmaceutically acceptable salts thereof, a preparation method and application thereof.

Technical Field

The tumor suppressor p53 exerts an antiproliferative effect in coping with various stresses, including cell growth arrest, DNA repair, apoptosis, and the like. Mice lacking p53 develop normally but tend to induce multiple tumors. The TP53 gene encoding the p53 protein is mutated or deleted in nearly 50% of human cancers, making the cells incapable of functioning as p53 tumor suppressors. 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 critical for the regulation of p 53-MDM 2 and MDMX (also known as MDM 4). Embryonic lethality caused by knocking out MDM2 and MDMX genes can be saved by knocking out TP53 genes of mice at the same time, and the effect of MDM2 and MDMX as p53 main negative endogenous regulator is clarified. In vitro studies showed that: MDM2 and MDMX inhibit the gene transcription function of p53 protein by their amino-terminal p53 binding domain acting on the Transcriptional Activation Domain (TAD) of p53 protein. In addition, MDM2 can promote ubiquitination and proteasome degradation of MDM2 itself, MDMX and p53 proteins. Conversely, P53 specifically binds to and activates transcription of the MDM 2P 2 promoter, forming an autoregulatory feedback loop, the MDM2-P53 feedback loop. MDM2 can also promote transport of p53 protein out of the nucleus, rendering p53 inaccessible to its targeting DNA, thereby reducing its transcriptional capacity. While for MDMX, it does not act as an E3 ubiquitin ligase like MDM2, it can form a stable heterodimer by the carboxy-terminal RING domain acting with the carboxy-terminal RING domain of MDM2 to promote MDM 2-mediated p53 ubiquitination.

Studies have shown that: the abnormal increase in levels of MDM2 and MDMX oncogenes in cancer cells, the inhibition of p 53-mediated gene transcription function, and the decrease in p53 levels, are closely related to the overgrowth of tumor cells, as compared to normal cells.

Compounds reported in the literature as RG7112 (NCT 00559533, NCT00623870, NCT01677780, NCT01164033, NCT01605526, NCT01143740 and NCT 01635296), RG7388 (Ding et al, J Med Chem 2013,56 (14), 5979-83), MI-77301 (NCT 01636479 and NCT 01985191) and AMG 232 (NCT 01723020 and NCT 02016729) can selectively block MDM2/p53 interactions. Compounds reported in SJ-172550 (Reed et al, J Biol Chem 2010,285 (14), 10786-96; bista et al, PLoS One 2012,7 (6), e 37518), CTX-1 (Karan et al, mol Cancer Ther 2016,15 (4), 574-582) and K-178 (Uesator et al, bioorg Med Chem 2016,24 (8), 1919-26) and the like selectively block MDMX/p53 interactions. Compounds reported in WK298 (Popowicz et al, cell Cycle 2010,9 (6), 1104-11), ATSP-7041 (Chang et al, proc Natl Acad Sci U S A, 2013,110 (36), E3445-54), RO-5963 (Graves et al, proc Natl Acad Sci U S A, 2012,109 (29), 11788-93) and ALRN-6924 (Carvajal et al, sci Transl Med 2018,10 (436)) and the like can inhibit both MDM2/p53 and MDMX/p53 interactions. Small molecule inhibitors block the interaction of MDM2/p53 and MDMX/p53 and have potential for the treatment of related diseases.

Disclosure of Invention

The object of the present invention is to provide a small molecule inhibitor blocking MDM2/p53 and/or MDMX/p53 interactions.

In a first aspect of the invention there is provided a compound as described by formula (I), an enantiomer, diastereomer or a pharmaceutically acceptable salt thereof,

wherein 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 or naphthyl group are replaced with a group selected from the group consisting of: halogen, deuterium, cyano, hydroxy, 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;

R ₆ is hydrogen and is takenSubstituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C3-C8 cycloalkyl;

R ₁ is hydrogen, -COCOOH, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted- (CH) ₂ ) _m -6-10 membered aryl, substituted or unsubstituted- (CH) ₂ ) _m -C3-C8 cycloalkyl, substituted or unsubstituted- (CH) ₂ ) _m -5-12 membered heteroaryl, substituted or unsubstituted- (CH) ₂ ) _m -5-13 membered heterocyclyl, -CO-substituted or unsubstituted 6-10 membered aryl, -CO-substituted or unsubstituted 3-10 membered cycloalkyl, -SO ₂ -substituted or unsubstituted 6-10 membered aryl, -CO-substituted or unsubstituted C1-C6 alkyl, -CO-substituted or unsubstituted 5-12 membered heteroaryl, -SO ₂ -a substituted or unsubstituted C1-C6 alkyl group;

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

R ₃ 、R ₅ each independently is 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;

m is independently at each

occurrence

0, 1, 2, 3 or 4;

R ₄ is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 4-8 membered heterocyclic group;

each of the above-described substitutions, unless otherwise defined, independently refers to the substitution of one or more hydrogen atoms on the group with a group selected from the group consisting of: halogen, deuterium, cyano, hydroxy, amino, nitro, C2-C4 alkynyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonylaminocarbonyl (C1-C4 alkyl SO) ₂ NHCO-), carboxyl, -CONH ₂ 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 alkyl Oxycarbonylamino, C1-C4 alkyl SO ₂ -, a part of C1-C4 alkyl-S (O) ₂ ) -C1-C4 alkylene-, carboxy-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.

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

wherein Ar, R ₁ 、R ₂ 、R ₃ 、R ₅ 、R ₆ The definition is as described above.

In another preferred embodiment, 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 or naphthyl group are replaced with a group selected from the group consisting of: halogen, deuterium, cyano, hydroxy, 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.

In another preferred embodiment, ar is a substituted or unsubstituted phenyl group, wherein the substitution is such that one or more hydrogen atoms in the phenyl group are replaced by a group selected from the group consisting of: halogen, deuterium, cyano, hydroxy, carboxy, amino, nitro, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl; the above-mentioned C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl is optionally further substituted with one or more groups selected from the group consisting of: halogen, deuterium, cyano, hydroxy, amino, nitro, carboxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino.

In another preferred embodiment, ar is a substituted or unsubstituted phenyl group, wherein the substitution is such that one or more hydrogen atoms in 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).

In another preferred embodiment, ar is a substituted or unsubstituted phenyl group, wherein the substitution is such that 1, 2, 3 or 4 hydrogen atoms in the phenyl group are replaced by a group selected from the group consisting of: F. cl. In another preferred embodiment, the substituent is located in the ortho or meta position.

In another preferred embodiment, R ₁ Is hydrogen, -COCOOH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted- (CH) ₂ ) _m -phenyl, substituted or unsubstituted- (CH) ₂ ) _m -C3-C6 cycloalkyl, substituted or unsubstituted- (CH) ₂ ) _m -5-12 membered heteroaryl, substituted or unsubstituted- (CH) ₂ ) _m -a 5-8 membered heterocyclyl, -CO-substituted or unsubstituted phenyl, -CO-substituted or unsubstituted 3-8 membered cycloalkyl, -SO 2-substituted or unsubstituted phenyl, -CO-substituted or unsubstituted C1-C4 alkyl, -CO-substituted or unsubstituted 5-12 membered heteroaryl, -SO 2-substituted or unsubstituted C1-C4 alkyl;

m is independently at each

occurrence

0, 1, 2 or 3;

the substitution means substitution with one or more groups selected from the group consisting of: halogen, cyano, amino, hydroxy, nitro, carboxy, C1-C4 alkoxy, -CONH ₂ C1-C4 alkyl-CONH-, C1-C4 alkyl-NHCO-, C1-C4 alkyl-S (O) ₂ ) -C1-C4 alkylene-, C1-C4 alkyl SO ₂ -, 6-to 10-membered aryl, C3-to C6-cycloalkyl, 5-to 7-membered heteroaryl, 5-to 7-membered heterocyclyl, carboxy-substituted C1-to C4-alkyl, hydroxy-substituted C1-to C4-alkyl, C1-to C4-alkyl SO ₂ NHCO-, (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.

In another preferred embodiment, R ₁ Selected from: H. -COCOOH, substituted or unsubstituted C1-C6 alkyl, -CO-substituted or unsubstituted C1-C6 alkyl, -SO 2-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- (CH) ₂ ) _m -6-10 membered aryl, -SO ₂ -substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted- (CH) ₂ ) _m -5-12 membered heteroaryl, -CO-substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted- (CH) ₂ ) _m -a 5-13 membered heterocyclyl;

by substituted is meant that 1, 2, 3 or 4 hydrogen atoms on the group are replaced by a group selected from the group consisting of: F. br, cl, C1-C4 alkyl, C1-C4 alkoxy, carboxyl, nitro, amino, hydroxyl, CN, 5-6 membered heteroaryl.

In another preferred embodiment, R ₂ Is substituted or unsubstituted- (CH) ₂ ) _m -phenyl, substituted or unsubstituted- (CH) ₂ ) _m -C3-C6 cycloalkyl, substituted or unsubstituted- (CH) ₂ ) _m -5-8 membered heteroaryl, substituted or unsubstituted C1-C4 alkyl;

wherein m is independently at each

occurrence

0, 1, 2 or 3;

the substitution means substitution with one or more groups selected from the group consisting of: amino, hydroxy, carboxy, C1-C4 alkoxy, -CONH ₂ C1-C4 alkyl-CONH-, C1-C4 alkyl-NHCO-, C1-C4 alkyl-S (O) ₂ ) -C1-C4 alkylene-, C1-C4 alkyl SO ₂ NHCO-, carboxy-substituted C1-C4 alkyl, di (C1-C4 alkyl) amino, mono (C1-C4 alkyl) amino, hydroxy-substituted C1-C4 alkyl, deuterium, fluorine, chlorine, bromine, cyano, nitro.

In another preferred embodiment, R ₂ Selected from substituted or unsubstituted- (CH) ₂ ) _m -phenyl, substituted or unsubstituted- (CH) ₂ ) _m -C3-C8 cycloalkyl, substituted or unsubstituted- (CH) ₂ ) _m -a 5-12 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl; by substituted is meant that 1, 2, 3 or 4 hydrogen atoms on the group are replaced by a group selected from the group consisting of: carboxyl, C1-C4 alkoxy, hydroxyl, carboxyl substituted C1-C4 alkyl.

In another preferred embodiment, R ₃ 、R ₅ Each independently is hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy.

In another preferred embodiment, R ₃ 、R ₅ Each independently selected from: F. cl, C1-C4 alkoxy.

In another preferred embodiment, R ₄ Selected from: a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-8 membered heterocyclic group; by substituted is meant that 1, 2, 3 or 4 hydrogen atoms on the group are replaced by a group selected from the group consisting of: C1-C4 alkyl.

In another preferred embodiment, R ₄ Is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted 5-7 membered heterocyclic group; the substitution means substitution with one or more groups selected from the group consisting of: C1-C4 alkyl, C1-C4 alkylcarbonyl.

In another preferred embodiment, R ₄ Is tert-butyl,

In another preferred embodiment, R ₆ Is hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl.

In another preferred embodiment, R ₆ Selected from: H. C1-C4 alkyl, cyclopropyl.

In another preferred embodiment, each substituent is the corresponding group in the particular compound.

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

In another preferred embodiment, the compound is selected from any of the compounds of sequence numbers 1-122.

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

In a second aspect of the invention there is provided a pharmaceutical composition comprising a compound as described in the first aspect, one or more of its enantiomers, diastereomers or pharmaceutically acceptable salts; and

a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition optionally further comprises pharmaceutically acceptable excipients selected from the group consisting of: binders, fillers, diluents, disintegrants, suspending agents, slow (controlled) release agents, lyoprotectants, coating agents, enteric materials, lubricants, glidants, anti-adherents, sweeteners, flavoring agents, plasticizers, opacifiers, solubilizers, humectants, solvents, osmotic pressure modifiers, colorants, pigments, surfactants, emulsifiers, water-soluble matrices, lipid-soluble matrices, oleaginous matrices, porogens, gelling agents, preservatives, buffers, chelating agents, antioxidants, or combinations thereof.

In a third aspect of the invention there is provided the use of a compound according to the first aspect, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, for the preparation of a small molecule inhibitor blocking MDM2/p53 and/or MDMX/p53 interactions; or for the preparation of a medicament for the treatment of a disease associated with the activity or expression of MDM2 or MDMX proteins.

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

Compared with the prior art, the invention has the main advantages that:

(1) The preparation method of the small molecular compound with the 4- (substituted aminomethyl) -5-neopentyl-N-substituent pyrrolidine-2-carboxamide structure has the advantages of mild reaction conditions, abundant and easily available raw materials, simple operation and post-treatment, good corresponding selectivity and the like. The compound has good MDM2-p53 and MDMX-p53 protein interaction inhibiting activity.

(2) Provides a small molecule inhibitor for MDM2-p53 and MDMX-p53 protein interaction, which has strong MDM2-p53 and MDMX-p53 protein interaction inhibition activity and is a potential anti-tumor drug.

Drawings

FIG. 1 shows the effect on intracellular protein expression levels following treatment of HCT116 cells with compound YL093 and the positive compound Nutlin-3 a.

Fig. 2 shows the relative spatial configuration of FE 071.

Fig. 3 shows the relative spatial configuration of FE 098.

Fig. 4 shows the relative spatial configuration of YL 141.

Detailed Description

The inventors of the present invention have studied intensively for a long time, and unexpectedly developed a small molecule compound having a structure of 4- (substituted aminomethyl) -5-neopentyl-N-substituted pyrrolidine-2-carboxamide and the like, which is capable of inhibiting MDM2-p53, MDMX-p53 protein interactions, regulating p 53-mediated gene expression in tumor cells, and thus can be used for inhibiting diseases related to MDM2-p53, MDMX-p53 interactions, such as prevention and treatment of cancer. Based on the above findings, the inventors have completed the present invention.

Compounds of formula (I)

The structure of the compound is shown as a general formula I, and each substituent is defined as above.

Preparation method

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

Route one

Step one: the aldehyde S1 is mixed with the substituted phenylacetonitrile S2 in a suitable solvent (e.g., methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, methylene chloride, or N, N-dimethylformamide, etc.). Adding appropriate alkali (A)Sodium alkoxide, sodium ethoxide, etc.), at room temperature or at a suitably elevated temperature (e.g., 40-60 ℃), to afford intermediate S3. Step two: s3 is mixed with the corresponding raw material S4 in a proper solvent (such as tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1, 2-dichloroethane, acetonitrile, etc.), silver fluoride and alkali (triethylamine, N-diisopropylethylamine, DBU, etc.) are added, and the reaction is carried out under the room temperature condition to obtain an intermediate S5. Step three: s5, obtaining an intermediate S6 (such as Pd/C hydrogen hydrogenation reduction, raney nickel hydrazine hydrate hydrogenation reduction and the like) through hydrogenation reduction reaction. Step four: s6 and FmocCl are mixed in a proper solvent (such as tetrahydrofuran, 2-methyltetrahydrofuran, methylene dichloride, acetonitrile, etc.), and alkali (triethylamine, N-diisopropylethylamine, DBU, etc.) is added, and the reaction is carried out under the room temperature condition to obtain an intermediate S7. Step five: s7 is dissolved in dichloromethane, trifluoroacetic acid is added, and the reaction is carried out at room temperature to obtain an intermediate S8. Step six: s8 is dissolved in a suitable solvent (for example, tetrahydrofuran, 2-methyltetrahydrofuran, methylene chloride, N, N-dimethylformamide or acetonitrile, etc.), a base (triethylamine, N-diisopropylethylamine, DBU, etc.) and a condensing agent (diphenylphosphinyl chloride, CDI, HATU, EDCI, etc.) are added, and after half an hour of reaction, an alcohol or an amine is added, and the reaction is carried out at room temperature to give an intermediate S9. Step seven: s9 is dissolved in a suitable solvent (e.g., N-dimethylformamide, etc.), piperidine is added, and the reaction is carried out at room temperature to give intermediate S10. Step eight: s10 and halocarbon R ₁ X(R ₁ Is an arylmethyl, aryl or fatty alkyl group) in a suitable solvent (e.g.: acetonitrile, dimethyl sulfoxide, N-dimethylformamide, toluene, benzene, etc.), and adding a base (for example: potassium carbonate, cesium carbonate, sodium carbonate, etc.), at room temperature or at a suitably elevated temperature (e.g., 30-50 ℃), to give the final product II.

Route two

Step one: s10 and R ₁ ' CHO is dissolved in a proper solvent (such as methanol, tetrahydrofuran, ethanol, 1, 2-dichloroethane, N-dimethylformamide, etc.), and a reducing reagent (sodium borohydride, sodium acetate, sodium cyanoborohydride, etc.) is added to obtain a final product II through reductive amination reaction.

Route three

Step one: s10 and R ₁ ' COX (acyl halide) is dissolved in a suitable solvent (e.g., tetrahydrofuran, dichloromethane, chloroform, 1, 2-dichloroethane, N-dimethylformamide, etc.), and a suitable base (triethylamine, DIEA, DBU, potassium carbonate, cesium carbonate, sodium bicarbonate, etc.) is added to obtain the final product II by acylation.

I can be prepared synthetically using the three synthetic strategies described above.

Example 1: synthesis of Compounds

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 (YH 018)

Step one: synthesis of (Z) -2- (4-chloro-2-fluorophenyl) -3- (3-chloro-2-fluorophenyl) acrylonitrile (YG 019)

4-chloro-2-fluorobenzonitrile (5 g,29.58 mmol), 3-chloro-2-fluorobenzaldehyde (4.54 g,28.7 mmol) was weighed into a 250mL round bottom flask, dissolved in 100mL methanol, 8.6mL of 5N sodium methoxide solution was added and reacted overnight at 50℃to cool to room temperature, filtered, the filter cake was washed with water, dried and weighed to give 7.5g, yield 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).

Step two: 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 (YG 035)

YG019 (3.72 g,12 mmol) was weighed into a 100mL reaction flask, dissolved with 50mL of methylene chloride, silver fluoride (1.53 g,12 mmol) and triethylamine (5 mL,19.2 mmol) were added, tert-butyl 2- ((3, 3-dimethylbutylidene) amino) acetate (2.5 g,12.56 mmol) was further added, reacted overnight at room temperature in the absence of light, saturated ammonium chloride solution was poured, filtered, the filtrate was extracted three times with methylene chloride, the filtrate was combined, the solvent was removed by distillation under reduced pressure, and the normal phase silica gel column was purified to 2.15g of the title compound in 34% yield. 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).

Step three: 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 (YG 155)

YG035 (3 g,5.7 mmol) was weighed into a 100mL reaction flask, dissolved with a mixed solvent of ethanol and tetrahydrofuran, 3g of Raney nickel was added, the temperature was raised to 55℃and 5mL of hydrazine hydrate was added dropwise, the reaction was stirred for 1h after the dropwise addition, cooled, filtered, the filtrate was distilled off under reduced pressure, and 875mg of the objective compound was obtained by purification on a normal phase silica gel column, the conversion was 29%. ¹ H NMR(500MHz,Methanol-d ₄ )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).

Step four: 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 (YG 156)

YG155 (280 mg,0.53 mmol) was weighed into a 50mL round bottom flask, dissolved in 10mL of dichloromethane, fmocCl (180 mg,0.69 mmol) and triethylamine (161 mg,1.59 mmol) were added, reacted overnight at room temperature, the solvent was removed under reduced pressure, 5mL of dichloromethane and 4mL of trifluoroacetic acid were added, reacted overnight at room temperature, the solvent was dried by spinning, extracted three times with dichloromethane, the organic phase was dried by spinning, and the product was purified by a normal phase column to give 404mg in 99% yield.

Step five: 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 (YL 090)

YG156 (114 mg,0.164 mol) was weighed and dissolved in THF, DIEA (169 mg,1.312 mmol) was added for reaction for 5min, diphenylphosphinoyl chloride (232 mg,0.984 mmol) was added for reaction for 30min, methyl 4-amino-3-methoxybenzoate (149 mg,0.82 mmol) was added for reaction overnight, the solvent was removed under reduced pressure, water was added, extraction 3 times with dichloromethane, the organic phase was dried by spinning and purified with normal phase silica gel column, 2mL of DMF solution containing 20% piperidine was added after the crude product was obtained, reaction was carried out for 30min at room temperature, extraction was carried out with ethyl acetate, drying of the organic phase was carried out by spinning and purification with normal phase column to obtain 40mg of the target compound with a yield of 38%. ¹ H NMR(500MHz,Methanol-d ₄ )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).

Step six: synthesis of 4- ((2R, 3S,4S, 5S) -4- (aminomethyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YH 018)

YL090 (20 mg,0.032 mmol) was weighed into a 50mL round bottom flask, lithium hydroxide monohydrate (7 mg,0.16 mmol) with THF/H ₂ O (v/v=2 mL/2 mL) was dissolved, stirred at room temperature overnight, the solvent was distilled off under reduced pressure, and 17mg of trifluoroacetate of the target compound was obtained by HPLC purification, with a yield of 74%. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.28 (d, j=8.4 hz, 1H), 7.65-7.58 (m, 2H), 7.46 (td, j=7.3, 1.7hz, 1H), 7.41 (t, j=8.6 hz, 1H), 7.35 (dd, j=8.8, 2.2hz, 1H), 7.30-7.14 (m, 3H), 4.52 (d, j=10.3 hz, 1H), 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, 3.3hz, 1H), 3.55-3.46 (m, 1H), 1.74-1.66 (m, 1H), 1.52 (dd, j=13.7, 11.4hz, 1H), 1.25 (s, ESS) and ESS-9 (s, C, ESS-C, M.3 Hz, ESS-MS calculated values ₃₁ H ₃₄ ³⁵ Cl ₂ F ₂ N ₃ O ₄ [M+H] ⁺ = 620.19, experimentally measured: 620.2.

end product 2:4- ((2R, 3S,4S, 5S) -4- ((4-bromobenzamide) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YM 011)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- ((4-bromobenzamide) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YM 011)

YL090 (50 mg,0.079 mmol) was weighed into a dried 50mL round bottom flask, dissolved in 10mL of dichloromethane, triethylamine (24 mg,0.236 mmol) and 4-bromobenzoyl chloride (26 mg,0.12 mmol) were added, stirred overnight at room temperature, and purified by spin-dry normal phase column to give crude YL141 mg, part YL141 (20 mg,0.024 mmol) was dissolved in THF/H ₂ O (v/v=2 mL/2 mL), lithium hydroxide monohydrate (5 mg,0.12 mmol) was added and stirred overnight at room temperature, the solvent was spin-dried, and HPLC purification afforded the trifluoroacetate salt of the target compound 9.5mg, 34% yield in two steps. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.24 (d, j=8.4 hz, 1H), 7.68-7.52 (m, 5H), 7.41 (H, j=8.7, 8.1hz, 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 theoretical calculated value C ₃₈ H ₃₇ ⁷⁹ Br ³⁵ Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 802.13, experimentally measured: 801.5.

end product 3:4- ((2R, 3S,4S, 5S) -4- (Acetaminophen-yl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YI 049)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- (Acetaminophen-yl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YI 049)

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) were taken, the procedure is as for final product 2 to give 29mg of trifluoroacetate as the target compound in 79% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.21 (d, j=8.4 hz, 1H), 7.62 (dd, j=8.4, 1.8hz, 1H), 7.58 (d, j=1.8 hz, 1H), 7.49 (dt, j=19.6, 7.0hz, 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 theoretical calculated value C ₃₃ H ₃₆ ³⁵ Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 662.20, experimentally measured: 662.2.

end product 4:4- ((2R, 3S,4S, 5S) -4- (propionylaminomethyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentyl pyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 102)

Step one: 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 (YL 102)

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) were taken, the procedure being followed for final product 2 to give 13mg of trifluoroacetate as the title compound in 55% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.24 (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 theoretical calculated C ₃₄ H ₃₈ ³⁵ Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 676.22, experimentally measured: 676.2.

final product 5:4- ((2R, 3S,4S, 5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -4- (cyclopropanecarboxamido ethyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 103)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -4- (cyclopropanecarboxamido ethyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 103)

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), steps see final product 2 to give 14.8mg of the trifluoroacetate salt of the title compound in 61% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.23 (d, j=8.4 hz, 1H), 7.63 (dd, j=8.4, 1.8hz, 1H), 7.60 (d, j=1.8 hz, 1H), 7.47 (dt, j=15.4, 7.3hz, 2H), 7.36-7.16 (m, 4H), 5.06-4.95 (m, 1H), 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 Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 688.22, experimentally measured: 688.2.

end product 6:4- ((2R, 3S,4S, 5S) -4- ((benzamide) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 104)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- ((benzamide) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 104)

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) were taken, the procedure being followed for final product 2 to give 13mg of trifluoroacetate as the title compound in 52% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.29 (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 theory calculated C ₃₈ H ₃₈ ³⁵ Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 724.22, experimentally measured: 724.2.

end product 7:4- ((2R, 3S,4S, 5S) -4- ((carboxyformylamino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YH 022)

Step one: 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 (YH 022)

YL090 (30 mg,0.047 mmol), oxalyl chloride monomethyl ester (8.7 mg,0.07 mmol), triethylamine (14 mg,0.14 mmol) and lithium hydroxide monohydrate (10 mg,0.24 mmol) were taken, the procedure is as for final product 2 to give the trifluoroacetate salt of the target compound 27.9mg, 74% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.25 (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, 2.9hz, 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, 10.1hz, 1H), 1.53 (d, j=14.4 hz, 1H), 1.02 (s, 9H) ESI-MS theory calculated C ₃₃ H ₃₄ ³⁵ Cl ₂ F ₂ N ₃ O ₇ [M+H] ⁺ = 692.17, experimentally measured: 692.1.

end product 8:4- ((2R, 3S,4S, 5S) -4- ((4-carboxybenzoylamino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YG 117)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- ((4-carboxybenzoylamino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YG 117)

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) were taken, and the procedure was as described for final product 2 to give 23.9mg of trifluoroacetate as the target compound in 58% yield. ¹ H NMR(400MHz,Methanol-d ₄ ) Delta 8.27 (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, 9) ESI-MS theory calculated C ₃₉ H ₃₈ ³⁵ Cl ₂ F ₂ N ₃ O ₇ [M+H] ⁺ = 768.20, experimentally measured: 768.2.

end product 9:4- ((2R, 3S,4S, 5S) -4- ((carboxymethanesulfonylamino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YI 001)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- ((carboxymethanesulfonylamino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YI 001)

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) were taken, step see final product 2 to give the trifluoro of the target compoundAcetate 10.4mg, yield 25%. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.25 (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 theoretical calculated C ₃₃ H ₃₆ ³⁵ Cl ₂ F ₂ N ₃ O ₈ S[M+H] ⁺ = 742.16, experimentally measured: 742.1.

end product 10:4- ((2R, 3S,4S, 5S) -4- ((3-carboxybenzenesulfonylamino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YI 004)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- ((3-carboxybenzenesulfonylamino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YI 004)

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) were taken, steps see final product 2 to give trifluoroacetate 6mg of the title compound in 14% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.44 (t, j=1.7 hz, 1H), 8.31-8.20 (m, 2H), 8.02 (dt, j=7.9, 1.3hz, 1H), 7.70 (t, j=7.8 hz, 1H), 7.61 (d, j=7.6 hz, 2H), 7.38 (t, j=7.4 hz, 1H), 7.27 (s, 1H), 7.19-7.06 (m, 2H), 7.03 (dd, j=13.0, 2.2hz, 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, 1.89), 1.69 (m, 1H), and 2.1 m-2 hz, 1H), 6.91 (s, 1H) ₃₈ H ₃₈ ³⁵ Cl ₂ F ₂ N ₃ O ₈ S[M+H] ⁺ = 804.17, experimentally measured: 804.2.

end product 11:4- ((2R, 3S,4S, 5S) -4- ((2-carboxybenzenesulfonylamino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YI 010)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- ((2-carboxybenzenesulfonylamino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YI 010)

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) were taken, steps see final product 2 to give the trifluoroacetate salt of the title compound 11.9mg in 40% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.22 (d, j=8.4 hz, 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, 2.2hz, 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, 1.9hz, 1H), 3.50-3.38 (m, 1H), 1.89-1.69 (m, 2H), 1.15 (s, 9H) and (ESI-9) ₃₈ H ₃₈ ³⁵ Cl ₂ F ₂ N ₃ O ₈ S[M+H] ⁺ = 804.17, experimentally measured: 804.2.

end product 12:4- ((2R, 3S,4S, 5S) -4- ((4-carboxybenzenesulfonylamino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YI 011)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- ((4-carboxybenzenesulfonylamino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YI 011)

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) were taken for steps see Final product 2 gave 9.5mg of trifluoroacetate salt of the target compound in 32% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) 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=7.4 hz, 1H), 7.30-7.19 (m, 1H), 7.18-7.10 (m, 2H), 7.06 (dd, j=13.0, 2.3hz, 1H), 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-C calculated theoretical value MS ₃₈ H ₃₈ ³⁵ Cl ₂ F ₂ N ₃ O ₈ S[M+H] ⁺ = 804.17, experimentally measured: 804.2.

end 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 (YH 020)

Step one: 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 (YH 020)

YL090 (20 mg,0.032 mmol) was weighed into a bottle, dissolved in 5mL acetonitrile, 4-fluoro-3 nitrobenzoic acid methyl ester (8 mg,0.038 mmol) and potassium carbonate (9 mg,0.064 mmol) were added, stirred overnight at room temperature, water was added, extracted three times with dichloromethane, the organic phase was dried by spinning and purified to give crude product, which was dissolved in THF/H ₂ The solution was mixed with O, lithium hydroxide monohydrate (7 mg,0.16 mmol) was added, stirred overnight at room temperature, and after spin-drying, HPLC purification afforded 14.7mg of the trifluoroacetate salt of the title compound in 51% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.65 (d, j=2.1 hz, 1H), 8.29 (d, j=8.4 hz, 1H), 8.11 (dd, j=9.0, 2.1hz, 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) ₃₈ H ₃₇ ³⁵ Cl ₂ F ₂ N ₄ O ₈ [M+H] ⁺ = 785.20, experimentally measured: 785.4.

end product 14:4- ((2R, 3S,4S, 5S) -4- (((carboxymethyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YH 017)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- (((carboxymethyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YH 017)

YL090 (20 mg,0.032 mmol) was weighed into a bottle, dissolved in 5mL acetonitrile, ethyl bromoacetate (6.3 mg,0.038 mmol) and potassium carbonate (9 mg,0.064 mmol) were added, stirred overnight at room temperature, water was added, extracted three times with dichloromethane, the organic phase was dried by spinning and purified to give crude product, the crude product was dissolved in THF/H ₂ The solution was mixed with O, lithium hydroxide monohydrate (7 mg,0.16 mmol) was added, stirred overnight at room temperature, and after spin-drying, HPLC purification afforded the trifluoroacetate salt of the title compound 16mg in 63% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.23 (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 theoretical calculated value C ₃₃ H ₃₆ ³⁵ Cl ₂ F ₂ N ₃ O ₆ [M+H] ⁺ = 678.19, experimentally measured: 678.2.

end product 15:4- ((2R, 3S,4S, 5S) -4- (((3-Nitrophenyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 139)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- (((3-nitrophenylmethyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 139)

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, the procedure being as described for end product 14 to give the trifluoroacetate salt of the title compound 17.4mg in 34% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.36 (dd, j=5.9, 2.7hz, 2H), 8.26 (d, j=8.4 hz, 1H), 7.83 (d, j=7.7 hz, 1H), 7.75 (t, j=8.2 hz, 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, 3H), 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 (d, j=10.0 hz, 1H), 4.33 (d, 3.96 hz, 1H), 3.92-3.83 (s, 1H), and ESS.24.9 hz (2H) ₃₈ H ₃₉ ³⁵ Cl ₂ F ₂ N ₄ O ₆ [M+H] ⁺ = 755.22, experimentally measured: 755.6.

end 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-carboxamide) -3-methoxybenzoic acid (YM 001)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YM 001)

YL090 (30 mg,0.047 mmol) was weighed into a reaction flask, dissolved with 10mL of 1, 2-dichloroethane, added with sodium borohydride acetate (30 mg,0.14 mmol), p-bromobenzaldehyde (13 mg,0.07 mmol) and 0.1mL of acetic acid, reacted overnight at room temperature, added with saturated sodium bicarbonate solution, extracted three times with dichloromethane, the organic phase was dried by spin-drying and then purified by normal phase column to give crude FE098, the crude was dissolved in THF/H ₂ O mixed solution, adding lithium hydroxide monohydrateThe compound (10 mg,0.24 mmol) was stirred overnight at room temperature and HPLC purified after spin-drying to give 19.7mg of the trifluoroacetate as the title compound in 46% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.26 (d, j=8.4 hz, 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=10.1 hz, 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, 2.8hz, 1H), 3.36-3.32 (m, 1H), 1.71 (d, j=13.4 hz, 1H), 1.51 (dd, j=11.4 hz, 1H), 4.20 (d, j=2.3 hz, 1H), 3.96 (d, j=10.1 hz, 1H), 3.36-3.32 (2H) ₃₈ H ₃₉ ⁷⁹ Br ³⁵ Cl ₂ F ₂ N ₃ O ₄ [M+H] ⁺ = 788.15, experimentally measured: 787.9.

end 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-carboxamide) -3-methoxybenzoic acid (YL 094)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YL 094)

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) were taken, and the procedure was as described for final product 14 to give 17mg of trifluoroacetate as the target compound in 42% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.27 (d, j=8.4 hz, 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=13.0 hz, 1H), 4.44-4.30 (m, 2H), 4.26 (d, j=11.3 hz, 1H), 3.98 (s, 3H), 3.81 (ddd, j=13.8, 9.5,3.2hz, 2H), 3.42 (d, j=13.9 hz, 1.74 hz), 7.16-7.08 (m, 2H), 4.44-4.30 (m, 1H), 4.26 (d, j=13.0 hz, 1H), 4.26 (d, 1.5hz, 1H) ₃₉ H ₄₀ ³⁵ Cl ₂ F ₂ N ₃ O ₆ [M+H] ⁺ = 754.23, experimentally measured: 754.1.

end 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-carboxamide) -3-methoxybenzoic acid (YH 015)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YH 015)

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) were taken, and the procedure was as described for final product 14 to give 26mg of trifluoroacetate as the target compound in 64% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) 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=7.2 hz, 1H), 7.24 (d, j=8.5 hz, 1H), 7.19-6.92 (m, 4H), 4.47 (d, j=10.1 hz, 1H), 4.36 (d, j=11.1 hz, 1H), 4.29 (s, 2H), 3.99-3.82 (m, 4H), 3.75 (d, j=14.2 hz, 1H), 3.36 (d, j=14.4 hz, 1H), 1.74 (d, j=13.6 hz, 1H), 1.65 (t, j=12.5 hz, 1H), 1.23 (s, 9H) —esi-MS calculated theoretical escs ₃₉ H ₄₀ ³⁵ Cl ₂ F ₂ N ₃ O ₆ [M+H] ⁺ = 754.23, experimentally measured: 754.1.

end 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-carboxamide) -3-methoxybenzoic acid (YH 014)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YH 014)

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) were taken, and the procedure was as described for final product 14 to give trifluoroacetate 22.8mg of the title compound in 56% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.24 (d, j=8.4 hz, 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=10.2 hz, 1H), 4.38-4.24 (m, 3H), 3.93 (s, 3H), 3.83 (d, j=10.1 hz, 1H), 3.72 (dd, j=14.2, 2.7hz, 1H), 3.34 (d, j=14.4 hz, 1H), 1.74 (d, j=13.5 hz, 1H), 1.61 (dd, j=10.2 hz, 1H), 4.38-4.24 (m, 3H), 3.93 (s, 3H), 3.83 (d, 3.7.7 hz, 1H) ₃₉ H ₄₀ ³⁵ Cl ₂ F ₂ N ₃ O ₆ [M+H] ⁺ = 754.23, experimentally measured: 754.1.

end product 20:4- ((2R, 3S,4S, 5S) -4- (((benzyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 115)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- (((benzyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 115)

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), steps see final product 14 to give trifluoroacetate 16.9mg of the title compound in 44% yield. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.27(d,J＝8.4Hz,1H),7.68–7.55(m,2H),7.54–7.37(m,6H),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＝10.0Hz,1H),3.69(dd,J＝14.2,2.6Hz,1H),3.38(d,J＝14.3Hz,1H),1.72(d,J＝13.3Hz,1H),1.51(dd,J＝13.6,11.5Hz,1H) Theoretical calculation C of ESI-MS of 1.24 (s, 9H) ₃₈ H ₄₀ ³⁵ Cl ₂ F ₂ N ₃ O ₄ [M+H] ⁺ = 710.24, experimentally measured: 710.1.

end product 21:4- ((2R, 3S,4S, 5S) -4- (((2-picolyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 091)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- (((2-picolyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 091)

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) were taken, the procedure is as for final product 14 to give the trifluoroacetate salt of the target compound 22mg in 57% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.66-8.59 (m, 1H), 8.27 (d, j=8.3 hz, 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=10.1 hz, 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, 2.5hz, 1H), 3.67 (d, j=14.1 hz, 1H), 1.83 (d, j=12.8 hz, 1H), 1.76 (dd, j=10.6 hz, 1H), 4.06 (d, j=10.6 hz, 1H), and 3.81 (s, 1H) ₃₇ H ₃₉ ³⁵ Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 711.23, experimentally measured: 711.3.

end product 22:4- ((2R, 3S,4S, 5S) -4- (((3-picolyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 092)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- (((3-picolyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 092)

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) were taken, the procedure is as for final product 14 to give 12mg of trifluoroacetate as the target compound in 31% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.73 (t, j=4.0 hz, 2H), 8.26 (dd, j=10.9, 8.4hz, 2H), 7.80 (dd, j=8.1, 5.3hz, 1H), 7.62 (dd, j=6.9, 2.0hz, 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 C ₃₇ H ₃₉ ³⁵ Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 711.23, experimentally measured: 711.3.

end product 23:4- ((2R, 3S,4S, 5S) -4- (((4-picolyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 093)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- (((4-picolyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 093)

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) were taken, the procedure is as for final product 14 to give trifluoroacetate 16mg of the title compound in 41% yield. ¹ H NMR(500MHz,Methanol-d ₄ )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=13.4 hz, 1H), 1.91 (dd, j=15.0, 9.9hz, 1H), 1.73 (d, j=14.8 hz, 1H), 1.06 (s, 9H). ESI-MS theoretical calculated C ₃₇ H ₃₉ ³⁵ Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 711.23, experimentally measured: 711.2.

end product 24:4- ((2R, 3S,4S, 5S) -4- (((2-hydroxyphenylmethyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 095)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- (((2-hydroxyphenylmethyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 095)

YL090 (30 mg,0.047 mmol), 2-hydroxybenzaldehyde (12 mg,0.094 mmol), sodium borohydride acetate (30 mg,0.14 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol) were taken, and the procedure was as described for end product 16 to give 17.6mg of trifluoroacetate as the target compound in 45% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.27 (d, j=8.4 hz, 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=10.1 hz, 1H), 4.35 (d, j=13.1 hz, 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, 11.5hz, 1H), 1.25 (ESI, 9H) ₃₈ H ₄₀ ³⁵ Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 726.23, experimentally measured: 726.2.

end product 25:4- ((2R, 3S,4S, 5S) -4- (((3-hydroxyphenylmethyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 096)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- (((3-hydroxyphenylmethyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 096)

YL090 (30 mg,0.047 mmol), 3-hydroxybenzaldehyde (12 mg,0.094 mmol), sodium borohydride acetate (30 mg,0.14 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol) were taken, and the procedure was as for final product 16 to give 17.4mg of trifluoroacetate as the target compound in 44% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.27 (d, j=8.3 hz, 1H), 7.66-7.54 (m, 2H), 7.43 (t, j=7.5 hz, 1H), 7.27 (t, j=7.8 hz, 1H), 7.23-7.04 (m, 4H), 6.96-6.76 (m, 4H), 4.38 (d, j=10.0 hz, 1H), 4.30 (d, j=11.4 hz, 1H), 4.19-4.05 (m, 2H), 3.96 (s, 3H), 3.81 (d, j=10.1 hz, 1H), 3.68 (dd, j=14.3, 2.4hz, 1H), 3.41 (t, j=17.2 hz, 1H), 1.71 (d, j=13.5 hz, 1H), 1.56-1.38 (m, 1H), 1.24 (ESI, 9 s, 3.96 (s, 3H) C-MS theoretical values ₃₈ H ₄₀ ³⁵ Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 726.23, experimentally measured: 726.1.

end product 26:4- ((2R, 3S,4S, 5S) -4- (((4-hydroxyphenylmethyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 097)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- (((4-hydroxyphenylmethyl) amino) methyl) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 097)

YL090 (30 mg,0.047 mmol), 4-hydroxybenzaldehyde (12 mg,0.094 mmol), sodium borohydride acetate (30 mg,0.14 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol), steps see final product 16 to give 21mg of trifluoroacetate as the target compound in 53% yield. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.27(d,J＝8.5Hz,1H),7.66–7.54(m, 2H), 7.49-7.41 (m, 1H), 7.29-6.99 (m, 6H), 6.97-6.79 (m, 3H), 4.40 (d, j=10.1 hz, 1H), 4.29 (d, j=11.4 hz, 1H), 4.14 (d, j=13.3 hz, 1H), 4.09 (d, j=13.2 hz, 1H), 3.97 (s, 3H), 3.77 (d, j=10.1 hz, 1H), 3.64 (dd, j=14.1, 2.5hz, 1H), 3.38 (d, j=14.3 hz, 1H), 1.70 (d, j=13.4 hz, 1H), 1.46 (dd, j=13.5, 11.6hz, 1H), 1.24 (s, 9H) ESI-MS calculated on theory C ₃₈ H ₄₀ ³⁵ Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 726.23, experimentally measured: 726.3.

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-carboxamide) -3-methoxybenzoic acid (YL 099)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YL 099)

YL090 (30 mg,0.047 mmol), 1-methyl-1H-pyrazole-4-carbaldehyde (10 mg,0.094 mmol), sodium borohydride acetate (30 mg,0.14 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol), steps see final product 16 to give trifluoroacetate 22.8mg of the title compound in 59% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.27 (d, j=8.4 hz, 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=10.1 hz, 1H), 4.30 (d, j=11.4 hz, 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, 2.8hz, 1H), 3.41 (d, j=14.2 hz, 1H), 1.71 (d, j=13.4 hz, 1H), 4.14.82 (d, j=2.3 hz, 1H), 1.6hz, 1H), and 16.6 hz (s, 1H) ₃₆ H ₄₀ ³⁵ Cl ₂ F ₂ N ₅ O ₄ [M+H] ⁺ = 714.24, experimentally measured: 714.3.

end 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-carboxamide) -3-methoxybenzoic acid (YL 100)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YL 100)

YL090 (30 mg,0.047 mmol), 1H-imidazole-4-carbaldehyde (9 mg,0.094 mmol), sodium borohydride acetate (30 mg,0.14 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol), steps see final product 16 to give 17.6mg of trifluoroacetate of the title compound in 46% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) 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, 9.9hz, 1H), 1.64 (d, j=14.4 hz, 1H), 1.07 (s, 9H) ESI-MS theoretical calculated value C ₃₅ H ₃₈ ³⁵ Cl ₂ F ₂ N ₅ O ₄ [M+H] ⁺ = 700.23, experimentally measured: 700.3.

end product 29:4- ((2R, 3S,4S, 5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -4- ((ethylamino) methyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 106)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -4- ((ethylamino) methyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 106)

YL090 (20 mg,0.03 mmol), acetaldehyde (13 mg,0.3 mmol), sodium borohydride acetate (64 mg,0.3 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (6 mg,0.15 mmol), steps see end product 16,13mg of trifluoroacetate of the target compound was obtained in 57% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.29 (d, j=8.4 hz, 1H), 7.69-7.57 (m, 2H), 7.47 (td, j=7.4, 1.7hz, 1H), 7.41 (t, j=8.6 hz, 1H), 7.36 (dd, j=8.7, 2.2hz, 1H), 7.32-7.16 (m, 3H), 4.44 (d, j=10.3 hz, 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, 11.5hz, 1H), 1.32 (t, j=7.3 hz, 1H), 3.99 (s, 3H), 3.93-3.78 (m, 2H), 3.21.21 (3 hz, 1H) ₃₃ H ₃₈ ³⁵ Cl ₂ F ₂ N ₃ O ₄ [M+H] ⁺ = 648.22, experimentally measured: 648.1.

end product 30:4- ((2R, 3S,4S, 5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -4- ((propylamino) methyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 121)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -4- ((propylamino) methyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YL 121)

YL090 (20 mg,0.03 mmol), propionaldehyde (9 mg,0.15 mmol), sodium borohydride acetate (32 mg,0.15 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (6 mg,0.15 mmol), steps see end product 16 to give trifluoroacetate 12.4mg of the title compound in 53% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.29 (d, j=8.4 hz, 1H), 7.68-7.56 (m, 2H), 7.51-7.44 (m, 1H), 7.40 (t, j=8.6 hz, 1H), 7.35 (dd, j=8.7, 2.1hz, 1H), 7.32-7.15 (m, 3H), 4.44 (d, j=10.2 hz, 1H), 4.31 (d, j=11.4 hz, 1H), 3.98 (s, 3H), 3.93-3.82 (m, 2H), 3.49 (t, j=14.3 hz, 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=7.2 hz, 1H), 3.93-3.82 (m, 2H), 3.49 (t, 1H), 3.08 (3H) ₃₄ H ₄₀ ³⁵ Cl ₂ F ₂ N ₃ O ₄ [M+H] ⁺ = 662.24, experimentally measured: 662.1.

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-carboxamide) -3-methoxybenzoic acid (YL 107)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YL 107)

YL090 (20 mg,0.03 mmol), tetrahydro-4H-pyran-4-one (4.4 mg,0.044 mmol), sodium borohydride acetate (19 mg,0.09 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (6 mg,0.15 mmol), steps see final product 16 to give 17.8mg of trifluoroacetate of the title compound in 72% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.29 (d, j=8.4 hz, 1H), 7.67-7.57 (m, 2H), 7.52-7.44 (m, 1H), 7.43-7.15 (m, 5H), 4.49 (d, j=10.2 hz, 1H), 4.34 (d, j=11.3 hz, 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-theoretical calculation of C ₃₆ H ₄₂ ³⁵ Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 704.25, experimentally measured: 704.2.

end 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-carboxamide) -3-methoxybenzoic acid (YL 108)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YL 108)

YL090 (20 mg,0.03 mmol), 1-methylpiperidin-4-one @5mg,0.045 mmol), sodium borohydride acetate (19 mg,0.09 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (6 mg,0.15 mmol), see final product 16, to give the desired compound as trifluoroacetate 17.6mg in 71% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.25 (d, j=8.4 hz, 1H), 7.67-7.51 (m, 3H), 7.47 (t, j=7.4 hz, 1H), 7.36-7.19 (m, 4H), 5.11-4.99 (m, 1H), 4.51 (d, j=9.9 hz, 1H), 4.41 (d, j=10.2 hz, 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=15.2 hz, 2H), 1.96-1.75 (m, 3H), 1.70 (d, j=14.3 hz, 1H), 1.09 (s, 9H) ESI-MS theoretical calculated value C ₃₇ H ₄₅ ³⁵ Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 717.28, experimentally measured: 717.3.

end 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-carboxamide) -3-methoxybenzoic acid (YL 109)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YL 109)

YL090 (25 mg,0.039 mmol) was weighed into a reaction flask, tert-butyl 4-formylpiperidine-1-carboxylate (13 mg,0.059 mmol), sodium borohydride acetate (25 mg,0.12 mmol) were added, dissolved with 1, 2-dichloroethane, 0.1mL acetic acid was added, reacted overnight at room temperature, dried by spin-drying and then dissolved with 5mL dichloromethane, 3mL trifluoroacetic acid was added, stirred at room temperature for 6h, dried by spin-drying and then water was added, extracted with dichloromethane, dried by spin-drying and then dissolved with tetrahydrofuran/water mixed solvent, lithium hydroxide monohydrate (8 mg,0.2 mmol) was added, dried overnight at room temperature and dried by spin-drying and then purified by HPLC to give 17.5mg of trifluoroacetate of the target compound in 54% yield. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.28(d,J＝8.4Hz,1H),7.66–7.58(m,2H),7.51–7.44(m,1H),7.42–7.35(m,2H),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=10.8 hz, 1H), 4.02 (d, j=10.2 hz, 1H), 3.96 (s, 3H), 3.92 (d, j=14.5 hz, 1H), 3.49-3.37 (m, 3H), 3.06-2.90 (m, 4H), 2.15-1.92 (m, 3H), 1.77 (d, j=13.5 hz, 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 Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 717.28, experimentally measured: 717.3.

end 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-carboxamide) -3-methoxybenzoic acid (YL 110)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YL 110)

YL090 (25 mg,0.039 mmol), tert-butyl 3-formylpiperidine-1-carboxylate (13 mg,0.059 mmol), sodium borohydride acetate (25 mg,0.12 mmol), 0.1mL acetic acid, 3mL trifluoroacetic acid and lithium hydroxide monohydrate (8 mg,0.2 mmol), the reaction steps were taken, see final product 33, to give 10.9mg of trifluoroacetate as the title compound in 34% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.27 (d, j=8.2 hz, 1H), 7.62 (d, j=8.2 hz, 2H), 7.57-7.14 (m, 6H), 4.72 (dd, j=10.2, 5.5hz, 1H), 4.40 (d, j=10.4 hz, 1H), 4.13 (d, j=9.5 hz, 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), and the theoretical ESI-MS calculated the C values ₃₇ H ₄₅ ³⁵ Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 717.28, experimentally measured: 717.6.

End 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-carboxamide) -3-methoxybenzoic acid (YL 111-1)

End 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-carboxamide) -3-methoxybenzoic acid (YL 111-2)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YL 111-1) 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-carboxamide) -3-methoxybenzoic acid (YL 111-2)

YL090 (25 mg,0.039 mmol), tert-butyl 2-formylpiperidine-1-carboxylate (13 mg,0.059 mmol), sodium borohydride acetate (25 mg,0.12 mmol), 0.1mL acetic acid, 3mL trifluoroacetic acid and lithium hydroxide monohydrate (8 mg,0.2 mmol), the reaction steps see final product 33, to give the trifluoroacetate YL 111-1.12 mg and YL 111-2.4 mg of the target compound, in 51% yield, the chirality on YL111-1 and YL111-2 piperidine being relative concepts, YL111-1 being designated as S configuration for convenience of expression, and correspondingly YL111-2 being designated as R configuration. YL111-1 ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.23 (d, j=8.4 hz, 1H), 7.68-7.55 (m, 3H), 7.48 (t, j=7.5 hz, 1H), 7.33-7.18 (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), 3.19 (d, j=13.3 hz, 1H), 3.09 (d, j=13.3 hz, 1H), 2.97 (td, j=12.6, 2.9hz, 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 (j=12.3 hz, 1H), and ESS 1.9 hz (s, 1H) ₃₇ H ₄₅ ³⁵ Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 717.28, experimentally measured: 718.0; YL111-2 ¹ HNMR(500MHz,Methanol-d ₄ )δ8.30(d,J＝8.4Hz,1H),7.71–7.52(m,3H),7.49(t,J＝7.4Hz,1H),7.35–7.19(m,4H),4.47(s,1H),3.91(s,3H),3.39(d, j=13.6 hz, 1H), 3.25 (d, j=12.9 hz, 1H), 3.18-3.01 (m, 2H), 2.96 (t, j=12.6 hz, 1H), 2.82 (dd, j=12.9, 4.8hz, 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, 11.3hz, 1H), 1.39-1.24 (m, 1H), 1.09 (s, 9H) ESI-MS theoretical calculated value C ₃₇ H ₄₅ ³⁵ Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 717.28, experimentally measured: 718.1.

end 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-carboxamide) -3-methoxybenzoic acid (YL 112-1)

End 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-carboxamide) -3-methoxybenzoic acid (YL 112-2)

YL090 (25 mg,0.039 mmol), tert-butyl 3-oxopyrrolidine-1-carboxylate (11 mg,0.059 mmol), sodium borohydride acetate (25 mg,0.12 mmol), 0.1mL acetic acid, 3mL trifluoroacetic acid and lithium hydroxide monohydrate (8 mg,0.2 mmol), the reaction steps see end product 33, to give the trifluoroacetate YL 112-1.6 mg and YL112-210.9mg of the target compound in 69% yield, the chirality on YL112-1 and YL1122-2 pyrrole being relative concepts, YL112-1 being designated as R configuration for convenience of expression, and correspondingly YL111-2 being designated as S configuration. YL112-1 ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.25 (d, j=8.4 hz, 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, 7.0hz, 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 calculated value C ₃₅ H ₄₁ ³⁵ Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 689.25, experimentally measured: 689.2; YL112-2 ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.26 (d, j=8.4 hz, 1H), 7.64 (dd, j=8.4, 1.8hz, 2H), 7.60 (d, j=1.8 hz, 1H), 7.47 (t, j=7.4 hz, 1H), 7.33-7.18 (m, 4H), 5.32-5.08 (m, 1H), 4.70-4.38 (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-theoretical calculation of MS C ₃₅ H ₄₁ ³⁵ Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 689.25, experimentally measured: 689.0.

end 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-carboxamide) -3-methoxybenzoic acid (YL 113)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YL 113)

YL090 (23 mg,0.036 mmol), 4-formyl-tetrahydro-2H-pyran (6 mg,0.054 mmol), sodium borohydride acetate (23 mg,0.11 mmol), 0.1mL acetic acid, 3mL trifluoroacetic acid and lithium hydroxide monohydrate (8 mg,0.2 mmol), the reaction steps were taken, see final product 33, 14mg of trifluoroacetate of the title compound was obtained in 47% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.29 (d, j=8.4 hz, 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=10.1 hz, 1H), 4.33 (d, j=11.3 hz, 1H), 4.02-3.92 (m, 5H), 3.92-3.84 (m, 2H), 3.55 (t, j=13.3 hz, 1H), 3.42 (tdd, j=11.8, 7.2,2.2hz, 2H), 3.00 (dd, j=6.8, 2.8hz, 2.2.8 hz), 2.02 (ttd, j=11.0, 7.1,3.3hz, 1H), 1.82 (d, j=13.69, 1 hz), 1.4.3.92-3.92 (m, 5H), 3.42 (d, 1.7 hz, 1H), 3.42 (t, 1.4hz, 1H), 3.42 (d, 1.7.2 hz, 2H) ₃₇ H ₄₄ ³⁵ Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 718.26, experimentally measured: 718.0.

end product 40:3- ((((2S, 3S,4S, 5R) -4- (3-chloro-2-fluorophenyl) -3- (4-chloro-2-fluorophenyl) -5- (((1 r, 4R)) -4-hydroxycyclohexyl) carbamoyl) -2-neopentylpyrrolidin-3-yl) methyl) amino) methyl) benzoic acid (YH 107)

Step one: 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 (YH 101)

YG155 (460 mg,0.87 mmol) was weighed into a reaction flask, dissolved with a proper amount of acetonitrile, added with methyl 3-bromomethylbenzoate (240 mg,1.05 mmol) and potassium carbonate (241 mg,1.75 mmol), stirred at room temperature overnight, extracted with dichloromethane, the organic phase was dried by spinning and then dissolved with 5mL of dichloromethane, added with 3mL of trifluoroacetic acid, stirred at room temperature overnight, dried with solvent and purified by a normal phase column to give 359mg of trifluoroacetate of the target compound in 66% yield. ¹ H NMR(500MHz,Methanol-d ₄ )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＝8.7,2.2Hz,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)。

Step two: synthesis of 3- (((((2S, 3S,4S, 5R) -4- (3-chloro-2-fluorophenyl) -3- (4-chloro-2-fluorophenyl) -5- (((1 r, 4R)) -4-hydroxycyclohexyl) carbamoyl) -2-neopentylpyrrolidin-3-yl) methyl) amino) methyl) benzoic acid (YH 107)

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 min, 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 stirred at room temperature overnight, water was added, extracted with ethyl acetate, the organic phase was dried by spinning and purified with normal phase column to give crude carboxylate precursor, the crude product was dissolved in tetrahydrofuran/water mixture and lithium hydroxide monohydrate (21 m g,0.5 mmol), stirring overnight at room temperature, spin-drying the solvent, and purifying by HPLC to obtain 18.8mg of the trifluoroacetate of the target compound in 23% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.06 (dd, j=4.6, 2.6hz, 2H), 7.62 (d, j=7.6 hz, 1H), 7.54 (t, j=7.9 hz, 1H), 7.44 (t, j=7.2 hz, 1H), 7.35 (t, j=7.1 hz, 1H), 7.30-7.15 (m, 3H), 7.01 (t, j=8.7 hz, 1H), 4.67-4.51 (m, 2H), 4.27 (d, j=9.2 hz, 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=14.5 hz, 1H), 2.27 (d, j=9.2 hz, 1H), 4.21-4.05 (m, 2H), 3.59 (j=11.3, 3.9hz, 1H), 3.38-3.32 (m, 1H), 3.24 (d, 1.10.10, 1H), 1.7-1 d (d, 1.7 hz, 1H), 1.7-1H (d, 1.7 hz, 1H) ₃₇ H ₄₄ ³⁵ Cl ₂ F ₂ N ₃ O ₄ [M+H] ⁺ = 702.27, experimentally measured: 702.2.

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 (YH 120)

Step one: 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 (YH 120)

YH101 (62 mg,0.1 mmol) was weighed into a reaction bottle, dissolved with 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 dried by spinning and then purified with a normal phase column to give crude carboxylate precursor, the crude product was dissolved in tetrahydrofuran/water mixture, lithium hydroxide monohydrate (21 mg,0.5 mmol) was added, stirred at room temperature overnight, the solvent was dried by spinning, and HPLC purification was performed to give 22.9mg of trifluoroacetate of the target compound in 28% yield. ¹ H NMR(500MHz,Methanol-d ₄ )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, 2.0hz, 1H), 3.35 (d, j=14.3 hz, 1H), 1.83 (dd, j=14.5, 10.6hz, 1H), 1.73-1.65 (m, 1H), 1.10 (s, 9H) ESI-MS theory, calculated value C ₃₆ H ₃₇ ³⁵ Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 697.22, experimentally measured: 697.1.

end 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 (YH 122)

Step one: 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 (YH 122)

YH101 (62 mg,0.1 mmol), DIEA (77 mg,0.6 mmol), diphenylphosphinyl chloride (71 mg,0.3 mmol), methylamine hydrochloride (27.2 mg,0.4 mmol) and lithium hydroxide monohydrate (21 mg,0.5 mmol) were taken, and the reaction steps were followed with reference to final product 41 to give trifluoroacetate 13.7mg of the title compound in 19% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.10-8.04 (m, 2H), 7.62 (dt, j=7.6, 1.6hz, 1H), 7.55 (t, j=7.6 hz, 1H), 7.49-7.42 (m, 1H), 7.34 (t, j=7.0 hz, 1H), 7.29-7.18 (m, 3H), 7.00 (t, j=8.8 hz, 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, 10.1hz, 1H), 1.67-1.53 (m, 1H), 1.04 (s, ESS, 9.6hz, 1H), 4.21-4.02 (m, 2H), 3.42 (d, j=14.1 hz, 1H) ₃₂ H ₃₆ ³⁵ Cl ₂ F ₂ N ₃ O ₃ [M+H] ⁺ = 618.21, experimentally measured: 618.1.

end 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 (YH 128)

Step one: 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 (YH 128)

YH101 (62 mg,0.1 mmol), DIEA (65 mg,0.5 mmol), diphenylphosphinyl chloride (71 mg,0.3 mmol), 2-aminoethanol (24.4 mg,0.4 mmol) and lithium hydroxide monohydrate (21 mg,0.5 mmol) were taken and the reaction steps were followed with reference to final product 41 to give 29.9mg of trifluoroacetate as the target compound in 39% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.09 (dt, j=7.7, 1.4hz, 1H), 8.06 (d, j=1.8 hz, 1H), 7.64 (dt, j=7.7, 1.5hz, 1H), 7.55 (t, j=7.7 hz, 1H), 7.45 (td, j=7.6, 7.2,1.6hz, 1H), 7.31-7.14 (m, 4H), 6.97 (t, j=8.6 hz, 1H), 4.74 (d, j=10.6 hz, 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 (d, j=13.8, 6.2, 4.7.89 hz, 1H), 4.9 (d, j=10.6 hz, 1H), 4.68 (d, j=9.9 hz, 1H), 4.9.9 hz, 1H), 4.29.12 (m, 1H), 3.36-3.58 (m, 1H) ₃₃ H ₃₈ ³⁵ Cl ₂ F ₂ N ₃ O ₄ [M+H] ⁺ = 648.22, experimentally measured: 648.2.

end product 44:3- (((((2S, 3S,4S, 5R) -4- (3-chloro-2-fluorophenyl) -3- (4-chloro-2-fluorophenyl) -5- (3-pyridinecarbamoyl) -2-neopentylpyrrolidin-3-yl) methyl) amino) methyl) benzoic acid (YH 129)

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Step one: synthesis of 3- (((((2S, 3S,4S, 5R) -4- (3-chloro-2-fluorophenyl) -3- (4-chloro-2-fluorophenyl) -5- (3-pyridinecarbamoyl) -2-neopentylpyrrolidin-3-yl) methyl) amino) methyl) benzoic acid (YH 129)

YH101 (62 mg,0.1 mmol), DIEA (65 mg,0.5 mmol), diphenylphosphinyl chloride (71 mg,0.3 mmol), 3-aminopyridine (37.6 mg,0.4 mmol) andlithium hydroxide monohydrate (21 mg,0.5 mmol), the reaction step was seen as final product 41 to give 24.2mg of the trifluoroacetate salt of the title compound in 30% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 9.28 (d, j=2.4 hz, 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=7.7 hz, 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=14.6, 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), 4.34-4.20 (m, 3H), 3.72 (dd, 2.14, 2.7 hz, 1H), 1.34-7.34 (1H), 1.14.7 hz, 1H) ₃₆ H ₃₇ ³⁵ Cl ₂ F ₂ N ₄ O ₃ [M+H] ⁺ = 681.22, experimentally measured: 681.2.

end 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 (FE 028)

Step one: 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 (FE 028)

YH101 (62 mg,0.1 mmol), DIEA (65 mg,0.5 mmol), diphenylphosphinyl chloride (71 mg,0.3 mmol), methyl 4-aminobenzoate (60 mg,0.4 mmol) and lithium hydroxide monohydrate (21 mg,0.5 mmol) were taken, and the reaction steps were followed by reference to final product 41 to give trifluoroacetate 11.8mg of the target compound in 14% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.15-8.07 (m, 2H), 7.97 (d, j=8.6 hz, 2H), 7.61 (tt, j=15.3, 7.6hz, 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 C ₃₈ H ₃₈ ³⁵ Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 724.22, experimentally measured: 724.2.

end 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 (FE 037)

Step one: 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 (FE 037)

YH101 (62 mg,0.1 mmol), DIEA (65 mg,0.5 mmol), diphenylphosphinyl chloride (71 mg,0.3 mmol), methyl 3-aminobenzoate (60 mg,0.4 mmol) and lithium hydroxide monohydrate (21 mg,0.5 mmol) were taken, and the reaction steps were followed by reference to final product 41 to give 9.1mg of trifluoroacetate as the objective compound in 11% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.16 (d, j=1.9 hz, 1H), 8.09 (dt, j=3.9, 1.8hz, 2H), 7.81-7.73 (m, 2H), 7.64 (d, j=7.6 hz, 1H), 7.56 (t, j=7.9 hz, 1H), 7.42 (td, j=7.8, 4.0hz, 2H), 7.31 (t, j=7.1 hz, 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.hz, 1H), 3.31 (t, j=8.7 hz, 1H), 7.12 (t, j=8.7 hz, 1H), 4.66 (d, 1H), 4.56 (t, j=9.9 hz, 1H) ₃₈ H ₃₈ ³⁵ Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 724.22, experimentally measured: 724.2.

end product 47:3- (((((2S, 3S,4S, 5R) -4- (3-chloro-2-fluorophenyl) -3- (4-chloro-2-fluorophenyl) -5- (4-carboxyphenylmethylcarbamoyl) -2-neopentylpyrrolidin-3-yl) methyl) amino) methyl) benzoic acid (FE 040)

Step one: synthesis of 3- (((((2S, 3S,4S, 5R) -4- (3-chloro-2-fluorophenyl) -3- (4-chloro-2-fluorophenyl) -5- (4-carboxyphenylmethylcarbamoyl) -2-neopentylpyrrolidin-3-yl) methyl) amino) methyl) benzoic acid (FE 040)

YH101 (62 mg,0.1 mmol), DIEA (65 mg,0.5 mmol), diphenylphosphinyl chloride (71 mg,0.3 mmol), methyl 4-aminomethylbenzoate hydrochloride (80 mg,0.4 mmol) and lithium hydroxide monohydrate (21 mg,0.5 mmol) were taken, and the reaction steps were followed by final product 41 to give 6.3mg of trifluoroacetate as the objective compound in 7% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.14-8.06 (m, 2H), 7.86 (d, j=8.0 hz, 2H), 7.65 (d, j=7.6 hz, 1H), 7.56 (t, j=7.7 hz, 1H), 7.48 (t, j=7.4 hz, 1H), 7.36-7.19 (m, 4H), 7.10 (d, j=8.0 hz, 2H), 7.00 (d, j=9.0 hz, 1H), 4.80 (d, j=10.5 hz, 1H), 4.76 (d, j=10.1 hz, 1H), 4.54 (d, j=15.4 hz, 1H), 4.29-4.18 (m, 4H), 3.60 (d, j=14.3 hz, 1H), 3.37 (d, j=14.3 hz, 1H), 1.90 (dd, j=14.7, 10.5hz, 1H), 4.76 (d, 1hz, 1H), and ESS 1.70 (d, 1hz, 1H) ₃₉ H ₄₀ ³⁵ Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 738.23, experimentally measured: 738.2.

end product 48:3- (((((2S, 3S,4S, 5R) -4- (3-chloro-2-fluorophenyl) -3- (4-chloro-2-fluorophenyl) -5- (4-carboxylic acid methyl phenylcarbamoyl) -2-neopentylpyrrolidin-3-yl) methyl) amino) methyl) benzoic acid (FE 041)

Step one: synthesis of 3- (((((2S, 3S,4S, 5R) -4- (3-chloro-2-fluorophenyl) -3- (4-chloro-2-fluorophenyl) -5- (4-carboxylic acid methylbenzoyl) -2-neopentylpyrrolidin-3-yl) methyl) amino) methyl) benzoic acid (FE 041)

YH101 (62 mg,0.1 mmol), DIEA (65 mg,0.5 mmol), diphenylphosphinyl chloride (71 mg,0.3 mmol), methyl 4-aminophenylacetate hydrochloride (80 mg,0.4 mmol) and lithium hydroxide monohydrate (21 mg,0.5 mmol) were taken, and the reaction steps were followed by reference to the final product 41 to give 4.7mg of trifluoroacetate as the objective compound in 6% yield. ¹ H NMR(500MHz,Methanol-d ₄ )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, 10.0hz, 2H), 4.32-4.20 (m, 3H), 3.63 (d, j=14.1 hz, 1H), 3.55 (s, 2H), 3.37 (d, j=14.4 hz, 1H), 1.84 (dd, j=14.5, 10.6hz, 1H), 1.72 (d, j=14.3 hz, 1H), 1.13 (s, 9H) ESI-MS theoretical calculated value C ₃₉ H ₄₀ ³⁵ Cl ₂ F ₂ N ₃ O ₅ [M+H] ⁺ = 738.23, experimentally measured: 738.2.

final product 49:4- ((2R, 3S,4S, 5S) -4- (aminomethyl) -4- (5-chloro-2-fluorophenyl) -3- (2-chlorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YM 031)

Step one: synthesis of (Z) -2- (5-chloro-2-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile (YK 008)

5-chloro-2-fluorophenylacetonitrile (2.81 g,20 mmol), 2-chlorobenzaldehyde (3.39 g,20 mmol) were weighed into a 250mL round bottom flask, dissolved in 100mL methanol, reacted overnight at 50℃with 4.8mL of 5N sodium methoxide solution, cooled to room temperature, filtered, and the filter cake was washed with water, dried, weighed to give 5.5g, and yield 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).

Step two: synthesis of (2R, 3S,4R, 5S) -3- (2-chlorophenyl) -4- (5-chloro-2-fluorophenyl) -4-cyano-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YK 010)

YK008 (5.5 g,18.8 mmol) was weighed into a 100mL reaction flask, dissolved with 50mL of dichloromethane, silver fluoride (2.4 g,18.8 mmol) and triethylamine (4.2 mL,30 mmol) were added, tert-butyl 2- ((3, 3-dimethylbutylene) amino) acetate (4.1 g,19 mmol) was further added, reacted overnight at room temperature in the absence of light, saturated ammonium chloride solution was poured, filtered, the filtrate was extracted three times with dichloromethane, the filtrates were combined, the solvent was removed by distillation under reduced pressure, and the normal phase silica gel column was purified to give 2.7g of the title compound in 28% yield. ¹ H NMR(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).

Step three: synthesis of (2R, 3S,4S, 5S) -4- (aminomethyl) -3- (2-chlorophenyl) -4- (5-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YK 010-2)

YK010 (2.7 g,5.3 mmol) is weighed into a 100mL reaction flask, dissolved with a mixed solvent of ethanol and tetrahydrofuran, 2.5g of Raney nickel is added, the temperature is raised to 55 ℃, 5mL of hydrazine hydrate is added dropwise, the reaction is stirred for 1h after the dripping, cooling, filtering, decompressing and distilling to remove filtrate, and the normal phase silica gel column is purified to obtain 553mg of target compound, wherein the conversion rate is 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,2H),1.63(d,J＝13.8Hz,1H),1.52(dd,J＝13.9,9.8Hz,1H),1.25(s,9H),1.03(s,9H).

Step four: 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 (YK 013)

YK010-2 (550 mg,1.08 mmol) was weighed into a 50mL round bottom flask, dissolved with 10mL of methylene chloride, fmocCl (418 mg,1.62 mmol) and triethylamine (578 mg,4.32 mmol) were added, reacted overnight at room temperature, the solvent was removed under reduced pressure, 5mL of methylene chloride and 4mL of trifluoroacetic acid were added, reacted overnight at room temperature, the solvent was dried by spinning, the methylene chloride was extracted three times, and the organic phase was dried by spinning, and the product was purified by normal phase column to give 469mg, yield 64%.

Step five: synthesis of methyl 4- ((2R, 3S,4S, 5S) -4- (aminomethyl) -3- (2-chlorophenyl) -4- (5-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamido) -3-methoxybenzoate (YK 017)

YK013 (469 mg,0.69 mol) was weighed and dissolved in THF, DIEA (445 mg,3.45 mmol) was added and reacted for 5min, diphenylphosphinoyl chloride (4819 mg,2.07 mmol) was added and reacted for 30min, methyl 4-amino-3-methoxybenzoate (502 mg,2.78 mmol) was addedThe solvent was removed overnight under reduced pressure, water was added, extraction was performed 3 times with dichloromethane, the organic phase was dried by spin-drying, then purified by normal phase silica gel column, 2mL of DMF solution containing 20% piperidine was added to the crude product, after 30min reaction at room temperature, extraction was performed with ethyl acetate, the organic phase was dried by spin-drying, and the normal phase column was purified to give 93mg of the target compound in 22% yield. ¹ H NMR(500MHz,Methanol-d ₄ )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＝14.3,3.3Hz,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).

Step six: synthesis of 4- ((2R, 3S,4S, 5S) -4- (aminomethyl) -3- (2-chlorophenyl) -4- (5-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamido) -3-methoxybenzoic acid (YM 031)

YK017 (28 mg,0.045 mmol) was weighed into a 50mL round bottom flask, lithium hydroxide monohydrate (10 mg,0.24 mmol) with THF/H ₂ O (v/v=2 mL/2 mL) was dissolved, stirred at room temperature overnight, the solvent was distilled off under reduced pressure, and 25mg of trifluoroacetate of the target compound was obtained by HPLC purification in 77% yield. ¹ H NMR(400MHz,Methanol-d ₄ ) Delta 8.27 (d, j=8.3 hz, 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, 2H), 4.31 (d, j=10.3 hz, 1H), 3.96 (s, 3H), 3.76 (dd, j=14.2, 3.3hz, 1H), 3.64 (d, j=14.2 hz, 1H), 1.76 (d, j=13.6 hz, 1H), 1.58 (dd, j=13.8, 11.4hz, 1H), 1.27 (s, 9H). ESI-MS theory calculated C ₃₁ H ₃₅ ³⁵ Cl ₂ FN ₃ O ₄ [M+H] ⁺ = 602.20, experimentally measured: 602.4.

end product 50:4- ((2R, 3R,4S, 5S) -4- (aminomethyl) -4- (5-chloro-2-fluorophenyl) -3- (3-chlorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YM 036)

Step one: synthesis of (Z) -2- (5-chloro-2-fluorophenyl) -3- (3-chlorophenyl) acrylonitrile (YK 028)

5-chloro-2-fluorophenylacetonitrile (8.48 g,50 mmol), 3-chlorobenzaldehyde (7 g,50 mmol) were weighed into a 250mL round bottom flask, dissolved in 100mL methanol, reacted overnight at 50℃with 5N sodium methoxide solution in 4.8mL, cooled to room temperature, filtered, and the filter cake was washed with water, dried, weighed to give 13.6g, 93% yield. 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＝6.7,2.6Hz,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).

Step two: synthesis of (2R, 3S,4R, 5S) -3- (3-chlorophenyl) -4- (5-chloro-2-fluorophenyl) -4-cyano-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YK 031)

YK028 (5.84 g,20 mmol) was weighed into a 100mL reaction flask, dissolved with 50mL of dichloromethane, silver fluoride (2.54 g,20 mmol) and triethylamine (4.5 mL,32 mmol) were added, tert-butyl 2- ((3, 3-dimethylbutylidene) amino) acetate (4.26 g,20 mmol) was further added, reacted overnight at room temperature in the dark, saturated ammonium chloride solution was poured, filtered, the filtrate was extracted three times with dichloromethane, the filtrates were combined, the solvent was distilled off under reduced pressure, and the normal phase silica gel column was purified to give 2.5g of the title compound in 25% yield. ¹ H NMR(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).

Step three: synthesis of (2R, 3S,4S, 5S) -4- (aminomethyl) -3- (3-chlorophenyl) -4- (5-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YK 035)

YK031 (3.5 g,6.9 mmol) was weighed into a 100mL reaction flask, dissolved in a mixed solvent of ethanol and tetrahydrofuran, 3.5g of Raney nickel was added, the temperature was raised to 55 ℃, 5mL of hydrazine hydrate was added dropwise, the reaction was stirred for 1h after the dropwise addition, cooling, filtering, distilling off the filtrate under reduced pressure, and the normal phase silica gel column was purified to obtain 490mg of the target compound with a conversion of 14%. ¹ H 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).

Step four: 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 (YK 039)

YK035 (692 mg,1.36 mmol) was weighed into a 50mL round bottom flask, dissolved in 10mL of dichloromethane, fmocCl (526 mg,2.04 mmol) and triethylamine (702 mg,5.44 mmol) were added, reacted overnight at room temperature, the solvent was removed under reduced pressure, 5mL of dichloromethane and 4mL of trifluoroacetic acid were added, reacted overnight at room temperature, the solvent was dried by spinning, extracted three times with dichloromethane, the organic phase was dried by spinning, and the product was purified by normal phase column to give 710mg, yield 77%.

Step five: synthesis of methyl 4- ((2R, 3S,4S, 5S) -4- (aminomethyl) -3- (3-chlorophenyl) -4- (5-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamido) -3-methoxybenzoate (YK 045)

YK039 (383 mg,0.57 mol) was weighed and dissolved in THF, DIEA (365 mg,2.85 mmol) was added for reaction for 5min, diphenylphosphinoyl chloride (404 mg,1.71 mmol) was added for reaction for 30min, methyl 4-amino-3-methoxybenzoate (410 mg,2.27 mmol) was added for reaction overnight, the solvent was removed under reduced pressure, water was added, extraction with dichloromethane was carried out 3 times, the organic phase was dried by spinning and then purified with a normal phase silica gel column, 2mL of 20% piperidine in DMF solution was added after the crude product was obtained, after reaction at room temperature for 30min, extraction with ethyl acetate was carried out, the organic phase was dried by spinning and HPLC purification was carried out to obtain 184mg of the target compound trifluoroacetate, yield was 44%. ¹ H NMR(500MHz,Methanol-d ₄ )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).

Step six: synthesis of 4- ((2R, 3S,4S, 5S) -4- (aminomethyl) -3- (3-chlorophenyl) -4- (5-chloro-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YM 036)

YK045 (33 mg,0.05 mmol) was weighed into a 50mL round bottom flask, lithium hydroxide monohydrate (10 mg,0.24 mmol) was added with THF/H ₂ O (v/v=2 mL/2 mL) was dissolved, stirred overnight at room temperature, the solvent was distilled off under reduced pressure, and 18.4mg of trifluoroacetate of the target compound was obtained by HPLC purification, with a yield of 51%. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.29 (d, j=8.4 hz, 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=7.4 hz, 1H), 4.55 (d, j=10.5 hz, 1H), 4.36 (d, j=11.1 hz, 1H), 3.95 (s, 3H), 3.68 (dd, j=14.3, 3.5hz, 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, 11.2hz, 1H), 1.24 (ESI, 9H) ₃₁ H ₃₅ ³⁵ Cl ₂ FN ₃ O ₄ [M+H] ⁺ = 602.20, experimentally measured: 602.3.

end 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-carboxamide) benzoic acid (YL 134)

Step one: synthesis of methyl 4- ((2R, 3S,4S, 5S) -4- (aminomethyl) -4- (5-chloro-2-fluorophenyl) -3- (2-chlorophenyl) -5-neopentylpyrrolidine-2-carboxamide) benzoate (YL 130)

YK013 (280 mg,0.41 mol) was weighed and dissolved in THF, DIEA (271 mg,2.1 mmol) was added for reaction for 5min, diphenylphosphinoyl chloride (298 mg,1.26 mmol) was added for reaction for 30min, methyl 4-aminobenzoate (250 mg,1.66 mmol) was added for reaction overnight, the solvent was removed under reduced pressure, water was added, extraction was performed 3 times with methylene chloride, the organic phase was dried by spinning and purified with normal phase silica gel column, 2mL of DMF solution containing 20% piperidine was added after obtaining crude product, extraction was performed with ethyl acetate at room temperature for 30min, the organic phase was dried by spinning and HPLC purification was performed to obtain 173mg of the target compound trifluoroacetate with 60% yield. ¹ H NMR(500MHz,Methanol-d ₄ )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).

Step two: 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-carboxamide) benzoic acid (YL 134)

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), steps see final product 14 to give 19.5mg of trifluoroacetate of the title compound in 74% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.65 (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=7.8 hz, 1H), 7.64-7.59 (m, 2H), 7.57 (d, j=7.9 hz, 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, 2.6hz, 1H), 7.11 (dd, j=13.0, 8.8hz, 1H), 4.86-4.82 (m, 2H), 4.78 (d, j=9.7 hz, 1H), 4.35 (d, j=15.3 hz), 4.3 hz, 4.9.2 hz, 1H), 7.37-7.31 (m, 2H), 7.23 (dd, j=6.9, 2H), 7.11 (dd, j=13.0, 8.8hz, 1H), 4.86-4.82 (d, 2hz, 1H), and ESS (d, 4.9.9.9 hz, 1H) ₃₆ H ₃₈ ³⁵ Cl ₂ FN ₄ O ₃ [M+H] ⁺ = 663.23, experimentally measured: 663.0.

end 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-carboxamide) benzoic acid (YL 135)

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Step one: 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-carboxamide) benzoic acid (YL 135)

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) were taken, and the procedure was followed with reference to final product 14 to give 16mg of trifluoroacetate as the target compound in 60% yield. ¹ H NMR(500MHz,Methanol-d ₄ )δ8.78–8.69(m,2H),8.44–8.38(m,1H),8.01–7.93(m,2H),7.89(dd,J＝8.0,5.5Hz,1H),7.83 (d, j=7.9 hz, 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, 9.6hz, 1H), 1.80 (d, j=15.1 hz, 1H), 1.06 (s, 9H) ₃₆ H ₃₈ ³⁵ Cl ₂ FN ₄ O ₃ [M+H] ⁺ = 663.23, experimentally measured: 663.0.

end 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-carboxamide) benzoic acid (YL 136)

Step one: 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-carboxamide) benzoic acid (YL 136)

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) were taken, the procedure being as described for end product 14 to give 14.6mg of trifluoroacetate as the target compound in 55% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.77-8.70 (m, 2H), 8.01-7.91 (m, 4H), 7.88 (d, j=7.9 hz, 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=4.2 hz, 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, 1.1 hz, 1H), 5.02 (d, j=10.1 hz, 1H), 5.10.02 (d, 1H), 3.3.3H) ₃₆ H ₃₈ ³⁵ Cl ₂ FN ₄ O ₃ [M+H] ⁺ = 663.23, experimentally measured: 663.0.

end 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 (YL 148)

Step one: 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 (YL 148)

YL130 (58 mg,0.1 mmol), 2-hydroxybenzaldehyde (24 mg,0.2 mmol), sodium borohydride acetate (64 mg,0.3 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol), steps see final product 16 to give trifluoroacetate 26mg of the title compound in 33% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 7.95 (d, j=8.7 hz, 2H), 7.58 (d, j=8.7 hz, 2H), 7.53 (d, j=7.8 hz, 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=10.2 hz, 1H), 4.59-4.47 (m, 2H), 4.34 (d, j=13.0 hz, 1H), 4.25 (d, j=13.0 hz, 1H), 3.93 (dd, j=14.1, 2.0hz, 1H), 3.66 (d, j=14.2 hz, 1.94-1.76 (m, 2H), 1.20 (s, 9H) theoretical calculation of ESI-MS C ₃₇ H ₃₉ ³⁵ Cl ₂ FN ₃ O ₄ [M+H] ⁺ = 678.23, experimentally measured: 678.2.

end 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 (YL 150)

Step one: 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 (YL 150)

YL130 (58 mg,0.1 mmol), 3-hydroxybenzaldehyde (24 mg,0.2 mmol), sodium borohydride acetate (64 mg,0.3 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol), steps see final product 16 to give trifluoroacetate 12.4mg of the title compound in 16% yield. ¹ H NMR(500MHz,Methanol-d ₄ )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 theoretical calculated value C ₃₇ H ₃₉ ³⁵ Cl ₂ FN ₃ O ₄ [M+H] ⁺ = 678.23, experimentally measured: 677.5.

end 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 (YL 143)

Step one: 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 (YL 143)

YL130 (58 mg,0.1 mmol), 4-hydroxybenzaldehyde (24 mg,0.2 mmol), sodium borohydride acetate (64 mg,0.3 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol), steps see final product 16 to give 14.4mg of trifluoroacetate of the title compound in 18% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 7.97 (d, j=8.5 hz, 2H), 7.59 (d, j=8.5 hz, 2H), 7.48 (dt, j=13.4, 3.8hz, 3H), 7.43-7.32 (m, 2H), 7.26 (d, j=8.2 hz, 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=14.5 hz, 1H), 4.24 (d, 1hz, 1H), and ESS of the theoretical value of (C, 9.9 s) ₃₇ H ₃₉ ³⁵ Cl ₂ FN ₃ O ₄ [M+H] ⁺ = 678.23, experimentally measured: 678.5.

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-carboxamide) benzoic acid (YM 003)

Step one: 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-carboxamide) benzoic acid (YM 003)

YL130 (58 mg,0.1 mmol), 4-formyltetrahydropyran (17 mg,0.15 mmol), sodium borohydride acetate (64 mg,0.3 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol), steps see final product 16 to afford 15.8mg of trifluoroacetate as the target compound in 20% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.01-7.93 (m, 2H), 7.75 (d, j=7.9 hz, 1H), 7.67-7.56 (m, 2H), 7.53-7.41 (m, 2H), 7.39-7.30 (m, 3H), 7.11 (dd, j=12.8, 8.8hz, 1H), 4.76 (d, j=10.4 hz, 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=14.1 hz, 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, 1.9 hz), 3.88 (ddd, 1.1, 1 hz), 3.88 (ddd, 1.1, 1.9hz, 1H), 3.88 (d, 1.1, 1H), 3.7 (d, 1.1 hz, 1H), 3.7 (d, 1.1H), 1.7 (d, 1.1 hz, 1H), 1.7 (1.7, 1hz, 1H) ₃₆ H ₄₃ ³⁵ Cl ₂ FN ₃ O ₄ [M+H] ⁺ = 670.26, experimentally measured: 670.5.

end 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-carboxamide) benzoic acid (YM 006)

Step one: 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-carboxamide) benzoic acid (YM 006)

YL130 (58 mg,0.1 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (32 mg,0.15 mmol), sodium borohydride acetate (64 mg,0.3 mmol), 0.1mL acetic acid, 3mL trifluoroacetic acid and lithium hydroxide monohydrate (8 mg,0.2 mmol), and vice versa were takenSee final product 33 for 20.4mg of trifluoroacetate salt of the desired compound in 30% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 7.97 (d, j=8.7 hz, 2H), 7.85 (d, j=7.9 hz, 1H), 7.62 (d, j=8.7 hz, 2H), 7.51-7.45 (m, 1H), 7.45-7.39 (m, 1H), 7.34 (d, j=4.3 hz, 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, 2.9hz, 2H), 2.86 (d, j=6.2 hz, 2H), 2.88 (m-1.88), 4.9 hz, 1H), 4.84-4.9 hz,1H (d, 1H), 4.88-4.9 s (d, 1H), and ESS (1H) ₃₆ H ₄₄ ³⁵ Cl ₂ FN ₄ O ₃ [M+H] ⁺ = 669.28, experimentally measured: 669.0.

end 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 (YM 004)

Step one: 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 (YM 004)

YL130 (58 mg,0.1 mmol), 1-methyl-4-formylpyrazole (17 mg,0.15 mmol), sodium borohydride acetate (64 mg,0.3 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol), steps see final product 16, give 21.8mg of trifluoroacetate of the title compound in 28% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.00-7.90 (m, 2H), 7.72 (s, 1H), 7.65-7.55 (m, 3H), 7.54-7.49 (m, 2H), 7.46 (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 (ddd, j=14.2, 11.2hz, 1H), 1.80 (d, j=14.0 hz, 1H), 4.7 (d, j=10.4 hz, 1H), 4.26-4.10 (1H), 1.9 (e.1H) ₃₅ H ₃₉ ³⁵ Cl ₂ FN ₅ O ₃ [M+H] ⁺ = 666.24, experimentally measured: 666.3.

End 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-carboxamide) benzoic acid (YL 151)

Step one: synthesis of (Z) -2- (5-methoxy-2-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile (YL 036)

5-methoxy-2-fluorophenylacetonitrile (823mg, 5 mmol), 2-chlorobenzaldehyde (705 mg,5 mmol) was weighed into a 250mL round bottom flask, dissolved in 100mL methanol, reacted overnight at 50℃with 5N sodium methoxide solution 1.5mL, cooled to room temperature, filtered, and the filter cake was washed with water, dried, weighed to give 1.36g, yield 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).

Step two: synthesis of (2R, 3S,4R, 5S) -3- (2-chlorophenyl) -4- (5-methoxy-2-fluorophenyl) -4-cyano-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YL 041)

YL036 (1.36 g,4.7 mmol) was weighed into a 100mL reaction flask, dissolved with 50mL of dichloromethane, silver fluoride (0.6 g,4.7 mmol) and triethylamine (1.05 mL,7.56 mmol) were added, tert-butyl 2- ((3, 3-dimethylbutylidene) amino) acetate (1 g,4.7 mmol) was further added, reacted overnight at room temperature in the dark, saturated ammonium chloride solution was poured in, filtered, the filtrate was extracted three times with dichloromethane, the filtrates were combined, the solvent was removed by distillation under reduced pressure, and the normal phase silica gel column was purified to give 0.53g of the title compound in 22% yield. 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,3H),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).

Step three: synthesis of (2R, 3S,4S, 5S) -4- (aminomethyl) -3- (2-chlorophenyl) -4- (5-methoxy-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YL 058)

YL041 (2.86 g,5.7 mmol) was weighed into a 100mL reaction flask, dissolved with a mixed solvent of ethanol and tetrahydrofuran, 2g of Raney nickel was added, the temperature was raised to 55 ℃, 5mL of hydrazine hydrate was added dropwise, the reaction was stirred for 1h after the dropwise addition, cooling, filtration, reduced pressure distillation was carried out to remove the filtrate, and a normal phase silica gel column was purified to obtain 537mg of the target compound with a conversion of 19%. ¹ H 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,2H),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).

Step four: 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 (YL 061)

YL058 (520 mg,1.03 mmol) was weighed into a 50mL round bottom flask, dissolved in 10mL of dichloromethane, fmocCl (390 mg,1.54 mmol) and triethylamine (531 mg,4.12 mmol) were added, reacted overnight at room temperature, the solvent was removed under reduced pressure, 5mL of dichloromethane and 4mL of trifluoroacetic acid were added, reacted overnight at room temperature, the solvent was dried by spinning, dichloromethane extraction was performed three times, the organic phase was dried by spinning, and the product was purified by normal phase column to give 607mg, yield 88%.

Step five: synthesis of methyl 4- ((2R, 3S,4S, 5S) -4- (aminomethyl) -3- (2-chlorophenyl) -4- (5-methoxy-2-fluorophenyl) -5-neopentylpyrrolidine-2-carboxamido) -3-methoxybenzoate (YL 066)

YL061 (603 mg,0.9 mmol) was weighed and dissolved in THF, DIEA (583 mg,4.5 mmol) was added to react for 5min, diphenylphosphinoyl chloride (640 mg,2.7 mmol) was added to react for 30min, methyl 4-aminobenzoate (266 mg,3.6 mmol) was added to react overnight, the solvent was removed under reduced pressure, water was added, extraction 3 times with dichloromethane, organic phase was dried by spin-drying followed by purification on normal phase silica gel column, 2mL of 20% piperidine in DMF solution was added after the crude product was obtained, after 30min reaction at room temperature, extraction with ethyl acetate, drying of the organic phase by spin-drying, HPLC purification to give the target compound73mg of trifluoroacetate salt and 12% of yield. ¹ H NMR(500MHz,Methanol-d ₄ )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).

Step six: synthesis of 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-carboxamide) benzoic acid (YL 151)

YL066 (32 mg,0.055 mmol), 4- (1H-tetrazol-5-YL) benzaldehyde (29 mg,0.16 mmol), sodium borohydride acetate (47 mg,0.22 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (12 mg,0.28 mmol), steps see final product 16 to yield 26.6mg of trifluoroacetate of the title compound in 58% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.14 (d, j=8.0 hz, 2H), 7.99-7.89 (m, 2H), 7.65 (d, j=8.1 hz, 2H), 7.61-7.53 (m, 2H), 7.48 (d, j=7.8 hz, 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=10.5 hz, 1H), 4.64 (d, j=10.5 hz, 1H), 4.41-4.24 (m, 2H), 3.90-3.77 (m, 1H), 3.72 (s, 3H), 3.60 (d, j=14.2 hz, 1H), 2.12-1.96 (m, 1H), 1.32-7.22 (s, 1H), 4.78 (d, j=10.5 hz, 1H), 4.64 (s, 1H), and ESS.14.1H ₃₉ H ₄₂ ³⁵ ClFN ₇ O ₄ [M+H] ⁺ = 726.30, experimentally measured: 725.8.

end product 61:4- ((2R, 3S,4S, 5S) -4- (benzoylaminomethyl) -3- (2-chlorophenyl) -4- (2-fluoro-5-methoxyphenyl) -5-neopentylpyrrolidine-2-carboxamido) benzoic acid (YL 154)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- (benzoylaminomethyl) -3- (2-chlorophenyl) -4- (2-fluoro-5-methoxyphenyl) -5-neopentylpyrrolidine-2-carboxamido) benzoic acid (YL 154)

YL066 (20 mg,0.034 mmol) was taken,benzoyl chloride (7 mg,0.05 mmol), triethylamine (10 mg,0.096 mmol) and lithium hydroxide monohydrate (7 mg,0.16 mmol), steps see final product 2 to yield 13.3mg of the trifluoroacetate salt of the target compound in 50% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.04-7.95 (m, 2H), 7.83 (d, j=7.9 hz, 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=15.0 hz, 1H), 3.95 (d, j=15.0 hz, 1H), 3.65 (s, 3H), 1.95-1.73 (m, 2H), 1.02 (s, 9H) ESI-MS calculated C ₃₈ H ₄₀ ³⁵ ClFN ₃ O ₅ [M+H] ⁺ = 672.26, experimentally measured: 672.4.

end product 62:4- ((2R, 3S,4S, 5S) -4- ((benzylamino) methyl) -3- (2-chlorophenyl) -4- (2-fluoro-5-methoxyphenyl) -5-neopentylpyrrolidine-2-carboxamide) benzoic acid (YL 155)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- ((benzylamino) methyl) -3- (2-chlorophenyl) -4- (2-fluoro-5-methoxyphenyl) -5-neopentylpyrrolidine-2-carboxamide) benzoic acid (YL 155)

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), steps see final product 14 to yield 13.9mg of trifluoroacetate as the target compound in 53% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 7.95 (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 theoretical calculated value C ₃₈ H ₄₂ ³⁵ ClFN ₃ O ₄ [M+H] ⁺ = 658.28, experimentally measured: 657.9.

end 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-carboxamide) benzoic acid (YL 156)

Step one: 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-carboxamide) benzoic acid (YL 156)

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) were taken, the procedure was as described for end product 14 to give 19.5mg of trifluoroacetate as the target compound in 75% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.63 (d, j=4.9 hz, 1H), 8.04 (td, j=7.8, 1.7hz, 1H), 7.95 (d, j=8.5 hz, 2H), 7.69 (d, j=7.9 hz, 1H), 7.64-7.52 (m, 4H), 7.44 (ddd, j=8.2, 5.6,3.2hz, 1H), 7.37-7.29 (m, 2H), 7.07-6.92 (m, 2H), 6.66 (dd, j=6.6, 2.9hz, 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, 1H), 1.93 (d, j=14.5 hz), and 14.1 hz, and calculating the theoretical value of (es) of (es.9.s, 9 s, ESS.9 ₃₇ H ₄₁ ³⁵ ClFN ₄ O ₄ [M+H] ⁺ = 659.28, experimentally measured: 658.5.

end 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-carboxamide) benzoic acid (YL 157)

Step one: 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-carboxamide) benzoic acid (YL 157)

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) were taken, and the procedure was followed with reference to final product 14 to give 12.1mg of trifluoroacetate of the target compound in the yield46％。 ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.74 (d, j=2.0 hz, 1H), 8.71 (dd, j=5.4, 1.4hz, 1H), 8.35 (d, j=8.0 hz, 1H), 8.00-7.92 (m, 2H), 7.84 (dd, j=8.0, 5.4hz, 1H), 7.78 (d, j=7.9 hz, 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=10.4 hz, 1H), 7.64-7.54 (m, 2H), 7.44 (ddd, j=8.2, 6.3, 2hz, 2.4hz, 1H), 7.35-7.24 (m, 2H), 7.01 (dd, j=13.1, 9.0hz, 1H), 6.93 (d, 3.9, 3.60 (j=3.2 hz), 6.8, 1H), 6.60 (d, 3.8, 1H), 3.0hz, 3.9, 1H), 3.9 (2H) ₃₇ H ₄₁ ³⁵ ClFN ₄ O ₄ [M+H] ⁺ = 659.28, experimentally measured: 658.6.

end 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-carboxamide) benzoic acid (YL 158)

Step one: 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-carboxamide) benzoic acid (YL 158)

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) were taken, the procedure was as for final product 14 to give 18.6mg of trifluoroacetate of the title compound in 72% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.80-8.71 (m, 2H), 8.00 (d, j=6.1 hz, 2H), 7.98-7.92 (m, 2H), 7.88 (d, j=7.9 hz, 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=10.2 hz, 1H), 5.09-4.99 (m, 2H), 4.16 (d, j=16.1 hz), 4.09 (d, j=16.1 hz), 3.70 (d, 1 hz), 3.3 hz, 3.2 hz), 6.57 (d, j=3.0 hz, 1H), 6.15 (j=3.9.0 hz, 1H), 6.23 (d, j=6.9.0 hz, 1H), 5.23 (j=1H), 5.9.9 (j=3.0 hz, 1H) ₃₇ H ₄₁ ³⁵ ClFN ₄ O ₄ [M+H] ⁺ = 659.28, experimentally measured: 658.5.

end 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-carboxamide) -3-methoxybenzoic acid (YM 048)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YM 048)

YL090 (20 mg,0.03 mmol), 1-methylindole-3-carbaldehyde (8 mg,0.047 mmol), sodium borohydride acetate (20 mg,0.09 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (6 mg,0.15 mmol), steps see final product 16 to give 7.9mg of trifluoroacetate of the title compound in 30% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.25 (d, j=8.5 hz, 1H), 7.66 (d, j=8.0 hz, 1H), 7.62 (d, j=1.8 hz, 1H), 7.59 (dd, j=8.5, 1.8hz, 1H), 7.52 (d, j=8.3 hz, 1H), 7.40-7.30 (m, 3H), 7.25 (t, j=7.5 hz, 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, 2.2hz, 1H), 6.99-6.88 (m, 3H), 6.78 (s, 1H), 4.48 (d, j=13.9 hz, 1H), 3.9hz, 1H) ₄₁ H ₄₃ ³⁵ Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 763.26, experimentally measured: 762.9.

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-carboxamide) -3-methoxybenzoic acid (YM 050)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YM 050)

YL090 (20 mg,0.03 mmol), quinoline-4-carbaldehyde (7.4 mg,0.047 mmol), sodium borohydride acetate (20 mg,0.09 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (6 mg,0.15 mmol), steps see final product 16 to give 10mg of trifluoroacetate as the title compound in 38% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ9.07 (d, j=5.4 hz, 1H), 8.49 (d, j=8.5 hz, 1H), 8.23 (t, j=8.5 hz, 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, 1.00, 1H), 1.00 (s, 1H), and esh) ₄₁ H ₄₁ ³⁵ Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 761.25, experimentally measured: 761.2.

end product 95:4- ((2R, 3S,4S, 5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentyl-4- (nicotinamide methyl) pyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YM 061)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -5-neopentyl-4- (nicotinamide methyl) pyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YM 061)

YL090 (20 mg,0.03 mmol), nicotinyl chloride (8 mg,0.047 mmol), triethylamine (12 mg,0.12 mmol) and lithium hydroxide monohydrate (6 mg,0.15 mmol) were taken, the procedure was followed for end product 2 to give the trifluoroacetate salt of the title compound in 79% yield. ¹ H NMR(500MHz,Methanol-d ₄ )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＝8.6Hz,1H),7.31–7.23(m,2H),7.21(t,J＝80hz, 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 Cl ₂ F ₂ N ₄ O ₅ [M+H] ⁺ = 725.21, experimentally measured: 725.3.

end product 96:4- ((2R, 3S,4S, 5S) -3- (3-chloro-2-fluorophenyl) -4- (4-chloro-2-fluorophenyl) -4- (isonicotinamide methyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YM 062)

Step one: 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 (YM 062)

YL090 (20 mg,0.03 mmol), isonicotinyl chloride (8 mg,0.047 mmol), triethylamine (12 mg,0.12 mmol) and lithium hydroxide monohydrate (6 mg,0.15 mmol) were taken, the procedure is as for final product 2 to give the trifluoroacetate salt of the title compound 17.3mg in 69% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.79-8.67 (m, 2H), 8.28 (d, j=8.3 hz, 1H), 7.63 (ddd, j=10.8, 5.4,1.7hz, 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 theory calculated C ₃₇ H ₃₇ ³⁵ Cl ₂ F ₂ N ₄ O ₅ [M+H] ⁺ = 725.21, experimentally measured: 725.1.

end product 100:4- ((2R, 3R,4S, 5S) -3- (3-chlorophenyl) -4- (4-chlorophenyl) -4- ((ethyl (pyridin-4-ylmethyl) amino) methyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid

Step one: synthesis of (Z) -3- (3-chlorophenyl) -2- (4-chlorophenyl) acrylonitrile (YM 068)

4-Chlorophenylacetonitrile (3.02 g,20 mmol), 3-chlorobenzaldehyde (2.8 g,20 mmol) was weighed into a 250mL round bottom flask, dissolved with 100mL of methanol, added with 6mL of 5N sodium methoxide solution, reacted overnight at 50℃and cooled to room temperature, filtered, the filter cake was washed with water, dried and weighed to give 4.5g with 82% yield. ¹ H NMR(500MHz,Chloroform-d)δ7.85–7.75(m,2H),7.63–7.56(m,2H),7.48–7.35(m,5H).

Step two: synthesis of (2R, 3S,4R, 5S) -3- (3-chlorophenyl) -4- (4-chlorophenyl) -4-cyano-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YM 070)

YM068 (4.48 g,16 mmol) was weighed into a 100mL reaction flask, dissolved with 50mL of methylene chloride, silver fluoride (2 g,16 mmol) and triethylamine (3.6 mL,26 mmol) were added, tert-butyl 2- ((3, 3-dimethylbutylidene) amino) acetate (4.13 g,16 mmol) was further added, reacted overnight at room temperature in the absence of light, poured into a saturated ammonium chloride solution, filtered, the filtrate was extracted three times with methylene chloride, the filtrates were combined, the solvent was distilled off under reduced pressure, and the normal phase silica gel column was purified to give 4.56g of the target compound in 59% yield. ¹ H NMR(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＝8.4Hz,1H),1.58(dd,J＝14.3,9.4Hz,1H),1.36(s,9H),1.35–1.31(m,1H),0.89(s,9H).

Step three: synthesis of (2R, 3S,4S, 5S) -4- (aminomethyl) -3- (3-chlorophenyl) -4- (4-chlorophenyl) -5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YM 073)

YM070 (4.56 g,9.4 mmol) was weighed into a 100mL reaction flask, dissolved in a mixed solvent of ethanol and tetrahydrofuran, 3g of Raney nickel was added, the temperature was raised to 55 ℃, 5mL of hydrazine hydrate was added dropwise, the reaction was stirred for 1h after the dropwise addition, cooling, filtration, distillation under reduced pressure to remove the filtrate, and purification on a normal phase silica gel column gave 1.03g of the target compound with a conversion 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＝7.7Hz,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).

Step four: 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 (YM 075)

YM073 (1030 mg,2.1 mmol) was weighed into a 50mL round bottom flask, dissolved in 10mL of methylene chloride, fmocCl (812 mg,3.15 mmol) and triethylamine (1.08 g,8.4 mmol) were added, reacted overnight at room temperature, the solvent was removed under reduced pressure, 5mL of methylene chloride and 4mL of trifluoroacetic acid were added, reacted overnight at room temperature, the solvent was dried by spinning, methylene chloride was extracted three times, and the organic phase was dried by spinning, and the product was purified by a normal phase column to give 1.3g in 93% yield.

Step five: synthesis of methyl 4- ((2R, 3S,4S, 5S) -4- (aminomethyl) -3- (3-chlorophenyl) -4- (4-chlorophenyl) -5-neopentylpyrrolidine-2-carboxamido) -3-methoxybenzoate (YM 078)

YM075 (264 mg,0.4 mol) was weighed and dissolved in DCM, DIEA (258 mg,2 mmol) was added for reaction for 5min, diphenylphosphinoyl chloride (284 mg,1.2 mmol) was added for reaction for 30min, methyl 4-amino-3-methoxybenzoate (290 mg,1.6 mmol) was added for reaction overnight, the solvent was removed under reduced pressure, water was added, extraction 3 times with dichloromethane, the organic phase was dried by spinning and then purified with normal phase silica gel column, 2mL of DMF solution containing 20% piperidine was added after the crude product was obtained, after reaction for 30min at room temperature, extraction was performed with ethyl acetate, the organic phase was dried by spinning and purification was performed with normal phase column to obtain 20mg of the target compound with 7% yield.

Step six: synthesis of methyl 4- ((2R, 3R,4S, 5S) -3- (3-chlorophenyl) -4- (4-chlorophenyl) -4- ((ethylamino) methyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoate (YM 080)

YM078 (20 mg,0.033 mmol) was dissolved in 1, 2-dichloroethane (5 mL), acetaldehyde (15 mg,0.3 mmol), sodium borohydride acetate (64 mg,0.3 mmol) and acetic acid (0.1 mL) were added, the reaction was continued overnight at room temperature, and then the reaction was completed, distilled under reduced pressure and purified by a normal phase column to give 11mg,52% of the objective compound. ¹ H NMR(500MHz,Methanol-d ₄ )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＝29.2Hz,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)。

Step seven: synthesis of 4- ((2R, 3R,4S, 5S) -3- (3-chlorophenyl) -4- (4-chlorophenyl) -4- ((ethyl (pyridin-4-ylmethyl) amino) methyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YM 081)

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, the procedure was as described for final product 14 to give 1.6mg of trifluoroacetate as the target compound in 18% yield. Theoretical calculation value of ESI-MS C ₃₉ H ₄₅ ³⁵ Cl ₂ N ₄ O ₄ [M+H] ⁺ = 703.28, experimentally measured: 703.4.

end 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-carboxamide) -3-methoxybenzoic acid (YM 091)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YM 091)

YM89 (see YL090, 25mg,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) were taken, and the procedure was followed with reference to final product 14 to give 12.6mg of trifluoroacetate of the title compound in 39% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 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, 8.7hz, 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 theoretical calculated C ₃₇ H ₃₉ ³⁵ Cl ₂ F ₂ N ₄ O ₄ [M+H] ⁺ = 711.2, experimentally measured: 711.1.

end 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-carboxamide) -3-methoxybenzoic acid (YM 092)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YM 092)

YL090 (30 mg,0.047 mmol), 2-methoxypyridine-4-carbaldehyde (10 mg,0.07 mmol), sodium cyanoborohydride (9 mg,0.14 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (6 mg,0.15 mmol), steps see final product 16 to give 18.6mg of trifluoroacetate of the title compound in 47% yield. ¹ H NMR(400MHz,Methanol-d ₄ ) Delta 8.24 (dd, j=12.2, 6.8hz, 2H), 7.60 (d, j=10.0 hz, 2H), 7.45 (q, j=5.8 hz, 1H), 7.28 (d, j=8.7 hz, 1H), 7.18 (t, j=8.5 hz, 4H), 7.00 (d, j=5.4 hz, 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, 4H), 1.63 (d, j=11.7 hz, 1H), 1.21 (s, ESS, 9 s, ESS, C-MS calculated as the theoretical value ₃₈ H ₄₁ ³⁵ Cl ₂ F ₂ N ₄ O ₅ [M+H] ⁺ = 741.24, experimentally measured: 741.3.

End 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-carboxamide) -3-methoxybenzoic acid (YM 094)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YM 094)

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), acetic acid 0.1mL and lithium hydroxide monohydrate (6 mg,0.15 mmol), the procedure was as described for final product 16 to give 12.5mg of trifluoroacetate as the objective compound in 30% yield. ¹ H NMR(400MHz,Methanol-d ₄ ) δ8.31 (d, j=5.3 hz, 1H), 8.23 (d, j=8.5 hz, 1H), 7.66 (d, j=3.5 hz, 1H), 7.60 (d, j=7.7 hz, 2H), 7.37 (t, j=7.5 hz, 1H), 7.31 (d, j=5.4 hz, 1H), 7.23-6.93 (m, 5H), 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) —i-MS theoretical value of ESC ₃₉ H ₄₀ ³⁵ Cl ₂ F ₂ N ₅ O ₄ [M+H] ⁺ = 750.24, experimentally measured: 750.1.

end 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-carboxamide) -3-methoxybenzoic acid (YM 099)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YM 099)

YL090 (30 mg,0.047 mmol), 3-fluoropyridine-4-carbaldehyde (19 mg,0.14 mmol), sodium cyanoborohydride (18 mg,0.28 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol), steps see final product 16 to give 15.3mg of trifluoroacetate of the title compound in 38.5% yield. ¹ H NMR(500MHz,Methanol-d ₄ )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(dJ=10.1 hz, 1H), 4.17 (d, j=2.6 hz, 2H), 3.87 (s, 3H), 3.42 (d, j=13.8 hz, 1H), 3.35 (d, j=13.7 hz, 1H), 1.80 (dd, j=14.5, 9.9hz, 1H), 1.69 (d, j=14.4 hz, 1H), 1.10 (s, 9H) ESI-MS theoretical calculated C ₃₇ H ₃₈ ³⁵ Cl ₂ F ₃ N ₄ O ₄ [M+H] ⁺ = 729.22, experimentally measured: 729.4.

end 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-carboxamide) -3-methoxybenzoic acid (YM 100)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YM 100)

YL090 (30 mg,0.047 mmol), 3-hydroxypyridine-4-carbaldehyde (12 mg,0.094 mmol), sodium cyanoborohydride (12 mg,0.19 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol), steps see final product 16 to give 21.7mg of trifluoroacetate of the title compound in 55% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.32-8.24 (m, 2H), 8.22 (d, j=8.4 hz, 1H), 7.85 (d, j=5.6 hz, 1H), 7.69-7.52 (m, 3H), 7.47 (t, j=7.5 hz, 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, 9.9hz, 1H), 1.72 (d, j=14.6 hz, 1H), 1.08 (s, 9H) —esi-MS theoretical calculation value of esc-MS ₃₇ H ₃₉ ³⁵ Cl ₂ F ₂ N ₄ O ₅ [M+H] ⁺ = 727.23, experimentally measured: 727.2.

end 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-carboxamide) -3-methoxybenzoic acid (YM 105)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YM 105)

YL090 (30 mg,0.047 mmol), 2-hydroxypyridine-4-carbaldehyde (12 mg,0.094 mmol), sodium cyanoborohydride (12 mg,0.19 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol), steps see final product 16 to afford trifluoroacetate 19.3mg of the title compound in 49% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.24 (d, j=8.8 hz, 1H), 7.67-7.58 (m, 2H), 7.51 (d, j=6.7 hz, 1H), 7.49-7.43 (m, 1H), 7.42-7.13 (m, 5H), 6.58 (d, j=1.7 hz, 1H), 6.43 (dd, j=6.7, 1.8hz, 1H), 4.75 (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) theoretical calculation of C-MS ₃₇ H ₃₉ ³⁵ Cl ₂ F ₂ N ₄ O ₅ [M+H] ⁺ = 727.23, experimentally measured: 727.4.

end 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-carboxamide) -3-methoxybenzoic acid (YM 106)

Step one: 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-carboxamide) -3-methoxybenzoic acid (YM 106)

YL090 (30 mg,0.047 mmol), 2-hydroxypyridine-5-carbaldehyde (12 mg,0.094 mmol), sodium cyanoborohydride (12 mg,0.19 mmol), acetic acid 0.1mL and lithium hydroxide monohydrate (10 mg,0.24 mmol), steps see final product 16 to give trifluoroacetate 14 of the target compoundmg, yield 35%. ¹ H NMR(500MHz,Methanol-d ₄ ) δ8.28 (d, j=8.5 hz, 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=9.3 hz, 1H), 4.47 (d, j=10.1 hz, 1H), 4.32 (d, j=11.2 hz, 1H), 4.07 (s, 2H), 3.97 (s, 3H), 3.85 (d, j=10.1 hz, 1H), 3.74 (dd, j=14.0, 2.9hz, 1H), 3.38 (d, j=14.2 hz, 1H), 1.72 (d, j=13.4 hz, 1H), 1.59 (dd, j=13.6, 11.4hz, 1H), and 3.97 (s, 3.9, 3H) calculate the theoretical value of (es, i.25.s, i.9H) ₃₇ H ₃₉ ³⁵ Cl ₂ F ₂ N ₄ O ₅ [M+H] ⁺ = 727.23, experimentally measured: 727.4.

end 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-carboxamide) -3-methoxybenzoic acid (YM 117)

Step one: synthesis of (Z) -2- (4-chloro-2-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile (YI 091)

2-chlorobenzaldehyde (2.82 g,20 mmol), 4-chloro-2-fluorobenzonitrile (3.4 g,20 mmol), 5N sodium methoxide in methanol 4.8mL, the reaction step was referred to step one of final product 1, to give the objective product 5.46g, 93% yield. ¹ H NMR(500MHz,Chloroform-d)δ8.11(dd,J＝5.5,3.8Hz,1H),7.94(s,1H),7.57(t,J＝8.3Hz,1H),7.52–7.46(m,1H),7.44–7.37(m,2H),7.29–7.20(m,2H).

Step two: synthesis of (2R, 3R,4R, 5S) -4- (4-chloro-2-fluorophenyl) -3- (2-chlorophenyl) -4-cyano-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YI 097-1)

YI091 (5.46 g,18.6 mmol), agF (2.36 g,18.6 mmol), triethylamine 4mL and tert-butyl (E) -2- (((3, 3-dimethylbutylidene) amino) acetate (3.97 g,18.6 mmol), the reaction steps were referred to step two of final product 1 to give the desired product 4g in 43% yield. 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,1H),7.09–7.03(m,1H),4.92(d,J＝6.7Hz,1H),4.18–4.10(m,1H),4.08(d,J＝6.7Hz,1H),1.72–1.57(m,1H),1.40(s,9H),1.30(dd,J＝14.4,1.1Hz,1H),0.92(s,9H).

Step three: synthesis of (2R, 3R,4S, 5S) -4- (aminomethyl) -4- (4-chloro-2-fluorophenyl) -3- (2-chlorophenyl) -5-neopentane-2-carboxylic acid tert-butyl ester (YI 097-2)

YI097-1 (4 g,7.91 mmol), nickel powder 4g, hydrazine hydrate 10mL, reaction step see step three of final product 1, to yield the target product 1g, 24% yield. 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).

Step four: 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 (YI 100)

YI097-2 (480 mg,1.93 mmol), fmocCl (745 mg,2.89 mmol), DIEA (996 mg,7.72 mmol) and trifluoroacetic acid 4mL, the reaction step was referred to step four of final product 1 to give the desired product 1.12g in 86% yield.

Step five: synthesis of methyl 4- ((2R, 3R,4S, 5S) -4- (aminomethyl) -4- (4-chloro-2-fluorophenyl) -3- (2-chlorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoate (YI 105)

YI100 (270 mg,0.4 mmol), methyl 4-amino-3-methoxybenzoate (290 mg,1.6 mmol), diphenylphosphinyl chloride (283 mg,1.2 mmol), DIEA (255 mg,2 mmol) and piperidine 0.4mL, the reaction steps were seen in step five of final product 1 to give 67mg of the desired product in 27% yield. ¹ H NMR(500MHz,Methanol-d ₄ )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).

Step six: 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-carboxamide) -3-methoxybenzoic acid (YM 117)

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) were taken, and the procedure was as described for final product 14 to give 12.3mg of trifluoroacetate as the target compound in 34.6% yield. ¹ H NMR(500MHz,Methanol-d ₄ ) Delta 8.80-8.68 (m, 2H), 8.23 (d, j=8.5 hz, 1H), 7.90 (d, j=6.0 hz, 2H), 7.79 (d, j=7.9 hz, 1H), 7.62 (dd, j=8.4, 1.8hz, 1H), 7.57 (d, j=1.8 hz, 1H), 7.44 (ddd, j=8.2, 5.9,2.7hz, 1H), 7.38-7.29 (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 (ddj=14.9, 10.1 hz), 1.83 (d, 1.83 hz), 7.23-7.10 (m, 3H), and ESS.11 (s, 1H) ₃₇ H ₃₉ ³⁵ Cl ₂ FN ₄ O ₄ [M+H] ⁺ = 693.2, experimentally measured: 693.4.

end 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-carboxamide) -3-methoxybenzoic acid (YM 123)

Step one: synthesis of (Z) -2- (4-chloro-2-fluorophenyl) -3- (4-chlorophenyl) acrylonitrile (YI 037)

P-chlorobenzaldehyde (1.4 g,10 mmol), 4-chloro-2-fluorobenzonitrile (1.7 g,10 mmol), 5N sodium methoxide in methanol 3mL, the reaction step was referred to step one of final product 1 to give the objective product 2.78g in 95% yield. ¹ H NMR(500MHz,Chloroform-d)δ7.85–7.78(m,2H),7.57–7.50(m,2H),7.48–7.42(m,2H),7.25–7.18(m,2H).

Step two: synthesis of (2R, 3R,4R, 5S) -4- (4-chloro-2-fluorophenyl) -3- (4-chlorophenyl) -4-cyano-5-neopentylpyrrolidine-2-carboxylic acid tert-butyl ester (YI 040)

YI037 (2.7 g,9.1 mmol), agF (1.16 g,9.1 mmol), triethylamine 2.1mL and (E) -2- (((3, 3-dimethylbutylidene) amino) ethyl acetate) Tert-butyl acid (1.94 g,9.1 mmol), reaction step see step two of final product 1, gives the desired product 1.57g, 34% yield. ¹ H NMR(500MHz,Chloroform-d)δ7.32(t,J＝8.5Hz,1H),7.26–7.21(m,2H),7.18(dd,J＝12.3,2.1Hz,1H),7.11(dd,J＝8.7,2.4Hz,3H),4.23(d,J＝7.9Hz,1H),4.13(d,J＝7.8Hz,1H),4.06(dd,J＝9.2,1.2Hz,1H),1.60(ddd,J＝14.4,9.2,1.1Hz,1H),1.37(s,9H),1.29(dd,J＝14.3,1.2Hz,1H),0.89(s,9H).

Step three: synthesis of (2R, 3R,4S, 5S) -4- (aminomethyl) -4- (4-chloro-2-fluorophenyl) -3- (4-chlorophenyl) -5-neopentane-2-carboxylic acid tert-butyl ester (YI 051)

YI040 (1.57 g,3.1 mmol), nickel powder 1.57g, hydrazine hydrate 10mL, the reaction step is referred to as step three of final product 1, to obtain 584mg of the target product with a yield of 37%.

Step four: 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 (YI 054)

YI051 (284 mg,1.15 mmol), fmocCl (385 mg,1.49 mmol), DIEA (552 mg,4.6 mmol) and trifluoroacetic acid 4mL, the reaction step was referred to step four of final product 1 to give 722mg of the desired product in 95% yield.

Step five: synthesis of methyl 4- ((2R, 3R,4S, 5S) -4- (aminomethyl) -4- (4-chloro-2-fluorophenyl) -3- (4-chlorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoate (YI 059)

YI054 (271mg, 0.4 mmol), methyl 4-amino-3-methoxybenzoate (290 mg,1.6 mmol), diphenylphosphinyl chloride (283 mg,1.2 mmol), DIEA (255 mg,2 mmol) and piperidine 0.4mL, the reaction steps were seen in step five of final product 1 to give the desired product 80mg in 32% yield. ¹ H NMR(400MHz,Methanol-d ₄ )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).

Step six: 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-carboxamide) -3-methoxybenzoic acid (YM 123)

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 are seen in final product 14 to give the desired product 17mg in 32% yield. ¹ H NMR(400MHz,Methanol-d ₄ ) Delta 8.75 (d, j=6.0 hz, 2H), 8.26 (d, j=8.4 hz, 1H), 7.95 (d, j=6.2 hz, 2H), 7.63 (dd, j=8.4, 1.8hz, 1H), 7.56 (d, j=1.8 hz, 1H), 7.41-7.28 (m, 3H), 7.28-7.04 (m, 4H), 5.52 (d, j=10.6 hz, 1H), 4.67 (d, j=9.2 hz, 1H), 4.34 (d, j=10.6 hz, 1H), 4.16-3.89 (m, 2H), 3.77 (s, 3H), 3.28 (s, 1H), 3.01 (d, j=13.3 hz, 1H), 2.08-1.90 (m, 1H), 1.70 (d, j=15.00 hz, 1H), 4.34 (s, 1H), 4.16-3 s, 1H) ₃₇ H ₃₉ ³⁵ Cl ₂ FN ₄ O ₄ [M+H] ⁺ = 693.2, experimentally measured: 693.3.

end product 121:4- ((2R, 3S,4S, 5S) -4- (4-chlorophenyl) -3- (3-chlorophenyl) -5-neopentyl-4- (((pyridin-4-ylmethyl) amino) methyl) pyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YM 125)

Step one: synthesis of 4- ((2R, 3S,4S, 5S) -4- (4-chlorophenyl) -3- (3-chlorophenyl) -5-neopentyl-4- (((pyridin-4-ylmethyl) amino) methyl) pyrrolidine-2-carboxamide) -3-methoxybenzoic acid (YM 125)

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), the reaction steps were seen in final product 14 to give the desired product 6mg in 19% yield. ¹ H NMR(400MHz,Methanol-d ₄ )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＝10.7Hz,1H),4.40(d,J＝9.5Hz,1H),4.12(d,J＝15.8Hz,1H),4.08–3.90(m,2H),3.78(s,3H),3.25(d,J＝13.5Hz,1H),3.04(d,J＝13.4Hz,1H),2.12–1.85(m,1H),1.68(d,J＝15.0Hz,1H),1.00 (s, 9H.) theoretical calculation C of ESI-MS ₃₇ H ₄₁ ³⁵ Cl ₂ N ₄ O ₄ [M+H] ⁺ =675.2, experimentally measured: 675.3.

end 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-carboxamide) -3-methoxybenzoic acid (YM 129)

Step one: synthesis of (Z) -2- (4-chloro-2-fluorophenyl) -3- (2, 3-dichlorophenyl) acrylonitrile (YI 116)

2, 3-dichlorobenzaldehyde (3.5 g,20 mmol), 4-chloro-2-fluorophenylacetonitrile (3.4 g,20 mmol), 4.8mL of 5N sodium methoxide in methanol, the reaction step was referred to as step one of final product 1, to obtain 6.23g of the objective product in 95% yield. ¹ H NMR(500MHz,Chloroform-d)δ7.98–7.89(m,2H),7.62–7.54(m,2H),7.39–7.32(m,1H),7.28(dd,J＝2.1,0.9Hz,1H),7.23(d,J＝2.1Hz,1H).

Step two: 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 (YI 124-1)

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

Step three: 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 (YI 124-2)

YI124-1 (4.57 g,8.5 mmol), nickel powder 4.5g, hydrazine hydrate 10mL, the reaction steps refer to step three of final product 1, the purpose is achieved1.04g of the target product was obtained in 23% yield. 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).

Step four: 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 (YI 126)

YI124-2 (1.04 g,1.91 mmol), fmocCl (740 mg,2.87 mmol), DIEA (986 mg,7.62 mmol) and trifluoroacetic acid 4mL, the reaction step was referred to step four of final product 1 to give the desired product 1.08g in 80% yield.

Step five: synthesis of methyl 4- ((2R, 3R,4S, 5S) -4- (aminomethyl) -4- (4-chloro-2-fluorophenyl) -3- (2, 3-dichlorophenyl) -5-neopentylpyrrolidine-2-carboxamide) -3-methoxybenzoate (YI 129)

YI126 (284 mg,0.4 mmol), methyl 4-amino-3-methoxybenzoate (290 mg,1.6 mmol), diphenylphosphinic chloride (283 mg,1.2 mmol), DIEA (255 mg,2 mmol) and piperidine 0.4mL, the reaction steps were seen in step five of final product 1 to give the desired product 46mg in 18% yield.

Step six: 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-carboxamide) -3-methoxybenzoic acid (YM 129)

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 were seen in final product 14 to give the desired product 5.2mg in 34% yield. ¹ H NMR(500MHz,Methanol-d ₄ )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),7.27–7.18(m,2H),7.18–7.07(m,1H),4.69(d,J＝10.1Hz,1H),4.61(s,1H),4.14(d,J＝15.9Hz,1H),4.10(d,J＝15.9Hz,1H),3.85(s,3H),3.39–3.34(m,2H),1.84(d,J＝5.2Hz,2H),1.14 (s, 9H.) theoretical calculation C of ESI-MS ₃₇ H ₃₉ ³⁵ Cl ₃ FN ₄ O ₄ [M+H] ⁺ =727.2, experimentally measured: 727.2.

the following compounds in table 1 can be synthesized by selecting the corresponding raw materials:

basic information on the compounds of Table 1

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Example 2: binding constant Ki value of FP detection Compound to MDMX protein

His-tagged MDMX (14-111, C17S) was expressed in E.coli, purified first with Ni affinity column followed by Superdex75 molecular sieve, resulting in MDMX protein purity greater than 95% and protein concentration of 12.5. Mu.M. FAM-labeled PDI polypeptide (FAM-PDI) [ Cancer Res 2007,67,8810-8817 ]]As a fluorescent-labeled molecular probe, the dissociation constant K of the MDMX/FAM-PDI interaction _d 2.1nM.

96-well plates were purchased from Corning company (Black, # 3694). The multifunctional enzyme-labeled instrument is manufactured by TECAN company, and the model is as follows: SPARK 10M. Detection buffer: 10mM Tris (pH 7.5), 200mM NaCl (Sigma), 0.01% Tween-20 and 0.01% Triton X-100 (Sigma), and the experimental water was Millipore-Q pure water.

Compounds to be tested were first dissolved in DMSO to 20mM standard stock solution. The standard mother liquor of test compound was then diluted with DMSO in the EP tube to a working sample solution, the prepared working sample solution concentration = 25 times the highest sample concentration required on the test plate (25 x test compound solution), and the compound was diluted in a 3-fold gradient in the EP tube for use.

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

a1-A3 wells served as blank: 100uL of detection buffer was added. a4-A6 wells served as negative signal reference group: mu.L of buffer containing only 5nM of fluorescently labeled molecular probe was added. a7-A9 wells served as positive reference group: mu.L of a mixed solution containing 5nM of fluorescent-labeled molecular probe and 60nM of MDMX protein was added.

After the reaction plate was covered with aluminum foil paper and the 96-well plate was placed on a 96-well plate shaking table and incubated at room temperature for 1 hour, fluorescence polarization mP values at Ex485nm/Em530nm were read with an enzyme-labeled instrument. The measured mP value is plotted against the compound concentration gradient, and the sample compound concentration corresponding to the median of the mP maximum value and the minimum value is the IC of the combination of the compound and the protein ₅₀ Value ([ I)] ₅₀ )。

According to this IC ₅₀ Value ([ I)] ₅₀ ) Calculating the binding rate constant of the compound and the protein by using a formula

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

Wherein [ L ]] ₅₀ Representing the concentration of the fluorescent labeling molecular probe in the test system 50% of (2); [ P ]] ₀ Represents MDMX protein concentration, K in the above test system _d Is the dissociation constant of the protein and the fluorescent-labeled molecular probe.

Using the above procedure, K was measured for the compounds of the examples inhibiting MDMX/p53 interaction _i The values are shown in table 2 below. Experimental data indicate that the compounds have the activity of inhibiting MDMX/p53 interaction.

Table 2: example Compounds inhibit MDMX/p53 interaction Activity

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* Represent K _i Between 100,000nM and 10,000 nM; * Represents K _i Between 10,000nM and 100 nM;

experimental data shows that the activity of the synthesized novel compound combined with MDMX is similar to or remarkably improved with that of a positive compound RG7388 (CAS: 1229705-06-9).

Example 3

Binding force constant Ki value of FP detection compound and MDM2 protein

His-tagged MDM2 (1-118) was expressed in E.coli, purified with Ni affinity column followed by Superdex75 molecular sieve, resulting in MDMX protein purity greater than 95% and protein concentration of 151. Mu.M. FAM-labeled PDI polypeptide (FAM-PDI) [ Cancer Res 2007,67,8810-8817 ]]As a fluorescent-labeled molecular probe, the dissociation constant K of the MDM2/FAM-PDI interaction _d 0.7nM.

96-well plates were purchased from Corning company (Black, # 3694). The multifunctional enzyme-labeled instrument is manufactured by TECAN company, and the model is as follows: SPARK 10M. Detection buffer: 100mM potassium phosphate (pH 8.0), 100ug/mL Bovine-r-globulin (Sigma) and 0.01% Trition X-100 (Sigma), the experimental water was Millipore-Q pure water.

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

a1-A3 wells served as blank: 100. Mu.L of detection buffer was added. a4-A6 wells served as negative signal reference group: mu.L of buffer containing only 2nM of fluorescently labeled molecular probes was added. a7-A9 wells served as positive reference group: mu.L of a mixed solution containing 2nM of the fluorescent-labeled molecular probe and 20nM of MDM2 protein was added.

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

Wherein [ L ]] ₅₀ Representing 50% of the concentration of the fluorescent marker molecular probe in the test system; [ P ]] ₀ Represents the MDM2 protein concentration, K in the test system _d Is the dissociation constant of the protein and the fluorescent-labeled molecular probe.

By using the method, the measurement is carried outObtaining K for inhibiting MDM2/p53 interaction by the Compounds of the examples _i The values are shown in Table 3. Experimental data shows that the compounds have very good activity in inhibiting MDM2/p53 interaction, and the Ki values of the compounds 1-15, 17-39, 41, 44-46 and 48 are all below 10nM, which is significantly better than Nutlin-3a.

Table 3: example Compounds inhibit MDM2/p53 interaction Activity

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* Represent K _i Between 100,000nM and 10,000 nM; * Represents K _i Between 10,000nM and 100 nM; * Represents K _i Between 100nM and 10 nM; * Represents K _i <10nM。

Experimental data shows that the activity of the synthesized novel compound combined with MDM2 is similar to or remarkably improved with that of a positive compound Nutlin-3a.

Example 4: testing compounds for their ability to inhibit cell growth in a variety of human tumor cells

The sample to be tested was dissolved with 100% dimethyl sulfoxide to prepare a 20mM compound mother solution. The compound was diluted with 100% dimethyl sulfoxide to the highest concentration required for the experiment (1 mM or 10 mM).

First, 145. Mu.L of complete medium was added to the B1-G1 wells of a 96-well flat-bottomed transparent cell culture plate, and 100. Mu.L of complete medium was added to the B2-G12 wells, respectively. Then, 5. Mu.L of 1mM or 10mM compound solution was added to each of the B1-D1 and E1-G1 wells, and the mixture was diluted to B12-D12 and E12-G12 in a 3-fold gradient. Finally, 50 μl of the test cell solution was added to each well, and the cell densities of each well were respectively: HCT116, RKO and Hela were around 3000, H460 and U2-OS were around 5000, SW480 and MCF-7 were around 8000, and the total volume per well was 150. Mu.L. In the experiment, two control groups were set up in addition to the compounds tested: 1) Cells and medium were added, but no compound control was added; 2) Only complete medium was added, no cells, no compound group. After incubating the 96-well plates in a 37℃cell incubator containing 5% carbon dioxide for 4 days, 15uL of CCK-8 reagent was added to each well, followed by incubation at 37℃for 2-3 hours. The absorbance at a wavelength of 450nm was read with a TECAN microplate reader.

The effect of different concentrations of compounds on cell activity was calculated using the following formula: [ absorbance of experimental group-absorbance of complete medium alone (cell-free compound-free group)/(absorbance of cell-free compound-free group) -absorbance of complete medium alone (cell-free compound-free group) ×100%.

Processing the above data with GraphPad Prism 6 software, and obtaining IC ₅₀ The values are the concentrations of the corresponding compounds at which the inhibition of cell growth is 50%.

Table 4: example Compounds Activity to inhibit cell growth

# represents IC ₅₀ Between 100,000nM and 10,000 nM; # represents IC ₅₀ Between 10,000nM and 1000 nM; the # # represents IC ₅₀ Between 1,000nM and 100nM, # # # represents IC ₅₀ Less than 100nM.

And \indicates that the result was not tested.

Experimental data indicate that: the compounds tested in the tables all showed greater cell growth inhibition than Nutlin3a in the p53 wild-type cell lines (HCT 116, H460, hela, US-OS, MCF-7 and RKO) and greater cell growth inhibition than Nutlin3a in the p53 mutated SW480 cell line.

Example 5 Western Blot detection of the effects of Nutlen-3 a, YL93 on biomarker proteins p53, p21, MDM2, MDM4, caspase-3 and PARP in HCT116 cells

HCT116 cells were spread evenly on a 6-well plate after pancreatin digestion, placed in a 37 ℃ cell incubator containing 5% carbon dioxide for culturing for 24 hours, the original culture medium was removed after complete adherence, fresh culture mediums containing different concentrations of compounds were added to each well of the 6-well plate, and DMSO groups were used as blank controls and placed in the 37 ℃ cell incubator for culturing for 24 hours. After the incubation, the 6-well plate was removed, and after removal of the compound-containing medium, 1mL of ice-incubated 1 XPBS was added to each well and washed once. 100uLRIPA cell lysate was added to each well, cells were lysed on ice for 30 min, and after centrifugation at 14000 rpm for 30 min at 4℃cell lysate was taken. The BCA protein concentration detection kit was used to determine the concentration of each protein sample. 20ug of protein was subjected to SDS-PAGE per well, and the protein was transferred to nitrocellulose membrane. The nitrocellulose membrane was blocked with 5% nonfat dry milk 1 XTBST (20mM Tris,150mM NaCl,pH 7.6,0.1%Tween-20) solution at room temperature for 2 hours and then washed with 1 XTBST for 5X 5 minutes. Subsequently, primary antibodies to the corresponding proteins (p 53, p21, MDM2, MDM4, caspase-3, PARP, GAPDH) were added and incubated overnight at 4 ℃. After removal of primary antibody on the next day, membranes were washed with 1×tbst for 5×5 min, the corresponding secondary antibody was added, and after incubation for 2 hours at room temperature, membranes were washed with 1×tbst for 5×5 min. Finally, ECL luminescence kit (Thermo Scientific) detects and analyzes the bands of the corresponding proteins. The read pictures are processed by photoshop and power point to obtain corresponding picture data.

Experimental data show that the compound YL093 can improve the expression level of intracellular p53, p21, MDM2 and MDMX proteins, and promote the conversion of intracellular Caspase-3 and PARP to splicing Caspase-3 and splicing PARP. Since elevation of p21 results in cell cycle arrest, production of spliced Caspase-3, spliced PARP, indicates that cells enter apoptosis.

In addition, the expression level of MDM2 and p21 proteins can be significantly increased at 0.3125. Mu.M for compound YL093, while the positive compound Nutlin3a has a cellular function of similar intensity to YL093 at 5. Mu.M. For intracellular p21, the ability of MDM2 protein to affect, YL093 is more than 10-fold more active than Nutlin3a.

The above data illustrate: YL093 can promote cell cycle arrest and apoptosis of HCT-116 intestinal cancer cells. The activity of YL093 is significantly stronger than the MDM2 inhibitor Nutlin3a, widely reported in the literature.

Example 6: determination of the relative spatial configuration of Compounds

FE071 (10 mg) was weighed into a 10mL glass sample bottle, 1.5mL diethyl ether was added, then 2mL n-hexane was slowly added, 3 small holes were punched with a needle after sealing with aluminum foil, and a single crystal was grown by standing at room temperature for 2 days, and the diffraction data and results of the X-ray single crystal diffraction test compound were as shown in Table 5 below: the crystal data indicate the relative steric configuration of FE71 as shown in fig. 2.

TABLE 5X-ray Single Crystal diffraction test Compound diffraction data

FE098 (10 mg) was weighed into a 10mL glass sample bottle, 1.5mL of diethyl ether was added, then 2mL of n-hexane was slowly added, 3 small holes were punched with a needle after sealing with an aluminum foil, and a single crystal was grown by standing at room temperature for 2 days, and diffraction data and results of the X-ray single crystal diffraction test compound are shown in Table 6 below: the crystal data indicate the relative steric configuration of FE098 as shown in fig. 3.

TABLE 6X-ray Single Crystal diffraction test Compound diffraction data

YL141 (10 mg) was weighed into a 10mL glass sample bottle, 1.5mL diethyl ether was added, then 2mL n-hexane was slowly added, 3 small holes were punched with a needle after sealing with aluminum foil, and a single crystal was grown by standing at room temperature for 2 days, and the diffraction data and the results of the X-ray single crystal diffraction test compound are shown in Table 7 below: the crystal data indicate the relative steric configuration of YL141 as shown in fig. 4.

TABLE 7X-ray Single Crystal diffraction test Compound diffraction data

The above experimental data indicate that FE071, FE098 and YL141 are methyl ester-containing compounds before hydrolysis of end product 15 (YL 139), end product 16 (YM 001) and end product 2 (YM 011), respectively, and that the three crystal structure data indicate that the site of substitution reaction of m-nitrobenzyl bromide with YL090 SN2, the site of reductive amination of p-bromobenzaldehyde with YL090, and the site of reductive amination of p-bromobenzoyl chloride with YL090, respectively, are all at primary amine positions, thereby providing substitution, reductive amination and acylation of YL090 and its analogues at primary fatty amine positions, respectively.

All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims

1. A compound of formula (I), an enantiomer, diastereomer or a pharmaceutically acceptable salt thereof,

R ₆ is hydrogen, substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted C3-C8 cycloalkyl;

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

each of the above-described substitutions, unless otherwise defined, independently refers to one or more of the groupsThe hydrogen atoms are substituted with groups selected from the group consisting of: halogen, deuterium, cyano, hydroxy, amino, nitro, C2-C4 alkynyl, C1-C4 alkylsulfonyl, C1-C4 alkylsulfonylaminocarbonyl (C1-C4 alkyl SO) ₂ NHCO-), carboxyl, -CONH ₂ 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 alkyl SO ₂ -, a part of C1-C4 alkyl-S (O) ₂ ) -C1-C4 alkylene-, carboxy-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.

2. The compound of claim 1, wherein the compound has a structure according to formula (II):

wherein Ar, R ₁ 、R ₂ 、R ₃ 、R ₅ 、R ₆ The definition of claim 1.

3. A compound according to claim 1 wherein Ar is a substituted or unsubstituted phenyl group, said substitution being such that one or more hydrogen atoms on the phenyl group are replaced by a group selected from the group consisting of: halogen, deuterium, cyano, hydroxy, carboxy, amino, nitro, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl; the above-mentioned C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl is optionally further substituted with one or more groups selected from the group consisting of: halogen, deuterium, cyano, hydroxy, amino, nitro, carboxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino.

4. The compound of claim 1, wherein R ₁ Is hydrogen, -COCOOH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted- (CH) ₂ ) _m -phenyl, substituted or unsubstituted- (CH) ₂ ) _m -C3-C6 cycloalkyl, substituted or unsubstituted- (CH) ₂ ) _m -5-12 membered heteroaryl, substituted or unsubstituted- (CH) ₂ ) _m -a 5-8 membered heterocyclyl, -CO-substituted or unsubstituted phenyl, -CO-substituted or unsubstituted 3-8 membered cycloalkyl, -SO 2-substituted or unsubstituted phenyl, -CO-substituted or unsubstituted C1-C4 alkyl, -CO-substituted or unsubstituted 5-12 membered heteroaryl, -SO 2-substituted or unsubstituted C1-C4 alkyl;

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

5. The compound of claim 1, wherein R ₂ Is substituted or unsubstituted- (CH) ₂ ) _m -phenyl, substituted or unsubstituted- (CH) ₂ ) _m -C3-C6 cycloalkyl, substituted or unsubstituted- (CH) ₂ ) _m -5-8 membered heteroaryl, substituted or unsubstituted C1-C4 alkyl;

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

the substitution means substitution with one or more groups selected from the group consisting of: amino, hydroxy, carboxy, C1-C4 alkoxy, -CONH ₂ C1-C4 alkyl-CONH-, C1-C4 alkyl-NHCO-, C1-C4 alkylradical-S (O) ₂ ) -C1-C4 alkylene-, C1-C4 alkyl SO ₂ NHCO-, carboxy-substituted C1-C4 alkyl, di (C1-C4 alkyl) amino, mono (C1-C4 alkyl) amino, hydroxy-substituted C1-C4 alkyl, deuterium, fluorine, chlorine, bromine, cyano, nitro.

6. The compound of claim 1, wherein R ₃ 、R ₅ Each independently is hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy.

7. The compound of claim 1, wherein R ₆ Is hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl.

8. The compound of claim 1, wherein the compound is selected from the group consisting of:

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9. a pharmaceutical composition comprising: the compound of claim 1, one or more of its enantiomers, diastereomers, or pharmaceutically acceptable salts; and a pharmaceutically acceptable carrier.

10. The use of a compound, enantiomer, diastereomer or pharmaceutically acceptable salt thereof according to claim 1 for the preparation of a small molecule inhibitor that blocks MDM2/p53 and/or MDMX/p53 interactions; or for the manufacture of a medicament for the treatment of a disease associated with the activity or the expression of MDM2 or MDMX proteins, preferably said disease associated with the activity or the expression of MDM2 or MDMX proteins is selected from the group consisting of: glioma, liposarcoma, cutaneous melanoma, squamous cell carcinoma, retinoblastoma, breast carcinoma, esophageal carcinoma, lung cancer, ovarian cancer, gastric cancer, bladder carcinoma, liver cancer, soft tissue sarcoma, chronic lymphocytic leukemia, acute myelogenous leukemia, lymphoma, osteosarcoma and colon cancer.