CN117946025A

CN117946025A - 1-Oxygen-2, 8-diazacyclic sunflower ketone derivative and synthetic method and application thereof

Info

Publication number: CN117946025A
Application number: CN202410099899.0A
Authority: CN
Inventors: 莫冬亮; 罗艳; 陆艳娇; 赵瑜
Original assignee: Guangxi Normal University
Current assignee: Guangxi Normal University
Priority date: 2024-01-24
Filing date: 2024-01-24
Publication date: 2024-04-30

Abstract

The invention discloses a series of 1-oxo-2, 8-diazacyclic sunflower ketone derivatives, and a synthesis method and application thereof, and belongs to the technical field of medicines. The test result of the applicant shows that the derivative has good inhibition effect on NO release by lipopolysaccharide-induced mouse macrophage RAW 264.7, shows good anti-inflammatory activity, and can be used for preparing medicines for treating inflammation.

Description

1-Oxygen-2, 8-diazacyclic sunflower ketone derivative and synthetic method and application thereof

Technical Field

The invention relates to a 1-oxygen-2, 8-diazacyclic sunflower ketone derivative, and a synthetic method and application thereof, belonging to the technical field of medicines.

Background

Medium-sized (8-12) nitrogen heterocycles are an extremely important class of compounds that exist in a range of natural and non-natural products, and these compounds also exhibit great potential in drug discovery, where the backbones of nitrogen-containing heterodecatomic rings exist in many different natural products and biologically significant compound molecules, for example muramine, protopine and dysazecine are a class of alkaloids found in plants of the genus corydaline that possess a benzoquinolizine structural backbone. At present, a great deal of literature researches report that the pharmacological activity of the compound can be used for inhibiting neuron excitability (Phytochemistry 2018,150,85-92), has a certain inhibition effect on gastric acid secretion, has antibacterial, antiviral, anti-inflammatory and other activities (Chin.J.Vet.Sci.2008,12,1098–1101&Journal of Animal Science and Veterinary Medicine,2013,32,3-5.).Picraphylline, is alkaloid in Rauvolfia plants, has good pharmacological activity, and can be used for resisting malaria, inflammation, cytotoxicity, antioxidants, ulcers and other pharmacological effects (Asian Pac.J. trop.Med.2014,7, 1-8). However, efficient construction of such backbones remains a significant challenge due to unfavorable inter-ring interactions and entropy effects of the mesocyclic compounds. Therefore, the development of new strategies to construct nitrogen-containing heterodecacyclic compounds is of great importance.

Disclosure of Invention

The invention aims to provide a series of 1-oxo-2, 8-diazacyclic sunflower ketone derivatives with novel structure and better anti-inflammatory activity, and a synthesis method and application thereof.

In order to solve the technical problems, the invention adopts the following technical scheme:

The 1-oxygen-2, 8-diazacyclic sunflower ketone derivative is a compound with a structure shown in the following formula (I) or pharmaceutically acceptable salt thereof:

Wherein:

R ¹ represents unsubstituted or monosubstituted phenyl, or is unsubstituted thienyl; wherein the substituent is C _1～6 alkyl, alkoxy or halogen atom;

R ² represents a hydrogen atom, or an unsubstituted or monosubstituted phenyl group, or an unsubstituted or monosubstituted styryl group; wherein the substituent is C _1～6 alkyl, alkoxy or halogen atom;

R ³ represents a hydrogen atom, a methyl group, an ethyl group, an n-butyl group or a halogen atom, or is a substituted C _1～6 alkyl group;

R ⁴ represents a hydrogen atom or a phenyl group, or an unsubstituted or monosubstituted C _1～4 alkyl group, or an unsubstituted or monosubstituted C _1～4 alkoxy group;

R ⁵ represents a hydrogen atom;

r ⁶ represents methyl, ethyl or phenyl;

R ⁷ represents a hydrogen atom or a methyl group;

R ⁸ represents methyl, allyl or phenylpropargyl, or is unsubstituted or monosubstituted benzyl.

Further, the 1-oxo-2, 8-diazacyclohexanone derivative of the invention may be specifically any one of the following compounds 3aa to 3 al:

3aa：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ba：R¹＝4-OMe-Ph,R²＝CH₂-CH₂-4-OMe-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ca：R¹＝4-Me-Ph,R²＝CH₂-CH₂-4-Me-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3da：R¹＝4-Cl-Ph,R²＝CH₂-CH₂-4-Cl-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ea：R¹＝4-CF₃-Ph,R²＝CH₂-CH₂-4-CF₃-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3fa：R¹＝3-Br-Ph,R²＝CH₂-CH₂-3-Br-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ga：R¹＝2-Br-Ph,R²＝CH₂-CH₂-2-Br-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ha：R¹＝Ph,R²＝Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ia：R¹＝Ph,R²＝4-OMe-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ja：R¹＝Ph,R²＝4-F-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ka：R¹＝Ph,R²＝2-Br-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3la：R¹＝4-Br-Ph,R²＝Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ma：R¹＝4-CF₃-Ph,R²＝Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3na：R¹＝2-thienyl,R²＝Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3oa：R¹＝Ph,R²＝H,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3pa：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝H,R⁴＝n-Bu,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3qa：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Ph,R⁴＝Et,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ra：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Ph,R⁴＝H,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3sa：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝H,R⁴＝(CH₂)₄Cl,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ta：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝H,R⁴＝(CH₂)₃CO₂Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ua：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³+R⁴＝Cyclopentane,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3va：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³+R⁴＝Cyclohexane,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3wa：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³+R⁴＝Cycloheptane,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3xa：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³+R⁴＝pyran,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ya：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³+R⁴＝spirocyclic,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Bn;

3ab：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝CH₂-4-OMe-Ph;

3ac：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝CH₂-4-Br-Ph;

3ad：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝CH₂-4-CF₃-Ph;

3ae：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝CH₂-3-Me-Ph;

3af：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝CH₂-2-Me-Ph;

3ag：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Me;

3ah：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝allyl;

3ai：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝Me,R⁸＝Phenylpropargyl;

3aj：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Me,R⁷＝H,R⁸＝Bn;

3ak：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Et,R⁷＝H,R⁸＝Bn;

3al：R¹＝Ph,R²＝CH₂-CH₂-Ph,R³＝Me,R⁴＝Me,R⁵＝H,R⁶＝Ph,R⁷＝H,R⁸＝Bn.

The synthesis method of the 1-oxygen-2, 8-diazacyclic sunflower ketone derivative mainly comprises the following steps: placing a compound shown in the following formula (II) and a compound shown in the formula (III) in an organic solvent, adding an alkaline substance and a catalyst, and reacting under the condition of heating or no heating to obtain a crude product of a target compound;

Wherein:

R ⁵ represents a hydrogen atom;

r ⁶ represents methyl, ethyl or phenyl;

R ⁷ represents a hydrogen atom or a methyl group;

R ⁸ represents methyl, allyl or phenylpropargyl, or is unsubstituted or monosubstituted benzyl;

x represents a bromine atom or a chlorine atom.

In order to further increase the yield of the target compound, it is preferable that the reaction is carried out under an inert atmosphere (such as nitrogen, argon, helium, or the like).

In the above synthesis method, the reaction is preferably carried out at a temperature lower than 100 ℃, and more preferably at a temperature of from room temperature to 80 ℃. The reaction was monitored by TLC trace until the reaction was complete. According to the experience of the applicant, when the reaction is carried out at normal temperature or room temperature, the reaction time is preferably controlled to be 10 to 20 hours.

In the above synthetic method, the organic solvent may be one or more selected from benzene, toluene, cyclohexane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, dichloromethane, acetone, chloroform, n-hexane and dioxane; acetonitrile, toluene or tetrahydrofuran are preferably used. The amount of the organic solvent to be used may be determined as required, and is usually preferably such that the starting materials to be reacted are sufficiently dissolved, specifically, the total amount of the organic solvent used for all the starting materials is usually 1 to 5mL based on 0.1mmol of the compound represented by the formula (II).

In the above synthesis method, the alkaline substance may be a conventional choice in the prior art, preferably one or a combination of two or more selected from the group consisting of tripotassium phosphate, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, pyridine, triethylamine and N, N-diisopropylethylamine; further preferred is potassium carbonate or cesium carbonate. The amount of the catalyst is preferably 0.1 to 2.0 times the amount of the compound substance represented by the formula (II).

In the above synthesis method, the catalyst may be one or a combination of two or more selected from copper salt, ytterbium salt and scandium salt. Wherein the copper salt is preferably one or more than two selected from copper bromide, copper iodide, copper chloride, copper sulfate, ketone acetate, copper triflate, cuprous bromide, cuprous iodide and cuprous chloride; ytterbium salt is preferably ytterbium triflate; the scandium salt is preferably scandium triflate. The amount of the catalyst is preferably 0.1 to 0.2 times the amount of the compound substance represented by the formula (II).

In the synthesis method of the invention, the compound shown in the formula (II) as the raw material is an N-alkenyl alpha, beta-unsaturated nitrone derivative, which can be synthesized by referring to the prior literature (D.Kontokosta, D.S.Muller, D.L.Mo, W.H.Pace, R.A.Simpon, L.L.Anderson, beilstein J.org, chem.2015,11,2097), and can also be synthesized by designing a synthesis route at will, and the details are not described here. The related raw material shown in the formula (III) is an alpha-halogenated amide reagent, which can be directly purchased from the market (such as 2-bromo-2-methyl-N-benzyl propionamide, 2-bromo-2-methyl-N-benzyl acetamide, 2-bromo-2-methyl-N-methoxy propionamide and the like), and can also be synthesized by referring to the prior literature (Chin.J. org. Chem.2019,39, 1970-1975).

In the synthesis method, the dosage ratio of the raw materials is stoichiometric ratio.

The crude product of the compound of the formula (I) is prepared by the method, and the method also comprises the step of purifying the prepared crude product of the target compound. Specifically, the compound of formula (I) may be purified by conventional purification methods to increase the purity of the compound, such as silica gel thin layer chromatography or silica gel column chromatography, or by recrystallization. The eluent used in chromatography and the solvent used in recrystallization are the same, and can be prepared from petroleum ether and ethyl acetate according to the ratio of 20:1 to 10:1, or a mixed solvent consisting of n-hexane and ethyl acetate according to a volume ratio of 20:1 to 10:1 by volume ratio.

The applicant finds that the 1-oxo-2, 8-diazacyclic sunflower ketone derivative has good anti-inflammatory activity through experiments, and based on the fact, the invention also provides application of the 1-oxo-2, 8-diazacyclic sunflower ketone derivative or pharmaceutically acceptable salt thereof in preparing medicines for treating inflammation, and further application in preparing medicines for treating inflammation caused by lipopolysaccharide.

Further, the present invention also includes a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of the above-described 1-oxo-2, 8-diazacyclohexanone derivative or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

Compared with the prior art, the invention provides a series of 1-oxygen-2, 8-diazacyclic sunflower ketone derivatives with novel structures and a synthesis method thereof. The test result of the applicant shows that part of target compounds have good inhibition effect on NO release in mouse macrophage RAW 264.7 induced by lipopolysaccharide, and can be used for preparing medicines for treating inflammation.

Detailed Description

In order to better explain the technical scheme of the present invention, the present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.

The N-alkenyl α, β -unsaturated nitrone derivatives (i.e., compounds represented by formula (II)) referred to in the following examples were synthesized by referring to the following synthetic routes:

Wherein,

R ⁵ represents a hydrogen atom.

The specific synthesis method comprises the following steps: cu (OAc) ₂ (0.3 mmol,54 mg), alpha, beta-unsaturated oxime substrate S1 (0.3 mmol) and alkenylboronic acid S2 (0.9 mmol) were placed in a reaction tube, 3mL of 1, 2-dichloroethane was added, then pyridine (3 mmol,0.24 mL) was added, stirring was performed at 25℃for 12-24 hours, water (10 mL) was added to the resultant reaction, extraction was performed with dichloromethane (2X 10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 to 1:1, volume ratio) to obtain product 1 (i.e., N-alkenylalpha, beta-unsaturated nitrone of the compound represented by formula (II)).

The alpha-haloamide reagent (i.e., the compound of formula (III)) referred to in each of the following examples was synthesized according to the following synthetic route:

Wherein R ⁶ represents methyl, ethyl or phenyl; r ⁷ represents a hydrogen atom or a methyl group; r ⁸ represents methyl, allyl or phenylpropargyl, or is unsubstituted or monosubstituted benzyl; x represents a bromine atom.

The specific synthesis method comprises the following steps: in a 100mL round bottom flask was added benzyloxy hydroxylamine hydrochloride S4 (2.0 g,12.5mmol,1.0 eq), dichloromethane (50 mL) and triethylamine (1.75 mL,12.5mmol,1.0 eq) and the reaction mixture was then cooled to 0deg.C in an ice-water bath. Then, taking alpha-halogenated acyl bromide compound S3 (12.5 mmol,1.0 eq) and dropwise adding the alpha-halogenated acyl bromide compound into the reaction mixture, continuously stirring at 0 ℃ for reaction for 4 hours, and then moving the mixture to room temperature and stirring for 5 minutes; 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 in vacuo. Separating the residue by silica gel column chromatography (petroleum ether/ethyl acetate=4:1-1:1, volume ratio) to obtain a product 2 (namely a compound alpha-halogenated amide reagent shown in a formula (III)).

Example 1

The 1-oxo-2, 8-diazacyclohexanone derivatives of the invention were synthesized according to the following synthetic route.

The specific synthesis method comprises the following steps: under argon atmosphere, N-alkenyl alpha, beta-unsaturated nitrone substrate 1 (0.2 mmol), alpha-halogenated amide reagent 2 (0.4 mmol, wherein X represents bromine atom), copper triflate (0.04 mmol) and potassium carbonate (0.4 mmol) are taken and placed in a reaction tube, acetonitrile (2 mL) is added, stirring reaction is carried out for 10-20 h (TLC monitoring reaction is carried out at room temperature until the reaction is completed), the obtained reactant is decompressed and the solvent is removed, silica gel column chromatography separation (petroleum ether/ethyl acetate=20:1-10:1, volume ratio) is carried out on the residue, and the target product 3 (namely the compound 1-oxo-2, 8-diaza-annular sunflower ketone derivative shown in the formula (I) is obtained. The different target products are characterized as follows:

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);¹³C NMR(100MHz,CDCl₃):δ173.2,159.8,140.0,136.9,135.1,134.7,133.8,131.9,129.4,129.0,128.6,128.2,128.0,127.8,127.7,127.2,126.6,120.3,84.8,74.7,48.7,39.4,28.7,24.6,17.3,14.5;IR(thin film)3441,2976,1660,1370,964,695cm^-1;HRMS(ESI)m/z calcd for C₃₂H₃₅N₂O₃(M+H)⁺495.2642,found 495.2655. having the formula:

3ba: the oily ,40mg,36％yield.¹H 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＝16.4Hz,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 C₃₄H₃₉N₂O₅(M+H)⁺555.2853,found 555.2839. has the following structural formula:

3ca: the solid ,68mg,65％yield.Mp:71-72℃;¹H 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);¹³C NMR(100MHz,CDCl₃):δ173.3,160.0,137.8,137.1,136.8,135.2,134.4,134.2,133.7,131.8,129.7,129.4,129.3,128.2,128.0,127.7,126.5,119.4,84.7,74.5,48.3,39.5,28.7,24.6,21.2,21.2,17.3,14.5;IR(thin film)3273,2931,1650,1372,965,639cm^-1;HRMS(ESI)m/z calcd for C₃₄H₃₉N₂O₃(M+H)⁺523.2955,found 523.2968. has the following structural formula:

3da: the solid ,62mg,55％yield.Mp:152-153℃;¹H 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);¹³C NMR(100MHz,CDCl₃):δ173.3,159.4,138.5,135.3,135.1,134.4,134.0,133.5,133.0,130.7,129.5,129.2,129.1,128.9,128.4,128.0,127.7,120.6,84.9,74.8,48.1,39.3,28.8,24.5,17.3,14.4;IR(thin film)3444,2981,1656,1264,965,694cm^-1;HRMS(ESI)m/z calcd for C₃₂H₃₃Cl₂N₂O₃(M+H)⁺563.1863,found 563.1846. has the following structural formula:

3ea solid ,79mg,63％yield.Mp: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),3.49-3.39(m,1H),1.77(s,3H),1.75(s,3H),1.60(s,3H),0.80(d,J＝6.8Hz,3H);¹³C NMR(100MHz,CDCl₃):δ173.3,159.1,144.0,140.2,135.0,134.8,134.3,130.7,129.6,128.4,128.2,128.0,126.7,126.1(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 C₃₄H₃₃ F₆N₂O₃(M+H)⁺631.2390,found 631.2401. has the following structural formula:

3fa: the solid ,39mg,30％yield.Mp:100-101℃;¹H 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),3.41-3.27(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):δ173.3,159.2,142.2,139.0,135.1,134.6,134.1,131.0,130.7,130.6,130.5,130.4,130.2,129.6,129.0,128.4,128.0,126.3,125.5,123.0,122.9,121.3,84.9,75.0,48.3,39.1,28.8,24.4,17.2,14.4;IR(thin film)3456,2966,1641,1460,968,692cm^-1;HRMS(ESI)m/z calcd for C₃₂H₃₃Br₂N₂O₃(M+H)⁺651.0852,found 651.0882. has the following structural formula:

3ga: the solid ,70mg,54％yield.Mp:170-171℃;¹H NMR(400MHz,CDCl₃):δ7.64(d,J＝7.6Hz,1H),7.57-7.54(m,2H),7.43-7.39(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);¹³C NMR(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 C₃₂H₃₃Br₂N₂O₃(M+H)⁺651.0852,found 651.0880. has the following structural formula:

3ha: the solid ,76mg,81％yield.Mp:123-124℃;¹H 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);¹³C 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 C₃₀H₃₃N₂O₃(M+H)⁺469.2486,found 469.2486. has the following structural formula:

3ia: the solid ,59mg,59％yield.Mp: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＝10.4Hz,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);¹³C 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 for C₃₁H₃₅N₂O₄(M+H)⁺499.2591,found 499.2603. has the following structural formula:

3ja: the solid ,83mg,85％yield.Mp:77-78℃;¹H 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),130.9,130.1,130.0,129.4,129.1,128.3,128.0,127.7,127.2,115.4(d,J＝21.9Hz),84.5,74.8,48.7,39.2,28.7,25.1,16.3,14.2;¹⁹FNMR(470MHz,CDCl₃)δ-112.8;IR(thin film)3658,2964,1651,1371,911,697cm^-1;HRMS(ESI)m/z calcd for C₃₀H₃₂FN₂O₃(M+H)⁺487.2391,found 487.2400. has the following structural formula:

3ka: the solid ,105mg,96％yield.Mp:60-61℃;¹H NMR(400MHz,CDCl₃):δ7.64-7.62(m,1H),7.45(d,J＝7.6Hz,1H),7.39-7.34(m,4H),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):δ172.6,160.6,139.5,134.7,133.9,133.2,133.1,132.9,131.9,129.6,129.4,128.6,128.5,128.3,128.0,127.4,127.0,124.4,84.7,74.8,49.7,39.9,28.8,25.1,16.9,14.3;IR(thin film)3468,2130,1640,1383,909,694cm^-1;HRMS(ESI)m/z calcd for C₃₀H₃₂BrN₂O₃(M+H)⁺547.1591,found 547.1605. has the following structural formula

3La: the solid ,0.069mg,63％yield.Mp:60-61℃;¹H 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);¹³C 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 C₃₀H₃₂BrN₂O₃(M+H)⁺547.1591,found 547.1591. has the following structural formula:

3ma: the solid ,78mg,73％yield.Mp:70-71℃;¹H 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＝10.5Hz,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);¹³C NMR(125MHz,CDCl₃):δ173.0,160.0,144.4,137.2,135.2,133.7,129.9,129.7,129.5,129.4,128.4,128.3,128.2,128.1,127.9,126.0,125.9,84.7,75.0,48.6,39.0,28.8,25.1,16.2,14.2;¹⁹F NMR(470MHz,CDCl₃)δ-62.4;IR(thin film)3645,2962,1654,1325,805,699cm^-1;HRMS(ESI)m/z calcd for C₃₁H₃₂F₃N₂O₃(M+H)⁺537.2360,found 537.2368. has the following structural formula:

3na solid ,42mg,44％yield.Mp: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);¹³C NMR(100MHz,CDCl₃):δ173.1,160.2,143.5,136.5,135.1,133.7,130.5,129.8,129.5,128.4,128.3,128.2,128.0,127.0,124.8,124.1,84.6,74.8,44.2,40.5,28.7,25.1,16.2,14.2;IR(thin film)3664,2968,1654,1369,910,698cm^-1;HRMS(ESI)m/z calcd for C₂₈H₃₁N₂O₃S(M+H)⁺475.2050,found 475.2064. has the following structural formula:

3oa solid ,30mg,38％yield.¹H 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 C₂₄H₂₉N₂O₃(M+H)⁺393.2173,found 393.2162. has the following structural formula:

3pa solid ,53mg,51％yield.Mp:149-150℃;¹H 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),1.75(s,3H),1.61(s,3H),1.26-1.18(m,4H),1.12-1.07(m,2H),0.77-0.74(m,3H);¹³C NMR(125MHz,CDCl₃):δ173.2,154.0,140.0,137.0,135.5,135.2,133.9,131.8,129.5,129.0,128.6,128.3,128.0,127.9,127.7,127.2,126.8,121.0,85.6,74.7,48.3,44.3,30.4,30.1,28.8,24.3,22.4,13.8;IR(thin film)3028,2938,1633,1454,958,693cm^-1;HRMS(ESI)m/z calcd for C₃₄H₃₉N₂O₃(M+H)⁺523.2955,found 523.2965. has the following structural formula:

3qa solid ,69mg,61％yield.Mp:87-88℃;¹H 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,3H),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);¹³C NMR(125MHz,CDCl₃):δ173.0,160.0,140.5,136.7,135.3,135.2,135.0,134.2,132.0,129.5,129.1,128.7,128.5,128.3,128.1,128.0,127.8,127.6,127.5,127.2,126.7,121.7,85.8,74.7,49.1,47.1,28.7,24.4,21.6,12.5;IR(thin film)3655,2904,1651,1451,966,696cm^-1;HRMS(ESI)m/z calcd for C₃₈H₃₉N₂O₃(M+H)⁺571.2955,found 571.2969. has the following structural formula:

3ra solid ,71mg,66％yield.Mp: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＝15.5Hz,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);¹³C 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 C₃₆H₃₅N₂O₃(M+K)⁺543.2642,found 543.2662. has the following structural formula:

3sa solid ,33mg,30％yield.Mp:136-137℃;¹H 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,3H),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 calcd for C₃₄H₃₈ClN₂O₃(M+H)⁺557.2565,found 557.2573. has the following structural formula:

3ta solid ,35mg,31％yield.Mp:130-131℃;¹H 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);¹³C 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 C₃₅H₃₉Cl₂N₂O₅(M+H)⁺567.2853,found 567.2831. has the following structural formula:

3ua: the solid 81mg,80％yield.Mp:136-137℃;¹H 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),2.32-2.23(m,1H),1.91-1.79(m,3H),1.75(s,3H),1.68-1.66(m,1H),1.61(s,3H);¹³C 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/z calcd for C₃₃H₃₅N₂O₃(M+H)⁺507.2642,found 507.2639. has the following structural formula:

3va: the solid ,73mg,70％yield.Mp: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),4.80-4.75(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,1H),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);¹³C 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(thin film)3482,2936,1647,1370,967,696cm^-1;HRMS(ESI)m/z calcd for C₃₄H₃₇N₂O₃(M+K)⁺521.2799,found 521.2817. has the following structural formula:

3wa solid ,99mg,93％yield.Mp:64-65℃;¹H 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 calcd for C₃₅H₃₉N₂O₃(M+H)⁺535.2955,found 535.2951. has the following structural formula:

3xa: solid ,79mg,76％yield.Mp:53-54℃;¹H 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);¹³C NMR(100MHz,CDCl₃):δ173.3,155.5,139.0,136.6,135.1,134.3,134.2,132.4,129.5,129.2,128.7,128.3,128.0,127.9,127.5,126.7,120.1,85.1,74.7,67.4,66.5,44.3,42.7,29.3,28.9,24.4;IR(thin film)3477,2964,1648,1370,909,696cm^-1;HRMS(ESI)m/z calcd for C₃₃H₃₅N₂O₄(M+H)⁺523.2591,found 523.2604. having the structural formula:

3ya solid ,52mg,45％yield.Mp:187-188℃;¹H 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),4.15-4.09(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);¹³C 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 C₃₆H₃₉N₂O₅(M+H)⁺579.2853,found 579.2845. has the following structural formula:

3ab: the solid ,68mg,65％yield.Mp: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);¹³C 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 C₃₃H₃₇N₂O₄(M+H)⁺525.2748,found 525.2756. has the following structural formula:

solid ,62mg,54％yield.Mp:139-140℃;¹H 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):δ173.4,159.9,139.9,136.8,134.7,134.2,133.8.132.1,131.2,131.0,129.1,128.7,128.0,127.7,127.3,126.6,122.4,120.2,84.8,73.8,48.8,39.5,28.8,24.6,17.3,14.5;IR(thin film)3491,2972,1949,1374,966,690cm^-1;HRMS(ESI)m/z calcd for C₃₂H₃₄BrN₂O₃(M+H)⁺573.1747,found 573.1756. has the following structural formula:

3ad: the solid ,68mg,61％yield.Mp:64-65℃;¹H 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);¹³C 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;¹⁹F NMR(376MHz,CDCl₃)δ-62.6;HRMS(ESI)m/z calcd for C₃₃H₃₄F₃N₂O₃(M+H)⁺563.2516,found 563.2533. has the following structural formula:

3ae: the solid ,62mg,61％yield.Mp:170-171℃;¹H 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);¹³C 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(thin film)3467,2914,1650,1252,975,695cm^-1;HRMS(ESI)m/z calcd for C₃₃H₃₇N₂O₃(M+H)⁺509.2799,found 509.2802. has the following structural formula:

3af: the solid ,69mg,68％yield.Mp:180-181℃;¹H NMR(400MHz,CDCl₃):δ7.45-7.40(m,3H),7.36-7.32(m,3H),7.28-7.25(m,4H),7.20-7.18(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),3.39-3.33(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);¹³C NMR(100MHz,CDCl₃):δ173.1,159.8,140.1,138.5,137.0,134.3,133.9,133.0.131.8,131.0,129.9,129.0,128.7,128.6,127.8,127.2,126.5,125.4,120.4,84.8,73.0,48.7,39.4,28.8,24.6,18.9,17.4,14.5;IR(thin film)3665,2964,1660,1272,975,708cm^-1;HRMS(ESI)m/z calcd for C₃₃H₃₇N₂O₃(M+H)⁺509.2799,found 509.2778. has the following structural formula:

3ag: the solid ,61mg,73％yield.Mp:168-169℃;¹H 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):δ172.9,159.8,140.1,136.7,134.5,133.3,132.0,129.1,128.7,127.9,127.8,127.2,126.5,120.1,84.7,60.1,48.8,39.5,28.7,24.6,17.4,14.5;IR(thin film)3454,2921,1644,1265,965,740cm^-1;HRMS(ESI)m/z calcd for C₂₆H₃₁N₂O₃(M+H)⁺419.2329,found 419.2317. has the following structural formula:

3ah: solid ,45mg,51％yield.Mp:190-191℃;¹H 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);¹³C NMR(100MHz,CDCl₃):δ173.5,159.8,140.2,136.9,134.6,133.9,132.6,132.0,129.1,128.7,127.9,127.8,127.2,126.6,120.3,119.6,84.8,73.7,48.8,39.5,29.0,24.6,17.3,14.5;IR(thin film)3479,2935,1745,1350,952,694cm^-1;HRMS(ESI)m/z calcd for C₂₈H₃₃N₂O₃(M+H)⁺445.2486,found 445.2475. having the structural formula:

3ai: the solid ,43mg,41％yield.Mp:160-161℃;¹H 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);¹³C 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 calcd for C₃₄H₃₅N₂O₃(M+H)⁺519.2642,found 519.2632. has the following structural formula:

3aj: the solid ,49mg,51％yield.Mp: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＝11.2Hz,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);¹³C NMR(100MHz,CDCl₃):δ170.8,160.8,139.7,136.7,135.6,135.0,132.8,132.0,129.4,129.3,129.0,128.6,128.3,128.0,127.9,127.8,127.2,126.6,119.8,80.7,74.9,48.5,39.5,19.8,16.9,14.5;IR(thin film)3453,2971,1661,1369,967,696cm^-1;HRMS(ESI)m/z calcd for C₃₁H₃₃N₂O₃(M+H)⁺481.2486,found 481.2475. has the following structural formula:

3ak solid ,60mg,61％yield.Mp:165-166℃;¹H 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＝11.2Hz,1H),4.90-4.87(m,1H),4.84-4.78(m,2H),3.55-3.49(m,1H),3.43-3.38(m,1H),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):δ170.0,160.6,139.7,136.8,135.6,135.1,132.7,131.9,129.4,129.0,128.6,128.3,128.0,127.9,127.8,127.2,126.6,119.9,85.2,74.9,48.5,39.5,27.1,16.9,14.5,10.0;IR(thin film)3443,2932,1669,1252,975,697cm^-1;HRMS(ESI)m/z calcd for C₃₂H₃₅N₂O₃(M+H)⁺495.2642,found 495.2623. has the following structural formula:

3al solid ,72mg,66％yield.Mp:187-188℃;¹H NMR(400MHz,CDCl₃):δ7.50-7.48(m,2H),7.44-7.40(m,2H),7.37-7.34(m,7H),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＝11.2Hz,1H),4.69(s,1H),3.50-3.43(m,2H),1.81(s,3H),0.74(d,J＝5.6Hz,3H);¹³C 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(thin film)3465,2943,1665,1355,931,694cm^-1;HRMS(ESI)m/z calcd for C₃₆H₃₅N₂O₃(M+H)⁺543.2642,found 543.2623. has the following structural formula:

example 2: preparation of Compounds 3aa, 3ba, 3ta, 3ya, 3ab

Compound 3aa: example 1 was repeated except that acetonitrile was replaced with dichloromethane, copper triflate was replaced with copper iodide, potassium carbonate was replaced with pyridine, and the reaction was carried out at 50 ℃ until completion. The residue obtained was purified by column chromatography on silica gel (n-hexane/ethyl acetate=20:1 to 10:1, volume ratio) to give a yellow solid with a yield of 75%. And the compound is determined to be the compound 3aa through nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum characterization.

Compound 3ba: example 1 was repeated except that tetrahydrofuran was used instead of acetonitrile, ytterbium triflate was used instead of copper triflate, sodium hydroxide was used instead of potassium carbonate, and the reaction was carried out at 80℃until completion. This gave a colourless oil in 36% yield. And the compound is determined to be 3ba by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum characterization.

Compound 3ta: example 1 was repeated except that benzene was used instead of acetonitrile, scandium triflate was used instead of copper triflate, triethylamine was used instead of potassium carbonate, and the reaction was completed at room temperature. A white solid was obtained in 31% yield. The compound 3ta is determined by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum characterization.

Compound 3ya: example 1 was repeated except that the reaction was not carried out under argon protection but carried out in air. A white solid was obtained in 45% yield. The compound 3ya is determined by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum characterization.

Compound 3ab: example 1 was repeated, except that the mixture was prepared from acetone and n-hexane in an amount of 1:1, replacing acetonitrile with a mixed solvent composed of volume ratio, replacing copper triflate with cuprous chloride, replacing potassium carbonate with sodium tert-butoxide, and reacting at room temperature until the reaction is completed. A white solid was obtained in 65% yield. The compound is determined to be 3ab through nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum characterization.

Experimental example 1: in vitro anti-inflammatory Activity test of 1-oxo-2, 8-diazacyclic sunflower ketone derivatives of the invention

1. Testing of RAW264.7 cell (mouse mononuclear macrophage leukemia cell) viability of compound and control indometacin at concentration of 100 mu M by MTT method

1. Digestion and seeding of test cells: test cells were cultured for RAW 264.7 to log phase, digested with 0.25% trypsin, added with medium containing 10% fetal bovine serum, and sterilized plastic pipette was blown to single cell suspension, inoculated into 96 well plates, and 180. Mu.L of PBS buffer was added to each well plate for four weeks, to reduce medium evaporation.

2. Cell lines were dosed: when cells in the wells grow to about 70% of the whole well area, 20 mu L of medicine is added to each well, the medicine is diluted to 100 mu M, the mixture is tapped by hand, 5 compound wells (parallel experiments) are arranged, blank wells (without medicine) and zeroing wells (culture medium containing 10% fetal bovine serum) are arranged in each 96 well plate, the culture medium is continuously put into an incubator, and the survival condition of the cells is observed under a microscope.

3. Measuring plate: adding medicine and continuously culturing for 48 hours, adding 10 mu L of MTT (methyl thiazolyl tetrazolium) into each hole for dyeing, tapping by hand, continuously culturing for 4-6 hours, then discarding a culture medium in the hole, adding 100 mu L of DMSO into each hole, vibrating on a micro vibrator for 10 minutes to fully dissolve the generated formazan, transferring to an enzyme-linked immunosorbent assay (ELISA) instrument for detecting the light absorption value of each hole, and processing data by PASW software. The experimental results are shown in Table 1.

TABLE 1 MTT assay to detect the effect of compounds on RAW264.7 cell viability

The applicant explores the effect of partial target compounds on the survival rate of RAW 264.7 cells by using an MTT method, and can see that the compound containing chlorine, bromine and cinnamyl substitution has a certain inhibition effect on the survival of the cells at the concentration of 100 mu M. Thus, we further explored the effect of a partially less toxic compound of interest on the amount of NO release in cells with lipopolysaccharide induction.

2.Griess assay for inhibition of lipopolysaccharide (lipopolysaccharides, LPS) -induced release of NO by mouse macrophage RAW 264.7 by a partially low-toxicity target compound

Compounds 3aa, 3ba, 3ha, 3ta, 3ya, 3ab, 3al showed very low toxicity to RAW 264.7 cells, and thus the inventors further tested the effect of these compounds on inhibiting LPS-induced release of NO by RAW 264.7 cells.

Experimental method and experimental results:

1. Inoculation and pretreatment of cells: RAW 264.7 cells growing to logarithmic phase were inoculated into 24-well culture plates at 400. Mu.L per well, a control group, an LPS stress model group (1. Mu.g/mL LPS), and a different concentration drug test group (6.25, 12.5, 25, 50. Mu.g/m L) were set, the control group and the LPS stress model group were added with a medium having a final concentration of 0.1% DMSO, the test group was pretreated with different concentration drug solutions for 1 hour and then added with 1. Mu.g/mL LPS for 24 hours together, and cell supernatants were collected.

Griess assay for NO release: taking diluted serial concentration gradient standard reagents and cell culture supernatant to be tested into 96-well plates, wherein each well is 0.05mL, and operating according to the instruction of a kit, wherein the specific steps are as follows:

(1) GRIESS REGENT 1 reagent at room temperature was added in an amount of 0.05mL per well, and the mixture was allowed to stand for 10min.

(2) GRIESS REGENT 2 reagent at room temperature was added in an amount of 0.05mL per well, and the mixture was allowed to stand for 10min.

(3) And measuring the absorbance at 540nm to obtain a standard curve, and determining the concentration of NO in the sample to be measured.

The ability of compounds 3aa, 3ba, 3ha, 3ta, 3ya, 3ab, 3al to inhibit LPS-induced mouse macrophage NO release at a concentration of 6.25 μm was tested using the Griess method. The test results are shown in Table 2.

TABLE 2 Effect of different compounds on NO release from RAW264.7 cells at the same concentration (6.25. Mu.M)

From the test results, most of target compounds have the effect of inhibiting NO in cells, which is equivalent to the effect of indomethacin as an anti-inflammatory drug. The above results further demonstrate that the 1-oxo-2, 8-diazacyclohexanone derivatives of the invention have potent anti-inflammatory activity.

Claims

1. 1-Oxo-2, 8-diazacyclohexanone derivatives of the structure represented by the following formula (I):

Wherein:

R ⁵ represents a hydrogen atom;

r ⁶ represents methyl, ethyl or phenyl;

R ⁷ represents a hydrogen atom or a methyl group;

2. The 1-oxo-2, 8-diazacyclohexanone derivative of claim 1, characterized by being specifically any one of the following compounds 3aa to 3 al:

3. The method for synthesizing the 1-oxo-2, 8-diazacyclohexanone derivative according to claim 1, characterized in that a compound represented by the following formula (II) and a compound represented by the following formula (III) are taken to be placed in an organic solvent, an alkaline substance and a catalyst are added, and the reaction is carried out under heating or non-heating conditions, so as to obtain a crude product of a target compound;

Wherein:

R ⁵ represents a hydrogen atom;

r ⁶ represents methyl, ethyl or phenyl;

R ⁷ represents a hydrogen atom or a methyl group;

x represents a bromine atom or a chlorine atom.

4. A synthetic method according to claim 3, characterized in that the reaction is carried out under protection of an inert atmosphere.

5. The synthetic method according to claim 3 or 4, wherein the reaction is carried out at a temperature of less than 100 ℃.

6. The synthesis method according to claim 3 or 4, wherein,

The organic solvent is one or more than two selected from benzene, toluene, cyclohexane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, dichloromethane, acetone, chloroform, n-hexane and dioxane;

The alkaline substance is one or more than two selected from tripotassium phosphate, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, pyridine, triethylamine and N, N-diisopropylethylamine;

The catalyst is one or the combination of more than two of copper salt, ytterbium salt and scandium salt.

7. The method according to claim 3 or 4, further comprising the step of purifying the crude target compound.

8. Use of a 1-oxo-2, 8-diazacyclohexanone derivative of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of inflammation.

9. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of the 1-oxo-2, 8-diazacyclohexanone derivative of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.