12-aryl-11h-benzo[b]indeno[1,2-e][1,4]oxazepine compounds, processes for their preparation and uses thereof

Abstract

The application belongs to the technical field of chemical medicine preparation, and particularly relates to a 12-aryl-11H-benzo[b]indeno[1,2-e][1,4]oxazepine compound and a preparation method and application thereof. The structure of the compound is shown as formula I. The preparation method of the application is as follows: under a protective gas atmosphere, a compound with a structure of formula II and a compound with a structure of formula III are used as reaction substrates, a solvent, an oxidant and an additive are added, and heating reaction is carried out, and the compound is obtained. The compound provided by the application has significant biological activity and application function, can be applied to preparation of medicines for preventing or treating cancers, such as ovarian cancer, nasopharyngeal cancer and colon cancer, and the preparation method of the application is simple in operation, wide in substrate applicability, can be used for amplification reaction of a gram scale, and has a broad market prospect. Formula I.

Description

Technical Field

[0001] This application belongs to the field of chemical drug preparation technology, specifically relating to a 12-aryl-11H-benzo[b]indo[1,2-e][1,4]oxazapine compound, its preparation method, and its application. Background Technology

[0002] Oxapine, a typical oxygen- and nitrogen-containing heterocyclic compound, is widely found in nature and possesses excellent biological and pharmacological activities. Therefore, the synthesis and application of compounds based on the oxazapine skeleton have attracted considerable attention from researchers. For example, loxapine (Fitton A, Heel RC, ... Drugs 1990, 40 (722.) is a compound containing the dibenzoxazine skeleton. It is an orally active dopamine inhibitor and 5-HT receptor antagonist, commonly used clinically to treat acute and chronic schizophrenia and treatment-resistant behavioral disorders, and has antidepressant and anti-anxiety effects. Amoxapine and nitroxazepine also have antidepressant and antipsychotic effects (Cohen BM, Harris PQ, Altesman RI, et al.). Am. J. Psychiatry, 1982, 139 , 1165.). The drug structure with the dibenzoxazine skeleton is shown below:

[0003] .

[0004] On the other hand, indene fused ring derivatives are an important class of natural products, pesticides and pharmaceutical intermediates with broad-spectrum biological activities, such as antibacterial, herbicidal, insecticidal and anticancer effects. The design, synthesis and application of molecules based on benzo[a]indene[b]oxa[a]azine fused ring skeleton molecules are of great significance and have good application prospects in the fields of pesticides and pharmaceuticals.

[0005] Therefore, developing a class of novel oxazapine compounds, providing an efficient and practical preparation method, and exploring their applications in medicine, agricultural chemistry, and other fields are of significant innovative importance and application value. This invention aims to fill the gaps in existing technologies and provide new compound entities with potentially excellent biological activity and drug-like properties. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and provide a 12-aryl-11H-benzo[b]indo[1,2-e][1,4]oxazapine compound, its preparation method, and its application. Specifically, the following technical solution is adopted:

[0007] In a first aspect, the present invention provides a 12-aryl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine compound, the structure of which is shown in Formula I:

[0008] Formula I;

[0009] Among them, R 1 It is selected from at least one of hydrogen, C1-C10 alkyl, C1-C10 alkoxy, fluorinated alkoxy, halogen atom and nitro;

[0010] R 2 It is selected from at least one of hydrogen, C1-C10 alkyl, C1-C10 alkoxy, fluorinated alkoxy and halogen atom;

[0011] R 3 It is selected from at least one of hydrogen, C1-C10 alkyl, C1-C10 alkoxy / sulfur / silyl, amino, nitro, fluorinated alkyl, and halogen atoms.

[0012] As a further preferred embodiment, R 1 Selected from one of hydrogen, methyl, trifluoromethyl, methoxy, fluorine, chlorine and bromine;

[0013] R 2 It is selected from one of hydrogen, methyl, methoxy, tert-butyl, nitro, fluorine, chlorine and bromine;

[0014] R 3 It is selected from one of hydrogen, methyl, methoxy, isopropyl, tert-butyl, nitro, trifluoromethyl, hydroxy, trimethylsilyl, methylthio, fluorine, chlorine and bromine.

[0015] As a further preferred embodiment, the 12-aryl-11H-benzo[b]indo[1,2-e][1,4]oxazapine compound is one of the compounds shown in the following structural formulas:

[0016] .

[0017] Secondly, the present invention provides a method for preparing the above-mentioned 12-aryl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine compound, characterized by comprising the following steps:

[0018] Under a protective gas atmosphere, using compounds of formula II and formula III as reaction substrates, solvents, oxidants and additives were added and heated to obtain the 12-aryl-11H-benzo[b]indo[1,2-e][1,4]oxazapine compound;

[0019] The structural formulas of compounds with formula II and compounds with formula III are shown below:

[0020] Formula II; Formula III.

[0021] As a further preferred embodiment, the compound of Formula II is selected from 1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene, 2-isocyano-4-methoxy-1-((3-phenylprop-2-yn-1-yl)oxy)benzene, 2-isocyano-4-methyl-1-((3-phenylprop-2-yn-1-yl)oxy)benzene, 4-chloro-2-isocyano-1-((3-phenylprop-2-yn-1-yl)oxy)benzene, 2-isocyano-1-((3-phenylprop-2-yn-1-yl)oxy)-4-trifluoromethyl)benzene, 4-bromo-2-isocyano At least one of the following: 1-((3-phenylprop-2-yn-1-yl)oxy)benzene, 4-bromo-1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene, 4-chloro-1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene, 1-isocyano-2-((3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)oxy)benzene, 1-bromo-3-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene, and 2-isocyano-1-methyl-3-((3-phenylprop-2-yn-1-yl)oxy)benzene;

[0022] The compound of Formula III is selected from at least one of 4-methylphenylboronic acid, 4-tert-butylphenylboronic acid, 4-methoxyphenylboronic acid, 4-methylthiophenylboronic acid, 4-fluorophenylboronic acid, 4-trimethylsilylphenylboronic acid, N,N-diphenylaminophenylboronic acid, 4-iodophenylboronic acid, 4-bromophenylboronic acid, 4-chlorophenylboronic acid, 4-fluorophenylboronic acid, 4-trifluoromethylphenylboronic acid, and phenylboronic acid.

[0023] As a further preferred embodiment, the oxidant is one of manganese acetylacetone and manganese acetate;

[0024] The additive is at least one selected from tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide (DTBP), N,N-dimethylaminopyridine (DMAP), 1,8-dioctyl-1,3,6,8-tetraazacyclododecane (DBU), triethylenediamine (DABCO), sodium carbonate, cesium carbonate, potassium tert-butoxide, and silver carbonate.

[0025] As a further preferred embodiment, the molar ratio of the compound of formula II, the compound of formula III, the oxidant and the additive is 0.9~1.1:1.8~2.2:2.7~3.3:1.8~2.2.

[0026] As a further preferred embodiment, the solvent is at least one selected from dichloroethane, 1,4-dioxane, toluene, chlorobenzene, acetone, chloroform, and diethyl ether;

[0027] The heating reaction temperature is 60 ℃~80 ℃, and the heating reaction time is 36 h~48 h.

[0028] Thirdly, the present invention provides the use of the above-mentioned 12-aryl-11H-benzo[b]indo[1,2-e][1,4]oxazapine compound in the preparation of medicaments for the prevention or treatment of cancer.

[0029] As a further preferred embodiment, the cancer includes ovarian cancer, nasopharyngeal cancer, or colon cancer.

[0030] The beneficial effects of this invention are as follows:

[0031] (1) The compounds provided by the present invention have significant biological activity and application functions, and can be used in the preparation of drugs for the prevention or treatment of cancer, such as ovarian cancer, nasopharyngeal carcinoma and colon cancer. According to the data results, compounds 3e and 3h show significant biological activity against ovarian cancer cells, nasopharyngeal cancer cells and colon cancer cells, and have good inhibitory effects. Therefore, they have good application prospects in the preparation of drugs for the treatment of ovarian cancer, nasopharyngeal carcinoma and colon cancer.

[0032] (2) The preparation method provided by the present invention is simple to operate, has wide substrate applicability, can be used for gram-scale scaled reactions, and has broad market prospects. Detailed Implementation

[0033] The technical solutions in the embodiments of this application will be clearly and completely described below with reference to the embodiments of this application. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0034] This invention provides a series of 12-aryl-11H-benzo[b]indo[1,2-e][1,4]oxazapine compounds and their preparation method, the specific process of which is as follows:

[0035] Using the compounds shown in Formula II and Formula III as reaction substrates, an oxidant, an additive, and a solvent were added and the reaction was carried out under heating to obtain the 12-aryl-11H-benzo[b]indo[1,2-e][1,4]oxazapine compound;

[0036] The structures of the compounds represented by Formula II and Formula III are as follows:

[0037] Formula II; Formula III.

[0038] Taking compound 3a as an example, its synthetic route is as follows:

[0039]

[0040] The specific process is as follows: Under argon atmosphere, 0.9-1.1 equivalents of 1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene and 1.8-2.2 equivalents of p-methylphenylboronic acid, along with 2.7-3.3 equivalents of manganese acetylacetonate as an oxidant and 1.8-2.2 equivalents of silver carbonate as an additive, are added to chlorobenzene (0.1M). The reaction is carried out at 70 °C for 40-42 hours to efficiently prepare 12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine. The reaction process is monitored by TLC. After the reaction is completed, the mixture is concentrated under vacuum and purified by rapid column chromatography.

[0041] The principle of this route is as follows: p-methylphenylboronic acid (2a) is oxidized by trivalent manganese salt to generate p-methylphenyl radical. The p-methoxyphenyl radical attacks the isonitrile carbon atom of 1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene (1a) to generate an imine carbon radical intermediate. This radical intermediate undergoes intramolecular cyclization and attacks the alkyne bond to obtain a seven-membered ring olefin carbon radical intermediate. The olefin carbon intermediate undergoes intramolecular radical cyclization with the ortho position of the aromatic ring from boric acid to construct a new five-membered ring radical intermediate. This radical intermediate is oxidized by trivalent manganese salt to obtain a cationic intermediate. The cationic intermediate undergoes a deprotonation process to obtain the target product 3a.

[0042] Example 1

[0043] A 2-methyl-12-phenyl-11H-benzo[b]indo[1,2-e][1,4]oxazapine series compound (3a) has the following structural formula:

[0044]

[0045] Its preparation process specifically includes the following steps:

[0046] Under argon atmosphere, 1.0 equivalent of 1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene (1a) and 2.0 equivalent of p-methylphenylboronic acid (2a), 3.0 equivalent of manganese acetylacetonate as an oxidant and 2.0 equivalent of silver carbonate as an additive were added to chlorobenzene (0.1M). The reaction was carried out at 70 °C for 40 hours. The reaction process was monitored by TLC. After the reaction was completed, the product was concentrated under vacuum and purified by rapid column chromatography to obtain the product 2-methyl-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine series compounds (3a), with a yield of 77%.

[0047] The test results are as follows:

[0048] 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.5 Hz, 1H), 7.72–7.69 (m, 1H), 7.52–7.43 (m, 3H), 7.36 (d, J = 6.8 Hz, 2H), 7.23–7.16 (m, 2H), 7.10 (d, J = 7.6Hz, 1H), 7.06–7.01 (m, 2H), 4.96 (s, 2H), 2.39 (s, 3H).

[0049] 13 C NMR (100 MHz, CDCl3) δ 166.3, 153.5, 146.6, 143.5, 140.6, 140.0,134.3, 133.4, 132.4, 129.0, 128.9, 128.7, 127.9, 124.5, 122.1, 121.5, 121.4, 68.6, 21.9.

[0050] HRMS (ESI) m / z: Calculated for C 23 H 17 NO + (M+H + ): 324.1388; Found: 324.1383.

[0051] Example 2

[0052] A 2,7-dimethyl-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine series compound (3b) has the following structural formula:

[0053]

[0054] Its preparation process specifically includes the following steps:

[0055] Under argon atmosphere, 1.0 equivalent of 2-isocyano-4-methyl-1-((3-phenylprop-2-yn-1-yl)oxy)benzene (1b), 2.0 equivalent of p-methylphenylboronic acid (2a), 3.0 equivalent of manganese acetylacetonate as an oxidant, and 2.0 equivalent of silver carbonate as an additive were added to chlorobenzene (0.1 M). The reaction was carried out at 70 °C for 40 hours. The reaction process was monitored by TLC. After the reaction was completed, the product was concentrated under vacuum and purified by rapid column chromatography to obtain 2,7-dimethyl-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine (3b), with a yield of 58%.

[0056] The test results are as follows:

[0057] 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.4 Hz, 1H), 7.60 – 7.42 (m, 4H), 7.37 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 7.06 (s, 1H), 6.99 (d, J = 7.9Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 4.92 (s, 2H), 2.37 (s, 6H).

[0058] 13 C NMR (100 MHz, CDCl3) δ 166.2, 151.3, 146.4, 143.5, 140.5, 139.6,134.3, 134.0, 133.6, 132.5, 129.7, 129.0, 128.9, 128.8, 128.7, 127.9, 122.1,121.4, 121.1, 68.6, 21.9, 20.5.

[0059] HRMS (ESI) m / z: Calculated for C 24 H 19 NO + (M+H + ): 338.1541; Found: 338.1539.

[0060] This example mainly investigates the suitability of 2-isocyano-4-methyl-1-((3-phenylprop-2-yn-1-yl)oxy)benzene with an electron-donating (methyl) substrate at the para position. The results show that this substrate can give 2,7-dimethyl-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine 3b in good yield.

[0061] Example 3

[0062] A 7-chloro-2-methyl-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine series compound (3c) has the following structural formula:

[0063]

[0064] Its preparation process specifically includes the following steps:

[0065] Under argon atmosphere, 1.0 equivalent of 4-chloro-2-isocyano-1-((3-phenylprop-2-yn-1-yl)oxy)benzene (1c), 2.0 equivalent of p-methylphenylboronic acid (2a), 3.0 equivalent of manganese acetylacetonate as an oxidant, and 2.0 equivalent of silver carbonate as an additive were added to chlorobenzene (0.1M). The reaction was carried out at 70 °C for 42 hours. The reaction process was monitored by TLC. After the reaction was completed, the product was concentrated under vacuum and purified by rapid column chromatography to obtain 7-chloro-2-methyl-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine (3c), with a yield of 65%.

[0066] The test results are as follows:

[0067] 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.2 Hz, 1H), 7.69 (s, 1H), 7.57 –7.44 (m, 3H), 7.36 (d, J = 7.2 Hz, 2H), 7.11 (t, J = 7.2 Hz, 2H), 7.05 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.91 (s, 2H), 2.37 (s, 3H).

[0068] 13C NMR (100 MHz, CDCl3) δ 167.4, 152.2, 147.5, 143.5, 141.0, 140.8,134.1, 132.6, 132.2, 129.2, 129.1, 128.9, 128.7, 128.5, 128.3, 128.1, 122.6, 122.3, 121.6, 68.7, 21.9.

[0069] HRMS (ESI) m / z: Calculated for C 23 H 16 ClNO + (M+H + ): 358.0998; Found: 358.0993.

[0070] This example mainly investigates the applicability of 4-chloro-2-isocyano-1-((3-phenylprop-2-yn-1-yl)oxy)benzene with an electron-withdrawing (chlorine) group at the para position. The results show that this substrate can give 7-chloro-2-methyl-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine 3c in good yield.

[0071] Example 4

[0072] A 7-bromo-2-methyl-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine compound (3d) has the following structural formula:

[0073]

[0074] Its preparation process specifically includes the following steps:

[0075] Under argon atmosphere, 1.0 equivalent of 4-bromo-2-isocyano-1-((3-phenylprop-2-yn-1-yl)oxy)benzene (1d), 2.0 equivalent of p-methylphenylboronic acid (2a), 3.0 equivalent of manganese acetylacetonate as an oxidant, and 2.0 equivalent of silver carbonate as an additive were added to chlorobenzene (0.1M). The reaction was carried out at 70 °C for 42 hours. The reaction process was monitored by TLC. After the reaction was completed, the product was concentrated under vacuum and purified by rapid column chromatography to obtain 7-bromo-2-methyl-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine (3d), with a yield of 59%.

[0076] 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J= 7.2 Hz, 1H), 7.51 – 7.40 (m, 4H), 7.29 (d, J = 6.8 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 7.03 (d, J = 7.6Hz, 1H), 6.98 (s, 1H), 4.86 (s, 2H), 2.30 (s, 3H).

[0077] 13 C NMR (100 MHz, CDCl3) δ 166.6, 154.0, 147.2, 143.5, 140.8, 139.1,134.5, 134.1, 132.2, 129.2, 128.8, 128.7, 128.3, 128.1, 127.7, 124.7, 122.3,121.5, 121.4, 68.7, 21.9.

[0078] HRMS (ESI) m / z: Calculated for C 23 H 16 BrNO + (M+H + ): 402.0498; Found: 402.0488.

[0079] This example mainly investigated the applicability of 4-bromo-2-isocyano-1-((3-phenylprop-2-yn-1-yl)oxy)benzene as an electron-withdrawing (bromine) substrate at the para position. The results showed that this substrate could give 7-bromo-2-methyl-12-phenyl-11H-benzo[b]indo[1,2-e][1,4]oxazapine 3d in good yield.

[0080] Example 5

[0081] A 2-methyl-12-phenyl-7-(trifluoromethyl)-11H-benzo[b]indeno[1,2-e][1,4]oxazapine series compound (3e) has the following structural formula:

[0082]

[0083] Its preparation process specifically includes the following steps:

[0084] Under argon atmosphere, 1.0 equivalent of 2-isocyano-1-((3-phenylprop-2-yn-1-yl)oxy)-4-(trifluoromethyl)benzene (1e), 2.0 equivalent of p-methylphenylboronic acid (2a), 3.0 equivalent of manganese acetylacetonate as an oxidant, and 2.0 equivalent of silver carbonate as an additive were added to chlorobenzene (0.1 M). The reaction was carried out at 70 °C for 42 hours. The reaction process was monitored by TLC. After the reaction was completed, the product was concentrated under vacuum and purified by rapid column chromatography to obtain 2-methyl-12-phenyl-7-(trifluoromethyl)-11H-benzo[b]indeno[1,2-e][1,4]oxazapine (3e), with a yield of 44%.

[0085] 1 H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.54– 7.48 (m, 3H), 7.42 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 7.2 Hz, 2H), 7.12 (d, J =8.0 Hz, 2H), 7.06 (s, 1H), 4.96 (s, 2H), 2.37 (s, 3H).

[0086] 13 C NMR (150 MHz, CDCl3) δ 167.6, 155.8, 147.9, 143.4, 141.1, 139.7,133.9, 131.9, 130.7 (q, J = 3.8 Hz), 129.3, 128.8, 128.7, 128.2, 127.8, 126.8(q, J = 33.0 Hz), 125.4 (q, J = 3.6 Hz), 123.9 (q, J = 270.0 Hz), 122. 4, 122.2, 121. 6, 68.6, 21.9.

[0087] 19 F NMR (376 MHz, CDCl3) δ -62.1.

[0088] HRMS (ESI) m / z: Calculated for C 23 H 16 F3NO +(M+H + ): 392.1257; Found: 392.1257.

[0089] This example mainly investigates the applicability of 2-isocyano-1-((3-phenylprop-2-yn-1-yl)oxy)-4-(trifluoromethyl)benzene with an electron-withdrawing (trifluoromethyl) substrate at the para position. The results show that this substrate can give 2-methyl-12-phenyl-7-(trifluoromethyl)-11H-benzo[b]indeno[1,2-e][1,4]oxazapine 3e in good yield.

[0090] Example 6

[0091] A 2-methyl-12-(3-(trifluoromethyl)phenyl)-11H-benzo[b]indeno[1,2-e][1,4]oxazapine series compound (3f) has the following structural formula:

[0092]

[0093] Its preparation process specifically includes the following steps:

[0094] Under argon atmosphere, 1.0 equivalent of 1-isocyano-2-((3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)oxy)benzene (1f), 2.0 equivalent of p-methylphenylboronic acid (2a), 3.0 equivalent of manganese acetylacetonate as an oxidant, and 2.0 equivalent of silver carbonate as an additive were added to chlorobenzene (0.1M). The reaction was carried out at 70 °C for 42 hours, and the reaction process was monitored by TLC. After the reaction was completed, the product was concentrated under vacuum and purified by rapid column chromatography to obtain 2-methyl-12-(3-(trifluoromethyl)phenyl)-11H-benzo[b]indeno[1,2-e][1,4]oxazapine (3f), with a yield of 62%.

[0095] The test results are as follows:

[0096] 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 7.77 – 7.70 (m, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.22– 7.17 (m, 2H), 7.09 (d, J= 7.6 Hz, 1H), 7.05 – 6.98 (m, 1H), 6.55 (s, 1H), 4.66 (s, 2H), 2.31 (s, 3H).

[0097] 13 C NMR (100 MHz, CDCl3) δ 165.7, 153.2, 145.3, 144.1, 140.9, 139.6,133.7, 133.2, 132.0, 131.4, 130.7, 130.1, 129.4, 128.8, 128.0, 126.5 (q, J =5.0 Hz), 124.5, 123.7 (q, J = 271.8 Hz), 121.8, 121.5, 121.3, 68.6, 21.8.

[0098] 19 F NMR (376 MHz, CDCl3) δ -60.0.

[0099] HRMS (ESI) m / z: Calculated for C 24 H 16 F3NO + (M+H + ): 392.1267; Found: 392.1257.

[0100] This example mainly investigates the applicability of substrates with an electron-withdrawing group (trifluoromethylfluoro) at the meta position of isonitrile phenyl. The results show that the substrate can give 2-methyl-12-(3-(trifluoromethyl)phenyl)-11H-benzo[b]indo[1,2-e][1,4]oxazapine 3f in good yield.

[0101] Example 7

[0102] A 3g compound of the 12-(4-fluorophenyl)-2-methyl-11H-benzo[b]indo[1,2-e][1,4]oxazapine series has the following structural formula:

[0103]

[0104] Its preparation process specifically includes the following steps:

[0105] Under argon atmosphere, 1.0 equivalent of 1-((3-(4-fluorophenyl)prop-2-yn-1-yl)oxy)-2-isocyanbenzene (1 g), 2.0 equivalent of p-methylphenylboronic acid (2a), 3.0 equivalent of manganese acetylacetonate as an oxidant, and 2.0 equivalent of silver carbonate as an additive were added to chlorobenzene (0.1 M). The reaction was carried out at 70 °C for 42 hours. The reaction process was monitored by TLC. After the reaction was completed, the product was concentrated under vacuum and purified by rapid column chromatography to obtain 12-(4-fluorophenyl)-2-methyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine (3 g), yield: 78%.

[0106] The test results are as follows:

[0107] 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.6 Hz, 1H), 7.72 – 7.68 (m, 1H), 7.39 – 7.31 (m, 2H), 7.25 – 7.18 (m, 4H), 7.11 (d, J = 7.2 Hz, 1H), 7.06 – 7.03(m, 1H), 7.01 (s, 1H), 4.92 (s, 2H), 2.37 (s, 3H).

[0108] 13 C NMR (100 MHz, CDCl3) δ 166.0, 163.1 (d, J = 248.1 Hz), 153.4, 145.5,143.4, 140.6, 140.0, 134.2, 133.4, 130.7 (d, J = 8.1 Hz), 129.1, 128.7, 128.4(d, J = 3.4 Hz), 128.0, 124.6, 121.9, 121.5 (d, J = 5.5 Hz), 115.9 (d, J = 21.6Hz), 68.4, 21.9.

[0109] 19 F NMR (376 MHz, CDCl3) δ -111.4.

[0110] HRMS (ESI) m / z: Calculated for C 23 H 16 FNO+ (M+H + ): 342.1299; Found: 342.1289.

[0111] This example mainly investigated the applicability of isonitriles with electron-withdrawing (fluorine) substrates at the para position. The results showed that the substrate could yield 3 g of 12-(4-fluorophenyl)-2-methyl-11H-benzo[b]indo[1,2-e][1,4]oxazapine in excellent yield.

[0112] Example 8

[0113] A 2-fluoro-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine series compound (3h) has the following structural formula:

[0114]

[0115] Its preparation process specifically includes the following steps:

[0116] Under argon atmosphere, 1.0 equivalent of 1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene (1a) and 2.0 equivalent of p-fluorophenylboronic acid (2b), 3.0 equivalent of manganese acetylacetonate as an oxidant and 2.0 equivalent of silver carbonate as an additive were added to chlorobenzene (0.1 M). The reaction was carried out at 70 °C for 40 hours. The reaction process was monitored by TLC. After the reaction was completed, the product was concentrated under vacuum and purified by rapid column chromatography to obtain the product 2-fluoro-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine series compounds (3h), yield: 48%.

[0117] The test results are as follows:

[0118] 1 H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 5.2, 8.0 Hz, 1H), 7.73– 7.70 (m,1H), 7.54 – 7.46 (m, 3H), 7.35 (d, J =8.0 Hz,2H), 7.23 – 7.20 (m, 2H), 7.07 –7.03 (m, 1H), 6.98 (d, J = 8.8 Hz, 2H), 4.97 (s, 2H).

[0119] 13 C NMR (100 MHz, CDCl3) δ 164.8, 164.7 (d, J= 247.3 Hz), 153.4, 145.5 (d, J = 9.1 Hz), 145.0, 139.8, 133.5, 132.5, 131.8, 129.7, 129.4 (d, J = 9.4 Hz), 128.8 (d, J = 6.3 Hz), 124.7, 122.8 (d, J = 9.4 Hz), 121.5, 113.5 (d, J = 22.8 Hz), 109.3 (d, J = 25.2 Hz), 68.3.

[0120] 19 F NMR (376 MHz, CDCl3) δ -110.0.

[0121] HRMS (ESI) m / z: Calculated for C 22 H 14 FNO + (M+H + ): 328.1132; Found: 328.1132.

[0122] This example mainly investigated the applicability of arylboronic acid as an electron-withdrawing (fluorine) substrate at the para position. The results showed that the substrate could yield 2-fluoro-12-phenyl-11H-benzo[b]indo[1,2-e][1,4]oxazapine 3h in good yield.

[0123] Example 9

[0124] A 2-(tert-butyl)-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine series compound (3i) has the following structural formula:

[0125]

[0126] Its preparation process specifically includes the following steps:

[0127] Under argon atmosphere, 1.0 equivalent of 1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene (1a), 2.0 equivalent of p-tert-butylphenylboronic acid (2c), 3.0 equivalent of manganese acetylacetonate as an oxidant, and 2.0 equivalent of silver carbonate as an additive were added to chlorobenzene (0.1 M). The reaction was carried out at 70 °C for 40 hours. The reaction process was monitored by TLC. After the reaction was completed, the product was concentrated under vacuum and purified by rapid column chromatography to obtain product 2-(tert-butyl)-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine (3i), yield: 65%.

[0128] The test results are as follows:

[0129] 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.6 Hz, 1H), 7.73– 7.70 (m, 1H), 7.53 -7.43 (m, 3H), 7.37 (d, J = 6.8 Hz, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.29 (s,1H), 7.22– 7.15 (m, 2H), 7.05– 7.02 (m, 1H), 4.94 (s, 2H), 1.32 (s, 9H).

[0130] 13 C NMR (100 MHz, CDCl3) δ 166.3, 154.0, 153.5, 146.8, 143.2, 140.1,134.3, 133.4, 132.5, 129.1, 129.0, 128.9, 128.8, 128.7, 124.5, 124.3, 121.5, 121.3, 118.5, 68.6, 35.3, 31.4.

[0131] HRMS (ESI) m / z: Calculated for C 26 H 23 NO + (M+H + ): 366.1851; Found: 366.1852.

[0132] This embodiment mainly investigates the applicability of arylboronic acid to a substrate with an electron-donating (tert-butyl) group at the para position. The results show that the substrate can give 2-(tert-butyl)-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine 3i in good yield.

[0133] Example 10

[0134] A 2-(methylthio)-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine (3j) has the following structural formula:

[0135]

[0136] Its preparation process specifically includes the following steps:

[0137] Under argon atmosphere, 1.0 equivalent of 1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene (1a), 2.0 equivalent of p-methylthiophenylboronic acid (2d), 3.0 equivalent of manganese acetylacetonate as an oxidant, and 2.0 equivalent of silver carbonate as an additive were added to chlorobenzene (0.1 M). The reaction was carried out at 70 °C for 42 hours. The reaction process was monitored by TLC. After the reaction was completed, the product was concentrated under vacuum and purified by rapid column chromatography to obtain product 2-(methylthio)-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine (3j), yield: 52%.

[0138] The test results are as follows:

[0139] 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.6 Hz, 1H), 7.71 – 7.69 (m, 1H), 7.53 – 7.43 (m, 3H), 7.35 (d, J = 6.8 Hz, 2H), 7.22 – 7.17 (m, 2H), 7.15 – 7.12(m, 2H), 7.04 – 7.02 (m, 1H), 4.95 (s, 2H), 2.49 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.6, 153.5, 145.9, 143.8, 141.7, 140.0, 133.6, 133.4, 132.1,129.4, 129.2, 128.9, 128.8, 124.6, 124.2, 121.9, 121.5, 119.4, 68.5, 15.8.HRMS (ESI) m / z: Calculated for C 23 H 17 SNO + (M+H + ): 356.1094; Found: 356.1104.

[0140] This example primarily investigates the applicability of a substrate with a phenyl borate at the para-electron-donating (methylthio) position. The results demonstrate that this substrate yields 2-(methylthio)-12-phenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine 3j in good yield.

[0141] Example 11

[0142] A 12-phenyl-2-(trimethylsilyl)-11H-benzo[b]indeno[1,2-e][1,4]oxazapine series compound (3k) has the following structural formula:

[0143]

[0144] Its preparation process specifically includes the following steps:

[0145] Under argon atmosphere, 1.0 equivalent of 1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene (1a), 2.0 equivalent of p-trimethylsilylphenylboronic acid (2e), 3.0 equivalent of manganese acetylacetonate as an oxidant, and 2.0 equivalent of silver carbonate as an additive were added to chlorobenzene (0.1 M). The reaction was carried out at 70 °C for 40 hours. The reaction process was monitored by TLC. After the reaction was completed, the product was concentrated under vacuum and purified by rapid column chromatography to obtain 12-phenyl-2-(trimethylsilyl)-11H-benzo[b]indeno[1,2-e][1,4]oxazapine (3k), with a yield of 66%.

[0146] The test results are as follows:

[0147] 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J= 7.2 Hz, 1H), 7.74 – 7.72 (m, 1H), 7.55 – 7.46 (m, 4H), 7.40 – 7.36 (m, 3H), 7.23 – 7.18 (m, 2H), 7.06 – 7.03(m, 1H), 4.96 (s, 2H), 0.27 (s, 9H).

[0148] 13 C NMR (100 MHz, CDCl3) δ 166.4, 153.6, 147.1, 143.5, 142.3, 140.1,137.5, 133.5, 132.9, 132.4, 129.2, 129.1, 128.9, 128.7, 128.5, 125.3, 124.6,121.5, 120.8, 68.6, 1.0.

[0149] HRMS (ESI) m / z: Calculated for C 25 H 23 NOSi + (M+H + ): 382.1632; Found: 382.1622.

[0150] This example mainly investigates the applicability of a substrate with a phenyl borate para-electron-donating group (trimethylsilyl). The results show that the substrate can give 12-phenyl-2-(trimethylsilyl)-11H-benzo[b]indeno[1,2-e][1,4]oxazapine 3k in good yield.

[0151] Example 12

[0152] A N,N,12-triphenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazacycloheptane-2-amine (3l) has the following structural formula:

[0153]

[0154] Its preparation process specifically includes the following steps:

[0155] Under argon atmosphere, 1.0 equivalent of 1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene (1a), 2.0 equivalent of p-methylphenylboronic acid (2f), 3.0 equivalent of manganese acetylacetonate as oxidant, and 2.0 equivalent of silver carbonate as additive were added to chlorobenzene (0.1M). The reaction was carried out at 70 °C for 40 hours. The reaction process was monitored by TLC. After the reaction was completed, the mixture was concentrated under vacuum and purified by rapid column chromatography to obtain product N, N,12-triphenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazacycloheptane-2-amine (3l), with a yield of 50%.

[0156] The test results are as follows:

[0157] 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 1H), 7.69 (dd, J = 7.1, 2.3Hz, 1H), 7.44 – 7.35 (m, 3H), 7.28 – 7.21 (m, 6H), 7.20 – 7.15 (m, 2H), 7.12(d, J = 7.6 Hz, 4H), 7.05 – 7.00 (m, 4H), 6.92 (dd, J = 8.0, 1.9 Hz, 1H), 4.95(s, 2H).

[0158] 13 C NMR (100 MHz, CDCl3) δ 165.6, 153.4, 150.3, 147.4, 145.6, 144.5,140.2, 137.4, 133.2, 132.1, 130.3, 129.5, 129.3, 129.0, 128.8, 128.7, 128.6,124.7, 124.6, 123.4, 122.6, 121.5, 116.9, 68.7.

[0159] HRMS (ESI) m / z: Calculated for C 34 H 24 N2O + (M+H + ): 477.1960; Found: 477.1961.

[0160] This embodiment mainly investigated the applicability of electron-donating (N,N-diphenyl)phenylboronic acid substrates. The results showed that the substrate could yield N,N,12-triphenyl-11H-benzo[b]indeno[1,2-e][1,4]oxazacycloheptane-2-amine 3l in good yield.

[0161] Example 13

[0162] Bioactivity tests of compounds 3e and 3h prepared in Examples 5 and 8, respectively, using the CCK-8 assay, were performed on ovarian cancer cells A2780, nasopharyngeal cancer cells C666, and mouse colon cancer cells CT26. The results showed that both compounds 3e and 3h exhibited significant bioactivity, with corresponding IC50 values ​​of [missing information]. 50 The specific values ​​are shown in Table 1:

[0163] Table 1. Half-maximal inhibitory concentrations (IC50) of compounds 3e, 3h, and the control (cisplatin) against cancer cells.

[0164]

[0165] Based on the data in Table 1 above, it is clear that the novel compounds obtained using the preparation method provided in this application exhibit good inhibitory effects on ovarian cancer cells A2780, nasopharyngeal cancer cells C666, and mouse colon cancer cells CT26. The results are similar to those of the control (cisplatin), with compound 3h showing a slightly better inhibitory effect than the control (cisplatin). This indicates that compounds 3e and 3h in this application have promising applications in the preparation of drugs for ovarian cancer, nasopharyngeal carcinoma, and colon cancer.

[0166] The embodiments of this application have been described above. Specific examples have been used to illustrate the principles and implementation methods of this application. The description of the above embodiments is only for the purpose of helping to understand the core ideas of this application. However, this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A 12-aryl-11H-benzo[b]indo[1,2-e][1,4]oxazapine compound, characterized in that, Its structure is shown in Equation I: Equation I; in, R 1 Selected from one of hydrogen, methyl, trifluoromethyl, methoxy, fluorine, chlorine and bromine; R 2 It is selected from one of hydrogen, methyl, methoxy, tert-butyl, nitro, fluorine, chlorine and bromine; R 3 It is selected from one of hydrogen, methyl, methoxy, isopropyl, tert-butyl, nitro, trifluoromethyl, hydroxy, trimethylsilyl, methylthio, fluorine, chlorine and bromine.

2. The 12-aryl-11H-benzo[b]indo[1,2-e][1,4]oxazapine compound according to claim 1, characterized in that, The 12-aryl-11H-benzo[b]indeno[1,2-e][1,4]oxazapine compound is one of the compounds shown in the following structural formulas: 。 3. The method for preparing the 12-aryl-11H-benzo[b]indo[1,2-e][1,4]oxazapine compound according to any one of claims 1-2, characterized in that, Includes the following steps: Under a protective gas atmosphere, using compounds of formula II and formula III as reaction substrates, solvents, oxidants and additives were added and heated to obtain the 12-aryl-11H-benzo[b]indo[1,2-e][1,4]oxazapine compound; The structural formulas of compounds with formula II and compounds with formula III are shown below: Formula II; Formula III.

4. The preparation method according to claim 3, characterized in that, The compounds of Formula II are selected from 1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene, 2-isocyano-4-methoxy-1-((3-phenylprop-2-yn-1-yl)oxy)benzene, 2-isocyano-4-methyl-1-((3-phenylprop-2-yn-1-yl)oxy)benzene, 4-chloro-2-isocyano-1-((3-phenylprop-2-yn-1-yl)oxy)benzene, 2-isocyano-1-((3-phenylprop-2-yn-1-yl)oxy)4-trifluoromethyl)benzene, 4-bromo-2-isocyano-1-(( At least one of the following: 3-phenylprop-2-yn-1-yl)oxy)benzene, 4-bromo-1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene, 4-chloro-1-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene, 1-isocyano-2-((3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)oxy)benzene, 1-bromo-3-isocyano-2-((3-phenylprop-2-yn-1-yl)oxy)benzene and 2-isocyano-1-methyl-3-((3-phenylprop-2-yn-1-yl)oxy)benzene; The compound of Formula III is selected from at least one of 4-methylphenylboronic acid, 4-tert-butylphenylboronic acid, 4-methoxyphenylboronic acid, 4-methylthiophenylboronic acid, 4-fluorophenylboronic acid, 4-trimethylsilylphenylboronic acid, N,N-diphenylaminophenylboronic acid, 4-iodophenylboronic acid, 4-bromophenylboronic acid, 4-chlorophenylboronic acid, 4-fluorophenylboronic acid, 4-trifluoromethylphenylboronic acid, and phenylboronic acid.

5. The preparation method according to claim 4, characterized in that, The oxidant is one of manganese acetylacetone and manganese acetate; The additive is silver carbonate.

6. The preparation method according to claim 5, characterized in that, The molar ratio of the compound of Formula II, the compound of Formula III, the oxidant and the additive is 0.9~1.1:1.8~2.2:2.7~3.3:1.8~2.

2.

7. The preparation method according to claim 3, characterized in that, The solvent is at least one selected from dichloroethane, 1,4-dioxane, toluene, chlorobenzene, acetone, chloroform, and diethyl ether. The heating reaction temperature is 60 ℃~80 ℃, and the heating reaction time is 36 h~48 h.

8. The use of the 12-aryl-11H-benzo[b]indo[1,2-e][1,4]oxazapine compound according to any one of claims 1-2 in the preparation of a medicament for the prevention or treatment of cancer.

9. The application according to claim 8, characterized in that, The cancers mentioned include ovarian cancer, nasopharyngeal cancer, or colon cancer.

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