Pb2 / jak dual-targeted inhibitors and uses thereof

Abstract

This application discloses a PB2 / JAK dual-target inhibitor and its application. The general formula of the PB2 / JAK dual-target inhibitor is shown in formula (I) or formula (II). The PB2 / JAK dual-target inhibitor of this application has both antiviral and anti-inflammatory activities, providing a new drug for the prevention and treatment of PB2-dominated viral replication-related diseases or JAK pathway-dominated inflammation-related diseases.

Description

Technical Field

[0001] This application relates to the field of biomedical technology, and in particular to a PB2 / JAK dual-target inhibitor and its application. Background Technology

[0002] Influenza virus is a single-stranded, negative-sense RNA virus, classified into four types—A, B, C, and D—based on their antigenic gene characteristics (Nat Microbiol, 2016, 1, 16050). In recent years, frequent outbreaks of influenza have seriously endangered human and animal health. Early marketed antiviral drugs included M2 ion channel inhibitors such as amantadine and rimantadine, and norepinephrine (NA) inhibitors such as oseltamivir, zanamivir, and peramivir. Due to drug resistance, M2 ion channel inhibitors are no longer recommended in clinical treatment (Vaccine 2003, 21, 1796-1800). NA inhibitors, such as oseltamivir, must be administered within 48 hours of infection to achieve satisfactory therapeutic effects. Furthermore, some viral mutations have shown resistance to oseltamivir, such as the H275Y mutation in the NA sequence of the novel H1N1 virus, the N294S mutation in the NA sequence of avian influenza virus, and the R292K mutation in the NA sequence of H7N9 virus. The emergence of these oseltamivir-resistant strains limits the therapeutic effect of oseltamivir in individuals with high viral loads but weakened immune function, such as children or elderly patients.

[0003] Drug development targeting influenza virus RNA polymerase (RdRp) has become a hot topic in recent years. RdRp, composed of three subunits—PB1, PB2, and PA—plays a crucial role in viral genome transcription and replication. The "first-in-class" drug pimozide, jointly developed by Vertex Pharmaceuticals and Janssen Pharmaceuticals, inhibits viral replication by preventing the viral PB2 subunit from binding to the 7-methylguanine nucleotide cap domain of host mRNA. However, due to unsatisfactory results in Phase III clinical trials, its efficacy was insufficient to provide a standard of care higher than currently available. Janssen Pharmaceuticals announced the termination of further development of the drug in 2020. These drugs only possess anti-influenza virus activity and cannot combine antiviral and anti-inflammatory activities. Furthermore, they require administration in the early stages of viral infection for optimal therapeutic effect. However, in reality, most people only seek medical attention and medication 48 hours after viral infection and after the onset of obvious and severe symptoms, rendering antiviral drugs like pimozide ineffective.

[0004] Innate immunity is our first line of defense in detecting and clearing viral infections. After a virus enters a target cell, pattern recognition receptors (PRRs) recognize viral components and promote the production of interferon (IFN). Secreted IFN binds to its respective receptor and activates the JAK-STAT pathway, leading to the production of hundreds of downstream antiviral IFN-stimulating genes and the secretion of pro-inflammatory cytokines (Viruses, 2021, 13, 2379). Although optimal activation of the innate immune system during viral infection is crucial for viral clearance, acute viral infection can also lead to disease progression through immune-mediated host tissue damage. Secreted pro-inflammatory cytokines can cause local and systemic inflammation, resulting in overactivation of the innate immune system. This overactivation can induce massive, excessive production and secretion of IFNs, pro-inflammatory and anti-inflammatory cytokines, and chemokines, leading to a cytokine storm. JAK inhibitors are highly effective in reducing type I IFN-driven inflammation. JAK inhibitors, by inhibiting JAK kinase activity, can reduce the inflammatory response and cytokine storm induced by viral infection. However, current JAK inhibitors do not possess both antiviral and anti-inflammatory dual activity.

[0005] In summary, it is of great significance to develop a small molecule inhibitor that has both antiviral and anti-inflammatory activities. Summary of the Invention

[0006] To overcome the shortcomings of existing technologies and provide protection to the body in the later stages of viral infection, aiming to achieve both antiviral and anti-inflammatory effects while killing the virus and preventing excessive immune responses, this application provides a PB2 / JAK dual-target inhibitor and its application. The following technical solution is adopted in this application:

[0007] The first aspect of this application discloses a PB2 / JAK dual-target inhibitor and its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound, wherein the general formula of the PB2 / JAK dual-target inhibitor is shown in formula (I) or formula (II):

[0008]

[0009] R1 is selected from: -H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C6-C 10 Aryl), C2-C 10 alkenyl, C2-C 10 alkynyl group;

[0010] R2 is selected from: -(C0-C6 alkylene)-COO(C 0-10 Alkyl), -(C0-C6 alkylene)-O(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-CON(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-CON(C 0-10 Alkyl)(C 0-10 (halogenated alkyl), C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-N(C 0-10 Alkyl)CO(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)CON(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -(C0-C6 alkylene)-S(C 0-10 Alkyl), -(C0-C6 alkylene)-SO(C 0-10 Alkyl), -(C0-C6 alkylene)-SO2(C 0-10 Alkyl), -(C0-C6 alkylene)-SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-OCO(C 0-10 Alkyl), -(C0-C6 alkylene)-CON(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-CO(C 0-10 alkyl);

[0011] R3 is selected from: C1-C 10 Alkyl, -(C0-C6 alkylene)-O(C 0-10 Alkyl), -H, -(C0-C6 alkylene)-OCO(C 0-10Alkyl), -(C0-C6 alkylene)-OCO(CHNH2)(C 0-10 Alkyl), -(C0-C6 alkylene)-OCO(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-OCO(C 0-10 Halogenated alkyl), -(C0-C6 alkylene)-OCO(C3-C 10 (halogenated cycloalkyl), C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-N(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)CO(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)CON(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -(C0-C6 alkylene)-S(C 0-10 Alkyl), -(C0-C6 alkylene)-SO(C 0-10 Alkyl), -(C0-C6 alkylene)-SO2(C 0-10 Alkyl), -(C0-C6 alkylene)-SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-COO(C 0-10 Alkyl), -(C0-C6 alkylene)-CON(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-CO(C 0-10 alkyl);

[0012] R4 is selected from: -H, C3-C 10 cycloalkyl, C3-C 10 Halogenated cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups;

[0013] R5 and R6 are each independently selected from: -H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups;

[0014] R7 is selected from: -OH, halogen, C1-C6 alkyl;

[0015] X is selected from: N, -CR8; R8 is selected from: -H, halogen, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl); wherein the H on the alkyl, aryl, cycloalkyl, or heterocyclic group is optionally substituted by one or more groups selected from the following: H, =O, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, -N(C) 0-10 Alkyl)(C0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl);

[0016] Y represents a halogen;

[0017] Ring A is a single ring with 4, 5, 6, 7, or 8 elements.

[0018] In one implementation of this application, R1 is selected from: -H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 Cycloalkyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic groups).

[0019] In one implementation of this application, R1 is selected from: -H, C1-C5 alkyl, -(C0-C6 alkylene)-(C3-C5 cycloalkyl), -(C0-C6 alkylene)-(4-6 membered heterocyclic group), and particularly preferably, R1 is selected from: -H, C1-C5 alkyl, C3-C5 cycloalkyl, 4-6 membered heterocyclic group.

[0020] In one implementation of this application, R1 is selected from: -H.

[0021] In one implementation of this application, R2 is selected from: -(C0-C6 alkylene)-COO(C 0-10 Alkyl), -(C0-C6 alkylene)-O(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-CON(C 0-10 Alkyl)(C 0-10Alkyl), -(C0-C6 alkylene)-CON(C 0-10 Alkyl)(C 0-10 (halogenated alkyl), C1-C 10 alkyl.

[0022] In one implementation of this application, R2 is selected from: -COO(C 0-10 Alkyl), -(C0-C6 alkylene)-O(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Halogenated alkyl groups and C1-C5 alkyl groups.

[0023] In one implementation of this application, R2 is selected from:

[0024] -H、

[0025] In one implementation of this application, R3 is selected from: C1-C1 10 Alkyl, -(C0-C6 alkylene)-O(C 0-10 Alkyl), -H, -(C0-C6 alkylene)-OCO(C 0-10 Alkyl), -(C0-C6 alkylene)-OCO(CHNH2)(C 0-10 Alkyl), -(C0-C6 alkylene)-OCO(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-OCO(C 0-10 Halogenated alkyl), -(C0-C6 alkylene)-OCO(C3-C 10 (Halogenated cycloalkyl groups).

[0026] In one implementation of this application, R3 is selected from: C1-C5 alkyl groups, -O(C 0-10 Alkyl), -H, -OCO(C) 0-10 Alkyl group), -OCO(CHNH2)(C 0-10 Alkyl), -OCO (C3-C) 10 cycloalkyl), -OCO(C 0-10 Halogenated alkyl groups), -OCO (C3-C) 10 (Halogenated cycloalkyl groups).

[0027] In one implementation of this application, R3 is selected from: -H、

[0028] In one implementation of this application, R4 is selected from: -H, C3-C 10 Cycloalkyl.

[0029] In one implementation of this application, R4 is selected from: -H, In one implementation of this application, R5 and R6 are each independently selected from: -H, C1-C 10 alkyl.

[0030] In one implementation of this application, R5 and R6 are each independently selected from: -H, C1-C5 alkyl groups.

[0031] In one implementation of this application, R5 and R6 are each independently selected from: -H, In one implementation of this application, R7 is -OH.

[0032] In one implementation of this application, R8 is -H.

[0033] In one implementation of this application, Y is -F.

[0034] In one implementation of this application, the A ring is a cycloalkylene ring or a heteroalkylene ring.

[0035] In one implementation of this application, ring A is a cycloalkylene moiety.

[0036] In one implementation of this application, ring A is a subcyclohexyl group.

[0037] In one implementation of this application, ring A is... In one implementation of this application, the PB2 / JAK dual-target inhibitor includes at least one of the following structures:

[0038]

[0039] The second aspect of this application discloses a pharmaceutical composition comprising a PB2 / JAK dual-target inhibitor as described in the first aspect of this application, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, and comprising one or more pharmaceutically acceptable excipients.

[0040] The third aspect of this application discloses an application comprising: the use of a PB2 / JAK dual-target inhibitor as described in the first aspect of this application, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, in the preparation of a medicament for the prevention and / or treatment of PB2-dominant viral replication-related diseases, and / or in a medicament for JAK pathway-dominant inflammation-related diseases.

[0041] In one implementation of this application, the disease related to viral replication dominated by PB2 is an influenza virus infection-related disease;

[0042] In one implementation of this application, the influenza virus includes at least one of influenza A virus, influenza B virus, influenza C virus, and influenza D virus.

[0043] In one implementation of this application, the influenza virus includes at least one of the subtypes H1N1, H3N2, H5N1, H7N7, H7N9, and H9N2.

[0044] In one implementation of this application, inflammation-related diseases dominated by the JAK pathway include at least one of the following: autoimmune diseases and inflammatory diseases.

[0045] In one implementation of this application, the autoimmune disease includes at least one of the following: psoriatic arthritis, juvenile arthritis, Casterman's disease, systemic lupus erythematosus, Sjögren's syndrome, multiple sclerosis, inflammatory bowel disease, Bechtel disease, myasthenia gravis, type I diabetes, immunoglobulin nephropathy, autoimmune thyroid disease, psoriasis, scleroderma, lupus nephritis, dry eye syndrome, vasculitis, dermatomyositis, polymyositis, and neuromyelitis optica.

[0046] In one implementation of this application, the inflammatory disease includes at least one of the following: viral infection-related inflammation, atopic dermatitis, contact dermatitis, eczema, pruritus, food allergy, bronchial asthma, eosinophilic pneumonia, chronic obstructive pulmonary disease, allergic rhinitis, chronic sinusitis, eosinophilic sinusitis, nasal polyps, allergic conjunctivitis, osteoarthritis, ankylosing spondylitis, Kawasaki disease, Burger's disease, polyarteritis nodosa, and IgA vasculitis.

[0047] In one implementation of this application, the inflammatory disease is an inflammation related to influenza virus infection.

[0048] The beneficial effects of this application are as follows:

[0049] The PB2 / JAK dual-target inhibitor of this application has both antiviral and anti-inflammatory activities, providing a new drug for the prevention and treatment of PB2-dominated viral replication-related diseases or JAK pathway-dominated inflammation-related diseases. Detailed Implementation

[0050] The present application will now be described in further detail through specific embodiments. In the following embodiments, many details are described to facilitate a better understanding of the present application. However, those skilled in the art will readily recognize that some features may be omitted in different situations, or may be replaced by other materials or methods. In some cases, certain operations related to the present application are not shown or described in the specification. This is to avoid obscuring the core parts of the present application with excessive description. For those skilled in the art, detailed description of these related operations is not necessary; the relevant operations can be fully understood based on the description in the specification and general technical knowledge in the art.

[0051] Furthermore, the features, operations, or characteristics described in the specification can be combined in any suitable manner to form various embodiments. Simultaneously, the steps or actions in the method description can be rearranged or adjusted in a manner readily apparent to those skilled in the art. Therefore, the various orders in the specification are merely for the clear description of a particular embodiment and do not imply a mandatory order, unless otherwise stated that a particular order must be followed. Unless otherwise defined, all scientific and technical terms used in this application have the same meaning as commonly understood by those skilled in the art to which this application relates.

[0052] The term "alkyl" refers to a straight-chain or branched hydrocarbon radical that does not contain unsaturated bonds and is connected to the rest of the molecule by single bonds. Typical alkyl groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. In this application, CO alkyl refers to H, i.e., CO-10 alkyl (or CO-C10 alkyl) includes H and C1-10 alkyl (or C1-C10 alkyl).

[0053] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by the loss of two hydrogen atoms from an alkane molecule. It can be straight-chain or branched and is connected to the rest of the molecule by a single bond. Typical alkylene groups described herein have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In this application, CO alkylene refers to a single bond; that is, CO-10 alkylene (or CO-C10 alkylene) includes both single bonds and C1-10 alkylene (or C1-C10 alkylene).

[0054] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 monocyclic and / or fused rings, containing 3 to 18 carbon atoms, preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl.

[0055] The term "alkoxy" refers to a substituent formed when the hydrogen in a hydroxyl group is replaced by an alkyl group, such as alkoxy groups containing 1-10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, etc.

[0056] The term "haloalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with a halogen atom (such as fluorine, chlorine, bromine or iodine), such as -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0057] The term "halocycloalkyl" refers to a group formed when one or more hydrogen atoms in a cycloalkyl group are replaced by halogen atoms (such as fluorine, chlorine, bromine, or iodine), which may be the same or different. If further substitution is to be made in a halocycloalkyl group, the substitution can occur independently of each other in each case, either as a single substitution or multiple substitution, on all the hydrogen-carrying carbon atoms.

[0058] The term "aryl" refers to a monocyclic or polycyclic free radical, including polycyclic free radicals containing a monoaryl group and / or a fused aryl group, such as those containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. The C6-C12 aryl group mentioned in this application refers to an aryl group containing 6-12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc.

[0059] The term "heterocyclic group" refers to a 3- to 18-membered non-aromatic ring group containing 2 to 17 carbon atoms and 1 to 10 heteroatoms. Heterocyclic groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and can include fused, spirocyclic, or bridged ring systems. Heterocyclic groups can be partially saturated (heteroaryl) or fully saturated (heterocyclic alkyl). Suitable heteroaryl groups in the compounds of this application contain one, two, or three heteroatoms selected from N, O, S, and P atoms. These heteroaryl groups include, for example, coumarin (including 8-coumarin), quinolinyl (including 8-quinolinyl, isoquinolinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrroloyl, thiopheneyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazoleyl, indolyl, isoyndolyl, indazoleyl, inazinyl, phthalazinyl, pteridinyl, purineyl, oxadiazolyl, thiadiazolyl, furazolidyl, pyridazinyl, triazinyl, cenolinyl, benzimidazolyl, benzofuranyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, benzooxazolyl, quinazolinyl, naphthidyl, and furanopyridinyl. Suitable heterocyclic alkyl groups in the compounds of this application contain one, two, or three heteroatoms selected from N, O, or S atoms. These heterocyclic alkyl groups include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothiophenyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, oxothiohexacyclohexyl, piperazine, aziridine, oxohexacyclohexyl, thiohexacyclohexyl, homopiperidinyl, oxopropane, thiopropane, acrylonitrile, oxoaziridine, diaziridine, etc. Heptyl, triacetyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiaalkyl, dithiopentyl, dihydropyranyl, dihydrothiophenyl, pyrazolinyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinazinyl.

[0060] The term "pharmaceutically acceptable salt" includes acid addition salts and base addition salts.

[0061] The term "stereoisomer" includes enantiomers, diastereomers, and geometric isomers. Some compounds in this application have cyclic hydrocarbon groups that can be substituted on more than one carbon atom, in which case all their geometric forms, including cis and trans, and mixtures thereof, are within the scope of this application.

[0062] The term "solvent" refers to the physical bond between a compound of this application and one or more solvent molecules. This physical bond includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvents include solution phases and separable solvates. Representative solvates include ethanolides, methanolides, etc.

[0063] The term "prodrug" refers to a Formula I compound that is suitable for administration to patients without excessive toxicity, irritation, or allergic reactions, and is effective for its intended purpose. Prodrugs include acetals, esters, and zwitterionic forms. Prodrugs are converted in the body, such as through hydrolysis in the blood, to yield the parent compound.

[0064] The term "treatment" refers to the prevention, cure, reversal, reduction, mitigation, minimization, suppression, cessation, and / or cessation of one or more clinical symptoms of a disease after its onset.

[0065] The term "prevention" refers to the treatment taken before a disease develops to avoid, minimize, or prevent the disease from developing or progressing.

[0066] The term "autoimmune disease" refers to diseases caused by the body's immune response to its own antigens, resulting in damage to its own tissues.

[0067] The term "inflammation" refers to the body's defensive response to stimuli, manifested as redness, swelling, heat, pain, and functional impairment. It can be infectious inflammation caused by infection, or non-infectious inflammation not caused by infection, such as inflammation caused by immune responses (e.g., various types of hypersensitivity reactions, inflammation caused by some autoimmune diseases). The term "inflammatory disease" refers to a disease characterized by inflammation.

[0068] Currently, no antiviral drug possesses both anti-influenza and anti-inflammatory properties, and all must be administered after early viral infection. However, in reality, most people only seek medical attention and take medication after 48 hours of viral infection and the onset of obvious and severe symptoms, rendering antiviral drugs ineffective.

[0069] In this application, a dual-target inhibitor with PB2 and JAK was synthesized by modifying the substituents of the pyrimidine ring, the core and substituents of the azaindole ring, and the amino side chain connected to the pyrimidine ring. It can effectively prevent excessive immune response in patients while killing viruses. It can exert dual antiviral and anti-inflammatory effects not only in the early stage of viral infection but also in the later stage of viral infection, thus protecting the patient's body. It has very good application prospects and research value.

[0070] The present application will be further described in detail below through specific embodiments. These embodiments are only for further illustration and should not be construed as limiting the present application. In these embodiments, unless otherwise specified, the reagents and instruments used are all commercially available, and the experimental operations are performed in accordance with the product instructions and standard experimental procedures.

[0071] Example 1

[0072] The reaction route is shown below:

[0073]

[0074] Step 1: Synthesis of compound A-2

[0075] Compound A-1 (30.0 g, 0.22 mol) was dissolved in 130 mL of anhydrous DMF at 0 °C, and NBS (41.1 g, 0.23 mol) was added in portions. The reaction was stirred at 0 °C for 1 h, and TLC showed that the starting material was completely reacted. The reaction was then heated to room temperature, and 400 mL of ice water was added to the reaction solution, followed by 120 mL of saturated Na2SO3 aqueous solution. After stirring at room temperature for 30 min, the mixture was filtered, the filter cake was washed with water, and dried under vacuum to obtain a white solid A-2 (36.5 g, 0.17 mol, yield 77%). 1 HNMR (400MHz, DMSO-d6) δ12.24(s,1H),8.32–8.25(m,1H),7.83(d,J=2.8Hz,1H),7.73(dd,J=8.9,2.9Hz,1H).

[0076] Step 2: Synthesis of compound A-3

[0077] Compound A-2 (10.0 g, 46.5 mmol) was dissolved in 70 mL of anhydrous DMF. 60% NaH (3.0 g, 74.4 mmol) was added in portions under ice bath conditions. The reaction was stirred at 0 °C for 30 min. Then, TsCl (12.4 g, 65.1 mmol) was added in portions, and the temperature was slowly raised to room temperature. After stirring at room temperature for 2 h, TLC confirmed the reaction was complete. The reaction solution was slowly poured into 200 mL of ice water and stirred at room temperature for 1 h to allow TsCl to react fully with the water. The pH was adjusted to 9-10 with saturated NaHCO3 solution. The mixture was filtered, the filter cake was washed with water, and dried under vacuum to obtain a white solid A-3 (12.4 g, 33.6 mmol, yield 72%). 1HNMR (600MHz, DMSO-d6) δ8.48(dd,J=2.8,1.4Hz,1H),8.32(s,1H),8.01(d,J=8.4Hz,2H),7.93(dd,J=8.3,2.7Hz,1H),7.44(d,J=8.1Hz,2H),2.35(s,3H).

[0078] Step 3: Synthesis of compound A-4

[0079] At room temperature, potassium acetate (8.0 g, 81.3 mmol) and DPPF palladium dichloride (2.0 g, 2.71 mmol) were added to a solution of compound A-3 (10.0 g, 27.1 mmol) and bis(pinacol) borate (10.2 g, 40.0 mmol) in 1,4-dioxane (80.00 mL). The mixture was stirred at 100 °C for 12 h under argon protection. The reaction solution was cooled to room temperature, and the crude product was filtered through diatomaceous earth. The filtrate was diluted with ethyl acetate (150 mL), and the organic phase was washed twice with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 40:1 to 10:1) to give a white solid A-4 (9.5 g, 22.7 mmol, yield 84%). 1 H NMR (400MHz, CDCl3) δ8.27 (ddd, J=8.0, 2.8, 1.4Hz, 1H), 8.18 (s, 1H), 8.09–8 .01(m,2H),7.90–7.77(m,1H),7.29–7.26(m,2H),2.37(s,3H),1.26(s,12H).

[0080] Step 4: Synthesis of compound A-5

[0081] Compound A-4 (5.0 g, 12.0 mmol) and 2-chloro-4-methylthio-5-fluoropyrimidine (3.2 g, 18.0 mmol) were dissolved in DME (40.0 mL) and water (8.0 mL) at room temperature. Sodium carbonate (3.8 g, 36.0 mmol) and tetrakis(triphenylphosphine)palladium (690.0 mg, 0.6 mmol) were added, respectively. The mixture was stirred at 90 °C for 12 h under argon protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed three times with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane:methanol = 80:1 to 20:1) to give a white solid A-5 (2.8 g, 6.5 mmol, yield 54%). 1H NMR (400MHz, CDCl3) δ8.65–8.61(m,2H),8.50–8.46(m,2H),8.11–8.06(m,2H),7.40–7.33(m,2H),2.75(s,3H),2.35(s,3H).

[0082] Step 5: Synthesis of compound A-6

[0083] Compound A-5 (2.0 g, 4.6 mmol) was dissolved in 20 mL of anhydrous DCM. m-CPBA (1.6 g, 9.2 mmol) was added in portions under ice bath conditions. The reaction was stirred at 0 °C for 30 min, then slowly heated to room temperature. After stirring at room temperature for 24 h, TLC confirmed the reaction was complete. The reaction was quenched by adding 5 mL of saturated Na₂S₂O₃ solution dropwise under ice bath conditions. The pH was adjusted to 9-10 with saturated NaHCO₃ solution. The mixture was extracted three times with dichloromethane (40 mL × 3). The combined organic phases were washed three times with saturated brine (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and precipitated with 20 mL of MTBE and 5 mL of ethyl acetate. A large amount of solid precipitated. The solid was filtered, and the filter cake was washed three times with ethyl acetate (2 mL × 3). The solid was dried under vacuum to give a pale yellow solid A-6 (1.2 g, 2.6 mmol, yield 57%). MS m / z: 449.04 [M+l] + .

[0084] Step 6: Synthesis of compound A-7

[0085] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in a mixed solvent of 10 mL of 1,4-dioxane and 2 mL of acetonitrile at room temperature. D(-)-isovaline (387 mg, 3.3 mmol) and sodium carbonate (699 mg, 6.6 mmol) were added. The reaction was stirred at 130 °C for 10 h, and TLC was used to confirm complete reaction of the starting material. The reaction solution was cooled to room temperature, diluted with water (10 mL), and the pH was adjusted to 3-4 with 2N dilute hydrochloric acid. The solution was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed three times with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 120:1 to 80:1) to give a white solid A-7 (802 mg, 1.6 mmol, yield 73%). 1H NMR (400MHz, CDCl3) δ8.40(dd,J=9.0,2.9Hz,1H),8.35(s,1H),8.27(dd,J=2.9,1.2Hz,1H),8.08–8.03(m,3H),7.26(d,J=5.2Hz,2H) ,5.56(d,J=2.4Hz,1H),2.35(s,3H),2.26(dd,J=14.0,7.3Hz,1H),2.10(dd,J=13.9,7.3Hz,1H),1.73(s,3H),0.91(t,J=7.5Hz,3H).

[0086] Step 7: Synthesis of compound YYJ-001

[0087] Compound A-7 (501 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 120:1 to 80:1) to give a white solid YYJ-001 (316 mg, 0.91 mmol, yield 91%). MS m / z: 347.70 [M+l] + . 1 H NMR (600MHz, DMSO-d6) δ12.44(s,1H),12.25(s,1H),8.46(dd,J=9.8,2.9Hz,1H),8.22(d,J=3.8Hz,2H),8.10(d,J=2. 8Hz, 1H), 7.52 (s, 1H), 2.17 (dd, J = 14.0, 7.3Hz, 1H), 1.93 (dd, J = 14.0, 7.3Hz, 1H), 1.54 (s, 3H), 0.87 (t, J = 7.5Hz, 3H).

[0088] Step 8: Synthesis of compound YYJ-002

[0089] Compound YYJ-001 (90 mg, 0.26 mmol) was dissolved in 3 mL of tetrahydrofuran at room temperature, and 0.52 mL of 1 M LiAlH4 tetrahydrofuran solution (0.52 mmol) was added dropwise. The reaction was stirred at 45 °C for 12 h, and the reaction proceeds were confirmed to be complete by TLC. The reaction solution was cooled to room temperature and diluted with ethyl acetate. The reaction was quenched by adding sodium sulfate decahydrate in portions. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 1:1) to give a white solid YYJ-002 (63 mg, 0.19 mmol, yield 73%). MS m / z: 334.19 [M+l] + . 1 H NMR (600MHz, DMSO-d6) δ12.27(s,1H),8.43(dd,J=9.8,2.8Hz,1H),8.28(d,J=1.5Hz,1H),8.17(d,J=3.9Hz,1H),8.11(d,J=2.8Hz,1H),6.31(s,1H) ,4.97(s,1H),3.79(d,J=10.8Hz,1H),3.60(s,1H),2.13(dd,J=14.0,7.3 Hz, 1H), 1.90 (dd, J = 14.0, 7.3Hz, 1H), 1.42 (s, 3H), 0.83 (t, J = 7.5Hz, 3H).

[0090] Example 2

[0091] The reaction route is shown below:

[0092]

[0093] Step 1: Synthesis of compound B-1

[0094] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of THF at room temperature. Methyl (R)-2-amino-2-methylbutyrate hydrochloride (553 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and TLC analysis showed complete reaction of the starting material. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted three times with ethyl acetate (20 mL × 3). The combined organic phases were washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give a white solid B-1 (980 mg, 1.9 mmol, yield 86%). 1HNMR (400MHz, CDCl3) δ8.48(dd,J=8.9,2.8Hz,1H),8.44(s,1H),8.30(dd,J=2.8,1.2Hz,1H),8.09(dd,J=8.6,2.4Hz,3H),7.28(d,J=8.2Hz, 2H),5.59(s,1H),3.77(s,3H),2.37(s,3H),2.28(dd,J=13.8,7.5Hz,1H),2.10(dd,J=13.7,7.5Hz,1H),1.77(s,3H),0.93(t,J=7.4Hz,3H).

[0095] Step 2: Synthesis of compound YYJ-003

[0096] Compound B-1 (515 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a methanol solution of sodium methoxide (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid YYJ-003 (347 mg, 0.96 mmol, yield 96%). 1 H NMR (600MHz, DMSO-d6) δ12.26(s,1H),8.39(dd,J=9.7,2.9Hz,1H),8.27(s,1H),8.23(d,J=3.8Hz,1H),8.03(d,J=2.8Hz,1H ),7.75(s,1H),3.51(s,3H),2.16(dd,J=14.0,7.4Hz,1H),1.91(dd,J=14.0,7.3Hz,1H),1.54(s,3H),0.86(t,J=7.5Hz,3H).

[0097] Example 3

[0098] The reaction route is shown below:

[0099]

[0100] Step 1: Synthesis of compound C-1

[0101] Compound A-7 (1.96 g, 3.9 mmol) was dissolved in 30 mL of dichloromethane at room temperature. Ammonium chloride (294 mg, 5.5 mmol), HATU (1.9 g, 5.0 mmol), and TEA (1.2 g, 11.7 mmol) were added. The reaction was stirred at room temperature for 12 h, and the reaction proceeds were determined to be complete by TLC. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted three times with dichloromethane (30 mL × 3). The organic phases were combined, washed three times with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1 to 2:1) to give a white solid C-1 (1.4 g, 2.7 mmol, yield 69%). 1 H NMR (400MHz, CDCl3) δ8.29 (dd, J=2.9, 1.2Hz, 1H), 8.20 (dd, J=9.0, 2.9Hz, 1H) ,8.11(s,1H),7.98(d,J=8.5Hz,2H),7.86(d,J=3.0Hz,1H),7.68(s,1H),7.22 (d,J=8.2Hz,2H),6.60(s,1H),5.50(d,J=2.4Hz,1H),2.32(s,3H),2.16(dd,J =13.8,7.4Hz,1H),2.01(d,J=6.5Hz,1H),1.62(s,3H),1.00(t,J=7.5Hz,3H).

[0102] Step 2: Synthesis of compound C-2

[0103] Compound C-1 (1.0 g, 2.0 mmol) was dissolved in 10 mL of THF, and 4 mL of 1 M BH3 tetrahydrofuran solution (4.0 mmol) was added dropwise under ice bath conditions. The reaction was stirred at 60 °C for 10 h, and the reaction proceeded to completion as determined by TLC. The reaction was quenched dropwise with methanol (5 mL) under ice bath conditions. The mixture was extracted three times with ethyl acetate (20 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1 to 15:1) to give a white solid C-2 (535 mg, 1.1 mmol, yield 55%). MS m / z: 486.94 [M+l] + .

[0104] Step 3: Synthesis of compound YYJ-004

[0105] Compound C-2 (486 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material was completely reacted. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 70:1 to 50:1) to give a white solid YYJ-004 (316 mg, 0.95 mmol, yield 95%). 1 HNMR (600MHz, DMSO-d6) δ8.43(dd,J=9.8,2.9Hz,1H),8.30–8.27(m,1H),8.16(d,J=3.9Hz,1H),8.11(s,1H),6.56(s,1H),3.02(d,J= 12.8Hz, 1H), 2.72 (d, J = 12.8Hz, 1H), 2.05 (dd, J = 14.0, 7.3Hz, 1H), 1.97 (dd, J = 14.0, 7.2Hz, 1H), 1.41 (s, 3H), 0.82 (t, J = 7.5Hz, 3H).

[0106] Example 4

[0107] The reaction route is shown below:

[0108]

[0109] Step 1: Synthesis of compound D-1

[0110] Compound A-7 (1.96 g, 3.9 mmol) was dissolved in 15 mL of LDM at room temperature. 2,2,2-trifluoroethylamine hydrochloride (745 mg, 5.5 mmol), HATU (1.9 g, 5.0 mmol), and TEA (1.2 g, 11.7 mmol) were added. The reaction mixture was stirred at room temperature for 12 h, and TLC analysis showed complete reaction of the starting material. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The combined organic phases were washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1 to 3:1) to give a white solid D-1 (1.47 g, 2.5 mmol, yield 64%). 1H NMR (400MHz, CDCl3) δ8.45(s,1H),8.30(dd,J=2.8,1.2Hz,1H),8.17(d,J=2.8Hz,1H),8.09(d,J=8.4Hz,2H),7.28(d,J=8.3Hz, 2H), 6.52(t,J=6.5Hz,1H),5.49(s,1H),4.08–3.84(m,2H),2.37(s,3H),2.25–2.07(m,2H),1.73(s,3H),0.96(t,J=7.5Hz,3H).

[0111] Step 2: Synthesis of compound YYJ-005

[0112] Compound D-1 (583 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a methanol solution of sodium methoxide (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid YYJ-005 (377 mg, 0.88 mmol, yield 88%). 1 HNMR(600MHz,DMSO-d6)δ12.19(s,1H),8.44–8.38(m,2H),8.24(s,1H),8.22(d,J=3.7Hz,1H),8.06(d,J=2.8Hz,1H),7.29(s,1H),3.7 6(dddd,J=33.2,15.4,9.8,5.0Hz,2H),2.17(dq,J=14.9,7.5Hz,1H),1.94(dq,J=14.8,7.5Hz,1H),1.53(s,3H),0.80(t,J=7.5Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ174.6, 157.0 (d, J = 6.6Hz), 155.7 (d, J = 239.9Hz), 150.1 (d, J = 10.6Hz), 145.8, 143.9 (d, J = 255.7Hz), 138.7 (d, J = 18. 1Hz), 131.3 (d, J = 28.9Hz), 131.0, 124.6 (q, J = 279.7Hz), 117.9 (d, J = 7.8Hz), 115.2 (d, J = 21.7Hz), 113.8 (d, J = 4.0Hz), 60.0, 29.6, 21.5, 7.8.

[0113] Example 5

[0114] The reaction route is shown below:

[0115]

[0116] Step 1: Synthesis of compound E-1

[0117] Compound A-7 (1.96 g, 3.9 mmol) was dissolved in 25 mL of LCM at room temperature, and 2,2-difluoroethylamine hydrochloride (646 mg, 5.5 mmol), HATU (1.9 g, 5.0 mmol), and TEA (1.2 g, 11.7 mmol) were added. The reaction was stirred at room temperature for 12 h, and the reaction proceeds were determined by TLC to be complete. The reaction solution was cooled to room temperature and extracted three times with dichloromethane (30 mL × 3). The organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 2:1) to give a white solid E-1 (1.41 g, 2.5 mmol, yield 64%). 1 HNMR (400MHz, CDCl3) δ8.48–8.44(m,2H),8.30(dd,J=2.8,1.2Hz,1H),8.15(d,J=2. 9Hz,1H),8.09(d,J=8.3Hz,2H),7.28(d,J=8.2Hz,2H),6.50(t,J=6.0Hz,1H),5.90–5 .60(m,1H),5.56(s,1H),3.64(tdd,J=14.8,6.2,4.1Hz,2H),2.37(s,3H),2.22(dd,J =14.1, 7.3Hz, 1H), 2.09 (dd, J = 14.1, 7.3Hz, 1H), 1.73 (s, 3H), 0.95 (t, J = 7.4Hz, 3H).

[0118] Step 2: Synthesis of compound YYJ-006

[0119] Compound E-1 (564 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a methanol solution of sodium methoxide (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid YYJ-006 (332 mg, 0.81 mmol, yield 81%). 1 H NMR (600MHz, DMSO-d6) δ12.22(s,1H),8.44(dd,J=9.8,2.8Hz,1H),8.25(d,J=1.2Hz,1H),8.24–8.20(m,2H),8.09(d,J=2.8Hz,1H),7.31(s,1H), 5.76(tt,J=56.5,4.2Hz,1H),3.41–3.37(m,2H),2.15(dq,J=14.9,7.5H z,1H),1.95(dq,J=14.7,7.4Hz,1H),1.53(s,3H),0.80(t,J=7.5Hz,3H). 13 CNMR(151MHz,DMSO-d6)δ174.7,157.0(d,J=6.7Hz),155.7(d,J=240.1Hz), 150.1(d,J=10.6Hz),145.9,143.9(d,J=255.6Hz),138.7(d,J=18.0Hz),131 .4(d,J=28.9Hz),130.9,117.9(d,J=7.9Hz),115.1(d,J=21.7Hz),114.4(t, J=240.5Hz), 113.9 (d, J=4.1Hz), 59.9, 41.5 (t, J=26.8Hz), 29.5, 21.6, 7.9.

[0120] Example 6

[0121] The reaction route is shown below:

[0122]

[0123] Step 1: Synthesis of compound YYJ-007

[0124] Compound C-1 (500 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC was used to determine if the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 70:1 to 25:1) to give a white solid YYJ-007 (229 mg, 0.66 mmol, yield 66%). 1 HNMR (600MHz, DMSO-d6) δ12.24(s,1H),8.50(dd,J=9.9,2.8Hz,1H),8.25(dd,J=2.9,1.4Hz,1H),8.21(d,J=3.7Hz,1H),8.15(d ,J=2.8Hz,1H),7.40(s,1H),7.14(s,1H),7.09(s,1H),2.14(ddp,J=21.4,14.5,7.4Hz,2H),1.59(s,3H),0.78(t,J=7.4Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ175.8, 157.0 (d, J = 6.7Hz), 155.7 (d, J = 240.0Hz), 150.3 (d, J = 10.1Hz), 145.9, 143.8 (d, J = 255.3Hz), 138. 3(d,J=18.3Hz), 131.3(d,J=28.9Hz), 131.1, 117.9(d,J=7.7Hz), 115.2(d,J=21.5Hz), 113.8(d,J=3.3Hz), 60.0, 29.0, 22.0, 8.1.

[0125] Example 7

[0126] The reaction route is shown below:

[0127]

[0128] Step 1: Synthesis of compound F-1

[0129] Compound A-7 (1.96 g, 3.9 mmol) was dissolved in 25 mL of DCM at room temperature. Methylamine hydrochloride (371 mg, 5.5 mmol), HATU (1.9 g, 5.0 mmol), and TEA (1.2 g, 11.7 mmol) were added. The reaction mixture was stirred at room temperature for 12 h, and TLC analysis showed complete reaction of the starting material. The reaction solution was cooled to room temperature and extracted three times with dichloromethane (30 mL × 3). The combined organic phases were washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to give a white solid F-1 (978 mg, 1.9 mmol, yield 49%). 1 HNMR(400MHz, CDCl3)δ8.47(dd,J=9.0,2.8Hz,1H),8.45(s,1H),8.28(dd,J=2.9,1 .2Hz,1H),8.10(d,J=3.1Hz,1H),8.07(d,J=8.5Hz,2H),7.27(dd,J=8.8,0.9Hz,2H) ,6.20(d,J=4.9Hz,1H),5.87(d,J=2.6Hz,1H),2.88(d,J=4.8Hz,3H),2.36(s,3H),2 .35–2.31(m,1H),2.00(dd,J=14.1,7.3Hz,1H),1.73(s,3H),0.90(t,J=7.4Hz,3H).

[0130] Step 2: Synthesis of compound YYJ-008

[0131] Compound F-1 (515 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material was completely reacted. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed three times with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 70:1 to 30:1) to give a white solid YYJ-008 (299 mg, 0.83 mmol, yield 83%). 1HNMR (600MHz, DMSO-d6) δ12.23(s,1H),8.44(dd,J=9.8,2.8Hz,1H),8.25(s,1H),8.20(d,J=3.8Hz,1H),8.13(d,J=2.8Hz,1H),7.76(q,J=4. 5Hz,1H),7.23(s,1H),2.54(d,J=4.5Hz,3H),2.11(dq,J=14.9,7.5Hz,1H),2.01(dq,J=14.6,7.4Hz,1H),1.53(s,3H),0.77(t,J=7.4Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ174.1, 157.0 (d, J = 6.7Hz), 155.7 (d, J = 239.9Hz), 150.3 (d, J = 10.4Hz), 145.9, 143.9 (d, J = 255.6Hz), 138.4 ( d, J=18.0Hz), 131.3 (d, J=28.9Hz), 131.0, 117.9 (d, J=7.7Hz), 115.1 (d, J=21.7Hz), 113.9 (d, J=4.0Hz), 60.0, 29.3, 26.2, 22.1, 8.1.

[0132] Example 8

[0133] The reaction route is shown below:

[0134]

[0135] Step 1: Synthesis of compound G-1

[0136] Compound A-7 (1.96 g, 3.9 mmol) was dissolved in 25 mL of DCM at room temperature. Dimethylamine hydrochloride (448 mg, 5.5 mmol), HATU (1.9 g, 5.0 mmol), and TEA (1.2 g, 11.7 mmol) were added. The reaction was stirred at room temperature for 12 h, and the reaction proceeds were determined by TLC to be complete. The reaction solution was cooled to room temperature and extracted three times with dichloromethane (30 mL × 3). The organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 2:1) to give a white solid G-1 (1.11 g, 2.1 mmol, yield 54%). 1HNMR (400MHz, CDCl3) δ8.58–8.53(m,2H),8.29(dd,J=2.9,1.2Hz,1H),8.12–8.08(m,3H),7.27(d,J=7.9Hz,2H),6.05(s,1H ), 3.07 (s, 6H), 2.48 (dd, J = 14.2, 7.3Hz, 1H), 2.37 (s, 3H), 2.08 (dd, J = 14.2, 7.3Hz, 1H), 1.79 (s, 3H), 0.90 (t, J = 7.5Hz, 4H).

[0137] Step 2: Synthesis of compound YYJ-009

[0138] Compound G-1 (528 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material was completely reacted. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 80:1 to 40:1) to give a white solid YYJ-009 (307 mg, 0.83 mmol, yield 83%). 1 HNMR (600MHz, DMSO-d6) δ12.21(s,1H),8.47(dd,J=9.8,2.8Hz,1H),8.24(dd,J=2.8,1.4Hz,1H),8.22(d,J=3.9Hz,1H),8.16(d,J=2.8Hz,1 H),7.73(s,1H),2.97(s,3H),2.74(s,3H),2.19(dt,J=15.9,8.1Hz,1H),1.95(dq,J=14.7,7.4Hz,1H),1.51(s,3H),0.81(t,J=7.5Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ172.2, 157.3 (d, J = 6.6Hz), 155.7 (d, J = 239.9Hz), 149.6 (d, J = 10.8Hz), 145.9, 143.3 (d, J = 255.8Hz), 138.8 (d, J=18.0Hz),131.5,131.3(d,J=28.9Hz),117.8(d,J=7.9Hz),115.2(d,J=21.7Hz),113.9(d,J=4.2Hz),59.8,37.1(2C),29.1,22.1,8.0.

[0139] Example 9

[0140] The reaction route is shown below:

[0141]

[0142] Step 1: Synthesis of compound H-1

[0143] Compound A-7 (1.96 g, 3.9 mmol) was dissolved in 25 mL of DCM at room temperature. Ethylamine hydrochloride (448 mg, 5.5 mmol), HATU (1.9 g, 5.0 mmol), and TEA (1.2 g, 11.7 mmol) were added. The reaction was stirred at room temperature for 12 h, and the reaction proceeds were determined by TLC to be complete. The reaction solution was cooled to room temperature and extracted three times with dichloromethane (30 mL × 3). The organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:1 to 3:1) to give a white solid H-1 (1.06 g, 2.0 mmol, yield 51%). 1 HNMR(400MHz, CDCl3)δ8.50(dd,J=9.0,2.8Hz,1H),8.47(s,1H),8.29(dd,J=2.8,1.2Hz, 1H),8.12(d,J=3.0Hz,1H),8.08(d,J=8.5Hz,2H),7.28(d,J=7.9Hz,2H),6.05(t,J=5.7Hz ,1H),5.89(s,1H),3.36(ddd,J=7.1,5.7,3.0Hz,2H),2.41(d,J=7.3Hz,1H),2.37(s,3H) ,1.99(dd,J=14.1,7.3Hz,1H),1.74(s,3H),1.09(t,J=7.2Hz,3H),0.91(t,J=7.4Hz,3H).

[0144] Step 2: Synthesis of compound YYJ-010

[0145] Compound H-1 (528 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a methanol solution of sodium methoxide (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) to give a white solid YYJ-010 (322 mg, 0.87 mmol, yield 87%). 1 HNMR(600MHz,DMSO-d6)δ12.22(s,1H),8.47(dd,J=9.9,2.9Hz,1H),8.24(dd,J =2.8,1.4Hz,1H),8.20(d,J=3.8Hz,1H),8.13(d,J=2.8Hz,1H),7.83(t,J=5.8H z,1H),7.18(s,1H),3.08–3.01(m,2H),2.12(dq,J=14.9,7.5Hz,1H),2.03(dq, J=14.6,7.4Hz,1H),1.54(s,3H),0.82(t,J=7.1Hz,3H),0.78(t,J=7.5Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ173.2, 157.0 (d, J = 6.7Hz), 155.7 (d, J = 239.8Hz), 150.2 (d, J = 10.3Hz), 145.9, 143.8 (d, J = 255.5Hz), 138.5 (d, J =18.2Hz), 131.3 (d, J = 28.9Hz), 131.0, 117.9 (d, J = 7.7Hz), 115.2 (d, J = 21.6Hz), 113.9 (d, J = 3.9Hz), 59.9, 33.7, 29.4, 22.0, 14.8, 8.0.

[0146] Example 10

[0147] The reaction route is shown below:

[0148]

[0149] Step 1: Synthesis of Compound I-1

[0150] Compound A-7 (1.96 g, 3.9 mmol) was dissolved in 25 mL of LCM at room temperature. Isopropylamine hydrochloride (515 mg, 5.5 mmol), HATU (1.9 g, 5.0 mmol), and TEA (1.2 g, 11.7 mmol) were added. The reaction was stirred at room temperature for 12 h, and the reaction proceeds were determined by TLC to be complete. The reaction solution was cooled to room temperature and extracted three times with dichloromethane (30 mL × 3). The organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:1 to 3:1) to give a clear oily substance I-1 (1.09 g, 2.0 mmol, yield 51%). 1 HNMR(400MHz, CDCl3)δ8.52(dd,J=9.0,2.8Hz,1H),8.47(s,1H),8.29(dd,J=2.8,1.2Hz,1H) ,8.12(d,J=3.1Hz,1H),8.08(d,J=8.5Hz,2H),7.28(d,J=7.8Hz,2H),5.93(s,1H),5.81(d,J= 7.9Hz,1H),4.15–4.09(m,1H),2.41(dd,J=14.2,7.3Hz,1H),2.37(s,3H),1.96(dd,J=14.2, 7.3Hz, 1H), 1.74 (s, 3H), 1.12 (d, J = 6.6Hz, 3H), 1.06 (d, J = 6.5Hz, 3H), 0.89 (t, J = 7.4Hz, 3H).

[0151] Step 2: Synthesis of compound YYJ-011

[0152] Compound I-1 (543 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a methanol solution of sodium methoxide (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give a white solid YYJ-011 (350 mg, 0.90 mmol, yield 90%). 1HNMR (600MHz, DMSO-d6) δ12.22(s,1H),8.48(dd,J=9.9,2.8Hz,1H),8.24(s,1H),8.20(d,J=3.7Hz,1H),8.14(d,J=2.7Hz,1H),7.53(d,J=8.1Hz,1 H),7.09(s,1H),3.90(dh,J=13.8,7.0Hz,1H),2.15–2.02(m,2H),1.55(s ,3H),0.91(d,J=6.6Hz,3H),0.86(d,J=6.6Hz,3H),0.78(t,J=7.5Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ172.3, 157.0 (d, J = 6.7Hz), 155.7 (d, J = 239.9Hz), 150.2 (d, J = 10.2Hz), 145.9, 143.8 (d, J = 255.3Hz), 138.4 (d, J = 1 8.1Hz), 131.3 (d, J = 28.9Hz), 131.0, 117.9 (d, J = 7.7Hz), 115.2 (d, J = 21.7Hz), 113.9 (d, J = 4.0Hz), 59.9, 40.5, 29.3, 22.2, 22.1, 21.9, 8.0.

[0153] Example 11

[0154] The reaction route is shown below:

[0155]

[0156] Step 1: Synthesis of compound J-1

[0157] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of LMF at room temperature, and 2-amino-2-methyl-1-propanol (294 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and the reaction proceeded to completion by TLC. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3), and the organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1 to 3:1) to give a white solid J-1 (947 mg, 2.0 mmol, yield 91%). 1HNMR (400MHz, CDCl3) δ8.49(dd,J=8.9,2.8Hz,1H),8.41(s,1H),8.29(dd,J=3.0,1.2Hz,1H),8.09(d,J=8.4Hz,2H),8. 07(d,J=3.2Hz,1H),7.28(d,J=8.3Hz,2H),5.23(d,J=3.2Hz,1H),3.85(s,2H),2.37(s,3H),1.55(s,6H),1.42(s,1H).

[0158] Step 2: Synthesis of compound YYJ-012

[0159] Compound J-1 (474 ​​mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a methanol solution of sodium methoxide (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give a white solid YYJ-012 (259 mg, 0.81 mmol, yield 81%). 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.45(dd,J=9.8,2.9Hz,1H),8.29(dd,J=2.9,1.5Hz,1H),8.17(d,J=4.0H z, 1H), 8.14 (d, J = 2.5Hz, 1H), 6.46 (d, J = 2.1Hz, 1H), 5.05 (t, J = 5.9Hz, 1H), 3.66 (d, J = 6.0Hz, 2H), 1.49 (s, 6H).

[0160] Example 12

[0161] The reaction route is shown below:

[0162]

[0163] Step 1: Synthesis of compound K-1

[0164] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of LDM at room temperature. 1-Aminocyclopropanol (287 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and TLC analysis showed complete reaction of the starting material. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The combined organic phases were washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid K-1 (660 mg, 1.4 mmol, yield 64%). MS m / z: 471.86 [M+l] + .

[0165] Step 2: Synthesis of compound YYJ-013

[0166] Compound K-1 (471 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a methanol solution of sodium methoxide (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give a white solid YYJ-013 (263 mg, 0.83 mmol, yield 83%). 1 H NMR (400MHz, DMSO-d6) δ12.26(s,1H),8.58(dd,J=10.0,2.9Hz,1H),8.27(dd,J=2.9,1.5Hz,1H),8.19(s,1H),8.14( d,J=4.0Hz,1H),7.91(s,1H),4.84(t,J=5.7Hz,1H),3.70(d,J=5.7Hz,2H),0.95–0.90(m,2H),0.83(d,J=4.8Hz,2H).

[0167] Example 13

[0168] The reaction route is shown below:

[0169]

[0170] Step 1: Synthesis of compound L-1

[0171] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of LDM at room temperature. 1-Aminocyclobutane-methanol (334 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and TLC analysis showed complete reaction of the starting material. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The combined organic phases were washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to give a white solid L-1 (728 mg, 1.5 mmol, yield 68%). MS m / z: 485.81 [M+l] + .

[0172] Step 2: Synthesis of compound YYJ-014

[0173] Compound L-1 (485 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a methanol solution of sodium methoxide (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material was completely reacted. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) to give a white solid YYJ-014 (275 mg, 0.83 mmol, yield 83%). 1 H NMR (400MHz, DMSO-d6) δ12.25(s,1H),8.43(dd,J=9.8,2.9Hz,1H),8.27(dd,J=2.9,1.5Hz,1H),8.13(dd,J=14. 0,3.3Hz,2H),7.37(s,1H),4.92(t,J=5.8Hz,1H),3.84(d,J=5.9Hz,2H),2.40–2.25(m,4H),1.93–1.80(m,2H).

[0174] Example 14

[0175] The reaction route is shown below:

[0176]

[0177] Step 1: Synthesis of compound M-1

[0178] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of DMF at room temperature. (3-aminooxetane-3-yl)methanol (340 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and TLC analysis showed complete reaction of the starting material. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The combined organic phases were washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give a white solid M-1 (633 mg, 1.3 mmol, yield 59%). MS m / z: 487.99 [M+l] + .

[0179] Step 2: Synthesis of compound YYJ-015

[0180] Compound M-1 (487 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 50:1 to 30:1) to give a white solid YYJ-015 (266 mg, 0.80 mmol, yield 80%). MS m / z: 334.11 [M+l] + .

[0181] Example 15

[0182] The reaction route is shown below:

[0183]

[0184] Step 1: Synthesis of compound N-1

[0185] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of LMF at room temperature. D-aminopropanol (248 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and TLC analysis showed complete reaction of the starting material. The reaction mixture was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The combined organic phases were washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid N-1 (781 mg, 1.7 mmol, yield 77%). MS m / z: 459.86 [M+l] + .

[0186] Step 2: Synthesis of compound YYJ-016

[0187] Compound N-1 (459 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material was completely reacted. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 50:1 to 30:1) to give a white solid YYJ-016 (214 mg, 0.70 mmol, yield 70%). 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),8.43(dd,J=9.8,2.9Hz,1H),8.27(dd,J=2.9,1.5Hz,1H),8.21(d,J=2.6Hz,1H),8.14(d,J=4.0Hz,1H),7 .27(d,J=7.9Hz,1H), 4.86(t,J=5.7Hz,1H), 4.34(p,J=6.8Hz,1H), 3.59(dt,J=11.2,5.7Hz,1H), 3.47(t,J=6.0Hz,1H), 1.25(d,J=6.7Hz,3H).

[0188] Example 16

[0189] The reaction route is shown below:

[0190]

[0191] Step 1: Synthesis of compound O-1

[0192] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of L-MF at room temperature. L-aminopropanol (248 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and TLC analysis showed complete reaction of the starting material. The reaction mixture was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The combined organic phases were washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid O-1 (643 mg, 1.4 mmol, yield 64%). MS m / z: 459.86 [M+l] + .

[0193] Step 2: Synthesis of compound YYJ-017

[0194] Compound O-1 (459 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 50:1 to 30:1) to give a white solid YYJ-017 (226 mg, 0.74 mmol, yield 74%). 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),8.43(dd,J=9.8,2.9Hz,1H),8.27(dd,J=2.9,1.5Hz,1H),8.21(d,J=2.6Hz,1H),8.14(d,J=4.0Hz,1H),7 .27(d,J=7.9Hz,1H), 4.86(t,J=5.7Hz,1H), 4.34(p,J=6.8Hz,1H), 3.59(dt,J=11.2,5.7Hz,1H), 3.47(t,J=6.0Hz,1H), 1.25(d,J=6.7Hz,3H).

[0195] Example 17

[0196] The reaction route is shown below:

[0197]

[0198] Step 1: Synthesis of compound P-1

[0199] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of LMF at room temperature, and L-2-amino-1-butanol (294 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and the reaction proceeds were determined by TLC to be complete. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3), and the organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid P-1 (616 mg, 1.3 mmol, yield 59%). 1 H NMR (600MHz, CDCl3) δ8.49 (dd, J=9.5, 1.5Hz, 2H), 8.30 (d, J=2.5Hz, 1H), 8.09 (d, J=8.1Hz,3H),7.28(d,J=8.2Hz,2H),5.23(d,J=8.4Hz,1H),4.37–4.30(m,1H),3.9 4–3.89(m,1H),3.82(dt,J=10.4,4.7Hz,1H),2.38(s,3H),2.17(t,J=5.3Hz,1H), 1.81(dt,J=14.2,7.1Hz,1H), 1.72(dt,J=14.3,7.4Hz,1H), 1.07(t,J=7.4Hz,3H).

[0200] Step 2: Synthesis of compound YYJ-018

[0201] Compound P-1 (474 ​​mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material was completely reacted. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 55:1 to 25:1) to give a white solid YYJ-018 (243 mg, 0.76 mmol, yield 76%). 1H NMR (400MHz, DMSO-d6) δ12.24 (s, 1H), 8.45 (dd, J=9.9, 2.9Hz, 1H), 8.28 (t, J= 2.1Hz,1H),8.21(s,1H),8.14(d,J=4.0Hz,1H),7.18(d,J=8.3Hz,1H),4.76(t, J=5.6Hz,1H),4.21(d,J=5.9Hz,1H),3.56(ddt,J=29.3,11.1,5.8Hz,2H),1.7 6(dt,J=13.1,6.2Hz,1H), 1.59(dt,J=14.2,7.5Hz,1H), 0.95(t,J=7.4Hz,3H).

[0202] Example 18

[0203] The reaction route is shown below:

[0204]

[0205] Step 1: Synthesis of compound Q-1

[0206] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of LMF at room temperature, and D-2-amino-1-butanol (294 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and the reaction proceeded to completion by TLC. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3), and the organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid Q-1 (521 mg, 1.1 mmol, yield 50%). 1 H NMR (600MHz, CDCl3) δ8.49 (dd, J=9.5, 1.5Hz, 2H), 8.30 (d, J=2.5Hz, 1H), 8.09 (d, J=8.1Hz,3H),7.28(d,J=8.2Hz,2H),5.23(d,J=8.4Hz,1H),4.37–4.30(m,1H),3.9 4–3.89(m,1H),3.82(dt,J=10.4,4.7Hz,1H),2.38(s,3H),2.17(t,J=5.3Hz,1H), 1.81(dt,J=14.2,7.1Hz,1H), 1.72(dt,J=14.3,7.4Hz,1H), 1.07(t,J=7.4Hz,3H).

[0207] Step 2: Synthesis of compound YYJ-019

[0208] Compound Q-1 (474 ​​mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material was completely reacted. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 55:1 to 25:1) to give a white solid YYJ-019 (252 mg, 0.79 mmol, yield 79%). 1 H NMR (400MHz, DMSO-d6) δ12.24 (s, 1H), 8.45 (dd, J=9.9, 2.9Hz, 1H), 8.28 (t, J= 2.1Hz,1H),8.21(s,1H),8.14(d,J=4.0Hz,1H),7.18(d,J=8.3Hz,1H),4.76(t, J=5.6Hz,1H),4.21(d,J=5.9Hz,1H),3.56(ddt,J=29.3,11.1,5.8Hz,2H),1.7 6(dt,J=13.1,6.2Hz,1H), 1.59(dt,J=14.2,7.5Hz,1H), 0.95(t,J=7.4Hz,3H).

[0209] Example 19

[0210] The reaction route is shown below:

[0211]

[0212] Step 1: Synthesis of compound R-1

[0213] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of DMF at room temperature. D-2-amino-3-methyl-1-butanol (340 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and TLC analysis showed complete reaction of the starting material. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The combined organic phases were washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid R-1 (536 mg, 1.1 mmol, yield 50%).1 H NMR (400MHz, CDCl3) δ8.51–8.46(m,2H),8.30(dd,J=2.9,1.2Hz,1H),8.11–8.05(m,3H),7.28(d,J=7.9Hz,2H),5.26(d,J=8.0Hz,1 H),4.25(dtd,J=9.2,6.0,3.7Hz,1H),3.89(qd,J=11.1,4.8Hz,2H),2.37(s,3H),2.14–2.07(m,1H),1.07(dd,J=13.1,6.8Hz,6H).

[0214] Step 2: Synthesis of compound YYJ-020

[0215] Compound R-1 (488 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 55:1 to 25:1) to give a white solid YYJ-020 (243 mg, 0.73 mmol, yield 73%). 1 H NMR (600MHz, DMSO-d6) δ12.24(s,1H),8.46(dd,J=9.8,2.9Hz,1H),8.28(s,1H),8.20(d,J=2.8Hz,1H),8.14(d,J=3.9Hz,1H),7. 16(d,J=8.6Hz,1H),4.65(t,J=5.5Hz,1H),4.22(s,1H),3.63(dp,J=23.6,6.1Hz,2H),2.07–2.02(m,1H),0.97(t,J=7.5Hz,6H).

[0216] Example 20

[0217] The reaction route is shown below:

[0218]

[0219] Step 1: Synthesis of compound S-1

[0220] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of L-MF at room temperature. L-2-amino-3-methyl-1-butanol (340 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and the reaction proceeded to completion by TLC. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid S-1 (488 mg, 1.0 mmol, yield 45%). 1 HNMR (400MHz, CDCl3) δ8.51–8.46(m,2H),8.30(dd,J=2.9,1.2Hz,1H),8.11–8.05(m,3H),7.28(d,J=7.9Hz,2H),5.26(d,J=8.0Hz, 1H), 4.25 (dtd, J=9.2, 6.0, 3.7Hz, 1H), 3.89 (qd, J=11.1, 4.8Hz, 2H), 2.37 (s, 3H), 2.14–2.07 (m, 1H), 1.07 (dd, J=13.1, 6.8Hz, 6H).

[0221] Step 2: Synthesis of compound YYJ-021

[0222] Compound S-1 (488 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material was completely reacted. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 55:1 to 25:1) to give a white solid YYJ-021 (243 mg, 0.73 mmol, yield 73%). 1H NMR (600MHz, DMSO-d6) δ12.24(s,1H),8.46(dd,J=9.8,2.9Hz,1H),8.28(s,1H),8.20(d,J=2.8Hz,1H),8.14(d,J=3.9Hz,1H),7. 16(d,J=8.6Hz,1H),4.65(t,J=5.5Hz,1H),4.22(s,1H),3.63(dp,J=23.6,6.1Hz,2H),2.07–2.02(m,1H),0.97(t,J=7.5Hz,6H).

[0223] Example 21

[0224] The reaction route is shown below:

[0225]

[0226] Step 1: Synthesis of compound T-1

[0227] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in a mixed solvent of 10 mL of 1,4-dioxane and 2 mL of acetonitrile at room temperature. L-isovaline (387 mg, 3.3 mmol) and sodium carbonate (699 mg, 6.6 mmol) were added. The reaction was stirred at 130 °C for 10 h, and the reaction proceeds were determined to be complete by TLC. The reaction solution was cooled to room temperature, diluted with water (10 mL), and the pH was adjusted to 3-4 with 2N dilute hydrochloric acid. The solution was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 120:1 to 80:1) to give a white solid T-1 (903 mg, 1.8 mmol, yield 82%). 1 HNMR (400MHz, CDCl3) δ8.40(dd,J=9.0,2.9Hz,1H),8.35(s,1H),8.27(dd,J=2.9,1.2Hz,1H),8.08–8.03(m,3H),7.26(d,J=5.2Hz,2H ), 5.56 (d, J = 2.4Hz, 1H), 2.35 (s, 3H), 2.26 (dd, J = 14.0, 7.3Hz, 1H), 2.10 (dd, J = 13.9, 7.3Hz, 1H), 1.73 (s, 3H), 0.91 (t, J = 7.5Hz, 3H).

[0228] Step 2: Synthesis of compound T-2

[0229] Compound T-1 (130 mg, 0.26 mmol) was dissolved in 3 mL of tetrahydrofuran at room temperature, and 0.52 mL of 1 M LiAlH4 tetrahydrofuran solution (0.52 mmol) was added dropwise. The reaction was stirred at 45 °C for 12 h, and the reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature and diluted with ethyl acetate. The reaction was quenched by adding sodium sulfate decahydrate in portions. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1 to 4:1) to give white solid T-2 (93 mg, 0.19 mmol, yield 73%). 1 HNMR(400MHz, CDCl3)δ8.48(dd,J=8.9,2.9Hz,1H),8.39(s,1H),8.29(dd,J=3.0,1.2Hz, 1H),8.10(d,J=8.4Hz,2H),8.08(d,J=3.2Hz,1H),7.28(d,J=8.2Hz,2H),5.11(d,J=3.3H z,1H),4.41(s,1H),3.94(d,J=11.5Hz,1H),3.84(d,J=11.5Hz,1H),2.37(s,3H),2.08(d d, J=14.3, 7.4Hz, 1H), 1.87 (dd, J=14.2, 7.3Hz, 1H), 1.45 (s, 3H), 0.98 (t, J=7.5Hz, 3H).

[0230] Step 3: Synthesis of compound YYJ-022

[0231] Compound T-2 (49 mg, 0.1 mmol) was dissolved in 2 mL of methanol at room temperature, and 1 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 1:1) to give a white solid YYJ-022 (23 mg, 0.07 mmol, yield 70%). MS m / z: 334.19 [M+l] + . 1H NMR (600MHz, DMSO-d6) δ12.27(s,1H),8.43(dd,J=9.8,2.8Hz,1H),8.28(d,J=1.5Hz,1H),8.17(d,J=3.9Hz,1H),8.11(d,J=2.8Hz,1H),6.31(s,1H) ,4.97(s,1H),3.79(d,J=10.8Hz,1H),3.60(s,1H),2.13(dd,J=14.0,7.3 Hz, 1H), 1.90 (dd, J = 14.0, 7.3Hz, 1H), 1.42 (s, 3H), 0.83 (t, J = 7.5Hz, 3H).

[0232] Example 22

[0233] The reaction route is shown below:

[0234]

[0235] Step 1: Synthesis of compound U-2

[0236] Compound U-1 (2.17 g, 10.0 mmol) was dissolved in 25 mL of DMF at room temperature. Trifluoroethylamine (371 mg, 15.0 mmol), HATU (1.49 g, 5.0 mmol), and DIPEA (3.88 g, 30.0 mmol) were added. The reaction was stirred at room temperature for 12 h, and the reaction proceeds were determined to be complete by TLC. The reaction solution was diluted with water (30 mL), and the pH was adjusted to 3-4 with 2N dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate (40 mL × 3). The organic phases were combined and washed three times with saturated brine (40 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude white solid U-2 (2.68 g, 9.0 mmol, yield 90%). 1 HNMR (400MHz, CDCl3) δ3.92 (qd, J = 9.1, 6.4Hz, 2H), 2.81 (s, 3H), 1.89 (q, J = 7.5Hz, 2H), 1.44 (s, 9H), 0.87 (t, J = 7.5Hz, 3H).

[0237] Step 2: Synthesis of compound U-3

[0238] Compound U-2 (2.39 g, 8.0 mmol) was dissolved in 30 mL of LCM at room temperature, and 10 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 12 h, and the reaction proceeded to completion by TLC. The reaction solution was diluted with water (30 mL), and the pH was adjusted to neutral with saturated NaHCO3 solution. The mixture was extracted three times with dichloromethane (30 mL × 3), and the organic phases were combined. The mixture was washed three times with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid crude product U-3 (951 mg, 4.8 mmol, yield 60%). 1 H NMR(400MHz,MeOD)δ4.11–4.02(m,1H),3.97–3.88(m,1H),2.83(s,3H),2.02 (dd, J=15.0, 7.6Hz, 1H), 1.89 (dd, J=15.0, 7.5Hz, 1H), 0.98 (d, J=7.6Hz, 3H).

[0239] Example 23

[0240] The reaction route is shown below:

[0241]

[0242] Step 1: Synthesis of compound V-2

[0243] To a bromoform (5 mL) solution of compound V-1 (300 mg, 1.97 mmol), tert-butyl nitrite (406 mg, 3.94 mmol) was added. The mixture was stirred at 130 °C for 2 hours, and the reaction proceeds were monitored by TLC until complete. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to remove bromoform. 10 mL of ethyl acetate was added, and the mixture was filtered. The filter cake was washed three times with ethyl acetate (2 mL × 3) and dried under vacuum to give a yellow solid V-2 (300.00 mg, yield 70.50%). 1 HNMR (600MHz, CDCl3) δ12.54 (s, 1H), 8.56 (t, J = 2.2Hz, 1H), 7.70 (dd, J = 7.3, 2.6Hz, 1H).

[0244] Step 2: Synthesis of compound V-3

[0245] Compound V-2 (300 mg, 1.39 mmol) was dissolved in 10 mL of anhydrous DMF. 60% NaH (60 mg, 1.5 mmol) was added in portions under ice bath conditions. The reaction was stirred at 0 °C for 30 min, followed by the addition of triphenylchloromethane (418 mg, 1.5 mmol) in portions, and the temperature was slowly raised to room temperature. After stirring at room temperature for 12 h, TLC analysis showed that the reaction proceeds were complete. The reaction solution was cooled to room temperature, and the reaction was quenched with water (10 mL). The mixture was extracted three times with ethyl acetate (10 mL × 3). The combined organic phases were washed three times with saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 70:1 to 50:1) to give a white solid V-3 (350 mg, 0.76 mmol, yield 55%). 1 H NMR (600MHz, DMSO-d6) δ8.41 (dd, J=2.8, 1.4Hz, 1H), 8.03 (dd, J=7.9, 2.8Hz, 1H), 7.31–7.19 (m, 15H).

[0246] Step 3: Synthesis of compound V-4

[0247] Potassium acetate (225 mg, 2.29 mmol) and DPPF palladium dichloride (55.6 mg, 0.076 mmol) were added to a 1,4-dioxane (7 mL) solution of compound V-3 (350 mg, 0.76 mmol) and bis(pinacol) borate (291 mg, 1.15 mmol). The mixture was stirred at 100 °C for 12 h under argon protection. The reaction solution was cooled to room temperature, and the crude product was filtered through diatomaceous earth. The filtrate was diluted with ethyl acetate (10 mL), and the organic phase was washed twice with saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid crude product V-4 (300 mg, 0.59 mmol, yield 78%). MS m / z: 504.24 [M+l] + .

[0248] Example 24

[0249] The reaction route is shown below:

[0250]

[0251] Step 1: Synthesis of compound W-2

[0252] Compound W-1 (367 mg, 2.2 mmol) was dissolved in 10 mL of THF at room temperature. U-3 (654 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 55 °C for 12 h, and the reaction proceeds were determined to be complete by TLC. The reaction solution was cooled to room temperature, diluted with water (15 mL), and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed three times with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 8:1) to give a white solid W-2 (625 mg, 1.9 mmol, yield 86%). 1 HNMR(400MHz, CDCl3)δ7.94(d,J=2.7Hz,1H),6.34(s,1H),6.06(s,1H),4.06–3.89(m,2 H), 2.55–2.43 (m, 1H), 1.87 (dt, J = 14.7, 7.4Hz, 1H), 1.72 (s, 3H), 0.87 (t, J = 7.5Hz, 3H).

[0253] Step 2: Synthesis of compound W-3

[0254] At room temperature, compounds W-2 (329 mg, 1.0 mmol) and V-4 (758 mg, 1.5 mmol) were dissolved in 2-methyltetrahydrofuran (20.0 mL) and water (5.0 mL), respectively. Potassium phosphate (636 mg, 3.0 mmol), tris(dibenzylacetone)dipalladium (92 mg, 0.1 mmol), and 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl (95 mg, 0.2 mmol) were added. The mixture was stirred at 80 °C for 12 h under argon protection, and the reaction was confirmed by TLC to be complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate (10 mL), washed three times with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1 to 5:1) to give a white solid W-3 ​​(336 mg, 0.5 mmol, yield 50%). 1HNMR (600MHz, CDCl3) δ8.49(dd,J=8.3,2.9Hz,1H),8.21(d,J=2.9Hz,1H),8.13(d,J=1.6Hz,1H),7.98(s,1H),7.24(s,15 H), 5.24 (s, 1H), 3.58 (dt, J = 16.0, 8.3Hz, 1H), 3.05–2.98 (m, 1H), 2.20–2.14 (m, 2H), 1.65 (s, 3H), 0.93 (t, J = 7.2Hz, 3H).

[0255] Step 3: Synthesis of compound YYJ-023

[0256] Compound W-3 ​​(336 mg, 0.5 mmol) was dissolved in 5 mL of LCM at room temperature, and 10 mL of trifluoroacetic acid (1.14 g, 10 mmol) and triethylsilane (1.16 mg, 10 mmol) were added. The reaction was stirred at room temperature for 12 h, and the reaction proceeds were confirmed to be complete by TLC. The reaction solution was diluted with water (10 mL), and the pH was adjusted to neutral with saturated NaHCO3 solution. The mixture was extracted three times with dichloromethane (15 mL × 3), and the organic phases were combined. The organic phases were washed three times with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 to 1:1) to give a white solid W-4, namely compound YYJ-023 (142 mg, 0.33 mmol, yield 66%). 1 H NMR (600MHz, DMSO-d6) δ8.60(dd,J=2.8,1.4Hz,1H),8.57(t,J=6.4Hz,1H),8.54(dd,J=9.2,2.8Hz,1H),8.38(d,J=3.5Hz,1H), 7.51(s,1H),3.80–3.76(m,2H),2.20(dq,J=14.9,7.5Hz,1H),2.03(dt,J=14.7,7.4Hz,1H),1.61(s,3H),0.82(t,J=7.5Hz,3H).

[0257] Example 25

[0258] The reaction route is shown below:

[0259]

[0260] Step 1: Synthesis of compound X-2

[0261] At room temperature, compound X-1 (350 mg, 2.1 mmol) was dissolved in 5 mL of acetonitrile and 5 mL of water, and silver nitrate (713 mg, 4.2 mmol) and cyclopropylformic acid (534 mg, 6.2 mmol) were added, respectively. The reaction solution was heated to 80 °C, and then an aqueous solution of ammonium persulfate (958 mg, 4.2 mmol) (1 mL) was added dropwise. The mixture was stirred at 80 °C for 12 h, and the reaction was confirmed by TLC to be complete. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed three times with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:1 to 60:1) to give white solid X-2 (393 mg, 1.9 mmol, yield 90%). 1 HNMR (400MHz, CDCl3) δ2.25 (ttd, J = 8.0, 4.7, 1.6Hz, 1H), 1.28–1.21 (m, 2H), 1.21–1.16 (m, 2H).

[0262] Step 2: Synthesis of compound X-3

[0263] Compound X-2 (455 mg, 2.2 mmol) was dissolved in 10 mL of THF at room temperature. U-3 (654 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 55 °C for 12 h, and the reaction proceeds were determined to be complete by TLC. The reaction solution was cooled to room temperature, diluted with water (15 mL), and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed three times with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 8:1) to give a white solid X-3 (701 mg, 1.9 mmol, yield 86%). 1 HNMR (400MHz, CDCl3) δ6.56(s,1H),5.63(s,1H),3.96(qdd,J=9.0,6.4,2.7Hz,2H),2.32(dt,J=14.9,7.4Hz,1H),2.19–2. 11(m,1H),1.98–1.87(m,1H),1.67(s,3H),1.16(dt,J=4.7,3.2Hz,2H),1.04(dd,J=5.9,2.3Hz,2H),0.87(d,J=7.5Hz,3H).

[0264] Step 3: Synthesis of compound X-4

[0265] At room temperature, compounds X-3 (369 mg, 1.0 mmol) and V-4 (758 mg, 1.5 mmol) were dissolved in 2-methyltetrahydrofuran (20.0 mL) and water (5.0 mL), respectively. Potassium phosphate (636 mg, 3.0 mmol), tris(dibenzylacetone)dipalladium (92 mg, 0.1 mmol), and 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl (95 mg, 0.2 mmol) were added. The mixture was stirred at 80 °C for 12 h under argon protection, and the reaction was confirmed by TLC to be complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate (10 mL), washed three times with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1 to 5:1) to give white solid X-4 (427 mg, 0.6 mmol, yield 60%). 1 HNMR(400MHz, CDCl3)δ8.60(s,1H),8.30(dd,J=8.3,2.9Hz,1H),8.12(dd,J=2.9,1.3Hz,1H) ,7.23(d,J=1.3Hz,15H),5.03(d,J=3.0Hz,1H),3.50(dq,J=17.5,8.8Hz,1H),2.82(ddd,J=15 .0,9.5,5.7Hz,1H),2.34–2.26(m,1H),2.22(dd,J=14.0,7.3Hz,1H),2.11(dd,J=14.0,7.2Hz ,1H),1.62(s,3H),1.27(d,J=2.7Hz,2H),1.14(dd,J=8.1,3.7Hz,2H),0.93(t,J=7.4Hz,3H).

[0266] Step 4: Synthesis of compound YYJ-024

[0267] Compound X-4 (356 mg, 0.5 mmol) was dissolved in 5 mL of LCM at room temperature, and 10 mL of trifluoroacetic acid (1.14 g, 10 mmol) and triethylsilane (1.16 mg, 10 mmol) were added. The reaction was stirred at room temperature for 12 h, and the reaction proceeds were determined to be complete by TLC. The reaction solution was diluted with water (10 mL), and the pH was adjusted to neutral with saturated NaHCO3 solution. The solution was extracted three times with dichloromethane (15 mL × 3), and the organic phases were combined. The organic phases were washed three times with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 to 1:1) to give a white solid X-5, namely compound YYJ-024 (164 mg, 0.35 mmol, yield 70%). 1HNMR (600MHz, CDCl3) δ8.55(dd,J=2.8,1.5Hz,1H),8.42(dd,J=8.3,2.8Hz,1H),7.75(d,J=6.7Hz,1H),5.35(s,1H),3.95–3.84(m,2H),2.33(dtd ,J=9.9,5.2,2.6Hz,1H),2.23(ddt,J=16.2,13.8,7.2Hz,2H),1.77(s,3H ),1.35–1.31(m,2H),1.15(dq,J=7.1,4.0Hz,2H),0.99(t,J=7.5Hz,3H).

[0268] Example 26

[0269] The reaction route is shown below:

[0270]

[0271] Step 1: Synthesis of compound Y-1

[0272] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of LMF at room temperature. 1-Amino-2-methyl-2-propanol (294 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and TLC analysis showed complete reaction of the starting material. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The combined organic phases were washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid Y-1 (663 mg, 1.4 mmol, yield 64%). 1 HNMR(400MHz, CDCl3)δ8.54–8.49(m,2H),8.30(dd,J=2.9,1.2Hz,1H),8.12–8.06(m,3H),7.2 8(d,J=8.4Hz,2H),5.60(s,1H),3.66(d,J=5.9Hz,2H),2.38(s,3H),2.17(s,1H),1.38(s,6H).

[0273] Step 2: Synthesis of compound YYJ-025

[0274] Compound Y-1 (474 ​​mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a methanol solution of sodium methoxide (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give a white solid YYJ-025 (265 mg, 0.83 mmol, yield 83%). 1 H NMR (400MHz, DMSO-d6) δ12.26(s,1H),8.48(dd,J=9.9,2.9Hz,1H),8.27(dd,J=2.9,1.5Hz,1H),8.22( s, 1H), 8.16 (d, J = 3.9Hz, 1H), 7.31 (t, J = 6.3Hz, 1H), 4.68 (s, 1H), 3.55 (d, J = 6.1Hz, 2H), 1.18 (s, 6H).

[0275] Example 27

[0276] The reaction route is shown below:

[0277]

[0278] Step 1: Synthesis of compound Z-1

[0279] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of LMF at room temperature. (S)-3-amino-2-methyl-2-hydroxybutane (340 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and the reaction proceeds were determined by TLC to be complete. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to give a white solid Z-1 (731 mg, 1.5 mmol, yield 68%). 1H NMR (400MHz, CDCl3) δ8.53–8.48(m,2H),8.30(dd,J=2.9,1.3Hz,1H),8.11–8.06(m,3H),7.29(d,J=8.3H z,2H),5.40(d,J=8.8Hz,1H),4.40–4.31(m,1H),2.38(s,3H),1.96(s,1H),1.35(dd,J=8.2,6.1Hz,9H).

[0280] Step 2: Synthesis of compound YYJ-026

[0281] Compound Z-1 (488 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a methanol solution of sodium methoxide (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material was completely reacted. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) to give a white solid YYJ-026 (277 mg, 0.83 mmol, yield 83%). 1 H NMR (400MHz, DMSO-d6) δ12.26(s,1H),8.45(dd,J=9.8,2.9Hz,1H),8.28(dd,J=2.8,1.4Hz,1H),8.22(d,J=2.4Hz,1H),8.16 (d, J = 3.9 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 4.58 (s, 1H), 4.40 (p, J = 6.9 Hz, 1H), 1.24 (d, J = 6.7 Hz, 3H), 1.18 (d, J = 11.4 Hz, 6H).

[0282] Example 28

[0283] The reaction route is shown below:

[0284]

[0285] Step 1: Synthesis of compound AA-1

[0286] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of LMF at room temperature. 3-Amino-2,3-dimethyl-2-butanol (387 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and TLC analysis showed complete reaction of the starting material. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The combined organic phases were washed three times with saturated brine (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid AA-1 (552 mg, 1.1 mmol, yield 50%). 1 H NMR(400MHz, CDCl3)δ8.51(dd,J=8.9,2.8Hz,1H),8.41(s,1H),8.30(dd,J=2.9,1.2Hz,1H),8.13–8 .07(m,3H),7.29(d,J=8.4Hz,2H),5.46(s,1H),4.93(s,1H),2.38(s,3H),1.59(s,6H),1.31(s,6H).

[0287] Step 2: Synthesis of compound YYJ-027

[0288] Compound AA-1 (502 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC was used to determine if the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 55:1 to 25:1) to give a white solid YYJ-027 (274 mg, 0.79 mmol, yield 79%). 1 HNMR(400MHz,DMSO-d6)δ12.30(s,1H),8.45(dd,J=9.8,2.9Hz,1H),8.29(dd,J=2.9,1.5Hz,1H), 8.21(d,J=3.8Hz,1H),8.11(d,J=2.8Hz,1H),6.38(s,1H),5.58(s,1H),1.56(s,6H),1.22(s,6H).

[0289] Example 29

[0290] The reaction route is shown below:

[0291]

[0292] Step 1: Synthesis of compound BB-1

[0293] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of LMF at room temperature. (1R,2S)-2-aminocyclohexanol hydrochloride (500 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and the reaction proceeded to completion by TLC. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid BB-1 (500 mg, 1.0 mmol, yield 45%). 1 HNMR (400MHz, CDCl3) δ8.51(s,1H),8.47(dd,J=9.0,2.9Hz,1H),8.30(dd,J=2.8,1.2Hz,1H),8.10(d,J=1.7Hz,1H),8.09–8.05(m,2H),7.28(d, J=8.4Hz,2H),5.53(d,J=7.9Hz,1H),4.31–4.22(m,1H),4.17(s,1H),2. 38(s,3H),1.95–1.85(m,3H),1.83–1.72(m,3H),1.27(d,J=5.1Hz,2H).

[0294] Step 2: Synthesis of compound YYJ-028

[0295] Compound BB-1 (500 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a sodium methoxide methanol solution (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material was completely reacted. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 55:1 to 25:1) to give a white solid YYJ-028 (252 mg, 0.73 mmol, yield 73%). 1HNMR(400MHz, DMSO-d6)δ12.26(s,1H),8.41(dd,J=9.9,2.9Hz,1H),8.28(dd,J=3.0,1.5Hz,1H),8.21(s,1H),8.16(d,J=3.9Hz,1H ), 6.82 (d, J = 7.3Hz, 1H), 4.83 (d, J = 3.9Hz, 1H), 4.14–4.04 (m, 2H), 1.85–1.70 (m, 4H), 1.60 (d, J = 9.8Hz, 2H), 1.42 (d, J = 9.7Hz, 2H).

[0296] Example 30

[0297] The reaction route is shown below:

[0298]

[0299] Step 1: Synthesis of compound CC-1

[0300] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of LMF at room temperature. (1S,2S)-2-aminocyclohexanol hydrochloride (500 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and the reaction proceeded to completion by TLC. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give a white solid CC-1 (500 mg, 1.0 mmol, yield 45%). 1 HNMR (400MHz, CDCl3) δ8.54–8.49(m,2H),8.30(dd,J=2.9,1.2Hz,1H),8.12–8.07(m,3H),7.28(d,J=8.5Hz,2H),5.13(d,J=6.9Hz,1H),4.09– 3.99(m,1H),3.56(tt,J=9.5,4.1Hz,1H),2.38(s,3H),2.21(td,J=16. 4,3.7Hz,2H),1.91–1.78(m,2H),1.57–1.42(m,2H),1.41–1.32(m,2H).

[0301] Step 2: Synthesis of compound YYJ-029

[0302] Compound CC-1 (500 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a methanol solution of sodium methoxide (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material had reacted completely. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 55:1 to 25:1) to give a white solid YYJ-029 (252 mg, 0.73 mmol, yield 73%). 1 HNMR (400MHz, DMSO-d6) δ12.24(s,1H),8.48(dd,J=9.9,2.9Hz,1H),8.28(dd,J=2.9,1.4Hz,1H),8.20(d,J=2.5Hz,1H),8.12(d,J=4.0Hz,1H),7.3 2(d,J=7.6Hz,1H),4.73(d,J=5.0Hz,1H),4.01–3.89(m,1H),3.55(td,J= 9.8,4.9Hz,1H),2.12–1.94(m,2H),1.79–1.65(m,2H),1.38–1.24(m,4H).

[0303] Example 31

[0304] The reaction route is shown below:

[0305]

[0306] Step 1: Synthesis of compound DD-1

[0307] Compound A-6 (1.0 g, 2.2 mmol) was dissolved in 10 mL of LMF at room temperature. (S)-3-amino-2,4-dimethylpentane-2-ol (433 mg, 3.3 mmol) and DIPEA (853 mg, 6.6 mmol) were added. The reaction was stirred at 70 °C for 10 h, and the reaction proceeded to completion by TLC. The reaction solution was cooled to room temperature, and the reaction was quenched with water (20 mL). The mixture was extracted three times with ethyl acetate (30 mL × 3). The organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to give a white solid DD-1 (773 mg, 1.5 mmol, yield 68%). 1HNMR(400MHz, CDCl3)δ8.51(dd,J=9.0,2.8Hz,1H),8.48(s,1H),8.29(q,J=1.3Hz,1H),8.10–8.06(m,3H),7.29(s,2H),5.59(d,J=9.9Hz,1H),4.29(d d,J=10.1,2.6Hz,1H),2.38(s,3H),2.35(dd,J=6.8,2.5Hz,1H),1.82(s,1 H), 1.45 (s, 3H), 1.27 (s, 3H), 1.05 (d, J = 6.7Hz, 3H), 1.00 (d, J = 6.8Hz, 3H).

[0308] Step 2: Synthesis of compound YYJ-030

[0309] Compound DD-1 (516 mg, 1.0 mmol) was dissolved in 5 mL of methanol at room temperature, and 2 mL of a methanol solution of sodium methoxide (25% w / w) was added dropwise. The reaction was stirred at room temperature for 1 h, and TLC analysis showed that the starting material was completely reacted. The pH was adjusted to 7 with saturated NH4Cl solution, and the mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) to give a white solid YYJ-030 (300 mg, 0.83 mmol, yield 83%). 1 HNMR(400MHz, DMSO-d6)δ12.27(s,1H),8.44(dd,J=9.8,2.9Hz,1H),8.28(dd,J=3.0,1.5Hz,1H),8.22(d,J=2.3Hz,1H),8.19(d,J=3.9Hz,1H), 6.48(d,J=9.6Hz,1H),4.60(s,1H),4.31(dd,J=10.5,3.2Hz,1H),2.28(td,J=6.8,3.4Hz,1H),1.26(s,3H),1.14(s,3H),0.97(d,J=6.7Hz,6H).

[0310] Example 32

[0311] The reaction route is shown below:

[0312]

[0313] Synthesis of compound YYJ-031

[0314] Compound YYJ-013 (159 mg, 0.5 mmol) was dissolved in 3 mL of toluene at room temperature. Isobutyric acid (53 mg, 0.6 mmol), DMAP (61 mg, 0.5 mmol), CMPI (383 mg, 1.5 mmol), and TEA (152 mg, 1.5 mmol) were added. The reaction was stirred at 100 °C for 2 h, and the reaction proceeds were determined to be complete by TLC. The reaction solution was cooled to room temperature, and excess isobutyric acid was neutralized with saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined and washed three times with saturated brine (10 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 2:1) to give a white solid YYJ-031 (155 mg, 0.4 mmol, yield 80%). 1 HNMR (400MHz, DMSO-d6) δ12.26(s,1H),8.57(dd,J=10.0,2.9Hz,1H),8.28(dd,J=3.0,1.5Hz,1H),8.21(d,J=2.9Hz,1 H),8.17(d,J=3.9Hz,1H),8.01(s,1H),4.36(s,2H),2.47–2.40(m,1H),1.06(d,J=6.9Hz,4H),1.01(d,J=7.0Hz,6H).

[0315] Example 33

[0316] The reaction route is shown below:

[0317]

[0318] Synthesis of compound YYJ-032

[0319] Compound YYJ-013 (159 mg, 0.5 mmol) was dissolved in 3 mL of toluene at room temperature. L-valine (70 mg, 0.6 mmol), DMAP (61 mg, 0.5 mmol), CMPI (383 mg, 1.5 mmol), and TEA (152 mg, 1.5 mmol) were added. The reaction was stirred at 100 °C for 2 h, and TLC was used to confirm complete reaction of the starting material. The reaction solution was cooled to room temperature, and excess L-valine was neutralized with saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (10 mL × 3). The combined organic phases were washed three times with saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to give a white solid YYJ-032 (167 mg, 0.4 mmol, yield 80%). MS m / z: 417.18 [M+l]+ .

[0320] Example 34

[0321] The reaction route is shown below:

[0322]

[0323] Synthesis of compound YYJ-033

[0324] Compound YYJ-013 (159 mg, 0.5 mmol) was dissolved in 3 mL of toluene at room temperature. Cyclohexane (77 mg, 0.6 mmol), DMAP (61 mg, 0.5 mmol), CMPI (383 mg, 1.5 mmol), and TEA (152 mg, 1.5 mmol) were added. The reaction was stirred at 100 °C for 2 h, and the reaction proceeded to completion as determined by TLC. The reaction solution was cooled to room temperature, and excess cyclohexane was neutralized with saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (10 mL × 3). The combined organic phases were washed three times with saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to give a white solid YYJ-033 (171 mg, 0.4 mmol, yield 80%). MS m / z: 428.19 [M+l] + .

[0325] Example 35

[0326] The reaction route is shown below:

[0327]

[0328] Synthesis of compound YYJ-034

[0329] Compound YYJ-013 (159 mg, 0.5 mmol) was dissolved in 3 mL of toluene at room temperature. Butyric acid (53 mg, 0.6 mmol), DMAP (61 mg, 0.5 mmol), CMPI (383 mg, 1.5 mmol), and TEA (152 mg, 1.5 mmol) were added. The reaction was stirred at 100 °C for 2 h, and TLC was used to confirm complete reaction of the starting material. The reaction solution was cooled to room temperature, excess butyric acid was neutralized with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate (10 mL × 3). The combined organic phases were washed three times with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to give a white solid YYJ-034 (155 mg, 0.4 mmol, yield 80%). MS m / z: 388.15 [M+l]+ .

[0330] Example 36

[0331] The reaction route is shown below:

[0332]

[0333] Synthesis of compound YYJ-035

[0334] Compound YYJ-013 (159 mg, 0.5 mmol) was dissolved in 3 mL of toluene at room temperature. Difluoroacetic acid (58 mg, 0.6 mmol), DMAP (61 mg, 0.5 mmol), CMPI (383 mg, 1.5 mmol), and TEA (152 mg, 1.5 mmol) were added. The reaction was stirred at 100 °C for 2 h, and the reaction proceeds were determined to be complete by TLC. The reaction solution was cooled to room temperature, and excess difluoroacetic acid was neutralized with saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate (10 mL × 3). The combined organic phases were washed three times with saturated brine (10 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 2:1) to give a white solid YYJ-035 (158 mg, 0.4 mmol, yield 80%). 1 HNMR(400MHz, CDCl3)δ9.68(s,1H),8.61(dd,J=9.4,2.8Hz,1H),8.24(s,1H),8.19(d,J=2.6Hz,1H),8.12(d ,J=3.2Hz,1H),5.88(t,J=53.3Hz,1H),5.56(s,1H),4.61(s,2H),1.22–1.20(m,2H),1.18(d,J=3.8Hz,2H).

[0335] Example 37

[0336] The reaction route is shown below:

[0337]

[0338] Synthesis of compound YYJ-036

[0339] Compound YYJ-013 (159 mg, 0.5 mmol) was dissolved in 3 mL of toluene at room temperature. 4,4-Difluorocyclohexanecarboxylic acid (98 mg, 0.6 mmol), DMAP (61 mg, 0.5 mmol), CMPI (383 mg, 1.5 mmol), and TEA (152 mg, 1.5 mmol) were added. The reaction was stirred at 100 °C for 2 h, and TLC was used to confirm complete reaction of the starting material. The reaction solution was cooled to room temperature, and excess 4,4-difluorocyclohexanecarboxylic acid was neutralized with saturated sodium bicarbonate solution. Extraction was performed three times with ethyl acetate (10 mL × 3). The combined organic phases were washed three times with saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to give a white solid YYJ-036 (185 mg, 0.4 mmol, yield 80%). MS m / z: 464.17 [M+l] + .

[0340] Example 38

[0341] The anti-influenza virus activity of the compound was detected by the CCK-8 colorimetric method combined with the CPE effect assay.

[0342] (1) MDCK cells were fed at a rate of 2 × 10⁻⁶ 5 The cells were seeded at a density of 1 cell / mL in 96-well plates and cultured overnight at 37°C in a 5% CO2 cell culture incubator until the cells grew into a monolayer.

[0343] (2) Discard the cell culture medium and wash twice with autoclaved sterile PBS. Dilute the virus solution (100 TCID50) with FBS-free DMEM medium. 50 ), 100 μL / well was added to the cells, and a blank control group was set up. The cells were incubated at 37°C and 5% CO2 for 1 h.

[0344] (3) Discard the virus solution and serially dilute the compound with DMEM medium containing 0.5 μg / mL TPCK-trypsin without FBS. Add 200 μL / well to the cells and set up a blank control group, a virus control group and a positive drug control group. Continue to incubate in a 37℃, 5% CO2 cell culture incubator for 36-48h.

[0345] (4) Observe the lesions in the virus control group and use a microscope to observe and photograph the CPE effect in the compound treatment group.

[0346] (5) Discard the drug-containing culture medium, mix DMEM without FBS and CCK-8 at a ratio of 20:1, add 100 μL / well to the cells, and continue to incubate in a 37℃, 5% CO2 cell culture incubator for 1 h.

[0347] (6) After 1 hour, the absorbance value was detected at 450 nm using an ELISA reader. The inhibition rate of the compound against influenza A at the corresponding concentration was calculated based on the absorbance value: Inhibition rate (%) = [1 - (A drug group - A blank group) / (A virus group - A blank group)] × 100%.

[0348] The inhibition rate of the compound was analyzed using nonlinear fitting with GraphPad Prism software to obtain the EC50 of the compound. 50 Values. The experimental results are shown in Table 1.

[0349] Table 1. Anti-H1N1 virus activity of compounds in MDCK cells.

[0350] Compound <![CDATA[H1N1EC 50 ]]> Compound <![CDATA[H1N1EC 50 ]]> YYJ-001 17.22 μM YYJ-018 17.51 nM YYJ-002 0.030 μM YYJ-019 19.66 nM YYJ-003 0.28 μM YYJ-020 10.34 nM YYJ-004 3.22 nM YYJ-021 4.34 nM YYJ-005 2.49 μM YYJ-022 3.11 nM YYJ-006 11.52 μM YYJ-023 0.415 μM YYJ-007 invalid YYJ-024 1.579 μM YYJ-008 3.21 μM YYJ-025 33.33 nM YYJ-009 invalid YYJ-026 16.92 nM YYJ-010 4.03 μM YYJ-027 48.84 nM YYJ-011 11.72 μM YYJ-028 3.658 nM YYJ-012 20 nM YYJ-029 7.166 nM YYJ-013 7.61 nM YYJ-030 169.2 nM YYJ-014 5.62 nM YYJ-031 116.8 nM YYJ-015 19.66 nM YYJ-032 >500 nM YYJ-016 6.86 nM YYJ-033 136.6 nM YYJ-017 4.60 nM YYJ-034 90.76 nM Pimodivir 0.22 nM YYJ-035 30.61 nM Desicitinib 8.88 μM YYJ-036 127.0 nM

[0351] Table 1 shows that the JAK inhibitor dicitinib has micromolar anti-influenza virus activity, EC50, and 1,000 mg / L of 1,000 mg / L. 50 The activity level was 8.88 μM, more than 40,000 times lower than that of the positive control drug pimozide. Structure-activity relationship analysis showed that the amide or carboxyl structure of the side chain of the compound was unfavorable to anti-H1N1 activity, while the F atom on the pyrimidine ring and the F atom on the azidazole ring could significantly improve antiviral activity. For example, compounds YYJ-023 and YYJ-024 showed about 10 times higher activity than dicintinib. After modifying the side chain of dicintinib, replacing the original amide structure with amino and alcoholic hydroxyl groups, the activity was greatly improved. For example, compounds YYJ-002, YYJ-004, and YYJ-013 to YYJ-022 all showed nanomolar antiviral activity at the cellular level, and the activity gap with pimozide was reduced from 40,000 times to several tens of times.

[0352] Example 39

[0353] FP assay to detect the inhibitory activity of compounds on PB2 protein

[0354] FP assays were performed in black 96-well plates (Corning) using FITC-labeled m7GTP (EDA-m7GTP-ATTO488; Jena Bioscience) as the detection probe. 1 μM of influenza A virus PB2cap was added to a buffer containing 50 mM HEPES (pH 7.2), 0.5 mM EDTA, 100 mM KCl, and 1 mM DTT, followed by the addition of FITC-m7GTP to a final concentration of 20 nM. The mixture was incubated at room temperature for 30 minutes. Subsequently, a small molecule compound dissolved in DMSO was added to the mixture, and incubation was continued at room temperature for another 30 minutes. The total reaction volume was 50 μL, containing 2% DMSO. Finally, fluorescence signals were measured in fluorescence polarization mode using a BioTek SynergyNeo2 multimode microplate reader with excitation at 480 nm and emission at 520 nm. The inhibition rate of the compound was analyzed using nonlinear fitting with GraphPadPrism software to obtain the IC50 of the compound. 50 Values. The experimental results are shown in Table 2.

[0355] Table 2 shows the inhibitory activity of some compounds against the influenza PB2 target.

[0356] Compound <![CDATA[PB2IC 50 ]]> Compound <![CDATA[PB2IC 50 ]]> YYJ-002 0.5998 μM YYJ-003 4.496 μM YYJ-004 29.12 μM YYJ-013 0.6681 μM YYJ-014 2.65 μM YYJ-016 94.73 μM YYJ-017 4.17 μM YYJ-018 0.629 μM YYJ-021 0.2203 μM YYJ-022 0.558 μM YYJ-025 5.671 μM YYJ-026 3.429 μM YYJ-027 6.419 μM YYJ-028 0.532 μM YYJ-029 0.453 μM YYJ-030 2.193 μM Ensitrelvir 0.1311 μM Desicitinib Invalid Pimodivir 0.1472 μM

[0357] The results in Table 2 show that the inhibitory activity of the novel compounds synthesized in this application against the PB2 target is largely comparable to that of pimozidevir and onradivir, which is consistent with their antiviral activity. In particular, compounds YYJ-002, YYJ-021, YYJ-013, YYJ-018, YYJ-022, YYJ-028, and YYJ-029 exhibit PB2 protein inhibition at the nanomolar level. Dicitinib did not show any activity against the PB2 target.

[0358] Example 40

[0359] The test compound inhibited JAK2 enzyme activity in vitro.

[0360] The compound was diluted using DMSO (manufacturer: Hipure Chem, catalog number: D6889). It was then diluted using an Echo 655 (Beckman). Transfer 100 nL of the compound to a 384 reaction plate (PerkinElmer, catalog number: 6007290) using a 655 SYSTEM. Prepare a 2× kinase solution using 1× kinase reaction buffer (50 mM Hepes, 10 mM MgCl2, 0.01% Brij-35, 1 mM EGTA, 2 mM DTT). Transfer 5 μL of JAK2 (0.1 nM, Carna, catalog number: 08-045) solution to the 384 reaction plate. Centrifuge at 1000 rpm for 1 minute and incubate at 25°C for 10 minutes. Prepare a 2× substrate (IGF1Rtide: 0.5 mg / mL) and ATP (1 μM, Promega, catalog number: V915B) mixture using kinase reaction buffer. Add 5 μL of the substrate and ATP mixture to the reaction plate and begin the reaction. Centrifuge at 1000 rpm for 1 minute. Incubate at 25°C for 60 minutes. Transfer 5 μL of LADP-Glo ​​to a 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Transfer 10 μL of the assay solution to a 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Read the chemiluminescence signal using a multi-functional microplate reader (model: PHERAstar FSX, manufacturer: BMG). Set the negative control reading to 0% inhibition rate and the positive control reading to 100% inhibition rate. Calculate the inhibition rate of each test solution, and then perform data analysis using GraphPad8 software. Utilize a nonlinear fitting formula to obtain the IC50 of the compound. 50 (Half-maximal inhibitory concentration), the experimental results are shown in Table 3.

[0361] Table 3 shows the inhibitory activity of the tested compounds against the JAK2 isotype.

[0362]

[0363] Table 3 shows that dicitinib and tofacitinib exhibited JAK2 inhibitory activities of 14.3 nM and 1.6 nM, respectively, with all compounds in this application showing JAK2 target inhibition of less than 0.5 μM. YYJ-002, YYJ-013, YYJ-014, and YYJ-022 showed inhibitory effects on JAK subtypes of less than 0.1 μM, similar to dicitinib. In summary, the compounds in this application can exert dual-target inhibitory effects on JAK and PB2, and exhibit good anti-H1N1 activity, demonstrating both antiviral and autoimmune modulatory effects.

[0364] Example 41

[0365] CCK-8 assay for compound toxicity to MDCK cells

[0366] The cytotoxicity of the test compound to MDCK cells was determined using a CCK-8 assay kit. MDCK cells (2.5 × 10⁶ cells per well) were then cultured. 4 Cells were seeded in 96-well plates and incubated overnight at 37°C and 5% CO2. The culture medium was then removed, and different concentrations of the test compound were added, followed by incubation for 2 days. Afterward, 10 μL of CCK-8 reagent was added to each well, and incubation was continued for 2 hours. The optical density (OD) at 450 nm was measured using a microplate reader, and the 50% cytotoxicity concentration (Cd) of the test compound at 1 h and 2 h was calculated. 50 ).

[0367] Table 4. Cytotoxicity of compounds on MDCK cells (CC) 50

[0368]

[0369] The above results show that the compound of this application exhibits micromolar-level effects on MDCK cells, with weak cytotoxicity and good safety.

[0370] The above description, in conjunction with specific embodiments, provides a further detailed explanation of this application and should not be construed as limiting the specific implementation of this application to these descriptions. Those skilled in the art to which this application pertains can make several simple deductions or substitutions without departing from the concept of this application.

Claims

1. A PB2 / JAK dual-target inhibitor and its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound, wherein the general formula of the PB2 / JAK dual-target inhibitor is shown in formula (I) or formula (II): in, R1 is selected from: -H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C6-C 10 Aryl), C2-C 10 alkenyl, C2-C 10 alkynyl group; R2 is selected from: -(C0-C6 alkylene)-COO(C 0-10 Alkyl), -(C0-C6 alkylene)-O(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-CON(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-CON(C 0-10 Alkyl)(C 0-10 (halogenated alkyl), C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-N(C 0-10 Alkyl)CO(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)CON(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -(C0-C6 alkylene)-S(C 0-10 Alkyl), -(C0-C6 alkylene)-SO(C 0-10 Alkyl), -(C0-C6 alkylene)-SO2(C 0-10 Alkyl), -(C0-C6 alkylene)-SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-OCO(C 0-10 Alkyl), -(C0-C6 alkylene)-CON(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-CO(C 0-10 alkyl); R3 is selected from: C1-C 10 Alkyl, -(C0-C6 alkylene)-O(C 0-10 Alkyl), -H, -(C0-C6 alkylene)-OCO(C 0-10 Alkyl), -(C0-C6 alkylene)-OCO(CHNH2)(C 0-10 Alkyl), -(C0-C6 alkylene)-OCO(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-OCO(C 0-10 Halogenated alkyl), -(C0-C6 alkylene)-OCO(C3-C 10 (halogenated cycloalkyl), C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-N(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)CO(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)CON(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -(C0-C6 alkylene)-S(C 0-10 Alkyl), -(C0-C6 alkylene)-SO(C 0-10 Alkyl), -(C0-C6 alkylene)-SO2(C 0-10 Alkyl), -(C0-C6 alkylene)-SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-COO(C 0-10 alkyl), -(C0-C6 alkylene)-CON(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-CO(C 0-10 alkyl); R4 is selected from: -H, C3-C 10 cycloalkyl, C3-C 10 Halogenated cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups; R5 and R6 are each independently selected from: -H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups; R7 is selected from: -OH, halogen, C1-C6 alkyl; X is selected from: N, -CR8; R8 is selected from: -H, halogen, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl); wherein the H on the alkyl, aryl, cycloalkyl, or heterocyclic group is optionally substituted by one or more groups selected from the following: H, =O, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl); Y represents a halogen; Ring A is a single ring with 4, 5, 6, 7, or 8 elements.

2. The PB2 / JAK dual-target inhibitor as described in claim 1, characterized in that, R1 is selected from: -H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 Cycloalkyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); Preferably, R1 is selected from: -H, C1-C5 alkyl, -(C0-C6 alkylene)-(C3-C5 cycloalkyl), -(C0-C6 alkylene)-(4-6 membered heterocyclic group); particularly preferably, R1 is selected from: -H, C1-C5 alkyl, C3-C5 cycloalkyl, 4-6 membered heterocyclic group; Preferably, R1 is selected from: -H.

3. The PB2 / JAK dual-target inhibitor as described in claim 1, characterized in that, R2 is selected from: -(C0-C6 alkylene)-COO(C 0-10 Alkyl), -(C0-C6 alkylene)-O(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-CON(C 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-CON(C 0-10 Alkyl)(C 0-10 (halogenated alkyl), C1-C 10 alkyl; Preferably, R2 is selected from: -COO(C 0-10 Alkyl), -(C0-C6 alkylene)-O(C 0-10 Alkyl), -(C0-C6 alkylene)-N(C 0-10 Alkyl)(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Haloalkyl), C1-C5 alkyl; Preferably, R2 is selected from:

4. The PB2 / JAK dual-target inhibitor as described in claim 1, characterized in that, R3 is selected from: C1-C 10 Alkyl, -(C0-C6 alkylene)-O(C 0-10 Alkyl), -H, -(C0-C6 alkylene)-OCO(C 0-10 Alkyl), -(C0-C6 alkylene)-OCO(CHNH2)(C 0-10 Alkyl), -(C0-C6 alkylene)-OCO(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-OCO(C 0-10 Halogenated alkyl), -(C0-C6 alkylene)-OCO(C3-C 10 (halogenated cycloalkyl); Preferably, R3 is selected from: C1-C5 alkyl groups, -O(C 0-10 Alkyl), -H, -OCO(C) 0-10 Alkyl group), -OCO(CHNH2)(C 0-10 Alkyl), -OCO (C3-C) 10 cycloalkyl), -OCO(C 0-10 Halogenated alkyl groups), -OCO (C3-C) 10 (halogenated cycloalkyl); Preferably, R3 is selected from:

5. The PB2 / JAK dual-target inhibitor as described in claim 1, characterized in that, R4 is selected from: -H, C3-C 10 cycloalkyl; Preferably, R4 is selected from: -H, 6. The PB2 / JAK dual-target inhibitor as described in claim 1, characterized in that, R5 and R6 are each independently selected from: -H, C1-C 10 alkyl; Preferably, R5 and R6 are each independently selected from: -H, C1-C5 alkyl; Preferably, R5 and R6 are each independently selected from: -H, 7. The PB2 / JAK dual-target inhibitor as described in claim 1, characterized in that, R7 is -OH; Preferably, R8 is -H; Preferably, Y is -F.

8. The PB2 / JAK dual-target inhibitor as described in claim 1, characterized in that, The A ring is a cycloalkylene or heteroalkylene; Preferably, ring A is a cycloalkylene group; Preferably, ring A is a cyclohexylene group; Preferably, ring A is 9. The PB2 / JAK dual-target inhibitor according to any one of claims 1 to 8, characterized in that, The PB2 / JAK dual-target inhibitor comprises at least one of the following structures:

10. A pharmaceutical composition, characterized in that, Includes the PB2 / JAK dual-target inhibitor as described in any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, and includes one or more pharmaceutically acceptable excipients.

11. The use of a PB2 / JAK dual-target inhibitor as described in any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, in the preparation of medicaments for the prevention and / or treatment of diseases related to PB2-dominant viral replication, and / or in medicaments for diseases related to inflammation dominated by the JAK pathway.

12. The application according to claim 11, characterized in that, The diseases associated with PB2-dominated viral replication are influenza virus infection-related diseases; Preferably, the influenza virus includes at least one of influenza A virus, influenza B virus, influenza C virus, and influenza D virus; Preferably, the influenza virus includes at least one of the subtypes H1N1, H3N2, H5N1, H7N7, H7N9, and H9N2; Preferably, the inflammation-related diseases dominated by the JAK pathway include at least one of the following: autoimmune diseases and inflammatory diseases; Preferably, the autoimmune disease includes at least one of the following: psoriatic arthritis, juvenile arthritis, Castellman's disease, systemic lupus erythematosus, Sjögren's syndrome, multiple sclerosis, inflammatory bowel disease, Bechtel disease, myasthenia gravis, type I diabetes, immunoglobulin nephropathy, autoimmune thyroid disease, psoriasis, scleroderma, lupus nephritis, dry eye syndrome, vasculitis, dermatomyositis, polymyositis, and neuromyelitis optica. Preferably, the inflammatory disease includes at least one of the following: viral infection-related inflammation, atopic dermatitis, contact dermatitis, eczema, pruritus, food allergy, bronchial asthma, eosinophilic pneumonia, chronic obstructive pulmonary disease, allergic rhinitis, chronic sinusitis, eosinophilic sinusitis, nasal polyps, allergic conjunctivitis, osteoarthritis, ankylosing spondylitis, Kawasaki disease, Burger's disease, polyarteritis nodosa, and IgA vasculitis; Preferably, the inflammatory disease is influenza virus infection-related inflammation.

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