Imidazolone compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses an imidazolone compound as well as a pharmaceutical composition and application thereof, the structure of the imidazolone compound is shown as a formula I, and the invention discloses application of the imidazolone compound in preparation of medicines for preventing and / or treating diseases related to MAGL. Comprise depression, anxiety disorder, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuropathic pain, inflammatory pain, cancerous pain, epilepsy, cancer, alcoholic fatty liver, non-alcoholic fatty liver disease, hepatic fibrosis, cholestasis, nephropathy, sepsis, inflammatory bowel disease and other related diseases. # imgabs0 #

Description

Technical field:

[0001] The present invention relates to an imidazolone compound, a pharmaceutical composition and an application thereof, and in particular to an imidazolone compound having monoacylglycerol esterase inhibitory activity, a pharmaceutical composition and an application thereof. Background technology:

[0002] The endocannabinoid system (ECS) is a biological regulatory system present in the central nervous system and peripheral tissues of most vertebrates. It is involved in regulating many physiological processes, including the balance of cells, tissues, organs, and the body, brain development, neurotransmitter release and synaptic plasticity, and cytokine release from microglia. It is considered a potential strategy for treating a variety of diseases, including central nervous system diseases, pain, cancer, and metabolic diseases. Studies have found that the endocannabinoid system is mainly composed of cannabinoid receptors (CB1, CB2), endocannabinoids (AEA, 2-AG), enzymes responsible for the synthesis and degradation of endocannabinoids, and related endocannabinoid transporters.

[0003] Monoacylglycerol esterase (MAGL) is a membrane-bound serine hydrolase found in the central nervous system and peripheral tissues such as the liver, kidney, testes, lung, prostate, and small intestine. MAGL activity plays a central role in various biological systems, particularly endocannabinoid signaling and AA metabolism. MAGL is a key enzyme for the hydrolysis of the endocannabinoid 2-AG and plays a dominant role in regulating 2-AG levels in the body. It participates in the regulation of endocannabinoid signaling networks and is implicated in diverse physiological processes, including pain, inflammation, food intake, cognition, depression, and neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. MAGL is also a key metabolic enzyme and has been implicated in the development and progression of liver disease through diverse mechanisms. It also participates in complex mechanisms in peripheral diseases such as lipid and glucose metabolism. Endocannabinoid signaling plays an important role in both central and peripheral tissues. Therefore, inhibition of MAGL holds promise as a target for central nervous system disorders, pain, or liver disease.

[0004] To date, most MAGL inhibitors are irreversible. Although these irreversible inhibitors have efficient inhibitory activity and high selectivity, their irreversible mechanism of action leads to long-term activation of CB receptors, resulting in side effects such as CB1 desensitization, catalepsy, and motor impairment, which are not conducive to clinical application. Therefore, the development of new MAGL inhibitors is of great significance. Summary of the invention:

[0005] Purpose of the invention: The first purpose of the present invention is to provide an imidazolidone compound, the second purpose is to provide a pharmaceutical composition comprising the compound, and the third purpose is to provide an application of the compound and the pharmaceutical composition thereof in the preparation of drugs.

[0006] Technical solution: The present invention provides an imidazolidone compound having a structure shown in Formula I, or its cis-trans isomers, or its pharmaceutically acceptable salts:

[0007]

[0008] in:

[0009] R1 is selected from a chemical bond, an aromatic ring substituted or unsubstituted by Ra, or a 5-7 membered heteroaromatic ring substituted or unsubstituted by Rb having 1-3 atoms selected from nitrogen, oxygen or sulfur;

[0010] R2 is selected from an aromatic ring substituted or unsubstituted by Rc or an unsaturated heterocyclic ring substituted or unsubstituted by Rd:

[0011] R3 is selected from an aromatic ring substituted or unsubstituted by Re or a 5-7 membered heteroaromatic ring substituted or unsubstituted by Rf having 1-3 atoms selected from nitrogen, oxygen or sulfur;

[0012] Ra, Rb, Rc, Rd, Re and Rf are each independently selected from H, halogen, -OH, amino, -CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 acyloxy.

[0013] In some embodiments of the present invention, R1 is selected from a chemical bond, a C6-C10 aromatic ring substituted or unsubstituted by Ra, or a 5-7 membered heteroaromatic ring having one or two nitrogen, oxygen, or sulfur atoms substituted or unsubstituted by Rb. In some specific examples, the C6-C10 aromatic ring is selected from a benzene ring. In some specific examples, the 5-7 membered heteroaromatic ring having one or two nitrogen, oxygen, or sulfur atoms is selected from a thiophene ring, a furan ring, a pyrrole ring, or a pyridine ring. In some specific examples, R1 is selected from a chemical bond, a benzene ring, a thiophene ring, or a furan ring.

[0014] In some embodiments of the present invention, R2 is selected from a C6-C10 aromatic ring substituted or unsubstituted by Rc, or a 5-10 membered unsaturated heterocyclic ring having 1-3 selected from nitrogen, oxygen, sulfur, C(=O) or C(=S) substituted or unsubstituted by Rd. In some specific examples, the C6-C10 aromatic ring includes a benzene ring or a naphthalene ring. In other specific examples, the 5-10 membered unsaturated heterocyclic ring having 1-3 selected from nitrogen, oxygen, sulfur, C(=O) or C(=S) includes benzomorpholine, benzopyrrolidine, quinoline, isoquinoline, benzopiperidine, benzimidazole, benzothiazole, benzofuran, benzothiophene, indole, In some more specific examples, R2 is selected from a benzene ring substituted or unsubstituted by Rc, a phenyl ring substituted or unsubstituted by Rd, Substituted or unsubstituted by Rd or substituted or unsubstituted by Rd

[0015] In some examples, Ra, Rb, Rc, Rd, Re, and Rf are each independently selected from H, halogen, -OH, amino, -CN, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, or O or S forms a carbonyl or thiol group with the C in R2. In some examples, the number of Ra, Rb, Rc, Rd, Re, and Rf is each independently 1, 2, or 3.

[0016] In some embodiments of the present invention, R3 is selected from a C6-C10 aromatic ring substituted or unsubstituted by Re or a 5-7 membered heteroaromatic ring having 1-2 nitrogen, oxygen, or sulfur atoms substituted or unsubstituted by Rf. In some specific examples, the C6-C10 aromatic ring is selected from a benzene ring. In some specific examples, the 5-7 membered heteroaromatic ring having 1 or 2 nitrogen, oxygen, or sulfur atoms is selected from a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a pyrazole ring, an imidazole ring, or a pyridine ring. In some specific examples, R3 is selected from a benzene ring substituted or unsubstituted by Re, a pyridine ring substituted or unsubstituted by Rf, a thiophene ring substituted or unsubstituted by Rf, an oxazole ring substituted or unsubstituted by Rf, or an isoxazole ring substituted or unsubstituted by Rf.

[0017] In some embodiments of the present invention, Re and Rf are each independently selected from halogen, specifically selected from F, Cl, and Br.

[0018] In some embodiments, the present invention provides an imidazolidone compound shown in the following structure, or its cis-trans isomers, or a pharmaceutically acceptable salt thereof:

[0019]

[0020]

[0021] "Pharmaceutically acceptable salts" can be synthesized from parent compounds containing acid or basic groups by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. When the compound contains relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts, or similar salts. When the compound contains relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, ferulic acid, suberic acid, fumaric acid, lactic acid, pyruvic acid, mandelic acid, phthalic acid, Similar acids such as benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid and methanesulfonic acid; organic acid salts also include salts of organic acids such as amino acids (such as arginine, etc.) and glucuronic acid. When certain specific compounds contain basic and acidic functional groups, they can be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubility in polar solvents.

[0022] The present invention also provides a pharmaceutical composition comprising the imidazolone compound of the present invention or its cis-trans isomers, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0023] The "pharmaceutically acceptable carrier" described in the present invention can be an excipient widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition. They can also provide methods to dissolve the active ingredient at a desired rate after administration to the subject, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0024] The pharmaceutical compositions of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0025] The pharmaceutical compositions of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ophthalmic, rectal, topical, or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention can also be in a controlled-release or sustained-release dosage form (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry powder formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and lozenges.

[0026] The present invention also provides a method for preparing the imidazolidone compound:

[0027] The compound of formula (IV) is used as the starting material and reacts with aromatic aldehyde in the presence of sodium acetate. Oxazolone is synthesized to obtain a compound as shown in formula (II), and finally the compound as shown in formula (II) is ring-opened under the conditions of TEA and ammonium carbamate, and then heated to 90°C and DBU is added to cyclize again to obtain a compound as shown in formula (I)

[0028]

[0029] The compound represented by formula (IV) can be prepared by the following route: using formula IV-a as a raw material to undergo an amide condensation reaction with glycine ethyl ester hydrochloride to obtain an ester intermediate IV-b, and then the ester intermediate is hydrolyzed with alkaline to obtain IV.

[0030]

[0031] The compound represented by formula (IV-a1) can be prepared by the following route: compound 1 is used as a raw material to undergo Suzuki reaction with substituted phenylboronic acid to obtain compound 2, and compound 2 is hydrolyzed with alkaline to obtain IV-a1.

[0032]

[0033] The present invention also provides use of the imidazolone compound or its cis-trans isomers, or its pharmaceutically acceptable salt, or a drug combination containing the same in the preparation of a monoacylglycerol esterase inhibitor drug.

[0034] The present invention also provides the use of the imidazolidone compound or its cis-trans isomers, or a pharmaceutically acceptable salt thereof, or a drug combination containing the same in the preparation of a drug for treating monoacylglycerol esterase-related diseases, wherein the monoacylglycerol esterase-related diseases include depression, anxiety, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuralgia, inflammatory pain, cancer pain, epilepsy, cancer, alcoholic fatty liver disease, non-alcoholic fatty liver disease, liver fibrosis, cholestasis, nephropathy, sepsis or inflammatory bowel disease.

[0035] Unless otherwise specified, the terms used in this invention have the following definitions:

[0036] The term "alkyl" refers to a saturated aliphatic hydrocarbon group of 1 to 4 carbon atoms, including straight-chain and branched groups, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc. The alkyl group may be substituted or unsubstituted.

[0037] The term "haloalkyl" denotes a halogen-substituted alkyl group, preferably an alkyl group as defined above, which is substituted by one or more halogen atoms, which may be the same or different, for example -CH2Cl, -CF3, -CH2CF3, -CH2CCl3, etc.

[0038] The term "alkoxy" refers to -O-(unsubstituted alkyl) or -O-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. "C1-C4 alkoxy" refers to a linear or branched alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, and the like. A linear or branched alkoxy group having 1 to 4 carbon atoms is preferred, with methoxy or ethoxy being particularly preferred.

[0039] The term "unsaturated heterocycle" refers to a 3-12 membered aromatic or non-aromatic heterocycle containing 1-3 heteroatoms selected from O, N, S, C(=O) or C(=S), and includes bicyclic groups. Further examples include, but are not limited to, benzimidazolyl, benzofuranyl, benzopyranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, dihydroindolinyl, indolyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolyl pyridazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, azepine hexallydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl and tetrahydrothiophenyl and N-oxides thereof. Attachment of the heterocyclic substituents may be via a carbon atom or via a heteroatom.

[0040] The term "aromatic ring" refers to an all-carbon monocyclic or bicyclic group of 1 to 10 carbon atoms with a completely conjugated π electron system. Non-limiting examples include phenyl and naphthyl. Aryl groups can be substituted or unsubstituted. The term "carbonyl group" refers to an organic functional group composed of two atoms, carbon and oxygen, joined by a double bond (C=O).

[0041] The term "halogen" denotes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. Specific implementation method:

[0042] In order to further illustrate the present invention, a series of examples are given below. These examples are purely illustrative and are only used to specifically describe the present invention, and should not be understood as limiting the present invention.

[0043] Example 1: Synthesis of 2-(5-chloro-2-hydroxyphenyl)-5-(3-phenoxybenzylidene)-3,5-dihydro-4H-imidazol-4-one (III-1)

[0044] (5-Chloro-2-hydroxybenzoyl)glycine ethyl ester (2)

[0045]

[0046] 5-Chlorosalicylic acid (1035.4 mg, 6.0 mmol), HOBT (891.6 mg, 6.6 mmol), EDCI (1265.2 mg, 6.6 mmol), and TEA (1517.8 mg, 15 mmol) were dissolved in N,N-dimethylformamide and molecular sieves were added. A solution of glycine ethyl ester hydrochloride (921.2 mg, 6.6 mmol) in DMF was added under an ice bath. After removing the ice bath, the mixture was stirred at room temperature under Ar protection for approximately 5 h. After completion of the reaction, TLC was performed. The reaction solution was diluted with 20 mL of water, and the aqueous phase was extracted with ethyl acetate (16 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), and then dried over anhydrous sodium sulfate for at least 2 h. The filtrate was filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 1305 mg of a white powdery solid in an 84.4% yield. 1 HNMR (300MHz, DMSO-d6) δ12.13(s,1H),9.21(t,J=5.7Hz,1H),7.92(d,J=2.7Hz,1H),7.46(dd,J=8.8 ,2.7Hz,1H),6.98(d,J=8.8Hz,1H),4.14(t,J=7.1Hz,2H),4.10-4.04(m,2H),1.20(t,J=7.1Hz,3H).

[0047] (5-Chloro-2-hydroxybenzoyl)glycine (3)

[0048]

[0049] Intermediate 2 (485 mg, 111.88 mmol) was dissolved in tetrahydrofuran, and a 10% sodium hydroxide solution (226 mg, 5.65 mmol) was added. The mixture was stirred at 50°C for 2 h. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the tetrahydrofuran. An appropriate amount of water was added. The pH was adjusted to 2-3 with dilute hydrochloric acid under ice-cooling, and the mixture was filtered and dried to obtain 367 mg of a white solid (yield: 85.0%). 1 H NMR (300MHz, DMSO-d6) δ12.81(s,1H),12.26(s,1H),9.17(t,J=5.7Hz,1H),7.94(d,J= 2.7Hz, 1H), 7.46 (dd, J=8.8, 2.7Hz, 1H), 6.98 (d, J=8.8Hz, 1H), 4.00 (d, J=5.6Hz, 2H).

[0050] 4-Chloro-2-(5-oxo-4-(3-phenoxybenzylidene)-4,5-dihydrooxazol-2-yl)phenylacetate (5)

[0051]

[0052] Intermediate 3 (395 mg, 1.84 mmol) and m-phenoxybenzaldehyde (401 mg, 2.02 mmol) were dissolved in acetic anhydride. Sodium acetate (408 mg, 3.0 mmol) was added and the reaction was stirred at 110°C for 2.5 hours. After completion of the reaction, monitored by TLC, the reaction was quenched with 10 mL of saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2) and then dried over anhydrous sodium sulfate for at least 2 hours. The filtrate was filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford 100 mg of a yellow solid powder in a 35.0% yield. 1 HNMR(300MHz,DMSO-d6)δ8.04-7.88(m,3H),7.88-7.80(m,1H),7.55(t,J=8.1Hz,1H), 7.44(dd,J=9.4,4.8Hz,4H),7.21(d,J=9.7Hz,2H),7.08(d,J=7.9Hz,2H),2.32(s,3H).

[0053] 2-(5-chloro-2-hydroxyphenyl)-5-(3-phenoxybenzylidene)-3,5-dihydro-4H-imidazol-4-one (Ⅲ-1)

[0054]

[0055] Intermediate 5 (314 mg, 0.72 mmol), ammonium carbamate (62 mg, 0.80 mmol), and TEA (73 mg, 0.72 mmol) were dissolved in N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 0.5 hour, then transferred to 55°C and refluxed for 0.5-1 hour. After completion of the reaction of III-7, DBU (55 mg, 0.36 mmol) was added, and the temperature was raised to 90°C and refluxed for approximately 4 hours. After completion of the reaction, as monitored by TLC, the reaction mixture was diluted with 15 mL of brine. The aqueous phase was extracted with tetrahydrofuran (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2) and then dried over anhydrous sodium sulfate for at least 2 hours. The filtrate was filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:tetrahydrofuran = 1:1) to afford 153 mg of a yellow solid powder in a yield of 54.1%. 1 H NMR (300MHz, DMSO-d6) δ12.54 (s, 2H), 7.96 (d, J = 2.6Hz, 1H), 7.79-7.73 (m, 2H), 7.58-7.49(m,2H),7.47-7.39(m,2H),7.18(t,J=7.4Hz,1H),7.13-7.05(m,5H).

[0056] Example 2: Synthesis of 2-(5-chloro-2-hydroxyphenyl)-5-(3-(pyridin-3-yloxy)benzylidene)-3,5-dihydro-4H-imidazol-4-one (III-2)

[0057] 3-(Pyridin-3-yloxy)benzaldehyde (7)

[0058]

[0059] 3-Hydroxybenzaldehyde (936 mg, 7.67 mmol) and 3-bromopyridine (1817 mg, 11.50 mmol) were dissolved in anhydrous dioxane. Cesium carbonate (3749 mg, 11.50 mmol), N,N-dimethylglycine hydrochloride (214 mg, 1.53 mmol), and cuprous oxide (146 mg, 0.77 mmol) were added sequentially. The reaction was refluxed at 120°C under argon for approximately 48 hours. After completion of the reaction, the mixture was filtered through Celite. The filtrate was collected and concentrated under reduced pressure to remove the dioxane. The reaction mixture was then diluted with 20 mL of water. The aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (15 mL x 2) and dried over anhydrous sodium sulfate for at least 2 hours. The filtrate was filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to afford 916 mg of a light yellow oil in a 60% yield. 1H NMR (300MHz, DMSO-d6) δ9.99 (s, 1H), 8.48-8.42 (m, 2H), 7.74 (dt, J = 7.5, 1.3Hz, 1H),7.66(t,J=7.7Hz,1H),7.55(ddd,J=8.4,2.8,1.5Hz,1H),7.51-7.42(m,3H).

[0060] 4-Chloro-2-(5-oxo-4-(3-(pyridin-3-yloxy)benzylidene)-4,5-dihydrooxazol-2-yl)phenyl acetate (8)

[0061]

[0062] The same synthesis method as intermediate 5 was adopted, using intermediate 3 and intermediate 7 as raw materials to obtain 100 mg of yellow powdery solid with a yield of 31.4%. 1 H NMR (300MHz, DMSO-d6) δ8.48-8.40(m,2H),8.03-7.96(m,2H),7.94(d,J=2.6Hz,1H),7.84(dd,J=8. 7,2.6Hz,1H),7.63-7.50(m,2H),7.50-7.42(m,3H),7.24(ddd,J=8.2,2.5,1.1Hz,1H),2.32(s,3H).

[0063] 2-(5-chloro-2-hydroxyphenyl)-5-(3-(pyridin-3-yloxy)benzylidene)-3,5-dihydro-4H-imidazol-4-one (Ⅲ-2)

[0064]

[0065] The same synthesis method as that of III-1 was used, and intermediate 8 was used as the raw material to obtain 230 mg of yellow solid powder with a yield of 53.2%. 1 H NMR(300MHz, DMSO-d6)δ8.47-8.38(m,2H),7.95(d,J=2.6Hz,1H),7.83-7.75(m,2H),7.60-7.49(m ,3H),7.46(dd,J=8.4,4.5Hz,1H),7.17(dd,J=8.1,2.5Hz,1H),7.13(s,1H),7.06(d,J=8.9Hz,1H).

[0066] Example 3: Synthesis of 5-(3-(4-chlorophenoxy)benzylidene)-2-(3-chlorophenyl)-3,5-dihydro-4H-imidazol-4-one (III-3)

[0067] (3-Chlorobenzoyl)glycine ethyl ester (10)

[0068]

[0069] The same synthetic method as intermediate 2 was used, using 3-chlorobenzoic acid and glycine ethyl ester hydrochloride as raw materials to obtain 960 mg of light yellow-white solid powder with a yield of 39.3%. 1 H NMR(300MHz, DMSO-d6)δ9.10(t,J=5.8Hz,1H),7.90(t,J=1.9Hz,1H),7.86-7.80(m,1H),7.67-7.61 (m,1H),7.53(t,J=7.9Hz,1H),4.12(q,J=7.1Hz,2H),4.00(d,J=5.8Hz,2H),1.20(t,J=7.1Hz,3H).

[0070] (3-Chlorobenzoyl)glycine (11)

[0071]

[0072] The same synthesis method as intermediate 3 was adopted, using intermediate 10 as raw material to obtain 760 mg of white solid with a yield of 90.5%. 1 H NMR (300MHz, DMSO-d6) δ9.00(t,J=5.9Hz,1H),7.91(t,J=1.9Hz,1H),7.83(dt,J=7.7,1. 4Hz, 1H), 7.63 (ddd, J=8.0, 2.2, 1.2Hz, 1H), 7.53 (t, J=7.8Hz, 1H), 3.93 (d, J=5.9Hz, 2H).

[0073] 4-(3-(4-chlorophenoxy)benzylidene)-2-(3-chlorophenyl)oxazol-5(4H)-one (13)

[0074]

[0075] The same synthesis method as intermediate 5 was used, with intermediate 11 and 3-(4-chlorophenoxy)benzaldehyde as raw materials to obtain 560 mg of a yellow powdery solid with a yield of 53.2%. 1 H NMR (300MHz, DMSO-d6) δ8.06(t,J=1.9Hz,1H),7.94-7.78(m,4H),7.67(t,J=7.9Hz,1H),7.60-7.50(m,3H),7.39(s,1H),7.27-7.16(m,3H).

[0076] 5-(3-(4-chlorophenoxy)benzylidene)-2-(3-chlorophenyl)-3,5-dihydro-4H-imidazol-4-one (Ⅲ-3)

[0077]

[0078] The same synthesis method as that of III-1 was used, and intermediate 13 was used as the raw material to obtain 560 mg of yellow solid powder with a yield of 53.2%. 1 H NMR (300MHz, DMSO-d6) δ12.15(s,1H),8.22-8.17(m,1H),8.05(t,J=1.8Hz,1H),7.91-7.80(m,2H),7.72 (ddd,J=8.0,2.1,1.1Hz,1H),7.63(t,J=7.9Hz,1H),7.57-7.46(m,3H),7.22-7.14(m,3H),7.05(s,1H).

[0079] Example 4: Synthesis of 2-(5-chloro-2-hydroxyphenyl)-5-(3-(4-chlorophenoxy)benzylidene)-3,5-dihydro-4H-imidazol-4-one (III-4)

[0080] 4-Chloro-2-(4-(3-(4-chlorophenoxy)benzylidene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl acetate (14)

[0081]

[0082] The same synthesis method as that of intermediate 5 was adopted, using intermediate 3 and compound 12 as raw materials to obtain 427 mg of yellow powdery solid with a yield of 55.0%. 1 H NMR (300MHz, DMSO-d6) δ7.99 (dd, J=7.2, 2.2Hz, 3H), 7.84 (dd, J=8.7, 2.7Hz, 1H), 7.57 (t, J= 8.1Hz,1H),7.46(dt,J=8.6,3.8Hz,4H),7.24-7.17(m,1H),7.14-7.07(m,2H),2.32(s,3H).

[0083] 2-(5-chloro-2-hydroxyphenyl)-5-(3-(4-chlorophenoxy)benzylidene)-3,5-dihydro-4H-imidazol-4-one (Ⅲ-4)

[0084]

[0085] The same synthesis method as that of III-1 was used, and intermediate 14 was used as the raw material to obtain 65 mg of yellow solid powder with a yield of 20.5%.1 H NMR (300MHz, DMSO-d6) δ13.02(s,1H),12.50(d,J=66.6Hz,1H),8.42(s,1H),8.06(s,1H),7.96(t,J=2.8H z,2H),7.80-7.70(m,1H),7.58-7.50(m,1H),7.48-7.42(m,2H),7.19-7.02(m,3H),6.92(d,J=8.8Hz,1H).

[0086] Example 5: Synthesis of 2-(3-chlorophenyl)-5-(3-phenoxybenzylidene)-3,5-dihydro-4H-imidazol-4-one (III-5)

[0087] 2-(3-Chlorophenyl)-4-(3-phenoxybenzylidene)oxazol-5(4H)-one (15)

[0088]

[0089] The same synthesis method as intermediate 5 was adopted, using intermediate 4 and intermediate 11 as raw materials to obtain 75 mg of yellow powdery solid with a yield of 55.3%. 1 H NMR (300MHz, DMSO-d6) δ8.09-8.04(m,1H),7.86-7.76(m,4H),7.66(t,J=7.8Hz,1H),7.5 8-7.47(m,3H),7.38-7.29(m,2H),7.24(ddd,J=8.2,2.6,1.0Hz,1H),7.20-7.14(m,2H).

[0090] 2-(3-chlorophenyl)-5-(3-phenoxybenzylidene)-3,5-dihydro-4H-imidazol-4-one (Ⅲ-5)

[0091]

[0092] The same synthesis method as that of III-1 was used, and intermediate 15 was used as the raw material to obtain 165 mg of yellow solid powder with a yield of 46.2%. 1H NMR (300MHz, DMSO-d6) δ12.13(s,1H),8.18(t,J=2.0Hz,1H),7.99(t,J=1.9Hz,1H),7.82(dt,J=7.7,1.4Hz,1H),7.78- 7.67(m,2H),7.61(t,J=7.9Hz,1H),7.49(td,J=7.8,4.2Hz,3H),7.30(t,J=7.4Hz,1H),7.21-7.12(m,3H),7.03(s,1H).

[0093] Example 6: Synthesis of 6-{4-oxydeoxy-5-[(Z)-[3-(phenyloxy)phenyl]methylidene]-4,5-dihydro-3H-imidazol-2-yl}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-3-one (III-6)

[0094] 3-(2-Chloroacetylamino)-4-hydroxybenzoic acid (18)

[0095]

[0096] The raw material 3-amino-4-hydroxybenzoic acid (16,306 mg, 2 mmol) was dissolved in 2 mL of methyl isobutyl ketone, and 2 mL of NaHCO solution was added. Chloroacetyl chloride (17,360 μL, 4.8 mmol) was slowly added under ice-cooling. After the addition, the reaction solution was brought to room temperature and stirred for 10 minutes. The reaction was then refluxed at 120°C for 4 hours. After completion of the reaction as monitored by TLC, heating was discontinued, dilute hydrochloric acid was added to adjust the pH to 3, and the mixture was filtered to obtain 320 mg of a pale yellow solid (70% yield). 1 H NMR(400MHz,DMSO-d6)δ(ppm):12.51(s,1H),10.87(s,1H),9.53(s,1H),8.55(d ,J=1.6Hz,1H),7.60(dd,J=8.4,2.1Hz,1H),6.95(d,J=8.4Hz,1H),4.40(s,2H).

[0097] 3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (19)

[0098]

[0099] Intermediate 18 (300 mg, 1.3 mmol) was dissolved in 5 mL of DMF, and KCO (270 mg, 1.95 mmol) was added. The reaction was stirred at 50°C for 2 h. After TLC monitoring of the reaction completion, saturated sodium bicarbonate solution was added, followed by dilute hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine and dried over anhydrous sodium sulfate overnight. The anhydrous sodium sulfate was removed by filtration. The filtrate was concentrated under reduced pressure and petroleum ether was added to precipitate a yellow-brown solid. The solid was filtered and dried to obtain 222 mg of Intermediate 19 as a yellow-brown solid in an 89% yield. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.80 (s, 1H), 10.88 (s, 1H), 7.51 (d, J = 8.9Hz, 2H), 7.01 (d, J = 8.1Hz, 1H), 4.66 (s, 2H).

[0100] (3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonyl)glycine ethyl ester (20)

[0101]

[0102] The synthesis method was similar to that of Intermediate 2 to obtain Intermediate 20, a white solid (135 mg) with a yield of 75%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.87 (s, 1H), 8.80 (d, J = 6.1Hz, 1H), 7.45 (d, J = 8.7Hz, 1H), 7.42 (s, 1H), 7.02(d,J=8.3Hz,1H),4.64(s,2H),4.11(q,J=7.1Hz,2H),3.95(d,J=5.8Hz,2H),1.20(t,J=7.2Hz,3H).

[0103] (3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonyl)glycine (21)

[0104]

[0105] The synthesis method was similar to that of Intermediate 3 to obtain Intermediate 21, a light orange solid (11112 mg) with a yield of 88%. 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.56 (s, 1H), 10.86 (s, 1H), 8.71 (t, J = 5.9Hz, 1H), 7.45 (dd, J = 8 .3,2.1Hz,1H),7.42(d,J=2.0Hz,1H),7.01(d,J=8.3Hz,1H),4.64(s,2H),3.88(d,J=5.8Hz,2H).

[0106] (Z)-6-(5-oxo-4-(3-phenoxybenzylidene)-4,5-dihydrooxazol-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (22)

[0107]

[0108] The synthesis method was similar to that of intermediate 5 to obtain intermediate 22, 30 mg of a yellow powdery solid, with a yield of 12%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 11.03 (s, 1H), 8.14-8.11 (m, 1H), 7.88 (d, J = 7.7Hz, 1H), 7.58 (d, J = 1.9Hz, 1H), 7.57- 7.54(m,1H),7.54-7.50(m,3H),7.38-7.32(m,1H),7.31(s,1H),7.25-7.19(m,3H),7.19-7.17(m,1H),4.79(s,2H).

[0109] 6-{4-Oxylidene-5-[(Z)-[3-(phenyloxy)phenyl]methylidene]-4,5-dihydro-3H-imidazol-2-yl}-3,4-dihydro-2H-benzo[b][1,4]oxazepine-3-one (III-6)

[0110]

[0111] The same synthesis method as that of III-1 was used, and intermediate 22 was used as the raw material to obtain 59 mg of yellow solid powder with a yield of 29.5%. 1H NMR (300MHz, DMSO-d6) δ12.08(s,1H),11.04(s,1H),8.10(t,J=2.0Hz,1H),7.90(d,J=7.7Hz,1H),7.69(d,J=2.1Hz,1H),7.52(dd,J=8.5,2 .1Hz,1H),7.45(td,J=8.0,2.0Hz,3H),7.22(t,J=7.3Hz,1H),7.12(t,J=7.7Hz,3H),7.04(dd,J=8.3,2.6Hz,1H),6.94(s,1H),4.71(s,2H).

[0112] Example 7: Synthesis of 7-{4-oxyylidene-5-[(Z)-[3-(phenyloxy)phenyl]methylidene]-4,5-dihydro-3H-imidazol-2-yl}-1,2-dihydroquinolin-2-one (III-7)

[0113] Ethyl {[(2-oxoylidene-1H-quinolin-7-yl)carbonyl]amino}acetate (24)

[0114]

[0115] The same synthesis method as intermediate 2 was used to obtain 440 mg of a pale yellowish-white solid powder with a yield of 46.6% using 2-oxo-1,2-dihydroquinoline-7-carboxylic acid as the starting material. 1 H NMR (400MHz, DMSO-d6) δ11.94(s,1H),9.08(t,J=5.9Hz,1H),7.95(d,J=9.6Hz,1H),7.78(d,J=1.6Hz,1H),7.76(d,J=8.2Hz,1H ),7.61(dd,J=8.2,1.6Hz,1H),6.59(dd,J=9.6,1.4Hz,1H),4.12(q,J=7.1Hz,2H),4.01(d,J=5.8Hz,2H),1.21(t,J=7.1Hz,3H).

[0116] N-[(2-Oxylidene-1H-quinolin-7-yl)carbonyl]glycine (25)

[0117]

[0118] The synthesis method was similar to that of Intermediate 3 to obtain Intermediate 25 as a white solid (386 mg) with a yield of 97.7%. 1H NMR (400MHz, DMSO-d6) δ11.93(s,1H),8.96(t,J=5.9Hz,1H),7.95(d,J=9.5Hz,1H),7.79(d,J=1.6Hz, 1H),7.75(d,J=8.2Hz,1H),7.61(dd,J=8.1,1.6Hz,1H),6.58(d,J=9.6Hz,1H),3.93(d,J=5.9Hz,2H).

[0119] 7-{5-Oxylidene-4-[(Z)-[3-(phenyloxy)phenyl]methylidene]-4H,5H-1,3-oxazacyclopentyl-2-yl}-1,2-dihydroquinolin-2-one (26)

[0120]

[0121] The same synthesis method as that of intermediate 5 was adopted, using intermediate 25 and intermediate 4 as raw materials to obtain 100 mg of yellow powdery solid with a yield of 31.4%. 1 H NMR (300MHz, DMSO-d6) δ12.06 (s, 1H), 8.12 (t, J = 2.0Hz, 1H), 8.02 (d, J = 9.6 Hz,1H),7.91(dd,J=4.9,3.3Hz,2H),7.86-7.81(m,1H),7.60-7.55(m,1H), 7.54(t,J=2.2Hz,1H),7.53-7.46(m,2H),7.36(d,J=5.7Hz,2H),7.24-7.20 (m,1H),7.19(q,J=2.2Hz,1H),7.16(d,J=1.7Hz,1H),6.67(d,J=9.6Hz,1H).

[0122] 7-{5-Oxylidene-4-[(Z)-[3-(phenyloxy)phenyl]methylidene]-4,5-dihydro-1H-imidazol-2-yl}-1,2-dihydroquinolin-2-one (III-7)

[0123]

[0124] The same synthesis method as that of III-1 was used, and intermediate 26 was used as the starting material to obtain 144 mg of yellow solid powder with a yield of 74.1%. 1H NMR (400MHz, DMSO-d6) δ12.04(s,1H),8.14(t,J=2.0Hz,1H),8.08(d,J=1.6Hz, 1H),8.00(d,J=9.6Hz,1H),7.91(d,J=7.7Hz,1H),7.84(d,J=8.3Hz,1H),7.69(d d,J=8.2,1.7Hz,1H),7.46(ddd,J=10.8,6.1,2.8Hz,3H),7.29-7.23(m,2H),7.1 5-7.11(m,2H),7.07(dd,J=7.9,2.6Hz,1H),6.99(s,1H),6.62(d,J=9.5Hz,1H).

[0125] Example 8: Synthesis of 2-[5-(3-fluorophenyl)furan-2-yl]-5-[(Z)-[3-(phenyloxy)phenyl]methylene]-3H-imidazol-4-one (III-8)

[0126] Methyl 5-(3-fluorophenyl)furan-2-carboxylate (29)

[0127]

[0128] The raw materials, 3-fluorophenylboronic acid (28, 3.7 g, 2.4 mmol) and methyl 5-bromofuran-2-carboxylate (27, 4.5 g, 2 mmol), were dissolved in 40 mL of 1,4-dioxane. Pd(PPh3)2Cl2 and 32 mL of aqueous Na2CO3 solution were added, and the reaction was heated to 90°C and refluxed for 3 h. After completion of the reaction as monitored by TLC, heating was stopped, the reaction mixture was cooled to room temperature, and brine was added to dilute the reaction solution. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed twice with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated by evaporation under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 32:1) to obtain 4.5 mg of intermediate 29 as a white solid in a 92% yield. 1 H NMR (300MHz, DMSO-d6) δ7.70-7.66(m,1H),7.66-7.62(m,1H),7.54(td,J=8.1,5.9H z,1H),7.45(d,J=3.7Hz,1H),7.29(d,J=3.7Hz,1H),7.28-7.21(m,1H),3.84(s,3H).

[0129] 5-(3-Fluorophenyl)furan-2-carboxylic acid (30)

[0130]

[0131] The same synthesis method as intermediate 3 was adopted, using intermediate 29 as raw material to obtain 4.2 g of white solid with a yield of 98.3%. 1 H NMR (300MHz, DMSO-d6) δ13.24(s,1H),7.64(ddt,J=7.9,6.7,1.5Hz,2H),7.53(td,J=8.1,5.9Hz,1H),7.33(d,J=3.7Hz,1H),7.29-7.17(m,2H).

[0132] Ethyl ({[5-(3-fluorophenyl)furan-2-yl]carbonyl}amino)acetate (31)

[0133]

[0134] The same synthesis method as intermediate 2 was adopted, using intermediate 30 and glycine ethyl ester hydrochloride as raw materials to obtain 4.3 g of white solid powder with a yield of 72.9%. 1 H NMR (300MHz, DMSO-d6) δ9.03(t,J=6.0Hz,1H),7.83(ddd,J=10.4,2.6,1.5Hz,1H),7.77(dt,J=7.9,1.2Hz,1H),7. 52(td,J=8.0,6.0Hz,1H),7.26-7.17(m,3H),4.13(q,J=7.1Hz,2H),4.01(d,J=6.0Hz,2H),1.21(t,J=7.1Hz,3H).

[0135] N-{[5-(3-Fluorophenyl)furan-2-yl]carbonyl}glycine (32)

[0136]

[0137] The same synthesis method as intermediate 3 was adopted, using intermediate 31 as raw material to obtain 3.75 g of white solid with a yield of 95.8%. 1 H NMR (300MHz, DMSO-d6) δ13.03(s,1H),7.75(t,J=6.4Hz,1H),7.61(ddd,J=9.0,2.3,1.2Hz,1H),7.42(ddd,J=9.0,7.8,5.1Hz,1H), 7.32(dt,J=12.1,2.1Hz,1H),7.22(s,1H),7.13(d,J=5.7Hz,1H),7.07(dddd,J=10.2,7.9,2.2,1.3Hz,1H),3.91(d,J=6.4Hz,2H).

[0138] 2-[5-(3-Fluorophenyl)furan-2-yl]-4-[(Z)-[3-(phenyloxy)phenyl]methylidene]-1,3-oxazacyclopentan-5-one (33)

[0139]

[0140] The same synthesis method as intermediate 5 was adopted, using intermediate 32 and intermediate 4 as raw materials to obtain 41 mg of yellow powdery solid with a yield of 55.8%. 1 H NMR (400MHz, DMSO-d6) δ8.05(t,J=1.9Hz,1H),7.94-7.89(m,1H),7.70(dt,J=5.5,1.7Hz,1H),7.68(q,J=2.0Hz,1H),7.65-7.58(m,2H),7.55(t ,J=8.0Hz,1H),7.48(d,J=1.6Hz,1H),7.47-7.44(m,2H),7.35-7.29(m, 2H),7.24-7.20(m,1H),7.18(dq,J=6.6,1.3Hz,1H),7.15-7.10(m,2H).

[0141] 2-[5-(3-Fluorophenyl)furan-2-yl]-5-[(Z)-[3-(phenyloxy)phenyl]methylidene]-3H-imidazol-4-one (III-8)

[0142]

[0143] The same synthesis method as that of III-1 was used, and intermediate 33 was used as the raw material to obtain 100 mg of yellow solid powder with a yield of 40.0%. 1 H NMR (300MHz, DMSO-d6) δ12.25(s,1H),8.12(t,J=1.9Hz,1H),7.90-7.80(m,2H),7.76(d,J=7.8Hz,1H),7.56(td,J=8.0,6.0Hz,1H),7.51-7. 42(m,3H),7.40(t,J=2.8Hz,2H),7.27(dd,J=8.6,2.6Hz,1H),7.20(t,J=7.3Hz,1H),7.13(d,J=1.2Hz,1H),7.11-7.05(m,2H),6.98(s,1H).

[0144] Example 9: Synthesis of 2-[5-(3-fluorophenyl)thiophen-2-yl]-5-[(Z)-[3-(phenyloxy)phenyl]methylene]-3H-imidazol-4-one (III-9)

[0145] Methyl 5-(3-fluorophenyl)thiophene-2-carboxylate (35)

[0146]

[0147] The same synthesis method as 29 was used, with 5-bromothiophene-2-carboxylic acid methyl ester (34) and 3-fluorophenylboronic acid (28) as raw materials to obtain 399 mg of white solid powder with a yield of 74.6%. 1 H NMR (300MHz, DMSO-d6) δ7.82(d,J=4.0Hz,1H),7.70(d,J=4.0Hz,1H),7.69-7.63(m,1H),7.59(dt,J =7.7,1.4Hz,1H),7.50(td,J=8.0,6.0Hz,1H),7.25(dddd,J=9.1,8.2,2.6,1.0Hz,1H),3.84(s,3H).

[0148] 5-(3-Fluorophenyl)thiophene-2-carboxylic acid (36)

[0149]

[0150] The same synthesis method as intermediate 3 was adopted, using intermediate 35 as raw material to obtain 310 mg of white solid with a yield of 82.6%. 1 H NMR (300MHz, DMSO-d6) δ13.40(s,1H),7.79(d,J=7.0Hz,1H),7.62(ddd,J=7.1,2.2,1.2Hz,1H),7.43(ddd,J =7.8,7.1,5.0Hz,1H),7.28(dt,J=12.1,2.1Hz,1H),7.25(s,1H),7.06(dddd,J=10.2,7.9,2.2,1.3Hz,1H).

[0151] Ethyl ({[5-(3-fluorophenyl)thiophen-2-yl]carbonyl}amino)acetate (37)

[0152]

[0153] The same synthesis method as intermediate 2 was used, with intermediate 366 and glycine ethyl ester hydrochloride as raw materials to obtain 281 mg of white solid powder with a yield of 65.5%. 1H NMR (300MHz, DMSO-d6) δ9.03(t,J=5.9Hz,1H),7.80(d,J=3.9Hz,1H),7.65(d,J=3.9Hz,1H),7.60(dt,J=10.3,2.2Hz,1H),7.55(dt,J=7.8,1.3H z,1H),7.49(td,J=7.8,5.8Hz,1H),7.21(dddd,J=9.1,8.1,2.6,1.2Hz,1H),4.13(q,J=7.1Hz,2H),4.00(d,J=5.9Hz,2H),1.21(t,J=7.1Hz,3H).

[0154] N-{[5-(3-Fluorophenyl)thiophen-2-yl]carbonyl}glycine (38)

[0155]

[0156] The same synthesis method as intermediate 3 was adopted, using intermediate 35 as raw material to obtain 310 mg of white solid with a yield of 82.6%. 1 H NMR (300MHz, DMSO-d6) δ13.03(s,1H),8.19(t,J=6.0Hz,1H),7.80(d,J=7.0Hz,1H),7.63(ddd,J=7.1,2.2,1.2Hz,1H), 7.43(ddd,J=7.8,7.1,5.1Hz,1H),7.34-7.25(m,2H),7.06(dddd,J=10.2,7.9,2.2,1.3Hz,1H),3.96(d,J=6.0Hz,2H).

[0157] 2-[5-(3-Fluorophenyl)thiophen-2-yl]-4-[(Z)-[3-(phenyloxy)phenyl]methylidene]-1,3-oxazacyclopentan-5-one (39)

[0158]

[0159] The same synthesis method as that of intermediate 5 was adopted, using intermediate 32 and intermediate 4 as raw materials to obtain 252 mg of yellow powdery solid with a yield of 79.3%. 1H NMR (300MHz, DMSO-d6) δ8.08-8.04(m,1H),7.88(d,J=4.0Hz,1H),7.85-7.79(m,2H),7.77-7.70(m,1H),7.69-7.64(m,1H),7.62-7.54(m,1H ),7.54-7.51(m,1H),7.51-7.46(m,2H),7.34-7.28(m,1H),7.28(d,J=1.7Hz,1H),7.26-7.22(m,1H),7.21-7.17(m,1H),7.16-7.12(m,2H).

[0160] 2-[5-(3-Fluorophenyl)thiophen-2-yl]-5-[(Z)-[3-(phenyloxy)phenyl]methylidene]-3H-imidazol-4-one (III-9)

[0161]

[0162] The same synthesis method as that of III-1 was used, and intermediate 33 was used as the raw material to obtain 111 mg of yellow solid powder with a yield of 44.5%. 1 H NMR (300MHz, DMSO-d6) δ12.23(s,1H),8.15(t,J=1.9Hz,1H),7.88(d,J=4.0Hz,1H),7.80-7.74(m,2H),7.61(tt,J=13.6,9.0Hz, 3H),7.48(ddt,J=7.9,4.7,2.8Hz,3H),7.32-7.24(m,1H),7.24-7.17(m,1H),7.17-7.12(m,2H),7.12-7.07(m,1H),6.95(s,1H).

[0163] Example 10: Synthesis of 5-[(Z)-{3-[(4-chlorophenyl)oxy]phenyl}methylidene]-2-[5-(3-fluorophenyl)furan-2-yl]-3H-imidazol-4-one (III-10)

[0164] 3-[(4-Chlorophenyl)oxy]benzene-1-carboxaldehyde (42)

[0165]

[0166] Dissolve 4-chlorophenol (40,510 mg, 4 mmol) and 3-formylphenylboronic acid (41,660 mg, 4.4 mmol) in 20 mL of anhydrous dichloromethane. Then, add anhydrous copper acetate (726 mg, 4 mmol) and pyridine (316 mg, 4 mmol) in this order. Stir the reaction at room temperature for approximately 12 hours. After TLC analysis, concentrate under reduced pressure to remove the dichloromethane. Dilute the reaction solution with 10 mL of water, extract the aqueous phase with ethyl acetate (8 mL x 3), combine the organic phases, wash with saturated brine (10 mL x 2), and dry over anhydrous sodium sulfate for at least 2 hours. Filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain 200 mg of a light yellow, transparent oil in a yield of 21.5%. 1 H NMR (300MHz, DMSO-d6) δ9.98 (s, 1H), 7.72 (dt, J = 7.5, 1.3Hz, 1H), 7.64 (t, J = 7.7 Hz,1H),7.52-7.43(m,3H),7.40(ddd,J=7.9,2.6,1.2Hz,1H),7.15-7.08(m,2H).

[0167] 4-[(Z)-{3-[(4-chlorophenyl)oxy]phenyl}methylidene]-2-[5-(3-fluorophenyl)furan-2-yl]-1,3-oxazacyclopentan-5-one (43)

[0168]

[0169] The same synthesis method as intermediate 5 was adopted, using intermediate 42 and intermediate 32 as raw materials to obtain 65 mg of yellow powdery solid with a yield of 14.0%. 1 H NMR (300MHz, DMSO-d6) δ8.04(t,J=1.9Hz,1H),7.96(d,J=7.8Hz,1H),7.75-7.69(m,1H),7.68(q,J=2.0Hz,1H),7.61(dd,J=8.0,4. 9Hz,2H),7.57(d,J=7.9Hz,1H),7.52(d,J=4.8Hz,1H),7.50-7.47(m,2H),7.35-7.29(m,2H),7.23-7.18(m,1H),7.17-7.13(m,2H).

[0170] 5-[(Z)-{3-[(4-chlorophenyl)oxy]phenyl}methylidene]-2-[5-(3-fluorophenyl)furan-2-yl]-3H-imidazol-4-one (III-10)

[0171]

[0172] The same synthesis method as that of III-1 was used, and intermediate 33 was used as the raw material to obtain 111 mg of yellow solid powder with a yield of 44.5%. 1 H NMR (300MHz, DMSO-d6) δ12.21(s,1H),8.14(t,J=2.0Hz,1H),7.90-7.83(m,2H),7.80(d,J=7.9Hz,1H),7.61-7.55(m,1H),7 .54-7.49(m,3H),7.45-7.40(m,2H),7.26(td,J=8.6,2.7Hz,2H),7.17(d,J=2.3Hz,1H),7.15(d,J=2.3Hz,1H),6.98(s,1H).

[0173] Example 11: Synthesis of 2-[5-(3-chloro-5-fluorophenyl)furan-2-yl]-5-[(Z)-[3-(phenyloxy)phenyl]methylene]-3H-imidazol-4-one (III-11)

[0174] Methyl 5-(3-chloro-5-fluorophenyl)furan-2-carboxylate (45)

[0175]

[0176] The same synthesis method as 29 was used to obtain 1.56 g of white solid powder with 5-bromothiophene-2-carboxylic acid methyl ester (27) and (5-chloro-3-fluorophenyl)boranediol (44) as raw materials. The yield was 83.7%. 1 H NMR (300 MHz, DMSO-d6) 1 H NMR (300MHz, DMSO) δ7.73 (t, J=1.5Hz, 1H), 7.66 (ddd, J=9.6, 2.4, 1.4Hz, 1H), 7.50 (dt,J=8.8,2.1Hz,1H),7.47(d,J=3.7Hz,1H),7.41(d,J=3.7Hz,1H),3.85(s,3H).

[0177] 5-(3-Chloro-5-fluorophenyl)furan-2-carboxylic acid (46)

[0178]

[0179] The same synthesis method as intermediate 3 was adopted, using intermediate 45 as the starting material to obtain 460 mg of a white solid with a yield of 96.4%. 1H NMR (300MHz, DMSO-d6) δ13.07 (s, 1H), 7.48 (t, J = 2.1Hz, 1H), 7.40 (s, 1H), 7.2 8(dt,J=12.1,2.2Hz,1H), 7.18(dt,J=12.1,2.1Hz,1H), 6.93(d,J=5.7Hz,1H).

[0180] Ethyl ({[5-(3-chloro-5-fluorophenyl)furan-2-yl]carbonyl}amino)acetate (47)

[0181]

[0182] The same synthesis method as intermediate 2 was used, with intermediate 46 and glycine ethyl ester hydrochloride as raw materials to obtain 195 mg of white solid powder with a yield of 31.3%. 1 H NMR (300MHz, DMSO-d6) δ9.10(t,J=6.0Hz,1H),7.94(t,J=1.5Hz,1H),7.85(ddd,J=9.9,2.4,1.4Hz,1H),7.45(dt,J=8.7,2. 1Hz,1H),7.35(d,J=3.6Hz,1H),7.23(d,J=3.6Hz,1H),4.13(q,J=7.1Hz,2H),4.02(d,J=6.0Hz,2H),1.21(t,J=7.1Hz,3H).

[0183] N-{[5-(3-chloro-5-fluorophenyl)furan-2-yl]carbonyl}glycine (48)

[0184]

[0185] The same synthesis method as intermediate 3 was adopted, using intermediate 47 as raw material to obtain 107.4 mg of white solid, with a yield of 60.2%. 1 H NMR (300MHz, DMSO-d6) δ13.03(s,1H),9.09(t,J=6.0Hz,1H),7.49(t,J=2.2Hz,1H),7.29(dt,J=12.3, 2.2Hz,1H),7.22(s,1H),7.18(dt,J=12.1,2.1Hz,1H),7.14(d,J=5.7Hz,1H),3.91(d,J=6.4Hz,2H).,

[0186] 2-[5-(3-chloro-5-fluorophenyl)furan-2-yl]-4-[(Z)-[3-(phenyloxy)phenyl]methylidene]-1,3-oxazacyclopentan-5-one (49)

[0187]

[0188] The same synthesis method as that of Intermediate 5 was adopted, using Intermediate 48 and Intermediate 4 as raw materials to obtain 65 mg of yellow powdery solid with a yield of 14.0%. 1 H NMR (300MHz, DMSO-d6) δ8.04-7.99(m,1H),7.91(d,J=7.7Hz,1H),7.77(t,J=1.7Hz,1H),7.65(ddd,J=9.4,2.4,1.4Hz,1H),7.60(d,J=3.8Hz,1H),7.5 6(d,J=4.0Hz,1H),7.54(d,J=3.2Hz,1H),7.53-7.50(m,1H),7.49-7.41(m, 2H),7.31(s,1H),7.22-7.18(m,1H),7.18-7.14(m,1H),7.14-7.08(m,2H).

[0189] 2-[5-(3-chloro-5-fluorophenyl)furan-2-yl]-5-[(Z)-[3-(phenyloxy)phenyl]methylidene]-3H-imidazol-4-one (III-11)

[0190]

[0191] The same synthesis method as that of III-1 was used, and intermediate 33 was used as the raw material to obtain 111 mg of yellow solid powder with a yield of 44.5%. 1 H NMR (300MHz, DMSO-d6) δ12.22(s,1H),8.15(dt,J=7.7,2.2Hz,1H),8.13(s,1H),7.88-7.83(m,2H),7.52(t,J=2.1Hz,1H),7.41(t,J=7.7Hz, 1H),7.37-7.34(m,2H),7.34-7.31(m,1H),7.18(dt,J=12.1,2.2Hz,1H),7.12(dt,J=7.3,1.3Hz,1H),7.10-7.05(m,2H),7.03-6.99(m,2H).

[0192] Example 12: Synthesis of 2-[5-(3-fluorophenyl)furan-2-yl]-5-[(Z)-[3-(pyridin-2-yloxy)phenyl]methylene]-3H-imidazol-4-one (III-12)

[0193] 3-(Pyridin-2-yloxy)benzene-1-carboxaldehyde (52)

[0194]

[0195] 3-Hydroxybenzaldehyde (51, 1 g, 7.67 mmol) and 2-bromopyridine (50, 2.63 g, 11.50 mmol) were dissolved in anhydrous dioxane. Cesium carbonate (5.42 g, 11.50 mmol), N,N-dimethylglycine hydrochloride (232.3 mg, 1.53 mmol), and cuprous oxide (105.7 mg, 0.77 mmol) were added sequentially. The reaction was refluxed at 120°C under argon for approximately 48 hours. After completion of the reaction, monitored by TLC, the mixture was filtered through Celite. The filtrate was collected and concentrated under reduced pressure to remove the dioxane. The reaction solution was then diluted with 20 mL of water. The aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (15 mL x 2) and dried over anhydrous sodium sulfate for at least 2 hours. The filtrate was filtered and concentrated under reduced pressure, and then purified by column chromatography (petroleum ether:ethyl acetate=6:1) to obtain 1.2 g of a khaki solid with a yield of 73.5%. 1 H NMR(300MHz, DMSO-d6)δ10.02(s,1H),8.17(dd,J=5.0,1.9Hz,1H),7.96-7.86(m,1H),7.78(dt,J=7.6,1.3Hz,1H),7 .71-7.61(m,2H),7.50(ddd,J=8.0,2.5,1.2Hz,1H),7.18(ddd,J=7.2,5.0,0.9Hz,1H),7.14(dd,J=8.2,0.9Hz,1H).

[0196] 2-[5-(3-Fluorophenyl)furan-2-yl]-4-[(Z)-[3-(pyridin-2-yloxy)phenyl]methylidene]-1,3-oxazacyclopentan-5-one (53)

[0197]

[0198] The same synthesis method as intermediate 5 was adopted, using intermediate 52 and intermediate 4 as raw materials to obtain 219 mg of yellow powdery solid with a yield of 51.4%. 1H NMR (300MHz, DMSO-d6) δ8.20 (ddd, J=4.9, 2.1, 0.8Hz, 1H), 8.13 (t, J=1.9Hz, 1H), 8. 05(dt,J=7.9,1.3Hz,1H),7.92(ddd,J=8.2,7.2,2.0Hz,1H),7.71-7.67(m,1H),7.66 (dd,J=2.8,1.5Hz,2H),7.57(d,J=2.7Hz,1H),7.56-7.51(m,1H),7.47(d,J=3.8Hz, 1H), 7.33 (q, J=1.7Hz, 2H), 7.29 (ddd, J=8.2, 2.5, 1.0Hz, 2H), 7.16 (d, J=0.9Hz, 1H).

[0199] 2-[5-(3-Fluorophenyl)furan-2-yl]-5-[(Z)-[3-(pyridin-2-yloxy)phenyl]methylidene]-3H-imidazol-4-one (III-12)

[0200]

[0201] The same synthesis method as III-1 was used, using intermediate 53 as the raw material to obtain 69.8 mg of yellow solid powder with a yield of 38.8%. 1 H NMR (300 MHz, DMSO-d6) δ 1 H NMR (300MHz, DMSO) δ12.26 (s, 1H), 8.22-8.15 (m, 2H), 8.02 (d, J = 7.8Hz, 1H), 7. 91(ddd,J=8.9,7.2,2.0Hz,1H),7.82(dt,J=10.2,2.2Hz,1H),7.75(d,J=7.8Hz, 1H),7.60-7.53(m,1H),7.53-7.47(m,2H),7.41(d,J=3.8Hz,1H),7.26(td,J=8 .5,2.5Hz,1H),7.18(td,J=7.5,3.5Hz,2H),7.12(d,J=8.3Hz,1H),7.01(s,1H).

[0202] Example 13: Synthesis of 5-[(Z)-{3-[(6-chloropyridin-3-yl)oxy]phenyl}methylidene]-2-[5-(3-fluorophenyl)furan-2-yl]-3H-imidazol-4-one (III-13)

[0203]

[0204] The same synthesis method as intermediate 52 was used, using m-hydroxybenzaldehyde as the starting material to obtain 933 mg of a yellow transparent oil with a yield of 65.6%. 1 H NMR(300MHz, DMSO-d6)δ9.99(s,1H),8.31(dd,J=3.0,0.7Hz,1H),7.78-7.72(m,1H),7.70-7.65(m, 1H),7.64-7.62(m,1H),7.59(d,J=0.7Hz,1H),7.57-7.53(m,1H),7.48(ddd,J=8.0,2.6,1.2Hz,1H).

[0205] 4-[(Z)-{3-[(6-chloropyridin-3-yl)oxy]phenyl}methylidene]-2-[5-(3-fluorophenyl)furan-2-yl]-1,3-oxazacyclopentan-5-one (55)

[0206]

[0207] The same synthesis method as intermediate 5 was adopted, using intermediate 54 and intermediate 32 as raw materials to obtain 306 mg of yellow powdery solid with a yield of 76.9%. 1 H NMR(300MHz,DMSO-d6)δ8.35(d,J=3.0Hz,1H),8.07-8.00(m,2H),7.76-7.67(m,3H),7.65(dd,J=5.7,3 .4Hz,2H),7.60(d,J=7.9Hz,2H),7.50(d,J=4.0Hz,1H),7.33(s,1H),7.28(ddd,J=8.0,6.1,2.2Hz,2H).

[0208] 5-[(Z)-{3-[(6-chloropyridin-3-yl)oxy]phenyl}methylidene]-2-[5-(3-fluorophenyl)furan-2-yl]-3H-imidazol-4-one (III-13)

[0209]

[0210] The same synthesis method as III-1 was used, using intermediate 53 as the raw material to obtain 170 mg of yellow solid powder with a yield of 68.1%. 1 H NMR (300 MHz, DMSO-d6) δ 1H NMR (300MHz, DMSO) δ12.34(s,1H),8.36(d,J=2.9Hz,1H),8.15(d,J=2.4Hz,1H),7.92(d,J=7.8Hz,1H),7.89-7.83(m,1H),7.79(d,J=7 .8Hz,1H),7.67(dd,J=8.7,3.0Hz,1H),7.63-7.50(m,3H),7.47(d,J=12.3Hz,2H),7.30-7.22(m,1H),7.22-7.16(m,1H),6.99(s,1H).

[0211] Example 14: Synthesis of 2-[5-(3-fluorophenyl)furan-2-yl]-5-[(Z)-[3-(thiophen-2-yloxy)phenyl]methylene]-3H-imidazol-4-one (III-14)

[0212] 3-(Thiophen-2-yloxy)benzene-1-carboxaldehyde (56)

[0213]

[0214] The same synthetic method as intermediate 52 was adopted, using m-hydroxybenzaldehyde and 2-bromothiophene as raw materials to obtain 115.4 mg of yellow transparent oil with a yield of 9.2%. 1 H NMR(300MHz, DMSO-d6)δ9.98(s,1H),7.72(dt,J=7.5,1.3Hz,1H),7.64(t,J=7.7Hz,1H),7.52(ddd,J=2.7,1.4,0.5Hz,1H) ,7.47(ddd,J=8.0,2.7,1.2Hz,1H),7.17(dd,J=5.8,1.6Hz,1H),6.94(dd,J=5.8,3.8Hz,1H),6.78(dd,J=3.7,1.5Hz,1H).

[0215] 2-[5-(3-Fluorophenyl)furan-2-yl]-4-[(Z)-[3-(thiophen-2-yloxy)phenyl]methylidene]-1,3-oxazacyclopentan-5-one (57)

[0216]

[0217] The same synthesis method as intermediate 5 was used, using intermediate 56 and intermediate 32 as raw materials to obtain 306 mg of yellow powdery solid with a yield of 76.9%. 1 H NMR (300 MHz, DMSO-d6) δ 1H NMR (300MHz, DMSO) δ8.20 (s, 1H), 7.89 (d, J = 7.7Hz, 1H), 7.73 (d, J = 8.0Hz, 2H), 7.62 (dd, J = 7.8, 5.1Hz, 2H), 7.54 (t, J = 8.0Hz, 1H) ,7.48(d,J=3.9Hz,1H),7.36-7.22(m,3H),7.16(dd,J=5.8,1.5Hz,1H),6.95(dd,J=5.8,3.7Hz,1H),6.80(dd,J=3.7,1.6Hz,1H).

[0218] 2-[5-(3-Fluorophenyl)furan-2-yl]-5-[(Z)-[3-(thiophen-2-yloxy)phenyl]methylidene]-3H-imidazol-4-one (III-14)

[0219]

[0220] The same synthesis method as that of III-1 was used, and intermediate 57 was used as the starting material to obtain 85 mg of yellow solid powder with a yield of 47.8%. 1 H NMR(300MHz,DMSO-d6)δ12.26(s,1H),8.32-8.27(m,1H),7.90-7.76(m,3H),7.57(td,J=8.1,6.0Hz,1H),7.51-7.45(m,2 H),7.43(d,J=3.8Hz,1H),7.26(td,J=8.7,2.6Hz,1H),7.20-7.14(m,2H),7.00-6.92(m,2H),6.79(dd,J=3.8,1.6Hz,1H).

[0221] Example 15: Synthesis of 5-[(Z)-{3-[(5-chlorothiophen-2-yl)oxy]phenyl}methylidene]-2-[5-(3-fluorophenyl)furan-2-yl]-3H-imidazol-4-one (III-15)

[0222] 3-[(5-Chlorothien-2-yl)oxy]benzene-1-carboxaldehyde (58)

[0223]

[0224] The same synthesis method as intermediate 52 was adopted, using m-hydroxybenzaldehyde and 2-bromothiophene as raw materials to obtain 500 mg of yellow transparent oil with a yield of 24.8%. 1H NMR (300MHz, DMSO-d6) δ10.00(s,1H),7.74(dt,J=7.6,1.3Hz,1H),7.65(t,J=7.8Hz,1H),7.57(dd, J=2.8,1.3Hz,1H),7.51(ddd,J=8.1,2.7,1.1Hz,1H),7.01(d,J=4.1Hz,1H),6.73(d,J=4.1Hz,1H).

[0225] 4-[(Z)-{3-[(5-chlorothiophen-2-yl)oxy]phenyl}methylidene]-2-[5-(3-fluorophenyl)furan-2-yl]-1,3-oxazacyclopentan-5-one (59)

[0226]

[0227] The same synthesis method as intermediate 5 was adopted, using intermediate 58 and intermediate 32 as raw materials to obtain 63 mg of yellow powdery solid with a yield of 64.55%. 1 H NMR (300MHz, DMSO-d6) δ8.21(t,J=2.1Hz,1H),7.96(d,J=7.7Hz,1H),7.78-7.71(m,2H),7.65(d,J=3.8Hz,1H),7.64-7. 59(m,1H),7.56(t,J=7.9Hz,1H),7.51(d,J=3.9Hz,1H),7.35-7.26(m,3H),7.01(d,J=4.1Hz,1H),6.75(d,J=4.2Hz,1H).

[0228] 5-[(Z)-{3-[(5-chlorothien-2-yl)oxy]phenyl}methylidene]-2-[5-(3-fluorophenyl)furan-2-yl]-3H-imidazol-4-one (III-15)

[0229]

[0230] The same synthesis method as III-1 was used, using intermediate 59 as the starting material to obtain 14 mg of yellow solid powder with a yield of 28.0%. 1 H NMR (300MHz, DMSO-d6) δ12.30(s,1H),8.34(s,1H),7.84(q,J=9.4Hz,3H),7.56(d,J=10 .1Hz,2H),7.46(s,2H),7.24(q,J=8.6Hz,2H),7.07-6.93(m,2H),6.73(d,J=4.1Hz,1H).

[0231] Example 16: Synthesis of 2-[4-(3-fluorophenyl)phenyl]-5-[(Z)-[3-(phenyloxy)phenyl]methylene]-3H-imidazol-4-one (III-16)

[0232] Methyl 4-(3-fluorophenyl)benzoate (61)

[0233]

[0234] The same synthesis method as 29 was used, with methyl 4-bromobenzoate (60) and 3-fluorophenylboronic acid (28) as raw materials to obtain 399 mg of white solid powder with a yield of 74.6%. 1 H NMR (300MHz, DMSO-d6) δ8.09-7.99(m,2H),7.92-7.82(m,2H),7.63(p,J=1.6Hz,1H),7. 60(dd,J=2.4,1.5Hz,1H),7.54(td,J=8.1,6.1Hz,1H),7.33-7.20(m,1H),3.88(s,3H).

[0235] 4-(3-Fluorophenyl)benzoic acid(62)

[0236]

[0237] The same synthesis method as intermediate 3 was adopted, using intermediate 61 as raw material to obtain 465 mg of white solid, with a yield of 99.0%. 1 H NMR (300MHz, DMSO-d6) δ12.71(s,1H),8.14-8.06(m,2H),7.62-7.55(m,2H),7.44(ddd,J=8.1,2.1,1 .2Hz,1H),7.39-7.33(m,1H),7.15(dt,J=12.2,2.2Hz,1H),7.04(dddd,J=9.9,7.7,2.2,1.2Hz,1H).

[0238] Ethyl ({[4-(3-fluorophenyl)phenyl]carbonyl}amino)acetate (63)

[0239]

[0240] The same synthesis method as intermediate 2 was adopted, using intermediate 62 and glycine ethyl ester hydrochloride as raw materials to obtain 472 mg of white solid powder with a yield of 72.8%. 1H NMR (300MHz, DMSO-d6) δ9.02(t,J=5.9Hz,1H),8.01-7.94(m,2H),7.89-7.82(m,2H),7.62(p,J=1.7Hz,1H),7.60(d,J=1.8H z,1H),7.54(td,J=8.0,6.2Hz,1H),7.28-7.21(m,1H),4.13(q,J=7.1Hz,2H),4.02(d,J=5.9Hz,2H),1.21(t,J=7.1Hz,3H).

[0241] N-{[4-(3-Fluorophenyl)phenyl]carbonyl}glycine (64)

[0242]

[0243] The same synthesis method as intermediate 3 was adopted, using intermediate 61 as raw material to obtain 465 mg of white solid, with a yield of 99.0%. 1 H NMR (300MHz, DMSO-d6) δ13.03(s,1H),7.93-7.84(m,2H),7.74(t,J=6.7Hz,1H),7.67-7.59(m,2H),7.44(ddd,J=8.1,2.2,1 .1Hz,1H),7.39-7.32(m,1H),7.15(dt,J=12.2,2.2Hz,1H),7.04(dddd,J=9.9,7.7,2.2,1.2Hz,1H),3.86(d,J=6.6Hz,2H).

[0244] 2-[4-(3-Fluorophenyl)phenyl]-4-[(Z)-[3-(phenyloxy)phenyl]methylidene]-1,3-oxazacyclopentyl-5-one (65)

[0245]

[0246] The same synthesis method as intermediate 5 was adopted, using intermediate 64 and intermediate 4 as raw materials to obtain 600 mg of yellow powdery solid with a yield of 81.5%. 1 H NMR(400MHz, DMSO-d6)δ8.14(t,J=2.0Hz,1H),8.00-7.90(m,4H),7.80-7.76(m,1H),7.74-7.67(m,2H),7.59-7.5 0(m,4H),7.46-7.40(m,1H),7.32(s,1H),7.31-7.27(m,1H),7.24(ddd,J=8.3,2.6,1.0Hz,1H),7.21-7.16(m,2H).

[0247] 2-[4-(3-fluorophenyl)phenyl]-5-[(Z)-[3-(phenyloxy)phenyl]methylidene]-3H-imidazol-4-one (III-16)

[0248]

[0249] The same synthesis method as III-1 was used, using intermediate 65 as the raw material to obtain 111 mg of yellow solid powder with a yield of 44.5%. 1H NMR(300MHz,DMSO-d6)δ12.13(s,1H),8.27-8.24(m,1H),8.02-7.90(m,4H),7 .75-7.72(m,1H),7.71(t,J=1.7Hz,1H),7.69(p,J=1.6Hz,1H),7.62-7.56(m,1 H),7.54(d,J=1.4Hz,1H),7.51(d,J=2.7Hz,1H),7.47(d,J=7.9Hz,1H),7.43-7 .36(m,1H),7.33-7.24(m,1H),7.17(ddd,J=7.5,6.5,2.0Hz,3H),7.00(s,1H).

[0250] Example 17: Synthesis of 5-{5-oxyylidene-4-[(Z)-[3-(phenyloxy)phenyl]methylene]-4,5-dihydro-1H-imidazol-2-yl}-2,3-dihydro-1H-benzo[d]imidazol-2-one (III-17)

[0251] 2-Oxylidene-1,3-dihydrobenzo[d]imidazole-5-carboxylic acid (66)

[0252]

[0253] The same synthetic method as intermediate 3 was used, using 2-oxyylidene-1,3-dihydrobenzo[d]imidazole-5-carboxylic acid methyl ester as the starting material to obtain 910 mg of a white solid with a yield of 98.1%. 1 H NMR (300MHz, DMSO-d6) δ12.54(s,1H),11.01(s,1H),10.87(d,J=1.9Hz,1H),7.61(dd,J=8.2,1.6Hz,1H),7.47(d,J=1.6Hz,1H),7.00(d,J=8.2Hz,1H).

[0254] Ethyl {[(2-oxoylidene-1,3-dihydrobenzo[d]imidazol-5-yl)carbonyl]amino}acetate (67)

[0255]

[0256] The same synthesis method as intermediate 2 was adopted, using intermediate 66 and glycine ethyl ester hydrochloride as raw materials to obtain 823.7 mg of white solid powder with a yield of 60.1%. 1 H NMR (300MHz, DMSO-d6) δ10.89(d,J=11.3Hz,2H),8.78(t,J=5.9Hz,1H),7.53(dd,J=8.2,1.7Hz,1H),7.46( d,J=1.6Hz,1H),6.98(d,J=8.1Hz,1H),4.11(q,J=7.1Hz,2H),3.96(d,J=5.8Hz,2H),1.20(t,J=7.1Hz,3H).

[0257] N-[(2-Oxylidene-1,3-dihydrobenzo[d]imidazol-5-yl)carbonyl]glycine (68)

[0258]

[0259] The same synthesis method as intermediate 3 was adopted, using intermediate 61 as raw material to obtain 465 mg of white solid, with a yield of 99.0%. 1 H NMR (300MHz, DMSO-d6) δ12.56(s,1H),10.89(d,J=11.3Hz,2H),8.29(d,J=2.0Hz,1H),7.95(t,J=6.7Hz,1H),7.78-7.67(m,2H),3.86(d,J=6.6Hz,2H).

[0260] 5-{5-Oxylidene-4-[(Z)-[3-(phenyloxy)phenyl]methylidene]-5H,4H-1,3-oxazacyclopentyl-2-yl}-2,3-dihydro-1H-benzo[d]imidazol-2-one (69)

[0261]

[0262] The same synthesis method as that of Intermediate 5 was adopted, using Intermediate 68 and Intermediate 4 as raw materials to obtain 600 mg of yellow powdery solid with a yield of 81.5%. 1H NMR (400MHz, DMSO-d6) δ9.72(d,J=1.7Hz,1H),9.65(d,J=1.5Hz,1H),8.94(d,J =2.4Hz,1H),8.21(d,J=8.8Hz,1H),8.11-8.07(m,1H),7.75(dd,J=8.8,2.2Hz, 1H),7.68(t,J=2.2Hz,1H),7.58(s,1H),7.39(t,J=7.7Hz,1H),7.37-7.32(m,2 H),7.11(tt,J=7.5,1.4Hz,1H),7.07(dt,J=7.5,2.4Hz,1H),7.03-6.97(m,2H).

[0263] 5-{5-Oxylidene-4-[(Z)-[3-(phenyloxy)phenyl]methylidene]-4,5-dihydro-1H-imidazol-2-yl}-2,3-dihydro-1H-benzo[d]imidazol-2-one (III-17)

[0264]

[0265] Using the same synthetic method as III-1, intermediate 65 was used as the starting material to obtain 111 mg of a yellow solid powder in a 44.5% yield. 1H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 3H), 8.16 (t, J = 2.0 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 8.2, 1.7 Hz, 1H), 7.52-7.41 (m, 3H), 7.29-7.20 (m, 1H), 7.14 (d, J = 1.3 Hz, 1H), 7.12-7.02 (m, 3H), 6.87 (s, 1H).

[0266] Example 18: Synthesis of 5-[(Z)-{3-[(5-chloropyridin-3-yl)oxy]phenyl}methylidene]-2-[5-(3-fluorophenyl)furan-2-yl]-3H-imidazol-4-one (III-18)

[0267] 3-[(5-chloropyridin-3-yl)oxy]benzene-1-carboxaldehyde (70)

[0268]

[0269] The same synthesis method as intermediate 52 was used, using m-hydroxybenzaldehyde as the starting material to obtain 368 mg of a yellow transparent oil with a yield of 67.0%. 1H NMR (300MHz, DMSO-d6) δ10.00(s,1H),8.49(dd,J=2.0,0.5Hz,1H),8.42(dd,J=2.5,0.5Hz,1H),7.82 -7.73(m,2H),7.68(t,J=7.8Hz,1H),7.58(dd,J=2.6,1.4Hz,1H),7.50(ddd,J=8.0,2.6,1.1Hz,1H).

[0270] 4-[(Z)-{3-[(5-chloropyridin-3-yl)oxy]phenyl}methylidene]-2-[5-(3-fluorophenyl)furan-2-yl]-1,3-oxazacyclopentan-5-one (71)

[0271]

[0272] The same synthesis method as that of Intermediate 5 was adopted, using Intermediate 70 and Intermediate 32 as raw materials to obtain 600 mg of yellow powdery solid with a yield of 81.5%. 1 H NMR (400MHz, DMSO-d6) δ8.48(dd,J=6.1,2.2Hz,2H),8.10-8.03(m,2H),7.78(t,J=2.2Hz,1H),7.75-7.67(m,2 H),7.66(d,J=3.8Hz,1H),7.60(tt,J=8.3,2.9Hz,2H),7.49(d,J=3.8Hz,1H),7.34(s,1H),7.32-7.22(m,2H).

[0273] 5-[(Z)-{3-[(5-chloropyridin-3-yl)oxy]phenyl}methylidene]-2-[5-(3-fluorophenyl)furan-2-yl]-3H-imidazol-4-one (III-18)

[0274]

[0275] Using the same synthetic method as III-1, intermediate 65 was used as the starting material to obtain 111 mg of a yellow solid powder in a 44.5% yield. 1H NMR (300 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.48 (dd, J = 9.9, 2.3 Hz, 2H), 8.19-8.12 (m, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.85 (dd, J = 10.4, 2.5 Hz, 1H), 7.77 (dd, J = 5.2, 2.8 Hz, 2H), 7.56 (ddd, J = 12.7, 9.4, 7.0 Hz, 2H), 7.49-7.40 (m, 2H), 7.31-7.15 (m, 2H), 7.01 (s, 1H).

[0276] Example 19: Synthesis of 2-(Benzo[2,1-c][1,2,5]oxadiazacyclopentane-5-yl)-4-[(Z)-[3-(phenyloxy)phenyl]methylene]-1H-imidazol-5-one (III-19)

[0277] Ethyl [(Benzo[2,1-c][1,2,5]oxadiazacyclopentan-5-ylcarbonyl)amino]acetate (72)

[0278]

[0279] The same synthetic method as intermediate 2 was used, using benzo[2,1-c][1,2,5]oxadiazacyclopentane-5-carboxylic acid and glycine ethyl ester hydrochloride as raw materials to obtain 665 mg of white solid powder with a yield of 43.7%. 1 H NMR(300MHz,DMSO-d6)δ9.39(t,J=5.9Hz,1H),8.54(d,J=1.3Hz,1H),8.17(dd,J=9.4,1.1Hz,1H) ,7.95(dd,J=9.4,1.4Hz,1H),4.14(q,J=7.1Hz,2H),4.07(d,J=5.8Hz,2H),1.22(t,J=7.1Hz,3H).

[0280] N-(Benzo[2,1-c][1,2,5]oxadiazacyclopentan-5-ylcarbonyl)glycine (73)

[0281]

[0282] The same synthesis method as intermediate 3 was used, using intermediate 72 as the starting material to obtain 580 mg of a white solid with a yield of 99.3%. 1H NMR (300MHz, DMSO-d6) δ12.58(s,1H),9.20(d,J=2.3Hz,1H),8.71(d,J=8.6Hz,1H),7.97-7.90(m,2H),3.86(d,J=6.6Hz,2H).

[0283] 2-(Benzo[2,1-c][1,2,5]oxadiazacyclopentan-5-yl)-4-[(Z)-[3-(phenyloxy)phenyl]methylidene]-1,3-oxadiazacyclopentan-5-one(74)

[0284]

[0285] The same synthesis method as that of Intermediate 5 was adopted, using Intermediate 73 and Intermediate 4 as raw materials to obtain 283.4 mg of yellow powdery solid with a yield of 71.9%. 1 H NMR (300MHz, DMSO-d6) δ8.69(t,J=1.2Hz,1H),8.38(dd,J=9.4,1.1Hz,1H),8.15(t,J=2.0Hz,1H),7.84(d,J=7.7Hz,1H) ,7.79(dd,J=9.4,1.4Hz,1H),7.64-7.55(m,3H),7.51(d,J=6.2Hz,2H),7.33(dd,J=7.6,2.5Hz,1H),7.27-7.21(m,2H).

[0286] 2-(Benzo[2,1-c][1,2,5]oxadiazacyclopent-5-yl)-4-[(Z)-[3-(phenyloxy)phenyl]methylidene]-1H-imidazol-5-one (III-19)

[0287]

[0288] Using the same synthetic method as III-1, intermediate 74 was used as the starting material to obtain 27 mg of a yellow solid powder in a 15.8% yield. 1H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.60 (s, 1H), 8.27-8.18 (m, 2H), 7.81 (d, J = 9.5 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.59-7.51 (m, 2H), 7.48-7.40 (m, 2H), 7.21 (dd, J = 8.4, 5.6 Hz, 3H), 7.13 (s, 1H).

[0289] Example 20: Synthesis of 5-[(Z)-{3-[(5-chlorothiophen-2-yl)oxy]phenyl}methylidene]-2-[4-(3-fluorophenyl)phenyl]-3H-imidazol-4-one (III-20)

[0290]

[0291] The same synthesis method as that of Intermediate 5 was adopted, using Intermediate 58 and Intermediate 64 as raw materials to obtain 283.4 mg of yellow powdery solid with a yield of 71.9%. 1 H NMR (300MHz, DMSO-d6) δ8.42(s,1H),8.06(d,J=8.4Hz,2H),8.03(d,J=1.9Hz,2H),7.83(d,J=7.9Hz,3H),7 .70(d,J=5.6Hz,1H),7.67(s,1H),7.63(s,1H),7.37(s,1H),7.24(d,J=4.1Hz,2H),6.83(d,J=4.1Hz,1H).

[0292] 5-[(Z)-{3-[(5-chlorothiophen-2-yl)oxy]phenyl}methylidene]-2-[4-(3-fluorophenyl)phenyl]-3H-imidazol-4-one (III-20)

[0293]

[0294] Using the same synthetic method as III-1, intermediate 75 was used as the starting material to obtain 14 mg of a yellow solid powder in a yield of 28.0%. 1H NMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.55 (s, 1H), 8.11 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 7.9 Hz, 1H), 7.70 (s, 1H), 7.67 (s, 1H), 7.58 (q, J = 7.7 Hz, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.28-7.23 (m, 2H), 7.03 (s, 1H), 6.82 (d, J = 4.2 Hz, 1H).

[0295] Example 21: Synthesis of 6-{4-oxyylidene-5-[(Z)-[3-(phenyloxy)phenyl]methylidene]-4,5-dihydro-3H-imidazol-2-yl}-2,3-dihydro-1H-indol-2-one (III-21)

[0296] Ethyl {[(2-oxoylidene-2,3-dihydro-1H-indol-6-yl)carbonyl]amino}acetate (76)

[0297]

[0298] The same synthetic method as intermediate 2 was used, using 2-oxyylidene-2,3-dihydro-1H-indole-6-carboxylic acid and glycine ethyl ester hydrochloride as raw materials to obtain 346 mg of white solid powder with a yield of 38.5%. 1 H NMR (300MHz, DMSO-d6) δ10.60(s,1H),8.93(t,J=5.9Hz,1H),7.47(dd,J=7.7,1.5Hz,1H),7.36 -7.24(m,2H),4.11(q,J=7.1Hz,2H),3.96(d,J=5.8Hz,2H),3.54(s,2H),1.20(t,J=7.1Hz,3H).

[0299] N-[(2-Oxylidene-2,3-dihydro-1H-indol-6-yl)carbonyl]glycine (77)

[0300]

[0301] The same synthesis method as intermediate 3 was used, using intermediate 72 as the starting material to obtain 580 mg of a white solid with a yield of 99.3%. 1 H NMR (300MHz, DMSO-d6) δ11.56(s,1H),10.59(s,1H),8.95(t,J=6.7Hz,1H),7.70(dd,J=8.4,2.2 Hz,1H),7.60(d,J=2.1Hz,1H),7.42-7.37(m,1H),3.86(d,J=6.6Hz,2H),3.41(d,J=0.7Hz,2H).

[0302] 6-{5-Oxylidene-4-[(Z)-[3-(phenyloxy)phenyl]methylidene]-5H,4H-1,3-oxazacyclopentyl-2-yl}-2,3-dihydro-1H-indol-2-one (78)

[0303]

[0304] The same synthesis method as intermediate 5 was adopted, using intermediate 7 and intermediate 4 as raw materials to obtain 251.2 mg of yellow powdery solid with a yield of 42.3%. 1H NMR (300MHz, DMSO-d6) δ10.61(s,1H),8.13-8.05(m,1H),7.80(d,J=2.1Hz,1H),7.75(dd,J=8.8,2.2Hz,1H),7.68( dd,J=2.6,1.9Hz,1H),7.58(s,1H),7.44-7.30(m,4H),7.14-7.04(m,2H),7.04-6.98(m,2H),3.41(d,J=0.7Hz,2H).

[0305] 6-{4-Oxylidene-5-[(Z)-[3-(phenyloxy)phenyl]methylidene]-4,5-dihydro-3H-imidazol-2-yl}-2,3-dihydro-1H-indol-2-one (III-21)

[0306]

[0307] Using the same synthetic method as III-1, intermediate 78 was used as the starting material to obtain 45 mg of a yellow solid powder in an 18.0% yield. 1H NMR (300 MHz, DMSO-d6) δ 12.06 (s, 1H), 10.59 (s, 1H), 8.17-8.11 (m, 2H), 8.01 (d, J = 2.1 Hz, 1H), 7.92-7.83 (m, 2H), 7.47 (dq, J = 8.8, 0.7 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.38-7.31 (m, 2H), 7.16-7.05 (m, 2H), 7.04-6.98 (m, 2H), 3.41 (d, J = 0.7 Hz, 2H).

[0308] Example 22: Synthesis of 2-[5-(3-fluorophenyl)furan-2-yl]-5-[(Z)-[3-(1,3-oxazacyclopentyl-2-yloxy)phenyl]methylene]-3H-imidazol-4-one (III-22)

[0309] 3-(1,3-Oxaazacyclopentan-2-yloxy)benzene-1-carboxaldehyde(79)

[0310]

[0311] The same synthetic method as intermediate 52 was adopted, using m-hydroxybenzaldehyde and 2-bromoisoxazole as raw materials to obtain 237 mg of yellow transparent oil with a yield of 37.0%. 1H NMR(300MHz,DMSO-d6)δ9.94(s,1H),8.59(dd,J=2.5,1.9Hz,1H),8.21(dt,J=7 .5,2.6Hz,1H),7.66-7.57(m,2H),7.41(d,J=7.7Hz,1H),6.83(d,J=0.7Hz,1H).

[0312] 2-[5-(3-Fluorophenyl)furan-2-yl]-4-[(Z)-[3-(1,3-oxazacyclopentan-2-yloxy)phenyl]methylidene]-1,3-oxazacyclopentan-5-one (80)

[0313]

[0314] The same synthesis method as that of Intermediate 5 was adopted, using Intermediate 79 and Intermediate 32 as raw materials to obtain 560 mg of yellow powdery solid with a yield of 78.5%. 1 H NMR (300MHz, DMSO-d6) δ8.20(d,J=1.6Hz,1H),8.12-8.07(m,1H),7.94(d,J=1.6Hz,1H),7.80(t,J=2.3Hz,1H),7.72 (d,J=7.7Hz,1H),7.64-7.55(m,2H),7.44-7.35(m,2H),7.33-7.27(m,1H),7.12(d,J=7.7Hz,1H),7.09-7.01(m,2H).

[0315] 2-[5-(3-Fluorophenyl)furan-2-yl]-5-[(Z)-[3-(1,3-oxazacyclopentyl-2-yloxy)phenyl]methylidene]-3H-imidazol-4-one (III-22)

[0316]

[0317] Using the same synthetic method as III-1, starting from intermediate 80, 76 mg of a yellow solid powder was obtained in a 46.5% yield. 1H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.18-8.11 (m, 2H), 7.94 (d, J = 1.6 Hz, 1H), 7.87-7.81 (m, 2H), 7.63 (ddd, J = 8.9, 2.2, 1.1 Hz, 1H), 7.43-7.33 (m, 3H), 7.12-7.01 (m, 3H).

[0318] Example 23: In vitro MAGL enzyme inhibition activity test

[0319] MAGL can hydrolyze 2-AG in cells to produce arachidonic acid and glycerol. Different enzyme activities catalyze the production of different amounts of product for a given amount of substrate. Enzyme activity can be assessed by measuring the amount of product. Using Cayman's MAGL inhibitor screening kit, according to the instructions, a certain concentration of MAGL was diluted, and buffer was added. Then, compounds of varying concentrations were added. A blank control group, an initial enzyme activity group, and a JZL-195 positive control group were set up. After a 5-minute incubation, the substrate 4-nitrophenylacetate (4-NPA) was added to initiate the reaction. After an additional 10-minute incubation, the change in absorbance before and after hydrolysis was measured using a microplate reader to indirectly measure MAGL enzyme activity. Finally, the compound's inhibition rate was calculated.

[0320] The specific results are shown in Table 1, which indicate that the compounds of the present invention have good inhibitory activity.

[0321] Table 1

[0322]

[0323] Example 24: Liver microsome stability experiment

[0324] Liver metabolic stability is an important pharmacokinetic property in drug evaluation, affecting drug clearance, half-life, and oral bioavailability. Compounds III-15, 16, and 20, which exhibited strong MAGL enzyme inhibitory activity, were selected for liver microsome stability testing.

[0325] (1) Reagent preparation

[0326] a. Buffer preparation: Buffer A is 0.1 M potassium dihydrogen phosphate buffer containing 1.0 mM EDTA; Buffer B is 0.1 M potassium dihydrogen phosphate buffer containing 1.0 mM EDTA; Buffer A is used to titrate 700 mL of buffer B to a pH of 7.4 to obtain buffer C, which contains 0.1 M potassium phosphate buffer and 1.0 mM EDTA.

[0327] b Preparation of reference substance (ketanserin) and test compound spike solutions: Dissolve ketanserin and test compound in DMSO to a final concentration of 10 mM stock solution. Dilute 10 μL of the compound DMSO stock solution with 190 μL of acetonitrile to prepare a 500 μM spike solution. Then, on ice, add 1.5 μL of the 500 μM spike solution and 18.75 μL of 20 mg / mL liver microsomes to 479.75 μL of buffer C to prepare a 1.5 μM spike solution containing 0.75 mg / mL liver microsomes.

[0328] c. Dissolve NADPH in buffer C to obtain a 6 mM NADPH stock solution.

[0329] (2) Operation method

[0330] A 1.5 μM solution of liver microsomes (containing the internal standard imipramine) at 0, 5, 15, 30, and 45 minutes was added to the assay plates on ice. At 0 minutes, 135 μL of acetonitrile containing the internal standard was added to the wells of the 0-minute plate, followed by 15 μL of NADPH stock solution as a control. The remaining assay plates were preincubated at 37°C for 5 minutes. Then, 15 μL of NADPH stock solution was added to all assay plates to initiate the reaction and time the reaction. At 5, 15, 30, and 45 minutes, 135 μL of acetonitrile containing the internal standard was added to the wells of the corresponding assay plates to terminate the reaction. After termination, the plates were shaken on a shaker (600 rpm / min) for 10 minutes and then centrifuged for 15 minutes. Finally, 50 μL of the supernatant in each assay plate well was transferred to a 96-well plate containing 50 μL of ultrapure water, and the contents of compounds III-15, 16, and 20 were analyzed by LC / MS.

[0331] Table 2

[0332]

Claims

1. An imidazolone compound having a structure as shown in Formula I, or a cis-trans isomer thereof, or a pharmaceutically acceptable salt thereof: in: R1 is selected from a chemical bond, an aromatic ring substituted or unsubstituted by Ra, or a 5-7 membered heteroaromatic ring substituted or unsubstituted by Rb having 1-3 atoms selected from nitrogen, oxygen or sulfur; R2 is selected from an aromatic ring substituted or unsubstituted by Rc or an unsaturated heterocyclic ring substituted or unsubstituted by Rd: R3 is selected from an aromatic ring substituted or unsubstituted by Re or a 5-7 membered heteroaromatic ring substituted or unsubstituted by Rf having 1-3 atoms selected from nitrogen, oxygen or sulfur; Ra, Rb, Rc, Rd, Re and Rf are each independently selected from H, halogen, -OH, amino, -CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 acyloxy.

2. The imidazolone compound according to claim 1, or its cis-trans isomers, or its pharmaceutically acceptable salt, characterized in that: R1 is selected from a chemical bond, a C6-C10 aromatic ring substituted or unsubstituted by Ra, or a 5-7 membered heteroaromatic ring having 1 or 2 selected from nitrogen, oxygen or sulfur, substituted or unsubstituted by Rb; preferably, the C6-C10 aromatic ring is selected from a benzene ring; preferably, the 5-7 membered heteroaromatic ring having 1 or 2 selected from nitrogen, oxygen or sulfur is selected from a thiophene ring, a furan ring, a pyrrole ring or a pyridine ring; more preferably, R1 is selected from a chemical bond, a benzene ring, a thiophene ring or a furan ring.

3. The imidazolone compound according to claim 1, or its cis-trans isomers, or its pharmaceutically acceptable salt, characterized in that: R2 is selected from a C6-C10 aromatic ring substituted or unsubstituted by Rc, or a 5-10 membered unsaturated heterocyclic ring having 1-3 atoms selected from nitrogen, oxygen, sulfur, C(=O) or C(=S) substituted or unsubstituted by Rd; preferably, the C6-C10 aromatic ring includes a benzene ring or a naphthalene ring; preferably, the 5-10 membered unsaturated heterocyclic ring having 1-3 atoms selected from nitrogen, oxygen, sulfur, C(=O) or C(=S) includes benzomorpholine, benzopyrrolidine, quinoline, isoquinoline, benzopiperidine, benzimidazole, benzothiazole, benzofuran, benzothiophene, indole, More preferably, R2 is selected from a benzene ring substituted or unsubstituted by Rc, a phenyl ring substituted or unsubstituted by Rd Substituted or unsubstituted by Rd or substituted or unsubstituted by Rd 4. The imidazolone compound according to claim 1, or its cis-trans isomers, or its pharmaceutically acceptable salt, characterized in that: Ra, Rb, Rc, Rd, Re and Rf are each independently selected from H, halogen, -OH, amino, -CN, methyl, ethyl, methoxy, ethoxy, trifluoromethyl.

5. The imidazolone compound according to claim 1, or its cis-trans isomers, or its pharmaceutically acceptable salt, characterized in that: R3 is selected from a C6-C10 aromatic ring substituted or unsubstituted by Re or a 5-7 membered heteroaromatic ring having 1-2 atoms selected from nitrogen, oxygen or sulfur and substituted or unsubstituted by Rf; preferably, the C6-C10 aromatic ring is selected from a benzene ring; preferably, the 5-7 membered heteroaromatic ring having 1 or 2 atoms selected from nitrogen, oxygen or sulfur is selected from a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a pyrazole ring, an imidazole ring or a pyridine ring; more preferably, R3 is selected from a benzene ring substituted or unsubstituted by Re, a pyridine ring substituted or unsubstituted by Rf, a thiophene ring substituted or unsubstituted by Rf, an oxazole ring substituted or unsubstituted by Rf, or an isoxazole ring substituted or unsubstituted by Rf.

6. The imidazolone compound according to claim 1, or its cis-trans isomers, or its pharmaceutically acceptable salts, characterized in that: Re and Rf are each independently selected from halogen, preferably F, Cl, or Br.

7. An imidazolidone compound represented by the following structure, or its cis-trans isomers, or a pharmaceutically acceptable salt thereof:

8. A method for preparing an imidazolidone compound of formula I according to any one of claims 1 to 7, the route of which is as follows: Preferably, the compound represented by formula IV can be prepared by the following route:

9. A pharmaceutical composition comprising the imidazolone compound according to any one of claims 1 to 7 or its cis-trans isomers, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. Use of the imidazolone compound according to any one of claims 1 to 7 or its cis-trans isomers, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of a monoacylglycerol esterase inhibitor.

11. Use of the imidazolidone compound according to any one of claims 1 to 7 or its cis-trans isomers, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating monoacylglycerol esterase-related diseases, wherein preferably, the monoacylglycerol esterase-related diseases include depression, anxiety, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuralgia, inflammatory pain, cancer pain, epilepsy, cancer, alcoholic fatty liver disease, non-alcoholic fatty liver disease, liver fibrosis, cholestasis, nephropathy, sepsis or inflammatory bowel disease.

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