CN119490449A - Hydroxamic acid compounds containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, preparation method and application thereof - Google Patents
Hydroxamic acid compounds containing N-benzyl-2-(5-phenylpyridin-2-yl)acetamide, preparation method and application thereof Download PDFInfo
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Abstract
The invention 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, pharmaceutically acceptable salts and hydrates thereof, a preparation method, a pharmaceutical composition containing the compound and application of the compound in preventing and/or treating any one or two related diseases among Histone Deacetylase (HDACs) and c-Src kinase. The structure of the compound is shown as a general formula I.
Description
Technical Field
The invention 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, pharmaceutically acceptable salts and hydrates thereof, a preparation method, a pharmaceutical composition containing the compound and application of the compound in preventing and/or treating any one or two related diseases among Histone Deacetylase (HDACs) and c-Src kinase.
Background
Histone Deacetylases (HDACs) are closely related to epigenetic events, which play an important role in gene expression by increasing the density of histone positive charges by removing the histone terminal lysines, and thus the binding of positively charged histones to negatively charged DNA is tighter, which can reduce the expression of certain genes including cancer suppressor genes. Given that it finds its aberrant expression in a variety of cancers, HDACs have become one of the hot targets of research in the field of cancer therapy.
The HDAC inhibitor has the characteristics of inhibiting cancer cell proliferation, promoting apoptosis, having small toxic and side effects and the like, so the HDAC inhibitor is developed as a novel anti-tumor medicament. 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.
Related researches show that the HDAC inhibitor and other target inhibitors, such as tubulin (tubulin) inhibitors, immune checkpoint (immunecheckpoint) inhibitors, endothelial Growth Factor (EGFR) inhibitors and the like, show obvious synergistic effects on solid tumor treatment, and lay a solid theoretical foundation for the design of double-target or even multi-target inhibitors based on HDAC.
The c-Src kinase is highly expressed in various solid tumors, such as lung cancer, breast cancer, rectal cancer, pancreatic cancer and the like. The c-Src kinase is an oncoprotein encoded by the proto-oncogene c-Src. In tumor tissues, c-Src kinase loses its precise negative regulation ability, its expression level is remarkably improved and activation is continued. Abnormally activated c-Src kinase plays a number of biological functions in the development, progression, and progression of tumors, such as apoptosis, cell adhesion, proliferation, migration and invasion, angiogenesis, and the like. Thus, c-Src kinase inhibitors have attracted a wide range of attention in the field of solid tumor therapy. Given the great potential demonstrated by HDAC inhibitors and c-Src kinase inhibitors in tumor therapy, a series of HDAC/c-Src kinase dual-target inhibitors were prepared using a "hybrid molecule" strategy based on the high degree of chemical modification of the CAP region of the HDAC inhibitor.
Disclosure of Invention
The invention aims to provide a hydroxamic acid compound containing N-benzyl-2- (5- (4-methylphenyl) pyridine-2-yl) acetamide, a pharmaceutically acceptable salt, a hydrate, a preparation method and a pharmaceutical composition containing the compound, and application of the compound in preventing and/or treating any one or two diseases related to Histone Deacetylase (HDACs), c-Src kinase.
In order to achieve the above purpose, the invention adopts the technical scheme that:
hydroxamic acid compounds containing N-benzyl-2- (5-phenylpyridin-2-yl) acetamide, wherein the compounds are shown in a general formula I, isomers corresponding to the compounds and pharmaceutically acceptable salts or hydrates thereof;
wherein,
R is H or F;
r 1 is
R 3 is a C 1-C10 hydrocarbyl group,Wherein the method comprises the steps of ,n＝1～4,Z＝OH,NH2,n'＝0～3,Z'＝H,OH,NH2,N(CH3)2,N(C2H5)2;
R 2 is C 1-C14 alkyl, C 2-C14 alkenyl, C 2-C14 alkynyl, fused ring, fused heterocyclic, C 1-C14 alkyl, aryl, heteroaryl, unsubstituted or substituted with at least one of halogen, C 1-C6 alkyl, C 2-C6 alkenyl, C 1-C6 alkanoyl, C 1-C6 alkoxy, -NR 4、C1-C6 alkylamino, -SR 4、C1-C6 alkylthio, a six-membered ring containing at least one heteroatom, or aryl containing at least one heteroatom;
R 4 is C 1-C14 alkyl.
Preferably, the compound is shown in a general formula I, an isomer corresponding to the compound and pharmaceutically acceptable salt or hydrate thereof;
In the formula,
R is H;
r 1 is
R 2 is C 1-C14 alkyl, C 2-C10 alkenyl, C 2-C10 alkynyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, indolyl, indolinyl, carbazolyl, purinyl, phthalazinyl, benzofuranyl, benzothienyl, 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 1-C10 alkyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, wherein the following groups are halogen, C 1-C6 alkyl, C35 acyl, C5338 alkyl, N-containing 35-to-membered SR, or a six membered heteroaryl group containing at least one or two 35 alkyl groups;
R 4 is C 1-C14 alkyl.
Further preferably, the compound is shown in a general formula I, an isomer corresponding to the compound and a pharmaceutically acceptable salt or hydrate thereof;
In the formula,
R is H;
r 1 is
R 2 is C 1-C14 alkyl, C 2-C10 alkenyl, C 2-C10 alkynyl,
Naphthyl, quinolinyl, isoquinolinyl, quinolyl, indolyl, indolinyl, carbazolyl, purinyl, phthalazinyl, benzofuranyl, benzothienyl, 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 substituted with at least one C 2-C6 alkenyl, halogen, pyridine, pyrimidine, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl;
x is C, N, O or S.
Further in preference, the compound is shown in a general formula I, an isomer corresponding to the compound and a pharmaceutically acceptable salt or hydrate thereof;
In the formula,
R is H;
r 1 is
R 2 is C 1-C10 alkyl, C 2-C10 alkenyl, C 2-C10 alkynyl, Pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrimidinyl, optionally substituted with at least one C 2-C6 alkenyl, halogen, pyridinyl, pyrimidinyl;
x is C, N, O or S.
More preferably, the compound is represented by the general formula I, the corresponding isomer of the compound, and the pharmaceutically acceptable salt or hydrate thereof:
In the formula,
R is H;
r 1 is
R 2 is C 3-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl,
The compound shown in the general formula I or pharmaceutically acceptable salt thereof comprises acid addition salts formed by the compound shown in the general formula I and inorganic acid or organic acid, wherein the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, and 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.
A composition comprising a hydroxamic acid compound having N-benzyl-2- (5-phenylpyridin-2-yl) acetamide, the composition comprising any of the hydroxamic acid compounds, a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.
The application of a hydroxamic acid compound or a composition containing N-benzyl-2- (5-phenylpyridin-2-yl) acetamide, wherein the compound shown in the general formula I, an isomer corresponding to the compound and pharmaceutically acceptable salt or hydrate thereof, or the application of the pharmaceutical composition in preparing a medicament for preventing and/or treating diseases related to Histone Deacetylase (HDACs) and/or c-Src tyrosine kinase.
The compound shown in the general formula I, the isomer corresponding to the compound and the pharmaceutically acceptable salt or hydrate thereof, or the application of the pharmaceutical composition in preparing medicaments 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 infection and fungal infection.
The compounds of the present invention and pharmaceutical compositions comprising the compounds of the present invention are useful in the prevention and/or treatment of diseases associated with HDAC and/or c-Src tyrosine kinase
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 to treat diseases related to abnormal expression of HDACs, such as colorectal cancer, liver cancer, lung cancer, pancreatic cancer, gastric cancer, renal cancer, breast cancer, ovarian cancer, skin cancer, head and neck cancer, lymphoma, leukemia, neurodegenerative diseases, malaria, bacterial infection, fungal infection and the like.
The hydroxamic acid compounds containing N-benzyl-2- (5- (4-methylphenyl) pyridin-2-yl) acetamide described in the present invention are prepared by one of the following eight routes.
Route one:
route two:
Route three:
route four:
route five:
Route six:
Route seven:
Route eight:
Detailed Description
The present invention will be described in detail with reference to specific examples, but the scope of the present invention is not limited to the examples.
EXAMPLE 1 preparation of 5- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) -N-hydroxypentanamide (I-1):
step (1) preparation of 2- (5-bromopyridin-2-yl) acetonitrile
5-Bromo-2-fluoropyridine (10.00 g,28.41 mmol) was dissolved in tetrahydrofuran with stirring, 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 above mixed solution in portions, and the addition was completed, and the reaction was maintained at 0℃for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, extracted with methylene chloride (150 ml. Times.3) and water (250 ml), the aqueous phase was discarded, the organic phases were combined, the organic solvent was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column to give 2- (5-bromopyridin-2-yl) acetonitrile (8.41 g, yield 75.60%) as an orange yellow oily liquid.
Step (2) preparation of methyl 2- (5-bromopyridin-2-yl) acetate
Concentrated sulfuric acid (45.00 g,429.00 mmol) was added dropwise to a solution of 2- (5-bromopyridin-2-yl) acetonitrile (8.41 g,42.90 mmol) in methanol (82 ml) with stirring at 0℃and slowly warmed to reflux under condensation until the reaction was complete. After the completion of the reaction, it was cooled to room temperature, the reaction solution was slowly added to a saturated aqueous sodium carbonate solution (200 ml), dichloromethane (200 ml×3) was extracted, the aqueous phase was discarded, the organic phases were combined, the organic solvent was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column to give methyl 2- (5-bromopyridin-2-yl) acetate (8.04 g, yield 81.75%) as an orange-yellow solid.
Step (3) preparation of N-benzyl-2- (5-bromopyridin-2-yl) acetamide
Methyl 2- (5-bromopyridin-2-yl) acetate (8.04 g,35.10 mmol) was dissolved in anisole (8 ml) with stirring at room temperature, benzylamine (46 ml, 0.426 mol) was added dropwise to the above mixed solution, and the mixture was heated to reflux under condensation until the reaction was completed. After the reaction was completed, the reaction solution was left standing overnight at-20℃with a large amount of solid precipitated, the solvent was removed by suction filtration, and the solid was washed to white with a small amount of toluene to give the product N-benzyl-2- (5-bromopyridin-2-yl) acetamide (7.07 g, yield 66.24%).
Step (4) preparation of N-benzyl-2- (5- (4-hydroxyphenyl) pyridin-2-yl) acetamide
N-benzyl-2- (5-bromopyridin-2-yl) acetamide (5.00 g,16.40 mmol) was sufficiently dissolved in ethylene glycol dimethyl ether (55 ml), tetrakis (triphenylphosphine) palladium (760 mg,0.66 mmol) was added thereto, and stirred at room temperature for 10 minutes, and sodium carbonate (5.23 g,49.30 mmol) in water (2 ml) and 4-hydroxyphenylboronic acid pinacol ester (5.41 g,24.70 mmol) were sequentially added to the above mixed solution, and the temperature was raised until the condensation reflux was reached, until the reaction was completed. After the completion of the reaction, it was cooled to room temperature, the solid in the reaction mixture was removed by adsorption with celite, the solvent was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column to give N-benzyl-2- (5- (4-hydroxyphenyl) pyridin-2-yl) acetamide as a milky white solid (4.59 g, 89% yield).
Step (5) preparation of methyl 4- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) butyrate
N-benzyl-2- (5- (4-hydroxyphenyl) pyridin-2-yl) acetamide (150 mg,0.47 mmol) was dissolved in DMF (3 ml) at 0℃with stirring, sodium hydrogen (17 mg,0.71 mmol) was added in portions, and methyl 4-bromobutyrate (105. Mu.L, 0.61 mmol) was added dropwise thereto. After completion of the reaction, ethyl acetate (50 ml×3) was extracted with water (100 ml), the aqueous phase was discarded, the organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column to give methyl 4- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) butyrate (84 mg, yield 41.36%) as a milky white solid.
Step (6) preparation of 4- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) -N-hydroxybutyramide (I-1)
Sodium hydroxide (59 mg,1.47 mmol) was dissolved in 50% aqueous hydroxylamine (604 mg,9.16 mmol) at 0 ℃ with stirring, methyl 4- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) butyrate (84 mg,0.18 mmol) in methanol: tetrahydrofuran=1:1 solution (7 ml) was added dropwise thereto, and after 0.5 hours, the reaction was allowed to proceed to completion at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, 5ml of water was added thereto, 1mol/L hydrochloric acid solution was added dropwise thereto to ph=6, and a solid was precipitated, suction-filtered and dried to give 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℃.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]+.
The compounds of examples 2-11 were prepared by the preparation of example 1, with the appropriate choice of starting materials.
EXAMPLE 2 preparation of 5- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) -N-hydroxypentanamide (I-2)
5- (4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) -N-hydroxypentanamide (I-2) as a milky white solid, yield 66.43％,mp:195.7～201.4℃.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,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),3.71(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]+.
EXAMPLE 3 preparation of 6- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) -N-hydroxyhexanamide (I-3)
6- (4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) -N-hydroxyhexanamide (I-3) as a milky white solid, yield 68.43％,mp:226.5～228.2℃.1H 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]+.
EXAMPLE 4 preparation of 7- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) -N-hydroxyheptanamide (I-4)
7- (4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) -N-hydroxyheptanamide (I-4) as a milky white solid, yield 63.00％,mp:181.1～181.8℃.1H 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]+.
EXAMPLE 5 preparation of 8- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) -N-hydroxyoctanoamide (I-5)
8- (4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) -N-hydroxyoctanoic acid amide (I-5) as a milky white solid, yield 60.50％,mp:176.7～179.2℃.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]+.
EXAMPLE 6 preparation of 3- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) -N-hydroxypropionamide (I-6)
3- ((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) -N-hydroxypropionamide (I-6) as a pale yellow solid, yield 71％,mp:177.4～180.8℃.1H 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]+.
EXAMPLE 7 preparation of 4- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) -N-hydroxybutyramide (I-7)
4- ((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) -N-hydroxybutyramide (I-7) cream solid, yield 62.31％,mp:183.7～187.9℃.1H 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]+.
EXAMPLE 8 preparation of 5- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) -N-hydroxypentanamide (I-8)
5- ((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) -N-hydroxypentanamide (I-8) as a milky white solid, yield 68.67％,mp:197.0～200.9℃.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]+.
EXAMPLE 9 preparation of 6- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) -N-hydroxyhexanamide (I-9)
6- ((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) -N-hydroxyhexanamide (I-9) as a pale yellow solid, yield 72.50％,mp:172.3～174.5℃.1H 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]+.
EXAMPLE 10 preparation of 7- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) -N-hydroxyheptanamide (I-10)
7- ((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) -N-hydroxyheptanamide (I-10) as a pale yellow solid, yield 70.44％,mp:149.3～152.1℃.1H 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]+.
EXAMPLE 11 preparation of 8- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) -N-hydroxyoctanoamide (I-11)
8- ((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) -N-hydroxyoctanoic acid amide (I-11) as a milky white solid, yield 68.00％,mp:178.2～181.1℃.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]+.
EXAMPLE 12 preparation of N 1 - (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) -N 5 -hydroxygluta-namide (I-12)
Step (1) preparation of 5- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-ylphenyl) amino) -5-oxopentanoic acid
To a solution of 2- (5- (4-aminophenyl) pyridin-2-yl) -N-benzylacetamide (300 mg,0.95 mmol) in dimethylformamide (5 ml) was added sequentially glutaric acid (150 mmol,1.13 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (539 mg,1.42 mmol), diisopropylethylamine (188. Mu.L, 1.13 mmol) with stirring at room temperature until the reaction was completed. After completion of the reaction, the solid was removed by filtration, ethyl acetate (50 ml. Times.3) and water (150 ml) were extracted, the organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column to give 5- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-ylphenyl) amino) -5-oxopentanoic acid (183 mg, 45.00%) as a milky white solid.
Step (2) preparation of methyl 5- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-ylphenyl) amino) -5-oxopentanoate
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) was added dropwise 1 drop of concentrated sulfuric acid under stirring at room temperature, and the mixture was warmed to reflux. After completion of the reaction, the solvent was distilled off under reduced pressure, ethyl acetate (50 ml. Times.3) and 1mol/L sodium carbonate solution (100 ml) were extracted, the organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column to give methyl 5- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-ylphenyl) amino) -5-oxopentanoate (98 mg, 51.75%) as a pale yellow solid.
Step (3) preparation of N 1 - (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) -N 5 -hydroxyglutaramide (I-12)
The same procedure was followed in step (6) of example 1 to give N 1 - (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) -N 5 -hydroxyglutaramide as a pale yellow solid (Ⅰ-12)(64mg,65.20％),mp:228.6～231.5℃.1H NMR(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＝8.1Hz,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]+.
The compounds of examples 13-15 were prepared by the preparation method of example 12, with the appropriate choice of starting materials.
EXAMPLE 13 preparation of N 1 - (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) -N 6 -hydroxy adipamide (I-13)
N 1 - (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) -N 6 -hydroxyhexanediamide (I-13) as a pale yellow solid, yield 65.20％,mp:235.3～236.1℃.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＝8.0Hz,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]+.
EXAMPLE 14 preparation of N 1 - (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) -N 7 -hydroxypimelamide (I-14)
N 1 - (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) -N 7 -hydroxypimelamide (I-14) as a pale yellow solid, yield 67.00％,mp:247.6～249.1℃.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,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]+.
EXAMPLE 15 preparation of N 1 - (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) -N 8 -hydroxyoctanediamide (I-15)
N 1 - (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) -N 8 -hydroxyoctanediamide (I-15) as a pale yellow solid, yield 64.33％,mp:252.6～253.1℃.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]+.
EXAMPLE 16 preparation of (E) -3- (3- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) phenyl) -N-hydroxyacrylamide (I-16)
Step (1) preparation of methyl 3-methylcinnamate
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) under stirring at 0℃and after the addition, the mixture was warmed to reflux by condensation until the reaction was completed. After the completion of the reaction, the solution was adjusted to ph=7 with 1mol/L sodium carbonate solution, dichloromethane (50 ml×3) was extracted, the organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 3-methylcinnamate (543 mg, yield 100.00%) as a white solid.
Step (2) preparation of methyl 3-bromomethyl cinnamate
N-bromosuccinimide (603 mg,3.39 mmol) and azobisisobutyronitrile (51 mg,0.31 mmol) were added sequentially to a solution of methyl 3-methylcinnamate (543 mg,3.08 mmol) in carbon tetrachloride (15 ml) with stirring at room temperature, and the addition was completed, and the temperature was raised to reflux by condensation until the reaction was completed. After the completion of the reaction, the organic phase was washed once with saturated sodium hydrogencarbonate solution (100 ml) and saturated sodium chloride solution (100 ml), the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 3-bromomethylcinnamate (575 mg, yield 73.45%) as a pale pink solid.
Step (3) preparation of methyl (E) -3- (3- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) acrylate
To a solution of 2- (5- (4-aminophenyl) pyridin-2-yl) -N-benzylacetamide (150 mg,0.47 mmol) in dimethylformamide (3 ml) was added methyl 3-bromomethylcinnamate (145 mg,0.57 mmol), potassium carbonate (98 mg,0.71 mmol), potassium iodide (63 mg,0.38 mmol) in this order at room temperature, and the mixture was stirred until the reaction was completed. After completion of the reaction, ethyl acetate (50 ml) was extracted 3 times with water (100 ml), the organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column to give methyl (203 mg, 87.52%) of (E) -3- (3- (((4- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) acrylate as a milky white solid.
Step (4) preparation of (E) -3- (3- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) phenyl) -N-hydroxyacrylamide (I-16)
The same procedure is followed as in step (6) of example 1. To give (E) -3- (3- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) phenyl) -N-hydroxyacrylamide as a pale yellow solid (Ⅰ-16)(148mg,73.75％),mp:277.2～279.5℃.1H NMR(600MHz,DMSO-d6)δ8.67(d,J＝1.4Hz,1H),8.64-8.59(m,1H),7.87(dd,J＝7.9,1.9Hz,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]+.
The compounds of examples 17-19 were prepared by the preparation of example 16 by the selection of the appropriate starting materials.
EXAMPLE 17 preparation of (E) -3- (4- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) phenyl) -N-hydroxyacrylamide (I-17)
(E) -3- (4- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) phenyl) -N-hydroxyacrylamide (I-17) as a 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＝8.0,2.0Hz,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＝8.7Hz,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]+.
EXAMPLE 18 preparation of (E) -3- (3- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) phenyl) -N-hydroxyacrylamide (I-18)
(E) -3- (3- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) phenyl) -N-hydroxyacrylamide (I-18) as a pale yellow solid, yield 78.31％,mp:266.3～268.5℃.1H 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]+.
EXAMPLE 19 preparation of (E) -3- (4- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) phenyl) -N-hydroxyacrylamide (I-19)
(E) -3- (4- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) phenyl) -N-hydroxyacrylamide (I-19) as a pale yellow solid, yield 78.31％,mp:231.2～235.5℃.1H NMR(600MHz,DMSO-d6)δ10.82(s,1H),8.84(s,1H),8.72(t,J＝6.0Hz,1H),8.14(d,J＝8.2Hz,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]+.
EXAMPLE 20 preparation of (E) -3- (3- (N- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) sulfanyl) phenyl) -N-hydroxyacrylamide (I-20)
Step (1) preparation of N-benzyl-2- (5- (4- ((3-bromophenyl) sulfamido) phenyl) pyridin-2-yl) acetamide
To a solution of 2- (5- (4-aminophenyl) pyridin-2-yl) -N-benzylacetamide (200 mg,0.63 mmol) in dimethylformamide (4 ml) was added 4-bromobenzenesulfonyl chloride (193 mg,0.76 mmol) in portions with stirring at room temperature, pyridine (0.25 ml) was added dropwise thereto, and the reaction was continued after the dropwise addition. After the reaction was completed, ethyl acetate (50 ml. Times.3) was extracted with water (100 ml), the organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column to give N-benzyl-2- (5- (4- ((4-bromophenyl) sulfamido) phenyl) pyridin-2-yl) acetamide (255 mg, 76.20%) as a milky white solid.
Step (2) preparation of methyl (E) -3- (4- (N- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) sulfamoyl) phenyl) acrylate
To a solution of N-benzyl-2- (5- (4- ((4-bromophenyl) sulfamido) phenyl) pyridin-2-yl) acetamide (255 mg,0.59 mmol) in dimethylformamide (5 ml) was added methyl acrylate (55. Mu.L), palladium acetate (2 mg,0.001 mmol), tris (o-methylphenyl) phosphine (6 mg,0.019 mmol), triethylamine (230. Mu.L, 1.66 mmol) in this order under stirring at room temperature, and the mixture was warmed to 100℃under nitrogen. After the completion of the reaction, the solid in the reaction mixture was removed by adsorption with celite, the celite was washed with ethyl acetate (70 ml. Times.3), the organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column to give methyl (E) -3- (4- (N- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) sulfamoyl) phenyl) acrylate as a pale yellow solid (150 mg, yield 58.34%).
Step (3) preparation of (E) -3- (4- (N- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) sulfanyl) phenyl) -N-hydroxyacrylamide (I-20)
In the same manner as in step (6), there was obtained (E) -3- (4- (N- (4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) sulfanyl) phenyl) -N-hydroxyacrylamide (I-20) as a pale yellow solid (77 mg, yield) 49.59％),mp:233.4～235.1℃.1H 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,1H),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]+.
EXAMPLE 21 preparation of 4- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxybenzoamide (I-21)
Step (1) methyl 4-bromomethylbenzoate
Light pink solid methyl 4-bromomethylbenzoate (129 mg, 87.93% yield) was prepared using the corresponding starting material required for example 16, step (2) and example 21, route three.
Step (2) preparation of methyl 4- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) benzoate
Preparation of milky white solid methyl 4- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) benzoate (213 mg, 97.12%) using the desired corresponding starting material of step (3) of scheme three example 16.
Step (3) 4- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxybenzoamide (I-21)
Preparation of pale yellow solid 4- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxybenzoamide (I-21) (200 mg, yield) Using the corresponding starting material as required in example 1, step (6) and example 21 91.87％),mp:218.2～220.3℃.1H 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]+.
The compounds of examples 22-28 were prepared by the procedure of example 21, with appropriate choice of starting materials.
EXAMPLE 22 preparation of 4- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -N-hydroxybenzoamide (I-22)
4- ((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -N-hydroxybenzoamide (I-22) as a pale yellow solid, yield 60.87％,mp:220.2～223.5℃.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]+.
EXAMPLE 23 preparation of 6- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxynicotinamide (I-23)
6- (((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxynicotinamide (I-23) as a pale yellow solid, yield 70.89％,mp:215.2～217.6℃.1H 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]+.
EXAMPLE 24 preparation of 6- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -N-hydroxynicotinamide (I-24)
6- (((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -N-hydroxynicotinamide (I-24) as a pale yellow solid, yield 60.32％,mp:210.2～213.7℃.1H 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-MS m/z:469.16[M+H]+.
EXAMPLE 25 preparation of 5- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxypyridine-amide (I-25)
5- (((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxypyridine amide (I-25) as a pale yellow solid, yield 56.83％,mp:184.0～185.8℃.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]+.
EXAMPLE 26 preparation of 5- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -N-hydroxypyridine carboxamide (I-26)
5- ((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -N-hydroxypyridine carboxamide (I-26) as a pale yellow solid, yield 64.27％,mp:190.1～194.8℃.1H 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-MS m/z:469.23[M+H]+.
EXAMPLE 27 preparation of 2- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxypyrimidinamide (I-27)
2- (((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxypyrimidine-5-carboxamide (I-27) as a pale yellow solid, yield 58.33％,mp:180.1～182.8℃.1H 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]+.
EXAMPLE 28 preparation of 2- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -N-hydroxypyrimidine-5-carboxamide (I-28)
2- ((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -N-hydroxypyrimidine-5-carboxamide (I-28) as a pale yellow solid, yield 66.12％,mp:190.7～192.8℃.1H 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]+.
EXAMPLE 29 preparation of 2- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxythiazole-4-carboxamide (I-29)
Step (1) preparation of methyl 2-methyl-4-thiazolecarboxylate
To a solution of 2-methylthiazole-4-carboxylic acid (700 mg,4.89 mmol) in methanol (25 ml) was slowly added dropwise concentrated sulfuric acid (671 mg,6.85 mmol) with stirring at 0℃and the mixture was warmed to reflux reaction under condensation. After the completion of the reaction, 1mol/L sodium carbonate solution was added dropwise to the reaction mixture to ph=7, the ethyl acetate (50 ml) was extracted three times, the organic phases were combined, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give methyl 2-methyl-4-thiazolecarboxylate as a white solid (642 mg, yield 84.16%).
Preparation of methyl 2-bromomethyl-4-thiazolecarboxylate
Using the desired starting materials for example 16, step (2) and example 29, methyl 2-bromomethyl-4-thiazolecarboxylate was obtained as a milky white solid (181 mg, 18.74% yield).
Step (3) preparation of methyl 2- ((4- (6- (2- (benzylamino-) 2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) thiazole-4-carboxylate
Using the corresponding starting materials of step (3) of scheme III example 16 and example 29, methyl 2- ((4- (6- (2- (benzylamino-) 2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) thiazole-4-carboxylate (195 mg, 87.49%) was obtained as a white solid.
Step (4) preparation of 2- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxythiazole-4-carboxamide (I-27)
Using the procedure of example 1, step (6) and example 29, the desired starting materials were collected to give 2- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxythiazole-4-carboxamide (I-29) (148 mg, yield 75.56％),mp:175.0～177.6℃.1H 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]+.
The compounds of examples 30-32 were prepared by following the procedure for the preparation of example 29, with appropriate choice of starting materials.
EXAMPLE 30 preparation of 2- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -N-hydroxythiazole-5-carboxamide (I-30)
2- (((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -N-hydroxythiazole-5-carboxamide (I-30) as a pale yellow solid, yield 79.76％,mp:176.3～177.9℃.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]+.
EXAMPLE 31 preparation of 2- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxythiazole-5-carboxamide (I-31)
2- (((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -N-hydroxythiazole-5-carboxamide (I-31) as a pale yellow solid, yield 77.76％,mp:207.4～209.6℃.1H 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,3H),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]+.
EXAMPLE 32 preparation of 2- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -N-hydroxythiazole-5-carboxamide (I-32)
2- (((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -N-hydroxythiazole-5-carboxamide (I-32) as a pale yellow solid, yield 75.89％,mp:212.0～215.8℃.1H 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,1H),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]+.
The compounds of examples 33-36 were prepared by following the procedure for the preparation of example 16 using the synthetic route of route seven and selecting the appropriate starting materials
EXAMPLE 33 preparation of 4- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -3-fluoro-N-hydroxybenzoamide (I-33)
4- (((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -3-fluoro-N-hydroxybenzoamide (I-33) as a 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]+.
EXAMPLE 34 preparation of 4- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -3-fluoro-N-hydroxybenzoamide (I-34)
4- ((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -3-fluoro-N-hydroxybenzoamide (I-34) as a pale yellow solid, yield 75.87％,mp:216.8～219.3℃.1H 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]+.
EXAMPLE 35 preparation of 4- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -2-fluoro-N-hydroxybenzoamide (I-35)
4- (((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) -2-fluoro-N-hydroxybenzoamide (I-35) as a pale yellow solid, yield 76.12％,mp:209.2～212.3℃.1H 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),7.90(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]+.
EXAMPLE 36 preparation of 4- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -2-fluoro-N-hydroxybenzoamide (I-36)
4- ((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) -2-fluoro-N-hydroxybenzoamide (I-36) as a pale yellow solid, yield 77.89％,mp:221.2～224.6℃.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]+.
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):
step (1) preparation of tert-butyl 4- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) piperidine-1-carboxylate
N-benzyl-2- (5- (4-aminophenyl) pyridin-2-yl) acetamide (200 mg,0.63 mmol) was dissolved in 5ml DMF, 1-Boc-4-bromopiperidine (250 mg,0.95 mmol), K 2CO3 (156 mg,1.12 mmol) were added to the solution in succession with stirring at room temperature, stirred at room temperature for 10min, then slowly warmed to 60℃for 8h, after completion of the reaction, extracted with ethyl acetate (50 ml. Times.3) and water (100 ml), the organic phases were combined, dried over Na 2SO4, the solvent was distilled off under reduced pressure, and the residue was isolated 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.
Step (2) preparation of N-benzyl-2- (5- (4- ((piperidin-4-ylmethyl) amino) phenyl) pyridin-2-yl) acetamide
Tert-butyl 4- (((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenyl) amino) methyl) piperidine-1-carboxylate (167 mg,0.33 mmol) was dissolved in 5ml Dichloromethane (DCM), 1ml CF 3 COOOH was added thereto with stirring at room temperature and stirring was continued for 4h. After completion of the reaction, the pH was adjusted to neutral with saturated Na 2CO3, extracted with dichloromethane (50 ml. Times.3) and water (100 ml), the organic phases were combined, anhydrous Na 2SO4 was dehydrated, and the solvent was distilled off 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.
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
N-benzyl-2- (5- (4- ((piperidin-4-ylmethyl) amino) phenyl) pyridin-2-yl) acetamide (137 mg,0.33 mmol) was dissolved in 5ml DMF and methyl 2-chloropyrimidine-5-carboxylate (57 mg,033 mmol), N-diisopropylethylamine (DIPEA, 0.50mmol, 87. Mu.L) was added to the solution in sequence with stirring at room temperature and the reaction was continued with stirring for 8h. After the reaction was completed, extracted with ethyl acetate (50 ml×3) and water (100 ml), the organic phases were combined, anhydrous Na 2SO4 was removed by water, the solvent was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column 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.
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)
The same procedure was followed in step (6) of example 1 to give 2- (4- ((4- (6- (2- (benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) piperidin-1-yl) -N-hydroxypyrimidine-5-carboxamide as a pale yellow solid (Ⅰ-37)(60mg,47.20％)mp:185.2～187.8℃.1H 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),4.22(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]+.
The compound of example 38 was prepared by the procedure of example 37, selecting the appropriate starting materials
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)
2- (4- ((4- (6- (2- (Benzylamino) -2-oxoethyl) pyridin-3-yl) phenoxy) methyl) piperidin-1-yl) -N-hydroxypyrimidine-5-carboxamide (I-38) as a pale yellow solid, yield 53.41％,mp:196.6～199.8℃.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]+.
Example 39 in vitro anti-tumor cell proliferation Activity test of Compounds of interest
The CCK8 method is adopted to test the in vitro antiproliferative activity of the target compound on HT29, CNE2 and A549 cell lines. The desired cells were removed in a liquid nitrogen tank, shaken in a 37 ℃ water bath until the cells were thawed, the cell suspension was added to a centrifuge tube containing 9ml of PBS, centrifuged at 600rpm, the PBS was removed by pipetting, the cells were resuspended in 1ml of medium, the cell suspension was transferred to a 10cM dish, and the cells were placed in a 37 ℃ 5% co 2 incubator for culture. When the cells were cultured to the appropriate density, the medium was aspirated, the residual medium was washed with PBS, PBS was aspirated, 2ml of pancreatin was added to digest the cells, after termination of digestion with medium, the cells were collected into a centrifuge tube, centrifuged at 800rpm, and resuspended. Cell suspensions (4000/well) of specific density were prepared in 96-well plates using fresh medium, 100 μl of cell suspension was added per well for experimental and negative control groups, and the blank group was added with equal amounts of medium. The culture was performed in an incubator at 37℃in a 5% CO 2 environment for 24 hours. 100ul of medium containing different concentrations of compound was added to the experimental group, 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. After incubation at 37℃for 48h with 5% CO 2, 10 μl of CCK8 was added per well and incubation was continued for 2.5h, absorbance was measured with an ELISA reader at 450nm, three independent experiments were performed, and IC 50 was calculated using GraphPadPrsm 8.0.
TABLE 1 antiproliferative activity results of target compounds on HT29, CNE2 and A549
a The values in the table are the average of three tests
EXAMPLE 40 in vitro anti-tumor cell proliferation Activity test of Compounds of interest
The MTT method is adopted to test the in vitro antiproliferative activity of the target compound on three cell lines of A549, MCF-7 and HT-29. Log phase cells were collected, cell suspension concentrations were adjusted, 100 μl was added to each well of 96-well plates, and plated (a 549: 2000/well, MCF-7: 2000/well, HT-29: 6000/well). Incubate at 5% CO 2, 37 ℃ until cell monolayers are confluent at the bottom of the wells, incubate for 24 hours. 5 gradients of 0.001 mol, 0.01 mol, 0.1 mol, 1 mol, 10 mol) were added and 3 multiplex wells were placed per well of 100 ul. Incubate at 5% CO 2, 37 ℃ for 72 hours and observe under an inverted microscope. The culture broth was discarded, 100. Mu.l MTT solution (2.5 mg/ml) was added to each well, and the culture was continued for 4 hours. If the drug reacts with MTT, the culture solution can be removed after centrifugation, and after careful 2-3 times of PBS, the culture solution containing MTT can be added. The culture was terminated, the MTT solution was discarded, 100. Mu.l of dimethyl sulfoxide was added to each well, and the mixture was shaken on a shaker to dissolve the crystals sufficiently. Absorbance was measured for each well at OD490 nm in an enzyme-linked immunosorbent assay. IC 50 was calculated using graphpadprism 8.0.
TABLE 2 antiproliferative activity results of target compounds on A549, MCF-7 and HT-29
a The values in the table are the average of three tests.
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| WO2000063197A1 (en) * | 1999-04-19 | 2000-10-26 | Sumitomo Pharmaceuticals Company, Limited | Hydroxamic acid derivative |
| CN1450991A (en) * | 2000-09-01 | 2003-10-22 | 诺瓦提斯公司 | Hydroxamate derives useful as deacetylase inhibitors |
| US20040198830A1 (en) * | 2000-09-29 | 2004-10-07 | Watkins Clare J. | Carbamic acid compounds comprising an ether linkage as hdac inhibitors |
| CN106977425A (en) * | 2017-04-01 | 2017-07-25 | 清华大学深圳研究生院 | Hydroxamic acid derivs with dnmt rna and histon deacetylase (HDAC) inhibitory activity and preparation method and application |
| CN108314676A (en) * | 2017-01-18 | 2018-07-24 | 上海医药工业研究院 | The aminopyridine analog derivative and its antitumor application thereof of the segment containing hydroxamic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2000063197A1 (en) * | 1999-04-19 | 2000-10-26 | Sumitomo Pharmaceuticals Company, Limited | Hydroxamic acid derivative |
| CN1450991A (en) * | 2000-09-01 | 2003-10-22 | 诺瓦提斯公司 | Hydroxamate derives useful as deacetylase inhibitors |
| US20040198830A1 (en) * | 2000-09-29 | 2004-10-07 | Watkins Clare J. | Carbamic acid compounds comprising an ether linkage as hdac inhibitors |
| CN108314676A (en) * | 2017-01-18 | 2018-07-24 | 上海医药工业研究院 | The aminopyridine analog derivative and its antitumor application thereof of the segment containing hydroxamic acid |
| CN106977425A (en) * | 2017-04-01 | 2017-07-25 | 清华大学深圳研究生院 | Hydroxamic acid derivs with dnmt rna and histon deacetylase (HDAC) inhibitory activity and preparation method and application |
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