Multifunctional compound targeting QC and CB2R as well as preparation method and application of multifunctional compound

Abstract

The invention provides a multifunctional compound targeting QC and CB2R and a preparation method and application thereof, the general formula of the chemical structure of the multifunctional compound is shown in the specification, the multifunctional compound can target QC and CB2R proteins and has both QC inhibitory activity and CB2R agonist activity, and a new strategy is provided for treatment of QC and / or CB2R abnormity related diseases. In addition, the invention provides a preparation method of the multifunctional compound, raw materials are easy to obtain, and steps are simple and feasible. Therefore, the multifunctional compound provided by the invention remarkably expands the diversity of molecular structures of compounds targeting QC and CB2R, and can be widely used for preparing medicines, diagnostic reagents and the like for treating diseases related to QC abnormality and / or CB2R abnormality.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a multifunctional compound targeting QC and CB2R, its preparation method, and its applications. Background Technology

[0002] Central nervous system (CNS) diseases are a complex group of illnesses involving the brain, spinal cord, and neural networks. Due to their complex pathological mechanisms and scarcity of therapeutic targets, they have become a major challenge for modern medicine, forcing researchers to search for intervention targets from multiple dimensions of pathological mechanisms. Taking neurodegenerative diseases as an example, Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline and behavioral disorders, accounting for 60%-80% of dementia cases in the elderly. The etiology of AD remains unclear. Clinically, patients exhibit memory loss that gradually worsens, language impairment, and personality changes, ultimately leading to complete dependence on others and imposing a heavy economic and care burden on families and society.

[0003] The typical pathological features of Alzheimer's disease (AD) reveal the necessity of multi-target intervention: abnormal deposition of β-amyloid (Aβ) forming senile plaques, excessive phosphorylation of Tau protein leading to neurofibrillary tangles, and the resulting neuronal death and synapse loss together constitute the "death triangle" of cognitive collapse. Researchers have proposed several hypotheses regarding the pathogenesis of AD, such as the Aβ cascade hypothesis. Aβ plaques form and deposit in different areas of the brain. These plaques are recognized by the brain as foreign substances, triggering inflammatory and immune responses by activating microglia and releasing cytokines, ultimately leading to cell death and neurodegeneration. Glutaminyl cyclase (QC) is a cyclase that catalyzes the formation of pyroglutamate from N-terminal glutamine and glutamate after the translation of active peptides or proteins. QC can catalyze the cyclization of N-terminal glutamine in Aβ to form pE-Aβ. Studies have shown that pE-Aβ accounts for more than 50% of the total plaques in the brain during AD. Compared to Aβ, pE-Aβ exhibits stronger neurotoxicity, higher stability and resistance to enzymatic degradation, and faster aggregation, further promoting Aβ aggregation. Therefore, high QC expression is a key factor in the pathogenesis and development of Alzheimer's disease (AD), and the development of QC inhibitors can intervene in the AD course by blocking the generation of toxic Aβ. Simultaneously, the core pathological features of AD are accompanied by synaptic connection disruption, neuronal death, and brain network dysfunction. Against this backdrop, activating cannabinoid receptor subtype 2 (CB2R) shows promise as an important strategy for intervening in the pathological process of AD. At the neuroprotective level, CB2R activation can inhibit the neuroinflammatory storm caused by excessive microglial activation and reduce extracellular excitotoxicity by enhancing glutamate transport. Simultaneously, it bidirectionally regulates the antioxidant system (increasing SOD activity / inhibiting prooxidases) to alleviate neuronal oxidative damage. At the synaptic remodeling level, CB2R activation significantly enhances neurogenesis in the hippocampus, promotes the integration of newly generated neurons into functional networks, and repairs damaged neuronal dendritic complexity and synaptic density by upregulating molecules such as brain-derived neurotrophic factor (BDNF), thus rebuilding the neural circuit basis of memory encoding and slowing the progression of brain atrophy. This multidimensional effect maintains the basis of neuronal survival and directly repairs the structural carriers of cognitive function, providing a breakthrough direction for AD treatment. Therefore, developing highly active CB2R agonists is essential.

[0004] Developing multifunctional compounds targeting QC and CB2R—a strategy that simultaneously blocks the generation of toxic proteins at the pathological source and repairs neural network function—not only opens up new avenues for AD treatment but also provides new ideas for the research and development of innovative drugs for central nervous system-related diseases. However, compounds targeting the multifunctional QC and CB2R have not yet been reported.

[0005] Therefore, existing technologies still need to be improved and developed. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the purpose of this invention is to provide a multifunctional compound targeting QC and CB2R, its preparation method and application, which aims to act on multiple targets related to central nervous system diseases. This synergistic effect can enable the drug to exert better efficacy and produce fewer side effects.

[0007] The technical solution of the present invention is as follows:

[0008] Firstly, a multifunctional compound targeting QC and CB2R is provided, with the following general structural formula: In unit A, R1 is C 5-12 Aromatic rings, C 5-12 Aromatic heterocyclic compounds, C 5-12 adipose ring and C 5-12 One of the aliphatic heterocycles, where R2 is hydrogen and C. 1-6 Alkyl, C 5-12 Aromatic rings and C 5-12 One of the aromatic heterocyclic compounds, where R3 is hydrogen and C. 1-6 Alkyl and C 1-6 One of the alkoxy groups; in unit B, R4 is a monosubstituted or polysubstituted at different positions, where R4 is hydrogen, C 1-3 Alkyl, C 1-3 One or more of alkoxy and halogen, R4 linking group is an imidazole ring or a triazole ring, the carbon atom n in the alkyl chain is an integer from 1 to 4; in the C unit, R5 is monosubstituted or polysubstituted at different positions, R5 is hydrogen, C 1-6 Alkyl, C 1-6 One or more of alkoxy groups and halogens.

[0009] In the preferred embodiment, in unit A, R1 is one of a benzene ring, a six-membered aliphatic ring, a seven-membered aliphatic ring, an adamantane ring, a piperidine ring, a methylpiperazine ring, and a morpholine ring; R2 is one of hydrogen, methyl, and a benzene ring; and R3 is one of hydrogen, methyl, ethyl, propyl, butyl, and methoxy.

[0010] In the preferred embodiment, in unit B, R4 is hydrogen and / or methyl, and the carbon atom n in the alkyl chain is 3.

[0011] In the preferred embodiment, in unit C, R5 is one of hydrogen, methyl, methoxy, and fluorine.

[0012] In a preferred embodiment, the multifunctional compound targeting QC and CB2R has one of the following chemical structural formulas:

[0013]

[0014]

[0015]

[0016] In a second aspect, a method for preparing a multifunctional compound as described in the first aspect is provided, comprising the steps of:

[0017] Raw material I and raw material II were coupled under the first reaction conditions to prepare intermediate i;

[0018] Intermediate i and starting material III were subjected to a bromination reaction under the second reaction conditions to prepare intermediate ii;

[0019] Intermediate II and starting material IV were subjected to an SN2 reaction under the third reaction conditions to prepare intermediate III;

[0020] Intermediate III was subjected to ester hydrolysis under the fourth reaction conditions to prepare intermediate IV;

[0021] The multifunctional compound was prepared by amide condensation reaction of intermediate IV and starting material V under the fifth reaction conditions;

[0022] The structural formula of raw material I is as follows: The structural formula of raw material II is: The structural formula of intermediate i is The structural formula of raw material III is The structural formula of intermediate II is The structural formula of raw material IV is The structural formula of intermediate iii is The structural formula of intermediate iv is The structural formula of raw material V is H2N-R1.

[0023] In a preferred embodiment, the first reaction conditions include: a temperature of 0-150℃, a time of 8-12h, a solvent of one or more of water, acetone, acetonitrile, tetrahydrofuran, dioxane, and N,N-dimethylformamide, an acid-binding agent of one or more of potassium carbonate, sodium carbonate, and cesium carbonate, and a catalyst of divalent palladium catalyst.

[0024] In a further preferred embodiment, the divalent palladium catalyst is one or more of palladium acetate, palladium diphenylphosphine ferrocene dichloride, and palladium dichlorotriphenylphosphine.

[0025] In a preferred embodiment, the second reaction conditions include: a temperature of 50-150°C, a time of 12-24 h, a solvent of one or more of acetone, acetonitrile, tetrahydrofuran, dioxane, and N,N-dimethylformamide, and an acid-binding agent selected from one or more of potassium carbonate, sodium carbonate, and triethylamine.

[0026] In a preferred embodiment, the third reaction conditions include: a temperature of 50-150°C, a time of 12-24 h, and a solvent of one or more of acetone, acetonitrile, tetrahydrofuran, dioxane, and N,N-dimethylformamide.

[0027] In a preferred embodiment, the fourth reaction conditions include: a temperature of 50-70°C, a time of 0.5-3 hours, a solvent of methanol or ethanol, and a catalyst of acid or alkali.

[0028] In a further preferred embodiment, the acid is one or more of sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, and methanesulfonic acid; and / or, the base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

[0029] In the preferred embodiment, the fifth reaction conditions include: a temperature of 0-30°C, a time of 6-8 hours, a solvent of dichloromethane or chloroform, and condensing reagents of 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0030] Thirdly, there is an application of the multifunctional compound as described in the first aspect, in which the multifunctional compound is used to prepare medicaments and / or diagnostic kits for diseases related to QC and / or CB2R abnormalities.

[0031] Beneficial effects: The multifunctional compounds targeting QC and CB2R provided by this invention significantly expand the molecular structural diversity of compounds targeting QC and CB2R. Moreover, the raw materials are readily available and the preparation method is simple and feasible. They can be widely used in the development of drugs and diagnostic reagents for the treatment of diseases related to QC and / or CB2R abnormalities, such as for the development of drugs and diagnostic reagents for diseases related to the central nervous system. Attached Figure Description

[0032] Figure 1 This is a schematic diagram of simulated docking between the multifunctional compound and QC and CB2R proteins in this invention; where A represents the docking result between the multifunctional compound and QC protein, and B represents the docking result between the multifunctional compound and CB2R protein. Detailed Implementation

[0033] This invention provides a multifunctional compound targeting QC and CB2R, its preparation method, and its applications. To make the objectives, technical solutions, and effects of this invention clearer and more explicit, the invention is further described in detail below. It should be understood that the specific embodiments described herein are only for explaining the invention and are not intended to limit the invention.

[0034] This invention provides a multifunctional compound targeting QC and CB2R, with the following general structural formula:

[0035] In unit A, R1 is C 5-12 Aromatic rings, C 5-12 Aromatic heterocyclic compounds, C 5-12 adipose ring and C 5-12 One of the aliphatic heterocycles, where R2 is hydrogen and C. 1-6 Alkyl, C 5-12 Aromatic rings and C 5-12 One of the aromatic heterocyclic compounds, where R3 is hydrogen and C. 1-6 Alkyl and C 1-6 One of the alkoxy groups; in unit B, R4 is a monosubstituted or polysubstituted at different positions, where R4 is hydrogen, C 1-3 Alkyl, C 1-3 One or more of alkoxy and halogen, R4 linking group is an imidazole ring or a triazole ring, the carbon atom n in the alkyl chain is an integer from 1 to 4; in the C unit, R5 is monosubstituted or polysubstituted at different positions, R5 is hydrogen, C 1-6 Alkyl, C 1-6 One or more of alkoxy groups and halogens.

[0036] Specifically, such as Figure 1 As shown in Figure A, QC is a single zinc ion metalloenzyme. The B unit in the multifunctional compound of this invention can enter the active pocket of QC and interact with the Zn at the bottom of the QC protein's active site. 2+ Chelation subsequently inhibits its activity; furthermore, such as Figure 1 As shown in Figure B, this multifunctional compound can also enter the active pocket of CB2R. The active pocket of CB2R is mainly composed of hydrophobic residues. The benzamide structure in unit A can be embedded in the ligand-binding pocket, mainly undergoing van der Waals forces, π-π conjugation, and hydrophobic interactions. Furthermore, the biphenyl planar structure formed by units A and C allows it to rotate within the pocket, optimizing contact with surrounding residues. The methoxy group in unit A has a hydrogen bond interaction with SER-285. Based on the above analysis, this multifunctional compound can bind tightly to both QC and CB2R proteins simultaneously. Therefore, compounds with this structure can serve as multifunctional compounds targeting both QC and CB2R, exhibiting significant activity.

[0037] In some embodiments, in unit A, R1 is one of a benzene ring, a six-membered aliphatic ring, a seven-membered aliphatic ring, an adamantane ring, a piperidine ring, a methylpiperazine ring, and a morpholine ring; R2 is one of hydrogen, methyl, and a benzene ring; and R3 is one of hydrogen, methyl, ethyl, propyl, butyl, and methoxy, but is not limited thereto.

[0038] In some embodiments, in unit B, R4 is hydrogen and / or methyl, and the carbon atom n in the alkyl chain is 3, but not limited thereto.

[0039] In some embodiments, R5 in unit C is one of hydrogen, methyl, methoxy, and fluorine, but is not limited thereto.

[0040] In some embodiments, the chemical structural formula of the multifunctional compound targeting QC and CB2R can be:

[0041]

[0042] One of them, but not limited to this.

[0043] The multifunctional compounds targeting QC and CB2R provided by this invention are all publicly disclosed for the first time, possessing significant scientific importance and research value for the development of innovative lead drugs for central nervous system-related diseases. These multifunctional compounds can be widely applied in the research of network-targeted drugs for central nervous system-related diseases, drugs for treating QC and / or CB2R-related diseases, or the development of related diagnostic kits.

[0044] This invention provides a method for preparing the multifunctional compound as described above, comprising the following steps:

[0045] Raw material I and raw material II were coupled under the first reaction conditions to prepare intermediate i;

[0046] Intermediate i and starting material III were subjected to a bromination reaction under the second reaction conditions to prepare intermediate ii;

[0047] Intermediate II and starting material IV were subjected to an SN2 reaction under the third reaction conditions to prepare intermediate III;

[0048] Intermediate III was subjected to ester hydrolysis under the fourth reaction conditions to prepare intermediate IV;

[0049] The multifunctional compound was prepared by amide condensation reaction of intermediate IV and starting material V under the fifth reaction conditions;

[0050] The structural formula of raw material I is as follows: The structural formula of raw material II is: The structural formula of intermediate i is The structural formula of raw material III is The structural formula of intermediate II is The structural formula of raw material IV is The structural formula of intermediate iii is The structural formula of intermediate iv is The structural formula of raw material V is H2N-R1.

[0051] In some embodiments, the first reaction conditions include: a temperature of 0-150°C, a time of 8-12 h, a solvent of one or more of water, acetone, acetonitrile, tetrahydrofuran, dioxane, and N,N-dimethylformamide, an acid-binding agent of one or more of potassium carbonate, sodium carbonate, and cesium carbonate, and a catalyst of divalent palladium catalyst, but are not limited thereto.

[0052] In some more specific embodiments, the divalent palladium catalyst is one or more of palladium acetate, palladium diphenylphosphine ferrocene dichloride, and palladium dichlorotriphenylphosphine, but is not limited thereto, and may also be a complex of these divalent palladium catalysts, such as [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane complex (DPPF).

[0053] In some embodiments, the second reaction conditions include: a temperature of 50-150°C, a time of 12-24 h, a solvent of one or more of acetone, acetonitrile, tetrahydrofuran, dioxane, and N,N-dimethylformamide, and an acid-binding agent selected from one or more of potassium carbonate, sodium carbonate, and triethylamine, but not limited thereto.

[0054] In some embodiments, the third reaction conditions include, but are not limited to, a temperature of 50-150°C, a time of 12-24 h, and a solvent of one or more of acetone, acetonitrile, tetrahydrofuran, dioxane, and N,N-dimethylformamide.

[0055] In some embodiments, the fourth reaction conditions include, but are not limited to: a temperature of 50-70°C, a time of 0.5-3 h, a solvent of methanol or ethanol, and a catalyst of acid or base.

[0056] In some more specific embodiments, the acid is one or more of sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, and methanesulfonic acid, but is not limited thereto; and / or, the base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate, but is not limited thereto.

[0057] In some embodiments, the fifth reaction conditions include, but are not limited to: a temperature of 0-30°C, a time of 6-8 h, a solvent of dichloromethane or chloroform, and condensing reagents of 1-hydroxybenzotriazole (HOBT) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl).

[0058] This invention provides an application of the multifunctional compound described above, using the multifunctional compound to prepare drugs and / or diagnostic kits for diseases related to QC and / or CB2R abnormalities.

[0059] In some embodiments, the drug may be a pharmaceutically acceptable salt, including lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, iron salts, copper salts, organic ammonium salts, hydrochloride salts, phosphates, acetates, propionates, oxalates, citrates, etc.

[0060] The present invention will be further explained and illustrated below through specific embodiments.

[0061] Example 1

[0062] Preparation of N-((3s, 5s, 7s)-adamantane-1-yl)-4-methoxy-5-methyl-2'-(3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxamide:

[0063] a) 2-Aminophenylboronic acid (1.2 mmol, 1.2 equiv) and methyl 5-bromo-2-methoxy-3-methylbenzoate (1 mmol, 1 equiv) were dissolved in a 1:1 mixture of 1,4-dioxane and saturated potassium carbonate solution (1:1) (10 mL). A catalyst, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane complex (DPPF, 0.06 mmol, 0.06 equiv), was added. The reaction mixture was kept under nitrogen protection and reacted overnight at 100 °C. After the reaction, the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Column chromatography was used to prepare methyl 2'-amino-4-methoxy-5-methyl-[1,1'-biphenyl]-3-carboxylic acid, yield: 67%.

[0064] b. Using acetonitrile as solvent, add 1 equivalent of methyl 2'-amino-4-methoxy-5-methyl-[1,1'-biphenyl]-3-carboxylic acid, then add 3 equivalents of potassium carbonate, stir for 10 min, and finally add 3 equivalents of 1,3-dibromopropane dropwise, stir, and react at 80 °C for 24 h. After the reaction is complete, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent by vacuum distillation, and prepare methyl 2'-(3-bromopropyl)amino)-4-methoxy-5-methyl-[1,1'-biphenyl]-3-carboxylic acid by column chromatography, yield: 26%;

[0065] c. Using N,N-dimethylformamide as solvent, add 1 equivalent of 4-methylimidazole, then add 1 equivalent of triphenylchloromethane, and then add 2 equivalents of triethylamine dropwise. Start stirring and stir at room temperature for 2 hours. After the reaction is complete, filter the reaction system directly. Wash the precipitate three times with n-hexane and dry the precipitate in an oven to finally obtain 4-methyl-1-triphenylmethyl-1H-imidazole, yield: 77%.

[0066] d. Using acetonitrile as solvent, add 1 equivalent of methyl 2'-(3-bromopropyl)amino)-4-methoxy-5-methyl-[1,1'-biphenyl]-3-carboxylic acid, followed by 1.5 equivalents of 4-methyl-1-triphenylmethyl-1H-imidazolium. Stirring is started, and the reaction is carried out at 85°C for 24 h. After the reaction is complete, the reaction system is distilled under reduced pressure to remove the solvent. Add an appropriate amount of methanol as solvent, and then add 1 equivalent of trifluoroacetic acid dropwise. The reaction is carried out at 65°C for 3 h. After the reaction is complete, the system is cooled to room temperature, and the reaction system is distilled under reduced pressure to remove the solvent. The pH is adjusted to weakly alkaline with saturated sodium bicarbonate aqueous solution, and the mixture is extracted three times with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Column chromatography is used to prepare methyl 4-methoxy-5-methyl-2'-((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid, yield: 16%.

[0067] e. Using methanol as solvent, methyl 4-methoxy-5-methyl-2'-((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid was added, followed by 1 equivalent of saturated sodium hydroxide aqueous solution. The mixture was stirred and reacted at 60°C for 2 hours. After the reaction was completed, the pH was adjusted to weakly acidic with 10% hydrochloric acid. The reaction system was then distilled under reduced pressure to remove the solvent. Anhydrous ethanol was added and the mixture was filtered to remove inorganic salts, yielding 4-methoxy-5-methyl-2'-(3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid, with a yield of 90%.

[0068] f. Using dichloromethane as a solvent, add 1 equivalent of 4-methoxy-5-methyl-2'-(3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid, then add 1 equivalent of 1-hydroxybenzotriazole and 1 equivalent of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, start stirring, react at 0°C for 0.5 h, then add 1.5 equivalents of (3s, 5s, 7s)-adamantane-1-amine, and react overnight at room temperature. After the reaction was complete, the system was poured into water, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Column chromatography was then used to prepare N-((3s, 5s, 7s)-adamantane-1-yl)-4-methoxy-5-methyl-2'-(3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxamide, with the following chemical structural formula: Its total yield was 2.5%.

[0069] The structural characterization data of N-((3s,5s,7s)-adamantane-1-yl)-4-methoxy-5-methyl-2'-(3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxamide are as follows:1 H NMR(500MHz, CDCl3)δ7.88(dd,J=11.2,2.4Hz,1H),7.54(d,J=4.2Hz,1H),7.37-7.32(m,1H),7 .29(d,J=2.3Hz,1H),7.21(td,J=7.7,1.7Hz,1H),7.05(dd,J=7.4,1.6Hz,1H),6.79-6.72(m,2H ),6.62(d,J=8.0Hz,1H),3.93(dt,J=20.9,7.0Hz,2H),3.83(s,3H),3.10(dt,J=14.2,6.7Hz,2H ),2.35(s,3H),2.17-2.08(m,11H),2.02-1.94(m,3H),1.77-1.69(m,6H).HRMS(ESI):calcdfor C 32 H 40 N4O2 512.6980, found [M+H] + 513.3275.

[0070] Example 2

[0071] Preparation of N-cyclohexyl-4-methoxy-5-methyl-2'-(3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxamide:

[0072] a) 2-Aminophenylboronic acid (1.2 mmol, 1.2 equiv) and methyl 5-bromo-2-methoxy-3-methylbenzoate (1 mmol, 1 equiv) were dissolved in a 1:1 mixture of 1,4-dioxane and saturated potassium carbonate solution (1:1) (10 mL). A catalyst, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane complex (DPPF, 0.06 mmol, 0.06 equiv), was added. The reaction mixture was kept under nitrogen protection and reacted overnight at 100 °C. After the reaction, the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Column chromatography was used to prepare methyl 2'-amino-4-methoxy-5-methyl-[1,1'-biphenyl]-3-carboxylic acid, yield: 73%.

[0073] b. Using acetonitrile as solvent, add 1 equivalent of methyl 2'-amino-4-methoxy-5-methyl-[1,1'-biphenyl]-3-carboxylic acid, then add 3 equivalents of potassium carbonate, stir for 10 min, and finally add 3 equivalents of 1,3-dibromopropane dropwise, stir, and react at 80 °C for 24 h. After the reaction is complete, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent by vacuum distillation, and prepare methyl 2'-(3-bromopropyl)amino)-4-methoxy-5-methyl-[1,1'-biphenyl]-3-carboxylic acid by column chromatography, yield: 23%;

[0074] c. Using N,N-dimethylformamide as solvent, add 1 equivalent of 4-methylimidazole, then add 1 equivalent of triphenylchloromethane, and then add 2 equivalents of triethylamine dropwise. Start stirring and stir at room temperature for 2 hours. After the reaction is complete, filter the reaction system directly. Wash the precipitate three times with n-hexane and dry the precipitate in an oven to finally obtain 4-methyl-1-triphenylmethyl-1H-imidazole, yield: 78%.

[0075] d. Using acetonitrile as solvent, add 1 equivalent of methyl 2'-(3-bromopropyl)amino)-4-methoxy-5-methyl-[1,1'-biphenyl]-3-carboxylic acid, followed by 1.5 equivalents of 4-methyl-1-triphenylmethyl-1H-imidazolium. Stirring is started, and the reaction is carried out at 85°C for 24 h. After the reaction is complete, the reaction system is distilled under reduced pressure to remove the solvent. Add an appropriate amount of methanol as solvent, and then add 1 equivalent of trifluoroacetic acid dropwise. The reaction is carried out at 65°C for 3 h. After the reaction is complete, the system is cooled to room temperature, and the reaction system is distilled under reduced pressure to remove the solvent. The pH is adjusted to weakly alkaline with saturated sodium bicarbonate aqueous solution, and the mixture is extracted three times with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Column chromatography is used to prepare methyl 4-methoxy-5-methyl-2'-((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid, yield: 18%.

[0076] e. Using methanol as solvent, methyl 4-methoxy-5-methyl-2'((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid was added, followed by 1 equivalent of saturated sodium hydroxide aqueous solution. The mixture was stirred and reacted at 60°C for 2 hours. After the reaction was completed, the pH was adjusted to weakly acidic with 10% hydrochloric acid. The reaction system was then distilled under reduced pressure to remove the solvent. Anhydrous ethanol was added and the mixture was filtered to remove inorganic salts, yielding 4-methoxy-5-methyl-2'((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid, with a yield of 93%.

[0077] f. Using dichloromethane as solvent, add 1 equivalent of 4-methoxy-5-methyl-2'-((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid, then add 1 equivalent of 1-hydroxybenzotriazole and 1 equivalent of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride. Start stirring and react at 0°C for 0.5 h. Add 1.5 equivalents of cyclohexylamine and react overnight at room temperature. After the reaction is complete, pour the system into water, extract three times with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, distill under reduced pressure, and prepare N-cyclohexyl-4-methoxy-5-methyl-2'-(3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxamide by column chromatography. Its chemical structural formula is: Its total yield was 2.7%.

[0078] The structural characterization data of N-cyclohexyl-4-methoxy-5-methyl-2'-(3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxamide are as follows: 1 H NMR (500MHz, CDCl3) δ7.95 (d, J = 8.0 Hz, 1H), 7.77 (dd, J = 12.1, 2.1 Hz, 1H), 7.43 (dd, J = 7.9, 1.3 Hz, 1H), 7.23 (ddd, J = 8. 4,7.5,1.6Hz,2H),7.09(dd,J=7.5,1.6Hz,1H),7.03(d,J=2.1Hz,1H),6.81-6.73(m,2H),6.63(dt,J=8.3,1.6Hz,1H),4 .07-3.96(m,2H),3.94(s,4H),3.90(s,3H),3.11(dt,J=14.0,6.7Hz,2H),2.18(dd,J=30.4,0.9Hz,3H),2.06-1.94(m,4 H),1.74(dq,J=13.6,4.2Hz,2H),1.62(dt,J=13.1,3.9Hz,1H),1.51-1.39(m,2H),1.36-1.22(m,4H).HRMS(ESI):calcd for C 28 H 36 N4O2460.6220, found [M+H] + 461.2968.

[0079] Example 3

[0080] N-Cyclohexyl-4,5-dimethoxy-2'((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxamide:

[0081] a) 2-Aminophenylboronic acid (1.2 mmol, 1.2 equiv) and methyl 5-bromo-2,3-dimethoxybenzoate (1 mmol, 1 equiv) were dissolved in a 1:1 mixture of 1,4-dioxane and saturated potassium carbonate solution (1:1) (10 mL). A catalyst, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane complex (DPPF, 0.06 mmol, 0.06 equiv), was added. The reaction mixture was kept under nitrogen protection and reacted overnight at 100 °C. After the reaction, the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The resulting product was methyl 2'-amino-4,5-dimethoxy-[1,1'-biphenyl]-3-carboxylic acid by column chromatography, yield: 61%.

[0082] b. Using acetonitrile as solvent, add 1 equivalent of methyl 2'-amino-4,5-dimethoxy-[1,1'-biphenyl]-3-carboxylic acid, then add 3 equivalents of potassium carbonate, stir for 10 min, and finally add 3 equivalents of 1,3-dibromopropane dropwise, stir, and react at 80 °C for 24 h. After the reaction is complete, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent by vacuum distillation, and prepare methyl 2'-((3-bromopropyl)amino)-4,5-dimethoxy-[1,1'-biphenyl]-3-carboxylic acid by column chromatography, yield: 24%;

[0083] c. Using N,N-dimethylformamide as solvent, add 1 equivalent of 4-methylimidazole, then add 1 equivalent of triphenylchloromethane, and then add 2 equivalents of triethylamine dropwise. Start stirring and stir at room temperature for 2 hours. After the reaction is complete, filter the reaction system directly. Wash the precipitate three times with n-hexane and dry the precipitate in an oven to finally obtain 4-methyl-1-triphenylmethyl-1H-imidazole, yield: 78%.

[0084] d. Using acetonitrile as solvent, add 1 equivalent of methyl 2'((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid, followed by 1.5 equivalents of 4-methyl-1-triphenylmethyl-1H-imidazolium. Stir and react at 85°C for 24 h. After the reaction is complete, distill the reaction system under reduced pressure to remove the solvent. Add an appropriate amount of methanol as solvent, and then add 1 equivalent of trifluoroacetic acid dropwise. React at 65°C for 3 h. After the reaction is complete, let the system cool to room temperature, then distill the reaction system under reduced pressure to remove the solvent. Adjust the pH to weakly alkaline with saturated sodium bicarbonate aqueous solution, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, distill under reduced pressure, and prepare methyl 4,5-dimethoxy-2'((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid by column chromatography. Yield: 15%.

[0085] e. Using methanol as solvent, methyl 4,5-dimethoxy-2'-((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid was added, followed by 1 equivalent of saturated sodium hydroxide aqueous solution. The mixture was stirred and reacted at 60°C for 2 hours. After the reaction was completed, the pH was adjusted to weakly acidic with 10% hydrochloric acid. The reaction system was then distilled under reduced pressure to remove the solvent. Anhydrous ethanol was added and the mixture was filtered to remove inorganic salts, yielding 4,5-dimethoxy-2'-((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid, with a yield of 92%.

[0086] f. Using dichloromethane as solvent, add 1 equivalent of 4,5-dimethoxy-2'((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid, then add 1 equivalent of 1-hydroxybenzotriazole and 1 equivalent of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride. Start stirring and react at 0°C for 0.5 h. Add 1.5 equivalents of cyclohexylamine and react overnight at room temperature. After the reaction is complete, pour the system into water, extract three times with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, distill under reduced pressure, and prepare N-cyclohexyl-4,5-dimethoxy-2'((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxamide by column chromatography. Its chemical structural formula is: Its total yield was 2.0%.

[0087] The structural characterization data of N-cyclohexyl-4,5-dimethoxy-2'((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxamide are as follows: 1H NMR (500MHz, CDCl3) δ7.95 (d, J = 8.0 Hz, 1H), 7.77 (dd, J = 12.1, 2.1 Hz, 1H), 7.43 (dd, J = 7.9, 1.3 Hz, 1H), 7.23 (ddd, J = 8. 4,7.5,1.6Hz,2H),7.09(dd,J=7.5,1.6Hz,1H),7.03(d,J=2.1Hz,1H),6.81-6.73(m,2H),6.63(dt,J=8.3,1.6Hz,1H),4 .07-3.96(m,2H),3.94(s,4H),3.90(s,3H),3.11(dt,J=14.0,6.7Hz,2H),2.18(dd,J=30.4,0.9Hz,3H),2.06-1.94(m,4 H),1.74(dq,J=13.6,4.2Hz,2H),1.62(dt,J=13.1,3.9Hz,1H),1.51-1.39(m,2H),1.36-1.22(m,4H).HRMS(ESI):calcd for C 28 H 36 N4O3476.6210, found [M+H] + 477.2887.

[0088] Example 4

[0089] Preparation of N-cyclohexyl-4-methoxy-2'((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxamide:

[0090] a) 2-Aminophenylboronic acid (1.2 mmol, 1.2 equiv) and methyl 5-bromo-2-methoxybenzoate (1 mmol, 1 equiv) were dissolved in a 1:1 mixture of 1,4-dioxane and saturated potassium carbonate solution (1:1) (10 mL). A catalyst, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane complex (DPPF, 0.06 mmol, 0.06 equiv), was added. The reaction mixture was kept under nitrogen protection and reacted overnight at 100 °C. After the reaction, the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. 2'-Amino-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid methyl ester was prepared by column chromatography, yield: 67%.

[0091] b. Using acetonitrile as solvent, add 1 equivalent of methyl 2'-amino-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid, then add 3 equivalents of potassium carbonate, stir for 10 min, and finally add 3 equivalents of 1,3-dibromopropane dropwise, stir, and react at 80 °C for 24 h. After the reaction is complete, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent by vacuum distillation, and prepare methyl 2'-(3-bromopropyl)amino)-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid by column chromatography, yield: 26%;

[0092] c. Using N,N-dimethylformamide as solvent, add 1 equivalent of 4-methylimidazole, then add 1 equivalent of triphenylchloromethane, and then add 2 equivalents of triethylamine dropwise. Start stirring and stir at room temperature for 2 hours. After the reaction is complete, filter the reaction system directly. Wash the precipitate three times with n-hexane and dry the precipitate in an oven to finally obtain 4-methyl-1-triphenylmethyl-1H-imidazole, yield: 77%.

[0093] d. Using acetonitrile as solvent, add 1 equivalent of methyl 2'-(3-bromopropyl)amino)-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid, followed by 1.5 equivalents of 4-methyl-1-triphenylmethyl-1H-imidazolium. Stirring is started, and the reaction is carried out at 85°C for 24 h. After the reaction is complete, the reaction system is distilled under reduced pressure to remove the solvent. Add an appropriate amount of methanol as solvent, and then add 1 equivalent of trifluoroacetic acid dropwise. The reaction is carried out at 65°C for 3 h. After the reaction is complete, the system is cooled to room temperature, and the reaction system is distilled under reduced pressure to remove the solvent. The pH is adjusted to weakly alkaline with saturated sodium bicarbonate aqueous solution, and the mixture is extracted three times with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. Column chromatography is used to prepare methyl 4-methoxy-2'-((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid, yield: 16%.

[0094] e. Using methanol as solvent, methyl 4-methoxy-2'-((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid was added, followed by 1 equivalent of saturated sodium hydroxide aqueous solution. The mixture was stirred and reacted at 60°C for 2 hours. After the reaction was completed, the pH was adjusted to weakly acidic with 10% hydrochloric acid. The reaction system was then distilled under reduced pressure to remove the solvent. Anhydrous ethanol was added and the mixture was filtered to remove inorganic salts, yielding 4-methoxy-2'-(3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid, with a yield of 90%.

[0095] f. Using dichloromethane as solvent, add 1 equivalent of 4-methoxy-2'-(3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxylic acid, then add 1 equivalent of 1-hydroxybenzotriazole and 1 equivalent of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride. Stir and react at 0°C for 0.5 h. Add 1.5 equivalents of cyclohexylamine and react overnight at room temperature. After the reaction is complete, pour the system into water, extract three times with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, distill under reduced pressure, and prepare N-cyclohexyl-4-methoxy-2'-((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxamide by column chromatography. Its chemical structural formula is: Its total yield was 2.5%.

[0096] The structural characterization data of N-cyclohexyl-4-methoxy-2'((3-(5-methyl-1H-imidazol-1-yl)propyl)amino)-[1,1'-biphenyl]-3-carboxamide are as follows: 1 H NMR (500MHz, CDCl3) δ8.29(dd,J=11.9,2.4Hz,1H),7.81(t,J=7.2Hz,1H),7.45(ddd,J=8.4,2.4,1.1Hz,1H),7.40(s, 1H),7.22(td,J=7.8,1.7Hz,1H),7.07(ddd,J=8.6,6.3,1.8Hz,2H),6.78(ddd,J=7.4,2.6,1.1Hz,1H),6.76-6.72(m,1 H),6.63(d,J=8.1Hz,1H),4.01(s,3H),3.95(dt,J=23.7,6.9Hz,2H),3.09(dt,J=13.2,6.5Hz,2H),2.17(d,J=29.3Hz, 3H),2.05-1.92(m,4H),1.77-1.68(m,2H),1.66-1.58(m,1H),1.51-1.39(m,2H),1.35-1.23(m,4H).HRMS(ESI):calcd for C 27 H 34 N4O2446.5950, found [M+H] + 447.2737.

[0097] Example 5

[0098] The compounds in Table 1 were used to test the inhibitory activity of QC enzymes.

[0099] Reagent preparation:

[0100] HEPES buffer (pH=7.0): Weigh 0.596 g of 4-hydroxyethylpiperazine ethanesulfonic acid (HEPES) powder, dissolve in 90 mL of deionized water, adjust the pH to 7.0 with 1 M NaOH, and then bring the volume to 100 mL. Store at 4 °C.

[0101] PAP buffer (pH 9.0): Weigh 1.211 g of tris(hydroxymethyl)aminomethane (Tris) and 0.077 g of dithiothreitol (DTT), dissolve in 90 mL of deionized water, adjust the pH to 9.0, and then bring the volume to 100 mL. Store at -20°C.

[0102] Compound preparation: Weigh the solid powder of the compound to be tested, add dimethyl sulfoxide (DMSO) to prepare a 10 mM stock solution, and store at -20℃. During the experiment, dilute to multiple concentration gradients using HEPES buffer according to the required concentration of the specific compound.

[0103] QC solution: BCA quantitative protein concentration is 0.75 mg / mL, store at -80℃. Before the experiment, dilute with HEPES buffer 1500 times to 0.5 μg / mL, mix well and place on ice for later use.

[0104] Gln-AMC solution: 66 mM 2-amino-N1-(4-methyl-2-oxo-4a,8a-dihydro-2H-chromen-7-yl)pentanediamide (Gln-AMC), stored at -20°C. Before experiments, dilute 330-fold to 200 μM with HEPES buffer, mix well, and place on ice.

[0105] PAP solution: 3 mg / mL pyroglutamyl peptidase (PAP), stored at -80°C. Before the experiment, dilute 300 times with PAP buffer to 10 μg / mL, mix well, and store on ice.

[0106] Add 40 μL of QC solution and 10 μL of the test compound / PBD-150 (positive control) / DMSO (negative control) diluted with HEPES buffer, or 50 μL of HEPES buffer (blank control), to a black 96-well plate and incubate at 25 °C and 200 rpm for 2 min. Add 50 μL of Gln-AMC solution to each well and incubate at 25 °C and 200 rpm for 10 min. Add 100 μL of PAP solution to each well and incubate at 25 °C and 200 rpm for 60 min, then perform a single-wavelength scan (EX / EM = 360 nm / 445 nm).

[0107] Inhibition rate (%) = (DMSO - Cpd) / (DMSO - Blank) × 100%. Where DMSO represents the fluorescence value of the DMSO group; Cpd represents the fluorescence value of the inhibitor group; and Blank represents the fluorescence value of the group without enzyme. The results are shown in Table 1.

[0108] Example 6

[0109] The CB2R agonist activity was tested using the compounds listed in Table 1:

[0110] Prepare 1× stimulation buffer according to the LANCE Ultra cAMP kit instructions; prepare 10× working solutions of GW-405833 (positive control) and the test compound; digest HEK293T cells stably transfected with CB2 with trypsin, centrifuge, and then resuspend in 1× stimulation buffer. After counting, seed cells into 384-well plates; add the prepared test compound solution to the corresponding wells and incubate at 37°C for 10 min; for the agonist mode, add the trichodin solution to the cell wells and incubate at 37°C for 30 min to induce cAMP production; dilute Eu-cAMP to the working concentration with detection buffer and add it to the corresponding wells in the plate; dilute Ultra-anti-cAMP with detection buffer. TM Dilute to the working concentration and add to the corresponding wells in the plate. After centrifugation, incubate at room temperature. After incubation, read the signal values ​​at emission wavelengths of 665 nm and 620 nm using a microplate reader. Simultaneously, use cAMP standards for serial 10-fold dilutions, measure the signal values, and fit a standard curve. Substitute the signal values ​​of the test compound into the standard curve equation to convert them to cAMP concentration. Plot an agonist response curve with cAMP concentration on the ordinate and the concentration of the test compound on the abscissa, and calculate the EC50. 50 The measurement results are shown in Table 1.

[0111] Table 1. Results of QC inhibition and CB2R agonist activity tests of the compounds.

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118] In summary, the series of novel structural compounds of this invention significantly expand the molecular structural diversity of multifunctional compounds targeting QC and CB2R. The raw materials are readily available, the preparation methods are simple and feasible, and the activity against QC and CB2R is significant. As lead compounds, they have the potential to be further developed into innovative drugs.

[0119] It should be understood that the application of the present invention is not limited to the examples above. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims.

Claims

1. A multifunctional compound targeting QC and CB2R, characterized in that, Its general structural formula is: In unit A, R1 is C 5-12 Aromatic rings, C 5-12 Aromatic heterocyclic compounds, C 5-12 adipose ring and C 5-12 One of the aliphatic heterocycles, where R2 is hydrogen and C. 1-6 Alkyl, C 5-12 Aromatic rings and C 5-12 One of the aromatic heterocyclic compounds, where R3 is hydrogen and C. 1-6 Alkyl and C 1-6 One of the alkoxy groups; in unit B, R4 is a monosubstituted or polysubstituted at different positions, where R4 is hydrogen, C 1-3 Alkyl, C 1-3 One or more of alkoxy and halogen, R4 linking group is an imidazole ring or a triazole ring, the carbon atom n in the alkyl chain is an integer from 1 to 4; in the C unit, R5 is monosubstituted or polysubstituted at different positions, R5 is hydrogen, C 1-6 Alkyl, C 1-6 One or more of alkoxy groups and halogens.

2. The multifunctional compound targeting QC and CB2R according to claim 1, characterized in that, R1 is one of benzene ring, six-membered aliphatic ring, seven-membered aliphatic ring, adamantane ring, piperidine ring, methylpiperazine ring, and morpholine ring; R2 is one of hydrogen, methyl, and benzene ring; and R3 is one of hydrogen, methyl, ethyl, propyl, butyl, and methoxy.

3. The multifunctional compound targeting QC and CB2R according to claim 1, characterized in that, R4 is hydrogen and / or methyl, and the alkyl chain has 3 carbon atoms n.

4. The multifunctional compound targeting QC and CB2R according to claim 1, characterized in that, R5 is one of hydrogen, methyl, methoxy, and fluorine.

5. The multifunctional compound targeting QC and CB2R according to claim 1, characterized in that, The multifunctional compound targeting QC and CB2R has one of the following chemical structural formulas:

6. A method for preparing a multifunctional compound as described in any one of claims 1-5, characterized in that, Including the following steps: Raw material I and raw material II were coupled under the first reaction conditions to prepare intermediate i; Intermediate i and starting material III were subjected to a bromination reaction under the second reaction conditions to prepare intermediate ii; Intermediate II and starting material IV were subjected to an SN2 reaction under the third reaction conditions to prepare intermediate III; Intermediate III was subjected to ester hydrolysis under the fourth reaction conditions to prepare intermediate IV; The multifunctional compound was prepared by amide condensation reaction of intermediate IV and starting material V under the fifth reaction conditions; The structural formula of raw material I is as follows: The structural formula of raw material II is: The structural formula of intermediate i is The structural formula of raw material III is The structural formula of intermediate II is The structural formula of raw material IV is The structural formula of intermediate iii is The structural formula of intermediate iv is The structural formula of raw material V is H2N-R1.

7. The preparation method according to claim 6, characterized in that, The first reaction conditions include: a temperature of 0-150℃, a time of 8-12h, a solvent of one or more of water, acetone, acetonitrile, tetrahydrofuran, dioxane and N,N-dimethylformamide, an acid-binding agent of one or more of potassium carbonate, sodium carbonate and cesium carbonate, and a catalyst of divalent palladium catalyst. The second reaction conditions include: a temperature of 50-150℃, a time of 12-24h, a solvent of one or more of acetone, acetonitrile, tetrahydrofuran, dioxane and N,N-dimethylformamide, and an acid-binding agent selected from one or more of potassium carbonate, sodium carbonate and triethylamine. The third reaction conditions include: a temperature of 50-150℃, a time of 12-24h, and a solvent of one or more of acetone, acetonitrile, tetrahydrofuran, dioxane, and N,N-dimethylformamide. The fourth reaction conditions include: a temperature of 50-70℃, a time of 0.5-3h, a solvent of methanol or ethanol, and a catalyst of acid or base. The fifth reaction conditions include: a temperature of 0-30℃, a time of 6-8h, a solvent of dichloromethane or chloroform, and condensation reagents of 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

8. The preparation method according to claim 7, characterized in that, The divalent palladium catalyst is one or more of palladium acetate, palladium dichloride diphenylphosphine ferrocene dichloride, and palladium dichlorotriphenylphosphine. The acid is one or more of sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, or methanesulfonic acid; The alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, or sodium bicarbonate.

9. An application of a multifunctional compound as described in any one of claims 1-5, characterized in that, The multifunctional compound is used to prepare drugs and / or diagnostic kits for diseases related to QC and / or CB2R abnormalities.

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