Hydroxamic acid compounds and uses thereof

Abstract

The application discloses a kind of hydroxamic acid compounds and application thereof, the hydroxamic acid compound is compound with following chemical structure general formula or its chemical isomer or its salt: the compound of the application has good histone deacetylase inhibitory activity, shows better inhibitory activity to various tumor cells, and the inhibitory effect on normal cells is weak, and toxicity is small, is suitable as antitumor drug development.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, in particular to hydroxamic acid compounds and the use thereof. BACKGROUND

[0002] Tumor is a major disease threatening human health, and the treatment of tumor has been closely watched by the world. Traditional chemotherapeutic drugs non-specifically block cell division to cause cell death, and in killing tumor cells, also destroy normal cells of the human body. And many cytotoxic drugs have limited treatment range, and are prone to cause treatment-related adverse reactions.

[0003] In recent years, with the continuous improvement of molecular biology technology and further understanding of the pathogenesis of tumor from the cell and molecular levels, as well as the rapid development of combinatorial chemistry, structure-based drug design and computer science, tumor biological therapy has made great progress and entered the era of molecular targeted therapy. Targeted anticancer drugs can target specific pathways, prevent tumor growth and reduce toxicity to normal cells. Their common characteristics are: non-cytotoxicity and tumor cell targeting; cell regulation and stabilization; generally cannot reach dose-limiting toxicity and maximum tolerated dose in clinical studies; can kill chemotherapeutic insensitive or drug-resistant tumor cells, and have better effect when used with conventional treatment (radiotherapy, chemotherapy).

[0004] Many anti-tumor targets have been discovered, among which histone deacetylases are important targets for the development of new anti-cancer drugs. The factors leading to abnormal expression of tumor genes and activity of gene expression products come from two aspects of changes, namely genetics and epigenetics. Epigenetics refers to a type of gene expression regulation that affects the transcriptional activity of genes without involving changes in DNA sequence, and its molecular basis mainly involves two aspects: one is methylation modification of DNA, and the other is acetylation modification of histone proteins. Histone acetylation and deacetylation of chromatin are one of the key links in regulating gene expression, and two types of enzymes determine the degree of histone acetylation, namely histone acetyltransferases (HAT) and histone deacetylases (HDAC). Histone acetylation can activate the transcription process of specific genes, while HDAC inhibits the transcription and expression of genes. At the same time, HDAC also has an important influence on the acetylation-deacetylation process of non-histone proteins, including transcription factors, signal transduction proteins, DNA repair enzymes, etc., and these target proteins play a decisive role in the regulation of gene expression. In summary, through the influence on the acetylation process of histone and non-histone proteins, HDAC plays an extremely important role in epigenetic regulation, and the abnormality of this regulation mechanism is closely related to the occurrence and development of tumors. The development of small molecule drugs targeting HDAC, an important molecular target affecting epigenetics, has become a hot spot in the field of international tumor targeted therapy.

[0005] Histone deacetylase inhibitors can be divided into four categories according to their structures: benzamides, hydroxamic acids, fatty acids and cyclic peptides. SAHA (also known as Vorinostat) belongs to hydroxamic acids, and is the first histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma. Its application in the treatment of solid tumors is also in the clinical trial stage, which marks the end of the concept verification research stage of HDAC as a novel drug target, and also indicates that HDAC inhibitors have broad prospects for development as anti-tumor drugs.

[0006] Hydroxamic acid HDAC inhibitors are composed of three parts of aromatic ring, aliphatic chain and hydroxamic acid, which are enzyme surface recognition area, connection area and metal binding area (zinc ion binding area) respectively. In order to find a compound with better enzyme activity than SAHA, researchers have carried out a lot of research on this kind of compound, in which the hydroxamic acid group of the metal binding area is kept unchanged, and the enzyme surface recognition area and the connection area are optimized in structure, so as to find a derivative with higher activity, selectivity and safety as the main research direction of hydroxamic acid inhibitor. While improving the anti-tumor activity, reducing the influence on normal tissues or cells is a topic of great concern.

[0007] The present application aims to obtain a series of compounds by means of drug design and synthesis, to carry out enzyme inhibition and tumor inhibition tests in vitro, and to find a more ideal anti-tumor drug than the marketed drug SAHA. SUMMARY

[0008] In order to make up for the shortcomings of the prior art, the present application discloses a kind of hydroxamic acid compound and its application as an anti-tumor drug to meet the needs of clinical application.

[0009] In order to achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0010] The hydroxamic acid compound is a compound having the following general chemical structure or a chemical isomer or a salt thereof:

[0011]

[0012] Among them,

[0013] R is hydrogen, methyl, methoxy, trifluoromethyl or halogen;

[0014] X is NH, O or S.

[0015] The above-mentioned hydroxamic acid compound specifically includes the following compounds:

[0016] 4-((4-(1H-indole-2-carbonyl)piperazin-1-yl)methyl)-N-hydroxybenzamide,

[0017] 4-((4-(5-fluoro-1H-indole-2-carbonyl)piperazin-1-yl)methyl)-N-hydroxybenzamide,

[0018] N-hydroxy-4-((4-(5-methoxy-1H-indole-2-carbonyl)piperazin-1-yl)methyl)benzamide,

[0019] 4-((4-(benzofuran-2-carbonyl)piperazin-1-yl)methyl)-N-hydroxybenzamide,

[0020] N-hydroxy-4-((4-(5-(trifluoromethyl)benzofuran-2-carbonyl)piperazin-1-yl)methyl)benzamide,

[0021] 4-((4-(5-chlorobenzo[b]thiophene-2-carbonyl)piperazin-1-yl)methyl)-N-hydroxybenzamide, or

[0022] 4-((4-(5-chlorobenzo[b]thiophene-2-carbonyl)piperazin-1-yl)methyl)-N-hydroxybenzamide, or

[0023] N-hydroxy-4-((4-(6-methoxybenzo[b]thiophene-2-carbonyl)piperazin-1-yl)methyl)benzamide.

[0024] The foregoing hydroxamic acid compound, the salt includes hydrochloride, hydrobromide, sulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonic acid or methanesulfonate.

[0025] The foregoing hydroxamic acid compound is used for preparing a medicine for treating tumor.

[0026] The foregoing use, the tumor includes liver cancer, lung cancer, breast cancer, esophageal cancer, gastric cancer, nasopharyngeal carcinoma, ovarian cancer, bladder cancer, rectal cancer, skin cancer and lymphoma.

[0027] The foregoing use, the tumor is selected from non-small cell lung cancer and colorectal cancer.

[0028] The compound of the present application can be administered to mammals (including human) in need of tumor treatment in the form of a composition by oral, injection and the like.

[0029] The composition includes a therapeutically effective amount of hydroxamic acid compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0030] The carrier refers to the carrier in the pharmaceutical field, for example: diluent, excipient such as water; binder such as cellulose derivative, gelatin, polyvinylpyrrolidone and the like; filler such as starch and the like; disintegrant such as calcium carbonate, sodium bicarbonate; in addition, other auxiliary agents such as flavoring agent and sweetening agent can also be added in the composition.

[0031] The composition of the present application can be prepared into conventional solid preparation such as tablet, capsule and the like for oral administration; it can also be prepared into injection and the like for injection.

[0032] The various dosage forms of the composition of the present application can be prepared by the method in the pharmaceutical field, wherein the content of the active ingredient hydroxamic acid compound is 0.1% to 99.5% (weight ratio) of the weight of the composition.

[0033] The hydroxamic acid compound of the present application can be administered to mammals, including humans, in a clinical setting by oral or injection, with oral administration being preferred. The dosage is 0.0001 mg / kg to 200 mg / kg of body weight per day. The optimal dosage varies from individual to individual, and the dosage is usually small at the beginning and then gradually increased.

[0034] Compared with the prior art, the compound of the present application has the following beneficial effects:

[0035] 1) The compound of the present application has good HDAC enzyme inhibitory activity and good inhibitory activity on various tumor cells of the human body.

[0036] 2) The compound of the present application has weak inhibitory effect on normal cells while effectively inhibiting tumor cells, showing good selective inhibitory activity and having good anti-tumor clinical application prospect.

[0037] In summary, the compound of the present application has smaller toxic side effects when used as an anti-tumor drug and is more easily used as an anti-tumor drug. DETAILED DESCRIPTION

[0038] The present application will be further described in detail below in combination with examples. The following examples are only used to illustrate the present application and are not used to limit the scope of the present application.

[0039] Example 1: A hydroxamic acid compound characterized by being a compound having the following general chemical structure or a chemical isomer or a salt thereof:

[0040]

[0041] wherein,

[0042] R is hydrogen, methyl, methoxy, trifluoromethyl or halogen;

[0043] X is NH, O or S.

[0044] For the convenience of understanding the present application, the following specific compounds and salts thereof are preferred in the compound of formula V, but the present application is not limited to the following compounds:

[0045] Table 1

[0046]

[0047]

[0048] The hydroxamic acid compound can be salted with inorganic acid or organic acid to obtain a salt form of the hydroxamic acid compound, and the salt is hydrochloride, hydrobromide, sulfate, bisulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonate or methanesulfonate.

[0049] Preferably, the salt form of the hydroxamic acid compound is selected from hydrochloride, hydrobromide, bisulfate, malate, maleate, succinate, p-toluenesulfonate or methanesulfonate.

[0050] More preferably, the salt form of the hydroxamic acid compound is selected from hydrochloride, acetate, sulfate, tartrate or malate.

[0051] According to the above-mentioned salt form of the hydroxamic acid compound, the salt is obtained by salting the hydroxamic acid compound with corresponding inorganic acid or organic acid, and the inorganic acid or organic acid is selected from acid, hydrobromic acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, tannic acid, citric acid, trifluoroacetic acid, malic acid, maleic acid, succinic acid, p-toluenesulfonic acid or methanesulfonic acid.

[0052] The general method for preparing the hydroxamic acid compound is as follows:

[0053]

[0054] The above-mentioned preparation method can further comprise the reaction of the hydroxamic acid compound with inorganic acid (or inorganic base) or organic acid (or organic base) to cool and precipitate the salt of the compound of formula V.

[0055] The compound of the present application can be administered to mammals (including humans) in need of tumor treatment in the form of a composition by oral administration, injection and the like.

[0056] The composition comprises a therapeutically effective amount of the hydroxamic acid compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0057] The carrier refers to the carrier commonly used in the pharmaceutical field, for example: diluent, excipient such as water; binder such as cellulose derivative, gelatin, polyvinylpyrrolidone and the like; filler such as starch and the like; disintegrant such as calcium carbonate, sodium bicarbonate; in addition, other auxiliary agents such as flavoring agent and sweetening agent can also be added to the composition.

[0058] The composition of the present application can be prepared into conventional solid preparations such as tablets, capsules and the like for oral administration; it can also be prepared into injection dosage forms for injection.

[0059] The various dosage forms of the composition of the present application can be prepared by conventional methods in the pharmaceutical field, wherein the content of the active ingredient, the hydroxamic acid compound, is 0.1 to 99.5% by weight based on the weight of the composition.

[0060] The hydroxamic acid compound of the present application can be administered to mammals, including humans, in a clinical setting by oral or injection, with oral administration being preferred. The dosage is 0.0001 mg / kg to 200 mg / kg body weight per day. The optimal dosage varies from individual to individual, and generally starts with a small dosage, which is gradually increased.

[0061] Example 2: Synthesis of 4-((4-(1H-indole-2-carbonyl)piperazin-1-yl)methyl)-N- hydroxybenzamide (T1):

[0062]

[0063] Prepared according to the general synthetic procedure, the synthetic route is as follows:

[0064]

[0065] Synthesis of methyl 4-(4-(1H-indole-2-carbonyl)piperazin-1-yl)methyl)benzoate:

[0066] Dissolve 0.50 g (3.10 mmol) of indole-2-carboxylic acid in 15 mL of N,N-dimethylformamide, add 0.63 g (6.21 mmol) of triethylamine and 0.79 g (3.10 mmol) of O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), stir at room temperature for 30 min, add 0.76 g (3.26 mmol) of methyl 4-(piperazin-1-ylmethyl)benzoate, stir at room temperature overnight, and check the completion of the reaction by TLC. Add 15% sodium chloride solution dropwise to the reaction liquid, and solid precipitates at room temperature for 2 h, filter under suction, and dry in vacuum to obtain 0.934 g of white solid with a yield of 79.8%.

[0067] Synthesis of 4-((4-(1H-indole-2-carbonyl)piperazin-1-yl)methyl)-N-hydroxybenzamide (T1):

[0068] To a solution of 2.00 g (29 mmol) of hydroxylamine hydrochloride and 2.09 g (32 mmol) of potassium hydroxide in 50 mL of methanol, stirring at room temperature for 2 h, the precipitated potassium chloride solid was filtered, 0.588 g (1.56 mmol) of intermediate 6a was added to the above filtrate, and the reaction was carried out at 40 °C for 3 h. TLC detection showed that the reaction was complete. The pH value of the reaction solution was adjusted to 7.0 with 2N hydrochloric acid, and a solid was precipitated. Filtration, the mother liquor was evaporated under reduced pressure, diluted with 30 mL of water, extracted with ethyl acetate (20 mL x 3), the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a white solid (T1) 0.422 g, with a yield of 71.5%. ESI-MS m / z [M+H]+: 379.10; 1 H NMR (400 MHz, DMSO-d6) δ: 11.60-11.53 (m, 1H), 11.17 (s, 1H), 9.04 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.2, 3.8 Hz, 3H), 7.18 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 1.8 Hz, 1H), 3.92-3.64 (m, 4H), 3.57 (s, 2H), 2.45 (t, J = 5.0 Hz, 4H).

[0069] Example 3: Synthesis of 4-((4-(5-fluoro-1H-indole-2-carbonyl)piperazin-1-yl)methyl)-N- hydroxybenzamide (T2):

[0070]

[0071] T2 was prepared according to the general procedure. ESI-MS m / z [M+H]+: 397.16; 1 H NMR (400 MHz, DMSO-d6) δ: 11.60-11.56 (m, 1H), 11.15 (s, 1H), 9.04 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.2, 3.8 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 3.92-3.64 (m, 4H), 3.52 (s, 2H), 2.44 (t, J = 5.0 Hz, 4H).

[0072] Example 4: Synthesis of N-hydroxy-4-((4-(5-methoxy-lH-indole-2-carbonyl)piperazin-l- yl)methyl)benzamide (T3):

[0073]

[0074] T3 was prepared according to the general procedure. ESI-MS m / z [M+H]+: 409.19; 1H NMR (400 MHz, DMSO-d6) δ: 11.71 - 11.65 (m, 1H), 11.15 (s, 1H), 9.03 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.2, 3.8 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 3.92 - 3.64 (m, 4H), 3.79 (s, 3H), 3.52 (s, 2H), 2.44 (t, J = 5.0 Hz, 4H).

[0075] Example 5: Synthesis of 4-((4-(benzofuran-2-carbonyl)piperazin-l-yl)methyl)-N- hydroxybenzamide (T4):

[0076]

[0077] T4 was prepared according to the general procedure. ESI-MS m / z [M+H]+: 380.15; 1 H NMR (400 MHz, DMSO-d6) δ: 11.60 - 11.54 (m, 1H), 9.04 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.2, 3.8 Hz, 3H), 7.18 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 1.8 Hz, 1H), 3.92 - 3.64 (m, 4H), 3.57 (s, 2H), 2.45 (t, J = 5.0 Hz, 4H).

[0078] Example 6: Synthesis of N-hydroxy-4-((4-(5-(trifluoromethyl)benzofuran-2-carbonyl)piperazin-l- yl)methyl)benzamide (T5):

[0079]

[0080] Prepared according to the general procedure T5. ESI-MS m / z [M+H]+: 448.14; 1H NMR (400 MHz, DMSO-d6) δ: 11.78 (m, 1H), 9.04 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.41 (dd, J = 8.2, 3.8 Hz, 3H), 7.18 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.76 (d, J = 1.8 Hz, 1H), 3.92 - 3.64 (m, 4H), 3.53 (s, 2H), 2.41 (t, J = 5.0 Hz, 4H).

[0081] Example 7: Synthesis of 4-((4-(benzo[b]thiophene-2-carbonyl)piperazin-1-yl)methyl)-N- hydroxybenzamide (T6):

[0082]

[0083] Prepared according to the general procedure T6. ESI-MS m / z [M+H]+: 396.13; 1 1H NMR (400 MHz, DMSO-d6) δ: 11.71 - 11.73 (m, 1H), 9.10 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.2, 3.8 Hz, 3H), 7.17 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 3.92 - 3.94 (m, 4H), 3.53 (s, 2H), 2.41 (t, J = 5.0 Hz, 4H).

[0084] Example 8: Synthesis of 4-((4-(5-chlorobenzo[b]thiophene-2-carbonyl)piperazin-1-yl)methyl)-N- hydroxybenzamide (T7):

[0085]

[0086] T7 was prepared according to the general procedure. ESI-MS m / z [M+H]+: 430.09; 1H NMR (400 MHz, DMSO-d6) δ: 11.75 (m, 1H), 9.04 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.41 (dd, J = 8.2, 3.8 Hz, 3H), 7.18 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.74 (d, J = 1.8 Hz, 1H), 3.92 - 3.99 (m, 4H), 3.51 (s, 2H), 2.43 (t, J = 5.0 Hz, 4H).

[0087] Example 9: Synthesis of N-hydroxy-4-((4-(6-methoxybenzo[b]thiophene-2- carbonyl)piperazin-1-yl)methyl)benzamide (T8)

[0088]

[0089] T8 was prepared according to the general procedure. ESI-MS m / z [M+H]+: 410.14; 1H NMR (400 MHz, DMSO-d6) δ: 11.71 - 11.85 (m, 1H), 9.03 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.2, 3.8 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 3.92 - 3.64 (m, 4H), 3.77 (s, 3H), 3.52 (s, 2H), 2.42 (t, J = 5.0 Hz, 4H).

[0090] Example 10: In vitro HDACs enzyme inhibition activity of the compounds

[0091] The K340-100 kit produced by Biovision was selected to test the IC50 of the compounds for HDACs enzyme. The experimental operation was performed according to the kit instructions. The experimental results are shown in Table 2.

[0092] Table 2

[0093] Compound HDACs IC 50 (nM) SAHA 95.12 T1 89.21 T2 56.30 T3 144.5 T4 34.62 T5 201.2 T6 79.03 T7 50.27 T8 168.7

[0094] From the above table, it can be seen that the compounds of the present application have strong inhibitory activity on HDAC, and the inhibitory activity of compounds T1, T2, T4, T6 and T7 is better than that of the positive control drug SAHA.

[0095] Example 11: Anti-proliferative activity test of the compounds

[0096] Selected tumor cells: HCT116 (human colon cancer cells), A549 (human lung adenocarcinoma cells), Hut78 (T lymphocyte leukemia cells), H1993 (human lung cancer non-small cell); SAHA as control drug, CCK-8 method was used to test the anti-proliferation activity. The specific results are shown in Table 3 (unit: IC 50 μM):

[0097] Table 3

[0098]

[0099]

[0100] From the above table, it can be seen that some of the compounds of the present application tested have good anti-tumor cell proliferation activity, among which the anti-proliferation activity of the compounds on HCT116 (human colon cancer cells), A549 (human lung adenocarcinoma cells) and H1993 (human lung cancer non-small cell) is better than that of the positive control SAHA.

[0101] Example 12: Test of the effect of the compound on normal cells

[0102] The in vitro inhibitory activity of the compounds of the present application on normal cells MRC-5 (human embryonic lung cells), HL-7702 (human liver cells), HEK-293 (embryonic kidney cells) was tested. The specific results are as follows:

[0103] Table 4

[0104] Compound MRC-5 HL-7702 HEK-293 SAHA 2.83 12.42 5.31 T1 15.31 20.33 11.62 T2 >30 19.02 >30 T4 18.11 27.39 >30 T6 >30 >30 19.60 T7 21.35 >30 22.34

[0105] From Table 4, it can be seen that the compounds of the present application have weaker inhibitory activity on normal cells than the control drug SAHA, have lower toxic side effects, and are more likely to be used as tumor drugs with lower toxic side effects.

[0106] Example 13: Use of hydroxamic acid compounds in the preparation of a tumor treatment drug.

[0107] Tablet preparation:

[0108] Preparation method: any one of the compounds in Examples 2-9 or a pharmaceutically acceptable salt thereof is mixed with sucrose, corn starch, moistened with water, stirred uniformly, dried, crushed and sieved, calcium stearate is added, mixed uniformly, and then compressed into tablets. Each tablet weighs 200 mg, and the active ingredient content is 10 mg.

[0109] Example 14: Use of hydroxamic acid compounds in the preparation of a tumor treatment drug.

[0110] Injection preparation:

[0111] Water for injection 80 mg

[0112] Preparation method: the active ingredient is dissolved in water for injection, mixed uniformly, filtered, and the obtained solution is divided into ampoule bottles under sterile conditions, 10 mg per bottle, and the active ingredient content is 2 mg per bottle.

[0113] In summary, the present application has been tested by pharmacological tests, the compounds of the present application have strong inhibitory effect on HDAC enzyme (Example 10), the compounds of the present application have strong inhibitory activity on HDAC, and the inhibitory activity of compounds T1, T2, T4, T6 and T7 is better than that of the positive control drug SAHA.

[0114] Some compounds of the present application were selected for anti-proliferation test, and the experimental results showed that the compounds of the present application have good anti-tumor cell proliferation activity, and the anti-proliferation activity of the compounds on HCT116 (human colon cancer cells), A549 (human lung adenocarcinoma cells) and H1993 (human lung cancer non-small cell) is better than that of the positive control SAHA. At the same time, the inhibitory activity of the compounds on normal cells is weak, and has lower toxic side effects, indicating that it has lower toxic side effects when used as an anti-tumor drug, and is easy to be used as a tumor drug.

[0115] Although the present application has been disclosed as above with preferred embodiments, it is not intended to limit the present application, and any person skilled in the art can make possible changes and modifications to the technical solutions of the present application by using the disclosed methods and technical contents without departing from the spirit and scope of the present application. Therefore, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present application, which does not deviate from the technical solutions of the present application, belongs to the protection scope of the technical solutions of the present application.

Claims

1. A hydroxamic acid compound characterized by: A compound having the following general chemical structure: ； or a salt thereof, wherein the compound is specifically selected from the following compounds: 4-((4-(1H-indole-2-carbonyl)piperazin-1-yl)methyl)-N-hydroxybenzamide, 4-((4-(5-fluoro-1H-indole-2-carbonyl)piperazin-1-yl)methyl)-N-hydroxybenzamide, N-hydroxy-4-((4-(5-methoxy-1H-indole-2-carbonyl)piperazin-1-yl)methyl)benzamide, 4-((4-(benzofuran-2-carbonyl)piperazin-1-yl)methyl)-N-hydroxybenzamide, N-hydroxy-4-((4-(5-(trifluoromethyl)benzofuran-2-carbonyl)piperazin-1-yl)methyl)benzamide, 4-((4-(benzo[b]thiophene-2-carbonyl)piperazin-1-yl)methyl)-N-hydroxybenzamide, 4-((4-(5-chlorobenzo[b]thiophene-2-carbonyl)piperazin-1-yl)methyl)-N-hydroxybenzamide, or N-hydroxy-4-((4-(6-methoxybenzo[b]thiophene-2-carbonyl)piperazin-1-yl)methyl)benzamide.

2. The hydroxamic acid compound according to claim 1, characterized by: The salt is selected from hydrochloride, hydrobromide, sulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonate or mesylate.

3. Use of the hydroxamic acid compound of claim 1 or 2 in the preparation of a medicament for treating a tumor.

4. Use according to claim 3, characterized in that: The tumor is selected from liver cancer, lung cancer, breast cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, ovarian cancer, bladder cancer, rectal cancer, skin cancer and lymphoma.

5. Use according to claim 4, characterized in that: The tumor is selected from non-small cell lung cancer and colorectal cancer.

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