A class of pyrimidinequinoline derivatives and their preparation method and application

Abstract

The present invention discloses a class of pyrimidine quinoline derivatives including prodrugs and their preparation methods and applications. The structure of the pyrimidine quinoline derivative is shown in formula (I); wherein R1 is hydrogen, C 1～4 Alkyl, C 1～4 Halogenated alkyl, C 4～7 Heterocyclic aromatic group, C 4～7 substituted heterocyclic aryl, benzyl or substituted benzyl, saccharide, amino acid; R2, R3, R4 and R5 are each independently hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, hydroxy, amino or substituted amino, C 1～4 Haloalkyl or halogen, saccharide, amino acid; R6 is substituted or unsubstituted five-membered heterocycle, substituted or unsubstituted six-membered heterocycle, substituted or unsubstituted C 8～12 The compounds of the present invention have a good inhibitory effect on 5 types of cancer cells, and the inhibitory IC of most compounds is 50 The values ​​were lower than 20 μM; the IC values ​​of some compounds were 50 The value is even lower than 5μM, and its inhibitory effect is extremely significant, and it can be prepared into an anti-cancer drug for application.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and more particularly to a class of pyrimidinequinoline derivatives including prodrugs, and preparation methods and applications thereof. Background Art

[0002] Heterocyclic compounds are widely distributed in nature, accounting for nearly one-third of all known organic compounds. Many important natural and synthetic pharmaceuticals, as well as highly effective and low-toxic pesticides, contain heterocyclic structures. Therefore, heterocyclic compounds have broad application prospects in new pharmaceuticals, pesticides, and materials. The synthesis of structurally diverse heterocycles has long been a hot area of ​​research in synthetic organic chemistry. Pyrimidine-quinoline compounds, with their remarkable and broad biological activities, have become a hot topic among medicinal chemists today. They possess a variety of pharmacological activities, including antimicrobial, antifungal, anticancer, antiviral, analgesic, and anti-inflammatory properties. They hold great promise for research and development, and further development is warranted. Summary of the Invention

[0003] The present invention aims to provide a class of pyrimidine quinoline derivatives. The compounds of the present invention show significant inhibitory effects on a variety of cancer cells, especially human non-small cell carcinoma cells, human colon cancer cell lines, human cervical cancer cells and human esophageal squamous cell carcinoma cells. Most of the compounds have an inhibitory IC of 1. 50 The values ​​were lower than 20 μM; the IC values ​​of some compounds were 50 The value is even lower than 5μM, and its inhibitory effect is extremely significant, and it can be prepared into an anti-cancer drug for application.

[0004] Another object of the present invention is to provide a method for preparing the pyrimidinequinoline derivative.

[0005] Another object of the present invention is to provide applications of the pyrimidinequinoline derivatives.

[0006] The above-mentioned object of the present invention is achieved through the following solutions:

[0007] A class of pyrimidine quinoline derivatives, the structure of which is shown in formula (I):

[0008]

[0009] Wherein, R1 is hydrogen, C 1～4 Alkyl, C 1～4 Halogenated alkyl, benzyl, substituted benzyl, C 4～7 Heterocyclic aromatic group, C 4～7 substituted heterocyclic aromatic groups, sugar groups, or amino acids;

[0010] R2, R3, R4 and R5 are each independently hydrogen, halogen, C1～4 Alkyl, C 1～4 Alkoxy, hydroxy, amino, substituted amino, C 1～4 halogenated alkyl, saccharide or amino acid;

[0011] R6 is a substituted or unsubstituted five-membered heterocycle, a substituted or unsubstituted six-membered heterocycle, a substituted or unsubstituted C 8～12 fused heterocyclic rings;

[0012] wherein the substituted benzyl, C 4～7 Substituted heterocyclic aryl, substituted amino, substituted five-membered heterocyclic, substituted six-membered heterocyclic and substituted C 8～12 The substituents in the fused heterocyclic ring are hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, C 1～4 haloalkyl or halogen;

[0013] The heterocyclic ring is a ring containing N, O or S.

[0014] Preferably, R1 is hydrogen, C 1～2 Alkyl, C 1～2 a haloalkyl group, a benzyl group, a substituted benzyl group, a saccharyl group, or an amino acid;

[0015] R2, R3, R4 and R5 are each independently hydrogen, halogen, C 1～2 Alkyl, C 1～2 Alkoxy, C 1～2 Haloalkyl, hydroxy, amino, substituted amino, saccharide or amino acid;

[0016] R6 is a pyrrole ring, a substituted or unsubstituted benzimidazole ring, a substituted or unsubstituted pyridine ring, a substituted or unsubstituted pyrimidine ring, or a substituted or unsubstituted quinazoline ring;

[0017] The substituents in the substituted benzyl, substituted amino, substituted pyridine ring, substituted benzimidazole ring, substituted pyrimidine ring and substituted quinazoline are hydroxyl, C 1～2 Alkyl, C 1～2 Alkoxy, C 1～2 Haloalkyl or halogen.

[0018] Preferably, R1 is hydrogen, methyl, ethyl, fluoromethyl, trifluoromethyl, trifluoroethyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl or 4-methoxybenzyl.

[0019] Preferably, when R6 is a pyrrole ring, the structure of the pyrimidinequinoline derivative is as shown in formula (II):

[0020]

[0021] When R6 is a substituted or unsubstituted benzimidazole ring, the structure of the pyrimidinequinoline derivative is shown in formula (III):

[0022] R7 is hydrogen, C 1～2 Alkyl, C 1～2 Alkoxy, C 1～2 haloalkyl or halogen;

[0023] When R6 is a substituted or unsubstituted pyridine ring, the structure of the pyrimidinequinoline derivative is shown in formula (IV):

[0024] R8 is hydrogen, C 1～2 Alkyl, C 1～2 Alkoxy, C 1～2 haloalkyl or halogen;

[0025] When R6 is a substituted or unsubstituted pyrimidine ring, the structure of the pyrimidinequinoline derivative is shown in formulas (V-1) to (V-3):

[0026]

[0027] R9 is hydrogen, C1-2 alkyl, C1-2 alkoxy, C1-2 haloalkyl or halogen;

[0028] When R6 is a substituted or unsubstituted quinazoline, the structure of the pyrimidine quinoline derivative is shown in formula (VI):

[0029] R 10 For hydrogen, C 1～2 Alkyl, C 1～2 Alkoxy, C 1～2 Preferably, the structure of the pyrimidine quinoline derivative is any of the following structures:

[0030]

[0031] More preferably, the structure of the pyrimidinequinoline derivative is any one of the following structures:

[0032]

[0033] The present invention also protects the preparation method of the pyrimidine quinoline derivative. When R5 is hydrogen, the preparation process is:

[0034]

[0035] S1. The substituted 2-amino-5-methylphenol compound represented by formula (1) and the acyl chloride compound represented by formula (2) are mixed in an organic solvent under an inert gas atmosphere, pyridine is added, and the reaction is carried out at room temperature to obtain the intermediate represented by formula (3);

[0036] S2. The intermediate of formula (3) is mixed with trifluoromethanesulfonic acid in an organic solvent and reacted at room temperature to obtain the intermediate of formula (4);

[0037] S3. The intermediate of formula (4) is reacted with R1-Br in an organic solvent dissolved in an alkaline salt by heating to obtain the intermediate of formula (5);

[0038] S4. The intermediate of formula (5) is dissolved in an organic solvent with oxalyl chloride, and DMF is added dropwise. The mixture is heated to react to obtain the intermediate of formula (6);

[0039] S5. Under an inert gas atmosphere, lithium diisopropylamide, tetrahydrofuran and tri-n-butyltin hydride solution are mixed and reacted; after the reaction is completed, the temperature is lowered to -78 to -20 ° C; the compound of formula (7) is added, and the temperature is raised to room temperature to react to obtain the intermediate of formula (8);

[0040] S6. The intermediate of formula (6), the intermediate of formula (8), and Pd(PPh3)2Cl2 are dissolved in an organic solvent in an inert gas atmosphere and heated to react. After the reaction is completed, the target product can be obtained.

[0041]

[0042] When R5 is halogen, C 1～4 Alkyl, C 1～4 Alkoxy, hydroxy, amino, substituted amino, C 1～4 When alkyl halide, glycosyl or amino acid is used, the preparation process is as follows:

[0043]

[0044]

[0045] S2-1. The compound of formula (2-1) and the compound of formula (2-2) are mixed and dissolved in an organic solvent containing a basic salt and heated to react to obtain a compound of formula (2-3);

[0046] S2-2. The compound of formula (2-3) is dissolved in an anhydrous organic solvent and reacted with m-CPBA under ice bath conditions to obtain a compound of formula (2-4);

[0047] S2-3. The compound of formula (2-4) is dissolved in an organic solvent with triphenylphosphine under an inert gas atmosphere, trichloroacetonitrile is added, and the reaction is heated to 100-130 ° C to obtain a compound of formula (2-5);

[0048] S2-4. Under an inert gas atmosphere, lithium diisopropylamide, tetrahydrofuran and tri-n-butyltin hydride solution are mixed and reacted; after the reaction is completed, the temperature is cooled to -78 to -20 ° C; the compound of formula (7) is added, and the temperature is raised to room temperature to react to obtain the intermediate of formula (8);

[0049] S2-5. The intermediate described in formula (2-5), the intermediate described in formula (8), and Pd(PPh3)2Cl2 are mixed and dissolved in an organic solvent in an inert gas atmosphere, and heated to react. After the reaction is completed, the target product can be obtained.

[0050] Preferably, the reactions are carried out under anhydrous and oxygen-free conditions; the inert gas is nitrogen or argon.

[0051] Preferably, the reaction solvent for all reactions is one or more of tetrahydrofuran, dichloromethane, dimethylformamide, dimethyl sulfoxide or acetonitrile.

[0052] Preferably, in step S1, the reaction temperature is -25 to 22°C; in steps S3 and S2-1, the alkaline salt is K2CO3 or Na2CO3; the reaction temperatures of steps S3, S4 and step S2-1 are all 70 to 100°C; the reaction temperature of step S5 is 22 to 25°C; and the reaction temperature of step S6 is 100 to 130°C.

[0053] More preferably, the reaction temperature of step S2-1 is 85° C., and the reaction is carried out for 6 to 20 hours. After the reaction is completed, the reaction solution is allowed to cool to room temperature. The solution is filtered through diatomaceous earth, rinsed with EA, and the solvent is evaporated under reduced pressure. The solution is separated and purified by column chromatography to obtain a yellow solid compound of formula (2-3).

[0054] More preferably, the reaction of step S2-2 is carried out for 6 to 12 hours; after the reaction is completed, DCM is added to dilute, sodium bisulfite and sodium bicarbonate are added respectively, and after stirring for a period of time, the mixture is filtered through diatomaceous earth, rinsed with DCM, and the solvent is evaporated under reduced pressure; and the mixture is separated and purified by column chromatography to obtain a yellow oily compound of formula (2-4).

[0055] More preferably, the reaction of step S2-3 is carried out for 1 to 5 hours. After the reaction is completed, the reaction solution is allowed to cool to room temperature, filtered through diatomaceous earth, rinsed with EA, and the solvent is evaporated under reduced pressure. The solution is separated and purified by column chromatography to obtain the compound of formula (2-5) as a yellow oil.

[0056] The use of the pyrimidinequinoline derivatives in the preparation of anticancer drugs is also within the protection scope of the present invention.

[0057] Preferably, the anticancer drug is a drug for cervical cancer, colon cancer, non-small cell lung cancer, esophageal squamous cell carcinoma, gastric adenocarcinoma, breast cancer, liver cancer or chronic myeloid leukemia.

[0058] Compared with the prior art, the present invention has the following beneficial effects:

[0059] The compounds of the present invention have novel structures and show significant inhibitory effects on a variety of cancer cells, especially human non-small cell carcinoma cells, human colon cancer cell lines, human cervical cancer cells, human esophageal squamous cell carcinoma cells and human promyelocytic leukemia cells. Most of the compounds have an inhibitory IC of 0. 50 The values ​​were lower than 20 μM; especially compounds 1, 2, 5-9, 13-17, 23, 24, 26-28, 30-35, 38, 39, 42-44, 51 and 55, which had IC values ​​of 0. 50 The values ​​were lower than 10 μM; especially compounds 1, 2, 13, 14, 23, 27, 30-33, 35, 42, 51 and 55, which had IC 50 The value is lower than 5μM, and its inhibitory effect is extremely significant, and it can be prepared into an anticancer drug for application.

[0060] In addition, the preparation method of the compound of the present invention is simple, can be produced and prepared on an industrial scale, and is easy to promote and apply. DETAILED DESCRIPTION

[0061] The present invention is further described in detail below with reference to specific examples. The examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods used in the following examples are conventional methods unless otherwise specified; the materials and reagents used are commercially available reagents and materials unless otherwise specified.

[0062] The structures of the compounds prepared in the following examples are shown in Table 1.

[0063] Table 1 Compound structures

[0064]

[0065]

[0066]

[0067] Example 1 Preparation of pyrimidine quinoline derivatives

[0068] Preparation process of compound 1:

[0069]

[0070] Weigh 0.3g of QM15 into a 25mL two-necked flask, add 35mg of Pd(PPh3)2Cl2, seal the reaction vessel, replace the atmosphere with argon, add 3mL of anhydrous DMF, stir at room temperature for 10min, add 0.55mL (0.627g) of 2-tri-n-butylstannylpyridine, heat in an oil bath at 110°C, and react overnight. Cool to room temperature, add 50mL of ethyl acetate and 100mL of water, shake well, separate the organic phase, extract the aqueous phase with ethyl acetate (20mL x 2), combine the organic phases, wash with saturated NaCl solution (150mL x 2), dry over anhydrous MgSO4, filter, and evaporate the solvent under reduced pressure. Purify by flash column chromatography (20% EA / PE), and evaporate the solvent under reduced pressure to obtain 240mg of a yellow oil. (XM013-LG02, P101) Yield: 65.6%, yellow solid.

[0071] Compound 1: 1 H NMR (400MHz, CDCl3) δ8.72–8.70(m,2H),8.59(d,J=8.8Hz,1H),8.26(d,J=8.4Hz,1H),7.86(td, J=2,7.6Hz,1H),7.49–7.42(m,2H),7.35–7.32(m,1H),7.08(dd,J=1.6,7.6Hz,1H),4.12(s,3H).

[0072] 13 C NMR (100MHz, CDCl3) δ156.3,155.5,155.1,149.0,139.7,136.9,136.8,129.4,127.0,123.9,122.1,119.5,119.4,108.0,56.14.

[0073] The preparation process of compound 2-6 is the same as compound 1, except that a different compound QM15 is used.

[0074] Compound 2: 1 H NMR (500MHz, CDCl3) δ8.76(d,J=8Hz,1H),8.72(d,J=5Hz,1H),8.62(d,J=8.5Hz,1H),8.26(d,J=9Hz,1H),7.84(t,J=7.5Hz,1H),7. 46–7.41(m,2H),7.34(dd,J=8.5Hz,2H),7.25(s,1H),7.16(dd,J=7.5Hz,2H),6.88(dd,J=2,8.5Hz,1H),5.43(s,2H),3.84(s,3H).

[0075] 13 C NMR (125MHz, CDCl3) δ159.8,156.4,154.9,154.8,149.0,140.2,139.0,136.8,129 .6,129.5,126.9,123.9,122.0,120.2,119.2,113.5,112.2,111.0,71.02,55.22.

[0076] Compound 4: 1 H NMR (400MHz, DMSO) δ8.60(d,J=4.8Hz,1H),8.57(d,J=8.4Hz,1H),8.49(s,1H),8.45(d,J=8.8Hz,1H),7.58(dd,J=1.2,8Hz,1H) ,7.53(t,J=8Hz,1H),7.37–7.31(m,4H),7.47(d,J=7.6Hz,1H),6.92(dd,J=2,8Hz,1H),5.41(s,2H),3.79(s,3H),2.45(s,3H).

[0077] 13 C NMR(100MHz,DMSO)δ159.4,155.2,154.1,154.0,149.0,147.8,139.4,139.1,136.9,129.4, 129.0,127.2,125.3,121.6,119.9,118.8,118.7,112.8,112.4,111.2,69.65,54.96,20.72.

[0078] Compound 5: 1 H NMR (500MHz, CDCl3) δ8.71(d,J=8.5Hz,1H),8.65(d,J=2Hz,1H),8.57(d,J=9Hz,1H),8.25(d,J=8.5Hz,1H),7.80(dd,J=2.5,8.5H z,1H),7.46–7.42(m,2H),7.33(t,J=8Hz,1H),7.22(s,1H),7.17–7.13(m,2H),6.89(dd,J=2,8Hz,1H),5.41(s,2H),3.84(s,3H).

[0079] 13C NMR (125MHz, CDCl3) δ159.8,154.7,154.6,153.8,147.9,147.8,140.1,138.8,136.9,126 .6,132.5,129.6,127.1,122.7,120.1,119.2,119.0,113.4,112.4,111.0,70.95,55.22.

[0080] Compound 6: 1 H NMR (400MHz, CDCl3) δ8.70(d,J=8.8Hz,1H),8.54(d,J=8.8Hz,1H),8.40(d,J=2.8Hz,1H),8.22(d,J=8.4Hz,1H),7.45–7.40(m,2H),7.36–7. 31(m,2H),7.23(s,1H),7.17(d,J=7.6Hz,1H),7.12(dd,J=1.2,7.2Hz,1H),6.88(dd,J=2.4,8Hz,1H),5.42(s,2H),3.94(s,3H),3.84(s,3H).

[0081] 13 C NMR (125MHz, CDCl3) δ179.9,167.2,156.3,155.9,154.8,154.6,136.7,136.5,129.6,126.5, 122.8,121.2,120.2,119.4,119.3,118.9,113.6,113.5,112.3,111.0,71.06,55.73,55.26.

[0082] Example 2

[0083] Preparation process of compound 7:

[0084]

[0085] 1. Preparation of QM08

[0086] Weigh 5.0 g of 2,8-quinolinediol into a 500 mL two-necked flask, add 7.72 g of K₂CO₃ and 300 mL of acetonitrile, and stir at room temperature. Add 4.8 mL (6.86 g) of 3-methoxybenzyl bromide, heat to reflux, and react overnight. Add 300 mL of ethyl acetate and 300 mL of water to the reaction mixture, mix thoroughly, and separate the organic phase. The aqueous phase is extracted twice with ethyl acetate (100 mL x 2). The combined organic phases are washed with saturated NaCl solution (400 mL x 2), dried over anhydrous MgSO₄, filtered, and the solvent evaporated under reduced pressure. Purification by column chromatography (75% EA / PE) yields 6.36 g of a white solid.

[0087] 2. Preparation of QM21

[0088] 3.3g of QM08 and 10.09g of phosphorus oxybromide were weighed into a dry 250mL two-necked flask. Under an argon atmosphere, 30mL of anhydrous 1,2-dichloroethane was added and the mixture was heated to reflux and allowed to react overnight. TLC confirmed the completion of the reaction, and the mixture was allowed to cool to room temperature. The mixture was poured into 50mL of ice water and extracted three times with ethyl acetate (150mL x 3). The combined organic phases were washed sequentially with saturated NaHCO₃ solution (200mL x 2) and saturated NaCl solution (200mL x 2). The mixture was dried over anhydrous MgSO₄, filtered, and the solvent was evaporated under reduced pressure. Purification by column chromatography (10% EA / PE) yielded 2.0g of a white solid.

[0089] 3. Preparation of Compound 7

[0090] Weigh 0.35g of QM21 into a 25mL two-necked flask, then add 86mg of lithium chloride, 358mg of N-Boc-pyrrole-2-boronic acid pinacol ester, and 59mg of Pd(PPh3)4, respectively. Seal the reaction vessel and replace the argon atmosphere. Add 5mL of anhydrous toluene and 5mL of anhydrous ethanol, respectively, and stir at room temperature for 10 minutes. Weigh 270mg of sodium carbonate into a 5mL Eppendorf tube and dissolve thoroughly in 1.27mL of water to make a 2M solution. This solution is then poured into the two-necked flask and heated in an oil bath at 80°C overnight. Cool to room temperature, add 80mL of ethyl acetate and 150mL of water, and shake thoroughly. Separate the organic phase, extract the aqueous phase with ethyl acetate (50mL x 2). Combine the organic phases and wash with saturated NaCl solution (150mL x 2). Dry over anhydrous MgSO4, filter, and evaporate the solvent under reduced pressure. The product was separated and purified by flash column chromatography (10% EA / PE) to obtain 200 mg of a yellow solid.

[0091] Compound 7: 1H NMR (500MHz, CDCl3) δ10.18(s,1H),8.03(d,J=8.5Hz,1H),7.70(d,J=9Hz,1H),7.36–7.29(m,3H),7.15–7.09(m,3H ),6.92(s,1H),6.88(dd,J=2,8Hz,1H),6.84(t,J=1.5Hz,1H),6.30(s,1H),6.32(s,1H),5.34(s,2H),3.81(s,3H).

[0092] 13 C NMR (125MHz, CDCl3) δ159.8,154.0,149.3,140.0,138.9,136.2,132.1,129.6,127.9, 125.2,120.9,120.4,119.6,118.0,113.5,112.8,111.6,110.1,108.9,71.32,55.22.

[0093] Preparation of compound 8:

[0094]

[0095] Weigh 0.25g of QM15 into a 25mL two-necked flask, then add 89mg of lithium chloride, 370mg of N-Boc-pyrrole-2-boronic acid pinacol ester, and 461mg of Pd(PPh3). Seal the reaction vessel and replace the argon atmosphere. Add 5mL of anhydrous toluene and 5mL of anhydrous ethanol, respectively, and stir at room temperature for 10 minutes. Weigh 278mg of sodium carbonate into a 5mL Eppendorf tube and dissolve thoroughly in 1.3mL of water to make a 2M solution. Pour the solution into the two-necked flask and heat in an 80°C oil bath for overnight reaction. Cool to room temperature, add 80mL of ethyl acetate and 150mL of water, shake thoroughly, and separate the organic phase. Extract the aqueous phase with ethyl acetate (50mL x 2). Combine the organic phases and wash with saturated NaCl solution (150mL x 2). Dry over anhydrous MgSO4, filter, and evaporate the solvent under reduced pressure. Purify by flash column chromatography (15% EA / PE) to yield 75mg of a yellow solid.

[0096] Compound 8: 1 H NMR (400MHz, CDCl3) δ10.39(s,1H),8.03(d,J=8.8Hz,1H),7.72(d,J=8.8Hz,1H),7.37–7.32(m, 2H),7.02(dd,J=2.4,6.8Hz,1H),6.99(s,1H),6.85(d,J=3.2Hz,1H),6.32(s,1H),4.06(s,3H).

[0097] 13 C NMR (100MHz, CDCl3) δ154.6,149.5,139.5,136.2,132.0,127.7,125.2,121.0,119.7,118.2,110.1,109.0,108.2,55.85.

[0098] Example 3

[0099] Preparation process of compound 9:

[0100]

[0101] Weigh 187 mg of 8-methoxyquinoline-2-aldehyde into a 50-well flask, add 5 mL of ethanol and 125 mg of sodium bisulfite, and stir at room temperature for 4 hours. Dissolve 108 mg of o-phenylenediamine in 3 mL of DMF and add to the reaction mixture. Heat to reflux in an 85°C oil bath and react for 3 hours. Cool to room temperature. Add 40 mL of ethyl acetate and 20 mL of water, shake well, and separate the organic phase. Extract the aqueous phase with ethyl acetate (20 mL x 2). Combine the organic phases and wash with saturated NaCl solution (40 mL x 2). Dry over anhydrous MgSO4, filter, and evaporate the solvent under reduced pressure. Purify by column chromatography (50% EA / PE) to yield 30 mg of a yellow solid.

[0102] Compound 9: 1 H NMR (400MHz, CDCl3) δ11.57(s,1H),8.60(d,J=8.8Hz,2H),8.28(d,J=8.4Hz,1H),7.88(dd,J=5.2,4.8,2.0,1.6Hz,1H) ,7.53~7.49(m,2H),7.46(dd,J=8.4,8.0,1.6,1.2Hz,1H),7.31~7.29(m,2H),7.11(dd,J=7.6,1.2Hz,1H),4.10(s,3H).

[0103] Preparation process of compound 10:

[0104]

[0105] 1. Preparation of XM-A0001

[0106] Weigh 3.00 g of 2-methyl-8-hydroxyquinoline into a 100 mL two-necked flask, then add 5.21 g of K₂CO₃, 0.31 g of KI, 19 mL of acetone, and 3.2 mL (4.55 g) of 3-methoxybenzyl bromide. Stir and heat to reflux overnight. Evaporate the acetone under reduced pressure, add 60 mL of ethyl acetate and 40 mL of H₂O, extract, and separate the organic layer. Extract the aqueous layer with ethyl acetate (20 mL x 2). Combine the organic layers and wash with saturated NaCl (50 mL x 2). Dry over anhydrous MgSO₄, filter, and evaporate the solvent under reduced pressure. Recrystallize from 10% ethyl acetate / cyclohexane to yield 4.08 g of white crystals.

[0107] 2. Preparation of XM-A0002

[0108] 4.19 g of XM_A0001 was weighed into a 100 mL two-necked flask, followed by 2.09 g of SeO2. The reaction apparatus was sealed and the nitrogen atmosphere was replaced. 30 mL of 1,4-dioxane was added and the mixture was stirred at 80°C for 2 h. The mixture was allowed to cool to room temperature, filtered, and the filtrate was evaporated to dryness under reduced pressure. The solid was then dried under vacuum. 30 mL of dichloromethane was added and shaken to dissolve most of the solid. The mixture was allowed to stand overnight. Insoluble matter was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure. The product was then purified by column chromatography (10% EA / PE) to yield 3.38 g of the product.

[0109] 3. Preparation of Compound 10

[0110] Weigh 880 mg of XM_A0002 into a 100-mouth flask, add 15 mL of ethanol and 375 mg of sodium bisulfite, and stir at room temperature for 4 hours. Dissolve 325 mg of o-phenylenediamine in 9 mL of DMF and add to the reaction mixture. Heat to reflux in an oil bath at 85°C for 3 hours, then cool to room temperature. Add 120 mL of ethyl acetate and 60 mL of water, shake well, and separate the organic phase. The aqueous phase is extracted with ethyl acetate (60 mL x 2). The combined organic phases are washed with saturated NaCl solution (120 mL x 2), dried over anhydrous MgSO4, filtered, and the solvent evaporated under reduced pressure. Purification by column chromatography (40% EA / PE) yields 100 mg of a yellow solid.

[0111] (NB-4, P75)

[0112] Compound 10: 1H NMR (400MHz, CDCl3) δ11.96(s,1H),8.57(d,J=8.4Hz,2H),8.30(d,J=8.8Hz,1H),7.80(d,J=8.0Hz,1H),7.52~7.47(m,2H),7.22~7.16( m,2H),7.11(t,J=8.0,7.2Hz,1H),7.04(t,J=8.4,7.6Hz,1H),6.92~6.91(m,3H),6.66(dd,J=8.0,2.0Hz,1H),5.22(s,2H),3.62(s,3H).

[0113] 13 C NMR (100MHz, CDCl3) δ159.5,154.4,150.9,147.5,144.2,139.6,137.7,137.0,134.3,129.8 ,129.4,127.4,123.8,122.3,120.3,120.0,119.9,113.5,113.2,111.2,110.6,71.2,55.0.

[0114] Example 4

[0115] Preparation process of compound 11:

[0116]

[0117] Weigh 293 mg of XM_A0002 into a 50 mL round-bottom flask, add 12.5 mL of acetonitrile, and stir at room temperature. Add 126 mg of o-aminobenzylamine and stir until uniform. Then add 280 mg of 2-iodobenzoic acid. Maintain the reaction system at 25°C and let it react for 7 h. Add 60 mL of ethyl acetate and 60 mL of water, shake until uniform, and separate the organic phase. The aqueous phase is extracted with ethyl acetate (30 mL x 2). The combined organic phases are washed with saturated NaCl solution (60 mL x 2). Dry over anhydrous MgSO4, filter, and evaporate the solvent under reduced pressure. Purify by column chromatography (30-80% EA / PE) to obtain 62 mg of a yellow solid.

[0118] Compound 11: 1H NMR (400MHz, CDCl3) δ9.65 (s, 1H), 8.81 (d, J = 8.4Hz, 1H), 8.34 (d, J = 8.4Hz, 1 H),8.26(d,J=8.4Hz,1H),8.03~7.96(m,2H),7.71(td,J=7.6,08Hz,2H),7.47 ~7.42(m,2H),7.31(t,J=8.0,7.6Hz,1H),7.20~7.16(m,2H),7.10(dd,J=6.8 ,2.0Hz,1H),6.86(dd,J=8.4,8.0,2.4,2.0Hz,1H),5.50(s,2H),3.82(s,3H).

[0119] 13 C NMR (100MHz, CDCl3) δ161.1,160.0,159.9,155.1,153.9,150.7,140.5,138.6,137.0,134.6,129.9 ,129.7,129.1,128.3,127.8,127.3,124.2,121.7,119.8,119.4,113.7,112.4,110.5,71.1,55.3.

[0120] Example 5

[0121] Preparation process of compound 14:

[0122]

[0123] S1. Preparation of 8-((3-methoxybenzyl)oxy)quinolin-2(1H)-one (QM08)

[0124] Weigh 5.0 g of 2,8-quinolinediol into a 500 mL two-necked flask, add 7.72 g of K₂CO₃ and 300 mL of acetonitrile, and stir at room temperature. Add 4.8 mL (6.86 g) of 3-methoxybenzyl bromide, heat to reflux, and react overnight. Add 300 mL of ethyl acetate and 300 mL of water to the reaction mixture, mix thoroughly, and separate the organic phase. The aqueous phase is extracted twice with ethyl acetate (100 mL x 2). The combined organic phases are washed with saturated NaCl solution (400 mL x 2), dried over anhydrous MgSO₄, filtered, and the solvent evaporated under reduced pressure. Purification by column chromatography (75% EA / PE) yields 6.36 g of a white solid.

[0125] S2. Preparation of 2-chloro-8-((3-methoxybenzyl)oxy)quinoline (QM13)

[0126] 2.53 g of QM08 was weighed into a dry 250 mL two-necked flask. Under argon, 75 mL of chlorobenzene, 4.8 mL of P℃13, 0.25 mL of anhydrous pyridine, and 0.06 mL of anhydrous DMF were added sequentially. The mixture was heated to reflux and allowed to react overnight. TLC was used to monitor the reaction. The mixture was allowed to cool to room temperature. The pH was adjusted to 8 with supersaturated NaHCO₃ and extracted three times with ethyl acetate (75 mL x 3). The organic phases were combined and washed sequentially with saturated NaHCO₃ solution (150 mL x 2) and saturated NaCl solution (150 mL x 2). The mixture was dried over anhydrous MgSO₄, filtered, and the solvent was evaporated under reduced pressure. Purification by column chromatography (10% EA / PE) yielded 1.38 g of a white solid.

[0127] Preparation of S3.2-(tributylstannyl)pyrimidine (QM17)

[0128] Under nitrogen, 5 mL of lithium diisopropylamide (LDA, 2.0 M in THF / Hexane) and 10 mL of anhydrous THF were stirred and cooled to -2°C. A solution of tri-n-butyltin hydride (2.91 g in 10 mL of dry THF) was slowly added dropwise through a dropping funnel. The temperature was maintained for 1 hour. The mixture was cooled to -78°C and a solution of 2-chloropyrimidine (1.15 g in 10 mL of dry THF) was slowly added dropwise through a dropping funnel. The temperature was maintained for 2 hours. The mixture was warmed to 0°C and 20 mL of saturated NH4Cl solution was slowly added dropwise. After addition, the mixture was brought to room temperature and stirred for 30 minutes. The mixture was extracted with ethyl acetate three times (30 mL x 3). The combined organic phases were washed with saturated NaCl solution (50 mL x 2). The mixture was dried over anhydrous MgSO4, filtered, and the solvent was evaporated under reduced pressure. Purification by flash column chromatography (5% EA / PE) afforded 1.19 g of a yellow solid.

[0129] Preparation of S4 compound 14

[0130] Weigh 0.967 g of QM13 into a 100 mL two-necked flask, add 0.226 g of Pd(PPh3)2Cl2, seal the reaction apparatus, and replace the argon atmosphere; add 32 mL of anhydrous DMF, stir at room temperature for 10 min, add 1.19 g of QM17, heat in an oil bath at 115°C, and react overnight; cool to room temperature, add 160 mL of ethyl acetate and 100 mL of water, shake evenly, separate the organic phase, extract the aqueous phase with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated NaCl solution (150 mL × 2); dry over anhydrous MgSO4, filter, and evaporate the solvent under reduced pressure. The product was purified by flash column chromatography (80% EA / PE) to obtain a yellow oil. The oil was dissolved in 20 mL of ethyl acetate and 2 M HCl / AcOEt solution was added until no yellow precipitate formed. The product was filtered, washed with an appropriate amount of ethyl acetate, and dried in vacuo to obtain 448 mg of a yellow solid, which was the target compound 14.

[0131] Compound 14: Yield 448mg (33.4%), yellow solid. 1 H NMR (500MHz, DMSO) δ9.09(d,J=5.0Hz,2H),8.64(d,J=8.5Hz,1H),8.57(d,J=8.5Hz,1H),7.68(t,J=5.0Hz,1H),7.65(s,1H),7.61(t,J=8.0Hz ,1H),7.39(d,J=7.5Hz,1H),7.31(t,J=8.0Hz,1H),7.21(s,1H),7.11(d,J=7.5Hz,1H),6.89(dd,J=8.0,3.0Hz,1H),5.43(s,2H),3.76(s,3H).

[0132] 13 C NMR (125MHz, DMSO) δ161.8,159.3,158.0,154.6,152.2,138.6,138.4,138.1,12 9.6,129.4,128.5,121.6,121.0,119.9,119.7,113.4,113.0,111.7,70.0,55.0.

[0133] The preparation process of compounds 15 to 23 is the same as that of compound 14, except that in the preparation process of compound QM08, different raw materials are used to replace 3-methoxybenzyl bromide to obtain the target product.

[0134] Compound 12: 1H NMR(400MHz,Chloroform-d)δ9.54(s,2H),9.30(s,1H),8.29(d,J=8.5Hz,1H),7.91(d,J=8.5Hz,1H),7.47(dd,J= 6.1,1.5Hz,2H),7.33(t,J=7.8Hz,1H),7.24–7.06(m,3H),6.88(dd,J=8.3,2.5Hz,1H),5.40(s,2H),3.84(s,3H).

[0135] 13 C NMR (100MHz, CDCl3) δ159.92,158.73,155.67,154.77,150.54,140.82,138.52,137.53,132.81,129.71 ,128.89,127.61,119.96,119.22,118.38,113.56,112.41,111.33,77.38,77.06,76.74,70.94,55.30.

[0136] Compound 13: 1 H NMR(400MHz,Chloroform-d)δ9.34(d,J=1.5Hz,1H),8.88(d,J=5.3Hz,1H),8.68(dd,J=5.2,1.4Hz,1H),8.64(d,J=8.6Hz,1H),8.31(d,J=8.5Hz,1H ),7.50–7.46(m,2H),7.34(t,J=7.9Hz,1H),7.21(t,J=2.0Hz,1H),7.18– 7.14(m,2H),6.90(ddd,J=8.3,2.7,1.0Hz,1H),5.41(s,2H),3.84(s,3H).

[0137] 13 C NMR (100MHz, CDCl3) δ162.98,159.91,158.70,157.84,154.93,152.52,140.35,138.69,137.18,130.32,12 9.66,128.05,120.12,119.27,119.12,118.26,113.41,112.58,111.08,77.36,77.04,76.72,71.01,55.27.

[0138] Compound 15: 1H NMR (500MHz, CDCl3) δ8.97(d,J=5.0Hz,2H),8.61(d,J=8.5Hz,1H),8.31(d,J=8.5Hz,1H),7.53(t ,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),7.34(t,J=5.0Hz,1H),7.08(d,J=8.0Hz,1H),4.10(s,3H).

[0139] 13 C NMR (125MHz, CDCl3) δ163.8,157.8,156.1,153.4,140.2,137.0,129.7,128.0,121.0,120.4,119.1,107.7,55.9.

[0140] Compound 16: 1 H NMR(500MHz,DMSO)δ9.09(d,J=4.9Hz,2H),8.61–8.53(m,2H),7.69(t,J=4.9Hz,1H),7.47(s,1H),7.36–7.30(m,2H ),7.24(t,J=1.9Hz,1H),7.14(d,J=7.6Hz,1H),6.92(dd,J=8.3,2.5Hz,1H),5.42(s,2H),3.78(s,3H),2.51(s,3H).

[0141] 13 C NMR (125MHz, DMSO) δ161.82,159.85,158.59,158.51,153.42,151.32,139.35,138.84,136.60,130. 05,129.94,122.15,121.55,120.27,119.27,119.21,114.50,114.01,113.60,70.61,55.43,22.26.

[0142] Compound 17: 1H NMR (400MHz, DMSO) δ9.06(d,J=4.9Hz,2H),8.59–8.47(m,2H),7.64(t,J=4.9Hz,1H),7.42(dd,J=9.2,2.7Hz,1H),7.38–7.29( m,2H),7.22(dd,J=2.6,1.5Hz,1H),7.12(dt,J=7.6,1.2Hz,1H),6.93(ddd,J=8.3,2.7,1.0Hz,1H),5.43(s,2H),3.78(s,3H).

[0143] 13 C NMR (100MHz, DMSO) δ163.14,162.41,159.97,159.86,158.43,157.02,156.90,153.00,138.44,137. 33,130.11,122.54,121.69,120.41,114.11,113.76,103.09,102.87,102.47,102.17,70.84,55.50.

[0144] Compound 18: 1 H NMR (400MHz, DMSO) δ9.06(d,J=4.9Hz,2H),8.56(d,J=8.6Hz,1H),8.50(d,J=8.7Hz,1H),7.76(d,J=2.2Hz,1H),7.65(t,J=4.9Hz,1H),7.38(d,J=2.2 Hz,1H),7.34(t,J=7.9Hz,1H),7.22(dd,J=2.6,1.5Hz,1H),7.12(dt,J=7. 7,1.2Hz,1H),6.93(ddd,J=8.3,2.7,1.0Hz,1H),5.44(s,2H),3.78(s,3H).

[0145] 13 C NMR(100MHz,DMSO)δ159.85,158.46,155.97,138.79,138.53,137.01,132.79,1 30.10,122.66,121.78,120.36,118.87,114.08,113.68,112.21,70.79,55.50.

[0146] The preparation route of compound 19 is:

[0147]

[0148] 200 mg (0.606 mmol, 1.0 eq) of 5QL-04, 246.3 mg (0.667 mmol, 1.1 eq) of 2-(tri-n-butyltin)pyrimidine, and 245 mg (0.061 mmol, 0.1 eq) of Pd(PPh3)2Cl were weighed separately into a 25 mL two-necked flask. The reaction apparatus was sealed and replaced with argon. 3 mL of anhydrous DMF was added, and the mixture was heated in an oil bath at 110°C overnight. After cooling to room temperature, 30 mL of ethyl acetate and 100 mL of water were added and shaken thoroughly. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated NaCl solution (150 mL x 2). The mixture was dried over anhydrous MgSO4, filtered, and the solvent was evaporated under reduced pressure. Purification by flash column chromatography (80% EA / PE + 0.5% TEA) afforded a yellow oil; the oil was dissolved in 5 mL of anhydrous THF, and 2 M HCl / AcOEt solution was added until no further yellow precipitate formed; the mixture was filtered, washed with an appropriate amount of THF, and dried in vacuo to afford 55 mg of a red solid; yield: 24.3%.

[0149] Compound 19: 1 H NMR (400MHz, DMSO) δ9.09(d,J=4.9Hz,2H),8.75(d,J=8.8Hz,1H),8.56(d,J=8.8Hz,1H),7.68(t,J=4.9Hz,1H),7.34–7.27(m,2H),7. 22(t,J=2.0Hz,1H),7.12(d,J=7.5Hz,1H),7.04(d,J=8.6Hz,1H),6.89(dd,J=7.9,2.6Hz,1H),5.38(s,2H),3.97(s,3H),3.76(s,3H).

[0150] 13 C NMR (100MHz, DMSO) δ162.58,159.82,158.52,153.33,148.85,148.13,139.53,139.41,133.09,129.96,122.01,121.52, 120.80,120.20,113.82,113.51,112.79,106.43,71.06,56.48,55.47,40.59,40.38,40.17,39.96,39.75,39.54,39.33.

[0151] Compound 20: 11H NMR (400 MHz, DMSO) δ 9.07 (d, J = 4.9 Hz, 2H), 8.58–8.47 (m, 2H), 7.66 (t, J = 4.9 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.22–7.18 (m, 1H), 7.10 (dd, J = 7.1, 4.8 Hz, 2H), 7.02 (d, J = 2.5 Hz, 1H), 6.91 (dd, J = 8.2, 2.5 Hz, 1H), 5.42 (s, 2H), 3.91 (s, 3H), 3.77 (s, 3H).

[0152] 13 13C NMR (100 MHz, DMSO) δ 162.08, 159.90, 159.61, 158.49, 154.90, 149.85, 138.73, 137.89, 134.99, 131.06, 130.10, 121.98, 121.82, 120.15, 113.97, 113.53, 105.16, 98.47, 70.61, 56.23, 55.52, 40.62, 40.47, 40.41, 40.32, 40.21, 40.00, 39.79, 39.58, 39.37.[[ID=..]]

[0153] Compound 21: 1 1H NMR (500 MHz, DMSO) δ 9.12 (d, J = 4.7 Hz, 2H), 8.84 (d, J = 8.6 Hz, 1H), 8.41 (d, J = 8.6 Hz, 1H), 7.74 (t, J = 4.8 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.15 (s, 1H), 6.86 (dd, J = 8.2, <2.5 Hz, 1H), 5.25 (s, 2H), 4.09 (d, J = 7.7 Hz, 6H), 3.73 (s, 3H).

[0154] 13 13C NMR (125 MHz, DMSO) δ 159.69, 158.72, 154.75, 152,30, 141.65, 139.52, 136.29, 132.85, 129.74, 122.75, 121.36, 117.43, 116.54, 114.68, 114.01, 98.10, 75.70, 57.79, 57.12, 55.48, 40.48, 40.32, 40.15, 39.98, 39.81, 39.65, 39.48.

[0155] Compound 22: 1 H NMR (500MHz, DMSO-d6) δ9.14(d,J=4.3Hz,2H),8.80(d,J=8.2Hz,1H),8.49(d,J=8.0Hz,1H),7.99(d,J=8.7H z,1H),7.81–7.74(m,2H),7.33–7.15(m,6H),6.85(d,J=7.8Hz,1H),5.41(s,2H),4.06(s,3H),3.71(s,3H).

[0156] 13 C NMR (125MHz, DMSO) δ160.66,159.68,158.77,153.82,151.78,141.80,139.50,139.41,139.36,129.77,124.76,124. 72,122.75,121.25,118.47,114.53,114.11,75.67,57.60,55.50,40.51,40.35,40.18,40.01,39.84,39.68,39.51.

[0157] Compound 23: 1 H NMR (400MHz, DMSO-d6) δ9.21(d,J=4.7Hz,2H),8.22(s,1H),7.89–7.83(m,1H),7.77(t,J=8.1Hz,1H),7.68(d,J=7.8Hz,1H),7.3 6(t,J=7.9Hz,1H),7.25(s,1H),7.17(q,J=6.4,5.7Hz,1H),6.95(dd,J=8.2,2.4Hz,1H),5.53(s,2H),4.40(s,3H),3.79(s,3H).

[0158] 13 C NMR (101MHz, DMSO) δ168.53,159.95,159.00,158.80,157.93,150.78,150.22,138.06,130.22,129.78,123.80,122.11, 120.16,115.01,114.46,114.22,113.60,101.21,71.20,58.97,55.60,40.61,40.41,40.20,39.99,39.78,39.57,39.36.

[0159] Example 6

[0160] Preparation process of compound 25:

[0161]

[0162] S1. Preparation of (E)-3-ethoxy-N-(2-hydroxy-4-methylphenyl)acrylamide (LQM-01)

[0163] 9.43 g of 3-ethoxyacrylic acid (81.20 mmol, 1.0 eq) was weighed into a dry 250 mL round-bottom flask and added to 100 mL of anhydrous DCM under a nitrogen atmosphere. Subsequently, 60.90 mL of oxalyl chloride (121.80 mmol, 1.5 eq, 2.0 M in DCM) was slowly added dropwise at 0°C and the reaction was stirred overnight at room temperature. The solvent was evaporated under reduced pressure to obtain the acyl chloride. Separately, 10 g of 2-amino-5-methylphenol (81.20 mmol, 1.0 eq) was weighed into a dry 500 mL two-necked flask and added to 150 mL of anhydrous DCM under a nitrogen atmosphere. 100 mL of anhydrous DCM was added to the acyl chloride and the acyl chloride was transferred to the reaction mixture at 0°C. Finally, 13.07 mL of anhydrous pyridine (162.40 mmol, 2.0 eq) was added and the reaction was stirred overnight at room temperature. After TLC tracking, the reaction mixture was poured into 250 mL of ice water and extracted with DCM (250 mL x 2). The organic phases were combined. The organic phases were washed sequentially with 5% HCl solution (250 mL x 2), saturated NaHCO₃ (250 mL x 2), and saturated NaCl (250 mL x 2), dried over anhydrous MgSO₄, filtered, and the solvent evaporated under reduced pressure to yield a yellow-brown solid. After dissolution with a small amount of DCM, the product was recrystallized from petroleum ether and allowed to stand overnight. Filtration and the filter cake was washed thoroughly with petroleum ether to yield 10.97 g of a yellow solid; yield: 61.0%.

[0164] S2. Preparation of 8-hydroxy-6-methylquinolin-2(1H)-one (LQM-02)

[0165] 10.97 g of LQM-01 (49.58 mmol, 1.0 eq) was weighed into a dry 500 mL round-bottom flask. 150 mL of anhydrous DCM was added, and 24.79 mL (49.58 mmol, 1.0 eq) of trifluoromethanesulfonic acid was slowly added dropwise to the reaction mixture. The reaction was stirred at room temperature overnight. After TLC monitoring, the solvent was evaporated under reduced pressure. The reaction mixture was poured into 150 mL of ice water and extracted with DCM (150 mL x 3). The resulting organic phases were combined and washed sequentially with saturated NaHCO₃ (150 mL x 3) and saturated NaCl (150 mL x 3), dried over anhydrous MgSO₄, filtered, and the solvent evaporated under reduced pressure. 6.70 g of a brown solid (mixture) was obtained.

[0166] Preparation of S3.8-((3-methoxybenzyl)oxy)-6-methylquinolin-2(1H)-one(LQM-03)

[0167] A mixture of 8.0 g of LQM-02 (45.67 mmol, 1.0 eq) was placed in a dry 250 mL two-necked flask. 12.62 g of KCO (91.33 mmol, 2.0 eq) and 100 mL of acetonitrile were added, followed by the addition of 7.03 mL of 3-methoxybenzyl bromide (50.23 mmol, 1.1 eq). The mixture was heated to 85°C and allowed to react overnight. After TLC monitoring, the reaction mixture was allowed to cool to room temperature. The mixture was filtered through celite, rinsed with EA, and the solvent was evaporated under reduced pressure. Purification by column chromatography (80% EA / PE) afforded 9.0 g of a white solid in a 66.7% yield.

[0168] Preparation of S4.2-chloro-8-((3-methoxybenzyl)oxy)-6-methylquinoline(LQM-04)

[0169] 9.0 g of LQM-03 (30.47 mmol, 1.0 eq) was weighed into a dry 250 mL two-necked flask, 100 mL of DCE was added, 30.47 mL of oxalyl chloride (60.95 mmol, 2.0 eq, 2.0 M in DCM) was slowly added, and 2 drops of anhydrous DMF were added thereto. The mixture was heated to 85°C. ℃ The reaction was allowed to react overnight. After TLC monitoring, the reaction mixture was allowed to cool to room temperature, 50 mL of saturated NaHCO₃ solution was added with stirring, and the mixture was extracted with DCM (150 mL x 2). The combined organic phases were washed with saturated NaCl solution (150 mL x 2), dried over anhydrous MgSO₄, filtered, and the solvent evaporated under reduced pressure. Column chromatography (10% EA / PE) was used for purification to obtain 4.50 g of a white solid. Yield: 47.0%.

[0170]

[0171] Preparation of S5.5-methoxy-2-(tributylstannyl)pyrimidine (LMD-01)

[0172] 3 g (20.8 mmol, 1.0 eq) of 2-chloro-5-methoxypyrimidine and 1.2 mg (1.08 mmol, 0.05 eq) of Pd(PPh3)4 were weighed into a 100 mL two-necked flask. Under argon, 20 mL of anhydrous toluene was added and stirred. Then, 15 mL (31.1 mmol, 1.5 eq) of hexabutylditin was added and the mixture was heated to reflux and allowed to react overnight. After cooling to room temperature, 150 mL of ethyl acetate and 250 mL of water were added to the reaction mixture and mixed thoroughly. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL x 2) and washed with saturated NaCl solution (200 mL x 2). The mixture was dried over anhydrous MgSO4, filtered, and the solvent was evaporated under reduced pressure. Purification by flash column chromatography (10% EA / PE) afforded 2.9 g of a colorless, transparent liquid in a 35.8% yield.

[0173] S6. Preparation of Compound 25

[0174] Weigh 0.4 g (1.0 eq) of LQM-04, 0.56 g (1.1 eq) of LMD-01, and 90 mg (0.1 eq) of Pd(PPh3)2Cl2 into a 25 mL two-necked flask. Seal the reaction apparatus and replace the argon atmosphere. Add 3 mL of anhydrous DMF, heat in an oil bath at 110°C, and react overnight. Cool to room temperature, add 40 mL of ethyl acetate and 100 mL of water, and shake thoroughly. Separate the organic phase, extract the aqueous phase with ethyl acetate (30 mL x 2), combine the organic phases, and wash with saturated NaCl solution (150 mL x 2). Dry over anhydrous MgSO4, filter, and evaporate the solvent under reduced pressure. The product was purified by flash column chromatography (80% EA / PE + 0.5% TEA) to give a yellow oil. The oil was dissolved in 5 mL of THF, and 2 M HCl / AcOEt solution was added until no more yellow precipitate formed. The product was filtered, washed with an appropriate amount of THF, and dried in vacuo to give 75 mg of a yellow solid. Yield: 30.2%.

[0175] Compound 25: 1H NMR (500MHz, DMSO) δ8.81(s,2H),8.63(d,J=8.6Hz,1H),8.53(d,J=8.6Hz,1H),7.48(s,1H),7.39–7.32(m,2H),7.23(t ,J=1.9Hz,1H),7.15(d,J=7.5Hz,1H),6.93(dd,J=8.2,2.5Hz,1H),5.43(s,2H),4.04(s,3H),3.79(s,3H),2.51(s,3H).

[0176] 13 C NMR (125MHz, DMSO) δ159.87,153.87,153.81,152.47,150.61,144.6,140.15,139.28,138.69, 130.10,129.55,121.15,120.35,119.31,114.96,114.06,113.70,70.78,57.04,55.55,22.28.

[0177] The preparation process of compounds 24, 26-32 is the same as that of compound 25, except that in the preparation process of compound LQM-01, different raw materials are used to replace 2-amino-5-methylphenol to obtain the target product.

[0178] Compound 24: 1 H NMR (500MHz, CDCl3) δ8.62(s,2H),8.54(d,J=8.5Hz,1H),8.26(d,J=8.5Hz,1H),7.43–7.38(m,2H),7.29(d,J=6Hz,1H) ,7.17(s,1H),7.13(d,J=7.5Hz,1H),7.05(d,J=7Hz,1H),6.84(d,J=8.5Hz,1H),5.46(s,2H),4.00(s,3H),3.81(s,3H).

[0179] 13 C NMR (125MHz, CDCl3) δ159.9,157.0,155.1,153.3,153.0,143.8,140.4,138.7,136.9, 129.6,129.5,127.4,120.9,119.7,119.3,113.6,112.3,110.6,71.02,56.15,55.29.

[0180] Compound 26: 1H NMR (500MHz, DMSO) δ8.76 (s, 2H), 8.48 (q, J = 8.7Hz, 2H), 7.40 (dd, J = 9.3, 2.6Hz, 1H), 7.34 (d, J = 7.9Hz, 1H), 7.32–7. 29(m,1H),7.21–7.19(m,1H),7.12(dd,J=7.5,1.4Hz,1H),6.95–6.91(m,1H),5.41(s,2H),4.01(s,3H),3.78(s,3H).

[0181] 13 C NMR (125MHz, DMSO) δ161.90,159.85,156.65,156.07,153.37,152.86,144.36,138.44,137.21,1 30.10,124.13,122.21,120.83,120.48,114.29,114.08,113.85,103.07,102.43,70.89,55.52.

[0182] Compound 27: 1 H NMR (400MHz, DMSO) δ8.77(s,2H),8.51(d,J=8.7Hz,1H),8.46(d,J=8.8Hz,1H),7.73(d,J=2.1Hz,1H),7.39–7.31(m,2H),7. 21(dd,J=2.6,1.5Hz,1H),7.12(dt,J=7.6,1.2Hz,1H),6.93(dd,J=8.3,2.7Hz,1H),5.43(s,2H),4.02(s,3H),3.78(s,3H).

[0183] 13 C NMR (100MHz, DMSO) δ159.85,155.72,153.69,153.42,144.38,138.54,138.50,137.05,132. 33,130.10,129.73,122.32,120.44,118.87,114.07,113.77,112.23,70.83,56.83,55.52.

[0184] Compound 28: 11H NMR (500 MHz, DMSO) δ 8.79 (s, 2H), 8.67–8.36 (m, 2H), 7.33 (t, J = 7.7 Hz, 1H), 7.19 (s, 1H), 7.12 (d, J = 8.5 Hz, 2H), 7.05 (s, 1H), 6.92 (d, J = 8.1 Hz, 1H), 5.42 (s, 2H), 4.02 (s, 3H), 3.91 (s, 3H), 3.77 (s, 3H).

[0185] 13 13C NMR (125 MHz, DMSO) δ 159.90, 159.45, 154.35, 154.02, 153.66, 149.33, 144.55, 138.94, 138.59, 130.62, 130.15, 121.60, 120.26, 114.01, 113.66, 105.47, 98.58, 70.76, 57.01, 56.30, 55.56, 40.53, 40.36, 40.20, 40.03, 39.87, 39.70, 39.53.

[0186] Compound 29: 1 1H NMR (400 MHz, Methanol-d4) δ 8.83 (s, 2H), 8.36 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.23–7.14 (m, 2H), 6.96 (dd, J = 8.3, 2.5 Hz, 1H), 5.52 (s, 2H), 4.50 (s, 3H), 4.14 (s, 3H), 3.83 (s, 3H).

[0187] 13 13C NMR (101 MHz, MeOD) δ 十七点九六, 一百六十点二二, 一百五十五点六八, 一百四十八点九八, 一百四十八点一三, 一百四十七点四二, 一百四十四点三五, 一百三十六点八七, 一百二十九点七四, 一百二十九点六七, 一百二十九点五五, 一百二十一点六六, 一百一十九点六七, 一百一十五点二七, 一百一十四点四九, 一百一十三点七九,一百一十三点一五, 九十九点三一, 七十一点七三, 五十八点二六, 五十六点二五, 五十四点四三, 四十八点二四, 四十八点零三, 四十八点二, 四十八点零, 四十七点儿八, 四十七点儿六, 四十七点儿四, 四十七点儿二, 四十七点儿

[0188] It should be noted that there seems to be an error in the "13C NMR" translation of line 13. The correct translation of "δ 170.96, 160.22, 155.68, 148.98, 148.13, 147.42, 144.35, 136.87, 129.74, 129.67, 129.55, 121.66, 119.67, 115.27, 114.49, 113.79, 113.15, 99.31, 71.73, 58.26, 56.25, 54.Compound 30: 1H NMR (400MHz, CDCl3) δ8.65(d,J=5.6Hz,1H),8.61(d,J=8.5Hz,1H),8.28(d,J=8.5Hz,1H),7.46–7.43(m,2H),7.28(d,J=8.4Hz,1H ),7.16(d,J=8Hz,1H),7.09(d,J=8.8Hz,2H),6.83(d,J=8.4Hz,1H),6.77(d,J=5.6Hz,1H),5.44(s,2H),4.18(s,3H),3.79(s,3H).

[0189] HRMS (IT-TOF): C 22 H 19 N3O3for[M+H]+, calculated 374.1499, found 374.1493.

[0190] Compound 31: 1 H NMR(500MHz,DMSO-d6)δ8.82(d,J=5.8Hz,1H),8.59–8.45(m,2H),7.31–7.24(m,2H),7.17–7.12(m, 2H),7.07–6.94(m,2H),6.89(d,J=8.2Hz,1H),5.43(s,2H),4.19(s,3H),3.91(s,3H),3.74(s,3H).

[0191] 13 C NMR (125MHz, DMSO) δ171.34,160.19,159.83,155.16,138.73,137.64,135.52,131.79,130.05,121.78,119.85 ,113.54,108.97,105.28,98.52,70.41,56.31,55.61,55.53,40.49,40.33,40.16,39.99,39.83,39.66,39.49.

[0192] Compound 32: 1H NMR (500MHz, Methanol-d4) δ8.79(d,J=5.8Hz,1H),8.38(s,1H),8.04(dd,J=8.4,1.0Hz,1H),7.88(t,J=8.2Hz,1H),7.81(dd,J=8.1,1.1Hz, 1H),7.37(t,J=7.9Hz,1H),7.22–7.18(m,2H),7.16(d,J=5.8Hz,1H),7 .01–6.97(m,1H),5.46(s,2H),4.52(s,3H),4.01(s,3H),3.84(s,3H).

[0193] 13 C NMR(126MHz,MeOD)δ171.14,170.38,160.16,158.05,154.86,148.40,136.83,130.10,129.78,129.66,122.09,120.19,114 .85,114.42,113.90,113.61,111.06,99.88,71.86,58.39,54.46,54.02,48.14,47.96,47.79,47.62,47.45,47.28,47.11.

[0194] Example 7

[0195] Preparation process of compound 66: Steps S1 to S4 are the same as in Example 6;

[0196]

[0197] Preparation of S5.4-methyl-2-(tributylstannyl)pyrimidine (LMD-05)

[0198] Under argon, 26 mL of lithium diisopropylamide (LDA, 52.5 mmol, 1.5 eq, 2.0 M in THF / Hexane) and 20 mL of anhydrous THF were stirred and cooled to 0°C. Then, 14 mL of tri-n-butyltin hydride solution (52.5 mmol, 1.5 eq) was slowly added dropwise. The temperature was maintained for 1 hour. The mixture was cooled to -78°C and 2-chloro-4-methylpyrimidine solution (4.5 g in 10 mL of dry THF) was slowly added dropwise. The temperature was maintained for 2 hours. The mixture was warmed to 0°C and continued to react for 1 hour. 50 mL of saturated NH4Cl solution was added. After addition, the mixture was brought to room temperature and stirred for 30 minutes. The mixture was extracted with ethyl acetate three times (100 mL x 3). The organic phases were combined and washed with saturated NaCl solution (200 mL x 2). The mixture was dried over anhydrous MgSO4, filtered, and the solvent was evaporated under reduced pressure. The product was separated and purified by flash column chromatography (5% EA / PE) to obtain 4.05 g of a colorless transparent liquid; the yield was 30.2%.

[0199] S6. Preparation of Compound 34

[0200] Weigh 400 mg (1.0 eq) of LQM-04, 0.54 g (1.1 eq) of LMD-05, and 90 mg (0.1 eq) of Pd(PPh3)2Cl2 into a 25 mL two-necked flask. Seal the reaction apparatus and replace the argon atmosphere. Add 3 mL of anhydrous DMF, heat in an oil bath at 110°C, and react overnight. Cool to room temperature, add 30 mL of ethyl acetate and 100 mL of water, and shake thoroughly. Separate the organic phase, extract the aqueous phase with ethyl acetate (30 mL x 2). Combine the organic phases and wash with saturated NaCl solution (150 mL x 2). Dry over anhydrous MgSO4, filter, and evaporate the solvent under reduced pressure. Purification by flash column chromatography (80% EA / PE + 0.5% TEA) afforded a yellow oil; the oil was dissolved in 5 mL of THF, and 2 M HCl / AcOEt solution was added until no further yellow precipitate formed; the mixture was filtered, washed with an appropriate amount of THF, and dried in vacuo to afford 95 mg of a yellow solid; yield: 34.3%.

[0201] Compound 34: 1 H NMR (500MHz, DMSO) δ8.94(d,J=5.1Hz,1H),8.60(d,J=8.6Hz,1H),8.55(d,J=8.5Hz,1H),7.61(d,J=5.3Hz,1H),7.48(s,1H),7.3 8–7.31(m,2H),7.23(d,J=2.3Hz,1H),7.16(d,J=7.5Hz,1H),6.92(dd,J=8.2,2.4Hz,1H),5.43(s,2H),3.77(s,3H),2.65(s,3H).

[0202] 13 C NMR (125MHz, DMSO) δ169.06,160.85,159.85,157.45,153.19,150.83,139.54,139.25,138.8, 130.03,121.66,121.54,120.15,119.29,114.74,113.86,113.59,70.66,55.53,24.36,22.32.

[0203] The preparation process of compounds 33 and 35 to 40 is the same as that of compound 34, except that in the preparation process of compound LQM-01, different raw materials are used to replace 2-amino-5-methylphenol to obtain the target product.

[0204] Compound 33: 1 H NMR (500MHz, CDCl3) δ8.8(d,J=5Hz,1H),8.61(d,J=8.5Hz,1H),8.28(d,J=8.5Hz,1H),7.44–7.41(m,2H),7.29(d,J=7.5Hz,1H),7.2 1(d,J=5Hz,1H),7.17(s,1H),7.14(d,J=7.5Hz,1H),7.06(d,J=7Hz,1H),6.84(d,J=8Hz,1H),5.46(s,2H),3.80(s,3H),2.69(s,3H).

[0205] 13 C NMR (125MHz, CDCl3) δ168.1,163.5,159.9,157.2,155.1,153.7,140.4,138.6,136.9,129 .8,129.6,127.7,121.4,120.2,119.7,119.3,113.6,112.4,110.5,71.08,55.31,24.38.

[0206] Compound 35: 11H NMR (400 MHz, DMSO) δ 8.90 (d, J = 5.1 Hz, 1H), 8.53 (d, J = 8.6 Hz, 1H), 8.49 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 5.1 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.21 (dd, J = 2.6, 1.5 Hz, 1H), 7.13 (dt, J = 7.5, 1.2 Hz, 1H), 6.92 (ddd, J = 8.3, 2.7, 0.9 Hz, 1H), 5.44 (s, 2H), 3.77 (s, 3H), 2.63 (s, 3H).

[0207] 13 13C NMR (100 MHz, DMSO) δ 168.63, 162.49, 159.85, 157.49, 156.95, 156.83, 152.86, 138.47, 137.41, 137.34, 137.28, 130.08, 122.60, 121.12, 120.26, 113.98, 113.67, 103.03, 102.44, 70.82, 55.51, 24.40.

[0208] Compound 36: 1 1H NMR (400 MHz, DMSO) δ 8.90 (d, J = 5.1 Hz, 1H), 8.53 (d, J = 8.6 Hz, 1H), 8.49 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 5.1 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.21 (dd, J = 2.6, 1.5 Hz, 1H), 7.13 (dt, J = 7.5, 1.2 Hz, 1H), 6.92 (ddd, J = 8.3, 2.7, 0.9 Hz, 1H), 5.44 (s, 2H), 3.77 (s, 3H), 2.63 (s, 3H).

[0209] 13 13C NMR (125 MHz, DMSO) δ 168.54, 162.54, 159.85, 157.58, 155.92, 138.73, 138.57, 136.97, 132.77, 130.06, 122.72, 121.17, 120.21, 118.91, 113.96, 113.61, 112.33, 70.78, 55.51, 24.39.

[0210] Compound 37: 1 H NMR (500MHz, CDCl3) δ8.72(s,2H),8.52(d,J=8.5Hz,1H),8.26(d,J=8.5Hz,1H),7.42–7.38(m,2H),7.29(d,J=6Hz,1H) ,7.18(s,1H),7.13(d,J=7.5Hz,1H),7.05(d,J=7Hz,1H),6.84(d,J=8.5Hz,1H),5.46(s,2H),3.81(s,3H),2.67(s,3H).

[0211] Compound 38: 1 H NMR(400MHz, DMSO)δ8.95(s,2H),8.63(dd,J=8.7,1.7Hz,1H),8.55(dd,J=8.6,1.7Hz,1H),7.47(s,1H),7.39–7.2 9(m,2H),7.22(d,J=2.4Hz,1H),7.13(d,J=7.5Hz,1H),6.96–6.87(m,1H),5.42(s,2H),3.78(s,3H),2.41(s,3H).

[0212] 13 C NMR(100MHz,DMSO)δ159.85,158.53,158.38,152.69,150.47,139.93,139.60,138.69,132.19, 130.05,129.91,121.30,120.20,119.28,114.85,114.01,113.52,70.65,55.53,22.31,15.66.

[0213] Compound 39: 1 H NMR(500MHz,DMSO)δ8.90(s,2H),8.60–8.45(m,2H),7.41(dd,J=9.0,2.6Hz,1H),7.37–7.28(m,2H),7 .21(s,1H),7.11(d,J=7.4Hz,1H),6.92(dd,J=8.1,2.2Hz,1H),5.43(s,2H),3.78(s,3H),2.38(s,3H).

[0214] 13C NMR (125MHz, DMSO) δ162.06,160.80,159.86,158.24,156.90,152.96,138.47,137.42,137.30,137.25, 131.16,130.10,122.40,120.34,114.08,113.69,103.08,102.91,102.45,102.20,70.82,55.52,15.58.

[0215] Compound 40: 1 H NMR (500MHz, DMSO) δ8.91(s,2H),8.54(dd,J=8.7,2.2Hz,1H),8.47(dd,J=8.7,2.2Hz,1H),7.74(d,J=2.2Hz,1H),7 .38–7.30(m,2H),7.21(s,1H),7.11(d,J=7.5Hz,1H),6.92(d,J=7.9Hz,1H),5.43(s,2H),3.78(s,3H),2.39(s,3H).

[0216] 13 C NMR (125MHz, DMSO) δ160.71,159.85,158.25,155.87,153.83,138.70,138.55,136.98,132.62, 131.29,130.08,130.01,122.51,120.29,118.87,114.06,113.61,112.22,70.75,55.51,15.58.

[0217] Example 8

[0218] Preparation process of compound 42: Steps S1 to S4 are the same as in Example 6;

[0219]

[0220] S5. Preparation of 4,6-dimethyl-2-(tributylstannyl)pyrimidine (LMD-02)

[0221] Under argon, 15.24 mL of lithium diisopropylamide (LDA, 30.47 mmol, 1.1 eq, 2.0 M in THF / Hexane) and 20 mL of anhydrous THF were stirred and cooled to 0°C. Then, 8.2 mL of tri-n-butyltin hydride solution (30.47 mmol, 1.1 eq) was slowly added dropwise. The temperature was maintained for 1 hour. The mixture was cooled to -78°C and 2-chloro-4,6-dimethylpyrimidine solution (3.95 g in 10 mL of dry THF) was slowly added dropwise. The temperature was maintained for 2 hours. The mixture was warmed to 0°C and the reaction continued for 1 hour. After the addition was complete, 50 mL of saturated NH4Cl solution was added and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate three times (100 mL x 3). The organic phases were combined and washed with saturated NaCl solution (250 mL x 2). The mixture was dried over anhydrous MgSO4, filtered, and the solvent was evaporated under reduced pressure. The product was separated and purified by flash column chromatography (5% EA / PE) to obtain 2.69 g of a colorless transparent liquid; yield: 30.9%.

[0222] S6. Preparation of Compound 42

[0223] Weigh 0.2 g (1.0 eq) of LQM-04, 0.28 g (1.1 eq) of LMD-02, and 45 mg (0.1 eq) of Pd(PPh3)2Cl2 into a 25 mL two-necked flask. Seal the reaction apparatus and replace the argon atmosphere. Add 3 mL of anhydrous DMF, heat in an oil bath at 110°C, and react overnight. Cool to room temperature, add 40 mL of ethyl acetate and 100 mL of water, and shake thoroughly. Separate the organic phase, extract the aqueous phase with ethyl acetate (30 mL x 2), combine the organic phases, and wash with saturated NaCl solution (150 mL x 2). Dry over anhydrous MgSO4, filter, and evaporate the solvent under reduced pressure. The product was purified by flash column chromatography (80% EA / PE + 0.5% TEA) to give a yellow oil. The oil was dissolved in 5 mL of THF, and 2 M HCl / AcOEt solution was added until no yellow precipitate formed. The product was filtered, washed with an appropriate amount of THF, and dried in vacuo to give 65 mg of a yellow solid. Yield: 38.5%.

[0224] The preparation process of compounds 41, 43, and 44 is the same as that of compound 42, except that in the preparation process of compound LQM-01, different raw materials are used to replace 2-amino-5-methylphenol to prepare the target product.

[0225] Compound 42: 11H NMR (500 MHz, DMSO) δ 8.71 (d, J = 8.6 Hz, 1H), 8.55 (d, J = 8.6 Hz, 1H), 7.55 (s, 1H), 7.52 (s, 1H), 7.41 (d, J = 1.5 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 6.92 (dd, J = 8.2, 2.6 Hz, 1H), 5.41 (s, 2H), 3.76 (s, 3H), 2.60 (s, 6H), 2.52 (s, 3H).

[0226] 13 13C NMR (125 MHz, DMSO) δ 168.19, 159.88, 158.98, 149.36, 140.84, 140.30, 138.60, 130.12, 130.03, 121.59, 121.43, 119.99, 119.38, 115.36, 113.71, 113.62, 70.79, 55.56, 23.75, 22.34.

[0227] Compound 41: 1 1H NMR (500 MHz, CDCl3) δ 8.62 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.42–7.41 (m, 2H), 7.28 (d, J = 8.5 Hz, 1H), 7.17–7.16 (m, 2H), 7.08 (s, 1H), 7.06 (d, J = 7 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 5.46 (s, 2H), 3.80 (s, 3H), 2.64 (s, 6H).

[0228] 13 13C NMR (100 MHz, CDCl3) δ 167.5, 163.1, 159.9, 155.0, 153.9, 140.2, 138.5, 136.9, 129.6, 128.5, 127.6, 121.6, 119.8, 119.7, 119.4, 113.6, 112.5, 110.4, 71.07, 55.31, 24.02. <[

[0229] Compound 43: 1H NMR (500MHz, DMSO) δ8.58–8.48(m,2H),7.49(d,J=3.0Hz,1H),7.45(dd,J=9.0,2.6Hz,1H),7.37–7.29(m,2H),7.20 (q,J=2.3Hz,1H),7.13(dd,J=7.7,2.8Hz,1H),6.91(dd,J=8.3,2.4Hz,1H),5.43(s,2H),3.76(s,3H),2.59(s,6H).

[0230] 13 C NMR (125MHz, DMSO) δ168.00,160.66,160.42,151.40,138.24,138.10,130.20, 130.03,122.61,121.06,120.06,113.83,113.58,102.74,70.88,55.52,23.65.

[0231] Compound 44: 1 H NMR (400MHz, DMSO) δ8.50(s,2H),7.76(d,J=2.1Hz,1H),7.46(s,1H),7.39(d,J=2.2Hz,1H),7.32(t,J=7.9Hz,1H ),7.23–7.19(m,1H),7.14(d,J=7.6Hz,1H),6.91(dd,J=8.2,2.6Hz,1H),5.44(s,2H),3.76(s,3H),2.58(s,6H).

[0232] 13 C NMR (100MHz, DMSO) δ167.80,161.72,159.87,155.74,137.25,132.93,130.14,130. 02,122.84,120.68,120.06,119.01,113.84,113.54,112.62,70.86,55.54,23.88.

[0233] Example 9

[0234] Preparation process of compound 63: Steps S1 to S4 are the same as in Example 6;

[0235]

[0236] S5. Preparation of 2-chloro-5-(ethoxymethoxy)pyrimidine (LMD-13-1)

[0237] 5.0 g (38.31 mmol, 1.0 eq) of 2-chloro-5-hydroxypyrimidine and 10.6 g (76.61 mmol, 2.0 eq) of K₂CO₃ were weighed into a 100 mL eggplant-shaped flask. Under nitrogen, 20 mL of anhydrous DMF was added and stirred. Then, 9 mL (95.76 mmol, 2.5 eq) of chloromethyl ether was added and stirred at room temperature for 1 h. Approximately 60 mL of saturated NaHCO₃ solution was injected into the reaction mixture and stirred. 150 mL of ethyl acetate and 150 mL of saturated NaHCO₃ solution were added to the reaction mixture and mixed thoroughly. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (50 mL x 2) and washed with saturated NaCl solution (200 mL x 2). The mixture was dried over anhydrous MgSO₄, filtered, and the solvent was evaporated under reduced pressure. Purification by flash column chromatography (10% EA / PE) afforded 2.23 g of a colorless, transparent liquid in a 31.2% yield.

[0238] Preparation of S6.5-(ethoxymethoxy)-2-(tributylstannyl)pyrimidine(LMD-13-2)

[0239] 2.23 g (11.82 mmol, 1.0 eq) of LMD-13-1 and 415 mg (0.59 mmol, 0.05 eq) of Pd(PPh3)2Cl2 were weighed into a 100 mL two-necked flask. Under argon, 20 mL of anhydrous 1,4-dioxane was added and stirred. Then, 6.57 mL (13.01 mmol, 1.1 eq) of hexabutylditin was added. The mixture was heated to reflux and allowed to react overnight. After cooling to room temperature, the reaction solution was filtered through celite and the solvent was evaporated under reduced pressure. Purification by flash column chromatography (5% EA / PE) afforded 1.1 g of a colorless, transparent liquid in a 30.1% yield.

[0240] S7. Preparation of Compound 46

[0241] Weigh 0.2 g (1.0 eq) of LQM-04, 0.31 g (1.1 eq) of LMD-13-2, and 45 mg (0.1 eq) of Pd(PPh3)2Cl2 into a 25 mL two-necked flask. Seal the reaction apparatus and replace the argon atmosphere. Add 3 mL of anhydrous DMF, heat in an oil bath at 110°C, and react overnight. Cool to room temperature, add 40 mL of ethyl acetate and 100 mL of water, and shake thoroughly. Separate the organic phase, extract the aqueous phase with ethyl acetate (30 mL x 2). Combine the organic phases and wash with saturated NaCl solution (150 mL x 2). Dry over anhydrous MgSO4, filter, and evaporate the solvent under reduced pressure. Purification by flash column chromatography (40% EA / PE + 0.5% TEA) afforded a yellow oil; the oil was dissolved in 5 mL of THF, and 2 M HCl / AcOEt solution was added until no further yellow precipitate formed; the mixture was filtered, washed with an appropriate amount of THF, and dried in vacuo to afford 55 mg of a yellow solid; yield: 32.5%.

[0242] The preparation process of compounds 45 and 47 to 50 is the same as that of compound 45, except that in the preparation process of compound LQM-01, different raw materials are used to replace 2-amino-5-methylphenol to obtain the target product.

[0243] Compound 45: 1 H NMR (400MHz, DMSO) δ8.66(d,J=8.8Hz,1H),8.63(s,2H),8.54(d,J=8.8Hz,1H),7.67(d,J=8Hz,1H),7.61(t,J=7.6,8Hz,1H),7. 42(d,J=7.6Hz,1H),7.32(t,J=8Hz,1H),7.23(s,1H),7.13(d,J=7.6Hz,1H),6.91(dd,J=6.8Hz,1H),5.45(s,2H),3.78(s,3H).

[0244] 13 C NMR (125MHz, DMSO) δ159.3,152.8,152.7,152.2,151.8,144.8,139.3,138.4,136 .9,129.5,128.9,128.1,120.5,119.9,119.6,113.4,113.0,112.0,70.11,54.96.

[0245] Compound 46: 1H NMR (500MHz, DMSO) δ11.54(s,1H),8.74–8.63(m,3H),8.55(d,J=8.6Hz,1H),7.52(s,1H),7.41(s,1H),7.35(t,J=7 .8Hz,1H),7.25(s,1H),7.14(d,J=7.5Hz,1H),6.93(dd,J=8.2,2.5Hz,1H),5.45(s,2H),3.79(s,3H),2.51(s,3H).

[0246] 13 C NMR (125MHz, DMSO) δ159.90,153.19,151.81,150.21,145.46,141.05,139.48,138.60,134. 01,130.10,129.48,120.94,120.23,119.37,115.34,114.10,113.58,70.83,55.54,22.28.

[0247] Compound 47: 1 H NMR (500MHz, DMSO) δ11.20(s,1H),8.62(s,2H),8.50(s,2H),7.42(dd,J=9.0,2.6Hz,1H),7.34(dd,J=9.7,5 .8Hz,2H),7.24–7.20(m,1H),7.12(d,J=7.5Hz,1H),6.93(dd,J=8.2,2.5Hz,1H),5.43(s,2H),3.78(s,3H).

[0248] 13 C NMR (125MHz, DMSO) δ161.91,159.87,153.96,152.46,145.22,144.58,138.37,138.00,136.44,1 30.11,129.48,122.06,120.36,114.12,113.73,103.19,103.01,102.73,102.49,70.91,55.51.

[0249] Compound 48: 1H NMR (500MHz, DMSO) δ11.23(s,1H),8.62(s,2H),8.54–8.44(m,2H),7.74(d,J=2.1Hz,1H),7.37(d,J=2.1Hz,1H),7.3 4(t,J=7.9Hz,1H),7.25–7.19(m,1H),7.11(d,J=7.5Hz,1H),6.93(dd,J=7.9,2.6Hz,1H),5.43(s,2H),3.79(s,3H).

[0250] 13 C NMR (125MHz, DMSO) δ159.86,155.37,154.06,153.47,152.47,145.22,138.50,137.98,137. 45,132.34,130.10,129.68,122.17,120.31,118.92,114.09,113.65,112.43,70.83,55.50.

[0251] Compound 49: 1 H NMR(500MHz, Methanol-d4)δ9.10(d,J=8.7Hz,1H),8.84(d,J=8.8Hz,1H),8.62(s,2H),7.42–7.39(m,1H),7.39–7.33(m ,2H),7.23(d,J=2.4Hz,1H),7.17(d,J=7.5Hz,1H),6.97(dd,J=8.3,2.4Hz,1H),5.51(s,2H),4.04(s,3H),3.84(s,3H).

[0252] 13 C NMR(125MHz,MeOD)δ161.83,160.26,154.32,149.08,146.41,145.81,145.21,144.37,136.65,131.45,129.66,125.26, 120.07,119.67,113.92,113.07,108.34,98.31,71.88,55.71,54.43,48.11,47.94,47.78,47.60,47.44,47.26,47.09.

[0253] Compound 50: 1H NMR (500MHz, Methanol-d4) δ8.63(s,2H),8.30(s,1H),7.99(dd,J=8.5,2.4Hz,1H),7.80(dt,J=8.0,4.1Hz,1H),7.73(dd,J=8.0,2.4H z,1H),7.35(td,J=8.1,2.5Hz,1H),7.20(s,1H),7.15(d,J=7.7Hz,1H),6.95(d,J=8.4Hz,1H),5.50(s,2H),4.48(s,3H),3.84(s,3H).

[0254] 13 C NMR(125MHz,MeOD)δ170.81,160.22,154.61,149.15,148.03,146.19,145.12,136.91,129.63,129.41,121.51,119.54 ,115.23,114.49,113.77,112.97,99.00,71.63,58.20,54.43,48.12,47.94,47.78,47.71,47.60,47.43,47.27,47.09.

[0255] Example 10

[0256] Preparation process of compound 52: Steps S1 to S4 are the same as in Example 6;

[0257]

[0258] Preparation of S5.5-fluoro-2-(tributylstannyl)pyrimidine (LMD-11)

[0259] 5g (37.73mmol, 1.0eq) of 2-chloro-5-fluoropyrimidine and 2.65g (3.77mmol, 0.1eq) of Pd(PPh3)2Cl2 were weighed into a 250mL two-necked flask. Under argon, 40mL of anhydrous 1,4-dioxane was added and stirred. Then, 26g (45.28mmol, 1.2eq) of hexabutylditin was added. The mixture was heated to reflux and allowed to react overnight. After cooling to room temperature, the reaction mixture was filtered through celite and the solvent was evaporated under reduced pressure. Purification by flash column chromatography (10% EA / PE) afforded 1.01g of the product as a colorless, transparent liquid in a 31.2% yield.

[0260] S6. Preparation of Compound 52

[0261] Weigh 0.2 g (1.0 eq) of LQM-04, 0.27 g (1.1 eq) of LMD-02, and 45 mg (0.1 eq) of Pd(PPh3)2Cl2 into a 25 mL two-necked flask. Seal the reaction apparatus and replace the argon atmosphere. Add 3 mL of anhydrous DMF, heat in an oil bath at 110°C, and react overnight. Cool to room temperature, add 40 mL of ethyl acetate and 100 mL of water, and shake thoroughly. Separate the organic phase, extract the aqueous phase with ethyl acetate (30 mL x 2), combine the organic phases, and wash with saturated NaCl solution (150 mL x 2). Dry over anhydrous MgSO4, filter, and evaporate the solvent under reduced pressure. Purification by flash column chromatography (40% EA / PE + 0.5% TEA) afforded a yellow oil; the oil was dissolved in 5 mL of THF, and 2 M HCl / AcOEt solution was added until no further yellow precipitate formed; the mixture was filtered, washed with an appropriate amount of THF, and dried in vacuo to afford 30 mg of a yellow solid; yield: 30.1%.

[0262] The preparation process of compounds 51, 53, and 54 is the same as that of compound 52, except that in the preparation process of compound LQM-01, different raw materials are used to replace 2-amino-5-methylphenol to prepare the target product.

[0263] Compound 52: 1 H NMR (400MHz, DMSO) δ9.16 (s, 2H), 8.47 (q, J = 8.6Hz, 2H), 7.44 (s, 1H), 7.39 (t, J = 7.9Hz, 1H), 7.34–7. 24(m,2H),7.19(d,J=7.5Hz,1H),6.98(dd,J=8.2,2.6Hz,1H),5.44(s,2H),3.84(s,3H),2.55(s,3H).

[0264] 13 C NMR (100MHz, DMSO) δ159.83,154.71,146.37,146.16,139.14,138.67,138.47,136. 88,130.02,129.59,121.61,120.38,119.11,113.93,113.66,70.42,55.51,22.28.

[0265] Compound 51: 1H NMR (400MHz, CDCl3) δ8.82(s,2H),8.56(d,J=8.5Hz,1H),8.30(d,J=8.5Hz,1H),7.48–7.44(m,2H),7.29(d,J=8Hz,1H) ,7.17(s,1H),7.12(d,J=7.5Hz,1H),7.06(d,J=7Hz,1H),6.84(d,J=8.5Hz,1H),5.47(s,2H),3.81(s,3H),3.81(s,3H).

[0266] 13 C NMR (125MHz, CDCl3) δ159.9,158.8,155.2,152.6,145.6,145.4,140.5,138.8,137 .1,129.6,128.5,127.9,121.1,119.6,119.1,113.5,112.1,110.8,71.04,55.29.

[0267] Compound 53: 1 H NMR (400MHz, DMSO) δ9.17(s,2H),8.56(q,J=8.6Hz,2H),7.79(s,1H),7.42(t,J=7.9Hz,1H),7. 35–7.27(m,2H),7.18(d,J=7.5Hz,1H),6.99(dd,J=8.2,2.6Hz,1H),5.48(s,2H),3.84(s,3H).

[0268] 13 C NMR(100MHz,DMSO)δ159.87,154.71,146.37,146.16,139.14,138.67,138.47,1 36.67,130.12,129.59,120.59,120.43,118.97,114.09,113.74,70.79,55.53.

[0269] Compound 54: HRMS (IT-TOF): C21H15N3O2F2 for [M+H]+, calculated 380.1205, found 380.1199.

[0270] Example 11

[0271] Preparation process of compound 55:

[0272]

[0273] 200 mg (0.667 mmol, 1.0 eq) of QM13, 0.325 g (0.733 mmol, 1.1 eq) of LMD-13-2, and 250 mg (66.7 μmol, 0.1 eq) of Pd(PPh3)2Cl were weighed into a 25 mL two-necked flask. The reaction apparatus was sealed and replaced with argon. 3 mL of anhydrous DMF was added and the mixture was heated in an oil bath at 110°C overnight. After cooling to room temperature, 30 mL of ethyl acetate and 100 mL of water were added and shaken thoroughly. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated NaCl solution (150 mL x 2), dried over anhydrous MgSO4, filtered, and the solvent was evaporated under reduced pressure. Purification by flash column chromatography (75% EA / PE) afforded 92 mg of a yellow oil. Yield: 33.1%.

[0274] Compound 55: 1 H NMR (400MHz, CDCl3) δ8.73(s,2H),8.55(d,J=8.8Hz,1H),8.26(d,J=8.8Hz,1H),7.54–7.52(m,2H),7.28(t,J=8Hz,1H),7.18(s,1H),7.12(d,J =7.6Hz,1H),7.06(dd,J=6.8Hz,1H),6.84(dd,J=8Hz,1H),5.45(s,2H),5.35(s,2H),3.81(s,3H),3.76(q,J=7.2Hz,2H),1.23(q,J=7.2Hz,3H).

[0275] 13 C NMR (125MHz, CDCl3) δ159.8,157.6,155.0,153.3,151.0,145.8,140.3,138.6,136.8,129.6, 128.5,127.4,120.9,119.7,119.3,113.6,112.2,110.5,93.52,70.99,64.98,55.24,14.99.

[0276] Biological activity of the compound of Example 12

[0277] The inhibitory effect of the test compound on different cancer cells is tested using the following specific testing methods:

[0278] (1) Cells in the logarithmic growth phase were cultured at a rate of 5x10 3 / well concentration was seeded in 96-well plates and then placed in an incubator (37°C, 5% CO2) for culture;

[0279] (2) After the cells were incubated in the incubator for 24 hours, the original culture medium was removed and the experiment was divided into a blank control group and a drug-treated group. The culture medium of the blank group was replaced with full culture medium, and the drug group was treated with the drug concentration designed in the experiment;

[0280] (3) The treated cells were placed in an incubator for 48 hours and then taken out. 10 μL of CCK8 was added to each well. After being placed in an incubator for about 2 hours, the cells were taken out and the absorbance value (wavelength 450 nm) was measured in a multifunctional microplate reader. The cell survival was calculated based on the absorbance value. Three replicate wells were set up for each treatment group.

[0281] (4) GraphPad prism7 software was used for graphical analysis.

[0282] The types of cancer cells tested are shown in Table 2.

[0283] Table 2 Cancer cell types tested

[0284] Abbreviation of cancer cell type Full name of cancer cell type culture medium A549 Human non-small cell carcinoma cells High glucose DMEM + 10% FBS HCT116 Human colon cancer cell line High glucose DMEM + 10% FBS HeLa human cervical cancer cells High glucose DMEM + 10% FBS Kyse150 human esophageal squamous cell carcinoma cells High glucose DMEM + 10% FBS HL-60 human promyelocytic leukemia cells High Glucose 1640+10% FBS

[0285] Using cisplatin (DDP) as a positive control, the IC values ​​of each compound against the above five cancer cells were measured. 50 The values ​​are shown in Table 3.

[0286] Table 3 Activity of compounds

[0287]

[0288]

[0289] Note: "na" in Table 2 means "not available", which means that the test was not conducted. "++++" in the table means IC 50 Below 5 μM; “+++” indicates IC 50 At 5-10 μM; “++” indicates IC 50 At 10-20 μM; “+” indicates IC 50 At >20 μM.

[0290] As can be seen from Table 3, the compounds provided in the above examples all showed significant inhibitory effects on the above five types of cancer cells, especially compounds 1, 2, 5-9, 13-17, 23, 24, 26-28, 30-35, 38, 39, 42-44, 51 and 55, which had IC 50 The values ​​were lower than 10 μM; especially compounds 1, 2, 13, 14, 23, 27, 30-33, 35, 42, 51 and 55, which had IC 50 The value is lower than 5μM, and its inhibitory effect is extremely significant, and it can be prepared into an anticancer drug for application.

[0291] Finally, it should be noted that the above embodiments are intended only to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Those skilled in the art will readily appreciate that other variations or modifications may be made based on the above descriptions and concepts. It is not necessary and impossible to provide an exhaustive list of all possible implementations. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the claims of the present invention.

Claims

1. A pyrimidinequinoline derivative, characterized in that: The pyrimidine quinoline derivative has the following chemical structure: 、 、 、 、 、 I II III IV V 、 、 、 、 or VI VII VIII IX X 。 XI 2. The method for preparing the pyrimidinequinoline derivative according to claim 1, wherein When the pyrimidinequinoline derivative has the chemical structure described in I, II, III, IV, VI, VII, VIII, IX, X and XI, the preparation process is: ； S1. The compound represented by formula (1) and the acyl chloride compound represented by formula (2) are mixed and dissolved in an organic solvent under an inert gas atmosphere, and pyridine is added to react to obtain the intermediate represented by formula (3); S2. The intermediate of formula (3) is mixed with trifluoromethanesulfonic acid in an organic solvent and reacted at room temperature to obtain the intermediate of formula (4); S3. The intermediate of formula (4) is reacted with R1-Br in an organic solvent containing a basic salt by heating to obtain the intermediate of formula (5); S4. The intermediate of formula (5) and oxalyl chloride are dissolved in an organic solvent, and DMF is added dropwise. The mixture is heated to react to obtain the intermediate of formula (6); S5. Under an inert gas atmosphere, lithium diisopropylamide, tetrahydrofuran, and tri-n-butyltin hydride solution are mixed and reacted; after the reaction is completed, the temperature is lowered to -78 to -20°C; the compound of formula (7) is added, and the temperature is raised to room temperature to react to obtain the intermediate of formula (8); S6. The intermediate of formula (6), the intermediate of formula (8), and Pd(PPh3)2Cl2 are dissolved in an organic solvent in an inert gas atmosphere and heated to react. After the reaction is completed, the target product can be obtained; ； When the pyrimidinequinoline derivative has the chemical structure described in V, the preparation process is: S2-1. The compound of formula (2-1) and the compound of formula (2-2) are mixed and dissolved in an organic solvent containing a basic salt, and heated to react to obtain a compound of formula (2-3); S2-2. The compound of formula (2-3) is dissolved in an anhydrous organic solvent and m-CPBA is added under ice bath conditions to react to obtain the compound of formula (2-4); S2-3. The compound of formula (2-4) is dissolved in an organic solvent with triphenylphosphine under an inert gas atmosphere, trichloroacetonitrile is added, and the mixture is heated to 100-130°C to react to obtain the compound of formula (2-5); S2-4. Under an inert gas atmosphere, lithium diisopropylamide, tetrahydrofuran, and tri-n-butyltin hydride solution are mixed and reacted; after the reaction is completed, the temperature is lowered to -78 to -20°C; the compound of formula (7) is added, and the temperature is raised to room temperature to react to obtain the intermediate of formula (8); S2-5. The intermediate of formula (2-5), the intermediate of formula (8), and Pd(PPh3)2Cl2 are dissolved in an organic solvent in an inert gas atmosphere and heated to react. After the reaction is completed, the target product can be obtained.

3. The method for preparing the pyrimidinequinoline derivative according to claim 2, wherein: The reactions are all carried out under anhydrous and oxygen-free conditions; the inert gas is nitrogen or argon.

4. The method for preparing the pyrimidinequinoline derivative according to claim 2, wherein: In step S1, the reaction temperature is -25 to 22°C; the reaction temperatures of steps S3, S4 and step S2-1 are all 70 to 100°C; and the reaction temperature of step S6 is 100 to 130°C.

5. Use of the pyrimidinequinoline derivative according to claim 1 in the preparation of an anticancer drug; the anticancer drug is a drug for cervical cancer, colon cancer, non-small cell lung cancer, gastrointestinal squamous cell carcinoma or chronic myeloid leukemia.

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