Fused ring diimide derivatives, their preparation and use

Abstract

The present invention provides a fused ring diimide derivative having a chemical structure represented by Formula I. The present invention also provides a method for producing the same. The fused ring diimide derivative of the present invention has excellent antitumor activity and is significantly superior to similar compounds in antiproliferative activity against various cancer cells. [Formula 1] TIFF2023544790000036.tif31170

Description

[Technical field]

[0001] The present invention relates to fused ring diimide derivatives, their preparation methods and uses, which belong to the field of medicinal chemistry. [Background technology]

[0002] Diimide compounds are one of the important substances in the field of medicinal chemistry and have many noteworthy pharmacological activities.

[0003] After further condensation of diimide with some condensed rings, it forms a unique planar structure, greatly reduces the molecular volume, and can be embedded between the base pairs of the DNA double strand, causing DNA double helix melting, which has special application value for cell proliferation diseases such as cancer, etc. The condensed ring condensed with diimide can be various condensed rings with conjugated unsaturated structures, and can be carbon rings or hetero rings, such as naphthalene, anthracene, pyridocarbazole, etc., and many of the compounds with these structures have been reported to have antitumor activity, but few compounds have entered the clinical stage.

[0004] Amonafide is one of the representative compounds, and its molecular structure is a planar structure formed by condensation of a naphthalene ring and a diimide ring, and it has been reported to have cytotoxic activity against various cancer cells, such as colon cancer, lung cancer, stomach cancer, esophageal cancer, and leukemia. Antisoma has been using amonafide in Phase III clinical trials for the treatment of acute myeloid leukemia, but has discontinued development due to poor response rates. [ka]

[0005] Currently, the industry is researching other fused ring diimide compounds to obtain better potential active drugs, but it is still difficult to find compounds with stronger activity than amonafide. Summary of the Invention

[0006] An object of the present invention is to provide a fused ring diimide compound having superior properties.

[0007] According to a first aspect, the present invention provides a compound having a fused ring diimide structure represented by formula I: [ka] In formula I,

[0008] A is a fused ring fused to the diimide through 2-3 atoms, A may be optionally substituted;

[0009] m or n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0010] R 1 , R 2 or R 3 is selected from the group consisting of nitrogen, oxygen, and sulfur; R 1 , R 2 or R 3 is nitrogen or sulfur, R 1 , R 2 or R 3 is optionally substituted, R 1 and R 2 may optionally be joined together to form a ring.

[0011] In some examples, in formula I, R 1 , R 2 or R 3 is nitrogen, R 1 , R 2 or R 3 is optionally further substituted.

[0012] In some examples, in formula I, R 1 , R 2 or R 3 is sulfur, R 1 , R 2 or R 3may optionally form a sulfone or sulfoxide with oxo.

[0013] In some examples, in formula I above, A is a fused ring having a conjugated unsaturated structure.

[0014] In some examples, in formula I above, A is a fused ring formed by a carbocycle and a heterocycle.

[0015] In some instances, A is condensed with the diimide through 2-3 atoms to form a planar structure. Preferably, A is condensed with the diimide through 2-3 carbon atoms to form a planar structure.

[0016] In some examples, in formula I above, A is a fused two-ring, a fused three-ring, a fused four-ring, or a fused five-ring.

[0017] In some examples, in formula I, A is selected from the group consisting of naphthalene, anthracene, phenanthrene, naphthacene, chrysene, pyrene, perylene, quinolyl, acridine, pyrrolopyridine, pyridocarbazole, naphtho[1,2-b]furyl, benzimidazole, or benzimidazole[1,2-C]quinolyl. Preferably, A is selected from the group consisting of naphthalene, anthracene, phenanthrene, pyrene, perylene, or naphtho[1,2-b]furyl.

[0018] In some examples, in the formula I, A is optionally substituted with a group selected from the group consisting of an alkyl group, an alkoxy group, a nitro group, a cyano group, a hydroxyl group, an amino group, an imino group, a tertiary amino group, or a halogen, and the alkyl and alkoxy groups among the substituents are optionally further substituted with a hydroxyl group or a halogen.Preferably, A is substituted with a group selected from the group consisting of a C1-C5 alkyl group, a C1-C5 alkoxy group, a nitro group, a cyano group, an imino group, a tertiary amino group, or a halogen.

[0019] In some examples, in formula I above, m or n is 1, 2, 3, 4, 5 or 6.

[0020] In some examples, in formula I, R 1 and R 2 is oxygen or sulfur.

[0021] In some examples, in formula I, R 1 and / or R 2 is nitrogen.

[0022] In some examples, in formula I, R 1 and R 2 is nitrogen.

[0023] In some examples, in formula I, R 1 and / or R 2 is nitrogen and R 1 and / or R 2 is substituted with a group selected from the group consisting of an alkyl group, an alkoxy group, an imino group, a tertiary amino group, a nitro group, or a nitroso group, and the alkyl group and the alkoxy group among the substituents may be further substituted with a hydroxyl group or a halogen. 1 and / or R 2 is substituted with a group selected from the group consisting of a C1-C5 alkyl group, a C1-C5 alkoxy group, an imino group, a tertiary amino group, a nitro group, or a nitroso group.

[0024] In some examples, in formula I, R 1 is nitrogen and is substituted with a group selected from the group consisting of an alkyl group, an alkoxy group, a tertiary amino group, and a nitro group. 1 is substituted with a group selected from the group consisting of a C1-C5 alkyl group, a C1-C5 alkoxy group, a tertiary amino group, and a nitro group.

[0025] In some examples, in formula I, R 2 is nitrogen and is substituted with a group selected from the group consisting of an alkyl group and an alkoxy group.2 is substituted with a group selected from the group consisting of a C1-C5 alkyl group and a C1-C5 alkoxy group.

[0026] In some examples, in formula I, R 1 and R 2 and together form a ring. Preferably, R 1 and R 2 together form a six-membered ring.

[0027] In some examples, in formula I, R 3 is oxygen or sulfur, and R 3 is substituted with a group selected from the group consisting of an alkyl group, a halogenated alkyl group, an alkoxy group, an alkoxyalkyl group, a nitro group, or a nitroso group, and the alkyl group, alkoxy group, or alkoxyalkyl group among the substituents may be further substituted with a hydroxyl group or a halogen. 3 is substituted with a group selected from the group consisting of a C1-C5 alkyl group, a halo C1-C5 alkyl group, a C1-C5 alkoxy group, a C1-C5 alkoxy group, a C1-C5 alkyl group, a nitro group, or a nitroso group.

[0028] In some examples, in formula I, R 3 is nitrogen and R 3 is mono- or di-substituted with a group selected from the group consisting of an alkyl group, a halogenated alkyl group, an alkoxy group, an alkoxyalkyl group, a nitro group, and a nitroso group. 3 is mono- or di-substituted with a group selected from the group consisting of a C1-C5 alkyl group, a halo C1-C5 alkyl group, a C1-C5 alkoxy group, a C1-C5 alkoxy group, a C1-C5 alkyl group, a nitro group, and a nitroso group.

[0029] In some examples, in formula I, R 3 is nitrogen and R 3is disubstituted with two identical or different groups selected from the group consisting of a C1-C5 alkyl group, a halo C1-C5 alkyl group, a C1-C5 alkoxy group, a C1-C5 alkoxy group, a C1-C5 alkyl group, a nitro group, and a nitroso group.

[0030] In some examples, in formula I, R 1 , R 2 and R 3 are each nitrogen. Preferably, R 3 is mono- or di-substituted with a group selected from the group consisting of an alkyl group, a halogenated alkyl group, an alkoxy group, an alkoxyalkyl group, a nitro group, and a nitroso group. 3 is mono- or di-substituted with a group selected from the group consisting of a C1-C5 alkyl group, a halo C1-C5 alkyl group, a C1-C5 alkoxy group, a C1-C5 alkoxy group, a C1-C5 alkyl group, a nitro group, and a nitroso group. 1 , R 2 and R 3 are both nitrogen and R 3 When is mono- or di-substituted, some preferred compounds of formula I have better properties, eg, greater activity.

[0031] In some examples, in formula I, R 1 , R 2 and R 3 are each nitrogen. Preferably, R 3 is disubstituted with two identical or different groups selected from the group consisting of a C1-C5 alkyl group, a halo C1-C5 alkyl group, a C1-C5 alkoxy group, a C1-C5 alkoxy group, a C1-C5 alkyl group, a nitro group, and a nitroso group. 1 , R 2 and R 3 is nitrogen and R 3 When is disubstituted, some preferred compounds of formula I have better properties, eg, greater activity.

[0032] In some examples, in the formula I, the C1-C5 alkyl group includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an s-butyl group, an isobutyl group, a t-butyl group, an n-pentyl group, and the like, and the halogen includes a fluorine group, a chlorine group, a bromine group, and an iodine group.

[0033] According to a second aspect, the present invention provides a method for producing ... composition comprising the steps of: [ka]

[0034] A method for preparing a compound of formula I, comprising reacting I-M7 with I-M8 to produce I, wherein A, m, n, R 1 , R 2 , R 3 is as mentioned above.

[0035] In some instances, the reaction of I-M7 with I-M8 is carried out in the presence of a base.

[0036] In some instances, the base is selected from the group consisting of sodium hydroxide, potassium carbonate, cesium carbonate, or sodium phosphate.

[0037] Compounds of formula I-M7 and I-M8 may be commercially available or may be obtained by chemical synthesis.

[0038] In some examples, I-M7 can be prepared by the following method: [ka]

[0039] First, I-M4 and I-M5 are reacted to produce I-M6, which is then treated in the presence of an acid to produce I-M7, in which A, m, n, R 1 , R 2 is as mentioned above.

[0040] Compounds of formula I-M4 may be commercially available or obtained by chemical synthesis.

[0041] In some examples, I-M4 can be prepared by the following method: [ka]

[0042] First, I-M1 and I-M2 are reacted to produce I-M3, which is then hydrogenated to produce I-M4, where X is a halogen and m, n, R 1 , R 2 is as mentioned above.

[0043] According to a third aspect, the present invention provides the use of a compound of formula I as hereinbefore described in the manufacture of a medicament for treating a cell proliferative disorder.

[0044] In some instances, the cell proliferative disorder is cancer.

[0045] According to a fourth aspect, the present invention provides a method for treating a cell proliferative disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I as described above.

[0046] In some instances, the cell proliferative disorder is cancer. Specific examples of the present invention are the following: Item 1 A fused ring diimide derivative represented by formula I: [ka] (In formula I, A is a fused ring which is fused to the diimide through 2-3 atoms, and A may be optionally substituted; m or n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R 1 、R 2 or R 3 is selected from the group consisting of nitrogen, oxygen, and sulfur; R 1、R 2 or R 3 is nitrogen or sulfur, R 1 、R 2 or R 3 is optionally substituted, R 1 and R 2 may optionally be joined together to form a ring. Section 2 In formula I, R 1 、R 2 or R 3 is nitrogen, R 1 、R 2 or R 3 Item 3. The fused ring diimide derivative according to item 1, wherein Section 3 Item 3. The fused ring diimide derivative according to item 1, wherein in formula I, A is a fused ring having a conjugated unsaturated structure. Section 4 Item 2. The fused ring diimide derivative according to item 1, wherein in formula I, A is a fused two-ring, a fused three-ring, a fused four-ring, or a fused five-ring. Section 5 Item 2. The fused ring diimide derivative according to item 1, wherein in 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. Section 6 In the formula I, A is selected from the group consisting of naphthalene, anthracene, phenanthrene, naphthacene, chrysene, pyrene, perylene, quinolyl, acridine, pyrrolopyridine, pyridocarbazole, naphtho[1,2-b]furyl, benzimidazole, and benzimidazole[1,2-C]quinolyl. Section 7 Item 7. The fused ring diimide derivative according to item 6, wherein in formula I, A is selected from the group consisting of naphthalene, anthracene, phenanthrene, pyrene, perylene, and naphtho[1,2-b]furyl. Section 8 Item 2. The fused ring diimide derivative according to item 1, wherein in formula I, A is substituted with an alkyl group, an alkoxy group, a nitro group, a cyano group, an amino group, an imino group, a tertiary amino group, or a halogen atom. Section 9 Item 9. The fused ring diimide derivative according to item 8, wherein in formula I, A is substituted with a C1-C5 alkyl group, a C1-C5 alkoxy group, a nitro group, a cyano group, an imino group, a tertiary amino group, or a halogen. Item 10 Item 2. The fused ring diimide derivative according to item 1, wherein in formula I, m or n is 1, 2, 3, 4, 5 or 6. Section 11 In formula I, R 1 or / and R 2 Item 2. The fused ring diimide derivative according to Item 1, wherein R is oxygen or sulfur. Item 12 In formula I, R 1 or / and R2 Item 2. The fused ring diimide derivative according to Item 1, wherein R is nitrogen. Section 13 In formula I, R 1 or / and R 2 Item 13. The fused ring diimide derivative according to item 12, wherein is substituted with an alkyl group, an alkoxy group, an imino group, a tertiary amino group, a nitro group, or a nitroso group. Section 14 In formula I, R 1 or / and R 2 is substituted with a C1-C5 alkyl group, a C1-C5 alkoxy group, an imino group, a tertiary amino group, a nitro group, or a nitroso group. Section 15 In formula I, R 1 Item 13. The fused ring diimide derivative according to item 12, wherein is substituted with an alkyl group, an alkoxy group, a tertiary amino group, or a nitro group. Section 16 In formula I, R 2 Item 13. The fused ring diimide derivative according to item 12, wherein is substituted with an alkyl group or an alkoxy group. Section 17 In formula I, R 1 and R 2 is nitrogen and R 1 and R 2 and are combined together to form a ring. Section 18 In formula I, R 1 and R 2 Item 18. The fused ring diimide derivative according to item 17, wherein Section 19 In formula I, R 3 Item 2. The fused ring diimide derivative according to Item 1, wherein R is oxygen or sulfur. Section 20 In formula I, R 3 Item 20. The fused ring diimide derivative according to item 19, wherein is substituted with an alkyl group, a halogenated alkyl group, an alkoxy group, an alkoxyalkyl group, a nitro group, or a nitroso group. Section 21 In formula I, R 3 is substituted with a C1-C5 alkyl group, a halo C1-C5 alkyl group, a C1-C5 alkoxy group, a C1-C5 alkoxy group, a C1-C5 alkyl group, a nitro group, or a nitroso group. Section 22 In formula I, R 3 Item 2. The fused ring diimide derivative according to Item 1, wherein R is nitrogen. Section 23 In formula I, R 3 Item 23. The fused ring diimide derivative according to item 22, wherein is mono- or di-substituted with a group selected from the group consisting of an alkyl group, a halogenated alkyl group, an alkoxy group, an alkoxyalkyl group, a nitro group, or a nitroso group. Section 24 In formula I, R 3 is disubstituted with two identical or different groups selected from the group consisting of a C1-C5 alkyl group, a halo C1-C5 alkyl group, a C1-C5 alkoxy group, a C1-C5 alkoxy group, a C1-C5 alkyl group, a nitro group, or a nitroso group. Section 25 [ka] and reacting a compound of formula I-M7 with a compound of formula I-M8 according to the above reaction scheme to produce a compound of formula I, wherein A, m, n, R 1 、R 2 and R 3 A method for producing a fused ring diimide derivative represented by formula I, which is as described in any one of items 1 to 24. Section 26 Item 26. The method according to item 25, wherein the compound of formula I-M7 and the compound of formula I-M8 are reacted in the presence of a base. Section 27 The compound of formula I-M7 may be prepared by the following method: [ka] According to the above reaction scheme, the compound of formula I-M4 is first reacted with the compound of formula I-M5 to produce the compound of formula I-M6, and then I-M6 is treated in the presence of an acid to produce the compound I-M7. 1 and R 2 Item 26. The method according to item 25, which is as described in any one of items 1 to 24. Section 28 The compound of formula I-M4 may be prepared by the following method: [ka] According to the above reaction scheme, first, the compound of formula I-M1 is reacted with the compound of formula I-M2 to produce the compound of formula I-M3, and then the compound of formula I-M3 is hydrogenated to obtain the compound of formula I-M4, where X in the reaction scheme is halogen, and m, n, R 1 and R 2 Item 28. The method according to item 27, which is as described in any one of items 1 to 24. Section 29 Item 25. Use of the fused ring diimide derivative according to any one of Items 1 to 24 in the manufacture of a drug for treating a cell proliferative disease. Item 30 30. The use of claim 29, wherein the cell proliferative disease is cancer. Effect of the Invention

[0047] The fused ring diimide derivative according to the present invention is a novel compound. Research has shown that it has excellent antitumor activity, and has significant inhibitory effect on human colon cancer cells, lung cancer cells and leukemia cells. Its antitumor activity is significantly superior to that of similar compounds, and it has broad application prospects. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] The present invention will be further described below with reference to examples, and some preferred compounds are illustrated, but the examples are not intended to limit the compounds and technical effects of the present invention.

[0049] Example 1: Compound I-01

[0050] Reaction scheme: [ka]

[0051] Compound I-01 was prepared according to the reaction scheme, specifically as follows:

[0052] 1.1 Preparation of intermediate I-01-M3: Compound I-01-M2 (3.20 g, 20 mmol) was dissolved in 30 mL DMF, and the mixture was added with K 2 CO 3 (4.16 g, 30 mmol), NaI (3.00 g, 20 mmol) and compound I-01-M1 (5.70 g, 20 mmol) were added in that order and reacted at 30 °C overnight. After the reaction was completed, pure water (120 ml) was added to the reaction solution, which was then extracted three times with ethyl acetate (180 ml) and diluted with anhydrous MgSO 4 The mixture was dried at 40° C., filtered, and the mother liquor was concentrated and purified by column chromatography to obtain intermediate I-01-M3 (4.46 g, 12.2 mmol) in a yield of 61%.

[0053] 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, the mixture was purged with hydrogen gas three times, and the mixture was reacted overnight at normal pressure. The mixture was filtered through diatomaceous earth, and the mother liquor was concentrated to obtain colorless oily intermediate I-01-M4 (2.80 g, 12.1 mmol). The yield was 99.2%.

[0054] 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 added to a reaction flask in this order, and the mixture was heated to 80°C and reacted for 2 hours. The mixture was then cooled, concentrated, and purified by column chromatography to obtain intermediate I-01-M6 (3.66 g, 8.9 mmol). The yield was 73.6%.

[0055] 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), reacted at room temperature overnight, filtered, and dried to obtain intermediate I-01-M7 (2.58 g, 8.3 mmol). The yield was 93.3%.

[0056] 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 added to a reaction flask in that order, cooled to 0°C, and intermediate I-01-M7 (2.58 g, 8.3 mmol) was added in several portions, reacted at 0°C overnight, washed with water (15 ml), and then cooled with anhydrous MgSO. 4 The mixture was dried at 40° C., filtered, and the mother liquor was concentrated and purified by column chromatography to obtain compound I-01 (2.07 g, 4.6 mmol). The yield was 55.4%. Product Identification: 1 H-NMR (400MHz, d 6-DMSO)δ:1.38-1.52(4H,m),2.55(2H,t,J=6.8Hz),2.78(2H,t,J=6.8Hz),3.18(2H,t,J=6.5Hz),3.26(2H,t ,J=6.5Hz),5.18(4H,s),6.11(1H,m),7.52(2H,m),7.87(2H,dd,J=2.3,8.1Hz),7.93(2H,dd,J=2.3,8.0Hz).

[0057] Example 2: Compound I-02 [ka]

[0058] Compound I-02 was obtained by referring to the method of Example 1. Product Identification: 1 H-NMR (400MHz, d 6 -DMSO)δ:1.33-1.48(4H,m),3.20(2H,t,J=6.8Hz),3.28(2H,t,J=6.8Hz),3.58(2H,t,J=6.5Hz),4.32 (2H,t,J=6.5Hz),5.12(4H,s),7.48(2H,m),7.89(2H,dd,J=2.3,8.1Hz),7.95(2H,dd,J=2.3,8.0Hz).

[0059] Example 3: Compound I-03 [ka]

[0060] Compound I-03 was prepared according to the reaction scheme, specifically as follows:

[0061] 3.1 Synthesis of intermediate I-03-M3: Compound I-03-M2 (2.92 g, 20 mmol) was dissolved in 30 mL DMF, and the mixture was added with K 2 CO 3(4.16 g, 30 mmol), NaI (3.00 g, 20 mmol), and compound I-03-M1 (5.14 g, 20 mmol) were added in that order, and the reaction was allowed to proceed overnight at 30° C. After completion of the reaction, pure water (120 ml) was added to the reaction solution, which was then extracted three times with ethyl acetate (180 ml), and anhydrous MgSO 4 The mixture was dried at 40° C., filtered, and the mother liquor was concentrated and purified by column chromatography to obtain intermediate I-03-M3 (3.75 g, 11.6 mmol) in a yield of 58%.

[0062] 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, the mixture was purged with hydrogen gas three times, and the mixture was reacted overnight at normal pressure. The mixture was filtered through diatomaceous earth, and the mother liquor was concentrated to obtain colorless oily intermediate I-03-M4 (2.19 g, 11.6 mmol). The yield was 100%.

[0063] 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 added to a reaction flask in this order, and the mixture was heated to 80°C and reacted for 2 hours. The mixture was then cooled, concentrated, and purified by column chromatography to obtain intermediate I-03-M6 (3.85 g, 9.3 mmol). The yield was 80.2%.

[0064] 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), reacted at room temperature overnight, filtered, and dried to obtain intermediate I-03-M7 (2.80 g, 8.9 mmol) in a yield of 95.7%.

[0065] 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 added to a reaction flask in that order, cooled to 0°C, and intermediate I-03-M7 (2.80 g, 8.9 mmol) was added in several portions, reacted at 0°C overnight, washed with water (25 ml), and then cooled with anhydrous MgSO 4 The mixture was dried at 40° C., filtered, and the mother liquor was concentrated and purified by column chromatography to obtain compound I-03 (2.60 g, 5.8 mmol). The yield was 65.2%. Product Identification: 1 H-NMR (400MHz, d 6 -DMSO)δ:2.85(2H,t,J=6.8Hz),3.18(2H,t,J=6.8Hz),3.35(2H,t,J=6.5Hz),3.80(2H,t,J=6.5Hz),4.53(2H,s),6.31(1 H,m),7.78(1H,m),8.22(1H,dd,J=2.3,8.1Hz),8.30(1H,dd,J=2.3,8.1Hz),8.78(1H,d,J=2.3Hz),8.95(1H,d,J=2.3Hz).

[0066] Example 4: Compound I-04 [ka]

[0067] Compound I-04 was obtained by referring to the method of Example 3. Product Identification: 1 H-NMR (400MHz, d 6 -DMSO)δ:1.37-1.53(4H,m),2.53(2H,t,J=6.8Hz),2.79(2H,t,J=6.8Hz),3.20(2H,t,J=6.5Hz),3.29(2H,t,J=6.5Hz),3.38 (2H,t,J=6.5Hz),3.62(2H,t,J=6.5Hz),6.21(1H,m),7.50(2H,m),7.91(2H,dd,J=2.3,8.0Hz),7.98(2H,dd,J=2.3,8.0Hz).

[0068] Example 5: Compound I-05 [ka]

[0069] Compound I-05 was obtained by referring to the method of Example 3. Product Identification: 1 H-NMR (400MHz, d 6 -DMSO)δ:1.42-1.53(4H,m),2.53(2H,t,J=6.8Hz),2.63(3H,s),2.78(3H,s),2.83(2H,t,J=6.8Hz),2.92(6H,s),3.12(2H,t,J=6.5Hz),3.33(2 H,t,J=6.5Hz),3.45(3H,s),6.83(1H,d,J=8.0Hz),7.48(1H,m),7.78(1H,d,J=8.0Hz),7.88(1H,dd,J=2.3,8.0Hz),7.98(1H,dd,J=2.3,8.0Hz).

[0070] Example 6: Compound I-06 [ka]

[0071] Compound I-06 was obtained by referring to the method of Example 3. Product Identification: 1 H-NMR (400MHz, d 6 -DMSO)δ:1.83(2H,m),2.48(2H,t,J=6.8Hz),2.68(3H,s),2.91(6H,s),3.12(2H,t,J=6.5Hz),4.25(2H,s),5.78(1H,m),6.2 1(1H,m),6.78(1H,d,J=8.0Hz),7.45(1H,m),7.77(1H,d,J=8.0Hz),7.85(1H,dd,J=2.3,8.0Hz),7.95(1H,dd,J=2.3,8.0Hz).

[0072] Example 7: Compound I-07 [ka]

[0073] Compound I-07 was obtained by referring to the method of Example 3. Product Identification: 1 H-NMR (400MHz, d 6 -DMSO)δ:1.23(3H,t,J=6.8Hz),1.45-1.75(6H,m),2.65(3H,s),3.06(2H,t,J=6.8Hz),3.15(2H,q,J=6.8Hz),3.25-3.38(4H,m),3.58(2H,t,J =6.5Hz),3.68(3H,s),6.01(1H,m),6.88(1H,d,J=2.3Hz),7.02(1H,dd,J=2.3,8.0Hz),7.67(1H,dd,J=2.3,8.0Hz),8.42(1H,s),8.49(1H,s).

[0074] Example 8: Compound I-08

[0075] [ka] Compound I-08 was obtained by referring to the method of Example 3. Product Identification: 1 H-NMR (400MHz, d 6 -DMSO)δ:2.63(6H,s),3.22(2H,t,J=6.8Hz),3.36(3H,s),3.63(2H,t,J=6.5Hz),5.73(2H,s),6.03(1H,m) ,6.85(1H,d,J=2.3Hz),7.01(1H,dd,J=2.3,8.0Hz),7.63(1H,dd,J=2.3,8.0Hz),8.38(1H,s),8.51(1H,s).

[0076] Example 9: Compound I-9 [ka]

[0077] Compound I-09 was obtained by referring to the method of Example 3. Product Identification: 1 H-NMR (400MHz, d 6-DMSO)δ:1.25-1.30(4H,m),1.45-1.53(4H,m),2.52(2H,t,J=6.8Hz),2.68(6H,s),3.08(2H,t,J=6.8Hz),4.51(2H,s),6.07(1H,m),7.30(2H,m ),7.58(1H,m),7.86(1H,dd,J=2.3,8.0Hz),7.95(1H,dd,J=2.3,8.0Hz),8.03(1H,dd,J=2.3,8.0Hz),8.20(1H,dd,J=2.3,8.0Hz),8.62(1H,s).

[0078] Example 10: Compound I-10 [ka]

[0079] Compound I-10 was obtained by referring to the method of Example 3. Product Identification: 1 H-NMR (400MHz, d 6 -DMSO)δ:1.69(2H,m),2.52(2H,t,J=6.8Hz),2.68(6H,s),2.82(2H,t,J= 6.8Hz),3.12(2H,t,J=6.8Hz),3.28(2H,t,J=6.8Hz),6.03(1H,m),7.25(2 H,m),7.63(1H,m),7.83(1H,dd,J=2.3,8.0Hz),7.98(1H,dd,J=2.3,8.0Hz),8.06(1H,dd,J=2.3,8.0Hz),8.25(1H,dd,J=2.3,8.0Hz),8.68(1H,s).

[0080] Example 11: Compound I-11 [ka]

[0081] Compound I-11 was obtained by referring to the method of Example 3. Product Identification: 1H-NMR(400MHz,d6-DMSO)δ:1.42-1.53(4H,m),2.55(2H,t,J=6.8Hz),2.70(3H,s), 2.88(3H,s),3.10(2H,t,J=6.8Hz),3.28(3H,s),3.58(2H,t,J=6.8Hz),4.12(2H,t ,J=6.8Hz),4.52(2H,s),7.33(2H,m),7.62(1H,m),7.88(1H,dd,J=2.3,8.0Hz),8. 02(1H,dd,J=2.3,8.0Hz),8.09(1H,dd,J=2.3,8.0Hz),8.22(1H,dd,J=2.3,8.0Hz).

[0082] Example 12: Compound 1-12

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[0083] The method of Example 3 was obtained by referring to the compound I-12. The identity of the product: 1 H-NMR (400MHz, d 6 -DMSO)δ:1.23(3H,t,J=6.3Hz),1.42(2H,m),1.57(2H,m),2.61(2H,t,J=6.8Hz),2.70(3H,s),2.92(2H,t,J=6.3Hz),4.16(2H,t,J=6.7Hz),4.7 6(2H,s),7.52-7.65(3H,m),7.80(1H,dd,J=2.3,8.0Hz),7.91(1H,dd,J=2.3,8.1Hz),8.03(1H,dd,J=2.3,8.2Hz),8.27(1H,dd,J=2.3,8.1Hz).

[0084] Example 13: Compound 1-13

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[0085] The method of Example 3 was obtained by referring to the compound I-13. The identity of the product: 1 H-NMR (400MHz, d 6-DMSO)δ:1.43-1.55(4H,m),2.48(2H,t,J=6.8Hz),2.58(3H,s),2.62(3H,s),2.78(3H,s),3.12(2H,t,J=6.8Hz),3.18(2H,t,J=6.8Hz),4.42(2H ,s),7.38(2H,m),7.65(1H,m),7.83(1H,dd,J=2.3,8.0Hz),7.97(1H,dd,J=2.3,8.0Hz),8.12(1H,dd,J=2.3,8.0Hz),8.25(1H,dd,J=2.3,8.0Hz).

[0086] Example 14: Compound 1-14

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[0087] The method of Example 3 was obtained by referring to the compound I-14. The identity of the product: 1 H-NMR (400MHz, d 6 -DMSO)δ:2.43(6H,s),2.60(3H,s),2.72-2.83(4H,m),3.12(2H,t,J=6.8Hz),3.18 (2H,t,J=6.8Hz),3.25(3H,s),3.32(2H,t,J=6.8Hz),3.69(2H,t,J=6.8Hz),5.88(1 H,m),7.68-7.78(2H,m),8.01(1H,m),8.12(1H,dd,J=2.3,8.0Hz),8.36(1H,s),8. 48(1H,dd,J=2.3,8.0Hz),8.89(1H,dd,J=2.3,8.0Hz),9.21(1H,dd,J=2.3,8.0Hz).

[0088] Example 15: Compound 1-15

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[0089] The method of Example 3 was obtained by referring to the compound I-15. The identity of the product: 1 H-NMR (400MHz, d 6-DMSO)δ:1.28(3H,t,J=6.8Hz),2.68(3H,s),2.72-2.83(4H,m),3.12(2H,q,J= 6.8Hz),3.30(3H,s),3.38(2H,t,J=6.8Hz),3.46(2H,t,J=6.8Hz),5.93(1H,m), 7.65-7.72(2H,m),7.98(1H,m),8.10(1H,dd,J=2.3,8.0Hz),8.33(1H,s),8.45( 1H,dd,J=2.3,8.0Hz),8.88(1H,dd,J=2.3,8.0Hz),9.18(1H,dd,J=2.3,8.0Hz).

[0090] Example 16: Compound I-16 [ka]

[0091] Compound I-16 was obtained by referring to the method of Example 3. Product Identification: 1 H-NMR (400MHz, d 6 -DMSO)δ:1.42-1.58(4H,m),2.68(3H,s),3.02(2H,t,J=6.8Hz),3.18(2H,t,J=6.8Hz),3.33(2H,t,J=6.8Hz),3.98(2H,t,J=6.8Hz),7.73-7.82(2 H,m),7.01(1H,m),8.12(1H,dd,J=2.3,8.0Hz),8.33(1H,s),8.47(1H,dd,J=2.3,8.0Hz),8.93(1H,dd,J=2.3,8.0Hz),9.23(1H,dd,J=2.3,8.0Hz).

[0092] Example 17: Compound I-17 [ka]

[0093] Compound I-17 was obtained by referring to the method of Example 3. Product Identification: 1 H-NMR (400MHz, d 6-DMSO)δ:1.25-1.58(8H,m),2.42(2H,t,J=6.8Hz),2.66(3H,s),3.12(2H,t,J=6.8Hz),4.45(2H,s),5.98(1H,m),7.68(1H,dd, J=2.3,8.0Hz),8.02-8.12(2H,m),8.35(1H,s),8.47(1H,dd,J=2.3,8.0Hz),8.67(1H,d,J=2.3Hz),9.12(1H,dd,J=2.3,8.0Hz).

[0094] Example 18: Compound I-18 [ka]

[0095] Compound I-18 was obtained by referring to the method of Example 3. Product Identification: 1 H-NMR (400MHz, d 6 -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 .8Hz),7.32-7.45(3H,m),7.80-7.88(4H,m),8.02(1H,d,J=8.1Hz),8.10(1H,d,J=8.2Hz).

[0096] Example 19: Compound I-19 [ka]

[0097] Compound I-19 was obtained by referring to the method of Example 3. Product Identification: 1 H-NMR (400MHz, d 6-DMSO)δ:1.31(6H,d,J=6.8Hz),1.43-1.55(4H,m),2.92(2H,t,J=6.8Hz),3.32(2H,t,J=6.8Hz),5.45(2H,s),6.38(1H,m),6.68(1 H,d,J=3.2Hz),7.43(1H,d,J=3.2Hz),7.48(1H,d,J=8.0Hz),7.77(1H,dd,J=2.3,8.0Hz),7.86(1H,dd,J=2.3,8.0Hz),7.93(1H,s).

[0098] Example 20: Compound I-20 [ka]

[0099] Compound I-20 was obtained by referring to the method of Example 3. Product Identification: 1 H-NMR (400MHz, d 6 -DMSO)δ:1.49-1.58(4H,m),2.52(2H,t,J=6.8Hz),2.78(2H,t,J=6.8Hz),3. 18(2H,t,J=6.8Hz),3.32(3H,s)3.45(2H,t,J=6.8Hz),3.55(3H,s),5.88(1H, m),6.38(1H,m),6.65(1H,d,J=3.2Hz),7.42(1H,d,J=3.2Hz),7.53(1H,d,J=8 .0Hz),7.69(1H,dd,J=2.3,8.0Hz),7.83(1H,dd,J=2.3,8.0Hz),7.88(1H,s).

[0100] Example 21: Compound I-21 [ka]

[0101] Compound I-21 was obtained by referring to the method of Example 3. Product Identification: 1 H-NMR (400MHz, d 6-DMSO)δ:2.68(2H,s),2.82(2H,t,J=6.8Hz),3.26(2H,t,J=6.8Hz),4.45(2H,s),5.35(2H,s),6.63(1H,d,J=3.2Hz) ,7.48(1H,d,J=3.2Hz),7.52(1H,d,J=8.0Hz),7.73(1H,dd,J=2.3,8.0Hz),7.82(1H,dd,J=2.3,8.0Hz),7.91(1H,s).

[0102] Example 22: Study of the antitumor activity of compounds of formula I

[0103] Study objective: To test the antiproliferative activity of the compounds of the present invention against multiple types of tumor cells.

[0104] 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 invention; positive drug amonafide; and comparative compounds 1d, 1. Among them, compound 1d is "1d" described in the literature Journal of Cancer Molecules, 2010, 5(2): p 41-47), compound 1 is "component 1" described in the literature Journal of Experimental Therapeutics and Oncology, 2005, 5: p 15-22, both of which were prepared by the method described in the literature, and positive drug amonafide was a commercially available product. [ka]

[0105] Test cells: human colon cancer cells (HT-29, COLO 205), human lung cancer cells (NCI-H460, A549), human leukemia cells (HL-60, U-937).

[0106] Test method: Each tumor cell was individually processed. The cells were cultured in culture medium at 37°C for 24 hours before use. Cells in the logarithmic growth phase were harvested, treated with trypsinase to prepare a cell suspension, centrifuged, and the cells were pelleted and resuspended in a small amount of fresh medium to prepare a reserve cell solution. This stock solution was diluted to the required cell concentration. Each cell concentration is shown in Table 1.

[0107] [Table 1]

[0108] A 96-well plate was taken and a blank control group, a cell control group, and a compound group were placed. For the blank control group, only 10% PBS was added per well, while for the cell control group and the compound group, 100 μL of cells at the above concentrations were added per well and filled with 200 μL of 10% PBS. The plate was cultured overnight in a cell incubator. 100 μL of each test compound at different dilution concentrations was added to the compound group, and the dilution concentrations of the compounds are shown in Table 2.

[0109] [Table 2]

[0110] After the injection, the plate was incubated in an incubator for 96 hours, 22 μL of sodium lysoazurin solution (Alarm blue, SIGMA R7017) was added to each well, the plate was placed in the incubator and incubated again for 4 hours. After removing the plate, it was shaken for 10 seconds, and the fluorescence value of each well was recorded at 530 / 590 nm.

[0111] The above procedure was repeated three times.

[0112] Compound ICs were calculated using Prism7 software. 50 The IC value was calculated. 50were divided into different levels according to the magnitude of the values, 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:

[0113] [Table 3]

[0114] The test results show that the antitumor activity of the compounds of the present invention is generally superior to that of the positive drug amonafide.Comparison between the compounds of the present invention and similar compounds shows that the inhibitory activity of the compounds of the present invention against tumor cells is generally significantly superior to that of compound 1d and compound 1.In particular, in the case of colon cancer cells, the activity of some preferred compounds (e.g., compounds I-03, I-04) reaches more than 50 times that of similar compounds.

[0115] Compound 1d and compound 1 are both structural modifications of amonafide, modified at the alkylamino position on the right side of amonafide, but in the present test, their overall antitumor activity is not as good as amonafide. The difference in activity between the compound of formula I of the present invention and compounds 1d and 1 is due to the fact that the alkylamino group on the right side of amonafide is modified by the heteroatom (R 1 ) is introduced, and this heteroatom (R 1 ) and the heteroatom (R 2 This suggests that separating the aryl group from the aryl group by a carbon chain or a carbon ring is very important for improving activity.

[0116] The present invention has been described in detail above by using general descriptions, specific embodiments, etc. Based on the present invention, those skilled in the art can make some modifications or improvements to the present invention while maintaining the spirit of the present invention, and all of these modifications or improvements shall fall within the protection scope of the present invention.

Claims

1. A fused ring diimide derivative represented by formula I: 【Chemistry 1】 (In formula I, A is selected from the group consisting of naphthalene, anthracene, phenanthrene, and naphtho[1,2-b]furan, and is a fused ring condensed with the diimide through 2-3 atoms, and A is optionally substituted with an alkyl group, an alkoxy group, a nitro group, a cyano group, an amino group, an imino group, a tertiary amino group, or a halogen; m or n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R １ is selected from nitrogen or oxygen, R ２ is selected from nitrogen or oxygen, R １ Or R ２ When is nitrogen, R １ Or / and R ２ is hydrogenated or substituted with an alkyl group, an alkoxy group or a nitro group, R １ and R ２ is nitrogen, R １ and R ２ When all of R are substituted, １ and R ２ and optionally taken together to form a ring, R ３ is selected from nitrogen or sulfur, R ３ is hydrogenated and / or substituted with a group selected from the group consisting of an alkyl group, a halogenated alkyl group, an alkoxy group, or a nitroso group, provided that when R 3 is hydrogenated, R ３ When is nitrogen, hydrogenated R ３ Ha-NH ２ Instead, R ３ When is sulfur, R ３ is not -SH, R １ , R ２ and R ３ When both are nitrogen, R ３ is not monosubstituted with a propyl group. 【Request 2】 【Chemistry 2】 and reacting a compound of formula I-M7 with a compound of formula I-M8 according to the above reaction scheme to produce a compound of formula I, wherein A, m, n, R １ , R ２ and R ３ A method for producing a fused ring diimide derivative represented by formula I, as described in claim 1.

3. The compound of formula I-M7 was prepared by the following method: 【Chemistry 3】 According to the above reaction scheme, the compound of formula I-M4 is first reacted with the compound of formula I-M5 to produce the compound of formula I-M6, and then I-M6 is treated in the presence of an acid to obtain the compound I-M7. １ and R ２ The method of claim 2, wherein the process is as described in claim 1.

4. The compound of formula I-M4 is prepared by the following method: 【Chemistry 4】 According to the above reaction scheme, First, the compound of formula I-M1 is reacted with the compound of formula I-M2 to produce the compound of formula I-M3, and then the compound of formula I-M3 is hydrogenated to obtain the compound of formula I-M4, where X in the reaction formula is a halogen, and m, n, R １ and R ２ The method of claim 3, wherein the process is as defined in claim 1.

5. A pharmaceutical for treating a cell proliferative disease, comprising the fused ring diimide derivative according to claim 1.

6. The pharmaceutical composition according to claim 5 , wherein the cell proliferative disease is cancer.

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