Hydroxamic acid compounds containing n-benzyl-2-(5-phenylpyridin-2-yl)acetamides, methods of preparation and uses

Abstract

The application belongs to the technical field of medicines, and relates to a hydroxamic acid compound containing N-benzyl-2-(5-(4-methylphenyl)pyridin-2-yl)acetamide and a pharmaceutically acceptable salt, a hydrate, a preparation method and a pharmaceutical composition containing the compound, and an application for preventing and / or treating diseases related to any one and / or both of histone deacetylase (HDACs) and c-Src kinase. The structure of the compound is shown in general formula I.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to an isohydroxamic acid compound containing N-benzyl-2-(5-(4-methylphenyl)pyridin-2-yl)acetamide, its pharmaceutically acceptable salts, hydrates, preparation methods, and pharmaceutical compositions comprising said compound, as well as its use for the prevention and / or treatment of diseases associated with any one and / or two of histone deacetylases (HDACs) and c-Src kinases. Background Technology

[0002] Histone deacetylases (HDACs) are closely related to epigenetics and play a crucial role in gene expression. By removing terminal lysine residues from histones, they increase the positive charge density of histones, leading to a stronger binding of positively charged histones to negatively charged DNA and thus reducing the expression of certain genes, including tumor suppressor genes. Given their aberrant expression observed in various cancers, HDACs have become a popular research target in cancer therapy.

[0003] HDAC inhibitors have been developed as novel anti-tumor drugs due to their ability to inhibit cancer cell proliferation, promote apoptosis, and have few toxic side effects. Although HDAC inhibitors have been successfully used to treat hematologic malignancies and lymphomas, they have not achieved ideal results in the treatment of solid tumors, which greatly limits their clinical application.

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

[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 an oncoprotein encoded by the proto-oncogene c-Src. In tumor tissues, c-Src kinase loses its precise negative regulatory capacity, and its expression level is significantly increased and persistently activated. Abnormally activated c-Src kinase plays many biological functions in tumorigenesis and development, such as apoptosis, cell adhesion, proliferation, migration and invasion, and angiogenesis. Therefore, c-Src kinase inhibitors have attracted widespread attention in the field of solid tumor treatment. Given the great potential shown by HDAC inhibitors and c-Src kinase inhibitors in tumor treatment, and based on the high chemical modifiability of the CAP region of HDAC inhibitors, a series of dual-target HDAC / c-Src kinase inhibitors have been prepared using a "hybrid molecule" strategy. Summary of the Invention

[0006] The object of this invention is to provide an isohydroxamic acid compound containing N-benzyl-2-(5-(4-methylphenyl)pyridin-2-yl)acetamide, its pharmaceutically acceptable salts, hydrates, preparation methods, and pharmaceutical compositions comprising said compound, as well as its use for the prevention and / or treatment of diseases associated with any one and / or two of histone deacetylases (HDACs) and c-Src kinases.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] A hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, the compound being as shown in general formula I, the corresponding isomer of the compound, and its pharmaceutically acceptable salt or hydrate;

[0009]

[0010] in,

[0011] R is either H or F;

[0012] R1 is

[0013] R3 is C1-C 10 hydrocarbon group Wherein, n=1~4, Z=OH,NH2, n'=0~3, Z'=H,OH,NH2,N(CH3)2,N(C2H5)2;

[0014] R2 is C1-C 14 Alkyl, C2-C 14 alkenyl, C2-C 14 Alkyne group, fused ring, fused heterocyclic group, unsubstituted or substituted by at least one of the following groups, C1-C 14 Alkyl, aryl, heteroaryl; wherein the following groups are halogens, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkylacyl, C1-C6 alkoxy, -NR4, C1-C6 alkylamino, -SR4, C1-C6 alkylthio, a six-membered ring containing at least one heteroatom, or an aryl group containing at least one heteroatom;

[0015] R4 is C1-C 14 alkyl.

[0016] Preferably, the compound is a compound of general formula I, the corresponding isomer of the compound, and its pharmaceutically acceptable salt or hydrate;

[0017] In the formula,

[0018] R is H;

[0019] R1 is

[0020] R2 is C1-C 14 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, indole, indolyl, carbazole, purine, phthalazinyl, benzofuranyl, benzothiophene, benzotriazolyl, 7H-pyrrolo[2,3-D]pyrimidine, 5H-pyrrolo[2,3-D]pyrimidine, 1H-pyrrolo[2,3-D]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, thieno[3,2-D]pyrimidine, thieno[2,3-D]pyrimidine, C1-C unsubstituted or substituted with at least one of the following groups. 10 Alkyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl; wherein the following groups are halogens, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkylacyl, C1-C6 alkoxy, -NR4, C1-C6 alkylamino, -SR4, C1-C6 alkylthio, a six-membered ring containing one or two N atoms, or an aryl group containing at least one heteroatom;

[0021] R4 is C1-C 14 alkyl.

[0022] Further preferably, the compound is a compound of general formula I, the corresponding isomer of the compound, and its pharmaceutically acceptable salt or hydrate;

[0023] In the formula,

[0024] R is H;

[0025] R1 is

[0026] R2 is C1-C 14 Alkyl, C2-C 10 alkenyl, C2-C 10 acetylinyl

[0027] Naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, indoleyl, indolyl, carbazoleyl, purineyl, phthalazinyl, benzofuranyl, benzothiopheneyl, benzotriazolyl, 7H-pyrrolo[2,3-D]pyrimidine, 5H-pyrrolo[2,3-D]pyrimidine, 1H-pyrrolo[2,3-D]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, thiopheno[ [3,2-D]pyrimidine, thieno[2,3-D]pyrimidine, unsubstituted or substituted with at least one C2-C6 alkenyl group, halogen, pyridine, pyrroleyl, furanyl, thienoyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, pyridinyl, pyrazinyl, pyrazinyl;

[0028] X is selected from C, N, O, or S.

[0029] Further preferably, the compound is a compound of general formula I, the corresponding isomer of the compound, and its pharmaceutically acceptable salt or hydrate;

[0030] In the formula,

[0031] R is H;

[0032] R1 is

[0033] R2 is C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 acetylinyl Pyrrole, furanyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl;

[0034] X is selected from C, N, O, or S.

[0035] More preferably, the compound is a compound of general formula I, its corresponding isomer, or its pharmaceutically acceptable salt or hydrate:

[0036] In the formula,

[0037] R is H;

[0038] R1 is

[0039] R2 is a C3-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group.

[0040] The compound represented by Formula I or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt comprises 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.

[0041] A composition comprising an isohydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, the composition comprising any one of the isohydroxamic acid compounds and its pharmaceutically acceptable salt or hydrate and a pharmaceutically acceptable carrier.

[0042] The use of an isohydroxamic acid compound or composition containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, the compound of general formula I, the corresponding isomer of the compound and its pharmaceutically acceptable salt or hydrate, or the pharmaceutical composition thereof, in the preparation of a preventive and / or therapeutic remedy for diseases associated with histone deacetylases (HDACs) and / or c-Src tyrosine kinases.

[0043] The compound represented by general formula I, its corresponding isomers and their pharmaceutically acceptable salts or hydrates, or the pharmaceutical composition thereof, may be used in the preparation of drugs 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.

[0044] The compounds of the present invention and pharmaceutical compositions comprising the compounds of the present invention may be used in the prevention and / or treatment of diseases associated with HDAC and / or c-Src tyrosine kinase.

[0045] The isohydroxamic acid compounds containing N-benzyl-2-(5-(4-methylphenyl)pyridin-2-yl)acetamide and their pharmaceutical compositions are used as HDAC inhibitors to treat diseases related to abnormal HDAC expression, such as 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.

[0046] The isohydroxamic acid compounds containing N-benzyl-2-(5-(4-methylphenyl)pyridin-2-yl)acetamide described in this invention are prepared using one of the following eight routes.

[0047] Route 1:

[0048]

[0049] Route 2:

[0050]

[0051] Route 3:

[0052]

[0053] Route 4:

[0054]

[0055] Route 5:

[0056]

[0057] Route Six:

[0058]

[0059] Route 7:

[0060]

[0061] Route 8:

[0062] Detailed Implementation

[0063] The present invention will be described in detail below through specific embodiments, but the scope of the present invention is not limited to the scope of the embodiments described herein.

[0064] Example 1: Preparation of 5-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxypentanamide (Ⅰ-1):

[0065] Step (1): Preparation of 2-(5-bromopyridin-2-yl)acetonitrile

[0066]

[0067] 5-Bromo-2-fluoropyridine (10.00 g, 28.41 mmol) was dissolved in tetrahydrofuran at 0 °C with stirring. Acetonitrile (1.17 g, 28.41 mmol) was added dropwise to the mixture, followed by the addition of potassium bis(trimethylsilane)amino (22.67 g, 56.82 mmol) in portions. After the addition was complete, the reaction was maintained at 0 °C for 2 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the mixture was extracted with dichloromethane (150 ml × 3) and water (250 ml). The aqueous phase was discarded, and the organic phases were combined. The organic solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain an orange-yellow oily liquid, 2-(5-bromopyridin-2-yl)acetonitrile (8.41 g, yield 75.60%).

[0068] Step (2): Preparation of methyl 2-(5-bromopyridin-2-yl)acetate

[0069]

[0070] At 0°C, under stirring, concentrated sulfuric acid (45.00 g, 429.00 mmol) was added dropwise to a methanol (82 ml) solution of 2-(5-bromopyridin-2-yl)acetonitrile (8.41 g, 42.90 mmol). After the addition was complete, the temperature was slowly raised to reflux until the reaction was complete. After the reaction was complete, the solution was cooled to room temperature, and the reaction mixture was slowly added to a saturated sodium carbonate aqueous solution (200 ml). The mixture was extracted with dichloromethane (200 ml × 3), the aqueous phase was discarded, the organic phases were combined, and the organic solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain an orange-yellow solid methyl 2-(5-bromopyridin-2-yl)acetate (8.04 g, yield 81.75%).

[0071] Step (3): Preparation of N-benzyl-2-(5-bromopyridin-2-yl)acetamide

[0072]

[0073] Under stirring at room temperature, methyl 2-(5-bromopyridin-2-yl)acetate (8.04 g, 35.10 mmol) was dissolved in anisole (8 ml). Benzylamine (46 ml, 0.421 mol) was added dropwise to the mixture. After the addition was complete, the mixture was heated to reflux until the reaction was complete. After the reaction was complete, the reaction solution was left to stand at -20°C overnight. A large amount of solid precipitated out. The solvent was removed by filtration, and the solid was washed with a small amount of toluene until it turned white, yielding the product N-benzyl-2-(5-bromopyridin-2-yl)acetamide (7.07 g, yield 66.24%).

[0074] Step (4): Preparation of N-benzyl-2-(5-(4-hydroxyphenyl)pyridin-2-yl)acetamide

[0075]

[0076] N-Benzyl-2-(5-bromopyridin-2-yl)acetamide (5.00 g, 16.40 mmol) was fully dissolved in ethylene glycol dimethyl ether (55 ml), and tetrakis(triphenylphosphine)palladium (760 mg, 0.66 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Sodium carbonate (5.23 g, 49.30 mmol), water (2 ml), and 4-hydroxyphenylboronic acid linalool ester (5.41 g, 24.70 mmol) were added sequentially to the mixture. After the addition was complete, the mixture was heated to reflux until the reaction was complete. After the reaction was complete, the mixture was cooled to room temperature, and the solid in the reaction solution was removed by diatomaceous earth adsorption. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain a milky white solid N-benzyl-2-(5-(4-hydroxyphenyl)pyridin-2-yl)acetamide (4.59 g, yield 89%).

[0077] Step (5): Preparation of methyl 4-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)butyrate

[0078]

[0079] At 0 °C, under stirring, N-benzyl-2-(5-(4-hydroxyphenyl)pyridin-2-yl)acetamide (150 mg, 0.47 mmol) was dissolved in DMF (3 ml), and sodium hydrogen (17 mg, 0.71 mmol) was added in portions, followed by dropwise addition of methyl 4-bromobutyrate (105 μL, 0.61 mmol). After the reaction was complete, the mixture was extracted with ethyl acetate (50 ml × 3) and water (100 ml), the aqueous phase was discarded, the organic phases were combined, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give a milky white solid methyl 4-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)butyrate (84 mg, yield 41.36%).

[0080] Step (6): Preparation of 4-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxybutyramide (Ⅰ-1)

[0081]

[0082] Sodium hydroxide (59 mg, 1.47 mmol) was dissolved in a 50% aqueous solution of hydroxylamine (604 mg, 9.16 mmol) at 0 °C with stirring. A methanol:tetrahydrofuran solution (7 ml) of methyl 4-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)butyrate (84 mg, 0.18 mmol) was added dropwise. After 0.5 hours, the reaction was allowed to proceed to room temperature until completion. After the reaction was complete, the solvent was removed under reduced pressure, and 5 ml of water was added. 1 mol / L hydrochloric acid solution was added dropwise until the pH reached 6, resulting in the precipitation of a solid. The solid was filtered and dried to obtain a milky white solid, 4-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxybutyramide (Ⅰ-1) (49 mg, yield 58.12%), mp: 167.3–170.4 °C. 1 H NMR (600MHz, DMSO-d6) δ10.41(s,1H),8.75(s,1H),8.61(s,1H),7.97(d,J=8.1Hz,1H),7.64(d,J=8.7Hz,2H),7.40(s,1H),7 .32(s,2H),7.28(s,2H),7.23(s,1H),7.04(s,2H),4.31(s,2H),4.01(s,2H),3.71(s,2H),2.14(s,2H),1.95(s,2H).ESI-MS m / z:420.16[M+H]+; 442.11[M+Na]+.

[0083] Following the preparation method of Example 1, appropriate raw materials were selected to prepare the compounds of Examples 2-11.

[0084] Example 2: Preparation of 5-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxypentanamide (Ⅰ-2)

[0085]

[0086] 5-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxypentanamide (Ⅰ-2) is a milky white solid with a yield of 66.43% and an mp of 195.7–201.4 °C. 1H NMR (600MHz, DMSO-d6) δ8.74(d,J=1.9Hz,1H),8.62(t,J=5.7Hz,1H),7.96(dd,J=8.1,2.3Hz ,1H),7.64(d,J=8.6Hz,2H),7.39(d,J=8.1Hz,1H),7.32(t,J=7.4Hz,2H),7.27(d,J=7.3Hz,2 H),7.23(t,J=7.1Hz,1H),7.04(d,J=8.6Hz,2H),4.30(d,J=5.9Hz,2H),4.01(t,J=6.1Hz,2H) ,3.71(s,2H),2.02(t,J=7.1Hz,2H),1.75-1.68(m,2H),1.65(dt,J=13.7,6.8Hz,2H).ESI-MS m / z:434.24[M+H] + .

[0087] Example 3: Preparation of 6-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxyhexanoamide (Ⅰ-3)

[0088]

[0089] 6-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxyhexanoamide (Ⅰ-3) is a milky white solid with a yield of 68.43% and an mp of 226.5–228.2 °C. 1 H NMR (600MHz, DMSO-d6) δ8.75(d,J=2.2Hz,1H),8.64(t,J=5.7Hz,1H),7.97(dd,J=8.0,2.3Hz,1H),7. 65(d,J=8.6Hz,2H),7.40(d,J=8.1Hz,1H),7.33(t,J=7.5Hz,2H),7.28(d,J=7.3Hz,2H),7.24(t,J=7 .2Hz,1H),7.05(d,J=8.6Hz,2H),4.31(d,J=5.9Hz,2H),4.01(t,J=6.4Hz,2H),3.72(s,2H),1.93(t, J=7.3Hz,2H),1.77-1.70(m,2H),1.55(dt,J=15.1,7.5Hz,2H),1.40(dt,J=15.3,7.7Hz,2H).ESI-MS m / z:448.25[M+H] + 470.22 [M+Na] + .

[0090] Example 4: Preparation of 7-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxyheptanamide (Ⅰ-4)

[0091]

[0092] 7-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxyheptanamide (Ⅰ-4) is a milky white solid with a yield of 63.00% and an mp of 181.1–181.8 °C. 1 H NMR (600MHz, DMSO-d6) δ10.35(s,1H),8.75(d,J=2.1Hz,1H),8.68(s,1H),8.63(t,J=5.8Hz,1H),7.97(dd,J= 8.1,2.4Hz,1H),7.65(d,J=8.7Hz,2H),7.41(d,J=8.1Hz,1H),7.33(t,J=7.5Hz,2H),7.28(d,J=7.2Hz,2H),7. 25(t,J=7.2Hz,1H),7.05(d,J=8.7Hz,2H),4.31(d,J=5.9Hz,2H),4.02(t,J=6.4Hz,2H),3.72(s,2H),1.97(t ,J=7.3Hz,2H),1.77-1.69(m,2H),1.57-1.49(m,2H),1.43(dt,J=15.1,7.5Hz,2H),1.37-1.28(m,2H).ESI-MS m / z:462.27[M+H] + 484.23 [M+Na] + .

[0093] Example 5: Preparation of 8-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxyoctamide (Ⅰ-5)

[0094]

[0095] 8-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxyoctamide (Ⅰ-5) is a milky white solid with a yield of 60.50% and an mp of 176.7–179.2 °C. 1H NMR (600MHz, DMSO-d6) δ10.34(s,1H),8.75(d,J=2.2Hz,1H),8.67(s,1H),8.63(t,J=5.8Hz,1H),7.97(dd,J=7. 9,2.4Hz,1H),7.65(d,J=8.5Hz,2H),7.41(d,J=7.9Hz,1H),7.33(t,J=7.4Hz,2H),7.28(d,J=7.1Hz,2H),7.25( t,J=7.2Hz,1H),7.05(d,J=8.5Hz,2H),4.31(d,J=6.0Hz,2H),4.02(t,J=6.5Hz,2H),3.72(s,2H),1.95(t,J=7. 4Hz,2H),1.76-1.70(m,2H),1.54-1.48(m,2H),1.45-1.39(m,2H),1.37-1.31(m,2H),1.30-1.24(m,2H).ESI-MS m / z:476.30[M+H] + .

[0096] Example 6: Preparation of 3-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxypropionamide (Ⅰ-6)

[0097]

[0098] 3-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxypropionamide (Ⅰ-6) is a pale yellow solid with a yield of 71% and an mp of 177.4–180.8 °C. 1 H NMR (600MHz, DMSO-d6) δ10.44(s,1H),8.60(t,J=6.1Hz,1H),7.89(dd,J=8.1,2.5Hz ,1H),7.48(d,J=8.2Hz,2H),7.33(dd,J=16.2,7.9Hz,3H),7.28(d,J=7.5Hz,2H),7. 24(t,J=7.3Hz,1H),6.69(d,J=8.3Hz,2H),5.88(t,J=6.0Hz,1H),4.31(d,J=5.9Hz, 2H),4.10(q,J=5.3Hz,2H),3.69(s,2H),2.26(t,J=7.0Hz,2H),1.25(s,1H).ESI-MS m / z:405.13[M+H]+; 427.10[M+Na] + .

[0099] Example 7: Preparation of 4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxybutyramide (Ⅰ-7)

[0100]

[0101] 4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxybutyramide (Ⅰ-7) is a milky white solid with a yield of 62.31% and an mp of 183.7–187.9 °C. 1 H NMR (600MHz, DMSO-d6) δ10.42(s,1H),8.68(d,J=2.5Hz,1H),8.61(t,J=6.0Hz,1H),7.87 (dd,J=8.1,2.5Hz,1H),7.49-7.41(m,2H),7.35-7.29(m,3H),7.29-7.24(m,2H),7.23(t, J=7.3Hz,1H),6.66(d,J=8.6Hz,2H),5.91(t,J=5.7Hz,1H),4.30(d,J=6.0Hz,2H),3.68( s,2H),3.04(q,J=6.6Hz,2H),2.07(t,J=7.4Hz,2H),1.99(dt,J=12.6,7.1Hz,2H).ESI-MS m / z:419.14[M+H] + .

[0102] Example 8: Preparation of 5-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxypentanamide (Ⅰ-8)

[0103]

[0104] 5-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxypentanamide (Ⅰ-8) is a milky white solid with a yield of 68.67% and an mp of 197.0–200.9 °C. 1H NMR (600MHz, DMSO-d6) δ8.67(d,J=2.1Hz,1H),8.58(t,J=5.9Hz,1H),7.87(dd,J=8.2,2. 3Hz,1H),7.39(dd,J=8.4,2.5Hz,3H),7.28(t,J=7.5Hz,2H),7.19(dd,J=15.1,7.5Hz,3H ),6.66(d,J=8.4Hz,2H),5.31(s,2H),4.26(t,J=6.3Hz,2H),3.70(t,J=7.6Hz,1H),1.98 (s,1H),1.92(t,J=7.3Hz,2H),1.82(s,1H),1.56-1.47(m,2H),1.2-1.26(m,2H).ESI-MS m / z:433.26[M+H] + 455.23 [M+Na] + .

[0105] Example 9: Preparation of 6-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxyhexanoamide (Ⅰ-9)

[0106]

[0107] 6-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxyhexanoamide (Ⅰ-9) is a pale yellow solid with a yield of 72.50% and an mp of 172.3–174.5 °C. 1 H NMR (600MHz, DMSO-d6) δ10.34(s,1H),8.67(d,J=1.9Hz,1H),8.65(s,1H),8.60(t,J=5.9Hz,1H) ,7.86(dd,J=8.2,2.3Hz,1H),7.39(d,J=8.3Hz,3H),7.28(t,J=7.4Hz,2H),7.20(t,J=9.1Hz,3H ),6.66(d,J=8.4Hz,2H),5.31(s,2H),4.27(ddd,J=35.4,15.3,5.9Hz,2H),3.71(t,J=7.5Hz,1H ),1.98(s,1H),1.91(t,J=7.4Hz,2H),1.80(s,1H),1.50-1.41(m,2H),1.21-1.26(m,4H).ESI-MS m / z:447.23[M+H] + 469.29 [M+Na] + .

[0108] Example 10: Preparation of 7-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxyheptamide (Ⅰ-10)

[0109]

[0110] 7-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxyheptanamide (Ⅰ-10) is a pale yellow solid with a yield of 70.44% and an mp of 149.3–152.1 °C. 1 H NMR(600MHz,DMSO-d6)δ8.67(s,1H),8.63(t,J=5.5Hz,1H),7.91-7.84(m,1H),7.40(d,J=8 .2Hz,3H),7.29(t,J=7.3Hz,2H),7.21(t,J=8.2Hz,3H),6.67(d,J=8.2Hz,2H),5.31(s,2H), 4.28(ddd,J=41.5,15.1,5.8Hz,2H),3.72(t,J=7.5Hz,1H),1.99(s,1H),1.88(t,J=7.1Hz, 2H),1.80(s,1H),1.44(dt,J=14.7,7.5Hz,2H),1.24(ddd,J=20.8,14.7,7.0Hz,6H).ESI-MS m / z:461.31[M+H] + 483.29 [M+Na] + .

[0111] Example 11: Preparation of 8-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxyoctamide (Ⅰ-11)

[0112]

[0113] 8-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxyoctanoamide (Ⅰ-11) is a milky white solid with a yield of 68.00% and an mp of 178.2–181.1 °C. 1H NMR (600MHz, DMSO-d6) δ10.33(s,1H),8.68(s,1H),8.60(t,J=5.5Hz,1H),7.87(d,J=7.6Hz, 1H),7.40(d,J=7.8Hz,3H),7.28(t,J=7.1Hz,2H),7.21(t,J=9.1Hz,3H),6.67(d,J=8.0Hz,2H ),5.32(s,2H),4.31(dd,J=15.1,5.5Hz,1H),4.24(dd,J=14.9,5.5Hz,1H),3.72(t,J=7.2Hz, 1H),2.00(s,1H),1.93(t,J=7.0Hz,2H),1.80(s,1H),1.47(s,2H),1.27-1.17(m,8H).ESI-MS m / z:475.32[M+H] + 497.29 [M+Na] + .

[0114] Example 12: N 1 -(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 5 Preparation of 1-hydroxyglutaramide (I-12)

[0115] Step (1): Preparation of 5-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-ylphenyl)amino)-5-oxopentanoic acid

[0116]

[0117] Under stirring at room temperature, glutaric acid (150 mmol, 1.13 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (539 mg, 1.42 mmol), and diisopropylethylamine (188 μL, 1.13 mmol) were added sequentially to a solution of 2-(5-(4-aminophenyl)pyridin-2-yl)-N-benzylacetamide (300 mg, 0.95 mmol) in dimethylformamide (5 mL). The reaction was allowed to proceed until completion. After the reaction was complete, the solid was removed by filtration, and the mixture was extracted with ethyl acetate (50 mL × 3) and water (150 mL). The organic phases were combined, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain a milky white solid 5-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-ylphenyl)amino)-5-oxovalerate (183 mg, 45.00%).

[0118] Step (2): Preparation of methyl 5-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-ylphenyl)amino)-5-oxovalerate

[0119]

[0120] Under stirring at room temperature, one drop of concentrated sulfuric acid was added dropwise to a methanol (8 mL) solution of 5-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-ylphenyl)amino)-5-oxovalerate (183 mg, 0.42 mmol), and the mixture was heated to reflux. After the reaction was complete, the solvent was removed by vacuum distillation, and the mixture was extracted with ethyl acetate (50 mL × 3) and 1 mol / L sodium carbonate solution (100 mL). The organic phases were combined, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to give a pale yellow solid methyl 5-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-ylphenyl)amino)-5-oxovalerate (98 mg, 51.75%).

[0121] Step (3): N 1 -(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 5 Preparation of 1-hydroxyglutaramide (I-12)

[0122]

[0123] Following the same procedure as in Example 1, step (6), a pale yellow solid N was obtained. 1 -(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 5 1-Hydroxyglutamate (I-12) (64 mg, 65.20%), mp: 228.6~231.5℃. 1HNMR(600MHz,DMSO-d6)δ10.40(s,1H),10.07(s,1H),8.78(d,J=1.9Hz,1H),8.63(t,J=5.8Hz ,1H),8.00(dd,J=8.1,2.3Hz,1H),7.73(d,J=8.5Hz,2H),7.67(d,J=8.6Hz,2H),7.42(d,J=8.1 Hz,1H),7.33(t,J=7.5Hz,2H),7.28(d,J=7.2Hz,2H),7.25(t,J=7.2Hz,1H),4.31(d,J=5.9Hz ,2H),3.73(s,2H),2.35(t,J=7.3Hz,2H),2.03(t,J=7.4Hz,2H),1.83(p,J=7.3Hz,2H).ESI-MS m / z:447.23[M+H] + 469.26 [M+Na] + .

[0124] Following the preparation method of Example 12, appropriate raw materials were selected to prepare the compounds of Examples 13-15.

[0125] Example 13: N 1 -(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 6 Preparation of 1-hydroxyhexadiamide (Ⅰ-13)

[0126]

[0127] N 1 -(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 6 1-Hydroxyhexadiamide (Ⅰ-13) is a pale yellow solid with a yield of 65.20% and an mp of 235.3–236.1 °C. 1H NMR (600MHz, DMSO-d6) δ10.38(s,1H),10.03(s,1H),8.78(s,1H),8.70(s,1H),8.63(t,J=5. 5Hz,1H),8.00(d,J=8.0Hz,1H),7.73(d,J=8.1Hz,2H),7.67(d,J=8.4Hz,2H),7.42(d,J=8.0 Hz,1H),7.33(t,J=7.3Hz,2H),7.28(d,J=7.2Hz,2H),7.25(t,J=7.0Hz,1H),4.31(d,J=5.7H z,2H),3.73(s,2H),2.34(t,J=6.5Hz,2H),1.99(t,J=6.6Hz,2H),1.64-1.51(m,4H).ESI-MS m / z:461.25[M+H] + 483.24 [M+Na] + .

[0128] Example 14: N 1 -(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 7 Preparation of 1-hydroxyheptanediamide (I-14)

[0129]

[0130] N 1 -(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 7 -Hydroxyheptanamide (Ⅰ-14) is a pale yellow solid with a yield of 67.00% and an mp of 247.6–249.1 °C. 1H NMR (600MHz, DMSO-d6) δ10.35(s,1H),10.01(s,1H),8.78(d,J=2.1Hz,1H),8.68(s,1H),8.63(t,J=5.9Hz,1H),8. 00(dd,J=8.1,2.4Hz,1H),7.73(d,J=8.6Hz,2H),7.67(d,J=8.7Hz,2H),7.42(d,J=8.1Hz,1H),7.33(t,J=7.5Hz,2 H),7.28(d,J=7.1Hz,2H),7.25(t,J=7.2Hz,1H),4.31(d,J=5.9Hz,2H),3.73(s,2H),2.33(t,J=7.4Hz,2H),1.96( t,J=7.4Hz,2H),1.61(dt,J=15.1,7.5Hz,2H),1.53(dt,J=15.0,7.4Hz,2H),1.29(dt,J=15.4,7.7Hz,2H).ESI-MS m / z:475.26[M+H] + 497.25 [M+Na] + .

[0131] Example 15: N 1 -(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 8 Preparation of 1-hydroxyoctadiamide (I-15)

[0132]

[0133] N 1 -(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 8 -Hydroxyoctadiamide (Ⅰ-15) is a pale yellow solid with a yield of 64.33% and an mp of 252.6–253.1 °C. 1H NMR (600MHz, DMSO-d6) δ10.34(s,1H),10.01(s,1H),8.78(s,1H),8.67(s,1H),8.63(t,J=5.2Hz,1H),8. 00(dd,J=8.0,1.8Hz,1H),7.73(d,J=8.4Hz,2H),7.67(d,J=8.5Hz,2H),7.42(d,J=8.1Hz,1H),7.33(t,J =7.4Hz,2H),7.28(d,J=7.3Hz,2H),7.25(t,J=7.1Hz,1H),4.31(d,J=5.8Hz,2H),3.73(s,2H),2.33(t,J =7.2Hz,2H),1.95(t,J=7.3Hz,2H),1.65-1.58(m,2H),1.51(dd,J=13.7,6.9Hz,2H),1.30(s,4H).ESI-MS m / z:489.27[M+H] + 511.23 [M+Na] + .

[0134] Example 16: Preparation of (E)-3-(3-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)phenyl)-N-hydroxyacrylamide (I-16)

[0135] Step (1): Preparation of methyl 3-methylcinnamate

[0136]

[0137] Under stirring at 0°C, 5 drops of concentrated sulfuric acid were added dropwise to a methanol (15 ml) solution of 3-methylcinnamic acid (500 mg, 3.08 mmol). After the addition was complete, the temperature was raised to reflux until the reaction was complete. After the reaction was complete, the solution was adjusted to pH 7 with 1 mol / L sodium carbonate solution, extracted with dichloromethane (50 ml × 3), the organic phases were combined, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to give a white solid methyl 3-methylcinnamate (543 mg, yield 100.00%).

[0138] Step (2): Preparation of methyl 3-bromomethylcinnamate

[0139]

[0140] Under stirring at room temperature, N-bromosuccinimide (603 mg, 3.39 mmol) and azobisisobutyronitrile (51 mg, 0.31 mmol) were added sequentially to a carbon tetrachloride (15 mL) solution of methyl 3-methylcinnamate (543 mg, 3.08 mmol). After the addition was complete, the mixture was heated to reflux until the reaction was complete. After the reaction was complete, the organic phase was washed once each with saturated sodium bicarbonate solution (100 mL) and saturated sodium chloride solution (100 mL). The solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography to obtain a light pink solid of methyl 3-bromomethylcinnamate (575 mg, yield 73.45%).

[0141] Step (3): Preparation of (E)-3-(3-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)acrylate

[0142]

[0143] At room temperature, methyl 3-bromomethyl cinnamate (145 mg, 0.57 mmol), potassium carbonate (98 mg, 0.71 mmol), and potassium iodide (63 mg, 0.38 mmol) were added sequentially to a solution of 2-(5-(4-aminophenyl)pyridin-2-yl)-N-benzylacetamide (150 mg, 0.47 mmol) in dimethylformamide (3 mL). After the addition was complete, the mixture was stirred until the reaction was complete. After the reaction was complete, the mixture was extracted three times with ethyl acetate (50 mL) and water (100 mL). The organic phases were combined, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain a milky white solid (E)-3-(3-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)acrylate (203 mg, 87.52%).

[0144] Step (4): Preparation of (E)-3-(3-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)phenyl)-N-hydroxyacrylamide (I-16)

[0145]

[0146] The procedure was the same as step (6) in Example 1 of the same route. A pale yellow solid (E)-3-(3-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)phenyl)-N-hydroxyacrylamide (I-16) (148 mg, 73.75%) was obtained, mp: 277.2-279.5 °C. 1H NMR(600MHz,DMSO-d6)δ8.67(d,J=1.4Hz,1H),8.64-8.59(m,1H),7.87(dd,J=7.9,1.9 Hz,1H),7.53(s,1H),7.44(d,J=8.3Hz,2H),7.36(d,J=6.3Hz,1H),7.32(dd,J=12.6,5 .3Hz,4H),7.27(d,J=7.3Hz,2H),7.25-7.19(m,3H),6.70(d,J=8.3Hz,2H),6.58(t,J= 6.0Hz,1H),6.44(d,J=16.2Hz,1H),4.31(dd,J=19.3,5.5Hz,4H),3.68(s,2H).ESI-MS m / z:493.27[M+H] + 515.25 [M+Na] + .

[0147] Following the preparation method of Example 16, appropriate raw materials were selected to prepare the compounds of Examples 17-19.

[0148] Example 17: Preparation of (E)-3-(4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)phenyl)-N-hydroxyacrylamide (I-17)

[0149]

[0150] (E)-3-(4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)phenyl)-N-hydroxyacrylamide (I-17) pale yellow solid, yield 73.90%, mp: 221.6~224.0℃. 1H NMR (600MHz, DMSO-d6) δ8.66(d,J=1.4Hz,1H),8.59(t,J=5.3Hz,1H),7.85(dd,J=8.0,2.0 Hz,1H),7.46(d,J=7.8Hz,2H),7.42(d,J=8.4Hz,2H),7.36(d,J=7.8Hz,2H),7.31(t,J=8.7 Hz,3H),7.26(d,J=7.3Hz,2H),7.22(dd,J=13.2,5.6Hz,2H),6.67(d,J=8.4Hz,2H),6.56( t,J=5.7Hz,1H),6.39(d,J=15.8Hz,1H),4.30(dd,J=17.0,5.7Hz,4H),3.67(s,2H).ESI-MS m / z:493.28[M+H] + 515.26 [M+Na] + .

[0151] Example 18: Preparation of (E)-3-(3-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)phenyl)-N-hydroxyacrylamide (I-18)

[0152]

[0153] (E)-3-(3-(((4-(6-(2-(benzylamino)-2-oxyethyl)pyridin-3-yl)phenoxy)methyl)phenyl)-N-hydroxyacrylamide (I-18) pale yellow solid, yield 78.31%, mp: 266.3~268.5℃. 1 H NMR(600MHz,DMSO-d6)δ10.79(s,1H),8.80(d,J=2.4Hz,1H),8.67(t,J=6.0Hz,1H),8 .07(d,J=7.6Hz,1H),7.74-7.64(m,3H),7.54(d,J=7.4Hz,1H),7.46(p,J=7.4Hz,4H), 7.32(t,J=7.5Hz,2H),7.28(d,J=7.4Hz,2H),7.24(t,J=7.2Hz,1H),7.16(d,J=8.4Hz ,2H),6.50(d,J=15.8Hz,1H),5.21(s,2H),4.30(d,J=5.9Hz,2H),3.17(s,2H).ESI-MS m / z:494.24[M+H] + .

[0154] Example 19: Preparation of (E)-3-(4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)phenyl)-N-hydroxyacrylamide (I-19)

[0155]

[0156] (E)-3-(4-(((4-(6-(2-(benzylamino)-2-oxyethyl)pyridin-3-yl)phenoxy)methyl)phenyl)-N-hydroxyacrylamide (I-19) pale yellow solid, yield 78.31%, mp: 231.2~235.5℃. 1 H NMR (600MHz, DMSO-d6) δ10.82(s,1H),8.84(s,1H),8.72(t,J=6.0Hz,1H),8.14(d,J=8.2H z,1H),7.71(d,J=8.3Hz,2H),7.61(d,J=7.9Hz,2H),7.51(d,J=7.6Hz,3H),7.47(d,J=15. 8Hz,1H),7.33(t,J=7.5Hz,2H),7.29(d,J=7.5Hz,2H),7.25(t,J=7.2Hz,1H),7.16(d,J=8 .3Hz,2H),6.48(d,J=15.8Hz,1H),5.22(s,2H),4.31(d,J=5.9Hz,2H),3.79(s,2H).ESI-MS m / z:494.24[M+H] + .

[0157] Example 20: Preparation of (E)-3-(3-(N-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)sulfanyl)phenyl)-N-hydroxyacrylamide (I-20)

[0158] Step (1): Preparation of N-benzyl-2-(5-(4-((3-bromophenyl)sulfonamido)phenyl)pyridin-2-yl)acetamide

[0159]

[0160] Under stirring at room temperature, 4-bromobenzenesulfonyl chloride (193 mg, 0.76 mmol) was added in portions to a solution of 2-(5-(4-aminophenyl)pyridin-2-yl)-N-benzylacetamide (200 mg, 0.63 mmol) in dimethylformamide (4 ml). Pyridine (0.25 ml) was then added dropwise. After the addition was complete, the reaction continued. After the reaction was complete, the mixture was extracted with ethyl acetate (50 ml × 3) and water (100 ml). The organic phases were combined, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a milky white solid N-benzyl-2-(5-(4-((4-bromophenyl)sulfonamido)phenyl)pyridin-2-yl)acetamide (255 mg, 76.20%).

[0161] Step (2): Preparation of (E)-3-(4-(N-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)aminosulfonyl)phenyl)methyl acrylate

[0162]

[0163] Under stirring at room temperature, methyl acrylate (55 μL), palladium acetate (2 mg, 0.001 mmol), tris(o-methylphenyl)phosphine (6 mg, 0.019 mmol), and triethylamine (230 μL, 1.66 mmol) were added sequentially to a solution of N-benzyl-2-(5-(4-((4-bromophenyl)sulfonamido)phenyl)pyridin-2-yl)acetamide (255 mg, 0.59 mmol) in dimethylformamide (5 mL). After the addition was complete, the mixture was kept under nitrogen protection and the temperature was raised to 100 °C for reaction. After the reaction was completed, the solid in the reaction solution was removed by adsorption with diatomaceous earth. The diatomaceous earth was washed with ethyl acetate (70 ml × 3), the organic phases were combined, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain (E)-3-(4-(N-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)aminosulfonyl)phenyl)methyl acrylate, a pale yellow solid (150 mg, yield 58.34%).

[0164] Step (3): Preparation of (E)-3-(4-(N-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)sulfanyl)phenyl)-N-hydroxyacrylamide (Ⅰ-20)

[0165]

[0166] Following the same route, step (6) yielded (E)-3-(4-(N-(4-(6-(2-(benzylamino)-2-oxyethyl)pyridin-3-yl)phenyl)sulfanyl)phenyl)-N-hydroxyacrylamide (Ⅰ-20) pale yellow solid (77 mg, yield 49.59%), mp: 233.4~235.1℃. 1 H NMR (600MHz, DMSO-d6) δ8.70(d,J=2.2Hz,1H),8.59(t,J=5.7Hz,1H),7.92(dd,J=8.1,2.4Hz ,1H),7.80(d,J=8.3Hz,2H),7.71(d,J=8.3Hz,2H),7.58(d,J=8.5Hz,2H),7.45(d,J=15.5Hz, 1H),7.37(d,J=8.1Hz,1H),7.31(t,J=7.5Hz,2H),7.26(d,J=7.2Hz,2H),7.23(t,J=7.2Hz,1 H),7.18(d,J=8.5Hz,2H),6.53(d,J=15.8Hz,1H),4.29(d,J=5.9Hz,2H),3.69(s,2H).ESI-MS m / z:543.22[M+H] + .

[0167] Example 21: Preparation of 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxybenzamide (Ⅰ-21)

[0168] Step (1): Methyl 4-bromomethylbenzoate

[0169]

[0170] A light pink solid methyl 4-bromomethylbenzoate (129 mg, yield 87.93%) was prepared using the raw materials required in step (2) of Example 16 of Route 3 and Example 21.

[0171] Step (2): Preparation of methyl 4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)benzoate

[0172]

[0173] Methyl 4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)benzoate (213 mg, 97.12%) was prepared using the raw materials required in step (3) of Example 16 of Route 3 and Example 21.

[0174] Step (3): 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxybenzamide (Ⅰ-21)

[0175]

[0176] The pale yellow solid 4-(((4-(6-(2-(benzylamino)-2-oxyethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxybenzamide (Ⅰ-21) (200 mg, yield 91.87%) was prepared using the raw materials required in Example 1 and Example 21, with an mp of 218.2~220.3℃. 1 H NMR (600MHz, DMSO-d6) δ8.67(d,J=1.8Hz,1H),8.60(t,J=5.5Hz,1H),7.86(dd,J=8.1,2.2Hz,1H),7.69(d,J=8.0Hz,2H),7.43(d,J=8.5Hz,2H),7.32 (s,5H),7.27(d,J=7.2Hz,2H),7.24(t,J=7.3Hz,1H),6.68(d,J=8.5Hz,2H ),6.54(t,J=5.9Hz,1H),4.31(dd,J=13.8,5.8Hz,4H),3.68(s,2H).ESI-MS m / z:467.25[M+H] + 489.22 [M+Na] + .

[0177] Following the preparation method of Example 21, appropriate raw materials were selected to prepare the compounds of Examples 22-28.

[0178] Example 22: Preparation of 4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxybenzamide (Ⅰ-22)

[0179]

[0180] 4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxybenzamide (Ⅰ-22) is a pale yellow solid with a yield of 60.87% and an mp of 220.2–223.5 °C. 1H NMR(600MHz,DMSO-d6)δ11.26(s,1H),9.09(s,1H),8.77(s,1H),8.67(s,1H),8.00( d,J=8.1Hz,1H),7.78(d,J=7.8Hz,2H),7.67(d,J=8.2Hz,2H),7.54(d,J=7.8Hz,2H), 7.42(d,J=8.1Hz,1H),7.32(t,J=7.4Hz,2H),7.28(d,J=7.4Hz,2H),7.24(t,J=7.3Hz ,1H),7.14(d,J=8.2Hz,2H),5.24(s,2H),4.30(d,J=5.8Hz,2H),3.72(s,2H).ESI-MS m / z:468.18[M+H] + .

[0181] Example 23: Preparation of 6-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxynicotinamide (Ⅰ-23)

[0182]

[0183] 6-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxynicotinamide (Ⅰ-23) is a pale yellow solid with a yield of 70.89% and an mp of 215.2–217.6 °C. 1 H NMR (600MHz, DMSO-d6) δ8.85(d,J=1.1Hz,1H),8.66(d,J=1.8Hz,1H),8.59(t,J=5.5Hz ,1H),7.99(dd,J=8.0,1.7Hz,1H),7.86(dd,J=8.1,2.3Hz,1H),7.43(d,J=8.6Hz,2H),7 .35-7.29(m,4H),7.26(d,J=7.0Hz,2H),7.23(t,J=7.2Hz,1H),6.68(d,J=8.6Hz,2H),6 .62(t,J=6.0Hz,1H),4.40(d,J=5.9Hz,2H),4.29(d,J=5.8Hz,2H),3.67(s,2H).ESI-MS m / z:468.24[M+H] + 490.22 [M+Na] + .

[0184] Example 24: Preparation of 6-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxynicotinamide (Ⅰ-24)

[0185]

[0186] 6-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxynicotinamide (Ⅰ-24) is a pale yellow solid with a yield of 60.32% and an mp of 210.2–213.7 °C. 1 H NMR (600MHz, DMSO-d6) δ11.44(s,1H),9.26(s,1H),8.91(d,J=2.1Hz,1H),8.77(d,J=2.4Hz,1H),8 .67(t,J=6.0Hz,1H),8.16(dd,J=8.1,2.3Hz,1H),8.02(dd,J=8.1,2.5Hz,1H),7.72-7.66(m,2H),7 .63(d,J=8.1Hz,1H),7.43(d,J=8.1Hz,1H),7.32(t,J=7.5Hz,2H),7.30-7.26(m,2H),7.26-7.21(m ,1H),7.19-7.12(m,2H),5.31(s,2H),4.30(d,J=5.9Hz,2H),3.73(s,2H).ESI-MSm / z:469.16[M+H] + .

[0187] Example 25: Preparation of 5-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxypyridine amide (Ⅰ-25)

[0188]

[0189] 5-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxypyridine amide (Ⅰ-25) is a pale yellow solid with a yield of 56.83% and an mp of 184.0–185.8 °C. 1H NMR (600MHz, DMSO-d6) δ8.66(s,1H),8.59(s,2H),7.92(s,2H),7.86(d,J=6.8Hz,1H),7.44(d,J=8.0Hz,2H),7.31(dd,J=13.0,7.6Hz,3H),7.26(d, J=7.3Hz,2H),7.23(t,J=7.1Hz,1H),6.69(d,J=7.8Hz,2H),6.63(t,J=5.3Hz,1H),4.44(d,J=3.3Hz,2H),4.29(d,J=5.8Hz,2H),3.67(s,2H).ESI-MS m / z:468.24[M+H] + .

[0190] Example 26: Preparation of 5-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxypyridinecarboxamide (Ⅰ-26)

[0191]

[0192] 5-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxypyridinecarboxamide (Ⅰ-26) is a pale yellow solid with a yield of 64.27% and an mp of 190.1–194.8 °C. 1 H NMR (600MHz, DMSO-d6) δ11.44(s,1H),9.26(s,1H),8.91(d,J=2.1Hz,1H),8.77(d,J=2.4Hz,1H),8 .67(t,J=6.0Hz,1H),8.16(dd,J=8.1,2.3Hz,1H),8.02(dd,J=8.1,2.5Hz,1H),7.72-7.66(m,2H),7 .63(d,J=8.1Hz,1H),7.43(d,J=8.1Hz,1H),7.32(t,J=7.5Hz,2H),7.30-7.26(m,2H),7.26-7.21(m ,1H),7.19-7.12(m,2H),5.31(s,2H),4.30(d,J=5.9Hz,2H),3.73(s,2H).ESI-MSm / z:469.23[M+H] + .

[0193] Example 27: Preparation of 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxypyrimidineamide (Ⅰ-27)

[0194]

[0195] 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxypyrimidine-5-carboxamide (Ⅰ-27) is a pale yellow solid with a yield of 58.33% and an mp of 180.1–182.8 °C. 1 H NMR(600MHz,DMSO-d6)δ11.06(s,1H),8.99(s,1H),8.75(s,1H),8.68(s,2H),8.62(s ,1H),7.97(d,J=8.3Hz,1H),7.65(d,J=8.3Hz,2H),7.41(d,J=8.2Hz,1H),7.33(t,J= 7.5Hz,2H),7.28(d,J=7.4Hz,2H),7.25(d,J=7.4Hz,1H),7.07(d,J=8.3Hz,2H),4.78 (d,J=13.0Hz,2H),4.31(d,J=6.0Hz,2H),3.93(d,J=6.4Hz,2H),3.72(s,2H).ESI-MS m / z:469.15[M+H] + .

[0196] Example 28: Preparation of 2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxypyrimidine-5-carboxamide (Ⅰ-28)

[0197]

[0198] 2-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxypyrimidine-5-carboxamide (Ⅰ-28) is a pale yellow solid with a yield of 66.12% and an mp of 190.7–192.8 °C. 1 H NMR (600MHz, DMSO-d6) δ9.10(s,2H),8.75(d,J=2.4Hz,1H),8.64(s,1H),7.97(dd,J=7.5,2.3Hz,1H),7.65(d,J=8.3Hz,2H),7.40(d,J =8.1Hz,1H),7.33(t,J=7.5Hz,2H),7.30-7.21(m,3H),7.10(d,J=8.3Hz,2H),5.42(s,2H),4.31(d,J=5.9Hz,2H),3.72(s,2H).ESI-MS m / z:470.18[M+H] + .

[0199] Example 29: Preparation of 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxythiazol-4-carboxamide (Ⅰ-29)

[0200] Step (1): Preparation of methyl 2-methyl-4-thiazolyl carboxylate

[0201]

[0202] Under stirring at 0°C, concentrated sulfuric acid (671 mg, 6.85 mmol) was slowly added dropwise to a methanol (25 mL) solution of 2-methylthiazolyl-4-carboxylic acid (700 mg, 4.89 mmol). After the addition was complete, the mixture was heated to reflux. After the reaction was complete, 1 mol / L sodium carbonate solution was added dropwise to the reaction solution until the pH reached 7. The mixture was extracted three times with ethyl acetate (50 mL), and the organic phases were combined. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to give a white solid methyl 2-methyl-4-thiazolyl carboxylate (642 mg, yield 84.16%).

[0203] Step (2): Preparation of methyl 2-bromomethyl-4-thiazolic acid

[0204]

[0205] Using the raw materials required in step (2) of Example 16 of Route 3 and Example 29, a milky white solid methyl 2-bromomethyl-4-thiazocarboxylate (181 mg, yield 18.74%) was obtained.

[0206] Step (3): Preparation of methyl 2-((4-(6-(2-(benzylamino-)2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)thiazole-4-carboxylic acid

[0207]

[0208] Using the same raw materials required in step (3) of Example 16 of Route 3 and Example 29, a white solid methyl 2-((4-(6-(2-(benzylamino-)2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)thiazole-4-carboxylic acid (195 mg, yield 87.49%) was obtained.

[0209] Step (4): Preparation of 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxythiazol-4-carboxamide (Ⅰ-27)

[0210]

[0211] Using the raw materials required in step (6) of Example 1 and Example 29 of Route 1, a pale yellow solid 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxythiazol-4-carboxamide (Ⅰ-29) (148 mg, yield 75.56%), mp: 175.0~177.6℃ was obtained. 1 H NMR(600MHz,DMSO-d6)δ11.21(s,1H),9.08(s,1H),8.68(s,1H),8.59(t,J=5.6Hz,1H) ,8.09(s,1H),7.88(d,J=7.9Hz,1H),7.48(d,J=8.3Hz,2H),7.34(d,J=8.1Hz,1H),7.31 (t,J=7.5Hz,2H),7.26(d,J=7.2Hz,2H),7.23(t,J=7.2Hz,1H),6.90(t,J=5.4Hz,1H),6 .73(d,J=8.4Hz,2H),4.63(d,J=5.1Hz,2H),4.29(d,J=5.9Hz,2H),3.68(s,2H).ESI-MS m / z:474.17[M+H] + .

[0212] Following the preparation method of Example 29, appropriate raw materials were selected to prepare the compounds of Examples 30-32.

[0213] Example 30: Preparation of 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxythiazol-5-carboxamide (Ⅰ-30)

[0214]

[0215] 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxythiazol-5-carboxamide (Ⅰ-30) is a pale yellow solid with a yield of 79.76% and an mp of 176.3–177.9 °C. 1H NMR (600MHz, DMSO-d6) δ9.36 (s, 1H), 8.77 (dd, J = 2.5, 0.8Hz, 1H), 8.66 (t, J = 6.0Hz, 1H) ,8.23(s,1H),7.99(dd,J=8.1,2.5Hz,1H),7.76-7.65(m,2H),7.44-7.38(m,1H),7.32( t,J=7.6Hz,2H),7.30-7.26(m,2H),7.26-7.22(m,1H),7.22-7.17(m,2H),5.52(s,2H), 4.30(d,J=5.9Hz,2H),4.13(q,J=5.3Hz,1H),3.72(s,2H),3.17(d,J=5.2Hz,2H).ESI-MS m / z:475.15[M+H] + .

[0216] Example 31: Preparation of 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxythiazol-5-carboxamide (Ⅰ-31)

[0217]

[0218] 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxythiazol-5-carboxamide (Ⅰ-31) is a pale yellow solid with a yield of 77.76% and an mp of 207.4–209.6 °C. 1 H NMR (600MHz, DMSO-d6) δ8.68(d,J=2.0Hz,1H),8.59(t,J=5.7Hz,1H),7.88(dd,J =8.1,2.2Hz,1H),7.84(s,1H),7.46(d,J=8.4Hz,2H),7.32(dd,J=16.2,7.9Hz,3 H),7.26(d,J=7.3Hz,2H),7.23(t,J=7.1Hz,1H),6.81(t,J=5.7Hz,1H),6.72(d, J=8.5Hz,2H),4.55(d,J=5.8Hz,2H),4.29(d,J=5.9Hz,2H),3.67(s,2H).ESI-MS m / z: 474.18 [M+H] + .

[0219] Example 32: Preparation of 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxythiazol-5-carboxamide (Ⅰ-32)

[0220]

[0221] 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxythiazol-5-carboxamide (Ⅰ-32) is a pale yellow solid with a yield of 75.89% and an mp of 212.0–215.8 °C. 1 H NMR (600MHz, DMSO-d6) δ11.32(s,1H),8.85(d,J=2.3Hz,1H),8.72(t,J=6.0Hz, 1H),8.30(s,1H),8.15(d,J=8.3Hz,1H),7.81-7.69(m,2H),7.53(d,J=8.1Hz,1 H),7.34(t,J=7.5Hz,2H),7.31-7.27(m,2H),7.26(dd,J=7.1,1.8Hz,1H),7.23 (dd,J=9.2,2.5Hz,2H),5.53(s,2H),4.31(d,J=5.9Hz,2H),3.79(s,2H).ESI-MS m / z: 475.19 [M+H] + .

[0222] Following the synthetic route of Route 7 and the preparation method of Example 16, and selecting appropriate starting materials, the compounds of Examples 33-36 were obtained.

[0223] Example 33: Preparation of 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-3-fluoro-N-hydroxybenzamide (Ⅰ-33)

[0224]

[0225] 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-3-fluoro-N-hydroxybenzamide (Ⅰ-33) yellow solid, yield 71.02%, mp: 201.3~204.8℃. 1H NMR (600MHz, DMSO-d6) δ11.28(s,1H),8.78(d,J=2.3Hz,1H),8.68(t,J=5.9Hz,1H),8.11(d,J=7.9Hz,1H),7.60-7.49(m,5H),7.47(t,J=7.8Hz,1H) ,7.33(t,J=7.5Hz,2H),7.28(d,J=7.5Hz,2H),7.25(t,J=7.2Hz,1H),6.71 (d,J=8.5Hz,2H),4.43(s,2H),4.31(d,J=5.9Hz,2H),3.79(s,3H).ESI-MS m / z:485.14[M+H] + .

[0226] Example 34: Preparation of 4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-3-fluoro-N-hydroxybenzamide (Ⅰ-34)

[0227]

[0228] 4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-3-fluoro-N-hydroxybenzamide (Ⅰ-34) is a pale yellow solid with a yield of 75.87% and an mp of 216.8–219.3 °C. 1 H NMR (600MHz, DMSO-d6) δ11.35(s,0H),8.89(s,1H),8.71(t,J=6.1Hz,1H),8.25(d,J =8.2Hz,1H),7.75(d,J=8.2Hz,2H),7.67(dt,J=13.9,7.9Hz,2H),7.63-7.57(m,2H), 7.34(t,J=7.4Hz,2H),7.29(d,J=7.4Hz,2H),7.25(t,J=7.2Hz,1H),7.20(d,J=8.2Hz ,2H),5.28(s,2H),4.32(d,J=5.9Hz,2H),3.84(s,3H),1.24(d,J=6.2Hz,1H).ESI-MS m / z:486.20[M+H] + .

[0229] Example 35: Preparation of 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-2-fluoro-N-hydroxybenzamide (Ⅰ-35)

[0230]

[0231] 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-2-fluoro-N-hydroxybenzamide (Ⅰ-35) is a pale yellow solid with a yield of 76.12% and an mp of 209.2–212.3 °C. 1 H NMR (600MHz, DMSO-d6) δ10.92(s,1H),9.18(s,1H),8.72(d,J=2.4Hz,1H),8.60(t,J=6.0Hz,1H),7.9 0(dd,J=8.2,2.5Hz,1H),7.46(d,J=8.3Hz,2H),7.43(d,J=2.3Hz,1H),7.43-7.39(m,2H),7.35-7.30 (m,1H),7.27(d,J=7.6Hz,1H),7.22(dd,J=8.2,6.6Hz,2H),7.18(d,J=7.2Hz,1H),7.17-7.12(m,2H) ,6.96(d,J=7.5Hz,2H),6.73-6.63(m,3H),5.33(s,2H),4.41-4.27(m,2H),4.18-4.09(m,2H).ESI-MS m / z:485.12[M+H] + .

[0232] Example 36: Preparation of 4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-2-fluoro-N-hydroxybenzamide (Ⅰ-36)

[0233]

[0234] 4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-2-fluoro-N-hydroxybenzamide (Ⅰ-36) is a pale yellow solid with a yield of 77.89% and an mp of 221.2–224.6 °C. 1H NMR (600MHz, DMSO-d6) δ8.76(d,J=2.3Hz,1H),8.64(d,J=6.0Hz,1H),7.98(dd,J=8.1,2 .4Hz,1H),7.68(d,J=8.2Hz,2H),7.58(t,J=7.6Hz,1H),7.41(d,J=8.1Hz,1H),7.37(t, J=7.7Hz,2H),7.33(t,J=7.4Hz,2H),7.28(d,J=7.6Hz,2H),7.24(t,J=7.4Hz,1H),7.15 (d,J=8.3Hz,2H),5.25(s,2H),4.31(d,J=5.9Hz,2H),3.72(s,2H),1.24(s,1H).ESI-MS m / z:486.12[M+H] + .

[0235] Example 37: Preparation of 2-(4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide (Ⅰ-37):

[0236] Step (1): Preparation of tert-butyl 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)piperidine-1-carboxylic acid

[0237]

[0238] N-Benzyl-2-(5-(4-aminophenyl)pyridin-2-yl)acetamide (200 mg, 0.63 mmol) was dissolved in 5 ml of DMF. 1-Boc-4-bromopiperidine (250 mg, 0.95 mmol) and K2CO3 (156 mg, 1.12 mmol) were added sequentially to the solution under stirring at room temperature. After stirring at room temperature for 10 min, the temperature was slowly increased to 60 °C and reacted for 8 h. After the reaction was completed, the mixture was extracted with ethyl acetate (50 ml × 3) and water (100 ml). The organic phases were combined, and water was removed with anhydrous Na2SO4. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain a pale yellow solid 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (167 mg, 53.08%).

[0239] Step (2): Preparation of N-benzyl-2-(5-(4-((piperidin-4-ylmethyl)amino)phenyl)pyridin-2-yl)acetamide

[0240]

[0241] 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)piperidin-1-carboxylic acid tert-butyl ester (167 mg, 0.33 mmol) was dissolved in 5 mL of dichloromethane (DCM). Under stirring at room temperature, 1 mL of CF3COOOH was added, and stirring continued for 4 h. After the reaction was complete, the pH was adjusted to neutral with saturated Na2CO3, and then extracted with dichloromethane (50 mL × 3) and water (100 mL). The organic phases were combined, and water was removed with anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain a yellow solid N-benzyl-2-(5-(4-((piperidin-4-ylmethyl)amino)phenyl)pyridin-2-yl)acetamide (137 mg, 99.99%).

[0242] Step (3): Preparation of methyl 2-(4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylate

[0243]

[0244] N-Benzyl-2-(5-(4-((piperidin-4-ylmethyl)amino)phenyl)pyridin-2-yl)acetamide (137 mg, 0.33 mmol) was dissolved in 5 mL of DMF. Methyl 2-chloropyrimidine-5-carboxylic acid (57 mg, 0.33 mmol) and N,N-diisopropylethylamine (DIPEA, 0.50 mmol, 87 μL) were added sequentially to the solution under stirring at room temperature, and the reaction was continued for 8 h. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 3) and water (100 mL). The organic phases were combined, water was removed with anhydrous Na₂SO₄, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a pale yellow solid, methyl 2-(4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylate (127 mg, 70.09%).

[0245] Step (4): Preparation of 2-(4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide (Ⅰ-37)

[0246]

[0247] Following the same procedure as in Example 1, step (6), a pale yellow solid 2-(4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide (Ⅰ-37) (60 mg, 47.20%) mp: 185.2~187.8℃ was obtained. 1 H NMR(600MHz,DMSO-d6)δ8.71-8.60(m,4H),7.95-7.80(m,1H),7.41(dd,J=15.9,8.2Hz,3H),7.29(t, J=7.3Hz,2H),7.21(t,J=7.6Hz,3H),6.66(d,J=8.5Hz,2H),5.30(s,2H),4.68(d,J=12.9Hz,2H),4.2 2(dd,J=15.1,5.8Hz,1H),3.41(d,J=10.3Hz,81H),3.34(d,J=17.2Hz,19H),2.81(s,2H),2.00(dt,J =15.1,5.8Hz,1H),1.85(d,J=12.7Hz,1H),1.74(d,J=14.5Hz,2H),1.46(s,1H),1.23(s,3H)..ESI-MS m / z:552.21[M+H] + .

[0248] Following the preparation method of Example 37, and selecting appropriate raw materials, the compound of Example 38 was prepared.

[0249] Example 38: Preparation of 2-(4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide (I-38)

[0250]

[0251] 2-(4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide (Ⅰ-38) is a pale yellow solid with a yield of 53.41% and an mp of 196.6–199.8 °C. 1H NMR (600MHz, DMSO-d6) δ11.05(s,1H),8.98(s,1H),8.79-8.73(m,1H),8.67(s,2H),8.62(t,J=6.0Hz,1H),8.02- 7.92(m,2H),7.65(d,J=8.2Hz,2H),7.40(d,J=8.0Hz,1H),7.32(t,J=7.5Hz,2H),7.27(d,J=7.5Hz,2H),7.23(t,J =7.2Hz,1H),7.06(d,J=8.2Hz,2H),4.78(d,J=13.0Hz,2H),4.30(d,J=5.9Hz,2H),3.93(d,J=6.3Hz,2H),3.71(s, 2H),3.00(t,J=12.5Hz,2H),2.89(s,1H),2.73(s,1H),2.13(s,1H),1.92-1.86(m,2H),1.32-1.20(m,4H).ESI-MS m / z:553.21[M+H] + .

[0252] Example 39: In vitro antitumor cell proliferation activity test of the target compound

[0253] The CCK8 assay was used to test the in vitro antiproliferative activity of the target compound against three cell lines: HT29, CNE2, and A549. Cells were removed from a liquid nitrogen tank and thawed by continuous shaking in a 37°C water bath. The cell suspension was added to a centrifuge tube containing 9 ml PBS, centrifuged at 600 rpm, the PBS was removed, and the cells were resuspended in 1 ml of culture medium. The cell suspension was transferred to 10 cM culture dishes and cultured in a 37°C, 5% CO2 incubator. When the cells reached the appropriate density, the culture medium was removed, residual medium was washed with PBS, the PBS was removed again, 2 ml of trypsin was added to digest the cells, and culture medium was added to stop the digestion. The cells were then collected in centrifuge tubes, centrifuged at 800 rpm, and resuspended. Cells were counted using a cell counting chamber. A specific density cell suspension (4000 cells / well) was prepared with fresh culture medium and added to each well of a 96-well plate. 100 μl of cell suspension was added to each well of the experimental and negative control groups, and an equal volume of culture medium was added to the blank control group. Cells were cultured at 37°C, 5% CO2 for 24 h. The experimental group was added with 100 μL of culture medium containing different concentrations of compounds, the negative control group was added with an equal volume of culture medium containing DMSO, and the blank group was added with an equal volume of culture medium. Incubation was performed at 37℃ and 5% CO2 for 48 h. After incubation, 10 μL of CCK8 was added to each well, and incubation continued for 2.5 h. Absorbance was measured at 450 nm using a microplate reader. Three independent experiments were performed. IC50 was calculated. 50 Calculated using GraphPadPrism 8.0.

[0254] Table 1. Results of the antiproliferative activity of the target compounds against HT29, CNE2, and A549.

[0255]

[0256] a The values ​​in the table are the averages of three trials.

[0257] Example 40: In vitro antitumor cell proliferation activity test of the target compound

[0258] The MTT assay was used to test the in vitro antiproliferative activity of the target compound against three cell lines: A549, MCF-7, and HT-29. Logarithmic-phase cells were collected, and the cell suspension concentration was adjusted. 100 μl of the cell suspension was added to each well of a 96-well plate (A549: 2000 cells / well, MCF-7: 2000 cells / well, HT-29: 6000 cells / well). The plates were incubated at 37°C with 5% CO2 for 24 hours until a monolayer covered the bottom of the wells. A concentration gradient of the drug was then added (5 gradients: 0.001 μl, 0.01 μl, 0.1 μl, 1 μl, and 10 μl), 100 μl per well, with three replicates. The plates were incubated at 37°C with 5% CO2 for 72 hours and observed under an inverted microscope. The culture medium was discarded, and 100 μl of MTT solution (2.5 mg / ml) was added to each well. The plates were then cultured for another 4 hours. If the drug reacts with MTT, centrifuge first, discard the culture medium, carefully rinse 2-3 times with PBS, then add culture medium containing MTT. Terminate the culture, discard the MTT solution, add 100 μl of dimethyl sulfoxide to each well, and shake on a shaker to fully dissolve the crystals. Measure the absorbance of each well at OD490 nm using an ELISA reader. IC50 50 Calculated using GraphPadPrism 8.0.

[0259] Table 2. Results of the antiproliferative activity of the target compounds against A549, MCF-7, and HT-29.

[0260]

[0261] a The values ​​in the table are the averages of the three trials.

Claims

1. A hydroxamic acid compound comprising N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, characterized by: Compounds as shown in Formula I, their corresponding isomers, and their pharmaceutically acceptable salts. Formula I In the formula, R is H; R1 is , , , , ; R2is C1-C 14 alkyl, thiazolyl, unsubstituted or substituted by at least one of the following groups: halogen, C2-C6alkenyl, six-membered ring containing one or two N atoms, phenyl, pyridyl, pyrimidinyl; 2. The N-benzyl-2-(5-phenylpyridin-2-yl)acetamide-containing hydroxamic acid compound according to claim 1, characterized by: Compounds as shown in Formula I, their corresponding isomers, and their pharmaceutically acceptable salts. In the formula, R is H; R1 is , , , , ; R2is C1-C 14 alkyl, , , thiazolyl, phenyl, pyridyl, pyrimidinyl, which is unsubstituted or substituted by at least one C2-C6alkenyl, halogen.

3. The N-benzyl-2-(5-phenylpyridin-2-yl)acetamide-containing hydroxamic acid compound according to claim 1, characterized by: Compounds as shown in Formula I, their corresponding isomers, and their pharmaceutically acceptable salts. In the formula, R is H; R1 is , , , , ; R2is C1-C 14 alkyl, , , , , , , , , , , thiazolyl, pyridyl, pyrimidinyl, which are unsubstituted or substituted by at least one C2-C6alkenyl, halogen.

4. The N-benzyl-2-(5-phenylpyridin-2-yl)acetamide-containing hydroxamic acid compound according to claim 1, characterized by: Compounds as shown in Formula I, their corresponding isomers, and their pharmaceutically acceptable salts. In the formula, R is H; R1 is , , , , ; R2is C1-C 10 alkyl, , thiazolyl, pyridyl, pyrimidinyl, which is unsubstituted or substituted by at least one C2-C6alkenyl, halogen.

5. A hydroxamic acid compound comprising N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, characterized by: The compounds are as follows: 5-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxybutyramide; 5-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxypentanamide; 6-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxyhexanoamide; 7-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxyheptamide; 8-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxyoctamide; 3-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxypropionamide; 4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxybutyramide; 5-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxypentanamide; 6-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxyhexanoamide; 7-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxyheptamide; 8-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxyoctamide; N 1 - (4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 5 - hydroxyglutarimide; N 1 - (4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 6 - hydroxyadipamide; N 1 - (4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 7 - hydroxyheptanediamide; N 1 -(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 8 -Hydroxyoctadiamide; (E)-3-(3-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)phenyl)-N-hydroxyacrylamide; (E)-3-(4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)phenyl)-N-hydroxyacrylamide; (E)-3-(3-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)phenyl)-N-hydroxyacrylamide; (E)-3-(4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)phenyl)-N-hydroxyacrylamide; (E)-3-(3-(N-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)sulfanyl)phenyl)-N-hydroxyacrylamide; 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N- hydroxybenzamide; 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N- hydroxybenzamide; 6-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N- hydroxynicotinamide; 6-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N- hydroxynicotinamide; 5-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N- hydroxypyridinecarboxamide; 5-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N- hydroxypyridinecarboxamide; 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N- hydroxythiazole-4-carboxamide; 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N- hydroxythiazole-4-carboxamide; 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N- hydroxythiazole-4-carboxamide; 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N- hydroxythiazole-4-carboxamide; 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N- hydroxythiazole-4-carboxamide; 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-3- fluoro-N-hydroxybenzamide; 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-3- fluoro-N-hydroxybenzamide; 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-3- fluoro-N-hydroxybenzamide; 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-3- fluoro-N-hydroxybenzamide; 2-(4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)piperidin- 1 -yl)-N-hydroxythiazole-5-carboxamide; 2-(4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)piperidin- 1 -yl)-N-hydroxythiazole-5-carboxamide; ​ 6. The N-benzyl-2-(5-phenylpyridin-2-yl)acetamide hydroxamic acid compound according to any one of claims 1 to 5, characterized in that: The pharmaceutically acceptable salt includes acid addition salt of the compound of general formula I with inorganic acid 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-toluene sulfonic acid.

7. A composition of a hydroxamic acid compound comprising N-benzyl-2-(5- phenylpyridin-2-yl)acetamide, characterized in that: The composition comprises the hydroxamic acid compound of any one of claims 1-5 and pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.

8. Use of an N-benzyl-2-(5-phenylpyridin-2-yl)acetamide-containing hydroxamic acid compound or composition according to claim 1 or 7, characterized in that: The compound of general formula I, the isomer corresponding to the compound and the pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 7 are used for preparing the drug for preventing and / or treating the disease related to histone deacetylase (HDACs) and / or c-Src tyrosine kinase.

9. Use according to claim 8, characterized in that: The compound of general formula I, the isomer corresponding to the compound and the pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 7 are used for preparing the drug for preventing and / or treating 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.

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