RIPK1 inhibitor and preparation method therefor and pharmaceutical use thereof

Abstract

The present invention relates to a novel compound for inhibiting receptor interacting protein kinase 1 (RIPK1), and a use thereof in the preparation of drugs for treating or preventing RIPK1-mediated diseases. Specifically, the present invention relates to a compound represented by the general formula or a tautomer thereof, or a pharmaceutically acceptable composition comprising same.

Description

TECHNICAL FIELD The present disclosure relates to a novel compound for inhibiting receptor-interacting protein kinase 1 (RIPK1) and use thereof in preparing a medicament for treating or preventing a RIPK1-mediated disease. Specifically, the present disclosure relates to a compound represented by a general formula, a tautomer thereof, or a pharmaceutically acceptable composition thereof. BACKGROUND Receptor-interacting protein kinase 1 (RIPK1) is a key signaling protein in the TNF receptor signaling pathway. It has an amino-terminal (N-terminal) kinase domain, a carboxyl-terminal (C-terminal) death domain, and a receptorinteracting protein homotypic interacting motif (RHIM) intermediate domain, and can bind to other RHIM-containing proteins. The C-terminal death domain mediates homodimerization and heterodimerization with other death domaincontaining proteins (e.g., FADD, TNFR1, and Fas), while the N-terminal kinase domain mediates autophosphorylation in trans to facilitate its own activation. RIPK1 drives apoptosis and programmed necrosis by two different mechanisms. Apoptosis is mediated by caspases, while RIPK1 and its downstream RIPK3 and MLKL will activate the programmed cell necrosis pathway in the absence of apoptotic conditions. The important role of RIPK1 in driving cell death and inflammation, the established safety of inhibiting RIPK1 kinase activity in humans, and the presence of a unique allosteric pocket for kinase regulation are major factors contributing to the prominence of RIPK1 as a therapeutic target. Therefore, RIPK1 has gradually become one of the effective targets for treating various diseases such as autoimmune diseases, inflammation, and neurodegenerative diseases, and a plurality of RIPK1 inhibitors have demonstrated their efficacy and safety in preclinical models and clinical trials. Among them, Necrostatin-1s (Nec-1s) is the first small molecule inhibitor of RIPK1 kinase developed. ABBV-668 from Abbvie and SAR443122 from Sanofi are both in phase II clinical trials for ulcerative colitis, the registered clinical trial indication for SIR1-365 from Sironax is systemic inflammation, and the clinical trial indications for the brain penetrant SAR443820 from Sanofi are amyotrophic lateral sclerosis and multiple sclerosis. Stroke is an acute cerebrovascular disease. It is classified into ischemic stroke and hemorrhagic stroke. The latter is caused by a sudden rupture of blood vessels in the brain, and the former is caused by the inability of blood to flow into the brain due to blockage of blood vessels. Among them, the ischemic stroke has a higher incidence rate than the hemorrhagic stroke, accounting for 60%-70% of the total number of cerebral stroke cases. Stroke is characterized by high incidence, high mortality, and high disability rate. The pathological process of ischemic stroke includes excitotoxicity, oxidative stress, inflammatory response, and the like. The therapeutic mechanism of the marketed drug edaravone is to play an antioxidant role through free radical scavenging, thereby achieving neuroprotection. After the occurrence of ischemic stroke, apoptosis occurring in the penumbra of the brain (the area around the ischemic core) is salvageable, and RIPK1 is a key part of the necroptosis signaling pathway. In addition, since TNFR2 has a protective effect in the central nervous system and RIPK1 kinase does not stimulate signals via TNFR2, RIPK1 is a safer target for the treatment of central nervous system diseases as compared to TNF inhibitors. The small molecule inhibitors for RIPK1 kinase activity developed at present mainly focus on the treatment of peripheral inflammation, and have the defects of insufficient specificity, poor inhibitory activity and the like. Therefore, we have developed a small molecule compound with RIPK1 inhibitory activity, antioxidant capacity, and free radical scavenging capacity to treat ischemic stroke by resisting oxidation and blocking programmed cell necrosis, so as to meet the huge market demand. SUMMARY The present disclosure provides a compound represented by Formula (A), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, (A) wherein: X1 is selected from the group consisting of CH or N; X1a is selected from the group consisting of CR1a or N; X1b is selected from the group consisting of CR1b or N; X1c is selected from the group consisting of CR1c or N; X1d is selected from the group consisting of CR1d or N; X1e is selected from the group consisting of CR1e or N; R1a, R1b, R1c, R1d, and R1e are each independently selected from the group consisting of: H, halogen, C1-6 alkyl, -(C=O)-NH-OH, or cyano; R2a, R2b, and R2c are each independently selected from the group consisting of: H, halogen, or C1-6 alkyl; *    X ...... ■ ■   n    X3 ^5 A is selected from the group consisting of        X4     or X2 is selected from the group consisting of CR2 or N; X3 is selected from the group consisting of CR3 or N; X4 is selected from the group consisting of CR4 or N; X5 is selected from the group consisting of CR5 or N; R2, R3, R4, and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; L is selected from the group consisting of a single bond, C1-3 alkylene, -NH-, -O-, or     ^'; B is selected from the group consisting of N or / R8 nA V N OH ; R7 is selected from the group consisting of O, O O OH ^KrOH , or       R9    ; O kA.r OH A N i R8 is selected from the group consisting of: H, C1-6 alkyl, C1-6 haloalkyl,      R9   , or cyano; R9 is selected from the group consisting of: H or C1-6 alkyl. In some embodiments of the present disclosure, further provided is a compound represented by Formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: X1 is selected from the group consisting of CH or N; R1a, R1b, R1c, R1d, and R1e are each independently selected from the group consisting of: H, halogen, C1-6 alkyl, or cyano; R2a, R2b, and R2c are each independently selected from the group consisting of H or halogen; ...... • •     „   X3 y X5 A is selected from the group consisting of     X4 X2* II X5 or  X3 X4 A X2 is selected from the group consisting of CR2 or N; X3 is selected from the group consisting of CR3 or N; X4 is selected from the group consisting of CR4 or N; X5 is selected from the group consisting of CR5 or N; R2, R3, R4, and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; A N^ B is selected from the group consisting of     N or      OH . In some embodiments of the present disclosure, provided is the compound of Formula (A) or (I), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein L is selected from the group consisting of a single bond, C1-3 alkylene (e.g., -CH2-, -CH2CH2-, -CH2CH2CH2-, or -O CH(CH3)-), -NH-, -O-, or     ^'; (1) k X AV4 W ...... ..-   X3v.Xs     X3v4  X3v-.X5     X3vA,t A is selected from the group consisting of        X4    ,        X4 *4      X4    , or      X4 < ; X2 is selected from the group consisting of CR2; X3 is selected from the group consisting of CR3; X4 is selected from the group consisting of CR4; X5 is selected from the group consisting of CR5; R2, R3, R4, and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; or (2) A is selected from the group consisting of )¾^ x4 , or X2 is selected from the group consisting of N; X3 is selected from the group consisting of CR3; X4 is selected from the group consisting of CR4; X5 is selected from the group consisting of CR5; R3, R4, and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; or (3) A is selected from the group consisting of L\  X2 V      _.X 2p     2X X2p X3x4X5 or X2 is selected from the group consisting of N; X3 is selected from the group consisting of N; X4 is selected from the group consisting of CR4; X5 is selected from the group consisting of CR5; R4 and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; or (4) vup* yL^x^  y X2 v y X2 X X X J5  XX X P A is selected from the group consisting of       3 x4 5 ,       3 x4 ^,    3 x4 5 , or    3 x4 X2 is selected from the group consisting of N; X3 is selected from the group consisting of CR3; X4 is selected from the group consisting of N; X5 is selected from the group consisting of CR5; R3 and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; or (5) Vl  x2 y yL\^X2.   y X2 y   X^^x ^ ]\ X X \\   X5  P f Ml   X5 .                               . .           x3 .,x5        x3 -A /    x3 ,x5        x3 A is selected from the group consisting of        x4    ,        x4 x',      x4    , or      x4 X2 is selected from the group consisting of N; X3 is selected from the group consisting of CR3; X4 is selected from the group consisting of CR4; X5 is selected from the group consisting of N; R3 and R4 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; or (6) % L   X2  < -^^^^^2^  >VX2y^ Il |                Il X5     ' II I " Il    X5 A is selected from the group consisting of       3 X4 5 ,       3 X4 ^,    3X4 5 , or 3X4 A; X2 is selected from the group consisting of CR2; X3 is selected from the group consisting of N; X4 is selected from the group consisting of CR4; X5 is selected from the group consisting of N; R2 and R4 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; other groups are as defined herein. In some embodiments of the present disclosure, provided is the compound represented by Formula (A) or Formula (I), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein R2 R2 O O O , R3 R5 R3 R5 R5, R2 N^N R4    , or R3 R4      , R4      , R4      , R4    , R4      , R3 A is selected from the group consisting of        R4     , ,        R4 O   R2 N.^N ,         R4 R2 R5 ,       R4 O R2 , R3 O R4 R5 R4      , R2 , R2, R3, R4, and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; other groups are as defined herein. In some embodiments of the present disclosure, provided is the compound represented by Formula (A) or Formula (I), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein A is selected from the group consisting of R5 is selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; other groups are as defined herein. In some embodiments of the present disclosure, provided is the compound represented by Formula (A) or Formula (I), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein / * N': B is selected from the group consisting of x:: N or      Oh ; the carbon atom with “*” is a chiral carbon atom present in the form of a single (R)- or (S)- enantiomer or in a form enriched with one enantiomer; other groups are as defined herein. In some embodiments of the present disclosure, provided is the compound represented by Formula (A) or Formula (I), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein (S)T \ (R)k. X S-'X. V N        N     -\-N'X B is selected from the group consisting of      N ,      N , or     OH ; other groups are as defined herein. In some embodiments of the present disclosure, provided is the compound represented by Formula (A) or Formula (I), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein R1a, R1b, R1c, R1d, and R1e are each independently selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, -(C=O)-NH-OH, or cyano; R2a, R2b, and R2c are each independently selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R2, R3, R4, and R5 are each independently selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; / R8          O         O -.X Z;’~ X" R7 is selected from the group consisting of      O , \ N         , or      R9   ; R8 is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-O X^m- OH X N 1 trifluoroethyl, 2,2,2-trichloroethyl,      R9   , or cyano; R9 is selected from the group consisting of: H, methyl, ethyl, n-propyl, or isopropyl; other groups are as defined herein. In some embodiments of the present disclosure, provided is the compound represented by Formula (I), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein R1a, R1b, R1c, R1d, and R1e are each independently selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, or cyano; R2a, R2b, and R2c are each independently selected from the group consisting of: H, F, Cl, Br, or I; R2, R3, R4, and R5 are each independently selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; other groups are as defined herein. In some embodiments of the present disclosure, provided is a compound represented by Formula (IIA) or (IIB), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, R1c 1 O N I N R1d R1e (S) R1b N 1a O R2b R2c R2a (IIA) wherein: X1 is selected from the group consisting of CH or N; R1a, R1b, R1c, R1d, and R1e are each independently selected from the group consisting of: H, halogen, C1-6 alkyl, or cyano; R2a, R2b, and R2c are each independently selected from the group consisting of H or halogen; X2 A       X2 ...... ■ ■     .   X3 v' X5 A is selected from the group consisting of     X4     or X2 is selected from the group consisting of CR2 or N; X3 is selected from the group consisting of CR3 or N; X4 is selected from the group consisting of CR4 or N; X5 is selected from the group consisting of CR5 or N; R2, R3, R4, and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy. In some embodiments of the present disclosure, provided is the compound represented by Formula (IIA) or (IIB), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein nr T" nr > X3  2X5         Xsw'''  .^ A is selected from the group consisting of     X4     or      X4 ^'; X2 is selected from the group consisting of CR2; X3 is selected from the group consisting of CR3; X4 is selected from the group consisting of CR4; X5 is selected from the group consisting of CR5; R2, R3, R4, and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; other groups are as defined herein. In some embodiments of the present disclosure, provided is the compound represented by Formula (IIA) or (IIB), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein A is selected from the group consisting of T T X3X4X5 qf r or X3X4  ^; X2 is selected from the group consisting of N; X3 is selected from the group consisting of CR3; X4 is selected from the group consisting of CR4; X5 is selected from the group consisting of CR5; R3, R4, and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; other groups are as defined herein. In some embodiments of the present disclosure, provided is the compound represented by Formula (IIA) or (IIB), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein A is selected from the group consisting of 4 V X3Y^5 X4 or X2 is selected from the group consisting of N; X3 is selected from the group consisting of N; X4 is selected from the group consisting of CR4; X5 is selected from the group consisting of CR5; R4 and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; other groups are as defined herein. In some embodiments of the present disclosure, provided is the compound represented by Formula (IIA) or (IIB), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein A is selected from the group consisting of X3y.X5 X4 X2 is selected from the group consisting of N; X3 is selected from the group consisting of CR3; X4 is selected from the group consisting of N; X5 is selected from the group consisting of CR5; R3 and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; other groups are as defined herein. In some embodiments of the present disclosure, provided is the compound represented by Formula (IIA) or (IIB), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein A is selected from the group consisting of X3y.X5 X4 or X2 is selected from the group consisting of N; X3 is selected from the group consisting of CR3; X4 is selected from the group consisting of CR4; X5 is selected from the group consisting of N; R3 and R4 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; other groups are as defined herein. In some embodiments of the present disclosure, provided is the compound represented by Formula (IIA) or (IIB), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein X2-A   ^VX^x -p  p x5 X3 ' X5      X3y^V A is selected from the group consisting of     X4     or      X4 < ; X2 is selected from the group consisting of CR2; X3 is selected from the group consisting of N; X4 is selected from the group consisting of CR4; X5 is selected from the group consisting of N; R2 and R4 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; other groups are as defined herein. In some embodiments of the present disclosure, provided is the compound represented by Formula (IIA) or (IIB), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein R5 is selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy; other groups are as defined herein. In some embodiments of the present disclosure, provided is the compound represented by Formula (IIA) or (IIB), the pharmaceutically acceptable salt thereof, or the stereoisomer thereof described above, wherein R1a, R1b, R1c, R1d, and R1e are each independently selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, or cyano; R2a, R2b, and R2c are each independently selected from the group consisting of: H, F, Cl, Br, or I; X2 '    VVX2v A is selected from the group consisting of    3 X4 5 or 3 X4    ; X2 is selected from the group consisting of CR2 or N; X3 is selected from the group consisting of CR3 or N; X4 is selected from the group consisting of CR4 or N; X5 is selected from the group consisting of CR5 or N; R2, R3, R4, and R5 are each independently selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n- propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments of the present disclosure, provided are compound shown below, pharmaceutically acceptable salts thereof, or stereoisomers thereof: F F N 17 16 F O N I N Cl Cl Br 65 F F Cl 74 OOH N 86 94 NN 81 84 92 69 Br F 82 85 93 NH Oh N'N^ Ox / V- N J Oh O , OH Br =N 114 113     F F F F (±)-96    F The present disclosure also provides a pharmaceutical composition, which comprises any one of the compounds or pharmaceutically acceptable salts thereof described above and a pharmaceutically acceptable carrier. The pharmaceutical composition may be prepared in various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections, or various sustained-release and controlled-release preparations. The pharmaceutical composition may be administered orally or parenterally (e.g., intravenously, subcutaneously, or topically). The administration dose may be suitably adjusted depending on the age, gender, and type of disease of a patient, and is generally about 1-1000 mg per day. The present disclosure also provides use of the compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, or the pharmaceutical composition described above in treating and / or preventing a disease in a patient, and use of the compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, or the pharmaceutical composition described above in preparing a medicament. The present disclosure also provides use of the compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, or the pharmaceutical composition thereof described above in preparing a medicament for treating or preventing a receptor-interacting protein kinase 1 (RIPK1)-mediated related disease or a disease caused by programmed cell necrosis. The receptorinteracting protein kinase 1 (RIPK1)-mediated related disease or the disease caused by programmed cell necrosis includes diseases / disorders that are susceptible to modulation, at least in part, via programmed necrosis, apoptosis, or production of inflammatory cytokines, such as inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, juvenile idiopathic arthritis (systemic-onset juvenile idiopathic arthritis (SoJIA)), and psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren’s syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, osteoarthritis, liver injury / liver disease (nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen toxicity, and hepatotoxicity), nonalcoholic fatty liver disease (NAFLD), kidney damage / kidney injury (nephritis, kidney transplantation, surgery, and administration of nephrotoxic drugs, e.g., cis-platinum, and acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplanted organs, tissues, and cells), reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, ischemic brain injury, traumatic brain injury, allergic disease (including asthma and atopic dermatitis), peripheral nerve injury, burns, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener’s granulomatosis, pulmonary sarcoidosis, Behcet’s disease, interleukin-1 converting enzyme (ICE, also known as caspase-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neoplastic tumors, periodontitis, NEMO-mutation (also known as mutation of NF-k-B essential modulator gene (KKy or IKKG), particularly NEMO-deficiency syndrome, HOIL-1 deficiency (as known as RBCK1), and heme-oxidized IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial and viral infections (such as influenza, staphylococcus, and mycobacterium (tuberculosis)), lysosomal storage disease (which is particularly Gaucher’s disease, and includes GM2 gangliosidosis, a-mannosidosis, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon’s disease, Fabry’s disease, Farber’s disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe’s disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick’s disease, neuronal ceroid lipofuscinosis, Pompe’s disease, pycnodysostosis, Sandhoff’s disease, Schindler’s disease, sialidosis, familial amaurotic idiocy, and Wolman’s disease), Stevens-Johnson syndrome, toxic epidermal necrolysis, glaucoma, spinal cord injury, fibrosis, complement-mediated cytotoxicity, cancer (including pancreatic cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, melanoma, metastatic tumors, breast cancer, and nonsmall cell lung cancer (NSCLC)), radiation-induced necrosis, ischemic kidney damage, ocular ischemia, cerebral hemorrhage, subarachnoid hemorrhage, acute liver failure and radiation protection / alleviation, auditory disorders such as noise-induced hearing loss and drugs associated with ototoxicity (e.g., cis-platinum) or for in vitro treatment of cells to preserve viability and functions. Definitions and Explanations Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase, when not specifically defined, should not be considered indefinite or unclear, but should be construed according to its common meaning. When referring to a trade name, it is intended to refer to its corresponding commercial product or its active ingredient. The term “pharmaceutically acceptable” is described in the present disclosure for the compounds, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio. The term “pharmaceutically acceptable salt” described in the present disclosure refers to a salt of the compound of the present disclosure, which is prepared from the compound having particular substituents of the present disclosure and a relatively nontoxic acid or base. When the compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Examples of the pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts, and also include salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid. Certain particular compounds of the present disclosure contain basic functional groups, such that the compounds are allowed to be converted into any acid addition salts. Certain compounds of the present disclosure may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereoisomers, geometric isomers, and individual isomers are all included within the scope of the present disclosure. Compounds of the present disclosure comprise one or more asymmetric centers (also known as chiral centers), such as a chiral carbon or a chiral-SO-moiety. The stereochemistry of a chiral carbon center present in the compound of the present disclosure is generally indicated by the compound name and / or chemical structure shown herein. The compounds of the present disclosure containing one or more chiral centers may exist in the form of racemic mixtures, diastereomeric mixtures, enantiomerically enriched mixtures, diastereomerically enriched mixtures, or enantiomerically or diastereomerically pure individual stereoisomers. For example: * N'^ i                                                . =1 N , wherein the carbon atom with “*” is a chiral carbon atom that may be present in the form of a single (R)- or (S)- enantiomer or in a form enriched with one enantiomer, or may be present in the form of a racemic mixture. The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated herein, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereoisomerically enriched mixtures, all of which fall within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and mixtures thereof are encompassed within the scope of the present disclosure. Unless otherwise stated, the term “enantiomer” refers to stereoisomers that are mirror images of each other. Unless otherwise stated, the term “geometric isomer” results from the inability of a single bond of a ring carbon atom or a double bond to rotate freely. Unless otherwise stated, the term “diastereoisomer” refers to stereoisomers whose molecules have two or more chiral centers and are not mirror images of each other. Unless otherwise stated, “(D)” or “(+)” stands for dextrorotation, “(L)” or “(-)” stands for levorotation, and “(DL)” or “(±)” stands for racemization. Unless otherwise stated, the absolute configuration of a stereogenic center is represented by a wedged solid bond (    ) and a wedged dashed bond (    ), and the relative configuration of a stereogenic center is represented by a straight solid bond (    ) and a straight dashed bond (   ). A wavy line ( -  ) represents a wedged solid bond ( -^ ) or a wedged dashed bond (    ), or a wavy line ( -  ) represents a straight solid bond (    ) and a straight dashed bond (    ). The pharmaceutically acceptable salt of the present disclosure may be synthesized from the parent compound containing an acid radical or a basic group by conventional chemical methods. In general, the salt is prepared by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture thereof. The term “pharmaceutically acceptable carrier” refers to any preparation or carrier medium that is capable of delivering an effective amount of the active substance of the present disclosure, does not interfere with the biological activity of the active substance, and has no toxic or side effects in a host or a patient; representative carriers include, but are not limited to: binders, fillers, lubricants, disintegrants, wetting agents, dispersing agents, solubilizers, suspending agents, etc. The present disclosure is intended to include all isotopes of atoms present in the compounds of the present disclosure. Isotopes include those atoms having the same atomic number but different mass numbers. As a general and nonlimiting example, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13C and 14C. Isotopically labeled compounds of the present disclosure may generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise used. Unless otherwise specified, “alkyl” is used to refer to a linear or branched saturated hydrocarbon group, and it may be monosubstituted (e.g., -CH2F) or polysubstituted (e.g., -CF3) and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). For example, C1-C6 represents 1 to 6 carbons, and C1-6 is selected from the group consisting of C1, C2, C3, C4, C5, or C6. Examples of alkyl include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, and t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, and 1-ethylpropyl), hexyl (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl), and the like. Unless otherwise specified, “halogen”, by itself or as part of another substituent, refers to a fluorine, chlorine, bromine, or iodine atom. Unless otherwise specified, the term “cyano” refers to the group -CN. Unless otherwise specified, “alkoxy” is used to represent the alkyl (including cycloalkyl or haloalkyl) having the specified number of carbon atoms connected through an oxygen bridge. Typical alkoxy includes C1-6 alkoxy, e.g., alkoxy of C1, C2, C3, C4, C5, and C6, cycloalkoxy of C3, C4, C5, and C6, and haloalkoxy of C1, C2, C3, C4, C5, and C6. Examples of alkoxy include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, t-butoxy, n-pentyloxy, S-pentyloxy, hexyloxy, and 2-ethylbutoxy. Examples of cycloalkoxy include, but are not limited to: cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. Examples of haloalkoxy include, but are not limited to: fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy. Unless otherwise specified, “haloalkyl” is used to refer to an alkyl group substituted with one or more halogen atoms, wherein the alkyl group is as defined herein. For example, the term “C1-C6 haloalkyl” is intended to include C1, C2, C3, C4, C5, and C6 alkyl, etc., substituted with one or more halogen atoms. Unless otherwise specified, examples of C1-C6 haloalkyl include, but are not limited to: fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and pentachloroethyl. Unless otherwise specified, the term “cycloalkyl” includes any stable cyclic or polycyclic hydrocarbon group in which any carbon atom is saturated, and it may be monosubstituted or polysubstituted and may be monovalent, divalent, or polyvalent. Typical cycloalkyl includes C3-6 cycloalkyl, for example, C3, C4, C5, or C6 cycloalkyl, i.e., 3membered, 4-membered, 5-membered, or 6-membered cycloalkyl. Examples of these cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Unless otherwise specified, the term “oxo” refers to the divalent group =O. Compounds are named either manually or by ChemDraw® software, and supplier’s catalog names are given for commercially available compounds. DETAILED DESCRIPTION The present disclosure is further illustrated below with reference to specific examples and test examples, but the scope of the present disclosure is not limited in any way. The compound structure of the present disclosure was determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (5) was given in parts per million (ppm). The NMR analysis was performed by using an AVANCE III600 nuclear magnetic resonance apparatus, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as determination solvents and tetramethylsilane (TMS) as an internal standard. The LC-MS analysis was performed by using a Japan Shimadzu LCMS2020 mass spectrometer. The HPLC analysis was performed by using a Japan Shimadzu LC20A liquid chromatograph. The Yantai Jiangyou silica gel plate was adopted as a thin layer chromatography silica gel plate. The specification adopted by the TLC was 0.2 mm ± 0.03 mm, and the specification adopted by the thin layer chromatography for product separation and purification was 0.4 mm-0.5 mm. Unless otherwise specifically stated in the examples, SFC resolution conditions are as follows: column model: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 pm); mobile phase: [CO2-i-PrOH / ACN]; B%: 40%, isocratic elution mode. In the description of the following examples, the reagent abbreviations used and the corresponding reagent names are as follows: Reagent abbreviation Reagent name tBuXPhonsPd G3 [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1 '-biphenyl)-2-(2'-amino-1,1 '-biphenyl)]palladium(II) methanesulfonate tBuXPhosPdG4 Methanesulfonato(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1 '-biphenyl)(2'-methylamino-1,1 '-biphenyl-2-yl)palladium(II) PyBrOP Bromotripyrrolidinophosphonium hexafluorophosphate HATU O-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate TFA Trifluoroacetic acid Example 1: Synthesis of Compounds 1, 1A, and 1B F 1 Synthetic route: 1-3 1-5 1-6 1-7 1 Step 1: synthesis of compound 1-2 Compound 1-1 (25 g, 159.02 mmol, 24.51 mL, 1 eq) and compound 1-bromo-3-iodobenzene (53.99 g, 190.83 mmol, 24.33 mL, 1.2 eq) were dissolved in anhydrous dimethyl sulfoxide (250 mL), and then cuprous iodide (6.06 g, 31.80 mmol, 0.2 eq), L-proline (1.83 g, 15.90 mmol, 0.1 eq), and potassium carbonate (21.98 g, 159.02 mmol, 1 eq) were added. The mixture was allowed to react at 100 °C for 12 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was poured into water (1 L) and extracted with ethyl acetate (1 L x 3). The organic phase was washed with saturated brine (1 L x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was pre-adsorbed onto silica gel and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to give compound 1-2 (34 g, 108.90 mmol, 68.48% yield) in the form of a light yellow oil. MS (ESI) m / z = 312.0 [M+H]+. 1H NMR (400 MHz, CDCI3) 5 7.17 - 7.07 (m, 1H), 7.05 (s, 1H), 6.98 - 6.92 (m, 1H), 6.85 (dd, J = 1.6, 8.4 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.64 (td, J = 3.6, 12.4 Hz, 2H), 2.88 - 2.76 (m, 2H), 2.45 (ddd, J = 4.0, 7.2, 11.0 Hz, 1H), 2.08 - 1.97 (m, 2H), 1.93 - 1.79 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H). Step 2: synthesis of compound 1-3 Compound 1-2 (31 g, 99.29 mmol, 1 eq) and di-tert-butyl hydrazodicarboxylate (23.06 g, 99.29 mmol, 22.18 mL, 1 eq) were dissolved in anhydrous toluene (310 mL), and then tBuXPhons G3 (7.89 g, 9.93 mmol, 0.1 eq) and cesium carbonate (64.70 g, 198.59 mmol, 2 eq) were added. The mixture was heated to 100 °C and allowed to react for 12 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was poured into water (1.5 L), extracted with ethyl acetate (1 L x 3), washed with saturated brine (1 L x 2), filtered, dried, and concentrated. The residue was pre-adsorbed onto silica gel, and the crude product was purified by normal-phase silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to give compound 1-3 (32.7 g, 70.54 mmol, 64.58% yield) in the form of a white solid. (ESI) m / z = 464.3 [M+H]+. 1H NMR (400 MHz, CDCl3) 5 = 7.19 (t, J = 8.0 Hz, 1H), 7.07 - 6.96 (m, 1H), 6.88 (br d, J = 7.6 Hz, 1H), 6.75 (dd, J = 2.0, 8.4 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.63 (td, J = 3.6, 12.4 Hz, 2H), 2.79 (br s, 2H), 2.48 - 2.37 (m, 1H), 2.04 - 1.96 (m, 2H), 1.94 - 1.80 (m, 2H), 1.50 (s, 18H), 1.30 - 1.26 (m, 3H). Step 3: synthesis of compound 1-4 Compound 1-3 (32.7 g, 70.54 mmol, 1 eq) was dissolved in methanol (120 mL), tetrahydrofuran (120 mL), and water (120 mL), and then lithium hydroxide monohydrate (8.88 g, 211.62 mmol, 3 eq) was added. The mixture was allowed to react at 30 °C for 2 h. After TLC (petroleum ether:ethyl acetate = 5:1) showed that the starting material was consumed completely and new spots were generated, the reaction solution was adjusted to pH = 6 with diluted hydrochloric acid, extracted with ethyl acetate (300 mL x 3), washed with saturated brine (500 mL x 2), dried, and concentrated to give compound 1-4 (34.3 g, crude product) in the form of a yellow solid, which was directly used in the next step. (ESI) m / z = 436.3 [M+H]+. 1H NMR (400 MHz, CDCl3) 5 7.19 - 7.12 (m, 1H), 7.01 (br s, 1H), 6.87 (br d, J = 5.6 Hz, 2H), 6.72 (br d, J = 8.0 Hz, 1H), 3.58 (br d, J = 12.0 Hz, 2H), 2.80 - 2.69 (m, 2H), 2.44 - 2.35 (m, 1H), 1.99 (br d, J = 12.4 Hz, 2H), 1.82 (q, J = 10.6 Hz, 2H), 1.49 (s, 18H). Step 4: synthesis of compound 1-6 An aqueous sodium hydroxide solution (1 M, 738.90 mL, 1.05 eq) was added dropwise to a solution of compound 1-5 (100 g, 703.72 mmol, 77.16 mL, 1 eq) and compound acetaldehyde (116.25 g, 1.06 mol, 148.09 mL, 40% purity, 1.5 eq) in water (600 mL) at 0 °C. The reaction solution was allowed to react at 25 °C for 18 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was filtered, and the filter cake was washed with water (200 mL x 2). The filtered solid was collected to give a product, compound 1-6 (100 g, 463.90 mmol, 65.92% yield), in the form of a yellow solid. (ESI) m / z = 169.3 [M+H]+. Step 5: synthesis of compound 1-7 A solution of compound 1-6 (10 g, 59.47 mmol, 1 eq) in tetrahydrofuran (50 mL) was added slowly and dropwise to a solution of hydrazine hydrate (15.04 g, 300.44 mmol, 14.57 mL, 5.05 eq) in tetrahydrofuran (50 mL) at 25 °C for over 1 h. After the dropwise addition, the reaction solution was allowed to react at 25 °C for 2 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was concentrated under reduced pressure. The residue was purified by normal-phase silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to give product 1-7 (6 g, 29.64 mmol, 49.84% yield) in the form of a white solid. (ESI) m / z = 183.0 [M+H]+. 1H NMR (400 MHz, CDCI3) 5 6.95 - 6.84 (m, 2H), 6.81 (d, J = 1.4 Hz, 1H), 6.71 (tt, J = 2.4, 8.8 Hz, 1H), 4.71 (t, J = 10.2 Hz, 1H), 3.16 (ddd, J = 1.8, 10.8, 17.0 Hz, 1H), 2.65 (ddd, J = 1.6, 9.4, 17.0 Hz, 1H). Step 6: synthesis of compound 1-8 Compound 1-4 (1 g, 2.30 mmol, 1 eq) and compound 1-7 (627.43 mg, 3.44 mmol, 1.5 eq) were dissolved in anhydrous dichloromethane (15 mL), and then bromotripyrrolidinophosphonium hexafluorophosphate (1.28 g, 2.76 mmol, 1.2 eq) and N,N-diisopropylethylamine (890.28 mg, 6.89 mmol, 1.20 mL, 3 eq) were added. The mixture was allowed to react at 20 °C for 2 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated, and the residue was pre-adsorbed onto silica gel. The crude product was purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give compound 18 (1.2 g, 2.00 mmol, 87.15% yield) in the form of a yellow solid. (ESI) m / z = 600.4 [M+H]+. Step 7: synthesis of compound 1-9 Compound 1-8 (600 mg, 1.00 mmol, 1 eq) was dissolved in anhydrous dichloromethane (7.5 mL), and then trifluoroacetic acid (2.30 g, 20.19 mmol, 1.5 mL, 20.18 eq) was added at 0 °C. After the addition, the mixture was allowed to react at 20 °C for 2 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated under reduced pressure to give compound 1-9 (395 mg, 988.89 nmol, 98.83% yield) in the form of a yellow oil. (ESI) m / z = 400.2 [M+H]+. Step 8: synthesis of compound 1 Compound 1-9 (395 mg, 988.89 nmol, 1 eq) was dissolved in acetonitrile (5 mL), and then compound ethyl acetoacetate (128.70 mg, 988.89 nmol, 125.19 uL, 1 eq) was added. The mixture was heated to 60 °C and allowed to react for 1 h. After LCMS analysis showed that the starting material was consumed completely and a product was generated, the reaction solution was separated and purified by an ODS C18 preparative reverse-phase column chromatography [water (formic acid)-acetonitrile system] to give a crude product. The crude product was then subjected to silica gel column chromatography [n-hexane-ethanol system], and the fractions were concentrated under reduced pressure. Deionized water was added to the residue, and the mixture was lyophilized to give compound 1 (90 mg, 192.03 nmol, 19.42% yield, 99.32% purity) in the form of a white solid. (ESI) m / z = 466.2 [M+H]+. 1H NMR (400 MHz, CDCl3) 5 7.49 (t, J = 2.0 Hz, 1H), 7.36 - 7.32 (m, 1H), 7.27 - 7.23 (m, 1H), 6.97 (s, 1H), 6.78 (dd, J = 1.9, 8.1 Hz, 1H), 6.74 - 6.66 (m, 3H), 5.34 (dd, J = 5.0, 12.0 Hz, 1H), 3.83 - 3.74 (m, 2H), 3.50 - 3.38 (m, 3H), 3.29 - 3.20 (m, 1H), 2.91 - 2.75 (m, 3H), 2.20 (s, 3H), 2.07 - 2.00 (m, 1H), 1.98 - 1.90 (m, 3H). 1A Step 9: synthesis of compounds 1-8A and 1-8B Compound 1-8 (5 g, 8.34 mmol, 1 eq) was purified by chiral resolution [carbon dioxide-acetonitrile / ethanol (0.1% ammonium hydroxide solution)] to give compound 1-8A (2.7 g, 4.50 mmol, 54% yield) in the form of a yellow solid and compound 1-8B (2.2 g, 3.67 mmol, 44% yield) in the form of a yellow solid. SFC: column model: (s,s) WHELK-O1 (250 mm x 30 mm, 10 ^m); mobile phase: [CO2-ACN / EtOH (0.1% NH3H2O)]; B%: 60%, isocratic elution mode. Compound 1-8A (retention time = 1.243 min); compound 1-8B (retention time = 2.433 min). Compound 1A (473 mg, 1.00 mmol, 23.57% yield, white solid) was obtained using a synthesis method similar to that of compound 1. (ESI) m / z = 466.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.50 (s, 1H), 7.38 - 7.30 (m, 1H), 7.27 - 7.21 (m, 1H), 6.98 (s, 1H), 6.79 (br d, J = 7.4 Hz, 1H), 6.75 - 6.64 (m, 3H), 5.34 (dd, J = 5.0, 12.0 Hz, 1H), 3.83 - 3.74 (m, 2H), 3.49 - 3.39 (m, 2H), 3.31 - 3.19 (m, 1H), 2.92 - 2.74 (m, 3H), 2.20 (s, 3H), 2.07 - 1.99 (m, 1H), 1.98 - 1.86 (m, 3H). SFC (column model: Lux 3 ^m Cellulose-4 50 x 4.6 mm I.D., 3 ^m; mobile phase: Phase A for CO2, and Phase B for MeOH (0.05% DEA); gradient elution: 30% to 60% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 Bar); retention time = 1.755 min. Compound 1B (841 mg, 1.79 mmol, 55.10% yield, 99.14% purity, white solid) was obtained using a synthesis method similar to that of compound 1. (ESI) m / z = 466.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.48 (s, 1H), 7.35 - 7.30 (m, 1H), 7.27 - 7.22 (m, 1H), 6.97 (s, 1H), 6.77 (dd, J = 1.6, 8.2 Hz, 1H), 6.73 - 6.66 (m, 3H), 5.34 (dd, J = 5.2, 12.0 Hz, 1H), 3.84 - 3.74 (m, 2H), 3.50 - 3.37 (m, 3H), 3.30 - 3.18 (m, 1H), 2.92 - 2.73 (m, 3H), 2.20 (s, 3H), 2.06 - 1.99 (m, 1H), 1.98 - 1.87 (m, 3H). SFC (column model: Lux 3 ^m Cellulose-2 50 x 4.6 mm I.D., 3 ^m; mobile phase: Phase A for CO2, and Phase B for MeOH (0.05% DEA); gradient elution: 30% to 60% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 Bar); retention time = 2.353 min. Second synthesis method of compound 1B: 1B-1 1B-2 1B-3 F Br 1B-5 Boc F O N - N H N NH2 1B-6 F 1B Step 1: synthesis of compound 1B-1 Compound 1-Boc-4-piperidinecarboxylic acid (6.25 g, 27.26 mmol) was dissolved in dichloromethane (50 mL) at room temperature, and then bromotripyrrolidinophosphonium hexafluorophosphate (13.43 g, 28.80 mmol) was added, and diisopropylethylamine (3.55 g, 27.45 mmol, 4.78 mL) was added dropwise. The mixture was stirred for 5 min, and then compound 1-7 (5 g, 27.45 mmol) was added. The mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated by rotary evaporation to remove dichloromethane, followed by concentration. The residue was purified by normal-phase chromatography (silica, petroleum ether / ethyl acetate = 3 / 1) and concentrated to dryness by rotary evaporation to give intermediate 1B-1 (8.92 g, 20.63 mmol, yellow oil, 75.17% yield). (ESI) m / z = 416.2 [M+Na]+. Step 2: synthesis of compound 1B-2 Compound 1B-1 (8 g, 4.58 mmol) was dissolved in dichloromethane (12.5 mL), and the solution was stirred at 20 °C. Hydrogen chloride / dioxane (2 M, 266.58 mmol, 133.29 mL) was added. The reaction solution was stirred at 20 °C for 4 h. The reaction mixture was subjected to suction filtration to give a white solid, and the filter cake was washed twice with dichloromethane (5 mL) to give intermediate 1B-2 (8 g, white solid powder, 97.70% yield). (ESI) m / z = 294.2 [M+H]+. Step 3: synthesis of compound 1B-3 Intermediate 1B-2 (8 g, 24.26 mmol) was added to ethanol (25 mL), and an aqueous sodium hydroxide solution (19.75 mL, 1 M, 3.07 mmol) was then added to the mixed solution. The mixture was stirred at 20 °C for 30 min, and then dichloromethane (10 mL) was added. The mixed solution was separated into two layers and transferred to a separating funnel, and then the organic phase was discharged. The aqueous phase was extracted twice with dichloromethane (10 mL). The organic phase was concentrated by rotary evaporation to give an oil. The oil was dissolved in ethanol (25 mL), and L-camphorsulfonic acid (5.64 g, 24.26 mmol) was added. The mixture was stirred at 60 °C for 30 min. The reaction solution was concentrated by rotary evaporation, and the residue was slurried with ethanol (16 mL). The mixture was then concentrated by rotary evaporation to remove ethanol, thus giving an orange solid. Ethanol (96 mL) was added to the orange solid, and the mixture was stirred and warmed to 60 °C until the reaction solution was clear. The reaction solution was then naturally cooled, recrystallized, and subjected to suction filtration to give L-camphorsulfonate of intermediate 1B-3 (2 g, white solid, 12.98% yield). SFC (column model: Chiralpak IG-3 50 x 4.6 mm I.D., 3 um; mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); gradient elution: EtOH (0.05% DEA) in CO2 from 5% to 40%, flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 Bar); retention time = 1.841 min. Steps 4-6: synthesis of compound 1B Compound 1B was obtained by using L-camphorsulfonate of intermediate 1B-3 and a synthesis method similar to that of compound 1. SFC (column model: Lux 3 um Cellulose-2 50 x 4.6 mm I.D., 3 ^m; mobile phase: Phase A for CO2, and Phase B for MeOH (0.05% DEA); gradient elution: 30% to 60% MeOH (0.05% DEA) in CO2, flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 Bar); retention time = 2.353 min. Example 2: Synthesis of Compounds 2, 2A, and 2B Synthetic route: 1-4 SFC N\ 2A N N. Step 1: synthesis of compound 2-1 Intermediate 2-1 (yellow solid) was obtained using a synthesis method similar to that in Example 1. (ESI) m / z = 564.4 [M+H]+. Step 2: synthesis of compounds 2A-1 and 2B-1 Compound 2-1 (1.8 g, 3.19 mmol) was subjected to chiral resolution, and the fractions were concentrated under reduced pressure to give 2A-1 (850 mg, 1.43 mmol, 44.86% yield, retention time = 1.411 min) and 2B-1 (830 mg, 1.40 mmol, 43.81% yield, retention time = 1.647 min) in the form of light yellow solids. Step 3: synthesis of compounds 2, 2A, and 2B Compound 2 (white solid) was obtained by using compound 2-1 and a synthesis method similar to that in Example 1, (ESI) m / z = 430.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 11.61 - 10.89 (m, 1H), 7.35 - 7.29 (m, 2H), 7.26 -7.17 (m, 4H), 7.15 - 7.06 (m, 3H), 6.85 - 6.72 (m, 1H), 5.44 - 5.18 (m, 2H), 3.77 - 3.66 (m, 2H), 3.55 - 3.42 (m, 1H), 3.28 - 3.20 (m, 1H), 2.86 - 2.72 (m, 2H), 2.71 - 2.63 (m, 1H), 2.09 (s, 3H), 1.94 - 1.86 (m, 1H), 1.82 - 1.74 (m, 1H), 1.71 - 1.58 (m, 2H). Compound 2A (white solid hydrochloride) was obtained by using compound 2A-1 and a synthesis method similar to that in Example 1, (ESI) m / z = 430.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 8.14 - 7.62 (m, 2H), 7.55 (br s, 2H), 7.39 - 7.05 (m, 7H), 5.50 (s, 1H), 5.34 (dd, J = 4.6, 11.8 Hz, 1H), 3.80 - 3.37 (m, 6H), 2.70 (br dd, J = 4.6, 18.8 Hz, 1H), 2.29 - 1.88 (m, 7H). SFC (column model: Chiralpak AD-3 50 x 4.6 mm I.D., 3 um; mobile phase: Phase A for CO2, and Phase B for IPA (0.05% DEA); gradient elution: IPA (0.05% DEA) in CO2 from 20% to 60%, flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 Bar); retention time = 1.922 min. Compound 2B (white solid hydrochloride) was obtained by using compound 2B-1 and a synthesis method similar to that in Example 1, (ESI) m / z = 430.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 8.09 - 7.58 (m, 2H), 7.57 - 7.42 (m, 2H), 7.42 - 7.04 (m, 7H), 5.48 (s, 1H), 5.34 (dd, J = 4.6, 11.8 Hz, 1H), 3.72 - 3.43 (m, 6H), 2.76 - 2.64 (m, 1H), 2.24 - 1.88 (m, 7H). SFC (column model: Chiralpak AD-3 50 x 4.6 mm I.D., 3 um; mobile phase: Phase A for CO2, and Phase B for IPA (0.05% DEA); gradient elution: IPA (0.05% DEA) in CO2 from 20% to 60%, flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 Bar); retention time = 2.258 min. Example 3: Synthesis of Compound 3 Synthetic route: 1-1 3-1 H2Nx XBOC 3-3 3-2 Step 1: synthesis of compound 3-1 Potassium carbonate (8.79 g, 63.61 mmol, 2 eq) was added to a solution of compound 1-1 (5 g, 31.80 mmol, 4.90 mL, 1 eq) and compound 2-bromo-6-fluoropyridine (5.60 g, 31.80 mmol, 1 eq) in acetonitrile (50 mL). The reaction solution was allowed to react at 60 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was filtered, and the filtrate was purified by normal-phase silica gel column chromatography (ethyl acetate:petroleum ether = 1:0 to 5:1) and then concentrated under reduced pressure to give compound 3-1 (8.4 g, 26.82 mmol) in the form of a light yellow oil. (ESI) m / z = 313.0 [M+H]+. Step 2: synthesis of compound 3-2 Cesium carbonate (10.92 g, 33.53 mmol, 3 eq) and tBuXPhosPdG4 (998.33 mg, 1.12 mmol, 0.1 eq) were added to a solution of compound 3-1 (3.5 g, 11.18 mmol, 1 eq) and compound tert-butyl carbazate (2.22 g, 16.76 mmol, 1.5 eq) in dioxane (50 mL). The reaction solution was allowed to react at 100 °C for 12 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was filtered, and the filtrate was poured into water (200 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by normal-phase silica gel column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:1) and then concentrated under reduced pressure to give compound 3-2 (3.8 g, 10.43 mmol, 93.30% yield) in the form of a brownish-black solid. (ESI) m / z = 365.1 [M+H]+. Step 3: synthesis of compound 3-3 Lithium hydroxide monohydrate (656.33 mg, 15.64 mmol, 3 eq) was added to a solution of compound 3-2 (1.9 g, 5.21 mmol, 1 eq) in methanol (20 mL) and water (2 mL). The reaction solution was allowed to react at 30 °C for 4 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was adjusted to pH 5-6 with a 2 M aqueous hydrochloric acid solution and then extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by normal-phase silica gel column chromatography (ethyl acetate:petroleum ether = 5:1 to 1:5) and then concentrated under reduced pressure to give compound 3-3 (0.3 g, 847.24 mmol, 16.25% yield) in the form of a brownish-black solid. (ESI) m / z = 337.1 [M+H] +. Step 4: synthesis of compound 3-4 Compound 3-3 (450 mg, 1.34 mmol, 1 eq) and compound 5-phenyl-4,5-dihydro-1H-pyrazole (215.12 mg, 1.47 mmol, 1.1 eq) were dissolved in anhydrous dichloromethane (12 mL), and then bromotripyrrolidinophosphonium hexafluorophosphate (748.36 mg, 1.61 mmol, 1.2 eq) and N,N-diisopropylethylamine (518.67 mg, 4.01 mmol, 699.02 uL, 3 eq) were added. The mixture was allowed to react at 20 °C for 2 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated, and the residue was preadsorbed onto silica gel. The crude product was purified by normal-phase silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to give compound 3-4 (350 mg, 753.40 nmol, 56.32% yield) in the form of a yellow solid. (ESI) m / z = 465.3 [M+H]+. Step 5: synthesis of compound 3-5 Compound 3-4 (320 mg, 688.83 nmol, 1 eq) was dissolved in anhydrous dichloromethane (6 mL), and then trifluoroacetic acid (1.84 g, 16.16 mmol, 1.2 mL, 23.45 eq) was added at 0 °C. The mixture was allowed to react at 20 °C for 1 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated to give compound 3-5 (250 mg, 685.98 umol, 99.59% yield) in the form of a yellow oil. (ESI) m / z = 365.2 [M+H]+. Step 6: synthesis of compound 3 Compound 3-5 (250 mg, 685.98 Limol, 1 eq) was dissolved in acetonitrile (5 mL), and then compound ethyl acetoacetate (89.27 mg, 685.98 umol, 86.84 liL, 1 eq) was added. The mixture was heated to 60 °C and allowed to react for 16 h. After LCMS analysis showed that the starting material was consumed completely and a product was generated, the reaction solution was separated and purified by preparative reverse-phase chromatography [water (formic acid)-acetonitrile system] to give a crude product. The crude product was then subjected to silica gel column chromatography [n-hexane-ethanol system], and the fractions were concentrated under reduced pressure. Deionized water was added to the residue, and the mixture was lyophilized to give compound 3 (41.1 mg, 89.70 umol, 13.08% yield, 93.96% purity) in the form of a white solid. (ESI) m / z = 431.1 [M+H]+. 1H NMR (400 MHz, CDCh) 5 13.67 - 12.10 (m, 1H), 7.59 (t, J = 8.2 Hz, 1H), 7.34 - 7.30 (m, 2H), 7.27 - 7.22 (m, 1H), 7.18 - 7.10 (m, 3H), 7.00 (s, 1H), 6.47 (d, J = 8.6 Hz, 1H), 5.43 - 5.32 (m, 2H), 4.08 - 3.95 (m, 2H), 3.49 - 3.35 (m, 2H), 3.16 - 3.03 (m, 2H), 2.84 (ddd, J = 1.8, 4.8, 18.8 Hz, 1H), 2.25 (s, 3H), 2.08 - 1.94 (m, 2H), 1.91 - 1.78 (m, 2H). Example 4: Synthesis of Compound 4 4 Synthetic route: Step 1: synthesis of compound 4-1 Compound 3-3 (450 mg, 1.34 mmol, 1 eq) and compound 1-7 (365.55 mg, 2.01 mmol, 1.5 eq) were dissolved in anhydrous dichloromethane (12 mL), and then bromotripyrrolidinophosphonium hexafluorophosphate (748.36 mg, 1.61 mmol, 1.2 eq) and N,N-diisopropylethylamine (518.67 mg, 4.01 mmol, 699.02 LL, 3 eq) were added. The mixture was allowed to react at 20 °C for 2 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated, and the residue was pre-adsorbed onto silica gel. The crude product was purified by normal-phase silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to give compound 4-1 (290 mg, 579.37 mmol, 43.31% yield) in the form of a yellow oil. (ESI) m / z = 501.3 [M+H]+. Step 2: synthesis of compound 4-2 Compound 4-1 (260 mg, 519.44 Lmol, 1 eq) was dissolved in anhydrous dichloromethane (6 mL), and then trifluoroacetic acid (1.84 g, 16.16 mmol, 1.2 mL, 31.10 eq) was added at 0 °C. The mixture was allowed to react at 20 °C for 1 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated to give compound 4-2 (100 mg, 249.74 nmol, 48.08% yield) in the form of a yellow oil. (ESI) m / z = 401.2 [M+H]+. Step 3: synthesis of compound 4 Compound 4-2 (80 mg, 199.79 nmol, 1 eq) was dissolved in ethanol (2.5 mL), and then ethyl acetoacetate (26.00 mg, 199.79 nmol, 25.29 uL, 1 eq) was added. The mixture was heated to 50 °C and allowed to react for 16 h. After LCMS analysis showed that the starting material was consumed completely and a product was generated, the reaction solution was separated and purified by ODS C18 reverse-phase column chromatography [water (formic acid)-acetonitrile system] and then lyophilized to give compound 4 (6.8 mg, 14.15 Limol, 7.08% yield, 97.07% purity). (ESI) m / z = 467.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 7.80 - 7.41 (m, 1H), 7.25 (s, 1H), 7.11 (t, J = 9.0 Hz, 1H), 6.84 (d, J = 6.8 Hz, 3H), 5.34 (dd, J = 4.8, 11.8 Hz, 2H), 4.61 - 3.93 (m, 2H), 3.48 (dd, J = 12.2, 19.0 Hz, 1H), 3.38 (m, 2H), 3.12 - 2.82 (m, 2H), 2.75 (dd, J = 5.0, 18.6 Hz, 1H), 2.17 (s, 3H), 1.92 (d, J = 10.8 Hz, 1H), 1.83 - 1.70 (m, 1H), 1.66 - 1.42 (m, 2H). Example 5: Synthesis of Compound 5 F Synthetic route: O                                      0 Boc                                              Boc 1-1                                      5-1                                               5-2                                                5-3 Step 1: synthesis of compound 5-1 Potassium carbonate (14.65 g, 106.02 mmol, 2 eq) was added to a solution of compound 1-1 (10 g, 63.61 mmol, 9.80 mL, 1.2 eq) and 5-bromo-chloropyridine (10.20 g, 53.01 mmol, 1 eq) in N,N-dimethylformamide (100 mL). The reaction solution was allowed to react at 120 °C for 12 h. After LCMS analysis showed that a small amount of starting material remains and the main peak was the target product, the reaction solution was poured into water (1 L), extracted with ethyl acetate (400 mL x 3), washed with brine (400 mL x 3), dried over anhydrous sodium sulfate, and concentrated in vacuum, and the filtrate was purified by normal-phase silica gel column chromatography (ethyl acetate:petroleum ether = 1:0 to 9:1) and then concentrated under reduced pressure to give compound 5-1 (10.6 g, 33.85 mmol, 63.85% yield) in the form of a light yellow oil. (ESI) m / z = 313.0 [M+H]+. Step 2: synthesis of compound 5-2 Cesium carbonate (33.08 g, 101.54 mmol, 3 eq) and methanesulfonato(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (1.51 g, 1.69 mmol, 0.05 eq) were added to a solution of compound 5-1 (10.6 g, 33.85 mmol, 1 eq) and compound di-tert-butyl hydrazodicarboxylate (11.79 g, 50.77 mmol, 11.34 mL, 1.5 eq) in dioxane (100 mL). The reaction solution was allowed to react at 100 °C for 12 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was filtered, and the resulting crude product was purified by normalphase silica gel column chromatography (ethyl acetate:petroleum ether = 1:10 to 2:1) and then concentrated under reduced pressure to give compound 5-2 (12 g, 25.83 mmol, 76.32% yield) in the form of a pale yellow oil. (ESI) m / z = 465.3 [M+H]+. Step 3: synthesis of compound 5-3 Lithium hydroxide monohydrate (309.33 mg, 12.92 mmol, 3 eq) was added to a solution of compound 5-2 (2 g, 4.31 mmol, 1 eq) in methanol (10 mL), tetrahydrofuran (10 mL), and water (10 mL). The reaction solution was allowed to react at 20 °C for 12 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was adjusted to pH 5-6 with a 2 M aqueous hydrochloric acid solution and then extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 5-3 (1.5 g, 2.78 mmol, 64.65% yield, 81% purity) in the form of a pale yellow solid. (ESI) m / z = 435.3 [M-H]+. Step 4: synthesis of compound 5-4 N,N-Diisopropylethylamine (1.60 g, 12.37 mmol, 2.15 mL, 3 eq) and bromotripyrrolidinophosphonium hexafluorophosphate (2.88 g, 6.19 mmol, 1.5 eq) were added to a solution of compound 5-3 (1.8 g, 4.12 mmol, 1 eq) and compound 1-7 (1.05 g, 5.77 mmol, 1.4 eq) in dichloromethane (20 mL). The reaction solution was allowed to react at 20 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was directly filtered. The resulting crude product was purified by normal-phase silica gel column chromatography (ethyl acetate:petroleum ether = 1:0 to 2:1) and then concentrated under reduced pressure to give compound 5-4 (2 g, 3.33 mmol, 80.75% yield) in the form of a yellow gel. (ESI) m / z = 601.4 [M+H]+. Step 5: synthesis of compound 5-5 A solution of hydrochloric acid in dioxane (2 M, 20 mL) was added to compound 5-4 (2 g, 4.25 mmol, 1 eq). The reaction solution was allowed to react at 20 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was directly concentrated under reduced pressure to give a crude product of compound 5-5 (1.7 g), which was directly used in the next step. (ESI) m / z = 401.1 [M+H]+. Step 6: synthesis of compound 5 Compound 5-5 (1.7 g, 4.25 mmol, 1 eq) was dissolved in ethanol (17 mL), and then compound ethyl acetoacetate (552.52 mg, 4.25 mmol, 537.47 liL, 1 eq) was added. The mixture was heated to 60 °C and allowed to react for 12 h. After LCMS analysis showed that the starting material was consumed completely and a product was generated, the reaction solution was filtered, and the filtrate was separated and purified by preparative reverse-phase chromatography [water (formic acid)-acetonitrile system] and then lyophilized to give compound 5 (457.2 mg, 931.10 pmol, 21.93% yield). (ESI) m / z = 467.1 [M+H]+. 1H NMR (400 MHz, CDCI3) 5 8.59 (d J = 2.6 Hz, 1H), 7.90 (dd, J = 9.2, 2.6 Hz, 1H), 6.98 (s, 1H), 6.73 - 6.64 (m, 4H), 5.33 (dd, J = 12.0, 5.0 Hz, 1H), 4.39 - 4.28 (m, 2H), 3.50 - 3.29 (m, 4H), 3.04 - 2.90 (m, 2H), 2.78 (ddd, J = 18.8, 5.0, 1.6 Hz, 1H), 2.19 (s, 3H), 2.01 - 1.79 (m, 4H). Example 6: Synthesis of Compound 6 Synthetic route: O 6-5 6-4 N'NH2 H N' Boc Boc , NHBoc 6-2        Boc H N N Boc 6-3 Boc Step 1: synthesis of compound 6-1 (2S)-Pyrrolidine-2-carboxylic acid (732.34 mg, 6.36 mmol, 0.1 eq), cuprous iodide (2.42 g, 12.72 mmol, 0.2 eq), and potassium carbonate (8.79 g, 63.61 mmol, 1 eq) were added to a solution of the starting material 1-1 (10 g, 63.61 mmol, 9.80 mL, 1 eq) and the starting material p-bromoiodobenzene (21.59 g, 76.33 mmol, 1.2 eq) in dimethyl sulfoxide (100 mL). The mixture was purged with nitrogen three times and then stirred at 100 °C for 18 h in a nitrogen atmosphere. After LCMS analysis showed that the reaction was completed, the mixture was poured into water (200 mL) and extracted twice with dichloromethane (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give intermediate 6-1 (12.5 g, 41.54% yield, pale yellow solid). (ESI) m / z = 312.0 [M+H]+. Step 2: synthesis of compound 6-2 tBuXphos Pd G3 (1.27 g, 1.60 mmol, 0.1 eq) and cesium carbonate (15.65 g, 48.05 mmol, 3 eq) were added to a solution of intermediate 6-1 (7.5 g, 24.02 mmol, 5.37 mL, 1 eq) and the compound di-tert-butyl hydrazodicarboxylate (5.58 g, 24.02 mmol, 5.37 mL, 1.5 eq) in toluene (70 mL). The mixture was purged with nitrogen three times and then stirred at 110 °C for 18 h. After LCMS analysis showed that the reaction was completed, the mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0 to 7 / 3) to give intermediate 6-2 (5 g, 67.35% yield, pale yellow solid). (ESI) m / z = 464.3 [M+H]+. Step 3: synthesis of compound 6-3 A 1 M aqueous lithium hydroxide solution (1 M, 32.36 mL, 3 eq) was added to a solution of intermediate 6-2 (5 g, 10.79 mmol, 1 eq) in methanol (100 mL). The mixture was stirred at 25 °C for 18 h. After LCMS analysis showed that the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to remove methanol. The reaction solution was then adjusted to pH = 5-6 with 1 N aqueous hydrochloric acid solution in an ice bath and extracted twice with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate 6-3 (4.5 g, 94.074% yield, pale yellow solid). (ESI) m / z = 436.2 [M+H]+. Step 4: synthesis of compound 6-4 Compound 6-3 (500 mg, 1.15 mmol, 1 eq) and compound 1-7 (250.97 mg, 1.38 mmol, 1.2 eq) were added to anhydrous dichloromethane (7.5 mL), and bromotripyrrolidinophosphonium hexafluorophosphate (802.81 mg, 1.72 mmol, 1.5 eq) and N,N-diisopropylethylamine (741.90 mg, 5.74 mmol, 999.86 uL, 5 eq) were added to the reaction solution. The mixture was allowed to react at 25 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by normal-phase silica gel column chromatography (petroleum ether / ethyl acetate = 30%-50%) to give compound 6-4 (600 mg, 83.05% yield, 95.3% purity) in the form of a colorless oil. (ESI) m / z = 600.4 [M+H]+. 1H NMR (400 MHz, CDCI3) 5 7.26 - 7.20 (m, 1H), 6.97 (s, 1H), 6.88 (br d, J = 9.2 Hz, 2H), 6.76 - 6.65 (m, 4H), 5.34 (dd, J = 4.8, 12.2 Hz, 1H), 3.70 (br d, J = 9.2 Hz, 2H), 3.50 - 3.37 (m, 1H), 3.28 - 3.17 (m, 1H), 2.87 - 2.72 (m, 3H), 2.03 - 1.88 (m, 4H), 1.49 (s, 18H). Step 5: synthesis of compound 6-5 Compound 6-4 (500 mg, 833.80 umol, 1 eq) was added to a solution of hydrochloric acid in dioxane (20 mL), and the mixture was stirred at 25 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated to dryness by rotary evaporation to give compound 6-5, which was directly used in the next step. (ESI) m / z = 400.2 [M+H]+. Step 6: synthesis of compound 6 Compound 6-5 (330 mg, 826.16 umol, 1 eq) was added to absolute ethanol (10 mL), and then ethyl acetoacetate (107.52 mg, 826.16 umol, 104.59 uL, 1 eq) was added to the reaction solution. The mixture was stirred at 25 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by preparative reverse-phase column chromatography (C18 column, 0.1% formic acid solution) and lyophilized to give compound 6 (8 mg, 17.10 umol, 2.07% yield, 99.48% purity) in the form of a white solid. (ESI) m / z = 466.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 11.32 - 10.88 (m, 1H), 7.46 (br d, J = 8.8 Hz, 2H), 7.24 (s, 1H), 7.17 - 7.07 (m, 1H), 6.97 (br d, J = 9.2 Hz, 2H), 6.90 - 6.78 (m, 2H), 5.44 - 5.19 (m, 2H), 3.80 - 3.66 (m, 2H), 3.54 - 3.42 (m, 1H), 3.24 - 3.18 (m, 1H), 2.80 - 2.70 (m, 3H), 2.08 (s, 3H), 1.96 - 1.87 (m, 1H), 1.82 - 1.75 (m, 1H), 1.74 - 1.58 (m, 2H). Example 7: Synthesis of Compound 7 Synthetic route: Step 1: synthesis of compound 7-1 N,N-Diisopropylethylamine (1.78 g, 13.78 mmol, 2.40 mL, 3 eq) was added to a solution of intermediate 6-3 (2 g, 4.59 mmol, 1 eq) and intermediate 5-phenyl-4,5-dihydro-1H-pyrazole (1.01 g, 6.89 mmol, 1.5 eq) in dichloromethane (20 mL). The reaction system was cooled to 0 °C, and then PyBrOP (3.21 g, 6.89 mmol, 1.5 eq) was added in portions. The reaction solution was stirred at 25 °C for 2 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give intermediate 7-1 (2.2 g, 84.99% yield, pale yellow solid). (ESI) m / z = 564.3[M+H]+. Step 2: synthesis of compound 7-2 A 2 M solution of hydrochloric acid in dioxane (2 M, 6 mL, 13.53 eq) was added to a solution of intermediate 7-1 in dioxane (6 mL). The mixture was stirred at 25 °C for 18 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure to give intermediate 7-2 (354 mg, crude product, pale yellow solid). (ESI) m / z = 364.1[M+H]+. Step 3: preparation of compound 7 Ethyl acetoacetate (172.80 mg, 1.33 mmol, 168.09 uL, 1.5 eq) was added to a solution of intermediate 7-2 (300 mg, 826.16 nmol, 1 eq) in acetonitrile (10 mL). The mixture was stirred at 60 °C for 1 h. After LCMS analysis showed that the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by reverse-phase column chromatography (C18 column, 0.1% aqueous hydrochloric acid solution) and lyophilized to give hydrochloride of 7 (46.8 mg, white solid, 10.74% yield). (ESI) m / z = 430.1 [M+H]+. 1HNMR (400 MHz, DMSO-d6) 5 8.17 - 7.56 (m, 5H), 7.38 - 7.22 (m, 4H), 7.14 (d, J = 7.4 Hz, 2H), 5.52 (s, 1H), 5.35 (dd, J = 4.6, 11.8 Hz, 1H), 3.81 - 3.33 (m, 6H), 2.76 - 2.64 (m, 1H), 2.35 - 2.05 (m, 6H), 1.97 (br d, J = 12.8 Hz, 1H). Example 8: Synthesis of Compound 8 F 8 Synthetic route: 0                                       0                                         o Step 1: synthesis of compound 8-1 Diisopropylethylamine (13.01 g, 100.69 mmol, 17.54 mL, 3 eq) was added to a solution of compound 1-1 (5.28 g, 33.56 mmol, 5.17 mL, 1 eq) and compound 2,4-dichloropyrimidine (5 g, 33.56 mmol, 1 eq) in dimethyl sulfoxide (50 mL). The reaction solution was allowed to react at 20 °C for 2 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was poured into water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by normal-phase silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) and concentrated under reduced pressure to give compound 8-1 (8 g, 29.66 mmol, 88.37% yield) in the form of a light white oil. (ESI) m / z = 270.0 [M+H]+. 1H NMR (400 MHz, CDCI3) 5 = 7.95 (d, J = 6.0 Hz, 1H), 6.34 (d, J = 6.0 Hz, 1H), 4.40 - 4.12 (m, 2H), 4.09 (q, J = 7.2 Hz, 2H), 3.05 (ddd, J = 3.2, 11.2, 13.6 Hz, 2H), 2.54 (tt, J = 4.2, 10.8 Hz, 1H), 1.97 - 1.90 (m, 2H), 1.78 - 1.57 (m, 2H), 1.22 - 1.17 (m, 3H) Step 2: synthesis of compound 8-2 Cesium carbonate (23.08 g, 70.84 mmol, 3 eq) and [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (1.88 g, 2.36 mmol, 0.1 eq) were added to a solution of compound 8-1 (6.369 g, 23.61 mmol, 1 eq) and di-tert-butyl hydrazodicarboxylate (8.23 g, 35.42 mmol, 7.91 mL, 1.5 eq) in toluene (65 mL). The reaction solution was allowed to react at 100 °C for 12 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was directly filtered. The resulting crude product was purified by normal-phase silica gel column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:1) and then concentrated under reduced pressure to give compound 8-2 (2.485 g, 4.80 mmol, 20.35% yield, 90% purity) in the form of a brownish-yellow solid. (ESI) m / z = 466.3 [M+H]+. Step 3: synthesis of compound 8-3 Lithium hydroxide monohydrate (806.39 mg, 19.22 mmol, 4 eq) was added to a solution of compound 8-2 (2.485 g, 4.80 mmol, 1 eq) in methanol (10 mL), water (10 mL), and tetrahydrofuran (10 mL). The reaction solution was allowed to react at 20 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was adjusted to pH = 6 with 1 M aqueous hydrochloric acid solution and extracted with ethyl acetate (50 mL x 3). The reaction solution was filtered, and the filter cake was directly concentrated under reduced pressure to give compound 8-3 (1.1 g, 2.61 mmol, 54.30% yield, 80% purity) in the form of a white solid. (ESI) m / z = 436.3 [M-H]+. Step 4: synthesis of compound 8-4 N,N-Diisopropylethylamine (574.63 mg, 4.45 mmol, 774.43 uL, 3 eq) and bromotripyrrolidinophosphonium hexafluorophosphate (829.08 mg, 1.78 mmol, 1.2 eq) were added to a solution of compound 8-3 (500 mg, 1.48 mmol, 1 eq) and compound 1-7 (404.97 mg, 2.22 mmol, 1.5 eq) in dichloromethane (15 mL). The reaction solution was allowed to react at 30 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was directly concentrated under reduced pressure. The resulting crude product was purified by normal-phase silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) and concentrated under reduced pressure to give compound 8-4 (508 mg, 992.65 umol, 66.98% yield, 98% purity) in the form of a yellow oil. (ESI) m / z = 502.2 [M+H]+. Step 5: synthesis of compound 8-5 Trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 13.29 eq) was added dropwise to a solution of compound 8-4 (508 mg, 1.01 mmol, 1 eq) in dichloromethane (5 mL) at 20 °C. The reaction solution was allowed to react at 20 °C for 2 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was directly concentrated under reduced pressure to give compound 8-5 (400 mg, crude product), which was directly used in the next step. (ESI) m / z = 402.3 [M+H]+. Step 6: synthesis of compound 8 A solution of compound 8-5 (400 mg, 996.48 umol, 1 eq) and compound ethyl acetoacetate (155.62 mg, 1.20 mmol, 151.38 uL, 1.2 eq) in methanol (4 mL) was heated to 70 °C and stirred for 2 h in a nitrogen atmosphere, and then an aqueous sodium hydroxide solution (3 M, 4.8 mL, 14.45 eq) was added to the reaction solution. The resulting mixture was allowed to react at 70 °C for 1 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely and a product was generated, the reaction solution was adjusted to pH = 7 with glacial acetic acid and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then separated and purified by preparative reverse-phase chromatography [water (formic acid)-acetonitrile system] and lyophilized to give compound 8 (87.6 mg, 179.28 pmol, 17.99% yield, 95.67% purity). (ESI) m / z = 468.2 [M+H]+. 1H NMR (400 MHz, CDCh) 5 12.9 (brs, 1H) 7.92 (d, J = 6.4 Hz, 1H), 6.93 (s, 1H), 6.63 (br d, J = 2.4 Hz, 1H), 6.62 - 6.55 (m, 2H), 6.26 (d, J = 6.6 Hz, 1H), 5.33 (s, 1H), 5.25 (dd, J = 5.2, 11.8 Hz, 1H), 4.55 - 4.15 (m, 2H), 3.34 (s, 2H), 3.19 - 3.05 (m, 2H), 2.78 - 2.67 (m, 1H), 2.20 (s, 3H), 2.05 - 1.94 (m, 1H), 1.94 - 1.84 (m, 1H), 1.75 (br s, 2H) Example 9: Synthesis of Compound 10 10A                       1OB                     IOC Synthetic route: !0_j                         10C-5                                     10C-6                                   IOC Step 1: synthesis of compounds 10A / B-2 and 10C-2 Compound 1-[(tert-butoxy)carbonyl]-3,3-difluoropiperidine-4-carboxylic acid (1.84 g, 6.94 mmol, 1 eq) was dissolved in anhydrous dichloromethane (20 mL), and compound 5-phenyl-4,5-dihydro-1H-pyrazole (1.22 g, 8.32 mmol, 1.2 eq), N,N-diisopropylethylamine (4.48 g, 34.68 mmol, 6.04 mL, 5 eq), and bromotripyrrolidinophosphonium hexafluorophosphate (4.85 g, 10.41 mmol, 1.5 eq) were added successively with stirring at room temperature. The mixture was stirred at room temperature for 12 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated with silica gel and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give compound 10A / B-2 (1 g, 2.54 mmol, crude product) with low polarity in the form of a light yellow solid and compound 10C-2 (1.23 g, 3.13 mmol, crude product) with high polarity in the form of a light yellow oil. (ESI) m / z = 338.1 [M+H-tBu]+. (ESI) m / z = 338.1 [M+H-tBu]+ Step 2: synthesis of compound 10A / B-3 Compound 10A / B-2 (1.00 g, 2.54 mmol, 1 eq) was dissolved in a 2 N solution of hydrochloric acid in methanol (20 mL). The mixture was stirred at room temperature for 2 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated. The residue was subjected to preparative reverse-phase chromatography and lyophilized to give compound 10A / B-3 (275 mg, 833.91 Limol, 32.81% yield) in the form of a white solid. (ESI) m / z = 294.1 [M+H]+. Step 3: synthesis of compound 10A / B-4 Compound 10A / B-3 (175.00 mg, 530.67 Lmol, 1 eq, HCl) was dissolved in anhydrous dichloromethane (10 mL), and 3-bromobenzeneboronic acid (319.72 mg, 1.59 mmol, 3 eq), copper acetate (289.16 mg, 1.59 mmol, 3 eq), triethylamine (429.59 mg, 4.25 mmol, 590.90 LL, 8 eq), and 4A molecular sieves (300 mg) were added successively with stirring. The mixture was stirred at room temperature for 12 h in an oxygen atmosphere. After LCMS analysis showed that there was remaining starting material and a product was present, the reaction solution was filtered, and the filter cake was washed several times with dichloromethane. The filtrate was concentrated, and then silica gel was added. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 0-18%) to give compound 10A / B-4 (63 mg, 140.53 Lmol, 26.48% yield) in the form of a yellow solid. (ESI) m / z = 448.0 [M+H]+. Step 4: synthesis of compounds 10A-5 and 10A-B Compound 10A / B-4 (1.19 g, 2.65 mmol, 1 eq) was dissolved in anhydrous toluene (40 mL), and compounds di-tert-butyl hydrazodicarboxylate (739.88 mg, 3.19 mmol, 711.42 LL, 1.2 eq), cesium carbonate (1.73 g, 5.31 mmol, 2 eq), and          [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (210.86 mg, 265.45 Lmol, 0.1 eq) were added successively. The reaction solution was heated to 100 °C and stirred for 1.3 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was filtered, and the filter cake was washed with dichloromethane (100 mL x 3). The filtrate was concentrated, and then silica gel was added. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 0-36%) to give a product, which was then subjected to chiral resolution to give compound 10A-5 (700 mg, crude) in the form of a light yellow solid and compound 10B-5 (645 mg, crude) in the form of a light yellow solid. (ESI) m / z = 600.3 [M+H]+. (ESI) m / z = 600.3 [M+H]+. Step 5: synthesis of compound 10A-6 Compound 10A-5 (700.00 mg, 1.17 mmol, 1 eq) was dissolved in a prepared dichloromethane / trifluoroacetic acid (5 / 1, 12 mL) solution. The mixture was stirred at room temperature for 1.5 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated to give compound 10A-6 (599 mg, crude, TFA) in the form of a yellow oil. (ESI) m / z = 400.2 [M+H]+. Step 6: synthesis of compound 10A Compound 10A-6 (599 mg, 1.17 mmol, 1 eq, TFA) was dissolved in acetonitrile (10 mL), and ethyl acetoacetate (151.82 mg, 1.17 mmol, 147.69 LL, 1 eq) was added. The mixture was warmed to 60 °C and allowed to react for 1 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated, and then silica gel was added. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 0-54%) to give a crude product. The crude product was subjected to preparative reverse-phase chromatography and lyophilized to give compound 10A (196.3 mg, 421.37 Lmol, 36.12% yield) in the form of a grayish-white solid. (ESI) m / z = 466.2 [M+H]+. 1H NMR (400 MHz, CDCI3) 5 7.46 (br s, 1H), 7.41 - 7.30 (m, 3H), 7.28 - 7.21 (m, 2H), 7.16 (br d, J = 7.0 Hz, 2H), 7.02 (br s, 1H), 6.78 - 6.68 (m, 1H), 5.44 (br dd, J = 4.6, 11.8 Hz, 1H), 4.16 - 4.01 (m, 1H), 3.95 - 3.77 (m, 1H), 3.57 - 3.33 (m, 5H), 3.29 - 3.17 (m, 1H), 2.85 (br dd, J = 2.8, 18.8 Hz, 1H), 2.20 (s, 5H). SFC (column model: Chiralcel OJ-3 50 x 4.6 mm I.D., 3 gm; mobile phase: Phase A for CO2, and Phase B for IPA (0.05% DEA); gradient elution: IPA (0.05% DEA) in CO2 from 20% to 60%, flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 Bar); retention time = 1.374 min. Steps 7: synthesis of compound 10B Compound 10B was obtained using a synthesis method similar to that of compound 10A. (ESI) m / z = 466.1 [M+H]+. 1H NMR (400 MHz, CDCl3) 5 7.46 (br s, 1H), 7.41 - 7.30 (m, 3H), 7.27 (s, 2H), 7.16 (br d, J = 6.8 Hz, 2H), 7.03 (s, 1H), 6.73 (br d, J = 8.2 Hz, 1H), 5.44 (br dd, J = 4.2, 11.8 Hz, 1H), 4.15 - 4.02 (m, 1H), 3.93 - 3.78 (m, 1H), 3.56 -3.33 (m, 5H), 3.29 - 3.17 (m, 1H), 2.85 (br dd, J = 3.0, 18.8 Hz, 1H), 2.20 (s, 5H). SFC (column model: Chiralcel OJ-3 50 x 4.6 mm I.D., 3 gm; mobile phase: Phase A for CO2, and Phase B for IPA (0.05% DEA); gradient elution: IPA (0.05% DEA) in CO2 from 20% to 60%, flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 Bar); retention time = 1.591 min. Step 8: synthesis of compound 10C Compound 10C was obtained using a synthesis method similar to that of compound 10A. (ESI) m / z =466.1 [M+H]+. 1H NMR (400 MHz, CDCl3) 5 7.47 (s, 1H), 7.41 - 7.30 (m, 3H), 7.27 - 7.23 (m, 2H), 7.19 (d, J = 7.6 Hz, 2H), 7.00 (d, J = 1.2 Hz, 1H), 6.74 (dd, J = 1.4, 8.2 Hz, 1H), 5.43 (dd, J = 5.2, 11.8 Hz, 1H), 4.20 - 4.07 (m, 1H), 3.83 (ddd, J = 6.0, 12.6, 18.6 Hz, 1H), 3.65 - 3.56 (m, 1H), 3.52 - 3.35 (m, 4H), 3.27 - 3.16 (m, 1H), 2.89 - 2.79 (m, 1H), 2.20 (s, 4H), 2.16 - 2.04 (m, 1H). Example 10: Synthesis of Compound 11 Compounds 11A and 11B were obtained using a synthesis method similar to that of compound 10A. Synthesis of compounds 11A and 11B Compound 11A was in the form of a grayish-white solid. (ESI) m / z = 448.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 11.33 (s, 1H), 7.36 - 7.30 (m, 2H), 7.30 - 7.18 (m, 4H), 7.18 - 7.08 (m, 3H), 6.78 (br d, J = 8.4 Hz, 1H), 5.44 -5.07 (m, 3H), 4.03 - 3.89 (m, 1H), 3.71 (br d, J = 12.0 Hz, 1H), 3.58 - 3.41 (m, 2H), 3.13 - 2.95 (m, 1H), 2.92 - 2.78 (m, 1H), 2.75 - 2.67 (m, 1H), 2.10 (s, 4H), 1.65 (br dd, J = 3.4, 14.0 Hz, 1H). Compound 11B was in the form of a white solid. (ESI) m / z = 448.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 11.33 (m, 1H), 7.34 - 7.28 (m, 2H), 7.28 - 7.18 (m, 4H), 7.17 - 7.08 (m, 3H), 6.78 (br d, J = 8.0 Hz, 1H), 5.53 - 5.22 (m, 3H), 4.02 (br t, J = 11.8 Hz, 1H), 3.74 (br d, J = 12.4 Hz, 1H), 3.57 - 3.37 (m, 2H), 3.15 - 2.97 (m, 1H), 2.85 (br t, J = 11.6 Hz, 1H), 2.68 (ddd, J = 1.6, 5.0, 19.0 Hz, 1H), 2.18 - 2.01 (m, 4H), 1.72 - 1.60 (m, 1H). Example 11: Synthesis of Compound 12 Synthetic route: Step 1: synthesis of compound 12-2 Compound 12-1 (2 g, 12.81 mmol, 1 eq) and compound p-toluenesulfonyl hydrazide (2.38 g, 12.81 mmol, 1 eq) were added to dioxane (20 mL). The reaction solution was stirred at 25 °C for 12 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure to give a crude product of 122 (4.15 g, crude product, 89.284% purity) in the form of a yellow solid. (ESI) m / z = 325.2 [M+H]+. Step 2: synthesis of compound 12-3 Compound 12-2 (4.15 g, 12.79 mmol, 1 eq) was dissolved in dioxane (40 mL), and then compound 3-bromobenzeneboronic acid (3.21 g, 15.99 mmol, 1.25 eq) and cesium carbonate (6.25 g, 19.19 mmol, 1.5 eq) were added. The reaction solution was stirred at 110 °C for 16 h. After TLC showed that the reaction was completed, the reaction mixture was filtered and then concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 0-30%) to give compound 12-3 (430 mg, 1.37 mmol, 10.74% yield) in the form of a colorless oil. (ESI) m / z = 297.0 / 299.0 [M+H]+. 1H NMR (400 MHz, CDCh) 5 7.38 - 7.28 (m, 2H), 7.20 - 7.09 (m, 2H), 3.70 (s, 3H), 2.55 - 2.45 (m, 1H), 2.36 (tt, J = 3.6, 12.0 Hz, 1H), 2.19 - 2.07 (m, 2H), 2.06 - 1.90 (m, 2H), 1.69 - 1.57 (m, 2H), 1.56 - 1.40 (m, 2H). Step 3: synthesis of compound 12-4 Compound 12-3 (350 mg, 1.18 mmol, 1 eq) was added to methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL), and then lithium hydroxide monohydrate (247.10 mg, 5.89 mmol, 5 eq) was added. The reaction solution was stirred at 20 °C for 12 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure and then adjusted to pH = 4 with 1 M hydrochloric acid. Then, the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 12-4 (330 mg, crude product, 96.73% yield) in the form of a white solid. (ESI) m / z = 281.0 / 283.0 [M-H]+. 1H NMR (400 MHz, CDCI3) 5 11.11 - 10.06 (m, 1H), 7.37 - 7.31 (m, 2H), 7.20 - 7.11 (m, 2H), 2.51 (tt, J = 3.6, 12.0 Hz, 1H), 2.41 (tt, J = 3.6, 12.0 Hz, 1H), 2.23 - 2.11 (m, 2H), 2.06 - 1.93 (m, 2H), 1.69 -1.46 (m, 4H). Step 4: synthesis of compound 12-5 Compound 12-4 (20 g, 68.22 mmol, 1 eq) and compound 5-phenyl-4,5-dihydro-1H-pyrrole (255.56 mg, 1.75 mmol, 1.5 eq) were dissolved in dichloromethane (4 mL), and then N,N-diisopropylethylamine (753.11 mg, 5.83 mmol, 1.01 mL, 5 eq) and bromotripyrrolidinophosphonium hexafluorophosphate (814.94 mg, 1.75 mmol, 1.5 eq) were added. The reaction solution was stirred at 25 °C for 1 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 0-35%) to give compound 12-5 (10 g, 24.17 mmol, 35.43% yield, 95.054% purity) in the form of a white solid. (ESI) m / z = 411.1 / 413.1 [M+H]+. Step 5: synthesis of compound 12-6 Compound 12-5 (180 mg, 437.60 Limol, 1 eq) was dissolved in toluene (3 mL), and then di-tert-butyl hydrazodicarboxylate (101.64 mg, 437.60 Limol, 97.73 uL, 1 eq), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (34.76 mg, 43.76 Limol, 0.1 eq), and cesium carbonate (427.74 mg, 1.31 mmol, 3 eq) were added. The reaction solution was purged with nitrogen three times and then stirred at 100 °C for 12 h. After LCMS analysis showed that the reaction was completed, the reaction mixture was filtered and then concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 100 / 1 to 5 / 1) to give compound 12-6 (180 mg, 295.01 Lmol, 67.42% yield) in the form of a yellow oil. (ESI) m / z = 563.4 [M+H]+. Step 6: synthesis of compound 12-7 Compound 12-6 (180 mg, 319.89 Lmol, 1 eq) was dissolved in dichloromethane (4 mL), and then trifluoroacetic acid (1.66 g, 14.60 mmol, 1.08 mL, 45.63 eq) was added. The reaction solution was stirred at 25 °C for 1 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure to give a crude product of 12-7 (115 mg, crude product, 85.734% purity) in the form of a yellow oil. (ESI) m / z = 363.3 [M+H]+. Step 7: synthesis of compound 12 Compound 12-7 (115 mg, 317.27 Lmol, 1 eq) was dissolved in acetonitrile (3 mL), and then ethyl acetoacetate (49.55 mg, 380.72 Lmol, 48.20 LL, 1.2 eq) was added. The reaction solution was stirred at 60 °C for 1 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure to give a residue. The crude product was purified by TLC (silica, petroleum ether:ethyl acetate = 0:1) to give a crude product, which was then purified by high performance liquid chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 um; mobile phase: [water (FA)-ACN]; gradient: 40%-70% B, 9 min) and lyophilized to give 12 (65.1 mg, 151.92 Lmol, 47.88% yield) in the form of a white solid. (ESI) m / z = 429.1 [M+H]+. 1H NMR (400 MHz, CDCl3) 5 7.74 - 7.68 (m, 2H), 7.32 (dt, J = 5.2, 7.4 Hz, 3H), 7.26 - 7.22 (m, 1H), 7.19 - 7.14 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 5.39 (dd, J = 4.8, 12.0 Hz, 1H), 3.48 - 3.38 (m, 3H), 3.28 - 3.16 (m, 1H), 2.87 - 2.74 (m, 1H), 2.64 - 2.52 (m, 1H), 2.24 - 2.18 (m, 3H), 2.11 - 1.95 (m, 4H), 1.75 - 1.59 (m, 4H). Example 12: Synthesis of Compound 13 F Compound 13 (white solid) was obtained using a synthesis method similar to that of compound 12. (ESI) m / z = 465.2 [M+H]+. 1H NMR (400 MHz, CDCI3) 5 7.77 - 7.65 (m, 2H), 7.38 - 7.28 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 6.77 - 6.61 (m, 3H), 5.34 (dd, J = 4.8, 12.0 Hz, 1H), 3.54 - 3.34 (m, 3H), 3.28 - 3.14 (m, 1H), 2.77 (ddd, J = 1.6, 4.8, 18.8 Hz, 1H), 2.64 - 2.55 (m, 1H), 2.26 - 2.17 (m, 3H), 2.15 - 1.90 (m, 4H), 1.74 - 1.51 (m, 4H). Example 13: Synthesis of Compound 14 Synthetic route: Step 1: synthesis of compound 14-2 Compound 14-1 (5 g, 23.62 mmol, 1 eq, HCl), compound 1-bromo-3-iodobenzene (8.02 g, 28.35 mmol, 3.61 mL, 1.2 eq), cuprous iodide (899.79 mg, 4.72 mmol, 0.2 eq), potassium carbonate (3.26 g, 23.62 mmol, 1 eq), and L-proline (271.97 mg, 2.36 mmol, 0.1 eq) were added to a dimethyl sulfoxide solution (50 mL). The mixture was stirred at 100 °C for 12 h in a nitrogen atmosphere. After LCMS analysis showed 79.9% of the target compound, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by normal phase column chromatography (petroleum ether / ethyl acetate = 1-25%) to give compound 14-2 (3.18 g, 9.41 mmol, 39.83% yield) in the form of a colorless oil. (ESI) m / z = 330.1 / 332.1 [M+H]+. 1H NMR (400 MHz, CDCl3) 5 7.22 - 7.11 (m, 1H), 7.11 - 7.07 (m, 1H), 7.03 - 6.96 (m, 1H), 6.94 - 6.85 (m, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.66 - 3.47 (m, 2H), 3.26 - 3.04 (m, 2H), 2.35 - 2.14 (m, 2H), 2.13 - 2.01 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H). Step 2: synthesis of compound 14-3 Compound 14-2 (3.18 g, 9.63 mmol, 1 eq) was added to toluene (15 mL), and di-tert-butyl hydrazodicarboxylate (2.24 g, 9.63 mmol, 2.15 mL, 1 eq), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (765.04 mg, 963.08 nmol, 0.1 eq), and cesium carbonate (6.28 g, 19.26 mmol, 2 eq) were added to the reaction solution. The mixture was stirred at 100 °C for 3 h in a nitrogen atmosphere. After LCMS analysis showed 44.2% of the target compound, the reaction solution was poured into water (30 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 0-20%) to give compound 14-3 (3.06 g, 6.27 mmol, 65.12% yield) in the form of a brown oil. (ESI) m / z = 482.3 [M+H]+. Step 3: synthesis of compound 14-4 Compound 14-3 (3 g, 6.23 mmol, 1 eq) was added to methanol (5 mL), water (10 mL), and tetrahydrofuran (10 mL), and lithium hydroxide monohydrate (1.31 g, 31.15 mmol, 5 eq) was added to the reaction solution. The mixture was stirred at 50 °C for 2 h. After LCMS analysis showed 98% of the target product, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then water (20 mL) was added to the reaction mixture. Hydrochloric acid (1 M) was added at 0 °C to adjust the pH to 4-5. The mixture was extracted with ethyl acetate (90 mL x 3), dried over anhydrous sodium sulfate, and filtered and concentrated under reduced pressure to give compound 14-4 (2.7 g, crude) in the form of a white solid. (ESI) m / z = 454.2 [M+H]+. Step 4: synthesis of compound 14-5 Compound 14-4 (500 mg, 1.10 mmol, 1 eq) and compound 5-phenyl-4,5-dihydro-1H-pyrrole (241.77 mg, 1.65 mmol, 1.5 eq) were dissolved in dichloromethane (10 mL), and then bromotripyrrolidinophosphonium hexafluorophosphate (770.97 mg, 1.65 mmol, 1.5 eq) and N,N-diisopropylethylamine (712.47 mg, 5.51 mmol, 960.20 liL, 5 eq) were added. The mixture was stirred at 25 °C for 1 h. After LCMS analysis showed 62.9% of the target compound, the reaction solution was filtered and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0-30%) to give compound 14-5 (460 mg, 718.06 Limol, 65.13% yield) in the form of a white solid. (ESI) m / z = 582.4 [M+H]+. Step 5: synthesis of compound 14-6 Compound 14-5 (300 mg, 786.48 Lmol, 1 eq) was dissolved in dichloromethane (16 mL), and then trifluoroacetic acid (6.14 g, 53.85 mmol, 4 mL) was added. The mixture was stirred at 25 °C for 2 h. After LCMS analysis showed 61.4% of the target compound, the reaction solution was filtered and then concentrated under reduced pressure to give compound 14-6 (300 mg, crude product) in the form of a tawny oil, which was directly used in the next step. (ESI) m / z = 382.3 [M+H]+. Step 6: synthesis of compound 14 Compound 14-6 (300 mg, 786.48 Lmol, 1 eq) and compound ethyl acetoacetate (102.35 mg, 786.48 Lmol, 99.57 LL, 1 eq) were added to an acetonitrile solution (3 mL). The mixture was stirred at 60 °C for 1 h. After LCMS analysis showed 79.6% of the target compound, the reaction solution was filtered and then concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 0-25%), and then the residue was purified by high performance liquid chromatography (C18 column, 0.1% formic acid solution) to give compound 14 (101.7 mg, 226.67 Lmol, 28.82% yield) in the form of a pink solid. (ESI) m / z = 448.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 11.46 - 11.23 (m, 1H), 7.39 - 7.28 (m, 4H), 7.28 - 7.21 (m, 2H), 7.20 - 7.10 (m, 3H), 6.78 (s, 1H), 5.48 - 5.22 (m, 2H), 3.66 - 3.56 (m, 2H), 3.51 - 3.40 (m, 1H), 3.10 - 2.97 (m, 2H), 2.70 - 2.60 (m, 1H), 2.46 - 2.27 (m, 2H), 2.17 - 2.01 (m, 5H). Example 14: Synthesis of Compound 15 Compound 15 (white solid) was obtained using a synthesis method similar to that of compound 14. (ESI) m / z = 484.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 11.59 - 11.03 (m, 1H), 7.33 - 7.27 (m, 2H), 7.26 - 7.22 (m, 1H), 7.14 (tt, J = 2.4, 9.2 Hz, 2H), 6.85 (br dd, J = 2.0, 8.0 Hz, 3H), 5.43 (dd, J = 4.4, 11.6 Hz, 1H), 5.40 - 5.23 (m, 1H), 3.61 (br d, J = 11.6 Hz, 2H), 3.48 - 3.39 (m, 1H), 3.03 (br t, J = 12.4 Hz, 2H), 2.72 (ddd, J = 1.6, 4.8, 19.2 Hz, 1H), 2.42 -2.27 (m, 2H), 2.14 - 2.06 (m, 5H). Example 15: Synthesis of Compound 44 44 Synthetic route: IB                                     44-1                                      44 Step 1: synthesis of compound 44-1 Nitrosobenzene (115.05 mg, 1.07 mmol, 1 eq) and potassium carbonate (29.69 mg, 214.83 Limol, 0.2 eq) were added to a solution of compound 1B (500 mg, 1.07 mmol, 1 eq) in methanol (10 mL). The mixture was stirred at 60 °C for 3 h. After LCMS analysis showed 37% of the target compound, the reaction mixture was filtered and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1-30%) to give compound 44-1 (160 mg, 244.42 Limol, 22.76% yield) in the form of a red solid. (ESI) m / z = 555.2 [M+H]+. Step 2: synthesis of compound 44 Compound 44-1 (160 mg, 288.50 Lmol, 1 eq) was dissolved in a tetrahydrofuran solution (3 mL), and then HCl (2 M, 1.00 mL, 6.93 eq) was added. The mixture was stirred at 20 °C for 1 h. After LCMS analysis showed 69.54% of the target compound, the reaction mixture was filtered and then concentrated under reduced pressure to give a residue. The residue was purified by high performance liquid chromatography (C18 column, 0.1% ammonium hydroxide solution) to give compound 44 (46.60 mg, 90.41 nmol, 31.34% yield) in the form of a yellow solid. (ESI) m / z = 498.2 [M+H]+. 1H NMR (400 MHz, DMSO- d6) 5 10.50 - 10.18 (m, 1H), 7.25 (s, 1H), 7.16 - 7.08 (m, 2H), 6.90 (s, 1H), 6.85 (dd, J = 2.0, 8.4 Hz, 2H), 6.71 (dd, J = 1.2, 8.0 Hz, 1H), 6.58 (br d, J = 8.0 Hz, 1H), 5.35 (dd, J = 4.8, 12 Hz, 1H), 3.77 - 3.66 (m, 2H), 3.54 - 3.43 (m, 2H), 2.83 - 2.69 (m, 3H), 2.00 - 1.85 (m, 4H), 1.82 - 1.74 (m, 1H), 1.72 -1.56 (m, 2H). Example 16: Synthesis of Compound 45 45 Synthetic route: 1-6 Boc / - O HO 45-1 Boc HO 45-2 45-4 45-3 F NHBoc 45-5 N, Boc F 45-6 F 45 Step 1: synthesis of compound 45-1 (2S)-2-[Diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine (3.87 g, 11.89 mmo, 0.2 eq) was added to chloroform (300 mL), and compound 1-6 (10 g, 59.47 mmol, 1 eq) and compound N-Boc-hydroxylamine (9.50 g, 71.37 mmol, 1.2 eq) were added at 0 °C. The reaction solution was stirred at 20 °C for 16 h. After TLC analysis showed that the reaction was completed, the reaction solution 45-1 (17 g) was a yellow liquid, which was directly used in the next step without post-treatment and purification. (ESI) m / z = 302.1 [M+H]+. Step 2: synthesis of compound 45-2 Absolute methanol (150 mL) was added to the above reaction solution, and sodium borohydride (4.27 g, 112.85 mmol, 2 eq) was added at 0 °C. The reaction solution was stirred at 20 °C for 16 h. After LCMS analysis showed that the reaction was completed, a saturated aqueous ammonium chloride solution (500 mL) was added slowly at 0 °C to quench the reaction, and the mixture was extracted with dichloromethane (300 mL x 3). All organic phases were washed with a saturated aqueous sodium chloride solution (500 mL), dried over anhydrous sodium sulfate solid, filtered, and concentrated to give a crude product, which was purified by column chromatography (silica, petroleum ether:ethyl acetate = 50:1 to 0:1, TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.4)) to give compound 45-2 (5 g, 15.66 mmol, 27.76% yield, 95.00% purity) in the form of a yellow gel. (ESI) m / z = 326.1 [M+Na]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.25 - 7.13 (m, 1H), 7.02 - 6.90 (m, 2H), 6.72 (tt, J = 2.4, 8.8 Hz, 1H), 5.18 (dd, J = 4.8, 10.8 Hz, 1H), 3.90 - 3.70 (m, 2H), 2.71 - 2.45 (m, 1H), 2.37 (dddd, J = 3.6, 7.2, 10.9, 14.6 Hz, 1H), 2.05 - 1.98 (m, 1H), 1.52 - 1.40 (m, 9H). Step 3: synthesis of compound 45-3 Compound 45-2 (2 g, 6.59 mmol, 1 eq) and cyanomethylenetributylphosphorane (3.18 g, 13.19 mmol, 2 eq) were added to anhydrous toluene (100 mL). The reaction solution was stirred at 80 °C for 16 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated to give a crude product, which was purified by column chromatography (silica, petroleum ether:ethyl acetate = 20:1 to 4:1, TLC (petroleum ether:ethyl acetate = 5:1, Rf = 0.6)) to give compound 45-3 (5 g, 15.66 mmol, 92.33% yield, 95.6% purity) in the form of a yellow oil. (ESI) m / z = 186.1 [M-99]+. Step 4: synthesis of compound 45-4 Compound 45-3 (300.00 mg, 501.10 nmol, 1 eq) was added to a 2 M solution of hydrochloric acid in dioxane (30 mL). The reaction solution was stirred at 20 °C for 1 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 45-4 (650 mg, 2.93 mmol, hydrochloride) in the form of a yellow oil. (ESI) m / z = 186.2 [M+H]+. Step 5: synthesis of compound 45-5 Compound 45-4 (637.77 mg, 2.88 mmol, 1.25 eq, hydrochloride), compound 1-4 (1 g, 2.30 mmol, 1 eq), bromotripyrrolidinophosphonium hexafluorophosphate (1.61 g, 3.44 mmol, 1.5 eq), and diisopropylethylamine (1.48 g, 11.48 mmol, 5 eq) were added to anhydrous dichloromethane (10 mL). The reaction solution was stirred at 20 °C for 12 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica, petroleum ether:ethyl acetate = 10:0 to 0:1, Rf = 0.5) to give compound 45-5 (1.2 g, 1.94 mmol, 84.58% yield, 97.54% purity) in the form of a yellow oil. (ESI) m / z = 603.3 [M+H]+. Step 6: synthesis of compound 45-6 Compound 45-5 (650 mg, 1.08 mmol, 1 eq) and trifluoroacetic acid (3 mL) were added to anhydrous dichloromethane (12 mL). The reaction solution was stirred at 20 °C for 1 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure to give product 11 (430 mg, 1.00 mmol, TFA salt) in the form of a yellow oil. (ESI) m / z = 403.1 [M+H]+. Step 7: synthesis of compound 45 Compound 45-6 (430 mg, 1.07 mmol, 1 eq, trifluoroacetate) and ethyl acetoacetate (139.05 mg, 1.07 mmol, 135.27 liL, 1 eq) were added to acetonitrile (6 mL). The reaction solution was stirred at 60 °C for 1 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 10:0-1:1, TLC (petroleum ether:ethyl acetate = 2:1, Rf = 0.3)), then concentrated under reduced pressure, and then purified by high performance liquid chromatography (column model: Phenomenex luna C18 150 x 40 mm x 15 ^m, mobile phase: [water (FA)-acetonitrile], gradient: 30%-60% B, 15 min) to give compound 45 (343 mg, 709.29 nmol, 66.38% yield, 99.94% purity) in the form of a white solid. (ESI) m / z = 469.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.52 (t, J = 2.0 Hz, 1H), 7.40 - 7.33 (m, 1H), 7.31 - 7.29 (m, 1H), 6.92 - 6.77 (m, 3H), 6.73 (tt, J = 2.4, 8.8 Hz, 1H), 5.42 (dd, J = 6.0, 8.8 Hz, 1H), 4.31 (dt, J = 3.2, 7.8 Hz, 1H), 3.98 - 3.88 (m, 1H), 3.87 - 3.73 (m, 2H), 3.46 (s, 2H), 3.02 - 2.77 (m, 4H), 2.40 - 2.30 (m, 1H), 2.23 (s, 3H), 2.15 - 2.08 (m, 1H), 2.04 - 1.89 (m, 3H). Example 17: Synthesis of Compound 46 Synthetic route: O NH N 46-2                   46-3 46 Step 1: synthesis of compound 46-2 Compound 46-1 (10 g, 80.57 mmol, 8.42 mL, 1 eq) and compound (formylmethylene)triphenylphosphorane (24.52 g, 80.57 mmol, 1 eq) were added to tetrahydrofuran (60 mL). The mixture was allowed to react at 80 °C for 4 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated under reduced pressure to give a crude product, which was purified by normal-phase column chromatography (petroleum ether / ethyl acetate = 0-10%) to give compound 46-2 (7.8 g, 45.35 mmol, 56.29% yield, 87.3% purity) in the form of a pale yellow oil. (ESI) m / z = 151.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 9.74 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 16.0 Hz, 1H), 7.61 (dt, J = 1.6, 7.6 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.19 - 7.14 (m, 1H), 6.81 (dd, J = 7.6, 16.0 Hz, 1H). Step 2: synthesis of compound 46-3 Hydrazine hydrate (8.51 g, 166.50 mmol, 8.24 mL, 5 eq) was added to tetrahydrofuran (50 mL), and then a solution of compound 46-2 (5 g, 33.30 mmol, 1 eq) in tetrahydrofuran (50 mL) was added slowly. The mixture was stirred at 25 °C for 2 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated under reduced pressure to give a crude product, which was purified by normal-phase column chromatography (petroleum ether / ethyl acetate = 10%-30%) to give compound 46-3 (3.3 g, 10.05 mmol, 30.18% yield) in the form of a pale yellow oil. (ESI) m / z = 165.3 [M+H]+. Step 3: synthesis of compound 46-4 Bromotripyrrolidinophosphonium hexafluorophosphate (1.28 g, 2.74 mmol, 1.5 eq) and N,N-diisopropylethylamine (1.18 g, 9.14 mmol, 1.59 mL, 5 eq) were added to a solution of compound 46-3 (795.80 mg, 1.83 mmol, 1 eq) and compound 1-4 (600 mg, 1.83 mmol, 1 eq) in dichloromethane (12 mL). The reaction solution was allowed to react at 25 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated under reduced pressure to give a crude product, which was purified by normal-phase column chromatography (petroleum ether / ethyl acetate = 30%-50%) to give compound 46-4 (690 mg, 1.14 mmol, 62.30% yield) in the form of a pale yellow solid. (ESI) m / z = 582.4 [M+H]+. Step 4: synthesis of compound 46-5 Trifluoroacetic acid (2.6 mL) was added to a solution of compound 46-4 (650 mg, 1.12 mmol, 1 eq) in dichloromethane (13 mL). The reaction solution was left to react at 25 °C for 1 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was concentrated under reduced pressure to give a crude product 64-5 (430 mg, crude product) in the form of a pale yellow oil, which was directly used in the next step. (ESI) m / z = 382.3 [M+H]+. Step 5: synthesis of compound 46 Compound ethyl acetoacetate (146.71 mg, 1.13 mmol, 142.71 liL, 1 eq) was added to a solution of compound 46-5 (430 mg, 1.13 mmol, 1 eq) in acetonitrile (8 mL). The mixture was stirred at 60 °C for 1 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by normalphase column chromatography (petroleum ether / ethyl acetate = 50%-70%) and then separated and purified by preparative reverse-phase chromatography [water (formic acid)-acetonitrile system] and lyophilized to give compound 46 (158.00 mg, 350.85 nmol, 31.12% yield, 99.37% purity) in the form of a white solid. (ESI) m / z = 448.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.48 (t, J = 2.0 Hz, 1H), 7.34 - 7.30 (m, 1H), 7.27 - 7.22 (m, 2H), 7.11 - 7.08 (m, 2H), 7.07 - 7.02 (m, 1H), 6.99 (t, J = 1.6 Hz, 1H), 6.77 (dd, J = 1.6, 8.0 Hz, 1H), 5.59 (dd, J = 5.2, 12.0 Hz, 1H), 3.78 (br d, J = 12.4 Hz, 2H), 3.42 (s, 3H), 3.30 - 3.20 (m, 1H), 2.90 - 2.78 (m, 3H), 2.20 (s, 3H), 2.07 - 2.00 (m, 1H), 1.98 - 1.88 (m, 3H). Compounds 47-56 were synthesized with reference to the synthesis method of compound 46, and the characterization data for the compounds are as follows: No. Structure Spectral characterization data 47 \=^N   k          .N^ / Y i  « UJ  0 47 (ESI) m / z = 448.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.48 (s, 1H), 7.35 - 7.28 (m, 2H), 7.27 - 7.22 (m, 1H), 7.00 - 6.91 (m, 3H), 6.85 (td, J = 2.0, 9.6 Hz, 1H), 6.78 (br d, J = 7.2 Hz, 1H), 5.37 (dd, J = 4.8, 11.8 Hz, 1H), 3.77 (br d, J = 12.4 Hz, 2H), 3.49 -3.38 (m, 3H), 3.30 - 3.19 (m, 1H), 2.91 - 2.75 (m, 3H), 2.20 (s, 3H), 2.06 - 1.98 (m, 1H), 1.98 - 1.85 (m, 3H). 48 E o 0 AAp 0 48 (ESI) m / z = 448.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.49 (t, J = 2.2 Hz, 1H), 7.38 - 7.30 (m, 1H), 7.27 - 7.22 (m, 1H), 7.18 - 7.10 (m, 2H), 7.05 - 6.95 (m, 3H), 6.78 (dd, J = 1.8, 8.2 Hz, 1H), 5.36 (dd, J = 4.8, 11.8 Hz, 1H), 3.82 - 3.71 (m, 2H), 3.50 - 3.36 (m, 3H), 3.29 - 3.18 (m, 1H), 2.91 - 2.74 (m, 3H), 2.20 (s, 3H), 2.03 -1.94 (m, 2H), 1.93 - 1.83 (m, 2H). 49 fi>....... , V=N    k .NR YY « UY 0 49 (ESI) m / z = 466.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.50 (s, 1H), 7.37 - 7.32 (m, 1H), 7.27 - 7.22 (m, 1H), 7.08 (dt, J = 6.4, 8.6 Hz, 1H), 7.00 (s, 1H), 6.87 - 6.76 (m, 3H), 5.53 (dd, J = 5.4, 12.2 Hz, 1H), 3.77 (br d, J = 12.4 Hz, 2H), 3.49 - 3.37 (m, 3H), 3.30 -3.19 (m, 1H), 2.93 - 2.75 (m, 3H), 2.20 (s, 3H), 2.07 - 1.98 (m, 1H), 1.97 - 1.85 (m, 3H). 50 \=^n ^NvYzN'Y L J o 50 (ESI) m / z = 466.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.45 (br s, 1H), 7.35 - 7.28 (m, 1H), 7.26 - 7.18 (m, 2H), 7.03 (s, 1H), 6.88 (t, J = 8.6 Hz, 2H), 6.81 - 6.70 (m, 1H), 5.70 (dd, J = 6.4, 12.4 Hz, 1H), 3.80 - 3.68 (m, 2H), 3.46 - 3.35 (m, 3H), 3.25 - 3.10 (m, 1H), 2.94 (br dd, J = 6.6, 18.6 Hz, 1H), 2.89 - 2.76 (m, 2H), 2.19 (s, 3H), 1.98 - 1.75 (m, 4H). 51 F~~O-F0 AYp Y V=^N   \^N\zAs / NxZ U J o 51 v (ESI) m / z = 466.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.48 (s, 1H), 7.37 - 7.29 (m, 1H), 7.27 - 7.22 (m, 1H), 7.06 - 6.99 (m, 1H), 6.99 (s, 1H), 6.97 - 6.89 (m, 1H), 6.81 - 6.73 (m, 2H), 5.55 (dd, J = 5.2, 12.1 Hz, 1H), 3.83 - 3.73 (m, 2H), 3.42 (s, 3H), 3.31 -3.19 (m, 1H), 2.92 - 2.75 (m, 3H), 2.20 (s, 3H), 2.09 - 2.00 (m, 1H), 1.99 - 1.87 (m, 3H). 52 Y,     , F \ 11               N^\ o uw7 VN   ^Qf 52 (ESI) m / z = 484.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.46 (t, J = 2.0 Hz, 1H), 7.33 - 7.29 (m, 1H), 7.26 - 7.21 (m, 1H), 7.04 - 7.00 (m, 1H), 6.75 (dd, J = 1.6, 8.0 Hz, 1H), 6.70 - 6.62 (m, 2H), 5.63 (dd, J = 6.4, 12.8 Hz, 1H), 3.75 (br t, J = 12.4 Hz, 2H), 3.42 (s, 3H), 3.22 - 3.11 (m, 1H), 2.91 (ddd, J = 1.6, 6.4, 18.6 Hz, 1H), 2.86 - 2.77 (m, 2H), 2.19 (s, 3H), 1.95 - 1.87 (m, 3H), 1.83 - 1.77 (m, 1H). 53 f~0-fo      Y F hyY^yy, \^N 53 (ESI) m / z = 484.2 [M+H]+. 1H NMR (400 MHz, CHLO ROFORM-d) 5 7.47 - 7.43 (m, 1H), 7.33 - 7.29 (m, 1H), 7.26 - 7.21 (m, 1H), 7.03 (s, 2H), 6.82 (ddt, J = 2.0, 3.6, 9.2 Hz, 1H), 6.75 (dd, J = 1.6, 8.0 Hz, 1H), 5.68 (dd, J = 6.4, 12.4 Hz, 1H), 3.75 (br t, J = 12.0 Hz, 2H), 3.42 (s, 3H), 3.22 - 3.13 (m, 1H), 2.94 (ddd, J = 1.2, 6.4, 18.8 Hz, 1H), 2.87 - 2.77 (m, 2H), 2.19 (s, 3H), 1.96 - 1.87 (m, 3H), 1.85 - 1.77 (m, 1H). 54 Y^ 54 (ESI) m / z = 484.1 [M+H]+. 1H NMR (400 MHz, CHLO ROFORM-d) 5 7.52 - 7.48 (m, 1H), 7.36 - 7.32 (m, 1H), 7.27 - 7.23 (m, 1H), 7.00 (t, J = 1.6 Hz, 1H), 6.97 - 6.86 (m, 2H), 6.79 (dd, J = 1.6, 8.0 Hz, 1H), 5.50 (dd, J = 5.4, 12.0 Hz, 1H), 3.83 - 3.74 (m, 2H), 3.51 - 3.40 (m, 3H), 3.29 - 3.19 (m, 1H), 2.92 - 2.75 (m, 3H), 2.20 (s, 3H), 2.06 - 1.90 (m, 4H). 55 F 55 (ESI) m / z = 502.2 [M+H]+. 1H NMR (400 MHz, CHLO ROFORM-d) 5 7.46 (s, 1H), 7.36 - 7.29 (m, 1H), 7.26 - 7.20 (m, 1H), 7.08 - 6.94 (m, 2H), 6.76 (dd, J = 1.6, 8.2 Hz, 1H), 5.69 (dd, J = 6.6, 12.8 Hz, 1H), 3.75 (br t, J = 10.8 Hz, 2H), 3.51 - 3.38 (m, 3H), 3.24 - 3.12 (m, 1H), 2.95 (dd, J = 6.4, 18.8 Hz, 1H), 2.88 - 2.77 (m, 2H), 2.19 (s, 3H), 1.98 - 1.88 (m, 3H), 1.80 (br d, J = 3.4 Hz, 1H). 56 \   F \^N         J ° 56 (ESI) m / z = 520.2 [M+H]+. 1H NMR (400 MHz, CHLO ROFORM-d) 5 7.46 (s, 1H), 7.31 (s, 1H), 7.27 - 7.22 (m, 1H), 7.04 (s, 1H), 6.76 (br d, J = 8.0 Hz, 1H), 5.65 (dd, J = 6.4, 12.8 Hz, 1H), 3.80 - 3.72 (m, 2H), 3.49 - 3.40 (m, 3H), 3.21 - 3.12 (m, 1H), 2.93 (ddd, J = 1.2, 6.4, 18.8 Hz, 1H), 2.82 (br s, 2H), 2.20 (s, 3H), 1.95 - 1.78 (m, 4H). Example 18: Synthesis of Compound 61 Synthetic route: IB-6 Step 1: synthesis of compound 61 Compound 1B-6 (133 mg, 332.97 nmol, 1 eq) was dissolved in acetonitrile (3 mL), and then compound ethyl propionylacetate (57.60 mg, 399.56 nmol, 1.2 eq) was added. The reaction solution was stirred at 60 °C for 1 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 0-100%), then purified by high performance liquid chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 nm; mobile phase: [water (FA)-ACN]; gradient: 30%-60% B, 10 min), and lyophilized to give compound 61 (92.7 mg, 193.32 nmol, 58.06% yield) in the form of a white solid. (ESI) m / z = 480.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.51 (t, J = 2.0 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.27 - 7.23 (m, 1H), 6.98 (t, J = 1.6 Hz, 1H), 6.78 (dd, J = 1.8, 8.2 Hz, 1H), 6.73 - 6.66 (m, 3H), 5.34 (dd, J = 5.2, 12.0 Hz, 1H), 3.82 - 3.73 (m, 2H), 3.50 - 3.39 (m, 3H), 3.30 - 3.19 (m, 1H), 2.92 - 2.74 (m, 3H), 2.53 (q, J = 7.6 Hz, 2H), 2.06 - 1.99 (m, 1H), 1.99 - 1.87 (m, 3H), 1.25 (t, J = 7.6 Hz, 3H). Example 19: Synthesis of Compound 62 F Synthetic route: F IB-6 nh2 NH F 62 Step 1: synthesis of compound 62 Compound 1B-6 (133 mg, 332.97 umol, 1 eq) was dissolved in acetonitrile (3 mL), and then compound ethyl isobutyrylacetate (63.21 mg, 399.56 umol, 64.43 uL, 1.2 eq) was added. The reaction solution was stirred at 60 °C for 1 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 0-100%), then purified by high performance liquid chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 um: mobile phase: [water (FA)-ACN]; gradient: 35%-65% B, 10 min), and lyophilized to give compound 62 (90.4 mg, 180.24 umol, 54.13% yield) in the form of a grayish-white solid. (ESI) m / z = 494.2 [M+H]+. 1H NMR (400 MHz, CHLOR OFORM-d) 5 7.52 (t, J = 2.0 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.27 - 7.22 (m, 1H), 6.98 (t, J = 1.4 Hz, 1H), 6.77 (dd, J = 2.0, 8.0 Hz, 1H), 6.74 - 6.66 (m, 3H), 5.34 (dd, J = 5.0, 12.0 Hz, 1H), 3.83 - 3.72 (m, 2H), 3.49 - 3.38 (m, 3H), 3.31 - 3.19 (m, 1H), 2.91 - 2.75 (m, 4H), 2.06 - 1.99 (m, 1H), 1.98 - 1.87 (m, 3H), 1.25 (d, J = 6.8 Hz, 6H). Example 20: Synthesis of Compounds 63A-D F 63A 63B 63D 63C Compounds 63A-D were obtained using a synthesis method similar to that of compound 10A. Compound 63A (ESI) m / z = 502.2 [M+H]+, 1H NMR (400 MHz, CHLOROFORM-d) 5 7.50 (t, J = 2.0 Hz, 1H), 7.43 (dd, J = 1.6, 8.0 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.05 (s, 1H), 6.85 - 6.66 (m, 4H), 5.42 (dd, J = 4.8, 12.0 Hz, 1H), 4.16 - 4.02 (m, 1H), 3.88 (ddd, J = 6.0, 12.8, 18.6 Hz, 1H), 3.59 - 3.39 (m, 5H), 3.32 - 3.19 (m, 1H), 2.84 (ddd, J = 1.6, 4.8, 19.0 Hz, 1H), 2.34 - 2.13 (m, 5H). SFC (column model: Chiralpak IC-3 50 x 4.6 mm I.D., 3 ^m; mobile phase: Phase A for CO2, and Phase B for MeOH (0.05% DEA); gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%, flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 Bar); retention time = 2.170 min. Compound 63B (ESI) m / z = 502.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.50 (t, J = 2.0 Hz, 1H), 7.43 (dd, J = 1.2, 8.0 Hz, 1H), 7.31 - 7.29 (m, 1H), 7.05 (s, 1H), 6.82 - 6.67 (m, 4H), 5.42 (dd, J = 4.8, 12.0 Hz, 1H), 4.16 - 4.02 (m, 1H), 3.88 (ddd, J = 6.0, 12.8, 18.6 Hz, 1H), 3.61 - 3.38 (m, 5H), 3.31 - 3.19 (m, 1H), 2.84 (ddd, J = 1.6, 4.8, 19.0 Hz, 1H), 2.33 - 2.12 (m, 5H). SFC (column model: Chiralpak IC-3 50 x 4.6 mm I.D., 3 ^m; mobile phase: Phase A for CO2, and Phase B for MeOH (0.05% DEA); gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 Bar); retention time = 2.606 min. Compound 63C (ESI) m / z = 502.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.51 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.03 (s, 1H), 6.83 - 6.67 (m, 4H), 5.42 (dd, J = 5.2, 12.0 Hz, 1H), 4.22 - 4.08 (m, 1H), 3.95 - 3.79 (m, 1H), 3.72 - 3.61 (m, 1H), 3.57 - 3.36 (m, 4H), 3.21 (br t, J = 9.2 Hz, 1H), 2.92 - 2.79 (m, 1H), 2.33 -2.20 (m, 4H), 2.18 - 2.07 (m, 1H). SFC (column model: Chiralpak AD-3 50 x 4.6 mm I.D., 3 ^m; mobile phase: Phase A for CO2, and Phase B for IPA (0.05% DEA); gradient elution: IPA (0.05% DEA) in CO2 from 20% to 60%; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 Bar); retention time = 1.294 min. Compound 63D (ESI) m / z = 502.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.51 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.03 (s, 1H), 6.85 - 6.67 (m, 4H), 5.42 (dd, J = 5.2, 12.0 Hz, 1H), 4.22 - 4.05 (m, 1H), 3.96 - 3.79 (m, 1H), 3.72 - 3.59 (m, 1H), 3.56 - 3.36 (m, 4H), 3.21 (br t, J = 9.8 Hz, 1H), 2.90 - 2.76 (m, 1H), 2.34 -2.19 (m, 4H), 2.17 - 2.04 (m, 1H). SCF (column model: Chiralpak AD-3 50 x 4.6 mm I.D., 3 ^m; mobile phase: Phase A for CO2, and Phase B for IPA (0.05% DEA); gradient elution: IPA (0.05% DEA) in CO2 from 20% to 60%; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 Bar); retention time = 1.549 min. Example 21: Synthesis of Compound 64 ci Synthetic route: Cl 64-4 Step 1: synthesis of compound 64-2 Hydrazine hydrate (7.67 g, 150.06 mmol, 7.43 mL, 98% purity, 5 eq) was added to a tetrahydrofuran solution (100 mL), and a solution of compound p-chlorocinnamaldehyde (5 g, 30.01 mmol, 1 eq) in tetrahydrofuran (100 mL) was added slowly. The reaction solution was stirred at 25 °C for 1 h. After LCMS analysis showed that the target compound was the major component, the reaction solution was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1-50%) to give compound 64-2 (5 g, 16.59 mmol, 55.29% yield, 59.95% purity) in the form of a yellow solid. (ESI) m / z = 181.1 [M+H]+. Step 2: synthesis of compound 64-3 Compound 64-2 (497.71 mg, 2.76 mmol, 1.5 eq) and compound 1-4 (800.00 mg, 1.84 mmol, 1 eq) were dissolved in a dichloromethane solution (10 mL), and then bromotripyrrolidinophosphonium hexafluorophosphate (1.03 g, 2.20 mmol, 1.2 eq) and N,N-diisopropylethylamine (712.22 mg, 5.51 mmol, 959.87 uL, 3 eq) were added slowly. The reaction solution was stirred at 25 °C for 12 h. After LCMS analysis showed that the reaction was completed, the reaction solution was filtered and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1-50%) to give compound 64-3 (800 mg, 1.13 mmol, 61.55% yield) in the form of a yellow solid. (ESI) m / z = 598.3 [M+H]+. Step 3: synthesis of compound 64-4 Compound 64-3 (600 mg, 1.00 mmol, 1 eq) was dissolved in dichloromethane (4 mL), and then trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 13.42 eq) was added. The mixture was stirred at 25 °C for 1 h. After LCMS analysis showed that the main peak was the target product, the reaction solution was filtered and then concentrated under reduced pressure to give a residue, thus giving compound 64-4 (500 mg, crude) in the form of a yellow oil. (ESI) m / z = 398.0 [M+H]+. Step 4: synthesis of compound 64 Compound 64-4 (500 mg, 976.71 umol, 1 eq, TFA) and compound ethyl acetoacetate (127.11 mg, 976.71 umol, 123.65 uL, 1 eq) were added to an acetonitrile solution (10 mL). The mixture was stirred at 60 °C for 1 h. After LCMS analysis showed that the target compound was generated, the reaction solution was filtered and then concentrated under reduced pressure to give a residue. The residue was purified by high performance liquid chromatography (C18 column, 0.1% formic acid solution) to give compound 64 (56.30 mg, 118.84 umol, 12.17% yield) in the form of a yellow solid. (ESI) m / z = 464.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.48 (t, J = 2.0 Hz, 1H), 7.35 - 7.28 (m, 3H), 7.27 - 7.21 (m, 1H), 7.13 - 7.08 (m, 2H), 6.99 - 6.96 (m, 1H), 6.80 - 6.74 (m, 1H), 5.39 - 5.30 (m, 1H), 3.82 - 3.72 (m, 2H), 3.48 - 3.38 (m, 3H), 3.26 - 3.15 (m, 1H), 2.81 (br s, 3H), 2.19 (s, 3H), 2.04 - 1.93 (m, 2H), 1.91 - 1.89(m, 2H). Compounds 65-66, 69-72, 74, and 108 were synthesized with reference to the synthesis method of compound 64, and the characterization data for the compounds are as follows: No. Structure Spectral characterization data 65 Cl / <Y^O a \=^N Y / N.      / N^ / YY « U J o 65 (ESI) m / z = 482.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.48 (s, 1H), 7.34 - 7.30 (m, 1H), 7.25 (s, 1H), 7.10 (d, J = 9.2 Hz, 2H), 7.07 - 7.01 (m, 1H), 6.99 (s, 1H), 6.77 (dd, J = 2.0, 8.0 Hz, 1H), 5.53 (dd, J = 5.2, 12.0 Hz, 1H), 3.77 (br d, J = 12.4 Hz, 2H), 3.42 (s, 3H), 3.28 - 3.18 (m, 1H), 2.90 - 2.76 (m, 3H), 2.20 (s, 3H), 2.04 - 1.88 (m, 4H). 66 Br A An^p a V=N   k ,N.   / - A . / YY « U A o 66 (ESI) m / z = 526.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.48 (s, 1H), 7.36 - 7.29 (m, 1H), 7.27 - 7.20 (m, 3H), 7.03 -6.92 (m, 2H), 6.77 (dd, J = 1.8, 8.0 Hz, 1H), 5.51 (dd, J = 5.4, 12.0 Hz, 1H), 3.77 (br d, J = 12.4 Hz, 2H), 3.51 - 3.34 (m, 3H), 3.30 -3.16 (m, 1H), 2.94 - 2.72 (m, 3H), 2.19 (s, 3H), 2.03 - 1.98 (m, 1H), 1.96 - 1.82 (m, 3H). 69 • Y Q z-z o< / (ESI) m / z = 464.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.49 (t, J = 2.0 Hz, 1H), 7.40 - 7.36 (m, 1H), 7.35 - 7.31 (m, 1H), 7.27 - 7.24 (m, 1H), 7.21 (s, 2H), 7.01 - 6.98 (m, 1H), 6.96 (t, J = 1.6 Hz, 1H), 6.78 (dd, J = 1.6, 8.0 Hz, 1H), 5.73 (dd, J = 5.2, 12.0 Hz, 1H), 3.83 - 3.75 (m, 2H), 3.51 (ddd, J = 1.6, 12.0, 18.8 Hz, 1H), 3.42 (s, 2H), 3.29 (ddd, J = 4.0, 11.2, 15.2 Hz, 1H), 2.93 - 2.81 (m, 2H), 2.72 (ddd, J = 1.6, 5.2, 18.8 Hz, 1H), 2.20 (s, 3H), 2.11 -1.93 (m, 4H). 70 CD cAd z-z ' o O Z-z °yY^ (ESI) m / z = 508.0 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.57 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.35 - 7.30 (m, 1H), 7.29 - 7.27 (m, 1H), 7.23 (s, 1H), 7.16 - 7.10 (m, 1H), 6.95 (s, 2H), 6.78 (dd, J = 2.0, 8.0 Hz, 1H), 5.71 (dd, J = 5.2, 12.0 Hz, 1H), 3.79 (br dd, J = 4.0, 12.0 Hz, 2H), 3.52 (dd, J = 12.0, 18.8 Hz, 1H), 3.42 (s, 2H), 3.34 - 3.24 (m, 1H), 2.94 - 2.80 (m, 2H), 2.70 (dd, J = 5.2, 18.8 Hz, 1H), 2.20 (s, 3H), 2.12 - 1.95 (m, 4H). 71 AY° 0 , >■ \      z-z Yyu LL (ESI) m / z = 482.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.48 (s, 1H), 7.36 - 7.30 (m, 1H), 7.25 (s, 1H), 6.97 (d, J = 8.8 Hz, 3H), 6.77 (br d, J = 8.8 Hz, 2H), 5.32 (dd, J = 5.2, 12.0 Hz, 1H), 3.82 - 3.73 (m, 2H), 3.42 (s, 3H), 3.28 - 3.19 (m, 1H), 2.91 - 2.81 (m, 2H), 2.81 - 2.74 (m, 1H), 2.20 (s, 3H), 1.93 (br s, 4H). 72 jrV0 z-z 0 LL (ESI) m / z = 526.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.49 (s, 1H), 7.36 - 7.32 (m, 1H), 7.27 - 7.23 (m, 1H), 7.15 (td, J = 2.0, 8.0 Hz, 1H), 7.11 (s, 1H), 6.98 (s, 1H), 6.84 - 6.77 (m, 2H), 5.32 (dd, J = 5.2, 12.0 Hz, 1H), 3.82 - 3.73 (m, 2H), 3.42 (s, 3H), 3.29 - 3.20 (m, 1H), 2.91 - 2.82 (m, 2H), 2.81 - 2.74 (m, 1H), 2.20 (s, 3H), 2.04 - 1.90 (m, 4H). 74 0 0 0 AAp VNyyNY y \ o 74 (ESI) m / z = 464.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 11.97 - 10.67 (m, 1H), 7.40 - 7.29 (m, 2H), 7.28 - 7.16 (m, 4H), 7.15 - 7.06 (m, 2H), 6.79 (br d, J = 7.8 Hz, 1H), 5.33 (br dd, J = 4.8, 11.8 Hz, 2H), 3.73 (br d, J = 9.4 Hz, 2H), 3.54 - 3.47 (m, 1H), 3.26 - 3.21 (m, 1H), 2.87 - 2.65 (m, 3H), 2.10 (s, 3H), 1.90 (br d, J = 12.6 Hz, 1H), 1.83 - 1.75 (m, 1H), 1.74 - 1.54 (m, 2H). 108 Br o 0 k^N'v^x / N^ / 1! J o 108 (ESI) m / z = 508.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.52 - 7.43 (m, 3H), 7.36 - 7.31 (m, 1H), 7.27 - 7.22 (m, 1H), 7.09 - 7.03 (m, 2H), 7.00 - 6.96 (m, 1H), 6.78 (dd, J = 1.6, 8.4 Hz, 1H), 5.34 (dd, J = 5.2, 12 Hz, 1H), 3.82 - 3.73 (m, 2H), 3.50 - 3.39 (m, 3H), 3.29 - 3.18 (m, 1H), 2.91 - 2.76 (m, 3H), 2.21 (s, 3H), 2.04 - 1.94 (m, 2H), 1.93 - 1.91 (s, 2H). Example 22: Synthesis of Compound 67 0 Synthetic route: Step 1: synthesis of compound 67-2 Compound methyl 4-piperidinecarboxylate (5 g, 27.83 mmol, 1 eq) and compound 3-bromobenzoic acid (6.15 g, 30.62 mmol, 1.1 eq) were dissolved in anhydrous dichloromethane (100 mL), and then N,N-diisopropylethylamine (8.99 g, 69.58 mmol, 12.12 mL, 2.5 eq) and HATU (11.64 g, 30.62 mmol, 1.1 eq) were added. The mixture was allowed to react at 20 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated, and the residue was pre-adsorbed onto silica gel. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-30%) to give compound 67-2 (9.0 g, 27.59 mmol, 99.13% yield) in the form of a colorless oil. (ESI) m / z = 326.1 [M+H]+. Step 2: synthesis of compound 67-3 Compound 67-2 (4.5 g, 13.80 mmol, 1 eq) and di-tert-butyl hydrazodicarboxylate (4.81 g, 20.69 mmol, 4.62 mL, 1.5 eq) were dissolved in toluene (80 mL), and then cesium carbonate (13.48 g, 41.39 mmol, 3 eq) and tBuXPhosPdG3 (1.10 g, 1.38 mmol, 0.1 eq) were added. The mixture was purged with N2 three times and then stirred at 100 °C for 12 h in a N2 atmosphere. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated, and the residue was pre-adsorbed onto silica gel. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-30%) to give compound 67-3 (5.5 g, 10.76 mmol, 78.00% yield) in the form of a yellow oil. (ESI) m / z = 478.2 [M+H]+. Step 3: synthesis of compound 67-4 Compound 67-4 (5.5 g, 11.52 mmol, 1 eq) was dissolved in tetrahydrofuran (40 mL) and water (10 mL), and then lithium hydroxide (827.45 mg, 34.55 mmol, 3 eq) was added. The mixture was stirred at 20 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated to dryness by rotary evaporation to give compound 67-4 (5.0 g, 10.16 mmol, 94.23% yield) in the form of an off-white solid. (ESI) m / z = 464.2 [M+H]+. Step 4: synthesis of compound 67-5 Compound 67-4 (500 mg, 1.08 mmol, 1 eq) and compound N-(3,5-difluorobenzyl)hydroxylamine (441.98 mg, 1.62 mmol, 1.5 eq, TFA) were dissolved in anhydrous dichloromethane (10 mL) at 0 °C, and then N,N- diisopropylethylamine (418.24 mg, 3.24 mmol, 563.67 nL, 3 eq) and n-butyl phosphoric anhydride (50% in ethyl acetate) (1.17 g, 1.62 mmol, 50% purity, 1.5 eq) were added. The mixture was stirred at 20 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated, and the residue was pre-adsorbed onto silica gel. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-100%) to give compound 67-5 (370 mg, 575.46 nmol, 53.35% yield) in the form of a colorless oil. (ESI) m / z = 605.3 [M+H]+. Step 5: synthesis of compound 67-6 Compound 67-6 (370 mg, 611.93 nmol, 1 eq) was dissolved in anhydrous dichloromethane (5 mL), and then trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 22.00 eq) was added. The mixture was stirred at 20 °C for 1 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated to give compound 67-6 (300 mg, 508.19 nmol, 83.05% yield) in the form of a pale yellow oil. (ESI) m / z = 405.3 [M+H]+. Step 5: synthesis of compound 67 Compound 67-6 (300 mg, 578.67 nmol, 1 eq, TFA) and compound ethyl acetoacetate (75.31 mg, 578.67 ^mol, 73.26 nL, 1 eq) were added to an acetonitrile solution (5 mL). The mixture was stirred at 60 °C for 1 h. After LCMS analysis showed that the starting material was consumed completely and a product was generated, the reaction solution was separated and purified by preparative reverse-phase chromatography [water (formic acid)-acetonitrile system] and lyophilized to give compound 67 (146.60 mg, 310.73 umol, 53.70% yield). (ESI) m / z = 471.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 11.92 - 11.29 (m, 1H), 10.09 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.23 - 7.09 (m, 2H), 6.94 (d, J = 6.4 Hz, 2H), 5.36 (s, 1H), 4.73 (s, 2H), 4.48 (dd, J = 2.0, 5.2 Hz, 1H), 3.67 (s, 1H), 3.15 (d, J = 10.4 Hz, 2H), 2.88 (s, 1H), 2.12 (s, 3H), 1.93 - 1.65 (m, 2H), 1.53 (s, 2H). Example 23: Synthesis of Compound 102 Synthesis steps: Step 1: synthesis of compound 102 Compound 67-6 (255 mg, 578.40 umol, 1 eq, HCl salt) and ethyl trifluoroacetoacetate (127.79 mg, 694.08 umol, 1.2 eq) were added to acetic acid (2 mL). The reaction solution was stirred at 80 °C for 1.5 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure to give a crude product, which was purified by high performance liquid chromatography (column model: Phenomenex luna C18 150 x 25 mm x 10 um: mobile phase: [water (FA)-acetonitrile]; gradient: 24%-54% acetonitrile; 25 min) to give product 102 (49.70 mg, 94.46 umol, 16.33% yield, 99.68% purity) in the form of a yellow solid. 1H NMR (400 MHz, DMSO-d6) 5 10.08 (s, 1H), 7.84 (br d, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.19 - 7.08 (m, 1H), 6.94 (br d, J = 6.6 Hz, 2H), 5.88 (s, 1H), 4.73 (s, 2H), 4.63 - 4.38 (m, 1H), 3.65 (br dd, J = 2.8, 4.4 Hz, 1H), 3.15 (br s, 3H), 2.98 - 2.82 (m, 1H), 1.92 - 1.65 (m, 2H), 1.63 - 1.45 (m, 2H). Compound 104 was synthesized with reference to the synthesis method of compound 102, and the characterization data are as follows: No. Structure Spectral characterization data 104 O-z 1 / ^° £ n (ESI) m / z = 507.1 [M+H]+. 1H NMR 400 MHz, DMSO-d6) 5 12.70 (br s, 1H), 10.01 (br s, 1H), 7.85 - 7.78 (m, 1H), 7.73 (t, J = 1.6 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.13 - 7.06 (m, 2H), 7.04 (br d, J = 10.0 Hz, 1H), 5.95 (s, 1H), 4.72 (br s, 2H), 4.59 - 4.35 (m, 1H), 3.72 - 3.56 (m, 1H), 3.14 (br d, J = 10.4 Hz, 2H), 2.98 - 2.80 (m, 1H), 1.94 - 1.64 (m, 2H), 1.54 (br d, J = 10.4 Hz, 2H). Example 24: Synthesis of Compound 68 Synthetic route: 68-5 NHBoc I Nx Boc Step 1: synthesis of compound 68-2 Compound 68-1 (10 g, 48.15 mmol, 1 eq) was dissolved in N,N-dimethylformamide (150 mL), and then compound 1-bromo-3-iodobenzene (13.62 g, 48.15 mmol, 6.14 mL, 1 eq), potassium carbonate (13.31 g, 96.29 mmol, 2 eq), L-proline (2.22 g, 19.26 mmol, 0.4 eq), and cuprous iodide (1.83 g, 9.63 mmol, 0.2 eq) were added. The mixture was purged with nitrogen three times and then mixed and stirred at 90 °C for 12 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely, the reaction mixture was poured into water (1000 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was washed with saturated brine (300 mL X 2), dried over anhydrous sodium sulfate, and filtered and concentrated in vacuum to give a crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-30%) to give compound 68-2 (6.0 g, 18.39 mmol, 38.20% yield) in the form of a yellow oil. (ESI) m / z = 326.1 / 328.1 [M+H]+. Step 2: synthesis of compound 68-3 Compound 68-2 (3.0 g, 9.20 mmol, 1 eq) and compound di-tert-butyl hydrazodicarboxylate (3.20 g, 13.79 mmol, 3.08 mL, 1.5 eq) were dissolved in toluene (40 mL), and then cesium carbonate (8.99 g, 227.59 mmol, 3 eq) and [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (730.51 mg, 919.60 nmol, 0.1 eq) were added. The mixture was purged with nitrogen three times and then stirred at 100 °C for 12 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely, the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL X 3). The organic phase was washed with saturated brine (200 mL X 2), dried over anhydrous sodium sulfate, and filtered and concentrated in vacuum to give a crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 0-25%) to give compound 68-3 (3.8 g, 7.53 mmol, 81.83% yield) in the form of a pale yellow oil. (ESI) m / z = 478.3 [M+H]+. Step 3: synthesis of compound 68-4 Compound 68-3 (3.7 g, 17.75 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), and water (5 mL), and then lithium hydroxide monohydrate (1.63, 38.74 mmol, 5 eq) was added. The mixture was stirred at 50 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated, adjusted to pH = 3-4 with 1 N hydrochloric acid, and extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness by rotary evaporation to give compound 68-4 (2.9 g, 5.42 mmol, 70.02% yield) in the form of a yellow oil. (ESI) m / z = 450.3 [M+H]+. Step 4: synthesis of compound 68-5 Compound 68-4 (700 mg, 1.56 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL) at 0 °C, and then N-methylimidazole (396.33 mg, 4.83 mmol, 384.78 nL, 3.1 eq) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (480.59 mg, 1.71 mmol, 1.1 eq) were added. Then, compound 1-7 (684 mg, 2.50 mmol, 1.5 eq) was added to the reaction solution at 0 °C. The mixture was stirred at 50 °C for 2 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated, poured into water (50 mL), and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and filtered and concentrated in vacuum to give a crude product. The crude product was separated and purified by preparative reverse-phase chromatography [water (neutral)-acetonitrile system] and lyophilized to give compound 68-5 (275 mg, 445.01 nmol, 28.58% yield) in the form of a pale yellow solid. (ESI) m / z = 614.4 [M+H]+. Step 5: synthesis of compound 68-6 Compound 68-5 (265 mg, 431.81 nmol, 1 eq) was dissolved in anhydrous dichloromethane (5 mL), and then trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 22.40 eq) was added. The mixture was stirred at 25 °C for 1 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated to give compound 68-6 (252 mg, 346.84 nmol, 80.32% yield) in the form of a yellow oil. (ESI) m / z = 414.3 [M+H]+. Step 6: synthesis of compound 68 Compound 68-6 (250 mg, 473.95 nmol, 1 eq, TFA) was dissolved in anhydrous acetonitrile (3 mL), and then compound ethyl acetoacetate (61.68 mg, 473.95 nmol, 1 eq) was added. The mixture was stirred at 60 °C for 1 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was separated and purified by preparative reverse-phase chromatography [water (formic acid)-acetonitrile system] and lyophilized to give compound 68 (120.70 mg, 251.71 Lmol, 60.35% yield) in the form of a yellow solid. (ESI) m / z = 480.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.44 (t, J = 2.0 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.26 - 7.21 (m, 1H), 6.95 (s, 1H), 6.75 (dd, J = 2.0, 8.0 Hz, 1H), 6.71 - 6.65 (m, 3H), 5.37 (dd, J = 4.8, 12.0 Hz, 1H), 3.42 (s, 2H), 3.41 - 3.26 (m, 3H), 3.13 (ddd, J = 3.2, 9.6, 12.4 Hz, 1H), 3.04 (ddd, J = 2.8, 9.6, 12.4 Hz, 1H), 2.67 (ddd, J = 1.6, 4.8, 18.6 Hz, 1H), 2.53 - 2.44 (m, 2H), 2.20 (s, 3H), 1.83 - 1.76 (m, 2H), 1.43 (s, 3H). Compound 86 was synthesized with reference to the synthesis method of compound 68, and the characterization data for the compound are as follows: No. Structure Spectral characterization data 86 (ESI) m / z = 482.3 [M+H]+. 1H NMR (400 MHz, CHLO ROFORM-d) 5 7.53 (s, 1H), 7.38 - 7.32 (m, 1H), 7.30 - 7.27 (m, 1H), 7.06 (s, 1H), 6.91 - 6.79 (m, 1H), 6.78 - 6.64 (m, 3H), 5.40 (dd, J = 4.8, 12.0 Hz, 1H), 4.58 - 4.42 (m, 1H), 3.59 (br d, J = 11.6 Hz, 2H), 3.50 - 3.37 (m, 3H), 3.29 (br t, J = 11.6 Hz, 2H), 2.78 (br dd, J = 4.8, 18.8 Hz, 1H), 2.52 - 2.37 (m, 2H), 2.20 (s, 3H), 1.85 (br dd, J = 7.2, 10.0 Hz, 2H). Example 25: Synthesis of Compound 81 Synthetic route: Step 1: synthesis of compound 81 Compound 1B-6 (290 mg, 665.29 nmol, 1 eq, HCl) was dissolved in absolute methanol (5 mL), and then compound methyl 3-oxopropionate (475.43 mg, 4.66 mmol, 7 eq) was added. The mixture was warmed to 70 °C and allowed to react for 0.5 h. After LCMS analysis showed that there was remaining starting material and a product was present, the reaction solution was filtered, and the filtrate was purified by preparative reverse-phase chromatography and then lyophilized to give compound 81 (35.2 mg, 76.74 nmol, 11.54% yield) in the form of a grayish-white solid. (ESI) m / z = 452.1 [M+H]+. 1H NMR (400 MHz, CHLOROFO RM-d) 5 7.47 (s, 2H), 7.36 - 7.31 (m, 1H), 7.29 (s, 1H), 6.98 (s, 1H), 6.80 (br d, J = 8.0 Hz, 1H), 6.74 - 6.64 (m, 3H), 5.34 (dd, J = 5.0, 12.0 Hz, 1H), 3.83 - 3.73 (m, 2H), 3.50 (s, 2H), 3.44 (br dd, J = 12.2, 18.8 Hz, 1H), 3.31 - 3.19 (m, 1H), 2.91 - 2.73 (m, 3H), 2.06 - 1.98 (m, 1H), 1.96 - 1.87 (m, 3H). Example 26: Synthesis of Compound 82 Synthetic route: >B-6                                    82-1                                          82 Step 1: synthesis of compound 82-1 Compound 1B-6 (420 mg, 817.98 nmol, 1 eq, TFA salt) and compound dimethyl butynedioate (139.49 mg, 981.58 nmol, 1.2 eq) were added to absolute methanol (10 mL), and then triethylamine (165.54 mg, 1.64 mmol, 2 eq) was then added at 0 °C. The reaction solution was stirred at 60 °C for 4 h. After LCMS analysis showed that the reaction was completed, the reaction solution was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica, petroleum ether:ethyl acetate = 10:1 to 0:1, TLC (petroleum ether:ethyl acetate = 0:1, Rf = 0.35)) to give compound 82-1 (240 mg, 423.57 Limol, 51.78% yield) in the form of a yellow oil. (ESI) m / z = 510.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 12.16 - 11.74 (m, 1H), 7.33 - 7.26 (m, 1H), 7.22 (br d, J = 15.2 Hz, 2H), 7.16 - 7.04 (m, 2H), 6.95 (dd, J = 1.6, 8.0 Hz, 1H), 6.84 (br d, J = 6.4 Hz, 2H), 5.94 (s, 1H), 5.35 (dd, J = 5.2, 12.0 Hz, 1H), 3.84 - 3.67 (m, 5H), 3.48 (br dd, J = 11.8, 18.4 Hz, 1H), 3.25 (td, J = 3.7, 7.5 Hz, 1H), 2.85 - 2.70 (m, 3H), 1.95 - 1.87 (m, 1H), 1.85 - 1.75 (m, 1H), 1.72 - 1.58 (m, 2H). Step 2: synthesis of compound 82 Compound 82-1 (210 mg, 412.17 nmol, 1 eq) was added to absolute methanol (1 mL) and anhydrous tetrahydrofuran (4 mL), and then aqueous hydroxylamine solution (3.27 g, 49.46 mmol, 50% purity, 120 eq) and sodium hydroxide (1 M, 824.33 uL, 2 eq) were added slowly at 0 °C. The reaction solution was stirred at 50 °C for 5 h. After LCMS analysis showed that the reaction was completed, the reaction solution was adjusted to pH = 7 with formic acid and filtered to give a filtrate. The filtrate was purified by high performance liquid chromatography (column: Phenomenex luna C18 150 x 40 mm x 15 um, mobile phase: [water (FA)-acetonitrile], gradient: 22%-52% B, 15 min) to give compound 82 (62.9 mg, 122.35 nmol, 29.69% yield) in the form of a grayish-white solid. (ESI) m / z = 511.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 12.38 - 11.30 (m, 1H), 10.88 (s, 1H), 8.90 (br s, 1H), 7.36 - 7.21 (m, 3H), 7.19 -7.07 (m, 2H), 6.97 - 6.78 (m, 3H), 5.83 (s, 1H), 5.35 (dd, J = 4.8, 12.0 Hz, 1H), 3.86 - 3.71 (m, 2H), 3.48 (br dd, J = 12.0, 18.8 Hz, 1H), 3.27 - 3.20 (m, 1H), 2.89 - 2.68 (m, 3H), 1.92 (br d, J = 12.0 Hz, 1H), 1.84 - 1.75 (m, 1H), 1.74 - 1.56 (m, 2H). Compounds 98-100 were synthesized with reference to the synthesis method of compound 82, and the characterization data for the compounds are as follows: No. Structural formula Spectral characterization data 98 A A   H \^N 0 98 (ESI) m / z = 495.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 7.49 (br s, 1H), 7.34 (br s, 1H), 7.29 - 7.23 (m, 2H), 7.21 - 7.14 (m, 2H), 7.14 - 7.08 (m, 1H), 6.89 (br dd, J = 1.6, 8.0 Hz, 1H), 6.87 - 6.80 (m, 2H), 5.79 (s, 1H), 5.35 (dd, J = 5.2, 12.0 Hz, 1H), 3.84 - 3.74 (m, 2H), 3.50 - 3.46 (m, 1H), 3.25 - 3.23 (m, 1H), 2.87 - 2.77 (m, 2H), 2.76 - 2.70 (m, 1H), 1.92 (br d, J = 11.6 Hz, 1H), 1.84 - 1.75 (m, 1H), 1.73 - 1.57 (m, 2H). 99 F \\ / ) N o                          ill 0 99 (ESI) m / z = 477.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 12.50 (s, 1H), 7.35 - 7.27 (m, 1H), 7.24 (t, J = 1.2 Hz, 1H), 7.17 (t, J = 2.0 Hz, 1H), 7.12 (tt, J = 2.4, 9.2 Hz, 1H), 7.04 (dd, J = 1.2, 8.0 Hz, 1H), 6.98 (dd, J = 2.0, 8.4 Hz, 1H), 6.87 - 6.81 (m, 2H), 6.15 (s, 1H), 5.34 (dd, J = 5.2, 12.0 Hz, 1H), 3.83 - 3.72 (m, 2H), 3.53 - 3.44 (m, 1H), 3.27 - 3.21 (m, 1H), 2.89 - 2.77 (m, 2H), 2.77 - 2.69 (m, 1H), 1.91 (br d, J = 12.8 Hz, 1H), 1.82 - 1.74 (m, 1H), 1.72 - 1.55 (m, 2H). 100 F Vn L J ° 100 (ESI) m / z = 520.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 13.03 -12.19 (m, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.22 (br d, J = 15.2 Hz, 2H), 7.12 (dt, J = 2.4, 9.2 Hz, 1H), 7.08 - 7.04 (m, 1H), 7.00 - 6.92 (m, 1H), 6.84 (br d, J = 6.4 Hz, 2H), 5.85 (s, 1H), 5.35 (dd, J = 5.2, 12.0 Hz, 1H), 3.80 - 3.73 (m, 2H), 3.51 (br s, 1H), 3.23 - 3.21 (m, 1H), 2.86 -2.77 (m, 2H), 2.77 - 2.70 (m, 1H), 1.96 - 1.87 (m, 1H), 1.83 - 1.76 (m, 1H), 1.73 - 1.56 (m, 2H). Example 27: Synthesis of Compound 83 83 Synthetic route: IB-3                                  83-1                                      83 Step 1: synthesis of compound 83-1 Compound 1B-3 (1 g, 1.90 mmol, 1 eq) was dissolved in acetonitrile (10 mL), and then N,N-diisopropylethylamine (491.78 mg, 3.81 mmol, 662.78 uL, 2 eq) and compound methyl 6-chloro-pyrimidine-4-carboxylate (328.32 mg, 1.90 mmol, 1 eq) were added. The mixture was heated to 80 °C and stirred for 2 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated, and silica gel was added. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 0-100%) to give compound 83-1 (800 mg, 1.86 mmol, 97.92% yield) in the form of a grayish-white solid. (ESI) m / z = 430.1 [M+H]+. Step 2: synthesis of compound 83 Compound 83-1 (700 mg, 1.63 mmol, 1 eq) was dissolved in methanol (10 mL), and then a 50% aqueous hydroxylamine solution (1.62 g, 24.45 mmol, 15 eq) was added. The mixture was warmed to 70 °C and allowed to react for 5 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was filtered, and the filter cake was washed successively with methanol (20 mL x 3) and acetonitrile (20 mL x 3) and then dried to give compound 83 (347.2 mg, 788.53 nmol, 48.37% yield) in the form of a white solid. (ESI) m / z = 431.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 11.62 - 11.04 (m, 1H), 9.38 - 8.90 (m, 1H), 8.49 (d, J = 0.8 Hz, 1H), 7.24 (d, J = 6.2 Hz, 2H), 7.17 - 7.04 (m, 1H), 6.92 - 6.74 (m, 2H), 5.34 (dd, J = 5.0, 12.0 Hz, 1H), 4.64 - 4.28 (m, 2H), 3.56 - 3.37 (m, 2H), 3.18 - 2.99 (m, 2H), 2.74 (ddd, J = 1.6, 5.0, 19.0 Hz, 1H), 1.94 (br d, J = 11.4 Hz, 1H), 1.80 (br d, J = 11.6 Hz, 1H), 1.60 - 1.38 (m, 2H). Example 28: Synthesis of Compound 84 Synthetic route: Step 1: synthesis of compound 84-1 Copper acetate (1.04 g, 5.71 mmol, 3 eq), triethylamine (1.54 g, 15.22 mmol, 2.12 mL, 8 eq), and 4A molecular sieves (1 g) were added to a solution of compound 1B-3 (1 g, 1.90 mmol, 1 eq) and compound 3- methoxycarbonylphenylboronic acid in dichloromethane (10 mL). The mixture was purged with oxygen three times and then stirred at 25 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was filtered, and the filtrate was concentrated in vacuum to give a crude product. The crude product was purified by normal-phase column chromatography (ethyl acetate / petroleum ether = 10%-30%) to give compound 84-1 (460 mg, 1.03 mmol, 54.13% yield) in the form of a yellow oil. (ESI) m / z = 428.3 [M+H]+. Step 2: synthesis of compound 84 An aqueous sodium hydroxide solution (1 M, 1.78 mL, 2 eq) and an aqueous hydroxylamine hydrochloride solution (7.05 g, 106.68 mmol, 50% purity, 120 eq) were added to a solution of compound 84-1 (380 mg, 889.01 Limol, 1 eq) in methanol (1 mL) and tetrahydrofuran (4 mL). The mixture was stirred at 70 °C for 1 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was adjusted to pH = 7 with formic acid, concentrated in vacuum to remove tetrahydrofuran and methanol, and then extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, and filtered and concentrated in vacuum to give a crude product. The crude product was separated and purified by preparative reverse-phase chromatography [water (formic acid)-acetonitrile system] and lyophilized to give compound 84 (126.90 mg, 294.30 nmol, 33.10% yield) in the form of a pink solid. (ESI) m / z = 429.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 11.11 (br s, 1H), 8.94 (br s, 1H), 7.27 (s, 1H), 7.24 (t, J = 4.0 Hz, 2H), 7.16 - 7.09 (m, 2H), 7.07 (dd, J = 2.4, 8.4 Hz, 1H), 6.87 - 6.80 (m, 2H), 5.34 (dd, J = 4.8, 12.0 Hz, 1H), 3.79 (dt, J = 3.2, 7.6 Hz, 2H), 3.48 (ddd, J = 1.2, 12.0, 19.2 Hz, 1H), 3.27 - 3.20 (m, 1H), 2.86 - 2.76 (m, 2H), 2.76 - 2.70 (m, 1H), 1.91 (br d, J = 12.4 Hz, 1H), 1.82 - 1.74 (m, 1H), 1.72 - 1.55 (m, 2H). Example 29: Synthesis of Compound 85 Synthetic route: 85 Step 1: synthesis of compound 85-2 Compound methyl 3-formylbenzoate (6.1 g, 37.16 mmol, 1 eq) and compound (formylmethylene)triphenylphosphorane (11.31 g, 37.16 mmol, 1 eq) were dissolved in a tetrahydrofuran solution (50 mL). The reaction solution was stirred at 80 °C for 4 h. After TLC analysis showed that the reactant was consumed completely and a new spot was formed, the reaction solution was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1-50%) to give compound 85-2 (3.8 g, 18.62 mmol, 50.11% yield) in the form of a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) 5 9.67 (d, J = 7.6 Hz, 1H), 8.17 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.49 - 7.42 (m, 2H), 6.72 (dd, J = 7.2, 16.0 Hz, 1H), 3.90 - 3.86 (m, 3H). Step 2: synthesis of compound 85-3 Hydrazine hydrate (537.15 mg, 10.52 mmol, 520.50 uL, 1 eq) was added to a tetrahydrofuran solution (20 mL), and then a solution of compound 85-2 (2 g, 10.52 mmol, 1 eq) in tetrahydrofuran (20 mL) was added slowly. The reaction solution was stirred at 25 °C for 1 h. After LCMS analysis showed that the target compound was present, the reaction solution was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1-30%) to give compound 85-3 (1.1 g, 2.04 mmol, 19.44% yield) in the form of a yellow solid. (ESI) m / z = 205.1 [M+H]+. Step 3: synthesis of compound 85-4 Compound 85-3 (1.1 g, 5.39 mmol, 1 eq) and compound 1-4 (2.81 g, 6.46 mmol, 1.2 eq) were dissolved in a dichloromethane solution (15 mL), and then bromotripyrrolidinophosphonium hexafluorophosphate (3.01 g, 6.46 mmol, 1.2 eq) and N,N-diisopropylethylamine (2.09 g, 16.16 mmol, 2.81 mL, 3 eq) were added slowly. The mixture was stirred at 25 °C for 1 h. After LCMS analysis showed that the reaction was completed, the reaction solution was filtered and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1-50%) to give compound 85-4 (2 g, 3.12 mmol, 57.84% yield) in the form of a yellow solid. (ESI) m / z = 622.4 [M+H]+. Step 4: synthesis of compound 85-5 Compound 85-4 (700 mg, 1.13 mmol, 1 eq) was dissolved in tetrahydrofuran (8 mL) and methanol (2 mL), and then an aqueous hydroxylamine solution (743.77 mg, 11.26 mmol, 10 eq) and sodium hydroxide (1 M, 2.25 mL, 2 eq) were added slowly at 0 °C. The mixture was stirred at 60 °C for 0.5 h. After LCMS analysis showed that the reaction was completed, the reaction solution was filtered and then concentrated under reduced pressure to give a residue. The residue was purified by high performance liquid chromatography (C18 column, 0.1% formic acid solution) to give compound 85-5 (230 mg, 359.45 umol, 31.93% yield) in the form of a yellow solid. (ESI) m / z = 623.2 [M+H]+. Step 5: synthesis of compound 85-6 Compound 85-5 (230 mg, 369.35 umol, 1 eq) was dissolved in dichloromethane (4 mL), and then trifluoroacetic acid (3.53 g, 30.96 mmol, 2.30 mL, 83.83 eq) was added. The mixture was stirred at 25 °C for 1 h. After LCMS analysis showed that the main peak was the target product, the reaction solution was filtered and concentrated under reduced pressure to give compound 85-6 (156 mg, crude, TFA) in the form of a yellow oil. (ESI) m / z = 423.2 [M+H]+. Step 6: synthesis of compound 85 Compound 85-6 (156 mg, 290.77 umol, 36.81 uL, 1 eq, TFA) and compound ethyl acetoacetate (37.84 mg, 290.77 umol, 36.81 uL, 1 eq) were added to an acetonitrile solution (2 mL). The mixture was stirred at 60 °C for 1 h. After LCMS analysis showed that the target compound was generated, the reaction solution was filtered and then concentrated under reduced pressure to give a residue. The residue was purified by high performance liquid chromatography (C18 column, 0.1% formic acid solution) to give compound 85 (52.40 mg, 106.74 umol, 36.71% yield) in the form of a white solid. (ESI) m / z = 489.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) 5 11.32 - 11.14 (m, 1H), 9.26 - 8.87 (m, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.29 - 7.23 (m, 3H), 7.22 -7.18 (m, 1H), 7.11 (br d, J = 7.6 Hz, 1H), 6.79 (br d, J = 8.0 Hz, 1H), 5.46 - 5.18 (m, 2H), 3.72 (br d, J = 11.6 Hz, 2H), 3.57 - 3.49 (m, 1H), 3.31 - 3.22 (m, 2H), 2.84 - 2.67 (m, 3H), 2.10 (s, 3H), 1.95 - 1.76 (m, 2H), 1.74 - 1.54 (m, 2H). Example 30: Synthesis of Compound 92 F Synthetic route: 82-1                                                  92-1                                                   92 Step 1: synthesis of compound 92-1 Compound 82-1 (400 mg, 785.08 umol, 1 eq) and trimethyltin hydroxide (2.13 g, 11.78 mmol, 15 eq) were added to anhydrous dichloroethane (8 mL). The reaction solution was stirred at 80 °C for 24 h. After LCMS analysis showed that the reaction was completed, the reaction solution was cooled to room temperature, and then a saturated aqueous potassium fluoride solution (15 mL) was added. The resulting mixture was stirred for 0.5 h and then filtered to give a filtrate, and the filtrate was extracted with dichloromethane (15 mL x 2). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to reverse-phase chromatography (water (0.1% HCl)-acetonitrile, 0-40%) to give intermediate 92-1 (300 mg, 548.93 Limol, 69.92% yield) in the form of a brown solid. (ESI) m / z = 496.3 [M+H]+. Step 2: synthesis of compound 92 Compound 92-1 (150 mg, 302.74 Lmol, 1 eq), compound N-methylhydroxylamine hydrochloride (75.85 mg, 908.22 Lmol, 3 eq), diisopropylethylamine (195.63 mg, 1.51 mmol, 263.66 LL, 5 eq), and PYBROP (211.70 mg, 454.11 Lmol, 1.5 eq) were added to anhydrous N,N-dimethylformamide (2 mL). The reaction solution was stirred at 20 °C for 12 h. After LCMS analysis showed that the reaction was completed, the reaction solution was filtered under reduced pressure to give a filtrate, which was purified by high performance liquid chromatography to give product 92 (5.08 mg, 9.50 Lmol, 3.14% yield, 98.11% purity) in the form of a yellow solid. (ESI) m / z = 525.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 11.91 (br s, 1H), 9.91 (br s, 1H), 7.33 - 7.20 (m, 3H), 7.17 - 7.05 (m, 2H), 6.96 - 6.80 (m, 3H), 5.87 (s, 1H), 5.35 (dd, J = 5.0, 12.0 Hz, 1H), 3.81 - 3.71 (m, 2H), 3.53 - 3.41 (m, 3H), 3.25 (br s, 2H), 2.90 -2.70 (m, 3H), 1.92 (br d, J = 11.8 Hz, 1H), 1.84 - 1.75 (m, 1H), 1.74 - 1.56 (m, 2H). Compounds 93 and 124 were synthesized with reference to the synthesis method of compound 92, and the characterization data for the compounds are as follows: No. Structure Spectral characterization data 93 '7: •• AYi Y oh l J ° 93 (ESI) m / z = 539.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 11.72 (br s, 1H), 9.69 (br s, 1H), 7.39 - 7.19 (m, 3H), 7.17 - 7.04 (m, 2H), 6.96 - 6.78 (m, 3H), 5.87 (s, 1H), 5.35 (dd, J = 4.8, 12.0 Hz, 1H), 4.01 - 3.56 (m, 4H), 3.52 - 3.43 (m, 1H), 3.23 (br s, 1H), 2.89 - 2.69 (m, 3H), 1.97 - 1.87 (m, 1H), 1.84 - 1.75 (m, 1H), 1.74 - 1.55 (m, 2H), 1.18 (t, J = 6.8 Hz, 3H). 124 Y?        % / °H Yo Y YY « YY 0 124 J (ESI) m / z = 543.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 12.28 - 11.23 (m, 1H), 10.39 - 9.55 (m, 1H), 7.24 (s, 1H), 7.20 (br s, 1H), 7.11 (tt, J = 2.2, 9.4 Hz, 1H), 6.99 (br d, J = 10.4 Hz, 1H), 6.84 (dd, J = 2.2, 8.4 Hz, 2H), 6.69 (br d, J = 12.8 Hz, 1H), 5.74 (br d, J = 4.6 Hz, 1H), 5.34 (dd, J = 5.0, 11.8 Hz, 1H), 3.78 (dt, J = 3.6, 7.6 Hz, 2H), 3.52 - 3.43 (m, 3H), 3.27 - 3.24 (m, 2H), 2.91 - 2.80 (m, 2H), 2.74 (ddd, J = 1.4, 5.0, 18.8 Hz, 1H), 1.96 -1.86 (m, 1H), 1.83 - 1.73 (m, 1H), 1.70 - 1.53 (m, 2H). Example 31: Synthesis of Compound 96 Synthetic route: Step 1: synthesis of compound 96-1 Compound 1B-3 (700 mg, 1.33 mmol, 1 eq) was dissolved in anhydrous dichloromethane (30 mL), and compound 3-bromo-5-fluorophenylboronic acid (874.25 mg, 4.00 mmol, 3 eq), copper acetate (725.68 mg, 4.00 mmol, 3 eq), triethylamine (1.08 g, 10.65 mmol, 1.48 mL, 8 eq), and 4A molecular sieves (1.4 g) were added successively with stirring. The mixture was stirred at room temperature for 12 h in an oxygen atmosphere. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was filtered, and the filter cake was washed with dichloromethane (30 mL x 3). The filtrate was concentrated, and silica gel was added. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 1-18%) to give compound 96-1 (350 mg, 750.60 Limol, 56.36% yield) in the form of a blue gel. (ESI) m / z = 466.0 / 468.0 [M+H]+. Step 2: synthesis of compound 96-2 Compound 96-1 (300 mg, 643.37 Lmol, 1 eq) was dissolved in anhydrous toluene (3 mL), and di-tert-butyl hydrazodicarboxylate (179.33 mg, 772.05 Lmol, 172.43 LL, 1.2 eq), cesium carbonate (419.25 mg, 1.29 mmol, 2 eq), and tBuXPhos Pd G3 (51.11 mg, 64.34 Lmol, 0.1 eq) were added successively. The reaction solution was heated to 100 °C and stirred for 1 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was filtered, and the filter cake was washed with dichloromethane (20 mL x 3). The filtrate was concentrated and then purified by column chromatography (petroleum ether / ethyl acetate = 025%) to give compound 96-2 (360 mg, 582.85 Lmol, 90.59% yield) in the form of a blue solid. (ESI) m / z = 618.2 [M+H]+. Step 3: synthesis of compound 96-3 Compound 96-2 (340 mg, 550.47 Lmol, 1 eq) was dissolved in a prepared dichloromethane:trifluoroacetic acid (5:1, 2.5 mL) solution. The mixture was stirred at room temperature for 1 h. After LCMS analysis showed that a small amount of starting material remains and a product was generated, the reaction solution was concentrated to give compound 96-3 (292 mg, crude, TFA) in the form of a yellow oil. (ESI) m / z = 418.1 [M+H]+. Step 4: synthesis of compound 96 Compound 96-3 (292 mg, 549.44 Lmol, 1 eq, TFA) was dissolved in acetonitrile (5 mL), and ethyl acetoacetate (71.50 mg, 549.44 Lmol, 69.56 LL, 1 eq) was added. The mixture was warmed to 60 °C and allowed to react for 1 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated and then purified by column chromatography (petroleum ether / ethyl acetate = 0-44%) to give a crude product. The crude product was subjected to preparative reverse-phase chromatography and lyophilized to give compound 96 (155.4 mg, 321.19 Lmol, 58.46% yield) in the form of a grayish-white solid. (ESI) m / z = 484.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.31 (s, 1H), 7.15 - 7.08 (m, 1H), 6.98 (s, 1H), 6.75 - 6.64 (m, 3H), 6.46 - 6.39 (m, 1H), 5.33 (dd, J = 5.0, 12.0 Hz, 1H), 3.83 - 3.71 (m, 2H), 3.51 - 3.37 (m, 3H), 3.32 - 3.20 (m, 1H), 2.94 - 2.73 (m, 3H), 2.20 (s, 3H), 2.06 - 1.97 (m, 1H), 1.96 - 1.82 (m, 3H). Compounds 97, 125, and 126 were synthesized with reference to the synthesis method of compound 96, and the characterization data for the compounds are as follows: No. Structural formula Spectral characterization data 97 ’ cT ’ Q m Z-z (ESI) m / z = 484.2 [M+H]+. 1H NMR (400 MHz, CHLOROF ORM-d) 5 7.06 (t, J = 9.2 Hz, 1H), 6.99 - 6.93 (m, 2H), 6.88 (td, J = 3.6, 9.2 Hz, 1H), 6.74 - 6.66 (m, 3H), 5.34 (dd, J = 5.2, 12.0 Hz, 1H), 3.68 - 3.57 (m, 2H), 3.51 - 3.41 (m, 1H), 3.40 (s, 2H), 3.26 - 3.15 (m, 1H), 2.85 - 2.73 (m, 3H), 2.19 (s, 3H), 2.05 - 1.97 (m, 1H), 1.96 - 1.86 (m, 3H). 125 F 0 -n 125     I 1X3 Cl (ESI) m / z = 500.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 57.44 (br s, 1H), 7.37 (br s, 1H), 6.98 (s, 1H), 6.77 - 6.62 (m, 4H), 5.41 - 5.27 (m, 1H), 3.84 - 3.72 (m, 2H), 3.51 - 3.38 (m, 3H), 3.33 - 3.17 (m, 1H), 2.95 - 2.73 (m, 3H), 2.20 (s, 3H), 2.06 - 1.97 (m, 1H), 1.97 - 1.84 (m, 3H) 126 = d ’ O'       Z--' H-Z (ESI) m / z = 544.1 / 546.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.49 (td, J = 1.6, 11.2 Hz, 2H), 7.02 -6.95 (m, 1H), 6.86 (t, J = 1.8 Hz, 1H), 6.77 - 6.61 (m, 3H), 5.33 (dd, J = 5.2, 12.0 Hz, 1H), 3.82 - 3.70 (m, 2H), 3.51 - 3.38 (m, 3H), 3.32 - 3.20 (m, 1H), 2.95 - 2.72 (m, 3H), 2.19 (s, 3H), 2.04 - 1.97 (m, 1H), 1.93 - 1.83 (m, 3H). Example 32: Synthesis of Compounds 112A and 112B Synthetic route: ■ / NH V N 112-3 F 112-5A NHBoc N, Boc F N 112A 112-5B 112-6A 112-6B 112B Step 1: synthesis of compound 112-2 Compound 112-1 (30 g, 239.81 mmol, 1 eq) and compound (formylmethylene)triphenylphosphorane (72.98 g, 239.81 mmol, 1 eq) were dissolved in anhydrous tetrahydrofuran (150 mL). The mixture was stirred at 80 °C for 4 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated, and silica gel was added. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 30%-40%) to give compound 112-2 (42 g, 205.64 mmol, 85.75% yield) in the form of a yellow solid. (ESI) m / z = 152.2 [M+H]+. Step 2: synthesis of compound 112-3 Hydrazine hydrate (8.45 g, 165.41 mmol, 8.19 mL, 98% purity, 5 eq) was added to tetrahydrofuran (10 mL), and then a solution of compound 112-2 (5 g, 33.08 mmol, 1 eq) in tetrahydrofuran (50 mL) was added slowly. The mixture was stirred at 25 °C for 2 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated, and silica gel was added. The mixture was purified by column chromatography (ethyl acetate / petroleum ether = 40%-50%) to give compound 112-3 (3.5 g, crude) in the form of a yellow oil. (ESI) m / z = 166.1 [M+H]+. Step 3: synthesis of compound 112-4 Bromotripyrrolidinophosphonium hexafluorophosphate (14.39 g, 30.88 mmol, 1.5 eq) and N,N-diisopropylethylamine (13.30 g, 102.93 mmol, 17.93 mL, 5 eq) were added to a solution of compound 112-3 (3.4 g, 20.59 mmol, 1 eq) and compound 1-4 (7.17 g, 16.47 mmol, 0.8 eq) in dichloromethane (40 mL). The reaction solution was stirred at 25 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated to give a crude product. The crude product was separated and purified by preparative reverse-phase chromatography [water (formic acid)-acetonitrile system] (column model: Phenomenex luna C18 (250 x 70 mm, 10 um); mobile phase: [water (FA)-ACN]; gradient elution: 45%-75% B over 20 min) and lyophilized to give compound 112-4 (2.8 g, 4.73 mmol, 23.03% yield) in the form of a yellow solid. (ESI) m / z = 583.3 [M+H]+. Step 4: synthesis of compounds 112-5A and 112-5B Compound 112-4 (2.8 g, 4.73 mmol, 1 eq) was purified by chiral resolution [carbon dioxide-acetonitrile / ethanol (0.1% ammonium hydroxide solution)] (column model: DAICEL CHIRALCEL OX (250 mm x 30 mm, 10 Lim); mobile phase: [CO2-ACN / i-PrOH (0.1% NH3H2O)]; B%: 35%, isocratic elution mode) to give compound 112-5A (1.06 g, 1.79 mmol, 37.34% yield) in the form of a yellow solid ((ESI) m / z = 583.4 [M+H]+) and compound 112-5B (1.18 g, 2.03 mmol, 42.14% yield) ((ESI) m / z = 583.4 [M+H]+). Step 5: synthesis of compound 112-6A Trifluoroacetic acid (4 mL) was added to a solution of compound 112-5A (1 g, 1.72 mmol, 1 eq) in dichloromethane (20 mL). The reaction solution was left to react at 25 °C for 1 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was concentrated under reduced pressure to give a crude product 112-6A (850 mg, crude, TFA) in the form of a pale yellow oil, which was directly used in the next step. (ESI) m / z = 383.3 [M+H]+. Step 5: synthesis of compounds 112A and 112B Compound 112-6A (850 mg, 1.71 mmol, 1 eq, TFA) was dissolved in acetonitrile (10 mL), and then compound ethyl acetoacetate (267.38 mg, 2.05 mmol, 260.10 uL, 1.2 eq) was added. The mixture was warmed to 60 °C and allowed to react for 1 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by preparative reverse-phase chromatography (column model: Waters Xbridge BEH C18 250 x 50 mm x 10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient elution: 10%-40% B over 20 min) and lyophilized to give compound 112A (391.97 mg, 836.66 ^mol, 48.87% yield) in the form of a yellow solid. (ESI) m / z = 449.3 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 8.39 (d, J = 2.4 Hz, 1H), 8.32 (s, 1H), 7.48 (s, 1H), 7.35 - 7.30 (m, 1H), 7.27 - 7.22 (m, 1H), 7.19 (br d, J = 8.8 Hz, 1H), 7.02 (s, 1H), 6.77 (br d, J = 8.0 Hz, 1H), 5.42 (dd, J = 5.2, 12.0 Hz, 1H), 3.77 (br d, J = 12.4 Hz, 2H), 3.55 - 3.45 (m, 1H), 3.42 (s, 2H), 3.28 - 3.18 (m, 1H), 2.89 - 2.80 (m, 3H), 2.20 (s, 3H), 2.02 - 1.96 (m, 1H), 1.95 - 1.87 (m, 3H). Compound 112B (306.11 mg, 650.66 umol, 38.00% yield, yellow solid) was synthesized with reference to the synthesis method of compound 112A. (ESI) m / z = 449.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 8.39 (d, J = 2.4 Hz, 1H), 8.32 (s, 1H), 7.51 - 7.44 (m, 1H), 7.36 - 7.29 (m, 1H), 7.27 - 7.22 (m, 1H), 7.19 (td, J = 2.4, 8.8 Hz, 1H), 7.01 (s, 1H), 6.80 - 6.72 (m, 1H), 5.42 (dd, J = 5.2, 12.0 Hz, 1H), 3.77 (br d, J = 12.4 Hz, 2H), 3.49 (ddd, J = 1.6, 12.0, 18.8 Hz, 1H), 3.42 (s, 2H), 3.29 - 3.18 (m, 1H), 2.89 - 2.79 (m, 3H), 2.19 (s, 3H), 2.01 - 1.86 (m, 4H). Compounds 113A and 113B were synthesized with reference to the synthesis method of compound 112A, and the characterization data for the compounds are as follows: No. Structure Spectral characterization data 113A F N \\J "-X 113A F (ESI) m / z = 467.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) 5 8.48 (d, J = 2.8 Hz, 1H), 8.30 (t, J = 1.6 Hz, 1H), 7.48 (td, J = 2.4, 9.6 Hz, 1H), 7.29 (s, 1H), 7.13 (br s, 1H), 6.96 (br d, J = 10.4 Hz, 1H), 6.63 - 6.55 (m, 1H), 5.42 (dd, J = 5.2, 12.0 Hz, 1H), 5.35 - 5.25 (m, 1H), 3.76 (br d, J = 12.4 Hz, 2H), 3.52 (ddd, J = 1.2, 12.0, 19.2 Hz, 1H), 3.28 - 3.21 (m, 1H), 2.90 - 2.78 (m, 3H), 2.10 (s, 3H), 1.89 (br d, J = 12.8 Hz, 1H), 1.79 (br d, J = 11.2 Hz, 1H), 1.70 - 1.54 (m, 2H) 113B (ESI) m / z = 468.1 [M+H]+. 1H NMR(400 MHz, DMSO-d6) 5 8.48 (d, J= 2.8 Hz, 1H), 8.30 (t, J = 1.6 Hz, 1H), 7.48 (td, J = 2.4, 9.6 Hz, 1H), 7.29 (s, 1H), 7.13 (br s, 1H), 6.96 (br d, J = 10.4 Hz, 1H), 6.63 - 6.55 (m, 1H), 5.42 (dd, J = 5.2, 12.0 Hz, 1H), 5.35 - 5.25 (m, 1H), 3.76 (br d, J = 12.4 Hz, 2H), 3.52 (ddd, J = 1.2, 12.0, 19.2 Hz, 1H), 3.28 - 3.21 (m, 1H), 2.90 - 2.78 (m, 3H), 2.10 (s, 3H), 1.89 (br d, J = 12.8 Hz, 1H), 1.79 (br d, J = 11.2 Hz, 1H), 1.70 - 1.54 (m, 2H) Example 33: Synthesis of Compound 127 F Synthetic route: Step 1: synthesis of compound 127-1 Compound 1B-3 (1 g, 1.90 mmol, 1 eq), compound 3-bromobenzyl bromide (523.06 mg, 2.09 mmol, 1.1 eq), and triethylamine (577.55 mg, 5.71 mmol, 3 eq) were added to anhydrous dichloromethane (20 mL). The reaction solution was stirred at 20 °C for 2 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated to give a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0-64%) to give compound 127-1 (640 mg, 1.38 mmol, 72.37% yield) in the form of a yellow solid. (ESI) m / z = 462.1 / 464.1[M+H]+. Step 2: synthesis of compound 127-2 Compound 3 (640 mg, 1.38 mmol, 1 eq), di-tert-butyl hydrazodicarboxylate (385.85 mg, 1.66 mmol, 1.2 eq), cesium carbonate (902.06 mg, 2.77 mmol, 2 eq), and [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (109.96 mg, 138.43 Limol, 0.1 eq) were added to anhydrous toluene (10 mL). The reaction solution was heated to 100 °C and stirred for 1 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was filtered and concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 0-70%) to give compound 127-2 (750 mg, 1.04 mmol, 74.80% yield) in the form of a yellow solid. (ESI) m / z = 614.5 [M+H]+. Step 3: synthesis of compound 127-3 Compound 127-2 (750 mg, 1.22 mmol, 1 eq) was dissolved in a prepared dichloromethane:trifluoroacetic acid (5:1, 12 mL) solution. The mixture was stirred at room temperature for 1 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated to give compound 127-3 (644 mg, crude product, TFA) in the form of a yellow oil. (ESI) m / z = 414.2 [M+H]+. Step 4: synthesis of compound 127 Compound 127-3 (644 mg, 1.22 mmol, 1 eq, TFA) was dissolved in acetonitrile (10 mL), and ethyl acetoacetate (158.89 mg, 1.22 mmol, 1 eq) was added. The mixture was warmed to 60 °C and allowed to react for 1 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 0-100%) to give a crude product. The crude product was purified by preparative reverse-phase chromatography (preparative column: Waters Xbridge C18 150 x 50 mm x 10 um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient elution: 25%-55% B over 11.0 min) and lyophilized to give compound 127 (323.5 mg, 667.95 umol, 54.71% yield) in the form of a white solid. (ESI) m / z = 480.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.83 - 7.70 (m, 2H), 7.33 (t, J = 8.2 Hz, 1H), 7.17 (br d, J = 7.6 Hz, 1H), 6.93 (s, 1H), 6.74 - 6.60 (m, 3H), 5.32 (dd, J = 4.8, 12.0 Hz, 1H), 3.54 (s, 2H), 3.49 - 3.32 (m, 3H), 3.14 - 3.01 (m, 1H), 2.94 (br dd, J = 5.2, 9.6 Hz, 2H), 2.81 - 2.69 (m, 1H), 2.21 (s, 3H), 2.16 - 2.01 (m, 2H), 1.91 -1.77 (m, 4H). Compounds 128 and 133 were synthesized with reference to the synthesis method of compound 127, and the characterization data for the compounds are as follows: No. Structure Spectral characterization data 128 v O YY n 128 (ESI) m / z = 494.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.76 - 7.65 (m, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H), 6.73 - 6.65 (m, 3H), 5.33 (dd, J = 5.2, 12.0 Hz, 1H), 3.49 - 3.36 (m, 3H), 3.17 - 3.03 (m, 3H), 2.92 - 2.81 (m, 2H), 2.76 (ddd, J = 1.6, 5.2, 18.8 Hz, 1H), 2.63 (br d, J = 6.6 Hz, 2H), 2.21 (s, 5H), 1.96 - 1.82 (m, 4H). 133 F fAQ       / yAv1 A 4 ,N N I 133 (ESI) m / z = 494.3[M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.77 (br s, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.19 (br d, J = 7.2 Hz, 1H), 6.93 (s, 1H), 6.75 - 6.62 (m, 3H), 5.32 (dd, J = 4.8, 12.0 Hz, 1H), 3.71 - 3.49 (m, 1H), 3.48 - 3.35 (m, 3H), 3.21 - 2.87 (m, 3H), 2.75 (br dd, J = 4.0, 18.8 Hz, 1H), 2.23 (s, 3H), 2.19 - 1.97 (m, 2H), 1.95 - 1.71 (m, 4H), 1.55 - 1.31 (m, 3H). Example 34: Synthesis of Compound 129 Synthetic route: Step 1: synthesis of compound 129-1 Triethylamine (2.22 g, 21.96 mmol, 3.06 mL, 2 eq) was added to a solution of 1,1 -carbonyldiimidazole (2.14 g, 13.17 mmol, 1.2 eq) in tetrahydrofuran (20 mL), and then a solution of compound 1-7 (2 g, 10.98 mmol, 1 eq) in tetrahydrofuran (20 mL) was added. The reaction solution was stirred at 25 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely, the reaction solution was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 40%-50%) to give compound 129-1 (1.3 g, 4.52 mmol, 41.15% yield) in the form of a yellow solid. (ESI) m / z = 277.1 [M+H]+. Step 2: synthesis of compound 129-2 Triethylamine (879.14 mg, 8.69 mmol, 1.21 mL, 3 eq) and compound 1 -(3-bromophenyl)piperazine (1.05 g, 4.34 mmol, 1.5 eq) were added to a solution of compound 129-1 (800 mg, 2.90 mmol, 1 eq) in dimethyl sulfoxide (10 mL). The reaction solution was allowed to react at 100 °C for 12 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was poured into water (100 mL) and then extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness by rotary evaporation. The resulting crude product was purified by normal-phase silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) and concentrated under reduced pressure to give compound 129-2 (1.3 g, 2.49 mmol, 85.92% yield) in the form of a yellow solid. (ESI) m / z = 449.0 / 451.0 [M+H]+. Step 3: synthesis of compound 129-3 Compound di-tert-butyl hydrazodicarboxylate (930.57 mg, 4.01 mmol, 894.78 liL, 1.5 eq), cesium carbonate (2.61 g, 8.01 mmol, 3 eq), and [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (212.17 mg, 267.09 lmol, 0.1 eq) were added to a solution of compound 129-2 (1.2 g, 2.67 mmol, 1 eq) in toluene (15 mL). The reaction solution was allowed to react at 100 °C for 1 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was directly concentrated to dryness by rotary evaporation. The resulting crude product was purified by normal-phase silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) and then concentrated under reduced pressure to give compound 129-3 (1 g, 1.66 mmol, 62.33% yield) in the form of a yellow solid. (ESI) m / z = 601.3 [M+H]+. Step 4: synthesis of compound 129-4 Trifluoroacetic acid (7.68 g, 67.31 mmol, 5.00 mL, 80.86 eq) was added to a solution of compound 129-3 (500 mg, 832.42 umol, 1 eq) in dichloromethane (20 mL). The reaction solution was allowed to react at 25 °C for 1 h. TLC analysis showed that the starting material was consumed completely and a new spot with large polarity was generated, the reaction solution was directly concentrated to dryness by rotary evaporation to give compound 129-4 (420 mg, trifluoroacetate) in the form of a yellow oil. (ESI) m / z = 401.3 [M+H]+. Step 5: synthesis of compound 129 Compound 129-4 (420 mg, 816.41 umol, 1 eq, trifluoroacetate) was dissolved in acetonitrile (10 mL), and then compound ethyl acetoacetate (127.50 mg, 979.69 umol, 124.03 uL, 1.2 eq) was added. The mixture was allowed to react at 60 °C for 1 h. After LCMS analysis showed that the starting material was consumed completely and a product was generated, the reaction solution was concentrated. The crude product was separated and purified by reversephase chromatography (column model: C18 spherical 20-35 um 100A, mobile phase: water (0.1% FA)-ACN, gradient elution: 0-42%, 20 min) to give compound 129 (266.90 mg, 572.15 umol, 70.08% yield, 100% purity) in the form of a white solid. (ESI) m / z = 467.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.52 (t, J = 1.8 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.32 - 7.28 (m, 1H), 6.90 - 6.81 (m, 3H), 6.80 - 6.67 (m, 2H), 5.37 - 5.31 (m, 1H), 3.87 -3.81 (m, 2H), 3.74 - 3.72 (m, 2H), 3.45 (s, 2H), 3.29 - 3.27 (m, 3H), 3.22 - 3.20 (m, 2H), 2.77 - 2.64 (m, 1H), 2.20 (s, 3H) Compounds 130, 132, 136, 141, 143, and 144 were synthesized with reference to the synthesis method of compound 129, and the characterization data for the compounds are as follows: No. Structure Spectral characterization data 130 V=N o 130 (ESI) m / z = 466.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 57.77 - 7.69 (m, 2H), 7.33 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.84 (s, 3H), 6.70 (tt, J = 2.4, 8.8 Hz, 1H), 5.35 (t, J = 10.8 Hz, 1H), 4.55 - 4.45 (m, 1H), 4.36 (td, J = 2.0, 13.6 Hz, 1H), 3.44 (s, 2H), 3.31 (ddd, J = 1.6, 11.6, 18.4 Hz, 1H), 3.06 - 2.89 (m, 2H), 2.83 - 2.73 (m, 1H), 2.67 (ddd, J = 1.2, 10.4, 18.4 Hz, 1H), 2.21 (s, 3H), 1.95 - 1.83 (m, 3H), 1.73 - 1.62 (m, 1H). 132 F / —N   V _ / ( ?N          / \ \_— / ~N 1 >32 r (ESI) m / z = 480.3 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.76 - 7.63 (m, 2H), 7.33 - 7.28 (m, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.84 - 6.79 (m, 3H), 6.73 - 6.65 (m, 1H), 5.37 - 5.24 (m, 1H), 4.34 -4.17 (m, 2H), 3.44 (s, 2H), 3.29 - 3.27 (m, 1H), 2.91 - 2.72 (m, 2H), 2.69 - 2.53 (m, 3H), 2.26 - 2.17 (m, 3H), 1.85 - 1.60 (m, 3H), 1.36 -1.31 (m, 1H), 1.25 -1.20 (m, 1H). 136 A J    A o     X I A      jN ° AAn-y X laAa 136 (ESI) m / z = 452.2[M+H]+. 1H NMR (400 MHz, CHLOR OFORM-d) 5 7.74 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.80 - 6.73 (m, 3H), 6.72 - 6.65 (m, 1H), 5.30 -5.25 (m, 1H), 4.33 - 4.17 (m, 2H), 4.00 - 3.80 (m, 2H), 3.44 (s, 2H), 3.32 - 3.30 (m, 1H), 3.00 - 2.88 (m, 3H), 2.70 - 2.63 (m, 1H), 2.21 (s, 3H). 141 A A J    n o      N- A 1 J      N^O o uoA 141 (ESI) m / z = 482.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.59 - 7.53 (m, 1H), 7.42 (t, J = 2.0 Hz, 1H), 7.32 - 7.27 (m, 1H), 6.77 (br d, J = 1.6 Hz, 3H), 6.69 (tt, J = 2.4, 8.8 Hz, 1H), 6.59 (dd, J = 2.4, 8.0 Hz, 1H), 5.29 (dd, J = 6.4, 12.0 Hz, 1H), 5.03 - 4.93 (m, 1H), 4.62 - 4.49 (m, 2H), 4.33 - 4.16 (m, 2H), 3.43 (s, 2H), 3.35 (ddd, J = 1.6, 12.4, 18.4 Hz, 1H), 2.80 (td, J = 6.8, 14.0 Hz, 1H), 2.69 (ddd, J = 1.6, 6.4, 18.4 Hz, 1H), 1.26 (d, J = 7.2 Hz, 6H). 143 f^xvf     \ A A   A 0 < ,N         Xx \=n A A } N xA H 143 (ESI) m / z = 453.2 [M+H]+. 1H NMR (400 MHz, DMSO- d6) 5 12.26 -9.92 (m, 1H), 7.14 - 7.07 (m, 2H), 7.00 (s, 1H), 6.99 - 6.83 (m, 4H), 6.64 - 6.34 (m, 1H), 6.34 - 6.25 (m, 1H), 5.31 (s, 1H), 5.23 (dd, J = 6.8, 12.2 Hz, 1H), 4.37 (br d, J = 2.0 Hz, 2H), 4.22 - 4.09 (m, 1H), 3.82 (br d, J = 1.2 Hz, 2H), 3.37 (ddd, J = 1.6, 12.2, 18.8 Hz, 1H), 2.63 (ddd, J = 1.6, 6.8, 18.4 Hz, 1H), 2.09 (s, 3H). 144 A J    A Y o     N' X I “     Xo / naA 144 (ESI) m / z = 454.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.55 - 7.50 (m, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 6.78 (br d, J = 2.0 Hz, 3H), 6.69 (tt, J = 2.4, 8.8 Hz, 1H), 6.60 (dd, J = 2.4, 8.0 Hz, 1H), 5.29 (dd, J = 6.4, 12.4 Hz, 1H), 5.02 - 4.94 (m, 1H), 4.63 - 4.49 (m, 2H), 4.33 - 4.13 (m, 2H), 3.44 (s, 2H), 3.35 (ddd, J = 1.2, 12.4, 18.4 Hz, 1H), 2.69 (ddd, J = 1.6, 6.4, 18.4 Hz, 1H), 2.21 (s, 3H). Example 35: Synthesis of Compound 131 Synthetic route: F 131-2 F Br F F^ 131-5 131-3 Step 1: synthesis of compound 131-1 N,N-diisopropylethylamine (3.04 g, 23.50 mmol, 4.09 mL, 3 eq), bromotripyrrolidinophosphonium hexafluorophosphate (4.38 g, 9.40 mmol, 1.2 eq), and compound 3-Boc-3-azabicyclo[3.2.1]octane-8-carboxylic acid (1.71 g, 9.40 mmol, 1.2 eq) were added to a solution of compound 1-7 (2 g, 7.83 mmol, 1 eq) in dichloromethane (20 mL). The reaction solution was allowed to react at room temperature for 12 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by normal-phase silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) and then concentrated under reduced pressure to give compound 131-1 (2.1 g, 4.21 mmol, 53.68% yield) in the form of a yellow oil. (ESI) m / z = 442.1 [M+Na]+. Step 2: synthesis of compound 131-2 A solution of hydrochloric acid in methanol (40 mL) was added to compound 131-1 (2.1 g, 5.01 mmol, 1 eq). The reaction solution was allowed to react at room temperature for 2 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was concentrated under reduced pressure to give compound 131-2 (2.1 g, crude product, HCl) in the form of a yellow oil. (ESI) m / z = 320.1 [M+H]+. Step 3: synthesis of compound 131-3 Compound 3-bromobenzeneboronic acid (3.39 g, 16.86 mmol, 3 eq), molecular sieves (2 g, 5.62 mmol, 1 eq), triethylamine (4.55 g, 44.97 mmol, 6.26 mL, 8 eq), and copper acetate (3.06 g, 16.86 mmol, 3 eq) were added to a solution of compound 131-2 (2 g, 5.62 mmol, 1 eq, HCl) in dichloromethane (30 mL). The reaction solution was allowed to react at room temperature for 12 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by normal-phase silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) and then concentrated under reduced pressure to give compound 131-3 (1 g, 1.92 mmol, 34.13% yield, 91% purity) in the form of a yellow oil. (ESI) m / z = 474.1 / 476.1 [M+H]+. Step 4: synthesis of compound 131-4 Di-tert-butyl hydrazodicarboxylate (587.62 mg, 2.53 mmol, 565.02 uL, 1.2 eq), cesium carbonate (1.37 g, 4.22 mmol, 2 eq), and [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (167.47 mg, 210.82 nmol, 0.1 eq) were added to a solution of compound 131-3 (1 g, 2.11 mmol, 1 eq) in toluene (10 mL). The reaction solution was allowed to react at 100 °C for 1 h in a nitrogen atmosphere. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by normalphase silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) and then concentrated under reduced pressure to give compound 131-4 (1 g, 1.37 mmol, 65.20% yield) in the form of a yellow oil. (ESI) m / z = 626.3 [M+H]+. Step 5: synthesis of compound 131-5 Dichloromethane (40 mL) and a trifluoroacetic acid solution (10 mL) were added to compound 131-4 (1 g, 1.60 mmol, 1 eq). The reaction solution was allowed to react at room temperature for 1 h. After LCMS analysis showed that the starting material was consumed completely and the main peak was the target product, the reaction solution was concentrated under reduced pressure to give compound 131-5 (679 mg, 1.60 mmol, 99.85% yield) in the form of a yellow oil, which was directly used in the next step. (ESI) m / z = 426.2 [M+H]+. Step 6: synthesis of compound 131 Compound 131-5 (679 mg, 1.60 mmol, 1 eq) was dissolved in acetonitrile (6 mL), and then compound ethyl acetoacetate (228.46 mg, 1.76 mmol, 222.24 pL, 1.1 eq) was added. The reaction solution was allowed to react at 60 °C for 1 h. After LCMS analysis showed that the starting material was consumed completely and a product was generated, the reaction solution was concentrated. The crude product was separated and purified by preparative reverse-phase chromatography (preparative column: Unisil 3-100 C18 Ultra 150 x 50 mm x 3 pm; mobile phase: [H2O (0.225% FA)-ACN]; gradient elution: 43%-73% B over 15.0 min) to give compound 131 (363.6 mg, 736.77 pmol, 46.17% yield, 99.6% purity) in the form of a white solid. (ESI) m / z = 492.2[M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.40 - 7.30 (m, 1H), 7.26 - 7.24 (m, 1H), 7.23 - 7.18 (m, 1H), 6.96 (s, 1H), 6.74 - 6.59 (m, 4H), 5.33 (dd, J = 5.2, 11.8 Hz, 1H), 3.63 (ddd, J = 3.6, 7.2, 10.8 Hz, 1H), 3.47 - 3.36 (m, 4H), 3.23 - 3.16 (m, 1H), 3.07 - 2.99 (m, 1H), 2.80 - 2.72 (m, 2H), 2.65 (br d, J = 1.2 Hz, 1H), 2.23 - 2.16 (m, 3H), 1.97 - 1.63 (m, 5H). Compounds 135, 137, 138, 139, and 142 were synthesized with reference to the synthesis method of compound 131, and the characterization data for the compounds are as follows: No. Structure Spectral characterization data 135 V ji %N VN-Z % O Cn w 135 (ESI) m / z = 438.1 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.37 - 7.31 (m, 1H), 7.27 - 7.23 (m, 1H), 7.07 (s, 1H), 6.98 - 6.92 (m, 2H), 6.87 - 6.80 (m, 1H), 6.66 -6.56 (m, 1H), 6.40 - 6.34 (m, 1H), 5.33 - 5.32 (m, 1H), 5.36 -5.29 (m, 1H), 4.15 - 4.05 (m, 4H), 3.48 - 3.44 (m, 1H), 3.43 (s, 2H), 3.10 - 3.03 (m, 1H), 2.98 - 2.91 (m, 1H), 2.20 (s, 3H). 137 F ft 137 Q (ESI) m / z = 452.2 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.82 - 7.72 (m, 2H), 7.33 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 6.92 (s, 1H), 6.77 - 6.64 (m, 3H), 5.37 - 5.23 (m, 1H), 4.07 - 3.94 (m, 1H), 3.76 - 3.61 (m, 4H), 3.46 - 3.27 (m, 5H), 2.83 - 2.70 (m, 1H), 2.20 (s, 3H). 138 138 (ESI) m / z = 452.1[M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.26 - 7.07 (m, 3H), 7.00 (d, J = 1.4 Hz, 1H), 6.75 - 6.67 (m, 3H), 6.42 (br d, J = 7.6 Hz, 1H), 5.34 (dd, J = 4.8, 12.0 Hz, 1H), 3.94 (br t, J = 7.8 Hz, 1H), 3.67 (br t, J= 8.8 Hz, 1H), 3.55 - 3.38 (m, 6H), 2.85 - 2.77 (m, 1H), 2.38 -2.28 (m, 2H), 2.19 (s, 3H). 139 F y.AO'Yy? V      O 139 (ESI) m / z = 466.2[M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.78 (s, 2H), 7.34 (t, J = 7.8 Hz, 1H), 7.21 (br d, J = 5.6 Hz, 1H), 6.92 (s, 1H), 6.73 - 6.66 (m, 3H), 5.30 (dd, J = 5.0, 12.0 Hz, 1H), 3.86 - 3.63 (m, 3H), 3.48 - 3.35 (m, 3H), 3.07 (br d, J = 2.4 Hz, 1H), 2.92 - 2.81 (m, 1H), 2.80 - 2.72 (m, 1H), 2.68 - 2.48 (m, 2H), 2.21 (s, 3H), 2.19 - 2.09 (m, 2H). 142 F Xh-ZXX Q* K f fl ,%A 1^ / -N f x 142 0 (ESI) m / z = 480.3 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) 5 7.84 - 7.74 (m, 2H), 7.34 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.92 (s, 1H), 6.77 - 6.63 (m, 3H), 5.37 - 5.23 (m, 1H), 4.08 - 3.93 (m, 1H), 3.75 - 3.59 (m, 4H), 3.47 - 3.29 (m, 5H), 2.88 - 2.71 (m, 2H), 1.26 (d, J = 6.8 Hz, 6H). Test Example 1. In Vitro Assay for Inhibitory Activity Against RIPK1 1.1 Test objective: to test the in vitro inhibitory activity of the compounds of the present disclosure against RIPK1. 1.2 Test materials Material Manufacturer Cat. No. ADP-GloTM Promega V9102 DMSO Sigma D8418-1L ATP Promega V915B DTT Sigma D0632 MnCl2 Sigma M1787 BSA PerkinElmer PE,CR84-100 RIPK1 Biotrus M1-A327 Kinase Assay Buffer I Signalchem K01-09 MBP Protein Signalchem M42-51N 384-well white plate Greiner 784075 384-well clear plate Labcyte PP-0200 96-well plate Thermo 249944 Pipette tip (10 pL) Biohit 790014 Pipette tip (200 pL) Biohit LH-B790204 Pipette tip (1000 pL) Corning T-1000-B 1.3 Test instruments Instrument Manufacturer Model Centrifuge Eppendorf 5810R Echo liquid handling system Labcyte 655 Microplate reader PerkinElmer EnVision 2014 1.4 Test method First, 50 pL of the test compound was added to a 384-well dilution plate, and the test compound was serially diluted 1:3 with DMSO. The diluted test compound solution in each row was transferred to a 384-well assay plate at 50 nL / well with Echo (except for the control wells), and DMSO was used as a control, with 2 replicates set for each column. The enzyme working solution (RIPK1 at a final concentration of 50 nM and 1x enzyme buffer) was added to the 384-well assay plate at 2.5 pL / well (except for the control wells). For the control wells, 2.5 pL of 1x enzyme buffer (DTT at a final concentration of 0.05 mM, 2.5 mM MnCh, 1 x Kinase Assay Buffer I, and H2O) was added. After the addition, the 384-well assay plate was centrifuged at 1000 RPM for 1 min and incubated at 25 °C for 10 min. Then, 2.5 pL of substrate working solution (ATP at a final concentration of 60 pL, 0.2 mg / mL MBP protein, and 1 x enzyme buffer) was added to each well, and the plate was incubated at 25 °C for 120 min. Then, 4 lL of ADP-Glo reagent (from an ADP-glo kit) was added to each well. The plate was centrifuged at 1000 RPM for 1 min and incubated at 25 °C for 60 min. Finally, 8 pL of kinase assay reagent (from an ADP-glo kit) was added to each well. The plate was centrifuged at 1000 RPM for 1 min and incubated at 25 °C for 60 min. Readings were taken using Envision 2104, and inhibition rates were calculated. Data were processed using XLfit 5.3.1.3 software, and IC50 values of the compounds were obtained using a non-linear fitting formula. The results are shown in Table 1. In the table, A represents that IC50 < 300 nM, B represents that 300 nM < IC50 < 3000 nM, and C represents that IC50 > 3000 nM. Table 1. Results of in vitro assay for inhibitory activity of compounds of the present disclosure against RIPK1 Compound RIPK1 Function ADP IC50 (pM) Compound RIPK1 Function ADP IC50 (pM) Compound RIPK1 Function ADP IC50 (pM) 1 A 53 B 98 A 1A C 54 A 99 A 1B A 55 B 100 A 2 A 56 B 102 B 2A C 61 A 104 A 2B A 62 A 108 B 3 A 63A C 112A A 4 A 63B A 112B C 5 B 63C C 113A C 6 A 63D B 113B B 7 B 64 B 124 B 8 A 65 B 125 B 10A C 66 B 126 B 10B A 67 B 127 A 10C B 68 B 128 C 11A B 69 B 129 B 11B B 70 B 130 C 12 C 71 A 131 C 13 C 72 B 132 B 14 B 74 B 133 B 15 B 81 A 135 C 44 A 82 A 136 B 45 A 83 A 137 B 46 A 84 A 138 C 47 A 85 C 139 B 48 B 86 B 141 B 49 B 92 A 142 B 50 B 93 A 143 B 51 A 96 A 144 B 52 B 97 A Test Example 2. Assay for DPPH Free Radical Scavenging Capacity 2.1 Test objective: to test the DPPH free radical scavenging capacity of the compounds of the present disclosure. 2.2 Test materials Material Manufacturer Cat. No. Dimethyl sulfoxide Sigma D2650 D4Plus dispensehead cassette Tecan 30097371 T8Plus dispensehead cassette Tecan 30097370 96-well plate Corning 3599 Absolute ethanol Sangon A500737 2,2-Diphenyl-1 -picrylhydrazyl(DPPH) MCE HY-112053 2.3 Test instruments Instrument Manufacturer Model Digital Dispenser Tecan HP D300 Microplate reader FlexStation 3 Molecular Devices Centrifuge Eppendorf 5425R Tissue grinder Shanghai Jingxin JXFSTPRP-CL-48 Dry bath incubator Hm-Kylin GL-150B 2.4 Test method 20 pL of the test compound was first added to a 96-well plate and serially diluted 1:2 with DMSO. Then, 200 pL of 200 pM DPPH prepared with absolute ethanol as the solvent was added to each well, and the plate was incubated in the dark at room temperature for 30 min after gentle shaking. The absorbance value at 517 nm was measured using a microplate reader. The DPPH scavenging rate was calculated using the following formula: DPPH scavenging rate % = (1 - Ai / A0) x 100%, where Ai represents the absorbance value of the sample, and A0 represents the absorbance value of the DMSO control group. Data were processed using XLfit 5.3.1.3 software, and IC50 values of the compounds were obtained using a non-linear fitting formula. The results are shown in Table 2. In the table, A represents that EC50 < 100 pM, B represents that 100 pM < EC50 < 500 pM, and C represents that EC50 > 500 pM. Table 2. Results of assay for DPPH free radical scavenging capacity of compounds of present disclosure Compound Free radical scavenging DPPH EC50 (pM) Compound Free radical scavenging DPPH EC50 (pM) Compound Free radical scavenging DPPH EC50 (pM) 1 A 63B A 98 A 1B A 67 A 100 B 2 A 68 A 102 B 2A A 71 B 113A B 2B A 81 A 113B B 3 B 82 A 125 A 6 B 83 C 126 A 7 A 96 A 127 A 10B A 97 A 128 B 62 A Test Example 3. MDA-Based Assay for Anti-Lipid Peroxidation Capacity 2.1 Test objective: to test the anti-lipid peroxidation capacity of the compounds of the present disclosure based on MDA. 2.2 Test materials Material Manufacturer Cat. No. DPBS( 1x) Corning 21-031-CVC Dimethyl sulfoxide Sigma D2650 D4Plus dispensehead cassette Tecan 30097371 T8Plus dispensehead cassette Tecan 30097370 96-well plate Corning 3599 Ascorbic acid ST1434 Beyotime Lipid oxidation (MDA) assay kit S0131M Beyotime 2.3 Test instruments Instrument Manufacturer Model Digital Dispenser Tecan HP D300 Microplate reader FlexStation 3 Molecular Devices Centrifuge Eppendorf 5425R Tissue grinder Shanghai Jingxin JXFSTPRP-CL-48 Dry bath incubator Hm-Kylin GL-150B 2.4 Test method First, brain tissue homogenate was prepared as follows: An adult male SD rat was anesthetized with isoflurane and then sacrificed by cervical dislocation; the whole brain was taken out and washed twice in DPBS; the meninges were peeled off, and the brain was transferred to a 50 mL centrifuge tube containing 10 mL of DPBS, cut into pieces with scissors, and aliquoted into ten 1.5 mL centrifuge tubes. Three grinding beads were added to each tube, and the grinding was performed at 90 Hz for 60 min, with the process repeated three times. The ground tissue homogenate was transferred to a new 50 mL centrifuge tube, DPBS was added to reach a total volume of 30 mL, and the mixture was sufficiently mixed. Then, 20 pL of the test compound was added to the 96-well plate and serially diluted 1:3 with DMSO. Then, 100 pL of brain tissue homogenate, 50 pL of DPBS, and 50 pL of 200 pg / mL vitamin C were added successively, and a series of concentration standards were prepared as standard curves. After shaking, the plate was incubated at 37 °C for 1 h, and then 400 uL of MDA working solution was added. The plate was heated at 100 °C for 15 min. After cooling to room temperature, the plate was centrifuged at 1000 g for 10 min, and 200 uL of the supernatant was pipetted into another new plate. The absorbance value at 532 nm was measured using a microplate reader. The scavenging rate of the compounds for MDA was calculated using the following formula: MDA scavenging rate % = [((A1 - A0) - (A2 - A0)) / ((A1 - A0) - (A3 - A0))] x 100%, where A1 refers to the absorbance value of the high control group, A2 refers to the absorbance value of the sample, A3 refers to the absorbance value of the low control group, and A0 refers to the absorbance value of the blank group. Data were processed using XLfit 5.3.1.3 software, and IC50 values of the compounds were obtained using a non-linear fitting formula. The results are shown in Table 3. In the table, A represents that EC50 < 25 pM, B represents that 25 pM < EC50 < 250 pM, and C represents that EC50 > 250 pM. Table 3. Results of MDA-based assay for anti-lipid peroxidation capacity of compounds of present disclosure Compound Antioxidant MDA EC50 (pM) Compound Antioxidant MDA EC50 (pM) Compound Antioxidant MDA EC50 (pM) 1 A 63B A 98 B 1B A 67 A 100 A 2 A 68 A 102 A 2A A 71 C 113A A 2B A 81 A 113B A 3 B 82 A 125 A 6 A 83 A 126 A 7 A 96 A 127 A 10B A 97 A 128 A 62 A In conclusion, the compounds of the present disclosure exhibit excellent biological activity in inhibiting programmed cell necrosis, free radical scavenging capacity, and anti-lipid peroxidation capacity, and thus can be used for preventing or treating ischemic stroke or other related diseases.

Claims

1. A compound represented by Formula (A), a pharmaceutically acceptable salt thereof, or a stereoisomerthereof,X1cX1dR7(A)wherein,X1 is selected from the group consisting of CH or N;X1a is selected from the group consisting of CR1a or N;X1b is selected from the group consisting of CR1b or N;X1c is selected from the group consisting of CR1c or N;X1d is selected from the group consisting of CR1d or N;X1e is selected from the group consisting of CR1e or N;R1a, R1b, R1c, R1d, and R1e are each independently selected from the group consisting of: H, halogen, C1-6 alkyl, -(C=O)-NH-OH, or cyano;R2a, R2b, and R2c are each independently selected from the group consisting of: H, halogen, or C1-6 alkyl;LYX2^...... • • r X3 ^ X5        X3 yA / A is selected from the group consisting of        X4     or        X4    ;X2 is selected from the group consisting of CR2 or N;X3 is selected from the group consisting of CR3 or N;X4 is selected from the group consisting of CR4 or N;X5 is selected from the group consisting of CR5 or N;R2, R3, R4, and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy;O.          ...             A.L is selected from the group consisting of a single bond, C1-3 alkylene, -NH-, -O-, or     e';A N%  V'N'^B is selected from the group consisting of    N or     Oh ;NA8       O      okNy   H O   OH.R7 is selected from the group consisting of      O , X N          , or      R9   ;ONOHIR8 is selected from the group consisting of: H, C1-6 alkyl, C1-6 haloalkyl,      R9   , or cyano;R9 is selected from the group consisting of: H or C1-6 alkyl.

2. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof according to claim 1, wherein the compound has a structural formula of Formula (I), whereinOnN^zA, B, X1, X2, X3, X4, X5, R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2, R3, R4, and R5 are as defined in claim 1.

3. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof according toclaim 1 or 2, wherein / * N•                                                                             • •                 \ iB is selected from the group consisting of W N(S)V  V / " N-\ i\= N , orthe carbon atom with “*” is a chiral carbon atom present in the form of a single (R)- or (S)- enantiomer orin a form enriched with one enantiomer.

4. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof according to anyone of claims 1-3, whereinA is selected from the group consisting ofX3x4X5Vy X2y\X3x4X5L is selected from the group consisting of a single bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -NH-, -O-, orO(1)X2 is selected from the group consisting of CR2;X3 is selected from the group consisting of CR3;X4 is selected from the group consisting of CR4;X5 is selected from the group consisting of CR5;R2, R3, R4, and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy;or(2)X2 is selected from the group consisting of N;X3 is selected from the group consisting of CR3;X4 is selected from the group consisting of CR4;X5 is selected from the group consisting of CR5;R3, R4, and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy;or(3)X2 is selected from the group consisting of N;X3 is selected from the group consisting of N;X4 is selected from the group consisting of CR4;X5 is selected from the group consisting of CR5;R4 and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy;or(4)X2 is selected from the group consisting of N;X3 is selected from the group consisting of CR3;X4 is selected from the group consisting of N;X5 is selected from the group consisting of CR5;R3 and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy;or(5)X2 is selected from the group consisting of N;X3 is selected from the group consisting of CR3;X4 is selected from the group consisting of CR4;X5 is selected from the group consisting of N;R3 and R4 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy;or(6)X2 is selected from the group consisting of CR2;X3 is selected from the group consisting of N;X4 is selected from the group consisting of CR4;X5 is selected from the group consisting of N;R2 and R4 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy.5.The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof according to anyone of claims 1-4, whereinA is selected from the group consisting of        R4      ,         R4R2OOR4      ,          R4R4     ,          R4R4OR4R4R2O       v5 XU V N ■R3   N R5,      R4O               R2X y ANR3A / nAO R2R4R2, R3, R4, and R5 are each independently selected from the group consisting of: H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy.

6. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof according to any one of claims 1-5, whereinR1a, R1b, R1c, R1d, and R1e are each independently selected from the group consisting of: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, -(C=O)-NH-OH, or cyano;R2a, R2b, and R2c are each independently selected from the group consisting of: H, F, Cl, Br, I, methyl,ethyl, n-propyl, or isopropyl;R2, R3, R4, and R5 are each independently selected from the group consisting of: H, F, Cl, Br, I, methyl,ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy;R7 is selected from the group consisting oforOA N OHR9    ;R8 is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-OJX OH \ Ndichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,      R9   , or cyano;R9 is selected from the group consisting of: H, methyl, ethyl, n-propyl, or isopropyl.

7. The compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof according toclaim 1, wherein the compound is selected from the group consisting of:FF17     NO CNOf15FFNIN20NHOhF9483 N N84OFO9395 F96N-I N^zOH■■O    N,'■”’    ■07        ' F9798FOFOH104BrON NFN / \N'N112113     FF114FFF(±)-62(±)-96    F90(±)-1278. A pharmaceutical composition, comprising the compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof according to any one of claims 1-7, and a pharmaceutically acceptable carrier.

9. Use of the compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof according to any one of claims 1-7 or the composition according to claim 8 in preparing a medicament for treating or preventing a receptor-interacting protein kinase 1 (RIPK1)-mediated related disease or a disease caused by programmed cell necrosis.

10. The use according to claim 9, wherein the receptor-interacting protein kinase 1 (RIPK1)-mediated related disease comprises: inflammatory bowel disease, psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, arthritis, lupus, systemic lupus erythematosus (SLE), Sjogren’s syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, osteoarthritis, liver injury / liver disease, nonalcoholic fatty liver disease (NAFLD), kidney damage / kidney injury, celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection, reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA), myocardial infarction (MI), atherosclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, ischemic brain injury, traumatic brain injury, allergic disease, peripheral nerve injury, burns, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener’s granulomatosis, pulmonary sarcoidosis, Behcet’s disease, interleukin-1 converting enzyme (ICE, also known as caspase-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neoplastic tumors, periodontitis, NEMO-mutation (NF-k-B essential modulator gene (IKKy or IKKG mutation)), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial and viral infections, lysosomal storage disease, Stevens-Johnson syndrome, toxic epidermal necrolysis, glaucoma, spinal cord injury, fibrosis, complement-mediated cytotoxicity, cancer, radiation-induced necrosis, ocular ischemia, cerebral hemorrhage, subarachnoid hemorrhage, acute liver failure and radiation protection / alleviation, auditory disorders such as noise-induced hearing loss and drugs associated with ototoxicity or for in vitro treatment of cells to preserve viability and functions.

11. The use according to claim 10, wherein the inflammatory bowel disease comprises Crohn’s disease and ulcerative colitis; the arthritis comprises rheumatoid arthritis, spondyloarthritis, gout, juvenile idiopathic arthritis, systemic-onset juvenile idiopathic arthritis (SoJIA), and psoriatic arthritis; the liver injury / liver disease comprises nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen toxicity, and hepatotoxicity; the kidney damage / kidney injury comprises nephritis, acute kidney injury (AKI) caused by kidney transplantation, surgery, and administration of nephrotoxic drugs, and ischemic kidney damage; the transplant rejection comprises rejection of transplanted organs, tissues, and cells; the cerebrovascular accident comprises ischemic stroke and hemorrhagic stroke; the allergic disease comprises asthma and atopic dermatitis; the NEMO-mutation comprises NEMO-deficiency syndrome, HOIL-1 deficiency (RBCK1), and heme-oxidized IRP2 ubiquitin ligase-1 deficiency; the bacterial and viral infections comprise influenza, Staphylococcus, and Mycobacterium tuberculosis; the lysosomal storage 91disease comprises Gaucher’s disease, GM2 gangliosidosis, a-mannosidosis, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon’s disease, Fabry’s disease, Farber’s disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe’s disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick’s disease, neuronal ceroid lipofuscinosis, Pompe’s disease, pycnodysostosis, Sandhoff’s disease, Schindler’s disease, sialidosis, familial amaurotic idiocy, and Wolman’s disease; the cancer comprises pancreatic cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, melanoma, metastatic tumors, breast cancer, kidney cancer, and non-small cell lung cancer (NSCLC).