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

RIPK1 inhibitor, preparation method thereof and medical application thereof Technical Field

[0001] The present invention relates to novel compounds that inhibit receptor-interacting protein kinase 1 (RIPK1) and their use in preparing drugs for treating or preventing RIPK1-mediated diseases, particularly compounds represented by the general formula, tautomers thereof, or pharmaceutically acceptable compositions thereof. Background Art

[0002] Receptor-interacting protein kinase 1 (RIPK1) is a key signaling protein in the TNF receptor signaling pathway. It possesses an amino-terminal (N-terminal) kinase domain, a carboxy-terminal (C-terminal) death domain, and a receptor-interacting protein homotypic interacting motif (RHIM) intermediate domain, which binds to other RHIM-containing proteins. The C-terminal death domain mediates homodimerization and heterodimerization with other death domain-containing proteins (such as FADD, TNFR1, and Fas), while the N-terminal kinase domain mediates autophosphorylation in trans to promote its own activation. RIPK1 drives apoptosis and programmed necrosis through two distinct mechanisms. Apoptosis is mediated by caspases, while in the absence of apoptotic conditions, RIPK1 and its downstream proteins RIPK3 and MLKL activate the programmed necrosis pathway.

[0003] The key role of RIPK1 in driving cell death and inflammation, the established safety profile of inhibiting human RIPK1 kinase activity, and the presence of a unique kinase-regulating allosteric pocket are the main factors contributing to the prominence of RIPK1 as a therapeutic target. Consequently, RIPK1 has gradually become an effective target for the treatment of a variety of diseases, including autoimmune, inflammatory, and neurodegenerative diseases. Several RIPK1 inhibitors have demonstrated efficacy and safety in preclinical models and clinical trials. Among them, Necrostatin-1s (Nec-1s) is the first small molecule inhibitor of RIPK1 kinase to be developed. AbbVie's ABBV-668 and Sanofi's SAR443122 are both in Phase II clinical trials for ulcerative colitis. Viterelon's SIR1-365 is registered for clinical trials for systemic inflammation, while Sanofi's brain penetrant SAR443820 is in clinical trials for amyotrophic lateral sclerosis and multiple sclerosis.

[0004] Stroke is an acute cerebrovascular disease, classified as ischemic or hemorrhagic, depending on the sudden rupture or blockage of a cerebral blood vessel, which prevents blood from flowing to the brain. Ischemic stroke is more common than hemorrhagic stroke, accounting for 60% to 70% of all strokes. Stroke is characterized by high morbidity, mortality, and disability. The pathological process of ischemic stroke includes excitotoxicity, oxidative stress, and inflammation. The therapeutic mechanism of the marketed drug edaravone is to act as an antioxidant through free radical scavenging, thereby providing neuroprotection. After ischemic stroke, apoptosis in the cerebral penumbra (surrounding the ischemic core) is reversible, and RIPK1 is a key component of the necroptosis signaling pathway. Furthermore, because TNFR2 has protective effects in the central nervous system, and RIPK1 kinase does not signal through TNFR2, RIPK1 is a safer target for the treatment of central nervous system diseases than TNF inhibitors.

[0005] Currently developed small-molecule inhibitors of RIPK1 kinase activity primarily focus on the treatment of peripheral inflammation, but suffer from shortcomings such as insufficient specificity and poor inhibitory activity. Therefore, we are developing small-molecule compounds that combine RIPK1 inhibitory activity with antioxidant and free radical scavenging capabilities to treat ischemic stroke through antioxidant activity and blocking programmed cell necrosis, thereby addressing the significant market demand. Summary of the Invention

[0006] The present invention provides a compound represented by formula (A), a pharmaceutically acceptable salt or stereoisomer thereof:

[0007] in:

[0008] X1 is selected from CH or N;

[0009] X 1a Selected from CR 1a or N;

[0010] X 1b Selected from CR 1b or N;

[0011] X 1c Selected from CR 1c or N;

[0012] X 1d Selected from CR 1d or N;

[0013] X 1e Selected from CR 1e or N;

[0014] R 1a 、R 1b 、R1c 、R 1d 、R 1e Each independently selected from: H, halogen, C 1-6 Alkyl, -(C=O)-NH-OH, or cyano;

[0015] R 2a 、R 2b 、R 2c Each independently selected from: H, halogen, or C 1-6 alkyl;

[0016] A is selected from

[0017] X2 is selected from CR2 or N;

[0018] X3 is selected from CR3 or N;

[0019] X4 is selected from CR4 or N;

[0020] X5 is selected from CR5 or N;

[0021] R2, R3, R4, R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy;

[0022] L is selected from a single bond, C 1-3 Alkylene, -NH-, -O-, or

[0023] B is selected from

[0024] R7 is selected from:

[0025] R8 is selected from: H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, or cyano;

[0026] R9 is selected from: H, C 1-6 alkyl.

[0027] In some embodiments of the present invention, there are further provided compounds represented by formula (I), pharmaceutically acceptable salts or stereoisomers thereof:

[0028] in:

[0029] X1 is selected from CH or N;

[0030] R 1a 、R 1b 、R 1c 、R 1d 、R1e Each independently selected from: H, halogen, C 1-6 Alkyl, or cyano;

[0031] R 2a 、R 2b 、R 2c Each independently selected from: H, halogen;

[0032] A is selected from

[0033] X2 is selected from CR2 or N;

[0034] X3 is selected from CR3 or N;

[0035] X4 is selected from CR4 or N;

[0036] X5 is selected from CR5 or N;

[0037] R2, R3, R4, R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy;

[0038] B is selected from

[0039] In some embodiments of the present invention, the compound represented by the above formula (A) or (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0040] L is selected from a single bond, C 1-3 Alkylene (e.g., -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-), -NH-, -O-, or (1)

[0041] A is selected from

[0042] X2 is selected from CR2;

[0043] X3 is selected from CR3;

[0044] X4 is selected from CR4;

[0045] X5 is selected from CR5;

[0046] R2, R3, R4, R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy; or

[0047] (2)

[0048] A is selected from

[0049] X2 is selected from N;

[0050] X3 is selected from CR3;

[0051] X4 is selected from CR4;

[0052] X5 is selected from CR5;

[0053] R3, R4, R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy; or

[0054] (3)

[0055] A is selected from

[0056] X2 is selected from N;

[0057] X3 is selected from N;

[0058] X4 is selected from CR4;

[0059] X5 is selected from CR5;

[0060] R4 and R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy; or

[0061] (4)

[0062] A is selected from

[0063] X2 is selected from N;

[0064] X3 is selected from CR3;

[0065] X4 is selected from N;

[0066] X5 is selected from CR5;

[0067] R3 and R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy; or

[0068] (5)

[0069] A is selected from

[0070] X2 is selected from N;

[0071] X3 is selected from CR3;

[0072] X4 is selected from CR4;

[0073] X5 is selected from N;

[0074] R3 and R4 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy; or

[0075] (6)

[0076] A is selected from

[0077] X2 is selected from CR2;

[0078] X3 is selected from N;

[0079] X4 is selected from CR4;

[0080] X5 is selected from N;

[0081] R2, R4 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy;

[0082] Other groups are as defined herein.

[0083] In some embodiments of the present invention, the compound represented by the above formula (A) or formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0084] A is selected from

[0085] R2, R3, R4, R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy;

[0086] Other groups are as defined herein.

[0087] In some embodiments of the present invention, the compound represented by the above formula (A) or formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0088] A is selected from

[0089] R5 is selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy;

[0090] Other groups are as defined herein.

[0091] In some embodiments of the present invention, the compound represented by the above formula (A) or formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0092] B is selected from

[0093] The carbon atom marked with "*" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer;

[0094] Other groups are as defined herein.

[0095] In some embodiments of the present invention, the compound represented by the above formula (A) or formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0096] B is selected from

[0097] Other groups are as defined herein.

[0098] In some embodiments of the present invention, the compound represented by the above formula (A) or formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0099] R 1a 、R 1b 、R 1c 、R 1d 、R 1e Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, -(C=O)-NH-OH, or cyano;

[0100] R 2a 、R 2b 、R 2c Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0101] 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, and isopropoxy.

[0102] R7 is selected from:

[0103] 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-trifluoroethyl, 2,2,2-trichloroethyl, or cyano;

[0104] R9 is selected from the group consisting of: H, methyl, ethyl, n-propyl, isopropyl;

[0105] Other groups are as defined herein.

[0106] In some embodiments of the present invention, the compound represented by the above formula (I), its pharmaceutically acceptable salt or stereoisomer, wherein,

[0107] R 1a 、R 1b 、R 1c 、R 1d 、R 1e Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, or cyano;

[0108] R 2a 、R 2b 、R 2c Each independently selected from: H, F, Cl, Br, or I;

[0109] 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, and isopropoxy.

[0110] Other groups are as defined herein.

[0111] In other embodiments of the present invention, provided are compounds represented by formula (IIA) or (IIB), or pharmaceutically acceptable salts or stereoisomers thereof:

[0112] in:

[0113] X1 is selected from CH or N;

[0114] R 1a 、R 1b 、R 1c 、R 1d 、R 1e Each independently selected from: H, halogen, C 1-6 Alkyl, or cyano;

[0115] R 2a 、R 2b 、R 2c Each independently selected from: H, halogen;

[0116] A is selected from

[0117] X2 is selected from CR2 or N;

[0118] X3 is selected from CR3 or N;

[0119] X4 is selected from CR4 or N;

[0120] X5 is selected from CR5 or N;

[0121] R2, R3, R4, R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy.

[0122] In some embodiments of the present invention, the compound represented by the above formula (IIA) or (IIB), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0123] A is selected from

[0124] X2 is selected from CR2;

[0125] X3 is selected from CR3;

[0126] X4 is selected from CR4;

[0127] X5 is selected from CR5;

[0128] R2, R3, R4, R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy;

[0129] Other groups are as defined herein.

[0130] In some embodiments of the present invention, the compound represented by the above formula (IIA) or (IIB), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0131] A is selected from

[0132] X2 is selected from N;

[0133] X3 is selected from CR3;

[0134] X4 is selected from CR4;

[0135] X5 is selected from CR5;

[0136] R3, R4, R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy;

[0137] Other groups are as defined herein.

[0138] In some embodiments of the present invention, the compound represented by the above formula (IIA) or (IIB), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0139] A is selected from

[0140] X2 is selected from N;

[0141] X3 is selected from N;

[0142] X4 is selected from CR4;

[0143] X5 is selected from CR5;

[0144] R4 and R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy;

[0145] Other groups are as defined herein.

[0146] In some embodiments of the present invention, the compound represented by the above formula (IIA) or (IIB), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0147] A is selected from

[0148] X2 is selected from N;

[0149] X3 is selected from CR3;

[0150] X4 is selected from N;

[0151] X5 is selected from CR5;

[0152] R3 and R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy;

[0153] Other groups are as defined herein.

[0154] In some embodiments of the present invention, the compound represented by the above formula (IIA) or (IIB), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0155] A is selected from

[0156] X2 is selected from N;

[0157] X3 is selected from CR3;

[0158] X4 is selected from CR4;

[0159] X5 is selected from N;

[0160] R3 and R4 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy;

[0161] Other groups are as defined herein.

[0162] In some embodiments of the present invention, the compound represented by the above formula (IIA) or (IIB), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0163] A is selected from

[0164] X2 is selected from CR2;

[0165] X3 is selected from N;

[0166] X4 is selected from CR4;

[0167] X5 is selected from N;

[0168] R2, R4 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy;

[0169] Other groups are as defined herein.

[0170] In some embodiments of the present invention, the compound represented by the above formula (IIA) or (IIB), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0171] A is selected from

[0172] R5 is selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy;

[0173] Other groups are as defined herein.

[0174] In some embodiments of the present invention, the compound represented by the above formula (IIA) or (IIB), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0175] R 1a 、R 1b 、R 1c 、R 1d 、R 1e Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, or cyano;

[0176] R 2a 、R 2b 、R 2c Each independently selected from: H, F, Cl, Br, or I;

[0177] A is selected from

[0178] X2 is selected from CR2 or N;

[0179] X3 is selected from CR3 or N;

[0180] X4 is selected from CR4 or N;

[0181] X5 is selected from CR5 or N;

[0182] 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, and isopropoxy.

[0183] In some embodiments of the present invention, provided are the following compounds, pharmaceutically acceptable salts or stereoisomers thereof:

[0184] The present invention also provides a pharmaceutical composition comprising any one of the above compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral solutions, granules, injections, or various sustained-release formulations. The pharmaceutical composition can be administered orally or parenterally (e.g., intravenously, subcutaneously, or topically). The dosage can be appropriately adjusted based on the patient's age, sex, and disease type, with a typical daily dose of about 1-1000 mg.

[0185] The present invention also provides the use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition for treating and / or preventing patient diseases, and the use of the above-mentioned compound or its pharmaceutically acceptable salt or stereoisomer or pharmaceutical composition in preparing a drug. The present invention also provides the use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition in preparing a drug, which is a drug for treating or preventing related diseases mediated by receptor-interacting protein kinase 1 (RIPK1) or diseases caused by programmed cell necrosis. The receptor-interacting protein kinase 1 (RIPK1) Diseases mediated by RIPK1 or diseases caused by programmed cell death include diseases / disorders that are easily regulated at least in part by programmed cell death, apoptosis or the production of inflammatory cytokines; for example, 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), Arthritis (SoJIA), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, osteoarthritis, liver damage / liver disease (non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen poisoning, hepatotoxicity), non-alcoholic fatty liver disease (NAFLD), kidney damage / kidney injury (renal Inflammation, kidney transplantation, surgery, administration of nephrotoxic drugs such as cisplatin, acute kidney injury (AKI), celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of the transplanted organ, tissue, or cells), reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington disease, Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis (ALS) , progressive supranuclear palsy (PSP), neonatal brain injury, neonatal anoxic brain injury, ischemic brain injury, traumatic brain injury, allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, burns, multiple sclerosis, type 1 diabetes mellitus, type 2 diabetes mellitus, obesity, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1)-associated febrile syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis,Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neoplastic tumors, periodontitis, NEMO-mutations (mutations in the NF-κ-B essential regulator gene (also known as IKKγ or IKKG)), particularly NEMO-deficiency syndrome, HOIL-1 deficiency (also known as RBCK1), heme-oxidized IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematologic and solid organ malignancies leukemia, bacterial and viral infections (such as influenza, staphylococcal and mycobacterial (tuberculosis)), lysosomal storage diseases (particularly, Gaucher disease, and including GM2 gangliosidosis, α-mannosidosis, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile urinary tract infection, sialidosis, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialidosis, Tay-Sachs disease, and Wolman disease), Stevens-Johnson syndrome, toxic epidermal necrolysis, glaucoma, spinal cord injury Myeloid injury, fibrosis, complement-mediated cytotoxicity, cancer (including pancreatic cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, melanoma, metastases, breast cancer, non-small cell lung cancer (NSCLC)), radiation-induced necrosis, ischemic renal damage, ocular ischemia, cerebral hemorrhage, subarachnoid hemorrhage, acute liver failure and radiation protection / mitigation, auditory disorders such as noise-induced hearing loss and drugs associated with ototoxicity (such as cisplatin) or for treating cells in vitro to preserve viability and function.

[0186] Definition and Description

[0187] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0188] The term "pharmaceutically acceptable" as used herein refers to compounds, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0189] The "pharmaceutically acceptable salts" mentioned in the present invention refer to salts of the compounds of the present invention, which are prepared by reacting the compounds with specific substituents discovered by the present invention with relatively non-toxic acids and bases. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts; and also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic functional groups and can be converted into any acid addition salt.

[0190] Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

[0191] The compounds of the present invention contain one or more asymmetric centers (also known as chiral centers), such as chiral carbons or chiral -SO- moieties. The stereochemistry of the chiral carbon centers present in the compounds of the present invention is generally indicated in the compound names and / or chemical structures shown herein. The compounds of the present invention containing one or more chiral centers can exist as racemic mixtures, diastereomeric mixtures, enantiomerically enriched mixtures, diastereomerically enriched mixtures, or as enantiomerically or diastereomerically pure individual stereoisomers. For example: The carbon atom marked with "*" is a chiral carbon atom, which may exist in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer, or in the form of a racemic mixture.

[0192] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0193] Unless otherwise indicated, the term "enantiomer" refers to stereoisomers that are mirror images of one another.

[0194] Unless otherwise indicated, the term "geometric isomers" refers to the inability of a ring to rotate freely about double bonds or single bonds of ring carbon atoms.

[0195] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0196] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0197] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed key

[0198] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, the salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.

[0199] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative of a carrier that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient, including but not limited to: binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0200] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

[0201] Unless otherwise specified, "alkyl" is used to refer to a straight or branched saturated hydrocarbon group, which can be monosubstituted (such as -CH2F) or polysubstituted (such as -CF3), and can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). For example, C1-C6 means 1 to 6 carbon atoms, C1-6 Selected from C1, C2, C3, C4, C5, C6; examples of alkyl include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl), etc.

[0202] Unless otherwise stated, "halogen," by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom.

[0203] Unless otherwise specified, the term "cyano" refers to the group -CN.

[0204] Unless otherwise specified, "alkoxy" is used to represent an alkyl group (including cycloalkyl or haloalkyl) having the specified number of carbon atoms attached through an oxygen bridge. Typical alkoxy groups include C 1-6 Alkoxy groups, such as C1, C2, C3, C4, C5, and C6 alkoxy groups, C3, C4, C5, and C6 cycloalkoxy groups, and C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, S-pentoxy, hexoxy, and 2-ethylbutoxy groups. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy groups. Examples of haloalkoxy groups 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.

[0205] Unless otherwise specified, "haloalkyl" is used to indicate an alkyl group substituted with one or more halogen atoms, wherein the alkyl group has the meaning as described herein. For example, the term "C1-C6 haloalkyl" is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups substituted with one or more halogen atoms. Unless otherwise specified, examples of C1-C6 haloalkyl groups 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.

[0206] Unless otherwise specified, the term "cycloalkyl" includes any stable cyclic or polycyclic hydrocarbon radical, any carbon atom of which is saturated, which may be monosubstituted or polysubstituted, and which may be monovalent, divalent, or polyvalent. Typical cycloalkyl radicals include C3-6 Cycloalkyl, for example: C3, C4, C5, C6 cycloalkyl, i.e. 3-membered, 4-membered, 5-membered, or 6-membered cycloalkyl. Examples of these cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0207] Unless otherwise specified, the term "oxo" refers to a divalent radical =0.

[0208] Compounds are manually or Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0209] The present invention is further described below with reference to specific embodiments and test examples, but they are not intended to limit the scope of the present invention in any form.

[0210] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0211] NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed on an AVANCE III 600 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0212] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Shimadzu LCMS2020 mass spectrometer, and HPLC was performed using a Shimadzu LC20A liquid chromatograph.

[0213] The thin layer chromatography silica gel plate used was Yantai Jiangyou silica gel plate, the specification used for TLC was 0.2mm±0.03mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm.

[0214] Unless otherwise specified in the examples, the SFC separation conditions were as follows: column model: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm); mobile phase: [CO 2 -i -PrOH / ACN]; B%: 40%, isocratic elution mode.

[0215] In the description of the following examples, the abbreviations of the reagents used and the corresponding reagent names are as follows:

[0216] Example 1: Synthesis of Compounds 1, 1A, and 1B

[0217] Synthesis route:

[0218] Step 1: Synthesis of compound 1-2

[0219] 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 copper 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 and reacted at 100 ° C under nitrogen protection for 12 hours. After the reaction of the starting materials was complete, the reaction solution was poured into water (1 L) and extracted with ethyl acetate (1 L * 3). The organic phase was washed with saturated brine (1 L * 2) and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain compound 1-2 (34 g, 108.90 mmol, yield 68.48%) as a light yellow oil. MS (ESI) m / z = 312.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.17-7.07(m,1H),7.05(s,1H),6.98-6.92(m,1H),6.85(dd,J=1.6,8.4Hz,1H),4.17(q,J=7.2Hz,2H),3.64(td,J =3.6,12.4Hz,2H),2.88-2.76(m,2H),2.45(ddd,J=4.0,7.2,11.0Hz,1H),2.08-1.97(m,2H),1.93-1.79(m,2H),1.28(t,J=7.2Hz,3H).

[0220] Step 2: Synthesis of Compounds 1-3

[0221] Compound 1-2 (31 g, 99.29 mmol, 1 eq) and di-tert-butylazidooxalic acid (23.06 g, 99.29 mmol, 22.18 mL, 1 eq) were dissolved in anhydrous toluene (310 mL). tBuXPhons G3 (7.89 g, 9.93 mmol, 0.1 eq) and cesium carbonate (64.70 g, 198.59 mmol, 2 eq) were added and heated to 100°C under nitrogen for 12 hours. LCMS monitoring confirmed the completion of the reaction. The reaction mixture was poured into water (1.5 L), extracted with ethyl acetate (1 L*3), washed with saturated brine (1 L*2), filtered, dried, concentrated, and mixed. The crude product was purified by normal phase silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to afford compound 1-3 (32.7 g, 70.54 mmol, 64.58% yield) as a white solid. (ESI) m / z = 464.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ = 7.19 (t, J = 8.0Hz, 1H), 7.07-6.96 (m, 1H), 6.88 (br d,J=7.6Hz,1H),6.75(dd,J=2.0,8.4Hz,1H),4.16(q,J=7.2Hz,2H),3.63(td,J=3.6,12.4Hz,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).

[0222] Step 3: Synthesis of Compounds 1-4

[0223] Compound 1-3 (32.7 g, 70.54 mmol, 1 eq) was dissolved in methanol (120 mL), tetrahydrofuran (120 mL), and water (120 mL). Lithium hydroxide monohydrate (8.88 g, 211.62 mmol, 3 eq) was added and reacted at 30°C for 2 hours. TLC (petroleum ether:ethyl acetate = 5:1) confirmed complete consumption of the starting material and the formation of new spots. The reaction solution was adjusted to pH 6 with dilute hydrochloric acid and extracted with ethyl acetate (300 mL*3). The solution was washed with saturated brine (500 mL*2), dried, and concentrated to afford compound 1-4 (34.3 g, crude) as a yellow solid, which was used directly in the next step. (ESI) m / z = 436.3 [M+H] + . 1HNMR (400MHz, CDCl3) δ7.19-7.12(m,1H),7.01(br s,1H),6.87(br d,J=5.6Hz,2H),6.72(br d,J=8.0Hz,1H),3.58(br d,J=12.0Hz,2H),2.80-2.69(m,2H),2.44-2.35(m,1H),1.99(br d,J=12.4Hz,2H),1.82(q,J=10.6Hz,2H),1.49(s,18H).

[0224] Step 4: Synthesis of Compounds 1-6

[0225] To a solution of compound 1-5 (100 g, 703.72 mmol, 77.16 mL, 1 eq) and acetaldehyde (116.25 g, 1.06 mol, 148.09 mL, 40% purity, 1.5 eq) in water (600 mL) was added dropwise a 1 M aqueous sodium hydroxide solution (738.90 mL, 1.05 eq) at 0°C. The reaction mixture was allowed to react at 25°C for 18 hours. LCMS analysis confirmed complete reaction of the starting materials, with the main peak being the desired product. The reaction mixture was filtered, and the filter cake was washed with water (200 mL x 2). The solid was collected and the product, compound 1-6 (100 g, 463.90 mmol, 65.92% yield), was obtained as a yellow solid. (ESI) m / z = 169.3 [M+H] + .

[0226] Step 5: Synthesis of Compounds 1-7

[0227] To a solution of hydrazine hydrate (15.04 g, 300.44 mmol, 14.57 mL, 5.05 eq) in tetrahydrofuran (50 mL) was slowly added dropwise over 1 hour. The reaction mixture was allowed to react at 25°C for 2 hours. LCMS showed complete reaction of the starting material and the main peak was the desired product. The reaction mixture was concentrated under reduced pressure, and the residue was purified by normal phase silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to afford product 1-7 (6 g, 29.64 mmol, 49.84% yield) as a white solid. (ESI) m / z = 183.0 [M+H] + . 1H NMR (400MHz, CDCl3) δ6.95-6.84(m,2H),6.81(d,J=1.4Hz,1H),6.71(tt,J=2.4,8.8Hz,1H),4. 71(t,J=10.2Hz,1H), 3.16(ddd,J=1.8,10.8,17.0Hz,1H), 2.65(ddd,J=1.6,9.4,17.0Hz,1H).

[0228] Step 6: Synthesis of Compounds 1-8

[0229] 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 tripyrrolidinylphosphonium bromide 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 hours. After the reaction was complete, as determined by LCMS, the reaction solution was concentrated and sampled. The crude product was purified by normal phase silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to afford compound 1-8 (1.2 g, 2.00 mmol, 87.15% yield) as a yellow solid. (ESI) m / z = 600.4 [M+H] + .

[0230] Step 7: Synthesis of Compound 1-9

[0231] Compound 1-8 (600 mg, 1.00 mmol, 1 eq) was dissolved in anhydrous dichloromethane (7.5 mL) and trifluoroacetic acid (2.30 g, 20.19 mmol, 1.5 mL, 20.18 eq) was added at 0°C. The mixture was allowed to react for 2 hours at 20°C. LCMS confirmed the complete reaction. The reaction mixture was concentrated under reduced pressure to yield compound 1-9 (395 mg, 988.89 μmol, 98.83% yield) as a yellow oil. (ESI) m / z = 400.2 [M+H] + .

[0232] Step 8: Synthesis of Compound 1

[0233] Compound 1-9 (395 mg, 988.89 μmol, 1 eq) was dissolved in acetonitrile (5 mL) and then ethyl acetoacetate (128.70 mg, 988.89 μmol, 125.19 μL, 1 eq) was added. The mixture was heated to 60°C for 1 hour. LCMS confirmed the complete consumption of the starting material and the formation of the product. The reaction solution was purified by ODS C18 reverse-phase preparative column chromatography (water (formic acid)-acetonitrile) to obtain a crude product. The crude product was further purified by silica gel column chromatography (n-hexane-ethanol). The fraction was concentrated under reduced pressure and lyophilized with deionized water to obtain compound 1 (90 mg, 192.03 μmol, yield 19.42%, purity 99.32%) as a white solid. (ESI) m / z = 466.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.49 (t, J = 2.0Hz, 1H), 7.36-7.32 (m, 1H), 7.27-7.23 ( m,1H),6.97(s,1H),6.78(dd,J=1.9,8.1Hz,1H),6.74-6.66(m,3H),5.34(d d,J=5.0,12.0Hz,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).

[0234] Step 9: Synthesis of compounds 1-8A and 1-8B

[0235] Compound 1-8 (5 g, 8.34 mmol, 1 eq) was purified by chiral resolution [carbon dioxide-acetonitrile / ethanol (0.1% aqueous ammonia)] to afford compound 1-8A (2.7 g, 4.50 mmol, 54% yield) as a yellow solid and compound 1-8B (2.2 g, 3.67 mmol, 44% yield) as a yellow solid. SFC: Column type: (s,s) WHELK-O1 (250 mm*30 mm, 10 μm); Mobile phase: [CO₂-ACN / EtOH (0.1% NH₃H₂O)]; B%: 60%, isocratic elution mode. Compound 1-8A (retention time = 1.243 min) and compound 1-8B (retention time = 2.433 min) were obtained.

[0236] Compound 1A (473 mg, 1.00 mmol, yield 23.57%) was obtained as a white solid using a similar synthesis method to compound 1. (ESI) m / z = 466.1 [M+H] + . 1H NMR (400MHz, CHLOROFORM-d) δ = 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=7.4Hz,1H),6.75-6.64(m,3H),5.34(dd,J=5.0,12.0Hz,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 type: Lux 3μm Cellulose-4 50*4.6mm ID, 3μm; 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.

[0237] Compound 1B (841 mg, 1.79 mmol, 55.10% yield, 99.14% purity) was obtained as a white solid using a similar synthesis method to compound 1. (ESI) m / z = 466.2 [M+H] + . 1 H NMR(400MHz,CHLOROFORM-d)δ7.48(s,1H),7.35-7.30(m,1H),7.27-7.22(m,1H),6.97(s,1H),6.77(dd,J=1.6,8.2Hz,1H),6.73-6.66(m,3H),5.34(d d,J=5.2,12.0Hz,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 type: Lux 3μm Cellulose-2 50*4.6mm ID, 3μm; 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.

[0238] The second synthesis method of compound 1B:

[0239] Step 1: Synthesis of compound 1B-1

[0240] Compound 1-Boc-4-piperidinecarboxylic acid (6.25 g, 27.26 mmol) was dissolved in 50 mL of dichloromethane at room temperature. Tris-pyrrolidinylphosphonium bromide hexafluorophosphate (13.43 g, 28.80 mmol) was added, and diisopropylethylamine (3.55 g, 27.45 mmol, 4.78 mL) was added dropwise. After stirring for 5 minutes, compound 1-7 (5 g, 27.45 mmol) was added. The mixture was stirred at room temperature for 5 hours. The dichloromethane was removed by rotary evaporation, and the reaction mixture was concentrated and purified by normal phase chromatography (silica, petroleum ether / ethyl acetate = 3 / 1). After spin drying, intermediate 1B-1 (8.92 g, 20.63 mmol, yellow oil, 75.17% yield) was obtained. (ESI) m / z = 416.2 [M+Na] + .

[0241] Step 2: Synthesis of compound 1B-2

[0242] Compound 1B-1 (8 g, 4.58 mmol) was dissolved in dichloromethane (12.5 mL). The mixture was stirred at 20°C and hydrogen chloride / dioxane (2 M, 266.58 mmol, 133.29 mL) was added. The reaction mixture was stirred at 20°C for 4 hours. The reaction mixture was filtered to obtain a white solid, and the filter cake was washed twice with 5 mL of dichloromethane. Intermediate 1B-2 (8 g, white solid powder, 97.70% yield) was obtained. (ESI) m / z = 294.2 [M+H] + .

[0243] Step 3: Synthesis of compound 1B-3

[0244] Intermediate 1B-2 (8 g, 24.26 mmol) was added to ethanol (25 mL), and then sodium hydroxide aqueous solution (19.75 mL, 1 M, 3.07 mmol) was added to the mixture. After stirring at 20°C for 30 minutes, dichloromethane (10 mL) was added. The mixture separated into two layers and was transferred to a separatory funnel. The organic phase was released and the aqueous phase was extracted twice with dichloromethane (10 mL). The organic phase was concentrated by rotary evaporation to obtain an oil. The oil was dissolved in ethanol (25 mL), and L-camphorsulfonic acid (5.64 g, 24.26 mmol) was added and stirred at 60°C for 30 minutes. The reaction solution was rotary evaporated and 16 mL of ethanol was added to slurry. The ethanol was removed by rotary evaporation again to obtain an orange solid. To the orange solid, 96 mL of ethanol was added, and the mixture was stirred and heated to 60°C until the reaction solution became clear. The mixture was then allowed to cool naturally, recrystallized, and filtered to obtain the L-camphorsulfonic acid salt of intermediate 1B-3 (2 g, white solid, 12.98% yield). SFC (column model: Chiralpak IG-3 50*4.6 mm ID, 3 μm; 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.

[0245] Steps 4-6: Synthesis of compound 1B

[0246] The L-camphorsulfonic acid salt of intermediate 1B-3 was synthesized using a similar method to compound 1 to obtain compound 1B. SFC (column type: Lux 3μm Cellulose-2 50*4.6mm ID, 3μm; 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.

[0247] Example 2: Synthesis of Compounds 2, 2A, and 2B

[0248] Synthesis route:

[0249] Step 1: Synthesis of compound 2-1

[0250] Intermediate 2-1 (yellow solid) was obtained by a similar synthesis method as in Example 1. (ESI) m / z = 564.4 [M+H] + .

[0251] Step 2: Synthesis of compounds 2A-1 and 2B-1

[0252] Compound 2-1 (1.8 g, 3.19 mmol) was chirally resolved, and the fractions were concentrated under reduced pressure to give 2A-1 (850 mg, 1.43 mmol, yield 44.86%, retention time = 1.411 min) and 2B-1 (830 mg, 1.40 mmol, yield 43.81%, retention time = 1.647 min) as light yellow solids.

[0253] Step 3: Synthesis of compounds 2, 2A and 2B

[0254] Compound 2-1 was synthesized using a method similar to that of Example 1 to obtain compound 2 (white solid), (ESI) m / z = 430.1 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ11.61-10.89(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).

[0255] Compound 2A-1 was synthesized using a method similar to that of Example 1 to obtain compound 2A. Compound 2A was a white solid hydrochloride salt, (ESI) m / z = 430.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.14-7.62(m,2H),7.55(br s,2H),7.39-7.05(m,7H),5.50(s,1H),5.34(dd,J=4.6,11.8Hz,1H),3.80-3.37(m,6H),2.70(br dd,J=4.6,18.8Hz,1H),2.29-1.88(m,7H).

[0256] SFC (column model: Chiralpak AD-3 50*4.6mm ID, 3μm; 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: 3mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar) retention time = 1.922min.

[0257] Compound 2B-1 was synthesized using a method similar to that in Example 1 to obtain compound 2B. Compound 2B was obtained as a white solid hydrochloride salt (ESI) m / z = 430.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.09-7.58(m,2H),7.57-7.42(m,2H),7.42-7.04(m,7H),5.48(s,1 H), 5.34 (dd, J = 4.6, 11.8Hz, 1H), 3.72-3.43 (m, 6H), 2.76-2.64 (m, 1H), 2.24-1.88 (m, 7H).

[0258] SFC (column model: Chiralpak AD-3 50*4.6mm ID, 3μm; 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: 3mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar) retention time = 2.258min.

[0259] Example 3: Synthesis of Compound 3

[0260] Synthesis route:

[0261] Step 1: Synthesis of compound 3-1

[0262] 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 2-bromo-6-fluoropyridine (5.60 g, 31.80 mmol, 1 eq) in acetonitrile (50 mL). The reaction mixture was allowed to react at 60°C for 12 hours. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was filtered, and the filtrate was purified by normal-phase silica gel column chromatography (ethyl acetate:petroleum ether = 1:0 to 5:1) and concentrated under reduced pressure to yield compound 3-1 (8.4 g, 26.82 mmol) as a light yellow oil. (ESI) m / z = 313.0 [M+H] + .

[0263] Step 2: Synthesis of compound 3-2

[0264] To a solution of compound 3-1 (3.5 g, 11.18 mmol, 1 eq) and tert-butyl carbazate (2.22 g, 16.76 mmol, 1.5 eq) in dioxane (50 mL) were added cesium carbonate (10.92 g, 33.53 mmol, 3 eq) and tBuXPhosPdG4 (998.33 mg, 1.12 mmol, 0.1 eq). The reaction mixture was incubated at 100°C under nitrogen for 12 hours. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was filtered, and the filtrate was poured into water (200 mL) and 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 crude product was purified by normal-phase silica gel column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:1) and concentrated under reduced pressure to afford compound 3-2 (3.8 g, 10.43 mmol, 93.30% yield) as a brownish-black solid. (ESI) m / z = 365.1 [M+H] + .

[0265] Step 3: Synthesis of compound 3-3

[0266] To a solution of compound 3-2 (1.9 g, 5.21 mmol, 1 eq) in methanol (20 mL) and water (2 mL) was added lithium hydroxide monohydrate (656.33 mg, 15.64 mmol, 3 eq). The reaction mixture was reacted at 30°C under nitrogen for 4 hours. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was adjusted to pH 5-6 with 2M aqueous hydrochloric acid and 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 crude product was purified by normal phase silica gel column chromatography (ethyl acetate:petroleum ether = 5:1 to 1:5) and concentrated under reduced pressure to afford compound 3-3 (0.3 g, 847.24 mmol, 16.25% yield) as a brownish-black solid. (ESI) m / z = 337.1 [M+H] + .

[0267] Step 4: Synthesis of compound 3-4

[0268] Compound 3-3 (450 mg, 1.34 mmol, 1 eq) and 5-phenyl-4,5-dihydro-1H-pyrazole (215.12 mg, 1.47 mmol, 1.1 eq) were dissolved in anhydrous dichloromethane (12 mL). Tris-pyrrolidinylphosphonium bromide hexafluorophosphate (748.36 mg, 1.61 mmol, 1.2 eq) and N,N-diisopropylethylamine (518.67 mg, 4.01 mmol, 699.02 μL, 3 eq) were added and reacted at 20°C for 2 hours. After the reaction was complete, as determined by LCMS, the reaction solution was concentrated and sampled. The crude product was purified by normal phase silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to afford compound 3-4 (350 mg, 753.40 μmol, yield 56.32%) as a yellow solid. (ESI) m / z = 465.3 [M+H] + .

[0269] Step 5: Synthesis of compound 3-5

[0270] Compound 3-4 (320 mg, 688.83 μmol, 1 eq) was dissolved in anhydrous dichloromethane (6 mL) and trifluoroacetic acid (1.84 g, 16.16 mmol, 1.2 mL, 23.45 eq) was added at 0°C. The mixture was then reacted at 20°C for 1 hour. After the reaction was complete, LCMS confirmed the reaction. The reaction solution was concentrated to yield compound 3-5 (250 mg, 685.98 μmol, 99.59% yield) as a yellow oil. (ESI) m / z = 365.2 [M+H] + .

[0271] Step 6: Synthesis of compound 3

[0272] Compound 3-5 (250 mg, 685.98 μmol, 1 eq) was dissolved in acetonitrile (5 mL) and then ethyl acetoacetate (89.27 mg, 685.98 μmol, 86.84 μL, 1 eq) was added. The mixture was heated to 60°C and allowed to react for 16 hours. LCMS analysis confirmed the complete consumption of the starting material and the formation of the product. The reaction solution was purified by reverse phase preparative chromatography (water (formic acid)-acetonitrile) to obtain a crude product. This crude product was further separated by silica gel column chromatography (n-hexane-ethanol). The fractions were concentrated under reduced pressure and lyophilized with deionized water to yield compound 3 (41.1 mg, 89.70 μmol, 13.08% yield, 93.96% purity) as a white solid. (ESI) m / z = 431.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ13.67-12.10(m,1H),7.59(t,J=8.2Hz,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=8.6Hz,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=1.8,4.8,18.8Hz,1H),2.25(s,3H),2.08-1.94(m,2H),1.91-1.78(m,2H).

[0273] Example 4: Synthesis of Compound 4

[0274] Synthesis route:

[0275] Step 1: Synthesis of compound 4-1

[0276] 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). Tris-pyrrolidinylphosphonium bromide 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 and reacted at 20°C for 2 hours. After the reaction was complete, as determined by LCMS, the reaction solution was concentrated and sampled. The crude product was purified by normal phase silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to afford compound 4-1 (290 mg, 579.37 mmol, 43.31% yield) as a yellow oil. (ESI) m / z = 501.3 [M+H]+ .

[0277] Step 2: Synthesis of compound 4-2

[0278] Compound 4-1 (260 mg, 519.44 μmol, 1 eq) was dissolved in anhydrous dichloromethane (6 mL) and trifluoroacetic acid (1.84 g, 16.16 mmol, 1.2 mL, 31.10 eq) was added at 0°C. The mixture was then reacted at 20°C for 1 hour. After the reaction was complete, LCMS confirmed the reaction. The reaction solution was concentrated to yield compound 4-2 (100 mg, 249.74 μmol, 48.08% yield) as a yellow oil. (ESI) m / z = 401.2 [M+H] + .

[0279] Step 3: Synthesis of compound 4

[0280] Compound 4-2 (80 mg, 199.79 μmol, 1 eq) was dissolved in ethanol (2.5 mL) and ethyl acetoacetate (26.00 mg, 199.79 μmol, 25.29 μL, 1 eq) was added. The mixture was heated to 50°C and reacted for 16 hours. LCMS analysis confirmed the complete consumption of the starting material and the formation of the product. The reaction solution was purified by ODS C18 reverse-phase column chromatography [water (formic acid)-acetonitrile system] and lyophilized to obtain compound 4 (6.8 mg, 14.15 μmol, yield 7.08%, purity 97.07%). (ESI) m / z = 467.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.80-7.41(m,1H),7.25(s,1H),7.11(t,J=9.0Hz,1H), 6.84(d,J=6.8Hz,3H),5.34(dd,J=4.8,11.8Hz,2H),4.61-3.93(m,2H),3.48(dd ,J=12.2,19.0Hz,1H),3.38(m,2H),3.12-2.82(m,2H),2.75(dd,J=5.0,18.6Hz, 1H), 2.17 (s, 3H), 1.92 (d, J = 10.8Hz, 1H), 1.83-1.70 (m, 1H), 1.66-1.42 (m, 2H).

[0281] Example 5: Synthesis of Compound 5

[0282] Synthesis route:

[0283] Step 1: Synthesis of compound 5-1

[0284] 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 mixture was allowed to react at 120°C for 12 hours. LCMS analysis indicated the presence of a small amount of starting material and the main peak was the desired product. The reaction mixture 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 vacuo. 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 afford compound 5-1 (10.6 g, 33.85 mmol, 63.85% yield) as a light yellow oil. (ESI) m / z = 313.0 [M+H] + .

[0285] Step 2: Synthesis of compound 5-2

[0286] To a solution of compound 5-1 (10.6 g, 33.85 mmol, 1 eq) and di-tert-butylazideoxalic acid (11.79 g, 50.77 mmol, 11.34 mL, 1.5 eq) in dioxane (100 mL) were added cesium carbonate (33.08 g, 101.54 mmol, 3 eq) and methanesulfonic acid (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). The reaction mixture was incubated at 100°C under nitrogen for 12 hours. LCMS analysis indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was filtered, and the resulting crude product was purified by normal-phase silica gel column chromatography (ethyl acetate:petroleum ether = 1:10 to 2:1) and concentrated under reduced pressure to afford compound 5-2 (12 g, 25.83 mmol, 76.32% yield) as a light yellow oil. (ESI) m / z = 465.3 [M+H] + .

[0287] Step 3: Synthesis of compound 5-3

[0288] 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) was added lithium hydroxide monohydrate (309.33 mg, 12.92 mmol, 3 eq). The reaction mixture was reacted at 20°C under nitrogen for 12 hours. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was adjusted to pH 5-6 with 2M aqueous hydrochloric acid and 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 yield compound 5-3 (1.5 g, 2.78 mmol, 64.65% yield, 81% purity) as a pale yellow solid. (ESI) m / z = 435.3 [MH] + .

[0289] Step 4: Synthesis of compound 5-4

[0290] 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) were added N,N-diisopropylethylamine (1.60 g, 12.37 mmol, 2.15 mL, 3 eq) and tripyrrolidinylphosphonium bromide hexafluorophosphate (2.88 g, 6.19 mmol, 1.5 eq). The reaction mixture was allowed to react at 20°C for 12 hours. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was directly filtered. The crude product was purified by normal phase silica gel column chromatography (ethyl acetate:petroleum ether = 1:0 to 2:1) and concentrated under reduced pressure to afford compound 5-4 (2 g, 3.33 mmol, 80.75% yield) as a yellow gel. (ESI) m / z = 601.4 [M+H] + .

[0291] Step 5: Synthesis of compound 5-5

[0292] To compound 5-4 (2 g, 4.25 mmol, 1 eq) was added a 2M solution of dioxane hydrochloride (20 mL). The reaction mixture was allowed to react at 20°C for 12 hours. LCMS analysis indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was then concentrated under reduced pressure to afford crude compound 5-5 (1.7 g), which was used directly in the next step. (ESI) m / z = 401.1 [M+H] + .

[0293] Step 6: Synthesis of compound 5

[0294] Compound 5-5 (1.7 g, 4.25 mmol, 1 eq) was dissolved in ethanol (17 mL) and then ethyl acetoacetate (552.52 mg, 4.25 mmol, 537.47 μL, 1 eq) was added. The mixture was heated to 60°C and reacted for 12 hours. LCMS analysis confirmed complete consumption of the starting material and the formation of the product. The reaction mixture was filtered, and the filtrate was purified by reverse phase preparative purification using water (formic acid)-acetonitrile, followed by lyophilization to yield compound 5 (457.2 mg, 931.10 μmol, 21.93% yield). (ESI) m / z = 467.1 [M+H] + . 1 H NMR(400MHz, CDCl3) δ8.59(d,J=2.6Hz,1H),7.90(dd,J=9.2,2.6Hz,1H),6.98(s,1H),6.73-6.64(m,4H),5.33(dd,J=12.0,5.0Hz, 1H),4.39-4.28(m,2H),3.50-3.29(m,4H),3.04-2.90(m,2H),2.78(ddd,J=18.8,5.0,1.6Hz,1H),2.19(s,3H),2.01-1.79(m,4H).

[0295] Example 6: Synthesis of Compound 6

[0296] Synthesis route:

[0297] Step 1: Synthesis of compound 6-1

[0298] (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 starting material 1-1 (10 g, 63.61 mmol, 9.80 mL, 1 eq) and starting material p-bromoiodobenzene (21.59 g, 76.33 mmol, 1.2 eq) in dimethyl sulfoxide (100 mL). The atmosphere was purged with nitrogen three times, and the mixture was stirred at 100°C under nitrogen for 18 hours. After the reaction was complete as determined by LCMS, 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 obtain intermediate 6-1 (12.5 g, yield 41.54%, light yellow solid). (ESI) m / z = 312.0 [M+H] + .

[0299] Step 2: Synthesis of compound 6-2

[0300] 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 di-tert-butylazideoxalic acid (5.58 g, 24.02 mmol, 5.37 mL, 1.5 eq) in toluene (70 mL). The atmosphere was purged with nitrogen three times and the mixture was stirred at 110°C for 18 hours. After completion of the reaction as determined by LCMS, the mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 7 / 3) to afford intermediate 6-2 (5 g, 67.35% yield, pale yellow solid). (ESI) m / z = 464.3 [M+H]+.

[0301] Step 3: Synthesis of compound 6-3

[0302] A 1M aqueous lithium hydroxide solution (1M, 32.36mL, 3eq) was added to a methanol solution (100mL) of intermediate 6-2 (5g, 10.79mmol, 1eq) and stirred at 25°C for 18 hours. After the reaction was complete as determined by LCMS, the reaction solution was filtered and concentrated under reduced pressure to remove methanol. The pH was then adjusted to 5-6 with a 1N aqueous hydrochloric acid solution under ice-cooling, and the mixture was extracted twice with ethyl acetate (100mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 6-3 (4.5g, 94.074% yield, light yellow solid). (ESI) m / z = 436.2 [M+H] + .

[0303] Step 4: Synthesis of compound 6-4

[0304] 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). Tris-pyrrolidinylphosphonium bromide hexafluorophosphate (802.81 mg, 1.72 mmol, 1.5 eq) and N,N-diisopropylethylamine (741.90 mg, 5.74 mmol, 999.86 μL, 5 eq) were added to the reaction solution and reacted at 25°C for 12 hours. After the reaction was complete, as determined by LCMS, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase silica gel chromatography (petroleum ether / ethyl acetate = 30%-50%) to obtain compound 6-4 (600 mg, 83.05% yield, 95.3% purity) as a colorless oil. (ESI) m / z = 600.4 [M+H]+ . 1 H NMR (400MHz, CDCl3) δ7.26-7.20(m,1H),6.97(s,1H),6.88(br d,J=9.2Hz,2H),6.76-6.65(m,4H),5.34(dd,J=4.8,12.2Hz,1H),3.70(br d,J=9.2Hz,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).

[0305] Step 5: Synthesis of compound 6-5

[0306] Compound 6-4 (500 mg, 833.80 μmol, 1 eq) was added to dioxane hydrochloride (20 mL) and stirred at 25°C for 12 hours. LCMS confirmed that the reaction was complete, and the resulting compound 6-5 was dried and used directly in the next step. (ESI) m / z = 400.2 [M+H] + .

[0307] Step 6: Synthesis of compound 6

[0308] Compound 6-5 (330 mg, 826.16 μmol, 1 eq) was added to anhydrous ethanol (10 mL). Ethyl acetoacetate (107.52 mg, 826.16 μmol, 104.59 μL, 1 eq) was added to the reaction mixture and stirred at 25°C for 12 hours. After the reaction was complete as determined by LCMS, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase preparative column (C18 column, 0.1% formic acid solution) and lyophilized to obtain compound 6 (8 mg, 17.10 μmol, yield 2.07%, purity 99.48%) as a white solid. (ESI) m / z = 466.1 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ11.32-10.88(m,1H),7.46(br d,J=8.8Hz,2H),7.24(s,1H),7.17-7.07(m,1H),6.97(br d,J=9.2Hz,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).

[0309] Example 7: Synthesis of Compound 7

[0310] Synthesis route:

[0311] Step 1: Synthesis of compound 7-1

[0312] 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 PyBrOP (3.21 g, 6.89 mmol, 1.5 eq) was added portionwise. The reaction solution was stirred at 25°C for 2 hours. After completion of the reaction as determined by LCMS, the reaction solution was concentrated under reduced pressure. Purification by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) afforded intermediate 7-1 (2.2 g, 84.99% yield, pale yellow solid). (ESI) m / z = 564.3 [M+H] + .

[0313] Step 2: Synthesis of compound 7-2

[0314] A 2M hydrochloric acid solution in dioxane (2M, 6 mL, 13.53 eq) was added to a solution of intermediate 7-1 in dioxane (6 mL), and the mixture was stirred at 25°C for 18 hours. After the reaction was complete as determined by LCMS, the reaction solution was concentrated under reduced pressure to give intermediate 7-2 (354 mg, crude product, light yellow solid). (ESI) m / z = 364.1 [M+H] + .

[0315] Step 3: Preparation of compound 7

[0316] Ethyl acetoacetate (172.80 mg, 1.33 mmol, 168.09 μL, 1.5 eq) was added to a solution of intermediate 7-2 (300 mg, 826.16 μmol, 1 eq) in acetonitrile (10 mL) and stirred at 60°C for 1 hour. After completion of the reaction as determined by LCMS, the reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by reverse phase chromatography (C18 column, 0.1% aqueous hydrochloric acid) and lyophilized to obtain the hydrochloride salt of 7 (46.8 mg, white solid, 10.74% yield). (ESI) m / z = 430.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.17-7.56(m,5H),7.38-7.22(m,4H),7.14(d,J=7.4Hz,2H),5.52(s,1H) ,5.35(dd,J=4.6,11.8Hz,1H),3.81-3.33(m,6H),2.76-2.64(m,1H),2.35-2.05(m,6H),1.97(br d,J=12.8Hz,1H).

[0317] Example 8: Synthesis of Compound 8

[0318] Synthesis route:

[0319] Step 1: Synthesis of compound 8-1

[0320] 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) was added diisopropylethylamine (13.01 g, 100.69 mmol, 17.54 mL, 3 eq). The reaction mixture was allowed to react at 20°C for 2 hours. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture 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 product 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 yield compound 8-1 (8 g, 29.66 mmol, 88.37% yield) as a pale white oil. (ESI) m / z = 270.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ = 7.95 (d, J = 6.0Hz, 1H), 6.34 (d, J = 6.0Hz, 1H), 4.40-4.12 (m, 2H), 4.09 (q, J = 7.2Hz, 2H), 3.05 ( ddd,J=3.2,11.2,13.6Hz,2H),2.54(tt,J=4.2,10.8Hz,1H),1.97-1.90(m,2H),1.78-1.57(m,2H),1.22-1.17(m,3H)

[0321] Step 2: Synthesis of compound 8-2

[0322] To a solution of compound 8-1 (6.369 g, 23.61 mmol, 1 eq) and di-tert-butylazideoxalic acid (8.23 g, 35.42 mmol, 7.91 mL, 1.5 eq) in toluene (65 mL) were added 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)]methanesulfonatepalladium(II)] (1.88 g, 2.36 mmol, 0.1 eq). The reaction mixture was reacted at 100°C under nitrogen for 12 hours. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was directly filtered, and the resulting crude product was purified by normal-phase silica gel column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:1) and concentrated under reduced pressure to yield compound 8-2 (2.485 g, 4.80 mmol, 20.35% yield, 90% purity) as a brownish-yellow solid. (ESI) m / z = 466.3 [M+H] + .

[0323] Step 3: Synthesis of compound 8-3

[0324] 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) was added lithium hydroxide monohydrate (806.39 mg, 19.22 mmol, 4 eq). The reaction mixture was allowed to react at 20°C for 12 hours. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was adjusted to pH 6 with 1 M aqueous hydrochloric acid and extracted with ethyl acetate (50 mL x 3). The reaction mixture was filtered, and the filter cake was directly concentrated under reduced pressure to yield compound 8-3 (1.1 g, 2.61 mmol, 54.30% yield, 80% purity) as a white solid. (ESI) m / z = 436.3 [MH] + .

[0325] Step 4: Synthesis of compound 8-4

[0326] 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) were added N,N-diisopropylethylamine (574.63 mg, 4.45 mmol, 774.43 μL, 3 eq) and tripyrrolidinylphosphonium bromide hexafluorophosphate (829.08 mg, 1.78 mmol, 1.2 eq). The reaction mixture was allowed to react at 30°C for 12 hours. LCMS analysis indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by normal-phase silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) and then concentrated under reduced pressure to afford compound 8-4 (508 mg, 992.65 μmol, 66.98% yield, 98% purity) as a yellow oil. (ESI) m / z = 502.2 [M+H] + .

[0327] Step 5: Synthesis of compound 8-5

[0328] To a solution of compound 8-4 (508 mg, 1.01 mmol, 1 eq) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 13.29 eq) dropwise at 20°C. The reaction mixture was allowed to react at 20°C for 2 hours. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was directly concentrated under reduced pressure to afford compound 8-5 (400 mg, crude product), which was used directly in the next step. (ESI) m / z = 402.3 [M+H] + .

[0329] Step 6: Synthesis of compound 8

[0330] A solution of compound 8-5 (400 mg, 996.48 μmol, 1 eq) and ethyl acetoacetate (155.62 mg, 1.20 mmol, 151.38 μL, 1.2 eq) in methanol (4 mL) was heated to 70°C under nitrogen and stirred for 2 hours. A 3 M aqueous sodium hydroxide solution (4.8 mL, 14.45 eq) was then added to the reaction mixture and allowed to react at 70°C under nitrogen for 1 hour. LCMS confirmed the complete consumption of the starting material and the formation of the product. The reaction mixture 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 product was then isolated and purified by reverse phase preparative (water (formic acid)-acetonitrile) and lyophilized to yield compound 8 (87.6 mg, 179.28 μmol, 17.99% yield, 95.67% purity). (ESI) m / z = 468.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ12.9(brs,1H)7.92(d,J=6.4Hz,1H),6.93(s,1H),6.63(br d,J=2.4Hz,1H),6.62-6.55(m,2H),6.26(d,J=6.6Hz,1H),5.33(s,1H),5.25(dd,J=5.2,11.8Hz,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)

[0331] Example 9: Synthesis of Compound 10

[0332] Synthesis route:

[0333] Step 1: Synthesis of compounds 10A / B-2 and 10C-2

[0334] 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 tripyrrolidinylphosphonium bromide hexafluorophosphate (4.85 g, 10.41 mmol, 1.5 eq) were added in sequence under stirring at room temperature, followed by stirring at room temperature for 12 hours. After the reaction was complete, the reaction mixture was concentrated by adding silica gel and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1). The less polar compound 10A / B-2 (1 g, 2.54 mmol, crude) was obtained as a light yellow solid, and the more polar compound 10C-2 (1.23 g, 3.13 mmol, crude) was obtained as a light yellow oil. (ESI) m / z = 338.1 [M+H-tBu] + .(ESI)m / z=338.1[M+H-tBu] +

[0335] Step 2: Synthesis of compound 10A / B-3

[0336] Compound 10A / B-2 (1.00 g, 2.54 mmol, 1 eq) was dissolved in 2N methanolic hydrochloric acid (20 mL) and stirred at room temperature for 2 hours. LCMS monitored the reaction for complete reaction. The reaction mixture was concentrated, subjected to reverse phase purification, and lyophilized to afford compound 10A / B-3 (275 mg, 833.91 μmol, 32.81% yield) as a white solid. (ESI) m / z = 294.1 [M+H] + .

[0337] Step 3: Synthesis of compound 10A / B-4

[0338] Compound 10A / B-3 (175.00 mg, 530.67 μmol, 1 eq, HCl) was dissolved in anhydrous dichloromethane (10 mL) and stirred. 3-Bromophenylboronic 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 μL, 8 eq), and 4A molecular sieves (300 mg) were added sequentially. The mixture was stirred at room temperature under oxygen for 12 hours. LCMS confirmed the presence of product and the presence of residual starting material. The reaction mixture was filtered, and the filter cake was washed several times with dichloromethane. The filtrate was concentrated and added to silica gel. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 0-18%) to afford compound 10A / B-4 (63 mg, 140.53 μmol, 26.48% yield) as a yellow solid. (ESI) m / z = 448.0 [M+H] + .

[0339] Step 4: Synthesis of compounds 10A-5 and 10A-B

[0340] Compound 10A / B-4 (1.19 g, 2.65 mmol, 1 eq) was dissolved in anhydrous toluene (40 mL). Di-tert-butylazidooxalic acid (739.88 mg, 3.19 mmol, 711.42 μL, 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)]methanesulfonatepalladium(II)] (210.86 mg, 265.45 μmol, 0.1 eq) were added sequentially. The reaction mixture was heated to 100°C under nitrogen and stirred for 1.3 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (100 mL x 3). The filtrate was concentrated, added to silica gel, and purified by column chromatography (petroleum ether / ethyl acetate = 0-36%) to obtain the product. The product was then subjected to chiral separation to obtain compound 10A-5 (700 mg, crude) as a light yellow solid and compound 10B-5 (645 mg, crude) as a light yellow solid. (ESI) m / z = 600.3 [M+H] + .(ESI)m / z=600.3[M+H] + .

[0341] Step 5: Synthesis of compound 10A-6

[0342] Compound 10A-5 (700.00 mg, 1.17 mmol, 1 eq) was dissolved in a 5 / 1 dichloromethane / trifluoroacetic acid solution (12 mL) and stirred at room temperature for 1.5 hours. LCMS confirmed the complete reaction. The reaction mixture was concentrated to afford compound 10A-6 (599 mg, crude, TFA) as a yellow oil. (ESI) m / z = 400.2 [M+H] + .

[0343] Step 6: Synthesis of compound 10A

[0344] 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 μL, 1 eq) was added. The reaction mixture was heated to 60°C for 1 hour. LCMS monitored the reaction until completion. The reaction mixture was concentrated, then added to silica gel and purified by column chromatography (petroleum ether / ethyl acetate = 0-54%) to obtain the crude product. The crude product was then lyophilized by reverse phase preparative chromatography to obtain compound 10A (196.3 mg, 421.37 μmol, 36.12% yield) as an off-white solid. (ESI) m / z = 466.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.46(br s,1H),7.41-7.30(m,3H),7.28-7.21(m,2H),7.16(br d,J=7.0Hz,2H),7.02(br s,1H),6.78-6.68(m,1H),5.44(br dd,J=4.6,11.8Hz,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=2.8,18.8Hz,1H),2.20(s,5H). SFC (column model: Chiralcel OJ-3 50*4.6mm ID, 3μm; 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: 3mL / min; detector: PDA; column temperature: 35°C; back pressure: 100Bar) retention time = 1.374min.

[0345] Step 7: Synthesis of compound 10B

[0346] Compound 10B was obtained using a similar synthesis method to compound 10A. (ESI) m / z = 466.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.46(br s,1H),7.41-7.30(m,3H),7.27(s,2H),7.16(br d,J=6.8Hz,2H),7.03(s,1H),6.73(br d,J=8.2Hz,1H),5.44(br dd,J=4.2,11.8Hz,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=3.0,18.8Hz,1H),2.20(s,5H). SFC (column model: Chiralcel OJ-3 50*4.6mm ID, 3μm; 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: 3mL / min; detector: PDA; column temperature: 35°C; back pressure: 100Bar) retention time = 1.591min.

[0347] Step 8: Synthesis of Compound 10C

[0348] Compound 10C was obtained using a similar synthesis method to compound 10A. (ESI) m / z = 466.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.47(s,1H),7.41-7.30(m,3H),7.27-7.23(m,2H),7.19(d,J=7 .6Hz,2H),7.00(d,J=1.2Hz,1H),6.74(dd,J=1.4,8.2Hz,1H),5.43(dd,J=5.2,11.8Hz ,1H),4.20-4.07(m,1H),3.83(ddd,J=6.0,12.6,18.6Hz,1H),3.65-3.56(m,1H),3.5 2-3.35(m,4H),3.27-3.16(m,1H),2.89-2.79(m,1H),2.20(s,4H),2.16-2.04(m,1H).

[0349] Example 10: Synthesis of Compound 11

[0350] Compounds 11A and 11B were obtained using a synthetic method similar to that of compound 10A.

[0351] Synthesis of compounds 11A and 11B

[0352] Compound 11A is an off-white solid. (ESI) m / z = 448.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.33(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=8.4Hz,1H),5.44-5.07(m,3H),4.03-3.89(m,1H),3.71(br d,J=12.0Hz,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=3.4,14.0Hz,1H).

[0353] Compound 11B is a white solid. (ESI) m / z = 448.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.33(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=8.0Hz,1H),5.53-5.22(m,3H),4.02(br t,J=11.8Hz,1H),3.74(br d,J=12.4Hz,1H),3.57-3.37(m,2H),3.15-2.97(m,1H),2.85(br t, J=11.6Hz, 1H), 2.68 (ddd, J=1.6, 5.0, 19.0Hz, 1H), 2.18-2.01 (m, 4H), 1.72-1.60 (m, 1H).

[0354] Example 11: Synthesis of Compound 12

[0355] Synthesis route:

[0356] Step 1: Synthesis of compound 12-2

[0357] Compound 12-1 (2 g, 12.81 mmol, 1 eq) and p-toluenesulfonyl hydrazide (2.38 g, 12.81 mmol, 1 eq) were added to dioxane (20 mL), and the reaction mixture was stirred at 25°C for 12 hours. LCMS indicated the reaction was complete, and the product was concentrated under reduced pressure to afford crude product 12-2 (4.15 g, crude product, 89.284% purity) as a yellow solid. (ESI) m / z = 325.2 [M+H] + .

[0358] Step 2: Synthesis of compound 12-3

[0359] Compound 12-2 (4.15 g, 12.79 mmol, 1 eq) was dissolved in dioxane (40 mL), followed by the addition of 3-bromophenylboronic acid (3.21 g, 15.99 mmol, 1.25 eq) and cesium carbonate (6.25 g, 19.19 mmol, 1.5 eq). The reaction mixture was stirred at 110°C for 16 hours. TLC indicated the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 0-30%) to obtain compound 12-3 (430 mg, 1.37 mmol, 10.74% yield) as a colorless oil. (ESI) m / z = 297.0 / 299.0 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.38-7.28(m,2H),7.20-7.09(m,2H),3.70(s,3H),2.55-2.45(m,1H),2.36(t t,J=3.6,12.0Hz,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).

[0360] Step 3: Synthesis of compound 12-4

[0361] Compound 12-3 (350 mg, 1.18 mmol, 1 eq) was added to methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL), followed by the addition of lithium hydroxide monohydrate (247.10 mg, 5.89 mmol, 5 eq). The reaction mixture was stirred at 20°C for 12 hours. LCMS indicated the reaction was complete, and the mixture was concentrated under reduced pressure and the pH was adjusted to 4 with 1 M hydrochloric acid. The mixture was then extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield compound 12-4 (330 mg, crude product, 96.73% yield) as a white solid. (ESI) m / z = 281.0 / 283.0 [MH] + . 1 H NMR (400MHz, CDCl3) δ11.11-10.06(m,1H),7.37-7.31(m,2H),7.20-7.11(m,2H),2.51(tt,J=3.6,1 2.0Hz, 1H), 2.41 (tt, J = 3.6, 12.0Hz, 1H), 2.23-2.11 (m, 2H), 2.06-1.93 (m, 2H), 1.69-1.46 (m, 4H).

[0362] Step 4: Synthesis of compound 12-5

[0363] Compound 12-4 (20 g, 68.22 mmol, 1 eq) and 5-phenyl-4,5-dihydro-1H-pyrrole (255.56 mg, 1.75 mmol, 1.5 eq) were dissolved in dichloromethane (4 mL). N,N-diisopropylethylamine (753.11 mg, 5.83 mmol, 1.01 mL, 5 eq) and tripyrrolidinylphosphonium bromide hexafluorophosphate (814.94 mg, 1.75 mmol, 1.5 eq) were then added. The reaction mixture was stirred at 25°C for 1 hour. LCMS indicated the reaction was complete, and the mixture was concentrated under reduced pressure to obtain a residue. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 0-35%) to obtain compound 12-5 (10 g, 24.17 mmol, 35.43% yield, 95.054% purity) as a white solid. (ESI) m / z = 411.1 / 413.1 [M+H] + .

[0364] Step 5: Synthesis of compound 12-6

[0365] Compound 12-5 (180 mg, 437.60 μmol, 1 eq) was dissolved in toluene (3 mL), followed by the addition of di-tert-butyl azidedicarboxylate (101.64 mg, 437.60 μmol, 97.73 μL, 1 eq), [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II)] (34.76 mg, 43.76 μmol, 0.1 eq), and cesium carbonate (427.74 mg, 1.31 mmol, 3 eq). After replacing the atmosphere with nitrogen three times, the reaction solution was stirred at 100°C for 12 hours. LCMS indicated the reaction was complete, and the reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 100 / 1 to 5 / 1) to obtain product 12-6 (180 mg, 295.01 μmol, yield 67.42%) as a yellow oil. (ESI) m / z = 563.4 [M+H] + .

[0366] Step 6: Synthesis of compound 12-7

[0367] Compound 12-6 (180 mg, 319.89 μmol, 1 eq) was dissolved in dichloromethane (4 mL), followed by the addition of trifluoroacetic acid (1.66 g, 14.60 mmol, 1.08 mL, 45.63 eq). The reaction mixture was stirred at 25°C for 1 hour. LCMS indicated the reaction was complete, and the reaction mixture was concentrated under reduced pressure to yield the crude product 12-7 (115 mg, crude, 85.734% purity) as a yellow oil. (ESI) m / z = 363.3 [M+H] + .

[0368] Step 7: Synthesis of compound 12

[0369] Compound 12-7 (115 mg, 317.27 μmol, 1 eq) was dissolved in acetonitrile (3 mL), followed by the addition of ethyl acetoacetate (49.55 mg, 380.72 μmol, 48.20 μL, 1.2 eq). The reaction was stirred at 60°C for 1 hour. LCMS indicated the reaction was complete, and the residue was concentrated under reduced pressure to afford a crude product. The crude product was then purified by TLC (silica gel, petroleum ether:ethyl acetate = 0:1) to afford the product. The product was then purified by HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; gradient: 40%-70% B over 9 min) and lyophilized to afford 12 (65.1 mg, 151.92 μmol, yield 47.88%) as a white solid. (ESI) m / z = 429.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.74-7.68 (m, 2H), 7.32 (dt, J = 5.2, 7.4Hz, 3H), 7.26-7 .22(m,1H),7.19-7.14(m,2H),7.05(d,J=7.6Hz,1H),6.97(s,1H),5.39(dd, J=4.8,12.0Hz,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).

[0370] Example 12: Synthesis of Compound 13

[0371] Compound 13 was obtained as a white solid using a similar synthesis method to compound 12. (ESI) m / z = 465.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.77-7.65(m,2H),7.38-7.28(m,1H),7.05(d,J=7.6Hz,1H),6.97(s,1H),6.77-6.61(m,3H),5.34(dd,J=4.8,12.0Hz,1H),3. 54-3.34(m,3H),3.28-3.14(m,1H),2.77(ddd,J=1.6,4.8,18.8Hz,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).

[0372] Example 13: Synthesis of Compound 14

[0373] Synthesis route:

[0374] Step 1: Synthesis of compound 14-2

[0375] Compound 14-1 (5 g, 23.62 mmol, 1 eq, HCl), 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 (50 mL) solution and stirred at 100°C under nitrogen for 12 hours. LCMS analysis showed 79.9% of the target compound. The reaction mixture 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 obtain the crude product. The crude product was purified by normal column chromatography (petroleum ether / ethyl acetate = 1-25%) to obtain compound 14-2 (3.18 g, 9.41 mmol, yield 39.83%) as a colorless oil. (ESI) m / z = 330.1 / 332.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 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

[0376] Compound 14-2 (3.18 g, 9.63 mmol, 1 eq) was added to toluene (15 mL). Di-tert-butyl azidedicarboxylate (2.24 g, 9.63 mmol, 2.15 mL, 1 eq), palladium(II) [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate (765.04 mg, 963.08 μmol, 0.1 eq), and cesium carbonate (6.28 g, 19.26 mmol, 2 eq) were added to the reaction mixture. The mixture was stirred at 100°C under nitrogen for 3 hours. LCMS analysis showed 44.2% of the target compound. The reaction mixture 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 yield the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 0-20%) to afford compound 14-3 (3.06 g, 6.27 mmol, yield 65.12%) as a brown oil. (ESI) m / z = 482.3 [M+H] + .

[0377] Step 3: Synthesis of compound 14-4

[0378] Compound 14-3 (3 g, 6.23 mmol, 1 eq) was added to methanol (5 mL), water (10 mL), and tetrahydrofuran (10 mL). Lithium hydroxide monohydrate (1.31 g, 31.15 mmol, 5 eq) was added to the reaction mixture, and the mixture was stirred at 50°C for 2 hours. LCMS analysis showed 98% of the desired product. The reaction mixture was concentrated under reduced pressure to remove the solvent. Water (20 mL) was then added to the reaction mixture, and the pH was adjusted to 4-5 with hydrochloric acid (1 M) at 0°C. The mixture was extracted with ethyl acetate (90 mL x 3), dried over anhydrous sodium sulfate, and filtered and concentrated under reduced pressure to yield compound 14-4 (2.7 g, crude) as a white solid. (ESI) m / z = 454.2 [M+H] + .

[0379] Step 4: Synthesis of compound 14-5

[0380] Compound 14-4 (500 mg, 1.10 mmol, 1 eq) and 5-phenyl-4,5-dihydro-1H-pyrrole (241.77 mg, 1.65 mmol, 1.5 eq) were dissolved in dichloromethane (10 mL). Tris-pyrrolidinylphosphonium bromide hexafluorophosphate (770.97 mg, 1.65 mmol, 1.5 eq) and N,N-diisopropylethylamine (712.47 mg, 5.51 mmol, 960.20 μL, 5 eq) were then added and stirred at 25°C for 1 hour. LCMS detected 62.9% of the target compound. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. Purification by column chromatography (petroleum ether / ethyl acetate = 0-30%) afforded compound 14-5 (460 mg, 718.06 μmol, 65.13% yield) as a white solid. (ESI) m / z = 582.4 [M+H] + .

[0381] Step 5: Synthesis of compound 14-6

[0382] Compound 14-5 (300 mg, 786.48 μmol, 1 eq) was dissolved in dichloromethane (16 mL), followed by the addition of trifluoroacetic acid (6.14 g, 53.85 mmol, 4 mL). The mixture was stirred at 25°C for 2 hours. LCMS analysis indicated 61.4% of the target compound. The reaction mixture was filtered and concentrated under reduced pressure to afford compound 14-6 (300 mg, crude) as a brown oil. This was used directly in the next step. (ESI) m / z = 382.3 [M+H] + .

[0383] Step 6: Synthesis of compound 14

[0384] Compound 14-6 (300 mg, 786.48 μmol, 1 eq) and ethyl acetoacetate (102.35 mg, 786.48 μmol, 99.57 μL, 1 eq) were added to an acetonitrile (3 mL) solution and stirred at 60°C for 1 hour. LCMS analysis showed 79.6% of the target compound. The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product. After purification by column chromatography (petroleum ether / ethyl acetate = 0-25%), the residue was purified by high-performance liquid chromatography (C18 column, 0.1% formic acid solution) to obtain compound 14 (101.7 mg, 226.67 μmol, yield 28.82%) as a pink solid. (ESI) m / z = 448.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.46-11.23(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).

[0385] Example 14: Synthesis of Compound 15

[0386] Compound 15 was obtained as a white solid using a similar synthesis method to compound 14. (ESI) m / z = 484.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.59-11.03(m,1H),7.33-7.27(m,2H),7.26-7.22(m,1H),7.14(tt,J=2.4,9.2Hz,2H),6.85(br dd,J=2.0,8.0Hz,3H),5.43(dd,J=4.4,11.6Hz,1H),5.40-5.23(m,1H),3.61(br d,J=11.6Hz,2H),3.48-3.39(m,1H),3.03(br t, J=12.4Hz, 2H), 2.72 (ddd, J=1.6, 4.8, 19.2Hz, 1H), 2.42-2.27 (m, 2H), 2.14-2.06 (m, 5H).

[0387] Example 15: Synthesis of Compound 44

[0388] Synthesis route:

[0389] Step 1: Synthesis of compound 44-1

[0390] Nitrosobenzene (115.05 mg, 1.07 mmol, 1 eq) and potassium carbonate (29.69 mg, 214.83 μmol, 0.2 eq) were added to a solution of compound 1B (500 mg, 1.07 mmol, 1 eq) in methanol (10 mL) and stirred at 60°C for 3 hours. LCMS analysis showed 37% of the title compound. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. Purification by column chromatography (SiO2, petroleum ether / ethyl acetate = 1-30%) afforded compound 44-1 (160 mg, 244.42 μmol, 22.76% yield) as a red solid. (ESI) m / z = 555.2 [M+H] + .

[0391] Step 2: Synthesis of compound 44

[0392] Compound 44-1 (160 mg, 288.50 μmol, 1 eq) was dissolved in tetrahydrofuran (3 mL), and HCl (2 M, 1.00 mL, 6.93 eq) was added. The mixture was stirred at 20°C for 1 hour. LCMS analysis showed 69.54% of the target compound. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. High-performance liquid chromatography (HPLC) (C18 column, 0.1% ammonia solution) was used to purify compound 44 (46.60 mg, 90.41 μmol, yield: 31.34%) as a yellow solid. (ESI) m / z = 498.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.50-10.18(m,1H),7.25(s,1H),7.16-7.08(m,2H), 6.90(s,1H),6.85(dd,J=2.0,8.4Hz,2H),6.71(dd,J=1.2,8.0Hz,1H),6.58(br d,J=8.0Hz,1H),5.35(dd,J=4.8,12Hz,1H),3.77-3.66(m,2H),3.54-3.43(m,2 H),2.83-2.69(m,3H),2.00-1.85(m,4H),1.82-1.74(m,1H),1.72-1.56(m,2H).

[0393] Example 16: Synthesis of Compound 45

[0394] Synthesis route:

[0395] Step 1: Synthesis of compound 45-1

[0396] To chloroform (300 mL) was added (2S)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine (3.87 g, 11.89 mmol, 0.2 eq). Compound 1-6 (10 g, 59.47 mmol, 1 eq) and N-Boc-hydroxylamine (9.50 g, 71.37 mmol, 1.2 eq) were then added at 0°C. The reaction was stirred at 20°C for 16 hours. TLC indicated the reaction was complete. The reaction solution 45-1 (17 g) was a yellow liquid and was directly used in the next step without post-treatment or purification. (ESI) m / z = 302.1 [M+H] + .

[0397] Step 2: Synthesis of compound 45-2

[0398] Anhydrous methanol (150 mL) was added to the above reaction mixture, followed by sodium borohydride (4.27 g, 112.85 mmol, 2 eq) at 0°C. The reaction mixture was stirred at 20°C for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was quenched by slowly adding saturated aqueous ammonium chloride (500 mL) at 0°C, then extracted with dichloromethane (300 mL x 3). The organic phase was washed with saturated aqueous sodium chloride (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification was performed by column chromatography (silica, petroleum ether:ethyl acetate = 50:1 to 0:1, TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.4)) to afford compound 45-2 (5 g, 15.66 mmol, 27.76% yield, 95.00% purity) as a yellow colloid. (ESI) m / z = 326.1 [M+Na] + . 1 H NMR(400MHz,CHLOROFORM-d)δ7.25-7.13(m,1H),7.02-6.90(m,2H),6.72(tt,J=2.4,8.8Hz,1H),5.18(dd,J=4.8,10.8Hz,1 H),3.90-3.70(m,2H),2.71-2.45(m,1H),2.37(dddd,J=3.6,7.2,10.9,14.6Hz,1H),2.05-1.98(m,1H),1.52-1.40(m,9H).

[0399] Step 3: Synthesis of compound 45-3

[0400] Compound 45-2 (2 g, 6.59 mmol, 1 eq) and cyanomethylenetri-n-butylphosphine (3.18 g, 13.19 mmol, 2 eq) were added to anhydrous toluene (100 mL), and the reaction mixture was stirred at 80°C for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated to obtain 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 obtain compound 45-3 (5 g, 15.66 mmol, 92.33% yield, 95.6% purity) as a yellow oil. (ESI) m / z = 186.1 [M-99] + .

[0401] Step 4: Synthesis of compound 45-4

[0402] Compound 45-3 (300.00 mg, 501.10 μmol, 1 eq) was added to 2M dioxane hydrochloride (30 mL), and the reaction mixture was stirred at 20°C for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to afford compound 45-4 (650 mg, 2.93 mmol, hydrochloride) as a yellow oil. (ESI) m / z = 186.2 [M+H] + .

[0403] Step 5: Synthesis of compound 45-5

[0404] Compound 45-4 (637.77 mg, 2.88 mmol, 1.25 eq, hydrochloride), compound 1-4 (1 g, 2.30 mmol, 1 eq), tripyrrolidinylphosphonium bromide 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 mixture was stirred at 20°C for 12 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica, petroleum ether:ethyl acetate = 10:0 to 0:1, Rf = 0.5) to obtain compound 45-5 (1.2 g, 1.94 mmol, 84.58% yield, 97.54% purity) as a yellow oil. (ESI) m / z = 603.3 [M+H] + .

[0405] Step 6: Synthesis of compound 45-6

[0406] Compound 45-5 (650 mg, 1.08 mmol, 1 eq) and trifluoroacetic acid (3 mL) were added to anhydrous dichloromethane (12 mL), and the reaction mixture was stirred at 20°C for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to afford product 11 (430 mg, 1.00 mmol, TFA salt) as a yellow oil. (ESI) m / z = 403.1 [M+H] + .

[0407] Step 7: Synthesis of compound 45

[0408] Compound 45-6 (430 mg, 1.07 mmol, 1 eq, trifluoroacetate) and ethyl acetoacetate (139.05 mg, 1.07 mmol, 135.27 μL, 1 eq) were added to acetonitrile (6 mL). The reaction was stirred at 60°C for 1 hour. LCMS indicated the reaction was complete. The reaction solution was concentrated under reduced pressure and the crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 10:0 to 1:1, TLC (petroleum ether:ethyl acetate = 2:1, Rf = 0.3). After concentration under reduced pressure, the crude product was purified by high-performance liquid chromatography (HPLC) using a Phenomenex Luna C18 column (150*40 mm*15 μm), mobile phase: water (FA)-acetonitrile, gradient: 30%-60% B over 15 min) to afford compound 45 (343 mg, 709.29 μmol, 66.38% yield, 99.94% purity) as a white solid. (ESI) m / z = 469.2 [M+H] + . 1 H NMR(400MHz,CHLOROFORM-d)δ7.52(t,J=2.0Hz,1H),7.40-7.33(m,1H),7.31-7.29( m,1H),6.92-6.77(m,3H),6.73(tt,J=2.4,8.8Hz,1H),5.42(dd,J=6.0,8.8Hz,1H),4 .31(dt,J=3.2,7.8Hz,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).

[0409] Example 17: Synthesis of Compound 46

[0410] Synthesis route:

[0411] Step 1: Synthesis of compound 46-2

[0412] Compound 46-1 (10 g, 80.57 mmol, 8.42 mL, 1 eq) and formylmethyltriphenylphosphine (24.52 g, 80.57 mmol, 1 eq) were added to tetrahydrofuran (60 mL) and reacted at 80°C for 4 hours. After the reaction was complete, as determined by LCMS, the reaction solution was concentrated under reduced pressure to obtain a crude product. This crude product was purified by normal phase chromatography (petroleum ether / ethyl acetate = 0-10%) to obtain compound 46-2 (7.8 g, 45.35 mmol, 56.29% yield, 87.3% purity) as a light yellow oil. (ESI) m / z = 151.2 [M+H] + . 1 H NMR(400MHz,CHLOROFORM-d)δ9.74(d,J=8.0Hz,1H),7.68(d,J=16.0Hz,1H),7.61(dt,J=1.6,7.6H z,1H),7.48-7.41(m,1H),7.23(t,J=7.6Hz,1H),7.19-7.14(m,1H),6.81(dd,J=7.6,16.0Hz,1H).

[0413] Step 2: Synthesis of compound 46-3

[0414] Hydrazine hydrate (8.51 g, 166.50 mmol, 8.24 mL, 5 eq) was added to tetrahydrofuran (50 mL), and compound 46-2 (5 g, 33.30 mmol, 1 eq) dissolved in tetrahydrofuran (50 mL) was slowly added. The mixture was stirred at 25°C for 2 hours. After the reaction was complete, as determined by LCMS, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by normal phase chromatography (petroleum ether / ethyl acetate = 10%-30%) to obtain compound 46-3 (3.3 g, 10.05 mmol, 30.18% yield) as a light yellow oil. (ESI) m / z = 165.3 [M+H] + .

[0415] Step 3: Synthesis of compound 46-4

[0416] 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) were added tripyrrolidinylphosphonium bromide 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). The reaction mixture was allowed to react at 25°C for 12 hours. After the reaction was complete, LCMS confirmed the reaction was complete and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase chromatography (petroleum ether / ethyl acetate = 30%-50%) to afford compound 46-4 (690 mg, 1.14 mmol, 62.30% yield) as a light yellow solid. (ESI) m / z = 582.4 [M+H] + .

[0417] Step 4: Synthesis of compound 46-5

[0418] To a solution of compound 46-4 (650 mg, 1.12 mmol, 1 eq) in dichloromethane (13 mL) was added trifluoroacetic acid (2.6 mL). The reaction mixture was allowed to react at 25°C for 1 hour. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was concentrated under reduced pressure to afford crude product 64-5 (430 mg, crude) as a pale yellow oil, which was used directly in the next step. (ESI) m / z = 382.3 [M+H] + .

[0419] Step 5: Synthesis of compound 46

[0420] To a solution of compound 46-5 (430 mg, 1.13 mmol, 1 eq) in acetonitrile (8 mL) was added ethyl acetoacetate (146.71 mg, 1.13 mmol, 142.71 μL, 1 eq). The mixture was stirred at 60°C for 1 hour. LCMS analysis indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction solution was concentrated under reduced pressure to yield the crude product. The crude product was purified by normal phase chromatography (petroleum ether / ethyl acetate = 50%-70%), followed by reverse phase preparative separation and purification using water (formic acid)-acetonitrile, and lyophilized to yield compound 46 (158.00 mg, 350.85 μmol, 31.12% yield, 99.37% purity) as a white solid. (ESI) m / z = 448.1 [M+H] + . 1H NMR(400MHz,CHLOROFORM-d)δ7.48(t,J=2.0Hz,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=1.6Hz,1H),6.77(dd,J=1.6,8.0Hz,1H),5.59(dd,J=5.2,12.0Hz,1H),3.78(br d,J=12.4Hz,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).

[0421] Referring to the synthesis method of compound 46, compounds 47-56 were synthesized. The characterization data of each compound are as follows:

[0422] Example 18: Synthesis of Compound 61

[0423] Synthesis route:

[0424] Step 1: Synthesis of compound 61

[0425] Compound 1B-6 (133 mg, 332.97 μmol, 1 eq) was dissolved in acetonitrile (3 mL), followed by the addition of ethyl propionyl acetate (57.60 mg, 399.56 μmol, 1.2 eq). The reaction was stirred overnight at 60°C for 1 hour. LCMS indicated completion of the reaction, and the product was concentrated under reduced pressure to yield a crude product. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 0-100%). It was then purified by high-performance liquid chromatography (HPLC column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; gradient: 30%-60% B over 10 min) and lyophilized to yield compound 61 (92.7 mg, 193.32 μmol, 58.06% yield) as a white solid. (ESI) m / z = 480.2 [M+H] + . 1H NMR(400MHz,CHLOROFORM-d)δ7.51(t,J=2.0Hz,1H),7.37-7.31(m,1H),7.27-7.23(m,1 H),6.98(t,J=1.6Hz,1H),6.78(dd,J=1.8,8.2Hz,1H),6.73-6.66(m,3H),5.34(dd,J=5. 2,12.0Hz,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=7.6Hz, 2H), 2.06-1.99 (m, 1H), 1.99-1.87 (m, 3H), 1.25 (t, J=7.6Hz, 3H).

[0426] Example 19: Synthesis of Compound 62

[0427] Synthesis route:

[0428] Step 1: Synthesis of compound 62

[0429] Compound 1B-6 (133 mg, 332.97 μmol, 1 eq) was dissolved in acetonitrile (3 mL), followed by the addition of ethyl isobutyrylate (63.21 mg, 399.56 μmol, 64.43 μL, 1.2 eq). The reaction was stirred overnight at 60°C for 1 hour. LCMS indicated completion of the reaction, and the product was concentrated under reduced pressure to yield a residue. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 0-100%). The product was then purified by high-performance liquid chromatography (HPLC column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; gradient: 35%-65% B over 10 min) and lyophilized to yield compound 62 (90.4 mg, 180.24 μmol, 54.13% yield) as an off-white solid. (ESI) m / z = 494.2 [M+H] + . 1H NMR (400 MHz, CHLOR OFORM-d)δ7.52(t,J=2.0Hz,1H),7.37-7.31(m,1H),7.27-7.22(m,1H),6.98 (t,J=1.4Hz,1H),6.77(dd,J=2.0,8.0Hz,1H),6.74-6.66(m,3H),5.34(dd,J= 5.0,12.0Hz,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=6.8Hz,6H).

[0430] Example 20: Synthesis of Compounds 63A-D

[0431] Compounds 63A-D were obtained using a synthetic method similar to compound 10A.

[0432] Compound 63A (ESI) m / z = 502.2 [M+H] + , 1 H NMR(400MHz,CHLOROFORM-d)δ7.50(t,J=2.0Hz,1H),7.43(dd,J=1.6,8.0Hz,1 H),7.32-7.29(m,1H),7.05(s,1H),6.85-6.66(m,4H),5.42(dd,J=4.8,12.0H z,1H),4.16-4.02(m,1H),3.88(ddd,J=6.0,12.8,18.6Hz,1H),3.59-3.39(m, 5H), 3.32-3.19 (m, 1H), 2.84 (ddd, J=1.6, 4.8, 19.0Hz, 1H), 2.34-2.13 (m, 5H). SFC (column model: Chiralpak IC-3 50*4.6mm ID, 3μm; 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: 3mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar) retention time = 2.170 min.

[0433] Compound 63B (ESI) m / z = 502.2 [M+H] + . 1H NMR(400MHz,CHLOROFORM-d)δ7.50(t,J=2.0Hz,1H),7.43(dd,J=1.2,8.0Hz,1H),7 .31-7.29(m,1H),7.05(s,1H),6.82-6.67(m,4H),5.42(dd,J=4.8,12.0Hz,1H),4.1 6-4.02(m,1H),3.88(ddd,J=6.0,12.8,18.6Hz,1H),3.61-3.38(m,5H),3.31-3.19 (m,1H),2.84(ddd,J=1.6,4.8,19.0Hz,1H),2.33-2.12(m,5H).SFC (column model: Chiralpak IC-3 50 x 4.6 mm ID, 3 μm column; 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.

[0434] Compound 63C (ESI) m / z = 502.2 [M+H] + .1H NMR(400MHz,CHLOROFORM-d)δ7.51(s,1H),7.43(d,J=8.0Hz,1H),7.32-7.29(m,1H),7.03(s,1H),6.83-6.67(m,4H) ,5.42(dd,J=5.2,12.0Hz,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=9.2Hz,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*4.6mm ID, 3μm column; 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: 3mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar. Retention time: 1.294min.

[0435] Compound 63D (ESI) m / z = 502.2 [M+H]+ . 1 H NMR(400MHz,CHLOROFORM-d)δ7.51(s,1H),7.43(d,J=8.4Hz,1H),7.32-7.29(m,1H),7.03(s,1H),6.85-6.67(m,4H) ,5.42(dd,J=5.2,12.0Hz,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=9.8Hz,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 ID, 3 μm column; 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.

[0436] Example 21: Synthesis of Compound 64

[0437] Synthesis route:

[0438] Step 1: Synthesis of compound 64-2

[0439] Hydrazine hydrate (7.67 g, 150.06 mmol, 7.43 mL, 98% purity, 5 eq) was added to a solution of tetrahydrofuran (100 mL). A solution of p-chlorocinnamaldehyde (5 g, 30.01 mmol, 1 eq) in tetrahydrofuran (100 mL) was slowly added. The reaction was stirred at 25°C for 1 hour. LCMS showed that the target compound was primarily present. Purification by column chromatography (SiO2, petroleum ether / ethyl acetate = 1-50%) was performed to obtain compound 64-2 (5 g, 16.59 mmol, yield: 55.29%, purity: 59.95%) as a yellow solid. (ESI) m / z = 181.1 [M+H] + .

[0440] Step 2: Synthesis of compound 64-3

[0441] 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 dichloromethane (10 mL). Tris-pyrrolidinylphosphonium bromide hexafluorophosphate (1.03 g, 2.20 mmol, 1.2 eq) and N,N-diisopropylethylamine (712.22 mg, 5.51 mmol, 959.87 μL, 3 eq) were slowly added. The reaction mixture was stirred at 25°C for 12 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1-50%). Compound 64-3 (800 mg, 1.13 mmol, yield: 61.55%) was obtained as a yellow solid. (ESI) m / z = 598.3 [M+H] + .

[0442] Step 3: Synthesis of compound 64-4

[0443] Compound 64-3 (600 mg, 1.00 mmol, 1 eq) was dissolved in dichloromethane (4 mL), followed by the addition of trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 13.42 eq) and stirred at 25°C for 1 hour. LCMS analysis indicated the main peak to be the desired product. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. Compound 64-4 (500 mg, crude) was obtained as a yellow oil. (ESI) m / z = 398.0 [M+H] + .

[0444] Step 4: Synthesis of compound 64

[0445] Compound 64-4 (500 mg, 976.71 μmol, 1 eq, TFA) and ethyl acetoacetate (127.11 mg, 976.71 μmol, 123.65 μL, 1 eq) were added to an acetonitrile (10 mL) solution and stirred at 60°C for 1 hour. LCMS confirmed the presence of the target compound. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. High-performance liquid chromatography (HPLC) (C18 column, 0.1% formic acid solution) afforded compound 64 (56.30 mg, 118.84 μmol, yield: 12.17%) as a yellow solid. (ESI) m / z = 464.2 [M+H] + . 1H NMR(400MHz,CHLOROFORM-d)δ7.48(t,J=2.0Hz,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).

[0446] Referring to the synthesis method of compound 64, compounds 65-66, 69-72, 74 and 108 were synthesized. The characterization data of each compound are as follows:

[0447] Example 22: Synthesis of Compound 67

[0448] Synthesis route:

[0449] Step 1: Synthesis of compound 67-2

[0450] Methyl 4-piperidinate (5 g, 27.83 mmol, 1 eq) and 3-bromobenzoic acid (6.15 g, 30.62 mmol, 1.1 eq) were dissolved in anhydrous dichloromethane (100 mL). 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 and reacted at 20°C for 12 hours. After the reaction was complete, as determined by LCMS, the reaction solution was concentrated and sampled. The crude product was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 0-30%) to afford compound 67-2 (9.0 g, 27.59 mmol, 99.13% yield) as a colorless oil. (ESI) m / z = 326.1 [M+H] + .

[0451] Step 2: Synthesis of compound 67-3

[0452] Compound 67-2 (4.5 g, 13.80 mmol, 1 eq) and di-tert-butylazidooxalic acid (4.81 g, 20.69 mmol, 4.62 mL, 1.5 eq) were dissolved in toluene (80 mL). Cesium carbonate (13.48 g, 41.39 mmol, 3 eq) and tBuXPhosPdG3 (1.10 g, 1.38 mmol, 0.1 eq) were added. The atmosphere was purged with nitrogen three times, and the mixture was stirred at 100°C under nitrogen for 12 hours. After the reaction was complete, as determined by LCMS, the reaction solution was concentrated and sampled. The crude product was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 0-30%) to afford compound 67-3 (5.5 g, 10.76 mmol, 78.00% yield) as a yellow oil. (ESI) m / z = 478.2 [M+H] + .

[0453] Step 3: Synthesis of compound 67-4

[0454] Compound 67-4 (5.5 g, 11.52 mmol, 1 eq) was dissolved in tetrahydrofuran (40 mL) and water (10 mL), and lithium hydroxide (827.45 mg, 34.55 mmol, 3 eq) was added. The mixture was stirred at 20°C for 12 hours. After the reaction was complete, LCMS confirmed that the reaction mixture was concentrated and dried to give compound 67-4 (5.0 g, 10.16 mmol, 94.23% yield) as an off-white solid. (ESI) m / z = 464.2 [M+H] + .

[0455] Step 4: Synthesis of compound 67-5

[0456] At 0°C, 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). N,N-diisopropylethylamine (418.24 mg, 3.24 mmol, 563.67 μL, 3 eq) and n-butylphosphonic anhydride (50% ethyl acetate solution) (1.17 g, 1.62 mmol, 50% purity, 1.5 eq) were added. The mixture was stirred at 20°C for 12 hours. After the reaction was complete as determined by LCMS, the reaction solution was concentrated and sampled. The crude product was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 0-100%) to afford compound 67-5 (370 mg, 575.46 μmol, 53.35% yield) as a colorless oil. (ESI) m / z = 605.3 [M+H] + .

[0457] Step 5: Synthesis of compound 67-6

[0458] Compound 67-6 (370 mg, 611.93 μmol, 1 eq) was dissolved in anhydrous dichloromethane (5 mL) and trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 22.00 eq) was added. The mixture was stirred at 20°C for 1 hour. LCMS confirmed the complete reaction. The reaction solution was concentrated to afford compound 67-6 (300 mg, 508.19 μmol, 83.05% yield) as a light yellow oil. (ESI) m / z = 405.3 [M+H] + .

[0459] Step 5: Synthesis of compound 67

[0460] Compound 67-6 (300 mg, 578.67 μmol, 1 eq, TFA) and ethyl acetoacetate (75.31 mg, 578.67 μmol, 73.26 μL, 1 eq) were added to an acetonitrile solution (5 mL) and stirred at 60°C for 1 hour. LCMS confirmed the complete consumption of the starting material and the formation of the product. The reaction solution was separated and purified by reverse phase preparative (water (formic acid)-acetonitrile system) and lyophilized to obtain compound 67 (146.60 mg, 310.73 μmol, 53.70% yield). (ESI) m / z = 471.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.92-11.29 (m, 1H), 10.09 (s, 1H), 7.81 (d, J = 8.0Hz, 1H),7.73(s,1H),7.48(t,J=7.6Hz,1H),7.23-7.09(m,2H),6.94(d,J=6.4Hz, 2H),5.36(s,1H),4.73(s,2H),4.48(dd,J=2.0,5.2Hz,1H),3.67(s,1H),3.15 (d,J=10.4Hz,2H),2.88(s,1H),2.12(s,3H),1.93-1.65(m,2H),1.53(s,2H).

[0461] Example 23: Synthesis of Compound 102

[0462] Synthesis steps:

[0463] Step 1: Synthesis of compound 102

[0464] Compound 67-6 (255 mg, 578.40 μmol, 1 eq, HCl salt) and ethyl trifluoroacetoacetate (127.79 mg, 694.08 μmol, 1.2 eq) were added to acetic acid (2 mL). The reaction was stirred at 80°C for 1.5 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was then purified by HPLC using a Phenomenex Luna C18 150*25 mm*10 μm column, mobile phase: water (FA)-acetonitrile, gradient: 24% to 54% acetonitrile. The product 102 (49.70 mg, 94.46 μmol, 16.33% yield, 99.68% purity) was obtained over 25 minutes as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),7.84(br d,J=8.0Hz,1H),7.76(s,1H),7.57(t,J=8.0Hz,1H),7.36(d,J=7.6Hz,1H),7.19-7.08(m,1H),6.94(br d,J=6.6Hz,2H),5.88(s,1H),4.73(s,2H),4.63-4.38(m,1H),3.65(br dd,J=2.8,4.4Hz,1H),3.15(br s,3H),2.98-2.82(m,1H),1.92-1.65(m,2H),1.63-1.45(m,2H).

[0465] Referring to the synthesis method of compound 102, compound 104 was synthesized, and the characterization data are as follows:

[0466] Example 24: Synthesis of Compound 68

[0467] Synthesis route:

[0468] Step 1: Synthesis of compound 68-2

[0469] Compound 68-1 (10 g, 48.15 mmol, 1 eq) was dissolved in N,N-dimethylformamide (150 mL), followed by the addition of 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). The atmosphere was purged with nitrogen three times, and then stirred at 90°C under a nitrogen atmosphere for 12 hours. After the reaction was complete as determined by LCMS, the reaction mixture was poured into water (1000 mL) and extracted with ethyl acetate (300 mL × 3). The organic phase was washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, and concentrated under vacuum filtration to obtain the 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, yield 38.20%) as a yellow oil. (ESI) m / z = 326.1 / 328.1 [M+H] + .

[0470] Step 2: Synthesis of compound 68-3

[0471] Compound 68-2 (3.0 g, 9.20 mmol, 1 eq) and di-tert-butylazidooxalic acid (3.20 g, 13.79 mmol, 3.08 mL, 1.5 eq) were dissolved in toluene (40 mL), and cesium carbonate (8.99 g, 227.59 mmol, 3 eq) and methanesulfonic acid (2-di-tert-butylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl) palladium (II) (730.51 mg, 919.60 μmol, 0.1 eq) were added. The mixture was replaced with nitrogen three times. , then stirred at 100°C under a nitrogen atmosphere for 12 hours. After the reaction of the starting materials was complete, as determined by LCMS, 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 concentrated under vacuum filtration to obtain the crude product. The crude product was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 0-25%) to obtain compound 68-3 (3.8 g, 7.53 mmol, yield 81.83%) as a light yellow oil. (ESI) m / z = 478.3 [M+H] + .

[0472] Step 3: Synthesis of compound 68-4

[0473] Compound 68-3 (3.7 g, 17.75 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), and water (5 mL). Lithium hydroxide monohydrate (1.63 g, 38.74 mmol, 5 eq) was added and stirred at 50°C for 12 hours. LCMS confirmed that the reaction was complete. The reaction solution was concentrated and the pH was adjusted to 3-4 with 1N hydrochloric acid. The organic phase was washed with ethyl acetate (30 mL x 2) and saturated brine, dried over anhydrous sodium sulfate, and dried to give compound 68-4 (2.9 g, 5.42 mmol, 70.02% yield) as a yellow oil. (ESI) m / z = 450.3 [M+H] + .

[0474] Step 4: Synthesis of compound 68-5

[0475] At 0°C, compound 68-4 (700 mg, 1.56 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL), and N-methylimidazole (396.33 mg, 4.83 mmol, 384.78 μL, 3.1 eq) and tetramethylchlorouronium hexafluorophosphate (480.59 mg, 1.71 mmol, 1.1 eq) were added. Compound 1-7 (684 mg, 2.50 mmol, 1.5 eq) was then added to the reaction solution at 0°C, and the mixture was stirred at 50°C for 2 hours. After the reaction of the starting material was complete, as determined by LCMS, the reaction solution was concentrated and poured into water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product. The crude product was isolated and purified by reverse phase preparation [water (neutral)-acetonitrile system] and then lyophilized to obtain compound 68-5 (275 mg, 445.01 μmol, yield 28.58%) as a light yellow solid. (ESI) m / z = 614.4 [M+H] + .

[0476] Step 5: Synthesis of compound 68-6

[0477] Compound 68-5 (265 mg, 431.81 μmol, 1 eq) was dissolved in anhydrous dichloromethane (5 mL) and trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL, 22.40 eq) was added. The mixture was stirred at 25°C for 1 hour. LCMS confirmed the complete reaction of the starting material. The reaction solution was concentrated to afford compound 68-6 (252 mg, 346.84 μmol, 80.32% yield) as a yellow oil. (ESI) m / z = 414.3 [M+H] + .

[0478] Step 6: Synthesis of compound 68

[0479] Compound 68-6 (250 mg, 473.95 μmol, 1 eq, TFA) was dissolved in anhydrous acetonitrile (3 mL) and then ethyl acetoacetate (61.68 mg, 473.95 μmol, 1 eq) was added. The mixture was stirred at 60°C for 1 hour. After the reaction was complete, the reaction solution was purified by reverse phase preparative (water (formic acid)-acetonitrile) and lyophilized to yield compound 68 (120.70 mg, 251.71 μmol, 60.35% yield) as a yellow solid. (ESI) m / z = 480.2 [M+H] + . 1 H NMR(400MHz,CHLOROFORM-d)δ7.44(t,J=2.0Hz,1H),7.33-7.28(m,1H),7.26-7.21(m,1H),6.95 (s,1H),6.75(dd,J=2.0,8.0Hz,1H),6.71-6.65(m,3H),5.37(dd,J=4.8,12.0Hz,1H),3.42(s,2H ),3.41-3.26(m,3H),3.13(ddd,J=3.2,9.6,12.4Hz,1H),3.04(ddd,J=2.8,9.6,12.4Hz,1H),2.6 7(ddd,J=1.6,4.8,18.6Hz,1H),2.53-2.44(m,2H),2.20(s,3H),1.83-1.76(m,2H),1.43(s,3H).

[0480] Referring to the synthesis method of compound 68, compound 86 was synthesized. The characterization data of the compound are as follows:

[0481] Example 25: Synthesis of Compound 81

[0482] Synthesis route:

[0483] Step 1: Synthesis of compound 81

[0484] Compound 1B-6 (290 mg, 665.29 μmol, 1 eq, HCl) was dissolved in anhydrous methanol (5 mL) and methyl 3-oxopropanoate (475.43 mg, 4.66 mmol, 7 eq) was added. The mixture was heated to 70°C and reacted for 0.5 hours. LCMS analysis indicated the presence of product and residual starting material. The reaction mixture was filtered, and the filtrate was purified by reverse phase preparative purification and lyophilized to afford compound 81 (35.2 mg, 76.74 μmol, yield: 11.54%) as an off-white solid. (ESI) m / z = 452.1 [M+H] +. 1 H NMR(400MHz,CHLOROFO RM-d)δ7.47(s,2H),7.36-7.31(m,1H),7.29(s,1H),6.98(s,1H),6.80(br d,J=8.0Hz,1H),6.74-6.64(m,3H),5.34(dd,J=5.0,12.0Hz,1H),3.83-3.73(m,2H),3.50(s,2H),3.44(br dd,J=12.2,18.8Hz,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).

[0485] Example 26: Synthesis of Compound 82

[0486] Synthesis route:

[0487] Step 1: Synthesis of compound 82-1

[0488] Compound 1B-6 (420 mg, 817.98 μmol, 1 eq, TFA salt) and dimethyl butynedioate (139.49 mg, 981.58 μmol, 1.2 eq) were added to anhydrous methanol (10 mL). Triethylamine (165.54 mg, 1.64 mmol, 2 eq) was then added at 0°C. The reaction mixture was stirred at 60°C for 4 hours. LCMS indicated the reaction was complete. The product was concentrated under reduced pressure to afford 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 afford compound 82-1 (240 mg, 423.57 μmol, yield 51.78%) as a yellow oil. (ESI) m / z = 510.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.16-11.74(m,1H),7.33-7.26(m,1H),7.22(br d,J=15.2Hz,2H),7.16-7.04(m,2H),6.95(dd,J=1.6,8.0Hz,1H),6.84(br d,J=6.4Hz,2H),5.94(s,1H),5.35(dd,J=5.2,12.0Hz,1H),3.84-3.67(m,5H),3.48(br dd,J=11.8,18.4Hz,1H),3.25(td,J=3.7,7.5Hz,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).

[0489] Step 2: Synthesis of compound 82

[0490] Compound 82-1 (210 mg, 412.17 μmol, 1 eq) was added to anhydrous methanol (1 mL) and anhydrous tetrahydrofuran (4 mL). Hydroxylamine aqueous solution (3.27 g, 49.46 mmol, 50% purity, 120 eq) and sodium hydroxide (1 M, 824.33 μL, 2 eq) were slowly added at 0°C. The reaction was stirred at 50°C for 5 hours. LCMS indicated the reaction was complete. The pH of the reaction solution was adjusted to 7 with formic acid, and the filtrate was filtered. The product was then purified by HPLC (column: Phenomenex luna C18 150*40 mm*15 μm, mobile phase: [water (FA)-acetonitrile], gradient: 22%-52% B, 15 min) to afford compound 82 (62.9 mg, 122.35 μmol, 29.69% yield) as an off-white solid. (ESI) m / z = 511.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.38-11.30(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=4.8,12.0Hz,1H),3.86-3.71(m,2H),3.48(br dd,J=12.0,18.8Hz,1H),3.27-3.20(m,1H),2.89-2.68(m,3H),1.92(br d,J=12.0Hz,1H),1.84-1.75(m,1H),1.74-1.56(m,2H).

[0491] Referring to the synthesis method of compound 82, compounds 98-100 were synthesized. The characterization data of each compound are as follows:

[0492] Example 27: Synthesis of Compound 83

[0493] Synthesis route:

[0494] Step 1: Synthesis of compound 83-1

[0495] Compound 1B-3 (1 g, 1.90 mmol, 1 eq) was dissolved in acetonitrile (10 mL), followed by the addition of N,N-diisopropylethylamine (491.78 mg, 3.81 mmol, 662.78 μL, 2 eq) and methyl 6-chloro-pyrimidine-4-carboxylate (328.32 mg, 1.90 mmol, 1 eq). The mixture was then heated to 80°C and stirred for 2 hours. After the reaction was complete, as determined by LCMS, the reaction solution was concentrated and silica gel was added. Purification by column chromatography (petroleum ether / ethyl acetate = 0-100%) afforded compound 83-1 (800 mg, 1.86 mmol, yield: 97.92%) as an off-white solid. (ESI) m / z = 430.1 [M+H] + .

[0496] Step 2: Synthesis of compound 83

[0497] Compound 83-1 (700 mg, 1.63 mmol, 1 eq) was dissolved in methanol (10 mL), and a 50% aqueous solution of hydroxylamine (1.62 g, 24.45 mmol, 15 eq) was added. The mixture was heated to 70°C and reacted for 5 hours. LCMS monitored the reaction until complete. The reaction mixture was filtered, and the filter cake was washed sequentially with methanol (20 mL × 3) and acetonitrile (20 mL × 3). The filter cake was then dried to afford compound 83 (347.2 mg, 788.53 μmol, yield: 48.37%) as a white solid. (ESI) m / z = 431.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.62-11.04(m,1H),9.38-8.90(m,1H),8.49(d,J=0.8Hz,1H),7.24(d,J=6.2Hz,2H),7.17-7.04(m,1H),6.92-6.74 (m,2H),5.34(dd,J=5.0,12.0Hz,1H),4.64-4.28(m,2H),3.56-3.37(m,2H),3.18-2.99(m,2H),2.74(ddd,J=1.6,5.0,19.0Hz,1H),1.94(br d,J=11.4Hz,1H),1.80(br d,J=11.6Hz,1H),1.60-1.38(m,2H).

[0498] Example 28: Synthesis of Compound 84

[0499] Synthesis route:

[0500] Step 1: Synthesis of compound 84-1

[0501] To a solution of compound 1B-3 (1 g, 1.90 mmol, 1 eq) and 3-methoxycarbonylphenylboronic acid in dichloromethane (10 mL) were added 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). The mixture was purged with oxygen three times and stirred at 25°C for 12 hours. After the reaction was complete as determined by LCMS, the reaction solution was filtered and the filtrate was concentrated in vacuo to obtain the crude product. The crude product was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 10% to 30%) to obtain compound 84-1 (460 mg, 1.03 mmol, yield: 54.13%) as a yellow oil. (ESI) m / z = 428.3 [M+H] + .

[0502] Step 2: Synthesis of compound 84

[0503] To a solution of compound 84-1 (380 mg, 889.01 μmol, 1 eq) in methanol (1 mL) and tetrahydrofuran (4 mL) was added aqueous sodium hydroxide solution (1 M, 1.78 mL, 2 eq) and aqueous hydroxylamine hydrochloride solution (7.05 g, 106.68 mmol, 50% purity, 120 eq), and the mixture was stirred at 70°C for 1 hour. After the reaction was complete, the pH of the reaction solution was adjusted to 7 with formic acid, concentrated in vacuo to remove tetrahydrofuran and methanol, and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield the crude product. The crude product was isolated and purified by reverse phase preparative (water (formic acid)-acetonitrile system) and lyophilized to yield compound 84 (126.90 mg, 294.30 μmol, yield: 33.10%) as a pink solid. (ESI) m / z = 429.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.11(br s,1H),8.94(br s,1H),7.27(s,1H),7.24(t,J=4.0Hz,2H),7.16-7.09(m,2H),7.07(dd,J=2.4,8.4Hz,1H),6.87-6.80(m,2H),5.34(dd,J=4.8,12.0Hz, 1H),3.79(dt,J=3.2,7.6Hz,2H),3.48(ddd,J=1.2,12.0,19.2Hz,1H),3.27-3.20(m,1H),2.86-2.76(m,2H),2.76-2.70(m,1H),1.91(br d,J=12.4Hz,1H),1.82-1.74(m,1H),1.72-1.55(m,2H).

[0504] Example 29: Synthesis of Compound 85

[0505] Synthesis route:

[0506] Step 1: Synthesis of compound 85-2

[0507] Methyl 3-formaldehydebenzoate (6.1 g, 37.16 mmol, 1 eq) and formylmethyltriphenylphosphine (11.31 g, 37.16 mmol, 1 eq) were dissolved in tetrahydrofuran (50 mL) and stirred at 80°C for 4 hours. Thin-layer chromatography showed complete consumption of the reactants, with the formation of a new spot. Purification by column chromatography (SiO2, petroleum ether / ethyl acetate = 1-50%) afforded compound 85-2 (3.8 g, 18.62 mmol, yield: 50.11%) as a yellow solid.1 H NMR(400MHz,CHLOROFORM-d)δ9.67(d,J=7.6Hz,1H),8.17(s,1H),8.04(d,J=7.8Hz,1H),7 .69(d,J=8.0Hz,1H),7.49-7.42(m,2H),6.72(dd,J=7.2,16.0Hz,1H),3.90-3.86(m,3H).

[0508] Step 2: Synthesis of compound 85-3

[0509] Hydrazine hydrate (537.15 mg, 10.52 mmol, 520.50 μL, 1 eq) was added to a solution of tetrahydrofuran (20 mL), followed by the slow addition of a solution of compound 85-2 (2 g, 10.52 mmol, 1 eq) in tetrahydrofuran (20 mL). The reaction was stirred at 25°C for 1 hour. LCMS indicated the detection of the target compound. Purification by column chromatography (SiO2, petroleum ether / ethyl acetate = 1-30%) afforded compound 85-3 (1.1 g, 2.04 mmol, 19.44% yield) as a yellow solid. (ESI) m / z = 205.1 [M+H] + .

[0510] Step 3: Synthesis of compound 85-4

[0511] 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 dichloromethane (15 mL), followed by the slow addition of tripyrrolidinylphosphonium bromide 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). The mixture was stirred at 25°C for 1 hour. LCMS analysis indicated the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. Purification by column chromatography (SiO2, petroleum ether / ethyl acetate = 1-50%) afforded compound 85-4 (2 g, 3.12 mmol, yield: 57.84%) as a yellow solid. (ESI) m / z = 622.4 [M+H] + .

[0512] Step 4: Synthesis of compound 85-5

[0513] Compound 85-4 (700 mg, 1.13 mmol, 1 eq) was dissolved in tetrahydrofuran (8 ml) and methanol (2 ml). Aqueous hydroxylamine (743.77 mg, 11.26 mmol, 10 eq) and sodium hydroxide (1 M, 2.25 mL, 2 eq) were slowly added at 0°C. The mixture was stirred at 60°C for 0.5 h. LCMS indicated the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. High-performance liquid chromatography (HPLC) (C18 column, 0.1% formic acid solution) afforded compound 85-5 (230 mg, 359.45 μmol, yield: 31.93%) as a yellow solid. (ESI) m / z = 623.2 [M+H] + .

[0514] Step 5: Synthesis of compound 85-6

[0515] Compound 85-5 (230 mg, 369.35 μmol, 1 eq) was dissolved in dichloromethane (4 mL), followed by the addition of trifluoroacetic acid (3.53 g, 30.96 mmol, 2.30 mL, 83.83 eq). The mixture was stirred at 25°C for 1 hour. LCMS indicated the main peak was the desired product. The reaction mixture was filtered and concentrated under reduced pressure to afford compound 85-6 (156 mg, crude, TFA) as a yellow oil. (ESI) m / z = 423.2 [M+H] + .

[0516] Step 6: Synthesis of compound 85

[0517] Compound 85-6 (156 mg, 290.77 μmol, 36.81 μL, 1 eq, TFA) and ethyl acetoacetate (37.84 mg, 290.77 μmol, 36.81 μL, 1 eq) were added to an acetonitrile (2 mL) solution and stirred at 60°C for 1 hour. LCMS confirmed the presence of the target compound. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. High-performance liquid chromatography (HPLC) (C18 column, 0.1% formic acid solution) afforded compound 85 (52.40 mg, 106.74 μmol, yield: 36.71%) as a white solid. (ESI) m / z = 489.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.32-11.14(m,1H),9.26-8.87(m,1H),7.60(d,J=7.8Hz,1H ),7.54(s,1H),7.40(t,J=7.6Hz,1H),7.29-7.23(m,3H),7.22-7.18(m,1H),7.11(br d,J=7.6Hz,1H),6.79(br d,J=8.0Hz,1H),5.46-5.18(m,2H),3.72(br d,J=11.6Hz,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).

[0518] Example 30: Synthesis of Compound 92

[0519] Synthesis route:

[0520] Step 1: Synthesis of compound 92-1

[0521] Compound 82-1 (400 mg, 785.08 μmol, 1 eq) and trimethyltin hydroxide (2.13 g, 11.78 mmol, 15 eq) were added to anhydrous dichloroethane (8 mL), and the reaction mixture was stirred at 80°C for 24 hours. LCMS indicated the reaction was complete. After cooling the reaction mixture to room temperature, saturated aqueous potassium fluoride (15 mL) was added and stirred for 0.5 hours. The mixture was then filtered to obtain a filtrate, which was extracted with dichloromethane (15 mL x 2). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by reverse phase chromatography (water (0.1% HCl)-acetonitrile, 0-40%) to afford intermediate 92-1 (300 mg, 548.93 μmol, 69.92% yield) as a brown solid. (ESI) m / z = 496.3 [M+H] + .

[0522] Step 2: Synthesis of compound 92

[0523] Compound 92-1 (150 mg, 302.74 μmol, 1 eq), N-methylhydroxylamine hydrochloride (75.85 mg, 908.22 μmol, 3 eq), diisopropylethylamine (195.63 mg, 1.51 mmol, 263.66 μL, 5 eq), and PYBROP (211.70 mg, 454.11 μmol, 1.5 eq) were added to anhydrous N,N-dimethylformamide (2 mL). The reaction was stirred at 20°C for 12 hours. LCMS indicated the reaction was complete. The reaction solution was filtered under reduced pressure to obtain a filtrate, which was purified by HPLC to afford product 92 (5.08 mg, 9.50 μmol, 3.14% yield, 98.11% purity) as a yellow solid. (ESI) m / z = 525.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.91(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=5.0,12.0Hz,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=11.8Hz,1H),1.84-1.75(m,1H),1.74-1.56(m,2H).

[0524] Referring to the synthesis method of compound 92, compounds 93 and 124 were synthesized. The characterization data of each compound are as follows:

[0525] Example 31: Synthesis of Compound 96

[0526] Synthesis route:

[0527] Step 1: Synthesis of compound 96-1

[0528] Compound 1B-3 (700 mg, 1.33 mmol, 1 eq) was dissolved in anhydrous dichloromethane (30 mL) and stirred. 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 sequentially. The mixture was stirred at room temperature under oxygen for 12 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (30 mL x 3). The filtrate was concentrated and added to silica gel. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 1-18%) to afford compound 96-1 (350 mg, 750.60 μmol, yield: 56.36%) as a blue gum. (ESI) m / z = 466.0 / 468.0 [M+H] + .

[0529] Step 2: Synthesis of compound 96-2

[0530] Compound 96-1 (300 mg, 643.37 μmol, 1 eq) was dissolved in anhydrous toluene (3 mL). Di-tert-butylazidooxalic acid (179.33 mg, 772.05 μmol, 172.43 μL, 1.2 eq), cesium carbonate (419.25 mg, 1.29 mmol, 2 eq), and tBuXPhos Pd G3 (51.11 mg, 64.34 μmol, 0.1 eq) were added sequentially. The reaction mixture was heated to 100°C under nitrogen and stirred for 1 hour. LCMS confirmed the reaction was complete. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (20 mL x 3). The filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 0-25%) to afford compound 96-2 (360 mg, 582.85 μmol, yield: 90.59%) as a blue solid. (ESI) m / z = 618.2 [M+H] + .

[0531] Step 3: Synthesis of compound 96-3

[0532] Compound 96-2 (340 mg, 550.47 μmol, 1 eq) was dissolved in a 5:1 dichloromethane:trifluoroacetic acid solution (2.5 mL) and stirred at room temperature for 1 hour. LCMS analysis indicated a small amount of residual starting material and the presence of product. The reaction mixture was concentrated to afford compound 96-3 (292 mg, crude, TFA) as a yellow oil. (ESI) m / z = 418.1 [M+H] + .

[0533] Step 4: Synthesis of compound 96

[0534] Compound 96-3 (292 mg, 549.44 μmol, 1 eq, TFA) was dissolved in acetonitrile (5 mL) and ethyl acetoacetate (71.50 mg, 549.44 μmol, 69.56 μL, 1 eq) was added. The reaction mixture was heated to 60°C for 1 hour. LCMS confirmed the complete reaction. The reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 0-44%) to obtain the crude product. The crude product was then lyophilized by reverse phase preparative reaction to obtain compound 96 (155.4 mg, 321.19 μmol, yield: 58.46%) as an off-white solid. (ESI) m / z = 484.1 [M+H] + . 1 H NMR(400MHz,CHLOROFORM-d)δ7.31(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).

[0535] Referring to the synthesis method of compound 96, compounds 97, 125, and 126 were synthesized. The characterization data of each compound are as follows:

[0536] Example 32: Synthesis of Compounds 112A and 112B

[0537] Synthesis route:

[0538] Step 1: Synthesis of compound 112-2

[0539] Compound 112-1 (30 g, 239.81 mmol, 1 eq) and formylmethyltriphenylphosphine (72.98 g, 239.81 mmol, 1 eq) were dissolved in anhydrous tetrahydrofuran (150 mL) and stirred at 80°C for 4 hours. LCMS confirmed the complete reaction. The reaction solution was concentrated, added to silica gel, and purified by column chromatography (ethyl acetate / petroleum ether = 30%-40%) to afford compound 112-2 (42 g, 205.64 mmol, 85.75% yield) as a yellow solid. (ESI) m / z = 152.2 [M+H] + .

[0540] Step 2: Synthesis of compound 112-3

[0541] Hydrazine hydrate (8.45 g, 165.41 mmol, 8.19 mL, 98% purity, 5 eq) was added to tetrahydrofuran (10 mL) and compound 112-2 (5 g, 33.08 mmol, 1 eq) dissolved in tetrahydrofuran (50 mL) was slowly added. The mixture was stirred at 25°C for 2 hours. LCMS confirmed the complete reaction. The reaction solution was concentrated and added to silica gel. Purification by column chromatography (ethyl acetate / petroleum ether = 40%-50%) afforded compound 112-3 (3.5 g, crude) as a yellow oil. (ESI) m / z = 166.1 [M+H] + .

[0542] Step 3: Synthesis of compound 112-4

[0543] 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) were added tripyrrolidinylphosphonium bromide 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). The reaction mixture was stirred at 25°C for 12 hours. LCMS confirmed the complete reaction of the starting material. The reaction mixture was concentrated to obtain the crude product. The crude product was then isolated and purified by reverse phase chromatography (water (formic acid)-acetonitrile) (Phenomenex luna C18 column (250*70 mm, 10 μm); mobile phase: water (FA)-ACN; gradient elution: 45%-75% B over 20 min) and lyophilized to afford compound 112-4 (2.8 g, 4.73 mmol, 23.03% yield) as a yellow solid. (ESI) m / z = 583.3 [M+H] + .

[0544] Step 4: Synthesis of compounds 112-5A and 112-5B

[0545] Compound 112-4 (2.8 g, 4.73 mmol, 1 eq) was purified by chiral separation [carbon dioxide-acetonitrile / ethanol (0.1% ammonia)] (column model: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 μm); mobile phase: [CO2-ACN / i-PrOH (0.1% NH3H2O)]; B%: 35%, isocratic elution mode) to obtain compound 112-5A (1.06 g, 1.79 mmol, yield 37.34%) as a yellow solid, (ESI) m / z = 583.4 [M+H] +Compound 112-5B (1.18 g, 2.03 mmol, 42.14% yield), (ESI) m / z = 583.4 [M+H] + .

[0546] Step 5: Synthesis of compound 112-6A

[0547] To a solution of compound 112-5A (1 g, 1.72 mmol, 1 eq) in dichloromethane (20 mL) was added trifluoroacetic acid (4 mL). The reaction mixture was incubated at 25°C for 1 hour. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was concentrated under reduced pressure to afford crude product 112-6A (850 mg, crude, TFA) as a pale yellow oil, which was used directly in the next step. (ESI) m / z = 383.3 [M+H] + .

[0548] Step 5: Synthesis of compounds 112A and 112B

[0549] Compound 112-6A (850 mg, 1.71 mmol, 1 eq, TFA) was dissolved in acetonitrile (10 mL) and ethyl acetoacetate (267.38 mg, 2.05 mmol, 260.10 μL, 1.2 eq) was added. The mixture was heated to 60°C for 1 hour. LCMS confirmed the complete reaction. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase preparative chromatography (Waters Xbridge BEH C18 250*50 mm*10 μm column; mobile phase: [water(NH4HCO3)-ACN]; gradient elution: 10%-40% B over 20 min) and lyophilized to obtain compound 112A (391.97 mg, 836.66 μmol, 48.87% yield) as a yellow solid. (ESI) m / z = 449.3 [M+H] + . 1H NMR(400MHz,CHLOROFORM-d)δ8.39(d,J=2.4Hz,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=8.8Hz,1H),7.02(s,1H),6.77(br d,J=8.0Hz,1H),5.42(dd,J=5.2,12.0Hz,1H),3.77(br d,J=12.4Hz,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).

[0550] Referring to the synthesis method of compound 112A, compound 112B (306.11 mg, 650.66 μmol, yield 38.00%) was synthesized as a yellow solid. (ESI) m / z = 449.2 [M+H] + . 1 H NMR(400MHz,CHLOROFORM-d)δ8.39(d,J=2.4Hz,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=2.4,8.8Hz,1H),7.01(s,1H),6.80-6.72(m,1H),5.42(dd,J=5.2,12.0Hz,1H),3.77(br d,J=12.4Hz,2H),3.49(ddd,J=1.6,12.0,18.8Hz,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).

[0551] Compounds 113A and 113B were synthesized by referring to the synthesis method of compound 112A. The characterization data of each compound are as follows:

[0552] Example 33: Synthesis of Compound 127

[0553] Synthesis route:

[0554] Step 1: Synthesis of compound 127-1

[0555] Compound 1B-3 (1 g, 1.90 mmol, 1 eq), 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 mixture was stirred at 20°C for 2 hours. LCMS confirmed the complete reaction. The reaction mixture was concentrated to obtain a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0-64%) to obtain compound 127-1 (640 mg, 1.38 mmol, 72.37% yield) as a yellow solid. (ESI) m / z = 462.1 / 464.1 [M+H] + .

[0556] Step 2: Synthesis of compound 127-2

[0557] Compound 3 (640 mg, 1.38 mmol, 1 eq), di-tert-butylazideoxalic acid (385.85 mg, 1.66 mmol, 1.2 eq), cesium carbonate (902.06 mg, 2.77 mmol, 2 eq), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (109.96 mg, 138.43 μmol, 0.1 eq) were added to anhydrous toluene (10 mL). The reaction mixture was heated to 100°C under nitrogen and stirred for 1 hour. LCMS confirmed the reaction was complete. The reaction mixture was filtered, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 0-70%) to afford Compound 127-2 (750 mg, 1.04 mmol, 74.80% yield) as a yellow solid. (ESI) m / z = 614.5 [M+H] + .

[0558] Step 3: Synthesis of compound 127-3

[0559] Compound 127-2 (750 mg, 1.22 mmol, 1 eq) was dissolved in a 5:1 solution of dichloromethane:trifluoroacetic acid (12 mL) and stirred at room temperature for 1 hour. LCMS confirmed the complete reaction. The reaction mixture was concentrated to afford compound 127-3 (644 mg, crude, TFA) as a yellow oil. (ESI) m / z = 414.2 [M+H] + .

[0560] Step 4: Synthesis of compound 127

[0561] 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 heated to 60°C for 1 hour. LCMS confirmed the complete reaction. The reaction solution was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 0-100%) to obtain the crude product. The crude product was then lyophilized by reverse phase preparative chromatography (preparative column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient elution: 25%-55% B over 11.0 min.) to afford Compound 127 (323.5 mg, 667.95 μmol, 54.71% yield) as a white solid. (ESI) m / z = 480.2 [M+H] + . 1 H NMR(400MHz,CHLOROFORM-d)δ7.83-7.70(m,2H),7.33(t,J=8.2Hz,1H),7.17(br d,J=7.6Hz,1H),6.93(s,1H),6.74-6.60(m,3H),5.32(dd,J=4.8,12.0Hz,1H),3.54(s,2H),3.49-3.32(m,3H),3.14-3.01(m,1H),2.94(br dd,J=5.2,9.6Hz,2H),2.81-2.69(m,1H),2.21(s,3H),2.16-2.01(m,2H),1.91-1.77(m,4H).

[0562] Compounds 128 and 133 were synthesized by referring to the synthesis method of compound 127. The characterization data of each compound are as follows:

[0563] Example 34: Synthesis of Compound 129

[0564] Synthesis route:

[0565] Step 1: Synthesis of compound 129-1

[0566] To a solution of 1,1-carbonyldiimidazole (2.14 g, 13.17 mmol, 1.2 eq) in tetrahydrofuran (20 mL) was added triethylamine (2.22 g, 21.96 mmol, 3.06 mL, 2 eq), followed by a solution of compound 1-7 (2 g, 10.98 mmol, 1 eq) in tetrahydrofuran (20 mL). The reaction was stirred at 25°C for 12 hours. LCMS confirmed the complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 40-50%) to afford compound 129-1 (1.3 g, 4.52 mmol, 41.15% yield) as a yellow solid. (ESI) m / z = 277.1 [M+H] + .

[0567] Step 2: Synthesis of compound 129-2

[0568] To a solution of compound 129-1 (800 mg, 2.90 mmol, 1 eq) in dimethyl sulfoxide (10 mL) were added triethylamine (879.14 mg, 8.69 mmol, 1.21 mL, 3 eq) and 1-(3-bromophenyl)piperazine (1.05 g, 4.34 mmol, 1.5 eq). The reaction mixture was allowed to react at 100°C for 12 hours. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried to dryness. The crude product was purified by normal-phase silica gel column chromatography (petroleum ether:ethyl acetate = 100:1-3:1) and concentrated under reduced pressure to afford compound 129-2 (1.3 g, 2.49 mmol, 85.92% yield) as a yellow solid. (ESI) m / z = 449.0 / 451.0 [M+H] + .

[0569] Step 3: Synthesis of compound 129-3

[0570] To a solution of compound 129-2 (1.2 g, 2.67 mmol, 1 eq) in toluene (15 mL) were added di-tert-butylazidooxalate (930.57 mg, 4.01 mmol, 894.78 μL, 1.5 eq), cesium carbonate (2.61 g, 8.01 mmol, 3 eq), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (212.17 mg, 267.09 μmol, 0.1 eq). The reaction mixture was incubated at 100°C under nitrogen for 1 hour. LCMS analysis indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was directly dried by rotary evaporation, and the resulting crude product was purified by normal phase silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) and concentrated under reduced pressure to afford compound 129-3 (1 g, 1.66 mmol, 62.33% yield) as a yellow solid. (ESI) m / z = 601.3 [M+H] + .

[0571] Step 4: Synthesis of compound 129-4

[0572] To a solution of compound 129-3 (500 mg, 832.42 μmol, 1 eq) in dichloromethane (20 mL) was added trifluoroacetic acid (7.68 g, 67.31 mmol, 5.00 mL, 80.86 eq). The reaction mixture was incubated at 25°C for 1 hour. TLC analysis revealed the complete disappearance of the starting material and the generation of a new, highly polar spot. The reaction mixture was then directly dried to afford compound 129-4 (420 mg, trifluoroacetate salt) as a yellow oil. (ESI) m / z = 401.3 [M+H] + .

[0573] Step 5: Synthesis of compound 129

[0574] Compound 129-4 (420 mg, 816.41 μmol, 1 eq, trifluoroacetate salt) was dissolved in acetonitrile (10 ml), followed by the addition of ethyl acetoacetate (127.50 mg, 979.69 μmol, 124.03 μL, 1.2 eq) and the reaction was allowed to proceed at 60°C for 1 hour. LCMS confirmed the complete consumption of the starting material and the formation of the product. The reaction solution was concentrated, and the crude product was purified by reverse phase chromatography (C18 spherical 20-35 μm 100A column, mobile phase: water (0.1% FA)-ACN, gradient elution: 0-42% over 20 min) to afford compound 129 as a white solid (266.90 mg, 572.15 μmol, 70.08% yield, 100% purity). (ESI) m / z = 467.1 [M+H] + . 1H NMR(400MHz,CHLOROFORM-d)δ7.52(t,J=1.8Hz,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)

[0575] Referring to the synthesis method of compound 129, compounds 130, 132, 136, 141, 143, and 144 were synthesized. The characterization data of each compound are as follows:

[0576] Example 35: Synthesis of Compound 131

[0577] Synthesis route:

[0578] Step 1: Synthesis of compound 131-1

[0579] To a solution of compound 1-7 (2 g, 7.83 mmol, 1 eq) in dichloromethane (20 mL) were added N,N-diisopropylethylamine (3.04 g, 23.50 mmol, 4.09 mL, 3 eq), tripyrrolidinylphosphonium bromide hexafluorophosphate (4.38 g, 9.40 mmol, 1.2 eq), and 3-Boc-3-azabicyclo[3.2.1]octane-8-carboxylic acid (1.71 g, 9.40 mmol, 1.2 eq). The reaction mixture was allowed to react at room temperature for 12 hours. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was concentrated under reduced pressure, and the 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 afford compound 131-1 (2.1 g, 4.21 mmol, 53.68% yield) as a yellow oil. (ESI) m / z = 442.1 [M + Na] + .

[0580] Step 2: Synthesis of compound 131-2

[0581] To compound 131-1 (2.1 g, 5.01 mmol, 1 eq) was added a solution of methanolic hydrochloric acid (40 mL). The reaction mixture was allowed to react at room temperature for 2 hours. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was concentrated under reduced pressure to afford compound 131-2 (2.1 g, crude, HCl) as a yellow oil. (ESI) m / z = 320.1 [M+H] + .

[0582] Step 3: Synthesis of compound 131-3

[0583] To a solution of compound 131-2 (2 g, 5.62 mmol, 1 eq, HCl) in dichloromethane (30 mL) were added 3-bromophenylboronic 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). The reaction mixture was allowed to react at room temperature for 12 hours. LCMS analysis indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was concentrated under reduced pressure, and the 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 afford compound 131-3 (1 g, 1.92 mmol, 34.13% yield, 91% purity) as a yellow oil. (ESI) m / z = 474.1 / 476.1 [M+H] + .

[0584] Step 4: Synthesis of compound 131-4

[0585] To a solution of compound 131-3 (1 g, 2.11 mmol, 1 eq) in toluene (10 mL) were added di-tert-butylazidooxalate (587.62 mg, 2.53 mmol, 565.02 μL, 1.2 eq), cesium carbonate (1.37 g, 4.22 mmol, 2 eq), and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (167.47 mg, 210.82 μmol, 0.1 eq). The reaction mixture was incubated at 100°C under nitrogen for 1 hour. LCMS analysis indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was concentrated under reduced pressure, and 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 afford compound 131-4 (1 g, 1.37 mmol, 65.20% yield) as a yellow oil. (ESI) m / z = 626.3 [M+H] + .

[0586] Step 5: Synthesis of compound 131-5

[0587] Compound 131-4 (1 g, 1.60 mmol, 1 eq) was added with dichloromethane (40 mL) and trifluoroacetic acid (10 mL). The reaction mixture was allowed to react at room temperature for 1 hour. LCMS monitoring indicated the complete disappearance of the starting material and the main peak was the desired product. The reaction mixture was concentrated under reduced pressure to afford compound 131-5 (679 mg, 1.60 mmol, 99.85% yield) as a yellow oil, which was used directly in the next step. (ESI) m / z = 426.2 [M+H] + .

[0588] Step 6: Synthesis of compound 131

[0589] Compound 131-5 (679 mg, 1.60 mmol, 1 eq) was dissolved in acetonitrile (6 ml), followed by the addition of ethyl acetoacetate (228.46 mg, 1.76 mmol, 222.24 μL, 1.1 eq). The reaction mixture was allowed to react at 60°C for 1 hour. LCMS confirmed the complete consumption of the starting material and the formation of the product. The reaction mixture was concentrated, and the crude product was isolated and purified using a reverse phase preparative column (Unisil 3-100C18 Ultra 150*50mm*3μm; mobile phase: [H2O (0.225% FA)-ACN]; gradient elution: 43%-73% B over 15.0 min) to afford Compound 131 (363.6 mg, 736.77 μmol, 46.17% yield, 99.6% purity) as a white solid. (ESI) m / z = 492.2 [M+H] + .1H NMR(400MHz,CHLOROFORM-d)δ7.40-7.30(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 ,11.8Hz,1H),3.63(ddd,J=3.6,7.2,10.8Hz,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=1.2Hz,1H),2.23-2.16(m,3H),1.97-1.63(m,5H).

[0590] Referring to the synthesis method of compound 131, compounds 135, 137, 138, 139, and 142 were synthesized. The characterization data of each compound are as follows:

[0591] Experimental Example 1. In vitro inhibitory activity test of RIPK1

[0592] 1.1 Experimental purpose: To test the in vitro inhibitory activity of the compounds of the present invention on RIPK1.

[0593] 1.2 Test materials

[0594] 1.3 Test instruments

[0595] 1.4 Test methods

[0596] First, add 50 μL of test compound to a 384-well dilution plate. Serially dilute the test compound 1:3 using DMSO. Using an Echo, transfer 50 nL of the diluted test compound solution from each row to the wells of the 384-well assay plate, excluding the control wells. DMSO is used as a control. Two replicates are performed per column. Add 2.5 μL of enzyme working solution (final concentration 50 nM RIPK1, 1x enzyme buffer) to all wells except the control wells. Add 2.5 μL of 1x enzyme buffer (final concentration 0.05 mM DTT, 2.5 mM MnCl2, 1x Kinase Assay Buffer I, H2O) to the control wells. After addition, centrifuge the 384-well assay plate at 1000 RPM for 1 minute and incubate at 25°C for 10 minutes. Then, add 2.5 μL of substrate working solution (final concentration 60 μL ATP, 0.2 mg / mL MBP protein, 1x enzyme buffer) to each well and incubate at 25°C for 120 minutes. Then, 4 μL of ADP-Glo ​​reagent (from the ADP-glo kit) was added to each well, centrifuged at 1000 RPM for 1 minute, and incubated at 25°C for 60 minutes. Finally, 8 μL of kinase detection reagent (from the ADP-glo kit) was added to each well, centrifuged at 1000 RPM for 1 minute, and incubated at 25°C for 60 minutes. Envision 2104 was used to read the data, calculate the inhibition rate, and process the data using XLfit 5.3.1.3 software. The IC value of the compound was obtained using a nonlinear fitting formula. 50 The results are shown in Table 1. Where A represents: IC 50 <300nM; B represents: 300nM≤IC 50 <3000nM; C represents: IC 50 ≥3000nM.

[0597] Table 1 Test results of the in vitro inhibitory activity of the compounds of the present invention on RIPK1

[0598] Test Example 2. DPPH free radical scavenging ability test

[0599] 2.1 Experimental purpose: To test the DPPH free radical scavenging ability of the compounds of the present invention.

[0600] 2.2 Experimental Materials

[0601] 2.3 Test instruments

[0602] 2.4 Test methods

[0603] First, add 20 μL of the test compound to a 96-well plate and dilute it continuously in a 1:2 ratio using DMSO. Then add 200 μL of 200 μM DPPH prepared with anhydrous ethanol as the solvent to each well, shake gently and incubate at room temperature in the dark for 30 minutes. Detect the absorbance at 517 nm using a microplate reader. Calculate the DPPH clearance rate using the following formula: DPPH clearance rate % = (1-Ai / A0) * 100%, where Ai refers to the sample absorbance value and A0 refers to the DMSO control group absorbance value. Use XLfit 5.3.1.3 software to process the data and use the nonlinear fitting formula to obtain the IC value of the compound. 50 The results are shown in Table 2. Where A represents: EC 50 <100μM; B represents: 100μM ≤ EC 50 <500μM; C represents: EC 50 ≥500μM.

[0604] Table 2 DPPH free radical scavenging ability test results of the compounds of the present invention

[0605] Test Example 3. MDA Anti-lipid Peroxidation Ability Test

[0606] 2.1 Experimental purpose: To test the MDA anti-lipid peroxidation ability of the compounds of the present invention.

[0607] 2.2 Test materials

[0608] 2.3 Test instruments

[0609] 2.4 Test methods

[0610] First, brain tissue homogenate was prepared: an adult male Sprague-Dawley rat was anesthetized with isoflurane and sacrificed by cervical dislocation. The whole brain was removed and washed twice in DPBS. The meninges were stripped and transferred to a 50-mL centrifuge tube containing 10 mL of DPBS. The brain was minced with scissors and divided into ten 1.5-mL centrifuge tubes. Three grinding beads were added to each tube and the mixture was ground at 90 Hz for 60 minutes three times. The ground tissue homogenate was transferred to a fresh 50-mL centrifuge tube, DPBS was added to a total volume of 30 mL, and the mixture was mixed. Next, 20 μL of the test compound was added to a 96-well plate and serially diluted 1:3 in DMSO. Then, 100 μL of brain tissue homogenate, 50 μL of DPBS, and 50 μL of 200 μg / mL vitamin C were added, along with a series of standard concentrations as a standard curve. After shaking, the mixture was incubated at 37°C for 1 hour. Then, 400 μL of MDA working solution was added and the mixture was heated at 100°C for 15 minutes. After cooling to room temperature, centrifuge at 1000g for 10 minutes, aspirate 200μL of supernatant into another new plate, and detect the absorbance at 532nm using a microplate reader. The MDA clearance rate of the compound was calculated by the following formula: MDA clearance rate % = [((A1-A0)-(A2-A0)) / ((A1-A0)-(A3-A0))]*100%, where A1 refers to the absorbance value of the high control group, A2 refers to the sample absorbance value, A3 refers to the low control group absorbance value, and A0 refers to the blank group absorbance value. The data were processed using XLfit5.3.1.3 software, and the IC value of the compound was obtained using a nonlinear fitting formula. 50 The results are shown in Table 3. Where A represents: EC 50 <25μM; B represents: 25μM≤EC 50 <250μM; C represents: EC 50 ≥250μM.

[0611] Table 3 MDA anti-lipid peroxidation ability test results of the compounds of the present invention

[0612] In summary, the compounds of the present invention have excellent biological activity of inhibiting programmed cell necrosis, free radical scavenging ability and anti-lipid peroxidation ability, and can thus be used to prevent or treat ischemic stroke or other related diseases.

Claims

1. A compound represented by formula (A), a pharmaceutically acceptable salt or stereoisomer thereof: in, X1 is selected from CH or N; X 1a Selected from CR 1a or N; X 1b Selected from CR 1b or N; X 1c Selected from CR 1c or N; X 1d Selected from CR 1d or N; X 1e Selected from CR 1e or N; R 1a 、R 1b 、R 1c 、R 1d 、R 1e Each independently selected from: H, halogen, C 1-6 Alkyl, -(C=O)-NH-OH, or cyano; R 2a 、R 2b 、R 2c Each independently selected from: H, halogen, or C 1-6 alkyl; A is selected from X2 is selected from CR2 or N; X3 is selected from CR3 or N; X4 is selected from CR4 or N; X5 is selected from CR5 or N; R2, R3, R4, R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy; L is selected from a single bond, C 1-3 Alkylene, -NH-, -O-, or B is selected from R7 is selected from: R8 is selected from: H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, or cyano; R9 is selected from: H, C 1-6 alkyl.

2. The compound according to claim 1, its pharmaceutically acceptable salt or stereoisomer, characterized in that The compound has the structural formula (I), Among them: A, B, X1, X2, X3, X4, X5, R 1a 、R 1b 、R 1c 、R 1d 、R 1e 、R 2a 、R 2b 、R 2c , R2, R3, R4, R5 are as defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: B is selected from The carbon atom marked with "*" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof, in, A is selected from L is selected from a single bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -NH-, -O-, or (1) X2 is selected from CR2; X3 is selected from CR3; X4 is selected from CR4; X5 is selected from CR5; R2, R3, R4, R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy; or (2) X2 is selected from N; X3 is selected from CR3; X4 is selected from CR4; X5 is selected from CR5; R3, R4, R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy; or (3) X2 is selected from N; X3 is selected from N; X4 is selected from CR4; X5 is selected from CR5; R4 and R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy; or (4) X2 is selected from N; X3 is selected from CR3; X4 is selected from N; X5 is selected from CR5; R3 and R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy; or (5) X2 is selected from N; X3 is selected from CR3; X4 is selected from CR4; X5 is selected from N; R3 and R4 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy; or (6) X2 is selected from CR2; X3 is selected from N; X4 is selected from CR4; X5 is selected from N; R2, R4 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or stereoisomer thereof, in, A is selected from R2, R3, R4, R5 are each independently selected from: H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 1a 、R 1b 、R 1c 、R 1d 、R 1e Each is independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, -(C=O)-NH-OH, or cyano; R 2a 、R 2b 、R 2c Each is independently selected from: 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: 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-trifluoroethyl, 2,2,2-trichloroethyl, or cyano; R9 is selected from the group consisting of: H, methyl, ethyl, n-propyl, isopropyl; 7. The compound according to claim 1, its pharmaceutically acceptable salt or stereoisomer, wherein the compound is selected from:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

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

10. The use according to claim 9, wherein the receptor-interacting protein kinase 1 (RIPK1)-mediated related diseases include: Inflammatory bowel disease, psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, arthritis, lupus, systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, osteoarthritis, liver damage / liver disease, non-alcoholic fatty liver disease (NAFLD), kidney damage / kidney damage, celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection Irregularities, solid organ reperfusion injury, 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 anoxic brain injury, ischemic brain injury, traumatic brain injury, allergic diseases, peripheral nerve injury, burns, multiple sclerosis, type I diabetes, type II Diabetes mellitus, obesity, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1)-associated febrile syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neoplastic tumors, periodontitis, mutations in NEMO-(NF-κ-B essential regulator gene (IKKγ or IKKG mutations), linear ubiquitin chain assembly complex ( LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial and viral infections, lysosomal storage diseases, 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 / mitigation, auditory disorders such as noise-induced hearing loss and drugs associated with ototoxicity or for treating cells in vitro to preserve viability and function.

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

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