CN115703737A - Hydroxypyridones compounds and application thereof as antibiotic sensitizer for overcoming drug resistance of bacterial biofilm - Google Patents

Hydroxypyridones compounds and application thereof as antibiotic sensitizer for overcoming drug resistance of bacterial biofilm Download PDF

Info

Publication number
CN115703737A
CN115703737A CN202110901353.9A CN202110901353A CN115703737A CN 115703737 A CN115703737 A CN 115703737A CN 202110901353 A CN202110901353 A CN 202110901353A CN 115703737 A CN115703737 A CN 115703737A
Authority
CN
China
Prior art keywords
compound
reaction
solvent
chloride
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202110901353.9A
Other languages
Chinese (zh)
Inventor
陈卫民
林静
刘君
侯劲松
孟影
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jinan University
Original Assignee
Jinan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jinan University filed Critical Jinan University
Priority to CN202110901353.9A priority Critical patent/CN115703737A/en
Publication of CN115703737A publication Critical patent/CN115703737A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention belongs to the field of medicines, and discloses a hydroxypyridones compound and application thereof as an antibiotic sensitizer for overcoming drug resistance of a bacterial biofilm. The hydroxypyridone structural derivative is shown as a formula I, the hydroxypyridone is used as a mother nucleus, hydrophobic carbon chains are introduced into N-1, C-2 and C-6 positions, aromatic rings are substituted at different positions, and a heterocyclic structure containing sulfydryl is designed and synthesized to obtain a series of hydroxypyridone compounds, and the obtained compounds mostly have excellent antibacterial biofilm activity. After the antibiotic is combined with common antibiotics for clinically treating pseudomonas aeruginosa, the sensitivity of the antibiotics to drug-resistant bacteria is enhanced, and the antibacterial ability of the antibiotics to different clinical drug-resistant strains is improved.
Figure DDA0003199887650000011

Description

Hydroxypyridones compounds and application thereof as antibiotic sensitizer for overcoming drug resistance of bacterial biofilm
Technical Field
The invention belongs to the field of medicines, and particularly relates to hydroxypyridones compounds, a preparation method thereof and application thereof as a sensitizer of antibiotics for overcoming drug resistance of bacterial biofilms.
Background
The number of deaths worldwide due to bacterial infections is about 1600 million each year, and more than 70% of these refractory chronic infections are associated with resistance caused by the formation of biofilms by bacteria (biotechnol. Adv.,2013, 31. The biological membrane is a membrane-like structure formed by adhering a polymeric matrix secreted by microorganisms to the outside of a medium and used for wrapping the microorganisms in the medium. When bacteria form a biological membrane, the bacteria in the membrane are not easy to be eliminated by a host immune system due to the shielding effect of the biological membrane, so that the bacteriostatic efficacy of antibiotics is reduced, and the tolerance of antibacterial drugs is obviously improved. Therefore, the antibacterial agent can inhibit the formation of bacterial biofilms, reduce the drug resistance of bacteria, improve the bacteriostatic efficacy of antibiotics, and is expected to relieve the problems of drug resistance of bacteria and chronic infection which is difficult to heal.
Bacterial biofilm formation is regulated mainly by three major systems, the bacterial Quorum Sensing (QS), the GacS signal transduction system, and the 3',5' -cyclic diguanosine (c-di-GMP) regulatory system (BioMed res. Int, 2015, 1. The bacterial quorum sensing system is a communication mechanism of bacteria interaction depending on signal molecules, and mainly comprises three systems of las, rhl and PQS which are mutually related, wherein the las and the rhl system use N-Acyl Homoserine Lactones (AHLs) as the signal molecules, and the PQS system uses 2-heptyl-3-hydroxy-4 (1H) -quinolone (PQS) as the signal molecules. The three systems are combined with corresponding transcription factors (lasR, rhlR and pqsR) through corresponding signal molecules to form a compound to regulate the expression of target genes, so that the expression levels of a series of genes are changed, and the regulation of the behaviors of bacterial groups, such as the secretion of virulence factors, the regulation of the movement capacity of bacteria, the formation of biofilms and the like, is realized. As the research on bacterial quorum sensing systems is the most complete, the research and development of the biofilm inhibitor based on a bacterial biofilm formation regulation system are mainly focused on the bacterial quorum sensing systems (SAJBiotechnol., 2014,1 (1): 1-9), and the strategies of competitively inhibiting the activation of corresponding transcription factors (lasR, rhlR and pqsR) by using signal molecules AHLs and PQS analogues, hydrolyzing the signal molecules by using signal molecule degrading enzymes and the like are included. Unfortunately, no bacterial quorum sensing inhibitors are currently successfully used in the clinic, and therefore, the development of novel antibiotic sensitizers against bacterial biofilm resistance is necessary and clinically significant.
Disclosure of Invention
In order to overcome the disadvantages and shortcomings of the prior art, the primary object of the present invention is to provide a hydroxypyridone compound, which overcomes the resistance of bacteria to antibiotics by inhibiting the formation of bacterial biofilms, and has the potential to be used as a novel antibacterial agent.
The invention also aims to provide a preparation method of the hydroxypyridones compound.
The invention further aims to provide the application of the hydroxypyridones compound as an antibiotic sensitizer for overcoming the drug resistance of bacterial biofilms.
The purpose of the invention is realized by the following scheme:
a class of hydroxypyridone derivatives has a chemical structure shown in formula I:
Figure BDA0003199887630000021
wherein R is 1 Is one of methyl, ethyl, propyl, butyl and pentyl; r 2 Is H, or aminomethyl (-CH) 2 NH-), amidomethyl (-CH) 2 NHCO-), sulfonamidomethyl (-CH) 2 NHSO 2 -) is connected with one of straight-chain alkyl, substituted aryl and heterocyclic aromatic mercapto structures with 5-6 carbon atoms; r 3 Is methyl, or one of straight-chain alkane amidomethyl with 5-6 carbon atoms and substituted aromatic amidomethyl.
Preferably, the hydroxypyridone derivative has a chemical structure as shown in the following:
Figure BDA0003199887630000022
the preparation method of the hydroxypyridone derivative specifically comprises the following steps:
(1.1) reacting kojic acid, benzyl chloride and sodium hydroxide in a solvent, and purifying reaction liquid obtained after the reaction is finished to obtain a compound 1;
(1.2) placing the compound 1 and methylamine in a solvent for reaction, and purifying the obtained reaction liquid to obtain a compound 2;
(1.3) placing the compound 2, triphenylphosphine, DEAD (diethyl azodicarboxylate) and phthalimide in a solvent for reaction, and purifying the obtained reaction liquid to obtain a compound 3;
(1.4) heating and refluxing the compound 3 and hydrazine hydrate in a solvent for reaction, and purifying the obtained reaction liquid to obtain a compound 4;
(1.5) Compound 4 with acid chloride (R) 4 COCl) and pyridine react in a solvent, and the compound obtained by purifying the obtained reaction liquid is a compound 5a-5d;
(1.6) reacting the compounds 5a-5d with Pd/C in a solvent under a hydrogen atmosphere, and purifying the obtained reaction liquid to obtain compounds 6a-6d;
the synthetic route at this time is:
Figure BDA0003199887630000031
carrying out reflux reaction on the reaction in the step (1.1) in a solvent at the temperature of 80 ℃ for 24 hours; the solvent in step (1.1) is preferably methanol; the purification method in the step (1.1) is to add water for washing after the reaction solution is decompressed and concentrated, separate out solid and filter to obtain a product 1;
the reaction in the step (1.2) is carried out for 24 hours at room temperature; the solvent in step (1.2) is preferably methanol; the purification method in the step (1.2) is to add a solvent (ethyl acetate) for washing after the reaction solution is decompressed and concentrated, separate out solids and filter the solids to obtain a product 2;
the solvent in the step (1.3) is anhydrous tetrahydrofuran; the reaction in the step (1.3) is to carry out reaction for 24 hours at room temperature after feeding at 0 ℃; the purification method in the step (1.3) is to extract the reaction solution by dichloromethane after decompression and concentration, and purify the extracted organic matter by a column chromatography method to obtain a compound 3;
the reaction in the step (1.4) refers to reflux reaction in a solvent at 78 ℃ for 3-4h; the solvent in the step (1.4) is preferably ethanol; the purification method in the step (1.4) is to dissolve the reaction solution after decompression and concentration in water, adjust the pH value to 12-13 by 10M sodium hydroxide solution, extract by a solvent, and purify the organic matter obtained by extraction by a column chromatography method to obtain a compound 4;
acyl chloride R described in step (1.5) 4 The COCl is preferably one of hexanoyl chloride, p-trifluoromethylbenzoyl chloride, p-methoxybenzoyl chloride and 2- (4-fluorophenyl) acetyl chloride;
the reaction in the step (1.5) refers to reacting in a solvent at room temperature for 6h, and then purifying to obtain compounds 5a-5d; the solvent described in step (1.5) is preferably anhydrous DMF (N, N-dimethylformamide).
The reaction in the step (1.6) is carried out in a solvent at room temperature for 12 hours; the solvent in step (1.6) is preferably methanol; the purification method in the step (1.6) is to suction-filter the reaction solution by using kieselguhr, concentrate under reduced pressure to obtain a solid, and recrystallize the solid by using a solvent to obtain compounds 6a-6d;
(2.1) putting kojic acid into thionyl chloride for reaction, continuously reacting the crude product with zinc powder and concentrated hydrochloric acid, and purifying the obtained reaction solution to obtain a compound 7;
(2.2) reacting the compound 7 with formaldehyde under an alkaline condition, and purifying the obtained reaction liquid to obtain a compound 8;
(2.3) reacting the compound 8 with benzyl chloride and an aqueous solution of sodium hydroxide in a solvent, and purifying the reaction solution obtained after the reaction is finished to obtain a compound 9;
(2.4) reacting the compound 9 with 3, 4-dihydropyran and p-toluenesulfonic acid to obtain an intermediate, then placing the intermediate and methylamine in a solvent for reaction, and purifying to obtain a compound 10a;
(2.5) placing the compound 10a, triphenylphosphine, DIAD (diethyl azodicarboxylate) and phthalimide in a solvent for reaction to obtain a compound 11a;
(2.6) heating the compound 11a and hydrazine hydrate in a solvent for reflux reaction to obtain a compound 12a;
(2.7) reacting the compound 12a with chloroacetyl chloride and triethylamine in a solvent to obtain a compound 13;
(2.8) placing the compound 13 and boron trichloride in a solvent for reaction to obtain a compound 14;
(2.9) reacting Compound 14 with
Figure BDA0003199887630000041
And potassium hydroxide in a solvent to give compounds 15a-15j, wherein
Figure BDA0003199887630000042
Corresponding are the compounds 2-mercaptobenzimidazole, 5-nitro-2-mercaptobenzimidazole, 5-cyano-2-mercaptobenzimidazole, 2-mercapto-5-methylbenzoxazole, 5-chloro-2-mercaptobenzoxazole, 2-mercapto-6-methylbenzothiazole, 6-fluoro-2-mercaptobenzothiazole, 2-mercapto-6-nitrobenzothiazole, 2-mercaptoimidazole or 2-mercaptothiazole.
The synthetic route at this time is:
Figure BDA0003199887630000043
the step (2.1) of putting kojic acid in thionyl chloride for reaction refers to reacting for 2 hours at room temperature; the continuous reaction with the zinc powder and the concentrated hydrochloric acid means that the reaction lasts for 5 hours at the temperature of 70-80 ℃; recrystallizing to obtain a product 7;
the reaction in the step (2.2) is carried out at room temperature overnight; the purification method in the step (2.2) is to slowly add concentrated hydrochloric acid to adjust the pH =1, separate out a large amount of solid, and filter to obtain a product 7;
the reaction in the step (2.3) refers to reflux reaction at 80 ℃ in a solvent overnight to obtain a product 9; the solvent is preferably methanol;
the reaction of the compound 9, the 3, 4-dihydropyran and the p-toluenesulfonic acid in the step (2.4) refers to a reaction in a solvent at normal temperature for 3 hours; the subsequent reaction with methylamine in a solvent means that the reaction is carried out for 12 hours at 75 ℃ in ethanol, and then the reaction is carried out for 4 hours with 2mol/L diluted hydrochloric acid in ethanol by reflux to obtain a product 10a;
the reaction in the step (2.5) is to react for 24 hours at room temperature after feeding anhydrous tetrahydrofuran at 0 ℃ to obtain a compound 11a;
the reaction in the step (2.6) refers to reflux reaction in ethanol solvent at 78 ℃ for 3-4h to obtain a compound 12a;
the reaction in the step (2.7) refers to a reaction in a solvent for 3 hours at room temperature to obtain a compound 13; the solvent is preferably anhydrous DMF (N, N-dimethylformamide);
the reaction in the step (2.8) refers to a reaction in a solvent for 3 hours at room temperature to obtain a compound 14; the solvent is preferably anhydrous DCM (dichloromethane);
the reaction described in step (2.9) refers to a reaction in a solvent at 55 ℃ overnight to give compounds 15a-15j; the solvent is preferably methanol.
(3.1) reaction of Compound 9 with 3, 4-dihydropyran and p-toluenesulfonic acid to give an intermediate, which is then reacted with R 1 NH 2 (R 1 One of methyl, ethyl, propyl, butyl and pentyl) in a solvent for reaction, and purifying to obtain a compound 10b-10e;
(3.2) placing the compounds 10b-10e, triphenylphosphine, DIAD (diethyl azodicarboxylate) and phthalimide in a solvent for reaction to obtain compounds 11b-11e;
(3.3) heating the compound 11b-11e and hydrazine hydrate in a solvent for reflux reaction to obtain a compound 12b-12e;
(3.4) Compound 12b-12e, acid chloride (R) 5 COCl) or sulfonyl chloride (R) 5 SO 2 Cl) and pyridine react in anhydrous DMF (N, N-dimethylformamide), and the obtained reaction liquid is purified to obtain compounds 16a-16r;
(3.5) reacting the compound 16a-16r with Pd/C in a solvent under a hydrogen atmosphere, and purifying the obtained reaction liquid to obtain a compound 17a-17r;
the synthetic route at this time is:
Figure BDA0003199887630000051
the reaction of the compound 9 with 3, 4-dihydropyran and p-toluenesulfonic acid in the step (3.1) refers to a reaction in a solvent at normal temperature for 3 hours; after and R 1 NH 2 The reaction in the solvent means that the mixture reacts in ethanol at 75 ℃ for 12h, and then the mixture reacts with 2mol/L dilute hydrochloric acid in ethanol under reflux for 4h to obtain products 10b-10e;
the reaction in the step (3.2) is to react for 24 hours at room temperature after feeding in solvent anhydrous tetrahydrofuran at 0 ℃ to obtain a compound 11b-11e;
the reaction in the step (3.3) refers to reflux reaction in a solvent at 78 ℃ for 3-4h to obtain a compound 12b-12e;
the acyl chloride in the step (3.4) is one of heptanoyl chloride, hexanoyl chloride, p-methoxybenzoyl chloride, p-trifluoromethylbenzoyl chloride, p-methoxybenzoyl chloride, m-methoxybenzoyl chloride, o-methoxybenzoyl chloride and 2- (4-fluorophenyl) acetyl chloride; the sulfonyl chloride in the step (3.4) is p-methoxybenzenesulfonyl chloride.
The reaction in the step (3.4) is carried out in anhydrous DMF for 6h at room temperature; the purification method in the step (3.1) is to add the reaction solution into water, extract the reaction solution by dichloromethane, and purify the organic matter obtained by extraction by a column chromatography method to obtain a compound 16a-16r;
the reaction in the step (3.5) is carried out for 12h at room temperature in a solvent methanol under a hydrogen atmosphere; the purification method in the step (3.2) is to suction-filter the reaction solution by using kieselguhr, concentrate under reduced pressure, and recrystallize the obtained solid by using methanol to obtain the compound 17a-17r.
The hydroxypyridone compound disclosed by the invention can be used for preparing a bacterial biofilm inhibitor mainly by inhibiting the formation of a bacterial biofilm, and especially can be applied to preparing a sensitizer for the pseudomonas aeruginosa inhibitor.
The pseudomonas aeruginosa inhibitor can be at least one of quinolone antibiotics (ciprofloxacin), aminoglycoside antibiotics (tobramycin) and colistin;
the pseudomonas aeruginosa is one of pseudomonas aeruginosa PAO1, pseudomonas aeruginosa 1121, pseudomonas aeruginosa 1167, pseudomonas aeruginosa FB and pseudomonas aeruginosa 1129.
The hydroxypyridone compound pseudomonas aeruginosa inhibitor can improve the sensitivity of the clinically-isolated pseudomonas aeruginosa drug-resistant strain after being combined with the antibiotic when the concentration is only 20 mu M.
The hydroxypyridone compound in the pharmaceutical composition can also be a medicinal salt or a solvate of the hydroxypyridone compound. It is well known that the solvated forms and salts of a compound do not generally affect the biological activity of the compound itself.
The pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) The invention takes hydroxypyridone as a lead compound, modifies and reforms N-1, C-2 and C-6 positions of the hydroxypyridone, designs and synthesizes a series of hydroxypyridone compounds, and is applied to the development of bacterial biofilm inhibitors, wherein, when 17k, N-1 position butyl is substituted, and C-2 position is substituted by p-methoxy benzene ring, the biofilm inhibition activity is superior to that of positive control compound azithromycin, and the inhibitor is a novel efficient biofilm inhibitor.
(2) 15b,17e,17f,17i,17j,17k,17l,17m,17o and 17r (MIC is more than 512 mu M) compounds with excellent biomembrane inhibition activity in hydroxypyridone compounds inhibit standard strains PAO1 of pseudomonas aeruginosa and clinically separated pseudomonas aeruginosa drug-resistant strains (1121, 1167, FB and 1129) when the concentration is 20 mu M and the clinically common antibiotics (ciprofloxacin, tobramycin and colistin) are combined, so that the sensitivity of the antibiotics to drug-resistant bacteria is enhanced, and the antibacterial ability of the antibiotics to different clinically drug-resistant strains is improved.
Drawings
FIG. 1 is a graph of experimental results of different concentrations of compounds on a zebrafish infection model.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto.
The reagents used in the examples are commercially available without specific reference.
Example 1 preparation of N- ((5- (benzyloxy) -1-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) hexanamide (5 a)
Intermediate compound 4 (see "J.Med. Chem.2004,47 (25), 6349-6362.") (350mg, 1.4 mmol) was placed in a 25mL dry two-necked flask, 8mL of anhydrous DMF was added under nitrogen protection, and hexanoyl chloride (0.3mL, 2.1mmol) was added dropwise at 0 ℃ followed by anhydrous pyridine (0.6 mL,7.0 mmol) and reacted at room temperature for 6 hours. After the reaction, 8mL of water was added to quench the reaction. Extraction with dichloromethane three times, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, purification by column chromatography, eluent dichloromethane/methanol =30/1, to give 5a as white oily liquid 277mg, yield: 57.9 percent. 1 H NMR(400MHz,CDCl 3 )δ8.35(t,J＝4.4Hz,1H),7.41–7.32(m,5H),6.95(s,1H),6.29(s,1H),5.07(s,2H),4.31(d,J＝5.4Hz,2H),3.55(s,3H),2.43–2.24(m,2H),1.66(p,J＝7.4Hz,2H),1.36–1.28(m,4H),0.88(t,J＝6.7Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ14.0,22.4,25.3,31.6,36.1,40.0,41.0,72.0,117.6,127.8,128.4,128.7,129.6,136.3,146.5,147.6,172.6,173.9.
Example 2 preparation of n- ((5- (benzyloxy) -1-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4- (trifluoromethyl) benzamide (5 b)
Compound 5a was synthesized from intermediate compound 4 (400mg, 1.6 mmol) and p-trifluoromethylbenzoyl chloride (0.4 ml,2.4 mmol) to give 5b as a pale yellow oily liquid 264mg, yield: 39.4 percent. 1 H NMR(400MHz,CDCl 3 )δ9.63(s,1H),8.31(d,J＝7.8Hz,2H),7.62(d,J＝7.9Hz,2H),7.23(s,5H),6.99(s,1H),6.25(s,1H),4.90(s,2H),4.51(d,J＝4.2Hz,2H),3.59(s,3H). 13 C NMR(100MHz,CDCl 3 )δ29.7,41.2,71.9,100.0,118.4,125.2(q, 3 J C-F ＝3.5Hz),127.7,128.4,128.5,128.6,132.9(q, 2 J C-F ＝32.9Hz),135.6,145.9,147.8,165.9,172.3.
Example 3 preparation of N- ((5- (benzyloxy) -1-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzamide (5 c)
Compound 5a was synthesized using intermediate compound 4 (300mg, 1.2mmol) and p-methoxybenzoyl chloride (0.4ml, 1.8mmol) as starting materials to give 5c as a white oily liquid 454mg, yield: 99.9 percent. 1 H NMR(400MHz,CDCl 3 )δ9.04(s,1H),8.15(d,J＝8.8Hz,2H),7.26(s,5H),6.94(s,1H),6.89(d,J＝8.8Hz,2H),6.31(s,1H),4.95(s,2H),4.50(d,J＝5.0Hz,2H),3.82(s,3H),3.56(s,3H). 13 C NMR(100MHz,CDCl 3 )δ29.7,41.1,55.3,72.0,113.6,118.3,125.7,127.8,128.3,128.6,129.7,136.1,162.3.
Example 4 preparation of N- ((5- (benzyloxy) -1-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -2- (4-fluorophenyl) acetamide (5 d)
Starting from intermediate compound 4 (300mg, 1.2mmol) and 2- (4-fluorophenyl) acetyl chloride (0.3 mL, 1.8mmol), compound 5a was synthesized to give 5d as a white oily liquid 264mg, yield: 57.5 percent. 1 H NMR(400MHz,CDCl 3 )δ8.82(s,1H),7.40–7.29(m,7H),7.01–6.91(m,3H),6.31(s,1H),5.05(s,2H),4.28(d,J＝5.3Hz,2H),3.59(s,2H),3.52(s,3H). 13 C NMR(100MHz,CDCl 3 )δ40.1,41.2,42.0,72.0,115.2(d, 2 J C-F ＝21.4Hz),115.4,127.8,128.5,128.7,129.4,130.8(d, 3 J C-F ＝7.9Hz),131.2(d, 4 J C-F ＝3.1Hz),136.0,146.6,160.7(d, 1 J C-F ＝245.7Hz),171.5.
Example 5 preparation of N- ((5-hydroxy-1-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) hexanamide (6 a)
The intermediate compound 5a (277mg, 0.81mmol) was placed in a single-neck reaction flask, dissolved in 10mL of methanol, added with 27mg of Pd/C (l 0% palladium on carbon), evacuated, replaced with hydrogen gas three times, and reacted at room temperature for 12 hours. After the reaction was completed, the reaction solution was filtered with celite, the filtrate was collected and concentrated under reduced pressure to obtain a solid, and the solid was recrystallized from methanol to obtain 182mg of 6a as a white solid, yield: 88.9%, purity: 98.69%, melting point: 182.4-183.4 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.34(t,J＝5.6Hz,1H),7.42(s,1H),6.09(s,1H),4.21(d,J＝5.7Hz,2H),3.59(s,3H),2.17(t,J＝7.4Hz,2H),1.53(p,J＝7.4Hz,2H),1.36–1.15(m,4H),0.86(t,J＝7.0Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ14.3,22.3,25.4,31.4,35.6,39.2,112.3,124.8,145.8,147.2,170.8,172.8.HRMS(ESI):calcd for C 13 H 20 N 2 O 3 [M+H] + ＝253.1547,found[M+H] + ＝253.1549.
Example 6 preparation of n- ((5-hydroxy-1-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4- (trifluoromethyl) benzamide (6 b)
Compound 6a was synthesized using intermediate compound 5b to give 6b as a white solid 152mg, yield: 73.8%, purity: 99.40%, melting point: 269.6-270.5 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.28(t,J＝5.3Hz,1H),8.12(d,J＝8.1Hz,2H),7.89(d,J＝8.3Hz,2H),7.46(s,1H),6.16(s,1H),4.46(d,J＝5.5Hz,2H),3.67(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ39.4,40.1,112.5,123.0,125.0,125.9(q, 3 J C-F ＝3.8Hz),128.8,131.7,132.0(q, 2 J C-F ＝31.9Hz),137.9,145.3,147.3,165.8,170.8.HRMS(ESI):calcd for C 15 H 13 F 3 N 2 O 3 [M+H] + ＝327.0951,found[M+H] + ＝327.0950.
Example 7 preparation of N- ((5-hydroxy-1-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzamide (6 c)
Compound 6a was synthesized using intermediate compound 5c to give 6c as a white solid 226mg, yield: 65.8%, purity: 99.05%, melting point: 270.4-272.0 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.88(s,1H),7.90(d,J＝8.7Hz,2H),7.44(s,1H),7.03(d,J＝8.8Hz,2H),6.12(s,1H),4.40(d,J＝5.4Hz,2H),3.82(s,3H),3.66(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ40.3,55.8,112.3,114.1,124.8,126.4,129.7,145.9,147.3,162.3,166.3,170.8.HRMS(ESI):calcd for C 15 H 16 N 2 O 4 [M+H] + ＝289.1183,found[M+H] + ＝289.1191.
Example 8 preparation of 2- (4-fluorophenyl) -N- ((5-hydroxy-1-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) acetamide (6 d)
Compound 6a was synthesized using intermediate compound 5d to give 6d as a white solid 207mg, yield: 78.9%, purity: 98.62%, melting point: 204.4-204.9 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.60(t,J＝5.3Hz,1H),7.42(s,1H),7.31(dd,J＝5.7,8.5Hz,2H),7.13(t,J＝8.9Hz,2H),6.11(s,1H),4.23(d,J＝5.6Hz,2H),3.55(s,3H),3.52(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ39.5,41.6,112.5,115.3(d, 2 J C-F ＝21.3Hz),124.9,131.3,131.4(d, 3 J C-F ＝8.1Hz),132.7(d, 4 J C-F ＝3.1Hz),145.5,147.3,160.3,161.5(d, 1 J C-F ＝243.1Hz),162.7,170.8.HRMS(ESI):calcd for C 15 H 15 FN 2 O 3 [M+H] + ＝291.1139,found[M+H] + ＝291.1127.
Example 9 preparation of 1, 6-dimethyl-2-chloroacetamidomethyl-3-benzyloxy-4-pyridone (13)
Intermediate compound 12a (see "J.Med. Chem.2004,47 (25), 6349-6362.") (3g, 11.6 mmol) was placed inAdding 30mL of anhydrous DMF (dimethyl formamide) into a 100mL dry double-mouth bottle containing a magnetic stirrer under the protection of nitrogen, dropwise adding chloroacetyl chloride (1.05mL, 13.94mmol) at 0 ℃, then dropwise adding anhydrous triethylamine (1.93mL, 13.94mmol), reacting at room temperature for 3 hours, separating out a large amount of white powder after TLC monitoring reaction is finished, carrying out suction filtration, washing a filter cake for three times by ethyl acetate, and collecting the filter cake to obtain a compound 13 as a white solid (3.67g, yield = 94.50%); 1 H NMR(400MHz,CDCl 3 )δ7.37(d,J＝10.1Hz,1H),7.33–7.26(m,4H),7.26–7.25(m,1H),6.32(s,1H),5.18(s,2H),4.41(d,J＝5.7Hz,2H),3.99(d,J＝4.7Hz,2H),3.46(s,3H),2.24(s,3H). 13 C NMR(100MHz,CDCl 3 )δ173.04,166.42,147.52,146.26,140.12,137.03,128.92,128.59,128.40,118.74,73.16,42.36,36.37,35.34,20.97.
example 10 preparation of 1, 6-dimethyl-2-chloroacetamidomethyl-3-hydroxy-4-pyridone (14)
The compound 13 (3.5g, 0.01mol) was placed in a 100mL dry two-necked flask containing a magnetic stirrer, 30mL of anhydrous dichloromethane was added under nitrogen protection, a dichloromethane solution of boron trichloride (30mL, 0.03mol, 1mol/L) was slowly added dropwise at 0 ℃, the temperature was naturally raised to room temperature, and stirring was carried out for 3 hours. TLC monitoring reaction is finished, methanol is added to quench reaction, reaction liquid is decompressed and concentrated to obtain a crude product, and the crude product is recrystallized by pure methanol to obtain compound 14 as a white solid (1.4 g, yield = 57.20%); 1 H NMR(400MHz,DMSO-d 6 )δ9.01(s,1H),7.31(s,1H),4.66(d,J＝5.2Hz,1H),4.13(s,2H),3.88(s,3H),2.57(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ166.98,160.00,148.86,143.38,139.70,113.16,42.77,35.39,21.08.
example 11 preparation of 1, 6-dimethyl-2- ((2-benzimidazolyl) -thioacetamidomethyl) -3-hydroxy-4-pyridone (15 a)
Compound 2-mercaptobenzimidazole (96.13mg, 0.67mmol) and potassium hydroxide (52.18mg, 0.93mmol) were placed in a 25mL dry two-necked flask with a magnetic stir bar, 3mL dry methanol was added under nitrogen, after dissolution, intermediate compound 14 (150mg, 0.61mmol) was added, and stirring was carried out at 55 ℃ for 6h. TLC monitoring reaction, solid separating out, natural cooling to room temperature, filteringTo obtain a residue, and recrystallizing the crude product with methanol to obtain 163mg of compound 15a as a white solid, yield: 74.50%, purity: 96.36%, melting point: 264.3-265.6 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.02(s,1H),7.44-7.42(m,2H),7.17-7.14(m,1H),7.12(s,1H),4.63(d,J＝5.4Hz,2H),4.10(s,2H),3.74(s,3H),2.45(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ168.21,161.29,150.11,148.45,143.73,138.46,122.30,113.06,38.91,35.25,35.14,20.94.HRMS(ESI)m/z calcd for C 17 H 18 N 4 O 3 S[M+H] + 359.1172,found 359.1164.
Example 12 preparation of 1, 6-dimethyl-2- ((5-nitro-2-benzimidazolyl) -thioacetamidomethyl) -3-hydroxy-4-pyridone (15 b)
Compound 15a was prepared starting from intermediate 14 (150mg, 0.61mmol) and 5-nitro-2-mercaptobenzimidazole (130.98mg, 0.67mmol) to give compound 15b as a brown solid 140mg, yield: 56.90%, purity: 95.13%, melting point: 235.3-236.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.73(s,1H),8.25(d,J＝2.1Hz,1H),8.06(dd,J＝8.8,2.2Hz,1H),7.58(d,J＝8.8Hz,1H),6.14(s,1H),4.48(d,J＝4.8Hz,2H),4.13(s,2H),3.43(s,3H),2.24(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ169.34,167.49,146.69,146.13,142.58,129.53,119.41,118.00,112.96,105.19,36.15,35.13,35.06,20.72.HRMS(ESI)m/z calcd for C 17 H 17 N 5 O 5 S[M+H] + 404.1023,found 404.1030.
Example 13 preparation of 1, 6-dimethyl-2- ((5-cyano-2-benzimidazolyl) -thioacetamidomethyl) -3-hydroxy-4-pyridone (15 c)
Compound 15a was prepared using intermediate 14 (100mg, 0.41mmol) and 5-cyano-2-mercaptobenzimidazole (92.86mg, 0.53mmol) as starting materials to give compound 15c as a white solid 115mg, yield: 73.10%, purity: 97.65%, melting point: 266.8-267.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.72(t,J＝4.9Hz,1H),7.91(s,1H),7.53(dt,J＝8.3,4.9Hz,2H),6.13(s,1H),4.47(d,J＝5.0Hz,2H),4.10(s,2H),3.42(s,3H),2.24(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ169.84,167.52,146.53,146.29,128.83,125.76,120.47,112.89,103.75,35.92,35.08,35.03,20.71.HRMS(ESI)m/z calcd for C 18 H 17 N 5 O 3 S[M+H] + 384.1125,found 384.1122.
Example 14 preparation of 1, 6-dimethyl-2- ((5-methyl-2-benzoxazolyl) -thioacetamidomethyl) -3-hydroxy-4-pyridone (15 d)
Compound 15a was prepared using intermediate 14 (100mg, 0.41mmol) and 2-mercapto-5-methylbenzoxazole (98mg, 0.53mmol) as starting materials to give compound 15d as a white solid 98mg, yield: 64.00%, purity: 95.12%, melting point: 246.4-247.8 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.27(s,1H),7.21(d,J＝8.1Hz,1H),7.10(s,1H),6.81(d,J＝7.6Hz,1H),6.15(s,1H),4.67(s,2H),3.57(s,3H),2.33(s,3H),2.30(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ169.99,162.53,146.83,146.75,146.30,143.49,133.23,128.37,121.50,116.54,112.93,108.58,38.33,36.13,21.56,20.74.HRMS(ESI)m/z calcd for C 18 H 19 N 3 O 4 S[M+H] + 374.1169,found 374.1173.
Example 15 preparation of 1, 6-dimethyl-2- ((5-chloro-2-benzoxazolyl) -thioacetamidomethyl) -3-hydroxy-4-pyridone (15 e)
Compound 15a was prepared using intermediate 14 (100mg, 0.41mmol) and 5-chloro-2-mercaptobenzoxazole (98.94mg, 0.53mmol) as starting materials, to give compound 15e as a white solid 80mg, yield: 49.50%, purity: 95.44%, melting point: 217.3-219.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.77(s,1H),7.68(dd,J＝10.0,5.1Hz,2H),7.36(dd,J＝8.6,1.7Hz,1H),6.14(s,1H),4.49(d,J＝4.6Hz,2H),4.17(s,2H),3.46(s,3H),2.27(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ169.87(s),166.57(s),166.46(s),150.54(s),146.57(s),146.34(s),142.96(s),129.42(s),128.70(s),124.73(s),118.38(s),112.93(s),111.96(s),35.95(s),35.80(s),35.15(s),20.75(s).HRMS(ESI)m/z calcd for C 17 H 16 ClN 3 O 4 S[M+H] + 394.0623,found 394.0625.
Example 16 preparation of 1, 6-dimethyl-2- ((6-methyl-2-benzothiazolyl) -thioacetamidomethyl) -3-hydroxy-4-pyridone (15 f)
Compound 15a was prepared using intermediate 14 (100mg, 0.41mmol) and 2-mercapto-6-methylbenzothiazole (96.62mg, 0.53mmol) as starting materials to give compound 15f as a white solid 93mg, yield: 58.20%, purity: 95.15%, melting point: 253.1-254.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.74(t,J＝5.0Hz,1H),7.79(s,1H),7.64(d,J＝8.3Hz,1H),7.26(d,J＝8.3Hz,1H),6.14(s,1H),4.49(d,J＝5.0Hz,2H),4.14(s,2H),3.42(s,3H),2.40(s,3H),2.23(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ169.85,167.02,165.16,151.14,146.54,146.33,135.36,134.67,128.81,128.18,121.91,121.03,112.93,36.77,35.95,35.0,21.40,20.72.HRMS(ESI)m/z calcd for C 18 H 19 N 3 O 3 S 2 [M+H] + 390.0941,found390.0940.
Example 17 preparation of 1, 6-dimethyl-2- ((6-fluoro-2-benzothiazolyl) -thioacetamidomethyl) -3-hydroxy-4-pyridone (15 g)
Compound 15a was prepared using intermediate 14 (100mg, 0.41mmol) and 6-fluoro-2-mercaptobenzothiazole (113.92mg, 0.62mmol) as starting materials, yielding compound 15g as a white solid 88mg, yield: 54.60%, purity: 95.34%, melting point: 241.4-243.2 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.73(t,J＝4.8Hz,1H),7.95(dd,J＝8.7,2.6Hz,1H),7.77(dd,J＝8.9,4.9Hz,1H),7.32(td,J＝9.0,2.7Hz,1H),6.13(s,1H),4.49(d,J＝5.0Hz,2H),4.15(s,2H),3.44(s,3H),2.24(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ169.87,166.94,159.60(d, 1 J C-F ＝241Hz),146.44(d, 2 J C-F ＝25Hz),136.49(d, 4 J C-F ＝12Hz),128.72,122.52(d, 5 J C-F ＝9Hz),115.10,114.94,112.89,108.95(d, 3 J C-F ＝17Hz),36.85,35.95,35.13,20.73.HRMS(ESI)m/z calcd for C 17 H 16 FN 3 O 3 S 2 [M+H] + 394.0690,found 394.0692.
Example 18 preparation of 1, 6-dimethyl-2- ((6-nitro-2-benzothiazolyl) -thioacetamidomethyl) -3-hydroxy-4-pyridone (15 h)
The intermediate 14 (100mg, 0.41mmol) and 2-mercapto-6-nitrobenzothiazole (194.2mg, 0.62mmol) were used as starting materials to prepare compound 15a, which was 121mg as a yellow solid 15h, yield: 70.20%, purity: 95.07%, melting point: 235.9-237.4 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.07(d,J＝2.3Hz,1H),8.82(t,J＝4.6Hz,1H),8.27(dd,J＝9.0,2.3Hz,1H),7.91(d,J＝9.0Hz,1H),6.24(s,1H),4.51(d,J＝4.8Hz,2H),4.25(s,2H),3.51(s,3H),2.29(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ174.80,168.99,166.70,156.84,146.79,146.07,144.04,143.78,135.9,129.76,123.46,122.46,121.51,119.32,118.27,113.37,112.99,37.02,36.32,35.22,20.80.HRMS(ESI)m/z calcd for C 17 H 16 N 4 O 5 S 2 [M+H] + 421.0635,found 421.0632.
Example 19 preparation of 1, 6-dimethyl-2- ((2-imidazolyl) -thioacetamidomethyl) -3-hydroxy-4-pyridone (15 i)
Compound 15a was prepared using intermediate 14 (100mg, 0.41mmol) and 2-mercaptoimidazole (61.58mg, 0.62mmol) as starting materials to give compound 15i as a pink solid 96mg, yield: 75.90%, purity: 95.13%, melting point: 251.7-253.9 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.59(s,1H),7.01(s,2H),6.12(s,1H),4.44(d,J＝3.8Hz,2H),3.72(s,2H),3.41(s,3H),2.27(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ169.83,168.46,146.57,146.23,138.85,128.85,112.87,36.91,35.94,34.87,20.75.HRMS(ESI)m/z calcd for C 13 H 16 N 4 O 3 S[M+H] + 309.1016,found 309.1007.
Example 20 preparation of 1, 6-dimethyl-2- ((2-thiazolyl) -thioacetamidomethyl) -3-hydroxy-4-pyridone (15 j)
Compound 15a was prepared using intermediate 14 (100mg, 0.41mmol) and 2-mercaptothiazole (72.07mg, 0.62mmol) as starting materials to give compound 15j as a white solid 93mg, yield: 69.70%, purity: 95.99%, melting point: 217.3-219.4 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.64(t,J＝4.9Hz,1H),7.67(dd,J＝17.5,3.4Hz,2H),6.13(s,1H),4.46(d,J＝5.0Hz,2H),3.99(s,2H),3.44(s,3H),2.28(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ169.82,167.23,163.67,146.58,146.29,143.12,128.77,121.06,112.90,37.46,35.95,35.02,20.77.HRMS(ESI)m/z calcd for C 13 H 15 N 3 O 3 S 2 [M+H] + 326.0628,found 326.0628.
Example 21 preparation of 3- (benzyloxy) -1-ethyl-2- (hydroxymethyl) -6-methylpyridin-4 (1H) -one (10 b)
Compound 9 (J.Med.chem.2004, 47 (25), 6349-6362. Details of the synthesis method are reported) (6.00g, 24mmol) was placed in a 250mL two-necked flask, dissolved by adding 100mL of anhydrous dichloromethane, followed by addition of p-toluenesulfonic acid (172mg, 1mmol), slowly added dropwise 3, 4-dihydro-2H-pyran (4.50mL, 1mmol), and reacted at room temperature for 3 hours. After the reaction is finished, adding 5% sodium carbonate solution to quench the reaction, extracting with dichloromethane for three times, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain yellow liquid. The yellow liquid is dissolved in 40mL of ethanol, 20mL of ethylamine is added, and the tube is sealed and the reaction is carried out at 75 ℃ for 12h. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a brown liquid. The brown liquid was dissolved in 50mL of ethanol, and 19mL of 2M hydrochloric acid was added thereto, followed by reflux reaction for 4 hours. After the reaction was completed, ethanol was spin-dried, 40mL of water was added, and the mixture was washed with 40mL of diethyl ether, the aqueous layer was retained, the aqueous layer was extracted with 10M sodium hydroxide solution, pH =13, three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a solid, which was recrystallized with dichloromethane to obtain 2.40g of brown crystals. Yield: 36.1 percent. 1 H NMR(400MHz,DMSO-d 6 )δ7.50–7.27(m,5H),6.17(s,1H),5.47(t,J＝5.3Hz,1H),5.03(s,2H),4.50(d,J＝5.3Hz,2H),4.10(q,J＝7.1Hz,2H),2.34(s,3H),1.24(t,J＝7.1Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ15.9,19.6,43.0,54.0,73.1,118.5,128.2,128.6,128.8,138.2,142.9,145.5,147.5,172.8.
Example 22 preparation of 3- (benzyloxy) -2- (hydroxymethyl) -6-methyl-1-propylpyridin-4 (1H) -one (10 c)
Compound 10b was synthesized using intermediate compound 9 to give 10c as brown crystals 2.34g, yield: 32.0 percent. 1 H NMR(400MHz,DMSO-d 6 )δ7.46–7.28(m,5H),6.16(s,1H),5.47(t,J＝5.3Hz,1H),5.03(s,2H),4.49(d,J＝5.2Hz,2H),4.03–3.88(m,2H),3.34(s,3H),2.33(s,3H),1.62(dq,J＝7.4,14.9Hz,2H),0.89(t,J＝7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ11.3,19.7,23.9,49.4,54.1,73.1,118.4,128.2,128.6,128.8,138.2,143.0,145.3,147.6,172.8.
Example 23 preparation of 3- (benzyloxy) -1-butyl-2- (hydroxymethyl) -6-methylpyridin-4 (1H) -one (10 d)
Compound 10b was synthesized using intermediate compound 9 to give 10d as brown crystals 2.10g, yield: 28.8 percent. 1 H NMR(400MHz,DMSO-d 6 )δ7.46–7.29(m,5H),6.16(s,1H),5.48(t,J＝5.2Hz,1H),5.03(s,2H),4.49(d,J＝4.7Hz,2H),4.11–3.94(m,2H),2.33(s,3H),1.58(p,J＝8.2Hz,2H),1.32(h,J＝7.3Hz,2H),0.92(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ13.9,19.9,32.5,47.7,54.1,73.1,118.5,128.2,128.6,128.8,138.2,143.0,145.4,147.6,172.8.
Example 24 preparation of 3- (benzyloxy) -2- (hydroxymethyl) -6-methyl-1-pentylpyridin-4 (1H) -one (10 e)
Compound 10b was synthesized using intermediate compound 9 to give 10e as a white solid 1.20g, yield: 15.8 percent. 1 H NMR(400MHz,DMSO-d 6 )δ7.47–7.29(m,5H),6.17(s,1H),5.52(s,1H),5.03(s,2H),4.49(s,2H),4.05–3.95(m,2H),2.33(s,3H),1.60(p,J＝7.3Hz,2H),1.31(td,J＝5.5,13.7,14.5Hz,4H),0.88(t,J＝6.9Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ14.3,19.7,22.1,28.8,30.2,47.9,54.1,73.1,118.5,128.2,128.6,128.8,138.1,143.0,145.3,147.6,172.8.
Example 25 preparation of 2- ((3- (benzyloxy) -1-ethyl-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) isoindole-1, 3-dione (11 b)
Compound 10b (2.40g, 9mmol), phthalimide (2.77g, 11mmol) and triphenylphosphine oxide (1.56g, 11mmol) were placed in a dry 250mL two-necked flask and added to 40mL of anhydrous tetrahydrofuran under nitrogen. After stirring at 0 ℃ for 30 minutes, diisopropyl azodicarboxylate (1.67mL, 11mmol) was slowly added dropwise, and after completion of dropwise addition, the temperature was slowly increasedThe mixture is stirred for 24 hours to room temperature. After the reaction is finished, concentrating under reduced pressure, drying tetrahydrofuran in a spinning mode, adding 50mL of water into residual liquid, extracting with 100mL of dichloromethane for three times, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography, wherein an eluent is dichloromethane/methanol =15/1, so that 4.51g of yellow solid is obtained, and the yield is: 81.8 percent. 1 H NMR(400MHz,DMSO-d 6 )δ7.84(s,4H),7.34(dd,J＝1.7,7.6Hz,2H),7.26(dd,J＝3.6,9.0Hz,3H),6.21(s,1H),5.13(s,2H),4.85(s,2H),4.09(q,J＝7.0Hz,2H),3.35(s,3H),2.35(s,3H),1.16(t,J＝7.1Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ15.7,19.9,34.7,43.8,71.4,100.0,118.9,123.6,128.1,128.4,128.8,131.9,135.0,138.0,146.7,147.2,167.8,172.2.
Example 26 preparation of 2- ((3- (benzyloxy) -6-methyl-4-oxo-1-propyl-1, 4-dihydropyridin-2-yl) methyl) isoindole-1, 3-dione (11 c)
Compound 11b was synthesized using intermediate compound 10c to give 11c as a yellow solid 3.41g, yield: 99.6 percent. 1 H NMR(400MHz,DMSO-d 6 )δ7.84(d,J＝1.7Hz,4H),7.35(d,J＝7.5Hz,2H),7.30–7.19(m,3H),6.20(s,1H),5.15(s,2H),4.82(s,2H),4.08–3.80(m,2H),3.36(s,3H),2.34(s,3H),1.62–1.47(m,2H),0.84(t,J＝7.2Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ10.9,20.1,23.8,34.8,49.9,71.4,118.9,123.6,128.1,128.4,128.9,131.9,135.0,137.9,138.0,146.6,147.3,167.9,172.3.
Example 27 preparation of 2- ((3- (benzyloxy) -1-butyl-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) isoindole-1, 3-dione (11 d)
Compound 11b was synthesized using intermediate compound 10d to give 11d as a yellow solid 4.04g, yield: 95.2 percent. 1 H NMR(400MHz,DMSO-d 6 )δ7.84(s,4H),7.39–7.33(m,2H),7.31–7.22(m,3H),6.21(s,1H),5.16(s,2H),4.83(s,2H),4.09–3.84(m,2H),2.34(s,3H),1.47(p,J＝8.1Hz,2H),1.25(h,J＝7.3Hz,2H),0.80(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ13.9,19.6,20.1,32.5,34.7,48.5,71.4,118.9,123.6,128.1,128.4,131.9,135.1,138.0,146.7,147.3,167.9,172.3.
Example 28 preparation of 2- ((3- (benzyloxy) -6-methyl-4-oxo-1-pentyl-1, 4-dihydropyridin-2-yl) methyl) isoindole-1, 3-dione (11 e)
Compound 11b was synthesized using intermediate compound 10e to give 11e as a yellow solid 2.02g, yield: 94.2 percent. 1 H NMR(400MHz,CDCl 3 )δ7.77(dd,J＝3.0,5.6Hz,2H),7.70(dd,J＝3.0,5.6Hz,2H),7.47(dd,J＝1.5,7.8Hz,2H),7.30–7.19(m,3H),6.35(s,1H),5.39(s,2H),4.67(s,2H),4.09–3.94(m,2H),2.33(s,3H),1.56–1.41(m,2H),1.33–1.17(m,4H),0.94–0.81(m,3H). 13 C NMR(100MHz,CDCl 3 )δ13.8,20.5,22.3,28.5,30.7,34.4,48.7,72.1,119.7,123.4,127.9,128.0,129.6,131.8,134.2,137.1,137.2,145.9,146.8,167.6,173.3.
Example 29 preparation of 2- (aminomethyl) -3- (benzyloxy) -1-ethyl-6-methylpyridin-4 (1H) -one (12 b)
Compound 11b (4.51g, 11mmol) was dissolved in 26mL of ethanol, 8.6mL of 5.5% hydrazine hydrate was added, heated under reflux for 4 hours, concentrated under reduced pressure after reaction, the residue was added to 25mL of water, 10M NaOH was added to adjust the solution pH =12, dichloromethane was extracted three times, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and column chromatography purification was performed with dichloromethane/methanol =20/1 as eluent to obtain 2.11g of a white solid, yield: 70.7 percent. 1 H NMR(400MHz,DMSO-d 6 )δ7.48–7.28(m,5H),6.16(s,1H),5.08(s,2H),4.09(q,J＝7.1Hz,2H),3.68(s,2H),2.32(s,3H),1.20(t,J＝7.1Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ16.0,19.7,36.5,42.7,72.5,118.4,128.3,128.7,128.9,138.3,144.6,145.0,147.1,172.7.
Example 30 preparation of 2- (aminomethyl) -3- (benzyloxy) -6-methyl-1-propylpyridin-4 (1H) -one (12 c)
Compound 12a was synthesized using intermediate compound 11c to give 12c as a yellow solid 2.80g, yield: 57.8 percent. 1 H NMR(400MHz,DMSO-d 6 )δ7.45–7.28(m,5H),6.15(s,1H),5.09(s,2H),4.01–3.91(m,2H),3.67(s,2H),2.31(s,3H),1.58(dq,J＝7.4,14.9Hz,2H),0.88(t,J＝7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ11.2,19.9,24.0,36.7,49.1,72.5,118.3,128.3,128.7,129.0,138.2,144.8,147.3,172.7.
Example 31 preparation of 2- (aminomethyl) -3- (benzyloxy) -1-butyl-6-methylpyridin-4 (1H) -one (12 d)
Compound 12a was synthesized using intermediate compound 11d to give 12d as a yellow solid 1.84g, yield: 65.5 percent. 1 H NMR(400MHz,DMSO-d 6 )δ7.45–7.28(m,5H),6.14(s,1H),5.09(s,2H),4.07–3.90(m,2H),3.66(s,2H),2.32(s,3H),1.55(dt,J＝8.4,15.8Hz,2H),1.32(h,J＝7.3Hz,2H),0.91(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ13.9,19.8,19.9,32.6,36.7,47.4,72.5,118.3,128.3,128.7,129.0,138.2,144.8,147.2,172.6.
Example 32 preparation of 2- (aminomethyl) -3- (benzyloxy) -6-methyl-1-pentylpyridin-4 (1H) -one (12 e)
Compound 12a was synthesized using intermediate compound 11e to give 12e as a yellow solid 2.15g, yield: 98.6 percent. 1 H NMR(400MHz,CDCl 3 )δ7.30–7.15(m,5H),6.22(s,1H),5.16(s,2H),3.90–3.80(m,2H),3.57(s,2H),2.19(s,3H),1.45(p,J＝7.5Hz,2H),1.21(pd,J＝4.3,5.3,7.9Hz,4H),0.79(t,J＝6.9Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ13.8,20.1,22.1,28.6,30.5,36.7,47.9,72.7,119.0,128.1,128.3,129.3,137.4,143.3,144.8,146.3,173.4.
Example 33 preparation of n- ((3- (benzyloxy) -1-ethyl-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) heptanamide (16 a)
The intermediate compound 12b (400mg, 1.5 mmol) was placed in a 25mL dry two-necked flask, and 8mL of anhydrous DMF was added dropwise under nitrogen protection, and heptanoyl chloride (0.3mL, 2.3mmol) was added dropwise at 0 ℃ followed by anhydrous pyridine (0.6 mL,7.0 mmol) and reacted at room temperature for 6 hours. After the reaction, 8mL of water was added to quench the reaction. Extraction with dichloromethane three times, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, purification by column chromatography, eluent dichloromethane/methanol =30/1, to give 16a as white oily liquid 455mg, yield: 57.9 percent. 1 H NMR(400MHz,CDCl 3 )δ7.30(s,5H),6.27(s,2H),5.18(s,2H),4.28(d,J＝5.8Hz,2H),4.02–3.80(m,2H),2.26(s,3H),2.10–1.90(m,2H),1.49(q,J＝7.1Hz,3H),1.31–1.11(m,9H),0.83(t,J＝6.7Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ14.1,15.7,20.1,22.5,25.4,29.0,31.5,34.2,36.0,43.6,72.8,119.3,128.4,128.5,129.2,137.2,140.6,146.1,146.5,173.2.
Example 34 preparation of N- ((3- (benzyloxy) -1-ethyl-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) hexanamide (16 b)
Compound 16a was synthesized using intermediate compound 12b (400mg, 1.5mmol) and hexanoyl chloride (0.4ml, 2.3mmol) as starting materials to give 16b as a pale yellow oily liquid 333mg, yield: 60.0 percent. 1 H NMR(400MHz,CDCl 3 )δ7.34(s,5H),6.32(s,1H),5.24(s,2H),4.30(d,J＝5.8Hz,2H),3.96(d,J＝5.6Hz,2H),2.37–2.13(m,3H),2.01(t,J＝7.5Hz,2H),1.52(p,J＝7.6Hz,2H),1.24(dq,J＝6.2,6.6,14.2Hz,7H),0.87(d,J＝11.6Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ13.9,15.7,20.0,22.4,25.1,31.4,34.2,36.1,43.6,72.8,119.4,128.6,129.3,137.3,140.6,146.3,173.2.
Example 35 preparation of n- ((3- (benzyloxy) -1-ethyl-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzamide (16 c)
Compound 16a was synthesized using intermediate compound 12b (400mg, 1.5mmol) and p-methoxybenzoyl chloride (0.3ml, 2.3mmol) as starting materials to give 16c as a pale yellow oily liquid 601mg, yield: 93.3 percent. 1 H NMR(400MHz,CDCl 3 )δ7.68(dd,J＝6.9,8.7Hz,2H),7.47–7.19(m,5H),6.88(d,J＝7.9Hz,2H),6.35(t,J＝6.8Hz,1H),5.30(d,J＝6.6Hz,2H),4.54(d,J＝5.3Hz,2H),4.07(d,J＝7.0Hz,2H),3.84(s,3H),2.30(s,3H),1.27(t,J＝6.9Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ15.8,20.1,35.0,43.7,55.4,73.1,113.6,119.5,125.7,128.5,129.2,137.3,140.4,146.3,162.4,166.8,173.1.
Example 36 preparation of n- ((3- (benzyloxy) -6-methyl-4-oxo-1-propyl-1, 4-dihydropyridin-2-yl) methyl) -4- (trifluoromethyl) benzamide (16 d)
Compound 16a was synthesized starting from intermediate compound 12c (300mg, 1.3 mmol) and p-trifluoromethylbenzoyl chloride (0.3 ml,2.0 mmol) to give 16d as a pale yellow oily liquid 420mg, yield: 70.0 percent. 1 H NMR(400MHz,DMSO-d 6 )δ9.02(s,1H),8.07(d,J＝8.1Hz,2H),7.84(d,J＝8.3Hz,2H),7.47–7.23(m,5H),6.24(s,1H),5.14(s,2H),4.57(d,J＝4.6Hz,2H),3.86–3.74(m,2H),2.34(s,3H),1.59(dq,J＝7.0,14.6Hz,2H),0.83(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO)δ11.1,19.9,23.9,35.5,49.8,72.6,118.7,125.7(q, 3 J C-F ＝3.7Hz),128.3,128.6,128.9,138.1,139.8,146.6,147.7,165.7,172.5.
Example 37 preparation of n- ((3- (benzyloxy) -6-methyl-4-oxo-1-propyl-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzamide (16 e)
Compound 16a was synthesized using intermediate compound 12c (350mg, 1.3 mmol) and p-methoxybenzoyl chloride (0.3 ml,2.0 mmol) as starting materials to give 16e as a pale yellow oily liquid 311mg, yield: 56.9 percent. 1 H NMR(300MHz,CDCl 3 )δ7.66(d,J＝8.7Hz,2H),7.33(dd,J＝7.9,21.0Hz,5H),6.88(d,J＝8.7Hz,2H),6.69(s,1H),6.38(s,1H),5.31(s,2H),4.52(d,J＝5.6Hz,2H),3.97–3.87(m,2H),3.85(d,J＝6.0Hz,3H),2.30(s,3H),1.71–1.48(m,2H),0.95(t,J＝7.4Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ10.8,20.3,24.3,35.1,50.1,55.4,73.1,113.7,119.4,125.7,128.4,128.6,129.1,137.2,140.8,146.2,146.6,162.4,166.7,173.0.
Example 38 preparation of n- ((3- (benzyloxy) -6-methyl-4-oxo-1-propyl-1, 4-dihydropyridin-2-yl) methyl) -3-methoxybenzamide (16 f)
Compound 16a was synthesized using intermediate compound 12c (350mg, 1.2mmol) and m-methoxybenzoyl chloride (0.3ml, 1.8mmol) as starting materials to give 16f as a white oily liquid 377mg, yield: 74.7 percent. 1 H NMR(400MHz,CDCl 3 )δ7.41–7.17(m,8H),7.03(d,J＝8.6Hz,1H),6.32(s,1H),5.39–5.20(m,2H),4.53(d,J＝5.8Hz,2H),3.83(s,3H),2.29(d,J＝3.2Hz,3H),1.62(h,J＝7.3Hz,2H),0.96(t,J＝7.3Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ10.8,20.2,24.3,35.2,50.0,55.5,73.0,112.5,118.1,119.4,128.4,128.5,129.0,129.4,134.9,137.2,140.3,146.4,159.7,167.1,173.1.
Example 39 preparation of N- ((3- (benzyloxy) -6-methyl-4-oxo-1-propyl-1, 4-dihydropyridin-2-yl) methyl) -2-methoxybenzamide (16 g)
By the middle ofStarting from body compound 12c (350mg, 1.2mmol) and o-methoxybenzoyl chloride (0.3ml, 1.8mmol), compound 16a was synthesized to give 16g of a white oily liquid 377mg, yield: 74.7 percent. 1 H NMR(400MHz,CDCl 3 )δ8.41(s,1H),8.10(d,J＝9.4Hz,1H),7.37(ddt,J＝6.7,13.2,46.5Hz,5H),7.02(t,J＝7.5Hz,1H),6.88(d,J＝8.3Hz,1H),6.36(s,1H),5.37(s,2H),4.56(s,2H),4.09(s,2H),3.66(s,3H),2.31(s,3H),1.83–1.56(m,2H),0.99(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO)δ6.1,15.6,19.7,30.5,45.4,51.0,68.3,106.6,115.0,115.9,116.3,123.4,123.7,124.1,127.3,128.5,132.8,136.4,141.2,141.9,152.8,160.4,168.6.
Example 40 preparation of N- ((3- (benzyloxy) -6-methyl-4-oxo-1-propyl-1, 4-dihydropyridin-2-yl) methyl) -2- (4-fluorophenyl) acetamide (16 h)
Compound 16a was synthesized starting from intermediate compound 12c (350mg, 1.3 mmol) and 2- (4-fluorophenyl) acetyl chloride (0.3 ml,2.0 mmol) to give 16h as a pale yellow oily liquid 413mg, yield: 75.4 percent. 1 H NMR(400MHz,CDCl 3 )δ7.36–7.26(m,5H),7.23(dd,J＝5.4,8.5Hz,2H),6.96(d,J＝17.3Hz,2H),6.28(s,1H),5.18(s,2H),4.32(d,J＝5.7Hz,2H),3.86–3.72(m,2H),3.46(s,2H),2.25(s,3H),1.54(dt,J＝7.5,16.1Hz,2H),0.89(t,J＝7.4Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ10.7,20.2,24.2,34.8,42.1,50.0,72.9,115.3(d, 2 J C-F ＝21.5Hz),119.3,128.3,128.5,128.9,130.7(d, 3 J C-F ＝7.8Hz),137.3,140.5,146.5,160.7(d, 1 J C-F ＝246.3Hz),170.8,173.1.
Example 41 preparation of N- ((3- (benzyloxy) -1-butyl-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) hexanamide (16 i)
Compound 16a was synthesized from intermediate compound 12d (350mg, 1.2mmol) and hexanoyl chloride (0.3 ml, 1.8mmol) to give 16i as a pale yellow oily liquid 385mg, yield: 80.0 percent. 1 H NMR(300MHz,CDCl 3 )δ7.35(s,5H),6.33(s,1H),5.27(s,2H),4.27(s,2H),4.00–3.74(m,2H),2.29(s,3H),2.04–1.93(m,2H),1.51(dq,J＝7.0,7.5,14.4Hz,4H),1.41–1.17(m,6H),0.90(dt,J＝7.2,18.2Hz,6H). 13 C NMR(75MHz,CDCl 3 )δ13.7,13.9,19.7,20.2,22.3,25.2,31.4,33.0,34.4,36.2,48.4,72.8,119.5,128.4,128.6,129.4,137.4,140.7,146.0,146.3,173.0,173.1.
Example 42 preparation of n- ((3- (benzyloxy) -1-butyl-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4- (trifluoromethyl) benzamide (16 j)
Compound 16a was synthesized starting from intermediate compound 12d (350mg, 1.2mmol) and p-trifluoromethylbenzoyl chloride (0.3ml, 1.8mmol) to give 16j as a pale yellow oily liquid 391mg, yield: 69.2 percent 1 H NMR(400MHz,CDCl 3 )δ8.52(s,1H),8.10(d,J＝7.2Hz,2H),7.64(d,J＝7.4Hz,2H),7.24(d,J＝6.9Hz,5H),6.17(s,1H),5.07(s,2H),4.58(s,2H),4.04–3.70(m,2H),2.24(s,3H),1.57(s,2H),1.33(d,J＝7.3Hz,2H),0.89(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ13.6,19.8,20.0,32.9,35.5,48.7,73.1,119.1,125.3(q, 3 J C-F ＝3.8Hz),128.0,128.2,128.3,128.4,137.0,140.3,146.7,166.1,173.0.
Example 43 preparation of N- ((3- (benzyloxy) -1-butyl-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzamide (16 k)
Compound 16a was synthesized using intermediate compound 12d (350mg, 1.2mmol) and p-methoxybenzoyl chloride (0.3ml, 1.8mmol) as starting materials to give 16k as a pale yellow oily liquid 313mg, yield: 60.0 percent. 1 H NMR(300MHz,CDCl 3 )δ7.66(d,J＝8.8Hz,2H),7.42–7.23(m,5H),6.88(d,J＝8.8Hz,2H),6.68(s,1H),6.35(s,1H),5.31(s,2H),4.52(d,J＝5.7Hz,2H),4.01–3.91(m,2H),3.84(s,3H),2.30(s,3H),1.56(p,J＝7.7,8.4Hz,2H),1.38(dt,J＝7.3,15.0Hz,2H),0.92(t,J＝7.3Hz,3H). 13 C NMR(75MHz,CDCl 3 )δ13.7,19.8,20.2,33.1,35.2,48.6,55.4,73.1,113.6,119.4,125.7,128.4,128.6,129.1,129.1,137.2,140.7,146.3,146.5,162.4,166.7,173.0.
Example 44 preparation of N- ((3- (benzyloxy) -1-butyl-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -3-methoxybenzamide (16 l)
The intermediate compound 12d (350mg, 1.2mmol) and m-methoxybenzoyl chloride (0.3mL, 1.8mmol) are used as raw materials to synthesize the compoundCompound 16a was obtained as a white oily liquid 385mg in 16l, yield: 88.6 percent. 1 H NMR(400MHz,CDCl 3 )δ7.44(s,1H),7.35–7.22(m,7H),7.02(dt,J＝2.0,7.4Hz,1H),6.27(s,1H),5.23(s,2H),4.54(d,J＝5.6Hz,2H),3.97–3.87(m,2H),3.82(s,3H),2.25(s,3H),1.55(p,J＝7.9,8.5Hz,2H),1.36(dt,J＝7.4,15.0Hz,2H),0.90(t,J＝7.3Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ13.7,19.8,20.2,33.0,35.3,48.6,55.5,73.0,112.4,118.1,119.4,128.3,128.5,129.0,129.4,134.9,137.2,140.3,146.4,159.7,167.1,173.1.
Example 45 preparation of N- ((3- (benzyloxy) -1-butyl-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -2-methoxybenzamide (16 m)
Compound 16a was synthesized starting from intermediate compound 12d (350mg, 1.2mmol) and o-methoxybenzoyl chloride (0.3ml, 1.8mmol) to give 16m as a white oily liquid 374mg, yield: 71.7 percent. 1 H NMR(400MHz,CDCl 3 )δ8.42(t,J＝5.9Hz,1H),8.12(dd,J＝1.8,7.8Hz,1H),7.53–7.22(m,6H),7.04(t,J＝7.4Hz,1H),6.90(d,J＝8.3Hz,1H),6.39(s,1H),5.40(s,2H),4.58(d,J＝5.6Hz,2H),4.15(s,2H),3.68(s,3H),2.33(s,3H),1.60(p,J＝7.7,8.2Hz,2H),1.44(h,J＝7.3Hz,2H),0.97(t,J＝7.3Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ13.8,19.8,20.4,33.3,35.3,48.7,55.8,73.0,111.3,119.8,120.6,121.1,128.1,128.4,128.8,132.0,133.2,137.6,141.1,145.9,146.7,157.6,165.2,173.3.
Example 46 preparation of N- ((3- (benzyloxy) -1-butyl-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -2- (4-fluorophenyl) acetamide (16 n)
Compound 16a was synthesized starting from intermediate compound 12d (350mg, 1.3mmol) and 2- (4-fluorophenyl) acetyl chloride (0.3ml, 1.8mmol) to give 16n as a pale yellow oily liquid 413mg, yield: 75.4 percent. 1 H NMR(300MHz,CDCl 3 )δ7.37–7.26(m,5H),7.26–7.18(m,2H),6.96(t,J＝8.7Hz,2H),6.88(s,1H),6.28(s,1H),5.18(s,2H),4.31(d,J＝5.7Hz,2H),3.90–3.74(m,2H),3.45(s,2H),2.25(s,3H),1.49(p,J＝8.3,9.0Hz,2H),1.39–1.27(m,2H),0.91(t,J＝7.2Hz,3H). 13 C NMR(75MHz,CDCl 3 )δ13.6,19.7,20.2,33.0,34.9,42.1,48.5,73.0,115.3(d, 2 J C-F ＝21.5Hz),119.4,128.3,128.5,128.9,128.9,130.7(d, 3 J C-F ＝8.9Hz),137.3,140.6,146.5,160.7(d, 1 J C-F ＝246.3Hz),170.8,173.0.
Example 47 preparation of N- ((3- (benzyloxy) -6-methyl-4-oxo-1-pentyl-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzamide (16 o)
Compound 16a was synthesized using intermediate compound 12d (350mg, 1.3mmol) and p-methoxybenzoyl chloride (0.3ml, 1.8mmol) as starting materials to give 16o as a pale yellow oily liquid 320mg, yield: 54.9 percent. 1 H NMR(400MHz,CDCl 3 )δ7.67(d,J＝8.7Hz,2H),7.31(ddd,J＝7.0,17.4,24.9Hz,5H),6.88(d,J＝8.8Hz,2H),6.33(s,1H),5.30(s,2H),4.52(d,J＝5.7Hz,2H),4.02–3.89(m,2H),3.84(s,3H),2.29(s,3H),1.62–1.50(m,2H),1.38–1.23(m,4H),0.87(t,J＝6.7Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ13.9,20.3,22.3,28.6,30.8,35.2,48.7,55.4,73.0,113.6,119.5,125.7,128.4,128.5,129.1,129.2,137.3,140.6,146.3,162.4,166.7,173.1.
Example 48 preparation of N- ((3- (benzyloxy) -1-ethyl-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzenesulfonamide (16 p)
Compound 16a was synthesized starting from intermediate compound 12b (300mg, 1.1mmol) and p-methoxybenzenesulfonyl chloride (372mg, 1.7mmol) to give 16p as a white oily liquid 221mg, yield: 43.3 percent. 1 H NMR(400MHz,CDCl 3 )δ7.77(d,J＝8.8Hz,2H),7.36(t,J＝7.3Hz,1H),7.31–7.21(m,3H),7.06(dd,J＝8.0,23.3Hz,4H),6.33(s,1H),5.15(s,2H),4.03(q,J＝7.0Hz,2H),3.94(s,3H),3.85(d,J＝6.8Hz,2H),2.30(s,3H),1.32–1.23(m,3H). 13 C NMR(100MHz,CDCl 3 )δ15.6,20.0,38.5,43.1,55.7,72.7,114.3,119.5,128.6,129.4,130.5,136.8,137.8,146.9,163.2.
Example 49 preparation of N- ((3- (benzyloxy) -6-methyl-4-oxo-1-propyl-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzenesulfonamide (16 q)
The intermediate compound 12c (350mg, 1.2mmol) and p-methoxybenzenesulfonyl chloride (372mg, 1.7 mmol) are used as raw materials, and the synthesis method is implementedWith compound 16a, 16q was obtained as 275mg of a white oily liquid, yield: 60.2 percent. 1 H NMR(400MHz,CDCl 3 )δ7.81–7.70(m,2H),7.37(t,J＝7.4Hz,1H),7.31–7.23(m,2H),7.14–6.98(m,4H),6.40(s,1H),5.18(s,2H),3.94(s,3H),3.92–3.82(m,4H),2.32(s,3H),1.60(q,J＝7.7Hz,2H),0.98(t,J＝7.4Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ10.7,20.2,24.1,38.6,49.6,55.7,72.8,114.3,128.6,128.6,129.3,129.4,130.5,136.8,150.4,163.1.
Example 50 preparation of N- ((3- (benzyloxy) -1-butyl-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzenesulfonamide (16 r)
Compound 16a was synthesized using intermediate compound 12d (350mg, 1.2mmol) and p-methoxybenzenesulfonyl chloride (372mg, 1.8mmol) as starting materials to give 16r as a white oily liquid 305mg, yield: 66.8 percent. 1 H NMR(400MHz,CDCl 3 )δ7.81(d,J＝8.9Hz,2H),7.35–7.22(m,4H),7.04(dd,J＝8.0,24.1Hz,4H),6.27(s,1H),5.09(s,2H),3.92(s,5H),3.85(s,2H),2.25(s,3H),1.57–1.34(m,4H),0.96(t,J＝7.3Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ13.7,19.7,20.1,32.8,38.6,47.9,55.7,72.7,114.2,119.3,128.5,129.2,129.4,130.7,136.9,137.9,146.9,163.0,172.9.
Example 51 preparation of N- ((1-ethyl-3-hydroxy-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) heptanamide (17 a)
The intermediate compound 16a (455mg, 0.81mmol) was placed in a single-neck reaction flask, dissolved in 10mL of methanol, added with 45.5mg of Pd/C (l 0% palladium on carbon), evacuated, replaced three times with hydrogen gas, and reacted at room temperature for 12 hours. After the reaction was completed, the reaction solution was filtered through celite, the filtrate was collected and concentrated under reduced pressure to obtain a solid, and the solid was recrystallized from methanol to obtain 17a as a white solid 249mg, yield: 70.6%, purity: 99.82%, melting point: 145.3-146.0 ℃. 1 H NMR(400MHz,CDCl 3 )δ6.29(s,1H),4.63(s,2H),4.24(s,2H),2.37(s,3H),2.21(t,J＝7.6Hz,2H),1.77–1.47(m,2H),1.27(s,9H),0.86(t,J＝5.9Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ14.1,15.9,20.3,22.5,25.5,28.9,31.5,34.5,36.4,43.8,114.5,130.2,144.5,146.9,169.7,173.5.HRMS(ESI):calcd for C 16 H 26 N 2 O 3 [M+H] + ＝295.2016,found[M+H] + ＝295.2016.
Example 52 preparation of N- ((1-ethyl-3-hydroxy-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) hexanamide (17 b)
Compound 17a was synthesized using intermediate compound 16b to give 17b as a white solid 90mg, yield: 52.6%, purity: 99.89%, melting point: 151.5-152.1 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ8.20(s,1H),6.13(s,1H),4.40(d,J＝5.1Hz,2H),3.95(q,J＝7.0Hz,2H),2.34(s,3H),2.10(t,J＝7.4Hz,2H),1.49(p,J＝7.4Hz,2H),1.23(dt,J＝6.8,14.0Hz,7H),0.85(t,J＝7.0Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ14.3,15.8,19.9,22.3,25.3,31.4,34.1,35.4,43.1,113.5,128.7,145.6,146.6,169.9,172.8.HRMS(ESI):calcd for C 15 H 24 N 2 O 3 [M+H] + ＝281.1860,found[M+H] + ＝281.1868.
Example 53 preparation of N- ((1-ethyl-3-hydroxy-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzamide (17 c)
Compound 17a was synthesized using intermediate compound 16c to give 17c as a white solid 321mg, yield: 72.5%, purity: 96.92%, melting point: 231.7-232.6 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.65(s,1H),7.89(d,J＝8.2Hz,2H),6.97(d,J＝8.2Hz,2H),6.14(s,1H),4.62(d,J＝4.4Hz,2H),4.01(q,J＝6.8Hz,2H),3.80(s,3H),2.35(s,3H),1.22(t,J＝6.9Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ15.9,19.9,35.1,43.3,55.8,113.4,113.9,126.5,128.4,129.8,145.7,146.8,162.2,166.3,169.9.HRMS(ESI):calcd for C 17 H 20 N 2 O 4 [M+H] + ＝317.1496,found[M+H] + ＝317.1494.
Example 54 preparation of n- ((3-hydroxy-6-methyl-4-oxo-1-propyl-1, 4-dihydropyridin-2-yl) methyl) -4- (trifluoromethyl) benzamide (17 d)
Compound 17a was synthesized using intermediate compound 16d to give 17d as a white solid 284mg, yield: 84.6%, purity: 96.18%, melting point: 256.4-257.5 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.06(s,1H),8.10(d,J＝8.1Hz,2H),7.83(d,J＝8.3Hz,2H),6.15(s,1H),4.67(d,J＝4.8Hz,2H),3.97–3.77(m,2H),2.35(s,3H),1.64(dq,J＝7.3,14.9Hz,2H),0.87(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ11.2,20.0,23.9,35.3,49.6,113.4,125.7(q, 3 J C-F ＝3.8Hz),128.0,128.9,138.1,145.9,146.9,165.7,169.9.HRMS(ESI):calcd for C 18 H 19 F 3 N 2 O 3 [M+H] + ＝369.1421,found[M+H] + ＝369.1416.
Example 55 preparation of N- ((3-hydroxy-6-methyl-4-oxo-1-propyl-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzamide (17 e)
Compound 17a was synthesized using intermediate compound 16e to give 17e as a white solid 284mg, yield: 84.6%, purity: 97.28%, melting point: 246.6-246.9 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.67(t,J＝4.7Hz,1H),7.90(d,J＝8.9Hz,2H),6.97(d,J＝8.9Hz,2H),6.14(s,1H),4.64(d,J＝4.8Hz,2H),3.90–3.83(m,2H),3.80(s,3H),2.34(s,3H),1.62(dq,J＝7.2,14.9Hz,2H),0.85(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ11.2,20.0,24.0,35.0,49.6,55.8,113.4,113.9,126.5,128.6,129.8,145.8,146.7,162.1,166.3,169.9.HRMS(ESI):calcd for C 18 H 22 N 2 O 4 [M+H] + ＝331.1652,found[M+H] + ＝331.1649.
Example 56 preparation of n- ((3-hydroxy-6-methyl-4-oxo-1-propyl-1, 4-dihydropyridin-2-yl) methyl) -3-methoxybenzamide (17 f)
Compound 17a was synthesized using intermediate compound 16f to give 17f as a white solid 190mg, yield: 64.5%, purity: 99.89%, melting point: 208.1-209.2 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.84(t,J＝4.8Hz,1H),7.54–7.44(m,2H),7.36(t,J＝7.9Hz,1H),7.09(dd,J＝1.9,8.2Hz,1H),6.14(s,1H),4.65(d,J＝4.9Hz,2H),3.91–3.83(m,2H),3.79(s,3H),2.34(s,3H),1.63(dq,J＝7.3,15.0Hz,2H),0.86(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ11.2,20.0,23.9,35.1,49.6,55.8,112.9,113.4,117.8,120.3,128.4,129.8,135.6,145.9,146.8,159.6,166.5,169.9.HRMS(ESI):calcd for C 18 H 22 N 2 O 4 [M+H] + ＝331.1652,found[M+H] + ＝331.1654.
Example 57 preparation of N- ((3-hydroxy-6-methyl-4-oxo-1-propyl-1, 4-dihydropyridin-2-yl) methyl) -2-methoxybenzamide (17 g)
Compound 17a was synthesized using 16g of intermediate compound to give 17g as a white solid 211mg, yield: 71.8%, purity: 98.89%, melting point: 200.9-202.2 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.69(t,J＝5.5Hz,1H),7.81(dd,J＝1.8,7.7Hz,1H),7.48(ddd,J＝1.8,7.4,9.1Hz,1H),7.13(d,J＝8.3Hz,1H),7.04(t,J＝7.1Hz,1H),6.13(s,1H),4.65(d,J＝5.6Hz,2H),4.08–3.96(m,2H),3.88(s,3H),2.34(s,3H),1.66(dq,J＝7.3,14.9Hz,2H),0.94(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ11.2,20.2,23.9,35.0,49.6,56.5,112.6,113.8,121.1,122.5,129.6,131.0,133.1,145.6,146.7,157.5,165.2,169.8.HRMS(ESI):calcd for C 18 H 22 N 2 O 4 [M+H] + ＝331.1652,found[M+H] + ＝331.1650.
Example 58 preparation of 2- (4-fluorophenyl) -N- ((3-hydroxy-6-methyl-4-oxo-1-propyl-1, 4-dihydropyridin-2-yl) methyl) acetamide (17 h)
Compound 17a was synthesized with intermediate compound 16h to give 17h as a white solid 274mg, yield: 84.1%, purity: 99.84%, melting point: 200.5-201.2 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.52(s,1H),7.29(dd,J＝5.6,8.7Hz,2H),7.12(t,J＝8.9Hz,2H),6.13(s,1H),4.41(d,J＝5.1Hz,2H),3.82–3.71(m,2H),3.45(s,2H),2.32(s,3H),1.55(dq,J＝7.4,15.0Hz,2H),0.80(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ11.1,20.0,23.9,34.4,41.4,49.4,113.5,115.2(d, 2 J C-F ＝21.2Hz),128.7,131.2(d, 3 J C-F ＝8.1Hz),132.8(d, 4 J C-F ＝3.0Hz),145.8,146.7,160.3(d, 1 J C-F ＝242.8Hz),169.9,170.6.HRMS(ESI):calcd for C 18 H 21 FN 2 O 3 [M+H] + ＝333.1609,found[M+H] + ＝333.1606.
Example 59 preparation of N- ((1-butyl-3-hydroxy-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) hexanamide (17 i)
Compound 17a was synthesized using intermediate compound 16i to give 17i as a white solid 242mg, yield: 81.9%, purity: 99.56%, melting point: 214.7-215.8 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.17(t,J＝4.9Hz,1H),6.12(s,1H),4.39(s,2H),3.90–3.73(m,2H),2.33(s,3H),2.10(t,J＝7.4Hz,2H),1.53(ddt,J＝7.4,14.6,29.6Hz,4H),1.41–1.15(m,6H),0.92(t,J＝7.3Hz,3H),0.85(t,J＝7.0Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ13.9,14.3,19.8,20.0,22.3,25.3,31.4,32.6,34.1,35.4,47.8,113.4,128.7,145.8,146.6,169.9,172.8.HRMS(ESI):calcd for C 17 H 28 N 2 O 3 [M+H] + ＝309.2173,found[M+H] + ＝309.2171.
Example 60 preparation of n- ((1-butyl-3-hydroxy-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4- (trifluoromethyl) benzamide (17 j)
Compound 17a was synthesized using intermediate compound 16j to give 17j as a white solid 233mg, yield: 73.5%, purity: 99.80%, melting point: 252.1-253.1 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.07(s,1H),8.10(d,J＝8.1Hz,2H),7.84(d,J＝8.3Hz,2H),6.15(s,1H),4.68(d,J＝4.7Hz,2H),4.04–3.72(m,2H),2.35(s,3H),1.59(p,J＝8.6Hz,2H),1.29(h,J＝7.4Hz,2H),0.83(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ13.8,19.8,32.6,35.3,48.1,113.4,123.0,125.6(q, 3 J C-F ＝3.6Hz),125.7,128.0,128.9,131.6(q, 2 J C-F ＝32.2Hz),138.0,145.9,146.9,165.7,169.9.HRMS(ESI):calcd for C 19 H 21 F 3 N 2 O 3 [M+H] + ＝383.1577,found[M+H] + ＝383.1571.
Example 61 preparation of n- ((1-butyl-3-hydroxy-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzamide (17 k)
Compound 17a was synthesized using intermediate compound 16k to give 17k as a white solid 240mg, yield: 76.8%, purity: 96.01%, melting point: 254.6-253.8 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.66(t,J＝4.5Hz,1H),7.90(d,J＝8.8Hz,2H),6.97(d,J＝8.8Hz,2H),6.14(s,1H),4.64(d,J＝4.7Hz,2H),3.97–3.85(m,2H),3.80(s,3H),2.34(s,3H),1.57(p,J＝8.3,8.8Hz,2H),1.28(dt,J＝7.4,14.8Hz,2H),0.81(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ13.8,19.8,20.0,32.6,35.0,48.0,55.8,113.4,113.8,126.4,128.5,129.8,145.8,146.8,162.1,166.2,169.9.HRMS(ESI):calcd for C 19 H 24 N 2 O 4 [M+H] + ＝345.1809,found[M+H] + ＝345.1805.
Example 62 preparation of N- ((1-butyl-3-hydroxy-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -3-methoxybenzamide (17 l)
Compound 17a was synthesized using intermediate compound 16l to give 17l as a white solid 257mg, yield: 84.8%, purity: 98.27%, melting point: 213.0-214.3 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.84(t,J＝4.7Hz,1H),7.53–7.45(m,2H),7.36(t,J＝7.9Hz,1H),7.09(dd,J＝2.9,7.8Hz,1H),6.14(s,1H),4.65(d,J＝4.8Hz,2H),3.96–3.83(m,2H),3.79(s,3H),2.34(s,3H),1.65–1.47(m,2H),1.28(h,J＝7.4Hz,2H),0.82(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ13.8,19.8,20.0,32.6,35.2,48.1,55.8,112.9,113.4,117.8,120.3,128.3,129.8,135.6,145.8,146.8,159.6,166.5,169.9.HRMS(ESI):calcd for C 19 H 24 N 2 O 4 [M+H] + ＝345.1809,found[M+H] + ＝345.1805.
Example 63 preparation of N- ((1-butyl-3-hydroxy-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -2-methoxybenzamide (17 m)
Compound 17a was synthesized using intermediate compound 16m to give 17m as a white solid 257mg, yield: 84.8%, purity: 98.03%, melting point: 185.6-187.4 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.68(s,1H),7.82(dd,J＝1.8,7.7Hz,1H),7.52–7.45(m,1H),7.13(d,J＝8.2Hz,1H),7.04(t,J＝7.8Hz,1H),6.14(s,1H),4.66(d,J＝5.6Hz,2H),4.14–3.99(m,2H),3.88(s,3H),2.34(s,3H),1.61(p,J＝8.5Hz,2H),1.37(h,J＝7.3Hz,2H),0.92(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ13.9,19.8,20.1,32.5,35.0,48.1,56.5,112.6,113.9,121.1,122.4,129.6,131.0,133.1,145.5,146.7,157.5,165.2,169.8.HRMS(ESI):calcd for C 19 H 24 N 2 O 4 [M+H] + ＝345.1809,found[M+H] + ＝345.1805.
Example 64 preparation of N- ((1-butyl-3-hydroxy-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -2- (4-fluorophenyl) acetamide (17 n)
Compound 17a was synthesized using intermediate compound 16n to give 17n as a white solid 285mg, yield: 84.8%, purity: 99.03%, melting point: 191.7 to 192.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.50(s,1H),7.34–7.24(m,2H),7.17–7.07(m,2H),6.13(s,1H),4.39(s,2H),3.94–3.73(m,2H),3.45(s,2H),2.33(s,3H),1.53(p,J＝7.6,8.1Hz,2H),1.26(h,J＝7.4Hz,2H),0.86(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ13.8,19.7,20.0,32.5,34.4,41.4,47.8,113.5,115.2(d, 2 J C-F ＝21.2Hz),128.6,131.3(d, 3 J C-F ＝8.1Hz),132.8(d, 4 J C-F ＝3.0Hz),145.8,146.7,160.3(d, 1 J C-F ＝242.9Hz),169.9,170.6.HRMS(ESI):calcd for C 19 H 23 FN 2 O 3 [M+H] + ＝347.1765,found[M+H] + ＝347.1762.
Example 65 preparation of n- ((3-hydroxy-6-methyl-4-oxo-1-pentyl-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzamide (17 o)
Compound 17a was synthesized using intermediate compound 16o to give 17o as a white solid 183mg, yield: 72.9%, purity: 95.26%, melting point: 182.3-183.6 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.67(s,1H),7.90(d,J＝8.8Hz,2H),6.97(d,J＝8.8Hz,2H),6.14(s,1H),4.64(d,J＝4.6Hz,2H),3.80(s,3H),2.34(s,3H),1.58(s,2H),1.21(s,4H),0.78(t,J＝6.8Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ14.3,20.0,22.1,28.7,30.4,35.0,48.2,55.8,113.4,113.8,126.4,128.5,129.8,145.8,146.8,162.1,166.2,169.9.HRMS(ESI):calcd for C 20 H 26 N 2 O 4 [M+H] + ＝359.1965,found[M+H] + ＝359.1955.
Example 66 preparation of N- ((1-ethyl-3-hydroxy-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzenesulfonamide (17 p)
Compound 17a was synthesized using intermediate compound 16p to give 17p as a white solid 131mg, yield: 77.6%, purity: 99.87%, melting point: 222.1-223.1 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ7.80(d,J＝8.8Hz,2H),7.15(d,J＝8.8Hz,2H),6.10(s,1H),4.05(s,4H),3.86(s,3H),2.33(s,3H),1.21(t,J＝6.5Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ15.7,19.8,38.0,42.7,56.1,113.5,114.9,126.3,129.4,131.6,146.0,146.6,162.8,169.8.HRMS(ESI):calcd for C 16 H 20 N 2 O 5 S[M+H] + ＝353.1166,found[M+H] + ＝353.1162.
Example 67 preparation of N- ((3-hydroxy-6-methyl-4-oxo-1-propyl-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzenesulfonamide (17 q)
Compound 17a was synthesized with intermediate compound 16q to give 17q as a white solid 173mg, yield: 78.6%, purity: 95.17%, melting point: 184.4-185.9 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ7.80(d,J＝8.9Hz,2H),7.15(d,J＝8.9Hz,2H),6.09(s,1H),4.02(s,2H),3.95–3.88(m,2H),3.86(s,3H),2.32(s,3H),1.61(dq,J＝7.2,14.9Hz,2H),0.88(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ11.0,19.9,23.7,38.1,49.0,56.1,113.4,114.9,126.3,129.4,131.6,146.2,146.6,162.8,169.8.HRMS(ESI):calcd for C 17 H 22 N 2 O 5 S[M+H] + ＝367.1322,found[M+H] + ＝367.1320.
Example 68 preparation of N- ((1-butyl-3-hydroxy-6-methyl-4-oxo-1, 4-dihydropyridin-2-yl) methyl) -4-methoxybenzenesulfonamide (17 r)
The intermediate compound 16r is synthesized with compound 17a to obtain 17r is a white solid 225mg, yield: 73.8%, purity: 96.59%, melting point: 167.3-168.9 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ7.80(d,J＝8.8Hz,2H),7.15(d,J＝8.9Hz,2H),6.09(s,1H),4.02(s,2H),3.98–3.90(m,2H),3.86(s,3H),2.32(s,3H),1.56(p,J＝8.6Hz,2H),1.28(dt,J＝9.1,18.1Hz,2H),0.91(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ13.9,19.7,19.9,32.4,38.1,47.5,56.1,113.4,114.9,126.3,129.4,131.6,146.1,146.6,162.8,169.8.HRMS(ESI):calcd for C 18 H 24 N 2 O 5 S[M+H] + ＝381.1479,found[M+H] + ＝381.1474.
EXAMPLE 69 determination of the anti-biofilm Activity of Compounds
The experimental method comprises the following steps: stock compound (100 mM) was prepared first with cell-grade DMSO and then with ABTGC medium ((B medium (0.1% MgCl) 2 ,0.1％CaCl 2 ,0.1％FeCl 3 ) 10% of a10,0.2% of glucose, 0.2% of bd casein amino acids)) to dilute the stock solution compound to be tested to a certain concentration for later use; overnight cultured bacteria were taken and the OD of the overnight bacteria was determined 600 The bacteria were diluted to OD 600 Adding the mixture into a 96-well plate after the concentration is 0.05, arranging a medicine adding group, a Blank group (only adding culture medium) and a Control group (only adding bacteria and a positive Control group), sealing the periphery of the 96-well plate by 200 mu L of liquid culture medium to prevent edge effect caused by volatilization, and arranging 6 compound wells for each group of data; the well-planted bacterial plate is wrapped by a 96-well plate in a preservative film mode to prevent the culture solution from volatilizing, and is placed in an incubator at 37 ℃ for static culture for 24 hours; taking out the 96-well plate, and sucking out the bacteria liquid from each hole by using a liquid transfer gun; washing each well with 150 μ L PBS for 3 times, and air drying; adding 150 mu L of methanol into each hole of the dried 96-hole plate, and fixing for 30min at room temperature; sucking methanol away, air drying, adding 150 μ L of 0.1% crystal violet per well, and dyeing for 15min; the crystal violet was aspirated and washed with 200 μ L of PBS buffer until there was no violet; after drying, 150. Mu.L of 33% glacial acetic acid was added to each well to dissolve crystal violet, and the solution was shaken and shaken well on a micro-shaker to measure OD 570 (ii) a The data were analyzed using the Spss data analysis software and their anti-biofilm activity was calculated. The experimental results are as follows: results of anti-biofilm ActivitySee table 1.
TABLE 1 anti-biofilm inhibitory Activity of the hydroxypyridone derivatives prepared in the examples and Positive control Azithromycin
Figure BDA0003199887630000221
From Table 1, 10 15b,17e,17f,17i,17j,17k,17l,17m,17o,17r derivatives having biofilm inhibitory activity were found, of which 17k exhibited the optimum biofilm inhibitory activity (IC) 50 =4.53 μ M), and the anti-biofilm activity was superior to that of the positive control azithromycin.
Example 70 Minimum Inhibitory Concentration (MIC) assay for bacteria
The experimental method comprises the following steps: first, a stock solution of the compound (100 mM) was prepared with cell-grade DMSO, and then the ABTGC medium (B medium (0.1% 2 ,0.1％CaCl 2 ,0.1％FeCl 3 ) Adding 10% of a10,0.2% of glucose, 0.2% of bd casein amino acids) to the test stock solution compound, diluting the test stock solution compound to a certain concentration for later use; overnight-cultured bacteria were taken and OD of overnight bacteria was measured 600 Diluting the bacteria to OD 600 Adding into 96-well plate after 0.05, setting drug adding group, blank group (only adding culture medium), and Control group (only adding bacteria and positive Control group), setting 6 multiple wells for each group of data, placing in 37 deg.C incubator, standing and culturing for 24 hr, taking out 96-well plate from incubator, and measuring OD of bacteria in each well with microplate reader 600 And (4) detecting the bactericidal capacity of the compound.
The experimental results are as follows: to further investigate whether the series of derivatives have synergistic effect with antibiotics, we firstly tested the MIC of the series of derivatives, specifically as shown in table 1, and found that the MIC of the series of derivatives is >512 μ M from table 1, and verified that the series of derivatives have no bactericidal ability below 512 μ M.
Example 71 MIC assay for antibiotic combination
The experimental method comprises the following steps: first, a stock solution of the compound (100 mM) was prepared in cell-grade DMSO, and then the ABTGC medium (B medium (0.1% 2 ,0.1％CaCl 2 ,0.1％FeCl 3 ) Adding 10% of a10,0.2% of glucose, 0.2% of bd casein amino acids.) the stock solution compound to be tested is diluted to 40 μ M for use; overnight cultured bacteria were taken and the OD of the overnight bacteria was determined 600 Diluting the bacteria to OD 600 After 0.05, adding the mixture into a 96-well plate, wherein the culture solution of the bacteria containing the medicine is 100 mu L (the concentration is 40 mu M), the diluted bacteria is 100 mu L, a Blank group (only adding culture medium), a Control group (only adding bacteria) and an experimental group (different antibiotic concentrations) are simultaneously arranged, 6 multiple wells are arranged for each group of data, and the culture solution is placed in an incubator at 37 ℃ for standing and culturing for 24 hours; the 96-well plate was removed from the incubator, and the OD of the bacteria per well was measured using a microplate reader 600 And (4) detecting the bactericidal capacity of the compound.
The experimental results are as follows: to further verify that the series of derivatives can improve the sensitivity of antibiotics when combined with antibiotics, we combined 10 compounds with optimal Biofilm inhibitory activity 15b,17e,17f,17i,17j,17k,17l,17m,17o,17r with common antibiotics for clinical treatment of Pseudomonas aeruginosa, and Pseudomonas aeruginosa standard model strain PAO1 (ATCC 15692), pseudomonas aeruginosa resistant strain clinically isolated in hospital affiliated to nan river university (1121, 1167, FB, 1129) (Pseudomonas aeruginosa 1121, pseudomonas aeruginosa 1167, pseudomonas aeruginosa FB, pseudomonas aeruginosa 1129 are all reported in "Liu J, hou J S, li Y B, et al. Novel 2-situated 3-hydro-1, 6-dimethyl pyridin-4 (1H) -as Dual-Biofilm Inhibitors of Pseudomonas aeruginosa [ J ] J, journal of chemical, chemical (63): 10921-10945."), and the results of all experiments are shown in table 2, the series of derivatives 15b,17e,17f,17i,17j,17k,17l,17m,17o and 17r are combined with clinically used Pseudomonas aeruginosa infection antibacterial agents quinolone antibiotics (ciprofloxacin), aminoglycoside antibiotics (tobramycin) and colistin at the concentration of 20 μ M, so that the sensitivity of the antibiotics to drug-resistant bacteria is enhanced, and the antibacterial ability of the antibiotics to different clinically resistant strains is improved.
TABLE 2 MIC of hydroxypyridone derivatives 15b,17e,17f,17i,17j,17k,17l,17m,17o,17r (20. Mu.M) prepared in the examples in combination with the antibiotics ciprofloxacin, tobramycin and colistin
Figure BDA0003199887630000231
Figure BDA0003199887630000241
/: antibiotic only controls
Example 72 bacterial infection model detection of Zebra Fish
The experimental method comprises the following steps:
methylene blue solution (1 g/mL): weighing 10.0g of the water, and dissolving the water in 10mL of zebra fish feeding water purification system; zebrafish embryo culture water (eg water): adding 1mL of Meilan liquid (1 g/mL) into 100mL of water in a zebra fish breeding water purification system, and mixing to prepare zebra fish embryo culture water (egg water); phenylthiourea (PTU) (3%): 0.30g of the extract was weighed and dissolved in 10mL of water of a zebrafish breeding water purification system. Diluting with zebra fish embryo culture water with the concentration of 0.003%; tricaine (10 mg/mL): 1.0g of the extract was weighed and dissolved in 10mL of water of a zebra fish breeding water purification system. The concentration of the solution used was 0.1mg/mL, and the solution was diluted with zebrafish embryo culture water. The experiment was carried out using AB wild type zebra fish and the zebra fish were cultured at a water temperature of 28 ℃. Bacterial cultures were grown for 24 hours at 37 ℃ with shaking (200 rpm). Growth of Pseudomonas aeruginosa cultures to OD 600 After =1.2, the bacteria were diluted to inoculation density OD 600 =0.1, different concentrations of shoot apex compound 17k (10 μ M and 20 μ M) were added and grown with bacterial culture shaking (200 rpm) at 37 ℃ for 24 hours. The next day, the bacteria were centrifuged at 3000rpm for 10 minutes and resuspended in fish water at the desired concentration. Embryonic zebrafish, 3 days old (dpf), were first soaked in PTU embryo culture medium containing 40 μ g/mL tricaine. The embryonated fish enters an anesthetic state after 5 min. At this point the fish was moved onto a glass slide and set, and the tail was cut at the tail with a sterile sharp scalpel blade. The young fish with broken tail were quickly washed 3 times back in tricaine-free PTU embryo fluid (to remove the anesthetic residue) and continued to be cultured in PTU embryo fluid. Immediately dip 20 wounded embryos into petri dishes containing bacterial suspension (fish water as control) and then dispense them into 6-well plates (v/v: (v/v))Corning/Costar, NY, usa). Survival at different incubation times was recorded and observed under LEICA fluorescence microscope and photographed.
The experimental results are as follows: the experimental result of the compound 17k on the bacterial infection model of the zebra fish is shown in fig. 1, the compound 17k effectively improves the survival rate of the zebra fish when the concentration is 20 mu M, and the 17k is further verified to have the advantage of further druggability.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (10)

1. A class of hydroxypyridones derivatives is characterized by having a chemical structure as shown in formula I:
Figure FDA0003199887620000011
wherein R is 1 Is one of methyl, ethyl, propyl, butyl and pentyl; r 2 Is H, or a group which is connected with one of aminomethyl, amido methyl and sulfamide methyl and one of straight-chain alkyl with 5-6 carbon atoms, substituted aromatic hydrocarbon and heterocyclic aromatic hydrocarbon mercapto structure; r 3 Is methyl, or one of straight-chain alkane amidomethyl with 5-6 carbon atoms and substituted aromatic amidomethyl.
2. The hydroxypyridone derivative according to claim 1, which has the following chemical structure:
Figure FDA0003199887620000012
3. a method for producing a hydroxypyridone derivative according to claim 2, comprising the steps of:
(1.1) reacting kojic acid, benzyl chloride and sodium hydroxide in a solvent, and purifying reaction liquid obtained after the reaction is finished to obtain a compound 1;
(1.2) putting the compound 1 and methylamine into a solvent for reaction, and purifying the obtained reaction liquid to obtain a compound 2;
(1.3) placing the compound 2, triphenylphosphine, diethyl azodicarboxylate and phthalimide in a solvent for reaction, and purifying the obtained reaction liquid to obtain a compound 3;
(1.4) heating and refluxing the compound 3 and hydrazine hydrate in a solvent for reaction, and purifying the obtained reaction liquid to obtain a compound 4;
(1.5) Compound 4 with acid chloride R 4 COCl and pyridine react in a solvent, the obtained reaction liquid is purified to obtain compounds 5a-5d, and the acyl chloride R 4 COCl corresponds to hexanoyl chloride, p-trifluoromethylbenzoyl chloride, p-methoxybenzoyl chloride or 2- (4-fluorophenyl) acetyl chloride;
(1.6) reacting the compounds 5a-5d with Pd/C in a solvent under a hydrogen atmosphere, and purifying the obtained reaction liquid to obtain compounds 6a-6d;
the synthetic route at this time is:
Figure FDA0003199887620000021
(2.1) putting kojic acid into thionyl chloride for reaction, continuously reacting the crude product with zinc powder and concentrated hydrochloric acid, and purifying the obtained reaction solution to obtain a compound 7;
(2.2) reacting the compound 7 with formaldehyde under an alkaline condition, and purifying the obtained reaction liquid to obtain a compound 8;
(2.3) reacting the compound 8 with benzyl chloride and an aqueous solution of sodium hydroxide in a solvent, and purifying the reaction solution obtained after the reaction is finished to obtain a compound 9;
(2.4) reacting the compound 9 with 3, 4-dihydropyran and p-toluenesulfonic acid to obtain an intermediate, then placing the intermediate and methylamine in a solvent for reaction, and purifying to obtain a compound 10a;
(2.5) placing the compound 10a, triphenylphosphine, diethyl azodicarboxylate and phthalimide in a solvent for reaction to obtain a compound 11a;
(2.6) heating the compound 11a and hydrazine hydrate in a solvent for reflux reaction to obtain a compound 12a;
(2.7) reacting the compound 12a with chloroacetyl chloride and triethylamine in a solvent to obtain a compound 13;
(2.8) placing the compound 13 and boron trichloride in a solvent for reaction to obtain a compound 14;
(2.9) reacting Compound 14 with
Figure FDA0003199887620000022
And potassium hydroxide in a solvent to give compounds 15a-15j, wherein
Figure FDA0003199887620000023
Corresponding to 2-mercaptobenzimidazole, 5-nitro-2-mercaptobenzimidazole, 5-cyano-2-mercaptobenzimidazole, 2-mercapto-5-methylbenzoxazole, 5-chloro-2-mercaptobenzoxazole, 2-mercapto-6-methylbenzothiazole, 6-fluoro-2-mercaptobenzothiazole, 2-mercapto-6-nitrobenzothiazole, 2-mercaptoimidazole or 2-mercaptothiazole;
the synthetic route at this time is:
Figure FDA0003199887620000031
(3.1) reaction of Compound 9 with 3, 4-dihydropyran and p-toluenesulfonic acid to give an intermediate, which is then reacted with R 1 NH 2 Reacting in solvent, and purifying to obtain compound 10b-10e;
(3.2) placing the compound 10b-10e, triphenylphosphine, diethyl azodicarboxylate and phthalimide in a solvent for reaction to obtain a compound 11b-11e;
(3.3) heating the compound 11b-11e and hydrazine hydrate in a solvent for reflux reaction to obtain a compound 12b-12e;
(3.4) Compound 12b-12e, acid chloride R 5 COCl or sulfonyl chloride R 5 SO 2 Cl and pyridine react in anhydrous DMF, and the obtained reaction liquid is purified to obtain compounds 16a-16R, wherein the acyl chloride R 5 COCl is one of heptanoyl chloride, hexanoyl chloride, p-methoxybenzoyl chloride, p-trifluoromethylbenzoyl chloride, p-methoxybenzoyl chloride, m-methoxybenzoyl chloride, o-methoxybenzoyl chloride and 2- (4-fluorophenyl) acetyl chloride; the sulfonyl chloride R 5 SO 2 Cl is p-methoxybenzenesulfonyl chloride;
(3.5) reacting the compound 16a-16r with Pd/C in a solvent under a hydrogen atmosphere, and purifying the obtained reaction liquid to obtain a compound 17a-17r;
the synthetic route at this time is:
Figure FDA0003199887620000032
4. the process for producing a hydroxypyridone derivative according to claim 3, wherein:
carrying out reflux reaction on the reaction in the step (1.1) in a solvent at the temperature of 80 ℃ for 24 hours; the solvent in the step (1.1) is methanol;
the reaction in the step (1.2) is carried out for 24 hours at room temperature; the solvent in the step (1.2) is methanol;
the solvent in the step (1.3) is anhydrous tetrahydrofuran; the reaction in the step (1.3) is carried out at room temperature for 24 hours after feeding at 0 ℃;
the reaction in the step (1.4) refers to reflux reaction in a solvent at 78 ℃ for 3-4h; the solvent in the step (1.4) is ethanol;
the reaction in the step (1.5) is carried out for 6 hours at room temperature in a solvent; the solvent described in step (1.5) is preferably anhydrous DMF;
the reaction in the step (1.6) is carried out for 12 hours at room temperature in a solvent; the solvent in the step (1.6) is methanol;
the step (2.1) of putting kojic acid in thionyl chloride for reaction refers to reacting for 2 hours at room temperature; the continuous reaction with the zinc powder and the concentrated hydrochloric acid means that the reaction lasts for 5 hours at the temperature of 70-80 ℃;
the reaction in the step (2.2) is carried out at room temperature overnight;
the reaction in the step (2.3) refers to reflux reaction at 80 ℃ in a solvent overnight to obtain a product 9; the solvent is methanol;
the reaction of the compound 9, 3, 4-dihydropyran and p-toluenesulfonic acid in the step (2.4) refers to a reaction in a solvent at normal temperature for 3 hours; the subsequent reaction with methylamine in solvent means that the reaction is carried out for 12h at 75 ℃ in ethanol, and then the reaction is carried out for 4h with diluted hydrochloric acid in ethanol under reflux to obtain a product 10a;
the reaction in the step (2.5) is to react for 24 hours at room temperature after feeding anhydrous tetrahydrofuran at 0 ℃ to obtain a compound 11a;
the reaction in the step (2.6) refers to reflux reaction in ethanol solvent at 78 ℃ for 3-4h to obtain a compound 12a;
the reaction in the step (2.7) is carried out for 3 hours at room temperature in a solvent to obtain a compound 13; the solvent is anhydrous DMF;
the reaction in the step (2.8) refers to a reaction in a solvent for 3 hours at room temperature to obtain a compound 14; the solvent is anhydrous DCM;
the reaction described in step (2.9) refers to a reaction in a solvent at 55 ℃ overnight to give compounds 15a-15j; the solvent is methanol.
5. The process for producing a hydroxypyridone derivative according to claim 3, wherein:
the reaction of the compound 9 with 3, 4-dihydropyran and p-toluenesulfonic acid in the step (3.1) is carried out in a solvent at normal temperature for 3 hours; said post and R 1 NH 2 The reaction in the solvent means that the mixture reacts in ethanol at 75 ℃ for 12h and then reacts with dilute hydrochloric acid in ethanol under reflux for 4h to obtain products 10b-10e;
the reaction in the step (3.2) is to carry out reaction for 24 hours at room temperature after feeding materials in solvent anhydrous tetrahydrofuran at 0 ℃, so as to obtain compounds 11b-11e;
the reaction in the step (3.3) refers to reflux reaction in a solvent at 78 ℃ for 3-4h to obtain a compound 12b-12e;
the reaction in the step (3.4) is carried out in anhydrous DMF at room temperature for 6h;
the reaction in the step (3.5) is carried out in a solvent methanol at room temperature for 12 hours in a hydrogen atmosphere.
6. Use of a hydroxypyridone derivative according to claim 1 or 2 for the preparation of a sensitizer for a pseudomonas aeruginosa inhibitor.
7. The use of a hydroxypyridone derivative according to claim 6, in the preparation of a sensitizer for pseudomonas aeruginosa inhibitor, wherein:
the pseudomonas aeruginosa inhibitor is at least one of quinolone antibiotics, aminoglycoside antibiotics and colistin; preferably at least one of ciprofloxacin, tobramycin and colistin.
8. The use of a hydroxypyridone derivative according to claim 6, in the preparation of a sensitizer for pseudomonas aeruginosa inhibitor, wherein:
the pseudomonas aeruginosa is one of pseudomonas aeruginosa PAO1, pseudomonas aeruginosa 1121, pseudomonas aeruginosa 1167, pseudomonas aeruginosa FB and pseudomonas aeruginosa 1129.
9. The use of a hydroxypyridone derivative according to claim 6, in the preparation of a sensitizer for pseudomonas aeruginosa inhibitor, wherein:
the concentration of the hydroxypyridone derivative is more than or equal to 20 mu M.
10. The use of a hydroxypyridone derivative according to claim 6, in the preparation of a sensitizer for pseudomonas aeruginosa inhibitor, wherein:
the hydroxypyridone compound in the pharmaceutical composition can also be a medicinal salt or a solvate of the hydroxypyridone compound;
the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients.
CN202110901353.9A 2021-08-06 2021-08-06 Hydroxypyridones compounds and application thereof as antibiotic sensitizer for overcoming drug resistance of bacterial biofilm Pending CN115703737A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110901353.9A CN115703737A (en) 2021-08-06 2021-08-06 Hydroxypyridones compounds and application thereof as antibiotic sensitizer for overcoming drug resistance of bacterial biofilm

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110901353.9A CN115703737A (en) 2021-08-06 2021-08-06 Hydroxypyridones compounds and application thereof as antibiotic sensitizer for overcoming drug resistance of bacterial biofilm

Publications (1)

Publication Number Publication Date
CN115703737A true CN115703737A (en) 2023-02-17

Family

ID=85179025

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110901353.9A Pending CN115703737A (en) 2021-08-06 2021-08-06 Hydroxypyridones compounds and application thereof as antibiotic sensitizer for overcoming drug resistance of bacterial biofilm

Country Status (1)

Country Link
CN (1) CN115703737A (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104327020A (en) * 2014-10-15 2015-02-04 暨南大学 Furanone derivative for resisting infection and preparation method and use thereof
US20170217897A1 (en) * 2014-08-06 2017-08-03 Zhigan Jiang Quinolone derivatives as antibacterials
CN107089978A (en) * 2016-02-17 2017-08-25 复旦大学 Thiazolidinone derivatives and its production and use
CN108191746A (en) * 2018-02-02 2018-06-22 暨南大学 A kind of novel hydroxyl pyridine compounds and preparation method and application
US20180265496A1 (en) * 2015-08-18 2018-09-20 Jinan University Substituted quinolone derivatives, or pharmaceutically acceptable salts or stereoisomers thereof, and pharmaceutical compositions and use thereof
CN109912532A (en) * 2019-03-05 2019-06-21 暨南大学 Benzothiazole compound and its application in preparation bacterial biof iotalm inhibitor

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170217897A1 (en) * 2014-08-06 2017-08-03 Zhigan Jiang Quinolone derivatives as antibacterials
CN104327020A (en) * 2014-10-15 2015-02-04 暨南大学 Furanone derivative for resisting infection and preparation method and use thereof
US20180265496A1 (en) * 2015-08-18 2018-09-20 Jinan University Substituted quinolone derivatives, or pharmaceutically acceptable salts or stereoisomers thereof, and pharmaceutical compositions and use thereof
CN107089978A (en) * 2016-02-17 2017-08-25 复旦大学 Thiazolidinone derivatives and its production and use
CN108191746A (en) * 2018-02-02 2018-06-22 暨南大学 A kind of novel hydroxyl pyridine compounds and preparation method and application
CN109912532A (en) * 2019-03-05 2019-06-21 暨南大学 Benzothiazole compound and its application in preparation bacterial biof iotalm inhibitor

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JUN LIU ET AL.: "Novel 2‑Substituted 3‑Hydroxy-1, 6-dimethylpyridin-4(1H)‑ones as Dual-Acting Biofilm Inhibitors of Pseudomonas aeruginosa", 《J. MED. CHEM.》, vol. 63, 31 August 2020 (2020-08-31), pages 10921 - 10945 *
高雅婷等: "铜绿假单胞菌的群体感应系统及其抑制剂研究进展", 《中国抗生素杂志》, vol. 43, no. 11, 30 November 2018 (2018-11-30), pages 1338 - 1343 *

Similar Documents

Publication Publication Date Title
JP4927533B2 (en) Substituted pyridine derivatives useful for the treatment of cancer and other diseases
CN103508961B (en) Antitumor drug
CN102391287B (en) Levo-fluoroquinolone C3 bisazole methyl sulfide, preparation method and application thereof
EP0385237A3 (en) 2-(1-piperazinyl)-4-phenylcycloalkanopyridine derivatives, processes for the production thereof, and pharmaceutical composition containing the same
JP5229853B2 (en) Novel bicyclic urea derivatives useful for the treatment of cancer and other diseases
ES2548035T3 (en) Heteroarylmethyl amides
US20050096363A1 (en) Activator of peroxisome proliferator-activated receptor delta
CN105753814A (en) Substituted nitrogen heterocyclic derivative and application thereof
KR20050058442A (en) Compound Having TGF β Inhibitory Activity and Medicinal Composition Containing the Same
KR20010014030A (en) Quinoline-indole antimicrobial agents, uses and compositions related thereto
US11780841B2 (en) 3,6-methano-1H-pyrrolo[3,2-b]pyridine and 3,6-methano-1H-pyrrolo[3,2-c]pyridine compounds and medicaments using same
CN105611927A (en) Compounds for inhibiting drug-resistant strains of HIV-1 integrase
CN104411311A (en) Substituted benzamides and their uses
AU1053899A (en) Novel amide compounds and drugs containing the same
Malik et al. Synthesis and Antimicrobial Evaluation of N-Substituted-5-Benzylidene-2, 4-Thiazolidinedione Derivatives: Synthesis of N-substituted-5-benzylidene-2, 4-thiazolidinediones
CN115703737A (en) Hydroxypyridones compounds and application thereof as antibiotic sensitizer for overcoming drug resistance of bacterial biofilm
CN107445935A (en) A kind of hesperetin analog derivative of amide groups substitution and its preparation and as the application in the medicine of anti-inflammatory
CN104059062A (en) Benzothiazole and triazolediheterocycle-containing fused ring compound and application thereof
JPH0673012A (en) 4-iminoquinoline, its preparation and its use
CN111108083B (en) Use of aminomethylene cyclohexane 1, 3-dione compounds
CN115707698A (en) 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-formamide compound, and preparation method and application thereof
CN103288803B (en) Benzimidazole amides compound and its preparation method and application
CN105906598A (en) Chrysin derivative as well as preparation method and application thereof
CN107163030B (en) Micromolecular heterocyclic compound with pyrazole mother nucleus and application thereof in preparing antibacterial and antitumor drugs
CN111747946B (en) 5-benzofuran-1, 3, 4-thiadiazole-2-substituted amide compound and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination