Hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridine-2-yl) acetamide as well as preparation method and application of hydroxamic acid compound

Abstract

The invention belongs to the technical field of medicines, and relates to a hydroxamic acid compound containing N-benzyl-2-(5-(4-methylphenyl) pyridine-2-yl) acetamide, pharmaceutically acceptable salt, hydrate and a preparation method of the hydroxamic acid compound, and a pharmaceutical composition containing the 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. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and relates to a hydroxamic acid compound containing N-benzyl-2-(5-(4-methylphenyl)pyridin-2-yl)acetamide and a pharmaceutically acceptable salt and hydrate thereof, a preparation method and a pharmaceutical composition containing the compound, and an application of the compound in preventing and / or treating diseases related to any one and / or both of histone deacetylases (HDACs) and c-Src kinases. Background Art

[0002] Histone deacetylases (HDACs) are closely related to epigenetics and play an important role in gene expression. They increase the positive charge density of histones by removing the terminal lysine of histones, so that the positively charged histones bind more tightly to the negatively charged DNA, which can reduce the expression of certain genes including tumor suppressor genes. Given that their abnormal expression has been found in many cancers, HDACs have become one of the hot targets for research in the field of cancer treatment.

[0003] HDAC inhibitors have the characteristics of inhibiting cancer cell proliferation, promoting apoptosis, and having few toxic side effects, and therefore have been developed as a new type of anti-tumor drug. Although HDAC inhibitors have been successfully used in 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 scope.

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

[0005] c-Src kinase is highly expressed in many solid tumors, such as lung cancer, breast cancer, colorectal cancer, pancreatic cancer, etc. c-Src kinase is an oncoprotein encoded by the proto-oncogene c-Src. In tumor tissues, c-Src kinase loses its precise negative regulatory ability, its expression level is significantly increased and 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, angiogenesis, etc. Therefore, c-Src kinase inhibitors have attracted widespread attention in the field of solid tumor treatment. In view of the great potential shown by HDAC inhibitors and c-Src kinase inhibitors in tumor treatment, a series of HDAC / c-Src kinase dual-target inhibitors were prepared using the "hybrid molecule" strategy based on the high chemical modifiability of the CAP region of HDAC inhibitors. Summary of the invention

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

[0007] To achieve the above purpose, 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 a compound represented by general formula I, the corresponding isomer of the compound and a pharmaceutically acceptable salt or hydrate thereof;

[0009]

[0010] in,

[0011] R is H or F;

[0012] R 1 for

[0013] R 3 C 1 -C 10 Hydrocarbon, Where n = 1 to 4, Z = OH, NH 2 , n'=0~3, Z'=H, OH, NH 2 ,N(CH 3 ) 2 ,N(C 2 H 5 ) 2 ;

[0014] R 2 C 1 -C 14 Alkyl, C 2 -C 14 Alkenyl, C 2 -C 14 Alkynyl, fused ring, fused heterocyclic group, unsubstituted or substituted by at least one of the following groups C 1 -C 14 Alkyl, aryl, heteroaryl; wherein the following groups are halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 1-C 6 Alkyl acyl, C 1 -C 6 Alkoxy, -NR 4 , C 1 -C 6 Alkylamino, -SR 4 , C 1 -C 6 an alkylthio group, a six-membered ring containing at least one heteroatom, or an aryl group containing at least one heteroatom;

[0015] R 4 C 1 -C 14 alkyl.

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

[0017] In the formula,

[0018] R is H;

[0019] R 1 for

[0020] R 2 C 1 -C 14 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 alkynyl, naphthyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, indolyl, carbazolyl, purinyl, phthalazinyl, benzofuranyl, benzothiophenyl, benzotriazolyl, 7H-pyrrolo[2,3-D]pyrimidine, 5H-pyrrolo[2,3-D]pyrimidine, 1H-pyrrolo[2,3-D]pyridine, [1,2,4]triazolo[1,5-a]pyridine, thieno[3,2-D]pyrimidine, thieno[2,3-D]pyrimidine, C unsubstituted or substituted with at least one of the following groups 1 -C 10 alkyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl; wherein the following groups are halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 1 -C 6 Alkyl acyl, C 1 -C 6 Alkoxy, -NR 4 , C1 -C 6 Alkylamino, -SR 4 , C 1 -C 6 an alkylthio group, a six-membered ring containing one or two N atoms, or an aryl group containing at least one heteroatom;

[0021] R 4 C 1 -C 14 alkyl.

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

[0023] In the formula,

[0024] R is H;

[0025] R 1 for

[0026] R 2 C 1 -C 14 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl,

[0027] naphthyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, indolyl, carbazolyl, purinyl, phthalazinyl, benzofuranyl, benzothiophenyl, benzotriazolyl, 7H-pyrrolo[2,3-D]pyrimidine, 5H-pyrrolo[2,3-D]pyrimidine, 1H-pyrrolo[2,3-D]pyridine, [1,2,4]triazolo[1,5-a]pyridine, thieno[3,2-D]pyrimidine, thieno[2,3-D]pyrimidine, unsubstituted or substituted with at least one C 2 -C 6 alkenyl, halogen, pyridine, pyrimidine substituted pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;

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

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

[0030] In the formula,

[0031] R is H;

[0032] R 1 for

[0033] R 2 C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, unsubstituted or replaced by at least one C 2 -C 6 alkenyl, halogen, pyridine, pyrimidine substituted pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl;

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

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

[0036] In the formula,

[0037] R is H;

[0038] R 1 for

[0039] R 2 C 3 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl,

[0040] The compound represented by the general formula I or its pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt includes the acid addition salt formed by the compound of the general formula I and the following inorganic acids 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 of a hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, the composition comprising any one of the hydroxamic acid compounds and a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier.

[0042] A use of a hydroxamic acid compound or composition containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, wherein the compound represented by general formula I, the corresponding isomer of the compound and a pharmaceutically acceptable salt or hydrate thereof, or the pharmaceutical composition is used in the preparation of a drug for preventing and / or treating diseases associated with histone deacetylases (HDACs) and / or c-Src tyrosine kinases.

[0043] The use of the compound represented by general formula I, the corresponding isomers of the compound and their pharmaceutically acceptable salts or hydrates, or the pharmaceutical composition in the preparation of drugs 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 diseases, malaria, bacterial infections, and fungal infections.

[0044] The compounds of the present invention and the pharmaceutical compositions containing the compounds of the present invention can be used in the prevention and / or treatment of diseases related to HDAC and / or c-Src tyrosine kinase

[0045] The hydroxamic acid compound containing N-benzyl-2-(5-(4-methylphenyl)pyridin-2-yl)acetamide and the pharmaceutical composition thereof are used as HDAC inhibitors for the treatment of diseases related to abnormal HDACs 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 infection, fungal infection, etc.

[0046] The hydroxamic acid compound containing N-benzyl-2-(5-(4-methylphenyl)pyridin-2-yl)acetamide of the present invention is prepared by 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 6:

[0058]

[0059] Route 7:

[0060]

[0061] Route 8:

[0062] DETAILED DESCRIPTION

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

[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] At 0°C, under stirring, 5-bromo-2-fluoropyridine (10.00 g, 28.41 mmol) was dissolved in tetrahydrofuran, acetonitrile (1.17 g, 28.41 mmol) was added dropwise thereto, and potassium bis(trimethylsilyl)amide (22.67 g, 56.82 mmol) was added to the mixed solution in batches. After the addition was completed, the mixture was kept at 0°C for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the mixture was extracted with dichloromethane (150 ml×3) and water (250 ml). The aqueous phase was discarded, the organic phases were combined, the organic solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain 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 conditions, 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 condensation reflux until the reaction was completed. After the reaction was completed, it was cooled to room temperature, and the reaction solution was slowly added to a saturated sodium carbonate aqueous solution (200 ml), extracted with dichloromethane (200 ml×3), the aqueous phase was discarded, the organic phases were combined, the organic solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain an orange-yellow solid 2-(5-bromopyridin-2-yl)acetic acid methyl ester (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, 2-(5-bromopyridin-2-yl) methyl acetate (8.04g, 35.10mmol) was dissolved in anisole (8ml), and benzylamine (46ml, 0.421mol) was added dropwise to the mixed solution. After the addition, the mixture was heated to reflux under condensation until the reaction was completed. After the reaction was completed, the reaction solution was allowed to stand at -20°C overnight, and a large amount of solid was precipitated. The solvent was removed by suction filtration, and the solid was rinsed with a small amount of toluene until it turned white, resulting in the product N-benzyl-2-(5-bromopyridin-2-yl) acetamide (7.07g, 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 (5.00g, 16.40mmol) was fully dissolved in ethylene glycol dimethyl ether (55ml), tetrakis(triphenylphosphine)palladium (760mg, 0.66mmol) was added thereto, and stirred at room temperature for 10 minutes; sodium carbonate (5.23g, 49.30mmol) water (2ml) solution and 4-hydroxyphenylboronic acid naphthalene alcohol ester (5.41g, 24.70mmol) were added to the above mixed solution in sequence, and the mixture was heated to condensation reflux until the reaction was completed. After the reaction was completed, the mixture was cooled to room temperature, and the solid in the reaction solution was removed by diatomaceous earth adsorption, and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain a milky white solid N-benzyl-2-(5-(4-hydroxyphenyl)pyridin-2-yl)acetamide (4.59g, yield 89%).

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

[0078]

[0079] At 0°C, under stirring conditions, N-benzyl-2-(5-(4-hydroxyphenyl)pyridin-2-yl)acetamide (150 mg, 0.47 mmol) was dissolved in DMF (3 ml), sodium hydrogen (17 mg, 0.71 mmol) was added in batches, and methyl 4-bromobutyrate (105 μL, 0.61 mmol) was added dropwise thereto. After the reaction was completed, ethyl acetate (50 ml×3) and water (100 ml) were extracted, the aqueous phase was discarded, the organic phases were combined, the solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain 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] At 0°C, sodium hydroxide (59 mg, 1.47 mmol) was dissolved in 50% aqueous hydroxylamine solution (604 mg, 9.16 mmol) under stirring, and a solution of 4-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)butyric acid methyl ester (84 mg, 0.18 mmol) in methanol:tetrahydrofuran = 1:1 (7 ml) was added dropwise. After 0.5 hours, the mixture was moved to room temperature for reaction until completion. After the reaction was completed, the solvent was evaporated under reduced pressure, 5 ml of water was added, and 1 mol / L hydrochloric acid solution was added dropwise until pH = 6. Solid precipitated, which 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. 1H 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] According to the preparation method of Example 1, appropriate raw materials were selected to prepare the compounds of Example 2 to Example 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 mp of 195.7-201.4°C. 1 H NMR (600 MHz, DMSO-d 6 )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,2H),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),3.7 1(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-hydroxyhexanamide (I-3)

[0088]

[0089] 6-(4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxyhexanamide (I-3) is a milky white solid with a yield of 68.43% and mp of 226.5-228.2°C. 1 H NMR (600 MHz, DMSO-d 6 )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-hydroxyheptylamide (I-4)

[0091]

[0092] 7-(4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxyheptylamide (I-4) was obtained as a milky white solid. Yield: 63.00%. MP: 181.1-181.8°C. 1 H NMR (600 MHz, DMSO-d 6)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-hydroxyoctanamide (I-5)

[0094]

[0095] 8-(4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)-N-hydroxyoctanamide (I-5) is a milky white solid with a yield of 60.50% and mp of 176.7-179.2°C. 1 H NMR (600 MHz, DMSO-d 6)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,2 H),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) was obtained as a pale yellow solid. Yield: 71%. MP: 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) was obtained as a milky white solid. Yield: 62.31%, mp: 183.7-187.9°C. 1 H NMR (600 MHz, DMSO-d 6 )δ10.42(s,1H),8.68(d,J=2.5Hz,1H),8.61(t,J=6.0Hz,1H),7.87(dd,J=8.1,2.5H z,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,1 H),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) was obtained as a milky white solid. Yield: 68.67%. MP: 197.0-200.9°C. 1 H NMR (600 MHz, DMSO-d 6)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,1 H),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-hydroxyhexanamide (I-9)

[0106]

[0107] 6-((4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxyhexanamide (I-9) was obtained as a pale yellow solid. Yield: 72.50%. MP: 172.3-174.5°C. 1 H NMR (600 MHz, DMSO-d 6 )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),1.9 8(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-hydroxyheptylamide (I-10)

[0109]

[0110] 7-((4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxyheptylamide (I-10) was a pale yellow solid with a yield of 70.44% and mp of 149.3-152.1°C. 1 H NMR (600 MHz, DMSO-d 6 )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-hydroxyoctanamide (I-11)

[0112]

[0113] 8-((4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)-N-hydroxyoctanamide (I-11) was obtained as a milky white solid. Yield: 68.00%. MP: 178.2-181.1°C. 1 H NMR (600 MHz, DMSO-d 6)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 -Hydroxyglutaramide (I-12)

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

[0116]

[0117] To a solution of 2-(5-(4-aminophenyl)pyridin-2-yl)-N-benzylacetamide (300 mg, 0.95 mmol) in dimethylformamide (5 ml) was added glutaric acid (150 mmol, 1.13 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (539 mg, 1.42 mmol), and diisopropylethylamine (188 μL, 1.13 mmol) in sequence under stirring at room temperature until the reaction was completed. After the reaction was completed, the solid was filtered out, and the mixture was extracted with ethyl acetate (50 ml×3) and water (150 ml). The organic phases were combined, and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain a milky white solid 5-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-ylphenyl)amino)-5-oxopentanoic acid (183 mg, 45.00%).

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

[0119]

[0120] Under stirring at room temperature, 1 drop of concentrated sulfuric acid was added to a solution of 5-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-ylphenyl)amino)-5-oxopentanoic acid (183 mg, 0.42 mmol) in methanol (8 ml), and the temperature was raised to condensation reflux. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, 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 evaporation under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain a pale yellow solid 5-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-ylphenyl)amino)-5-oxopentanoic acid methyl ester (98 mg, 51.75%).

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

[0122]

[0123] The same operation as step (6) of Example 1 was performed to obtain a light yellow solid N 1 -(4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 5 -Hydroxyglutaramide (I-12) (64 mg, 65.20%), mp: 228.6~231.5℃. 1 HNMR (600 MHz, DMSO-d 6 )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=8.1Hz,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] According to the preparation method of Example 12, appropriate starting materials were selected to prepare the compounds of Example 13-Example 15.

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

[0126]

[0127] N 1 -(4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 6 -Hydroxyadipamide (I-13) pale yellow solid, yield 65.20%, mp: 235.3~236.1℃. 1 H NMR (600 MHz, DMSO-d 6 )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=8.0Hz,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=5.7Hz,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 -Hydroxypimelamide (I-14)

[0129]

[0130] N 1 -(4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 7-Hydroxypimelanediamide (I-14) was a pale yellow solid with a yield of 67.00% and mp: 247.6-249.1°C. 1 H NMR (600 MHz, DMSO-d 6 )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,2H),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 -Hydroxyoctanamide (Ⅰ-15)

[0132]

[0133] N 1 -(4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)-N 8 -Hydroxyoctanamide (I-15) was a pale yellow solid with a yield of 64.33% and mp of 252.6-253.1°C. 1 H NMR (600 MHz, DMSO-d 6)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=7.2H z,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 solution of 3-methylcinnamic acid (500 mg, 3.08 mmol) in methanol (15 ml). After the addition was complete, the temperature was raised to condensation reflux until the reaction was completed. After the reaction was completed, 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 evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain white solid 3-methylcinnamic acid methyl ester (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 to a solution of methyl 3-methylcinnamate (543 mg, 3.08 mmol) in carbon tetrachloride (15 ml) in sequence. After the addition was completed, the temperature was raised to condensation reflux until the reaction was completed. After the reaction was completed, the organic phase was washed once with a saturated sodium bicarbonate solution (100 ml) and a saturated sodium chloride solution (100 ml) in sequence, and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain a light pink solid methyl 3-bromomethylcinnamate (575 mg, yield 73.45%).

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

[0142]

[0143] At room temperature, methyl 3-bromomethylcinnamate (145 mg, 0.57 mmol), potassium carbonate (98 mg, 0.71 mmol), and potassium iodide (63 mg, 0.38 mmol) were added to a solution of 2-(5-(4-aminophenyl)pyridin-2-yl)-N-benzylacetamide (150 mg, 0.47 mmol) in dimethylformamide (3 ml) in sequence. After the addition, the mixture was stirred until the reaction was completed. After the reaction was completed, ethyl acetate (50 ml) and water (100 ml) were extracted three times, the organic phases were combined, the solvent was evaporated under reduced pressure, and the residue was separated and 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 same operation as step (6) of Example 1 of Route 1 was performed to obtain 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%), 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] According to the preparation method of Example 16, appropriate starting 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) was a pale yellow solid with a yield of 73.90% and mp of 221.6 to 224.0°C. 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-oxoethyl)pyridin-3-yl)phenoxy)methyl)phenyl)-N-hydroxyacrylamide (Ⅰ-18) was a pale yellow solid with a yield of 78.31%, and mp: 266.3-268.5°C. 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-oxoethyl)pyridin-3-yl)phenoxy)methyl)phenyl)-N-hydroxyacrylamide (I-19) was a pale yellow solid with a yield of 78.31%, mp: 231.2-235.5°C. 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)sulfonyl)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 batches to a solution of 2-(5-(4-aminophenyl)pyridin-2-yl)-N-benzylacetamide (200 mg, 0.63 mmol) in dimethylformamide (4 ml), and pyridine (0.25 ml) was added dropwise thereto. After the dropwise addition, the reaction was continued. After the reaction was completed, ethyl acetate (50 ml×3) and water (100 ml) were extracted, the organic phases were combined, the solvent was evaporated under reduced pressure, and the residue was separated and 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)-methyl 3-(4-(N-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)aminosulfonyl)phenyl)acrylate

[0162]

[0163] 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) was added methyl acrylate (55 μL), palladium acetate (2 mg, 0.001 mmol), tri(o-methylphenyl)phosphine (6 mg, 0.019 mmol) and triethylamine (230 μL, 1.66 mmol) in sequence under stirring at room temperature. After the addition was completed, the mixture was protected with nitrogen 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 on diatomaceous earth, ethyl acetate (70 ml×3) was used to wash the diatomaceous earth, the organic phases were combined, the solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain (E)-3-(4-(N-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)aminosulfonyl)phenyl)acrylate as a light 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)sulfonyl)phenyl)-N-hydroxyacrylamide (I-20)

[0165]

[0166] In the same route as step (6), (E)-3-(4-(N-(4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)sulfonyl)phenyl)-N-hydroxyacrylamide (I-20) was obtained as a pale yellow solid (77 mg, yield 49.59%), mp: 233.4~235.1°C. 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] Light pink solid methyl 4-bromomethylbenzoate (129 mg, yield 87.93%) was prepared by using step (2) of Example 16 of Route 3 and the corresponding raw materials required for Example 21.

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

[0172]

[0173] Using step (3) of Example 16 of Route 3 and the corresponding raw materials required for Example 21, a milky white solid methyl 4-((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)benzoate (213 mg, 97.12%) was prepared.

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

[0175]

[0176] The light yellow solid 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxybenzamide (Ⅰ-21) (200 mg, yield 91.87%) was prepared using step (6) of Example 1 of Route 1 and the corresponding raw materials required for Example 21, mp: 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] According to the preparation method of Example 21, appropriate starting materials were selected to prepare the compounds of Example 22 to Example 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) was a pale yellow solid with a yield of 60.87%. mp: 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) was obtained as a pale yellow solid. Yield: 70.89%. MP: 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) was obtained as a pale yellow solid. Yield: 60.32%. MP: 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-hydroxypicolinamide (I-25)

[0188]

[0189] 5-(((4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxypicolinamide (Ⅰ-25) was obtained as a pale yellow solid with a yield of 56.83%. mp: 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-hydroxypicolinamide (I-26)

[0191]

[0192] 5-((4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxypicolinamide (Ⅰ-26) was a pale yellow solid with a yield of 64.27% and 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) was obtained as a pale yellow solid with a yield of 58.33%. mp: 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) was obtained as a pale yellow solid with a yield of 66.12%. The mp was 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-hydroxythiazole-4-carboxamide (I-29)

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

[0201]

[0202] Under stirring at 0°C, concentrated sulfuric acid (671 mg, 6.85 mmol) was slowly added dropwise to a solution of 2-methylthiazole-4-carboxylic acid (700 mg, 4.89 mmol) in methanol (25 ml). After the addition was completed, the temperature was raised to condensation reflux for reaction. After the reaction was completed, 1 mol / L sodium carbonate solution was added dropwise to the reaction solution until pH = 7, and ethyl acetate (50 ml) was used for extraction three times. The organic phases were combined, and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain methyl 2-methyl-4-thiazolecarboxylate (642 mg, yield 84.16%) as a white solid.

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

[0204]

[0205] Using step (2) of Example 16 of Route 3 and the corresponding raw materials required by Example 29, a milky white solid 2-bromomethyl-4-thiazolecarboxylic acid methyl ester (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-carboxylate

[0207]

[0208] Using step (3) of Example 16 of Route 3 and the corresponding raw materials required by Example 29, a white solid 2-((4-(6-(2-(benzylamino-)2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)thiazole-4-carboxylic acid methyl ester (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-hydroxythiazole-4-carboxamide (I-27)

[0210]

[0211] Using step (6) of Example 1 of Route 1 and the corresponding raw materials required by Example 29, a light yellow solid 2-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxythiazole-4-carboxamide (I-29) (148 mg, yield 75.56%) was obtained, mp: 175.0~177.6℃. 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] According to the preparation method of Example 29, appropriate starting 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-hydroxythiazole-5-carboxamide (I-30)

[0214]

[0215] 2-(((4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxythiazole-5-carboxamide (I-30) was obtained as a pale yellow solid. Yield: 79.76%. MP: 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-hydroxythiazole-5-carboxamide (I-31)

[0217]

[0218] 2-(((4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)-N-hydroxythiazole-5-carboxamide (Ⅰ-31) was obtained as a pale yellow solid. Yield: 77.76%, mp: 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-hydroxythiazole-5-carboxamide (I-32)

[0220]

[0221] 2-(((4-(6-(2-(Benzylamino)-2-oxoethyl)pyridin-3-yl)phenoxy)methyl)-N-hydroxythiazole-5-carboxamide (Ⅰ-32) was a pale yellow solid with a yield of 75.89%. mp: 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] Using the synthetic route of route 7, according to the preparation method of Example 16, selecting appropriate raw materials, the compounds of Examples 33 to 36 were prepared

[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) was obtained as a pale yellow solid. Yield: 75.87%, mp: 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) was obtained as a pale yellow solid. Yield: 76.12%. MP: 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) was obtained as a pale yellow solid. Yield: 77.89%. MP: 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-carboxylate

[0237]

[0238] N-Benzyl-2-(5-(4-aminophenyl)pyridin-2-yl)acetamide (200 mg, 0.63 mmol) was dissolved in 5 ml of DMF, and 1-Boc-4-bromopiperidine (250 mg, 0.95 mmol), K 2 CO 3 (156 mg, 1.12 mmol), stirred at room temperature for 10 min, slowly heated to 60 ° C for 8 h, after the reaction was completed, extracted with ethyl acetate (50 ml × 3) and water (100 ml), combined the organic phases, anhydrous Na 2 SO 4 The water was removed and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography to give tert-butyl 4-(((4-(6-(2-(benzylamino)-2-oxoethyl)pyridin-3-yl)phenyl)amino)methyl)piperidine-1-carboxylate (167 mg, 53.08%) as a pale yellow solid.

[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)piperidine-1-carboxylic acid tert-butyl ester (167 mg, 0.33 mmol) was dissolved in 5 ml of dichloromethane (DCM), and 1 ml of CF was added thereto under stirring at room temperature. 3 COOOH, continue stirring for 4 h. After the reaction is complete, add saturated Na 2 CO 3 Adjust the pH to neutral, extract with dichloromethane (50 ml × 3) and water (100 ml), combine the organic phases, and add anhydrous Na 2 SO 4 Water was removed and the solvent was evaporated under reduced pressure to give N-benzyl-2-(5-(4-((piperidin-4-ylmethyl)amino)phenyl)pyridin-2-yl)acetamide (137 mg, 99.99%) as a yellow solid.

[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, and 2-chloropyrimidine-5-carboxylic acid methyl ester (57 mg, 033 mmol) and N,N-diisopropylethylamine (DIPEA, 0.50 mmol, 87 μL) were added to the solution in sequence under stirring at room temperature, and the reaction was continued by stirring for 8 h. After the reaction was completed, ethyl acetate (50 ml × 3) and water (100 ml) were used for extraction, and the organic phases were combined and anhydrous Na 2 SO 4 The water was removed and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography to give 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%) as a pale yellow solid.

[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] The same operation as step (6) of Example 1 of Route 1 was performed to obtain a light 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℃. 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] According to the preparation method of Example 37, appropriate raw materials were selected to prepare the compound of Example 38

[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) was obtained as a pale yellow solid with a yield of 53.41%. The mp was 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 anti-tumor cell proliferation activity test of target compounds

[0253] The CCK8 method was used to test the in vitro antiproliferative activity of the target compound on three types of cell lines: HT29, CNE2 and A549. The required cells were taken out from the liquid nitrogen tank and shaken continuously in a 37°C water bath until the cells thawed. The cell suspension was added to a centrifuge tube containing 9 ml PBS, centrifuged at 600 rpm, PBS was removed, and the cells were resuspended in 1 ml of culture medium. The cell suspension was transferred to a 10 cm culture dish and the cells were placed in a 37°C, 5% CO 2 Culture in an incubator. When the cells reach an appropriate density, remove the culture medium, add PBS to wash the residual culture medium, remove PBS, add 2 ml of trypsin to digest the cells, add culture medium to terminate the digestion, collect the cells into a centrifuge tube, centrifuge at 800 rpm, and resuspend. Count using a cell counting plate, use fresh culture medium to make a specific density cell suspension (4000 / well) in a 96-well plate, add 100 μl of cell suspension to each well of the experimental group and negative control group, and add an equal amount of culture medium to the blank group. Incubate in an incubator at 37°C, 5% CO 2 The experimental group was added with 100ul of medium containing different concentrations of compounds, the negative control group was added with an equal amount of medium containing DMSO, and the blank group was added with an equal amount of medium. Incubate at 37°C, 5% CO 2 After incubation for 48 h, 10 μl CCK8 was added to each well and cultured for 2.5 h. The absorbance was measured at 450 nm using an ELISA reader. Three independent experiments were performed. 50Calculated using GraphPad Prism 8.0.

[0254] Table 1 Antiproliferative activity results of target compounds against HT29, CNE2 and A549

[0255]

[0256] a The values ​​in the table are the average values ​​of three tests.

[0257] Example 40: In vitro anti-tumor cell proliferation activity test of target compounds

[0258] The MTT method was used to test the in vitro antiproliferative activity of the target compounds against three types of cell lines: A549, MCF-7 and HT-29. The cells in the logarithmic phase were collected, the concentration of the cell suspension was adjusted, and 100 μl was added to each well of a 96-well plate and plated (A549: 2000 cells / well, MCF-7: 2000 cells / well, HT-29: 6000 cells / well). 5% CO 2 , incubate at 37°C until the cell monolayer covers the bottom of the well, incubate for 24 hours. Add drugs with a concentration gradient, set 5 gradients (0.001umol, 0.01umol, 0.1umol, 1umol, 10umol), 100ul per well, set 3 replicates. 5% CO 2 , incubate at 37℃ for 72 hours, and observe under an inverted microscope. Discard the culture medium, add 100μl MTT solution (2.5mg / ml) to each well, and continue to culture for 4h. If the drug can react with MTT, centrifuge first and then discard the culture medium, carefully rinse with PBS 2-3 times, and then add the culture medium containing MTT. Terminate the culture, discard the MTT solution, add 100μl dimethyl sulfoxide to each well, and shake on a shaker to fully dissolve the crystals. Measure the absorbance of each well at OD490 nm in an enzyme-linked immunosorbent assay. IC 50 Calculated using GraphPad Prism 8.0.

[0259] Table 2 Antiproliferative activity results of target compounds on A549, MCF-7 and HT-29

[0260]

[0261] a The values ​​in the table are the average values ​​of three tests.

Claims

1. A hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, characterized in that: The compound is a compound represented by general formula I, the corresponding isomer of the compound, and a pharmaceutically acceptable salt or hydrate thereof; in, R is H or F; R1 is R3 is C1-C 10 Hydrocarbon, Wherein, n=1~4, Z=OH, NH2, n'=0~3, Z'=H, OH, NH2, N(CH3)2, N(C2H5)2; R2 is C1-C 14 Alkyl, C2-C 14 Alkenyl, C2-C 14 Alkynyl, fused ring, fused heterocyclic group, C1-C 14 Alkyl, aryl, heteroaryl; wherein the following groups are halogen, 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 containing at least one heteroatom; R4 is C1-C 14 alkyl.

2. The hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide according to claim 1, characterized in that: The compound is a compound represented by general formula I, the corresponding isomer of the compound, and a pharmaceutically acceptable salt or hydrate thereof; In the formula, R is H; R1 is R2 is C1-C 14 Alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl, naphthyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, indolyl, carbazolyl, purinyl, phthalazinyl, benzofuranyl, benzothiophenyl, benzotriazolyl, 7H-pyrrolo[2,3-D]pyrimidine, 5H-pyrrolo[2,3-D]pyrimidine, 1H-pyrrolo[2,3-D]pyridine, [1,2,4]triazolo[1,5-a]pyridine, thieno[3,2-D]pyrimidine, thieno[2,3-D]pyrimidine, C1-C2 unsubstituted or substituted with at least one of the following groups: 10 Alkyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl; wherein the following groups are halogen, 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 containing at least one heteroatom; R4 is C1-C 14 alkyl.

3. The hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide according to claim 1, characterized in that: The compound is a compound represented by general formula I, the corresponding isomer of the compound, and a pharmaceutically acceptable salt or hydrate thereof; In the formula, R is H; R1 is R2 is C1-C 14 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, naphthyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, indolyl, carbazolyl, purinyl, phthalazinyl, benzofuranyl, benzothiophenyl, benzotriazolyl, 7H-pyrrolo[2,3-D]pyrimidine, 5H-pyrrolo[2,3-D]pyrimidine, 1H-pyrrolo[2,3-D]pyridine, [1,2,4]triazolo[1,5-a]pyridine, thieno[ 3,2-D]pyrimidine, thieno[2,3-D]pyrimidine, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl; X is selected from C, N, O or S.

4. The hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide according to claim 3, characterized in that: The compound is a compound represented by general formula I, the corresponding isomer of the compound, and a pharmaceutically acceptable salt or hydrate thereof; In the formula, R is H; R1 is R2 is C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, Pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, unsubstituted or substituted with at least one C2-C6 alkenyl, halogen, pyridine, pyrimidine; X is selected from C, N, O or S.

5. The hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide according to any one of claims 1 to 4, characterized in that: The compound represented by the general formula I or its pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt includes the acid addition salt formed by the compound of the general formula I and the following inorganic acids 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.

6. A composition of a hydroxamic acid compound containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, characterized in that: The composition comprises any one of the hydroxamic acid compounds according to claims 1 to 4 and a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier.

7. Use of a hydroxamic acid compound or composition containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide according to claim 1 or 6, characterized in that: The compound represented by the general formula I according to claim 1, the corresponding isomers of the compound and their pharmaceutically acceptable salts or hydrates, or the pharmaceutical composition according to claim 7 is used in the preparation of preventive and / or therapeutic drugs for diseases related to histone deacetylases (HDACs) and / or c-Src tyrosine kinases.

8. The use according to claim 7, characterized in that: The use of the compound represented by general formula I according to claim 1, the corresponding isomers of the compound and pharmaceutically acceptable salts or hydrates thereof, or the pharmaceutical composition according to claim 6 in the preparation of drugs 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 diseases, malaria, bacterial infections, and fungal infections.

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