PROTAC derivative targeting PDE4 and application thereof

Abstract

The invention discloses a PROTAC derivative targeting PDE4 and application of the PROTAC derivative. The compound has the activity of resisting inflammation and treating acute lung injury.

Description

Technical Field

[0001] The present application belongs to the field of medical technology, and specifically relates to PROTAC derivatives with anti-inflammatory and acute lung injury therapeutic activities and targeting PDE4. Background Art

[0002] Acute lung injury (ALI) is a disease caused by pneumonia, sepsis, inhalation of toxic substances, severe trauma, shock or other factors that can cause pulmonary edema or hypoxic respiratory failure. If it is not treated promptly and effectively in the early stage, it may quickly progress to acute respiratory distress syndrome (ARDS). The pathological mechanism of acute lung injury is the damage of pathogenic factors to alveolar epithelial cells and microvascular endothelial cells.

[0003] PDE4 is an enzyme that specifically hydrolyzes cAMP and 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. PDE4 inhibitors can regulate intracellular cAMP levels, which can cause reduced activation and recruitment of inflammatory cells and related cytokines, as well as reduced release of cytokines and other bioactive substances by lung structural cells (such as alveolar and bronchial epithelial cells, airway smooth muscle cells, microvascular endothelial cells, fibroblasts, etc.), playing a broad anti-inflammatory role. PDE4 inhibitors can effectively inhibit epithelial-mesenchymal transition that leads to small airway remodeling, reduce fibroblast profibrotic activation and collagen accumulation, and reduce the concentration of chemokines associated with fibrosis. In addition, PDE4 inhibitors can reduce airway inflammation, airway hyperresponsiveness, and cough.

[0004] Protein degradation targeted chimera (PROTAC) is a novel drug design strategy that utilizes the ubiquitin-proteasome protein degradation mechanism in cells to degrade proteins. PROTAC technology has attracted widespread attention in the industry due to its breakthrough advantages brought by its unique mechanism of action, especially for undruggable targets, and is considered to be one of the most promising new technologies to break through the current bottleneck of small molecule drug development. The core concept of PROTAC technology is to use artificial small molecule compounds to summon a specific ubiquitin ligase and degrade proteins by achieving ubiquitination of target proteins. PROTAC generally consists of three parts: target protein binding ligand, E3 ligase binding ligand, and Linker that links the two. PROTAC drugs bind to target proteins and E3 ligases through their own two ligands, respectively, to form a target protein-PROTAC-E3 ligase ternary complex, thereby initiating the ubiquitination process to degrade proteins. PROTAC can be detached from the target protein and E3 ligase, and the released PROTAC will continue to repeat the degradation process of the next protein to achieve recycling in cells.

[0005] Traditional small molecule drugs are prone to drug resistance and are limited to acting on receptors and enzymes with clear ligand binding sites. PROTAC technology has three advantages: the potential to treat undruggable targets, the potential to overcome drug resistance, and the ability to work through catalysis. Therefore, small molecules targeting PDE4 were PROTAC-designed to synthesize a series of PDE4-PROTAC compounds that inhibit PDE4B enzymes and degrade PDE4B proteins. Summary of the invention

[0006] One or more embodiments of the present application provide a compound of Formula I or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof.

[0007]

[0008] in

[0009] L is

[0010] R 1 and R 2 Each independently

[0011] X and Y are each independently N or NH, O or S, and at least one of X and Y is N;

[0012] G 1 and G 2 Each independently is a bond, CH 2 or O, and G 1 and G 2 Not a key at the same time;

[0013] n and m are each independently 1, 2, 3 or 4.

[0014] In one or more embodiments, R 1 for R 2 for

[0015] In one or more embodiments, X is N and Y is NH, O or S.

[0016] In one or more embodiments, G 1 and G 2 Not at the same time it is O.

[0017] In one or more embodiments, G 1 is C, n is 1, 2, or 3, and G 2 is C, and m is 1, 2, or 3.

[0018] In one or more embodiments, G 1 is C, n is 1, 2, or 3, and G 2 is 0, and m is 1, 2, or 3. In one or more embodiments, L is

[0019] In one or more embodiments, the compound of the present application is

[0020]

[0021]

[0022]

[0023] One or more embodiments of the present application provide an intermediate compound for preparing the compound of the present application, wherein the intermediate compound is

[0024]

[0025] One or more embodiments of the present application provide a method for preparing the compound of the present application, which comprises (1)

[0027]

[0028] a) reacting a compound of formula I and a compound of formula II in the presence of DIPEA at 50°C-100°C for 2-8 hours;

[0029] b) reacting the product compound of formula III obtained in step a) with HCl-dioxane at 20° C.-50° C. for 1-3 hours;

[0030] c) reacting the product compound of formula IV obtained in step b) with a compound of formula V as an aromatic carboxylic acid at 20° C.-50° C. for 8-12 hours to obtain a compound of formula VI; (2)

[0032]

[0033] d) reacting the product compound of formula IV obtained in step b) with the compound of formula VII at 20° C.-50° C. for 8-12 hours;

[0034] e) reacting the product compound of formula VIII obtained in step d) with HCl-dioxane at 20° C.-50° C. for 1-3 hours;

[0035] f) reacting the compound of formula IX obtained in step e) with a compound of formula V as an aromatic carboxylic acid at 20° C. to 50° C. for 8 to 12 hours to obtain a compound of formula XI;

[0036] or (3)

[0038]

[0039] g) reacting a compound of formula V as an aromatic carboxylic acid with a compound of formula XIII at 20° C. to 50° C. for 10 to 14 hours;

[0040] h) reacting the product compound of formula XIV obtained in step g) with HCl-dioxane at 20° C.-50° C. for 1-3 hours;

[0041] i) reacting the compound of formula XVI at 20°C-50°C for 2-4 hours in the presence of a Dess-Martin periodinane, adding the product compound of formula XV obtained in step h) and glacial acetic acid after post-treatment, reacting at 20°C-50°C for 1-4 hours, and then reacting with sodium triacetoxyborohydride at 20°C-50°C for 14-18 hours to obtain a compound of formula XVII;

[0042] Where R 1 , R 2 ,X,Y,n,m,G 1 , G 2 As described above.

[0043] One or more embodiments of the present application provide a pharmaceutical composition comprising the compound of the present application and a pharmaceutically acceptable auxiliary material or excipient.

[0044] 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 drug for preventing and / or treating inflammatory diseases, respiratory diseases, skin diseases, immune system diseases, and acute lung injury.

[0045] One or more embodiments of the present application provide a compound of the present application for use as a medicament.

[0046] One or more embodiments of the present application provide the pharmaceutical composition of the present application, which is used as a medicament.

[0047] 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, immune system diseases, and acute lung injury.

[0048] One or more embodiments of the present application provide a compound or composition of the present application for preventing and / or treating a PDE4-mediated disease.

[0049] One or more embodiments of the present application provide a compound or composition of the present application for inhibiting PDE4.

[0050] One or more embodiments of the present application provide a method for preventing and / or treating inflammatory diseases, respiratory diseases, skin diseases, immune system diseases, and acute lung injury, which comprises administering a compound or composition of the present application to a subject in need thereof.

[0051] One or more embodiments of the present application provide a method for preventing and / or treating a PDE4-mediated disease, which comprises administering a compound or composition of the present application to a subject in need thereof.

[0052] One or more embodiments of the present application provide a method for inhibiting PDE4, which comprises administering a compound or composition of the present application to a subject in need thereof.

[0053] In one or more embodiments, the inflammatory disease is an inflammatory skin disease.

[0054] In one or more embodiments, the respiratory disease is chronic obstructive pulmonary disease, acute lung injury or asthma.

[0055] In one or more embodiments, the skin disease is psoriasis or atopic dermatitis.

[0056] In one or more embodiments, the immune system disease is systemic lupus erythematosus or rheumatoid arthritis.

[0057] One or more embodiments of the present application provide use of the compound of the present application or the pharmaceutical composition of the present application in the preparation of a drug or a PDE4 inhibitor for preventing and / or treating a PDE4-mediated disease.

[0058] In one or more embodiments, the PDE4 is PDE4B.

[0059] 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:

[0060] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0061] The term "amino" refers to -NH 2 .

[0062] The term "hydroxy" refers to -OH.

[0063] "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.

[0064] "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.

[0065] "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.

[0066] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be, for example, a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably a 5- to 8-membered heteroaryl. The 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the heteroaryl ring can be oxidized to various oxidation states. Heteroaryl can be connected to a heteroatom or a carbon atom, and can be a bridged ring or a spiro ring, and non-limiting examples include cyclopyridyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridinyl, pyrrolopyridinyl. Heteroaryl is optionally further substituted by one or more substituents.

[0067] "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated non-aromatic heterocyclic ring, which can be, for example, a 5- to 10-membered (e.g., 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 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 spirocycle. Non-limiting examples of “heterocyclyl” or “heterocycle” include oxirane, oxirane, aziridine, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, 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.

[0068] "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.

[0069] "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.

[0070] "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.

[0071] "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.

[0072] "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.

[0073] "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.

[0074] "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.

[0075] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0076] "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.

[0077] In one or more embodiments, Formula I is

[0078]

[0079] In formula (a), L is

[0080] In one or more embodiments, Formula I is

[0081]

[0082] In formula (b), L is

[0083] In one or more embodiments, Formula I is

[0084]

[0085] In formula (c), L is

[0086] BRIEF DESCRIPTION OF THE DRAWINGS

[0087] Figure 1A The results of Activity Example 2 showing that the compound of the present application degrades PDE4B.

[0088] Figure 1B The results of the targeted degradation of PDE4B by the compound 9m of the present application in Activity Example 2 at different concentrations are shown.

[0089] Figure 2 The DC of compound 9m in Example 3 against PDE4B 50 The test results.

[0090] Figure 3 and Figure 4 It represents the expression levels of inflammatory factors TNF-α and IL-6 in the Raw264.7 cell model after being treated with different concentrations of compound 9m in Activity Example 4.

[0091] Figure 5 This figure shows the changes in body weight of mice in Activity Example 7.

[0092] Figure 6 This is a picture showing HE staining of lung tissue in Example 7.

[0093] Figure 7 It indicates the inhibitory effect of the inflammatory cells in the bronchoalveolar lavage fluid and the inflammatory factors IL-6, IL-1β, and TNF-α in the mouse acute lung injury model in Example 7. DETAILED DESCRIPTION

[0094] 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.

[0095] Preparation Example

[0096] Example 1 Synthesis of intermediate 8a:

[0097]

[0098] (1) Synthesis of Compound 16

[0099]

[0100] Weigh 3g of compound 3,4-dihydroxybenzaldehyde (compound 15, 21.72mmol, 1.0equiv.) and 6.91g of sodium carbonate (65.16mmol, 3.0equiv.), dissolve in 30mL N,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 materials 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. The organic phase is concentrated and 1.4g of white solid product (compound 16) is obtained by silica gel column chromatography, with a yield of 34%. The obtained compound 16 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results are: 1 H NMR (500 MHz, CDCl 3 )δ9.90(s,1H),7.53(d,J=2.0Hz,1H),7.44(dd,J=8.5,2.0Hz,1H),7.26(d,J=8.5Hz,1H),6.66(t,J=73.5Hz,1H).ESI-HRMS m / z: calculated value is C 8 H 6 O 3 F 2 Na + [M+Na] + , 211.0177; the measured value is 211.0166.

[0101] (2) Synthesis of Compound 17

[0102]

[0103] Weigh 2.1g of compound 16 (11.16mmol, 1.0equiv.), add 3.09g of potassium carbonate (22.32mmol, 2.0equiv.), add 20mL of N,N-dimethylformamide, and finally add 2.26g of bromomethylcyclopropane (16.74mmol, 1.5equiv.), react at 80°C for 8 hours, TLC detects that the raw material reacts completely, and water is added to quench the reaction. Use ethyl acetate to extract 3 times, and wash the organic phase with saturated sodium chloride solution. The organic phase is concentrated and subjected to rapid column chromatography to obtain 2.3g of a yellow oily product (compound 17), with a yield of 85%. The obtained compound 17 is identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results are: 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.

[0104] (3) Synthesis of Compound 18

[0105]

[0106] 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 1 hour, cool to room temperature, add 2g of compound 17 (8.26mmol, 1.0equiv.) in methanol and 4mL of ammonia water to the above solution, stir at room temperature, detect the reaction by TLC, remove methanol by rotary evaporation, add water, extract with ethyl acetate 3 times, wash the organic phase with saturated sodium chloride solution once, 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%. The obtained compound 18 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 O 2 N 2 F 5 + [M+H] + , 349.1; the measured value is 349.1.

[0107] (4) Synthesis of Compound 8a

[0108]

[0109] 415 mg of compound 18 (1.19 mmol, 1.0 equiv.) was weighed and dissolved in a mixed solvent of ethanol and water at a ratio of 1:1, 953 mg of sodium hydroxide (23.80 mmol, 20.0 equiv.) was added, and the mixture was stirred at 80°C for 4 h, monitored by TLC, and 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 solid was filtered and dried to obtain 322 mg of yellow solid product compound 8a, with a yield of 83%. The obtained compound 8a was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were as follows: 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.

[0110] Example 2 Synthesis of Intermediate 8b

[0111]

[0112] (1) Synthesis of Compound 19

[0113]

[0114] 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. 2 Under protection, after stirring for 10 min, 5.0 g of compound 17 (20.64 mmol, 1.0 equiv.) was added, and the reaction was continued overnight at room temperature. TLC was monitored. 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. The reaction was monitored by TLC, and water was added to quench the reaction. Ethyl acetate was used for extraction 3 times, and the organic phase was washed with a saturated sodium chloride solution. The organic phase was concentrated and 3.6 g of a white solid product (compound 19) was obtained by flash column chromatography with a yield of 51%.

[0115] The obtained compound 19 was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (600 MHz, DMSO-d 6 )δ8.97 (s, 1H), 7.64-7.58 (m, 2H), 7.36 (s, 1H), 7.22 (t, J=73.8 Hz, 1H), 4.00 (d, J=7.2 Hz, 2H), 3.85 (s, 3H), 1.32-1.22 (m, 1H), 0.63-0.55 (m, 2H), 0.42-0.36 (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.

[0116] (2) Synthesis of compound 8b

[0117]

[0118] 3 g of compound 19 (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 solid was filtered and dried to obtain 2.8 g of yellow solid compound 8b, with a yield of 97%.

[0119] The obtained compound 8b 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=2.0Hz, 1H), 7.66 (dd, J=8.4, 2.0Hz, 1H), 7.26 (t, J=8.4Hz, 1H), 6.72 (t , J=74.8Hz, 1H), 3.96 (d, J=6.8Hz, 2H), 1.38-1.28 (m, 1H), 0.71-0.64 (m, 2H), 0.40-0.35 (m, 2H). 13 C NMR (101 MHz, CDCl 3 )δ165.7, 162.1, 151.0, 145.3, 142.9, 133.8, 124.5, 122.8, 120.0, 117.2 (t, J = 259.3 Hz), 112.6, 74.4, 10.1, 3.4 (2×C). 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.

[0120] Example 3 Synthesis of Intermediate 8c

[0121]

[0122] (1) Synthesis of Compound 20

[0123]

[0124] Referring to the synthesis of compound 19 in Example 2, compound 17 and D-cysteine ​​methyl ester hydrochloride were reacted to obtain a yellow solid product with a yield of 15%. The obtained compound 20 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.

[0125] (2) Synthesis of compound 8c

[0126]

[0127] Referring to the synthesis of compound 8b in Example 2, a yellow solid product compound 8c was obtained with a yield of 84%. The obtained compound 8c 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). 13 C NMR (101 MHz, CDCl 3 )δ167.6, 164.5, 150.7, 148.5, 142.1, 130.7, 127.7, 122.5, 119.7, 115.9 (t, J = 258.8 Hz), 112.0, 74.0, 10.0, 3.2 (2×C). 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.

[0128] Example 4 Synthesis of Intermediates 3a-3f

[0129]

[0130] (1) Synthesis of compounds 2a-2f:

[0131]

[0132] 2.0 g of compound 1 (7.24 mmol, 1.0 equiv.) was dissolved in 10.0 mL of N, N-dimethylformamide solution, and then a suitable amine reagent (8.69 mmol, 1.2 equiv.) and N, N-diisopropylethylamine (DIPEA, 14.48 mmol, 2.0 equiv.) were added to the above solution, and the reaction was heated at 90° C. for 4 hours and monitored by thin layer chromatography. After the reaction was completed, water was added to quench, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and flash column chromatography was performed to obtain compounds 2a-2f.

[0133] The compounds 2a-2f are arranged in the following order:

[0134]

[0135] (2) Synthesis of compounds 3a-f:

[0136]

[0137] 500 mg of compound 2a-2f was dissolved in 9.0 mL of DCM, and 3 mL of hydrogen chloride 1,4-dioxane solution was added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the solid was collected by filtration and dried to obtain yellow-green solid 3a-f with a yield of 75-89%.

[0138] (3) Synthesis of compound 2a:

[0139] The amine reagent selected was mono-Boc-ethylenediamine (CAS No.: 57260-73-8) to obtain compound 2a with a yield of 25%; 1 HNMR (500 MHz, DMSO-d 6 )δ11.09 (s, 1H), 7.57 (dd, J=8.5, 7.0 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 7.05-6.95 (m, 2H), 6.71 (t, J=6.0 Hz, 1H), 5.05 (dd, J=12.5, 5.5 Hz, 1H), 3.39-3.34 (m, 2H), 3.14-3.09 (m, 2H), 2.92-2.85 (m, 1H), 2.63-2.51 (m, 2H), 2.04-1.99 (m, 1H), 1.36 (s, 9H).ESI-MS m / z: calculated value is C20 H 24 O 6 N 4 Na + [M+Na] + , 439.2; the measured value is 439.2.

[0140] (4) Synthesis of compound 2b:

[0141] The amine reagent selected was N-Boc-1,3-propylenediamine (CAS No.: 75178-96-0) to obtain compound 2b with a yield of 25%; 1 H NMR (500 MHz, DMSO-d 6 ) δ11.09 (s, 1H), 7.57 (dd, J=8.5, 7.0Hz, 1H), 7.08 (d, J=8.5Hz, 1H), 7.02 (d , J=7.0Hz, 1H), 6.91 (t, J=6.0Hz, 1H), 6.66 (t, J=6.0Hz, 1H), 5.05 (dd, J=12. 5, 5.5Hz, 1H), 3.33-3.29 (m, 2H), 3.02-2.97 (m, 2H), 2.92-2.85 (m, 1H), 2.6 3-2.51(m, 2H), 2.05-2.00(m, 1H), 1.69-1.63(m, 2H), 1.37(s, 9H).ESI-HRMS m / z: calculated value is C 21 H 26 O 6 N 4 Na + [M+Na] + , 453.1745; the measured value is 453.1731.

[0142] (5) Synthesis of compound 2c:

[0143] The amine reagent selected was (4-aminobutyl) carbamic acid tert-butyl ester (CAS No.: 68076-36-8) to obtain compound 2c with a yield of 27%; 1 H NMR (500 MHz, DMSO-d 6) δ11.08 (s, 1H), 7.57 (dd, J=8.5, 7.0Hz, 1H), 7.10 (d, J=8.5Hz, 1H), 7.02 (d, J=7 .0Hz, 1H), 6.82 (t, J=6.0Hz, 1H), 6.54 (t, J=6.0Hz, 1H), 5.05 (dd, J=13.0, 5.5Hz, 1H), 3.31-3.26 (m, 2H), 2.98-2.92 (m, 2H), 2.91-2.84 (m, 1H), 2.62-2.51 (m, 2H), 2.05-2.00 (m, 1H), 1.57-1.51 (m, 2H), 1.48-1.41 (m, 2H), 1.36 (s, 9H). ESI-HRMS m / z: calculated value is C 22 H 28 O 6 N 4 Na + [M+Na] + , 467.1901; the measured value is 467.1876.

[0144] (6) Synthesis of compound 2d:

[0145] The amine reagent selected was N-(5-aminopentyl)carbamic acid tert-butyl ester (CAS No.: 51644-96-3) to obtain compound 2d with a yield of 42%; 1 H NMR (500 MHz, DMSO-d 6 ) δ11.09 (s, 1H), 7.57 (dd, J=8.5, 7.0Hz, 1H), 7.08 (d, J=8.5Hz, 1H), 7.01 (d, J=7.0Hz , 1H), 6.77 (t, J=6.0Hz, 1H), 6.51 (t, J=6.0Hz, 1H), 5.05 (dd, J=13.0, 5.5Hz, 1H), 3.29 -3.25 (m, 2H), 2.94-2.90 (m, 2H), 2.89-2.84 (m, 1H), 2.62-2.51 (m, 2H), 2.06-2.00 (m, 1H), 1.59-1.53 ​​(m, 2H), 1.43-1.38 (m, 2H), 1.36 (s, 9H), 1.33-1.28 (m, 2H). ESI-HRMS m / z: calculated value is C 23 H 30 O 6 N 4 Na + [M+Na] + , 481.2058; the measured value is 481.2039.

[0146] (7) Synthesis of compound 2e:

[0147] The amine reagent selected was (6-aminohexyl) carbamic acid tert-butyl ester (CAS No.: 51857-17-1) to obtain compound 2e with a yield of 47%; 1 H NMR (500 MHz, DMSO-d 6 )δ11.08 (s, 1H), 7.57 (dd, J=8.5, 7.0Hz, 1H), 7.08 (d, J=8.5Hz, 1H), 7.02 (d, J=7.0Hz , 1H), 6.75 (t, J=6.0Hz, 1H), 6.52 (t, J=6.0Hz, 1H), 5.05 (dd, J=13.0, 5.5Hz, 1H), 3.30 -3.26 (m, 2H), 2.92-2.88 (m, 2H), 2.88-2.84 (m, 1H), 2.61-2.51 (m, 2H), 2.05-2.00 (m, 1H), 1.59-1.52 (m, 2H), 1.40-1.37 (m, 2H), 1.36 (s, 9H), 1.34-1.26 (m, 4H). ESI-HRMS m / z: calculated value is C 24 H 32 O 6 N 4 Na + [M+Na] + , 495.2214; the measured value is 495.2190.

[0148] (8) Synthesis of Compound 2f:

[0149] The amine reagent selected was tert-butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate (CAS No.: 153086-78-3) to obtain compound 2f with a yield of 41%; 1 H NMR (500 MHz, DMSO-d 6)δ11.09 (s, 1H), 7.58 (dd, J=8.5, 7.0Hz, 1H), 7.13 (d, J=8.5Hz, 1H), 7.03 (d, J=7.0Hz, 1H), 6 .72 (t, J=6.0Hz, 1H), 6.60 (t, J=6.0Hz, 1H), 5.06 (dd, J=13.0, 5.5Hz, 1H), 3.62 (t, J=5.5Hz, 2H), 3.57-3.54 (m, 2H), 3.52-3.50 (m, 2H), 3.48-3.45 (m, 2H), 3.38 (t, J=6.0 Hz, 2H), 3.08-3.03 (m, 2H), 2.92-2.84 (m, 1H), 2.62-2.51 (m, 2H), 2.05-2.00 (m, 1H), 1.35 (s, 9H). ESI-HRMS m / z: calculated value is C 24 H 32 O 8 N 4 Na + [M+Na] + , 527.2112; the measured value is 527.2097.

[0150] Example 5 Synthesis of Compound 5a:

[0151]

[0152] (1) Synthesis of compound 4a:

[0153]

[0154] 500 mg of compound 3f (1.1 mmol, 1.0 equiv.) and 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetic acid (CAS No.: 156478-71-6) (1.21 mmol, 1.1 equiv.) were dissolved in 5.0 mL of N,N-dimethylformamide, and O-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.1 mmol, 1.0 equiv., CAS No.: 148893-10-1) and N,N-diisopropylethylamine (DIPEA, 5.5 mmol, 5.0 equiv.) were added. The reaction was stirred at room temperature for 10 h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench the reaction, and the reaction was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated. The yellow-green solid compound 4a was obtained by flash column chromatography with a yield of 44%.

[0155] The obtained compound 4a was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1H NMR (500 MHz, DMSO-d 6 ) δ11.08 (s, 1H), 7.71 (t, J=6.0Hz, 1H), 7.58 (dd, J=8.5, 7.0Hz, 1H), 7.14 (d, J=8.5Hz, 1H), 7.04 (d, J =7.0Hz, 1H), 6.61 (t, J = 6.0Hz, 1H), 5.05 (dd, J = 13.0, 5.5Hz, 1H), 3.62 (t, J = 5.5Hz, 2H), 3.57-3.51 (m , 4H), 3.49-3.45 (m, 2H), 3.43 (t, J = 6.0 Hz, 2H), 3.32-3.29 (m, 4H), 3.26-3.22 (m, 2H), 2.91 (s, 2H), 2.89-2.84 (m, 1H), 2.62-2.51 (m, 2H), 2.35 (t, J = 5.5 Hz, 4H), 2.05-2.00 (m, 1H), 1.37 (s, 9H). ESI-HRMS m / z: calculated value is C 30 H 43 O 9 N 6 + [M+H] + , 631.3086; the measured value is 631.3058.

[0156] (2) Synthesis of compound 5a:

[0157]

[0158] 500 mg of compound 4a was dissolved in 9.0 mL of DCM, and 3 mL of hydrogen chloride 1,4-dioxane solution was added to the above solution. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the solid was collected by filtration and dried to obtain a yellow-green solid 5a. The yield was 78%.

[0159] The obtained compound 5a was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification result was: 1 H NMR (500 MHz, DMSO-d 6)δ11.09 (s, 1H), 9.89 (br, 1H), 8.61 (br, 1H), 7.59 (dd, J=8.5, 7.0Hz, 1H), 7.15 (d, J=8 .5Hz, 1H), 7.04 (d, J=7.0Hz, 1H), 6.60 (br, 1H), 5.05 (dd, J=13.0, 5.5Hz, 1H), 3.91-3. 80 (m, 2H), 3.63-3.61 (m, 2H), 3.58-3.53 (m, 6H), 3.49-3.44 (m, 6H), 3.39-3.34 (m, 4H), 3.29-3.26 (m, 2H), 2.93-2.85 (m, 1H), 2.63-2.51 (m, 2H), 2.05-2.00 (m, 1H). ESI-HRMS m / z: calculated value is C 25 H 35 O 7 N 6 + [M+H] + , 531.2562; the measured value is 531.2537.

[0160] Example 6 Synthesis of Compounds 7a-7b:

[0161]

[0162] 1.0 g of compound 6 (3.65 mmol, 1.0 equiv.) was dissolved in 5.0 mL of N,N-dimethylformamide, 5-bromo-1-pentanol or 6-bromo-1-hexanol (7.30 mmol, 2.0 equiv.) was added, and NaHCO 3 (14.60mmol, 4.0equiv.) and KI (0.37mmol, 0.1equiv.) were reacted at 80°C for 8h and monitored by thin layer chromatography. After the reaction was completed, water was added to quench, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to flash column chromatography to obtain white solid compound 7a-7b.

[0163] The compounds 7a and 7b are arranged in the following order:

[0164]

[0165] (1) Compound 7a, yield 48%; The obtained compound 7a was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (500 MHz, DMSO-d 6)δ11.11 (br, 1H), 7.80 (dd, J=8.5, 7.0 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.43 (d, J=7.5 Hz, 1H), 5.08 (dd, J=13.0, 5.5 Hz, 1H), 4.40 (br, 1H), 4.19 (t, J=6.5 Hz, 2H), 3.42-3.40 (m, 2H), 2.92-2.84 (m, 1H), 2.63-2.50 (m, 2H), 2.06-2.00 (m, 1H), 1.79-1.73 (m, 2H), 1.51-1.45 (m, 4H).ESI-MS m / z: calculated value is C 18 H 21 O 6 N 2 + [M+H] + , 361.1; the measured value is 361.1.

[0166] (2) Compound 7b, yield 45%; The obtained compound 7b was identified by nuclear magnetic resonance spectroscopy and mass spectrometry, and the identification results were: 1 H NMR (500 MHz, DMSO-d 6 )δ11.10 (s, 1H), 7.80 (dd, J=8.5, 7.0Hz, 1H), 7.50 (d, J=8.5Hz, 1H), 7.43 (d, J=7 .0Hz, 1H), 5.08 (dd, J=13.0, 5.5Hz, 1H), 4.35 (t, J=5.5Hz, 1H), 4.19 (t, J=6.5Hz , 2H), 3.42-3.38 (m, 2H), 2.92-2.84 (m, 1H), 2.63-2.50 (m, 2H), 2.06-2.00 (m, 1H), 1.78-1.72 (m, 2H), 1.48-1.41 (m, 4H), 1.38-1.33 (m, 2H). ESI-HRMS m / z: calculated value is C 19 H 22 O 6 N 2 Na + [M+Na] + , 397.1370; the measured value is 397.1350.

[0167] Example 7 Synthesis of Compounds 12a-12c:

[0168]

[0169] (1) Synthesis of compounds 11a-11c:

[0170]

[0171] Compound 8a-c (1.54 mmol, 1.0 equiv.) and tert-butyl piperazine-1-carboxylate (CAS No.: 57260-71-6, 1.69 mmol, 1.1 equiv.) were dissolved in DCM, and N-hydroxy-7-azabenzotriazole (CAS No.: 39968-33-7, HOAT, 1.69 mmol, 1.1 equiv.), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.69 mmol, 1.1 equiv.) and N-methylmorpholine (NMM, 1.69 mmol, 1.1 equiv.) were added at room temperature, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the crude product was concentrated in vacuo, and then flash column chromatography was performed to obtain intermediates 11a-11c as pale yellow solids.

[0172] The compounds 11a-11c are arranged in the following order:

[0173]

[0174] (2) Synthesis of compound 11a:

[0175] The reactant 8a was selected to obtain compound 11a with a yield of 83%; 1 H NMR (500 MHz, DMSO-d 6 )δ13.01 (s, 1H), 7.81-7.55 (m, 3H), 7.26 (d, J=8.5 Hz, 1H), 7.12 (t, J=74.5 Hz, 1H), 4.34-3.98 (m, 2H), 3.97 (d, J=7.0 Hz, 2H), 3.77-3.52 (m, 2H), 3.40 (t, J=5.5 Hz, 4H), 1.42 (s, 9H), 1.32-1.28 (m, 1H), 0.62-0.59 (m, 2H), 0.40-0.36 (m, 2H). ESI-HRMS m / z: calculated value is C 24 H 31 O 5 N 4 F 2 + [M+H] + , 493.2257; the measured value is 493.2233.

[0176] (3) Synthesis of compound 11b:

[0177] The reactant was selected as 8b to obtain compound 11b with a yield of 72%; 1 H NMR (500 MHz, DMSO-d6 )δ8.66 (s, 1H), 7.62-7.60 (m, 2H), 7.36 (s, 1H), 7.21 (t, J=74.5 Hz, 1H), 4.00 (d, J=7.0 Hz, 2H), 3.96-3.85 (m, 2H), 3.66-3.55 (s, 2H), 3.41 (t, J=5.0 Hz, 4H), 1.42 (s, 9H), 1.30-1.26 (m, 1H), 0.61-0.58 (m, 2H), 0.40-0.37 (m, 2H). ESI-HRMS m / z: calculated value is C 24 H 30 O 6 N 3 F 2 + [M+H] + , 494.2097; the measured value is 494.2060.

[0178] (4) Synthesis of compound 11c:

[0179] The reactant selected 8c to obtain compound 11c, yield: 69%; 1 H NMR (500 MHz, DMSO-d 6 )δ8.18 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.5, 2.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 74.0 Hz, 1H), 4.01 (d, J = 7.0 Hz, 2H), 3.73-3.62 (m, 4H), 3.45-3.40 (m, 4H), 1.42 (s, 9H), 1.30-1.27 (m, 1H), 0.61-0.58 (m, 2H), 0.40-0.37 (m, 2H). ESI-HRMS m / z: calculated value is C 24 H 30 O 5 N 3 F 2 S + [M+H] + , 510.1869; the measured value is 510.1829.

[0180] (5) Synthesis of compounds 12a-12c:

[0181]

[0182] 300 mg of compound 11a-11c was dissolved in 9.0 mL of DCM, and 3 mL of hydrogen chloride 1,4-dioxane solution was added to the above solution. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the solid was collected by filtration and dried to obtain light yellow solids 12a-12c.

[0183] The compounds 12a-12c are arranged in the following order:

[0184]

[0185] (6) Synthesis of compound 12a:

[0186] The reactant 11a was selected to obtain compound 12a with a yield of 76%; 1 H NMR (500 MHz, DMSO-d 6 )δ13.44 (br, 1H), 7.80 (d, J=6.0 Hz, 2H), 7.60 (d, J=8.5 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.12 (t, J=74.5 Hz, 1H), 3.99 (d, J=7.0 Hz, 2H), 3.57-3.46 (m, 4H), 3.13 (t, J=5.5 Hz, 4H), 1.30-1.25 (m, 1H), 0.61-0.56 (m, 2H), 0.39-0.35 (m, 2H), NH (1H, not observed). ESI-HRMS m / z: calculated value is C 19 H 23 O 3 N 4 F 2 + [M+H] + , 393.1733; the measured value is 393.1736.

[0187] (7) Synthesis of compound 12b:

[0188] The reactant 11b was selected to obtain compound 12b with a yield of 78%; 1 H NMR (500 MHz, DMSO-d 6)δ8.62(s,1H),7.62-7.58(m,2H),7.35(s,1H),7.21(t,J=74.0Hz,1H),4.00(d,J=7.0Hz,2H),3.88-3.84(m,2H),3.65-3.56(m,2H),2.84-2.79(m,4H),1.89(s,1H),1.29-1.24(m,1H),0.60-0.57(m,2H),0.40-0.36(m,2H).ESI-HRMS m / z: calculated value is C 19 H 22 O 4 N 3 F 2 + [M+H] + , 394.1573; the measured value is 393.1553.

[0189] (8) Synthesis of compound 12c:

[0190] The reactant 11c was selected to obtain compound 12c with a yield of 76%; 1 H NMR (500 MHz, DMSO-d 6 )δ9.57 (s, 1H), 8.27 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.5, 2.0 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.20 (t, J = 74.0 Hz, 1H), 4.09-4.02 (m, 2H), 4.01 (d, J = 7.0 Hz, 2H), 3.95-3.83 (m, 2H), 3.20-3.17 (t, J = 5.2 Hz, 4H), 1.30-1.26 (m, 1H), 0.61-0.58 (m, 2H), 0.40-0.36 (m, 2H). ESI-HRMS m / z: calculated value is C 19 H 22 O 3 N 3 F 2 S + [M+H] + , 410.1344; the measured value is 410.1361.

[0191] Example 8 Synthesis of Compounds 9a-9r:

[0192]

[0193] Compounds 8a-8c (0.16 mmol, 1.0 equiv.) and compounds 3a-3f (0.18 mmol, 1.1 equiv.) were dissolved in N,N-dimethylformamide, and HATU (0.16 mmol, 1.0 equiv.) and DIPEA (0.80 mmol, 5.0 equiv.) were added to react at room temperature for 10 h. After the reaction was completed, water was added to quench, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to flash column chromatography to obtain compounds 9a-9r.

[0194] The compounds 9a-9r are arranged in the following order:

[0195]

[0196]

[0197] Example 9 Synthesis of Compounds 10a-10c:

[0198]

[0199] Compounds 8a-8c (0.16 mmol, 1.0 equiv.) and compound 5a (0.18 mmol, 1.1 equiv.) were dissolved in N,N-dimethylformamide, and HATU (0.16 mmol, 1.0 equiv.) and DIPEA (0.80 mmol, 5.0 equiv.) were added to react at room temperature for 10 h. After the reaction was completed, water was added to quench, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to flash column chromatography to obtain compounds 10a-10c.

[0200] The compounds 10a-10c are arranged in the following order:

[0201]

[0202] Example 10 Synthesis of Compounds 13a-13f:

[0203]

[0204] Compound 7a-7b (0.13 mmol, 1.0 equiv.) was dissolved in 1,2-dichloroethane, and Dess-Martin Periodinane (CAS No.: 87413-09-0, 0.26 mmol, 2.0 equiv.) was added, and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate and saturated sodium thiosulfate solutions were added, and the mixture was stirred for 10 minutes. The organic phase was collected, and the aqueous phase was extracted once with 1,2-dichloroethane, and the organic phases were combined. Compounds 12a-12c and glacial acetic acid were added, and the mixture was stirred at room temperature for 1 hour. The mixture was cooled in an ice-water bath, and then sodium triacetoxyborohydride (NaBH(OAc)) was added. 3 , 0.39 mmol, 3.0 equiv.), reacted at room temperature for 16 hours, and after completion of the reaction, concentrated in vacuo to obtain a crude product, which was then purified by flash column chromatography to obtain white solid compounds 13a-13f.

[0205] The compounds 13a-13f are arranged in the following order:

[0206]

[0207] Example 11 Synthesis of Compound 9a:

[0208] Synthesis steps Referring to Example 8, compound 8a and compound 3a reacted to obtain compound 9a, yield: 32%; 1 HNMR (500 MHz, DMSO-d 6 )δ13.01 (br, 1H), 11.08 (s, 1H), 8.24 (br, 1H), 7.82-7.70 (m, 2H), 7.59 (dd, J=8.5, 7.0Hz, 2H ), 7.32-7.26 (m, 2H), 7.13 (t, J=74.5Hz, 1H), 7.03 (d, J=7.0Hz, 1H), 6.82 (d, J=6.0Hz, 1H), 5 .05 (dd, J=12.5, 5.5Hz, 1H), 3.97 (d, J=7.0Hz, 2H), 3.52-3.46 (m, 4H), 2.92-2.83 (m, 1H), 2. 62-2.51(m, 2H), 2.05-1.99(m, 1H), 1.33-1.28(m, 1H), 0.62-0.58(m, 2H), 0.40-O.36(m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ172.8, 170.1, 168.7, 167.3, 162.7, 150.1, 146.4, 144.9, 140.0, 137.0, 136.2, 132.2, 128.3, 121.3, 120.8, 117.7, 117.4, 116.7 (t, J = 256.5 Hz), 111.2, 110.6, 109.2, 73.2, 48.5, 41.8, 37.6, 31.0, 22.2, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 30 H 28 O 7 N 6 F 2 Na + [M+Na] + , 645.1880; the measured value is 645.1878.

[0209] Example 12 Synthesis of Compound 9b:

[0210] Synthesis steps Referring to Example 8, compound 8a and compound 3b reacted to obtain compound 9b, yield: 51%; 1 HNMR (500 MHz, DMSO-d 6 )δ13.54 (br, 1H), 11.19 (br, 1H), 8.19 (br, 1H), 7.88 (s, 1H), 7.70 (s, 1H), 7.67 (d, J = 8.5Hz, 1H), 7.58-7.55 (m, 1 H), 7.24 (d, J=8.0Hz, 1H), 7.13 (t, J=74.5Hz, 1H), 7.12 (d, J=8.5Hz, 1H), 7.01 (d, J=7.0Hz, 1H), 6.82-6.79 (m, 1H) , 5.04 (dd, J=13.0, 5.5Hz, 1H), 3.99 (d, J=7.0Hz, 2H), 3.34-3.33 (m, 2H), 3.33-3.30 (m, 2H), 2.92-2.84 (m, 1H), 2 .60-2.53(m, 2H), 2.04-1.99(m, 1H), 1.82-1.77(m, 2H), 1.30-1.27(m, 1H), 0.61-0.57(m, 2H), 0.38-0.35(m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ173.2, 170.4, 169.0, 167.6, 162.7, 150.3, 146.5, 145.0, 140.2, 139.4, 136.6, 132.5, 130.5, 128.5, 121.5, 118.1, 117.5, 116.9 (t, J = 257.0 Hz), 111.5, 110.7, 109.3, 73.4, 55.1, 48.7, 36.0, 31.2, 31.0, 22.4, 10.2, 3.3 (2×C). ESI-HRMS m / z: calculated for C 31 H 30 O 7 N 6 F 2 Na + [M+Na] + , 659.2036; the measured value is 659.2036.

[0211] Example 13 Synthesis of Compound 9c:

[0212] Synthesis steps Referring to Example 8, compound 8a and compound 3c reacted to obtain compound 9c, yield: 56%; 1 HNMR (500 MHz, DMSO-d 6 )δ8.11 (br, 1H), 7.78 (d, J=2.5Hz, 1H), 7.71 (s, 1H), 7.61 (dd, J=8.5, 2.0Hz, 1H), 7.57-7.54 (m, 1H), 7.24 (d, J=8. 0Hz, 1H), 7.11 (t, J=74.0Hz, 1H), 7.11-7.09 (m, 1H), 7.00 (d, J=6.5Hz, 1H), 6.57 (t, J=6.0Hz, 1H), 5.04 (dd, J=12. 5, 5.5Hz, 1H), 3.94 (d, J=6.5Hz, 2H), 3.33 (d, J=6.0Hz, 2H), 3.29 (d, J=5.5Hz, 2H), 2.91-2.86 (m, 1H), 2.61-2.52 ( m, 2H), 2.05-1.99 (m, 1H), 1.60-1.58 (m, 4H), 1.30-1.25 (m, 1H), 0.60-0.57 (m, 2H), 0.37-0.34 (m, 2H), NH (2H, not observed). 13 C NMR (101 MHz, DMSO-d 6)δ173.0 (2×C), 170.3 (2×C), 169.0, 167.4, 161.9, 150.1, 146.5, 145.5, 140.0, 136.4, 132.3, 128.7, 121.4, 117.9, 117.3, 116.8 (t, J = 257.0 Hz), 111.3, 110.5, 109.1, 72.9, 48.6, 41.7, 38.0, 31.1, 27.0, 26.4, 22.3, 10.1, 3.2 (2×C). ESI-HRMS m / z: calculated for C 32 H 32 O 7 N 6 F 2 Na + [M+Na] + , 673.2193; the measured value is 673.2181.

[0213] Example 14 Synthesis of Compound 9d:

[0214] Synthesis steps Referring to Example 8, compound 8a and compound 3d reacted to obtain compound 9d, yield: 30%; 1 HNMR (500 MHz, DMSO-d 6 ) δ12.99 (br, 1H), 11.09 (s, 1H), 7.96 (t, J = 6.0Hz, 1H), 7.75 (d, J = 8.0Hz, 2H), 7.61-7.54 (m, 2H), 7.27 (d, J = 9 .0Hz, 1H), 7.12 (t, J=74.5Hz, 1H), 7.09 (d, J=8.5Hz, 1H), 7.01 (d, J=7.0Hz, 1H), 6.53 (t, J=6.0Hz, 1H), 5.04 ( dd, J=12.5, 5.5Hz, 1H), 3.95 (d, J=7.0Hz, 2H), 3.30-3.23 (m, 4H), 2.91-2.84 (m, 1H), 2.62-2.51 (m, 2H), 2.05 -1.99 (m, 1H), 1.63-1.52 (m, 4H), 1.41-1.33 (m, 2H), 1.32-1.26 (m, 1H), 0.62-0.57 (m, 2H), 0.38-0.34 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ172.8, 170.1, 169.0, 167.3, 162.0, 150.1, 146.4, 144.7, 139.9, 137.3, 136.3, 132.2, 128.3, 121.3, 120.5, 117.7, 117.2, 116.7 (t, J = 256.5 Hz), 111.2, 110.4, 109.0, 73.1, 48.5, 41.8, 38.1, 31.0, 29.3, 28.5, 23.8, 22.2, 10.0, 3.0 (2×C). ESI-HRMS m / z: calculated for C 33 H 34 O 7 N 6 F 2 Na + [M+Na] + , 687.2349; the measured value is 687.2328.

[0215] Example 15 Synthesis of Compound 9e:

[0216] Synthesis steps Referring to Example 8, compound 8a and compound 3e reacted to obtain compound 9e, yield: 36%; 1 HNMR (500 MHz, DMSO-d 6 )δ8.01 (br, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.61 (dd, J=8.0, 2.0Hz, 1H), 7.58-7.55 (m, 1H), 7.24 (d, J=8.5Hz, 1H), 7.12 (t , J=74.5Hz, 1H), 7.08 (d, J=8.5Hz, 1H), 7.01 (d, J=7.0Hz, 1H), 6.53 (t, J=6.0Hz, 1H), 5.04 (dd, J=13.0, 5.5Hz, 1H), 3.95 (d , J=7.0Hz, 2H), 3.29 (d, J=7.0Hz, 2H), 3.24 (d, J=7.0Hz, 2H), 2.91-2.84 (m, 1H), 2.63-2.52 (m, 2H), 2.05-1.99 (m, 1H), 1.6 1-1.57(m, 2H), 1.53-1.49(m, 2H), 1.41-1.32(m, 4H), 1.30-1.27(m, 1H), 0.62-0.57(m, 2H), 0.38-0.35(m, 2H), NH(2H, not observed). 13 C NMR (101 MHz, DMSO-d 6)δ173.0(2×C), 170.3(2×C), 169.0, 167.4, 150.1, 146.5, 145.4, 139.9, 136.4, 132.3, 129.8, 128.5, 121.4, 117.8, 117.3, 116.8(t, J=257.0Hz), 111.2, 110.5, 109.0, 73.2, 48.6, 41.9, 38.3, 31.1, 29.5, 28.7, 26.3, 26.2, 22.2, 10.1, 3.1(2×C).ESI-HRMS m / z: calculated for C 34 H 36 O 7 N 6 F 2 Na + [M+Na] + , 701.2506; the measured value is 701.2498.

[0217] Example 16 Synthesis of Compound 9f:

[0218] Synthesis steps Referring to Example 8, compound 8a and compound 3f reacted to obtain compound 9f, yield: 43%; 1 HNMR (500 MHz, DMSO-d 6 )δ12.98 (br, 1H), 11.07 (s, 1H), 7.86 (s, 1H), 7.79-7.67 (m, 2H), 7.57 (d, J=7.5Hz, 1H), 7.54 (dd, J=8.5, 7.0Hz, 1H), 7.2 4 (d, J=8.0Hz, 1H), 7.11 (t, J=74.5Hz, 1H), 7.08 (d, J=8.5Hz, 1H), 7.01 (d, J=7.0Hz, 1H), 6.60 (t, J=6.0Hz, 1H), 5.05 (dd, J=13.0, 5.5Hz, 1H), 3.95 (d, J=7.0Hz, 2H), 3.63 (t, J=5.5Hz, 2H), 3.60-3.56 (m, 4H), 3.54 (t, J=6.0Hz, 2H), 3.46-3.40 (m , 4H), 2.90-2.80(m, 1H), 2.61-2.51(m, 2H), 2.04-1.99(m, 1H), 1.31-1.26(m, 1H), 0.61-0.57(m, 2H), 0.39-0.34(m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ172.8, 170.1, 168.9, 167.3, 162.1, 150.1, 146.4, 144.8, 140.0, 137.0, 136.1, 132.1, 128.2, 121.3, 120.6, 117.6, 117.4, 116.7 (t, J = 256.5 Hz), 111.1, 110.6, 109.2, 73.1, 69.7, 69.6, 69.2, 68.9, 48.6, 41.7, 38.0, 31.0, 22.1, 10.0, 3.0 (2×C). ESI-HRMS m / z: calculated for C 34 H 36 O 9 N 6 F 2 Na + [M+Na] + , 733.2404; the measured value is 733.2388.

[0219] Example 17 Synthesis of Compound 9g:

[0220] Synthesis steps Referring to Example 8, compound 8b and compound 3a reacted to obtain compound 9g, yield: 57%; 1 HNMR (600 MHz, DMSO-d 6 ) δ11.09 (s, 1H), 8.71 (s, 1H), 8.62 (t, J = 5.4Hz, 1H), 7.65 (d, J = 1.8Hz, 1H), 7.62 (dd, J = 8.4, 1.8Hz, 1H), 7.5 8 (dd, J=8.4, 7.2Hz, 1H), 7.37 (d, J=8.4Hz, 1H), 7.28 (d, J=8.4Hz, 1H), 7.22 (t, J=73.8Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 6.83 (t, J=6.0Hz, 1H), 5.05 (dd, J=12.6, 5.4Hz, 1H), 3.99 (d, J=6.6Hz, 2H), 3.53-3.47 (m, 4H), 2.91- 2.84 (m, 1H), 2.61-2.51 (m, 2H), 2.05-1.99 (m, 1H), 1.30-1.25 (m, 1H), 0.62-0.58 (m, 2H), 0.40-0.37 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ172.8, 170.1, 168.7, 167.3, 160.4, 159.9, 150.2, 146.3, 142.3, 142.0, 137.3, 136.2, 132.3, 124.2, 121.3, 119.1, 117.3, 116.5 (t, J = 256.5 Hz), 111.8, 110.6, 109.3, 73.3, 48.6, 41.5, 37.9, 31.0, 22.2, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 30 H 27 O 8 N 5 F 2 Na + [M+Na] + , 646.1720; the measured value is 646.1707.

[0221] Example 18 Synthesis of Compound 9h:

[0222] Synthesis steps Referring to Example 8, compound 8b and compound 3b reacted to obtain compound 9h, yield: 61%; 1 HNMR (500 MHz, DMSO-d 6 )δ11.10 (s, 1H), 8.70 (s, 1H), 8.53 (t, J=6.0Hz, 1H), 7.66 (d, J=2.0Hz, 1H), 7.63 (dd, J=8.5, 2.0Hz, 1H), 7.58 (t, J=8.0Hz, 1H), 7.36 (s, 1H), 7.22 (t, J=74.0Hz, 1H), 7.11 (d, J=8.5Hz, 1H), 7.02 (d, J=7.0Hz, 1H), 6.81 (t, J =6.0Hz, 1H), 5.04 (dd, J = 12.5, 5.5Hz, 1H), 3.99 (d, J = 6.5Hz, 2H), 3.42-3.35 (m, 4H), 2.90-2.87 (m, 1H), 2.62 -2.51 (m, 2H), 2.04-1.99 (m, 1H), 1.83-1.78 (m, 2H), 1.31-1.27 (m, 1H), 0.62-0.58 (m, 2H), 0.40-0.37 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ173.0, 170.2, 168.8, 167.4, 160.2, 159.9, 150.2, 146.3, 142.3, 142.0, 137.5, 136.4, 132.4, 124.3, 121.3, 119.1, 117.2, 116.6 (t, J = 257.0 Hz), 111.8, 110.5, 109.2, 73.3, 55.0, 48.6, 35.9, 31.1, 28.8, 22.2, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated for C 31 H 29 O 8 N 5 F 2 Na + [M+Na] + , 660.1876; the measured value is 660.1855.

[0223] Example 19 Synthesis of Compound 9i:

[0224] Synthesis steps Referring to Example 8, compound 8b and compound 3c reacted to obtain compound 9i, yield: 63%; 1 HNMR (500 MHz, DMSO-d 6 ) δ11.08 (s, 1H), 8.68 (s, 1H), 8.40 (t, J = 6.0Hz, 1H), 7.65 (d, J = 2.0Hz, 1H), 7.61 (dd, J = 8.5, 2.0Hz, 1H), 7.56 (dd , J=8.5, 7.0Hz, 1H), 7.36 (d, J=8.5Hz, 1H), 7.21 (t, J=74.0Hz, 1H), 7.12 (d, J=8.5Hz, 1H), 7.01 (d, J=7.0Hz, 1H), 6 .57 (t, J=6.0Hz, 1H), 5.04 (dd, J=13.0, 5.5Hz, 1H), 3.99 (d, J=7.0Hz, 2H), 3.33-3.27 (m, 4H), 2.91-2.85 (m, 1H), 2 .62-2.53(m, 2H), 2.05-2.00(m, 1H), 1.63-1.57(m, 4H), 1.31-1.27(m, 1H), 0.62-0.57(m, 2H), 0.40-0.36(m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ173.0, 170.3, 169.0, 167.4, 160.0, 159.9, 150.2, 146.5, 142.2, 142.0, 137.5, 136.4, 132.3, 124.3, 121.3, 119.2, 117.4, 116.6 (t, J = 257.0 Hz), 111.8, 110.5, 109.1, 73.4, 48.6, 41.6, 38.2, 31.1, 26.7, 26.3, 22.3, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated for C 32 H 31 O 8 N 5 F 2 Na + [M+Na] + , 674.2033; the measured value is 674.2017.

[0225] Example 20 Synthesis of Compound 9j:

[0226] Synthesis steps Referring to Example 8, compound 8b and compound 3d reacted to obtain compound 9j, yield: 40%; 1 HNMR (500 MHz, DMSO-d 6 )δ11.09 (s, 1H), 8.67 (s, 1H), 8.35 (t, J=6.0Hz, 1H), 7.65 (d, J=2.0Hz, 1H), 7.61 (dd, J=8.5, 2.0Hz, 1H), 7.57 (dd, J=8 .5, 7.0Hz, 1H), 7.37 (d, J=8.0Hz, 1H), 7.21 (t, J=74.0Hz, 1H), 7.10 (d, J=8.5Hz, 1H), 7.01 (d, J=7.0Hz, 1H), 6.53 (t, J= 6.0Hz, 1H), 5.04 (dd, J=13.0, 5.5Hz, 1H), 3.99 (d, J=7.0Hz, 2H), 3.31-3.24 (m, 4H), 2.91-2.84 (m, 1H), 2.61-2.51 (m, 2 H), 2.05-1.99(m, 1H), 1.63-1.54(m, 4H), 1.41-1.34(m, 2H), 1.31-1.26(m, 1H), 0.62-0.58(m, 2H), 0.40-0.36(m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ172.8, 170.1, 169.0, 167.3, 159.8, 159.7, 150.1, 146.4, 142.1, 142.0, 137.5, 136.3, 132.2, 124.3, 121.2, 119.1, 117.2, 116.5 (t, J = 256.5 Hz), 111.8, 110.4, 109.0, 73.3, 48.5, 41.8, 38.3, 31.0, 28.9, 28.4, 23.7, 22.2, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 33 H 33 O 8 N 5 F 2 Na + [M+Na] + , 688.2189; the measured value is 688.2167.

[0227] Example 21 Synthesis of Compound 9k:

[0228] Synthesis steps Referring to Example 8, compound 8b and compound 3e reacted to obtain compound 9k, yield: 52%; 1 HNMR (500 MHz, DMSO-d 6 ) δ11.09 (s, 1H), 8.67 (s, 1H), 8.33 (t, J=6.0Hz, 1H), 7.65 (d, J=2.0Hz, 1H), 7.61 (dd, J=8.5, 2.0Hz, 1H), 7.56 (dd, J=8.5, 7 .0Hz, 1H), 7.37-7.35 (m, 1H), 7.21 (t, J=74.0Hz, 1H), 7.08 (d, J=8.5Hz, 1H), 7.01 (d, J=7.0Hz, 1H), 6.52 (d, J=6.5Hz, 1H), 5.05 (dd, J=13.0, 5.5Hz, 1H), 3.99 (d, J=7.0Hz, 2H), 3.31-3.27 (m, 2H), 3.27-3.23 (m, 2H), 2.92-2.84 (m, 1H), 2.61-2.51 ( m, 2H), 2.05-2.00 (m, 1H), 1.61-1.51 (m, 4H), 1.40-1.32 (m, 4H), 1.30-1.26 (m, 1H), 0.61-0.58 (m, 2H), 0.40-0.36 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ172.8, 170.1, 169.0, 167.3, 159.8, 159.7, 150.1, 146.4, 142.0, 141.9, 137.5, 136.3, 132.2, 124.3, 121.2, 119.1, 117.2, 116.5 (t, J = 256.5 Hz), 111.8, 110.4, 109.0, 73.3, 48.5, 41.8, 38.4, 31.0, 29.2, 28.6, 26.2, 26.1, 22.2, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 34 H 35 O 8 N 5 F 2 Na + [M+Na] + , 702.2346; the measured value is 702.2311.

[0229] Example 22 Synthesis of Compound 91:

[0230] Synthesis steps Referring to Example 8, compound 8b and compound 3f reacted to obtain compound 91, yield: 39%; 1 HNMR (500 MHz, DMSO-d 6 )δ11.07 (s, 1H), 8.75-8.62 (m, 1H), 8.21 (t, J=6.0Hz, 1H), 7.63 (d, J=2.0Hz, 1H), 7.59 (dd, J=8.0, 2.0Hz, 1H), 7.53 (dd, J=8.5, 7.0Hz, 1H), 7.37-7.33 (m, 1H), 7.20 (t, J=74.0Hz, 1H), 7.08 (d, J=9.0Hz, 1H), 7.00 (d, J=7.0Hz, 1H), 6.58 (t, J=6 .0Hz, 1H), 5.04 (dd, J=13.0, 5.5Hz, 1H), 3.98 (d, J=7.0Hz, 2H), 3.63 (t, J=5.5Hz, 2H), 3.60-3.54 (m, 6H), 3.46-3.41 (m, 4H), 2.90-2.84(m, 1H), 2.60-2.51(m, 2H), 2.05-2.00(m, 1H), 1.30-1.27(m, 1H), 0.61-0.57(m, 2H), 0.39-0.36(m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ172.9, 170.2, 169.0, 167.4, 160.0, 159.9, 150.2, 146.4, 142.2, 142.0, 137.3, 136.3, 132.1, 124.2, 121.3, 119.1, 117.4, 116.6 (t, J = 257.0 Hz), 111.7, 110.7, 109.3, 73.3, 69.7, 69.6, 68.9, 68.9, 48.6, 41.7, 38.3, 31.0, 22.2, 10.0, 3.2 (2×C). ESI-HRMS m / z: calculated for C 34 H 35 O 10 N 5 F 2 Na + [M+Na] + , 734.2244; the measured value is 734.2223.

[0231] Example 23 Synthesis of Compound 9m:

[0232] Synthesis steps Referring to Example 8, compound 8c and compound 3a reacted to obtain compound 9m, yield: 43%; 1 HNMR (500 MHz, DMSO-d 6 )δ11.08 (s, 1H), 8.78 (t, J=6.0Hz, 1H), 8.32 (s, 1H), 7.71 (d, J=2.0Hz, 1H), 7.62 (dd, J=8.5, 2.0Hz, 1H), 7.59 (dd, J=8.5, 7.0Hz, 1H), 7.32 (dd, J=8.5, 4.0Hz, 2H), 7.20 (t, J=74.0Hz, 1H), 7.03 (d, J=7.0Hz, 1H), 6.84 (d, J=6.0Hz, 1H), 5.05 (dd, J=13.0, 5.5Hz, 1H), 4.03 (d, J=7.5Hz, 2H), 3.56-3.49 (m, 4H), 2.92-2.8 4(m, 1H), 2.61-2.51(m, 2H), 2.04-1.99(m, 1H), 1.31-1.27(m, 1H), 0.63-0.58(m, 2H), 0.41-0.37(m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ172.8, 170.1, 168.7, 167.3, 166.2, 161.0, 150.5, 150.3, 146.3, 141.7, 136.2, 132.2, 130.7, 124.5, 121.3, 119.4, 117.3, 116.6 (t, J = 256.5 Hz), 112.1, 110.6, 109.3, 73.4, 48.5, 41.5, 38.2, 31.0, 22.2, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 30 H 27 O 7 N 5 F 2 NaS + [M+Na] + , 662.1491; the measured value is 662.1478.

[0233] Example 24 Synthesis of Compound 9n:

[0234] Synthesis steps Referring to Example 8, compound 8c and compound 3b reacted to obtain compound 9n, yield: 55%; 1 HNMR (500 MHz, DMSO-d 6 )δ11.10 (s, 1H), 8.69 (t, J=6.0Hz, 1H), 8.30 (s, 1H), 7.72 (d, J=2.0Hz, 1H), 7.62 (dd, J=8.5, 2.0Hz, 1H), 7.57 (dd , J=8.5, 7.0Hz, 1H), 7.32 (d, J=8.0Hz, 1H), 7.20 (t, J=74.0Hz, 1H), 7.12 (d, J=8.5Hz, 1H), 7.02 (d, J=7.0Hz, 1H), 6 .81 (t, J=6.0Hz, 1H), 5.05 (dd, J=13.0, 5.5Hz, 1H), 4.03 (d, J=7.0Hz, 2H), 3.43-3.36 (m, 4H), 2.92-2.84 (m, 1H), 2 .61-2.51(m, 2H), 2.04-1.99(m, 1H), 1.87-1.80(m, 2H), 1.32-1.27(m, 1H), 0.62-0.57(m, 2H), 0.40-0.36(m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ172.8, 170.1, 168.8, 167.3, 166.1, 160.6, 150.7, 150.3, 146.3, 141.7, 136.2, 132.3, 130.7, 124.2, 121.3, 119.4, 117.2, 116.6 (t, J = 256.5 Hz), 112.1, 110.4, 109.2, 73.3, 48.5, 40.1, 36.3, 31.0, 28.9, 22.2, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 31 H 29 O 7 N 5 F 2 NaS + [M+Na] + , 676.1648; the measured value is 676.1630.

[0235] Example 25 Synthesis of Compound 9o:

[0236] Synthesis steps Referring to Example 8, compound 8c and compound 3c reacted to obtain compound 9o, yield: 54%; 1 HNMR (500 MHz, DMSO-d 6 )δ11.08 (s, 1H), 8.58 (t, J=6.0Hz, 1H), 8.28 (s, 1H), 7.72 (d, J=2.0Hz, 1H), 7.62 (dd, J=8.5, 2.0Hz, 1H), 7.55 (dd , J=8.5, 7.0Hz, 1H), 7.31 (d, J=8.0Hz, 1H), 7.19 (t, J=74.0Hz, 1H), 7.11 (d, J=8.5Hz, 1H), 7.00 (d, J=7.0Hz, 1H), 6 .59 (t, J=6.0Hz, 1H), 5.04 (dd, J=13.0, 5.5Hz, 1H), 4.02 (d, J=7.0Hz, 2H), 3.39-3.33 (m, 4H), 2.91-2.84 (m, 1H), 2 .61-2.51(m, 2H), 2.05-1.99(m, 1H), 1.66-1.59(m, 4H), 1.31-1.26(m, 1H), 0.62-0.57(m, 2H), 0.40-0.36(m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ172.8, 170.1, 168.9, 167.3, 166.1, 160.4, 150.8, 150.3, 146.4, 141.7, 136.2, 132.2, 130.7, 124.1, 121.3, 119.4, 117.2, 116.6 (t, J = 256.5 Hz), 112.1, 110.4, 109.0, 73.3, 48.5, 41.5, 38.4, 31.0, 26.8, 26.3, 22.2, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 32 H 31 O 7 N 5 F 2 NaS + [M+Na] + , 690.1804; the measured value is 690.1802.

[0237] Example 26 Synthesis of Compound 9p:

[0238] Synthesis steps Referring to Example 8, compound 8c and compound 3d reacted to obtain compound 9p, yield: 66%; 1 HNMR (500 MHz, DMSO-d 6 )δ11.09 (s, 1H), 8.53 (t, J=6.0Hz, 1H), 8.26 (s, 1H), 7.72 (d, J=2.0Hz, 1H), 7.62 (dd, J=8.5, 2.0Hz, 1H), 7.56 (dd, J=8 .5, 7.0Hz, 1H), 7.31 (d, J=8.5Hz, 1H), 7.19 (t, J=74.0Hz, 1H), 7.10 (d, J=8.5Hz, 1H), 7.01 (d, J=7.0Hz, 1H), 6.53 (t, J= 6.0Hz, 1H), 5.04 (dd, J=13.0, 5.5Hz, 1H), 4.03 (d, J=7.0Hz, 2H), 3.33-3.27 (m, 4H), 2.92-2.84 (m, 1H), 2.62-2.51 (m, 2 H), 2.04-1.99(m, 1H), 1.65-1.57(m, 4H), 1.43-1.36(m, 2H), 1.31-1.27(m, 1H), 0.63-0.57(m, 2H), 0.41-0.36(m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ172.8, 170.1, 168.9, 167.3, 166.1, 160.3, 150.8, 150.3, 146.4, 141.7, 136.3, 132.2, 130.7, 124.0, 121.3, 119.4, 117.2, 116.6 (t, J = 256.5 Hz), 112.1, 110.4, 109.0, 73.3, 48.5, 41.8, 38.6, 31.0, 29.1, 28.4, 23.8, 22.2, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 33 H 33 O 7 N 5 F 2 NaS + [M+Na] + , 704.1961; the measured value is 704.1956.

[0239] Example 27 Synthesis of Compound 9q:

[0240] Synthesis steps Referring to Example 8, compound 8c and compound 3e reacted to obtain compound 9q, yield: 65%; 1 HNMR (500 MHz, DMSO-d 6 ) δ11.09 (s, 1H), 8.51 (t, J=6.0Hz, 1H), 8.26 (s, 1H), 7.72 (d, J=2.0Hz, 1H), 7.62 (dd, J=8.5, 2.0Hz, 1H), 7.56 (dd, J=8 .5, 7.0Hz, 1H), 7.31 (d, J=8.5Hz, 1H), 7.19 (t, J=74.0Hz, 1H), 7.08 (d, J=8.5Hz, 1H), 7.01 (d, J=7.0Hz, 1H), 6.53 (t, J= 6.0Hz, 1H), 5.05 (dd, J=13.0, 5.5Hz, 1H), 4.02 (d, J=7.0Hz, 2H), 3.32-3.26 (m, 4H), 2.91-2.84 (m, 1H), 2.61-2.51 (m, 2 H), 2.05-2.00(m, 1H), 1.61-1.53(m, 4H), 1.41-1.33(m, 4H), 1.30-1.26(m, 1H), 0.62-0.57(m, 2H), 0.41-0.36(m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ172.8, 170.1, 169.0, 167.3, 166.1, 160.3, 150.8, 150.3, 146.4, 141.7, 136.3, 132.2, 130.7, 124.0, 121.3, 119.4, 117.2, 116.6 (t, J = 256.5 Hz), 112.1, 110.4, 109.0, 73.3, 48.5, 41.8, 38.7, 30.1, 29.3, 28.6, 26.2, 26.1, 22.1, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 34 H 35 O 7 N 5 F 2 NaS + [M+Na] + , 718.2117; the measured value is 718.2114.

[0241] Example 28 Synthesis of Compound 9r:

[0242] Synthesis steps: Referring to Example 8, compound 8c and compound 3f were reacted to obtain compound 9r, with a yield of 46%; 1 H NMR (400 MHz, DMSO-d 6 )δ11.06 (s, 1H), 8.43 (t, J=6.0Hz, 1H), 8.27 (s, 1H), 7.69 (d, J=2.0Hz, 1H), 7.58 (dd, J=8.4, 2.0Hz, 1H), 7.53 (t, J=8.4Hz , 1H), 7.29 (d, J=8.0Hz, 1H), 7.17 (t, J=74.4Hz, 1H), 7.05 (d, J=8.8Hz, 1H), 7.00 (d, J=7.6Hz, 1H), 6.57 (t, J=6.0, 1H), 5. 04 (dd, J=12.8, 5.6Hz, 1H), 4.01 (d, J=6.8Hz, 2H), 3.66-3.59 (m, 4H), 3.59-3.56 (m, 4H), 3.49-3.46 (m, 2H), 3.43-3.40 (m , 2H), 2.88-2.79(m, 1H), 2.60-2.53(m, 2H), 2.06-2.00(m, 1H), 1.31-1.27(m, 1H), 0.62-0.57(m, 2H), 0.40-0.35(m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ172.9, 170.2, 169.0, 167.4, 166.2, 160.5, 150.5, 150.3, 146.4, 141.7, 136.2, 132.1, 130.6, 124.4, 121.3, 119.4, 117.4, 116.6 (t, J = 257.0 Hz), 111.9, 110.7, 109.2, 73.3, 69.8, 69.7, 68.9, 68.8, 48.6, 41.7, 38.7, 31.0, 22.2, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 34 H 35 O 9 N 5 F 2 NaS + [M+Na] + , 750.2016; the measured value is 750.2016.

[0243] Example 29 Synthesis of Compound 10a:

[0244] Synthesis steps Referring to Example 9, compound 8a and 5a were reacted to obtain compound 10a, yield: 58%; 1 H NMR (500 MHz, DMSO-d 6 )δ13.01 (br, 1H), 11.08 (br, 1H), 7.77 (t, J=6.0Hz, 1H), 7.76-7.62 (m, 2H), 7.57-7.50 (m, 2H), 7.24 (d, J=8.5Hz, 1H), 7.11 (t, J=74.0Hz , 1H), 7.10 (d, J=7.0Hz, 1H), 7.02 (d, J=7.0Hz, 1H), 6.59 (t, J=6.0Hz, 1H), 5.05 (dd, J=13.0, 5.5Hz, 1H), 4.47-3.97 (m, 2H), 3.96 (d, J=7. 0Hz, 2H), 3.87-3.63 (m, 2H), 3.62 (t, J=5.5Hz, 2H), 3.58-3.53 (m, 4H), 3.46-3.43 (m, 4H), 3.26 (dd, J=12.0, 5.5Hz, 2H), 2.96-2.93 (m, 2H ), 2.91-2.85(m, 1H), 2.61-2.51(m, 2H), 2.49-2.45(m, 4H), 2.04-2.00(m, 1H), 1.31-1.27(m, 1H), 0.61-0.58(m, 2H), 0.39-0.36(m, 2H). 13 C NMR (151 MHz, DMSO-d 6)δ172.8, 170.1, 169.1, 169.0, 167.3, 162.1, 150.1, 146.4, 144.2, 139.9, 136.2, 132.1, 129.7128.4, 123.6, 121.5, 117.8, 117.4, 116.7 (t, J = 256.5 Hz), 111.2, 110.7, 109.3, 73.1, 69.8, 69.6, 69.0, 68.9, 61.0, 56.1, 53.0, 48.6, 46.0, 41.7, 38.2, 31.0, 22.2, 18.6, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 40 H 46 O 10 N 8 F 2 Na + [M+Na] + , 859.3197; the measured value is 859.3170.

[0245] Example 30 Synthesis of Compound 10b:

[0246] Synthesis steps: Referring to Example 9, compound 8b was reacted with 5a to obtain compound 10b, with a yield of 69%; 1 HNMR (500 MHz, DMSO-d 6 )δ11.09 (s, 1H), 8.61 (s, 1H), 7.78 (t, J=5.5Hz, 1H), 7.61-7.53 (m, 3H), 7.34 (s, 1H), 7, 20 (t, J=74.0Hz, 1H), 7.10 (d, J= 8.5Hz, 1H), 7.02 (d, J=7.0Hz, 1H), 6.58 (t, J=6.0Hz, 1H), 5.05 (dd, J=13.0, 5.5Hz, 1H), 3.99 (d, J=7.0Hz, 2H), 3.97-3.83 (m, 2H), 3.62 (t, J=5.5Hz, 4H), 3.58-3.52 (m, 4H), 3.47-3.42 (m, 4H), 3.28-3.23 (m, 2H), 3.01-2.92 (m, 2H), 2.92-2.86 (m , 1H), 2.63-2.53(m, 2H), 2.07-2.O0(m, 1H), 1.30-1.27(m, 1H), 1.27-1.23(m, 4H), 0.62-0.55(m, 2H), 0.41-0.34(m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ172.9, 170.2, 169.0, 167.4, 160.1, 159.4, 151.8, 150.2, 146.4, 143.3 , 142.0, 136.8, 136.3, 132.1, 124.3, 121.3, 119.2, 117.5, 116.6 (t, J=25 7.0Hz), 111.8, 110.8, 109.3, 73.3, 69.8, 69.6, 69.1, 68.9, 53.6, 48.6, 4 1.7, 38.3, 31.0, 28.1, 22.2, 18.1, 16.8, 12.6, 10.0, 3.2 (2×C).ESI-HRMS m / z: calculated value is C 40 H 45 O 11 N 7 F 2 Na + [M+Na] + , 860.3037; the measured value is 860.3014.

[0247] Example 31 Synthesis of Compound 10c:

[0248] Synthesis steps: Referring to Example 9, carboxylic acid compound 8c was reacted with 5a to obtain compound 10c, with a yield of 51%; 1 H NMR (500 MHz, DMSO-d 6 )δ11.08 (s, 1H), 8.11 (s, 1H), 7.78 (t, J=6.0Hz, 1H), 7.58 (d, J=2.0Hz, 1H), 7.57-7.52 (m, 2H), 7.30 (d, J=8.5Hz, 1H), 7.17 (t, J= 74.0Hz, 1H), 7.10 (d, J=8.5Hz, 1H), 7.02 (d, J=7.0Hz, 1H), 6.58 (t, J=6.0, 1H), 5.04 (dd, J=12.5, 5.5Hz, 1H), 3.99 (d, J=7.0Hz, 2 H), 3.72-3.65 (m, 4H), 3.60 (t, J=5.5Hz, 2H), 3.56-3.52 (m, 4H), 3.48-3.36 (m, 6H), 3.27-3.23 (m, 2H), 2.97-2.94 (m, 2H), 2.91- 2.84(m, 1H), 2.61-2.52(m, 2H), 2.49-2.46(m, 2H), 2.05-2.00(m, 1H), 1.30-1.24(m, 1H), 0.60-0.57(m, 2H), 0.39-0.36(m, 2H). 13 C NMR (101 MHz, DMSO-d6 )δ172.9, 170.2, 169.1, 169.0, 167.4, 165.7, 162.O, 150.5, 150.3, 146.4 , 141.5, 136.3, 132.1, 130.7, 124.4, 121.5, 119.1, 117.4, 116.6 (t, J=25 7.0Hz), 111.8, 110.8, 109.3, 73.2, 69.8, 69.6, 69.1, 68.9, 60.9, 53.1, 5 2.5, 48.6, 46.8, 42.0, 41.7, 38.2, 31.0, 22.2, 10.0, 3.2 (2×C).ESI-HRMS m / z: calculated value is C 40 H 45 O 10 N 7 F 2 NaS + [M+Na] + , 876.2809; the measured value is 876.2807.

[0249] Example 32 Synthesis of Compound 13a:

[0250] Synthesis steps Referring to Example 10, compound 12a and compound 7a reacted to obtain compound 13a, yield: 28%; 1 H NMR (500 MHz, DMSO-d 6 )δ13.04 (br, 1H), 11.10 (br, 1H), 7.80 (dd, J=8.5, 7.5Hz, 1H), 7.78-7.62 (m, 2H), 7.56 (d, J=5.5Hz, 1H), 7.51 (d, J=8.5Hz, 1H) , 7.44 (d, J=7.0Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 7.11 (t, J=74.5Hz, 1H), 5.07 (dd, J=13.0, 5.5Hz, 1H), 4.21 (t, J=6.5Hz, 2H), 4.2 0-3.98 (m, 2H), 3.97 (d, J=7.0Hz, 2H), 3.79-3.53 (m, 2H), 2.91-2.83 (m, 1H), 2.61-2.51 (m, 2H), 2.42-2.36 (m, 4H), 2.31 (t, J= 7.0Hz, 2H), 2.05-2.00(m, 1H), 1.82-1.75(m, 2H), 1.55-1.45(m, 4H), 1.31-1.27(m, 1H), 0.62-0.57(m, 2H), 0.40-0.36(m, 2H). 13 CNMR (151 MHz, DMSO-d6 )δ172.8, 170.0, 166.9, 165.3, 162.2, 156.0, 150.1, 144.4, 139.9, 137.0, 133.3, 129.7, 128.4, 123.4, 121.5, 119.8, 117.8, 116.7 (t, J = 256.5 Hz), 116.2, 115.1, 111.2, 73.1, 68.8, 57.7, 53.0, 48.7, 46.3, 42.1, 40.1, 31.3, 28.3, 25.8, 23.3, 22.1, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 37 H 41 O 8 N 6 F 2 + [M+H] + , 735.2948; the measured value is 735.2947.

[0251] Example 33 Synthesis of Compound 13b:

[0252] Synthesis steps Referring to Example 10, compound 12a and compound 7b reacted to obtain compound 13b, yield: 33%; 1 H NMR (500 MHz, DMSO-d 6 )δ13.06(br,1H),11.13(br 1H), 7.80 (dd, J=8.5, 7.5Hz, 1H), 7.76-7.71 (m, 1H), 7.71-7.62 (m, 1H), 7.57 (d, J=8.5Hz, 1H), 7.51 (d, J=8.5Hz, 1H), 7.43 (d, J=7.0 Hz, 1H), 7.24 (d, J=8.5Hz, 1H), 7.11 (t, J=74.5Hz, 1H), 5.07 (dd, J=13.0, 5.5Hz, 1H), 4.20 (t, J=6.5Hz, 2H), 4.19-3.97 (m, 2H), 3.96 (d, J=7.0Hz, 2H), 3.74-3.53 (m, 2H), 2.91-2.84 (m, 1H), 2.61-2.51 (m, 2H), 2.38 (t, J=5.0Hz, 4H), 2.29 (t, J=7.5Hz, 2H), 2.05-2.00 (m, 1H), 1.78-1.74 (m, 2H), 1.50-1.44 (m, 4H), 1.39-1.33 (q, J=8.0Hz, 2H), 1.30-1.26 (m, 1H), 0.61-0.57 (m, 2H), 0.39-0.35 (m, 2H).13 C NMR (151 MHz, DMSO-d 6 )δ172.8, 170.0, 166.9, 165.3, 162.1, 156.0, 150.1, 144.3, 139.9, 137.0, 133.3, 129.7, 128.5, 123.4, 121.4, 119.8, 117.8, 116.7 (t, J = 256.5 Hz), 116.2, 115.1, 111.2, 73.1, 68.8, 57.8, 53.1, 48.7, 46.3, 42.0, 40.1, 31.0, 28.4, 26.6, 26.2, 25.2, 22.0, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 38 H 43 O 8 N 6 F 2 + [M+H] + , 749.3105; the measured value is 749.3101.

[0253] Example 34 Synthesis of Compound 13c:

[0254] Synthesis steps Referring to Example 10, compound 12b and compound 7a reacted to obtain compound 13c, yield: 37%; 1 H NMR (600 MHz, DMSO-d 6 ) δ11.10 (s, 1H), 8.62 (s, 1H), 7.80 (dd, J=8.4, 7.2Hz, 1H), 7.61 (d, J=1.8Hz, 1H), 7.59 (dd, J=8.4, 1.8Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.43 (d, J=7.2Hz, 1H), 7.35 (d, J=8.4Hz, 1H), 7.21 (t, J=74.4Hz, 1H), 5.07 (dd, J=13.2, 5.4Hz, 1H), 4.21 (t, J=6.3Hz, 2H), 4. 00 (d, J=7.2Hz, 2H), 3.93-3.81 (m, 2H), 3.66-3.53 (m, 2H), 2.90-2.84 (m, 1H), 2.60-2.51 (m, 2H), 2.40 (t, J=5.4Hz, 4H), 2.32 (t, J=7.2Hz, 2H), 2.04-2.00(m, 1H), 1.80-1.75(m, 2H), 1.54-1.46(m, 4H), 1.28-1.24(m, 1H), 0.60-0.57(m, 2H), 0.40-0.36(m, 2H).13 C NMR (151 MHz, DMSO-d 6 )δ172.8, 170.0, 166.9, 165.3, 160.0, 159.3, 156.0, 150.2, 143.0, 142.0, 137.0, 136.9, 133.2, 124.3, 121.3, 119.8, 119.1, 116.5 (t, J = 256.5 Hz), 116.2, 115.1, 111.8, 73.3, 68.8, 57.6, 53.2, 52.5, 48.7, 46.2, 41.9, 30.9, 28.3, 25.8, 23.3, 22.0, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 37 H 40 O 9 N 5 F 2 + [M+H] + , 736.2789; the measured value is 736.2800.

[0255] Example 35 Synthesis of Compound 13d:

[0256] Synthesis steps Referring to Example 10, compound 12b and compound 7b reacted to obtain compound 13d, yield: 25%; 1 H NMR (600 MHz, DMSO-d 6)δ11.10 (s, 1H), 8.62 (s, 1H), 7.80 (dd, J=8.4, 7.2Hz, 1H), 7.61 (d, J=1.8Hz, 1H), 7.59 (dd, J=8.4, 1.8Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.43 (d, J=7.2Hz, 1H), 7.35 (d, J=8.4Hz, 1H), 7.21 (t, J=74.4Hz, 1H), 5.07 (dd, J=12.6, 5.4Hz, 1H), 4.20 (t, J=6.6Hz, 2H), 4.00 (d, J=7 .2Hz, 2H), 3.92-3.81(m, 2H), 3.66-3.55(m, 2H), 2.90-2.84(m, 1H), 2.61-2.51(m, 2H), 2.39(t, J=4.8Hz, 4H), 2.30(t, J=7.2Hz, 2H), 2.04-2.00(m, 1H), 1.79-1.73(m, 2H), 1.51-1.42(m, 4H), 1.39-1.32(m, 2H), 1.28-1.24(m, 1H), 0.61-0.57(m, 2H), 0.40-0.36(m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ172.8, 170.0, 166.9, 165.3, 160.0, 159.3, 156.0, 150.2, 143.0, 142.0, 137.0, 136.9, 133.2, 124.3, 121.3, 119.8, 119.1, 116.5 (t, J = 256.5 Hz), 116.2, 115.1, 111.8, 73.3, 68.8, 57.6, 53.3, 52.5, 48.7, 46.2, 41.9, 30.9, 28.4, 26.5, 26.1, 25.2, 22.0, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 38 H 42 O 9 N 5 F 2 + [M+H] + , 750.2945; the measured value is 750.2912.

[0257] Example 36 Synthesis of Compound 13e:

[0258] Synthesis steps Referring to Example 10, compound 12c and compound 7a reacted to obtain compound 13e, yield: 23%; 1 H NMR (600 MHz, DMSO-d6 )δ11.09 (s, 1H), 8.12 (s, 1H), 7.80 (dd, J=8.4, 7.2Hz, 1H), 7.60 (d, J=1.8Hz, 1H), 7.54 (dd, J=8.4, 1.8Hz, 1H), 7.51 (d, J=8 .4Hz, 1H), 7.43 (d, J=7.2Hz, 1H), 7.31 (d, J=8.4Hz, 1H), 7.18 (t, J=74.4Hz, 1H), 5.07 (dd, J=12.6, 5.4Hz, 1H), 4.21 (t, J=6. 6Hz, 2H), 4.00 (d, J=7.2Hz, 2H), 3.68-3.61 (m, 4H), 2.90-2.84 (m, 1H), 2.60-2.51 (m, 2H), 2.45-2.38 (m, 4H), 2.33 (t, J=7.2 Hz, 2H), 2.04-1.99 (m, 1H), 1.80-1.75 (m, 2H), 1.54-1.46 (m, 4H), 1.29-1.25 (m, 1H), 0.60-0.57 (m, 2H), 0.39-0.36 (m, 2H). 13 C NMR (151 MHz, DMSO-d 6 )δ172.8, 170.0, 166.9, 165.6, 165.3, 161.9, 156.0, 150.5, 150.3, 141.5, 137.0, 133.2, 130.7, 124.1, 121.5, 119.8, 119.1, 116.5 (t, J = 256.5 Hz), 116.2, 115.1, 111.8, 73.2, 68.8, 57.6, 53.1, 52.5, 48.7, 46.8, 42.0, 31.0, 28.3, 25.8, 23.3, 22.0, 9.9, 3.1 (2×C). ESI-HRMS m / z: calculated for C 37 H 40 O 8 N 5 F 2 S + [M+H] + , 752.2560; the measured value is 752.2555.

[0259] Example 37 Synthesis of Compound 13f:

[0260] Synthesis steps: Referring to Example 10, compound 12c was reacted with compound 7b to obtain compound 13f, yield: 27%; 1H NMR (500 MHz, DMSO-d 6) δ11.10 (s, 1H), 8.12 (s, 1H), 7.82-7.78 (m, 1H), 7.60 (d, J = 2.0Hz, 1H), 7.54 (dd, J = 8.5, 2.0Hz, 1H), 7.51 (d, J = 8.5Hz, 1H), 7 .43 (d, J=7.0Hz, 1H), 7.30 (d, J=8.0Hz, 1H), 7.18 (t, J=74.0Hz, 1H), 5.07 (dd, J=12.5, 5.5Hz, 1H), 4.20 (t, J=6.5Hz, 2H), 4.00 (d, J=7.0Hz, 2H), 3.69-3.60 (m, 4H), 2.91-2.83 (m, 1H), 2.61-2.51 (m, 2H), 2.45-2.35 (m, 4H), 2.31 (t, J=7.0Hz, 2H), 2.05-2. 00 (m, 1H), 1.79-1.73 (m, 2H), 1.50-1.43 (m, 4H), 1.38-1.33 (m, 2H), 1.31-1.27 (m, 1H), 0.61-0.56 (m, 2H), O.40-O.35 (m, 2H). 13 CNMR (101 MHz, DMSO-d 6 )δ172.9, 170.1, 166.9, 165.6, 165.4, 162.0, 156.1, 150.5, 150.3, 141.5, 137.1, 133.3, 130.8, 124.2, 121.5, 119.8, 119.2, 116.6 (t, J = 257.0 Hz), 116.2, 115.2, 111.8, 73.2, 68.8, 57.7, 53.2, 52.6, 48.8, 46.9, 42.1, 31.0, 28.4, 26.6, 26.2, 25.3, 22.1, 10.0, 3.1 (2×C). ESI-HRMS m / z: calculated for C 38 H 42 O 8 N 5 F 2 S + [M+H] + , 766.2717; the measured value is 766.2711.

[0261] Active Examples

[0262] Activity Example 1 The following method was used to test the PDE4B (PDE4B1) bioenzyme activity of the compounds of the present application. 1. Preparation of reaction buffer and reaction termination solution (reagents see Table 1)

[0263] (1) Preparation of 1x reaction buffer

[0264] 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.

[0265] (2) Preparation of reaction termination solution

[0266] The reaction termination solution was prepared by mixing IMAP Progressive Binding Buffer A (5×), IMAP Progressive Binding Buffer B (5×), and IMAP Progressive Binding Reagent (provided by IMAP FP IPP Explorer Kit) according to the instruction manual.

[0267] 2. Compound Preparation

[0268] (1) Compound dilution

[0269] 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.

[0270] (2) Transfer compounds to 384 reaction plates

[0271] 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.

[0272] 3. Enzymatic reaction

[0273] (1) Prepare 2x enzyme solution

[0274] PDE4B1 was added to 1x reaction buffer to form a 2x enzyme solution (final concentration of PDE4B1: 0.00625 μg / ml).

[0275] (2) Prepare 2 times the substrate solution

[0276] 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).

[0277] (3) Add enzyme solution to the 384-well plate

[0278] 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.

[0279] (4) Add substrate solution to the 384-well plate to start the enzymatic reaction

[0280] 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.

[0281] (5) Termination of enzyme reaction

[0282] 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.

[0283] 4. Read data and calculate data using EnVision

[0284] Readings were taken with EnVision.

[0285] 5. Calculation of inhibition rate

[0286] 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%.

[0287] Table 1 Reagent information

[0288] name brand Part Number PDE4B1 BPS 60041 Trequinsin TOCRIS 2337 / 10 IMAP FP IPP Kit Molecular Device R8124 FAM-CAMP Molecular Device R7506

[0289] The PDE4B enzyme inhibition effect of the compounds provided in the examples of the present application was determined according to the above method, and the results are shown in Table 2. Table 2 shows the results of the determination of the PDE4B enzyme inhibition effect of the compounds of the present application, and the compound numbers in Table 2 correspond to the numbers of the compounds in the examples of the present application.

[0290] Table 2 The results of the determination of the inhibitory effect of the compounds of the present application on PDE4B enzyme (1 μM)

[0291] Compound Inhibition rate (%) Compound Inhibition rate (%) Compound Inhibition rate (%) 9a 66.4 9l 34.2 10c 96.6 9b 68 9m 54.7 13a 57.6 9c 53.7 9n 62.6 13b 65 9d 58.1 9o 55.6 13c 46.6 9e 75.9 9p 52.7 13d 55.4 9f 91 9q 66.3 13e 91.8 9g 27.7 9r 80.8 13f 95.4 9h 46.7 10a 78.5 9i 27.3 10b 84.7

[0292] Activity Example 2 Determination of the ability of the compounds of the present application to target and degrade PDE4B

[0293] The following method was used to determine the ability of the compounds of the present application to target and degrade PDE4B:

[0294] 1. Cell culture: Mouse mononuclear macrophage Raw 264.7 cells were cultured in DMEM high-glucose medium supplemented with 10% (V / V) FBS, 100 μg / mL penicillin and 100 μg / mL streptomycin. The culture conditions were 37°C, 5% CO 2 The cells were passaged when they reached 80% confluence.

[0295] 2. Cell lysis: Take the 6-well plate out of the incubator, discard the culture medium, wash three times with PBS, and add 200 μl of cell lysis solution (RIPA + protease and phosphatase inhibitors) to each well.

[0296] 3. Protein quantification: The protein concentration of each sample was determined using the BCA method and the protein concentration of each sample was adjusted.

[0297] 4. Preparation of electrophoresis samples: Mix 20 μL of 5× loading buffer with 80 μL of leveled sample, boil for 10 minutes, and centrifuge at 12,000 rpm for 10 minutes.

[0298] 5. Use precast gel for protein electrophoresis, add 10 μL sample to each well, start at 80V, and switch to 120V after entering the separation gel.

[0299] 6. After electrophoresis is completed, transfer to the membrane under the conditions of 100V for 2h.

[0300] 7. Take out the PVDF membrane after transfer and block it with 5% skimmed milk powder for 1 hour.

[0301] 8. After blocking, wash three times with TBST, 15 min each time, and incubate with primary antibody overnight at 4°C.

[0302] 9. Recover the primary antibody, wash three times with TBST, 15 min each time, and incubate with secondary antibody at room temperature for 1 h.

[0303] 10. Discard the secondary antibody and wash three times with TBST, 15 min each time.

[0304] 11. Development.

[0305] 12. Results

[0306] The ability of compounds 9a-9r, 10a-10c, and 13a-13f of the present application to target and degrade PDE4B is as follows: Figure 1AAs shown (dosing concentration: 30 μM; stimulation method: pre-dosing for 2 h, 1 μg / mL LPS stimulation for 6 h), compound 9m significantly targeted and degraded PDE4B at a dosing concentration of 30 μM.

[0307] The ability of compound 9m of the present application to target and degrade PDE4B at different concentrations is as follows Figure 1B As shown (stimulation method: pre-administration for 2 hours, 1 μg / mL LPS stimulation for 6 hours), compound 9m targeted degradation of PDE4B showed a certain concentration dependence.

[0308] Effect of Compound 9m of Activity Example 3 on DC of PDE4B 50 Detection

[0309] Implementation steps: Refer to Activity Example 2, import the data into Graphpad Prism 8.0 to calculate DC 50 , the calculation formula is as follows: Y = 100 / (1+10^((LogDC 50 -X)*Hillslope)).

[0310] DC of compound 9m 50 Value Figure 2 shown.

[0311] Activity Example 4 Study on the inhibitory effect of 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)thiazole-4-carboxamide (Compound 9m, 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2-((2-(2,6-dioxopiperidin-3-y1)-1,3-dioxoisoindolin-4-y1)amino)ethyl)thiazole-4-carboxamide) on Raw264.7 cell inflammation.

[0312] An inhibition test of the expression level of cellular inflammatory factors was performed on 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)thiazole-4-carboxamide (compound 9m, 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2-((2-(2,6-dioxopiperidin-3-y1)-1,3-dioxoisoindolin-4-yl)amino)ethyl)thiazole-4-carboxamide) using conventional ELISA method.

[0313] 1. Cell Culture

[0314] Mouse mononuclear macrophage Raw 264.7 cells were cultured in DMEM high-glucose medium supplemented with 10% (V / V) FBS, 100 μg / mL penicillin, and 100 μg / mL streptomycin. The culture conditions were 37°C, 5% CO 2 The cells were passaged when they reached 80% confluence.

[0315] 2. Cellular administration and induction of cellular inflammation

[0316] 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 control group, LPS stimulation group and drug administration group (compound 9m). Carefully remove the culture medium, add fresh complete culture medium containing the compound to the drug administration group, and add an equal volume of DMSO to the blank control group and LPS stimulation group. After 1 hour, 1 μg / mL LPS was added to all groups except the blank control group for 4 hours to induce cell inflammation. Take out the well plate and perform ELISA experiment according to the instructions of the kit.

[0317] 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.

[0318] The secretion of mouse IL-6 and TNF-α in the culture medium supernatant was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The specific steps are as follows:

[0319] (1) Reagent preparation

[0320] ① After taking it out of the refrigerator, place it at room temperature and equilibrate for 20 minutes. ② Dilute the washing solution (20×) with double distilled water to 1× 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 1.5 ml centrifuge tubes, add 250 μL of standard diluent to each tube in advance, and dilute the standard in multiples to obtain a total of six standard concentrations. Finally, add the diluted standards to the pre-coated plate wells in turn, and add the standard diluent directly as 0 pg / mL concentration, for a total of seven standard concentrations.

[0321] (2) Operation steps

[0322] 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.

[0323] 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.

[0324] ③ Wash the plate 5 times and pat dry on thick absorbent paper for the last wash.

[0325] 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.

[0326] ⑤ Wash the plate 5 times and pat dry on thick absorbent paper for the last wash.

[0327] ⑥Add horseradish peroxidase-labeled streptavidin 100 μL / well. Seal the reaction wells with a sealing film (white), and incubate at room temperature in the dark for 20 minutes.

[0328] ⑦ Wash the plate 5 times and pat dry on thick absorbent paper for the last wash.

[0329] 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.

[0330] ⑨Add 50 μL / well of stop solution, mix well, and immediately measure the expression levels of TNF-α and IL-6.

[0331] ⑩Results: Figure 3 and Figure 4 As shown, compared with the LPS group, compound 9m significantly downregulated the expression of TNF-α and IL-6 in a dose-dependent manner.

[0332] Liver microsomal metabolic stability test of active example 5 compound 9m

[0333] The liver microsomal metabolic stability experiment was carried out on 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)thiazole-4-carboxamide (Compound 9m, 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2-((2-(2,6-dioxopiperidin-3-y1)-1,3-dioxoisoindolin-4-y1)amino)ethyl)thiazole-4-carboxamide).

[0334] 0.5 μM compound was incubated with liver microsomes (1 mg / mL) at 37°C. 100 μL of the reaction solution was taken at each time point of 0, 5, 15, 30, 45 and 60 minutes. 200 μL of acetonitrile containing internal standard was added to 100 μL of the reaction solution to extract the test compound. The resulting mixture was centrifuged and the supernatant was analyzed by LC-MS / MS. The results are shown in Table 3.

[0335] Table 3 Results of liver microsomal metabolic stability test of compound 9m

[0336]

[0337] In vivo pharmacokinetic study of compound 9m of active example 6

[0338] In vivo pharmacokinetic studies were performed on 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)thiazole-4-carboxamide (Compound 9m, 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)thiazole-4-carboxamide

[0339] Six 5-6 week old male ICR mice were randomly divided into two groups. Compound 9m was first dissolved in phosphate buffered saline containing DMSO and 5% Tween-80, and then orally (PO, 10 mg / kg) and intravenously (IV, 5 mg / kg) were administered after fasting for 12 hours, and food was given 4 hours after administration. Blood was collected at each time point, IV blood collection point (5min, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h), PO blood collection point (0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h). Blood was collected through the submandibular vein or other appropriate methods, and each sample was collected about 30 μL / time point, K2-EDTA anticoagulation, and placed on ice after collection. After blood sample collection, it was placed on ice and centrifuged within 1 hour to separate plasma (centrifugation conditions: 6800g, 6 minutes, 2-8°C). Plasma samples were stored at -80°C before analysis. Plasma concentrations of ICR mice were analyzed using LC-MS / MS (Agilent 1260 Infinity LC system and Agilent 6460 triple quadrupole mass spectrometer system).

[0340] The in vivo pharmacokinetic results of compound 9m are shown in Table 4, which show that compound 9m has good bioavailability (F=20.99%).

[0341] Table 4 In vivo pharmacokinetic results of compound 9m

[0342] parameter iv (5 mg / kg) parameter Po (10 mg / kg) <![CDATA[AUC (0-t) (mg / mL)]]> 2618±715 <![CDATA[AUC (0-t) (mg / mL)]]> 1099±263 <![CDATA[AUC (0-∞) (mg / mL)]]> 2622±715 <![CDATA[AUC (0-∞) (mg / mL)]]> 1108±264 <![CDATA[C 0 (ng / mL)]]> 12452±8196 <![CDATA[C max (ng / mL)]]> 989±151 <![CDATA[T 1 / 2 (h)]]> 0.59±0.14 <![CDATA[T 1 / 2 (h)]]> 1.05±0.18 <![CDATA[V z (mL / kg)]]> 1823±1044 <![CDATA[T max (h)]]> 0.25±0 CL(mL / h / kg) 2026±656 F(％) 20.99±5.04

[0343] Anti-inflammatory effect of compound 9m in mice with acute lung injury induced by lipopolysaccharide

[0344] The anti-inflammatory protective effect of 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)thiazole-4-carboxamide (compound 9m, 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2-((2-(2,6-dioxopiperidin-3-y1)-1,3-dioxoisoindolin-4-y1)amino)ethyl)thiazole-4-carboxamide) on mice with lipopolysaccharide-induced acute lung injury was studied.

[0345] 1. Purpose of the experiment

[0346] The anti-inflammatory effect of compound 9m was investigated on mice with lipopolysaccharide-induced acute lung injury.

[0347] 2. Experimental Materials

[0348] Experimental animals: 40 Balb / c male mice, age: 6-7 weeks; weight: about 18-22g

[0349] Animal grouping, modeling, and sampling

[0350] Experimental instruments: heating stirrer, paraffin slicer, microscope, syringe, microplate reader, balance, oven, refrigerated centrifuge, etc.

[0351] Experimental reagents: HE staining related reagents, PBS solution, etc., ELISA kits for IL-1β, IL-6 and TNF-α

[0352] 3. Animal Experiments

[0353] 1. Establishment of mouse model of acute lung injury induced by lipopolysaccharide: ① Modeling drug - LPS; ② Modeling method - LPS was instilled into the trachea after 7 days of pretreatment with therapeutic drugs.

[0354] 2. Animal grouping: blank group, model group, treatment group (three doses: low, medium and high: 20 mg / kg, 40 mg / kg, 80 mg / kg), 8 animals in each group; body weight was measured every day. Figure 5 .

[0355] 3. Animal administration: The animals were gavaged with low (20 mg / kg), medium (40 mg / kg), and high (80 mg / kg) doses of compound 9m. The model group was gavaged with an equal volume of normal saline once a day for 7 consecutive days. LPS was instilled through the trachea on the 7th day. Blood was collected from the eye sockets 24 hours later, and serum was collected.

[0356] 4. Animal sampling: Blood was collected from the eye sockets of mice after anesthesia, and alveolar lavage fluid and lung tissue were obtained after euthanasia.

[0357] 5. Index observation: pathological morphology of mouse lung tissue, ELISA method to detect inflammatory factors IL-1β, IL-6, TNF-α, etc.

[0358] IV. Experimental Results

[0359] The weight changes of mice are shown in Figure 5 , indicating that compound 9m is less toxic.

[0360] Pathological changes observed under the microscope Figure 6 In the model group, the alveolar wall of the lung tissue of mice was thickened, the alveolar cavity was narrowed or disappeared, accompanied by a small amount of inflammatory cells and lymphocyte infiltration, occasional perivascular edema and a small amount of bleeding; compared with the model group, the structural damage of the lung tissue, the thickening of the alveolar wall, and the infiltration of inflammatory cells in the drug group were alleviated, which showed a good anti-inflammatory effect.

[0361] Figure 7 The results showed that compound 9m at different concentrations had an inhibitory effect on the total number of inflammatory cells in bronchoalveolar lavage fluid as well as the inflammatory factors IL-6, IL-1β, and TNF-α, indicating that it has a good effect in treating acute lung injury.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof in L is R1 and R2 are each independently X and Y are each independently N or NH, O or S, and at least one of X and Y is N; G1 and G2 are each independently a bond, CH2 or O, and G1 and G2 are not a bond at the same time; n and m are each independently 1, 2, 3 or 4.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof, wherein R1 is R2 is Preferably, X is N, Y is NH, O or S; preferably, G1 and G2 are not O at the same time; preferably, G1 is CH2, n is 1, 2, or 3, and G2 is CH2, m is 1, 2, or 3; or G1 is C, n is 1, 2, or 3, and G2 is O, m is 1, 2, or 3; preferably, L is 3. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof, wherein the formula I is L is the fragment according to claim 1 or 2.

4. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof, wherein the formula I is L is the fragment according to claim 1 or 2.

5. The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, polymorph, cocrystal or deuterated form thereof, wherein the formula I is L is the fragment according to claim 1 or 2.

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, wherein the intermediate compound is 8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable adjuvant or excipient.

9. A method for preparing a compound according to any one of claims 1 to 6, comprising (1) a) reacting a compound of formula I and a compound of formula II in the presence of DIPEA at 50° C.-100° C. for 2-8 hours; b) reacting the product compound of formula III obtained in step a) with HCl-dioxane at 20° C.-50° C. for 1-3 hours; c) reacting the product compound of formula IV obtained in step b) with a compound of formula V as an aromatic carboxylic acid at 20° C.-50° C. for 8-12 hours to obtain a compound of formula VI; (2) d) reacting the product compound of formula IV obtained in step b) with the compound of formula VII at 20° C.-50° C. for 8-12 hours; e) reacting the product compound of formula VIII obtained in step d) with HCl-dioxane at 20° C.-50° C. for 1-3 hours; f) reacting the compound of formula IX obtained in step e) with a compound of formula V as an aromatic carboxylic acid at 20° C.-50° C. for 8-12 hours to obtain a compound of formula XI; or (3) g) reacting a compound of formula V as an aromatic carboxylic acid with a compound of formula XIII at 20° C. to 50° C. for 10 to 14 hours; h) reacting the product compound of formula XIV obtained in step g) with HCl-dioxane at 20° C.-50° C. for 1-3 hours; i) reacting the compound of formula XVI at 20°C-50°C for 2-4 hours in the presence of a Dess-Martin periodinane, adding the product compound of formula XV obtained in step h) and glacial acetic acid after post-treatment, reacting at 20°C-50°C for 1-4 hours, and then reacting with sodium triacetoxyborohydride at 20°C-50°C for 14-18 hours to obtain a compound of formula XVII; Wherein R1, R2, X, Y, n, m, G1 and G2 are as described in any one of claims 1 to 6.

10. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating inflammatory diseases, respiratory diseases, skin diseases, immune system diseases, and acute lung injury; more preferably, the inflammatory disease is an inflammatory skin disease; more preferably, the respiratory disease is chronic obstructive pulmonary disease, acute lung injury or asthma; more preferably, the skin disease is psoriasis or atopic dermatitis; more preferably, the immune system disease is systemic lupus erythematosus or rheumatoid arthritis.

11. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating a PDE4-mediated disease or a PDE4 inhibitor; preferably, the PDE4 is PDE4B.

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