Novel biphenyl derivatives, their preparation method and medical uses

Abstract

The present invention relates to the field of medicinal chemistry and discloses biphenyl derivatives with PD-1 / PD-L1 inhibitory activity, methods for preparing them, and uses thereof. The present invention also discloses compositions containing the biphenyl derivatives with PD-1 / PD-L1 inhibitory activity or their pharmaceutically acceptable salts and a pharmaceutically acceptable carrier, and their use in preparing PD-1 / PD-L1 inhibitors. The compounds of the present invention can be used in the treatment of tumors.

Description

[Technical field]

[0001] The present invention relates to the field of medicinal chemistry, in particular to biphenyl derivatives with PD-1 / PD-L1 inhibitory activity, preparation methods, and pharmaceutical compositions containing these compounds and their use in tumor treatment. [Background technology]

[0002] In recent years, tumor immunotherapy has become a focus in the field of tumor treatment. Different from traditional therapeutic methods directly targeting tumor cells, tumor immunotherapy utilizes the body's own immune system to kill tumor cells. Activation of immune checkpoint pathways inhibits the activation of T cells, prevents the excessive activation of the body's immune system, maintains normal immune tolerance of the body, and prevents the occurrence of self-immune diseases. Tumors cause themselves and some lymphocytes to excessively activate immune checkpoint pathways, which causes the occurrence of tumor immune evasion. In these immune checkpoints, excessive activation of PD-1 / PD-L1 plays a very important role in tumor development. Blocking the PD-1 / PD-L1 interaction can reactivate the immune system and kill tumor cells, and has shown good therapeutic effects in treating tumors such as melanoma, colon cancer, and non-small cell lung cancer in clinical trials (Clinical and Translational Oncology, 2019, 21:702-712; The Oncologist, 2019, 24(Suppl 1):S31-S41; Human Vaccines & Immunotherapeutics,2014,10(11):3111-6; Journal of Medicinal Chemistry,2020,63(22):13825-13850).

[0003] Since 2014, several PD-1 or PD-L1 monoclonal antibody drugs have been approved and marketed. These monoclonal antibody drugs have made breakthroughs in the clinical treatment of various tumors. The survival time of many tumor patients has been significantly extended, and some patients' symptoms have been completely alleviated. Although monoclonal antibody drugs have remarkable clinical effects, the long half-life of mab drugs and the long binding time with the target cause severe immune-related adverse reactions. Mab drugs have a complicated manufacturing process, high cost, and are difficult to store and transport, so ordinary patients can only lament for "medicine". Compared with monoclonal antibodies, small molecule drugs have the advantages of low cost, oral administration, ability to cross biological barriers, easy transportation and storage, good membrane permeability, non-immunogenicity, etc. International application WO2015034820A discloses PD-1 / PD-L1 small molecule inhibitors, but there is a lack of research on their B-ring induction group. In the absence of existing technical information, the present inventors unexpectedly developed novel biphenyl derivatives with PD-1 / PD-L1 inhibitory activity, including derivatives containing a 1,2,3-triazole heterocycle. Summary of the Invention

[0004] The present invention provides biphenyl derivatives with PD-1 / PD-L1 inhibitory activity, their preparation methods, and pharmaceutical applications as PD-1 / PD-L1 inhibitors.

[0005] In the present invention, the PD-1 / PD-L1 inhibitory effect refers to the reduction or blocking of the interaction between PD-1 and PD-L1. For example, the inhibitory effect of a compound on PD-1 / PD-L1 can be quantitatively measured by existing techniques or the method described in Example 22 of the present invention.

[0006] Specifically, the present invention provides a biphenyl derivative represented by the general formula (I) or a pharma- ceutically acceptable salt thereof: [ka] (I) During the ceremony, X and Y each represent O, NH, S or CH2, m=0, 1 or 2, n=1, 2, 3 or 4, and p=0 or 1.

[0007] A represents a substituted phenyl group or aromatic heterocyclic group, the aromatic heterocyclic group being a five- or six-membered aromatic ring containing 1 to 3 O, N or S atoms, the substituent being H, F, Cl, Br, CN, NH2, OH, CF3, OCF3, a C1-C3 alkyl group or a C1-C3 alkoxy group.

[0008] L represents -CH2O-, -CH2NH-, -CONH-, -NHCO-, -OCH2-, -NH- or -CH=CH-.

[0009] R 1 and R 2 are NR 7 R 8 , OR 8 or a substituted C4-C6 azacycloalkyl group.

[0010] Here, R 7 represents hydrogen or a C1-C3 alkyl group.

[0011] R 8 represents a substituted C1 to C6 alkyl group. The substituent is OH, NH2, COOH, an amide group, an ester group, or an alkoxy group, and may be mono- or poly-substituted.

[0012] The substituted C4-C6 azacycloalkyl group is a substituted pyrrolidin-1-yl, a substituted piperidin-1-yl, a substituted morpholin-1-yl, a substituted piperazin-1-yl or a substituted azetidin-1-yl, wherein the substituents are OH, NH2, COOH, an amide group, an ester group, an alkoxy group, and may be mono- or poly-substituted.

[0013] R 3 and R 4respectively represent H, F, Cl, Br, CN, CF3, C1-C3 alkyl group or cyclopropyl. R 5 represents H, F, Cl, Br, CN, NH2, OH, CF3, OCF3, a C1-C3 alkyl group, or a C1-C3 alkoxy group.

[0014] R 6 represents H, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a substituted phenyl group or a substituted aromatic heterocyclic group, the aromatic heterocyclic group being a five- or six-membered aromatic ring containing 1 to 3 O, N or S atoms, the substituent being H, F, Cl, Br, CN, an amide group, a sulfonamide group, a methylsulfonyl group or a trifluoromethyl group.

[0015] The biphenyl derivative represented by the general formula (I) of the present invention is preferably a 1,2,3-triazole heterocyclic derivative.

[0016] Preferably, X and Y are O, m is 1, n is 2 or 3, and p is 1.

[0017] Preferably, A is a 1,4-substituted 1,2,3-triazole ring.

[0018] It is preferred that L is -CH2O-.

[0019] R 1 and R 2 teeth [ka] , [ka] , [ka] , [ka] ,

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[0020] R 1 and R 2 teeth [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] or [ka] It is more preferable to show

[0021] R 3 and R 4 preferably denotes -CH3 or Cl.

[0022] R 5 is preferably Cl.

[0023] R 6 is -H or [ka] (5-cyanopyridin-3-yl).

[0024] In the compound of the present invention, X and Y represent O, m=1, p=1, A represents a 1,4-substituted 1,2,3-triazole ring, and L represents -CH2O-, that is, as shown in the following general formula (II). [ka] (II) Here, n=2 or 3.

[0025] R 1 and R 2 are OH, [ka] , [ka] or [ka] Here, R 8 represents CH3, CH2CH3, CH2CH2OH, formyl group, acetyl group, cyclopropyl group, etc., and R 9 and R 10 respectively represent H, OH, COOH, CH2COOH, CH2NH2, CH2OH, CH2CH2OH, F, Cl, Br, CH3, CH2CH3, cyclopropyl, etc., and R 11 is OH, NH2, NHCH3, NHCH2CH3, CH3, OCH3, OCH2CH3, OC(CH3)3, OCH(CH3)2, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] R 12 are CONH2, NHCOCH3, OH, CH2OH, CH2CH2OH, COOH, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] etc., R 13 stands for H, CH3, CH2CH3, CH2OH, CH2CH2OH, etc., and R 14 and R 15 are H, COOH, NH2, F, Cl, Br, CH3, CH2CH3, CH2OH, CH2CH2OH, CONH2, cyclopropyl,

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[0026] R 3 and R 4 respectively represent F, Cl, Br, CN or CH3, and R 5 represents H, F, Cl, Br, CH3 or OCH3, and R 6 is H or [ka] Shows.

[0027] Furthermore, R 1 and R 2 are respectively [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] ,

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[0028] Furthermore, R 1 and R 2 are respectively [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] or [ka] is preferred.

[0029] Preferably, R 3 and R 4 is CH3 and R 5 is Cl, and R 6 is H or [ka] It is.

[0030] The biphenyl derivative represented by general formula (I) of the present invention is preferably II-1, II-2, II-3, II-4, II-5, II-7, II-8, II-9, II-10, II-11, II-12, II-13, II-14, II-15, II-16, II-18, II-19, II-20 or II-21. The compound as above or a pharma- ceutically acceptable salt thereof, wherein the pharma-ceutically acceptable salt is an acid addition salt formed by a compound of general formula (I) with hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, mesylic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

[0031] The compound (I) of the present invention can be prepared by the following method.

[0032] X and Y are O, m=1, n=2 or 3, p=1, A is a 1,4-substituted 1,2,3-triazole ring, R 5 When represents Cl and L represents -CH2O-, the preparation method is as follows:

[0033] Preparation of intermediate IX: [ka] Here, R 3 The definitions are the same as those described above.

[0034] Compound III is first reacted with sulfuric acid to form a salt, then reacted with sodium nitrite to obtain a diazonium salt, and finally hydrolyzed to obtain compound IV. The reaction temperature is selected from 0 to 110°C, preferably 25 to 100°C.

[0035] Compound IV is reacted with 1,3-dibromopropane or 1,4-dibromobutane to prepare compound V. The alkali used is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate, preferably potassium carbonate. The solvent used is selected from acetone, acetonitrile, dioxane, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) or a mixed solvent composed of any two of them, preferably acetone.

[0036] Compound V is reacted with azidotrimethylsilane to prepare compound VI. The solvent used is selected from acetone, acetonitrile, dioxane, N,N-dimethylformamide, dimethylsulfoxide, or a mixed solvent composed of any two of them, and preferably N,N-dimethylformamide is used. The reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C.

[0037] Compound VI is reacted with 3,3-diethoxy-1-propyne to prepare compound VII. The catalyst used is copper sulfate, copper chloride, copper bromide, cuprous chloride, cuprous bromide, cuprous iodide or copper powder, preferably cuprous iodide. The solvent used is tetrahydrofuran, 1,4-dioxane, acetonitrile, ethanol, methanol, ethylene glycol dimethyl ether, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide (DMAc) or a mixed solvent composed of the above solvents and water, preferably acetonitrile and water. The reaction temperature is selected from 0 to 80°C, preferably 20 to 50°C.

[0038] Compound VIII is prepared from compound VII under the action of an acid. The acid used is selected from hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, trifluoroacetic acid, mesylic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and preferably trifluoroacetic acid is used. The solvent used is selected from ethyl acetate, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dioxane, N,N-dimethylformamide, dimethylsulfoxide, or a mixed solvent composed of any two of them, and preferably dichloromethane is used. The reaction temperature is selected from 0 to 80°C, and preferably from 25 to 40°C.

[0039] Compound VIII is reacted with bis(pinacolato)diboron to prepare compound IX. The solvent used is selected from toluene, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, ethanol, acetonitrile, acetone, water or a mixed solvent composed of any two of them, preferably 1,4-dioxane. The alkali used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, potassium bicarbonate, potassium carbonate or triethylamine, preferably potassium acetate. The catalyst used is selected from tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (Pd(dppf)Cl2), bis(triphenylphosphino)palladium chloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2) or (1,1'-bis(diphenylphosphino)ferrocene)nickel chloride (NiCl2(dppf)), preferably Pd(dppf)Cl2 is used. The reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C.

[0040] Preparation of Compound II: [ka] Here, R 1 , R 2 , R 3 , R 4 and R 6 The definitions are the same as those described above.

[0041] Compound X is reacted with SOCl2 in methanol solution to prepare XI.

[0042] Compound XII is prepared by reduction with compound XI. The solvent used is selected from dichloromethane, tetrahydrofuran, methanol, ethanol, N,N-dimethylacetamide or dioxane, preferably methanol. The reducing agent selected is selected from lithium aluminum tetrahydrogen, sodium borohydride or potassium borohydride, preferably lithium aluminum tetrahydrogen. The reaction temperature is selected from -5°C to 50°C, preferably 0 to 25°C.

[0043] Compound XII is subjected to a bromination reaction to prepare compound XIII. The bromination reagent used is selected from N-bromo succinimide (NBS), phosphorus tribromide, carbon tetrabromide, or hydrobromic acid, and preferably phosphorus tribromide is used. The solvent used is selected from dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, acetonitrile, or a mixed solvent composed of the above solvents, and preferably dichloromethane is used. The reaction temperature is selected from -5°C to 50°C, and preferably 0 to 25°C.

[0044] Compound XIII is reacted with 5-chloro-2,4-dihydroxybenzaldehyde under alkaline conditions to prepare compound XIV by Williamson etherification. The solvent used is selected from acetone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, or a mixed solvent composed of the above solvents, and preferably acetonitrile is used. The alkali used is selected from sodium hydride, potassium tert-butoxide, sodium ethoxide, sodium methoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogen carbonate, or potassium hydrogen carbonate, and preferably sodium hydrogen carbonate is used. The reaction temperature is selected from 0°C to 100°C, and preferably 25 to 80°C.

[0045] Compound XIV is reacted with compound IX by Suzuki reaction to prepare compound XV. The solvent used is selected from toluene, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water, or a mixed solvent composed of any two of the solvents, preferably a mixed solvent of 1,4-dioxane and water is used. The alkali used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, potassium bicarbonate, potassium carbonate, or triethylamine, preferably potassium carbonate is used. The catalyst used is selected from Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(OAc)2, or NiCl2(dppf), preferably Pd(PPh3)4 is used. The reaction temperature is selected from 50 to 120°C, preferably 60°C to 100°C.

[0046] Compound XV is reacted with iodomethane or 5-(chloromethyl)smokenitrile under alkaline conditions to prepare compound XVI by Williamson reaction. The solvent used is selected from acetone, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, or a mixed solvent composed of any two of these solvents, and preferably acetonitrile is used. The alkali used is selected from sodium hydride, sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, or lithium hydroxide, and preferably potassium carbonate is used. The reaction temperature is selected from 0°C to 100°C, and preferably 25 to 80°C.

[0047] Compound XVI is subjected to a reductive amination reaction with an amine compound to prepare the target compound II. The solvent used is selected from toluene, N,N-dimethylformamide, dichloromethane, dichloroethane, trichloromethane, carbon tetrachloride, methanol, 1,4-dioxane, tetrahydrofuran, ethanol, acetonitrile, acetone, or a mixed solvent composed of two of the above solvents, preferably a mixed solvent composed of dichloromethane and methanol. The reducing agent used is selected from sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, potassium borohydride, or sodium dithionite, preferably sodium triacetoxyborohydride. The reaction temperature is selected from 0°C to 80°C, preferably 0 to 50°C.

[0048] The present invention also provides a pharmaceutical composition comprising the compound of the above general formula (I) (including chiral isomers) or a pharma- ceutically acceptable salt thereof and a pharma-ceutically acceptable carrier. The compound can be made into a general pharmaceutical preparation such as a tablet, capsule, syrup, suspension, or injection by adding a pharma-ceutically acceptable carrier, and general pharmaceutical additives such as flavorings, sweeteners, liquid or solid fillers or diluents can be added.

[0049] The pharmaceutical composition of the present invention can be administered by any method known to those skilled in the art, such as oral, rectal, sublingual, pulmonary, transdermal, iontophoretic, vaginal, or intranasal administration. The pharmaceutical composition of the present invention is preferably administered outside the gastrointestinal tract, such as subcutaneous, intradermal, or intravenous injection. The dosage varies depending on the formulation type, expected duration of action, and the condition of the subject to be treated, and the effective amount required for actual treatment can be determined by a physician according to the actual situation (patient's condition, body weight, etc.). For a general adult, the dosage of the pharmaceutical composition of the present invention is calculated based on the compound of general formula (I), and can be 1ng-10g per kg of adult body weight, preferably 10μg-100mg per kg of body weight.

[0050] The application of the compound of the present invention, or its hydrate, solvate, crystal or pharma- ceutically acceptable salt, in the preparation of a drug for inhibiting PD-1 / PD-L1 protein-protein interaction is also within the scope of protection of the present invention.In addition, the present invention also provides a method for treatment, comprising administering a therapeutically effective amount of the compound of the present invention, or its hydrate, solvate, crystal or pharma-ceutically acceptable salt, to a subject in need of inhibiting PD-1 / PD-L1 interaction.

[0051] The present invention also provides a use of the compound of the present invention represented by general formula (I) or its hydrate, solvate, crystal or pharma- ceutically acceptable salt in the preparation of an antitumor drug.Furthermore, the present invention also provides a method of treatment comprising administering a therapeutically effective amount of the compound of the present invention represented by general formula (I) or its hydrate, solvate, crystal or pharma-ceutically acceptable salt to a subject suffering from a tumor.

[0052] Preferably, the PD-1 / PD-L1 inhibitors of the present invention can be used in the preparation of a medicament for treating cancer, such as non-small cell lung cancer, colon cancer or malignant melanoma.

[0053] Compared with existing technologies, the present invention has the following significant beneficial effects:

[0054] (1) The novel biphenyl derivatives of the present invention can significantly inhibit the PD-1 / PD-L1 interaction, and their activity is significantly superior to that of the known BMS-202. Of particular importance, the biphenyl compounds of the present invention can inhibit the CD3 +It can significantly block the inhibitory effect on T cells and has the effect of promoting the secretion of immune factor INF-γ by T cells. In the experiment of co-culture of tumor cells and T cells, the promoting effect of the biphenyl compound of the present invention on the expression of INF-γ is significantly higher than that of the positive drug BMS-202 and slightly lower than that of pembrolizumab (5 μg / mL), so it has the effect of enhancing the anti-tumor activity of T cells. Therefore, the biphenyl derivative of the present invention can be used as an immune checkpoint PD-1 / PD-L1 inhibitor in the preparation of tumor immunotherapy drugs. According to the pharmacological experiment, in the homogeneous time-resolved fluorescence experiment (HTRF), the biphenyl derivative of the present invention can produce a good inhibitory effect on the interaction of PD-1 / PD-L1. In the surface plasmon resonance experiment, the biphenyl derivative of the present invention has a very good affinity for human PD-L1. The biphenyl derivative of the present invention can fully inhibit the binding of PD-1 / PD-L1, and can also restore the vitality of T cells and promote the secretion of immune factor INF-γ, so it can be used in tumor immunotherapy. The preferred 1,2,3-triazole heterocyclic derivatives of the present invention have particularly excellent activity, which has great practical significance and potential application prospects for the development of biphenyl PD-1 / PD-L1 inhibitors.

[0055] (2) The synthetic route of the biphenyl derivative of the present invention is well designed and easy to utilize, the raw materials are cheap and easy to obtain, the synthetic method is safe and eco-friendly, and easy to be scaled up for production.

[0056] (3) It is widely applicable and can be used as an active ingredient drug to treat various cancers or tumors associated with the immune checkpoint PD-1 / PD-L1.

[0057] (4) The biphenyl derivative of the present invention is highly safe in use. [Brief description of the drawings]

[0058] [Figure 1] Effect of compounds on INF-γ expression in co-culture experiments. [Diagram 2]1 shows the results of an acute toxicity test of the compound of the present invention. [Diagram 3] The effect of compounds II-1 and II-18 on in vivo antitumor activity in C57BL / 6 mice transplanted with humanized MC38-hPD-L1 cells (influence of tumor volume). [Figure 4] Figure 2 shows the effect of compounds II-1 and II-18 on in vivo antitumor activity in C57BL / 6 mice with humanized MC38-hPD-L1 cells transplanted into the mouse model (influence of tumor mass). [Diagram 5] In the in vivo mouse experiment, the stimulatory effects of compound II-1 (25 mg / kg, ip, bid) and II-18 (25 mg / kg, po, bid) on the CD3+CD4+ T cell subgroups in mice were examined. [Figure 6] In the in vivo mouse experiment, the stimulatory effects of compound II-1 (25 mg / kg, ip, bid) and II-18 (25 mg / kg, po, bid) on the CD3+CD8+ T cell subgroups in mice were examined. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0059] The present invention will be described in detail below with reference to specific examples.

[0060] Example 1 (4-((3'-(3-(4-(((1-carboxyl-2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)serine (II-1:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 teeth [ka] Then, synthesis of n=3) Synthesis of 3-bromo-2-methylphenol (IV-1) Add 3-bromo-2-methylaniline (5.00 g, 26.9 mmol) to a three-neck flask, slowly add sulfuric acid solution (65 mL, 1 mmol / L) while stirring, and a large amount of insoluble white solid will precipitate. After the addition, lower the temperature of the reaction solution to 0-5 °C, slowly add 30% sodium nitrite solution (2.23 g, 32.3 mmol), and a yellow insoluble material will form. After the addition, lower the temperature to 0-5 °C and stir for 30 minutes. Add toluene (30 mL), raise the temperature to 100 °C, and react for 1 hour. After the reaction liquid becomes clear and transparent, the reaction is stopped, cooled to room temperature, and ethyl acetate (50 mL x 3) is extracted. The organic phases are combined, washed with water (30 mL x 2) and saturated sodium chloride solution (20 mL), respectively, dried over anhydrous sodium sulfate, suction filtered, and the solvent is removed under reduced pressure. The product is purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain 4.83 g of white needle-like crystals, the yield is 96.1%, and the mp is 95.0-98.0 ° C.

[0061] 1 H NMR (300 MHz, Chloroform-d) δ 7.19 (dd, J = 8.0, 1.2 Hz, 1H, ArH), 6.97 (t, J = 8.0 Hz, 1H, ArH), 6.76 (d, J = 7.9 Hz, 1H, ArH), 4.82 (s, 1H, OH), 2.38 (s, 3H, CH3).

[0062] Synthesis of 1-(1-bromo-3-(3-bromopropoxy)-2-methylbenzene (V-1) Dissolve 3-bromo-2-methylphenol (5.00 g, 26.7 mmol), 1,3-dibromopropane (8.13 mL, 80.1 mmol), and potassium carbonate (9.23 g, 66.8 mmol) in acetone (50 mL), raise the temperature to reflux, and react for 4 hours, then monitor the complete reaction of the raw materials by TLC (petroleum ether: ethyl acetate = 15:1). Stop heating and cool to room temperature. Add the reaction liquid to ice water (100 mL), extract with ethyl acetate (50 mL × 3), combine the organic phase, wash with water (30 mL × 2) and saturated sodium chloride solution (20 mL × 2), respectively, dry with anhydrous sodium sulfate, filter with suction, remove the solvent under reduced pressure to obtain the crude product, which is purified by column chromatography (petroleum ether 100%) to obtain 6.98 g of a colorless transparent liquid, with a yield of 84.8%.

[0063] 1 H NMR (300 MHz, Chloroform-d) δ 7.16 (dd, J = 8.1, 1.2 Hz, 1H, ArH), 7.00 (td, J = 8.1, 0.6 Hz, 1H, ArH), 6.79 (dd, J = 8.2, 1.2 Hz, 1H, ArH), 4.10 (t, J = 5.7Hz, 2H, OC H 2), 3.62 (t, J = 6.4 Hz, 2H, BrC H 2), 2.39-2.32 (m, 2H, CH2C H 2CH2), 2.31 (s, 3H, C H 3).

[0064] Synthesis of 1-(3-azidopropoxy)-3-bromo-2-methylbenzene (VI-1) Compound V-1 (6.00 g, 19.5 mmol), trimethylsilane azide (3.08 mL, 23.4 mmol), CsF (4.44 g, 29.3 mmol), and DMF (30 mL) were added to the flask in sequence, and the temperature was raised to 50 °C. After 4 hours of reaction, the complete reaction of the raw materials was monitored by TLC (petroleum ether:ethyl acetate = 30:1), heating was stopped, and the mixture was cooled to room temperature. The reaction solution was slowly added to ice water (60 mL), extracted with ethyl acetate (40 mL x 3), and the organic phases were combined, washed with water (40 mL x 2) and saturated sodium chloride solution (30 mL x 2), respectively, dried over anhydrous sodium sulfate, suction filtered, and the solvent was removed under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain 4.91 g of a colorless transparent liquid, with a yield of 93.4%.

[0065] 1 H NMR (300 MHz, Chloroform-d) δ 7.22 (dd, J = 8.1, 1.2 Hz, 1H, ArH), 7.11 (td, J = 8.1, 3.6 Hz, 1H,ArH), 6.83 (dd, J = 8.2, 1.1 Hz, 1H, ArH), 4.10 (t, J = 5.9 Hz, 2H, OCH2), 3.60 (t, J = 6.7 Hz, 2H, CH2N3), 2.34 (d, J = 5.7 Hz, 3H, CH3), 2.21 - 2.07 (m, 2H, CH2C H 2CH2).

[0066] Synthesis of 1-(3-(3-bromo-2-methylphenoxy)propyl)-4-(diethoxymethyl)-1H-1,2,3-triazole (VII-1) Compound VI-1 (4.50 g, 16.7 mmol), 3,3-diethoxy-1-propyne (2.88 mL, 20.1 mmol), cuprous iodide (0.16 g, 0.84 mmol), and acetonitrile (30 mL) were added to the eggplant flask in that order, and the temperature was raised to 30 °C to react. The completion of the raw materials was monitored by TLC (petroleum ether: ethyl acetate = 8:1) for about 12 hours, and then heating was stopped and the mixture was cooled to room temperature. Filter with suction to remove insoluble matter, slowly add the filtrate to water (50 mL), extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with water (30 mL x 2) and saturated sodium chloride solution (30 mL x 2), dry over anhydrous sodium sulfate, filter with suction, remove the solvent under reduced pressure to obtain the crude product, which is purified by column chromatography to obtain 4.89 g of a colorless transparent liquid, the yield is 73.8%, and can be used directly in the next step reaction.

[0067] Synthesis of 1-(3-(3-bromo-2-methylphenoxy)propyl)-1H-1,2,3-triazole-4-formaldehyde (VIII-1) Compound VII-1 (4.50 g, 11.3 mmol) and dichloromethane (30 mL) are added to a recovery flask in turn, and trifluoroacetic acid (3.54 mL, 47.6 mmol) is slowly added dropwise. After stirring at room temperature for 1 hour, the reaction of the raw material is monitored by TLC (petroleum ether: ethyl acetate = 4:1), and the pH is adjusted to 7 with saturated sodium bicarbonate. Extract with dichloromethane (30 mL x 2), combine the organic phases, wash with water (30 mL x 2) and saturated sodium chloride solution (30 mL x 2), dry with anhydrous sodium sulfate, suction filter, remove the solvent under reduced pressure to obtain the crude product, which is purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain 3.25 g of white solid powder, the yield is 89.0%, and the mp is 94.0 - 96.0 °C.

[0068] 1H NMR (300 MHz, Chloroform-d) δ 10.15 (s, 1H, CHO), 8.12 (s, 1H, ArH), 7.19 (d, J = 8.0 Hz, 1H, ArH), 7.00 (t, J = 8.1 Hz, 1H, ArH), 6.72 (d, J = 8.2 Hz, 1H, ArH), 4.69 (t, J = 7.0 Hz, 2H, NCH2), 4.00 (t, J = 5.7 Hz, 2H, OCH2), 2.50 (p, J = 6.3 Hz, 2H, CH2C H 2CH2), 2.33 (s, 3H, CH3).

[0069] Synthesis of 1-(3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)-1H-1,2,3-triazole-4-formaldehyde (IX-1) Compound VIII-1 (3.00 g, 9.25 mmol), bis(pinacolato)diboron (2.83 g, 11.1 mmol), and potassium acetate (2.28 g, 23.2 mmol) were dissolved in 1,4-dioxane (15 mL), and under N2 protection, Pd(dppf)Cl2 (0.34 g, 0.47 mmol) was added, and the temperature was raised to 80 °C for 12 h. Complete reaction of the raw materials was monitored by TLC (petroleum ether:ethyl acetate = 4:1), and the heating was stopped and the mixture was cooled to room temperature. The reaction mixture was slowly added to ice water (30 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with water (20 mL x 2) and saturated sodium chloride solution (20 mL x 2), respectively, dried over anhydrous sodium sulfate, suction filtered, and the solvent was removed under reduced pressure to obtain a crude product, which was separated by column chromatography to obtain 2.71 g of white solid powder, the yield was 78.9%, and the mp was 137.0-139.0 ° C.

[0070] 1H NMR (300 MHz, Chloroform-d) δ 10.02 (s, 1H, CHO), 8.94 (s, 1H, ArH), 7.20 (dd, J = 7.4, 1.2 Hz, 1H, ArH), 7.12 (t, J = 7.5 Hz, 1H, ArH), 6.99 (dd, J = 8.2, 1.6 Hz, 1H, ArH), 4.66 (t, J = 6.9 Hz, 2H, NCH2), 3.97 (t, J = 5.9 Hz, 2H, OCH2), 2.38 (p, J = 6.5 Hz, 2H, CH2C H 2CH2), 2.30 (s, 3H, ArCH3), 1.30 (s, 12H, CH3).

[0071] Synthesis of methyl 3-bromo-2-methylbenzoate (XI-1) Dissolve 3-bromo-2-methylbenzoic acid (X-1) (10.0 g, 46.7 mmol) in methanol (50 mL) and lower the temperature to 0 °C. Slowly add thionyl chloride (4.07 mL, 56.1 mmol), then raise the temperature to 65 °C and reflux for 3 hours. Monitor the complete reaction of the raw materials by TLC (petroleum ether:ethyl acetate = 8:1), stop heating, and cool to room temperature. Evaporate the solvent under reduced pressure to obtain 10.65 g of white solid powder, with a yield of 99.9% and an mp of 31.0-33.0 °C. (Literature value: 30-31 °C (1) Zhang, Peng; Journal of Medicinal Chemistry 2010, V53(16), P6112-6121 CAPLUS).

[0072] 1 H NMR (300 MHz, Chloroform-d) δ 7.72 (d, J = 8.5 Hz, 1H, ArH), 7.68 (d, J = 8.6 Hz, 1H, ArH), 7.09 (t, J = 7.8 Hz, 1H, ArH), 3.90 (s, 3H, OCH3), 2.63 (s, 3H, CH3).

[0073] Synthesis of 3-bromo-2-methylbenzenemethanol (XII-1) Dissolve compound XI-1 (10.50 g, 46.1 mmol) in anhydrous tetrahydrofuran (50 mL), protect with nitrogen gas, lower the temperature to 0 °C, slowly add LiAlH4 (3.10 g, 55.3 mmol) in several portions, then remove the ice bath and stir at room temperature for 30 minutes. Monitor the complete reaction of the raw materials with TLC (petroleum ether: ethyl acetate = 8: 1), slowly add saturated NH4Cl solution dropwise until no bubbles are generated, dilute with ethyl acetate (100 mL), suction filter to remove insoluble matter, wash the organic phase with water (50 mL × 2) and saturated sodium chloride solution (50 mL × 2), respectively, dry with anhydrous sodium sulfate, suction filter, remove the solvent under reduced pressure, and obtain 9.21 g of white solid powder, the yield is 99.9%, and the mp is 103.0-104.0 °C.

[0074] 1 H NMR (300 MHz, DMSO-d6) δ 7.49 (d, J = 8.0 Hz, 1H, ArH), 7.39 (d, J = 7.7 Hz, 1H, ArH), 7.12 (t, J = 7.7 Hz, 1H, ArH), 5.26 (br, 1H, CH2O H ), 4.52 (s, 2H, CH2), 2.30 (s, 3H, CH3).

[0075] Synthesis of 1-bromo-3-(methylbromide)-2-methylbenzene (XIII-1) Compound XII-1 (2.58 g, 12.8 mmol) was dissolved in dichloromethane (20 mL) and the temperature was lowered to 0 °C. Phosphorus tribromide (1.82 mL, 19.2 mmol) was slowly added and the reaction was allowed to proceed at room temperature overnight. The reaction was monitored for completeness by TLC (petroleum ether:ethyl acetate=15:1-8:1), and a small polar spot was formed. The pH was adjusted to alkaline with saturated sodium bicarbonate, and the mixture was extracted with dichloromethane (20 mL x 3), washed with saturated sodium chloride solution (30 mL x 3), washed with water (30 mL x 3), dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain 3.30 g of a colorless, transparent oily liquid, with a yield of 97.4% and an mp of 30.0-31.5 °C.

[0076] 1 H NMR (300 MHz, Chloroform-d) δ 7.52 (dd, J = 8.0, 1.5 Hz, 1H, ArH), 7.27 (s, 1 / 2H, ArH), 7.24 (s, 1 / 2H, ArH), 7.02 (t, J = 7.8 Hz, 1H, ArH), 4.52 (s, 2H, CH2), 2.48 (s, 3H, CH3).

[0077] Synthesis of 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde (XIV-1) Compound XIII-1 (5.00 g, 18.9 mmol), 5-chloro-2,4-dihydroxybenzaldehyde (3.27 g, 18.9 mmol), and sodium bicarbonate (3.97 g, 47.3 mmol) were dissolved in acetonitrile (50 mL), the temperature was raised to 80 °C, and after 12 hours of reaction, the formation of new dopants was monitored by TLC (petroleum ether: ethyl acetate = 8:1 to 4:1) and the reaction was stopped. The reaction solution was added to water (150 mL), and suction filtration was performed to obtain a white powder solid, which was dried in vacuum, and the crude product was subjected to column chromatography to obtain 1.87 g of a white solid powder, with a yield of 27.5% and an mp of 178.0-181.0 °C.

[0078] 1H NMR (300 MHz, Chloroform-d) δ 11.20 (s, 1H, ArO H ), 10.04 (s, 1H, CHO), 7.57 (d, J = 8.1 Hz, 1H, ArH), 7.41 (d, J = 7.5 Hz, 1H, ArH), 7.09 (t, J = 7.8 Hz, 1H, ArH), 6.88 (s, 1H, ArH), 5.10 (s, 2H, CH2), 2.45 (s, 3H, CH3).

[0079] Synthesis of 1-(3-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-1H-1,2,3-triazole-4-formaldehyde (XV-1) Compound XIV-1 (5.20 g, 14.7 mmol), compound IX-1 (4.97 g, 13.4 mmol), and 1,4-dioxane (60 mL) were added to a recovery flask in that order, potassium carbonate (5.18 g, 37.5 mmol) was dissolved in water (6 mL), the reaction liquid was added, and Pd(PPh3)4 (1.55 g, 1.34 mmol) was added under nitrogen gas protection, and the reaction was carried out at 80 °C for 12 hours. After a white insoluble matter precipitated and the complete reaction of the raw materials was monitored by TLC (petroleum ether: ethyl acetate = 4:1), heating was stopped and the mixture was cooled to room temperature. The reaction mixture was added to water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with water (50 mL x 2) and saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, suction filtered, and the solvent was removed under reduced pressure to obtain a dark brown solid. The solid was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 3.70 g of yellow solid powder, the yield was 48.6%, and the mp was 161.0-164.0 °C.

[0080] 1H NMR (400 MHz, DMSO-d6) δ 11.20 (d, J = 1.9 Hz, 1H, OH), 10.05 (s, 1H, CHO), 10.02 (s, 1H, CHO), 8.96 (s, 1H, ArH), 7.71 (s, 1H, ArH), 7.51 (dd, J = 7.8, 1.5 Hz, 1H, ArH), 7.30 (t, J = 7.6 Hz, 1H, ArH), 7.21 (t, J = 7.9 Hz, 1H, ArH), 7.09 (dd, J = 7.6, 1.6 Hz, 1H, ArH), 6.94 (dd, J = 8.4, 1.1 Hz, 1H, ArH), 6.89 (s, 1H, ArH), 6.69 (dd, J = 7.6, 1.1 Hz, 1H, ArH), 5.32 (s, 2H, ArOCH2), 4.69 (t, J = 6.9 Hz, 2H, NC H 2CH2), 4.16 - 3.95 (m, 2H, OC H 2CH2), 2.41 (p, J = 6.8 Hz, 2H, CH2C H 2CH2), 2.01 (s, 3H, CH3), 1.80 (s, 3H, CH3).

[0081] Synthesis of 5-((4-chloro-2-formyl-5-((3'-(3-(4-formyl-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)smokenitrile (XVI-1) Compound XV (2.88 g, 5.54 mmol), 5-(chloromethyl)smonitrile (1.15 g, 6.10 mmol), cesium carbonate (5.40 g, 16.7 mmol), potassium iodide (0.05 g, 0.28 mmol), and N,N-dimethylformamide (15 mL) were added to the flask in that order, and the temperature was raised to 80 °C and reacted for 6 hours. After monitoring the complete reaction of the raw materials by TLC, heating was stopped and the mixture was cooled to room temperature. The reaction mixture was slowly added to ice water (50 mL), suction filtered to precipitate solids, and the filtrate was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with water (20 mL x 2) and saturated sodium chloride (20 mL x 2), respectively, dried over anhydrous sodium sulfate, suction filtered, and the solvent was removed under reduced pressure to obtain a dark brown solid. The solid was purified by column chromatography (petroleum ether: ethyl acetate = 15:1-8:1) to obtain 2.29 g of yellow solid powder, the yield was 65.0%, and the mp was 57.0-59.0 °C.

[0082] 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H, CHO), 10.02 (s, 1H, CHO), 9.06 (s, 1H, ArH), 8.87 (d, J = 2.0 Hz, 1H, ArH), 8.51 (d, J = 2.4 Hz, 1H, ArH), 8.30 (t, J = 2.2 Hz, 1H, ArH), 7.73 (s, 1H, ArH), 7.53 (dd, J = 7.7, 1.4 Hz, 1H, ArH), 7.34 - 7.27 (m, 2H, ArH), 7.21 (t, J = 7.9 Hz, 1H, ArH), 7.10 (dd, J = 7.7, 1.4 Hz, 1H, ArH), 6.94 (d, J = 8.0 Hz, 1H, ArH), 6.70 (d, J = 7.4 Hz, 1H, ArH), 5.45 (s, 2H, ArOCH2), 5.43 (d, J = 2.5 Hz, 2H, ArOCH2), 4.69 (t, J = 6.9 Hz, 2H, NCH2), 4.15 - 4.04 (m, 2H, OCH2), 2.41 (p, J = 6.6 Hz, 2H, CH2C H 2CH2), 2.04 (s, 3H, ArCH3), 1.82 (s, 3H, ArCH3).

[0083] Synthesis of (4-((3'-(3-(4-(((1-carboxyl-2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)serine (II-1) Compound XVI-1 (0.28 g, 0.44 mmol) and methyl serine chloride (274 mg, 1.76 mmol) were dissolved in dichloromethane (10 mL), stirred at room temperature for 30 min, slowly added NaBH(OAc)3 (1.49 g, 7.04 mmol), and reacted at room temperature for 2 h. The reaction was stopped by monitoring the complete reaction of the raw materials by TLC. The pH was adjusted to 7 with saturated sodium bicarbonate solution, extracted with dichloromethane (10 mL x 2), and the organic phases were combined, washed with water (10 mL x 2) and saturated sodium chloride solution (10 mL x 2), respectively, dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure to obtain a dark brown solid, which was purified by thin layer plate (dichloromethane:methanol = 20:1) to obtain 120 mg of a colorless viscous liquid. Dissolve it in methanol (1 mL) and tetrahydrofuran (1 mL) and add it to a recovery flask, add lithium hydroxide monohydrate (20 mg, 0.45 mmol) and react at room temperature for 3 hours. Monitor the complete reaction of the raw materials by TLC (dichloromethane:methanol = 10:1), evaporate and remove the organic solvent under reduced pressure, adjust the pH of the residue to 6-7 with 0.5 M NaOH, precipitate a solid, filter it with suction, and dry it to obtain 70 mg of brown solid powder, with a yield of 19.5%.

[0084] 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H, ArH), 8.73 (s, 1H, ArH), 8.31 (s, 1H, ArH), 8.25 (s, 1H, ArH), 7.60 (s, 1H,ArH), 7.51 (d, J = 7.08 Hz, 1H, ArH), 7.31 - 7.26 (m, 1H, ArH), 7.25 - 7.20 (m, 2H, ArH), 7.10 (d, J = 7.4 Hz, 1H, ArH), 6.96 (d, J = 8.0 Hz, 1H, ArH), 6.72 (d, J = 7.2 Hz, 1H, ArH), 5.33 (s, 4H, ArOCH2), 4.62 (t, J = 6.6 Hz, 2H, NCH2), 4.19 - 4.17 (m, 2H, ArCH2), 4.10 (s, 2H, ArCH2), 4.06 (d, J = 6.4 Hz, 2H, OCH2), 3.88 - 3.69 (m, 4H, 2C H 2OH), 3.64 - 3.41 (m, 2H, CH), 2.37 - 2.34 (m, 2H, CH2C H 2CH2), 2.06 (s, 3H, ArCH3), 1.84 (s, 3H, ArCH3).

[0085] HRMS (ESI): m / z [M+H] + .Calcd for C 41 H 45 ClN7O9: 814.2967, Found: 814.2987.

[0086] Example 2 5-((4-chloro-2-(((2-hydroxyethyl)amino)methyl)-5-((3'-(3-(4-(((2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)smokenitrile (II-2:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 teeth [ka] Then, synthesis of n=3) Compound XVI-1 (0.20 g, 0.31 mmol) and ethanolamine (57 μL, 0.95 mmol) were dissolved in a mixture of dichloromethane (4 mL) and methanol (2 mL), stirred at room temperature for 30 min, slowly added NaBH(OAc)3 (0.81 g, 3.80 mmol), and reacted at room temperature for 2 h. The reaction was stopped when the raw materials were completely reacted by TLC. The pH was adjusted to 7 with saturated sodium bicarbonate solution, and extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with water (10 mL x 2) and saturated sodium chloride solution (10 mL x 2), respectively, dried over anhydrous sodium sulfate, suction filtered, and the solvent was removed under reduced pressure to obtain a pale yellow viscous liquid. The mixture was purified by thin layer plate (dichloromethane:methanol = 20:1-15:1) to obtain 32 mg of yellow solid powder, the yield was 12.9%, and the mp was 61.0-64.0 °C.

[0087] 1H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H, ArH), 8.61 (s, 1H, ArH), 7.96 (s, 1H, ArH), 7.54 (s, 1H, ArH), 7.47 (dd, J = 7.6, 1.4 Hz, 1H, ArH), 7.34 (s, 1H, ArH), 7.31 - 7.29 (m, 1H, ArH), 7.28-7.27 (m, 1H, ArH), 7.20 (t, J = 7.9 Hz, 1H, ArH), 7.15 (dd, J = 7.6, 1.5 Hz, 1H, ArH), 6.80 (dd, J = 11.5, 7.4Hz, 1H, ArH), 6.63 (s, 1H, ArH), 5.17 (s, 2H, ArCH2O), 5.07 (s, 2H, ArCH2O), 4.63 (t, J = 6.9 Hz, 2H, NCH2), 4.15 - 4.05 (m, 2H, OC H 2CH2CH2), 3.95 (s, 2H, ArC H 2NH), 3.81 (s, 2H, ArC H 2NH), 3.73 - 3.65 (m, 4H, C H 2OH), 2.88 - 2.83 (m, 4H, NHC H 2CH2OH) 2.47 (p, J = 6.9 Hz, 2H, CH2C H 2CH2), 2.10 (s, 3H, ArCH3), 1.94 (s, 3H, ArCH3).

[0088] Example 3 N-(2-((4-((3'-(3-(4-(((2-acetylaminoethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)ethyl)acetamide (II-3:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 teeth [ka] Then, synthesis of n=3) Compound XVI-1 (0.20 g, 0.31 mmol) and N-acetylethylenediamine (0.10 g, 0.95 mmol) were dissolved in dichloromethane (5 mL) and added to the reaction flask in turn. The mixture was stirred at room temperature for 30 min, and then NaBH(OAc)3 (0.81 g, 3.80 mmol) was slowly added and the mixture was allowed to react at room temperature for 2 h. The reaction was stopped when the raw materials were completely reacted by TLC. The pH was adjusted to 7 with saturated sodium bicarbonate solution, and extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with water (10 mL x 2) and saturated sodium chloride (10 mL x 2), respectively, dried over anhydrous sodium sulfate, suction filtered, and the solvent was removed under reduced pressure to obtain the crude product, which was separated by column chromatography (dichloromethane:methanol = 50:1 to 20:1) to obtain a pale yellow viscous liquid, which was purified by thin layer plate (dichloromethane:methanol = 20:1 to 15:1) to obtain 61 mg of yellow solid powder, the yield was 24.0%, and the mp was 68.0-70.0 °C.

[0089] 1H NMR (400 MHz, Chloroform-d) δ 8.69 (s, 1H, ArH), 8.63 (s, 1H, ArH), 7.97 (s, 1H, ArH), 7.55 (s, 1H, ArH), 7.45 (d, J = 7.2 Hz, 1H, ArH), 7.37 (s, 1H, ArH), 7.29 - 7.21 (m, 1H, ArH), 7.20 (t, J = 7.9 Hz, 1H, ArH), 7.15 (d, J = 7.6 Hz, 1H, ArH), 6.80 (dd, J = 13.0, 7.9 Hz, 2H, ArH), 6.64 (s, 1H, ArH), 6.51 (s, 1H, CONH), 6.42 (s, 1H, CONH), 5.16 (s, 2H, ArCH2O), 5.10 (s, 2H, ArCH2O), 4.63 (t, J = 6.9 Hz, 2H, NCH2), 4.10 - 4.01 (m, 2H, OCH2), 3.93 (s, 2H, ArC H 2NH), 3.82 (s, 2H, ArC H 2NH), 3.43 - 3.35 (m, 4H, CONHC H 2), 3.07 (s, 2H, NH), 2.82 (t, J = 5.8 Hz, 4H, NHC H 2CH2), 2.48 - 2.35 (m, 2H, CH2C H 2CH2), 2.10 (s, 3H, ArCH3), 1.98 (s, 3H, ArCH3), 1.97 (s, 3H, CH3), 1.94 (s, 3H, CH3).

[0090] Example 4 1-(4-((3'-(3-(4-((2-carbamoylpyrrolidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)pyrrolidine-2-carboxamide (II-4:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 teeth [ka] Then, synthesis of n=3) Compound XVI-1 (0.20 g, 0.31 mmol) and L-prolinamide (0.11 g, 0.95 mmol) were dissolved in dichloromethane (5 mL) and added to the reaction flask in turn and stirred at room temperature for 30 min. NaBH(OAc)3 (0.81 g, 3.80 mmol) was slowly added and the reaction was allowed to proceed at room temperature for 2 h. The presence of a large amount of raw material was monitored by TLC (dichloromethane:methanol=10:1), and NaBH(OAc)3 (0.40 g, 1.90 mmol) was added and the reaction was continued for 4 h to stop the reaction. The pH was adjusted to 7 with saturated sodium bicarbonate solution, and extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with water (10 mL x 2) and saturated sodium chloride (10 mL x 2), respectively, dried over anhydrous sodium sulfate, suction filtered, and the solvent was removed under reduced pressure to obtain the crude product, which was separated by column chromatography (dichloromethane:methanol = 50:1-20:1) to obtain a pale yellow viscous liquid, which was further purified by thin layer plate (dichloromethane:methanol = 15:1-10:1) to obtain 53 mg of yellow solid powder, the yield was 20.3%, and the mp was 98.0-101.0 °C.

[0091] 11H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H, ArH), 8.59 (s, 1H, ArH), 7.94 (s, 1H, ArH), 7.47 - 7.45 (m, 2H, ArH), 7.31 (s, 1H, CONH2), 7.26 (d, J = 7.5 Hz, 2H, ArH), 7.19 (t, J = 7.9 Hz, 1H, ArH), 7.14 (d, J = 7.6 Hz, 1H, ArH), 6.82 (d, J = 8.1 Hz, 1H, ArH), 6.78 (d, J = 7.6 Hz, 1H, ArH), 6.65 - 6.60 (m, 1H, ArH), 5.76 (d, J = 4.0 Hz, 1H, CONH2), 5.55 (s, 1H, CONH2), 5.15 (s, 2H, ArCH2O), 5.06 (s, 2H, ArCH2O), 4.66 - 4.57 (m, 2H, NCH2), 4.08 - 3.98 (m, 2H, OCH2), 3.95 - 3.90 (m, 2H, ArCH2), 3.79 (d, J = 13.8 Hz, 1H, ArCH2), 3.44 (d, J = 12.1 Hz, 1H, ArCH2), 3.21 - 3.15 (m, 1H, 1 / 2pyrrolidine-CH2), 3.15 - 3.07 (m, 2H, pyrrolidine-CH), 3.05 - 2.95 (m, 1H, 1 / 2pyrrolidine-CH2), 2.51 - 2.34 (m, 4H, pyrrolidine-CH2), 2.25 - 2.16 (m, 2H, CH2 CH 2CH2), 2.10 (s, 3H, ArCH3), 1.95 (s, 3H, ArCH3) 1.93 - 1.88 (m, 2H, pyrrolidine-CH2), 1.81 - 1.71 (m, 4H, pyrrolidine-CH2).

[0092] Example 5 (4-((3'-(3-(4-(((carboxymethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)glycine (II-5:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 teeth [ka] Then, synthesis of n=3) Compound XVI-1 (0.20 g, 0.31 mmol) and glycine methyl hydrochloride (0.11 g, 0.95 mmol) were used as raw materials, and the process was the same as that of compound II-1. 35 mg of yellow solid powder was obtained, with a yield of 14.8%. In methanol, the salt was formed by saturating with a methanol solution of hydrogen chloride, and 39.56 mg of yellow solid powder was obtained, with a yield of 98.9%.

[0093] 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 2.0 Hz, 1H, ArH), 8.72 (d, J = 2.3 Hz, 1H, ArH ), 8.27 (t, J = 2.1 Hz, 1H, ArH), 8.16 (s, 1H, ArH), 7.51 (s, 1H, ArH), 7.49 (d, J = 7.6 Hz, 1H, ArH), 7.27 (t, J = 7.6 Hz, 1H, ArH), 7.21 (t, J = 8.0 Hz, 1H, ArH), 7.16 (s, 1H, ArH), 7.10 (d, J = 7.2 Hz, 1H, ArH), 6.94 (d, J = 7.6 Hz, 1H, ArH), 6.70 (d, J = 7.4 Hz, 1H, ArH), 5.31 (s, 4H, 2 ArCH2O), 4.59 (t, J = 6.9 Hz, 2H, NCH2), 4.12 - 4.08 (m, 2H, OCH2), 4.02 (s, 2H, ArCH2), 3.95 (s, 2H, ArCH2), 3.22 (s, 2H, CH2CO), 3.14 (s, 2H, CH2CO), 2.34 (m, 2H, CH2C H 2CH2), 2.04 (s, 3H, ArCH3), 1.82 (s, 3H, ArCH3).

[0094] Example 6 (4-((3'-(2-(4-(((1-carboxyl-2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)serine (II-6: R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 teeth [ka] (n=2) Synthesis of 1-bromo-3-(2-bromoethoxy)-2-methylbenzene (V-2) Compound IV-1 (4.20 g, 18.3 mmol) and 1,2-dibromoethane (4.75 mL, 54.9 mmol) were used as raw materials, and the process was the same as that for compound V-1 to obtain 3.94 g of a colorless transparent liquid with a yield of 73.7%.

[0095] MS (ESI): m / z [M+H] + .Calcd for C9H 11 OBr2:291.9. Found: 291.9.

[0096] 1 H NMR (300 MHz, Chloroform-d) δ 7.24 (d, J = 8.1 Hz, 1H, ArH), 7.05 (t, J = 8.1 Hz, 1H, ArH), 6.80 (d, J = 8.2 Hz, 1H, ArH), 4.33 (t, J =6.1Hz, 2H, OCH2), 3.71 (t, J = 6.0 Hz, 2H, CH2Br), 2.39 (s, 3H, CH3).

[0097] 1-(2-azidoethoxy)-3-bromo-2-methylbenzene (VI-2) Starting from compound V-2 (5.00 g, 17.1 mmol) and TMSN3 (2.69 mL, 20.52 mmol), the process was the same as that for compound VI-1 to obtain 4.15 g of a colorless transparent liquid with a yield of 95.3%.

[0098] 1H NMR (300 MHz, Chloroform-d) δ 7.49 (d, J = 7.9Hz, 1H, ArH), 7.02 (t, J =7.5Hz, 1H, ArH), 6.79(d, J = 8.1 Hz, 1H, ArH), 4.25 (t, J= 5.8 Hz, 2H, OCH2), 3.86 (t, J =5.9 Hz, 2H, CH2N3), 2.37 (s, 3H, CH3).

[0099] 1-(2-(3-bromo-2-methylphenoxy)ethyl)-4-(diethoxymethyl)-1H-1,2,3-triazole (VII-2) Starting from compound VI-2 (4.00 g, 15.6 mmol) and 3,3-diethoxy-1-propyne (2.00 g, 15.6 mmol), the process was the same as for compound VII-1 to obtain 4.32 g of a white solid, which was directly used in the next step without any further treatment.

[0100] 1-(2-(3-bromo-2-methylphenoxy)ethyl)-1H-1,2,3-triazole-4-formaldehyde (VIII-2) Starting from compound VII-2 (4.32 g, 11.2 mmol), the process was the same as that for compound VIII-1, and 2.53 g of white solid was obtained, with a two-step yield of 52.3% and mp of 102.0-104.0 °C.

[0101] 1 H NMR (300 MHz, Chloroform-d) δ 10.18 (s, 1H, CHO), 8.30 (s, 1H, ArH), 7.23 (d, J = 8.1 Hz, 1H, ArH), 7.02 (t, J = 8.2Hz, 1H, ArH), 6.73 (d, J= 8.1Hz, 1H, ArH), 4.91 (t, J =5.1Hz, 2H, NCH2), 4.42 (t, J = 5.1Hz, 2H, CH2O), 2.27 (s, 3H, CH3).

[0102] 1-(2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)-1H-1,2,3-triazole-4-formaldehyde (IX-2) Starting from compound VIII-2 (2.50 g, 8.06 mmol), the process was the same as that of compound IX-1 to obtain 2.45 g of white solid powder, with a yield of 85.3% and mp of 106.5-109.0 °C.

[0103] 1 H NMR (300 MHz, Chloroform-d) δ 10.19 (s, 1H, CHO), 8.37 (s, 1H, ArH), 7.43 (dd, J = 7.5, 1.2 Hz, 1H, ArH), 7.17 (t, J = 7.8 Hz, 1H, ArH), 6.87 (dd, J = 8.2, 1.3 Hz, 1H, ArH), 4.91 (t, J = 5.4 Hz, 2H, NCH2), 4.39 (t, J = 5.5 Hz, 2H, OCH2), 2.40 (s, 3H, CH3), 1.38 (s, 12H, (CH3)4).

[0104] 1-(2-((3'-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)ethyl)-1H-1,2,3-triazole-4-formaldehyde (XV-2) Compound XIV (1.00 g, 2.81 mmol) and compound IX-2 (1.21 g, 3.37 mmol) were used as raw materials, and the process was the same as that of compound XV-1. The product was purified by column chromatography (petroleum ether:ethyl acetate=2:1) ​​to obtain 0.85 g of yellow solid powder, with a yield of 59.7% and mp of 138.0-140.0 °C.

[0105] 1H NMR (300 MHz, Chloroform-d) δ 11.48 (s, 1H, OH), 10.19 (s, 1H, CHO), 9.74 (s, 1H, CHO), 8.35 (s, 1H, ArH), 7.59 (s, 1H, ArH), 7.23 (t, J = 7.9 Hz, 1H, ArH), 7.14 (d, J = 7.6, Hz, 2H, ArH), 7.02 (t, J = 8.2 Hz, 1H, ArH), 6.67 (s, 1H, ArH), 6.54 (d, J = 8.1 Hz, 1H, ArH), 6.41 (d, J = 8.2 Hz, 1H, ArH), 5.24 (s, 2H, ArCH2O), 4.95 (t, J = 4.9 Hz, 2H, NCH2), 4.43 - 4.38 (t, J = 4.9 Hz, 2H, OCH2), 2.09 (s, 3H, ArCH3), 2.07 (s, 3H, ArCH3).

[0106] 5-((4-chloro-2-formyl-5-((3'-(2-(4-formyl-1H-1,2,3-triazol-1-yl)ethoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)smokenitrile (XVI-2) Compound XV-2 (0.70 g, 1.38 mmol), 5-(chloromethyl)smonitrile (0.31 g, 1.66 mmol), cesium carbonate (1.34 g, 4.14 mmol), potassium iodide (11 mg, 0.07 mmol), and N,N-dimethylformamide (15 mL) were added to the flask in order, and the temperature was raised to 80 °C and reacted for 6 h. The complete reaction of the raw materials was monitored by TLC, and the heating was stopped and the mixture was cooled to room temperature. The reaction mixture was slowly poured into ice water, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with water (20 mL x 2) and saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, suction filtered, and the solvent was removed under reduced pressure to obtain a dark brown solid, which was purified by column chromatography (petroleum ether: ethyl acetate = 15:1 to 8:1) to obtain 0.48 g of pale yellow solid powder, the yield was 55.8%, and the mp was 69.0 - 71.0 °C.

[0107] 1 H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 1H, CHO), 10.05 (s, 1H, CHO), 8.99 (s, 1H, ArH), 8.78 (d, J = 2.0 Hz, 1H, ArH), 8.76 (d, J = 2.3 Hz, 1H, ArH), 8.32 (t, J = 2.1 Hz, 1H, ArH), 7.75 (s, 1H, ArH), 7.54 (d, J = 7.0 Hz, 1H, ArH), 7.34 - 7.28 (m, 2H, ArH), 7.25 (t, J = 7.9 Hz, 1H, ArH), 7.09 (d, J = 6.2 Hz, 1H, ArH), 7.03 (d, J = 7.5 Hz, 1H, ArH), 6.74 (d, J = 7.3 Hz, 1H, ArH), 5.47 (s, 2H, ArCH2O), 5.44 (s, 2H, ArCH2O), 4.96 (t, J = 5.3 Hz, 2H, NCH2), 4.57 - 4.51 (m, 2H, OCH2), 2.03 (s, 3H, ArCH3), 1.70 (s, 3H, ArCH3).

[0108] Synthesis of (4-((3'-(2-(4-(((1-carboxyl-2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)serine (II-6) Compound XVI-2 (0.30 g, 0.48 mmol) and serine methyl chloride (0.27 g, 1.93 mmol) are dissolved in dichloromethane (5 mL) and added to the reaction flask in turn, stirred at room temperature for 30 min, slowly added NaBH(OAc)3 (1.64 g, 7.72 mmol) and reacted at room temperature for 2 h. Monitor the complete reaction of the raw materials by TLC and stop the reaction. Adjust the pH to 7 with saturated sodium bicarbonate solution, extract with dichloromethane (10 mL x 2), combine the organic phases, wash with water (10 mL x 2) and saturated sodium chloride solution (10 mL x 2), dry with anhydrous sodium sulfate, filter with suction, remove the solvent under reduced pressure to obtain the crude product, and separate it by column chromatography (dichloromethane:methanol = 100:1 to 40:1) to obtain 153 mg of a colorless viscous liquid. Dissolve it in methanol (1.0 mL) and tetrahydrofuran (1.0 mL) and add it to a recovery flask, add lithium hydroxide monohydrate (21 mg, 0.46 mmol) and react at room temperature for 3 hours. Monitor the complete reaction of the raw materials by TLC (dichloromethane:methanol = 10:1), evaporate and remove the organic solvent under reduced pressure, adjust the pH of the residue to 6-7 with 0.5 M NaOH, precipitate a solid, filter it with suction, and dry it to obtain 0.12 g of yellow solid powder, with a yield of 31.1%.

[0109] 1H NMR (300 MHz, DMSO-d6) δ 8.76 (d, J = 2.1 Hz, 1H, ArH), 8.53 (d, J = 2.2 Hz, 1H, ArH), 8.30 (s, 1H, ArH), 7.99 (d, J = 2.0 Hz, 1H, ArH), 7.69 - 7.46 (m, 3H, ArH), 7.33 - 7.15 (m, 3H, ArH), 7.07 (d, J = 7.6 Hz, 1H, ArH), 6.92 (d, J = 7.1 Hz, 1H, ArH), 5.31 (s, 2H, ArCH2O), 5.18 (s, 2H ArCH2O), 4.88 (s, 2H, OCH2), 4.46 (t, J = 4.7 Hz, 2H, NCH2), 4.24 (s, 2H, ArCH2), 4.09 (dd, J = 13.7, 3.9 Hz, 2H, ArCH2), 3.95-3.83 (m, 4H, C H 2OH), 3.46 (t, 1H, J = 3.7 Hz, CHCO2H), 3.37 (t, 1H, J = 3.7 Hz, CHCO2H), 2.44 (s, 3H, ArCH3), 1.98 (s, 3H, ArCH3).

[0110] Example 7 (4-((3'-(3-(4-(((1-carboxyl-2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)serine (II-7:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 is H, n=3) synthesis Synthesis of 1-(3-((3'-((2-chloro-4-formyl-5-methoxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-1H-1,2,3-triazole-4-formaldehyde (XVI-3) Compound XV-1 (0.72 g, 1.38 mmol), CH3I (0.30 g, 2.07 mmol), and potassium carbonate (0.38 g, 2.76 mmol) were dissolved in N,N-dimethylformamide (10 mL) and reacted at room temperature for 6 hours. The complete reaction of the raw materials was monitored by TLC, heating was stopped, and the mixture was cooled to room temperature. The reaction solution was slowly added to ice water (30 mL), extracted with ethyl acetate (10 mL x 3), and the organic phases were combined and washed with water (10 mL x 2) and saturated sodium chloride solution (10 mL x 2), respectively, dried over anhydrous sodium sulfate, suction filtered, and the solvent was removed under reduced pressure to obtain the crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 8: 1-4: 1) to obtain 0.53 g of white solid powder, with a yield of 71.7%.

[0111] 1 H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H, CHO), 10.04 (s, 1H, CHO), 9.00 (s, 1H, ArH), 7.71 (s, 1H, ArH), 7.57 (d, J = 6.2 Hz, 1H, ArH), 7.34 (t, J = 7.8 Hz, 1H, ArH), 7.23 (t, J = 7.9 Hz, 1H, ArH), 7.15 (s, 1H, ArH), 7.12 (d, J = 6.0 Hz, 1H, ArH), 6.96 (d, J = 8.4 Hz, 1H, ArH), 6.72 (d, J = 7.6 Hz, 1H, ArH), 5.47 (s, 2H, CH2O), 4.71 (t, J = 6.8 Hz, 2H, NC H 2CH2), 4.14 - 4.05 (m, 2H, OCH2), 4.03 (s, 3H, OCH3), 2.43 (t, J = 6.6 Hz, 2H, CH2C H2CH2), 2.06 (s, 3H, ArCH3), 1.81 (s, 3H, ArCH3).

[0112] Synthesis of (4-((3'-(3-(4-(((1-carboxyl-2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)serine (II-7) Compound XVI-3 (250 mg, 0.47 mmol) and serine methyl chloride (182 mg, 1.17 mmol) were used as raw materials, and the process was the same as that for compound II-1 to obtain 42 mg of brown solid powder, with a yield of 12.6%.

[0113] 1 H NMR (300 MHz, DMSO-d6) δ 8.19 (d, J = 2.8 Hz, 1H, ArH), 7.64 (d, J = 5.4 Hz, 1H, ArH), 7.50 (dd, J = 11.0, 6.7 Hz, 1H, ArH), 7.33 - 7.13 (m, 2H, ArH), 7.12 - 6.99 (m, 2H, ArH), 6.93 (d, J = 8.1 Hz, 1H, ArH), 6.66 (t, J = 7.5 Hz, 1H, ArH), 5.34 (s, 2H, ArCH2O), 4.61 (t, J = 7.0 Hz, 2H, NCH2), 4.13 - 3.93 (m, 6H, C H 2OH / ArCH2 / OC H 2), 3.89 (s, 3H, OCH3), 3.81 - 3.69 (m, 2H, C H 2OH), 3.66 (s, 2H, ArCH2), 3.25 - 3.12 (m, 2H, CHCO2H), 2.40 - 2.21 (m, 2H, CH2C H 2CH2), 2.03 (s, 3H, ArCH3), 1.83 (s, 3H, ArCH3).

[0114] Example 8 1-(4-((3'-(3-(4-((2-carbamoylpyrrolidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)pyrrolidine-2-formamide (II-8:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 is H, n=3) synthesis Starting from compound XVI-3 (250 mg, 0.47 mmol) and L-prolinamide (134 mg, 1.17 mmol), the process was the same as that for compound II-4, and 49 mg of brown solid powder was obtained with a yield of 14.3%.

[0115] 1 H NMR (400 MHz, Chloroform-d) δ 7.64 (br, 1H, 1 / 2CONH2), 7.51 (d, J = 7.4 Hz, 1H, ArH), 7.47 (s, 1H, ArH), 7.38 - 7.26 (m, 1H, 1 / 2CONH2), 7.25 (s, 1H, ArH), 7.24 - 7.17 (m, 2H, ArH), 7.14 (d, J = 6.8 Hz, 1H, ArH), 6.82 (d, J = 8.1 Hz, 1H, ArH), 6.79 (d, J = 7.5 Hz, 1H, ArH), 6.59 (s, 1H, ArH), 5.95 - 5.76 (br, 1H, 1 / 2CONH2), 5.66 (br, 1H, 1 / 2CONH2), 5.20 (s, 2H, ArCH2O), 4.63 (t, J = 6.4 Hz, 2H, NCH2), 4.09-4.00 (m, 2H, OCH2), 3.99 - 3.93 (m, 2H, ArCH2N), 3.82 (s, 3H, OCH3), 3.35 - 3.25 (m, 1H, C HCO), 3.22 - 3.09 (m, 2H, ArCH2N), 3.00 - 2.91 (m, 1H, C H CO), 2.52 - 2.43 (m, 4H, 2CH2-prolinamide), 2.35 - 2.18 (m, 4H, 2CH2-prolinamide&CH2C H 2CH2), 2.16 (s, 3H, ArCH3), 2.02 - 1.91 (m, 5H, ArCH3, CH2-prolinamide), 1.82 - 1.70 (m, 4H, CH2-prolinamide).

[0116] HRMS (ESI): m / z [M+Na] + calculated for C 39 H 49 ClN7O5, 752.3303. Found:752.3301.

[0117] Example 9 2-(((1-(3-((3'-((2-chloro-4-(((2-hydroxyethyl)amino)methyl)-5-methoxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-1H-1,2,3-triazol-4-yl)methyl)ethane-1-alcohol (II-9:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 is H, n=3) synthesis Compound XVI-3 (200 mg, 0.38 mmol) and ethanolamine (69.4 mg, 1.12 mmol) were used as raw materials, and the process was the same as that for compound II-2 to obtain 35 mg of yellow solid powder with a yield of 14.8%.

[0118] 1H NMR (300 MHz, Chloroform-d) δ 7.61 (d, J = 7.7 Hz, 1H, ArH), 7.57 (s, 1H, ArH), 7.54 (d, J = 7.7 Hz, 1H, ArH), 7.47 (d, J = 7.7 Hz, 1H, ArH), 7.39 (s, 1H, ArH), 7.27 - 7.10 (m, 2H, ArH), 6.84 (t, J = 7.8 Hz, 2H, ArH), 6.62 (s, 1H, NH), 6.57 (s, 1H, NH), 5.24 (s, 2H, ArCH2O), 5.18 (s, 2H, OH), 4.67 (t, J = 6.8 Hz, 2H, NCH2), 4.12 - 4.04 (m, 2H, OCH2), 3.98 (s, 2H, ArCH2N), 3.88 (s, 3H, OCH3), 3.86 (s, 2H, ArCH2N), 3.72 - 3.69 (m, 4H, NHCH2C H 2), 3.54 (s, 2H, NH), 2.87 (t, J = 5.3 Hz, 4H, NHC H 2CH2), 2.51 - 2.46 (m, 2H, CH2 CH 2CH2) 2.14 (s, 3H, ArCH3), 1.96 (s, 3H, ArCH3).

[0119] HRMS (ESI): m / z [M+Na] + calculated for C 33 H 43 ClN5O5, 646.2772. Found: 646.2778.

[0120] Example 10 N-(2-((4-((3'-(3-(4-(((2-acetylaminoethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)amino)ethyl)acetamide (II-10:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 is H, n=3) synthesis Compound XVI-3 (200 mg, 0.37 mmol) and N-acetylethylenediamine (151 mg, 1.48 mmol) were used as raw materials, and the process was the same as that for compound II-3. 72 mg of yellow solid powder was obtained, with a yield of 27.2% and an mp of 48.0-50.0 °C.

[0121] 1 H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H, CONH), 8.02 (s, 1H, CONH), 7.54 (d, J = 8.2 Hz, 1H, ArH), 7.45 (s, 1H, ArH), 7.35 (s, 1H, ArH), 7.28 (d, J = 7.6 Hz, 1H, ArH), 7.25 - 7.20 (m, 1H, ArH), 7.08 - 7.01 (m, 1H, ArH), 7.00 - 6.95 (m, 2H, ArH), 6.71 (d, J = 8.0 Hz, 1H, ArH), 5.30 (s, 2H, ArCH2O), 4.59 - 4.55 (m, 2H, NCH2), 4.10 - 4.00 (m, 2H, OCH2), 3.85 (s, 3H, OCH3), 3.83 (s, 2H, ArCH2N), 3.74 (s, 2H, ArCH2N), 3.60 (s, 1H, NH), 3.51 (s, 1H, NH), 3.20 - 3.12 (m, 4H, CONHCH2), 2.60 - 2.48 (m, 2H, CH2 CH 2CH2), 2.40 - 2.25 (m, 4H, NH CH 2), 2.06 (s, 3H, ArCH3), 1.87 (s, 3H, ArCH3), 1.81 (s, 6H, COCH3).

[0122] HRMS (ESI): m / z [M+H] +calculated for C 37 H 49 ClN7O5, 706.3484. Found: 706.3477.

[0123] Example 11 (R)-1-((1-(3-((3'-((2-chloro-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-5-methoxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-1H-1,2,3-triazol-4-yl)methyl)pyrrolidine-3-alcohol (II-11:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 is H, n=3) synthesis Compound XVI-3 (300 mg, 0.56 mmol) and R-3-pyrrolidinol chloride (0.35 mg, 2.81 mmol) were used as raw materials, and the process was the same as that for compound II-3. 120 mg of white solid powder was obtained with a yield of 32.9%.

[0124] 1 H NMR (300 MHz, Chloroform-d) δ 7.69 (s, 1H, ArH), 7.53 (d, J = 7.6 Hz, 1H, ArH), 7.42 (s, 1H, ArH), 7.33 (s, 1H, ArH), 7.22 (t, J = 7.8 Hz, 1H, ArH), 7.17 (d, J = 7.3 Hz, 1H, ArH), 6.83 (t, J = 7.8 Hz, 2H, ArH), 6.63 (s, 1H, ArH), 5.25 (s, 2H, ArCH2O), 4.67 (t, J = 6.8 Hz, 2H, NCH2), 4.55 - 4.32 (m, 2H, OCH2), 4.13 - 3.99 (m, 2H, C HOH), 3.94 (s, 2H, ArCH2N), 3.87 (s, 3H, OCH3), 3.86 (s, 2H, ArCH2N), 3.21 (q, J = 9.2 Hz, 1H, pyrrolidine-CH2), 3.13 - 2.98 (m, 2H, pyrrolidine-CH2), 2.94 - 2.80 (m, 2H, pyrrolidine-CH2), 2.79 -2.70 (m, 1H, pyrrolidine-CH2), 2.70 - 2.55 (m, 2H, pyrrolidine-CH2), 2.54 - 2.44 (m, 2H, CH2C H 2CH2), 2.36 - 2.17 (m, 2H, pyrrolidine-CH2), 2.14 (s, 3H, ArCH3), 1.96 (s, 3H, ArCH3), 1.93 - 1.79 (m, 2H, pyrrolidine-CH2).

[0125] HRMS (ESI): m / z [M+H] + calculated for C 37 H 47 ClN5O5, 676.3266. Found: 676.3256.

[0126] Example 12 3-((4-((3'-(3-(4-(((2-carboxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)amino)propionic acid (II-12:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 is H, n=3) synthesis Compound XVI-3 (210 mg, 0.39 mmol) and β-ethyl alanine hydrochloride (0.52 mg, 1.57 mmol) were used as raw materials, and the process was the same as that for compound II-7 to obtain 157 mg of yellow solid powder with a yield of 57.6%.

[0127] 1 H NMR (300 MHz, DMSO-d6+D2O) δ 8.20 (s, 1H, ArH), 7.54 (d, J = 7.5 Hz, 1H, ArH), 7.51 (s, 1H, ArH), 7.31 (t, J = 7.5 Hz, 1H, ArH), 7.23 (t, J = 8.0 Hz, 1H, ArH), 7.10 (d, J = 7.7 Hz, 1H, ArH), 7.04 (s, 1H, ArH), 6.96 (d, J = 8.1 Hz, 1H, ArH), 6.72 (d, J = 7.5 Hz, 1H, ArH), 5.36 (s, 2H, ArCH2O), 4.62 (t, J = 7.0 Hz, 2H, NCH2), 4.11 - 4.03 (m, 2H, OCH2), 4.02 (s, 2H, ArCH2N), 3.93 (s, 2H, ArCH2N), 3.91 (s, 3H, OCH3), 3.00 - 2.88 (m, 4H, NHC H 2), 2.50 - 2.42 (m, 4H, C H 2CO2H& CH2C H 2CH2), 2.38 - 2.35 (m, 2H, C H 2CO2H), 2.06 (s, 3H, ArCH3), 1.84 (s, 3H, ArCH3).

[0128] HRMS (ESI): m / z [M+H] + , calculated for C 35 H 43 ClN5O7680.2851. Found: 680.2834. Example 13 1-(4-((3'-(3-(4-((2-carboxypiperidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)piperidine-2-carboxylic acid (II-13:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 is H, n=3) synthesis Compound XVI-3 (300 mg, 0.56 mmol) and piperidine-2-methyl formate hydrochloride (0.43 mg, 2.81 mmol) were used as raw materials, and the process was the same as that for compound II-7 to obtain 106 mg of yellow solid powder, with a yield of 24.8%.

[0129] 1 H NMR (400 MHz, Chloroform-d) δ 8.10 (s, 1H, ArH), 7.68 (s, 1H, ArH), 7.55 (dd, J = 7.7, 1.4 Hz, 1H, ArH), 7.31 (d, J = 15.1 Hz, 1H, ArH), 7.20 (t, J = 7.9 Hz, 1H, ArH), 7.13 (s, 1H, ArH), 7.10 (dd, J = 7.6, 1.4 Hz, 1H, ArH), 6.93 (d, J = 7.8 Hz, 1H, ArH), 6.70 (d, J = 7.3 Hz, 1H, ArH), 5.46 (s, 2H, ArCH2O), 4.59 (t, J = 6.9 Hz, 2H, NCH2), 4.01 (s, 3H, OCH3), 3.79 - 3.56 (m, 4H, ArCH2 / OCH2), 3.53 (s, 2H, ArCH2), 3.08 - 2.97 (m, 2H, CH), 2.47-2.39 (m, 2H, CH2C H2CH2), 2.36-2.29 (m, 2H, piperidine -CH2), 2.04 (s, 3H, ArCH3), 1.84 (s, 3H, ArCH3), 1.72 - 1.61 (m, 4H, piperidine-CH2), 1.57 -1.57 (m, 4H, piperidine-CH2), 1.38 -1.28 (m, 4H, piperidine-CH2).

[0130] HRMS (ESI): m / z [M+H] + , calculated for C 41 H 51 ClN5O7, 760.3477. Found: 760.3482.

[0131] Example 14 (R)-1-((1-(3-((3'-((2-chloro-4-(((R)-3-hydroxypiperidin-1-yl)methyl)-5-methoxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-1H-1,2,3-triazol-4-yl)methyl)piperidine-3-alcohol (II-14:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 is H, n=3) synthesis Compound XVI-3 (200 mg, 0.37 mmol) and R-piperidine-2-methyl formate hydrochloride (0.23 mg, 1.50 mmol) were used as raw materials, and the process was the same as that for compound II-3 to obtain 179 mg of yellow solid powder, with a yield of 67.86%.

[0132] 1H NMR (400 MHz, Chloroform-d) δ 7.52 (m, 2H, ArH), 7.34 (s, 1H, ArH), 7.20 (t, J = 8.0 Hz, 1H, ArH), 7.15 (d, J = 7.4 Hz, 2H, ArH), 6.81 (t, J = 7.7 Hz, 2H, ArH), 6.59 (s, 1H, ArH), 5.20 (s, 2H, ArCH2O), 4.65 (t, J = 7.1 Hz, 2H, NCH2), 4.06 - 4.01 (m, 2H, OCH2), 3.91 - 3.86 (m, 1H, C H OH), 3.85 - 3.82 (m, 1H, C H OH), 3.82 (s, 3H, OCH3), 3.73 (s, 2H, ArCH2), 3.55 (s, 2H, ArCH2), 2.63 -2.53 (m, 4H, piperidine-CH2), 2.49 (p, J = 6.9 Hz, 2H, CH2C H 2CH2), 2.44 -2.28 (m, 4H, piperidine-CH2), 2.13 (s, 3H, ArCH3), 1.96 (s, 3H, ArCH3), 1.89 -1.76 (m, 2H, piperidine-CH2), 1.69 -1.49 (m, 6H, piperidine-CH2).

[0133] Example 15 (4-((3'-(3-(4-(((1-carboxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)alanine (II-15:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 is H, n=3) Compound XVI-3 (210 mg, 0.39 mmol) and β-ethyl alanine hydrochloride (241 mg, 1.57 mmol) were used as raw materials, and the process was the same as that for compound II-3. The product was purified by column chromatography (dichloromethane:methanol = 80:1 to 30:1) to obtain 157 mg of a yellow-brown solid powder, with a yield of 57.6%.

[0134] 1 H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 1H, ArH), 7.56 (s, 1H, ArH), 7.52 (d, J = 7.2 Hz, 1H, ArH), 7.28 (t, J = 7.7 Hz, 1H, ArH), 7.21 (t, J = 7.8 Hz, 1H, ArH), 7.07 (d, J = 6.5 Hz, 1H, ArH), 7.01 (s, 1H, ArH), 6.94 (d, J = 8.3 Hz, 1H, ArH), 6.69 (d, J = 7.5 Hz, 1H, ArH), 5.35 (s, 2H, ArOCH2), 4.61 (t, J = 7.0 Hz, 2H, NCH2), 4.22 -4.07 (m, 2H, OCH2), 3.87 (s, 3H, OCH3), 4.08 - 4.00 (m, 6H, ArCH2& CH CH3), 2.41 - 2.25 (m, 2H, CH2 CH 2CH2), 2.03 (s, 3H, ArCH3), 1.80 (s, 3H, ArCH3), 1.38 (t, J = 6.8 Hz, 6H, CH3).

[0135] HRMS (ESI): m / z[M+H] + , calculated for C 35 H 43 ClN5O7, 680.2851. Found: 680.28394.

[0136] Example 16 (4-((3'-(3-(4-(((1-carboxyl-2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dichloride-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)serine (II-16:R 1 and R 2 teeth [ka] So, R 3 and R 4 is Cl, R 5 is Cl, R 6 teeth [ka] Then, synthesis of n=3) Synthesis of 1-bromo-3-(3-bromopropoxy)-2-chlorobenzene (V-3) 3-Bromo-2-chlorophenyl (10.00g, 48.2 mmol) and 1,3-dibromopropane (29.40 g, 144.6 mmol) were used as raw materials, and the process was the same as that for compound V-1. After purification by column chromatography, a colorless transparent oily liquid was obtained with a yield of 14.57 g, 92.0%.

[0137] 1 H NMR (300 MHz, Chloroform-d) δ 7.26 (dd, J = 8.1, 1.4 Hz, 1H, ArH), 7.10 (t, J = 8.2 Hz, 1H, ArH), 6.91 (dd, J = 8.3, 1.4 Hz, 1H, ArH), 4.19 (t, J = 5.7 Hz, 2H, OCH2), 3.69 (t, J = 6.3 Hz, 2H, CH2Br), 2.47 -2.31 (m, 2H, CH2C H 2CH2).

[0138] Synthesis of 1-(3-azidopropoxy)-3-bromo-2-chlorobenzene (VI-3) Compound V-3 (10.00 g, 30.7 mmol) and TMSN3 (4.84 mL, 36.8 mmol) were used as raw materials, and the process was the same as that for compound VI-1. After purification by column chromatography, 8.62 g of a colorless transparent oily liquid was obtained with a yield of 98.3%.

[0139] 1 H NMR (300 MHz, DMSO-d6) δ 7.37 (dd, J = 7.8, 1.7 Hz, 1H, ArH), 7.28 (t, J = 8.0 Hz, 1H, ArH), 7.21 (dd, J = 8.2, 1.7 Hz, 1H, ArH), 4.18 (t, J = 6.1 Hz, 2H, OCH2), 3.57 (t, J = 6.7 Hz, 2H, NCH2), 2.04 (p, J = 6.4 Hz, 2H, CH2C H 2CH2).

[0140] Synthesis of 1-(3-(3-bromo-2-chlorophenoxy)propyl)-4-(diethoxymethyl)-1H-1,2,3-triazole (VII-3) Compound VI-3 (4.82 g, 16.6 mmol) and propionaldehyde diethyl acetal (2.34 g, 18.26 mmoL) were used as raw materials, and the process was the same as that for compound VII-1. After purification by column chromatography, 6.68 g of a colorless transparent viscous liquid was obtained, which was directly used in the next step reaction.

[0141] Synthesis of 1-(3-(3-bromo-2-chlorophenoxy)propyl)-1H-1,2,3-triazole-4-formaldehyde (VIII-3) Starting from compound VII-3 (6.68 g, 16.0 mmol) and trifluoroacetic acid (7 mL), the process was the same as that for compound VIII-1, and 4.17 g of white solid powder was obtained with a yield of 75.9% and an mp of 112-114 °C.

[0142] 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H, CHO), 8.98 (s, 1H, ArH), 7.37 (dd, J = 8.0, 1.5 Hz, 1H, ArH), 7.27 (t, J = 8.1 Hz, 1H, ArH), 7.18 (dd, J = 8.3, 1.6 Hz, 1H, ArH), 4.69 (t, J = 6.9 Hz, 2H, NCH2), 4.14 (t, J = 5.9 Hz, 2H, OCH2), 2.42 (p, J = 6.8 Hz, 2H, CH2C H 2CH2).

[0143] Synthesis of 1-(3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)phenoxy)propyl)-1H-1,2,3-triazole-4-formaldehyde (IX-3) Starting from compound VIII-3 (6.42 g, 18.6 mmol) and B2Pin2 (5.68 g, 22.36 mmol), the process was the same as that for compound IX-1, and 5.07 g of pale yellow solid powder was obtained with a yield of 75.6% and an mp of 53.0-54.0 °C.

[0144] 1 H NMR (300 MHz, Chloroform-d) δ 10.17 (s, 1H, CHO), 8.20 (s, 1H, ArH), 7.42 (dd, J = 7.9, 1.7 Hz, 1H, ArH), 7.25 (td, J = 7.8, 1.7 Hz, 1H, ArH), 6.91 (dd, J = 8.2, 1.5 Hz, 1H, ArH), 4.79 (t, J = 6.7 Hz, 2H, NCH2), 4.06 (t, J = 5.6 Hz, 2H, OCH2), 2.55 (p, J = 6.6 Hz, 2H, CH2C H 2CH2), 1.96 (s, 12H, CH3).

[0145] Synthesis of methyl 3-bromo-2-chlorobenzoate XI-2) Starting from 3-bromo-2-chlorobenzeneformic acid (5.22 g, 22.17 mmol) and SOCl2 (1.93 mL, 26.6 mmol), the process was the same as that of compound XI-1, and 5.49 g of a colorless, transparent, viscous liquid was obtained with a yield of 99.3%.

[0146] 1 H NMR (300 MHz, DMSO-d6) δ 8.01 (dd, J = 8.1, 1.5 Hz, 1H, ArH), 7.79 (dd, J = 7.7, 1.6 Hz, 1H, ArH), 7.43 (t, J = 7.9 Hz, 1H, ArH), 3.91 (s, 3H, OCH3).

[0147] Synthesis of (3-bromo-2-chlorobenzene)methanol (XII-2) Starting from compound XI-2 (12.84 g, 51.5 mmol) and LiAlH4 (2.35 g, 61.8 mmol), the process was the same as that for compound XII-1, and 7.80 g of a colorless, transparent, viscous liquid was obtained with a yield of 68.4%.

[0148] 1 H NMR (300 MHz, DMSO-d6) δ 7.70 (dd, J = 7.9, 1.7 Hz, 1H, ArH), 7.64 - 7.55 (m, 1H, ArH), 7.34 (t, J = 7.8 Hz, 1H, ArH), 5.60 (t, J = 5.6 Hz, 1H, CH2O H ), 4.61 (d, J = 5.0 Hz, 2H, C H 2OH).

[0149] Synthesis of 1-bromo-3-(bromomethyl)-2-chlorobenzene (XIII-2) Starting from compound XII-2 (6.40 g, 28.9 mmol) and PBr3 (14.37 g, 43.34 mmol), the process was the same as that for compound XIII-1, and 8.15 g of a colorless transparent liquid was obtained with a yield of 93.6%.

[0150] 1 H NMR (300 MHz, Chloroform-d) δ 7.59 (dd, J = 8.0, 1.5 Hz, ArH), 7.39(dd, J = 7.7, 1.6 Hz, ArH), 7.12 (t, J = 7.8 Hz, ArH), 4.61(s, 2H, CH2).

[0151] Synthesis of 4-((3-bromo-2-chlorobenzyl)-oxy)-5-chloro-2-hydroxybenzaldehyde (XIV-2) Compound XIII-2 (5.00 g, 17.6 mmol) and 5-chloro-2,4-dihydroxybenzaldehyde (3.03 g, 17.6 mmol) were used as raw materials, and the process was the same as that for compound XIV-1. 2.35 g of white powder was obtained, with a yield of 35.5% and an mp of 158.0-160.0 °C.

[0152] 1 H NMR (300 MHz, Chloroform-d) δ 11.41 (s, 1H, OH), 9. 71 (s, 1H, CHO), 7.62 (d, J = 6.5 Hz, 1H, ArH), 7.56 (s, 1H, ArH), 7.42 (dd, J = 7.1, 2.2 Hz, 1H, ArH), 7.34-7.26(m, 1H, ArH), 6.58 (s, 1H, ArH), 5.27 (s, 2H, CH2).

[0153] Synthesis of 5-((4-chloro-5-((2,2'-dichloride-3'-(3-(4-formyl-1H-1,2,3-triazol-1-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)sumonitrile (XVI-4) Synthesis of 5-((5-((3-bromo-2-chlorobenzyl)oxy)-4-chloro-2-formylphenoxy)methyl)smokenitrile (1) Compound XIV-2 (1.00 g, 2.66 mmol), 5-(chloromethyl)smokenitrile (0.60 g, 3.19 mmol), K2CO3 (1.10 g, 7.98 mmol), KI (0.02 g, 0.13 mmol), and DMF (10 mL) were added to a recovery flask, the temperature was raised to 80 °C, and the mixture was reacted for 6 h. The complete reaction of the raw materials was monitored by TLC (petroleum ether: ethyl acetate = 1:1), heating was stopped, and the mixture was cooled to room temperature. The mixture was diluted with ice water (20 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated sodium chloride solution (20 mL × 3), and dried over anhydrous magnesium sulfate. The solid was removed by suction filtration, and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain 0.60 g of yellow solid powder, the yield was 46.1%, and the mp was 140.0-142.0°C.

[0154] 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H, CHO), 8.75 (d, J = 2.0 Hz, 1H, ArH), 8.73 (d, J = 2.3 Hz, 1H, ArH), 8.28 (t, J = 2.1 Hz, 1H, ArH), 7.73 (s, 1H, ArH), 7.71 -7.65 (m, 1H, ArH), 7.59 -7.54 (m, 1H, ArH), 7.46 -7.43 (m, 1H, ArH), 7.25 (s, 1H, ArH), 5.45 (s, 2H, OCH2), 5.42 (s, 2H, OCH2).

[0155] Synthesis of 5-((4-chloro-5-((2,2'-dichloride-3'-(3-(4-formyl-1H-1,2,3-triazol-1-yl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)sumonitrile (XVI-4) Compound IX-2 (1.29 g, 2.62 mmol) and compound 1 (1.23 g, 3.14 mmol) were used as raw materials, and the process was the same as that for compound XVI-1. 0.87 g of yellow-white solid powder was obtained with a yield of 49.0% and an mp of 58.0-60.0 °C.

[0156] 1 H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H, CHO), 10.05 (s, 1H, CHO), 8.99 (s, 1H, ArH), 8.82 (s, 1H, ArH), 8.64 (s, 1H, ArH), 8.09 (s, 1H, ArH), 7.76-7.70 (m, 2H, ArH), 7.60 - 7.54 (m, 1H, ArH), 7.49-7.42 (m, 2H, ArH), 7.34 (s, 1H, ArH), 7.25 (d, J = 8.8 Hz, 1H, ArH), 7.09 (d, J = 7.8 Hz, 1H, ArH), 5.55 (s, 2H, CH2O), 5.44 (s, 2H, CH2O), 4.71 (t, J = 6.7 Hz, 2H, NC H 2CH2), 4.18 (t, J = 6.0 Hz, 2H, OCH2), 2.49 -2.29 (m, 2H, CH2C H 2CH2).

[0157] Synthesis of (4-((3'-(3-(4-(((1-carboxyl-2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dichloride-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)serine (II-15) Compound XVI-4 (200 mg, 0.30 mmol) and serine methyl chloride (184 mg, 1.18 mmol) were used as raw materials, and the process was the same as that for compound II-1 to obtain 83 mg of brown solid powder, with a yield of 32.9%.

[0158] 1H NMR (300 MHz, DMSO-d6) δ 8.81 (s, 1H, ArH), 8.63 (s, 1H, ArH), 8.17 (s, 1H, ArH), 8.11 (t, J = 2.1 Hz, 1H, ArH), 7.72 - 7.66 (m, 1H, ArH), 7.58 - 7.52 (m, 1H, ArH), 7.48 - 7.38 (m, 3H, ArH), 7.25 - 7.18 (m, 2H, ArH), 7.11 (d, J = 7.5 Hz, 1H, ArH), 5.40 (d, J = 5.5 Hz, 2H, ArCH2O), 5.29 (s, 2H, ArCH2O), 4.61 (t, J = 6.8 Hz, 2H, NCH2), 4.13 - 4.11 (m, 2H, ArCH2N), 4.10 - 4.05 (m, 2H, OCH2), 4.02 (s, 2H, ArCH2N), 3.77 -3.61 (m, 4H, 2C H 2OH), 3.27 (t, J = 5.1 Hz, 1H, CH CO2H), 3.21 (t, J = 5.2 Hz, 1H, CH CO2H), 2.39 -2.35 (m, 2H, CH2C H 2CH2). Example 17 (4-((3'-(3-(4-(((carboxymethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dichloride-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)glycine (II-17:R 1 and R 2 teeth [ka] So, R 3 and R 4 is Cl, R 5 is Cl, R 6 teeth [ka] Then, synthesis of n=3) Compound XVI-4 (200 mg, 0.30 mmol) and glycine methyl hydrochloride (148 mg, 1.18 mmol) were used as raw materials, and the process was the same as that for compound II-1 to obtain 76 mg of a brown solid powder, with a yield of 32.3%.

[0159] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H, ArH), 8.61 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.11 (s, 1H, ArH), 7.67 (d, J = 3.6 Hz, 1H, ArH), 7.57 (s, 1H, ArH), 7.56 - 7.51 (m, 1H, ArH), 7.42 (dd, J = 8.5, 4.3 Hz, 2H, ArH), 7.22 - 7.19 (m, 2H, ArH), 7.09 (d, J = 7.4 Hz, 1H, ArH), 5.38 (s, 2H, ArCH2O), 5.32 (s, 2H, ArCH2O), 4.61 (t, J = 6.5 Hz, 2H, NCH2), 4.14 (s, 2H, ArC H 2), 4.12 - 4.08 (m, 2H, OC H 2CH2), 4.03 (s, 2H, ArC H 2), 3.43 (s, 2H, NHC H 2CO), 3.35 (s, 2H, NHC H 2CO), 2.40 - 2.30 (m, 2H, CH2C H 2CH2). Example 18 (5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(4-((((R)-1-ethoxy-3-hydroxy-1-oxopropan-2-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-D-serine ethyl (II-18:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 teeth [ka] (n=3) Compound XVI-1 (0.20 g, 0.31 mmol), triethylamine (0.26 mL, 1.89 mmol), and D-ethyl serine chloride (0.32 g, 1.89 mmol) were used as raw materials, and the process was the same as that of II-2 to obtain 0.14 g of yellow solid powder, with a yield of 46.1%.

[0160] 1 H NMR (400 MHz, Chloroform-d) δ 8.89 (s, 2H, ArH), 8.24 (s, 1H , ArH), 7.54 (s, 1H , ArH), 7.48 (d, J = 7.5 Hz, 1H , ArH), 7.34 (s, 1H, ArH), 7.30 -7.26 (m, 2H, ArH), 7.16 (d, J = 7.5 Hz, 1H, ArH), 6.84 (d, J = 8.2 Hz, 1H, ArH), 6.79 (d, J = 8.2 Hz, 1H, ArH), 6.63 (s, 1H, ArH), 5.20 (s, 2H, ArCH2O), 5.14 (s, 2H, ArCH2O), 4.63 (t, J = 6.9 Hz, 2H, NCH2), 4.29 -4.14 (m, 4H, O CH 2CH3), 4.11 -4.01(m, 4H, CH 2OH & OCH2), 3.92 - 3.86 (m, 2H, C H 2OH), 3.83 -3.80 (m, 2H, ArCH2N), 3.67 -3.60 (m, 2H, ArC H 2NH), 3.51 (t, J = 5.2 Hz, 1H, CHCO), 3.41 (t, J = 5.4 Hz, 1H, CHCO), 2.51 -2.34 (m, 2H, CH2 CH2CH2), 2.08 (s, 3H, ArCH3), 1.95 (s, 3H, ArCH3), 1.32 - 1.21 (m, 6H, OCH2 CH 3).

[0161] HRMS (ESI): m / z [M+H] + , calculated for C 45 H 53 ClN7O9, 870.3593. Found: 870.3589. Example 19 (5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(4-((((R)-1-methoxy-3-hydroxy-1-oxopropan-2-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-D-serine methyl (II-19: R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 teeth [ka] (n=3) Compound XVI-1 (0.28 g, 0.44 mmol), triethylamine (0.24 mL, 1.76 mmol), and D-methyl serine chloride (274 mg, 1.76 mmol) were used as raw materials, and the process was the same as that of II-2 to obtain 0.12 g of yellow solid powder, with a yield of 32.4%.

[0162] 11H NMR (400 MHz, Chloroform-d) δ 8.91 - 8.89 (m, 2H, ArH), 8.26 (s, 1H, ArH), 7.56 (s, 1H, ArH), 7.47 (dd, J = 7.6, 1.4 Hz, 1H, ArH), 7.35 (s, 1H, ArH), 7.30 - 7.26 (m, 1H, ArH), 7.21 (t, J = 7.9 Hz, 1H, ArH), 7.16 (dd, J = 7.6, 1.4 Hz, 1H, ArH), 6.83 (d, J = 8.2 Hz, 1H, ArH), 6.79 (dd, J = 7.6, 1.1 Hz, 1H, ArH), 6.64 (s, 1H, ArH), 5.19 (s, 2H, ArCH2O), 5.16 (s, 2H, ArCH2O), 4.64 (t, 2H, J = 4.0 Hz, NC H 2), 4.10 - 4.02 (m, 4H, CH 2OH & OCH2), 3.92 - 3.87 (m, 2H, C H 2OH), 3.83 - 3.80 (m, 2H, ArC H 2NH), 3.76 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.70 - 3.63 (m, 2H, ArC H 2NH), 3.54 (t, J = 5.1 Hz, 1H, CHCO), 3.46 (t, J = 6.1 Hz, 1H, CHCO), 2.51 - 2.43 (m, 2H, CH2 CH 2CH2), 2.11 (s, 3H, ArCH3), 1.95 (s, 3H, ArCH3).

[0163] HRMS (ESI): m / z [M+H] + 、calculated for C 43 H 49 ClN7O9, 842.3280. Found: 842.3261. Example 20 (5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(4-(((2-ethoxy-2-oxoethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)glycine ethyl (II-20: R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 teeth [ka] (n=3) Compound XVI-1 (0.20 g, 0.31 mmol), ethyl glycine hydrochloride (0.26 g, 1.89 mmol), and triethylamine (0.26 mL, 1.89 mmol) were used as raw materials, and the process was the same as that of II-2 to obtain 0.11 g of a yellow viscous material, with a yield of 40.1%.

[0164] 1 H NMR (300 MHz, Chloroform-d) δ 8.97 (s, 2H, ArH), 8.32 (s, 1H, ArH), 7.63 (s, 1H, ArH), 7.55 (d, J = 7.6 Hz, 1H, ArH), 7.45 (s, 1H, ArH), 7.38 (m, 1H, ArH), 7.29 (d, J = 7.9 Hz, 1H, ArH), 7.25 - 7.21 (m, 1H, ArH), 6.90 (d, J = 8.2 Hz, 1H, ArH), 6.86 (d, J = 7.5 Hz, 1H, ArH), 6.72 (s, 1H, ArH), 5.26 (s, 2H, ArCH2O), 5.22 (s, 2H, ArCH2O), 4.71 (t, J = 6.9 Hz, 2H, NCH2), 4.27 (q, J = 7.1 Hz, 4H, C H2CH3), 4.13 (q, J = 5.3, 4.7 Hz, 2H, OC H 2), 4.04 (s, 2H, ArC H 2NH), 3.87 (s, 2H ArC H 2NH), 3.55 (s, 2H, NHC H 2CO), 3.51 (s, 2H, NHC H 2CO), 2.54 (q, J = 6.4 Hz, 2H, CH2C H 2CH2), 2.19 (s, 3H, ArCH3), 2.03 (s, 3H, ArCH3), 1.36 (t, 3H, J = 7.0 Hz, ArCH3), 1.35 (t, 3H, J = 7.2 Hz, ArCH3).

[0165] HRMS (ESI): m / z [M+H] + , calculated for C 43 H 49 ClN7O7, 840.3382. Found: 840.3363. Example 21 ((1-(3-((3'-((2-chloro-4-((((R)1-ethoxy-3-hydroxy-1-oxopropyl-2-yl)amino)methyl)-5-methoxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)-1H-1,2,3-triazol-4-yl)methyl)-D-serine ethyl (II-21:R 1 and R 2 teeth [ka] So, R 3 and R 4 is -CH3, R 5 is Cl, R 6 is H, n=3) Compound XVI-3 (0.20 g, 0.37 mmol), D-ethyl serine chloride (0.38 g, 2.22 mmol), and triethylamine (0.31 mL, 2.22 mmol) were used as raw materials, and the process was the same as that of II-2 to obtain 0.16 g of a pale yellow viscous product with a yield of 57.1%.

[0166] 1 H NMR (300 MHz, Chloroform-d) δ 7.58 (s, 1H, ArH), 7.53 (d, J = 7.3 Hz, 1H, ArH), 7.33 (s, 1H, ArH), 7.28 (s, 1H, ArH), 7.23 (t, J = 7.9 Hz, 1H, ArH), 7.19 - 7.15 (m, 1H, ArH), 6.84 (t, J = 8.8 Hz, 2H, ArH), 6.62 (s, 1H, ArH), 5.22 (s, 2H, ArCH2O), 4.66 (t, J = 6.8 Hz, 2H, NC H 2), 4.28 (q, J = 7.1 Hz, 2H, OC H 2CH3), 4.20 (q, J = 7.1 Hz, 2H, OC H 2CH3), 4.18 - 4.02 (m, 4H, CH 2OH & OCH2), 3.96 - 3.91 (m, 2H, C H 2OH), 3.88 (s, 3H, OCH3), 3.84 - 3.80 (m, 2H, ArC H 2NH), 3.76 -3.66 (m, 4H, C H 2CH3), 3.56 - 3.53 (m, 1H, CHCO), 3.45 (t, J = 5.2 Hz, 1H, CHCO), 2.51 (d, J = 6.2 Hz, 2H, CH2C H 2CH2), 2.14 (s, 3H, ArCH3), 1.98 (s, 3H, ArCH3), 1.30 (t, J = 7.4 Hz, 6H, CH2C H 3).

[0167] HRMS (ESI): m / z [M+H]+ , calculated for C 39 H 51 ClN5O9, 768.3375. Found: 768.3360. Example 22 The pharmacological experiments of some compounds of the present invention and the results thereof are as follows:

[0168] 1. Evaluation of the inhibitory activity of the compounds of the present invention against hPD-1 / hPD-L1 interaction Purpose of the experiment: To detect the inhibitory activity of the compounds of the present invention against PD-1 / PD-L1 using the hPD-1 / hPD-L1 binding assay kit (CISBIO).

[0169] Experimental principle: HTRF (Homogeneous Time-Resolved Fluorescence) is a technique for detecting analytes in pure liquid phase systems. It mainly uses the energy transfer of two fluorophores, which are divided into the energy donor europium (Eu+) and the energy acceptor. When the donor is excited by an external source (flash, laser, etc.) and is within a sufficiently close distance with the acceptor, it can transfer the energy resonance to the acceptor, which is excited with a specific wavelength. By utilizing HTRF technology, this assay can perform simple and rapid characterization of compounds and antibody blocking agents in a high-throughput format. Eu + By using anti-Tag1 labeled with Europium (HTRF energy donor) and anti-Tag2 labeled with XL665 (HTRF energy acceptor), the interaction between PD-L1 and PD-1 can be detected. When Tag1 and Tag2 are used, the PD-L1 protein and the PD-1 protein are respectively represented, and the Eu + and XL665 bind to PD-L1 and PD-1, respectively, via the antibody, forming a complex. When PD-L1 and PD-1 approach each other and bind, Eu +After being excited by an external laser, it triggers fluorescence resonance energy transfer to XL665, which then emits specifically at 665 nm. The specific signal is directly proportional to the degree of PD1 / PD-L1 interaction. Therefore, compounds or antibodies that block PD-1 / PD-L1 interaction will cause a decrease in the HTRF signal.

[0170] Experimental materials: The reagent kit used was the hPD-1 / hPD-L1 binding assay kit purchased from CISBIO, and the 96-well plate was also purchased from CISBIO.

[0171] Measurement equipment: Perkin Elmer, Model: EnVision.

[0172] Test compounds: Compounds II-1 to II-21 prepared in the present invention. Dissolve in DMSO and dilute with diluent buffer. The concentration of DMSO is 0.5% or less.

[0173] Experimental process: Use hPD-1 / hPD-L1 binding assay kits. Set up negative, positive and dosing groups, with two duplicate wells in each group. For the positive control group, add 2 μL of diluent, 4 μL of PD-L1 diluted according to the instructions and 4 uL of PD-1 to a 96-well plate. For the negative control group, add 6 μL of diluent and 4 μL of PD-L1 to a 96-well plate. For the dosing group, add 2 μL of the compound of the present invention (or positive compound BMS-202), 4 μL of PD-L1 and 4 μL of PD-1 sequentially to a 96-well plate. Blank the plate using a plate blanking film, centrifuge at 1000 rpm for 1 minute and incubate at room temperature for 15 minutes. Then add Anti-Tag-Eu3 diluted with Buffer to the 96-well plate. +Mix equal volumes of Anti-tag-XL665 evenly, then add 10 μL of the mixture to each well, blank the plate, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 2 hours. Remove the blanking film from the plate, and use EnVision to read the fluorescence intensity at 665 nm and 615 nm, and calculate the ratio: Signal 665 nm / Signal 620 nm*10. 4 Calculate the IC of the compound using Graphpad. 50 In this experiment, BMS-202 of WO2015034820 patent of BMS Company is used as the positive drug, and the activity data is referred to Table 1.

[0174] A represents 0.10-10 nM, B represents 10.01-100 nM, and C represents 100.01 nM to 1 μM.

[0175] Table 1. Inhibitory activity of compounds against hPD-1 / hPD-L1 interaction [Table 1] The experimental results show that the compounds of the present invention have significant PD-1 / PD-L1 inhibitory activity, indicating that the biphenyl compounds of the present invention can be used to prepare PD-1 / PD-L1 inhibitor antitumor drugs.

[0176] 2. Testing the affinity of the compounds of the present invention with hPD-L1 protein Experimental principle: When an incident light beam is incident on the interface of two media with different refractive indexes (such as a gold or silver plating layer on a glass surface) at a critical angle, it can induce resonance of the metal free electrons. Due to the resonance, the electrons absorb a certain amount of light, which greatly weakens the reflected light within a certain angle. Among them, the incident angle that makes the reflected light completely disappear within a certain angle is called the SPR angle. The SPR angle changes with the change in the surface refractive index, and the change in refractive index is directly proportional to the mass of biomolecules that bind to the metal surface. The reversible binding / dissociation between molecules causes a real-time change in the refractive index near the gold film, and this phenomenon is recorded in real time by Biacore.

[0177] Experimental Reagents: Fc-hPD-L1 protein is purchased from Acro Biosystems, PBS-P+ buffer 10x buffer, 10 mM glycine pH 1.5, and Series S Sensor Chip Protein A chip are purchased from GE Healthcare Bio-sciences.

[0178] Experimental Method: Test compounds were dissolved in DMSO to make a stock solution with a final concentration of 10 mM, then diluted 1x with 1.05x PBS-P+, and further diluted 4-fold with 1x PBS-P+ buffer containing 5% DMSO. Fc-PD-L1 protein was diluted to 10μg / mL with 1x PBS-P+ solution containing 5% DMSO, and captured on Protein A chip at a flow rate of 10μl / min for 120s. Dual channels were used for each experiment, one channel was used to capture the ligand and the other channel was used as the reference channel. Analytes were prepared at the time of use, and at least five concentrations were set for each analyte, with the concentration selection depending on the analyte, and the analytes were flowed through two channels at 30μl / min for 90s. Solvent calibration was used to eliminate the effect of DMSO, 50% DMSO in 1x PBS-P+ solution was used to wash the flow path, and 10 mM glycine pH 1.5 at 30 μl / min for 30 s was used to regenerate the chip surface, and the experimental temperature was 25°C. The KD value was calculated using the 1:1 binding model using Biacore T200 Evaluation software. The data are shown in Table 2. A represents 0.10-100 nM, and B represents 100.01-1000 nM.

[0179] Table 2. Affinity values ​​of compounds and hPD-L1 [Table 2] The experimental results show that all of the compounds of the present invention can bind to PD-L1 protein with very high affinity, and the biphenyl compounds of the present invention have strong inhibitory activity against PD-L1 protein.

[0180] 3. Experiment of the effect of the compound of the present invention in inhibiting the expression of T cell secreted INF-γ by blocking PD-L1 Experimental principle: Hep3B-OS8-hPDL1 cells (Shanghai Ruizhi Chemical Research Co., Ltd.) stably express hPD-L1 protein on their surface. CD3+ T cells (Shanghai Ruizhi Chemical Research Co., Ltd.) express PD-1 on their surface. When the two cell lines are co-cultured, hPD-L1 on the surface of Hep3B-OS8-hPDL1 cells interacts with PD-1 protein on the surface of CD3+ T cells, thereby inhibiting the activation, proliferation, and expression of immune factor INF-γ of CD3+ T cells. When the compound blocks the interaction of PD-1 / PD-L1, it releases the inhibition on CD3+ T cells and promotes the expression of INF-γ.

[0181] Experimental process: Whole blood was added to EDTA anticoagulant tubes and PBMCs were isolated by density gradient centrifugation. CD3+ T cells were further isolated from PBMCs using the EasySepTM Human T Cell Isolation Kit and resuspended cells in RPMI-1640 complete medium at a concentration of 5 × 10 5 Treat Hep3B-OS8-hPDL1 cells with 10 μg / mL mitomycin, incubate at 37 °C for 1.5 h, wash 4 times with PBS, and resuspend cells in RPMI-1640 complete medium to a concentration of 5 × 10 5Hep3B-OS8-hPDL1 (50 μL / well) and T cells (100 μL / well) were added to a 96-well round-bottom microplate. 4× pembrolizumab (50 μL / well) and 4× the compound to be measured (50 μL / well) were prepared in RPMI-1640 complete medium, and the prepared compound and pembrolizumab were added to the corresponding wells (final concentration of pembrolizumab is 5 μg / mL), making the total volume 200 μL. Three concentration gradients were set up for each drug, and the double wells, pembrolizumab, and BMS-202 were the positive control groups. The cells were cultured for 72 hours in a 5% CO2 incubator at 37°C. After centrifugation at 350×g for 5 minutes, 150 μL of the supernatant was collected and IFN-γ secretion was examined by ELISA. Data processing was performed using GrapdPad Prism6.

[0182] The results are shown in Figure 1. Note: Significant differences can be calculated using one-way analysis of variance (ANOVA). *P < 0.05, **P < 0.01, ***P < 0.001 vs. Blank. The experimental results clearly show that all the compounds of the present invention can release the inhibitory effect on CD3+ T cells and significantly promote the expression of INF-γ by blocking PD-1 / PD-L1 interaction. The compounds of the present invention promote the expression of INF-γ in a dose-dependent manner, which is significantly higher than the effect of BMS-202 and only slightly lower than the effect of pembrolizumab (5μg / mL), and therefore have the effect of enhancing the antitumor activity of T cells. Therefore, the biphenyl compounds of the present invention can be used as immune checkpoint PD-1 / PD-L1 inhibitors in the preparation of tumor immunotherapy drugs.

[0183] 4. Acute toxicity test of the compound of the present invention Objective of the experiment: In order to obtain a safe dosage of the compounds, compounds II-1 and II-18 (250 mg / kg and 125 mg / kg) and BMS-202 (125 mg / kg) were administered by intraperitoneal injection, respectively, and the condition of the mice was observed.

[0184] Experimental process: C57BL / 6 mice were used and kept in a quarantine room for 3 days. They were randomly divided into 5 groups, with 5 mice in each group. They were administered the drug via intraperitoneal injection (0.2 mL / 20 g), and the mice were observed and weighed.

[0185] Experimental results: As shown in Figure 2, after intraperitoneal injection, none of the mice in the compound II-1 and II-18 (250 mg / kg and 125 mg / kg) groups died or lost weight. After intraperitoneal injection of BMS-202 (125 mg / kg), the mice showed severe convulsions, tremors and other symptoms, and lost weight significantly, indicating that the compound of the present invention is safer than BMS-202.

[0186] 5. Antitumor effect of the compound of the present invention in mice Experimental objective: In order to accurately evaluate the antitumor effect of the compound in the body, the antitumor effect of the compound was evaluated using an MC38-hPDL1 cell transplantation model in humanized C57BL / 6 mice (Shanghai Nanfang Model Biotechnology Co., Ltd.).

[0187] Experimental process: Colon cancer cells MC38-hPDL1 were cultured in an incubator at 37℃ with 5% CO2, and the culture medium was DMEM culture medium containing 10% inactivated fetal bovine serum. The cells were grown to full capacity, i.e., subcultured every 3-4 days.

[0188] Cells in logarithmic growth phase were taken, resuspended in PBS, and counted to determine the cell concentration at 1.0 x 10 7 Using a 1 mL syringe, inoculate the cell suspension subcutaneously into the right flank rib of C57BL / 6J-hPDL1 mice at 100 μL per mouse, giving approximately 1.0 × 10 cells / mL. 6 The mean tumor volume was approximately 40–60 mm 3 Mice were observed daily until

[0189] After the modeling was successful, the mice were placed in a quarantine room for 3 days and then reared in an SPF experimental environment. The size of the transplanted tumors in the mice was measured with a caliper, and mice that met the experimental requirements were selected and randomly divided into 4 groups, 5 mice per cage. The average tumor volume of each group was about 54 mm. 3 II-1 (25 mg / kg) was administered by intraperitoneal injection, or II-1 (25 mg / kg) and II-18 (25 mg / kg) were administered by intragastric injection, twice daily. Body weight changes and tumor volumes were measured every two days. Tumor volume (TV) was calculated using the formula: (TV=1 / 2×length×width×width). After 14 days of administration, the mice were sacrificed, and tumor tissues were taken, weighed, photographed, and the data were processed using Graphpad Prism. The spleens were taken, polished, and analyzed by flow cytometer for CD3+ / -1. + CD4 + CD8 + T cell proliferation was measured. Calculation formula: relative tumor proliferation rate T / C % = T RTV / C RTV *100%. (T RTV Treatment group RTV, C RTV : negative control group RTV).

[0190] Experimental results: Figure 3 shows that, compared with the model blank group, both compound II-1 (peritoneal injection group) and II-18 (intragastric injection group) can significantly inhibit the growth of colon cancer (relative tumor inhibition rates are 45.8% and 49.6%, respectively), but compound II-1 (intragastric injection group) has a weaker inhibitory effect on tumor growth. By comparing the chemical structures of compound II-1 and II-18, it can be seen that the two carboxyl groups in the II-1 molecule were esterified to obtain the pre-drug type II-18, and its oral administration significantly improved the antitumor effect. Figure 4 shows that the tumor weight also embodies the excellent antitumor effect (*p<0.05) of compound II-1 (peritoneal injection group) and II-18 (intragastric injection group). Figures 5 and 6 show that the proposed compounds II-1 (intraperitoneal injection group) and II-18 (intragastric injection group) inhibited CD3 + CD4 + T cells and CD3+ CD8 + These results suggest that it is possible to promote the proliferation of T cell subgroups.

Claims

1. A compound represented by general formula II or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, n=2 or 3; R ３ and R ４ are H, F, Cl, Br, CN, and CF, respectively. ３ , C １ -C ３ or a cyclopropyl group, R ５ are H, F, Cl, Br, CN, and NH. ２ , O.H., C.F. ３ , O.C.F. ３ , C １ -C ３ or an alkyl group of １ -C ３ represents an alkoxy group represented by the formula: R ６ is H, C １ -C ３ Alkyl groups of C １ -C ３ halogenated alkyl group of C ３ -C ６ a cycloalkyl group, a substituted phenyl group, or a substituted aromatic heterocyclic group, wherein the aromatic heterocyclic group is a five- or six-membered aromatic ring containing 1 to 3 O, N, or S atoms, and the substituents are H, F, Cl, Br, CN, an amide group, a sulfonylamido group, a methanesulfonyl group, or a trifluoromethyl group; R １ and R ２ are, respectively, 【Chemistry 2】 where R ８ is CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ OH, formyl group, acetyl group, and cyclopropyl group; R ９ and R １０ are H, OH, COOH, and CH ２ COOH, CH ２ N.H. ２ , C.H. ２ O.H., C.H. ２ CH ２ OH, F, Cl, Br, CH ３ , C.H. ２ CH ３ , a cyclopropyl group; R １１ OH, NH ２ , N.H.H. ３ , N.H.H. ２ CH ３ , C.H. ３ , O.C.H. ３ , O.C.H. ２ CH ３ , O.C. (CH ３ ) ３ , OCH(CH ３ ) ２ , 【Chemistry 3】 indicates R １２ , CONH ２ , N.H.C.O. ３ , O.H., C.H. ２ O.H., C.H. ２ CH ２ OH, COOH, 【Chemistry 4】 indicates R １３ is H, CH ３ , C.H. ２ CH ３ , C.H. ２ O.H., C.H. ２ CH ２ OH, R １４ and R １５ are H, COOH, and NH, respectively. ２ , F, Cl, Br, CH ３ , C.H. ２ CH ３ , C.H. ２ O.H., C.H. ２ CH ２ OH, CONH ２ , a cyclopropyl group, 【Chemistry 5】 W represents CH ２ , O, NH, N-CH ３ , N-CH ２ CH ３ , N-CH ２ CH ２ OH, N-COCH ３ wherein q represents 0 or 1; A compound or a pharma- ceutically acceptable salt thereof.

2. R ３ and R ４ are F, Cl, Br, CN, or CH ３ indicates R ５ are H, F, Cl, Br, and CH ３ or OCH ３ indicates R ６ represents H or 5-cyanopyridin-3-yl 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

3. R １ and R ２ are respectively 【Chemistry 6】 indicates R ３ and R ４ are CH ３ indicates R ５ represents Cl, R ６ represents H or 5-cyanopyridin-3-yl 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

4. The compound is (4-((3'-(3-(4-(((1-carboxyl-2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)serine; 5-((4-chloro-2-(((2-hydroxyethyl)amino)methyl)-5-((3'-(3-(4-(((2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile, N-(2-((4-((3'-(3-(4-(((2-acetylaminoethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)amino)ethyl)acetamide, 1-(4-((3'-(3-(4-((2-aminoformylpyrrolidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)pyrrolidine-2-carboxamide, (4-((3'-(3-(4-(((carboxymethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)glycine, (4-((3'-(3-(4-(((1-carboxyl-2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)serine, 1-(4-((3'-(3-(4-((2-aminoformylpyrrolidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)pyrrolidine-2-formamide, 2-(((1-(3-((3'-((2-chloro-4-(((2-hydroxyethyl)amino)methyl)-5-methoxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxyl)propyl)-1H-1,2,3-triazol-4-yl)methyl)ethane-1-alcohol, N-(2-((4-((3'-(3-(4-(((2-acetylaminoethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)amino)ethyl)acetamide, (R)-1-((1-(3-((3'-((2-chloro-4-(((R)-3-hydroxylpyrrolidin-1-yl)methyl)-5-methoxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxyl)propyl)-1H-1,2,3-triazol-4-yl)methyl)pyrrolidine-3-alcohol, 3-((4-((3'-(3-(4-(((2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)amino)propyl acid, 1-(4-((3'-(3-(4-((2-carboxylpiperidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)piperidine-2-carboxylic acid, (R)-1-((1-(3-((3'-((2-chloro-4-(((R)-3-hydroxylpiperidin-1-yl)methyl)-5-methoxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxyl)propyl)-1H-1,2,3-triazol-4-yl)methyl)piperidine-3-alcohol, (4-((3'-(3-(4-(((1-hydroxyethyl)amino)methyl)-1H-1,2,3-triazolyl-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-methoxybenzyl)alanine, (4-((3'-(3-(4-(((1-carboxyl-2-hydroxyethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)serine, (5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(4-((((R)-1-ethoxy-3-hydroxyl-1-oxypropan-2-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-D-serine ethyl, (5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(4-((((R)-1-methoxy-3-hydroxyl-1-oxypropan-2-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-D-serine methyl, (5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3'-(3-(4-(((2-ethoxy-2-oxoethyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)ethyl glycine, or ((1-(3-((3'-((2-chloro-4-((((R)1-ethoxy-3-hydroxyl-1-oxopropyl-2-yl)amino)methyl)-5-methoxyphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxyl)propyl)-1H-1,2,3-triazol-4-yl)methyl)-D-serine ethyl, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

5. The pharma- ceutically acceptable salt is an acid addition salt formed by a compound according to any one of claims 1 to 4 and an acid, the acid being hydrochloric, hydrobromic, sulfuric, carbonic, oxalic, citric, succinic, tartaric, phosphoric, lactic, pyruvic, acetic, maleic, mesylic, benzenesulfonic, p-toluenesulfonic or ferulic acid.

5. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof.

6. A method for producing the compound according to claim 2, comprising the steps of: 【Chemistry 7】 is A manufacturing method comprising the steps of:

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof in the manufacture of a PD-1 / PD-L1 inhibitor drug.

9. 13. Use of a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof in the manufacture of an antitumor medicament.

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