Hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridine-2-yl) acetamide and application

Abstract

The invention belongs to the technical field of medicines, and relates to a hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridine-2-yl) acetamide, pharmaceutically acceptable salts, hydrates and a preparation method of the hydroxamic acid compound and a pharmaceutical composition containing the hydroxamic acid compound. The invention also relates to application of the compound in preventing and / or treating diseases related to any one and / or two of histone deacetylase (HDACs) and c-Src kinase. The structure of the compound is shown as a general formula I in the specification.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a hydroxamic acid compound of N-benzyl-2-(5-phenylpyridin-2-yl)acetamide and application thereof for preventing and / or treating diseases related to any one and / or both of histone deacetylases (HDACs) and c-Src kinase. BACKGROUND

[0002] Histone deacetylases (HDACs) are closely related to epigenetics, and play an important role in gene expression by removing the lysine at the end of the histone to increase the positive charge density of the histone, so that the positively charged histone is more closely combined with the negatively charged DNA, which can reduce the expression of some genes including tumor suppressor genes. Since abnormal expression of HDACs is found in various cancers, HDACs have become one of the popular targets in the field of cancer treatment.

[0003] HDAC inhibitors have the characteristics of inhibiting cancer cell proliferation, promoting apoptosis, and small toxic side effects, and thus are developed as a new type of anti-tumor drug. Although HDAC inhibitors have been successfully applied to the treatment of hematological tumors and lymphomas, they have not achieved ideal results in the treatment of solid tumors, which greatly limits their clinical application range.

[0004] Relevant studies have shown that HDAC inhibitors and other target inhibitors, such as tubulin inhibitors, immune checkpoint inhibitors, and endothelial growth factor (EGFR) inhibitors, have shown obvious synergistic effects in the treatment of solid tumors, which lays a solid theoretical foundation for the design of HDAC-based dual-target and even multi-target inhibitors.

[0005] c-Src kinase is highly expressed in various solid tumors, such as lung cancer, breast cancer, rectal cancer, and pancreatic cancer. c-Src kinase is a cancer protein encoded by the proto-oncogene c-Src. In tumor tissues, c-Src kinase loses its precise negative regulation ability, its expression level is significantly increased and is continuously activated. Abnormally activated c-Src kinase plays many biological functions in the occurrence and development of tumors, such as apoptosis, cell adhesion, proliferation, migration and invasion, and vascular formation. Therefore, c-Src kinase inhibitors have attracted widespread attention in the field of solid tumor treatment. In view of the great potential of HDAC inhibitors and c-Src kinase inhibitors in tumor treatment, based on the high chemical modifiability of the CAP region of HDAC inhibitors, a series of HDAC / c-Src kinase dual-target inhibitors are prepared by using the "hybrid molecule" strategy. SUMMARY

[0006] The present application aims to provide a hydroxamic acid compound containing N-benzyl-2-(5-(4-methylphenyl)pyridin-2-yl)acetamide and its pharmaceutically acceptable salt, hydrate, preparation method and pharmaceutical composition containing the compound, and application for preventing and / or treating diseases related to any one of histone deacetylase (HDACs), c-Src kinase and / or both.

[0007] To achieve the above-mentioned purpose, the technical scheme of the present application is as follows:

[0008] A hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, the compound being as shown in general formula I, corresponding isomers and pharmaceutically acceptable salts or hydrates thereof.

[0009]

[0010] In the formula, R1 is

[0011] R2 is In the formula, n1 is a positive integer of 2-6.

[0012] R3 is H, C1-C 10 alkyl, C3-C 10 cycloalkyl C1-C 10 alkyl, aromatic C1-C 10 alkyl, aromatic amido; R4 is

[0013] X and Y can be the same or different and are selected from H or F, and n2 is a positive integer of 2-7.

[0014] Preferably, the compound is as shown in general formula I, corresponding isomers and pharmaceutically acceptable salts or hydrates thereof.

[0015] In the formula, R1 is

[0016] R1 is

[0017] R2 is In the formula, n1 is 3, 4 or 5.

[0018] R3 is H, n-butyl, 3-methylbutyl, 2-cyclohexylethyl, 2-phenylethyl, α-naphthylethyl, 2-(2-methylindol-3-yl), pyrimidin-2-yl amido, quinolin-4-yl amido;

[0019] R4 is

[0020] When X is H, Y is F; when X is F, Y is H.

[0021] n2 = 3, 4, 5 or 6.

[0022] The pharmaceutically acceptable salt of the compound of the general formula I is an acid addition salt of the compound of the general formula I with the following inorganic or organic acid; the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; the organic acid is acetic acid, propionic acid, trifluoroacetic acid, ethanedioic acid, propanedioic acid, butanedioic acid, pentanedioic acid, citric acid, salicylic acid, tartaric acid or p-toluenesulfonic acid.

[0023] A composition of a hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, the composition containing the compound of the general formula I, corresponding isomers and pharmaceutically acceptable salts or hydrates thereof.

[0024] Use of a hydroxamic acid compound or composition containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, the compound of the general formula I, corresponding isomers and pharmaceutically acceptable salts or hydrates thereof, or the composition in the preparation of a medicament for the prevention and / or treatment of diseases associated with histone deacetylases (HDACs) and / or c-Src tyrosine kinase.

[0025] Use of the compound of the general formula I, corresponding isomers and pharmaceutically acceptable salts or hydrates thereof, or the pharmaceutical composition of claim 4 in the preparation of a medicament for the prevention and / or treatment of colorectal cancer, liver cancer, lung cancer, pancreatic cancer, gastric cancer, kidney cancer, breast cancer, ovarian cancer, skin cancer, head and neck cancer, lymphoma, leukemia, neurodegenerative disease, malaria, bacterial infection, fungal infection.

[0026] The hydroxamic acid compound containing N-benzyl-2-(5-(4-methylphenyl)pyridin-2-yl)acetamide according to the present application is prepared by one of the following ten routes according to the different substituents.

[0027] Route one:

[0028]

[0029] Route two:

[0030]

[0031] Route three:

[0032]

[0033] Route four:

[0034]

[0035] Route five:

[0036]

[0037] Route Six:

[0038]

[0039] Route Seven:

[0040]

[0041] Route Eight:

[0042]

[0043] Route Nine:

[0044]

[0045] Route Ten:

[0046] DETAILED DESCRIPTION

[0047] The present application is described in detail below with specific reference being made to the following examples. It is to be understood that the application is not limited to the examples described, but rather the scope of the present application is to be defined by the appended claims.

[0048] Example 1: Preparation of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)oxy)ethyl)amino)methyl)phenyl)prop-2-enoic acid (I-1)

[0049] Step (1): Preparation of 2-(5-bromopyridin-2-yl)acetonitrile

[0050]

[0051] At 0°C, 5-bromo-2-fluoropyridine (10.00 g, 28.41 mmol) was dissolved in tetrahydrofuran and acetonitrile (1.17 g, 28.41 mmol) was added dropwise thereto. Then, potassium bis(trimethylsilyl)amide (22.67 g, 56.82 mmol) was added in portions to the mixture. After the addition was completed, the reaction was maintained at 0°C for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resulting mixture was extracted with dichloromethane (150 ml x 3) and water (250 ml). The water layer was discarded and the organic layers were combined. The organic solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 2-(5-bromopyridin-2-yl)acetonitrile (8.41 g, 75.60% yield) as an orange-yellow oily liquid.

[0052] Step (2): Preparation of methyl 2-(5-bromopyridin-2-yl)acetate

[0053]

[0054] Concentrated sulfuric acid (45.00 g, 429.00 mmol) was added dropwise to a solution of 2-(5-bromopyridin-2-yl)acetonitrile (8.41 g, 42.90 mmol) in methanol (82 ml) at 0 °C with stirring, and the temperature was slowly increased to reflux until the reaction was complete. After the reaction was complete, the reaction was cooled to room temperature, and the reaction was slowly added to saturated aqueous sodium carbonate solution (200 ml), and extracted with dichloromethane (200 ml x 3). The aqueous phase was discarded, and the organic phases were combined and the organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 2-(5-bromopyridin-2-yl)methyl acetate (8.04 g, 81.75% yield) as an orange-yellow solid.

[0055] Step (3): Preparation of N-benzyl-2-(5-bromopyridin-2-yl)acetamide

[0056]

[0057] Methyl 2-(5-bromopyridin-2-yl)acetate (8.04 g, 35.10 mmol) was dissolved in anisole (8 ml) at room temperature with stirring, and benzylamine (46 ml, 0.421 mol) was added dropwise to the mixture. The temperature was increased to reflux until the reaction was complete. After the reaction was complete, the reaction was left to stand at -20 °C overnight, and a large amount of solid was precipitated. The solid was filtered and washed with a small amount of toluene to give N-benzyl-2-(5-bromopyridin-2-yl)acetamide (7.07 g, 66.24% yield) as a white solid.

[0058] Step (4): Preparation of N-benzyl-2-(5-(4-hydroxyphenyl)pyridin-2-yl)acetamide

[0059]

[0060] N-benzyl-2-(5-bromopyridin-2-yl)acetamide (5.00 g, 16.40 mmol) was dissolved in ethylene glycol dimethyl ether (55 ml) at room temperature with stirring, and tetrakis(triphenylphosphine)palladium (760 mg, 0.66 mmol) was added thereto. After stirring for 10 minutes at room temperature, a solution of sodium carbonate (5.23 g, 49.30 mmol) in water (2 ml) and 4-hydroxyphenylboronic acid pinacol ester (5.41 g, 24.70 mmol) were sequentially added to the mixture, and the temperature was increased to reflux until the reaction was complete. After the reaction was complete, the reaction was cooled to room temperature, and the solid was removed by adsorption on celite. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give N-benzyl-2-(5-(4-hydroxyphenyl)pyridin-2-yl)acetamide (4.59 g, 89.21% yield) as a milky white solid.

[0061] Step (5): Preparation of tert-butyl (2-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)ethyl)carbamate

[0062]

[0063] N-benzyl-2-(5-(4-((2-aminoethyl)oxy)phenyl)pyridin-2-yl)acetamide (803.71 mg, 51.34% yield) was obtained as a light brown solid. MS (ESI): m / z = 406.2 (M+H)+.

[0064] Step (6): Preparation of 2-(5-(4-((2-aminoethyl)oxy)phenyl)pyridin-2-yl)-N-benzylacetamide

[0065]

[0066] N-benzyl-2-(5-(4-((2-aminoethyl)oxy)phenyl)pyridin-2-yl)acetamide (803.71 mg, 51.34% yield) was obtained as a light brown solid. MS (ESI): m / z = 406.2 (M+H)+.

[0067] Step (7): Preparation of methyl (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)oxy)ethyl)amino)methyl)phenyl)prop-2-enoate

[0068]

[0069] (2E)-3-(4-(((2-((4-(6-(2-(Benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)amino)methyl)phenyl)prop-2-enoic acid methyl ester (332.36 mg, yield 45.23%) was obtained as a light yellow oily liquid by stirring 2-(5-(4-((2-aminoethyl)oxy)phenyl)pyridin-2-yl)-N-benzylacetamide (500.00 mg, 1.38 mmol) in a 100 mL tomato bottle with DMF (20 mL), adding anhydrous potassium carbonate (344.12 mg, 2.49 mmol) and 4-bromomethylcinnamate methyl ester (420.62 mg, 1.66 mmol) thereto, and stirring at 35°C for 6 h. The reaction mixture was extracted with ethyl acetate (50 mL x 3), the organic layers were combined, dried over anhydrous Na2SO4, filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)amino)methyl)phenyl)prop-2-enoic acid methyl ester (332.36 mg, yield 45.23%) as a light yellow oily liquid.

[0070] Step (8): Preparation of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)amino)methyl)phenyl)prop-2-enoic acid (I-1)

[0071]

[0072] (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)amino)methyl)phenyl)prop-2-enoic acid methyl ester (165.42 mg, 0.31 mmol) was dissolved in a 100 mL tomato bottle with 50% aqueous hydroxylamine solution (818.41 mg, 12.42 mmol), and the mixture was stirred at 0°C. A methanol / tetrahydrofuran (THF:MeOH = 1:1, 10 mL) solution of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)amino)methyl)phenyl)prop-2-enoic acid methyl ester (165.42 mg, 0.31 mmol) was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the solvent was removed from the mixture under reduced pressure, 2 mL of water was added to the mixture, and the pH was adjusted to 6 with 1 mol / L hydrochloric acid solution while stirring at room temperature. A large amount of solid was precipitated, which was filtered, washed with a small amount of water, and dried to obtain (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)amino)methyl)phenyl)prop-2-enoic acid (I-1) (124.67 mg, yield 75.17%) as a light yellow solid, mp: 169.2-172.5°C. 1H NMR (600 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.03 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.62 (t, J = 6.0 Hz, 1H), 7.97 (dd, J = 8.1, 2.5 Hz, 1H), 7.68 - 7.45 (m, 5H), 7.40 (d, J = 8.2 Hz, 2H), 7.35 - 7.21 (m, 5H), 7.06 (d, J = 8.8 Hz, 2H), 6.46 (t, J = 16.0 Hz, 1H), 4.31 (d, J = 5.9 Hz, 2H), 4.10 (t, J = 5.7 Hz, 2H), 3.80 (s, 2H), 3.72 (s, 2H), 2.88 (t, J = 5.7 Hz, 2H). ESI-MS m / z: 537.11 [M+H] + ; 558.98 [M+Na] + .

[0073] Example 2: Preparation of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3- yl)phenyl)oxy)ethyl)(butyl)amino)methyl)phenyl)prop-2-enoic acid (I-2)

[0074] Step (1): Preparation of N-benzyl-2-(5-(4-((2-(butylamino)ethyl)oxy)phenyl)pyridin-2- yl)acetamide

[0075]

[0076] The operation is the same as Route 1 Example 1 Step (7), to get N-benzyl-2-(5-(4-((2- (butylamino)ethyl)oxy)phenyl)pyridin-2-yl)acetamide (213.43 mg, yield 37.39%) of light yellow oily liquid.

[0077] Step (2): Preparation of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3- yl)phenyl)oxy)ethyl)(butyl)amino)methyl)phenyl)prop-2-enoic acid methyl ester

[0078]

[0079] The operation is the same as Route 1 Example 1 Step (7), to get (2E)-3-(4-(((2-((4-(6-(2- (benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)(butyl)amino)methyl)phenyl)prop- 2-enoic acid methyl ester (174.32 mg, yield 42.41%) of light yellow oily liquid.

[0080] Step (3): Preparation of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl) pyridin-3-yl) phenyl)oxy) ethyl) (butyl) amino) methyl) phenyl) prop-2-enoic acid (I-2)

[0081]

[0082] The operation is the same as that in Route 1, Example 1, Step (8) to obtain yellow solid (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl) pyridin-3-yl) phenyl)oxy) ethyl) (butyl) amino) methyl) phenyl) prop-2-enoic acid (I-2) (53.33 mg, yield 46.17%), mp: 104.8-107.9 °C. 1 H NMR (600 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.08 (s, 1H), 8.80 (d, J = 2.3 Hz, 1H), 8.68 (t, J = 5.8 Hz, 1H), 8.02 (dd, J = 8.1, 2.4 Hz, 1H), 7.63 (m, 5H), 7.49-7.42 (m, 3H), 7.41-7.28 (m, 5H), 7.08 (d, J = 8.5 Hz, 2H), 6.50 (d, J = 15.9 Hz, 1H), 4.37 (d, J = 5.8 Hz, 2H), 4.17 (t, J = 5.9 Hz, 2H), 3.76 (m, 4H), 2.88 (t, J = 5.8 Hz, 2H), 1.50 (t, J = 7.4 Hz, 2H), 1.40-1.21 (m, 4H), 0.90 (t, J = 7.3 Hz, 3H). ESI-MS m / z: 693.21 [M+H] + .

[0083] The compounds of Examples 3-7 were prepared according to the preparation method of Example 2 by selecting appropriate starting materials

[0084] Example 3: Preparation of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl) pyridin-3-yl) phenyl)oxy) ethyl) (3-methylbutyl) amino) methyl) phenyl) prop-2-enoic acid (I-3)

[0085]

[0086] (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)(3- methylbutyl)amino)methyl)phenyl)prop-2-en-1 -hydroxamic acid (I-3) red brown solid, yield 42.25%, mp: 80.1-82.3 °C. 1 H NMR (600 MHz, DMSO-d6) δ 10.73 (s, 1H), 9.03 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.62 (t, J = 6.1 Hz, 1H), 7.96 (dd, J = 8.1, 2.5 Hz, 1H), 7.69-7.44 (m, 5H), 7.43-7.36 (m, 3H), 7.35-7.21 (m, 5H), 7.02 (d, J = 8.8 Hz, 2H), 6.44 (d, J = 15.8 Hz, 1H), 4.31 (d, J = 5.9 Hz, 2H), 4.11 (t, J = 5.8 Hz, 2H), 3.72 (s, 2H), 3.68 (s, 2H), 2.83 (t, J = 5.8 Hz, 2H), 1.60 (m, 1H), 1.39-1.22 (m, 4H), 0.82 (d, J = 6.6 Hz, 6H). ESI-MS m / z: 607.27 [M+H] + ; 629.20 [M+Na] + .

[0087] Example 4: Preparation of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3- yl)phenyl)oxy)ethyl)(2-(naphthalen-1-yl)ethyl)amino)methyl)phenyl)prop-2-en-1 - hydroxamic acid (I-4)

[0088]

[0089] (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3- yl)phenyl)oxy)ethyl)(2-(naphthalen-1-yl)ethyl)amino)methyl)phenyl)prop-2-en-1 - hydroxamic acid (I-4) brown solid, yield 67.37%, mp: 86.3-89.2 °C. 1HNMR (600 MHz, DMSO-d6) δ 8.75 (d, J = 2.4 Hz, 1H), 8.64 (t, J = 5.5 Hz, 1H), 7.97 (dd, J = 8.1, 2.5 Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.52 - 7.22 (m, 16H), 7.02 (d, J = 8.4 Hz, 2H), 6.46 (d, J = 15.8 Hz, 1H), 4.31 (d, J = 5.8 Hz, 2H), 4.13 (t, J = 5.9 Hz, 2H), 3.84 (s, 2H), 3.72 (s, 2H), 3.24 (t, J = 7.8 Hz, 2H), 3.02 (t, J = 5.8 Hz, 2H), 2.85 (t, J = 7.6 Hz, 2H). ESI-MS m / z: 691.32 [M+H] + ; 713.23 [M+Na] + .

[0090] Example 5: Preparation of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)(2- phenylethyl)amino)methyl)phenyl)prop-2-en-1-olate (I-5)

[0091]

[0092] (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)(2- phenylethyl)amino)methyl)phenyl)prop-2-en-1-olate (I-4) Brown solid, yield 65.43%, mp: 74.9-79.1 °C. 1 H NMR (600 MHz, DMSO-d6) δ 8.75 (d, J = 2.3 Hz, 1H), 8.63 (t, J = 6.0 Hz, 1H), 7.97 (dd, J = 8.1, 2.5 Hz, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.53 - 7.41 (m, 3H), 7.41 - 7.15 (m, 13H), 7.02 (d, J = 8.8 Hz, 2H), 6.44 (d, J = 15.8 Hz, 1H), 4.31 (d, J = 5.9 Hz, 2H), 4.11 (t, J = 5.9 Hz, 2H), 3.78 (s, 2H), 3.72 (s, 2H), 2.92 (t, J = 5.8 Hz, 2H), 2.78 (s, 4H). ESI-MS m / z: 641.26 [M+H] + ; 663.21 [M+Na] +.

[0093] Example 6: Preparation of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl) pyridin-3-yl) phenyl)oxy) ethyl) (2-cyclohexylethyl) amino) methyl) phenyl) prop-2- enoic acid (I-6)

[0094]

[0095] (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl) pyridin-3-yl) phenyl)oxy) ethyl) (2-cyclohexylethyl) amino) methyl) phenyl) prop-2- enoic acid (I-6) Red brown solid, yield 49.62%, mp: 77.5-80.2 °C. 1 H NMR (600 MHz, DMSO-d6) δ 10.73 (s, 1H), 9.02 (s, 1H), 8.75 (d, J = 2.3 Hz, 1H), 8.62 (t, J = 5.9 Hz, 1H), 7.96 (dd, J = 8.1, 2.5 Hz, 1H), 7.68 - 7.43 (m, 5H), 7.39 (t, J = 8.7 Hz, 3H), 7.35 - 7.21 (m, 5H), 7.03 (d, J = 8.7 Hz, 2H), 6.44 (d, J = 15.9 Hz, 1H), 4.31 (d, J = 5.9 Hz, 2H), 4.12 (t, J = 5.7 Hz, 2H), 3.72 (s, 2H), 3.68 (s, 2H), 2.83 (t, J = 5.8 Hz, 2H), 2.54 (s, 4H), 1.57 (m, 5H), 1.40 (d, J = 2.7 Hz, 2H), 1.37 - 1.24 (m, 4H), 1.21 - 1.01 (m, 4H). ESI-MS m / z: 647.22 [M+H] + .

[0096] Example 7: Preparation of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl) pyridin-3-yl) phenyl)oxy) ethyl) (2-(2-methyl-1H-indol-3-yl) ethyl) amino) methyl) phenyl) prop-2- enoic acid (I-7)

[0097]

[0098] (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)(2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)prop-2-enoic acid (I-7) brown yellow solid, yield 56.53%, mp: 70.2-74.1 °C. 1 H NMR (600 MHz, DMSO-d6) δ 10.74 (s, 1H), 10.64 (s, 1H), 9.03 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.63 (t, J = 5.9 Hz, 1H), 7.97 (dd, J = 8.1, 2.5 Hz, 1H), 7.74 - 7.44 (m, 5H), 7.41 (dd, J = 8.2, 2.0 Hz, 3H), 7.35 - 7.17 (m, 7H), 7.03 (d, J = 8.8 Hz, 2H), 6.94 (t, J = 7.5 Hz, 1H), 6.45 (d, J = 15.7 Hz, 1H), 4.31 (d, J = 5.9 Hz, 2H), 4.14 (t, J = 5.9 Hz, 2H), 3.83 (s, 2H), 3.72 (s, 2H), 2.99 (t, J = 5.9 Hz, 2H), 2.86 - 2.77 (m, 2H), 2.74 - 2.64 (m, 2H), 2.26 (s, 3H). ESI-MS m / z: 694.24 [M+H] + ; 716.22 [M+Na] + .

[0099] Example 8: Preparation of 5-((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)(2-(2-methyl-1H-indol-3-yl)ethyl)amino)-5-oxovalecic acid (I-8)

[0100] Step (1): Preparation of 5-((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)(2-(2-methyl-1H-indol-3-yl)ethyl)amino)-5-oxovaleric acid methyl ester

[0101]

[0102] Methyl 5-((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)(2-(2-methyl-1H-indol-3-yl)ethyl)amino)-5-oxopentanoate (465.33 mg, yield 75.08%) was obtained as yellow-brown oil by the same method as in Route 1, Example 1, Step (8).

[0103] Step (2): Preparation of 5-((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)(2-(2-methyl-1H-indol-3-yl)ethyl)amino)-5-oxopentanoic acid (I-8)

[0104]

[0105] The operation was the same as in Route 1, Example 1, Step (8), to obtain 5-((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)(2-(2-methyl-1H-indol-3-yl)ethyl)amino)-5-oxopentanoic acid (I-8) (301.22 mg, yield 71.32%) as brown-yellow solid, mp: 90.1-93.6 °C. 1H NMR (600 MHz, DMSO-d6) δ 10.73 (d, J = 2.3 Hz, 1H), 10.36 (d, J = 2.9 Hz, 1H), 8.74 (s, 1H), 8.61 (t, J = 6.6 Hz, 2H), 7.96 (dd, J = 8.1, 2.0 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.35 - 7.19 (m, 7H), 7.08 - 6.89 (m, 5H), 4.30 (d, J = 5.9 Hz, 2H), 4.12 - 4.07 (m, 2H), 3.71 (s, 2H), 3.67 - 3.60 (m, 2H), 3.49 (m, 2H), 2.93 - 2.82 (m, 2H), 2.44 (t, J = 7.3 Hz, 2H), 2.30 (d, J = 7.9 Hz, 3H), 2.23 (t, J = 7.3 Hz, 2H), 1.84 (m, 2H). ESI-MS m / z: 648.19 [M+H] + ; 670.20 [M+Na] + .

[0106] Following the preparation procedure of Example 8, selecting appropriate starting materials, the compounds of Examples 9-11 were prepared.

[0107] Example 9: Preparation of 6-((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3- yl)phenyl)oxy)ethyl)(2-(2-methyl-lH-indol-3-yl)ethyl)amino)-6-oxovinylhexan-1-ol (I-9)

[0108]

[0109] 6-((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)(2-(2-methyl- lH-indol-3-yl)ethyl)amino)-6-oxovinylhexan-l-ol (I-9) was obtained as brownish yellow solid in 68.01% yield, mp: 106.9-109.9 °C. 1H NMR (600 MHz, DMSO-d6) δ 10.72 (d, J = 2.2 Hz, 1H), 10.34 (d, J = 2.5 Hz, 1H), 8.77-8.72 (m, 2H), 8.69-8.58 (m, 2H), 7.96 (dd, J = 8.1, 2.1 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.35-7.19 (m, 7H), 7.11-6.89 (m, 5H), 4.30 (d, J = 5.8 Hz, 2H), 4.12-4.08 (m, 2H), 3.71 (s, 2H), 3.65 (m, 2H), 3.55-3.44 (m, 2H), 2.87 (m, 2H), 2.30 (d, J = 9.6 Hz, 3H), 2.18-1.83 (m, 4H), 1.55 (s, 2H), 1.35 (s, 2H). ESI-MS m / z: 662.22 [M+H] + ; 684.20 [M+Na] + .

[0110] Example 10: Preparation of 7-((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3- yl)phenyl)oxy)ethyl)(2-(2-methyl-lH-indol-3-yl)ethyl)amino)-7-oxoheptanoic acid (I-10)

[0111]

[0112] 7-((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)(2-(2-methyl- lH-indol-3-yl)ethyl)amino)-7-oxoheptanoic acid (I-10) yellow solid, yield 52.51%, mp: 79.2-82.7 °C. 1HNMR (600 MHz, DMSO-d6) δ 10.72 (d, J = 20.5 Hz, 1H), 10.34 (d, J = 2.5 Hz, 1H), 8.74 (s, 1H), 8.66 (s, 1H), 8.62 (t, J = 5.9 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 7.8 Hz, 1H), 7.35-7.18 (m, 7H), 7.08-6.89 (m, 5H), 4.30 (d, J = 5.8 Hz, 2H), 4.13-4.08 (m, 2H), 3.71 (s, 2H), 3.65 (m, 2H), 3.54-3.45 (m, 2H), 2.95-2.81 (m, 2H), 2.29 (d, J = 9.4 Hz, 3H),

[0113] 2.12-1.84 (m, 4H), 1.53 (m, 2H), 1.33 (m, 4H). ESI-MS m / z: 676.21 [M+H] + ; 698.21 [M+Na] + .

[0114] Example 11: Preparation of 8-((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3- yl)phenyl)oxy)ethyl)(2-(2-methyl-lH-indol-3-yl)ethyl)amino)-8-oxovinyl octanoic acid (I-11)

[0115]

[0116] 8-((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)(2-(2-methyl- lH-indol-3-yl)ethyl)amino)-8-oxovinyl octanoic acid (I-11) brown solid, yield 50.61%, mp: 67.4-71.3 °C. 1H NMR (600 MHz, DMSO-d6) δ 10.72 (d, J = 2.3 Hz, 1H), 10.35 (d, J = 2.1 Hz, 1H), 8.74 (s, 1H), 8.68 (s, 1H), 8.63 (t, J = 6.0 Hz, 1H), 7.96 (dd, J = 8.1, 2.2 Hz, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.41-7.39 (m, 1H), 7.35-7.21 (m, 7H), 7.08-6.89 (m, 5H), 4.30 (d, J = 5.8 Hz, 2H), 4.16-4.05 (m, 3H), 3.71 (s, 2H), 3.68-3.60 (m, 2H), 3.55 (s, 2H), 2.94-2.82 (m, 2H), 2.29 (d, J = 4.6 Hz, 3H), 2.09-1.84 (m, 4H), 1.46 (m, 4H), 1.33-1.20 (m, 4H). ESI-MS m / z: 690.35 [M+H] + ; 712.27 [M+Na] + .

[0117] Example 12: Preparation of (4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)ethyl)(2-(2-methyl-lH-indol-3-yl)ethyl)amino)methyl)phenyl)methane hydroxamic acid (I-12)

[0118] Step (1): Preparation of methyl 4-(((2-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)ethyl)(2-(2-methyl-lH-indol-3-yl)ethyl)amino)methyl)benzoate

[0119]

[0120] The operation is the same as route 1 example 1 step (7), to get light brown oil liquid 4-(((2-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)ethyl)(2-(2-methyl-lH-indol-3- yl)ethyl)amino)methyl)benzoic acid methyl ester (210.29 mg, yield 54.33%).

[0121] Step (2): Preparation of (4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)oxy)ethyl)(2-(2-methyl-lH-indol-3-yl)ethyl)amino)methyl)phenyl)methane hydroxamic acid (I-12)

[0122]

[0123] Operating the same route as Example 1 step (8), brown solid (4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)oxy)ethyl)(2-(2-methyl-lH-indol-3- yl)ethyl)amino)methyl)phenyl)methanonic acid (I-12) (151.36 mg, yield 78%) was obtained, mp: 85.3-87.9 °C. 1 H NMR (600 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.62 (t, J = 6.0 Hz, 1H), 7.96 (dd, J = 8.1, 2.6 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 8.8, 2.9 Hz, 2H), 7.54-7.11 (m, 11H), 7.01 (dd, J = 8.8, 2.5 Hz, 2H), 6.96-6.89 (m, 1H), 6.84 (m, 1H), 4.31 (d, J = 5.8 Hz, 2H), 4.09 (d, J = 5.8 Hz, 2H), 3.85 (s, 2H), 3.72 (s, 2H), 2.98 (t, J = 5.8 Hz, 2H), 2.86-2.76 (m, 2H), 2.73-2.65 (m, 2H), 2.25 (s, 3H). ESI-MS m / z: 668.47 [M+H] + 690.42 [M+Na] + .

[0124] According to the preparation method of Example 12, the appropriate starting materials were selected to prepare the compounds of Examples 13-14.

[0125] Example 13: Preparation of (4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)oxy)ethyl)(2-(2-methyl-lH-indol-3-yl)ethyl)amino)methyl)-2- fluorophenyl)methanonic acid (I-13)

[0126]

[0127] 4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)oxy)ethyl)(2-(2-methyl-lH-indol-3-yl)ethyl)amino)methyl)-2- fluorophenyl)methanonic acid (I-13) brown solid, yield 71.47%, mp: 65.0-68.9 °C. 1H NMR (600 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.66 (s, 1H), 9.18 (s, 1H), 8.76 (d, J = 2.5 Hz, 1H), 8.63 (t, J = 5.9 Hz, 1H), 7.98 (dd, J = 8.1, 2.5 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.38 - 7.18 (m, 9H), 7.03 (d, J = 8.3 Hz, 2H), 6.95 (t, J = 7.1 Hz, 1H), 6.87 (t, J = 7.3 Hz, 1H), 4.31 (d, J = 5.9 Hz, 2H), 4.17 - 4.09 (m, 2H), 3.86 (s, 2H), 3.72 (s, 2H), 2.99 (s, 2H), 2.83 (s, 2H), 2.72 (s, 2H), 2.27 (s, 3H). ESI-MS m / z: 686.48 [M+H] + .

[0128] Example 14: Preparation of (4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl) phenyloxy)ethyl)(2-(2-methyl-lH-indol-3-yl)ethyl)amino)methyl)-3-fluorophenyl)methane hydroxamic acid (I-14)

[0129]

[0130] (4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl) phenyloxy)ethyl)(2-(2-methyl-lH-indol-3-yl)ethyl)amino)methyl)-3-fluorophenyl)methane hydroxamic acid (I-14) brown solid, yield 70.17%, mp: 86.6-90.4 °C. 1H NMR (600 MHz, DMSO-d6) δ 11.28 (s, 1H), 10.66 (s, 1H), 9.13 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.62 (t, J = 5.9 Hz, 1H), 7.97 (dd, J = 8.1, 2.5 Hz, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.57 (s, 1H), 7.52 (d, J = 11.6 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.36 - 7.17 (m, 8H), 7.02 (d, J = 8.8 Hz, 2H), 6.94 (t, J = 7.5 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 4.31 (d, J = 5.9 Hz, 2H), 4.14 (t, J = 5.9 Hz, 2H), 3.89 (s, 2H), 3.72 (s, 2H), 3.01 (t, J = 5.9 Hz, 2H), 2.85 - 2.79 (m, 2H), 2.74 - 2.67 (m, 2H), 2.26 (s, 3H). ESI-MS m / z: 686.36 [M+H] + .

[0131] Example 15: Preparation of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)((pyrimidin-2-ylamino)methyl)carbamoyl)amino)methyl)phenyl)prop-2-enoic acid (I-15)

[0132] Step (1): Preparation of methyl (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)((pyrimidin-2-ylamino)methyl)carbamoyl)amino)methyl)phenyl)prop-2-enoate

[0133]

[0134] Methyl (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)oxy)ethyl)amino)methyl)phenyl)prop-2-enoate (200.00 mg, 0.37 mmol) was placed in a 100 mL vial, dissolved with DMF (10 mL), at 0 °C, (pyrimidin-2- ylcarbamic acid phenyl ester (96.46 mg, 0.45 mmol), triethylamine (45.54 mg, 0.45 mmol) were added, after addition, transferred to room temperature, reacted for 4 h, after reaction, extracted with ethyl acetate (50 mL x 3), the organic phase was combined, dried with anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure, the residue was separated and purified by silica gel column chromatography, to obtain a light brown oil liquid: methyl (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)oxy)ethyl)((pyrimidin-2-ylamino)carbonyl)amino)methyl)phenyl)prop-2- enoate (179.61 mg, yield 74.37%).

[0135] Step (2): Preparation of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)oxy)ethyl)((pyrimidin-2-ylamino)carbonyl)amino)methyl)phenyl)prop-2- enoic acid (I-15)

[0136]

[0137] The operation was the same as that in Route 1 Example 1 Step (8), to obtain a light brown solid (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)oxy)ethyl)((pyrimidin-2-ylamino)carbonyl)amino)methyl)phenyl)prop-2- enoic acid (I-15) (124.19 mg, yield 71.46%), mp: 166.5-169.4 °C. 1H NMR (600 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.47 (s, 1H), 9.04 (s, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.63 (t, J = 6.0 Hz, 1H), 8.60 (d, J = 4.8 Hz, 2H), 7.98 (dd, J = 8.1, 2.5 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.43 - 7.21 (m, 10H), 7.09 - 7.06 (m, 2H), 6.46 (d, J = 15.9 Hz, 1H), 4.72 (s, 2H), 4.31 (d, J = 5.9 Hz, 2H), 4.21 (t, J = 5.4 Hz, 2H), 3.75 (s, 2H). ESI-MS m / z: 658.34 [M+H] + .

[0138] Following the preparation procedure of Example 15, selecting the appropriate starting materials, the compound of Example 16 was prepared.

[0139] Example 16: Preparation of (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)((quinolin-4-ylamino)methyl)carbonyl)amino)methyl)phenyl)prop-2-enoic acid (I-16)

[0140]

[0141] (2E)-3-(4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)((quinolin-4-ylamino)methyl)carbonyl)amino)methyl)phenyl)prop-2-enoic acid (I-16) Brownish gray solid, yield 67.28%, mp: 149.5-153.4 °C. 1H NMR (600 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.90 (s, 1H), 8.75 (dd, J = 6.8, 3.7 Hz, 2H), 8.63 (t, J = 5.9 Hz, 1H), 7.97 (t, J = 7.5 Hz, 2H), 7.85 (d, J = 5.1 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.67-7.63 (m, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.48-7.37 (m, 4H), 7.36-7.18 (m, 6H), 7.05 (d, J = 8.5 Hz, 2H), 6.46 (d, J = 15.8 Hz, 1H), 4.83 (s, 2H), 4.31 (d, J = 5.9 Hz, 4H), 3.94 (s, 2H), 3.72 (s, 2H). ESI-MS m / z: 707.38 [M+H] + .

[0142] Example 17: Preparation of (4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3- yl)phenyl)oxy)ethyl)((pyrimidin-2-ylamino)methylene)amino)methyl)-3-fluorophenyl) methanamine hydroxamic acid (I-17)

[0143] Step (1): Preparation of methyl 4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3- yl)phenyl)oxy)ethyl)amino)methyl)-3-fluorobenzoate

[0144]

[0145] The operation is the same as route 1 example 1 step (7), to get light green oily liquid methyl 4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3-yl)phenyl)oxy)ethyl)amino)methyl)-3-fluorobenzoate (323.37 mg, yield 54.22%).

[0146] Step (2): Preparation of methyl 4-(((2-((4-(6-(2-(benzylamino)-2-oxovinyl)pyridin-3- yl)phenyl)oxy)ethyl)((pyrimidin-2-ylamino)methylene)amino)methyl)-3-fluorobenzoate

[0147]

[0148] The operation is the same as the example 15 step (1) of route five, to get light yellow oil liquid 4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)oxy)ethyl)((pyrimidin-2-ylamino)carbonyl)amino)methyl)-3-fluorobenzoic acid methyl ester (121 mg, yield 68%).

[0149] Step (3): Preparation of (4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)oxy)ethyl)((pyrimidin-2-ylamino)carbonyl)amino)methyl)-3-fluorophenyl)methane hydroxamic acid (I-17)

[0150]

[0151] The operation is the same as the example 1 step (8) of route one, to get yellow solid 4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)oxy)ethyl)((pyrimidin-2-ylamino)carbonyl)amino)methyl)-3-fluorophenyl)methane hydroxamic acid (I-17) (61.36 mg, yield 51.16%), mp: 170.2-172.4 ℃. 1 H NMR (600 MHz, DMSO-d6) δ 11.30 (s, 1H), 9.53 (s, 1H), 9.14 (s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.63 (t, J = 5.9 Hz, 1H), 8.59 (d, J = 4.8 Hz, 2H), 7.98 (dd, J = 8.1, 2.5 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.61-7.53 (m, 2H), 7.43 (m, 2H), 7.35-7.22 (m, 5H), 7.07 (m, 3H), 4.78 (s, 2H), 4.31 (d, J = 5.9 Hz, 2H), 4.23 (t, J = 5.5 Hz, 2H), 3.83 (s, 2H), 3.72 (s, 2H). ESI-MS m / z: 650.30 [M+H] + .

[0152] According to the preparation method of example 17, select the appropriate raw materials to prepare the compound of example 18.

[0153] Example 18: Preparation of (4-(((2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)oxy)ethyl)((pyrimidin-2-ylamino)carbonyl)amino)methyl)-3-fluorophenyl)methane hydroxamic acid (I-18)

[0154]

[0155] (4-(((2-((4-(6-(2-(benzylamino)-2-oxylideneethyl)pyridin-3-yl)phenyl)oxy)ethyl)((quinoline-4-ylamino)carbonyl)amino)methyl)-3-fluorophenyl)methanehydroxyline (I-18) brown solid, yield 47.12%, mp: 148.8-151.9℃. 1 H NMR (600MHz, DMSO-d6) δ11.31(s,1H),9.01(d,J=3.9Hz,1H),8.75(dd,J=6.4,3.7Hz,2H),8.6 2(t,J=6.0Hz,1H),8.07(d,J=8.5Hz,1H),7.97(t,J=9.9Hz,2H),7.80(d,J=5.0Hz,1H),7.74(t ,J=7.8Hz,1H),7.67-7.63(m,2H),7.62-7.47(m,4H),7.40(d,J=8.1Hz,1H),7.36-7.20(m,6H ),7.03(d,J=8.6Hz,2H),4.89(s,2H),4.31(d,J=5.9Hz,4H),3.99(s,2H),3.72(s,2H).ESI-MS m / z:699.32[M+H] + .

[0156] Example 19: Preparation of (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)propyl)-indole-5-yl)-N-hydroxyacrylamide (I-19)

[0157] Step (1): Preparation of (E)-3-(indole-5-yl)methyl acrylate

[0158]

[0159] Indole-5-carboxaldehyde (400.00 mg, 2.76 mmol) and methoxyformylmethylenetriphenylphosphine (1.11 g, 3.31 mmol) were added to a reaction flask, and dichloromethane (10 mL) was added to dissolve them completely. The mixture was heated to 45 °C and refluxed for 12 h. After the reaction was completed, the mixture was cooled to room temperature, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to give a white solid (E)-3-(indole-5-yl)methyl acrylate (535.52 mg, yield 96.51%).

[0160] Step (2): Preparation of (E)-3-(1-(3-bromopropyl)-indole-5-yl)methyl acrylate

[0161]

[0162] (E)-3-(l-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)propyl)- indol-5-yl)acrylic acid methyl ester was prepared by the procedure described in Example 1, Step (3) using (E)-3-(l-(3-bromopropyl)-indol-5-yl)acrylic acid methyl ester (213.4 mg, 0.62 mmol) and N-benzyl-2-(5-(4-hydroxyphenyl)pyridin-2-yl)acetamide (132.17 mg, 0.42 mmol).

[0163] Step (3): Preparation of (E)-3-(l-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)propyl)-indol-5-yl)acrylic acid methyl ester

[0164]

[0165] (E)-3-(l-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)propyl)- indol-5-yl)acrylic acid methyl ester was prepared by the procedure described in Example 1, Step (3) using (E)-3-(l-(3-bromopropyl)-indol-5-yl)acrylic acid methyl ester (213.4 mg, 0.62 mmol) and N-benzyl-2-(5-(4-hydroxyphenyl)pyridin-2-yl)acetamide (132.17 mg, 0.42 mmol).

[0166] Step (4): Preparation of (E)-3-(l-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)propyl)-indol-5-yl)-N-hydroxyacrylamide (1-19)

[0167]

[0168] The operation is the same as that in Route 1, Example 1, Step (8) to give (E)-3-(l-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)propyl)-indol-5-yl)-N- hydroxyacrylamide (1-19) as a light yellow solid (82.92 mg, yield 67.31%), mp: 150.7-153.9 °C. 1 H NMR (600 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.93 (s, 1H), 8.75 (d, J = 2.3 Hz, 1H), 8.62 (t, J = 6.0 Hz, 1H), 7.97 (dd, J = 8.1, 2.5 Hz, 1H), 7.74 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.58-7.49 (m, 2H), 7.47-7.19 (m, 9H), 7.04 (d, J = 8.3 Hz, 2H), 6.50 (d, J = 3.0 Hz, 1H), 4.39 (t, J = 6.7 Hz, 2H), 4.30 (d, J = 5.8 Hz, 2H), 3.95 (t, J = 5.9 Hz, 2H), 3.71 (s, 2H), 2.27-2.20 (m, 2H). ESI-MS m / z: 561.23 [M] + ; 562.22 [M+H] + .

[0169] The compounds of Examples 20-30 are prepared according to the preparation method of Example 19 by selecting appropriate starting materials

[0170] Example (20): Preparation of (E)-3-(l-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)propyl)-indol-5-yl)-N-hydroxyacrylamide (1-20)

[0171]

[0172] (E)-3-(l-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)propyl)-indol-5- yl)-N-hydroxyacrylamide (1-20) white solid, yield 69.20%, mp: 135.1-138.7 °C. 1H NMR (600 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.94 (s, 1H), 8.74 (d, J = 2.3 Hz, 1H), 8.62 (t, J = 5.8 Hz, 1H), 7.96 (dd, J = 8.1, 2.4 Hz, 1H), 7.75 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.60-7.48 (m, 2H), 7.46 (d, J = 3.1 Hz, 1H), 7.39 (t, J = 7.3 Hz, 2H), 7.35-7.21 (m, 6H), 7.03 (d, J = 8.4 Hz, 2H), 6.50 (d, J = 3.0 Hz, 1H), 4.34-4.25 (m, 4H), 4.03 (t, J = 6.3 Hz, 2H), 3.72 (s, 2H), 1.94 (t, J = 7.6 Hz, 2H), 1.70 (t, J = 7.5 Hz, 2H). ESI-MS m / z: 575.32 [M] + 597.31 [M + Na] + .

[0173] Example 21: Preparation of (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)propyl)-indol-5-yl)-N-hydroxyacrylamide (I-21)

[0174]

[0175] (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)propyl)-indol-5- yl)-N-hydroxyacrylamide (I-21) was obtained as a light yellow solid in 67.84% yield, mp: 130.6-133.0 °C. 1 H NMR (600 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.93 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.60 (t, J = 6.0 Hz, 1H), 7.85 (dd, J = 8.2, 2.5 Hz, 1H), 7.73 (s, 1H), 7.62-7.43 (m, 3H), 7.43-7.30 (m, 5H), 7.30-7.12 (m, 5H), 6.65 (d, J = 8.5 Hz, 2H), 6.47 (d, J = 3.1 Hz, 1H), 4.34-4.16 (m, 5H), 3.76 (s, 2H), 3.51 (s, 2H), 1.87-1.55 (m, 4H), 0.98-0.76 (m, 2H). ESI-MS m / z: 589.33 [M] + 590.30 [M + H]+ .

[0176] Example 22: Preparation of (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)amino)propyl)-indol-5-yl)-N-hydroxyacrylamide (I-22)

[0177]

[0178] (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)propyl)- indol-5-yl)-N-hydroxyacrylamide (I-22) was obtained as a light yellow solid in 71.32% yield, mp: 132.6-135.5 °C. 1 H NMR (600 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.94 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.62 (t, J = 5.8 Hz, 1H), 7.96 (dd, J = 8.0, 2.4 Hz, 1H), 7.74 (s, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.59-7.50 (m, 2H), 7.46-7.20 (m, 8H), 7.01 (d, J = 8.5 Hz, 2H), 6.49 (d, J = 3.0 Hz, 1H), 6.38 (d, J = 15.7 Hz, 1H), 4.31 (d, J = 5.9 Hz, 2H), 4.22 (t, J = 6.9 Hz, 2H), 3.99 (t, J = 6.3 Hz, 2H), 3.72 (s, 2H), 1.80 (dt, J = 32.8, 7.6 Hz, 4H). ESI-MS m / z: 560.30 [M] + ; 561.30 [M+H] + .

[0179] Example 23: Preparation of (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)amino)butyl)-indol-5-yl)-N-hydroxyacrylamide (I-23)

[0180]

[0181] (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)butyl)- indol-5-yl)-N-hydroxyacrylamide (I-23) was obtained as a light yellow solid in 68.53% yield, mp: 124.6-128.9 °C. 1H NMR (600 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.93 (s, 1H), 8.65 (d, J = 2.9 Hz, 1H), 8.62 - 8.49 (m, 1H), 7.84 (dd, J = 8.2, 2.4 Hz, 1H), 7.71 (s, 1H), 7.60 - 7.42 (m, 3H), 7.42 - 7.31 (m, 4H), 7.31 - 7.09 (m, 5H), 6.66 (d, J = 8.6 Hz, 2H), 6.45 (d, J = 3.2 Hz, 1H), 6.37 (d, J = 15.8 Hz, 1H), 4.34 - 3.99 (m, 6H), 3.69 (t, J = 7.6 Hz, 1H), 1.23 (s, 5H). ESI-MS m / z: 574.32 [M] + ; 575.29 [M + H] + .

[0182] Example 24: Preparation of (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)amino)pentyl)-indol-5-yl)-N-hydroxyacrylamide (I-24)

[0183]

[0184] (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)pentyl)- indol-5-yl)-N-hydroxyacrylamide (I-24) was obtained as a light yellow solid in 67.13% yield, mp: 127.5-130.1 °C. 1 H NMR (600 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.94 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.57 (t, J = 6.0 Hz, 1H), 7.86 (dd, J = 8.2, 2.5 Hz, 1H), 7.73 (s, 1H), 7.59 - 7.43 (m, 3H), 7.38 (dp, J = 8.3, 4.2 Hz, 5H), 7.29 - 7.13 (m, 5H), 6.75 - 6.61 (m, 2H), 6.47 (d, J = 3.0 Hz, 1H), 6.38 (d, J = 15.7 Hz, 1H), 5.31 (s, 2H), 4.25 (qt, J = 13.3, 6.8 Hz, 3H), 4.16 - 4.01 (m, 2H), 1.25 (s, 6H). ESI-MS m / z: 588.35 [M] + ; 589.31 [M + H] + .

[0185] Example 25: Preparation of (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)propyl)-indol-6-yl)-N-hydroxyacrylamide (I-25)

[0186]

[0187] (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)propyl)-indol-6-yl)-N-hydroxyacrylamide (I-25) was obtained as a light yellow solid in 71.25% yield, mp: 164.9-166.7 °C. 1 H NMR (600 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.77 (s, 1H), 8.70 (d, J = 6.3 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.4 Hz, 3H), 7.52-7.48 (m, 1H), 7.46 (d, J = 3.0 Hz, 1H), 7.43 (d, J = 3.1 Hz, 1H), 7.22-7.15 (m, 4H), 7.05 (d, J = 8.7 Hz, 3H), 6.50-6.42 (m, 3H), 4.02-3.79 (m, 3H), 3.17 (s, 5H), 2.31-2.20 (m, 2H), 1.23 (s, 2H). ESI-MS m / z: 561.24 [M] + ; 562.23 [M+H] + ; 583.24 [M+Na] + .

[0188] Example 26: Preparation of (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)propyl)-indol-6-yl)-N-hydroxyacrylamide (I-26)

[0189]

[0190] (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)propyl)-indol-6-yl)-N-hydroxyacrylamide (I-26) was obtained as a light yellow solid in 73.04% yield, mp: 142.2-145.7 °C. 1H NMR (600 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.97 (s, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.62 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.64 - 7.54 (m, 3H), 7.53 - 7.48 (m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.28 (tq, J = 15.1, 7.2 Hz, 6H), 7.03 (d, J = 8.1 Hz, 2H), 6.47 (d, J = 2.7 Hz, 2H), 4.31 (d, J = 5.8 Hz, 4H), 4.08 - 3.98 (m, 2H), 3.72 (s, 2H), 3.18 (d, J = 5.2 Hz, 1H), 1.95 (s, 2H), 1.71 (s, 2H). ESI-MS m / z: 575.23 [M] + ; 576.20 [M + H] + .

[0191] Example 27: Preparation of (E)-3-(l-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)propyl)-indol-6-yl)-N-hydroxyacrylamide (I-27)

[0192]

[0193] (E)-3-(l-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)propyl)-indol-6-yl)-N-hydroxyacrylamide (I-27) pale yellow solid, yield 73.17%, mp: 131.2-132.3 °C. 1H NMR (600 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.97 (s, 1H), 8.74 (d, J = 2.3 Hz, 1H), 8.62 (s, 1H), 8.00 - 7.90 (m, 1H), 7.73 (s, 1H), 7.59 (dd, J = 26.5, 8.2 Hz, 4H), 7.29 (tt, J = 12.9, 6.9 Hz, 7H), 7.01 (d, J = 8.4 Hz, 2H), 6.50 - 6.43 (m, 2H), 4.31 (d, J = 5.7 Hz, 2H), 4.23 (d, J = 6.2 Hz, 2H), 3.99 (t, J = 6.4 Hz, 2H), 3.72 (s, 2H), 3.43 - 3.38 (m, 2H), 1.78 (d, J = 7.2 Hz, 2H), 1.45 - 1.37 (m, 2H), 1.25 (d, J = 9.3 Hz, 2H). ESI-MS m / z: 589.26 [M] + ; 590.23 [M + H] + .

[0194] Example 28: Preparation of (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)amino)propyl)-indol-6-yl)-N-hydroxyacrylamide (I-28)

[0195]

[0196] (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)propyl)- indol-6-yl)-N-hydroxyacrylamide (I-28) brown solid, yield 58.27%, mp: 155.6-158.5 °C. 1 H NMR (600 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.67 (d, J = 2.4 Hz, 1H), 8.62 (t, J = 6.0 Hz, 1H), 7.85 (dd, J = 8.2, 2.5 Hz, 1H), 7.71 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.45 - 7.34 (m, 5H), 7.29 - 7.14 (m, 7H), 6.66 (d, J = 8.4 Hz, 2H), 6.44 (d, J = 3.2 Hz, 1H), 5.31 (s, 2H), 4.49 - 4.44 (m, 3H), 4.24 (dt, J = 13.2, 6.1 Hz, 4H), 3.78 (t, J = 7.4 Hz, 1H), 2.00 (d, J = 9.3 Hz, 2H). ESI-MS m / z: 560.28 [M] +; 561.27 [M+H] + .

[0197] Example 29: Preparation of (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)amino)butyl)-indol-6-yl)-N-hydroxyacrylamide (I-29)

[0198]

[0199] (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)butyl)- indol-6-yl)-N-hydroxyacrylamide (I-29) was obtained as a brown red solid in 66.14% yield, mp: 150.6-154.8 °C. 1 H NMR (600 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.96 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 7.85 (dd, J = 8.2, 2.5 Hz, 1H), 7.69 (s, 1H), 7.60 (d, J = 15.8 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.43 - 7.35 (m, 4H), 7.31 - 7.06 (m, 6H), 6.73 - 6.62 (m, 2H), 6.42 (d, J = 3.0 Hz, 1H), 5.76 (s, 1H), 5.31 (s, 2H), 4.24 (t, J = 5.5 Hz, 2H), 4.17 (t, J = 7.2 Hz, 2H), 3.70 (t, J = 7.5 Hz, 1H), 2.12 - 1.97 (m, 1H), 1.81 (p, J = 7.3 Hz, 3H), 1.24 (s, 3H). ESI-MS m / z: 574.25 [M] + ; 575.23 [M+H] + .

[0200] Example 30: Preparation of (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)amino)pentyl)-indol-6-yl)-N-hydroxyacrylamide (I-30)

[0201]

[0202] (E)-3-(1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)pentyl)- indol-6-yl)-N-hydroxyacrylamide (I-30) was obtained as a brown red solid in 70.24% yield, mp: 133.6-135.2 °C. 1H NMR (600 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.96 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.58 (t, J = 6.0 Hz, 1H), 7.85 (dd, J = 8.2, 2.5 Hz, 1H), 7.72 (dd, J = 5.8, 3.3 Hz, 1H), 7.68 (d, J = 3.4 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 3.1 Hz, 1H), 7.39 (s, 1H), 7.38 (d, J = 1.9 Hz, 2H), 7.30 - 7.21 (m, 3H), 7.21 - 7.14 (m, 3H), 6.66 (d, J = 8.2 Hz, 2H), 6.43 (d, J = 3.1 Hz, 1H), 4.44 (d, J = 2.6 Hz, 1H), 4.30 - 4.18 (m, 4H), 1.98 (s, 2H), 1.64 (p, J = 6.7 Hz, 1H), 1.43 - 1.33 (m, 2H). ESI-MS m / z: 588.32 [M] + ; 589.29 [M+H] + .

[0203] Example 31: Preparation of 1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)propyl)-N-hydroxy-indole-5-carboxamide (I-31)

[0204] Step (1): Preparation of methyl indole-5-carboxylate

[0205]

[0206] Methyl indole-5-carboxylate (1.00 g, 6.21 mmol) was added to a reaction bottle, stirred and dissolved in methanol (20 mL), stirred at 0°C, 10 drops of 98% concentrated sulfuric acid were slowly added dropwise, after dropping, it was transferred to 75°C reflux reaction for 4h. After the reaction was completed, the solution was adjusted to pH 7 with saturated sodium carbonate solution at 0°C, extracted with ethyl acetate (50 mL x 3) for three times, combined the organic phase, anhydrous Na2SO4 was used to remove water, the solvent was removed under reduced pressure, the residue was separated and purified by silica gel column chromatography to obtain white solid methyl indole-5-carboxylate (1.84 g, yield 95.20%).

[0207] Step (2): Preparation of methyl 1-(3-bromopropyl)-indole-5-carboxylate

[0208]

[0209] Following the procedure for Route Seven, Example 19, Step (2), 1-(3- bromopropyl)-indole-5-carboxylic acid methyl ester was obtained as a milky white oil (688.87 mg, yield 55.63%).

[0210] Step (3): Preparation of 1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)propyl)-indole-5-carboxylic acid methyl ester

[0211]

[0212] Following the procedure for Route Seven, Example 19, Step (3), 1-(3-(4-(6-(2- (benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)propyl)-indole-5-carboxylic acid methyl ester was obtained as a yellow oil (311.36 mg, yield 76.84%).

[0213] Step (4): Preparation of 1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)propyl)-N-hydroxy-indole-5-carboxamide (I-31)

[0214]

[0215] Following the procedure for Route One, Example 1, Step (8), 1-(3-(4-(6-(2- (benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)propyl)-N-hydroxy-indole-5- carboxamide (I-31) was obtained as a yellow solid (257.25 mg, yield 82.90%), 161.3-164.5 °C. 1 H NMR (600 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.85 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.63 (s, 1H), 8.03 (s, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.55 (s, 2H), 7.47 (d, J = 3.1 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.37 - 7.21 (m, 6H), 7.04 (d, J = 8.4 Hz, 2H), 6.55 (d, J = 3.0 Hz, 1H), 4.41 (t, J = 6.7 Hz, 2H), 4.31 (d, J = 5.8 Hz, 2H), 3.95 (t, J = 5.9 Hz, 2H), 3.72 (s, 2H), 2.27 - 2.21 (m, 2H). ESI-MS m / z: 535.18 [M] + ; 536.18 [M+H] + ; 557.17 [M+Na] + .

[0216] The compounds of Examples 32-36 were prepared according to the procedure of Example 31, selecting the appropriate starting materials.

[0217] Example 32: Preparation of l-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)butyl)-N-hydroxy-indole-5-carboxamide (I-32)

[0218]

[0219] 1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)butyl)-N-hydroxy- indole-5-carboxamide (I-32) yellowish solid, yield 81.19%, mp: 170.9-174.6 °C. 1 H NMR (600 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.84 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.01 (s, 1H), 7.85 (dd, J = 8.3, 2.5 Hz, 1H), 7.57 (d, J = 9.6 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.43 - 7.35 (m, 4H), 7.28 (t, J = 7.2 Hz, 2H), 7.24 - 7.15 (m, 3H), 6.67 (d, J = 8.1 Hz, 2H), 6.50 (d, J = 3.1 Hz, 1H), 5.31 (s, 2H), 4.25 (dd, J = 11.0, 5.8 Hz, 2H), 4.16 (t, J = 7.2 Hz, 2H), 4.10 (q, J = 5.3 Hz, 1H), 3.69 (t, J = 7.5 Hz, 1H), 3.18 (d, J = 5.0 Hz, 3H), 1.24 (s, 3H). ESI-MS m / z: 549.22 [M] + ; 550.20 [M+H] + ; 571.17 [M+Na] + .

[0220] Example 33: Preparation of l-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)pentyl)-N-hydroxy-indole-5-carboxamide (I-33)

[0221]

[0222] 1-(3-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)pentyl)-N- hydroxy-indole-5-carboxamide (I-33) yellowish solid, yield 83.71%, mp: 162.4-166.7 °C. 1 H NMR (600 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.83 (d, J = 1.7 Hz, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.62 (t, J = 6.0 Hz, 1H), 8.02 (s, 1H), 7.96 (dd, J = 8.1, 2.5 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 1.6 Hz, 1H), 7.55 (s, 1H), 7.48 (d, J = 3.1 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.36 - 7.17 (m, 6H), 7.00 (d, J = 8.6 Hz, 2H), 6.53 (d, J = 3.1 Hz, 1H), 4.30 (d, J = 5.9 Hz, 2H), 4.27 - 4.19 (m, 3H), 3.98 (t, J = 6.4 Hz, 2H), 3.71 (s, 2H), 1.82 (dd, J = 18.9, 13.2, 3H), 1.74 (d, J = 7.8 Hz, 2H), 0.88 (dt, J = 22.9, 7.2 Hz, 2H). ESI-MS m / z: 563.31 [M] + ; 564.30 [M+H] + ; 585.31 [M+Na] + .

[0223] Example 34: Preparation of 1-(3-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)amino)propyl)-N-hydroxy-indole-5-carboxamide (I-34)

[0224]

[0225] 1-(3-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)amino)propyl)-N-hydroxy-indole-5-carboxamide (I-34) brownish red solid, yield 65.01%, mp: 156.2-158.3 °C. 1H NMR (600 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.84 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.61 (t, J = 6.0 Hz, 1H), 8.02 (d, J = 1.7 Hz, 1H), 7.86 (dd, J = 8.2, 2.5 Hz, 1H), 7.56 (dd, J = 8.6, 1.6 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 3.1 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.36 (s, 1H), 7.34 (s, 1H), 7.28 - 7.15 (m, 6H), 6.67 (s, 1H), 6.65 (s, 1H), 6.52 (d, J = 3.1 Hz, 1H), 4.33 - 4.18 (m, 5H), 3.77 (dd, J = 8.5, 6.0 Hz, 1H), 1.98 (s, 2H), 1.24 (s, 2H). ESI-MS m / z: 534.21 [M] + ; 535.23 [M + H] + .

[0226] Example 35: Preparation of 1-(3-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)amino)butyl)-N-hydroxy-indole-5-carboxamide (I-35)

[0227]

[0228] 1-(3-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)butyl)-N- hydroxy-indole-5-carboxamide (I-35) brown solid, yield 72.62%, mp: 147.5-149.4 °C. 1H NMR (600 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.85 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.62 (t, J = 5.8 Hz, 1H), 7.96 (dd, J = 8.1, 2.5 Hz, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 2.0 Hz, 2H), 7.51 (d, J = 3.2 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.35 - 7.21 (m, 7H), 7.02 (d, J = 8.5 Hz, 2H), 6.55 (d, J = 3.1 Hz, 1H), 4.30 (t, J = 6.9 Hz, 5H), 4.10 (d, J = 5.4 Hz, 2H), 4.03 (t, J = 6.4 Hz, 3H), 3.72 (s, 2H), 1.93 (q, J = 7.1 Hz, 2H), 1.70 (q, J = 7.2 Hz, 3H). ESI-MS m / z: 548.22 [M] + ; 549.21 [M+H] + .

[0229] Example 36: Preparation of 1-(3-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)amino)pentyl)-N-hydroxy-indole-5-carboxamide (I-36)

[0230]

[0231] 1-(3-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)pentyl)-N- hydroxy-indole-5-carboxamide (I-36) brown solid, yield 79.23%, mp: 156.2-158.3 °C. 1H NMR (600 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.83 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.57 (t, J = 6.0 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.85 (dd, J = 8.2, 2.5 Hz, 1H), 7.56 (dd, J = 8.7, 1.7 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 3.2 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 2.2 Hz, 2H), 7.35 (s, 1H), 7.29 - 7.22 (m, 2H), 7.18 (td, J = 4.8, 2.8 Hz, 3H), 6.67 (s, 1H), 6.65 (s, 1H), 6.51 (d, J = 3.1 Hz, 1H), 5.31 (s, 2H), 4.48 - 4.42 (m, 3H), 4.28 - 4.22 (m, 2H), 4.14 (q, J = 6.3 Hz, 2H), 3.68 (dd, J = 8.6, 6.6 Hz, 1H), 3.17 (d, J = 5.3 Hz, 1H), 1.25 (d, J = 7.7 Hz, 6H). ESI-MS m / z: 562.31 [M] + ; 563.30 [M+H] + .

[0232] Example 37: Preparation of 5-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)methyl)-indole-2-carboxamide (I-37)

[0233] Step (1): Preparation of methyl 5-methylindole-2-carboxylate

[0234]

[0235] The procedure was same as Route Nine, Example 31, step (1) to afford methyl 5- methylindole-2-carboxylate (981.94 mg, yield 91%) as a white solid.

[0236] Step (2): Preparation of methyl l-(tert-butoxycarbonyl)-5-methylindole-2- carboxylate

[0237]

[0238] Into a reaction flask was placed 5-methylindole-2-carboxylic acid methyl ester (200.00 mg, 1.06 mmol) and 4-dimethylaminopyridine DMAP (12.94 mg 0.11 mmol), dichloromethane (10 mL) was added to dissolve completely, then Boc20 (346.12 mg, 1.59 mmol) and N,N-diisopropylethylamine DIPEA (13.80 mg, 0.11 mmol) were added dropwise at room temperature, the reaction was stirred at room temperature for 1 h. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1-(tert-butoxycarbonyl)-5-methylindole-2-carboxylic acid methyl ester (290.22 mg, yield 94.2%) as a white solid.

[0239] Step (3): Preparation of 1-(tert-butoxycarbonyl)-5-bromomethylindole-2-carboxylic acid methyl ester

[0240]

[0241] Into a reaction flask was placed 1-(tert-butoxycarbonyl)-5-methylindole-2-carboxylic acid methyl ester (300.00 mg, 1.03 mmol), carbon tetrachloride (10 mL) was added to dissolve at room temperature, azobisisobutyronitrile AIBN (67.71 mg, 0.41 mmol) was slowly added, after the solid disappeared, N-bromosuccinimide NBS (275.39 mg, 1.55 mmol) was slowly added, after the addition was completed, it was transferred to 75°C reflux reaction for 12 h. After the reaction was completed, the reaction liquid was cooled to room temperature, the solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography to obtain 1-(tert-butoxycarbonyl)-5-bromomethylindole-2-carboxylic acid methyl ester (272.07 mg, yield 71.6%) as a light yellow solid.

[0242] Step (4): Preparation of 1-(tert-butoxycarbonyl)-2-methyl-5-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-indole-2-carboxylic acid methyl ester

[0243]

[0244] The operation was the same as that in Example 19, Step (3) of Route Seven to obtain 1-(tert-butoxycarbonyl)-2-methyl-5-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-indole-2-carboxylic acid methyl ester (315.17 mg, yield 51.15%) as a yellow oil.

[0245] Step (5): Preparation of 5-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-indole-2-carboxylic acid methyl ester

[0246]

[0247] Methyl 1-(tert-butoxycarbonyl)-2-methyl-5-((4-(6-(2-(benzylamino)-2- oxoethyl)pyridin-3-yl)phenoxy)methyl)-indole-2-carboxylate (153.19 mg, 0.25 mmol) was added to a reaction flask, 4 mol / L hydrochloric acid ethyl acetate solution (10 mL, 40.00 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the organic phase was extracted with ethyl acetate (50 mL x 3) and 1 mol / L sodium hydroxide solution (30 mL x 3) three times, combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a yellow solid of methyl 5-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-indole-2-carboxylate (115.93 mg, yield 90.15%).

[0248] Step (6): Preparation of 5-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenoxy)methyl)-indole-2-carboxamide (I-37)

[0249]

[0250] The operation was the same as that in Route 1 Example 1 Step (8), and a light yellow solid of 5-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-indole-2-carboxamide (I-37) (52.15 mg, yield 71.61%) was obtained, mp: 188.2-192.1 °C. 1 H NMR (600 MHz, DMSO-d6) δ 11.63 (s, 1H), 11.23 (s, 1H), 9.10 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.78-7.61 (m, 4H), 7.52 (s, 1H), 7.47-7.04 (m, 8H), 6.98 (d, J = 11.5 Hz, 1H), 5.20 (d, J = 3.9 Hz, 1H), 4.40 (t, J = 5.6 Hz, 1H), 4.32 (dd, J = 12.6, 5.3 Hz, 2H), 4.22 (t, J = 6.5 Hz, 2H), 3.71 (s, 1H), 3.51 (s, 3H), 3.06 (d, J = 8.4 Hz, 2H), 2.89 (s, 1H), 2.73 (s, 1H). ESI-MS m / z: 507.19 [M] + .

[0251] The compound of Example 38 was prepared according to the preparation method of Example 37 by selecting appropriate starting materials

[0252] Example 38: Preparation of 5-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3- yl)phenyl)amino)methyl)-indole-2-carboxamide (I-38)

[0253]

[0254] 5-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-indole- 2-carboxamide (I-38) was obtained as a light yellow solid in 75.2% yield, mp: 158.2-162.3 °C. 1 H NMR (600 MHz, DMSO-d6) δ 11.56 (s, 1H), 11.21 (s, 1H), 8.86 (d, J = 2.3 Hz, 1H), 8.69 (t, J = 5.9 Hz, 1H), 8.27 (d, J = 10.2 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.44 (s, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.17-7.04 (m, 5H), 6.97 (d, J = 8.6 Hz, 3H), 6.90 (t, J = 6.0 Hz, 3H), 3.40 (s, 1H), 1.23 (d, J = 3.5 Hz, 3H). ESI-MS m / z: 506.23 [M] + 507.25 [M+H] + .

[0255] Example 39: In vitro anti-tumor cell proliferation activity test of the target compound

[0256] MTT method was used to test the in vitro anti-proliferative activity of the target compounds on A549, MCF-7 and HT-29 three cell lines. Collect the logarithmic phase cells, adjust the cell suspension concentration, add 100 μL to each well of the 96-well plate, plate (A549: 2000 cells / well, MCF-7: 2000 cells / well, HT-29: 6000 cells / well). Incubate at 37°C, 5% CO2, until the cell monolayer covers the bottom of the well, incubate for 24 hours. Add drug concentration gradient, set 5 gradients 0.001 umol, 0.01 umol, 0.1 umol, 1 umol, 10 umol), 100 uL per well, set 3 replicate wells. Incubate at 37°C, 5% CO2, for 72 hours, and observe under an inverted microscope. Discard the culture medium, add 100 μL of MTT solution (2.5 mg / mL) to each well, continue to culture for 4 h. If the drug can react with MTT, centrifuge and discard the culture medium, rinse 2-3 times with PBS, and then add MTT-containing culture medium. Terminate the culture, discard the MTT solution, add 100 μL of dimethyl sulfoxide to each well, and shake on a shaker to dissolve the crystals. Measure the absorbance of each well at OD490 nm on an enzyme-linked immunosorbent assay instrument. IC 50 The results were calculated using GraphPad Prism 8.0.

[0257] Table 1 Anti-proliferative activity of target compounds on A549, MCF-7 and HT-29

[0258]

[0259]

[0260]

[0261] The compounds obtained by the application described above have certain effects on in vitro anti-tumor cell proliferation activity, and some compounds have higher effects than the positive control.

[0262] Example 40: In vitro anti-tumor cell proliferation activity test of target compounds

[0263] Add HDAC assay buffer II, diluted trichostatin A or inhibitors to the appropriate wells of the microplate. Heat the 2x substrate solution and HDAC assay buffer to the assay temperature. Pour the refrigerated, undiluted HDAC into the heated buffer. Add diluted HDAC to all wells (except the "no enzyme control" wells). Start the HDAC reaction by adding diluted substrate (25 μL) to each well and mix well. Allow the HDAC reaction to proceed for the desired time, then add the pre-prepared Fluor de Developer II (50 μL), and stop the reaction. Incubate the plate at room temperature (or 30°C) for at least 45 min. Read the samples for emission light in the 440-460 nm range in a microplate reader fluorometer.

[0264]

Claims

1. A hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, characterized in that: Compounds such as those represented by general formula I, their corresponding isomers, and their pharmaceutically acceptable salts or hydrates; Where R1 is R2 is Where n1 is a positive integer between 2 and 6; R3 is H, C1-C 10 Alkyl, C3-C 10 cycloalkyl C1-C 10 Alkyl, aromatic C1-C 10 Alkyl, aromatic aminoformyl; R4 is X and Y can be the same or different and are selected from H or F, where n² = 2-7 ​​positive integers.

2. The isohydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide according to claim 1, characterized in that: The compounds are those represented by general formula I, their corresponding isomers, and their pharmaceutically acceptable salts or hydrates; In the formula, R1 is R2 is Where n1 = 3, 4 or 5; R3 can be H, n-butyl, 3-methylbutyl, 2-cyclohexylethyl, 2-phenylethyl, α-naphthylethyl, 2-(2-methylindol-3-yl), pyrimidin-2-ylcarbamoyl, or quinoline-4-ylcarbamoyl. R4 is When X is H, Y is F; when X is F, Y is H. n2 = 3, 4, 5 or 6.

3. The isohydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide according to claim 1 or 2, characterized in that: The pharmaceutically acceptable salt of the compound represented by Formula I is an acid addition salt formed by the compound of Formula I with the following inorganic or organic acids: the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid; the organic acid is acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, citric acid, salicylic acid, tartaric acid, or p-toluenesulfonic acid.

4. A composition of an isohydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, characterized in that: The composition comprises a compound of general formula I as described in claim 1, the corresponding isomer, and a pharmaceutically acceptable salt or hydrate thereof.

5. The use of an isohydroxamic acid compound or composition containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide as described in claim 1 or 4, characterized in that: The compound of general formula I of claim 1, the corresponding isomer and its pharmaceutically acceptable salt or hydrate, or the composition of claim 4, may be used in the preparation of a medicament for the prevention and / or treatment of diseases related to histone deacetylases (HDACs) and / or c-Src tyrosine kinases.

6. The application according to claim 5, characterized in that: The compound of general formula I of claim 1, its corresponding isomer and its pharmaceutically acceptable salt or hydrate, or the pharmaceutical composition of claim 4, may be used in the preparation of a drug for the prevention and / or treatment of colorectal cancer, liver cancer, lung cancer, pancreatic cancer, gastric cancer, kidney cancer, breast cancer, ovarian cancer, skin cancer, head and neck cancer, lymphoma, leukemia, neurodegenerative diseases, malaria, bacterial infections, and fungal infections.

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