A benzimidazole ternary annular compound, a pharmaceutically acceptable salt thereof and application thereof

Abstract

This invention provides a benzimidazole three-membered cyclic compound, its pharmaceutically acceptable salt, and its applications. The benzimidazole three-membered cyclic compound of this invention targets TRIM24, and is designed to have the structure shown in Formula I. This type of compound not only targets TRIM24 but also targets BRPF1 with equivalent potency. Furthermore, this type of compound also shows preliminary inhibitory effects on other bromine domains. This type of compound shows good proliferation inhibitory effects on various tumor cell lines, suggesting its potential as a broad-spectrum antitumor drug.

Description

Technical Field

[0001] This invention belongs to the field of chemical and pharmaceutical technology, and relates to a benzimidazole ternary cyclic compound, its pharmaceutically acceptable salt, and its applications. Background Technology

[0002] Epigenetic targets are among the most rapidly developing drug research targets in recent years, with their involvement in the study of various disease-related mechanisms and the corresponding chemical drug research flourishing. Epigenetics, proposed in contrast to classical genetics, primarily involves histone modification. Histones, as the only proteins involved in the formation of chromatin structure, undergo tail modifications in various ways, among which histone acetylation is considered key to opening chromatin structure and promoting gene transcription. Bromodomains have chromatin localization functions due to their specific recognition of acetylated lysine residues in histone tails, and the bromodomains of different proteins can be localized to different chromatin locations due to structural differences. Therefore, bromodomains can act as structural proteins, mediating the interaction between other functional modules of bromodomain-containing proteins or other proteins with chromatin, participating in life activities such as histone modification, chromatin remodeling, transcription factor recruitment, and enhancer or regulatory factor complex assembly, thereby regulating transcription initiation and elongation. Because bromodomain-containing proteins usually have various other modules with different structures and functions besides the bromodomain module. Bromodomains may couple with other modules and participate in various life processes, including the development of multiple diseases, primarily cancer. Therefore, inhibiting bromodomains can interfere with the binding of bromodomain-containing proteins to chromatin, thereby hindering disease progression.

[0003] Bromodomains were first discovered in 1992 by Kennison's team on different proteins from three species: human, Drosophila, and yeast. Bromodomains are approximately 110 amino acids long and possess a highly conserved 4-helix bundle tertiary structure. Currently, 61 bromodomains within 46 bromodomain-containing proteins have been reported. These bromodomains are classified into eight subfamilies based on sequence and structural conservation, with TRIM24 and BRPF1 belonging to subfamilies five and four, respectively.

[0004] The most effective way to inhibit the function of the bromine domain using chemical means is to develop highly efficient small-molecule inhibitors that target the bromine domain. Since the advent of JQ1, the first highly efficient inhibitor targeting the second subfamily of proteins (BET family) in 2010, research on bromine domain inhibitors has attracted much attention and has achieved remarkable results in BET bromine domain inhibitors. Related drugs are currently in clinical trials. The promising clinical application prospects of inhibitors targeting the BET bromine domain indirectly support the possibility that bromine domain inhibitors may become targeted drugs for the clinical treatment of diseases, primarily cancer. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a benzimidazole ternary cyclic compound, its pharmaceutically acceptable salt, and its applications.

[0006] To achieve this objective, the present invention adopts the following technical solution:

[0007] On one hand, the present invention provides a benzimidazole three-membered cyclic compound and its pharmaceutically acceptable salt, wherein the benzimidazole three-membered cyclic compound has the structure shown in Formula I:

[0008]

[0009] Where X and W are selected from O or S;

[0010] Y is selected from -CH- or N;

[0011] L is selected from -CH2-, -CO-, or -SO2-;

[0012] M is selected from N or -CO-;

[0013] M and R 1 The bond between connected carbon atoms is represented by S / D, where S is a single bond and D is a double bond, indicating whether the bond is a single bond or a double bond.

[0014] R1 is selected from H, hydroxyl, amino, C1-C3 alkoxy, C1-C3 alkylamino, C1-C4 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 alkoxyalkyl, and C1-C3 alkylaminoalkyl.

[0015] R2 is selected from H, -C(R) a (R) b )R c -SO2R d -COR e ;

[0016] The R a R bEach group is independently selected from H, hydroxyl, amino, halogen, C1-C6 straight-chain alkyl, C3-C6 branched alkyl, C3-C6 cycloalkyl, C3-C6 heterocyclic alkyl; or a group in which at least one CH2 atom of the C1-C6 straight-chain alkyl or C3-C6 branched alkyl is replaced by O, N, or S in a non-adjacent manner, or a group in which at least one hydrogen atom of the C1-C6 straight-chain alkyl, C3-C6 branched alkyl, C3-C6 cycloalkyl, or C3-C6 heterocyclic alkyl is replaced by a halogen;

[0017] The R c R d R e Each group is independently selected from H, halogens, or any group from groups (i), (ii), and (iii) below:

[0018] (i) A substituted or unsubstituted C1-C10 straight-chain or branched alkyl group, a substituted or unsubstituted C2-C10 alkenyl or alkynyl group, or a group in which at least one CH2 group of the substituted or unsubstituted C1-C10 straight-chain or branched alkyl group, a substituted or unsubstituted C2-C10 alkenyl or alkynyl group is replaced by O, N, or S in a non-adjacent manner; the substitution is at least one of halogen, C1-C4 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, or C3-C6 heterocyclic alkyl.

[0019] (ii) substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkenyl or substituted or unsubstituted C3-C10 heterocycloalkyl, wherein the heterocycloalkyl comprises at least one heteroatom selected from O, N or S;

[0020] (iii) Substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups;

[0021] The substitution refers to substitution via D, halogen, alkyl, nitro, cyano, haloalkyl, hydroxyalkyl, aminoalkyl, -OR f -NHR g -OCOR h -COOR i -NHCOR j -CONHR k -COR l -NHSO2R m or -SO2NHR n Replace; the R f R g R h R i R j R k R l R m R nEach group is independently selected from H, C1-C6 straight-chain alkyl, C1-C6 branched alkyl, C1-C6 cyclic alkyl, C3-C6 heterocyclic alkyl; or at least one CH2 group among the C1-C6 straight-chain alkyl and C1-C6 branched alkyl groups is replaced by O, N, or S in a non-adjacent manner.

[0022] R3 is selected from H, nitro, cyano, halogen, alkyl, and -OR. o -NHR p -OCOR q -COOR r -NHCOR s -CONHR t -COR u The R o R p R q R r R s R t R u Each group is independently selected from H, substituted or unsubstituted C1-C6 straight-chain or branched alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted five- or six-membered aryl or heteroaryl; or at least one CH2 group of substituted or unsubstituted C1-C6 straight-chain or branched alkyl is replaced by O, N, or S in a non-adjacent manner; the substitution is by at least one of D, halogen, hydroxyl, amino, methylamino, ethylamino, C1-C4 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or C3-C6 heterocycloalkyl;

[0023] R4 is selected from H, nitro, cyano, halogen, alkyl, and -OR. v -NHR w -OCOR x -COOR y -NHCOR z -CONHR aa -COR ab ;

[0024] The R v R w R x R y R z R aa R abEach group is independently selected from H, aminoalkyl, nitrogen-containing heterocyclic alkyl, and alkyl containing 1 to 2 nitrogen-containing heterocyclic alkyl groups; the groups attached to the amino nitrogen atom and the heterocyclic nitrogen atom are H, substituted or unsubstituted C1 to C6 straight-chain alkyl, substituted or unsubstituted C1 to C6 branched alkyl, substituted or unsubstituted C3 to C6 cyclic alkyl, and substituted or unsubstituted C3 to C6 heterocyclic alkyl; at least one CH2 group among the substituted or unsubstituted C1 to C6 straight-chain alkyl and substituted or unsubstituted C1 to C6 branched alkyl is replaced by O, N, or S in a non-adjacent manner, and the substitution is at least one of halogen, C1 to C4 alkyl, C1 to C3 alkoxy, C3 to C6 cyclic alkyl, or C3 to C6 heterocyclic alkyl.

[0025] In this invention, benzimidazole-based ternary cyclic compounds with the structure shown in Formula I were designed targeting TRIM24. These compounds not only target TRIM24 but also target BRPF1 with equivalent potency. Furthermore, these compounds also showed preliminary inhibitory effects on other bromine domains. These compounds exhibited good proliferation-inhibiting effects on various tumor cell lines, suggesting their potential as broad-spectrum antitumor drugs.

[0026] In this invention, the alkyl group refers to a saturated straight-chain or branched alkane group, and the carbon chain has a maximum of 6 carbon atoms. Representative saturated straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl; saturated branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylbutyl, 2,3-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylbutyl, 2,3 ...3-dimethylbutyl, 2,3-dimethylbutyl, 2,4-dimethylhexyl, 2,5-dimethyl Methylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl.

[0027] In this invention, the halogen refers to the four atoms F, Cl, Br, and I. The haloalkyl refers to an alkyl group substituted with at least one halogen atom.

[0028] In this invention, the aryl group refers to phenyl and aromatic groups derived from phenyl, such as naphthyl. It can be selected from, but is not limited to, phenyl, anthracene, fluorenyl, indene, azulel, naphthyl, or 5,6,7,8-tetrahydronaphthyl.

[0029] In this invention, the heteroaryl group comprises aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, and 11-14 membered tricyclic systems, and contains at least one heteroatom selected from O, N, and S. It may be selected from, but is not limited to, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl, thiophene, pyrroleyl, pyridinyl, pyrimidinyl, oxadiazolyl, thiazolyl, isothiazolyl, quinolinyl, pyridazinyl, pyrazinyl, triazinyl, triazolyl, thiazolyl, isoquinolinyl, indazole, indolyl, benzofuranyl, indazinyl, imidazopyridinyl, tetrazolyl, benzimidazolyl, benzothiazolyl, and benzo[] Thiadiazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzo1,3-dioxopentyl, benzo1,4-dioxane, 2-oxo-benzopyranyl, isoquinolinyl, indololinyl, 1H-indazolyl, 1H-benzo[d]imidazolyl, 1H-indolyl, benzo[d][1,3]dioxacyclopentenyl, benzo[d]thiazolyl or H-pyrazole-3(2H)-keto.

[0030] In this invention, the heterocyclic alkyl group has a saturated cyclic structure, is non-aromatic, and contains at least one heteroatom selected from O, N, and S. It may be selected from, but is not limited to, piperidinyl, piperazineyl, morpholinyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydropyranyl, tetrahydrothiophenyl, dioxane, acridineyl, acridineyl, oxadicyclopropane, oxadicyclopropane, or thioadicyclopropane.

[0031] In this invention, the heteroatom generally refers to atoms other than carbon and hydrogen atoms. Preferably, it is selected from O, N, S, and the four halogen atoms.

[0032] In this invention, the definition of a group specifies the range of the number of carbon atoms in the group. The definition of the number of carbon atoms represents each integer that can be selected within the specified range. For example, C1 to C3 alkoxy means that the number of carbon atoms in the alkoxy group is 1, 2 or 3. Similarly, C3 to C6 heterocyclic alkyl means that the number of carbon atoms in the heterocyclic alkyl group is 3, 4, 5 or 6.

[0033] Preferably, R1 is methyl, ethyl, or methoxy;

[0034] Preferably, R2 is any one of the following groups: hydrogen, methyl, The wavy line represents the connection site of the functional group;

[0035] Preferably, R3 is ethoxy, propoxy, butoxy, cyclopropanemethoxy, cyclobutanemethoxy, or cyclopentanemethoxy.

[0036] Preferably, R3 is n-propyloxy group;

[0037] Preferably, R4 is hydrogen, The wavy line represents the connection site of the functional group.

[0038] Preferably, when M is N, X and W are O, and R3 is n-propyloxy, the benzimidazole ternary cyclic compound has the structure shown in Formula Ia:

[0039]

[0040] R1, R2, and R4 have the same defined range as in Equation I.

[0041] Preferably, when M is -CO-, X is O, L is methylene, R3 is n-propyloxy, R1 is methyl, and R4 is H, the benzimidazole ternary cyclic compound has the structure shown in Formula Ib:

[0042]

[0043] R2 has the same defined range as in Equation I.

[0044] Preferably, the benzimidazole ternary cyclic compound is any one of the following compounds:

[0045] 3-Methyl-7-(benzenesulfonyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0046] 7-((3,4-dimethoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0047] 3,7-Dimethyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0048] 3-Methyl-5-(3-propoxybenzyl)-7-p-methylbenzenesulfonyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0049] 3-Methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol [4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0050] 7-Ethylsulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0051] 7-Butylsulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0052] 7-((3-bromo-4-methoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0053] 7-((5-bromo-2-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0054] 7-((5-chloro-2-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0055] 7-((2-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0056] 7-((3-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0057] 7-((4-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0058] 7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0059] 7-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0060] 3-Methyl-7-((2-oxo-2H-chromene-6-yl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0061] 7-((4-cyanophenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0062] 7-((4-methoxycarbonylphenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0063] 7-((4-ethoxycarbonylphenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0064] 3-Methyl-7-((4-methanesulfonylphenyl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0065] 7-((4-bromophenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0066] 7-((6-chloropyridin-3-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0067] 7-((6-methoxypyridin-3-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0068] 7-((3,5-dichlorophenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0069] 7-((2,6-dichlorophenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0070] 3-Methyl-5-(3-propoxybenzyl)-7-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0071] 7-((3,5-dimethyl-isoxazo-4-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0072] 7-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0073] 3-Methyl-7-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0074] 3-Methyl-7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0075] 3-Methyl-7-(morpholinosulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0076] 3-Methyl-7-(piperidin-1-sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0077] 7-(cyclopropylsulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0078] 7-(dimethylaminosulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0079] 3-Methyl-5-(3-propoxybenzyl)-7-propylsulfonyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0080] 7-(3,4-Dimethoxybenzoyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0081] 7-(3,5-Dimethylisoxazole-4-carbonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazole-6-one

[0082] 7-Cyclopropanecarbonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0083] 7-(3,4-Dimethoxybenzyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0084] 3-Methyl-5-(3-propoxybenzyl)-7-propyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0085] 3-Methyl-7-(1-methylcyclopropyl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0086] 7-(tert-butylsulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0087] 7-(isopropylsulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0088] 3-Methyl-7-(phenylsulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0089] 7-((3,4-dimethoxyphenyl)sulfonamide)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0090] 3,7-Dimethyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0091] 3-Methoxy-7-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0092] 3-Methoxy-7-methyl-5-(3-propoxybenzoyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0093] 5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0094] 3-Methyl-5-(3-((1-methylpiperidin-4-yl)oxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0095] 5-(3-(4-(dimethylamino)butoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0096] 3-Methyl-5-(3-(piperidin-4-methoxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0097] 3-Methyl-5-(3-(piperidin-3-methoxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0098] 3-Methyl-5-(3-((1-methylpiperidin-4-yl)methoxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0099] 3-Methyl-5-(3-((1-methylpiperidin-3-yl)methoxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0100] 7-(cyclopropylsulfonyl)-5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0101] 5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-7-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0102] 7-((3,4-dimethoxyphenyl)sulfonyl)-5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0103] 5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-7-propyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0104] 7-(cyclopropylsulfonyl)-3-methyl-5-(3-((1-methylpiperidin-3-yl)methoxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0105] 7-(cyclopropanecarbonyl)-3-methyl-5-(3-((1-methylpiperidin-3-yl)methoxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0106] 7-((3,4-dimethoxyphenyl)sulfonyl)-5-(3-(4-(dimethylamino)butoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazol-6-one.

[0107] Preferably, the benzimidazole ternary cyclic compound is any one of the following compounds:

[0108] 3-Methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0109] 3-Methyl-7-(ethylsulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0110] 7-((3,4-dimethoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0111] 7-((3-bromo-4-methoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0112] 7-((4-methoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0113] 3-Methyl-5-(3-propoxyphenyl)-7-((4-trifluoromethoxy)phenyl)sulfonyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0114] 7-((3-methoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0115] 7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0116] 7-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0117] 3-Methyl-7-((4-(methanesulfonyl)phenyl)sulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0118] 7-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazol[4',5':4,5]benzo[1,2-d]oxazol-2,6(3H)-dione

[0119] 3-Methyl-7-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazol[4',5':4,5]benzo[1,2-d]oxazol-2,6(3H)-dione

[0120] 3-Methyl-7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazol[4',5':4,5]benzo[1,2-d]oxazol-2,6(3H)-dione

[0121] 7-((2-amino-4-methylthiazolyl-5-yl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0122] 3-Methyl-7-(morpholinosulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0123] 7-(dimethylaminosulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0124] 3-Methyl-5-(3-propoxyphenyl)-7-((trifluoromethyl)sulfonyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0125] 3-Methyl-7-(methanesulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0126] 7-(ethanesulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0127] 3-Methyl-5-(3-propoxyphenyl)-7-(propanesulfonyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0128] 7-(butyrylyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0129] 7-((2-(1,3-dioxoisoindoline-2-yl)ethyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0130] 2-((3-methyl-2,6-dioxo-5-(3-propoxybenzyl)-2,3,5,6-tetrahydro-7H-imidazolium[4',5':4,5]benzo[1,2-d]oxazol-7-yl)sulfonyl)methyl acetate

[0131] 3,7-Dimethyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0132] 2-(3-methyl-2,6-dioxo-5-(3-propoxybenzyl)-2,3,5,6-tetrahydro-7H-imidazolium[4',5':4,5]benzo[1,2-d]oxazol-7-yl)methyl acetate

[0133] 3-Methyl-5-(3-propoxyphenyl)-7-propyl-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0134] 7-(3,4-Dimethoxybenzyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione.

[0135] On the other hand, the present invention provides a pharmaceutically acceptable salt, isomer, racemate, prodrug, cocrystallization complex, hydrate, solvate, or isotopically labeled compound of the benzimidazole ternary cyclic compound as described above.

[0136] In this invention, isomers refer to compounds with the same chemical composition but different spatial arrangements of atoms. They mainly include diastereomers and enantiomers. A diastereomer is a stereoisomer having two or more non-symmetrical centers and whose structures are not mirror images of each other; an enantiomer is a stereoisomer of a compound whose structures cannot overlap and are mirror images of each other.

[0137] In this invention, the racemic mixture refers to an equimolar mixture of two enantiomers.

[0138] In this invention, the prodrug refers to a compound containing a metabolically biodegradable structural fragment, along with the metabolizable fragment, formed by introducing certain groups into the bulk compound. Typically, the prodrug is converted into the active drug, i.e., the bulk compound, in vivo through metabolic enzyme treatment. During the compound preparation stage, the compound can be prepared into a prodrug form via methods such as esterification for use in drug preparation.

[0139] On the other hand, the present invention provides the use of the benzimidazole ternary cyclic compounds, pharmaceutically acceptable salts, isomers, racemates, prodrugs, cocrystallized complexes, hydrates, solvates, or isotopically labeled compounds as described above in the preparation of inhibitors of bromine domain proteins TRIM24 and / or BRPF1.

[0140] On the other hand, the present invention provides the use of the benzimidazole ternary cyclic compounds as described above, and their pharmaceutically acceptable salts, isomers, racemates, prodrugs, cocrystallized complexes, hydrates, solvates, or isotopically labeled compounds in the preparation of medicaments for treating diseases by inhibiting the TRIM24 or BRPF1 bromine domain.

[0141] In this invention, the disease includes tumors, infections, or immune-related diseases.

[0142] In this invention, the tumor includes all tumors that exceed the normal rate of tissue proliferation, including malignant tumors and tumors or cysts, polyps, nodules, etc. that have a tendency to develop malignantly.

[0143] In this invention, tumors include, but are not limited to: leukemia (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, acute eosinophilic leukemia, acute erythroblastic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute promyelocytic leukemia, mixed leukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, adult T-cell leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, mast cell leukemia). Diseases including: Woldanström's macroglobulinemia, polycythemia vera, lymphomas (e.g., large cell lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, marginal zone B-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (diffuse large B-cell lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, small lymphocytic lymphoma, splenic marginal zone lymphoma, heavy chain disease, mantle cell lymphoma, malt lymphoma, precursor T-lymphoblastic lymphoma), anaplastic large cell lymphoma, Burkitt's lymphoma, lymphangioma, lymphangiosarcoma, acute lymphangiosarcoma, lymphangioendothelial sarcoma, lymphoepithelioma, AIDS-related lymphoma, primary central nervous system lymphoma), angiosarcoma, hemangioblastoma, and vascular... Malignant tumors of the perithelial cell line, myeloid sarcoma, multiple myeloma, fibroma, fibrosarcoma, ameloblastic fibroma, giant cell fibroblastoma, malignant fibrous histiocytoma, neurofibroma, dermatofibroma, myxoma, myxosarcoma, myxoid tumor, lipoma, liposarcoma, muscle tissue tumor, angiomyolipoma, mycoid myxoid liposarcoma, adipose tissue tumor, bone tumor, osteosarcoma, giant cell tumor of bone, chondroma, chondrosarcoma, cementum endothelial sarcoma, mesothelioma, synovial sarcoma, Ewing's tumor, rhabdomyosarcoma, rhabdomyosarcoma, leiomyosarcoma, alveolar rhabdomyosarcoma, alveolar soft sarcoma, colon tumor, nephroblastoma, adrenal tumor, clear cell sarcoma of the kidney, acral hidradenoma, eosinophilic adenoma, pleomorphic adenoma Melanoma, Acral melanoma, Germ cell tumor, Endodermal sinus tumor, Embryonic carcinoma, Endocrine gland tumor, Trophoblastic tumor, Meningioma, Chordoma, Spinal cord tumor, Neuroma, Astrocytoma, Neuroepithelial tumor, Paraganglioma, Acoustic neuroma, Malignant peripheral nerve sheath tumor, Tubuloblastoma, Neuroblastoma, Glioma, Follicular astrocytoma, Glioblastoma multiforme, Optic nerve sheath meningioma, Retinoblastoma, Visual pathway glioma, Germ cell tumor, Androblastoma, Mediastinal germ cell tumor, Testicular interstitial cell tumor, Seminoma, Granulosa cell tumor, Dysgerminoma, Multiple endocrine tumors, Pineal cell tumor, Pituitary cell tumor, Brown tumor, SomatostatinomaChoroid plexus papilloma, craniopharyngioma, small round cell tumor, skin cancer, Merkel cell carcinoma, sebaceous gland carcinoma, cystic gland carcinoma, basal cell carcinoma, sweat gland carcinoma, medullary carcinoma, brain cancer, squamous cell carcinoma, verrucous carcinoma, eye cancer, nasopharyngeal carcinoma, oral cancer, laryngeal cancer, deadly midline carcinoma, esophageal cancer, bronchial cancer, thyroid cancer, undifferentiated thyroid carcinoma, papillary thyroid carcinoma, medullary thyroid carcinoma, breast cancer, triple-negative breast cancer, invasive lobular carcinoma, papillary carcinoma, papillary gland carcinoma, medullary breast carcinoma, ovarian cancer, uterine cancer, cervical cancer. Cancer, vulvar cancer or vaginal cancer, choriocarcinoma, gestational choriocarcinoma, peritoneal cancer, stomach cancer, intestinal cancer, small bowel cancer, colorectal cancer, pancreatic cancer, prostate cancer, castration-resistant prostate cancer, small cell carcinoma, testicular cancer, embryonal carcinoma, adenocarcinoma, adenoid cystic carcinoma, kidney cancer, adrenal cortical carcinoma, renal cell carcinoma, renal medullary carcinoma, liver cancer, bile duct cancer, biliary tract cancer, gallbladder cancer, hepatoblastic carcinoma, bladder cancer, transitional cell carcinoma, urachal carcinoma, urogenital cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, metastatic cell carcinoma.

[0144] Compared with the prior art, the present invention has the following beneficial effects:

[0145] This invention provides compounds that can act as inhibitors of the bromine domains of TRIM24 or BRPF1. These compounds can effectively inhibit the bromine domains of these proteins, interfering with their binding to chromatin, thereby regulating the transcription of related genes, causing changes in downstream pathways, and thus affecting the progression of diseases, primarily tumors. Therefore, the compounds and compositions provided by this invention can be used to prepare probe molecules for studying mechanisms related to tumor development or clinical therapeutic drugs for tumor-related diseases. Detailed Implementation

[0146] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0147] In this invention, the compounds A and B involved in the embodiments have the following structures:

[0148]

[0149] Compound A, when R4 is H, can be prepared by the general synthetic method shown in Scheme 1.

[0150] Option 1:

[0151]

[0152] Different R2 groups correspond one-to-one with the structures represented by the letters a to aq. The R2 groups a to aq in Examples 1-15 are listed below:

[0153]

[0154] In step a, raw material 1-1 is reacted with iodopropane at 80°C for 2 hours and 20 minutes in the presence of potassium hydroxide using DMF as the reaction solvent.

[0155] Step b involves reacting phosphorus tribromide with DCM as the reaction solvent at room temperature for 20 minutes.

[0156] In step c, raw materials 1-3 are reacted with propyl 4-methylbenzenesulfonate at 95°C for 4 hours in the presence of potassium carbonate using NMP as the reaction solvent.

[0157] Step d involves reacting the mixture of methanol and sodium hydroxide aqueous solution at room temperature for 1.5 hours.

[0158] In step e, toluene was used as the reaction solvent to react with thionyl chloride at 110°C for 4 hours.

[0159] In step f, raw materials 1-8 are reacted with hydroxylamine hydrochloride in an ethanol-water mixed solvent system at 80°C for 2 hours under the action of sodium acetate.

[0160] In step g, DMF was used as the reaction solvent, and the reaction was carried out at 100°C for 5 hours in the presence of acetic anhydride and sodium acetate.

[0161] In step h, concentrated sulfuric acid was used as the reaction solvent, and fuming nitric acid was reacted with it in an ice bath for 1 hour, and then the reaction was continued at room temperature for 1 hour.

[0162] In step i, raw materials 1-17 are reacted with thionyl chloride at 70°C for 22 hours using methanol as the reaction solvent.

[0163] In step j, methanol was used as the reaction solvent, and hydroxylamine hydrochloride was reacted with potassium hydroxide at room temperature for 3 hours.

[0164] In step k, tetrahydrofuran was used as the reaction solvent to react with CDI at 85°C for 1 hour.

[0165] In step 1, DMF was used as the reaction solvent, and methyl p-toluenesulfonate was reacted with sodium hydride in an ice bath for 16 hours.

[0166] Step m involves reacting concentrated sulfuric acid with fuming nitric acid at room temperature for 15 minutes.

[0167] Step n uses 1,4-dioxane as the reaction solvent and reacts with ammonia at 100°C overnight to synthesize intermediate 3-methyl-5-nitrobenzo[d]isoxazole-6-amine, which is used to synthesize intermediates 1-12c-d of Examples 1-15c-d and 1-16c-d; the reaction is stopped by heating to 85°C in an aqueous methylamine solution to synthesize intermediates 1-12e of Examples 1-15e and 1-16e; the reaction is stopped by heating with 4-methylbenzenesulfonamide in the presence of sodium hydride using DMF as the reaction solvent at 80°C for 12 hours to synthesize intermediates 1-12f of Examples 1-15f; the reaction is stopped by heating to 75°C in a methylamine solution to synthesize intermediates 1-23 of Examples 1-26 and 27.

[0168] In step o, intermediate 3-methyl-5-nitrobenzo[d]isoxazole-6-amine was reacted with the corresponding R2 group chloride in the presence of sodium hydride using DMF as the reaction solvent and at room temperature for 3 days to synthesize intermediates 1-12c-d of Examples 1-15c-d and 1-16c-d.

[0169] Step p uses ethanol as the reaction solvent and reacts with stannous chloride in the presence of concentrated hydrochloric acid at 80°C for 12 hours to synthesize intermediates 1-13c-d of Examples 1-15c-d and 1-16c-d. Acetic acid is added to the above reaction conditions, and the reaction is continued for 3.5 hours to synthesize intermediates 1-13e of Examples 1-15e and 1-16e. DMF is used as the reaction solvent and reacts with stannous chloride in the presence of pyridine at room temperature for 20 minutes to synthesize intermediates 1-13f of Examples 1-15f. In an ethanol-ethyl acetate mixed solvent system, stannous chloride is reacted with concentrated hydrochloric acid at 80°C for 20 minutes to synthesize intermediates 1-24 of Examples 1-26 and 27.

[0170] Step q uses tetrahydrofuran as the reaction solvent and triethylamine to react with triphosgene under argon protection and an ice bath for 13 minutes to 4 hours to synthesize intermediates 1-14c-f and 1-25 of Examples 1-15c-f, 1-16c-e, 1-26, and 27.

[0171] Step r involves reacting intermediates 1-3 with DMF as the reaction solvent in the presence of potassium carbonate at room temperature for 10 hours to 2.5 days, resulting in synthesis Examples 1-15c-d, f, and 1-26; the reaction is then carried out at 70°C for 14 hours, resulting in synthesis Examples 1-15e; and finally, using DMF as the reaction solvent, intermediates 1-7 with triethylamine at room temperature for 11 hours to 2.5 days, resulting in synthesis Examples 1-16c-e and 1-27.

[0172] Steps s. Examples 1-15f: Using tetrahydrofuran as the reaction solvent, under the action of TBAF, the reaction was carried out for 1.5 hours under argon protection and at room temperature to synthesize Example 1-15g.

[0173] In step t, Examples 1-15g were synthesized by reacting the corresponding R2 group chlorides with DCM as the reaction solvent in the presence of triethylamine, DMAP, and molecular sieves at room temperature for 20 minutes to 4 days, resulting in Examples 1-15a~b, h~ag, ak~o; and by reacting the corresponding R2 group bromides with DMF as the reaction solvent in the presence of potassium carbonate at 70°C for 4 days, resulting in Examples 1-15ap; and by reacting the corresponding R2 group iodides with DMF at room temperature for 2 days, resulting in Examples 1-15aq.

[0174] Step u intermediate 1-11 undergoes 4 reaction steps to synthesize Examples 1-15ah~j. For detailed synthesis procedures, please refer to the description in the synthesis section of the examples.

[0175] Compound A, when L is methylene, R1 is methyl, and R4 is not H, can be prepared by the general synthetic method shown in Scheme 2.

[0176] Option 2:

[0177]

[0178] In Scheme 2, the different R2 and R4 groups correspond one-to-one with the structures represented by the letters a to g. The R4 groups of a to g in Examples 2-8 are listed below:

[0179]

[0180] In Scheme 2, the different R2 and R4 groups correspond one-to-one with the structures represented by the letters a to g. The R4 groups a to g in Examples 2-9 are listed below:

[0181]

[0182] In step a, raw material 2-1 is reacted with iodopropane at 80°C for 30 minutes using DMF as the reaction solvent and potassium carbonate in the presence of potassium carbonate.

[0183] In step b, intermediate 2-2 undergoes a two-step reaction: first, with tetrahydrofuran as the reaction solvent, it reacts with acetic anhydride in the presence of potassium carbonate at room temperature for 14 hours; then, with DCM as the reaction solvent, it reacts with phosphorus tribromide in an ice bath for 15 minutes to synthesize intermediate 2-3.

[0184] In step c, intermediates 1-14f reacted with intermediates 2-3 in the presence of potassium carbonate using DMF as the reaction solvent at room temperature for 2.5 hours.

[0185] Step d uses tetrahydrofuran as the reaction solvent and reacts for 4 hours under TBAF protection and at -20°C.

[0186] In step e, DCM was used as the reaction solvent, and SEMCl was reacted with DIPEA and DMAP at room temperature for 12 hours.

[0187] Step f involves reacting the mixture of methanol and sodium hydroxide aqueous solution at room temperature for 1.5 hours.

[0188] Step g, intermediates 2-7, undergo 2-4 reaction steps to synthesize Examples 2-8a-g. For detailed procedures, please refer to the description in the synthesis section of the examples.

[0189] Step h: Examples 2-8a-c, e-f: Using DCM as the reaction solvent, in the presence of triethylamine, DMAP, and molecular sieves, the corresponding R2 group chlorides were reacted at room temperature for 4 to 48 hours to synthesize Examples 2-9a-c, e-f; Examples 2-8d: Using DMF as the reaction solvent, in the presence of potassium carbonate, the corresponding R2 group iodides were reacted at room temperature for 16 hours to synthesize Examples 2-9d.

[0190] Step i: Intermediate 1-14d undergoes 4 steps of reaction to synthesize Example 2-9g. See the description in the synthesis section of the examples for details.

[0191] Compound B can be prepared by the general synthetic method shown in Scheme 3.

[0192] Option 3:

[0193]

[0194] In Scheme 3, different R2 groups correspond one-to-one with the structures represented by the letters a to z. The R2 groups of a to z in Example 3-11 are listed below:

[0195]

[0196] In step a, raw material 3-1 is reacted with iodopropane at 80°C for 3.5 hours in the presence of potassium hydroxide using DMF as the reaction solvent.

[0197] In step b, hydroxylamine hydrochloride is reacted with sodium acetate in an ethanol-water mixed solvent system at 80°C for 2 hours.

[0198] In step c, methanol was used as the reaction solvent, and hydrogen was reacted with palladium / carbon and concentrated hydrochloric acid at room temperature for 2.5 hours.

[0199] In step d, raw materials 3-5 are reacted with hydroxylamine hydrochloride in methanol as the reaction solvent under the action of potassium hydroxide for 2.5 hours at room temperature.

[0200] Step e uses tetrahydrofuran as the reaction solvent and reacts at room temperature for 5 hours in the presence of PPh3 and DIAD.

[0201] In step f, DMF is used as the reaction solvent, and iodomethane is reacted with cesium carbonate and potassium iodide at room temperature for 2 hours.

[0202] Step g uses concentrated sulfuric acid as the reaction solvent and reacts with fuming nitric acid in an ice bath for 45 minutes.

[0203] In step h, DMF was used as the reaction solvent, and the reaction was carried out in a sealed tube at 100°C for 14 hours under the action of DIPEA.

[0204] In step i, ethyl acetate was used as the reaction solvent, and stannous chloride was reacted with concentrated hydrochloric acid at 80°C for 2 hours.

[0205] Step j uses tetrahydrofuran as the reaction solvent and reacts with triphosgene in the presence of triethylamine under argon protection and an ice bath for 15 minutes.

[0206] Step k uses DCM as the reaction solvent and reacts with the corresponding R2 group chloride in the presence of triethylamine, DMAP, and molecular sieves at room temperature for 30 minutes to 4 days, synthesizing Examples 3-13a to v; using DMF as the reaction solvent and reacting with potassium carbonate in the presence of potassium carbonate, reacts with the corresponding R2 group halide (halogen selected from chlorine, bromine, and iodine) at 70°C for 70 minutes to 14 hours, synthesizing Examples 3-13x to z; using acetone as the reaction solvent and reacting with potassium carbonate in the presence of potassium carbonate, reacts with the corresponding R2 group iodide at 60°C for 2.5 days, synthesizing Examples 3-13w.

[0207] Example

[0208] To facilitate understanding of the present invention, the following embodiments are provided. These embodiments are merely illustrative and should not be construed as limiting the scope of the invention.

[0209] The abbreviations used in this invention are listed below:

[0210] DMF (N,N-dimethylformamide), DCM (dichloromethane), EA (ethyl acetate), NMP (N-methylpyrrolidone), CDI (N,N'-carbonyldiimidazole), TBAF (tetrabutylammonium fluoride), DMAP (4-dimethylaminopyridine), DIPEA (N,N-diisopropylethylamine), SEMCl (2-(trimethylsilyl)ethoxymethyl chloride), DIAD (diisopropyl azodicarbonate), DMF-DMA (N,N-dimethylformamide-dimethyl acetal).

[0211] Option 1 will be implemented as follows:

[0212] Intermediate 1-3: 1-Bromomethyl-3-propoxybenzene

[0213]

[0214] Step 1: Synthesis of 3-propoxybenzyl alcohol (1-2)

[0215]

[0216] 3-Hydroxybenzyl alcohol (1-1, 11.07 g, 89.17 mmol) was added to 120 mL of DMF. While stirring, potassium hydroxide (15.01 g, 267.52 mmol), iodopropane (0.88 mL, 9.03 mmol), and 2 mL of water were added sequentially. The reaction was carried out at 80 °C for 2 h 20 min. After the reaction was complete, the mixture was cooled to room temperature. 500 mL of water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation under reduced pressure to obtain a crude brown solution (15 g, yield: 100%). 1H NMR(500MHz,DMSO-d6)δ7.20(t,J=7.8Hz,1H),6.91–6.84(m,2H),6.77(dd,J=8.2,2.6Hz,1H),5.13(t,J =5.8Hz,1H),4.46(d,J=5.8Hz,2H),3.90(t,J=6.6Hz,2H),1.72(h,J=7.1Hz,2H),0.97(t,J=7.4Hz,3H).

[0217] Step 2: Synthesis of 1-bromomethyl-3-propoxybenzene (1-3)

[0218]

[0219] Compounds 1-2 (14.65 g, 88.14 mmol) were dissolved in 200 mL of dichloromethane. Phosphorus tribromide (8.37 mL, 88.14 mmol) was added dropwise through a glass dropping funnel while stirring at room temperature. The reaction was terminated after 20 min at room temperature. The reaction solution was then slowly added dropwise to crushed ice and quenched in ice water under an ice-water bath. The mixture was extracted with dichloromethane, and the resulting organic layer was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain a reddish-brown liquid crude product (19.18 g, yield: 95%). The product was used directly in the next reaction.

[0220] Intermediate 1-7: 3-Propoxybenzoyl chloride

[0221]

[0222] Step 1: Synthesis of methyl 3-propoxybenzoate (1-5)

[0223]

[0224] Methyl 3-hydroxybenzoate (1-4, 1.4 g, 9.0 mmol), propyl 4-methylbenzenesulfonate (2.9 g, 13.5 mmol), and potassium carbonate (3.7 g, 27.0 mmol) were added sequentially to 8 mL of NMP and reacted at 95 °C for 4 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 10:1) to give a colorless liquid (1.1 g, yield: 64%). 1H NMR(500MHz,DMSO-d6)δ7.53(d,J=7.6Hz,1H),7.46–7.38(m,2H),7.25–7.18(m,1H ),3.97(t,J=6.5Hz,2H),3.84(s,3H),1.74(h,J=7.1Hz,2H),0.98(t,J=7.4Hz,3H).

[0225] Step 2: Synthesis of 3-propoxybenzoic acid (1-6)

[0226]

[0227] Intermediate 1-5 (1.0 g, 5.3 mmol) was dissolved in 16 mL of methanol, followed by the addition of 2N NaOH aqueous solution, and the reaction was allowed to proceed at room temperature for 1.5 h. The methanol was removed by rotary evaporation under reduced pressure, and the pH was adjusted to 2–3 with dilute hydrochloric acid solution, precipitating a white solid. The solid was then filtered under reduced pressure to obtain a white powder (1.1 g, yield: 100%). ¹H NMR (500 MHz, DMSO-d⁶) δ 12.93 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.46–7.34 (m, 2H), 7.17 (dd, J = 8.3, 2.6 Hz, 1H), 3.97 (t, J = 6.5 Hz, 2H), 1.74 (h, J = 7.0 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H).

[0228] Step 3: Synthesis of 3-propoxybenzoyl chloride (1-7)

[0229]

[0230] Intermediate 1-6 (1.1 g, 6.2 mmol) was dissolved in 15 mL of toluene, and then thionyl chloride (3.2 mL, 44.4 mmol) was added through a glass dropping funnel at room temperature. The reaction mixture was then reacted at 110 °C for 4 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give a colorless liquid (1.2 g, yield: 98%). The product was used directly in the next reaction step.

[0231] Intermediate 1-11: 6-Fluoro-3-methyl-5-nitrobenzo[d]isoxazole

[0232]

[0233] Step 1: Synthesis of 1-(4-fluoro-2-hydroxyphenyl)ethane-1-one oxime (1-9)

[0234]

[0235] 1-(4-fluoro-2-hydroxyphenyl)ethane-1-one (1-8, 8.5 g, 54.8 mmol) was dissolved in 85 mL of an ethanol-water mixture (3:1), followed by the addition of hydroxylamine hydrochloride (6.3 g, 90.7 mmol) and sodium acetate (7.3 g, 89.0 mmol). The reaction mixture was then reacted at 80 °C for 1.5 h. The reaction solution was cooled to room temperature, and the ethanol was removed by rotary evaporation under reduced pressure. A suitable amount of water was added to the mixture, and the mixture was filtered under reduced pressure. The filter cake was washed with water and then filtered again until a constant weight was obtained, yielding a light pink powder (8.3 g, yield: 89%). 1H NMR (400MHz, CDCl3-d) δ11.59(s,1H),7.58(s,1H),7.38(dd,J=8.8,6.4Hz,1H) ,6.67(dd,J=10.3,2.6Hz,1H),6.62(ddd,J=8.8,8.0,2.7Hz,1H),2.34(s,3H).

[0236] Step 2: Synthesis of 6-fluoro-3-methylbenzo[d]isoxazole (1-10)

[0237]

[0238] Intermediate 1-9 (8.2 g, 48.3 mmol) was dissolved in DMF, and sodium acetate (8.9 g, 109.2 mmol) and acetic anhydride (10.64 mL, 112.5 mmol) were added. The mixture was reacted at 100 °C for 5 h. After cooling to room temperature, the reaction solution was extracted with ethyl acetate. The organic layer was washed successively with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 15:1–10:1) to give white crystals (5.3 g, yield: 72%). ¹H NMR (400 MHz, DMSO-d6) δ 7.91 (dd, J = 8.8, 5.3 Hz, 1H), 7.66 (d, J = 9.9 Hz, 1H), 7.33–7.23 (m, 1H), 2.55 (s, 3H).

[0239] Step 3: Synthesis of 6-fluoro-3-methyl-5-nitrobenzo[d]isoxazole (1-11)

[0240]

[0241] Intermediate 1-10 (5.3 g, 34.6 mmol) was dissolved in 18 mL of concentrated sulfuric acid in an ice bath, and fuming nitric acid (1.45 mL, 34.6 mmol) was added dropwise through a glass dropping funnel. The reaction was continued at room temperature for 1 h after reacting in an ice bath. The reaction mixture was quenched dropwise in ice water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography to give a white solid (5.5 g, yield: 80%). ¹H NMR (400 MHz, CDCl₃-d) δ 8.46 (d, J = 7.0 Hz, 1H), 7.45 (d, J = 10.0 Hz, 1H), 2.65 (s, 3H).

[0242] Intermediate: 3-methyl-5-nitrobenzo[d]isoxazole-6-amine

[0243]

[0244] Intermediate 1-11 (1.7 g, 8.44 mmol) was dissolved in 34 mL of 1,4-dioxane, and 30 mL of ammonia (25%) was added with stirring at room temperature. The reaction mixture was reacted overnight at 100 °C. The reaction solution was cooled to room temperature, and 1,4-dioxane was removed under reduced pressure. Water was then added, precipitating a bright orange powder (1.53 g, yield: 93%). ¹H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.54 (s, 2H), 6.96 (s, 1H), 2.48 (s, 3H).

[0245] Intermediate 1-13d: N-(5-yl-3-methylbenzo[d]isoxazol-6-yl)-3,4-dimethoxybenzenesulfonamide

[0246]

[0247] Step 1: Synthesis of 3,4-dimethoxy-N-(3-methyl-5-nitrobenzo[d]isoxazol-6-yl)benzenesulfonamide (1-12d)

[0248]

[0249] The intermediate 3-methyl-5-nitrobenzo[d]isoxazole-6-amine (232 mg, 1.2 mmol) was dissolved in 6 mL of DMF. Sodium hydride powder (144 mg, 3.6 mmol) was added at room temperature for 10 min to activate the reaction. Then, 3,4-dimethoxybenzenesulfonyl chloride (568 mg, 2.4 mmol) was added, and the reaction was continued at room temperature for 3 days. After the reaction was complete, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed repeatedly with water, then washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 5:1–2:1) to give a yellow solid (150 mg, yield: 32%). 1H NMR (400MHz, DMSO-d6) δ10.47(s,1H),8.62(s,1H),7.53(s,1H),7.39(d,J=8.6Hz ,1H),7.34(s,1H),7.07(d,J=8.6Hz,1H),3.80(s,3H),3.76(s,3H),2.55(s,3H).

[0250] Step 2: Synthesis of N-(5-yl-3-methylbenzo[d]isoxazol-6-yl)-3,4-dimethoxybenzenesulfonamide (1-13d)

[0251]

[0252] Intermediate 1-13d (150 mg, 0.4 mmol) was added to 10 mL of ethanol, and stannous chloride dihydrate (258 mg, 1.1 mmol) and 0.2 mL of concentrated hydrochloric acid were added with stirring at room temperature. The mixture was then reacted at 80 °C for 12 h. After removing the solvent under reduced pressure, the pH of the mixture was adjusted to approximately 7 with dilute sodium hydroxide solution. The product was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic layer was then desorbed under reduced pressure to remove ethyl acetate, yielding a brown solid (11 mg, yield: 80%). ¹H NMR (400 MHz, DMSO-d6) δ 7.32–7.26 (m, 2H), 7.15 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 2.38 (s, 3H).

[0253] Intermediate 1-13c: N-(5-amino-3-methylbenzo[d]isoxazol-6-yl)benzenesulfonamide

[0254]

[0255] The synthesis method is as described in Examples 1-13d, yielding a brown powder with a yield of 93%. ¹H NMR (400MHz, DMSO-d6) δ 7.75 (d, J = 7.5Hz, 2H), 7.63 (t, J = 7.3Hz, 1H), 7.54 (t, J = 7.6Hz, 2H), 7.09 (s, 1H), 6.86 (s, 1H), 6.60 (s, 2H), 2.38 (s, 3H).

[0256] Intermediate 1-13e: N6,3-dimethylbenzo[d]isoxazole-5,6-diamine

[0257]

[0258] Step 1: Synthesis of N,3-dimethyl-5-nitrobenzo[d]isoxazole-6-amine (1-12e)

[0259]

[0260] At room temperature, 10 mL of 40% methylamine aqueous solution was added to intermediate 1-11 (0.9 g, 4.7 mmol), followed by gradual heating to 85 °C. The reaction was stopped, and the reaction solution was cooled to room temperature. Water was added to precipitate the solid, which was then filtered under reduced pressure to give an orange-red powder (0.8 g, yield: 81%). ¹H NMR (400 MHz, DMSO-d⁶) δ 8.68 (s, ¹H), 8.24–8.16 (m, ¹H), 6.95 (s, ¹H), 2.97 (d, J = 5.0 Hz, ³H).

[0261] Step 2: Synthesis of N6,3-dimethylbenzo[d]isoxazole-5,6-diamine (1-13e)

[0262]

[0263] 40 mL of ethanol was added to intermediate 1-12e (750 mg, 3.6 mmol), followed by stannous chloride dihydrate (4.1 g, 18.1 mmol), 2.5 mL of concentrated hydrochloric acid, and 10 mL of acetic acid. The reaction mixture was reacted at 80 °C for 3.5 h. The reaction solution was cooled to room temperature, and ethanol and acetic acid were removed by rotary evaporation under reduced pressure. Water was added, and the pH was adjusted to approximately 7 with a dilute sodium hydroxide aqueous solution. The product was extracted with ethyl acetate until the organic layer showed a light fluorescent color. The organic layers were then combined and washed with water and saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a gray solid (615 mg, yield: 96%). 1H NMR (500MHz, DMSO-d6) δ6.72 (s, 1H), 6.47 (s, 1H), 5.46 (d, J = 5.0 Hz, 1H), 4.54 (s, 2H), 2.79 (d, J = 4.8 Hz, 3H), 2.34 (s, 3H).

[0264] Intermediate 1-13f: N-(5-amino-3-methylphenyl[d]isoxazol-6-yl)-4-methylbenzenesulfonamide

[0265]

[0266] Step 1: Synthesis of 4-methyl-N-(3-methyl-5-nitrobenzene[d]isoxazol-6-yl)benzenesulfonamide (1-12f)

[0267]

[0268] 4-Methylbenzenesulfonamide (3.7 g, 21.4 mmol) was dissolved in 40 mL of anhydrous DMF, and then sodium hydride powder (1.6 g, 40.8 mmol) (60%) was slowly added with stirring at room temperature, and the reaction was continued for 20 min. Intermediate 1-11 (4 g, 20.4 mmol) was added to the reaction solution, and the reaction was carried out at 80 °C for 12 h. The reaction solution was cooled to room temperature, quenched with water, and the product was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid solution, water, and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and petroleum ether was added to precipitate crystals. After filtration under reduced pressure, a yellow powder crude product (4.9 g, yield: 56%) was obtained. 1H NMR (500MHz, DMSO-d6) δ10.55(s,1H),8.62(s,1H),7.69(d,J=8.2Hz,2H),7.50(s,1H),7.37(d,J=7.7Hz,2H),2.55(s,3H),2.35(s,3H).

[0269] Step 2: Synthesis of N-(5-amine-3-methylbenzene[d]isoxazol-6-yl)-4-methylbenzenesulfonamide (1-13f)

[0270]

[0271] Intermediate 1-12f (4.9 g, 14.1 mmol) was added to 60 mL of DMF, followed by pyridine (10 mL) and stannous chloride dihydrate (15.9 g, 70.6 mmol), and the reaction was carried out at room temperature for 20 min. The reaction solution was quenched with water, and the product was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid solution, water, and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed from the organic layer by rotary evaporation under reduced pressure to obtain a yellow powder crude product (3.8 g, yield: 84%). ¹H NMR (500 MHz, DMSO-d6) δ 7.63 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.11 (s, 1H), 6.86 (s, 1H), 6.74–5.59 (m, 2H), 2.38 (s, 3H), 2.34 (s, 3H).

[0272] Intermediate 1-14e: 3,7-dimethyl-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0273]

[0274] Intermediate 1-13e (375 mg, 2.1 mmol) was dissolved in 100 mL of tetrahydrofuran. Under ice bath and argon protection, triethylamine (1 mL, 7.2 mmol) was added via syringe. Then, triphosgene (861 mg, 2.9 mmol) was dissolved in 5 mL of tetrahydrofuran and added to the reaction solution in small, repeated injections via syringe. The reaction was continued for 13 min under ice bath. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. Saturated sodium bicarbonate solution was added, followed by extraction with dichloromethane. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light pink powder (181 mg, yield: 42%). MS (ESI) m / z [MH]-calcd 202.07; found 202.2.

[0275] Intermediate 1-14c: 3-methyl-7-benzenesulfonyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0276]

[0277] Using intermediates 1-13c as raw materials, the synthesis method is as described in Examples 1-14e, yielding a white powder with a yield of 38%. ¹H NMR (500MHz, DMSO-d6) δ 11.80 (s, 1H), 8.10 (d, J = 7.6Hz, 2H), 8.03 (s, 1H), 7.80 (t, J = 7.5Hz, 1H), 7.67 (t, J = 7.8Hz, 2H), 7.34 (s, 1H), 2.53 (s, 3H).

[0278] Intermediate 1-14d: 7-((3,4-dimethoxyphenyl)sulfonyl)-3-methyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0279]

[0280] Using intermediates 1-13d as raw materials, the synthesis method was as described in Examples 1-14e, yielding a light brown powder with a yield of 30%. ¹H NMR (400MHz, DMSO-d6) δ 8.22 (s, 1H), 7.96 (s, 1H), 7.80 (dd, J = 8.7, 2.3Hz, 1H), 7.49 (d, J = 2.3Hz, 1H), 7.18 (d, J = 8.8Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 2.53 (s, 3H).

[0281] Intermediate 1-14f: 3-methyl-7-p-toluenesulfonyl-5,7-dihydro-6H-imidazol [4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0282]

[0283] Compound 1-13f (3.7 g, 11.7 mmol) was dissolved in 130 mL of tetrahydrofuran. Under ice bath and argon protection, triethylamine (4.9 mL, 35.2 mmol) was added via syringe. Then, triphosgene (3.5 g, 11.7 mmol) was dissolved in 10 mL of tetrahydrofuran and added to the reaction solution in small, repeated injections via syringe. The reaction was continued under ice bath for 18 min. The reaction solution was quenched in pre-cooled saturated sodium bicarbonate solution, and the solvent was removed by concentration under reduced pressure. The product was then extracted multiple times with ethyl acetate. The organic layers were combined and washed sequentially with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure until white crystals precipitated. The mixture was then filtered under reduced pressure, and the filter cake was washed with a small amount of ethyl acetate-petroleum ether mixed solvent (1:1) to obtain a white crystalline powder (2.9 g, yield: 72%). 1H NMR (500MHz, DMSO-d6) δ 8.00 (s, 1H), 7.97 (d, J = 8.0Hz, 2H), 7.46 (d, J = 7.9Hz, 2H), 7.33 (s, 1H), 2.52 (s, 3H), 2.38 (s, 3H).

[0284] Example 1-15c: 3-Methyl-7-(benzenesulfonyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0285]

[0286] Intermediate 1-14c (50 mg, 0.15 mmol), 4 mL DMF, and potassium carbonate (21 mg, 0.15 mmol) were added sequentially, and the reaction was carried out at room temperature for 10 min. Intermediate 1-3 (38 mg, 0.17 mmol) was then added, and the reaction was continued at room temperature for 11 h. The reaction solution was quenched with water, and the product was extracted with ethyl acetate. The organic layer was washed several times with water and then with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 3:1 to 2:1) to give a white powder (36.4 mg, yield: 51%). 1H NMR (500MHz, DMSO-d6) δ8.17–8.07(m,3H),7.81(t,J=7.5Hz,1H),7.72–7.62(m,3H),7.15(t,J=7.8Hz,1H),6.83–6.76( m,2H),6.69(d,J=7.6Hz,1H),4.99(s,2H),3.80(t,J=6.5Hz,2H),2.51(s,3H),1.72–1.62(m,2H),0.93(t,J=7.4Hz,3H).

[0287] Example 1-15d: 7-((3,4-dimethoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0288]

[0289] Using intermediates 1-14d and 1-3 as raw materials, the synthesis method is as described in Examples 1-15c, yielding a light yellow powder with a yield of 55%. 1H NMR(500MHz, DMSO-d6)δ8.12(s,1H),7.75(dd,J=8.6,2.2Hz,1H),7.69(s,1H),7.53(d,J=2.2Hz,1H),7.20–7.13(m,2H),6.84–6.78(m,2H), 6.72(d,J=7.5Hz,1H),5.01(s,2H),3.84(s,3H),3.81(t,J=6.5Hz,2H),3.77(s,3H),2.51(s,3H),1.70–1.62(m,2H),0.92(t,J=7.4Hz,3H).

[0290] Example 1-15e: 3,7-Dimethyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol [4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0291]

[0292] Intermediate 1-14e (50 mg, 0.24 mmol), intermediate 1-3 (64 mg, 0.28 mmol), potassium carbonate (50 mg, 0.36 mmol), and 3 mL of DMF were added sequentially, and the mixture was reacted at 70 °C for 14 h. The reaction solution was cooled to room temperature, diluted with water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic layers were concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 3:1) to give a light pink powder (34 mg, yield: 40%). 1HNMR(500MHz,DMSO-d6)δ7.52(s,1H),7.50(s,1H),7.22(t,J=7.9Hz,1H),6.92(s,1H),6.88(d,J=7.6Hz,1H),6.8 2(dd,J=8.1,1.8Hz,1H),5.06(s,2H),3.88(t,J=6.5Hz,2H),3.42(s,3H),1.73–1.65(m,2H),0.94(t,J=7.4Hz,3H).

[0293] Example 1-15f: 3-Methyl-5-(3-propoxybenzyl)-7-p-methylbenzenesulfonyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0294]

[0295] Using intermediates 1-14f and 1-3 as raw materials, the synthesis method is as described in Examples 1-15c, yielding a white powder with a yield of 98%. ¹H NMR (500MHz, CDCl₃-d) δ 8.20 (s, ¹H), 8.05 (d, J = 7.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.19 (t, J = 7.9 Hz, 1H), 6.86 (s, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.78–6.72 (m, 2H), 4.94 (s, 2H), 3.91–3.79 (m, 2H), 2.49 (s, 3H), 2.43 (s, 3H), 1.76 (h, J = 7.2 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H).

[0296] Example 1-15g: 3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0297]

[0298] Compound 1-15f (7 g, 14.3 mmol) was added to 300 mL of anhydrous tetrahydrofuran. Then, under argon protection, a 1N tetrabutylammonium fluoride THF solution (26.7 mL, 26.7 mmol) was added to the reaction mixture through a glass dropping funnel. After reacting at room temperature for 1.5 h, ethyl acetate was added to the reaction mixture to extract the product. The organic mixture was washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 2:1–1:2) to give a light blue-gray powder (4.5 g, yield: 94%). 1H NMR(500MHz,DMSO-d6)δ11.39(s,1H),7.44(s,1H),7.27–7.19(m,2H),6.91(s,1H),6.87(d,J=7.6Hz,1H),6.82 (d,J=8.2Hz,1H),5.02(s,2H),3.88(t,J=6.5Hz,2H),2.47(s,3H),1.69(h,J=7.1Hz,2H),0.94(t,J=7.4Hz,3H).

[0299] Example 1-15a: 7-Ethylsulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0300]

[0301] 1-15 g (80 mg, 0.24 mmol) of the compound was dissolved in 20 mL of dichloromethane, followed by the sequential addition of 4A molecular sieve powder (100 mg), triethylamine (97 mg, 0.96 mmol), 4-dimethylaminopyridine (6.1 mg, 0.05 mmol), and ethylsulfonyl chloride (62 mg, 0.48 mmol). The reaction was carried out at room temperature for 3 days. The reaction solution was then purified directly by silica gel column chromatography (PE:EA = 5:1 to 3:1) to give a white powder (48 mg, yield: 47%). 1H NMR (400MHz, CD3OD-d4) δ7.97(s,1H),7.41(s,1H),7.25(t,J=8.1Hz,1H),6.97–6.90(m,2H),6.85(d,J=7.9Hz,1H),5.14(s,2H) ,3.90(t,J=6.5Hz,2H),3.82(q,J=7.3Hz,2H),2.52(s,3H),1.76(h,J=7.1Hz,2H),1.38(t,J=7.4Hz,3H),1.01(t,J=7.4Hz,3H).

[0302] Example 1-15b: 7-Butylsulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0303]

[0304] Using compounds 1-15g and butylsulfonyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 72%. ¹H NMR (400MHz, CD₃OD-d₄) δ 7.96 (s, 1H), 7.42 (s, 1H), 7.24 (t, J = 7.9Hz, 1H), 6.96–6.90 (m, 2H), 6.84 (d, J = 7.9Hz, 1H), 5.13 (s, 2H), 3.90 (t, J = 6.7Hz, 2H), 3.81 (t, J = 7.8Hz, 2H), 2.53 (s, 3H), 1.85–1.70 (m, 4H), 1.45 (h, J = 7.4Hz, 3H), 1.00 (t, J = 7.5Hz, 3H), 0.90 (t, J = 7.4Hz, 3H).

[0305] Example 1-15h: 7-((3-bromo-4-methoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0306]

[0307] Using compound 1-15g and 3-bromo-4-methoxybenzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 72%. 1H NMR (500MHz, DMSO-d6) δ8.28(d,J=2.4Hz,1H),8.18–8.10(m,2H),7.71(s,1H),7.34(d,J=8.9Hz,1H),7.16(t,J=7.9Hz,1H),6.86–6.78( m,2H),6.73(d,J=7.6Hz,1H),5.00(s,2H),3.95(s,3H),3.82(t,J=6.5Hz,2H),2.51(s,3H),1.67(h,J=7.1Hz,2H),0.93(t,J=7.4Hz,3H).

[0308] Example 1-15i: 7-((5-bromo-2-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0309]

[0310] Using compounds 1-15 g and 5-bromo-2-methoxybenzenesulfonyl chloride as starting materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 51%. ¹H NMR (500 MHz, CDCl₃-d) δ 8.36 (s, 1H), 8.12 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.93 (s, 1H), 6.86–6.78 (m, 3H), 6.69 (s, 1H), 4.96 (s, 2H), 3.84 (t, J = 6.6 Hz, 2H), 3.45 (s, 3H), 2.53 (s, 3H), 1.76 (p, J = 7.0 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H).

[0311] Example 1-15j: 7-((5-chloro-2-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0312]

[0313] Using compound 1-15g and 5-chloro-2-methoxybenzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 68%. 1H NMR (500MHz, CDCl3-d) δ8.22(s,1H),8.12(s,1H),7.56(d,J=8.9Hz,1H),7.22(t,J=7.9Hz,1H),6.93(s,1H),6.87(d,J=8.9Hz,1H),6.80( d,J=7.7Hz,2H),6.69(s,1H),4.96(s,2H),3.84(t,J=6.5Hz,2H),3.45(s,3H),2.53(s,3H),1.76(h,J=7.1Hz,2H),1.01(t,J=7.4Hz,3H).

[0314] Example 1-15k: 7-((2-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0315]

[0316] Using compound 1-15g and 2-methoxybenzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 80%. 1H NMR(500MHz, CDCl3-d)δ8.25(dd,J=8.0,1.7Hz,1H),8.14(s,1H),7.65–7.59(m ,1H),7.21(t,J=7.9Hz,1H),7.17(t,J=7.7Hz,1H),6.93(d,J=8.4Hz,1H),6.91 (s,1H),6.79(dd,J=7.9,2.0Hz,2H),6.70(s,1H),4.95(s,2H),3.83(t,J=6.6H z, 2H), 3.48 (s, 3H), 2.52 (s, 3H), 1.76 (h, J = 7.1Hz, 2H), 1.00 (t, J = 7.4Hz, 3H).

[0317] Example 1-15l: 7-((3-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0318]

[0319] Using compounds 1-15g and 3-methoxybenzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 66%. 1H NMR (500MHz, CDCl3-d) δ8.18(s,1H),7.73(d,J=8.6Hz,1H),7.69(s,1H),7.44(t,J=8.1Hz,1H),7.23–7.17(m,2H),6.87(s,1H),6.80(d,J=8.1Hz,1 H),6.76(d,J=7.6Hz,1H),6.74(s,1H),4.96(s,2H),3.85(s,3H),3.82(t ,J=6.5Hz,2H),2.49(s,3H),1.76(h,J=7.1Hz,2H),1.00(t,J=7.4Hz,3H).

[0320] Example 1-15m: 7-((4-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0321]

[0322] Using compound 1-15g and 4-methoxybenzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 60%. 1H NMR (500MHz, CDCl3-d) δ8.19(s,1H),8.11(d,J=9.0Hz,2H),7.20(t,J=7.9Hz,1H),7.00(d,J=9.0Hz,2H),6.86(s,1H),6.80(dd,J=8.3,2 .4Hz,1H),6.77–6.73(m,2H),4.95(s,2H),3.87(s,3H),3.83(t,J=6.5Hz,2H),2.49(s,3H),1.76(h,J=7.2Hz,2H),1.00(t,J=7.4Hz,3H).

[0323] Example 1-15n: 7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0324]

[0325] Using compounds 1-15 g and 2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl chloride as starting materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 94%. ¹H NMR (500 MHz, CDCl₃-d) δ 8.16 (s, 1H), 7.72–7.64 (m, 2H), 7.21 (t, J = 7.9 Hz, 1H), 6.97 (d, J = 9.2 Hz, 1H), 6.87 (s, 1H), 6.84–6.75 (m, 3H), 4.96 (s, 2H), 4.34–4.24 (m, 4H), 3.85 (t, J = 6.5 Hz, 2H), 2.49 (s, 3H), 1.76 (h, J = 7.1 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H).

[0326] Example 1-15o: 7-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0327]

[0328] Using compounds 1-15 g and 2,3-dihydrobenzofuran-5-sulfonyl chloride as starting materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 100%. ¹H NMR (500 MHz, CDCl₃-d) δ 8.18 (s, 1H), 8.01–7.94 (m, 2H), 7.21 (t, J = 7.9 Hz, 1H), 6.90–6.84 (m, 2H), 6.83–6.74 (m, 3H), 4.96 (s, 2H), 4.68 (t, J = 8.8 Hz, 2H), 3.84 (t, J = 6.5 Hz, 2H), 3.27 (t, J = 8.8 Hz, 2H), 2.49 (s, 3H), 1.76 (h, J = 7.1 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H).

[0329] Example 1-15p: 3-Methyl-7-((2-oxo-2H-chromene-6-yl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol [4', 5': 4, 5]benzo[1,2-d]isoxazol-6-one

[0330]

[0331] Using compound 1-15g and 2-oxo-2H-chromene-6-sulfonyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 61%. ¹H NMR (500MHz, CDCl₃-d) δ 8.40 (d, J = 2.2Hz, 1H), 8.27 (dd, J = 8.8, 2.3Hz, 1H), 8.20 (s, 1H), 7.79 (d, J = 9.7Hz, 1H), 7.47 (d, J = 8.8Hz, 1H), 7.20 (t, J = 7.9Hz, 1H), 6.91 (s, 1H), 6.80 ( dd,J=8.3,2.5Hz,1H),6.76(d,J=7.6Hz,1H),6.72(s,1H),6.55(d,J=9.7Hz,1H),4.94( s, 2H), 3.84 (t, J = 6.5Hz, 2H), 2.50 (s, 3H), 1.75 (h, J = 7.1Hz, 2H), 0.99 (t, J = 7.4Hz, 3H).

[0332] Example 1-15q: 7-((4-cyanophenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0333]

[0334] Using compounds 1-15g and 4-cyanobenzenesulfonyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 82%. ¹H NMR (500MHz, CDCl₃-d) δ 8.30 (d, J = 8.1Hz, 2H), 8.17 (s, 1H), 7.86 (d, J = 8.3Hz, 2H), 7.21 (t, J = 7.9Hz, 1H), 6.92 (s, 1H), 6.81 (d, J = 8.2Hz, 1H), 6.75 (d, J = 7.6Hz, 1H), 6.71 (s, 1H), 4.94 (s, 2H), 3.85 (t, J = 6.5Hz, 2H), 2.50 (s, 3H), 1.77 (h, J = 7.1Hz, 2H), 1.01 (t, J = 7.4Hz, 3H).

[0335] Example 1-15r: 7-((4-methoxycarbonylphenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0336]

[0337] Using compounds 1-15g and 4-methoxycarbonylbenzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 87%. 1H NMR(500MHz, CDCl3-d)δ8.25(d,J=8.6Hz,2H),8.22–8.18(m,3H),7.19(t,J=7.9Hz,1H),6.89(s,1H),6.80(dd,J=8.2,2.4Hz,1H),6.75( d,J=7.9Hz,1H),6.73(s,1H),4.94(s,2H),3.95(s,3H),3.82(t,J=6.5Hz,2H),2.50(s,3H),1.75(h,J=7.1Hz,2H),0.99(t,J=7.4Hz,3H).

[0338] Example 1-15s: 7-((4-ethoxycarbonylphenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0339]

[0340] Using compounds 1-15g and 4-ethoxycarbonylbenzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 66%. 1H NMR (500MHz, CDCl3-d) δ8.24(d,J=7.2Hz,2H),8.23–8.18(m,3H),7.19(t,J=7.9Hz,1H),6.89(s,1H),6.79(d,J=8.4Hz,1H),6.74(d,J=8.0Hz ,2H),4.94(s,2H),4.41(q,J=7.4Hz,2H),3.86–3.80(m,2H),2.50(s,3H),1.75(h,J=7.1Hz,2H),1.39(t,J=7.2Hz,3H),0.99(t,J=7.4Hz,3H).

[0341] Example 1-15t: 3-Methyl-7-((4-methanesulfonylphenyl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0342]

[0343] Using compounds 1-15g and 4-methanesulfonylbenzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 45%. 1H NMR (500MHz, CDCl3-d) δ8.40(d,J=8.6Hz,2H),8.19(s,1H),8.14(d,J=8.6Hz,2H),7.22(t,J=7.9Hz,1H),6.92(s,1H),6.81(dd,J=8.6,2 .4Hz,1H),6.79–6.74(m,2H),4.95(s,2H),3.86(t,J=6.6Hz,2H),3.09(s,3H),2.51(s,3H),1.77(h,J=7.1Hz,2H),1.01(t,J=7.4Hz,3H).

[0344] Example 1-15u: 7-((4-bromophenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0345]

[0346] Using compound 1-15 g and 4-bromobenzenesulfonyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 14%. ¹H NMR (500 MHz, CDCl₃-d) δ 8.17 (s, 1H), 8.04 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.7 Hz, 2H), 7.21 (t, J = 7.9 Hz, 1H), 6.89 (s, 1H), 6.81 (dd, J = 7.8, 2.2 Hz, 1H), 6.77–6.72 (m, 2H), 4.95 (s, 2H), 3.84 (t, J = 6.6 Hz, 2H), 2.50 (s, 3H), 1.77 (h, J = 7.1 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H).

[0347] Example 1-15v: 7-((6-chloropyridin-3-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0348]

[0349] Using compounds 1-15g and 6-chloropyridine-3-sulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 74%. 1H NMR(500MHz, CDCl3-d)δ9.11(d,J=2.7Hz,1H),8.45(dd,J=8.5,2.5Hz,1H),8.16(s,1H),7.54(d,J=8.5Hz,1H),7.24–7.20(m,1H),6.93(s,1H),6.8 1(dd,J=8.2,2.6Hz,1H),6.79–6.76(m,1H),6.75(s,1H),4.95(s,2H),3.8 5(t,J=6.5Hz,2H),2.51(s,3H),1.84–1.72(m,2H),1.01(t,J=7.4Hz,3H).

[0350] Example 1-15w: 7-((6-methoxypyridin-3-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0351]

[0352] Using compounds 1-15 g and 6-chloropyridine-3-sulfonyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 75%. ¹H NMR (500 MHz, CDCl₃-d) δ 8.95 (s, 1H), 8.28 (dd, J = 9.0, 2.5 Hz, 1H), 8.18 (s, 1H), 7.21 (t, J = 7.8 Hz, 1H), 6.89 (s, 1H), 6.84 (d, J = 9.0 Hz, 1H), 6.83–6.75 (m, 3H), 4.96 (s, 2H), 4.01 (s, 3H), 3.84 (t, J = 6.6 Hz, 2H), 2.50 (s, 3H), 1.76 (h, J = 7.1 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H).

[0353] Example 1-15x: 7-((3,5-dichlorophenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0354]

[0355] Using compounds 1-15 g and 3,5-dichlorobenzenesulfonyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 53%. ¹H NMR (500 MHz, CDCl₃-d) δ 8.15 (s, 1H), 8.09–8.01 (m, 2H), 7.65 (s, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.93 (s, 1H), 6.84–6.79 (m, 2H), 6.77 (s, 1H), 4.97 (s, 2H), 3.85 (t, J = 6.5 Hz, 2H), 2.51 (s, 3H), 1.77 (h, J = 7.1 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H).

[0356] Example 1-15y: 7-((2,6-dichlorophenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0357]

[0358] Using compounds 1-15 g and 2,6-dichlorobenzenesulfonyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 88%. ¹H NMR (500 MHz, CDCl₃-d) δ 8.13 (s, 1H), 7.55–7.49 (m, 2H), 7.47–7.43 (m, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.93 (s, 1H), 6.83–6.76 (m, 2H), 6.72 (s, 1H), 4.98 (s, 2H), 3.84 (t, J = 6.6 Hz, 2H), 2.51 (s, 3H), 1.76 (h, J = 7.1 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H).

[0359] Example 1-15z: 3-Methyl-5-(3-propoxybenzyl)-7-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0360]

[0361] Using compounds 1-15 g and 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride as starting materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 91%. ¹H NMR (500 MHz, CDCl₃-d) δ 8.21 (s, 1H), 7.24–7.21 (m, 1H), 6.89 (s, 1H), 6.82–6.73 (m, 3H), 4.97 (s, 2H), 3.85 (t, J = 6.5 Hz, 2H), 3.77 (s, 3H), 2.63 (s, 3H), 2.50 (s, 3H), 2.32 (s, 3H), 1.82–1.73 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H).

[0362] Example 1-15aa: 7-((3,5-dimethyl-isoxazo-4-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0363]

[0364] Using compounds 1-15 g and 3,5-dimethyl-isoxazole-4-sulfonyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 76%. ¹H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.77 (s, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.88 (s, 1H), 6.84 (d, J = 8.0 Hz, 2H), 5.04 (s, 2H), 3.86 (t, J = 6.5 Hz, 2H), 2.73 (s, 3H), 2.53 (s, 3H), 2.27 (s, 3H), 1.69 (h, J = 7.1 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0365] Example 1-15ab: 7-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0366]

[0367] Using compound 1-15 g and 1,2-dimethyl-1H-imidazol-4-sulfonyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 74%. ¹H NMR (500 MHz, CDCl₃-d) δ 8.23 ​​(s, 1H), 7.83 (s, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.87 (s, 1H), 6.84–6.78 (m, 3H), 4.97 (s, 2H), 3.87 (t, J = 6.6 Hz, 2H), 3.65 (s, 3H), 2.49 (s, 3H), 2.35 (s, 3H), 1.77 (h, J = 7.1 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H).

[0368] Example 1-15ac: 3-Methyl-7-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0369]

[0370] Using compound 1-15g and 1-methyl-1H-pyrazole-3-sulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 75%. 1H NMR (500MHz, CDCl3-d) δ8.18(s,1H),7.46(d,J=2.3Hz,1H),7.23(t,J=7.9Hz,1H),7.08(d,J=2.4Hz,1H),6.89(s,1H),6.84(d,J=7.7H z,1H),6.83–6.78(m,2H),4.99(s,2H),3.94(s,3H),3.87(t,J=6.6Hz,2H),2.49(s,3H),1.77(h,J=7.2Hz,2H),1.01(t,J=7.4Hz,3H).

[0371] Example 1-15ad: 3-Methyl-7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0372]

[0373] Using compound 1-15 g and 1-methyl-1H-pyrazole-4-sulfonyl chloride as starting materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 84%. ¹H NMR (500 MHz, CDCl₃-d) δ 8.20 (s, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 7.23 (7.23, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.85–6.76 (m, 3H), 4.98 (s, 2H), 3.96 (s, 3H), 3.86 (t, J = 6.6 Hz, 2H), 2.50 (s, 3H), 1.78 (p, J = 7.1 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H).

[0374] Example 1-15ae: 3-Methyl-7-(morpholinosulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0375]

[0376] Using compounds 1-15g and morpholine sulfonyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 77%. ¹H NMR (500MHz, DMSO-d6) δ 7.84 (s, 1H), 7.73 (s, 1H), 7.26 (t, J = 7.9Hz, 1H), 6.97 (s, 1H), 6.93 (d, J = 7.6Hz, 1H), 6.85 (dd, J = 8.2, 2.5Hz, 1H), 5.10 (s, 2H), 3.89 (t, J = 6.5Hz, 2H), 3.67–3.62 (m, 4H), 3.45–3.40 (m, 4H), 2.52 (s, 3H), 1.69 (h, J = 7.1Hz, 2H), 0.94 (t, J = 7.4Hz, 3H).

[0377] Example 1-15af: 3-Methyl-7-(piperidin-1-sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0378]

[0379] Using compounds 1-15 g and piperidine-1-sulfonyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 63%. ¹H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.72 (s, 1H), 7.25 (t, J = 7.9 Hz, 1H), 6.97–6.90 (m, 2H), 6.85 (dd, J = 8.3, 2.4 Hz, 1H), 5.10 (s, 2H), 3.89 (t, J = 6.5 Hz, 2H), 3.42–3.36 (m, 4H), 2.52 (s, 3H), 1.69 (h, J = 7.1 Hz, 2H), 1.57–1.42 (m, 6H), 0.94 (t, J = 7.4 Hz, 3H).

[0380] Example 1-15ag: 7-(cyclopropylsulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0381]

[0382] Using compounds 1-15g and cyclopropylsulfonyl chloride as starting materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 78%. ¹H NMR (400MHz, CDCl₃-d) δ 7.97 (s, 1H), 7.29–7.24 (m, 1H), 6.94 (s, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.87–6.82 (m, 2H), 5.07 (s, 2H), 3.89 (t, J = 6.5 Hz, 2H), 3.32–3.25 (m, 1H), 2.51 (s, 3H), 1.78 (h, J = 7.1 Hz, 2H), 1.60–1.57 (m, 2H), 1.24–1.18 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).

[0383] Example 1-15ak: 7-(dimethylaminosulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0384]

[0385] Using compounds 1-15g and dimethylaminosulfonyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 97%. ¹H NMR (500MHz, CD₃OD-d₄) δ 7.88 (s, 1H), 7.35 (s, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.92–6.89 (m, 2H), 6.82 (dd, J = 8.4, 2.4 Hz, 1H), 5.11 (s, 2H), 3.89 (t, J = 6.5 Hz, 2H), 3.08 (s, 6H), 2.51 (s, 3H), 1.75 (h, J = 7.0 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H).

[0386] Example 1-15al: 3-Methyl-5-(3-propoxybenzyl)-7-propylsulfonyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0387]

[0388] Using compounds 1-15g and propylsulfonyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 47%. ¹H NMR (500MHz, DMSO-d6) δ 7.87 (s, 1H), 7.75 (s, 1H), 7.25 (t, J = 7.9 Hz, 1H), 6.96 (s, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.85 (dd, J = 8.2, 2.5 Hz, 1H), 5.10 (s, 2H), 3.89 (t, J = 6.5 Hz, 2H), 3.87–3.84 (m, 2H), 2.53 (s, 3H), 1.78–1.65 (m, 4H), 0.97–0.92 (m, 6H).

[0389] Example 1-15am: 7-(3,4-dimethoxybenzoyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0390]

[0391] Using compounds 1-15 g and 3,4-dimethoxybenzoyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 66%. ¹H NMR (400 MHz, CDCl₃-d) δ 8.05 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.46 (s, 1H), 7.28 (d, J = 2.7 Hz, 1H), 7.03–6.81 (m, 5H), 5.08 (s, 2H), 3.99 (s, 3H), 3.97 (s, 3H), 3.91 (t, J = 6.5 Hz, 2H), 2.56 (s, 3H), 1.88–1.73 (m, 2H), 1.04 (t, J = 7.5 Hz, 3H).

[0392] Example 1-15an: 7-(3,5-dimethylisoxazole-4-carbonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazole-6-one

[0393]

[0394] Using compounds 1-15 g and 3,5-dimethylisoxazole-4-carbonyl chloride as starting materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 31%. ¹H NMR (400 MHz, CDCl₃-d) δ 8.24 (s, 1H), 7.32–7.26 (m, 1H), 7.03 (s, 1H), 6.95–6.83 (m, 3H), 5.08 (s, 2H), 3.91 (t, J = 6.6 Hz, 2H), 2.57 (s, 6H), 2.39 (s, 3H), 1.86–1.76 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H).

[0395] Example 1-15ao: 7-cyclopropanecarbonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0396]

[0397] Using compounds 1-15g and cyclopropaneformyl chloride as raw materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 74%. ¹H NMR (500MHz, DMSO-d6) δ 8.25 (s, 1H), 7.63 (s, 1H), 7.24 (t, J = 7.9 Hz, 1H), 7.00 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.84 (dd, J = 8.2, 2.5 Hz, 1H), 5.11 (s, 2H), 3.90 (t, J = 6.5 Hz, 2H), 3.51–3.46 (m, 1H), 1.69 (h, J = 7.1 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0398] Example 1-15ap: 7-(3,4-dimethoxybenzyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0399]

[0400] 1-15 g (80 mg, 0.24 mmol) of compound, potassium carbonate (100 mg, 0.72 mmol), 3 mL of DMF, and 3,4-dimethoxybenzyl bromide (111 mg, 0.48 mmol) were added sequentially to a reaction flask, and the mixture was reacted at 70 °C for 4 days. The reaction solution was cooled to room temperature, and an appropriate amount of water was added. The product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:EA = 20:1) to give a white powder (72 mg, yield: 46%). 1HNMR(500MHz, CDCl3-d)δ7.24(t,J=7.9Hz,1H),7.03(s,1H),6.95–6.79(m,7H),5.13(s,2H),5.10 (s,2H),3.91–3.84(m,5H),3.83(s,3H),2.48(s,3H),1.77(h,J=7.1Hz,2H),1.00(t,J=7.4Hz,3H).

[0401] Example 1-15aq: 3-Methyl-5-(3-propoxybenzyl)-7-propyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0402]

[0403] 1-15 g (80 mg, 0.24 mmol) of the compound, potassium carbonate (100 mg, 0.72 mmol), 3 mL of DMF, and iodopropane (82 mg, 0.48 mmol) were added sequentially to a reaction flask, and the mixture was reacted at room temperature for 2 days. A suitable amount of water was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 6:1–5:1) to give a white powder (70 mg, yield: 78%). 1H NMR (500MHz, CDCl3-d) δ7.24(t,J=7.8Hz,1H),7.11(s,1H),6.90–6.83(m,3H),6.81(dd,J=8.2,2.5Hz,1H),5.09(s,2H),3 .95(t,J=7.3Hz,2H),3.87(t,J=6.6Hz,2H),2.50(s,3H),1.85(h,J=7.4Hz,2H),1.77(h,J=7.2Hz,2H),1.05–0.97(m,6H).

[0404] Example 1-15ah: 3-Methyl-7-(1-methylcyclopropyl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0405]

[0406] Using intermediates 1-15 and 1-methylcyclopropylsulfonamide as starting materials, the synthetic route is as described in Examples 1-15f, yielding a white powder with an overall yield of 24%. ¹H NMR (500 MHz, CD₃OD-d₄) δ 7.99 (s, ¹H), 7.42 (s, ¹H), 7.25 (t, J = 8.2 Hz, ¹H), 6.96–6.91 (m, 2H), 6.88–6.82 (m, ¹H), 5.14 (s, 2H), 3.90 (t, J = 6.5 Hz, 2H), 2.53 (s, 3H), 1.86–1.82 (m, 2H), 1.76 (h, J = 7.2 Hz, 2H), 1.50 (s, 3H), 1.11–1.06 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).

[0407] Example 1-15ai: 7-(tert-butylsulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0408]

[0409] Using intermediates 1-15 and tert-butylsulfonamide as starting materials, the synthetic route is as described in Examples 1-15f, yielding a white powder with an overall yield of 27%. ¹H NMR (400MHz, CD₃OD-d₄) δ 7.93 (s, 1H), 7.41 (s, 1H), 7.25 (t, J = 8.1 Hz, 1H), 6.94 (s, 2H), 6.85 (d, J = 8.4 Hz, 1H), 5.14 (s, 2H), 3.90 (t, J = 6.4 Hz, 2H), 2.53 (s, 3H), 1.76 (h, J = 7.1 Hz, 2H), 1.56 (s, 9H), 1.01 (t, J = 7.3 Hz, 3H).

[0410] Example 1-15aj: 7-(isopropylsulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0411]

[0412] Using intermediates 1-15 and isopropyl sulfonamide as starting materials, the synthetic route is as described in Examples 1-15f, yielding a white powder with an overall yield of 29%. ¹H NMR (400MHz, CD₃OD-d₄) δ 7.93 (s, 1H), 7.40 (s, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.94–6.89 (m, 2H), 6.83 (d, J = 7.9 Hz, 1H), 5.13 (s, 2H), 4.17–4.04 (m, 1H), 3.89 (t, J = 6.4, 2.2 Hz, 2H), 2.52 (s, 3H), 1.75 (h, J = 7.1 Hz, 2H), 1.45 (s, 3H), 1.43 (s, 3H), 1.00 (t, J = 7.6 Hz, 3H).

[0413] Example 1-16c: 3-Methyl-7-(phenylsulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0414]

[0415] Intermediate 1-14c (44 mg, 0.13 mmol) was dissolved in 3 mL of DMF, and triethylamine (0.06 mL, 0.4 mmol) was added under ice bath conditions. After reacting for 15 min, intermediate 1-7 (40 mg, 0.2 mmol) was added, and the mixture was brought to room temperature and reacted for 11 h. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 5:1 to 1:1) to give a white powder (35.2 mg, yield: 53%). 1H NMR (500MHz, DMSO-d6) δ8.19(s,2H),8.11(d,J=7.9Hz,2H),7.81(t,J=7.3Hz,1H),7.66(t,J=7.6Hz,2H),7.40(t,J=7.8Hz, 1H),7.37–7.30(m,2H),7.20(d,J=7.9Hz,1H),3.89(t,J=6.3Hz,2H),2.57(s,3H),1.77–1.67(m,2H),0.97(t,J=7.3Hz,3H).

[0416] Example 1-16d: 7-((3,4-dimethoxyphenyl)sulfonamide)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0417]

[0418] Using intermediates 1-14d and 1-7 as raw materials, the synthesis method is as described in Examples 1-16c, yielding a white powder with a yield of 99%. 1H NMR(500MHz,DMSO-d6)δ8.19(s,1H),8.17(s,1H),7.75(dd,J=8.7,2.2Hz,1H), 7.48(d,J=2.2Hz,1H),7.41(t,J=7.9Hz,1H),7.37(s,1H),7.33(d,J=7.6Hz,1H ),7.20(dd,J=8.3,1.9Hz,1H),7.18(d,J=8.8Hz,1H),3.90(t,J=6.5Hz,2H),3. 83(s,3H),3.76(s,3H),2.56(s,3H),1.76–1.68(m,2H),0.96(t,J=7.4Hz,3H).

[0419] Example 1-16e: 3,7-Dimethyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazol [4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0420]

[0421] Using intermediates 1-14d and 1-7 as raw materials, the synthesis method was as described in Examples 1-16c (except that the solvent was changed to DMSO), yielding a white powder with a yield of 40%. ¹H NMR (500MHz, DMSO-d6) δ 8.15 (s, 1H), 7.64 (s, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.35–7.30 (m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 3.97 (t, J = 6.5 Hz, 2H), 3.35 (s, 3H), 2.56 (s, 3H), 1.81–1.70 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

[0422] Intermediate 1-25: 3-methoxy-7-methyl-5,7-dihydro-6H-imidazol [4', 5': 4, 5]benzo[1, 2-d]isoxazol-6-one

[0423]

[0424] Step 1: Synthesis of methyl 4-fluoro-2-hydroxybenzoate (1-18)

[0425]

[0426] 4-Fluoro-2-hydroxybenzoic acid (1-17, 24.8 g, 0.16 mol) was dissolved in 400 mL of anhydrous methanol. Thionyl chloride (65 mL) was added dropwise through a glass dropping funnel under ice bath conditions, and the reaction was carried out at 70 °C for 22 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. All solvents were removed from the organic solvent under reduced pressure to give a white crystalline powder (25.6 g, yield: 94%). ¹H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.88–7.82 (m, 1H), 7.02–6.77 (m, 2H), 3.88 (s, 3H).

[0427] Step 2: Synthesis of 4-fluoro-N,2-dihydroxybenzamide (1-19)

[0428]

[0429] Intermediate 1-18 (25.5 g, 0.15 mol) was added to 500 mL of anhydrous methanol, followed by the sequential addition of hydroxylamine hydrochloride (41.7 g, 0.6 mol) and potassium hydroxide (67.3 g, 1.2 mol) under ice bath conditions. The reaction mixture was reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and ice water was added. The pH was adjusted to 6 with dilute hydrochloric acid under ice bath conditions, resulting in the precipitation of a white solid. The solid was filtered under reduced pressure. The filter cake was washed with water and transferred to a single-necked flask. The solid was rotary evaporated under reduced pressure to constant weight, yielding a white powder (16.7 g, yield: 65%). ¹H NMR (500 MHz, DMSO-d6) δ 13.0–9.0 (bs, 2H), 7.73 (t, J = 7.8 Hz, 1H), 6.69 (d, J = 9.9 Hz, 2H).

[0430] Step 3: Synthesis of 6-fluorobenzo[d]isoxazole-3(2H)-one (1-20)

[0431]

[0432] Intermediate 1-19 (16.6 g, 0.97 mol) was added to 500 mL of anhydrous tetrahydrofuran, and heated to 85 °C with stirring. CDI (70.8 g, 0.44 mol) was added in multiple portions, and the reaction was maintained at this temperature for 60 min. The reaction solution was cooled to room temperature, and the solvent was removed by rotary evaporation under reduced pressure. The solution was then placed in an ice bath, quenched with ice water, and the pH was adjusted to 3–4 with dilute hydrochloric acid, precipitating a solid. The mixture was filtered under reduced pressure, the filter cake was washed with water, and filtered again under reduced pressure until a constant weight was obtained, yielding a white powder (12 g, yield: 81%). ¹H NMR (500 MHz, DMSO-d6) δ 12.49 (s, 1H), 7.78 (s, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.20 (t, J = 9.2 Hz, 1H).

[0433] Step 4: Synthesis of 6-fluoro-3-methoxybenzo[d]isoxazole (1-21)

[0434]

[0435] Intermediate 1-20 (12 g, 78.4 mmol) was dissolved in 100 mL of DMF. Sodium hydride powder (9.42 g, 235.3 mmol) (60%) was added at 0 °C. After reacting for 20 min, methyl p-toluenesulfonate (29.2 g, 156.9 mmol) was diluted with 8 mL of DMF and added dropwise through a glass dropping funnel. The reaction was continued for 16 h. The reaction solution was quenched in ice water, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the organic layer was purified by silica gel column chromatography (pure PE) to give a white powder (8.2 g, yield: 62%). 1H NMR (500MHz, DMSO-d6) δ7.81–7.75 (m, 1H), 7.62 (d, J = 8.7Hz, 1H), 7.25 (t, J = 9.0Hz, 1H), 4.10 (s, 3H).

[0436] Step 5: Synthesis of 6-fluoro-3-methoxy-5-nitrobenzene[d]isoxazole (1-22)

[0437]

[0438] Intermediate 1-21 (8.1 g, 48.5 mmol) was dissolved in 30 mL of concentrated sulfuric acid under ice bath conditions. Fuming nitric acid (3.06 mL, 72.75 mmol) was added dropwise through a glass dropping funnel, and the reaction flask was transferred to room temperature and reacted for 15 min. The reaction solution was quenched in ice water, precipitating a solid. The solid was filtered under reduced pressure, and the filter cake was washed with water and filtered until a constant weight was obtained, yielding a pale yellow powder (8.7 g, yield: 84%). ¹H NMR (500 MHz, DMSO-d⁶) δ 8.61 (d, J = 6.1 Hz, 1H), 8.07 (d, J = 10.8 Hz, 1H), 4.15 (s, 3H).

[0439] Step 6: Synthesis of 3-methoxy-N-methyl-5-nitrobenzene[d]isoxazole-6-amine (2-23)

[0440]

[0441] The intermediate (1-22, 1 g) was added to a methanol solution of methylamine (45%), and the reaction was terminated by gradually heating to 75 °C. The reaction solution was cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, water was added to precipitate the solid, and the solid was filtered under reduced pressure until the filter cake reached constant weight. The filter cake was dissolved in ethyl acetate and purified by silica gel column chromatography (PE:EA = 6:1) to give an orange powder (735 mg, yield: 70%). ¹H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.21 (s, 1H), 6.88 (s, 1H), 4.08 (s, 3H), 2.95 (d, J = 4.8 Hz, 3H).

[0442] Step 7: Synthesis of 3-methoxy-N 6 Methylbenzo[d]isoxazole-5,6-diamine (1-24)

[0443]

[0444] Intermediate 1-23 (700 mg, 3.4 mmol) was added to 40 mL of an ethanol-ethyl acetate mixture (3:1). Stannous chloride dihydrate (3.5 g, 15.7 mmol) was dissolved in 6 mL of concentrated hydrochloric acid and added to the mixture with stirring. The mixture was reacted at 80 °C for 20 min. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then subjected to the addition of ice water. The pH was adjusted to 6–7 with dilute sodium hydroxide solution in an ice bath. The product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain a brownish-yellow powder (597 mg, yield: 98%). ¹H NMR (500 MHz, DMSO-d6) δ 6.64 (s, 1H), 6.38 (s, 1H), 5.50 (s, 1H), 4.56 (s, 2H), 3.98 (s, 3H), 2.77 (d, J = 4.8 Hz, 3H).

[0445] Step 8: Synthesis of 3-methoxy-7-methyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one (1-25)

[0446]

[0447] Using intermediate 1-24 as a starting material, the synthesis method is the same as that for intermediate 1-14e, yielding a white powder with a yield of 60%. ¹H NMR (500 MHz, DMSO-d6) δ 11.06 (s, ¹H), 7.36 (s, ¹H), 7.04 (s, ¹H), 4.07 (s, ³H), 3.31 (s, ³H).

[0448] Examples 1-26: 3-Methoxy-7-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0449]

[0450] Using intermediates 1-25 and 1-3 as raw materials, the synthesis method was as described in Examples 1-15c, yielding a white powder with a yield of 74%. ¹H NMR (500MHz, DMSO-d6) δ 7.47 (s, 1H), 7.31 (s, 1H), 7.21 (t, J = 7.9Hz, 1H), 6.93 (s, 1H), 6.87 (d, J = 7.7Hz, 1H), 6.82 (d, J = 8.2Hz, 1H), 5.07 (s, 2H), 4.06 (s, 3H), 3.87 (t, J = 6.6Hz, 2H), 3.42 (s, 3H), 1.69 (h, J = 7.1Hz, 2H), 0.94 (t, J = 7.1Hz, 3H).

[0451] Examples 1-27: 3-Methoxy-7-methyl-5-(3-propoxybenzoyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0452]

[0453] Using intermediates 1-25 and 1-7 as raw materials, the synthesis method is as described in Examples 1-16c, yielding a white powder with a yield of 80%. ¹H NMR (500 MHz, CDCl₃-d) δ 8.17 (s, ¹H), 7.38 (t, J = 8.4 Hz, ¹H), 7.29 (d, J = 7.5 Hz, ¹H), 7.26 (d, J = 2.9 Hz, ¹H), 7.13 (d, J = 8.1 Hz, ¹H), 6.99 (s, ¹H), 4.17 (s, ³H), 3.97 (t, J = 6.5 Hz, 2H), 3.40 (s, ³H), 1.82 (h, J = 6.0, 5.0 Hz, 2H), 1.07–1.01 (m, ³H).

[0454] Option 2 will be implemented as follows:

[0455] Intermediate 2-3: 3-Bromomethyl-5-propoxyphenylacetic acid ester

[0456]

[0457] Step 1: Synthesis of 3-hydroxymethyl-5-propoxyphenol (2-2)

[0458]

[0459] Using 3,5-dihydroxybenzyl alcohol (2-1) and iodopropane as starting materials, the synthesis method is as described in intermediates 1-2, yielding a brown liquid in 34% yield. ¹H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 6.35–6.28 (m, 2H), 6.16 (s, 1H), 5.06 (t, J = 6.1 Hz, 1H), 4.36 (d, J = 5.2 Hz, 2H), 3.83 (t, J = 6.4 Hz, 2H), 1.69 (h, J = 7.2 Hz, 2H), 0.95 (t, J = 7.9 Hz, 3H).

[0460] Step 2: Synthesis of 3-bromomethyl-5-propoxyphenylacetic acid ester (2-3)

[0461]

[0462] (i) Intermediate 2-2 (7.9 g, 43.4 mmol) was dissolved in 280 mL of anhydrous tetrahydrofuran, followed by the addition of potassium carbonate (7.2 g, 52.0 mmol), and the reaction was carried out in an ice bath for 10 min. Acetic anhydride (5.3 g, 52.0 mmol) was dissolved in 80 mL of anhydrous tetrahydrofuran and added dropwise to the reaction solution in an ice bath, and the reaction was carried out at room temperature for 14 h. The reaction solution was filtered under reduced pressure. The filter cake was washed with dichloromethane, and the filtrates were combined and concentrated under reduced pressure. The main product (PE:EA = 4:1 to 3:1) was rapidly obtained by silica gel column chromatography to give a colorless liquid (6.3 g, yield: 65%).

[0463] (ii) The above (6.3 g, 28.1 mmol) was dissolved in 150 mL of dichloromethane and transferred to an ice bath. Phosphorus tribromide (3.0 g, 11.2 mmol) was dissolved in 125 mL of dichloromethane and added dropwise to the reaction solution. The reaction was allowed to proceed for 15 min. The reaction was quenched by adding cold saturated sodium bicarbonate solution under ice bath conditions, and the product was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 20:1-10-1) to give a yellow liquid (3.94 g, yield: 32%). 1H NMR(500MHz,DMSO-d6)δ6.92(s,1H),6.78(s,1H),6.68(s,1H),4.65(s,2H),3. 92 (t, J = 6.5 Hz, 2H), 2.25 (s, 3H), 1.71 (h, J = 7.0 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H).

[0464] Intermediate 2-7: 5-(3-hydroxy-5-propoxyphenyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-5,7-dihydro-6H-imidazol [4', 5': 4, 5]benzo[1, 2-d]isoxazo-6-one

[0465]

[0466] Step 1: Synthesis of 3-((3-methyl-6-oxo-7-p-methylbenzenesulfonyl-6,7-dihydro-5H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-5-yl)methyl-5-propoxyphenylacetic acid ester (2-4)

[0467]

[0468] Using intermediates 1-14f and 2-3 as raw materials, the synthesis method was as described in Examples 1-15f, yielding a white powder with a yield of 99%. ¹H NMR (500MHz, DMSO-d6) δ 8.10 (s, 1H), 8.00 (d, J = 8.0Hz, 2H), 7.68 (s, 1H), 7.46 (d, J = 8.0Hz, 2H), 6.70 (s, 1H), 6.63 (s, 1H), 6.58 (s, 1H), 4.99 (s, 2H), 3.82 (t, J = 6.5Hz, 2H), 2.38 (s, 3H), 2.22 (s, 3H), 1.66 (h, J = 7.3Hz, 2H), 0.92 (t, J = 7.4Hz, 3H).

[0469] Step 2: Synthesis of 3-((3-methyl-6-oxo-6,7-dihydro-5H-imidazol[4',5':4,5]benzo[1,2-d]isoxazol-5-yl)methyl-5-propoxyphenylacetic acid ester (2-5)

[0470]

[0471] Using intermediates 2-4 as raw materials, the synthesis method was as described in Examples 1-15g, and the reaction temperature was lowered from room temperature to -20℃ to obtain a white crude powder with a yield of 100%. ¹H NMR (500MHz, DMSO-d6) δ 11.40 (s, 1H), 7.44 (s, 1H), 7.25 (s, 1H), 6.82 (s, 1H), 6.64 (s, 2H), 5.02 (s, 2H), 3.87 (t, J = 6.0Hz, 2H), 2.48 (s, 3H), 2.21 (s, 3H), 1.68 (h, J = 8.1, 7.4Hz, 2H), 0.93 (t, J = 7.4Hz, 3H).

[0472] Step 3: Synthesis of 3-((3-methyl-6-oxo-7-((2-trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-5-yl)methyl-5-propoxyphenylacetic acid ester (2-6)

[0473]

[0474] Intermediate 2-5 (3.6 g, 9.2 mmol) was dissolved in 100 mL of freshly distilled dichloromethane, followed by the sequential addition of DIPEA (6.4 mL, 36.6 mmol) and DMAP (112 mg, 0.9 mmol). After thorough mixing, SEMCl (4.9 mL, 27.5 mmol) was diluted with 50 mL of freshly distilled dichloromethane and slowly added dropwise through a glass dropping funnel at room temperature. The reaction was continued for 12 h. The solution was then purified directly by silica gel column chromatography (PE:EA = 5:1 to 1:1) to give a colorless liquid (4.3 g, yield: 89%). 1H NMR (500MHz, DMSO-d6) δ7.61(s,1H),7.57(s,1H),6.81(s,1H),6.65(s,2H),5.37(s,2H),5.09(s,2H),3.87(t,J=6.5Hz,2H),3. 59(t,J=7.9Hz,2H),2.50(s,3H),2.20(s,3H),1.68(h,J=7.2Hz,2H),0.93(t,J=7.4Hz,3H),0.85(t,J=7.9Hz,2H),-0.10(s,9H).

[0475] Step 4: Synthesis of 5-(3-hydroxy-5-propoxyphenyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one(2-7)

[0476]

[0477] Intermediate 2-6 (2.63 g, 5.0 mmol) was added to 55 mL of methanol, followed by 16.7 mL of 3N sodium hydroxide solution (50 mmol), and the reaction was carried out at room temperature for 1.5 h. Under ice bath conditions, the pH of the reaction mixture was adjusted to 6 with dilute hydrochloric acid, and 3–4 spoonfuls of sodium chloride powder were added. The reaction mixture was concentrated under reduced pressure, and the product was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain a white powder (2.4 g, yield: 99%). 1H NMR(500MHz,DMSO-d6)δ9.41(s,1H),7.60(s,1H),7.52(s,1H),6.34(s,1H),6.27(s,1H),6.20(s,1H),5.37(s,2H),4.99(s,2H),3.80( t,J=6.5Hz,2H),3.59(t,J=7.9Hz,2H),2.50(s,3H),1.65(h,J=7.1Hz,2H),0.92(t,J=7.4Hz,3H),0.85(t,J=7.9Hz,2H),-0.09(s,9H).

[0478] Example 2-8a: 5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0479]

[0480] (i) Intermediate 2-7 (98 mg, 0.2 mmol) and cesium carbonate (198 mg, 0.6 mmol) were added to 3 mL of DMSO, followed by 3-bromo-N,N-dimethyl-1-propylamine hydrobromide (74 mg, 0.3 mmol). The reaction mixture was reacted at 80 °C for 16.5 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and rapidly purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the main compound as a colorless liquid (60 mg, yield 52%). No structural characterization was performed, and the reaction proceeded directly to the next step.

[0481] (ii) Add 60 mg of the crude product obtained in the previous step to 3 mL of tetrahydrofuran, followed by 4 mL of tetrahydrofuran solution containing 1 N TBAF, and react at 70 °C for 24 h. The reaction solution was diluted with dichloromethane, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (first pre-eluting the silica gel column with petroleum ether containing 0.1% triethylamine, then eluting with DCM:MeOH = 40:1) to obtain a white solid (20 mg, yield: 43%; two-step yield: 22%). 1H NMR (500MHz, DMSO-d6) δ11.39(s,1H),7.44(s,1H),7.25(s,1H),6.49(s,1H),6.45(s,1H),6.37(s,1H),4.97(s,2H),3.93(t,J= 6.3Hz, 2H), 3.86 (t, J = 6.5Hz, 2H), 2.48 (s, 5H), 2.24 (s, 6H), 1.83 (p, J = 6.6Hz, 2H), 1.67 (h, J = 7.0Hz, 2H), 0.93 (t, J = 7.4Hz, 3H).

[0482] Example 2-8c: 3-Methyl-5-(3-((1-methylpiperidin-4-yl)oxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0483]

[0484] Using intermediates 2-7 and N-methyl-4-piperidinyl p-toluenesulfonate as raw materials, the synthesis method is as described in Examples 2-8a, except that the reaction solvent in step (i) is replaced with DMF, yielding a white solid. The two-step yield is 22%. 1H NMR(500MHz,DMSO-d6)δ11.40(s,1H),7.46(s,1H),7.25(s,1H),6.50(s,1H),6.47(s,1H),6.40(s,1H),4.96(s,2H),4.3 7(s,1H),3.85(t,J=6.6Hz,2H),2.85–2.65(m,2H),2.48(s,3H),2.40–2.30(m,2H),1.96–1.86(m,2H),1.75–1.60(m,4H).

[0485] Example 2-8b: 5-(3-(4-(dimethylamino)butoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0486]

[0487] (i) Intermediate 2-7 (800 mg, 1.7 mmol) and potassium carbonate (380 mg, 2.7 mmol) were added to 5 mL of DMF, followed by 1,4-dibromobutane (2 g, 9.3 mmol), and the mixture was reacted at room temperature for 22 h.

[0488] (ii) Add 13 mL of a tetrahydrofuran solution of 2N dimethylamine to the above reaction solution and continue the reaction at room temperature for 1 day. Quench the reaction solution with water and extract with ethyl acetate (with a small amount of methanol as a dissolving agent). Wash the organic layer with water and saturated sodium chloride solution, dry with anhydrous sodium sulfate, and remove the solvent by rotary evaporation under reduced pressure to give the main compound as a light purple liquid (528 mg, yield 55%). Proceed directly to the next step without structural characterization.

[0489] (iii) Dissolve a portion of the above crude product (126 mg) in 3 mL of tetrahydrofuran, then add 3 mL of tetrahydrofuran solution containing 1 N TBAF, and react at 70 °C for 14 h. Cool the reaction solution to room temperature, remove the solvent by rotary evaporation under reduced pressure, add a small amount of water, and extract with dichloromethane. Wash the organic layer with saturated sodium chloride solution and dry with anhydrous sodium sulfate. Concentrate the organic layer under reduced pressure and purify by silica gel column chromatography (first pre-elut the silica gel column with petroleum ether containing 0.1% triethylamine, then elute with DCM:MeOH = 40:1) to give a white solid (73 mg, yield: 74%; three-step yield: 41%). 1H NMR(500MHz,DMSO-d6)δ11.40(s,1H),7.44(s,1H),7.25(s,1H),6.48(s,1H),6.45(s,1H),6.37(s,1H),4.97(s,2H),3.91(t ,J=6.3Hz,2H),3.86(t,J=6.5Hz,2H),2.48(s,5H),2.29(s,6H),1.71–1.63(m,4H),1.60–1.52(m,2H),0.93(t,J=7.4Hz,3H).

[0490] 2-8d: 3-Methyl-5-(3-(piperidin-4-methoxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0491]

[0492] (i) Intermediate 2-7 (1 g, 2.1 mmol) and cesium carbonate (1.4 g, 4.3 mmol) were added to 10 mL of DMF, followed by N-Boc-4-piperidinyl p-toluenesulfonate (1.2 g, 3.2 mmol). The reaction mixture was reacted at 80 °C for 22 h. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to give a crude brown liquid containing the main compound (2.03 g, 100% yield). No characterization was performed, and the reaction proceeded directly to the next step.

[0493] (ii) Add 20 mL of tetrahydrofuran and 20 mL of 1 N TBAF tetrahydrofuran solution to the above crude product (2.03 g), and react at 70 °C for 24 h. Cool the reaction solution to room temperature, remove the solvent by rotary evaporation under reduced pressure, add a small amount of water, and extract with ethyl acetate. Wash the organic layer with saturated sodium chloride solution and dry with anhydrous sodium sulfate. Concentrate the organic layer under reduced pressure, and rapidly separate the major product (DCM:MeOH = 50:1–20:1) by silica gel column chromatography to give a white solid (788 mg, yield: 69%). Proceed directly to the next step without characterization.

[0494] (iii) Add 3 mL of dichloromethane and 2 mL of trifluoroacetic acid to the crude product (788 mg) and react at room temperature for 5 min. Quench the reaction solution with saturated sodium bicarbonate solution in an ice bath and extract with dichloromethane. Wash the organic layer with saturated sodium bicarbonate solution and saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then purify by silica gel column chromatography (DCM:MeOH = 20:1–10:1) to obtain a yellow powder (312 mg, yield: 50%). 1H NMR(500MHz,DMSO-d6)δ11.41(s,1H),8.66(s,1H),7.44(s,1H),7.26(s,1H),6.51 (s,1H),6.44(s,1H),6.39(s,1H),4.97(s,2H),3.87(t,J=6.5Hz,2H),3.80(d,J=6 .2Hz,2H),3.28–3.22(m,2H),2.90–2.80(m,2H),2.48(s,3H),2.03–1.94(m,1H),1 .89–1.81(m,2H),1.67(h,J=7.1Hz,2H),1.50–1.40(m,2H),0.93(t,J=7.4Hz,3H).

[0495] Example 2-8e: 3-Methyl-5-(3-(piperidin-3-methoxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0496]

[0497] Using intermediates 2-7 and N-Boc-piperidine-3-methoxytrifluorocarbamate as starting materials, the synthesis method was as described in Examples 2-8e, yielding a yellow powder in three steps with a yield of 30%. ¹H NMR (500 MHz, DMSO-d6) δ 7.44 (s, 1H), 7.25 (s, 1H), 6.47 (s, 1H), 6.46 (s, 1H), 6.37 (s, 1H), 4.96 (s, 2H), 3.85 (t, J = 6.5 Hz, 2H), 3.74 (d, J = 6.5 Hz, 2H), 3.03–2.95 (m, 1H), 2.86–2.79 ( m,1H),2.48(s,3H),2.45–2.41(m,1H),2.34–2.26(m,1H),1.84–1.72(m,2H),1.66(h,J=7 .1Hz,2H),1.59–1.51(m,1H),1.38–1.29(m,1H),1.19–1.09(m,1H),0.93(t,J=7.4Hz,3H).

[0498] Example 2-8f: 3-Methyl-5-(3-((1-methylpiperidin-4-yl)methoxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazol [4', 5': 4, 5]benzo[1,2-d]isoxazol-6-one

[0499]

[0500] Compound 2-8d (133 mg, 0.21 mmol) was added to 6 mL of methanol and 2 mL of dichloromethane, followed by sodium cyanoborohydride (40 mg, 0.63 mmol) and formaldehyde aqueous solution (37%, 0.5 mL). The reaction was carried out at room temperature for 15 h. The solvent was removed by rotary evaporation under reduced pressure. The crude product was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the major product (DCM:MeOH = 80:1–40:1) was rapidly separated by silica gel column chromatography to give a light brown powder (50 mg, yield: 51%). 1H NMR (500MHz, CDCl3-d) δ7.23(s,1H),6.89(s,1H),6.44(s,1H),6.41(s,1H),6.34(s,1H),5.04(s,2H),3.85(t,J=6.6Hz,2H),3.75(d,J=6.3Hz,2H ),3.02–2.95(m,2H),2.49(s,3H),2.34(s,3H),2.08–2.02(m,2H),1.86– 1.79(m,2H),1.78–1.70(m,3H),1.52–1.44(m,2H),0.98(t,J=7.4Hz,3H).

[0501] Example 2-8g: 3-methyl-5-(3-((1-methylpiperidin-3-yl)methoxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0502]

[0503] Using compounds 2-8e as raw materials, the synthesis method is as described in Examples 2-8f, yielding a white powder with a yield of 18%. 1H NMR(500MHz,DMSO-d6)δ11.40(s,1H),7.44(s,1H),7.25(s,1H),6.49(s,1H),6.46(s,1H),6.39(s,1H),4.97(s,2H),3.89–3.74(m,4H),3.10–2 .95(m,2H),2.48(s,3H),2.42–2.30(m,3H),2.08–1.95(m,2H),1.74–1. 63(m,4H),1.60–1.49(m,1H),1.20–1.09(m,2H),0.93(t,J=7.4Hz,3H).

[0504] Example 2-9a: 7-(cyclopropylsulfonyl)-5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0505]

[0506] Using compounds 2-8a and cyclopropylsulfonyl chloride as raw materials, the following synthesis method was used as in Examples 1-15a, yielding a light yellow powder with a yield of 77%. 1H NMR (500MHz, CDCl3-d) δ7.97(s,1H),6.95(s,1H),6.43(s,2H),6.39(s,1H),5. 01(s,2H),3.97(t,J=6.4Hz,2H),3.86(t,J=6.6Hz,2H),3.28(tt,J=8.3,4.8Hz, 1H),2.52(s,3H),2.47(d,J=7.4Hz,2H),2.28(s,6H),1.96(q,J=6.9Hz,2H),1.7 7(h,J=7.2Hz,2H),1.61–1.55(m,2H),1.23–1.18(m,2H),1.00(t,J=7.4Hz,3H).

[0507] Example 2-9b: 5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-7-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)-5,7-dihydro-6H-imidazol[4',5':4,5]benzo[1,2-d]isoxazo-6-one

[0508]

[0509] Using compounds 2-8a and 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 43%. 1H NMR (500MHz, CDCl3-d) δ8.21(s,1H),6.90(s,1H),6.36(s,1H),6.33(s,2H),4.92(s,2H),3.94(t,J=6.3Hz,2H),3.82(t,J=6.6Hz,2H),3.76(s, 3H),2.63(s,3H),2.54(t,J=7.3Hz,2H),2.51(s,3H),2.33(s,6H),2.32 (s,3H),2.00–1.96(m,2H),1.76(h,J=7.1Hz,2H),1.00(t,J=7.4Hz,3H).

[0510] Example 2-9c: 7-((3,4-dimethoxyphenyl)sulfonyl)-5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0511]

[0512] Using compounds 2-8a and 3,4-dimethoxybenzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 48%. 1H NMR (500MHz, CDCl3-d) δ8.18(s,1H),7.80(dd,J=8.6,2.2Hz,1H),7.65(d,J=2.3Hz,1H),6.95(d,J=8.7Hz,1H),6.89(s,1H),6.36(s,2H),6.34(s,1 H),4.90(s,2H),3.93(s,6H),3.81(t,J=6.5Hz,2H),2.50(s,5H),2.30(s ,6H), 1.95(p,J=6.6Hz,2H), 1.74(h,J=7.1Hz,2H), 0.99(t,J=7.4Hz,3H).

[0513] Example 2-9d: 5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-7-propyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0514]

[0515] Using compounds 2-8a and iodopropane as raw materials, the synthesis method is as described in Examples 1-15ar, yielding a white powder with a yield of 48%. 1H NMR (500MHz, DMSO-d6) δ7.63(s,1H),7.53(s,1H),6.51(s,1H),6.47(s,1H),6.40(s,1H),5.04(s,2H),3.99(t,J=6.1Hz,2H),3.92(t,J=7.0Hz,2 H),3.86(t,J=6.6Hz,2H),3.18–3.12(m,2H),2.74(s,6H),2.13–2.05(m, 2H),1.77–1.63(m,4H),0.93(t,J=7.4Hz,3H),0.88(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ160.0,159.6,159.0,154.8,154.3,139.1,132.9,126.9,115.3,105.9,1 05.8,99.8,98.8,89.4,69.0,64.8,54.0,43.8(2C),42.3,42.0,23.8,21.9,20.8,10.3,9.7,8.4.

[0516] Example 2-9e: 7-(cyclopropylsulfonyl)-3-methyl-5-(3-((1-methylpiperidin-3-yl)methoxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazol [4', 5': 4, 5]benzo[1,2-d]isoxazol-6-one

[0517]

[0518] Using 2-8 g of compound and cyclopropylsulfonyl chloride as starting materials, the synthesis method was as described in Examples 1-15a, yielding a white powder with a yield of 39%. ¹H NMR (400 MHz, CDCl₃-d) δ 7.97 (s, ¹H), 7.26 (s, ¹H), 6.98 (s, ¹H), 6.49 (s, ¹H), 6.37 (s, ¹H), 6.34 (s, ¹H), 5.01 (s, 2H), 3.92–3.85 (m, 3H), 3.80–3.74 (m, ¹H), 3.60–3.46 (m, 2H), 3.31–3.23 (m, 1H), 2. 90–2.80(m,1H),2.78(s,1H),2.70–2.60(m,2H),2.53(s,3H),2.45–2.30(m,1H),1.97–1.86(m,2H ),1.83–1.73(m,2H),1.61–1.55(m,2H),1.49–1.35(m,1H),1.25–1.17(m,2H),1.05–0.98(m,3H).

[0519] Example 2-9f: 7-(cyclopropanecarbonyl)-3-methyl-5-(3-((1-methylpiperidin-3-yl)methoxy)-5-propoxybenzyl)-5,7-dihydro-6H-imidazol [4', 5': 4, 5]benzo[1,2-d]isoxazol-6-one

[0520]

[0521] Using 2-8 g of compound and cyclopropaneyl chloride as starting materials, the following synthesis method was used as described in Examples 1-15a, yielding a white powder with a yield of 38%. ¹H NMR (500 MHz, CDCl₃-d) δ 7.97 (s, ¹H), 6.96 (s, ¹H), 6.44 (s, ¹H), 6.42 (s, ¹H), 6.37 (s, ¹H), 5.01 (s, 2H), 3.87 (t, J = 6.6 Hz, 2H), 3.82–3.79 (m, ¹H), 3.78–3.73 (m, ¹H), 3.32–3.25 (m, ¹H), 3.07–2.9 6(m,1H),2.92–2.83(m,1H),2.52(s,3H),2.37(s,3H),2.27–2.21(m,1H),2.14–2.06(m,1H),2. 02–1.94(m,1H),1.83–1.70(m,6H),1.61–1.55(m,2H),1.23–1.18(m,2H),1.01(t,J=7.4Hz,3H). .

[0522] Example 2-9g: 7-((3,4-dimethoxyphenyl)sulfonyl)-5-(3-(4-(dimethylamino)butoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6H-imidazolium[4',5':4,5]benzo[1,2-d]isoxazol-6-one

[0523]

[0524] (i) Intermediate 1-14d (153 mg, 0.39 mmol) was added to 3 mL of anhydrous DMF, followed by potassium carbonate (43 mg, 0.31 mmol). After reacting at room temperature for 10 min, intermediate 2-3 (124 mg, 0.43 mmol) was dissolved in 1 mL of anhydrous DMF and added dropwise to the reaction solution. The reaction was continued at room temperature for 2 h.

[0525] (ii) Add sodium hydroxide aqueous solution to the reaction solution until the pH of the reaction solution is 11-12, and stir at room temperature for 21.5 h until the reaction solution is clear. Adjust the pH of the reaction solution to 5-6 with dilute hydrochloric acid solution, and extract the product with ethyl acetate. Wash the organic layer with water and saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and recrystallize with petroleum ether to obtain a white crystalline powder (85 mg, yield: 37%). Do not perform structural characterization and proceed directly to the next step.

[0526] (iii) Add the above powder (85 mg, 0.15 mmol) to 3 mL of DMF, then add potassium carbonate (32 mg, 0.23 mmol) and 1,4-dibromobutane (2 g, 9.3 mmol), and react at room temperature for 24 h.

[0527] (iv) Add 0.5 mL of a tetrahydrofuran solution of 2N dimethylamine to the above reaction solution and react at 50 °C for 12 h. Quench the reaction solution with a small amount of water and extract with dichloromethane. Wash the organic layer with water and saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then purify by silica gel column chromatography (first pre-elut the silica gel column with petroleum ether containing 0.1% triethylamine, then elute with DCM:MeOH = 20:1 to 15:1) to obtain a white powder (73 mg, yield: 73%; four-step yield: 27%). 1H NMR(500MHz,DMSO-d6)δ8.12(s,1H),7.77(dd,J=8.6,2.3Hz,1H),7.69(s,1 H),7.55(d,J=2.3Hz,1H),7.18(d,J=8.7Hz,1H),6.39–6.34(m,3H),4.95(s, 2H),3.86–3.82(m,5H),3.80–3.76(m,5H),2.51(s,3H),2.25(t,J=7.1Hz,2H ), 2.13 (s, 6H), 1.69–1.59 (m, 4H), 1.51–1.44 (m, 2H), 0.91 (t, J = 7.4Hz, 3H).

[0528] Option 3 will be implemented as follows:

[0529] Intermediate 3-4: (3-propoxyphenyl)methylamine

[0530] Step 1: Synthesis of 3-propoxybenzaldehyde (3-2)

[0531]

[0532] 3-Hydroxybenzaldehyde (3-1, 5.5 g, 44.7 mmol) was added to 50 mL of DMF, followed by potassium hydroxide (7.5 g, 134.1 mmol), water (2 mL), and iodopropane (6.5 mL, 67.1 mmol). The reaction mixture was reacted at 80 °C for 3.5 h. The reaction solution was cooled to room temperature, water was added, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to give a colorless liquid (6.7 g, yield: 91%). 1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),7.55–7.48(m,i2H),7.41(s,1H),7.27(d,J =7.2Hz, 1H), 4.00 (t, J = 6.6Hz, 2H), 1.74 (h, J = 7.2Hz, 2H), 0.99 (t, J = 7.5Hz, 3H).

[0533] Step 2: Synthesis of 3-propoxybenzaldehyde oxime (3-3)

[0534]

[0535] Intermediate 3-2 (570 mg, 3.5 mmol) was added to an ethanol-water mixture (3:1), followed by hydroxylamine hydrochloride (386 mg, 5.6 mmol) and sodium acetate (456 mg, 5.6 mmol). The mixture was reacted at 80 °C for 30 min. The reaction solution was cooled to room temperature, and the solvent was removed by rotary evaporation under reduced pressure. The product was extracted with ethyl acetate after adding water. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to give a light brown liquid (630 mg, yield: 100%). 1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),8.09(s,1H),7.29(t,J=7.9Hz,1H),7.17–7.11(m,2H),6 .93(dd,J=8.2,2.5Hz,1H),3.93(t,J=6.5Hz,2H),1.73(h,J=7.1Hz,2H),0.98(t,J=7.4Hz,4H).

[0536] Step 3: Synthesis of (3-propoxyphenyl)methylamine (3-4)

[0537]

[0538] Intermediate 3-3 (630 mg, 3.5 mmol) was added to 20 mL of methanol, followed by palladium on carbon (375 mg, 3.5 mmol) and concentrated hydrochloric acid (2 mL). The reaction was carried out under hydrogen protection for 2.5 h. Diatomaceous earth was placed on filter paper and moistened with methanol. The reaction solution was filtered under reduced pressure, the filter cake was washed with methanol, and the filtrate was diluted with water and concentrated under reduced pressure to remove most of the methanol. The pH of the mixture was adjusted to 13 with dilute sodium hydroxide solution, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to give a light brown liquid (630 mg, yield: 64%). 1H NMR (400MHz, DMSO-d6) δ7.17(t,J=7.8Hz,1H),6.91(s,1H),6.85(d,J=7.5Hz,1H),6.73(dd,J=8 .3, 2.6Hz, 1H), 3.90 (t, J = 6.5Hz, 2H), 3.66 (s, 2H), 1.72 (h, J = 7.1Hz, 2H), 0.97 (t, J = 7.4Hz, 3H).

[0539] Intermediate 3-11: 6-amino-3-methyl-5-((3-propoxyphenyl)amino)benzo[d]oxazol-2(3H)-one

[0540]

[0541] Step 1: Synthesis of 5-fluoro-N,2-dihydroxybenzamide (3-6)

[0542]

[0543] Using methyl 5-fluoro-2-hydroxybenzoate (3-5) as a starting material, the synthesis method is as described in intermediate 1-19, yielding a white powder with a yield of 88%. ¹H NMR (400MHz, DMSO-d6) δ 11.42 (s, 2H), 9.41 (s, 1H), 7.50 (dd, J = 9.6, 3.2Hz, 1H), 7.25 (td, J = 8.7, 3.1Hz, 1H), 6.92 (dd, J = 9.1, 4.7Hz, 1H).

[0544] Step 2: Synthesis of 5-fluorobenzo[d]oxazol-2(3H)-one (3-7)

[0545]

[0546] Intermediate 3-6 (7.7 g, 45.2 mmol) was added to 600 mL of anhydrous tetrahydrofuran, followed by triphenylphosphine (14.8 g, 56.5 mmol) and DIAD (11.2 mL, 56.5 mmol). The reaction mixture was reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, water was added, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 10:1–5:1) to give a white powder (6.9 g, yield: 64%). MS (ESI) m / z [MH]-calcd. 152.02; found 152.0.

[0547] Step 3: Synthesis of 5-fluoro-3-methylbenzo[d]oxazol-2(3H)-one (3-8)

[0548]

[0549] Intermediate 3-7 (10.92 g, 71.3 mmol) was added to 150 mL of DMF, followed by cesium carbonate (29 g, 89.1 mmol), potassium iodide (1.2 g, 7.1 mmol), and iodomethane (5.5 mL, 89.1 mmol). The reaction was allowed to proceed at room temperature for 1.5 h. The reaction solution was concentrated, water was added to precipitate the solid, and the solid was filtered under reduced pressure until the filter cake reached constant weight, yielding a white crystalline powder (9.9 g, yield: 83%). ¹H NMR (400 MHz, DMSO-d6) δ 7.34 (dd, J = 8.7, 4.3 Hz, 1H), 7.28 (dd, J = 8.5, 2.7 Hz, 1H), 6.93 (ddd, J = 10.1, 8.8, 2.7 Hz, 1H), 3.31 (s, 3H).

[0550] Step 4: Synthesis of 5-fluoro-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one (3-9)

[0551]

[0552] Intermediate 3-8 (9.9 g, 59.4 mmol) was dissolved in 30 mL of concentrated sulfuric acid. Fuming nitric acid (3.7 mL, 89.0 mmol) was added dropwise through a glass dropping funnel under ice bath conditions, and the reaction was continued for 45 min. The reaction solution was quenched in ice water under ice bath conditions, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 5:1–3:1) to give a light yellow crystalline powder (6.45 g, yield: 51%). ¹H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 6.3 Hz, 1H), 7.65 (d, J = 11.2 Hz, 1H), 3.38 (s, 3H).

[0553] Step 5: Synthesis of 3-methyl-6-nitro-5-((3-propoxyphenyl)amino)benzo[d]oxazol-2(3H)-one (3-10)

[0554]

[0555] Intermediate 3-9 (800 mg, 4.8 mmol), intermediate 3-4 (1.16 g, 5.5 mmol), DIPEA (2.9 mL), and 10 mL LDM were added to a sealed tube and reacted at 100 °C for 13.5 h. The reaction solution was cooled to room temperature, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 5:1 to 1:1) to give a brownish-red solid powder (0.74 g, yield: 43%). 1H NMR (400MHz, DMSO-d6) δ9.00(t,J=6.0Hz,1H),7.96(s,1H),7.26(t,J=7.8Hz,1H),7.03–6.96(m,2H),6.83(dd,J=8.3,2.5H z,1H),6.75(s,1H),4.63(d,J=5.9Hz,2H),3.90(t,J=6.5Hz,2H),3.26(s,3H),1.71(h,J=7.1Hz,2H),0.96(t,J=7.4Hz,3H).

[0556] Step 6: Synthesis of 6-amino-3-methyl-5-((3-propoxyphenyl)amino)benzo[d]oxazol-2(3H)-one (3-11)

[0557]

[0558] Intermediate 3-10 (655 mg, 1.8 mmol) was dissolved in 20 mL of ethyl acetate, followed by the addition of stannous chloride dihydrate (2.1 g, 9.7 mmol), and the reaction was carried out at 80 °C for 2 h. After cooling the reaction solution to room temperature, water was added, and the pH was adjusted to 6–7 with dilute sodium hydroxide solution. The product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain a pale yellow-green powder (278 mg, yield: 46%). 1H NMR (400MHz, DMSO-d6) δ7.22(t,J=7.8Hz,1H),7.00–6.93(m,2H),6.82–6.76(m,1H),6.63(s,1H),6.36(s,1H),4.96(t,J=6.0 Hz, 1H), 4.55 (s, 2H), 4.28 (d, J = 5.9Hz, 2H), 3.90 (t, J = 6.5Hz, 2H), 3.17 (s, 3H), 1.71 (h, J = 7.1Hz, 2H), 0.96 (t, J = 7.4Hz, 3H).

[0559] Example 3-12: 3-Methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0560]

[0561] Compound 3-11 (236 mg, 0.72 mmol) was dissolved in 20 mL of freshly distilled tetrahydrofuran. Under ice bath and argon protection, triethylamine (4.9 mL, 35.2 mmol) was added via syringe. Triphosgene (3.5 g, 11.7 mmol) was dissolved in 6 mL of tetrahydrofuran and added to the reaction solution in small, repeated injections via syringe. The reaction was continued for 15 min under ice bath. The reaction solution was filtered under reduced pressure, and the filter cake was washed with ethyl acetate. The solvent was removed by rotary evaporation under reduced pressure. Dilute sodium bicarbonate solution was added to the crude product, and the product was extracted with ethyl acetate. The organic layer was washed successively with water and saturated sodium bicarbonate solution, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 2:1–1:3) to give a white powder (115 mg, yield: 45%). 1HNMR(500MHz,DMSO-d6)δ11.01(s,1H),7.22(t,J=7.9Hz,1H),7.15(s,1H),7.07(s,1H),6.89(s,1H),6.86(d,J=7.6Hz,1H) ,6.81(dd,J=8.3,2.6Hz,1H),4.97(s,2H),3.88(t,J=6.5Hz,2H),3.29(s,3H),1.69(h,J=7.1Hz,2H),0.94(t,J=7.4Hz,3H).

[0562] Example 3-13a: 3-Methyl-7-(ethylsulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0563]

[0564] Using compounds 3-12 and benzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 69%. 1H NMR (500MHz, DMSO-d6) δ8.05(d,J=7.5Hz,2H),7.83(s,1H),7.80(t,J=7.5Hz,1H),7.65(t,J=7.9Hz,2H),7.34(s,1H),7.13(t,J=7.9Hz,1H),6.79(d d,J=8.2,1.8Hz,1H),6.75(s,1H),6.63(d,J=7.6Hz,1H),4.94(s,2H),3.8 0(t,J=6.5Hz,2H),3.30(s,3H),1.72–1.64(m,2H),0.94(t,J=7.4Hz,3H).

[0565] Example 3-13b: 7-((3,4-dimethoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0566]

[0567] Using compounds 3-12 and 3,4-dimethoxybenzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 65%. 1H NMR(400MHz, DMSO-d6)δ7.83(s,1H),7.67(dd,J=8.6,2.2Hz,1H),7.48(d,J=2.2Hz,1H),7.34(s,1H),7.18–7.10(m,2H),6.83–6.77(m, 2H), 6.65 (d, J = 7.6Hz, 1H), 4.95 (s, 2H), 3.82 (d, J = 9.1Hz, 5H), 3.75 (s, 3H), 3.30 (s, 3H), 1.67 (h, J = 7.1Hz, 2H), 0.93 (t, J = 7.4Hz, 3H).

[0568] Example 3-13c: 7-((3-bromo-4-methoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0569]

[0570] Using compounds 3-12 and 3-bromo-4-methoxybenzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 81%. 1H NMR (500MHz, DMSO-d6) δ8.21(d,J=2.3Hz,1H),8.07(dd,J=8.9,2.3Hz,1H),7.84(s,1H),7.36(s,1H),7.33(d,J=9.0Hz,1H),7.14(t,J=8.1Hz,1H) ,6.83–6.78(m,2H),6.66(d,J=7.5Hz,1H),4.95(s,2H),3.95(s,3H),3.8 2(t,J=6.5Hz,2H),3.31(s,3H),1.71–1.63(m,2H),0.93(t,J=7.4Hz,3H).

[0571] Example 3-13d: 7-((4-methoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0572]

[0573] Using compounds 3-12 and 4-methoxybenzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 88%. 1 HNMR(500MHz,DMSO-d6)δ7.98(d,J=8.8Hz,2H),7.98(s,1H),7.81(s,1H),7.33(s,1H),7.17–7.10(m,3H),6.82–6.76(m,2H), 6.64(d,J=7.5Hz,1H),4.94(s,2H),3.84(s,3H),3.81(t,J=6.5Hz,2H),3.30(s,3H),1.71–1.64(m,2H),0.93(t,J=7.4Hz,3H).

[0574] Example 3-13e: 3-Methyl-5-(3-propoxyphenyl)-7-((4-trifluoromethoxy)phenyl)sulfonyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0575]

[0576] Using compounds 3-12 and 4-(trifluoromethoxy)benzenesulfonyl chloride as raw materials, the following synthesis method was used as described in Examples 1-15a, yielding a white powder with a yield of 92%. 1H NMR (500MHz, DMSO-d6) δ8.21(d,J=8.9Hz,2H),7.83(s,1H),7.65(d,J=8.5Hz,2H),7.37(s,1H),7.12(t,J=7.8Hz,1H),6.83–6 .76(m,2H),6.64(d,J=7.5Hz,1H),4.95(s,2H),3.82(t,J=6.5Hz,2H),3.31(s,3H),1.72–1.64(m,2H),0.93(t,J=7.4Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ158.8,154.0,152.7,150.1,137.5,137.0,135.2,130.4(2C),129.7,129. 4,126.1,121.6(2C),120.7,119.1,118.8,113.6,113.4,96.6,91.9,68.8,44.0,28.4,21.9,10.3.

[0577] Example 3-13f: 7-((3-methoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0578]

[0579] Using compounds 3-12 and 3-methoxybenzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 93%. 1 HNMR(500MHz,DMSO-d6)δ7.84(s,1H),7.63–7.59(m,1H),7.56(t,J=8.0Hz,1H),7.53–7.50(m,1H),7.39–7.33(m,2H),7.14(t,J=7.8Hz,1H),6. 83–6.77(m,2H),6.65(d,J=7.6Hz,1H),4.96(s,2H),3.82(t,J=6.5Hz,2 H),3.79(s,3H),3.30(s,3H),1.72–1.64(m,2H),0.94(t,J=7.4Hz,3H). 13C NMR(101MHz,DMSO-d6)δ159.5,158.8,154.0,150.1,137.9,137.5,137.1,131.1,129.8(2C),129.3 ,126.0,121.0,119.2,118.8,113.5,113.5,112.1,96.6,91.8,68.8,55.8,44.0,28.3,21.9,10.3.

[0580] Example 3-13g: 7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0581]

[0582] Using compounds 3-12 and 2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl chloride as raw materials, the following synthesis method was used as described in Examples 1-15a, yielding a white powder with a yield of 87%. 1 H NMR(500MHz, DMSO-d6)δ7.81(s,1H),7.56–7.48(m,2H),7.35(s,1H),7.15(t,J=7.8Hz,1H),7.09(d,J=8.6Hz,1H),6.84–6.79(m,2H),6.66(d, J=7.6Hz,1H),4.95(s,2H),4.36–4.31(m,2H),4.30–4.25(m,2H),3.84( t,J=6.5Hz,2H),3.30(s,3H),1.73–1.64(m,2H),0.94(t,J=7.4Hz,3H).

[0583] Example 3-13h: 7-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0584]

[0585] Using compounds 3-12 and 2,3-dihydrobenzofuran-5-sulfonyl chloride as raw materials, the following synthesis method was used as in Examples 1-15a, yielding a white powder with a yield of 73%. 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.84(dd,J=8.6,2.1Hz,1H),7.81(s,1H) ,7.35(s,1H),7.18–7.12(m,1H),6.96(d,J=8.6Hz,1H),6.83–6.78(m,2H),6. 68(d,J=7.7Hz,1H),4.95(s,2H),4.65(t,J=8.9Hz,2H),3.83(t,J=6.5Hz,2H) ,3.30(s,3H),3.21(t,J=8.8Hz,2H),1.72–1.62(m,2H),0.94(t,J=7.4Hz,3H).

[0586] Example 3-13i: 3-Methyl-7-((4-(methanesulfonyl)phenyl)sulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0587]

[0588] Using compounds 3-12 and 4-(methanesulfonyl)benzenesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 68%. 1 H NMR (500MHz, DMSO-d6) δ8.34(d,J=8.2Hz,2H),8.20(d,J=8.2Hz,2H),7.85(s,1H),7.40(s,1H),7.14(t,J=7.9Hz,1H),6.87(s,1H),6.80(d d,J=8.2,2.6Hz,1H),6.62(d,J=7.6Hz,1H),4.94(s,2H),3.85(t,J=6.5Hz,2H),3.31(s,3H),1.68(h,J=7.1Hz,2H),0.94(t,J=7.4Hz,3H).

[0589] Example 3-13j: 7-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazol[4',5':4,5]benzo[1,2-d]oxazol-2,6(3H)-dione

[0590]

[0591] Using compounds 3-12 and 1,2-dimethyl-1H-imidazol-4-sulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 62%.1 H NMR (500MHz, DMSO-d6) δ8.20(s,1H),7.67(s,1H),7.33(s,1H),7.20(t,J=7.7Hz,1H),6.88–6.80(m,2H),6.76(d,J=7.4Hz ,1H),4.97(s,2H),3.88(t,J=6.2Hz,2H),3.61(s,3H),3.31(s,3H),2.23(s,3H),1.73–1.65(m,2H),0.95(t,J=7.1Hz,3H).

[0592] Example 3-13k: 3-Methyl-7-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazol [4', 5': 4, 5]benzo[1,2-d]oxazol-2,6(3H)-dione

[0593]

[0594] Using compounds 3-12 and 1-methyl-1H-pyrazole-3-sulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 73%. 1 H NMR (500MHz, DMSO-d6) δ7.97(d,J=2.4Hz,1H),7.67(s,1H),7.37(s,1H),7.22(t,J=7.8Hz,1H),6.99(d,J=2.4Hz,1H),6.87 –6.81(m,2H),6.77(d,J=7.6Hz,1H),4.98(s,2H),3.90–3.84(m,5H),3.31(s,3H),1.73–1.65(m,2H),0.95(t,J=7.4Hz,3H).

[0595] Example 3-13l: 3-Methyl-7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazol[4',5':4,5]benzo[1,2-d]oxazol-2,6(3H)-dione

[0596]

[0597] Using compounds 3-12 and 1-methyl-1H-pyrazole-4-sulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 87%. 1H NMR (500MHz, DMSO-d6) δ8.68(s,1H),8.03(s,1H),7.73(s,1H),7.37(s,1H),7.19(t,J=7.8Hz,1H),6.86–6.80(m,2H),6.74( d,J=7.6Hz,1H),4.97(s,2H),3.87(s,3H),3.85(t,J=6.4Hz,2H),3.31(s,3H),1.69(h,J=7.1Hz,2H),0.95(t,J=7.3Hz,3H).

[0598] Example 3-13m: 7-((2-amino-4-methylthiazolyl-5-yl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0599]

[0600] Using compounds 3-12 and 2-acetamido-4-methylthiazole-5-sulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 30%. 1 H NMR (500MHz, DMSO-d6) δ8.00(s,1H),7.33(s,1H),7.23(t,J=7.9Hz,1H),6.96(d,J=1.8Hz,1H),6.91(d,J=7.7Hz,1H),6.84(d d,J=8.2,2.2Hz,1H),5.04(s,2H),3.89(t,J=6.5Hz,2H),3.32(s,3H),2.66(s,3H),1.73–1.66(m,2H),0.95(t,J=7.4Hz,3H).

[0601] Example 3-13n: 3-Methyl-7-(morpholinosulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0602]

[0603] Using compounds 3-12 and morpholine sulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 98%. 1H NMR (500MHz, DMSO-d6) δ7.58(s,1H),7.41(s,1H),7.26(t,J=7.9Hz,1H),6.95(s,1H),6.91(d,J=7.7Hz,1H),6.85(d,J=8.0Hz,1H),5.05(s,2H),3. 89(t,J=6.4Hz,2H),3.65–3.58(m,5H),3.40–3.35(m,4H),3.35–3.30(m, 1H), 3.16–3.12 (m, 1H), 1.70 (h, J=7.0, 6.5Hz, 2H), 0.95 (t, J=7.4Hz, 3H).

[0604] Example 3-13o: 7-(dimethylaminosulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0605]

[0606] Using compounds 3-12 and dimethylaminosulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 73%. 1 H NMR(500MHz,DMSO-d6)δ7.57(s,1H),7.39(s,1H),7.25(t,J=7.8Hz,1H),6.95(s,1H),6.91–6.82(m,2H) ,5.05(s,2H),3.89(t,J=6.4Hz,2H),3.32(s,3H),2.98(s,6H),1.74–1.66(m,2H),0.95(t,J=7.3Hz,3H).

[0607] Example 3-13p: 3-Methyl-5-(3-propoxyphenyl)-7-((trifluoromethyl)sulfonyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0608]

[0609] Using compounds 3-12 and trifluoromethanesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 36%. 1H NMR (500MHz, DMSO-d6) δ7.58(s,1H),7.51(s,1H),7.26(t,J=7.9Hz,1H),6.97(s,1H),6.92(d,J=7.6Hz,1H),6. 87(d,J=8.1Hz,1H),5.09(s,2H),3.89(t,J=6.5Hz,2H),3.31(s,3H),1.74–1.66(m,2H),0.95(t,J=7.4Hz,3H).

[0610] Example 3-13q: 3-Methyl-7-(methanesulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0611]

[0612] Using compounds 3-12 and methanesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 89%. 1 H NMR (500MHz, DMSO-d6) δ7.60(s,1H),7.41(s,1H),7.25(t,J=7.9Hz,1H),6.97(s,1H),6.90(d,J=7.6Hz,1H),6.85(dd,J= 8.2,1.9Hz,1H),5.05(s,2H),3.90(t,J=6.5Hz,2H),3.67(s,3H),3.33(s,3H),1.74–1.66(m,2H),0.95(t,J=7.4Hz,3H).

[0613] Example 3-13r: 7-(ethanesulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0614]

[0615] Using compounds 3-12 and ethanesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 79%. 1H NMR (500MHz, DMSO-d6) δ7.60(s,1H),7.42(s,1H),7.25(t,J=7.9Hz,1H),6.95(s,1H),6.89(d,J=7.6Hz,1H),6.85(dd,J=8.1,1.9Hz,1H) ,5.06(s,2H),3.89(t,J=6.5Hz,2H),3.82(q,J=7.2Hz,2H),3.32(s,3H),1.74–1.65(m,2H),1.23(t,J=7.3Hz,3H),0.95(t,J=7.4Hz,3H).

[0616] Example 3-13s: 3-Methyl-5-(3-propoxyphenyl)-7-(propanesulfonyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0617]

[0618] Using compounds 3-12 and propanesulfonyl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 57%. 1 H NMR (500MHz, DMSO-d6) δ7.60(s,1H),7.43(s,1H),7.25(t,J=7.9Hz,1H),6.93(d,J=1.8Hz,1H),6.90(d,J=7.7Hz,1H),6.85(dd ,J=8.2,2.1Hz,1H),5.06(s,2H),3.89(t,J=6.5Hz,2H),3.83–3.77(m,2H),3.32(s,3H),1.74–1.63(m,4H),0.98–0.89(m,6H).

[0619] Example 3-13t: 7-(butyrylyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0620]

[0621] Using compounds 3-12 and butyryl chloride as raw materials, the synthesis method is as described in Examples 1-15a, yielding a white powder with a yield of 85%. 1H NMR(500MHz,DMSO-d6)δ7.60(s,1H),7.43(s,1H),7.25(t,J=7.9Hz,1H),6.93( s,1H),6.90(d,J=7.6Hz,1H),6.85(dd,J=8.2,2.5Hz,1H),5.06(s,2H),3.89(t, J=6.5Hz,2H),3.86–3.79(m,2H),3.33(s,3H),1.69(h,J=7.1Hz,2H),1.61(p,J= 7.5Hz, 2H), 1.34 (h, J = 7.4Hz, 2H), 0.95 (t, J = 7.4Hz, 3H), 0.80 (t, J = 7.3Hz, 3H).

[0622] Example 3-13u: 7-((2-(1,3-dioxoisoindoline-2-yl)ethyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0623]

[0624] Using compounds 3-12 and 2-(1,3-dioxoisoindoline-2-yl)ethane-1-sulfonyl chloride as raw materials, the following synthesis method was used as described in Examples 1-15a, yielding a white powder with a yield of 87%. 1 H NMR (500MHz, DMSO-d6) δ7.67–7.62(m,2H),7.51–7.45(m,2H),7.29–7.23(m,2H),7.01–6.96(m,2H),6.91(d,J=7.6Hz,1H),6.87(dd,J=8.0Hz,1. 6Hz,1H),4.88(s,2H),4.41(t,J=5.9Hz,2H),4.04(t,J=6.0Hz,2H),3.92 (t,J=6.5Hz,2H),3.21(s,3H),1.74–1.66(m,2H),0.95(t,J=7.4Hz,3H).

[0625] Example 3-13v: 2-((3-methyl-2,6-dioxo-5-(3-propoxybenzyl)-2,3,5,6-tetrahydro-7H-imidazolium[4',5':4,5]benzo[1,2-d]oxazol-7-yl)sulfonyl)methyl acetate

[0626]

[0627] Using compounds 3-12 and methyl 2-(chlorosulfonyl)acetate as raw materials, the following synthesis method was used as described in Examples 1-15a, yielding a white powder with a yield of 36%. 1 H NMR (500MHz, DMSO-d6) δ7.55(s,1H),7.40(s,1H),7.25(t,J=7.9Hz,1H),6.94(s,1H),6.91(d,J=7.6Hz,1H),6.85(dd,J=8 .2, 2.5Hz, 1H), 5.07 (s, 4H), 3.89 (t, J = 6.5Hz, 2H), 3.46 (s, 3H), 3.32 (s, 3H), 1.69 (h, J = 7.1Hz, 2H), 0.94 (t, J = 7.4Hz, 3H).

[0628] Example 3-13w: 3,7-Dimethyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0629]

[0630] Compound 3-12 (47.6 mg, 0.13 mmol), methyl iodide (180 mg, 1.3 mmol), and potassium carbonate (102 mg, 0.74 mmol) were added to 6 mL of acetone and reacted at 60 °C for 2.5 days. The solvent was removed by rotary evaporation under reduced pressure, water was added, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:DCM:EA = 2:5:1) to give a white powder (14 mg, yield: 28%). 1H NMR (400MHz, DMSO-d6) δ7.37(s,1H),7.26–7.18(m,2H),6.91(s,1H),6.86(d,J=7.5Hz,1H),6.82(dd,J=8.3,2.5H z,1H),5.02(s,2H),3.88(t,J=6.6Hz,2H),3.37(s,3H),3.31(s,3H),1.69(h,J=7.1Hz,2H),0.95(t,J=7.5Hz,3H).

[0631] Example 3-13x: methyl 2-(3-methyl-2,6-dioxo-5-(3-propoxybenzyl)-2,3,5,6-tetrahydro-7H-imidazolium[4',5':4,5]benzo[1,2-d]oxazol-7-yl)acetate

[0632]

[0633] Using compounds 3-12 and methyl chloroacetate as starting materials, the synthesis method is as described in Examples 1-15aq, yielding a white powder with a yield of 73%. ¹H NMR (400MHz, DMSO-d6) δ 7.45 (s, 1H), 7.27–7.19 (m, 2H), 6.90–6.84 (m, 2H), 6.82 (dd, J = 8.1, 2.4Hz, 1H), 5.05 (s, 2H), 4.80 (s, 2H), 3.87 (t, J = 6.5Hz, 2H), 3.69 (s, 3H), 3.31 (s, 3H), 1.69 (h, J = 7.1Hz, 2H), 0.94 (t, J = 7.4Hz, 3H).

[0634] Example 3-13y: 3-Methyl-5-(3-propoxyphenyl)-7-propyl-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0635]

[0636] Using compound 3-12 and iodopropane as starting materials, method 1-15aq was synthesized to give a white powder in 84% yield. ¹H NMR (500MHz, DMSO-d6) δ 7.46 (s, 1H), 7.24–7.19 (m, 2H), 6.88 (s, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.81 (dd, J = 8.2, 2.5 Hz, 1H), 5.03 (s, 2H), 3.89–3.82 (m, 4H), 3.30 (s, 3H), 1.72–1.63 (m, 4H), 0.93 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H).

[0637] Example 3-13z: 7-(3,4-dimethoxybenzyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2H-imidazolium[4',5':4,5]benzo[1,2-d]oxazolium-2,6(3H)-dione

[0638]

[0639] Using compounds 3-12 and 3,4-dimethoxybenzyl bromide as raw materials, the synthesis method is as described in Examples 1-15aq, yielding a white powder with a yield of 27%. 1H NMR (400MHz, DMSO-d6) δ7.37(d,J=1.9Hz,1H),7.26–7.19(m,2H),7.01(s,1H),6.91–6.85(m,4H),6.82(d,J=8.3Hz,1H),5.07( s,2H),5.01(s,2H),3.86(t,J=6.4Hz,2H),3.69(s,3H),3.68(s,3H),3.29(s,3H),1.68(h,J=7.0Hz,2H),0.94(t,J=7.3Hz,3H).

[0640] Bioactivity test

[0641] The compounds in the embodiments listed in this invention were tested for their protein and cellular activity.

[0642] The activity assay for the protein level was performed using the amplified luminescence proximity homogeneous assay screen (Alphascreen) technique.

[0643] Experimental objective: To evaluate the binding force between the compound and the bromine domain.

[0644] Experimental system: 10× experimental buffer (MOPS, CHAPS, NaF, BSA), double-distilled water, peptide solution, test protein solution, compound dilution solution, and detection kit.

[0645] Experimental Methods: All components were mixed to prepare a 150 μL reaction system and incubated at room temperature in the dark for 1.5 hours. After homogenization by pipetting under dark conditions, the reaction solution was transferred to an uncovered 384-well white opaque plate (40 μL / well, 3 replicates). The plate was centrifuged at 1000 rpm for one minute at room temperature, and the signal value of each well was measured. The Enspire homogeneous luminescent immunoassay system used emitted detectable light at 520-620 nm after excitation at 680 nm. By detecting the emitted light signal value, the curve relationship between the light signal value and the compound concentration was fitted using Graphpad Prism 7 software to determine the half-maximal inhibitory concentration (IC50). 50 The IC value can be used to calculate the single-point inhibition rate using Excel software. 50 The value represents the strength of the bond; the smaller the value, the stronger the bond.

[0646] The test results of the compounds described in the embodiments on the Alphascreen experiment are shown in Tables 1 and 2 below.

[0647] Table 1. Results of protein-level activity assays for the compounds.

[0648]

[0649]

[0650] Table 2. Results of selectivity tests of compounds on bromine-domain proteins.

[0651]

[0652]

[0653] As can be seen from the data in Table 1 above, IC 50 The value represents the strength of the binding force between the compound and the protein. The smaller the value, the stronger the binding force. The compounds tested in Table 1 all showed a clear inhibitory trend on the inhibition curves, and most of the compounds had binding activities at the micromolar level or above, indicating good inhibitory activity.

[0654] As shown in Table 2 above, the representative compounds described in this application generally exhibit a significant bias in their inhibitory effects on TRIM24 or BRPF1 bromodomain proteins, with single-point inhibitory activity exceeding 90% for these proteins. The single-point inhibitory activity against most other bromodomain-containing proteins is generally below 50%, indicating a good selective inhibitory effect on the TRIM24 or BRPF1 bromodomain.

[0655] The cellular activity assay employed a cell viability test using the Celltiter-Glo reagent kit. The Celltiter-Glo kit, developed by Promega, is a chemiluminescent assay kit for the rapid detection of viable cell numbers. The cell viability assay described in this invention tested the ability of the compounds to inhibit cell proliferation in 29 human tumor cell lines.

[0656] Experimental objective: To test the ability of the compound to inhibit tumor cell proliferation.

[0657] Experimental Methods: Cells were collected and diluted with culture medium. 500–1000 cells per well were seeded into 384-well opaque white plates with a cover. Compound dilution buffer was added, and cells were cultured in a cell culture incubator for 3–6 days. The culture plates were then removed from the incubator and allowed to stand at room temperature. After equilibration to room temperature, Celltiter-Glo reagent was added and thoroughly mixed on a benchtop shaker. After standing at room temperature for 10 minutes, the plates were centrifuged at 1000 rpm for 1 minute at room temperature. Fluorescence signal values ​​were detected using an Enspire homogeneous chemiluminescence immunoassay system. Graphpad Prism 7 software was used to fit the curve relationship between fluorescence signal values ​​and compound concentration to determine the half-maximal effective concentration (EC50). 50 EC value. 50 The value represents the strength of the ability to inhibit cell proliferation; the smaller the value, the stronger the inhibitory ability.

[0658] The test results of the compounds described in the embodiments in the cell survival experiment are shown in Table 3 below.

[0659] Table 3 shows the results of the inhibitory activities of the compounds on the proliferation of various tumor cell lines.

[0660]

[0661]

[0662] As can be seen from the data in Table 3, the representative compounds in this invention have micromolar levels of inhibitory activity against cell proliferation in 29 tumor cell lines, indicating their potential for broad-spectrum inhibition of tumor development.

[0663] The applicant declares that this invention illustrates the benzimidazole three-membered cyclic compounds, their pharmaceutically acceptable salts, preparation methods, and applications through the above embodiments. However, this invention is not limited to the above embodiments, meaning that this invention does not necessarily rely on the above embodiments for implementation. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of raw materials for the products of this invention, additions of auxiliary components, and selection of specific methods all fall within the protection and disclosure scope of this invention.

Claims

1. A benzimidazole-based three-membered cyclic compound, characterized in that, The benzimidazole-type three-membered cyclic compound has the structure shown in Formula I: ； Where X and W are selected from O; Y is selected from -CH-; L is selected from -CH2- or -CO-; M is selected from N or -CO-; The bond between the carbon atoms connected to M and R1 is represented by S / D, where S is a single bond and D is a double bond, indicating whether the bond is a single or double bond. When M is selected from N, the bond between the carbon atoms connected to M and R1 is a double bond; when M is selected from -CO-, the bond between the carbon atoms connected to M and R1 is a single bond. R1 is selected from C1~C3 alkoxy and C1~C4 alkyl; R2 is selected from H, -C(R) a (R) b )R c , where R a Selected from hydrogen, R b R is selected from H, C1-C6 straight-chain alkyl groups, or at least one CH2 group of C1-C6 straight-chain alkyl groups in which O is replaced in a non-adjacent manner. c R2 is selected from hydrogen; or R2 is selected from any of the following groups: ； ， The wavy line represents the connection site of the functional group; R3 is n-propyloxy group; R4 represents hydrogen, C1-C6 alkyl, , , , , , , The wavy line represents the connection site of the functional group.

2. The benzimidazole ternary cyclic compound according to claim 1, characterized in that, R1 is methyl, ethyl, or methoxy.

3. The benzimidazole ternary cyclic compound according to claim 1, characterized in that, R2 is any one of the following groups: hydrogen, methyl, , , , , , ； , The wavy line represents the connection site of the functional group.

4. The benzimidazole ternary cyclic compound according to claim 1, characterized in that, The benzimidazole ternary cyclic compound has the structure shown in Formula Ia: ； R1, R2, L, and R4 have the same defined range as in Equation I.

5. The benzimidazole ternary cyclic compound according to claim 1, characterized in that, The benzimidazole ternary cyclic compound has the structure shown in Formula Ib: ； R2 has the same defined range as in Equation I.

6. A benzimidazole-based three-membered cyclic compound, characterized in that, The benzimidazole three-membered cyclic compound is any one of the following compounds: 3-Methyl-7-(benzenesulfonyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((3,4-dimethoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3,7-Dimethyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-5-(3-propoxybenzyl)-7-p-methylbenzenesulfonyl-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-Ethylsulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-Butylsulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((3-bromo-4-methoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((5-bromo-2-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((5-chloro-2-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((2-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((3-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((4-methoxyphenyl)sulfonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((2,3-dihydrobenzo[ b [1,4]dioxin-6-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-7-((2-oxo-2-) H -chromen-6-yl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((4-cyanophenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((4-methoxycarbonylphenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((4-ethoxycarbonylphenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-7-((4-methanesulfonylphenyl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((4-bromophenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((6-chloropyridin-3-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((6-methoxypyridin-3-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((3,5-dichlorophenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((2,6-dichlorophenyl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-5-(3-propoxybenzyl)-7-((1,3,5-trimethyl-1 H -pyrazol-4-yl)sulfonyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((3,5-dimethyl-isoxazo-4-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((1,2-dimethyl-1) H -imidazol-4-yl)sulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-7-((1-methyl-1) H -pyrazol-3-yl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-7-((1-methyl-1) H -pyrazol-4-yl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-7-(morpholinosulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-7-(piperidine-1-sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-(cyclopropylsulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-(dimethylaminosulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-5-(3-propoxybenzyl)-7-propylsulfonyl-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-(3,4-Dimethoxybenzoyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-(3,5-Dimethylisoxazol-4-carbonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-Cyclopropanecarbonyl-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-(3,4-Dimethoxybenzyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-5-(3-propoxybenzyl)-7-propyl-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-7-(1-methylcyclopropyl)sulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-(tert-butylsulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-(isopropylsulfonyl)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-7-(phenylsulfonyl)-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((3,4-dimethoxyphenyl)sulfonamide)-3-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3,7-Dimethyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methoxy-7-methyl-5-(3-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methoxy-7-methyl-5-(3-propoxybenzoyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-5-(3-((1-methylpiperidin-4-yl)oxy)-5-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 5-(3-(4-(dimethylamino)butoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-5-(3-(piperidin-4-methoxy)-5-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-5-(3-(piperidin-3-methoxy)-5-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-5-(3-((1-methylpiperidin-4-yl)methoxy)-5-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 3-Methyl-5-(3-((1-methylpiperidin-3-yl)methoxy)-5-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-(cyclopropylsulfonyl)-5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-7-((1,3,5-trimethyl-1 H -pyrazol-4-yl)sulfonyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((3,4-dimethoxyphenyl)sulfonyl)-5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 5-(3-(3-(dimethylamino)propoxy)-5-propoxybenzyl)-3-methyl-7-propyl-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-(cyclopropylsulfonyl)-3-methyl-5-(3-((1-methylpiperidin-3-yl)methoxy)-5-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-(cyclopropanecarbonyl)-3-methyl-5-(3-((1-methylpiperidin-3-yl)methoxy)-5-propoxybenzyl)-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one 7-((3,4-dimethoxyphenyl)sulfonyl)-5-(3-(4-(dimethylamino)butoxy)-5-propoxybenzyl)-3-methyl-5,7-dihydro-6 H -imidazolium[4',5':4,5]benzo[1,2- d Isoxazol-6-one.

7. A benzimidazole-based three-membered cyclic compound, characterized in that, The benzimidazole three-membered cyclic compound is any one of the following compounds: 3-Methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 3-Methyl-7-(ethylsulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 7-((3,4-dimethoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 7-((3-bromo-4-methoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 7-((4-methoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 3-Methyl-5-(3-propoxyphenyl)-7-((4-trifluoromethoxy)phenyl)sulfonyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 7-((3-methoxyphenyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 7-((2,3-dihydrobenzo[ b [1,4]dioxin-6-yl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 7-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 3-Methyl-7-((4-(methanesulfonyl)phenyl)sulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 7-((1,2-dimethyl-1) H -imidazol-4-yl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 3-Methyl-7-((1-methyl-1) H -pyrazol-3-yl)sulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 3-Methyl-7-((1-methyl-1) H -pyrazol-4-yl)sulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 7-((2-amino-4-methylthiazolyl-5-yl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 3-Methyl-7-(morpholinosulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 7-(dimethylaminosulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 3-Methyl-5-(3-propoxyphenyl)-7-((trifluoromethyl)sulfonyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 3-Methyl-7-(methanesulfonyl)-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 7-(ethanesulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 3-Methyl-5-(3-propoxyphenyl)-7-(propanesulfonyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 7-(butyrylyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 7-((2-(1,3-dioxoisoindoline-2-yl)ethyl)sulfonyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 2-((3-methyl-2,6-dioxo-5-(3-propoxybenzyl)-2,3,5,6-tetrahydro-7) H -imidazolium[4',5':4,5]benzo[1,2- d Oxazol-7-yl)sulfonyl)methyl acetate 3,7-Dimethyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 2-(3-methyl-2,6-dioxo-5-(3-propoxybenzyl)-2,3,5,6-tetrahydro-7 H -imidazolium[4',5':4,5]benzo[1,2- d methyl oxazol-7-yl)acetate 3-Methyl-5-(3-propoxyphenyl)-7-propyl-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-Diketone 7-(3,4-Dimethoxybenzyl)-3-methyl-5-(3-propoxyphenyl)-5,7-dihydro-2 H -imidazolium[4',5':4,5]benzo[1,2- d Oxazole-2,6(3) H )-dione.

8. A pharmaceutically acceptable salt of a benzimidazole ternary cyclic compound according to any one of claims 1-7.

9. The use of any one of the benzimidazole ternary cyclic compounds according to claims 1-7 or the pharmaceutically acceptable salt according to claim 8 in the preparation of a bromine domain protein TRIM24 inhibitor.

10. The use of any benzimidazole ternary cyclic compound according to any one of claims 1-7 or the pharmaceutically acceptable salt according to claim 8 in the preparation of a medicament for treating tumors, infections or immune-related diseases by inhibiting the bromine domain of TRIM24.

11. The use of a benzimidazole ternary cyclic compound or a pharmaceutically acceptable salt thereof in the preparation of a bromine domain protein BRPF1 inhibitor, said benzimidazole ternary cyclic compound having the following structure: ； Where X and W are selected from O; Y is selected from -CH-; L is selected from -CH2-; M is selected from N or -CO-; The bond between the carbon atoms connected to M and R1 is represented by S / D, where S is a single bond and D is a double bond, indicating whether the bond is a single or double bond. When M is selected from N, the bond between the carbon atoms connected to M and R1 is a double bond; when M is selected from -CO-, the bond between the carbon atoms connected to M and R1 is a single bond. R1 is selected from C1~C4 alkyl groups; R2 is selected from H or The wavy line represents the bonding site of the functional group. R3 is n-propyloxy group; R4 is , , , , , , The wavy line represents the connection site of the functional group.

12. Use of a benzimidazole ternary cyclic compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors, infections, or immune-related diseases by inhibiting the BRPF1 bromine domain, said benzimidazole ternary cyclic compound having the following structure: ； Where X and W are selected from O; Y is selected from -CH-; L is selected from -CH2-; M is selected from N or -CO-; The bond between the carbon atoms connected to M and R1 is represented by S / D, where S is a single bond and D is a double bond, indicating whether the bond is a single or double bond. When M is selected from N, the bond between the carbon atoms connected to M and R1 is a double bond; when M is selected from -CO-, the bond between the carbon atoms connected to M and R1 is a single bond. R1 is selected from C1~C4 alkyl groups; R2 is selected from H or The wavy line represents the bonding site of the functional group. R3 is n-propyloxy group; R4 is , , , , , , The wavy line represents the connection site of the functional group.

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