CN114105947A

CN114105947A - Quinoline derivatives

Info

Publication number: CN114105947A
Application number: CN202010879210.8A
Authority: CN
Inventors: 张贵民; 张君香; 孙士正; 刘忠
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2020-08-27
Filing date: 2020-08-27
Publication date: 2022-03-01

Abstract

The invention relates to the technical field of medicines, in particular to a quinoline derivative; the preparation method of the quinoline derivative comprises the following steps: dissolving the compound II and the compound III in 10% alkaline water solution for refluxing, cooling to room temperature after the reaction is finished, acidifying, washing and drying to obtain a quinoline derivative compound I; the method provides a class of quinoline derivatives, the quinoline derivative compound I has a strong antiviral effect, and the quinoline derivative compound I which can be used for preparing anti-influenza virus drugs is novel in structure, simple in synthesis process, green and environment-friendly, has a strong inhibitory effect on influenza viruses and has an excellent application prospect, and organic solvents can be recycled and reused.

Description

Quinoline derivatives

Technical Field

The invention belongs to the field of organic chemistry and pharmaceutical synthesis, and particularly relates to quinoline derivatives.

Background

The H1N1 swine-derived influenza virus (S-OIV) pandemic in 2009 during which the need to develop additional protection against influenza virus was felt. In response to an epidemic situation, many schools or offices in different countries are forced to be shut down to prevent the spread of S-OIV, followed by mass immunization of people at higher risk of infection, which further evidences the threat of influenza to human life. Despite the relatively low virulence of the recent S-OIV infection compared to previous epidemics, the scientific uncertainty of the evolution of the virulent strain by the new influenza strain requires the necessary precautions to be taken to control the virus.

Currently, vaccination and anti-influenza medication are the primary means of defending against seasonal and pandemic influenza threats. The effectiveness of a vaccine is limited because it is only used to prevent major circulating virus strains. The disadvantage of influenza vaccines is the need for a new vaccine as a precaution against rapidly spreading S-OIV, unlike the common seasonal influenza. Up to now, only four anti-influenza drugs are approved for the treatment or prevention of influenza infection: amantadine and rimantadine (M2 ion channel blocker inhibits the ion channel formed by M2 protein, which is the release of viral ribonucleoprotein particles (vRNP) into host cells); oseltamivir and zanamivir (neuraminidase inhibitors, interfering with the release of new viruses from infected cells). Recently, another neuraminidase inhibitor, ranimivir (Laninamivir), has been approved for use in japan. However, influenza viruses may develop resistance to these drugs, such as highly pathogenic avian influenza type H5N1 virus. Therefore, there is a need to develop new anti-influenza drugs.

The research uses a 4-carboxylic acid-quinoline ring as a mother nucleus framework, a series of anti-influenza virus drugs with novel structures are derived through 2-position substitution, 6-position substitution and 2-position substituent changing design, and the activity of anti-influenza A virus (H1N 1: WSN/33 strain) is measured, so that a lead compound with better anti-influenza A virus activity is obtained.

Disclosure of Invention

In view of the deficiencies of the prior art, the present application provides in a first aspect a compound represented by formula i:

wherein R is selected from Het; het is selected from benzene ring, naphthalene ring, pyridine ring and piperonyl ring, Het is optionally substituted by 1 or 2 substituents, and each substituent is independently selected from C1-C4 alkane, nitro, halogen, halogenated alkyl, benzene ring or methoxy.

The physiologically acceptable salt thereof includes sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like.

Further preferably, the quinoline derivative compound I is selected from the following compounds or pharmaceutically acceptable salts thereof:

a second aspect of the present application relates to a process for the preparation of a quinoline derivative compound of formula I, wherein the reaction is as follows:

a preparation method of a quinoline derivative compound shown as a formula I specifically comprises the following steps:

dissolving the compound II and the compound III in a 10% aqueous alkali solution, refluxing, finishing the reaction, cooling to room temperature, acidifying by a 3N HCl aqueous solution until the pH value is 1, washing and drying to obtain the compound I.

Preferably, the base is selected from one or a combination of potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, sodium tert-butoxide and potassium tert-butoxide.

Preferably, the feeding molar ratio of the compound II to the base is 1: 3 to 5.

Preferably, the feeding molar ratio of the compound II to the compound III is 1: 1 to 1.5;

preferably, the reaction time is 40-50 h.

Wherein the compound III is prepared by the following method:

dissolving the compound V, the compound IV and alkali in an organic solvent, heating to reflux, detecting by TLC, finishing the reaction, cooling to room temperature, washing, drying, and concentrating under reduced pressure to obtain a compound III, wherein the synthetic route is as follows:

preferably, the base is selected from K₂CO₃、Na₂CO₃、KHCO₃、NaHCO₃、Cs₂CO₃N-methylmorpholine or a combination thereof, wherein K is particularly preferred₂CO₃。

Preferably, the molar ratio of compound V to base is 1: 1 to 3.

Preferably, the molar ratio of compound V to compound iv is 1: 1 to 1.5.

Preferably, the solvent is selected from toluene, DMSO, DMF, acetonitrile.

In a third aspect, the invention also relates to the use of quinoline derivative compound I, which is characterized in that the quinoline derivative compound I can be used for preparing biological activity for treating or preventing influenza virus induced cytopathic effect (CPE), used for inhibiting the proliferation of influenza A/WSN/33 virus in vitro in a non-therapeutic way or used in combination.

The results of in vitro anti-influenza virus activity screening show that the quinoline derivative compound I has stronger inhibitory activity to influenza A/WSN/33 virus, and the activity of part of the compound is higher than that of the control medicament 1 a. Therefore, the compound of the invention can be used for preparing anti-influenza virus medicines.

Compared with the prior art, the invention has the main advantages that:

(1) the invention provides a quinoline derivative.

(2) The quinoline derivative compound I provided by the invention has a strong antiviral effect and can be used for preparing anti-influenza virus medicines.

(3) The quinoline derivative compound I provided by the invention has the advantages of novel structure, simple synthesis process, environmental protection, recyclable organic solvent, strong inhibition effect on influenza viruses and good application prospect.

Detailed Description

The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed. Both compound V and compound IV used in the examples were obtained from commercial sources and synthesized in the laboratory.

Preparation of compound iii:

example 1

Compound V (127.0g, 1.0mol), Compound IV-1 (156.0g, 1.0mol) and K₂CO₃(414.0g, 3.0mol) was dissolved in DMF (100ml) and heated to reflux, TCL checked, reaction was complete, cooled to room temperature, filtered, washed with deionised water (50ml), dried and concentrated under reduced pressure to give intermediate III-1, yield: 72.6 percent; HPLC purity: 99.57 percent.

¹HNMR(400Hz,CDCl₃)δ:7.21(t,J＝6.9Hz,2H,Ph-H),6.94(dd,J＝5.9Hz,10.1Hz,2H,Ph-H),6.80(t,J＝5.5Hz,1H,Ph-H),3.14-3.06(m,4H,Pyridine-H),2.36(m,1H,Pyridine-H),2.08(s,3H,-COCH₃),1.87(m,2H,Pyridine-H),1.62(m,2H,Pyridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.5,149.6,129.6(2C),121.9,114.3(2C),52.1(2C),46.7,28.1,27.3(2C)；

ESI-HRMS:m/z＝204.1310[M+H]+

Example 2

Compound V (127.0g, 1.0mol), compound IV-2 (202.4g, 1.1mol) and Na₂CO₃(212.0g, 2.0mol) in DMSO (100ml), heated to reflux, TCL checked, reaction completed, cooled to room temperature, filtered, washed with deionized water (50ml), dried, concentrated under reduced pressure to afford intermediate III-2, yield: 71.3 percent; HPLC purity: 99.48 percent.

¹HNMR(400Hz,CDCl₃)δ:6.89(m,2H,Ph-H),6.68(m,2H,Ph-H),3.16-3.05(m,4H,Pyridine-H),2.60(q,2H,-CH₂CH₃),2.35(m,1H,Pyridine-H),2.07(s,3H,-COCH₃),1.85(m,2H,Pyridine-H),1.60(m,2H,Pyridine-H),1.18(t,3H,-CH₂ ₃CH)；

¹³CNMR(100MHz,CDCl₃)δ:210.4,150.0,137.9,128.6(2C),112.8(2C),52.3(2C),46.7,28.2,28.1,27.3(2C),14.5；

ESI-HRMS:m/z＝232.1623[M+H]+

Example 3

Compound V (127.0g, 1.0mol), compound IV-3 (226.1g, 1.3mol) and KHCO₃(300.4g, 3.0mol) was dissolved in DMF (100ml), heated to reflux, TCL checked, reaction was complete, cooled to room temperature, filtered, washed with deionized water (50ml), dried, concentrated under reduced pressure to give intermediate iii-3, yield: 72.5 percent; HPLC purity: 99.45 percent.

¹HNMR(400Hz,CDCl₃)δ:7.02(t,J＝6.6Hz,2H,Ph-H),6.71(t,J＝7.6Hz,2H,Ph-H),3.14-3.04(m,4H,Pyridine-H),2.38(m,1H,Pyridine-H),2.09(s,3H,-COCH₃),1.80(m,2H,Pyridine-H),1.64(m,2H,Py ridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.7,156.8,145.2,116.4(2C),115.9(2C),52.2(2C),46.6,28.1,27.1(2C)；

ESI-HRMS:m/z＝222.1216[M+H]+

Example 4

Compound V (127.0g, 1.0mol), Compound IV-4 (335.9g, 1.5mol) and NaHCO₃(252.0g, 3.0mol) was dissolved in acetonitrile (100ml), heated to reflux, TCL checked, reaction was complete, cooled to room temperature, filtered, washed with deionized water (50ml), dried, and concentrated under reduced pressure to give intermediate iii-4, yield: 71.9 percent; HPLC purity: 99.46 percent.

¹HNMR(400Hz,CDCl₃)δ:7.29(t,J＝5.6Hz,2H,Ph-H),6.61(t,J＝4.6Hz,2H,Ph-H),3.11-3.04(m,4H,Pyridine-H),2.37(m,1H,Pyridine-H),2.06(s,3H,-COCH₃),1.87(m,2H,Pyridine-H),1.63(m,2H,Py ridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.4,156.1,126.0(3C),124.1,113.2(2C),52.1(2C),46.3,28.2,27.6；

ESI-HRMS:m/z＝272.1184[M+H]+

Example 5

Compound V (127.0g, 1.0mol), compound IV-5 (281.3g, 1.4mol) and Na₂CO₃(318.0g, 3.0mol) was dissolved in toluene (100ml), heated to reflux, TCL checked, reaction was complete, cooled to room temperature, filtered, washed with deionized water (50ml), dried, and concentrated under reduced pressure to give intermediate iii-5, yield: 72.8 percent; HPLC purity: 99.50 percent.

¹HNMR(400Hz,CDCl₃)δ:8.04(m,2H,Ph-H),7.01(d,J＝4.3Hz,2H,Ph-H),3.14-3.06(m,4H,Pyrid ine-H),2.33(m,1H,Pyridine-H),2.08(s,3H,-COCH₃),1.87-1.63(m,4H,Pyridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.6,155.7,137.4,124.8(2C),112.3(2C),52.3(2C),46.8,28.4,27.5；

ESI-HRMS:m/z＝249.1161[M+H]+

Example 6

Compound V (127.0g, 1.0mol), Compound IV-6 (186.0g, 1mol) and Cs₂CO₃(325.8g, 1.0mol) in DMSO (100ml), heated to reflux, TCL checked, reaction completed, cooled to room temperature, filtered, washed with deionized water (50ml), dried, concentrated under reduced pressure to afford intermediate III-2, yield: 70.5 percent; HPLC purity: 99.40 percent.

¹HNMR(400Hz,CDCl₃)δ:6.73(dd,J＝4.3Hz,9.8Hz,2H,Ph-H),6.65(dd,J＝5.3Hz,12.0Hz,2H,Ph-H),3.81(s,3H,-OCH₃),3.15-3.06(m,4H,Pyridine-H),2.36(m,1H,Pyridine-H),2.08(s,3H,-COCH₃),1.88-1.63(m,4H,Pyridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.6,152.8,141.9,115.3(2C),115.2(2C),55.8,52.1,46.8,28.1,27.5；

ESI-HRMS:m/z＝234.1416[M+H]+

Example 7

Compound V (127.0g, 1.0mol), Compound IV-7 (239.2g, 1.3mol) and N-methylmorpholine (303.5g, 3.0mol) were dissolved in toluene (100ml), heated to reflux, tested by TCL, at the end of the reaction, cooled to room temperature, filtered, washed with deionized water (50ml), dried, and concentrated under reduced pressure to give intermediate III-7, yield: 73.1 percent; HPLC purity: 99.53 percent.

¹HNMR(400Hz,CDCl₃)δ:6.81(t,J＝6.3Hz,1H,Ph-H),6.75(d,J＝3.3Hz,1H,Ph-H),6.53(m,1H,Ph-H),3.15-3.03(m,4H,Pyridine-H),2.32(m,1H,Pyridine-H),2.21(s,3H,Ph-CH₃),2.19(s,3H,Ph-CH₃),2.03(s,3H,-COCH₃),1.88-1.63(m,4H,Pyridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.3,147.8,136.1,129.8,126.3,113.9,109.8,52.4,46.5,28.3,27.1,18.8(2C)；

ESI-HRMS:m/z＝232.1623[M+H]+

Example 8

Compound V (127.0g, 1.0mol), compound IV-8 (237.6g, 1.1mol) and K₂CO₃(276.4g, 2.0mol) was dissolved in acetonitrile (100ml), heated to reflux, tested by TCL, the reaction was complete, cooled to room temperature,filtration, washing with deionized water (50ml), drying, and concentration under reduced pressure gave intermediate iii-8, yield: 7 percent; HPLC purity: 99.45 percent.

¹HNMR(400Hz,CDCl₃)δ:6.59(d,J＝6.1Hz,1H,Ph-H),6.41(t,J＝5.3Hz,1H,Ph-H),6.37(d,J＝5.5Hz,1H,Ph-H),3.83(s,3H,-OCH₃),3.76(s,3H,-OCH₃),3.16-3.01(m,4H,Pyridine-H),2.35(m,1H,Pyridine-H),2.08(s,3H,-COCH₃),1.85-1.61(m,4H,Pyridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.5,150.7,142.9,139.3,112.9,107.6,98.4,56.1(2C),52.2(2C),46.8,28.2,27.4；

ESI-HRMS:m/z＝264.1521[M+H]+

Example 9

Compound V (127.0g, 1.0mol), compound IV-9 (299.9g, 1.5mol) and Na₂CO₃(248.0g, 2.0mol) in DMF (100ml) was heated to reflux, TCL checked, reaction was complete, cooled to room temperature, filtered, washed with deionized water (50ml), dried, and concentrated under reduced pressure to give intermediate III-9 in yield: 71.2 percent; HPLC purity: 99.44 percent.

¹HNMR(400Hz,CDCl₃)δ:6.58(t,J＝6.6Hz,1H,Ph-H),6.44(t,J＝5.6Hz,1H,Ph-H),6.35(d,J＝4.5H z,1H,Ph-H),5.97(s,2H,-O-CH₂-O-),3.14-3.01(m,4H,Pyridine-H),2.36(m,1H,Pyridine-H),2.07(s,3H-COCH₃),1.83-1.59(m,4H,Pyridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.4,148.2,142.9,138.3,112.8,107.9,101.2,98.5,52.3(2C),46.6,28.4,27.5；

ESI-HRMS:m/z＝248.1208[M+H]+

Example 10

Compound V (127.0g, 1.0mol), compound IV-10 (206.0g, 1mol) and KHCO₃(200.2g, 2.0mol) was dissolved in acetonitrile (100ml), heated to reflux, TCL checked, reaction was complete, cooled to room temperature, filtered, washed with deionized water (50ml), dried, and concentrated under reduced pressure to give intermediate iii-10, yield: 71.9 percent; HPLC purity: 99.50 percent.

¹HNMR(400Hz,CDCl₃)δ:7.71(m,1H,Ph-H),7.62(m,1H,Ph-H),7.55(m,1H,Ph-H),7.54(d,J＝4.6Hz,1H,Ph-H),7.33(m,1H,Ph-H),7.30(m,1H,Ph-H),6.97(d,J＝4.6Hz,1H,Ph-H),3.14-3.01(m,4H,Py ridine-H),2.36(m,1H,Pyridine-H),2.08(s,3H,-COCH₃),1.87-1.61(m,4H,Pyridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.4,146.3,136.2,130.4,128.1,127.9,127.0,126.9,122.8,116.1,105.6,52.0(2C),46.9,28.5,27.3；

ESI-HRMS:m/z＝254.1467[M+H]+

Example 11

Compound V (127.0g, 1.0mol), Compound IV-11 (263.9g, 1.1mol), and Cs₂CO₃(325.84g, 1.0mol) in DMSO (100ml) was heated to reflux, TCL checked, reaction was complete, cooled to room temperature, filtered, washed with deionized water (50ml), dried, and concentrated under reduced pressure to afford intermediate III-11, yield: 71.7 percent; HPLC purity: 99.47 percent.

¹HNMR(400Hz,CDCl₃)δ:6.73(m,2H,Ph-H),6.65(m,2H,Ph-H),3.17-3.01(m,4H,Pyridine-H),2.30(m,1H,Pyridine-H),2.08(s,3H,-COCH₃),1.81-1.58(m,4H,Pyridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.5,141.9,140.1,129.7,115.3(2C),115.2(2C),52.3(2C),46.5,28.2,27.3；

ESI-HRMS:m/z＝288.1133[M+H]+

Example 12

Compound V (127.0g, 1.0mol), compound IV-12 (255.0g, 1.5mol) and KHCO₃(200.3g, 2.0mol) was dissolved in toluene (100ml), heated to reflux, TCL checked, reaction was complete, cooled to room temperature, filtered, washed with deionized water (50ml), dried, and concentrated under reduced pressure to give intermediate iii-12, yield: 70.9 percent; HPLC purity: 99.41 percent.

¹HNMR(400Hz,CDCl₃)δ:7.15(m,1H,Ph-H),7.01(m,1H,Ph-H),6.80(d,J＝3.6Hz,1H,Ph-H),6.47(m,1H,Ph-H),3.12-3.03(m,4H,Pyridine-H),2.36(m,1H,Pyridine-H),2.27(s,3H,Ph-CH₃),2.10(s,3H,-COCH₃),1.85-1.58(m,4H,Pyridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.3,138.1,129.5,128.5,123.3,119.9,118.5,49.9(2C),46.5,28.2,27.4,21.3；

ESI-HRMS:m/z＝218.1467[M+H]+

Example 13

Compound V (127.0g, 1.0mol), Compound IV-13 (268.7g, 1.4mol) and N-methylmorpholine (202.3g, 2.0mol) were dissolved in DMF (100ml) and heated to reflux, TCL checked, reaction was complete, cooled to room temperature, filtered, washed with deionized water (50ml), dried, and concentrated under reduced pressure to give intermediate III-13, yield: 72.7 percent; HPLC purity: 99.48 percent.

¹HNMR(400Hz,CDCl₃)δ:7.30(m,1H,Ph-H),6.81(m,1H,Ph-H),6.48(m,1H,Ph-H),3.15-3.05(m,4H,Pyridine-H),2.37(m,1H,Pyridine-H),2.08(s,3H,-COCH₃),1.87-1.59(m,4H,Pyridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.5,147.9,146.8,139.0,115.5,111.5,104.4,52.0(2C),46.5,28.2,27.2；

ESI-HRMS:m/z＝240.1122[M+H]+

Example 14

Compound V (127.0g, 1.0mol), Compound IV-14 (157.0g, 1mol) and NaHCO₃(210.0g, 3.0mol) was dissolved in acetonitrile (100ml), heated to reflux, TCL checked, reaction was complete, cooled to room temperature, filtered, washed with deionized water (50ml), dried, and concentrated under reduced pressure to give intermediate iii-14, yield: 72.4 percent; HPLC purity: 99.44 percent.

¹HNMR(400Hz,CDCl₃)δ:8.04(d,J＝5.2Hz,1H,Ph-H),7.92(m,1H,Ph-H),7.36(m,1H,Ph-H),7.15(m,1H,Ph-H),3.14-3.01(m,4H,Pyridine-H),2.38(m,1H,Pyridine-H),2.11(s,3H,-COCH₃),1.87-1.60(m,4H,Pyridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.6,147.0,138.8,135.8,124.7,118.8,52.1(2C),46.5,28.4,27.5；

ESI-HRMS:m/z＝205.1263[M+H]+

Example 15

Compound V (127.0g, 1.0mol), compound IV-15 (278.4g, 1.2mol) and KHCO₃(100.1g, 1.0mol) in DMF (100ml), heated to reflux, TCL checked, reaction completed, cooled to room temperature, filtered, washed with deionized water (50ml), dried, concentrated under reduced pressure to afford intermediate iii-15, yield: 72.1 percent; HPLC purity: 99.43 percent.

¹HNMR(400Hz,CDCl₃)δ:7.75(m,2H,Ph-H),7.49(m,2H,Ph-H),7.41(m,3H,Ph-H),6.92(m,2H,Ph-H),3.13-3.01(m,4H,Pyridine-H),2.32(m,1H,Pyridine-H),2.06(s,3H,-COCH₃),1.87-1.64(m,4H,Pyridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.8,148.5,140.8,133.3,129.2(2C),128.8(2C),127.9(2C),127.6,112.7(2C),52.1(2C),46.9,28.0,27.3；ESI-HRMS:

m/z＝280.1263[M+H]+

Example 16

Compound V (127.0g, 1.0mol), Compound IV-16 (274.4g, 1.5mol) and K₂CO₃(276.4g, 3.0mol) was dissolved in toluene (100ml), heated to reflux, TCL checked, reaction was complete, cooled to room temperature, filtered, washed with deionized water (50ml), dried, and concentrated under reduced pressure to give intermediate iii-16, yield: 71.7 percent; HPLC purity: 99.42 percent.

¹HNMR(400Hz,CDCl₃)δ:7.12(m,2H,Ph-H),6.72(m,2H,Ph-H),3.16-3.00(m,4H,Pyridine-H),2.35(m,1H,Pyridine-H),2.07(s,3H,-COCH₃),1.87-1.64(m,4H,Pyridine-H)；

¹³CNMR(100MHz,CDCl₃)δ:210.7,147.4,129.7(2C),127.2,115.7(2C),52.0(2C),46.3,28.0,27.1；

ESI-HRMS:m/z＝238.0920[M+H]+

Preparation of Compound I

Example 17

Preparation of target Compound I-1:

dissolving compound II (165.0g, 1.0mol) and intermediate III-1 (203.0g, 1.0mol) in 10% potassium hydroxide aqueous solution (2240ml, 4.0mol), refluxing for 45H, cooling to room temperature, acidifying with 3NHCl aqueous solution to pH1, standing for 30min, filtering, and recovering H₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-1 as a brown solid, m.p.: 189 and 191 ℃ yield: 78.5%, HPLC purity: 99.91 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.21(s,1H,-COOH),8.36(t,J＝8.1Hz,1H,5-quinoline-H),8.17(d,J＝4.3Hz,1H,8-quinoline-H),7.97(s,1H,3-quinoline-H),7.33(t,J＝4.5Hz,1H,7-quinoline-H),7.21(t,J＝6.0Hz,2H,Ph-H),6.94(d,J＝8.6Hz,2H,Ph-H),6.80(m,1H,Ph-H),3.14-3.04(m,4H,Piperidine-H),2.78(m,1H,Piperidine-H),1.74-1.49(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:167.7,157.1,156.2,149.6,147.4,133.0,129.6(2C),128.4,127.6,124.4,121.9,120.5,114.3(2C),108.4,50.9(2C),34.3,25.7(2C).

ESI-HRMS(m/z):351.1431[M+H]+

Example 18

Preparation of target Compound I-2:

dissolving compound II (165.0g, 1mol) and compound III-2 (277.2g, 1.2mol) in 10% sodium hydroxide aqueous solution (1600ml, 4.0mol), refluxing for 42H, cooling to room temperature, acidifying with 3N HCl aqueous solution to pH1, standing for 30min, filtering, and adding H₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-2 as a brown solid, m.p.: 199-: 77.3%, HPLC purity: 99.89 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.20(s,1H,-COOH),8.35(t,J＝8.2Hz,1H,5-quinoline-H),8.15(d,J＝4.3Hz,1H,8-quinoline-H),8.01(s,1H,3-quinoline-H),7.34(t,J＝4.6Hz,1H,7-quinoline-H),6.89(d,J＝6.1Hz,2H,Ph-H),6.68(t,J＝8.2Hz,2H,Ph-H),3.14-3.05(m,4H,Piperidine-H),2.77(m,1H,Piperidine-H),2.60(q,2H,-CH2-CH3),1.74-1.48(m,4H,Piperidine-H),1.18(t,3H,J＝7.4Hz,-CH2-CH3).

¹³CNMR(100Hz,[D6]DMSO)δ:166.4,164.6,144.3,135.5,132.5,128.9(2C),128.6(4C),127.9,127.7(2C),125.9,123.1,49.8,44.4,33.9,28.2,25.1.15.5,14.5.

ESI-HRMS(m/z):379.1744[M+H]+

Example 19

Preparation of target Compound I-3:

dissolving compound II (165.0g, 1mol) and intermediate III-3 (222.12.0g, 1.5mol) in 10% lithium hydroxide aqueous solution (958ml, 4.0mol), refluxing for 48H, cooling to room temperature, acidifying with 3N HCl aqueous solution to pH1, standing for 30min, filtering, and adding H₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-3 as a brown solid, m.p.: 191 ℃ 193 ℃, yield: 80.41%, HPLC purity: 99.93 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.19(s,1H,-COOH),8.34(t,J＝8.3Hz,1H,5-quinoline-H),8.15(d,J＝4.5Hz,1H,8-quinoline-H),8.01(s,1H,3-quinoline-H),7.30(t,J＝4.2Hz,1H,7-quinoline-H),7.02(t,J＝12.0Hz,2H,Ph-H),6.71(t,J＝6.0Hz,1H,Ph-H),3.14-3.05(m,4H,Piperidine-H),2.77(m,1H,Piperidine-H),1.75-1.50(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:167.6,157.3,156.8,156.2,147.4,145.4,133.3,128.4,127.7,124.4,120.5,116.4(2C),115.9(2C),108.3,51.0(2C),33.9,25.9(2C).

ESI-HRMS(m/z):369.1336[M+H]+

Example 20

Preparation of target Compound I-4:

dissolving compound II (165.0g, 1.0mol) and intermediate III-4 (271.1g, 1.0mol) in 10% sodium hydride water solution (1200ml, 5.0mol), refluxing for 50H, cooling to room temperature, acidifying with 3N HCl water solution to pH1, standing for 30min, filtering, and adding H₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-4 as a brown solid, m.p.: 189 and 191 ℃ yield: 79.5%, HPLC purity: 99.91 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.18(s,1H,-COOH),8.37(t,J＝8.0Hz,1H,5-quinoline-H),8.17(d,J＝5.6Hz,1H,8-quinoline-H),7.99(s,1H,3-quinoline-H),7.35(t,J＝4.4Hz,1H,7-quinoline-H),7.30(t,J＝6.0Hz,2H,Ph-H),6.61(dd,J＝8.9,2.1Hz,2H,Ph-H),3.15-3.02(m,4H,Piperidine-H),2.80(m,1H,Piperidine-H),1.75-1.51(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:167.5,157.1,156.3,156.1,146.9,133.0,128.5,127.6,126.0(3C),121.4,124.1,120.5,113.3(2C),108.8,50.7(2C),34.3,25.7(2C).

ESI-HRMS(m/z):419.1304[M+H]⁺

Example 21

Preparation of target Compound I-5:

dissolving compound II (165.0g, 1.0mol) and intermediate III-5 (248g, 1.0mol) in 10% potassium hydride aqueous solution (2000ml, 5.0mol), refluxing for 50H, placing the reaction solution in a low-temperature cooling liquid circulating pump, acidifying to pH1 with 3N HCl aqueous solution, standing for 30min, and reacting with H₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-5 as a brown solid, m.p.: 200 ℃ and 201 ℃, yield: 77.9%, HPLC purity: 99.90 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.19(s,1H,-COOH),8.38(,1H,5-quinoline-H),8.20(t,J＝8.2Hz,1H,8-quinoline-H),8.04-7.98(m,3H,3-quinoline-H,Ph-H),7.29(t,J＝4.3Hz,1H,7-quinoline-H),7.02(d,J＝6.3Hz,2H,Ph-H),3.15-3.02(m,4H,Piperidine-H),2.80(m,1H,Piperidine-H),1.75-1.51(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:168.0,157.2,156.2,155.7,147.4,137.4,133.0,128.4,127.5,124.8(2C),124.4,120.5,112.3(2C),108.3,50.7(2C),34.3,25.6(2C).

ESI-HRMS(m/z):396.1281[M+H]+

Example 22

Preparation of target Compound I-6:

dissolving compound II (165.0g, 1.0mol) and intermediate III-6 (326.3g, 1.4mol) in 10% sodium tert-butoxide aqueous solution (2880ml, 3.0mol) for refluxing for 45H, placing the reaction solution in a low-temperature cooling solution circulating pump, acidifying to pH1 with 3N HCl aqueous solution, standing for 30min, and reacting with H₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-6 as a brown solid, m.p.: 148 ℃ and 150 ℃, yield: 78.1%, HPLC purity: 99.89 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.21(s,1H,-COOH),8.35(t,J＝8.1Hz,1H,5-quinoline-H),8.15(d,J＝9.1Hz,1H,8-quinoline-H),7.98(s,1H,3-quinoline-H),7.34(t,J＝4.6Hz,1H,7-quinoline-H),6.73(d,J＝8.0Hz,2H,Ph-H),6.65(d,J＝8.2Hz,2H,Ph-H),3.81(s,3H,Ph-OCH3),3.11-3.04(m,4H,Piperidine-H),2.75(m,1H,Piperidine-H),1.74-1.46(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:167.9,157.1,156.2,152.8,147.4,141.9,133.0,128.4,127.5,124.4,120.5,115.3(2C),115.2(2C),108.4,55.8,50.9(2C),34.4,25.7(2C).

ESI-HRMS(m/z):381.1536[M+H]⁺

Example 23

Preparation of target Compound I-7:

dissolving compound II (165.0g, 1.0mol) and intermediate III-7 (254.3g, 1.1mol) in 10% potassium tert-butoxide aqueous solution (3360ml, 3.0mol) and refluxing for 40H, placing the reaction solution in a low-temperature cooling solution circulating pump, acidifying with 3N HCl aqueous solution to pH1, standing for 30min, and reacting with H₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-7 as a brown solid, m.p.: 198 ℃ and 200 ℃, yield: 79.5%, HPLC purity: 99.92 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.21(s,1H,-COOH),8.36(t,J＝8.5Hz,1H,5-quinoline-H),8.16(d,J＝12.0Hz,1H,8-quinoline-H),7.98(s,1H,3-quinoline-H),7.33(t,J＝4.6Hz,1H,7-quinoline-H),6.81(t,J＝7.2Hz,1H,Ph-H),6.75(d,J＝4.1Hz,1H,Ph-H),6.53(d,d,J＝5.3Hz,1H,Ph-H),3.16-3.02(m,4H,Piperidine-H),2.80(m,1H,Piperidine-H),2.21(s,3H,Ph-CH3),2.19(s,3H,Ph-CH3),1.74-1.49(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:166.7,157.2,156.4,147.8,147.4,136.1,133.0,129.8,128.4,127.5,126.3,124.4,120.5,113.9,109.8,108.3,50.7(2C),34.3,25.6(2C),18.8(2C).

ESI-HRMS(m/z):379.1744[M+H]+

Example 24

Preparation of target Compound I-8:

dissolving compound II (165.0g, 1.0mol) and intermediate III-8 (263.1g, 1.1mol) in 10% potassium hydroxide aqueous solution (1680ml, 3.0mol), refluxing for 40H, placing the reaction solution in a low-temperature cooling solution circulating pump, acidifying with 3N HCl aqueous solution to pH1, standing for 30min, and allowing the reaction solution to stand for H₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-8 as a brown solid, m.p.: 200 ℃ and 201 ℃, yield: 77.9%, HPLC purity: 99.88 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.20(s,1H,-COOH),8.36(t,J＝7.8Hz,1H,5-quinoline-H),8.16(d,J＝4.8Hz,1H,8-quinoline-H),7.98(s,1H,3-quinoline-H),7.33(t,J＝6.0Hz,1H,7-quinoline-H),6.59(d,J＝3.8Hz,1H,Ph-H),6.41(t,J＝5.1Hz,1H,Ph-H),6.37(s,1H,Ph-H),3.92(s,3H,-OCH3),3.83(s,3H,Ph-OCH3),3.76(s,3H,Ph-OCH3),3.16-3.02(m,4H,Piperidine-H),2.80(m,1H,Piperidine-H),2.21(s,3H,Ph-CH3),2.19(s,3H,Ph-CH3),1.74-1.49(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:167.7,157.4,156.2,150.7,147.4,142.9,139.3,133.0,128.4,127.5,124.4,120.6,112.9,108.4,98.4,58.1(2C),50.8(2C),34.4,25.5(2C).

ESI-HRMS(m/z):411.1642[M+H]+

Example 25

Preparation of target Compound I-9:

dissolving compound II (165.0g, 1.0mol) and intermediate III-9 (296.5g, 1.2mol) in 10% sodium hydroxide aqueous solution (2500ml, 5.0mol) for refluxing for 48H, placing the reaction solution in a low-temperature cooling solution circulating pump, acidifying to pH1 with 3N HCl aqueous solution, standing for 30min, and carrying out H reaction₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-9 as a brown solid, m.p.: 262-263 ℃ and yield: 80.01%, HPLC purity: 99.92 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.20(s,1H,-COOH),8.36(t,J＝8.1Hz,1H,5-quinoline-H),8.16(d,J＝3.9Hz,1H,8-quinoline-H),7.98(s,1H,3-quinoline-H),7.33(t,J＝4.2Hz,1H,7-quinoline-H),6.57(d,J＝6.4Hz,1H,Ph-H),6.40(t,J＝5.3Hz,1H,Ph-H),6.37(s,1H,Ph-H),5.97(s,2H,-OCH2O-),3.14-3.02(m,4H,Piperidine-H),2.81(m,1H,Piperidine-H),1.74-1.47(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:167.3,157.1,156.2,148.2,147.5,142.8,138.3,133.1,128.4,127.4,124.5,120.6,112.6,108.1,107.6,101.2,98.4,50.5(2C),34.4,25.7(2C).

ESI-HRMS(m/z):395.1329[M+H]+

Example 26

Preparation of target Compound I-10:

dissolving compound II (165.0g, 1.0mol) and intermediate III-10 (303.8g, 1.2mol) in 10% potassium hydroxide aqueous solution (2800ml, 5.00mol) and refluxing for 40h, and adding the reaction solution to low-temperature cooling solutionAcidifying with 3N HCl aqueous solution to pH1 in circulating pump, standing for 30min, and reacting with hydrogen₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-10 as a brown solid, m.p.: 302-: 78.7%, HPLC purity: 99.87 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.23(s,1H,-COOH),8.33(t,J＝8.3Hz,1H,5-quinoline-H),8.15(d,J＝6.0Hz,1H,8-quinoline-H),7.98(s,1H,3-quinoline-H),7.71(t,J＝6.4Hz,1H,Ph-H),7.62(t,J＝5.7Hz,1H,Ph-H),7.55(t,J＝8.5Hz,1H,Ph-H),7.54(d,J＝4.4Hz,1H,Ph-H),7.33(t,J＝7.0Hz,1H,Ph-H),7.30(t,J＝3.6Hz,1H,Ph-H),6.97(s,1H,Ph-H),3.14-3.05(m,4H,Piperidine-H),2.79(m,1H,Piperidine-H),1.77-1.47(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:167.6,158.1,156.2,147.5,146.3,136.2,133.1,130.4,128.4,128.1,127.9,127.5,127.0,126.9,124.4,122.8,120.5,116.1,108.3,105.6,50.9(2C),34.4,25.6(2C).

ESI-HRMS(m/z):401.1587[M+H]+

Example 27

Preparation of target Compound I-11:

dissolving compound II (165.0g, 1.0mol) and intermediate III-11 (430.7g, 1.5mol) in 10% sodium hydroxide aqueous solution (2500ml, 5.00mol), refluxing for 50H, placing the reaction solution in a low-temperature cooling solution circulating pump, acidifying with 3N HCl aqueous solution to pH1, standing for 30min, and reacting with H₂O (20ml × 2) was rinsed twice and dried in vacuo to give the title compound I-11 as a white solid, m.p.: 184 ℃ and 186 ℃, yield: 78.5%, HPLC purity: 99.88 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.23(s,1H,-COOH),8.36(t,J＝8.5Hz,1H,5-quinoline-H),8.17(d,J＝6.8Hz,1H,8-quinoline-H),7.98(s,1H,3-quinoline-H),7.34(t,J＝4.3Hz,1H,7-quinoline-H),6.73(d,J＝7.0Hz,2H,Ph-H),6.65(d,J＝8.2Hz,2H,Ph-H),3.13-3.04(m,4H,Pipe ridine-H),2.80(m,1H,Piperidine-H),1.74-1.46(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:167.5,157.2,156.4,147.7,141.9,140.1,133.2,129.7,128.4,127.5,124.5,120.6,115.3(2C),115.2(2C),108.2,51.0(2C),34.5,25.5(2C).

ESI-HRMS(m/z):435.1254[M+H]⁺

Example 28

Preparation of target Compound I-12:

dissolving compound II (165.0g, 1.0mol) and intermediate III-12 (217.2g, 1.0mol) in 10% calcium hydroxide aqueous solution (2996ml, 4.00mol), refluxing for 50H, placing the reaction solution in a low-temperature cooling solution circulating pump, acidifying to pH1 with 3N HCl aqueous solution, standing for 30min, and reacting with H₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-11 as a brown solid, m.p.: 204 ℃ and 206 ℃, yield: 81.4%, HPLC purity: 99.93 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.23(s,1H,-COOH),8.33(t,J＝8.3Hz,1H,5-quinoline-H),8.14(d,J＝4.5Hz,1H,8-quinoline-H),8.00(s,1H,3-quinoline-H),7.33(t,J＝4.6Hz,1H,7-quinoline-H),7.15(d,J＝7.0Hz,1H,Ph-H),7.01(t,J＝6.4Hz,1H,Ph-H),6.80(s,1H,Ph-H),6.47(t,J＝5.7Hz,1H,Ph-H),3.13-3.04(m,4H,Piperidine-H),2.80(m,1H,Piper idine-H),2.27(s,3H,Ph-CH3),1.74-1.45(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:167.5,157.3,156.4,147.5,138.1,133.1,129.5,128.4,128.3,127.5,124.5,123.3,120.6,119.9,118.5,108.4,51.1(2C),34.7,25.8(2C),21.4.

ESI-HRMS(m/z):365.1587[M+H]⁺

Example 29

Preparation of target Compound I-13:

dissolving compound II (165.0g, 1.0mol) and intermediate III-13 (310.8g, 1.3mol) in 10% potassium hydroxide aqueous solution (1680ml, 3.00mol), refluxing for 40H, placing the reaction solution in a low-temperature cooling solution circulating pump, acidifying to pH1 with 3NHCl aqueous solution, standing for 30min, and reacting with H₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-11 as a brown solid, m.p.: 219 ℃ 221 ℃, yield: 79.9%, HPLC purity: 99.90 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.22(s,1H,-COOH),8.35(t,J＝8.6Hz,1H,5-quinoline-H),8.19(d,J＝8.3Hz,1H,8-quinoline-H),7.98(s,1H,3-quinoline-H),7.34(t,J＝4.2Hz,1H,7-quinoline-H),7.30(d,J＝6.0Hz,1H,Ph-H),6.81(d,J＝7.6,1H,Ph-H),6.48(t,J＝5.8Hz,1H,Ph-H),3.13-3.04(m,4H,Piperidine-H),2.79(m,1H,Piperidine-H),1.74-1.49(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:167.6,157.1,156.2,147.9,147.4,146.8,139.0,133.0,128.4,127.5,124.4,120.7,115.5,111.5,108.3,104.4,51.0(2C),34.3,25.6(2C).

ESI-HRMS(m/z):387.1242[M+H]⁺

Example 30

Preparation of target Compound I-14:

compound ii (165.0g, 1.0mol) and intermediate iii-14 (285.7g, 1.4mol) were dissolved in 10% aqueous sodium hydroxide (2000ml, 4.0mol) and refluxed for 45h, and the reaction solution was put into a low-temperature coolant circulating pump, acidified to pH1 with 3n hcl aqueous solution, left to stand for 30min, brown solid, melting point: 211 ℃ and 213 ℃, yield: 77.1%, HPLC purity: 99.87 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.20(s,1H,-COOH),8.36(t,J＝8.5Hz,1H,5-quinoline-H),8.17(d,J＝7.9Hz,1H,8-quinoline-H),8.04(d,J＝4.1Hz,1H,Pyridine-H),7.98(s,1H,3-quinoline-H),7.92(d,J＝7.4,1H,Pyridine-H),7.36(t,J＝8.3Hz,1H,Pyridine-H),7.33(t,J＝4.6Hz,1H,7-quinoline-H),7.15(d,J＝6.4Hz,1H,Pyridine-H),3.15-3.04(m,4H,Piperidine-H),2.78(m,1H,Piperidine-H),1.76-1.49(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:167.9,157.1,156.4,147.4,147.0,138.8,135.8,133.3,128.4,127.5,124.7,124.4,120.6,118.8,108.3,50.8(2C),34.3,25.6(2C).

ESI-HRMS(m/z):352.1383[M+H]⁺

Example 31

Preparation of target Compound I-15:

dissolving the compound II (165.0g, 1.0mol) and the intermediate III-15 (307.1g, 1.1mol) in 10% calcium hydroxide aqueous solution (3745ml, 5.0mol) for refluxing for 45h, ending the reaction, putting the reaction liquid into a low-temperature cooling liquid circulating pump, acidifying to pH1 with 3N HCl aqueous solution, standing for 30min, brown solid, melting point: 189 ℃ and 201 ℃, yield: 79.4%, HPLC purity: 99.90 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.20(s,1H,-COOH),8.36(t,J＝8.5Hz,1H,5-quinoline-H),8.17(d,J＝7.0Hz,1H,8-quinoline-H),8.04(d,J＝4.7Hz,1H,Pyridine-H),7.98(s,1H,3-quinoline-H),7.75(d,J＝5.6,2H,Ph-H),7.49(dd,J＝8.9,2.4Hz,2H,Ph-H),7.41(m,3H,Ph-H),7.33(t,J＝4.3Hz,1H,7-qu inoline-H),6.92(d,J＝6.2Hz,2H,Ph-H),3.15-3.04(m,4H,Piperidine-H),2.78(m,1H,Piperidine-H),1.76-1.49(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:167.9,157.1,156.4,148.5,147.4,140.8,133.3,133.0,129.2(2C),128.8(2C),128.4,127.9(2C),127.6,127.5,124.4,120.5,112.7(2C),108.3,50.8(2C),34.3,25.8(2C).

ESI-HRMS(m/z):427.1744[M+H]⁺

Example 32

Preparation of target Compound I-16:

compound II (165.0g, 1.0mol) and intermediate III-15 (355.6g, 1.5mol) were dissolved in 10% aqueous potassium hydroxide (2240ml, 4.0mol) and refluxed for 50h, and the reaction solution was put into a low-temperature cooling solution circulating pump, acidified to pH1 with 3N HCl aqueous solution, and left to stand for 30min, brown solid, melting point: 308 ℃ and 310 ℃, yield: 78.7%, HPLC purity: 99.86 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.22(s,1H,-COOH),8.35(t,J＝8.2Hz,1H,5-quinoline-H),8.16(d,J＝7.4Hz,1H,8-quinoline-H),7.98(s,1H,3-quinoline-H),7.35(t,J＝4.2Hz,1H,7-quinoline-H),7.12(d,J＝4.8Hz,2H,Ph-H),6.72(d,J＝8.7Hz,2H,Ph-H),3.15-3.04(m,4H,Piperidine-H),2.77(m,1H,Pip eridine-H),1.74-1.44(m,4H,Piperidine-H).

¹³CNMR(100Hz,[D6]DMSO)δ:167.8,157.2,156.4,152.8,147.7,147.4,133.1,129.7(2C),127.5,127.2,124.4,120.5,115.7(2C),108.4,50.9(2C),34.4,25.7(2C).

ESI-HRMS(m/z):385.1041[M+H]⁺

Example 33 (Compound III, lower endpoint excluded)

Preparation of target Compound I-1:

dissolving compound II (165.0g, 1.0mol) and intermediate III-1 (162.4g, 0.8mol) in 10% potassium hydroxide aqueous solution (1120ml, 2.0mol), refluxing for 35H, placing the reaction solution in a low-temperature cooling solution circulating pump, acidifying to pH1 with 3N HCl aqueous solution, standing for 30min, filtering, and reacting with H₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-1 as a brown solid, m.p.: 189 and 191 ℃ yield: 62.1%, HPLC purity: 99.71 percent.

¹HNMR(400Hz,CDCl₃-[D6]DMSO)δ:13.21(s,1H,-COOH),8.36(t,J＝8.1Hz,1H,5-quinoline-H),8.17(d,J＝4.3Hz,1H,8-quinoline-H),7.97(s,1H,3-quinoline-H),7.33(t,J＝4.5Hz,1H,7-quinoline-H),7.21(t,J＝6.0Hz,2H,Ph-H),6.94(d,J＝8.6Hz,2H,Ph-H),6.80(m,1H,Ph-H),3.14-3.04(m,4H,Piperi dine-H),2.78(m,1H,Piperidine-H),1.74-1.49(m,4H,Piperidine-H).

ESI-HRMS(m/z):351.1431[M+H]+

Example 34 (Compound III, top end point out)

Preparation of target Compound I-2:

dissolving compound II (165.0g, 1mol) and compound III-2 (415.8g, 1.8mol) in 10% sodium hydroxide aqueous solution (2800ml, 7.0mol), refluxing for 60H, placing the reaction solution in a low-temperature cooling liquid circulating pump, acidifying with 3N HCl aqueous solution to pH1, standing for 30min, filtering, and removing H₂O (20ml × 2) was eluted twice and dried in vacuo to give the title compound I-2 as a brown solid, m.p.: 199-: 61.4%, HPLC purity: 99.70 percent.

ESI-HRMS(m/z):351.1431[M+H]+

Test method and results of antiviral Activity of Compound

The virus source is as follows: influenza A/WSN/33 was produced using a 12 plasmid-based reverse genetics system described by Fodor et al.

The determination method comprises the following steps: 96-well tissue culture plates were seeded with MDCK cells (200mL) at a cell density of 1.1X 10⁵cellsmL^-1Dulbecco's Modified Eagle's Medium (DMEM) containing 10% Fetal Bovine Serum (FBS) was used. Plates were incubated at 37 ℃ for 24-30 hours and cells were used at-90% confluence. Virus (100 TCID) to be mixed with different concentrations of test compound₅₀) Cells were added and the plates were incubated at 37 ℃ for 1 hour. After adsorption, infected cells were treated with 50ml serum-free DMEM (E)₀: DMEM with penicillin [100UmL ]^-1]Streptomycin [100mg/mL ]]1-Glutamine [2mm ]]Non-essential amino acid mixture [0.1mm]And trypsin [2.5mg/mL ]^-1]) And 0.1% DMSO coverage. The plates were incubated at 37 ℃ for 72 hours. At the end of the incubation period, cells were fixed by treatment with 4% formaldehyde (100mL) for 1 hour at room temperature. After removal of formaldehyde, cells were stained with 0.1% crystal violet for 15 minutes at room temperature, after which the cells were washed, dried, and the density of the wells was measured at 570 nm. The concentration of test compound required to reduce virus-induced CPE by 50% relative to the virus control is expressed as IC₅₀The value is obtained. All assays were performed at least twice and in triplicate.

With 1a^[10]As a positive control, compounds I-1-16 were assayed for inhibition of virus-induced cytopathic effect (CPE) (IC) in MDCK cells₅₀Measurement). The results are shown in Table 1.

In vitro experiments show that the compounds I-1-16 of the invention have stronger inhibitory activity to influenza A/WSN/33, and the activity of most compounds is superior to that of a control drug 1a, wherein the inhibitory activity of the compounds I-7 and the compounds I-13 to the influenza A/WSN/33 is strongest. Therefore, the compound prepared by the invention can be used for preparing anti-influenza virus medicines, and the compound has the advantages of simple synthesis method, cheap and easily-obtained raw materials, high product purity, suitability for industrial production and good application prospect.

Claims

1. A quinoline derivative is shown in a formula I, and the structural formula is as follows:

r is selected from Het; het is selected from benzene ring, naphthalene ring, pyridine ring and piperonyl ring, Het is optionally substituted by 1 or 2 substituents, and each substituent is independently selected from C1-C4 alkane, nitro, halogen, halogenated alkyl, benzene ring or methoxy.

2. A process for the preparation of quinoline derivative compound I according to claim 1, wherein the reaction is represented by the formula:

3. the method of preparing derivative compound I according to claim 2, comprising the steps of: and dissolving the compound II and the compound III in a 10% alkaline water solution for refluxing, cooling to room temperature after the reaction is finished, washing and drying to obtain the compound I.

4. The method according to claim 3, wherein the base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof.

5. The preparation method according to claim 3, wherein the feeding molar ratio of the compound II to the base is 1: 3 to 5.

6. The preparation method according to claim 3, wherein the feeding molar ratio of the compound II to the compound III is 1: 1 to 1.5.

7. The preparation method according to claim 3, wherein the reaction time is 40-50 h.

8. The preparation method according to claim 2, wherein the synthetic route of the compound III is as follows:

9. the method of claim 8, wherein the method comprises the steps of: dissolving the compound V, the compound IV and alkali in an organic solvent, and heating and refluxing to obtain a compound III.

10. Use of derivative compound I according to claim 1 and salts thereof for the preparation of a biological activity for the treatment or prevention of influenza virus induced cytopathic effect (CPE), for the non-therapeutic inhibition of influenza a/WSN/33 virus proliferation in vitro or a combination thereof.