Difluoromethoxy phenyl PDE4 inhibitor and application thereof

Abstract

The invention discloses a difluoromethoxy phenyl PDE4 inhibitor and application thereof. The compound has the effects of resisting inflammation, treating psoriasis, treating lung injury, treating chronic obstructive pulmonary disease and the like.

Description

Technical Field

[0001] The present application belongs to the field of medical technology, and specifically relates to a difluoromethoxyphenyl PDE4 inhibitor, which has the effects of anti-inflammatory, treatment of psoriasis, treatment of lung injury, and treatment of chronic obstructive pulmonary disease. Background Art

[0002] Inflammation is a common and frequently occurring disease that threatens human health. There are many causes of inflammation, including bacteria, viruses, rickettsia, mycoplasma, fungi, etc. Inflammation caused by biological pathogens is also called infection. The human body has a complex structure, and different parts of the body will have different degrees of inflammation. For example, pneumonia, gastroenteritis, hepatitis, appendicitis, pancreatitis, pharyngitis, prostatitis, vaginitis, periarthritis of the shoulder, otitis media, etc. are representative.

[0003] Phosphodiesterase (PDE) is a hydrolase that hydrolyzes two second messenger cyclic nucleotides in cells - cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) - into biologically inactive linear nucleotides. Phosphodiesterase (PDE) contains 11 subfamilies and plays a key role in regulating cell function by metabolizing the 3′-cyclic phosphate bond of cAMP and cGMP. PDE4 is a subtype of PDE.

[0004] PDE4 is a cAMP-specific enzyme that converts the second messenger cAMP into 5'-AMP. On the other hand, cAMP has a great influence on multiple functions of inflammatory cell pathways. Increased intracellular cAMP levels inhibit T cell activation, regulate the function of macrophages and neutrophils, and cause bronchodilation. Increasing intracellular cAMP levels can also inhibit fibrosis, the release of inflammatory cytokines and chemokines, the biological activity of proteases, the generation of biologically active oxygen systems, and the production of arachidonic acid metabolites. Summary of the invention

[0005] One or more embodiments of the present application provide a compound of Formula I or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof.

[0006]

[0007] in

[0008] R 1 and R 2 Each independently And R 1 and R 2 Different

[0009] X 1 , X2 , X 3 , X 4 , X 5 When present, each is independently C or N, at least two of which are N;

[0010] R 3 When present, it is C6-14 aryl, five to fourteen membered heteroaryl, C6-10 cycloalkyl, five to fourteen membered heterocyclyl, C1-C6 alkyl, C1-C6 cycloalkyl, halogen, cyano; optionally, the C6-14 aryl, five to fourteen membered heteroaryl, C6-10 cycloalkyl, or five to fourteen membered heterocyclyl is substituted by one or more halogen, halo-substituted C1-C6 alkyl, carbonyl, C1-C6 alkyl, C1-C6 alkoxy, carboxyl, cyano, hydroxyl, carbonyl, phenyl-SO 2 -, nitro, C1-C6 alkyloxycarbonyl; the five to fourteen membered heteroaryl or five to fourteen membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S; preferably, the halogen is F, Cl, Br or I;

[0011] R 4 When present, it is C6-14 aryl or five to fourteen membered heteroaryl; optionally, the C6-14 aryl or five to fourteen membered heteroaryl is substituted by one or more substituents selected from halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and C1-C6 alkoxy; the five to fourteen membered heteroaryl or five to fourteen membered heterocyclyl contains 1-3 heteroatoms selected from N, O and S; preferably, the halogen is F, Cl, Br or I;

[0012] L, when present, is NH or O; preferably NH;

[0013] m, when present, is 1 or 2;

[0014] n, when present, is 1 or 2;

[0015] p is 0, 1, or 2 when present;

[0016] q is 0, 1, or 2 when present;

[0017] do not exist simultaneously;

[0018] Each dashed line independently represents the presence or absence of a bond.

[0019] In one or more embodiments, R 1 for R 2 for

[0020] In one or more embodiments, R 1 for R2 for

[0021] In one or more embodiments, R 1 for R 2 for

[0022] In one or more embodiments, X 1 NH, X 2 N, X 3 C, X 4 and X 5 is CH, n is 1, and m is 2.

[0023] In one or more embodiments, X 1 , X 3 and X 5 N, X 2 C, X 4 is CH, n is 2, and m is 1.

[0024] In one or more embodiments, X 1 , X 2 , X 3 , X 4 N, X 5 is CH, n is 1, and m is 2.

[0025] In one or more embodiments, X 1 NH, X 2 , X 3 N, X 4 , X 5 Does not exist, n is 1, m is 0.

[0026] In one or more embodiments, R 3 When present, it is C6-10 aryl, five to ten membered heteroaryl, C6-10 cycloalkyl, five to ten membered heterocyclyl, C1-C4 alkyl, or C1-C4 cycloalkyl.

[0027] In one or more embodiments, the C6-10 aryl, five- to ten-membered heteroaryl, C6-10 cycloalkyl, or five- to ten-membered heterocyclic group is substituted by 1, 2, or 3 halogen, halogenated C1-C4 alkyl, carbonyl, C1-C4 alkyl, C1-C4 alkoxy, carboxyl, cyano, hydroxyl, carbonyl, phenyl-SO 2 -, nitro, or a C1-C4 alkyloxycarbonyl substituent.

[0028] In one or more embodiments, the five- to ten-membered heteroaryl or five- to ten-membered heterocyclyl contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0029] In one or more embodiments, the halogen is F, Cl, or Br.

[0030] In one or more embodiments, R 4 When present it is C6-10 aryl or a five to ten membered heteroaryl.

[0031] In one or more embodiments, the C6-10 aryl or five- to ten-membered heteroaryl is substituted with one or more substituents selected from halogen and C1-C4 alkyl.

[0032] In one or more embodiments, the five- to fourteen-membered heteroaryl or five- to fourteen-membered heterocyclyl contains one or two heteroatoms selected from N, O and S.

[0033] In one or more embodiments, the halogen is F, Cl, or Br.

[0034] In one or more embodiments, Formula I is Among them, R 1 Each independently R 2 Each independently R 3 Each independently

[0035]

[0036] In one or more embodiments, Formula I is Where R 1 Each independently R 2 Each independently R 3 Each independently

[0037]

[0038] In one or more embodiments, Formula I is Where R 1 Each independently R 2 Each independently R 3 Each independently

[0039]

[0040] In one or more embodiments, Formula I is R 1 Each independently R 2 Each independently R 3 Each independently

[0041]

[0042] In one or more embodiments, Formula I is Where R 1 Each independently R 2 Each independently R 3 Each independently

[0043] In one or more embodiments, Formula I is R 1 Each independently R 2 Each independently R 3 Each independently

[0044] In one or more embodiments, I is R 1 for R 2 for R 4 for

[0045]

[0046] In one or more embodiments, the cocrystal or deuterated compound of the present application:

[0047]

[0048]

[0049]

[0050]

[0051] One or more embodiments of the present application provide an intermediate compound for preparing the compound of the present application, which is the following compound:

[0052]

[0053] One or more embodiments of the present application provide a method for preparing the compound of the present application, which comprises (1)

[0055]

[0056] a) reacting the compound of formula I with the compound of formula II at 60°C-100°C for 10-14 hours;

[0057] b) subjecting the product compound of formula III obtained in step a) to a hydrolysis reaction at 20° C.-50° C. for 2-6 hours;

[0058] c) reacting the product compound of formula IV obtained in step b) with R 3 -NH 2 React at 20°C-50°C for 10-14 hours to obtain a compound of formula V; (2)

[0060]

[0061] d) reacting the compound of formula VI with the compound of formula VII at 60° C.-100° C. with stirring for 10-14 hours;

[0062] e) stirring the product compound of formula VIII obtained in step d) at 60° C.-100° C. for hydrolysis reaction for 2-6 hours;

[0063] f) reacting the product compound of formula IX obtained in step e) with R 3 -NH 2 The reaction is stirred at 20°C-50°C for 10-14 hours to obtain a compound of formula X; (3)

[0065]

[0066] g) stirring the compound of formula XI and the compound of formula XII at 20°C-50°C for 0.5-1 hour, adding the compound of formula XIII, and reacting at 80°C-120°C for 1-3 hours;

[0067] h) reacting the product compound of formula XIV obtained in step g) with the compound of formula XV at 80° C.-120° C. for 1-3 hours;

[0068] i) reacting the compound of formula XVI obtained in step h) with R 3 -B(OH)2 The reaction was carried out at 80°C-120°C for 4-8 hours to obtain a compound of formula XVII;

[0069] or (4)

[0071]

[0072] j) stirring the compound of formula XI and the compound of formula XII at 20°C-50°C for 0.5-1 hour, adding the compound of formula XIII, and reacting at 80°C-120°C for 1-3 hours;

[0073] k) reacting the product compound of formula XIV obtained in step g) with R 4 COOH is stirred at 20°C-50°C for 1-3 hours to obtain a compound of formula XVIII;

[0074] in

[0075] R 1 , R 2 , R 3 , R 4 As described above.

[0076] One or more embodiments of the present application provide a pharmaceutical composition comprising a compound of the present application and a pharmaceutically acceptable auxiliary material or excipient.

[0077] One or more embodiments of the present application provide use of the compound of the present application or the pharmaceutical composition of the present application in the preparation of a medicament for preventing and / or treating inflammatory diseases, respiratory diseases, skin diseases, or immune system diseases.

[0078] One or more embodiments of the present application provide use of the compound of the present application or the pharmaceutical composition of the present application in the preparation of a drug or a PDE4 inhibitor for preventing and / or treating a PDE4-mediated disease.

[0079] One or more embodiments of the present application provide a compound of the present application for use as a medicament.

[0080] One or more embodiments of the present application provide the pharmaceutical composition of the present application, which is used as a medicament.

[0081] One or more embodiments of the present application provide a compound or composition of the present application for preventing and / or treating inflammatory diseases, respiratory diseases, skin diseases, or immune system diseases.

[0082] One or more embodiments of the present application provide a compound or composition of the present application for preventing and / or treating a PDE4-mediated disease.

[0083] One or more embodiments of the present application provide a compound or composition of the present application for inhibiting PDE4.

[0084] One or more embodiments of the present application provide a method for preventing and / or treating inflammatory diseases, respiratory diseases, skin diseases, or immune system diseases, which comprises administering a compound or composition of the present application to a subject in need thereof.

[0085] One or more embodiments of the present application provide a method for preventing and / or treating a PDE4-mediated disease, which comprises administering a compound or composition of the present application to a subject in need thereof.

[0086] One or more embodiments of the present application provide a method for inhibiting PDE4, which comprises administering a compound or composition of the present application to a subject in need thereof.

[0087] In one or more embodiments, the inflammatory disease is an inflammatory skin disease.

[0088] In one or more embodiments, the respiratory disease is chronic obstructive pulmonary disease, lung injury or asthma.

[0089] In one or more embodiments, the skin disease is psoriasis or atopic dermatitis.

[0090] In one or more embodiments, the immune system disease is systemic lupus erythematosus or rheumatoid arthritis.

[0091] The following is an explanation of the terms used in the technical solution of the present application. As used in the specification and the appended claims, unless otherwise specifically stated, the terms of the present application have the following meanings:

[0092] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0093] The term "amino" refers to -NH 2 .

[0094] The term "hydroxy" refers to -OH.

[0095] "Alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.

[0096] "Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy and cyclobutyloxy. The definition of alkyl is the same as that of "alkyl" described above.

[0097] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be, for example, a monocyclic ring of 6 to 8 carbon atoms (e.g., 6, 7, 8 carbon atoms), a bicyclic ring of 6 to 12 carbon atoms (e.g., 6, 7, 8, 9, 10, 11, 12 carbon atoms), or a tricyclic ring system of 10 to 14 carbon atoms (e.g., 10, 11, 12, 13, 14 carbon atoms), which can be a bridged ring or a spirocyclic ring, and non-limiting examples include phenyl and naphthyl. The aryl group can be optionally further substituted by one or more substituents.

[0098] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be, for example, a five- to eight-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a five- to fourteen-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14-membered) bicyclic ring, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably a five- to eight-membered heteroaryl, and 1 to 4 (e.g., 1, 2, 3, 4) N, S selectively substituted in the ring of the heteroaryl can be oxidized to various oxidation states. The heteroaryl can be attached to a heteroatom or a carbon atom, and the heteroaryl can be a bridged ring or a spirocyclic ring, and non-limiting examples include cyclic pyridyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridinyl, pyrrolopyridinyl. The heteroaryl group is optionally further substituted with one or more substituents.

[0099] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated non-aromatic heterocyclic ring, which can be, for example, a 5- to 10-membered (e.g., 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 14-membered (e.g., 10, 11, 12, 13, 14-membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S optionally substituted in the ring of the "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; the "heterocyclyl" or "heterocycle" can be attached to a heteroatom or a carbon atom; the "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of “heterocyclyl” or “heterocycle” include oxirane, oxirane, aziridine, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxetanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, pyridinyl, piperidinyl, piperidinyl, homopiperidinyl, pyrid ... pyranyl, thiophene, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl oxazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3 .1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The "heterocyclyl" or "heterocycle" may be optionally further substituted by one or more substituents.

[0100] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, which can be, for example, a monocyclic, bicyclic or polycyclic ring of 6 to 10 carbon atoms (e.g., 6, 7, 8, 9, 10 carbon atoms), preferably 6 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. When the cycloalkyl is substituted, it can be optionally further substituted by one or more substituents.

[0101] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0102] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0103] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0104] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0105] "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

[0106] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

[0107] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0108] "Optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group.

[0109] In one or more embodiments, Formula I is Where R 5 for

[0110] In one or more embodiments, Formula I is Where R 6 for

[0111] In one or more embodiments, Formula I is Where R 7 for

[0112] In one or more embodiments, Formula I is Where R 8 for

[0113] In one or more embodiments, Formula I is Where R 9 for

[0114] In one or more embodiments, Formula I is Where R 1 0 is

[0115] In one or more embodiments, Formula I is Where R 11 for

[0116]

[0117] In one or more embodiments, Formula I is Where R 12 for

[0118]

[0119] In one or more embodiments, Formula I is Where R 13 for

[0120] BRIEF DESCRIPTION OF THE DRAWINGS

[0121] Figure 1It shows the phenotypic manifestation of the mouse back skin in Activity Example 6.

[0122] Figure 2 The PASI and body weight changes of mice in Activity Example 6 are shown.

[0123] Figure 3 The following are pathological pictures of mouse skin in Activity Example 6.

[0124] Figure 4 This is a picture showing immunohistochemical staining of mouse back skin with Ki-67 antibody in Example 6.

[0125] Figure 5 The results show that compound A5 in Example 6 has a down-regulating effect on IL-1β, IL-17A and TNF-α inflammatory factors in mouse skin tissue.

[0126] Figure 6 The COPD model in mice and the changes in body weight in Activity Example 7 are shown.

[0127] Figure 7 It represents the lung function evaluation index in Active Example 7.

[0128] Figure 8 Shows the pathological picture of lung tissue in Active Example 7.

[0129] Fig. 9 It indicates the inhibitory effect on inflammatory cells in bronchoalveolar lavage fluid and inflammatory factors IL-8 (CXCL1 / KC / N51), TNF-α, and MMP9 in the mouse COPD model in Example 7.

[0130] Fig.10 It indicates the inhibitory effect on inflammatory cells in the alveolar lavage fluid and inflammatory factors IL-6, IL-1β, and TNF-α in the mouse ALI model in Example 8.

[0131] Fig.11 This is a picture showing HE staining of lung tissue in Example 8.

[0132] Fig.12 This is a Masson's staining micrograph of lung tissue from Example 8. Specific embodiments

[0133] The present invention will be further described below in conjunction with specific embodiments. These embodiments are only for the purpose of explanation and are not intended to limit the scope and essence of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work are within the scope of protection of the present invention.

[0134] Example 1 Synthesis of Compounds A1-A28

[0135] (1) Synthesis of Compound 2

[0136]

[0137] Weigh 3g of compound 3,4-dihydroxybenzaldehyde (21.72mmol, 1.0equiv.) and 6.91g of sodium carbonate (65.16mmol, 3.0equiv.), dissolve in 30mLN,N-dimethylformamide (DMF), and finally add 3.44g of ethyl difluorochloroacetate (21.72mmol, 1.0equiv.), react at 80°C for 8 hours, detect the reaction of the raw material by TLC, and quench the reaction by adding water. Use ethyl acetate to extract 3 times, and wash the organic phase with saturated sodium chloride solution. Concentrate the organic phase and obtain 1.4g of white solid product (compound 2) by rapid column chromatography, with a yield of 34%.

[0138] The obtained compound 2 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (500 MHz, CDCl 3 )δ9.90(s,1H),7.53(d,J=2.0Hz,1H),7.44(dd,J=8.5,2.0Hz,1H),7.26(d,J=8.5Hz,1H),6.66(t,J=73.5Hz,1H).ESI-HRMS m / z: calculated value is C 8 H 6 0 3 F 2 Na + [M+Na] + , 211.0177; the measured value is 211.0166.

[0139] (2) Synthesis of compound 3:

[0140]

[0141] Weigh 2.1g of compound 2 (11.16mmol, 1.0equiv.), add 3.09g of potassium carbonate (22.32mmol, 2.0equiv.), add 20mL of N,N-dimethylformamide, and finally add 2.26g of bromomethylcyclopropane (16.74mmol, 1.5equiv.), react at 80°C for 8 hours, detect the complete reaction of the raw materials by TLC, and quench the reaction by adding water. Use ethyl acetate to extract 3 times, and wash the organic phase with saturated sodium chloride solution. Concentrate the organic phase and obtain 2.3g of yellow oily product (compound 3) by rapid column chromatography, with a yield of 85%.

[0142] The obtained compound 3 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (500 MHz, DMSO-d 6 )δ9.94(s,1H),7.59-7.54(m,2H),7.39(d,J=8.0Hz,1H),7.28(t,J=73.5Hz,1H),3.98(d,J=7.0Hz,2H),1.30-1.21(m,1H),0.61-0.55(m,2H),0.39-0.33(m,2H).ESI-MS m / z: calculated value is C 12 H 13 0 3 F 2 + [M+H] + , 243.1; the measured value is 243.1.

[0143] (3) Synthesis of compound 4:

[0144]

[0145] 1.50 g of compound 3 (6.19 mmol, 1.0 equiv.) was dissolved in 15 mL of DMF solution, and then 1.03 g of methyl 2,3-diaminobenzoate (6.19 mmol, 1.0 equiv.) and 1.41 g of sodium metabisulfite (7.43 mmol, 1.2 equiv.) were added, and the mixture was heated to 80° C. for 12 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain 1.51 g of compound 4 by flash column chromatography, with a yield of 62%.

[0146] The obtained compound 4 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (500 MHz, CDCl 3 ) δ10.71 (br, 1H), 7.87 (d, J = 8.0Hz, 1H), 7.76 (d, J = 7.5Hz, 1H), 7.59 (s, 1H), 7.34 (d, J = 8.5Hz, 1H), 7.19 (t, J = 8.5Hz, 1H), 7.09 (d, J=8.5Hz, 1H), 6.65 (t, J=75.0Hz, 1H), 3.88 (s, 3H), 3.82 (d, J=7.0Hz, 2H), 1.23-1.20 (m, 1H), 0.59-0.55 (m, 2H), 0.29-0.26 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ165.8, 152.6, 149.9, 144.6, 141.4, 134.5, 127.7 (2×C), 124.6, 124.4, 121.8, 121.0, 120.5, 116.7 (t, J=256.5 Hz), 113.4, 73.3, 52.2, 10.1, 3.1 (2×C). ESI-MS m / z: calculated value is C 20 H 19 O 4 N 2 F 2 + [M+H] + , 389.1; the measured value is 389.1.

[0147] (4) Synthesis of Compound 5:

[0148]

[0149] 1.97 g of compound 4 (5.07 mmol, 1.0 equiv.) was dissolved in 20 mL of a mixed solvent of ethanol and water in a volume ratio of 1:1, and then 2.03 g of sodium hydroxide (50.7 mmol, 10.0 equiv.) was added, and the mixture was heated to 50°C for reaction, and monitored by thin layer chromatography. After the reaction was completed, ethanol was removed by rotary evaporation, the temperature was lowered to room temperature, the pH was adjusted to 6 with dilute hydrochloric acid, and the solid was filtered and dried to obtain 1.65 g of compound 5, with a yield of 87%.

[0150] The obtained compound 5 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (400 MHz, CD 3 OD) δ 7.89-7.84 (m, 2H), 7.76-7.72 (m, 2H), 7.30-7.26 (m, 2H), 6.87 (t, J = 75.2 Hz, 1H), 4.06 (d, J = 6.8 Hz, 2H), 1.42-1.35 (m, 1H), 0.69-0.65 (m, 2H), 0.43-0.41 (m, 2H), NH (not observed), OH (not observed). ESI-HRMS m / z: calculated value is C 19 H 17 04N 2 F 2 +[M+H] + , 375.1151; the measured value is 375.1160.

[0151] (5) Synthesis of Compounds A1-A28:

[0152]

[0153] 50 mg of compound 5 (0.13 mmol, 1.0 equiv.) was dissolved in 1 mL of DMF, and then N, N-diisopropylethylamine (DIPEA, 0.26 mmol, 2.0 equiv.) and O-(7-azabenzotriazole-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU, 0.13 mmol, 1.0 equiv.) were added, and finally an amine reagent (0.16 mmol, 1.2 equiv.) was added, and the mixture was reacted at room temperature for 12 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the organic phase was concentrated and subjected to flash column chromatography to obtain compounds A1-A28.

[0154] The compounds A1-A28 are as follows:

[0155]

[0156] Example 2 Synthesis of Compounds B1-B4

[0157] (1) Synthesis of Compound 6:

[0158]

[0159] 820 mg of compound 3 (3.38 mmol, 1.0 equiv.) was dissolved in 10 mL of DMF solution, and then 560 mg of methyl 3,4-diaminobenzoate (3.38 mmol, 1.0 equiv.) and 770 mg of sodium pyrosulfite (4.06 mmol, 1.2 equiv.) were added, and the mixture was heated to 80°C for 12 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the organic phase was concentrated. 930 mg of compound 6 was obtained by flash column chromatography, with a yield of 71%.

[0160] The obtained compound 6 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (400 MHz, DMSO-d 6)δ13.27 (br, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.68 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.21 (t, J = 74.0 Hz, 1H), 4.02 (d, J = 7.2 Hz, 2H), 3.87 (s, 3H), 1.35-1.28 (m, 1H), 0.64-0.59 (m, 2H), 0.43-0.39 (m, 2H). ESI-HRMS m / z: calculated value is C 20 H 19 04N 2 F 2 + [M+H] + , 389.1307; the measured value is 389.1323.

[0161] (2) Synthesis of Compound 7:

[0162]

[0163] 1.0 g of compound 6 (2.57 mmol, 1.0 equiv.) was dissolved in 10 mL of a mixed solvent of ethanol and water in a volume ratio of 1:1, and then 1.03 g of sodium hydroxide (25.7 mmol, 10.0 equiv.) was added, and the mixture was heated to 50°C for reaction, and monitored by thin layer chromatography. After the reaction was completed, ethanol was removed by rotary evaporation, the temperature was lowered to room temperature, the pH was adjusted to 6 with dilute hydrochloric acid, the precipitated solid was filtered, and dried to obtain 610 mg of compound 7, with a yield of 63%.

[0164] The obtained compound 7 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (500 MHz, DMSO-d 6 )δ8.20 (d, J=1.5Hz, 1H), 7.95 (d, J=2.0Hz, 1H), 7.85 (dd, J=8.5, 1.5Hz, 1H), 7.82 (dd, J=8.5, 2.0Hz, 1H), 7.66 (d, J=8.5Hz, 1H), 7. 36 (d, J=8.5Hz, 1H), 7.19 (t, J=74.5Hz, 1H), 4.03 (d, J=7.0Hz, 2H), 1.34-1.28 (m, 1H), 0.63-0.58 (m, 2H), 0.42-0.38 (m, 2H), OH (not observed), NH (not observed).ESI-HRMS m / z: The calculated value is C 19 H 17 04N2 F 2 + [M+H] + , 375.1151; the measured value is 375.1164.

[0165] (3) Synthesis of Compounds B1-B4:

[0166]

[0167] 50 mg of compound 7 (0.13 mmol, 1.0 equiv.) was dissolved in 1 mL of DMF, and then N, N-diisopropylethylamine (DIPEA, 0.26 mmol, 2.0 equiv.) and O-(7-azabenzotriazole-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU, 0.13 mmol, 1.0 equiv.) were added, and finally an amine reagent (0.16 mmol, 1.2 equiv.) was added, and the mixture was reacted at room temperature for 12 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the organic phase was concentrated and subjected to rapid column chromatography to obtain compounds B1-B4.

[0168] The compounds B1-B4 are as follows:

[0169]

[0170] Example 3 Synthesis of C series compounds

[0171] (1) Synthesis of Compound 8:

[0172]

[0173] 606 mg of compound 3 (2.50 mmol, 1.0 equiv.) was dissolved in 6 mL of DMF solution, and then 468 mg of 4-bromo-o-phenylenediamine (2.50 mmol, 1.0 equiv.) and 585 mg of sodium pyrosulfite (3.08 mmol, 1.2 equiv.) were added, and the mixture was heated to 80°C for 12 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the organic phase was concentrated. After flash column chromatography, 603 mg of compound 8 was obtained, with a yield of 59%.

[0174] The obtained compound 8 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (500 MHz, DMSO-d 6)δ13.08 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.81-7.74 (m, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.37-7.33 (m, 2H), 7.19 (s, 1H), 4.02 (d, J = 7.0 Hz, 2H), 1.35-1.28 (m, 1H), 0.63-0.59 (m, 2H), 0.42-0.39 (m, 2H). ESI-HRMS m / z: calculated value is C 18 H 16 0 2 N 2 F 2 Br + [M+H] + , 409.0358; the measured value is 409.0357.

[0175] (2) Synthesis of Compounds C1-C3:

[0176]

[0177] 100 mg of compound 8 (0.24 mmol, 1.0 equiv.) was dissolved in a mixed solvent of 2 mL of DMF and 0.5 mL of water, and then a boric acid reagent (0.29 mmol, 1.2 equiv.) was added, 0.05 equiv. of [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride and 83 mg of potassium carbonate (0.6 mmol, 2.5 equiv.) were added to the above solution, heated to 95° C. for 12 h, and monitored by thin layer chromatography. After the reaction was completed, water was added to quench, extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, the organic phase was concentrated, and compounds C1-C3 were obtained by flash column chromatography.

[0178] The compounds C1-C3 are as follows:

[0179]

[0180] Example 4 Synthesis of D series compounds

[0181] (1) Synthesis of compound 10:

[0182]

[0183] 1.0 g of compound 9 (6.57 mmol, 1.0 equiv.) was dissolved in 10 mL of DMF solution, and then 1.82 g of potassium carbonate (13.14 mmol, 2.0 equiv.) and 1.33 g of bromomethylcyclopropane (9.86 mmol, 1.5 equiv.) were added, and the mixture was heated to 80° C. for 8 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the organic phase was concentrated. 1.28 g of compound 10 was obtained by flash column chromatography with a yield of 95%.

[0184] The obtained compound 10 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (400 MHz, DMSO-d 6 )δ9.81(s,1H),7.53(dd,J=8.4,2.0Hz,1H),7.33(d,J=2.0Hz,1H),7.16(d,J=8.4Hz,1H),3.88(s,3H),3.85(d,J=7.2Hz,2H),1.26-1.18(m,1H),0.59-0.55(m,2H),0.34-0.31(m,2H).ESI-MS m / z: calculated value is C 12 H 15 0 3 +[M+H] + , 207.1; the measured value is 207.1.

[0185] (2) Synthesis of compound 11:

[0186]

[0187] 1.0 g of compound 10 (4.84 mmol, 1.0 equiv.) was dissolved in 10 mL of DMF solution, and then 810 mg of methyl 3,4-diaminobenzoate (4.84 mmol, 1.0 equiv.) and 1.1 g of sodium metabisulfite (5.81 mmol, 1.2 equiv.) were added, and the mixture was heated to 80° C. for 12 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the organic phase was concentrated. 1.30 g of compound 11 was obtained by flash column chromatography with a yield of 76%.

[0188] The obtained compound 11 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6)δ8.16 (d, J=1.5 Hz, 1H), 7.87-7.81 (m, 2H), 7.77 (dd, J=8.5, 2.0 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 3.91 (s, 3H), 3.89 (d, J=7.0 Hz, 2H), 3.87 (s, 3H), 1.30-1.21 (m, 1H), 0.62-0.56 (m, 2H), 0.37-0.31 (m, 2H). ESI-MS m / z: calculated value is C 20 H 21 O 4 N 2 + [M+H] + , 353.1; the measured value is 353.1.

[0189] (3) Synthesis of compound 12:

[0190]

[0191] 768 mg of compound 11 (2.18 mmol, 1.0 equiv.) was dissolved in 10 mL of a mixed solvent of ethanol and water in a volume ratio of 1:1, and then 872 mg of sodium hydroxide (21.79 mmol, 10.0 equiv.) was added, and the mixture was heated to 50°C for reaction, and monitored by thin layer chromatography. After the reaction was completed, ethanol was removed by rotary evaporation, the temperature was lowered to room temperature, the pH was adjusted to 6 with dilute hydrochloric acid, the precipitated solid was filtered, and dried to obtain 693 mg of compound 12, with a yield of 94%.

[0192] The obtained compound 12 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6 )δ8.24(s,1H),8.03-8.01(m,1H),7.95-7.93(m,2H),7.81(d,J=8.5Hz,1H),7.28(d,J=9.5Hz,1H),3.97(d,J=7.0Hz,2H),3.91(s,3H),1.35-1.29(m,1H),0.63-0.60(m,2H),0.38-0.36(m,2H),OH(not observed),NH(not observed).ESI-HRMS m / z:calcd for C 19 H 19 O 4 N 2 + [M+H] +, 339.1339; the measured value is 339.1344.

[0193] (4) Synthesis of Compounds D1-D3:

[0194]

[0195] 50 mg of compound 12 (0.15 mmol, 1.0 equiv.) was dissolved in 1 mL of DMF, and then N, N-diisopropylethylamine (DIPEA, 0.30 mmol, 2.0 equiv.) and O-(7-azabenzotriazole-1-yl)-NN, N', N'-tetramethyluronium hexafluorophosphate (HATU, 0.15 mmol, 1.0 equiv.) were added, and finally an amine reagent (0.18 mmol, 1.2 equiv.) was added, and the mixture was reacted at room temperature for 12 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the organic phase was concentrated and subjected to flash column chromatography to obtain compounds D1-D3.

[0196] The compounds D1-D3 are as follows:

[0197]

[0198] Example 5 Synthesis of E series compounds

[0199] (1) Synthesis of compound 13:

[0200]

[0201] 1.0 g of compound 1 (7.24 mmol, 1.0 equiv.) was dissolved in 10 mL of DMF solvent, and then 0.72 g of sodium hydroxide (18.10 mmol, 2-5 equiv.) and 2.52 g of ethyl difluorochloroacetate (15.93 mmol, 2.2 equiv.) were added, and the mixture was heated to 80° C. for 12 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the organic phase was concentrated. 0.93 g of compound 13 was obtained by flash column chromatography with a yield of 54%.

[0202] The obtained compound 13 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (400 MHz, CDCl 3)δ9.91(s,1H),7.75-7.73(m,2H),7.39(d,J=8.8Hz,1H),6.64(t,J=72.8Hz,1H),6.59(t,J=72.8Hz,1H).ESI-MS m / z: calculated value is C 9 H 7 0 3 F 4 + [M+H] + , 239.0; the measured value is 239.0.

[0203] (2) Synthesis of compound 14:

[0204]

[0205] 500 mg of compound 13 (2.10 mmol, 1.0 equiv.) was dissolved in 5 mL of DMF solution, and then 349 mg of methyl 2,3-diaminobenzoate (2.10 mmol, 1.0 equiv.) and 439 mg of sodium metabisulfite (2.31 mmol, 1.1 equiv.) were added, and the mixture was heated to 80°C for 12 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride aqueous solution, and the ethyl acetate layer was dried with anhydrous sodium sulfate. The organic phase was concentrated and flash column chromatography was performed to obtain 405 mg of compound 14 with a yield of 50%.

[0206] The obtained compound 14 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (400 MHz, CDCl 3 )δ10.75 (br, 1H), 8.04 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.93-7.91 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 6.65 (t, J = 73.2 Hz, 1H), 6.62 (t, J = 72.8 Hz, 1H), 4.03 (s, 3H). ESI-HRMS m / z: calculated value is C 17 H 13 O 4 N 2 F 4 + [M+H] + , 385.0806; the measured value is 385.0801.

[0207] (3) Synthesis of compound 15:

[0208]

[0209] 200 mg of compound 14 (0.52 mmol, 1.0 equiv.) was dissolved in 4 mL of a mixed solvent of ethanol and water in a volume ratio of 1:1, and then 40 mg of sodium hydroxide (1.04 mmol, 2.0 equiv.) was added, and the mixture was heated to 50°C for reaction, and monitored by thin layer chromatography. After the reaction was completed, ethanol was removed by rotary evaporation, the temperature was lowered to room temperature, the pH was adjusted to 6 with dilute hydrochloric acid, the precipitated solid was filtered, and dried to obtain 174 mg of compound 15, with a yield of 90%.

[0210] The obtained compound 15 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry. 1 H NMR (500 MHz, DMSO-d 6 )δ12.57 (br, 1H), 8.33 (s, 1H), 8.30 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.84 (dd, J = 7.5, 1.0 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.49-7.19 (m, 3H), NH (not observed). ESI-HRMS m / z: calculated value is C 16 H 11 O 4 N 2 F 4 + [M+H] + , 371.0649; the measured value is 371.0652.

[0211] (4) Synthesis of Compounds E1-E13:

[0212]

[0213] 50 mg of compound 15 (0.14 mmol, 1.0 equiv.) was dissolved in 1 mL of DMF, and then N, N-diisopropylethylamine (DIPEA, 0.28 mmol, 2.0 equiv.) and O-(7-azabenzotriazole-1-yl)-NN, N', N'-tetramethyluronium hexafluorophosphate (HATU, 0.14 mmol, 1.0 equiv.) were added, and finally an amine reagent (0.17 mmol, 1.2 equiv.) was added, and the mixture was reacted at room temperature for 12 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate, and the organic phase was concentrated and subjected to flash column chromatography to obtain compounds E1-E13.

[0214] The compounds E1-E13 are as follows:

[0215]

[0216] Example 6 Synthesis of F series compounds

[0217] (1) Synthesis of compound 17:

[0218]

[0219] The synthesis steps refer to the synthesis of compound 2. 3,4-Dihydroxyacetophenone and ethyl difluorochloroacetate are reacted to obtain a white solid product with a yield of 36%.

[0220] The obtained compound 17 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (600 MHz, CDCl 3 )δ7.63 (d, J=1.8 Hz, 1H), 7.51 (dd, J=9.0, 2.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.64 (t, J=73.2 Hz, 1H), 6.33 (br, 1H), 2.58 (s, 3H). ESI-HRMS m / z: calculated value is C 9 H 8 0 3 F 2 Na + [M+Na] + , 225.0334; the measured value is 225.0311;

[0221] (2) Synthesis of Compound 18:

[0222]

[0223] The synthesis steps were similar to those of compound 3, and 2.2 g of a yellow oily product was obtained with a yield of 56%.

[0224] The obtained compound 18 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (400 MHz, DMSO-d 6 )δ7.87 (dd, J=8.4, 2.0Hz, 1H), 7.69 (d, J=2.0Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 7.17 (t, J=74.4Hz, 1 H), 3.99 (d, J=7.2Hz, 2H), 2.53 (s, 3H), 1.30-1.23 (m, 1H), 0.65-0.52 (m, 2H), 0.43-0.27 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ196.8, 149.6, 143.7, 134.7, 121.8, 120.0, 116.4 (t, J = 257.0 Hz), 113.2, 73.2, 26.7, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 13 H 14 : 3 F 2 Na + [M+Na] + , 279.0803; the measured value is 279.0808.

[0225] (3) Synthesis of Compound 19:

[0226]

[0227] 2.0 g of compound 18 (7.81 mmol, 1.0 equiv.) and 1.13 g of N, N-dimethylformamide dimethyl acetal (9.37 mmol, 1.2 equiv.) were weighed and put into a reaction bottle, 2 mL of N, N-dimethylformamide was added, and the mixture was stirred at 120°C for 12 hours. When the raw material was no longer reduced, water was added, and the mixture was extracted with ethyl acetate three times. The organic phase was washed with water once, washed with a saturated sodium chloride aqueous solution, and dried with anhydrous sodium sulfate. The organic phase was concentrated and flash column chromatography was performed to obtain 1.8 g of compound 19, with a yield of 74%.

[0228] The obtained compound 19 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (400 MHz, DMSO-d 6 )δ7.70 (d, J=12.4Hz, 1H), 7.57-7.47 (m, 2H), 7.19 (d, J=8.0Hz, 1H), 7.16 (t, J=74.4Hz, 1H), 5.81 (d, J=12.4Hz, 1H), 3.94 (d, J=6.8Hz, 2H), 3.14 (s, 3H), 2.92 (s, 3H), 1.29-1.19 (m, 1H), 0.61-0.49 (m, 2H), 0.42-0.30 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ184.4, 154.4, 149.5, 141.8, 138.5, 120.1 (2×C), 116.6 (t, J=256.4 Hz), 112.9, 90.7, 73.0, 44.5, 37.2, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 16 H19 0 3 NF2Na + [M+Na] + , 334.1225; the measured value is 334.1225.

[0229] (4) Synthesis of Compound 20:

[0230]

[0231] 2.48 g of compound 19 (8 mmol, 1.0 equiv.) and 1.46 g of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester (24 mmol, 3.0 equiv.) were placed in a reaction flask, 10 mL of acetic acid was added, and the mixture was stirred at 80°C for 12 hours. When the raw material was no longer reduced, water was added, and the mixture was extracted with ethyl acetate three times. The organic phase was washed with a saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate. The organic phase was concentrated and subjected to rapid column chromatography to obtain 2.6 g of compound 20, with a yield of 84%.

[0232] The obtained compound 20 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (400 MHz, DMSO-d 6 )δ8.72 (d, J=4.4 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.71 (dd, J=8.4, 2.0 Hz, 1H), 7.45-7.39 (m, 2H), 7.28 (s, 1H), 7.27 (t, J=74.0 Hz, 1H), 3.99 (d, J=6.8 Hz, 2H), 3.88 (s, 3H), 1.42-1.26 (m, 1H), 0.66-0.51 (m, 2H), 0.43-0.24 (m, 2H). ESI-HRMS m / z: calculated value is C 19 H 17 O 4 N 3 F 2 Na + [M+Na] + , 412.1079; the measured value is 412.1083.

[0233] (5) Synthesis of Compound 21:

[0234]

[0235] The synthesis steps were similar to those of compound 5, and a yellow solid product was obtained with a yield of 96%.

[0236] The obtained compound 21 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (400 MHz, DMSO-d 6 )δ8.58 (d, J = 4.4 Hz, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 4.0 Hz, 1H), 7.25 (t, J = 74.0 Hz, 1H), 6.95 (s, 1H), 3.99 (d, J = 6.8 Hz, 2H), 1.37-1.30 (m, 1H), 0.65-0.54 (m, 2H), 0.39-0.26 (m, 2H), OH (not observed). ESI-HRMS m / z: calculated for C 18 H 15 O 4 N 3 F 2 Na + [M+Na] + , 398.0923; the measured value is 398.0909.

[0237] (6) Synthesis of Compounds F1-F13:

[0238]

[0239] 100 mg of compound 21 (0.31 mmol, 1.0 equiv.) was dissolved in DMF, and then 117 mg of HATU (0.31 mmol, 1.0 equiv.), amine reagent (0.31 mmol, 1.0 equiv.) and 80 mg of DIPEA (0.62 mmol, 2.0 equiv.) were added. The reaction was stirred at 50°C and monitored by TLC. Water was added to quench the reaction, and the reaction was extracted with ethyl acetate. The organic phase was washed with water three times and with a saturated sodium chloride aqueous solution. The ethyl acetate layer was dried with anhydrous sodium sulfate, concentrated by rotary evaporation, and silica gel was added to mix the sample. Compounds F1-F13 were obtained by purification by flash column chromatography.

[0240] The compounds F1-F13 are as follows:

[0241]

[0242] Example 7 Synthesis of G series compounds

[0243] (1) Synthesis of Compound 22:

[0244]

[0245] The synthesis steps were similar to those of compound 20. Compound 19 was reacted with methyl 3-aminopyrazole-4-carboxylate to obtain a yellow solid product with a yield of 56%.

[0246] The obtained compound 22 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (500 MHz, CDCl 3 )δ8.79(d, J=4.5 Hz, 1H), 8.61(s, 1H), 7.70(d, J=2.0 Hz, 1H), 7.51(dd, J=8.5, 2.0 Hz, 1H), 7.33(d, J=8.5 Hz, 1H), 7.07(d, J=4.5 Hz, 1H), 6.74(t, J=74.5 Hz, 1H), 3.97(s, 3H), 3.94(d, J=7.0 Hz, 2H), 1.39-1.27(m, 1H), 0.76-0.52(m, 2H), 0.41-0.32(m, 2H).ESI-HRMS m / z: calculated value is C 19 H 17 O4N 3 F 2 Na + [M+Na] + , 412.1079; the measured value is 412.1072.

[0247] (2) Synthesis of compound 23:

[0248]

[0249] The synthesis steps were similar to those of compound 5, and a yellow solid product was obtained with a yield of 98%.

[0250] The obtained compound 23 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (600 MHz, DMSO-d 6 )δ8.62(d, J=4.2 Hz, 1H), 8.33(s, 1H), 7.80(d, J=1.8 Hz, 1H), 7.74(dd, J=8.4,1.8 Hz, 1H), 7.38(d, J=8.4 Hz, 1H), 7.24(d, J=4.2 Hz, 1H), 7.23(t, J=73.8 Hz, 1H), 3.98(d, J=7.2 Hz, 2H), 1.35-1.24(m, 1H), 0.64-0.54(m, 2H), 0.40-0.30(m, 2H).OH(not observed).ESI-HRMS m / z: calculated for C 18 H 15O4 N3 F 2 Na + [M+Na] + , 398.0923; the measured value is 398.0915.

[0251] (3) Synthesis of Compounds G1-G21:

[0252]

[0253] 100 mg of compound 23 (0.31 mmol, 1.0 equiv.) was dissolved in DMF, and then 117 mg of HATU (0.31 mmol, 1.0 equiv.), amine reagent (0.31 mmol, 1.0 equiv.) and 80 mg of DIPEA (0.62 mmol, 2.0 equiv.) were added. The reaction was stirred at room temperature and monitored by TLC. When there was no starting material, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with water three times, and then with a saturated sodium chloride aqueous solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and silica gel was added to mix the sample. Compounds G1-G21 were obtained by purification by flash column chromatography.

[0254] The compounds G1-G21 are as follows:

[0255]

[0256] Example 8 Synthesis of H series compounds

[0257] (1) Synthesis of compound 24:

[0258]

[0259] Weigh 3.0 g of compound 3 (12.38 mmol, 1.0 equiv.), add 4.0 g of sodium hydroxide (99.04 mmol, 8.0 equiv.), add 30 mL of a mixed solution of methanol and water (volume ratio of 10:1), and finally add 4.2 g of 30% hydrogen peroxide (37.14 mmol, 3.0 equiv.), react at 50 ° C for 2 hours, and use TLC to detect that the raw material reaction is complete. Use dilute hydrochloric acid to adjust to acidity. A large amount of solid precipitates, then filter and vacuum dry to obtain 2.4 g of compound 24, with a yield of 69%.

[0260] The obtained compound 24 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6)δ7.60-7.54 (m, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 74.0 Hz, 1H), 3.94 (d, J = 7.0 Hz, 2H), 1.29-1.23 (m, 1H), 0.61-0.54 (m, 2H), 0.38-0.33 (m, 2H). ESI-HRMS m / z: calculated value is C 12 H 12 O 4 F 2 + [M+H] + , 281.0596; the measured value is 281.0507.

[0261] (2) Synthesis of Compound 25:

[0262]

[0263] 1.66 g of compound 24 (6.5 mmol, 1.0 equiv.) was weighed and placed in flask a, 1.4 g of N, N'-carbonyldiimidazole (6.5 mmol, 1.0 equiv.) was added, 10 mL of NN-dimethylformamide solvent was added, and the mixture was stirred at room temperature for 0.5 hours. Another flask b was added, 1.5 g of aminoguanidine bicarbonate (7.8 mmol, 1.2 equiv.) and 1.8 g of potassium carbonate (13.0 mmol, 2.0 equiv.) were added, and the mixture was stirred at room temperature for 15 minutes. The reaction solution in flask a was added to flask b, and the mixture was stirred at room temperature for 1 hour, and then the mixture was heated to 100°C and reacted for two hours. TLC detected that the reaction of the raw material was complete, and water was added to quench the reaction. Ethyl acetate was used for extraction 3 times, and the organic phase was washed with a saturated sodium chloride solution. The organic phase was concentrated, and 403 mg of compound 25 was obtained by flash column chromatography, with a yield of 21%.

[0264] The obtained compound 25 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6 )δ12.08(s,1H),7.55(s,1H),7.45(dd,J=8.0,1.5Hz,1H),7.18(d,J=8.5Hz,1H),7.09(t,J=74.5Hz,1H),6.06(s,2H),3.91(d,J=6.5Hz,2H),1.35-1.27(m,1H),0.61-0.54(m,2H),0.40-0.33(m,2H).ESI-HRMS m / z: calculated value is C 13 H 15 O 2 N4 F 2 + [M+H] + , 297.1158; the measured value is 297.1163.

[0265] (3) Synthesis of Compound 26:

[0266]

[0267] Weigh 403 mg of compound 25 (1.28 mmol, 1.0 equiv.), add 232 mg of 2-bromomalonaldehyde (1.54 mmol, 1.2 equiv.), add 4 mL of acetic acid, stir at room temperature for 10 minutes, heat to 100 ° C, react for 2 hours, detect the complete reaction of the raw material by TLC, and quench the reaction by adding water. Use ethyl acetate to extract 3 times, and wash the organic phase with saturated sodium chloride solution. The organic phase is concentrated and the product 274.5 mg of compound 26 is obtained by flash column chromatography with a yield of 52%.

[0268] The obtained compound 26 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6 )δ9.87 (d, J=2.5 Hz, 1H), 8.96 (d, J=2.5 Hz, 1H), 7.85-7.78 (m, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.20 (t, J=74.5 Hz, 1H), 4.01 (d, J=7.0 Hz, 2H), 1.34-1.24 (m, 1H), 0.64-0.56 (m, 2H), 0.45-0.38 (m, 2H). ESI-HRMS m / z: calculated value is C 16 H 13 O 2 N 4 F 2 + [M+H] + , 411.0263; the measured value is 411.0251.

[0269] (4) Synthesis of Compounds H1-H6:

[0270]

[0271] Weigh 70 mg of compound 26 (0.17 mmol, 1.0 equiv.), add 45 mg of sodium carbonate (0.43 mmol, 2.5 equiv.), add different boric acid reagents (0.25 mmol, 1.5 equiv.), add 1 mL of N, N-dimethylformamide solvent, and finally add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.01 mmol, 0.05 equiv.), operate in an oxygen-free environment, react at 100°C for 6 hours, detect the complete reaction of the raw material by TLC, and quench the reaction by adding aqueous solution. Use ethyl acetate to extract 3 times, wash the organic phase with saturated sodium chloride solution, concentrate the organic phase, and obtain compounds H1-H6 by rapid column chromatography.

[0272] The compounds H1-H6 are as follows:

[0273]

[0274] Example 9 Synthesis of J series compounds

[0275] (1) Synthesis of Compounds J1-J6:

[0276]

[0277] Weigh the carboxylic acid compound (0.24mmol, 1.2equiv), add HATU (0.16mmol.1.0equiv), then add DIPEA (0.32mmol, 2.0equiv), add 1mL DMF as solvent, stir at room temperature for 10 minutes, and finally add compound 25 (0.16mmol, 1.0equiv). After stirring and reacting at room temperature for 2 hours, TLC is used to detect that the raw material reaction is complete, and an aqueous solution is added to quench the reaction. Use ethyl acetate to extract 3 times, and wash the organic phase with a saturated sodium chloride solution. The organic phase is concentrated and compounds J1-J6 are obtained by rapid column chromatography.

[0278] The compounds J1-J6 are as follows:

[0279]

[0280] Example 10 Synthesis of Compound A1:

[0281] The synthesis steps were as in Example 1, and 2,6-difluorobenzylamine was selected as the amine reagent in the last step to obtain compound A1 with a yield of 12%; 1 H NMR (500 MHz, DMSO-d 6) δ13.46 (s, 1H), 10.44 (t, J = 6.0Hz, 1H), 7.94 (d, J = 2.0Hz, 1H), 7.88 (d, J = 7.5Hz, 1H), 7.79 (dd, J=8.5, 2.0Hz, 1H), 7.74 (d, J=8.0Hz, 1H), 7.47-7.41 (m, 2H), 7.39- 7.36 (m, 1H), 7.23 (t, J=74.0Hz, 1H), 7.16 (t, J=8.0Hz, 2H), 4.81 (d, J=5.5Hz, 2H) , 4.05 (d, J=7.0Hz, 2H), 1.39-1.33 (m, 1H), 0.68-0.63 (m, 2H), 0.45-0.41 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ164.1, 160.8 (dd, J = 244.5, 7.5 Hz, 2×C), 151.2, 150.2, 141.7, 140.9, 135.2, 130.2 (t, J = 9.0 Hz), 127.0, 122.9, 122.6, 121.6, 121.3, 119.3, 116.6 (t, J = 256.5 Hz), 115.2, 114.6 (t, J = 19.5 Hz), 112.4, 111.7 (dd, J = 19.5, 4.5 Hz, 2×C), 73.2, 30.4, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 26 H 21 O 3 N 3 F 4 Na + [M+Na] + , 522.1411; the measured value is 522.1405.

[0282] Example 11 Synthesis of Compound A2:

[0283] The synthesis steps were as in Example 1, and 2,4-difluorobenzylamine was selected as the amine reagent in the last step to obtain compound A2 with a yield of 54%; 1 H NMR (500 MHz, DMSO-d 6) δ13.44 (br, 1H), 10.35 (t, J = 6.0Hz, 1H), 7.92 (d, J = 1.5Hz, 1H), 7.90 (d, J = 7.5Hz, 1H ), 7.82(dd, J=8.0, 1.5Hz, 1H), 7.75(d, J=8.0Hz, 1H), 7.60-7.55(m, 1H), 7.41-7.37(m , 2H), 7.29-7.24 (m, 1H), 7.22 (t, J=69.0Hz, 1H), 7.10-7.08 (m, 1H), 4.74 (d, J=6.0Hz , 2H), 4.01 (d, J=7.0Hz, 2H), 1.36-1.28 (m, 1H), 0.64-0.61 (m, 2H), 0.41-0.38 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 ) δ164.6, 164.6 (dd, J=245.0, 12.0Hz), 160.5 (dd, J=245.0, 12.0Hz), 151.3, 150. 2, 141.6, 141.0, 135.3, 131.0 (dd, J=15.0, 6.0Hz), 127.0, 122.9, 122.7, 122.6 (dd , J = 15.0, 4.5.0 Hz), 121.8, 121.3, 119.5, 116.6 (t, J = 258.0 Hz), 115.2, 112.6, 111.5 (dd, J = 21.0, 3.0 Hz), 103.9 (t, J = 25.5 Hz), 73.2, 36.4, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 26 H 21 O 3 N 3 F 4 Na + [M+Na] + , 522.1411; the measured value is 522.1402.

[0284] Example 12 Synthesis of Compound A3:

[0285] The synthesis steps were as in Example 1. In the last step, 2-methylaminopyrimidine (CAS No.: 75985-45-4) was selected as the amine reagent to obtain compound A3 with a yield of 22%. 1 H NMR (500 MHz, DMSO-d 6) δ13.43 (br, 1H), 10.90 (br, 1H), 8.90 (d, J = 4.5Hz, 2H), 8.08 (dd, J = 8.5, 1.5Hz , 1H), 8.02 (d, J=1.5Hz, 1H), 7.92 (d, J=7.5Hz, 1H), 7.78 (d, J=8.0Hz, 1H), 7.49- 7.48(m, 2H), 7.40-7.37(m, 1H), 7.22(t, J=74.5Hz, 1H), 4.93(d, J=5.0Hz, 2H), 4.03 (d, J=7.0Hz, 2H), 1.35-1.28 (m, 1H), 0.63-0.59 (m, 2H), 0.39-0.36 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ166.2, 164.5, 157.6 (2×C), 151.2, 150.1, 141.6, 141.2, 135.3, 127.2, 122.8, 122.6, 121.9, 121.5, 120.0, 119.9, 116.6 (t, J=256.5 Hz), 115.0, 112.8, 73.4, 45.8, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 24 H 22 0 3 N 5 F 2 + [M+H] + , 466.1685; the measured value is 466.1677.

[0286] Example 13 Synthesis of Compound A4:

[0287] The synthesis steps were similar to those in Example 1. In the last step, 4-aminopyridine was selected as the amine reagent to obtain compound A4 with a yield of 38%. 1 H NMR (500 MHz, DMSO-d 6)δ13.63 (br, 1H), 12.47 (br, 1H), 8.54 (d, J = 5.5Hz, 2H), 8.03 (d, J = 1.5Hz, 1H), 7.99 (d, J=7.0Hz, 1H), 7.94 (dd, J=8.5, 2.0Hz, 1H), 7.86 (d, J=7.5Hz, 1 H), 7.83 (d, J=6.0Hz, 2H), 7.46-7.43 (m, 2H), 7.25 (t, J=74.5Hz, 1H), 4.12 (d, J=7.0Hz, 2H), 1.41-1.35 (m, 1H), 0.67-0.65 (m, 2H), 0.45-0.43 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ163.8, 151.6, 150.6 (2×C), 150.1, 145.4, 141.7, 140.9, 135.3, 126.6, 123.4, 123.0, 121.4, 121.0, 119.7, 116.5 (t, J=256.5 Hz), 116.3, 113.7 (2×C), 112.7, 73.3, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated value is C 24 H 21 O 3 N 4 F 2 + [M+H] + , 451.1576; the measured value is 451.1564.

[0288] Example 14 Synthesis of Compound A5:

[0289] The synthesis steps were similar to those in Example 1. In the last step, 2-aminothiazole was selected as the amine reagent to obtain compound A5 with a yield of 42%. 1 H NMR (500 MHz, DMSO-d 6 ) δ13.66 (br, 1H), 13.59 (br, 1H), 7.99 (d, J = 7.5Hz, 2H), 7.85 (t, J = 8.5Hz, 2H), 7.57 (d, J = 3.5Hz, 1H), 7.46-7.42 (m, 2H), 7. 33 (d, J=3.5Hz, 1H), 7.23 (t, J=74.0Hz, 1H), 4.05 (d, J=7.0Hz, 2H), 1.42-1.33 (m, 1H), 0.68-0.64 (m, 2H), O.45-O.42 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ162.3, 157.6, 151.7, 150.1, 141.8, 141.0, 138.1, 135.3, 126.3, 123.3, 123.0, 121.4, 119.5, 119.2, 116.7, 116.6 (t, J = 256.5 Hz), 114.2, 112.6, 73.4, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated value is C 22 H 19 0 3 N 4 SF 2 + [M+H] + , 457.1140; the measured value is 457.1095.

[0290] Example 15 Synthesis of Compound A6:

[0291] The synthesis steps were similar to those in Example 1. In the last step, 6-aminobenzothiazole was selected as the amine reagent to obtain compound A6 with a yield of 95%. 1 H NMR (500 MHz, DMSO-d 6 )δ13.61 (br, 1H), 12.46 (br, 1H), 9.32 (s, 1H), 8.84 (d, J = 2.0Hz, 1H), 8.10 (d, J = 8.5H z, 1H), 8.06 (d, J=1.5Hz, 1H), 8.02 (d, J=7.5Hz, 1H), 7.96 (dd, J=8.5, 1.5Hz, 1H), 7.9 0 (dd, J=9.0, 2.0Hz, 1H), 7.84 (d, J=8.0Hz, 1H), 7.47-7.40 (m, 2H), 7.25 (t, J=74.0Hz , 1H), 4.14 (d, J=7.0Hz, 2H), 1.41-1.34 (m, 1H), 0.68-0.64 (m, 2H), 0.46-0.43 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ163.1, 155.1, 151.5, 150.2, 149.5, 141.7, 140.9, 136.7, 135.3, 134.7, 129.7, 126.8, 123.3, 123.0, 121.6, 121.4, 119.7, 119.1, 116.6 (t, J = 256.5 Hz), 115.9, 112.7, 112.0, 73.3, 10.1, 3.1 (2×C). ESI-HRMS m / z: calculated for C 26 H 21 O 3 N4 SF 2 + [M+H] + , 507.1297; the measured value is 507.1249.

[0292] Example 16 Synthesis of Compound A7:

[0293] The synthesis steps were as in Example 1. In the last step, 2-methylbenzothiazol-6-amine (CAS No.: 2941-62-0) was selected as the amine reagent to obtain compound A7 with a yield of 56%. 1 H NMR (500 MHz, DMSO-d 6 )δ13.59 (br, 1H), 12.40 (br, 1H), 8.71 (d, J = 1.5Hz, 1H), 8.04 (d, J = 2.0Hz, 1H), 8.00 ( d, J=7.5Hz, 1H), 7.94 (dd, J=8.0, 1.5Hz, 1H), 7.91 (d, J=9.0Hz, 1H), 7.83 (d, J=8.0Hz , 1H), 7.78 (dd, J=8.5, 2.0Hz, 1H), 7.46-7.40 (m, 2H), 7.25 (t, J=74.0Hz, 1H), 4.12 (d , J=7.0Hz, 2H), 2.79 (s, 3H), 1.41-1.34 (m, 1H), 0.68-0.64 (m, 2H), 0.45-0.43 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ165.9, 162.9, 151.4, 150.1, 149.3, 141.7, 140.8, 136.2, 136.0, 135.3, 126.7, 123.2, 123.0, 122.1, 121.7, 121.4, 119.6, 118.6, 116.6 (t, J = 256.5 Hz), 115.8, 112.6, 111.7, 73.2, 19.7, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated value is C 27 H 23 O 3 N 4 SF 2 + [M+H] + , 521.1453; the measured value is 521.1436.

[0294] Example 17 Synthesis of Compound A8:

[0295] The synthesis steps were similar to those in Example 1. In the last step, 2-aminobenzothiazole was selected as the amine reagent to obtain compound A8 with a yield of 32%. 1 H NMR (500 MHz, DMSO-d 6 ) δ13.80 (br, 1H), 13.72 (br, 1H), 8.06 (d, J = 2.0Hz, 1H), 8.05 (d, J = 7.5Hz, 2H), 7.92-7.89 (m, 2H), 7.80 (d, J = 8.0Hz, 1H), 7.52-7.47 ( m, 3H), 7.36 (t, J=7.5Hz, 1H), 7.25 (t, J=74.5Hz, 1H), 4.13 (d, J=7.0Hz, 2H), 1.45-1.37 (m, 1H), 0.71-0.67 (m, 2H), 0.48-0.45 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ163.2, 157.6, 151.9, 150.2, 148.7, 141.9, 141.2, 135.4, 131.8, 129.7, 126.5, 126.4, 123.8, 123.5, 121.9, 121.4, 120.6, 119.6, 118.9, 117.2, 116.6 (t, J = 256.5 Hz), 112.8, 73.3, 10.1, 3.3 (2×C). ESI-HRMS m / z: calculated for C 26 H 21 O 3 N 4 SF 2 + [M+H] + , 507.1297; the measured value is 507.1254.

[0296] Example 18 Synthesis of Compound A9:

[0297] The synthesis steps were as in Example 1, and 3,4-difluorobenzylamine was selected as the amine reagent in the last step to obtain compound A9 with a yield of 32%; 1 H NMR (500 MHz, DMSO-d 6)δ13.43 (s, 1H), 10.29 (t, J=6.0Hz, 1H), 7.93-7.89 (m, 2H), 7.85 (dd, J=8.5, 2.0Hz , 1H), 7.76 (dd, J=8.0, 1.0Hz, 1H), 7.54-7.49 (m, 1H), 7.42 (dd, J=8.5, 2.0Hz, 1H), 7 .38 (t, J=8.0Hz, 2H), 7.32-7.29 (m, 1H), 7.21 (t, J=74.0Hz, 1H), 4.72 (d, J=5.5Hz, 2 H), 3.99 (d, J=7.0Hz, 2H), 1.33-1.27 (m, 1H), 0.63-0.59 (m, 2H), 0.39-0.35 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 ) δ164.7, 151.3, 150.1, 149.3 (dd, J=243.0, 13.5Hz), 148.4 (dd, J=242.0, 13. 5Hz), 141.6, 141.0, 137.5 (t, J=4.5Hz), 135.3, 127.0, 123.9 (dd, J=7.5, 3.0H z), 122.9, 122.6, 121.9, 121.3, 119.7, 117.5 (d, J = 16.5 Hz), 116.6 (t, J = 256.5 Hz), 116.3 (d, J = 18.0 Hz), 115.1, 112.7, 73.2, 41.7, 9.9, 3.0 (2×C). ESI-HRMS m / z: calculated for C 26 H 22 O 3 N 3 F 4 + [M+H] + , 500.1592; the measured value is 500.1579.

[0298] Example 19 Synthesis of Compound A10:

[0299] The synthesis steps were similar to those in Example 1. In the last step, 3,5-difluorobenzylamine was selected as the amine reagent to obtain compound A10 with a yield of 17%. 1 H NMR (600 MHz, DMSO-d 6)δ13.44(br, 1H), 10.31(br, 1H), 7.94(s, 1H), 7.91-7.87(m, 2H), 7.77(d, J=7.8Hz, 1H), 7.39-7.35(m, 2H), 7.21(t, J=74.4Hz, 1H), 7.17( d, J=6.6Hz, 2H), 7.13-7.09 (m, 1H), 4.76 (d, J=5.4Hz, 2H), 4.00 (d, J=7.2Hz, 2H), 1.34-1.27 (m, 1H), 0.62-0.59 (m, 2H), 0.38-0.36 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ164.9, 162.5 (dd, J=245.0, 13.0 Hz, 2×C), 151.4, 150.1, 144.6 (t, J=9.0 Hz), 141.6, 141.1, 135.3, 127.1, 122.9, 122.7, 121.9, 121.2, 119.7, 116.7 (t, J=257.0 Hz), 115.2, 112.7, 110.2 (dd, J=19.0, 6.0 Hz, 2×C), 102.3 (t, J=25.0 Hz), 73.2, 42.1, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 26 H 22 O 3 N 3 F 4 + [M+H] + , 500.1592; the measured value is 500.1562.

[0300] Example 20 Synthesis of Compound A11:

[0301] The synthesis steps were similar to those in Example 1. In the last step, 2,3-difluorobenzylamine was selected as the amine reagent to obtain compound A11 with a yield of 74%. 1 H NMR (500 MHz, DMSO-d 6) δ13.44 (br, 1H), 10.39 (s, 1H), 7.94 (s, 1H), 7.89 (d, J = 7.5Hz, 1H), 7.84 (d, J = 8.5Hz, 1H), 7.77 (d, J = 8.0Hz, 1H), 7.41-7.33 (m, 4H), 7.22 ( t, J=74.0Hz, 1H), 7.22-7.18 (m, 1H), 4.81 (d, J=6.0Hz, 2H), 4.01 (d, J=7.0Hz, 2H), 1.36-1.29 (m, 1H), 0.65-0.59 (m, 2H), 0.42-0.36 (m, 2H). 13 CNMR (151 MHz, DMSO-d 6 )δ164.6, 151.3, 150.1, 149.7 (dd, J=243.0, 12.0Hz), 148.0 (dd, J=244.5, 13 .5Hz), 141.6, 141.0, 135.3, 129.0 (d, J=12.0Hz), 127.1, 124.9 (d, J=6.0Hz) , 124.8 (2×C), 122.8 (d, J=36.0Hz), 121.7, 121.2, 119.5, 116.6 (t, J=256.5H z), 116.3 (d, J=16.5Hz), 115.2, 112.6, 73.2, 36.5, 9.9, 3.1 (2×C).ESI-HRMS m / z: calculated value is C 26 H 22 O 3 N 3 F 4 + [M+H] + , 500.1592; the measured value is 500.1559.

[0302] Example 21 Synthesis of Compound A12:

[0303] The synthesis steps were similar to those in Example 1. In the last step, 2,5-difluorobenzylamine was selected as the amine reagent to obtain compound A12 with a yield of 14%. 1 H NMR (500 MHz, DMSO-d 6)δ13.49 (br, 1H), 10.34 (s, 1H), 7.96 (s, 1H), 7.87 (dd, J=14.0, 8.0Hz, 2H), 7.77 (d, J=8.0Hz, 1H), 7.44-7.33 (m, 3H), 7.33-7.28 (m, 1H), 7.2 2 (t, J=74.0Hz, 1H), 7.21-7.15 (m, 1H), 4.83-4.66 (m, 2H), 4.02 (d, J=7.00Hz, 2H), 1.37-1.26 (m, 1H), 0.66-0.56 (m, 2H), 0.45-0.34 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 ) δ164.7, 158.2 (d, J = 238.5Hz), 156.5 (d, J = 240.0Hz), 151.3, 150.1, 141.6, 14 1.0, 135.3, 128.4 (dd, J=18.0, 7.5Hz), 127.1, 122.9, 122.6, 121.8, 121.2, 119. 6, 116.8 (dd, J = 24.0, 9.0 Hz), 116.6 (t, J = 256.5 Hz), 116.0 (dd, J = 24.0, 4.5 Hz), 115.3 (dd, J = 24.0, 9.0 Hz), 115.2, 112.6, 73.2, 36.7, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 26 H 22 O 3 N 3 F 4 + [M+H] + , 500.1592; the measured value is 500.1558.

[0304] Example 22 Synthesis of Compound A13:

[0305] The synthesis steps were similar to those in Example 1. In the last step, 2-fluorobenzylamine was selected as the amine reagent to obtain compound A13 with a yield of 87%. 1 H NMR (600 MHz, DMSO-d 6)δ13.52 (s, 1H), 10.37 (t, J = 6.0Hz, 1H), 7.96-7.92 (m, 1H), 7.90 (d, J = 7.2Hz, 1H), 7.82 ( dd, J=8.4, 1.8Hz, 1H), 7.76 (d, J=8.4Hz, 1H), 7.54 (t, J=7.8Hz, 1H), 7.38 (dd, J=16.2, 8. 4Hz, 3H), 7.28-7.23 (m, 1H), 7.22 (t, J=73.8Hz, 1H), 7.20 (d, J=7.2Hz, 1H), 4.77 (d, J=6. 0Hz, 2H), 4.01 (d, J=7.2Hz, 2H), 1.35-1.30 (m, 1H), 0.64-0.60 (m, 2H), 0.41-0.38 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ164.5, 160.5 (d, J = 243.0 Hz), 151.2, 150.1, 141.6, 141.0, 135.3, 129.8 (d, J = 4.5 Hz), 129.3 (d, J = 7.5 Hz), 127.1, 1261 (d, J = 15.0 Hz), 124.6 (d, J = 4.5 Hz), 122.9, 122.6, 121.8, 121.3, 119.5, 116.6 (t, J = 256.5 Hz), 115.3, 115.2 (d, J = 6.0 Hz), 112.5, 73.3, 36.8, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 26 H 23 O 3 N 3 F 3 + [M+H] + , 482.1686; the measured value is 482.1660.

[0306] Example 23 Synthesis of Compound A14:

[0307] The synthesis steps were as in Example 1, and 2,4,6-trifluorobenzylamine was selected as the amine reagent in the last step to obtain compound A14 with a yield of 83%; 1 H NMR (400 MHz, DMSO-d 6)δ13.44(br, 1H), 10.45(br, 1H), 7.93(s, 1H), 7.87(d, J=7.6Hz, 1H), 7.80(d , J=8.4Hz, 1H), 7.74 (d, J=7.6Hz, 1H), 7.43 (d, J=6.8Hz, 1H), 7.36 (t, J=8.0H z, 1H), 7.24 (t, J=78.4Hz, 1H), 7.24-7.17 (m, 2H), 4.75 (d, J=5.2Hz, 2H), 4.0 4(d, J=7.2Hz, 2H), 1.40-1.31(m, 1H), 0.67-0.62(m, 2H), 0.44-0.41(m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ164.2, 161.6 (dt, J = 245.0, 17.0 Hz), 161.1 (ddd, J = 246.0, 15.0, 11.0 Hz, 2×C), 151.2, 150.2, 141.6, 140.9, 135.3, 127.0, 122.9, 122.7, 121.6, 121.3, 119.3, 116.7 (t, J = 257.0 Hz), 115.3, 112.4, 111.5 (td, J = 4.0, 4.0 Hz), 100.8 (t, J = 26.0 Hz, 2×C), 73.2, 30.2, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 26 H 21 O 3 N 3 F 5 + [M+H] + , 518.1498; the measured value is 518.1481.

[0308] Example 24 Synthesis of Compound A15:

[0309] The synthesis steps were as shown in Example 1. In the last step, 2-(aminomethyl)naphthalene (CAS No.: 2018-90-8) was used as the amine reagent to obtain compound A15 with a yield of 24%. 1 H NMR (500 MHz, DMSO-d 6)δ13.44(br, 1H), 10.45(t, J=5.5Hz, 1H), 7.98(s, 1H), 7.96-7.90(m, 3H), 7.88(s, 1H), 7 .87-7.85(m, 1H), 7.78(t, J=7.5Hz, 2H), 7.64(d, J=8.5Hz, 1H), 7.52-7.47(m, 2H), 7.40( t, J=8.0Hz, 1H), 7.29 (d, J=8.5Hz, 1H), 7.18 (t, J=74.0Hz, 1H), 4.91 (d, J=6.0Hz, 2H), 3. 86 (d, J=7.0Hz, 2H), 1.24-1.17 (m, 1H), 0.56-0.50 (m, 2H), 0.28-0.22 (d, J=5.06Hz, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ164.6, 151.2, 150.1, 141.5, 141.1, 137.0, 135.3, 133.0, 132.2, 128.2, 127.6, 127.5, 127.0, 126.3, 126.0, 125.8, 125.3, 122.9, 122.7, 122.1, 121.2, 119.5, 116.6 (t, J = 256.5 Hz), 115.1, 112.5, 73.1, 42.9, 9.9, 3.0 (2×C). ESI-HRMS m / z: calculated for C 30 H 26 O 3 N 3 F 2 + [M+H] + , 514.1937; the measured value is 514.1961.

[0310] Example 25 Synthesis of Compound A16:

[0311] The synthesis steps were as in Example 1. The last step was to use 2-aminomethylpyrazine (Pyrazin-2-ylmethanamine, CAS No.: 20010-99-5) as the amine reagent to obtain compound A16 with a yield of 26%. 1 H NMR (600 MHz, DMSO-d 6) δ13.44 (s, 1H), 10.67 (t, J = 5.4Hz, 1H), 8.80 (s, 1H), 8.70 (t, J = 1.8Hz, 1H), 8.59 (d , J=2.4Hz, 1H), 8.00-7.96 (m, 2H), 7.90 (d, J=7.2Hz, 1H), 7.77 (d, J=8.4Hz, 1H), 7.4 4(d, J=8.4Hz, 1H), 7.38 (t, J=7.8Hz, 1H), 7.22 (t, J=74.4Hz, 1H), 4.91 (d, J=5.4Hz, 2H), 4.02 (d, J=7.2Hz, 2H), 1.34-1.29 (m, 1H), 0.63-0.60 (m, 2H), 0.40-0.37 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ164.8, 153.7, 151.3, 150.1, 144.0, 143.7, 143.3, 141.6, 141.1, 135.3, 127.1, 122.8, 122.6, 121.8, 121.4, 119.8, 116.6 (t, J = 256.5 Hz), 115.1, 112.7, 73.3, 42.7, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 24 H 22 O 3 N 5 F 2 + [M+H] + , 466.1685; the measured value is 466.1706.

[0312] Example 26 Synthesis of Compound A17:

[0313] The synthesis steps were as in Example 1. The last step of the amine reagent was 2-aminomethylpyridine (CAS No.: 3731-51-9) to obtain compound A17 with a yield of 90%. 1 H NMR (500 MHz, DMSO-d 6)δ13.43 (br, 1H), 10.72 (t, J = 5.0Hz, 1H), 8.65 (d, J = 4.5Hz, 1H), 8.04-7.96 (m, 2H), 7.92 (d , J=7.5Hz, 1H), 7.81 (t, J=7.5Hz, 1H), 7.77 (d, J=8.0Hz, 1H), 7.49 (d, J=8.0Hz, 1H), 7.44 (d, J=8.0Hz, 1H), 7.39-7.36 (m, 1H), 7.34 (t, J=6.5Hz, 1H), 7.22 (t, J=74.0Hz, 1H), 4.83 (d, J= 5.5Hz, 2H), 4.00 (d, J=7.0Hz, 2H), 1.36-1.27 (m, 1H), 0.64-0.58 (m, 2H), 0.41-0.34 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ164.6, 157.7, 151.2, 150.1, 149.1, 141.6, 141.1, 136.9, 135.3, 127.2, 122.8, 122.6, 122.3, 122.0, 121.5, 121.4, 119.8, 116.6 (t, J = 256.5 Hz), 115.0, 112.7, 73.4, 44.8, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 25 H 23 O 3 N 4 F 2 + [M+H] + , 465.1733; the measured value is 465.1765.

[0314] Example 27 Synthesis of Compound A18:

[0315] The synthesis steps were as in Example 1. The last step of the amine reagent was 3-aminomethylpyridine (CAS No.: 3731-52-0) (CAS No.: 3731-52-0) to obtain compound A18 with a yield of 23%; 1 H NMR (600 MHz, DMSO-d 6) δ13.46 (br, 1H), 10.32 (s, 1H), 8.71 (d, J = 2.4Hz, 1H), 8.50 (dd, J = 4.8, 1.8H z, 1H), 7.94-7.88 (m, 2H), 7.87-7.82 (m, 2H), 7.76 (d, J=7.8Hz, 1H), 7.41-7.3 9 (m, 1H), 7.38-7.35 (m, 2H), 7.21 (t, J=73.8Hz, 1H) 4.75 (d, J=6.0Hz, 2H), 4. 00(d, J=7.2Hz, 2H), 1.34-1.28(m, 1H), 0.63-0.60(m, 2H), 0.42-0.39(m, 2H). 13 CNMR (151 MHz, DMSO-d 6 )δ164.8, 151.3, 150.1, 148.9, 148.3, 141.5, 141.0, 135.3, 135.2, 135.1, 127.1, 123.6, 122.8, 122.6, 121.9, 121.2, 119.6, 116.6 (t, J = 256.5 Hz), 115.1, 112.6, 73.2, 40.4, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 25 H 23 O 3 N 4 F 2 + [M+H] + , 465.1733; the measured value is 465.1768.

[0316] Example 28 Synthesis of Compound A19:

[0317] The synthesis steps were as in Example 1. In the last step, the amine reagent was N-methyl-3-aminopyrazole (CAS No.: 1904-31-0) to obtain compound A19 with a yield of 88%. 1 H NMR (500 MHz, DMSO-d 6) δ13.55 (br, 1H), 12.43 (s, 1H), 8.03 (d, J = 2.00Hz, 1H), 7.98 (d, J = 7.5Hz, 1H), 7.85 (dd, J=8.5, 2.0Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.65 (d, J=2.0Hz, 1H), 7.46 (d, J=8.5H z, 1H), 7.42 (t, J=7.5Hz, 1H), 7.21 (t, J=74.0Hz, 1H), 6.71 (d, J=2.0Hz, 1H), 4.09 (d, J=7.0Hz, 2H), 3.83 (s, 3H), 1.42-1.35 (m, 1H), 0.68-0.63 (m, 2H), 0.46-0.41 (m, 2H). 13 CNMR (151 MHz, DMSO-d 6 )δ161.7, 151.3, 150.1, 146.9, 141.7, 140.8, 135.3, 131.4, 126.8, 123.0, 122.9, 121.4, 121.3, 119.4, 116.6 (t, J = 256.5 Hz), 115.6, 112.6, 96.5, 73.3, 38.4, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated value is C 23 H 22 O 3 N 5 F 2 + [M+H] + , 454.1685; the measured value is 454.1713.

[0318] Example 29 Synthesis of Compound A20:

[0319] The synthesis steps were as in Example 1. In the last step, 4-aminomethyltetrahydropyran (CAS No.: 130290-79-8) was selected as the amine reagent to obtain compound A20 with a yield of 55%. 1 H NMR (500 MHz, DMSO-d 6)δ13.53 (br, 1H), 9.99 (s, 1H), 8.00-7.92 (m, 1H), 7.86 (dd, J=19.5, 8.11Hz, 2H), 7.7 4(d, J=8.0Hz, 1H), 7.40 (d, J=8.50Hz, 1H), 7.38-7.33 (m, 1H), 7.21 (t, J=74.0Hz, 1H), 4.04 (d, J=7.0Hz, 2H), 3.89 (d, J=11.0Hz, 2H), 3.32 (t, J=12.0Hz, 4H), 1.94-1.79 (m, 1H), 1.72 (d, J=13.0Hz, 2H), 1.45-1.23 (m, 3H), 0.67-0.56 (m, 2H), 0.44-0.35 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ164.5, 151.2, 150.1, 141.5, 140.9, 135.3, 127.1, 122.7, 122.6, 122.3, 121.3, 119.4, 116.6 (t, J = 256.5 Hz), 114.9, 112.5, 73.2, 66.8 (2×C), 44.4, 35.1, 30.4 (2×C), 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 25 H 28 O 4 NF 2 + [M+H] + , 472.2042; the measured value is 472.2080.

[0320] Example 30 Synthesis of Compound A21:

[0321] The synthesis steps were similar to those in Example 1. Aniline was selected as the amine reagent in the last step to obtain compound A21 with a yield of 42%. 1 H NMR (400 MHz, DMSO-d 6)δ13.64 (br, 1H), 12.28 (br, 1H), 8.05 (d, J = 1.6Hz, 1H), 7.98 (d, J = 7.6Hz, 1H), 7.92 (dd, J=8.4, 1.6Hz, 1H), 7.88 (d, J=7.6Hz, 2H), 7.82 (d, J=7.6Hz, 1 H), 7.46-7.40 (m, 4H), 7.25 (t, J=74.0Hz, 1H), 7.16 (t, J=7.6Hz, 1H), 4.10 (d, J=7.2Hz, 2H), 1.40-1.34(m, 1H), 0.68-0.63(m, 2H), 0.45-0.41(m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ162.8, 151.4, 150.1, 141.6, 140.8, 139.0 (2×C), 135.3, 129.1 (2×C), 126.8, 123.7, 123.1, 122.9, 121.8, 121.3, 119.5, 119.3, 116.6 (t, J=257.0 Hz), 115.7, 112.5, 73.2, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated value is C 25 H 22 O 3 N 3 F 2 + [M+H] + , 450.1624; the measured value is 450.1631.

[0322] Example 31 Synthesis of Compound A22:

[0323] The synthesis steps were similar to those in Example 1. Benzylamine was selected as the amine reagent in the last step to obtain compound A22 with a yield of 29%. 1 H NMR (400 MHz, DMSO-d 6 )δ13.44(br, 1H), 10.32(br, 1H), 7.92-7.87(m, 2H), 7.78-7.36(m, 2H), 7.47(d, J=7.6Hz, 2H), 7.40-7.27(m, 5H), 7.21( t, J=74.0Hz, 1H), 4.72 (d, J=5.2Hz, 2H), 3.95 (d, J=6.8Hz, 2H), 1.34-1.26 (m, 1H), 0.64-0.59 (m, 2H), 0.39-0.36 (m, 2H). 13 CNMR (101 MHz, DMSO-d 6)δ164.5, 151.2, 150.1, 141.6, 141.0, 139.4, 135.3, 128.6 (2×C), 127.4 (2×C), 127.0, 122.9, 122.7, 122.0, 121.3, 119.8, 119.5, 116.6 (t, J=257.0 Hz), 115.1, 112.5, 73.2, 42.8, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 26 H 24 O 3 N 3 F 2 + [M+H] + , 464.1780; the measured value is 464.1819.

[0324] Example 32 Synthesis of Compound A23:

[0325] The synthesis steps were as in Example 1. In the last step, 1-methyl-4-aminopyrazole (CAS No.: 69843-13-6) was selected as the amine reagent to obtain compound A23 with a yield of 62%. 1 H NMR (500 MHz, DMSO-d 6 )δ13.77(br, 1H), 11.90(s, 1H), 8.19(s, 1H), 8.09(d, J=2.0Hz, 1H), 7.98 (dd, J=8.5, 2.0Hz, 1H), 7.94 (d, J=7.5Hz, 1H), 7.79 (d, J=8.0Hz, 1H), 7.75 (s, 1H), 7.41 (d, J=8.0Hz, 2H), 7.24 (t, J=74.5Hz, 1H), 4.12 (d, J=7.0Hz, 2 H), 3.87 (s, 3H), 1.39-1.32 (m, 1H), 0.66-0.62 (m, 2H), 0.45-0.41 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ161.6, 151.4, 150.1, 141.5, 140.7, 135.3, 130.0, 126.8, 122.8, 121.6 (2×C), 121.5, 121.4, 121.3, 119.9, 116.6 (t, J=256.5 Hz), 115.4, 112.7, 73.3, 38.8, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 23 H 22 O 3 N 5 F2 + [M+H] + , 454.1685; the measured value is 454.1703.

[0326] Example 33 Synthesis of Compound A24:

[0327] The synthesis steps were as in Example 1. In the last step, 2-methoxy-5-(aminomethyl)pyridine (CAS No.: 262295-96-5) was used as the amine reagent to obtain compound A24 with a yield of 58%. 1 H NMR (500 MHz, DMSO-d 6 )δ14.11(br, 1H), 10.28(s, 1H), 8.31-8.25(m, 1H), 8.07(d, J=2.0Hz, 1H), 7.88(d, J=7.5Hz, 2H), 7.81 (dd, J=8.5, 2.5Hz, 1H), 7.75 (d, J=8.0Hz, 1H), 7.34 (d, J=8.0Hz, 2H), 7.22 (t, J=74.0Hz, 1H), 6.82 (d, J=8.5Hz, 1H), 4.65 (d, J=5.5Hz, 2H), 4.03 (d, J =7.0Hz, 2H), 3.84(s, 3H), 1.33-1.27(m, 1H), 0.63-0.58(m, 2H), 0.42-0.38(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ164.6, 162.8, 151.3, 150.1, 145.9, 141.5, 140.9, 138.9, 135.4, 128.1, 127.1, 122.7, 122.5, 121.9, 121.2, 119.6, 116.6 (t, J = 256.5 Hz), 115.1, 112.9, 110.4, 73.2, 53.1, 39.7, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 26 H 25 O 4 N 4 F 2 + [M+H] + , 495.1838; the measured value is 495.1865.

[0328] Example 34 Synthesis of Compound A25:

[0329] The synthesis steps were similar to those in Example 1. In the last step, the amine reagent was 4-hydrazinobenzoic acid to obtain compound A25 with a yield of 22%. 1H NMR (500 MHz, DMSO-d 6 ) δ13.53 (br, 1H), 12.39 (br, 1H), 11.33 (br, 1H), 8.85 (s, 1H), 7.98 (s, 1H), 7.90 (d, J = 8.0Hz, 2H), 7.84 (d, J = 8.0Hz, 1H), 7.79 (d, J = 8.5Hz, 2H), 7 .49-7.35(m, 2H), 7.20(t, J=74.5Hz, 1H), 6.89(d, J=8.5Hz, 2H), 4.00(d , J=7.0Hz, 2H), 1.35-1.23(m, 1H), 0.65-0.51(m, 2H), 0.44-0.26(m, 2H). 13 C NMR (126 MHz, DMSO-d 6 )δ167.3, 164.8, 152.9, 151.7, 150.1, 141.6, 141.0, 135.3, 131.0 (2×C), 127.1, 123.0, 122.8, 121.4, 120.8, 120.4, 119.9, 116.6 (t, J=257.5 Hz), 115.6, 112.8, 111.0 (2×C), 73.3, 9.9, 3.0 (2×C). ESI-HRMS m / z: calculated value is C 26 H 23 O 5 N 4 F 2 + [M+H] + , 509.1631; the measured value is 509.1678.

[0330] Example 35 Synthesis of Compound A26:

[0331] The synthesis steps were similar to those in Example 1. The last step was to select 3-aminopyridine as the amine reagent to obtain compound A26 with a yield of 86%. 1 H NMR (400 MHz, DMSO-d 6) δ13.60 (br, 1H), 12.31 (br, 1H), 8.96 (s, 1H), 8.36 (d, J = 5.6Hz, 2H), 8.02 (d, J = 1.6Hz, 1H), 7.97 (d, J = 7.6Hz, 1H), 7.92 (dd, J = 8.4, 1.6Hz, 1H), 7 .81(d, J=7.6Hz, 1H), 7.46-7.42(m, 3H), 7.24(t, J=74.0Hz, 1H), 4.09(d , J=6.8Hz, 2H), 1.41-1.31(m, 1H), 0.68-0.63(m, 2H), 0.46-0.42(m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ163.4, 151.4, 150.1, 144.6, 141.7, 141.1, 141.0, 140.9, 135.7, 135.3, 126.6, 126.3, 124.0, 123.2, 122.9, 121.3, 119.7, 116.6 (t, J = 257.0 Hz), 116.0, 112.6, 73.3, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated for C 24 H 21 O 3 N 4 F 2 + [M+H] + , 451.1576; the measured value is 451.1624.

[0332] Example 36 Synthesis of Compound A27:

[0333] The synthesis steps were similar to those in Example 1. In the last step, 2-aminopyridine was selected as the amine reagent to obtain compound A27 with a yield of 20%. 1 H NMR (400 MHz, DMSO-d 6 )δ13.63 (br, 1H), 12.86 (br, 1H), 8.41-8.39 (m, 2H), 8.12 (d, J=2.0Hz, 1H), 8.02 (dd, J=7.6, 0.8Hz, 1H), 7.91-7.84 (m, 3H), 7.47-7.4 3 (m, 2H), 7.25 (t, J=74.0Hz, 1H), 7.21-7.18 (m, 1H), 4.10 (d, J=6.8Hz, 2H), 1.43-1.36 (m, 1H), 0.69-0.64 (m, 2H), 0.46-0.42 (m, 2H). 13 C NMR (101 MHz, DMSO-d6 )δ163.1, 152.2, 151.4, 150.1, 148.5, 141.7, 141.0, 138.5, 135.4, 126.8, 123.3, 122.9, 121.3, 121.2, 119.8, 119.3, 116.6 (t, J = 257.0 Hz), 116.2, 113.5, 112.6, 73.2, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated value is C 24 H 21 O 3 N 4 F 2 + [M+H] + , 451.1576; the measured value is 451.1623.

[0334] Example 37 Synthesis of Compound A28:

[0335] The synthesis steps were similar to those in Example 1. In the last step, 5-aminoindole was selected as the amine reagent to obtain compound A28 with a yield of 79%. 1 H NMR (400 MHz, DMSO-d 6 ) δ13.57 (br, 1H), 12.20 (br, 1H), 11.12 (br, 1H), 8.24 (d, J = 1.6Hz, 1H), 8.07 (d, J = 2. 0Hz, 1H), 8.01 (dd, J=7.6, 0.8Hz, 1H), 7.92 (dd, J=8.4, 2.0Hz, 1H), 7.80 (d, J=8.4Hz, 1H), 7.49-7.41(m, 4H), 7.38(t, J=4.9Hz, 1H), 7.25(t, J=74.4Hz, 1H), 6.47-6.46(m, 1H), 4.13 (d, J=7.2Hz, 2H), 1.43-1.35 (m, 1H), 0.69-0.64 (m, 2H), 0.46-0.43 (m, 2H). 13 CNMR (101 MHz, DMSO-d 6 )δ162.2, 151.2, 150.2, 141.6, 140.8, 135.3, 133.0, 131.2, 127.8, 126.9, 126.2, 123.0, 122.9, 122.5, 121.4, 119.4, 116.6 (t, J = 257.0 Hz), 115.3, 114.6, 112.4, 111.7, 110.4, 101.3, 73.2, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated for C 27 H23 O 3 N 4 F 2 + [M+H] + , 489.1733; the measured value is 489.1778.

[0336] Example 38 Synthesis of Compound A29:

[0337]

[0338] 70 mg of compound 5 (0.19 mmol, 1.0 equiv.) was dissolved in 1 mL DMF, and then 5 mg of DMAP (0.04 mmol, 0.2 equiv.) and 49 mg of N, N′-disuccinimidyl carbonate (0.19 mmol, 1.0 equiv.) were added, and the reaction was carried out at room temperature for 12 h, and monitored by thin layer chromatography. After the reaction was completed, it was extracted with ethyl acetate, the organic phase was washed with a saturated sodium chloride aqueous solution, the ethyl acetate layer was dried with anhydrous sodium sulfate, and the organic phase was concentrated. After flash column chromatography, 72 mg of compound A29 was obtained, with a yield of 80%.

[0339] The obtained compound A29 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: Conformer A: 1 H NMR (500 MHz, DMSO-d 6 ) δ12.74 (s, 1H), 8.16 (d, J = 8.0Hz, 1H), 8.06 (d, J = 2.0Hz, 1H), 8.04 (dd, J = 7.5, 1.0Hz, 1H), 7.95 (dd, J = 17.5, 2.0Hz, 1H), 7.48-7.42 (m, 1H), 7.34 (d, J=8.5Hz, 1H), 7.21 (t, J=74.0Hz, 1H), 4.05 (d, J=7.0Hz, 2H), 2.96 (s, 4H), 1.36-1.30 (m, 1H), 0.64-0.59 (m, 2H), 0.43-0.39 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ170.6(2×C), 160.8, 153.4, 150.1, 144.9, 141.6, 136.5, 127.4, 127.3, 125.2, 122.3, 120. 9, 119.9, 116.6 (t, J=256.5Hz), 114.2, 112.6, 73.3, 25.7 (2×C), 10.0, 3.1 (2×C).Conformer B: 1 HNMR (500 MHz, DMSO-d6 )δ13.46 (s, 1H), 7.99 (d, J=3.5Hz, 1H), 7.98 (d, J=2.5Hz, 1H), 7.95 (dd, J=17.5, 2.0Hz, 1H), 7.85 (dd, J=8.5, 2.0Hz, 1H), 7.48-7.42 (m, 1H), 7.39 (d, J=8.0Hz, 1H), 7.22 (t, J=74.0Hz, 1H), 4.03 (d, J=6.5Hz, 2H), 2.93 (s, 4H), 1.36-1.30 (m, 1H), 0.64-0.59 (m, 2H), 0.43-0.39 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ170.4 (2×C), 160.8, 153.1, 149.9, 143.2, 141.5, 135.1, 126.8, 125.4, 122.2, 121.2, 120.7, 118.4, 116.6 (t, J=256.5 Hz), 113.6, 108.3, 73.3, 25.6 (2×C), 10.0, 3.0 (2×C). ESI-MS m / z: calculated value is C 23 H 20 O6N 3 F 2 + [M+H] + , 472.1; the measured value is 472.1.

[0340] Example 39 Synthesis of Compound A30:

[0341]

[0342] 300 mg of compound 3 (1.24 mmol, 1.0 equiv.) was dissolved in 5 mL of DMF solution, and then 232 mg of 3-bromo-o-phenylenediamine (1.24 mmol, 1.0 equiv.) and 235 mg of sodium pyrosulfite (1.24 mmol, 1.0 equiv.) were added, and the mixture was heated to 80°C for 12 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride aqueous solution, and the ethyl acetate layer was dried with anhydrous sodium sulfate. The organic phase was concentrated and flash column chromatography was performed to obtain 201 mg of compound A30 with a yield of 40%.

[0343] The obtained compound A30 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6)δ13.24 (s, 1H), 7.96-7.78 (m, 2H), 7.58 (s, 1H), 7.43 (dd, J=8.0, 1.0Hz, 1H), 7.36 (d, J=8.5Hz, 1H), 7.20 (t, J=74 .0Hz, 1H), 7.16 (t, J=8.0Hz, 1H), 4.04 (d, J=7.0Hz, 2H), 1.35-1.29 (m, 1H), 0.64-0.60 (m, 2H), 0.43-0.40 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ151.2, 150.1, 142.1, 141.3, 135.7, 127.7, 124.7, 123.8, 121.2, 119.5, 116.6 (t, J = 256.5 Hz), 112.3, 111.7, 111.0, 73.3, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 18 H 16 O 2 N 2 F 2 Br + [M+H] + , 409.0358; the measured value is 409.0354.

[0344] Example 40 Synthesis of Compound B1:

[0345] The synthesis steps refer to Example 2. In the last step, 2,4-difluorobenzylamine is selected as the amine reagent to obtain compound B1 with a yield of 90%. Conformer A: 1 H NMR (600 MHz, DMSO-d 6 )δ13.20(br,1H),9.09(br,1H),8.27(s,1H),7.92(s,1H),7.84-7.76(m,2H),7 .71 (d, J=7.8Hz, 1H), 7.45 (dd, J=15.6, 8.4Hz, 1H), 7.37 (d, J=8.4Hz, 1H), 7.25- 7.21 (m, 1H), 7.21 (t, J = 74.4Hz, 1H), 7.08-7.04 (m, 1H), 4.52 (d, J = 5.4Hz, 2H), 4.04 (d, J=7.2Hz, 2H), 1.35-1.29 (m, 1H), 0.63-0.60 (m, 2H), 0.42-0.40 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6) δ 166.8, 161.3 (dd, J = 243.0, 12.0 Hz), 160.0 (dd, J = 243.0, 12.0 Hz), 152.7, 150.1, 145.9, 141.3, 137.2, 130.7 (dd, J = 15.0, 3.0 Hz), 128.6, 127.9, 122.8 (dd, J = 15.0, 3.0 Hz), 122.4, 121.3, 119.3, 118.2, 116.6 (t, J = 256.5 Hz), 112.4, 111.3 (dd, J = 21.0, 4.5 Hz), 111.1, 103.6 (t, J = 25.5 Hz), 73.3, 36.2, 10.0, 3.1 (2×C). Conformer B: 1 H NMR (600 MHz, DMSO-d 6 ) δ 13.18 (br, 1H), 9.04 (br, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.84 - 7.76 (m, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.45 (dd, J = 15.6, 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.25 - 7.21 (m, 1H), 7.21 (t, J = 74.4 Hz, 1H), 7.08 - 7.04 (m, 1H), 4.52 (d, J = 5.4 Hz, 2H), 4.04 (d, J = 7.2 Hz, 2H), 1.35 - 1.29 (m, 1H), 0.63 - 0.60 (m, 2H), 0.42 - 0.40 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 ) δ 166.8, 161.3 (dd, J = 243.0, 12.0 Hz), 160.0 (dd, J = 243.0, 12.0 Hz), 152.1, 150.1, 143.3, 141.3, 134.7, 130.7 (dd, J = 15.0, 3.0 Hz), 128.1, 127.9, 122.8 (dd, J = 15.0, 3.0 Hz), 122.4, 121.3, 119.3, 118.2, 116.6 (t, J = 256.5 Hz), 112.4, 111.3 (dd, J = 21.0, 4.5 Hz), 110.9, 103.6 (t, J = 25.5 Hz), 73.3, 36.2, 10.0, 3.1 (2×C). ESI-HRMS m / z: Calculated for C 26 H 22 O 3 N 3 F 4 +[M+H] + , 500.1592; the measured value is 500.1599.

[0346] Example 41 Synthesis of Compound B2:

[0347] The synthesis steps refer to Example 2. In the last step, the amine reagent is 2-methylaminopyrimidine (CAS No.: 75985-45-4) to obtain compound B2 with a yield of 93%. Conformer A: 1 H NMR (500 MHz, DMSO-d 6 )δ13.14(br, 1H), 9.04(br, 1H), 8.78(d, J=5.0Hz, 2H), 8.31-8.20(m, 1H), 7. 92 (d, J=2.0Hz, 1H), 7.85-7.79 (m, 2H), 7.75-7.67 (m, 1H), 7.40 (t, J=5.0Hz, 1H), 7.37 (d, J=8.5Hz, 1H), 7.20 (t, J=74.0Hz, 1H), 4.71 (d, J=5.5Hz, 2H), 4. 04(d, J=7.0Hz, 2H), 1.36-1.29(m, 1H), 0.65-0.60(m, 2H), 0.44-0.39(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ167.4, 166.7, 157.3 (2×C), 152.5, 150.1, 145.9, 141.2, 137.1, 128.8, 127.9, 122.4, 121.2, 1 19.8, 119.2, 118.2, 116.6 (t, J=256.5Hz), 112.4, 111.0, 73.2, 45.5, 10.0, 3.1 (2×C).Conformer B: δ13.14 (br, 1H), 9.04 (br, 1H), 8.78 (d, J=5.0Hz, 2H), 8.17-8.04 (m, 1H), 7 .92(d, J=2.0Hz, 1H), 7.85-7.79(m, 2H), 7.65-7.55(m, 1H), 7.40(t, J=5.0Hz, 1H), 7.37 (d, J=8.5Hz, 1H), 7.20 (t, J=74.0Hz, 1H), 4.71 (d, J=5.5Hz, 2H), 4. 04(d, J=7.0Hz, 2H), 1.36-1.29(m, 1H), 0.65-0.60(m, 2H), 0.44-0.39(m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 167.4, 166.7, 157.3 (2×C), 152.1, 150.1, 143.3, 141.2, 134.7, 128.3, 127.9, 122.4, 121.2, 119.8, 119.2, 118.2, 116.6 (t, J=256.5 Hz), 112.4, 111.0, 73.2, 45.5, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 24 H 22 O 3 N 5 F 2 + [M+H] + , 466.1685; the measured value is 466.1687.

[0348] Example 42 Synthesis of Compound B3:

[0349] The synthesis steps refer to Example 2. In the last step, 4-aminopyridine is selected as the amine reagent to obtain compound B3 with a yield of 35%. Conformer A: 1 H NMR (500 MHz, DMSO-d 6 ) δ13.28 (br, 1H), 10.60 (br, 1H), 8.48 (d, J = 5.5Hz, 2H), 8.39-8.09 (m, 1H), 7.94 (s, 1H), 7.87 (d, J = 8.5Hz, 1H), 7.85-7.80 (m, 3H), 7. 72 (s, 1H), 7.77-7.62 (m, 1H), 7.21 (t, J=74.0Hz, 1H), 4.05 (d, J=7.0Hz, 2H), 1.36-1.29 (m, 1H), 0.65-0.60 (m, 2H), 0.44-0.39 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ166.8, 152.6, 150.3 (2×C), 150.1, 146.2, 143.2, 141.4, 137.8, 128.0, 127.8, 122.9, 121.3, 1 19.3, 118.9, 116.6 (t, J=256.5Hz), 114.0 (2×C), 112.4, 111.4, 73.3, 10.0, 3.1 (2×C).Conformer B: 1 H NMR (500 MHz, DMSO-d 6) δ13.28 (br, 1H), 10.60 (br, 1H), 8.48 (d, J = 5.5Hz, 2H), 8.39-8.09 (m, 1H), 7.94 (s, 1H), 7.87 (d, J = 8.5Hz, 1H), 7.85-7.80 (m, 3H), 7. 72 (s, 1H), 7.77-7.62 (m, 1H), 7.21 (t, J=74.0Hz, 1H), 4.05 (d, J=7.0Hz, 2H), 1.36-1.29 (m, 1H), 0.65-0.60 (m, 2H), 0.44-0.39 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ166.8, 152.6, 150.3 (2×C), 150.1, 146.2, 143.2, 141.4, 134.6, 128.0, 127.8, 122.0, 121.3, 119.3, 118.9, 116.6 (t, J=256.5 Hz), 114.0 (2×C), 112.4, 111.4, 73.3, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 24 H 21 O 3 N 4 F 2 + [M+H] + , 451.1576; the measured value is 451.1571.

[0350] Example 43 Synthesis of Compound B4:

[0351] The synthesis steps refer to Example 2. In the last step, the amine reagent is 4-hydrazinebenzonitrile to obtain compound B4 with a yield of 41%. Conformer A: 1 H NMR (500 MHz, DMSO-d 6 )δ13.22 (br, 1H), 10.55 (br, 1H), 8.81 (s, 1H), 8.30 (s, 1H), 7.93 (s, 1H), 7.87-7.79 (m, 2H), 7.76 (d, J = 8.0Hz, 1H), 7.58 (d, J = 8.5Hz, 2H), 7.38 ( d, J=8.5Hz, 1H), 7.21 (t, J=74.0Hz, 1H), 6.87 (d, J=8.5Hz, 2H), 4.04 (d, J=7.00Hz, 2H), 1.37-1.28(m, 1H), 0.66-0.58(m, 2H), 0.45-0.38(m, 2H). 13 C NMR (151 MHz, DMSO-d6 )δ166.8, 153.3, 152.9, 150.1, 146.3, 141.4, 137.6, 133.5 (2×C), 127.8, 126.8, 122.5, 121.3, 119.4, 1 18.6, 118.3, 116.6 (t, J=256.5Hz), 112.5, 111.8 (2×C), 111.3, 98.9, 73.3, 10.0, 3.1 (2×C).Conformer B: 1 H NMR (500 MHz, DMSO-d 6 )δ13.20 (br, 1H), 10.50 (br, 1H), 8.81 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.87-7.79 (m, 2H), 7.64 (d, J = 8.0Hz, 1H), 7.58 (d, J = 8.5Hz, 2H), 7.38 ( d, J=8.5Hz, 1H), 7.21 (t, J=74.0Hz, 1H), 6.87 (d, J=8.5Hz, 2H), 4.04 (d, J=7.00Hz, 2H), 1.37-1.28(m, 1H), 0.66-0.58(m, 2H), 0.45-0.38(m, 2H). 13 CNMR (151 MHz, DMSO-d 6 )δ166.7, 153.3, 152.3, 150.1, 143.3, 141.3, 134.7, 133.5 (2×C), 127.8, 126.3, 121.4, 120.1, 119.3, 118.6, 118.3, 116.6 (t, J=256.5 Hz), 112.4, 111.8 (2×C), 111.1, 98.9, 73.3, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 26 H 22 O 3 N 5 F 2 + [M+H] + , 490.1685; the measured value is 490.1637.

[0352] Example 44 Synthesis of Compound B5:

[0353]

[0354] 100 mg of compound 7 (0.27 mmol, 1.0 equiv.) was dissolved in 1 mL DMF, and then 33 mg of DMAP (0.27 mmol, 1.0 equiv.) and 67 mg of N, N′-disuccinimidyl carbonate (0.27 mmol, 1.0 equiv.) were added, and the mixture was reacted at room temperature for 12 h, and monitored by thin layer chromatography. After the reaction was completed, the mixture was extracted with ethyl acetate, the organic phase was washed with a saturated sodium chloride aqueous solution, the ethyl acetate layer was dried with anhydrous sodium sulfate, and the organic phase was concentrated. 77 mg of compound B5 was obtained by flash column chromatography, with a yield of 61%.

[0355] The obtained compound B5 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: Conformer A: 1 H NMR (500 MHz, DMSO-d 6 )δ13.48 (br, 1H), 8.39 (s, 1H), 7.99-7.91 (m, 2H), 7.83 (dd, J=8.5, 2.0Hz, 1H), 7.80-7.72 (m, 1H), 7.40 (d, J=8.5Hz, 1H ), 7.22 (t, J=74.0Hz, 1H), 4.04 (d, J=7.0Hz, 2H), 2.91 (s, 4H), 1.36-1.29 (m, 1H), 0.65-0.60 (m, 2H), 0.43-0.39 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ170.5(2×C), 162.3, 154.7, 150.1, 148.7, 141.8, 140.0, 127.3, 124.4, 121.5, 121.2, 119. 7, 117.8, 116.6 (t, J=256.5Hz), 114.0, 112.6, 73.3, 25.6 (2×C), 10.0, 3.1 (2×C).Conformer B: 1 H NMR (500 MHz, DMSO-d 6 )δ13.48 (br, 1H), 8.24 (s, 1H), 7.99-7.91 (m, 2H), 7.90-7.85 (m, 1H), 7.83 (dd, J=8.5, 2.0Hz, 1H), 7.40 (d, J=8.5Hz, 1H ), 7.22 (t, J=74.0Hz, 1H), 4.04 (d, J=7.0Hz, 2H), 2.91 (s, 4H), 1.36-1.29 (m, 1H), 0.65-0.60 (m, 2H), 0.43-0.39 (m, 2H). 13 CNMR (151 MHz, DMSO-d6 )δ170.5 (2×C), 162.3, 153.6, 150.1, 143.4, 141.6, 135.0, 127.3, 123.6, 121.5, 121.2, 119.6, 117.8, 116.6 (t, J=256.5 Hz), 112.7, 112.4, 73.3, 25.6 (2×C), 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 23 H 20 O 6 N 3 F 2 + [M+H] + , 472.1315; the measured value is 472.1299.

[0356] Example 45 Synthesis of Compound C1:

[0357] The synthesis steps refer to Example 3. In the last step, pyridine-4-boric acid (CAS No.: 1692-15-5) was selected as the boronic acid reagent to obtain compound C1 with a yield of 31%. Conformer A: 1 H NMR (500 MHz, DMSO-d 6 )δ13.15 (s, 1H), 8.63 (t, J=6.5Hz, 2H), 8.13 (s, 1H), 7.94 (d, J=4.0Hz, 1H), 7.81 (d, J=9.0Hz, 1H), 7.80-7.77 (m, 2H), 7.77-7.73 (m, 1H), 7.70 -7.66 (m, 1H), 7.37 (d, J = 8.0Hz, 1H), 7.20 (t, J = 74.0Hz, 1H), 4.04 (d, J = 7.0Hz, 2H), 1.36-1.30 (m, 1H), 0.64-0.60 (m, 2H), 0.44-0.40 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ152.0, 150.2, 150.1 (2×C) 147.9, 144.6, 141.2, 135.9, 131.9, 128.0, 121.8, 121.4, 121.3 (2×C), 119.4, 119.2, 116.6 (t, J=256.5Hz), 112.3, 112.0, 73.2, 10.0, 3.1 (2×C).Conformer B: 1 H NMR (500 MHz, DMSO-d 6)δ13.10 (s, 1H), 8.63 (t, J = 6.5Hz, 2H), 7.94 (d, J = 4.0Hz, 1H), 7.90 (s, 1H), 7.81 (d, J = 9.0Hz, 1H), 7.77-7.73 (m, 2H), 7.70-7.66 (m, 1H), 7.65 -7.62 (m, 1H), 7.37 (d, J = 8.0Hz, 1H), 7.20 (t, J = 74.0Hz, 1H), 4.04 (d, J = 7.0Hz, 2H), 1.36-1.30 (m, 1H), 0.64-0.60 (m, 2H), 0.44-0.40 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ151.8, 150.2, 150.1 (2×C), 147.8, 144.4, 141.2, 135.7, 131.2, 128.0, 121.4, 121.3 (2×C), 121.1, 119.1, 117.2, 116.6 (t, J=256.5 Hz), 112.2, 109.6, 73.2, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 23 H 20 O 2 N 3 F 2 + [M+H] + , 408.1518; the measured value is 408.1517.

[0358] Example 46 Synthesis of Compound C2:

[0359] The synthesis steps refer to Example 3. In the last step, 3,4-dimethoxyphenylboronic acid is selected as the boronic acid reagent to obtain compound C2 with a yield of 89%. Conformer A: 1 H NMR (500 MHz, DMSO-d 6)δ12.94(br,1H),7.92(d,J=2.0Hz,1H),7.79(dd,J=8.5,2.0Hz,1H),7.78-7.52(m,2H),7.50(d,J=8.5Hz,1H),7.36(d,J=8.5Hz,1H),7.26(d,J=2.0Hz,1H),7.22(dd,J=8.5,2.0Hz,1H),7.19(t,J=75.5Hz,1H),7.05(d,J=2.5Hz,1H),4.04(d,J=7.0Hz,2H),3.87(s,3H),3.80(s,3H),1.35-1.31(m,1H),0.65-0.60(m,2H),0.44-0.40(m,2H). 13 CNMR(151MHz,DMSO-d 6 )δ151.0,150.1,149.1,148.1,144.4,141.0,135.7,134.6,134.0,128.3,121.9,121.3,118.9,116.7(t,J=256.5Hz),116.5,112.3,112.1,111.4,110.8,108.8,73.2,55.6,55.5,10.0,3.1(2×C).Conformer B: 1 H NMR(500MHz,DMSO-d 6 )δ12.94(br,1H),7.92(d,J=2.0Hz,1H),7.79(dd,J=8.5,2.0Hz,1H),7.78-7.52(m,2H),7.50(d,J=8.5Hz,1H),7.36(d,J=8.5Hz,1H),7.26(d,J=2.0Hz,1H),7.22(dd,J=8.5,2.0Hz,1H),7.19(t,J=75.5Hz,1H),7.05(d,J=2.5Hz,1H),4.04(d,J=7.0Hz,2H),3.87(s,3H),3.80(s,3H),1.35-1.31(m,1H),O.65-O.60(m,2H),O.44-O.40(m,2H). 13 CNMR(151MHz,DMSO-d 6)δ151.0, 150.1, 149.1, 148.1, 143.0, 141.0, 135.3, 134.6, 134.3, 128.3, 121.9, 121.3, 118.9, 116.7 (t, J = 256.5 Hz), 116.5, 112.3, 112.1, 111.4, 110.8, 108.8, 73.2, 55.6, 55.5, 10.0, 3.1 (2×C). ESI-MS m / z: calculated value is C 26 H 25 O 4 N 2 F 2 + [M+H] + , 467.2; the measured value is 467.2.

[0360] Example 47 Synthesis of Compound C3:

[0361] The synthesis steps refer to Example 3. In the last step, the boronic acid reagent is 1-(phenylsulfonyl)-3-indoleboric acid (CAS No.: 129271-98-3) to obtain compound C3 with a yield of 46%. Conformer A: 1 H NMR (500 MHz, DMSO-d 6 )δ13.04 (s, 1H), 8.10 (dd, J=8.0, 1.5Hz, 3H), 8.06 (d, J=8.5Hz, 1H), 8.05-7.95 (m, 1H), 7.9 4(d, J=2.0Hz, 1H), 7.88 (d, J=8.0Hz, 1H), 7.81 (dd, J=8.5, 2.0Hz, 1H), 7.80-7.71 (m, 1H), 7 .71-7.68(m, 1H), 7.62-7.54(m, 3H), 7.44(t, J=8.0Hz, 1H), 7.39-7.35(m, 2H), 7.20(t, J=7 4.0Hz, 1H), 4.04 (d, J=7.0Hz, 2H), 1.36-1.30 (m, 1H), 0.64-0.60 (m, 2H), 0.44-0.40 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ151.3, 150.1, 144.3, 141.1, 137.0, 135.6, 134.9, 134.7, 129.9, 129.0, 128.2, 126.9, 126.8, 125.2, 124.2, 124.0, 123.3, 1 23.1, 122.3, 121.3, 120.5, 119.3, 119.0, 117.9, 116.7 (t, J=256.5Hz), 113.6, 112.2, 111.8, 73.2, 10.0, 3.1 (2×C).Conformer B: 1 H NMR (500 MHz, DMSO-d 6 )δ13.04 (s, 1H), 8.10 (dd, J=8.0, 1.5Hz, 3H), 8.06 (d, J=8.5Hz, 1H), 8.05-7.95 (m, 1H), 7.9 4(d, J=2.0Hz, 1H), 7.88 (d, J=8.0Hz, 1H), 7.81 (dd, J=8.5, 2.0Hz, 1H), 7.80-7.71 (m, 1H), 7 .71-7.68(m, 1H), 7.62-7.54(m, 3H), 7.44(t, J=8.0Hz, 1H), 7.39-7.35(m, 2H), 7.20(t, J=7 4.0Hz, 1H), 4.04 (d, J=7.0Hz, 2H), 1.36-1.30 (m, 1H), 0.64-0.60 (m, 2H), 0.44-0.40 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ151.2, 150.1, 143.5, 141.1, 137.0, 135.6, 134.8, 134.6, 129.9, 128.9, 128.2, 126.9, 126.0, 125.1, 124.2, 123.9, 123.3, 123.0, 122.3, 121.3, 120.4, 119.3, 118.9, 117.9, 116.7 (t, J = 256.5 Hz), 113.5, 112.2, 110.3, 73.2, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 32 H 26 O 4 N 3 SF 2 + [M+H] + , 586.1607; the measured value is 586.1598.

[0362] Example 48 Synthesis of Compound D1:

[0363] The synthesis steps refer to Example 4. In the last step, 2,4-difluorobenzylamine is selected as the amine reagent to obtain compound D1 with a yield of 77%. Conformer A: 1 H NMR (500 MHz, DMSO-d 6 )δ12.97(br, 1H), 9.02(br, 1H), 8.22(s, 1H), 7.81-7.75(m, 2H), 7.74(dd, J=8 .5, 2.0Hz, 1H), 7.66 (d, J=8.5Hz, 1H), 7.48-7.42 (m, 1H), 7.25-7.19 (m, 1H), 7 .10 (d, J=8.5Hz, 1H), 7.09-7.04 (m, 1H), 4.52 (d, J=5.5Hz, 2H), 3.90 (s, 3H), 3 .89 (d, J=7.0Hz, 2H), 1.30-1.23 (m, 1H), 0.61-0.57 (m, 2H), O.36-0.31 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ166.9, 161.3 (dd, J=244.5, 12.0Hz), 160.O (dd, J=244.5, 12.0Hz), 153.7, 1 50.0, 149.O, 146.1, 137.2, 130.7 (dd, J=10.5, 6.0Hz), 128.O, 122.9 (dd, J=15 .O, 3.0Hz), 122.2, 121.9, 119.7, 117.8, 112.8, 111.3 (dd, J=21.O, 3.0Hz), 11 0.7, 110.O, 103.6 (t, J=25.5Hz), 72.9, 55.6, 36.2, 10.2, 3.2 (2×C).Conformer B: 1 H NMR (500 MHz, DMSO-d 6)δ12.97(br, 1H), 8.98(br, 1H), 8.04(s, 1H), 7.81-7.75(m, 2H), 7.74(dd, J=8 .5, 2.0Hz, 1H), 7.55 (d, J=8.5Hz, 1H), 7.48-7.42 (m, 1H), 7.25-7.19 (m, 1H), 7 .10 (d, J=8.5Hz, 1H), 7.09-7.04 (m, 1H), 4.52 (d, J=5.5Hz, 2H), 3.90 (s, 3H), 3 .89(d, J=7.0Hz, 2H), 1.30-1.23(m, 1H), 0.61-0.57(m, 2H), 0.36-0.31(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ166.8, 161.3 (dd, J=244.5, 12.0Hz), 160.0 (dd, J=244.5, 12.0Hz), 153.1, 1 49.9, 149.0, 143.5, 134.7, 130.7 (dd, J=10.5, 6.0Hz), 127.7, 122.9 (dd, J=15 .0, 3.0Hz), 122.2, 121.0, 119.6, 117.8, 112.8, 111.3 (dd, J=21.0, 3.0Hz), 11 0.6, 110.0, 103.6 (t, J=25.5Hz), 72.9, 55.6, 36.2, 10.2, 3.2 (2×C).ESI-HRMS m / z: calculated value is C 26 H 23 O 3 N 3 F 2 Na + [M+Na] + , 486.1600; the measured value is 486.1617.

[0364] Example 49 Synthesis of Compound D2:

[0365] The synthesis steps refer to Example 4. In the last step, the amine reagent is 2-methylaminopyrimidine (CAS No.: 75985-45-4) to obtain compound D2 with a yield of 75%. Conformer A: 1 H NMR (500 MHz, DMSO-d 6) δ 12.97 (br, 1H), 9.02 (s, 1H), 8.78 (d, J = 5.0 Hz, 2H), 8.30 - 8.00 (m, 1H), 7.84 - 7.77 (m, 2H), 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.69 - 7.53 (m, 1H), 7.39 (t, J = 5.0 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 4.71 (d, J = 6.0 Hz, 2H), 3.91 (s, 3H), 3.89 (d, J = 7.0 Hz, 2H), 1.29 - 1.22 (m, 1H), 0.62 - 0.56 (m, 2H), 0.37 - 0.31 (m, 2H). 13 C NMR (151 MHz, DMSO - d 6 ) δ 167.5, 166.8, 157.3 (2×C), 153.6, 150.0, 149.0, 146.1, 137.2, 128.1, 122.2, 121.9, 119.7, 119.6, 117.8, 112.8, 110.6, 110.0, 72.9, 55.6, 45.5, 10.2, 3.2 (2×C). Conformer B: 1 H NMR (500 MHz, DMSO - d 6 ) δ 12.97 (br, 1H), 9.02 (s, 1H), 8.78 (d, J = 5.0 Hz, 2H), 8.30 - 8.00 (m, 1H), 7.84 - 7.77 (m, 2H), 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.69 - 7.53 (m, 1H), 7.39 (t, J = 5.0 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 4.71 (d, J = 6.0 Hz, 2H), 3.91 (s, 3H), 3.89 (d, J = 7.0 Hz, 2H), 1.29 - 1.22 (m, 1H), 0.62 - 0.56 (m, 2H), 0.37 - 0.31 (m, 2H). 13 C NMR (151 MHz, DMSO - d 6 ) δ 167.5, 166.8, 157.3 (2×C), 153.2, 150.0, 149.0, 143.5, 134.7, 128.1, 122.2, 121.1, 119.7, 119.6, 117.8, 112.8, 110.6, 110.0, 72.9, 55.6, 45.5, 10.2, 3.2 (2×C). ESI - HRMS m / z: Calculated for C 24 H 23 O 3 N 5 Na+ [M+Na] + , 452.1693; the measured value is 452.1709.

[0366] Example 50 Synthesis of Compound D3:

[0367] The synthesis steps refer to Example 4. In the last step, the amine reagent is 6-aminobenzothiazole to obtain compound D3 with a yield of 23%. Conformer A: 1 H NMR (600 MHz, DMSO-d 6 ) δ13.07 (br, 1H), 10.55 (br, 1H), 9.30 (d, J = 1.8Hz, 1H), 8.74 (dd, J = 7.8, 1.8Hz, 1 H), 8.36 (s, 1H), 8.07 (dd, J=9.0, 2.4Hz, 1H), 7.90-7.85 (m, 2H), 7.81-7.78 (m, 1H) , 7.78-7.75 (m, 1H), 7.74 (d, J=8.4Hz, 1H), 7.16 (dd, J=8.4, 3.6Hz, 1H), 3.94 (d, J= 6.6Hz, 2H), 3.87(s, 3H), 1.33-1.28(m, 1H), 0.63-0.60(m, 2H), 0.40-0.37(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ166.3, 154.9, 154.0, 150.9, 149.4, 148.3, 146.4, 137.5, 137.3, 134.1, 128.6, 122.8, 122.4, 122.1, 120.0, 119.8, 118.3, 112.8, 112.0, 111.2, 110.9, 73.0, 55.6, 10.3, 3.3 (2×C).Conformer B: 1 H NMR (600 MHz, DMSO-d 6) δ13.03 (br, 1H), 10.48 (br, 1H), 9.30 (d, J = 1.8Hz, 1H), 8.74 (dd, J = 7.8, 1.8Hz, 1 H), 8.12 (s, 1H), 8.07 (dd, J=9.0, 2.4Hz, 1H), 7.90-7.85 (m, 2H), 7.81-7.78 (m, 1H) , 7.78-7.75 (m, 1H), 7.62 (d, J=8.4Hz, 1H), 7.16 (dd, J=8.4, 3.6Hz, 1H), 3.94 (d, J= 6.6Hz, 2H), 3.87(s, 3H), 1.33-1.28(m, 1H), 0.63-0.60(m, 2H), 0.40-0.37(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ166.2, 154.8, 153.3, 150.8, 149.3, 148.2, 143.4, 137.3, 134.7, 134.1, 128.2, 122.8, 122.2, 121.5, 119.9, 119.6, 117.9, 112.7, 112.0, 111.0, 110.8, 73.0, 55.6, 10.3, 3.3 (2×C). ESI-HRMS m / z: calculated for C 26 H 23 O 3 N 4 S + [M+H] + , 471.1485; the measured value is 471.1438.

[0368] Example 51 Synthesis of Compound E1:

[0369] The synthesis steps were similar to those in Example 5. In the last step, 2-aminothiazole was selected as the amine reagent to obtain compound E1 with a yield of 50%. 1 H NMR (500 MHz, DMSO-d 6 )δ13.80 (br, 1H), 13.39 (s, 1H), 8.24-8.17 (m, 2H), 8.04 (d, J = 7.5Hz, 1H), 7.89 (d, J = 8.0Hz, 1H), 7.68 (d, J = 8.5Hz, 1 H), 7.61 (d, J=3.5Hz, 1H), 7.48-7.44 (m, 1H), 7.37 (t, J=73.0Hz, 1H), 7.34 (d, J=3.5Hz, 1H), 7.31 (t, J=72.5Hz, 1H). 13 CNMR (151 MHz, DMSO-d 6)δ162.3, 157.5, 150.7, 144.1, 141.8, 140.9, 138.1, 135.4, 126.6, 125.3, 123.5, 123.3, 121.2, 120.1, 119.4, 116.9, 116.5 (t, J = 259.5 Hz), 116.3 (t, J = 259.5 Hz), 114.2. ESI-HRMS m / z: calculated value is C 19 H 13 O 3 N 4 F 4 S + [M+H] + , 453.0639; the measured value is 453.0614.

[0370] Example 52 Synthesis of Compound E2:

[0371] The synthesis steps were as in Example 5. In the last step, 6-aminobenzothiazole was selected as the amine reagent to obtain compound E2 with a yield of 76%. 1 H NMR (400 MHz, DMSO-d 6 )δ14.06 (br, 1H), 12.42 (br, 1H), 9.31 (s, 1H), 8.77 (s, 1H), 8.33 (s, 1H), 8.29 (d, J=8.4Hz, 1H), 8.09 (d , J=8.8Hz, 1H), 8.00 (d, J=8.8Hz, 1H), 7.91 (d, J=8.8Hz, 1H), 7.83 (d, J=8.0Hz, 1H), 7.64-7.19 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 )δ163.0, 155.1, 150.5, 149.5, 143.4, 142.0, 140.8, 136.7, 135.5, 134.7, 126.8, 125.1, 123.3, 123.2 (2×C), 121.8, 121.4, 119.2, 118.9, 116.7 (t, J=258.0 Hz), 116.4 (t, J=258.0 Hz), 116.1, 111.9. ESI-HRMS m / z: calculated for C 23 H 15 O 3 N 4 F 4 S + [M+H] + , 503.0796; the measured value is 503.0771.

[0372] Example 53 Synthesis of Compound E3:

[0373] The synthesis steps were as in Example 5. In the last step, 2,6-difluorobenzylamine was selected as the amine reagent to obtain compound E3 with a yield of 47%. 1 H NMR (500 MHz, DMSO-d 6 )δ13.82 (br, 1H), 1O.39 (s, 1H), 8.20 (s, 1H), 8.19-8.14 (m, 1H), 7.89 (d, J = 7.5Hz, 1H), 7.76 (d, J = 8.0Hz, 1H), 7.62 (d, J = 8.5Hz, 1H) , 7.46-7.41 (m, 1H), 7.39-7.35 (m, 1H), 7.37 (t, J=73.0Hz, 1H), 7.33 (t, J=73.0Hz, 1H), 7.15 (t, J=8.0Hz, 2H), 4.80 (d, J=5.5Hz, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ164.1, 160.9 (dd, J = 246.0, 9.0 Hz, 2×C), 150.2, 143.7, 141.8, 140.8, 135.4, 130.1 (t, J = 10.5 Hz), 127.1, 124.9, 122.9 (d, J = 22.5 Hz), 121.7, 121.0, 119.8, 116.5 (t, J = 259.5 Hz), 116.4 (t, J = 259.5 Hz), 115.5, 114.5, 114.4, 111.7 (dd, J = 19.5, 4.5 Hz, 2×C), 30.5. ESI-HRMS m / z: calculated for C 23 H 16 O 3 N 3 F 6 + [M+H] + , 496.1090; the measured value is 496.1061.

[0374] Example 54 Synthesis of Compound E4:

[0375] The synthesis steps were similar to those in Example 5. In the last step, 2,4-difluorobenzylamine was selected as the amine reagent to obtain compound E4 with a yield of 55.7%. 1 H NMR (500 MHz, DMSO-d 6)δ13.56 (br, 1H), 10.27 (s, 1H), 8.25-8.09 (m, 2H), 7.90 (d, J = 7.5Hz, 1H), 7.78 (d, J = 8.0Hz, 1H), 7.62-7.53 (m, 2H), 7.39 (t , J=8.0Hz, 1H), 7.35 (t, J=73.0Hz, 1H), 7.30 (t, J=73.0Hz, 1H), 7.28-7.23 (m, 1H), 7.10-7.06 (m, 1H), 4.72 (d, J=5.5Hz, 2H). 13 C NMR (151 MHz, DMSO-d 6 ) δ164.5, 161.6 (dd, J=243.0, 12.0Hz), 160.4 (dd, J=246.0, 12.0Hz), 150.2, 143. 7, 141.8, 140.9, 135.4, 131.0 (dd, J=9.0, 6.0Hz), 127.0, 125.1, 123.1, 122.9, 12 2.5 (dd, J = 15.0, 4.5 Hz), 121.9, 121.1, 119.8, 116.5 (t, J = 259.5 Hz), 116.3 (t, J = 259.5 Hz), 115.4, 111.4 (dd, J = 21.0, 3.0 Hz), 103.9 (t, J = 25.5 Hz), 36.5. ESI-HRMS m / z: calculated for C 23 H 16 O 3 N 3 F 6 + [M+H] + , 496.1090; the measured value is 496.1061.

[0376] Example 55 Synthesis of Compound E5:

[0377] The synthesis steps were similar to those in Example 5. Aniline was selected as the amine reagent in the last step to obtain compound E5 with a yield of 80%. 1 H NMR (500 MHz, DMSO-d 6) δ13.71 (br, 1H), 12.19 (s, 1H), 8.28 (s, 1H), 8.24 (dd, J = 8.5, 2.0Hz, 1H), 8.00 (d, J = 7.5Hz, 1H), 7.88 (d, J = 8.0Hz, 2H), 7.84 (d , J=8.0Hz, 1H), 7.65 (d, J=8.5Hz, 1H), 7.47-7.41 (m, 3H), 7.40 (t, J=73.0Hz, 1H), 7.37 (t, J=73.0Hz, 1H), 7.16 (t, J=7.5Hz, 1H). 13 C NMR (151 MHz, DMSO-d 6 )δ162.7, 150.3, 143.5, 141.9, 140.7, 139.0, 135.4, 129.1 (2×C), 126.8, 124.9, 123.7 (2×C), 123.3, 123.1, 122.0, 121.4, 119.3 (2×C), 116.6 (t, J=259.5 Hz), 116.3 (t, J=259.5 Hz), 115.9. ESI-HRMS m / z: calculated value is C 22 H 16 O 3 N 3 F 4 + [M+H]+, 446.1122; found: 446.1103.

[0378] Example 56 Synthesis of Compound E6:

[0379] The synthesis steps refer to Example 5. In the last step, the amine reagent is 2-(aminomethyl)naphthalene (CAS No.: 2018-90-8) to obtain compound E6 with a yield of 70%; 1 H NMR (500 MHz, DMSO-d 6 )δ13.57 (br, 1H), 10.36 (t, J=5.5Hz, 1H), 8.15 (s, 1H), 8.13 (d, J=9.0Hz, 1H), 7.95 (d, J=5.5Hz, 2H), 7.93-7.86 (m, 3H), 7.78 (d, J=8.0Hz, 1 H), 7.63 (d, J=8.5Hz, 1H), 7.51-7.48 (m, 3H), 7.40 (d, J=8.0Hz, 1H), 7.32 (t, J=73.0Hz, 1H), 7.25 (t, J=73.0Hz, 1H), 4.89 (d, J=5.5Hz, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ164.5, 150.2, 143.6, 141.8, 140.9, 137.0, 135.4, 133.0, 132.2, 128.2, 127.6, 127.5, 127.0, 126.2, 126.0, 125.7, 125.5, 125.1, 123.1, 122.9, 122.2, 121.0, 119.8, 116.5 (t, J = 259.5 Hz), 116.3 (t, J = 259.5 Hz), 115.3, 43.0. ESI-HRMS m / z: calculated for C 27 H 20 O 3 N 3 F 4 + [M+H] + , 510.1435; the measured value is 510.1403.

[0380] Example 57 Synthesis of Compound E7:

[0381] The synthesis steps were similar to those in Example 5. In the last step, 2,3-difluorobenzylamine was selected as the amine reagent to obtain compound E7 with a yield of 65%. 1 H NMR (500 MHz, DMSO-d 6 ) δ14.18 (br, 1H), 10.33 (t, J = 6.0Hz, 1H), 8.31 (s, 1H), 8.28 (d, J = 8.5Hz, 1H), 7.89 (d, J = 7.5Hz, 1H), 7.78 (d, J = 8.0Hz, 1H), 7.57 (d, J = 8.5H z, 1H), 7.39 (d, J=7.5Hz, 1H), 7.37 (t, J=73.0Hz, 1H), 7.36 (t, J=73.0Hz, 1H), 7.36-7.31 (m, 2H), 7.23-7.21 (m, 1H), 4.81 (d, J=6.0Hz, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ164.6, 150.3, 149.7 (dd, J=243.0, 12.0Hz), 147.9 (dd, J=243.0, 12.0Hz), 1 43.5, 141.9, 140.9, 135.4, 128.9 (d, J=10.5Hz), 127.1, 125.1, 124.8 (dd, J=7. 5, 4.5 Hz), 124.7 (t, J = 4.5 Hz), 123.0, 122.8, 121.8, 121.0, 119.8, 116.5 (t, J = 259.5 Hz), 116.3 (t, J = 259.5 Hz), 116.2 (d, J = 16.5 Hz), 115.4, 36.5. ESI-HRMS m / z: calculated value is C 23 H 16 O 3 N 3 F 6 + [M+H] + , 496.1090; the measured value is 496.1064.

[0382] Example 58 Synthesis of Compound E8:

[0383] The synthesis steps were as in Example 5. In the last step, 2,4,6-trifluorobenzylamine was selected as the amine reagent to obtain compound E8 with a yield of 43%. 1 H NMR (400 MHz, DMSO-d 6 )δ13.63 (br, 1H), 10.36 (br, 1H), 8.14-8.13 (m, 2H), 7.89 (d, J = 7.2Hz, 1H), 7.77 (d, J = 8.0Hz, 1H), 7.64 (d, J = 8.8Hz, 1H ), 7.38 (t, J=8.0Hz, 1H), 7.37 (t, J=72.8Hz, 1H), 7.32 (t, J=72.8Hz, 1H), 7.23 (t, J=8.8Hz, 2H), 4.75 (d, J=5.2Hz, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ164.2, 161.6 (dt, J = 245.0, 17.0 Hz), 161.1 (ddd, J = 246.0, 15.0, 11.0 Hz, 2×C), 150.2, 143.8, 141.9, 140.8, 135.4, 127.0, 124.9, 123.1, 123.0, 121.7, 121.2, 119.8, 116.5 (t, J = 258.0 Hz), 116.4 (t, J = 258.0 Hz), 115.5, 111.4 (td, J = 21.0, 4.0 Hz), 100.8 (t, J = 28.0 Hz, 2×C), 30.4. ESI-HRMS m / z: calculated for C 23 H 15 O 3 N 3 F 7 + [M+H] + , 514.0996; the measured value is 514.0972.

[0384] Example 59 Synthesis of Compound E9:

[0385] The synthesis steps were as in Example 5. The last step of the amine reagent was 2-methoxy-5-(aminomethyl)pyridine (CAS No.: 262295-96-5) to obtain compound E9 with a yield of 71%. 1 H NMR (400 MHz, DMSO-d 6 )δ13.59 (br, 1H), 10.20 (br, 1H), 8.26 (s, 1H), 8.16 (d, J = 8.8Hz, 1H), 8.12 (s , 1H), 7.91 (d, J=7.6Hz, 1H), 7.81 (dd, J=8.8, 2.4Hz, 1H), 7.77 (d, J=8.0Hz, 1H ), 7.57 (d, J=8.4Hz, 1H), 7.39 (t, J=8.0Hz, 1H), 7.35 (t, J=72.8Hz, 1H), 7.29 (t, J=72.8Hz, 1H), 6.82 (d, J=7.8Hz, 1H), 4.65 (d, J=5.6Hz, 2H), 3.83 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6)δ164.5, 162.9, 150.2, 145.9, 143.6, 141.8, 140.9, 138.9, 135.4, 128.0, 127.0, 125.1, 123.1, 123.0, 122.1, 121.1, 119.7, 116.5 (t, J = 259.0 Hz), 116.4 (t, J = 259.0 Hz), 115.3, 110.5, 53.1, 38.3. ESI-HRMS m / z: calculated value is C 23 H 19 O 4 N 4 F 4 + [M+H] + , 491.1337; the measured value is 491.1316.

[0386] Example 60 Synthesis of Compound E10:

[0387] The synthesis steps were as in Example 5. The last step of the amine reagent was 2-aminomethylpyrazine (Pyrazin-2-ylmethanamine, CAS No.: 20010-99-5) to obtain compound E10 with a yield of 75%. 1 H NMR (400 MHz, DMSO-d 6 )δ13.63 (br, 1H), 10.68 (br, 1H), 8.79 (s, 1H), 8.71 (s, 1H), 8.61 (d, J = 2.0Hz, 1H), 8.31 (dd, J = 8.4, 1.6Hz, 1H), 8.28 (s, 1H), 7.92 (d, J = 7.2Hz, 1H), 7.79 (d, J=7.6Hz, 1H), 7.65 (d, J=8.4Hz, 1H), 7.40 (t, J=7.6Hz, 1H), 7.38 (t, J=72.8Hz, 1H), 7.31 (t, J=72.8Hz, 1H), 4.91 (d, J=4.8Hz, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ164.8, 153.5, 150.2, 144.0 (2×C), 143.8, 143.3, 141.8, 141.1, 135.4, 127.2, 125.4, 123.1, 122.9, 122.0, 121.1, 120.2, 116.6 (t, J = 258.7 Hz), 116.4 (t, J = 258.4 Hz), 115.4, 42.8. ESI-HRMS m / z: calculated value is C 21 H 16 O 3 N5 F 4 + [M+H] + , 462.1184; the measured value is 462.1153.

[0388] Example 61 Synthesis of Compound E11:

[0389] The synthesis steps were similar to those in Example 5. Benzylamine was selected as the amine reagent in the last step to obtain compound E11 with a yield of 79%. 1 H NMR (400 MHz, DMSO-d 6 ) δ13.60 (br, 1H), 10.26 (br, 1H), 8.16-8.14 (m, 2H), 7.93 (d, J = 7.2Hz, 1H), 7.78 (dd, J = 8.0, 0.8Hz, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.49-7.45 (m, 2H), 7.42-7.36 (m, 3H), 7.36 (t, J=72.8Hz, 1H), 7.31-7.27 (m, 1H), 7.30 (t, J=72.8Hz, 1H), 4.72 (d, J=4.8Hz, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ164.4, 150.2, 143.7, 141.8, 140.9, 139.4, 135.4, 128.6 (2×C), 127.4 (2×C), 127.0, 169.9, 125.1, 123.1, 123.0, 122.2, 121.1, 119.9, 116.5 (t, J = 259.0 Hz), 116.4 (t, J = 259.0 Hz), 115.3, 42.9. ESI-HRMS m / z: calculated value is C 23 H 18 O 3 N 3 F 4 + [M+H] + , 460.1279; the measured value is 460.1250.

[0390] Example 62 Synthesis of Compound E12:

[0391] The synthesis steps were as in Example 5. The last step of the amine reagent was 4-aminomethyltetrahydropyran (CAS No.: 130290-79-8) to obtain compound E12 with a yield of 65%. 1 H NMR (400 MHz, DMSO-d 6)δ14.33(br, 1H), 9.9(br, 1H), 8.31-8.28(m, 2H), 7.87(d, J=7.2Hz, 1H), 7.76 (d, J=8.0Hz, 1H), 8.61-7.58 (m, 1H), 7.42 (t, J=73.2Hz, 1H), 7.39 (t, J=72.8Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 3.88 (dd, J=7.2, 3.2Hz, 2H), 3.39-3 .29(m, 4H), 1.92-1.82(m, 1H), 1.73(d, J=12.4Hz, 2H), 1.42-1.33(m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ164.5, 150.2, 143.4, 141.9, 140.8, 135.5, 127.1, 125.0, 122.9, 122.8, 122.3, 121.1, 119.5, 116.5 (t, J = 259.0 Hz), 116.4 (t, J = 259.0 Hz), 115.2, 66.8 (2×C), 44.5, 35.1, 30.5 (2×C). ESI-HRMS m / z: calculated value is C 22 H 22 O 4 N 3 F 4 + [M+H] + , 468.1541; the measured value is 468.1518.

[0392] Example 63 Synthesis of Compound E13:

[0393] The synthesis steps were similar to those in Example 5. The last step was to use 2-aminomethylpyridine (CAS No.: 3731-51-9) as the amine reagent to obtain compound E13 with a yield of 67%. 1 H NMR (400 MHz, DMSO-d 6)δ13.61 (br, 1H), 10.74 (br, 1H), 8.69 (d, J = 4.4Hz, 1H), 8.34 (dd, J = 8.4, 2.0 Hz, 1H), 8.29 (s, 1H), 7.94 (d, J=7.2Hz, 1H), 7.84-7.77 (m, 2H), 7.65 (d, J=8. 5Hz, 1H), 7.49 (d, J=8.4Hz, 1H), 7.41 (d, J=8.0Hz, 1H), 7.38 (t, J=72.8Hz, 1H ), 7.35 (dd, J=7.2, 1.2Hz, 1H), 7.30 (t, J=73.2Hz, 1H), 4.83 (d, J=4.8Hz, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ164.5, 157.5, 150.2, 149.0, 143.9, 141.8, 141.1, 137.0, 135.4, 127.2, 125.4, 123.0, 122.9, 122.4, 122.2, 121.7, 121.1, 120.4, 116.7 (t, J = 259.0 Hz), 116.4 (t, J = 259.0 Hz), 115.3, 40.1. ESI-HRMS m / z: calculated for C 22 H 17 O 3 N 4 F 4 + [M+H] + , 461.1231; the measured value is 461.1203.

[0394] Example 64 Synthesis of Compound F1:

[0395] The synthesis steps were similar to those in Example 6. In the last step, 2,4,6-trifluorobenzylamine was selected as the amine reagent to obtain compound F1 with a yield of 41%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.86 (t, J=5.6Hz, 1H), 8.67 (d, J=4.4Hz, 1H), 7.93 (d, J=2.0Hz, 1H), 7.77 (dd, J=2.0Hz, 8.4Hz, 1H), 7.41-7.36 (m, 2H), 7.26 (t, J=7 4.0Hz, 1H), 7.19-7.11 (m, 3H), 4.51 (d, J=5.6Hz, 2H), 3.97 (d, J=7.2Hz, 2H), 1.34-1.26 (m, 1H), 0.62-0.53 (m, 2H), 0.36-0.27 (m, 2H). 13C NMR (101 MHz, DMSO-d 6 )δ161.4 (dd, J=245, 20 Hz), 161.3 (ddd, J=247, 16, 11 Hz, 2×C), 161.1, 150.6, 149.9, 149.7, 149.4, 145.0, 141.8, 128.0, 122.4, 120.5, 116.5 (t, J=257.2 Hz), 115.6, 111.0 (td, J=19.3, 4.5 Hz), 109.5, 100.5 (t, J=28.2 Hz, 2×C), 96.9, 73.2, 30.8, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 25 H 19 O 3 N 4 F 5 Na + [M+Na] + , 541.1270; the measured value is 541.1255.

[0396] Example 65 Synthesis of Compound F2:

[0397] The synthesis steps were similar to those in Example 6. In the last step, 2,4-difluorobenzylamine was selected as the amine reagent to obtain compound F2 with a yield of 51%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.99 (t, J=6.4Hz, 1H), 8.69 (d, J=4.4Hz, 1H), 7.93 (d, J=2.0Hz, 1H), 7.8 3(dd, J=8.4, 2.0Hz, 1H), 7.44-7.36 (m, 3H), 7.26 (t, J=74.0Hz, 1H), 7.25- 7.19(m, 1H), 7.19(s, 1H), 7.07-7.00(m, 1H), 4.50(d, J=6.0Hz, 2H), 3.99( d, J=7.2Hz, 2H), 1.34-1.26 (m, 1H), 0.64-0.50 (m, 2H), 0.37-0.26 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ161.5 (dd, J=244, 12 Hz), 161.4, 159.9 (dd, J=246, 12 Hz), 150.6, 150.0, 149.7, 149.5, 145.0, 141.8, 130.6 (dd, J=10, 6 Hz), 128.0, 122.5, 122.4 (dd, J=15, 4 Hz), 120.5, 116.5 (t, J=257.2 Hz), 115.6, 111.4 (dd, J=21, 3 Hz), 109.5, 103.7 (t, J=25.7 Hz), 96.9, 73.2, 35.7, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 25 H 20 O 3 N 4 F 4 Na + [M+Na] + , 523.1364; the measured value is 523.1356.

[0398] Example 66 Synthesis of Compound F3:

[0399] The synthesis steps were similar to those in Example 6. In the last step, 2,5-difluorobenzylamine was selected as the amine reagent to obtain compound F3 with a yield of 61%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.04 (t, J=6.4Hz, 1H), 8.70 (d, J=4.4Hz, 1H), 7.95 (d, J=2.0Hz, 1H), 7.82 (dd, J=8.4, 2.0Hz, 1H), 7.43 (d, J=4.4Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 7.28-7.23 (m, 1H ), 7.26 (t, J=74.0Hz, 1H), 7.20 (s, 1H), 7.19-7.10 (m, 2H), 4.52 (d, J=6.0Hz, 2H) , 4.01 (d, J=6.8Hz, 2H), 1.32-1.25 (m, 1H), 0.66-0.51 (m, 2H), 0.38-0.21 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ161.6, 158.2 (dd, J = 240, 2 Hz), 156.0 (dd, J = 239, 2 Hz), 150.6, 150.0, 149.6, 149.5, 145.0, 141.8, 128.3 (dd, J = 17.6, 7.4 Hz), 128.0, 122.5, 120.5, 116.7 (dd, J = 24.4, 8.8 Hz), 116.5 (t, J = 258.4 Hz), 115.5 (dd, J = 23, 5 Hz), 115.6, 115.2 (dd, J = 24, 8 Hz), 109.6, 96.9, 73.2, 36.1, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 25 H 20 O 3 N 4 F 4 Na + [M+Na] + , 523.1364; the measured value is 523.1358.

[0400] Example 67 Synthesis of Compound F4:

[0401] The synthesis steps were similar to those in Example 6. In the last step, 2,6-difluorobenzylamine was selected as the amine reagent to obtain compound F4 with a yield of 53%. 1 H NMR (500 MHz, DMSO-d 6 )δ8.79 (t, J=5.5Hz, 1H), 8.67 (d, J=4.5Hz, 1H), 7.94 (d, J=2.0Hz, 1H), 7.78 (dd, J=8.5, 2.0Hz, 1H), 7.44-7.35 (m, 3H), 7.26 (t, J=74.5Hz, 1H) ), 7.16 (s, 1H), 7.07 (t, J=7.5Hz, 2H), 4.57 (d, J=6.0Hz, 2H), 3.99 (d, J=7.0Hz, 2H), 1.38-1.24 (m, 1H), 0.66-0.53 (m, 2H), 0.38-0.27 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ161.1 (dd, J=247.5, 9.0 Hz, 2×C), 160.9, 150.5, 149.9, 149.7, 149.4, 144.9, 141.8, 129.8, 128.0, 122.4, 120.5, 116.5 (t, J=256.5 Hz), 115.6, 114.2 (t, J=18.0 Hz), 111.5 (dd, J=19.5, 4.5 Hz, 2×C), 109.4, 96.8, 73.2, 31.1, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 25 H 20 O 3 N 4 F 4 Na + [M+Na] + , 523.1364; the measured value is 523.1359.

[0402] Example 68 Synthesis of Compound F5:

[0403] The synthesis steps were similar to those in Example 6. Aniline was selected as the amine reagent in the last step to obtain compound F5 with a yield of 48%. 1 H NMR (400 MHz, CDCl 3 )δ8.79 (s, 1H), 8.61 (d, J = 4.4Hz, 1H), 7.74 (d, J = 2.0Hz, 1H), 7.68 (d, J = 8.0Hz, 2H), 7.57 (dd, J = 8.4, 2.0Hz, 1H), 7.44-7.35 (m, 4H), 7.16 (t, J=7.6Hz, 1H), 7.02 (d, J=4.0Hz, 1H), 6.80 (t, J=74.8Hz, 1H), 3.98 (d, J=6.8Hz, 2H), 1.44-1.34 (m, 1H), 0.70-0.59 (m, 2H), 0.43-0.32 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ160.1, 150.8, 150.1, 150.0, 149.4, 144.9, 141.9, 138.4, 128.7 (2×C), 127.9, 124.1, 122.6, 120.6, 120.4 (2×C), 117.8 (t, J=257.1 Hz), 115.9, 109.5, 97.2, 73.4, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 24 H 20 O 3 N 4 F2 Na + [M+Na] + , 473.1396; the measured value is 473.1394.

[0404] Example 69 Synthesis of Compound F6:

[0405] The synthesis steps were similar to those in Example 6. Benzylamine was selected as the amine reagent in the last step to obtain compound F6 with a yield of 52%. 1 H NMR (400 MHz, CDCl 3 )δ8.58 (d, J=4.4Hz, 1H), 7.64 (d, J=2.0Hz, 1H), 7.49 (dd, J=8.4, 2.0Hz, 1H), 7.38 (s, 1H), 7.35-7.33 (m, 5H), 7.33-7.28 (m, 2H), 6.96 (d . 13 C NMR (101 MHz, DMSO-d 6 )δ161.3, 150.5, 150.0 (2×C), 149.4, 144.9, 141.8, 139.5, 128.3 (2×C), 128.0, 127.2 (2×C), 126.8, 122.5, 120.5, 116.5 (t, J=257.1 Hz), 115.6, 109.5, 96.8, 73.2, 42.2, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 25 H 22 O 3 N 4 F 2 Na + [M+Na] + , 487.1552; the measured value is 487.1552.

[0406] Example 70 Synthesis of Compound F7:

[0407] The synthesis steps were as in Example 6. The last step of the amine reagent was 2-methylaminopyrimidine (CAS No.: 75985-45-4) to obtain compound F7 with a yield of 35%. 1 H NMR (600 MHz, DMSO-d 6)δ8.87 (t, J=5.4Hz, 1H), 8.76 (d, J=4.8Hz, 2H), 8.69 (d, J=4.8Hz, 1H), 7.94 (d, J=1.8Hz, 1H), 7.84 (dd, J=8.4, 1.8Hz, 1H), 7.44-7.38 (m, 3H) , 7.24 (t, J=73.8Hz, 1H), 7.18 (s, 1H), 4.71 (d, J=5.4Hz, 2H), 4.01 (d, J=6.6Hz, 2H), 1.32-1.23 (m, 1H), 0.57-0.50 (m, 2H), 0.33-0.25 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ166.6, 161.4, 157.5 (2×C), 150.7, 150.1, 149.8, 149.6, 145.0, 141.9, 128.1, 122.6, 120.7, 120.0, 116.6 (t, J=258.8 Hz), 115.7, 109.6, 96.9, 73.4, 44.9, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated value is C 23 H 20 O 3 N 6 F 2 Na + [M+Na] + , 489.1457; the measured value is 489.1459.

[0408] Example 71 Synthesis of Compound F8:

[0409] The synthesis steps were as in Example 6. The last step of the amine reagent was 4-aminomethyltetrahydropyran (CAS No.: 130290-79-8) to obtain compound F8 with a yield of 40%. 1 H NMR (600 MHz, DMSO-d 6)δ8.66(s, 1H), 8.43(s, 1H), 7.97(s, 1H), 7.79(d, J=8.4Hz, 1H), 7.39(s, 2H), 7.26 (t, J=72.0Hz, 1H), 7.14 (s, 1H), 4.02 (d, J=7.2Hz, 2H), 3.83 (d, J=11.4Hz , 2H), 3.25 (t, J=11.4Hz, 2H), 3.19 (s, 2H), 1.81 (s, 1H), 1.57 (d, J=12.6Hz, 2H ), 1.34-1.26(m, 1H), 1.23-1.15(m, 2H), 0.66-0.49(m, 2H), 0.45-0.26(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ161.3, 150.5, 150.2, 150.0, 149.4, 144.9, 141.8, 128.0, 122.4, 120.6, 116.5 (t, J = 258.0 Hz), 115.6, 109.3, 96.7, 73.2, 66.8 (2×C), 44.4, 35.0, 30.5 (2×C), 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 24 H 26 O 4 N 4 F 2 Na + [M+Na] + , 495.1814; the measured value is 495.1817.

[0410] Example 72 Synthesis of Compound F9:

[0411] The synthesis steps were similar to those in Example 6. In the last step, 2-aminothiazole was selected as the amine reagent to obtain compound F9 with a yield of 61%. 1 H NMR (400 MHz, CDCl 3 )δ10.07 (br, 1H), 8.66 (dd, J=7.6, 0.8Hz, 1H), 7.84 (d, J=2.0Hz, 1H), 7.58-7.49 (m, 2H), 7.40 (d, J=7.6Hz, 1H), 7.36 (d, J=0.9Hz, 1H), 7.29 (d . 13C NMR (151 MHz, DMSO-d 6 )δ159.8, 157.8, 150.9, 149.9, 149.5, 147.8, 145.0, 142.0, 137.8, 127.8, 122.8, 120.5, 116.5 (t, J = 256.5 Hz), 115.9, 114.3, 109.8, 97.8, 73.4, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 21 H 17 O 3 N 5 F 2 SNa + [M+Na] + , 480.0912; the measured value is 480.0893.

[0412] Example 73 Synthesis of Compound F10:

[0413] The synthesis steps were similar to those in Example 6. In the last step, 2,3-difluorobenzylamine was selected as the amine reagent to obtain compound F10 with a yield of 45%. 1 H NMR (600 MHz, CD 3 OD) δ8.56 (d, J=4.2Hz, 1H), 7.83 (d, J=1.8Hz, 1H), 7.67 (dd, J=7.8, 1.2Hz, 1H), 7.3 0 (d, J=7.8Hz, 1H), 7.20 (d, J=4.2Hz, 1H), 7.19-7.16 (m, 1H), 7.15-7.12 (m, 1H), 7. 14 (s, 1H), 7.11-7.06 (m, 1H), 6.90 (t, J=75.0Hz, 1H), 4.65 (s, 2H), 3.97 (d, J=7.2H z, 2H), 1.35-1.24 (m, 1H), 0.66-0.56 (m, 2H), 0.40-0.30 (m, 2H), NH (notobserved). 13 C NMR (151 MHz, CD 3OD) δ164.2, 151.7 (dd, J=246.0, 13.5Hz), 151.6, 151.5, 151.4, 150.8, 149. 9 (dd, J=259.5, 12Hz), 147.6, 144.0, 129.7, 129.4 (d, J=10.5Hz), 125.5 (t, J =4.5Hz), 125.4 (dd, J=6.0, 4.5Hz), 123.7, 122.8, 117.8 (t, J=258.0Hz), 117 .2 (d, J=18.0Hz), 116.7, 110.6, 98.2, 75.1, 37.5, 11.0, 3.6 (2×C).ESI-HRMS m / z: calculated value is C 25 H 20 O 3 N 4 F 4 Na + [M+Na] + , 523.1364; the measured value is 523.1369.

[0414] Example 74 Synthesis of Compound F11:

[0415] The synthesis steps were similar to those in Example 6. The last step was to use 3-aminomethylpyridine (CAS No.: 3731-52-0) as the amine reagent to obtain compound F11 with a yield of 33%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.24 (t, J=6.0Hz, 1H), 9.19 (d, J=8.0Hz, 1H), 8.58 (d, J=2.0Hz, 1H), 8.46 (dd, J=4.8, 1.6Hz, 1H), 7.90 (d, J=2.0Hz, 1H), 7.87-7.81 (m, 2H), 7.75 (d J=8.0Hz, 1H), 7.39-7.33 (m, 2H), 7.23 (t, J=74.0Hz, 1H), 7.09 (d, J=0.8Hz, 1H), 4.52 (d, J= 6.0Hz, 2H), 4.05 (d, J=6.8Hz, 2H), 1.33-1.27 (m, 1H), 0.64-0.57 (m, 2H), 0.43-0.36 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ161.3, 155.3, 150.8, 150.1, 149.0, 148.2 (2×C), 142.0, 136.5, 135.3, 135.0, 134.3, 123.5, 120.9, 120.3, 116.6 (t, J=256.8 Hz), 112.8, 107.6, 96.6, 73.3, 40.0, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 24 H 21 O 3 N 5 F 2 Na + [M+Na] + , 488.1505; the measured value is 488.1513.

[0416] Example 75 Synthesis of Compound F12:

[0417] The synthesis steps were similar to those of Example 6. In the last step, 1-methyl-4-aminopyrazole (CAS No.: 69843-13-6) was used as the amine reagent to obtain compound F12 with a yield of 47%. 1 H NMR (400 MHz, DMSO-d 6 ) δ10.56 (s, 1H), 9.25 (d, J = 7.6Hz, 1H), 7.91 (d, J = 2.0Hz, 1H), 7.89-7.83 (m, 2H), 7.65 (d, J = 2.0Hz, 1H), 7.35 (d, J = 8.0Hz, 1H), 7.30 (s, 1H), 7.24 (t, J=74.4Hz, 1H), 6.60 (d, J=2.4Hz, 1H), 4.06 (d, J=6.8Hz, 2H), 3.80 (s, 3H), 1.33-1.26 (m, 1H), 0.65-0.57 (m, 2H), 0.42-0.39 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ158.8, 155.4, 150.3, 150.1, 148.2, 146.1, 142.0, 136.6, 134.3, 131.3, 120.9, 120.3, 116.6 (t, J = 256.7 Hz), 112.9, 107.7, 97.4, 96.8, 73.3, 38.5, 10.1, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 22 H 20 O 3 N 6 F 2 Na + [M+Na]+ , 477.1457; the measured value is 477.1469.

[0418] Example 76 Synthesis of Compound F13:

[0419] The synthesis steps refer to Example 6. In the last step, 2-(aminomethyl)naphthalene (CAS No.: 2018-90-8) was selected as the amine reagent to obtain compound F13 with a yield of 50%; 1 H NMR (500 MHz, DMSO-d 6 )δ9.22 (t, J=6.5Hz, 1H), 9.18 (d, J=7.5Hz, 1H), 7.92-7.77 (m, 7H), 7.54 (dd, J=8.0, 1.5Hz, 1H), 7.51-7.43 (m, 2H), 7.35 (d, J=8.5Hz, 1H), 7 .22 (t, J=74.5Hz, 1H), 7.12 (s, 1H), 4.68 (d, J=6.0Hz, 2H), 4.05 (d, J=7.0Hz, 2H), 1.32-1.25 (m, 1H), 0.63-0.54 (m, 2H), 0.42-0.36 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ161.2, 155.3, 150.9, 150.1, 148.2, 142.0, 137.1, 136.5, 134.3, 132.9, 132.1, 127.9, 127.5 (2×C), 126.2, 126.0, 125.7, 125.5, 120.9, 120.3, 116.6 (t, J=256.5 Hz), 112.9, 107.5, 96.6, 73.3, 42.5, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 29 H 24 O 3 N 4 F 2 Na + [M+Na] + , 537.1709; the measured value is 537.1685.

[0420] Example 77 Synthesis of Compound G1:

[0421] The synthesis steps were as in Example 7. In the last step, 2,4,6-trifluorobenzylamine was selected as the amine reagent to obtain compound G1 with a yield of 49%. 1 H NMR (600 MHz, DMSO-d 6)δ8.84 (d, J=4.8Hz, 1H), 8.60 (s, 1H), 8.45 (t, J=6.0Hz, 1H), 7.82 (d, J=2.4H z, 1H), 7.77 (dd, J=8.4, 1.8Hz, 1H), 7.50 (d, J=4.2Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 7.25 (t, J=74.4Hz, 1H), 7.19 (t, J=8.4Hz, 2H), 4.64 (d, J=6.0Hz, 2H), 3. 98(d, J=7.2Hz, 2H), 1.38-1.24(m, 1H), 0.65-0.51(m, 2H), 0.42-0.21(m, 2H). 13 CNMR (151 MHz, DMSO-d 6 )δ161.5 (dt, J=244.5, 16.5 Hz), 161.1 (ddd, J=247.5, 16.5, 12 Hz, 2×C), 160.8, 152.1, 149.5, 146.6, 146.4, 145.6, 142.1, 127.7, 122.8, 120.5, 116.5 (t, J=258.0 Hz), 115.9, 111.4 (td, J=19.5, 4.5 Hz), 109.4, 104.7, 100.7 (dd, J=30.0, 27.0 Hz, 2×C), 73.4, 30.2, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 25 H 19 O 3 N 4 F 5 Na + [M+Na] + , 541.1270; the measured value is 541.1277.

[0422] Example 78 Synthesis of Compound G2:

[0423] The synthesis steps were as in Example 7. In the last step, 2,4-difluorobenzylamine was selected as the amine reagent to obtain compound G2 with a yield of 38%. 1 H NMR (600 MHz, DMSO-d 6)δ8.86 (d, J=4.8Hz, 1H), 8.64 (s, 1H), 8.53 (t, J=6.0Hz, 1H), 7.84 (d, J=2.4Hz, 1H), 7 .78 (dd, J=8.4, 1.8Hz, 1H), 7.52 (d, J=4.8Hz, 1H), 7.49-7.43 (m, 1H), 7.42 (d, J=8.4Hz , 1H), 7.26 (t, J=73.8Hz, 1H), 7.25-7.21 (m, 1H), 7.09-7.01 (m, 1H), 4.62 (d, J=6.0Hz , 2H), 3.99 (d, J=7.2Hz, 2H), 1.35-1.25 (m, 1H), 0.64-0.56 (m, 2H), 0.40-0.33 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 ) δ161.4 (dd, J=243, 12Hz), 161.2, 160.2 (dd, J=246, 12Hz), 152.0, 149.5, 146. 7, 146.4, 145.7, 142.1, 130.7 (dd, J=9.0, 6.0Hz), 127.7, 122.8, 122.7 (dd, J=15 , 3.0 Hz), 120.5, 116.5 (t, J = 258.0 Hz), 116.0, 111.4 (dd, J = 21.0, 4.5 Hz), 109.4, 104.9, 103.8 (t, J = 25.5 Hz), 73.4, 35.7 (d, J = 3.7 Hz), 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 25 H 20 O 3 N 4 F 4 Na + [M+Na] + , 523.1364; the measured value is 523.1369.

[0424] Example 79 Synthesis of Compound G3:

[0425] The synthesis steps were as in Example 7. In the last step, 2,5-difluorobenzylamine was selected as the amine reagent to obtain compound G3 with a yield of 45%. 1 H NMR (400 MHz, DMSO-d 6)δ8.88 (d, J=4.8Hz, 1H), 8.65 (s, 1H), 8.59 (t, J=6.4Hz, 1H), 7.84 (d, J=1.6Hz, 1 H), 7.78 (dd, J=8.4, 2.0Hz, 1H), 7.53 (d, J=4.4Hz, 1H), 7.42 (d, J=4.4Hz, 1H), 7.3 0-7.24 (m, 1H), 7.27 (t, J=74.0Hz, 1H), 7.21-7.13 (m, 2H), 4.64 (d, J=6.0Hz, 2H) , 3.99 (d, J=6.8Hz, 2H), 1.35-1.27 (m, 1H), 0.67-0.52 (m, 2H), 0.44-0.24 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ161.3, 158.1 (dd, J=237.0, 1.5Hz), 156.2 (dd, J=238.5, 1.5Hz), 152.O, 149.5 , 146.7, 146.3, 145.7, 142.1, 128.6 (dd, J=17.7, 7.6Hz), 127.7, 122.8, 120.5, 11 6.7 (dd, J = 18.0, 7.5 Hz), 116.5 (t, J = 258.0 Hz), 115.9, 115.6 (dd, J = 24.0, 9.0 Hz), 115.1 (dd, J = 24.0, 9.0 Hz), 109.4, 104.9, 73.4, 36.1, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 25 H 20 : 3 N 4 F 4 Na + [M+Na] + , 523.1364; the measured value is 523.1371.

[0426] Example 80 Synthesis of Compound G4:

[0427] The synthesis steps were as in Example 7. In the last step, 2,6-difluorobenzylamine was selected as the amine reagent to obtain compound G4 with a yield of 53%. 1 H NMR (400 MHz, DMSO-d 6)δ8.86 (d, J=4.4Hz, 1H), 8.61 (s, 1H), 8.46 (t, J=5.6Hz, 1H), 7.82 (d, J=2. 0Hz, 1H), 7.78 (dd, J=8.4, 2.0Hz, 1H), 7.52 (d, J=4.4Hz, 1H), 7.44-7.37 (m, 2H), 7.26 (t, J=74.0Hz, 1H), 7.18-7.06 (m, 2H), 4.69 (d, J=6.0Hz, 2H), 3.98 (d, J=7.2Hz, 2H), 1.35-1.27(m, 1H), 0.63-0.54(m, 2H), 0.39-0.31(m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ161.0 (dd, J=245.0, 8.0 Hz, 2×C), 160.8, 152.1, 149.5, 146.6, 146.4, 145.6, 142.1, 130.0 (t, J=10 Hz), 127.7, 122.8, 120.5, 116.5 (t, J=257.2 Hz), 115.9, 114.6 (t, J=19.1 Hz), 111.7 (dd, J=18.0, 6.0 Hz, 2×C), 109.4, 104.8, 73.4, 30.4, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 25 H 20 O 3 N 4 F 4 Na + [M+Na] + , 523.1364; the measured value is 523.1371.

[0428] Example 81 Synthesis of Compound G5:

[0429] The synthesis steps refer to Example 7. The last step is to select aniline as the amine reagent to obtain compound G5. The yield is 46%. 1 HNMR (400 MHz, DMSO-d 6)δ10.14 (s, 1H), 8.96 (d, J = 4.4Hz, 1H), 8.76 (s, 1H), 7.86 (d, J = 6.0Hz, 1H), 7.82 (dd, J = 8.4, 2.4Hz, 1H), 7.62-7.73 (m, 2H), 7.60 (d, J = 4.4Hz, 1H) ), 7.44-7.37(m, 3H), 7.28(t, J=74.0Hz, 1H), 7.14-7.10(m, 1H), 4.00(d , J=6.8Hz, 2H), 1.36-1.28(m, 1H), 0.63-0.58(m, 2H), 0.39-0.36(m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ159.5, 152.2, 149.5, 146.7, 146.6, 145.9, 142.2, 138.7, 129.1 (2×C), 127.6, 123.6, 122.9, 120.5, 119.4 (2×C), 116.5 (t, J=257.1 Hz), 116.0, 109.7, 105.1, 73.4, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 24 H 20 O 3 N 4 F 2 Na + [M+Na] + , 473.1396; the measured value is 473.1403.

[0430] Example 82 Synthesis of Compound G6:

[0431] The synthesis steps were as in Example 7. Benzylamine was selected as the amine reagent in the last step to obtain compound G6 with a yield of 35%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.84 (d, J=4.4Hz, 1H), 8.66 (s, 1H), 8.53 (t, J=6.0Hz, 1H), 7.83 (d, J=2.0Hz, 1 H), 7.79 (dd, J=8.4, 2.0Hz, 1H), 7.51 (d, J=4.4Hz, 1H), 7.42 (d, J=8.4Hz, 1H), 7.3 9-7.32 (m, 4H), 7.27 (t, J = 74.0Hz, 1H), 7.27-7.23 (m, 1H), 4.62 (d, J = 6.1Hz, 2H) , 3.99 (d, J=7.0Hz, 2H), 1.38-1.23 (m, 1H), O.73-O.50 (m, 2H), O.46-O.23 (m, 2H).13 C NMR (101 MHz, DMSO-d 6 )δ161.2, 151.9, 149.5, 146.6, 146.3, 145.7, 142.1, 139.7, 128.5 (2×C), 127.7, 127.3 (2×C), 126.9, 122.8, 120.5, 115.9, 115.9 (t, J=257.1 Hz), 109.3, 105.1, 73.4, 42.0, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 25 H 22 O 3 N 4 FWf + [M+Na] + , 487.1552; the measured value is 487.1560.

[0432] Example 83 Synthesis of Compound G7:

[0433] The synthesis steps were as in Example 7. The last step of the amine reagent was 4-aminomethyltetrahydropyran (CAS No.: 130290-79-8) to obtain compound G7 with a yield of 40%. 1 H NMR (500 MHz, DMSO-d 6 )δ8.85 (d, J=4.5Hz, 1H), 8.60 (s, 1H), 8.14 (t, J=6.5Hz, 1H), 7.83 (d, J=2.5Hz, 1H), 7.7 8(dd, J=8.5, 2.0Hz, 1H), 7.50 (d, J=4.5Hz, 1H), 7.40 (d, J=2.0Hz, 1H), 7.26 (t, J=74.0Hz , 1H), 3.99 (d, J=7.0Hz, 2H), 3.85 (dd, J=11.5, 2.5Hz, 2H), 3.33-3.23 (m, 4H), 1.87-1.7 4 (m, 1H), 1.61 (d, J = 10.5, 2H), 1.36-1.25 (m, 3H), 0.63-0.55 (m, 2H), 0.43-0.30 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ161.2, 151.8, 149.5, 146.5, 146.3, 145.5, 142.1, 127.7, 122.8, 120.5, 116.5 (t, J = 258.7 Hz), 115.9, 109.2, 105.3, 73.4, 66.7 (2×C), 43.9, 35.2, 30.4 (2×C), 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 24 H 26 O 4 N 4 F 2 Na + [M+Na] + , 495.1814; the measured value is 495.1829.

[0434] Example 84 Synthesis of Compound G8:

[0435] The synthesis steps were similar to those in Example 7. In the last step, 2-aminothiazole was selected as the amine reagent to obtain compound G8 with a yield of 34%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.54 (s, 1H), 9.02 (d, J = 4.8Hz, 1H), 8.87 (s, 1H), 7.86 (d, J = 2.0Hz, 1H ), 7.81 (dd, J=8.4, 2.0Hz, 1H), 7.66 (d, J=4.8Hz, 1H), 7.53 (d, J=2.0Hz, 1H ), 7.44 (d, J = 8.4Hz, 1H), 7.30-7.29 (m, 1H), 7.30 (t, J = 78.0Hz, 1H), 4.00 ( d, J=7.2Hz, 2H), 1.37-1.24(m, 1H), 0.65-0.54(m, 2H), O.43-O.30(m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ158.5, 157.3, 152.9, 149.5, 147.2, 146.9, 145.9, 142.3, 137.8, 127.4, 123.0, 120.5, 116.5 (t, J = 257.1 Hz), 116.0, 114.0, 110.2, 102.9, 73.4, 9.9, 3.1 (2×C) ESI-HRMS m / z: calculated value is C 21 H 17 O 3 N 5 F 2 SNa + [M+Na] +, 480.0912; the measured value is 480.0930.

[0436] Example 85 Synthesis of Compound G9:

[0437] The synthesis steps were similar to those in Example 7. In the last step, 6-aminobenzothiazole was selected as the amine reagent to obtain compound G9 with a yield of 43%. 1 H NMR (600 MHz, DMSO-d 6 ) δ10.34 (s, 1H), 9.29 (s, 1H), 8.95 (d, J = 4.2Hz, 1H), 8.77 (s, 1H), 8.68 (d, J = 2.4Hz, 1 H), 8.07 (d, J=9.0Hz, 1H), 7.86 (d, J=2.0Hz, 1H), 7.81 (dd, J=8.4, 1.8Hz, 1H), 7.77 (d d, J=9.0, 2.4Hz, 1H), 7.59 (d, J=4.8Hz, 1H), 7.43 (d, J=8.4Hz, 1H), 7.27 (t, J=73.8Hz , 1H), 4.01 (d, J=7.2Hz, 2H), 1.37-1.25 (m, 1H), 0.72-0.53 (m, 2H), 0.43-0.32 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ159.7, 154.9, 152.3, 149.6, 149.4, 146.7, 146.6, 145.9, 142.2, 136.4, 134.5, 127.6, 123.2, 122.9, 120.5, 119.1, 116.5 (t, J = 256.5 Hz), 116.0, 112.0, 109.7, 105.0, 73.5, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 25 H 19 O 3 N 5 F 2 SNa + [M+Na] + , 530.1069; the measured value is 530.1081.

[0438] Example 86 Synthesis of Compound G10:

[0439] The synthesis steps were similar to those in Example 7. In the last step, 2,3-difluorobenzylamine was selected as the amine reagent to obtain compound G10 with a yield of 40%. 1 H NMR (400 MHz, DMSO-d 6)δ8.87 (d, J=4.8Hz, 1H), 8.65 (s, 1H), 8.60 (t, J=6.0Hz, 1H), 7.83 (d, J=1.6Hz, 1 H), 7.79 (dd, J=8.4, 2.0Hz, 1H), 7.53 (d, J=4.8Hz, 1H), 7.42 (d, J=8.4Hz, 1H), 7.3 8-7.30 (m, 1H), 7.27 (t, J=74.0Hz, 1H), 7.25-7.15 (m, 2H), 4.70 (d, J=5.6Hz, 2H) , 3.99 (d, J=6.8Hz, 2H), 1.35-1.28 (m, 1H), 0.63-0.56 (m, 2H), 0.40-0.33 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ161.3, 151.9, 149.6 (dd, J=244.5, 12.0Hz), 149.5, 147.8 (dd, J=244.5, 1 2.0Hz), 146.7, 146.3, 145.6, 142.1, 129.1 (d, J=10.5Hz), 127.7, 124.7 (dd, J=7.5, 4.5Hz), 124.5 (t, J=3.0Hz), 122.8, 120.5, 116.5 (t, J=258.0Hz), 116 .0 (d, J=16.5Hz), 115.9, 109.3, 104.9, 73.4, 35.8, 9.9, 3.1 (2×C).ESI-HRMS m / z: calculated value is C 25 H 20 O 3 N 4 F 4 Na[M+Na] + , 523.1364; the measured value is 523.1383.

[0440] Example 87 Synthesis of Compound G11:

[0441] The synthesis steps were as in Example 7. The last step of the amine reagent was 3-aminomethylpyridine (CAS No.: 3731-52-0) to obtain compound G11 with a yield of 57%. 1 H NMR (500 MHz, DMSO-d 6)δ8.84 (d, J=4.5Hz, 1H), 8.64 (s, 1H), 8.63-8.56 (m, 2H), 8.46 (dd, J=5.0, 2.0Hz, 1H) , 7.84 (d, J=2.0Hz, 1H), 7.78 (dd, J=8.5, 2.0Hz, 2H), 7.50 (d, J=4.5Hz, 1H), 7.44-7.3 9 (m, 1H), 7.36 (ddd, J=8.0, 5.0, 1.0Hz, 1H), 7.24 (t, J=74.0Hz, 1H), 4.64 (d, J=6.0Hz , 2H), 3.99 (d, J=7.0Hz, 2H), 1.36-1.24 (m, 1H), 0.64-0.46 (m, 2H), 0.42-0.31 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ161.3, 151.9, 149.5, 148.6, 147.9, 146.7, 146.3, 145.7 (2×C), 142.1, 135.4, 127.7, 123.6, 122.8, 120.5, 116.5 (t, J=258.7 Hz), 116.0, 109.3, 105.0, 73.4, 40.1, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 24 H 22 O 3 N 5 F 2 + [M+H] + , 466.1685; the measured value is 466.1695.

[0442] Example 88 Synthesis of Compound G12:

[0443] The synthesis steps were as in Example 7. In the last step, 1-methyl-4-aminopyrazole (CAS No.: 69843-13-6) was selected as the amine reagent to obtain compound G12 with a yield of 44%. 1 H NMR (400 MHz, DMSO-d 6) δ10.36 (s, 1H), 8.97 (d, J = 4.4Hz, 1H), 8.73 (s, 1H), 7.86 (d, J = 1.6Hz, 1H), 7. 80 (dd, J=8.4, 2.0Hz, 1H), 7.63 (d, J=2.0Hz, 1H), 7.60 (d, J=4.8Hz, 1H), 7.43 ( d, J=8.4Hz, 1H), 7.28 (t, J=74.4Hz, 1H), 6.60 (d, J=2.0Hz, 1H), 4.00 (d, J=7.2 Hz, 2H), 3.78 (s, 3H), 1.35-1.27 (m, 1H), 0.67-0.55 (m, 2H), 0.43-0.31 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ158.2, 152.3, 149.5, 146.7, 146.6, 146.3, 145.7, 142.2, 131.4, 127.6, 122.9, 120.5, 116.5 (t, J = 257.2 Hz), 116.0, 109.7, 104.6, 96.2, 73.4, 38.3, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 22 H 20 O 3 N 6 F 2 Na + [M+Na] + , 477.1457; the measured value is 477.1469.

[0444] Example 89 Synthesis of Compound G13:

[0445] The synthesis steps refer to Example 7. In the last step, the amine reagent is 2-(aminomethyl)naphthalene (CAS No.: 2018-90-8) to obtain compound G13 with a yield of 52%. 1 H NMR (500 MHz, DMSO-d 6 )δ8.83 (d, J=4.5Hz, 1H), 8.67 (s, 1H), 8.64 (t, J=6.0Hz, 1H), 7.93-7.82 (m, 5H), 7.78 (dd, J=8.0, 1.5Hz, 1H), 7.56-7.46 (m, 4H), 7.42 (d, J= 6.8Hz, 1H), 7.26 (t, J=74.5Hz, 1H), 4.79 (d, J=6.0Hz, 2H), 3.99 (d, J=7.0Hz, 2H), 1.32-1.30 (m, 1H), 0.64-0.55 (m, 2H), 0.41-0.30 (m, 2H).13 C NMR (101 MHz, DMSO-d 6 )δ161.3, 152.0, 149.6, 146.7, 146.4, 145.8, 142.1, 137.4, 133.0, 132.2, 128.1, 127.8, 127.6 (2×C), 126.3, 126.0, 125.8, 125.5, 122.8, 120.6, 116.6 (t, J=257.1 Hz), 115.9, 109.4, 105.2, 73.4, 42.3, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated value is C 29 H 24 O 3 N 4 F 2 Na + [M+Na] + , 537.1709; the measured value is 537.1682.

[0446] Example 90 Synthesis of Compound G14:

[0447] The synthesis steps were as in Example 7. The last step of the amine reagent was 2-methoxy-5-(aminomethyl)pyridine (CAS No.: 262295-96-5) to obtain compound G14 with a yield of 50%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.83 (d, J=4.4Hz, 1H), 8.63 (s, 1H), 8.50 (t, J=6.0Hz, 1H), 8.18 (d, J=2.0Hz, 1H), 7.82 (d, J=2.0Hz, 1H), 7.78 (dd, J=8.4, 2.0Hz, 1H), 7.72 (dd, J=8.8, 2.8Hz, 1H), 7.50 (d, J=4.8Hz, 1H) , 7.41 (d, J = 8.4Hz, 1H), 7.27 (t, J = 74.0Hz, 1H), 6.79 (d, J = 8.8Hz, 1H), 4.54 (d, J = 6.0Hz, 2H), 3.98 (d, J=7.2Hz, 2H), 3.82 (s, 3H), 1.34-1.26 (m, 1H), 0.64-0.54 (m, 2H), 0.40-0.32 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ162.8, 161.2, 151.9, 149.5, 146.6, 146.3, 145.9, 145.7, 142.1, 139.0, 128.3, 127.7, 122.8, 120.5, 116.6 (t, J = 257.1 Hz), 115.9, 110.4, 109.3, 105.1, 73.4, 53.1, 39.1, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 25 H 23 O 4 N 5 F 2 Na + [M+Na] + , 518.1610; the measured value is 518.1626.

[0448] Example 91 Synthesis of Compound G15:

[0449] The synthesis steps were similar to those in Example 7. In the last step, 6-aminoindole was selected as the amine reagent to obtain compound G15 with a yield of 55%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.10 (s, 1H), 10.05 (s, 1H), 8.96 (d, J = 4.8Hz, 1H), 8.74 (s, 1H), 8.02 (s, 1H), 7.87 (d, J=1.6Hz, 1H), 7.82 (dd, J=8.4, 2.0Hz, 1H), 7.58 (d, J=4. 4Hz, 1H), 7.45-7.31 (m, 4H), 7.28 (t, J=74.0Hz, 1H), 6.43 (s, 1H), 4.01 (d , J=6.8Hz, 2H), 1.37-1.25(m, 1H), 0.69-0.54(m, 2H), 0.44-0.28(m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ159.2, 152.0, 149.6, 146.5, 146.4, 145.8, 142.1, 132.9, 130.6, 127.7, 127.7, 126.2, 122.9, 120.5, 116.6 (t, J = 257.2 Hz), 115.9, 114.9, 111.6, 110.9, 109.5, 105.6, 101.2, 73.4, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated for C 26 H 21 O 3 N 5 F 2 Na+ [M+Na] + , 512.1505; the measured value is 512.1521.

[0450] Example 92 Synthesis of Compound G16:

[0451] The synthesis steps were similar to those in Example 7. In the last step, 4-aminopyridine was selected as the amine reagent to obtain compound G16 with a yield of 39%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.37 (s, 1H), 8.97 (d, J = 4.8Hz, 1H), 8.81 (s, 1H), 8.52-8.46 (m, 2H), 7.8 6(d, J=2.0Hz, 1H), 7.81 (dd, J=8.4, 2.0Hz, 1H), 7.75 (dd, J=4.8, 1.6Hz, 2H) , 7.62 (d, J = 4.8Hz, 1H), 7.43 (d, J = 8.4Hz, 1H), 7.29 (t, J = 74.0Hz, 1H), 4.00 (d, J=6.8Hz, 2H), 1.34-1.29(m, 1H), O.65-O.56(m, 2H), 0.39-0.35(m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ160.3, 152.5, 150.6 (2×C), 149.5, 146.9, 146.7, 146.0, 145.3, 142.2, 127.5, 122.9, 120.5, 116.5 (t, J=257.3 Hz), 116.0, 113.5 (2×C), 109.9, 104.7, 73.4, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 23 H 20 O 3 N 5 F 2 + [M+H] + , 452.1529; the measured value is 452.1560.

[0452] Example 93 Synthesis of Compound G17:

[0453] The synthesis steps were as in Example 7. The last step of the amine reagent was 3-aminopentane (CAS No.: 616-24-0) to obtain compound G17 with a yield of 44%. 1 H NMR (500 MHz, DMSO-d 6)δ8.86 (d, J=4.5Hz, 1H), 8.60 (s, 1H), 7.85-7.75 (m, 3H), 7.50 (d, J=4.5Hz, 1H), 7.42 (s, 1H), 7.29 (t, J=74.5Hz, 1H), 3.99 (d, J=7.0Hz, 2H) , 3.94-3.82 (m, 1H), 1.67-1.39 (m, 2H), 1.54-1.43 (m, 2H), 1.36-1.24 (m, 1H), 0.90 (t, J=7.5Hz, 6H), 0.63-0.55 (m, 2H), 0.43-0.31 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ161.0, 152.0, 149.6, 146.5, 146.4, 145.6, 142.1, 127.8, 122.8, 120.5, 116.6 (t, J = 257.3 Hz), 115.9, 109.3, 105.3, 73.4, 50.8, 27.2 (2×C), 10.3 (2×C), 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 23 H 26 O 3 N 4 F 2 Na + [M+Na] + , 467.1865; the measured value is 467.1861.

[0454] Example 94 Synthesis of Compound G18:

[0455] The synthesis steps were similar to those in Example 7. Cyclohexylamine was selected as the amine reagent in the last step to obtain compound G18 with a yield of 48%. 1 H NMR (600 MHz, DMSO-d 6 )δ8.86 (d, J=4.8Hz, lH), 8.60 (s, lH), 7.99 (d, J=7.8Hz, 1H), 7.83 (d, J=2.4Hz, 1H), 7.79 (dd, J=8.4, 2.4Hz, 1H), 7.51 (d, J=4.8Hz, 1H), 7.41 (d, J=8.4Hz, 1H), 7.26 (t, J= 73.8Hz, 1H), 3.99 (d, J=7.2Hz, 2H), 3.92-3.84 (m, 1H), 1.93-1.87 (m, 2H), 1.77-1.68 (m, 2H), 1.66-1.52 (m, 1H), 1.46-1.21 (m, 6H), 0.64-0.49 (m, 2H), O.44-0.29 (m, 2H).13 C NMR (151 MHz, DMSO-d 6 )δ160.1, 151.8, 149.5, 146.4, 146.3, 145.5, 142.1, 127.7, 122.8, 120.5, 116.5 (t, J=258. 8Hz), 115.9, 109.2, 105.3, 73.4, 46.9, 32.7 (2×C), 25.2 (2×C), 24.3, 9.9, 3.1 (2×C). HPLC: t R 3.26 min, purity 99.31%. ESI-HRMS m / z: calculated value is C 24 H 26 O 3 N 4 F 2 Na + [M+Na] + , 479.1865; the measured value is 479.1847.

[0456] Example 95 Synthesis of Compound G19:

[0457] The synthesis steps were similar to those in Example 7. In the last step, isobutylamine was selected as the amine reagent to obtain compound G19 with a yield of 39%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.86 (d, J=4.8Hz, 1H), 8.61 (s, 1H), 8.15 (t, J=6.0Hz, 1H), 7.83 (d, J=2.0Hz, 1H ), 7.78 (dd, J=8.4, 2.0Hz, 1H), 7.51 (d, J=4.8Hz, 1H), 7.41 (d, J=8.4Hz, 1H), 7.26 (t, J=74.0Hz, 1H), 3.99 (d, J=7.2Hz, 2H), 3.23 (t, J=6.4Hz, 2H), 1.94-1.77 (m, 1H ), 1.36-1.25 (m, 1H), 0.94 (d, J=6.8Hz, 6H), 0.63-0.56 (m, 2H), 0.40-0.33 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ161.1, 151.9, 149.6, 146.5, 146.4, 145.6, 142.1, 127.8, 122.8, 120.5, 116.6 (t, J = 257.1 Hz), 115.9, 109.3, 105.4, 73.4, 45.7, 28.4, 20.1 (2×C), 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C22 H 24 O 3 N 4 F 2 Na + [M+Na] + , 453.1709; the measured value is 453.1708.

[0458] Example 96 Synthesis of Compound G20:

[0459] The synthesis steps were similar to those in Example 7. Cyclopropylamine was selected as the amine reagent in the last step to obtain compound G20 with a yield of 47%. 1 H NMR (500 MHz, DMSO-d 6 )δ8.68 (d, J=4.5Hz, 1H), 8.39 (d, J=4.5Hz, 1H), 7.99 (d, J=2.0Hz, 1H), 7.83 (dd, J=8.5, 2.5Hz, 1H), 7.43-7.40 (m, 2H), 7.26 (t, J=74.0Hz , 1H), 7.15 (s, 1H), 4.03 (d, J=7.0Hz, 2H), 2.92-2.83 (m, 1H), 1.39-1.29 (m, 1H), 0.76-0.68 (m, 2H), 0.66-0.57 (m, 4H), 0.44-0.27 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ162.5, 150.4, 150.1, 149.9, 149.4, 144.8, 141.8, 127.9, 122.5, 120.5, 116.5 (t, J = 258.0 Hz), 115.8, 109.2, 96.5, 73.3, 22.7, 9.9, 5.8 (2×C), 3.1 (2×C). ESI-HRMS m / z: calculated value is C 21 H 20 O 3 N 4 F 2 Na + [M+Na] + , 437.1396; the measured value is 437.1374.

[0460] Example 97 Synthesis of Compound G21:

[0461] The synthesis steps were as in Example 7. Neopentylamine (CAS No.: 5813-64-9) was selected as the amine reagent in the last step to obtain compound G21 with a yield of 49%. 1 H NMR (500 MHz, DMSO-d 6)δ8.87 (d, J=4.5Hz, 1H), 8.61 (s, 1H), 8.17 (t, J=6.5Hz, 1H), 7.84 (d, J=2. 0Hz, 1H), 7.79 (dd, J=8.5, 2.0Hz, 1H), 7.51 (d, J=4.5Hz, 1H), 7.42 (d, J=7. 0Hz, 1H), 7.19 (t, J=74.0Hz, 1H), 3.99 (d, J=7.0Hz, 2H), 3.23 (d, J=6.0Hz, 2H), 1.38-1.27(m, 1H), 0.96(s, 9H), 0.64-0.56(m, 2H), 0.40-0.32(m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ161.2, 152.0, 149.5, 146.6, 146.4, 145.6, 142.1, 127.7, 122.8, 120.5, 116.6 (t, J = 257.1 Hz), 115.9, 109.3, 105.3, 73.4, 49.4, 32.0, 27.2 (3×C), 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 23 H 26 O 3 N 4 F 2 Na + [M+Na] + , 467.1865; the measured value is 467.1849.

[0462] Example 98 Synthesis of Compound H1:

[0463] The synthesis steps were similar to those in Example 8. In the last step, 3-methylphenylboronic acid was selected as the boronic acid reagent to obtain compound H1 with a yield of 98%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.75 (d, J=2.4Hz, 1H), 9.24 (d, J=2.4Hz, 1H), 7.88 (d, J=1.6Hz, 1H), 7.84 (dd, J=8.4, 2.0Hz, 1H), 7.71 (s, 1H), 7.66 (d, J=7.6Hz, 1H), 7.43 (t, J=7.6Hz, 1H), 7. 36 (d, J=8.4Hz, 1H), 7.29 (d, J=7.6Hz, 1H), 7.21 (t, J=74.4Hz, 1H), 4.03 (d, J=7. 2Hz, 2H), 2.41 (s, 3H), 1.35-1.28 (m, 1H), 0.65-0.57 (m, 2H), 0.45-0.37 (m, 2H).13 CNMR (151 MHz, DMSO-d 6 )δ164.2, 154.8, 154.8, 150.1, 141.7, 138.6, 133.7, 132.7, 129.3, 129.2, 128.4, 127.8, 124.2, 124.1, 121.3, 119.5, 116.6 (t, J = 258.0 Hz), 112.3, 73.1, 21.1, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 23 H 21 F 2 N 4 O 2 + [M+H] + , 423.1627; the measured value is 423.1638.

[0464] Example 99 Synthesis of Compound H2:

[0465] The synthesis steps were as in Example 8. In the last step, 2-methylphenylboronic acid was selected as the boronic acid reagent to obtain compound H2 with a yield of 19%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.52 (d, J=2.0Hz, 1H), 8.93 (d, J=2.0Hz, 1H), 7.90 (d, J=1.8Hz, 1H), 7.86 (dd, J=8.4, 2.0Hz, 1H), 7.43-7.31 (m, 5H) , 7.23 (t, J=74.4Hz, 1H), 4.03 (d, J=7.2Hz, 2H), 2.35 (s, 3H), 1.35-1.28 (m, 1H), 0.61-0.58 (m, 2H), 0.47-0.36 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ164.6, 156.9, 155.1, 150.6, 142.1, 136.7, 136.1, 133.5, 131.2, 131.0, 129.4, 128.9, 126.9, 125.0, 121.7, 120.0, 117.1, 112.7, 73.6, 20.4, 10.5, 3.6 (2×C). ESI-HRMS m / z: calculated for C 23 H 21 O 2 N 4 F 2 + [M+H] +, 423.1627; the measured value is 423.1633.

[0466] Example 100 Synthesis of Compound H3:

[0467] The synthesis steps were similar to those in Example 8. In the last step, 4-nitrobenzeneboronic acid was used as the boronic acid reagent to obtain compound H3 with a yield of 45%. 1 H NMR (400 MHz, DMSO-d 6 ) δ9.94 (s, 1H), 9.33 (s, 1H), 8.36 (d, J = 8.0Hz, 2H), 8.17 (d, J = 8.0Hz, 2H), 7.91-7.77 (m, 2H), 7.36 (d, J = 8. 0Hz, 1H), 7.20 (t, J=74.4Hz, 1H), 4.02 (d, J=6.8Hz, 2H), 1.35-1.29 (m, 1H), 0.61-0.60 (m, 2H), 0.42 (s, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ165.1, 155.6, 155.2, 150.5, 147.8, 142.2, 140.0, 135.7, 128.8 (2×C), 128.6, 124.7 (2×C), 122.3, 121.7, 120.0, 117.1, 112.7, 73.6, 10.5, 3.6 (2×C). ESI-HRMS m / z: calculated value is C 22 H 18 O 4 N 5 F 2 + [M+H] + , 454.1321; the measured value is 454.1360.

[0468] Example 101 Synthesis of Compound H4:

[0469] The synthesis steps were as in Example 8. In the last step, the boronic acid reagent was 1-methyl-indazole-6-boronic acid (CAS No.: 1150114-80-9) to obtain compound H4 with a yield of 31%. 1 H NMR (500 MHz, DMSO-d 6)δ9.87 (d, J=2.4Hz, 1H), 9.40 (d, J=2.4Hz, 1H), 8.23 ​​(s, 1H), 8.13-8.10 (m, 1H), 7.95-7.88 (m, 2H), 7.85 (dd, J=8.0, 2.0Hz, 1H), 7.64 (d, J =9.8Hz, 1H), 7.36 (s, 1H), 7.40-7.01 (m, 1H), 4.14 (s, 3H), 4.04 (d, J = 7.0Hz, 2H), 1.35-1.29 (m, 1H), O.66-O.57 (m, 2H), O.47-O.36 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ164.7, 155.6, 155.3, 150.5, 142.1, 140.5, 134.5, 133.0, 131.0, 128.8, 124.7, 123.7, 122.2, 121.7, 120.0, 119.9, 117.1, 112.7, 108.9, 73.6, 35.9, 10.5, 3.6 (2×C). ESI-MS m / z: calculated for C 24 H 21 F 2 N 6 O 2 + [M+H] + , 463.2; the measured value is 463.2.

[0470] Example 102 Synthesis of Compound H5:

[0471] The synthesis steps were as in Example 8. In the last step, the boronic acid reagent was benzothiophene-2-boric acid (CAS No.: 98437-23-1) to obtain compound H5 with a yield of 17%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.87 (d, J=2.8Hz, 1H), 9.35 (d, J=2.8Hz, 1H), 8.13 (s, 1H), 8.09-8.03 (m, 1H), 7.97-7.79 (m, 3H), 7.48-7.42 (m, 2H), 7 .38 (d, J=8.4Hz, 1H), 7.22 (t, J=74.4Hz, 1H), 4.03 (d, J=6.8Hz, 2H), 1.33 (s, 1H), 0.66-0.56 (m, 2H), O.47-O.35 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ164.5, 155.0, 154.0, 150.2, 141.9, 140.1, 139.1, 135.3, 133.4, 128.3, 125.6, 125.4, 124.2, 123.0, 122.8, 121.4, 119.7, 118.9, 116.7 (t, J = 258.2 Hz), 112.4, 73.3, 10.1, 3.3 (2×C). ESI-HRMS m / z: calculated value is C 24 H 19 O 2 N 4 F 2 S + [M+H] + , 465.1191; the measured value is 465.1201.

[0472] Example 103 Synthesis of Compound H6:

[0473] The synthesis steps were as in Example 8. In the last step, the boronic acid reagent was 1-methylindole-5-boric acid (CAS No.: 192182-55-1) to obtain compound H6 with a yield of 45%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.70 (d, J=2.4Hz, 1H), 9.28 (d, J=2.4Hz, 1H), 8.09-8.01 (m, 1H), 7.89 (d, J=2. 0Hz, 1H), 7.84 (dd, J=8.4, 2.0Hz, 1H), 7.68-7.57 (m, 2H), 7.42 (d, J=2.8Hz, 1H), 7 .36 (d, J=8.2Hz, 1H), 7.21 (t, J=74.4Hz, 1H), 6.53 (d, J=3.2Hz, 1H), 4.03 (d, J=6 .8Hz, 2H), 3.84(s, 3H), 1.33-1.31(m, 1H), 0.66-0.56(m, 2H), O.47-O.36(m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ164.0, 155.4, 154.6, 150.2, 141.7, 136.6, 133.0, 131.1, 128.8, 128.6, 125.8, 123.7, 121.4, 120.5, 119.6, 119.5, 116.8 (t, J = 258.3 Hz), 112.3, 110.9, 101.2, 73.2, 32.8, 10.1, 3.2 (2×C). ESI-HRMS m / z: calculated value is C 25 H 22 O2 N 5 F 2 + [M+H] + , 462.1736; the measured value is 462.1740.

[0474] Example 104 Synthesis of Compound J1:

[0475] The synthesis steps were as in Example 9. In the last step, 6-bromonicotinic acid was selected as the acid reagent to obtain compound J1 with a yield of 39%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.06 (d, J=2.4Hz, 1H), 8.42 (dd, J=8.4, 2.4Hz, 1H), 7.96-7.85 (m, 3H), 7.58 (s, 1H), 7.55 (dd, J=6.8, 1.6Hz, 1H), 7.26 ( d, J=6.8Hz, 1H), 7.16 (t, J=74.4Hz, 1H), 3.94 (d, J=6.8Hz, 2H), 1.30-1.23 (m, 1H), 0.64-0.51 (m, 2H), 0.42-0.30 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ165.6, 159.8, 159.2, 152.6, 150.3, 145.8, 141.9, 141.8, 128.6, 128.5, 128.1, 121.6, 119.6, 117.1, 112.7, 73.4, 10.5, 3.5 (2×C). ESI-MS m / z: calculated value is C 19 H 16 O 3 N 5 F 2 + [M+H] + , 502.0; the actual measured value is 502.0.

[0476] Example 105 Synthesis of Compound J2:

[0477] The synthesis steps were as in Example 9. In the last step, 4-oxazolecarboxylic acid (CAS No.: 23012-13-7) was selected as the acid reagent to obtain compound J2 with a yield of 19%. 1 H NMR (600 MHz, DMSO-d 6)δ9.44 (s, 1H), 8.66 (s, 1H), 7.89 (s, 2H), 7.76 (dd, J=8.4, 1.2Hz, 1H), 7.71 (d, J=1.8Hz, 1H), 7.27 (d, J=8.4Hz , 1H), 7.17 (t, J=74.4Hz, 1H), 4.00 (d, J=6.6Hz, 2H), 1.31-1.23 (m, 1H), 0.63-0.54 (m, 2H), 0.43-0.32 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ159.5, 158.7, 158.5, 152.6, 149.9, 148.8, 141.4, 131.3, 128.1, 121.0, 119.6, 116.6 (t, J = 256.5 Hz), 112.5, 73.1, 10.0, 3.1 (2×C). ESI-MS m / z: calculated value is C 17 H 16 O 4 N 5 F 2 + [M+H] + , 392.1; the measured value is 392.1.

[0478] Example 106 Synthesis of Compound J3:

[0479] The synthesis steps were as in Example 9. In the last step, 2-methyl-4-thiazolecarboxylic acid (CAS No.: 35272-15-2) was selected as the acid reagent to obtain compound J3 with a yield of 17%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.22 (s, 1H), 7.87 (s, 2H), 7.69 (d, J = 8.8Hz, 2H), 7.28 (d, J = 7.6Hz, 1H), 7.17 (t, J = 74.0Hz, 1H ), 3.98 (d, J=6.0Hz, 2H), 2.74 (s, 3H), 1.37-1.29 (m, 1H), 0.63-0.54 (m, 2H), 0.43-0.34 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ166.1, 159.7, 159.6, 159.5, 150.3, 145.1, 141.7, 134.9, 128.7, 121.6, 119.8, 117.1, 112.8, 73.5, 19.3, 10.5, 3.5 (2×C). ESI-MS m / z: calculated value is C 23 H 200 3 N 5 F 2 S + [M+H] + , 422.1; the measured value is 422.1.

[0480] Example 107 Synthesis of Compound J4:

[0481] The synthesis steps were as in Example 9. In the last step, 1-methyl-1H-imidazole-5-carboxylic acid (CAS No.: 41806-40-0) was selected as the acid reagent to obtain compound J4 with a yield of 38%. 1 H NMR (600 MHz, DMSO-d 6 )δ8.51 (s, 1H), 8.08 (s, 1H), 7.79 (s, 2H), 7.65 (d, J=8.4Hz, 2H), 7.30-7.26 (m, 1H), 7.10 (t, J=74.4H z, 1H), 3.97 (d, J=6.6Hz, 2H), 3.94 (s, 3H), 1.31-1.20 (m, 1H), 0.64-0.55 (m, 2H), 0.45-0.33 (m, 2H). 13 CNMR (151 MHz, DMSO-d 6 )δ159.0, 158.8, 158.3, 149.9, 144.9, 142.1, 141.2, 128.3, 122.9, 121.2, 119.1, 116.7 (t, J = 258.0 Hz), 112.1, 73.0, 34.8, 10.0, 3.1 (2×C). ESI-MS m / z: calculated value is C 18 H 19 0 3 N 6 F 2 + [M+H] + , 405.1; the measured value is 405.1.

[0482] Example 108 Synthesis of Compound J5:

[0483] The synthesis steps were as in Example 9. In the last step, 8-isoquinolinecarboxylic acid (CAS No.: 61563-43-7) was selected as the acid reagent to obtain compound J5 with a yield of 30%. 1 H NMR (500 MHz, DMSO-d 6)δ9.45 (s, 1H), 8.57 (d, J = 6.0Hz, 1H), 8.40 (d, J = 8.5Hz, 1H), 8.28 (d, J = 7 .0Hz, 1H), 7.99 (s, 2H), 7.86-7.82 (m, 1H), 7.45 (d, J=2.0Hz, 1H), 7.33 (dd , J=8.5, 2.0Hz, 1H), 7.18 (d, J=8.5Hz, 1H), 7.10 (t, J=74.0Hz, 1H), 3.84 ( d, J=6.5Hz, 2H), 1.24-1.11(m, 1H), 0.59-0.49(m, 2H), 0.35-0.24(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ167.3, 159.1, 158.7, 153.1, 149.7, 144.1, 141.2, 133.1, 132.3, 131.8, 129.1, 128.2, 127.9, 126.3, 121.1, 119.0, 117.7, 116.6 (t, J = 256.5 Hz), 112.2, 72.9, 9.9, 3.0 (2×C). ESI-HRMS m / z: calculated value is C 23 H 19 0 3 N 5 F 2 + [M+H] + , 452.1529; the measured value is 452.1504.

[0484] Example 109 Synthesis of Compound J6:

[0485] The synthesis steps were as in Example 9. In the last step, quinoline-4-carboxylic acid (CAS No.: 486-74-8) was selected as the acid reagent to obtain compound J6 with a yield of 27%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.11 (s, 1H), 8.16 (d, J=8.4Hz, 1H), 8.06 (s, 2H), 7.97-7.79 (m, 3H), 7.67 (t, J=7.6Hz, 1H), 7.41 (s, 1H), 7.27 (s, 1H), 7.1 5 (d, J=8.4Hz, 1H), 7.09 (t, J=74.0Hz, 1H), 3.82 (d, J=6.8Hz, 2H), 1.36-1.27 (m, 1H), 0.63-0.47 (m, 2H), 0.41-0.16 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ167.2, 160.3-159.9 (m), 158.9, 150.5, 149.8, 148.2, 141.7, 139.1, 130.6, 130.0, 128.4 (2×C), 125.5, 123.8, 121.5, 121.0, 119.5, 117.0, 112.6, 73.4, 10.4, 3.5 (2×C). ESI-HRMS m / z: calculated value is C 23 H 20 0 3 N 5 F 2 + [M+H] + , 452.1529; the measured value is 452.1528.

[0486] Active Examples

[0487] Activity Example 1 Test of the Inhibitory Activity of the Compounds of the Application on PDE4 (PDE4B1, PDE4D2) Enzyme

[0488] The present invention adopts the following method to carry out biological test on the compound of the present application:

[0489] 1. Preparation of reaction buffer and reaction stop solution (reagents see Table 1)

[0490] (1) Preparation of 1x reaction buffer

[0491] IMAP reaction buffer (provided by IMAP FP IPP Explorer Kit) containing 0.1% BSA (5×) was diluted into 1× reaction buffer containing 1 mM DTT.

[0492] (2) Preparation of reaction termination solution

[0493] The reaction termination solution was prepared by mixing IMAP Progressive Binding Buffer A (5×), IMAP Progressive Binding Buffer B (5×), and IMAP Progressive Binding Reagent (provided by IMAP FP IPP Explorer Kit) according to the instruction manual.

[0494] 2. Compound Preparation

[0495] (1) Compound dilution

[0496] Prepare a solution with a concentration of 100 times the final concentration of the compound to be tested. Use an automatic microporous pipette (PrecisionPRC384U) to dilute the compound gradient to the set number of concentration points as follows: For a 5-fold dilution, add 50 μL of the starting concentration of the compound DMSO solution to well A2 on the Echo 384-well plate, and add 40 μL of 100% DMSO to wells A3-A11; take 10 μL of the compound from well A2 and add well A3, mix well, and make 5-fold dilutions in turn, diluting 10 concentration points; add 40 μL of 100% DMSO to wells A1 and A12.

[0497] (2) Transfer compounds to 384 reaction plates

[0498] Use the Echo550 instrument to transfer 200 nL of the diluted compound from the Echo384-well plate to a 384-well reaction plate, and transfer 200 nL of 100% DMSO to both the negative control and the positive control.

[0499] 3. Enzymatic reaction

[0500] (1) Prepare 2x enzyme solution

[0501] PDE4B1 was added to 1x reaction buffer to form a 2x enzyme solution (final concentration of PDE4B1: 0.00625 μg / ml).

[0502] (2) Prepare 2 times the substrate solution

[0503] For the enzyme PDE4B1, FAM-labeled cAMP was added to 1x reaction buffer to form a 2x substrate solution (final concentration of FAM-cAMP: 0.1 μM).

[0504] (3) Add enzyme solution to the 384-well plate

[0505] Add 10 μL of 2x enzyme solution to each well of a 384-well reaction plate. For the no-enzyme control well, replace the enzyme solution with 10 μL of 1x reaction buffer. Centrifuge at 1000 rpm for 1 min and incubate at room temperature for 15 min.

[0506] (4) Add substrate solution to the 384-well plate to start the enzymatic reaction

[0507] Add 10 μL of 2x substrate solution to each well of the 384-well reaction plate. Centrifuge at 1000 rpm for 1 min. The reaction was continued for 30 minutes.

[0508] (5) Termination of enzyme reaction

[0509] 60 μL of the reaction stop solution was added to each well of the 384-well reaction plate to terminate the reaction, and the plate was incubated at room temperature for 60 minutes on a shaker at 600 rpm in the dark.

[0510] 4. Read data and calculate data using EnVision

[0511] Readings were taken with EnVision.

[0512] 5. Calculation of Inhibition Rate and IC 50 Curve Fitting

[0513] Data were copied from EnVision, where the maximum value refers to the reading of the DMSO control and the minimum value refers to the reading of the no enzyme activity control. Inhibition rate (%) = (maximum value - sample value) / (maximum value - minimum value) × 100%.

[0514] The data were imported into MS Excel and IC fitted using XLFit excel add-in version 5.4.0.8 50 value;

[0515] Fitting formula: Y = Bottom + (Top-Bottom) / (1 + (IC 50 / X)^HillSlope)

[0516] The detection method for PDE4D2 refers to PDE4B1.

[0517] Table 1 Reagent information

[0518]

[0519] The inhibitory effect of the compounds of the present application on PDE4 (PDE4B1, PDE4D2) enzyme was determined according to the above method. The results are shown in Tables 2 and 3.

[0520] Table 2 The results of the determination of the inhibitory effect of the compounds of the present invention on PDE4B1 enzyme

[0521] Compound Inhibition rate (%) Compound Inhibition rate (%) Compound Inhibition rate (%) Roflumilast 96.9％ A17 93.9％ B4 76.2％ A1 94.4％ A18 91.1％ B5 62.2％ A2 94.0％ A19 94.1％ C1 81.4％ A3 95.5％ A20 94.6％ C2 80.9％ A4 65.6％ A21 83.8％ C3 25.8％ A5 89.9％ A22 92.2％ D1 23.3％ A6 79.3％ A23 93.6％ D2 42.5％ A1 56.8％ A24 93.4％ D3 49.2％ A8 53.1％ A25 96.2％ E1 68.0％ A9 90.6％ A26 90.1％ E2 70.2％ A10 82.4％ A27 81.6％ E8 73.3％ A11 91.9％ A28 93.5％ E9 93.2％ A12 88.8％ A29 91.5％ E10 95.3％ A13 85.2％ A30 79.2％ E11 92.0％ A14 88.6％ B1 24.8％ E12 92.7％ A15 90.1％ B2 62.3％ A16 93.3％ B3 62.3％

[0522] Table 3 The results of the determination of the inhibitory effect of the compounds of the present invention on PDE4D2 enzyme

[0523]

[0524]

[0525] IC of the compound of Activity Example 2 for PDE4B1 and PDE4D2 50 The detection implementation steps refer to the activity example 1 to obtain IC 50 value.

[0526] IC of the compound 50 The values ​​are shown in Table 4.

[0527] Table 4 IC of compounds of the present invention 50 value

[0528] Compound PDE4B1(nM) PDE4D2(nM) A1 9.35±2.51 5.192±0.2686 A2 10.66±2.66 5.295±1.65 A3 0.4373±0.164 0.1769±0.07129 A5 48.82±2.76 5.915±1.325 A6 15.55±10.22 15.31±1.151 A9 40.51±6.79 Not tested A11 8.43±1.02 7.45±2.26 A12 14.2±1.68 Not tested A15 10.8±2.84 10.15±4.29 A16 4.4±0.48 2.07±0.18 A17 3.75±0.57 1.95±0.3 A18 23.8±2.55 Not tested A19 5.13±1.49 4.33±0.5 A20 2.09±0.18 1.15±0.14 A22 10.75±1.26 5.04±0.92 A23 7.85±1.02 3.28±0.34 A24 9.33±1.29 3.82±0.68 A25 5.94±0.66 2.9±0.17 A26 8.04±0.87 8.35±2.35 A28 5.66±0.92 2.66±0.26 A29 142.4±17.6 81.2±16.03

[0529] Activity Example 3 In vitro liver microsomal metabolic stability experiment of 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound A5, 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(thiazol-2-y1)-1H-benzo[d]imidazole-4-carboxamide) and evaluation of its effect on cardiac ion channels (hERG experiment).

[0530] 0.5 μM compound A5 was incubated with liver microsomes (1 mg / mL) at 37°C. 100 μL of the reaction solution was taken at 0, 5, 15, 30, 45 and 60 minutes. 200 μL of acetonitrile containing internal standard was added to 100 μL of the reaction solution to extract the test compound. The obtained mixture was centrifuged and the supernatant was analyzed by LC-MS / MS. The results are shown in Table 5. It can be seen that the half-life of compound A5 in human liver microsomes is 421.75 minutes, and the IC in the hERG experiment is 0.17777. 50 Greater than 30 μM, indicating that compound A5 has essentially no cardiotoxicity.

[0531] Table 5 In vitro metabolic stability of liver microsomes and hERG experimental results of compound A5

[0532]

[0533] Active Example 4 In vitro Caco-2 permeability assay of 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound A5, 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide)

[0534] Compound A5 was subjected to Caco-2 monolayer analysis. Under the same conditions, the transport of compound A5 from the apical side to the basolateral side (AB) and from the opposite direction (BA) was measured simultaneously. Propranolol and nadolol were used as hypertonic and hypotonic controls, respectively. Digoxin was used as a positive control for PGP-mediated drug efflux. After washing the monolayer three times with Hanks balanced salt solution (HBSS, Sigma-Aldrich), compound A5 was diluted and added to the appropriate wells (apical side pH 6.8, basolateral pH 7.4). Incubate at 37°C for 95 min. Samples were collected from the donor side at 5 min and 95 min, and samples were collected from the acceptor side at 35 min and 95 min after incubation. The concentration of the samples was determined by liquid chromatography-mass spectrometry (LC-MS) / mass spectrometry. The average value is the average of three independent experiments, and each experiment was repeated three times.

[0535] The results are shown in Table 6.

[0536] Table 6 In vitro Caco-2 permeability measurement results of compound A5

[0537]

[0538] In vivo pharmacokinetic study of active example 5 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound A5, 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide)

[0539] Fifteen male SPF SD rats were used. The oral administration dose of compound A5 was designed to be 10 mg / kg, and the intravenous injection dose of compound A5 was designed to be 5 mg / kg. Blood was collected from the oral administration group before (0 min) and 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after administration, and blood was collected from the intravenous group before (0 min) and 5 min, 15 min, 1 h, 2 h, 4 h, 8 h and 24 h after administration. About 0.3 mL of whole blood was collected from the orbital venous plexus or the jugular venous plexus each time into a pre-labeled heparinized blood collection tube. The blood sample was temporarily stored in an ice box, then centrifuged at 4500 rpm for 10 min to separate the plasma, and the concentration of each drug in the plasma was determined by the established LC-MS method. The blood drug concentration data were processed using DAS 3.3.0, and the main pharmacokinetic parameters were calculated using a non-compartmental model.

[0540] The results are shown in Table 7.

[0541] Table 7 Pharmacokinetic data of compound A5 in SD rats

[0542] parameter iv (5 mg / kg) parameter Po (10 mg / kg) <![CDATA[AUC (0-t) (mg / mL)]]> 23216±2413 <![CDATA[AUC (0-t) (mg / mL)]]> 2129±650 <![CDATA[AUC (0-∞) (mg / mL)]]> 23221±2417 <![CDATA[AUC (0-∞) (mg / mL)]]> 2163±667 <![CDATA[C 0 (ng / mL)]]> 38072±4918 <![CDATA[C max (ng / mL)]]> 219±55 <![CDATA[T 1 / 2 (h)]]> 1.97±0.51 <![CDATA[T 1 / 2 (h)]]> 3.75±0.69 <![CDATA[V ss (L / kg)]]> 0.60±0.11 <![CDATA[T max (h)]]> 3.00±1.73 CL(L / h / kg) 0.21±0.02 F(％) 4.59±1.4

[0543] Active Example 6 Study on the Anti-psoriatic Effect of 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound A5, 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide) on Mice

[0544] 1. Purpose of the experiment

[0545] The therapeutic effect of compound A5 on imiquimod-induced psoriasis in mice was investigated.

[0546] 2. Experimental Materials

[0547] Experimental animals: 56 Balb / c male mice, age: 6-8 weeks; body weight: about 18-22 g.

[0548] Experimental instruments: heating stirrer, paraffin slicer, microscope, syringe, microplate reader, balance, oven, refrigerated centrifuge, etc.

[0549] Experimental reagents: HE staining related reagents, PBS solution, etc., imiquimod, ELISA kits of IL-1β, IL-17A, and TNF-α.

[0550] 3. Animal Experiments

[0551] 1. Establishment of mouse psoriasis model and drug administration

[0552] ① Shave the 2cm×3cm area on the back of the mouse three days before modeling. Observe the shaving effect, and shave the villi and new hair at the beginning of modeling.

[0553] ② The mice were randomly divided into 7 groups: blank group, model group (5% IMQ 62.5 mg / d, for 9 consecutive days), compound group (0.3%, 0.6%, 1.2%), positive control group (roflumilast, 0.3%), and excipient group (only applied cream excipient formula), 8 mice in each group, for a total of 56 mice.

[0554] Blank group: Starting from the first day of psoriasis modeling, no treatment was given to the mice.

[0555] Model group: Starting from the first day, 62.5 mg of 5% IMQ was applied to the exposed skin on the back of mice every day to establish a psoriasis model, and the application lasted for 9 consecutive days.

[0556] Positive control group: Starting from the first day of psoriasis modeling, 62.5 mg of 5% IMQ was applied to the exposed skin of the back of mice every day. Starting from the third day, 62.5 mg of 5% IMQ was applied to the exposed skin of the back of mice in the morning. 4 hours later, 62.5 mg of roflumilast cream (0.3%) was applied to each mouse for 7 consecutive days.

[0557] Compound groups (0.3%, 0.6%, 1.2%): Starting from the first day of psoriasis modeling, 62.5 mg of 5% IMQ was applied to the exposed skin on the back of mice every day. Starting from the third day, 62.5 mg of 5% IMQ was applied to the exposed skin on the back of mice in the morning. After 4 hours, each group of mice was treated with low, medium and high doses of compound cream respectively for 7 consecutive days.

[0558] Excipient group: Starting from the first day of psoriasis modeling, 62.5 mg of the cream formula was applied to the exposed skin on the back of the mice every day for 7 consecutive days.

[0559] 2. Scoring of Psoriasis Area and Severity Index (PASI) and Phenotypic Observation in Mice

[0560] 2.1 PSAI scoring of mice

[0561] The PASI score was performed by observing the degree of scaling, erythema, and hypertrophy of the skin on the back of the mice with the naked eye. The PASI score rule is to select erythema, scaling, and hypertrophy to evaluate the severity of psoriasis. After scoring, take pictures and record the results. Figure 1 The model group showed obvious psoriasis characteristics, while the plaque, thickness and erythema of the drug-treated group were significantly reduced, that is, the application of compound A5 can significantly alleviate the symptoms of psoriasis. The mice were weighed every day to observe the changes in their weight. Figure 2 The mice were weighed continuously for 10 days, and there was no significant change in body weight, indicating that compound A5 had no obvious toxicity to mice.

[0562] 2.2 Mouse killing and sampling

[0563] The mice were euthanized by intraperitoneal overdose of 0.3% sodium pentobarbital solution.

[0564] 2.3 Paraffin embedding and sectioning of skin tissue

[0565] 1) Cut the entire layer of skin parallel to the spine and fix it in 10% neutral formaldehyde solution for more than 24 hours.

[0566] 2) Place the trimmed tissue block in an embedding box and wash it with running water for 24 hours to completely remove residual formaldehyde.

[0567] 3) Dehydrating the tissue in an alcohol gradient, specifically: 70% alcohol for 12 h, 80% alcohol for 1.5 h, 95% alcohol I for 45 min, 95% alcohol II for 30 min, 100% alcohol I for 25 min, and 100% alcohol II for 20 min.

[0568] 4) After dehydration, place the tissue in an alcohol / xylene (1:1, v / v) solution for 20 min.

[0569] 5) Soak the tissue in xylene I for 20 minutes and then in xylene II for 10 minutes.

[0570] 6) Place the tissue in pre-melted paraffin I and paraffin II in an oven at 60-65°C for 1 hour each.

[0571] 7) Pour a small amount of embedding paraffin into the preheated metal embedding frame, place the skin tissue block in it, perpendicular to the embedding frame, with the bottom flat, pour paraffin again, embed the tissue, and cool it.

[0572] 8) Paraffin sectioning: Fix the tissue paraffin block on the Leica slicer, slice the slices to a thickness of 5 μM, and slice them continuously. Use toothless forceps to place the slices in 40°C water for spreading, pick up the slices with a glass slide, bake the slices at 60°C for 2 hours, and store them in a slice box at room temperature for later use.

[0573] 2.4 HE staining

[0574] 1) Dewaxing and hydration: Place the skin tissue paraffin sections in xylene I and xylene II for 15 min each, then place them in 100% ethanol I and ethanol II for 3 min each, 95% ethanol I and ethanol II for 3 min each, 80% ethanol for 3 min, and double distilled water for 1 min;

[0575] 2) Hematoxylin staining for 15 min, then wash off the excess stain on the slide;

[0576] 3) 1% hydrochloric acid ethanol (99 mL 70% ethanol + 1 mL concentrated hydrochloric acid) color separation for 3 seconds, the cell nucleus and chromatin should be clear under the microscope;

[0577] 4) Rinse with running water for 15 minutes, and then with distilled water for 1 minute;

[0578] 5) Eosin for 2 minutes, rinse with running water for 1 minute;

[0579] 6) Dehydration with 80% and 100% ethanol for 2 seconds and 7 minutes respectively;

[0580] 7) Xylene I and II for 5 min each;

[0581] 8) Sealing: Take the slide out of xylene II, add neutral gum to the tissue, gently cover with a coverslip, and let it dry naturally;

[0582] 9) Observation: Observe pathological changes under a microscope, take photos and analyze.

[0583] like Figure 3 As shown, the skin thickness in the model group was thickened and a large number of inflammatory cells infiltrated. The inflammatory cells in the drug-treated group (compound A5) were significantly reduced. The reduced skin thickness indicated that the drug-treated group had a protective effect on the skin in a dose-dependent manner.

[0584] 2.5Ki-67 antibody immunohistochemical staining

[0585] 1) Place the skin tissue paraffin sections in an oven and bake at 60°C for 1 hour.

[0586] 2) Dewaxing: xylene 10 min three times → anhydrous ethanol I 5 min → anhydrous ethanol II 5 min → 95% ethanol 5 min → 85% ethanol 5 min → 75% ethanol 5 min → ddH 2 O 5min.

[0587] 3) Antigen repair: Prepare 400 ml of antigen repair solution (800 mL dd H 2 (20 mL) was boiled with PBS (3 g sodium citrate + 400 mg citric acid and then fixed to 1000 mL), and the slices were placed in a beaker and boiled for 20 min. After cooling, the slices were rinsed with PBS 3 times, each time for 3 min.

[0588] 4) Add 3% hydrogen peroxide and incubate at room temperature for 5 min. Wash the sections 3 times with PBS, each time for 3 min.

[0589] 5) Remove PBS and add 10% goat serum blocking solution at room temperature for 1 hour.

[0590] 6) Remove goat serum, shake dry and directly add primary antibody, incubate in a wet box at 4°C overnight (about 14 hours).

[0591] 7) Remove the slices, rewarm for 30 minutes, and rinse with PBS three times, 3 minutes each time.

[0592] 8) Remove PBS, add secondary antibody for immunohistochemistry to each sample, incubate at room temperature for 15 min, and rinse with PBS three times, 3 min each time.

[0593] 9) Dry the slices and immediately place them on a microscope. DAB was added for staining. After color development, the slices were rinsed with PBS for 5 minutes.

[0594] 10) Hematoxylin re-staining for 40 seconds → Rinse with running water for 2 minutes → Revert to blue for 7 seconds → Rinse with running water for 10-15 minutes → Use dd H 2 O soak for 5 minutes.

[0595] 11) 95% ethanol (1 min) → anhydrous ethanol I (1 min) → anhydrous ethanol II (1 min) → xylene (1 min) → xylene (1 min) → xylene (1 min) and seal the slides with neutral gum.

[0596] The results are as follows Figure 4 As shown, the expression of Ki-67 antibody in the model group cells was significantly increased, while the expression in the drug-treated group (compound A5) was significantly reduced, indicating that the compound has a significant inhibitory effect on skin thickening.

[0597] 4. Expression of pro-inflammatory cytokines in the skin of psoriasis mice after different treatments

[0598] ① Protein levels of IL-1β, IL-17A, and TNF-α in skin lesions

[0599] 1) Take 100 mg of lesioned skin and put it in an EP tube. Add 1 mL of normal saline and grind it using a pre-cooled tissue grinder.

[0600] 2) Centrifuge once at 3500 rpm and once at 12000 rpm at 4°C, take the supernatant, determine the protein concentration in the skin tissue abrasive fluid by BCA method, and determine the content of IL-1β, IL-17A, and TNF-α by ELISA kit according to the instructions of the kit.

[0601] The results are as follows Figure 5 As shown, compound A5 has a down-regulating effect on IL-1β, IL-17A and TNF-α inflammatory factors, indicating that compound A5 has a therapeutic effect on psoriasis inflammation.

[0602] Active Example 7 Study on the therapeutic effect of 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound A5, 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide) on chronic obstructive pulmonary disease in mice

[0603] 1. Purpose of the experiment

[0604] The therapeutic effect of compound A5 on chronic obstructive pulmonary disease (COPD) induced by lipopolysaccharide combined with smoke fumigation in mice was investigated.

[0605] 2. Experimental Materials

[0606] Experimental animals: C57BL / 6 male mice, 48 mice, age: 6-8 weeks; body weight: about 18-22 g.

[0607] Experimental instruments: heating stirrer, whole-body exposure fumigation box, paraffin slicer, microscope, syringe, microplate reader, balance, oven, refrigerated centrifuge, etc.

[0608] Experimental reagents: HE staining related reagents, PBS solution, lipopolysaccharide, and ELISA kit.

[0609] 3. Animal Experiments

[0610] 1. Establishment of a mouse model of chronic obstructive pulmonary disease

[0611] The mice in the normal group were placed in IVC cages for breeding, and the mice in the fumigation group were subjected to the fumigation test. The fumigation steps were as follows: the mice were placed in a fumigation box, a cigarette was inserted into the fumigation box and ignited, and the fumigation box was closed. The initial fumigation conditions were 5 cigarettes / h, 2 hours each time (20 minutes of ventilation every hour), twice a day, once in the morning and afternoon, with a 4-hour interval between the morning and afternoon, 6 days / week. In the first 2 weeks, the number of cigarettes was gradually increased (giving the fumigated mice a period of adaptation to avoid excessive smoke causing the death of mice) until the number of cigarettes increased to 12 cigarettes / h, and this condition was maintained until the 147th day (a total of 21 weeks). The mice in the fumigation group were instilled with LPS by tube on the 1st day and 14th day after the model was established, with a dose of 75μg / 20g, and the mice in the normal group were instilled with an equal amount of saline. The mice were exposed to SPF animal rooms outside the fumigation time.

[0612] 2. Grouped medication

[0613] Blank group mice: normal + Vehicle group;

[0614] Mice in the smoked group were randomly divided into the model + vehicle group, model + A5 low-dose group (5 mg / kg), model + A5 medium-dose group (15 mg / kg), model + A5 high-dose group (45 mg / kg), and model + Roflumilast (Rof) control group (5 mg / kg), with 8 mice in each group. Drug administration began 17 weeks after the smoked treatment, and was continuously administered by gavage for 4 weeks, once a day.

[0615] Preparation of drug solution: dissolve sodium carboxymethyl cellulose CMC-Na in pure water to prepare a 0.5% solution, heat and stir until completely dissolved, cool to room temperature, dissolve compound A5 in the 0.5% CMC-Na solution, break it into a suspension with an ultrasonic crusher, and store it at 4°C.

[0616] 3. Detection indicators to evaluate drug efficacy

[0617] (1) Observation: Observe the activity, hair, food intake, breathing, body weight, etc. of each group of rats. Weigh the rats 1 hour before feeding each week to observe changes in body weight. Figure 6 It can be seen that the body weight of the model group was significantly reduced compared with the blank group, and the body weight of the drug group recovered to a certain extent after drug administration, indicating that the drug is relatively safe.

[0618] (2) Pulmonary function evaluation:

[0619] The lung function of mice was tested using an experimental small animal pulmonary function tester. The main indicators included functional residual capacity (FRC), forced expiratory volume at 50 ms / forced vital capacity (FEV50 / FVC), and forced expiratory volume at 20 ms / forced vital capacity (FEV20 / FVC).

[0620] according to Figure 7 It can be seen that the functional residual capacity FRC of the model group was significantly increased compared with the blank group, indicating that the alveoli may have airway closure, which is one of the key symptoms of COPD. After treatment with different concentrations of compound A5, FRC decreased to a certain extent, close to the blank group, indicating that the drug has a certain alleviating effect on the increase in FRC; FEV50 / FVC and FEV20 / FVC decreased to a certain extent compared with the blank group, indicating that the forced expiratory volume / forced vital capacity of mice was low, reflecting the degree of airway obstruction. After administration, FEV50 / FVC had a certain alleviating effect, indicating that compound A5 has the effect of alleviating chronic obstructive pulmonary disease.

[0621] (3) Pathological evaluation:

[0622] Paraffin sections

[0623] ① After intraperitoneal injection of sodium pentobarbital to anesthetize the mice, the thorax was opened to expose the chest cavity: the left lung lobe was taken and fixed in an embedding box with 10% formaldehyde solution for 24 hours, and washed with running water for 24 hours to completely remove the residual formaldehyde;

[0624] ② Dehydrate the tissue in an alcohol gradient, with the following steps: 70% alcohol overnight, 80% alcohol for 1.5 hours, 95% alcohol I for 45 minutes, 95% alcohol II for 30 minutes, 100% alcohol I for 25 minutes, and 100% alcohol II for 20 minutes;

[0625] ③ After dehydration, place the tissue in alcohol / xylene (1:1, v / v) solution for 20 min;

[0626] ④ Xylene transparent I, II 20min, 10min;

[0627] ⑤ Place the tissue in preheated melted paraffin I, paraffin II and embedding paraffin in an oven at 60-65℃ for 1 hour each.

[0628] ⑥ Pour a small amount of embedding paraffin into the preheated metal embedding frame, so that the tissue and the embedding frame are perpendicular, pour paraffin again, embed the tissue, and cool it down;

[0629] ⑦ Paraffin section: Fix the tissue paraffin block on the Leica slicer, slice with a thickness of 5 μm, and slice continuously. Use toothless forceps to place the slices in 40℃ water for spreading, pick up the slices with a slide, bake the slices at 60℃ for 2 hours, and store them in a slice box at room temperature for later use.

[0630] HE staining

[0631] ① Dewaxing and hydration: Put the tissue paraffin sections into xylene I and II for 15 minutes each, then put them into 100% ethanol I and ethanol II for 3 minutes each, 95% ethanol I and ethanol II for 3 minutes each, 80% ethanol for 3 minutes, and double distilled water for 1 minute;

[0632] ② Stain with hematoxylin for 15 minutes and wash away the excess stain on the slide;

[0633] ③ Use 1% hydrochloric acid ethanol (99mL 70% ethanol + 1mL concentrated hydrochloric acid) for color separation for 3s, and the cell nucleus and chromatin should be clear under the microscope;

[0634] ④ Rinse with running water for 15 minutes, and then with distilled water for 1 minute;

[0635] ⑤ Treat with eosin for 2 minutes and rinse with running water for 1 minute;

[0636] ⑥ Dehydrate with 80% ethanol and 100% ethanol for 2 seconds and 7 minutes respectively;

[0637] ⑦ Treat with xylene and xylene II for 5 min each;

[0638] ⑧ Sealing: Take the slide out of xylene II, add neutral gum on the tissue, gently cover with a coverslip, and let it dry naturally.

[0639] ⑨Observation: Observe pathological changes under a microscope, take photos and analyze.

[0640] Microscope observation (see Figure 8 ) found that the alveolar structure of the lung tissue of the blank control group was intact, and there was no inflammatory cell infiltration. The mice in the model group had broken alveolar walls, irregular alveolar expansion and fusion to form bullae, and the airway walls were significantly thickened. Inflammatory cell infiltration to varying degrees was seen in the lung interstitium, and dust cells formed by smoke particles were seen in the alveolar cavity. This is consistent with the pathological changes in the lung tissue of COPD mice. The alveolar walls of the mice in the drug group partially fused into bullae, the tracheal walls were slightly thickened, and there was infiltration of inflammatory cells in the lungs, but there was a trend of reduction compared with the model group, indicating that the drug has the effect of alleviating chronic obstructive pulmonary disease.

[0641] (4) Total number of inflammatory cells and expression levels of inflammatory factors IL-8 (CXCL1 / KC / N51), TNF-α, and MMP9 in bronchoalveolar lavage fluid

[0642] ① Total number of cells in mouse bronchoalveolar lavage (BALF) samples.

[0643] ② Centrifuge at 1000 rpm for 5 min at 4°C, take the supernatant, and determine the protein concentration in BALF by BCA method. Use ELISA kit to determine the content of IL-8 (CXCL1 / KC / N51), TNF-α and MMP9 according to the instructions of the kit.

[0644] Results Reference Fig. 9 Different concentrations of A5 drugs had inhibitory effects on the total number of inflammatory cells in bronchoalveolar lavage fluid and the inflammatory factors IL-8 (CXCL1 / KC / N51), TNF-α, and MMP9, indicating that compound A5 has a therapeutic effect on lung inflammation associated with chronic obstructive pulmonary disease.

[0645] Active Example 8 Study on the effect of 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound A5, 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide) in treating acute lung injury in mice

[0646] 1. Purpose of the experiment

[0647] The therapeutic effect of compound A5 on lipopolysaccharide-induced acute lung injury (ALI) model in mice was investigated.

[0648] 2. Experimental Materials

[0649] Experimental animals: 36 Balb / c male mice, age: 4-6 weeks; body weight: about 18-22 g.

[0650] Experimental instruments: heating stirrer, paraffin slicer, microscope, syringe, microplate reader, balance, oven, low-temperature centrifuge, etc.

[0651] Experimental reagents: HE staining related reagents, PBS solution, lipopolysaccharide, ELISA kit.

[0652] 3. Animal Experiments

[0653] 1. Establishment and administration of acute lung injury model in mice

[0654] The blank control group, model group (10 mg / kg LPS), roflumilast (Rof) positive drug group (4 mg / kg), and compound A5 group (8, 16, 32 mg / kg) were intragastrically administered once a day, with 6 mice in each group, and the model was established 7 days after intragastrically administering.

[0655] Preparation of drug solution: dissolve sodium carboxymethyl cellulose CMC-Na in pure water to prepare a 0.5% solution, heat and stir until completely dissolved, cool to room temperature, dissolve compound A5 in 0.5% CMC-Na solution, break it into a suspension with an ultrasonic crusher, and store it at 4°C.

[0656] Modeling: One hour after the last day of administration, mice were anesthetized intraperitoneally with 0.3% sodium pentobarbital solution, and each mouse was given 50 μL LPS (10 mg / kg) via trachea. After 24 hours of instillation, the mice were euthanized and bronchoalveolar lavage fluid was obtained. The mice were dissected and lung tissues were obtained for fixation and embedding.

[0657] 2. Detection indicators to evaluate drug efficacy

[0658] (1) Total number of inflammatory cells in bronchoalveolar lavage fluid (BALF)

[0659] After euthanizing the mice, the chest cavity was opened, the left lung was ligated, and the tissues around the trachea were bluntly separated with forceps to expose the trachea. A small cut was made on the trachea with scissors, and the tip of the 1mL syringe needle was cut off and polished to make it smooth. The polished syringe needle was inserted from the trachea to the carina, and a thread was passed under the trachea. The needle and trachea were ligated together to fix the needle, and 0.6mL of sterile saline was slowly injected. After repeated flushing, the lavage fluid was recovered, and the two lavage fluids were combined to obtain the bronchoalveolar lavage fluid. The collected BALF was centrifuged at 4℃ and 1000rpm for 5min, and the supernatant was aspirated into another centrifuge tube and stored at -20℃.

[0660] (2) Total number of inflammatory cells and expression levels of inflammatory factors IL-6, IL-1β, and TNF-α in bronchoalveolar lavage fluid

[0661] ①Use a cell counter to count the total number of cells in mouse bronchoalveolar lavage (BALF) samples.

[0662] ② Centrifuge at 1000 rpm for 5 min at 4°C, take the supernatant, determine the protein concentration in BALF by BCA method, and determine the content of IL-6, IL-1β, and TNF-α by ELISA kit according to the instructions of the kit.

[0663] The results are as follows Fig.10As shown, after intratracheal instillation of LPS, the total number of inflammatory cells and the expression of inflammatory factors IL-6, IL-1β, and TNF-α in the bronchoalveolar lavage fluid of the model group mice were significantly increased compared with the blank group. After the administration of compound A5, the total number of inflammatory cells and the expression of inflammatory factors IL-6, IL-1p, and TNF-α were significantly reduced compared with the model group, indicating that compound A5 has a therapeutic effect on lung inflammation caused by acute lung injury.

[0664] (3) Pathological evaluation:

[0665] Paraffin sections

[0666] ① After euthanizing the mice, the chest was opened to expose the chest cavity: the left lung lobe was fixed in an embedding box containing 10% formaldehyde solution for 24 hours, and then washed with running water for 24 hours to completely remove the residual formaldehyde;

[0667] ② Dehydrate the tissue in an alcohol gradient, with the following steps: 70% alcohol overnight, 80% alcohol for 1.5 hours, 95% alcohol I for 45 minutes, 95% alcohol II for 30 minutes, 100% alcohol I for 25 minutes, and 100% alcohol II for 20 minutes;

[0668] ③ After dehydration, place the tissue in alcohol / xylene (1:1, v / v) solution for 20 min;

[0669] ④ Xylene transparent I, II 20min, 10min;

[0670] ⑤ Place the tissue in preheated melted paraffin I, II and embedding paraffin in an oven at 60-65℃ for 1 hour each.

[0671] ⑥ Pour a small amount of embedding paraffin into the preheated metal embedding frame, place the tissue block in it, make the tissue and the embedding frame perpendicular, pour paraffin again, embed the tissue, and cool it down;

[0672] ⑦ Paraffin section: Fix the tissue paraffin block on the Leica slicer, slice with a thickness of 5 μm, and slice continuously. Use toothless forceps to place the slices in 40℃ water for spreading, pick up the slices with a slide, bake the slices at 60℃ for 2 hours, and store them in a slice box at room temperature for later use.

[0673] HE staining

[0674] ① Dewaxing and hydration: Put the tissue paraffin sections into xylene I and II for 15 min each, then put them into 100% ethanol I and II for 3 min each, 95% ethanol I and II for 3 min each, 80% ethanol for 3 min, and double distilled water for 1 min;

[0675] ②Hematoxylin staining for 15 minutes, then wash off the excess stain on the slide;

[0676] ③1% hydrochloric acid ethanol (99mL 70% ethanol + 1mL concentrated hydrochloric acid) color separation for 3s, the cell nucleus and chromatin should be clear under the microscope;

[0677] ④ Rinse with running water for 15 minutes, and then with distilled water for 1 minute;

[0678] ⑤ Eosin for 2 minutes, rinse with running water for 1 minute;

[0679] ⑥ Dehydrate with 80% and 100% ethanol for 2s and 7min respectively;

[0680] ⑦ Xylene I and II for 5 min each;

[0681] ⑧ Sealing: Take the slide out of xylene II, add neutral gum on the tissue, gently cover with a coverslip, and let it dry naturally.

[0682] ⑨Observation: Observe pathological changes under a microscope, take photos and analyze.

[0683] Microscope observation (see Fig.11 ), compared with the blank group, the alveoli in the model group collapsed and the alveolar wall thickened, and a large number of inflammatory cells infiltrated the intercellular space; compared with the model group, the low, medium and high dose groups of compound A5 could improve the alveolar wall thickening to varying degrees and reduce the infiltration of inflammatory cells, indicating that compound A5 has a therapeutic effect on lung inflammation caused by acute lung injury.

[0684] (5) Masson staining:

[0685] ① Paraffin sections were routinely dewaxed into distilled water.

[0686] ② According to the instructions of the Solebau Masson kit, mix reagents A1 and A2 in a ratio of 1:1 to prepare Weigert iron hematoxylin staining solution, add it to cover the slices and stain for 10 minutes.

[0687] ③ Wash away excess staining solution with distilled water, add acidic ethanol differentiation solution for 5-15 seconds, and wash with distilled water for 30 seconds.

[0688] ④Return to blue with Masson bluing solution for 3 minutes, then wash with distilled water for 30 seconds.

[0689] ⑤Stain with Ponceau fuchsin staining solution for 10 min.

[0690] ⑥ During the above operation, prepare weak acid working solution in the ratio of distilled water: weak acid solution = 2:1, and add weak acid working solution dropwise to wash for 30 seconds.

[0691] ⑦ Pour off excess liquid, add phosphomolybdic acid solution for 1 minute, and add weak acid working solution for 30 seconds.

[0692] ⑧ Pour off excess liquid, add aniline blue dye solution and dye for 1 minute. Add weak acid working solution and wash for 30 seconds.

[0693] ⑨ Rapid dehydration with 95% ethanol for 2-3 seconds, and dehydration with anhydrous ethanol twice, each time for 5 seconds.

[0694] ⑩ Clear with xylene twice, 2 min each time, and seal with neutral gum.

[0695] Microscopic observation showed (see Fig.12 ), compared with the blank group, the proportion of blue collagen fibers in the model group increased significantly; compared with the model group, the proportion of collagen fibers in the low, medium and high dose groups of compound A5 decreased to varying degrees, indicating that compound A5 has a therapeutic effect on alleviating pulmonary fibrosis caused by acute lung injury.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof in R1 and R2 are each independently And R1 and R2 are not the same X1, X2, X3, X4, X5 when present are each independently C or N, at least two of which are N; R3, when present, is C6-14 aryl, five to fourteen membered heteroaryl, C6-10 cycloalkyl, five to fourteen membered heterocyclyl, C1-C6 alkyl, C1-C6 cycloalkyl, halogen, cyano; optionally, the C6-14 aryl, five to fourteen membered heteroaryl, C6-10 cycloalkyl, or five to fourteen membered heterocyclyl is substituted with one or more substituents selected from halogen, halo-C1-C6 alkyl, carbonyl, C1-C6 alkyl, C1-C6 alkoxy, carboxyl, cyano, hydroxyl, carbonyl, phenyl-SO2-, nitro, C1-C6 alkyloxycarbonyl; the five to fourteen membered heteroaryl or five to fourteen membered heterocyclyl contains 1-3 heteroatoms selected from N, O and S; preferably, the halogen is F, Cl, Br or I; R4, when present, is C6-14 aryl or five to fourteen membered heteroaryl; optionally, the C6-14 aryl or five to fourteen membered heteroaryl is substituted by one or more substituents selected from halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and C1-C6 alkoxy; the five to fourteen membered heteroaryl or five to fourteen membered heterocyclyl contains 1-3 heteroatoms selected from N, O and S; preferably, the halogen is F, Cl, Br or I; L, when present, is NH or O; preferably NH; m, when present, is 1 or 2; n, when present, is 1 or 2; p is 0, 1, or 2 when present; q is 0, 1, or 2 when present; do not exist simultaneously; Each dashed line independently represents the presence or absence of a bond.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof, wherein R1 is R2 is Or R1 is R2 is Or R1 is R2 is 3. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof, wherein X1 is NH, X2 is N, X3, X4 and X5 are C, n is 1, and m is 2; or X1, X3 and X5 are N, X2 and X4 are C, n is 2, and m is 1; or X1, X2, X3, X4 are N, X5 is C, n is 1, and m is 2; or X1 is NH, X2, X3 are N, X4, and X5 do not exist, and n is 1 and m is 0.

4. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof, wherein R3 when present is C6-10 aryl, five to ten membered heteroaryl, C6-10 cycloalkyl, five to ten membered heterocyclyl, C1-C4 alkyl, or C1-C4 cycloalkyl; optionally, the C6-10 aryl, five to ten membered heteroaryl, C6-10 cycloalkyl, or five to ten membered heterocyclyl The five to ten-membered heteroaryl or the five to ten-membered heterocyclic group is substituted by 1, 2 or 3 substituents selected from halogen, halogenated C1-C4 alkyl, carbonyl, C1-C4 alkyl, C1-C4 alkoxy, carboxyl, cyano, hydroxyl, carbonyl, phenyl-SO2-, nitro, C1-C4 alkyloxycarbonyl; the five to ten-membered heteroaryl or the five to ten-membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S; preferably, the halogen is F, Cl, or Br. Preferably, R4, when present, is C6-10 aryl or five to ten membered heteroaryl; optionally, the C6-10 aryl five to fourteen membered heteroaryl is substituted by one or more substituents selected from halogen and C1-C4 alkyl; the five to fourteen membered heteroaryl or five to fourteen membered heterocyclyl contains 1 or 2 heteroatoms selected from N, O and S; preferably, the halogen is F, Cl, or Br.

5. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof, wherein Formula I is Preferably in, R1 is independently R2 is independently R3 is independently Preferably, Formula I is More preferably Where R1 is independently R2 is independently R3 is independently Preferably, Formula I is More preferably Where R1 is independently R2 is independently R3 is independently Preferably, wherein Formula I is More preferably Wherein, R1 is independently R2 is independently R3 is independently Preferably, Formula I is More preferably Where R1 is independently R2 is independently R3 is independently Preferably, Formula I is Where R1 is R2 is R4 is Preferably, Formula I is Where R5 is Preferably, Formula I is Where R6 is Preferably, Formula I is Where R7 is Preferably, Formula I is Where R8 is Preferably, Formula I is Where R9 is Preferably, Formula I is Where R10 is Preferably, Formula I is Where R 11 for Preferably, Formula I is Where R 12 for Preferably, Formula I is Where R 13 for 6. A compound or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof:

7. An intermediate compound, which is the following compound:

8. A method for preparing a compound according to any one of claims 1 to 5, comprising (1) a) reacting the compound of formula I with the compound of formula II at 60°C-100°C for 10-14 hours; b) subjecting the product compound of formula III obtained in step a) to a hydrolysis reaction at 20° C.-50° C. for 2-6 hours; c) reacting the product compound of formula IV obtained in step b) with R3-NH2 at 20°C-50°C for 10-14 hours to obtain a compound of formula V; (2) d) reacting the compound of formula VI with the compound of formula VII at 60° C.-100° C. with stirring for 10-14 hours; e) stirring the product compound of formula VIII obtained in step d) at 60° C.-100° C. for hydrolysis reaction for 2-6 hours; f) reacting the product compound of formula IX obtained in step e) with R3-NH2 at 20°C-50°C for 10-14 hours with stirring to obtain a compound of formula X; (3) g) stirring the compound of formula XI and the compound of formula XII at 20°C-50°C for 0.5-1 hour, adding the compound of formula XIII, and reacting at 80°C-120°C for 1-3 hours; h) reacting the product compound of formula XIV obtained in step g) with the compound of formula XV at 80° C.-120° C. for 1-3 hours; i) reacting the product compound of formula XVI obtained in step h) with R3-B(OH)2 at 80°C-120°C for 4-8 hours to obtain a compound of formula XVII; or (4) j) stirring the compound of formula XI and the compound of formula XII at 20°C-50°C for 0.5-1 hour, adding the compound of formula XIII, and reacting at 80°C-120°C for 1-3 hours; k) reacting the product compound of formula XIV obtained in step g) with R4COOH at 20°C-50°C with stirring for 1-3 hours to obtain a compound of formula XVIII; in R1, R2, R3, and R4 are as described in any one of claims 1 to 5.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable adjuvant or excipient.

10. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating inflammatory diseases, respiratory diseases, skin diseases, or immune system diseases; more preferably, the inflammatory disease is an inflammatory skin disease; more preferably, the respiratory disease is chronic obstructive pulmonary disease, lung injury or asthma; more preferably, the skin disease is psoriasis or atopic dermatitis; more preferably, the immune system disease is systemic lupus erythematosus or rheumatoid arthritis.

11. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating a PDE4-mediated disease or a PDE4 inhibitor.

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