FUSED RING DIIMIDE DERIVATIVE, PREPARATION METHOD AND USE THEREOF

Abstract

Provided is a fused ring diimide derivative having a chemical structure of formula I. Further provided is a preparation method therefor. The fused ring diimide derivative has excellent anti-tumor activity, and the anti-proliferative activity on various cancer cells is significantly better than that of similar compounds.

##STR00001##

Claims

1. A fused ring diimide derivative of formula I, ##STR00029## wherein, A is a optionally substituted fused ring with a conjugated unsaturated structure, which is fused with diimide through 2 to 3 atoms; m or n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and R.sub.1 or R.sub.2 is selected from the group consisting of N, O and S, R.sub.3 is N or S; when R.sub.1, R.sub.2 or R.sub.3 is N or S, R.sub.1, R.sub.2 or R.sub.3 is optionally substituted, and R.sub.1 optionally forms a ring together with R.sub.2; wherein, when R.sub.1, R.sub.2 and R.sub.3 are N, R.sub.3 is not mono-substituted by propyl.

2. The fused ring diimide derivative according to claim 1, wherein in formula I, when R.sub.1, R.sub.2 or R.sub.3 is N, R.sub.1, R.sub.2 or R.sub.3 is optionally substituted.

3. (canceled)

4. (canceled)

5. (canceled)

6. The fused ring diimide derivative according to claim 1, wherein in formula I, A is selected from the group consisting of naphthalene, anthracene, phenanthrene, tetracene, chrysene, pyrene, perylene, quinoline, acridine, pyrrolopyridine, pyridocarbazole, naphtho[1,2-b]furan, benzimidazole and benzimidazole[1,2-C]quinoline.

7. (canceled)

8. The fused ring diimide derivative according to claim 1, wherein in formula I, A is substituted by alkyl, alkoxy, nitro, cyano, amino, imino, tertiary amino or halogen.

9. (canceled)

10. (canceled)

11. The fused ring diimide derivative according to claim 1, wherein in formula I, R.sub.1 and/or R.sub.2 are/is O or S.

12. The fused ring diimide derivative according to claim 1, wherein in formula I, R.sub.1 and/or R.sub.2 are/is N.

13. The fused ring diimide derivative according to claim 12, wherein in formula I, R.sub.1 and/or R.sub.2 are/is substituted by alkyl, alkoxy, imino, tertiary amino, nitro or nitroso.

14. (canceled)

15. The fused ring diimide derivative according to claim 12, wherein in formula I, R.sub.1 is substituted by alkyl, alkoxy, tertiary amino or nitro.

16. The fused ring diimide derivative according to claim 12, wherein in formula I, R.sub.2 is substituted by alkyl or alkoxy.

17. The fused ring diimide derivative according to claim 1, wherein in formula I, R.sub.1 and R.sub.2 are N, and R.sub.1 forms a ring together with R.sub.2.

18. The fused ring diimide derivative according to claim 17, wherein in formula I, R.sub.1 forms a six-membered ring together with R.sub.2.

19. The fused ring diimide derivative according to claim 1, wherein in formula I, R.sub.3 is S.

20. The fused ring diimide derivative according to claim 19, wherein in formula I, R.sub.3 is substituted by alkyl, haloalkyl, alkoxy, alkoxyalkyl, nitro or nitroso.

21. (canceled)

22. The fused ring diimide derivative according to claim 1, wherein in formula I, R.sub.3 is N.

23. The fused ring diimide derivative according to claim 22, wherein in formula I, R.sub.3 is substituted by one or two substituents selected from the group consisting of alkyl, haloalkyl, alkoxy, alkoxyalkyl, nitro and nitroso.

24. (canceled)

25. A preparation method of the fused ring diimide derivative of formula I, comprising: ##STR00030## reacting a compound of formula I-M7 with a compound of formula I-M8 to obtain a compound of formula I according to the above reaction formula, R.sub.1 or R.sub.2 is selected from the group consisting of N, O and S, R.sub.3 is N or S: when R.sub.1, R.sub.2 or R.sub.3 is N or S, R.sub.1, R.sub.2 or R.sub.3 is optionally substituted, and R.sub.1 optionally forms a ring together with R.sub.2; wherein, when R.sub.1, R.sub.2 and R.sub.3 are N, R.sub.3 is not mono-substituted by propyl, A is selected from the group consisting of naphthalene, anthracene, phenanthrene, tetracene, chrysene, pyrene, perylene, quinoline, acridine, pyrrolopyridine, pyridocarbazole, naphtho[1,2-b]furan, benzimidazole and benzimidazole[1,2-Cl]quinoline, and m or n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

26. (canceled)

27. The preparation method according to claim 25, wherein the compound of formula I-M7 is prepared by a method comprising: reacting a compound of formula I-M4 with a compound of formula I-M5 to obtain a compound of formula I-M6 and treating the compound of formula I-M6 in the presence of an acid to obtain the compound of formula I-M7 according to the following reaction formula: ##STR00031##

28. The preparation method according to claim 27, wherein the compound of formula I-M4 is prepared by the method comprising: reacting a compound of formula I-M1 with a compound of formula I-M2 to obtain a compound of formula I-M3; and hydrogenating the compound of formula I-M3 to obtain the compound of formula I-M4 according to the following reaction formula: ##STR00032##

29. A method of treating a cell proliferative disease in a subject in need thereof, comprising administering an effective amount of the fused ring diimide derivative according to claim 1 to the subject.

30. The method according to claim 29, wherein the cell proliferative disease is cancer.

Description

DETAILED DESCRIPTION

[0050] The present disclosure is further described below with examples, and some preferred compounds will be exemplified. It should be noted that the examples are not intended to limit the compounds and technical effects of the present disclosure.

Example 1: Compound I-01

[0051] ##STR00007##

[0052] Compound I-01 was prepared according to the reaction formula, specifically as follows:

[0053] 1.1 Preparation of intermediate I-01-M3: compound I-01-M2 (3.20 g, 20 mmol) was dissolved in 30 mL of dimethyl formamide (DMF), and then K.sub.2CO.sub.3 (4.16 g, 30 mmol), NaI (3.00 g, 20 mmol) and compound I-01-M1 (5.70 g, 20 mmol) were added to the mixed solution successively, and the reaction mixture was stirred at 30° C. overnight. After the reaction, purified water (120 ml) was added, and the reaction solution was extracted three times with ethyl acetate (180 ml), dried with anhydrous MgSO.sub.4 and filtered. 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%.

[0054] 1.2 Preparation of intermediate I-01-M4: to a mixture of intermediate I-01-M3 (4.46 g, 12.2 mmol) in a solution of methanol (20 mL) was added 10% Pd/C (0.3 g), hydrogen replacement was performed three times, the reaction mixture was stirred overnight under normal pressure, then filtered with diatomite. The mother liquor was concentrated to obtain colorless oily intermediate I-01-M4 (2.80 g, 12.1 mmol), with a yield of 99.2%.

[0055] 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 successively to a reaction flask, the reaction mixture was heated to 8011 and stirred for 2 hours, cooled, then concentrated and purified by column chromatography to obtain intermediate I-01-M6 (3.66 g, 8.9 mmol), with a yield of 73.6%.

[0056] 1.4 Preparation of intermediate I-01-M7: intermediate I-01-M6 (3.66 g, 8.9 mmol) was dissolved into a 4% hydrogen chloride ethyl acetate solution (50 ml), the reaction mixture was stirred overnight at room temperature, then filtered and dried to obtain intermediate I-01-M7 (2.58 g, 8.3 mmol), with a yield of 93.3%.

[0057] 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 successively to a reaction flask and cooled to 01; intermediate I-01-M7 (2.58 g, 8.3 mmol) was added portion-wise, the reaction mixture was stirred at 01 overnight, washed with water (15 ml), dried with anhydrous MgSO.sub.4 and filtered. 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%. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 2: Compound I-02

[0058] ##STR00008##

[0059] Compound I-02 was prepared by referring to the method of Example 1. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-DMSO) δ: 1.33-1.48 (4H, m), 3.20 (2H, t, J=6.8 Hz), 3.28 (2H, t, J=6.8 Hz), 3.58 (2H, t, J=6.5 Hz), 4.32 (2H, t, J=6.5 Hz), 5.12 (4H, s), 7.48 (2H, m), 7.89 (2H, dd, J=2.3, 8.1 Hz), 7.95 (2H, dd, J=2.3, 8.0 Hz).

Example 3: Compound I-03

[0060] ##STR00009##

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

[0062] 3.2 Synthesis of intermediate I-03-M4: to a mixture of intermediate I-03-M3 (3.75 g, 11.6 mmol) in a solution of methanol (20 mL) was added 10% Pd/C (0.3 g), hydrogen replacement was performed three times, the reaction mixture was stirred overnight under normal pressure, then filtered with diatomite. The mother liquor was concentrated to obtain colorless oily intermediate I-03-M4 (2.19 g, 11.6 mmol), with a yield of 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 successively to a reaction flask, the reaction mixture was heated to 8011 and stirred for 2 hours, cooled, then concentrated and purified by column chromatography to obtain intermediate I-03-M6 (3.85 g, 9.3 mmol), with a yield of 80.2%.

[0064] 3.4 Synthesis of intermediate I-03-M7: intermediate I-03-M6 (3.85 g, 9.3 mmol) was dissolved into a 4% hydrogen chloride ethyl acetate solution (60 ml), the reaction mixture was stirred overnight at room temperature, then filtered and dried to obtain intermediate I-03-M7 (2.80 g, 8.9 mmol), with 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 successively to a reaction flask and cooled to 0□; intermediate I-03-M7 (2.80 g, 8.9 mmol) was added portion-wise, the reaction mixture was stirred at 0□ overnight, washed with water (25 ml), dried with anhydrous MgSO.sub.4 and filtered. The mother liquor was concentrated and purified by column chromatography to obtain compound I-03 (2.60 g, 5.8 mmol), with a yield of 65.2%. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 4: Compound I-04

[0066] ##STR00010##

[0067] Compound I-04 was prepared by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 5: Compound I-05

[0068] ##STR00011##

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

Example 6: Compound I-06

[0070] ##STR00012##

[0071] Compound I-06 was prepared by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 7: Compound I-07

[0072] ##STR00013##

[0073] Compound I-07 was prepared by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 8: Compound I-08

[0074] ##STR00014##

[0075] Compound I-08 was prepared by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 9: Compound I-09

[0076] ##STR00015##

[0077] Compound I-09 was prepared by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 10: Compound I-10

[0078] ##STR00016##

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

Example 11: Compound I-11

[0080] ##STR00017##

[0081] Compound I-11 was prepared by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 12: Compound I-12

[0082] ##STR00018##

[0083] Compound I-12 was prepared by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 13: Compound I-13

[0084] ##STR00019##

[0085] Compound I-13 was prepared by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 14: Compound I-14

[0086] ##STR00020##

[0087] Compound I-14 was prepared by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 15: Compound I-15

[0088] ##STR00021##

[0089] Compound I-15 was prepared by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 16: Compound I-16

[0090] ##STR00022##

[0091] Compound I-16 was prepared by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 17: Compound I-17

[0092] ##STR00023##

[0093] Compound I-17 was prepared by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 18: Compound I-18

[0094] ##STR00024##

[0095] Compound I-18 was prepared by referring to the method of Example 3. Product identification: 1H-NMR (400 MHz, d.sub.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=6.8 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).

Example 19: Compound I-19

[0096] ##STR00025##

[0097] Compound I-19 was prepare by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 20: Compound I-20

[0098] ##STR00026##

[0099] Compound I-20 was prepared by referring to the method of Example 3. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-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).

Example 21: Compound I-21

[0100] ##STR00027##

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

Example 22: Study on Anti-Tumor Activity of the Compound of Formula I

[0102] Objective: To test the anti-proliferative activity of the compound of the present disclosure against various tumor cells.

[0103] 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 and I-20; positive drug: Amonafide; and comparative compounds: 1d and 1. The Compound 1d refers to “1d” described in Journal of Cancer Molecules (2010,5 (2): p 41-47) and the Compound 1 refers to “Compound 1” described in Journal of Experimental Therapeutics and Oncology (2005,5: p 15-22), both Compounds 1d and 1 were prepared according to the method in the literature. The positive drug Amonafide is commercially available.

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[0104] Test cells: human colon cancer cells (HT-29, COLO 205), human lung cancer cells (NCI-H460, A549) and human leukemia cells (HL-60, U-937).

[0105] Test method: each tumor cell was tested separately. Cells were incubated in medium at 37 for 24 hours before use. The cells growing in an exponential growth phase were harvested and treated with trypsin to prepare a cell suspension, the cell suspension was centrifuged, then the cell pellet was resuspended in a small amount of fresh medium as a cell stock. The cell stock was diluted to required cell concentrations. The concentrations of each cell are as shown in Table 1:

TABLE-US-00001 TABLE 1 Concentrations of Each Cancer Cells Cell line Cell concentration (cells count/mL) HT-29 30000 COLO 205 15000 MCI-H460 15000 A549 20000 HL-60 30000 U-937 30000

[0106] The test was carried out on 96-well plates; blank control groups, cell control groups and compound treatment groups were set up. In the blank control groups, only 10% PBS was added to each well, while in the cell control groups and the compound treatment groups, 100 μL of cells at the above concentration were added to each well, and then each well was filled with 200 μL of 10% PBS. The plates were placed in an incubator overnight. In the compound treatment groups, 100 μL of each test compound at different dilution concentrations was added to each well, the dilution concentrations of the compounds are as shown in Table 2.

TABLE-US-00002 TABLE 2 Dilution Concentrations of Test Compounds Concentrations of NO. Compounds (μM) 1 200 2 66.7 3 22.2 4 7.41 5 2.47 6 0.823 7 0.274 8 0.0914

[0107] After the addition of the drug to each well was completed, the plates were cultured in an incubator for 96 hours, 22 μL of resazurin sodium solution (Alarm blue, SIGMA R7017) was added to each well. The plates were returned to the incubator for another 4 hours of incubation and then shaken for 10 seconds after being taken out. The fluorescence value of each well were recorded at 530/590 nm.

[0108] The above operations were repeated three times.

[0109] The IC.sub.50 value of each test compound was calculated by Prism7 software. IC.sub.50 was divided into different grades according to values, that is, 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 as shown in Table 3.

TABLE-US-00003 TABLE 3 IC.sub.50 Grades of Inhibitory Effects of Compounds on Tumor Cells Compounds HT-29 COLO205 NCI-H460 A549 HL-60 U-937 I-01 S S A S A S I-02 A A A A A A I-03 S SS A S S A I-04 SS S A A S S I-05 S S A A A A I-08 B A A A A A I-10 A S S A S A I-12 A A A A B B I-15 S A S A A S I-17 S A S S A S I-18 A B A A A B I-20 A A A S A A 1d C C D C C B 1 C C B A B C Amonafide B A B S A B

[0110] It can be seen from the test result that the anti-tumor activity of the compounds of the present disclosure is generally better than that of the positive drug Amonafide. As shown by the comparison between the compounds of the present disclosure and similar compounds, the overall inhibitory activity of the compounds of the present disclosure on tumor cells is significantly better than that of the Compound 1d and the Compound 1. Especially for colon cancer cells, the activity of some preferred compounds (such as Compounds 1-03 and 1-04) is 50 times more than that of similar compounds.

[0111] Both Compound 1d and Compound 1 are structurally modified compounds of Amonafide, they are obtained by modifying the alkylamino group on the right side of Amonafide, but their overall anti-tumor activity is inferior to that of Amonafide under the test condition of the present disclosure.

[0112] The difference in activity between the compounds of formula I of the present disclosure and Compound 1d as well as Compound 1 suggests that, in the modification of alkylamino group on the right side of Amonafide, it is very important for the improvement of activity to introduce a heteroatom (R.sub.1) and separate the heteroatom (R.sub.1) from the heteroatom (R.sub.2) connected to right-side carbonyl group with a carbon chain or a carbon ring.

[0113] Although the foregoing has been described the present disclosure in detail with the general description and specific embodiments, some modifications or improvements can be made by those skilled in the art on the basis of the present disclosure, and these modifications or improvements made without departing from the spirit of the present disclosure all fall within the scope of protection of the present disclosure as claimed.