A class of quinoline derivatives

Abstract

The invention relates to the field of medical technology, and in particular to a class of quinoline derivatives; a method for preparing the quinoline derivatives comprises: dissolving a compound II and a compound III in a 10% alkaline aqueous solution, refluxing, finishing the reaction, cooling to room temperature, acidifying, washing, and drying to obtain a quinoline derivative compound I; the method provides a class of quinoline derivatives, wherein the quinoline derivative compound I has a strong antiviral effect and can be used to prepare anti-influenza virus drugs; the synthesized quinoline derivative compound has a novel structure, a simple synthesis process, is green and environmentally friendly, and an organic solvent can be recycled and reused, exhibits a strong inhibitory effect on influenza viruses, and has excellent application prospects.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry and pharmaceutical synthesis, and specifically relates to a class of quinoline derivatives. Background Art

[0002] The need to develop additional defenses against influenza viruses was highlighted during the 2009 H1N1 swine-origin influenza virus (S-OIV) pandemic. In response to the outbreak, many schools and offices in different countries were forced to close to prevent the spread of S-OIV, followed by mass vaccination of populations at higher risk of infection, which further demonstrated the threat of influenza to human life. Although recent S-OIV infections have been of lower virulence compared to previous epidemics, scientific uncertainty regarding the evolution of virulent strains from novel influenza strains requires necessary precautions to control the virus.

[0003] Currently, vaccination and anti-influenza drug treatment are the main ways to protect against seasonal and pandemic influenza threats. But the effectiveness of the vaccine is limited because it is only used to protect against the main circulating virus strains. The disadvantage of influenza vaccines is that a new vaccine different from the general seasonal influenza is needed as a preventive measure against the rapidly spreading S-OIV. To date, only four anti-influenza drugs have been approved for the treatment or prevention of influenza infection: amantadine and rimantadine (M2 ion channel blockers inhibit the ion channel formed by the 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, laninamivir, was approved for use in Japan. However, influenza viruses may develop resistance to these drugs, such as the highly pathogenic avian influenza-like H5N1 virus. Therefore, the development of new anti-influenza drugs is very necessary.

[0004] This study uses the 4-carboxylic acid-quinoline ring as the core skeleton, and designs and derives a series of novel anti-influenza virus drugs through 2-position substitution and 6-position substitution as well as changing the 2-position substituent. The anti-influenza A virus (H1N1: WSN / 33 strain) activity is measured to obtain a lead compound with good anti-influenza A virus activity. Summary of the invention

[0005] In view of the deficiencies of the prior art, the first aspect of the present application provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:

[0006]

[0007] Wherein, R is selected from Het; Het is selected from benzene ring, naphthalene ring, pyridine ring, piperonyl ring, Het is optionally substituted by 1 or 2 substituents, each substituent is independently selected from C1-C4 alkane, nitro, halogen, haloalkyl, benzene ring or methoxy.

[0008] Physiologically acceptable salts thereof include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like.

[0009] Further preferably, the quinoline derivative compound I is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0010]

[0011] The second aspect of the present application relates to a method for preparing a quinoline derivative compound represented by formula I, and the reaction formula is as follows:

[0012]

[0013] A method for preparing a quinoline derivative compound represented by formula I comprises the following steps:

[0014] Compound II and Compound III were dissolved in 10% alkaline aqueous solution and refluxed. After the reaction was completed, the mixture was cooled to room temperature, acidified to pH=1 with 3N HCl aqueous solution, washed and dried to obtain Compound I.

[0015] Preferably, the base is selected from one of potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof.

[0016] Preferably, the molar ratio of the compound II to the base is 1:3-5.

[0017] Preferably, the molar ratio of compound II to compound III is 1:1 to 1.5;

[0018] Preferably, the reaction time is 40 to 50 hours.

[0019] Wherein compound III is prepared as follows:

[0020] Compound V, compound IV and a base are dissolved in an organic solvent, heated to reflux, and detected by TLC. When the reaction is complete, the mixture is cooled to room temperature, washed, dried, and concentrated under reduced pressure to obtain compound III. The synthetic route is as follows:

[0021]

[0022] Preferably, the base is selected from one or a combination of K2CO3, Na2CO3, KHCO3, NaHCO3, Cs2CO3, N-methylmorpholine, among which K2CO3 is particularly preferred.

[0023] Preferably, the molar ratio of the compound V to the base is 1:1-3.

[0024] Preferably, the molar ratio of compound V to compound IV is 1:1 to 1.5.

[0025] Preferably, the solvent is selected from toluene, DMSO, DMF, acetonitrile.

[0026] The third aspect of the present invention also relates to the use of quinoline derivative compound I, which is characterized in that it can be used to prepare biological activities for treating or preventing influenza virus-induced cytopathic effect (CPE), for in vitro non-therapeutic inhibition of influenza A / WSN / 33 virus proliferation, or a combination thereof.

[0027] The results of in vitro anti-influenza virus activity screening showed that quinoline derivative compound I exhibited strong inhibitory activity against influenza A / WSN / 33 virus, and some compounds had higher activity than control drug 1a. Therefore, the compounds of the present invention can be used to prepare anti-influenza virus drugs.

[0028] Compared with the prior art, the main advantages of the present invention include:

[0029] (1) The present invention provides a class of quinoline derivatives.

[0030] (2) The quinoline derivative compound I provided by the present invention has a strong antiviral effect and can be used to prepare anti-influenza virus drugs.

[0031] (3) The quinoline derivative compound I provided by the present invention has a novel structure, a simple synthesis process, is green and environmentally friendly, and the organic solvent can be recycled and reused. It exhibits a strong inhibitory effect on influenza virus and has excellent application prospects. DETAILED DESCRIPTION

[0032] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention, so simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed in the present invention. The compounds V and IV used in the examples are obtained from the market and synthesized in the laboratory.

[0033] Preparation of compound III:

[0034] Example 1

[0035]

[0036] Compound V (127.0 g, 1.0 mol), compound IV-1 (156.0 g, 1.0 mol) and K2CO3 (414.0 g, 3.0 mol) were dissolved in DMF (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-1, yield: 72.6%; HPLC purity: 99.57%.

[0037] 1 HNMR (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);

[0038] 13 CNMR(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);

[0039] ESI-HRMS: m / z=204.1310[M+H]+

[0040] Example 2

[0041]

[0042] Compound V (127.0 g, 1.0 mol), compound IV-2 (202.4 g, 1.1 mol) and Na2CO3 (212.0 g, 2.0 mol) were dissolved in DMSO (100 ml), heated to reflux, and detected by TCL. When the reaction was completed, the mixture was cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-2. Yield: 71.3%; HPLC purity: 99.48%.

[0043] 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 CH 3);

[0044] 13 CNMR(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;

[0045] ESI-HRMS: m / z=232.1623[M+H]+

[0046] Example 3

[0047]

[0048] Compound V (127.0 g, 1.0 mol), compound IV-3 (226.1 g, 1.3 mol) and KHCO3 (300.4 g, 3.0 mol) were dissolved in DMF (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-3, yield: 72.5%; HPLC purity: 99.45%.

[0049] 1 HNMR(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,Py ridine-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);

[0050] 13 CNMR(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);

[0051] ESI-HRMS: m / z=222.1216[M+H]+

[0052] Example 4

[0053]

[0054] Compound V (127.0 g, 1.0 mol), compound IV-4 (335.9 g, 1.5 mol) and NaHCO3 (252.0 g, 3.0 mol) were dissolved in acetonitrile (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-4, yield: 71.9%; HPLC purity: 99.46%.

[0055] 1 HNMR(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,Py ridine-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);

[0056] 13 CNMR(100MHz, CDCl3)δ:210.4,156.1,126.0(3C),124.1,113.2(2C),52.1(2C),46.3,28.2,27.6;

[0057] ESI-HRMS: m / z=272.1184[M+H]+

[0058] Example 5

[0059]

[0060] Compound V (127.0 g, 1.0 mol), compound IV-5 (281.3 g, 1.4 mol) and Na2CO3 (318.0 g, 3.0 mol) were dissolved in toluene (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-5, yield: 72.8%; HPLC purity: 99.50%.

[0061] 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);

[0062] 13 CNMR(100MHz, CDCl3)δ:210.6,155.7,137.4,124.8(2C),112.3(2C),52.3(2C),46.8,28.4,27.5;

[0063] ESI-HRMS: m / z=249.1161[M+H]+

[0064] Example 6

[0065]

[0066] Compound V (127.0 g, 1.0 mol), compound IV-6 (186.0 g, 1 mol) and Cs2CO3 (325.8 g, 1.0 mol) were dissolved in DMSO (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-2, yield: 70.5%; HPLC purity: 99.40%.

[0067] 1 HNMR (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, -OCH 3),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);

[0068] 13 CNMR(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;

[0069] ESI-HRMS: m / z=234.1416[M+H]+

[0070] Example 7

[0071]

[0072] Compound V (127.0 g, 1.0 mol), compound IV-7 (239.2 g, 1.3 mol) and N-methylmorpholine (303.5 g, 3.0 mol) were dissolved in toluene (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-7, yield: 73.1%; HPLC purity: 99.53%.

[0073] 1 HNMR (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);

[0074] 13 CNMR(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);

[0075] ESI-HRMS: m / z=232.1623[M+H]+

[0076] Example 8

[0077]

[0078] Compound V (127.0 g, 1.0 mol), compound IV-8 (237.6 g, 1.1 mol) and K2CO3 (276.4 g, 2.0 mol) were dissolved in acetonitrile (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-8, yield: 7%; HPLC purity: 99.45%.

[0079] 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);

[0080] 13 CNMR(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;

[0081] ESI-HRMS: m / z=264.1521[M+H]+

[0082] Example 9

[0083]

[0084] Compound V (127.0 g, 1.0 mol), compound IV-9 (299.9 g, 1.5 mol) and Na2CO3 (248.0 g, 2.0 mol) were dissolved in DMF (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-9, yield: 71.2%; HPLC purity: 99.44%.

[0085] 1 HNMR (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=4.5Hz,1H,Ph-H),5.97(s,2H,-O-CH2-O-),3.14-3.01(m,4H,Pyridine-H),2.36

[0086] (m,1H,Pyridine-H),2.07(s,3H-COCH3),1.83-1.59(m,4H,Pyridine-H);

[0087] 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;

[0088] ESI-HRMS: m / z=248.1208[M+H]+

[0089] Example 10

[0090]

[0091] Compound V (127.0 g, 1.0 mol), compound IV-10 (206.0 g, 1 mol) and KHCO3 (200.2 g, 2.0 mol) were dissolved in acetonitrile (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-10, yield: 71.9%; HPLC purity: 99.50%.

[0092] 1 HNMR(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);

[0093] 13 CNMR(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;

[0094] ESI-HRMS: m / z=254.1467[M+H]+

[0095] Embodiment 11

[0096]

[0097] Compound V (127.0 g, 1.0 mol), compound IV-11 (263.9 g, 1.1 mol) and Cs2CO3 (325.84 g, 1.0 mol) were dissolved in DMSO (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-11, yield: 71.7%; HPLC purity: 99.47%.

[0098] 1 HNMR(400Hz, CDCl3)δ:6.73(m,2H,Ph-H),6.65(m,2H,Ph-H),3.17-3.01(m,4H,Pyridi ne-H),2.30(m,1H,Pyridine-H),2.08(s,3H,-COCH3),1.81-1.58(m,4H,Pyridine-H);

[0099] 13 CNMR(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;

[0100] ESI-HRMS: m / z=288.1133[M+H]+

[0101] Example 12

[0102]

[0103] Compound V (127.0 g, 1.0 mol), compound IV-12 (255.0 g, 1.5 mol) and KHCO3 (200.3 g, 2.0 mol) were dissolved in toluene (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-12, yield: 70.9%; HPLC purity: 99.41%.

[0104] 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);

[0105] 13 CNMR(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;

[0106] ESI-HRMS: m / z=218.1467[M+H]+

[0107] Embodiment 13

[0108]

[0109] Compound V (127.0 g, 1.0 mol), compound IV-13 (268.7 g, 1.4 mol) and N-methylmorpholine (202.3 g, 2.0 mol) were dissolved in DMF (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-13, yield: 72.7%; HPLC purity: 99.48%.

[0110] 1 HNMR(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,4 H,Pyridine-H),2.37(m,1H,Pyridine-H),2.08(s,3H,-COCH3),1.87-1.59(m,4H,Pyridine-H);

[0111] 13 CNMR(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;

[0112] ESI-HRMS: m / z=240.1122[M+H]+

[0113] Embodiment 14

[0114]

[0115] Compound V (127.0 g, 1.0 mol), compound IV-14 (157.0 g, 1 mol) and NaHCO3 (210.0 g, 3.0 mol) were dissolved in acetonitrile (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-14, yield: 72.4%; HPLC purity: 99.44%.

[0116] 1 HNMR (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,

[0117] Pyridine-H),2.38(m,1H,Pyridine-H),2.11(s,3H,-COCH3),1.87-1.60(m,4H,Pyridine-H);

[0118] 13 CNMR(100MHz, CDCl3)δ:210.6,147.0,138.8,135.8,124.7,118.8,52.1(2C),46.5,28.4,27.5;

[0119] ESI-HRMS: m / z=205.1263[M+H]+

[0120] Embodiment 15

[0121]

[0122] Compound V (127.0 g, 1.0 mol), compound IV-15 (278.4 g, 1.2 mol) and KHCO3 (100.1 g, 1.0 mol) were dissolved in DMF (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-15, yield: 72.1%; HPLC purity: 99.43%.

[0123] 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);

[0124] 13 CNMR(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:

[0125] m / z=280.1263[M+H]+

[0126] Example 16

[0127]

[0128] Compound V (127.0 g, 1.0 mol), compound IV-16 (274.4 g, 1.5 mol) and K2CO3 (276.4 g, 3.0 mol) were dissolved in toluene (100 ml), heated to reflux, detected by TCL, the reaction was completed, cooled to room temperature, filtered, washed with deionized water (50 ml), dried, and concentrated under reduced pressure to obtain intermediate III-16, yield: 71.7%; HPLC purity: 99.42%.

[0129] 1 HNMR(400Hz, CDCl3)δ:7.12(m,2H,Ph-H),6.72(m,2H,Ph-H),3.16-3.00(m,4H,Pyridi ne-H),2.35(m,1H,Pyridine-H),2.07(s,3H,-COCH3),1.87-1.64(m,4H,Pyridine-H);

[0130] 13 CNMR(100MHz, CDCl3)δ:210.7,147.4,129.7(2C),127.2,115.7(2C),52.0(2C),46.3,28.0,27.1;

[0131] ESI-HRMS: m / z=238.0920[M+H]+

[0132] Preparation of Compound I

[0133] Embodiment 17

[0134] Preparation of target compound I-1:

[0135]

[0136] Compound II (165.0 g, 1.0 mol) and intermediate III-1 (203.0 g, 1.0 mol) were dissolved in 10% potassium hydroxide aqueous solution (2240 ​​ml, 4.0 mol) and refluxed for 45 h. After the reaction was completed, the mixture was cooled to room temperature, acidified to pH 1 with 3N HCl aqueous solution, allowed to stand for 30 min, filtered, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-1 as a brown solid with a melting point of 189-191°C. The yield was 78.5% and the purity by HPLC was 99.91%.

[0137] 1 HNMR(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-qui noline-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).

[0138] 13 CNMR(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).

[0139] ESI-HRMS(m / z):351.1431[M+H]+

[0140] Embodiment 18

[0141] Preparation of target compound I-2:

[0142]

[0143] Compound II (165.0 g, 1 mol) and compound III-2 (277.2 g, 1.2 mol) were dissolved in 10% aqueous sodium hydroxide solution (1600 ml, 4.0 mol) and refluxed for 42 h. After the reaction was completed, the mixture was cooled to room temperature, acidified to pH 1 with 3N HCl aqueous solution, allowed to stand for 30 min, filtered, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-2 as a brown solid with a melting point of 199-201°C. The yield was 77.3% and the purity by HPLC was 99.89%.

[0144] 1 HNMR (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

[0145] (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,Piperi dine-H), 2.60 (q, 2H, -CH2-CH3), 1.74-1.48 (m, 4H, Piperidine-H), 1.18 (t, 3H, J = 7.4Hz, -CH2-CH3).

[0146] 13 CNMR(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.

[0147] ESI-HRMS (m / z): 379.1744 [M+H]+

[0148] Embodiment 19

[0149] Preparation of target compound I-3:

[0150]

[0151] Compound II (165.0 g, 1 mol) and intermediate III-3 (222.12.0 g, 1.5 mol) were dissolved in 10% lithium hydroxide aqueous solution (958 ml, 4.0 mol) and refluxed for 48 h. After the reaction was completed, the mixture was cooled to room temperature, acidified to pH 1 with 3N HCl aqueous solution, allowed to stand for 30 min, filtered, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-3 as a brown solid with a melting point of 191-193°C. The yield was 80.41%, and the purity by HPLC was 99.93%.

[0152] 1 HNMR(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=4.2H z,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).

[0153] 13 CNMR(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).

[0154] ESI-HRMS (m / z): 369.1336 [M+H]+

[0155] Embodiment 20

[0156] Preparation of target compound I-4:

[0157]

[0158] Compound II (165.0 g, 1.0 mol) and intermediate III-4 (271.1 g, 1.0 mol) were dissolved in 10% sodium hydride aqueous solution (1200 ml, 5.0 mol) and refluxed for 50 h. After the reaction was completed, the mixture was cooled to room temperature, acidified to pH 1 with 3N HCl aqueous solution, allowed to stand for 30 min, filtered, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-4 as a brown solid with a melting point of 189-191°C. The yield was 79.5% and the purity by HPLC was 99.91%.

[0159] 1 HNMR(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).

[0160] 13 CNMR(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).

[0161] ESI-HRMS (m / z): 419.1304 [M+H] +

[0162] Embodiment 21

[0163] Preparation of target compound I-5:

[0164]

[0165] Compound II (165.0 g, 1.0 mol) and intermediate III-5 (248 g, 1.0 mol) were dissolved in 10% potassium hydride aqueous solution (2000 ml, 5.0 mol) and refluxed for 50 h. After the reaction was completed, the reaction solution was placed in a low-temperature cooling liquid circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The solution was allowed to stand for 30 min, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-5 as a brown solid with a melting point of 200-201°C. The yield was 77.9% and the HPLC purity was 99.90%.

[0166] 1 HNMR(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).

[0167] 13 CNMR(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).

[0168] ESI-HRMS (m / z): 396.1281 [M+H]+

[0169] Embodiment 22

[0170] Preparation of target compound I-6:

[0171]

[0172] Compound II (165.0 g, 1.0 mol) and intermediate III-6 (326.3 g, 1.4 mol) were dissolved in 10% aqueous sodium tert-butoxide solution (2880 ml, 3.0 mol) and refluxed for 45 h. After the reaction was completed, the reaction solution was placed in a low-temperature cooling liquid circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The mixture was allowed to stand for 30 min, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-6 as a brown solid with a melting point of 148-150°C. The yield was 78.1% and the HPLC purity was 99.89%.

[0173] 1 HNMR(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-qui noline-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,Pi peridine-H),2.75(m,1H,Piperidine-H),1.74-1.46(m,4H,Piperidine-H).

[0174] 13 CNMR(100Hz,[D6]DMSO)δ:167.9,157.1,156.2,152.8,147.4,141.9,133.0,128.4,1 27.5,124.4,120.5,115.3(2C),115.2(2C),108.4,55.8,50.9(2C),34.4,25.7(2C).

[0175] ESI-HRMS (m / z): 381.1536 [M+H] +

[0176] Embodiment 23

[0177] Preparation of target compound I-7:

[0178]

[0179] Compound II (165.0 g, 1.0 mol) and intermediate III-7 (254.3 g, 1.1 mol) were dissolved in 10% potassium tert-butoxide aqueous solution (3360 ml, 3.0 mol) and refluxed for 40 h. After the reaction was completed, the reaction solution was placed in a low-temperature cooling liquid circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The mixture was allowed to stand for 30 min, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-7 as a brown solid with a melting point of 198-200°C. The yield was 79.5% and the purity by HPLC was 99.92%.

[0180] 1 HNMR(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).

[0181] 13 CNMR(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).

[0182] ESI-HRMS (m / z): 379.1744 [M+H]+

[0183] Embodiment 24

[0184] Preparation of target compound I-8:

[0185]

[0186] Compound II (165.0 g, 1.0 mol) and intermediate III-8 (263.1 g, 1.1 mol) were dissolved in 10% potassium hydroxide aqueous solution (1680 ml, 3.0 mol) and refluxed for 40 h. After the reaction was completed, the reaction solution was placed in a low-temperature cooling liquid circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The solution was allowed to stand for 30 min, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-8 as a brown solid with a melting point of 200-201°C. The yield was 77.9% and the HPLC purity was 99.88%.

[0187] 1 HNMR(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-qu inoline-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,P iperidine-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).

[0188] 13 CNMR(100Hz,[D6]DMSO)δ:167.7,157.4,156.2,150.7,147.4,142.9,139.3,133.0,1 28.4,127.5,124.4,120.6,112.9,108.4,98.4,58.1(2C),50.8(2C),34.4,25.5(2C).

[0189] ESI-HRMS (m / z): 411.1642 [M+H]+

[0190] Embodiment 25

[0191] Preparation of target compound I-9:

[0192]

[0193] Compound II (165.0 g, 1.0 mol) and intermediate III-9 (296.5 g, 1.2 mol) were dissolved in 10% aqueous sodium hydroxide solution (2500 ml, 5.0 mol) and refluxed for 48 h. After the reaction was completed, the reaction solution was placed in a low-temperature cooling liquid circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The mixture was allowed to stand for 30 min, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-9 as a brown solid with a melting point of 262-263°C. The yield was 80.01% and the purity by HPLC was 99.92%.

[0194] 1 HNMR (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).

[0195] 13 CNMR(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).

[0196] ESI-HRMS (m / z): 395.1329 [M+H]+

[0197] Embodiment 26

[0198] Preparation of target compound I-10:

[0199]

[0200] Compound II (165.0 g, 1.0 mol) and intermediate III-10 (303.8 g, 1.2 mol) were dissolved in 10% potassium hydroxide aqueous solution (2800 ml, 5.00 mol) and refluxed for 40 h. After the reaction was completed, the reaction solution was placed in a low-temperature cooling liquid circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The mixture was allowed to stand for 30 min, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-10 as a brown solid with a melting point of 302-303°C. The yield was 78.7% and the purity by HPLC was 99.87%.

[0201] 1 HNMR(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-quino line-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),

[0202] 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).

[0203] 13 CNMR(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).

[0204] ESI-HRMS (m / z): 401.1587 [M+H]+

[0205] Embodiment 27

[0206] Preparation of target compound I-11:

[0207]

[0208] Compound II (165.0 g, 1.0 mol) and intermediate III-11 (430.7 g, 1.5 mol) were dissolved in 10% aqueous sodium hydroxide solution (2500 ml, 5.00 mol) and refluxed for 50 h. After the reaction was completed, the reaction solution was placed in a low-temperature cooling liquid circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The mixture was allowed to stand for 30 min, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-11 as a white solid with a melting point of 184-186°C. The yield was 78.5% and the purity by HPLC was 99.88%.

[0209] 1 HNMR(400Hz, CDCl3-[D6]DMSO)δ:13.23(s,1H,-COOH),8.36(t,J=8.5Hz,1H,5-quinolin e-H),8.17(d,J=6.8Hz,1H,8-quinoline-H),7.98(s,1H,3-quinoline-H),7.34(t,J=4.3

[0210] Hz,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).

[0211] 13 CNMR(100Hz,[D6]DMSO)δ:167.5,157.2,156.4,147.7,141.9,140.1,133.2,129.7,1 28.4,127.5,124.5,120.6,115.3(2C),115.2(2C),108.2,51.0(2C),34.5,25.5(2C).

[0212] ESI-HRMS (m / z): 435.1254 [M+H] +

[0213] Embodiment 28

[0214] Preparation of target compound I-12:

[0215]

[0216] Compound II (165.0 g, 1.0 mol) and intermediate III-12 (217.2 g, 1.0 mol) were dissolved in 10% calcium hydroxide aqueous solution (2996 ml, 4.00 mol) and refluxed for 50 h. After the reaction was completed, the reaction solution was placed in a low-temperature coolant circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The mixture was allowed to stand for 30 min, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-11 as a brown solid with a melting point of 204-206°C. The yield was 81.4% and the purity by HPLC was 99.93%.

[0217] 1 HNMR(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,

[0218] 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).

[0219] 13 CNMR(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.

[0220] ESI-HRMS (m / z): 365.1587 [M+H] +

[0221] Embodiment 29

[0222] Preparation of target compound I-13:

[0223]

[0224] Compound II (165.0 g, 1.0 mol) and intermediate III-13 (310.8 g, 1.3 mol) were dissolved in 10% potassium hydroxide aqueous solution (1680 ml, 3.00 mol) and refluxed for 40 h. After the reaction was completed, the reaction solution was placed in a low-temperature coolant circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The mixture was allowed to stand for 30 min, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-11 as a brown solid with a melting point of 219-221°C. The yield was 79.9% and the purity by HPLC was 99.90%.

[0225] 1 HNMR(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=5.8

[0226] Hz,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).

[0227] 13 CNMR(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).

[0228] ESI-HRMS (m / z): 387.1242 [M+H] +

[0229] Embodiment 30

[0230] Preparation of target compound I-14:

[0231]

[0232] Compound II (165.0 g, 1.0 mol) and intermediate III-14 (285.7 g, 1.4 mol) were dissolved in 10% aqueous sodium hydroxide solution (2000 ml, 4.0 mol) and refluxed for 45 h. After the reaction was completed, the reaction solution was placed in a low-temperature cooling liquid circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The solution was allowed to stand for 30 min to obtain a brown solid with a melting point of 211-213 °C. The yield was 77.1% and the HPLC purity was 99.87%.

[0233] 1 HNMR(400Hz, CDCl3-[D6]DMSO)δ:13.20(s,1H,-COOH),8.36(t,J=8.5Hz,1H,5-quinoline-H),8.17(d,J=7.9H z,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,Py ridine-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,P yridine-H),3.15-3.04(m,4H,Piperidine-H),2.78(m,1H,Piperidine-H),1.76-1.49(m,4H,Piperidine-H).

[0234] 13 CNMR(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).

[0235] ESI-HRMS (m / z): 352.1383 [M+H] +

[0236] Embodiment 31

[0237] Preparation of target compound I-15:

[0238]

[0239] Compound II (165.0 g, 1.0 mol) and intermediate III-15 (307.1 g, 1.1 mol) were dissolved in 10% calcium hydroxide aqueous solution (3745 ml, 5.0 mol) and refluxed for 45 h. After the reaction was completed, the reaction solution was placed in a low-temperature coolant circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The solution was allowed to stand for 30 min to obtain a brown solid with a melting point of 189-201°C. The yield was 79.4% and the purity by HPLC was 99.90%.

[0240] 1 HNMR (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, 1 H,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).

[0241] 13 CNMR(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).

[0242] ESI-HRMS (m / z): 427.1744 [M+H] +

[0243] Embodiment 32

[0244] Preparation of target compound I-16:

[0245]

[0246] Compound II (165.0 g, 1.0 mol) and intermediate III-15 (355.6 g, 1.5 mol) were dissolved in 10% potassium hydroxide aqueous solution (2240 ​​ml, 4.0 mol) and refluxed for 50 h. After the reaction was completed, the reaction solution was placed in a low-temperature coolant circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The solution was allowed to stand for 30 min to obtain a brown solid with a melting point of 308-310°C. The yield was 78.7% and the purity by HPLC was 99.86%.

[0247] 1 HNMR(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-quinoli ne-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,Piper idine-H),1.74-1.44(m,4H,Piperidine-H).

[0248] 13 CNMR(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).

[0249] ESI-HRMS (m / z): 385.1041 [M+H] +

[0250] Example 33 (Compound III except for the lower endpoint)

[0251] Preparation of target compound I-1:

[0252]

[0253] Compound II (165.0 g, 1.0 mol) and intermediate III-1 (162.4 g, 0.8 mol) were dissolved in 10% potassium hydroxide aqueous solution (1120 ml, 2.0 mol) and refluxed for 35 h. After the reaction was completed, the reaction solution was placed in a low-temperature cooling liquid circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The mixture was allowed to stand for 30 min, filtered, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-1 as a brown solid with a melting point of 189-191°C. The yield was 62.1% and the HPLC purity was 99.71%.

[0254] 1 HNMR(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-qui noline-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).

[0255] 13 CNMR(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).

[0256] ESI-HRMS(m / z):351.1431[M+H]+

[0257] Example 34 (Compound III except for the upper end point)

[0258] Preparation of target compound I-2:

[0259]

[0260] Compound II (165.0 g, 1 mol) and compound III-2 (415.8 g, 1.8 mol) were dissolved in 10% aqueous sodium hydroxide solution (2800 ml, 7.0 mol) and refluxed for 60 h. After the reaction was completed, the reaction solution was placed in a low-temperature cooling liquid circulation pump and acidified to pH 1 with 3N HCl aqueous solution. The mixture was allowed to stand for 30 min, filtered, rinsed twice with H2O (20 ml×2), and dried in vacuo to obtain the target compound I-2 as a brown solid with a melting point of 199-201°C. The yield was 61.4% and the HPLC purity was 99.70%.

[0261] 1 HNMR(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-qui noline-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).

[0262] 13 CNMR(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).

[0263] ESI-HRMS(m / z):351.1431[M+H]+

[0264] Test methods and results of antiviral activity of compounds

[0265] Virus source: Influenza A / WSN / 33 was generated using the 12-plasmid-based reverse genetics system described by Fodor et al.

[0266] Assay method: 96-well tissue culture plates were inoculated with MDCK cells (200 mL) at a cell density of 1.1 × 10 5 cellsmL -1, with Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS). The plates were incubated at 37°C for 24-30 hours, and the cells were used at 90% confluence. Viruses (100 TCID 50 ) were added to the cells and the plates were incubated at 37°C for 1 hour. After adsorption, the infected cells were washed with 50 ml serum-free DMEM (E0: DMEM containing penicillin [100 U mL -1 ], streptomycin [100 mg / mL], l-glutamine [2 mm], non-essential amino acid mixture [0.1 mm] and trypsin [2.5 mg / mL -1 ]) and covered with 0.1% DMSO. The plates were incubated at 37°C for 72 hours. At the end of the incubation period, the cells were fixed by treatment with 4% formaldehyde (100 mL) for 1 hour at room temperature. After removal of the formaldehyde, the cells were stained with 0.1% crystal violet for 15 minutes at room temperature, the cells were washed, dried, and the density of the wells was measured at 570 nm. The concentration of the test compound required to reduce the virus-induced CPE by 50% relative to the virus control was expressed as IC 50 All assays were performed at least twice and in triplicate.

[0267] Take 1a

[10] As a positive control, the inhibitory effects of compounds I-1 to 16 on virus-induced cytopathic effect (CPE) in MDCK cells (IC 50 The results are shown in Table 1.

[0268]

[0269]

[0270] In vitro experiments show that the compounds I-1 to 16 of the present invention exhibit strong inhibitory activity against influenza A / WSN / 33, and most of the compounds are more active than the control drug 1a, among which compounds I-7 and I-13 have the strongest inhibitory activity against influenza A / WSN / 33. Therefore, the compounds prepared by the present invention can be used to prepare anti-influenza virus drugs, and the synthesis method of such compounds is simple, the raw materials are cheap and easy to obtain, the product purity is high, and it is suitable for industrial production, and has a good application prospect.

Claims

1. A quinoline derivative is shown in formula I, and the structural formula is as follows: ， R is selected from Het; Het is selected from benzene ring, naphthalene ring, pyridine ring, piperonyl ring, Het is optionally substituted by 1 or 2 substituents, each substituent is independently selected from C1-C4 alkane, nitro, halogen, haloalkyl, benzene ring or methoxy.

2. A method for preparing a quinoline derivative as claimed in claim 1, characterized in that: The reaction formula is as follows: ， R is selected from Het; Het is selected from benzene ring, naphthalene ring, pyridine ring, piperonyl ring, Het is optionally substituted by 1 or 2 substituents, each substituent is independently selected from C1-C4 alkane, nitro, halogen, haloalkyl, benzene ring or methoxy.

3. The method for preparing the derivative according to claim 2, characterized in that: The specific steps include: Compound II and compound III are dissolved in a 10% alkaline aqueous solution and refluxed. After the reaction is completed, the mixture is cooled to room temperature, washed, and dried to obtain compound I.

4. The preparation method according to claim 3, characterized in that: The base is selected from one of 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, characterized in that: The molar ratio of the compound II to the base is 1:3-5.

6. The preparation method according to claim 3, characterized in that: The molar ratio of compound II to compound III is 1:1-1.

5.

7. The preparation method according to claim 3, characterized in that: The reaction time is 40 to 50 hours.

8. The preparation method according to claim 2, characterized in that: The synthetic route of compound III is as follows: 。 9. The preparation method according to claim 8, characterized in that: The preparation method comprises the following steps: dissolving compound V, compound IV and alkali in an organic solvent, heating and refluxing to obtain compound III.

10. Use of the derivative according to claim 1 in the preparation of a medicament for treating or preventing influenza A / WSN / 33 virus.

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