1, 4, 11-trioxo-10, 14-diazaspiro decanone as well as synthesis method and application of 1, 4, 11-trioxo-10, 14-diazaspiro decanone

Abstract

The invention discloses 1, 4, 11-trioxo-10, 14-diazaspiro decanone as well as a synthesis method and application thereof, and belongs to the technical field of medicines. The test result of the applicant shows that the compound has a good inhibiting effect on NO released by lipopolysaccharide-induced mouse macrophage RAW 264.7, shows good anti-inflammatory activity and can be used for preparing the medicine for treating inflammation.

Description

[0001] This application is a divisional application of "1-O-2,8-diazacyclic decanone derivatives and their synthesis methods and applications", the original application was filed on January 24, 2024, with application number 202410099899.0 and invention title: 1-O-2,8-diazacyclic decanone derivatives and their synthesis methods and applications. Technical Field

[0002] This invention relates to 1-oxo-2,8-diazacyclic decanone derivatives, their synthesis methods, and applications, belonging to the field of pharmaceutical technology. Background Technology

[0003] Medium-sized (8–12) nitrogen heterocycles are an extremely important class of compounds found in a range of natural and non-natural products. These compounds have shown great potential in drug discovery. The nitrogen-containing ten-membered ring skeleton is present in many different natural products and biologically significant compounds. For example, muramine, protopine, and dysazecine are alkaloids found in the genus *Corydalis*, possessing a benzoquinazine skeleton. Currently, numerous studies have reported the pharmacological activities of these compounds, such as their ability to inhibit neuronal excitability (Phytochemistry 2018, 150, 85-92), their inhibitory effect on gastric acid secretion, and their antibacterial, antiviral, and anti-inflammatory activities (Chin. J. Vet. Sci. 2008, 12, 1098–1101 & Journal of Animal Science and Veterinary Medicine, 2013, 32, 3-5). Picraphylline is a class of alkaloids from the plant Rauvolfia purpurea, possessing excellent pharmacological activities, such as antimalarial, anti-inflammatory, anti-cytotoxic, antioxidant, and anti-ulcer effects (Asian Pac. J. Trop. Med. 2014, 7, 1-8). However, due to unfavorable interring interactions and entropy effects in medium-ring compounds, the efficient construction of such skeletons remains a significant challenge. Therefore, developing new strategies to construct nitrogen-containing hetero-ten-membered ring compounds is of great importance. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a series of 1-oxo-2,8-diazacyclic decanone derivatives with novel structures and good anti-inflammatory activity, as well as their synthesis methods and applications.

[0005] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0006] The 1-oxo-2,8-diazacyclic decanone derivatives of this invention are compounds having the structure shown in formula (I) below, or pharmaceutically acceptable salts thereof:

[0007]

[0008] in:

[0009] R 1 This indicates an unsubstituted or monosubstituted phenyl group, or an unsubstituted thiophene group; wherein the substituent is C. 1～6 Alkyl, alkoxy, or halogen atoms;

[0010] R 2 This represents a hydrogen atom, or an unsubstituted or monosubstituted phenyl group, or an unsubstituted or monosubstituted styrene group; wherein the substituent is C. 1～6 Alkyl, alkoxy, or halogen atoms;

[0011] R 3 Represents a hydrogen atom, methyl, ethyl, n-butyl, or halogen atom, or a substituted C atom. 1～6 Alkyl groups;

[0012] R 4 Represents a hydrogen atom or a phenyl group, or an unsubstituted or monosubstituted C atom. 1～4 Alkyl groups, or unsubstituted or monosubstituted C4 groups. 1～4 alkoxy groups;

[0013] R 5 Represents a hydrogen atom;

[0014] R 6 Indicates methyl, ethyl, or phenyl;

[0015] R 7 Indicates a hydrogen atom or a methyl group;

[0016] R 8 It represents methyl, allyl, or phenylpropynyl, or unsubstituted or monosubstituted benzyl.

[0017] Furthermore, the 1-oxo-2,8-diazacyclic decanone derivative described in this invention can specifically be any one of the following compounds 3aa to 3al:

[0018] 3aa: R 1 =Ph,R 2 =CH2-CH2-Ph, R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0019] 3ba:R 1 =4-OMe-Ph,R 2 =CH2-CH2-4-OMe-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0020] 3ca:R 1 =4-Me-Ph,R 2 =CH2-CH2-4-Me-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0021] 3da:R 1 =4-Cl-Ph,R 2 =CH2-CH2-4-Cl-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0022] 3ea:R 1 =4-CF3-Ph,R 2 =CH2-CH2-4-CF3-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0023] 3fa:R 1 =3-Br-Ph,R 2 =CH2-CH2-3-Br-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0024] 3ga:R 1=2-Br-Ph,R 2 =CH2-CH2-2-Br-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0025] 3ha:R 1 =Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0026] 3ia:R 1 =Ph,R 2 =4-OMe-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0027] 3ja:R 1 =Ph,R 2 =4-F-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0028] 3ka:R 1 =Ph,R 2 =2-Br-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0029] 3la:R 1 =4-Br-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R7 =Me,R 8 =Bn;

[0030] 3ma:R 1 =4-CF3-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0031] 3na:R 1 =2-thienyl,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0032] 3oa:R 1 =Ph,R 2 =H,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0033] 3pa:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =H,R 4 =n-Bu,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0034] 3qa:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Ph,R 4 =Et,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0035] 3ra:R 1 =Ph,R 2=CH2-CH2-Ph,R 3 =Ph,R 4 =H,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0036] 3sa:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =H,R 4 =(CH2)4Cl,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0037] 3ta:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =H,R 4 =(CH2)3CO2Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0038] 3ua:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 +R 4 =Cyclopentane,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0039] 3va:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 +R 4 =Cyclohexane,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0040] 3wa:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 +R 4 =Cycloheptane,R 5=H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0041] 3xa:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 +R 4 =pyran,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0042] 3ya:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 +R 4 =spirocyclic,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0043] 3ab:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =CH2-4-OMe-Ph;

[0044] 3ac:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =CH2-4-Br-Ph;

[0045] 3ad:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =CH2-4-CF3-Ph;

[0046] 3ae:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =CH2-3-Me-Ph;

[0047] 3af:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =CH2-2-Me-Ph;

[0048] 3ag:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Me;

[0049] 3ah:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =allyl;

[0050] 3ai:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Phenylpropargyl;

[0051] 3aj:R 1 =Ph,R 2=CH2-CH2-Ph, R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =H,R 8 =Bn;

[0052] 3ak:R 1 =Ph,R 2 =CH2-CH2-Ph, R 3 =Me,R 4 =Me,R 5 =H,R 6 =Et,R 7 =H,R 8 =Bn;

[0053] 3al:R 1 =Ph,R 2 =CH2-CH2-Ph, R 3 =Me,R 4 =Me,R 5 =H,R 6 =Ph,R 7 =H,R 8 =Bn.

[0054] The method for synthesizing the 1-oxo-2,8-diazacyclic decanone derivative of the present invention mainly includes the following steps: taking the compound shown in formula (II) and the compound shown in formula (III) into an organic solvent, adding an alkaline substance and a catalyst, and reacting under heating or non-heating conditions to obtain the crude product of the target compound;

[0055]

[0056] in:

[0057] R 1 This indicates an unsubstituted or monosubstituted phenyl group, or an unsubstituted thiophene group; wherein the substituent is C. 1～6 Alkyl, alkoxy, or halogen atoms;

[0058] R 2 This represents a hydrogen atom, or an unsubstituted or monosubstituted phenyl group, or an unsubstituted or monosubstituted styrene group; wherein the substituent is C. 1～6 Alkyl, alkoxy, or halogen atoms;

[0059] R 3 Represents a hydrogen atom, methyl, ethyl, n-butyl, or halogen atom, or a substituted C atom. 1～6 Alkyl groups;

[0060] R4 Represents a hydrogen atom or a phenyl group, or an unsubstituted or monosubstituted C atom. 1～4 Alkyl groups, or unsubstituted or monosubstituted C4 groups. 1～4 alkoxy groups;

[0061] R 5 Represents a hydrogen atom;

[0062] R 6 Indicates methyl, ethyl, or phenyl;

[0063] R 7 Indicates a hydrogen atom or a methyl group;

[0064] R 8 It represents methyl, allyl or phenylpropynyl, or unsubstituted or monosubstituted benzyl;

[0065] X represents a bromine atom or a chlorine atom.

[0066] To further improve the yield of the target compound, the reaction is preferably carried out under an inert atmosphere (such as nitrogen, argon or helium).

[0067] In the above synthesis method, the reaction is preferably carried out at a temperature below 100°C, and more preferably at a temperature between room temperature and 80°C. The reaction is monitored by TLC until it is complete. Based on the applicant's experience, when the reaction is carried out at room temperature or room temperature, a reaction time of 10–20 hours is suitable.

[0068] In the above synthesis method, the organic solvent can be selected from one or more combinations of benzene, toluene, cyclohexane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, dichloromethane, acetone, chloroform, n-hexane, and dioxane; preferably acetonitrile, toluene, or tetrahydrofuran. The amount of organic solvent can be determined as needed, usually to the extent that it can fully dissolve the reactants. Specifically, based on 0.1 mmol of the compound shown in formula (II), the total amount of organic solvent used for all reactants is usually 1 to 5 mL.

[0069] In the above synthesis method, the alkaline substance can be a conventional choice from the prior art, preferably selected from one or more combinations of tripotassium phosphate, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, pyridine, triethylamine, and N,N-diisopropylethylamine; more preferably potassium carbonate or cesium carbonate. The amount of the catalyst is preferably 0.1 to 2.0 times the amount of the compound shown in formula (II).

[0070] In the above synthesis method, the catalyst can be one or a combination of two or more selected from copper salts, ytterbium salts, and scandium salts. Preferably, the copper salt is selected from one or a combination of two or more selected from copper bromide, copper iodide, copper chloride, copper sulfate, acetone, copper trifluoromethanesulfonate, cuprous bromide, cuprous iodide, and cuprous chloride; the ytterbium salt is preferably ytterbium trifluoromethanesulfonate; and the scandium salt is preferably scandium trifluoromethanesulfonate. The amount of catalyst used is preferably 0.1 to 0.2 times the amount of the compound shown in formula (II).

[0071] In the synthetic method described in this invention, the compound represented by formula (II) is an N-alkenyl α,β-unsaturated nitrone derivative, which can be synthesized with reference to existing literature (D. Kontokosta, DS Muller, DL Mo, WHPace, RA Simpon, LL Anderson, Beilstein J. Org, Chem. 2015, 11, 2097) or by designing a synthetic route of your choice, which will not be detailed here. The compound represented by formula (III) is an α-haloamide reagent, which can be directly purchased from the market (such as 2-bromo-2-methyl-N-benzylpropionamide, 2-bromo-2-methyl-N-benzylacetamide, 2-bromo-2-methyl-N-methoxypropionamide, etc.), or can be synthesized with reference to existing literature (Chin. J. Org. Chem. 2019, 39, 1970-1975).

[0072] In the synthesis method described in this invention, the proportions of each raw material are stoichiometric.

[0073] The method described above yields a crude product of compound (I), and the process also includes a purification step. Specifically, conventional purification methods can be used to improve the purity of compound (I), such as silica gel thin-layer chromatography or silica gel column chromatography, or recrystallization. The eluent used in chromatography is the same as the solvent used in recrystallization, which can be a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 10:1, or a mixed solvent of n-hexane and ethyl acetate in a volume ratio of 20:1 to 10:1.

[0074] The applicant discovered through experiments that the 1-oxo-2,8-diazacyclic decanone derivative of the present invention has good anti-inflammatory activity. Based on this, the present invention also provides the use of the above-mentioned 1-oxo-2,8-diazacyclic decanone derivative or its pharmaceutically acceptable salt in the preparation of medicaments for treating inflammation, and further, its use in the preparation of medicaments for treating inflammation caused by lipopolysaccharides.

[0075] Furthermore, the present invention also includes a pharmaceutical composition comprising a therapeutically effective dose of the above-described 1-oxo-2,8-diazacyclic decanone derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and at least one pharmaceutically acceptable carrier.

[0076] Compared with existing technologies, this invention provides a series of novel 1-oxo-2,8-diazacyclic decanone derivatives and their synthetic methods. The applicant's experimental results show that some of the target compounds of this invention have a good inhibitory effect on the release of NO in lipopolysaccharide-induced mouse RAW 264.7 macrophages, and can be used to prepare drugs for treating inflammation. Detailed Implementation

[0077] To better explain the technical solution of the present invention, the present invention will be further described in detail below with reference to the embodiments, but the implementation of the present invention is not limited thereto.

[0078] The N-alkenyl α,β-unsaturated nitrone derivatives (i.e., compounds represented by formula (II)) involved in the following embodiments were synthesized according to the following synthetic route:

[0079]

[0080] in,

[0081] R 1 This indicates an unsubstituted or monosubstituted phenyl group, or an unsubstituted thiophene group; wherein the substituent is C. 1～6 Alkyl, alkoxy, or halogen atoms;

[0082] R 2 This represents a hydrogen atom, or an unsubstituted or monosubstituted phenyl group, or an unsubstituted or monosubstituted styrene group; wherein the substituent is C. 1～6 Alkyl, alkoxy, or halogen atoms;

[0083] R 3 Represents a hydrogen atom, methyl, ethyl, n-butyl, or halogen atom, or a substituted C atom. 1～6 Alkyl groups;

[0084] R 4 Represents a hydrogen atom or a phenyl group, or an unsubstituted or monosubstituted C atom. 1～4 Alkyl groups, or unsubstituted or monosubstituted C4 groups. 1～4 alkoxy groups;

[0085] R 5 It represents a hydrogen atom.

[0086] The specific synthesis method is as follows: Cu(OAc)2 (0.3 mmol, 54 mg), α,β-unsaturated oxime substrate S1 (0.3 mmol) and alkenylboronic acid S2 (0.9 mmol) are placed in a reaction tube, 3 mL of 1,2-dichloroethane is added, and then pyridine (3 mmol, 0.24 mL) is added. The mixture is stirred at 25 °C for 12–24 h. Water (10 mL) is added to the resulting reaction mixture, and the mixture is extracted with dichloromethane (2 × 10 mL). The organic phases are combined, dried with anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure. The residue is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1–1:1, volume ratio) to obtain product 1 (i.e., the N-alkenyl α,β-unsaturated nitrone shown in formula (II)).

[0087] The α-haloamide reagents (i.e., the compounds shown in formula (III)) involved in the following examples were synthesized according to the following synthetic route:

[0088]

[0089] Among them, R 6 Indicates methyl, ethyl, or phenyl; R 7 Represents a hydrogen atom or a methyl group; R 8 It represents methyl, allyl, or phenylpropynyl, or an unsubstituted or monosubstituted benzyl group; X represents a bromine atom.

[0090] The specific synthesis method is as follows: Benzyloxyhydroxylamine hydrochloride S4 (2.0 g, 12.5 mmol, 1.0 eq), dichloromethane (50 mL), and triethylamine (1.75 mL, 12.5 mmol, 1.0 eq) were added to a 100 mL round-bottom flask, and the reaction mixture was then cooled to 0 °C in an ice-water bath. Next, α-haloacyl bromide compound S3 (12.5 mmol, 1.0 eq) was added dropwise to the reaction mixture, and the mixture was stirred at 0 °C for 4 h. The mixture was then moved to room temperature and stirred for 5 min; the reaction was then quenched with water. The resulting mixture was extracted three times with dichloromethane, then once with saturated sodium chloride solution, filtered, and concentrated under vacuum. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1 to 1:1, volume ratio) to give product 2 (i.e., the α-haloamide reagent shown in formula (III)).

[0091] Example 1

[0092] The 1-oxo-2,8-diazacyclic decanone derivatives of this invention were synthesized according to the following synthetic route.

[0093]

[0094] 3aa: R 1 =Ph,R 2=CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0095] 3ba:R 1 =4-OMe-Ph,R 2 =CH2-CH2-4-OMe-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0096] 3ca:R 1 =4-Me-Ph,R 2 =CH2-CH2-4-Me-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0097] 3da:R 1 =4-Cl-Ph,R 2 =CH2-CH2-4-Cl-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0098] 3ea:R 1 =4-CF3-Ph,R 2 =CH2-CH2-4-CF3-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0099] 3fa:R 1 =3-Br-Ph,R 2 =CH2-CH2-3-Br-Ph,R 3 =Me,R 4=Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0100] 3ga:R 1 =2-Br-Ph,R 2 =CH2-CH2-2-Br-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0101] 3ha:R 1 =Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0102] 3ia:R 1 =Ph,R 2 =4-OMe-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0103] 3ja:R 1 =Ph,R 2 =4-F-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0104] 3ka:R 1 =Ph,R 2 =2-Br-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0105] 3la:R 1 =4-Br-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0106] 3ma:R 1 =4-CF3-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0107] 3na:R 1 =2-thienyl,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0108] 3oa:R 1 =Ph,R 2 =H,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0109] 3pa:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =H,R 4 =n-Bu,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0110] 3qa:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Ph,R 4 =Et,R 5 =H,R6 =Me,R 7 =Me,R 8 =Bn;

[0111] 3ra:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Ph,R 4 =H,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0112] 3sa:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =H,R 4 =(CH2)4Cl,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0113] 3ta:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =H,R 4 =(CH2)3CO2Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0114] 3ua:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 +R 4 =Cyclopentane,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0115] 3va:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 +R 4 =Cyclohexane,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0116] 3wa:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 +R 4 =Cycloheptane,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0117] 3xa:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 +R 4 =pyran,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0118] 3ya:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 +R 4 =spirocyclic,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Bn;

[0119] 3ab:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =CH2-4-OMe-Ph;

[0120] 3ac:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =CH2-4-Br-Ph;

[0121] 3ad:R 1 =Ph,R 2 =CH2-CH2-Ph,R3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =CH2-4-CF3-Ph;

[0122] 3ae:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =CH2-3-Me-Ph;

[0123] 3af:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =CH2-2-Me-Ph;

[0124] 3ag:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =Me;

[0125] 3ah:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =Me,R 8 =allyl;

[0126] 3ai:R 1 =Ph,R 2 =CH2-CH2-Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6=Me,R 7 =Me,R 8 =Phenylpropargyl;

[0127] 3aj:R 1 =Ph,R 2 =CH2-CH2-Ph, R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R 7 =H,R 8 =Bn;

[0128] 3ak:R 1 =Ph,R 2 =CH2-CH2-Ph, R 3 =Me,R 4 =Me,R 5 =H,R 6 =Et,R 7 =H,R 8 =Bn;

[0129] 3al:R 1 =Ph,R 2 =CH2-CH2-Ph, R 3 =Me,R 4 =Me,R 5 =H,R 6 =Ph,R 7 =H,R 8 =Bn.

[0130] The specific synthesis method was as follows: Under an argon atmosphere, N-alkenyl α,β-unsaturated nitroketone substrate 1 (0.2 mmol), α-haloamide reagent 2 (0.4 mmol, where X represents a bromine atom in the structural formula of this raw material), copper trifluoromethanesulfonate (0.04 mmol), and potassium carbonate (0.4 mmol) were placed in a reaction tube, and acetonitrile (2 mL) was added. The mixture was stirred at room temperature for 10–20 h (TLC monitoring until complete). The solvent was removed from the obtained reactants under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1–10:1, volume ratio) to obtain target product 3 (i.e., the 1-oxo-2,8-diazacyclic decanone derivative shown in formula (I)). Different target products and their characterization are as follows:

[0131] 3aa: solid, 66mg, 67% yield; MP: 131–132℃; 1H NMR (400MHz, CDCl3): δ7.46-7.40(m,4H),7.35-7.24(m,8H),7.19-7.13(m,3H),6.72(d,J=16.4Hz,1H),6.65(d,J=16.0Hz,1H),5.78 (d,J=10.8Hz,1H),4.78(s,2H),3.55-3.49(m,1H),3.42-3.36(m,1H),1.77(s,3H),1.76(s,3H),1.59(s,3H),0.78(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ173.2,159.8,140.0,136.9,135.1,134.7,133.8,131.9,129.4,129.0,128.6,128.2,128.0,127.8,1 27.7,127.2,126.6,120.3,84.8,74.7,48.7,39.4,28.7,24.6,17.3,14.5; IR(thinfilm)3441,2976,1660,1370,964,695cm -1 HRMS(ESI)m / z calcd for C 32 H 35 N₂O₃(M+H) + 495.2642, found 495.2655. Its structure is as follows:

[0132]

[0133] 3ba: Oily, 40mg, 36% yield. 1 H NMR (400MHz, CDCl3): δ7.40-7.38(m,2H),7.31-7.30(m,2H),7.21-7.18(m,5H) ,6.96-6.94(m,2H),6.89-6.87(m,2H),6.65(d,J=16.0Hz,1H),6.50(d,J=16.4 Hz,1H),5.72(d,J=10.8Hz,1H),4.77(s,2H),3.85(s,3H),3.82(s,3H),3.49-3 .41(m,1H),3.38-3.32(m,1H),1.76(s,3H),1.58(s,6H),0.78(d,J=7.2Hz,3H); 13C NMR (150MHz, CDCl3): δ173.3,160.0,159.4,158.6,135.2,134.0,133.7,132.1,131.3,129.7,129.5,128. 7,128.3,128.0,127.8,118.3,114.4,114.1,84.7,74.5,55.3,47.8,39.6,28.7,24.6,17.4,14.5;IR(thin film)3465,2935,1645,1250,923,639cm -1 HRMS(ESI)m / z calcd for C 34 H 39 N₂O₅(M+H) + 555.2853, found 555.2839. Its structure is as follows:

[0134]

[0135] 3ca: solid, 68mg, 65% yield. MPa: 71-72℃; 1 H NMR (400MHz, CDCl3): δ7.36(d,J=8.0Hz,2H),7.31(d,J=6.8Hz,2H),7.24-7.13(m,9H),6.68-6.56(m,2H),5.78(d,J=10.8Hz,1H),4.76 (s,2H),3.51-3.46(m,1H),3.40-3.35(m,1H),2.39(s,3H),2.34(s,3H),1.76(s,3H),1.75(s,3H),1.58(s,3H),0.78(d,J=6.4Hz,3H); 13 C NMR (100MHz, CDCl3): δ173.3,160.0,137.8,137.1,136.8,135.2,134.4,134.2,133.7,131.8,129.7,129.4,1 29.3,128.2,128.0,127.7,126.5,119.4,84.7,74.5,48.3,39.5,28.7,24.6,21.2,21.2,17.3,14.5;IR(thin film)3273,2931,1650,1372,965,639cm -1 ;HRMS(ESI)m / z calcd forC 34 H 39 N₂O₃(M+H) +523.2955, found 523.2968. Its structure is as follows:

[0136]

[0137] 3da: Solid, 62mg, 55% yield. MP: 152-153℃; 1 H NMR (400MHz, CDCl3): δ7.41-7.36(m,4H),7.31-7.26(m,4H),7.22-7.12(m,5H),6.64(d,J=16.4Hz,1H),6.57(d,J=16.0Hz,1H),5.66 (d,J=10.8Hz,1H),4.79(s,2H),3.49-3.41(m,1H),3.36-3.30(m,1H),1.75(s,3H),1.73(s,3H),1.57(s,3H),0.78(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ173.3,159.4,138.5,135.3,135.1,134.4,134.0,133.5,133.0,130.7,129.5,129.2,129.1,128.9,1 28.4,128.0,127.7,120.6,84.9,74.8,48.1,39.3,28.8,24.5,17.3,14.4; IR(thinfilm)3444,2981,1656,1264,965,694cm -1 HRMS(ESI)m / z calcd for C 32 H 33 Cl2N2O3(M+H) + 563.1863, found 563.1846. Its structure is as follows:

[0138]

[0139] 3ea: solid, 79mg, 63% yield. MPa: 147-148℃; 1H NMR (400MHz, CDCl3): δ7.71(d,J=8.0Hz,2H),7.60(d,J=8.4Hz,2H),7.55(d, J=8.0Hz,2H),7.42(d,J=7.6Hz,2H),7.29-7.26(m,2H),7.18-7.08(m,3H),6. 74-6.65(m,2H),5.70(d,J=10.8Hz,1H),4.80(s,2H),3.55-3.51(m,1H),3.4 9-3.39(m,1H),1.77(s,3H),1.75(s,3H),1.60(s,3H),0.80(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ173.3,159.1,144.0,140.2,135.0,134.8,134.3,130.7,129.6,128.4,128.2,128.0,12 6.7,126.1(q,J=37.9Hz),125.5(q,J=270.5Hz),122.3,85.0,75.0,48.6,39.1,28.8,24.4,17.3,14.4; IR(thin film)3469,2942,1661,1327,967,696cm -1 HRMS(ESI)m / z calcd for C 34 H 33 F6N2O3(M+H) + 631.2390, found 631.2401. Its structure is as follows:

[0140]

[0141] 3fa: Solid, 39mg, 30% yield. MPa: 100-101℃; 1 H NMR (400MHz, CDCl3): δ7.59(s,1H),7.48(d,J=8.0Hz,1H),7.41(s,1H),7.38-7.32(m,3H),7.30-7.26(m,3H),7.22-7.16(m,4H),6.61-6.52(m ,2H),5.62(d,J=11.2Hz,1H),4.80(s,1H),3.49-3.43(m,1H),3.41-3.2 7(m,1H),1.75(s,3H),1.73(s,3H),1.59(s,3H),0.80(d,J=6.8Hz,3H); 13C NMR (100MHz, CDCl3): δ173.3,159.2,142.2,139.0,135.1,134.6,134.1,131.0,130.7,130.6,130.5,130.4,130.2,12 9.6,129.0,128.4,128.0,126.3,125.5,123.0,122.9,121.3,84.9,75.0,48.3,39.1,28.8,24.4,17.2,14.4;IR(thin film)3456,2966,1641,1460,968,692cm -1 HRMS(ESI)m / z calcd for C 32 H 33 Br2N2O3(M+H) + 651.0852, found 651.0882. Its structure is as follows:

[0142]

[0143] 3g g: solid, 70mg, 54% yield. MPa: 170-171℃; 1 H NMR (400MHz, CDCl3): δ7.64 (d, J = 7.6Hz, 1H), 7.57-7.54 (m, 2H), 7.43-7.3 9(m,1H),7.35-7.28(m,4H),7.20-7.11(m,5H),7.09-7.05(m,1H),6.60(d ,J=16.0Hz,1H),5.50(d,J=10.4Hz,1H),4.83(s,2H),4.17-4.11(m,1H),3 .54(s,1H),1.81(s,3H),1.79(s,3H),1.61(s,3H),0.81(d,J=6.8Hz,3H); 13 CNMR (100MHz, CDCl3): δ173.1,159.4,139.3,137.0,135.3,134.8,133.6,133.2,132.0,129.5,129.0,128.4,128. 3,128.1,127.9,127.5,126.9,126.7,125.8,124.1,123.8,84.9,75.0,46.4,39.1,28.6,24.7,17.3,13.7;IR(thin film)3478,2963,1663,1262,804,698cm -1 HRMS(ESI)m / z calcd for C32 H 33 Br2N2O3(M+H) + 651.0852, found 651.0880. Its structure is as follows:

[0144]

[0145] 3ha: solid, 76mg, 81% yield. MPa: 123-124℃; 1 H NMR (400MHz, CDCl3): δ7.43-7.36(m,5H),7.33-7.27(m,6H),7.11-7.06(m,4H),5.86(d,J=10.8Hz,1H),4.75(d,J=10.4Hz,1H ),4.68(d,J=10.8Hz,1H),3.50-3.45(m,1H),3.42-3.37(m,1H),1.90(s,3H),1.65(s,3H),1.13(s,3H),0.57(d,J=5.6Hz,3H); 13 C NMR (100MHz, CDCl3): δ172.9,160.4,139.9,136.2,135.0,133.8,130.9,129.8,129.2,129.0 ,128.1,128.0,127.8,127.6,127.0,84.3,74.6,48.5,39.0,28.6,25.0,16.0,14.1; IR(thin film)3482,2916,1662,1371,917,704cm -1 HRMS(ESI)m / z calcd for C 30 H 33 N₂O₃(M+H) + 469.2486, found 469.2486. Its structure is as follows:

[0146]

[0147] 3ia: Solid, 59mg, 59% yield. MPa: 113-114℃; 1H NMR (400MHz, CDCl3): δ7.44-7.40(m,2H),7.33-7.24(m,5H),7.12-7.09(m,5H),6.93(d,J=8.4Hz,2H),5.78(d,J=11.2Hz,1H),4.74(d,J=10.4H z,1H),4.67(d,J=10.4Hz,1H),3.83(s,3H),3.51-3.46(m,1H),3.41-3. 35(m,1H),1.88(s,3H),1.64(s,3H),1.19(s,3H),0.59(d,J=6.4Hz,3H); 13 C NMR (100MHz, CDCl3): δ173.0,160.6,159.3,140.2,135.9,135.1,131.1,129.8,129.3,129.0,128. 1,127.9,127.7,127.0,126.3,113.6,84.4,74.6,55.2,48.6,39.2,28.7,25.1,16.3,14.2;IR(thin film)3499,2971,1647,1372,910,699cm -1 ;HRMS(ESI)m / z calcd forC 31 H 35 N₂O₄(M+H) + 499.2591, found 499.2603. Its structure is as follows:

[0148]

[0149] 3ja: Solid, 83mg, 85% yield. MPa: 77-78℃; 1 H NMR (500MHz, CDCl3): δ7.44-7.41(m,2H),7.35-7.32(m,1H),7.30-7.28(m,2H), 7.27-7.25(m,3H),7.13(s,1H),7.12-7.11(m,2H),7.10-7.07(m,3H),5.85(d,J= 11.0Hz,1H),4.73(d,J=10.0Hz,1H),4.68(d,J=10.5Hz,1H),3.50-3.45(m,1H), 3.33-3.28(m,1H),1.88(s,3H),1.65(s,3H),1.19(s,3H),0.60(d,J=7.0Hz,3H); 13CNMR (125MHz, CDCl3): δ173.0,163.4(d,J=246.9Hz),160.5,139.8,135.4,135.0,131.7(d,J=8.3Hz),130.9,130.1,1 30.0,129.4,129.1,128.3,128.0,127.7,127.2,115.4(d,J=21.9Hz),84.5,74.8,48.7,39.2,28.7,25.1,16.3,14.2; 19 FNMR(470MHz, CDCl3)δ-112.8; IR(thin film)3658,2964,1651,1371,911,697cm -1 HRMS(ESI)m / z calcd for C 30 H 32 FN2O3(M+H) + 487.2391, found 487.2400. Its structure is as follows:

[0150]

[0151] 3ka: solid, 105mg, 96% yield. MPa: 60-61℃; 1 H NMR (400MHz, CDCl3): δ7.64-7.62(m,1H),7.45(d,J=7.6Hz,1H),7.39-7.34(m,4 H),7.32-7.30(m,2H),7.25(s,2H),7.21-7.20(m,3H),7.16-7.11(m,1H),6.27(d ,J=11.6Hz,1H),4.85(d,J=9.6Hz,1H),4.75(d,J=9.6Hz,1H),3.49-3.41(m,1H), 3.07-3.01(m,1H),1.90(s,3H),1.66(s,3H),1.28(s,3H),0.58(d,J=6.8Hz,3H); 13C NMR (100MHz, CDCl3): δ172.6,160.6,139.5,134.7,133.9,133.2,133.1,132.9,131.9,129.6,129.4,12 8.6,128.5,128.3,128.0,127.4,127.0,124.4,84.7,74.8,49.7,39.9,28.8,25.1,16.9,14.3;IR(thin film)3468,2130,1640,1383,909,694cm -1 HRMS(ESI)m / z calcd for C 30 H 32 BrN2O3(M+H) + 547.1591, found 547.1605. Its structural formula is as follows:

[0152]

[0153] 3la: Solid, 0.069 mg, 63% yield. MPa: 60-61℃; 1 H NMR (500MHz, CDCl3): δ7.48-7.46(m,1H),7.41-7.38(m,3H),7.33(d,J=8.0Hz, 1H),7.30-7.26(m,3H),7.21(d,J=7.5Hz,1H),7.15-7.09(m,5H),5.70(d,J=11 .5Hz,1H),4.78(d,J=10.5Hz,1H),4.70(d,J=11.0Hz,1H),3.45-3.41(m,1H),3 .35-3.31(m,1H),1.89(s,3H),1.66(s,3H),1.12(s,3H),0.59(d,J=6.5Hz,3H); 13 C NMR (125MHz, CDCl3): δ173.0,160.0,142.6,137.0,135.2,133.7,130.8,130.6,130.2,130.0,129.8 ,129.5,128.3,128.2,127.9,126.3,123.0,84.6,75.0,48.3,39.0,28.8,25.1,16.1,14.1; IR(thin film)3488,2967,1649,1325,911,693cm -1 HRMS(ESI)m / z calcd for C 30 H 32BrN2O3(M+H) + 547.1591, found 547.1591. Its structure is as follows:

[0154]

[0155] 3ma: Solid, 78mg, 73% yield. MPa: 70-71℃; 1 H NMR (500MHz, CDCl3): δ7.70-7.68(m,2H),7.42-7.39(m,4H),7.35-7.32(m,1H),7.30-7.26(m,3H),7.13-7.10(m,4H),5.73(d,J=10.5H z,1H),4.76(d,J=10.5Hz,1H),4.68(d,J=10.5Hz,1H),3.49-3.44(m,2H),1.89(s,3H),1.65(s,3H),1.14(s,3H),0.59(d,J=6.5Hz,3H); 13 C NMR (125MHz, CDCl3): δ173.0,160.0,144.4,137.2,135.2,133.7,129.9,129.7,129.5,129.4,1 28.4,128.3,128.2,128.1,127.9,126.0,125.9,84.7,75.0,48.6,39.0,28.8,25.1,16.2,14.2; 19 F NMR (470MHz, CDCl3) δ-62.4; IR (thin film) 3645, 2962, 1654, 1325, 805, 699cm -1 HRMS(ESI)m / zcalcd for C 31 H 32 F3N2O3(M+H) + 537.2360, found 537.2368. Its structure is as follows:

[0156]

[0157] 3na: solid, 42mg, 44% yield. MPa: 53-54℃; 1H NMR (400MHz, CDCl3): δ7.40-7.37(m,2H),7.33-7.26(m,4H),7.19-7.15(m,5H),7.05-7.03(m,1H),6.94(d,J=2.8Hz,1H),5.81(d,J=11.2Hz,1H),4 .78(d,J=10.4Hz,1H),4.70(d,J=10.8Hz,1H),3.77-3.72(m,1H),3.39-3 .35(m,1H),1.87(s,3H),1.61(s,3H),1.12(s,3H),0.70(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ173.1,160.2,143.5,136.5,135.1,133.7,130.5,129.8,129.5,128.4,12 8.3,128.2,128.0,127.0,124.8,124.1,84.6,74.8,44.2,40.5,28.7,25.1,16.2,14.2;IR(thin film)3664,2968,1654,1369,910,698cm -1 HRMS(ESI)m / z calcd for C 28 H 31 N₂O₃S(M+H) + 475.2050, found 475.2064. Its structure is as follows:

[0158]

[0159] 3oa: Solid, 30mg, 38% yield. 1 H NMR (400MHz, CDCl3): δ7.37-7.30(m,4H),7.24-7.22(m,2H),7.20-7.19(m,1H),7.04-7.01(m,4H),5.79(d,J=10.8Hz,1H),4. 68(d,J=10.0Hz,1H),4.61(d,J=10.4Hz,1H),3.43-3.30(m,2H),1.82(s,3H),1.58(s,3H),1.06(s,3H),0.52(d,J=6.8Hz,3H); 13C NMR (100MHz, CDCl3): δ173.0,160.6,140.0,136.3,135.1,133.9,131.0,129.9,129.4,129.0 ,128.3,128.2,127.9,127.7,127.1,84.5,74.7,48.6,39.2,28.7,25.1,16.2,14.1; IR(thin film)3465,2971,1743,1263,905,697cm -1 HRMS(ESI)m / z calcd for C 24 H 29 N₂O₃(M+H) + 393.2173, found 393.2162. Its structural formula is as follows:

[0160]

[0161] 3pa: solid, 53mg, 51% yield. MPa: 149-150℃; 1 H NMR (500MHz, CDCl3): δ7.46(d,J=7.5Hz,2H),7.41(d,J=7.5Hz,2H),7.35-7.32( m,3H),7.30-7.24(m,5H),7.18-7.11(m,3H),6.68(s,2H),6.56(d,J=7.0Hz,1H) ,5.74(d,J=11.0Hz,1H),4.79(s,2H),3.45-3.41(m,1H),3.23-3.18(m,1H),1.7 5(s,3H),1.61(s,3H),1.26-1.18(m,4H),1.12-1.07(m,2H),0.77-0.74(m,3H); 13 C NMR (125MHz, CDCl3): δ173.2,154.0,140.0,137.0,135.5,135.2,133.9,131.8,129.5,129.0,128.6,128.3,1 28.0,127.9,127.7,127.2,126.8,121.0,85.6,74.7,48.3,44.3,30.4,30.1,28.8,24.3,22.4,13.8;IR(thin film)3028,2938,1633,1454,958,693cm -1 HRMS(ESI)m / z calcd for C 34 H 39 N₂O₃(M+H)+ 523.2955, found 523.2965. Its structure is as follows:

[0162]

[0163] 3qa: Solid, 69mg, 61% yield. MPa: 87-88℃; 1 H NMR (500MHz, CDCl3): δ7.54(s,2H),7.44(d,J=6.5Hz,2H),7.37(d,J=7.5Hz,1H),7.34(d,J=7.0Hz ,1H),7.30(d,J=7.0Hz,2H),7.24-7.19(m,4H),7.17(s,1H),7.16(d,J=3.5Hz,1H),7.15-7.12(m,3 H),6.95(s,1H),6.56(d,J=15.0Hz,1H),6.45(d,J=13.5Hz,1H),5.88(d,J=10.0Hz,1H),4.83-4.78 (m,2H),4.09-4.04(m,1H),3.63(s,1H),1.84(s,3H),1.68(s,3H),1.42-1.26(m,2H),0.46(s,3H); 13 C NMR (125MHz, CDCl3): δ173.0,160.0,140.5,136.7,135.3,135.2,135.0,134.2,132.0,129.5,129.1,128.7,128.5,12 8.3,128.1,128.0,127.8,127.6,127.5,127.2,126.7,121.7,85.8,74.7,49.1,47.1,28.7,24.4,21.6,12.5; IR(thin film)3655,2904,1651,1451,966,696cm -1 HRMS(ESI)m / z calcd for C 38 H 39 N₂O₃(M+H) + 571.2955, found 571.2969. Its structure is as follows:

[0164]

[0165] 3ra: solid, 71mg, 66% yield. MPa: 87-88℃; 1H NMR (500MHz, CDCl3): δ7.63 (d, J = 7.5Hz, 2H), 7.45-7.42 (m, 2H), 7.36-7.33 (m ,5H),7.28-7.20(m,5H),7.16-7.13(m,4H),6.93(d,J=6.0Hz,2H),6.67(d,J=1 5.5Hz,1H),6.41(d,J=16.0Hz,1H),5.82(d,J=11.0Hz,1H),4.87(s,2H),4.00 -3.94(m,1H),3.49-3.45(m,1H),2.96-2.93(m,1H),1.84(s,3H),1.64(s,3H); 13 C NMR (125MHz, CDCl3): δ173.4,155.2,141.2,136.8,135.5,135.4,135.0,134.8,131.2,129.5,129.4,129.0,128 .6,128.4,128.3,128.2,127.6,127.3,127.1,126.8,126.1,121.4,86.2,74.9,42.2,33.8,29.0,24.5;IR(thin film)3489,2930,1655,1450,958,693cm -1 HRMS(ESI)m / z calcd for C 36 H 35 N2O3(M+K) + 543.2642, found 543.2662. Its structure is as follows:

[0166]

[0167] 3sa: solid, 33mg, 30% yield. MPa: 136-137℃; 1 H NMR (400MHz, CDCl3): δ7.46-7.40(m,4H),7.35-7.32(m,3H),7.30-7.26( m,5H),7.18-7.12(m,3H),6.72-6.64(m,2H),6.57(d,J=6.8Hz,1H),5.73( d,J=11.2Hz,1H),4.79(s,2H),3.47-3.36(m,3H),3.22(s,1H),1.75(s,3 H),1.71-1.66(m,1H),1.62(s,3H),1.45-1.39(m,1H),1.29-1.21(m,3H); 13C NMR (100MHz, CDCl3): δ173.1,153.5,139.7,136.9,135.1,134.0,132.0,129.5,129.1,128.6,128.3,128. 0,127.9,127.7,127.4,126.8,120.8,85.7,74.8,48.2,44.5,44.2,32.1,30.0,28.7,25.2,24.3;IR(thin film)3448,2940,1642,1453,967,694cm -1 ;HRMS(ESI)m / z calcdfor C 34 H 38 ClN2O3(M+H) + 557.2565, found 557.2573. Its structure is as follows:

[0168]

[0169] 3ta: solid, 35mg, 31% yield. MPa: 130-131℃; 1 H NMR (400MHz, CDCl3): δ7.38-7.32(m,4H),7.28-7.24(m,3H),7.22-7.17(m,5H), 7.10-7.02(m,3H),6.64(d,J=16.4Hz,1H),6.60(d,J=16.4Hz,1H),6.51(d,J=6. 8Hz,1H),5.64(d,J=11.2Hz,1H),4.71(s,2H),3.49(s,3H),3.3-3.33(m,1H),3. 17-3.12(m,1H),2.14-1.99(m,2H),1.67(s,3H),1.53(s,3H),1.34-1.09(m,4H); 13 C NMR (100MHz, CDCl3): δ173.3,173.1,153.3,139.6,136.8,135.1,135.0,134.0,131.9,129.4,129.1,128.6,128. 3,128.0,127.9,127.6,127.3,126.7,120.7,85.6,74.7,51.4,48.1,44.0,33.5,30.0,28.7,24.2,23.2;IR(thin film)3475,2934,1650,1352,969,694cm -1 HRMS(ESI)m / z calcd for C35 H 39 Cl2N2O5(M+H) + 567.2853, found 567.2831. Its structure is as follows:

[0170]

[0171] 3ua: Solid 81mg, 80% yield. MPa: 136-137℃; 1 H NMR (400MHz, CDCl3): δ7.46-7.40(m,5H),7.36-7.30(m,6H),7.27-7.23(m ,1H),7.20-7.14(m,3H),6.75-6.67(m,2H),5.83(d,J=10.8Hz,1H),4.80( s,2H),3.63-3.57(m,1H),3.41-3.38(m,1H),2.46-2.40(m,1H),2.32-2.2 3(m,1H),1.91-1.79(m,3H),1.75(s,3H),1.68-1.66(m,1H),1.61(s,3H); 13 C NMR (100MHz, CDCl3): δ173.1,167.2,140.8,136.9,135.1,134.8,133.3,131.7,129.4,129.0,128.7,128. 3,128.0,127.9,127.8,127.2,126.5,120.1,85.0,74.8,47.3,46.6,30.4,29.6,29.0,24.5,22.1;IR(thin film)3459,2938,1754,1376,966,709cm -1 HRMS(ESI)m / zcalcd for C 33 H 35 N₂O₃(M+H) + 507.2642, found 507.2639. Its structure is as follows:

[0172]

[0173] 3va: solid, 73mg, 70% yield. MPa: 70-71℃; 1H NMR (500MHz, CDCl3): δ7.46-7.41(m,4H),7.36-7.33(m,3H),7.29-7.28(m,4H),7.25(d ,J=5.5Hz,1H),7.18-7.12(m,3H),6.70-6.63(m,2H),5.78(d,J=11.0Hz,1H),4.80-4.7 5(m,2H),3.78-3.74(m,1H),3.55-3.52(m,1H),2.30(d,J=15.5Hz,1H),2.21-2.16(m,1 H),1.77(s,3H),1.57(s,3H),1.45-1.41(m,2H),1.39-1.34(m,2H),1.32-1.26(m,2H); 13 C NMR (125MHz, CDCl3): δ173.7,160.0,140.0,136.9,135.3,135.2,134.0,132.1,129.5,129.1,128.7,128.3,128.0,127.9,127.8, 127.2,126.7,120.5,84.8,74.6,45.4,40.8,29.2,29.0,25.5,24.8,24.4,21.0; IR(thinfilm)3482,2936,1647,1370,967,696cm -1 HRMS(ESI)m / z calcd for C 34 H 37 N2O3(M+K) + 521.2799, found 521.2817. Its structure is as follows:

[0174]

[0175] 3wa: Solid, 99mg, 93% yield. MPa: 64-65℃; 1 H NMR (400MHz, CDCl3): δ7.45-7.39(m,4H),7.36-7.23(m,8H),7.19-7.13(m,3H),6.70-6.59(m,2H),5.77(q,J=10.0Hz,1H),4.77(s,1H),3 .44-3.37(m,1H),2.30-2.25(m,1H),2.19-2.13(m,1H),1.84(d,J=5.2Hz,1H),1.77(s,3H),1.61(s,3H),1.59(s,3H),1.29-1.21(m,4H); 13C NMR (100MHz, CDCl3): δ173.3,164.1,140.4,137.1,135.2,135.0,133.4,131.5,129.5,129.0,128.7,128.3,128.0, 127.8,127.7,127.1,126.6,120.4,84.8,82.9,74.7,49.0,46.3,32.0,30.9,30.1,29.6,28.7,26.8,24.6;IR(thin film)3455,2967,1639,1374,814,693cm -1 ;HRMS(ESI)m / z calcdfor C 35 H 39 N₂O₃(M+H) + 535.2955, found 535.2951. Its structure is as follows:

[0176]

[0177] 3xa: solid, 79mg, 76% yield. MPa: 53-54℃; 1 H NMR (400MHz, CDCl3): δ7.48-7.42(m,4H),7.37-7.27(m,8H),7.20-7.14(m,3H),6.76-6.65(m,2H),5.81(d,J=11.2Hz,1H),4.82-4.76(m ,2H),4.07-3.97(m,2H),3.56(d,J=12.4Hz,1H),3.42-3.24(m,3H),2.61-2.53(m,1H),2.24(d,J=15.6Hz,1H),1.78(s,3H),1.59(s,3H); 13 C NMR (100MHz, CDCl3): δ173.3,155.5,139.0,136.6,135.1,134.3,134.2,132.4,129.5,129.2,128.7,1 28.3,128.0,127.9,127.5,126.7,120.1,85.1,74.7,67.4,66.5,44.3,42.7,29.3,28.9,24.4;IR(thin film)3477,2964,1648,1370,909,696cm -1 HRMS(ESI)m / z calcd for C 33 H 35 N₂O₄(M+H) +523.2591, found 523.2604. Its structure is as follows:

[0178]

[0179] 3ya: solid, 52mg, 45% yield. MPa: 187-188℃; 1 H NMR (400MHz, CDCl3): δ7.48-7.47(m,2H),7.44-7.40(m,2H),7.37-7.24(m,9H),7.18-7.11(m ,2H),6.79(d,J=16.0Hz,1H),6.67(d,J=16.0Hz,1H),5.73(d,J=11.2Hz,1H),4.77(s,2H),4.1 5-4.09(m,1H),4.03-4.02(m,1H),3.84-3.78(m,3H),3.69-3.66(m,1H),2.67-2.50(m,2H),2. 34-2.31(m,1H),2.03-2.00(m,1H),1.77(s,3H),1.72-1.64(m,1H),1.61(s,1H),1.59(s,3H); 13 C NMR (100MHz, CDCl3): δ173.4,158.2,140.2,137.9,136.9,135.8,135.2,134.1,131.7,129.4,129.3,129.0,128.8,128.7,128.6,128.3 ,128.2,128.0,127.8,127.1,126.7,120.3,108.3,85.0,78.1,74.7,64.8,64.1,46.1,40.4,33.7,32.4,28.9,27.3,24.4,18.4; IR(thin film)3468,2962,1740,1262,981,694cm -1 HRMS(ESI)m / z calcd for C 36 H 39 N₂O₅(M+H) + 579.2853, found 579.2845. Its structural formula is as follows:

[0180]

[0181] 3ab: Solid, 68mg, 65% yield. MPa: 130-131℃; 1H NMR (400MHz, CDCl3): δ7.46-7.40(m,4H),7.36-7.26(m,6H),7.25-7.22(m,4H),6.72-6.63(m,4H),5.79(d,J=10.8Hz,1H),4.75 -4.69(m,2H),3.68(s,3H),3.52-3.48(m,1H),3.42-3.36(m,1H),1.77(s,3H),1.76(s,3H),1,61(s,3H),0.78(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ173.2,159.8,159.7,140.1,136.9,134.4,134.0,131.9,131.0,129.0,128.7,127. 8,127.7,127.3,127.2,126.6,120.4,113.4,84.8,74.3,55.1,48.8,39.6,28.8,24.6,17.3,14.5;IR(thin film)3465,2934,1650,1252,965,694cm -1 HRMS(ESI)m / z calcd for C 33 H 37 N₂O₄(M+H) + 525.2748, found 525.2756. Its structure is as follows:

[0182]

[0183] 3ac. Solid, 62mg, 54% yield. MP: 139-140℃; 1 H NMR (400MHz, CDCl3): δ7.46-7.41(m,4H),7.36-7.26(m,8H),7.19-7.17(m,2H),6.70(d,J=16.0Hz,1H),6.64(d,J=15.6Hz,1H),5 .84(d,J=11.2Hz,1H),4.75-4.69(m,2H),3.56-3.50(m,1H),3.43-3.38(m,1H),1.77(s,6H),1.60(s,3H),0.79(d,J=6.8Hz,3H); 13C NMR (100MHz, CDCl3): δ173.4,159.9,139.9,136.8,134.7,134.2,133.8.132.1,131.2,131.0,129.1,12 8.7,128.0,127.7,127.3,126.6,122.4,120.2,84.8,73.8,48.8,39.5,28.8,24.6,17.3,14.5;IR(thin film)3491,2972,1949,1374,966,690cm -1 HRMS(ESI)m / z calcd for C 32 H 34 BrN2O3(M+H) + 573.1747, found 573.1756. Its structure is as follows:

[0184]

[0185] 3ad: Solid, 68mg, 61% yield. MPa: 64-65℃; 1 H NMR (400MHz, CDCl3):7.48-7.40(m,8H),7.37-7.33(m,3H),7.31(d,J=8.0Hz,2H),7.26(s,1H),6.72-6.61(m,2H),5.87(d ,J=10.8Hz,1H),4.86-4.79(m,2H),3.54-3.50(m,1H),3.44-3.39(m,1H),1.77(s,6H),1.59(s,3H),0.79(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ173.6,159.9,139.9,139.3,136.8,134.8,133.9,132.2,130.5,130.1,129.3,129.1 ,128.7,128.0,127.7,127.3,126.6,125.1,120.2,84.8,73.8,48.8,39.5,28.7,24.6,17.3,14.5; IR(thin film)3459,2090,1639,1383,950,694cm -1 ; 19 F NMR(376MHz, CDCl3)δ-62.6; HRMS(ESI)m / z calcd forC 33 H 34 F3N2O3(M+H)+ 563.2516, found 563.2533. Its structure is as follows:

[0186]

[0187] 3ae: Solid, 62mg, 61% yield. MPa: 170-171℃; 1 H NMR (400MHz, CDCl3): δ7.46-7.44(m,2H),7.42-7.40(m,2H),7.36-7.31(m,2H),7.29 -7.23(m,4H),7.11-7.05(m,3H),6.94-6.93(m,1H),6.71(d,J=16.4Hz,1H),6.63(d,J =15.6Hz,1H),5.72(d,J=10.8Hz,1H),4.78-4.73(m,2H),3.54-3.46(m,1H),3.40-3. 35(m,1H),2.16(s,3H),1.77(s,3H),1.76(s,3H),1.60(s,3H),0.78(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ173.2,159.8,140.1,137.6,136.9,135.0,134.6,133.9,131.8,130.4,129.0,128.7,127.9,127.8,127.7, 127.2,126.6,126.5,120.4,84.8,74.7,48.7,39.5,28.8,24.6,21.1,17.3,14.5; IR(thinfilm)3467,2914,1650,1252,975,695cm -1 HRMS(ESI)m / z calcd for C 33 H 37 N₂O₃(M+H) + 509.2799, found 509.2802. Its structural formula is as follows:

[0188]

[0189] 3af: Solid, 69mg, 68% yield. MPa: 180-181℃; 1H NMR (400MHz, CDCl3): δ7.45-7.40(m,3H),7.36-7.32(m,3H),7.28-7.25(m,4H),7.2 0-7.18(m,1H),7.00-6.99(m,2H),6.93-6.92(m,1H),6.71(d,J=16.0Hz,1H),6.61( d,J=16.0Hz,1H),5.69(d,J=10.8Hz,1H),4.83(s,2H),3.53-3.48(m,1H),3.39-3.3 3(m,1H),2.28(s,3H),1.77(s,3H),1.76(s,3H),1.65(s,3H),0.78(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ173.1,159.8,140.1,138.5,137.0,134.3,133.9,133.0.131.8,131.0,129.9,129.0,1 28.7,128.6,127.8,127.2,126.5,125.4,120.4,84.8,73.0,48.7,39.4,28.8,24.6,18.9,17.4,14.5;IR(thin film)3665,2964,1660,1272,975,708cm -1 HRMS(ESI)m / z calcd for C 33 H 37 N₂O₃(M+H) + 509.2799, found 509.2778. Its structure is as follows:

[0190]

[0191] 3ag: Solid, 61mg, 73% yield. MPa: 168-169℃; 1 H NMR (400MHz, CDCl3): δ7.47-7.44(m,2H),7.42-7.40(m,2H),7.35-7.30(m,5H),7.27-7.23(m,1H),6.69-6.61(m,2H),5. 99(d,J=10.4Hz,1H),3.60-3.55(m,4H),3.48-3.42(m,1H),1.80(s,3H),1.78(s,3H),1.72(s,3H),0.80(d,J=6.8Hz,3H); 13C NMR (100MHz, CDCl3): δ172.9,159.8,140.1,136.7,134.5,133.3,132.0,129.1,128.7,12 7.9,127.8,127.2,126.5,120.1,84.7,60.1,48.8,39.5,28.7,24.6,17.4,14.5;IR(thin film)3454,2921,1644,1265,965,740cm -1 HRMS(ESI)m / z calcd for C 26 H 31 N₂O₃(M+H) + 419.2329, found 419.2317. Its structure is as follows:

[0192]

[0193] 3ah: solid, 45mg, 51% yield. MPa: 190-191℃; 1 H NMR (400MHz, CDCl3): δ7.47-7.44(m,2H),7.42-7.40(m,2H),7.36-7.30(m,5H), 7.27-7.23(m,1H),6.70(d,J=15.6Hz,1H),6.65(d,J=16.0Hz,1H),6.00-5.97(m, 1H),5.94-5.86(m,1H),5.22-5.14(m,2H),4.27-4.25(m,2H),3.57-3.53(m,1H), 3.47-3.41(m,1H),1.79(s,3H),1.77(s,3H),1.70(s,3H),0.79(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ173.5,159.8,140.2,136.9,134.6,133.9,132.6,132.0,129.1,128.7,12 7.9,127.8,127.2,126.6,120.3,119.6,84.8,73.7,48.8,39.5,29.0,24.6,17.3,14.5;IR(thin film)3479,2935,1745,1350,952,694cm -1 HRMS(ESI)m / z calcd for C 28 H 33 N₂O₃(M+H) +445.2486, found 445.2475. Its structure is as follows:

[0194]

[0195] 3ai: Solid, 43mg, 41% yield. MPa: 160-161℃; 1 H NMR (400MHz, CDCl3): δ7.48-7.46(m,2H),7.40-7.31(m,9H),7.24-7.23(m,1H),7.17-7.13(m,3H),6.71-6.62(m,2H),6.21(d,J=10.8Hz,1H),4. 76(d,J=15.6Hz,1H),4.64(d,J=15.6Hz,1H),3.60-3.52(m,1H),3.48-3. 42(m,1H),1.80(s,3H),1.78(s,3H),1.72(s,3H),0.79(d,J=6.8Hz,3H); 13 C NMR (150MHz, CDCl3): δ173.9,160.0,140.1,136.8,134.8,134.7,131.9,131.5,129.1,128.7,128.2,128. 1,127.8,127.2,126.6,122.3,120.4,87.1,84.9,83.6,61.2,48.8,39.4,29.1,24.4,17.4,14.5;IR(thin film)3665,2974,1656,1262,998,680cm -1 ;HRMS(ESI)m / z calcdfor C 34 H 35 N₂O₃(M+H) + 519.2642, found 519.2632. Its structure is as follows:

[0196]

[0197] 3aj: Solid, 49mg, 51% yield. MPa: 147-148℃; 1H NMR (400MHz, CDCl3): δ7.46-7.40(m,4H),7.34-7.25(m,8H),7.19-7.13(m,3H),6.76(d,J=16.0Hz,1H),6.68(d,J=16.0Hz,1H),5.77(d,J=11.2 Hz,1H),5.02-4.97(m,1H),4.85-4.79(m,2H),3.53-3.47(m,1H),3.43- 3.38(m,1H),1.77(s,3H),1.61(d,J=7.2Hz,3H),0.78(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ170.8,160.8,139.7,136.7,135.6,135.0,132.8,132.0,129.4,129.3,129.0,12 8.6,128.3,128.0,127.9,127.8,127.2,126.6,119.8,80.7,74.9,48.5,39.5,19.8,16.9,14.5;IR(thin film)3453,2971,1661,1369,967,696cm -1 ;HRMS(ESI)m / z calcdfor C 31 H 33 N₂O₃(M+H) + 481.2486, found 481.2475. Its structure is as follows:

[0198]

[0199] 3ak: Solid, 60mg, 61% yield. MPa: 165-166℃; 1 H NMR (400MHz, CDCl3): δ7.46-7.40(m,4H),7.35-7.32(m,3H),7.29-7.23(m,5H),7 .18-7.12(m,3H),6.75(d,J=16.0Hz,1H),6.68(d,J=16.0Hz,1H),5.80(d,J=11.2 Hz,1H),4.90-4.87(m,1H),4.84-4.78(m,2H),3.55-3.49(m,1H),3.43-3.38(m,1 H),2.10-2.02(m,2H),1.78(s,3H),1.04(t,J=7.2Hz,3H),0.78(d,J=6.4Hz,3H); 13C NMR (100MHz, CDCl3): δ170.0,160.6,139.7,136.8,135.6,135.1,132.7,131.9,129.4,129.0,128.6,12 8.3,128.0,127.9,127.8,127.2,126.6,119.9,85.2,74.9,48.5,39.5,27.1,16.9,14.5,10.0;IR(thin film)3443,2932,1669,1252,975,697cm -1 HRMS(ESI)m / z calcd for C 32 H 35 N₂O₃(M+H) + 495.2642, found 495.2623. Its structure is as follows:

[0200]

[0201] 3al: solid, 72mg, 66% yield. MPa: 187-188℃; 1 H NMR (400MHz, CDCl3): δ7.50-7.48(m,2H),7.44-7.40(m,2H),7.37-7.34(m,7 H),7.29-7.25(m,6H),7.17-7.09(m,3H),6.84(d,J=15.6Hz,1H),6.74(d,J= 16.0Hz,1H),5.98(d,J=10.0Hz,1H),4.85(d,J=10.8Hz,1H),4.81(d,J=11.2 Hz,1H),4.69(s,1H),3.50-3.43(m,2H),1.81(s,3H),0.74(d,J=5.6Hz,3H); 13 C NMR (100MHz, CDCl3): δ169.0,161.3,141.1,139.5,137.9,136.7,135.9,135.2,132.9,132.3,129.5,129.1,128.7,128.5,128.4,128.3,128. 1,128.0,127.8,127.6,127.3,127.0,126.7,119.9,86.8,74.6,65.3,48.6,39.7,16.9,14.5; IR(thinfilm)3465,2943,1665,1355,931,694cm -1 HRMS(ESI)m / z calcd for C 36H 35 N₂O₃(M+H) + 543.2642, found 543.2623. Its structure is as follows:

[0202]

[0203] Example 2: Preparation of compounds 3aa, 3ba, 3ta, 3ya, and 3ab

[0204] Compound 3aa: Example 1 was repeated, except that dichloromethane was used instead of acetonitrile, copper iodide instead of copper trifluoromethanesulfonate, and pyridine instead of potassium carbonate. The reaction was carried out at 50°C until complete. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 20:1 to 10:1, volume ratio) to give a yellow solid in 75% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3aa.

[0205] Compound 3ba: Example 1 was repeated, except that tetrahydrofuran was used instead of acetonitrile, ytterbium trifluoromethanesulfonate was used instead of copper trifluoromethanesulfonate, and sodium hydroxide was used instead of potassium carbonate. The reaction was carried out at 80°C until complete. A colorless oil was obtained in 36% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3ba.

[0206] Compound 3ta: Example 1 was repeated, except that benzene was used instead of acetonitrile, scandium trifluoromethanesulfonate was used instead of copper trifluoromethanesulfonate, and triethylamine was used instead of potassium carbonate. The reaction was carried out to completion at room temperature. A white solid was obtained in 31% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3ta.

[0207] Compound 3ya: Example 1 was repeated, except that the reaction was carried out in air instead of under argon protection. A white solid was obtained in 45% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3ya.

[0208] Compound 3ab: Example 1 was repeated, except that a mixed solvent of acetone and n-hexane in a 1:1 volume ratio was used instead of acetonitrile, cuprous chloride was used instead of copper trifluoromethanesulfonate, and sodium tert-butoxide was used instead of potassium carbonate. The reaction was carried out to completion at room temperature. A white solid was obtained in 65% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3ab.

[0209] Experimental Example 1: In vitro anti-inflammatory activity experiment of the 1-oxo-2,8-diazacyclic decanone derivative of the present invention.

[0210] I. Determination of the viability of the compound and the control drug indomethacin at a concentration of 100 μM on RAW264.7 cells (mouse mononuclear macrophage leukemia cells) using the MTT assay.

[0211] 1. Digestion and seeding of test cells: Culture test cells in RAW 264.7 to the logarithmic growth phase, digest with 0.25% trypsin, add culture medium containing 10% fetal bovine serum, and mix with sterile plastic pipettes to form a single-cell suspension. Seed into 96-well plates, adding 180 μL to each well. Add 200 μL of PBS buffer around the perimeter of the 96-well plate to reduce culture medium evaporation.

[0212] 2. Adding drugs to the cell lines: When the cells in the wells have grown to cover about 70% of the total well area, add 20 μL of drug to each well to dilute the drug to 100 μM. Gently tap the well with your hand. Set up 5 replicates (parallel experiments). Set up blank wells (without drugs) and zeroing wells (culture medium containing 10% fetal bovine serum) on each 96-well plate. Continue to place the plate in an incubator and observe the cell survival under a microscope.

[0213] 3. Plate preparation: After adding the drug and continuing incubation for 48 hours, add 10 μL of MTT to each well for staining. Gently tap the plate and continue incubation for 4–6 hours. Then discard the culture medium in the wells, add 100 μL of DMSO to each well, and shake on a micro-shaker for 10 minutes to fully dissolve the generated formazan. Transfer the plate to an ELISA reader to detect the absorbance of each well, and then process the data using PASW software. The experimental results are shown in Table 1.

[0214] Table 1. Effects of compounds on RAW264.7 cell viability as determined by MTT assay

[0215]

[0216] The applicant used the MTT assay to investigate the effects of certain target compounds on the survival rate of RAW 264.7 cells. The results showed that at a compound concentration of 100 μM, compounds containing chlorine, bromine, and cinnamyl substitutions had a certain inhibitory effect on cell survival. Therefore, we further investigated the effects of some less toxic target compounds on NO release from lipopolysaccharide-induced cells.

[0217] II. Determination of the inhibitory effect of some low-toxicity target compounds on NO release from lipopolysaccharide (LPS)-induced mouse macrophage RAW 264.7 cells using the Griess method.

[0218] Compounds 3aa, 3ba, 3ha, 3ta, 3ya, 3ab, and 3al showed very low toxicity to RAW 264.7 cells. Therefore, the applicant further tested the effect of these compounds on inhibiting LPS-induced NO release from RAW 264.7 cells.

[0219] Experimental methods and results:

[0220] 1. Cell seeding and pretreatment: RAW 264.7 cells that have reached the logarithmic growth phase were seeded into 24-well culture plates at a density of 400 μL per well. There were control group, LPS stress model group (1 μg / mL LPS), and experimental groups with different drug concentrations (6.25, 12.5, 25, and 50 μg / mL). The control group and LPS stress model group were supplemented with medium with a final concentration of 0.1% DMSO. The experimental groups were pretreated with different concentrations of drug solution for 1 h and then treated with 1 μg / mL LPS for 24 h. The cell supernatant was collected.

[0221] 2. Griess method for determining NO release: Dilute a series of standard reagents at varying concentrations and the supernatant of the cell culture to be tested into a 96-well plate, 0.05 mL per well. Follow the kit instructions as follows:

[0222] (1) Add 0.05 mL of Griess Regent 1 reagent at room temperature to each well and let stand for 10 min.

[0223] (2) Add 0.05 mL of Griess Regent 2 reagent at room temperature to each well and let stand for 10 min.

[0224] (3) Measure the absorbance at 540 nm to obtain a standard curve and determine the NO concentration in the sample to be tested.

[0225] The ability of compounds 3aa, 3ba, 3ha, 3ta, 3ya, 3ab, and 3al to inhibit LPS-induced NO release from mouse macrophages at a concentration of 6.25 μM was detected using the Griess method. The test results are shown in Table 2.

[0226] Table 2. Effects of different compounds on NO release in RAW264.7 cells at the same concentration (6.25 μM).

[0227]

[0228] The test results show that most of the target compounds exhibit inhibitory effects on intracellular NO comparable to those of the anti-inflammatory drug indomethacin. These results further indicate that the 1-oxo-2,8-diazacyclic decanone derivatives described in this invention possess potential anti-inflammatory activity.

Claims

1. 1,4,11-trioxo-10,14-diazaspirocyclodecone or a pharmaceutically acceptable salt thereof, as shown in formula (I) below: in: R 1 Phenyl; R 2 Indicates styrene group; R 3 +R 4 =spirocyclic; R 5 Represents a hydrogen atom; R 6 Indicates methyl; R 7 Indicates methyl; R 8 It represents benzyl.

2. The method for synthesizing 1,4,11-trioxo-10,14-diazaspirocyclic decanone according to claim 1, characterized in that, Take the compound shown in formula (II) and the compound shown in formula (III) and place them in an organic solvent, add an alkaline substance and a catalyst, and react under heating or no heating conditions to obtain the crude product of the target compound; in: R 1 Phenyl; R 2 Indicates styrene group; R 3 +R 4 =spirocyclic; R 5 Represents a hydrogen atom; R 6 Indicates methyl; R 7 Indicates methyl; R 8 Indicates benzyl; X represents a bromine atom.

3. The synthesis method according to claim 2, characterized in that, The reaction is carried out under an inert atmosphere.

4. The synthesis method according to claim 2 or 3, characterized in that, The reaction was carried out at temperatures below 100°C.

5. The synthesis method according to claim 2 or 3, characterized in that, The organic solvent is selected from one or more of benzene, toluene, cyclohexane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, dichloromethane, acetone, chloroform, n-hexane, and dioxane; The alkaline substance is selected from one or more of the following: tripotassium phosphate, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, pyridine, triethylamine, and N,N-diisopropylethylamine. The catalyst is selected from one or more of copper salts, ytterbium salts, and scandium salts.

6. The synthesis method according to claim 2 or 3, characterized in that, It also includes a step of purifying the crude target compound obtained.

7. The use of 1,4,11-trioxo-10,14-diazaspirocyclodecone or a pharmaceutically acceptable salt thereof as described in claim 1 in the preparation of a medicament for treating inflammation.

8. A pharmaceutical composition comprising, as an active ingredient, a therapeutically effective dose of 1,4,11-trioxo-10,14-diazaspirocyclodecone or a pharmaceutically acceptable salt thereof as claimed in claim 1, and a pharmaceutically acceptable carrier.

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