PD-L1 / PARP7 targeting small-molecule derivative as well as preparation method and application thereof

Abstract

The invention discloses a PD-L1 / PARP7 targeting small-molecule derivative as well as a preparation method and application thereof, and provides a PD-L1 / PARP7 targeting small-molecule derivative with a structure as shown in a formula (I) or a formula (II), or an optical isomer, a racemate, a single enantiomer, a possible diastereoisomer, or an optical isomer, a racemate, a single enantiomer and a possible diastereoisomer of the PD-L1 / PARP7 targeting small-molecule derivative. Or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates and the like thereof. The invention also provides a preparation method of the PD-L1 / PARP7 targeting small molecule derivative and application of the compounds in preparation of medicines for treating cancers or infectious diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to small molecule derivatives targeting PD-L1 / PARP7 and preparation methods and applications thereof. Specifically, the present invention discloses a class of small molecule derivatives targeting PD-L1 / PARP7 and preparation methods thereof, and uses of such compounds in treating diseases related to PD-1 / PD-L1 and PRP7 signaling pathways. Background Art

[0002] Compared with large molecule antibody drugs, small molecule compounds have many advantages in pharmacodynamics and pharmacokinetics. For example, small molecule compounds have good oral bioavailability, high permeability to relevant tissues and tumor cells, reasonable half-life, etc., and small molecule compounds have the advantages of low toxicity, high selectivity and effectiveness. In addition, small molecule tumor immunotherapy drugs have the ability to cross cell membranes and other cell barriers, and can reach the target points in cells, thereby exerting anti-tumor immune effects. Although small molecule tumor immunotherapy drugs have many advantages and have achieved certain success in cancer treatment, the occurrence and development of tumors depend on multiple receptors or signal transduction pathways. Therefore, drugs targeting a single molecular mechanism (or pathway) face the following problems: 1) limited effectiveness; 2) easy to produce drug resistance. In response to this problem, in clinical practice, combination therapy is often used as a treatment method because it can both enhance efficacy and delay or inhibit tumor resistance. It has become the main trend of tumor and tumor immunotherapy. However, combination therapy also faces some challenges that need to be solved. For example: unpredictable drug-drug interactions between two molecular entities, complex pharmacokinetics, and high cost. Therefore, in recent years, designing and synthesizing two or more synergistic anti-tumor drugs into a single anti-tumor molecule through chemical means has gradually become an alternative strategy.

[0003] Tumor immunotherapy targeting PD-1 / PD-L1 has been a hot topic in recent years and has made some progress. Although no PD-1 / PD-L1 small molecule inhibitors have been approved for marketing, a series of small molecule compounds published by Bristol-Myers Squibb (BMS) have shown good antagonistic activity against PD-L1 in preclinical trials and have great potential for blocking the PD-1 / PD-L1 signaling pathway. PARP7 is a poly(ADP-ribose) polymerase that catalyzes the transfer of a single unit of ADP-ribose to a substrate, thereby changing its function. As a negative regulator of nucleic acid perception in tumor cells, inhibition of PARP7 has shown the effect of restoring the response of the type I interferon (IFN) signaling pathway to nucleic acids in tumor models. The restoration of this signal can directly inhibit cell proliferation and activate the immune system, both of which contribute to tumor regression. Given that both PD-1 / PD-L1 and PARP7 can kill tumors by improving the immune system; second, the combination of PD-1 antibodies and PARP7 inhibitors (NCT02660034, NCT03016338, and NCT03404960, etc.) has been successfully used in the treatment of tumors in the clinic; third, the successful development of dual-target inhibitors such as PD-L1 / CXCL12, PD-L1 / PARP1, and PD-L1 / HDAC, as well as the mechanistic connection between PD-L1 and PARP7, prompted us to design and synthesize a new type of PD-1 / PL-L1 and PARP7 dual-target inhibitors. Here, the new dual-target inhibitor can inhibit both PD-L1 and PARP7 at the same time, which has not been reported in any literature and is designed for the first time. Targeting PD-L1 and PARP7 at the same time is expected to produce superimposed immune anti-tumor effects, overcome the drug resistance caused by the use of single-target targeted drugs and the low response rate of PD-L1 antibodies alone. Research in this area is of great significance. It will lay a theoretical foundation for the development of new small molecule drugs that combine immunity and targeting. Summary of the invention

[0004] The purpose of the present invention is to provide a small molecule derivative with a novel structure targeting PD-L1 / PARP7 in view of the deficiencies in the prior art.

[0005] In a first aspect, the present invention provides a compound represented by formula (I) and formula (II) or its optical isomers, racemates, single enantiomers, possible diastereomers, or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates thereof:

[0006]

[0007] Where: Each independently selected from one of the following structural fragments, wherein R is -CN, -CF3 or -CH3, wherein m is any one of 1-4:

[0008]

[0009] L 1 Each independently selected from one of the following structural fragments:

[0010] Where n is any natural number from 1 to 10

[0011] L 2 Each independently selected from one of the following structural fragments:

[0012] Furthermore, the small molecule derivative targeting PD-L1 / PARP7 is any one of compounds 1 to 34 shown in the following structures:

[0013]

[0014]

[0015]

[0016]

[0017] The second aspect of the present invention is to provide a method for synthesizing the above-mentioned compound, including synthetic route 1, synthetic route 2 and synthetic route 3:

[0018] Synthesis route 1:

[0019]

[0020] The specific steps include:

[0021] (1) Add triphenylphosphine (PPh3) to the THF solution of compound A-1 and compound A-2, and then add diisopropyl azodicarboxylate (DIAD) solution dropwise to the reaction solution under ice bath conditions. After the addition is complete, return to room temperature and continue stirring for 24 hours to stop the reaction. Post-treatment and purification give intermediate A-3;

[0022] (2) To a dichloroethane solution of compounds A-3 and A-4, sodium triacetoxyborohydride (NaBH(OAc)3) was added, and the mixture was stirred at 80°C for 1-2 hours to stop the reaction. The intermediate A-5 was obtained after post-treatment.

[0023] (3) Add solid sodium hydroxide to a mixed solution of methanol and water of intermediate A-5, stir at room temperature for 4 hours, stop the reaction, and post-treat to obtain compound A-6;

[0024] (4) Add DIPEA, EDCI and HOBt to a dichloromethane solution of compounds A-6 and A-7, stir at room temperature for 6 h, stop the reaction, and post-treat to obtain intermediate A-8;

[0025] (5) Add trifluoroacetic acid to a dichloromethane solution of compound A-8, stir at room temperature for 0.5 h, stop the reaction, and post-treat to obtain intermediate A-9;

[0026] (6) DIPEA, EDCI and HOBt were added to the dichloromethane solution of intermediates A-9 and A-10, stirred at room temperature for 6 h, the reaction was stopped, and post-treatment was performed to obtain the small molecule derivative targeting PD-L1 / PARP7 shown in (I).

[0027] Synthesis route 2:

[0028]

[0029] The specific steps include:

[0030] (6) Add boron tribromide (BBr3) solution dropwise to a dichloromethane solution of compound B-1. After the addition, stir under ice bath for 0.5 h to stop the reaction. Post-treatment and purification are performed to obtain intermediate B-2.

[0031] (7) Add solid NaHCO3 to the DMF solution of intermediates B-2 and B-3, stir at 60 °C for 2 h, stop the reaction, and perform post-treatment and purification to obtain intermediate B-4;

[0032] (8) Add Cs2CO3 solid to the DMF solution of intermediates B-4 and B-5, stir at 80 °C for 2 h, stop the reaction, and perform post-treatment and purification to obtain intermediate B-6;

[0033] (9) Sodium triacetoxyborohydride (NaBH(OAc)3) was added to a dichloroethane solution of compounds B-6 and A-4. After the addition, the mixture was stirred at 80°C for 1-2 hours to stop the reaction. The intermediate B-7 was obtained after post-treatment and purification.

[0034] (10) Add solid sodium hydroxide to a mixed solution of methanol and water of intermediate B-7, stir at room temperature for 4 h, stop the reaction, and post-treat to obtain compound B-8;

[0035] (4) Add DIPEA, EDCI and HOBt to a dichloromethane solution of compounds B-8 and A-7, stir at room temperature for 6 h, stop the reaction, and post-treat to obtain intermediate B-9;

[0036] (5) Add trifluoroacetic acid to a dichloromethane solution of compound B-9, stir at room temperature for 0.5 h, stop the reaction, and post-treat to obtain intermediate B-10;

[0037] (6) DIPEA, EDCI and HOBt were added to the dichloromethane solution of intermediates B-10 and A-10, and the mixture was stirred at room temperature for 6 h. The reaction was stopped and post-treated to obtain the small molecule derivative targeting PD-L1 / PARP7 shown in (I).

[0038] Synthesis route three:

[0039]

[0040] The specific steps include:

[0041] DIPEA, EDCI and HOBt were added to the dichloromethane solution of compounds A-6 and C-1, and the mixture was stirred at room temperature for 6 h. The reaction was stopped and post-treated to obtain the small molecule derivative targeting PD-L1 / PARP7 shown in (II).

[0042] The second aspect of the present invention provides a pharmaceutical composition, which includes the compound or its stereoisomer described in the first aspect of the present invention, or its pharmaceutically acceptable salt, solvate or prodrug; and at least one other agent, wherein the other agent is an anticancer agent, a chemotherapeutic agent or an antiproliferative compound.

[0043] The third aspect of the present invention is to provide the use of the compound as described in the first aspect of the present invention, or its optical isomers, racemates, single enantiomers, possible diastereomers, or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, or the pharmaceutical composition as described in the second aspect of the present invention in the preparation of a drug for treating cancer or infectious diseases.

[0044] Preferably, the cancer is selected from the group consisting of bone cancer, head or neck cancer, pancreatic cancer, skin cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, including acute myeloid leukemia, The invention relates to leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, solid tumors in children, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, cancer of the renal pelvis, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, asbestos induced cancers, and combinations of said cancers.

[0045] Preferably, the infectious disease is a bacterial infectious disease, a viral infectious disease or a fungal infectious disease.

[0046] The fourth aspect of the present invention provides the above-mentioned compound, or its optical isomers, racemates, single enantiomers, possible diastereomers, or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, or the pharmaceutical composition as described in the second aspect of the present invention for use in regulating the immune response mediated by the PD-1 signaling pathway.

[0047] The fifth aspect of the present invention provides a method for inhibiting the growth and / or migration of tumor cells in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound or its stereoisomer as described in the first aspect of the present invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or the pharmaceutical composition as described in the second aspect of the present invention.

[0048] Preferably, the tumor cell is selected from the following cancers: bone cancer, head or neck cancer, pancreatic cancer, skin cancer, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, including The invention relates to acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, solid tumors in children, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, cancer of the renal pelvis, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, including asbestos induced cancers, and combinations of said cancers.

[0049] The sixth aspect of the present invention provides a method for treating bacterial, viral and fungal infections in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound or its stereoisomer as described in the first aspect of the present invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition as described in the second aspect of the present invention.

[0050] Preferably, infectious diseases include, but are not limited to, HIV, influenza, herpes, Giardia, malaria, Leishmania, pathogenic infections caused by hepatitis viruses (A, B, & C), herpes viruses (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein Barr (Epstein Barr) virus), adenovirus, influenza virus, arbovirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, polio virus, rabies virus, JC virus and arbovirus encephalitis virus, pathogenic infections caused by bacterial chlamydia, rickettsial bacteria, mycobacteria, staphylococcus, streptococcus, pneumonia coli, Legionella, diphtheria, salmonella, bacillus, cholera, tetanus, botulism, anthrax, plague, spirochetosis, and Lyme disease bacteria; pathogenic infections caused by the following fungi: Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Mucor (Mucor, oryzae, rhizophus), Sporothrix schenckii, Blastomyces dermatitidis dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum, and pathogenic infections caused by the following parasites: Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Girdia lambia, Cryptosporidium sp.), Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylus brasiliensis.

[0051] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

[0052] Compared with the prior art, the beneficial effects of the present invention are at least:

[0053] The compound provided by the present invention has dual targets of PD-L1 and PARP7, is a novel compound, improves the drug activity of anti-cancer and anti-infection, and is groundbreaking compared with simple structural modification. The present invention also provides a preparation method and use of small molecule derivatives targeting PD-L1 / PARP7, and the activity of these compounds in inhibiting PD-L1 and PARP7. The small molecule derivatives targeting PD-L1 / PARP7 in the present invention are expected to become candidate drugs for anti-tumor drugs and candidate drugs for anti-infective diseases, and treat various cancers and infectious diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 The effects of some compounds of the present invention on IFN-γ secretion;

[0055] Figure 2 This is the effect of some compounds of the present invention on the expression of hPD-L1 protein. DETAILED DESCRIPTION

[0056] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only intended to illustrate the present invention and are not intended to limit the scope of the present invention. The operating methods in the following examples where no specific conditions are indicated are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0057] Example 1: Preparation of Compound 1

[0058]

[0059] Step 1: Cesium carbonate (14.0 g, 42.8 mmol) was added to a solution of 1a (5.00 g, 28.6 mmol) and 1b (12.8 g, 142.8 mmol) in anhydrous acetonitrile (100 mL) at room temperature. The resulting solution was stirred at 25 ° C for 10 h. The reactants were then quenched by adding 200 mL of water. The resulting solution was extracted with 3×200 mL EtOAc, and the organic layers were combined and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo and the crude product was purified by silica gel column chromatography to obtain a light yellow liquid compound 1c (4.20 g, yield 61.7%). 1 H NMR(500MHz,DMSO-d6)δ6.69(dd,J=87.8,8.3Hz,1H),3.63–3.52(m,6H),3.29(dd,J=9.6,6.0Hz,1 H),3.14(dd,J=9.6,6.7Hz,1H),2.52(d,J=12.4Hz,2H),1.38(d,J=2.9Hz,9H),1.03–0.95(m,3H).

[0060] Step 2: In an ice bath, slowly add trifluoroacetic acid (TFA, 1.5 mL) to a solution of 1c (2.9 g, 11.1 mmol) in dichloromethane (30 mL). After the addition, gradually return the reaction solution to room temperature and stir for 6 h. After complete conversion, evaporate the solvent under reduced pressure to obtain intermediate 1d (crude product), which is used directly in the next stage without further purification.

[0061] Step 3: Add Et3N (10 mL) and EtOH (100 mL) and compound 1e (3.7 g, 11.1 mmol) to the crude intermediate 1d. The reaction mixture was stirred at 60 ° C for 12 h. The reaction was monitored by TLC. After complete conversion, water (200 mL) was added to the reaction solution to quench it, and then extracted with EtOAc (300 mL×3). The combined organic phase was washed with saturated brine (100 mL×2) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH=20:1, v / v) to obtain a colorless oil compound 1f (2.7 g, yield 54%)

[0062] Step 4: In an ice bath, slowly add trifluoroacetic acid (TFA, 1.5 mL) to a solution of 1f (2.7 g, 5.95 mmol) in dichloromethane (30 mL). After the addition, gradually return the reaction solution to room temperature and stir for 2 h. After complete conversion, add water (100 mL) to the reaction solution to quench, and then extract with DCM (200 mL × 2). The combined organic phase is washed with saturated brine (100 mL × 2) and dried over anhydrous sodium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (DCM / MeOH = 20:1, v / v) to obtain a colorless oil compound 1g (1.8 g, yield 94%). 1 HNMR(500MHz, CDCl3)δ7.71(s,1H),5.91(s,1H),3.95(s,1H),3.82–3.73(m,2H),3 .70(s,3H),3.69–3.60(m,2H),2.59(dd,J=6.6,5.5Hz,2H),1.32(d,J=6.6Hz,3H).

[0063] Step 5: At room temperature, slowly add NaOH (1.1 g, 27.8 mmol) to a mixed solution of 1 g (1.8 g, 5.6 mmol) of methanol (100 mL) and water (20 mL). After the addition, stir the reaction solution at room temperature for 12 h. After complete conversion, evaporate the solvent under reduced pressure. Add water (50 mL) to the residue and adjust the pH to 5-6 by slowly adding HCl (1 M) solution, and then extract with ethyl acetate (3×100 mL). The combined organic phase is washed with saturated brine (2×100 mL) and dried over anhydrous sodium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting crude product 1h is not purified and directly subjected to the next step of reaction.

[0064] Step 6: At room temperature, slowly add K2CO3 (3.8 g, 37.61 mmol) to a solution of 1i (3.00 g, 18.80 mmol) and 1j (4.20 g, 22.57 mmol) in NMP (50 mL). The reaction solution was stirred at 80 ° C for 3 h. After complete conversion, water (100 mL) was added to the reaction solution to quench, and then extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with saturated brine (2×100 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM 100%) to obtain a light yellow solid compound 1k (5.4 g, yield 92.2%).

[0065] Step 7: Add dioxane hydrochloride solution (15 mL) to a MeOH (30 mL) solution of compound 1k (5.3 g, 17.1 mmol) at room temperature. Stir the resulting solution at room temperature for 12 hours. After TLC detection, the reaction was complete. The reaction solution was filtered to obtain a filter cake, which was vacuum dried to obtain a yellow solid compound 1l (3.7 g, yield 88.2%), which was directly used in the next step without purification.

[0066] Step 8: At room temperature, DIPEA (1669.8 mg, 12.92 mmol), EDCI (1610.28 mg, 8.40 mmol) and HOBt (567.50 mg, 4.20 mmol) were added to a solution of 1h (1.00 g, 3.23 mmol) and 1l (872.9 mg, 3.55 mmol) in anhydrous DMF (15 mL). The reaction solution was stirred at 25 ° C for 6 hours. After complete conversion, water (100 mL) was added to the reaction solution to quench, and then extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with saturated brine (2×100 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a white solid compound 1m (920.0 mg, yield 57%).

[0067] Step 9: At room temperature, iron powder (791 mg, 9.20 mmol) and ammonium chloride (492.1 mg, 9.20 mmol) were added to a mixed solution of anhydrous ethanol (15 mL) and water (5 mL) of 1m (920.0 mg, 1.84 mmol). The reaction mixture was stirred at 60 ° C for 10 hours. After complete conversion, the reaction solution was filtered through diatomaceous earth, the filtrate was collected, and 100 mL of water was added to the filtrate. The resulting solution was extracted with 3×100 mL EtOAc, and the combined organic phase was washed with saturated brine (2×100 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain a white solid compound 1n (420 mg, yield 48.2%).

[0068] Step 10: At room temperature, DIPEA (100.62 mg, 0.78 mmol), EDCI (130.36 mg, 0.68 mmol) and HOBt (45.94 mg, 0.34 mmol) were added to a solution of 1n (120 mg, 0.26 mmol) and 1o (123.65 mg, 0.26 mmol) in anhydrous DMF (5 mL). The reaction solution was stirred at 25 ° C for 6 h. After complete conversion, water (50 mL) was added to the reaction solution to quench, and then extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with saturated brine (2×100 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH=20:1, v / v) to obtain the target compound 1 (164 mg, yield 68%). 1 HNMR(500MHz,DMSO-d6)δ12.45(s,1H),9.27(s,1H),8.64(s,2H),7.95(d,J=38.7Hz,1H),7.54–7. 25(m,7H),7.20(dd,J=7.7,1.5Hz,1H),6.35(s,2H),5.24–5.13(m,3H),4.27–4.12(m,1H),3.81–3. 59(m,13H),3.50(p,J=5.5Hz,6H),2.89–2.74(m,2H),2.59(t,J=6.5Hz,2H),2.21(s,3H),2.07(t,J =10.8Hz,1H),1.81(d,J=11.9Hz,1H),1.69–1.48(m,3H),1.42–1.30(m,1H),1.16(d,J=6.4Hz,3H).

[0069] Example 2: Preparation of Compound 2

[0070]

[0071] Step 1: At room temperature, DIPEA (2205.9 mg, 17.1 mmol), EDCI (2837.2 mg, 14.8 mmol) and HOBt (999.9 mg, 7.4 mmol) were added to a solution of 2a (1500.0 mg, 5.70 mmol) and 2b (858.76 mg, 6.84 mmol) in anhydrous DCM (20 mL). The reaction solution was stirred at 25 ° C for 6 h. After complete conversion, water (200 mL) was added to the reaction solution to quench, and then extracted with DCM (3×200 mL). The combined organic phase was washed with saturated brine (2×150 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH=49:1, v / v) to obtain a colorless oily liquid compound 2c (1488.5 mg, yield 78.1%). 1 HNMR(500MHz,DMSO-d6)δ8.01(s,1H),7.34(d,J=25.7Hz,5H),5.20–4.97(m,2H),4.67–4.51(m,1H),3.90(d,J=13.1Hz ,1H),3.58(s,3H),3.08(d,J=47.1Hz,1H),2.46(s,2H),2.04(d,J=13.1Hz,1H),1.73–1.47(m,3H),1.38–1.12(m,2H).

[0072] Step 2: At room temperature, slowly add Pd (400 mg) catalyst to a solution of 2c (1400.0 mg, 4.19 mmol) in methanol (15 mL). After the addition, place the reaction system under H2 environment. Stir the reaction solution at 25 °C overnight. After complete conversion, filter the reaction solution through diatomaceous earth, collect the filtrate, and concentrate to obtain a colorless oily liquid compound 2d (816.4 mg, yield 97.3%), which is directly used in the next step without purification.

[0073] Step 3: In an ice bath, slowly add diisopropyl azodicarboxylate (DIAD, 11.1 g, 54.9 mmol) solution to a solution of 2e (8.2 g, 41.2 mmol), 2f (5.0 g, 27.5 mmol) and PPh3 (14.4 g, 54.9 mmol) in anhydrous THF (150 mL). After the dropwise addition, the reaction solution gradually returns to room temperature and is stirred for 24 hours. After complete conversion, water (100 mL) is added to the reaction solution to quench, and then extracted with ethyl acetate (3×150 mL). The combined organic phase is washed with saturated brine (2×150 mL) and dried over anhydrous sodium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (PE / EA=3:1, v / v) to obtain a white solid compound 2g (5.0 g, yield 50.1%). 1 H NMR(500MHz,DMSO-d6)δ10.22(s,1H),7.53–7.44(m,3H),7.42–7.36(m,1H),7.35–7.28( m,3H),7.23(dd,J=7.6,1.5Hz,1H),6.43(s,2H),5.29(s,2H),3.84(s,6H),2.22(s,3H).

[0074] Step 4: At room temperature, sodium triacetoxyborohydride (NaBH(OAc)3, 663.37 mg, 3.13 mmol) was slowly added to a dichloroethane (15 mL) solution of 2d (300 mg, 1.5 mmol) and 2g (453.04, 1.25 mmol). After the addition, the reaction system was placed under N2 protection. The reaction solution was stirred at 85 ° C for 2 h. After complete conversion, water (50 mL) was added to the reaction solution to quench, and then extracted with DCM (3×50 mL). The combined organic phase was washed with saturated brine (2×50 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH=49:1, v / v) to obtain a white solid compound 2h (389.5 mg, yield 57%). 1H NMR (500MHz, CDCl3) δ7.94(s,1H),7.40–7.33(m,3H),7.32–7.21(m,5H),6.18(s,2H),5.02(s,2H),4.17(dd,J=17.9,6.6Hz,1H),3.91(dd,J=17. 9,5.3Hz,1H),3.85–3.69(m,7H),3.66(s,3H),3.33(d,J=12.0Hz,1H),2. 73(t,J=11.1Hz,1H),2.20(s,3H),2.05–1.90(m,2H),1.78–1.39(m,6H).

[0075] Step 5: At room temperature, slowly add NaOH (64 mg, 1.6 mmol) to a mixed solution of 2h (350 mg, 0.64 mmol) in methanol (4 mL) and water (1 mL). After the addition, stir the reaction solution at room temperature for 12 h. After complete conversion, evaporate the solvent under reduced pressure. Add water (50 mL) to the residue and adjust the pH to 5-6 by slowly adding HCl (1 M) solution, then extract with ethyl acetate (3×50 mL). The combined organic phase is washed with saturated brine (2×50 mL) and dried over anhydrous sodium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The crude product 2i is directly subjected to the next step without purification.

[0076] Step 6: At room temperature, DIPEA (147.06 mg, 1.14 mmol), EDCI (189.78 mg, 0.99 mmol) and HOBt (66.20 mg, 0.49 mmol) were added to a solution of 2i (200 mg, 0.38 mmol) and 1n (178.77 mg, 0.38 mmol) in anhydrous DCM (10 mL). The reaction solution was stirred at 25 ° C for 6 h. After complete conversion, water (50 mL) was added to the reaction solution to quench, and then extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with saturated brine (2×50 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH=20:1, v / v) to obtain the target compound 2 as a white solid (229.46 mg, yield 61.3%). 1H NMR (500MHz, DMSO-d6) δ12.45(s,1H),10.01(s,1H),8.54(s,2H),7.91(s,1H),7.82(t,J=5.1Hz,1H),7.51–7.43(m,3H),7. 41–7.35(m,1H),7.34–7.27(m,3H),7.20(dd,J=7.7,1.5Hz,1H),6.68(d,J=12.1Hz,1H),6.38(s,2H),6.27(dt,J=8.6,4.1H z,1H),5.16(s,2H),4.21–4.06(m,2H),3.96(dd,J=16.7,5.4Hz,1H),3.76(s,6H),3.74–3.60(m,7H),3.50(dt,J=9.0,5.2H z,6H),2.76–2.55(m,4H),2.22(s,3H),2.05–1.95(m,1H),1.80(d,J=12.8Hz,1H),1.67–1.37(m,4H),1.15(d,J=6.5Hz,3H).

[0077] Example 3: Preparation of Compound 3

[0078]

[0079] Step 1: Referring to the synthesis method of Step 1 in Example 2, a colorless oily liquid compound 3b was obtained. 1 HNMR(500MHz,DMSO-d6)δ8.01(s,1H),7.34(d,J=25.7Hz,5H),5.23–5.00(m,2H),4.57(d,J=4.3Hz,1H),3.90(d,J=13.1Hz,1H) ,3.58(s,3H),3.33–3.26(m,2H),3.19–2.98(m,1H),2.46(s,2H),2.04(d,J=13.1Hz,1H),1.67–1.47(m,3H),1.38–1.13(m,2H).

[0080] Step 2: Referring to the synthesis method of Step 2 in Example 2, the deprotected product 3c was obtained and used directly in the next reaction without purification.

[0081] Step 3: Referring to the synthesis method of step 4 in Example 2, a white solid compound 3d was obtained. 1H NMR(500MHz,DMSO-d6)δ7.60(t,J=6.2Hz,1H),7.53–7.42(m,3H),7.43–7.25(m,4H),7.21(d d,J=7.7,1.5Hz,1H),6.39(s,2H),5.17(s,2H),3.79(s,6H),3.57(s,3H),3.55–3.47(m,2H), 3.38–3.30(m,2H),3.22(d,J=11.7Hz,1H),2.65(d,J=11.5Hz,1H),2.57–2.51(m,3H),2.22( s,3H),2.02–1.87(m,1H),1.77(d,J=13.0Hz,1H),1.52(d,J=51.3Hz,2H),1.41–1.12(m,2H).

[0082] Step 4: Referring to the synthesis method of step 5 in Example 2, the hydrolyzate 3e was obtained and used directly in the next reaction without purification.

[0083] Step 5: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 3 (103 mg, 53.9%) was obtained. 1 H NMR (500MHz, DMSO-d6) δ12.45(s,1H),9.94(s,1H),8.51(s,2H),7.94(d,J=38.9Hz,1H),7.63(s,1H),7.52–7.43(m,3H),7.42 –7.36(m,1H),7.35–7.25(m,3H),7.21(dd,J=7.7,1.5Hz,1H),6.46–6.31(m,2H),5.27–5.10(m,3H),4.16(ddd,J=25.9,13.5, 6.5Hz,1H),3.79(s,6H),3.72–3.39(m,15H),3.29(dt,J=11.0,5.5Hz,1H),3.21(d,J=11.1Hz,1H),2.64(s,1H),2.60–2.52(m ,5H),2.22(s,3H),1.92(d,J=9.6Hz,1H),1.79(s,1H),1.52(d,J=46.7Hz,3H),1.42–1.35(m,1H),1.16(dd,J=5.0,1.3Hz,3H).

[0084] Example 4: Preparation of Compound 4

[0085]

[0086] Step 1: Referring to the synthesis method of Step 1 in Example 2, a colorless oily liquid compound 4b was obtained. 1 HNMR(500MHz,DMSO-d6)δ7.94(s,1H),7.50–7.23(m,5H),5.20–4.97(m,2H),4.58(d,J=4.4Hz,1H),3.91(d,J=13.0 Hz,1H),3.58(s,3H),3.25–2.97(m,3H),2.28(d,J=10.0Hz,2H),2.06(s,1H),1.76–1.50(m,5H),1.43–1.14(m,2H).

[0087] Step 2: Referring to the synthesis method of Step 2 in Example 2, the deprotected product 4c was obtained and used directly in the next reaction without purification.

[0088] Step 3: Referring to the synthesis method of step 4 in Example 2, a white solid compound 4d was obtained. 1 H NMR(500MHz,DMSO-d6)δ7.56–7.43(m,4H),7.42–7.27(m,4H),7.21(dd,J=7.6,1.4Hz,1H),6.40(s ,2H),5.17(s,2H),3.78(s,6H),3.58(s,3H),3.53(d,J=11.7Hz,1H),3.32–3.10(m,3H),2.67(dd,J =12.0,4.2Hz,1H),2.54(dd,J=10.4,3.4Hz,1H),2.34(t,J=7.4Hz,2H),2.23(s,3H),2.03–1.90(m, 1H),1.76(tdd,J=14.0,11.8,7.3Hz,3H),1.64–1.55(m,1H),1.54–1.31(m,2H),1.30–1.14(m,1H).

[0089] Step 4: Referring to the synthesis method of step 5 in Example 2, the hydrolyzate 4e was obtained and used directly in the next reaction without purification.

[0090] Step 5: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 4 (89 mg, 64.7%) was obtained. 1H NMR (500MHz, DMSO-d6) δ12.45(s,1H),9.93(d,J=3.6Hz,1H),8.62–8.57(m,1H),8.54(s,2H),7.95(d,J=38.3Hz,1H),7.56–7.43(m,3 H),7.43–7.36(m,1H),7.36–7.26(m,3H),7.22(dd,J=7.6,1.5Hz,1H),6.46(s,2H),5.32–5.12(m,3H),4.17–4.11(m,2H),3.81(s,5H ),3.77–3.43(m,15H),3.31(dq,J=13.6,6.7Hz,1H),3.19(dq,J=13.1,7.5,6.7Hz,2H),2.71(d,J=18.3Hz,1H),2.58(t,J=6.5Hz,2H) ,2.42–2.32(m,2H),2.23(d,J=9.0Hz,3H),2.04(d,J=13.2Hz,1H),1.87–1.60(m,6H),1.45–1.35(m,1H),1.16(dd,J=6.4,4.7Hz,3H).

[0091] Example 5: Preparation of Compound 5

[0092]

[0093] Step 1: Referring to the synthesis method of Step 1 in Example 2, a colorless oily liquid compound 5b was obtained. 1 HNMR(500MHz, CDCl3)δ7.40–7.22(m,5H),6.05(s,1H),5.11(q,J=11.3,10.6Hz,2H),4.72(s,1H),4 .06(s,1H),3.59(s,3H),3.30–3.06(m,2H),2.89(s,1H),2.25(t,J=7.2Hz,3H),1.86–1.29(m,10H).

[0094] Step 2: Referring to the synthesis method of Step 2 in Example 2, the deprotected product 5c was obtained and used directly in the next reaction without purification.

[0095] Step 3: Referring to the synthesis method of step 4 in Example 2, a white solid compound 5d was obtained. 1H NMR(500MHz, CDCl3)δ7.55(s,1H),7.39–7.19(m,8H),6.19(s,2H),5.02(s, 2H),3.74(s,6H),3.60(d,J=2.8Hz,1H),3.58(s,3H),3.39(dt,J=14.0,6.6 Hz,1H),3.28(d,J=12.0Hz,1H),3.18–3.08(m,1H),2.67(t,J=13.4Hz,1H), 2.29(t,J=7.2Hz,2H),2.21(s,3H),2.01–1.92(m,2H),1.85–1.33(m,10H).

[0096] Step 4: Referring to the synthesis method of step 5 in Example 2, the hydrolyzate 5e was obtained and used directly in the next reaction without purification.

[0097] Step 5: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 5 (93 mg, 55%) was obtained. 1 H NMR(500MHz,DMSO-d6)δ12.45(s,1H),9.82(s,1H),8.53(s,2H),7.91(s,1H),7.57–7.24(m,8H ),7.21(d,J=7.6Hz,1H),6.42(d,J=35.6Hz,2H),6.27(dt,J=8.5,4.1Hz,1H),5.19(d,J=22.2Hz ,2H),4.20–4.10(m,1H),3.89–3.43(m,19H),3.30–3.11(m,3H),2.73–2.52(m,4H),2.31(t,J= 7.2Hz,2H),2.23(d,J=6.1Hz,3H),2.05–1.88(m,1H),1.86–1.32(m,9H),1.15(d,J=6.5Hz,3H).

[0098] Example 6: Preparation of Compound 6

[0099]

[0100] Step 1: Referring to the synthesis method of Step 1 in Example 2, a colorless oily liquid compound 6b was obtained. 1HNMR(500MHz,DMSO-d6)δ7.52–7.41(m,2H),7.41–7.17(m,3H),6.39(s,1H),5.17(s,1H),3.78(s,3H),3.60–3.52(m,3H),3.29–3.17(m,1H),3 .08(ddt,J=24.9,13.0,6.7Hz,1H),2.66(d,J=12.2Hz,1H),2.33–2.19(m,3H),1.99–1.90(m,1H),1.79(d,J=13.0Hz,1H),1.70–1.14(m,10H).

[0101] Step 2: Referring to the synthesis method of Step 2 in Example 2, the deprotected product 6c was obtained and used directly in the next reaction without purification.

[0102] Step 3: Referring to the synthesis method of step 4 in Example 2, a white solid compound 6d was obtained.

[0103] Step 4: Referring to the synthesis method of step 5 in Example 2, the hydrolyzate 6e was obtained and used directly in the next reaction without purification.

[0104] Step 5: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 6 (125 mg, 66%) was obtained.

[0105] Example 7: Preparation of Compound 7

[0106]

[0107] Step 1: Referring to the synthesis method of Step 1 in Example 2, a colorless oily liquid compound 7b was obtained. 1 HNMR(500MHz,DMSO-d6)δ7.85(s,1H),7.49–7.21(m,5H),5.06(t,J=14.5Hz,2H),4.57(d,J=4.4Hz,1H),3.90(d,J =12.9Hz,1H),3.58(s,3H),3.27–2.96(m,3H),2.27(t,J=7.4Hz,2H),2.04(t,J=21.0Hz,1H),1.69–1.17(m,13H).

[0108] Step 2: Referring to the synthesis method of Step 2 in Example 2, the deprotected product 7c was obtained and used directly in the next reaction without purification.

[0109] Step 3: Referring to the synthesis method of step 4 in Example 2, a white solid compound 7d was obtained. 1H NMR (500MHz, CDCl3) δ7.44(t,J=6.0Hz,1H),7.39–7.33(m,3H),7.32–7.19(m,5H),6.19(s,2H),5.02(s,2H),3.74(s,6H),3.60(d,J=2.1Hz,1H),3. 58(s,3H),3.37(dq,J=14.5,7.2Hz,1H),3.11(tq,J=13.4,6.5Hz,1H),2.7 6–2.57(m,2H),2.27–2.18(m,5H),2.02–1.85(m,2H),1.73–1.26(m,14H).

[0110] Step 4: Referring to the synthesis method of step 5 in Example 2, the hydrolyzate 7e was obtained and used directly in the next reaction without purification.

[0111] Step 5: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 7 (71 mg, 49%) was obtained. 1 H NMR(500MHz,DMSO-d6)δ12.45(s,1H),9.82(s,1H),8.54(s,2H),7.91(s,1H),7.54–7 .18(m,8H),6.39(s,2H),6.27(dq,J=8.2,4.1Hz,1H),5.17(s,2H),4.14(dq,J=11.9,5 .9,5.4Hz,1H),3.96–3.44(m,18H),3.31–3.06(m,3H),2.79–2.52(m,4H),2.27(t,J=7 .4Hz,2H),2.22(s,2H),2.06–1.91(m,1H),1.86–1.28(m,13H),1.15(d,J=6.5Hz,3H).

[0112] Example 8: Preparation of Compound 8

[0113]

[0114] Step 1: Referring to the synthesis method of Step 1 in Example 2, a colorless oily liquid compound 8b was obtained. 1HNMR (500MHz, CDCl3) δ7.37–7.21(m,5H),5.90(d,J=51.6Hz,1H),5.11(t,J=10.5Hz,2H),4.06(s,1H),3. 59(s,3H),3.27–3.04(m,2H),2.78(s,1H),2.23(t,J=7.6Hz,3H),1.58–1.29(m,9H),1.28–1.11(m,13H).

[0115] Step 2: Referring to the synthesis method of Step 2 in Example 2, the deprotected product 8c was obtained and used directly in the next reaction without purification.

[0116] Step 3: Referring to the synthesis method of step 4 in Example 2, a white solid compound 8d was obtained.

[0117] Step 4: Referring to the synthesis method of step 5 in Example 2, the hydrolyzate 8e was obtained and used directly in the next reaction without purification.

[0118] Step 5: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 8 (59 mg, 47%) was obtained. 1 H NMR(500MHz,DMSO-d6)δ12.45(s,1H),9.80(s,1H),8.54(s,2H),7.95(d,J=38.4Hz,1H),7.52–7.42(m ,3H),7.41–7.35(m,1H),7.35–7.16(m,4H),6.39(s,2H),6.27(dt,J=8.6,4.2Hz,1H),5.28–5.11(m,2 H),4.14(d,J=8.5Hz,1H),3.78(s,6H),3.73–3.41(m,14H),3.29–3.03(m,3H),2.72–2.55(m,3H),2.2 4(d,J=18.3Hz,5H),1.99(t,J=20.9Hz,1H),1.85–1.34(m,9H),1.30–1.23(m,13H),1.16–1.13(m,3H).

[0119] Example 9: Preparation of Compound 9

[0120]

[0121] Step 1: Referring to the synthesis method of Step 1 in Example 2, a colorless oily liquid compound 9b was obtained. 1HNMR(500MHz,DMSO-d6)δ10.34(s,1H),7.99–7.88(m,2H),7.73(d,J=8.4Hz,2H),7.48–7.16(m,5H),5.08(q,J=13.6,12.8Hz,2H),4.80(dd, J=6.3,2.3Hz,1H),3.94(dd,J=15.3,11.1Hz,1H),3.83(s,3H),3.49–3.21(m,1H),2.21–2.06(m,1H),1.86–1.56(m,3H),1.45–1.25(m,2H).

[0122] Step 2: Referring to the synthesis method of Step 2 in Example 2, the deprotected product 9c was obtained and used directly in the next reaction without purification.

[0123] Step 3: Referring to the synthesis method of step 4 in Example 2, a white solid compound 9d was obtained. 1 H NMR(500MHz,DMSO-d6)δ9.68(s,1H),7.98–7.91(m,2H),7.88–7.78(m,2H),7.53–7.43(m,3H) ,7.42–7.35(m,1H),7.36–7.26(m,3H),7.20(dd,J=7.6,1.5Hz,1H),6.34(s,2H),5.13(s,2H), 3.82(s,3H),3.66(s,6H),3.60(d,J=12.0Hz,1H),3.49–3.40(m,2H),2.20(s,3H),2.14(t,J= 10.3Hz,1H),1.89–1.76(m,1H),1.70–1.49(m,3H),1.40(d,J=11.1Hz,1H),1.31–1.23(m,2H).

[0124] Step 4: Referring to the synthesis method of step 5 in Example 2, the hydrolyzate 9e was obtained and used directly in the next reaction without purification.

[0125] Step 5: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 9 (49 mg, 53%) was obtained. 1H NMR(500MHz,DMSO-d6)δ12.45(s,1H),10.13(s,1H),9.63(s,1H),8.70(s,2H),8.05–7.78(m,5H),7.50–7.4 2(m,3H),7.41–7.35(m,1H),7.34–7.26(m,3H),7.20(dd,J=7.6,1.4Hz,1H),6.47–6.31(m,2H),5.27–5.11(m ,3H),4.28–4.10(m,1H),3.76–3.64(m,12H),3.59–3.38(m,8H),2.87(s,2H),2.60(t,J=6.5Hz,2H),2.21(s ,3H),2.15(q,J=12.0,9.7Hz,1H),1.81(s,1H),1.73–1.48(m,4H),1.45–1.35(m,1H),1.17(d,J=6.9Hz,3H).

[0126] Example 10: Preparation of Compound 10

[0127]

[0128] Step 1: Referring to the synthesis method of Step 1 in Example 2, a colorless oily liquid compound 10b was obtained.

[0129] Step 2: Referring to the synthesis method of Step 2 in Example 2, the deprotected product 10c was obtained and used directly in the next reaction without purification.

[0130] Step 3: Referring to the synthesis method of step 4 in Example 2, a white solid compound 10d was obtained.

[0131] Step 4: Referring to the synthesis method of step 5 in Example 2, the hydrolyzate 10e was obtained and used directly in the next reaction without purification.

[0132] Step 5: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 10 (128 mg, 68%) was obtained. 1H NMR (500MHz, DMSO-d6) δ12.45(s,1H),10.32(s,1H),9.84(s,1H),8.97(d,J=1.9Hz,1H),8.69(d,J=0.7Hz,2H),8.43–8.2 2(m,2H),7.96(d,J=39.1Hz,1H),7.55–7.17(m,8H),6.37(s,2H),5.30–5.10(m,3H),4.18(ddd,J=26.7,14.0,7.2Hz,1H) ,3.85–3.65(m,12H),3.64–3.42(m,8H),2.90(dd,J=9.6,3.9Hz,1H),2.77(d,J=12.2Hz,1H),2.60(t,J=6.5Hz,2H),2.21 (s,3H),2.18–2.09(m,1H),1.87(d,J=12.2Hz,1H),1.70–1.50(m,3H),1.32(t,J=9.2Hz,2H),1.16(dd,J=6.6,5.0Hz,3H).

[0133] Example 11: Preparation of Compound 11

[0134]

[0135] Step 1: Referring to the synthesis method of Step 5 in Example 1, compound 11a (3.5 g, 88%) was obtained.

[0136] Step 2: Referring to the synthesis method of step 6 in Example 1, compound 11c (5.0 g, 84%) was obtained. 1 HNMR (500MHz, CDCl3) δ8.83 (s, 2H), 3.94–3.88 (m, 4H), 3.87 (s, 3H), 3.50 (dd, J = 6.4, 3.9Hz, 4H), 1.48 (s, 9H).

[0137] Step 3: Refer to the synthesis method of Step 7 in Example 1 to obtain compound 11d.

[0138] Step 4: Refer to the synthesis method of Step 8 in Example 1 to obtain compound 11e.

[0139] Step 5: Referring to the synthesis method of step 2 in Example 1, compound 11f was obtained, which was directly used in the next step without purification.

[0140] Step 6: Refer to the synthesis method of step 3 in Example 1 to obtain compound 11g.

[0141] Step 7: Referring to the synthesis method of step 4 in Example 1, a white solid compound 11h (476.0 mg, 36%) was obtained. 1 H NMR(500MHz, CDCl3)δ8.86(s,2H),7.67(s,1H),5.88–5.77(m,1H),5.53–5. 33(m,2H),3.95(dt,J=11.9,5.2Hz,4H),3.89(s,3H),3.88–3.81(m,2H),3. 73(td,J=5.0,2.7Hz,2H),3.65(dd,J=9.7,3.8Hz,1H),3.57(q,J=4.5Hz,2H ),3.50(dd,J=9.7,5.8Hz,1H),2.65(t,J=6.1Hz,2H),1.30(d,J=6.6Hz,3H).

[0142] Step 8: Referring to the synthesis method of step 5 in Example 1, the key intermediate 11i was obtained and used directly in the next reaction without purification.

[0143] Step 9: Referring to the synthesis method of Step 1 in Example 2, compound 11k (809 mg, 87%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ7.85(s,1H),7.50–7.23(m,5H),6.74(t,J=5.7Hz,1H),5.06(t,J=14.6Hz,2H),4.57(d,J=5.5Hz,1H),3. 90(d,J=13.0Hz,1H),3.24–2.98(m,3H),2.88(q,J=6.6Hz,2H),2.06(s,1H),1.67–1.48(m,3H),1.37(s,9H),1.36–1.14(m,11H).

[0144] Step 10: Referring to the synthesis method of step 2 in Example 2, compound 111 was obtained, which was directly used in the next step without purification.

[0145] Step 11: Refer to the synthesis method of step 4 in Example 2 to obtain compound 11m.

[0146] Step 12: Referring to the synthesis method of step 5 in Example 2, compound 11n was obtained, which was directly used in the next reaction without purification.

[0147] Step 13: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 11 (150 mg, 56%) was obtained. 1H NMR(500MHz,DMSO-d6)δ12.45(s,1H),8.76(s,2H),8.32(d,J=4.3Hz,1H),7.91(s,1H),7.53–7.26(m,8H),7 .21(d,J=7.6Hz,1H),6.38(s,2H),6.27(dt,J=8.5,4.1Hz,1H),5.17(s,2H),4.14(q,J=6.7,6.2Hz,1H),3.86 –3.73(m,10H),3.72–3.63(m,2H),3.58–3.45(m,7H),3.17(dq,J=53.9,5.9,5.1Hz,6H),2.71–2.52(m,4H),2 .22(s,3H),1.94(dt,J=12.1,5.3Hz,1H),1.77(d,J=11.2Hz,1H),1.63–1.30(m,10H),1.15(d,J=6.5Hz,3H).

[0148] Example 12: Preparation of Compound 12

[0149]

[0150] Step 1: Referring to the synthesis method of Step 1 in Example 2, a colorless oily liquid compound 12b (1.6 g, 84%) was obtained. 1 H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.45–7.24(m,5H),6.73(t,J=5.6Hz,1H),5.18–4.99(m,2H),4.61(d,J=5.5Hz,1H),3. 90(d,J=13.2Hz,1H),3.44–3.34(m,4H),3.28–3.00(m,5H),2.07(s,1H),1.67–1.48(m,3H),1.37(s,9H),1.34–1.17(m,2H).

[0151] Step 2: Referring to the synthesis method of Step 2 in Example 2, a colorless oily liquid compound 12c was obtained, which was directly used in the next step without purification.

[0152] Step 3: Referring to the synthesis method of step 4 in Example 2, a white solid compound 12d (180 mg, 63%) was obtained. 1H NMR(500MHz,DMSO-d6)δ7.55(t,J=6.0Hz,1H),7.52–7.43(m,3H),7.42–7.36(m,1H),7.36–7.25 (m,3H),7.21(dd,J=7.6,1.5Hz,1H),6.79–6.66(m,1H),6.38(s,2H),5.17(s,2H),3.78(s,6H),3 .51–3.35(m,5H),3.28–3.17(m,3H),3.06(q,J=5.9Hz,3H),2.72–2.61(m,1H),2.57(dd,J=10.4 ,3.4Hz,1H),2.22(s,3H),1.98–1.92(m,1H),1.86–1.75(m,1H),1.62–1.44(m,4H),1.35(s,9H).

[0153] Step 4: Referring to the synthesis method of Step 5 in Example 2, a white solid compound 12e was obtained, which was directly used in the next reaction without purification.

[0154] Step 5: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 12 (143 mg, 62%) was obtained. 1 H NMR (500MHz, DMSO-d6) δ12.45(s,1H),8.79(d,J=12.1Hz,2H),8.42(d,J=42.8Hz,1H),7.95(d,J=38 .6Hz,1H),7.54(s,1H),7.51–7.15(m,8H),6.48–6.32(m,2H),5.28–5.08(m,3H),4.16(dq,J=27.8,1 3.6,10.3Hz,1H),3.87–3.64(m,12H),3.61–3.37(m,15H),3.29–3.16(m,2H),2.73–2.52(m,4H),2.2 2(s,3H),2.02–1.87(m,1H),1.77(d,J=10.8Hz,1H),1.61–1.32(m,4H),1.15(dd,J=6.4,4.7Hz,3H).

[0155] Example 13: Preparation of Compound 13

[0156]

[0157] Step 1: Referring to the synthesis method of Step 1 in Example 2, a colorless oily liquid compound 13b was obtained.

[0158] Step 2: Referring to the synthesis method of Step 2 in Example 2, a colorless oily liquid compound 13c was obtained, which was directly used in the next step without purification.

[0159] Step 3: Referring to the synthesis method of step 4 in Example 2, a white solid compound 13d was obtained.

[0160] Step 4: Referring to the synthesis method of Step 5 in Example 2, a white solid compound 13e was obtained, which was directly used in the next reaction without purification.

[0161] Step 5: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 13 (330 mg, 47%) was obtained. 1 H NMR (500MHz, DMSO-d6) δ12.45(s,1H),8.78(s,2H),8.45(d,J=5.5Hz,1H),7.91(s,1H),7.62–7.42(m ,4H),7.42–7.36(m,1H),7.35–7.27(m,3H),7.20(d,J=7.7Hz,1H),6.38(s,2H),6.27(dt,J=8.5,4.2H z,1H),5.24–5.14(m,2H),4.27–4.07(m,2H),3.86–3.35(m,31H),3.22(d,J=12.0Hz,2H),2.76–2.53 (m,4H),2.22(s,3H),1.99–1.89(m,1H),1.85–1.55(m,3H),1.52–1.38(m,2H),1.15(d,J=6.5Hz,3H).

[0162] Example 14: Preparation of Compound 14

[0163]

[0164] Step 1: Referring to the synthesis method of Step 1 in Example 2, a colorless oily liquid compound 14b (703 mg, 81%) was obtained. 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.46–7.21(m,5H),6.74(t,J=5.7Hz,1H),5.22–4.99(m,2H),4.60(d,J=5.4Hz,1H),3.90(d,J=12.9Hz,1H) ,3.47(s,8H),3.44–3.34(m,4H),3.30–3.09(m,3H),3.06(p,J=7.4,6.0 Hz,2H),2.07(s,1H),1.66–1.45(m,3H),1.37(s,9H),1.34–1.17(m,2H).

[0165] Step 2: Referring to the synthesis method of Step 2 in Example 2, a colorless oily liquid compound 14c (650 mg, 73%) was obtained.

[0166] Step 3: Referring to the synthesis method of Step 4 in Example 2, a white solid compound 14d (541 mg, 61.3%) was obtained. 1 H NMR(500MHz, DMSO-d6)δ7.55(t,J=5.9Hz,1H),7.47(ddt,J=15.1,8.4,1.7Hz,3H),7.42–7.36(m,1H),7.35–7. 25(m,3H),7.21(dd,J=7.6,1.5Hz,1H),6.72(t,J=5.6Hz,1H),6.38(s,2H),5.16(s,2H),3.79(s,6H),3.58–3. 40(m,13H),3.38–3.33(m,2H),3.28–3.19(m,2H),3.04(q,J=6.0Hz,2H),2.66(d,J=11.7Hz,1H),2.56(dd,J=1 0.3, 3.5Hz, 1H), 2.22 (s, 3H), 1.99–1.89 (m, 1H), 1.79 (d, J = 12.9Hz, 1H), 1.42 (d, J = 52.8Hz, 4H), 1.36 (s, 9H).

[0167] Step 4: Referring to the synthesis method of Step 5 in Example 2, a white solid compound 14e was obtained, which was directly used in the next reaction without purification.

[0168] Step 5: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 14 (77 mg, 45%) was obtained. 1H NMR (500MHz, DMSO-d6) δ12.45(s,1H),8.78(s,2H),8.44(t,J=4.0Hz,1H),7.95(d,J=38. 5Hz,1H),7.67–7.17(m,9H),6.50–6.32(m,2H),5.33–5.05(m,3H),4.15(tdq,J=17.4,10. 5,5.6,5.2Hz,2H),3.91–3.60(m,13H),3.58–3.36(m,22H),3.29–3.16(m,2H),2.75–2.5 3(m,4H),2.22(d,J=6.6Hz,3H),2.06–1.90(m,1H),1.85–1.32(m,5H),1.17–1.14(m,3H).

[0169] Example 15: Preparation of Compound 15

[0170]

[0171] Step 1: Referring to the synthesis method of Step 1 in Example 2, a colorless oily liquid compound 15b was obtained. 1 HNMR(500MHz,DMSO-d6)δ7.93(s,1H),7.34(d,J=25.7Hz,5H),6.74(t,J=5.6Hz,1H),5.18–4.98(m,2H),4.60(d,J=5.4Hz,1H),3.91(d,J=1 2.5Hz,1H),3.49(d,J=4.1Hz,12H),3.45–3.34(m,4H),3.28–2.99(m,5H),2.07(s,1H),1.66–1.47(m,3H),1.37(s,9H),1.34–1.16(m,2H).

[0172] Step 2: Referring to the synthesis method of Step 2 in Example 2, a colorless oily liquid compound 15c was obtained, which was directly used in the next step without purification.

[0173] Step 3: Referring to the synthesis method of Step 4 in Example 2, a white solid compound 15d (650 mg, 73%) was obtained. 1H NMR(500MHz,DMSO-d6)δ7.55(t,J=5.9Hz,1H),7.47(ddt,J=15.1,8.4,1.7Hz,3H),7.42–7.36(m,1H),7.35–7.26(m,3H),7 .21(dd,J=7.6,1.5Hz,1H),6.72(t,J=5.6Hz,1H),6.38(s,2H),5.16(s,2H),3.79(s,6H),3.58–3.40(m,15H),3.35(t,J=6 .1Hz,2H),3.29–3.19(m,2H),3.04(q,J=6.0Hz,2H),2.66(d,J=11.7Hz,1H),2.56(dd,J=10.3,3.5Hz,1H),2.22(s,3H),1. 94(td,J=11.7,4.5Hz,1H),1.79(d,J=12.9Hz,1H),1.58(s,1H),1.48(s,1H),1.37(s,2H),1.36(s,9H),1.26–1.16(m,2H).

[0174] Step 4: Referring to the synthesis method of Step 5 in Example 2, a white solid compound 15e was obtained, which was directly used in the next reaction without purification.

[0175] Step 5: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 15 (112 mg, 64%) was obtained. 1 H NMR(500MHz,DMSO-d6)δ12.45(s,1H),8.78(s,2H),8.54–8.37(m,1H),7.91(s,1H),7.66–7.2 6(m,8H),7.20(d,J=7.9Hz,1H),6.42(d,J=36.6Hz,2H),6.32–6.22(m,1H),5.19(d,J=22.6Hz, 2H),4.24–4.07(m,2H),3.96–3.60(m,13H),3.59–3.35(m,26H),3.29–3.16(m,2H),2.58(q,J =13.6,10.0Hz,4H),2.22(s,3H),2.07–1.90(m,1H),1.85–1.32(m,5H),1.15(d,J=6.5Hz,3H).

[0176] Example 16: Preparation of Compound 16

[0177]

[0178] Step 1: In an ice bath, slowly drop a dichloromethane solution (5 mL) containing boron tribromide (BBr3, 1893.9 mg, 7.56 mmol) to a dichloromethane solution (15 mL) of 16a (1.0 g, 5.04 mmol). After the dropwise addition, stir for 0.5 h in an ice bath. After complete conversion, slowly drop a methanol solution to the reaction solution to quench the reaction, then add water (50 mL) to the reaction solution, and extract the resulting solution with 3×50 mL DCM. The combined organic phases are washed with saturated brine (100 mL×2) and dried over anhydrous sodium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting crude product is purified by silica gel column chromatography (PE / EA=4:1, v / v) to obtain a colorless oil compound 16b (1.26 g, yield 95.6%).

[0179] Step 2: At room temperature, solid sodium bicarbonate (NaHCO3, 2046.48 mg, 24.36 mmol) was slowly added to a DMF (30 mL) solution containing 16b (3500 mg, 13.4 mmol) and 16c (2101.9 mg, 12.18 mmol). The reaction mixture was stirred at 60 ° C for 2 h. The reaction was monitored by TLC. After complete conversion, water (100 mL) was added to the reaction solution to quench, and then extracted with DCM (3×300 mL). The combined organic phase was washed with saturated brine (200 mL×2) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / PE=3:7, v / v) to obtain a white solid compound 16d (3265.9 mg, yield 76%). 1 H NMR(500MHz,DMSO-d6)δ11.16(s,1H),10.04(s,1H),7.72(s,1H),7.54–7.44(m,3H),7 .42–7.29(m,4H),7.23(dd,J=7.6,1.5Hz,1H),6.87(s,1H),5.32(s,2H),2.21(s,3H).

[0180] Step 3: At room temperature, cesium carbonate solid (Cs2CO3, 739.6 mg, 2.27 mmol) was slowly added to a DMF (15 mL) solution containing 16d (500 mg, 1.42 mmol) and 16e (333.3 mg, 1.70 mmol). The reaction mixture was stirred at 80 ° C for 1.5 h. The reaction was monitored by TLC. After complete conversion, water (50 mL) was added to the reaction solution to quench it, and then extracted with DCM (3×50 mL). The combined organic phase was washed with saturated brine (2×50 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / PE=3:7, v / v) to obtain a white solid compound 16f (604.7 mg, yield 91%). 1 H NMR (500MHz, DMSO-d6) δ10.20(s,1H),7.95(dd,J=7.6,1.3Hz,1H),7.84(dd,J=7.8,1.3Hz,1H),7.78(td,J=7.6,1.4Hz,1H),7.72(s,1H),7.61(td,J=7 .6,1.4Hz,1H),7.55(dd,J=7.6,1.5Hz,1H),7.51–7.44(m,2H),7.43–7.30( m,5H),7.25(dd,J=7.6,1.5Hz,1H),5.57(s,2H),5.46(s,2H),2.26(s,3H).

[0181] Step 4: Referring to the synthesis method of Step 4 in Example 2, 16 g (308 mg, 69.8%) of a white solid compound was obtained.

[0182] Step 5: Referring to the synthesis method of Step 5 in Example 2, a white solid compound 16h was obtained, which was directly used in the next reaction without purification.

[0183] Step 6: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 16 (58 mg, 48%) was obtained. 1H NMR(500MHz,DMSO-d6)δ12.45(s,1H),8.77(s,2H),8.41(t,J=5.6Hz,1H), 7.96–7.89(m,2H),7.80–7.72(m,2H),7.67(t,J=5.9Hz,1H),7.58(ddd,J=7 .7,6.4,2.4Hz,1H),7.54–7.43(m,4H),7.42–7.26(m,4H),7.21(dd,J=7.7, 1.5Hz,1H),7.13(s,1H),6.27(dt,J=8.0,4.3Hz,1H),5.31(d,J=34.3Hz,4H ),4.15(p,J=6.3Hz,1H),3.87–3.63(m,6H),3.57–3.33(m,18H),3.25(dq, J=12.2,6.3Hz,2H),3.08(dq,J=13.5,5.6Hz,1H),2.77–2.64(m,2H),2.59( t,J=6.5Hz,2H),2.24(s,3H),1.85(dd,J=12.5,9.7Hz,1H),1.76–1.59(m,2 H),1.57–1.44(m,2H),1.34(dd,J=15.6,7.9Hz,1H),1.15(d,J=6.5Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ173.66,169.36,164.08,161.80,158.37,158.05,156.09,153.53,146.58,142.67,141.79, 140.20,135.63,134.42,133.96,133.89,131.01,130.30,130.22,129.75,129.65,129.05,128.72,128.29,127.44 ,126.05,120.84,117.71,116.81,113.91,111.91,100.86,73.90,70.04,69.97,69.86,69.45,68.94,67.98,67.44,55.37,52.63,51.53,48.97,45.01,44.02,43.66,41.13,39.38,38.51,33.20,30.18,25.05,23.66,18.01,16.33.

[0184] Example 17: Preparation of Compound 17

[0185]

[0186] Step 1: Refer to the synthesis method of step 3 in Example 16 to obtain white solid compound 17b. 1 H NMR (500MHz, DMSO-d6) δ10.24(s,1H),8.05(s,1H),7.87(dd,J=20.2,7.8Hz,2H),7.73(s,1H),7.65(t,J= 7.7Hz,1H),7.55–7.44(m,3H),7.42–7.37(m,1H),7.36–7.23(m,5H),5.43(d,J=20.8Hz,4H),2.24(s,3H).

[0187] Step 2: Referring to the synthesis method of step 4 in Example 2, a white solid compound 17c was obtained. 1 H NMR (500MHz, DMSO-d6) δ7.93(t,J=1.7Hz,1H),7.86–7.80(m,2H),7.70(t,J=5.9Hz,1H),7.63(t,J=7.8Hz,1H),7.52–7.42(m,4H ),7.42–7.35(m,1H),7.36–7.26(m,3H),7.21(dd,J=7.6,1.5Hz,1H),7.06(s,1H),6.71(t,J=5.7Hz,1H),5.26(d,J=34.7Hz,4H) ,3.55(d,J=13.7Hz,1H),3.41–3.34(m,7H),3.31–3.21(m,4H),3.12(dq,J=13.4,5.7Hz,1H),3.01(q,J=6.0Hz,2H),2.80–2.68( m,2H),2.23(s,3H),1.95–1.85(m,1H),1.77–1.70(m,1H),1.69–1.62(m,1H),1.59–1.46(m,2H),1.43–1.37(m,1H),1.35(s,9H).

[0188] Step 3: Referring to the synthesis method of Step 5 in Example 2, compound 17d was obtained, which was directly used in the next step without purification.

[0189] Step 4: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 17 (159 mg, 71%) was obtained. 13C NMR(126MHz,DMSO-d6)δ173.66,169.36,164.09,161.80,158.36,158.05,156.08,153.59,146.58,142.66,141.77, 139.10,132.81,132.22,131.47,131.26,130.25(d,J=5.5Hz),129.64,129.05,128.72,128.27,127.45,126.03,12 0.69,119.11,116.79,113.67,112.00,100.94,73.90,70.05,69.97,69.86,69.47(d,J=5.4Hz),69.32,67.92,67.4 4,55.38,53.07,51.51,48.97,45.00,44.02,43.66,41.13,39.37,38.52,33.19,30.26,25.13,23.62,18.02,16.30.

[0190] Example 18: Preparation of Compound 18

[0191]

[0192] Step 1: Referring to the synthesis method of step 3 in Example 16, a white solid 18b (1.2 g, 80.2%) was obtained. 1 HNMR (500MHz, DMSO-d6) δ10.25(s,1H),7.90(d,J=8.2Hz,2H),7.82–7.69(m,3H),7.55–7.20(m,9H),5.51(s,2H),5.41(s,2H),2.24(s,3H).

[0193] Step 2: Referring to the synthesis method of step 4 in Example 2, a white solid compound 18c (704.7 mg, 58%) was obtained. 1H NMR(500MHz,DMSO-d6)δ7.92–7.85(m,2H),7.76–7.63(m,3H),7.47(tt,J=7.5,1.5Hz,4H),7.43–7.36(m,1H),7.35– 7.25(m,3H),7.21(dd,J=7.7,1.5Hz,1H),7.05(s,1H),6.71(t,J=5.5Hz,1H),5.33(s,2H),5.22(s,2H),3.55(d,J=13 .8Hz,1H),3.48–3.35(m,7H),3.32–3.24(m,4H),3.20–3.11(m,1H),3.01(q,J=6.0Hz,2H),2.80–2.68(m,2H),2.23(s ,3H),1.90(dd,J=12.4,9.6Hz,1H),1.79–1.61(m,2H),1.52(p,J=14.5,13.9Hz,2H),1.43–1.37(m,1H),1.35(s,9H).

[0194] Step 3: Referring to the synthesis method of Step 5 in Example 2, compound 18d was obtained, which was directly used in the next reaction without purification.

[0195] Step 4: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 18 (133 mg, 53%) was obtained. 1H NMR(500MHz,DMSO-d6)δ12.45(s,1H),8.77(s,2H),8.40(t,J=5.6Hz,1H),7.91 (s,1H),7.90–7.84(m,2H),7.71(t,J=5.9Hz,1H),7.65(d,J=8.2Hz,2H),7.53– 7.43(m,4H),7.42–7.35(m,1H),7.35–7.24(m,3H),7.20(dd,J=7.5,1.5Hz,1H) ,7.04(s,1H),6.27(dq,J=8.1,4.0Hz,1H),5.33(s,2H),5.21(s,2H),4.15(p,J= 6.4Hz,1H),3.87–3.63(m,6H),3.59–3.47(m,7H),3.39(tq,J=17.8,6.4Hz,10H ),3.27(dt,J=13.5,3.0Hz,2H),3.18–3.10(m,1H),2.73(ddd,J=21.4,9.2,3.7 Hz,2H),2.59(t,J=6.5Hz,2H),2.22(s,3H),1.95–1.85(m,1H),1.80–1.61(m,2 H),1.53(q,J=12.2,10.3Hz,2H),1.37(q,J=11.6Hz,1H),1.15(d,J=6.5Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ173.68,169.35,164.09,161.80,158.37,158.04,156.04,153.57,146.58,143.15,142.65 ,141.76,135.60,134.40,132.96,131.16,130.21,129.64,129.05,128.73,128.46,128.26,127.45,126.02,120. 66,119.18,116.79,113.69,111.07,100.87,73.90,70.05,69.97,69.87,69.51(d,J=5.0Hz),69.45,67.97,67.44 ,55.38,52.96,51.49,48.97,45.00,44.02,43.66,41.13,39.36,38.54,33.19,30.28,25.14,23.62,18.02,16.30.

[0196] Example 19: Preparation of Compound 19

[0197]

[0198] Step 1: Refer to the synthesis method of step 3 in Example 16 to obtain white solid compound 19b. 1 H NMR(500MHz,DMSO-d6)δ10.21(s,1H),7.70(s,1H),7.57–7.44(m,4H),7.42–7.27(m,7H),7.25 (dt,J=7.7,1.8Hz,1H),7.22–7.15(m,1H),5.41(s,2H),5.35(s,2H),2.33(s,3H),2.24(s,3H).

[0199] Step 2: Referring to the synthesis method of step 4 in Example 2, a white solid compound 19c (320 mg, 56.9%) was obtained. 1 H NMR(500MHz,DMSO-d6)δ7.66(t,J=5.9Hz,1H),7.49–7.42(m,4H),7.41–7.36(m,1H),7.34–7.20(m,7H),7.18–7.1 3(m,1H),7.07(s,1H),6.70(t,J=5.6Hz,1H),5.20(d,J=29.7Hz,4H),3.53(d,J=13.7Hz,1H),3.36(dd,J=10.4,3.8 Hz, 6H), 3.31–3.17 (m, 5H), 3.08 (dq, J=13.4, 5.6Hz, 1H), 3.01 (q, J=6.0Hz, 2H), 2.80–2.63 (m, 2H), 2.31 (s, 3H), 2. 23(s,3H),1.95–1.82(m,1H),1.78–1.60(m,2H),1.51(q,J=14.5,14.0Hz,2H),1.38(d,J=6.8Hz,1H),1.35(s,9H).

[0200] Step 3: Referring to the synthesis method of Step 5 in Example 2, compound 19d was obtained, which was directly used in the next reaction without purification.

[0201] Step 4: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 19 (139 mg, 55%) was obtained. 1H NMR (500MHz, DMSO-d6) δ12.45(s,1H),8.77(s,2H),8.41(t,J=5.5Hz,1H),7.91(s,1H),7.67(t,J=5.9Hz,1H),7.51–7.35(m,5H),7 .34–7.19(m,7H),7.14(d,J=7.4Hz,1H),7.06(s,1H),6.27(dq,J=7.7,3.4Hz,1H),5.19(d,J=29.0Hz,4H),4.16(qt,J=18.0,9.2Hz ,1H),3.85–3.61(m,6H),3.58–3.33(m,17H),3.30–3.19(m,2H),3.06(dq,J=13.5,5.6Hz,1H),2.81–2.65(m,2H),2.59(t,J=6.5Hz ,2H),2.30(s,3H),2.23(s,3H),1.93–1.81(m,1H),1.78–1.61(m,2H),1.57–1.45(m,2H),1.44–1.33(m,1H),1.15(d,J=6.5Hz,3H).

[0202] Example 20: Preparation of Compound 20

[0203]

[0204] Step 1: Refer to the synthesis method of step 3 in Example 16 to obtain a white solid 20b. 1 H NMR (500MHz, DMSO-d6) δ10.22(s,1H),7.94(s,1H),7.87(d,J=7.7Hz,1H),7.73(d,J=6.2Hz,2H),7.68(t,J =7.7Hz,1H),7.58–7.28(m,8H),7.25(dd,J=7.6,1.5Hz,1H),5.46(d,J=48.4Hz,4H),2.25(d,J=9.3Hz,3H).

[0205] Step 2: Referring to the synthesis method of step 4 in Example 2, a white solid compound 20c was obtained.

[0206] Step 3: Referring to the synthesis method of Step 5 in Example 2, compound 20d was obtained, which was directly used in the next step without purification.

[0207] Step 4: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 20 (201 mg, 71%) was obtained. 1H NMR(500MHz,DMSO-d6)δ12.45(s,1H),8.77(s,2H),8.40(t,J=5.5Hz,1H),7.91(s,1H),7.84(s,1H),7.78(d,J=7.6Hz,1H),7.75–7.62(m,3H),7 .50–7.42(m,4H),7.42–7.35(m,1H),7.34–7.25(m,3H),7.21(dd,J=7.7 ,1.5Hz,1H),7.09(s,1H),6.27(dd,J=8.4,4.1Hz,1H),5.34(s,2H),5.21 (s,2H),4.22–4.10(m,1H),3.91–3.61(m,7H),3.59–3.34(m,18H),3.31 –3.23(m,2H),3.18–3.02(m,1H),2.80–2.65(m,2H),2.59(t,J=6.5Hz,2 H),2.22(s,3H),1.88(dd,J=12.3,9.5Hz,1H),1.68(ddd,J=41.1,10.8,5.5Hz,2H),1.57–1.44(m,2H),1.43–1.33(m,1H),1.15(d,J=6.5Hz,3H).

[0208] Example 21: Preparation of Compound 21

[0209]

[0210] Step 1: Refer to the synthesis method of step 3 in Example 16 to obtain a white solid 21b. 1 H NMR (500MHz, DMSO-d6) δ10.19(s,1H),8.76(d,J=2.3Hz,1H),8.59(dd,J=4.8,1.7Hz,1H),7.98(dt,J=7.9,2.0Hz,1H),7.72(s,1H),7.54(dd, J=7.6,1.5Hz,1H),7.51–7.44(m,3H),7.42–7.37(m,1H),7.37–7.30(m,4H),7.25(dd,J=7.6,1.5Hz,1H),5.44(d,J=6.3Hz,4H),2.25(s,3H).

[0211] Step 2: Referring to the synthesis method of step 4 in Example 2, a white solid compound 21c (356 mg, 78.3%) was obtained. 1H NMR (500MHz, DMSO-d6) δ8.70(d,J=2.2Hz,1H),8.56(dd,J=4.8,1.7Hz,1H),7.88(dt,J=7.9,2.0Hz,1H),7.70(q,J=6.0,5.5Hz,1H),7.5 4–7.42(m,5H),7.41–7.36(m,1H),7.36–7.27(m,3H),7.22(dd,J=7.7,1.5Hz,1H),7.13(s,1H),6.72(t,J=5.8Hz,1H),5.27(d,J=9.4Hz ,4H),3.51(d,J=13.8Hz,1H),3.37(ddd,J=12.0,4.7,1.8Hz,6H),3.32–3.20(m,5H),3.12(dq,J=13.4,5.6Hz,1H),3.01(q,J=6.0Hz,2H ),2.80–2.65(m,2H),2.24(s,3H),1.93–1.83(m,1H),1.79–1.61(m,2H),1.51(qt,J=11.0,4.9Hz,2H),1.42–1.37(m,1H),1.35(s,9H).

[0212] Step 3: Referring to the synthesis method of step 5 in Example 2, the reaction solution was spin-dried to obtain compound 21d, which was directly used in the next reaction without purification.

[0213] Step 4: Referring to the synthesis method of Step 6 in Example 2, a white solid target compound 21 (162 mg, 50%) was obtained. 1H NMR (500MHz, DMSO-d6) δ12.45(s,1H),8.74(s,2H),8.36(t,J=5.6Hz,1H),7.98–7.75(m,4H),7.70(t,J=6.0Hz,1H),7.62(t,J=7.7Hz, 1H),7.53–7.35(m,5H),7.35–7.24(m,3H),7.20(dd,J=7.7,1.5Hz,1H),7.06(s,1H),6.32–6.20(m,1H),5.25(d,J=35.5Hz,4H),4.11( dt,J=10.6,6.8Hz,1H),3.80–3.33(m,21H),3.30–3.08(m,4H),2.98(ddd,J=39.5,9.6,5.2Hz,2H),2.80–2.65(m,2H),2.45(t,J=6.0H z,2H),2.22(s,3H),1.89(t,J=10.8Hz,1H),1.78–1.60(m,2H),1.50(q,J=12.7,11.6Hz,2H),1.43–1.33(m,1H),1.13(d,J=6.5Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ173.66,169.25,164.36,160.66,158.37,157.88,156.07,153.59,146.56,142.65,141.77,135.60,134.4 0,132.80,132.22,131.47,131.25,130.25(d,J=5.7Hz),129.64,129.07(d,J=5.4Hz),128.72,128.28,127.44,126.02,120.69,1 19.11,116.24,113.66,111.99,100.93,73.85(d,J=10.4Hz),70.05,69.96,69.86,69.47,69.31,67.92,67.26(d,J=4.4Hz),55.3 8,53.07,51.51,50.95,50.76,50.30,49.64,48.92,42.04,39.34,38.52,34.72,30.26,25.13,23.62,17.98(d,J=4.6Hz),16.30.

[0214] Example 22: Preparation of Compound 22

[0215]

[0216] Step 1: Referring to the synthesis method of step 6 in Example 1, a pale yellow solid compound 22b (3.0 g, 71%) was obtained. 1 H NMR (500MHz, CDCl3) δ8.79(d,J=1.3Hz,1H),8.12(d,J=1.4Hz,1H),3.94(s,3H),3.81–3.69(m,4H),3.56(dd,J=6.5,4.1Hz,4H),1.47(s,9H).

[0217] Step 2: Referring to the synthesis method of step 5 in Example 1, the hydrolyzate 22c was obtained and used directly in the next step without purification.

[0218] Step 3: Referring to the synthesis method of Step 8 in Example 1, the condensation product 22d (470 mg, 72%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ8.59(d,J=1.3Hz,1H),8.29–8.18(m,2H),7.92(t,J=1.7Hz,1H),7.89–7.74(m,3H),7.69(t,J=5 .9Hz,1H),7.61(q,J=7.7Hz,1H),7.51–7.42(m,4H),7.42–7.35(m,1H),7.35–7.25(m,3H),7.20(dd,J=7.7,1.6Hz,1H),7. 05(s,1H),5.31–5.19(m,4H),3.68(dt,J=5.5,3.9Hz,4H),3.55(d,J=13.8Hz,1H),3.49–3.35(m,14H),3.31–3.20(m,2H), 3.18–3.07(m,1H),2.82–2.66(m,2H),2.22(s,3H),1.94–1.84(m,1H),1.79–1.60(m,2H),1.59–1.47(m,3H),1.42(s,9H).

[0219] Step 4: Referring to the synthesis method of step 2 in Example 1, the deprotected product 22e was obtained and used directly in the next reaction without purification.

[0220] Step 5: Referring to the synthesis method of Step 8 in Example 1, a white solid target product 22 (94 mg, 63%) was obtained. 1H NMR(500MHz,DMSO-d6)δ12.45(s,1H),8.60(d,J=1.3Hz,1H),8.29–8.19(m,2H),7.92(d,J=2.4Hz,2H),7.81(dq,J=8.1,1.7Hz,2H),7.70(t,J=6.0Hz,1H),7.61(t,J=7.8Hz,1H),7.50–7.43(m,4H),7.41–7.36(m,1H),7.35–7.24(m,3H),7.20(dd,J=7.6,1.5Hz,1H),7.06(s,1H),6.27(dd,J=8.5,4.1Hz,1H),5.25(d,J=36.9Hz,4H),4.23–4.09(m,1H),3.76–3.61(m,6H),3.61–3.35(m,18H),3.31–3.21(m,2H),3.18–3.09(m,1H),2.78–2.67(m,2H),2.59(t,J=6.4Hz,2H),2.22(s,3H),1.89(dd,J=12.4,9.6Hz,1H),1.79–1.61(m,2H),1.58–1.46(m,2H),1.43–1.35(m,1H),1.17–1.14(m,3H). 13 C NMR(126MHz,DMSO-d6)δ173.64,169.41,163.85,158.37,156.07,155.32,153.59,146.58,142.65,141.81(d,J=10.9Hz),139.10,135.60,134.40,133.34,132.79,132.21,131.46,131.23,130.25(d,J=5.6Hz),129.64,129.27,129.07,128.72,128.27,127.44,126.02,120.69,119.11,113.66,111.98,100.93,73.91,70.05,69.85(d,J=5.0Hz),69.52,69.32(d,J=4.3Hz),67.90,67.39,60.22,53.07,51.51,48.97,44.68,44.22,44.00,40.85,38.73,38.55,33.15,31.76,31.61,30.27(d,J=5.2Hz),29.50,25.13,23.62,22.56,21.22,18.01,16.30.

[0221] Example 23: Preparation of Compound 23

[0222]

[0223] Step 1: Referring to the synthesis method of step 6 in Example 1, a light yellow solid compound 23b was obtained.

[0224] Step 2: Referring to the synthesis method of step 5 in Example 1, the hydrolyzate 23c was obtained and used directly in the next step without purification.

[0225] Step 3: Referring to the synthesis method of Step 8 in Example 1, the condensation product 23d (365 mg, 74%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ8.72(s,2H),8.36(s,1H),7.93(q,J=2.3,1.6Hz,1H),7.85–7.79(m,2H),7.70(t,J=5.7Hz,1H),7.66 –7.58(m,1H),7.51–7.43(m,4H),7.42–7.36(m,1H),7.35–7.25(m,3H),7.24–7.18(m,1H),7.07(d,J=4.4Hz,1H),5.26(dd,J=3 4.1,4.0Hz,4H),3.86–3.71(m,2H),3.56(d,J=13.7Hz,1H),3.49–3.36(m,11H),3.33–3.21(m,4H),3.12(q,J=4.7,3.8Hz,5H), 2.80–2.67(m,5H),2.23(s,3H),1.96–1.83(m,1H),1.77–1.61(m,2H),1.60–1.45(m,2H),1.38(q,J=12.1Hz,1H),1.21(s,9H).

[0226] Step 4: Referring to the synthesis method of step 2 in Example 1, the deprotected product 23e was obtained and used directly in the next reaction without purification.

[0227] Step 5: Referring to the synthesis method of Step 8 in Example 1, a white solid target product 23 (201 mg, 60%) was obtained. 1H NMR(500MHz,DMSO-d6)δ12.44(d,J=6.2Hz,1H),8.73(d,J=10.5Hz,2H),8.36(dt,J=11.3,5.6Hz,1H),8.00–7.58(m,7H),7.49–7.43(m,3H),7.41–7.25(m,3H),7.21(dd,J=7.7,1.5Hz,1H),7.06(s,1H),6.23(ddd,J=12.6,8.4,4.2Hz,1H),5.36–5.17(m,4H),4.10(dt,J=12.4,6.1Hz,1H),3.74(t,J=6.3Hz,2H),3.65–3.33(m,19H),3.30–3.21(m,2H),3.19–3.06(m,4H),2.91(d,J=3.0Hz,2H),2.81(s,1H),2.78–2.67(m,2H),2.46(t,J=6.3Hz,1H),2.37(t,J=6.7Hz,1H),2.22(s,2H),1.95–1.84(m,1H),1.80–1.60(m,2H),1.58–1.46(m,2H),1.44–1.33(m,2H),1.12(dd,J=6.5,5.0Hz,3H). 13C NMR (126MHz, DMSO-d6) δ173.66, 170.58, 170.38, 164.27 (d, J = 13.0Hz), 162.24 (d, J=16.4Hz),158.36,156.07,153.59,146.54(d,J=6.2Hz),142.66,141.77,139.10, 135.60,134.40,132.80,132.22,131.47,131.25,130.27,130.22,129.64,129.03 (d,J=6.0Hz),128.72,128.27,127.44,126.02,120.68,119.10,116.31,116.04,11 3.67,112.00,100.94,73.81(d,J=5.3Hz),70.05,69.95,69.86,69.48,69.31,67. 91,67.61,67.32,61.19,55.38,53.05,51.51,48.90(d,J=8.3Hz),46.80,46.64,44 .92,39.32,38.52,36.27,35.95(d,J=6.4Hz),33.84,33.39,33.02,32.55,31.76,3 0.25,29.47(d,J=9.0Hz),29.17,25.98,25.12,23.62,22.56,17.97,16.30,14.41.

[0228] Example 24: Preparation of Compound 24

[0229]

[0230] Step 1: Referring to the synthesis method of step 6 in Example 1, a white solid compound 24b was obtained.

[0231] Step 2: Referring to the synthesis method of step 5 in Example 1, the hydrolyzed product 24c ( was obtained, which was directly used in the next step without purification.

[0232] Step 3: Referring to the synthesis method of Step 8 in Example 1, the condensation product 24d (450 mg, 67%) was obtained. 1HNMR (500MHz, DMSO-d6) δ8.74(s,2H),8.36(t,J=5.6Hz,1H),7.92(d,J=1.7Hz,1H),7.81(dt,J=8.1,1.6Hz,2H),7.70(t,J=5.9Hz,1H),7. 62(t,J=7.7Hz,1H),7.51–7.42(m,4H),7.41–7.35(m,1H),7.35–7.24(m,3H),7.21(dd,J=7.6,1.5Hz,1H),7.06(s,1H),5.26(d,J=33.4Hz ,4H),3.91–3.82(m,2H),3.74(q,J=6.9,6.4Hz,2H),3.59–3.34(m,13H),3.32–3.20(m,5H),3.11(dq,J=13.6,5.6Hz,1H),2.72(ddd,J=20 .5,9.1,3.8Hz,2H),2.23(s,3H),1.94–1.85(m,1H),1.82–1.61(m,4H),1.58–1.47(m,2H),1.36(t,J=12.1Hz,1H),1.27(d,J=24.0Hz,9H).

[0233] Step 4: Referring to the synthesis method of step 2 in Example 1, the deprotected product 24e was obtained and used directly in the next reaction without purification.

[0234] Step 5: Referring to the synthesis method of Step 8 in Example 1, a white solid target product 24 (192 mg, 56%) was obtained. 1H NMR(500MHz,DMSO-d6)δ12.44(d,J=2.5Hz,1H),8.74(d,J=1.3Hz,2H),8.37(q,J=5.1Hz,1H),7.99–7.85(m,2H),7.81(dt,J=7.6,1.6Hz,2H),7.75–7.59(m,2H),7.52–7.17(m,9H),7.06(s,1H),6.33–6.16(m,1H),5.38–5.15(m,4H),4.22–4.05(m,1H),3.95–3.69(m,4H),3.68–3.50(m,5H),3.46–3.33(m,13H),3.30–3.21(m,2H),3.11(dq,J=13.4,5.6Hz,1H),2.79–2.68(m,2H),2.49–2.41(m,2H),2.23(s,3H),1.95–1.85(m,1H),1.73(tdd,J=42.8,13.0,4.0Hz,4H),1.59–1.32(m,4H),1.11(dd,J=6.4,5.2Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ173.66,170.25,169.97,164.23,161.62,158.36,158.14,156.08,153.59,146.56(d,J=4.3Hz),142.66,141.77,139.10,135.60,134.41,132.81,132.22,131.47,131.26,130.27,129.65,129.04(d,J=4.5Hz),128.72,128.28,127.45,126.03,120.69,119.11,116.55,116.49,113.67,112.00,100.95,73.87(d,J=7.2Hz),70.05,69.96,69.87,69.47,69.32,67.92,67.54,67.43,55.38,53.07,51.51,48.94,47.45,46.80,46.61,46.01,45.76,44.86,39.33,38.52,33.00,32.81,31.76,31.61,30.27,29.49,29.17,26.64,25.13,24.88,23.62,22.56,17.94(d,J=5.9Hz),16.30,14.41.

[0235] Example 25: Preparation of Compound 25 (PD-29)

[0236]

[0237] Step 1: Referring to the synthesis method of step 6 in Example 1, a white solid compound 25b (1.5 g, 73%) was obtained. 1 H NMR (500MHz, CDCl3) δ8.79 (s, 2H), 3.81 (s, 5H), 3.65–3.48 (m, 4H), 3.25 (dd, J = 37.3, 11.3Hz, 2H), 2.94 (s, 2H), 1.38 (s, 9H).

[0238] Step 2: Referring to the synthesis method of step 5 in Example 1, the hydrolyzate 25c was obtained and used directly in the next step without purification.

[0239] Step 3: Referring to the synthesis method of Step 8 in Example 1, the condensation product 25d (300 mg, 87.9%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ8.73(s,2H),8.36(t,J=5.5Hz,1H),7.92(t,J=1.8Hz,1H),7.89–7.74(m,2H),7.69(t,J=5.8Hz,1H),7 .62(t,J=7.8Hz,1H),7.46(ddt,J=9.5,7.7,2.0Hz,4H),7.42–7.36(m,1H),7.35–7.24(m,3H),7.20(dd,J=7.7,1.5Hz,1H),7.05 (s,1H),5.25(d,J=35.9Hz,4H),3.74(d,J=10.5Hz,2H),3.59–3.34(m,17H),3.31–3.20(m,3H),3.20–3.06(m,4H),2.96(s,2H) ,2.80–2.67(m,2H),2.22(s,3H),1.88(t,J=11.3Hz,1H),1.78–1.69(m,1H),1.69–1.61(m,1H),1.58–1.45(m,3H),1.38(s,9H).

[0240] Step 4: Referring to the synthesis method of step 2 in Example 1, the deprotected product 25e was obtained and used directly in the next reaction without purification.

[0241] Step 5: Referring to the synthesis method of Step 8 in Example 1, a white solid target product 25 (103 mg, 67%) was obtained.

[0242] Example 26: Preparation of Compound 26

[0243]

[0244] Step 1: Referring to the synthesis method of step 6 in Example 1, a white solid compound 26b (1.0 g, 69%) was obtained. 1 H NMR(500MHz, CDCl3)δ8.79(d,J=10.7Hz,2H),3.81(s,3H),3.75–3.62(m,2H),3 .60–3.47(m,2H),3.46–3.20(m,4H),2.03–1.78(m,4H),1.39(d,J=3.1Hz,9H).

[0245] Step 2: Referring to the synthesis method of step 5 in Example 1, the hydrolyzate 26c was obtained and used directly in the next reaction without purification.

[0246] Step 3: Referring to the synthesis method of Step 8 in Example 1, the condensation product 26d (411 mg, 89%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ8.74(d,J=4.6Hz,2H),8.36(t,J=5.5Hz,1H),7.92(t,J=1.7Hz,1H),7.89–7.74(m,2H),7.70( t,J=5.9Hz,1H),7.61(q,J=7.7Hz,1H),7.46(td,J=8.1,1.5Hz,4H),7.41–7.36(m,1H),7.35–7.25(m,3H),7.20(dd,J= 7.7,1.5Hz,1H),7.06(s,1H),5.34–5.18(m,4H),3.66–3.33(m,18H),3.33–3.17(m,7H),3.11(dq,J=13.4,5.6Hz,1H), 2.79–2.66(m,2H),1.99–1.79(m,6H),1.76–1.69(m,1H),1.69–1.60(m,1H),1.58–1.46(m,2H),1.39(d,J=9.4Hz,9H).

[0247] Step 4: Referring to the synthesis method of step 2 in Example 1, the deprotected product 26e was obtained and used directly in the next reaction without purification.

[0248] Step 5: Referring to the synthesis method of Step 8 in Example 1, a white solid target product 26 (134 mg, 55%) was obtained. 1H NMR (500MHz, DMSO-d6) δ12.46(s,1H),8.74(d,J=6.4Hz,2H),8.36(t,J=5.2Hz,1H),7.95–7.85(m,2H),7.85–7.75(m,2H),7.70(t,J=5.9Hz ,1H),7.62(t,J=7.8Hz,1H),7.51–7.42(m,4H),7.42–7.35(m,1H),7.35–7.25(m,3H),7.20(dd,J=7.7,1.5Hz,1H),7.06(s,1H),6.27(td,J= 10.1,9.2,4.9Hz,1H),5.25(d,J=34.9Hz,4H),4.25–4.05(m,1H),3.71–3.33(m,22H),3.32–3.20(m,3H),3.17–3.07(m,1H),2.72(ddd,J=20 .9,9.4,3.6Hz,2H),2.45(dt,J=15.3,6.2Hz,2H),2.22(s,3H),2.00–1.60(m,7H),1.58–1.46(m,2H),1.45–1.33(m,1H),1.19–1.11(m,3H). 13 C NMR (126MHz, DMSO-d6) δ173.66,169.20,169.06,164.38,160.60,158.37,157.93,141.77,139.10,135.60,134.40,132.80,132.22 ,131.47,131.25,130.25(d,J=5.9Hz),129.65,129.08(d,J=5.9Hz),128.72,128.28,127.45,126.03,120.69,119.11,113.66,111 .99,100.93,73.88,70.05,69.96,69.86,69.48,69.31,67.92,67.28,55.66,55.38,55.28,54.33,53.07,51.52,48.97,48.76,47. 00,46.26(d,J=6.1Hz),45.64,44.87,39.34,38.52,34.91,34.75,34.39,34.20,33.58,30.26,29.46,25.13,23.62,17.99,16.30.

[0249] Example 27: Preparation of Compound 27

[0250]

[0251] Step 1: Referring to the synthesis method of step 5 in Example 1, the hydrolyzate 27a (780 mg, 91%) was obtained and used directly in the next step without purification.

[0252] Step 2: Referring to the synthesis method of Step 8 in Example 1, the condensation product 27b (780 mg, 91%) was obtained.

[0253] Step 3: Referring to the synthesis method of step 2 in Example 2, the deprotected product 27b (500 mg, 93%) was obtained and used directly in the next step without purification.

[0254] Step 4: Referring to the synthesis method of Step 8 in Example 1, the condensation product 27d (xx mg, xx%) was obtained.

[0255] Step 5: Referring to the synthesis method of step 2 in Example 2, the deprotected product 27e was obtained and used directly in the next step without purification.

[0256] Step 6: Referring to the synthesis method of step 4 in Example 1, the reductive amination product 27f (xx mg, xx%) was obtained.

[0257] Step 7: Referring to the synthesis method of step 2 in Example 1, 27 g of deprotected product was obtained, which was directly used in the next reaction without purification.

[0258] Step 8: Referring to the synthesis method of step 3 in Example 1, the substituted product 27h (xx mg, xx%) was obtained.

[0259] Step 9: Referring to the synthesis method of step 4 in Example 1, the target compound 27 (83 mg, 55%) was obtained. 1HNMR(500MHz,DMSO-d6)δ12.45(s,1H),8.46(s,2H),8.00–7.90(m,2H),7.81(d,J=7.9Hz,2H),7.62(t,J=7.7Hz,1H),7. 53–7.43(m,3H),7.42–7.26(m,5H),7.21(dd,J=7.7,1.5Hz,1H),7.08(s,1H),6.27(dq,J=7.1,3.4,2.9Hz,1H),5.26(d, J=19.8Hz,4H),4.15(p,J=6.6Hz,1H),3.86–3.36(m,23H),2.91(d,J=10.9Hz,1H),2.60(t,J=6.5Hz,2H),2.23(s,3H),2 .08(td,J=15.0,11.6,6.4Hz,1H),1.64(dd,J=19.1,6.2Hz,3H),1.47(s,2H),1.40–1.28(m,1H),1.15(d,J=6.5Hz,3H).

[0260] Example 28: Preparation of Compound 28

[0261]

[0262] Step 1: Referring to the synthesis method of Step 8 in Example 1, the condensation product 28b (780 mg, 91%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ7.42–7.27(m,5H),6.70(t,J=5.8Hz,1H),5.10(s,2H) ,3.52–3.35(m,8H),3.14(q,J=6.7Hz,2H),2.45(t,J=7.1Hz,2H),1.36(s,9H).

[0263] Step 2: Referring to the synthesis method of Step 2 in Example 2, the deprotected product 28c was obtained and used directly in the next step without purification.

[0264] Step 3: Referring to the synthesis method of Step 8 in Example 1, the condensation product 28d (910 mg, 82%) was obtained. 1HNMR(500MHz,DMSO-d6)δ7.34(d,J=18.9Hz,5H),6.71(s,1H),5.17–4.86(m,3H),3.85(d,J=12 .4Hz,1H),3.69–3.33(m,6H),3.31–2.71(m,5H),2.45(s,2H),1.88–1.49(m,4H),1.37(s,11H).

[0265] Step 4: Referring to the synthesis method of step 2 in Example 2, the deprotected product 28e was obtained and used directly in the next reaction without purification.

[0266] Step 5: Referring to the synthesis method of step 4 in Example 1, the reductive amination product 28f (380 mg, 45%) was obtained. 1 H NMR (500MHz, DMSO-d6) δ7.94 (s, 1H), 7.81 (ddd, J=7.3, 6.1, 1.6Hz, 2H), 7.62 (t, J=7.8Hz, 1H), 7.52–7. 43(m,3H),7.42–7.36(m,1H),7.35–7.25(m,4H),7.21(dd,J=7.7,1.5Hz,1H),7.08(s,1H),6.77–6.61(m ,1H),5.25(d,J=17.1Hz,4H),3.83–3.34(m,11H),3.13(q,J=6.7Hz,2H),2.90(d,J=11.2Hz,1H),2.44(t ,J=7.2Hz,2H),2.23(s,3H),2.09(d,J=13.7Hz,1H),1.62(d,J=20.5Hz,3H),1.46(s,2H),1.36(s,10H).

[0267] Step 6: Referring to the synthesis method of step 2 in Example 1, 28 g of deprotected product was obtained, which was directly used in the next reaction without purification.

[0268] Step 7: Referring to the synthesis method of Step 8 in Example 1, the target product 28 (101 mg, 54%) was obtained. 1HNMR (500MHz, DMSO-d6) δ12.45(s,1H),8.77(s,2H),8.44(t,J=6.8Hz,1H),7.92(d,J=13.4Hz,2H),7.81(t,J=7.1Hz ,2H),7.62(t,J=7.8Hz,1H),7.51–7.43(m,3H),7.41–7.26(m,5H),7.21(dd,J=7.6,1.5Hz,1H),7.08(s,1H),6.27(d d,J=8.6,4.2Hz,1H),5.25(d,J=17.3Hz,4H),4.20–4.09(m,1H),3.87–3.34(m,25H),2.90(d,J=10.2Hz,1H),2.59(t ,J=6.3Hz,4H),2.23(s,3H),2.15–2.02(m,1H),1.64(s,3H),1.46(s,2H),1.38–1.28(m,1H),1.15(d,J=6.5Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ169.68,169.36,164.09,161.81,158.36,158.03,156.15,153.58,146 .58,142.67,141.76,139.14,135.61,134.41,132.83,132.21,131.50,130.24,129.65,129.05 ,128.73,128.29,127.45,126.04,119.12,116.82,113.53,111.99,101.09,73.90,70.07,69.40,67.44,55.38,48.97,45.01,44.03,43.66,41.13,36.09,33.20,28.02,24.78,18.02,16.32.

[0269] Example 29: Preparation of Compound 29

[0270]

[0271] Step 1: Referring to the synthesis method of Step 8 in Example 1, the condensation product 29b (1.5 g, 75%) was obtained. 1HNMR(500MHz,DMSO-d6)δ7.43–7.29(m,5H),6.80(t,J=5.3Hz,1H),5.10(s,2H),3.52–3.3 4(m,8H),2.92(q,J=6.6Hz,2H),2.30(t,J=7.4Hz,2H),1.59(p,J=7.1Hz,2H),1.37(s,9H).

[0272] Step 2: Referring to the synthesis method of Step 2 in Example 2, the deprotected product 29c was obtained and used directly in the next step without purification.

[0273] Step 3: Referring to the synthesis method of Step 8 in Example 1, the condensation product 29d (903 mg, 81%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ7.34(d,J=21.2Hz,5H),6.81(s,1H),5.16–4.86(m,3H),3.85(d,J=12 .4Hz,1H),3.75–3.34(m,6H),3.32–2.67(m,5H),2.29(s,2H),1.90–1.48(m,6H),1.38(s,11H).

[0274] Step 4: Referring to the synthesis method of step 2 in Example 2, the deprotected product 29e was obtained and used directly in the next step without purification.

[0275] Step 5: Referring to the synthesis method of step 4 in Example 1, the reductive amination product 29f (320 mg, 52%) was obtained. 1 H NMR(500MHz,DMSO-d6)δ7.94(s,1H),7.82(t,J=7.2Hz,2H),7.62(t,J=7.7Hz,1H),7.53–7.43 (m,3H),7.42–7.35(m,1H),7.34–7.26(m,4H),7.21(dd,J=7.6,1.5Hz,1H),7.08(s,1H),6.79 (t,J=5.6Hz,1H),5.25(d,J=17.3Hz,4H),3.82–3.34(m,11H),2.92(q,J=6.9Hz,3H),2.28(s, 2H), 2.23 (s, 3H), 2.09 (d, J = 11.2Hz, 1H), 1.72–1.54 (m, 5H), 1.53–1.42 (m, 2H), 1.36 (s, 10H).

[0276] Step 6: Referring to the synthesis method of step 2 in Example 1, 29 g of deprotected product was obtained, which was directly used in the next reaction without purification.

[0277] Step 7: Referring to the synthesis method of Step 8 in Example 1, the target product 29 (110 mg, 62%) was obtained. 1 HNMR (500MHz, DMSO-d6) δ12.43(d,J=17.1Hz,1H),8.78(s,2H),8.35(s,1H),7.92(d,J=13.2Hz,2H),7.81(ddt,J=8.5,5.6,1.4Hz,2H),7.62(t ,J=7.8Hz,1H),7.52–7.43(m,3H),7.42–7.36(m,1H),7.35–7.26(m,4H),7.21(dd,J=7.6,1.5Hz,1H),7.08(s,1H),6.27(dd,J=8.6,4.2Hz,1H) ,5.25(d,J=17.8Hz,4H),4.14(dt,J=13.4,7.3Hz,1H),3.87–3.34(m,22H),3.25(q,J=7.1,6.5Hz,2H),2.90(d,J=10.5Hz,1H),2.59(t,J=6.5H z,2H),2.41–2.30(m,2H),2.23(s,3H),2.15–2.02(m,1H),1.81–1.56( m,5H),1.46(s,2H),1.33(q,J=10.4,9.3Hz,1H),1.15(d,J=6.5Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ171.00,169.36,163.96,161.82,158.36,158.02,156.16,153.56,146.5 8,142.67,141.76,139.14,135.61,134.41,132.83,132.21,131.49,130.24,129.65,129.05,12 8.73,128.29,127.45,126.03,119.12,117.04,113.53,111.99,101.09,73.90,70.07,69.40,67.44,55.38,48.97,45.02,44.03,43.67,41.14,39.10,33.20,28.01,25.14,24.74,18.02,16.32.

[0278] Example 30: Preparation of Compound 30

[0279]

[0280] Step 1: Referring to the synthesis method of Step 8 in Example 1, the condensation product 30b (1.8 g, 80%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ7.42–7.29(m,5H),6.78(t,J=5.6Hz,1H),5.10(s,2H),3.45(dq,J=6.6 ,3.7,3.0Hz,8H),2.90(q,J=6.5Hz,2H),2.30(t,J=7.4Hz,2H),1.52–1.37(m,4H),1.36(s,9H).

[0281] Step 2: Referring to the synthesis method of step 2 in Example 2, the deprotected product 30c was obtained and used directly in the next step without purification.

[0282] Step 3: Referring to the synthesis method of Step 8 in Example 1, the condensation product 30d (1.2 g, 77%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ7.34(d,J=21.2Hz,5H),6.79(s,1H),5.19–4.83(m,3H),3.85(d,J=12.4Hz,1H),3.69–3. 36(m,6H),3.31–3.12(m,1H),3.22–2.72(m,4H),2.30(s,2H),1.88–1.40(m,8H),1.37(s,9H),1.36–1.21(m,2H).

[0283] Step 4: Referring to the synthesis method of step 2 in Example 2, the deprotected product 30e was obtained and used directly in the next reaction without purification.

[0284] Step 5: Referring to the synthesis method of step 4 in Example 1, the reductive amination product 30f (356 mg, 47%) was obtained. 1HNMR(500MHz,DMSO-d6)δ7.94(s,1H),7.82(t,J=7.2Hz,2H),7.62(t,J=7.7Hz,1H),7.53–7.43(m,3H) ,7.42–7.35(m,1H),7.35–7.26(m,4H),7.21(dd,J=7.6,1.5Hz,1H),7.08(s,1H),6.78(d,J=5.8Hz,1H ),5.25(d,J=17.5Hz,4H),3.82–3.35(m,10H),3.32–3.27(m,1H),2.90(d,J=6.3Hz,3H),2.28(s,2H), 2.23(s,3H),2.09(s,1H),1.62(d,J=18.9Hz,3H),1.52–1.37(m,6H),1.36(s,9H),1.34–1.22(m,2H).

[0285] Step 6: Referring to the synthesis method of step 2 in Example 1, 30 g of deprotected product was obtained, which was directly used in the next reaction without purification.

[0286] Step 7: Referring to the synthesis method of Step 8 in Example 1, the target product 30 (98 mg, 59%) was obtained. 1 HNMR (500MHz, DMSO-d6) δ12.45(s,1H),8.78(s,2H),8.34(t,J=5.6Hz,1H),7.93(d,J=13.6Hz,2H),7.81(t,J=6.8Hz,2H),7.62(t,J=7. 7Hz,1H),7.50–7.44(m,3H),7.42–7.35(m,1H),7.34–7.26(m,4H),7.21(dd,J=7.7,1.5Hz,1H),7.08(s,1H),6.27(dd,J=8.5,4.2Hz,1H) ,5.25(d,J=18.1Hz,4H),4.14(dd,J=13.8,7.0Hz,1H),3.85–3.35(m,22H),3.28–3.20(m,2H),2.91(d,J=11.0Hz,1H),2.59(t,J=6.5Hz, 2H),2.32(s,2H),2.23(s,3H),2.11(d,J=10.5Hz,1H),1.63(t,J=13.1Hz,3H),1.56–1.43(m,6H),1.37–1.29(m,1H),1.17–1.14(m,3H). 13C NMR (126MHz, DMSO-d6) δ171.21,170.81,169.36,163.85,161.82,158.37,157.99,156.16,153.57,146. 58,142.67,141.76,139.14,135.60,134.41,132.82,132.20,131.47,130.24,129.64,129.05,128.72,1 28.29,127.44,126.03,119.12,117.04,113.52,111.99,101.08,73.90,70.08,69.40,67.44,60.22,48.97,45.02,44.04,43.67,41.14,39.11,33.20,29.32,28.00,24.75,22.65,21.21,18.01,16.31,14.54.

[0287] Example 31: Preparation of Compound 31

[0288]

[0289] Step 1: Referring to the synthesis method of Step 8 in Example 1, the condensation product 31b (1.1 g, 73%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ7.82(t,J=5.6Hz,1H),7.40–7.28(m,5H),7.24(t,J=5.6Hz,1H),6.78(t,J=5.7Hz,1H), 5.01(s,2H),3.13–2.99(m,4H),2.88(q,J=6.7Hz,2H),2.03(t,J=7.5Hz,2H),1.57(p,J=7.3Hz,2H),1.37(s,9H).

[0290] Step 2: Referring to the synthesis method of step 2 in Example 2, the deprotected product 31c was obtained and used directly in the next step without purification.

[0291] Step 3: Referring to the synthesis method of Step 8 in Example 1, the condensation product 31d (1.4 g, 82%) was obtained. 1HNMR(500MHz,DMSO-d6)δ7.92(s,1H),7.79(s,1H),7.34(d,J=28.7Hz,5H) ,6.78(t,J=5.4Hz,1H),5.20–5.02(m,2H),4.65–4.55(m,1H),3.91(d,J=13 .0Hz,1H),3.11(dq,J=11.7,6.6,5.1Hz,5H),2.89(q,J=6.7Hz,2H),2.15– 1.99(m,3H),1.57(dt,J=19.1,9.4Hz,5H),1.37(s,9H),1.34–1.19(m,2H).

[0292] Step 4: Referring to the synthesis method of step 2 in Example 2, the deprotected product 31e was obtained and used directly in the next reaction without purification.

[0293] Step 5: Referring to the synthesis method of step 4 in Example 1, the reductive amination product 31f (356 mg, 55%) was obtained. 1 H NMR (500MHz, DMSO-d6) δ7.94(t,J=1.7Hz,1H),7.86–7.71(m,4H),7.63(t,J=7.8Hz,1H),7.51–7.43(m,4H),7.43–7.35( m,1H),7.35–7.26(m,3H),7.21(dd,J=7.7,1.5Hz,1H),7.07(s,1H),6.76(t,J=5.6Hz,1H),5.26(d,J=33.6Hz,4H),3.52 (d,J=13.8Hz,1H),3.25(d,J=13.7Hz,1H),3.18–2.99(m,4H),2.86(q,J=6.7Hz,2H),2.73(ddd,J=25.7,10.9,3.6Hz,2H ),2.24(s,3H),2.05–1.84(m,3H),1.78–1.61(m,2H),1.53(dq,J=12.5,6.0,4.5Hz,4H),1.36(s,9H),1.29–1.16(m,2H).

[0294] Step 6: Referring to the synthesis method of step 2 in Example 1, 31 g of deprotected product was obtained, which was directly used in the next reaction without purification.

[0295] Step 7: Referring to the synthesis method of Step 8 in Example 1, the target product 31 (89 mg, 61%) was obtained. 1HNMR (500MHz, DMSO-d6) δ12.45(s,1H),8.77(s,2H),8.35(t,J=5.6Hz,1H),7.92(d,J=8.4Hz,2H),7.88–7.77(m,4H),7.62(t,J=7.8Hz,1H),7.50–7. 43(m,4H),7.41–7.36(m,1H),7.34–7.25(m,3H),7.21(dd,J=7.7,1.5Hz,1 H),7.05(s,1H),6.27(dd,J=8.5,4.2Hz,1H),5.25(d,J=34.3Hz,4H),4.14 (td,J=17.9,15.6,8.9Hz,1H),3.86–3.65(m,6H),3.57–3.47(m,7H),3.28 –3.02(m,7H),2.79–2.67(m,2H),2.59(t,J=6.5Hz,2H),2.26–2.21(m,3H) ,2.05(tt,J=10.4,5.4Hz,2H),1.93–1.85(m,1H),1.68(ddt,J=21.4,13.6 ,7.8Hz,4H),1.59–1.46(m,2H),1.43–1.33(m,1H),1.15(d,J=6.5Hz,3H).

[0296] Example 32: Preparation of Compound 32

[0297]

[0298] Step 1: Referring to the synthesis method of Step 8 in Example 1, the condensation product 32b (1.3 g, 77%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ7.75(d,J=7.6Hz,1H),7.46–7.22(m,5H),6.77(t ,J=5.7Hz,1H),5.07(s,2H),3.89(dt,J=13.9,3.8Hz,2H),3.73(tdt,J=10. 9,7.8,4.0Hz,1H),2.89(q,J=6.7Hz,4H),2.03(t,J=7.5Hz,2H),1.72(dt, J=13.0,3.6Hz,2H),1.57(p,J=7.3Hz,2H),1.37(s,9H),1.31–1.20(m,2H).

[0299] Step 2: Referring to the synthesis method of Step 2 in Example 2, the deprotected product 32c was obtained and used directly in the next step without purification.

[0300] Step 3: Referring to the synthesis method of Step 8 in Example 1, the condensation product 32d (1.2 g, 69%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ7.71(d,J=59.0Hz,1H),7.49–7.19(m,5H),6.78(s,1H),5.20–4.88(m,3H),4.34–3.59(m,4 H),3.48–3.35(m,1H),3.24–2.60(m,4H),2.03(t,J=7.4Hz,2H),1.89–1.48(m,8H),1.37(s,9H),1.35–0.96(m,4H).

[0301] Step 4: Referring to the synthesis method of step 2 in Example 2, the deprotected product 32e was obtained and used directly in the next reaction without purification.

[0302] Step 5: Referring to the synthesis method of step 4 in Example 1, the reductive amination product 32f (478 mg, 49%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ7.94(d,J=1.7Hz,1H),7.86–7.77(m,2H),7.72(dd,J=13.4,7.6Hz,1H),7.63(t,J=7.7Hz,1H),7.54–7. 44(m,3H),7.42–7.26(m,5H),7.21(dd,J=7.7,1.5Hz,1H),7.08(s,1H),6.76(t,J=5.5Hz,1H),5.33–5.20(m,4H),4.21(dd,J=25 .3,14.0Hz,2H),3.75(s,1H),3.51(d,J=12.9Hz,1H),3.42–3.24(m,3H),3.20–3.01(m,1H),2.88(q,J=6.7Hz,3H),2.70(dt,J=2 6.5,12.0Hz,1H),2.24(s,3H),2.01(t,J=7.6Hz,2H),1.78–1.53(m,7H),1.47(d,J=17.4Hz,2H),1.36(s,9H),1.33–1.22(m,3H).

[0303] Step 6: Referring to the synthesis method of step 2 in Example 2, 32 g of deprotected product was obtained, which was directly used in the next reaction without purification.

[0304] Step 7: Referring to the synthesis method of Step 8 in Example 1, the target product 32 (128 mg, 53%) was obtained. 1HNMR(500MHz,DMSO-d6)δ12.45(s,1H),8.77(s,2H),8.35(t,J=5.6Hz,1H),7.93(d,J=14.0Hz,2H),7.85–7.73(m,3H) ,7.66–7.59(m,1H),7.52–7.43(m,3H),7.42–7.26(m,6H),7.21(dd,J=7.8,1.5Hz,1H),7.08(s,1H),6.27(dd,J=8.6,4 .2Hz,1H),5.30–5.22(m,4H),4.29–4.11(m,3H),3.88–3.44(m,15H),3.27–3.03(m,4H),2.95–2.82(m,1H),2.70(dd,J =26.2,12.8Hz,1H),2.59(t,J=6.5Hz,2H),2.23(s,3H),2.14–2.00(m,3H),1.80–1.39(m,11H),1.15(d,J=6.5Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ171.53,169.36,163.91,161.82,158.36,158.02,156.15,153.59,146.5 8,142.67,141.77,139.15,135.62,134.42,132.83,132.22,131.49,130.25,129.65,129.06,12 8.74,128.30,127.46,126.04,119.12,117.01,113.55,111.99,95.89,73.90,70.06,69.40,67.44,55.38,48.97,45.02,44.04,43.68,41.14,39.08,33.47,33.20,29.50,25.86,18.01,16.33.

[0305] Example 33: Preparation of Compound 33

[0306]

[0307] Step 1: Referring to the synthesis method of Step 8 in Example 1, the condensation product 33b was obtained.

[0308] Step 2: Referring to the synthesis method of Step 2 in Example 2, the deprotected product 33c was obtained and used directly in the next step without purification.

[0309] Step 3: Referring to the synthesis method of Step 8 in Example 1, the condensation product 33d was obtained.

[0310] Step 4: Referring to the synthesis method of step 2 in Example 2, the deprotected product 33e was obtained and used directly in the next reaction without purification.

[0311] Step 5: Referring to the synthesis method of step 4 in Example 1, the reductive amination product 33f is obtained.

[0312] Step 6: Referring to the synthesis method of step 2 in Example 2, 33 g of deprotected product was obtained, which was directly used in the next reaction without purification.

[0313] Step 7: Referring to the synthesis method of Step 8 in Example 1, the target product 33 (142 mg, 59%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ12.45(s,1H),8.77(t,J=3.6Hz,2H),8.33(dd,J=13.9,6.6Hz,1H),7.93(d,J=13.3Hz,2H),7.81(d, J=7.8Hz,2H),7.71–7.58(m,2H),7.52–7.36(m,5H),7.35–7.25(m,3H),7.21(d,J=7.7Hz,1H),7.10–7.05(m,1H),6.27(dd,J= 8.4,4.2Hz,1H),5.26(d,J=25.0Hz,4H),4.20–4.06(m,1H),3.95–3.42(m,16H),3.32–3.16(m,3H),3.06–2.70(m,4H),2.59( t,J=6.5Hz,2H),2.40–2.25(m,2H),2.23(t,J=1.8Hz,3H),1.95(d,J=10.8Hz,1H),1.79–1.35(m,11H),1.15(d,J=6.5Hz,3H). 13C NMR(126MHz,DMSO-d6)δ170.72,169.36,163.95,161.81,158.37,158.01,156.09,153.57,146.5 8,142.67,141.77,139.15,135.63,134.42,132.80,132.22,131.48,130.25,129.65,129.06,128 .74,128.30,127.46,126.42,126.04,119.11,117.05,113.71,111.99,101.07,73.89,70.07,69.39,67.44,55.38,48.97,45.02,44.03,43.66,41.14,39.12,33.19,29.88,25.17,18.02,16.32.

[0314] Example 34: Preparation of Compound 34

[0315]

[0316] Step 1: Referring to the synthesis method of Step 8 in Example 1, the condensation product 34b (1.3 g, 76%) was obtained. 1 HNMR(500MHz,DMSO-d6)δ7.95(dt,J=24.8,5.7Hz,1H),7.43–7.15(m,5H),6.75(s,1H),5.24–4.88(m,2H),4.17(ddd,J=19.3,8.4,3.0Hz,1 H),3.55–3.34(m,9H),3.32–3.12(m,3H),3.05(p,J=5.8Hz,2H),2.09(dtd,J=42.9,11.3,9.8,6.5Hz,1H),1.92–1.67(m,3H),1.37(s,9H).

[0317] Step 2: Referring to the synthesis method of step 2 in Example 2, the deprotected product 34c was obtained and used directly in the next step without purification.

[0318] Step 3: Referring to the synthesis method of step 4 in Example 1, the reductive amination product 34d was obtained.

[0319] Step 4: Referring to the synthesis method of step 2 in Example 2, the deprotected product 34e was obtained and used directly in the next step without purification.

[0320] Step 5: Referring to the synthesis method of Step 8 in Example 1, the target product 34 (138 mg, 51%) was obtained.1 HNMR(500MHz,DMSO-d6)δ12.45(s,1H),8.78(s,2H),8.45(t,J=5.6Hz,1H),7.91(s,1 H),7.52–7.35(m,4H),7.34–7.25(m,3H),7.20(dd,J=7.7,1.5Hz,1H),6.39(s,2H),6. 27(dt,J=8.7,4.2Hz,1H),5.17(s,2H),4.17(ddd,J=20.3,11.0,4.5Hz,1H),3.85–3. 35(m,34H),2.59(t,J=6.5Hz,2H),2.21(s,3H),1.76–1.43(m,6H),1.17–1.13(m,3H).

[0321] Example 35: Determination of IC of the anti-PD-1 / PD-L1 binding of the compounds prepared in Examples 1-34 by in vitro HTRF assay 50

[0322] 1. Experimental Materials and Instruments

[0323] DMSO was from Sigma, product number: D5879; 384-well plate was from PerkinElmer, product number: 6007279. Anti-PD-1 blocking antibody (IC 50 :10nM) from Cisbio, product number: 64CUS000C-la; anti-PD-L1 blocking antibody (IC 50 :0.3 nM) from Cisbio, product number: 64CUS000C-lb; HTRF PD-1 / PD-L1 binding test kit from Cisbio, product number: 64PD1PEH.

[0324] 2. Reagent Preparation

[0325] 1. Prepare the test compound at 2X concentration in IX reaction buffer containing 4% DMSO;

[0326] 2. Tagl-PD-L1 protein and Tag2-PD1 protein were prepared in IX reaction buffer at concentrations of 50 nM and 10 nM, respectively. The final reaction concentrations were Tagl-PD-L1 10 nM and Tagl-PD-L1 2 nM.

[0327] 3. Anti-Tagl-Eu3+ antibody was prepared in IX concentration detection buffer at a ratio of 1:100;

[0328] 4. Anti-Tag2-XL665 antibody was prepared in IX concentration detection buffer at a ratio of 1:25;

[0329] 3. Experimental Procedure

[0330] 1. Add 5ul 2X test compound;

[0331] 2. Add 2.5ul Tagl-PD-L1 protein and Tag2-PD1 protein respectively, the total reaction system is 10ul, and react at 25℃ for 15 minutes;

[0332] 3. Add 5ul of anti-TagI-Eu3+ antibody and anti-Tag2-XL665 antibody respectively and react at 25℃ for 16 minutes;

[0333] 4. Use the fluorescence microplate reader HTRF plate reader program to read the two readings at wavelengths of 665nm and 620nm. Use the ratio of the two wavelengths to determine the activity of the compound, and use XLFIT5.0 (IDBS) to calculate the IC of the compound to be tested. 50 The test results are shown in Table 1.

[0334] Table 1 Test results of compounds inhibiting PD-1 / PD-L1 binding

[0335]

[0336] Note: + represents compound IC 50 >2.0uM; ++ represents compound 1.0uM <IC 50 ≤2.0uM; +++ represents compound 0.1uM <IC 50 ≤1.0uM; ++++ represents compound IC 50 ≤0.1uM

[0337] It can be seen from Table 1 that the exemplary compounds of the present invention have a certain inhibitory activity on the binding of PD-1 / PD-L1, and the inhibitory activity of some compounds on PD-1 / PD-L1 is significantly stronger than that of the positive control BMS-1.

[0338] Example 36: Determination of the inhibitory activity of the compounds prepared in Examples 1-34 on PARP7

[0339] Table 2 Test results of compounds inhibiting PARP7

[0340]

[0341] Note: + represents compound IC 50 >1000nM; ++ represents compound 100nM <IC 50≤1000nM; +++ represents compound 10nM <IC 50 ≤100nM; ++++ represents compound IC 50 ≤10nM

[0342] As can be seen from Table 2, the exemplary compounds of the present invention have certain inhibitory activity against PARP7.

[0343] Example 37: Determination of the effects of representative compounds prepared in Examples on IFN-γ secretion

[0344] The results are as follows Figure 1 As shown, from Figure 1 It can be seen that some of the compounds exemplified in the present invention can significantly promote the secretion of IFN-γ in a concentration-dependent manner.

[0345] Example 38: Determination of the effects of the compounds prepared in Examples 13 and 21 on the expression of hPD-L1 protein in MDA-MB-231 cells

[0346] The results are as follows Figure 2 As shown, from Figure 2 It can be seen that compound 13 and compound 21 of the present invention can significantly inhibit the expression of hPD-L1 in MDA-MB-231 cells in a concentration-dependent manner.

Claims

1. A small molecule derivative targeting PD-L1 / PARP7, or its optical isomers, racemates, single enantiomers, possible diastereomers, or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, characterized in that: The structural formula of the small molecule compound is shown in formula (I) or (II): Where: Each of the following structural fragments is independently selected, wherein R is -CN, -CF3 or -CH3, and m is any natural number from 1 to 4: L 1 Each independently selected from one of the following structural fragments: Where n is any natural number from 1 to 10; L 2 Each independently selected from one of the following structural fragments:

2. The small molecule derivative targeting PD-L1 / PARP7 according to claim 1, characterized in that: The small molecule derivative targeting PD-L1 / PARP7 is any one of compounds 1 to 34 shown in the following structures:

3. A method for preparing the compound according to any one of claims 1 to 2, characterized in that: Synthesis route 1: The specific steps include: (1) Add triphenylphosphine (PPh3) to the THF solution of compound A-1 and compound A-2, and then add diisopropyl azodicarboxylate (DIAD) solution dropwise to the reaction solution under ice bath conditions. After the addition is complete, return to room temperature and continue stirring for 24 hours to stop the reaction. Post-treatment and purification give intermediate A-3; (2) To a dichloroethane solution of compounds A-3 and A-4, sodium triacetoxyborohydride (NaBH(OAc)3) was added, and the mixture was stirred at 80°C for 1-2 hours to stop the reaction. The intermediate A-5 was obtained after post-treatment. (3) Add solid sodium hydroxide to a mixed solution of methanol and water of intermediate A-5, stir at room temperature for 4 hours, stop the reaction, and post-treat to obtain compound A-6; (4) Add DIPEA, EDCI and HOBt to a dichloromethane solution of compounds A-6 and A-7, stir at room temperature for 6 h, stop the reaction, and post-treat to obtain intermediate A-8; (5) Add trifluoroacetic acid to a dichloromethane solution of compound A-8, stir at room temperature for 0.5 h, stop the reaction, and post-treat to obtain intermediate A-9; (6) DIPEA, EDCI and HOBt were added to the dichloromethane solution of intermediates A-9 and A-10, stirred at room temperature for 6 h, the reaction was stopped, and post-treatment was performed to obtain the small molecule derivative targeting PD-L1 / PARP7 shown in (I).

4. A method for preparing the compound according to any one of claims 1 to 2, characterized in that: Synthesis route 2: The specific steps include: (1) Add boron tribromide (BBr3) solution dropwise to a dichloromethane solution of compound B-1. After the addition, stir under ice bath for 0.5 h to stop the reaction. Post-treatment and purification are performed to obtain intermediate B-2. (2) Add solid NaHCO3 to the DMF solution of intermediates B-2 and B-3, stir at 60°C for 2h, stop the reaction, and perform post-treatment and purification to obtain intermediate B-4; (3) Add Cs2CO3 solid to the DMF solution of intermediates B-4 and B-5, stir at 80°C for 2h, stop the reaction, and perform post-treatment and purification to obtain intermediate B-6; (4) Add sodium triacetoxyborohydride (NaBH(OAc)3) to a dichloroethane solution of compound B-6 and A-4, stir at 80°C for 1-2h, stop the reaction, and perform post-treatment and purification to obtain intermediate B-7; (5) Add solid sodium hydroxide to a mixed solution of methanol and water of intermediate B-7, stir at room temperature for 4 hours, stop the reaction, and post-treat to obtain compound B-8; (4) Add DIPEA, EDCI and HOBt to a dichloromethane solution of compounds B-8 and A-7, stir at room temperature for 6 h, stop the reaction, and post-treat to obtain intermediate B-9; (5) Add trifluoroacetic acid to a dichloromethane solution of compound B-9, stir at room temperature for 0.5 h, stop the reaction, and post-treat to obtain intermediate B-10; (6) DIPEA, EDCI and HOBt were added to the dichloromethane solution of intermediates B-10 and A-10, and the mixture was stirred at room temperature for 6 h. The reaction was stopped and post-treated to obtain the small molecule derivative targeting PD-L1 / PARP7 shown in (I).

5. A method for preparing the compound according to any one of claims 1 to 2, characterized in that: Synthesis route three: The specific steps include: DIPEA, EDCI and HOBt were added to the dichloromethane solution of compounds A-6 and C-1, and the mixture was stirred at room temperature for 6 h. The reaction was stopped and post-treated to obtain the small molecule derivative targeting PD-L1 / PARP7 shown in (II).

6. Use of the compound according to any one of claims 1 to 2, or its optical isomers, racemates, single enantiomers, possible diastereomers, or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates in the preparation of drugs for treating cancer or infectious diseases.

7. The use according to claim 6, characterized in that: The cancers include: bone cancer, head or neck cancer, pancreatic cancer, skin cancer, malignant melanoma of the skin or inside the eye, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, including acute myeloid leukemia, leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, solid tumors in children, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, cancer of the renal pelvis, central nervous system tumors, primary central nervous system lymphoma, tumor angiogenesis, spinal tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, asbestos induced cancers, and combinations of the above cancers.

8. The use according to claim 6 or 7, characterized in that: The infectious diseases include bacterial infectious diseases, viral infectious diseases or fungal infectious diseases.

9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a compound according to any one of claims 1 to 2 or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and at least one other agent, wherein the other agent comprises an anticancer agent, a chemotherapeutic agent or an antiproliferative compound.

10. Use of the compound according to any one of claims 1-2, or its optical isomers, racemates, single enantiomers, possible diastereomers, or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, or the pharmaceutical composition according to claim 9 in regulating an immune response mediated by the PD-1 signaling pathway.

Images