DIIMIDE DERIVATIVE, AND PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

Provided are a diimide derivative represented by formula I, a preparation method therefor and the use thereof. The diimide derivative has a good anti-tumor activity, and the anti-proliferative activity against various cancer cells is significantly better than those of similar compounds.

##STR00001##

Claims

1. A diimide derivative represented by formula I, ##STR00020## wherein in formula I, A is naphthalene or anthracene, fused with diimide through 3 carbon atoms; R.sub.1 is hydrogen, alkyloxy or nitro; m or n is 1, 2 or 3, and m+n4; R.sub.2 is alkyl; R.sub.3 is hydrogen or alkyl; and R.sub.4 or R.sub.5 is alkyl, haloalkyl or nitroso.

2. The diimide derivative according to claim 1, wherein the alkyl is C1-C4 alkyl, the alkyloxy is C1-C4 alkyloxy, and the haloalkyl is C1-C4 haloalkyl.

3. The diimide derivative according to claim 1, wherein A is naphthalene.

4. The diimide derivative according to claim 1, wherein R.sub.1 is nitro or C1-C4 alkyloxy.

5. The diimide derivative according to claim 1, wherein R.sub.3 is hydrogen.

6. The diimide derivative according to claim 1, wherein R.sub.2 forms a ring together with R.sub.3.

7. The diimide derivative according to claim 1, wherein R.sub.4 is C1-C4 haloalkyl, and R.sub.5 is nitroso.

8. The diimide derivative according to claim 1, wherein m and n are: m=1 and n=3, m=1 and n=2, or m=2 and n=2.

9. A method for preparing a diimide derivative represented by formula I, comprising: ##STR00021## reacting a compound of formula M7 with a compound of formula M8 in the presence of a base to generate a compound of formula I according to the above reaction formula; wherein A, m, n, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 in the reaction formula are as defined in claim 1.

10. The method according to claim 9, wherein the compound of formula M7 is prepared by a method comprising: ##STR00022## according to the above reaction formula, reacting a compound of formula M4 with a compound of formula M5 to generate a compound of formula M6, and treating the compound of formula M6 in the presence of an acid to obtain the compound of formula M7; wherein A is naphthalene or anthracene, fused with diimide through 3 carbon atoms; R.sub.1 is hydrogen, alkyloxy or nitro; m or n is 1, 2 or 3, and m+n4; R.sub.2 is alkyl; and R.sub.3 is hydrogen or alkyl.

11. The method according to claim 10, wherein the compound of formula M4 is prepared by a method comprising: ##STR00023## according to the above reaction formula, reacting a compound of formula M1 with a compound of formula M2 to generate a compound of formula M3, and hydrogenating the compound of formula M3 to obtain the compound of formula M4; wherein in the above reaction formula, X is halogen, Cbz is benzyloxycarbonyl and Boc is tert-butoxycarbonyl, m or n is 1, 2 or 3, and m+n4; R.sub.2 is alkyl; and R.sub.3 is hydrogen or alkyl.

12. A drug for treating a cell proliferative disease comprising the diimide derivative according to claim 1.

13. The drug according to claim 12, wherein the cell proliferative disease is cancer.

14. The drug according to claim 13, wherein the cancer is selected from the group consisting of digestive system tumor, respiratory system tumor and hematopoietic tumor.

15. A method for treating a cell proliferative disease, comprising administering a therapeutically effective amount of the diimide derivative according to claim 1 to a subject in need thereof.

16. The method according to claim 15, wherein the cell proliferative disease is cancer.

17. The method according to claim 16, wherein the cancer is selected from the group consisting of digestive system tumor, respiratory system tumor and hematopoietic tumor.

18. A method for treating a cell proliferative disease, comprising administering a therapeutically effective amount of the drug according to claim 12 to a subject in need thereof.

19. The method according to claim 18, wherein the cell proliferative disease is cancer.

20. The method according to claim 19, wherein the cancer is selected from the group consisting of digestive system tumor, respiratory system tumor and hematopoietic tumor.

Description

DETAILED DESCRIPTION

[0044] 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

##STR00007##

[0045] According to the reaction formula, the compound I-01 was prepared as follows: [0046] 1.1 Preparation of intermediate I-01-M3: compound I-01-M2 (3.48 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 (5.14 g, 20 mmol) were successively added into a resulting mixed solution to allow reaction at 30 C. overnight. After the reaction was completed, the reaction solution was added with purified water (120 mL), and extracted with ethyl acetate (180 mL) for three times, dried with anhydrous MgSO.sub.4 and filtered. The mother liquor was concentrated and purified by column chromatography to obtain the intermediate I-01-M3 (4.07 g, 11.6 mmol), with a yield of 58%. [0047] 1.2 Preparation of intermediate I-01-M4: the intermediate I-01-M3 (4.07 g, 11.6 mmol) was dissolved in methanol (25 mL), and then added with 10% Pd/C (0.3 g). The resulting solution was subjected to hydrogen replacement for three times, then reacted overnight under normal pressure, and filtered with diatomite. The mother liquor was concentrated to obtain colorless oily intermediate I-01-M4 (2.50 g, 11.5 mmol), with a yield of 99.1%. [0048] 1.3 Preparation of intermediate I-01-M6: the intermediate I-01-M4 (2.50 g, 11.5 mmol), ethanol (60 mL) and compound I-01-M5 (2.79 g, 11.5 mmol) were successively added into a reaction flask, the resulting mixture was heated to 80 C. for reaction for 2 h, cooled, then concentrated and purified by column chromatography to obtain the intermediate I-01-M6 (3.63 g, 8.2 mmol), with a yield of 71.3%. [0049] 1.4 Preparation of intermediate I-01-M7: the intermediate I-01-M6 (3.63 g, 8.2 mmol) was dissolved in a 4% hydrogen chloride ethyl acetate solution (50 mL) to allow reaction overnight at room temperature, filtered, and dried to obtain the intermediate I-01-M7 (2.67 g, 7.8 mmol), with a yield of 95.1%. [0050] 1.5 Synthesis of compound I-01: compound I-01-M8 (2.46 g, 9 mmol), dichloromethane (30 mL), and triethylamine (2.02 g, 20 mmol) were successively added into a reaction flask and cooled to 0 C., the intermediate I-01-M7 (2.67 g, 7.8 mmol) was added portion-wise to allow reaction overnight at 0 C. The reaction product was washed with water (20 mL), dried with anhydrous MgSO.sub.4 and filtered. The mother liquor was concentrated and purified by column chromatography to obtain the compound I-01 (2.14 g, 4.5 mmol), with a yield of 57.7%. Product identification: .sup.1H-NMR (400 MHZ, d.sub.6-DMSO) : 2.97 (s, 3H), 3.34-3.40 (m, 2H), 3.46-3.51 (m, 2H), 3.58 (t, J=6.5 Hz, 2H), 3.72-3.77 (m, 2H), 3.98-4.11 (m, 2H), 4.46 (t, J=6.2 Hz, 2H), 8.06 (dd, J=8.2, 7.4 Hz, 1H), 8.67-8.62 (dd, J=7.3, 1.1 Hz, 1H), 8.78 (dd, J=8.5, 1.1 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 9.00 (t, J=5.5 Hz, 1H), 9.48 (d, J=2.3 Hz, 1H).

Example 2: Compound I-02

##STR00008##

[0051] Compound I-02 was prepared with reference to the method of Example 1. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-DMSO) : 1.04 (t, J=7.6 Hz, 3H), 2.81-2.84 (m, 4H), 2.92 (s, 3H), 3.45-3.50 (m, 2H), 3.52-3.55 (m, 2H), 3.70 (t, J=2.9 Hz, 2H), 3.82 (t, J=2.9 Hz, 2H), 4.46 (t, J=4.6 Hz, 2H), 8.06 (dd, J=8.2, 7.4 Hz, 1H), 8.67-8.62 (dd, J=7.3, 1.1 Hz, 1H), 8.78 (dd, J=8.5, 1.1 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 9.00 (t, J=5.5 Hz, 1H), 9.48 (d, J=2.3 Hz, 1H).

Example 3: Compound I-03

##STR00009##

[0052] Compound I-03 was prepared with reference to the method of Example 1. Product identification: .sup.1H-NMR (400 MHZ, d.sub.6-DMSO) : 1.73-1.79 (m, 2H), 2.94 (s, 3H), 3.25 (t, J=5.1 Hz, 2H), 2.47-2.53 (m, 2H), 3.55 (t, J=2.9 Hz, 2H), 3.78 (t, J=2.9 Hz, 2H), 4.76 (d, J=2.9 Hz, 2H), 8.06 (dd, J=8.2, 7.4 Hz, 1H), 8.67-8.62 (dd, J=7.3, 1.1 Hz, 1H), 8.78 (dd, J=8.5, 1.1 Hz, 1H), 8.90 (d, J=2.3 Hz, 1H), 9.00 (t, J=5.5 Hz, 1H), 9.48 (d, J=2.3 Hz, 1H).

Example 4: Compound I-04

##STR00010##

[0053] Compound I-04 was prepared with reference to the method of Example 1. Product identification: .sup.1H-NMR (400 MHZ, d.sub.6-DMSO) : 1.04 (t, J=7.6 Hz, 3H), 1.18 (t, J=7.6 Hz, 3H), 2.64-2.68 (m, 4H), 2.96 (s, 3H), 3.28 (q, J=5.8 Hz, 2H), 3.44 (t, J=4.5 Hz 2H), 3.78-3.82 (m, 2H), 4.44 (t, J=4.4 Hz 2H), 8.06 (dd, J=8.2, 7.4 Hz, 1H), 8.67-8.62 (dd, J=7.3, 1.1 Hz, 1H), 8.81 (dd, J=8.5, 1.1 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 9.07 (t, J=5.5 Hz, 1H), 9.48 (d, J=2.3 Hz, 1H).

Example 5: Compound I-05

##STR00011##

[0054] Compound I-05 was prepared with reference to the method of Example 1. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-DMSO) : 2.98 (s, 3H), 3.16 (s, 3H), 3.44-3.47 (m, 2H), 3.56-3.63 (m, 4H), 4.33 (t, J=4.6 Hz, 2H), 8.06 (dd, J=8.2, 7.4 Hz, 1H), 8.67-8.62 (dd, J=7.3, 1.1 Hz, 1H), 8.81 (dd, J=8.5, 1.1 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 9.02 (t, J=5.5 Hz, 1H), 9.51 (d, J=2.3 Hz, 1H).

Example 6: Compound I-06

##STR00012##

[0055] Compound I-06 was prepared with reference to the method of Example 1. Product identification: .sup.1H-NMR (400 MHZ, d.sub.6-DMSO) : 1.17 (t, J=5.8 Hz, 6H), 2.87 (s, 3H), 3.15 (q, J=5.8 Hz, 4H), 3.22-3.25 (m, 2H), 3.38 (t, J=4.5 Hz, 2H), 3.89 (s, 3H), 4.86 (s, 2H), 7.65 (t, J=7.8 Hz, 1H), 8.06 (dd, J=8.2, 7.4 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 8.32-8.42 (m, 2H), 8.62-8.68 (m, 1H).

Example 7: Compound I-07

##STR00013##

[0056] Compound I-07 was prepared with reference to the method of Example 1. Product identification: .sup.1H-NMR (400 MHZ, d.sub.6-DMSO) : 1.77-1.83 (m, 2H), 2.91 (s, 3H), 2.94 (s, 6H), 3.25 (t, J=5.1 Hz, 2H), 3.54-3.58 (m, 2H), 4.84 (d, J=3.5 Hz, 2H), 7.65 (d, J=7.4 Hz, 1H), 7.83-7.86 (m, 2H), 8.43-8.52 (m, 4H).

Example 8: Compound I-08

##STR00014##

[0057] According to the reaction formula, compound I-08 was prepared by a specific method as follows: [0058] 8.1 Synthesis of intermediate I-08-M3: compound I-08-M2 (3.72 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-08-M1 (5.14 g, 20 mmol) were successively added into a resulting mixed solution to allow reaction overnight at 30 C. After the reaction was completed, the reaction solution was added with purified water (120 mL), extracted with ethyl acetate (180 mL) for three times, dried with anhydrous MgSO.sub.4 and filtered. The mother liquor was concentrated and purified by column chromatography to obtain the intermediate I-08-M3 (4.39 g, 12.1 mmol), with a yield of 60.5%. [0059] 8.2 Synthesis of intermediate I-08-M4: the intermediate I-08-M3 (4.39 g, 12.1 mmol) was dissolved in methanol (20 mL), and then added with 10% Pd/C (0.3 g). The resulting solution was subjected to hydrogen replacement for three times, reacted overnight under normal pressure, and filtered with diatomite. The mother liquor was concentrated to obtain the colorless oily intermediate I-08-M4 (2.75 g, 12.0 mmol), with a yield of 99.2%. [0060] 8.3 Synthesis of intermediate I-08-M6: the intermediate I-08-M4 (2.75 g, 12.0 mmol), ethanol (50 mL), and compound I-08-M5 (2.92 g, 12.0 mmol) were successively added into a reaction flask, the resulting mixture was heated to 80 C. for reaction for 2 h. The reaction product was cooled, concentrated and purified by column chromatography to obtain the intermediate I-08-M6 (4.22 g, 9.3 mmol), with a yield of 77.5%. [0061] 8.4 Synthesis of intermediate I-08-M7: the intermediate I-08-M6 (4.22 g, 9.3 mmol) was dissolved in a 4% hydrogen chloride ethyl acetate solution (60 mL) to allow reaction overnight at room temperature. The reaction product was filtered, and dried to obtain the intermediate I-08-M7 (3.12 g, 8.8 mmol), with a yield of 94.6%. [0062] 8.5 Synthesis of compound I-08: compound I-08-M8 (2.62 g, 9.6 mmol), dichloromethane (35 mL), and triethylamine (2.02 g, 20 mmol) were successively added into a reaction flask and cooled to 0 C., intermediate I-08-M7 (3.12 g, 8.8 mmol) was added portion-wise to allow reaction overnight at 0 C. The reaction product was 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 the compound I-08 (2.54 g, 5.2 mmol), with a yield of 59.1%. Product identification: .sup.1H-NMR (400 MHZ, d.sub.6-DMSO) :2.61-2.73 (m, 4H), 2.94-2.98 (m, 2H), 3.19-3.34 (m, 4H), 3.57 (t, J=2.9 Hz, 2H), 3.78 (t, J=2.9 Hz, 2H), 4.45 (t, J=4.6 Hz, 2H), 8.67-8.62 (dd, J=7.3, 1.1 Hz, 1H), 8.78 (dd, J=8.5, 1.1 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 9.00 (t, J=5.5 Hz, 1H), 9.48 (d, J=2.3 Hz, 1H).

Example 9: Compound I-09

##STR00015##

[0063] Compound I-09 was prepared with reference to the method of Example 1. Product identification: .sup.1H-NMR (400 MHZ, d.sub.6-DMSO) : 2.61-2.73 (m, 4H), 2.94-2.98 (m, 2H), 3.19-3.34 (m, 4H), 3.57 (t, J=2.9 Hz, 2H), 3.78 (t, J=2.9 Hz, 2H), 4.47 (t, J=4.6 Hz, 2H), 7.53 (t, J=6.1 Hz, 1H), 7.58-7.65 (m, 1H), 7.79 (t, J=7.8 Hz, 1H), 8.04-8.10 (m, 1H), 8.33-8.35 (m, 1H), 8.49 (d, J=6.3 Hz, 1H), 8.84 (s, 1H), 9.38 (d, J=7.8 Hz, 1H).

Example 10: Compound I-10

##STR00016##

[0064] Compound I-10 was prepared with reference to the method of Example 1. Product identification: .sup.1H-NMR (400 MHz, d.sub.6-DMSO) : 1.72-177 (m, 2H), 2.95 (s, 3H), 3.35-3.38 (m, 2H), 3.54 (t, J=2.9 Hz, 2H), 3.68 (t, J=5.1 Hz, 2H), 3.82 (t, J=2.9 Hz, 2H), 4.65 (s, 2H), 7.73-7.81 (m, 2H), 8.27 (d, J=6.2 Hz, 1H), 8.39-8.50 (m, 2H), 8.87 (d, J=6.2 Hz, 1H), 9.28 (d, J=2.6 Hz, 1H), 9.52 (d, J=7.9 Hz, 1H).

Example 11: Compound I-11

##STR00017##

[0065] Compound I-11 was prepared with reference to the method of Example 1. Product identification: .sup.1H-NMR (400 MHZ, d.sub.6-DMSO) : 2.94 (s, 3H), 2.95-3.05 (m, 2H), 3.40 (t, J=4.5 Hz, 2H), 3.56 (t, J=2.9 Hz, 2H), 3.80-3.82 (m, 2H), 3.84 (t, J=2.9 Hz, 2H), 4.49 (t, J=4.5 Hz, 2H), 7.53 (t, J=6.1 Hz, 1H), 7.59-7.66 (m, 1H), 7.78 (t, J=6.2 Hz, 1H), 8.04-8.10 (m, 2H), 8.33-8.35 (m, 1H), 8.49 (d, J=6.2 Hz, 1H), 8.73 (s, 1H), 9.38 (d, J=7.8 Hz, 1H).

Example 12: Compound I-12

##STR00018##

[0066] Compound I-12 was prepared with reference to the method of Example 1. Product identification: .sup.1H-NMR (400 MHZ, d.sub.6-DMSO) : 1.04 (t, J=7.2 Hz, 3H), 2.56 (q, J=5.8 Hz, 2H), 2.94 (t, J=4.4 Hz, 2H), 3.27-3.31 (m, 2H), 3.45 (t, J=4.4 Hz, 2H), 3.54 (t, J=2.9 Hz, 2H), 3.77 (t, J=2.9 Hz, 2H), 4.14 (t, J=4.6 Hz, 2H), 7.53 (t, J=6.2 Hz, 1H), 7.59-7.66 (m, 1H), 7.78 (t, J=6.2 Hz, 1H), 8.04-8.10 (m, 2H), 8.33-8.35 (m, 1H), 8.49 (d, J=6.2 Hz, 1H), 8.73 (s, 1H), 9.38 (d, J=7.8 Hz, 1H).

Example 13: Study on the In Vitro Antitumor Activity of the Compound of Formula I

[0067] Objective: to test the antiproliferative activity of the compound in the present disclosure against a variety of tumor cells.

[0068] Test compounds: compounds I-01, I-02, I-03, I-04, I-05, I-06, I-07, I-08, I-09, I-10, I-11, I-12 of the present disclosure; positive drugs: amonafide and lomustine; and comparative compounds: 1, 1d, Cob280, and Cob281. The compound 1 refers to compound 1 described in Journal of Experimental Therapeutics and Oncology, 2005, 5: p 15-22, the compound 1d refers to Id described in Journal of Cancer Molecules, 2010, 5 (2): p 41-47, the compound Cob280 refers to Cob280 described in Example 17a of patent WO2012104788, the compound Cob281 refers to Cob281 in Example 17b of patent WO2012104788, and they were all prepared according to the method in the literature. Amonafide and lomustine were commercially available.

##STR00019##

[0069] 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).

[0070] Test methods: each tumor cell was processed separately. Cells were cultured in a culture medium at 37 C. for 24 h for later use. The cells in the exponential growth phase were harvested, treated with trypsin to prepare a cell suspension, the cell suspension was centrifuged, and then the cell pellet was resuspended in a small amount of fresh culture medium as a stock cell solution. This stock solution was diluted to the desired cell concentration, and the concentration of each cell was as shown in Table 1:

TABLE-US-00001 TABLE 1 concentrations of each tumor cell Cell line Cell concentration (cell count/mL) HT-29 30000 COLO 205 15000 MCI-H460 15000 A549 20000 HL-60 30000 U-937 30000

[0071] A 96-well plate was taken, and blank control groups, cell control groups and compound treatment groups were set up. In the blank control groups, only 10% phosphate buffer saline (PBS) was added to each well. 100 L of cells at the above concentration were added into each well of the cell control groups and compound treatment groups. The remaining wells were filled with 200 L of 10% PBS. The plate was placed in an incubator overnight. 100 L of each test compound at different dilution concentrations was added into each well of the compound treatment groups, 10 and the dilution concentrations of the compound were as shown in Table 2.

TABLE-US-00002 TABLE 2 dilution concentration of test compound No. Compound concentration (M) 1 200 2 66.7 3 22.2 4 7.41 5 2.47 6 0.823 7 0.274 8 0.0914

[0072] After adding the drug, the plate was placed in an incubator to be cultured for 96 hours, 22 L of resazurin sodium solution (Alarm blue, SIGMA R7017) was added into each well, and the plate was returned to the incubator to be cultured for another 4 h. The plate was shaken for 10 s after being taken out. A fluorescence value of each well was tested at 530/590 nm.

[0073] The above operations were repeated for three times.

[0074] The IC.sub.50 value of each test compound was calculated with the Prism7 software. The IC.sub.50 was divided into different grades according to value, that is: SSS: <0.5 M, SS: 0.5-1 M; S: 1-5 M; A: 5-10 M; B: 11-20 M; C: 21-50 M; D: 51-100 M; E: >100 M. The main results are as shown in Table 3:

TABLE-US-00003 TABLE 3 IC.sub.50 grades of compound's inhibitory effect on tumor cells Compound HT-29 COLO 205 NCI-H460 A549 HL-60 U-937 I-01 SSS SSS SSS SS SSS SSS I-02 SS S S SS SS S I-03 S S S S S SS I-04 S A S S S S I-05 SS S S SS SS SS I-06 S A A S S S I-07 A S S A S A I-08 S SS S SS S SS I-09 S S S S S SS I-10 ISS SS S S SS ISS I-11 S S A S A S I-12 S SS S S SS S 1 C C B A B C 1d C C D C C B Cob280 A B B B A A Cob281 A B B A A A Amonafide B A B S A B Lomustine D E D E C B

[0075] Test results show that lomustine has a poor activity against various tumor cells, while amonafide has a better activity. The activities of compounds 1d, 1, Cob280 and Cob281 are not better than that of amonafide, and even is reduced. But surprisingly, the antitumor activity of the compound of the present disclosure is significantly better than that of amonafide, lomustine, and similar compounds 1d, 1, Cob280, and Cob281. The activities of some preferred compounds of the present disclosure are more than 100 times or above than those of similar compounds.

Example 22: Study on the In Vivo Anti-Tumor Effect of the Compounds of Formula I

[0076] Objective: to further test the in vivo antitumor effects of compounds of the present disclosure

[0077] Test compounds: I-01, I-08.

[0078] Test animals: 5-week-old female BALB/c nude mice were fed normally for 7 days, and mice with good physical conditions were selected for experiments.

[0079] Tumor cells: human colon cancer cells COLO 205 were subjected to cell culture in a RPMI-1640 medium containing 10% fetal bovine serum. The passaging was carried out for 1-2 times a week, with a passaging ratio of 1:3 to 1:6.

[0080] Modeling and grouping: COLO 205 cells in a logarithmic growth phase were harvested and injected into the anterior right mammary fat pad of nude mice with an injection volume of 510.sup.6 cells per animal to establish a COLO 205 transplanted tumor model. The animal status was observed regularly, tumor diameter was measured, and tumor volume was calculated. After the tumor volume reached approximately 150 mm.sup.3, tumor-bearing mice in good health and with similar tumor volumes were selected and randomly divided into a solvent control group, an I-01 group, and an I-08 group.

[0081] Administration: each test compound was dissolved in solvent, and each animal group was treated with corresponding compounds or blank solvent, respectively. The administration method was intragastric administration, with a dosage of 10 mg/kg, once a day, and a total of 21 times.

[0082] Result: on the last day of the experiment, tumor diameter and tumor weight were measured, tumor growth inhibition rate (GI) and tumor weight inhibition rate (IR) were calculated. The main results are as shown in Table 4.

[0083] Tumor growth inhibition rate=100%[1(TvtTvini)(CvtCvini)], where Tvt represents tumor volume of the treatment group at the end of the experiment, Tvini represents initial tumor volume of the treatment group, Cvt represents tumor volume of the solvent control group at the end of the experiment, and Cvini represents initial tumor volume of the solvent control group.

[0084] Tumor weight inhibition rate=100%(CwTw)Cw, where Cw represents tumor weight of the solvent control group at the end of the experiment, and Tw represents tumor weight of the treatment group at the end of the experiment.

TABLE-US-00004 TABLE 4 in vivo tumor inhibitory effects of compounds Tumor growth inhibition Tumor weight inhibition Compound rate (%) rate (%) I-01 75.3% 69.3% I-08 43.5% 31.2%

[0085] The test results show that the compound of the present disclosure also has a strong antitumor effect in vivo.

[0086] 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.