Amide compound and preparation and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to an amide compound based on a hydrophobic labeling technology and preparation and application thereof. The structural general formula H of the target product is shown in the specification, or pharmaceutically acceptable salts, solvent compounds or hydrates of the target product. The compound provided by the invention has dual mechanisms of inhibiting polymerization and degradation of tubulin, has an effect of inhibiting tumor proliferation, and has a good prospect in the aspect of development of antitumor drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to an amide compound based on hydrophobic labeling technology, its preparation method, and its application in anti-tumor treatment. Background Technology

[0002] Malignant tumors pose a serious threat to human health, being the second leading cause of death after cardiovascular disease. Microtubules are widely distributed in the cytoplasm of eukaryotic cells and are an important component of the cytoskeleton, playing crucial roles in various cellular processes, including mitosis, angiogenesis, tumor cell maturation, and cell signal transduction; therefore, tubulin is considered an attractive and promising target for the development of anti-tumor drugs. Based on different dynamic modes of influence on tubulin, classic microtubule-targeting drugs are mainly divided into two categories: microtubule stabilizers and microtubule polymerization inhibitors.

[0003] Targeted protein degraders are an emerging frontier in drug development, utilizing the ubiquitin-proteasome system (UPS) to selectively degrade target proteins (POIs), thereby providing a novel therapeutic approach. The related technologies for these degraders mainly fall into three categories: protein hydrolysis-targeted chimera technology, hydrophobic labeling technology, and molecular glue technology. Related reports can be found in: Nature Reviews Drug Discovery 2017; 16:101-14; Nature Reviews Drug Discovery 2019; 18:949-63; Chinese Chemical Letters 2023:109192.

[0004] Currently, some tubulin degraders have been reported as third-class microtubule-targeting drugs. Furthermore, tubulin degraders, especially incidentally discovered natural small molecule compounds, show great potential in overcoming multidrug resistance and reducing neurotoxicity. However, compared with highly active small molecule microtubule inhibitors, their antitumor activity is generally weaker. Related reports can be found in: International Journal of Molecular Sciences 2023; 24:13674; Investigational New Drugs 2012; 30:1813-9; Molecular Pharmacology 2019; 96:711-9.

[0005] Hydrophobic labeling technology is one of the important methods for developing small molecule degradative agents with high antitumor activity. Related reports can be found in: ACS Medicinal Chemistry Letters 2023; 14:12:1863-1868; Angewandte Chemie International Edition 2023, 3:20; 62(13):e202217246; Angewandte Chemie International Edition 2018, 12:21; 57(52):17043-17047.

[0006] The study of the antitumor activity of amide compounds based on hydrophobic labeling technology involved in this invention has not yet been reported in the literature. Summary of the Invention

[0007] The purpose of this invention is to design and synthesize an amide compound based on hydrophobic labeling technology that has a dual mechanism of inhibiting the polymerization and degradation of tubulin and has good anti-tumor activity, as well as its preparation method and its application in anti-tumor treatment.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] An amide compound based on hydrophobic labeling technology, wherein the compound is a compound represented by general formula H or a pharmaceutically acceptable salt, solvent compound or hydrate thereof;

[0010]

[0011] In the general formula H, n1 and n2 can be the same or different and are independently selected from integers between 1 and 5 (e.g., 1, 2, 3, 4 or 5), and X is selected from...

[0012] Preferably, the compound is a compound represented by general formula H or a pharmaceutically acceptable salt, solvent compound or hydrate thereof;

[0013] In the general formula H, n1 and n2 can be the same or different and are independently selected from integers between 1 and 3 (e.g., n1, n2, or n3), and X is selected from...

[0014] Further preferably, the compound represented by general formula H is:

[0015] Compound 1

[0016]

[0017] N 1-{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 -(1-adamantyl)succinamide

[0018] Compound 2

[0019]

[0020] N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 -(1-adamantyl)pentanediamide

[0021] Compound 3

[0022]

[0023] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 -(1-adamantyl)succinamide

[0024] Compound 4

[0025]

[0026] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 -(1-adamantyl)pentanediamide

[0027] Compound 5

[0028]

[0029] N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 -(2-adamantyl)succinamide

[0030] Compound 6

[0031]

[0032] N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 -(2-adamantyl)pentanediamide

[0033] Compound 7

[0034]

[0035] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 -(2-adamantyl)succinamide

[0036] Compound 8

[0037]

[0038] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 -(2-adamantyl)pentanediamide

[0039] Compound 9

[0040]

[0041] N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 -(1-adamantylmethyl)succinamide

[0042] Compound 10

[0043]

[0044] N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 -(1-adamantylmethyl)glutaramide

[0045] Compound 11

[0046]

[0047] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 -(1-adamantylmethyl)succinamide

[0048] Compound 12

[0049]

[0050] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5-(1-adamantylmethyl)glutaramide

[0051] Compound 13

[0052]

[0053] N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 -[1-(1-adamantyl)ethyl]butanediamide

[0054] Compound 14

[0055]

[0056] N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 -[1-(1-adamantyl)ethyl]pentanediamide

[0057] Compound 15

[0058]

[0059] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 -[1-(1-adamantyl)ethyl]butanediamide

[0060] Compound 16

[0061]

[0062] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 -[1-(1-adamantyl)ethyl]pentanediamide

[0063] Compound 17

[0064]

[0065] N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 -[3,5-dimethyladamantane-1-yl]succinamide

[0066] Compound 18

[0067]

[0068] N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 -[3,5-dimethyladamantane-1-yl]pentanediamide

[0069] Compound 19

[0070]

[0071] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 -[3,5-dimethyladamantane-1-yl]succinamide

[0072] Compound 20

[0073]

[0074] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 -[3,5-dimethyladamantane-1-yl]pentanediamide

[0075] Compound 21

[0076]

[0077] N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 -Cycloheptylbutyric acid

[0078] Compound 22

[0079]

[0080] N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 -Cycloheptylglutaramide

[0081] Compound 23

[0082]

[0083] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 -Cycloheptylbutyric acid

[0084] Compound 24

[0085]

[0086] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 -Cycloheptylglutaramide

[0087] Compound 25

[0088]

[0089] N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 2-(1-Cyclohexen-1-yl)ethyl]butanediamide

[0090] Compound 26

[0091]

[0092] N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 -[2-(1-cyclohexen-1-yl)ethyl]pentanediamide

[0093] Compound 27

[0094]

[0095] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 2-(1-Cyclohexen-1-yl)ethyl]butanediamide

[0096] Compound 28

[0097]

[0098] N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 -[2-(1-cyclohexen-1-yl)ethyl]pentanediamide

[0099] Compound 29

[0100]

[0101] N-{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-4-(octahydro-2H-isoindol-2-yl)-4-oxobutyramide

[0102] Compound 30

[0103]

[0104] N-{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-5-(octahydro-2H-isoindol-2-yl)-5-oxopentanamide

[0105] Compound 31

[0106]

[0107] N-{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-4-(octahydro-2H-isoindol-2-yl)-4-oxobutyramide

[0108] Compound 32

[0109]

[0110] N-{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-5-(octahydro-2H-isoindol-2-yl)-5-oxopentanamide

[0111] The salt is a salt formed by the compound represented by general formula H and an acid or base. The acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, and malic acid. The base is selected from sodium hydroxide, sodium carbonate, and potassium hydroxide. The hydrate of the compound represented by general formula H has any real number of water molecules of crystallization from 0 to 16.

[0112] A method for preparing amide compounds based on hydrophobic labeling technology, characterized in that amide compounds are obtained by using 2-fluoro-5-bromopyridine I as a raw material and undergoing reactions such as substitution, alcoholysis, aminolysis, Suzuki coupling, alkylation, deprotection, acylation, and condensation, as shown in the reaction formula:

[0113]

[0114] To elaborate further:

[0115] (1) 2-Fluoro-5-bromopyridine I was dissolved in anhydrous acetonitrile in anhydrous tetrahydrofuran, and sodium bis(trimethylsilyl)amino was added to give compound II by nucleophilic substitution reaction.

[0116] (2) Compound II was mixed with concentrated sulfuric acid and then dissolved in methanol to undergo alcoholysis to obtain compound III.

[0117] (3) Compound III was mixed with benzylamine and lanthanum trifluoromethanesulfonate to undergo an ester aminolysis reaction to obtain compound IV.

[0118] (4) Compound IV and 4-hydroxyphenylboronic acid pinacol ester were dissolved in toluene and water, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and potassium carbonate were added to give compound V by Suzuki coupling reaction.

[0119] (5) Compound V and tert-butoxycarbonylamino-substituted alkyl bromides are dissolved in N,N-dimethylformamide, potassium carbonate is added, and alkylation reaction is carried out to obtain compound VI; tert-butoxycarbonylamino-substituted alkyl bromides include: 2-tert-butoxycarbonylamino-1-ethyl bromide, 3-tert-butoxycarbonylamino-1-propyl bromide, 4-tert-butoxycarbonylamino-1-butyl bromide, 5-tert-butoxycarbonylamino-1-pentyl bromide, 6-tert-butoxycarbonylamino-1-hexyl bromide, etc.

[0120] (6) Compound VI was dissolved in dichloromethane, and hydrogen chloride-dioxane solution was added to remove tert-butoxycarbonyl group to obtain compound VII.

[0121] (7) Compound VII and diacid compounds are dissolved in N,N-dimethylformamide, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and diisopropylethylamine are added to undergo a condensation reaction to obtain compound VIII; diacid compounds include: succinic acid, glutaric acid, adipic acid, pimelic acid, octanoic acid, etc.

[0122] (8) Compound VIII is dissolved in N,N-dimethylformamide with an amine or alcohol containing a hydrophobic group, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and diisopropylethylamine are added to undergo a condensation reaction to obtain amide compound H; the amine compounds containing hydrophobic groups include: 1-adamantanamine, 2-adamantanamine, 1-adamantylmethylamine, 1-(1-adamantyl)ethylamine, 3, 5-Dimethyl-1-adamantanamine, 1-cyclopropylmethylamine, 1-cyclohexylmethylamine, cycloheptaneamine, 2-(1-cyclohexen-1-yl)ethylamine, 5-norbornene-2-methylamine, octahydro-2H-isoindole, aniline, 4-methylaniline, 3,4-dimethylaniline, benzylamine, 4-isopropylbenzylamine, dimethylamine, trimethylamine, etc.; alcohols containing hydrophobic groups include: 1-adamantanol, 2-adamantanol, 1-adamantylmethanol, etc.

[0123] To go even further:

[0124] (1) 2-Fluoro-5-bromopyridine I and anhydrous acetonitrile were dissolved in anhydrous tetrahydrofuran, and sodium bis(trimethylsilyl)amino was added to undergo a nucleophilic substitution reaction. After the reaction was completed, the mixture was quenched with saturated ammonium chloride aqueous solution, extracted with dichloromethane, washed with saturated brine, dried with anhydrous Na2SO4, and the solvent was removed under reduced pressure. The mixture was then subjected to column chromatography to obtain compound II. The molar ratio of compound I, anhydrous acetonitrile and sodium bis(trimethylsilyl)amino was 1:3 to 7:2 to 10. The reaction temperature was -78℃ to -20℃. The reaction time was 3 to 9 h.

[0125] (2) Compound II was mixed with concentrated sulfuric acid and then dissolved in methanol to undergo alcoholysis. After the reaction was completed, the remaining concentrated sulfuric acid in the system was neutralized with saturated potassium carbonate aqueous solution, extracted with dichloromethane, washed with saturated brine, dried with anhydrous Na2SO4, and the solvent was removed under reduced pressure. Compound III was obtained by column chromatography. The molar ratio of compound II, concentrated sulfuric acid and methanol was 1:5 to 10:10 to 20. The reaction temperature was 50℃ to 120℃. The reaction time was 24 to 48 h.

[0126] (3) Compound III was mixed with benzylamine and lanthanum trifluoromethanesulfonate to undergo an ester aminolysis reaction. After the reaction was completed, compound IV was obtained by slurrying with n-hexane. The molar ratio of compound III to lanthanum trifluoromethanesulfonate was 1:0.05 to 0.3. The reaction temperature was 30℃ to 70℃. The reaction time was 2 to 6 h.

[0127] (4) Compound IV and 4-hydroxyphenylboronic acid pinacol ester were dissolved in toluene and water, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and potassium carbonate were added to undergo a Suzuki coupling reaction. After the reaction was completed, the mixture was extracted with ethyl acetate, the residual metal was adsorbed with diatomaceous earth, washed with saturated brine, dried with anhydrous Na2SO4, the solvent was removed under reduced pressure, and compound V was obtained by column chromatography. The molar ratio of compound IV, 4-hydroxyphenylboronic acid pinacol ester, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and potassium carbonate was 1:1~2:0.03~0.4:2~5; the reaction temperature was 50℃~100℃; and the reaction time was 9~24h.

[0128] (5) Compound V and tert-butoxycarbonylamino-substituted alkyl bromides were dissolved in N,N-dimethylformamide, potassium carbonate was added, and an alkylation reaction was carried out. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with saturated brine, dried with anhydrous Na2SO4, and the solvent was removed under reduced pressure. The solvent was removed by column chromatography to obtain compound VI. The molar ratio of compound V to tert-butoxycarbonylamino-substituted alkyl bromides was 1:1 to 3. The reaction temperature was 60℃ to 90℃. The reaction time was 10 to 18 h. The tert-butoxycarbonylamino-substituted alkyl bromides included: 2-tert-butoxycarbonylamino-1-ethyl bromide, 3-tert-butoxycarbonylamino-1-propyl bromide, 4-tert-butoxycarbonylamino-1-butyl bromide, 5-tert-butoxycarbonylamino-1-pentyl bromide, 6-tert-butoxycarbonylamino-1-hexyl bromide, etc.

[0129] (6) Dissolve compound VI in dichloromethane, add 4M hydrogen chloride-dioxane solution, remove tert-butoxycarbonyl group, and after the reaction is complete, slurry with dichloromethane to obtain compound VII; wherein the molar ratio of compound VI to hydrogen chloride is 1:1 to 5; the reaction temperature is -20℃ to 20℃; and the reaction time is 1 to 3 h.

[0130] (7) Compound VII and diacid compounds were dissolved in N,N-dimethylformamide, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and diisopropylethylamine were added to undergo a condensation reaction. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The mixture was then subjected to column chromatography to obtain compound VIII. The molar ratio of compound VII, diacid compounds, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and diisopropylethylamine was 1:1~2:1~3:2~6. The reaction temperature was 0℃~50℃. The reaction time was 6~12h. The diacid compounds included succinic acid, glutaric acid, adipic acid, pimelic acid, octanoic acid, etc.

[0131] (8) Compound VIII was dissolved in N,N-dimethylformamide with an amine or alcohol containing a hydrophobic group. 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and diisopropylethylamine were added, and a condensation reaction was carried out. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The amide compound H was obtained by column chromatography. The molar ratio of compound VIII, the amine or alcohol containing a hydrophobic group, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and diisopropylethylamine was 1:1~5:1~4:2~1. 0; reaction temperature is 0℃~100℃; reaction time is 6~72h; amine compounds containing hydrophobic groups include: 1-adamantanamine, 2-adamantanamine, 1-adamantylmethylamine, 1-(1-adamantyl)ethylamine, 3,5-dimethyl-1-adamantanamine, 1-cyclopropylmethylamine, 1-cyclohexylmethylamine, cycloheptaneamine, 2-(1-cyclohexen-1-yl)ethylamine, 5-norbornene-2-methylamine, octahydro-2H-isoindole, aniline, 4-methylaniline, 3,4-dimethylaniline, benzylamine, 4-isopropylbenzylamine, xyleneamine, trimethylbenzylamine, etc.; alcohol compounds containing hydrophobic groups include: 1-adamantanol, 2-adamantanol, 1-adamantylmethanol, etc.

[0132] A pharmaceutical composition comprising a compound of general formula H or a pharmaceutically acceptable salt, solvent compound or hydrate thereof; wherein the content is 0.01 to 99% of the composition by mass.

[0133] Application of the compound or the composition: The use of the compound of general formula H or its pharmaceutically acceptable salt, solvent compound or hydrate or the composition in the preparation of antitumor drugs.

[0134] The tumor in question is a human breast cancer, lung cancer, or colorectal cancer tumor.

[0135] The method for preparing amide compounds based on hydrophobic labeling technology provided by this invention is simple, feasible, and has a high yield.

[0136] The present invention further provides the use of the above-mentioned amide compounds based on hydrophobic labeling technology and their salts and hydrates or the above-mentioned pharmaceutical compositions in the preparation of medicaments for treating tumor diseases, wherein the tumor is a human breast cancer, lung cancer or colorectal cancer cell line.

[0137] Amide compounds based on hydrophobic labeling technology have a dual mechanism of inhibiting the polymerization and degradation of tubulin, thus inhibiting tumor proliferation and showing promising potential for the treatment of tumors. Attached Figure Description

[0138] Figure 1 Results of microtubule polymerization inhibition activity test

[0139] Figure 2 Results of microtubule degradation activity test Detailed Implementation

[0140] The following examples will help to understand the present invention, but the content of the present invention is not limited to the examples given.

[0141] All reagents used in this invention are commercially available. The nuclear magnetic resonance spectra were measured using a Bruker AVANCE 400 nuclear magnetic resonance spectrometer, and the high-resolution mass spectrometry was measured using an Agilent Accurate-Mass Q-TOF 6530 (Agilent, Santa Clara, CA, USA) mass spectrometer.

[0142] Example 1: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 Preparation of 1-(1-adamantyl)succinamide

[0143] 2-Fluoro-5-bromopyridine (3.52 g, 0.02 mol) and anhydrous acetonitrile (4.11 g, 0.1 mol) were dissolved in anhydrous tetrahydrofuran. A 2M solution of sodium bis(trimethylsilyl)amino (60 mL, 0.12 mol) in anhydrous tetrahydrofuran was slowly added dropwise over 15 min with stirring at -30 °C. After the addition was complete, stirring continued for 3 h. After the reaction was complete, 100 mL of saturated ammonium chloride aqueous solution was added to quench the reaction mixture. The mixture was extracted with dichloromethane (300 mL × 2), and the organic layers were combined, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and separated by column chromatography (eluent: hexane: ethyl acetate = 5:1) to obtain 2.8 g of 2-(5-bromopyridine-2-yl)acetonitrile. The product was a yellow oil, yield: 71%.

[0144] 2-(5-bromopyridin-2-yl)acetonitrile (2.28 g, 11.6 mmol) was dissolved in 98% concentrated sulfuric acid (15 g) in methanol (25 g), and the mixture was stirred under reflux for 24 h. After the reaction was complete, the concentrated sulfuric acid in the reaction system was neutralized with 50 mL of saturated potassium carbonate aqueous solution, and the mixture was extracted with dichloromethane (300 mL × 2). The organic phases were combined, dried over anhydrous Na₂SO₄, and the solvent was removed under reduced pressure. The mixture was then separated by column chromatography (eluent: hexane: ethyl acetate = 5:1) to give 2.1 g of methyl 2-(5-bromopyridin-2-yl)acetate. The solid was yellow, yield: 79%.

[0145] Methyl 2-(5-bromopyridin-2-yl)acetate (3 g, 13 mmol), lanthanum trifluoromethanesulfonate (0.382 g, 0.652 mmol), and benzylamine (1.68 g, 15.65 mmol) were mixed and stirred at 50 °C for 2 h. After the reaction was complete, n-hexane (100 mL × 2) was added and stirred until a slurry was formed. The mixture was then filtered, and the filter cake was collected to give 3.5 g of N-benzyl-2-(5-bromopyridin-2-yl)acetamide. The solid was light brown, and the yield was 95%.

[0146] Under nitrogen protection, N-phenylmethyl-2-(5-bromopyridin-2-yl)acetamide (3.05 g, 10 mmol), pinacol ester of 4-hydroxyphenylboronic acid (2.2 g, 10 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.71 g, 1 mmol), and potassium carbonate (5.53 g, 40 mmol) were dissolved in toluene and water (v / v = 4 / 1), and stirred at 50 °C for 10 h. After the reaction was complete, the mixture was extracted with ethyl acetate (100 mL × 3), the organic layers were combined, residual metals were adsorbed onto diatomaceous earth (1 g), washed with saturated brine, dried over anhydrous Na₂SO₄, and separated by column chromatography (eluent: hexane: ethyl acetate = 1:2) to obtain 4.02 g of N-phenylmethyl-2-[5-(4-hydroxyphenyl)pyridin-2-yl]acetamide. The solid was light brown, yield: 66%.

[0147] N-Benzyl-2-[5-(4-hydroxyphenyl)pyridin-2-yl]acetamide (3.18 g, 10 mmol), 2-tert-butoxycarbonylamino-1-ethyl bromide (2.69 g, 12 mmol), and potassium carbonate (2.76 g, 20 mmol) were dissolved in N,N-dimethylformamide (10 mL), and stirred at 80 °C for 10 h. After the reaction was complete, the reaction system was cooled to room temperature, extracted with ethyl acetate (20 mL × 5), the organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, the solvent was removed under reduced pressure, and separated by column chromatography (eluent: hexane: ethyl acetate = 1:2) to give 4.02 g of 2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethylcarbamate tert-butyl ester. Pale yellow solid, yield: 87%.

[0148] 0.46 g (1 mmol) of 2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}carbamate tert-butyl ester was dissolved in dichloromethane (5 mL), and a 4M dioxane solution (1 mL) of hydrogen chloride was added at 0 °C. The mixture was stirred for 1 h. After the reaction was complete, the hydrogen chloride was removed by concentration under reduced pressure. The dichloromethane was then slurried (10 mL × 2), and the filter cake was collected by suction filtration to obtain 0.37 g of 2-{5-[4-(2-aminoethoxy)phenyl]pyridin-2-yl}-N-benzylmethylacetamide hydrochloride. The product was a brown solid, yield: 95%.

[0149] 2-{5-[4-(2-aminoethoxy)phenyl]pyridin-2-yl}-N-benzylmethylacetamide hydrochloride (0.40 g, 1 mmol) and succinic acid (0.12 g, 1 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.38 g, 1 mmol) and diisopropylethylamine (0.39 g, 3 mmol) were added. The mixture was stirred at room temperature for 6 h. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 5), the organic layers were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and distilled under reduced pressure. The solution was then subjected to column chromatography (eluent: dichloromethane:methanol = 20:1) to give 0.37 g of 4-{1-{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}amino}-4-oxobutyric acid. White solid, yield: 81%.

[0150] 4-{1-{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}amino}-4-oxobutyric acid (0.46 g, 1 mmol) and 1-adamantaneamine (0.15 g, 1 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.38 g, 1 mmol) and diisopropylethylamine (0.39 g, 3 mmol) were added. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the mixture was extracted with ethyl acetate (50 mL × 5), the organic layers were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and distilled under reduced pressure. The resulting product was then subjected to column chromatography (eluent: dichloromethane:methanol = 20:1) to obtain N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 0.51 g of 1-(1-adamantyl)succinamide. White solid, yield: 85%.

[0151] Preparation of N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 The overall yield of 1-(1-adamantyl)succinamide was 20.01%. 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=2.1Hz,1H),8.63(t,J=5.9Hz,1H),8.09(t,J=5.5Hz,1H) ,7.96(dd,J=8.1,2.4Hz,1H),7.65(d,J=8.8Hz,2H),7.41(d,J=8.1Hz,1H),7.36-7.19(m,6H ),7.06(d,J=8.8Hz,2H),4.31(d,J=5.9Hz,2H),4.03(dd,J=7.3,4.1Hz,2H),3.72(s,2H),3. 44(dd,J=11.2,5.6Hz,2H),2.34-2.22(m,4H),1.96(s,3H),1.86-1.89(m,6H),1.58(s,6H). 13 C NMR (100MHz, DMSO-d6) δ172.41,171.06,169.67,158.96,155.07,146.89,139.89,134.34,133.69,129.92,128.73,128.34 ,127.71,127.21,124.22,115.65,66.99,50.98,44.97,42.73,41.51,38.70,36.53,32.14,31.47,29.28.HRMS(ESI)calcd for C 36 H 42 N4O4[M+H] + :595.3279,found:595.3284.

[0152] Example 2: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 Preparation of 1-(1-adamantyl)pentanediamide

[0153] Except for using glutaric acid instead of succinic acid, N was prepared using the same method as in Example 1. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 1-(1-Adamantyl)pentanediamide. White solid, overall yield: 21.32%. 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=2.1Hz,1H),8.62(t,J=5.9Hz,1H),8.05(t,J=5.5Hz,1H),7.96( dd,J=8.1,2.4Hz,1H),7.65(d,J=8.8Hz,2H),7.40(d,J=8.1Hz,1H),7.35-7.21(m,5H),7.19(s,1H) ,7.07(d,J=8.8Hz,2H),4.30(d,J=5.9Hz,2H),4.04(t,J=5.7Hz,2H),3.71(s,2H),3.43(q,J=5.6Hz ,2H),2.08(t,J=7.6Hz,2H),1.98-2.02(m,5H),1.88-1.91(m,6H),1.72-1.63(m,2H),1.59(s,6H). 13 C NMR(100MHz,DMSO-d6)δ172.67,171.59,169.65,158.96,155.08,146.90,139.90,134.34,133.67,129.92,128.73,128.36,12 7.71,127.21,124.21,115.66,66.95,50.96,44.97,42.73,41.52,38.59,36.55,36.00,35.12,29.28,22.11.HRMS(ESI)calcd for C 37 H 44 N4O4[M+H] + :609.3435,found:609.3437.

[0154] Example 3: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 Preparation of 1-(1-adamantyl)succinamide

[0155] Except for replacing 2-tert-butoxycarbonylamino-1-propyl bromide with 3-tert-butoxycarbonylamino-1-ethyl bromide, N was prepared using the same method as in Example 1. 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 1-(1-Adamantyl)butanediamide. White solid, overall yield: 23.03%. 1H NMR (400MHz, DMSO-d6) δ8.74(d,J=2.1Hz,1H),8.62(t,J=5.8Hz,1H),7.96(dd,J=8.1,2. 4Hz,1H),7.89(t,J=5.5Hz,1H),7.64(d,J=8.7Hz,2H),7.40(d,J=8.1Hz,1H),7.34-7.21 (m,6H),7.04(d,J=8.8Hz,2H),4.31(d,J=5.9Hz,2H),4.04(t,J=6.3Hz,2H),3.72(s,2H) ,3.21(dd,J=12.4,6.5Hz,2H),2.26(s,4H),1.96(s,3H),1.90-1.84(m,8H),1.58(s,6H). 13 C NMR(100MHz,DMSO-d6)δ172.05,171.09,169.66,159.11,155.03,146.87,139.89,134.31,133.73,129.71,128.73,128.30,12 7.71,127.20,124.22,115.58,65.86,50.95,44.96,42.72,41.50,36.52,35.91,32.16,31.56,29.42,29.27.HRMS(ESI)calcd for C 37 H 44 N4O4[M+H] + :609.3435,found:609.3444.

[0156] Example 4: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 Preparation of 1-(1-adamantyl)pentanediamide

[0157] Except for replacing 2-tert-butoxycarbonylamino-1-propyl bromide with 3-tert-butoxycarbonylamino-1-ethyl bromide, N was prepared using the same method as in Example 2. 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 1-(1-Adamantyl)pentanediamide. White solid, overall yield: 22.22%. 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=2.2Hz,1H),8.62(t,J=5.9Hz,1H),7.96(dd,J=8.1,2.4Hz,1H) ,7.87(t,J=5.5Hz,1H),7.65(d,J=8.7Hz,2H),7.40(d,J=8.1Hz,1H),7.36-7.17(m,6H),7.04(d,J =8.8Hz,2H),4.31(d,J=5.9Hz,2H),4.04(t,J=6.3Hz,2H),3.72(s,2H),3.21(dd,J=12.5,6.6Hz, 2H), 2.06 (t, J = 7.5Hz, 2H), 2.03-1.95 (m, 5H), 1.93-1.84 (m, 9H), 1.72-1.64 (m, 2H), 1.59 (s, 6H). 13 C NMR (100MHz, DMSO-d6) δ172.32,171.61,169.66,159.10,155.03,146.88,139.89,134.32,133.72,129.73,128.73,128.33,127.71 ,127.21,124.21,115.59,65.89,50.96,44.97,42.73,41.52,36.55,36.03,35.92,35.26,29.40,29.29,22.19.HRMS(ESI)calcdfor C 38 H 46 N4O4[M+H] + :623.3592,found:623.3596.

[0158] Example 5: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 Preparation of 2-(2-adamantyl)succinamide

[0159] Except that 2-adamantaneamine was used instead of 1-adamantaneamine, N was prepared using the same method as in Example 1. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 2-(2-Adamantyl)butanediamide. White solid, overall yield: 20.61%. 1H NMR (400MHz, DMSO-d6) δ8.76(d,J=1.9Hz,1H),8.66(t,J=5.8Hz,1H),8.15(t,J=5.4Hz,1H),7.97(dd,J=8.1 ,2.3Hz,1H),7.73(d,J=7.5Hz,1H),7.65(d,J=8.7Hz,2H),7.42(d,J=8.1Hz,1H),7.36-7.20(m,5H),7.07(d ,J=8.7Hz,2H),4.33(d,J=5.9Hz,2H),4.04(t,J=5.6Hz,2H),3.83(d,J=7.1Hz,1H),3.75(s,2H),3.46(dd,J =11.0,5.4Hz,2H),2.41(dq,J=12.8,6.4Hz,4H),2.03-1.93(m,2H),1.82-1.63(m,10H),1.50-1.41(m,2H). 13 C NMR(100MHz,DMSO-d6)δ172.42,171.26,169.67,158.95,155.07,146.89,139.88,134.35,133.69,129.93,128.72,128.35,12 7.71,127.20,124.22,115.65,66.95,53.35,44.97,42.74,38.70,37.67,37.34,31.97,31.53,31.43,27.24.HRMS(ESI)calcd for C 36 H 42 N4O4[M+H] + :595.3279,found:595.3284.

[0160] Example 6: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 Preparation of 2-(2-adamantyl)pentanediamide

[0161] Except that 2-adamantaneamine was used instead of 1-adamantaneamine, N was prepared using the same method as in Example 2. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 -(2-adamantyl)pentanediamide. White solid, overall yield: 21.25%. 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=2.0Hz,1H),8.62(t,J=5.8Hz,1H),8.06(t,J=5.5Hz,1H),7.96(d d,J=8.1,2.4Hz,1H),7.68-7.60(m,3H),7.40(d,J=8.1Hz,1H),7.35-7.20(m,5H),7.07(d,J=8.7Hz ,2H),4.31(d,J=5.9Hz,2H),4.04(t,J=5.7Hz,2H),3.83(d,J=7.3Hz,1H),3.72(s,2H),3.44(q,J=5 .6Hz,2H),2.13(dt,J=17.4,7.5Hz,4H),2.01-1.93(m,2H),1.85-1.61(m,12H),1.50-1.40(m,2H). 13 C NMR(100MHz,DMSO-d6)δ172.68,171.71,169.65,158.95,155.08,146.89,139.90,134.34,133.67,129.92,128.73,128.35,127.7 1,127.21,124.21,115.66,66.94,53.25,44.97,42.72,38.59,37.68,37.37,35.20,32.01,31.45,27.25,22.27.HRMS(ESI)calcd for C 37 H 44 N4O4[M+H] + :609.3435,found:609.3441.

[0162] Example 7: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 Preparation of 2-(2-adamantyl)succinamide

[0163] Except that 2-adamantaneamine was used instead of 1-adamantaneamine, N was prepared using the same method as in Example 3. 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 2-(2-adamantyl)succinamide. White solid, overall yield: 22.72%. 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=2.3Hz,1H),8.61(t,J=5.8Hz,1H),7.97(dd,J=8.1,2.4Hz,1H),7.92(t,J=5.6 Hz,1H),7.70(d,J=7.6Hz,1H),7.65(d,J=8.7Hz,2H),7.40(d,J=8.1Hz,1H),7.35-7.21(m,5H),7.05(d,J=8.8Hz ,2H),4.31(d,J=5.9Hz,2H),4.04(t,J=6.3Hz,2H),3.81(d,J=7.3Hz,1H),3.72(s,2H),3.21(dd,J=12.5,6.6Hz, 2H),2.35(dt,J=36.7,6.7Hz,4H),2.00-1.94(m,2H),1.89-1.82(m,2H),1.82-1.61(m,12H),1.49-1.43(m,2H). 13 C NMR(100MHz,DMSO-d6)δ172.04,171.27,169.65,159.10,155.03,146.88,139.89,134.32,133.72,129.72,128.73,128.32,127.7 1,127.21,124.22,115.60,65.84,53.33,44.96,42.72,37.66,37.34,35.94,31.97,31.63,31.43,29.38,27.23.HRMS(ESI)calcd for C 37 H 44 N4O4[M+H] + :609.3435, found:609.3439. Example 8: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 Preparation of 2-(2-adamantyl)pentanediamide

[0164] Except that 2-adamantaneamine was used instead of 1-adamantaneamine, N was prepared using the same method as in Example 4. 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 -(2-adamantyl)pentanediamide. White solid, overall yield: 22.25%. 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=2.0Hz,1H),8.64(t,J=5.8Hz,1H),7.96(dd,J=8.1,2.4Hz,1H),7.90(t,J= 5.5Hz,1H),7.70-7.61(m,3H),7.41(d,J=8.1Hz,1H),7.35-7.20(m,5H),7.05(d,J=8.8Hz,2H),4.32(d,J=5. 9Hz,2H),4.04(t,J=6.3Hz,2H),3.84(d,J=7.4Hz,1H),3.73(s,2H),3.23(q,J=6.5Hz,2H),2.16(t,J=7.4Hz, 2H),2.09(t,J=7.5Hz,2H),2.01-1.94(m,2H),1.88(p,J=6.5Hz,2H),1.81-1.64(m,13H),1.50-1.42(m,2H). 13 C NMR(100MHz,DMSO-d6)δ172.34,171.73,169.69,159.11,155.01,146.88,139.88,134.34,133.75,129.73,128.73,128.31,127.71,1 27.21,124.23,115.58,65.88,53.27,44.95,42.75,37.67,37.37,35.94,35.23,32.03,31.45,29.40,27.26,22.35.HRMS(ESI)calcd for C 38 H 46 N4O4[M+H] + :623.3592,found:623.3597.

[0165] Example 9: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 Preparation of 1-(1-adamantylmethyl)succinamide

[0166] Except that 1-adamantaneamine was used instead of 1-adamantaneamine, N was prepared using the same method as in Example 1. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 1-(1-Adamantylmethyl)succinamide. White solid, overall yield: 19.93%. 1H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.62(t,J=5.5Hz,1H),8.11(t,J=5.3Hz,1H),7.97( dd,J=8.1,1.5Hz,1H),7.70-7.60(m,3H),7.41(d,J=8.1Hz,1H),7.35-7.21(m,5H),7.06( d,J=8.7Hz,2H),4.31(d,J=5.8Hz,2H),4.03(t,J=5.6Hz,2H),3.73(s,2H),3.44(q,J=5.6 Hz,2H),2.75(d,J=6.2Hz,2H),2.36(s,4H),1.89(s,3H),1.68-1.52(m,6H),1.40(s,6H). 13 C NMR(100MHz,DMSO-d6)δ172.33,171.96,169.70,158.94,155.04,146.90,139.87,134.38,133.70,129.91,128.73,128.35,12 7.71,127.21,124.25,115.65,66.93,50.58,44.93,42.74,40.24,38.68,37.01,34.05,31.54,31.37,28.18.HRMS(ESI)calcd for C 37 H 44 N4O4[M+H] + :609.3435,found:609.3445.

[0167] Example 10: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 Preparation of 1-(1-adamantylmethyl)pentanediamide

[0168] Except that 1-adamantaneamine was used instead of 1-adamantaneamine, N was prepared using the same method as in Example 2. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 1-(1-Adamantylmethyl)glutaramide. White solid, overall yield: 21.03%. 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=1.5Hz,1H),8.62(t,J=5.7Hz,1H),8.07(t,J=5.4Hz,1H),7.97(dd,J=8 .1,2.2Hz,1H),7.65(d,J=8.7Hz,2H),7.60(t,J=6.0Hz,1H),7.41(d,J=8.1Hz,1H),7.36-7.20(m,5H),7. 07(d,J=8.7Hz,2H),4.31(d,J=5.9Hz,2H),4.04(t,J=5.6Hz,2H),3.72(s,2H),3.44(q,J=5.6Hz,2H),2.7 5(d,J=6.2Hz,2H),2.11(t,J=7.4Hz,4H),1.90(s,3H),1.78-1.69(m,2H),1.68-1.52(m,6H),1.40(s,6H). 13 CNMR(100MHz,DMSO-d6)δ172.67,172.40,169.68,158.95,155.05,146.88,139.87,134.36,133.68,129.90,128.74,128.35,127. 70,127.22,124.24,115.64,66.93,50.50,44.94,42.72,40.30,38.59,37.01,35.30,35.28,34.03,28.16,22.24.HRMS(ESI)calcd for C 38 H 46 N4O4[M+H] + :623.3592,found:623.3602.

[0169] Example 11: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 Preparation of 1-(1-adamantylmethyl)succinamide

[0170] Except for using 1-adamantylmethylamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 3. 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 1-(1-Adamantylmethyl)succinamide. White solid, overall yield: 20.43%. 1H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.69(s,1H),7.98(d,J=7.9Hz,1H),7.93(t,J=5.3H z,1H),7.64(d,J=8.1Hz,3H),7.41(d,J=8.1Hz,1H),7.37-7.20(m,5H),7.05(d,J=8.5Hz, 2H),4.32(d,J=5.8Hz,2H),4.03(t,J=6.2Hz,2H),3.74(s,2H),3.21(q,J=6.3Hz,2H),2.7 4(d,J=6.1Hz,2H),2.42-2.27(m,4H),1.95-1.81(m,5H),1.68-1.51(m,6H),1.40(s,6H). 13 C NMR(100MHz,DMSO-d6)δ172.03,172.00,169.83,159.13,154.83,146.86,139.76,134.50,133.83,129.62,128.74,128.31,127.7 1,127.25,124.33,115.61,65.86,50.57,44.74,42.78,40.23,37.00,35.97,34.04,31.66,31.43,29.36,28.17.HRMS(ESI)calcd for C 38 H 46 N4O4[M+H] + :623.3592,found:623.3597.

[0171] Example 12: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 Preparation of 1-(1-adamantylmethyl)pentanediamide

[0172] Except that 1-adamantaneamine was used instead of 1-adamantaneamine, N was prepared using the same method as in Example 4. 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 1-(1-Adamantylmethyl)glutaramide. White solid, overall yield: 22.70%. 1H NMR (400MHz, DMSO-d6) δ8.75 (s, 1H), 8.63 (t, J = 5.6Hz, 1H), 7.96 (dd, J = 8.1, 2.0Hz, 1H), 7.89 (t, J = 5. 4Hz,1H),7.68-7.57(m,3H),7.40(d,J=8.1Hz,1H),7.35-7.20(m,5H),7.04(d,J=8.7Hz,2H),4.30(d, J=5.9Hz,2H),4.03(t,J=6.2Hz,2H),3.71(s,2H),3.21(dd,J=12.5,6.5Hz,2H),2.75(d,J=6.2Hz,2H) ,2.09(dd,J=16.8,7.8Hz,4H),1.93-1.82(m,5H),1.76-1.68(m,2H),1.66-1.52(m,6H),1.40(s,6H). 13 C NMR(100MHz,DMSO-d6)δ172.38,172.28,169.67,159.09,155.04,146.88,139.89,134.33,133.72,129.72,128.74,128.33,127.71,12 7.22,124.24,115.58,65.86,50.49,44.95,42.71,40.31,37.01,35.91,35.40,35.32,34.03,29.39,28.16,22.29.HRMS(ESI)calcdfor C 39 H 48 N4O4[M+H] + :637.3748,found:637.3759.

[0173] Example 13: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 Preparation of 1-[1-(1-adamantyl)ethyl]butanediamide

[0174] Except for using 1-(1-adamantyl)ethylamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 1. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 1-[1-(1-adamantyl)ethyl]butanediamide. White solid, overall yield: 20.49%. 1H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.62(t,J=5.6Hz,1H),8.11(t,J=5.4Hz,1H),7.96(dd,J=8.1, 2.0Hz,1H),7.65(d,J=8.6Hz,2H),7.42(t,J=8.4Hz,2H),7.34-7.21(m,5H),7.06(d,J=8.7Hz,2H),4 .31(d,J=5.9Hz,2H),4.03(t,J=5.7Hz,2H),3.72(s,2H),3.55-3.47(m,1H),3.44(dd,J=11.2,5.6H z,2H),2.40-2.30(m,4H),1.91(s,3H),1.68-1.52(m,7H),1.51-1.39(m,7H),0.90(d,J=6.9Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ172.35,171.09,169.66,158.95,155.07,146.90,139.88,134.35,133.68,129.93,128.72,128.34,127.71 ,127.21,124.22,115.66,66.94,52.36,44.96,42.74,38.68,38.40,37.14,36.03,31.65,31.54,28.28,14.66.HRMS(ESI)calcdfor C 38 H 46 N4O4[M+H] + :623.3592,found:623.3596.

[0175] Example 14: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 Preparation of 1-[1-(1-adamantyl)ethyl]pentanediamide

[0176] Except for using 1-(1-adamantyl)ethylamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 2. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 1-[1-(1-adamantyl)ethyl]glutaramide. White solid, overall yield: 21.12%. 1H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.63(t,J=5.4Hz,1H),8.08(t,J=5.0Hz,1H),7.97(d,J=8.0Hz,1H) ,7.65(d,J=8.4Hz,2H),7.45-7.36(m,2H),7.36-7.20(m,5H),7.07(d,J=8.4Hz,2H),4.31(d,J=5.8Hz,2H ),4.04(t,J=5.4Hz,2H),3.72(s,2H),3.52(dd,J=15.3,7.4Hz,1H),3.44(dd,J=10.2,4.8Hz,2H),2.18-2 .03(m,4H),1.91(s,3H),1.78-1.69(m,2H),1.66-1.53(m,6H),1.50-1.39(m,6H),0.90(d,J=6.8Hz,3H). 13 CNMR(100MHz,DMSO-d6)δ172.72,171.59,169.69,158.95,155.04,146.87,139.86,134.36,133.69,129.90,128.73,128.34,127.70, 127.22,124.24,115.65,66.93,52.27,44.95,42.73,38.60,38.45,37.14,35.95,35.42,35.30,28.26,22.33,14.72.HRMS(ESI)calcd for C 39 H 48 N4O4[M+H] + :637.3748,found:637.3755.

[0177] Example 15: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 Preparation of 1-[1-(1-adamantyl)ethyl]butanediamide

[0178] Except for using 1-(1-adamantyl)ethylamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 3. 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 1-[1-(1-adamantyl)ethyl]butanediamide. White solid, overall yield: 20.98%. 1H NMR(400MHz, DMSO-d6)δ8.75(d,J=2.0Hz,1H),8.64(t,J=5.8Hz,1H),7.99-7.91(m,2H),7.65(d,J=8.7Hz, 2H),7.45(d,J=9.5Hz,1H),7.40(d,J=8.1Hz,1H),7.35-7.21(m,5H),7.05(d,J=8.8Hz,2H),4.30(d,J=5.9H z,2H),4.03(t,J=6.3Hz,2H),3.71(s,2H),3.49(td,J=13.9,6.8Hz,1H),3.20(dd,J=13.3,7.3Hz,2H),2.38 -2.28(m,4H),1.91(s,3H),1.88-1.82(m,2H),1.65-1.53(m,6H),1.48-1.39(m,6H),0.89(d,J=6.9Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ171.98,171.12,169.66,159.11,155.03,146.88,139.89,134.32,133.73,129.71,128.73,128.31,127.71,1 27.21,124.22,115.60,65.86,52.34,44.96,42.72,38.39,37.14,36.01,35.96,31.76,31.59,29.37,28.27,14.67.HRMS(ESI)calcd for C 39 H 48 N4O4[M+H] + :637.3748,found:637.3756.

[0179] Example 16: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 Preparation of 1-[1-(1-adamantyl)ethyl]pentanediamide

[0180] Except for using 1-(1-adamantyl)ethylamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 4. 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 1-[1-(1-adamantyl)ethyl]butanediamide. White solid, overall yield: 23.19%. 1H NMR (400MHz, DMSO-d6) δ8.74(s,1H),8.62(s,1H),7.96(d,J=7.7Hz,1H),7.88(t,J=5.2Hz,1H),7.64 (d,J=8.5Hz,2H),7.43-7.35(m,2H),7.34-7.21(m,5H),7.04(d,J=8.5Hz,2H),4.31(d,J=5.8Hz,2H), 4.03(t,J=6.1Hz,2H),3.72(s,2H),3.55-3.46(m,1H),3.21(dd,J=12.3,6.3Hz,2H),2.14-2.02(m,4H ),1.94-1.83(m,5H),1.76-1.67(m,2H),1.67-1.53(m,6H),1.49-1.40(m,6H),0.90(d,J=6.9Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ172.30,171.52,169.67,159.10,155.02,146.87,139.88,134.34,133.73,129.72,128.73,128.33,127.71,1 27.22,124.23,115.59,65.88,52.24,44.94,42.73,38.46,37.15,35.96,35.92,35.43,29.40,28.26,22.37,14.74.HRMS(ESI)calcd for C 40 H 50 N4O4[M+H] + :651.3905,found:651.3900.

[0181] Example 17: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 Preparation of 3,5-dimethyladamantane-1-yl]succinamide

[0182] Except for using 3,5-dimethyl-1-adamantaneamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 1. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 -[3,5-Dimethyladamantane-1-yl]succinamide. White solid, overall yield: 19.99%. 1H NMR (400MHz, DMSO-d6) δ8.76(d,J=1.4Hz,1H),8.64(t,J=5.8Hz,1H),8.10(t,J=5.5Hz,1H),7.96(dd,J= 8.1,2.3Hz,1H),7.65(d,J=8.7Hz,2H),7.41(d,J=8.1Hz,1H),7.35-7.21(m,6H),7.07(d,J=8.8Hz,2H),4 .32(d,J=5.9Hz,2H),4.04(t,J=5.6Hz,2H),3.74(s,2H),3.45(dd,J=11.1,5.6Hz,2H),2.35-2.23(m,4H ),2.07-1.99(m,1H),1.76-1.68(m,2H),1.61-1.49(m,4H),1.31-1.18(m,4H),1.06(s,2H),0.78(s,6H). 13 CNMR(100MHz,DMSO-d6)δ172.42,171.15,169.69,158.96,155.05,146.90,139.87,134.36,133.70,129.92,128.73,128.35,127.71, 127.21,124.24,115.65,66.99,52.59,50.73,47.53,44.97,42.80,42.76,38.71,32.26,32.11,31.45,30.56,29.98.HRMS(ESI)calcd for C 38 H 46 N4O4[M+H] + :623.3592,found:623.3600.

[0183] Example 18: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 Preparation of 3,5-dimethyladamantane-1-yl]pentanediamide

[0184] Except for using 3,5-dimethyl-1-adamantaneamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 2. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 3,5-Dimethyladamantane-1-yl]glutaramide. White solid, overall yield: 21.18%. 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=1.9Hz,1H),8.63(t,J=5.7Hz,1H),8.07(t,J=5.4Hz,1H),7.96 (dd,J=8.1,2.3Hz,1H),7.65(d,J=8.7Hz,2H),7.41(d,J=8.1Hz,1H),7.35-7.20(m,6H),7.07(d, J=8.7Hz,2H),4.32(d,J=5.9Hz,2H),4.05(t,J=5.6Hz,2H),3.73(s,2H),3.47-3.42(m,2H),2.13 -1.98(m,5H),1.76-1.64(m,4H),1.60-1.51(m,4H),1.32-1.18(m,4H),1.07(s,2H),0.79(s,6H). 13 C NMR (100MHz, DMSO-d6) δ172.75,171.72,169.70,158.96,155.05,146.88,139.86,134.35,133.70,129.90,128.73,128.35,127.70,127. 21,124.23,115.66,66.94,52.59,50.76,47.53,44.97,42.81,42.75,38.61,36.01,35.14,32.26,30.57,29.98,22.14.HRMS(ESI)calcd for C 39 H 48 N4O4[M+Na] + :659.3568,found:659.3586.

[0185] Example 19: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 Preparation of 3,5-dimethyladamantane-1-yl]succinamide

[0186] Except for using 3,5-dimethyl-1-adamantaneamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 3. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 3,5-Dimethyladamantane-1-yl]glutaramide. White solid, overall yield: 20.43%. 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=2.1Hz,1H),8.63(t,J=5.8Hz,1H),7.96(dd,J=8.1,2.4Hz,1H),7.89(t, J=5.5Hz,1H),7.64(d,J=8.7Hz,2H),7.41(d,J=8.1Hz,1H),7.34-7.21(m,6H),7.05(d,J=8.7Hz,2H),4.32( d,J=5.9Hz,2H),4.04(t,J=6.3Hz,2H),3.73(s,2H),3.21(q,J=6.5Hz,2H),2.27(s,4H),2.06-1.98(m,1H) ,1.87(p,J=6.5Hz,2H),1.77-1.65(m,2H),1.60-1.49(m,4H),1.33-1.16(m,4H),1.06(s,2H),0.78(s,6H). 13 C NMR (100MHz, DMSO-d6) δ172.07,171.19,169.68,159.11,155.02,146.88,139.88,134.32,133.74,129.71,128.73,128.31,127.71,127. 21,124.22,115.60,65.88,52.58,50.74,47.53,44.98,42.80,42.74,35.95,32.25,32.18,31.58,30.56,29.98,29.43.HRMS(ESI)calcd for C 39 H 48 N4O4[M+H] + :637.3748,found:637.3749.

[0187] Example 20: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 Preparation of 3,5-dimethyladamantane-1-yl]pentanediamide

[0188] Except that 3,5-dimethyl-1-adamantaneamine was used instead of 1-adamantaneamine, N was prepared using the same method as in Example 4. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 3,5-Dimethyladamantane-1-yl]glutaramide. White solid, overall yield: 22.85%. 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=2.2Hz,1H),8.63(t,J=5.9Hz,1H),7.96(dd,J=8.1,2.4Hz,1H),7.88(t,J=5 .5Hz,1H),7.65(d,J=8.8Hz,2H),7.40(d,J=8.1Hz,1H),7.35-7.20(m,6H),7.04(d,J=8.8Hz,2H),4.31(d,J=5 .9Hz,2H),4.04(t,J=6.3Hz,2H),3.72(s,2H),3.22(dd,J=12.5,6.6Hz,2H),2.09-1.96(m,5H),1.87(p,J=6.5 Hz,2H),1.75-1.72(m,2H),1.71-1.63(m,2H),1.59-1.51(m,4H),1.31-1.19(m,4H),1.07(s,2H),0.79(s,6H). 13 C NMR (100MHz, DMSO-d6) δ172.34,171.69,169.68,159.10,155.03,146.88,139.88,134.32,133.73,129.73,128.73,128.33,127.71,127.21, 124.22,115.59,65.89,52.57,50.76,47.54,44.97,42.82,42.74,36.04,35.92,35.28,32.27,30.58,29.98,29.40,22.20.HRMS(ESI)calcd for C 40 H 50 N4O4[M+H] + :651.3905,found:651.3908.

[0189] Example 21: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 Preparation of cycloheptylbutyramide

[0190] Except for using cycloheptaneamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 1. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 -Cycloheptaylbutyramide. White solid, overall yield: 20.52%. 1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.68-8.58(m,1H),8.16-8.07(m,1H),7.96(d,J =7.2Hz,1H),7.73(d,J=7.4Hz,1H),7.65(d,J=8.2Hz,2H),7.41(d,J=7.9Hz,1H),7.3 5-7.20(m,5H),7.06(d,J=8.2Hz,2H),4.32(d,J=5.4Hz,2H),4.03(s,2H),3.73(s,3H ),3.48-3.43(m,2H),2.32(dd,J=12.5,5.0Hz,4H),1.72(s,2H),1.60-1.31(m,10H). 13 CNMR(100MHz,DMSO-d6)δ172.35,170.44,169.71,158.95,155.06,146.89,139.87,134.36,133.70,129.91,128.73,12 8.34,127.71,127.21,124.24,115.64,66.95,49.99,44.97,42.75,38.70,34.82,31.40,28.25,24.21.HRMS(ESI)calcd for C 33 H 40 N4O4[M+H] + :557.3122,found:557.3134.

[0191] Example 22: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 Preparation of cycloheptylglutaramide

[0192] Except for using cycloheptaneamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 2. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 -Cycloheptaylglutaramide. White solid, overall yield: 21.49%. 1H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.63(t,J=5.7Hz,1H),8.07(t,J=5.4Hz,1H),7.97(dd ,J=8.1,2.3Hz,1H),7.66(t,J=8.3Hz,3H),7.41(d,J=8.1Hz,1H),7.36-7.20(m,5H),7.07(d ,J=8.7Hz,2H),4.31(d,J=5.9Hz,2H),4.04(t,J=5.7Hz,2H),3.71(d,J=12.3Hz,3H),3.44(d d,J=11.2,5.6Hz,2H),2.06(dt,J=24.8,7.4Hz,4H),1.78-1.64(m,4H),1.61-1.31(m,10H). 13 C NMR(100MHz,DMSO-d6)δ172.68,170.85,169.69,158.95,155.06,146.89,139.87,134.35,133.68,129.90,128.73,128.35,12 7.70,127.22,124.24,115.65,66.93,49.89,44.96,42.73,38.59,35.31,35.15,34.88,28.24,24.22,22.07.HRMS(ESI)calcd for C 34 H 42 N4O4[M+H] + :571.3279,found:571.3282.

[0193] Example 23: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 Preparation of cycloheptylbutyramide

[0194] Except for using cycloheptaneamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 3. 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 -Cycloheptaylbutyramide. White solid, overall yield: 22.17%. 1H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.61(t,J=5.8Hz,1H),7.96(dd,J=8.1,2.3Hz,1H),7.90(t,J=5 .5Hz,1H),7.70(d,J=7.8Hz,1H),7.64(d,J=8.7Hz,2H),7.40(d,J=8.1Hz,1H),7.34-7.21(m,5H),7.0 4(d,J=8.8Hz,2H),4.31(d,J=5.9Hz,2H),4.03(t,J=6.3Hz,2H),3.73-3.67(m,3H),3.20(dd,J=12.7, 6.7Hz,2H),2.28(s,4H),1.89-1.82(m,2H),1.75-1.67(m,2H),1.59-1.44(m,6H),1.39-1.32(m,4H). 13 C NMR (100MHz, DMSO-d6) δ171.98,170.45,169.69,159.10,155.01,146.87,139.86,134.34,133.74,129.70,128.73,128.31,12 7.70,127.22,124.23,115.61,65.85,49.96,44.95,42.73,35.93,34.82,31.49,31.45,29.38,28.25,24.20.HRMS(ESI)calcd for C 34 H 42 N4O4[M+H] + :571.3279,found:571.3284.

[0195] Example 24: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 Preparation of cycloheptylglutaramide

[0196] Except for using cycloheptaneamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 4. 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 -Cycloheptaylglutaramide. White solid, overall yield: 21.62%. 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=2.1Hz,1H),8.63(t,J=5.9Hz,1H),7.96(dd,J=8.1,2.4Hz,1H),7.90(t ,J=5.5Hz,1H),7.69(d,J=7.9Hz,1H),7.65(d,J=8.8Hz,2H),7.41(d,J=8.1Hz,1H),7.35-7.21(m,5H),7. 05(d,J=8.8Hz,2H),4.32(d,J=5.9Hz,2H),4.04(t,J=6.3Hz,2H),3.76-3.66(m,3H),3.22(dd,J=12.5,6. 6Hz,2H),2.10-2.00(m,4H),1.92-1.84(m,2H),1.76-1.67(m,4H),1.60-1.42(m,6H),1.41-1.33(m,4H). 13 C NMR (100MHz, DMSO-d6) δ172.30,170.84,169.69,159.09,155.02,146.87,139.88,134.33,133.74,129.72,128.73,128.33,127.7 0,127.22,124.24,115.59,65.87,49.89,44.95,42.73,35.91,35.33,35.28,34.89,29.38,28.24,24.22,22.13.HRMS(ESI)calcd forC 35 H 44 N4O4[M+H] + :585.3435,found:585.3441.

[0197] Example 25: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 Preparation of 2-(1-cyclohexen-1-yl)ethyl]butanediamide

[0198] Except for using 2-(1-cyclohexen-1-yl)ethylamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 1. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 2-(1-Cyclohexen-1-yl)ethyl]butanediamide. White solid, overall yield: 19.78%. 1H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.63(t,J=5.7Hz,1H),8.12(t,J=5.3Hz,1H),7.97(dd,J=8.1,1.9Hz ,1H),7.74(t,J=5.4Hz,1H),7.65(d,J=8.6Hz,2H),7.40(d,J=8.1Hz,1H),7.34-7.21(m,5H),7.06(d,J=8 .6Hz,2H),5.36(s,1H),4.31(d,J=5.9Hz,2H),4.03(t,J=5.6Hz,2H),3.72(s,2H),3.46-3.44(m,2H),3.0 8(dd,J=13.6,6.7Hz,2H),2.37-2.25(m,4H),1.99(t,J=7.2Hz,2H),1.95-1.82(m,4H),1.57-1.43(m,4H). 13 C NMR(100MHz,DMSO-d6)δ172.29,171.55,169.71,158.94,155.04,146.88,139.85,135.43,134.37,133.69,129.89,128.74,128.35,127.7 0,127.23,124.25,122.25,115.66,66.93,44.94,42.72,38.68,37.99,37.64,31.32,31.30,28.16,25.15,22.89,22.41.HRMS(ESI)calcd for C 34 H 40 N4O4[M+H] + :569.3122,found:569.3122.

[0199] Example 26: N 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 5 Preparation of 2-(1-cyclohexen-1-yl)ethyl]pentanediamide

[0200] Except for using 2-(1-cyclohexen-1-yl)ethylamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 2. 1 -{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-N 4 2-(1-Cyclohexen-1-yl)ethyl]butanediamide. White solid, overall yield: 20.14%. 1H NMR (400MHz, DMSO-d6) δ8.76(s,1H),8.65(t,J=5.6Hz,1H),8.07(t,J=5.3Hz,1H),7.97(dd,J=8.1 ,1.8Hz,1H),7.71-7.61(m,3H),7.41(d,J=8.1Hz,1H),7.34-7.21(m,5H),7.07(d,J=8.6Hz,2H),5 .36(s,1H),4.32(d,J=5.9Hz,2H),4.04(t,J=5.6Hz,2H),3.74(s,2H),3.47-3.45(m,2H),3.10(dd ,J=13.4,6.8Hz,2H),2.14-1.96(m,6H),1.96-1.81(m,4H),1.77-1.68(m,2H),1.58-1.39(m,4H). 13 C NMR(100MHz,DMSO-d6)δ172.72,172.03,169.75,158.96,155.00,146.88,139.83,135.43,134.40,133.72,129.88,128.73,128.34,127.70,1 27.22,124.26,122.28,115.65,66.92,44.91,42.76,38.61,38.03,37.50,35.36,35.18,28.12,25.15,22.90,22.41,22.10.HRMS(ESI)calcd for C 35 H 42 N4O4[M+H] + :583.3279,found:583.3278.

[0201] Example 27: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 Preparation of 2-(1-cyclohexen-1-yl)ethyl]butanediamide

[0202] Except for replacing 1-adamantaneamine with 2-(1-cyclohexen-1-yl)ethylamine, N was prepared using the same method as in Example 3. 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 4 2-(1-Cyclohexen-1-yl)ethyl]butanediamide. White solid, overall yield: 20.87%. 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=2.1Hz,1H),8.62(t,J=5.9Hz,1H),7.96(dd,J=8.1,2.4Hz,1H),7.91(t,J= 5.5Hz,1H),7.73(t,J=5.6Hz,1H),7.64(d,J=8.7Hz,2H),7.40(d,J=8.1Hz,1H),7.34-7.21(m,5H),7.04(d,J =8.8Hz,2H),5.36(s,1H),4.31(d,J=5.9Hz,2H),4.03(t,J=6.3Hz,2H),3.72(s,2H),3.21(dd,J=13.0,7.0Hz ,2H),3.08(dd,J=14.0,6.5Hz,2H),2.29(s,4H),1.99(t,J=7.3Hz,2H),1.94-1.82(m,6H),1.57-1.43(m,4H). 13 C NMR(100MHz,DMSO-d6)δ171.90,171.55,169.68,159.10,155.02,146.88,139.88,135.45,134.33,133.73,129.71,128.73,128.31,127.70,1 27.22,124.22,122.22,115.59,65.85,44.96,42.73,38.01,37.65,35.93,31.42,31.38,29.38,28.17,25.14,22.89,22.41.HRMS(ESI)calcd for C 35 H 42 N4O4[M+H] + :583.3279,found:583.3279.

[0203] Example 28: N 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 Preparation of 2-(1-cyclohexen-1-yl)ethyl]pentanediamide

[0204] Except for using 2-(1-cyclohexen-1-yl)ethylamine instead of 1-adamantaneamine, N was prepared using the same method as in Example 4. 1 -{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-N 5 2-(1-Cyclohexen-1-yl)ethyl]glutaramide. White solid, overall yield: 22.37%.1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.63(t,J=5.5Hz,1H),7.96(dd,J=8.1,1.9Hz,1H),7.89(t,J=5.4Hz, 1H),7.69(t,J=5.5Hz,1H),7.65(d,J=8.6Hz,2H),7.41(d,J=8.1Hz,1H),7.34-7.21(m,5H),7.05(d,J=8.7H z,2H),5.36(s,1H),4.32(d,J=5.8Hz,2H),4.04(t,J=6.2Hz,2H),3.73(s,2H),3.22(dd,J=12.5,6.5Hz,2H) ,3.10(dd,J=13.4,6.8Hz,2H),2.11-1.97(m,6H),1.95-1.83(m,6H),1.76-1.67(m,2H),1.57-1.43(m,4H). 13 C NMR(100MHz,DMSO-d6)δ172.29,171.90,169.69,159.09,155.02,146.89 ,139.88,135.45,134.34,133.73,129.73,128.73,128.33,127.70,127. 22,124.22,122.26,115.58,65.86,44.94,42.73,38.06,37.48,35.90,3 5.37,35.30,29.39,28.12,25.15,22.89,22.41,22.13.HRMS(ESI)calcd for C 36 H 44 N4O4[M+H] + :597.3435,found:597.3441.

[0205] Example 29: Preparation of N-{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-4-(octahydro-2H-isoindol-2-yl)-4-oxobutyramide

[0206] N-{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-4-(octahydro-2H-isoindole-2-yl)-4-oxobutyramide was prepared using the same method as in Example 1, except that octahydro-2H-isoindole was used instead of 1-adamantaneamine. White solid, overall yield: 20.29%. 1H NMR (400MHz, DMSO) δ8.75(d,J=2.2Hz,1H),8.62(t,J=5.9Hz,1H),8.11(t,J=5.5Hz,1H),7.97(dd,J=8.1 ,2.4Hz,1H),7.65(d,J=8.8Hz,2H),7.40(d,J=8.1Hz,1H),7.34-7.21(m,5H),7.07(d,J=8.8Hz,2H),4.3 1(d,J=5.9Hz,2H),4.03(t,J=5.7Hz,2H),3.72(s,2H),3.47-3.39(m,3H),3.30-3.21(m,2H),3.19-3.13 (m,1H),2.48-2.32(m,4H),2.25-2.16(m,1H),2.12-2.04(m,1H),1.57-1.42(m,4H),1.37-1.27(m,4H). 13 CNMR(101MHz,DMSO)δ172.37,170.66,169.66,158.96,155.07,146.89,139.89,134.34,133.67,129.90,128.73,128.35,127.71,127.2 2,124.23,115.65,66.95,49.93,49.79,44.96,42.72,38.70,37.37,35.84,30.64,29.57,25.88,25.71,22.97,22.63.HRMS(ESI)calcd for C 34 H 40 N4O4[M+H] + :569.3122,found:569.3127.

[0207] Example 30: Preparation of N-{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-5-(octahydro-2H-isoindol-2-yl)-5-oxopentanamide

[0208] N-{2-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}ethyl}-5-(octahydro-2H-isoindole-2-yl)-5-oxopentanamide was prepared using the same method as in Example 2, except that octahydro-2H-isoindole-2-yl)-5-oxopentanamide was used. White solid, overall yield: 21.52%. 1H NMR (400MHz, DMSO) δ8.75(d,J=2.0Hz,1H),8.64(t,J=5.8Hz,1H),8.10(t,J=5.5Hz,1H),7.97(dd,J=8.1,2 .4Hz,1H),7.65(d,J=8.7Hz,2H),7.41(d,J=8.1Hz,1H),7.37-7.20(m,5H),7.06(d,J=8.8Hz,2H),4.32(d, J=5.9Hz,2H),4.05(t,J=5.6Hz,2H),3.73(s,2H),3.45(dd,J=11.1,5.5Hz,2H),3.34-3.20(m,2H),3.19-3 .12(m,2H),2.26-2.10(m,5H),2.09-2.01(m,1H),1.80-1.69(m,2H),1.52-1.36(m,4H),1.35-1.22(m,4H). 13 C NMR (101MHz, DMSO) δ172.75,171.11,169.68,158.98,155.07,146.88,139.88,134.33,133.67,129.90,128.73,128.34,127.71,127.21,1 24.23,115.61,67.00,50.02,49.63,44.97,42.74,38.63,37.35,35.77,35.10,33.26,25.85,25.67,22.89,22.66,21.11.HRMS(ESI)calcd for C 35 H 42 N4O4[M+H] + :583.3279,found:583.3284.

[0209] Example 31: Preparation of N-{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-4-(octahydro-2H-isoindol-2-yl)-4-oxobutyramide

[0210] N-{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-4-(octahydro-2H-isoindole-2-yl)-4-oxobutyramide was prepared using the same method as in Example 3, except that octahydro-2H-isoindole was used instead of 1-adamantaneamine. White solid, overall yield: 20.14%. 1H NMR (400MHz, DMSO) δ8.75 (d, J=1.8Hz, 1H), 8.64 (t, J=5.8Hz, 1H), 7.99-7.90 (m, 2H), 7.64 (d, J= 8.7Hz,2H),7.41(d,J=8.1Hz,1H),7.36-7.20(m,5H),7.05(d,J=8.7Hz,2H),4.32(d,J=5.9Hz,2 H),4.04(t,J=6.3Hz,2H),3.73(s,2H),3.41-3.39(m,1H),3.29-3.14(m,5H),2.49-2.29(m,4H) ,2.24-2.16(m,1H),2.12-2.03(m,1H),1.92-1.83(m,2H),1.57-1.39(m,4H),1.38-1.20(m,4H). 13 C NMR (101MHz, DMSO) δ172.06,170.74,169.70,159.12,155.01,146.86,139.88,134.32,133.74,129.69,128.73,128.30,127.70,127.21,124 .23,115.61,65.86,49.94,49.79,44.97,42.75,37.37,35.96,35.83,30.76,29.64,29.39,25.88,25.71,22.97,22.62.HRMS(ESI)calcdfor C 35 H 42 N4O4[M+H] + :583.3279,found:583.3284.

[0211] Example 32: Preparation of N-{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-5-(octahydro-2H-isoindol-2-yl)-5-oxopentanamide

[0212] N-{3-{4-[6-(2-benzylamino-2-oxoethyl)pyridin-3-yl]phenoxy}propyl}-5-(octahydro-2H-isoindole-2-yl)-5-oxopentanamide was prepared using the same method as in Example 4, except that octahydro-2H-isoindole was used instead of 1-adamantaneamine. White solid, overall yield: 22.82%. 1H NMR (400MHz, DMSO) δ8.78-8.68(m,2H),8.04-7.91(m,2H),7.64(d,J=8.8Hz,2H),7. 41(d,J=8.1Hz,1H),7.35-7.20(m,5H),7.04(d,J=8.8Hz,2H),4.31(d,J=5.9Hz,2H), 4.04(t,J=6.3Hz,2H),3.73(s,2H),3.38-3.31(m,1H),3.29-3.11(m,5H),2.26-2.04 (m,6H),1.93-1.84(m,2H),1.79-1.68(m,2H),1.55-1.37(m,4H),1.37-1.24(m,4H). 13 CNMR(101MHz,DMSO)δ172.45,171.18,169.72,159.10,155.04,146.85,139.89,134.32,133.71,129.72,128.71,128.31,127.70,127.19,124. 22,115.58,65.93,50.06,49.65,44.95,42.71,37.36,35.89,35.77,35.20,33.37,29.40,25.86,25.69,22.90,22.65,21.16.HRMS(ESI)calcd for C 36 H 44 N4O4[M+H] + :597.3435,found:597.3445.

[0213] Example 33: In vitro antiproliferative activity test of the compounds of the present invention

[0214] The methods and results for in vitro antiproliferative activity testing are as follows:

[0215] The specific steps are as follows:

[0216] (1) Take cells in the logarithmic growth phase at 3-5 × 10⁻⁵ times the normal concentration. 3 / well density seeded into 96-well plates.

[0217] (2) After incubating at 37°C in a CO2 incubator for 12 hours, the compound was diluted with serum-free medium to a concentration of 10 μg / mL and added to a 96-well plate for further incubation for 72 hours.

[0218] (3) Discard the supernatant, add 20 μL of freshly prepared 5 mg / mL MTT to each well, and incubate at 37°C for 4 hours. Discard the supernatant, add 150 μL of DMSO to each well, shake for 15 minutes to fully dissolve the formazan, and measure the absorbance (OD) at 492 nm.

[0219] Among them, colchicine, as reported in the literature, was a positive experimental group.

[0220] Cell lines: Human breast cancer cell line (MCF-7 cell line), human lung cancer cell line (A549 cell line), human colorectal cancer cell line (HCT-116 cell line).

[0221] Duration of action: 72 hours

[0222] Inhibition rate calculation formula:

[0223]

[0224] The inhibition rates (10 μg / mL) of each compound on the growth of the three types of tumor cells are shown in Table 1.

[0225] Table 1

[0226]

[0227]

[0228] As shown in Table 1, all compounds exhibited inhibition rates exceeding 70% against the three types of tumor cells at a concentration of 10.0 μg / mL. Among them, compound 6 showed the highest inhibition rate, comparable to that of the positive control colchicine against all three tested tumor cells.

[0229] The compounds of this invention were then used to further test their inhibitory effect on microtubule polymerization, their degradation effect on microtubules, and their antitumor activity in animals. Compound 6 was used as an example in the test.

[0230] Example 34: Microtubule polymerization inhibitory activity test of the compounds of the present invention

[0231] Experimental methods: Compound 6, which exhibited good in vitro anti-proliferative activity, was selected for microtubule polymerization inhibition activity testing. A commercially available porcine microtubule polymerization kit (Cytoskeleton, Cat.#BK011P) was used, and the kit was reconstructed according to its instruction manual.

[0232] The specific steps are as follows:

[0233] (1) Set the microplate reader to read once per minute for a total of 90 minutes. Excitation wavelength 365nm, emission wavelength 450nm.

[0234] (2) Place the 96-well plate in an ELISA reader and preheat it at 37°C for 10 minutes.

[0235] (3) Take out Buffer1, GTP stock, Tubulin Glycerol Buffer and Tubulin, thaw them quickly at room temperature, place them on ice, and prepare them into a mixture according to the proportions indicated in the operation manual.

[0236] (4) The above mixture and compound 6 were added to a 96-well plate. The microtubule stabilizer paclitaxel (PTX) and the microtubule polymerization inhibitor colchicine were used as controls. The plate was placed in an ELISA reader to monitor the changes in microtubules within 90 minutes, the absorbance (OD) was recorded, and the inhibition rate was calculated.

[0237] Inhibition rate calculation formula:

[0238]

[0239] The experimental results are shown in Figure 1: 10 μM compound 6 inhibited 76% of tubulin polymerization at 90 min, while 5 μM colchicine inhibited 89% of tubulin polymerization under the same conditions.

[0240] The experimental results above show that compound 6, similar to the positive control colchicine, has a mechanism of action that inhibits microtubule polymerization.

[0241] Example 35: Microtubule-degrading activity test of the compounds of the present invention

[0242] Experimental methods: Compound 6, which showed good in vitro antiproliferative activity, was selected and microtubule degradation was tested using Western spectroscopy.

[0243] The specific steps are as follows:

[0244] (1) Select MCF-7 tumor cells in the logarithmic growth phase, digest them with trypsin, and then prepare them with complete culture medium to a concentration of 5×10⁻⁶. 5 Two mL of cell suspension per well was seeded into each well of a 6-well plate.

[0245] (2) After culturing overnight, compound 6 with different concentration gradients was added, and the cells were collected after 24 hours.

[0246] (3) After extracting total protein, Western blot analysis was performed (GAPDH was used as the internal reference protein) to investigate the effect of compound 6 on the expression levels of α-tubulin and β-tubulin. The tubulin degradation rate was calculated using the following formula.

[0247] Microtubule degradation rate = [(protein content in blank control group - protein content in drug-treated group) / (protein content in blank control group)] × 100%

[0248] The experimental results are shown in Figure 2 and Table 2.

[0249] Table 2

[0250]

[0251] The experimental results above show that compound 6 achieved degradation rates of 52% and 44% for α-tubulin and β-tubulin at 5 μM, respectively, demonstrating that the compound has a mechanism for degrading intracellular tubulin levels.

[0252] Example 36: Animal in vivo antitumor activity test of the compounds of the present invention

[0253] Compound 6, which showed good in vitro antiproliferative activity, was selected for in vivo antitumor activity testing in animals. The model used was a mouse breast cancer (4T1 cell line) allogeneic transplantation model, and the positive control drug was paclitaxel, a commonly used clinical antitumor drug.

[0254] Experimental methods: Female Kunming mice weighing 18-22 grams and well-developed 4T1 tumor cells aged 7-11 days were selected. The tumor tissue was prepared into a cell suspension and inoculated subcutaneously into the right axilla of the mice, at a dose of approximately 1.0–2.0 × 10⁻⁶ cells / mL. 6 Cells / animal, randomly divided into cages 24 hours after inoculation, and administered the drug via tail vein injection every two days for 14 consecutive days. Animals were sacrificed 24 hours after drug withdrawal, and their body weight and tumor weight were measured. The average tumor weight of each group was calculated, and the tumor inhibition rate was calculated using the following formula and a t-test was performed.

[0255] Tumor inhibition rate = [(mean tumor weight in the blank control group - mean tumor weight in the treatment group) / (mean tumor weight in the blank control group)] × 100%

[0256] The experimental results are shown in Table 3.

[0257] Table 3

[0258]

[0259] The experimental results above show that compound 6 achieved a tumor inhibition rate of 70.5%, comparable to the positive control paclitaxel. Mouse weight data indicate that the mice in the positive control paclitaxel group gained weight slowly, while the mice in the compound 6 group maintained weight gain throughout the experiment, reaching a weight comparable to the blank control group at the end of the experiment. This suggests that compound 6 has low toxicity to mice and demonstrates good safety.

Claims

1. An amide compound, characterized in that, The compound is a compound represented by the general formula H or a pharmaceutically acceptable salt, solvent compound or hydrate thereof; In the general formula H, n1 and n2 can be the same or different and are each independently selected from integers between 1 and 5, and X is selected from...

2. The compound according to claim 1, characterized in that, The compound is a compound represented by general formula M or a pharmaceutically acceptable salt, racemate, solvent compound or hydrate thereof; In the general formula H, n1 and n2 can be the same or different and are each independently selected from integers between 1 and 3, and X is selected from...

3. The compound according to claim 1 or 2, characterized in that, The salt is a salt formed by the compound represented by general formula H and an acid or base. The acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, and malic acid. The base is selected from sodium hydroxide, sodium carbonate, and potassium hydroxide. The hydrate of the compound represented by general formula H has any real number of water molecules of crystallization from 0 to 16.

4. A method for preparing an amide compound as described in any one of claims 1 to 3, characterized in that, Using 2-fluoro-5-bromopyridine as a starting material, amide compounds were obtained through substitution, alcoholysis, aminolysis, Suzuki coupling, alkylation, deprotection, acylation, and condensation reactions. The reaction formulas are as follows:

5. The preparation method according to claim 4, characterized in that: (1) 2-Fluoro-5-bromopyridine I was dissolved in anhydrous acetonitrile in anhydrous tetrahydrofuran, and sodium bis(trimethylsilyl)amino was added to give compound II by nucleophilic substitution reaction. (2) Compound II was mixed with concentrated sulfuric acid and then dissolved in methanol to undergo alcoholysis to give compound III; (3) Compound III was mixed with benzylamine and lanthanum trifluoromethanesulfonate, and an ester aminolysis reaction was carried out to obtain compound IV; (4) Compound IV and 4-hydroxyphenylboronic acid pinacol ester were dissolved in toluene and water, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and potassium carbonate were added to give compound V by a Suzuki coupling reaction. (5) Compound V and tert-butoxycarbonylamino-substituted alkyl bromide compounds were dissolved in N,N-dimethylformamide, potassium carbonate was added, and alkylation reaction was carried out to obtain compound VI; (6) Compound VI was dissolved in dichloromethane, and a hydrogen chloride-dioxane solution was added to remove the tert-butoxycarbonyl group to obtain compound VII; (7) Compound VII and a dicarboxylic acid compound were dissolved in N,N-dimethylformamide, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and diisopropylethylamine were added to undergo a condensation reaction to obtain compound VIII; (8) Compound VIII and an amine or alcohol compound containing a hydrophobic group are dissolved in N,N-dimethylformamide, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and diisopropylethylamine are added to undergo a condensation reaction to obtain amide compound H.

6. A pharmaceutical composition, characterized in that: The composition comprises a compound of general formula H as described in any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvent compound, or hydrate thereof; and the content thereof is 0.01% to 99% of the composition by mass.

7. The use of the compound of claim 1 or the composition of claim 6, characterized in that: The use of the compound of general formula H as described in claim 1 or a pharmaceutically acceptable salt, solvent compound or hydrate thereof, or the composition of claim 6 in the preparation of an antitumor drug.

8. The application according to claim 7, characterized in that, The tumor in question is a human breast cancer, lung cancer, or colorectal cancer tumor.

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