Aza-cyclohydrazide compounds and uses thereof

Abstract

The present application belongs to the field of pharmaceutical chemistry, and relates to azacyclic hydrazine compounds and uses thereof. Specifically, the present application provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, racemate, prodrug or metabolite thereof, which exhibits good antitumor activity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and relates to a kind of azacyclic hydrazine compounds with anti-tumor activity or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, racemate, prodrug or metabolite, pharmaceutical composition comprising the same, and purposes thereof. BACKGROUND

[0002] Cancer is a malignant disease with high morbidity and mortality, and relatively poor treatment effect worldwide. In the global scope, anti-tumor drugs have become the first treatment area in the drug market. The commonly used anti-tumor drugs include cytotoxic drugs, hormone drugs, molecular targeted therapy drugs, biological response modifiers, tumor differentiation inducers, tumor angiogenesis inhibitors and drugs for adjuvant therapy of tumors, etc.

[0003] According to the research of World Health Organization, in 2020, there were 1929 million new cancer cases worldwide, of which 4573 million new cancer cases in China accounted for 23.7% of the world, ranking first, which is about twice the number of new cancer cases in the United States, which ranks second. In 2020, breast cancer has become the cancer with the highest incidence worldwide, and lung cancer ranks second, but lung cancer is the cancer with the highest mortality rate worldwide. The second is colorectal cancer, which ranks third in the number of cases, and the cancer mortality rate is only second to lung cancer. Therefore, the discovery and development of anti-tumor drugs have always been the focus of global scientists and the key issues of major health and survival problems faced by mankind.

[0004] At present, anti-tumor drugs have the characteristics of high toxicity and low selectivity. Therefore, it is of great significance to discover and develop new compounds with higher activity, better selectivity and lower toxicity. SUMMARY

[0005] Based on the scientific hypothesis that "cancer is a body ulcer" and "cancer treatment should be preceded by ulcer treatment", about 30000 compounds are designed and synthesized from a series of anti-inflammatory drugs or lead compounds. A series of small molecule compounds with novel structures as shown in formula I are synthesized by a large number of researches and optimized screening. It is surprisingly found that they all have high anti-tumor activity, good selectivity and low toxicity. These compounds or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, racemate, prodrug or metabolite, and its pharmaceutical composition can be used for treating or / and preventing cancer, such as lung cancer, breast cancer, colon cancer and melanoma.

[0006] The present application provides a compound with the structure of formula I or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, racemate, prodrug or metabolite:

[0007]

[0008] wherein,

[0009] R1, R2, R3, R4and R5are each independently selected from the group consisting of: -H, -R 10 , -O-R 11 ;

[0010] R6is selected from the group consisting of: -H, -R 10 ;

[0011] R7is selected from the group consisting of: -H, -R 10 , halogen;

[0012] R8and R9are each independently selected from the group consisting of: N, O, S;

[0013] R 10 and R 11 are each independently selected from the group consisting of: -H, -C 1-8 alkyl, -C 2-8 alkenyl, -C 3-8 cycloalkyl, -C 3-8 cycloalkenyl; said -C 3-8 cycloalkyl is optionally substituted with one or more -OH or halogen; preferably, R 10 and R 11 are each independently selected from the group consisting of: -H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 3-6 cycloalkyl, -C 3-6 cycloalkenyl;

[0014] and, when R1is -OH, R2, R3, R4and R5are not simultaneously -H; or, when R3is -OH, R1, R2, R4and R5are not simultaneously -H.

[0015] said "alkyl" refers to a saturated aliphatic hydrocarbon radical, which can be a straight chain or branched chain radical;

[0016] said "alkenyl" refers to an alkyl radical as defined above containing at least one carbon-carbon double bond, which can be a straight chain or branched chain radical;

[0017] said "cycloalkyl" refers to a saturated, monocyclic or polycyclic cyclic hydrocarbon substituent;

[0018] said "cycloalkenyl" refers to a partially unsaturated, monocyclic or polycyclic cyclic hydrocarbon substituent;

[0019] said "halogen" refers to fluorine, chlorine, bromine or iodine.

[0020] Preferably, in formula I, at least one of R1, R2, R3, R4and R5is selected from the group consisting of: -R 10 , -O-R11 ; said R 10 and R 11 are each independently selected from the group consisting of: -C 1-8 alkyl, -C 2-8 alkenyl, -C 3-8 cycloalkyl, -C 3-8 cycloalkenyl.

[0021] Preferably, in Formula I, R6 is selected from the group consisting of: -C 1-6 alkyl; more preferably from the group consisting of: -C 1-3 alkyl; further preferably from the group consisting of: -CH3.

[0022] Preferably, in Formula I, R7 is selected from the group consisting of: halogen; more preferably from the group consisting of: -F, -Cl, -Br; further preferably from the group consisting of: -F.

[0023] Preferably, in Formula I, R8 and R9 are each independently selected from the group consisting of: N and O; more preferably, R8 is selected from the group consisting of: N and R9 is selected from the group consisting of: O.

[0024] Preferably, in Formula I, R1, R3 and R5 are each independently selected from the group consisting of: -H, -OH, -O-C 1-6 alkyl, -O-C 2-6 alkenyl.

[0025] Preferably, in Formula I, R2 and R4 are each independently selected from the group consisting of: -H, -O-C 1-3 alkyl, -C 2-6 alkenyl.

[0026] Preferably, in Formula I, R1, R3 and R5 are each independently selected from the group consisting of: -H, -OH, -O-CH3, -O-CH2CH=CH2, -O-CH2CH=C(CH3)2, -O-(CH2)5CH3, -O-(CH2)3CH3.

[0027] Preferably, in Formula I, R2 and R4 are each independently selected from the group consisting of: -H, -OCH3, -CH2CH=CH2, -CH2CH=C(CH3)2.

[0028] Preferably, in Formula I, R2 is selected from the group consisting of: -CH2CH=CH2, -CH2CH=C(CH3)2.

[0029] In certain embodiments, the compounds of Formula I, and pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, racemates, prodrugs or metabolites thereof, are selected from the group consisting of:

[0030]

[0031]

[0032] The present application also provides a method for preparing a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, racemate, prodrug or metabolite thereof, comprising the following steps:

[0033]

[0034] Compound A is reacted with hydrazine hydrate to obtain compound B, and compound B is condensed with compound C to obtain a compound of Formula I. The definitions of R1, R2, R3, R4, R5, R6, R7, R8 and R9 are the same as described above.

[0035] Compound A can be directly obtained from the market. Compound C is obtained from commercially available benzaldehyde compounds through substitution reaction and optional rearrangement reaction.

[0036] In another aspect of the present application, the present application also provides a pharmaceutical composition comprising at least one compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, racemate, prodrug or metabolite thereof, and one or more pharmaceutically acceptable carriers.

[0037] In another aspect of the present application, the present application provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, racemate, prodrug or metabolite thereof, or a pharmaceutical composition for preventing and / or treating cancer, wherein the cancer is mainly lung cancer, breast cancer, colon cancer and melanoma.

[0038] The compound of the present application has strong tumor cell inhibition activity, and shows obvious selectivity, low killing effect on normal cells and low toxicity. The compound of the present application has anti-tumor activity, low toxicity, strong selectivity, mild synthesis method, simple operation, easy synthesis and suitability for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0039] Figure 1 Figure 4 is the growth curve of transplanted tumors of nude mice in different administration groups (Note: compared with the control group, **P<0.01, ***P<0.001).

[0040] Figure 2 Figure 5 is the effect of different administration groups on the weight of tumors of nude mice (Note: compared with the control group, ***P<0.001).

[0041] Figure 3 Figure 6 is the effect of different administration groups on the lung metastatic nodules of nude mice (Note: compared with the control group, **P<0.01, ***P<0.001). DETAILED DESCRIPTION

[0042] The present application is further described in connection with the following specific examples. It should be understood that these examples are intended to illustrate the application and are not intended to limit the scope of the application. Unless otherwise indicated, the test methods used in the following examples were conducted in accordance with conventional procedures for such reactions. The terms used in the present application are used only to describe and not to limit the particular embodiments. Unless otherwise defined herein, all technical and scientific terms used in the present application have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The techniques used in the present application are intended to be those commonly used in the art, including modifications and changes that would be apparent to one of ordinary skill in the art.

[0043] The experimental materials and reagents used in the following examples were commercially available unless otherwise specified.

[0044] The structures of the compounds described in the following examples were determined by nuclear magnetic resonance 1 H-NMR and 13 The measuring instrument of nuclear magnetic resonance used Agilent DD2 600MH nuclear magnetic resonance spectrometer, and the measuring solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard substance was tetramethylsilane (TMS).

[0045] The meanings of the abbreviations represented in the nuclear magnetic resonance (NMR) data in the following examples are as follows:

[0046] s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quartet doublet, ddd: double double doublet, ddq: double double triplet, ddd: double double double doublet, m: multiplet, br: broad, J: coupling constant, Hz: hertz, δ: chemical shift, the chemical shift (δ) value is given in units of parts per million (ppm).

[0047] Preparation of compound 10 of Example 1

[0048]

[0049] Step one: synthesis of compound 10-1

[0050] Take SM-1 (10.00 g), add 50 mL water stirring, add 60 mL hydrazine hydrate (85%), reflux reaction for 18 h, thin layer monitoring reaction process, after the disappearance of raw material directly low temperature for 24 h, the solid precipitate after filtration, washing with water, the filter cake dried under reduced pressure for 1 h, get yellow powder solid (compound 10-1) 9.25 g, yield 77.95%.

[0051] Step two: synthesis of compound 10-2

[0052] Take SM-2 (15.50 g), add 150 mL acetonitrile stirring, add potassium carbonate (34.10 g), allyl bromide (22.40 g), reaction at 55 ℃ for 3 h, thin layer monitoring reaction process; after the reaction was finished and washed with acetonitrile 3 times, 10 mL each time, the filtrate was concentrated under reduced pressure to get oil (compound 10-2) 20.22 g, yield 98.22%.

[0053] Step three: synthesis of compound 10-3

[0054] Take compound 10-2 (20.30 g), under argon protection, 200 ℃ for 7 h, thin layer monitoring reaction process raw material disappears, the reaction was terminated; weighing black viscous oil 18.56 g, column chromatography separation to get 11.60 g yellow oil compound 10-3, yield 57.14%.

[0055] Step four: synthesis of compound 10

[0056] Take compound 10-1 (100 mg), add 5 mL anhydrous ethanol stirring heating dissolution, add compound 10-3 (64.46 mg), reflux reaction for about 7.0 h, thin layer monitoring reaction process, after the reaction was finished column chromatography separation to get 79.2 mg yellow solid, compound 10, yield 57.22%.

[0057] 1 H NMR (600 MHz, CDCI3) δ 13.15 (s, 1H), 8.73 (s, 1H), 8.05 (s, 1H), 7.67 (d, J = 12.2 Hz, 1H), 7.51-7.48 (m, 2H), 7.00 (d, J = 8.2 Hz, 1H), 6.05-5.97 (m, 1H), 5.11-5.04 (m, 2H), 4.57-4.53 (m, 1H), 4.39-4.33 (m, 2H), 3.40-3.37 (m, 2H), 3.36-3.31 (m, 4H), 2.57 (br. s, 4H), 2.37 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H).

[0058] 13 C NMR (150 MHz, DMSO-d6) δ 173.95, (173.93), 160.56, 157.07, 156.05, (154.42), 148.01, 145.11, 140.17, (140.13), 136.69, 131.12, (131.02), 128.28, 127.38, 126.61, 125.27, 124.23, 121.40, (121.34), 115.59, 115.04, 109.38, 103.42, (103.27), 68.04, 55.25, 54.15, 50.07, (50.04), 45.99, 33.62, 17.84.

[0059] Preparation of compound 25 of example 2

[0060]

[0061] Step one: synthesis of compound 25-1

[0062] The same as the synthesis step of compound 10-1.

[0063] Step two: synthesis of compound 25-2

[0064] Sodium hydroxide (3.28 g) was weighed into 80 mL of water and cooled to 0-5°C. SM-2 (10.00 g) was added and stirred for 30 min. Isopentenyl bromide (16.10 g) was added dropwise over 30 min. The reaction was stirred at 0-10°C for 4 h. TLC was used to monitor the reaction progress. When the starting material was consumed, the reaction was completed. 40 mL of dichloromethane was added to extract the product. The organic phase was dried over anhydrous magnesium sulfate. After filtration, the organic phase was concentrated under reduced pressure to obtain 15.20 g of an oil. Column chromatography was used for separation and purification (eluent: PE:EA = 12:1) to obtain 2.40 g of compound 25-2, with a yield of 15.41%.

[0065] Step three: synthesis of compound 25

[0066] Compound 25-1 (110.1 mg, 1.0 eq) and compound 25-2 (85.4 mg) were weighed into 5 mL of ethanol and stirred to dissolve. The reaction was refluxed for 7 h. TLC was used to monitor the reaction progress. When the starting material was consumed, the reaction was terminated. The reaction was naturally cooled to room temperature. Filtration was performed. The filter cake was washed with anhydrous ethanol 2-3 times, 1-2 mL each time. Drying was performed to obtain 75.9 mg of a light yellow solid, with a yield of 47.25%.

[0067] 1H NMR (600 MHz, CDC13) δ 13.14 (s, 1H), 8.74 (s, 1H), 8.12 (s, 1H), 7.72 (d, J = 12.3 Hz, 1H), 7.54 (s, 1H), 7.53 (s, 1H), 6.95 (d, J = 8.7 Hz, 1H), 5.38 - 5.31 (m, 1H), 4.49 (d, J = 7.1 Hz, 1H), 4.44 - 4.30 (m, 2H), 3.38 (d, J = 7.5 Hz, 4H), 3.36 - 3.29 (m, 2H), 2.56 (br. s, 4H), 2.37 (s, 3H), 1.76 (s, 6H), 1.59 (d, J = 6.8 Hz, 3H).

[0068] 13 C NMR (150 MHz, CDC13) δ 175.31 (175.29), 161.86, 157.18, 156.94 (155.30), 149.17, 144.46, 139.69, (139.64), 134.50, 132.40 (132.31), 129.81, 127.83, 127.70, 126.51, 124.47, 122.29 (122.23), 121.96, 116.34, 110.60, 105.53 (105.37), 68.37, 55.88, 55.27, 50.73 (50.70), 46.53, 29.48, 25.93, 18.50, 18.06.

[0069] The present inventors have also synthesized the following compounds using a synthetic method similar to that of Example 1 and Example 2.

[0070] Table 1 Structural formula and data analysis of the compound of the present invention

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082] Example 3 in vitro activity study

[0083] Inhibitory activity of the compound of the present application on human non-small cell lung cancer cells (A549), human breast cancer cells (MCF-7), human melanoma cells (A375), human colon cancer cells (HCT-116).

[0084] 1. Test method: MTT method was used to study the inhibitory effect of the compound on cancer cell proliferation.

[0085] 2. Instruments and reagents are shown in Table 2 and Table 3.

[0086] Table 2 List of reagents

[0087]

[0088]

[0089] Table 3 List of instruments

[0090]

[0091] 3. Compound preparation

[0092] The compound was dissolved in DSMO and stored at room temperature under nitrogen for standby. The sample in DSMO was diluted step by step with culture solution to the required concentration.

[0093] 4. Test method

[0094] The specific steps are as follows: human non-small cell lung cancer cells (A549), human breast cancer cells (MCF-7), human melanoma cells (A375), human colon cancer cells (HCT-116) were cultured in DMEM medium containing 10% FBS (both 100 kU / L of penicillin and streptomycin) in a 5% CO2 37°C constant temperature incubator. When the cells reached 80-90% of the dish, they were passaged every 24 hours, and the fresh culture medium was replaced.

[0095] A549, MCF-7, A375 and HCT-116 cells were cultured in a 37°C, 5% CO2 incubator to the logarithmic growth phase, and were inoculated in a 96-well plate at a cell density of 4000 cells / well. After 24 hours, they were divided into blank control group (NC), positive drug group (1 μM), and test compound group (5 μM). After 24 hours of culture, 20 μL of MTT solution (5 mg·mL -1), continue to culture for 4h, carefully aspirate the culture solution, add DMSO solution 150μL to each well, shake for 10min to completely dissolve. Measure the absorbance value (OD) of each well at 490nm by microplate reader, and calculate the cell viability.

[0096] The compounds with strong cell inhibition effect are detected for IC 50 value based on real-time label-free dynamic cell analysis technology (RTCA). A549 cells and HCT-116 cells are cultured in a 37℃, 5% CO2 incubator to logarithmic growth phase, inoculated in a 96-well plate at a cell density of 2×10 4 6 / mL, 200μL per well, and divided into a normal group (NC) and each test compound group (0.01, 0.1, 1, 10, 50, 100μM) after 24h, and continue to culture for 48h. The IC 50 value of each effective compound is calculated (xCELLigence system).

[0097] The experimental data are expressed as mean ± standard deviation , and statistical analysis is performed by SPSS 20.0. One-way ANOVA is used for comparison between groups. P<0.05 indicates significant difference, and P<0.01 indicates extremely significant difference.

[0098] In this embodiment, the inhibitory activity and half inhibitory activity of the compounds of the present application on cancer cells are determined, as shown in Table 4 below.

[0099] Table 4 Inhibitory activity data of the compounds of the present application on cancer cells

[0100]

[0101]

[0102] Note: compared with NC, *P<0.05, **P<0.01.

[0103] As can be seen from the results in Table 4: in the study of A549 cell activity, the compounds of the present application have the effect of inhibiting cancer cells. Compounds 4, 10, 11, 12, 14, 17, 22 and 24 all show good inhibitory effect on cell activity, and are better than the positive control drug, especially compounds 3, 4, 10, 14, 17 and 24 have more obvious effect, and compounds 4, 10 and 14 have the best effect on lung cancer tumor.

[0104] In the study of MCF-7 cell viability, the compounds of the present application have the effect of inhibiting cancer cells. Among them, compounds 4, 6, 7, 9, compounds 11-25 all show good inhibitory effect on MCF-7 cell viability, and are better than the positive control drug, especially compounds 4, 7, 11, 12, 14, 16, 17, 18, 22, 24 and 25 have more obvious effect, and compounds 4, 7 and 14 have the best effect on anti-breast cancer tumor.

[0105] In the study of A375 cell viability, the compounds of the present application have the effect of inhibiting cancer cells. Among them, compounds 4, 6, 7, 10, 11, 12, 14-20, 22, 24 and 25 all show good inhibitory effect on A375 cell viability, and are better than the positive control drug, especially compounds 4, 6, 10, 11, 12, 14-17 and 24 have more obvious effect, and compounds 4, 10 and 14 have the best effect on anti-breast cancer tumor.

[0106] In the study of HCT-116 cell viability, the compounds of the present application have the effect of inhibiting cancer cells. Among them, compounds 4, 7, 10, 11, 12, 14, 16, 17, 19, 22, 24 all show good inhibitory effect on HCT-116 cell viability, and especially compounds 4, 7, 11, 12, 14, 16, 17, 22, 24 have more obvious effect, and compounds 4, 12 and 14 have the best effect on anti-breast cancer tumor.

[0107] Example 4 in vivo activity study

[0108] The in vivo anti-tumor activity of the compounds of the present application on human lung cancer was studied.

[0109] 1. Experimental materials: 18 SPF BALB / c male nude mice, 6 weeks old, body weight (20±2) g (Beijing Vito Lihua Experimental Animal Technology Co., Ltd.). A549 cell strain (Wuhan Punsai Life Science and Technology Co., Ltd.), laboratory cryopreservation transmission to the fourth generation. The main reagents and main instruments are shown in Table 5 and Table 6.

[0110] Table 5 Main reagents

[0111]

[0112] Table 6 Main instruments

[0113]

[0114] 2. Experimental method

[0115] (1) Cell culture

[0116] A549 cells were cultured in DMEM medium containing 10% fetal bovine serum, 1% penicillin-streptomycin, 1% non-essential amino acids, in a 37°C, 5% CO2 incubator with saturated humidity, and subcultured every other day.

[0117] (2) Mouse xenograft model

[0118] Grouping and modeling:

[0119] ① After 7 days of adaptive feeding, the mice were randomly divided into control group, compound 4 group and compound 14 group according to body weight, 6 mice in each group, and A549 lung cancer xenograft model was established.

[0120] ② Inoculation of cells: collect A549 lung cancer cells in logarithmic growth phase, resuspend with PBS, adjust the cell concentration to 1×10 7 / mL, subcutaneously inject in the right back of mice, 0.1 mL per mouse (1×10 6 cells), and about 7 days after inoculation, green bean-sized tumors can be seen in the right back of mice, indicating successful modeling.

[0121] Drug administration method:

[0122] After successful modeling, the compounds were administered, and the two compounds were injected into the mice at a dose of 20 μg / g, and the control group of mice was given normal saline of the same specification, once a day, for four consecutive weeks.

[0123] ① Measurement: observe and monitor the tumor growth of mice when the tumor starts to grow, and measure the maximum vertical diameter of the tumor length (a) and width (b) with a vernier caliper. Measure twice a day and record.

[0124] ② The formula for calculating the tumor volume is:

[0125] Calculate the tumor volume: tumor volume (mm 3 ) = 1 / 2ab 2 , monitor the tumor growth and draw the growth curve, and euthanize the mice with CO2 when the tumor volume of the control group reaches 1500 mm 3 .

[0126] ③ Tumor inhibition rate: after the administration is completed, the tumor is completely stripped and weighed, and the tumor inhibition rate of each group is calculated, tumor inhibition rate = (1- average tumor weight of the drug group / average tumor weight of the control group) x 100%.

[0127] ④ Lung tumor metastatic nodules: count the number of lung tumor metastatic nodules under a microscope.

[0128] (3) Statistical analysis

[0129] The experimental data were statistically analyzed by Graphpad Prism 8.0 software, the experimental results were expressed as mean ± standard error, the differences between groups were compared by One-Way ANOVA analysis, the comparison between two groups was performed by t test, and P<0.05 was considered to have statistically significant difference.

[0130] 3. Experimental results

[0131] 3.1 Effects of different drugs on the growth of transplanted tumors in nude mice

[0132] By calculating the tumor growth of each group of nude mice, the results showed that compared with the control group, from the second week to the fourth week, the tumor volume of compound 4 and compound 14 groups was significantly reduced (P<0.05, P<0.001), which could inhibit the tumor growth curve, and compound 14 had stronger inhibitory effect on tumor, as shown in Figure 1 Table 7.

[0133] Table 7. Effects of different drug groups on tumor volume (mm 3 , n=6)

[0134]

[0135] Note: compared with the control group, **P<0.01, ***P<0.001.

[0136] 3.2 Effects of different drug groups on tumor weight and tumor inhibition rate of nude mice

[0137] By calculating the tumor weight and tumor inhibition rate of each group, the results showed that compared with the control group, compounds 4 and 14 could significantly inhibit the tumor weight (P<0.001), and the tumor inhibition rates of compounds 4 and 14 were both higher than 50%, among which the tumor inhibition rate of compound 14 was 83.84%, which was better, as shown in Figure 2 Table 8.

[0138] Table 8. Effects of different drug groups on tumor weight and tumor inhibition rate (n=6)

[0139]

[0140] Note: compared with the control group, ***P<0.001.

[0141] 3.3 Effects of different drug groups on lung metastatic nodules of nude mice

[0142] By calculating the number of lung tumors of each group of nude mice, the results showed that the inhibition rate of lung nodular metastasis of compound 4 was 50.67% (P<0.01), and the inhibition rate of lung nodular metastasis of compound 14 was 74.67% (P<0.001), as shown in Figure 3 Table 9.

[0143] Table 9 Effect of different administration groups on lung metastatic nodules of nude mice (n=6)

[0144]

[0145] Note: Compared with the control group, **P<0.01, ***P<0.001.

[0146] Based on the above description of the invention, those skilled in the art can fully apply the present application, and all the same principles or similar modifications should be considered within the scope of the present application.

Claims

1. The following compounds or their pharmaceutically acceptable salts:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from:

3. Claim 1 of the compound or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from:

4. A pharmaceutical composition comprising at least one compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

5. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, or the pharmaceutical composition according to claim 4, in the preparation of a medicament for the prevention and / or treatment of cancer.

6. The use according to claim 5, wherein, The cancer in question is lung cancer, breast cancer, colon cancer, or melanoma.

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