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

Abstract

The application provides a benzimidazole ternary ring compound and a pharmaceutically acceptable salt and application thereof. The benzimidazole ternary ring compound of the application takes TRIM24 as a target, and a benzimidazole ternary ring compound with a structure shown in formula I is designed.

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] The bromodomain was first discovered in 1992 by Kennison's team on different proteins from three species: human, Drosophila, and yeast. The bromodomain is approximately 110 amino acids long and possesses a highly conserved 4-helix bundle tertiary structure. Currently, 61 bromodomains contained in 46 bromodomain-containing proteins have been reported. These bromodomains are classified into eight subfamilies based on sequence and structural conservation, with TRIM24 belonging to the fifth subfamily.

[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-based three-membered cyclic compound having the structure shown in Formula I:

[0008]

[0009] Where X is selected from O or S;

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

[0011] The R l Selected from C1-C10 straight-chain or branched alkyl, C2-C10 alkenyl or alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted azaaryl; wherein the substitution refers to substitution by D, C1-C6 alkyl, or C1-C6 alkoxy.

[0012] R3 is selected from H, nitro, cyano, halogen, alkyl, and -OR. m -NHR n -OCOR o -COOR p -NHCOR q -CONHR r -COR s ;

[0013] The R m R n R o R p R q R r R sEach 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;

[0014] R4 is selected from H, nitro, cyano, halogen, alkyl, and -OR. v -NHR w -OCOR x -COOR y -NHCOR z -CONHR aa -COR ab ;

[0015] The R v R w R x R y R z R aa R ab Each group is independently selected from H, aminoalkyl, azahexacyclic alkyl, or alkyl containing 1 to 2 azahexacyclic alkyl groups; the groups attached to the amino nitrogen atom and the heterocyclic nitrogen atom are selected from 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, or substituted or unsubstituted C3 to C6 heterocyclic alkyl; at least one CH2 group in the substituted or unsubstituted C1 to C6 straight-chain alkyl or substituted or unsubstituted C1 to C6 branched alkyl is replaced by O, N, or S in a non-adjacent manner, wherein the substitution is by at least one of halogen, C1 to C4 alkyl, C1 to C3 alkoxy, C3 to C6 cyclic alkyl, or C3 to C6 heterocyclic alkyl;

[0016] Z is selected from -CH2- or O; and

[0017] When Z is selected from -CH2-, R2 is selected from H, -C(R) a (R) b )R c -SO2R d -COR e ;

[0018] 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;

[0019] 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:

[0020] (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.

[0021] (ii) A substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted C3-C10 cycloalkenyl, or a substituted or unsubstituted C3-C10 heterocycloalkyl, wherein the heterocycloalkyl comprises at least one heteroatom selected from O, N, and S, and the substitution is at least one of halogen, C1-C4 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, or C3-C6 heterocycloalkyl.

[0022] (iii) Substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups; wherein the substitution refers to substitution via D (deuterium), 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 Rm R n Each group is independently selected from H, C1-C6 straight-chain alkyl, C1-C6 branched alkyl, C3-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;

[0023] When Z is selected from O, R2 is selected from -C(R j (R) k )R l ;

[0024] The R j R k Each is independently selected from H, C1-C6 straight-chain alkyl, C1-C6 branched alkyl, and C3-C6 cyclic alkyl.

[0025] In this invention, using TRIM24 as the target, benzimidazole ternary cyclic compounds with the structure shown in Formula I were designed. These compounds have good bromine domain inhibition activity.

[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, when X is O, R2 is methyl, R3 is n-propyloxy, and R4 is H, the benzimidazole ternary cyclic compound has the structure shown in Formula Ia:

[0034]

[0035] R1 has the same defined range as in Equation I.

[0036] Preferably, R1 is methyl or methoxy.

[0037] Preferably, the benzimidazole ternary cyclic compound is any one of the following compounds:

[0038] 3,8-Dimethyl-2-(3-propoxyphenyl)-3H-imidazol[4',5':5,6]benzo[1,2-d]isoxazole

[0039] 3,8-Dimethyl-2-(3-propoxyphenoxy)-3H-imidazol[4',5':5,6]benzo[1,2-d]isoxazole

[0040] 8-Methoxy-3-methyl-2-(3-propoxyphenyl)-3H-imidazol[4',5':5,6]benzo[1,2-d]isoxazole

[0041] 8-Methoxy-3-methyl-2-(3-propoxyphenoxy)-3H-imidazol[4',5':5,6]benzo[1,2-d]isoxazole.

[0042] 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.

[0043] 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.

[0044] In this invention, the racemic mixture refers to an equimolar mixture of two enantiomers.

[0045] 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.

[0046] 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 the bromine domain protein TRIM24.

[0047] 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 bromine domain.

[0048] In this invention, the disease includes tumors, infections, or immune-related diseases.

[0049] 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.

[0050] 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.

[0051] Compared with the prior art, the present invention has the following beneficial effects:

[0052] This invention provides compounds that can act as inhibitors of the bromine domain of TRIM24. These compounds can effectively inhibit the bromine domain of the aforementioned protein, interfering with its binding to chromatin, thereby regulating the transcription of related genes, causing changes in downstream pathways, and thus affecting the disease progression, primarily tumors. Therefore, the compounds and compositions provided by this invention can be used to prepare probe molecules for studying the mechanisms related to tumor development or clinical therapeutic drugs for tumor-related diseases. Detailed Implementation

[0053] 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.

[0054] In this invention, the embodiments involve compounds of formula C, with the following structure:

[0055]

[0056] It can be prepared by the following method:

[0057]

[0058] In step a, raw material 4-1 undergoes a two-step reaction: first, DMF is used as the reaction solvent, and iodopropane is reacted with potassium carbonate at 60°C for 9 hours; then, in a mixed system of DMF and sodium hydroxide aqueous solution, the reaction is carried out at room temperature for 2.5 hours to synthesize intermediate 4-2.

[0059] In step b, raw material 4-2 is reacted with iodopropane at 50°C for 30 minutes using DMF as the reaction solvent and potassium carbonate in the presence of potassium carbonate.

[0060] In step c, raw material 4-3 reacts with hydroxylamine hydrochloride in an ethanol-water mixed solvent system at 80°C for 70 minutes under the action of sodium acetate.

[0061] In step d, 1,4-dioxane was used as the reaction solvent to react with DMF-DMA at 100°C for 10 minutes to synthesize intermediate 4-8a.

[0062] Step e uses tetrahydrofuran as the reaction solvent and reacts with CDI at 85°C for 20 minutes.

[0063] In step f, DMF was used as the reaction solvent, and methyl p-toluenesulfonate was reacted with sodium hydride in an ice bath for 2.5 hours.

[0064] Step g uses concentrated sulfuric acid as the reaction solvent and reacts with fuming nitric acid at room temperature for 70 minutes to 2.5 hours.

[0065] In step h, intermediate 4-9a is placed in an aqueous solution of methylamine, or intermediate 4-9b is placed in a methanolic solution of methylamine. The reaction is stopped by heating from room temperature to 85°C to synthesize intermediate 4-10a or 4-10b.

[0066] In step i, ethanol is used as the reaction solvent, and stannous chloride is reacted with concentrated hydrochloric acid at 80°C for 2 to 4 hours.

[0067] In step j, DMF was used as the reaction solvent, and intermediate 4-2 was reacted with triethylamine and HBTU at room temperature for 17 to 23 hours.

[0068] Step k involves reacting the sample in acetic acid at 120°C for 3 to 3.5 hours, as described in Examples 4-13a to 13b.

[0069] Step 1 uses tetrahydrofuran as the reaction solvent and triphosgene in the presence of triethylamine, reacting for 20 minutes under argon protection and an ice bath.

[0070] Example

[0071] 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.

[0072] The abbreviations used in this invention are listed below:

[0073] DMF (N,N-dimethylformamide), DCM (dichloromethane), EA (ethyl acetate), PE (petroleum ether), CDI (N,N'-carbonyldiimidazole), DMF-DMA (N,N-dimethylformamide-dimethylacetal), HBTU (benzotriazole N,N,N',N'-tetramethylurea hexafluorophosphate).

[0074] The specific preparation process is as follows:

[0075] Intermediate 4-2: 2-(3-propoxyphenyl)acetic acid

[0076]

[0077] (i) Methyl 2-(3-hydroxyphenyl)acetate (4-1, 1.0 g, 6.0 mmol) was added to anhydrous DMF, followed by potassium carbonate (2.5 g, 18.1 mmol) and iodopropane (0.88 mL, 9.0 mmol). The reaction mixture was reacted at 60 °C for 9 h. After cooling the reaction solution to room temperature, 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 then rapidly obtained as the major product (PE:EA = 10:1) by silica gel column chromatography.

[0078] (ii) Dissolve the product obtained above in DMF, add dilute sodium hydroxide solution, adjust the pH to 13-14, and react at room temperature for 2.5 h. Adjust the pH to 1-2 with dilute hydrochloric acid solution, precipitate the solid, filter under reduced pressure, wash the filter cake with dilute hydrochloric acid solution, filter under reduced pressure until the filter cake reaches constant weight, and obtain a brown powder (402 mg, yield: 34%). 1 H NMR(500MHz,DMSO-d6)δ12.28(s,1H),7.20(t,J=7.7Hz,1H),6.81(s,2H),6.79(s,1 H), 3.90 (t, J = 6.5Hz, 2H), 3.52 (s, 2H), 1.72 (h, J = 7.1Hz, 2H), 0.97 (t, J = 7.4Hz, 3H).

[0079] Intermediate 4-4: 3-Propylphenol

[0080]

[0081] Resorcinol (4-3, 5.4 g, 49.3 mmol) was dissolved in anhydrous DMF, followed by the addition of potassium carbonate (10.2 g, 74.0 mmol) and iodopropane (8.8 g, 51.8 mmol). The reaction mixture was reacted at 50 °C for 30 min. After cooling the reaction solution to room temperature, it was filtered under reduced pressure, and the filter cake was washed with ethyl acetate. The pH of the filtrate was adjusted to 2–3 by adding dilute hydrochloric acid solution, 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 = 6:1) to give a light brown liquid (2.26 g, yield: 30%). 1 H NMR(500MHz,DMSO-d6)δ9.35(s,1H),7.02(t,J=8.1Hz,1H),6.35–6.31(m,2H),6 .30(s,1H),3.83(t,J=6.5Hz,2H),1.69(h,J=7.1Hz,2H),0.95(t,J=7.4Hz,3H).

[0082] Intermediate 4-11a: N 5 3-Dimethylbenzo[d]isoxazole-4,5-diamine

[0083]

[0084] Step 1: Synthesis of 1-(5-fluoro-2-hydroxyphenyl)ethane-1-one oxime (4-6)

[0085]

[0086] 5-Fluoro-2-hydroxyacetophenone (4-5, 9.92 g, 64.4 mmol) was dissolved in 120 mL of an ethanol-water mixture (3:1), followed by the addition of hydroxylamine hydrochloride (7.16 g, 103.0 mmol) and sodium acetate (8.45 g, 103.0 mmol). The reaction mixture was then reacted at 80 °C for 1.2 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 white crystalline powder (10.48 g, yield: 96%). 1 H NMR (400MHz, DMSO-d6) δ11.67(s,1H),11.33(s,1H),7.29(dd,J=10.2,3.1Hz,1H),7.08(td,J=8.5,3.1Hz,1H),6.87(dd,J=9.0,5.0Hz,1H),2.23(s,3H).

[0087] Step 2: Synthesis of 5-fluoro-3-methylbenzo[d]isoxazole (4-8a)

[0088]

[0089] Intermediate 4-6 (5.64 g) was dissolved in 22 mL of 1,4-dioxane under vigorous stirring, followed by the addition of DMF-DMA (25 mL). The mixture was then gradually heated to 100 °C and maintained at this temperature for 22 min. The reaction solution was cooled to room temperature, water was added, and the product 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 solvent was removed from the organic layer by rotary evaporation under reduced pressure, yielding a white powder (7.58 g, yield: 81%). 1 H NMR (400MHz, DMSO-d6) δ7.81–7.69 (m, 2H), 7.53 (td, J = 9.1, 2.6Hz, 1H), 2.54 (s, 3H).

[0090] Step 3: Synthesis of 5-fluoro-3-methyl-4-nitrobenzo[d]isoxazole (4-9a)

[0091]

[0092] Intermediate 4-8a (7.58 g, 50.2 mmol) was dissolved in 25 mL of concentrated sulfuric acid in an ice bath, and fuming nitric acid (2.1 mL, 50.2 mmol) was added dropwise through a glass dropping funnel. The reaction was continued at room temperature for 2.5 h after reacting in an ice bath for 1 h. 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 (PE:EA = 20:1–10:1) to give a yellow powder (4 g, yield: 41%). 1 H NMR (400MHz, DMSO-d6) δ 8.22 (dd, J = 9.2, 3.5 Hz, 1H), 7.93 (dd, J = 10.9, 9.2 Hz, 1H), 2.53 (s, 3H).

[0093] Step 4: Synthesis of N,3-dimethyl-4-nitrobenzo[d]isoxazole-5-amine (4-10a)

[0094]

[0095] 7 mL of 40% methylamine aqueous solution was added to intermediate 4-9a (1.05 g) at room temperature, and then the mixture was gradually heated 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 obtain an orange powder (0.94 g, yield: 85%). 1H NMR (500MHz, DMSO-d6) δ 8.68–8.59 (m, 1H), 8.00 (d, J = 9.5Hz, 1H), 7.40 (d, J = 9.6Hz, 1H), 3.06 (d, J = 5.0Hz, 3H), 2.59 (s, 3H).

[0096] Step 5: Synthesize N 5 3-Dimethylbenzo[d]isoxazole-4,5-diamine (4-11a)

[0097]

[0098] 25 mL of ethanol was added to intermediate 4-10a (940 mg, 4.54 mmol), followed by stannous chloride dihydrate (5.12 g, 22.68 mmol) and 6 mL of concentrated hydrochloric acid. The reaction mixture was reacted at 80 °C for 2 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 6–7 with dilute sodium hydroxide aqueous solution. The product was extracted with ethyl acetate, and the organic layers were 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 brownish-red solid (630 mg, yield: 78%). 1 H NMR (500MHz, DMSO-d6) δ6.82–6.77(m,1H),6.74–6.66(m,1H),5.07(s,2H),4.46(s,1H),2.73(s,3H),2.61(s,3H).

[0099] Example 4-13a: 3,8-Dimethyl-2-(3-propoxyphenyl)-3H-imidazol [4', 5': 5, 6]benzo[1, 2-d]isoxazole

[0100]

[0101] Step 1: N-(3-methyl-5-(methylamino)phenyl[d]isoxazol-4-yl)-2-(3-propoxyphenyl)acetamide (4-12a)

[0102]

[0103] Compound 4-11a (100 mg, 0.56 mmol) was added to anhydrous DMF, followed by triethylamine (0.12 mL, 0.84 mmol), HBTU (236 mg, 0.62 mmol), and intermediate 4-2 (120 mg, 0.62 mmol). The reaction mixture was reacted at room temperature for 23 h. 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, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:DCM:EA = 1:1:1) to give a brown liquid (140 mg, yield: 70%). 1 H NMR (500MHz, DMSO-d6) δ7.15(d,J=8.6Hz,1H),7.10(t,J=7.9Hz,1H),6.75(d,J=8.5Hz,1H),6.72(dd,J=8.3,2.4Hz,1H),6.60(d,J= 7.6Hz,1H),6.55(s,1H),5.86(s,2H),3.81(t,J=6.6Hz,2H),3.06(s,3H),2.65(s,3H),1.68(h,J=7.2Hz,2H),0.95(t,J=7.4Hz,3H).

[0104] Step 2: 3,8-Dimethyl-2-(3-propoxyphenyl)-3H-imidazol [4',5':5,6]benzo[1,2-d]isoxazole (4-13a)

[0105]

[0106] Acetic acid (20 mL) was added to intermediate 4-12a (140 mg), and the mixture was reacted at 120 °C for 3 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and water was added. The pH was adjusted to 10–11 with dilute sodium hydroxide solution, 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 = 2:1) to obtain a light yellow crystalline powder (117 mg, yield: 88%). 1 H NMR (500MHz, DMSO-d6) δ7.79(d,J=8.6Hz,1H),7.53(d,J=8.4Hz,1H),7.21(t,J=6.9Hz,1H),6.85(s,1H),6.79(d,J=7 .2Hz,2H),4.37(s,2H),3.87(t,J=7.3Hz,2H),3.79(s,3H),2.77(s,3H),1.68(h,J=6.7Hz,2H),0.94(t,J=6.9Hz,3H).

[0107] Example 4-15a: 3,8-Dimethyl-2-(3-propoxyphenoxy)-3H-imidazol [4', 5': 5, 6]benzo[1, 2-d]isoxazole

[0108]

[0109] Step 1: 3,8-Dimethyl-1,3-dihydro-2H-imidazolium[4',5':5,6]benzo[1,2-d]isoxazol-2-one (4-14a)

[0110]

[0111] Intermediate 4-11a (200 mg, 1.13 mmol) was dissolved in 5 mL of tetrahydrofuran. Under ice bath and argon protection, triethylamine (0.47 mL, 3.39 mmol) was added via syringe. Then, triphosgene (502 mg, 1.69 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 20 min under ice bath. The reaction solution was then added to ice-cold saturated sodium bicarbonate solution and extracted with EA. 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 = 3:1 to 1:1) to obtain a white powder (148 mg, yield: 65%). 1 HNMR (500MHz, DMSO-d6) δ11.76(s,1H),7.41(d,J=8.6Hz,1H),7.30(d,J=8.6Hz,1H),3.36(s,3H),2.64(s,3H).

[0112] Step 2: 3,8-Dimethyl-2-(3-propoxyphenoxy)-3H-imidazol [4',5':5,6]benzo[1,2-d]isoxazole (4-15a)

[0113]

[0114] (i) Phosphorus oxychloride (5 mL) was added to intermediate 4-14a (36 mg, 0.18 mmol), and the reaction was carried out at 110 °C for 3 h. After cooling the reaction solution to room temperature, it was quenched in ice water, 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, and the solvent was removed by rotary evaporation under reduced pressure to give a light yellow powder (40 mg, yield: 100%).

[0115] (ii) The crude product (40 mg, 0.18 mmol) was added to 3 mL of anhydrous DMF, followed by cesium carbonate (88 mg, 0.27 mmol) and intermediate 4-4 (30 mg, 0.2 mmol). The mixture was reacted at 100 °C for 4 h. After cooling the reaction solution to room temperature, 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 = 3:1) to give a white powder (41 mg, yield: 69%). 1 H NMR (500MHz, DMSO-d6) δ7.79(d,J=8.9Hz,1H),7.51(d,J=8.9Hz,1H),7.36(t,J=8.2Hz,1H),7.08(s,1H),6.98(d,J=8.2Hz ,1H),6.85(d,J=8.2Hz,1H),3.96(t,J=6.5Hz,2H),3.81(s,3H),2.63(s,3H),1.74(h,J=7.1Hz,2H),0.97(t,J=7.5Hz,3H).

[0116] Intermediate 4-11b: 3-methoxy-N 5 -Methylbenzo[d]isoxazole-4,5-diamine

[0117]

[0118] Step 1: 5-Fluorobenzo[d]isoxazole-3(2H)-one (4-7)

[0119]

[0120] 5-Fluoro-N,2-dihydroxybenzamide (3-6, 18.94 g, 0.11 mol) was added to 500 mL of anhydrous tetrahydrofuran, and heated to 85 °C with stirring. CDI (80.77 g, 0.5 mol) was added in several portions, and the reaction was maintained at this temperature for 20 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 (11.7 g, yield: 69%). 1 H NMR (400MHz, DMSO-d6) δ7.62–7.51(m,2H),7.51-7.43(m,1H).

[0121] Step 2: 5-Fluoro-3-methoxybenzo[d]isoxazole (4-8b)

[0122]

[0123] Intermediate 4-7 (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. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (pure PE) to give a white powder, yield: 44%. 1 H NMR (500MHz, DMSO-d6) δ7.76–7.67(m,1H),7.64–7.51(m,2H),4.11(s,3H).

[0124] Step 3: 5-Fluoro-3-methoxy-4-nitrobenzo[d]isoxazole (4-9b)

[0125]

[0126] Intermediate 4-8b (5.6 g, 33.53 mmol) was dissolved in 24 mL of concentrated sulfuric acid under ice bath conditions. Fuming nitric acid (2.1 mL, 50.3 mmol) was added dropwise through a glass dropping funnel, and the reaction flask was then transferred to room temperature and reacted for 70 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 yellow powder (5.3 g, yield: 75%). 1 H NMR (500MHz, DMSO-d6) δ8.12 (dd, J=9.4, 3.4Hz, 1H), 7.94 (t, J=9.9Hz, 1H), 4.11 (s, 3H).

[0127] Step 4: 3-Methoxy-N-methyl-4-nitrobenzo[d]isoxazole-5-amine (4-10b)

[0128]

[0129] Intermediate 4-9b (1 g) was added to a methanol solution (45%) of methylamine, and the reaction was gradually heated to 85 °C to terminate the reaction. 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 to obtain a yellow powder (768 mg, yield: 73%). 1H NMR (500MHz, DMSO-d6) δ8.28–8.21(m,1H),7.89(d,J=9.5Hz,1H),7.37(d,J=9.5Hz,1H),4.04(s,3H),3.01(d,J=5.1,3H).

[0130] Step 5: 3-Methoxy-N 5 -Methylbenzo[d]isoxazole-4,5-diamine (4-11b)

[0131]

[0132] Intermediate 4-10b (768 mg, 3.44 mmol) was added to 25 mL of ethanol. Stannous chloride dihydrate (3.88 g, 17.21 mmol) was dissolved in 7 mL of concentrated hydrochloric acid and added to the solution with stirring. The mixture was reacted at 80 °C for 4 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove ethanol, and then ice water was added. 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 give a purple powder (548 mg, yield: 82%). 1 H NMR (500MHz, DMSO-d6) δ6.73 (d, J = 7.1 Hz, 1H), 6.58 (d, J = 8.3 Hz, 1H), 5.16 (s, 2H), 4.56 (s, 1H), 4.05 (s, 3H), 2.72 (s, 3H).

[0133] Example 4-13b: 8-methoxy-3-methyl-2-(3-propoxyphenyl)-3H-imidazol [4', 5': 5, 6]benzo[1, 2-d]isoxazole

[0134]

[0135] Step 1: N-(3-methoxy-5-(methylamino)phenyl[d]isoxazol-4-yl)-2-(3-propoxyphenyl)acetamide (4-12b)

[0136]

[0137] Using intermediates 4-11b and 4-2 as raw materials, the synthesis method is the same as that for intermediate 4-12a, yielding a light brown powder with a yield of 73%. 1H NMR (500MHz, DMSO-d6) δ7.15(d,J=8.6Hz,1H),7.10(t,J=7.8Hz,1H),6.72(d,J=8.3Hz,1H),6.64(d,J=8.6Hz,1H),6.59(d,J=7.5 Hz,1H),6.54(s,1H),5.85(s,2H),4.07(s,3H),3.81(t,J=6.5Hz,2H),3.05(s,3H),1.68(h,J=6.8Hz,2H),0.95(t,J=7.3Hz,3H).

[0138] Step 2: 8-Methoxy-3-methyl-2-(3-propoxyphenyl)-3H-imidazol [4', 5': 5, 6]benzo[1, 2-d]isoxazole (4-13b)

[0139]

[0140] Using intermediate 4-12b as raw material, the synthesis method is as described in Examples 4-13a, yielding a light yellow powder with a yield of 72%. 1 HNMR (500MHz, DMSO-d6) δ7.80(d,J=8.9Hz,1H),7.45(d,J=8.9Hz,1H),7.21(t,J=7.9Hz,1H),6.84(s,1H),6.80(d,J =7.9Hz,2H),4.33(s,2H),4.15(s,3H),3.88(t,J=6.7Hz,2H),3.79(s,3H),1.69(h,J=7.4Hz,2H),1.00–0.92(m,3H).

[0141] Example 4-15b: 8-methoxy-3-methyl-2-(3-propoxyphenoxy)-3H-imidazol [4',5':5,6]benzo[1,2-d]isoxazole

[0142]

[0143] Step 1: 8-Methoxy-3-methyl-1,3-dihydro-2H-imidazolium[4',5':5,6]benzo[1,2-d]isoxazol-2-one (4-14b)

[0144]

[0145] Using intermediate 4-11b as a raw material, the synthesis method is the same as that of intermediate 4-14a, yielding a light yellow powder with a yield of 67%. 1HNMR (500MHz, DMSO-d6) δ11.71(s,1H),7.41(d,J=8.8Hz,1H),7.22(d,J=8.9Hz,1H),4.10(s,3H),3.34(s,3H).

[0146] Step 2: 8-Methoxy-3-methyl-2-(3-propoxyphenoxy)-3H-imidazol [4', 5': 5, 6]benzo[1, 2-d]isoxazole (4-15b)

[0147]

[0148] Using intermediate 4-14b as raw material, the synthesis method is as described in Examples 4-15a, yielding a white powder with a yield of 47% (the yields of the two steps are 78% and 60% respectively). 1 H NMR (500MHz, DMSO-d6) δ7.80(d,J=9.0Hz,1H),7.43(d,J=8.9Hz,1H),7.38(t,J=8.3Hz,1H),6.99(d,J=2.6Hz,1H),6.95(d,J=8 .1Hz, 1H), 6.89 (d, J = 8.1Hz, 1H), 4.08 (s, 3H), 3.96 (t, J = 6.6Hz, 2H), 3.81 (s, 3H), 1.74 (h, J = 7.2Hz, 2H), 0.98 (t, J = 7.5Hz, 3H).

[0149] Bioactivity test

[0150] The inhibitory activity of the compounds in the embodiments listed in this invention on the target proteins was tested.

[0151] The protein activity assay employed amplified luminescence proximity homogeneous assay screen (Alphascreen) technique. The objective was to evaluate the binding affinity between the compound and the bromine domain.

[0152] Experimental system: 10× experimental buffer (MOPS, CHAPS, NaF, BSA), double-distilled water, peptide solution, test protein solution, compound dilution solution, and detection kit.

[0153] 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.

[0154] The test results of the compounds described in the embodiments on the Alphascreen experiment are shown in Tables 1 and 2 below.

[0155] Table 1. Activity assay results of the compounds at the TRIM24 protein level.

[0156] compound 4-13a 4-13b 4-15a 4-15b <![CDATA[IC 50 (μM)]]> 28.8 44.22 45.61 14.14

[0157] As can be seen from the data in Table 1 above, IC 50 The value represents the strength of the binding affinity between the compound and the protein. The smaller the value, the stronger the binding affinity. All the compounds tested in Table 1 showed a clear inhibitory trend on the inhibition curves, with IC50 values ​​indicating strong binding affinity. 50 It exhibits good inhibitory activity at 14-45.61 μM. Therefore, the compound described in this invention has a good inhibitory effect on TRIM24 bromodomain proteins.

[0158] 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 three-membered cyclic compound has the structure shown in formula Ia: R1 is selected from C1-C3 alkyl or methoxy; Z is selected from -CH2- or O.

2. The benzimidazole ternary cyclic compound according to claim 1, characterized in that, The benzimidazole three-membered cyclic compound is any one of the following compounds: 3,8-Dimethyl-2-(3-propoxyphenyl)-3H-imidazol[4',5':5,6]benzo[1,2-d]isoxazole 3,8-Dimethyl-2-(3-propoxyphenoxy)-3H-imidazol[4',5':5,6]benzo[1,2-d]isoxazole 8-Methoxy-3-methyl-2-(3-propoxyphenyl)-3H-imidazol[4',5':5,6]benzo[1,2-d]isoxazole 3. A pharmaceutically acceptable salt of a benzimidazole ternary cyclic compound according to claim 1 or 2.

4. The use of the benzimidazole ternary cyclic compound according to claim 1 or 2, or the pharmaceutically acceptable salt according to claim 3, in the preparation of a bromine domain protein TRIM24 inhibitor.

5. The use of the benzimidazole ternary cyclic compound according to claim 1 or 2, or the pharmaceutically acceptable salt according to claim 3, in the preparation of a medicament for treating tumors, infections, or immune-related diseases by inhibiting the TRIM24 bromine domain.

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