PDE4B enzyme targeting compound and application thereof

Abstract

The invention relates to a compound targeting PDE4B enzyme and application thereof, in particular to a compound with a structure shown in a general formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, in the formula (I), Y and Z are independently selected from none or # imgabs0 #, R11 is selected from H, alkyl, chlorinated alkyl and C5-C6 rings; r1 and R2 are independently selected from H, alkyl containing a substituent group or not containing a substituent group, and C3-C10 rings containing a substituent group or not containing a substituent group, wherein the substituent groups comprise halogen, amide, amino, hydroxyl, carboxyl, nitro, cyano, alkyl, alkoxy, alkylthio, C3-C10 cycloalkyl, C4-C10 heterocycloalkyl, C6-C10 aryl or C5-C10 heteroaryl; and R3 is selected from H, a C1-C20 alkyl group, a C1-C20 hetero-alkyl group, a C3-C10 cycloalkyl group, a C4-C10 hetero-alkyl group, a C6-C10 aryl group and a C5-C10 hetero-aryl group which contain or do not contain a substituent group. # imgabs1 #

Description

Technical Field

[0001] The present application relates to the field of chemistry and pharmaceutical technology, and in particular to a compound targeting PDE4B enzyme and its application. Background Art

[0002] Alzheimer's disease (AD) is characterized by progressive memory loss. Existing studies have confirmed that neuroinflammation is closely related to cognitive dysfunction and runs through the entire disease progression of AD. Systemic inflammation, including central and peripheral inflammation, increases the pathological burden of AD and accelerates the progression of AD. Based on the pathological research of AD, people have proposed targets such as 5-hydroxytryptamine (5-HT) receptors, glycogen synthase kinase 3β (GSK-3β), histamine (H3) receptor third subtype, and phosphodiesterases (PDEs). Among them, phosphodiesterases (PDEs) are intracellular enzymes that can hydrolyze cAMP and cGMP into non-signaling molecules 5'-adenosine monophosphate (AMP) and 5'-guanosine (GMP), respectively. PDEs are a superfamily (including 11 isomers called PDE1-11) involved in proliferation, differentiation, apoptosis, gene expression, visual transduction, inflammation, and metabolic pathways. Studies have shown that there is a close connection between PDE (phosphodiesterase) and neurocognitive function, among which multiple PDE subtypes show correlation with mood swings and cognitive difficulties. Studies have found that PDE has a wide and uneven distribution pattern in different areas of the brain, especially in the hippocampus, cerebral cortex and striatum. These areas are crucial for cognitive activities such as memory, emotion regulation, perceptual processing and behavior control.

[0003] Recently, Armstrong P et al.

[111] found that PDE4B is associated with the pathogenesis of Alzheimer's disease (AD) based on a meta-analysis of genome-wide association study data. PDE4B encodes one of the four isoforms of cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase-4 (PDE4A-D). Rolipram is a first-generation cAMP-specific PDE4 inhibitor that can reverse memory deficits in AD mouse models and improve cognitive abilities in rodent models of stroke, traumatic brain injury, and Huntington's disease. Gong et al. found that rolipram reversed deficits in hippocampal long-term potentiation, contextual fear conditioning, and Morris water maze in 3-month-old APP / PS1 transgenic mice. The benefits of rolipram in AD models may be due to the inhibition of PDE4B, thereby reducing neuroinflammation.

[0004] Studies have shown that PDE4B-deficient mice display reduced production of TNF-α in response to inflammatory stimuli, and PDE4B NAMs blunt TNF-α production in monocytes both in vitro and in vivo. Therefore, PDE4B is a potential new therapeutic target for reducing neuroinflammation in AD. Summary of the invention

[0005] Based on the above content, the present invention combines the structural characteristics of catechol derivatives in the study with the correlation with their biological activities. The design of this series of molecules in the present invention shows that they may have more superior biological activity characteristics and overcome the above defects.

[0006] The first inventive point of the present invention is: a compound having a structure represented by general formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates or solvates,

[0007]

[0008] In formula (I), Y and Z are independently selected from none or Among them, R 11 is selected from H, alkyl, chloroalkyl, and a C5-C6 ring;

[0009] R1 and R2 are independently selected from H, alkyl with or without substitution, C3-C 10 The substituent includes halogen, amide, amino, hydroxyl, carboxyl, nitro, cyano, hydrocarbon, alkoxy, alkylthio, C3~C 10 Cycloalkyl, C4~C 10 Heterocycloalkyl, C6~C 10 Aryl or C5~C 10 heteroaryl;

[0010] R3 is selected from H, C1 to C2 with or without substituents 20 Alkyl, C1~C 20 Heteroalkyl, C3~C 10 Cycloalkyl, C4~C 10 Heterocycloalkyl, C6~C 10 Aryl, C5~C 10 Heteroaryl.

[0011] Furthermore, formula (I) is selected from the following structural formula (a) or structural formula (b):

[0012]

[0013] Wherein, R1 and R2 are independently selected from H, an alkyl group with or without a substituent, a C3-C6 ring with or without a substituent, wherein the substituent includes halogen, amide, amino, hydroxyl, carboxyl, nitro, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C5-C6 aryl or C5-C6 heteroaryl;

[0014] In formula (a), Y and Z are independently selected from none or Among them, R 11 Selected from H or C5-C6 heterocycle, the heterocycle here is preferably

[0015]

[0016] In formula (a), The structure is a single ring, a parallel ring structure of at least two rings combined together, or a series ring structure of at least two rings connected together by a bond;

[0017] In formula (a), R4 is selected from H / none, carbonyl, amide, amino, nitro, alkoxy, alkylthio, sulfone, C2-C 10 Alkyl, C1~C 10 Heteroalkyl, C3~C 10 Cycloalkyl, C4-C6 heterocycloalkyl, C6-C 10 Aryl, C5~C 10 heteroaryl;

[0018] In formula (b), m is an integer of 1 to 5, and R5 is selected from H, halogen, and hydroxyl.

[0019] Furthermore, the structure of formula (a) In At least one atom in the structure is connected to R4. When two or more atoms contain R4 at the same time or one atom contains two R4, each R4 is independently selected from H / none, carbonyl, amide, amino, nitro, alkoxy, alkylthio, sulfone, C2-C 10 Alkyl, C3~C 10 Heteroalkyl, C3~C 10 Cycloalkyl, C4-C6 heterocycloalkyl, C6-C 10 Aryl, C5~C 10 heteroaryl;

[0020] Preferably, the The structure is a five-membered ring, a six-membered ring, a parallel ring structure composed of two five-membered rings, two six-membered rings, or one five-membered ring and one six-membered ring, and a tandem ring structure composed of two five-membered rings, two six-membered rings, or one five-membered ring and one six-membered ring connected in series through bonds.

[0021] Furthermore, R1 and R2 are independently selected from H, C1 to C 10 Alkyl, C1~C 10 Halogenated alkyl, C3-C6 ring, Wherein, q is an integer from 1 to 5, R 13is a C3-C6 cycloalkyl / heterocycloalkyl / aryl group; in the aforementioned structures defined for R1 and R2, any one of the H groups may be substituted by a substituent;

[0022] In formula (a), The structure is Preferably, The structure is selected from

[0023] R6 and R9 are independently selected from Wherein, n is an integer from 1 to 5, R 10 is selected from H, halogen, labeled halogen, hydroxyl;

[0024] R7 is selected from H, halogen, hydroxyl, carboxyl, amide, C2-C 10 An alkyl group, an amino group, a nitro group, an alkoxy group, an alkylthio group or a substituent containing a cyclic structure.

[0025] R8 is selected from H, halogen, amino, hydroxyl, nitro, cyano, carbamoyl, substituted or unsubstituted C2-C 10 Alkyl, C2~C 10 C4-C6 heteroalkyl, C4-C6 cycloalkyl, C4-C6 heterocycloalkyl, C6-C 10 Aryl or C5~C 10 heteroaryl;

[0026] Preferably, when at least two halogens are present, the specific choice of halogen may be the same or different; preferably, the multiple halogens are the same.

[0027] Further, R1 and R2 are independently selected from H, methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoroisobutyl, Among them, R 13 for In the aforementioned structures defined for R1 and R2, any H may be substituted by a substituent, wherein the substituent includes halogen, amide, alkyl, and amino;

[0028] R6 and R9 are independently selected from n is an integer of 1-3, preferably 2.

[0029] R7 is selected from H, halogen, hydroxyl, C2-C5 alkyl; preferably R7 is selected from H, halogen, hydroxyl, methyl, ethyl, propyl;

[0030] R8 is selected from H, halogen, amino, hydroxyl, substituted or unsubstituted C4-C6 heterocycloalkyl; preferably R8 includes -OH, Where R 12 Selected from H, methyl, ethyl, propyl.

[0031] The heteroatom contained in the heteroalkyl group, heterocycloalkyl group or heteroaryl group is selected from an oxygen atom, a nitrogen atom, a phosphorus atom or a sulfur atom; preferably, the heteroatom is an oxygen atom or a nitrogen atom.

[0032] Further, at least one of the following compounds is included:

[0033]

[0034]

[0035] The second inventive point of the present invention is that when the above-mentioned compound contains F, the F can be optionally labeled 18 F is substituted, preferably, F in compounds 24, 27, 30, 33, 36, 39 in formula (I) can be 18 F replaced.

[0036] The third invention of the present invention is the use of the above-mentioned compound in the preparation of imaging probes.

[0037] The fourth inventive aspect of the present invention is the use of the above-mentioned compounds in the preparation of imaging agents for diagnosing Alzheimer's disease or in the preparation of drugs for treating Alzheimer's disease, depression and other neuropsychiatric diseases.

[0038] The fourth invention of the present invention is: a preparation, characterized in that it includes the compound described above.

[0039] Compared with the prior art, the advantages of the present invention are:

[0040] The compound targeting PDE4B of the present invention is a completely new structure, which is conducive to stabilizing the position of the compound at the active site, further improving affinity and selectivity. The present invention is used as two major categories of drugs for the treatment and diagnosis of Alzheimer's disease, depression and other neuropsychiatric diseases. The diagnostic drug is labeled by radionuclide F-18. They all show a strong growth inhibitory effect on U87MG cells, indicating that they have higher inhibition efficiency and radioactive tracer molecules have better brain clearance ability. The present invention can strongly inhibit the secretion of proinflammatory cytokine TNF-α by macrophages, showing its potential value in the treatment of central nervous system (CNS) diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1The inhibition rate of the compounds of the present application on the growth of MGU87 cells.

[0042] Specific implementation method

[0043] In order to make the purpose, technical solution and advantages of the present application more clear, the present application is further described in detail below. However, it should be understood that the description here is only used to explain the present application and is not used to limit the scope of the present application.

[0044] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present application, and the terms used herein in the specification of the present application are only for the purpose of describing specific embodiments and are not intended to limit the present application. The reagents and instruments used herein are all commercially available and can be found in Tables 1 and 2, and the characterization means involved can be found in the relevant descriptions in the prior art and will not be repeated herein.

[0045] Table 1 Experimental reagents used in the experiment

[0046]

[0047]

[0048]

[0049] Table 2 Experimental instruments used in the experiment

[0050]

[0051] In order to further understand the present application, the present application is further described in detail below in conjunction with the best embodiment.

[0052] Embodiment 1:

[0053] This embodiment provides a compound having a structure represented by general formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates or solvates,

[0054]

[0055] Wherein, in formula (I), Y and Z are independently selected from none or Among them, R 11 is selected from H, alkyl, chloroalkyl, and a C5-C6 ring;

[0056] in, The two ends of the ring serve as free bonds, connecting the ring and the carbonyl group;

[0057] R1 and R2 are independently selected from H, alkyl with or without substitution, C3-C10 The substituent includes halogen, amide, amino, hydroxyl, carboxyl, nitro, cyano, hydrocarbon, alkoxy, alkylthio, C3~C 10 Cycloalkyl, C4~C 10 Heterocycloalkyl, C6~C 10 Aryl or C5~C 10 heteroaryl;

[0058] R3 is selected from H, C1 to C2 with or without substituents 20 Alkyl, C1~C 20 Heteroalkyl, C3~C 10 Cycloalkyl, C4~C 10 Heterocycloalkyl, C5~C 10 Aryl, C5~C 10 Heteroaryl.

[0059] The pharmaceutically acceptable salts of this class of compounds are salts formed by the reaction of the compound with an acid or a base, wherein the acid is hydrochloric acid, hydrobromic acid, carbonic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid; and the base is an inorganic base or an organic amine containing a basic metal cation, an alkaline earth metal cation or an ammonium cation salt.

[0060] As a further preferred embodiment, formula (I) is selected from the following structural formula (a) or structural formula (b):

[0061]

[0062] Wherein, R1 and R2 are independently selected from H, an alkyl group with or without a substituent, a C3-C6 ring with or without a substituent, wherein the substituent includes halogen, amide, amino, hydroxyl, carboxyl, nitro, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C5-C6 aryl or C5-C6 heteroaryl;

[0063] In formula (a), Y and Z are independently selected from none or Among them, R 11 Selected from H or C5-C6 heterocycle, the heterocycle here is preferably

[0064]

[0065] In formula (a), The structure is a single ring, a parallel ring structure of at least two rings combined together, or a series ring structure of at least two rings connected together by a bond;

[0066] In formula (a), R4 is selected from H / none, carbonyl, amide, amino, nitro, alkoxy, alkylthio, sulfone, C2-C 10 Alkyl, C2~C 10 C4-C6 heteroalkyl, C4-C6 cycloalkyl, C4-C6 heterocycloalkyl, C5-C 10 Aryl, C5~C 10 heteroaryl;

[0067] In formula (b), m is an integer of 1 to 5, and R5 is selected from H, halogen, and hydroxyl.

[0068] As a further preferred embodiment, the structure of formula (a) In At least one atom in the structure is connected to R4. When two or more atoms contain R4 at the same time or one atom contains two R4, each R4 is independently selected from H / none, carbonyl, amide, amino, nitro, alkoxy, alkylthio, sulfone, C2-C 10 Alkyl, C4-C6 heterocycloalkyl, C5-C 10 Aryl, C5~C 10 Heteroaryl.

[0069] Preferably, the The structure is a five-membered ring, a six-membered ring, a parallel ring structure composed of two five-membered rings, two six-membered rings, or one five-membered ring and one six-membered ring, and a tandem ring structure composed of two five-membered rings, two six-membered rings, or one five-membered ring and one six-membered ring connected in series through bonds;

[0070] A five-membered ring is a saturated or unsaturated ring structure containing five C atoms;

[0071] A six-membered ring is a saturated or unsaturated ring structure containing six C atoms;

[0072] The parallel ring structure is a type of structure in which two adjacent rings are combined by sharing two atoms, for example,

[0073]

[0074] The tandem ring structure is a structure in which two adjacent rings are connected by a bond, for example

[0075] As a further preferred embodiment,

[0076] R1 and R2 are independently selected from H, C1-C 10 Alkyl, C1~C 10 Halogenated alkyl, C3-C6 ring, Wherein, q is an integer from 1 to 5, R 13 is a C3-C6 cycloalkyl / heterocycloalkyl / aryl group; in the aforementioned structures defined for R1 and R2, any one of the H groups may be substituted by a substituent;

[0077] In formula (a), The structure is Preferably, The structure is selected from Any of the aforementioned H-containing atoms may be connected to Z or the carbonyl group in the general formula;

[0078] Preferably, the structure in formula (a) Including furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyrrole, dihydropyrrole, tetrahydropyrrole, oxazole, thiazole, imidazole, pyrazole, pyridine, pyrimidine, pyran, cyclohexane, cyclopentane, cycloheptane, cyclohexene, cyclopentene, cycloheptene.

[0079] R6 and R9 are independently selected from Wherein, n is an integer from 1 to 5, R 10 is selected from H, halogen, labeled halogen, hydroxyl;

[0080] R7 is selected from H, halogen, hydroxy, carboxyl, amide, C2-C 10 An alkyl group, an amino group, a nitro group, an alkoxy group, an alkylthio group or a substituent containing a cyclic structure.

[0081] R8 is selected from H, halogen, amino, hydroxyl, nitro, cyano, carbamoyl, substituted or unsubstituted C2-C 10 Alkyl, C2~C 10 C4-C6 heteroalkyl, C4-C6 cycloalkyl, C4-C6 heterocycloalkyl, C5-C 10 Aryl or C5~C 10 heteroaryl;

[0082] Preferably, when at least two halogens are present, the specific choice of halogen may be the same or different; preferably, the multiple halogens are the same.

[0083] As a further preferred embodiment, R1 and R2 are independently selected from H, methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoroisobutyl, Among them, R 13 for In the aforementioned structures defined for R1 and R2, any H may be substituted by a substituent, wherein the substituent includes halogen, amide, alkyl, and amino;

[0084] R6 and R9 are independently selected from n is an integer of 1-3, preferably 2;

[0085] R7 is selected from H, halogen, hydroxyl, C2-C5 alkyl; preferably R7 is selected from H, halogen, hydroxyl, methyl, ethyl, propyl;

[0086] R8 is selected from H, halogen, amino, hydroxyl, substituted or unsubstituted C4-C6 heterocycloalkyl; preferably R8 includes -OH, Where R 12 Selected from H, methyl, ethyl, propyl.

[0087] The heteroatom contained in the heterocycloalkyl group is selected from an oxygen atom, a nitrogen atom, a phosphorus atom or a sulfur atom; preferably, the heteroatom is an oxygen atom or a nitrogen atom.

[0088] As a further preferred embodiment, at least one of the following compounds is included:

[0089]

[0090]

[0091] Example 2

[0092] This embodiment provides that when the above-mentioned compound contains F, the F may be optionally labeled 18 F is substituted, preferably, F in compounds 24, 27, 30, 33, 36, 39 in formula (I) can be 18 F replaced.

[0093] This embodiment provides the use of the above-mentioned compound in the preparation of imaging probes.

[0094] This embodiment provides the use of the above-mentioned compound in preparing an imaging agent for diagnosing Alzheimer's disease or in preparing a drug for treating Alzheimer's disease, depression and other neuropsychiatric diseases.

[0095] This embodiment provides a preparation, including the above-mentioned compound.

[0096] The present invention has a key interaction with the PDE4B enzyme: the catechol ring can also undergo a π-π stacking effect with the PHE446 residue, which is an important non-covalent interaction that is beneficial for stabilizing the position of the compound in the active site and further improving affinity and selectivity.

[0097] From the docking results of compound 11 and PDE4B protein, it can be seen that the oxygen atom on the five-membered ring of the right chain forms a hydrogen bond with glutamine (GLU442) in the protein structure, and the benzene ring in the mother nucleus forms a pi-pi bond with phenylalanine (PHE446), which is the key interaction with PDED4B. Compound 11 can be completely embedded in the cavity of protein PDE4B, thereby increasing the inhibitory effect of PDE4B enzyme.

[0098] From the docking results of compound 13 and PDE4B protein, it can be seen that the nitrogen atom on the left side of the compound forms a hydrogen bond with glutamine (GLN443) in the protein structure, and the benzene ring in the mother nucleus forms a pi-pi bond with phenylalanine (PHE446), which is the key interaction with PDED4B. Compound 13 can be completely embedded in the cavity of protein PDE4B, thereby increasing the inhibitory effect of PDE4B enzyme.

[0099] From the docking results of compound 30 and PDE4B protein, it can be seen that the pyrazole on the right side forms pi-pi bonds with phenylalanine (PHE446) and phenylalanine (PHE414) in the protein structure, which is the main interaction with the PDE4B enzyme. At the same time, the oxygen atom in the mother nucleus forms a hydrogen bond with aspartic acid phenylalanine (ASN283), and compound 30 can be completely embedded in the cavity of protein PDE4B, thereby increasing the inhibitory effect of PDE4B enzyme.

[0100] From the docking results of compound 27 and PDE4B protein, it can be seen that the benzene ring in the main structure of the compound forms a pi-pi bond with phenylalanine (PHE446) and phenylalanine (PHE414) in the protein structure, which is the main interaction with the PDE4B enzyme. Compound 27 can be completely embedded in the cavity of the protein PDE4B, thereby increasing the inhibitory effect of the PDE4B enzyme.

[0101] Example 3: Synthesis route of target compound 7

[0102]

[0103] Synthesis of compound 1: In an ice bath, add anhydrous THF (50 ml) to a clean 250 ml round-bottom flask, add NaH (2.436 g, 101.5 mmol) in batches, stir, and form a suspension until gas precipitation stops. Under nitrogen protection, dissolve 5-bromo-7-azaindole (10 g, 50.75 mmol) in 15 ml of anhydrous THF, add it to the above suspension at once, and stir at room temperature for half an hour. Dissolve TBS (15.3 g, 101.5 mmol) in 18 ml of anhydrous THF, add it to the above reaction solution, and stir overnight at room temperature. The reaction was detected by thin layer chromatography. When the reaction was completed, the mixture was extracted with ethyl acetate and saturated sodium chloride solution. The organic layer was dried with anhydrous Na2SO4, distilled under vacuum and concentrated. The concentrate was separated by silica gel column chromatography. The mobile phase conditions were: petroleum ether: ethyl acetate = 20:1. A light yellow pure compound 1 (8.086 g, 25.97 mmol) was obtained with a yield of 51.2%. 1H NMR (600MHz, DMSO-d6) δ8.28 (dd, J = 2.3, 0.7 Hz, 1H), 8.19 (dd, J = 2.3, 0.7 Hz, 1H), 7.52 (d, J = 3.5 Hz, 1H), 6.59 (dd, J = 3.5, 0.7 Hz, 1H), 0.85 (s, J = 0.7 Hz, 9H), 0.61 (s, J = 0.7 Hz, 6H).

[0104] Synthesis of compound 2: Compound 1 (1 g, 3.212 mmol), N-aminomorpholine (492.15 mg, 1.418 mmol) and cesium carbonate (2.093 g, 6.425 mmol) were dissolved in anhydrous 1,4-dioxane for standby use; Pd2(dba)3 (294 mg, 0.32 mmol) and Brettphos (344.86 mg, 0.642 mmol) were dissolved in 2 mL of anhydrous 1,4-dioxane under nitrogen protection. The mixture was stirred at 60 °C for 15 min and then cooled to room temperature under nitrogen protection. The standby solution was added to the reaction system and stirred overnight at 100 °C (the color of the system changed from orange-yellow to dark purple). After the reaction, the mixture was extracted, dried, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain a yellow solid compound 2 (280 mg, 0.87 mmol) with a yield of 27.1%. 1H NMR (600MHz, DMSO-d6) δ7.86(d,J=2.5Hz,1H),7.35(d,J=2.5Hz,1H),7.28(d,J=3.4Hz,1H ), 6.39 (d, J = 3.4Hz, 1H), 6.25 (s, 1H), 3.67 (s, 4H), 2.70 (s, 4H), 0.85 (s, 9H), 0.56 (s, 6H).

[0105] Synthesis of compound 3: Compound 2 (23 mg, 0.069 mmol) and tetrabutylammonium fluoride (126.59 mg, 0.484 mmol) were dissolved in anhydrous THF (1 ml) and stirred at room temperature for 2 h. After the reaction was completed by TLC (dichloromethane: methanol = 10: 1), the mixture was extracted three times with saturated sodium chloride solution and ethyl acetate, the organic phase was retained, and the retained organic phase was washed three times with saturated ammonium chloride solution, and finally dried with anhydrous sodium sulfate and concentrated in vacuum. The concentrate was purified by silica gel column chromatography, and the mobile phase conditions were dichloromethane: methanol = 40: 1 to obtain yellow solid compound 3 (13 mg, 0.060 mmol), with a yield of 86.4%. 1 H NMR (600MHz, DMSO-d6) δ11.19(s,1H),7.84(d,J=2.2Hz,1H),7.34(d,J=2.2Hz,1H),7.25 (q,J=2.6Hz,1H),6.20(q,J=2.2Hz,1H),6.13(s,1H),3.63(d,J=5.0Hz,4H),2.66(s,4H). 13 C NMR(600MHz, CDCl3)δ145.16,137.60,132.78,125.90,120.69,114.63,99.97,67.18,56.63.ESI-MS,[M+H] + :m / z=219.1281.

[0106] Synthesis of compound 4: Under the protection of inert gas N2, 4-difluoromethoxy-3-hydroxybenzaldehyde (100 mg, 0.531 mmol) and potassium carbonate (108.56 mg, 0.7867 mmol) were dissolved in anhydrous DMF, stirred, (bromomethyl) cyclohexane (282.38 mg, 1.59 mmol) was added to the reaction solution, and the reaction solution was stirred at 65°C. TLC was used to detect the progress of the reaction. After the reaction was completed, the reaction solution was cooled and filtered. The filtrate was extracted three times with ethyl acetate: brine, the extracted organic phases were combined and dried with anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a concentrated solution, which was purified by silica gel column chromatography, and the mobile phase conditions were petroleum ether: ethyl acetate = 20:1 to obtain a colorless oily compound 4 (148.3 mg, 0.49 mmol), with a yield of 93.1%. 1 H NMR(600MHz, DMSO-d6)δ9.95(s,1H),7.60(d,J=1.9Hz,1H),7.56(dd,J=8.2,1.9Hz,1H),7.39(d,J=8.1Hz,1H),7.23(t,J=73.7Hz,1H),3 .92(d,J=6.2Hz,2H),1.85-1.75(m,3H),1.75-1.68(m,2H),1.68-1.61(m,1H),1.30-1.21(m,2H),1.20-1.12(m,1H),1.11-1.02(m,2H).

[0107] Synthesis of compound 5: Compound 4 (281 mg, 0.988 mmol), potassium hydroxide (2.43 g) and methanol were placed in a clean 50 ml round-bottom flask, 1 ml of 30% H2O2 was slowly added dropwise, and stirred at room temperature for 2 h. The reaction progress of the reaction solution was detected by thin layer chromatography (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, 1 mL of water was added to quench the reaction, and 1 M HCl was added to adjust the pH of the reaction solution to 2. A large amount of white solid was precipitated, and filtered to remove the filter cake. Pure white solid compound 5 (267.8 mg, 0.863 mmol) was obtained with a yield of 90.3%. 1 H NMR (600MHz, DMSO-d6) δ7.61(d,J=2.0Hz,1H),7.57(dd,J=8.3,1.9Hz,1H),7.28(s,1H),7.28-7.03(m,1H),3.95(d,J=6.3Hz,2 H),3.88(ddd,J=11.3,4.5,1.8Hz,2H),3.35(dd,J=11.8,2.1Hz,2H),2.09-2.00(m,1H),1.70-1.62(m,2H),1.41-1.31(m,2H).

[0108] Synthesis of compound 6: Dissolve compound 5 (41.27 mg, 0.137 mmol) in ultra-dry dichloromethane, add 2 drops of ultra-dry DMF to the reaction system, place the round-bottom flask in an ice bath, cool to about 0°C, slowly add oxalyl chloride under nitrogen protection, stir at room temperature for 2-3 hours, remove the solvent by vacuum rotary evaporation, and set aside.

[0109] Synthesis of target compound 7: Compound 3 (30 mg, 0.137 mmol) was dissolved in ultra-dry DMF, and a few drops of triethylamine (41.59 mg, 0.411 mmol) were added to keep the reaction solution alkaline. Nitrogen was replaced three times with a three-way valve to keep the system in anhydrous and oxygen-free conditions for standby use; under nitrogen protection, compound 6 (37 mg, 0.116 mmol) was dissolved in ultra-dry DMF, and the dissolved reaction solution was slowly added dropwise to the above system (the color of the reaction solution quickly changed from orange clear liquid to yellow clear liquid), and heated at 40°C overnight with stirring. TLC (dichloromethane: methanol = 25: 1) was used to detect the degree of reaction, and the reaction solution was extracted three times with ethyl acetate and saturated sodium chloride solution. The extracted organic phases were combined and dried with anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a concentrated solution, which was purified by silica gel column chromatography, and the mobile phase conditions were dichloromethane: methanol = 20: 1 to obtain compound 7 (24 mg, 0.048 mmol), with a yield of 35%. 1 H NMR (600MHz, DMSO-d6) δ7.82(d,J=2.5Hz,1H),7.75(d,J=4.0Hz,1H),7.47(dd,J=17.5,2.2Hz,2H),7.37-7.31(m,2H),7.30-7.08(m,

[0110] 1H), 6.71 (d, J = 4.0Hz, 1H), 3.88-3.83 (m, 2H), 3.72-3.64 (m, 4H), 2.76-2.67 (m, 4H), 1.40-0.99 (m, 11H). 13 C NMR (400MHz, CDCl3) δ175.31,158.77,151.22,141.54,140.98,133.03,132.25,131.67,130.11,129.53,126.10,125.11,12 3.65,121.19,115.70,108.24,75.85,64.85,64.70,61.84,46.50,46.26,38.50,35.51,34.72,34.65.HRMS(ESI)m / z:[M+H] + Calcd for C 26H 31 F2N4O4 + ,501.2307;found,501.2310.

[0111] Example 4: Synthesis route of target compound 9

[0112]

[0113] Synthesis of compound 8:

[0114] 1) Synthesis of compound 8-1

[0115] The specific operation steps refer to "Synthesis of Compound 4". 4-difluoromethoxy-3-hydroxybenzaldehyde (500 mg, 2.658 mmol), bromomethylcyclopentane (2.16 g, 13.29 mmol), potassium carbonate (542.8 mg, 3.72 mmol) were dissolved in anhydrous DMF, and the reaction system was heated and stirred at 65 ° C overnight. After the reaction was completed, it was filtered, the filtrate was retained, and it was extracted with ethyl acetate and brine, the organic phase was collected, dried, filtered, and distilled under reduced pressure, and purified by silica gel column chromatography, and the mobile phase conditions were petroleum ether: ethyl acetate = 20:1. A colorless oil compound 8-1 (669 mg, 2.48 mmol) was obtained with a yield of 93.3%. 1 HNMR(600MHz, CDCl3) δ9.93(s,1H),7.48(d,J=1.9Hz,1H),7.43(dd,J=8.1,1.8Hz,1H),7.30(d,J=8.0Hz,1H),6.68( t,J=74.7Hz,1H),3.97(d,J=6.9Hz,2H),2.47-2.37(m,1H),1.91-1.82(m,2H),1.70-1.57(m,4H),1.41-1.32(m,2H).

[0116] 2) Synthesis of Compound 8-2

[0117] The specific operation steps refer to "Synthesis of Compound 5". Compound 8-1 (669 mg, 2.475 mmol), potassium hydroxide (1 g) and 5 ml of methanol are placed in a clean 50 ml round-bottom flask, 3 ml of 30% H2O2 is slowly added, and stirred at room temperature for 2 h. The reaction progress of the reaction solution is detected by thin layer chromatography (petroleum ether: ethyl acetate = 4:1). After the reaction is completed, 1 mL of water is added to quench the reaction, and 1 M HCl is added to adjust the pH of the reaction solution to 2. A large amount of white solid can be seen to precipitate, and it is filtered to remove the filter cake. Pure white solid compound 8-2 (597 mg, 2.087 mmol) is obtained with a yield of 84.4%. 1H NMR(600MHz,DMSO-d6)δ7.61(d,J=1.9Hz,1H),7.58-7.55(m,1H),7.29(d,J=0.9Hz,1H),7.28-7.03(m, 1H),3.97(d,J=6.9Hz,2H),2.38-2.27(m,1H),1.81-1.74(m,2H),1.66-1.50(m,4H),1.41-1.34(m,2H).

[0118] 3) Synthesis of Compound 8

[0119] Dissolve compound 8-2 (41.27 mg, 0.137 mmol) in ultra-dry dichloromethane, add 2 drops of ultra-dry DMF to the reaction system, put the round-bottom flask in an ice bath, cool it to about 0°C, slowly add oxalyl chloride under nitrogen protection, and stir at room temperature for 2-3h. Remove the solvent by vacuum rotary evaporation and set aside. No purification operation is performed, and go directly to the next step.

[0120] Synthesis of target compound 9: Compound 3 (100 mg, 0.458 mmol) was dissolved in ultra-dry DMF, and a few drops of triethylamine (139.03 mg, 1.374 mmol) were added to keep the reaction solution alkaline. Nitrogen was replaced three times with a three-way valve to keep the system in anhydrous and oxygen-free conditions for standby use; under nitrogen protection, compound 8 (116 mg, 0.382 mmol) was dissolved in ultra-dry DMF, and the dissolved reaction solution was slowly added dropwise to the above system (the color of the reaction solution quickly changed from orange clear liquid to yellow clear liquid), and heated at 40°C overnight with stirring. TLC (dichloromethane: methanol = 25: 1) was used to detect the degree of reaction, and the mixture was extracted with ethyl acetate and saturated brine. The organic phase was collected and dried with anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a concentrate, which was purified by silica gel column chromatography, and the mobile phase conditions were dichloromethane: methanol = 20: 1. Compound 9 (23 mg, 0.047 mmol) was obtained as a light yellow oil with a yield of 10.3%. 1 H NMR(600MHz,DMSO-d6)δ7.80(dd,J=48.6,2.4Hz,1H),7.70-7.53(m,1H),7 .49-7.33(m,2H),7.31-7.25(m,1H),7.25-7.05(m,1H),6.73-6.63(m,1H), 6.21-6.10(m,1H),3.93-3.77(m,2H),3.67-3.59(m,4H),2.66(s,4H),2.3 3-2.24(m,1H),1.79-1.45(m,6H),1.35-1.24(m,2H).HRMS(ESI)m / z:[M+H]+ Calcd for C25H29F2N4O4 + ,487.2151;found,487.2148.

[0121] Example 5: Synthesis route of target compound 11

[0122]

[0123] Synthesis of compound 10:

[0124] 1) Synthesis of compound 10-1

[0125] 4-Difluoromethoxy-3-hydroxybenzaldehyde (50 mg, 0.266 mmol), tetrahydrofurfuryl alcohol (32.58 mg, 0.319 mmol), triphenylphosphine (139.5 mg, 0.532 mmol) were dissolved in anhydrous THF, and nitrogen was protected. Di-tert-butyl azodicarboxylate (122.5 mg, 0.532 mmol) dissolved in toluene was slowly added dropwise while stirring at 0°C. After the reaction system was stirred at room temperature for 2-3 hours, the reaction progress was detected by thin layer chromatography (petroleum ether: ethyl acetate = 1:1), and the reaction solution was concentrated under reduced pressure. The reaction solution was extracted with 1M NaOH and ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a concentrated solution. It was purified by silica gel column chromatography, and the mobile phase conditions were petroleum ether: ethyl acetate = 8:1. A light yellow oily compound 10-1 (58 mg, 0.213 mmol) was obtained with a yield of 80.6%. 1 H NMR(600MHz, DMSO-d6)δ9.94(s,1H),7.64(d,J=1.8Hz,1H),7.58(dd,J=8.2,1.8Hz,1H),7.42-7.10(m,2H),4.26-4.17(m,1H),4.16-4.11(m ,1H),4.10-4.04(m,1H),3.82-3.76(m,1H),3.72-3.65(m,1H),2.05- 1.96(m,1H),1.94-1.87(m,1H),1.86-1.79(m,1H),1.77-1.67(m,1H).

[0126] 2) Synthesis of compound 10-2

[0127] The specific operation steps refer to "Synthesis of Compound 5". Compound 10-1 (58 mg, 0.213 mmol), potassium hydroxide (91 mg, 1.625 mmol) and 1 ml of methanol are placed in a clean 10 ml round-bottom flask, 1 ml of 30% H2O2 is slowly added dropwise, and stirred at room temperature for 2 h. The reaction progress of the reaction solution is detected by thin layer chromatography (petroleum ether: ethyl acetate = 4:1). After the reaction is completed, 1 mL of water is added to quench the reaction, and 1 M HCl is added to adjust the pH of the reaction solution to 2. A large amount of white solid can be seen to precipitate, and it is filtered to remove the filter cake. Pure white solid compound 10-2 (45 mg, 0.156 mmol) is obtained with a yield of 73.3%. 1 H NMR (400MHz, CDCl3) δ7.75-7.69(m,2H),7.22(d,J=8.1Hz,1H),6.71(t,J=74.6Hz,1H),4.40-4.29(m ,1H),4.15-4.09(m,2H),3.98-3.82(m,2H),2.16-2.07(m,1H),2.05-1.92(m,2H),1.89-1.79(m,1H).

[0128] 3) Synthesis of compound 10

[0129] Dissolve compound 10-2 (45 mg, 0.156 mmol) in ultra-dry DCM, add 2-3 drops of ultra-dry DMF to the reaction system, place the round-bottom flask in an ice bath, cool to about 0°C, slowly add oxalyl chloride under nitrogen protection, and stir at room temperature for 2-3 hours. Remove the solvent by vacuum rotary evaporation and set aside. No purification operation is performed, and proceed directly to the next step.

[0130] Synthesis of target compound 11: Compound 3 (30 mg, 0.137 mmol) was dissolved in ultra-dry DMF, 3 ml of ultra-dry pyridine was added to the system to keep the reaction solution alkaline, nitrogen was replaced three times with a three-way valve, and it was set aside; under nitrogen protection, compound 10 (39.5 mg, 0.124 mmol) was dissolved in ultra-dry DMF, and the dissolved reaction solution was slowly added dropwise to the above system (the color of the reaction solution quickly changed from brown-red clear liquid to reddish-brown clear liquid), and heated at 40°C overnight with stirring. TLC (dichloromethane: methanol = 10: 1) was used to detect the degree of reaction. After the reaction was completed, 10% NaHCO3 and ethyl acetate solution were used for extraction three times, and the organic phase was washed three times with saturated brine, the organic phase was collected, dried with anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a concentrate, and the concentrate was purified by silica gel column chromatography, and the mobile phase condition was dichloromethane: methanol = 20: 1. 1H NMR (600MHz, DMSO-d6) δ11.90(s,1H),8.16(s,1H),7.96(s,1H),7.52(d,J=59.5Hz,2H),7. 19(d,J=61.8Hz,3H),6.54(s,1H),4.31-3.46(m,9H),3.21-2.99(m,4H),1.94-1.65(m,4H). 13 C NMR (400MHz, CDCl3) δ149.94,143.45,141.69,134.27,126.95,121.78,121.52,120.51,118.81,116 .22,114.88,113.64,101.55,71.75,68.80,66.82,52.97,29.81,28.16,25.91.HRMS(ESI)m / z:[M+H] + Calcd for C24H27F2N4O5 + ,489.1944;found,489.1928.

[0131] Example 6: Synthesis route of target compound 13

[0132]

[0133] Synthesis of compound 12:

[0134] 1) Synthesis of compound 12-1

[0135] 4-Difluoromethoxy-3-hydroxybenzaldehyde (500mg, 2.66mmol), (tetrahydro-2H-pyran-4-yl)methanol (370.5mg, 3.19mmol), triphenylphosphine (1395mg, 5.32mmol) were dissolved in anhydrous THF, nitrogen protection, and di-tert-butyl azodicarboxylate (1224.9mg, 5.32mmol) dissolved in toluene was slowly added dropwise while stirring at 0°C. After the reaction system was stirred at room temperature for 2-3h, the reaction progress of the reaction solution was detected by thin layer chromatography (petroleum ether: ethyl acetate = 1:1). After the reaction was completed, the reaction solution was extracted with 1M sodium hydroxide and ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a concentrated solution. Purification was performed by silica gel column chromatography, and the mobile phase conditions were petroleum ether: ethyl acetate = 8:1. A light yellow oil compound 12-1 (58mg, 0.213mmol) was obtained with a yield of 80.6%. 1H NMR (400MHz, CDCl3) δ9.92 (s, 1H), 7.45 (d, J = 13.5Hz, 2H), 7.31 (s, 1H), 6.64 (m, 1H), 4.02 (d, J = 11.3Hz ,2H),3.92(s,2H),3.43(d,J=12.5Hz,2H),2.13(s,1H),1.75(d,J=13.2Hz,2H),1.50(d,J=10.5Hz,2H).

[0136] 2) Synthesis of compound 12-2

[0137] The specific operation steps refer to "Synthesis of Compound 5". Compound 12-1 (1.167g, 4.08mmol), potassium hydroxide (1.745g, 31.1mmol) and 10ml methanol are placed in a clean 10ml round-bottom flask, 9ml 30% H2O2 is slowly added dropwise, and stirred at room temperature for 2h. The reaction progress of the reaction solution is detected by thin layer chromatography (petroleum ether: ethyl acetate = 4:1). After the reaction is completed, 1mL of water is added to quench the reaction, and 1M HCl is added to adjust the pH of the reaction solution to 2. A large amount of white solid can be seen to precipitate, and it is filtered to remove the filter cake. Pure white solid compound 12-2 (1.1g, 3.64mmol) is obtained with a yield of 89%. 1 H NMR (600MHz, DMSO-d6) δ7.61(d,J=2.0Hz,1H),7.57(dd,J=8.3,1.9Hz,1H),7.28(s,1H),7.28-7.03(m,1H),3.95(d,J=6.3Hz,2 H),3.88(ddd,J=11.3,4.5,1.8Hz,2H),3.35(dd,J=11.8,2.1Hz,2H),2.09-2.00(m,1H),1.70-1.62(m,2H),1.41-1.31(m,2H).

[0138] 3) Synthesis of compound 12

[0139] Dissolve compound 12-2 (100 mg, 0.331 mmol) in ultra-dry DCM, add 2-3 drops of ultra-dry DMF to the reaction system, place the round-bottom flask in an ice bath, cool to about 0°C, slowly add oxalyl chloride under nitrogen protection, and stir at room temperature for 2-3 hours. Remove the solvent by vacuum rotary evaporation and set aside. Obtain yellow oily compound 12, no longer perform purification operation, and directly proceed to the next step.

[0140] Synthesis of target compound 13: Compound 3 (200 mg, 0.916 mmol) was dissolved in ultra-dry DMF, 3 ml of ultra-dry pyridine was added to the system to keep the reaction solution alkaline, nitrogen was replaced three times with a three-way valve, and it was set aside; under nitrogen protection, compound 12 (264 mg, 0.916 mmol) was dissolved in ultra-dry DMF, and the dissolved reaction solution was slowly added dropwise to the above system (the color of the reaction solution quickly changed from brown-red clear liquid to reddish-brown clear liquid), and heated at 40°C overnight with stirring. TLC (dichloromethane: methanol = 10: 1) was used to detect the degree of reaction. After the reaction was completed, 10% NaHCO3 and ethyl acetate were used for extraction, and the organic phase was washed three times with a saturated sodium chloride aqueous solution, the organic phase was collected and dried with anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a concentrate, and the concentrate was purified by silica gel column chromatography, and the mobile phase conditions were dichloromethane: methanol = 20: 1. Colorless pure compound 13 (45 mg, 0.092 mmol) was obtained with a yield of 10.1%. 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),7.95(d,J=6.1Hz,1H),7.86(d,J=2.5Hz,1H),7.38-7.26(m,3H),6.23(dd,J=3.3,1.8Hz,1H),6.15(s,1H), 3.66(t,J=4.7Hz,5H),3.39-3.35(m,1H),3.30(d,J=3.4Hz,4H),2.69(t ,J=4.6Hz,4H),2.09-1.90(m,1H),1.67-1.53(m,1H),1.33-1.14(m,3H). 13 C NMR (400MHz, CDCl3) δ172.03,150.06,141.53,137.98,134.22,132.90,126.80,125.63,121.45,116 .18,114.57,101.62,100.26,73.81,67.58,67.18,66.85,56.63,35.06,29.61.HRMS(ESI)m / z:[M+H] + Calcd for C25H29F2N4O5 + ,503.2100;found,503.2106.

[0141] Example 7: Synthesis route of target compound 15

[0142]

[0143] Synthesis of compound 14: The method is based on the synthesis steps of compound 12. Dissolve 4-benzyloxy-3-methoxybenzoic acid (100 mg, 0.39 mmol) in ultra-dry DCM at about 0°C, add 2-3 drops of ultra-dry DMF, slowly add oxalyl chloride under nitrogen protection, and stir at room temperature for 2-3 hours. Remove the solvent by vacuum rotary evaporation and set aside. Obtain yellow solid compound 14, no purification operation is performed, and directly proceed to the next step.

[0144] Synthesis of target compound 15: Compound 3 (50 mg, 0.229 mmol) and triethylamine (69.52 mg, 0.687 mmol) were dissolved in anhydrous DMF, and nitrogen was replaced three times with a three-way valve for standby use; under nitrogen protection, compound 14 (59.14 mg, 0.229 mmol) was dissolved in ultra-dry DMF, and the dissolved reaction solution was slowly added dropwise to the above system, heated at 40°C overnight and stirred. TLC (dichloromethane: methanol = 25: 1) was used to detect the degree of reaction. After the reaction was completed, ethyl acetate and saturated saline solution were used for extraction, and the organic phase was dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a concentrated solution, which was purified by silica gel column chromatography, and the mobile phase conditions were dichloromethane: methanol = 20: 1. Oily compound 15 (12 mg, 0.026 mmol) was obtained with a yield of 11.4%. 1 H NMR (600MHz, DMSO-d6) δ7.80(d,J=2.5Hz,1H),7.62(d,J=3.9Hz,1H),7.43(d,J=2.5Hz,1H ),7.41(d,J=2.1Hz,1H),7.40(d,J=1.4Hz,1H),7.38(d,J=2.1Hz,1H),7.37(d,J=1.8Hz,1H ),7.36(d,J=2.0Hz,1H),7.35-7.33(m,1H),7.10(d,J=8.5Hz,1H),6.70(s,1H),6.61(d,J =3.9Hz,1H),5.08(d,J=5.2Hz,2H),3.87(s,3H),3.66(t,J=4.7Hz,4H),2.73-2.64(m,4H). 13 C NMR (400MHz, DMSO-D6) δ166.20,153.01,147.05,141.98,141.03,136.81,131.68,128.46,128.14,12 7.96,127.84,125.69,124.91,123.28,115.08,111.57,110.99,105.30,70.13,66.38,55.84,55.23.

[0145] Example 8: Synthesis route of target compound 17

[0146]

[0147] Synthesis of compound 16:

[0148] 1) Synthesis of compound 16-1

[0149] The specific operation steps refer to "Synthesis of Compound 4". 4-difluoromethoxy-3-hydroxybenzaldehyde, bromomethylcyclopentane, and potassium carbonate are dissolved in anhydrous DMF, and the reaction system is heated and stirred at 65°C overnight. After the reaction is completed, filter, retain the filtrate, and extract it with ethyl acetate and brine, collect the organic phase, dry, filter, and distill under reduced pressure. Purify it by silica gel column chromatography, and the mobile phase condition is petroleum ether: ethyl acetate = 20:1. A colorless oil compound 16-1 is obtained with a yield of 93.3%.

[0150] 2) Synthesis of compound 16-2

[0151] The specific operation steps refer to "Synthesis of Compound 5". Compound 16-1, potassium hydroxide and 5 ml of methanol are placed in a clean 50 ml round-bottom flask, 3 ml of 30% H2O2 is slowly added, and stirred at room temperature for 2 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 4:1) is used to detect the reaction progress of the reaction solution. After the reaction is completed, 1 mL of water is added to quench the reaction, and 1 M HCl is added to adjust the pH of the reaction solution to 2. A large amount of white solid can be seen to precipitate, and the filter cake is removed after filtration. Pure white solid compound 16-2 is obtained with a yield of 84.4%.

[0152] 3) Synthesis of Compound 16

[0153] Dissolve compound 16-2 in ultra-dry dichloromethane, add 2 drops of ultra-dry DMF to the reaction system, place the round-bottom flask in an ice bath, cool to about 0°C, slowly add oxalyl chloride under nitrogen protection, and stir at room temperature for 2-3h. Remove the solvent by vacuum rotary evaporation and set aside. No purification operation is performed, and proceed directly to the next step.

[0154] Synthesis of target compound 17: 1H-pyrrolo[2,3-B]pyridine-5-ol (49.8 mg, 0.365 mmol) and triethylamine (221.6 mg, 2.19 mmol) were dissolved in anhydrous DMF, and nitrogen was replaced three times with a three-way valve for standby use; under nitrogen protection, compound 16 (100 mg, 0.365 mmol) was dissolved in ultra-dry DMF, and the dissolved reaction solution was slowly added dropwise to the above system, heated at 40°C overnight and stirred. TLC (dichloromethane: methanol = 25: 1) was used to detect the degree of reaction. After the reaction was completed, ethyl acetate and saturated saline solution were used for extraction, and the organic phase was dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a concentrated solution, which was purified by silica gel column chromatography, and the mobile phase conditions were dichloromethane: methanol = 15: 1. Oily compound 17 (89 mg, 0.237 mmol) was obtained with a yield of 64.8%. 1 H NMR (600MHz, DMSO-d6) δ11.79(s,1H),8.13(d,J=2.5Hz,1H),7.88(d,J=2.6,0.7Hz,1H),7.81(dd,J=8.4,2.0Hz,1H), 7.75(d,J=2.0Hz,1H),7.54(dd,J=3.4,2.5Hz,1H),7.39(d,J=8.3Hz,1H),7.23(t,J=73.6Hz,1H),6.48-6.42(m,1H),

[0155] 3.90-3.81(m,4H),3.77-3.72(m,1H),2.28-2.18(m,1H),2.04-1.95(m,1H). 13 CNMR(400MHz,DMSO-D6)δ165.04,163.07,148.71,146.77,145.36,141.97,136.85,128.4 8,127.18,124.09,121.61,121.24,120.19,116.54,100.72,79.35,72.59,66.94,32.80.

[0157] Example 9: Synthesis route of target compound 18

[0158]

[0159] 1) Synthesis of compound 18-1

[0160] For detailed operation steps, see "Synthesis of Compound 4". Dissolve 4-difluoromethoxy-3-hydroxybenzaldehyde (100 mg, 0.531 mmol) and potassium carbonate (108.56 mg, 0.7867 mmol) in DMF and stir. Add bromomethylcyclopropane (214.65 mg, 1.59 mmol) to the reaction solution. Stir the reaction solution at 65°C to obtain a crude product. Extract it with ethyl acetate and brine, and directly use it in the next step without further treatment.

[0161] 2) Synthesis of compound 18-2

[0162] For detailed steps, refer to the synthesis of "Compound 5". Compound 18-1 (97 mg, 0.400 mmol), potassium hydroxide (170.1 mg, 3.05 mmol), and methanol were placed in a clean round-bottom flask, and 0.5 ml of 30% H2O2 was slowly added dropwise, and stirred at room temperature for 2 h. After the reaction was completed, 1 mL of water was added to quench the reaction, and 1 M HCl was added to adjust the pH of the reaction solution to 2. A large amount of white solid was precipitated, and filtered to remove the filter cake. Pure white solid compound 18-2 (75 mg, 0.291 mmol) was obtained with a yield of 72.7%. 1 H NMR(400MHz, CDCl3)δ7.74(d,J=24.8Hz,2H),7.29(s,1H),6.78(t,J=74.9Hz,1H), 3.98(s,2H),1.34(d,J=12.0Hz,1H),0.71(d,J=11.0Hz,2H),0.41(d,J=8.9Hz,2H).

[0163] 3) Synthesis of compound 18-3

[0164] For detailed operation steps, see "Compound 6". Dissolve compound 18-2 (50 mg, 0.194 mmol) in ultra-dry dichloromethane, add 2 drops of ultra-dry DMF, cool in an ice bath to about 0°C, slowly add oxalyl chloride under nitrogen protection, stir at room temperature for 2-3 hours, remove the solvent by vacuum rotary evaporation, and set aside.

[0165] Example 10: Synthesis route of target compound 22

[0166]

[0167] Synthesis of compound 19: 2-bromo-4-nitrophenol (100 mg, 0.461 mmol), 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (67.6 mg, 0.307 mmol) and potassium carbonate (84.732 mg, 0.614 mmol) were added to a clean round-bottom flask, stirred at 75°C overnight, cooled and filtered, the filtrate was concentrated in vacuo, and purified by silica gel column chromatography with a mobile phase of petroleum ether:ethyl acetate = 4:1. Pure compound 19 (96.3 mg, 0.314 mmol) was obtained with a yield of 68%. 1 H NMR(400MHz,DMSO-d6)δ8.46-8.41(m,1H),8.31-8.23(m,1H),7.39-7.32(m,1H) ,4.64(p,J=5.2Hz,1H),4.40-4.32(m,2H),3.87-3.79(m,2H),3.58-3.50(m,4H).

[0168] Synthesis of compound 20: Under the protection of inert gas N2, compound 19 (300 mg, 0.98 mmol), N-methylpyrazole-4-boronic acid pinacol ester (224.3 mg, 1.078 mmol), DTBPF (72 mg, 0.098 mmol) and tripotassium phosphate (316.48 mg, 1.47 mmol) were placed in a clean round-bottom flask and stirred overnight at 110°C. After the reaction was completed, the mixture was cooled and filtered, and the filtrate was mixed with silica gel and dried, and purified by silica gel column chromatography, with the mobile phase condition of dichloromethane: methanol = 8:1. Pure compound 20 (203.78 mg, 0.663 mmol) was obtained with a yield of 68%. 1 H NMR (400MHz, DMSO-d6) δ8.42(d,J=2.9Hz,1H),8.33(d,J=0.7Hz,1H),8.12-8.06(m,2H),7.27 (d,J=9.2Hz,1H),4.76-4.69(m,1H),4.39-4.31(m,2H),3.93-3.82(m,5H),3.61-3.52(m,4H).

[0169] Synthesis of compound 21: Compound 20 (20 mg, 0.065 mmol) was added to a 10 ml clean round-bottom flask, dissolved in tetrahydrofuran (0.5 mL), methanol (0.5 mL), and water (0.2 mL), and iron powder (0.728 mg, 0.013 mmol) and ammonium chloride (0.696 mg, 0.013 mmol) were added. The mixture was stirred at 75 °C for 6 hours. The reaction was complete as detected by TLC. The mixture was filtered and the filtrate was concentrated. The mixture was purified by column chromatography (dichloromethane: methanol = 15:1) to give pure compound 21 (13.2 mg, 0.046 mmol) with a yield of 70.5%. 1 H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.75(s,1H),6.83-6.79(m,1H),6.79-6.34(m,2H),4.6 8(s,1H),4.03-3.94(m,2H),3.84(s,3H),3.78-3.72(m,2H),3.60-3.48(m,4H),2.95(s,2H). 13 C NMR (600MHz, CDCl3) δ148.33,140.69,138.23,129.87,123.07,118.62,115.17,114.58,114.09,72.55,69.99,68.65,61.81,38.94.ESI-MS,[M+H] + :m / z=278.1527.

[0170] Synthesis of target compound 22: Add compound 21 (172 mg, 0.62 mmol) to a clean 10 ml round-bottom flask, add anhydrous pyridine to dissolve, replace nitrogen three times with a three-way valve to ensure that the system is in an inert environment. Then dissolve compound 6 (161 mg, 0.75 mmol) in anhydrous DMF, add it to the above system at once under nitrogen protection, and stir at 40°C overnight. TCL detects the progress of the reaction. After the reaction is completed, cool to room temperature, extract three times with 10% sodium bicarbonate, brine, and ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate for half an hour, vacuum concentrate the organic phase, and column chromatograph the concentrate (dichloromethane: methanol = 10:1) to obtain clean compound 22 (115 mg, 0.26 mmol), with a yield of 33%. 1H NMR (600MHz, CD3OD) δ8.16(s,1H),7.93(s,1H),7.86(s,1H),7.63(s,1H),7.56-7.47(m,2H),7.22(d,J=8.3Hz,1H),7.02-6.95(m,1H),6 .80(t,J=74.7Hz,1H),4.24-4.14(m,2H),3.93-3.88(m,7H),3.77-3.72(m,2H),3.69-3.64(m,2H),1.94-1.67(m,6H),1.40-1.05(m,5H). 13 C NMR (600MHz, CD3OD) δ167.40,153.47,151.95,144.38,138.88,134.34,133.10,131.91,122.99,122.53,121.60,121.24,119.75,119.6 7,117.96,116.25,114.27,113.82,75.54,73.71,70.78,68.99,62.28,49.85,38.97,38.88,30.76,27.56,26.88.HRMS(ESI)m / z:[M+H] + Calcd for C 29 H 36 F2N3O6 + ,560.2566;found,560.2562.

[0171] Example 11: Synthesis route of target compound 24

[0172]

[0173] Synthesis of compound 23: Compound 22 (283 mg, 0.51 mmol) was added to a 10 mL round-bottom flask, and 1 ml of anhydrous dichloromethane and anhydrous triethylamine (204.91 mg, 2.02 mmol) were added. p-Toluenesulfonyl chloride (385 mg, 2.02 mmol) was dissolved in anhydrous dichloromethane (1 mL) and slowly added dropwise to the reaction system. After the addition was complete, it was stirred at room temperature overnight. The reaction progress was monitored by TLC, and 3 mL of water was added to quench the reaction. The mixture was extracted with DCM, and the organic phase was dried, concentrated, and recrystallized (methanol) to obtain 161 mg of a white solid product, compound 23, with a yield of 45%. 1H NMR(600MHz,CD3OD)δ8.08(s,1H),7.90(s,2H),7.71-7.64(m,3H),7.59-7.51(m,2H),7.28-7.21(m,3H),6.99-6.66(m,2H),4.24-4.19 (m,2H),4.11-4.04(m,2H),3.95-3.88(m,5H),3.82-3.70(m,4H),2.32(s,3H),1.94-1.70(m,6H),1.38-1.22(m,4H),1.18-1.10(m,2H). 13 CNMR(600MHz,CD3OD)δ166.15,152.12,150.69,145.04,143.10,137.42,133.10, 133.01,131.84,130.69,129.60,127.67,121.70,121.26,120.30,120.25,119.9 2,118.36,116.64,114.93,112.99,112.46,74.26,73.04,69.75,69.42,68.34,6 7.48,37.70,37.68,29.46,29.03,26.25,25.57,25.12,20.20.HRMS(ESI)m / z:[M+

[0174] H] + Calcd for C36H42F2N3O8S + ,714.2655;found,714.2660.

[0175] Synthesis of target compound 24: Compound 23 (66 mg, 0.119 mmol) was dissolved in 1 mL of tetrahydrofuran, 1.5 ml of TBAF (1 M tetrahydrofuran solution) was added, and the reaction system was placed at 65°C for 6 hours. The reaction was completed as detected by TLC, and the solvent was removed by concentration under reduced pressure. Column chromatography (dichloromethane: methanol = 10:1) gave 49.8 mg of pure compound 24, with a yield of 74.9%. 1H NMR(600MHz,CD3OD)δ8.12(s,1H),7.89(s,1H),7.82(d,J=2.6Hz,1H),7.59(s,1H ),7.53-7.44(m,2H),7.18(d,J=8.3Hz,1H),6.96(dd,J=8.7,2.7Hz,1H),6.76(t,J =74.7Hz,1H),4.16(dt,J=5.4,3.1Hz,2H),3.90-3.83(m,7H),3.70(t,J=4.8Hz,2H ),3.62(t,J=4.8Hz,2H),1.88-1.64(m,6H),1.35-1.18(m,3H),1.13-1.03(m,2H). 13 C NMR (600MHz, CD3OD) δ167.27,153.34,151.82,144.29,138.77,134.27,133.09,131.94,122.91,122.53,121.53,121.44,121.33,119.6 8,117.92,116.20,114.30,113.70,84.75,83.64,74.29,71.53,71.40,70.82,68.80,40.29,38.82,30.32,26.41.HRMS(ESI)m / z:[M+H] + Calcd for C29H35F3N3O5 + ,562.2523;found,562.2519.

[0176] Example 12: Synthesis route of target compound 25

[0177]

[0178] The operation method was the same as that of compound 22. Under an inert gas environment, 3 ml of anhydrous pyridine was added to dissolve compound 21 (100 mg, 0.36 mmol) and then 1 ml of anhydrous DCM was added. Compound 8 (50 mg, 0.16 mmol) was then dissolved in anhydrous DMF and stirred at 40°C overnight. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with 10% sodium bicarbonate, brine, and ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate for half an hour. The organic phases were concentrated in vacuo and the concentrate was subjected to column chromatography (dichloromethane: methanol = 10:1) to obtain clean compound 25 (104.3 mg, 0.19 mmol) with a yield of 53%. 1H NMR(600MHz,CD3OD)δ8.16(s,1H),7.93(s,1H),7.86(s,1H),7.64(s,1H),7.56-7.48(m,2 H),7.22(dd,J=8.3,2.0Hz,1H),7.00(dd,J=8.8,2.2Hz,1H),6.82(t,J=75.0,2.2Hz,1H),4 .22-4.18(m,2H),3.99(dd,J=6.9,2.2Hz,2H),3.94-3.89(m,5H),3.77-3.72(m,2H),3.69 -3.64(m,2H),2.46-2.37(m,1H),1.90-1.84(m,2H),1.73-1.59(m,4H),1.46-1.38(m,2H). 13 C NMR (600MHz, CD3OD) δ166.07,152.15,150.58,143.03,137.58,133.02,131.78,130.59,121.66,121.27,120.29,120.02,118.43,11 8.32,116.61,114.90,113.02,112.50,73.02,72.40,69.47,67.67,60.96,48.55,39.01,37.58,29.03,25.12.HRMS(ESI)m / z:[M+H] + Calcd for C28H34F2N3O6 + ,546.2410;found,546.2412.

[0179] Example 13: Synthesis route of target compound 27

[0180]

[0181] Synthesis of compound 26: The specific operation method is the same as compound 23, using anhydrous dichloromethane, compound 25 (50 mg, 0.073 mmol) anhydrous triethylamine (29.54 mg, 0.29 mmol), p-toluenesulfonyl chloride (27.83 mg, 0.15 mmol) dissolved in anhydrous dichloromethane (1 mL) and slowly added dropwise to the reaction system, stirred at room temperature overnight, the reaction was detected by TLC, water was added to quench, extracted with DCM, the organic phase was dried, concentrated and recrystallized to obtain 35 mg of a white solid product, yield: 70%. 1HNMR (600MHz, CD3OD) δ8.07 (s, 1H), 7.89 (t, J = 4.5Hz, 2H), 7.71-7.63 (m, 3H), 7.58-7.49 (m, 2H), 7.27-7.21 (m, 3H), 6. 99-6.67(m,2H),4.25-4.17(m,2H),4.09-4.04(m,2H),4.03-3.97(m,2H),3.92-3.88(m,3H),3.81-3.76(m,2H),3.75-

[0182] 3.69(m,2H),2.46-2.38(m,1H),2.32(t,J=4.2Hz,3H),1.92-1.83(m,2H),1.73-1.58(m,4H),1.47-1.37(m,2H),1.35-1.27(m,1H). 13 C NMR (400MHz, CD3OD) δ166.12,152.10,150.63,145.04,143.05,137.42,133.09,132.99,131.84,130.68,129.60,127.66,121.68,121.32,120 .29,120.23,120.00,118.35,118.31,116.60,114.89,113.04,112.45, 73.03,69.75,69.42,68.33,67.47,39.01,37.71,29.03,25.12,20.21.

[0183] Synthesis of target compound 27: The specific operation process is as follows: compound 24, 1 mL of tetrahydrofuran, compound 26 (50 mg, 0.119 mmol) and 1.5 ml of TBAF (1 M tetrahydrofuran solution), react at 65°C for 6 hours, the reaction is complete as detected by TLC, and the solvent is removed by concentration under reduced pressure. Column chromatography (dichloromethane: methanol = 10:1) gives 49.8 mg of pure compound 24, yield: 74.9%. 1H NMR (600MHz, CD3OD) δ8.17(s,1H),7.93(s,1H),7.86(s,1H),7.65(s,1H),7.57-7.48(m,2H),7.24(d,J=8.3Hz ,1H),7.03(dd,J=8.9,1.0Hz,1H),6.82(td,J=74.9,1.1Hz,1H),4.66-4.62(m,1H),4.59-4.54(m,1H),4.24-4 .19(m,2H),4.04-3.99(m,2H),3.94-3.92(m,2H),3.90(d,J=1.1Hz,3H),3.87-3.83(m,1H),3.81-3.78(m,1H) ,2.48-2.39(m,1H),1.93-1.84(m,2H),1.74-1.66(m,2H),1.65-1.57(m,J=4.0,3.5Hz,2H),1.49-1.40(m,2H). 13 C NMR (400MHz, CD3OD) δ166.01,152.06,150.59,143.04,137.47,132.99,131.80,130.65,121.64,121.18,120.24,120.16,119.94,1 18.39,116.65,112.95,112.42,83.44,82.33,74.20,70.24,70.11,69.53,67.51,37.64,37.51,29.43,25.56.HRMS(ESI)m / z:[M+H] + Calcd for C28H33F3N3O5 + ,548.2366;found,548.2364.

[0184] Example 14: Synthesis of Compound 28

[0185]

[0186] The operation method was the same as that of compound 22. In an inert gas environment, anhydrous pyridine, compound 21 (100 mg, 0.36 mmol), and anhydrous DCM were added to dissolve compound 10 (110.16 mg, 0.36 mmol), and stirred at 40°C overnight. After the reaction was completed, it was extracted three times with 10% sodium bicarbonate, brine, and ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate for half an hour, and the organic phases were concentrated in vacuo. The concentrate was subjected to column chromatography (dichloromethane: methanol = 10: 1) to obtain clean compound 28 (98.5 mg, 0.19 mmol) with a yield of 50%. 1H NMR (400MHz, CDCl3) δ8.52 (s, 1H), 7.89-7.80 (m, 2H), 7.67 (d, J = 2.7Hz, 1H), 7. 54(d,J=2.1Hz,1H),7.45-7.36(m,2H),7.12(d,J=8.2Hz,1H),6.82(d,J=1.0Hz ,1H),6.81-6.42(m,1H),4.28-4.21(m,1H),4.14-4.09(m,2H),4.05-3.95(m,2 H),3.90-3.79(m,7H),3.77-3.73(m,2H),3.66-3.60(m,2H),2.10-1.84(m,4H). 13 C NMR (400MHz, CDCl3) δ165.11,151.93,150.40,142.87,138.10,133.20,131.65,130.07,122.13,121.83,120.15,119.98,118.2 1,116.09,113.63,112.86,76.84,72.66,71.53,69.69,68.68,67.80,61.70,50.55,38.80,27.97,25.82.HRMS(ESI)m / z:[M+H] + Calcd for C 27 H32F2N3O7 + ,548.2202;found,548.2194.

[0187] Example 15: Synthesis route of target compound 30

[0188]

[0189] Synthesis of compound 29: The specific operation method is the same as compound 23, using anhydrous dichloromethane, compound 28 (50 mg, 0.091 mmol) anhydrous triethylamine (37 mg, 0.36 mmol), p-toluenesulfonyl chloride (34.68 mg, 0.18 mmol) dissolved in anhydrous dichloromethane (1 mL), stirred at room temperature overnight, the reaction was completed, water was added to quench the reaction, extracted with dichloromethane, the organic phase was collected, dried, concentrated, and recrystallized (methanol) to obtain 43.7 mg of white solid product, yield: 70.5%. 1H NMR (400MHz, CDCl3) δ8.12(s,1H),7.90(d,J=14.2Hz,3H),7.70(s,1H),7.45(m,4H),7.26(s,1H),7.21(d,1H),6.90(d,1H),6.60(t,J= 74.4Hz,1H),5.02(s,1H),4.18(m,2H),3.98(m,3H),3.89(m,7H),3.78(m,2H),3.67(m,2H),2.23(dd,J=14.7,22.3Hz,3H),1.98(s,4H). 13 C NMR (400MHz, CDCl3) δ173.81,164.67,152.12,149.35,144.21,143.57,138.23,133.32,131.43,130.02,122.54,122.49,120.00,119.68 ,119.44,118.51,118.15,115.91,114.87,113.31,113.12,79.06,72 .84,72.58,69.76,67.92,67.22,61.87,38.98,33.01,30.00,14.41.

[0191] Synthesis of target compound 30: The specific operation process is as follows: Compound 24, 1 mL of tetrahydrofuran, compound 29 (50 mg, 0.119 mmol) and 1.5 ml of TBAF (1 M tetrahydrofuran solution), stirred at 65°C for 6 hours, TLC was used to monitor the reaction progress, vacuum distillation, column chromatography (dichloromethane: methanol = 10: 1), 49.8 mg of pure compound 24 was obtained. Yield: 74.9%. 1HNMR(600MHz, CDCl3)δ8.04(s,1H),7.91(dd,J=13.2,1.6Hz,2H),7.71(s,1H),7.57(s,1H),7.44(d,J= 9.0Hz, 1H), 7.40-7.34 (m, 1H), 7.19 (dd, J=8.1, 1.7Hz, 1H), 6.89 (dd, J=8.8, 2.6Hz, 1H), 6.67 (t, J=74. 8,1.7Hz,1H),4.32-4.27(m,1H),4.21-4.16(m,2H),4.11-4.03(m,2H),3.92-3.88(m,6H),3.86-3.80( m,1H),3.79-3.76(m,2H),3.69-3.65(m,2H),2.11-2.04(m,1H),2.02-1.89(m,2H),1.82-1.76(m,1H). 13 C NMR (400MHz, CDCl3) δ164.74,152.07,150.76,143.03,138.29,133.36,131.52,129.97,122.59,122.22,119.94,119.58,11 9.44,118.19,117.76,116.03,113.76,113.18,72.55,71.72,69.77,68.76,67.94,61.89,38.98,28.08,25.87.ESI-MS,[MH] - :m / z=548.2172.

[0192] Example 16: Synthesis route of target compound 31

[0193]

[0194] The operation method was the same as that of compound 22. In an inert gas environment, anhydrous pyridine, compound 21 (100 mg, 0.36 mmol), and anhydrous DCM were added to dissolve compound 12 (115.2 mg, 0.36 mmol), and stirred at 40°C overnight. After the reaction was completed, it was extracted three times with 10% sodium bicarbonate, brine, and ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate for half an hour, and the organic phases were concentrated in vacuo. The concentrate was subjected to column chromatography (dichloromethane: methanol = 10: 1) to obtain clean compound 31 (121.6 mg, 0.21 mmol) with a yield of 60.2%. 1H NMR (600MHz, CD3OD) δ8.15(s,1H),7.93(s,1H),7.87(d,J=2.6Hz,1H),7.63(d,J=2.2Hz,1H),7.5 7-7.46(m,2H),7.22(d,J=8.3Hz,1H),6.98(d,J=8.9Hz,1H),6.81(t,J=74.5Hz,1H),4.19(dd,J=5 .7,3.4Hz,2H),4.00-3.96(m,2H),3.93(s,1H),3.92(s,4H),3.91-3.88(m,2H),3.78-3.72(m,2H ),3.68-3.64(m,2H),3.50-3.43(m,2H),2.12-2.04(m,1H),1.78-1.70(m,2H),1.50-1.40(m,2H). 13 C NMR (400MHz, CD3OD) δ165.96,152.14,150.40,143.08,137.56,133.02,131.79,130.61,121.66,121.12,120.26,120.20,120.17,11 8.41,116.69,114.98,113.05,112.50,73.31,72.40,69.46,67.67,67.27,60.97,48.55,37.59,34.91,29.28.HRMS(ESI)m / z:[M+H] + Calcd for C 28 H34F2N3O7 + ,562.2359;found,562.2362.

[0195] Example 17: Synthesis route of target compound 33

[0196]

[0197] Synthesis of compound 32: The specific operation method is the same as compound 23, using anhydrous dichloromethane, compound 31 (50 mg, 0.089 mmol) anhydrous triethylamine (37 mg, 0.36 mmol), and p-toluenesulfonyl chloride (34.68 mg, 0.18 mmol) dissolved in anhydrous dichloromethane, stirred overnight at room temperature. After the reaction is completed, water is added to quench, DCM is extracted, and the organic phase is dried, concentrated, and recrystallized to obtain 30.5 mg of white solid product compound 32, yield: 48.8%. 1H NMR (400MHz, CDCl3) δ8.12 (s, 1H), 7.88 (d, J = 20.9Hz, 2H), 7.78-7.69 (m, 3H), 7.58 (s, 1H), 7.49 (dd, J = 8. 8,2.6Hz,1H),7.39(dd,J=8.3,1.9Hz,1H),7.25-7.15(m,2H),6.88(d,J=8.8Hz,1H),6.58(t,J=74.5Hz,1 H),4.22-4.16(m,2H),4.12-4.08(m,2H),4.04-3.98(m,2H),3.90(d,J=7.9Hz,5H),3.85-3.79(m,2H),3. 77-3.71(m,2H),3.49-3.39(m,2H),2.37(s,3H),2.16-2.06(m,1H),1.79-1.66(m,2H),1.52-1.39(m,2H). 13 C NMR (400MHz, CDCl3) δ164.79,151.99,150.96,145.09,142.82,138.03,133.53,132.87,131.61,129.97,128.03,122.28,119.94,119.5 8,119.04,118.14,116.07,113.43,113.05,73.75,69.96,69.43,68.85,67.75,67.62,39.10,35.06,29.62,21.72.HRMS(ESI)m / z:[M+H] + Calcd for C35H40F2N3O9S + ,716.2447;found,716.2445.

[0198] Synthesis of target compound 33: The specific operation process is as follows: compound 24, 1 mL of tetrahydrofuran, compound 32 (50 mg, 0.071 mmol) and TBAF (1 M tetrahydrofuran solution), react at 65 ° C for 6 hours, monitor the reaction progress by TLC, distill under reduced pressure, column chromatography (dichloromethane: methanol = 10:1), to obtain 18.4 mg of clean product compound 33, yield: 46%. 1H NMR (600MHz, CDCl3) δ8.32(s,1H),7.88(d,J=26.5Hz,2H),7.70(s,1H),7.55(s,1H),7.45(dd,J=8.9,2. 6Hz,1H),7.37(dd,J=8.3,2.0Hz,1H),7.15(d,J=8.2Hz,1H),6.86(d,J=8.8Hz,1H),6.56(t,J=74.5Hz,1H ),4.18-4.12(m,2H),4.01-3.96(m,2H),3.89-3.87(m,2H),3.86(s,3H),3.83(d,J=6.5Hz,2H),3.78-3.7 4(m,2H),3.67-3.63(m,2H),3.47-3.37(m,2H),2.11-2.03(m,1H),1.74-1.65(m,2H),1.44-1.35(m,2H). 13 C NMR (400MHz,CDCl3)δ

[0199] 164.87,152.05,150.87,142.79,138.19,133.42,131.54,130.03,122.46,122.16,119.97,119.68,119.13,118.17,1 17.77,116.04,114.31,113.43,113.05,73.71,72.61,69.75,67.90,67.56,61.84,38.93,35.01,29.55.ESI-MS,[MH] - :m / z=2562.2316.

[0200] Example 18: Synthesis route of target compound 34

[0201]

[0202] The operation method was the same as that of compound 22. In an inert gas environment, anhydrous pyridine, compound 21 (100 mg, 0.36 mmol), and anhydrous DCM were added to dissolve compound 18-3 (99.4 mg, 0.36 mmol), and stirred overnight at 40°C. After column chromatography (dichloromethane: methanol = 10:1), clean compound 34 (light yellow solid, 101.9 mg, 0.20 mmol) was obtained with a yield of 55%. 1HNMR(600MHz,CD3OD)δ8.15(s,1H),7.93(s,1H),7.85(s,1H),7.65(s,1H),7.58-7.45(m,2H),7.23(d,J=8.4Hz,1H),7.04-6.73(m,2H) ,4.31-4.16(m,2H),4.00-3.89(m,7H),3.78-3.71(m,2H),3.71-3.59(m,2H),1.37-1.26(m,1H),0.73-0.58(m,2H),0.48-0.34(m,2H). 13 CNMR(400MHz, CDCl3)δ165.07,151.90,150.56,142.87,138.07,133.23,131.66,130.15,122.30,121.89,120.00,119.74,1 19.35,118.18,115.97,113.76,112.82,74.05,74.02,71.37,69.76,67.68,43.15,38.98,10.05,3.27.HRMS(ESI)m / z:[M+H] + Calcd for C 26 H30F2N3O6 + ,518.2097;found,518.2103.

[0203] Example 19: Synthesis route of target compound 36

[0204]

[0205] Synthesis of compound 35: The specific operation method is the same as compound 23, using anhydrous dichloromethane, compound 34 (40 mg, 0.077 mmol), anhydrous triethylamine (31.3 mg, 0.31 mmol), and p-toluenesulfonyl chloride (29.26 mg, 0.15 mmol) and stirring for 12 hours. After the reaction is complete, water is added to quench the reaction, and the organic phase is extracted and dried, concentrated, and recrystallized to obtain 13.6 mg of a white solid product. The yield is 27.2%. 1H NMR (600MHz, CD3OD) δ8.09 (s, 1H), 7.93-7.86 (m, 2H), 7.69 (dd, J = 18.6, 10.2 Hz,3H),7.55(dd,J=25.3,8.9Hz,2H),7.30-7.21(m,3H),7.04-6.75(m,2H),4 .22(s,2H),4.08(s,2H),4.00(s,2H),3.94-3.88(m,3H),3.76(d,4H),2.33( d,J=4.9Hz,3H),1.38-1.25(m,2H),0.65(d,J=8.4Hz,2H),0.45-0.34(m,2H). 13 C NMR (400MHz, CDCl3) δ164.95,151.98,150.71,142.97,138.14,133.33,131.63,130.16,122.49,122.06,119.97,119.64, 119.19,118.20,117.70,115.97,114.24,113.87,112.95,74.12,71.43,69.82,67.77,43.14,39.04,38.95,10.10,3.32.

[0206] Synthesis of target compound 36: For the specific operation process, see compound 24, tetrahydrofuran, compound 35 (60 mg, 0.09 mmol) and TBAF (1 M tetrahydrofuran solution), react at 65°C for 6 hours, and obtain 14.2 mg of pure compound 36 after column chromatography (dichloromethane: methanol = 10:1), with a yield of 30.4%. 1 H NMR (600MHz, CD3OD) δ8.20(s,1H),7.96(s,1H),7.90(s,1H),7.67(s,1H),7.56(dd,J=32.9,8.9Hz,2H),7.27(d,J=8.6Hz,1H),7.08-6.76(m ,2H),4.69-4.57(m,2H),4.29-4.21(m,2H),4.06-4.00(m,3H),3.98- 3.91(m,5H),3.89-3.80(m,2H),1.39-1.28(m,3H),0.71-0.64(m,2H). 13C NMR (600MHz, CDCl3) δ164.79,152.09,150.92,137.39,133.42,131.62,130.82,122.30,119.86,119.02,118.33,117.70,1 15.98,114.02,113.07,83.78,82.66,74.29,70.61,70.48,69.97,67.82,38.94,29.84,10.18,3.40.HRMS(ESI)m / z:[M+H] + Calcd for C26H29F3N3O5 + ,520.2053;found,520.2059.

[0207] Example 20: Synthesis of target compound 37

[0208]

[0209] The operation method was the same as that of compound 22. In an inert gas environment, anhydrous pyridine, compound 21 (120 mg, 0.43 mmol), and anhydrous DCM were dissolved in compound 16 (125.6 mg, 0.43 mmol), and stirred overnight at 40°C. Column chromatography (dichloromethane: methanol = 10:1) was performed to obtain a clean white solid product 37 (117 mg, 0.22 mmol) with a yield of 51.1%. 1 H NMR (400MHz, CDCl3) δ8.36 (s, 1H), 7.86 (d, J = 20.8Hz, 2H), 7.67 (s, 1H), 7.51 (s,1H),7.48-7.35(m,2H),7.15(d,J=8.2Hz,1H),6.84(d,J=8.9Hz,1H),6.58 (t,J=74.5Hz,1H),4.97(s,1H),4.19-4.11(m,2H),4.01-3.92(m,3H),3.92- 3.81(m,7H),3.77(s,2H),3.68-3.61(m,2H),2.69(s,1H),2.24-2.07(m,2H). 13C NMR (600MHz, CDCl3) δ165.04,152.01,149.02,143.49,138.00,133.12,131.53,130.12,122.09,120.21,120.04,118.14,117 .72,115.99,114.79,114.26,112.80,78.98,72.74,72.66,69.66,67.78,67.14,61.67,38.78,32.89.HRMS(ESI)m / z:[M+Na] + Calcd for C 26 H29F2N3NaO7 + ,556.1865;found,556.1865.

[0210] Example 21: Synthesis route of target compound 39

[0211]

[0212] The detailed operation method for the synthesis of compound 38 is the same as that of compound 23, anhydrous dichloromethane, compound 37 (30 mg, 0.043 mmol), anhydrous triethylamine (17.7 mg, 0.17 mmol), p-toluenesulfonyl chloride (16.34 mg, 0.086 mmol) are stirred overnight. After the reaction is completed, water is added to quench the reaction and the extraction is performed. The organic phase is dried, concentrated, and recrystallized to obtain 8.76 mg of a white solid product with a yield of 29.6%. 1 H NMR(600MHz, CDCl3)δ8.07(s,1H),7.91(d,J=27.8Hz,2H),7.79-7.70(m,3H),7.57(d,J=1.9H z,1H),7.53-7.47(m,1H),7.42(dd,J=8.3,1.9Hz,1H),7.25-7.21(m,2H),6.89(d,J=8.8Hz,1 H),6.61(t,J=74.5Hz,1H),5.06(s,1H),4.22-4.17(m,2H),4.14-4.09(m,2H),4.01-3.96(m, 3H),3.94-3.89(m,4H),3.85-3.79(m,2H),3.77-3.71(m,2H),2.38(s,3H),2.28-2.15(m,2H). 13C NMR (600MHz, CDCl3) δ164.74,152.09,150.28,145.08,143.50,138.15,131.49,130.19,129.98,128.06,122.63,119.95, 119.55,119.34,118.10,114.92,114.24,113.15,79.15,72.93,70.00,69.41,68.90,67.83,67.28,39.14,33.09,21.74.

[0213] Synthesis of target compound 39: The specific operation process is as follows: compound 24, tetrahydrofuran, compound 38 (70 mg, 0.1 mmol) and TBAF, reacted at 65°C for 6 hours, and column chromatography (dichloromethane: methanol = 10:1) gave 6.2 mg of pure product, yield: 11.6%. 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),8.13(s,1H),7.92(d,J=2.6Hz,1H),7.85(d,J=0.8Hz,1H),7.68(d, J=2.0Hz,1H),7.63(dd,J=8.4,2.0Hz,1H),7.55(dd,J=8.9,2.6Hz,1H),7.36-7.31(m,2H),7.17-6.97(m, 1H),5.24-5.20(m,1H),4.69-4.61(m,1H),4.58-4.50(m,1H),4.20-4.16(m,3H),3.92(d,J=4.3Hz,1H),3 .89(s,1H),3.87(d,J=1.6Hz,3H),3.86(s,4H),3.75-3.72(m,1H),2.31-2.21(m,1H),2.08-2.02(m,1H). 13 C NMR (400MHz, CDCl3) δ164.66,152.09,149.40,143.58,138.06,133.44,131.49,130.46,122.70,122.56,119.90,119.56,11 9.43,118.07,115.97,114.90,112.97,84.05,82.36,79.10,72.92,69.98,67.78,67.28,38.97,33.06.HRMS(ESI)m / z:[M+H] + Calcd for C26H29F3N3O6 + ,536.2002found,536.2005.

[0214] Example 22: Compound [ 18 Preparation of F]39

[0215]

[0216] Use an analytical balance to accurately weigh 10 mg of K2CO3, 5 mg of K 222 , 2 mg of labeled precursor. Dissolve K in ultrapure acetonitrile 222 , dissolve potassium carbonate in pure water and set aside.

[0217] The dissolved potassium carbonate and K 222 Add to 18 In the vial of F, under high-purity nitrogen at 100°C, blow dry the solvent in the vial, add 0.5ml of anhydrous acetonitrile and then blow dry with nitrogen, repeat this operation three times. Quickly add the precursor dissolved in 0.5ml of clean ultra-dry acetonitrile to the above reaction bottle, seal it with an aluminum cap, put it at 90°C, and heat it for 20 minutes. After the reaction is completed, open the bottle cap and add 2ml of pure water to observe whether there will be insolubility. Use a syringe to suck out the solution in the vial and inject it into the activated Sep-Pak C18 solid phase extraction column, flush the column with 2ml of pure water, blow air, and then flush the column with 10ml of pure water, blow air, in order to pass the negative ions. Then use 2ml of HPLC-grade methanol to elute the reaction product from the column into a new vial, and reduce the pressure to concentrate it to less than 1ml to ensure that it can be injected into the HPLC separation. And separate and purify it by Radio-HPLC. The mobile phase composition was methanol: pure water, ratio 1.61:0.39, total flow rate was 2 ml per minute, and the semi-preparative column model used was SP ODS-A C18 reversed phase semi-preparative column (5 μm, 10 mm × 250 mm). 18 F]39 preparation process, after HPLC separation [ 18 The radiochemical purity of F]39 was greater than 97%, and the labeling rate was about 21.3%.

[0218] The remaining compounds 41-47 were analyzed, and the results are shown in Table 3. Rolipram can be used as a benchmark, and its total score is 7.3936. According to the literature, its IC50 for cells is about 100 μM, indicating that it has certain inhibitory activity. However, among the newly designed molecules, even the lowest-scoring compound 47 (8.6589) has a score close to Rolipram, which shows that the compounds designed in this application may generally have good activity. Due to the high similarity with other target compounds and the basically consistent synthesis routes, the synthesis routes are no longer listed.

[0219] Table 3 Analysis of inhibitory activity of compounds 41-47

[0220] Molecular number Total-Score CLogP Brain volume Molecular weight 41 11.3357 1.17 1 422.1654 42 9.5181 2.46 -2 513.2376 43 11.0767 0.11 1 452.2060 44 11.6683 1.17 1 480.2373 45 9.4472 2.54 0 404.1184 46 8.8536 1.67 -1 499.2119 47 8.6589 0.06 -2 436.1758 Rolipram 7.3936 1.71 0 275.1521

[0221] Experimental Example 1: Cell Experiment

[0222] 1. Experimental Procedure

[0223] 1) Seed board:

[0224] U87MG cells were inoculated into culture bottles according to the culture requirements, and the prepared complete cell culture medium was added. 1% double antibody was added to the culture medium (to prevent cell contamination), and the culture dish was placed in a 37° C., 5% CO2 incubator for culture.

[0225] Add 100 μl of PBS solution to the wells around the 96-well plate (to prevent edge effect), and add cultured U87MG cells to the other wells to ensure that the cell density in each well is fixed at 5×10 3 Inoculate each well, add 100 μl of DMEM culture medium containing 10% fetal bovine serum into the 96-well plate for 12 h, observe the cell state with a confocal microscope, and proceed to the next cell experiment when the cells are no longer suspended but in a monolayer adherent state.

[0226] 2) Drug solution preparation:

[0227] The compounds of the present invention were respectively dissolved in dimethyl sulfoxide (DMSO) to prepare 5 mmol / L mother solutions for later use.

[0228] Positive drug: Rolipram was purchased from Sigma Company in the United States, dissolved in dimethyl sulfoxide (DMSO), and prepared into a 5 mmol / L stock solution for later use.

[0229] 3) Drug administration

[0230] First, use a pipette to remove the old complete culture medium, wash each well once with PBS, prepare the above-mentioned mother solutions of positive drugs and control drugs with complete culture medium to the required concentration, and add them to the 96-well plate containing cells with a pipette.

[0231] After incubation in a 37°C incubator for 24 hours, the cell status was observed under a microscope, the drug solution was changed, the old drug solution was sucked out with a spray gun, and new drug solution was added. The drug was administered for 2 days.

[0232] 2. CCK-8 assay to detect cell viability

[0233] Take out the 96-well plate that has been drugged for two days from the 37°C incubator, prepare a DMEM solution containing 10% CCK8 in a sterile liquid adding tank and set aside. Use a spray gun to suck out the complete medium with drugs in the 96-well plate, add the prepared basal medium containing 10% CCK8, add 100 μL to each well, and add 100 μL of DMEM to the second column. After the addition is completed, place the 96-well plate in a cell culture incubator at 37°C and incubate for 30 minutes. Use an enzyme reader to measure the absorbance value (ID value) of each well at a wavelength of 450nm, record the results and calculate the survival rate of U87MG cells. The absorbance values ​​measured by the enzyme reader are processed as shown in Table 4, and the inhibition rate of MGU87 cell growth is processed using GraphPad Prism 8 software as shown in Table 4. Figure 1 .

[0234] Table 4 Inhibition rate (IC) of the compounds of the present application on PDE4B 50 ,μM)

[0235] Compound <![CDATA[IC 50 (μM)]]> 7 7.55±0.138 9 3.285±0.35 11 0.816±0.00148 13 1.43±0.15 15 3.373±0.5 22 3.93±0.267 24 0.710±0.039 25 6.375±0.88 27 0.573±0.245 28 ～48 30 2.022±0.062 31 ～49 33 3.774±0.117 34 2.22±0.0792 36 2.42±0.175 37 ＞50 39 11.87±0.276 Rolipram 90.88±0.16

[0236] Conclusion: The XX catechol derivatives tested showed strong inhibitory effects on the growth of U87MG cells.

[0237] Experimental Example 2: Biodistribution experiment of radioligand [18F]39

[0238] Female normal mice weighing 18-22 g (n=5) were injected with about 20-30 μCi of [ 18 F]39 radiolabeled compound (dissolved in 0.1 ml of physiological saline with Tween added as a solubilizing agent).

[0239] The mice were killed 5min, 15min, 30min, 60min and 90min after injection respectively, and blood was collected immediately. The brain, heart, lung, liver, spleen, kidney, muscle, bone and tail of the mice were dissected and removed. The wet weight of each organ was weighed with an analytical balance, and the radioactivity count was measured. The uptake of each tissue was finally expressed as %ID / g, %ID / g=ID / g÷1%, where ID / g=tissue radioactivity count (counts)÷tissue mass (mg), and 1%=average value of 1%ID in each phase-tail radioactivity count / 100.

[0240] Radiolabeled compounds [ 1830 minutes after the F]39 was injected into the mouse, the peak of brain accumulation was reached, and the uptake was 5.20±0.84% ​​of the injected dose per gram of tissue (%ID / g). The clearance rate of the radioligand in the brain was good. After 60min and 90min of administration, the uptake in the brain decreased, falling to 2.79±0.17%ID / g and 2.18±0.22%ID / g, respectively. According to Table 5, it can be seen that at 5min, the radioactive drug has not yet begun to enter the brain. At 15min and 30min, the radioactive drug begins to enter the brain, and the ratio of the radioactive concentration in the brain tissue to the blood (brain / blood) is 1.60 and 1.35, respectively.

[0241] Table 5 Compounds [ 18 Table of distribution of F]39 in normal female mice (n=5)

[0242]

[0243] [ 18 F]39 exhibits a suitable lipid-water partition coefficient (logP value is 1.12±0.15), and it can effectively penetrate the blood-brain barrier. In vitro stability experiments show that the radioactive compound can maintain a high degree of stability in vitro. The results of animal in vivo distribution experiments show that [ 18 F]39 showed an increasing trend in bone resorption over the time period studied, with particularly significant increases at 60 and 90 minutes, suggesting that the compound has a problem with fluorine shedding in vivo. In addition, it also showed high initial radioactivity accumulation in the kidneys and lungs, although the uptake in these sites subsequently decreased rapidly over time, indicating a rapid clearance rate. Notably, the ligand also showed some degree of brain penetration, suggesting its potential as a candidate agent for imaging of PDE4B brain receptors.

[0244] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A compound having a structure represented by general formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that: In formula (I), Y and Z are independently selected from none or Among them, R 11 is selected from H, alkyl, haloalkyl, and a C5-C6 ring; R1 and R2 are independently selected from H, alkyl with or without substitution, C3-C 10 The substituent includes halogen, amide, amino, hydroxyl, carboxyl, nitro, cyano, hydrocarbon, alkoxy, alkylthio, C3~C 10 Cycloalkyl, C4~C 10 Heterocycloalkyl, C6~C 10 Aryl or C5~C 10 heteroaryl; R3 is selected from H, C1 to C2 with or without substituents 20 Alkyl, C1~C 20 Heteroalkyl, C3~C 10 Cycloalkyl, C4~C 10 Heterocycloalkyl, C6~C 10 Aryl, C5~C 10 Heteroaryl.

2. The compound according to claim 1, characterized in that Formula (I) is selected from the following structural formula (a) or structural formula (b): Wherein, R1 and R2 are independently selected from H, an alkyl group with or without a substituent, a C3-C6 ring with or without a substituent, wherein the substituent includes halogen, amide, amino, hydroxyl, carboxyl, nitro, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C5-C6 aryl or C5-C6 heteroaryl; In formula (a), Y and Z are independently selected from none or Among them, R 11 Selected from H or C5-C6 heterocycle, the heterocycle here is preferably In formula (a), The structure is a single ring, a parallel ring structure of at least two rings combined together, or a series ring structure of at least two rings connected together by a bond; In formula (a), R4 is selected from H / none, carbonyl, amide, amino, nitro, alkoxy, alkylthio, sulfone, C2-C 10 Alkyl, C1~C 10 Heteroalkyl, C3~C 10 Cycloalkyl, C4-C6 heterocycloalkyl, C6-C 10 Aryl, C5~C 10 heteroaryl; In formula (b), m is an integer of 1 to 5, and R5 is selected from H, halogen, and hydroxyl.

3. The compound according to claim 2, characterized in that Formula (a) structure In At least one atom in the structure is connected to R4. When two or more atoms contain R4 at the same time or one atom contains two R4, each R4 is independently selected from H / none, carbonyl, amide, amino, nitro, alkoxy, alkylthio, sulfone, C2-C 10 Alkyl, C3~C 10 Heteroalkyl, C3~C 10 Cycloalkyl, C4-C6 heterocycloalkyl, C6-C 10 Aryl, C5~C 10 heteroaryl; Preferably, the The structure is a five-membered ring, a six-membered ring, a parallel ring structure composed of two five-membered rings, two six-membered rings, or one five-membered ring and one six-membered ring, and a tandem ring structure composed of two five-membered rings, two six-membered rings, or one five-membered ring and one six-membered ring connected in series through bonds.

4. The compound according to claim 3, characterized in that R1 and R2 are independently selected from H, C1-C 10 Alkyl, C1~C 10 Halogenated alkyl, C3-C6 ring, Wherein, q is an integer from 1 to 5, R 13 is a C3-C6 cycloalkyl / heterocycloalkyl / aryl group; in the aforementioned structures defined for R1 and R2, any one of the H groups may be substituted by a substituent; In formula (a), The structure is Preferably, The structure is selected from R6 and R9 are independently selected from Wherein, n is an integer from 1 to 5, R 10 is selected from H, halogen, labeled halogen, hydroxyl; R7 is selected from H, halogen, hydroxyl, carboxyl, amide, C2-C 10 An alkyl group, an amino group, a nitro group, an alkoxy group, an alkylthio group or a substituent containing a cyclic structure. R8 is selected from H, halogen, amino, hydroxyl, nitro, cyano, carbamoyl, substituted or unsubstituted C2-C 10 Alkyl, C2~C 10 C4-C6 heteroalkyl, C4-C6 cycloalkyl, C4-C6 heterocycloalkyl, C6-C 10 Aryl or C5~C 10 heteroaryl; Preferably, when at least two halogens are present, the specific choice of halogen may be the same or different; preferably, the multiple halogens are the same.

5. The compound according to claim 4, characterized in that R1 and R2 are independently selected from H, methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoroisobutyl, Among them, R 13 for In the aforementioned structures defined for R1 and R2, any H may be substituted by a substituent, wherein the substituent includes halogen, amide, alkyl, and amino; R6 and R9 are independently selected from n is an integer of 1-3, preferably 2; R7 is selected from H, halogen, hydroxyl, C2-C5 alkyl; preferably R7 is selected from H, halogen, hydroxyl, methyl, ethyl, propyl; R8 is selected from H, halogen, amino, hydroxyl, substituted or unsubstituted C4-C6 heterocycloalkyl; preferably R8 includes -OH, Where R 12 Selected from H, methyl, ethyl, propyl; The heteroatom contained in the heteroalkyl group, heterocycloalkyl group or heteroaryl group is selected from an oxygen atom, a nitrogen atom, a phosphorus atom or a sulfur atom; preferably, the heteroatom is an oxygen atom or a nitrogen atom.

6. The compound according to claim 1, characterized in that Includes at least one of the following compounds:

7. The compound according to any one of claims 1 to 8, characterized in that When the compound contains F, the F may be optionally labeled 18 F is substituted, and F in the compounds 24, 27, 30, 33, 36, and 39 of the formula (I) described in claim 6 may be 18 F replaced.

8. Use of the compound according to any one of claims 1 to 6 in the preparation of imaging probes.

9. Use of the compound according to any one of claims 1 to 6 in the preparation of an imaging agent for diagnosing Alzheimer's disease or in the preparation of a medicament for treating Alzheimer's disease, depression and other neuropsychiatric diseases.

10. A preparation, characterized in that The invention comprises the compound according to any one of claims 1 to 6.

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