PD-L1 ANTAGONIST COMPOUND

Abstract

A compound of Formula (I) and a pharmaceutical composition thereof are provided, as well as a method for using the compounds of Formula (I) to prevent and / or treat disorders related to the immune system. (see Formula).

Description

PD-L1 ANTAGONIST COMPOUND FIELD OF THE INVENTION The present invention relates to a PD-L1 antagonist compound and a method of using the same to treat / prevent conditions related to the immune system. BACKGROUND OF THE INVENTION Due to its excellent efficacy and innovation, cancer immunotherapy was named the most important scientific breakthrough of the year by Science magazine in 2013. Cancer immunotherapy is expected to become an innovation in the field of tumor therapy after of surgery, chemotherapy, radiotherapy and targeted therapy. According to cancer immunotherapy, the immunogenicity of tumor cells and the sensitivity to effector cell destruction are improved, and the body's anti-tumor immune response is stimulated and improved by applying immunological principles and methods; and tumors are eliminated and tumor growth is inhibited by using immune cells and effector molecules to infuse the host in vivo and cooperating with the body's immune system. Cancer immunotherapy has attracted much attention recently and is the focus of tumor therapy. In recent years, the good news regarding cancer immunotherapy has continued. At present, it has shown strong antitumor activity in the treatment of some types of tumors, such as melanoma and non-small cell lung cancer, and cancer immunotherapy drugs have been approved by the EDA (Food Administration and Drugs, FDA) for clinical use. PD-1 (programmed death 1) is a member of the CD28 superfamily. Immunomodulation targeting PD-1 is of great importance in anti-tumor, anti-infectious, anti-autoimmune diseases, and organ transplant survival. Its ligand PD-L1 can also serve as a target and the corresponding antibody can also play the same role. PD-L1 (programmed cell death-Ligand 1) is a first-class transmembrane protein of 40 kDa in size. Under normal circumstances, the immune system will respond to foreign antigens that accumulate in the lymph nodes or spleen and promote the proliferation of antigen-specific T cells. Binding of PD-1 to PD-L1 can transmit inhibitory signals and reduce T cell proliferation. One way tumor cells can evade destruction by T cells is to produce PD-L1 on the surface of T cells. When PD-1 on the surface of cells Immune T cells recognize PD-L1, inhibitory signals can be transmitted, and T cells cannot detect tumor cells and send attack signals to tumor cells. PD-1 is a new immunotherapy that evades the immune system from exhausting tumor cells. The mechanism of PD-1 immunotherapy is to design specific protein antibodies against PD-1 or PD-L1, prevent the recognition process of PD-1 and PD-L1, and partially restore the function of T cells, so that T cells can destroy tumor cells. PD-1 is expressed on activated T cells, B cells, and myeloid cells with two ligands, PD-L1 and PD-L2. PD-L1 / L2 is expressed on antigen-presenting cells and PD-L1 is also expressed on various tissues. PD-1 binding to PD-L1 mediates co-inhibitory signaling of T cell activation, regulates T cell activation and proliferation, and plays a negative regulatory role similar to that of CTLA-4. Chinese scientist Chen Lieping's laboratory first discovered that PD-L1 is highly expressed in tumor tissues and regulates the function of tumor-infiltrating CD8 T cells. Therefore, immunoregulation targeting PD-1 / PD-L1 is of great importance against tumors. The US FDA has approved the marketing of a series of therapeutic monoclonal antibodies (mAbs) targeting the PD-1 / PD-L1 interaction. In addition to the development of related monoclonal antibodies, the search for small-molecule oral compounds that are convenient for cancer patients to target immune checkpoint inhibition is also a frontier domain of cancer immunotherapy. Small molecule compounds can cross the cell membrane and act on intracellular targets, so they have a wide range of applications. Second, small molecules usually have good bioavailability and compliance after chemical modification, which effectively prevents decomposition and inactivation of enzymes in the digestive intestine. Finally, the research on small molecules is also quite mature in many aspects, such as the production process, dosage form design, and mode of administration. Most monoclonal antibodies (mAbs) are administered by intravenous injection at high doses. Small molecule drugs, which are more suitable for oral administration, may reduce serious immune-related adverse effects. Compared with monoclonal antibodies, small molecule drug inhibitors have many other benefits, such as cheaper and more stable manufacturing costs, and better permeability to organs and tumors. Given the numerous advantages of small molecule pharmacokinetic properties, it will exhibit dosing flexibility in monotherapy or other combination regimens. The small molecule compounds of the present invention may provide an attractive treatment option for patients and physicians. SUMMARY OF THE INVENTION The present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, an isotopic derivative, an isomer, a solvate or a metabolite thereof. (R4)m Formula ινΐΛ / a / zuzz / uuou 1 or where Li is selected from -CRARB- and -C(O)-; L2, La are selected from -(CRCRD)P, -(CRcRD)P-NRa-(CRcRD)q-, -(CRcRD)P-O-(CRcRD)q- and -C(O)-; Wi, W2 each independently represent CRLo N; R1 each independently represents hydrogen, halogen, nitro, cyano or NRaRbo Ci-Ce alkyl, C3-C6 cycloalkyl, -O(Ci-Ce alkyl), -0(Co-Ce alkylene)(Cs-Cio heteroaryl), 0(Co -Ce alkylene)(5-10 membered heteroaryl), -0(Co-Ce alkylene)(C3-C6 cycloalkylene) or -0(Co-Ce alkylene)(3-6 membered heterocycloalkyl) substituted with 0, 1, 2 or 3 substituents; where the substituents are selected from -ORa, cyano, oxo, halogen, Ci-Ce alkyl, -(Ci-Ce alkylene)ORa, cyano Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, -C(O) Ra, -(Ci-Ce alkylene)C(O)Ra, -C(O)ORa, -(CiC6 alkylene)C(O)ORa, -NRaRb, -(Ci-Ce alkylene)NRaRb, -C(O) NRaRb, -SO2Ra, -C(O)NRaSO2Rby NRaC(O)Rb; R2, R3, R4, R5 each independently represent hydrogen, halogen, nitro, cyano, -NRaRb, -SO2Ra, -S(O)Ra, -P(O)RaRb, Ci-Ce alkyl, -O(Ci-Ce alkyl ), -O(C3-C6 cycloalkyl), halo(Ci-Ce alkyl) or C3-C6 cycloalkyl; Cy represents benzene ring or six-membered heteroaryl substituted by 0, 1, 2 or 3 R6, where the six-membered heteroaryl may optionally contain 1 or 2 nitrogen atoms; where R6 represents hydrogen, halogen, nitro, cyano, -NRaRb, -SO2Ra, -S(O)Rao P(O)RaRbo Ci-Ce alkyl, C3-C6 cycloalkyl, -O(Ci-Ce alkyl), -0( Co-Ce alkylene)(Cs-Cio aryl), -0(CoCe alkylene)(5-10 membered heteroaryl), «(Co-Ce alkylene)(C3-C6 cycloalkyl) or -0(Co-Ce alkylene)( 3-6 membered heterocycloalkyl) substituted with 0, 1, 2 or 3 substituents; where the substituents are selected from -ORa, cyano, oxo, halogen, Ci-Ce alkyl, -(Ci-Ce alkylene)ORa, cyano Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, -C(O) Ra, -(Ci-Ce alkylene)C(O)Ra, -C(O)ORa, -(CiC6 alkylene)C(O)ORa, -NRaRb, -(Ci-C6 alkylene)NRaRb, -C(O) NRaRb, -SO2Ra, -C(O)NRaSO2Rbo NRaC(O)Rb; Where RL represents hydrogen, Ci-Cs alkyl, -O(Ci-C6 alkyl), -O(C3-C& cycloalkyl), halogen, nitro, cyano, -NRaRb, halo(Ci-C6 alkyl) or Cs-Ce cycloalkyl; T and A each represent independently: -(Ci-Ce alkylene), -(Co-Ce alkylene)(C3-C12 cycloalkylene), -(Co-Ce alkylene)-(3-12 membered heterocycle), -(Co -Ce alkylene)-(Ce-Cio aryl) or -(Co-Ce alkylene)-(5-10 membered heteroaryl), substituted with 0, 1, 2 or 3 substituents, where the substituents are selected from: cyano, oxo , halogen, Ci-Ce alkyl, -(Co-Ce alkylene) ORa, cyano Ci-Ce alkyl, halo (Ci-Ce alkyl), C3-C8 cycloalkyl, -(Co-Ce alkylene)C(O)Ra, - (Co-Ce alkylene)C(O)ORa, -(Co-Ce alkenylene)C(O)ORa, -(Co-C6 alkylene)NRaRb, -C(O)NRaRb, -NRaSO2Rb, C(O)NRaSO2Rby - NRaC(O)Rb; Where, RA and RB each represent independently: hydrogen, Ci-Ce alkylene, -(C0-C3 alkylene) (C3-Ci2cycloalkyl), -(C0-C3 alkylene) (3-12 membered heterocycle), halo(Ci-Ce alkyl ) or halogen, or RA and RB together with the carbon atoms to which they are commonly attached form a 3-6 membered ring; Rc and RD represent each independently: hydrogen, Ci-Ce-alkyl, -(C0-C3 alkylene) (C3Ci2cycloalkyl), -(C0-C3 alkylene) (3-12 membered heterocycle), halo (Ci-Ce alkylene) or halogen , or Rcy RD together with the carbon atoms to which they are connected form a 3-6 membered ring; Ray Rbrepresent each independently: hydrogen, Ci-Ce-alkyl, halogenated(Ci-Ce alkyl), -(Co-Ce alkylene)OH, -(C0-C3 alkylene) (C3-Ci2cycloalkyl), -(C0-C3 alkylene ) (3-12 membered heterocycle), -(C0-C3 alkylene) (Ce-Cio aryl), -(C0-C3 alkylene) (5-10 membered heteroaromatic ring) or halo(Ci-Ce alkyl), or Ray Rb together with the atoms to which they are commonly attached form a 3-6 membered ring; Where, m, o, both independently represent 0, 1 or 2; Here, p, q, both independently represent 0, 1, 2 or 3. Preferably, the compound of formula (I) having the following structure of formula (II): iviA / a / zuzz / uuou 1 or where R1, R2, R3, R4, R5, R6, Li, b, b, T, A, Wi, W2, m, or as defined by the formula where r represents 0, 1, 2 or 3. Preferably, the compound of formula (I) has the following structure of formula (III): Where R1, R2, R3, R4, R5, R6, Li, b, b, T, A, Wi, W2, m, or as defined by formula (i); where W3 represents CRMo N; where RM represents hydrogen, C1-C6 alkyl, -O(Ci-Cb alkyl), -O(C3-C6 cycloalkyl), halogen, nitro, cyano, -NRaRb, halo(Ci-Ce alkyl) or C3-C6 cycloalkyl; where r represents 0, 1 or 2. Preferably, the compound of formula (I) has the following structure Where R1, R2, R3, R4, R5, R6, Li, b, b, T, A, Wi, W2, m, or as defined by formula (i); where W4 represents CRNo N; where RN represents hydrogen, Ci-Ce alkyl, -O(Ci-C6 alkyl), -O(C3-Ce cycloalkyl), halogen, nitro, cyano, -NRaRb, halo(Ci-C6 alkyl) or C3-C6 cycloalkyl; Where r represents 0, 1 or 2. In the compounds of the present invention, Li is selected from -CRARB-, where RA and RB are each independently selected from hydrogen, halogen, Ci-Ce alkyl and halo (Ci-Ce alkyl), preferably hydrogen. In the compounds of the present invention, b and b are each independently selected from -CRcRDy -CRcRD-NRa- (CRcRD)q-, wherein q is selected from 0, 1 or 2, wherein Rc and RD are each independently selected of hydrogen, halogen, Ci-C& alkyl and halo (Ci-C6 alkyl), preferably hydrogen. Rase independently selects from hydrogen, Ci-Ce alkyl, halo (Ci-Ce alkyl) and -(C0-C3 alkylene) C3-C12 cycloalkyl. In the compounds of the present invention, Wi and W2 each independently represent CH or N. In the compounds of the present invention, W3 represents CH or N. In the compounds of the present invention, W4 represents CH or N. In the compounds of the present invention, T, A each preferably independently represent -(Ci-Ce alkylene), -(Co-Ce alkylene)-(C3-C12 cycloalkyl) or (Co-Ce alkylene)-(heterocycle 3-12 members), substituted by 0, 1, 2 or 3 substituents, wherein the substituents are selected from: cyano, oxo, halogen, Ci-Ce alkyl, -(Co-Ce alkylene)ORa, cyano Ci- Ce alkyl, halo(Ci-Ce alkylene), C3-C8 cycloalkyl, -(Co-Ce alkylene)C(O)Ra,-(Co-Ce alkylene) C(O)ORa,-(Co-Ce alkenyl)C (O)ORa, -(Co-Ce alkylene)NRaRb, -C(O)NRaRb, -NRaSO2Rb, -C(O)NRaSO2Rb and -NRaC(O)Rb, where Ray Rb each independently represent hydrogen, Ci-Ce alkyl or halo(Ci-Ce alkyl). In the compounds of the present invention, T, A each preferably independently represents Ci-Ce alkyl, C3-C12 cycloalkyl or substituted 3-12 membered heterocycle with 0, 1 or 2 substituents, wherein the substituents are selected from: cyano, oxo, -ORa, -(Co-Ce alkylene)C(O)ORa, -(Co-C6 alkenylene)C(O)ORa, -NRaC(O)Rb, -NRaSO2Rb and -C(O)NRaSO2Rb, where Ray Rb each independently represent hydrogen, Ci-Ce alkyl, or halo (Ci-Ce alkyl). In the compounds of the present invention, T and A each preferably independently represent the following groups optionally substituted with 0, 1 or 2 (^CCy^VW N substituents: , where the substituents are selected from Ci-Ce alkyl, -ORa, -(Co-Ce alkylene)C(O)ORay -(Co-Ce alkenyl)C(O)ORa, where Ra represents hydrogen or Ci-Ce alkyl, preferably is hydrogen, where a represents 1, 2 or 3. In the compounds of the present invention, T, A each preferably independently represent the following groups: In the compounds of the present invention, T and A each preferably independently represent the following group optionally substituted with 0.1 or 2 substituents: R, where the substituents are selected from: Ci-Ce alkyl, -ORa and halogen, where King 5 Ra each independently represent hydrogen or Ci-Ce alkyl, where o represents 1, 2, 3 or 4. In the compounds of the present invention, T and A each preferably independently represents Re, where Re represents hydrogen or Ci-Ce alkyl, where a represents 1, 2, 3 or 4. In the compounds of the present invention, T, A each preferably independently represents: In the compounds of the present invention, R1 preferably represents -O(Ci-C6 alkylene), -0(Co-Ce alkylene) (C5-C10 aryl), -0(Co-C6 alkylene) (5-10 membered heteroaryl) , -0(CoCe alkylene) (C3-C6 cycloalkyl) or -0(Co-Ce alkylene) (3-6 membered heterocycloalkyl), substituted with 0, 1, 2 or 3 substituents, where the substituents are selected from: cyano , oxo, halogen, cyano Ci-Ce alkyl and Ci-Ce haloalkyl. In the compounds of the present invention, R2 preferably represents hydrogen, halogen, nitro, cyano, -SOzRa, Ci-Ce alkyl, halo (Ci-C6 alkyl) or C3-C6 cycloalkyl, where Ra represents hydrogen, Ci-Ce alkyl or halo ( Ci-C6 alkyl). In the compounds of the present invention, R3 and R4 each preferably independently represent hydrogen, halogen, nitro or cyano. In the compounds of the present invention, R5 preferably represents hydrogen, halogen, nitro, cyano, Ci-Ce alkyl, halo (Ci-Ce alkyl) or C3-C6 cycloalkyl. In the compounds of the present invention, R6 preferably represents hydrogen, halogen, nitro, cyano, -SChR3, Ci-Ce alkyl, halo(Ci-Ce alkyl) or C3-C6 cycloalkyl or -O(Ci-C6 alkyl), -0 (Co-Ce alkylene) (C5-C10 aryl), -0(Co-Ce alkylene) (5-10 membered heteroaryl), -0(Co-C6 alkylene) (C3-C6 cycloalkyl) or -0(Co- C6 alkylene) (3-6 membered heterocycloalkyl) substituted with 0.1, 2 or 3 substituents; where the substituents are selected from: cyano, oxo, halogen, cyanoCi-Ce alkyl and Ci-Ce haloalkyl. In the compounds of the present invention, RL preferably represents hydrogen or halogen. RM and RN each preferably and independently represent hydrogen. DETAILED DESCRIPTION OF THE INVENTION Specifically, the present invention provides compounds having the I o o o / , \ J O o ,z Yw CY \___ Φ w ° IZ Λ O COOH 0 ~~~N ^χΥΥ' °' OMe 0H L / 0H HN^ Cl^v r^>i =Ν V / ^OMe 0 ==YYnYCY Cl CY Η 1 Cl r O O c o -Z tY^ YY \___, Φ tY° IZ 0 o ZZ 8 Y) I -\ qhQ CY Y ° n( o o o z Y zz 80Y YY γζω Vu -^° / Y l 0 0 0 I __ / COOH ciVw YY1 Γ=Ν 0=YZn^O^ Cl 10 Η Y och3 0 °Y 2¾ ΥΥ \ Φ €Y° IZ 7 0 '54 °z-\ <CY \ QJ Ch IZ 0 0 Y ZI 2 \Y (B ----\ ΩY^ CYil ZZ 0 ' / 0 0 £00H Q0 ειΎΓΥ OMe 000Η t0 ci'^Y^Yl OMe ινΐΛ / a / zuzz / uuou i o Furthermore, the present invention also provides a pharmaceutical composition ινΐΛ / a / zuzz / uuou i o that includes a compound of the present invention and, optionally, further includes an additional therapeutic agent and / or an immune checkpoint inhibitor. The pharmaceutical compositions of the present invention may include a pharmaceutically acceptable carrier. Furthermore, the present invention also provides the use of a compound of the present invention or a pharmaceutical composition containing the compound of the present invention in the preparation of a medicament for the treatment of a disease or condition that can be treated by inhibiting binding. from PD-L1 to PD-1. Preferably, the disease is selected from the group consisting of tumors, cancers, viral infections, inflammation-related diseases and autoimmune diseases. The present invention also provides the use of a compound of the present invention or a pharmaceutical composition containing the compound of the present invention in the preparation of a medicament for the treatment of a disease or condition that responds to the inhibition of PD binding. -LI to PD -1. Preferably, the disease or condition is selected from the group consisting of tumors, cancers, viral infections, inflammation-related diseases and autoimmune diseases. Furthermore, the present invention also provides a method for the treatment of a disease or condition (preferably tumors, cancers, viral infections, inflammation-related diseases and autoimmune diseases) that can be treated by inhibiting the binding of PD-LI to PD. -1, which includes administering to a mammal in need thereof a compound or pharmaceutical composition of the present invention. The present invention also provides a method for the treatment of a disease or condition that responds to the inhibition of the binding of PD-LI to PD-1, including the administration to a mammal in need thereof of a compound or a pharmaceutical composition of the present invention. The term "disease or condition responsive to inhibition of PD-LI binding to PD-1" means any disease or condition in which: disease progression can be altered by inhibition of PD-LI binding to PD. -1, or may result in the alleviation, inhibition, elimination and improvement of diseases, conditions and disorders, or may prevent such diseases or conditions. Preferably, the disease or condition that responds to the inhibition of PD-LI binding to PD-1 is selected from the group consisting of tumors, cancers, viral infections, inflammation-related diseases and autoimmune diseases. The present invention also provides a method for inhibiting the binding of PD-LI to PD-1, which includes exposing the compound or pharmaceutical composition of the present invention to PD-LI and / or PD-1. In the above-mentioned embodiments related to the compounds, pharmaceutical compositions and uses and methods of use of the compounds or pharmaceutical compositions of the present invention, the compound of the present invention especially includes the form of a pharmaceutically acceptable salt thereof. Representative examples of inflammatory diseases, autoimmune diseases and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), diseases related to skin, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic inflammatory lung disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis, scleroderma , organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory diseases, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, lymphoma B-cell, T-cell lymphoma, myeloma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia, Hodgkin's disease, non- Hodgkin, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative tumor (MPN), diffuse large B-cell lymphoma and follicular lymphoma. Representative examples of cancers or tumors may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bones, brain cancer, neurocytoma, rectal cancer, colon cancer, familial adenomatous polyposis cancer, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, larynx cancer, hypopharyngeal cancer, tongue cancer, salivary glands, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, renal cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, corpus carcinoma, endometrial cancer, choriocarcinoma, pancreatic cancer, cancer prostate, testicular cancer, urinary system carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), adult leukemic T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung, non-small cell lung carcinoma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma or plasmacytoma. When a compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another therapeutic agent or immune checkpoint inhibitor for the treatment of cancer or tumors, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide enhanced anti-cancer effect. Representative examples of therapeutic agents for the treatment of a cancer or tumor may include, but are not limited to, inhibitors of cellular signal transduction, Chlorambucil, Melphalan, Cyclophosphamide, Ifosfamide, Busulfan, Carmustine, Lomustine, Streptozotocin, Cisplatin, Carboplatin, Oxaliplatin, Dacarbazine, Temozolomide, Procarbazine, Methotrexate, Fluorouracil, Cytarabine, Gemcitabine, Mercaptopurine, Fludarabine, Vinblastine, Vincristine, Vinorelbine, Paclitaxel, Docetaxel, Topotecan, Iñnotecan, Etoposide, Trabectedin, Dactinomycin, Doxorubicin, Epirubicin, Daunorubicin, Mito xantrone, Bleomycin, Mitomycin C , Ixabepilone, Tamoxifen, Flutamide, Gonadorelin Analogues, Megestrol, Prednisone, Dexamethasone, Methylprednisolone, Thalidomide, Interferon A, Calcium Folinate, Sirolimus, Sirolimus Lipids, Everolimus, Afatinib, Alisertib, Amuvatinib, Apatinib, Axitinib, Bortezomib, Bosutinib, Brivanib, Cabozantinib, Cediranib, Crenolanib, Crizotinib, Dabrafenib, Dacomitinib, Danusertib, Dasatinib, Dovitinib, Erlotinib, Foretinib, Ganetespib, Gefitinib, Ibrutinib, Icotinib, Imatinib, Inipañb, Lapatinib, Lenvatinib, Linifanib, Linsitinib, Masitinib, Momelotinib, Motesanib, Neratinib, Nilotinib, Niraparib, Oprozomib, Olaparib, Pazopanib, Pictiliisib, Ponatinib, Regorafenib, Rigosertib, Rucaparib, Ruxolitinib, Saracatinib, Saridegib, Sorafenib, Sunitinib, Telatinib, Tivantinib, Tivozanib, Tofacitinib, Trametinib, Vandetanib, Veliparib, Vemurafenib, Erivedge, Volasertib, Alemtuzumab, Bevacizumab, Brentuximab Vedotin, Catumaxomab, Cetuximab, Denosumab, Gemtuzumab, Ipilimumab, Nimotuzumab, Ofatumumab, Panitumumab, Rituximab, Tositumomab, Trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, inhibitors of IDO, anti-PD-1 antibodies, LAG3 antibodies, TIM-3 antibodies and anti-CTLA-4 antibodies, or any combination thereof. When a compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another therapeutic agent for the treatment of inflammatory diseases, autoimmune diseases and immune-mediated diseases, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide an enhanced therapeutic effect. Representative examples of therapeutic agents for the treatment of inflammatory diseases, autoimmune diseases and immune-mediated diseases may include, but are not limited to, steroidal drugs (for example, prednisone, prednisolone, methylprednisolone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNF a agents (e.g., etanercept, infliximab, adalimumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected from them can be included in the pharmaceutical compositions of the present invention. The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient in an effective amount ranging from 0.1 mg / kg body weight / day to 2,000 mg / kg body weight / day, preferably 1 mg / day. kg body weight / day to 1,000 mg / kg body weight / day for mammals including humans (body weight approximately 70 kg), and administered in a single or four divided doses per day, or on / off following a predetermined time. The dosage of the active ingredient can be adjusted according to a number of relevant factors, such as the condition of the subject to be treated, the type and severity of the disease, the frequency of administration and the doctor's opinion). In some cases, lower amounts than the above doses may be appropriate. If it does not cause harmful side effects, a larger amount than the previous dose can be used and the amount can be given in divided doses per day. Furthermore, the present invention also provides a method for the inhibition of the binding of PD-L1 to PD-1, including exposing the compound of the present invention, the pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention to PD. -L1. Definition of terms: It should be noted that, when reference is made herein to a compound having a specific structural formula, stereoisomers, diastereomers, enantiomers, racemic mixtures and isotopic derivatives thereof, as well as pharmaceutically acceptable salts, solvates and hydrates as alternative forms , are also generally contemplated. It is well known to those skilled in the art that a salt, solvate, hydrate of a compound is an alternative form of the compound that can be converted into the compound under conditions such that, as used herein, reference to a compound generally includes salts pharmaceutically acceptable thereof, and also includes solvates and hydrates thereof. Similarly, when a compound is referred to herein, prodrugs, metabolites, and nitrogen oxides thereof are generally also included. The pharmaceutically acceptable salt of the present invention may be formed using an inorganic acid or an organic acid, the pharmaceutically acceptable salt meaning a salt that is, within the scope of good medical judgment, suitable for use in contact with the tissues of humans and animals. inferior without undue toxicity, irritation and allergic response, consistent with a reasonable benefit / risk ratio. As noted below, salts may be prepared in situ during the final isolation and purification of the compounds of the present invention, or may be prepared by reacting the free base or free acid with a separate suitable reagent. For example, the free base can be reacted with a suitable acid. Furthermore, when the compounds of the present invention carry an acidic moiety, their suitable pharmaceutically acceptable salts may include metal salts, such as alkali metal salts (for example, sodium or potassium salts); and alkaline earth metal salts (for example, calcium or magnesium salts). Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (for example, acetic acid, acid oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or formed using other methods known in the prior art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfonate. , heptanoate, hexanoate, hydroiodide, 2hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate , phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate and valerate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium salts. Other pharmaceutically acceptable salts include non-toxic ammonium salts (where applicable), quaternary ammonium salts and ammonium cations formed with counterions, for example, halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, lower alkyl sulphonates and aryl sulphonates. . The pharmaceutically acceptable salts of the present invention can be prepared by a conventional method, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol and acetonitrile), adding an excess of an aqueous organic or inorganic acid to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt. The precursors or metabolites of the present invention may be those known in the art as long as the precursors or metabolites are converted into compounds by in vivo metabolism. For example, prodrugs refer to those of the compounds of the present invention that are, within the scope of good medical judgment, suitable for use in contact with the tissues of humans and lower animals without toxicity, irritation, undue allergic response and the like. , proportional to a reasonable benefit / risk ratio and effective for their intended use. The term prodrugs refers to compounds that rapidly produce the parent compounds of the aforementioned formulas by in vivo transformation, for example, by in vivo metabolism, or N-demethylation of a compound of the present invention. Solvate of the present invention means a physical association of a compound of the present invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonds. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate may be isolated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. Solvates can include stoichiometric or non-stoichiometric solvent molecules. Solvato encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates and isopropanolates. Solvation methods are well known in the art. The stereoisomerism of the present invention is divided into conformational shallowing and configurational shallowing, and configurational shallowing can also be divided into cis-trans isomerism and optical shallowing (i.e., optical shallowing). Conformational shallowness refers to a phenomenon of stereoisomerism in which the rotation or distortion of the carbon-carbon single bond of an organic molecule with a certain configuration causes the atoms or atomic groups of the molecule to produce different arrangements in space, and Common examples include the structures of alkanes and cycloalkanes, such as the chair and boat conformations found in the cyclohexane structure. Stereoisomers means that when the compounds of the present invention contain one or more asymmetric centers, therefore, they can serve as racemates and racemic mixtures, individual enantiomers, diastereomeric mixtures and individual diastereoisomers. The compounds of the present invention may have asymmetric centers, each of which produces two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds of the present invention may exist in the form of tautomers, which have different hydrogen bonding sites through the displacement of one or more double bonds. For example, ketone and its enol form are tautomers of keto-enol. Each tautomer and its mixtures are included in the compounds of the present invention. All enantiomers, diastereomers, racemates, mesomers, cis-transisomers, tautomers, geometric isomers, epimers and mixtures thereof of the compounds of Formula (I) are included within the scope of the present invention. An isotopic derivative of the present invention refers to a molecule in which a compound is labeled with an isotope in this patent. The isotopes commonly used as isotopic markers are: hydrogen isotopes, 2H and 3H; carbon isotope:nC,13C and14C; chlorine isotope: 35CI and 37CI; fluorine isotope:18F; iodine isotope: 123I and 125I; nitrogen isotopes: 13N and 15N; oxygen isotopes:15O,17O and18O and sulfur isotope35S. These isotopically labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Deuterium2H and carbon13C, in particular, are most widely used due to their ease of labeling and detection. Substitution of certain heavy isotopes, such as heavy hydrogen (2H), may improve metabolic stability, prolong half-life, and provide therapeutic advantages as a result of a reduced dose. Generally, starting from labeled starting materials, isotopically labeled compounds are synthesized using known synthesis techniques in the same manner as the synthesis of non-isotopically labeled compounds. The pharmaceutical compound or compositions of the present invention may be formulated in dosage forms, such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions or suspensions, for oral or parenteral administration (including intramuscular, intravenous and subcutaneous, and intratumoral injection) according to any of the conventional methods. The pharmaceutical compositions of the present invention for oral administration can be prepared by mixing the active ingredient with vehicles such as: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, magnesium stearate. calcium, gelatin, talc, surfactants, suspending agents, emulsifying agents and diluents. Examples of carriers employed in the injectable compositions of the present invention consist of water, saline solutions, dextrose solutions, glucose-like solutions, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, esters of acids. fatty acids, glycerides, surfactants, suspending agents and emulsifying agents. Additional features of the present invention will become apparent from the description of exemplary embodiments of the present invention which are presented for illustrative purposes and are not intended to be limiting thereof, and the following examples are prepared, isolated and characterized using the methods described in this document. The terms used in the present invention (including the specification and claims) are defined below, unless otherwise indicated. It should be noted that, in the description and the accompanying claims, the singular forms a, an and the include plural referents unless the context clearly indicates otherwise. Unless otherwise indicated, conventional methods of mass spectrometry, nuclear magnetics, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used. In this usage, the use of or or and means and / or unless otherwise indicated. Throughout the specification and claims, a given chemical formula or name will encompass all stereoisomers and optical isomers and racemates in which such isomers exist. Unless otherwise indicated, all chiral (enantiome and diastereomeric) and racemic forms are within the scope of the present invention. Many geometric isomers of C=C double bonds, C=N double bonds and ring systems may also be present in the compounds, and all of the stable isomers mentioned above are encompassed in the present invention. The cis- and trans-(or E- and Z-) geometric isomers of the compounds of the present invention are described herein and can be isolated as mixtures of isomers or as separate isomeric forms. The compounds of the present invention can be isolated in optically active or racemic forms. All methods for preparing the compounds of the present invention and the intermediates prepared therein are considered part of the present invention. When preparing enantiomeric or diastereomeric products, they can be isolated by conventional methods (for example, by chromatography or fractional crystallization). Depending on the process conditions, the final products of the present invention are obtained in free (neutral) or salt form. Both the free forms and salts of these final products are within the scope of the present invention. If desired, one form of the compound can be converted into another form. The free base or acid can be converted to a salt; the salt can be converted to the free compound or another salt; Mixtures of isomeric compounds of the present invention can be isolated into the individual isomers. The compounds, free forms and salts thereof of the present invention, can exist in a variety of tautomeric forms in which the hydrogen atoms are rearranged to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged. . It should be understood that all tautomeric forms that may exist are included in the present invention. Unless otherwise defined, the definitions of the substituents of the present invention are each independent and are not interrelated, for example, for Ra(or Rb) in the substituents, each is independent in the definition of different substituents. . Specifically, when a definition of Rb(or Rb) in one substituent is selected, it does not mean that Ra(or Rb) has the same definition in other substituents. More specifically, for example (a non-exhaustive list) for NRaRb, when the definition of Ra(or Rb) is selected from hydrogen, it does not mean that in -C(O)- NRaRb, Ra(or Rb) must be hydrogen. Unless otherwise defined, when a substituent is labeled as optionally substituted, the substituent is selected from, for example, the following substituents consisting of alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl , aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamine, disubstituted amino group (in which two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio , Ariltio, Alalalquiltio, Alaltiocarbonil, Alalalquiliocarbonil, alklsulfonil, arilsulfonil, arilalquilsulfonel, sulfonamide such as -so2nh2, replacement sulfonamide, nitro, cyano, carboxi, carbamoil as -conh2, carbamoil replaced as -conh alkyl rent or the where it exists are two substituents selected from alkyl, aryl or arylalkyl on the nitrogen, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and homopiperazinyl, and substituted heterocyclyl. As used herein, the term alkyl or alkylene is intended to include straight-chain and branched-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, C1-C6 alkyl indicates an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, n-pentyl, isopentyl and neopentyl. The term alkenyl denotes a straight-chain or branched hydrocarbon group containing one or more double bonds and typically 2 to 20 carbon atoms in length. For example, C2-C6 alkenyl contains 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl and l-methyl-2-buten-l-yl. The term alkynyl denotes a straight-chain or branched hydrocarbon group containing one or more triple bonds and typically 2 to 20 carbon atoms in length. For example, C2-C6 alkynyl contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl and 1-butynyl. The term alkoxy or alkyloxy refers to -O-alkyl. C1-C6 alkoxy (or alkyloxy) is intended to include Cl, C2, C3, C4, C5 and C6 alkoxy. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, alkylthio or thioalkoxy means an alkyl group, as defined above, with the specified number of carbon atoms attached through a sulfur bridge, for example, methylS- and ethyl-S-. The term carbonyl refers to an organic functional group (C=O) composed of two carbon and oxygen atoms joined by a double bond. The term aryl, alone or as part of a larger moiety such as aralkyl, aralkoxy, or aryloxyalkyl, refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 5 to 12 ring members, where at least one ring in the system is aromatic and where each ring in the system contains 3 to 7 ring members. In certain embodiments of the present invention, aryl refers to an aromatic ring system including, but not limited to, phenyl, iviA / a / zuzz / uuou 1 or biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl. . The term aralkyl or arylalkyl refers to an alkyl moiety attached to an aryl ring. Non-limiting examples include benzyl and phenethyl. The fused aryl group may be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring. For example, a dashed line drawn from a ring system indicates that the bond can be attached to any suitable ring atom. The term cycloalkyl refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl refers to branched or unbranched cyclic alkyl, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyls such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of cycloalkyl. Bicyclic alkyl includes bridged, spiro or fused cycloalkyl. The term cycloalkenyl refers to a monocyclic or bicyclic cyclic alkenyl group. Monocyclic cyclic alkenyl refers to branched or unbranched cyclic alkenyl, including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornenyl. Branched cycloalkenyls such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of cycloalkenyl. Bicyclic alkenyl includes bridged, spiro or fused cyclic alkenyl. Halo or halogen includes fluorine, chlorine, bromine and iodine. Haloalkyl is intended to include both straight and branched chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl. Examples of haloalkyl also include fluoroalkyl groups intended to include straight chain and branched saturated aliphatic hydrocarbon groups that have the specified number of carbon atoms and are substituted with one or more fluorine atoms. Haloalkoxy or haloalkyloxy indicates a haloalkyl group, as defined above, having the indicated number of carbon atoms linked through an oxygen bridge. For example, haloalkoxy C1-C6 is intended to include haloalkoxy Cl, C2, C3, C4, C5 and C6. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy and pentafluoroethoxy. Similarly, haloalkylthio or thiohaloalkoxy denotes a haloalkyl group, as defined above, having the indicated number of carbon atoms linked through a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-. In the present disclosure, the expression Cxl-Cx2 is used when referring to some substituent groups, which means that the number of carbon atoms in the substituent group can be from xl to x2. For example, C0-C8 means the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C1-C8 means the group contains 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C2-C8 means the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C3-C8 means the group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C4-C8 means the group contains 4, 5, 6, 7 or 8 carbon atoms, C0-C6 means the group contains 0, 1, 2, 3, 4, 5 or 6 atoms of carbon, C1-C6 means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C2-C6 means that the group contains 2, 3, 4, 5 or 6 carbon atoms, and C3- C6 means that the group contains 3, 4, 5 or 6 carbon atoms. In the present description, the term xl-x2 membered ring is used when referring to cyclic groups (such as aryl, heteroaryl, cycloalkyl and heterocycloalkyl), which means that the number of atoms in the ring group can be xl to x2. For example, the 3- to 12-membered cyclic group may be a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring, whose number of atoms in the ring may be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 3 to 6 membered ring means that the cyclic group may be a 3, 4, 5 or 6 membered ring, whose number of atoms in the ring may be 3, 4, 5 or 6; 3 to 8 membered ring means that the cyclic group can be a 3, 4, 5, 6, 7 or 8 membered ring, whose number of atoms in the ring can be 3, 4, 5, 6, 7 or 8 ; 3 to 9 membered ring means that the cyclic group can be a 3, 4, 5, 6, 7, 8 or 9 membered ring, whose number of atoms in the ring can be 3, 4, 5, 6, 7 .8 or 9; 4 to 7 membered ring means that the cyclic group may be a 4, 5, 6 or 7 membered ring, whose number of atoms in the ring may be 4, 5, 6 or 7; 5 to 8 membered ring means that the cyclic group may be a 5, 6, 7 or 8 membered ring, whose number of atoms in the ring may be 5, 6, 7 or 8; 5 to 12 membered ring means that the cyclic group can be a 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, whose number of atoms in the ring can be 5, 6, 7, 8 .9, 10, 11 or 12; and 6 to 12 membered ring means that the cyclic group can be a 6, 7, 8, 9, 10, 11 or 12 membered ring, whose number of atoms in the ring can be 6, 7, 8, 9, 10, lio 12. The ring atom may be a carbon atom or a heteroatom, for example, a heteroatom selected from N, O and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10 or more heteroatoms in the ring, for example, a heteroatom selected from N, O and S. In the present invention, one or more halogens can each be independently selected from fluorine, chlorine, bromine and iodine. The term heteroaryl means a stable 3-, 4-, 5-, 6- or 7-membered aromatic monocyclic or aromatic bicyclic or a 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic aromatic heterocycle, which is fully unsaturated, partially unsaturated and contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; and includes any polycyclic group in which any heterocycle defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms can optionally be oxidized. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, if defined). The heterocycle can be attached to its pendant group on any heteroatom or carbon atom resulting in a stable structure. If the resulting compound is stable, the heterocyclyl groups described here may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle can optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not more than 1. When the term heterocycle is used, it is intended to include heteroaryl. Examples of heteroaryl include, but are not limited to, acridinyl, azetidinyl, azocynyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl , cinolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, imidazopyridinyl, indolenyl, indolinyl , indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, or xadiazolyl, 1,2,3-oxadiazolyl, 1 f talazinyl , piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl pyrrolidonyl, pyrrolinyl, 2-pyrrolidonyl, 2H- pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5thiadiazinyl 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2 ,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 ,5-triazolyl, 1,3,4-triazolyl, thiantrenyl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinium, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 1,2,3,4-tetrahydroquinolinyl -tetrahydroisoquinolinyl, 5,6,7,8tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4tetrahydro-quinazolinyl. The term heteroaryl may also include biaryl structures formed from aryl and monocyclic heteroaryl as defined above, for example, but not limited to -phenylbipyridyl-, -phenylbipyrimidinyl, -pyridylbiphenyl, -pyridylbipyrimidinyl. -, pyrimidinylbiphenyl-; wherein the present invention also includes fused and spiro compounds containing, for example, the aforementioned heterocycles. As used herein, the term heterocycloalkyl refers to a monocyclic heterocycloalkyl system or a bicyclic heterocycloalkyl system, and also includes spiroheterocycles or bridged heterocycloalkyl groups. Monocyclic heterocycloalkyl refers to a saturated or unsaturated, but non-aromatic, cyclic alkyl system containing at least one heteroatom selected from O, N, S, P. Bicyclic heterocycloalkyl system refers to a heterocycloalkyl fused with a phenyl, or a cycloalkyl , or a cycloalkenyl, or a heterocycloalkyl, or a heteroaryl. Preferably, the heterocycloalkyl or heterocycle contains at least one or two heteroatoms selected from O, N and S. As used herein, the term bridged cycloalkyl refers to polycyclic compounds that share two or more carbon atoms, including bicyclic bridged cyclic hydrocarbons and polycyclic bridged cyclic hydrocarbons. The former are composed of two alicyclic rings that share more than two carbon atoms; the latter are bridged cyclic hydrocarbons consisting of more than three rings. As used herein, the term spirocycloalkyl refers to polycyclic hydrocarbons that share a carbon atom (referred to as a spiro atom) between single rings. As used herein, the term bridged cycloheteryl refers to polycyclic compounds that share two or more carbon atoms and contain at least one atom selected from O, N or S, including bicyclic bridged heterocycles and polycyclic bridged heterocycles. . As used herein, the term heterospirocyclyl refers to polycyclic hydrocarbons that share a carbon atom (referred to as a spiroatom) between individual rings and contain at least one heteroatom selected from O, N or S. As used herein, the term substituted means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that the normal valence is maintained and that the substitution results in a stable compound. As used herein, ring double bond is a double bond (e.g., C=C, C=N, or N=N) formed between two adjacent ring atoms. In the event that nitrogen atoms (e.g., amines) are present in the compounds of the present invention, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or peroxide of hydrogen) to obtain other compounds of the present invention. Therefore, the nitrogen atoms shown and claimed are considered to encompass both the nitrogen shown and its N-oxides to obtain the derivatives of the present invention. When a variable appears more than once in any composition or formula of a compound, its definition in each occurrence is independent of its definition in any other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, the group may be optionally substituted with up to three R groups, and at each occurrence R is selected independently of the definition of R. Additionally, combinations of substituents and / or variables are allowed only if such combinations result in stable compounds. As used herein, the term patient refers to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, ape / monkey, equine, bovine, porcine, canine, feline, etc.) and more preferably refer to humans. As used herein, the term effective amount means an amount of a drug or pharmaceutical agent (i.e., a compound of the present invention) that will elicit the biological or medical response of a tissue, system, animal or human that searched, for example, by a researcher or doctor. Furthermore, the term therapeutically effective amount means an amount that results in better treatment, cure, prevention or alleviation of a disease, condition or side effect, or a reduction in the rate of progression of a disease or condition, compared to a corresponding subject who does not receive such amount. An effective amount may be administered in one or more dosages, administrations or dosages and is not intended to be limited by the particular formulation or route of administration. The term also includes an effective amount that improves normal physiological function within its scope. As used herein, the term treatment includes its broad meaning and encompasses the therapeutic and / or prophylactic treatment of a subject. Specifically, the term treatment includes any treatment that results in the alleviation, inhibition, elimination and improvement and / or prevention of conditions, diseases, disorders, etc., such as the alleviation, reduction, modulation, improvement, elimination, prevention or improvement of their symptoms. Therapeutic treatment includes alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the generation of complications; improve potential metabolic syndrome; inhibit the development of a disease or condition, such as controlling the development of a disease or condition; alleviate an illness or condition; reduce illness or symptoms; alleviate complications resulting from the disease or condition, or treat symptoms resulting from the disease or condition. Prophylactic treatment includes prior treatment to prevent, block or delay, slow the onset or development or lessen the severity of the disease or condition. Likewise, a therapeutic agent also includes a medication or reagent that has a therapeutic and / or prophylactic treatment on a subject. The term medicinal or pharmaceutically acceptable is used herein to refer to compounds, materials, compositions and / or dosage forms as follows: within the scope of good medical judgment, suitable for use in contact with human tissues and animals without undue toxicity, irritation, allergic response and / or other problems or complications, consistent with a reasonable benefit / risk ratio. Specific pharmaceutical and medical terms The term cancer, as used herein, refers to uncontrolled abnormal growth of cells and is capable of metastasis (transmission) under certain conditions. This type of cancer includes, but is not limited to, solid tumors (for example, bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas, or other endocrine organs (for example, thyroid). , prostate, skin (melanoma) or hematological tumors (for example, aleukemic leukemia). The term administered in combination or similar terms, as used herein, refers to the administration of several selected therapeutic agents to a patient in the same or different modes of administration at the same or different times. The term improve or may improve, as used herein, means that the desired result can be increased or prolonged in potency or duration. Therefore, in enhancing the therapeutic effect of a drug, the term may potentiate refers to the ability of the drug to increase or prolong potency or duration in the system. Synergistic value, as used here, refers to the ability to maximize the capacity of another therapeutic agent in an ideal system. The term immunological disease refers to a disease or condition that responds adversely or detrimentally to endogenous or exogenous antigens. The result is usually cell dysfunction, or therefore destruction and dysfunction, or destruction of organs or tissues that can produce immune symptoms. The term kit is synonymous with product package. The term object, subject or patient includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as chimpanzees, apes and monkeys; agricultural animals such as cattle, horses, goats, sheep, pigs; domestic animals such as rabbits, canines; Experimental animals include rodents, such as rats, mice, and guinea pigs. Non-mammalian animals include, but are not limited to, birds and fish. In a preferred embodiment, the selected mammal is a human. As used herein, a pharmaceutical compound or composition, upon administration, may result in the improvement of a disease, symptom or condition, in particular the improvement of severity, delay of onset, alleviation of progression or reduction in the duration of the condition. Regardless of fixed administration or temporary administration, continuous administration or intermittent administration, it can be attributed to or related to administration. Administration route Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, aural, nasal and topical administration. Furthermore, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic and intranasal injections. The compounds of the present invention can be administered topically. In particular embodiments, the long-acting preparation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in another embodiment, the drug is administered by a targeted drug delivery system, for example, liposomes encapsulated by organ-specific antibodies. In this particular embodiment, the liposomes are selectively targeted to specific organs and absorbed. Pharmaceutical compositions and dosages. As used herein, the phrase pharmaceutically acceptable carrier means a pharmaceutical material, composition or vehicle, such as a liquid or solid filler, a diluent, an excipient, a manufacturing aid (e.g., lubricant, talc, stearate magnesium, calcium stearate or zinc stearate or stearic acid), or solvent encapsulation material, which refers to carrying or transporting the compound in question from one organ or part of the body to another organ or part of the body. Each vehicle must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. The term "pharmaceutical composition" means a composition that includes a compound of the present invention and, optionally, another pharmaceutically acceptable carrier. Pharmaceutically acceptable carrier means a means generally accepted in the art for the administration of a biologically active agent to an animal, (particularly a mammal), and includes, (i.e.) adjuvants, excipients or vehicles such as diluents, preservatives, fillers , flow regulators agents, disintegrants, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents. This depends on the mode of administration and the nature of the dosage form. The pharmaceutical compositions of the present invention may include a therapeutically effective amount of one or more compounds of the present invention formulated together with optionally one or more pharmaceutically acceptable carriers (additives) and / or diluents, and mg / kg / min. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses two, three or four times a day. The compounds are generally administered in the form of a mixture of suitable diluents, excipients or pharmaceutical vehicles (collectively referred to herein as pharmaceutically acceptable vehicles) suitably selected with respect to the intended form of administration (e.g., oral tablets, capsules, elixirs). , and syrups) and consistent with conventional pharmaceutical practice. Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1-95% by weight, based on the total weight of the composition. Typical capsules for oral administration contain at least one compound of the present invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was processed through a 60 mesh sieve and filled into No.l gelatin capsules. A typical injectable formulation can be prepared as follows: at least one compound of the present invention (250 mg) was placed in a vial in a sterile manner, and lyophilized and sealed in a sterile manner. For use, the contents of the vial were mixed with 2 ml of normal saline to produce an injectable formulation. The scope of the present invention includes (alone or in combination with a pharmaceutically acceptable carrier) pharmaceutical compositions containing a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, the compounds of the present invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more therapeutic agents (for example, anticancer agents or other pharmaceutically active agents). Regardless of the route of administration selected, the compounds of the present invention (which can be used in suitable hydrated forms) and / or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. subject. The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response, composition and mode of administration for a particular patient without being toxic. for the patient. The dosage level selected will depend on a variety of factors, including factors well known in the medical field such as the activity of the specific compound employed of the present invention, or an ester, salt or amide thereof; administration routes; administration time; the discharge rate of the specific compound used; absorption rate and extension; Treatment duration; other drugs, compounds and / or substances used in combination with the specific compounds used; the age, sex, weight, condition, general health and previous medical history of the patient being treated, as well as factors well known in the medical sector. A physician or veterinarian having ordinary skill in the art can easily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, to achieve the desired therapeutic effect, the physician or veterinarian may start with a relatively small amount of the compound of the present invention used in the pharmaceutical composition below the desired level and gradually increase the dose until the desired effect is achieved. In general, a suitable daily dose of a compound of the present invention will be the amount of the compound that is the lowest effective dose to produce a therapeutic effect. Such effective dosage will generally depend on such factors. In general, oral, intravenous, intracerebroventricular and subcutaneous doses of a compound of the present invention for a patient range from about 0.01 to about 50 mg / kg body weight / day. If desired, an effective daily dose of the active compound may be administered in two, three, four, five, six or more subdoses respectively at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the present invention, the medication is administered once a day. Although the compound of the present invention can be administered alone, it is preferably administered in the form of a pharmaceutical preparation (composition). Kit / Product Package Kits / packages of products for the treatment of the aforementioned indications are also described. These kits may consist of a carrier, a medication package, or a container box. The container box can be divided into multiple compartments to accommodate one or more containers, such as vials and test tubes, where each container contains a single component in the method. Suitable containers consist of bottles, vials, syringes and test tubes. The container is made of an acceptable glass or plastic material. For example, the container may contain one or more of the compounds described herein; The compound may exist in the form of a pharmaceutical composition or may exist as a mixture with other ingredients described herein. The container may have a sterile outlet (for example, the container may be an intravenous infusion bag or bottle and ινΐΛ / a / zuzz / uuou i or the stopper may be pierced with a hypodermic needle). Such kits may contain a compound and descriptions, labels or instructions for the method of use described herein. A typical kit may include one or more containers, each containing one or more materials (for example, reagents, concentrated stock solutions and / or equipment) to accommodate commercial promotions and user needs for the use of compounds. . Such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, bags, containers, bottles and / or tubes, including a list of contents and / or instructions for use, and the instructions are also included in the packaging. Incorporated. The entire set of instructions must be included. The label may be displayed on the container or closely related to it. The appearance of the label on the container means that the letters, numbers or other features of the label are affixed, molded or engraved on the container; The label may also appear on the container box or shipping box containing a variety of containers, such as on the product insert. A label may be used to indicate a particular therapeutic use of the content. The label may also indicate instructions for use of the contents, as described in the methods described above. All features described in this specification (including the claims, summary and accompanying drawings), and / or all steps involved in any method or process, may be present in any combination unless some features or steps are mutually exclusive in the same combination. The features mentioned above, or the features mentioned in the embodiments mentioned herein, may be combined in any combination. All features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by any alternative feature having the same, equivalent or similar purpose. Therefore, unless otherwise specified, the features described are only general examples of equivalent or similar features. The present invention will be described in detail below in relation to specific examples. It should be understood that these examples are only used to describe the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that are not specified with specific conditions are generally carried out according to conventional conditions or according to the conditions recommended by the manufacturer. All percentages, proportions, proportions or parts are calculated by weight unless otherwise indicated. The weight-volume percentage units in the present invention are well known to those skilled in the art and refer, for example, to the weight of solute in 100 milliliters of solution. Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as those familiar to experts in the field. Furthermore, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. The preferred embodiments and materials described herein are examples only. Specific examples When no preparation route is mentioned, the relevant intermediates are commercially available (e.g. from Sigma Aldrich, Alfa). Generic process Commercially available reagents were used without further purification. ^-NMR spectra were recorded on a Bruker instrument at 500 MHz. Chemical shift values ​​are represented in parts per million, i.e. δ (delta) values. The following abbreviation is used for the multiplicity of NMR signals: s = singlet, brs = width, d = doublet, t = triplet, m = multiplet. Coupling constants are listed in J values, measured in Hz. NMR and mass spectrum results are corrected for background peaks. Chromatograms refer to 100 mesh column chromatography performed on silica gel and performed under nitrogen pressure (flash chromatography). The TLC used to monitor the reaction refers to the TLC performed using a specific mobile phase and Merck F254 silica gel as the stationary phase. LC-MS experiments were measured under the following conditions: Apparatus: Thermo U3000, ALLtech ELSD, MSQ, ELSD and MSD combined UV detector (4:1 elution ratio). Column: Waters X-Bridge C-18, 3.5 pm, 4.6 x 50 mm; Column temperature: 30 °C. Gradient [time (min) / solvent B in A (%)]: 0.00 / 5.0, 0.70 / 95, 1.40 / 95,1.41 / 5,1.50 / 5. (Solvent A = 0.01% trifluoroacetic acid in water; Solvent B = 0.01% trifluoroacetic acid in acetonitrile). UV detection: 214 / 254 / 280 / 300nm; DAD detection: 200-400nm; flow rate: 4 ml / min; MS: ESI, 100-1500 m / z Preparative HPLC typically uses basic methods (acetonitrile and water gradient with 10 mM ammonium bicarbonate in water); Thermos U3000 AFC-3000; Column: Globalsil C-18 12 nm, 250 x 20 mm, 10 pm, or equivalent; Flow rate: 20 ml / min for separation. The synthesis of intermediate The preparation of the INT-1 compound: 2-Chloro-5-hydroxybenzoic acid (29.0 g, 168 mmol) was dissolved in tetrahydrofuran (100 ml) under a nitrogen atmosphere and borane was added dropwise in an ice bath (1.0 M in tetrahydrofuran solution, 336 ml). ). After dripping was completed, the reaction solution was raised to room temperature and stirred for 16 hours. TLC detected that the raw material had been completely consumed. Methanol was added dropwise to the reaction solution in an ice bath to quench the reaction until no more bubbles emerged. The solvent was concentrated to obtain a light yellow solid INT-la (26.6 g, yield: 99.8%). The compound INT-la (26.6 g, 168 mmol) and imidazole (11.5 g, 169 mmol) were dissolved in dichloromethane (300 ml). At 0°C, tert-butyldimethylsilyl chloride (25.5 g, 169 mmol) previously dissolved in dichloromethane (100 ml) was added in batches. The mixture was heated to 30°C and stirred for hours. The reaction was quenched with water (100 ml). The aqueous phase was extracted with dichloromethane (100 ml x 2). The combined organic phase was washed with saturated saline (500 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain a light yellow liquid INT-lb (33.4 g, yield: 73%). The compound INT-lb (8.0 g, 29.3 mmol) was dissolved in acetonitrile (100 ml), then triethylamine (14.8 g, 147 mmol), magnesium chloride (5.58 g, 58.6 mmol) and paraformaldehyde (8.80 g, 293 mmol) were added. mmol). The mixture was heated to 90°C under a nitrogen atmosphere and stirred vigorously for 20 hours. The reaction solution was diluted with water (100 ml). Adjust pH=3-4 with saturated aqueous solution of citric acid. The solution was extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with saturated saline (300 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain a white solid INT-lc (5.0 g, yield: 56.7%). Ή NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.23 (s, 1H), 7.58 (s, 1H), 7.25 (s, 1H), 4.72 (s, 2H), 0.96 (s, 9H), 0.14 (s, 6H). 5-Chloromethyl-3-cyanopyridine hydrochloride (3.20 g, 17.0 mmol) was dissolved in N,Ndimethylformamide (20 ml), in an ice bath Ν,Ν-diisopropylethylamine (5.48 g, 42.4 mmol) and potassium carbonate ( 5.86 g, 42.4 mmol). After stirring for 10 minutes, INT-lc (4.25 g, 14.1 mmol) and potassium iodide (234 mg, 1.41 mmol) were added to the reaction solution. The reaction solution in an ice bath was stirred for half an hour and then heated to 50°C and stirred for 16 hours. The reaction solution was cooled in an ice cell. After adding 100 ml, the solid precipitated. The solid was filtered, washed with water, dried, and then the crude solid was separated by silica gel column chromatography to obtain a white solid INT-ld (5.00 g, yield: 84.9%). MS (ESI): m / z 417.2 (M+H)+. The compound INT-ld (5.0 g, 12.0 mmol) was dissolved in toluene (10 ml), ethylene glycol (14.9 g, 240 mmol) and p-toluenesulfonic acid (228 mg, 1.20 mmol), and trimethyl orthoformate (2.55 mmol) were added. g, 24.0 mmol) was added dropwise. The mixture was heated to 80°C under a nitrogen atmosphere and stirred for 16 hours. The reaction solution was cooled in an ice bath and quenched with a saturated aqueous sodium bicarbonate solution (50 ml), the aqueous phase was extracted with ethyl acetate (100 ml x 2). The combined organic phase was washed with saturated saline (200 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain a white solid INT-le (5.50 g, yield: 99.5%). MS (ESI): m / z 461.2 (M+H)+. The INT-le compound (2.20 g, 4.77 mmol) was dissolved in tetrahydrofuran (10 ml) and tetrabutylammonium fluoride was added in a tetrahydrofuran solution (1 M, 7.16 ml). The reaction solution was stirred for half an hour at 30°C and diluted with water (30 ml). The aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was suspended with a mixture of ethyl acetate and petroleum ether (v / v = 3 / 100, 20 ml) and filtered to obtain a light yellow solid INT-lf (1.58 g, yield: 95.5%). MS (ESI): m / z 347.2 (M+H)+. The INT-lf compound (1.50 g, 4.33 mmol) was dissolved in dichloromethane (30 ml), Ν,Ν-diisopropylethylamine (1.68 g, 13.0 mmol) was added and, under 0 °C and a nitrogen atmosphere, methanesulfonic anhydride was added (1.51 g, 8.65 mmol). Then a mixture of Ν,Νdiisopropylethylamine (1.68 g, 13.0 mmol) and hydrochloric aciddioxane (4 M, 1.62 mL) in dichloromethane (10 mL) was added. The reaction solution was stirred for 16 hours at 25°C. The reaction was quenched with water (30 ml). The aqueous phase was extracted with dichloromethane (50 ml x 2). The combined organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain a light yellow solid INT-lg (1.40 g, yield: 88.6%). MS (ESI): m / z 365.2 (M+H)+. The compound INT-lg (1.36 g, 3.72 mmol), 4-bromo-lH-indazole (734 mg, 3.72 mmol) and potassium carbonate (1.03 g, 7.45 mmol) were dissolved in N,N-dimethylformamide (10 ml) . The mixture was stirred for 16 hours at 50°C. The reaction solution was cooled in an ice bath. After adding 100 ml of water, the solid precipitated, filtered, washed with water and dried. The crude solid thus obtained was separated by silica gel column chromatography to obtain a light yellow solid INT-lh (1.08 g, yield: 55.2%).XH NMR (500 MHz, DMSO-o6) δ 8.96 (d, 7 = 2.0 Hz, 1H), 8.82 (s, 1H), 8.27 (s, 1H), 8.05 (s, 1H), 7.70 (d, 7 = 8.5 Hz, 1H), 7.45 (s, 1H), 7.40 (d , 7= 7.5 Hz, 1H), 7.32 (t, 7= 7.5 Hz, 1H), 6.91 (s, 1H), 6.04 (s, 1H), 5.71 (s, 2H), 5.16 (s, 2H), 4.04 - 4.01 (m, 2H), 3.97 3.89 (m, 2H); MS (ESI): m / z 525.0 (M+H)+. The compound INT-lh (1.00 g, 1.90 mmol) was dissolved in tetrahydrofuran (20 ml) and hydrochloric acid (4.0 M aqueous solution, 5.0 ml). The reaction solution was stirred for 1 hour at 30°C, then neutralized with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with saturated saline solution (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated to obtain a light yellow solid INT-li (900 mg, yield: 98.2%). MS (ESI): m / z 481.0 (M+H)+ The compound INT-li (840 mg, 1.74 mmol) was dissolved in Ν,Ν-dimethylformamide (5 ml), O-isopropyl-L-serine tert-butyl ester (418 mg, 1.92 mmol) and acetic acid (209 mg , 3.48 mmol) and the reaction solution was stirred for 1 hour at 30°C. Then, sodium triacetoxyborohydride (1.48 g, 6.96 mmol) was added to the reaction solution. The reaction was stirred for 1 hour at 30 °C and then quenched with water (50 ml). The aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain a light yellow solid INT-lj (720 mg, yield: 60.5%). MS (ESI): m / z 682.1 (M+H)+. Intermediate INT-lj (1.00 g, 1.46 mmol), pinacol biboronate (558 mg, 2.20 mmol), potassium acetate (431 mg, 4.39 mmol) and Pd(dppf) Cb (107 mg, 0.15 mmol) were dissolved in dioxane (15 ml). The reaction solution was heated to 90°C and stirred overnight under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate (100 ml), filtered with diatomaceous earth, and washed with 100 ml of ethyl acetate. The filtrate obtained was concentrated. The residue was separated by silica gel column chromatography (dichloromethane / methanol, v / v = 20 / 1) to obtain a light yellow solid INT-1 (600 mg, yield: 56.1%). MS (ESI): m / z 730.7 (M+H)+. The preparation of the INT-2 compound: EITHER ινΐΛ / a / zuzz / uuou i o (S)-5-hydroxymethyl-2-pyrrolidone (10.0 g, 86.9 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml), phthalimide (12.8 g, 86.9 mmol) and triphenylphosphine (34.2 g, 130 mmol) were added ). Under an ice bath and a nitrogen atmosphere, diisopropyl azodicarboxylate (26.4 g, 130 mmol) was slowly added dropwise to the reaction solution. The reaction solution was raised to room temperature and stirred overnight. The resulting precipitate was filtered and dried to obtain a white solid INT-2a (11.4 g, yield: 53.7%). MS (ESI): m / z 245.1 M+H)+. Compound INT-2a (1.0 g, 4.09 mmol) was dissolved in ethanol (20 ml), 80% hydrazine hydrate (512 mg, 8.19 mmol) was added. The reaction solution was heated to 85°C and stirred for 2 hours. After cooling the reaction to room temperature, the resulting precipitate was filtered. The filtrate was concentrated and then dichloromethane (50 ml) was added. The filtrate was further filtered and concentrated to obtain a yellow oily liquid INT-2 (430 mg, yield: 92.0%).^ NMR (500 MHz, DMSO-¿¿) δ 7.65 (s, 1H), 3.43 - 3.37 ( m, 1H), 2.47 - 2.42 (m, 2H), 2.12 - 2.04 (m, 2H), 2.03 - 1.96 (m, 1H), 1.66 - 1.60 (m, 1H), 1.58 (s, 2H). The preparation of the INT-3 compound: ινΐΛ / a / zuzz / uuou 1 or Pinacol ester of 4-formylphenylboronic acid (4.50 g, 19.4 mmol) and l,3-dibromo-2-chlorobenzene (10.5 g, 38.8 mmol) were dissolved in a mixture of dioxane and water (60 mL, v / v=5 / l) and potassium carbonate (8.04 g, 58.2 mmol) and Pd(dppf) Cb (1.42 g, 1.94 mmol). The reaction solution under a nitrogen atmosphere was heated to 80°C and stirred for 3 hours. The reaction was quenched with water (100 ml). The aqueous phase was extracted with ethyl acetate (200 ml x 2). The combined organic phase was washed with saturated saline (200 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v - 4 / 1) to obtain a white solid INT-3a (3.7 g, yield: 64.6%). Compound INT-3a (1.00 g, 3.38 mmol) was dissolved in N,N-dimethylformamide (10 ml) and compound INT-2 (541 mg, 4.74 mmol) and acetic acid (203 mg, 3.38 mmol) were added sequentially. mmol). The resulting reaction solution was stirred for 1 hour at room temperature and then sodium triacetoxyborohydride (2.87 g, 13.5 mmol) was added. The resulting reaction solution was further stirred overnight at room temperature and the reaction was quenched with a saturated aqueous sodium bicarbonate solution (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed sequentially with water (100 ml) and saturated saline (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid INT-3b (1.41 g, yield: 99.5 %). MS (ESI): m / z 393.3 (M+H)+. Compound INT-3b (1.41 g, 3.58 mmol) was dissolved in dichloromethane (15 ml), triethylamine (725 mg, 7.16 mmol) and di-tert-butyl decarbonate (860 mg, 3.94 mmol) were added sequentially. The reaction solution at room temperature was stirred for 2 hours and diluted with 200 ml of dichloromethane. The organic phase was washed sequentially with water (100 ml) and saturated saline (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (dichloromethane / methanol, v / v = 20 / 1) to obtain a white solid INT-3 (1.55 g, yield: 87.6%).4Η NMR (500 MHz, DMSO -cfc) δ 7.78 (dd, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.44 - 7.25 (m, 6H), 4.53 - 4.39 (m, 2H), 3.80 - 3.70 (m, 1H), 3.26 - 3.10 (m, 2H), 2.17 - 1.99 (m, 3H), 1.76 - 1.66 (m, 1H), 1.38 (s, 9H); MS (ESI): m / z 493.3 (M+H)+. The preparation of the INT-4 compound: INT-4 From l,3-dibromo-2-toluene, referring to the synthesis of the compound INT-3, the white solid INT-4 was thus obtained. JH NMR (500 MHz, Chloroform-o) δ 7.76 (d, J= 7.2 Hz, 1H), 7.28 - 7.22 (m, 7H), 4.53 (s, 2H), 4.05 - 3.67 (m, 1H), 3.42 - 3.20 (m, 2H), 2.40 (s, 3H), 2.01 - 1.90 (m, 3H), 1.82 - 1.71 (m, 1H), 1.36 (s, 9H); MS (ESI): m / z 473.4 (M+H)+. The preparation of the INT-5 compound: INT-3a INT-5 Compound INT-3a (1.50 g, 5.08 mmol) was dissolved in Ν,Ν-dimethylformamide (20 ml) and, sequentially, (R)-3-hydroxypyrrolidine hydrochloride (1.88 g, 15.2 mmol) and acetate was added. of anhydrous sodium (1.25 g, 15.2 mmol). The reaction solution was stirred overnight at room temperature. Sodium triacetoxyborohydride (4.31 g, 20.3 mmol) was then added. The reaction solution at room temperature was further stirred for 2 hours and the reaction was quenched with a saturated aqueous sodium bicarbonate solution (100 ml). The aqueous phase was extracted with ethyl acetate (100 ml x 2). The combined organic phase was washed with saturated saline (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (dichloromethane / methanol, v / v = 20 / 1) to obtain a light yellow solid INT-5 (1.60 g, yield: 80.6%).!H NMR ( 500 MHz, Methanol-íá) δ 7.71 - 7.67 (m, 1H), 7.46 7.41 (m, 2H), 7.38 - 7.33 (m, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 4.41 - 4.31 (m, 1H), 3.81 - 3.66 (m, 2H), 2.88 - 2.83 (m, 1H), 2.83 - 2.76 (m, 1H), 2.64 - 2.58 (m, 1H), 2.56 - 2.51 (m, 1H), 2.22 - 2.12 (m, 1H), 1.79 - 1.70 (m, 1H); MS (ESI): m / z 366.1 (M+H)+. The preparation of the INT-6 compound: OMe INT-6 Starting from 4-bromo-2-methoxybenzaldehyde, referring to the last step of the Suzuki boron esterification reaction of compound INT-1, compound INT-6a was obtained. Starting from compound INT-6a, referring to the synthesis of compound INT-3, compound INT-6 was thus obtained. NMR (500 MHz, DMSO-¿¿) δ 7.78 (d, J= 8.0 Hz, 1H), 7.70 (s, 1H), 7.42 - 7.38 (m, 1H), 7.33 (t, J = 7.5 Hz, 1H) , 7.11 - 7.03 (m, 1H), 7.02 - 7.00 (m, 1H), 6.98 - 6.93 (m, 1H), 4.47-4.34 (m, 2H), 3.81 (s, 3H), 3.77 - 3.71 (m, 1H), 3.26 - 3.17 (m, 2H), 2.18 - 2.10 (m, 1H), 2.09 - 2.00 (m, 2H), 1.74 - 1.64 (m, 1H), 1.47 - 1.26 (m, 9H). MS (ESI): m / z 523.2 (M+H)+. ινΐΛ / a / zuzz / uuou i o The preparation of the INT-7 compound: The intermediate INT-li (1.00 g, 2.08 mmol), bis(pinacolato)diboron (635 mg, 2.50 mmol), Potassium acetate (612 mg, 6.24 mmol), and Pd(dppf)Cb (152 mg, 0.21 mmol) were dissolved. ). in dioxane solution (20 mL). The reaction solution was heated to 90 °C and stirred overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature and then diluted with ethyl acetate (100 ml), filtered with diatomaceous earth, and the filter cake was further washed with ethyl acetate (100 ml). The filtrate obtained was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 1 / 1) to obtain a light yellow solid INT-7a (940 mg, yield: 85.5%). MS (ESI): m / z 529.2 (M+H)+. Compound INT-7a (96.4 mg, 0.18 mmol) and compound INT-3 (75.0 mg, 0.15 mmol) were dissolved in a solvent mixture of dioxane and water (11 ml, v / v=10 / l) , potassium carbonate (63.0 mg, 0.46 mmol) and Pd(dppf)Cb (11.1 mg, 0.015 mmol). The mixture was heated to 80°C and stirred for 3 hours under a nitrogen atmosphere. Then, the reaction was quenched with water (50 ml). The aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by preparative thin layer chromatography (dichloromethane / methanol, v / v = 95 / 5) to obtain a light yellow solid INT-7 (120 mg, yield: 96.9%). MS (ESI): m / z 815.2 (M+H)+. The preparation of the INT-8 compound: Starting from the compound INT-lc and iodomethane, referring to the synthesis of INT-li, the compound INT-8b was obtained. IMS (ESI): m / z 379.1 (M+H)+. Starting from compound INT-8b, in reference to the synthesis of compound INT-7, compound INT-8c and compound INT-8 were obtained. Its spectral information is as follows: INT-8c: Ή NMR (500 1MHz, Chloroform-o) δ 10.31 (s, 1H), 8.50 (s, 1H), 7.83 (s, 1H), 7.69 (d, J = 7.0 Hz, 1H),7.47 ( d, J = 8.5 Hz, 1H), 7.44 - 7.37 (m, 1H), 6.42 (s, 1H), 5.73 (s, 2H), 3.60 (s, 3H), 1.42 (s, 12H); MS (ESI): m / z 427.3 (M+H)+. INT-8: MS (ESI): m / z 713.5 (IM+H)+. The preparation of the INT-9 compound: INT-8c From compound INT-8c and compound INT-6, compound INT9 was obtained by referring to the synthesis of compound INT-8. MS (ESI): m / z 743.6 (M+H)+. The preparation of the INT-10 compound: Starting from 3-bromo-2-chlorophenol, referred to the synthesis of the compound INT-7a, the compound INT-10a is obtained. IMS (ESI): m / z 253.3 (M-H)'. Starting from the compound INT-10a and 6-Chloro-2-methoxy-3-pyridiccarbaldehyde, with reference to the synthesis of the compound INT-3a, the compound INT-lOb is obtained. MS (ESI): m / z 262.0 (Μ-Η)’. The compound INT-10b (500 mg, 1.90 mmol) was dissolved in anhydrous dichloromethane (10 ml), Ν,Ν-diisopropylethylamine (490 mg, 3.80 mmol) was added and cooled in an ice bath to 0 °C, then trifluoromethanesulfonic anhydride was added. (804 mg, 2.85 mmol) was added slowly dropwise. The reaction solution was gradually warmed to room temperature and further stirred for 2 hours. The reaction was quenched with 50 ml of a saturated aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with 50 ml of saturated saline, dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain an orange oily substance INT-10 (482 mg, yield: 64.2%). MS (ESI): m / z 396.2 (M+H)+. The preparation of the INT-11 compound: f00Hcooch3cooch3rx. CH3I, K2CO3HCI / dioxane DMF L / - Ln> Boc Boc H HCI INT-11a INT-11 At 25°C, a reaction solution of N'N-dimethylformamide (3 mL) with (R)-l-Boc-3carboxypyrrolidine (1.00 g, 4.65 mmol), iodomethane (1.00 g, 7.05 mmol) and potassium carbonate ( 2.00 g, 14.5 mmol) dissolved was stirred for 3 hours. Subsequently, the reaction solution was diluted with (50 mL), extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with 50 ml of saturated saline, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oily matter INT-lla (1.00 g, yield: 93.9%). Dissolved hydrochloric acid (4 M in 1,4-dioxane solution, 5 mL) was added to dichloromethane solution (2 mL) with the compound INT-lla (1.00 g, 4.36 mmol). The reaction solution was stirred for 3 hours at 25°C. The resulting reaction solution was concentrated to obtain a yellow solid INT-11 (700 mg, yield: 96.9%).^ NMR (500 MHz, DMSO-06) δ 9.70 (brs, 2H), 3.66 (s, 3H), 3.42 - 3.35 (m, 1H), 3.30 - 3.22 (m, 2H), 3.19 - 3.13 (m, 2H), 2.22 - 2.14 (m, 1H), 2.06 1.99 (m, 1H). The preparation of the INT-12 compound: INT-8C INT-15 Starting from the compoundINT-8c and the compound INT-5, in reference to the synthesis of the compound INT-8, the compound INT-12 is obtained. MS (ESI): m / z 586.4 (M+H)+. The preparation of the INT-13 compound: SOCI2 MeOH Under ice bath conditions, thionyl chloride (11.7 g, 98.6 mmol) was added to a solution of methanol (20 ml) with 2-hydroxy-4-methylbenzoic acid (5.0 g, 32.9 mmol) dissolved. The reaction solution was stirred for 16 hours at 65°C. The reaction solution was concentrated and ethyl acetate (100 ml) and water (100 ml) were added to the residue. The organic phase was washed with saturated sodium bicarbonate solution (100 mL), saturated salt solution (100 mL), dried with anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oily matter INT-13a (5.25 g, performance: 96.1%). In N, N-dimethylformamide (30 ml) was added with the compound INT-13a (5.25 g, 31.6 mmol) dissolved iodomethane (5.83 g, 41.1 mmol) and potassium carbonate (8.73 g, 63.2 mmol). The reaction solution was stirred for 6 hours at 25°C. The reaction solution was concentrated and ethyl acetate (100 ml) and water (100 ml) were added to the residue. The organic phase was washed with saturated saline solution (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oily matter INT-13b (5.6 g, yield: 98.4%). In a methanol solution (15 ml) with the compound INT-13b (1.0 g, 5.55 mmol), dissolved silver triflate (1.57 g, 6.10 mmol) and iodine (1.55 g, 6.10 mmol) were added. The reaction solution was stirred for 2 hours at 25°C, then filtered and the filtrate was diluted with ethyl acetate (50 mL) and washed with aqueous sodium sulfite solution (5% w / w, 50 mL). and saturated saline solution (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated to obtain an orange solid INT-13 (1.6 g, yield: 94.2%). 1H NMR (500 MHz, chloroform-o) δ 8.20 (s, 1H), 6.86 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.45 (s, 3H); MS (ESI): m / z 306.9 (M+H)+. The preparation of the INT-14 compound: = M=r.uCIH H2NSOCI2, MeOH · INT-14 Thionyl chloride (185 mg, 1.55 mol) was added to a solution of methanol (3 ml) with trans-( / V-Boc-4-aminocyclohexyl)acetic acid (100 mg, 0.39 mmol) dissolved. The reaction solution was stirred for 3 hours at 70°C. The reaction solution was concentrated to obtain a white solid INT-14 (70 mg, yield: 86.7%). Ή NMR (500 MHz, DMSO-o6) δ 8.15 - 7.92 (m, 3H), 3.56 (s, 3H), 2.87 (s, 1H), 2.21 - 2.15 (m, 2H), 1.95 - 1.87 (m, 2H ), 1.74 - 1.66 (m, 2H), 1.63 - 1.53 (m, 1H), 1.35 - 1.25 (m, 2H), 1.06 - 0.95 (m, 2H). The preparation of the INT-15 compound: ινΐΛ / a / zuzz / uuou i o Under ice bath conditions, dissolved sodium methoxide (5.4 M in methanol solution, 1.11 ml) was added dropwise to a solution of methanol (10 ml) with 4-bromo-2,6difluorobenzaldehyde (1.10 g, 4.98 mmol ). The reaction solution under the same conditions was stirred for 3 hours. The reaction solution was quenched with hydrochloric acid (1 M aqueous solution, 12 ml) and stirred for 10 minutes. The solution obtained was further diluted with water (100 ml) and extracted with ethyl acetate (100 ml x 2). The combined organic phase was washed with saturated saline (150 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 10 / 1) to obtain a white solid INT-15a (660 mg, yield: 56.9%) and a white solid INT-15b (204 mg, yield: 16.7%). Compound INT-15:XH NMR (500 MHz, Chloroform-o) δ 10.36 (s, 1H), 6.97 - 6.93 (m, 2H), 3.94 (s, 3H). Compound INT-15b:XH NMR (500 MHz, Chloroform-o) δ 10.42 (s, 1H), 6.76 (s, 2H), 3.90 (s, 6H). Starting from the compound INT-15a, referring to the synthesis of the compound INT-6, the compound INT-15.XH is obtained NMR (500 MHz, DMSO-o6) δ 7.83 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.37 (t, J= 7.8 Hz, 1H), 6.90 - 6.86 (m, 2H), 4.54 - 4.50 (m, 2H), 3.84 ( s, 3H), 3.77 - 3.73 (m, 1H), 3.17 (d, J = 5.3 Hz, 2H), 2.12 - 2.02 (m, 3H), 1.71 - 1.65 (m, 1H), 1.40 - 1.32 (m, 9H); MS (ESI): m / z 541.5 (M+H)+. The preparation of the INT-16 compound INT-8c OMe Starting from the compound INT-8c and the compound INT-15, in reference to the synthesis of the compound INT-8, the compound INT-16 is obtained. MS (ESI): m / z 761.7 (M+H)+. The preparation of the INT-17 compound: INT-17 At 110°C, a solution of acetic acid and water (25 mL, v / v = 1 / 4) with S-2aminoadipic acid (5 g, 31 mmol) dissolved was stirred for 16 hours. The reaction solution was concentrated. The obtained residue was dissolved in ethanol, in which unreacted starting materials will not dissolve in ethanol. The filtrate was concentrated to obtain a white solid INT-17a (3 g, yield: 67.6%). MS (ESI): m / z 142.1 ((M-H)“ From the compound INT-17a, referring to the synthesis of the compound INT-13a, the colorless oily matter INT-17b was thus obtained. At 0°C, sodium borohydride (433 mg, 11.5 mmol) was added to an ethanol solution (10 ml) with the compound INT-17b (450 mg, 2.9 mmol) dissolved. The mixture obtained was stirred for 16 hours at room temperature. The reaction was quenched with a small amount of acetic acid and the resulting reaction solution was concentrated. The residue obtained was dissolved with dichloromethane. The organic phase was washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated to obtain colorless oily matter INT-17c (369 mg, yield: 99.8%). MS (ESI): m / z 130.2 (M+H)+. From the compound INT-17C, referring to the synthesis of the compound INT-2, the light yellow oily matter INT-17.JH NMR (500 MHz, DMSO-o6) δ 7.34 (s, 1H) was thus obtained. 3.22 - 3.06 (m, 1H), 2.59 - 2.42 (m, 2H), 2.18 - 1.98 (m, 2H), 1.75 (brs, 2H), 1.64 - 1.50 (m, 2H), 1.37-1.18 (m, 2H )„ The preparation of the INT-18 compound: Starting from the compound INT-15a, referring to the last step of the Suzuki boron esterification reaction of the compound INT-1 and the synthesis of the compound INT-3a, thus obtaining the compound INT-18a. Ή NMR (500 MHz, DMSO-06) δ 10.34 (s, 1H), 7.91 - 7.87 (m, 1H), 7.52 - 7.48 (m, 1H), 7.44 - 7.38 (m, 1H), 7.13 - 7.10 (m , 1H), 7.04 - 7.00 (m, 1H), 3.96 (s, 3H). Starting from the compound INT-18a, referring to the last step of the Suzuki boron esterification reaction of the compound INT-1, the compound INT-18.4H NMR (500 MHz, DMSO-O6) δ 10.31 (s, 1H) was thus obtained ), 7.68 - 7.64 (m, 1H), 7.55 - 7.51 (m, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.05 (s, 1H), 6.97 - 6.89 (m, 1H), 3.93 ( s, 3H), 1.31 (s, 12H); MS (ESI): m / z 391.7 (M+H)+. ινΐΛ / a / zuzz / uuou i o Synthesis of examples of compounds Example 1: INT-5, Pd(dppf)CI2, K2CO3dioxane, H2O HO' Starting from the compound INT-1 and the compound INT-5, with reference to the synthesis of the compound INT-7, the compound la is obtained. MS (ESI): m / z 889.9 (M+H)+. Compound la (20 mg, 0.022 mmol) was dissolved in dichloromethane (2 ml), trifluoroacetic acid (2 ml) was added, and the reaction solution was stirred at 25 °C for 6 hours. After concentrating the reaction solution, the residue was purified by preparative high-performance liquid chromatography to obtain a white solid 1 (6.5 mg, yield: 37.4%).TH NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 7.87 (s, 1H), 7.72 - 7.67 (m, 1H), 7.55 7.45 (m, 7H), 7.40 (d, J = 8.0 Hz, 2H), 7.18 - 7.15 (m, 1H), 6.83 (s, 1H), 5.74 - 5.69 (m, 2H), 5.11 - 5.05 (m, 2H), 4.24 - 4.18 (m, 1H), 3.93 (d, J = 14.5 Hz, 1H), 3.85 (d, J = 14.5 Hz, 1H), 3.65 (d, J = 13.0 Hz, 1H), 3.61 - 3.55 (m, 2H), 3.12 - 3.07 (m, 1H), 2.72 - 2.68 (m, 1H), 2.65 - 2.58 (m, 2H), 2.38 - 2.32 (m, 2H), 2.05 - 1.97 (m, 1H), 1.59 - 1.52 (m, 1H); MS (ESI): m / z 777.8 (M+H)+. Example 2: ΜΛ / a / ZUZZ / UUOU I or Compound 2 was obtained with reference to the synthesis of compound 1 from compound INT-1 and compound INT-4. Ή NMR (500 MHz, DMSO-06) δ 8.95 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.34 (t, J= 2.0 Hz, 1H), 7.84 (s , 1H), 7.71 - 7.64 (m, 2H), 7.55 (s, 1H), 7.46 - 7.37 (m, 6H), 7.34 - 7.31 (m, 1H), 7.28 (d, J= 7.5, 1H), 7.09 (d, J= 7.0 Hz, 1H), 6.86 (s, 1H), 5.71 (s, 2H), 5.14 - 5.08 (m, 2H), 3.96 - 3.84 (m, 2H), 3.79 - 3.74 (m, 2H ), 3.64 - 3.57 (m, 3H), 3.13 3.09 (m, 1H), 2.55 (d, J= 6.0 Hz, 2H), 2.15 - 2.05 (m, 3H), 1.99 (s, 3H), 1.73 - 1.67 (m, 1H); MS (ESI): m / z 784.3 (M+H)+. HOAc, NaBH(OAc)3□MF TFA DCM From compound INT-1 and compound INT-3a, compound 3a was obtained by referring to the synthesis of compound INT-7. MS(ESI): m / z 818.4 (M+H) +. Starting from compound 3a and morpholine, in reference to the reductive amination step in the synthesis of compound INT-3b, compound 3b is obtained. MS (ESI): m / z 889.9 (M+H)+. Starting from compound 3b, referring to the last de-Boc protection step in the synthesis of compound 1, compound 3 is obtained. NMR (500 MHz, DMSO-06) δ 8.95 (s, 1H), 8.84 (s, 1H ), 8.33 (s, 1H), 7.86 (s, 1H), 7.72-7.67 (m, 1H), 7.56-7.45 (m, 7H), 7.41 (d, J = 7.5 Hz, 2H), 7.17 (d, 7 = 7.0 Hz, 1H), 6.83 (s, 1H), 5.72 (s, 2H), 5.13 - 5.05 (m, 2H), 3.92 (d, 7 = 14.0 Hz, 1H), 3.85 (d, 7= 14.0 Hz, 1H), 3.63-3.56 (m, 6H), 3.52 (s, 2H), 3.13-3.06 (m, 1H), 2.40 (s, 4H); MS (ESI): m / z 777.6 (M+H)+. ινΐΛ / a / zuzz / uuou i o Example 4: Starting from compound 3a and N-methylethanolamine, with reference to the synthesis of compound 3, compound 4 was obtained. , 7 = 2.0 Hz, 1H), 8.33 (d, 7= 2.5 Hz, 1H), 7.87 (s, 1H), 7.71 (d, 7= 8.5 Hz, 1H), 7.56 (s, 1H), 7.55 - 7.46 (m, 6H), 7.41 (d, 7= 8.0 Hz, 2H), 7.17 (d, 7= 7.0 Hz, 1H), 6.84 (s, 1H), 5.72 (s, 2H), 5.14 - 5.06 (m, 2H), 3.96 (d, 7 = 14.0 Hz, 1H), 3.88 (d, 7 = 14.0 Hz, 1H), 3.69 - 3.63 (m, 1H), 3.61 - 3.58 (m, 1H), 3.57 (s, 2H ), 3.54 (t, 7= 6.5 Hz, 2H), 3.18 - 3.14 (m, 1H), 2.55 - 2.53 (m, 2H), 2.20 (s, 3H); MS (ESI): m / z 765.7 (M+H)+. Example 5: Starting from compound 3a and ethanolamine, with reference to the synthesis of compound 3, compound 5 was obtained. *H NMR (500 MHz, DMSO-P6) δ 8.94 (s, 1H), 8.83 (s, 1H), 8.32 ( s, 1H), 7.86 (s, 1H), 7.70 (d, J= 8.5 Hz, 1H), 7.56 - 7.50 (m, 3H), 7.49 - 7.43 (m, 6H), 7.17 (d, 7= 7.0 Hz , 1H), 6.83 (s, 1H), 5.72 (s, 2H), 5.13 - 5.05 (m, 2H), 3.90 (d, 7= 14.0 Hz, 1H), 3.86 - 3.80 (m, 3H), 3.60 - 3.54 (m, 2H), 3.51 (t, 7= 6.0 Hz, 2H), 3.10 - 3.05 (m, 1H), 2.65 (t, 7= 6.0 Hz, 2H); MS (ESI): m / z 751.4 (M+H)+. ινΐΛ / a / zuzz / uuou 1 or Starting from the compound INT-3a and N-methylethanolamine, in reference to the reductive amination step in the synthesis of the compound INT-3b, compound 6a was obtained. MS (ESI): m / z 354.2 (M+H)+. Under ice bath conditions, dissolved Ν,Ν-diisopropylethylamine (226 mg, 1.75 mmol) and methanesulfonic anhydride (203 mg, 1.17 mmol). The reaction solution was stirred for half an hour in an ice bath and heated to 25°C and stirred at the same temperature for 2 hours. The reaction solution was diluted with water (20 ml). The aqueous phase was extracted with dichloromethane (20 ml x 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered and concentrated, thus compound 6b was obtained. In an ice bath and nitrogen atmosphere, dissolved sodium hydride (60% w / w in kerosene) was added in tetrahydrofuran (5 ml) with (R)-(-)-3-hydroxytetrahydrofuran (103 mg, 1.17 mmol). , 46.8 mg). The reaction solution was stirred for half an hour in an ice bath and the obtained compound 6b was added. The resulting reaction solution was heated to 50°C and stirred overnight. After cooling to room temperature, the reaction solution was quenched with water (20 ml). The aqueous phase was extracted with ethyl acetate (20 ml x 2). The combined organic phase was washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by preparative thin layer chromatography (dichloromethane / methanol, v / v = 15 / 1) to obtain a yellow oily matter 6c (110 mg, yield: 44.4%). MS (ESI): m / z 424.3 (M+H)+. Starting from compound INT-1 and compound 6c, with reference to the synthesis of compound 1, the compound 6.4H NMR (500 MHz, DMSO-o6) δ 8.94 (d, J = 2.0 Hz, 1H), 8.84 ( d, J = 2.0 Hz, 1H), 8.34 - 8.32 (m, 1H), 7.86 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.55 - 7.45 (m, 7H), 7.40 (d , J= 8.0 Hz, 2H), 7.20 - 7.15 (m, 1H), 6.81 (s, 1H), 5.72 (s, 2H), 5.12 - 5.05 (m, 2H), 4.12 - 4.08 (m, 1H), 3.89 - 3.77 (m, 2H), 3.73 - 3.68 (m, 1H), 3.67 - 3.62 (m, 3H), 3.57 (s, 2H), 3.55 - 3.48 (m, 4H), 3.02 - 2.94 (m, 1H) ), 2.55 (t, J= 6.0 Hz, 2H), 2.20 (s, 3H), 1.94 - 1.83 (m, 2H); MS (ESI): m / z 835.7 (M+H)+. ινΐΛ / a / zuzz / uuou i o Example 7: INT-3 7a Under ice bath conditions, compound INT-3 (200 mg, 0.40 mmol) in tetrahydrofuran (2 ml) was added with sodium hydrogen (60% w / w in kerosene, 32.4 mg) and the reaction solution was placed in ice bath, conditions Continue stirring for half an hour. Then, methyl iodide (86 mg, 0.61 mmol) was added to the reaction solution at room temperature, the resulting reaction solution was stirred at room temperature overnight. The reaction solution was quenched with water (20 ml), the aqueous phase was extracted with ethyl acetate (20 ml x 2), the combined organic phases were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate , were filtered and concentrated. The residue was separated by silica gel column chromatography (dichloromethane / methanol, v / v = 10 / 1) to give 7a as a yellow oil (200 mg, yield: 97%). MS (ESI): m / z 507.4 (M+H)+. From compound INT-1 and compound 7a, compound 7 was obtained by referring to the synthesis of compound 1.XH NMR (500 MHz, DMSO-rá) δ 8.99 - 8.90 (m, 1H), 8.90 8.79 (m , 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.57 - 7.43 (m, 9H), 7.17 (d, J = 7.0 Hz, 1H) , 6.83 (s, 1H), 5.72 (s, 2H), 5.15 - 5.05 (m, 2H), 3.97 - 3.91 (m, 1H), 3.89 - 3.83 (m, 1H), 3.78 (s, 2H), 3.68 - 3.52 (m, 3H), 3.18 - 3.10 (m, 1H), 2.73 - 2.63 (m, 5H), 2.33 - 2.22 (m, 1H), 2.18 - 2.08 (m, 1H), 2.06 - 1.98 (m, 1H), 1.87 - 1.77 (m, 1H); MS (ESI): m / z 818.6 (M+H)+. Example 8: From compound INT-1 and compound INT-6, compound 8 was obtained by referring to the synthesis of compound 1.XH NMR (500 MHz, DMSO-o6) δ 8.95 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.88 (s, 1H), 7.74 - 7.68 (m, 2H), 7.57 7.49 (m, 4H), 7.48 - 7.45 (m, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.19 - 7.15 (m, 1H), 7.11 - 7.04 (m, 2H), 6.85 (s, 1H), 5.72 (s, 2H), 5.15 - 5.06 (m, 2H), 3.95 (d, J= 14.5 Hz, 1H), 3.87 (d, J = 14.5 Hz, 1H), 3.83 (s, 3H), 3.76 - 3.73 ( m, 2H), 3.66 - 3.62 (m, 2H), 3.61 - 3.55 (m, 1H), 3.15 - 3.11 (m, 1H), 2.58 - 2.54 (m, 2H), 2.14 - 2.06 (m, 3H), 1.74 - 1.66 (m, 1H); MS (ESI): m / z 834.7. (M+H)+. Starting from the compound INT-1 and l,3-dibromo-2-chlorobenzene, in reference to the last step of the Suzuki reaction in the synthesis of the compound INT-7, compound 9a was obtained. MS 15 (ESI): m / z 792.6 (M+H)+. From compound 9a, compound 9b was obtained with reference to the synthesis of compound INT-7a. MS (ESI): m / z 840.6 (M+H)+. Starting from compound 9b and 2-bromo-5-aldolpyridine, referring to the Suzuki reaction of the last step in the synthesis of compound INT-7, compound 9c was obtained. MS (ESI): m / z 819.4 (M+H)+. From compound 9c and compound INT-2, referring to the reductive amination step in the synthesis of compound INT-3b, compound 9d was obtained. MS (ESI): m / z 917.8 (M+H)+. From compound 9d, compound 9 is obtained by referring to the last step of the de-Boc step in the synthesis of compound 1. Ή NMR (500 MHz, DMSO-o6) δ 8.96 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.65 (d, J= 2.0 Hz, 1H), 8.33 (s, 1H), 7.92 - 7.83 (m, 2H), 7.75 - 7.66 (m, 3H), 7.65 - 7.55 (m, 3H), 7.52 - 7.44 (m, 1H), 7.21 - 7.14 (m, 1H), 6.86 (s, 1H), 5.73 (s, 2H), 5.15 - 5.05 (m, 2H), 3.99 - 3.73 (m, 4H), 3.69 - 3.55 (m, 3H), 3.21 - 3.15 (m, 1H), 2.58 - 2.52 (m, 2H), 2.18 - 2.03 (m, 3H), 1.75 - 1.64 (m, 1 HOUR); MS (ESI): m / z 805.8 (M+H)+. iviA / a / zuzz / uuou 1 or Starting from compound 9b and 5-bromo-2-pyridinecarboxaldehyde, with reference to the synthesis of compound 9, compound ΙΟ was obtained. Ψ NMR (500 MHz, DMSO-06) δ 8.95 (s, 1H), 8.84 (s, 1H), 8.64 (s, 1H), 8.33 (s, 1H), 7.96 (d, J= 8.0 Hz, 1H) , 7.90 (s, 1H), 7.74 - 7.69 (m, 2H), 7.62 - 7.44 (m, 6H), 7.18 (d, J = 7.0 Hz, 1H), 6.83 (s, 1H), 5.72 (s, 2H ), 5.14 - 5.05 (m, 2H), 3.93 3.73 (m, 4H), 3.68 - 3.50 (m, 3H), 3.03 - 2.94 (m, 1H), 2.58 (d, J = 6.2 Hz, 2H), 2.16 - 2.05 (m, 3H), 1.75 - 1.66 (m, 1H); MS (ESI): m / z 805.3 (M+H)+. Starting from compound 9b and 4-bromo-3-methoxybenzaldehyde, with reference to the synthesis of compound 9, compound 11 was obtained. Ή NMR (500 MHz, DMSO-o6) δ 8.88 (d, J = 2.0 Hz, 1H) , 8.77 (d, J= 2.0 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.73 (s, 1H), 7.66 - 7.59 (m, 2H), 7.47 (s, 1H), 7.45-7.37 (m , 3H), 7.32-7.28 (m, 1H), 7.15 - 7.08 (m, 2H), 7.05 (s, 1H), 6.93 (d, J= 7.7 Hz, 1H), 6.78 (s, 1H), 5.64 ( s, 2H), 5.06 - 5.00 (m, 2H), 3.87 - 3.82 (m, 1H), 3.80 - 3.75 (m, 1H), 3.74 - 3.67 (m, 6H), 3.58 - 3.56 (m, 1H), 3.51 - 3.50 (m, 1H), 3.04 - 2.99 (m, 1H), 2.51 - 2.47 (m, 2H), 2.08 - 1.99 (m, 3H), 1.68 - 1.59 (m, 1H); MS (ESI): m / z 834.7 (M+H)+. z0H Example 12: ινΐΛ / a / zuzz / uuou 1 or Starting from the pinacol ester of 4-formylbenzeneboronic acid and l,3-dibromo-2fluorobenzene, with reference to the synthesis of the compound INT-3a, the compound 12a.XH NMR (500 MHz, chloroform-d) δ 10.08 (s, 1H), 7.97 (d, J= 8.0 Hz, 2H), 7.70 (d, J= 8.0 Hz, 2H), 7.61 (t, J = 7.0 Hz, 1H), 7.40 (t, J= 7.0 Hz, 1H) , 7.14 (t, J= 7.5 Hz, 1H). Compound 12 was obtained from the synthesis of compound 12a, compound INT-2 and compound INT-1 with reference to the synthesis of compound INT-3 and compound 1.XH NMR (500 MHz, DMSO-06) δ 8.93 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.34 - 8.32 (m, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.64 - 7.57 (m, 4H), 7.53 (s, 1H), 7.51 - 7.42 (m, 4H), 7.30 - 7.26 (m, 1H), 6.85 (s, 1H), 5.72 (s, 2H), 5.15 - 5.07 (m, 2H), 3.90 (d, J = 14.5 Hz, 1H), 3.85 - 3.72 (m, 3H), 3.65 - 3.60 (m, 1H ), 3.56 (d, J = 5.5 Hz, 2H), 3.07 - 2.99 (m, 1H), 2.54 - 2.52 (m, 2H), 2.14 - 2.05 (m, 3H), 1.73 - 1.64 (m, 1H); MS (ESI): m / z 788.3 (M+H)+. Example 13: Starting from the pinacol ester of 4-formylbenzeneboronic acid and 2,6-dibromobenzonitrile, with reference to the synthesis of compound INT-3a, compound 13a was obtained. NMR (500 MHz, Chloroform-d) δ 10.11 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.71 (d, = 8.0 Hz, 2H ), 7.54 (t, 7 = 8.0 Hz, 1H), 7.47 (d, 7 = 8.0 Hz, 1H). Compound 13 was obtained from the synthesis of compound 13a, compound INT-2 and compound INT-1 with reference to the synthesis of compound INT-3 and compound l / H NMR (500 MHz, DMSO-o6) δ 8.94 (d, 7= 2.0 Hz, 1H), 8.81 (d, 7= 2.0 Hz, 1H), 8.31 - 8.29 (m, 1H), 8.07 (d, 7 = 2.5 Hz, 1H), 7.93-7.87 (m, 1H), 7.80 - 7.72 (m, 2H), 7.70 - 7.63 (m, 4H), 7.56 - 7.45 (m, 4H), 7.37 - 7.33 (m, 1H), 6.70 (s, 1H), 5.78 - 5.73 ( m, 2H), 5.06 - 4.99 (m, 2H), 3.90 (d, 7= 15.0 Hz, 1H), 3.84 - 3.75 (m, 3H), 3.71 (d, J= 15.0 Hz, 1H), 3.66 - 3.61 (m, 1H), 3.58 - 3.54 (m, 1H), 3.09 - 3.02 (m, 1H), 2.56 - 2.53 (m, 2H), 2.14 - 2.05 (m, 3H), 1.73 - 1.65 (m, 1H) ; MS (ESI): m / z 795.7 (M+H)+. Example 14: Starting from the pinacol ester of 4-formylbenzeneboronic acid and l-bromo-3iodobenzene, with reference to the synthesis of compound INT-3a, compound 14a was obtained. Compound 14 was obtained from the synthesis of compound 14a, compound INT-2 and compound INT-1 with reference to the synthesis of compound INT-3 and compound 1. NMR (500 MHz, DMSO-o6) δ 8.91 (d, 7= 2.0 Hz, 1H), 8.83 (d, 7= 2.0 Hz, 1H), 8.32 - 8.30 (m, 1H), 8.21 - 8.18 (m, 1H ), 7.96 - 7.94 (m, 1H), 7.76 - 7.71 (m, 4H), 7.69 - 7.62 (m, 3H), 7.55 (s, 1H), 7.51 - 7.44 (m, 3H), 7.38 (d, 7 = 7.0 Hz, 1H), 6.83 (s, 1H), 5.76 - 5.70 (m, 2H), 5.16 - 5.08 (m, 2H), 3.94 (d, 7= 14.0 Hz, 1H), 3.87 (d, 7= 14.0 Hz, 1H), 3.79 (d, 7= 14.0 Hz, 1H), 3.75 (d, 7= 14.0 Hz, 1H), 3.66-3.61 (m, 2H), 3.61-3.55 (m, 1H), 3.15- 3.12 (m, 1H), 2.54-2.52 (m, 2H), 2.13 - 2.04 (m, 3H), 1.72 - 1.64 (m, 1H); MS (ESI): m / z 770.7 (M+H)+. Example 15: At room temperature, 3-bromo-4-chloroaniline (2.06 g, 9.98 mmol) was dissolved in sulfuric acid (25% w / w aqueous solution, 40 ml) and stirred for half an hour. Then, the reaction solution was cooled to -5°C, an aqueous solution (10 ml) with predissolved sodium nitrite (826 mg, 12.0 mmol) was slowly added dropwise. After completion of dripping, the reaction solution was further stirred for 1 hour at -5°C. Subsequently, a mixed solution of ethyl acetate and water (50 mL, v / v = 3 / 2) with potassium iodide (3.31 g, 20.0 mmol) predissolved was added dropwise, during which the reaction temperature was ensured by below -5°C. The aqueous phase was further extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed sequentially with saturated sodium thiosulfate solution (100 ml x 2) and saline (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain a light yellow solid 15a (2.05 g, yield: 64.7%).Ή NMR (500 MHz, CDCh) δ 7.95 (d, J= 2.0 Hz , 1H), 7.57 -7.53 (m, 1H), 7.17 (d, J= 8.5 Hz, 1H). 4-formylphenylboronic acid pinacol ester (439 mg, 1.89 mmol) and compound 15a (500 mg, 1.58 mmol) were dissolved in a mixture of dioxane and water (10 ml, v / v=4 / l), bicarbonate of sodium (397 mg, 4.73 mmol) and Pd(dppf)CI2 (58 mg, 0.079 mmol). The reaction solution under a nitrogen atmosphere was heated to 80°C and stirred for 3 hours. The reaction was quenched with water (50 ml) and the aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with saturated saline (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 10 / 1) to obtain a yellow oily matter 15b (271 mg, yield: 58.2%). Starting from compound 15b, compound INT-2 and compound INT-1, with reference to the synthesis of compound INT-3 and compound 1, compound 15 is obtained.XH NMR (500 MHz, DMSO-06) δ 8.93 (s, 1H), 8.84 (s, 1H), 8.34 (s, 1H), 7.85 (s, 1H), 7.81 - 7.76 (m, 2H), 7.74 - 7.65 (m, 5H), 7.55 - 7.40 (m , 4H), 7.25 - 7.19 (m, 1H), 6.81 (s, 1H), 5.72 (s, 2H), 5.13 - 5.04 (m, 2H), 3.90 - 3.83 (m, 1H), 3.78 - 3.69 (m , 3H), 3.63 - 3.53 (m, 3H), 3.06 - 2.97 (m, 1H), 2.57 2.55 (m, 2H), 2.13 - 2.03 (m, 3H), 1.70 - 1.63 (m, 1H); MS (ESI): m / z 804.7 (M+H)+. ινΐΛ / a / zuzz / uuoui or Example 16: ινΐΛ / a / zuzz / uuou i o To a solution of 3-bromo-4-methylaniline (584 mg, 3.14 mmol) in N,Ndimethylformamide (3 ml) was added N-chlorosuccinimide at room temperature (419 mg, 3.14 mmol); The reaction was heated to 80°C. °C and stirred at this temperature for 1 hour. The reaction was quenched with water (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 10 / 1) to give 16a as a white solid (292 mg, yield: 42.2%). MHz, DMSO-ofe) δ 6.97 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 5.41 (s, 2H), 2.22 (s, 3H). Compound 16b was obtained by reference to the synthesis of compound INT-3a from pinacol ester of 4-formylbenzeneboronic acid and compound 16a. To a solution of compound 16b (100 mg, 0.41 mmol) in acetonitrile (1 mL) was added tere-butyl nitrite (50 mg, 0.49 mmol) and cuprous bromide (91 mg, 0.63 mmol) at room temperature; The reaction solution was heated to 60°C and stirred at this temperature for one hour. The reaction was quenched with water (20 ml) and the aqueous phase was extracted with ethyl acetate (20 ml x 2). The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 10 / 1) to give 16c (28 mg, yield: 22.2%) as a white solid. MHz, Coloroform-o) δ 10.09 (s, 1H), 8.02 - 7.95 (m, 2H), 7.56 (d, J = 8.2 Hz, 1H), 7.35 (d, J= 8.0 Hz, 2H), 7.08 (d , J = 8.2 Hz, 1H), 2.01 (s, 3H). Compound 16 was obtained from the synthesis of compound 16c, compound INT-2 and compound INT-1 with reference to the synthesis of compound INT-3 and compound l / H NMR (500 MHz, DMSO-O6) δ 8.98 - 8.88 (m, 1H), 8.85 - 8.77 (m, 1H), 8.32 - 8.23 ​​(m, 1H), 7.81 (s, 1H), 7.67 - 7.63 (m, 2H), 7.53 (s, 1H), 7.47 - 7.42 (m, 3H), 7.42 - 7.39 (m, 2H), 7.27 - 7.21 (m, 2H), 7.14 7.09 (m, 1H), 6.82 (s, 1H), 5.69 (s, 2H), 5.11 - 5.04 (m, 2H), 3.95 - 3.82 (m, 2H), 3.82 - 3.75 (m, 2Η), 3.66 - 3.61 (m, 2H), 3.59 - 3.55 (m, 1H), 3.17 - 3.13 (m, 1H), 2.62 - 2.56 (m, 2H), 2.14 - 2.10 (m, 1H), 2.08 ( s, 3H), 2.08 - 2.04 (m, 1H), 2.02 - 1.92 (m, 1H), 1.74 - 1.64 (m, 1H); MS (ESI): m / z 818.5 (M+H)+. iviA / a / zuzz / uuou 1 or Example 17: Starting from 3-bromo-4-chloroaniline and referring to the synthesis of compound 16, compound 17 was obtained. Ή NMR (500 MHz, DMSO-o6) δ 8.95 - 8.88 (m, 1H), 8.85 - 8.76 (m , 1H), 8.34 - 8.27 (m, 1H), 7.90 - 7.84 (m, 1H), 7.72 - 7.64 (m, 3H), 7.54 (d, J = 8.3 Hz, 1H), 7.49 7.40 (m, 4H) , 7.29 (d, 7 = 7.7 Hz, 2H), 7.14 (d, 7= 7.0 Hz, 1H), 6.73 (s, 1H), 5.68 (s, 2H), 5.09 4.99 (m, 2H), 3.80 - 3.71 (m, 2H), 3.66 (s, 2H), 3.63 - 3.57 (m, 1H), 3.42 - 3.34 (m, 2H), 3.21 3.16 (m, 1H), 2.56 - 2.52 (m, 2H), 2.13 - 2.04 (m, 3H), 1.70 - 1.64 (m, 1H); MS (ESI): m / z 838.2 (M+H)+. Example 18: Starting from 4-bromophenethyl alcohol, compound 18a was obtained by reference to the synthesis of compound INT-7a. MS (ESI): m / z 249.1 (M+H)+. Starting from compound 18a and l,3-dibromo-2-toluene, with reference to the synthesis of compound INT-3a, compound 18b was obtained. MS (ESI): m / z 311.0 (M+H)+. From compound 18b, compound 18c was obtained with reference to the synthesis of compound 6b. MS (ESI): m / z 389.0 (M+H)+. The acetonitrile solution (10 ml) was stirred for 16 hours. The reaction was quenched with water (30 ml) and the aqueous phase was extracted with ethyl acetate (30 ml x 2). The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (dichloromethane / methanol, v / v = 10 / 1) to give 18d as a yellow oil (140 mg, yield: 49.0%). EM (ESI): m / z 380.2 (M+H)+. From compound 18d and compound INT-1, compound 18 was obtained by referring to the synthesis of compound 1.XH NMR (500 MHz, DMSO-o6) δ 8.93 (d, J= 2.0 Hz, 1H), 8.83 (d, J= 2.0 Hz, 1H), 8.33 - 8.31 (m, 1H), 7.86 (s, 1H), 7.69 (d, J= 8.5 Hz, 1H), 7.53 - 7.51 (m, 2H), 7.48 - 7.45 (m, 2H), 7.44 - 7.41 (m, 2H), 7.34 - 7.32 (m, 3H), 7.16 (d, J= 7.0 Hz, 1H), 6.79 (s, 1H), 5.71 (s, 2H) , 5.08 (d, J = 3.0 Hz, 2H), 4.20 - 4.18 (m, 1H), 3.86 - 3.81 (m, 2H), 3.53 - 3.51 (m, 2H), 2.97 (t, J= 6.0 Hz, 1H ), 2.80 - 2.76 (m, 4H), 2.68 - 2.63 (m, 4H), 2.00 - 1.96 (m, 1H), 1.57 - 1.53 (m, 1H); MS (ESI): m / z 791.5 (M+H)+. Example 19: Starting from 4-bromophenylpropanol and with reference to the synthesis of compound 18, the compound 19.3H NMR (500 MHz, DMSO-06) δ 8.94 (d, J = 2.0 Hz, 1H), 8.84 (d, 7 = 2.0) was obtained Hz, 1H), 8.54 (s, 1H), 8.35 - 8.33 (m, 1H), 7.86 (s, 1H), 7.69 (d, 7 = 8.5 Hz, 1H), 7.55 - 7.51 (m, 2H), 7.49 - 7.42 (m, 5H), 7.30 (d, 7= 8.0 Hz, 2H), 7.16 (d, J= 7.0 Hz, 1H), 6.75 (s, 1H), 5.70 (s, 2H), 5.13-4.98 ( m, 2H), 4.22 - 4.15 (m, 2H), 3.71 - 3.64 (m, 2H), 3.24 - 3.17 (m, 3H), 2.71 - 2.63 (m, 3H), 2.56 - 2.53 (m, 1H), 2.42 - 2.38 (m, 3H), 2.30 - 2.27 (m, 1H), 2.01 - 1.93 (m, 1H), 1.79 1.73 (m, 2H), 1.56 - 1.50 (m, 1H); MS (ESI): m / z 805.7 (M+H)+. Example 20: N-chlorosuccinimide (639 mg, 4.78 mmol) was added portionwise to a solution of 2,6-dibromoaniline (1.00 g, 3.99 mmol) in acetonitrile (20 mL) at 25°C; The resulting reaction solution was stirred at the same temperature for 16 hours. Water was added to the reaction solution and a solid precipitated; The solid obtained was further washed with water and dried to obtain a white solid 20a (1.10 g, yield: 96.7%). Ή NMR (500 MHz, DMSO-ú6) δ 7.53 (s, 2H), 5.48 (s, 2H). Starting from compound 20a, in reference to the synthesis of compound 16c, where copper (I) bromide is replaced by cuprous chloride, compound 20b is obtained.XH NMR (500 MHz, DMSO-06) δ 8.00 (s, 2H). From compound 20b, compound 20 was obtained with reference to the synthesis of compound 12.XH NMR (500 MHz, DMSO-06) δ 8.95 - 8.88 (m, 1H), 8.83 - 8.76 (m, 1H), 8.32 8.23 (m, 1H), 7.90 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.68 - 7.64 (m, 1H), 7.61 - 7.58 (m, 1H), 7.56 - 7.41 (m, 7H), 7.21 - 7.14 (m, 1H), 6.79 - 6.66 (m, 1H), 5.70 (s, 2H), 5.13 - 5.01 (m, 2H), 3.83 3.70 (m, 4H), 3.61 (t, J = 6.5 Hz, 1H), 3.51 - 3.47 (m, 1H), 3.44 - 3.41 (m, 1H), 2.86 (s, 1H), 2.53 2.52 (m, 2H), 2.16 - 2.00 (m, 3H), 1.73 - 1.63 (m, 1H); MS (ESI): m / z 838.3 (M+H)+. Example 21: ινΐΛ / a / zuzz / uuou 1 or N-bromosuccinimide (6.28 g, 35.3 mmol) was added portionwise to 5-chloro-2methylaniline (2.00 g, 14.1 mmol) in acetonitrile (30 mL) to a 25 °C solution; The resulting reaction solution was stirred at the same temperature for 16 hours. The reaction was quenched with water (100 ml) and the aqueous phase was extracted with ethyl acetate (100 ml x 3). The organic phases were combined, washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain 21a (4.00 g, yield: 94.6%) as a dark red solid. s, 2H), 2.18 (s, 3H). Under a nitrogen atmosphere at 25°C, terebutyl nitrite (3.91 g, 33.4 mmol) was slowly added dropwise to a solution of compound 21a (4.00 g, 13.4 mmol) in ethanol (30 mL); The reaction solution was at 50 degrees with stirring for 2 hours. The reaction solution was cooled and concentrated, and the obtained residue was separated by silica gel column chromatography to obtain the white solid 21b (2.1 g, yield: 55.3%).XH NMR (500 MHz, Chloroform-d) δ 7.41 (s, 2H), 2.29 (s, 3H). From compound 21b, compound 21 was obtained with reference to the synthesis of compound 12.:H NMR (500 MHz, DMSO-06) δ 8.93 (d, J= 2.0 Hz, 1H), 8.82 (d, J= 2.0Hz, 1H), 8.31 - 8.29 (m, 1H), 7.84 (s, 1H), 7.72 - 7.63 (m, 2H), 7.53 (s, 1H), 7.48 - 7.39 (m, 5H), 7.33 - 7.25 (m, 2H), 7.13 (d, J= 7.0 Hz, 1H), 6.82 (s, 1H), 5.70 (s, 2H), 5.14 - 5.04 (m, 2H), 3.93 (d, J= 14.5 Hz, 1H), 3.85 (d , J= 14.5 Hz, 1H), 3.80 - 3.73 (m, 2H), 3.67 - 3.54 (m, 3H), 3.14 (t, J = 5.5 Hz, 1H), 2.54 - 2.53 (m, 2H), 2.38 ( s, 3H), 2.12 - 2.04 (m, 3H), 1.72 - 1.64 (m, 1H); MS (ESI): m / z 818.8 (M+H)+. Example 22: Starting from the compound INT-7 and tert-butyl glycine, compound 22 was obtained by referring to the reductive amination steps in the synthesis of the compound INT-lj and the de-Boc protecting group in the synthesis of the compound 1.XH NMR ( 500 MHz, DMSO-o6) δ 8.95 (d, J= 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.34 - 8.32 (m, 1H), 7.87 (s, 1H), 7.71 ( d, 7 = 8.5 Hz, 1H), 7.67 (s, 1H), 7.56 - 7.46 (m, 9H), 7.17 (d, 7 = 7.0 Hz, 1H), 6.86 (s, 1H), 5.73 (s, 2H ), 5.11 (s, 2H), 3.93 (s, 2H), 3.90 - 3.82 (m, 2H), 3.71 - 3.67 (m, 1H), 3.18 (s, 2H), 2.73 - 2.61 (m, 2H), 2.17 - 2.09 (m, 3H), 1.75 - 1.69 (m, 1H); MS (ESI): m / z 774.7 (M+H)+. Example 23: From compound INT-7 and serine isopropyl ester, compound 23 was obtained by referring to the synthesis of compound 22.XH NMR (500 MHz, DMSO-06) δ 8.97 (d, 7 = 1.9 Hz, 1H) , 8.83 (d, 7= 1.9 Hz, 1H), 8.30 (d, 7= 1.9 Hz, 1H), 7.87 (s, 1H), 7.74 - 7.68 (m, 2H), 7.55 - 7.43 (m, 9H), 7.17 (d, 7 = 7.0 Hz, 1H), 6.85 (s, 1H), 5.71 (s, 2H), 5.09 (s, 2H), 4.86 - 4.80 (m, 1H), 3.81 - 3.72 (m, 3H) , 3.66 - 3.60 (m, 2H), 3.54 (d, 7= 5.0 Hz, 2H), 3.19 (t, 7= 5.0 Hz, 1H), 2.56 2.54 (m, 2H), 2.14 - 2.07 (m, 3H) , 1.74 - 1.65 (m, 1H), 1.11 (d, J = 6.0 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H); MS (ESI): m / z 846.7 (M+H)+. Example 24: OH H.N. Starting from the compound INT-7 and ethanolamine, compound 24 was obtained taking as reference the synthesis of compound 22.XH NMR (500 MHz, DMSO-06) δ 8.96 (d, J = 2.0 Hz, 1H), 8.83 (d, J= 2.0 Hz, 1H), 8.29 (s, 1H), 7.87 (s, 1H), 7.71 (d, J= 9.5 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.52 - 7.43 ( m, 8H), 7.17 (d, J= 7.0 Hz, 1H), 6.84 (s, 1H), 5.72 (s, 2H), 5.09 (s, 2H), 3.79 (d, J = 13.5 Hz, 1H), 3.77 - 3.73 (m, 3H), 3.66 - 3.61 (m, 1H), 3.47 (t, J = 5.5 Hz, 2H), 2.59 (t, J = 5.5 Hz, 2H), 2.57 - 2.54 (m, 2H) , 2.15 - 2.06 (m, 3H), 1.72 - 1.66 (m, 1H); MS (ESI): m / z 760.6 (M+H)+. From compound INT-7 and proline tert-butyl ester, compound 25 was obtained by referring to the synthesis of compound 22. Ή NMR (500 MHz, DMSO-06) δ 8.95 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.35 - 8.33 (m, 1H), 7.88 (s, 1H), 7.72 - 7.68 (m, 2H), 7.55 -7.44 (m, 9H), 7.17 (d, J = 7.0 Hz, 1H), 6.82 (s, 1H), 5.72 (s, 2H), 5.14 - 5.06 (m, 2H), 3.98 (d, J = 14.0 Hz, 1H), 3.82 (d, J = 14.0 Hz, 1H), 3.77 (d, J= 7.5 Hz, 2H), 3.65 - 3.62 (m, 1H), 3.05 - 3.02 (m, 1H), 2.56 - 2.54 (m, 2H), 2.15 - 2.03 (m, 5H), 1.90 - 1.84 (m, 1H), 1.81 - 1.65 (m, 4H); MS (ESI): m / z 814.8 (M+H)+. From compound INT-lj, compound 26b was obtained by referring to the steps of reductive amination in the synthesis of compound INT-lj and boron esterification in the synthesis of compound INT-1. MS (ESI): m / z 744.6 (M+H)+. From compound 26b and compound INT-3, compound 26 was obtained by referring to the synthesis of compound 1.XH NMR (500 MHz, DMSO-C6) δ 8.94 (d, 7= 2.0 Hz, 1H), 8.80 (d, 7= 2.0 Hz, 1H), 8.27 (s, 1H), 7.87 (s, 1H), 7.72 - 7.68 (m, 2H), 7.57 - 7.43 (m, 9H), 7.17 (d, 7 = 7.0 Hz, 1H), 6.80 (s, 1H), 5.71 (s, 2H), 5.09 (s, 2H), 3.82 - 3.69 (m, 6H), 3.66 - 3.58 (m, 10 2H), 2.55 (d, 7 = 6.0 Hz, 2H), 2.28 (s, 3H), 2.14 - 2.07 (m, 3H), 1.74 - 1.66 (m, 1H); MS (ESI): m / z 818.8 (M+H)+. Example 27: From compound INT-7, compound 27a was obtained by referring to the step of the -Boc protecting group in the synthesis of compound 1. MS (ESI): m / z 715.5 (M+H)+. To compound 27a (45 mg, 0.054 mmol) in N'N-dimethylformamide (2 ml) at 25 °C was added (R)-3-hydroxypyrrolidine hydrochloride (21 mg, 0.14 mmol) and Ν,Ν-diisopropylethylamine ( 70mg, 0.54 mmol). mmol); The resulting reaction solution was stirred at the same temperature for one hour. Sodium triacetate borohydride (58 mg, 0.27 mmol) was then added and the reaction solution was further stirred at 25°C for 16 hours. Water (20 mL) was added to the reaction solution and extracted with ethyl acetate (15 mL x 2). The organic phase was concentrated and the residue was purified by preparative high-performance liquid chromatography column chromatography to obtain 27 as a white solid (10 mg, yield: 22.6%). Ή NMR (500 MHz, DMSO-C6) δ 8.93 (d, J= 2.0 Hz, 1H), 8.79 (d, J= 2.0 Hz, 1H), 8.26 - 8.24 (m, 1H), 7.85 (s, 1H) , 7.71 - 7.65 (m, 2H), 7.52 - 7.40 (m, 9H), 7.15 (d, J = 6.9 Hz, 1H), 6.80 (s, 1H), 5.69 (s, 2H), 5.07 (s, 2H ), 3.77 (d, J = 12.5 Hz, 1H), 3.74 (d, J = 12.5 Hz, 1H), 3.62 - 3.56 (m, 3H), 2.92 - 2.86 (m, 1H), 2.69 - 2.61 (m, 2H), 2.54 - 2.52 (m, 4H), 2.11 - 2.05 (m, 3H), 1.95 - 1.90 (m, 2H), 1.70 - 1.64 (m, 1H); MS (ESI): m / z 814.8 (M+H)+. Example 28: INT-7aCN Compound 28 was obtained from the synthesis of compound INT-7a, compound INT-6 and serine isopropyl ester with reference to the synthesis of compound INT-7 and compound 23.XH NMR (500 MHz, DMSO- fl6) δ 8.96 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.30 - 8.28 (m, 1H), 7.88 (s, 1H), 7.71 (d, J= 8.6 Hz, 1H), 7.68 (s, 1H), 7.56 - 7.47 (m, 4H), 7.46 (s, 1H), 7.42 (d, J= 7.7 Hz, 1H), 7.17 (d, J= 7.1 Hz, 1H ), 7.09 (d, J = 1.6 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.84 (s, 1H), 5.71 (s, 2H), 5.09 (s, 2H), 4.87 - 4.81 (m, 1H), 4.78 (t, J = 5.8 Hz, 1H), 3.83 (s, 3H), 3.77 (d, J = 14.7 Hz, 1H), 3.75 - 3.73 (m, 1H), 3.66 - 3.60 (m, 2H ), 3.54 (t, J= 5.6 Hz, 2H), 3.30 - 3.28 (m, 1H), 3.19 (t, J= 5.3 Hz, 1H), 2.56 (d, J= 6.0 Hz, 2H), 2.16 - 2.05 (m, 3H), 1.75 - 1.64 (m, 1H), 1.11 (d, J= 6.2 Hz, 3H), 1.09 (d, J= 6.2 Hz, 3H); MS (ESI): m / z 876.2 (M+H)+. Example 29: ethanolamine, with reference to the synthesis of compound INT-3, compound INT-7 and compound 23, the compound is obtained 29.4Η NMR (500 MHz, DMSO-o6) δ 8.97 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.33 - 8.31 (m, 1H), 7.85 (s, 1H), 7.83 (d, J= 7.5 Hz, 1H), 7.73 (d, J= 9.0 Hz, 1H) , Ί J?. (S, 1H), 7.69 - 7.65 (m, 1H), 7.60 - 7.54 (m, 2H), 7.52 - 7.47 (m, 2H), 7.32 (d, J= 7.5 Hz, 1H), 7.18 (d, J = 7.0 Hz, 1H), 6.87 (s, 1H), 5.72 (s, 2H), 5.11 (s, 2H), 3.92 (s, 3H), 3.80 (s, 2H), 3.72 (d, J = 4.0 Hz , 2H), 3.66 - 3.62 (m, 1H), 3.48 (t, J = 5.5 Hz, 2H), 2.64 (t, J= 5.5 Hz, 2H), 2.56 (d, J= 6.0 Hz, 2H), 2.14 - 2.07 (m, 3H), 1.74 - 1.66 (m, 1H); MS (ESI): m / z 791.6 (M+H)+. Example 30: CL INT-8 Starting from the compound INT-8 and O-isopropyl-L-serine tert-butyl ester, with reference to iviA / a / zuzz / uuou 1 or the synthesis of compound 22, compound 30 is obtained. *H NMR (500 MHz, DMSO -06) δ 7.91 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.56 - 7.44 (m, 9H), 7.17 (d, J = 7.0 Hz, 1H) , 6.72 (s, 1H), 5.75 (s, 2H), 3.89 (d, J = 14.5 Hz, 1H), 3.83 - 3.75 (m, 3H), 3.68 - 3.63 (m, 2H), 3.61 (s, 3H ), 3.60 - 3.57 (m, 1H), 3.14 (t, J = 5.5 Hz, 1H), 2.57 (d, J = 6.5 Hz, 2H), 2.16 - 2.07 (m, 3H), 1.74 1.67 (m, 1H ); MS (ESI): m / z 702.5 (M+H)+. Example 31: COOH h2n γ cooh OH Starting from the compound INT-8 and (R)-(-)-4-amino-3-hydroxybutyric acid, with reference to the synthesis of compound 27, the compound 31.4Η NMR (500 MHz, DMSO- 06) δ 7.90 (s, 1H), 7.77 (d, J= 8.5 Hz, 1H), 7.67 (s, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.43 (m, 7H), 7.17 (d , J= 7.0 Hz, 1H), 6.69 (s, 1H), 5.74 (s, 2H), 3.94 - 3.90 (m, 1H), 3.80 - 3.77 (m, 2H), 3.69 - 3.68 (m, 2H), 3.65 - 3.63 (m, 1H), 3.60 (s, 3H), 2.57 - 2.53 (m, 4H), 2.45 - 2.39 (m, 1H), 2.28 - 2.22 (m, 1H), 2.13 - 2.05 (m, 3H) ), 1.75 - 1.65 (m, 1H); MS (ESI): m / z 716.7 (M+H)+. Example 32: ινΐΛ / a / zuzz / uuou 1 or Starting from the compound INT-8 and glycine tert-butyl ester, with reference to the synthesis of compound 22, compound 32 is obtained. 'H NMR (500 MHz, DMSO-o6) δ 7.90 (s, 1H), 7.77 ( d, 7 = 9.0 Hz, 1H), 7.67 (s, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.42 (m, 7H), 7.17 (d, 7 = 7.0 Hz, 1H), 6.70 (s , 1H), 5.74 (s, 2H), 3.80 - 3.72 (m, 4H), 3.65 - 3.62 (m, 1H), 3.60 (s, 3H), 3.07 (s, 2H), 2.55 - 2.53 (m, 2H ), 2.14 - 2.07 (m, 3H), 1.72 - 1.66 (m, 1H); MS (ESI): m / z 672.6 (M+H)+. Example 33: Starting from compound INT-8 and compound INT-11, with reference to the synthesis of compound INT-5, compound 33a is obtained. MS (ESI): m / z 826.7 (M+H)+. At 25°C, dissolved lithium hydroxide (10 mg, 0.42 mmol) was added to the mixed solution of methanol and water (9 mL, v / v=8 / l) with compound 33a (90 mg, 0.11 mmol). The reaction solution was stirred for 1 hour at the same temperature. The reaction solution was concentrated and then diluted with saturated ammonium chloride. The aqueous phase was extracted with ethyl acetate (10 ml x 2). The combined organic phase was concentrated. The residue was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (4 ml, v / v = 3 / 1) and further reacted for 2 hours at 25°C. After concentrating the reaction solution, the residue was separated by preparative high-performance liquid chromatography to obtain a white solid 33 (10.3 mg, yield: 23.5%). s, 1H), 7.77 (d, 7= 8.5 Hz, 1H), 7.69 (s, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.43 (m, 6H), 7.37 (s, 1H), 7.17 (d, 7= 7.0 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 3.83 - 3.74 (m, 2H), 3.67 - 3.62 (m, 1H), 3.58 (s, 3H), 3.56 - 3.48 (m, 2H), 2.95 - 2.88 (m, 1H), 2.68 - 2.64 (m, 2H), 2.59 - 2.54 (m, 2H) ), 2.54 - 2.51 (m, 1H), 2.15 - 2.06 (m, 3H), 1.98 - 1.90 (m, 2H), 1.74 - 1.66 (m, 1H); MS (ESI): m / z 712.7 (M+H)+. ινΐΛ / a / zuzz / uuou 1 or Example 34: Starting from (R)-l-Boc-3-carboxypyrrolidine, referring to the synthesis of the compound INT11, compound 34a is obtained. Starting from compound 34a and compound INT-8, with reference to the synthesis of compound 33, compound 34 is obtained.XH NMR (500 MHz, DMSO-o6) δ 7.91 (s, 1H), ΊΠΊ (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.55 - 7.43 (m, 8H), 7.37 (s, 1H), 7.17 (d, 7 = 7.0 Hz, 1H), 6.67 (s, 1H), 5.73 ( s, 2H), 3.81 - 3.73 (m, 2H), 3.66 - 3.61 (m, 1H), 3.58 (s, 3H), 3.56 - 3.47 (m, 2H), 2.92 - 2.86 (m, 1H), 2.69 - 2.62 (m, 2H), 2.56 - 2.53 (m, 2H), 2.49 - 2.46 (m, 1H), 2.14 - 2.07 (m, 3H), 1.96 1.90 (m, 2H), 1.74 - 1.66 (m, 1H) ; MS (ESI): m / z 712.7 (M+H)+. Example 35: Compound 35a was obtained from N-Boc-(R)-3-carboxylic acid piperidine with reference to the synthesis of compound INT-11. From compound 35a and compound INT-8, compound 35 was obtained by referring to the synthesis of compound 33.3Η NMR (500 MHz, DMSO-06) δ 7.91 (s, 1H), 7.77 (d, 7= 8.5 Hz, 1H), 7.68 (s, 1H), 7.55 - 7.42 (m, 8H), 7.39 (s, 1H), 7.17 (d, 7= 7.0 Hz, 1H), 6.68 (s, 1H), 5.73 (s , 2H), 3.80 - 3.73 (m, 2H), 3.65 - 3.61 (m, 1H), 3.58 (s, 3H), 3.41 (s, 2H), 2.78 - 2.72 (m, 1H), 2.59 - 2.53 (m , 3H), 2.44 - 2.40 (m, 1H), 2.24 - 2.18 (m, 1H), 2.13 - 2.04 (m, 4H), 1.79 1.73 (m, 1H), 1.72 - 1.67 (m, 1H), 1.64 - 1.59 (m, 1H), 1.50 - 1.42 (m, 1H), 1.40 - 1.33 (m, 1H); MS (ESI): m / z 726.7 (M+H)+. Example 36: 36a ινΐΛ / a / zuzz / uuou 1 or Compound 36a was obtained from N-Boc-(S)-3-carboxylic acid piperidine with reference to the synthesis of compound INT-11. From compound 36a and compound INT-8, compound 36 was obtained by referring to the synthesis of compound 33.XH NMR (500 MHz, DMSO-P6) δ 7.91 (s, 1H), 7.77 (d, J= 8.5 Hz, 1H), 7.68 (s, 1H), 7.55 -7.50 (m, 2H), 7.49-7.43 (m, 6H), 7.39 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 3.83 - 3.74 (m, 2H), 3.66 - 3.63 (m, 1H), 3.58 (s, 3H), 3.42 (s, 2H), 2.77 - 2.73 ( m, 1H), 2.56 (m, 3H), 2.45 - 2.39 (m, 1H), 2.23 - 2.16 (m, 1H), 2.15 - 2.04 (m, 4H), 1.79 - 1.73 (m, 1H), 1.72 - 1.66 (m, 1H), 1.64 - 1.59 (m, 1H), 1.50 - 1.42 (m, 1H), 1.41 - 1.33 (m, 1H); MS (ESI): m / z 726.7 (M+H)+. Example 37: Starting from methyl 4-piperidinecarboxylate and the compound INT-8, with reference to the synthesis of compound 33, the compound 37 is obtained. (m, 1H), 7.67 (s, 1H), 7.53 - 7.46 (m, 7H), 7.35 (s, 1H), 7.32 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.69 ( s, 1H), 5.73 (s, 2H), 3.81 - 3.73 (m, 2H), 3.65 - 3.62 (m, 1H), 3.58 (s, 3H), 3.52 3.50 (m, 2H), 2.80 - 2.77 (m , 1H), 2.74 - 2.70 (m, 1H), 2.20 - 2.15 (m, 1H), 2.13 - 2.08 (m, 3H), 2.02 - 1.98 (m, 4H), 1.78 - 1.74 (m, 2H), 1.72 - 1.67 (m, 1H), 1.56 - 1.52 (m, 2H); MS (ESI): m / z 726.7 (M+H)+. Example 38: Starting from methyl 3-carboxylate azetidine hydrochloride and the compound INT8, with reference to the synthesis of compound 33, the compound 38.XH NMR (500 MHz, DMSO-o6) δ 7.90 (s, 1H), 7.77 is obtained (d, 7 = 8.5 Hz, 1H), 7.68 (s, 1H), 7.55 - 7.44 (m, 8H), 7.27 (s, 1H), 7.17 (d, 7= 7.0 Hz, 1H), 6.67 (s, 1H), 5.72 (s, 2H), 3.84 - 3.77 (m, 2H), 3.68 - 3.63 (m, 1H), 3.58 (s, 3H), 3.47 (s, 2H), 3.42 - 3.38 (m, 2H) , 3.23 - 3.17 (m, 3H), 2.58 (d, 7= 6.0 Hz, 2H), 2.16 - 2.06 (m, 3H), 1.74 - 1.66 (m, 1H); MS (ESI): m / z 698.7 (M+H)+. Example 39: Starting from methyl 4-aminomethyl-cyclohexanecarboxylate hydrochloride and the compound INT-8, with reference to the synthesis of compound 33, the compound 39.4H NMR (500 MHz, DMSO-c6) δ 7.91 (s, 1H) is obtained, 7.77 (d, 7= 8.5 Hz, 1H), 7.69 (s, 1H), 7.55 - 7.50 (m, 2H), 7.48 - 7.41 (m, 7H), 7.17 (d, 7= 7.0 Hz, 1H), 6.70 (s, 1H), 5.74 (s, 2H), 3.83 - 3.75 (m, 2H), 3.68 (s, 2H), 3.67-3.62 (m, 1H), 3.60 (s, 3H), 2.57 (d, 7 = 6.0 Hz, 2H), 2.40 (d, 7= 6.5 Hz, 2H), 2.15-2.06 (m, 4H), 1.88 (d, 7= 11.0 Hz, 2H), 1.80 (d, 7 = 11.0 Hz, 2H ), 1.74 - 1.67 (m, 1H), 1.43 - 1.37 (m, 1H), 1.32 - 1.22 (m, 2H), 0.94 - 0.84 (m, 2H); MS (ESI): m / z 754.8 (M+H)+. Example 40: Compound 40 was obtained by reference to the synthesis of compound 33 from methyl trans-4-aminocyclohexanecarboxylate hydrochloride and compound INT-8.XH NMR (500 MHz, DMSO-rá) δ 7.91 (s, 1Η), 7.79 (d, 7 = 8.5 Hz, 1H), 7.67 (s, 1H), 7.56 - 7.51 (m, 3H), 7.50 - 7.45 (m, 6H) , 7.18 (d, 7 = 7.0 Hz, 1H), 6.78 (s, 1H), 5.76 (s, 2H), 3.95 (s, 2H), 3.88 - 3.80 (m, 2H), 3.69 - 3.65 (m, 1H ), 3.64 (s, 3H), 2.81 (s, 1H), 2.62 (d, J= 6.5 Hz, 2H), 2.18 - 2.09 (m, 4H), 2.04 (d, 7 = 11.0 Hz, 2H), 1.94 (d, J= 11.0 Hz, 2H), 1.75 - 1.67 (m, 1H), 1.37 - 1.22 (m, 4H); MS (ESI): m / z 740.7 (M+H)+. ινΐΛ / a / zuzz / uuou i o Example 41: Compound 41 was obtained by reference to the synthesis of compound 33 from methyl cis-4-aminocyclohexanecarboxylate hydrochloride and compound INT-8.JH NMR (500 MHz, DMSO-O6) δ 7.91 (s, 1H), 7.78 (d, 7= 8.5 Hz, 1H), 7.67 (s, 1H), 7.56 - 7.51 (m, 3H), 7.50 - 7.45 (m, 6H), 7.18 (d, 7= 7.0 Hz, 1H), 6.76 (s, 1H), 5.76 (s, 2H), 3.92 - 3.78 (m, 4H), 3.69 - 3.66 (m, 1H), 3.63 (s, 3H), 2.87 - 2.83 (m, 1H), 2.61 (d , 7= 6.0 Hz, 2H), 2.46 - 2.44 (m, 1H), 2.15 - 2.07 (m, 3H), 2.00 - 1.92 (m, 2H), 1.81 - 1.67 (m, 3H), 1.53 - 1.44 (m , 4H); MS (ESI): m / z 740.7 (M+H)+. Example 42: Starting from trans-4-hydroxy-L-proline methyl ester hydrochloride and the compound INT-8, with reference to the synthesis of compound 33, the compound 42 is obtained.JH NMR (500 MHz, DMSO-O6) δ 7.91 (s, 1H), 7.77 (d, 7= 8.5 Hz, 1H), 7.67 (s, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.43 (m, 7H), 7.17 (d, J= 7.0 Hz, 1H), 6.69 (d, J= 7.0 Hz, 1H), 5.74 (s, 2H), 4.21-4.15 (m, 1H), 3.87-3.82 (m, 1H), 3.80 - 3.76 (m, 2H) , 3.67 - 3.62 (m, 2H), 3.61 - 3.57 (m, 3H), 3.50 - 3.45 (m, 1H), 3.21 3.19 (m, 1H), 2.58 - 2.53 (m, 3H), 2.13 - 2.07 (m , 3H), 2.02 - 1.90 (m, 1H), 1.81 - 1.75 (m, 1H), 1.73 - 1.67 (m, 1H); MS (ESI): m / z 728.7 (M+H)+. Example 43: ινΐΛ / a / zuzz / uuou 1 or Starting from methyl L-proline hydrochloride and the compound INT-8, with reference to the synthesis of compound 33, compound 43 is obtained. 'H NMR (500 MHz, DMSO-o6) δ 7.91 (s, 1H), 7.78 (d, J= 8.5 Hz, 1H), 7.69 (s, 1H), 7.55 - 7.43 (m, 10H), 7.17 (d, J= 7.0 Hz, 1H), 6.70 (s, 1H), 5.75 (s, 2H), 3.93 (d, J= 14.0 Hz, 1H), 3.84 - 3.77 (m, 3H), 3.67 - 3.62 (m, 1H), 3.60 (s, 3H), 3.37 - 3.33 (m, 1H), 3.10 - 3.04 (m, 1H), 2.59 - 2.52 (m, 3H), 2.14 - 2.05 (m, 4H), 1.90 - 1.83 (m, 1H), 1.80 - 1.74 (m, 1H), 1.73 - 1.66 (m, 2H); MS (ESI): m / z 712.7 (M+H)+. Example 44: Starting from the compound INT-8 and methyl 4-aminomethylbenzoate hydrochloride, with reference to the synthesis of the compound INT-5, compound 44a is obtained. MS (ESI): m / z 862.7 (M+H)+. Starting from compound 44a, in reference to the reductive amination step in the synthesis of compound INT-lj, compound 44b is obtained. MS (ESI): m / z 876.8 (M+H)+. Starting from compound 44b, with reference to the last two steps in the synthesis of compound 33, the compound 44 is obtained. Hz, 2H), 7.77 (d, 7 = 8.5 Hz, 1H), 7.68 (s, 1H), 7.54 - 7.50 (m, 2H), 7.49 - 7.44 (m, 7H), 7.40 (d, 7 = 7.5 Hz , 2H), 7.17 (d, 7= 7.0 Hz, 1H), 6.68 (s, 1H), 5.74 (s, 2H), 3.81 - 3.73 (m, 2H), 3.66 3.62 (m, 1H), 3.59 - 3.53 (m, 2H), 3.57 (s, 3H), 3.45 (s, 2H), 2.56 - 2.53 (m, 2H), 2.14 - 2.07 (m, 6H), 1.72 - 1.66 (m, 1H); MS (ESI): m / z 762.7 (M+H)+. Example 45: HOOC Starting from the compound INT-8 and methyl p-aminophenylacetate, compound 45 was obtained by referring to the synthesis of compound 44.XH NMR (500 MHz, DMSO-06) δ 7.90 (s, 1H), 7.77 (d, J= 8.5 Hz, 1H), 7.68 (s, 1H), 7.54 - 7.50 (m, 2H), 7.49 - 7.43 (m, 6H), 7.17 (d, J = 7.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.92 (s, 1H), 6.75 (s, 1H), 6.55 (d, J = 8.0 Hz, 2H), 5.72 (s, 2H), 4.41 (s, 2H), 3.81 - 3.73 (m , 2H), 3.66 - 3.61 (m, 4H), 3.35 (s, 2H), 2.98 (s, 3H), 2.58 - 2.53 (m, 2H), 2.14 - 2.06 (m, 3H), 1.74 - 1.66 (m , 1 HOUR); MS (ESI): m / z 762.7 (M+H)+. Example 46: Starting from the compound INT-8 and methyl p-aminobenzoate, compound 46 was obtained by referring to the synthesis of compound 44.XH NMR (500 MHz, DMSO-06) δ 7.91 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.74 - 7.70 (m, 2H), 7.64 - 7.60 (m, 5H), 7.59 - 7.50 (m, 3H), 7.50 - 7.46 (m, 1H), 7.17 (d, J= 7.1 Hz , 1H), 6.87 (s, 1H), 6.85 - 6.81 (m, 1H), 6.68 - 6.63 (m, 2H), 5.72 (s, 2H), 4.53 (s, 2H), 4.25 (s, 2H), 3.91 - 3.85 (m, 1H), 3.68 (s, 3H), 3.09 (s, 3H), 2.57 - 2.53 (m, 2H), 2.23 - 2.14 (m, 3H), 1.83 - 1.77 (m, 1H); MS (ESI): m / z 748.7 (M+H)+. Example 47: From compound INT-8 and hemostatic methyl acid hydrochloride, compound 47 was obtained by referring to the synthesis of compound 44.XH NMR (500 MHz, DMSO-06) δ 7.89 (s, 1H), 7.75 (d , 7 = 8.5 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.40 (m, 8H), 7.36 (s, 1H), 7.15 (d, 7 = 7.0 Hz, 1H), 6.65 (s, 1H) , 5.71 (s, 2H), 3.78 - 3.71 (m, 2H), 3.64 - 3.60 (m, 1H), 3.55 (s, 3H), 3.35 - 3.31 (m, 2H), 2.53 - 2.51 (m, 2H) , 2.13 - 2.07 (m, 4H), 2.07 (s, 3H), 2.01 - 1.96 (m, 1H), 1.85 - 1.76 (m, 4H), 1.71 - 1.65 (m, 1H), 1.46 - 1.39 (m, 1H), 1.28 - 1.17 (m, 3H), 0.82 - 0.73 (m, 2H); MS (ESI): m / z 768.4 (M+H)+. ινΐΛ / a / zuzz / uuou 1 or Example 48: Starting from 4-bromo-2-methylbenzaldehyde, referred to the esterification of boron in the synthesis step of the compound INT-7a, the compound 48a.XH NMR (500 MHz, DMSO-o6) δ 10.26 (s, 1H) is obtained. , 7.79 (d, 7= 7.5 Hz, 1H), 7.66 (d, 7= 7.5 Hz, 1H), 7.60 (s, 1H), 2.61 (s, 3H), 1.29 (s, 12H). Starting from compound 48a and l,3-dibromo-2-chlorobenzene, compound 48b was obtained by reference to the synthesis of compound INT-3a. NMR (500 MHz, DMSO-06) δ 10.27 (s, 1H), 7.89 (d, 7= 7.9 Hz, 1H), 7.85 - 7.81 (m, 1H), 7.48 - 7.34 (m, 4H), 2.66 (s , 3H). Compound 48 was obtained from the synthesis of compound 48b, compound INT-2, compound INT-8c and compound INT-11 with reference to the synthesis of compound INT-3, compound INT-8 and compound 33. NMR 1H), 7.30 - 7.23 (m, 2H), 7.14 (d, 7= 7.0 Hz, 1H), 6.66 (s, 1H), 5.71 (s, 2H), 3.74 - 3.67 (m, 2H), 3.65 - 3.61 (m, 1H), 3.56 (s, 3H), 3.52 - 3.48 (m, 2H), 2.92 - 2.85 (m, 1H), 2.64 - 2.61 (m, 2H), 2.59 - 2.56 (m, 2H), 2.34 (s, 3H), 2.11 - 2.05 (m, 3H), 1.94 - 1.89 (m, 2H), 1.71 - 1.66 (m, 1H); MS (ESI): m / z 726.2 (M+H)+. Example 49: CL From 4-bromo-2-chlorobenzaldehyde, compound 49 was obtained by referring to the synthesis of compound 48. Ή NMR (500 MHz, DMSO-06) δ 7.94 (s, 1H), 7.77 (d, 7 = 8.5 Hz , 1H), 7.69 (s, 1H), 7.65 (d, 7 = 7.9 Hz, 1H), 7.59 (d, 7 = 1.8 Hz, 1H), 7.57 - 7.45 (m, 5H), 7.37 (s, 1H) , 7.17 (d, 7= 7.0 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 3.90 - 3.80 (m, 2H), 3.70 - 3.61 (m, 1H), 3.58 (s, 3H ), 3.56 - 3.49 (m, 2H), 2.96 - 2.86 (m, 1H), 2.69 - 2.63 (m, 2H), 2.61 - 2.56 (m, 2H), 2.53 - 2.50 (m, 2H), 2.17 - 2.06 (m, 3H), 1.97 - 1.90 (m, 2H), 1.75 - 1.66 (m, 1H); MS (ESI): m / z 746.6 (M+H)+. Example 50: From 4-bromo-3-chlorobenzaldehyde, compound 50 was obtained by reference to the synthesis of compound 48.XH NMR (500 MHz, DMSO-06) δ 7.80 (s, 1H), 7.76 (d, 7= 8.5 Hz, 1H), 7.66 (s, 1H), 7.57 - 7.47 (m, 4H), 7.39 - 7.38 (m, 3H), 7.34 (s, 1H), 7.16 (d, 7= 7.0 Hz, 1H), 6.66 (s, 1H), 5.71 (s, 2H), 3.80 - 3.72 (m, 2H), 3.63 - 3.60 (m, 1H), 3.56 (s, 3H), 3.53 - 3.47 (m, 2H), 2.90 - 2.83 (m, 1H), 2.65 - 2.59 (m, 2H), 2.55 - 2.51 (m, 2H), 2.47 - 2.45 (m, 2H), 2.14 - 2.03 (m, 3H), 1.95 - 1.87 (m, 2H) , 1.72 - 1.63 (m, 1H); MS (ESI): m / z 746.5 (M+H)+. Example 51: From 4-bromo-2-(trifluoromethoxy)benzaldehyde, compound 51 was obtained by referring to the synthesis of the compound 48.4Η NMR (500 MHz, DMSO-o6) δ 7.96 (s, 1H), 7.82 - 7.73 (m , 2H), 7.69 (s, 1H), 7.61 - 7.50 (m, 5H), 7.51 - 7.48 (m, 1H), 7.38 (s, 1H), 7.19 (d, J = 7.0 Hz, 1H), 6.69 ( s, 1H), 5.75 (s, 2H), 3.88-3.80 (m, 2H), 3.65 (t, J= 6.5 Hz, 1H), 3.59 (s, 3H), 3.57 3.49 (m, 2H), 2.85 - 2.75 (m, 1H), 2.70 - 2.60 (m, 2H), 2.60 - 2.55 (m, 2H), 2.56 - 2.53 (m, 1H), 2.50 - 2.43 (m, 1H), 2.18 - 2.08 (m, 3H) ), 1.98 - 1.85 (m, 2H), 1.77 - 1.67 (m, 1H); MS (ESI): m / z 796.7 (M+H)+. Example 52: iviA / a / zuzz / uuou 1 or From compound INT-9 and compound INT-11, compound 52 was obtained by referring to the synthesis of compound 33.XH NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.68 (s, 1H), 7.57 - 7.47 (m, 4H), 7.42 (d, J= 7.7 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.09 (d, J= 1.7 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.75 - 3.72 (m, 2H), 3.66 - 3.62 (m, 1H), 3.59 (s, 3H), 3.55 - 3.50 (m, 2H), 2.95 - 2.87 (m, 1H), 2.70 - 2.62 (m, 2H), 2.60 - 2.54 (m, 2H), 2.53 - 2.51 (m, 2H), 2.17 - 2.04 (m, 3H), 1.97 - 1.90 (m, 2H), 1.75 - 1.65 (m, 1H); MS (ESI): m / z 742.2 (M+H)+. Example 53: Starting from the compound INT-9 and tert-butyl ester of O-tert-butyl-L-serine, with reference to the synthesis of compound 22, the compound 53.XH NMR (500 MHz, DMSO-06) δ 7.92 ( s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.55 - 7.48 (m, 5H), 7.42 (d, J= 7.7 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.10 (s, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.73 (s, 1H), 5.74 (s, 2H), 3.88 (d, J = 14.6 Hz, 1H ), 3.84 (s, 3H), 3.81 - 3.74 (m, 3H), 3.68 - 3.63 (m, 2H), 3.61 (s, 3H), 3.60 - 3.57 (m, 1H), 3.14 (t, J = 5.4 Hz, 1H), 2.62 - 2.57 (m, 2H), 2.18 - 2.04 (m, 3H), 1.76 - 1.66 (m, 1H); MS (ESI): m / z 732.6 (M+H)+. Example 54: From compound INT-9 and hemostatic methyl acid hydrochloride, compound 54 was obtained by referring to the synthesis of compound 33. NMR (500 MHz, DMSO-o6) δ 7.91 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.57 - 7.45 (m, 5H), 7.45 - 7.39 (m, 2H), 7.17 (d, 7 = 7.0 Hz, 1H), 7.09 (d, 7 = 1.6 Hz, 1H), 7.06 (d, 7= 7.2 Hz, 1H), 6.70 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.75 - 3.73 (m, 2H), 3.66 - 3.62 (m, 3H), 3.60 (s, 3H), 2.59 - 2.54 (m, 2H), 2.37 - 2.33 (m, 2H), 2.18 - 2.05 (m, 4H), 1.90 - 1.84 (m, 2H), 1.82 - 1.76 (m, 2H), 1.72 - 1.68 (m, 1H), 1.42 - 1.32 (m, 1H), 1.32 - 1.20 (m, 3H), 0.95 - 0.82 (m, 2H); MS (ESI): m / z 784.7 (M+H)+. Example 55: From compound INT-9 and methylhestatic acid hydrochloride, compound 55 was obtained by referring to the synthesis of compound 44. Ή NMR (500 MHz, DMSO-P6) δ 7.92 (s, 1H), 1J1 (d, 7 = 8.6 Hz, 1H), 7.67 (s, 1H), 7.56 - 7.46 (m, 4H), 7.42 (d, 7= U Hz, 1H), 7.38 (s, 1H), 7.17 (d, 7 = 7.0 Hz, 1H), 7.09 (d, 7= 1.6 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.79 - 3.71 (m, 2H), 3.66 - 3.62 (m, 1H), 3.58 (s, 3H), 3.36 (s, 2H), 2.58 - 2.56 (m, 2H), 2.15 - 2.06 (m, 9H), 1.89 - 1.80 (m, 4H), 1.74 - 1.66 (m, 1H), 1.51 - 1.42 (m, 1H), 1.33 - 1.23 (m, 2H), 0.88 0.76 (m, 2H); MS (ESI): m / z 798.7 (M+H)+. Example 56: Compound 56 was obtained from the synthesis of compound 33 from methyl trans-4-aminocyclohexanecarboxylate hydrochloride and compound INT-9.1H NMR (500 MHz, DMSO-O6) δ 7.89 (s, 1H), 7.74 (d, J= 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.43 (m, 4H), 7.42 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.05-7.01 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75-3.68 (m,2H), 3.65-3.59 (m, 3H), 3.58 (s, 3H), 2.56 2.52 (m, 2H), 2.32 - 2.24 (m, 1H), 2.14 - 2.03 (m, 4H) , 1.92 - 1.80 (m, 4H), 1.72 - 1.63 (m, 1H), 130 - 1.18 (m, 2H), 1.05 -0.95 (m, 2H); MS (ESI): m / z 770.7 (M+H)+. Example 57: ινΐΛ / a / zuzz / uuou 1 or Compound 57 was obtained from the synthesis of compound 44 from methyl trans-4-aminocyclohexanecarboxylate hydrochloride and compound INT-9.XH NMR (500 MHz, DMSO-O6) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.55 - 7.43 (m, 4H), 7.39 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.15 (d , J = 7.0 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H) , 3.75 - 3.67 (m, 2H), 3.64 - 3.59 (m, 1H), 3.57 (s, 3H), 3.44 (s, 2H), 2.56 - 2.52 (m, 2H), 2.39 - 2.31 (m, 1H) , 2.14 - 2.10 (m, 7H), 1.95 - 1.86 (m, 2H), 1.81 1.74 (m, 2H), 1.71 - 1.65 (m, 1H), 1.31 - 1.23 (m, 4H); MS (ESI): m / z 784.8 (M+H)+. Example 58: From compound INT-9 and compound INT-2, compound 58 was obtained by referring to the synthesis of compound 22.XH NMR (500 MHz, DMSO-o6) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.63 (s, 1H), 7.53 - 7.44 (m, 4H), 7.41 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.06 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H ), 3.76 - 3.68 (m, 2H), 3.66 - 3.59 (m, 4H), 3.58 (s, 3H), 2.56 - 2.52 (m, 2H), 2.47 - 2.42 (m, 2H), 2.14 - 2.03 (m , 6H), 1.70 - 1.60 (m, 2H); MS (ESI): m / z 741.8 (M+H)+. Example 59: COOH COOME OCH3INT-9 OCH359 Compound 59 was obtained from the synthesis of cis-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride and compound INT-9 with reference to compound 33. *H NMR (500 MHz, DMSO-06) δ 7.89 (s, 1H), 7.74 (d, J= 8.5 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.45 (m, 4H), 7.43 (s, 1H), 7.39 (d, J= 7.5 Hz, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 6.67 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H), 3.62 - 3.60 (m, 3H), 3.58 (s, 3H), 2.55 - 2.52 (m, 3H), 2.31 - 2.25 (m, 1H), 2.13 - 2.04 (m, 3H), 1.87 - 1.79 (m, 2H), 1.72 - 1.63 (m, 1H), 1.57 - 1.48 (m, 2H), 1.46 - 1.37 (m, 4H); MS (ESI): m / z 770.7 (M+H)+. Example 60: COOME OCH3INT-9 OCH360 From cis-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride and compound INT-9, compound 60 was obtained by referring to the synthesis of compound 44.XH NMR (500 MHz, DMSO-C6) δ 7.89 (s, 1H), 7.75 (d, J= 8.5 Hz, 1H), 7.66 (s, 1H), 7.53 - 7.44 (m, 4H), 7.40 (d, J= 7.5 Hz, 1H), 7.35 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.09 - 7.06 (m, 1H), 7.05 7.01 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H), 3.64 - 3.60 (m, 1H), 3.56 (s, 2H), 3.42 - 3.35 (m, 3H), 2.57 - 2.52 (m, 2H), 2.45 - 2.40 (m, 1H) ), 2.38 - 2.31 (m, 1H), 2.14 2.07 (m, 3H), 2.06 (s, 3H), 2.01 - 1.93 (m, 2H), 1.72 - 1.63 (m, 1H), 1.60 - 1.52 (m, 2H), 1.50 - 1.37 (m, 4H); MS (ESI): m / z 784.7 (M+H)+. Example 61: CHO INT-12 INT-11 ινΐΛ / a / zuzz / uuou 1 or Starting from compound INT-11 and compound INT-12, with reference to the synthesis of compound 33, compound 61 is obtained. NMR (500 MHz, DMSO-o6) δ 7.88 (s,lH), 7.75 (d, 7 = 8.5 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.48 - 7.43 (m, 4H), 7.41 - 7.36 (m, 2H), 7.35 (s,lH), 7.15 (d, 7 = 7.0 Hz, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 4.21 - 4.16 (m, 1H), 3.70 - 3.45 (m, 4H), 3.56 (s, 3H), 2.92 - 2.85 (m, 1H) , 2.72 - 2.66 (m, 1H), 2.64 - 2.57 (m, 3H), 2.45 - 2.40 (m, 3H), 2.36 - 2.32 (m, 1H), 2.02 - 1.96 (m, 1H), 1.95 - 1.88 ( m, 2H), 1.58 - 1.52 (m, 1H); MS (ESI): m / z 685.8 (M+H)+. Example 62: INT-12 CHO Starting from compound INT-12 and compound 35a, with reference to the synthesis of compound 33, compound 62 is obtained. NMR (500 MHz, DMSO-06) δ 7.90 (s, 1H), 7.77 (d, 7 = 8.5 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.45 (m, 4H), 7.42 - 7.37 (m, 3H), 7.17 (d, 7= 7.0 Hz, 1H), 6.67 (s, 1H) , 5.73 (s, 2H), 4.24 - 4.19 (m, 1H), 3.66 - 3.58 (m, 2H), 3.57 (s, 3H), 3.41 (s, 2H), 2.80 - 2.72 (m, 1H), 2.73 - 2.67 (m, 1H), 2.64 - 2.55 (m, 2H), 2.46 - 2.43 (m, 1H), 2.42 - 2.38 (m, 1H), 2.37 - 2.34 (m, 1H), 2.22 - 2.12 (m, 1H), 2.08 - 1.98 (m, 2H), 1.80 - 1.71 (m, 1H), 1.65 - 1.53 (m, 2H), 1.50 - 1.42 (m, 1H), 1.40 - 1.31 (m, 1H); MS (ESI): m / z 699.7 (M+H)+. Example 63: Starting from the compound INT-12 and hemostatic methyl ester hydrochloride, referring to the synthesis of compound 33, the compound 63.XH NMR (500 MHz, DMSO-06) δ 7.89 (s, 1Η), 7.76 (d, 7 = 8.5 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.45 (m, 4H), 7.42 - 7.38 (m, 3H), 7.17 (d, 7= 7.0 Hz , 1H), 6.67 (s, 1H), 5.73 (s, 2H), 4.24-4.18 (m, 1H), 3.64 (d, 7= 13.0 Hz, 1H), 3.60-3.56 (m, 6H), 2.73 - 2.67 (m, 1H), 2.64 - 2.60 (m, 1H), 2.46 - 2.42 (m, 1H), 2.37 - 2.34 (m, 1H), 2.31 (d, 7= 6.5 Hz, 2H), 2.12 - 2.06 ( m, 1H), 2.04 - 1.98 (m, 1H), 1.89 - 1.84 (m, 2H), 1.82 - 1.77 (m, 2H), 1.59 - 1.52 (m, 1H), 1.39 - 1.32 (m, 1H), 1.31 - 1.21 (m, 2H), 0.93 - 0.83 (m, 2H); MS (ESI): m / z 727.5 (M+H)+. Example 64: From (S)-3-hydroxypyrrolidine hydrochloride and compound INT-3a, compound 64a was obtained with reference to the synthesis of compound INT-5 and compound INT-8. MS (ESI): m / z 586.4 (M+H)+. Starting from compound 64a and compound INT-11, with reference to the synthesis of compound 33, compound 64.XH NMR (500 MHz, DMSO-rá) δ 7.88 (s, 1H), 7.75 (d, 7 = 8.5 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.47 - 7.42 (m, 4H), 7.39 (s, 1H), 7.37 (d, 7= 8.0 Hz, 1H), 7.35 (s, 1H), 7.15 (d, J= 7.0 Hz, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 4.22 - 4.15 (m, 1H), 3.64 - 3.57 (m, 2H), 3.56 (s, 3H) , 3.52 - 3.45 (m, 2H), 2.90 - 2.82 (m, 1H), 2.70 - 2.56 (m, 4H), 2.45 - 2.38 (m, 3H), 2.35 - 2.30 (m, 1H), 2.02 - 1.95 ( m, 1H), 1.94 - 1.86 (m, 2H), 1.62 - 1.50 (m, 1H); MS (ESI): m / z 685.5 (M+H)+. Example 65: Compound 65 was obtained from the synthesis of compound 64 from 3-hydroxyazetidine hydrochloride.1H NMR (500 MHz, DMSO-o6) δ 7.90 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H ), 7.54 - 7.50 (m, 2H), 7.49 - 7.44 (m, 4H), 7.38 - 7.33 (m, 3H), 7.17 (d, J = 7.0 Hz, 1H), 6.67 (s, 1H), 5.73 ( s, 2H), 5.34 - 5.26 (m, 1H), 4.23 - 4.19 (m, 1H), 3.61 (s, 2H), 3.58 (s, 3H), 3.56 - 3.46 (m, 6H), 2.94 - 2.88 ( m, 1H), 2.82 - 2.78 (m, 2H), 2.67 - 2.64 (m, 2H), 1.97 - 1.91 (m, 2H); MS (ESI): m / z 671.6 (M+H)+. Example 66: Starting from N-acetylethylenediamine and the compound INT-3a, compound 66a was obtained by reference to the synthesis of the compound INT-3. MS (ESI): m / z 481.2 (M+H)+. Starting from compound 66a, compound INT-8c and compound INT-11, referring to the synthesis of compound INT-8 and compound 33, compound 66 is obtained.XH NMR (500 MHz, DMSO-o6) δ 7.89 (s, 1H), 7.82 - 7.77 (m, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.47 - 7.40 (m, 6H), 7.35 (s, 1H) ), 7.15 (d, J = 7.0 Hz, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 3.73 (s, 2H), 3.56 (s, 3H), 3.52 - 3.47 (m, 2H) , 3.16 - 3.12 (m, 2H), 2.93 - 2.84 (m, 1H), 2.67 - 2.61 (m, 2H), 2.57 (t, J = 6.5 Hz, 2H), 2.45 - 2.42 (m, 2H), 1.96 - 1.87 (m, 2H), 1.77 (s, 3H); MS (ESI): m / z 700.2 (M+H)+. From (R)-5-hydroxymethyl-2-pyrrolidone and compound INT-3a, compound 67a was obtained by referring to the synthesis of compound INT-2 and compound INT-3. MS (ESI): m / z 493.2 (M+H)+. Compound 67 was obtained from the synthesis of compound 67a, the compound INT-8c and compound INT-11 with reference to the synthesis of compound INT-8 and compound 33.1H NMR (500 MHz, DMSO-oG) δ 7.88 (s, 1H), 7.74 (d, J= 8.5 Hz, 1H), 7.65 (s, 1H), 7.53 - 7.48 (m, 2H), 7.47 - 7.39 (m, 6H), 7.35 (s, 1H), 7.15 (d, J= 7.0 Hz, 1H), 6.65 (s , 1H), 5.71 (s, 2H), 3.77 - 3.71 (m, 2H), 3.64 - 3.59 (m, 1H), 3.56 (s, 3H), 3.52 - 3.48 (m, 2H), 2.91 - 2.83 (m , 1H), 2.66 - 2.60 (m, 2H), 2.55 - 2.51 (m, 2H), 2.47 - 2.45 (m, 2H), 2.15 - 2.04 (m, 3H), 1.95 - 1.88 (m, 2H), 1.72 - 1.64 (m, 1H); MS (ESI): m / z 712.6 (M+H)+. Example 68: ^NHBoc ^NHBoc HCI / dioxane ^9H c|----„H?NDCM 6' H DCM o ñ -------68a68b COOH ινΐΛ / a / zuzz / uuou 1 or N-tert-butoxycarbonyl-1,2-ethylenediamine (99 mg, 0.62 mmol) in dichloromethane (3 ml) was added sequentially with methanesulfonic anhydride (135 mg, 0.77 mmol) under ice bath conditions) and triethylamine (102 mg, 1.01 mmol).); The reaction solution was stirred under the same conditions for one hour. Saturated sodium bicarbonate solution (20 ml) was added to the reaction solution, followed by extraction with ethyl acetate (20 ml x 2). The combined organic phases were washed with saturated brine (30 ml) and dried over anhydrous sodium sulfate, the filtrate was concentrated to obtain a white solid 68a (160 mg, yield: 86.6%). To a solution of compound 68a (160 mg, 0.67 mmol) in dichloromethane (2 mL) was added hydrochloric acid (4 M solution in 1,4-dioxane, 1.7 mL); The reaction solution was stirred at 20°C for 16 hours. The reaction solution was concentrated to obtain yellow oil 68b (90 mg, yield: 76.8%).^ NMR (500 MHz, DMSO-o6) δ 8.14 (s, 3H), 7.36 (t, J = 6.0 Hz , 1H), 3.27 - 3.16 (m, 2H), 2.94 (s, 3H), 2.92 - 2.84 (m, 2H). From compound 68b, compound 68 was obtained by referring to the synthesis of compound 64. Ή NMR (500 MHz, DMSO-cG) δ 7.89 (s, 1H), 7.75 (d, J= 8.5 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.47 - 7.43 (m, 4H), 7.43 - 7.40 (m, 2H), 7.35 (s, 1H), 7.15 (d, J= 7.0 Hz, 1H), 6.94 (s, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 3.74 (s, 2H), 3.56 (s, 3H), 3.54 - 3.52 (m, 2H), 3.05 (t, J= 6.5 Hz, 2H ), 2.92 - 2.89 (m, 1H), 2.88 (s, 3H), 2.67 - 2.60 (m, 4H), 2.47 - 2.45 (m, 2H), 1.95 - 1.87 (m, 2H); MS (ESI): m / z 736.9 (M+H)+. Example 69: OH 69a Compound 69a was obtained from the synthesis of compound INT-11, compound INT-3a and compound INT-8c with reference to the synthesis of compound INT-5 and compound INT-8. MS (ESI): m / z 628.5 (M+H)+. From compound 69a and (R)-3-hydroxypyrrolidine hydrochloride, compound 69 was obtained by referring to the synthesis of compound 33.XH NMR (500 MHz, DMSO-06) δ 7.90 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.50 - 7.45 (m, 4H), 7.40 (d, 7 = 8.0 Hz, 2H), 7.37 (s, 1H), 7.17 ( d,7= 7.0 Hz, 1H), 6.67 (s, 1H), 5.73 (s, 2H), 4.20-4.15 (m, 1H), 3.66-3.59 10 (m, 2H), 3.58 (s, 3H), 3.53 (d, 7= 14.5 Hz, 1H), 3.48 (d, 7= 14.5 Hz, 1H), 2.96-2.91 (m, 1H), 2.74 (t, 7= 8.5 Hz, 1H), 2.66 - 2.62 (m , 2H), 2.61 - 2.58 (m, 1H), 2.42 - 2.32 (m, 4H), 2.01 - 1.94 (m, 3H), 1.56 - 1.49 (m, 1H); MS (ESI): m / z 685.3 (M+H)+. Example 70: From compound INT-11, 4-bromo-2-methoxybenzaldehyde and compound INT8c, and with reference to the synthesis of compound INT-5 and compound INT-8, compound 70a was obtained. MS (ESI): m / z 658.4 (M+H)+. From compound 70a and compound INT-2, compound 70 was obtained by referring to the synthesis of compound 33. NMR (500 MHz, DMSO-o6) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.53 - 7.44 (m, 4H), 7.41 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.0 Hz, 1H ), 7.09 - 7.07 (m, 1H), 7.06 - 7.02 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.80 (s, 3H), 3.62 - 3.59 (m, 4H), 3.58 - 3.56 (m, 4H), 2.95 - 2.89 (m, 1H), 2J1 - 2.71 (m, 1H), 2.70 - 2.65 (m, 1H), 2.58 - 2.52 (m, 2H), 2.47 - 2.43 (m , 2H), 2.11 - 2.02 (m, 3H), 1.98 - 1.92 (m, 2H), 1.67 - 1.60 (m, 1H); MS (ESI): m / z 742.7 (M+H)+. Example 71: From compound 70a and (R)-3-hydroxypyrrolidine hydrochloride, compound 71 was obtained by referring to the synthesis of compound 33.XH NMR (500 MHz, DMSO-06) δ 7.90 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.52 - 7.44 (m, 4H), 7.36 (d, J = 7.5Hz, 1H), 7.35 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.09 - 7.07 (m, 1H), 7.06 - 7.02 (m, 1H), 6.66 (s, 1H), 5.71 (s, 2H), 4.18 - 4.11 (m, 1H), 3.80 (s, 3H), 3.61 - 3.59 (m, 2H), 3.56 (s, 3H), 3.53 - 3.46 (m, 2H), 2.95 - 2.87 (m, 1H), 2.78 - 2.71 (m, 1H), 2.69 - 2.64 ( m, 1H), 2.64 - 2.53 (m, 4H), 2.41 - 2.35 (m, 1H), 2.34 - 2.29 (m, 1H), 1.99 1.92 (m, 3H), 1.55 - 1.48 (m, 1H); MS (ESI): m / z 715.8 (M+H)+. Dissolved potassium carbonate (231 mg, 1.67 mmol) was added to acetonitrile solution (6 ml) with methyl 4-(bromomethyl)-3-chlorobenzoate (200 mg, 0.76 mmol) and 4-bromoindazole (150 mg, 0.76 mmol). ). The reaction solution was kept at 65°C and stirred for 10 hours. The reaction solution was cooled to room temperature. Then, the filtrate was concentrated and the residue thus obtained was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 100 / 0 - 100 / 30) to obtain a white solid 72a (150 mg, yield: 52.1%). MS (ESI): m / z 379.2 (M+H)+. At -65°C, in a solution of dichloromethane (10 ml) with compound 72a (150 mg, 0.40 mmol), dissolved diisobutylaluminum hydride (1.5 M toluene solution, 0.79 ml) was slowly added dropwise. The resulting reaction solution was stirred for half an hour at the same temperature. Then, the reaction solution was quenched with methanol (2 mL), raised to room temperature, and stirred rigorously for 2 h after adding sodium potassium tartrate (10% w / w aqueous solution, 10 mL). Dichloromethane (20 ml) was added to the mixture thus obtained. The organic phase was further washed with saturated saline solution (30 ml), dried with anhydrous sodium sulfate. The filtrate was concentrated to obtain the colorless oily matter 72b (130 mg, yield: 93.6%). MS (ESI): m / z 351.1 (M+H)+. In a solution of dichloromethane (6 ml) with compound 72b (130 mg, 0.37 mmol) dissolved Dess-Martin oxidant (157 mg, 0.37 mmol) was added. The reaction solution was stirred for 1 hour at 25°C. Saturated sodium bicarbonate solution (20 ml) and dichloromethane (20 ml) were added to the reaction solution, the organic phase thus obtained was further washed with saturated salt solution (30 ml), dried with anhydrous sodium sulfate. The filtrate was concentrated and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 100 / 0 - 100 / 30) to obtain a colorless oily matter 72c (120 mg, yield : 92.8%). MS (ESI): m / z 349.1 (M+H)+. Starting from compound 72c, O-isopropyl-L-serine tert-butyl ester, and compound INT-3, with reference to the synthesis of compound INT-1 and compound 1, compound 72.XH NMR (500 MHz) is obtained. , DMSO-o6) δ 7.91 (s, 1H), 7.75 (d, J= 8.5 Hz, 1H), 7.69 (s, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.52 - 7.44 (m, 8H), 7.29 - 7.25 (m, 1H), 7.18 (d, J= 7.0 Hz, 1H), 6.92 (d, J= 8.0 Hz, 1H), 5.77 (s, 2H), 3.90 (d, J = 14.0 Hz, 1H), 3.81 - 3.76 (m, 3H), 3.65 - 3.63 (m, 1H), 3.62 - 3.56 (m, 2H), 3.09 (t, 7= 5.5 Hz, 1H), 2.57 - 2.54 (m, 2H), 2.13 - 2.07 (m, 3H), 1.74 - 1.67 (m, 1H); MS (ESI): m / z 672.5 (M+H)+. Example 73: To a solution of tetrachloromethane (8 ml) with methyl 2-methoxy-4-methylbenzoate (250 mg, 1.39 mmol) and N-bromosuccinimide (296 mg, 1.66 mmol), azobis(isobutyronyl) was added. ) dissolved (9.4 mg, 0.17 mmol). The reaction solution at 80°C was stirred for 16 hours. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 100 / 0 - 100 / 25) to obtain white solid 73a (204 mg, performance: 34.0%). From compound 73a, 4-bromoindazole, O-isopropyl-L-serine tert-butyl ester and compound INT-3, with reference to the synthesis of compound INT-1 and compound 1, compound 73 is obtained. ^ NMR (500 MHz, DMSO-o6) δ 8.18 - 8.16 (m, 2H), 7.87 (s, 1H), 7.77 (d, J= 8.6 Hz, 1H), 7.66 (s, 1H), 7.52 - 7.49 ( m, 1H), 7.48 - 7.25 (m, 5H), 7.13 (d, J= 7.0 Hz, 1H), 7.04 (s, 1H), 6.77 (d, J = 7.6 Hz, 1H), 5.68 (s, 2H ), 3.96-3.92 (m, 1H), 3.78 (d, J= 7.1 Hz, 2H), 3.75 (s, 3H), 3.69 - 3.61 (m, 2H), 3.60 - 3.51 (m, 2H), 3.14- 3.08 (m, 1H), 2.56 (d, J= 6.4 Hz, 2H), 2.12 - 2.06 (m, 3H), 1.73 - 1.65 (m, 1H); MS (ESI): m / z 668.7 (M+H)+. ινΐΛ / a / zuzz / uuou 1 or Example 74: OH Dissolved thionyl chloride (1.67 g, 14.1 mmol) was added to dichloromethane solution (10 ml) with methyl 6-hydroxymethyl nicotinate (470 mg, 2.81 mmol). The reaction solution was stirred for 3 hours at 25°C. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 100 - 40 / 100) to obtain white solid 74a (420 mg, yield: 80.5% ).MS (ESI): m / z 186.0 (M+H)+. Starting from compound 74a, with reference to the synthesis of compound 73, compound 74 is obtained. Ή NMR (500 MHz, DMSO-06) δ 8.49 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.77 - 7.69 (m, 2H), 7.67 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.48 - 7.44 (m, 6H), 7.15 (d, J = 7.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 5.77 (s, 2H), 3.91 (d, J = 13.5 Hz, 1H), 3.82 - 3.73 (m, 3H), 3.66 - 3.60 ( m, 1H), 3.60 - 3.53 (m, 2H), 3.09 (t, J = 5.5 Hz, 1H), 2.55 (d, J = 6.0 Hz, 2H), 2.16 2.03 (m, 3H), 1.78 - 1.61 ( m, 1H); MS (ESI): m / z 639.5 (M+H)+. Example 75: iviA / a / zuzz / uuou 1 or ΙΝΤ-13 Dissolved cuprous cyanide (322 mg, 3.59 mmol) was added to Ν,Ν-dimethylformamide solution (5 ml) with the compound INT-13 (550 mg, 1.80 mmol). The reaction solution was stirred for 16 hours at 120°C and nitrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 100 / 0 - 100 / 30) to obtain a white solid. 75a (210 mg, yield: 57.0%). Starting from compound 75a, referring to the synthesis of compound 73, the compound 75 is obtained. , 1H), 7.54 - 7.50 (m, 2H), 7.50 - 7.42 (m, 6H), 7.18 (d, J = 6.9 Hz, 1H), 6.92 (s, 1H), 5.82 (s, 2H), 3.85 ( d, J = 14.9 Hz, 1H), 3.80 - 3.73 (m, 3H), 3.71 (s, 3H), 3.64-3.60 (m, 2H), 3.60 - 3.54 (m, 1H), 3.15-3.11 (m, 1H), 2.55 - 2.54 (m, 2H), 2.13 - 2.06 (m, 3H), 1.71 - 1.67 (m, 1H); MS (ESI): m / z 693.2 (M+H)+. Example 76: Under ice bath conditions, a solution of concentrated sulfuric acid (0.5 mL) with potassium nitrate (56.1) was added dropwise to concentrated sulfuric acid (2 mL) with the compound INT-13b (100 mg, 0.55 mmol) dissolved. mg, 0.55 mmol) predissolved. Then, the reaction solution under the same conditions was stirred for half an hour. Ice water was added to the reaction solution, thus the precipitated solid was washed with ice water and dried to obtain the white solid 76a (115 mg, yield: 92.0%).XH NMR (500 MHz, DMSO-06) δ 8.39 (s, 1H), 7.29 (s, 1H), 3.95 (s, 3H), 3.82 (s, 3H), 2.64 (s, 3H). Starting from compound 76a, with reference to the synthesis of compound 73, the compound 76.4H NMR (500 MHz, DMSO-06) δ 8.29 (s, 1H), 7.96 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.53 (d, J= 7.5 Hz, 1H), 7.51-7.49 (m, 3H), 7.47 - 7.43 (m, 4H), 7.19 (d, J = 7.0 Hz, 1H), 6.13 (s, 1H), 6.11 (s, 1H), 3.87 (d, J = 15.4 Hz, 1H), 3.81 - 3.72 (m, 3H), 3.67 - 3.57 (m, 3H), 3.51 (s, 3H), 3.15 - 3.12 (m, 1H), 2.56 - 2.52 (m, 2H), 2.14 - 2.08 (m, 3H), 1.72 - 1.66 (m, 1H); MS (ESI): m / z 713.8 (M+H)+. Example 77: EITHER INT-13b NCS conc. H2SO4 OH Dissolved N-chlorosuccinimide (467 mg, 3.50 mmol) was added to concentrated sulfuric acid (3 ml) with the compound INT-13b (300 mg, 1.66 mmol). The reaction solution at 25°C was stirred for 2 hours. Ice water (25 mL) and ethyl acetate (25 mL) were added to the reaction solution. The organic phase was further washed with saturated sodium bicarbonate solution (30 mL) and saturated salt solution (30 mL) and dried with anhydrous sodium sulfate. The filtrate was concentrated to obtain a yellow solid 77a (360 mg, yield: 86.8%).XH NMR (500 MHz, DMSO-06) δ 7.74 (s, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 2.45 (s, 3H); MS (ESI): m / z 249.7 (M+H)+. Starting from compound 77a, with reference to the synthesis of compound 73, compound 77 is obtained. 7.67 (s, 1H), 7.65 (s, 1H), 7.56 - 7.50 (m, 2H), 7.48 - 7.43 (m, 6H), 7.17 (d, 7= 7.0 Hz, 1H), 5.81 (s, 2H) , 3.95 (d, 7= 14.5 Hz, 1H), 3.82-3.79 (m, 3H), 3.77 (s, 3H), 3.66 - 3.59 (m, 3H), 3.20 (t, 7= 5.1 Hz, 1H), 2.57 - 2.58 (m, 2H), 2.13 - 2.07 (m, 3H), 1.74-1.66 (m, 1H); MS (ESI): m / z 736.7 (M+H)+. Example 78: Under ice bath conditions, dissolved N-iodosuccinimide (731 mg, 3.25 mmol) was added to concentrated sulfuric acid (2 ml) with methyl 3-chloro-4methylbenzoate (500 mg, 2.71 mmol). The reaction solution was stirred for 2 hours at 25°C. Add ice water (50 ml) and ethyl acetate (50 ml) to the reaction solution. The organic phase was further washed with saturated sodium bicarbonate solution (50 mL) and saturated salt solution (50 mL) and dried with anhydrous sodium sulfate. The filtrate was concentrated and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 - 100 / 15) to obtain a white solid 78a (820 mg, yield: 97.5%). In a nitrogen atmosphere and 100°C, in methanol solution (5 mL) with compound 78a (1.00 g, 3.22 mmol), cuprous iodide (61.3 mg, 0.32 mmol), 1,10-phenanthroline (116 mg, 0.64 mmol) and cesium carbonate (2.10 g, 6.44 mmol) mixed were stirred for 24 hours. The reaction solution was filtered and the filtrate was concentrated. The residue was dissolved with methanol (5 ml) and thionyl chloride (1.4 ml) was added. The reaction solution thus obtained was stirred for 2 hours at 60°C. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution. The organic phase was further washed with saturated sodium bicarbonate solution (50 mL) and saturated salt solution (50 mL), dried with anhydrous sodium sulfate. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 100 / 0 - 100 / 5) to obtain a white solid 78b (480 mg, yield: 69.4%).* H NMR (500 MHz, Chloroform-o) δ 7.67 (d, J- 1.6 Hz, 1H), 7.39 (d, J = 1.6 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 2.31 (s, 3H). Starting from compound 78b, referring to the synthesis of compound 73, compound 78 is obtained.^ NMR (500 MHz, DMSO-o6) δ 8.22 (s, 1H), 7.77 (d, J= 8.5 Hz, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.52 - 7.48 (m, 2H), 7.46 - 7.43 (m, 5H), 7.14 - 7.11 (m, 3H), 5.67 (s, 2H), 3.94 ( d, J = 14.2 Hz, 1H), 3.81 - 3.78 (m, 2H), 3.77 (s, 3H), 3.65 - 3.61 (m, 4H), 3.15 - 3.09 (m, 1H), 2.57 - 2.55 (d, 7 = 6.0 Hz, 2H), 2.13 - 2.07 (m, 3H), 1.73 - 1.66 (m, 1H); MS (ESI): m / z 702.7 (M+H)+. Example 79: iviA / a / zuzz / uuou 1 or Starting from compound 78a, with reference to the synthesis of compound 75a, compound 79a is obtained. Starting from compound 79a, with reference to the synthesis of compound 73, compound 79 is obtained. 7.90 - 7.85 (m, 2H), 7.83 (s, 1H), 7.67 (s, 1H), 7.58 - 7.54 (m, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.48 - 7.42 (m, 5H), 7.18 (d, J = 7.1 Hz, 1H), 5.82 (s, 2H), 3.95 (d, 7 = 14.8 Hz, 1H), 3.81 - 3.74 (m, 3H), 3.653.62 (m, 1H ), 3.61 - 3.56 (m, 2H), 3.12 (t, 7- 5.3 Hz, 1H), 2.56 (d, 7= 6.1 Hz, 2H), 2.13 - 2.07 (m, 3H), 1.72 - 1.66 (m, 1 HOUR); MS (ESI): m / z 697.5 (M+H)+. 100 Example 80: In chloroform solution (35 ml) with 2-hydroxy-6-methylnicotinic acid (1.00 g, 6.53 mmol), dissolved iodomethane (3.24 g, 22.9 mmol) and silver carbonate (1.81 g, 6.55 mmol) were added. . The reaction solution at 65°C was stirred for 16 hours. The reaction solution was filtered and the filtrate was concentrated to obtain colorless oily matter 80a (390 mg, yield: 33.0%). 6.77 (d, J= 7.7 Hz, 1H), 4.03 (s, 3H), 3.87 (s, 3H), 2.48 (s, 3H); MS (ESI): m / z 182.0 (M+H)+. Dissolved N-chlorosuccinimide (321 mg, 2.40 mmol) was added to acetonitrile solution (10 ml) with compound 80a (363 mg, 2.00 mmol). The reaction solution at 70°C was stirred for 10 hours. The reaction solution was concentrated, the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v - 100 / 0 - 100 / 20) to obtain a colorless oily matter 80b (420 mg , performance: 97.2 %).4H NMR (500 MHz, DMSO-06) δ 8.09 (s, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.51 (s, 3H). Starting from compound 80b, with reference to the synthesis of compound 73, compound 80 is obtained. = 8.4 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.51 (m, 1H), 7.48 - 7.44 (m, 7H), 7.14 (d, J = 7.0 Hz, 1H), 5.82 (s, 2H) , 3.79 - 3.76 (m, 2H), 3.66 - 3.55 (m, 5H), 3.38 (s, 3H), 3.13 - 3.08 (m, 1H), 2.58 - 2.54 (m, 2H), 2.13 - 2.08 (m, 3H), 1.73 - 1.67 (m, 1H); MS (ESI): m / z 703.2 (M+H)+. Example 81: 101 Starting from 3-methoxy-4-methylbenzoic acid, with reference to the synthesis of compound 80b, the compound 81a.4H is obtained NMR (500 MHz, DMSO-O6) δ 13.25 (s, 1H), 7.32 (s, 1H) , 7.30 (s, 1H), 3.82 (s, 3H), 2.17 (s, 3H). Dissolved oxalyl chloride (345 mg, 2.72 mmol) and 1 drop of Ν,Ν-dimethylformamide were added to a dichloromethane solution (8 ml) with compound 81a (300 mg, 1.50 mmol). The reaction solution under conditions of 25°C was stirred for 3 hours, then the reaction solution was concentrated. The residue thus obtained was redissolved with dichloromethane (3 mL), then the solution was added to a solution of dichloromethane (8 mL) with 4-bromoindazole (265 mg, 1.35 mmol), 4-dimethylaminopyridine (18.3 mg, 0.15 mmol ) and triethylamine (302 mg). mg, 2.99 mmol) dissolved. The reaction solution was stirred for 16 hours at 25°C. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 100 / 0 - 100 / 20) to obtain a white solid 81b (410 mg, performance: 72.2%). Starting from compound 81b, with reference to the synthesis of compound 73a, compound 81c is obtained. Potassium carbonate (72 mg, 0.52 mmol). aggregate. The reaction solution was stirred for 1 hour at 25°C. Add ethyl acetate (20 ml) and water (20 ml) to the reaction solution. The organic phase was further washed with saturated saline solution (20 ml), dried with anhydrous sodium sulfate. The residue was separated by a silica gel thin layer chromatography plate (petroleum ether / ethyl acetate, v / v = 4 / 1) to obtain a white solid 81d (70 mg, yield: 45.0%). MS (ESI): m / z 594.4 (M+H)+. Starting from compound 81d, referring to the boron esterification step in the INT-1 synthesis process, compound 81e is obtained. MS (ESI): m / z 642.8 (M+H)+. At 90°C and nitrogen atmosphere, 1,4-dioxane solution (4 mL) with compound 81e (35 mg, 0.038 mmol), compound INT-3 (18.9 mg, 0.038 mmol), Pd(dppf)CI2 (2.8 mg, 0.0038 mmol) and potassium fluoride (6.7 mg, 0.11 mmol) mixed was stirred for 16 hours. The reaction solution was concentrated and the residue was separated by a silica gel thin layer chromatography plate (dichloromethane / methanol, v / v = 20 / 1) to obtain a colorless oily matter 81f (20 mg, yield: 36.7 %). MS (ESI): m / z 928.2 (M+H)+. Starting from compound 81f, compound 81 was obtained taking as reference the last Boc deprotection step in the synthesis of compound 1.XH NMR (500 MHz, DMSO-o6) δ 8.49 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.55 7.53 (m, 1H), 7.52 - 7.49 (m, 3H), 7.47 - 7.40 (m, 5H), 3.79 (s, 3H), 3.76 - 3.74 (m, 2H), 3.62 - 3.59 (m, 3H), 3.50 - 3.48 (m, 2H), 3.12 - 3.11 (m, 1H) ), 2.53 - 2.52 (m, 2H), 2.10 - 2.06 (m, 3H), 1.69 1.65 (m, 1H); MS (ESI): m / z 716.0 (M+H)+. ινΐΛ / a / zuzz / uuoui or 102 Example 82: Starting from compound 80b, sequentially referring to the bromination step of compound 73a, substitution step of compound 72a and ester hydrolysis and acid-amine condensation step in the synthesis process of compound INT-lld, compound 82a is obtained. MS (ESI): m / z 595.4 (M+H)+. Starting from compound 82a and compound INT-3, with reference to the last two steps in the synthesis process of compound 81, compound 82 is obtained.XH NMR (500 MHz, DMSO-06) δ 8.51 (d, 7= 7.0 Hz, 1H), 8.23 ​​(s, 1H), 7.88 (s, 1H), 7.76 (d, 7= 8.5 Hz, 1H), 7.68 (s, 1H), 7.55 - 7.45 (m, 7H), 7.15 ( d, 7= 7.0 Hz, 1H), 5.93 (s, 2H), 4.28 - 4.26 (m, 1H), 3.85 - 3.75 (m, 3H), 3.67 - 3.60 (m, 2H), 3.39 (s, 3H) , 2.59 (d, 7= 6.2 Hz, 2H), 2.14 - 2.07 (m, 3H), 1.72-1.69 (m, 1H); MS (ESI): m / z 717.2 (M+H)+. Example 83: At 80 °C, a solution of acetonitrile (20 ml) was dissolved with 4-bromoindazole (500 mg, 2.54 mmol) and l-fluoro-4-methyl-l,4-diazab¡cyclo[2.2] tetrafluoroborate .2]octane (4.49 g, 12.7 mmol). stirred for 15 hours. In the reaction solution, ethyl acetate (100 mL) was added, then the solution was washed with water (100 mL) and saturated saline solution (100 mL) and dried with anhydrous sodium sulfate. The residue was separated by silica gel column chromatography to obtain a white solid 83a (231 mg, yield: 42.3%). MS (ESI): m / z 215.1 (M+H)+. Starting from compound 83a, O-isopropyl-L-serine tert-butyl ester and compound INT-3, with reference to the synthesis of compound INT-8 and compound 1, the 103 compound 83.1H NMR (500 MHz, DMSO-o6) δ 7.84 - 7.79 (m, 1H), 7.66 (s, 1H), 7.62 - 7.58 (m, 1H), 7.52 - 7.43 (m, 8H), 7.17 ( d, J= 7.0 Hz, 1H), 6.84 (s, 1H), 5.62 (s, 2H), 3.91 - 3.79 (m, 4H), 3.67 (s, 3H), 3.65 - 3.56 (m, 3H), 3.17 - 3.15 (m, 1H), 2.60 - 2.55 (m, 2H), 2.14 - 2.09 (m, 3H), 1.73 - 1.67 (m, 1H); MS (ESI): m / z 720.6 (M+H)+. Example 84: At 25°C, a solution of N'N-dimethylformamide (3 ml) with dissolved 4-bromoindazole (200 mg, 1.02 mmol), N-chlorosuccinimide (149 mg, 1.12 mmol) was stirred for 15 hours. Ethyl acetate (50 mL) was added to the reaction solution, then the solution was washed with water (50 mL) and dried with saturated saline solution (50 mL), anhydrous sodium sulfate. The residue was separated by silica gel column chromatography to obtain a white solid 84a (122 mg, yield: 51.9%). MS (ESI): m / z 231.3 (M+H)+. Starting from compound 84a, with reference to the synthesis of compound 83, compound 84 is obtained. 7.59 - 7.55 (m, 1H), 7.50 - 7.47 (m, 2H), 7.45 - 7.39 (m, 6H), 7.11 (d, 7= 7.0 Hz, 1H), 6.84 (d, 7= 1.5 Hz, 1H) , 5.75 - 5.68 (m, 1H), 5.70 (s, 1H), 3.89 - 3.86 (m, 1H), 3.79 - 3.75 (m, 3H), 3.65 (s, 3H), 3.62 - 3.59 (m, 3H) , 3.14 - 3.12 (m, 1H), 2.54 (d, 7= 6.0 Hz, 2H), 2.11 - 2.06 (m, 3H), 1.70 - 1.65 (m, 1H); MS (ESI): m / z 736.5 (M+H)+. Example 85: Starting from the compound INT-8 and 5-aminoethyltetrazolium, compound 85 was obtained taking as reference the synthesis of compound 22.XH NMR (500 MHz, DMSO-c6) δ 7.86 (s, 1H), 7.74 (d, J= 8.5 Hz, 1H), 7.55 - 7.38 (m, 9H), 7.14 (d, J= 7.0 Hz, 1H), 6.71 (s, 1H), 5.72 (s, 2H), 3.95 - 3.91 (m, 2H), 3.79 - 3.71 (m, 4H), 3.65 - 3.62 (m, 1H), 3.57 (s, 3H), 2.55 (d, 7= 6.0 Hz, 2H), 2.15 - 2.04 (m, 3H), 1.72 - 1.61 (m , 1 HOUR); MS (ESI): m / z 696.1 (M+H)+. 104 Starting from the compound INT-lc, tere-butyl bromoacetate, 4-bromoindazole, and with reference to the synthesis of the compound INT-li, compound 86a was obtained. MS (ESI): m / z 479.4 (M+H)+. Compound 86 was obtained from the synthesis of compound INT-7 and compound 22 from compound 86a, compound INT-3 and ethanolamine.XH NMR (500 MHz, DMSO-o6) δ 7.88 (s, 1H), 7.77 (d, 7 = 8.5 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.41 (m, 9H), 7.15 (d, 7 = 6.9 Hz, 1H), 6.94 (s, 1H), 5.70 (s , 2H), 4.26 (s, 2H), 4.01 (s, 2H), 3.81 - 3.72 (m, 2H), 3.67 - 3.58 (m, 3H), 2.86 (t, 7 = 5.4 Hz, 2H), 2.57 - 2.50 (m, 2H), 2.13 - 2.04 (m, 3H), 1.72 - 1.64 (m, 1H); MS (ESI): m / z 702.4 (M+H)+. Example 87: From (R)-3-hydroxypyrrolidine hydrochloride, 4-bromo-2-methoxybenzaldehyde and compound INT-8c, compound 87a was obtained by referring to the synthesis of compound INT5 and compound INT-8. MS (ESI): m / z 616.4 (M+H)+. From compound 87a and compound INT-11, compound 87 was obtained by referring to the synthesis of compound 33.XH NMR (500 MHz, DMSO-06) δ 7.91 (s, 1H), 7.77 (d, 7= 8.5 Hz, 1H), 7.55 - 7.47 (m, 4H), 7.39 (d, 7= 7.5 Hz, 1H), 7.36 (s, 1H), 7.17 (d, 7= 7.0 Hz, 105 1Η), 7.08 (s, 1H), 7.06 (d, 7 = 7.5 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 4.23 - 4.17 (m, 1H), 3.82 (s, 3H ), 3.64 - 3.56 (m, 5H), 3.55 - 3.47 (m, 2H), 2.88 - 2.82 (m, 1H), 2.75 - 2.69 (m, 1H), 2.67 - 2.61 (m, 3H), 2.47 - 2.43 (m, 2H), 2.41 - 2.36 (m, 2H), 2.05 - 1.97 (m, 1H), 1.95 - 1.89 (m, 2H), 1.58 1.52 (m, 1H); MS (ESI): m / z 715.7 (M+H)+. Example 88: ινΐΛ / a / zuzz / uuou i o Starting from ethanolamine, 4-bromo-2-methoxybenzaldehyde and the compound INT-8c, with reference to the synthesis of the compound INT-3 and the compound INT-8, compound 88a was obtained. 10MS (ESI): m / z 690.4 (M+H)+. From compound 88a and compound INT-11, compound 88 was obtained by referring to the synthesis of compound 33. Ή NMR (500 MHz, DMSO-c6) δ 7.92 (s, 1H), 7.77 (d, 7= 8.5 Hz, 1H), 7.55 - 7.47 (m, 4H), 7.41 (d, 7 = 7.5 Hz, 1H), 7.37 (s, 1H), 7.17 (d, 7= 7.0 Hz, 1H), 7.11 (s, 1H), 7.09 - 7.04 (m, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.84 (s, 3H), 3.79 (d, 7= 3.5 Hz, 15 2H), 3.58 (s, 3H), 3.56 - 3.47 (m, 4H), 2.94 - 2.85 (m, 1H), 2.70 - 2.62 (m, 4H), 2.50 - 2.48 (m, 2H), 1.96 - 1.90 (m, 2H); MS (ESI): m / z 689.6 (M+H)+. 106 Example 89: From compound 76a, compound 89a was obtained by referring to the synthesis of compound 73. MS (ESI): m / z 925.5 (M+H)+. Zinc powder (32 mg, 0.49 mmol) was added to a solution of compound 89a (150 mg, 0.16 mmol) in acetic acid (3 mL), the reaction solution was stirred at 70°C for half an hour. The reaction solution was concentrated and the residue was subjected to preparative thin layer chromatography (dichloromethane / methanol, v / v = 20 / 1) to obtain 89b as a yellow oil (30 mg, yield: 20.7%). MS (ESI): m / z 895.9 (M+H)+. From compound 89b, compound 89 was obtained by referring to the last step of deprotecting Boc in the synthesis process of compound 1. NMR (500 MHz, DMSO-o6) δ 7.88 (s, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.54 - 7.42 (m, 8H), 7.14 (d, J= 6.9 Hz, 1H), 6.80 (s, 1H), 6.68 (s, 1H), 5.55 ( s, 2H), 5.00 - 4.95 (m, 1H), 3.84 - 3.73 (m, 4H), 3.63 (s, 3H), 3.60 - 3.51 (m, 3H), 3.04 - 3.02 (m, 1H), 2.56 - 2.52 (m, 2H), 2.13 - 2.06 (m, 3H), 1.73-1.66 (m, 1H); MS (ESI): m / z 683.1 (M+H)+. Example 90: 107 From l,3-dibromo-2-toluene, 4-bromo-2-methoxybenzaldehyde, compound INT2 and compound INT-8c, compound 90a was obtained by referring to the synthesis of compound INT-3 and compound INT-8 . MS (ESI): m / z 723.5 (M+H)+. From compound 90a and compound INT-11, compound 90 was obtained by referring to the synthesis of compound 33.1H NMR (500 MHz, DMSO-o6) δ 7.90 (s, 1H), 7.73 (d, J= 8.5 Hz, 1H), 7.66 (s, 1H), 7.49 (t, J= 8.5 Hz, 1H), 7.43 - 7.36 (m, 3H), 7.34 - 7.30 (m, 2H), 7.10 (d, J= 7.0 Hz, 1H), 7.03 (s, 1H), 7.00 (d, J= 7.0 Hz, 1H), 6.67 (s, 1H), 5.73 (s, 2H), 3.84 (s,3H ), 3.82 - 3.77 (m, 2H), 3.70 - 3.65 (m, 1H), 3.58 (s, 3H), 3.53 (d, J= 9.0 Hz, 2H), 2.95 - 2.88 (m,1H), 2.68 - 2.62 (m, 4H), 2.53 - 2.52 (m, 2H), 2.16 - 2.08 (m, 3H), 2.00 (s, 3H), 1.97 - 1.91 (m, 2H),1.75 - 1.68 (m, 1H); MS (ESI): m / z 722.3 (M+H)+. Starting from compound INT-10, compound INT-2, compound INT-8c and methyl 4-aminomethyl-cyclohexanecarboxylate hydrochloride, referring to the synthesis of compound INT-3, compound INT-8 and compound 44, compound91 is obtained. NMR - 7.49 (m, 3H), 7.43 - 7.32 (m, 2H), 7.18 (d, 7 = 7.0 Hz, 1H), 6.71 (s, 1H), 5.74 (s, 2H), 3.94 (s, 3H), 3.91 3.77 (m, 2H), 3.73 - 3.67 (m, 1H), 3.59 (s, 3H), 3.41 - 3.35 (m, 2H), 2.72 - 2.65 (m, 1H), 2.53 - 2.52 (m, 1H) , 2.19 - 2.01 (m, 9H), 1.91 - 1.79 (m, 4H), 1.77 - 1.68 (m, 1H), 1.53 - 1.40 (m, 1H), 1.34 1.21 (m, 2H), 0.88 - 0.78 (m , 2H); MS (ESI): m / z 799.7 (M+H)+. Example 92: 108 ινΐΛ / a / zuzz / uuou 1 or Starting from compound 76a, 4-bromoindazole, compound INT-6 is obtained, referring to the synthesis of compound 73a, compound 82a and compound INT-8, compound 92a. MS (ESI): m / z 754.5 (M+H)+. Starting from compound 92a and trans-4methyl aminocyclohexanate hydrochloride, with reference to the synthesis of compound 44, compound 92.XH NMR (500 MHz, DMSO-O6) δ 8.18 (s, 1H), 7.96 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.54 - 7.48 (m, 4H), 7.41 (d , J = 7.5 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.11 - 6.08 (m, 3H), 3.82 (s, 3H), 3.78 - 3.72 (m, 2H), 3.66 - 3.62 (m, 1H), 3.51 - 3.49 (m, 2H), 3.48 (s, 3H), 2.57 (d, 7 = 6.0 Hz, 2H), 2.46 - 2.36 (m, 2H), 2.13 (s, 3H), 2.11 - 2.07 (m, 3H), 1.94 - 1.89 (m, 2H), 1.82 - 1.77 (m , 2H), 1.72 - 1.65 (m, 1H), 1.32 - 1.26 (m, 4H); MS (ESI): m / z 795.7 (M+H)+. Example 93: Compound 93 was obtained by referring to the synthesis of compound 44 from methyl trans-4-aminocyclobutanecarboxylate hydrochloride and compound INT-9.XH NMR (500 MHz, DMSO-06) δ 7.90 (s, 1H), 7.75 (d, J= 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.44 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.33 (s, 1H), 7.15 (d , J= 7.5 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 7.01 (m, 1H), 6.68 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H), 3.64 - 3.60 (m, 1H), 3.57 (s, 3H), 3.30 - 3.24 (m, 2H), 3.04 - 2.98 (m, 1H), 2.84 - 2.79 (m, 1H), 2.55 - 2.50 (m, 2H), 2.20 - 2.12 (m, 2H), 2.12 2.03 (m, 5H), 1.91 (s, 3H), 1.70 - 1.64 (m, 1H); MS (ESI): m / z 756.6 (M+H)+. 109 Example 94: iviA / a / zuzz / uuou 1 or Compound 94 was obtained with reference to the synthesis of compound 44 from methyl (4-piperidine)acetate and compound INT-9. *H NMR (500 MHz, DMSO-06) δ 7.89 (s, 1H), 7.75 (d, 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.44 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.33 (s, 1H), 7.15 (d, J= 7.0 Hz, 1H), 7.09 - 7.06 (m, 1H), 7.05 - 7.01 (m, 1H), 6.68 (s, 1H) , 5.71 (s, 2H), 3.81 (s, 3H), 3.74 - 3.68 (m, 2H), 3.64 - 3.59 (m, 1H), 3.56 (s, 3H), 2.76 - 2.69 (m, 2H), 2.56 - 2.51 (m, 2H), 2.14 - 2.03 (m, 5H), 1.96 - 1.87 (m, 2H), 1.77 - 1.64 (m, 2H), 1.63 - 1.54 (m, 2H), 1.22 - 1.14 (m, 2H); MS (ESI): m / z 770.6 (M+H)+. Example 95: From compound INT-9 and compound INT-14, compound 95 was obtained by referring to the synthesis of compound 44.XH NMR (500 MHz, DMSO-06) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.53 - 7.44 (m, 4H), 7.39 (d, J = 7.5 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.08 - 7.05 (m, 1H), 7.05 - 7.01 (m, 1H), 6.67 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.72 - 3.69 (m, 2H), 3.64 - 3.58 (m, 1H), 3.56 (s, 3H), 3.44 - 3.35 (m, 2H), 2.54 - 2.51 (m, 2H), 2.35 - 2.29 (m, 1H), 2.12 - 2.10 ( m, 1H), 2.09 (s, 3H), 2.07 - 2.05 (m, 1H), 2.04 (d, J= 7.0 Hz, 2H), 1.76 - 1.71 (m, 4H), 1.69 - 1.63 (m, 1H) , 1.59 - 1.51 (m, 1H), 1.29 - 1.20 (m, 2H), 0.99 - 0.86 (m, 2H); MS (ESI): m / z 798.7 (M+H)+. 110 Example 96: OMe 96 ινΐΛ / a / zuzz / uuou 1 o Referring to the synthesis of compound 92, trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride was replaced with hemostatic methyl ester hydrochloride to obtain compound 96. Ή NMR (500 MHz, DMSO-o6) δ 8.21 (s, 1H), 7.98 (s, 1H), 7.80 (d, 7 = 8.5 Hz, 1H), 7.66 (s, 1H), 7.56 - 7.48 (m, 4H), 7.44 - 7.43 (m, 1H), 7.19 (d , 7 = 6.9 Hz, 1H), 7.13 - 7.11 (m, 1H), 7.09 - 7.07 (m, 1H), 6.13 - 6.11 (m, 3H), 3.85 (s, 3H), 3.80-3.79 (m, 2H ), 3.71 - 3.64 (m, 1H), 3.49 (s, 3H), 3.41 (s, 2H), 2.64 - 2.62 (m, 2H), 2.59-2.51 (m, 2H), 2.14 (s, 3H), 2.13 - 2.07 (m, 4H), 1.89 - 1.81 (m, 4H), 1.73 - 1.68 (m, 1H), 1.50 - 1.45 (m, 1H), 1.33 - 1.24 (m, 2H), 0.88 - 0.80 (m , 2H); MS (ESI): m / z 809.8 (M+H). Example 97: OEt 97b Br INT-2, INT-8C 'COOMe c2h5i, k2co3DMF From the compound 4-bromo-2-hydroxybenzaldehyde, compound 97a was obtained by referring to the boron esterification of the compound INT-7a and the synthesis of the compound INT-3a. From compound 97a, compound 97b is obtained by referring to the alkylation reaction step of compound INT-8a.JH NMR (500 MHz, DMSO-06) δ 10.40 (s, 1H), 7.86 - 7.82 (m, 1H), 7.74 (d, 7= 8.0 Hz, 1H), 7.47 - 7.43 (m, 1H), 7.37 (t, 7= 8.0 Hz, 1H), 7.24 (d, 7 = 1.4 Hz, 1H), 7.10 - 7.06 (m, 1H), 4.23 (q, 7= 7.0 Hz, 2H), 1.38 (t, 7= 7.0 Hz, 3H). From compound 97b, compound INT-2, compound INT-8c and hemostatic methyl ester hydrochloride, compound 97 was obtained by referring to the synthesis of compound 48.XH NMR (500 MHz, DMSO-06) δ 7.90 (s, 1H), 7.75 (d, 7= 8.5 Hz, 1H), 7.65 (s, 1H), 7.55 - 7.44 (m, 4H), 7.39 (d, 7 = Ί.Ί Hz, 1H), 7.36 (s, 1H), 7.15 (d, 7= 7.0 Hz, 1H), 7.05 (d, 7= 1.7 Hz, 1H), 7.04 - 7.00 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 4.08 (q, 7 = 6.9 Hz, 2H), 3.74 - 3.68 (m, 2H), 111 3.64 - 3.59 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H), 2.55 - 2.53 (m, 2H), 2.13 - 2.03 (m, 9H), 1.86 - 1.75 (m, 4H), 1.72 - 1.66 (m, 1H), 1.46 - 1.40 (m, 1H), 1.33 (t, J = 6.9 Hz, 3H), 1.27 - 1.21 (m, 2H), 0.84 - 0.75 (m, 2H); MS (ESI): m / z 812.8 (M+H). ΜΛ / a / ZUZZ / UUOU I or Example 98: o=% N Referring to the synthesis of compound 97, iodoethane was replaced with 2iodopropane to give compound 98.XH NMR (500 MHz, DMSO-06) δ 7.91 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H) , 7.64 (s, 1H), 7.55 - 7.43 (m, 4H), 7.39 (d, J = U Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.07 ( d, J = 1.6 Hz, 1H), 7.01 - 6.97 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 4.70 - 4.62 (m, 1H), 3.74 - 3.66 (m, 2H) , 3.64 - 3.60 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H), 2.54 - 2.52 (m, 2H), 2.13 - 2.03 (m, 9H), 1.89 - 1.78 (m, 4H) , 1.71 - 1.65 (m, 1H), 1.48 - 1.39 (m, 1H), 1.29 - 1.26 (m, 6H), 1.26 1.20 (m, 2H), 0.86 - 0.74 (m, 2H); MS (ESI): m / z 826.7 (M+H). Example 99: ^COOH SOCI2, MeOH N boc COOME INT-9 N H HCI 99a 0=% N H From (R)-N-Boc-3-tetrahydropyrrolacetic acid, compound 99a was obtained by referring to the synthesis of compound INT-14.XH NMR (500 MHz, DMSO-06) δ 9.27 - 8.91 (m, 2H ), 3.59 (s, 3H), 3.32 - 3.26 (m, 1H), 3.23 - 3.15 (m, 1H), 3.13 - 3.02 (m, 1H), 2.80 - 2.71 (m, 1H), 2.55 - 2.49 (m , 3H), 2.10 - 2.02 (m, 1H), 1.55 - 1.48 (m, 1H). From compound 99a and compound INT-9, compound 99 was obtained by referring to the synthesis of compound 44.XH NMR (500 MHz, DMSO-06) δ 7.90 (s, 1H), 7.75 (d, 7 = 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.45 (m, 4H), 7.40 (d, 7 = 7.5 Hz, 1H), 7.33 (s, 1H), 7.15 (d, 7 = 7.0 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.68 (m, 2H) , 3.64 - 3.60 (m, 1H), 3.56 (s, 3H), 3.48 (s, 2H), 2.68 - 2.62 (m, 1H), 2.55 - 2.51 (m, 2H), 2.47 - 2.42 (m, 2H) , 2.40 - 2.34 (m, 1H), 2.28 - 2.23 (m, 2H), 2.15 - 2.05 (m, 4H), 1.97 112 1.89 (m, 1H), 1.72 - 1.64 (m, 1H), 1.37 - 1.29 (m, 1H); MS (ESI): m / z 756.7 (M+H). ΜΛ / a / ZUZZ / UUOU I or Example 100: From compound INT-9 and hemostatic methyl acid hydrochloride, compound 100a is obtained referring to the synthesis of compound INT-5 and the last Boc deprotection step in the synthesis of compound 1. MS (ESI): m / z 798.7 (M+H). To compound 100a (40 mg, 0.050 mmol) in Ν,Ν-dimethylformamide (2 ml) was added formaldehyde (34% aqueous solution, 0.10 ml), acetic acid (6.0 mg, 0.10 mmol) and boron triacetate, hydride sodium (42 mg, 0.20 mmol); The reaction solution was stirred at 25°C for 2 hours. Saturated sodium bicarbonate solution (20 ml) was added to the reaction solution, followed by extraction with ethyl acetate (20 ml x 2). The combined organic phases were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate and concentrated to obtain a brown oily substance 100b (35 mg, yield: 84.5%). MS (ESI): m / z 826.7 (M+H). From compound 100b, compound 1OO was obtained by referring to the ester hydrolysis step in the synthesis of compound 33.XH NMR (500 MHz, DMSO-oG) δ 7.90 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.55 -7.45 (m, 5H), 7.44 (d, J= 7.5 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.09 - 7.07 ( m, 1H), 7.06 - 7.03 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.80 (s, 3H), 3.74 3.68 (m, 1H), 3.56 (s, 3H), 3.53 - 3.49 (m, 2H), 3.36 (s, 2H), 2.44 - 2.39 (m, 1H), 2.36 - 2.30 (m, 1H), 2.17 (s, 3H), 2.11 - 2.05 (m, 9H), 1.87 - 1.78 (m, 4H), 1.70 - 1.64 (m, 1H), 1.48 - 1.40 (m, 1H), 1.32 - 1.21 (m, 2H), 0.86 - 0.76 (m, 2H); MS (ESI): m / z 812.7 (M+H). Example 101: OCH3INT-16 C^COOH 113 Starting from the compound INT-16 and methyl cycloheximide hydrochloride, with reference to the synthesis of compound 44, compound 101 is obtained. NMR (500 MHz, DMSO-o6) δ 7.95 (s, 1H), 7.78 (d, J= 8.5 Hz, 1H), 7.65 (s, 1H), 7.57 - 7.49 (m, 4H), 7.38 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.00 - 6.96 (m, 2H), 6.69 (s, 1H), 5.73 (s, 2H), 3.87 (s, 3H), 3.79 - 3.71 (m, 2H), 3.61 - 3.59 (m, 1H), 3.58 (s, 3H), 3.36 (s, 2H), 2.53 - 2.51 (m, 2H), 2.13 - 2.03 (m, 6H), 2.09 (s, 3H), 1.88 - 1.78 (m, 4H), 1.70 - 1.62 (m, 1H), 1.49 - 1.41 ( m, 1H), 1.32 - 1.22 (m, 2H), 0.87 - 0.76 (m, 2H); MS (ESI): m / z 816.3 (M+H). Example 102: Starting from compound INT-15b, in reference to the synthesis of compound INT-3, compound 102a is obtained. MS (ESI): m / z 553.6 (M+H). Starting from compound 102a, compound INT-8c and hemostatic methyl hydrochloride hydrochloride, with reference to the synthesis of compound INT-8 and compound 44, compound 102 is obtained. Ή NMR (500 MHz, DMSO-o6) δ 7.93 (s, 1H), 7.78 (d, J= 8.5 Hz, 1H), 7.63 (s, 1H), 7.56 - 7.48 (m, 4H), 7.38 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.77 (s, 2H), 6.70 (s, 1H), 5.73 (s, 2H), 3.82 (s, 6H), 3.76 - 3.70 (m, 2H), 3.60 - 3.56 (m, 4H) , 3.36 (s, 2H), 2.53 - 2.52 (m, 2H), 2.13 - 2.04 (m, 9H), 1.89 - 1.79 (m, 4H), 1.70 - 1.61 (m, 1H), 1.50 - 1.42 (m, 1H), 1.32 - 1.23 (m, 2H), 0.87 0.77 (m, 2H); MS (ESI): m / z 828.5 (M+H). Example 103: INT-13 EITHER A Na+O' Cul, L-Proline, NaOH DMSO At 25°C, a solution of dimethyl sulfoxide (5 ml) with dissolved L-proline (132 mg, 1.14 mmol), sodium hydroxide (46 mg, 1.14 mmol) was stirred for 1 hour. Subsequently, the compound INT-13 (350 mg, 1.14 mmol), sodium methanesulfinate (1.17 g, 11.4 mmol), and cuprous iodide (218 mg, 1.14 mmol) were added. The resulting reaction solution was replaced with nitrogen 3 times and stirred for 2 hours under the conditions of nitrogen atmosphere and 120°C. The reaction solution 114 was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 1 / 1) to obtain a white solid 103a (232 mg, yield: 94.5%). , Chloroform-o) δ 8.48 (s, 1H), 6.89 (s, 1H), 3.98 (s, 3H), 3.89 (s, 3H), 3.07 (s, 3H), 2.74 (s, 3H); MS (ESI): m / z 259.1 (M+H). Starting from compound 103a, with reference to the synthesis of compound 92, compound 103 is obtained. = 8.5 Hz, 1H), 7.66 (s, 1H), 7.56 - 7.47 (m, 4H), 7.40 (d, J= 7.6 Hz, 1H), 7.18 (d, J= 7.0 Hz, 1H), 7.07 (d , J = 1.6 Hz, 1H), 7.06 - 7.02 (m, 1H), 6.31 (s, 1H), 6.14 (s, 2H), 3.82 (s, 3H), 3.76 - 3.67 (m, 2H), 3.64 - 3.59 (m, 1H), 3.48 (s, 2H), 3.47 (s, 3H), 3.21 (s, 3H), 2.56 - 2.52 (m, 2H), 2.39 - 2.33 (m, 1H), 2.11 (s, 3H), 2.11 - 2.07 (m, 3H), 2.07 - 2.04 (m, 1H), 1.94 - 1.87 (m, 2H), 1.82 - 1.76 (m, 2H), 1.71 - 1.64 (m, 1H), 1.32 - 1.23 (m, 4H); MS (ESI): m / z 828.2 (M+H). Example 104: ινΐΛ / a / zuzz / uuou 1 or Starting from the compound INT-9 and cis3-methyl aminocyclobutanecarboxylate hydrochloride, with reference to the synthesis of compound 44, the compound 104.XH NMR (500 MHz, DMSO-06) δ 7.90 (s, 1H), 7.75 ( d, J= 8.0 Hz, 1H), 7.66 (s, 1H),7.52 - 7.47 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.32 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.07 (s, 1H), 7.04 (d, J= 7.5 Hz, 1H), 6.68 (s, 1H), 5.72 (s, 2H), 3.81 (s, 3H), 3.75 - 3.68 (m, 2H), 3.64 - 3.60 (m, 1H), 3.57 (s, 3H), 3.26 (s, 2H), 2.82 - 2.75 (m, 1H), 2.67 - 2.60 (m, 1H), 2.57 - 2.52 (m, 2H), 2.23 - 2.17 (m, 2H), 2.14 - 2.04 (m, 3H), 1.94 - 1.87 (m, 2H), 1.92 (s, 3H), 1.71 - 1.64 (m, 1H); MS (ESI): m / z 755.9 (M+H). EITHER Example 105: Starting from the compound INT-9 and 4-aminobicyclo[2.2.2] octane-l-carboxylic acid methyl ester hydrochloride, with reference to the synthesis of compound 44, compound 105 is obtained. Ή NMR (500 MHz, DMSO-o6 ) δ 7.89 (s, 1H), 7.75 (d, J= 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.43 (m, 4H), 7.40 (d, J= 7.5 Hz, 1H), 7.38 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.05 - 7.02 (m, 1H), 6.66 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.74 - 3.68 (m, 2H), 3.64 - 3.59 (m, 1H), 3.57 (s, 3H), 3.41 (s, 2H), 2.56 - 2.52 (m, 2H) , 2.14 - 2.04 (m, 3H), 1.99 (s, 3H), 1.75 1.66 (m, 7H), 1.60 - 1.49 (m, 6H); MS (ESI): m / z 810.2 (M+H). iviA / a / zuzz / uuou 1 or Example 106: COOME OCH3INT-9 OMe 106 Starting from the compound INT-9 and methyl 6-aminospiro[3.3]heptane-2carboxylate hydrochloride, with reference to the synthesis of compound 44, the compound 106.XH NMR (500 MHz, DMSO-06) δ 7.90 (s) is obtained , 1H), 7.75 (d, J= 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.44 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.30 (s, 1H) , 7.15 (d, J = 7.0 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H ), 3.75 - 3.67 (m, 2H), 3.64 - 3.59 (m, 1H), 3.56 (s, 3H), 3.21 (s, 2H), 2.93 - 2.86 (m, 1H), 2.74 - 2.68 (m, 1H ), 2.55 - 2.52 (m, 2H), 2.20 - 1.98 (m, 9H), 1.88 (s, 3H), 1.80 - 1.74 (m, 1H), 1.72 - 1.65 (m, 2H); MS (ESI): m / z 796.2 (M+H). Example 107: Starting from compound 75a, with reference to the synthesis of compound 92, the compound 107.4H NMR (500 MHz, DMSO-06) δ 7.91 (s, 1H), 7.82 (d, 7 = 8.5 Hz, 1H), 7.70 is obtained (s, 1H), 7.65 (s, 1H), 7.53 - 7.46 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.17 (d, 7 = 7.0 Hz, 1H), 7.07 (d, 7 = 1.5 Hz, 1H), 7.06 - 7.02 (m, 1H), 6.90 (s, 1H), 5.80 (s, 2H), 3.81 (s, 3H), 3.71 (d, 7= 3.0 Hz, 2H), 3.69 (s, 3H), 3.63 - 3.60 (m, 1H), 3.47 (s, 2H), 2.54 - 2.52 (m, 2H), 2.39 - 2.36 (m, 1H), 2.12 - 2.06 (m, 4H), 2.10 (s, 3H), 1.93 - 1.88 (m, 2H), 1.81 - 1.76 (m, 2H), 1.70 - 1.66 (m, 1H), 1.30 - 1.25 (m, 116 4H); MS (ESI): m / z 775.3 (M+H). Example 108: Referring to the synthesis of compound 107, replacing trans-4-methyl aminocyclohexanate hydrochloride with compound INT-14, compound 108 is obtained. ), 7.83 (d, J= 8.5 Hz, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.54 7.46 (m, 4H), 7.42 (d, J= 7.5 Hz, 1H), 7.17 ( d, J= 7.0 Hz, 1H), 7.11 (s, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.92 (s, 1H), 5.80 (s, 2H), 3.87 - 3.78 (m, 2H ), 3.83 (s, 3H), 3.71 - 3.66 (m, 1H), 3.70 (s, 3H), 3.51 - 3.45 (m, 2H), 2.54 - 2.52 (m, 2H), 2.14 - 2.04 (m, 8H ), 1.78 - 1.68 (m, 5H), 1.59 - 1.53 (m, 1H), 1.31 - 1.21 (m, 2H), 0.98 - 0.90 (m, 2H); MS (ESI): m / z 789.1 (M+H). Example09: Starting from cis-(N-BOC-4-aminocyclohexyl)acetic acid, referred to the synthesis of the compound INT-14, the compound 109a.XH NMR (500 MHz, DMSO-06) δ 7.95 is obtained (brs, 3H), 3.57 (s, 3H), 3.18 - 3.08 (m, 1H), 2.27 (d, J = 7.5 Hz, 2H), 1.95 - 1.86 (m, 1H), 1.69 - 1.56 (m, 4H ), 1.54- 1.38 (m, 4H). Starting from compound 109a and compound INT-9, with reference to the synthesis of compound 44, the compound 109.4Η NMR (500 MHz, DMSO-06) δ 7.90 (s, 1H), 7.76 (d, J = 8.5) is obtained Hz, 1H), 7.65 (s, 1H), 7.54 - 7.46 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H ), 7.08 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.71 (d, 7 = 3.0 Hz, 2H), 3.64 - 3.59 (m, 1H), 3.57 (s, 3H), 3.43 (s, 2H), 2.56 - 2.52 (m, 2H), 2.36 - 2.31 (m, 1H), 2.21 - 2.16 (m, 2H), 2.13 - 2.04 (m, 3H), 2.07 (s, 3H), 1.98 - 1.91 (m, 1H), 1.72 - 1.66 (m, 1H), 1.61 - 1.53 (m, 2H), 1.51 - 1.39 ( m, 6H); MS (ESI): m / z 798.3 (M+H). 117 Example 110: Under ice bath conditions, dissolved boron tribromide (1 M in dichloromethane solution, 3.95 ml) was added dropwise to a dichloromethane solution (10 ml) with the compound INT-8b (500 mg, 1.32 mmol). The reaction solution under the same conditions was stirred for 1 hour. The reaction solution was quenched with ice water (30 ml), the resulting mixture was further stirred for half an hour. The aqueous phase was extracted (50 ml x 2) with dichloromethane. The combined organic phase was washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography to obtain a white solid 110a (370 mg, yield: 76.8%). MS (ESI): m / z 365.2 (M+H). Starting from compound 110a, referring to the alkylation reaction step of compound INT-8a, the compound MOh / H NMR (500 MHz, DMSO-o6) δ 10.21 (s, 1H), 8.13 (s, 1H) is obtained. , 7.79 (d, J= 8.3 Hz, 1H), 7.48 - 7.24 (m, 2H), 6.80 (s, 1H), 5.78 (s, 2H), 4.55 - 4.32 (m, 1H), 1.19 (d, J = 6.0 Hz, 6H). Starting from compound 110b, compound INT-6 and hemostatic methyl hydrochloride, taking compound INT-8 and compound 44 as reference, the synthesis of compound 110.XH NMR (500 MHz, DMSO-fl6) δ 7.92 ( s, 1H), 7.74 (d, J= 8.5 Hz, 1H), 7.64 (s, 1H), 7.54-7.45 (m, 4H), 7.43 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H) ), 7.15 (d, J= 7.0 Hz, 1H), 7.12 (s, 1H), 7.08 (d, J= 7.5 Hz, 1H), 6.41 (s, 1H), 5.72 (s, 2H), 4.20-4.12 (m, 1H), 3.86 - 3.82 (m, 2H), 3.84 (s, 3H), 3.71 - 3.66 (m, 1H), 3.33 (s, 2H), 2.73 - 2.63 (m, 2H), 2.14 - 2.06 (m, 9H), 1.87 - 1.77 (m, 4H), 1.72 - 1.68 (m, 1H), 1.48 - 1.39 (m, 1H), 1.30 - 1.22 (m, 2H), 1.05 (d, J= 6.0 Hz , 6H), 0.86 - 0.76 (m, 2H); MS (ESI): m / z 826.3 (M+H). 118 Example 111: 111a Starting from 2-fluoro-5-hydroxybenzoic acid, in reference to the synthesis of the compound INT-lc and the compound INT-8b, the compound llla.MS (ESI) is obtained: m / z 363.1 (M+H). Starting from compound Illa, compound INT-2 and hemostatic methyl hydrochloride, taking compound INT-8 and compound 44 as reference, the synthesis of compound 111 is obtained. *H NMR (500 MHz, DMSO-o6) δ 7.86 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.49 (m, 2H), 7.48 - 7.42 (m, 6H), 7.18 - 7.12 (m, 2H ), 6.88 (d, J = 6.0 Hz, 1H), 5.69 (s, 2H), 3.80 - 3.72 (m, 2H), 3.66 - 3.60 (m, 1H), 3.65 (s, 3H), 3.36 (s, 2H), 2.56 - 2.53 (m, 2H), 2.14 - 2.07 (m, 6H), 2.09 (s, 3H), 1.89 - 1.78 (m, 4H), 1.73 - 1.66 (m, 1H), 1.50 - 1.40 ( m, 1H), 1.31 1.22 (m, 2H), 0.85 - 0.76 (m, 2H); MS (ESI): m / z 752.3 (M+H). Example 112: Starting from 5-hydroxy-2-methylbenzoic acid, with reference to the synthesis of the compound INT-lc and the compound INT-8b, compound 112a is obtained. MS (ESI): m / z 359.2 (M+H). Starting from compound 112a, compound INT-8 and hemostatic methyl hydrochloride, with reference to the synthesis of compound INT-8 and compound 44, compound 112 is obtained. Ή NMR (500 MHz, DMSO-06) δ 7.89 ( s, 1H), 7.75 (d, 7 = 8.5 Hz, 1H), 7.66 (s, 1H), 7.55 - 7.46 (m, 4H), 7.44 (d, 7 = 7.5 Hz, 1H), 7.15 (d, 7 = 7.0 Hz, 1H), 7.12 (s, 2H), 7.09 (d, 7= 7.5 Hz, 1H), 6.60 (s, 1H), 5.66 (s, 2H), 3.88 - 3.82 (m, 2H), 3.85 (s, 3H), 3.72 - 3.67 (m, 1H), 3.57 (s, 3H), 3.43 - 3.40 (m, 2H), 2.67 (d, 7= 6.0 Hz, 2H), 2.25 (s, 3H), 2.18 - 2.04 (m, 9H), 1.89 - 1.80 (m, 4H), 1.76 - 1.68 (m, 1H), 1.55 - 1.45 (m, 1H), 1.32 - 1.23 (m, 2H), 0.86 - 0.75 (m , 2H); MS (ESI): m / z 778.4 (M+H). 119 Example 113: Starting from the compound INT-16 and methyl trans-4-aminocyclobutanecarboxylate hydrochloride, with reference to the synthesis of compound 101, compound 113 is obtained. NMR (500 MHz, DMSO-o6) δ 7.93 (s, 1H), 7.76 (d, 7 = 8.5 Hz, 1H), 7.62 (s, 1H), 7.56 - 7.45 (m, 4H), 7.34 (s, 1H), 7.15 (d, 7= 7.0 Hz, 1H), 7.02 - 6.93 (m, 2H), 6.68 (s, 1H), 5.72 (s, 2H), 3.86 (s, 3H), 3.83 - 3.72 (m, 2H), 3.62- 3.58 (m. 1H), 3.57 (s, 3H) ), 3.27 - 3.25 (m, 2H), 3.06 - 2.97 (m, 1H), 2.87 - 2.78 (m, 1H), 2.56 - 2.52 (m, 2H), 2.22 - 2.15 (m, 2H), 2.14 - 1.99 (m, 5H), 1.92 (s, 3H), 1.69 - 1.60 (m, 1H); MS (ESI): m / z 774.2 (M+H). Example 114: Starting from the compound INT-16 and trans-4-methyl aminocyclohexanate hydrochloride, with reference to the synthesis of compound 101, the compound 114 is obtained.JH NMR (500 MHz, DMSO-06) δ 7.92 (s, 1H), 7.76 (d, 7= 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.47 (m, 4H), 7.36 (s, 1H), 7.15 (d, 7 = 7.0 Hz, 1H), 6.98 - 6.93 ( m, 2H), 6.67 (s, 1H), 5.71 (s, 2H), 3.86 (s, 3H), 3.77 - 3.70 (m, 2H), 3.60 - 3.56 (m,l H), 3.57 (s, 3H) ), 3.45 (brs, 2H), 2.52 - 2.50 (m, 2H), 2.40 - 2.35 (m, 1H), 2.12 - 2.03 (m, 7H), 1.94 - 1.87 (m, 2H), 1.81 - 1.75 (m , 2H), 1.69 - 1.60 (m, 1H), 1.32 - 1.23 (m, 4H); MS (ESI): m / z 802.2 (M+H). 120 Example 115: Starting from compound INT-16 and compound 109a, with reference to the synthesis of compound 101, compound 115.NMR is obtained. (500 MHz, DMSO-06) δ 7.92 (s, 1H), 7.76 (d, 7 = 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.45 (m, 4H), 7.36 (s, 1H) , 7.15 (d, 7= 7.0 Hz, 1H), 6.99 6.93 (m, 2H), 6.67 (s, 1H), 5.71 (s, 2H), 3.86 (s, 3H), 3.78 - 3.69 (m, 2H) , 3.60 - 3.58 (m, 1H), 3.57 (s, 3H), 3.45 (s, 2H), 2.53 - 2.50 (m, 2H), 2.36 - 2.31 (m, 1H), 2.09 (s, 3H), 2.07 - 2.02 (m, 5H), 1.78 - 1.70 (m, 4H), 1.68 - 1.60 (m, 1H), 1.59 - 1.50 (m, 1H), 1.31 - 1.18 (m, 2H), 0.98 0.86 (m, 2H) ); MS (ESI): m / z 816.2 (M+H). Example 116: From the compound INT-16 and the methyl ester hydrochloride of 4-aminobicyclo[2.2.2]octane-l-carboxylic acid, with reference to the synthesis of compound 101, compound 116 is obtained. Ή NMR (500 MHz, DMSO -o6) δ 7.97 - 7.88 (m, 1H), 7.76 (d, 7= 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.47 (m, 4H), 7.38 (s, 1H), 7.15 ( d, 7= 7.0 Hz, 1H), 6.98 - 6.94 (m, 2H), 6.66 (s, 1H), 5.70 (s, 2H), 3.85 (s, 3H), 3.77 - 3.69 (m, 2H), 3.65 - 3.59 (m, 1H), 3.57 (s, 3H), 3.41 (s, 2H), 2.60 - 2.54 (m, 2H), 2.14 - 2.03 (m, 3H), 1.99 (s, 3H), 1.76 - 1.69 (m, 6H), 1.67 - 1.61 (m, 1H), 1.58 - 1.52 (m, 6H); MS (ESI): m / z 828.1 (M+H). Example 117: Br 121 Starting from 4-bromo-6-chloro indazole, referring to the synthesis of compound INT8 and compound 30, compound 117 is obtained. Ή NMR (500 MHz, DMSO-o6) δ 8.03 (s, 1H), 7.93 ( s, 1H), 7.66 (s, 1H), 7.55 - 7.44 (m, 8H), 7.24 (s, 1H), 6.78 (s, 1H), 5.74 (brs, 2H), 3.91 - 3.85 (m, 1H) , 3.79 - 3.76 (m, 2H), 3.69 - 3.57 (m, 7H), 3.15 - 3.08 (m, 1H), 2.57 - 2.55 (m, 2H), 2.15 - 2.07 (m, 3H), 1.74 - 1.66 ( m, 1H); MS (ESI): m / z 736.0 (M+H). Example 118: Starting from compound 118a, in reference to the synthesis of compound INT-14, compound 118b is obtained. Starting from compound 118b and compound INT-9, with reference to the synthesis of compound 44, compound 118 is obtained. Ή NMR (500 MHz, DMSO-P6) δ 7.90 (s, 1H), 7.75 (d, J= 8.5 Hz, 1H), 7.65 (s, 1H), 7.53 - 7.45 (m, 4H), 7.40 (d, 7= 7.5 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J= 7.5 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.04 (d, J= 8.5 Hz, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m , 2H), 3.65 - 3.59 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H), 2.56 - 2.52 (m, 2H), 2.14 - 2.03 (m, 10H), 1.80 - 1.73 (m , 2H), 1.72 - 1.65 (m, 3H), 1.58 - 1.53 (m, 1H), 1.44 - 1.36 (m, 1H), 0.97 0.86 (m, 2H), 0.83 - 0.75 (m, 2H); MS (ESI): m / z 812.2 (M+H). Example 119: 119a BOCHN11gbCIHH2N11gc Ph O Ph-p^ / ^OEt Ph' toluene, reflux Under a nitrogen atmosphere, a solution of toluene (15 ml) with dissolved tere-butyl 3oxocyclobutylcarbamate (1.0 g, 5.4 mmol) and ethoxyformylmethylenetriphenylphosphine (2.1 g, 5.9 mmol) was stirred for 6 hours at 110°C. Water (100 ml) and ethyl acetate (100 ml) were added to the reaction solution. The aqueous phase was further extracted with ethyl acetate (100 mL 122 χ 2). The combined organic phase was washed with saturated saline (200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was chromatographed on silica gel column to obtain a white solid 119a (1.1 g, yield: 79.8%). MS (ESI): m / z 256.3 (M+H). Under hydrogen atmosphere, a methanol solution (15 ml) with compound 119a (1.1 g, 4.3 mmol), Pd (10% w / w adsorbed on activated carbon, 150 mg) mixed was stirred overnight at 25°C. . The reaction solution was filtered. The filtrate was concentrated to obtain the white solid 119b (1.1 g, yield: 99.8%). MS(ESI): m / z 258.3 (M+H). In dichloromethane solution (15 ml) with compound 119b (1.1 g, 4.3 mmol) dissolved hydrochloric acid (4 M in 1,4-dioxane, 5.4 ml) was added. The resulting reaction solution at room temperature was stirred for 2 hours. The reaction solution was concentrated to obtain colorless oily matter 119c (0.83 g, yield: 99.5%). From compound 119c and compound INT-9, with reference to the synthesis of compound 44, compound 119 is obtained (judging by NMR, the compound should be a mixture of cis and trans isomers in a ratio of 6:4 ).XH NMR (500 MHz, DMSO-c6) δ 7.92 (s, 1H), 7.77 (d, 7 = 8.5 Hz, 1H), 7.68 (s, 1H), 7.55 - 7.47 (m, 4H), 7.42 ( d, 7 = 7.0 Hz, 1H), 7.34 (d, 7= 8.5 Hz, 1H), 7.17 (d, 7 = 7.0 Hz, 1H), 7.09 (d, 7= 1.5 Hz, 1H), 7.06 (dd, 7= 7.5, 1.5 Hz, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.77 - 3.69 (m, 2H), 3.66 - 3.61 (m, 1H), 3.58 (s, 3H), 3.25 (s, 2H), 3.03 - 2.95 (m, 0.4H), 2.74 - 2.69 (m, 0.6H), 2.58 - 2.54 (m, 2H), 2.43 - 2.35 (m, 1H) , 2.31 - 1.Π (m, 1.2H), 2.23 - 2.06 (m, 5H), 2.04 - 1.97 (m, 0.8H), 1.91 (s, 3H), 1.80 - 1.73 (m, 0.8H), 1.72 - 1.64 (m, 1H), 1.51 - 1.41 (m, 1.2H); MS (ESI): m / z 770.0 (M+H). Example 120: INT-9 Starting from trans-4-(Boc-amino)cyclohexylcarbaldehyde, with reference to compound 119a and compound 119c, the synthesis of compound 120b is obtained. MS (ESI): m / z 198.6 (M+H). Starting from compound 120b and compound INT-9, referring to the synthesis of compound 44, compound 120 is obtained. JH NMR (500 MHz, DMSO-06) δ 7.91 (s, 1H), 7.78 (d, 7= 8.5 Hz, 1H), 7.66 (s, 1H), 7.56 - 7.47 (m, 4H), 7.42 (d, 7= 7.7 Hz, 1H), 7.39 (s, 1H), 123 7.17 (d, 7 = 7.0 Hz, 1H), 7.10 (s, 1H), 7.09 - 7.05 (m, 1H), 6.77 - 6.71 (m, 1H), 6.69 (s, 1H), 5.73 (s, 2H) , 5.72 - 5.66 (m, 1H), 3.84 (s, 3H), 3.82 - 3.73 (m, 2H), 3.68 - 3.63 (m, 1H), 3.59 (s, 3H), 3.53 - 3.42 (m, 2H) , 2.61 - 2.56 (m, 2H), 2.44 - 2.36 (m, 1H), 2.17 - 2.06 (m, 7H), 1.86 - 1.75 (m, 4H), 1.75 - 1.66 (m, 1H), 1.40 - 1.27 ( m, 2H), 1.18 - 1.08 (m, 2H); MS (ESI): m / z 810.2 (M+H)o Example 121: Starting from compound 120a, with reference to the synthesis of compound 119, compound 121 is obtained. 7.67 (s, 1H), 7.56 - 7.46 (m, 4H), 7.41 (d, 7= 7.7 Hz, 1H), 7.38 (s, 1H), 7.17 (d, 7= 7.0 Hz, 1H), 7.08 (d , 7 = 1.7 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.68 (s, 1H), 5.72 (s, 2H), 3.83 (s, 3H), 3.77 - 3.69 (m, 2H), 3.66 - 3.61 (m, 1H), 3.58 (s, 3H), 3.46 (brs, 2H), 2.57 - 2.54 (m, 2H), 2.38 - 2.30 (m, 1H), 2.18 (t, 7= 7.5 Hz, 2H) , 2.15 - 2.05 (m, 6H), 1.81 - 1.65 (m, 5H), 1.38 (t, 7= 7.5 Hz, 2H), 1.29 - 1.17 (m, 2H), 1.17 - 1.08 (m, 1H), 0.92 - 0.82 (m, 2H); MS (ESI): m / z 812.2 (M+H). Starting from the compound INT-9, cyclopropylamine and methyl 4oxocyclohexanecarboxylate are obtained, with reference to the synthesis of compound 44, compound 122 and compound 123. 124 Composite 122:1H NMR (500 MHz, DMSO-o6) δ 7.91 (s, 1H), 7.76 (d, 7 = 8.5 Hz, 1H), 7.67 (s, 1H), 7.55 - 7.45 (m, 4H), 7.41 (d, 7= 7.5 Hz, 1H), 7.31 (s, 1H), 7.17 (d, 7 = 7.0 Hz, 1H), 7.09 - 7.07 (m, 1H), 7.07 - 7.03 (m, 1H), 6.66 ( s, 1H), 5.71 (s, 2H), 3.83 (s, 3H), 3.73 - 3.72 (m, 2H), 3.68 (s, 2H), 3.65 - 3.60 (m, 1H), 3.59 (s, 3H) , 2.56 - 2.53 (m, 2H), 2.46 - 2.42 (m, 1H), 2.14 - 2.03 (m, 5H), 1.93 - 1.87 (m, 2H), 1.83 - 1.78 (m, 2H), 1.72 - 1.67 ( m, 1H), 1.38 - 1.30 (m, 2H), 1.26 1.20 (m, 2H), 0.40 - 0.35 (m, 2H), 0.26 - 0.17 (m, 2H); MS (ESI): m / z 810.2 (M+H)o Compound 123: *H NMR (500 MHz, DMSO-o6) δ 7.89 (s, 1H), 7.74 (d, 7= 8.5 Hz, 1H), 7.65 (s, 1H), 7.52 - 7.45 (m, 4H), 7.40 (d, 7 = 7.5 Hz, 1H), 7.29 (s, 1H), 7.15 (d, 7= 7.0 Hz, 1H), 7.07 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 6.63 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.72 - 3.70 (m, 2H), 3.68 - 3.66 (m, 1H), 3.64 (s, 2H), 3.57 (s, 3H) ), 2.55 - 2.52 (m, 2H), 2.45 - 2.42 (m, 1H), 2.13 - 2.03 (m, 5H), 1.70 - 1.65 (m, 1H), 1.60 - 1.55 (m, 2H), 1.47 - 1.40 (m, 2H), 1.31 - 1.25 (m, 4H), 0.37 0.32 (m, 2H), 0.22 - 0.17 (m, 2H); MS (ESI): m / z 810.2 (M+H). Example 124: Referring to the synthesis of compound 110, isopropyl iodide is replaced with iodoethane, the compound is obtained 124.XH NMR (500 MHz, DMSO-06) δ 7.92 (s, 1H), 7.76 (d, J = 8.5 Hz , 1H), 7.68 (s, 1H), 7.55 - 7.47 (m, 4H), 7.42 (d, 7 = U Hz, 1H), 7.37 (s, 1H), 7.17 (d, 7 = 7.0 Hz, 1H) , 7.09 (d, 7= 1.6 Hz, 1H), 7.08 - 7.05 (m, 1H), 6.59 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.78 (q, 7= 7.0 Hz, 2H), 3.75 - 3.71 (m, 2H), 3.65 - 3.61 (m, 1H), 3.36 (brs, 2H), 2.56 - 2.53 (m, 2H), 2.14 - 2.03 (m, 6H), 2.08 ( s, 3H), 1.89 - 1.80 (m, 4H), 1.72 - 1.66 (m, 1H), 1.50 - 1.42 (m, 1H), 1.29 - 1.24 (m, 2H), 1.18 (t, 7= 7.0 Hz, 3H), 0.85 -0.79 (m, 2H); MS (ESI): m / z 812.2 (M+H). Example 125: Starting from the compound INT-9, trans-4-methylaminocyclohexanate hydrochloride and benzaldehyde, with reference to the synthesis of compound 44, the compound 125.XH NMR is obtained 125 (500 MHz, DMSO-06) δ 7.88 (s, 1H), 7.74 (d, 7 = 8.5 Hz, 1H), 7.65 (s, 1H), 7.53 - 7.43 (m, 4H), 7.44 (s, 1H ), 7.40 (d, 7= 7.5 Hz, 1H), 7.30 - 7.23 (m, 4H), 7.22- 7.13 (m, 2H), 7.08 - 7.06 (m, 1H), 7.057.02 (m, 1H), 6.62 (s, 1H), 5.68 (s, 2H), 3.81 (s, 3H), 3.77 - 3.70 (m, 2H), 3.66 - 3.61 (m, 1H), 3.57 (s, 2H), 3.54 (s, 3H), 3.51 (s, 2H), 2.59 - 2.54 (m, 2H), 2.41 - 2.36 (m, 1H), 2.14 - 2.04 (m, 4H), 1.94 - 1.87 (m, 2H), 1.84 - 1.79 ( m, 2H), 1.71 - 1.65 (m, 1H), 1.41 - 1.32 (m, 2H), 1.20 - 1.11 (m, 2H); MS (ESI): m / z 860.1 (M+H). Example 126: Starting from the compound INT-9, trans-4-methylaminocyclohexanate hydrochloride and cyclopropanecarbaldehyde, with reference to the synthesis of compound 44, the compound 126.XH NMR (500 MHz, DMSO-06) δ 7.91 (s, 1H) is obtained. 7.77 (d, 7= 8.5 Hz, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.55 - 7.46 (m, 4H), 7.41 (d, 7= 7.5 Hz, 1H), 7.17 (d , 7= 7.0 Hz, 1H), 7.10 - 7.08 (m, 1H), 7.08- 7.03 (m, 1H), 6.67 (s, 1H), 5.72 (s, 3H), 3.83 (s, 3H), 3.76 - 7.68 (m, 2H), 3.66 - 3.62 (m, 1H), 3.59 (s, 3H), 3.55 (s, 2H), 2.56 - 2.53 (m, 2H), 2.32 (d, 7= 6.0 Hz, 2H) , 2.15 - 2.05 (m, 4H), 1.93 - 1.88 (m, 2H), 1.80 - 1.73 (m, 2H), 1.72 - 1.66 (m, 1H), 1.30 - 1.21 (m, 5H), 0.75 - 0.69 ( m, 1H), 0.37 - 0.31 (m, 2H), 0.03 - 0.00 (m, 2H); MS (ESI): m / z 824.1 (M+H). Example 127: Referring to the synthesis of compound 110, isopropyl iodide is replaced with 2-bromoacetamide and the compound 127 is obtained. (d, 7= 8.5 Hz, 1H), 7.65 (s, 1H), 7.54 (s, 1H), 7.51 - 7.47 (m, 4H), 7.40 (d, 7= 7.5 Hz, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 7.15 (d, 7= 7.0 Hz, 1H), 7.07 (d, 7= 1.5 Hz, 1H), 7.06-7.02 (m, 1H), 6.79 (s, 1H), 5.68 (s, 2H), 4.28 (s, 2H), 3.81 (s, 3H), 3.72 (d, 7= 3.0 Hz, 2H), 3.64 - 3.61 (m, 1H), 3.43 (s, 2H), 2.58 - 2.55 (m, 2H), 2.15 - 2.09 (m, 6H), 2.08 (s, 3H), 1.83 - 1.76 (m, 4H), 1.69 - 1.66 (m, 1H), 1.46 - 1.43 (m, 1H) , 1.26 - 1.22 (m, 2H), 0.83 - 0.78 (m, 2H); MS (ESI): m / z 841.2 126 (Μ+Η). ινΐΛ / a / zuzz / uuou i o Example 128: Referring to the synthesis of compound 110, isopropyl iodide is replaced with 2-bromoacetic acid tert-butyl ester, the compound 128.XH NMR (500 MHz, DMSO-P6) δ 7.87 (s, 1H) is obtained, 7.73 (d, J= 8.5 Hz, 1H), 7.67 (s, 1H), 7.51 - 7.46 (m, 4H), 7.42 - 7.37 (m, 2H), 7.14 (d, J= 7.0 Hz, 1H), 7.07 (d, J= 1.5 Hz, 1H), 7.06 - 7.01 (m, 1H), 6.79 (s, 1H), 5.65 (s, 2H), 4.09 (brs, 2H), 3.81 (s, 3H), 3.73 - 3.69 (m, 2H), 3.63 - 3.60 (m, 1H), 3.41 (s, 2H), 2.54 - 2.52 (m, 2H), 2.33 - 2.28 (m, 1H), 2.20 (s, 3H), 2.12 - 2.05 (m, 5H), 1.86 - 1.80 (m, 4H), 1.71 - 1.66 (m, 1H), 1.59 - 1.50 (m, 1H), 1.29 - 1.23 (m, 2H), 0.87 - 0.80 (m, 2H) ); MS (ESI): m / z 843.2 (M+H). Example 129: From compound INT-9 and trans-4methyl aminocyclohexanate hydrochloride, with reference to the synthesis of compound 44 (the Boc deprotection of the last step is not included), compound 129a is obtained. MS (ESI): m / z 883.6 (M+H)» Starting from compound 129a and methanesulfonamide, referring to the condensation conditions of the acid and the amine in the synthesis of compound 82a and the last Boc deprotection step of compound 1, the compound 129.XH NMR (500 MHz, DMSO) is obtained -C6) δ 7.92 (s, 1H), 7.78 (d, J= 8.5 Hz, 1H), 7.67 (s, 1H), 7.56 - 7.47 (m, 4H), 7.44 (d, J = 7.5 Hz, 1H) , 7.41 (s, 1H), 7.17 (d, 7 = 7.0 Hz, 1H), 7.12 (s, 1H), 7.08 (d, 7 = 7.5 Hz, 1H), 6.70 (s, 1H), 5.73 (s, 2H) ), 3.85 (s, 3H), 3.84 - 3.79 (m, 2H), 3.71 - 3.65 (m, 1H), 3.59 (s, 3H), 3.53 (s, 2H), 3.05 (s, 3H), 2.65 ( d, 7= 6.0 Hz, 2H), 2.46 - 2.40 (m, 1H), 2.15 (s, 3H), 2.14 - 2.05 (m, 4H), 1.88 - 1.78 (m, 4H), 1.75 - 1.68 (m, 1H), 1.35 - 1.22 (m, 4H); MS (ESI): m / z 861.3 (M+H). Example 130: COOME HCI H2N OCH3INT-16 Starting from compound INT-16 and compound 118b, with reference to the synthesis of compound 101, compound 130.XH NMR (500 MHz, DMSO-o6) δ 7.93 (s, 1H), 7.75 (d, 7 = 8.5 Hz, 2H), 7.63 (s, 1H), 7.54 - 7.48 (m, 4H), 7.36 (s, 1H), 7.15 (d, 7= 7.0 Hz, 1H), 6.99 6.93 (m, 2H), 6.67 (s, 1H), 5.71 (s, 2H), 3.85 (s, 3H), 3.76 - 3.70 (m, 2H), 3.60 - 3.57 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H) ), 2.53 - 2.50 (m, 2H), 2.11 - 2.02 (m, 10H), 1.79 - 1.74 (m, 2H), 1.71 - 1.66 (m, 2H), 1.65 - 1.60 (m, 1H), 1.58 - 1.51 (m, 1H), 1.44 - 1.36 (m, 1H), 0.95 - 0.87 (m, 2H), 0.83 - 0.74 (m, 2H); MS (ESI): m / z 830.1 (M+H). Example31: CL OCH3INT-16 Cl < OMe 131 Starting from compound INT-16 and compound 121a, with reference to the synthesis of compound 101, compound 131 is obtained.XH NMR (500 MHz, DMSO-06) δ 7.92 (s, 1H), 7.76 (d, 7= 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.47 (m, 4H), 7.36 (s, 1H), 7.15 (d, 7= 7.0 Hz, 1H), 6.98 6.92 (m, 2H), 6.66 (s, 1H), 5.71 (s, 2H), 3.85 (s, 3H), 3.77 - 3.69 (m, 2H), 3.62 - 3.59 (m, 1H), 3.56 (s, 3H), 3.44 (s, 2H) ), 2.55 - 2.52 (m, 2H), 2.36 - 2.31 (m, 1H), 2.19 - 2.14 (m, 2H), 2.09 (s, 3H), 2.07 - 2.02 (m, 3H), 1.77 - 1.69 (m , 4H), 1.66 - 1.60 (m, 1H), 1.39 - 1.33 (m, 2H), 1.24 - 1.17 (m, 2H), 1.13 - 1.08 (m, 1H), 0.89 - 0.82 (m, 2H); MS (ESI): m / z 830.1 (M+H). 128 Example 132: From compound INT-16 and compound 120b, compound 132 was obtained by referring to the synthesis of compound 101. *H NMR (500 MHz, DMSO-o6) δ 7.92 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.54 - 7.47 (m, 4H), 7.37 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.99 - 6.94 (m, 2H) , 6.76 - 6.69 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 5.69 - 5.64 (m, 1H), 3.86 (s, 3H), 3.77 - 3.71 (m, 2H), 3.61 - 3.58 (m, 1H), 3.57 (s, 3H), 3.46 (s, 2H), 2.52 - 2.50 (m, 2H), 2.14 - 2.02 (m, 8H), 1.84 - 1.74 (m, 4H), 1.69 - 1.60 (m, 1H), 1.34 - 1.24 (m, 2H), 1.16 - 1.07 (m, 2H); MS (ESI): m / z 828.1 (M+H). Example 133: EITHER OMe 133 COOH Referring to the synthesis of compound 91, the hemostatic methyl hydrochloride is replaced with 4-aminobicyclo[2.2.2]octane-l-carboxylic acid methyl ester hydrochloride, the compound 133.XH NMR is obtained ( 500 MHz, DMSO-06) δ 7.87 (s, 1H), 7.82 (d, J= 7.5 Hz, 1H), 7.78 (d, J= 8.6 Hz, 1H), 7.68 - 7.64 (m, 2H), 7.58 - 7.49 (m, 3H), 7.40 (s, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.69 (s, 1H), 5.72 (s, 2H ), 3.92 (s, 3H), 3.76 - 3.68 (m, 2H), 3.66 - 3.62 (m, 1H), 3.59 (s, 3H), 3.43 (s, 2H), 2.60 - 2.54 (m, 2H), 2.16 - 2.07 (m, 3H), 2.01 (s, 3H), 1.77 - 1.65 (m, 7H), 1.61 - 1.54 (m, 6H); MS (ESI): m / z 811.1 (M+H). Example 134: o=\ N h With reference to the synthesis of compound 110, isopropyl iodide is replaced 129 with (S)-5-bromomethyl-2-pyrrolidone, the compound is obtained 134.4H NMR (500 MHz, DMSO-o6) δ 7.89 (s, 1H), 7.78 - 7.73 (m, 2H), 7.66 (s, 1H), 7.52 - 7.46 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.07 (s, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.72 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.80 - 3.76 (m, 1H), 3.75 - 3.72 (m, 1H) , 3.72 - 3.70 (m, 2H), 3.66 - 3.60 (m, 2H), 3.40 3.35 (m, 2H), 2.57 - 2.52 (m, 2H), 2.17 (d, J = 11.0 Hz, 1H), 2.12 - 2.08 (m, 6H), 2.08 (s, 3H), 2.06 - 2.04 (m, 1H), 1.87 - 1.75 (m, 5H), 1.70 - 1.64 (m, 1H), 1.47 - 1.40 (m, 1H), 1.30 - 1.20 (m, 3H), 0.85 - 0.77 (m, 2H); MS (ESI): m / z 881.2 (M+H). Example 135: Br OMe 135a Starting from compound 80b, 4-bromoindazole and compound INT-15, with reference to the synthesis of compound 73a and compound INT-16, compound 135a is obtained. MS (ESI): m / z 661.4 (M+H). Starting from compound 135a and 4-aminobicyclo[2.2.2]octane-l-carboxylic acid methyl ester hydrochloride, with reference to the synthesis of compound 101, compound 135 is obtained. Ή NMR (500 MHz, DMSO-06) δ 7.85 (s, 1H), 7.79 (d, J= 8.5 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.57 - 7.43 (m, 4H), 7.12 (d, J = 7.0 Hz, 1H), 6.96 (s, 1H), 6.94 (d, J = 8.5 Hz, 1H), 5.78 (s, 2H), 3.85 (s, 3H), 3.74 - 3.73 (m, 2H), 3.58 - 3.56 (m, 3H), 3.37 (s, 3H), 2.51-2.50 (m, 2H), 2.10 - 2.03 (m, 3H), 1.99 (s, 3H), 1.70 - 1.67 (m, 6H), 1.64 - 1.62 (m, 1H), 1.54 - 1.51 (m, 6H); MS (ESI): m / z 829.2 (M+H). 130 Example 136: ινΐΛ / a / zuzz / uuou 1 or Starting from the compound INT-16 and 3aminobicyclo[l.l.l]pentane-l-carboxylate methyl ester hydrochloride, with reference to the synthesis of compound 101, compound 136 is obtained. Ή NMR (500 MHz, DMSO-o6) δ 7.93 ( s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.56 - 7.46 (m, 4H), 7.33 (s, 1H), 7.15 (d, J= 7.0 Hz, 1H ), 7.00 - 6.94 (m, 2H), 6.67 (s, 1H), 5.72 (s, 2H), 3.86 (s, 3H), 3.78 - 3.70 (m, 2H), 3.57 (s, 3H), 3.56 - 3.52 (m, 1H), 3.40 (s, 2H), 2.55 - 2.52 (m, 2H), 2.10 - 2.03 (m, 6H), 1.89 (s, 6H), 1.68 - 1.60 (m, 1H); MS (ESI): m / z 786.0 (M+H). Example 137: Starting from compound INT-10, compound INT-2, compound 80b and 4bromoindazole, with reference to the synthesis of compound INT-3, compound 73a and compound 16, compound 137a is obtained. MS (ESI): m / z 644.3 (M+H). Starting from compound 137a and 4-aminobicyclo[2.2.2]octane-l-carboxylic acid methyl ester hydrochloride, with reference to the synthesis of compound 101, compound 137 is obtained. Ή NMR (500 MHz, DMSO-06) δ 7.83 - 7.80 (m, 3H), 7.70 - 7.65 (m, 3H), 7.55 (t, J = 7.5 Hz, 1H), 7.50 - 7.47 (m, 2H), 7.31 (d, J= 7.4 Hz, 1H ), 7.14 (d, J= 7.0 Hz, 1H), 5.80 (s, 2H), 3.92 (s, 3H), 3.73 - 3.71 (m, 2H), 3.65 - 3.63 (m, 1H), 3.39 (s, 3H), 3.36 (brs, 2H), 2.56 (d, J= 6.0 Hz, 2H), 2.14 - 2.07 (m, 3H), 2.00 (s, 3H), 1.72-1.68 (m, 7H), 1.56-1.52 (m, 6H); MS (ESI): m / z 812.1 (M+H)» 131 Example 138: XCOOH Referring to the synthesis of compound 107, compound INT-6 is replaced with compound INT-15, compound 138 is obtained. Ή NMR (500 MHz, DMSO-o6) δ 7.96 (s, 1H), 7.84 (d , J = 8.6 Hz, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.56 - 7.50 (m, 4H), 7.18 (d, J= 7.0 Hz, 1H), 6.99 - 6.97 (m, 2H), 6.92 (s, 1H), 5.82 (s, 2H), 3.87 (s, 3H), 3.76 - 3.73 (m, 2H), 3.71 (s, 3H), 3.62 - 3.58 (m, 1H), 3.49 (s, 2H), 2.60-2.55 (m, 2H), 2.45 - 2.35 (m, 1H), 2.12 (s, 3H), 2.10 - 2.04 (m, 3H), 1.94 - 1.92 (m, 2H), 1.81 - 1.79 (m, 2H), 1.69 - 1.62 (m, 1H), 1.34-1.23 (m, 5H); MS (ESI): m / z 793.0 (M+H). Example 139: Referring to the synthesis of compound 138, trans-4-methylaminocyclohexanate hydrochloride is replaced with trans-4-methylaminocyclohexanate hydrochloride, and compound 139 is obtained. Ή NMR (500 MHz, DMSO-06) δ 7.94 (s, 1H) , 7.82 (d, J= 8.5 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.55 - 7.48 (m, 4H), 7.17 (d, J= 7.1 Hz, 1H), 6.99 - 6.95 (m, 2H), 6.91 (s, 1H), 5.80 (s, 2H), 3.85 (s, 3H), 3.73 (d, J = 4.2 Hz, 2H), 3.69 (s, 3H), 3.58 - 3.56 (m, 1H), 3.26 (brs, 2H), 3.03 - 3.01 (m, 1H), 2.80 - 2.76 (m, 1H), 2.51 - 2.48 (m, 2H), 2.20 - 2.15 (m, 2H), 2.09 - 2.02 (m, 5H), 1.92 (s, 3H), 1.66 - 1.62 (m, 1H); MS (ESI): m / z 765.1 (M+H). Example 140: 132 Referring to the synthesis of compound 138, trans-4-methyl aminocyclohexanate hydrochloride is replaced with 4-aminobicyclo[2.2.2]octane1-carboxylic acid methyl ester hydrochloride, the compound 140.XH NMR (500 MHz, DMSO-o6) δ 7.95 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 7.56 - 7.49 (m, 4H), 7.18 (d, J = 7.0 Hz, 1H), 7.00 - 6.97 (m, 2H), 6.91 (s, 1H), 5.81 (s, 2H), 3.87 (s, 3H), 3.75 (d, 7= 4.5 Hz, 2H), 3.70 (s, 3H), 3.62 - 3.56 (m, 1H), 3.45 (s, 2H), 2.54 - 2.52 (m, 2H), 2.09 - 2.05 (m, 3H), 2.02 (s, 3H) , 1.75 - 1.72 (m, 6H), 1.68 1.63 (m, 1H), 1.59 - 1.56 (m, 6H); MS (ESI): m / z 819.0 (M+H). Example 141: Referring to the synthesis of compound 138, trans-4-methyl aminocyclohexanate hydrochloride is replaced with compound INT-14, compound 141 is obtained.XH NMR (500 MHz, DMSO-06) δ 7.94 (s, 1H ), 7.82 (d, 7 = 8.5 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.56 - 7.48 (m, 4H), 7.17 (d, 7= 7.0 Hz, 1H), 6.97 - 6.95 (m, 2H), 6.90 (s, 1H), 5.80 (s, 2H), 3.85 (s, 3H), 3.73 (d, 7 = 4.1 Hz, 2H), 3.69 (s, 3H), 3.58 - 3.55 (m, 1H), 3.46 (s, 2H), 2.52 - 2.49 (m, 2H), 2.36 - 2.33 (m, 1H), 2.10 (s, 3H), 2.08 - 2.01 (m, 5H), 1.77 - 1.70 (m, 4H), 1.66 - 1.61 (m, 1H), 1.58 -1.52 (m, 1H), 1.29 - 1.22 (m, 2H), 0.96 - 0.89 (m, 2H); MS (ESI): m / z 807.1 (M+H). Example 142: With reference to the synthesis of compound 92, compound INT-6 is replaced with compound INT-15, compound 142 is obtained.XH NMR (500 MHz, DMSO-06) δ 8.17 (s, 1H), 7.99 (s , 1H), 7.78 (d, 7= 8.5 Hz, 1H), 7.64 (s, 1H), 7.57 - 7.46 (m, 4H), 7.17 (d, 7= 7.0 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.10 (s, 1H), 6.09 (s, 2H), 3.86 (s, 3H), 3.73 (d, 7= 4.5 Hz, 2H), 3.59 - 3.55 (m, 1H), 3.49 (s, 2H) ), 3.48 (s, 3H), 2.53 - 2.51 (m, 2H), 2.43 - 2.37 (m, 1H), 2.13 (s, 3H), 2.11 - 2.01 (m, 4H), 1.95 - 1.86 (m, 2H ), 1.84 - 1.75 (m, 2H), 1.68 - 1.59 (m, 1H), 1.33 - 1.23 (m, 4H); MS (ESI): 133 m / z 813.3 (M+H). Example 143: F. h OMe 143 Referring to the synthesis of compound 142, trans-4-methylaminocyclohexanate hydrochloride is replaced with trans-4-methylaminocyclohexanate hydrochloride, and compound 143 is obtained.JH NMR (500 MHz, DMSO-o6) δ 8.13 (s, 1H) , 7.99 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.48 (m, 4H), 7.17 (d, 7= 6.5 Hz, 1H), 7.00 - 6.96 (m, 2H), 6.12 (s, 1H), 6.09 (s, 2H), 3.86 (s, 3H), 3.77 - 3.70 (m, 2H), 3.59 - 3.55 (m, 1H), 3.48 (s, 3H), 3.32 - 3.30 (m, 2H), 3.09 - 3.02 (m, 1H), 2.87 - 2.78 (m, 1H), 2.52 - 2.48 (m, 2H), 2.21 - 2.16 (m, 2H), 2.12 2.02 (m, 5H), 1.95 (s, 3H), 1.67 - 1.60 (m, 1H); MS (ESI): m / z 785.3 (M+H). Example 144: Referring to the synthesis of compound 142, trans-4-methyl aminocyclohexanate hydrochloride is replaced with compound INT-14, compound 144 is obtained. NMR (500 MHz, DMSO-06) δ 8.17 (s, 1H) , 7.98 (s, 1H), 7.78 (d, 7= 8.5 Hz, 1H), 7.63 (s, 1H), 7.57 - 7.47 (m, 4H), 7.17 (d, 7 = 6.5 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.09 (s, 1H), 6.09 (s, 2H), 3.86 (s, 3H), 3.77 - 3.70 (m, 2H), 3.59 - 3.55 (m, 1H), 3.49 (s, 2H), 3.48 (s, 3H), 2.54 - 2.50 (m, 2H), 2.36 - 2.33 (m, 1H), 2.13 (s, 3H), 2.10 - 2.02 (m, 5H), 1.78 - 1.70 (m, 4H), 1.67 - 1.64 (m, 1H), 1.57 - 1.52 (m, 1H), 1.32 - 1.21 (m, 2H), 0.98 - 0.88 (m, 2H); MS (ESI): m / z 827.1 (M+H). 134 Example 145: Referring to the synthesis of compound 142, methyl trans-4-aminocyclohexanate hydrochloride is replaced with 4-aminobicyclo[2.2.2]octane-l-carboxylic acid methyl ester hydrochloride, and the compound 145.XH NMR is obtained ( 500 MHz, DMSOdo) δ 8.18 (s, 1H), 7.98 (s, 1H), 7.78 (d, 7= 8.5 Hz, 1H), 7.63 (s, 1H), 7.56 - 7.47 (m, 4H), 7.17 ( d, J = 7.0 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.09 (s, 1H), 6.08 (s, 2H), 3.86 (s, 3H), 3.77 - 3.70 (m, 2H), 3.59 - 3.55 (m, 1H), 3.48 (s, 3H), 3.45 (s, 2H), 2.54 - 2.50 (m, 2H), 2.10 - 2.04 (m, 3H), 2.03 (s, 3H), 1.74 - 1.69 (m, 6H), 1.68 - 1.62 (m, 1H), 1.60 - 1.55 (s, 6H); MS (ESI): m / z 839.1 (M+H). Example 146: DMF, 150°CF>CCOOMe O' 'O What 146a In Ν,Ν-dimethylformamide solution (2 ml) with the compound INT-13 (50 mg, 0.16 mmol) and methyl fluorosulfonyl difluoroacetate (314 mg, 1.6 mmol) mixed cuprous iodide (156 mg, 0.82 mmol) was added. The mixture thus obtained under conditions of 150 degrees was stirred for 4 hours. The reaction solution was filtered and a mixture of ethyl acetate and water (100 ml, v / v = 1 / 1) was added to the filtrate. The organic phase thus obtained was washed with saturated saline solution (50 ml), dried with anhydrous sodium sulfate and concentrated. The residue was separated by silica gel column chromatography to obtain a white solid 146a (40 mg, yield: 98.7%).Ψ NMR (500 MHz, DMSO-o6) δ 7.92 (s, 1H), 7.27 (s, 1H), 3.90 (s, 3H), 3.80 (s, 3H); MS (ESI): m / z 249.0 (M+H). Starting from compound 146a, referring to the synthesis of compound 92, in which trans-4-methyl aminocyclohexanate hydrochloride is replaced by compound INT-14, compound 146 is obtained. Ή NMR (500 MHz, DMSO- 06) δ 7.95 (s, 1H), 7.70 (s, 1H), 7.67 - 7.62 (m, 2H), 7.54 - 7.46 (m, 4H), 7.40 (d, 7 = U Hz, 1H), 7.17 (d , 7 = 7.0 Hz, 1H), 7.07 (d, 7 = 1.6 Hz, 1H), 7.04 (dd, 7 = 7.5, 1.6 Hz, 1H), 6.32 (s, 1H), 5.82 (s, 2H), 3.82 (s, 3H), 3.71 (d, 7= 3.0 Hz, 2H), 3.65 - 3.59 (m, 1H), 3.48 (s, 2H), 3.46 (s, 3H), 2.55 - 2.53 (m, 2H), 2.37 - 2.33 (m, 1H), 2.12 - 2.06 135 (m, 6H), 2.02 (d, J = 7.1 Hz, 2H), 1.76 - 1.67 (m, 5H), 1.58 - 1.51 (m, 1H), 1.29 - 1.21 (m, 2H), 0.97 - 0.87 ( m, 2H); MS (ESI): m / z 832.2 (M+H). Example 147: Referring to the synthesis of compound 146, compound INT-6 is replaced with compound INT-15, compound 147.XH NMR (500 MHz, DMSO-o6) δ 7.98 (s, 1H), 7.70 (s , 1H), 7.68 - 7.61 (m, 2H), 7.57 - 7.47 (m, 4H), 7.17 (d, J = 7.0 Hz, 1H), 7.01 - 6.94 (m, 2H), 6.33 (s, 1H), 5.82 (s, 2H), 3.86 (s, 3H), 3.78 - 3.70 (m, 2H), 3.62 - 3.54 (m, 1H), 3.48 (s, 2H), 3.46 (s, 3H), 2.55 - 2.50 ( m, 2H), 2.36 - 2.31 (m, 1H), 2.10 (s, 3H), 2.09 - 2.01 (m, 5H), 1.77 - 1.69 (m, 4H), 1.67 - 1.61 (m, 1H), 1.59 - 1.52 (m, 1H), 1.31 - 1.24 (m, 2H), 0.97 - 0.88 (m, 2H); MS (ESI): m / z 850.1 (M+H). Example 148: Referring to the synthesis of compound 147, compound INT-14 is replaced with trans-4-methyl aminocyclohexanate hydrochloride, compound 148 is obtained.XH NMR (500 MHz, DMSO-06) δ 7.98 (s, 1H) , 7.70 (s, 1H), 7.69 - 7.61 (m, 2H), 7.57-7.46 (m, 4H), 7.17 (d, J= 7.0 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.33 (s , 1H), 5.82 (s, 2H), 3.86 (s, 3H), 3.78 - 3.68 (m, 2H), 3.61 - 3.55 (m, 1H), 3.48 (s, 2H), 3.46 (s, 3H), 2.56 - 2.50 (m, 2H), 2.39 - 2.33 (m, 1H), 2.10 (s, 3H), 2.09 2.02 (m, 4H), 1.94 - 1.87 (m, 2H), 1.82 - 1.74 (m, 2H) , 1.68 - 1.60 (m, 1H), 1.34 - 1.24 (m, 4H); MS (ESI): m / z 836.1 (M+H). 136 Example 149: COOH Referring to the synthesis of compound 147, compound INT-14 is replaced with trans-4-methyl aminocyclohexanate hydrochloride, and compound 149 is obtained. NMR (500 MHz, DMSO-06) δ 7.99 (s, 1H) , 7.69 - 7.62 (m, 3H), 7.57 - 7.47 (m, 4H), 7.17 (d, 7 = 6.9 Hz, 1H), 7.04 - 6.92 (m, 2H), 6.34 (s, 1H), 5.83 (s , 2H), 3.86 (s, 3H), 3.79 - 3.70 (m, 2H), 3.61 - 3.54 (m, 1H), 3.46 (s, 3H), 3.29 (s, 2H), 3.06 - 2.97 (m, 1H ), 2.83 - 2.75 (m, 1H), 2.56 - 2.52 (m, 2H), 2.19 - 2.14 (m, 2H), 2.11 - 2.01 (m, 5H), 1.91 (s, 3H), 1.68 - 1.61 (m , 1 HOUR); MS (ESI): m / z 808.1 (M+H). Example 150: Referring to the synthesis of compound 147, the compound INT-14 is replaced with 4-aminobicyclo[2.2.2]octane-l-carboxylic acid methyl ester hydrochloride, the compound 150.XH NMR is obtained ( 500 MHz, DMSO-o6) δ 7.98 (s, 1H), 7.72 (s, 1H), 7.67 - 7.61 (m, 2H), 7.58 - 7.47 (m, 4H), 7.17 (d, 7= 7.0 Hz, 1H ), 7.05 - 6.94 (m, 2H), 6.32 (s, 1H), 5.82 (s, 2H), 3.86 (s, 3H), 3.78 - 3.70 (m, 2H), 3.61 - 3.55 (m, 1H), 3.46 (s, 3H), 3.44 (s, 2H), 2.60 - 2.54 (m, 2H), 2.10 - 2.02 (m, 3H), 1.99 (s, 3H), 1.74 - 1.68 (m, 6H), 1.66 - 1.62 (m, 1H), 1.59 - 1.53 (m, 6H); MS (ESI): m / z 862.1 (M+H). Example 151: 137 Referring to the synthesis of compound 137, 4-aminobicyclo[2.2.2]octane-l-carboxylic acid methyl ester hydrochloride is replaced with trans-4methylaminocyclohexanate hydrochloride, compound 151 is obtained.JH NMR (500 MHz, DMSO-o6) δ 7.83 - 7.78 (m, 3H), 1J1 - 7.63 (m, 3H), 7.54 (t, J= 7.5 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.30 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 7.0 Hz, 1H), 5.80 (s, 2H), 3.90 (s, 3H), 3.70 (d, J= 3.5 Hz, 2H), 3.65 - 3.60 ( m, 1H), 3.39 (s, 2H), 3.37 (s, 3H), 2.55 - 2.53 (m, 2H), 2.37 - 2.33 (m, 1H), 2.12 - 2.05 (m, 4H), 2.08 (s, 3H), 1.93 - 1.87 (m, 2H), 1.78 - 1.73 (m, 2H), 1.71 - 1.66 (m, 1H), 1.29 - 1.23 (m, 4H); MS (ESI): m / z 786.0 (M+H). ινΐΛ / a / zuzz / uuou 1 or Example 152: Referring to the synthesis of compound 91, methyl 4-aminomethylcyclohexanecarboxylate hydrochloride is replaced with trans-4-methylaminocyclohexanate hydrochloride, and the compound 152.XH NMR (500 MHz, DMSO-o6) δ 7.88 (s, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.70 - 7.65 (m, 2H), 7.59 - 7.49 (m, 3H), 7.38 (s, 1H ), 7.32 (d, J= 7.4 Hz, 1H), 7.18 (d, J= 7.0 Hz, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.92 (s, 3H), 3.76 - 3.70 (m, 2H), 3.66 - 3.61 (m, 1H), 3.59 (s, 3H), 3.46 (s, 2H), 2.56 - 2.55 (m, 2H), 2.42 - 2.35 (m, 1H), 2.16 - 2.06 (m, 4H), 2.12 (s, 3H), 1.96 - 1.88 (m, 2H), 1.83 - 1.76 (m, 2H), 1.74 - 1.66 (m, 1H), 1.34 - 1.23 (m, 4H); MS (ESI): m / z 784.8 (M+H). Example 153: Referring to the synthesis of compound 57, compound INT-2 was replaced with compound INT-17 to obtain compound 153. *H NMR (500 MHz, DMSO-06) δ 7.91 (s, 1H), 7.77 (d , J= 8.5 Hz, 1H), 7.54 - 7.48 (m, 4H), 7.41 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.19 - 7.14 (m, 2H), 7.10 (brs, 1H), 7.07 - 7.03 (m, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.76 - 3.66 (m, 2H), 138 3.58 (s, 3H), 3.46 (s, 2H), 3.41 - 3.36 (m, 1H), 2.61 - 2.58 (m, 2H), 2.16 - 2.05 (m, 3H), 2.13 (s, 3H), 1.95 - 1.89 (m, 2H), 1.83 - 1.74 (m, 4H), 1.63 - 1.54 (m, 1H), 1.36 - 1.23 (m, 6H); MS (ESI): m / z 799.1 (M+H). Example 154: OH Lithium diisopropylamide (2.0 M in tetrahydrofuran, 2.6 mL) was added to a solution of l-chloro-2-bromo-4-fluorobenzene (1.0 g, 4.8 mmol) in tetrahydrofuran (6 at -78 °C). mL); The resulting reaction solution was stirred at the same temperature for 1 hour. Subsequently, N,N-dimethylformamide (1.7 g, 24 mmol) was added to the reaction solution and the resulting mixture was further stirred at -78°C for 1 hour. The reaction was quenched with aqueous ammonium chloride (40 ml, 5% w / w) and the aqueous phase was extracted with ethyl acetate (30 ml x 3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 10 / 1) to obtain white solid 154a (830 mg, yield: 73.2%). MS (ESI): m / z 237.1 (M+H). Compound 154a (830 mg, 3.5 mmol), hydrazine hydrate (2.0 ml, 85% analytical purity) in ethylene glycol dimethyl ether (5 ml) was stirred at 90 °C for 3 hours. After cooling the reaction, ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and he concentrated. The residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 10 / 1) to give 154b as a pale yellow solid (725 mg, yield: 89.6%). MS (ESI): m / z 231.0 (M+H). From compound 154b, compound 154 was obtained by reference to the synthesis of compound INT-9 and compound 30.XH NMR (500 MHz, DMSO-o6) δ 7.83 (d, J= 9.0 Hz, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.57 (d, J= 9.0 Hz, 1H), 7.55 - 7.53 (m, 2H), 7.48 (s, 1H), 7.43 - 7.39 (m, 2H), 7.07 - 7.02 (m, 2H), 6.75 (s, 1H), 5.73 (s, 2H), 3.88 - 3.84 (m, 1H), 3.82 (s, 3H), 3.79 - 3.73 (m, 3H), 3.65 - 3.64 (m, 1H), 3.62 (s, 3H), 3.60 - 3.55 (m, 2H), 3.13 - 3.11 (m, 1H), 2.59 - 2.54 (m, 2H), 2.11 - 2.06 (m, 3H), 1.71 - 1.65 (m, 1H); MS (ESI): m / z 765.9 (M+H). 139 Example 155: 4-Bromo-2-fluoroaniline (1.0 g, 5.3 mmol) in acetonitrile (10 ml) N-chlorosuccinimide (843 mg, 6.3 mmol) was added portionwise, the reaction was stirred at reflux for 2 hours. After cooling the reaction solution, 5% aqueous potassium carbonate solution (50 ml) was added, the resulting aqueous phase was extracted with dichloromethane (50 ml x 2). The combined organic phases were washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether as eluent) to give 155a as a white solid (1.0 g, yield: 84.6%).XH NMR (500 MHz, Chloroform-o) δ 7.21 (t, J= 2.0 Hz, 1H), 7.09 (dd, 7= 10.0, 2.0 Hz, 1H), 4.04 (brs, 2H). At room temperature, a solution of compound 155a (1.0 g, 4.5 mmol) in aqueous sulfuric acid (25% w / w) was stirred for half an hour, then cooled to −5 °C, and then nitrite was slowly added dropwise. of dissolved sodium (369 mg, 5.4 mmol) in water (5 ml). The reaction solution was further stirred at −5 °C for 1 hour, and at the same temperature, a mixed solution of ethyl acetate and water (50 ml, v / v = 3 / 2) was dissolved with potassium iodide ( 1.5 g, 8.9 mmol) was added slowly dropwise). The resulting reaction solution was reacted at room temperature for 1 hour. After separating the reaction solution, the aqueous phase was further extracted with ethyl acetate (30 mL x 2), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and They concentrated. The residue was separated by silica gel column chromatography (petroleum ether as eluent) to give 155b (800 mg, yield: 53.6%) as an oil ¡ηοοΙοΓοΛΗ NMR (500 MHz, Chloroformod) δ 7.45 (t, 7 = 2.0 Hz, 1H), 7.13 (dd, 7= 7.0, 2.0 Hz, 1H). Under a nitrogen atmosphere at 80°C, compound 155b (1.0 g, 3.0 mmol), pinacol ester of vinylboronic acid (1.4 g, 9.0 mmol), Pd(dppf)Cb (109 mg, 0.15 mmol) and acid were mixed. carbonic. A mixed solution of sodium hydride (504 mg, 6.0 mmol) in 1,4-dioxane and water (11 ml, v / v = 10 / 1) was stirred for 16 hours. The reaction solution was filtered through celite, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (petroleum ether as eluent) to obtain 155c (550 mg, yield: 58.7%) as an oil. colorless. 140 Potassium osmate dihydrate was added to a mixed solution of compound 155c (520 mg, 2.2 mmol) in 1,4-dioxane and water (6 ml, v / v = 1 / 1) at room temperature (8.1 mg, 0.02 mmol ) and sodium periodate (1.4 g, 6.6 mmol), the reaction solution was stirred at the same temperature for 2 hours. Water (30 ml) was added to the reaction solution, followed by extraction with ethyl acetate (30 ml x 2). The combined organic phases were washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 10 / 1) to give 155d as a colorless oil (400 mg, yield: 76.3%).^ NMR (500 MHz, Chloroform-o) δ 10.40 (brs, 1H), 7.48 (d, J= 1.5 Hz, 1H), 7.33 - 7.29 (m, 1H). Starting from compound 155d, referring to the synthesis of compound INT16 and compound 101, compound 155 is obtained.JH NMR (500 MHz, DMSO-o6) δ 7.93 (s, 1H), 7.76 (d, J= 8.5 Hz , 1H), 7.63 (s, 1H), 7.55-7.48 (m, 4H), 7.36 (s, 1H), 7.19-7.17 (m, 1H), 7.15 (d, J= 7.0 Hz, 1H), 7.11 - 7.09 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.85 (s, 3H), 3.85 - 3.83 (m, 2H), 3.62 - 3.57 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H), 2.54 - 2.51 (m, 2H), 2.11 - 2.04 (m, 8H), 1.86 - 1.77 (m, 4H), 1.67 - 1.61 (m, 1H), 1.48 - 1.39 ( m, 1H), 1.27 - 1.19 (m, 3H), 0.85 - 0.75 (m, 2H); MS (ESI): m / z 832.2 (M+H). Example 156: Sodium methoxide (1.8 g, 33.5 mmol) was added to a solution of methyl 4,6dichloronicotinate (4.6 g, 22.3 mmol) in tetrahydrofuran (40 ml); The resulting reaction was stirred at 50 °C for 16 hours. Water (100 ml) was added to the reaction solution, extracted with ethyl acetate (100 ml x 2). The combined organic phases were washed with saturated brine (150 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain 156a (2.8 g, yield: 62.2%) as a white solid. MS (ESI): m / z 202.1 (M+H). From compound 156a, compound 156b was obtained by referring to the synthesis of compound 72c. MS (ESI): m / z 172.1 (M+H). From compound 156b, compound 156 was obtained by reference to the synthesis of compound INT-10 and compound 133.XH NMR (500 MHz, DMSO-06) δ 8.24 (d, J= 1.7 Hz, 1H), 7.94 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.61 - 7.48 (m, 5H), 7.40 (s, 1H), 7.18 (d, J= 7.0 141 Hz, 1H), 6.68 (s, 1H), 5.72 (s, 2H), 3.88 (s, 3H), 3.86 (s, 2H), 3.65 - 3.60 (m, 1H), 3.58 (s, 3H), 3.43 (s, 2H), 2.66 - 2.56 (m, 2H), 2.15 - 2.05 (m, 3H), 2.00 (s, 3H), 1.77 - 1.67 (m, 7H), 1.61 - 1.52 (m, 6H); MS (ESI): m / z 811.1 (M+H). Example 157: INT-15a TsOH, cat. HC(OMe)3toluene NCS MeCN. 80°C 157a NaBH4 THF From compound INT-15a, compound 157a was obtained with reference to the synthesis of compound INT-le. MS (ESI): m / z 276.8 (M+H). From compound 157a, compound 157c was obtained by referring to the synthesis of 155c.XH NMR (500 MHz, DMSO-o6) δ 10.27 (s, 1H), 7.31 (d, J= 1.5 Hz, 1H), 6.19 (d, J = 1.5 Hz, 1H), 4.11 - 4.07 (m, 2H), 3.96 - 3.92 (m, 2H), 3.90 (s, 3H). At 0°C, sodium borohydride (29 mg, 0.77 mmol) was added to a solution of compound 157c (400 mg, 1.53 mmol) in tetrahydrofuran (20 mL), then the reaction was stirred at room temperature for half an hour. Saturated sodium bicarbonate solution (20 ml) was added to the reaction solution, followed by extraction with ethyl acetate (20 ml x 2). The combined organic phases were washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid 157d (400 mg, yield: 99.2%). MS (ESI): m / z 263.3 (M+H). From compound 157d, compound 157e was obtained by referring to the synthesis of compound INT-8c and compound INT-li. MS (ESI): m / z 445.5 (M+H)» From compound 157e, compound 157 was obtained by referring to the synthesis of compound 133.XH NMR (500 MHz, DMSO-06) δ 7.87 (s, 1H), 7.81 (d, J= 7.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.68 - 7.63 (m, 2H), 7.56 - 7.49 (m, 3H), 7.30 (d, J= 7.5 Hz, 1H), 7.17 (d, J = 7.0 Hz , 1H), 6.58 (s, 1H), 5.76 (s, 2H), 3.90 (s, 3H), 3.70 (d, J = 3.5 Hz, 2H), 3.64 - 3.61 (m, 1H), 3.60 (s, 3H), 3.45 (s, 2H), 2.54 (d, J = 6.0 Hz, 2H), 2.14 - 2.05 (m, 3H), 1.89 (s, 3H), 1.74 - 1.69 (m, 6H), 1.69 - 1.64 (m, 1H), 1.62 - 1.57 (m, 6H); MS (ESI): m / z 829.3 (M+H). 142 Example 158: Compound 158 is obtained from the synthesis of l-chloro-2-fluoro-4-bromoenzene and reference compound 154. *H NMR (500 MHz, DMSO-P6) δ 8.05 (s, 1H), 7.66 (s, 1H ), 7.56 - 7.49 (m, 4H), 7.45 - 7.39 (m, 2H), 7.16 (d, 7 = 7.6 Hz, 1H), 7.08 (d, 7= 1.6 Hz, 1H), 7.05 (dd, 7= 7.6, 1.6 Hz, 1H), 6.04 - 6.00 (m, 3H), 3.81 (s, 3H), 3.73 - 3.69 (m, 2H), 3.66 - 3.56 (m, 3H), 3.45 - 3.41 (m, 2H) , 3.38 (s, 3H), 3.25 - 3.22 (m, 1H), 2.55 - 2.50 (m, 2H), 2.11 - 2.05 (m, 3H), 1.71 - 1.65 (m, 1H); MS (ESI): m / z 766.0 (M+H). Example 159: The formaldehyde used in the reactivation amination step is changed to acetaldehyde to obtain a compound 159 according to the synthesis of compound 116.XH NMR (500 MHz, DMSO-O6) δ 7.92 (s, 1H), 7.76 (d, 7= 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 7.54 - 7.47 (m, 4H), 7.15 (d, 7= 7.0 Hz, 1H), 7.00 - 6.95 (m, 2H ), 6.64 (s, 1H), 5.70 (s, 2H), 3.86 (s, 3H), 3.77 3.71 (m, 2H), 3.62 - 3.57 (m, 1H), 3.60 (s, 3H), 3.56 (s , 2H), 2.57 - 2.50 (m, 4H), 2.10 - 2.03 (m, 3H), 1.72 - 1.66 (m, 6H), 1.65 - 1.61 (m, 1H), 1.56 - 1.51 (m, 6H), 0.78 (t, 7= 7.0 Hz, 3H); MS (ESI): m / z 842.1 (M+H). 143 Example 160: At 60°C, a solution of thionyl chloride (2 ml) was dissolved with 4(((benzyloxy)carbon¡l)amino)bicyclo[2.2.2]octane-l-carboxylic acid (150 mg, 0.49 mmol ) for 2 hours. After concentrating the reaction solution, the residue was dissolved with acetonitrile (3 ml) and trimethylsilylated diazomethane (2 M in n-hexane, 0.24 ml) was added. The resulting reaction solution at room temperature was stirred for 2 hours. Subsequently, at 0°C, triethylamine (0.13 mL), silver trifluoroacetate (154 mg, 0.70 mmol) and methanol (1 mL) were added to the previous solution. The resulting reaction solution at room temperature was stirred for 16 hours. The reaction solution was filtered. The filtrate was concentrated. The residue was separated by silica gel column chromatography to obtain a white solid 160a (50 mg, yield: 32.4%). s, 1H), 4.92 (s, 2H), 3.53 (s, 3H), 2.05 (s, 2H), 1.75 - 1.66 (m, 6H), 1.55 - 1.42 (m, 6H); MS (ESI): m / z 332.4 (M+H). At room temperature and hydrogen atmosphere, a solution of methanol (3 ml) with compound 160a (100 mg, 0.30 mmol) and palladium hydroxide (10% w / w adsorbed on activated carbon, 20 mg) was stirred for 1 hour. . The reaction solution was filtered with diatomaceous earth. The filtrate was concentrated and the residue was dissolved with dichloromethane (2 ml) and hydrochloric acid (4 M in ethyl acetate, 0.15 ml) was added dropwise. The resulting reaction solution was stirred for half an hour at room temperature. The reaction solution was concentrated to obtain a solid residue and washed with ethyl acetate to obtain a white solid 160b (60 mg, yield: 85.1%). MS (ESI): m / z 198.5 (M+H). Starting from compound INT-16 and compound 160b, with reference to the synthesis of compound 101, compound 160 is obtained.XH NMR (500 MHz, DMSO-o6) δ 7.93 (s, 1H), 7.76 (d, 7 = 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.47 (m, 4H), 7.40 (s, 1H), 7.16 (d, 7= 7.0 Hz, 1H), 6.98 6.95 (m, 2H), 6.67 (s, 1H), 5.72 (s, 2H), 3.87 (s, 3H), 3.79 - 3.71 (m, 2H), 3.65 - 3.59 (m, 1H), 3.58 (s, 3H), 3.41 (s, 2H) ), 2.60 - 2.54 (m, 2H), 2.14 - 2.03 (m, 3H), 1.99 (s, 3H), 1.96 (s, 2H), 1.76 - 1.69 (m, 1H), 1.60 - 1.46 (m, 12H ); MS (ESI): m / z 842.3 (M+H). 144 Example 161: Referring to the synthesis of compound 116, compound 161 was obtained by replacing 2-chloro-l,3-dibromobenzene with 2-methyl-l,3-dibromobenzene. JH NMR (500 MHz, DMSO-06) δ 7.92 (d, 7= 1.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.52 - 7.47 (m, 1H), 7.40 - 7.36 (m, 2H), 7.35 - 7.31 (m , 2H), 7.09 (d, 7 = 7.0 Hz, 1H), 6.93 - 6.88 (m, 2H), 6.65 (s, 1H), 5.72 (s, 2H), 3.87 (s, 3H), 3.78 - 3.71 ( m, 2H), 3.64 - 3.60 (m, 1H), 3.57 (s, 3H), 3.42 (s, 2H), 2.56 - 2.53 (m, 2H), 2.13 - 2.06 (m, 3H), 2.03 (s, 3H), 2.00 (s, 3H), 1.76 - 1.68 (m, 6H), 1.69 - 1.63 (m, 1H), 1.60 - 1.53 (m, 6H); MS (ESI): m / z 808.1 (M+H). Example 162: Starting from the compound INT-16 and trans-4-aminocyclohexanol, with reference to the synthesis of compound 101, the compound 162 is obtained.JH NMR (500 MHz, DMSO-o6) δ 7.93 (d, J = 1.0 Hz, 1H) , 7.76 (d, 7 = 8.5 Hz, 1H), 7.64 (s, 1H), 7.54 - 7.48 (m, 4H), 7.35 (s, 1H), 7.15 (d, 7 = 7.0 Hz, 1H), 6.98 - 6.94 (m, 2H), 6.67 (s, 1H), 5.71 (s, 2H), 4.43 (d, 7 = 4.5 Hz, 1H), 3.85 (s, 3H), 3.77 - 3.70 (m, 2H), 3.62 - 3.60 (m, 1H), 3.56 (s, 3H), 3.42 (s, 2H), 3.35 - 3.32 (m, 1H), 2.55 - 2.52 (m, 1H), 2.36 - 2.33 (m, 1H), 2.10 - 2.04 (m, 6H), 1.84 - 1.78 (m, 2H), 1.72 - 1.67 (m, 2H), 1.65 1.59 (m, 1H), 1.31 - 1.20 (m, 2H), 1.14 - 1.06 (m, 2H) ); MS (ESI): m / z 774.1 (M+H). Example 163: 145 With reference to the synthesis of compound 135, 4-aminobicyclo[2.2.2]octane-l-carboxylic acid methyl ester hydrochloride was replaced with trans-4-aminocyclohexanecarboxylic acid methyl ester hydrochloride to obtain the compound 163.4H NMR (500 MHz, DMSOdE) δ 7.88 - 7.83 (m, 1H), 7.81 - 7.75 (m, 1H), 7.71 - 7.61 (m, 2H), 7.55 - 7.44 (m, 4H), 7.15 - 7.09 (m, 1H), 6.99 - 6.92 (m, 2H), 5.83 - 5.76 (m, 2H), 3.88 - 3.83 (m, 3H), 3.76 - 3.70 (m, 2H), 3.59 3.54 (m, 1H), 3.40 - 3.38 (m, 2H), 3.37 - 3.36 (m, 3H), 2.51 - 2.50 (m, 2H), 2.35 - 2.30 (m, 1H), 2.10 - 2.03 (m, 6H), 1.90 - 1.81 (m , 3H), 1.76 - 1.69 (m, 2H), 1.68 - 1.61 (m, 1H), 1.24 - 1.16 (m, 4H); MS (ESI): m / z 803.1 (M+H). Example 164: Referring to the synthesis of compound 133, compound 164 was obtained by replacing 2-chloro-l,3-dibromobenzene with 2-methyl-l,3-dibromobenzene.JH NMR (500 MHz, DMSO-06) δ 7.81 - 7.77 (m, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.50 - 7.44 (m, 2H), 7.40 7.35 (m, 2H), 7.34 - 7.30 (m, 1H), 7.18 (d, J= 7 A Hz, 1H), 7.08 (d, J = 7.0 Hz, 1H), 6.65 (s, 1H), 5.70 (s, 2H), 3.88 ( s, 3H), 3.75 - 3.68 (m, 2H), 3.66 - 3.59 (m, 1H), 3.57 (s, 3H), 3.41 (s, 2H), 2.54 (d, J = 6.0 Hz, 2H), 2.15 - 2.05 (m, 3H), 2.09 (s, 3H), 1.99 (s, 3H), 1.75 - 1.69 (m, 6H), 1.69 - 1.65 (m, 1H), 1.59 - 1.52 (m, 6H); MS (ESI): m / z 791.0 (M+H). Example 165: At -78°C and a nitrogen atmosphere, diisobutylaluminum hydride (1 M in toluene, 30.6 ml) was slowly added dropwise to a solution of tetrahydrofuran (40 ml) with 5-bromo3-fluoro-2-pyri dinecarbonate (4.1 g, 20.4 mmol) dissolved. Then, the reaction solution was stirred at the same temperature for 2 hours. Then, water (50 ml) was added to the reaction solution and the solution was filtered with diatomaceous earth. The resulting filtrate was extracted with acetate 146 ethyl (50 mi x 2). The combined organic phase was washed with saturated saline (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain a white solid 165a (2.7 g, yield: 64.9%).MS (ESI): m / z 204.0 (M+H). From compound 165a, referring to the synthesis of compound 156a, compound 165b is obtained. MS (ESI): m / z 216.3 (M+H). Starting from compound 165b and 3-bromo-2-methylphenol, referring to the synthesis of compound INT-10 and compound 133, the compound 165.XH NMR (500 MHz, DMSO-úG) δ 8.44 (s, 1H), 7.83 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.52 - 7.48 (m, 1H), 7.46 - 7.43 (m, 1H), 7.42 - 7.38 (m, 2H), 7.37 - 7.33 (m, 1H), 7.19 (s, 1H), 7.09 (d, J = 6.9 Hz, 1H), 6.66 (s, 1H), 5.72 (s, 2H), 3.92 ( s, 3H), 3.78 - 3.69 (m, 2H), 3.67 - 3.60 (m, 1H), 3.58 (s, 3H), 3.43 - 3.38 (m, 2H), 2.55 (d, J= 6.0 Hz, 2H) , 2.15 - 2.06 (m, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.77 - 1.71 (m, 6H), 1.71 - 1.65 (m, 1H), 1.61 - 1.54 (m, 6H) ; MS (ESI): m / z 791.0 (M+H). Example 166: Referring to the synthesis of compound 135, compound 166 was obtained by replacing 2-chloro-l,3-dibromobenzene with 2-methyl-l,3-dibromobenzene.1H NMR (500 MHz, DMSO-O6) δ 7.87 (d, J = 1.0 Hz, 1H), 7.79 - 7.75 (m, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.50 - 7.46 (m, 1H), 7.41 - 7.37 (m, 1H), 7.36 - 7.29 (m, 2H), 7.09 - 7.05 (m, 1H), 6.95 - 6.89 (m, 2H), 5.82 (s, 2H), 3.88 (s, 3H), 3.80 - 3.72 (m, 2H), 3.65 - 3.55 (m, 1H), 3.38 (s, 3H), 3.35 - 3.30 (m, 2H), 2.54 - 2.50 (m, 2H), 2.13 - 2.05 (m, 3H), 2.02 (s, 6H), 1.76 - 1.70 (m, 6H), 1.69 - 1.64 (m, 1H), 1.60 - 1.53 (m, 6H); MS (ESI): m / z 809.1 (M+H). Example 167: 147 Referring to the synthesis of compound 133, compound INT-2 was replaced with compound 67a to obtain compound 167.1H NMR (500 MHz, DMSO-o6) δ 7.94 (s, 1H), 7.78 (d, 7 = 8.5 Hz, 1H), 7.69 (s, 1H), 7.57 - 7.49 (m, 4H), 7.39 (s, 1H), 7.16 (d, 7= 7.0 Hz, 1H), 7.05 - 6.97 (m, 2H), 6.69 (s, 1H), 5.72 (s, 2H), 3.87 (s, 3H), 3.78 - 3.71 (m, 2H), 3.59 - 3.53 (m, 1H), 3.58 (s, 3H), 3.42 (s, 2H) ), 2.54 - 2.53 (m, 2H), 2.11 - 2.04 (m, 3H), 2.00 (s, 3H), 1.75 - 1.70 (m, 6H), 1.67 - 1.63 (m, 1H), 1.60 - 1.54 (m , 6H); MS (ESI): m / z 828.1 (M+H). Example 168: Referring to the synthesis of compound 133, compound INT-2 was replaced with compound INT-18 to obtain compound 168.XH NMR (500 MHz, DMSO-o6) δ 7.94 (s, 1H), 7.78 (d, 7= 8.7 Hz, 1H), 7.55 - 7.50 (m, 4H), 7.39 (s, 1H), 7.19 - 7.11 (m, 2H), 7.01 - 6.97 (m, 2H), 6.69 (s, 1H), 5.72 (s, 2H), 3.87 (s, 3H), 3.75 - 3.70 (m, 2H), 3.58 (s, 3H), 3.42 (s, 2H), 3.36 3.35 (m, 1H), 2.53 - 2.52 (m, 2H), 2.12 - 2.07 (m, 2H), 2.00 (s, 3H), 1.76 - 1.70 (m, 8H), 1.58 - 1.54 (m, 7H), 1.34 - 1.27 (m, 1H); MS (ESI): m / z 842.1 (M+H). Example 169: Referring to the synthesis of compound 137, compound 169 was obtained by replacing 2-chloro-l,3-dibromobenzene with 2-methyl-l,3-dibromobenzene.XH NMR (500 MHz, DMSO-06) δ 7.81 (d, 7= 7.5 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.73 - 7.69 (m, 2H), 7.51 - 7.44 (m, 2H), 7.42 - 7.37 (m, 1H), 7.35 - 7.29 (m, 1H), 7.20 (d, 7= 7.5 Hz, 1H), 7.07 (d, 7= 7.5 Hz, 1H), 5.81 (s, 2H), 3.90 (s, 3H), 3.75 - 3.67 (m, 2H), 3.66 - 3.59 (m, 1H), 3.37 (s, 3H), 3.35 (s, 2H), 2.58 - 2.54 (m, 2H), 2.14 - 2.06 (m, 3H), 2.10 (s, 3H), 2.00 ( s, 3H), 1.75 - 1.66 (m, 7H), 1.61 - 1.44 (m, 6H); MS (ESI): m / z 792.2 (M+H). 148 Example 170: OMe 170 ,COOH At 0°C, a solution of water (50 mL) with sodium nitrite (10 g, 147 mmol) dissolved was slowly added dropwise to a mixed solution of acetonitrile and water (250 mL, v / v = 3 / 2 ) with 2-amino-5-bromo-3-methoxypyrazine (2 g, 9.8 mmol) and hydroiodic acid (57% w / w, 50 mL) predissolved. The reaction solution was heated to 50°C while stirring and reacted under the same conditions for 16 hours. The reaction solution was neutralized with 20% aqueous sodium hydroxide solution and extracted with ethyl acetate (100 ml x 2). The combined organic phase was washed with saturated sodium thiosulfate solution and saturated salt solution (150 ml each), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain a brown solid 170a (1.55 g, yield: 50.2%). Under a nitrogen atmosphere at -40 °C, isopropylmagnesium chloride-lithium chloride (1.3 M in tetrahydrofuran, 1.83 ml) was slowly added dropwise to a previously dissolved solution of compound 170a (500 mg, 1.6 mmol) in medium. tetrahydrofuran (10 ml). The reaction solution was further stirred for half an hour under the same conditions, and then N,N-dimethylformamide (1.2 ml) was slowly added after the temperature was raised to 15 °C; The resulting reaction solution was further stirred at 15 °C. for 2 hours. The reaction solution was neutralized with citric acid and extracted with ethyl acetate (50 ml x 2). The combined organic phases were washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain 170b as a pale yellow solid (300 mg, yield: 87.1%). MS (ESI): m / z 217.0 (M+H)» Starting from compound 165b and 3-bromo-2-methylphenol, with reference to the synthesis of compound INT-10 and compound 133, the compound 170.XH NMR (500 MHz, DMSO-06) δ 8.38 (s, 1H) was obtained ), 7.81 (s, 1H), 7.74 (d, 7 = 8.4 Hz, 1H), 7.67 (s, 1H), 7.53 (d, 7= 7.4 Hz, 1H), 7.51 7.46 (m, 1H), 7.44 - 7.37 (m, 3H), 7.09 (d, J= 7.0 Hz, 1H), 6.66 (s, 1H), 5.70 (s, 2H), 3.95 (s, 3H), 3.87 (s, 2H), 3.63 - 3.60 (m, 1H), 3.57 (s, 3H), 3.41 (s, 2H), 2.60 - 2.57 (m, 2H), 2.11 (s, 3H), 2.10 - 2.02 (m, 3H), 1.99 (s, 3H) ), 1.73 - 1.67 (m, 7H), 1.58 - 1.53 (m, 6H); MS (ESI): m / z 792.1 (M+H). 149 Example 171: From the compound INT-16, methyl trans-4-aminocyclohexanecarboxylate hydrochloride and tert-butyldimethylsiloxanylacetaldehyde, compound 171 was obtained by reference to the synthesis of the compound 125.XH NMR (500 MHz, DMSO-rá) δ 7.96 (s , 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.60 - 7.50 (m, 5H), 7.17 (d, J= 7.1 Hz, 1H), 7.09 - 6.99 (m, 2H), 6.69 (s, 1H), 5.73 (s, 2H), 3.89 (s, 3H), 3.85 - 3.80 (m, 2H), 3.78 - 3.47 (m, 5H), 3.60 (s, 3H), 2.56 - 2.53 (m, 2H), 2.16 - 2.04 (m, 5H), 1.94 - 1.87 (m, 2H), 1.81 - 1.65 (m, 4H), 1.63 - 1.53 (m, 1H), 1.31 - 1.20 (m, 4H); MS (ESI): m / z 832.0 (M+H). Example 172: Referring to the synthesis of compound 135, compound INT-2 was replaced with compound INT-18 to obtain compound 172. Ή NMR (500 MHz, DMSO-06) δ 7.88 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H), 7.57 - 7.47 (m, 4H), 7.17 - 7.12 (m, 2H), 7.01 - 6.96 (m, 2H), 5.81 (s, 2H), 3.88 (s, 3H), 3.76 - 3.69 (m, 2H), 3.38 (s, 3H), 3.36 - 3.29 (m, 3H), 2.57 - 2.53 (m, 2H), 2.15 - 2.05 (m, 2H), 2.00 (s, 3H), 1.79 - 1.68 (m, 8H), 1.60 - 1.52 (m, 7H), 1.35 - 1.28 (m, 1H); MS (ESI): m / z 843.1 (M+H). 150 Example 173: Concentrated sulfuric acid (1 ml) dissolved in potassium nitrate (55 mg, 0.54 mmol) was added dropwise to the previously dissolved methyl 3-chloro-4-methylbenzoate (100 mg, 0.54 mmol) at 0°C. The reaction solution was stirred under the same conditions for half an hour, then the reaction solution was poured into ice water and extracted with ethyl acetate (15 mL × 2). The combined organic phases were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give 173a (100 mg, yield: 80.4%) as a colorless oily substance.XH NMR ( 500 MHz, DMSO-o6) δ 8.13 (s, 1H), 7.93 (s, 1H), 3.83 (s, 3H), 2.44 (s, 3H). Starting from compound 173a and methyl trans-4aminocyclohexanecarboxylate hydrochloride, with reference to the synthesis of compound 72c and the reductive amination of compound 44, compound 173c was obtained. Zinc powder (44 mg, 0.67 mmol) was added to a solution of compound 173c (74 mg, 0.13 mmol) in acetic acid (4 ml); The resulting reaction solution was heated and stirred at 60 °C for 2 hours. After concentrating the reaction solution, ethyl acetate (20 ml) and saturated sodium bicarbonate solution (20 ml) were added, the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 173d. MS (ESI): m / z 519.0 (M+H). From compound 173d, compound INT-18 and compound INT-2, compound 173 was obtained by sequentially referring to the Suzuki reaction of compound INT-7, the reductive amination reaction of compound INT-3b and the reaction of ester hydrolysis 151 compound 33.1H NMR (500 MHz, DMSO-o6) δ 7.92 (s, 1H), 7.69 (d, 7 = 8.6 Hz, 1H), 7.64 (s, 1H), 7.55 - 7.46 (m, 4H), 7.15 (d, 7= 7.0 Hz, 1H), 7.04 (s, 1H), 6.98 - 6.96 (m, 2H), 6.23 (s, 1H), 5.60 (s, 2H), 5.38 (s, 2H), 3.86 ( s, 3H), 3.73 (d, 7= 4.3 Hz, 2H), 3.58 - 3.56 (m, 1H), 3.42 (s, 2H), 2.53 2.50 (m, 2H), 2.34 - 2.30 (m, 1H), 2.23 (brs, 1H), 2.10 - 1.95 (m, 3H), 2.03 (s, 3H), 1.92 - 1.86 (m, 2H), 1.77 -1.71 (m, 2H), 1.66 - 1.61 (m, 1H), 1.32 - 1.18 (m, 4H); MS (ESI): m / z 787.8 (M+H). Test example Detection of the biological activity of the inhibition of PD1 / PD-L1 signaling at the cellular level This detection method is used for the evaluation of the biological activity at the cellular level of the compounds of the present invention. Experimental principle This detection method uses the luciferase reporter gene method to detect the biological activity of the compound on the inhibition of PD-1 / PD-L1 signal at the cellular level.PD-l / NFAT - Reporter - Jurkat cells stably express human PD-1 and express the luciferase reporter gene regulated by NFAT elements; TCR / PD-L1 activator – CHO cells stably express human PD-L1 and TCR activating elements. When the two cell lines were cocultured, binding of PD-l / PD-L1 inhibited the TCR signaling pathway, thereby inhibiting the expression of the downstream NFAT-controlled luciferase reporter gene. PD-1 / PD-L1 inhibitor can be detected in luciferase activity. Experimental materials and equipment. PD-l / NFAT - Reporter - Jurkat cells (Cat. No. 60535) and TCR activator / PD-L1 CHO cells (Cat. No. 60536) were purchased from BPS Bioscience, PD-L1 antibody (Atezolizumab, Cat. No. A2004) was purchased from Selleck; Fluorescent Luciferase detection reagent (ONE-Glo™ Luciferase Assay System, Cat. No. E6120) was purchased from Promega Company; The multifunction microplate detector (Model SpectraMax ¡3x) was purchased from the company Molecular Devices. The main process of the experiment. PD-l / NFAT - Reporter - Jurkat cells and TCR activator / PD-L1 - CHO cells were cultured according to the routine cell culture protocol. TCR / PD-L1 activator: CHO cells were harvested and seeded in 96-well culture plates at 35,000 cells / well in a medium volume of 100 μΙ, and incubated at 37 °C overnight. The next day, the medium was discarded, the compound was added and incubated for 30 minutes. 152 while a solvent control (dimethyl sulfoxide, DMSO, final concentration of 0.1%) and PD-L1 antibody (Atezolizumab, final concentration of approximately 10 nM) were set as positive controls. PD-l / NFAT-reporter-Jurkat cells were then added. After culturing for 6 hours, luciferase activity was detected according to the instructions of the luciferase detection reagent. Using the PD-L1 antibody as a positive control, calculate the inhibition rate of PD-1 / PD-L1 binding of the test compound (%) = (chemiluminescence value of wells treated with the compound / mean value of the of chemiluminescence of the control wells with solvent-l) / (PD- Mean value of the chemiluminescence value of the antibody well Ll / mean value of the chemiluminescence value of the solvent control well - 1) χ 100%. According to the above detection method, the biological activity of the compounds of the present invention was evaluated at the cellular level, and the activity results are shown in the following table. Compound Number EC50 NFAT Luciferase (nM) Compound Number EC50 NFAT Luciferase (nM) 1 83 2 85 3 395 4 206 5 58 6 228 7 161 8 31 9 591 10 82 11 112 12 255 13 116 14 339 18 562 19 510 22 89 23 512 24 54 25 128 26 86 27 133 28 110 29 66 30 82 31 82 32 244 33 511 34 488 35 859 36 459 37 977 38 809 39 298 4 0 213 41 295 42 348 43 537 153 47 499 48 654 49 850 51 692 52 92 53 24 54 38 55 66 56 50 57 38 58 69 59 37 60 33 63 950 69 805 70 222 71 693 75 142 76 4 9 80 302 83 92 85 469 86 395 87 692 88 80 89 1110 90 150 91 92 92 15 93 21 94 142 95 15 96 45 97 273 98 520 99 62 100 745 101 87 102 735 103 208 104 46 105 20 106 43 107 20 108 63 109 44 110 495 111 1043 112 185 113 15 114 14 115 16 116 16 117 537 118 53 119 152 120 32 121 34 122 320 123 520 124 91 125 680 126 103 127 160 128 391 129 29 1 30 134 154 131 40 132 23 133 81 134 68 135 25 136 240 137 41 138 15 139 15 140 25 141 40 142 37 143 31 144 40 145 51 146 28 147 32 1 48 34 149 28 150 30 151 63 152 56 153 94 154 393 155 145 156 133 157 90 158 1011 159 37 160 46 161 75 162 44 163 26 164 105 165 98 166 49 167 53 168 69 169 59 170 265 171 40 172 32 173 222 Ref compound1 85 ινΐΛ / a / zuzz / uuou i o 1. The reference compound is from Example 40260 of patent US20180057455, Internal synthesis As can be seen from the above results, the compounds of the present invention can effectively inhibit PD-1 / PD-L1, with good PD-1 / 5 PD-L1 inhibitory activity.

Claims

1. A compound of formula (I) or one of its pharmaceutically acceptable salts, prodrugs, isotopic derivatives, isomers, solvates or metabolites: (R:% R3 R2 r^ji Xn / L3^_ XI 2 nM\ / Xl2'a T vu (R4)m Formula (I) Where, Li is selected from the groups: -CRARB- and -C(O)-; b, b are selected from the groups: -(CRCRD)P, -(CRcRD)P-NRa-(CRcRD)q-, -(CRcRD)PO-(CRcRD)q- and -C(O)-; Wi and W2 independently represent CRLo N; Each of R1 independently represents hydrogen, halogen, nitro, cyano or -NRaRb or CiCe alkyl, C3-C6 cycloalkyl, -O(Ci-C6 alkyl), -O(Co-Ce alkylene) (C3-C6 cycloalkyl) or -0(Co-C6 alkylene) (3-6 membered heterocycloalkyl) substituted with 0, 1, 2 or 3 substituents;the substituents are selected from: ORa, cyano, oxo, halogen, Ci-Ce alkyl, -(Ci-Ce alkylene) ORa, cyano Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C8 cycloalkyl, -C(O)Ra, -(Ci-Ce alkylene) C(O)Ra, -C(O)ORa, -(CiC6 alkyl) C(O)ORa, -NRaRb, -(Ci-C6 alkylene) NRaRb, -C(O)NRaRb, -SO2Ra, -C(O)NRaSO2Rb and NRaC(O)Rb; R2, R3, R4, R5 each independently represents hydrogen, halogen, nitro, cyano, -NRaRb, -SO2Ra, -S(O)Ra, -P(O)RaRb, Ci-Ce alkyl, -O(Ci-C6 alkyl), -O(C3-Ce cycloalkyl), halo(Ci-Ce alkyl) or C3-C6 cycloalkyl; Cy represents a benzene ring or a six-membered heteroaryl ring substituted by 0, 1, 2 or 3 R6, wherein the six-membered heteroaryl may optionally contain 1 or 2 nitrogen atoms;where R6 represents hydrogen, halogen, nitro, cyano, -NRaRb, -SO2Ra, -S(O)Ra, or -P(O)RaRb or Ci-Ce alkyl, -C3-C6 cycloalkyl, -O(Ci-C6 alkyl), -O(Co-Ce alkylene) (C5-C10 aryl), -O(Co-Ce alkylene) (5-10 membered heteroaryl), -O(CoCe alkylene) (C3-C6 cycloalkyl) or -O(Co-C6 alkylene) (3-6 membered heterocycloalkyl); substituted with 0, 1, 2 or 3 substituents, where the substituents selected from: -ORa, cyano, oxo, halogen, Ci-Cs alkyl, -(Ci-Ce alkylene)ORa, cyano Ci-Cb alkyl, C1-C6 haloalkyl, C3-C8 cycloalkane, -C(O)Ra, -(Ci-Ce alkylene) C(O)Ra, -C(O)ORa, -( Ci-Ce alkylene) C(O)ORa, -NRaRb, - (Ci-Ce iviA / a / zuzz / uuou 1 or 156 alkylene) NRaRb, -C(O)NRaRb, -SO2Ra, -C(O)NRaSO2Rb or -NRaC(O)Rb; Where, RL represents: hydrogen, Ci-Ce alkyl, -O(Ci-Ce alkyl), -O(C3-Ce cycloalkyl), halogen, nitro, cyano, -NRaRb, halo(Ci-Ce alkyl) or C3-C6 cycloalkyl;T and A each independently represent: -(Ci-Ce alkyl), -(Co-Ce alkylene)(C3-Ci2 cycloalkyl), -(Co-Ce alkylene)-(3-12 membered heterocycle), -(Co-Ce alkylene)-(C6-Ci aryl) or -(Co-Ce alkylene)-(5-10 membered heteroaryl), substituted with 0, 1, 2 or 3 substituents, wherein the substituents are selected from: cyano, oxo, halogen, Ci-Ce alkyl, -(Co-Ce alkylene)ORa, cyano Ci-Ce alkyl, halo (Ci-Ce alkyl), Cs-Cs cycloalkyl, -(Co-Ce alkylene)C(O)Ra, -(Co-Ce alkylene)C(O)ORa, -(Co-Ce alkenylene)C(O)ORa, -(Co-Ce alkylene)NRaRb, -C(O)NRaRb, -NRaSO2Rb, C(O)NRaSO2Rb and -NRaC(O)Rb; Where, RA and RB each independently represent: hydrogen, Ci-Ce alkyl, -(C0-C3 alkylene) (C3-Ci2 cycloalkyl), -(C0-C3 alkylene) (3-12 membered heterocycle), halo(Ci-Ce alkyl) or halogen, or RA and RB together with the carbon atoms to which they are commonly attached form a 3-6 membered ring;Rc and RD each independently represent: hydrogen, Ci-Ce-alkyl, -(C0-C3 alkylene) (C3C12 cycloalkyl), -(C0-C3 alkylene) (3-12 membered heterocycle), halo(Ci-C6 alkylene) or halogen, or Rc and RD together with the carbon atoms to which they are attached form a 3-6 membered ring; Ra and Rb each independently represent: hydrogen, Ci-Ce-alkyl, halo(Ci-Ce alkyl), -(CoCe alkylene)OH, -(C0-C3 alkylene) (Cs-Ci2 cycloalkyl), -(C0-C3 alkylene) (3-12 membered heterocycle), -(C0-C3 alkylene) (Ce-Cio aryl), -(C0-C3 alkylene) (5-10 membered heteroaromatic ring) or halo(Ci-Ce alkyl), or Ray Rb together with the atoms to which they are commonly attached form a 3-6 membered ring; Where, m, o, both independently represent 0, 1 or 2; Here, p, q, both independently represent 0, 1, 2 or 3.; 2. The compound of formula (I) or one of its pharmaceutically acceptable salts, prodrugs, isotopic derivatives, isomers, solvates or metabolites of claim 1, wherein said compound of formula (I) has the following structure of formula (II): (R5)o. R3 R2 ινΐΛ / a / zuzz / uuou 1 o 157 Where, R1, R2, R3, R4, R5, R6, Li, Lz, L3, T, A, Wi, W2, myo are as defined in claim 1; where r represents 0, 1, 2 or 3.

3. The compound of formula (I) or one of its pharmaceutically acceptable salts, prodrugs, isotopic derivatives, isomers, solvates or metabolites of claim 1, wherein said compound of formula (I) has the following structure of formula (III): Where, R1, R2, R3, R4, R5, R6, Li, Lz, L3, T, A, Wi, W2, myo are as defined in claim 1; Among them, W3 represents CRM or N; Where, RM represents: hydrogen, Ci-Ce alkyl, -O(Ci-Cs alkyl), -O(C3-Ce cycloalkyl), halogen, nitro, cyano, -NRaRb, halo(Ci-Ce alkyl) or C3-C6 cycloalkyl; Where r represents 0, 1 or 2.

4. The compound of formula (I) or a pharmaceutically acceptable salt, prodrug, isotopic derivative, isomer, solvate or metabolite thereof of claim 1, wherein said compound of formula (I) has the following structure of formula (IV): (R:% r3 r2 Where, R1, R2, R3, R4, R5, R6, Li, Lz, L3, T, A, Wi, W2, myo are as defined in claim 1; Among them, W4 represents CRNo N; Where, RN represents: hydrogen, Ci-Ce alkyl, -O(Ci-C6 alkyl), -O(C3-Ce cycloalkyl), halogen, nitro, cyano, -NRaRb, halogenated (Ci-Ce alkyl) or Cs-Cs cycloalkyl; Where r represents 0, 1 or 2.

5. The compound of any of claims 1 to 4, wherein Lise is selected from 158 -CRARB-, wherein RA and RBse are each independently selected from hydrogen, halogen, Ci-C& alkyl and halo (Ci-Ce alkyl), preferably hydrogen.

6. The compound of any one of claims 1 to 4, wherein L2 and l_3 are each independently selected from -CRcRD and -CRcRD -NRa- (CRcRD)q-, wherein q is selected from 0, 1 or 2, wherein Rc and RD are each independently selected from hydrogen, halogen, Ci-Ce alkyl and halo(Ci-Ce alkyl), preferably hydrogen. Ra is independently selected from hydrogen, Ci-Ce alkyl, halo(Ci-Ce alkyl) and -(C0-C3 alkylene)C3-C12 cycloalkyl.

7. The compound according to any one of claims 1 to 6, wherein Wi and W2 each independently represent CH or N.

8. The compound of any of claims 3, 5 or 6, wherein W3 represents CH or N.

9. The compound of any of claims 4 to 6, where W4 represents CH or N.

10. The compound according to any one of claims 1 to 9, wherein T and A each independently represent: -(Ci-Ce alkyl), -(Co-Ce alkylene)-(C3-C12 cycloalkyl) or -(Co-Ce alkylene)-(3-12 membered heterocycle), substituted by 0, 1, 2 or 3 substituents, wherein the substituents are selected from: cyano, oxo, halogen, Ci-Ce alkyl, -(CoCe alkylene)ORa, cyano Ci-Ce alkyl, halo(Ci-Ce alkyl), C3-C8 cycloalkyl, -(Co-Ce alkylene)C(O)Ra, (Co-Ce alkylene)C(O)ORa, -(Co-Ce alkenyl)C(O)ORa, -(Co-C6 alkylene)NRaRb, -C(O)NRaRb, -NRaSO2Rb, -C(O)NRaSO2Rby -NRaC(O)Rb, where Ra and Rb each independently represent hydrogen, CiCe alkyl or halo(Ci-Ce alkyl).

11. The compound of claim 10, wherein T and A each independently represent Ci-Ce alkyl, C3-C12 cycloalkyl or 3-12 membered heterocycle substituted with 0, 1 or 2 substituents, wherein the substituents are selected from: cyano, oxo, -ORa, -(Co-Cs alkylene)C(O)ORa, -(Co-C6 alkenyl)C(O)ORa, -NRaSO2Rb, -C(O)NRaSO2Rb and -NRaC(O)Rb, wherein Ray and Rb each independently represent hydrogen, Ci-Ce alkyl, or halo(Ci-Ce alkyl).

12. The compound of claim 11, wherein T and A each independently represent the following optionally substituted groups with 0, 1 or 2 substituents: 1 and \ (^Ta\vw N s , wherein the substituents are selected from Ci-Ce alkyl, -ORa, -(Co-Ce alkylene)C(O)ORa and -(Co-Ce alkenyl)C(O)ORa, wherein Ra represents hydrogen or Ci-Ce alkyl, preferably hydrogen, wherein a represents 1, 2 or 3.

13. The compound of claim 12, wherein T and A each independently represent the following groups:

17. The compound according to any one of claims 1 to 16, wherein R1 represents -O(Ci-Ce alkyl), -O(Co-C6 alkylene) (C5-C10 aryl), -O(Co-C6 alkylene) (5-10 membered heteroaryl), -O(Co-C6 alkylene) (C3-C6 cycloalkyl) or -O(Co-C6 alkylene) (36 membered heterocycloalkyl), substituted with 0, 1, 2 or 3 substituents, wherein the substituents are selected from: cyano, oxo, halogen, cyano Ci-Ce alkyl and C1-C6 haloalkyl.

18. The compound of any of claims 1 to 16, wherein R2 represents hydrogen, halogen, nitro, cyano, -SOzRa, Ci-Ce alkyl, halo(Ci-C6 alkyl) or C3-C6 cycloalkyl, wherein Ra represents hydrogen, Ci-Ce alkyl or halo(Ci-C6 alkyl).

19. The compound of any one of claims 1 to 16, wherein each of R3 and R4 independently represents hydrogen, halogen, nitro or cyano.

20. The compound of any one of claims 1 to 16, wherein R5 represents hydrogen, halogen, nitro, cyano, Ci-Ce alkyl, halo(Ci-Ce alkyl) or C3-C6 cycloalkyl.

21. The compound of any one of claims 1 to 16, wherein R6 represents hydrogen, halogen, nitro, cyano, -SÜ2Ra, Ci-Ce alkyl, halo(Ci-Ce alkyl) or C3-C6 cycloalkyl or -O(Ci-Ce alkyl), -O(Co-C6 alkylene) (C5-C10 aryl), -O(Co-C6 alkylene) (5-10 membered heteroaryl), O(Co-Ce alkylene) (C3-C6 cycloalkyl) or -O(Co-Ce alkylene) (3-6 membered heterocycloalkyl) substituted with 0, 1, 2 or 3 substituents; wherein the substituents are selected from: cyano, oxo, halogen, cyano-Ci-Ce alkyl and Ci-Ce haloalkyl. 161 22. The compound of any one of claims 1-21, wherein RL represents hydrogen or halogen.

23. The compound of any one of claims 3-21, wherein RM and RN each independently represent hydrogen. 5 24. Compounds having the following structures: 162 163 164 HOOC ΜΛ / a / ZUZZ / UUOU I or 165 ΜΛ / a / ZUZZ / UUOU I or och3 hooc'X'nYJ CI U OH d N c-vd ^vpcGdA hooc'^nYJ ci γΐ ° 'ΝΎ och3 h 0H HN \\ ) ° °=^X Η H OH HN d NC-YY YY r=NL >0 ^dddNd··7 ' od N 1 J O I H I d Y N J™ Λ. H nWv ¿i U °ΛΥ Η H OH ΥΓ HN ci-d~X CN o=^X Η HH HNZ \ / och3 OH 4vh HN Y ci---d~C OH Y0H HN d .odY? OH HN Y o2n^YY =.....oíe-0' OH -Qh HN T ci^dX .κΥίΥ V OH 4γΗ HN d =.....oíd3 MA / a / zuzz / uuem o 168 169 170 171 ΜΛ / a / ZUZZ oUU227 ΜΛ / a / ZUZZ / UUOU I o OMe 173 174 175 176 25. A pharmaceutical composition comprising a compound of any of claims 1 to 24 and optionally a pharmaceutically acceptable carrier.

26. Use of the compound of any of claims 1 or 24 or the pharmaceutical composition 5 of claim 25 in the manufacture of a medicament for the prevention or treatment of a disease or condition that responds to the inhibition of PD-L1 binding to PD1.

27. The use of claim 26, wherein the disease or disorder is selected from the group consisting of tumors, cancer, viral infections, inflammation-related diseases, and autoimmune diseases.

28. A method for treating a disease or condition that responds to inhibition of PD-L1 binding to PD-1, comprising administering to a mammal in need a compound of any of claims 1 to 24 or claim 25 of the pharmaceutical composition.

29. - A method for inhibiting the combination of PD-L1 and PD-1, comprising exposing the compound of any of claims 1 to 24 or the pharmaceutical composition of claim 25 to PD-L1 and / or PD-1.