Difluoromethoxy phenyl PDE4 and / or PDE7 inhibitor and application thereof

Abstract

The invention discloses a difluoromethoxy phenyl PDE4 and / or PDE7 inhibitor and application thereof. The difluoromethoxy phenyl PDE4 and / or PDE7 inhibitor can prevent and / or treat inflammatory diseases, respiratory diseases, skin diseases or immune system diseases.

Description

Technical Field

[0001] The present application belongs to the field of medical technology, and specifically relates to difluoromethoxyphenyl derivatives, which are inhibitors of PDE4 and / or PDE7, and can prevent and / or treat inflammatory diseases, respiratory diseases, skin diseases, or immune system diseases. Background Art

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

[0003] Bronchopneumonia, also known as lobular pneumonia, is caused by pathogens invading through the bronchi, causing inflammation of the bronchioles, terminal bronchioles and alveoli. Pathologically, it is mostly caused by Staphylococcus aureus, Pneumococcus and Streptococcus, which cause infections of the bronchioles, terminal bronchioles and their distal alveoli. The range of lesions is lobular, scattered and can also merge into pieces. Pathogenic bacteria spread from the bronchi or bronchioles, causing inflammatory congestion and edema of the alveolar walls and bronchiolar walls, and inflammatory exudates such as white blood cells, phagocytes, and cellulose fill the alveoli and bronchioles, forming lobular consolidation of the lungs. During the course of the disease, if the bronchioles are blocked to varying degrees, lobular emphysema or atelectasis may occur. Bronchopneumonia is more common in infants, the elderly and patients who have been bedridden for a long time and are weak. Patients who are in a coma or after surgery are also prone to infection. Clinically, fever, cough, foamy mucus or purulent sputum, chest pain and dyspnea can be seen, and dry rales can be heard by auscultation. Because the patient is weak and has low resistance, the body temperature and white blood cell count may not increase.

[0004] Psoriasis is an immune-mediated disease. Psoriasis is divided into four types according to clinical characteristics: vulgaris, pustular, erythrodermic and articular. Among them, vulgaris is the most common. The onset of psoriasis is characterized by redness of the skin, large-scale distribution of scales, and distribution in the shape of water droplets on various parts of the body. It is also accompanied by severe itching and burning symptoms. The important cells in the pathogenesis of psoriasis are DC, Th17, Th1 and keratinocytes. DC is activated by various stimuli to overproduce and secrete TNF-a, IL-23, and IL-12. IL-23 induces T cells to differentiate into Th17. Activated Th17 cells overproduce IL-17 and IL-22. TNF-a and IL-17 activate keratinocytes, promote epidermal hyperplasia, promote inflammatory cells (such as neutrophils), and induce the production of antimicrobial peptides (AMPs). The IL-12 produced by DC also induces Th1 to produce the cytokine IFN-γ, which aggravates psoriasis. Traditional therapeutic drugs have problems such as poor efficacy and toxic side effects. The demand for innovative drugs in clinical practice is constantly expanding, and more new small molecule compounds are urgently needed.

[0005] Phosphodiesterase (PDE) specifically hydrolyzes cyclic-3', 5'-adenosine monophosphate (cAMP) and cyclic-3', 5'-guanosine monophosphate (cGMP). As second messengers, cAMP and cGMP play an important role in cell signal transduction and many physiological processes. The PDE superfamily consists of 11 families, namely PDE1-PDE11, among which PDE4, PDE7 and PDE8 are cAMP-specific hydrolases that participate in important cellular reactions by regulating cAMP.

[0006] PDE4 is an enzyme that specifically hydrolyzes cAMP. Its family consists of four subtypes: PDE4A, PDE4B, PDE4C, and PDE4D. Each subtype has a corresponding gene encoding and has different cell distribution and functions. PDE4 is mainly distributed in airway smooth muscle cells and inflammatory cells and immune cells such as lymphocytes, mast cells, macrophages, neutrophils, eosinophils, basophils, monocytes, and epithelial cells, regulating the level of cAMP in these cells. Inhibition of PDE4 can cause an increase in the level of cAMP in inflammatory cells and immune regulatory cells, thereby inhibiting the function of inflammatory cells and relaxing airway smooth muscle. PDE4 is also expressed in fibroblasts. Selective PDE4 inhibitors can effectively inhibit the production of matrix metalloproteinases, showing the therapeutic value of inhibiting tissue remodeling in related lung diseases.

[0007] PDE7 is an important subtype of the PDEs isoenzyme multigene family and is also the main enzyme that specifically hydrolyzes cAMP. PDE7 is highly expressed in organs and tissues such as the pancreas, heart, brain, liver, thyroid, and ovaries. Studies have found that the biological function of PDE7 is similar to that of PDE4, and that PDE7 inhibitors are more effective in immune inflammation than PDE4 inhibitors, with fewer side effects, and may serve as a potential target for new anti-inflammatory immune drugs. In addition, studies have shown that the use of PDE7 inhibitors alone will not affect pro-inflammatory cells, but will enhance the effects of other drugs that can increase cAMP (such as PDE4 inhibitors). In most immune inflammatory cells, the simultaneous use of PDE4 and PDE7 inhibitors will achieve a dual inhibitory effect on inflammatory factors, which provides an effective therapeutic strategy for the treatment of related inflammatory diseases. Summary of the invention

[0008] One or more embodiments of the present application provide a difluoromethoxyphenyl derivative, which is an inhibitor of PDE4 and / or PDE7, and can prevent and / or treat inflammatory diseases, respiratory diseases, skin diseases, or immune system diseases.

[0009] One or more embodiments of the present application provide a compound of Formula I or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof.

[0010]

[0011] in

[0012] R 1 for

[0013] Ring A is a 5- to 10-membered heteroaryl group containing 1-3 (1, 2, or 3) heteroatoms selected from N, O, and S, wherein at least one heteroatom is N;

[0014] R 2 is H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, amino, phenyl, benzyl, or benzylamino;

[0015] n is 1, 2, 3 or 4;

[0016] *Indicates the connection location.

[0017] In one or more embodiments, the 5- to 10-membered heteroaryl is substituted with one or more substituents selected from C1-C6 alkyl and C1-C6 alkoxy.

[0018] In one or more embodiments, the 5- to 10-membered heteroaryl is a monocyclic heteroaryl or a fused-ring heteroaryl.

[0019] In one or more embodiments, Ring A is

[0020] In one or more embodiments, X 2 , Y 2 , Z 2 are each independently N or NH, O or S, and X 2 , Y 2 , Z 2 At least one of them is N or NH.

[0021] In one or more embodiments, X 2 Each independently is N, Y 2 , Z 2 are each independently N, O or S.

[0022] In one or more embodiments, Ring A is

[0023] In one or more embodiments, n is 2 or 3.

[0024] In one or more embodiments, the halogen is Br.

[0025] In one or more embodiments, the compound of the present application is

[0026]

[0027]

[0028] One or more embodiments of the present application provide an intermediate for preparing the compound of the present application, wherein the intermediate compound is

[0029]

[0030] One or more embodiments of the present application provide a method for preparing the compound of the present application, which comprises (1)

[0032]

[0033] a) reacting the compound of formula II with sodium acetate at 80°C-120°C for 1-2 hours, adding the compound of formula I, and reacting at 20°C-50°C for 1-8 hours;

[0034] b) hydrolyzing the compound of formula III obtained in step a) at 50° C.-90° C. for 1-8 hours;

[0035] c) reacting the product compound of formula IV obtained in step b) with RB环 -NHNH 2 React at 20°C-50°C for 5-7 hours to obtain a compound of formula V; (2)

[0037]

[0038] d) Compound VI, compound VII and K 2 CO 3 Stir at 20°C-50°C for 20-30 hours, then stir at -15°C until the solution turns orange-yellow, then add DBU and bromochloromethane at -20°C-0°C, and react at 20°C-50°C for 6-24 hours;

[0039] e) stirring the product compound of formula VIII obtained in step d) at 20° C.-50° C. for 8-12 hours for hydrolysis reaction;

[0040] f) reacting the product compound of formula IX obtained in step e) with R B环 -NHNH 2 React at 20℃-50℃ for 4-8 hours; (3)

[0042]

[0043] g) reacting the compound of formula XI with the compound of formula XII at 60° C.-100° C. for 10-14 hours;

[0044] h) hydrolyzing the compound of formula XIII obtained in step g) at 20° C.-50° C. for 2-6 hours;

[0045] i) reacting the compound of formula XIV obtained in step h) with R B环 -NHNH 2 React at 20℃-50℃ for 10-14 hours;

[0046] or (4)

[0048]

[0049] j) reacting the compound of formula XVI with the compound of formula XVII at 60° C.-100° C. with stirring for 10-14 hours;

[0050] k) stirring the product compound of formula XVIII obtained in step j) at 60° C.-100° C. for hydrolysis reaction for 2-6 hours;

[0051] 1) The product compound of formula XIX obtained in step k) is reacted with R B环 -NHNH 2Stir the reaction at 20°C-50°C for 10-14 hours;

[0052] Among them, R B环 for R 1 , R 2 , n as described above.

[0053] One or more embodiments of the present application provide a pharmaceutical composition comprising a compound of the present application and a pharmaceutically acceptable auxiliary material or excipient.

[0054] One or more embodiments of the present application provide use of the compound of the present application or the pharmaceutical composition of the present application in the preparation of a medicament for preventing and / or treating inflammatory diseases, respiratory diseases, skin diseases, or immune system diseases.

[0055] One or more embodiments of the present application provide the use of the compound of the present application or the pharmaceutical composition of the present application in the preparation of a medicament for preventing and / or treating a disease mediated by PDE4 and / or PDE7, an inhibitor of PDE4 or an inhibitor of PDE7, or an inhibitor of PDE7 and PDE7.

[0056] One or more embodiments of the present application provide a compound of the present application for use as a medicament.

[0057] One or more embodiments of the present application provide the pharmaceutical composition of the present application, which is used as a medicament.

[0058] One or more embodiments of the present application provide a compound or composition of the present application for preventing and / or treating inflammatory diseases, respiratory diseases, skin diseases, or immune system diseases.

[0059] One or more embodiments of the present application provide a compound or composition of the present application for preventing and / or treating a disease mediated by PDE4 and / or PDE7.

[0060] One or more embodiments of the present application provide a compound or composition of the present application for inhibiting PDE4 or PDE7.

[0061] One or more embodiments of the present application provide a compound or composition of the present application for inhibiting PDE4 and PDE7.

[0062] One or more embodiments of the present application provide a method for preventing and / or treating inflammatory diseases, respiratory diseases, skin diseases, or immune system diseases, which comprises administering a compound or composition of the present application to a subject in need thereof.

[0063] One or more embodiments of the present application provide a method for preventing and / or treating a disease mediated by PDE4 and / or PDE7, the method comprising administering a compound or composition of the present application to a subject in need thereof.

[0064] One or more embodiments of the present application provide a method for inhibiting PDE4 and / or PDE7, the method comprising administering a compound or composition of the present application to a subject in need thereof.

[0065] In one or more embodiments, the inflammatory disease is an autoinflammatory disease or bronchopneumonia.

[0066] The following is an explanation of the terms used in the technical solution of the present application. As used in the specification and the appended claims, unless otherwise specifically stated, the terms of the present application have the following meanings:

[0067] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0068] The term "amino" refers to -NH 2 .

[0069] The term "hydroxy" refers to -OH.

[0070] "Alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.

[0071] "Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy and cyclobutyloxy. The definition of alkyl is the same as that of "alkyl" described above.

[0072] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be, for example, a monocyclic ring of 6 to 8 carbon atoms (e.g., 6, 7, 8 carbon atoms), a bicyclic ring of 6 to 12 carbon atoms (e.g., 6, 7, 8, 9, 10, 11, 12 carbon atoms), or a tricyclic ring system of 10 to 14 carbon atoms (e.g., 10, 11, 12, 13, 14 carbon atoms), which can be a bridged ring or a spirocyclic ring, and non-limiting examples include phenyl and naphthyl. The aryl group can be optionally further substituted by one or more substituents.

[0073] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be, for example, a 5-8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, a 5-12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably a 5-8-membered heteroaryl, and 1 to 4 (e.g., 1, 2, 3, 4) N, S selectively substituted in the ring of the heteroaryl can be oxidized to various oxidation states. The heteroaryl can be attached to a heteroatom or a carbon atom, and the heteroaryl can be a bridged ring or a spirocyclic ring, and non-limiting examples include cyclic pyridyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridinyl, pyrrolopyridinyl. The heteroaryl is optionally further substituted by one or more substituents.

[0074] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated non-aromatic heterocyclic ring, which can be, for example, a 5- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably a 5- to 8-membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, 4) N and S optionally substituted in the ring of the "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; the "heterocyclyl" or "heterocycle" can be attached to a heteroatom or a carbon atom; the "heterocyclyl" or "heterocycle" can be a bridged ring or a spiro ring. Non-limiting examples of “heterocyclyl” or “heterocycle” include oxirane, oxirane, aziridine, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, pyridinyl, piperidinyl, piperidinyl, homopiperidinyl, furanyl, pyridinyl, piperidinyl, piperidinyl, homopiperidinyl, pyridinyl, piperidinyl, piperidinyl, py ... pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, py pyranyl, thiophene, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, oxazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3 .1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The "heterocyclyl" or "heterocycle" may be optionally further substituted by one or more substituents.

[0075] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, which can be, for example, a monocyclic, bicyclic or polycyclic ring of 6 to 10 carbon atoms (e.g., 6, 7, 8, 9, 10 carbon atoms), preferably 6 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. When the cycloalkyl is substituted, it can be optionally further substituted by one or more substituents.

[0076] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0077] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0078] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0079] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0080] "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

[0081] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

[0082] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0083] "Optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group.

[0084] In one or more embodiments, Formula I is R 3 for

[0085] In one or more embodiments, wherein Formula I is R 4 for

[0086] In one or more embodiments, wherein Formula I is R 5 for

[0087] In one or more embodiments, Formula I is R 6 for

[0088] In one or more embodiments, wherein Formula I is R 7 for

[0089] In one or more embodiments, wherein Formula I is R 8 for

[0090] In one or more embodiments, Formula I is R 9 for

[0091] In one or more embodiments, Formula I is R 1 0 is

[0092]

[0093] In one or more embodiments, Formula I is R 11 for BRIEF DESCRIPTION OF THE DRAWINGS

[0094] Figure 1 Represents the toxicity test of the compounds on Raw 264.7 cells.

[0095] Figure 2It represents the effect of the compound on the expression level of inflammatory factor TNF-α in LPS-induced Raw264.7 cells.

[0096] Figure 3 It represents the effect of the compound on the expression level of inflammatory factor IL-1β in Raw264.7 cells induced by LPS. Specific embodiments

[0097] The present invention will be further described below in conjunction with specific embodiments. These embodiments are only for the purpose of explanation and are not intended to limit the scope and essence of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work are within the scope of protection of the present invention.

[0098] Example 1 Synthesis of Intermediates 2, 3, 4, and 5

[0099] (1) Synthesis of Compound 2

[0100]

[0101] Weigh 3g of compound 3,4-dihydroxybenzaldehyde (21.72mmol, 1.0equiv.) and 6.91g of sodium carbonate (65.16mmol, 3.0equiv.), dissolve in 30mLN,N-dimethylformamide, and finally add 3.44g of ethyl difluorochloroacetate (21.72mmol, 1.0equiv.), react at 80°C for 8 hours, detect the complete reaction of the raw material by TLC, and add water to quench the reaction. Use ethyl acetate to extract 3 times, and wash the organic phase with saturated sodium chloride solution. Concentrate the organic phase, and obtain 1.4g of white solid product (compound 2) by rapid column chromatography, with a yield of 34%.

[0102] The obtained compound 2 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (500 MHz, CDCl 3 )δ9.90(s,1H),7.53(d,J=2.0Hz,1H),7.44(dd,J=8.5,2.0Hz,1H),7.26(d,J=8.5Hz,1H),6.66(t,J=73.0Hz,1H),6.43(br,1H).ESI-HRMS m / z: calculated value is C 8 H 6 O 3 F 2 Na + [M+Na] + , 211.0177; the measured value is 211.0166.

[0103] (2) Synthesis of Compound 3

[0104]

[0105] Weigh 2.1g of compound 2 (11.16mmol, 1.0equiv.), add 3.09g of potassium carbonate (22.32mmol, 2-0equiv.), add 20mL of N,N-dimethylformamide, and finally add 2.26g of bromomethylcyclopropane (16.74mmol, 1.5equiv.), react at 80°C for 8h, detect the complete reaction of the raw material by TLC, and quench the reaction by adding water. Extract with ethyl acetate 3 times, wash the organic phase with saturated sodium chloride solution. Concentrate the organic phase and obtain 2.3g of yellow oily product (compound 3) by rapid column chromatography, with a yield of 85%.

[0106] The obtained compound 3 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (500 MHz, DMSO-d 6 )δ9.94(s,1H),7.59-7.54(m,2H),7.39(d,J=8.0Hz,1H),7.28(t,J=73.5Hz,1H),3.98(d,J=7.0Hz,2H),1.30-1.21(m,1H),0.61-0.55(m,2H),0.39-0.33(m,2H).ESI-MS m / z: calculated value is C 12 H 13 O 3 F 2 + [M+H] + , 243.1; the measured value is 243.1.

[0107] (3) Synthesis of Compound 4

[0108]

[0109] 3.21 g of methyl 2-amino-3-hydroxypropionate hydrochloride (20.64 mmol, 1.0 equiv.) was dissolved in 69 mL of N,N-dimethylformamide, and 8.55 g of potassium carbonate (61.92 mmol, 3.0 equiv.) was added. 2After protection, 5.0 g of compound 3 (20.64 mmol, 1.0 equiv.) was added after stirring for 10 min, and the reaction was continued overnight at room temperature. After TLC monitoring, 12.28 g of bromochloroform (61.92 mmol, 3.0 equiv.) and 9.43 g of DBU (61.92 mmol, 3.0 equiv.) were added dropwise at -10 ° C. The reaction was continued for 24 h at room temperature. After TLC monitoring, water was added to quench the reaction. Ethyl acetate was used for extraction 3 times, and the organic phase was washed with a saturated sodium chloride solution. The organic phase was concentrated and subjected to rapid column chromatography to obtain 3.6 g of a white solid product with a yield of 51%.

[0110] The obtained compound 4 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (400 MHz, CDCl 3 )δ8.28 (s, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 8.4, 2.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.71 (t, J = 74.8 Hz, 1H), 3.98-3.92 (m, 5H), 1.35-1.28 (m, 1H), 0.70-0.64 (m, 2H), 0.37-0.34 (m, 2H). ESI-HRMS m / z: calculated value is C 16 H 15 O 5 NF 2 Na + [M+Na] + , 362.0811; the measured value is 362.0822.

[0111] (4) Synthesis of Compound 5

[0112]

[0113] 3 g of compound 4 (8.84 mmol, 1.0 equiv.) was weighed and dissolved in 15 mL of a 1:1 mixed solvent of ethanol and water, and 2.12 g of sodium hydroxide (53.04 mmol, 6.0 equiv.) was added. The mixture was stirred at room temperature and monitored by TLC. After the reaction was complete, the ethanol was removed by rotary evaporation, an appropriate amount of water was added, and the pH was adjusted to 6 with dilute hydrochloric acid. The mixture was filtered, and the solid was washed with water in small amounts several times, and dried to obtain 2.8 g of a yellow solid product with a yield of 97%.

[0114] The obtained compound 5 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (400 MHz, CDCl 3)δ8.39 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.26 (t, J = 8.4 Hz, 1H), 6.72 (t, J = 74.8 Hz, 1H), 3.96 (d, J = 6.8 Hz, 2H), 1.38-1.28 (m, 1H), 0.71-0.64 (m, 2H), 0.40-0.35 (m, 2H). ESI-MS m / z: calculated value is C 15 H 14 O 5 NF 2 + [M+H] + , 326.1; the measured value is 326.1.

[0115] Example 2 Synthesis of Intermediates 6 and 7

[0116] (1) Synthesis of Compound 6

[0117]

[0118] Weigh 4.46g of 3,3-dibromo-1.1.1-trifluoro-2-one (16.52mmol, 2.0equiv.) and 2.7g of sodium acetate (33.04mmol, 4.0equiv.) into a reaction bottle, add an appropriate amount of water to dissolve, stir at 100°C for 1h, cool to room temperature, add 2g of compound 3 (8.26mmol, 1.0equiv.) in methanol and 4mL of ammonia water to the above solution, stir at room temperature, and when TLC detects that the raw material is no longer reduced, remove methanol by rotary evaporation and add water. Extract with ethyl acetate 3 times, wash the organic phase once with saturated sodium chloride solution, and dry the organic phase with anhydrous sodium sulfate. Concentrate the organic phase and obtain 1.37g of yellow solid product by rapid column chromatography with a yield of 48%.

[0119] The obtained compound 6 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (400 MHz, CDCl 3 )δ12.56 (br, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.41 (s, 1H), 7.32 (dd, J = 8.4, 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.62 (t, J = 75.2 Hz, 1H), 3.72 (d, J = 7.2 Hz, 2H), 1.28-1.15 (m, 1H), 0.65-0.56 (m, 2H), 0.32-0.24 (m, 2H). ESI-MS m / z: calculated value is C 15 H 14 F5 N 2 O 2 + [M+H] + , 349.1; the measured value is 349.1.

[0120] (2) Synthesis of Compound 7

[0121]

[0122] The synthesis steps were similar to those of compound 5 to obtain a yellow solid product (compound 7) with a yield of 83%.

[0123] The obtained compound 7 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (400 MHz, DMSO-d 6 )δ13.28 (br, 1H), 7.96-7.56 (m, 3H), 7.27 (d, J=8.4 Hz, 1H), 7.14 (t, J=74.4 Hz, 1H), 3.98 (d, J=6.8 Hz, 2H), 1.35-1.22 (m, 1H), 0.64-0.55 (m, 2H), 0.42-0.34 (m, 2H). ESI-HRMS m / z: calculated value is C 15 H 14 O 4 N 2 F 2 Na + [M+Na] + , 347.0814; the measured value is 347.0800.

[0124] Example 3 Synthesis of Intermediates 8 and 9

[0125] (1) Synthesis of Compound 8

[0126]

[0127] The synthesis steps refer to the synthesis of compound 4. Compound 3 and D-cysteine ​​methyl ester hydrochloride are reacted to obtain a yellow solid product (compound 8) with a yield of 15%.

[0128] The obtained compound 8 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (400 MHz, CDCl 3)δ8.17 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.4, 2.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.70 (t, J = 75.2 Hz, 1H), 4.00-3.98 (m, 5H), 1.38-1.27 (m, 1H), 0.70-0.64 (m, 2H), 0.41-0.36 (m, 2H). ESI-HRMS m / z: calculated value is C 16 H 15 O 4 NF 2 SNa + [M+Na] + , 378.0582; the measured value is 378.0581.

[0129] (2) Synthesis of Compound 9

[0130]

[0131] The synthesis steps were similar to those of compound 5 to obtain a yellow solid product (compound 9) with a yield of 84%.

[0132] The obtained compound 9 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (500 MHz, DMSO-d 6 )δ8.18(s,1H),7.63(s,1H),7.51(d,J=8.5Hz,1H),7.28(d,J=8.0Hz,1H),7.18(t,J=74.0Hz,1H),4.01(d,J=7.0Hz,2H),1.32-1.24(m,1H),0.62-0.53(m,2H),0.45-0.33(m,2H),OH(not observed).ESI-MS m / z:calculated value is C 15 H 14 O 4 NF 2 S + [M+H] + , 342.1; the measured value is 342.1.

[0133] Example 4 Synthesis of Intermediates 10 and 11

[0134] (1) Synthesis of Compound 10

[0135]

[0136] 150 mg of compound 3 (0.62 mmol, 1.0 equiv.) was dissolved in 1.5 mL of N,N-dimethylformamide solvent, and then 103 mg of methyl 2,3-diaminobenzoate (0.62 mmol, 1.0 equiv.) and 141 mg of sodium pyrosulfite (0.74 mmol, 1.2 equiv.) were added, and the mixture was heated to 80°C for overnight reaction and monitored by thin layer chromatography. After the reaction, water was added, and the mixture was extracted with ethyl acetate three times. The ethyl acetate layer was dried with anhydrous sodium sulfate, and the solution was concentrated. 151 mg of compound 10 was obtained by column chromatography with a yield of 63%.

[0137] The obtained compound 10 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, CDCl 3 )δ10.71(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).ESI-MS m / z: calculated value is C 20 H 19 O 4 N 2 F 2 + [M+H] + , 389.1; the measured value is 389.1.

[0138] (2) Synthesis of Compound 11

[0139]

[0140] The synthesis steps were similar to those of compound 5 to obtain a white solid product (compound 11) with a yield of 87%.

[0141] The obtained compound 11 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (400 MHz, CD 3OD) 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). ESI-HRMS m / z: calculated value is C 19 H 17 O 4 N 2 F 2 + [M+H] + , 375.1151; the measured value is 375.1160.

[0142] Example 5 Synthesis of Intermediates 12, 13, and 14

[0143] (1) Synthesis of Compound 12

[0144]

[0145] 1.0 g of compound 1 (7.24 mmol, 1.0 equiv.) was dissolved in 10 mL of DMF solvent, and then 0.72 g of sodium hydroxide (18.10 mmol, 2.5 equiv.) and 2.52 g of ethyl difluorochloroacetate (15.93 mmol, 2.2 equiv.) were added, and the mixture was heated to 80° C. for 12 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the organic phase was concentrated. 0.93 g of compound 12 was obtained by flash column chromatography with a yield of 54%.

[0146] The obtained compound 12 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (400 MHz, CDCl 3 )δ9.91(s,1H),7.75-7.73(m,2H),7.39(d,J=8.8Hz,1H),6.64(t,J=72.8Hz,1H),6.59(t,J=72.8Hz,1H).ESI-MS m / z: calculated value is C 9 H 7 O 3 F 4 + [M+H] + , 239.0; the measured value is 239.0.

[0147] (2) Synthesis of Compound 13

[0148]

[0149] The synthesis steps were similar to those of compound 10. Compound 12 was reacted with methyl 2,3-diaminobenzoate to obtain a yellow solid product (compound 13) with a yield of 50%.

[0150] The obtained compound 13 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (400 MHz, CDCl 3 )δ10.75 (br, 1H), 8.04 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.93-7.91 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 6.65 (t, J = 73.2 Hz, 1H), 6.62 (t, J = 72.8 Hz, 1H), 4.03 (s, 3H). ESI-HRMS m / z: calculated value is C 17 H 13 O4N 2 F 4 + [M+H] + , 385.0806; the measured value is 385.0801.

[0151] (3) Synthesis of Compound 14

[0152]

[0153] The synthesis steps were similar to those of compound 5 to obtain a white solid product (compound 14) with a yield of 90%.

[0154] The obtained compound 14 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6 )δ12.57 (br, 1H), 12.52 (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). ESI-HRMS m / z: calculated value is C 16 H 11 O 4 N 2 F 4 + [M+H] +, 371.0649; the measured value is 371.0652.

[0155] Example 6 Synthesis of Intermediates 16, 17, 18, 19, 20

[0156] (1) Synthesis of Compound 16

[0157]

[0158] The synthesis steps refer to the synthesis of compound 2. 3,4-Dihydroxyacetophenone and ethyl difluorochloroacetate are reacted to obtain a white solid product (Compound 16) with a yield of 36%.

[0159] The obtained compound 16 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (600 MHz, CDCl 3 )δ7.63 (d, J=1.8 Hz, 1H), 7.51 (dd, J=9.0, 2.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.64 (t, J=73.2 Hz, 1H), 6.33 (br, 1H), 2.58 (s, 3H). ESI-HRMS m / z: calculated value is C 9 H 8 O 3 F 2 Na + [M+Na] + , 225.0334; the measured value is 225.0311.

[0160] (2) Synthesis of Compound 17

[0161]

[0162] The synthesis steps were similar to those of compound 3 to obtain a yellow oily product (compound 17) with a yield of 56%.

[0163] The obtained compound 17 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (400 MHz, DMSO-d 6 )δ7.87 (dd, J=8.4, 2.0 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). ESI-HRMS m / z: calculated value is C13 H 14 O 3 F 2 Na + [M+Na] + , 279.0803; the measured value is 279.0808.

[0164] (3) Synthesis of Compound 18

[0165]

[0166] Weigh 2g of compound 17 (7.81mmol, 1.0equiv.) and 1.13g of N,N-dimethylformamide dimethyl acetal (9.37mmol, 1.2equiv.) into a reaction bottle, add 2mL of N,N-dimethylformamide, stir overnight at 120°C, and monitor by TLC. After cooling to room temperature, add water to quench the reaction, extract with ethyl acetate 3 times, wash the organic phase once with a saturated sodium chloride solution, and dry the organic phase with anhydrous sodium sulfate. The organic phase is concentrated and subjected to rapid column chromatography to obtain 1.8g of a yellow solid product (compound 18) with a yield of 74%.

[0167] The obtained compound 18 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (400 MHz, DMSO-d 6 )δ7.70 (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), 1.27 (d, J = 8.1 Hz, 1H), 0.61-0.49 (m, 2H), 0.42-0.30 (m, 2H). ESI-HRMS m / z: calculated value is C 16 H 19 O 3 NF 2 Na + [M+Na] + , 334.1225; the measured value is 334.1225.

[0168] (4) Synthesis of Compound 19

[0169]

[0170] 2.48 g of compound 18 (8 mmol, 1.0 equiv.) and 1.46 g of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester (24 mmol, 3.0 equiv.) were weighed into a reaction bottle, 10 mL of acetic acid was added, and the mixture was stirred at 80°C overnight and monitored by TLC. After cooling to room temperature, water was added to quench the reaction, and the mixture was extracted with ethyl acetate three times, the organic phase was washed once with a saturated sodium chloride solution, and the organic phase was dried with anhydrous sodium sulfate. The organic phase was concentrated and subjected to rapid column chromatography to obtain 2.6 g of a white solid product (compound 19) with a yield of 84%.

[0171] The obtained compound 19 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (400 MHz, DMSO-d 6 )δ8.72 (d, J=4.4 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.71 (dd, J=8.4, 2.0 Hz, 1H), 7.45-7.39 (m, 2H), 7.28 (s, 1H), 7.27 (t, J=74.0 Hz, 1H), 3.99 (d, J=6.8 Hz, 2H), 3.88 (s, 3H), 1.42-1.26 (m, 1H), 0.66-0.51 (m, 2H), 0.43-0.24 (m, 2H). ESI-HRMS m / z: calculated value is C 19 H 17 O 4 N 3 F 2 Na + [M+Na] + , 412.1079; the measured value is 412.1083.

[0172] Synthesis of compound 20

[0173]

[0174] The synthesis steps were similar to those of compound 5 to obtain a yellow solid product (compound 20) with a yield of 96%.

[0175] The obtained compound 20 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (400 MHz, DMSO-d 6)δ8.58 (d, J = 4.4 Hz, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.78 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 4.0 Hz, 1H), 7.25 (t, J = 74.0 Hz, 1H), 6.95 (s, 1H), 3.99 (d, J = 6.8 Hz, 2H), 1.37-1.30 (m, 1H), 0.65-0.54 (m, 2H), 0.39-0.26 (m, 2H), OH (not observed). ESI-HRMS m / z: calculated for C 18 H 15 O 4 N 3 F 2 Na + [M+Na] + , 398.0923; the measured value is 398.0909.

[0176] Example 7 Synthesis of Intermediates 21 and 22

[0177] (1) Synthesis of Compound 21

[0178]

[0179] The synthesis steps were similar to those of compound 19. Compound 18 was reacted with methyl 3-aminopyrazole-4-carboxylate to obtain a yellow solid product (compound 21) with a yield of 56%.

[0180] The obtained compound 21 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, CDCl 3 )δ8.79(d, J=4.5 Hz, 1H), 8.61(s, 1H), 7.70(d, J=2.0 Hz, 1H), 7.51(dd, J=8.5, 2.0 Hz, 1H), 7.33(d, J=8.5 Hz, 1H), 7.07(d, J=4.5 Hz, 1H), 6.74(t, J=74.5 Hz, 1H), 3.97(s, 3H), 3.94(d, J=7.0 Hz, 2H), 1.39-1.27(m, 1H), 0.76-0.52(m, 2H), 0.41-0.32(m, 2H).ESI-HRMS m / z: calculated value is C 19 H 17 O 4 N 3 F 2 Na + [M+Na] +, 412.1079; the measured value is 412.1072.

[0181] (2) Synthesis of Compound 22

[0182]

[0183] The synthesis steps were similar to those of compound 5 to obtain a yellow solid product (compound 22) with a yield of 98%.

[0184] The obtained compound 22 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (600 MHz, DMSO-d 6 )δ8.62(d, J=4.2 Hz, 1H), 8.33(s, 1H), 7.80(d, J=1.8 Hz, 1H), 7.74(dd, J=8.4,1.8 Hz, 1H), 7.38(d, J=8.4 Hz, 1H), 7.24(d, J=4.2 Hz, 1H), 7.23(t, J=73.8 Hz, 1H), 3.98(d, J=7.2 Hz, 2H), 1.35-1.24(m, 1H), 0.64-0.54(m, 2H), 0.40-0.30(m, 2H).OH(not observed).ESI-HRMS m / z: calculated for C 18 H 15 O 4 N 3 F 2 Na + [M+Na] + , 398.0923; the measured value is 398.0915.

[0185] Example 8 Synthesis of Intermediates 23 and 24

[0186] (1) Synthesis of Compound 23

[0187]

[0188] The synthesis steps were similar to those of compound 6 to obtain a yellow solid product (compound 23) with a yield of 64%.

[0189] The obtained compound 23 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, CDCl 3)δ12.06 (br, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.53 (dd, J=8.5, 2.0 Hz, 1H), 7.49 (d, J=1.0 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.48 (t, J=73.0 Hz, 1H), 6.39 (t, J=73.0 Hz, 1H). ESI-HRMS m / z: calculated value is C 12 H 8 O 2 N 2 F 7 + [M+H] + , 345.0469; the measured value is 345.0429.

[0190] (2) Synthesis of Compound 24

[0191]

[0192] The synthesis steps were similar to those of compound 5 to obtain a brown solid product (compound 24) with a yield of 63%.

[0193] The obtained compound 24 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6 )δ13.47 (br, 1H), 13.23 (br, 1H), 8.14-7.85 (m, 3H), 7.46 (d, J=8.5 Hz, 1H), 7.27 (t, J=73.5 Hz, 2H). ESI-MS m / z: calculated value is C 12 H 9 O 4 N 2 F 4 + [M+H] + , 321.0; the measured value is 321.0.

[0194] Example 9 Synthesis of Intermediates 26 and 27

[0195] (1) Synthesis of Compound 26

[0196]

[0197] 3 g of 1,3-dimethyl-1H-purine-2,6(3H,9H)-dione (Compound 25, CAS No.: 58-55-9, 16.65 mmol, 1.0 equiv.) was dissolved in 30 mL of N,N-dimethylformamide, and then 6.9 g of potassium carbonate (49.95 mmol, 3.0 equiv.) and 4.5 g of ethyl 3-bromopropionate (24.98 mmol, 1.5 equiv.) were added, and the mixture was heated to 70° C. to react overnight, and monitored by thin layer chromatography. After the reaction was completed, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate three times. The ethyl acetate layer was dried with anhydrous sodium sulfate, and the solution was concentrated. 2.0 g of Compound 26 was obtained by column chromatography, and the yield was 43%.

[0198] The obtained compound 26 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (400 MHz, DMSO-d 6 )δ7.64 (s, 1H), 4.54 (t, J = 6.0 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.56 (s, 3H), 3.39 (s, 3H), 2.92 (t, J = 6.4 Hz, 2H), 121 (t, J = 7.2 Hz, 3H). ESI-HRMS m / z: calculated value is C 12 H 16 O 4 N 4 Na + [M+Na] + , 303.1064; the measured value is 303.1601.

[0199] (2) Synthesis of Compound 27

[0200]

[0201] 2 g (7.64 mmol, 1.0 equiv.) of compound 26 was dissolved in 5 mL of hydrazine hydrate, and the reaction was carried out at room temperature and monitored by thin layer chromatography. After the reaction was completed, an appropriate amount of water was added, and solids were precipitated. After suction filtration and drying, 1.5 g of compound 27 was obtained, and the yield was 79%.

[0202] The obtained compound 27 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6 )δ8.99(s,1H),7.92(s,1H),4.44(t,J=7.0Hz,2H),4.16(s,2H),3.41(s,3H),3.23(s,3H),2.61(t,J=6.5Hz,2H).ESI-HRMS m / z: calculated value is C10 H 14 O 3 N 6 Na + [M+Na] + , 289.1020; the measured value is 289.1041.

[0203] Example 10 Synthesis of Intermediates 28 and 29

[0204] (1) Synthesis of Compound 28

[0205]

[0206] The synthesis steps were similar to those of compound 26. Compound 25 was reacted with ethyl 4-bromobutyrate, and compound 28 was obtained by column chromatography with a yield of 48%.

[0207] The obtained compound 28 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6 )δ8.04 (s, 1H), 4.26 (t, J = 6.5 Hz, 2H), 4.00 (m, 2H), 3.41 (s, 3H), 3.21 (s, 3H), 2.27 (t, J = 7.5 Hz, 2H), 2.04 (m, 2H), 1.14 (t, J = 7.0 Hz, 3H). ESI-HRMS m / z: calculated value is C 13 H 18 O 4 N 4 Na + [M+Na] + , 317.1220; the measured value is 317.1215.

[0208] (2) Synthesis of Compound 29

[0209]

[0210] The synthesis steps were similar to those of compound 27. After filtration and drying, compound 29 was obtained with a yield of 86%.

[0211] The obtained compound 29 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6)δ8.96(s,1H),8.04(s,1H),4.25-4.20(m,2H),4.18-4.08(m,2H),3.41(s,3H),3.21(s,3H),2.02-1.95(m,4H).ESI-HRMS m / z: calculated value is C 11 H 16 O 3 N 6 Na + [M+Na] + , 303.1176; the measured value is 303.1204.

[0212] Example 11 Synthesis of Intermediates 31 and 32

[0213] (1) Synthesis of compound 31

[0214]

[0215] The synthesis steps were similar to those of compound 28. Compound 30 was reacted with ethyl 4-bromobutyrate, and compound 31 was obtained by column chromatography with a yield of 80%.

[0216] The obtained compound 31 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6 )δ4.29 (t, J = 7.0 Hz, 2H), 4.01-3.95 (m, 2H), 3.38 (s, 3H), 3.21 (s, 3H), 2.33 (t, J = 7.0 Hz, 2H), 2.05-1.98 (m, 2H), 1.14 (t, J = 7.0 Hz, 3H). ESI-HRMS m / z: calculated value is C 13 H 17 O 4 N 4 Br + [M+Na] + , 395.0325; the measured value is 395.0347.

[0217] (2) Synthesis of Compound 32

[0218]

[0219] The synthesis steps were similar to those of compound 27. After filtration and drying, compound 32 was obtained with a yield of 94%.

[0220] The obtained compound 32 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (500 MHz, DMSO-d6 )δ8.95 (br, 1H), 4.29-4.21 (m, 2H), 4.05-3.89 (m, 2H), 3.37 (d, J=3.0 Hz, 3H), 3.20 (s, 3H), 2.06-1.92 (m, 4H). ESI-HRMS m / z: calculated value is C 11 H 15 O 3 N 6 Br + [M+Na] + , 381.0281; the measured value is 381.0314.

[0221] Example 12 Synthesis of Intermediates 33, 34, and 35

[0222] (1) Synthesis of compound 33

[0223]

[0224] 1 g of compound 30 (3.86 mmol, 1.0 equiv.) was dissolved in 15 mL of ethylene glycol monomethyl ether, and then 0.62 g of benzylamine (5.79 mmol, 1.5 equiv.) was added, heated to 150°C, and refluxed for 24 h, monitored by thin layer chromatography. After the reaction was cooled, solids precipitated, which were filtered and washed with a small amount of water, and dried to obtain 0.96 g of compound 33, with a yield of 87%.

[0225] The obtained compound 33 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6 )δ11.57 (br, 1H), 9.98 (br, 1H), 7.69 (t, J = 6.5 Hz, 1H), 7.34-7.31 (m, 4H), 7.26-7.21 (m, 1H), 4.44 (d, J = 7.0 Hz, 2H), 3.34 (s, 3H), 3.18 (s, 3H). ESI-HRMS m / z: calculated value is C 14 H 15 O 2 N 5 Na + [M+Na] + , 308.1118; the measured value is 308.1112.

[0226] (2) Synthesis of compound 34

[0227]

[0228] The synthesis steps were similar to those of compound 26, and compound 34 was obtained by column chromatography with a yield of 72%.

[0229] The obtained compound 34 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6 )δ7.58 (t, J = 6.0 Hz, 1H), 7.38-7.29 (m, 4H), 7.27-7.22 (m, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.08 (t, J = 7.0 Hz, 2H), 4.01-3.94 (m, 2H), 3.32 (s, 3H), 3.17 (s, 3H), 2.28 (t, J = 8.0 Hz, 2H), 1.95-1.87 (m, 2H), 1.13 (t, J = 7.5 Hz, 3H). ESI-HRMS m / z: calculated value is C 20 H 25 O 4 N 5 Na + [M+Na] + , 422.1799; the measured value is 422.1799.

[0230] (3) Synthesis of Compound 35

[0231]

[0232] The synthesis steps were similar to those of compound 27. After filtration and drying, compound 35 was obtained with a yield of 69%.

[0233] The obtained compound 35 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6 )δ9.01(s,1H),7.73(t,J=6.0Hz,1H),7.37-7.30(m,4H),7.27-7.21(m,1H),4.56(d,J=6.0Hz,2H),4.15(s,2H),4.07(t,J=7.0Hz,2H),3.33(s,3H),3.17(s,3H),2.04-1.98(dd,J=9.5,6.5Hz,2H),1.90-1.83(m,2H).ESI-HRMS m / z: calculated value is C 18 H 23 0 3 N 7 Na + [M+Na] +, 408.1755; the measured value is 408.1755.

[0234] Example 13 Synthesis of Compounds A1-A4

[0235]

[0236] 50 mg of compound 5 (0.15 mmol, 1.0 equiv.) was weighed and dissolved in N, N-dimethylformamide, 59 mg of HATU (0.15 mmol, 1.0 equiv.) and 60 mg of DIPEA (0.45 mmol, 3.0 equiv.) were added, stirred at room temperature for 20 min, the corresponding hydrazide reagent (0.15 mmol, 1.0 equiv.) was added, and the reaction was carried out at room temperature for 6 h. Monitored by TLC, after the reaction of the raw material was complete, water was added to quench, extracted with ethyl acetate 3 times, washed once with saturated sodium chloride solution, the ethyl acetate layer was dried with anhydrous sodium sulfate, the solution was concentrated, and purified by column chromatography to obtain products A1-A4.

[0237] The compounds A1-A4 are as follows:

[0238]

[0239] Example 14 Synthesis of Compound A1

[0240] The synthesis steps were as in Example 13, and compound 27 was selected as the hydrazide reagent to obtain compound A1 with a yield of 62%; 1 HNMR (600 MHz, DMSO-d 6 )δ10.18(br, 1H), 10.06(br, 1H), 8.80(s, 1H), 8.00(s, 1H), 7.67(d, J=1.8Hz , 1H), 7.61 (dd, J=8.4, 1.8Hz, 1H), 7.37 (d, J=8.4Hz, 1H), 7.22 (t, J=74.4Hz, 1 H), 4.50 (t, J=6.6Hz, 2H), 3.99 (d, J=7.2Hz, 2H), 3.42 (s, 3H), 3.24 (s, 3H), 2. 83(t, J=6.6Hz, 2H), 1.31-1.26(m, 1H), 0.62-0.58(m, 2H), 0.40-0.37(m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ168.6, 160.1, 158.9, 154.4, 151.0, 150.1, 148.4, 143.0 (2×C), 142.1, 135.6, 124.1, 121.2, 119.0, 116.5 (t, J=258.0 Hz), 111.8, 105.8, 73.3, 42.5, 33.9, 29.4, 27.6, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 25 H 25 O 7 N 7 F 2 Na + [M+Na] + , 596.1676; the measured value is 596.1709.

[0241] Example 15 Synthesis of Compound A2

[0242] The synthesis steps were as in Example 13, and compound 29 was selected as the hydrazide reagent to obtain compound A2 with a yield of 31%; 1 HNMR (500 MHz, DMSO-d 6 )δ10.16(br, 1H), 10.02(br, 1H), 8.80(s, 1H), 8.13(s, 1H), 7.68(d, J=2.0Hz, 1H) , 7.62 (dd, J=8.5, 2.0Hz, 1H), 7.39-7.36 (m, 1H), 7.23 (t, J=74.0Hz, 1H), 4.30 (t, J=6.5Hz, 2H), 4.00 (d, J=6.5Hz, 2H), 3.43 (s, 3H), 3.24 (s, 3H), 2.16 (t, J=7.5Hz, 2H), 2.11-2.02(m, 2H), 1.31-1.25(m, 1H), 0.61-0.58(m, 2H), 0.40-0.37(m, 2H). 13 CNMR (151 MHz, DMSO-d 6 )δ170.3, 160.1, 159.0, 154.4, 151.1, 150.1, 148.6, 142.9, 142.7, 142.1, 135.7, 124.1, 121.3, 119.1, 116.5 (t, J = 256.5 Hz), 111.8, 106.0, 73.3, 45.6, 29.7, 29.5, 27.6, 26.1, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 26 H 27 O 7 N 7 F2 Na + [M+Na] + , 610.1832; the measured value is 610.1875.

[0243] Example 16 Synthesis of Compound A3

[0244] The synthesis steps were as in Example 13, and compound 32 was selected as the hydrazide reagent to obtain compound A3 with a yield of 39%; 1 HNMR (500 MHz, DMSO-d 6 )δ10.14 (br, 1H), 9.96 (br, 1H), 8.79 (s, 1H), 7.68 (d, J=2.0Hz, 1H), 7.62 (dd, J=8.0, 2.0Hz, 1H), 7.37 (d, J=7.5Hz, 1H), 7.22 (t, J=74.0Hz, 1H), 4.33 (t, J=7. 0Hz, 2H), 3.99 (d, J=6.5Hz, 2H), 3.40 (s, 3H), 3.24 (s, 3H), 2.24 (d, J=7.5Hz, 2H ), 2.08-1.97(m, 2H), 1.32-1.24(m, 1H), 0.62-0.58(m, 2H), 0.40-0.37(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ170.2, 160.1, 158.9, 153.5, 150.7, 150.1, 147.9, 142.9, 142.1, 135.6, 127.8, 124.1, 121.3, 119. 1, 116.5 (t, J=256.5Hz), 111.8, 108.2, 73.3, 46.3, 29.9, 29.5, 27.7, 25.6, 9.9, 3.1 (2×C).ESI-HRMS m / z:calcd for C 26 H 26 O 7 N 7 F 2 Br + [M+Na] + , 688.0937; found, 688.0994.

[0245] Example 17 Synthesis of Compound A4

[0246] The synthesis steps were as in Example 13, and compound 35 was selected as the hydrazide reagent to obtain compound A4 with a yield of 65%; 1 HNMR (500 MHz, DMSO-d 6)δ10.17 (br, 1H), 9.99 (br, 1H), 8.79 (s, 1H), 7.68 (d, J = 2.0Hz, 1H), 7.65 (t, J = 6.0Hz, 1H), 7.62 (dd , J=8.5, 2.0Hz, 1H), 7.39-7.35 (m, 3H), 7.35-7.29 (m, 2H), 7.25 (d, J=7.0Hz, 1H), 7.22 (t, J=74.5Hz , 1H), 4.58 (d, J=6.0Hz, 2H), 4.12 (t, J=6.5Hz, 2H), 3.99 (d, J=7.0Hz, 2H), 3.34 (s, 3H), 3.19 (s, 3H) , 2.21 (t, J=8.0Hz, 2H), 1.99-1.91 (m, 2H), 1.32-1.26 (m, 1H), 0.62-0.57 (m, 2H), 0.40-0.37 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ170.8, 160.1, 159.0, 153.4, 152.7, 151.0, 150.2, 148.5, 142.9, 142.1, 139.6, 135.6, 128.3 (2×C), 127.3 (2×C), 126.9, 124.1, 121.3, 119.1, 116.5 (t, J=256.5 Hz), 111.8, 101.7, 73.3, 45.8, 41.9, 30.1, 29.3, 27.2, 25.4, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 33 H 34 0 7 N 8 F 2 Na + [M+Na] + , 715.2411; the measured value is 715.2388.

[0247] Example 18 Synthesis of Compounds B1-B2

[0248]

[0249] 50 mg of compound 7 (0.15 mmol, 1.0 equiv.) was weighed and dissolved in N, N-dimethylformamide, 59 mg of HATU (0.15 mmol, 1.0 equiv.) and 60 mg of DIPEA (0.45 mmol, 3.0 equiv.) were added, stirred at room temperature for 20 min, the corresponding hydrazide reagent (0.15 mmol, 1.0 equiv.) was added, and the reaction was carried out at room temperature for 6 h. Monitored by TLC, water was added to quench the reaction after the raw material reaction was complete, extracted with ethyl acetate 3 times, washed once with saturated sodium chloride solution, the ethyl acetate layer was dried with anhydrous sodium sulfate, the solution was concentrated, and purified by column chromatography to obtain compound B1-B2.

[0250] The compounds B1-B2 are as follows:

[0251]

[0252] Example 19 Synthesis of Compound B1

[0253] The synthesis steps were as in Example 18, and compound 29 was selected as the hydrazide reagent to obtain compound B1 with a yield of 33%; 1 HNMR (500 MHz, DMSO-d 6 )δ13.10(br,1H),9.85(br,1H),9.68(s,1H),8.15(s,1H),7.87(s,1H),7.78(s , 1H), 7.61 (d, J=9.0Hz, 1H), 7.29-7.25 (m, 1H), 7.06 (t, J=74.5Hz, 1H), 4.31 (t, J=6.5Hz, 2H), 3.98(d, J=7.0Hz, 2H), 3.44(s, 3H), 3.25(s, 3H), 2.18-2.11(m, 2 H), 2.11-2.05(m, 2H), 1.34-1.27(m, 1H), 0.64-0.57(m, 2H), 0.41-0.36(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ175.6, 170.5, 154.4, 151.1, 150.1, 148.6, 145.2, 142.7, 142.4, 140.1, 128.2, 121.8, 121.3, 117.7, 116.7 (t, J = 256.5 Hz), 111.3, 106.0, 73.1, 45.6, 29.7, 29.5, 27.6, 26.1, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 26 H 28 O 6 N8 F 2 Na + [M+Na] + , 609.1992; the measured value is 609.2042.

[0254] Example 20 Synthesis of Compound B2

[0255] The synthesis steps were as in Example 18, and compound 35 was selected as the hydrazide reagent to obtain compound B2 with a yield of 56%. 1 HNMR (500 MHz, DMSO-d 6 )δ13.10(br,1H),9.85(br,1H),9.68(s,1H),8.15(s,1H),7.87(s,1H),7.78(s , 1H), 7.61 (d, J=9.0Hz, 1H), 7.29-7.25 (m, 1H), 7.06 (t, J=74.5Hz, 1H), 4.31 (t, J=6.5Hz, 2H), 3.98(d, J=7.0Hz, 2H), 3.44(s, 3H), 3.25(s, 3H), 2.18-2.11(m, 2 H), 2.11-2.05(m, 2H), 1.34-1.27(m, 1H), 0.64-0.57(m, 2H), 0.41-0.36(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ175.6, 170.5, 154.4, 151.1, 150.1, 148.6, 145.2, 142.7, 142.4, 140.1, 128.2, 121.8, 121.3, 117.7, 116.7 (t, J = 256.5 Hz), 111.3, 106.0, 73.1, 45.6, 29.7, 29.5, 27.6, 26.1, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 33 H 35 O 6 N 9 F 2 Na + [M+Na] + , 714.2571; the measured value is 714.2556.

[0256] Example 21 Synthesis of Compounds C1-C4

[0257]

[0258] 50 mg of compound 9 (0.15 mmol, 1.0 equiv.) was weighed and dissolved in N, N-dimethylformamide, 59 mg of HATU (0.15 mmol, 1.0 equiv.) and 60 mg of DIPEA (0.45 mmol, 3.0 equiv.) were added, stirred at room temperature for 20 min, the corresponding hydrazide reagent (0.15 mmol, 1.0 equiv.) was added, and the reaction was carried out at room temperature for 6 h. The reaction was monitored by TLC, and water was added to quench the reaction after the reaction of the raw material was complete, extracted with ethyl acetate 3 times, washed once with saturated sodium chloride solution, and the ethyl acetate layer was dried with anhydrous sodium sulfate. The solution was concentrated and purified by column chromatography to obtain compounds C1-C4.

[0259] The compounds C1-C4 are as follows:

[0260]

[0261] Example 22 Synthesis of Compound C1

[0262] The synthesis steps were as in Example 21, and compound 27 was selected as the hydrazide reagent to obtain compound C1 with a yield of 86%. 1 HNMR (600 MHz, DMSO-d 6 ) δ10.23 (br, 2H), 8.39 (s, 1H), 8.02 (s, 1H), 7.83 (d, J = 1.8Hz, 1H), 7.60 (dd, J = 7.8, 1.8Hz, 1H), 7.33-7.29 (m, 1H), 7.19 (t, J = 74.4Hz, 1H), 4.51 ( t, J=6.6Hz, 2H), 4.02 (d, J=6.6Hz, 2H), 3.43 (s, 3H), 3.25 (s, 3H), 2.86 (t , J=6.6Hz, 2H), 1.31-1.26(m, 1H), 0.62-0.58(m, 2H), 0.41-0.37(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ168.7, 166.4, 159.4, 154.4, 151.0, 150.3, 148.6, 148.5, 143.0, 141.7, 130.6, 125.5, 121.3, 119.4, 116.6 (d, J = 256.5 Hz), 111.9, 105.8, 73.3, 42.5, 33.9, 29.5, 27.6, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 25 H 25 O 6 N 7 F 2 SNa+ [M+Na] + , 612.1447; the measured value is 612.1417.

[0263] Example 23 Synthesis of Compound C2

[0264] The synthesis steps were as in Example 21, and compound 29 was selected as the hydrazide reagent to obtain compound C2 with a yield of 48%; 1 HNMR (600 MHz, DMSO-d 6 )δ10.33(br, 1H), 10.00(br, 1H), 8.40(s, 1H), 8.14(s, 1H), 7.84(d, J=2.4Hz, 1H) , 7.61 (dd, J=8.4, 1.8Hz, 1H), 7.31 (d, J=8.4Hz, 1H), 7.14 (t, J=74.4Hz, 1H), 4.31 ( t, J=6.6Hz, 2H), 4.03 (d, J=7.2Hz, 2H), 3.43 (s, 3H), 3.24 (s, 3H), 2.18 (t, J=7.2Hz , 2H), 2.13-2.06(m, 2H), 1.32-1.26(m, 1H), 0.64-0.58(m, 2H), 0.42-0.36(m, 2H). 13 CNMR (151 MHz, DMSO-d 6 )δ170.6, 166.4, 159.6, 154.4, 151.0, 150.3, 148.6 (2×C), 142.7, 141.7, 130.5, 125.6, 121.3, 119.4, 116.6 (d, J=256.5 Hz), 111.9, 106.0, 73.3, 45.6, 29.7, 29.4, 27.6, 26.1, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 26 H 27 O 6 N 7 F 2 SNa + [M+Na] + , 626.1604; the measured value is 626.1653.

[0265] Example 24 Synthesis of Compound C3

[0266] The synthesis steps were as in Example 21, and compound 32 was selected as the hydrazide reagent to obtain compound C3 with a yield of 23%; 1 HNMR (600 MHz, DMSO-d 6)δ10.28 (br, 1H), 10.04 (br, 1H), 8.36 (s, 1H), 7.82 (s, 1H), 7.60 (dd, J=8.4 , 1.8Hz, 1H), 7.33-7.29 (m, 1H), 7.19 (t, J=74.4Hz, 1H), 4.34 (t, J=7.2Hz, 2 H), 4.03 (d, J=6.6Hz, 2H), 3.40 (s, 3H), 3.24 (s, 3H), 2.27 (t, J=7.8Hz, 2H), 2.07-2.01(m, 2H), 1.32-1.26(m, 1H), 0.62-0.58(m, 2H), 0.40-0.37(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ170.3, 166.4, 159.4, 153.6, 150.7, 150.3, 148.8, 147.9, 141.7, 130.6, 127.8, 125.5, 121.3, 119.4, 116.6 (t, J = 256.5 Hz), 111.9, 108.3, 73.3, 46.4, 30.0, 29.6, 27.7, 25.7, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 26 H 26 O 6 N 7 F 2 BnN + [M+Na] + , 704.0709; the measured value is 704.0763.

[0267] Example 25 Synthesis of Compound C4

[0268] The synthesis steps were as in Example 21, and compound 35 was selected as the hydrazide reagent to obtain compound C4 with a yield of 67%; 1 HNMR (600 MHz, DMSO-d 6)δ10.32 (s, 1H), 10.02 (s, 1H), 8.37 (s, 1H), 7.84 (d, J = 1.8Hz, 1H), 7.64 (t, J = 6.0Hz, 1H), 7.61 (dd, J=7.8, 2.4Hz, 1H), 7.38 (d, J=7.2Hz, 2H), 7.35-7.29 (m, 3H), 7.24 (t, J=7.2Hz, 1H), 7.14 (t, J=74.4H z, 1H), 4.59 (d, J=6.0Hz, 2H), 4.14 (t, J=7.2Hz, 2H), 4.03 (d, J=7.2Hz, 2H), 3.34 (s, 3H), 3.19 (s, 3H) , 2.24 (d, J=7.8Hz, 2H), 2.00-1.93 (m, 2H), 1.32-1.26 (m, 1H), 0.62-0.59 (m, 2H), 0.40-0.38 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ171.0, 166.4, 159.5, 153.4, 152.7, 151.0, 150.3, 148.6, 148.5, 141.7, 139.6, 130.5, 128.3 (2×C), 127.3 (2×C), 126.9, 125.5, 121.3, 119.3, 116.6 (t, J=256.5 Hz), 111.9, 101.7, 73.3, 45.8, 41.9, 30.2, 29.3, 27.2, 25.5, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 33 H 34 O 6 N 8 F 2 NaS + [M+Na] + , 731.2182; the measured value is 731.2161.

[0269] Example 26 Synthesis of Compounds D1-D4

[0270]

[0271] 50 mg of compound 11 (0.13 mmol, 1.0 equiv.) was weighed and dissolved in N, N-dimethylformamide, 51 mg of HATU (0.13 mmol, 1.0 equiv.) and 52 mg of DIPEA (0.39 mmol, 3.0 equiv.) were added, stirred at room temperature for 20 min, the corresponding hydrazide reagent (0.13 mmol, 1.0 equiv.) was added, and the reaction was carried out at room temperature for 6 h. Monitored by TLC, water was added to quench the reaction after the raw material reaction was complete, extracted with ethyl acetate 3 times, washed once with saturated sodium chloride solution, the ethyl acetate layer was dried with anhydrous sodium sulfate, the solution was concentrated, and purified by column chromatography to obtain compounds D1-D4.

[0272] The compounds D1-D4 are as follows:

[0273]

[0274] Example 27 Synthesis of Compound D1

[0275] The synthesis steps were as shown in Example 26. Compound 27 was selected as the hydrazide reagent to obtain compound D1 with a yield of 28%. 1 HNMR (600 MHz, DMSO-d 6 ) δ12.46 (br, 1H), 11.15 (br, 1H), 8.12 (d, J = 1.8Hz, 1H), 8.00 (s, 1H), 7.91-7. 84 (m, 2H), 7.78 (d, J=7.8Hz, 1H), 7.42-7.36 (m, 2H), 7.23 (t, J=74.4Hz, 1H), 4. 56 (t, J=6.6Hz, 2H), 4.09 (d, J=7.2Hz, 2H), 3.40 (s, 3H), 3.22 (s, 3H), 2.92 (t, J=6.6Hz, 2H), 1.36-1.30 (m, 1H), 0.64-0.59 (m, 2H), 0.43-0.39 (m, 2H), NH (not observed). 13 C NMR (151 MHz, DMSO-d 6 )δ165.8, 160.5, 154.4, 151.5, 151.0, 150.2, 148.4, 142.6, 141.6, 140.6, 135.3, 127.0, 112.6, 122.7, 121.2, 120.0, 119.4, 116.6 (t, J = 256.5 Hz), 115.6, 112.8, 106.0, 73.3, 42.7, 34.1, 29.4, 27.6, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 29 H28 0 6 N 8 F 2 Na + [M+Na] + , 645.1992; the measured value is 645.2036.

[0276] Example 28 Synthesis of Compound D2

[0277] The synthesis steps were as in Example 26, and compound 29 was selected as the hydrazide reagent to obtain compound D2 with a yield of 78%; 1 HNMR (500 MHz, DMSO-d 6 )δ12.56(br, 1H), 11.04(br, 1H), 8.15(d, J=2.0Hz, 1H), 8.06(s, 1H), 7.89-7.83(m, 2H ), 7.77 (d, J = 8.0Hz, 1H), 7.40-7.35 (m, 2H), 7.20 (t, J = 74.5Hz, 1H), 4.31 (t, J = 6.5Hz, 2H), 4.06 (d, J=7.0Hz, 2H), 3.27 (s, 3H), 3.16 (s, 3H), 2.31 (t, J=7.5Hz, 2H), 2.19-2.1 1(m, 2H), 1.34-1.25(m, 1H), 0.59-0.54(m, 2H), 0.40-0.35(m, 2H), NH (notobserved). 13 C NMR (151 MHz, DMSO-d 6 )δ167.4, 160.2, 154.4, 151.4, 151.0, 150.3, 148.5, 142.7, 141.6, 140.6, 135.3, 127.0, 122.8, 122.6, 121.2, 120.1, 119.2, 116.7 (t, J = 256.5 Hz), 115.5, 112.8, 106.2, 73.4, 45.9, 29.8, 29.3, 27.5, 26.2, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 30 H 30 O 6 N 8 F 2 Na + [M+Na] + , 659.2149; the measured value is 659.2196.

[0278] Example 29 Synthesis of Compound D3

[0279] The synthesis steps were as in Example 26, and compound 32 was selected as the hydrazide reagent to obtain compound D3 with a yield of 15%; 1 HNMR (600 MHz, DMSO-d 6 )δ13.48(br, 1H), 12.57(s, 1H), 11.10(s, 1H), 8.17(d, J=2.4Hz, 1H), 7.86(t, J=7 .8Hz, 2H), 7.77(d, J=8.4Hz, 1H), 7.41-7.36(m, 2H), 7.22(t, J=74.4Hz, 1H), 4.34( t, J=6.6Hz, 2H), 4.08 (d, J=7.2Hz, 2H), 3.29 (s, 3H), 3.18 (s, 3H), 2.35 (t, J=7.2Hz , 2H), 2.15-2.07(m, 2H), 1.34-1.28(m, 1H), 0.60-0.56(m, 2H), 0.39-0.35(m, 2H). 13 CNMR (151 MHz, DMSO-d 6 )δ167.0, 160.0, 153.5, 151.3, 150.6, 150.2, 147.7, 141.6, 140.5, 135.1, 127.8, 126.9, 122.8, 122.6, 121.1, 120.1, 119.2, 116.6 (t, J = 256.5 Hz), 115.4, 112.8, 108.3, 73.4, 46.4, 29.7, 29.4, 27.6, 25.5, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 30 H 29 O 6 N 8 F 2 Br + [M+Na] + , 737.1254; the measured value is 737.1307.

[0280] Example 30 Synthesis of Compound D4

[0281] The synthesis steps were as in Example 26, and compound 35 was selected as the hydrazide reagent to obtain compound D4 with a yield of 38%; 1 HNMR (500 MHz, DMSO-d 6) δ13.47 (br, 1H), 12.47 (s, 1H), 11.01 (s, 1H), 8.16 (d, J = 2.0Hz, 1H), 7.88 (dd, J = 8.5, 2.0Hz, 2H), 7.78 (d, J=8.0Hz, 1H), 7.65 (t, J=6.0Hz, 1H), 7.41-7.35 (m, 4H), 7.31 (t, J=7.0Hz, 2H), 7.23 (d, J=7.0Hz, 1H), 7.21 (t, J=74.0Hz, 1H), 4.58 (d, J=5.5Hz, 2H), 4.17 (t, J=6.5Hz, 2H), 4.07 (d, J=7.0Hz, 2H), 3.32 (s, 3H), 3.17 ( s, 3H), 2.33 (t, J=7.5Hz, 2H), 2.05-1.98 (m, 2H), 1.32-1.24 (m, 1H), 0.57-0.52 (m, 2H), 0.37-0.33 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ167.9, 160.5, 153.5, 152.7, 151.4, 151.0, 150.2, 148.5, 141.6, 140.6, 139.6, 135.2, 128.3 (2×C), 127.3 (2×C), 127.0, 126.9, 122.7, 122.6, 121.2, 120.2, 119.3, 116.6 (t, J=256.5 Hz), 115.5, 112.9, 101.8, 73.3, 45.9, 42.0, 29.8, 29.3, 27.2, 25.3, 9.9, 3.0 (2×C). ESI-HRMS m / z: calculated for C 37 H 37 O 6 N 9 F 2 Na + [M+Na] + , 764.2727; the measured value is 764.2714.

[0282] Example 31 Synthesis of Compounds E1-E4

[0283]

[0284] 50 mg of compound 14 (0.13 mmol, 1.0 equiv.) was weighed and dissolved in N, N-dimethylformamide, 51 mg of HATU (0.13 mmol, 1.0 equiv.) and 52 mg of DIPEA (0.39 mmol, 3.0 equiv.) were added, stirred at room temperature for 20 min, the corresponding hydrazide reagent (0.13 mmol, 1.0 equiv.) was added, and the reaction was carried out at room temperature for 6 h. The reaction was monitored by TLC, and water was added to quench the reaction after the reaction of the raw material was complete, extracted with ethyl acetate 3 times, washed once with a saturated sodium chloride solution, and the ethyl acetate layer was dried with anhydrous sodium sulfate. The solution was concentrated and subjected to column chromatography to obtain compounds E1-E4.

[0285] The compounds E1-E4 are as follows:

[0286]

[0287] Example 32 Synthesis of Compound E1

[0288] The synthesis steps were as in Example 31, and compound 27 was selected as the hydrazide reagent to obtain compound E1 with a yield of 83%; 1 HNMR (500 MHz, DMSO-d 6 ) δ13.65 (s, 1H), 12.08 (s, 1H), 10.95 (s, 1H), 8.28 (d, J = 2.0Hz, 1H), 8.24 (dd, J = 8.5, 2.5Hz, 1H), 8.02 (s, 1H), 7.90 (d, J=7.5Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.62 (d, J=8.5Hz, 1H), 7.41 (t, J=8.0Hz, 1H), 7.36 (t, J=74.0Hz, 1H), 7.34 (t, J=73.0 Hz, 1H), 4.56 (t, J=6.5Hz, 2H), 3.41 (s, 3H), 3.24 (s, 3H), 2.92 (t, J=7.0Hz, 2H). 13 CNMR (151 MHz, DMSO-d 6 )δ166.5, 161.2, 154.4, 151.1, 150.3, 148.5, 143.7, 142.8 (2×C), 141.9, 140.5, 135.2, 126.8, 125.1, 123.1, 121.1, 120.3, 119.7, 116.5 (t, J = 256.5 Hz), 116.3 (t, J = 256.5 Hz), 115.8, 105.9, 42.6, 34.0, 29.4, 27.6. ESI-HRMS m / z: calculated for C 26 H 22 O6 N 8 F 4 Na + [M+Na] + , 641.1491; the measured value is 641.1533.

[0289] Example 33 Synthesis of Compound E2

[0290] The synthesis steps were as in Example 31, and compound 29 was selected as the hydrazide reagent to obtain compound E2 with a yield of 90%; 1 HNMR (500 MHz, DMSO-d 6 )δ13.63(br, 1H), 12.15(s, 1H), 10.85(s, 1H), 8.31(d, J=2.0Hz, 1H), 8.24(dd, J=9.0, 2.0Hz, 1H), 8.10 (s, 1H), 7.91 (d, J=7.5Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7. 60 (d, J=8.5Hz, 1H), 7.41 (t, J=8.0Hz, 1H), 7.35 (t, J=256.5Hz, 2H), 4.33 (t, J= 6.5Hz, 2H), 3.37 (s, 3H), 3.20 (s, 3H), 2.29 (t, J=7.0Hz, 2H), 2.18-2.10 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ168.2, 161.1, 154.4, 151.0, 150.3, 148.5, 143.5, 142.6, 142.0, 140.5, 135.2, 126.9, 124.9, 123.0, 123.0, 121.1, 120.4, 119.4, 116.5 (t, J = 258.0 Hz), 116.3 (t, J = 258.0 Hz), 115.7, 106.1, 45.7, 29.6, 29.3, 27.5, 26.1. ESI-HRMS m / z: calculated for C 27 H 24 O 6 N 8 F4F + [M+Na] + , 655.1647; the measured value is 655.1699.

[0291] Example 34 Synthesis of Compound E3

[0292] The synthesis steps were as shown in Example 31, and compound 32 was selected as the hydrazide reagent to obtain compound E3 with a yield of 23%; 1HNMR (500 MHz, DMSO-d 6 )δ13.64(br, 1H), 12.13(s, 1H), 10.86(s, 1H), 8.30(s, 1H), 8.25(dd, J=8.5, 2. 0Hz, 1H), 7.90 (d, J=7.5Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7.60 (d, J=8.5Hz, 1H), 7. 41 (t, J=7.5Hz, 1H), 7.35 (t, J=73.0Hz, 1H), 7.34 (t, J=73.0Hz, 1H), 4.37 (t, J= 7.0Hz, 2H), 3.34 (s, 3H), 3.22 (s, 3H), 2.35 (t, J=7.0Hz, 2H), 2.14-2.07 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ168.0, 161.0, 153.6, 150.7, 150.3, 147.8, 143.6, 142.0, 140.5, 135.2, 127.8, 126.9, 125.0, 123.0, 123.0, 121.1, 120.4, 119.5, 116.5 (t, J = 259.5 Hz), 116.3 (t, J = 258.0 Hz), 115.7, 108.4, 46.3, 29.6, 29.4, 27.7, 25.4. ESI-HRMS m / z: calculated for C 27 H 23 O 6 N 8 F 4 Br + [M+Na] + , 733.0752; the measured value is 733.0798.

[0293] Example 35 Synthesis of Compound E4

[0294] The synthesis steps were as in Example 31, and compound 35 was selected as the hydrazide reagent to obtain compound E4 with a yield of 30%; 1 HNMR (500 MHz, DMSO-d 6)δ13.64 (s, 1H), 12.04 (s, 1H), 10.80 (s, 1H), 8.30 (s, 1H), 8.25 (d, J=8.5Hz, 1H), 7.9 0 (d, J=7.5Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.64 (t, J=6.0Hz, 1H), 7.58 (d, J=8.5Hz, 1H) , 7.43-7.34 (m, 3H), 7.35-7.30 (m, 3H), 7.25-7.19 (m, 2H), 4.59 (d, J=7.5Hz, 2H), 4.17 (t, J=6.5Hz, 2H), 3.33 (s, 3H), 3.18 (s, 3H), 2.32 (t, J=7.5Hz, 2H), 2.05-1.97 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ168.8, 161.4, 153.5, 152.8, 151.0, 150.3, 148.4, 143.6, 142.0, 140.6, 139.6, 135.2, 128.3 (2×C), 128.2, 127.3 (2×C), 127.2, 126.9, 125.1, 123.0, 121.1, 120.4, 119.5, 116.5 (t, J = 256.5 Hz), 116.3 (t, J = 256.5 Hz), 115.7, 101.8, 45.9, 41.9, 29.9, 29.3, 27.2, 25.3. ESI-MS m / z: calculated value is C 34 H 31 O 6 N 9 F 4 Na + [M+Na] + , 762.2226; the measured value is 762.2204.

[0295] Example 36 Synthesis of Compounds F1-F4

[0296]

[0297] 50 mg of compound 20 (0.13 mmol, 1.0 equiv.) was weighed and dissolved in N, N-dimethylformamide, 51 mg of HATU (0.13 mmol, 1.0 equiv.) and 52 mg of DIPEA (0.39 mmol, 3.0 equiv.) were added, stirred at room temperature for 20 min, the corresponding hydrazide reagent (0.13 mmol, 1.0 equiv.) was added, and the reaction was carried out at room temperature for 6 h. Monitored by TLC, water was added to quench the reaction after the raw material reaction was complete, extracted with ethyl acetate 3 times, washed once with saturated sodium chloride solution, the ethyl acetate layer was dried with anhydrous sodium sulfate, the solution was concentrated, and purified by column chromatography to obtain compounds F1-F4.

[0298] The compounds F1-F4 are as follows:

[0299]

[0300] Example 37 Synthesis of Compound F1

[0301] The synthesis steps were as in Example 36, and compound 27 was selected as the hydrazide reagent to obtain compound F1 with a yield of 50%; 1 HNMR (600 MHz, DMSO-d 6 ) δ10.31 (br, 1H), 10.08 (br, 1H), 8.70 (d, J = 4.2Hz, 1H), 8.00 (s, 1H), 7.90 (dd, J = 8.4, 1. 8Hz, 1H), 7.89 (d, J=2.4Hz, 1H), 7.45 (d, J=4.8Hz, 1H), 7.38 (d, J=8.4Hz, 1H), 7.26 (t, J= 73.8Hz, 1H), 7.22 (s, 1H), 4.51 (t, J=6.6Hz, 2H), 4.03 (d, J=7.2Hz, 2H), 3.42 (s, 3H), 3.2 5(s, 3H), 2.85(t, J=6.6Hz, 2H), 1.33-1.27(m, 1H), 0.60-0.56(m, 2H), 0.37-0.34(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ168.6, 160.2, 154.4, 151.0, 150.7, 149.8, 149.5, 148.4, 148.2, 145.0, 142.9, 141.8, 127.8, 122.7, 120.5, 116.5 (t, J = 256.5 Hz), 115.7, 109.6, 105.8, 97.1, 73.3, 42.5, 33.9, 29.4, 27.6, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C28 H 27 O 6 N 9 F 2 Na + [M+Na] + , 646.1945; the measured value is 646.1983.

[0302] Example 38 Synthesis of Compound F2

[0303] The synthetic steps were as in Example 36, and compound 29 was selected as the hydrazide reagent to obtain compound F2 with a yield of 10%; 1 HNMR (500 MHz, DMSO-d 6 )δ10.28(br, 1H), 10.00(br, 1H), 8.70(d, J=4.5Hz, 1H), 8.12(s, 1H), 7.93-7.88(m, 2H), 7.45 (d, J=4.5Hz, 1H), 7.38 (d, J=8.0Hz, 1H), 7.26 (t, J=74.0Hz, 1H), 7.23 (s, 1H ), 4.31 (t, J=6.5Hz, 2H), 4.03 (d, J=7.0Hz, 2H), 3.43 (s, 3H), 3.24 (s, 3H), 2.19-2.14 (m, 2H), 2.12-2.05 (m, 2H), 1.34-1.28 (m, 1H), 0.60-0.56 (m, 2H), 0.37-0.34 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ170.5, 160.4, 154.4, 151.0, 150.7, 149.8, 149.5, 148.6, 148.3, 145.0, 142.7, 141.8, 127.8, 122.7, 120.5, 116.5 (t, J = 258.0 Hz), 115.7, 109.6, 106.0, 97.1, 73.3, 45.6, 29.7, 29.4, 27.6, 26.1, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 29 H 29 O 6 N 9 F 2 Na + [M+Na] + , 660.2101; the measured value is 660.2068.

[0304] Example 39 Synthesis of Compound F3

[0305] The synthesis steps were as in Example 36, and compound 32 was selected as the hydrazide reagent to obtain compound F3 with a yield of 32%; 1 HNMR (600 MHz, DMSO-d 6 )δ10.26(s, 1H), 10.00(s, 1H), 8.70(d, J=4.2Hz, 1H), 7.92-7.88(m, 2H), 7.45(d, J=4.6Hz, 1H), 7.38(d, J=8.4Hz, 1H), 7.21(s, 1H), 7.20(t, J=74.4Hz, 1H), 4.34(t , J=7.2Hz, 2H), 4.02 (d, J=6.6Hz, 2H), 3.39 (s, 3H), 3.23 (s, 3H), 2.26 (d, J=7.2Hz , 2H), 2.06-2.01(m, 2H), 1.33-1.28(m, 1H), 0.60-0.57(m, 2H), 0.37-0.35(m, 2H). 13 CNMR (151 MHz, DMSO-d 6 )δ170.3, 160.2, 153.5, 150.7, 150.6, 149.8, 149.5, 148.3, 147.9, 144.9, 141.8, 127.8, 127.8, 122.7, 120.5, 116.5 (t, J = 256.5 Hz), 115.6, 109.6, 108.2, 97.1, 73.3, 46.4, 29.9, 29.5, 27.7, 25.6, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 29 H 28 O 6 N 9 F 2 Br + [M+Na] + , 738.1206; the measured value is 738.1263.

[0306] Example 40 Synthesis of Compound F4

[0307] The synthesis steps were as in Example 36, and compound 35 was selected as the hydrazide reagent to obtain compound F4 with a yield of 40%; 1 HNMR (600 MHz, DMSO-d 6) δ10.28 (s, 1H), 10.02 (s, 1H), 8.70 (d, J = 4.2Hz, 1H), 7.91 (dd, J = 7.8, 1.8Hz, 1H), 7.89 (d, J = 2.4Hz, 1H), 7.64 (t, J=6.0Hz, 1H), 7.45 (d, J=4.2Hz, 1H), 7.37 (dd, J=8.4, 1.8Hz, 3H), 7.32 (t, J=7.2Hz, 2H), 7.26 (t, J=74.4Hz, 1H), 7 .24 (t, J=7.2Hz, 1H), 7.21 (s, 1H), 4.58 (d, J=6.0Hz, 2H), 4.13 (t, J=6.6Hz, 2H), 4.02 (d, J=7.2Hz, 2H), 3.34 (s, 3H ), 3.18 (s, 3H), 2.22 (t, J=7.8Hz, 2H), 1.99-1.93 (m, 2H), 1.33-1.28 (m, 1H), 0.59-0.56 (m, 2H), 0.37-0.34 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ170.8, 160.3, 153.4, 152.7, 151.0, 150.7, 149.8, 149.5, 148.5, 148.3, 145.0, 141.8, 139.6, 128.3 (2×C), 127.8, 127.3 (2×C), 126.9, 122.7, 120.5, 116.5 (t, J=256.5 Hz), 115.7, 109.6, 101.7, 97.1, 73.3, 45.8, 41.9, 30.2, 29.3, 27.2, 25.5, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated value is C 36 H 36 O 6 N 10 F 2 Na + [M+Na] + , 765.2680; the measured value is 765.2669.

[0308] Example 41 Synthesis of Compounds G1-G3

[0309]

[0310] 50 mg of compound 22 (0.13 mmol, 1.0 equiv.) was weighed and dissolved in N, N-dimethylformamide, 51 mg of HATU (0.13 mmol, 1.0 equiv.) and 52 mg of DIPEA (0.39 mmol, 3.0 equiv.) were added, stirred at room temperature for 20 min, the corresponding hydrazide reagent (0.13 mmol, 1.0 equiv.) was added, and the reaction was carried out at room temperature for 6 h. Monitored by TLC, water was added to quench the reaction after the raw material reaction was complete, extracted with ethyl acetate 3 times, washed once with saturated sodium chloride solution, the ethyl acetate layer was dried with anhydrous sodium sulfate, the solution was concentrated, and purified by column chromatography to obtain compounds G1-G3.

[0311] The compounds G1-G3 are as follows:

[0312]

[0313] Example 42 Synthesis of Compound G1

[0314] The synthesis steps were as in Example 41, and compound 27 was selected as the hydrazide reagent to obtain compound G1 with a yield of 84%; 1 HNMR (600 MHz, DMSO-d 6 )δ10.42(s, 1H), 9.79(s, 1H), 8.87(d, J=4.8Hz, 1H), 8.68(s, 1H), 8.02(s, 1H), 7.83(d, J=2.4Hz, 1H), 7.78 (dd, J=8.4, 1.8Hz, 1H), 7.54 (d, J=4.8Hz, 1H), 7.41 (d, J=8.4Hz, 1H), 7.26 (t, J=73.8Hz, 1H), 4.52 (t, J=6.6Hz, 2H), 3.99 (d, J=7.2Hz, 2H), 3.41 (s, 3H), 3.24 (s, 3H), 2.86 (t, J=6.6Hz, 2H), 1.33-1.27 (m, 1H), 0.61-0.57 (m, 2H), 0.38-0.35 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ168.0, 159.7, 154.4, 152.3, 151.1, 149.5, 148.4, 146.8, 146.5, 145.7, 142.9, 142.2, 127.6, 122.9, 120.5, 116.5 (t, J = 256.5 Hz), 116.0, 109.6, 105.9, 103.4, 73.4, 42.6, 33.9, 29.5, 27.6, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C28 H 27 O 6 N 9 F 2 Na + [M+Na] + , 646.1945; the measured value is 646.1930.

[0315] Example 43 Synthesis of Compound G2

[0316] Synthesis steps: Refer to Example 41, select compound 29 as hydrazide reagent to obtain compound G2, yield: 32%; 1 HNMR (500 MHz, DMSO-d 6 ) δ10.30 (s, 1H), 9.78 (s, 1H), 8.88 (d, J = 4.5Hz, 1H), 8.69 (s, 1H), 8.13 (s, 1H), 7.84 (d, J = 2. 0Hz, 1H), 7.79 (dd, J=8.5, 2.0Hz, 1H), 7.55 (d, J=4.5Hz, 1H), 7.42 (d, J=8.0Hz, 1H), 7.26 (t, J =74.0Hz, 1H), 4.31 (t, J = 6.5Hz, 2H), 4.00 (d, J = 7.0Hz, 2H), 3.43 (s, 3H), 3.24 (s, 3H), 2.20 ( t, J=7.5Hz, 2H), 2.14-2.06(m, 2H), 1.36-1.27(m, 1H), 0.63-0.57(m, 2H), 0.39-0.35(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ169.8, 159.8, 154.4, 152.3, 151.1, 149.5, 148.5, 146.7, 146.5, 145.7, 142.7, 142.1, 127.6, 122.8, 120.5, 116.5 (t, J = 256.5 Hz), 116.0, 109.6, 106.0, 103.4, 73.4, 45.6, 29.6, 29.4, 27.6, 26.0, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 29 H 29 O 6 N 9 F 2 Na + [M+Na] + , 660.2101; the measured value is 660.2149.

[0317] Example 44 Synthesis of Compound G3

[0318] The synthesis steps were as in Example 41, and compound 35 was selected as the hydrazide reagent to obtain compound G3 with a yield of 69%; 1 HNMR (500 MHz, DMSO-d 6 )δ10.30 (d, J=2.5Hz, 1H), 9.77 (d, J=2.5Hz, 1H), 8.87 (d, J=4.5Hz, 1H), 8.67 (s, 1H), 7.84 (d, J=2.0Hz, 1H), 7.79 (dd, J= 8.5, 2.0Hz, 1H), 7.64 (t, J=6.0Hz, 1H), 7.54 (d, J=4.5Hz, 1H), 7.42 (d, J=8.5Hz, 1H), 7.38 (dd, 2H), 7.34-7.30 (m, 2H), 7 .26 (t, J=74.5Hz, 1H), 7.24 (t, J=7.5Hz, 1H), 4.59 (d, J=5.5Hz, 2H), 4.14 (t, J=6.5Hz, 2H), 4.00 (d, J=7.0Hz, 2H), 3.34 ( s, 3H), 3.19 (s, 3H), 2.25 (t, J=7.5Hz, 2H), 2.03-1.93 (m, 2H), 1.34-1.27 (m, 1H), 0.61-0.58 (m, 2H), 0.39-0.35 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ170.2, 159.9, 153.4, 152.7, 152.3, 151.0, 149.5, 148.5, 146.7, 146.5, 145.6, 142.1, 139.6, 128.3 (2×C), 127.6, 127.3 (2×C), 126.9, 122.8, 120.5, 116.5 (t, J=258.0 Hz), 116.0, 109.6, 103.4, 101.8, 73.4, 45.8, 41.9, 30.0, 29.3, 27.2, 25.3, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 36 H 36 O 6 N 10 F 2 Na + [M+Na] + , 765.2680; the measured value is 765.2671.

[0319] Example 45 Synthesis of Compound H1

[0320]

[0321] 50 mg of compound 24 (0.13 mmol, 1.0 equiv.) was weighed and dissolved in N, N-dimethylformamide, 51 mg of HATU (0.13 mmol, 1.0 equiv.) and 52 mg of DIPEA (0.39 mmol, 3.0 equiv.) were added, stirred at room temperature for 20 min, 42 mg of compound 27 (0.13 mmol, 1.0 equiv.) was added, and the reaction was carried out at room temperature for 6 h. Monitored by TLC, water was added to quench the reaction after the raw material reaction was complete, extracted with ethyl acetate 3 times, washed once with saturated sodium chloride solution, the ethyl acetate layer was dried with anhydrous sodium sulfate, the solution was concentrated, and purified by column chromatography to obtain compound H1 with a yield of 15%;

[0322] The obtained compound H1 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (500 MHz, DMSO-d 6 )δ13.22 (br, 1H), 9.95 (s, 1H), 9.77 (s, 1H), 8.01 (s, 1H), 8.00 (s, 1H), 7.94 (d, J = 9.5Hz, 1H), 7.89 (s, 1H), 7.48 (d, J = 8.5Hz, 1H), 7.27 (t, J=73.5Hz, 1H), 7.24 (t, J=73.5Hz, 1H), 4.51 (t, J=6.5Hz, 2H), 3.42 (s, 3H), 3.24 (s, 3H), 2.81 (t, J=6.5Hz, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ173.9, 168.7, 160.9, 154.4, 151.0, 148.4, 144.2, 143.0, 142.1, 142.0, 135.4, 128.1, 123.2, 121.2, 118.2, 116.6 (t, J = 256.5 Hz), 116.4 (t, J = 256.5 Hz), 105.8, 42.6, 34.0, 29.4, 27.6. ESI-HRMS m / z: calculated value is C 22 H 20 O 6 N 8 F 4 Na + [M+Na] + , 591.1334; the measured value is 591.1382.

[0323] Active Examples

[0324] Activity Example 1 Detection of the Inhibition Rate of the Compounds of the Present Application on PDE4 (PDE4B1, PDE4D2) and PDE7A

[0325] 1. Preparation of reaction buffer and reaction stop solution (reagents see Table 1)

[0326] (1) Preparation of 1x reaction buffer

[0327] IMAP reaction buffer (provided by IMAP FP IPP Explorer Kit) containing 0.1% BSA (5×) was diluted into 1× reaction buffer containing 1 mM DTT.

[0328] (2) Preparation of reaction termination solution

[0329] The reaction termination solution was prepared by mixing IMAP process binding buffer A (5×), IMAP process binding buffer B (5×), and IMAP process binding reagent (Progressive Binding Reagent) (provided by IMAPFPIPPExplorer Kit) according to the instruction manual.

[0330] 2. Compound Preparation

[0331] (1) Compound dilution

[0332] Prepare a solution with a concentration of 100 times the final concentration of the compound to be tested. Use an automatic microporous pipette (PrecisionPRC384U) to dilute the compound gradient to the set number of concentration points as follows: For a 5-fold dilution, add 50 μL of the starting concentration of the compound DMSO solution to well A2 on the Echo 384-well plate, and add 40 μL of 100% DMSO to wells A3-A11; take 10 μL of the compound from well A2 and add well A3, mix well, and make 5-fold dilutions in turn, diluting 10 concentration points; add 40 μL of 100% DMSO to wells A1 and A12.

[0333] (2) Transfer compounds to 384 reaction plates

[0334] Use the Echo550 instrument to transfer 200 nL of the diluted compound from the Echo384-well plate to a 384-well reaction plate, and transfer 200 nL of 100% DMSO to both the negative control and the positive control.

[0335] 3. Enzymatic reaction

[0336] (1) Prepare 2x enzyme solution

[0337] PDE4B1 was added to 1x reaction buffer to form a 2x enzyme solution (final concentration of PDE4B1: 0.00625 μg / ml).

[0338] (2) Prepare 2 times the substrate solution

[0339] For the enzyme PDE4B1, FAM-labeled cAMP was added to 1x reaction buffer to form a 2x substrate solution (final concentration of FAM-cAMP: 0.1 μM).

[0340] (3) Add enzyme solution to the 384-well plate

[0341] Add 10 μL of 2x enzyme solution to each well of a 384-well reaction plate. For the no-enzyme control well, replace the enzyme solution with 10 μL of 1x reaction buffer. Centrifuge at 1000 rpm for 1 min and incubate at room temperature for 15 min.

[0342] (4) Add substrate solution to the 384-well plate to start the enzymatic reaction

[0343] Add 10 μL of 2x substrate solution to each well of the 384-well reaction plate. Centrifuge at 1000 rpm for 1 min. The reaction was continued for 30 minutes.

[0344] (5) Termination of enzyme reaction

[0345] 60 μL of the reaction stop solution was added to each well of the 384-well reaction plate to terminate the reaction, and the plate was incubated at room temperature for 60 minutes on a shaker at 600 rpm in the dark.

[0346] 4. Read data and calculate data using EnVision

[0347] Readings were taken with EnVision.

[0348] 5. Calculation of inhibition rate

[0349] Data were copied from EnVision, where the maximum value refers to the reading of the DMSO control and the minimum value refers to the reading of the no enzyme activity control. Inhibition rate (%) = (maximum value - sample value) / (maximum value - minimum value) × 100%.

[0350] For the detection method of PDE4D2 and PDE7A, refer to PDE4B1.

[0351] Table 1 Reagent information

[0352]

[0353]

[0354] The inhibitory effects of the compounds of the present application on PDE4 (PDE4B1, PDE4D2) and PDE7A enzymes were detected according to the above method. The results are shown in Table 2.

[0355] Table 2 Inhibition rate of the compounds of the present application on PDE4 (PDE4B1, PDE4D2) and PDE7A

[0356]

[0357] The following conclusions can be drawn from the above table: The compounds of the present application have relatively excellent inhibitory effects on targeting PDE4 (PDE4B1, PDE4D2) enzymes and / or PDE7A enzymes, that is, they have inhibitory effects on PDE4 (PDE4B1, PDE4D2) enzymes and / or PDE7A enzymes, among which compound D1, compound E2, compound F1, compound F2, compound D2 and compound F3 have particularly obvious inhibitory effects on the above targets.

[0358] Activity Example 2 Detection of cytotoxicity and anti-inflammatory ability of the compounds of the present application

[0359] This test was conducted on the compounds of the present application to test the inhibition of cytotoxicity and expression levels of cellular inflammatory factors.

[0360] 1. Cell Culture

[0361] Mouse mononuclear macrophage Raw 264.7 cells were cultured in DMEM high-glucose medium containing 10% (V / V) FBS, 100 μg / mL penicillin, and 100 μg / mL streptomycin. The culture conditions were 37°C and 5% CO. 2 The cells were passaged when they reached 80% confluence.

[0362] 2. Cellular administration and induction of cellular inflammation

[0363] The experiment was conducted using cells in the logarithmic growth phase. The cells were cultured at a rate of 2×10 5 / well of a 12-well plate and incubate at 37°C, 5% CO 2 Culture in an environment until the cells grow to 70% and set aside. Set up groups: blank group, positive control group (BRL50481) and drug-treated group (compound of the present application). Carefully remove the culture medium, add fresh complete culture medium containing the compound to the positive control group and the drug-treated group, and add an equal volume of DMSO to the blank group. After 1 hour, 1 μg / mL LPS was added to all groups except the blank group for 4 hours to induce cell inflammation. Take out the well plate and perform the Elisa experiment according to the instructions of the kit.

[0364] 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.

[0365] The secretion of mouse IL-1β and TNF-α in the culture medium supernatant was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The specific steps are as follows:

[0366] (1) Reagent preparation

[0367] ① Take out the sample from the refrigerator and place it at room temperature for 20 minutes. ② Dilute the washing solution (20×) to 1× with double distilled water to prepare the required washing solution. ③ Add the standard diluent to 1 bottle of standard according to the volume marked on the standard label and incubate at room temperature for 15 minutes. ④ Take 5 clean 1.5mL centrifuge tubes, add 250μL of standard diluent to each tube in advance, and dilute the standard in multiples to obtain six standard concentrations of 1000, 500, 250, 125, 62.5, and 31.25pg / mL. Finally, add the diluted standard to the pre-coated plate wells in turn, and add the standard diluent directly as 0pg / ml concentration, for a total of seven standard concentrations. ⑤ Add 300μL to each well, and proceed to the next wash after about 15-30 seconds. Wash the plate five times in total and pat it dry on paper.

[0368] (2) Operation steps

[0369] ① Calculate the number of pre-coated strips required for one experiment, take out the required strips and place them in the 96-well frame.

[0370] ② Add samples or standards of different concentrations into the corresponding wells at 100 μL / well, seal the reaction wells with a sealing film (transparent), and incubate at room temperature for 120 minutes.

[0371] ③ Wash the plate 5 times and pat dry on thick absorbent paper for the last wash.

[0372] ④ Add 100 μL / well of biotinylated antibody, seal the reaction wells with a sealing film (transparent), and incubate at room temperature for 60 minutes.

[0373] ⑤ Wash the plate 5 times and pat dry on thick absorbent paper for the last wash.

[0374] ⑥Add 100 μL / well of horseradish peroxidase-labeled Streptavidin, seal the reaction wells with a sealing film (white), and incubate at room temperature in the dark for 20 minutes.

[0375] ⑦ Wash the plate 5 times and pat dry on thick absorbent paper for the last wash.

[0376] ⑧Add 100 μL / well of TMB solution, seal the reaction wells with a sealing film (white), and incubate at room temperature in the dark for 20 minutes.

[0377] ⑨Add 50 μL / well of stop solution, mix well and measure the A450 value immediately.

[0378] The test results are as follows:

[0379] Depend on Figure 1 It can be seen that the compounds of the present application show almost no obvious cytotoxicity.

[0380] Depend on Figure 2 It can be seen that compound D4, compound C2, compound D2, compound E4, compound G2, etc. have a good inhibitory effect on the cellular inflammatory factor TNF-α.

[0381] Depend on Figure 3 It can be seen that compound D4, compound E4, compound G3, etc. have a good inhibitory effect on the cellular inflammatory factor IL-1β. The experimental results show that the compounds have a good effect in preventing and / or treating inflammatory diseases, respiratory diseases, skin diseases, or immune system diseases.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof in R1 is Ring A is a 5- to 10-membered heteroaryl group, comprising 1-3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N; optionally, the 5- to 10-membered heteroaryl group is substituted by one or more substituents selected from C1-C6 alkyl and C1-C6 alkoxy; R2 is H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, amino, phenyl, benzyl, or benzylamino; n is 1, 2, 3 or 4; *Indicates the connection location.

2. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof, wherein the 5- to 10-membered heteroaryl group is a monocyclic heteroaryl group or a condensed-ring heteroaryl group; Preferably, the A ring is X2, Y2, and Z2 are each independently N or NH, O or S, and at least one of X2, Y2, and Z2 is N or NH; preferably, X2 is each independently N, and Y2 and Z2 are each independently N, O or S.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof, wherein ring A is 4. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated substance thereof, wherein n is 2 or 3; preferably, the halogen is Br.

5. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof, wherein Formula I is R3 is Preferably, Formula I is R4 is Preferably, Formula I is R5 is Preferably, Formula I is R6 is Preferably, Formula I is R7 is Preferably, Formula I is R8 is Preferably, Formula I is R9 is Preferably, Formula I is R10 is Preferably, Formula I is R 11 for 6. A compound or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof, wherein the compound is 7. An intermediate compound, which is:

8. A method for preparing the compound according to any one of claims 1 to 5, comprising (1) a) reacting the compound of formula II with sodium acetate at 80°C-120°C for 1-2 hours, adding the compound of formula I, and reacting at 20°C-50°C for 1-8 hours; b) hydrolyzing the compound of formula III obtained in step a) at 50° C.-90° C. for 1-8 hours; c) reacting the product compound of formula IV obtained in step b) with R B环 -NHNH2 is reacted at 20°C-50°C for 5-7 hours to obtain a compound of formula V; (2) d) stirring the compound of formula VI, the compound of formula VII and K2CO3 at 20°C-50°C for 20-30 hours, then stirring at -15°C until the color turns orange-yellow, then adding DBU and bromochloromethane at -20°C-0°C, and reacting at 20°C-50°C for 6-24 hours; e) stirring the product compound of formula VIII obtained in step d) at 20° C.-50° C. for 8-12 hours for hydrolysis reaction; f) reacting the product compound of formula IX obtained in step e) with R B环 -NHNH2 reacts at 20℃-50℃ for 4-8 hours; (3) g) reacting the compound of formula XI with the compound of formula XII at 60° C.-100° C. for 10-14 hours; h) hydrolyzing the compound of formula XIII obtained in step g) at 20° C.-50° C. for 2-6 hours; i) reacting the compound of formula XIV obtained in step h) with R B环 -NHNH2 reacts at 20℃-50℃ for 10-14 hours; or (4) j) reacting the compound of formula XVI with the compound of formula XVII at 60° C.-100° C. with stirring for 10-14 hours; k) stirring the product compound of formula XVIII obtained in step j) at 60° C.-100° C. for hydrolysis reaction for 2-6 hours; l) reacting the product compound of formula XIX obtained in step k) with R B环 -NHNH2 was stirred at 20°C-50°C for 10-14 hours; in, R B环 for R1, R2, and n are as described in any one of claims 1 to 5.

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

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

11. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating a disease mediated by PDE4 and / or PDE7, an inhibitor of PDE4 or an inhibitor of PDE7, or an inhibitor of PDE4 and PDE7.

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