A fused ring diimide derivative, a method for preparing the same and use thereof

Abstract

The present application provides a fused ring diimide derivative, which has a chemical structure described in formula I. The present application also provides a preparation method thereof. The fused ring diimide derivative of the present application has excellent anti-tumor activity, and the anti-proliferation activity on various cancer cells is significantly better than that of similar compounds.

Description

TECHNICAL FIELD

[0001] The present application relates to a fused ring diimide derivative, its preparation method and use, belonging to the field of medicinal chemistry. BACKGROUND

[0002] Diimide compounds are an important class of substances in the field of medicinal chemistry, and have many pharmacological activities of interest.

[0003] When diimide is further fused with some fused rings, a unique planar structure can be formed, the molecular volume is greatly reduced, and it can be embedded between the base pairs of DNA double helix, causing the DNA double helix to unwind, thus having unique application value for cell proliferative diseases such as cancer. The fused ring fused with diimide can be various fused rings with conjugated unsaturated structure, which can be carbocyclic or heterocyclic, such as naphthalene, anthracene, pyridine carbazole, etc. There are many reports of antitumor activity of many of these compounds, but few compounds have entered the clinical stage.

[0004] Amonofide is a representative compound among them, and its molecular structure is fused with diimide ring to form a planar structure, which is reported to have cytotoxic activity against colon cancer, lung cancer, gastric cancer, esophageal cancer, leukemia and other cancer cells. Antisoma company pushed aminofide to the clinical III stage for the treatment of acute myeloid leukemia, but ultimately terminated the development because of poor efficacy.

[0005]

[0006] Currently, other fused ring diimide compounds are still being researched in the industry in order to obtain more optimal potential active drugs, but it is still difficult to find compounds with stronger activity than aminofide. SUMMARY

[0007] The purpose of the present application is to provide a fused ring diimide compound with more optimal properties.

[0008] In a first aspect, the present application provides a compound having a fused ring diimide structure shown in formula I,

[0009]

[0010] In formula I,

[0011] A is a fused ring, which is fused with diimide through 2-3 atoms, and A is optionally substituted;

[0012] m or n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0013] R1, R2, or R3is selected from the group consisting of nitrogen, oxygen, or sulfur; when R1, R2, or R3is nitrogen or sulfur, R1, R2, or R3may optionally be substituted, and R1and R2may optionally be taken together to form a ring.

[0014] In some embodiments, in the formula I, when R1, R2, or R3is nitrogen, R1, R2, or R3may optionally be further substituted.

[0015] In some embodiments, in the formula I, when R1, R2, or R3is sulfur, R1, R2, or R3may optionally be oxidized to form a sulfone or a sulfoxide.

[0016] In some embodiments, in the formula I, A is a fused ring having a conjugated unsaturated structure.

[0017] In some embodiments, in the formula I, A is a fused ring formed by a carbocycle and a carbocycle or a fused ring formed by a carbocycle and a heterocycle.

[0018] In some embodiments, A is fused to the imide through 2-3 atoms to form a planar structure. Preferably, A is fused to the imide through 2-3 carbon atoms to form a planar structure.

[0019] In some embodiments, in the formula I, A is a bicyclic fused ring, a tricyclic fused ring, a tetracyclic fused ring, or a pentacyclic fused ring.

[0020] In some embodiments, in the formula I, A is selected from the group consisting of naphthalene, anthracene, phenanthrene, tetracene, pyrene, perylene, quinoline, acridine, pyrrolopyridine, pyridocarbazole, naphtho[1,2-b]furan, benzimidazole, or benzoimidazo[1,2-c]quinoline. Preferably, A is selected from the group consisting of naphthalene, anthracene, phenanthrene, pyrene, perylene, or naphtho[1,2-b]furan.

[0021] In some embodiments, in the formula I, A can optionally be substituted with a group selected from the group consisting of alkyl, alkoxy, nitro, cyano, hydroxy, amino, imino, tertiary amine, or halogen; wherein the alkyl and alkoxy in the substituents can optionally be further substituted with hydroxy or halogen. Preferably, A is substituted with C1-C5 alkyl, C1-C5 alkoxy, nitro, cyano, imino, tertiary amine, or halogen.

[0022] In some embodiments, in the formula I, m or n is 1, 2, 3, 4, 5, or 6.

[0023] In some embodiments, in the formula I, R1and R2are oxygen or sulfur.

[0024] In some embodiments, in the formula I, R1and / or R2are nitrogen.

[0025] In some embodiments, in the formula I, R1and R2are nitrogen.

[0026] In some embodiments, in the formula I, R1and / or R2is nitrogen, and R1and / or R2is substituted with a group selected from alkyl, alkoxy, imino, tertiary amine, nitro, or nitroso; wherein the alkyl and alkoxy in the substituent group are optionally further substituted with hydroxyl or halogen. Preferably, R1and / or R2is substituted with a group selected from C1-C5 alkyl, C1-C5 alkoxy, imino, tertiary amine, nitro, or nitroso.

[0027] In some embodiments, in the formula I, R1is nitrogen, and is substituted with a group selected from alkyl, alkoxy, tertiary amine, nitro. Preferably, R1is substituted with a group selected from C1-C5 alkyl, C1-C5 alkoxy, tertiary amine, nitro.

[0028] In some embodiments, in the formula I, R2is nitrogen, and is substituted with a group selected from alkyl, alkoxy. Preferably, R2is substituted with a group selected from C1-C5 alkyl, C1-C5 alkoxy.

[0029] In some embodiments, in the formula I, R1and R2together form a ring. Preferably, R1and R2together form a six-membered ring.

[0030] In some embodiments, in the formula I, R3is oxygen or sulfur, and R3is substituted with a group selected from alkyl, haloalkyl, alkoxy, alkoxyalkyl, nitro, or nitroso; wherein the alkyl, alkoxy, alkoxyalkyl in the substituent group are optionally further substituted with hydroxyl or halogen. Preferably, R3is substituted with a group selected from C1-C5 alkyl, haloC1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkoxyC1-C5 alkyl, nitro, or nitroso.

[0031] In some embodiments, in the formula I, R3is nitrogen, and R3is mono- or di-substituted with a group selected from alkyl, haloalkyl, alkoxy, alkoxyalkyl, nitro, nitroso. Preferably, R3is mono- or di-substituted with a group selected from C1-C5 alkyl, haloC1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkoxyC1-C5 alkyl, nitro, nitroso.

[0032] In some embodiments, in the formula I, R3is nitrogen, and R3is di-substituted with two identical or different groups selected from C1-C5 alkyl, haloC1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkoxyC1-C5 alkyl, nitro, nitroso.

[0033] In some examples, R1, R2 and R3 are all nitrogen in the formula I. Preferably, R3 is mono- or di-substituted with two same or different groups selected from the group consisting of C1-C5 alkyl, halo-C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkoxy-C1-C5 alkyl, nitro, nitroso. When R1, R2 and R3 are all nitrogen and R3 is mono- or di-substituted, certain preferred compounds of formula I have more optimal properties, for example, have stronger activity.

[0034] In some examples, R1, R2 and R3 are all nitrogen in the formula I. Preferably, R3 is mono- or di-substituted with two same or different groups selected from the group consisting of C1-C5 alkyl, halo-C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkoxy-C1-C5 alkyl, nitro, nitroso. When R1, R2 and R3 are all nitrogen and R3 is mono- or di-substituted, certain preferred compounds of formula I have more optimal properties, for example, have stronger activity.

[0035] In some examples, the aforementioned C1-C5 alkyl includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, etc., and the halogen includes fluorine, chlorine, bromine, iodine.

[0036] In a second aspect, the present application provides a method for preparing a compound of formula I, comprising:

[0037]

[0038] reacting I-M7 with I-M8 to form I, wherein A, m, n, R1, R2, R3 are as previously described.

[0039] In some examples, the reaction of I-M7 with I-M8 is carried out in the presence of a base.

[0040] In some examples, the base is selected from the group consisting of sodium hydroxide, potassium carbonate, cesium carbonate or sodium phosphate.

[0041] The compound of formula I-M7 and the compound of formula I-M8 can be obtained commercially or can be chemically synthesized.

[0042] In some examples, the I-M7 can be prepared by the following method:

[0043]

[0044] reacting I-M4 with I-M5 to form I-M6, and then treating I-M6 in the presence of an acid to obtain I-M7, wherein A, m, n, R1, R2 are as previously described.

[0045] The compound of formula I-M4 can be obtained commercially or by chemical synthesis.

[0046] In some examples, the I-M4 can be prepared by the following method:

[0047]

[0048] The I-M4 can be prepared by reacting I-M1 with I-M2 to form I-M3, and then hydrogenating I-M3 to form I-M4; wherein X is halogen, m, n, R1, R2 are as described above.

[0049] In a third aspect, the present application provides a use of the compound of formula I as described above in the preparation of a medicament for treating a cell proliferative disease.

[0050] In some examples, the cell proliferative disease is cancer.

[0051] In a fourth aspect, the present application provides a method for treating a cell proliferative disease, which comprises administering to a subject in need thereof a therapeutically effective amount of the compound of formula I as described above.

[0052] In some examples, the cell proliferative disease is cancer.

[0053] The fused ring diimide derivative provided by the present application is a novel compound, and research has found that it has excellent anti-tumor activity, and has a significant inhibitory effect on human colon cancer cells, lung cancer cells and leukemia cells, and the anti-tumor activity is significantly better than that of similar compounds, and has a broad application prospect. DETAILED DESCRIPTION

[0054] The present application is further described below by way of examples, and some preferred compounds are exemplified. It should be noted that the examples are not a limitation on the compounds and technical effects of the present application.

[0055] Example 1: Compound I-01

[0056] Reaction formula:

[0057]

[0058] According to the reaction formula, the compound I-01 is prepared, and the specific process is as follows:

[0059] 1.1 Preparation of intermediate I-01-M3: Compound I-01-M2 (3.20 g, 20 mmol) was dissolved in 30 mL of DMF, then K2CO3 (4.16 g, 30 mmol), NaI (3.00 g, 20 mmol) and compound I-01-M1 (5.70 g, 20 mmol) were added successively to the mixture, and the reaction was carried out at 30 °C overnight. After the reaction was completed, purified water (120 ml) was added to the reaction solution, which was extracted with ethyl acetate (180 ml) three times, dried over anhydrous MgSO4, filtered, and the mother liquor was concentrated and purified by column chromatography to obtain intermediate I-01-M3 (4.46 g, 12.2 mmol) with a yield of 61%.

[0060] 1.2 Preparation of intermediate I-01-M4: Intermediate I-01-M3 (4.46 g, 12.2 mmol) was dissolved in methanol (20 mL), 10% Pd / C (0.3 g) was added, and the reaction was carried out under hydrogen replacement for 3 times at normal pressure overnight. The reaction solution was filtered through diatomite and concentrated to obtain intermediate I-01-M4 (2.80 g, 12.1 mmol) as a colorless oil with a yield of 99.2%.

[0061] 1.3 Preparation of intermediate I-01-M6: Intermediate I-01-M4 (2.80 g, 12.1 mmol), ethanol (55 ml) and compound I-01-M5 (2.40 g, 12.1 mmol) were successively added to a reaction bottle, which was heated to 80 °C for 2 hours, cooled, and concentrated. The reaction solution was purified by column chromatography to obtain intermediate I-01-M6 (3.66 g, 8.9 mmol) with a yield of 73.6%.

[0062] 1.4 Preparation of intermediate I-01-M7: Intermediate I-01-M6 (3.66 g, 8.9 mmol) was dissolved in 4% hydrogen chloride ethyl acetate solution (50 ml), and the reaction was carried out at room temperature overnight. The reaction solution was filtered and dried to obtain intermediate I-01-M7 (2.58 g, 8.3 mmol) with a yield of 93.3%.

[0063] 1.5 Synthesis of compound I-01: Compound I-01-M8 (2.50 g, 9 mmol), dichloromethane (27 ml) and triethylamine (2.02 g, 20 mmol) were successively added to a reaction bottle, which was cooled to 0 °C. Intermediate I-01-M7 (2.58 g, 8.3 mmol) was added in batches, and the reaction was carried out at 0 °C overnight. The reaction solution was washed with water (15 ml), dried over anhydrous MgSO4, filtered, and the mother liquor was concentrated and purified by column chromatography to obtain compound I-01 (2.07 g, 4.6 mmol) with a yield of 55.4%. The product was identified: 1H-NMR (400 MHz, d6-DMSO) δ: 1.38-1.52 (4H, m), 2.55 (2H, t, J = 6.8 Hz), 2.78 (2H, t, J = 6.8 Hz), 3.18 (2H, t, J = 6.5 Hz), 3.26 (2H, t, J = 6.5 Hz), 5.18 (4H, s), 6.11 (1H, m), 7.52 (2H, m), 7.87 (2H, dd, J = 2.3, 8.1 Hz), 7.93 (2H, dd, J = 2.3, 8.0 Hz).

[0064] Example 2: Compound I-02

[0065]

[0066] Referring to the method of Example 1, compound I-02 was prepared, and the product was identified: 1 H-NMR (400 MHz, d6-DMSO) δ: 1.38-1.52 (4H, m), 2.55 (2H, t, J = 6.8 Hz), 2.78 (2H, t, J = 6.8 Hz), 3.18 (2H, t, J = 6.5 Hz), 3.26 (2H, t, J = 6.5 Hz), 5.18 (4H, s), 6.11 (1H, m), 7.52 (2H, m), 7.87 (2H, dd, J = 2.3, 8.1 Hz), 7.93 (2H, dd, J = 2.3, 8.0 Hz).

[0067] Example 3: Compound I-03

[0068]

[0069] Compound I-03 was prepared according to the reaction formula, and the specific method was as follows:

[0070] 3.1 Synthesis of intermediate I-03-M3: Compound I-03-M2 (2.92 g, 20 mmol) was dissolved in 30 mL of DMF, and then K2CO3 (4.16 g, 30 mmol), NaI (3.00 g, 20 mmol), compound I-03-M1 (5.14 g, 20 mmol) were sequentially added to the mixture, and the reaction was carried out at 30°C overnight. After the reaction was completed, purified water (120 ml) was added to the reaction solution, extracted with ethyl acetate (180 ml) for 3 times, dried with anhydrous MgSO4, filtered, concentrated the mother liquor, and purified by column chromatography to obtain intermediate I-03-M3 (3.75 g, 11.6 mmol), with a yield of 58%.

[0071] 3.2 Synthesis of intermediate I-03-M4: Intermediate I-03-M3 (3.75 g, 11.6 mmol) was dissolved in methanol (20 mL), 10% Pd / C (0.3 g) was added, hydrogen was replaced for 3 times, the reaction was carried out at normal pressure overnight, diatomite was filtered, the mother liquor was concentrated, and intermediate I-03-M4 (2.19 g, 11.6 mmol) in the form of colorless oil was obtained in a yield of 100%.

[0072] 3.3 Synthesis of intermediate I-03-M6: Intermediate I-03-M4 (2.19 g, 11.6 mmol), ethanol (50 ml), and compound I-03-M5 (2.82 g, 11.6 mmol) were sequentially added to a reaction bottle, the reaction was carried out at 80°C for 2 hours, the reaction liquid was cooled and concentrated, and intermediate I-03-M6 (3.85 g, 9.3 mmol) was obtained by column chromatography purification in a yield of 80.2%.

[0073] 3.4 Synthesis of intermediate I-03-M7: Intermediate I-03-M6 (3.85 g, 9.3 mmol) was dissolved in 4% hydrogen chloride ethyl acetate solution (60 ml), the reaction was carried out at room temperature overnight, filtration and drying were performed, and intermediate I-03-M7 (2.80 g, 8.9 mmol) was obtained in a yield of 95.7%.

[0074] 3.5 Synthesis of compound I-03: Compound I-03-M8 (2.73 g, 10 mmol), dichloromethane (35 ml), and triethylamine (2.02 g, 20 mmol) were sequentially added to a reaction bottle, the reaction was carried out at 0°C overnight, the reaction liquid was washed with water (25 ml), dried with anhydrous MgSO4, filtered, and concentrated, and compound I-03 (2.60 g, 5.8 mmol) was obtained by column chromatography purification in a yield of 65.2%. The product was identified: 1 H-NMR (400 MHz, d6-DMSO) δ: 2.85 (2H, t, J = 6.8 Hz), 3.18 (2H, t, J = 6.8 Hz), 3.35 (2H, t, J = 6.5 Hz), 3.80 (2H, t, J = 6.5 Hz), 4.53 (2H, s), 6.31 (1H, m), 7.78 (1H, m), 8.22 (1H, dd, J = 2.3, 8.1 Hz), 8.30 (1H, dd, J = 2.3, 8.1 Hz), 8.78 (1H, d, J = 2.3 Hz), 8.95 (1H, d, J = 2.3 Hz).

[0075] Example 4: Compound I-04

[0076]

[0077] Referring to the method of Example 3, compound I-04 was prepared, and the product was identified: 1 H-NMR (400 MHz, d6-DMSO) δ: 1.37-1.53 (4H, m), 2.53 (2H, t, J = 6.8 Hz), 2.79 (2H, t, J = 6.8 Hz), 3.20 (2H, t, J = 6.5 Hz), 3.29 (2H, t, J = 6.5 Hz), 3.38 (2H, t, J = 6.5 Hz), 3.62 (2H, t, J = 6.5 Hz), 6.21 (1H, m), 7.50 (2H, m), 7.91 (2H, dd, J = 2.3, 8.0 Hz), 7.98 (2H, dd, J = 2.3, 8.0 Hz).

[0078] Example 5: Compound I-05

[0079]

[0080] Referring to the method of Example 3, compound I-05 was prepared, and the product was identified: 1 H-NMR (400 MHz, d6-DMSO) δ: 1.37-1.53 (4H, m), 2.53 (2H, t, J = 6.8 Hz), 2.79 (2H, t, J = 6.8 Hz), 3.20 (2H, t, J = 6.5 Hz), 3.29 (2H, t, J = 6.5 Hz), 3.38 (2H, t, J = 6.5 Hz), 3.62 (2H, t, J = 6.5 Hz), 6.21 (1H, m), 7.50 (2H, m), 7.91 (2H, dd, J = 2.3, 8.0 Hz), 7.98 (2H, dd, J = 2.3, 8.0 Hz).

[0081] Example 6: Compound I-06

[0082]

[0083] Referring to the method of Example 3, compound I-06 was prepared, and the product was identified: 1H-NMR (400 MHz, d6-DMSO) δ: 1.83 (2H, m), 2.48 (2H, t, J = 6.8 Hz), 2.68 (3H, s), 2.91 (6H, s), 3.12 (2H, t, J = 6.5 Hz), 4.25 (2H, s), 5.78 (1H, m), 6.21 (1H, m), 6.78 (1H, d, J = 8.0 Hz), 7.45 (1H, m), 7.77 (1H, d, J = 8.0 Hz), 7.85 (1H, dd, J = 2.3, 8.0 Hz), 7.95 (1H, dd, J = 2.3, 8.0 Hz).

[0084] Example 7: Compound I-07

[0085]

[0086] Compound I-07 was prepared according to the procedure of Example 3, and the product was identified: 1 H-NMR (400 MHz, d6-DMSO) δ: 1.23 (3H, t, J = 6.8 Hz), 1.45-1.75 (6H, m), 2.65 (3H, s), 3.06 (2H, t, J = 6.8 Hz), 3.15 (2H, q, J = 6.8 Hz), 3.25-3.38 (4H, m), 3.58 (2H, t, J = 6.5 Hz), 3.68 (3H, s), 6.01 (1H, m), 6.88 (1H, d, J = 2.3 Hz), 7.02 (1H, dd, J = 2.3, 8.0 Hz), 7.67 (1H, dd, J = 2.3, 8.0 Hz), 8.42 (1H, s), 8.49 (1H, s).

[0087] Example 8: Compound I-08

[0088]

[0089] Compound I-08 was prepared according to the procedure of Example 3, and the product was identified: 1 H-NMR (400 MHz, d6-DMSO) δ: 2.63 (6H, s), 3.22 (2H, t, J = 6.8 Hz), 3.36 (3H, s), 3.63 (2H, t, J = 6.5 Hz), 5.73 (2H, s), 6.03 (1H, m), 6.85 (1H, d, J = 2.3 Hz), 7.01 (1H, dd, J = 2.3, 8.0 Hz), 7.63 (1H, dd, J = 2.3, 8.0 Hz), 8.38 (1H, s), 8.51 (1H, s).

[0090] Example 9: Compound I-9

[0091]

[0092] Referring to the method of Example 3, compound I-09 was prepared, and the product was identified: 1 H-NMR (400 MHz, d6-DMSO) δ: 1.25-1.30 (4H, m), 1.45-1.53 (4H, m), 2.52 (2H, t, J = 6.8 Hz), 2.68 (6H, s), 3.08 (2H, t, J = 6.8 Hz), 4.51 (2H, s), 6.07 (1H, m), 7.30 (2H, m), 7.58 (1H, m), 7.86 (1H, dd, J = 2.3, 8.0 Hz), 7.95 (1H, dd, J = 2.3, 8.0 Hz), 8.03 (1H, dd, J = 2.3, 8.0 Hz), 8.20 (1H, dd, J = 2.3, 8.0 Hz), 8.62 (1H, s).

[0093] Example 10: Compound I-10

[0094]

[0095] Referring to the method of Example 3, compound I-10 was prepared, and the product was identified: 1 H-NMR (400 MHz, d6-DMSO) δ: 1.25-1.30 (4H, m), 1.45-1.53 (4H, m), 2.52 (2H, t, J = 6.8 Hz), 2.68 (6H, s), 3.08 (2H, t, J = 6.8 Hz), 4.51 (2H, s), 6.07 (1H, m), 7.30 (2H, m), 7.58 (1H, m), 7.86 (1H, dd, J = 2.3, 8.0 Hz), 7.95 (1H, dd, J = 2.3, 8.0 Hz), 8.03 (1H, dd, J = 2.3, 8.0 Hz), 8.20 (1H, dd, J = 2.3, 8.0 Hz), 8.62 (1H, s).

[0096] Example 11: Compound I-11

[0097]

[0098] Referring to the method of Example 3, compound I-11 was prepared, and the product was identified: 1H-NMR (400 MHz, d6-DMSO) δ: 1.42-1.53 (4H, m), 2.55 (2H, t, J = 6.8 Hz), 2.70 (3H, s), 2.88 (3H, s), 3.10 (2H, t, J = 6.8 Hz), 3.28 (3H, s), 3.58 (2H, t, J = 6.8 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.52 (2H, s), 7.33 (2H, m), 7.62 (1H, m), 7.88 (1H, dd, J = 2.3, 8.0 Hz), 8.02 (1H, dd, J = 2.3, 8.0 Hz), 8.09 (1H, dd, J = 2.3, 8.0 Hz), 8.22 (1H, dd, J = 2.3, 8.0 Hz).

[0099] Example 12: Compound I-12

[0100]

[0101] Referring to the method of Example 3, compound I-12 was prepared, and the product was identified: 1 H-NMR (400 MHz, d6-DMSO) δ: 1.23 (3H, t, J = 6.3 Hz), 1.42 (2H, m), 1.57 (2H, m), 2.61 (2H, t, J = 6.8 Hz), 2.70 (3H, s), 2.92 (2H, t, J = 6.3 Hz), 4.16 (2H, t, J = 6.7 Hz), 4.76 (2H, s), 7.52-7.65 (3H, m), 7.80 (1H, dd, J = 2.3, 8.0 Hz), 7.91 (1H, dd, J = 2.3, 8.1 Hz), 8.03 (1H, dd, J = 2.3, 8.2 Hz), 8.27 (1H, dd, J = 2.3, 8.1 Hz).

[0102] Example 13: Compound I-13

[0103]

[0104] Referring to the method of Example 3, compound I-13 was prepared, and the product was identified: 1H-NMR (400 MHz, d6-DMSO) δ: 1.43-1.55 (4H, m), 2.48 (2H, t, J = 6.8 Hz), 2.58 (3H, s), 2.62 (3H, s), 2.78 (3H, s), 3.12 (2H, t, J = 6.8 Hz), 3.18 (2H, t, J = 6.8 Hz), 4.42 (2H, s), 7.38 (2H, m), 7.65 (1H, m), 7.83 (1H, dd, J = 2.3, 8.0 Hz), 7.97 (1H, dd, J = 2.3, 8.0 Hz), 8.12 (1H, dd, J = 2.3, 8.0 Hz), 8.25 (1H, dd, J = 2.3, 8.0 Hz).

[0105] Example 14: Compound I-14

[0106]

[0107] Referring to the method of Example 3, compound I-14 was prepared, and the product was identified: 1 H-NMR (400 MHz, d6-DMSO) δ: 2.43 (6H, s), 2.60 (3H, s), 2.72-2.83 (4H, m), 3.12 (2H, t, J = 6.8 Hz), 3.18 (2H, t, J = 6.8 Hz), 3.25 (3H, s), 3.32 (2H, t, J = 6.8 Hz), 3.69 (2H, t, J = 6.8 Hz), 5.88 (1H, m), 7.68-7.78 (2H, m), 8.01 (1H, m), 8.12 (1H, dd, J = 2.3, 8.0 Hz), 8.36 (1H, s), 8.48 (1H, dd, J = 2.3, 8.0 Hz), 8.89 (1H, dd, J = 2.3, 8.0 Hz), 9.21 (1H, dd, J = 2.3, 8.0 Hz).

[0108] Example 15: Compound I-15

[0109]

[0110] Referring to the method of Example 3, compound I-15 was prepared, and the product was identified: 1H-NMR (400 MHz, d6-DMSO) δ: 1.28 (3H, t, J = 6.8 Hz), 2.68 (3H, s), 2.72-2.83 (4H, m), 3.12 (2H, q, J = 6.8 Hz), 3.30 (3H, s), 3.38 (2H, t, J = 6.8 Hz), 3.46 (2H, t, J = 6.8 Hz), 5.93 (1H, m), 7.65-7.72 (2H, m), 7.98 (1H, m), 8.10 (1H, dd, J = 2.3, 8.0 Hz), 8.33 (1H, s), 8.45 (1H, dd, J = 2.3, 8.0 Hz), 8.88 (1H, dd, J = 2.3, 8.0 Hz), 9.18 (1H, dd, J = 2.3, 8.0 Hz).

[0111] Example 16: Compound I-16

[0112]

[0113] Referring to the method of Example 3, Compound I-16 was prepared, and the product was identified: 1 H-NMR (400 MHz, d6-DMSO) δ: 1.42-1.58 (4H, m), 2.68 (3H, s), 3.02 (2H, t, J = 6.8 Hz), 3.18 (2H, t, J = 6.8 Hz), 3.33 (2H, t, J = 6.8 Hz), 3.98 (2H, t, J = 6.8 Hz), 7.73-7.82 (2H, m), 7.01 (1H, m), 8.12 (1H, dd, J = 2.3, 8.0 Hz), 8.33 (1H, s), 8.47 (1H, dd, J = 2.3, 8.0 Hz), 8.93 (1H, dd, J = 2.3, 8.0 Hz), 9.23 (1H, dd, J = 2.3, 8.0 Hz).

[0114] Example 17: Compound I-17

[0115]

[0116] Referring to the method of Example 3, Compound I-17 was prepared, and the product was identified: 1H-NMR (400 MHz, d6-DMSO) δ: 1.25-1.58 (8H, m), 2.42 (2H, t, J = 6.8 Hz), 2.66 (3H, s), 3.12 (2H, t, J = 6.8 Hz), 4.45 (2H, s), 5.98 (1H, m), 7.68 (1H, dd, J = 2.3, 8.0 Hz), 8.02-8.12 (2H, m), 8.35 (1H, s), 8.47 (1H, dd, J = 2.3, 8.0 Hz), 8.67 (1H, d, J = 2.3 Hz), 9.12 (1H, dd, J = 2.3, 8.0 Hz).

[0117] Example 18: Compound I-18

[0118]

[0119] Referring to the method of Example 3, Compound I-18 was prepared, and the product was identified by1H-NMR (400 MHz, d6-DMSO) δ: 1.43 (9H, s), 1.69 (2H, m), 2.45-2.76 (6H, m), 3.01-3.11 (4H, m), 3.25 (2H, t, J = 6.8 Hz), 7.32-7.45 (3H, m), 7.80-7.88 (4H, m), 8.02 (1H, d, J = 8.1 Hz), 8.10 (1H, d, J = 8.2 Hz).

[0120] Example 19: Compound I-19

[0121]

[0122] Referring to the method of Example 3, Compound I-19 was prepared, and the product was identified by1H-NMR (400 MHz, d6-DMSO) δ: 1.43 (9H, s), 1.69 (2H, m), 2.45-2.76 (6H, m), 3.01-3.11 (4H, m), 3.25 (2H, t, J = 6.8 Hz), 7.32-7.45 (3H, m), 7.80-7.88 (4H, m), 8.02 (1H, d, J = 8.1 Hz), 8.10 (1H, d, J = 8.2 Hz). 1 H-NMR (400 MHz, d6-DMSO) δ: 1.31 (6H, d, J = 6.8 Hz), 1.43-1.55 (4H, m), 2.92 (2H, t, J = 6.8 Hz), 3.32 (2H, t, J = 6.8 Hz), 5.45 (2H, s), 6.38 (1H, m), 6.68 (1H, d, J = 3.2 Hz), 7.43 (1H, d, J = 3.2 Hz), 7.48 (1H, d, J = 8.0 Hz), 7.77 (1H, dd, J = 2.3, 8.0 Hz), 7.86 (1H, dd, J = 2.3, 8.0 Hz), 7.93 (1H, s).

[0123] Example 20: Compound I-20

[0124]

[0125] Referring to the method of Example 3, compound I-20 was prepared, and the product was identified: 1 H-NMR (400 MHz, d6-DMSO) δ: 1.49-1.58 (4H, m), 2.52 (2H, t, J = 6.8 Hz), 2.78 (2H, t, J = 6.8 Hz), 3.18 (2H, t, J = 6.8 Hz), 3.32 (3H, s) 3.45 (2H, t, J = 6.8 Hz), 3.55 (3H, s), 5.88 (1H, m), 6.38 (1H, m), 6.65 (1H, d, J = 3.2 Hz), 7.42 (1H, d, J = 3.2 Hz), 7.53 (1H, d, J = 8.0 Hz), 7.69 (1H, dd, J = 2.3, 8.0 Hz), 7.83 (1H, dd, J = 2.3, 8.0 Hz), 7.88 (1H, s).

[0126] Example 21: Compound I-21

[0127]

[0128] Referring to the method of Example 3, compound I-21 was prepared, and the product was identified: 1 H-NMR (400 MHz, d6-DMSO) δ: 1.49-1.58 (4H, m), 2.52 (2H, t, J = 6.8 Hz), 2.78 (2H, t, J = 6.8 Hz), 3.18 (2H, t, J = 6.8 Hz), 3.32 (3H, s) 3.45 (2H, t, J = 6.8 Hz), 3.55 (3H, s), 5.88 (1H, m), 6.38 (1H, m), 6.65 (1H, d, J = 3.2 Hz), 7.42 (1H, d, J = 3.2 Hz), 7.53 (1H, d, J = 8.0 Hz), 7.69 (1H, dd, J = 2.3, 8.0 Hz), 7.83 (1H, dd, J = 2.3, 8.0 Hz), 7.88 (1H, s).

[0129] Example 22: Study of the Anti-tumor Activity of the Compound of Formula I

[0130] Purpose of the test: to test the anti-proliferative activity of the compounds of the application on various tumor cells.

[0131] Test compounds: compounds I-01, I-02, I-03, I-04, I-05, I-08, I-10, I-12, I-15, I-17, I-18, I-20 of the present application; positive drug amonofide; and comparative compounds 1d, 1. Compound 1d is "1d" in the literature Journal of Cancer Molecules, 2010, 5(2): p 41-47, and compound 1 is "compond 1" in the literature Journal of Experimental Therapeutics and Oncology, 2005, 5: p 15-22, both of which are prepared according to the literature method; and positive drug amonofide is from the market.

[0132]

[0133] Test cells: human colon cancer cells (HT-29, COLO 205), human lung cancer cells (NCI-H460, A549), human leukemia cells (HL-60, U-937).

[0134] Test method: Each tumor cell is operated. The cells are cultured at 37°C in the culture medium for 24 hours for standby. The cells in the exponential growth phase are taken, treated with trypsin to prepare a cell suspension, the cell suspension is centrifuged, and then the cell precipitate is resuspended in a small amount of fresh culture medium as a stock cell solution. The stock solution is diluted to the required cell concentration. Each cell concentration is shown in Table 1:

[0135] Table 1: Concentration of each tumor cell

[0136]

[0137]

[0138] Take a 96-well plate, set up a blank control group, a cell control group, and a compound group. The blank control group is added with only 10% PBS per well, and the cell control group and the compound group are added with 100 μL of the above-mentioned concentration of cells per well, and filled with 200 μL of 10% PBS. The plate is placed in an incubator overnight. The compound group is added with 100 μL of each test compound at different dilution concentrations, and the compound dilution concentrations are shown in Table 2.

[0139] Table 2: Dilution concentration of test compound

[0140] SEQ ID NO Concentration of compound (μM) 1 2 3 4 5 6 7 8 1 200 2 66.7 3 22.2 4 7.41 5 2.47 6 0.823 7 0.274 8 0.0914

[0141] After the completion of the addition, the plate was placed in an incubator for 96 hours, 22 μL of Alarmblue (SIGMA R7017) was added to each well, and the plate was returned to the incubator for another 4 hours. After removal, the plate was shaken for 10 seconds, and the fluorescence value of each well was recorded at 530 / 590 nm.

[0142] The above operation was repeated 3 times.

[0143] The Prism 7 software was used to calculate the IC 50 value of each test compound. The IC 50 values were divided into different grades according to their magnitude, i.e., SS: < 1 μM; S: 1-5 μM; A: 5-10 μM; B: 11-20 μM; C: 21-50 μM; D: 51-100 μM; E: > 100 μM. The main results are shown in Table 3:

[0144] Table 3: IC 50 grade of the inhibitory effect of the compounds on tumor cells

[0145]

[0146]

[0147] From the test results, it can be seen that the anti-tumor activity of the compounds of the present application is better than that of the positive drug, amonofide, as a whole. By comparing the compounds of the present application with similar compounds, it can be seen that the inhibitory activity of the compounds of the present application on tumor cells is significantly better than that of compound 1d and compound 1 as a whole. In particular, for colon cancer cells, the activity of some preferred compounds (e.g., compounds I-03, I-04) is more than 50 times that of similar compounds.

[0148] Compound 1d and compound 1 are both structural modifications of amonofide, and the modification is made at the right alkylamino position of amonofide, but in the test case of the present application, the overall anti-tumor activity is not as good as that of amonofide. The difference in activity between the compound of formula I of the present application and compound 1d and compound 1 suggests that in the modification of the right alkylamino of amonofide, the introduction of a heteroatom (R1) and the separation of the heteroatom (R1) and the heteroatom (R2) connected to the right carbonyl group with a carbon chain or a carbon ring are very important for the improvement of activity.

[0149] The present application has been described in detail above with general description and specific embodiments. Modifications or improvements can be made to the present application by those skilled in the art on the basis of the present application, and these modifications or improvements made without departing from the spirit of the present application are all within the scope of the present application.

Claims

1. A fused ring diimide derivative of the formula I, ###0001### wherein A is selected from naphthalene, anthracene, phenanthrene, naphthacene, tetracene, pyrene, perylene, quinoline, acridine, pyrrolopyridine, pyridocarbazole, naphtho[1,2-b]furan, benzimidazole or benzoimidazo[1,2-c]quinoline, which is fused to the diimide via 2-3 atoms, A is optionally substituted with C1-C5 alkyl, C1-C5 alkoxy, nitro, cyano, amino or halogen; m or n is 1, 2, 3, 4, 5 or 6; R1 or R2 is selected from nitrogen, oxygen or sulfur; when R1 or R2 is nitrogen, R1 or R2 is optionally substituted with C1-C5 alkyl, C1-C5 alkoxy, nitro or nitroso; or R1 and R2 optionally together form a six-membered ring; R3 is selected from nitrogen mono- or disubstituted with C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy, C1-C5 alkoxyC1-C5 alkyl, nitro or nitroso. ， 2. The fused ring diimide derivative according to claim 1, wherein A is selected from naphthalene, anthracene, phenanthrene, pyrene, perylene or naphtho[1,2-b]furan in formula I.

3. The fused ring diimide derivative according to claim 1, wherein R1 or / and R2 is oxygen or sulfur in formula I.

4. The fused ring diimide derivative according to claim 1, wherein R1 or / and R2 is nitrogen in formula I.

5. The fused ring diimide derivative according to claim 4, wherein R1 or / and R2 is substituted with C1-C5 alkyl, C1-C5 alkoxy, nitro or nitroso in formula I.

6. The fused ring diimide derivative according to claim 4, wherein R1 is substituted with C1-C5 alkyl, C1-C5 alkoxy, or nitro in formula I.

7. The fused ring diimide derivative according to claim 4, wherein R2 is substituted with C1-C5 alkyl or C1-C5 alkoxy in formula I.

8. The fused ring diimide derivative according to claim 1, wherein R1 and R2 are nitrogen and R1 and R2 together form a six-membered ring in formula I.

9. The fused ring diimide derivative according to claim 1, wherein R3 is disubstituted with two identical or different groups selected from C1-C5 alkyl, haloC1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkoxyC1-C5 alkyl, nitro or nitroso in formula I.

10. A process for the preparation of a fused ring diimide derivative of the formula I according to any one of claims 1 to 9, comprising: reacting a compound of the formula I-M7 with a compound of the formula I-M8 to form a compound of the formula I according to the reaction scheme. ###0002### I-M7 I-M8 I The reaction of the compound of the formula I-M7 with the compound of the formula I-M8 is carried out in the presence of a base. The compound of the formula I-M7 is prepared by the following process: The compound of the formula I-M4 is prepared by the following process: ​ ​ ​ ​ 11. The production method according to claim 10, wherein ​ 12. The production method according to claim 10, wherein, ​ ​ 13. The production method according to claim 12, wherein ​ According to the reaction formula, the compound of formula I-M1 is first reacted with the compound of formula I-M2 to generate the compound of formula I-M3, and then the compound of formula I-M3 is hydrogenated to generate the compound of formula I-M4; X in the reaction formula is halogen.

14. Use of the fused ring imide derivative of any one of claims 1-9 in the manufacture of a medicament for the treatment of a cell proliferative disorder.

15. The use of claim 14, wherein the cell proliferative disorder is cancer.

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