Difluoromethoxyphenyl PDE4 inhibitor and use thereof

Abstract

Disclosed are a difluoromethoxyphenyl PDE4 inhibitor represented by formula I and a use thereof. The compound has the effects of resisting inflammation, treating psoriasis, treating lung injury, treating chronic obstructive pulmonary disease, etc.

Description

Difluoromethoxyphenyl pde4 inhibitors and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and specifically relates to difluoromethoxyphenyl PDE4 inhibitors, which have the effects of anti-inflammation, treatment of psoriasis, treatment of lung injury, and treatment of chronic obstructive pulmonary disease. BACKGROUND

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

[0003] Phosphodiesterases (PDEs) are a family of hydrolases that function to hydrolyze the two intracellular second messengers cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), to the biologically inactive linear nucleotides. Phosphodiesterases (PDEs) comprise 11 subfamilies that play a key role in regulating cellular function by metabolizing the 3'-cyclic phosphate bond of cAMP and cGMP, and PDE4 is a subtype of PDE.

[0004] PDE4 is a cAMP-specific enzyme that converts the second messenger cAMP to 5'-AMP. On the other hand, cAMP has a great influence on the various functions of the inflammatory cell pathway. Elevated intracellular cAMP levels inhibit the activation of T cells, modulate the function of macrophages and neutrophils, and cause bronchodilation. Increasing intracellular cAMP levels also inhibits fibrosis, the release of inflammatory cytokines and chemokines, the biological activity of proteases, the production of biologically active oxygen systems, and the production of arachidonic acid metabolites.

[0005] SUMMARY

[0006] One or more embodiments of the present application provide a compound of Formula I or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, co-crystal, or deuteride thereof

[0007] wherein

[0008] R1and R2are each independently and R1and R2are not simultaneously

[0009] X1, X2, X3, X4, X5, when present, are each independently C or N, wherein at least two are N;

[0010] 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, said 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 the group consisting of halogen, halogenated C1-C6 alkyl, carbonyl, C1-C6 alkyl, C1-C6 alkoxy, carboxyl, cyano, hydroxyl, carbonyl, phenyl-SO2-, nitro, C1-C6 alkyl oxycarbonyl; said five- to fourteen-membered heteroaryl or five- to fourteen-membered heterocyclyl comprises 1-3 heteroatoms selected from the group consisting of N, O and S; preferably, said halogen is F, Cl, Br or I;

[0011] R4, when present, is C6-14 aryl or five- to fourteen-membered heteroaryl; optionally, said C6-14 aryl or five- to fourteen-membered heteroaryl is substituted with one or more substituents selected from the group consisting of halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, and C1-C6 alkoxy; said five- to fourteen-membered heteroaryl or five- to fourteen-membered heterocyclyl comprises 1-3 heteroatoms selected from the group consisting of N, O and S; preferably, said 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, when present, is 0, 1 or 2;

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

[0017] are not simultaneously present;

[0018] each dotted line independently represents a bond or no bond.

[0019] In one or more embodiments, R1is R2is

[0020] In one or more embodiments, R1is R2is

[0021] In one or more embodiments, R1is R2is

[0022] In one or more embodiments, X1is NH, X2is N, X3is C, X4and X5are CH, n is 1, and m is 2.

[0023] In one or more embodiments, X1, X3, and X5are N, X2is C, X4is CH, n is 2, and m is 1.

[0024] In one or more embodiments, X1, X2, X3, X4are N, X5is CH, n is 1, and m is 2.

[0025] In one or more embodiments, X1is NH, X2, X3are N, X4, X5are absent, n is 1, and m is 0.

[0026] In one or more embodiments, 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.

[0027] In one or more embodiments, the C6-10 aryl, five- to ten-membered heteroaryl, C6-10 cycloalkyl, or five- to ten-membered heterocyclyl is substituted with 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 alkyl oxycarbonyl.

[0028] In one or more embodiments, the five- to ten-membered heteroaryl or five- to ten-membered heterocyclyl comprises 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, R4, when present, is C6-10 aryl or 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 comprises 1 or 2 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 wherein each R1is independently each R2is independently each R3is independently

[0035] In one or more embodiments, Formula I is wherein each R1is independently each R2is independently each R3is independently In one or more embodiments, Formula I is wherein each R1is independently each R2is independently each R3is independently

[0036] In one or more embodiments, Formula I is each R1is independently each R2is independently each R3is independently

[0037] In one or more embodiments, Formula I is wherein each R1is independently each R2is independently each R3is independently

[0038] In one or more embodiments, Formula I is each R1is independently each R2is independently each R3is independently

[0039] In one or more embodiments, Formula I is R1is R2is R4is

[0040] In one or more embodiments, a co-crystal or deuterated form of a compound of the present application:

[0041] One or more embodiments of the present application provide intermediate compounds for preparing the compounds of the present application, which are the following compounds:

[0042] One or more embodiments of the present application provide a method for preparing the compounds of the present application, which comprises

[0043] (1)

[0044] a) reacting the compound of formula I with the compound of formula II at 60-100 °C for 10-14 hours;

[0045] b) subjecting the product compound of formula III obtained in step a) to a hydrolysis reaction at 20-50 °C for 2-6 hours;

[0046] c) reacting the product compound of formula IV obtained in step b) with R3-NH2 at 20-50 °C for 10-14 hours to obtain a compound of formula V;

[0047] (2)

[0048] d) stirring the compound of formula VI with the compound of formula VII at 60-100 °C for 10-14 hours;

[0049] e) subjecting the product compound of formula VIII obtained in step d) to a hydrolysis reaction at 60-100 °C for 2-6 hours;

[0050] f) stirring the product compound of formula IX obtained in step e) with R3-NH2 at 20-50 °C for 10-14 hours to obtain a compound of formula X;

[0051] (3)

[0052] g) stirring the compound of formula XI with the compound of formula XII at 20-50 °C for 0.5-1 hour, adding the compound of formula XIII, and reacting at 80-120 °C for 1-3 hours;

[0053] h) reacting the product compound of formula XIV obtained in step g) with the compound of formula XV at 80-120 °C for 1-3 hours;

[0054] i) reacting the product compound of formula XVI obtained in step h) with R3-B(OH)2 at 80-120 °C for 4-8 hours to obtain a compound of formula XVII;

[0055] or

[0056] (4)

[0057] j) stirring the compound of formula XI with the compound of formula XII at 20 °C to 50 °C for 0.5 to 1 hour, adding the compound of formula XIII, and reacting at 80 °C to 120 °C for 1 to 3 hours;

[0058] k) stirring the product of step g) the compound of formula XIV with R4COOH at 20 °C to 50 °C for 1 to 3 hours to obtain the compound of formula XVIII;

[0059] wherein

[0060] R1, R2, R3, R4are as described above.

[0061] One or more embodiments of the present application provide a pharmaceutical composition comprising a compound of the present application and a pharmaceutically acceptable excipient or vehicle.

[0062] One or more embodiments of the present application provide use of a compound of the present application or a pharmaceutical composition of the present application in the manufacture of a medicament for preventing and / or treating an inflammatory disease, a respiratory disease, a skin disease, or an immune system disease.

[0063] One or more embodiments of the present application provide use of a compound of the present application or a pharmaceutical composition of the present application in the manufacture of a medicament for preventing and / or treating a PDE4-mediated disease or a PDE4 inhibitor.

[0064] One or more embodiments of the present application provide a compound of the present application for use as a medicament.

[0065] One or more embodiments of the present application provide a pharmaceutical composition of the present application for use as a medicament.

[0066] One or more embodiments of the present application provide a compound or composition of the present application for use in preventing and / or treating an inflammatory disease, a respiratory disease, a skin disease, or an immune system disease.

[0067] One or more embodiments of the present application provide a compound or composition of the present application for use in preventing and / or treating a PDE4-mediated disease.

[0068] One or more embodiments of the present application provide a compound or composition of the present application for use in inhibiting PDE4.

[0069] One or more embodiments of the present application provide a method of preventing and / or treating an inflammatory disease, a respiratory disease, a skin disease, or an immune system disease, the method comprising administering to a subject in need thereof a compound or composition of the present application.

[0070] One or more embodiments of the present application provide a method of preventing and / or treating a PDE4-mediated disease, the method comprising administering to a subject in need thereof a compound or composition of the present application.

[0071] One or more embodiments of the present application provide a method of inhibiting PDE4, the method comprising administering to a subject in need thereof a compound or composition of the present application.

[0072] In one or more embodiments, the inflammatory disease is an inflammatory skin disease.

[0073] In one or more embodiments, the respiratory disease is chronic obstructive pulmonary disease, lung injury or asthma.

[0074] In one or more embodiments, the skin disease is psoriasis or atopic dermatitis.

[0075] In one or more embodiments, the immune system disease is systemic lupus erythematosus or rheumatoid arthritis.

[0076] The following terms used in the technical solutions of the present application are explained. As used in the specification and the appended claims, unless otherwise indicated, the terms have the following meanings:

[0077] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0078] The term "amino" means -NH2.

[0079] The term "hydroxy" means -OH.

[0080] "Alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, neopentyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, and various branched isomers thereof; when substituted, the alkyl group can be optionally further substituted with one or more substituents.

[0081] "Alkoxy" means a group formed by the substitution of at least one carbon atom of an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, s-butyloxy, t-butyloxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy. The definition of alkyl is the same as that described above for "alkyl".

[0082] "Aryl" means 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 of 10 to 14 carbon atoms (e.g., 10, 11, 12, 13, 14 carbon atoms), which can be fused or spiro, non-limiting examples including phenyl, naphthyl. The aryl group can be optionally further substituted with one or more substituents.

[0083] "Heteroaryl" means a substituted or unsubstituted aromatic ring which can be, for example, a monocyclic ring of 5 to 8 members (e.g., 3, 4, 5, 6, 7, 8 members), a bicyclic ring of 5 to 14 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 members), and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, preferably 5 to 8 membered heteroaryl, 1 to 4 (e.g., 1, 2, 3, 4) N, S in the ring of the heteroaryl group optionally substituted can be oxidized to various oxidation states. The heteroaryl group can be attached at a heteroatom or carbon atom, the heteroaryl group can be fused or spiro, non-limiting examples including, cinnolinyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridyl, pyrrolopyridyl. The heteroaryl group is optionally further substituted with one or more substituents.

[0084] "Heterocyclyl" or "heterocycle" means a saturated or unsaturated non-aromatic heterocycle, which for example can be a five- to ten-membered (e.g., 5, 6, 7, 8, 9, 10 membered) monocyclic, five- to twelve-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or ten- to fourteen-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 three- to eight-membered heterocyclyl. One to four (e.g., 1, 2, 3, 4) of the N, S in the ring of the "heterocyclyl" or "heterocycle" optionally substituted can be oxidized into various oxidation states; the "heterocyclyl" or "heterocycle" can be attached at a heteroatom or carbon atom; the "heterocyclyl" or "heterocycle" can be bridged or spirocyclic. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxiranyl, oxetanyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxananyl, azacycloheptanyl, oxacycloheptanyl, thiacycloheptanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridyl, piperidyl, homopiperidyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, 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-indolizinyl, quinolizinyl, N-pyridinylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azadamantanyl, and oxaspiro[3.3]heptyl. The "heterocyclyl" or "heterocycle" can be optionally further substituted with one or more substituents.

[0085] "Cycloalkyl" means a saturated cyclic hydrocarbon group, which for example can be 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, and the like. When the cycloalkyl is substituted, it can be optionally further substituted with one or more substituents.

[0086] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof means a salt of a compound of the present application that retains the biological effectiveness and properties of the free acids or bases and is obtained by reaction of the free acid with a non-toxic inorganic or organic base, or the free base with a non-toxic inorganic or organic acid.

[0087] "Pharmaceutical composition" means a mixture of one or more of the compounds of the present application, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, such as pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0088] "Carrier" means a material that does not itself induce the production of antibodies to it, and it does not have a significant stimulating effect on the biological activity and properties of the given compound.

[0089] "Excipient" means 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 and its derivatives, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, binders, and disintegrating agents.

[0090] "Prodrug" means a compound that is converted into a biologically, pharmaceutically or therapeutically active compound of the present application after administration to a subject. Prodrugs of the present application are prepared by modifying the amino or carboxyl groups of the compounds of the present application in such a way that the modifications are cleaved in vivo to give the parent compound. When a prodrug of the present application is administered to a mammalian subject, the prodrug is cleaved to form the free amino or carboxyl groups.

[0091] "Cocrystal" means a crystal formed by the combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure state of the API and the CCF are both solid at room temperature, and there is a fixed stoichiometric ratio between the components. Cocrystals are a kind of multi-component crystals, including binary cocrystals formed between two neutral solids, and multi-component cocrystals formed between a neutral solid and a salt or a solvate.

[0092] "Stereoisomer" means isomers that have the same molecular formula but differ in the arrangement of atoms in space. Stereoisomers include enantiomers (mirror image isomers), diastereomers (geometric isomers), and conformers.

[0093] "Optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance can or can not occur, and this description includes instances in which the event or circumstance occurs and instances in which it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group can or can not be present, and this description includes instances in which the heterocyclyl is substituted with alkyl, and instances in which the heterocyclyl is not substituted with alkyl.

[0094] In one or more embodiments, Formula I is wherein R5is

[0095] In one or more embodiments, Formula I is wherein R6is

[0096] In one or more embodiments, Formula I is wherein R7is

[0097] In one or more embodiments, Formula I is wherein R8is

[0098] In one or more embodiments, Formula I is wherein R9is

[0099] In one or more embodiments, Formula I is wherein R 10 is,

[0100] In one or more embodiments, Formula I is wherein R 11 is

[0101] In one or more embodiments, Formula I is wherein R 12 is

[0102] In one or more embodiments, Formula I is wherein R 13 is BRIEF DESCRIPTION OF DRAWINGS

[0103] Figure 1 shows the results of the anti-inflammatory activity of the compounds in Activity Example 3 on Raw 264.7 and Beas-2B cells.

[0104] Figure 2 shows the phenotypic presentation of the dorsal skin of the mice in Activity Example 7.

[0105] Figure 3 shows the changes in PASI and body weight of the mice in Activity Example 7.

[0106] Figure 4 shows the pathological pictures of the skin of the mice in the active example 7.

[0107] Figure 5 shows the Ki-67 antibody immunohistochemical staining pictures of the back skin of the mice in the active example 7.

[0108] Figure 6 shows the down-regulation of the inflammatory factors IL-1β, IL-17A and TNF-α in the skin tissue of the mice by compound A5 in the active example 7.

[0109] Figure 7 shows the COPD model of the mice and the body weight changes in the active example 8.

[0110] Figure 8 shows the lung function evaluation indexes in the active example 8.

[0111] Figure 9 shows the pathological pictures of the lung tissue in the active example 8.

[0112] Figure 10 shows the inhibitory effects of the inflammatory cells and the inflammatory factors IL-8 (CXCL1 / KC / N51), TNF-α and MMP9 in the bronchoalveolar lavage fluid of the COPD model of the mice in the active example 8.

[0113] Figure 11 shows the inhibitory effects of the inflammatory cells and the inflammatory factors IL-6, IL-1β and TNF-α in the bronchoalveolar lavage fluid of the ALI model of the mice in the active example 9.

[0114] Figure 12 shows the HE staining pictures of the lung tissue in the active example 9.

[0115] Figure 13 shows the Masson staining microscopic pictures of the lung tissue in the active example 9. DETAILED DESCRIPTION

[0116] The present application will be further described in conjunction with specific examples. These examples are for the purpose of illustration only and do not limit the scope and spirit of the present application. All other examples obtained by those of ordinary skill in the art based on the examples in the present application without creative efforts shall fall within the scope of the present application.

[0117] Synthesis of the compounds A1-A28 in example 1

[0118] (1) Synthesis of compound 2

[0119] Take 3 g of compound 3, 4-dihydroxybenzaldehyde (21.72 mmol, 1.0 equiv.) and 6.91 g of sodium carbonate (65.16 mmol, 3.0 equiv.) and dissolve in 30 mL of N, N-dimethylformamide (DMF), and finally add 3.44 g of ethyl difluoro chloroacetate (21.72 mmol, 1.0 equiv.), and react at 80°C for 8 hours. After the raw material is completely reacted by TLC detection, quench the reaction by adding water. Extract 3 times with ethyl acetate, and wash the organic phase with saturated sodium chloride solution. Concentrate the organic phase and purify by flash column chromatography to obtain 1.4 g of white solid product (compound 2) with a yield of 34%.

[0120] The obtained compound 2 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result is: 1 H NMR (500 MHz, CDC13) δ 9.90 (s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.5, 2.0 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 6.66 (t, J = 73.5 Hz, 1H). ESI-HRMS m / z: calculated value C8H6O3F2Na + [M+Na] + , 211.0177; found 211.0166.

[0121] (2) Synthesis of compound 3:

[0122] Take 2.1 g of compound 2 (11.16 mmol, 1.0 equiv.), add 3.09 g of potassium carbonate (22.32 mmol, 2.0 equiv.), add 20 mL of N, N-dimethylformamide, and finally add 2.26 g of bromomethylcyclopropane (16.74 mmol, 1.5 equiv.), and react at 80°C for 8 hours. After the raw material is completely reacted by TLC detection, quench the reaction by adding water. Extract 3 times with ethyl acetate, and wash the organic phase with saturated sodium chloride solution. Concentrate the organic phase and purify by flash column chromatography to obtain 2.3 g of yellow oily product (compound 3) with a yield of 85%.

[0123] The obtained compound 3 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result is: 1H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.59-7.54 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 73.5 Hz, 1H), 3.98 (d, J = 7.0 Hz, 2H), 1.30-1.21 (m, 1H), 0.61-0.55 (m, 2H), 0.39-0.33 (m, 2H). ESI-MS m / z: Calcd for C 12 H 13 O3F2 + [M+H] + , 243.1; Found 243.1.

[0124] (3) Synthesis of compound 4:

[0125] Compound 3 (1.50 g, 6.19 mmol, 1.0 equiv.) was dissolved in 15 mL of DMF solution, 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, heated to 80°C for 12h, TLC monitoring. After the reaction was completed, water was added to quench the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the organic phase was concentrated, and column chromatography was performed to obtain 1.51 g of compound 4 with a yield of 62%.

[0126] The obtained compound 4 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were as follows: 1 H NMR (500 MHz, CDCl3) δ 10.71 (br, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.59 (s, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.19 (t, J = 8.5 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.65 (t, J = 75.0 Hz, 1H), 3.88 (s, 3H), 3.82 (d, J = 7.0 Hz, 2H), 1.23-1.20 (m, 1H), 0.59-0.55 (m, 2H), 0.29-0.26 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 165.8, 152.6, 149.9, 144.6, 141.4, 134.5, 127.7 (2 x 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 x C). ESI-MS m / z: calcd for C 20 H 19 O4N2F2 + [M+H] + , 389.1; found 389.1.

[0127] (4) Synthesis of compound 5:

[0128] Compound 4 (1.97 g, 5.07 mmol, 1.0 equiv.) was dissolved in 20 mL of mixed solvent of ethanol and water (1:1), then 2.03 g of sodium hydroxide (50.7 mmol, 10.0 equiv.) was added, heated to 50 °C for reaction, and thin layer chromatography was used for monitoring. After the reaction was completed, the ethanol was removed by rotary evaporation, cooled to room temperature, and the pH was adjusted to 6 with dilute hydrochloric acid. The solid was extracted by suction filtration and dried to obtain 1.65 g of compound 5 with a yield of 87%.

[0129] The obtained compound 5 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were as follows: 1 H NMR (400 MHz, CD3OD) 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: calcd for C 19 H 17 O4N2F2 + [M+H] + , 375.1151; found 375.1160.

[0130] (5) Synthesis of compounds A1-A28:

[0131] Dissolve 50 mg of compound 5 (0.13 mmol, 1.0 equiv.) in 1 mL of DMF, then add N, N-diisopropylethylamine (DIPEA, 0.26 mmol, 2.0 equiv.) and O-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU, 0.13 mmol, 1.0 equiv.), and finally add the amine reagent (0.16 mmol, 1.2 equiv.), and react at room temperature for 12 h, and monitor by thin layer chromatography. After the reaction is completed, quench the reaction with water, extract with ethyl acetate, dry the ethyl acetate layer with anhydrous sodium sulfate, concentrate the organic phase, and purify by flash column chromatography to obtain compounds A1-A28.

[0132] The compounds A1-A28 are as follows:

[0133] Synthesis of compounds B1-B4

[0134] (1) Synthesis of compound 6:

[0135] Dissolve 820 mg of compound 3 (3.38 mmol, 1.0 equiv.) in 10 mL of DMF solution, then add 560 mg of methyl 3, 4-diaminobenzoate (3.38 mmol, 1.0 equiv.) and 770 mg of sodium metabisulfite (4.06 mmol, 1.2 equiv.), heat to 80°C and react for 12 h, and monitor by thin layer chromatography. After the reaction is completed, quench the reaction with water, extract with ethyl acetate, dry the ethyl acetate layer with anhydrous sodium sulfate, concentrate the organic phase, and purify by flash column chromatography to obtain 930 mg of compound 6 with a yield of 71%.

[0136] The obtained compound 6 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 13.27 (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 C 20 H 19 O4N2F2 + [M+H]+ 389.1307; found 389.1323.

[0137] (2) Synthesis of compound 7:

[0138] Dissolve 1.0 g of compound 6 (2.57 mmol, 1.0 equiv.) in 10 mL of mixed solvent of ethanol and water (1:1), then add 1.03 g of sodium hydroxide (25.7 mmol, 10.0 equiv.), heat to 50 °C and react, monitor by thin layer chromatography. After the reaction is completed, remove ethanol by rotary evaporation, cool to room temperature, adjust pH to 6 with dilute hydrochloric acid, and filter the precipitated solid. Dry to obtain 610 mg of compound 7, with a yield of 63%.

[0139] The obtained compound 7 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results are as follows: 1 H NMR (500 MHz, DMSO-d6) δ 8.20 (d, J = 1.5 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.5, 1.5 Hz, 1H), 7.82 (dd, J = 8.5, 2.0 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.19 (t, J = 74.5 Hz, 1H), 4.03 (d, J = 7.0 Hz, 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: calculated C 19 H 17 O4N2F2 + [M+H] + 375.1151; found 375.1164.

[0140] (3) Synthesis of compounds B1-B4:

[0141] 50 mg of compound 7 (0.13 mmol, 1.0 equiv.) was dissolved in 1 mL of DMF, followed by the addition of N,N-diisopropylethylamine (DIPEA, 0.26 mmol, 2.0 equiv.) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (HATU, 0.13 mmol, 1.0 equiv.), and finally an amine reagent (0.16 mmol, 1.2 equiv.). The reaction was carried out at room temperature for 12 h, monitored by thin-layer chromatography. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The organic phase was concentrated and subjected to rapid column chromatography to obtain compounds B1-B4.

[0142] The compounds B1-B4 are as follows:

[0143] Example 3 Synthesis of C-series compounds

[0144] (1) Synthesis of compound 8:

[0145] 606 mg of compound 3 (2.50 mmol, 1.0 equiv.) was dissolved in 6 mL of DMF solution, followed by the addition of 468 mg of 4-bromo-o-phenylenediamine (2.50 mmol, 1.0 equiv.) and 585 mg of sodium metabisulfite (3.08 mmol, 1.2 equiv.). The mixture was heated to 80 °C and reacted for 12 h, monitored by thin-layer chromatography. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The organic phase was concentrated and subjected to rapid column chromatography to obtain 603 mg of compound 8, in 59% yield.

[0146] Compound 8 was identified using nuclear magnetic resonance spectroscopy and mass spectrometry. The identification results were as follows: 1 ¹H NMR (500MHz, DMSO-d⁶) δ 13.08 (s, 1H), 7.88 (d, J = 2.0Hz, 1H), 7.81–7.74 (m, 2H), 7.56 (d, J = 8.5Hz, 1H), 7.37–7.33 (m, 2H), 7.19 (s, 1H), 4.02 (d, J = 7.0Hz, 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 O2N2F2Br + [M+H] + , 409.0358; the measured value is 409.0357.

[0147] (2) Synthesis of compound C1-C3:

[0148] Dissolve 100 mg of compound 8 (0.24 mmol, 1.0 equiv.) in 2 mL of DMF and 0.5 mL of water, add boronic acid reagent (0.29 mmol, 1.2 equiv.), add 0.05 equiv. of [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium and 83 mg of potassium carbonate (0.6 mmol, 2.5 equiv.) to the solution, heat to 95 °C for 12 h, monitor by thin layer chromatography. After the reaction is completed, quench with water, extract with ethyl acetate, dry the ethyl acetate layer with anhydrous sodium sulfate, concentrate the organic phase, and purify by flash column chromatography to obtain compound C1-C3.

[0149] The compound C1-C3 is as follows:

[0150] Synthesis of compounds in Example 4, series D

[0151] (1) Synthesis of compound 10:

[0152] Dissolve 1.0 g of compound 9 (6.57 mmol, 1.0 equiv.) in 10 mL of DMF, then add 1.82 g of potassium carbonate (13.14 mmol, 2.0 equiv.) and 1.33 g of bromomethylcyclopropane (9.86 mmol, 1.5 equiv.), heat to 80 °C for 8 h, monitor by thin layer chromatography. After the reaction is completed, quench with water, extract with ethyl acetate, dry the ethyl acetate layer with anhydrous sodium sulfate, concentrate the organic phase, and purify by flash column chromatography to obtain 1.28 g of compound 10 with a yield of 95%.

[0153] The obtained compound 10 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result is: 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.53 (dd, J = 8.4, 2.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.85 (d, J = 7.2 Hz, 2H), 1.26-1.18 (m, 1H), 0.59-0.55 (m, 2H), 0.34-0.31 (m, 2H). ESI-MS m / z: calculated C 12 H 15 O3 + [M+H] + , 207.1; found 207.1.

[0154] (2) Synthesis of compound 11:

[0155] Dissolve 1.0 g of compound 10 (4.84 mmol, 1.0 equiv.) in 10 mL of DMF solution, then add 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.), heat to 80°C for 12 h, and monitor by thin layer chromatography. After the reaction is completed, quench the reaction with water, extract with ethyl acetate, dry the ethyl acetate layer with anhydrous sodium sulfate, concentrate the organic phase, and purify by flash column chromatography to obtain 1.30 g of compound 11 with a yield of 76%.

[0156] The obtained compound 11 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result is: 1 H NMR (500 MHz, DMSO-d6) δ 8.16 (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 C 20 H 21 O4N2 + [M+H] + , 353.1; found 353.1.

[0157] (3) Synthesis of compound 12:

[0158] Dissolve 768 mg of compound 11 (2.18 mmol, 1.0 equiv.) in 10 mL of a mixed solvent of ethanol and water in a volume ratio of 1:1, then add 872 mg of sodium hydroxide (21.79 mmol, 10.0 equiv.), heat to 50°C, and monitor by thin layer chromatography. After the reaction is completed, remove the ethanol by rotary evaporation, cool to room temperature, adjust the pH to 6 with dilute hydrochloric acid, and filter to obtain a solid, which is dried to obtain 693 mg of compound 12 with a yield of 94%.

[0159] The obtained compound 12 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result is: 1H NMR (500 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.03-8.01 (m, 1H), 7.95-7.93 (m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 9.5 Hz, 1H), 3.97 (d, J = 7.0 Hz, 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 O4N2 + [M+H] + , 339.1339; found 339.1344.

[0160] (4) Synthesis of compounds D1-D3:

[0161] Dissolve 50 mg of compound 12 (0.15 mmol, 1.0 equiv.) in 1 mL of DMF, then add N,N-diisopropylethylamine (DIPEA, 0.30 mmol, 2.0 equiv.) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 0.15 mmol, 1.0 equiv.), and finally add the amine reagent (0.18 mmol, 1.2 equiv.), and react at room temperature for 12 h, monitored by thin layer chromatography. After the reaction is completed, quench the reaction with water, extract with ethyl acetate, dry the ethyl acetate layer with anhydrous sodium sulfate, concentrate the organic phase, and purify by flash column chromatography to obtain compounds D1-D3.

[0162] The compounds D1-D3 are as follows:

[0163] Example 5 Synthesis of compounds of series E

[0164] (1) Synthesis of compound 13:

[0165] To a solution of 1.0 g of compound 1 (7.24 mmol, 1.0 equiv.) in 10 mL of DMF, 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, which was monitored by thin layer chromatography. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by flash column chromatography to give 0.93 g of compound 13 with a yield of 54%.

[0166] The obtained compound 13 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were as follows: 1 H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 7.75-7.73 (m, 2H), 7.39 (d, J = 8.8 Hz, 1H), 6.64 (t, J = 72.8 Hz, 1H), 6.59 (t, J = 72.8 Hz, 1H). ESI-MS m / z: calculated C9H7O3F4 + [M+H] + , 239.0; found 239.0.

[0167] (2) Synthesis of compound 14:

[0168] To a solution of 500 mg of compound 13 (2.10 mmol, 1.0 equiv.) in 5 mL of DMF, 349 mg of methyl 2,3-diaminobenzoate (2.10 mmol, 1.0 equiv.) and 439 mg of sodium pyrosulfite (2.31 mmol, 1.1 equiv.) were added, and the mixture was heated to 80 °C for 12 h, which was monitored by thin layer chromatography. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by flash column chromatography to give 405 mg of compound 14 with a yield of 50%.

[0169] The obtained compound 14 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were as follows: 1H NMR (400 MHz, CDC13) δ 10.75 (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: calcd for C 17 H 13 O4N2F4 + [M+H] + , 385.0806; found, 385.0801.

[0170] (3) Synthesis of compound 15:

[0171] Dissolve 200 mg of compound 14 (0.52 mmol, 1.0 equiv.) in 4 mL of mixed solvent of ethanol and water with volume ratio of 1:1, then add 40 mg of sodium hydroxide (1.04 mmol, 2.0 equiv.), heat to 50°C for reaction, and monitor by thin layer chromatography. After the reaction is completed, remove ethanol by rotary evaporation, cool to room temperature, adjust pH to 6 with dilute hydrochloric acid, and filter to separate the solid, and dry to obtain 174 mg of compound 15 with a yield of 90%.

[0172] The obtained compound 15 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result is 1 H NMR (500 MHz, DMSO-d6) δ 12.57 (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: calcd for C 16 H 11 O4N2F4 + [M+H] + , 371.0649; found, 371.0652.

[0173] (4) Synthesis of compounds E1-E13:

[0174] Dissolve 50 mg of compound 15 (0.14 mmol, 1.0 equiv.) in 1 mL of DMF, then add N, N-diisopropylethylamine (DIPEA, 0.28 mmol, 2.0 equiv.) and O-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU, 0.14 mmol, 1.0 equiv.), and finally add the amine reagent (0.17 mmol, 1.2 equiv.), and react at room temperature for 12 h, and monitor by thin layer chromatography. After the reaction is completed, quench the reaction with water, extract with ethyl acetate, concentrate the organic phase, and purify by flash column chromatography to obtain compounds E1-E13.

[0175] The compounds E1-E13 are as follows:

[0176] Synthesis of compounds in series F

[0177] (1) Synthesis of compound 17:

[0178] The synthesis procedure is referenced to the synthesis of compound 2. Reaction of 3,4-dihydroxyacetophenone and ethyl difluorochloroacetate gives the white solid product in 36% yield.

[0179] The obtained compound 17 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results are as follows: 1 H NMR (600 MHz, CDC13) δ 7.63 (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: calcd for C9H8O3F2Na + [M+Na] + , 225.0334; found, 225.0311;

[0180] (2) Synthesis of compound 18:

[0181] The synthesis procedure is referenced to the synthesis of compound 3. The yellow oily product is obtained in 2.2 g in 56% yield.

[0182] The obtained compound 18 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results are as follows: 1H NMR (400 MHz, DMSO-d6) δ 7.87 (dd, J = 8.4, 2.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.17 (t, J = 74.4 Hz, 1H), 3.99 (d, J = 7.2 Hz, 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-d6) δ 196.8, 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 x C). ESI-HRMS m / z: calcd for C 13 H 14 O3F2Na + [M+Na] + , 279.0803; found 279.0808.

[0183] (3) Synthesis of compound 19:

[0184] Compound 18 (2.0 g, 7.81 mmol, 1.0 equiv.) and N,N-dimethylformamide dimethyl acetal (1.13 g, 9.37 mmol, 1.2 equiv.) were weighed into a reaction flask, 2 mL of N,N-dimethylformamide was added, stirred at 120 °C for 12 hours, and TLC was used to detect that the raw material was no longer reduced. Water was added, extracted with ethyl acetate for 3 times, washed the organic phase with water once, washed the organic phase with saturated aqueous sodium chloride solution, and dried the organic phase with anhydrous sodium sulfate. The organic phase was concentrated, and 1.8 g of compound 19 was obtained by flash column chromatography with a yield of 74%.

[0185] The obtained compound 19 was identified by nuclear magnetic resonance spectrum and mass spectrometry, and the identification results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 12.4 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.19 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 74.4 Hz, 1H), 5.81 (d, J = 12.4 Hz, 1H), 3.94 (d, J = 6.8 Hz, 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). 13C NMR (101 MHz, DMSO-d6) δ 184.4, 154.4, 149.5, 141.8, 138.5, 120.1 (2 x C), 116.6 (t, J = 256.4 Hz), 112.9, 90.7, 73.0, 44.5, 37.2, 10.0, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 16 H 19 O3NF2Na + [M+Na] + , 334.1225; found 334.1225.

[0186] (4) Synthesis of compound 20:

[0187] Into a reaction flask was placed 2.48 g of compound 19 (8 mmol, 1.0 equiv.) and 1.46 g of methyl 5-amino-lH-pyrazole-3-carboxylate (24 mmol, 3.0 equiv.), 10 mL of acetic acid was added, and stirred at 80 °C for 12 hours, TLC detection of raw materials no longer reduced. Add water, extracted with ethyl acetate 3 times, the organic phase was washed with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by flash column chromatography to give 2.6 g of compound 20, yield 84%.

[0188] The obtained compound 20 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (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: calcd for C 19 H 17 O4N3F2Na + [M+Na] + , 412.1079; found 412.1083.

[0189] (5) Synthesis of compound 21:

[0190] The synthesis step was referred to the synthesis of compound 5, and yellow solid product was obtained, yield 96%.

[0191] The resulting compound 21 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry techniques, and the identification results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (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: calcd for C 18 H 15 O4N3F2Na + [M+Na] + , 398.0923; found 398.0909.

[0192] (6) Synthesis of compounds F1-F13:

[0193] Take 100 mg of compound 21 (0.31 mmol, 1.0 equiv.) dissolved in DMF, and then add 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.). Stir the reaction at 50°C, monitor with TLC, quench with water, extract with ethyl acetate, wash the organic phase with water three times, wash the organic phase with saturated aqueous sodium chloride solution, dry the ethyl acetate layer with anhydrous sodium sulfate, concentrate by rotary evaporation, add silica gel to the sample, and purify by flash column chromatography to obtain compounds F1-F13.

[0194] The compounds F1-F13 are as follows:

[0195] Example 7 Synthesis of compounds in series G

[0196] (1) Synthesis of compound 22:

[0197] The synthesis step is referred to the synthesis of compound 20, and the reaction of compound 19 and methyl 3-aminopyrazole-4-carboxylate produces a yellow solid product with a yield of 56%.

[0198] The resulting compound 22 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry techniques, and the identification results were as follows:1 H NMR (500 MHz, CDC13) δ 8.79 (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: calcd for C 19 H 17 O4N3F2Na + [M+Na] + , 412.1079; found, 412.1072.

[0199] (2) Synthesis of compound 23:

[0200] The synthesis step refers to the synthesis of compound 5, and the yellow solid product is obtained with a yield of 98%.

[0201] The obtained compound 23 is identified by nuclear magnetic resonance spectrum and mass spectrometry, and the identification result is: 1 H NMR (600 MHz, DMSO-d6) δ 8.62 (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: calcd for C 18 H 15 O4N3F2Na + [M+Na] + , 398.0923; found, 398.0915.

[0202] (3) Synthesis of compounds G1-G21:

[0203] Take 100 mg of compound 23 (0.31 mmol, 1.0 equiv.) dissolved in DMF, add 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.). Stir the reaction at room temperature, monitor by TLC, when the starting material is consumed, quench with water, extract with ethyl acetate, wash the organic phase with water three times, wash the organic phase with saturated aqueous sodium chloride solution, dry the ethyl acetate layer over anhydrous sodium sulfate, concentrate by rotary evaporation, add silica gel to the sample, and purify by flash column chromatography to obtain compounds G1-G21.

[0204] The compounds G1-G21 are as follows:

[0205] Synthesis of compounds in Example 8

[0206] (1) Synthesis of compound 24:

[0207] Take 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 mixture of methanol and water (volume ratio 10:1), and finally add 4.2 g of 30% hydrogen peroxide (37.14 mmol, 3.0 equiv.). Stir at 50°C for 2 hours, then monitor by TLC until the starting material is consumed. Adjust to acidic with dilute hydrochloric acid. A large amount of solid precipitates, then filter and dry under vacuum to obtain 2.4 g of product, compound 24, in a yield of 69%.

[0208] The obtained compound 24 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results are as follows: 1 H NMR (500 MHz, DMSO-d6) δ 7.60-7.54 (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 C 12 H 12 O4F2 + [M+H] + , 281.0596; found 281.0507.

[0209] (2) Synthesis of compound 25:

[0210] Take 1.66 g of compound 24 (6.5 mmol, 1.0 equiv.) and place it in flask a. Add 1.4 g of N, N'-carbonyldiimidazole (6.5 mmol, 1.0 equiv.) and 10 mL of N, N-dimethylformamide solvent. Stir at room temperature for 0.5 h. Take another flask b and add 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.). Stir at room temperature for 15 min. Add the reaction solution in flask a to flask b and stir at room temperature for 1 h. Then, heat to 100°C and react for 2 h. TLC detection shows that the raw material has completely reacted. Quench the reaction by adding water. Extract 3 times with ethyl acetate and wash the organic phase with saturated sodium chloride solution. Concentrate the organic phase and purify by flash column chromatography to obtain 403 mg of compound 25, with a yield of 21%.

[0211] The obtained compound 25 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result is: 1 H NMR (500 MHz, DMSO-d6) δ 12.08 (s, 1H), 7.55 (s, 1H), 7.45 (dd, J = 8.0, 1.5 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.09 (t, J = 74.5 Hz, 1H), 6.06 (s, 2H), 3.91 (d, J = 6.5 Hz, 2H), 1.35-1.27 (m, 1H), 0.61-0.54 (m, 2H), 0.40-0.33 (m, 2H). ESI-HRMS m / z: calculated C 13 H 15 O2N4F2 + [M+H] + , 297.1158; found 297.1163.

[0212] (3) Synthesis of compound 26:

[0213] Take 403 mg of compound 25 (1.28 mmol, 1.0 equiv.) and add 232 mg of 2-bromomalonaldehyde (1.54 mmol, 1.2 equiv.). Add 4 mL of acetic acid and stir at room temperature for 10 min. Heat to 100°C and react for 2 h. TLC detection shows that the raw material has completely reacted. Quench the reaction by adding water. Extract 3 times with ethyl acetate and wash the organic phase with saturated sodium chloride solution. Concentrate the organic phase and purify by flash column chromatography to obtain 274.5 mg of compound 26, with a yield of 52%.

[0214] The obtained compound 26 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result is:1 H NMR (500 MHz, DMSO-d6) δ 9.87 (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: calcd for C 16 H 13 O2N4BrF2 + [M+H] + 411.0263; found 411.0251.

[0215] (4) Synthesis of compounds H1-H6:

[0216] Take 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 boronic acid reagents (0.25 mmol, 1.5 equiv.), add 1 mL of N, N-dimethylformamide solvent, and finally add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.01 mmol, 0.05 equiv.), which needs to be operated 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 an aqueous solution. Extract 3 times with ethyl acetate, wash the organic phase with saturated sodium chloride solution, concentrate the organic phase, and purify by flash column chromatography to obtain compounds H1-H6.

[0217] The compounds H1-H6 are as follows:

[0218] Synthesis of compounds of series J

[0219] (1) Synthesis of compounds J1-J6:

[0220] Carboxylic acid compound (0.24 mmol, 1.2 equiv) was added, followed by HATU (0.16 mmol. 1.0 equiv), then DIPEA (0.32 mmol, 2.0 equiv), 1 mL DMF as solvent, stirred at room temperature for 10 minutes, finally added compound 25 (0.16 mmol, 1.0 equiv), stirred at room temperature for 2 hours, TLC detection of raw materials, complete reaction, added water solution to quench the reaction. Extracted with ethyl acetate 3 times, washed the organic phase with saturated sodium chloride solution. The organic phase was concentrated and purified by flash column chromatography to obtain compounds J1-J6.

[0221] The compounds J1-J6 are as follows:

[0222] Synthesis of compound A1 in Example 10:

[0223] The synthesis step is referred to Example 1, and the last step of amine reagent is selected as 2,6-difluorobenzylamine to obtain compound A1, yield: 12%; 1 H NMR (500 MHz, DMSO-d6) δ 13.46 (s, 1H), 10.44 (t, J = 6.0 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.79 (dd, J = 8.5, 2.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.47-7.41 (m, 2H), 7.39-7.36 (m, 1H), 7.23 (t, J = 74.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 2H), 4.81 (d, J = 5.5 Hz, 2H), 4.05 (d, J = 7.0 Hz, 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-d6) δ 164.1, 160.8 (dd, J = 244.5, 7.5 Hz, 2 x 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 x C), 73.2, 30.4, 10.0, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 26 H 21 O3N3F4Na​+ [M+Na] + , 522.1411; found 522.1405.

[0224] Synthesis of compound A2:

[0225] Synthesis procedure as in example 1, last step amine reagent was selected as 2,4-difluorobenzylamine to give compound A2 in 54% yield; 1 H NMR (500 MHz, DMSO-d6) δ 13.44 (br, 1H), 10.35 (t, J = 6.0 Hz, 1H), 7.92 (d, J = 1.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.82 (dd, J = 8.0, 1.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.60-7.55 (m, 1H), 7.41-7.37 (m, 2H), 7.29-7.24 (m, 1H), 7.22 (t, J = 69.0 Hz, 1H), 7.10-7.08 (m, 1H), 4.74 (d, J = 6.0 Hz, 2H), 4.01 (d, J = 7.0 Hz, 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-d6) δ 164.6, 164.6 (dd, J = 245.0, 12.0 Hz), 160.5 (dd, J = 245.0, 12.0 Hz), 151.3, 150.2, 141.6, 141.0, 135.3, 131.0 (dd, J = 15.0, 6.0 Hz), 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 x C). ESI-HRMS m / z: Calcd for C 26 H 21 O3N3F4Na + [M+Na] + , 522.1411; found 522.1402.

[0226] Synthesis of compound A3:

[0227] The synthesis procedure was referred to Example 1, and the amine reagent was selected as 2-aminopyrimidine (CAS No.: 75985-45-4) in the last step to give compound A3 in yield of 22%; 1 H NMR (500 MHz, DMSO-d6) δ 13.43 (br, 1H), 10.90 (br, 1H), 8.90 (d, J = 4.5 Hz, 2H), 8.08 (dd, J = 8.5, 1.5 Hz, 1H), 8.02 (d, J = 1.5 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.49-7.48 (m, 2H), 7.40-7.37 (m, 1H), 7.22 (t, J = 74.5 Hz, 1H), 4.93 (d, J = 5.0 Hz, 2H), 4.03 (d, J = 7.0 Hz, 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-d6) δ 166.2, 164.5, 157.6 (2 x 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 x C). ESI-HRMS m / z: calcd for C 24 H 22 O3N5F2 + [M+H] + , 466.1685; found 466.1677.

[0228] Synthesis of compound A4 in Example 13:

[0229] The synthesis procedure was referred to Example 1, and the amine reagent was selected as 2-aminopyrimidine (CAS No.: 75985-45-4) in the last step to give compound A3 in yield of 22%; 1H NMR (500 MHz, DMSO-d6) δ 13.63 (br, 1H), 12.47 (br, 1H), 8.54 (d, J = 5.5 Hz, 2H), 8.03 (d, J = 1.5 Hz, 1H), 7.99 (d, J = 7.0 Hz, 1H), 7.94 (dd, J = 8.5, 2.0 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 6.0 Hz, 2H), 7.46 - 7.43 (m, 2H), 7.25 (t, J = 74.5 Hz, 1H), 4.12 (d, J = 7.0 Hz, 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-d6) δ 163.8, 151.6, 150.6 (2 x 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 x C), 112.7, 73.3, 10.0, 3.2 (2 x C). ESI-HRMS m / z: calcd for C 24 H 21 O3N4F2 + [M+H] + 451.1576; found 451.1564.

[0230] Synthesis of compound A5, Example 14:

[0231] Synthesis procedure as in Example 1, with the last step amine reagent was replaced by 2-aminothiazole to give compound A5 in 42% yield; 1 H NMR (500 MHz, DMSO-d6) δ 13.66 (br, 1H), 13.59 (br, 1H), 7.99 (d, J = 7.5 Hz, 2H), 7.85 (t, J = 8.5 Hz, 2H), 7.57 (d, J = 3.5 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.33 (d, J = 3.5 Hz, 1H), 7.23 (t, J = 74.0 Hz, 1H), 4.05 (d, J = 7.0 Hz, 2H), 1.42 - 1.33 (m, 1H), 0.68 - 0.64 (m, 2H), 0.45 - 0.42 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 163.1, 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 x C). ESI-HRMS m / z: calcd for C 22 H 19 O3N4SF2 + [M+H] + 457.1140; found 457.1095.

[0232] Synthesis of compound A6, Example 15:

[0233] Synthesis procedure as in Example 1, with the last step amine reagent selected as 6-aminobenzothiazole to give compound A6 in 95% yield; 1 H NMR (500 MHz, DMSO-d6) δ 13.61 (br, 1H), 12.46 (br, 1H), 9.32 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.96 (dd, J = 8.5, 1.5 Hz, 1H), 7.90 (dd, J = 9.0, 2.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.25 (t, J = 74.0 Hz, 1H), 4.14 (d, J = 7.0 Hz, 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-d6) δ 163.1, 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 x C). ESI-HRMS m / z: calcd for C 26 H 21 O3N4SF2 + [M+H] +Calcd 507.1297; Found 507.1249.

[0234] Synthesis of compound A7:

[0235] The synthetic procedure was referenced to example 1, the amine reagent was selected as 2-methylbenzothiazol-6-amine (CAS number: 2941-62-0) for the last step, to afford compound A7 in yield of 56%; 1 H NMR (500 MHz, DMSO-d6) δ 13.59 (br, 1H), 12.40 (br, 1H), 8.71 (d, J = 1.5 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.94 (dd, J = 8.0, 1.5 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.78 (dd, J = 8.5, 2.0 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.25 (t, J = 74.0 Hz, 1H), 4.12 (d, J = 7.0 Hz, 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-d6) δ 165.9, 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 x C). ESI-HRMS m / z: Calcd for C 27 H 23 O3N4SF2 + [M+H] + Calcd 521.1453; Found 521.1436.

[0236] Synthesis of compound A8:

[0237] The synthetic procedure was referenced to example 1, the amine reagent was selected as 2-amino benzothiazole for the last step, to afford compound A8 in yield of 32%; 1H NMR (500 MHz, DMSO-d6) δ 13.80 (br, 1H), 13.72 (br, 1H), 8.06 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 7.5 Hz, 2H), 7.92-7.89 (m, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.52-7.47 (m, 3H), 7.36 (t, J = 7.5 Hz, 1H), 7.25 (t, J = 74.5 Hz, 1H), 4.13 (d, J = 7.0 Hz, 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-d6) δ 163.2, 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 x C). ESI-HRMS m / z: calcd for C 26 H 21 O3N4SF2 + [M+H] + 507.1297; found 507.1254.

[0238] Synthesis of compound A9 of example 18:

[0239] Synthesis procedure as in example 1, last step amine reagent was chosen as 3,4-difluorobenzylamine to give compound A9 in 32% yield; 1 H NMR (500 MHz, DMSO-d6) δ 13.80 (br, 1H), 13.72 (br, 1H), 8.06 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 7.5 Hz, 2H), 7.92-7.89 (m, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.52-7.47 (m, 3H), 7.36 (t, J = 7.5 Hz, 1H), 7.25 (t, J = 74.5 Hz, 1H), 4.13 (d, J = 7.0 Hz, 2H), 1.45-1.37 (m, 1H), 0.71-0.67 (m, 2H), 0.48-0.45 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 164.7, 151.3, 150.1, 149.3 (dd, J = 243.0, 13.5 Hz), 148.4 (dd, J = 242.0, 13.5 Hz), 141.6, 141.0, 137.5 (t, J = 4.5 Hz), 135.3, 127.0, 123.9 (dd, J = 7.5, 3.0 Hz), 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 x C). ESI-HRMS m / z: calcd for C 26 H 22 O3N3F4 + [M+H] + , 500.1592; found 500.1579.

[0240] Synthesis of compound A10 of example 19:

[0241] Synthesis procedure as in example 1, last step amine reagent was chosen as 3,5-difluorobenzylamine to give compound A10 in 17% yield; 1 H NMR (600 MHz, DMSO-d6) δ 13.44 (br, 1H), 10.31 (br, 1H), 7.94 (s, 1H), 7.91-7.87 (m, 2H), 7.77 (d, J = 7.8 Hz, 1H), 7.39-7.35 (m, 2H), 7.21 (t, J = 74.4 Hz, 1H), 7.17 (d, J = 6.6 Hz, 2H), 7.13-7.09 (m, 1H), 4.76 (d, J = 5.4 Hz, 2H), 4.00 (d, J = 7.2 Hz, 2H), 1.34-1.27 (m, 1H), 0.62-0.59 (m, 2H), 0.38-0.36 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 164.9, 162.5 (dd, J = 245.0, 13.0 Hz, 2 x 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 x C), 102.3 (t, J = 25.0 Hz), 73.2, 42.1, 10.0, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 26 H 22 O3N3F4 + [M+H] + , 500.1592; found 500.1562.

[0242] Synthesis of compound A11

[0243] Synthesis procedure as in example 1, last step amine reagent was chosen as 2,3- difluorobenzylamine to give compound A11 in 74% yield; 1 H NMR (500 MHz, DMSO-d6) δ 13.44 (br, 1H), 10.39 (s, 1H), 7.94 (s, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.41 - 7.33 (m, 4H), 7.22 (t, J = 74.0 Hz, 1H), 7.22 - 7.18 (m, 1H), 4.81 (d, J = 6.0 Hz, 2H), 4.01 (d, J = 7.0 Hz, 2H), 1.36 - 1.29 (m, 1H), 0.65 - 0.59 (m, 2H), 0.42 - 0.36 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 164.6, 151.3, 150.1, 149.7 (dd, J = 243.0, 12.0 Hz), 148.0 (dd, J = 244.5, 13.5 Hz), 141.6, 141.0, 135.3, 129.0 (d, J = 12.0 Hz), 127.1, 124.9 (d, J = 6.0 Hz), 124.8 (2 x C), 122.8 (d, J = 36.0 Hz), 121.7, 121.2, 119.5, 116.6 (t, J = 256.5 Hz), 116.3 (d, J = 16.5 Hz), 115.2, 112.6, 73.2, 36.5, 9.9, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 26 H 22 O3N3F4 + [M+H] + , 500.1592; found 500.1559.

[0244] Synthesis of compound A12 of example 21:

[0245] Synthesis procedure as in example 1, last step amine reagent was chosen as 2,5-difluorobenzylamine to give compound A12 in 14% yield; 1 H NMR (500 MHz, DMSO-d6) δ 13.49 (br, 1H), 10.34 (s, 1H), 7.96 (s, 1H), 7.87 (dd, J = 14.0, 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.44 - 7.33 (m, 3H), 7.33 - 7.28 (m, 1H), 7.22 (t, J = 74.0 Hz, 1H), 7.21 - 7.15 (m, 1H), 4.83 - 4.66 (m, 2H), 4.02 (d, J = 7.00 Hz, 2H), 1.37 - 1.26 (m, 1H), 0.66 - 0.56 (m, 2H), 0.45 - 0.34 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 164.7, 158.2 (d, J = 238.5 Hz), 156.5 (d, J = 240.0 Hz), 151.3, 150.1, 141.6, 141.0, 135.3, 128.4 (dd, J = 18.0, 7.5 Hz), 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 x C). ESI-HRMS m / z: calcd for C 26 H 22 O3N3F4 + [M+H] + , 500.1592; found 500.1558.

[0246] Synthesis of compound A13 of example 22:

[0247] Synthesis procedure as in example 1, last step amine reagent was chosen as 2- fluorobenzylamine to give compound A13 in 87% yield; 1 H NMR (600 MHz, DMSO-d6) δ 13.52 (s, 1H), 10.37 (t, J = 6.0 Hz, 1H), 7.96-7.92 (m, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.82 (dd, J = 8.4, 1.8 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.38 (dd, J = 16.2, 8.4 Hz, 3H), 7.28-7.23 (m, 1H), 7.22 (t, J = 73.8 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 4.77 (d, J = 6.0 Hz, 2H), 4.01 (d, J = 7.2 Hz, 2H), 1.35-1.30 (m, 1H), 0.64-0.60 (m, 2H), 0.41-0.38 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 164.5, 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 x C). ESI-HRMS m / z: calcd for C 26 H 23 O3N3F3 + [M+H] + 482.1686; found 482.1660.

[0248] Synthesis of compound A14 of example 23:

[0249] Synthesis procedure as in example 1, last step amine reagent was chosen as 2,4,6-trifluorobenzylamine to give compound A14 in 83% yield; 1 H NMR (400 MHz, DMSO-d6) δ 13.44 (br, 1H), 10.45 (br, 1H), 7.93 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 6.8 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.24 (t, J = 78.4 Hz, 1H), 7.24 - 7.17 (m, 2H), 4.75 (d, J = 5.2 Hz, 2H), 4.04 (d, J = 7.2 Hz, 2H), 1.40 - 1.31 (m, 1H), 0.67 - 0.62 (m, 2H), 0.44 - 0.41 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 164.2, 161.6 (dt, J = 245.0, 17.0 Hz), 161.1 (ddd, J = 246.0, 15.0, 11.0 Hz, 2 x 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 x C), 73.2, 30.2, 10.0, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 26 H 21 O3N3F5 + [M+H] + 518.1498; found 518.1481.

[0250] Synthesis of compound A15 of example 24:

[0251] Synthesis step refer to example 1, last step amine reagent was chosen as 2- (aminomethyl)naphthalene (CAS number: 2018-90-8), to get compound A15 in yield of 24%; 1 H NMR (500 MHz, DMSO-d6) δ 13.44 (br, 1H), 10.45 (t, J = 5.5 Hz, 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 = 7.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.18 (t, J = 74.0 Hz, 1H), 4.91 (d, J = 6.0 Hz, 2H), 3.86 (d, J = 7.0 Hz, 2H), 1.24 - 1.17 (m, 1H), 0.56 - 0.50 (m, 2H), 0.28 - 0.22 (d, J = 5.06 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 164.6, 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 x C). ESI-HRMS m / z: calcd for C 30 H 26 O3N3F2 + [M+H] + 514.1937; found 514.1961.

[0252] Synthesis of compound A16 of example 25:

[0253] Synthesis procedure as in example 1, last step amine reagent was chosen as 2- aminomethylpyrazine (Pyrazin-2-ylmethanamine, CAS number: 20010-99-5) to give compound A16 in 26% yield; 1 H NMR (600 MHz, DMSO-d6) δ 13.44 (s, 1H), 10.67 (t, J = 5.4 Hz, 1H), 8.80 (s, 1H), 8.70 (t, J = 1.8 Hz, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.00 - 7.96 (m, 2H), 7.90 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.22 (t, J = 74.4 Hz, 1H), 4.91 (d, J = 5.4 Hz, 2H), 4.02 (d, J = 7.2 Hz, 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-d6) δ 164.8, 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 x C). ESI-HRMS m / z: calcd for C 24 H22 O3N5F2 + [M+H] + 466.1685; found 466.1706.

[0254] Synthesis of compound A17

[0255] The synthetic procedure was referenced to example 1, the amine reagent was chosen to be 2-aminomethylpyridine (CAS number: 3731-51-9) for the last step, to give compound A17 in 90% yield; 1 H NMR (500 MHz, DMSO-d6) δ 13.43 (br, 1H), 10.72 (t, J = 5.0 Hz, 1H), 8.65 (d, J = 4.5 Hz, 1H), 8.04 - 7.96 (m, 2H), 7.92 (d, J = 7.5 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.39 - 7.36 (m, 1H), 7.34 (t, J = 6.5 Hz, 1H), 7.22 (t, J = 74.0 Hz, 1H), 4.83 (d, J = 5.5 Hz, 2H), 4.00 (d, J = 7.0 Hz, 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-d6) δ 164.6, 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 x C). ESI-HRMS m / z: calcd for C 25 H 23 O3N4F2 + [M+H] + 465.1733; found 465.1765.

[0256] Synthesis of compound A18

[0257] The synthetic procedure was referenced to example 1, the amine reagent was chosen to be 3-aminomethylpyridine (CAS number: 3731-52-0) (CAS number: 3731-52-0) for the last step, to give compound A18 in 23% yield; 1H NMR (600 MHz, DMSO-d6) δ 13.46 (br, 1H), 10.32 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.50 (dd, J = 4.8, 1.8 Hz, 1H), 7.94-7.88 (m, 2H), 7.87-7.82 (m, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.41-7.39 (m, 1H), 7.38-7.35 (m, 2H), 7.21 (t, J = 73.8 Hz, 1H) 4.75 (d, J = 6.0 Hz, 2H), 4.00 (d, J = 7.2 Hz, 2H), 1.34-1.28 (m, 1H), 0.63-0.60 (m, 2H), 0.42-0.39 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 164.8, 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 x C). ESI-HRMS m / z: calcd for C 25 H 23 O3N4F2 + [M+H] + 465.1733; found 465.1768.

[0258] Synthesis of compound A19 of example 28:

[0259] Synthesis procedure as in example 1, last step amine reagent was chosen as N-methyl-3-aminopyrazole (CAS number: 1904-31-0) to get compound A19 in 88% yield; 1H NMR (500 MHz, DMSO-d6) δ 13.55 (br, 1H), 12.43 (s, 1H), 8.03 (d, J = 2.00 Hz, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.85 (dd, J = 8.5, 2.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 74.0 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 4.09 (d, J = 7.0 Hz, 2H), 3.83 (s, 3H), 1.42 - 1.35 (m, 1H), 0.68 - 0.63 (m, 2H), 0.46 - 0.41 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 161.7, 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 x C). ESI-HRMS m / z: calcd for C 23 H 22 O3N5F2 + [M+H] + , 454.1685; found 454.1713.

[0260] Synthesis of compound A20 of example 29:

[0261] Synthesis step refer to example 1, last step amine reagent is chosen as 4-aminomethyltetrahydropyran (CAS number: 130290-79-8), to get compound A20, yield: 55%; 1H NMR (400 MHz, DMSO-d6) δ 13.64 (br, 1H), 12.28 (br, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.92 (dd, J = 8.4, 1.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 2H), 7.82 (d, J = 7.6 Hz, 1H), 7.46 - 7.40 (m, 4H), 7.25 (t, J = 74.0 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 4.10 (d, J = 7.2 Hz, 2H), 1.40 - 1.34 (m, 1H), 0.68 - 0.63 (m, 2H), 0.45 - 0.41 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 164.5, 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 x C), 44.4, 35.1, 30.4 (2 x C), 10.0, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 25 H 28 O4NF2 + [M+H] + , 472.2042; found 472.2080.

[0262] Synthesis of compound A21 of example 30:

[0263] Synthesis procedure as in example 1, last step amine reagent was replaced by aniline to give compound A21 in 42% yield; 1 H NMR (400 MHz, DMSO-d6) δ 13.64 (br, 1H), 12.28 (br, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.92 (dd, J = 8.4, 1.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 2H), 7.82 (d, J = 7.6 Hz, 1H), 7.46 - 7.40 (m, 4H), 7.25 (t, J = 74.0 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 4.10 (d, J = 7.2 Hz, 2H), 1.40 - 1.34 (m, 1H), 0.68 - 0.63 (m, 2H), 0.45 - 0.41 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 162.8, 151.4, 150.1, 141.6, 140.8, 139.0 (2 x C), 135.3, 129.1 (2 x 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 x C). ESI-HRMS m / z: calcd for C 25 H 22 O3N3F2 + [M+H] + , 450.1624; found 450.1631.

[0264] Synthesis of compound A22 of example 31:

[0265] Synthesis procedure as example 1, last step amine reagent was replaced by benzylamine to give compound A22 in 29% yield; 1 H NMR (400 MHz, DMSO-d6) δ 13.44 (br, 1H), 10.32 (br, 1H), 7.92-7.87 (m, 2H), 7.78-7.36 (m, 2H), 7.47 (d, J = 7.6 Hz, 2H), 7.40-7.27 (m, 5H), 7.21 (t, J = 74.0 Hz, 1H), 4.72 (d, J = 5.2 Hz, 2H), 3.95 (d, J = 6.8 Hz, 2H), 1.34-1.26 (m, 1H), 0.64-0.59 (m, 2H), 0.39-0.36 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.5, 151.2, 150.1, 141.6, 141.0, 139.4, 135.3, 128.6 (2 x C), 127.4 (2 x 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 x C). ESI-HRMS m / z: calcd for C 26 H 24 O3N3F2 + [M+H] + , 464.1780; found 464.1819.

[0266] Synthesis of compound A23 of example 32:

[0267] The synthetic procedure was referred to example 1, the amine reagent was selected as 2- methoxy-5-(aminomethyl)pyridine (CAS Number: 262295-96-5) in the last step to give compound A24 in 58% yield; 1 H NMR (500 MHz, DMSO-d6) δ 13.77 (br, 1H), 11.90 (s, 1H), 8.19 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 8.5, 2.0 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.24 (t, J = 74.5 Hz, 1H), 4.12 (d, J = 7.0 Hz, 2H), 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-d6) δ 161.6, 151.4, 150.1, 141.5, 140.7, 135.3, 130.0, 126.8, 122.8, 121.6 (2 x 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 x C). ESI-HRMS m / z: calcd for C 23 H 22 O3N5F2 + [M+H] + , 454.1685; found 454.1703.

[0268] Example 33 Synthesis of compound A24:

[0269] The synthetic procedure was referred to example 1, the amine reagent was selected as 2- methoxy-5-(aminomethyl)pyridine (CAS Number: 262295-96-5) in the last step to give compound A24 in 58% yield; 1H NMR (500 MHz, DMSO-d6) δ 14.11 (br, 1H), 10.28 (s, 1H), 8.31-8.25 (m, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.81 (dd, J = 8.5, 2.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 74.0 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 4.65 (d, J = 5.5 Hz, 2H), 4.03 (d, J = 7.0 Hz, 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-d6) δ 164.6, 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 x C). ESI-HRMS m / z: calcd for C 26 H 25 O4N4F2 + [M+H] + , 495.1838; found 495.1865.

[0270] Synthesis of compound A25 of example 34:

[0271] Synthesis procedure as in example 1, last step amine reagent was replaced by 4- hydrazinobenzoic acid to give compound A25 in 22% yield; 1 H NMR (500 MHz, DMSO-d6) δ 14.11 (br, 1H), 10.28 (s, 1H), 8.31-8.25 (m, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.81 (dd, J = 8.5, 2.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 74.0 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 4.65 (d, J = 5.5 Hz, 2H), 4.03 (d, J = 7.0 Hz, 2H), 3.84 (s, 3H), 1.33-1.27 (m, 1H), 0.63-0.58 (m, 2H), 0.42-0.38 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 167.3, 164.8, 152.9, 151.7, 150.1, 141.6, 141.0, 135.3, 131.0 (2 x 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 x C), 73.3, 9.9, 3.0 (2 x C). ESI-HRMS m / z: calcd for C 26 H 23 O5N4F2 + [M+H] + , 509.1631; found 509.1678.

[0272] Synthesis of compound A26 of example 35:

[0273] Synthesis procedure as example 1, last step amine reagent was chosen as 3- aminopyridine to give compound A26 in 86% yield; 1 H NMR (400 MHz, DMSO-d6) δ 13.60 (br, 1H), 12.31 (br, 1H), 8.96 (s, 1H), 8.36 (d, J = 5.6 Hz, 2H), 8.02 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.92 (dd, J = 8.4, 1.6 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.46 - 7.42 (m, 3H), 7.24 (t, J = 74.0 Hz, 1H), 4.09 (d, J = 6.8 Hz, 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-d6) δ 163.4, 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 x C). ESI-HRMS m / z: calcd for C 24 H 21 O3N4F2 + [M+H] + , 451.1576; found 451.1624.

[0274] Example 36 Synthesis of compound A27:

[0275] The synthetic procedure was referenced to example 1, the amine reagent was selected as 2- aminopyridine in the last step to afford compound A27 in yield of 20%; 1 H NMR (400 MHz, DMSO-d6) δ 13.63 (br, 1H), 12.86 (br, 1H), 8.41-8.39 (m, 2H), 8.12 (d, J = 2.0 Hz, 1H), 8.02 (dd, J = 7.6, 0.8 Hz, 1H), 7.91-7.84 (m, 3H), 7.47-7.43 (m, 2H), 7.25 (t, J = 74.0 Hz, 1H), 7.21-7.18 (m, 1H), 4.10 (d, J = 6.8 Hz, 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) δ 163.1, 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 x C). ESI-HRMS m / z: calcd for C 24 H 21 O3N4F2 + [M+H] + 451.1576; found 451.1623.

[0276] Example 37 Synthesis of compound A28:

[0277] The synthetic procedure was referenced to example 1, the amine reagent was selected as 5- aminoindole in the last step to afford compound A28 in yield of 79%; 1H NMR (400 MHz, DMSO-d6) δ 13.57 (br, 1H), 12.20 (br, 1H), 11.12 (br, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 8.01 (dd, J = 7.6, 0.8 Hz, 1H), 7.92 (dd, J = 8.4, 2.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.49 - 7.41 (m, 4H), 7.38 (t, J = 4.9 Hz, 1H), 7.25 (t, J = 74.4 Hz, 1H), 6.47 - 6.46 (m, 1H), 4.13 (d, J = 7.2 Hz, 2H), 1.43 - 1.35 (m, 1H), 0.69 - 0.64 (m, 2H), 0.46 - 0.43 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 162.2, 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 x C). ESI-HRMS m / z: calcd for C 27 H 23 O3N4F2 + [M+H] + , 489.1733; found 489.1778.

[0278] Example 38 Synthesis of compound A29:

[0279] Compound 5 (0.19 mmol, 1.0 equiv.) was dissolved in 1 mL DMF, then 5 mg DMAP (0.04 mmol, 0.2 equiv.) and 49 mg N, N'-disuccinimidyl carbonate (0.19 mmol, 1.0 equiv.) were added, and the reaction was carried out at room temperature for 12 h, which was monitored by thin layer chromatography. After the reaction was completed, the organic phase was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The ethyl acetate layer was concentrated, and 72 mg of compound A29 was obtained by flash column chromatography with a yield of 80%.

[0280] The obtained compound A29 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry techniques, and the identification results were as follows: Conformer A: 1H NMR (500 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 8.04 (dd, J = 7.5, 1.0 Hz, 1H), 7.95 (dd, J = 17.5, 2.0 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.21 (t, J = 74.0 Hz, 1H), 4.05 (d, J = 7.0 Hz, 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-d6) δ 170.6 (2 x 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 = 256.5 Hz), 114.2, 112.6, 73.3, 25.7 (2 x C), 10.0, 3.1 (2 x C). Conformer B: 1 H NMR (500 MHz, DMSO-d6) δ 13.46 (s, 1H), 7.99 (d, J = 3.5 Hz, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.95 (dd, J = 17.5, 2.0 Hz, 1H), 7.85 (dd, J = 8.5, 2.0 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 74.0 Hz, 1H), 4.03 (d, J = 6.5 Hz, 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-d6) δ 170.4 (2 x 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 x C), 10.0, 3.0 (2 x C). ESI-MS m / z: Calcd for C 23 H 20 O6N3F2 + [M+H] + , 472.1 ; Found 472.1.

[0281] Synthesis of compound A30 of Example 39:

[0282] Dissolve 300 mg of compound 3 (1.24 mmol, 1.0 equiv.) in 5 mL of DMF solution, then add 232 mg of 3-bromophenylhydrazine (1.24 mmol, 1.0 equiv.) and 235 mg of sodium metabisulfite (1.24 mmol, 1.0 equiv.), heat to 80°C for 12 h, TLC monitoring. After the reaction is completed, quench the reaction with water, extract with ethyl acetate, wash the organic phase with saturated aqueous sodium chloride solution, dry the ethyl acetate layer with anhydrous sodium sulfate, concentrate the organic phase, and purify by flash column chromatography to obtain 201 mg of compound A30, with a yield of 40%.

[0283] The obtained compound A30 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results are as follows: 1 H NMR (500 MHz, DMSO-d6) δ 13.24 (s, 1H), 7.96-7.78 (m, 2H), 7.58 (s, 1H), 7.43 (dd, J = 8.0, 1.0 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.20 (t, J = 74.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 4.04 (d, J = 7.0 Hz, 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-d6) δ 151.2, 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 x C). ESI-HRMS m / z: calculated C 18 H 16 O2N2F2Br + [M+H] + , 409.0358; found 409.0354.

[0284] Synthesis of compound B1 of Example 40:

[0285] The synthesis steps are referred to Example 2, and the last step amine reagent is selected as 2,4-difluorobenzylamine to obtain compound B1, with a yield of 90%; Conformer A: 1H NMR (600 MHz, DMSO-d6) δ 13.20 (br, 1H), 9.09 (br, 1H), 8.27 (s, 1H), 7.92 (s, 1H), 7.84-7.76 (m, 2H), 7.71 (d, J = 7.8 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-d6) 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 x C). Conformer B: 1 H NMR (600 MHz, DMSO-d6) δ 13.20 (br, 1H), 9.09 (br, 1H), 8.27 (s, 1H), 7.92 (s, 1H), 7.84-7.76 (m, 2H), 7.71 (d, J = 7.8 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). 13C NMR (151 MHz, DMSO-d6) 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 x C). ESI-HRMS m / z: calcd for C 26 H 22 O3N3F4 + [M+H] + , 500.1592; found 500.1599.

[0286] Synthesis of compound B2 of example 41:

[0287] Synthesis step refer to example 2, the last step amine reagent is chosen as 2- methylaminopyrimidine (CAS number: 75985-45-4), to obtain compound B2, yield: 93%; Conformer A: 1 H NMR (500 MHz, DMSO-d6) δ 13.14 (br, 1H), 9.04 (br, 1H), 8.78 (d, J = 5.0 Hz, 2H), 8.31 - 8.20 (m, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.85 - 7.79 (m, 2H), 7.75 - 7.67 (m, 1H), 7.40 (t, J = 5.0 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.20 (t, J = 74.0 Hz, 1H), 4.71 (d, J = 5.5 Hz, 2H), 4.04 (d, J = 7.0 Hz, 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 x C), 152.5, 150.1, 145.9, 141.2, 137.1, 128.8, 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 x C). Conformer B: δ 13.14 (br, 1H), 9.04 (br, 1H), 8.78 (d, J = 5.0 Hz, 2H), 8.17-8.04 (m, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.85-7.79 (m, 2H), 7.65-7.55 (m, 1H), 7.40 (t, J = 5.0 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.20 (t, J = 74.0 Hz, 1H), 4.71 (d, J = 5.5 Hz, 2H), 4.04 (d, J = 7.0 Hz, 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-d6) δ 167.4, 166.7, 157.3 (2 x C), 152.5, 150.1, 145.9, 141.2, 137.1, 128.8, 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 x C). Conformer B: δ 13.14 (br, 1H), 9.04 (br, 1H), 8.78 (d, J = 5.0 Hz, 2H), 8.17-8.04 (m, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.85-7.79 (m, 2H), 7.65-7.55 (m, 1H), 7.40 (t, J = 5.0 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.20 (t, J = 74.0 Hz, 1H), 4.71 (d, J = 5.5 Hz, 2H), 4.04 (d, J = 7.0 Hz, 2H), 1.36-1.29 (m, 1H), 0.65-0.60 (m, 2H), 0.44-0.39 (m, 2H). 24 H 22 O3N5F2 + [M+H] + , 466.1685; found 466.1687.

[0288] Synthesis of compound B3 of example 42:

[0289] Synthesis step refer to example 2, the last step amine reagent is chosen as 4- aminopyridine, to obtain compound B3, yield: 35%; Conformer A: 1H NMR (500 MHz, DMSO-d6) δ 13.28 (br, 1H), 10.60 (br, 1H), 8.48 (d, J = 5.5 Hz, 2H), 8.39 - 8.09 (m, 1H), 7.94 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.85 - 7.80 (m, 3H), 7.72 (s, 1H), 7.77 - 7.62 (m, 1H), 7.21 (t, J = 74.0 Hz, 1H), 4.05 (d, J = 7.0 Hz, 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-d6) δ 166.8, 152.6, 150.3 (2 x C), 150.1, 146.2, 143.2, 141.4, 137.8, 128.0, 127.8, 122.9, 121.3, 119.3, 118.9, 116.6 (t, J = 256.5 Hz), 114.0 (2 x C), 112.4, 111.4, 73.3, 10.0, 3.1 (2 x C). Conformer B: 1 H NMR (500 MHz, DMSO-d6) δ 13.28 (br, 1H), 10.60 (br, 1H), 8.48 (d, J = 5.5 Hz, 2H), 8.39 - 8.09 (m, 1H), 7.94 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.85 - 7.80 (m, 3H), 7.72 (s, 1H), 7.77 - 7.62 (m, 1H), 7.21 (t, J = 74.0 Hz, 1H), 4.05 (d, J = 7.0 Hz, 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-d6) δ 166.8, 152.6, 150.3 (2 x 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 x C), 112.4, 111.4, 73.3, 10.0, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 24 H 21 O3N4F2 + [M+H] + 451.1576; found 451.1571.

[0290] Synthesis of compound B4:

[0291] Synthesis steps are referred to example 2, last step amine reagent is chosen as 4- hydrazine benzonitrile to give compound B4 in yield: 41%; Conformer A: 1 H NMR (500 MHz, DMSO-d6) δ 13.22 (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 = 8.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 1H), 7.21 (t, J = 74.0 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 4.04 (d, J = 7.00 Hz, 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) δ 166.8, 153.3, 152.9, 150.1, 146.3, 141.4, 137.6, 133.5 (2 x C), 127.8, 126.8, 122.5, 121.3, 119.4, 118.6, 118.3, 116.6 (t, J = 256.5 Hz), 112.5, 111.8 (2 x C), 111.3, 98.9, 73.3, 10.0, 3.1 (2 x C). Conformer B: 1 H NMR (500 MHz, DMSO-d6) δ 13.22 (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 = 8.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 1H), 7.21 (t, J = 74.0 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 4.04 (d, J = 7.00 Hz, 2H), 1.37-1.28 (m, 1H), 0.66-0.58 (m, 2H), 0.45-0.38 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 166.7, 153.3, 152.3, 150.1, 143.3, 141.3, 134.7, 133.5 (2 x 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 x C), 111.1, 98.9, 73.3, 10.0, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 26 H 22 O3N5F2 + [M+H] + , 490.1685; found 490.1637.

[0292] Synthesis of compound B5 of example 44:

[0293] Compound 7 (100 mg, 0.27 mmol, 1.0 equiv.) was dissolved in 1 mL of DMF, 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 reaction was allowed to proceed at room temperature for 12 h, which was monitored by thin layer chromatography. After the reaction was completed, the organic phase was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by flash column chromatography to obtain 77 mg of compound B5 with a yield of 61%.

[0294] The obtained compound B5 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry techniques, and the identification results were as follows: Conformer A: 1 H NMR (500 MHz, DMSO-d6) δ 13.48 (br, 1H), 8.39 (s, 1H), 7.99-7.91 (m, 2H), 7.83 (dd, J = 8.5, 2.0 Hz, 1H), 7.80-7.72 (m, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.22 (t, J = 74.0 Hz, 1H), 4.04 (d, J = 7.0 Hz, 2H), 2.91 (s, 4H), 1.36-1.29 (m, 1H), 0.65-0.60 (m, 2H), 0.43-0.39 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 170.5 (2 x 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 = 256.5 Hz), 114.0, 112.6, 73.3, 25.6 (2 x C), 10.0, 3.1 (2 x C). Conformer B: 1 H NMR (500 MHz, DMSO-d6) δ 13.48 (br, 1 H), 8.24 (s, 1 H), 7.99 - 7.91 (m, 2 H), 7.90 - 7.85 (m, 1 H), 7.83 (dd, J = 8.5, 2.0 Hz, 1 H), 7.40 (d, J = 8.5 Hz, 1 H), 7.22 (t, J = 74.0 Hz, 1 H), 4.04 (d, J = 7.0 Hz, 2 H), 2.91 (s, 4 H), 1.36 - 1.29 (m, 1 H), 0.65 - 0.60 (m, 2 H), 0.43 - 0.39 (m, 2 H). 13 C NMR (151 MHz, DMSO-d6) δ 170.5 (2 x 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 x C), 10.0, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 23 H 20 O6N3F2 + [M+H] + , 472.1315; found 472.1299.

[0295] Synthesis of compound C1 of example 45:

[0296] Synthesis steps refer to example 3, the last step boronic acid reagent is chosen as pyridine-4-boronic acid (CAS number: 1692-15-5) to give compound C1 in 31 % yield; Conformer A: 1H NMR (500 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.63 (t, J = 6.5 Hz, 2H), 8.13 (s, 1H), 7.94 (d, J = 4.0 Hz, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.80-7.77 (m, 2H), 7.77-7.73 (m, 1H), 7.70-7.66 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 74.0 Hz, 1H), 4.04 (d, J = 7.0 Hz, 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-d6) δ 152.0, 150.2, 150.1 (2 x C) 147.9, 144.6, 141.2, 135.9, 131.9, 128.0, 121.8, 121.4, 121.3 (2 x C), 119.4, 119.2, 116.6 (t, J = 256.5 Hz), 112.3, 112.0, 73.2, 10.0, 3.1 (2 x C). Conformer B: 1 H NMR (500 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.63 (t, J = 6.5 Hz, 2H), 7.94 (d, J = 4.0 Hz, 1H), 7.90 (s, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.77-7.73 (m, 2H), 7.70-7.66 (m, 1H), 7.65-7.62 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 74.0 Hz, 1H), 4.04 (d, J = 7.0 Hz, 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-d6) δ 151.8, 150.2, 150.1 (2 x C), 147.8, 144.4, 141.2, 135.7, 131.2, 128.0, 121.4, 121.3 (2 x 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 x C). ESI-HRMS m / z: calcd for C 23 H 20 O2N3F2 + [M+H] + , 408.1518; found 408.1517.

[0297] Synthesis of compound C2:

[0298] Synthesis steps refer to example 3, last step boronic acid reagent chosen 3,4-dimethoxybenzeneboronic acid, to give compound C2 in 89% yield; Conformer A: 1 H NMR (500 MHz, DMSO-d6) δ 12.94 (br, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.5, 2.0 Hz, 1H), 7.78 - 7.52 (m, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.22 (dd, J = 8.5, 2.0 Hz, 1H), 7.19 (t, J = 75.5 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 4.04 (d, J = 7.0 Hz, 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 C NMR (151 MHz, DMSO-d6) δ 151.0, 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 = 256.5 Hz), 116.5, 112.3, 112.1, 111.4, 110.8, 108.8, 73.2, 55.6, 55.5, 10.0, 3.1 (2 x C). Conformer B: 1 H NMR (500 MHz, DMSO-d6) δ 12.94 (br, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.5, 2.0 Hz, 1H), 7.78 - 7.52 (m, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.22 (dd, J = 8.5, 2.0 Hz, 1H), 7.19 (t, J = 75.5 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 4.04 (d, J = 7.0 Hz, 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). 13C NMR (151 MHz, DMSO-d6) δ 151.0, 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 x C). ESI-MS m / z: calcd for C 26 H 25 O4N2F2 + [M+H] + , 467.2; found 467.2.

[0299] Synthesis of compound C3 of example 47:

[0300] Synthesis step refer to example 3, last step boronic acid reagent is chosen 1- (phenylsulfonyl)-3-indoleboronic acid (CAS Number: 129271-98-3), compound C3 is obtained in yield of 46%; Conformer A: 1 H NMR (500 MHz, DMSO-d6) δ 13.04 (s, 1H), 8.10 (dd, J = 8.0, 1.5 Hz, 3H), 8.06 (d, J = 8.5 Hz, 1H), 8.05 - 7.95 (m, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.81 (dd, J = 8.5, 2.0 Hz, 1H), 7.80 - 7.71 (m, 1H), 7.71 - 7.68 (m, 1H), 7.62 - 7.54 (m, 3H), 7.44 (t, J = 8.0 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.20 (t, J = 74.0 Hz, 1H), 4.04 (d, J = 7.0 Hz, 2H), 1.36 - 1.30 (m, 1H), 0.64 - 0.60 (m, 2H), 0.44 - 0.40 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 151.3, 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, 123.1, 122.3, 121.3, 120.5, 119.3, 119.0, 117.9, 116.7 (t, J = 256.5 Hz), 113.6, 112.2, 111.8, 73.2, 10.0, 3.1 (2 x C). Conformer B: 1 H NMR (500 MHz, DMSO-d6) δ 13.04 (s, 1H), 8.10 (dd, J = 8.0, 1.5 Hz, 3H), 8.06 (d, J = 8.5 Hz, 1H), 8.05 - 7.95 (m, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.81 (dd, J = 8.5, 2.0 Hz, 1H), 7.80 - 7.71 (m, 1H), 7.71 - 7.68 (m, 1H), 7.62 - 7.54 (m, 3H), 7.44 (t, J = 8.0 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.20 (t, J = 74.0 Hz, 1H), 4.04 (d, J = 7.0 Hz, 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-d6) δ 151.3, 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, 123.1, 122.3, 121.3, 120.5, 119.3, 119.0, 117.9, 116.7 (t, J = 256.5 Hz), 113.6, 112.2, 111.8, 73.2, 10.0, 3.1 (2 x C). Conformer B: 32 H 26 O4N3SF2 + [M+H] + , 586.1607; found 586.1598.

[0301] Synthesis of compound D1 of Example 48:

[0302] The synthesis procedure refers to example 4, the last step amine reagent is chosen as 2,4-difluorobenzylamine to give compound D1 in 77% yield; Conformer A: 1 H NMR (500 MHz, DMSO-d6) δ 12.97 (br, 1H), 9.02 (br, 1H), 8.22 (s, 1H), 7.81-7.75 (m, 2H), 7.74 (dd, J = 8.5, 2.0 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.48-7.42 (m, 1H), 7.25-7.19 (m, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.09-7.04 (m, 1H), 4.52 (d, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.89 (d, J = 7.0 Hz, 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-d6) δ 166.9, 161.3 (dd, J = 244.5, 12.0 Hz), 160.0 (dd, J = 244.5, 12.0 Hz), 153.7, 150.0, 149.0, 146.1, 137.2, 130.7 (dd, J = 10.5, 6.0 Hz), 128.0, 122.9 (dd, J = 15.0, 3.0 Hz), 122.2, 121.9, 119.7, 117.8, 112.8, 111.3 (dd, J = 21.0, 3.0 Hz), 110.7, 110.0, 103.6 (t, J = 25.5 Hz), 72.9, 55.6, 36.2, 10.2, 3.2 (2 x C). Conformer B: 1 H NMR (500 MHz, DMSO-d6) δ 12.97 (br, 1H), 9.02 (br, 1H), 8.22 (s, 1H), 7.81-7.75 (m, 2H), 7.74 (dd, J = 8.5, 2.0 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.48-7.42 (m, 1H), 7.25-7.19 (m, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.09-7.04 (m, 1H), 4.52 (d, J = 5.5 Hz, 2H), 3.90 (s, 3H), 3.89 (d, J = 7.0 Hz, 2H), 1.30-1.23 (m, 1H), 0.61-0.57 (m, 2H), 0.36-0.31 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 167.5, 166.8, 157.3 (2 x 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 x C). ESI-HRMS m / z: calcd for C 26 H 23 O3N3F2Na + [M+Na] + , 486.1600; found 486.1617.

[0303] Synthesis of compound D2

[0304] Synthesis step refer to example 4, last step amine reagent select 2-methylaminopyrimidine (CAS number: 75985-45-4), to get compound D2, yield: 75%; Conformer A: 1 H NMR (500 MHz, DMSO-d6) δ 12.97 (br, 1 H), 9.02 (s, 1 H), 8.78 (d, J = 5.0 Hz, 2 H), 8.30 - 8.00 (m, 1 H), 7.84 - 7.77 (m, 2 H), 7.75 (dd, J = 8.5, 2.0 Hz, 1 H), 7.69 - 7.53 (m, 1 H), 7.39 (t, J = 5.0 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 1 H), 4.71 (d, J = 6.0 Hz, 2 H), 3.91 (s, 3 H), 3.89 (d, J = 7.0 Hz, 2 H), 1.29 - 1.22 (m, 1 H), 0.62 - 0.56 (m, 2 H), 0.37 - 0.31 (m, 2 H). 13 C NMR (151 MHz, DMSO-d6) δ 167.5, 166.8, 157.3 (2 x 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 x C). ESI-HRMS m / z: calcd for C 1H NMR (500 MHz, DMSO-d6) 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-d6) δ 167.5, 166.8, 157.3 (2 x 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 x C). ESI-HRMS m / z: calcd for C 24 H 23 O3N5Na + [M+Na] + , 452.1693; found 452.1709.

[0305] Synthesis of compound D3

[0306] Synthesis procedure as in example 4, last step amine reagent was chosen as 6-aminobenzothiazole to give compound D3 in 23% yield; Conformer A: 1 H NMR (600 MHz, DMSO-d6) δ 13.07 (br, 1H), 10.55 (br, 1H), 9.30 (d, J = 1.8 Hz, 1H), 8.74 (dd, J = 7.8, 1.8 Hz, 1H), 8.36 (s, 1H), 8.07 (dd, J = 9.0, 2.4 Hz, 1H), 7.90 - 7.85 (m, 2H), 7.81 - 7.78 (m, 1H), 7.78 - 7.75 (m, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.16 (dd, J = 8.4, 3.6 Hz, 1H), 3.94 (d, J = 6.6 Hz, 2H), 3.87 (s, 3H), 1.33 - 1.28 (m, 1H), 0.63 - 0.60 (m, 2H), 0.40 - 0.37 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 166.3, 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 x C). Conformer B: 1 H NMR (600 MHz, DMSO-d6) δ 13.03 (br, 1H), 10.48 (br, 1H), 9.30 (d, J = 1.8 Hz, 1H), 8.74 (dd, J = 7.8, 1.8 Hz, 1H), 8.12 (s, 1H), 8.07 (dd, J = 9.0, 2.4 Hz, 1H), 7.90-7.85 (m, 2H), 7.81-7.78 (m, 1H), 7.78-7.75 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.16 (dd, J = 8.4, 3.6 Hz, 1H), 3.94 (d, J = 6.6 Hz, 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-d6) δ 166.3, 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 x C). Conformer B: 26 H 23 O3N4S + [M+H] + 471.1485; found 471.1438.

[0307] Example 51 Synthesis of compound E1:

[0308] Synthesis procedure as in example 5, last step amine reagent was chosen as 2-aminothiazole to give compound E1 in 50% yield; 1H NMR (500 MHz, DMSO-d6) δ 13.80 (br, 1H), 13.39 (s, 1H), 8.24-8.17 (m, 2H), 8.04 (d, J = 7.5 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 3.5 Hz, 1H), 7.48-7.44 (m, 1H), 7.37 (t, J = 73.0 Hz, 1H), 7.34 (d, J = 3.5 Hz, 1H), 7.31 (t, J = 72.5 Hz, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 162.3, 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: calcd for C 19 H 13 O3N4F4S + [M+H] + , 453.0639; found 453.0614.

[0309] Synthesis of compound E2 of example 52:

[0310] Synthesis step refer to example 5, the last step amine reagent is selected as 6- aminobenzothiazole, to obtain compound E2, yield: 76%; 1 H NMR (400 MHz, DMSO-d6) δ 14.06 (br, 1H), 12.42 (br, 1H), 9.31 (s, 1H), 8.77 (s, 1H), 8.33 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.64 - 7.19 (m, 4H). 13C NMR (101 MHz, DMSO-d6) δ 163.0, 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 x 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: calcd for C 23 H 15 O3N4F4S + [M+H] + 503.0796; found 503.0771.

[0311] Synthesis of compound E3

[0312] Synthesis procedure as in example 5, last step amine reagent was chosen as 2,6-difluorobenzylamine to give compound E3 in 47% yield; 1 H NMR (500 MHz, DMSO-d6) δ 13.82 (br, 1H), 10.39 (s, 1H), 8.20 (s, 1H), 8.19-8.14 (m, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.46-7.41 (m, 1H), 7.39-7.35 (m, 1H), 7.37 (t, J = 73.0 Hz, 1H), 7.33 (t, J = 73.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 2H), 4.80 (d, J = 5.5 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 164.1, 160.9 (dd, J = 246.0, 9.0 Hz, 2 x 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 x C), 30.5. ESI-HRMS m / z: calcd for C 23 H 16 O3N3F6 + [M+H] +Calcd 496.1090; Found 496.1061.

[0313] Synthesis of compound E4:

[0314] The synthetic procedure was referenced to Example 5, the amine reagent was selected as 2,4-difluorobenzylamine in the last step to give compound E4 in yield of 55.7%; 1 H NMR (500 MHz, DMSO-d6) δ 13.56 (br, 1H), 10.27 (s, 1H), 8.25-8.09 (m, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.62-7.53 (m, 2H), 7.39 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 73.0 Hz, 1H), 7.30 (t, J = 73.0 Hz, 1H), 7.28-7.23 (m, 1H), 7.10-7.06 (m, 1H), 4.72 (d, J = 5.5 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 164.5, 161.6 (dd, J = 243.0, 12.0 Hz), 160.4 (dd, J = 246.0, 12.0 Hz), 150.2, 143.7, 141.8, 140.9, 135.4, 131.0 (dd, J = 9.0, 6.0 Hz), 127.0, 125.1, 123.1, 122.9, 122.5 (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: Calcd for C 23 H 16 O3N3F6 + [M+H] + Calcd 496.1090; Found 496.1061.

[0315] Synthesis of compound E5:

[0316] The synthetic procedure was referenced to Example 5, the amine reagent was selected as aniline in the last step to give compound E5 in yield of 80%; 1H NMR (500 MHz, DMSO-d6) δ 13.71 (br, 1H), 12.19 (s, 1H), 8.28 (s, 1H), 8.24 (dd, J = 8.5, 2.0 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.47 - 7.41 (m, 3H), 7.40 (t, J = 73.0 Hz, 1H), 7.37 (t, J = 73.0 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 162.7, 150.3, 143.5, 141.9, 140.7, 139.0, 135.4, 129.1 (2 x C), 126.8, 124.9, 123.7 (2 x C), 123.3, 123.1, 122.0, 121.4, 119.3 (2 x C), 116.6 (t, J = 259.5 Hz), 116.3 (t, J = 259.5 Hz), 115.9. ESI-HRMS m / z: calcd for C 22 H 16 O3N3F4 + [M+H] + , 446.1122; found 446.1103.

[0317] Synthesis of compound E6 of example 56:

[0318] Synthesis step refer to example 5, the last step amine reagent is chosen as 2-(aminomethyl)naphthalene (CAS number: 2018-90-8), to obtain compound E6, yield: 70%; 1 H NMR (500 MHz, DMSO-d6) δ 13.71 (br, 1H), 12.19 (s, 1H), 8.28 (s, 1H), 8.24 (dd, J = 8.5, 2.0 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.47 - 7.41 (m, 3H), 7.40 (t, J = 73.0 Hz, 1H), 7.37 (t, J = 73.0 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H). 13C NMR (151 MHz, DMSO-d6) δ 164.5, 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: calcd for C 27 H 20 O3N3F4 + [M+H] + , 510.1435; found 510.1403.

[0319] Synthesis of compound E7 of example 57:

[0320] Synthesis procedure as in example 5, last step amine reagent was chosen as 2,3- difluorobenzylamine to give compound E7 in yield: 65%; 1 H NMR (500 MHz, DMSO-d6) δ 14.18 (br, 1H), 10.33 (t, J = 6.0 Hz, 1H), 8.31 (s, 1H), 8.28 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 73.0 Hz, 1H), 7.36 (t, J = 73.0 Hz, 1H), 7.36-7.31 (m, 2H), 7.23-7.21 (m, 1H), 4.81 (d, J = 6.0 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 164.5, 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: calcd for C23 H 16 O3N3F6 + [M+H] + 496.1090; found 496.1064.

[0321] Synthesis of compound E8 of example 58:

[0322] The synthesis was referenced to example 5, the amine reagent was chosen as 2,4,6- trifluorobenzylamine for the last step, to afford compound E8 in 43% yield; 1 H NMR (400 MHz, DMSO-d6) δ 13.63 (br, 1H), 10.36 (br, 1H), 8.14-8.13 (m, 2H), 7.89 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.37 (t, J = 72.8 Hz, 1H), 7.32 (t, J = 72.8 Hz, 1H), 7.23 (t, J = 8.8 Hz, 2H), 4.75 (d, J = 5.2 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.2, 161.6 (dt, J = 245.0, 17.0 Hz), 161.1 (ddd, J = 246.0, 15.0, 11.0 Hz, 2 x 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 x C), 30.4. ESI-HRMS m / z: calcd for C 23 H 15 O3N3F7 + [M+H] + 514.0996; found 514.0972.

[0323] Synthesis of compound E9 of example 59:

[0324] The synthesis was referenced to example 5, the amine reagent was chosen as 2-methoxy-5- (aminomethyl)pyridine (CAS number: 262295-96-5) for the last step, to afford compound E9 in 71% yield; 1H NMR (400 MHz, DMSO-d6) δ 13.59 (br, 1H), 10.20 (br, 1H), 8.26 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.81 (dd, J = 8.8, 2.4 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 72.8 Hz, 1H), 7.29 (t, J = 72.8 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 4.65 (d, J = 5.6 Hz, 2H), 3.83 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 164.5, 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: calcd for C 23 H 19 O4N4F4 + [M+H] + 491.1337; found 491.1316.

[0325] Synthesis of compound E10 of example 60:

[0326] Synthesis procedure as in example 5 with the last step amine reagent selected as 2-aminomethylpyrazine (Pyrazin-2-ylmethanamine, CAS number: 20010-99-5) to afford compound E10 in 75% yield; 1H NMR (400 MHz, DMSO-d6) δ 13.63 (br, 1H), 10.68 (br, 1H), 8.79 (s, 1H), 8.71 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.31 (dd, J = 8.4, 1.6 Hz, 1H), 8.28 (s, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 72.8 Hz, 1H), 7.31 (t, J = 72.8 Hz, 1H), 4.91 (d, J = 4.8 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.8, 153.5, 150.2, 144.0 (2 x 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: calcd for C 21 H 16 O3N5F4 + [M+H] + , 462.1184; found 462.1153.

[0327] Synthesis of compound E11 of example 61:

[0328] Synthesis procedure as in example 5, last step amine reagent was replaced by benzylamine to give compound E11 in 79% yield; 1 H NMR (400 MHz, DMSO-d6) δ 13.63 (br, 1H), 10.68 (br, 1H), 8.79 (s, 1H), 8.71 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.31 (dd, J = 8.4, 1.6 Hz, 1H), 8.28 (s, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 72.8 Hz, 1H), 7.31 (t, J = 72.8 Hz, 1H), 4.91 (d, J = 4.8 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 164.4, 150.2, 143.7, 141.8, 140.9, 139.4, 135.4, 128.6 (2 x C), 127.4 (2 x 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: calcd for C 23 H 18 O3N3F4 + [M+H] + , 460.1279; found 460.1250.

[0329] Synthesis of compound E12 of example 62:

[0330] Synthesis step refer to example 5, the last step the amine reagent is chosen as 4-aminomethyltetrahydropyran (CAS number: 130290-79-8), to obtain compound E12, yield: 65%; 1 H NMR (400 MHz, DMSO-d6) δ 14.33 (br, 1H), 9.9 (br, 1H), 8.31-8.28 (m, 2H), 7.87 (d, J = 7.2 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 8.61-7.58 (m, 1H), 7.42 (t, J = 73.2 Hz, 1H), 7.39 (t, J = 72.8 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 3.88 (dd, J = 7.2, 3.2 Hz, 2H), 3.39-3.29 (m, 4H), 1.92-1.82 (m, 1H), 1.73 (d, J = 12.4 Hz, 2H), 1.42-1.33 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.5, 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 x C), 44.5, 35.1, 30.5 (2 x C). ESI-HRMS m / z: calcd for C 22 H 22 O4N3F4 + [M+H] + , 468.1541 ; found 468.1518.

[0331] Synthesis of compound E13:

[0332] The synthesis was reference to example 5, the amine reagent in the last step was selected as 2-aminomethylpyridine (CAS No.: 3731-51-9), afforded compound E13 in yield of 67%; 1 H NMR (400 MHz, DMSO-d6) δ 13.61 (br, 1H), 10.74 (br, 1H), 8.69 (d, J = 4.4 Hz, 1H), 8.34 (dd, J = 8.4, 2.0 Hz, 1H), 8.29 (s, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.84 - 7.77 (m, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 72.8 Hz, 1H), 7.35 (dd, J = 7.2, 1.2 Hz, 1H), 7.30 (t, J = 73.2 Hz, 1H), 4.83 (d, J = 4.8 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.5, 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: calcd for C 22 H 17 O3N4F4 + [M+H] + 461.1231; found 461.1203.

[0333] Synthesis of compound F1:

[0334] The synthesis was reference to example 6, the amine reagent in the last step was selected as 2,4,6-trifluorobenzylamine, afforded compound F1 in yield of 41%; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (t, J = 5.6 Hz, 1H), 8.67 (d, J = 4.4 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 7.41 - 7.36 (m, 2H), 7.26 (t, J = 74.0 Hz, 1H), 7.19 - 7.11 (m, 3H), 4.51 (d, J = 5.6 Hz, 2H), 3.97 (d, J = 7.2 Hz, 2H), 1.34 - 1.26 (m, 1H), 0.62 - 0.53 (m, 2H), 0.36 - 0.27 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 161.4 (dd, J = 245, 20 Hz), 161.3 (ddd, J = 247, 16, 11 Hz, 2 x 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 x C), 96.9, 73.2, 30.8, 9.9, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 25 H 19 O3N4F5Na + [M+Na] + 541.1270; found 541.1255.

[0335] Synthesis of compound F2

[0336] Synthesis procedure as in example 6, last step amine reagent was chosen as 2,4-difluorobenzylamine to give compound F2 in 51% yield; 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (t, J = 6.4 Hz, 1H), 8.69 (d, J = 4.4 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 8.4, 2.0 Hz, 1H), 7.44 - 7.36 (m, 3H), 7.26 (t, J = 74.0 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.19 (s, 1H), 7.07 - 7.00 (m, 1H), 4.50 (d, J = 6.0 Hz, 2H), 3.99 (d, J = 7.2 Hz, 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-d6) δ 161.5 (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 x C). ESI-HRMS m / z: calcd for C 25 H 20 O3N4F4Na + [M+Na] + , 523.1364; found 523.1356.

[0337] Synthesis of compound F3 of example 66:

[0338] Synthesis step refer to example 6, the last step amine reagent is selected as 2,5-difluorobenzylamine, to obtain compound F3, yield: 61 %; 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (t, J = 6.4 Hz, 1H), 8.70 (d, J = 4.4 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.4, 2.0 Hz, 1H), 7.43 (d, J = 4.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.26 (t, J = 74.0 Hz, 1H), 7.20 (s, 1H), 7.19 - 7.10 (m, 2H), 4.52 (d, J = 6.0 Hz, 2H), 4.01 (d, J = 6.8 Hz, 2H), 1.32 - 1.25 (m, 1H), 0.66 - 0.51 (m, 2H), 0.38 - 0.21 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 161.6, 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 x C). ESI-HRMS m / z: calcd for C 25 H 20 O3N4F4Na + [M+Na] + 523.1364; found 523.1358.

[0339] Synthesis of compound F4 of example 67:

[0340] Synthesis step refer to example 6, the last step amine reagent is selected as 2,6-difluorobenzylamine, to obtain compound F4, yield: 53%; 1 H NMR (500 MHz, DMSO-d6) δ 8.79 (t, J = 5.5 Hz, 1H), 8.67 (d, J = 4.5 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.5, 2.0 Hz, 1H), 7.44 - 7.35 (m, 3H), 7.26 (t, J = 74.5 Hz, 1H), 7.16 (s, 1H), 7.07 (t, J = 7.5 Hz, 2H), 4.57 (d, J = 6.0 Hz, 2H), 3.99 (d, J = 7.0 Hz, 2H), 1.38 - 1.24 (m, 1H), 0.66 - 0.53 (m, 2H), 0.38 - 0.27 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 161.1 (dd, J = 247.5, 9.0 Hz, 2 x 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 x C), 109.4, 96.8, 73.2, 31.1, 9.9, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 25 H 20 O3N4F4Na + [M+Na] + , 523.1364; found, 523.1359.

[0341] Synthesis of compound F5 of example 68:

[0342] Synthesis procedure as example 6, the last step amine reagent was replaced by aniline to give compound F5 in 48% yield; 1 H NMR (400 MHz, CDC13) δ 8.79 (s, 1H), 8.61 (d, J = 4.4 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.57 (dd, J = 8.4, 2.0 Hz, 1H), 7.44 - 7.35 (m, 4H), 7.16 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 4.0 Hz, 1H), 6.80 (t, J = 74.8 Hz, 1H), 3.98 (d, J = 6.8 Hz, 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-d6) δ 160.1, 150.8, 150.1, 150.0, 149.4, 144.9, 141.9, 138.4, 128.7 (2 x C), 127.9, 124.1, 122.6, 120.6, 120.4 (2 x C), 117.8 (t, J = 257.1 Hz), 115.9, 109.5, 97.2, 73.4, 9.9, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 24 H 20 O3N4F2Na + [M+Na] + , 473.1396; found, 473.1394.

[0343] Synthesis of compound F6:

[0344] The synthesis was performed according to the procedure described in example 6, the last step the amine reagent was replaced by benzylamine to give compound F6 in 52% yield; 1 H NMR (400 MHz, CDC13) δ 8.58 (d, J = 4.4 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 (s, 1H), 7.35 - 7.33 (m, 5H), 7.33 - 7.28 (m, 2H), 6.96 (d, J = 4.4 Hz, 1H), 6.74 (t, J = 74.8 Hz, 1H), 4.68 (d, J = 6.4 Hz, 2H), 3.84 (d, J = 6.8 Hz, 2H), 1.33 (s, 1H), 0.66 - 0.57 (m, 2H), 0.32 - 0.28 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 161.3, 150.5, 150.0 (2 x C), 149.4, 144.9, 141.8, 139.5, 128.3 (2 x C), 128.0, 127.2 (2 x 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 x C). ESI-HRMS m / z: calcd for C 25 H 22 O3N4F2Na + [M+Na] + 487.1552; found 487.1552.

[0345] Synthesis of compound F7:

[0346] The synthesis was performed according to the procedure described in example 6, the last step the amine reagent was replaced by 2-methylaminopyrimidine (CAS number: 75985-45-4) to give compound F7 in 35% yield; 1H NMR (600 MHz, DMSO-d6) δ 8.87 (t, J = 5.4 Hz, 1H), 8.76 (d, J = 4.8 Hz, 2H), 8.69 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.84 (dd, J = 8.4, 1.8 Hz, 1H), 7.44 - 7.38 (m, 3H), 7.24 (t, J = 73.8 Hz, 1H), 7.18 (s, 1H), 4.71 (d, J = 5.4 Hz, 2H), 4.01 (d, J = 6.6 Hz, 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-d6) δ 166.6, 161.4, 157.5 (2 x 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 x C). ESI-HRMS m / z: calcd for C 23 H 20 O3N6F2Na + [M+Na] + , 489.1457; found 489.1459.

[0347] Synthesis of compound F8 of example 71:

[0348] Synthesis step refer to example 6, last step amine reagent is chosen as 4-aminomethyltetrahydropyran (CAS number: 130290-79-8), to obtain compound F8, yield: 40%; 1 H NMR (600 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.43 (s, 1H), 7.97 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.39 (s, 2H), 7.26 (t, J = 72.0 Hz, 1H), 7.14 (s, 1H), 4.02 (d, J = 7.2 Hz, 2H), 3.83 (d, J = 11.4 Hz, 2H), 3.25 (t, J = 11.4 Hz, 2H), 3.19 (s, 2H), 1.81 (s, 1H), 1.57 (d, J = 12.6 Hz, 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). 13C NMR (151 MHz, DMSO-d6) δ 161.3, 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 x C), 44.4, 35.0, 30.5 (2 x C), 9.9, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 24 H 26 O4N4F2Na + [M+Na] + 495.1814; found 495.1817.

[0349] Synthesis of compound F9 of example 72:

[0350] Synthesis procedure as in example 6, last step amine reagent was chosen as 2-aminothiazole to give compound F9 in 61% yield; 1 H NMR (400 MHz, CDCl3) δ 10.07 (br, 1H), 8.66 (dd, J = 7.6, 0.8 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.58 - 7.49 (m, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 0.9 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 3.6 Hz, 1H), 6.74 (t, J = 74.8 Hz, 1H), 4.04 (d, J = 6.8 Hz, 2H), 1.44 - 1.32 (m, 1H), 0.76 - 0.63 (m, 2H), 0.44 - 0.40 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 159.8, 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 x C). ESI-HRMS m / z: calcd for C 21 H 17 O3N5F2SNa + [M+Na] + 480.0912; found 480.0893.

[0351] Synthesis of compound F10 of example 73:

[0352] The synthesis was performed according to the procedure described in Example 6, by choosing 2,3-difluorobenzylamine as the amine reagent in the last step, to give compound F10 in 45% yield; 1 H NMR (600 MHz, CD3OD) δ 8.56 (d, J = 4.2 Hz, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.67 (dd, J = 7.8, 1.2 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 4.2 Hz, 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 = 75.0 Hz, 1H), 4.65 (s, 2H), 3.97 (d, J = 7.2 Hz, 2H), 1.35-1.24 (m, 1H), 0.66-0.56 (m, 2H), 0.40-0.30 (m, 2H), NH (not observed). 13 C NMR (151 MHz, CD3OD) δ 164.2, 151.7 (dd, J = 246.0, 13.5 Hz), 151.6, 151.5, 151.4, 150.8, 149.9 (dd, J = 259.5, 12 Hz), 147.6, 144.0, 129.7, 129.4 (d, J = 10.5 Hz), 125.5 (t, J = 4.5 Hz), 125.4 (dd, J = 6.0, 4.5 Hz), 123.7, 122.8, 117.8 (t, J = 258.0 Hz), 117.2 (d, J = 18.0 Hz), 116.7, 110.6, 98.2, 75.1, 37.5, 11.0, 3.6 (2 x C). ESI-HRMS m / z: calcd for C 25 H 20 O3N4F4Na + [M+Na] + , 523.1364; found 523.1369.

[0353] Synthesis of compound F11

[0354] The synthesis was performed according to the procedure described in Example 6, by choosing 2,3-difluorobenzylamine as the amine reagent in the last step, to give compound F10 in 45% yield; 1H NMR (400MHz, DMSO-d6) δ9.24 (t, J=6.0Hz, 1H), 9.19 (d, J=8.0Hz, 1H), 8.58 (d, J=2.0H z, 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 (101MHz, DMSO-d6) δ 161.3, 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 = 256.8Hz), 112.8, 107.6, 96.6, 73.3, 40.0, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated values ​​are for C 24 H 21 O3N5F2Na + [M+Na] + , 488.1505; the measured value is 488.1513.

[0355] Example 75 Synthesis of compound F12:

[0356] The synthesis steps were as described in Example 6. In the final step, 1-methyl-4-aminopyrazole (CAS No.: 69843-13-6) was selected as the amine reagent to obtain compound F12 with a yield of 47%. 1 H NMR (400MHz, DMSO-d6) δ10.56 (s, 1H), 9.25 (d, J=7.6Hz, 1H), 7.91 (d, J=2.0 Hz, 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). 13C NMR (101MHz, DMSO-d6) δ 158.8, 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 = 256.7Hz), 112.9, 107.7, 97.4, 96.8, 73.3, 38.5, 10.1, 3.1 (2×C). ESI-HRMS m / z: calculated values ​​are for C 22 H 20 O3N6F2Na + [M+Na] + , 477.1457; the measured value is 477.1469.

[0357] Example 76 Synthesis of compound F13:

[0358] The synthesis steps were as described in Example 6. In the final 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 (500MHz, DMSO-d6) 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 (151MHz, DMSO-d6) δ 161.2, 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 = 256.5Hz), 112.9, 107.5, 96.6, 73.3, 42.5, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated values ​​are for C 29 H 24 O3N4F2Na + [M+Na] + , 537.1709; measured value is 537.1685.

[0359] Synthesis of compound G1:

[0360] The synthetic procedure was referenced to example 7, the amine reagent was selected as 2,4,6-trifluorobenzylamine in the last step to give compound G1 in 49% yield; 1 H NMR (600 MHz, DMSO-d6) δ 8.84 (d, J = 4.8 Hz, 1H), 8.60 (s, 1H), 8.45 (t, J = 6.0 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 8.4, 1.8 Hz, 1H), 7.50 (d, J = 4.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.25 (t, J = 74.4 Hz, 1H), 7.19 (t, J = 8.4 Hz, 2H), 4.64 (d, J = 6.0 Hz, 2H), 3.98 (d, J = 7.2 Hz, 2H), 1.38 - 1.24 (m, 1H), 0.65 - 0.51 (m, 2H), 0.42 - 0.21 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 161.5 (dt, J = 244.5, 16.5 Hz), 161.1 (ddd, J = 247.5, 16.5, 12 Hz, 2 x 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 x C), 73.4, 30.2, 9.9, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 25 H 19 O3N4F5Na + [M+Na] + 541.1270; found 541.1277.

[0361] Synthesis of compound G2:

[0362] The synthetic procedure was referenced to example 7, the amine reagent was selected as 2,4,6-trifluorobenzylamine in the last step to give compound G1 in 49% yield; 1H NMR (600 MHz, DMSO-d6) δ 8.86 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 8.53 (t, J = 6.0 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 8.4, 1.8 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 73.8 Hz, 1H), 7.25 - 7.21 (m, 1H), 7.09 - 7.01 (m, 1H), 4.62 (d, J = 6.0 Hz, 2H), 3.99 (d, J = 7.2 Hz, 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-d6) δ 161.4 (dd, J = 243, 12 Hz), 161.2, 160.2 (dd, J = 246, 12 Hz), 152.0, 149.5, 146.7, 146.4, 145.7, 142.1, 130.7 (dd, J = 9.0, 6.0 Hz), 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 x C). ESI-HRMS m / z: calcd for C 25 H 20 O3N4F4Na + [M+Na] + , 523.1364; found 523.1369.

[0363] Synthesis of compound G3

[0364] Synthesis procedure as in example 7, last step amine reagent was chosen as 2,5-difluorobenzylamine to give compound G3 in 45% yield; 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 8.59 (t, J = 6.4 Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 (d, J = 4.4 Hz, 1H), 7.42 (d, J = 4.4 Hz, 1H), 7.30 - 7.24 (m, 1H), 7.27 (t, J = 74.0 Hz, 1H), 7.21 - 7.13 (m, 2H), 4.64 (d, J = 6.0 Hz, 2H), 3.99 (d, J = 6.8 Hz, 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-d6) δ 161.3, 158.1 (dd, J = 237.0, 1.5 Hz), 156.2 (dd, J = 238.5, 1.5 Hz), 152.0, 149.5, 146.7, 146.3, 145.7, 142.1, 128.6 (dd, J = 17.7, 7.6 Hz), 127.7, 122.8, 120.5, 116.7 (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 x C). ESI-HRMS m / z: calcd for C 25 H 20 O3N4F4Na + [M+Na] + , 523.1364; found 523.1371.

[0365] Example 80 Synthesis of compound G4:

[0366] Synthesis procedure as in example 7, last step amine reagent was chosen as 2,6-difluorobenzylamine to give compound G4 in 53% yield; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 4.4 Hz, 1H), 8.61 (s, 1H), 8.46 (t, J = 5.6 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.52 (d, J = 4.4 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.26 (t, J = 74.0 Hz, 1H), 7.18 - 7.06 (m, 2H), 4.69 (d, J = 6.0 Hz, 2H), 3.98 (d, J = 7.2 Hz, 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-d6) δ 161.0 (dd, J = 245.0, 8.0 Hz, 2 x 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 x C), 109.4, 104.8, 73.4, 30.4, 9.9, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 25 H 20 O3N4F4Na + [M+Na] + 523.1364; found 523.1371.

[0367] Example 81 Synthesis of compound G5:

[0368] Synthesis procedure as in example 7, last step amine reagent was replaced by aniline to give compound G5 in 46% yield 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.96 (d, J = 4.4 Hz, 1H), 8.76 (s, 1H), 7.86 (d, J = 6.0 Hz, 1H), 7.82 (dd, J = 8.4, 2.4 Hz, 1H), 7.62 - 7.73 (m, 2H), 7.60 (d, J = 4.4 Hz, 1H), 7.44 - 7.37 (m, 3H), 7.28 (t, J = 74.0 Hz, 1H), 7.14 - 7.10 (m, 1H), 4.00 (d, J = 6.8 Hz, 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-d6) δ 159.5, 152.2, 149.5, 146.7, 146.6, 145.9, 142.2, 138.7, 129.1 (2 x C), 127.6, 123.6, 122.9, 120.5, 119.4 (2 x C), 116.5 (t, J = 257.1 Hz), 116.0, 109.7, 105.1, 73.4, 9.9, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 24 H 20 O3N4F2Na + [M+Na] + , 473.1396; found 473.1403.

[0369] Synthesis of compound G6 of example 82:

[0370] Synthesis procedure as in example 7, last step amine reagent was replaced by benzylamine to give compound G6 in 35% yield; 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 4.4 Hz, 1H), 8.66 (s, 1H), 8.53 (t, J = 6.0 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.51 (d, J = 4.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.39 - 7.32 (m, 4H), 7.27 (t, J = 74.0 Hz, 1H), 7.27 - 7.23 (m, 1H), 4.62 (d, J = 6.1 Hz, 2H), 3.99 (d, J = 7.0 Hz, 2H), 1.38 - 1.23 (m, 1H), 0.73 - 0.50 (m, 2H), 0.46 - 0.23 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 161.2, 151.9, 149.5, 146.6, 146.3, 145.7, 142.1, 139.7, 128.5 (2 x C), 127.7, 127.3 (2 x 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 x C). ESI-HRMS m / z: calcd for C 25 H 22 O3N4F2Na + [M+Na] + , 487.1552; found 487.1560.

[0371] Synthesis of compound G7:

[0372] The synthesis was performed according to the procedure described in example 7, the amine reagent was chosen as 4-aminomethyltetrahydropyran (CAS number: 130290-79-8) for the last step, to give compound G7 in 40% yield; 1 H NMR (500 MHz, DMSO-d6) δ 8.85 (d, J = 4.5 Hz, 1H), 8.60 (s, 1H), 8.14 (t, J = 6.5 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.78 (dd, J = 8.5, 2.0 Hz, 1H), 7.50 (d, J = 4.5 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.26 (t, J = 74.0 Hz, 1H), 3.99 (d, J = 7.0 Hz, 2H), 3.85 (dd, J = 11.5, 2.5 Hz, 2H), 3.33 - 3.23 (m, 4H), 1.87 - 1.74 (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-d6) δ 161.2, 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 x C), 43.9, 35.2, 30.4 (2 x C), 9.9, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 24 H 26 O4N4F2Na + [M+Na] + 495.1814; found 495.1829.

[0373] Synthesis of compound G8:

[0374] The synthesis was performed according to the procedure described in example 7, the amine reagent was chosen as 2-aminothiazole for the last step, to give compound G8 in 34% yield; 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.02 (d, J = 4.8 Hz, 1H), 8.87 (s, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.4, 2.0 Hz, 1H), 7.66 (d, J = 4.8 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.30 - 7.29 (m, 1H), 7.30 (t, J = 78.0 Hz, 1H), 4.00 (d, J = 7.2 Hz, 2H), 1.37 - 1.24 (m, 1H), 0.65 - 0.54 (m, 2H), 0.43 - 0.30 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 158.5, 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 x C) ESI-HRMS m / z: calcd for C 21 H 17 O3N5F2SNa + [M+Na] + , 480.0912; found 480.0930.

[0375] Synthesis of compound G9 of example 85:

[0376] Synthesis step refer to example 7, the last step amine reagent is chosen as 6-aminobenzothiazole, to obtain compound G9, yield: 43%; 1 H NMR (600 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.29 (s, 1H), 8.95 (d, J = 4.2 Hz, 1H), 8.77 (s, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.4, 1.8 Hz, 1H), 7.77 (dd, J = 9.0, 2.4 Hz, 1H), 7.59 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.27 (t, J = 73.8 Hz, 1H), 4.01 (d, J = 7.2 Hz, 2H), 1.37 - 1.25 (m, 1H), 0.72 - 0.53 (m, 2H), 0.43 - 0.32 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 159.7, 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 x C). ESI-HRMS m / z: calcd for C 25 H 19 O3N5F2SNa + [M+Na] + , 530.1069; found 530.1081.

[0377] Synthesis of compound G10 of example 86:

[0378] Synthesis procedure as in example 7, last step amine reagent was chosen as 2,3-difluorobenzylamine to give compound G10 in 40% yield; 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 8.60 (t, J = 6.0 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.38 - 7.30 (m, 1H), 7.27 (t, J = 74.0 Hz, 1H), 7.25 - 7.15 (m, 2H), 4.70 (d, J = 5.6 Hz, 2H), 3.99 (d, J = 6.8 Hz, 2H), 1.35 - 1.28 (m, 1H), 0.63 - 0.56 (m, 2H), 0.40 - 0.33 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 161.3, 151.9, 149.6 (dd, J = 244.5, 12.0 Hz), 149.5, 147.8 (dd, J = 244.5, 12.0 Hz), 146.7, 146.3, 145.6, 142.1, 129.1 (d, J = 10.5 Hz), 127.7, 124.7 (dd, J = 7.5, 4.5 Hz), 124.5 (t, J = 3.0 Hz), 122.8, 120.5, 116.5 (t, J = 258.0 Hz), 116.0 (d, J = 16.5 Hz), 115.9, 109.3, 104.9, 73.4, 35.8, 9.9, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 25 H 20 O3N4F4Na[M+Na] + , 523.1364; found 523.1383.

[0379] Synthesis of compound G11 of example 87:

[0380] Synthesis steps refer to example 7, the last step amine reagent was chosen as 3-aminomethylpyridine (CAS number: 3731-52-0) to give compound G11 in 57% yield; 1 H NMR (500 MHz, DMSO-d6) δ 8.84 (d, J = 4.5 Hz, 1H), 8.64 (s, 1H), 8.63 - 8.56 (m, 2H), 8.46 (dd, J = 5.0, 2.0 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.5, 2.0 Hz, 2H), 7.50 (d, J = 4.5 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.36 (ddd, J = 8.0, 5.0, 1.0 Hz, 1H), 7.24 (t, J = 74.0 Hz, 1H), 4.64 (d, J = 6.0 Hz, 2H), 3.99 (d, J = 7.0 Hz, 2H), 1.36 - 1.24 (m, 1H), 0.64 - 0.46 (m, 2H), 0.42 - 0.31 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 161.3, 151.9, 149.5, 148.6, 147.9, 146.7, 146.3, 145.7 (2 x 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 x C). ESI-HRMS m / z: calcd for C 24 H 22 O3N5F2 + [M+H] + 466.1685; found 466.1695.

[0381] Synthesis of compound G12 of example 88:

[0382] Synthesis steps refer to example 7, last step amine reagent chosen 1 -methyl-4- aminopyrazole (CAS number: 69843-13-6) to give compound G12 in 44% yield; 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.97 (d, J = 4.4 Hz, 1H), 8.73 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.80 (dd, J = 8.4, 2.0 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.28 (t, J = 74.4 Hz, 1H), 6.60 (d, J = 2.0 Hz, 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-d6) δ 158.2, 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 x C). ESI-HRMS m / z: calcd for C 22 H 20 O3N6F2Na + [M+Na] + 477.1457; found 477.1469.

[0383] Synthesis of compound G13:

[0384] The synthesis was reference to example 7, the amine reagent in the last step was selected as 2-(aminomethyl)naphthalene (CAS No.: 2018-90-8), to give compound G13 in yield of 52%; 1 H NMR (500 MHz, DMSO-d6) δ 8.83 (d, J = 4.5 Hz, 1H), 8.67 (s, 1H), 8.64 (t, J = 6.0 Hz, 1H), 7.93 - 7.82 (m, 5H), 7.78 (dd, J = 8.0, 1.5 Hz, 1H), 7.56 - 7.46 (m, 4H), 7.42 (d, J = 6.8 Hz, 1H), 7.26 (t, J = 74.5 Hz, 1H), 4.79 (d, J = 6.0 Hz, 2H), 3.99 (d, J = 7.0 Hz, 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-d6) δ 161.3, 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 x 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 x C). ESI-HRMS m / z: calcd for C 29 H 24 O3N4F2Na + [M+Na] + 537.1709; found 537.1682.

[0385] Synthesis of compound G14:

[0386] The synthesis was reference to example 7, the amine reagent in the last step was selected as 2-methoxy-5-(aminomethyl)pyridine (CAS No.: 262295-96-5), to give compound G14 in yield of 50%; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 4.4 Hz, 1H), 8.63 (s, 1H), 8.50 (t, J = 6.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.72 (dd, J = 8.8, 2.8 Hz, 1H), 7.50 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.27 (t, J = 74.0 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H), 3.98 (d, J = 7.2 Hz, 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-d6) δ 162.8, 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 x C). ESI-HRMS m / z: calcd for C 25 H 23 O4N5F2Na + [M+Na] + 518.1610; found 518.1626.

[0387] Synthesis of compound G15 of example 91:

[0388] Synthesis procedure as in example 7, with the last step amine reagent selected as 6-aminoindole to give compound G15 in 55% yield; 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.05 (s, 1H), 8.96 (d, J = 4.8 Hz, 1H), 8.74 (s, 1H), 8.02 (s, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 8.4, 2.0 Hz, 1H), 7.58 (d, J = 4.4 Hz, 1H), 7.45 - 7.31 (m, 4H), 7.28 (t, J = 74.0 Hz, 1H), 6.43 (s, 1H), 4.01 (d, J = 6.8 Hz, 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-d6) δ 159.2, 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 x C). ESI-HRMS m / z: calcd for C 26 H 21 O3N5F2Na + [M+Na] + found 512.1521.

[0389] Synthesis of compound G16 of example 92:

[0390] Synthesis procedure as in example 7, last step amine reagent was chosen as 4- aminopyridine to give compound G16 in 39% yield; 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.05 (s, 1H), 8.96 (d, J = 4.8 Hz, 1H), 8.74 (s, 1H), 8.02 (s, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 8.4, 2.0 Hz, 1H), 7.58 (d, J = 4.4 Hz, 1H), 7.45 - 7.31 (m, 4H), 7.28 (t, J = 74.0 Hz, 1H), 6.43 (s, 1H), 4.01 (d, J = 6.8 Hz, 2H), 1.37 - 1.25 (m, 1H), 0.69 - 0.54 (m, 2H), 0.44 - 0.28 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 160.3, 152.5, 150.6 (2 x 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 x C), 109.9, 104.7, 73.4, 9.9, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 23 H 20 O3N5F2 + [M+H] + , 452.1529; found 452.1560.

[0391] Synthesis of compound G17 of example 93:

[0392] Synthesis step refer to example 7, last step amine reagent is chosen as 3-aminopentane (CAS number: 616-24-0), to get compound G17, yield: 44%; 1 H NMR (500 MHz, DMSO-d6) δ 8.86 (d, J = 4.5 Hz, 1H), 8.60 (s, 1H), 7.85-7.75 (m, 3H), 7.50 (d, J = 4.5 Hz, 1H), 7.42 (s, 1H), 7.29 (t, J = 74.5 Hz, 1H), 3.99 (d, J = 7.0 Hz, 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 = 7.5 Hz, 6H), 0.63-0.55 (m, 2H), 0.43-0.31 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 161.0, 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 x C), 10.3 (2 x C), 9.9, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 23 H 26 O3N4F2Na + [M+Na] + , 467.1865; found 467.1861.

[0393] Synthesis of compound G18 of example 94:

[0394] The synthesis was performed according to the procedure described in Example 7, using cyclohexylamine as the amine reagent in the last step, to give compound G18 in 48% yield; 1 H NMR (600 MHz, DMSO-d6) δ 8.86 (d, J = 4.8 Hz, 1H), 8.60 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 8.4, 2.4 Hz, 1H), 7.51 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 73.8 Hz, 1H), 3.99 (d, J = 7.2 Hz, 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), 0.44 - 0.29 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 160.1, 151.8, 149.5, 146.4, 146.3, 145.5, 142.1, 127.7, 122.8, 120.5, 116.5 (t, J = 258.8 Hz), 115.9, 109.2, 105.3, 73.4, 46.9, 32.7 (2 x C), 25.2 (2 x C), 24.3, 9.9, 3.1 (2 x C). HPLC: t R 3.26 min, purity 99.31%. ESI-HRMS m / z: [M+Na] calcd for C 24 H 26 O3N4F2Na + [M+Na] + , 479.1865; found 479.1847.

[0395] Example 95 Synthesis of compound G19:

[0396] The synthesis was performed according to the procedure described in Example 7, using cyclohexylamine as the amine reagent in the last step, to give compound G18 in 48% yield; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 8.15 (t, J = 6.0 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.51 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 74.0 Hz, 1H), 3.99 (d, J = 7.2 Hz, 2H), 3.23 (t, J = 6.4 Hz, 2H), 1.94 - 1.77 (m, 1H), 1.36 - 1.25 (m, 1H), 0.94 (d, J = 6.8 Hz, 6H), 0.63 - 0.56 (m, 2H), 0.40 - 0.33 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 161.1, 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 x C), 10.0, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 22 H 24 O3N4F2Na + [M+Na] + , 453.1709; found 453.1708.

[0397] Synthesis of compound G20 of example 96:

[0398] Synthesis procedure as in example 7, last step amine reagent was replaced by cyclopropylamine to give compound G20 in 47% yield; 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 8.15 (t, J = 6.0 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.51 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 74.0 Hz, 1H), 3.99 (d, J = 7.2 Hz, 2H), 3.23 (t, J = 6.4 Hz, 2H), 1.94 - 1.77 (m, 1H), 1.36 - 1.25 (m, 1H), 0.94 (d, J = 6.8 Hz, 6H), 0.63 - 0.56 (m, 2H), 0.40 - 0.33 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 162.5, 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 x C), 3.1 (2 x C). ESI-HRMS m / z: calcd for C 21 H 20 O3N4F2Na + [M+Na] + , 437.1396; found 437.1374.

[0399] Synthesis of compound G21 of example 97:

[0400] Synthesis steps are referred to example 7, the last step amine reagent is selected as neopentylamine (CAS number: 5813-64-9) to give compound G21 in 49% yield; 1 H NMR (500 MHz, DMSO-d6) δ 8.87 (d, J = 4.5 Hz, 1H), 8.61 (s, 1H), 8.17 (t, J = 6.5 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.5, 2.0 Hz, 1H), 7.51 (d, J = 4.5 Hz, 1H), 7.42 (d, J = 7.0 Hz, 1H), 7.19 (t, J = 74.0 Hz, 1H), 3.99 (d, J = 7.0 Hz, 2H), 3.23 (d, J = 6.0 Hz, 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-d6) δ 161.2, 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 x C), 9.9, 3.1 (2 x C). ESI-HRMS m / z: calcd for C 23 H 26 O3N4F2Na + [M+Na] + , 467.1865; found 467.1849.

[0401] Synthesis of compound H1 of example 98:

[0402] The synthesis was performed according to the procedure described in Example 8, using 3-methylphenylboronic acid as boronic acid reagent in the last step, to give compound H1 in 98% yield; 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (d, J = 2.4 Hz, 1H), 9.24 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 8.4, 2.0 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.21 (t, J = 74.4 Hz, 1H), 4.03 (d, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.35 - 1.28 (m, 1H), 0.65 - 0.57 (m, 2H), 0.45 - 0.37 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 164.2, 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 x C). ESI-HRMS m / z: calcd for C 23 H 21 F2N4O2 + [M+H] + , 423.1627; found 423.1638.

[0403] Synthesis of compound H2

[0404] The synthesis was performed according to the procedure described in Example 8, using 2-methylphenylboronic acid as boronic acid reagent in the last step, to give compound H2 in 19% yield; 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (d, J = 2.0 Hz, 1H), 8.93 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.86 (dd, J = 8.4, 2.0 Hz, 1H), 7.43 - 7.31 (m, 5H), 7.23 (t, J = 74.4 Hz, 1H), 4.03 (d, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.35 - 1.28 (m, 1H), 0.61 - 0.58 (m, 2H), 0.47 - 0.36 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 164.6, 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 x C). ESI-HRMS m / z: calcd for C 23 H 21 O2N4F2 + [M+H] + , 423.1627; found 423.1633.

[0405] Synthesis of compound H3 of example 100:

[0406] Synthetic procedure: Refer example 8, last step boronic acid reagent was chosen as 4-nitrophenylboronic acid to get compound H3 in 45% yield; 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.33 (s, 1H), 8.36 (d, J = 8.0 Hz, 2H), 8.17 (d, J = 8.0 Hz, 2H), 7.91 - 7.77 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 74.4 Hz, 1H), 4.02 (d, J = 6.8 Hz, 2H), 1.35 - 1.29 (m, 1H), 0.61 - 0.60 (m, 2H), 0.42 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 165.1, 155.6, 155.2, 150.5, 147.8, 142.2, 140.0, 135.7, 128.8 (2 x C), 128.6, 124.7 (2 x C), 122.3, 121.7, 120.0, 117.1, 112.7, 73.6, 10.5, 3.6 (2 x C). ESI-HRMS m / z: calcd for C 22 H 18 O4N5F2 + [M+H] + , 454.1321; found 454.1360.

[0407] Synthesis of compound H4 of example 101:

[0408] Synthetic procedure: Refer example 8, last step boronic acid reagent was chosen as 1-methyl-indazole-6-boronic acid (CAS number: 1150114-80-9) to get compound H4 in 31% yield; 1H NMR (400 MHz, DMSO-d6) δ 9.87 (d, J = 2.4 Hz, 1H), 9.40 (d, J = 2.4 Hz, 1H), 8.23 (s, 1H), 8.13 - 8.10 (m, 1H), 7.95 - 7.88 (m, 2H), 7.85 (dd, J = 8.0, 2.0 Hz, 1H), 7.64 (d, J = 9.8 Hz, 1H), 7.36 (s, 1H), 7.40 - 7.01 (m, 1H), 4.14 (s, 3H), 4.04 (d, J = 7.0 Hz, 2H), 1.35 - 1.29 (m, 1H), 0.66 - 0.57 (m, 2H), 0.47 - 0.36 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.7, 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 x C). ESI-MS m / z: Calcd for C 24 H 21 F2N6O2 + [M+H] + , 463.2; Found 463.2.

[0409] Synthesis of compound H5 of example 102:

[0410] Synthesis steps are referred to example 8, the last step boronic acid reagent is chosen as benzothiophene-2-boronic acid (CAS Number: 98437-23-1) to give compound H5 in yield: 17%; 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (d, J = 2.4 Hz, 1H), 9.40 (d, J = 2.4 Hz, 1H), 8.23 (s, 1H), 8.13 - 8.10 (m, 1H), 7.95 - 7.88 (m, 2H), 7.85 (dd, J = 8.0, 2.0 Hz, 1H), 7.64 (d, J = 9.8 Hz, 1H), 7.36 (s, 1H), 7.40 - 7.01 (m, 1H), 4.14 (s, 3H), 4.04 (d, J = 7.0 Hz, 2H), 1.35 - 1.29 (m, 1H), 0.66 - 0.57 (m, 2H), 0.47 - 0.36 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 164.5, 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 x C). ESI-HRMS m / z: calcd for C 24 H 19 O2N4F2S + [M+H] + 465.1191; found 465.1201.

[0411] Synthesis of compound H6 of example 103:

[0412] Synthesis step refer to example 8, last step boronic acid reagent is chosen 1-methylindole-5-boronic acid (CAS number: 192182-55-1), to obtain compound H6, yield: 45%; 1 H NMR (400 MHz, DMSO-d6) δ 9.70 (d, J = 2.4 Hz, 1H), 9.28 (d, J = 2.4 Hz, 1H), 8.09 - 8.01 (m, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 8.4, 2.0 Hz, 1H), 7.68 - 7.57 (m, 2H), 7.42 (d, J = 2.8 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.21 (t, J = 74.4 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 4.03 (d, J = 6.8 Hz, 2H), 3.84 (s, 3H), 1.33 - 1.31 (m, 1H), 0.66 - 0.56 (m, 2H), 0.47 - 0.36 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.0, 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 x C). ESI-HRMS m / z: calcd for C 25 H 22 O2N5F2 + [M+H] +, 462.1736; found 462.1740.

[0413] Synthesis of compound J1 of example 104:

[0414] The synthetic procedure was referenced to example 9, the acid reagent was chosen as 6-bromonicotinic acid for the last step, to give compound J1 in 39% yield; 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 2.4 Hz, 1H), 8.42 (dd, J = 8.4, 2.4 Hz, 1H), 7.96 - 7.85 (m, 3H), 7.58 (s, 1H), 7.55 (dd, J = 6.8, 1.6 Hz, 1H), 7.26 (d, J = 6.8 Hz, 1H), 7.16 (t, J = 74.4 Hz, 1H), 3.94 (d, J = 6.8 Hz, 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-d6) δ 165.6, 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 x C). ESI-MS m / z: Calcd for C 19 H 16 O3N5BrF2 + [M+H] + , 502.0; found 502.0.

[0415] Synthesis of compound J2 of example 105:

[0416] The synthetic procedure was referenced to example 9, the acid reagent was chosen as 4-oxazolecarboxylic acid (CAS number: 23012-13-7) for the last step, to give compound J2 in 19% yield; 1 H NMR (600 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.66 (s, 1H), 7.89 (s, 2H), 7.76 (dd, J = 8.4, 1.2 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 74.4 Hz, 1H), 4.00 (d, J = 6.6 Hz, 2H), 1.31 - 1.23 (m, 1H), 0.63 - 0.54 (m, 2H), 0.43 - 0.32 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 159.5, 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 x C). ESI-MS m / z: calcd for C 17 H 16 O4N5F2 + [M+H] + , 392.1; found 392.1.

[0417] Synthesis of compound J3 of example 106:

[0418] The synthesis steps were referenced to example 9, the acid reagent was chosen as 2-methyl-4-thiazolecarboxylic acid (CAS Number: 35272-15-2) for the last step, to give compound J3 in 17% yield; 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 7.87 (s, 2H), 7.69 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 7.6 Hz, 1H), 7.17 (t, J = 74.0 Hz, 1H), 3.98 (d, J = 6.0 Hz, 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-d6) δ 166.1, 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 x C). ESI-MS m / z: calcd for C 23 H 20 O3N5F2S + [M+H] + , 422.1; found 422.1.

[0419] Synthesis of compound J4 of example 107:

[0420] The synthesis steps were referenced to example 9, the acid reagent was chosen as 1-methyl-1H-imidazole-5-carboxylic acid (CAS Number: 41806-40-0) for the last step, to give compound J4 in 38% yield; 1H NMR (600 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.08 (s, 1H), 7.79 (s, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.30-7.26 (m, 1H), 7.10 (t, J = 74.4 Hz, 1H), 3.97 (d, J = 6.6 Hz, 2H), 3.94 (s, 3H), 1.31-1.20 (m, 1H), 0.64-0.55 (m, 2H), 0.45-0.33 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 159.0, 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 x C). ESI-MS m / z: Calcd for C 18 H 19 O3N6F2 + [M+H] + , 405.1; found 405.1.

[0421] Synthesis of compound J5 of example 108:

[0422] Synthesis procedure as in example 9, with the last step acid reagent selected as 8- isoquinolinecarboxylic acid (CAS Number: 61563-43-7) to give compound J5 in 30% yield; 1 H NMR (500 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.57 (d, J = 6.0 Hz, 1H), 8.40 (d, J = 8.5 Hz, 1H), 8.28 (d, J = 7.0 Hz, 1H), 7.99 (s, 2H), 7.86-7.82 (m, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 8.5, 2.0 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.10 (t, J = 74.0 Hz, 1H), 3.84 (d, J = 6.5 Hz, 2H), 1.24-1.11 (m, 1H), 0.59-0.49 (m, 2H), 0.35-0.24 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 167.3, 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 x C). ESI-HRMS m / z: calcd for C 23 H 19 O3N5F2 + [M+H] + 452.1529; found 452.1504.

[0423] Synthesis of compound J6 of example 109:

[0424] Synthesis steps are referred to example 9, the last step acid reagent is chosen quinoline-4-carboxylic acid (CAS Number: 486-74-8), to give compound J6 in 27% yield; 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.06 (s, 2H), 7.97 - 7.79 (m, 3H), 7.67 (t, J = 7.6 Hz, 1H), 7.41 (s, 1H), 7.27 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 74.0 Hz, 1H), 3.82 (d, J = 6.8 Hz, 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-d6) δ 167.2, 160.3 - 159.9 (m), 158.9, 150.5, 149.8, 148.2, 141.7, 139.1, 130.6, 130.0, 128.4 (2 x C), 125.5, 123.8, 121.5, 121.0, 119.5, 117.0, 112.6, 73.4, 10.4, 3.5 (2 x C). ESI-HRMS m / z: calcd for C 23 H 20 O3N5F2 + [M+H] + 452.1529; found 452.1528.

[0425] Active examples

[0426] Activity Example 1 Test experiment for the PDE4 (PDE4B1, PDE4D2) enzyme inhibitory activity of the compounds of the present application

[0427] The compounds of the present application were biologically tested by the following method:

[0428] 1. Preparation of reaction buffer and reaction termination buffer (reagents see Table 1)

[0429] (1) Preparation of 1-fold reaction buffer

[0430] IMAP reaction buffer containing 0.1% BSA (5x) (provided by IMAP FP IPP Explorer Kit) was diluted to 1-fold reaction buffer containing 1 mM DTT.

[0431] (2) Preparation of reaction termination buffer

[0432] IMAP Progressive Binding Buffer A (5x), IMAP Progressive Binding Buffer B (5x), and IMAP Progressive Binding Reagent (provided by IMAP FP IPP Explorer Kit) were prepared according to the instructions to prepare the reaction termination buffer.

[0433] 2. Preparation of compounds

[0434] (1) Dilution of compounds

[0435] Prepare a solution of the compound at a final concentration of 100 times the concentration to be tested. Dilute the compound in gradient using an automated microplate pipette (Precision PRC384U) to the number of concentration points set, as follows: if diluting 5 times, add 50 μL of the starting concentration of the compound in DMSO to well A2 in an 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 to well A3, mix, and sequentially dilute 5 times to give 10 concentration points; add 40 μL of 100% DMSO to wells Al and A12.

[0436] (2) Transfer of compounds to 384 reaction plates

[0437] Transfer 200 nL of the compound from the diluted Echo 384-well plate described above to a 384-well reaction plate using an Echo 550 instrument, and transfer 200 nL of 100% DMSO to the negative and positive controls.

[0438] 3. Enzymatic reaction

[0439] (1) Prepare 2X enzyme solution

[0440] Add PDE4B1 to 1X reaction buffer to make 2X enzyme solution (PDE4B1 final concentration: 0.00625 μg / ml).

[0441] (2) Prepare 2X substrate solution

[0442] For enzyme PDE4B1, add FAM-labeled cAMP to 1X reaction buffer to make 2X substrate solution (FAM-cAMP final concentration: 0.1 μM).

[0443] (3) Add enzyme solution to 384-well plate

[0444] Add 10 μL of 2X enzyme solution to each well of the 384-well reaction plate. For enzyme activity control wells, replace enzyme solution with 10 μL of 1X reaction buffer. Centrifuge at 1000 rpm for 1 min and incubate at room temperature for 15 min.

[0445] (4) Add substrate solution to 384-well plate to start enzymatic reaction

[0446] Add 10 μL of 2X substrate solution to each well of the 384-well reaction plate. Centrifuge at 1000 rpm for 1 min. Incubate at 25°C for 30 min.

[0447] (5) Stop enzyme reaction

[0448] Add 60 μL of reaction stop solution to each well of the 384-well reaction plate to stop the reaction and incubate at room temperature with shaking at 600 rpm for 60 min in the dark.

[0449] 4. Read data with EnVision and calculate data

[0450] Read data with EnVision.

[0451] 5. Calculate inhibition and IC 50 Curve fitting

[0452] Copy data from EnVision, where the maximum value is the reading for the DMSO control and the minimum value is the reading for the enzyme activity control. Inhibition (%) = (maximum value - sample value) / (maximum value - minimum value) x 100%.

[0453] Import data into MS Excel and fit IC values with XLFit excel add-in version 5.4.0.8 50 ;

[0454] Fitting equation: Y = Bottom + (Top - Bottom) / (1 + (IC50 Slope)

[0455] For the detection of PDE4D2, refer to PDE4B1.

[0456] Table 1 Reagent information

[0457] The determination of the inhibitory effect of the compounds of the present application on PDE4 (PDE4B1, PDE4D2) enzymes was carried out according to the above method, and the results are shown in Table 2 and Table 3.

[0458] Table 2 Determination results of the inhibitory effect of the compounds of the present application on PDE4B1 enzyme

[0459] Table 3 Determination results of the inhibitory effect of the compounds of the present application on PDE4D2 enzyme

[0460] IC50values of the active Example 2 compounds on PDE4B1 and PDE4D2 50 detection

[0461] The determination was carried out according to the procedure of active Example 1 to obtain the IC 50 values.

[0462] The IC 50 values of the compounds are shown in Table 4.

[0463] Table 4 IC 50 values of the compounds of the present application

[0464] Active Example 3 Inhibition of inflammation of Raw 264.7 cells and Beas-2B cells by the compounds of the present application

[0465] The compounds of the present application were subjected to an inhibition test of the expression level of cell inflammatory factors by using a conventional ELISA method.

[0466] 1. Cell culture

[0467] The mouse monocyte macrophage Raw 264.7 cells and Beas-2B cells were cultured in DMEM high-sugar medium added with 10% (V / V) FBS, 100 U / mL penicillin and 100 μg / mL streptomycin. The culture condition was 37°C, 5% CO2, and the cells were subcultured when they reached 80% confluence.

[0468] 2. Cell administration and induction of cell inflammation

[0469] The cells in the logarithmic growth phase were used for the experiment, and the cells were seeded at a density of 2 x 10 5 / wells were seeded in 12-well plates and cultured at 37°C and 5% CO2 until 70% growth was achieved. Groups were set up: blank group, LPS-stimulated group, positive control group (roflumilast), and drug-treated group (the compound of this application). The culture medium was carefully removed. For the positive control and drug-treated groups, fresh complete culture medium containing the compound was added; for the blank group and LPS-stimulated group, an equal volume of DMSO was added. After 1 hour, except for the blank group, 1 μg / mL LPS was added to each well for 4 hours to induce cell inflammation. The plates were then removed, and ELISA experiments were performed according to the kit instructions.

[0470] Collect the culture medium supernatant: Collect the supernatant into a 1.5 mL EP tube, centrifuge at 1000 rpm for 10 minutes, and use the supernatant for ELISA detection of cytokines.

[0471] The secretion of IL-6, TNF-α, and IL-1β was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The procedure was performed according to the kit's instructions, as follows:

[0472] (1) Reagent preparation

[0473] ① Remove from the refrigerator and allow to equilibrate to room temperature for 20 minutes. ② Dilute the washing buffer (20X) with double-distilled water to 1X to prepare the required washing buffer. ③ Add the standard diluent to one bottle of standard according to the volume indicated on the standard label and incubate at room temperature for 15 minutes. ④ Take five clean 1.5mL centrifuge tubes, pre-add 250μL of standard diluent to each tube, and perform serial dilutions of the standard to obtain a total of six standard concentrations. Finally, add the diluted standards sequentially to the wells of the pre-coated plate, adding the standard diluent directly as the 0 pg / mL concentration; a total of seven standard concentrations are obtained.

[0474] (2) Operation steps

[0475] ①. Calculate the number of pre-coated strips required for one experiment, and take out the required strips and place them in a 96-well frame.

[0476] ②. Add the sample or standard of different concentrations to the corresponding well at a rate of 100 μL / well, seal the reaction well with a sealing film (transparent), and incubate at room temperature for 120 minutes.

[0477] ③. Wash the board 5 times, and pat it dry on thick absorbent paper on the last wash.

[0478] ④. Add 100 μL of biotinylated antibody to each well, seal the wells with a clear sealing film, and incubate at room temperature for 60 minutes.

[0479] ⑤. Wash the board 5 times, and on the last wash, place it on thick absorbent paper and pat it dry.

[0480] 6. Add 100 μL / well of horseradish peroxidase labeled Streptavidin, cover the wells with sealing membrane (white), and incubate at room temperature for 20 minutes.

[0481] 7. Wash the plate 5 times, and the last time, tap dry on thick absorbent paper.

[0482] 8. Add 100 μL / well of color developing agent TMB solution, cover the wells with sealing membrane (white), and incubate at room temperature for 20 minutes.

[0483] 9. Add 50 μL / well of stop solution, mix well, and immediately measure A450 value.

[0484] The test results are shown in Figure 1.

[0485] As shown in Figure 1A, compounds A5, A15, A23, A25, A26 and A28 down-regulate the expression of IL-6 and TNF-α in Raw264.7 cells, and compounds A5, A15, A23 and A28 down-regulate the expression of IL-1β in Raw264.7 cells; in Figure 1B, compound A5 significantly down-regulates the expression of IL-6 and TNF-α in Beas-2B cells; and as shown in Figure 1C, the IC 50 were 30.06 ± 5.553 μM and 29.49 ± 6.279 μM.

[0486] Metabolic stability experiment of 2-(3-(cyclopropylmethoxy)-4- (difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (compound A5) in vitro in liver microsomes and evaluation of its effect on cardiac ion channels (hERG experiment).

[0487] 0.5 μM of compound A5 was incubated with liver microsomes (1 mg / mL) at 37°C. 100 μL of reaction solution was taken at 0, 5, 15, 30, 45 and 60 minutes, respectively. 200 μL of acetonitrile containing internal standard was added to 100 μL of reaction solution to extract the test compound. The resulting mixture was centrifuged, and the supernatant was analyzed by LC-MS / MS. The results are shown in Table 5, which shows that the half-life of compound A5 in human liver microsomes is 421.75 minutes, and the IC 50 More than 30 μM, indicating that compound A5 has essentially no cardiotoxicity.

[0488] Table 5. Results of in vitro liver microsomal metabolic stability and hERG experiments for Compound A5

[0489] 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)

[0490] Caco-2 monolayer analysis was performed for Compound A5. Transport of Compound A5 from apical to basolateral (A-B) and in the opposite direction (B-A) was measured simultaneously under the same conditions. Propranolol and nadolol were used as high and low permeability 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 pH 6.8, basolateral pH 7.4). Incubation was performed at 37 °C for 95 min. Samples were collected from the donor side at 5 min and 95 min, and from the acceptor side at 35 min and 95 min after incubation. Concentrations of samples were determined using liquid chromatography-mass spectrometry (LC-MS) / mass spectrometry. Mean values are the average of three independent experiments, each performed in triplicate.

[0491] Results are shown in Table 6.

[0492] Table 6. Results of in vitro Caco-2 permeability assay of Compound A5

[0493] In vivo pharmacokinetic experiment of 2-(3-(cyclopropylmethoxy)-4- (difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound A5)

[0494] SPF level SD rats, 15 male, were used. The designed gavage dose of compound A5 was 10 mg / kg, and the designed intravenous injection dose of compound A5 was 5 mg / kg. The blood samples of the gavage group were collected at 0 min before administration and 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after administration, and the blood samples of the intravenous group were collected at 0 min before administration 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 plexus or the jugular plexus into a pre-labeled heparinized blood collection tube each time. The blood samples were temporarily stored in an ice box, and then centrifuged at 4500 rpm for 10 min to separate the plasma, which was used to determine the concentration of each drug in the plasma by the established LC-MS method. The blood concentration data were processed by DAS 3.3.0, and the main pharmacokinetic parameters were calculated by using a non-compartment model.

[0495] The results are shown in Table 7.

[0496] Table 7 Pharmacokinetic data of compound A5 in SD rats

[0497] Study on the effect of active example 7 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 against psoriasis

[0498] I. Purpose of the experiment

[0499] To investigate the therapeutic effect of compound A5 on imiquimod-induced psoriasis in mice.

[0500] II. Experimental materials

[0501] Experimental animals: 56 Balb / c male mice, 6-8 weeks old, weighing about 18-22 g.

[0502] Experimental instruments: heating stirrer, paraffin microtome, microscope, syringe, microplate reader, balance, oven, refrigerated centrifuge, etc.

[0503] Experimental reagents: HE staining related reagents, PBS solution, etc., imiquimod, ELISA kit for IL-1β, IL-17A and TNF-α.

[0504] III. Animal experiment

[0505] 1. Establishment of mouse psoriasis model and administration

[0506] ① The back of the mouse 2 cm x 3 cm area, three days before modeling to shave. Observe the shaving effect, and the hair and the new hair that grows out of the shaving.

[0507] ② The mice were randomly divided into 7 groups: blank group, model group (5% IMQ 62.5mg / d, for 9 consecutive days), compound group (0.3%, 0.6%, 1.2%), positive control group (Roflumilast, 0.3%), auxiliary material group (only apply cream auxiliary material formula), 8 in each group, a total of 56.

[0508] Blank group: from the first day of psoriasis modeling, do not do anything to the mice.

[0509] Model group: from the first day, apply 62.5mg 5% IMQ to the back of the mouse bare skin every day, establish a psoriasis model, and apply for 9 consecutive days.

[0510] Positive control group: from the first day of psoriasis modeling, apply 62.5mg 5% IMQ to the back of the mouse bare skin every day, from the third day, apply 62.5mg 5% IMQ to the back of the mouse bare skin every morning, 4h later, apply 62.5mg Roflumilast cream (0.3%) to each mouse, for 7 consecutive days.

[0511] Compound group (0.3%, 0.6%, 1.2%): from the first day of psoriasis modeling, apply 62.5mg 5% IMQ to the back of the mouse bare skin every day, from the third day, apply 62.5mg 5% IMQ to the back of the mouse bare skin every morning, 4h later, apply low, medium and high dose compound cream to each group of mice for treatment, for 7 consecutive days.

[0512] Auxiliary material group: from the first day of psoriasis modeling, apply 62.5mg of the prepared cream to the back of the mouse bare skin every day, for 7 consecutive days.

[0513] 2. Scoring of psoriasis area and severity index (PASI) and phenotype observation of mice

[0514] 2.1 Scoring of mice PASI

[0515] The degree of scaling, the size of erythema, and the degree of skin thickening of the back skin of the mice were observed by naked eyes, and the PASI score was processed. The PASI score rule: select the erythema, scaling, and thickening degree to evaluate the severity of psoriasis. After scoring, photographing and recording were performed as shown in Figure 2. The model group showed obvious psoriasis characteristics, while the scaling, thickness and erythema of the administration group were significantly reduced, that is, the application of compound A5 can significantly alleviate the symptoms of psoriasis. The body weight of the mice was weighed every day, and the body weight change of the mice was observed, as shown in Figure 3. The body weight of the mice did not change significantly after continuous weighing for 10 days, indicating that compound A5 had no obvious toxicity to the mice.

[0516] 2.2 Mouse sacrifice and sample collection

[0517] Euthanasia treatment was performed by intraperitoneal injection of an overdose of 0.3% sodium pentobarbital solution.

[0518] 2.3 Paraffin embedding and sectioning of skin tissue

[0519] 1) Cut the full-thickness skin parallel to the vertebral line and place it in 10% neutral formaldehyde solution for fixation for more than 24 h.

[0520] 2) Place the trimmed tissue block in the embedding box and wash with running water for 24 h to completely remove residual formaldehyde.

[0521] 3) Dehydrate the tissue with alcohol gradient, specific steps: 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.

[0522] 4) After dehydration, place the tissue in an alcohol / dichloromethane (1:1, v / v) solution for 20 min.

[0523] 5) Place the tissue in dichloromethane I for 20 min and then in dichloromethane II for 10 min.

[0524] 6) Place the tissue in preheated melted paraffin I and paraffin II at 60-65°C for 1 h each.

[0525] 7) Pour a small amount of embedding paraffin into a preheated metal embedding frame, place the skin tissue block in it vertically, and place it flat at the bottom. Pour the paraffin again to embed the tissue, and cool it.

[0526] 8) Paraffin sectioning: Fix the tissue paraffin block on a Leica microtome, section thickness is 5 μM, continuous sectioning. Place the section in 40°C water with a toothless forceps for expansion, then use a glass slide to fish the section, and after 2 h of 60°C baking, store it in a section box at room temperature for future use.

[0527] 2.4 HE staining

[0528] 1) Dewaxing and hydration: put the skin tissue paraffin section into xylene I and xylene II for 15 min, then into 100% ethanol I and ethanol II for 3 min, 95% ethanol I and ethanol II for 3 min, 80% ethanol for 3 min, and distilled water for 1 min, respectively.

[0529] 2) Stain with hematoxylin for 15 min, wash with water, and load the slide with excess dye;

[0530] 3) Stain with 1% hydrochloric acid ethanol (99 mL 70% ethanol + 1 mL concentrated hydrochloric acid) for 3 s, and observe the nucleus and chromatin under a microscope;

[0531] 4) Rinse with running water for 15 min, and distilled water for 1 min;

[0532] 5) Stain with eosin for 2 min, and rinse with running water for 1 min;

[0533] 6) Dehydrate with 80% and 100% ethanol for 2 s and 7 min, respectively;

[0534] 7) Xylene I and II for 5 min, respectively;

[0535] 8) Mounting: take the slide out of xylene II, add neutral gum at the tissue, cover the slide with a cover glass, and dry naturally;

[0536] 9) Observation: observe the pathological changes under a microscope, take photos, and analyze.

[0537] As shown in FIG. 4, the skin thickness of the model group is thickened, and a large number of inflammatory cells infiltrate. The inflammatory cells of the administration group (compound A5) are significantly reduced, and the skin thickness is reduced, indicating that the administration group protects the skin and has a dose-dependent effect.

[0538] 2.5 Ki-67 antibody immunohistochemical staining

[0539] 1) Put the skin tissue paraffin section in an oven, and bake the section at 60°C for 1 h.

[0540] 2) Dewaxing: xylene for 10 min three times, anhydrous ethanol I for 5 min, anhydrous ethanol II for 5 min, 95% ethanol for 5 min, 85% ethanol for 5 min, 75% ethanol for 5 min, and ddH2O for 5 min.

[0541] 3) Antigen repair: boil 400 mL of antigen repair solution (800 mL dd H2O + 3 g sodium citrate + 400 mg citric acid, and then make up to 1000 mL) in advance, put the section in a beaker and boil for 20 min, and then cool the section and wash the section with PBS three times for 3 min each time.

[0542] 4) Add 3% hydrogen peroxide dropwise, incubate at room temperature for 5 min, wash the section with PBS for 3 times, 3 min each time.

[0543] 5) Remove PBS, add 10% goat serum blocking solution dropwise, incubate at room temperature for 1 h.

[0544] 6) Remove goat serum, directly add primary antibody after spinning dry, incubate in a wet box at 4°C overnight (about 14 h).

[0545] 7) Take out the section, rewarm for 30 min, wash with PBS for 3 times, 3 min each time.

[0546] 8) Remove PBS, add secondary antibody for immunohistochemistry dropwise to each sample, incubate at room temperature for 15 min, wash with PBS for 3 times, 3 min each time.

[0547] 9) Spin dry the section, immediately place it on a microscope, add DAB staining dropwise, wash with PBS for 5 min after color development.

[0548] 10) Hematoxylin counterstain for 40 s → wash with running water for 2 min → return to blue for 7 s → wash with running water for 10-15 min → soak with dd H2O for 5 min.

[0549] 11) 95% ethanol (1 min) → anhydrous ethanol I (1 min) → anhydrous ethanol II (1 min) → xylene (1 min) → xylene (1 min) → xylene (1 min) neutral resin mounting.

[0550] The results are shown in Figure 5, which shows that the expression amount of Ki-67 antibody in the model group is significantly increased, while the expression amount in the administration group (compound A5) is significantly reduced, and the compound has a significant inhibitory effect on skin thickening.

[0551] Four, expression of pro-inflammatory cytokines in the skin of psoriasis mice after different treatments

[0552] ① Protein levels of IL-1β, IL-17A and TNF-α in skin lesion tissues

[0553] 1) Take 100 mg of lesion skin into an ep tube, add 1 mL of normal saline, and use a pre-cooled tissue grinder to grind.

[0554] 2) Centrifuge at 3500 rpm and 12000 rpm at 4°C for once, take the supernatant, determine the protein concentration in the skin tissue grinding solution by BCA method, and determine the contents of IL-1β, IL-17A and TNF-α by ELISA kit, according to the instructions of the kit.

[0555] The results are shown in Figure 6. 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.

[0556] Study on the therapeutic effect of 2-(3-(cyclopropylmethoxy)-4- (difluoromethoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (compound A5) on chronic obstructive pulmonary disease in mice

[0557] I. Purpose of the experiment

[0558] To investigate the therapeutic effect of compound A5 on chronic obstructive pulmonary disease (COPD) induced by lipopolysaccharide combined with smoking in mice.

[0559] II. Experimental materials

[0560] Experimental animals: 48 C57BL / 6 male mice, 6-8 weeks old, weighing about 18-22g.

[0561] Experimental instruments: heating stirrer, whole-body exposure smoke box, paraffin sectioning machine, microscope, syringe, enzyme label instrument, balance, oven, refrigerated centrifuge, etc.

[0562] Experimental reagents: HE staining related reagents, PBS solution, lipopolysaccharide, and ELISA kit.

[0563] III. Animal experiment

[0564] 1. Establishment of mouse model of chronic obstructive pulmonary disease

[0565] The normal group mice were placed in IVC cages for feeding, and the smoke group mice were subjected to smoke test. The smoke steps were as follows: the mice were placed in the smoke box, the cigarette was inserted into the middle of the smoke box and lit, and the smoke box was closed. The initial smoke condition was 5 cigarettes / h, 2h each time (20min ventilation every 1h), 2 times a day, once in the morning and once in the afternoon, with an interval of 4h, 6 days / week. The number of cigarettes was increased sequentially within the first 2 weeks (to give the smoke mice an adaptation period to avoid excessive smoke causing mouse death) until the number of cigarettes increased to 12 / h, and this condition was maintained until the 147th day (21 weeks). The smoke group mice were intratracheally instilled with LPS on the 1st and 14th day of modeling, with a dose of 75μg / 20g, and the normal group mice were instilled with the same amount of normal saline. In addition to the smoke time, the mice were exposed to SPF animal room for feeding.

[0566] 2. Group administration

[0567] Blank group mice: normal + vehicle group;

[0568] Smoke group mice: randomly divided into 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), model + Roflumilast (Rof) control group (5 mg / kg), 8 mice in each group. After smoking for 17 weeks, drug administration was started, and intragastric administration was performed once a day for 4 consecutive weeks.

[0569] Drug solution preparation: 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, then dissolve compound A5 in the 0.5% CMC-Na solution, and use an ultrasonic disruptor to break it into a suspension, and store at 4°C.

[0570] 3. Evaluation of drug efficacy by detection index

[0571] (1) Observation: observe the activity, hair, food intake, respiration, body weight, etc. of rats in each group. Weigh the rats 1 hour before feeding every week to observe the changes in body weight. According to Figure 7, the body weight of the model group is significantly lower than that of the blank group, and the body weight of the drug administration group has a certain rebound after administration, indicating that the drug is relatively safe.

[0572] (2) Lung function evaluation:

[0573] Use the experimental animal lung function tester to test the lung function of mice, and the main indicators include functional residual capacity (FRC), forced expiratory volume at 50 ms / forced vital capacity (FEV50 / FVC), forced expiratory volume at 20 ms / forced vital capacity (FEV20 / FVC), etc.

[0574] As can be seen from Figure 8, the functional residual capacity FRC of the model group is significantly higher than that of the blank group, indicating that there may be airway closure in the alveoli, which is one of the key symptoms of chronic obstructive pulmonary disease. 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 effect on relieving the increase in FRC; FEV50 / FVC and FEV20 / FVC are lower than those of the blank group, indicating that the forced expiratory volume / forced vital capacity of the mice is low, reflecting the degree of airway obstruction. After administration, FEV50 / FVC has a certain relieving effect, indicating that compound A5 has the effect of relieving chronic obstructive pulmonary disease.

[0575] (3) Pathological evaluation:

[0576] Paraffin section

[0577] ①After the mice were anesthetized by intraperitoneal injection of an overdose of sodium pentobarbital, the chest was opened to expose the thoracic cavity: the left lung lobe was taken and fixed in an embedding box containing 10% formaldehyde solution for 24 h, and then washed with running water for 24 h to completely remove residual formaldehyde;

[0578] ②The tissue was subjected to alcohol gradient dehydration, and the specific steps were as follows: 70% alcohol overnight, 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;

[0579] ③After dehydration, the tissue was placed in an alcohol / dimethylbenzene (1:1, v / v) solution for 20 min;

[0580] ④The tissue was subjected to dimethylbenzene transparency I and II for 20 min and 10 min, respectively;

[0581] ⑤The tissue was placed in preheated melted paraffin I, paraffin II, and embedding paraffin in an oven at 60-65°C for 1 h each.

[0582] ⑥A small amount of embedding paraffin was poured into a preheated metal embedding frame, and the tissue was placed in a vertical direction with the embedding frame. Then, the tissue was embedded by pouring paraffin again, and cooled to obtain the embedded tissue;

[0583] ⑦Paraffin sectioning: the tissue paraffin block was fixed on a Leica microtome, and the section thickness was 5 μm. The section was placed in 40°C water for 15 min, and then taken out with a toothless forceps. After the section was placed on a glass slide, the slide was baked at 60°C for 2 h, and then stored in a section box at room temperature for use.

[0584] HE staining

[0585] ①Deparaffinization and hydration: the tissue paraffin section was placed in dimethylbenzene I and II for 15 min each, and then placed in 100% ethanol I and II for 3 min each, 95% ethanol I and II for 3 min each, 80% ethanol for 3 min, and distilled water for 1 min;

[0586] ②The section was dyed with hematoxylin for 15 min, and then washed with water to remove excess dye on the glass slide;

[0587] ③The section was differentiated with 1% hydrochloric acid ethanol (99 mL 70% ethanol + 1 mL concentrated hydrochloric acid) for 3 s. Under a microscope, the cell nucleus and chromatin were observed to be clear;

[0588] ④The section was washed with running water for 15 min to return to blue, and then washed with distilled water for 1 min;

[0589] ⑤The section was treated with eosin for 2 min, and then washed with running water for 1 min;

[0590] ⑥The section was dehydrated with 80% ethanol and 100% ethanol for 2 s and 7 min, respectively;

[0591] ⑦Dehydrate: treat each slide with xylene and xylene II for 5 min each.

[0592] ⑧Mounting: remove the slide from xylene II, add neutral balsam at the tissue, cover with a cover glass, and dry naturally.

[0593] ⑨Observation: observe the pathological changes under a microscope, take photos, and analyze.

[0594] Microscopic observation (see Figure 9) found that the lung tissue of the blank control group had complete alveolar structure and no inflammatory cell infiltration. The model group mice had alveolar wall rupture, irregularly enlarged and fused alveoli, formed lung bullae, significantly thickened airway wall, and different degrees of inflammatory cell infiltration in the lung interstitium, and dust cells formed by smoke dust particles were visible in the alveolar cavity. It is consistent with the pathological changes of COPD mouse lung tissue. The alveolar wall of the drug group mice partially fused into lung bullae, the tracheal wall was slightly thickened, and inflammatory cells infiltrated in the lung, but the trend was reduced compared with the model group, indicating that the drug had the effect of alleviating chronic obstructive pulmonary disease.

[0595] (4) Total number of inflammatory cells and expression levels of inflammatory factors IL-8 (CXCL1 / KC / N51), TNF-α, and MMP9 in the bronchoalveolar lavage fluid

[0596] ①Total number of cells in the mouse bronchoalveolar lavage (BALF) sample.

[0597] ②Centrifuge at 1000 rpm for 5 min at 4°C, take the supernatant, determine the protein concentration in the BALF by the BCA method, determine the contents of IL-8 (CXCL1 / KC / N51), TNF-α, and MMP9 by the ELISA kit, and operate according to the instructions of the kit.

[0598] The results are shown in Figure 10. Different concentrations of A5 drug have inhibitory effects on the total number of inflammatory cells and inflammatory factors IL-8 (CXCL1 / KC / N51), TNF-α, and MMP9 in the bronchoalveolar lavage fluid, indicating that compound A5 has a therapeutic effect on chronic obstructive pulmonary disease-related lung inflammation.

[0599] Study on the effect of active example 9 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 acute lung injury in mice

[0600] I. Purpose of the experiment

[0601] To investigate the therapeutic effect of compound A5 on the acute lung injury model (ALI) induced by lipopolysaccharide in mice.

[0602] II. Experimental materials

[0603] Experimental animals: 36 Balb / c male mice, 4-6 weeks old, weighing about 18-22g.

[0604] Experimental instruments: heating stirrer, paraffin sectioning machine, microscope, syringe, enzyme label instrument, balance, oven, low temperature centrifuge, etc.

[0605] Experimental reagents: HE staining related reagents, PBS solution, lipopolysaccharide, ELISA kit, etc.

[0606] III. Animal experiment

[0607] 1. Establishment of acute lung injury model in mice and drug administration

[0608] Blank control group, model group (10mg / kg LPS), Roflumilast (Rof) positive drug group (4mg / kg), compound A5 group (8, 16, 32mg / kg), once a day by gavage, 6 mice in each group, modeling after 7 days of gavage administration.

[0609] Drug solution preparation method: dissolve carboxymethylcellulose sodium CMC-Na in pure water to prepare a 0.5% solution, heat and stir until completely dissolved, cool to room temperature, then dissolve compound A5 in the 0.5% CMC-Na solution, break into suspension with ultrasonic disrupter, store at 4℃.

[0610] Modeling: 1h after the last day of drug administration, the mice were anesthetized with 0.3% sodium pentobarbital solution, and each mouse was given 50μL LPS (10mg / kg) through the trachea, instilled for 24h, then euthanized and took the lung alveolar lavage fluid. Dissect the mouse and fix the lung tissue for embedding.

[0611] 2. Evaluation of drug efficacy by detecting indicators

[0612] (1) Total number of inflammatory cells in alveolar lavage fluid (BALF)

[0613] After euthanasia, open the chest, ligate the left lung, bluntly dissect the tissue around the trachea with forceps, expose the trachea, cut a small hole on the trachea with scissors, cut off the needle tip of a 1 mL syringe and polish it smooth, put the polished syringe needle into the trachea to the carina, pass a thread from under the trachea, and ligate the needle and the trachea to fix the needle, slowly inject 0.6 mL of sterile normal saline, and then recover the lavage fluid after repeated flushing. Combine the two lavage fluids, and the combined fluid is the bronchoalveolar lavage fluid. Centrifuge the collected BALF at 1000 rpm for 5 min at 4°C, and then transfer the supernatant to another centrifuge tube and store it at -20°C.

[0614] (2) Total number of inflammatory cells and expression levels of inflammatory factors IL-6, IL-1β and TNF-α in the bronchoalveolar lavage fluid

[0615] ① The total number of cells in the mouse bronchoalveolar lavage (BALF) sample was counted using a cell counter.

[0616] ② The supernatant was obtained by centrifugation at 1000 rpm for 5 min at 4°C, and the protein concentration in the BALF was determined by the BCA method. The contents of IL-6, IL-1β and TNF-α were determined by ELISA kit according to the instructions of the kit.

[0617] The results are shown in Figure 11. After intratracheal instillation of LPS, the total number of inflammatory cells and the expression levels of inflammatory factors IL-6, IL-1β and TNF-α in the bronchoalveolar lavage fluid of the model group were significantly increased compared with the blank group. After administration of compound A5, the total number of inflammatory cells and the expression levels of inflammatory factors IL-6, IL-1β 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.

[0618] (3) Pathological evaluation:

[0619] Paraffin section

[0620] ① After euthanasia, open the chest to expose the chest cavity: take the left lobe and fix it in a embedding box containing 10% formaldehyde solution for 24 h, and wash it with running water for 24 h to completely remove residual formaldehyde;

[0621] ② Dehydrate the tissue by alcohol gradient, the specific steps are as follows: 70% alcohol overnight, 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;

[0622] ③ After dehydration, the tissue is placed in an alcohol / dimethylbenzene (1:1, v / v) solution for 20 min;

[0623] ④ 20 min and 10 min in dimethylbenzene clearing I and II, respectively;

[0624] (5) Put the tissue into the preheated melted paraffin I, II and embedding paraffin in the oven at 60-65°C for 1 h.

[0625] (6) Pour a small amount of embedding paraffin into the preheated metal embedding frame, put the tissue block into it, make the tissue vertical to the embedding frame, pour paraffin again, embed the tissue, and cool it down.

[0626] (7) Paraffin section: Fix the tissue paraffin block on the Leica section machine, the section thickness is 5 μm, and continuous sectioning is performed. Put the section into 40°C water for spreading with a toothless forceps, then take it out with a glass slide, and after baking at 60°C for 2 h, store it in a section box at room temperature for standby.

[0627] HE staining

[0628] (1) Dewaxing and hydration: Put the tissue paraffin section into xylene I and II for 15 min, then into 100% ethanol I and II for 3 min, 95% ethanol I and II for 3 min, 80% ethanol for 3 min, and distilled water for 1 min, respectively;

[0629] (2) Hematoxylin staining for 15 min, and wash the excess dye on the glass slide with water;

[0630] (3) 1% hydrochloric acid ethanol (99 mL 70% ethanol + 1 mL concentrated hydrochloric acid) for 3 s, and observe the clear nucleus and chromatin under a microscope;

[0631] (4) Rinse with running water for 15 min to return blue, and then with distilled water for 1 min;

[0632] (5) Eosin for 2 min, and rinse with running water for 1 min;

[0633] (6) Dehydrate with 80% and 100% ethanol for 2 s and 7 min, respectively;

[0634] (7) Xylene I and II for 5 min, respectively;

[0635] (8) Mounting: Take the glass slide out of xylene II, add neutral gum at the tissue site, gently cover with a cover glass, and naturally dry.

[0636] (9) Observation: Observe the pathological changes under a microscope, take photos, and analyze.

[0637] Microscopic observation (see FIG. 12), compared with the blank group, the alveolar collapse and alveolar wall thickening of the model group, and a large number of inflammatory cell infiltrations in the intercellular space; compared with the model group, the low, medium and high dose groups of compound A5 can improve the alveolar wall thickening to different degrees, and can reduce the inflammatory cell infiltration, indicating that compound A5 has a therapeutic effect on lung inflammation caused by acute lung injury.

[0638] (5) Masson staining:

[0639] ①Paraffin sections were routinely deparaffinated to distilled water.

[0640] ②According to the operation manual of Solerbio Masson kit, Weigert iron hematoxylin staining solution was prepared by mixing reagent A1 and A2 at 1:1 ratio before use, and then added dropwise to cover the sections for 10 min.

[0641] ③Excess staining solution was washed off with distilled water, and then differentiation solution of acidic ethanol was added dropwise for 5-15 s, and then washed with distilled water for 30 s.

[0642] ④Masson blue solution was returned to blue for 3 min, and then washed with distilled water for 30 s.

[0643] ⑤Eosin staining solution was used for 10 min.

[0644] ⑥During the above operation, weak acid working solution was prepared by mixing distilled water and weak acid solution at a ratio of 2:1, and then added dropwise for 30 s.

[0645] ⑦Excess liquid was poured off, and then phosphomolybdic acid solution was added for 1 min. Weak acid working solution was added for 30 s.

[0646] ⑧Excess liquid was poured off, and then aniline blue staining solution was added for 1 min. Weak acid working solution was added for 30 s.

[0647] ⑨95% ethanol was used for rapid dehydration for 2-3 s, and then absolute ethanol was used for dehydration twice, each for 5 s.

[0648] ⑩Xylene was used for transparency twice, each for 2 min, and then neutral gum was used for fixation.

[0649] Microscopic observation showed (see Figure 13) that 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 different degrees, indicating that compound A5 had a remission treatment effect on pulmonary fibrosis caused by acute lung injury.

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, co-crystal, or deuterated form thereof wherein R1and R2are each independently and R1and R2are not simultaneously X1, X2, X3, X4, X5, when present, are each independently C or N, wherein at least two 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 the group consisting of halogen, halo C1-C6 alkyl, carbonyl, C1-C6 alkyl, C1-C6 alkoxy, carboxyl, cyano, hydroxyl, carbonyl, phenyl-SO2-, nitro, C1-C6 alkyl oxycarbonyl; the five- to fourteen-membered heteroaryl or five- to fourteen-membered heterocyclyl comprises 1-3 heteroatoms selected from the group consisting of 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 with one or more substituents selected from the group consisting of halogen, halo C1-C6 alkyl, C1-C6 alkyl, and C1-C6 alkoxy; the five- to fourteen-membered heteroaryl or five- to fourteen-membered heterocyclyl comprises 1-3 heteroatoms selected from the group consisting of 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, when present, is 0, 1, or 2; q, when present, is 0, 1, or 2; not simultaneously present; each dotted line independently represents a bond present or absent.

2. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, co-crystal, 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, co-crystal, 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, X5 are absent, n is 1, and m is 0.

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, co-crystal, 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 is substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, halo C1-C4 alkyl, carbonyl, C1-C4 alkyl, C1-C4 alkoxy, carboxyl, cyano, hydroxyl, carbonyl, phenyl-SO2-, nitro, C1-C4 alkyl oxycarbonyl; the five- to ten-membered heteroaryl or five- to ten-membered heterocyclyl comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S; preferably, the halogen is F, Cl, or Br. Preferably, R4, when present, is C6-10 aryl or a five- to ten-membered heteroaryl; optionally, said C6-10 aryl five- to fourteen-membered heteroaryl is substituted with one or more substituents selected from the group consisting of halogen and C1-C4 alkyl; said five- to fourteen-membered heteroaryl or five- to fourteen-membered heterocyclyl comprises 1 or 2 heteroatoms selected from the group consisting of N, O and S; preferably, said halogen is F, CI, or Br.

5. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, co-crystal, or deuterated form thereof, wherein Formula I is Preferably is wherein, each R1is independently each R2is independently each R3is independently Preferably, formula I is More preferably wherein each R1is independently R2is each independently R3are each independently Preferably, formula I is More preferably wherein each R1is independently R2is each independently R3are each independently Preferably, wherein formula I is More preferably wherein each R1is independently R2is each independently R3are each independently Preferably, formula I is More preferably wherein each R1is independently R2is each independently R3are each independently Preferably, formula I is wherein R1is R2 is R4 is Preferably, formula I is wherein R5is Preferably, formula I is wherein R6 is Preferably, formula I is wherein R7is Preferably, formula I is wherein R8is Preferably, formula I is wherein R9 is Preferably, formula I is wherein R 10 is, Preferably, formula I is wherein R 11 is Preferably, formula I is wherein R 12 is Preferably, formula I is wherein R 13 is 6. A compound or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, co-crystal, or deuterated form thereof:

7. An intermediate compound which is the following compound:

8. A process for the preparation of a compound according to any one of claims 1-5, comprising a) reacting a compound of formula I with a compound of formula II at 60-100 °C for 10-14 hours; b) subjecting the product of step a), a compound of formula III, to a hydrolysis reaction at 20-50 °C for 2-6 hours; c) reacting the product of step b), a compound of formula IV, with R3-NH2 at 20-50 °C for 10-14 hours to give a compound of formula V; d) stirring a compound of formula VI with a compound of formula VII at 60-100 °C for 10-14 hours; e) subjecting the product of step d), a compound of formula VIII, to a hydrolysis reaction at 60-100 °C for 2-6 hours; f) stirring the product of step e), a compound of formula IX, with R3-NH2 at 20-50 °C for 10-14 hours to give a compound of formula X; g) stirring a compound of formula XI with a compound of formula XII at 20-50 °C for 0.5-1 hour, adding a compound of formula XIII, and reacting at 80-120 °C for 1-3 hours; h) reacting the product of step g), a compound of formula XIV, with a compound of formula XV at 80-120 °C for 1-3 hours; i) reacting the product of step h), a compound of formula XVI, with R3-B(OH)2 at 80-120 °C for 4-8 hours to give a compound of formula XVII; or j) stirring a compound of formula XI with a compound of formula XII at 20-50 °C for 0.5-1 hour, adding a compound of formula XIII, and reacting at 80-120 °C for 1-3 hours; k) stirring the product of step g), a compound of formula XIV, with R4COOH at 20-50 °C for 1-3 hours to give a compound of formula XVIII; wherein R1, R2, R3, R4 are as defined in any one of claims 1-5. (1) 9. A pharmaceutical composition comprising a compound according to any one of claims 1-6 and a pharmaceutically acceptable adjuvant or excipient.

10. Use of a compound according to any one of claims 1-6 or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the prevention and / or treatment of an inflammatory disease, a respiratory disease, a skin disease, or an immune system disease; 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. ​ (2) ​ ​ ​ (3) ​ ​ ​ ​ (4) ​ ​ ​ ​ ​ ​ 11. Use of a compound of any one of claims 1-6 or a pharmaceutical composition of claim 9 for the manufacture of a medicament or PDE4 inhibitor for the prevention and / or treatment of a PDE4 mediated disease.

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