CN110240590A - A kind of pyrimidine quinoline and its preparation method and application - Google Patents

Abstract

It include prodrug and its preparation method and application the invention discloses a kind of pyrimidine quinoline.Shown in the structure such as formula (I) of the pyrimidine quinoline；Wherein, R₁For hydrogen, C_1~4Alkyl, C_1~4Halogenated alkyl, C_4~7Heterocyclic aryl, C_4~7Substituted heterocycle aryl, benzyl or substituted benzyl, glycosyl, amino acid；R₂、R₃、R₄And R₅It is each independently hydrogen, C_1~4Alkyl, C_1~4Alkoxy, hydroxyl, amino or substituted-amino, C_1~4Halogenated alkyl or halogen, glycosyl, amino acid；R₆For substituted or non-substituted five-ring heterocycles, substituted or non-substituted hexa-member heterocycle, substituted or non-substituted C_8~12Thick and heterocycle.Compound of the present invention has good inhibiting effect, the inhibition IC of majority of compounds for 5 kinds of cancer cells₅₀Value is lower than 20 μM；The IC of part of compounds₅₀Even lower than 5 μM of value, inhibiting effect is extremely significant, can be prepared as anticancer drug and is applied.

Description

A kind of pyrimidine quinoline and its preparation method and application

Technical field

The present invention relates to field of pharmaceutical chemistry technology, more particularly, to a kind of pyrimidine quinoline include prodrug and Preparation method and application.

Background technique

Heterocyclic compound is distributed widely in nature, and quantity almost accounts for the one third of known organic compound, many Pesticide of important natural drug, synthetic drug and high-efficiency low-toxicity etc. is all containing the structure of heterocyclic compound；Therefore, heterocyclic compound Object has wide practical use in fields such as new medicine, novel pesticide and new materials, synthesizes the heterocycle with structure diversity always It is the hot fields of Synthetic Organic Chemistry research.Pyrimidine-quinolines are become with its significant and extensive bioactivity works as One of the hot spot of modern Pharmaceutical Chemist research, it has antimicrobial, antimycotic, anticancer, antiviral, analgesia and anti-inflammatory etc. a variety of Pharmacological activity has greatly research and development prospect, it is necessary to further be developed.

Summary of the invention

The purpose of the present invention is to provide a kind of pyrimidine quinolines.Compound of the present invention is for a variety of cancer cells Show significant inhibiting effect, especially people's non-small cell cancer cell, human colon cancer cell strain, human cervical carcinoma cell and people Esophageal squamous cell has good inhibiting effect, inhibition IC of the majority of compounds to this 5 kinds of cancer cells₅₀Value is lower than 20 μM； The IC of part of compounds₅₀Even lower than 5 μM of value, inhibiting effect is extremely significant, can be prepared as anticancer drug and is applied.

Another object of the present invention is to provide the preparation methods of the pyrimidine quinoline.

A further object of the present invention is to provide the applications of the pyrimidine quinoline.

Above-mentioned purpose of the invention is achieved by following scheme:

A kind of pyrimidine quinoline, shown in the structure such as formula (I) of the pyrimidine quinoline:

Wherein, R₁For hydrogen, C_1~4Alkyl, C_1~4Halogenated alkyl, benzyl, substituted benzyl, C_4~7Heterocyclic aryl, C_4~7Replace miscellaneous Cyclophane base, glycosyl or amino acid；

R₂、R₃、R₄And R₅It is each independently hydrogen, halogen, C_1~4Alkyl, C_1~4Alkoxy, hydroxyl, amino, substituted-amino, C_1~4Halogenated alkyl, glycosyl or amino acid；

R₆For substituted or non-substituted five-ring heterocycles, substituted or non-substituted hexa-member heterocycle, substituted or non-substituted C_8~12It is thick and Heterocycle；

The wherein substituted benzyl, C_4~7Substituted heterocycle aryl, substituted-amino, substituted five-membered heterocycle, replace hexa-member heterocycle and Substituted C_8~12Substituent group in thick and heterocycle is respectively hydroxyl, C_1~4Alkyl, C_1~4Alkoxy, C_1~4Halogenated alkyl or halogen；

Heterocycle therein is the ring containing N, O or S.

Preferably, the R₁For hydrogen, C_1~2Alkyl, C_1~2Halogenated alkyl, benzyl, substituted benzyl, glycosyl or amino acid；

R₂、R₃、R₄And R₅It is each independently hydrogen, halogen, C_1~2Alkyl, C_1~2Alkoxy, C_1~2Halogenated alkyl, hydroxyl, ammonia Base, substituted-amino, glycosyl or amino acid；

R₆For pyrrole ring, substituted or non-substituted benzimidazole ring, substituted or non-substituted pyridine ring, substituted or non-substituted pyrimidine Ring, substituted or non-substituted quinazoline；

Wherein substituted benzyl, substituted-amino, substituted pyridines ring, substituted benzimidazole ring, substituted pyrimidines ring and substitution quinoline azoles Substituent group in quinoline is respectively hydroxyl, C_1~2Alkyl, C_1~2Alkoxy, C_1~2Halogenated alkyl or halogen.

Preferably, the R₁For hydrogen, methyl, ethyl, methyl fluoride, trifluoromethyl, trifluoroethyl, benzyl, 2- methylbenzyl, 3- methylbenzyl, 4- methylbenzyl, 2- trifluoromethyl benzyl, 3- trifluoromethyl benzyl, 4- trifluoromethyl benzyl, 2- methoxybenzyl Base, 3- methoxy-benzyl or 4- methoxy-benzyl.

Preferably, work as R₆When for pyrrole ring, shown in the structure such as formula (II) of the pyrimidine quinoline:

Work as R₆When for substituted or non-substituted benzimidazole ring, shown in the structure such as formula (III) of the pyrimidine quinoline:

R₇For hydrogen, C_1~2Alkyl, C_1~2Alkoxy, C_1~2Halogenated alkyl or halogen；

Work as R₆When for substituted or non-substituted pyridine ring, shown in the structure such as formula (IV) of the pyrimidine quinoline:

R₈For hydrogen, C_1~2Alkyl, C_1~2Alkoxy, C_1~2Halogenated alkyl or halogen；

Work as R₆When for substituted or non-substituted pyrimidine ring, structure such as formula (V -1)~(V -3) of the pyrimidine quinoline It is shown:

R₉For hydrogen, C₁~₂Alkyl, C₁~₂Alkoxy, C₁~₂Halogenated alkyl or halogen；

Work as R₆When for substituted or non-substituted quinazoline, shown in the structure such as formula (VI) of the pyrimidine quinoline:

R₁₀For hydrogen, C_1~2Alkyl, C_1~2Alkoxy, C_1~2Halogenated alkyl or halogen.It is preferred that Ground, the following any shown structure of the structure of the pyrimidine quinoline:

It is highly preferred that the following any shown structure of the structure of the pyrimidine quinoline:

The present invention also protects the preparation method of the pyrimidine quinoline simultaneously, works as R₅When for hydrogen, preparation process are as follows:

S1. replace chloride compounds shown in 2- amino-5-methylphenol compound and formula (2) in indifferent gas shown in formula (1) It is miscible in organic solvent under body atmosphere, pyridine is added, reacts at room temperature to obtain formula (3) described intermediate；

S2. formula (3) intermediate and trifluoromethanesulfonic acid it is miscible in organic solvent, room temperature reaction, obtain formula (4) it is described in Mesosome；

S3. formula (4) intermediate and R₁- Br heats reaction in the organic solvent for being dissolved in basic salt, and it is described to obtain formula (5) Intermediate；

S4. formula (5) intermediate and oxalyl chloride are miscible in organic solvent, and DMF is added dropwise, and heating reaction obtains formula (6) The intermediate；

S5. under atmosphere of inert gases, lithium diisopropylamine, tetrahydrofuran and the mixing of three n-butyltin hydride solution are simultaneously Reaction；To be cooled to -78~-20 DEG C after reaction；Addition formula (7) described compound, is warming up to room temperature reaction, obtains formula (8) The intermediate；

S6. formula (6) intermediate, formula (8) intermediate, Pd (PPh₃)₂Cl₂In atmosphere of inert gases, it is miscible in In organic solvent, heating reaction, band can obtain target product after reaction；

Work as R₅For halogen, C_1~4Alkyl, C_1~4Alkoxy, hydroxyl, amino, substituted-amino, C_1~4Halogenated alkyl, glycosyl or ammonia When base acid, preparation process are as follows:

S2-1. formula (2-1) compound and formula (2-2) compound are miscible in the organic solvent dissolved with basic salt, and heating is anti- It answers, formula (2-3) compound can be obtained；

S2-2. it formula (2-3) compound and is dissolved in anhydrous organic solvent, and m-CPBA reaction is added under condition of ice bath and is Formula (2-4) compound can be obtained；

S2-3. formula (2-4) compound is miscible in organic solvent with triphenylphosphine under atmosphere of inert gases, and trichlorine is added Acetonitrile is heated to 100~130 DEG C of reactions, can obtain formula (2-5) compound；

S2-4. under atmosphere of inert gases, lithium diisopropylamine, tetrahydrofuran and the mixing of three n-butyltin hydride solution And it reacts；To be cooled to -78 to -20 DEG C after reaction；Addition formula (7) described compound, is warming up to room temperature reaction, obtains formula (8) intermediate；

S2-5. formula (2-5) intermediate, formula (8) intermediate, Pd (PPh₃)₂Cl₂In atmosphere of inert gases, mix It is dissolved in organic solvent, heating reaction, band can obtain target product after reaction.

Preferably, the reaction carries out under anhydrous and oxygen free condition；The inert gas is nitrogen or argon gas.

Preferably, the reaction dissolvent of all reactions is tetrahydrofuran, methylene chloride, dimethyl methyl nitrosourea, dimethyl Asia One of sulfone or acetonitrile are a variety of.

Preferably, in step S1, reaction temperature is -25~22 DEG C；In step S3 and S2-1, the basic salt is K₂CO₃Or Na₂CO₃；Step S3, the reaction temperature of S4 and step S2-1 are 70~100 DEG C；The reaction temperature of step S5 is 22~25 DEG C； The reaction temperature of step S6 is 100~130 DEG C.

It is highly preferred that the reaction temperature of step S2-1 is 85 DEG C, 6~20h is reacted；To after reaction, stand reaction solution To room temperature；Filtration over celite, EA are rinsed, evaporated under reduced pressure solvent；Column chromatography isolates and purifies, and yellow solid formula (2- can be obtained 3) compound.

It is highly preferred that 6~12h of reaction of step S2-2；To which DCM dilution after reaction, is added, it is separately added into sulfurous acid Hydrogen sodium and sodium bicarbonate, after stirring a period of time, filtration over celite, DCM is rinsed, evaporated under reduced pressure solvent；Column chromatography separation is pure Change, yellow oil formula (2-4) compound can be obtained.

It is highly preferred that 1~5h of reaction of step S2-3；To after reaction, stand reaction solution to room temperature.Filter diatom Soil, EA are rinsed, evaporated under reduced pressure solvent；Column chromatography isolates and purifies, and yellow oil formula (2-5) compound can be obtained.

The pyrimidine quinoline is preparing the application in anticancer drug also within protection scope of the present invention.

Preferably, the anticancer drug is anti-cervical cancer, colon cancer, non-small cell lung cancer, food intestines squamous carcinoma, sdenocarcinoma of stomach, cream The drug of gland cancer, liver cancer or chronic myelogenous leukemia.

Compared with prior art, the invention has the following advantages:

Compound structure of the present invention is novel, shows significant inhibiting effect for a variety of cancer cells, especially People's non-small cell cancer cell, human colon cancer cell strain, human cervical carcinoma cell, Human esophageal squamous cell cancer cell and human promyelocytic leukemia are thin Born of the same parents have good inhibiting effect, inhibition IC of the majority of compounds to this 5 kinds of cancer cells₅₀Value is lower than 20 μM；Especially chemical combination Object 1,2,5~9,13~17,23,24,26~28,30~35,38,39,42~44,51 and 55, to above-mentioned 5 kinds of cancer cells IC₅₀Value is lower than 10 μM；Especially compound 1,2,13,14,23,27,30~33,35,42,51 and 55, to above-mentioned cancer cell IC₅₀Value is lower than 5 μM, and inhibiting effect is extremely significant, can be prepared as anticancer drug and is applied.

In addition, the preparation method of compound of the present invention is simple, can industrially large-scale production and preparation, be convenient for It promotes and applies.

Specific embodiment

The present invention is made combined with specific embodiments below and further being elaborated, the embodiment is served only for explaining this Invention, is not intended to limit the scope of the present invention.Test method as used in the following examples is normal unless otherwise specified Rule method；Used material, reagent etc., unless otherwise specified, for the reagent and material commercially obtained.

The structure of the compound of following embodiment preparation is as shown in table 1.

1 compound structure of table

Embodiment 1 prepares pyrimidine quinoline

The preparation process of compound 1:

QM15 0.3g is weighed in bis- mouthfuls of flasks of 25mL, Pd (PPh is added₃)₂Cl₂35mg, confined reaction device, displacement Argon gas protection；Anhydrous DMF 3mL is added, stirs 10min at room temperature, tri- normal-butyl stannylpyridine 0.55mL of 2- is added (0.627g), 110 DEG C of oil bath heatings, reaction is overnight.It is cooled to room temperature, ethyl acetate 50mL and water 100mL is added, shaking is equal It is even, organic phase is separated, water phase is extracted (20mL × 2) with ethyl acetate, is merged organic phase, is washed with the saturation NaCl solution of saturation Wash (150mL × 2)；Anhydrous MgSO₄It dries, filters, decompression boils off solvent.Rapid column chromatography isolates and purifies (20%EA/PE), subtracts Pressure boils off solvent, obtains yellow oil 240mg.(XM013-LG02, P101) Yield:65.6%, yellow olid.

Compound 1:¹H NMR (400MHz, CDCl3) δ 8.72-8.70 (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)

¹³C 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.

The preparation process of compound 2-6 is with compound 1, the difference is that the compound Q M15 used is different.

Compound 2:¹H NMR (500MHz, CDCl3) δ 8.76 (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).

¹³C 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.

Compound 4:¹H NMR (400MHz, DMSO) δ 8.60 (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).

¹³C 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.

Compound 5:¹H NMR (500MHz, CDCl3) δ 8.71 (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=2.5,8.5Hz, 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).

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.

Compound 6:¹H NMR (400MHz, CDCl3) δ 8.70 (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).

¹³C 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.

Embodiment 2

The preparation process of compound 7:

1, the preparation of QM08

2,8- quinoline diol 5.0g is weighed in bis- mouthfuls of flasks of 500mL, 7.72g K is added₂CO₃With 300mL acetonitrile, room temperature Lower stirring；It is added 3- methoxybenzyl bromine 4.8mL (6.86g), is heated to flowing back, reaction is overnight.300mL acetic acid second is added in reaction solution Ester and 300mL water are uniformly mixed, and separate organic phase, and water phase extracts 2 times (100mL × 2) with ethyl acetate, merges organic phase, are used It is saturated NaCl solution washing (400mL × 2)；Anhydrous MgSO₄It dries, filters, decompression boils off solvent.Column chromatographic isolation and purification (75%EA/PE) obtains white solid 6.36g.

2, the preparation of QM21

QM08 3.3g and tribromo oxygen phosphorus 10.09g are weighed in dry bis- mouthfuls of flasks of 250mL, under argon atmosphere protection, Anhydrous 1,2- dichloroethanes 30mL is added, is heated to flowing back, reaction is overnight.TLC tracks end of reaction, and standing is cooled to room temperature； It is poured into 50mL ice water, extracts 3 times (150mL × 3) with ethyl acetate, merge organic phase, successively with the NaHCO of saturation₃Solution It washs (200mL × 2), saturation NaCl solution washing (200mL × 2)；Anhydrous MgSO₄It dries, filters, decompression boils off solvent.Column Chromatography purifies (10%EA/PE), obtains white solid 2.0g.

3, the preparation of compound 7

QM21 0.35g is weighed in bis- mouthfuls of flasks of 25mL, is separately added into lithium chloride 86mg, N-Boc- pyrroles -2- boric acid frequency Any alcohol ester 358mg, Pd (PPh₃)₄59mg, confined reaction device, displacement argon gas protection；Sequentially add dry toluene 5mL and anhydrous Ethyl alcohol 5mL, stirs 10min at room temperature, weighs sodium carbonate 270mg in 5mLEp pipe, and 1.27mL water is added and sufficiently dissolves, makes into 2M solution is then injected into two mouthfuls of flasks, 80 DEG C of oil bath heatings, and reaction is overnight.It is cooled to room temperature, ethyl acetate 80mL is added With water 150mL, shaking uniformly, separates organic phase, and water phase is extracted (50mL × 2) with ethyl acetate, merges organic phase, with saturation Saturation NaCl solution wash (150mL × 2)；Anhydrous MgSO₄It dries, filters, decompression boils off solvent.Rapid column chromatography separation is pure Change (10%EA/PE), obtains yellow solid 200mg.

Compound 7:¹H NMR (500MHz, CDCl3) δ 10.18 (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)

¹³C 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.

The preparation of compound 8:

QM15 0.25g is weighed in bis- mouthfuls of flasks of 25mL, is separately added into lithium chloride 89mg, N-Boc- pyrroles -2- boric acid frequency Any alcohol ester 370mg, Pd (PPh₃)₄61mg, confined reaction device, displacement argon gas protection；Sequentially add dry toluene 5mL and anhydrous Ethyl alcohol 5mL, stirs 10min at room temperature, weighs sodium carbonate 278mg in 5mLEp pipe, and 1.3mL water is added and sufficiently dissolves, makes into 2M Solution is then injected into two mouthfuls of flasks, 80 DEG C of oil bath heatings, and reaction is overnight.Be cooled to room temperature, be added ethyl acetate 80mL and Water 150mL, shaking uniformly, separate organic phase, and water phase is extracted (50mL × 2) with ethyl acetate, merge organic phase, with saturation It is saturated NaCl solution washing (150mL × 2)；Anhydrous MgSO₄It dries, filters, decompression boils off solvent.Rapid column chromatography isolates and purifies (15%EA/PE) obtains yellow solid 75mg.

Compound 8:¹H NMR (400MHz, CDCl3) δ 10.39 (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).

¹³C 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.

Embodiment 3

The preparation process of compound 9:

8- methoxy quinoline -2- aldehyde 187mg is weighed in 50 2 mouthfuls of flasks, ethyl alcohol 5mL and sodium hydrogensulfite 125mg is added, 4h is stirred at room temperature；O-phenylenediamine 108mg is dissolved in 3mL DMF, is added in reaction, and 85 DEG C of oil bath heatings are reacted to flowing back 3h；It is cooled to room temperature.Ethyl acetate 40mL and water 20mL is added, shaking uniformly, separates organic phase, water phase is taken out with ethyl acetate It mentions (20mL × 2), merges organic phase, wash (40mL × 2) with the saturation NaCl solution of saturation；Anhydrous MgSO₄It dries, filters, Decompression boils off solvent.Column chromatographic isolation and purification (50%EA/PE), obtains yellow solid 30mg.

Compound 9:¹H NMR (400MHz, CDCl3) δ 11.57 (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)

The preparation process of compound 10:

1, the preparation of XM-A0001

2- methyl -8-hydroxyquinoline 3.00g is weighed in bis- mouthfuls of flasks of 100mL, sequentially adds K₂CO₃5.21g KI 0.31g, acetone 19mL, 3- methoxybenzyl bromine 3.2mL (4.55g)；It is stirred and heated to reflux, reaction is overnight.Decompression boils off third 60mL ethyl acetate, 40mL H is added in ketone₂O, extraction, separates organic layer；Aqueous layer with ethyl acetate extracts (20mL × 2), merges Organic layer washs (50mL × 2) with saturation NaCl；Anhydrous MgSO4 is dried, filtered, and decompression boils off solvent.With 10% acetic acid second Ester/hexamethylene recrystallization, obtains white crystal 4.08g.

2, the preparation of XM-A0002

XM_A0001 4.19g is weighed in bis- mouthfuls of flasks of 100mL, 2.09g SeO is added₂, confined reaction device, displacement N₂ Protection；Isosorbide-5-Nitrae-dioxane 30mL, 80 DEG C of stirring 2h is added；It stands to room temperature, filtering, filtrate decompression is evaporated, and is dried in vacuo Solid；30mL methylene chloride is added, shaking is dissolved most of solid, stood overnight.Filtering removal insoluble matter, filtrate decompression are steamed Dry, column chromatographic isolation and purification (10%EA/PE) is final to obtain product 3.38g.

3, the preparation of compound 10

XM_A0002 880mg is weighed in 100 2 mouthfuls of flasks, ethyl alcohol 15mL and sodium hydrogensulfite 375mg, room temperature is added Lower stirring 4h；O-phenylenediamine 325mg is dissolved in 9mL DMF, is added in reaction, and 85 DEG C of oil bath heatings react 3h to flowing back；It is cold But to room temperature.Ethyl acetate 120mL and water 60mL is added, shaking uniformly, separates organic phase, water phase is extracted with ethyl acetate (60mL × 2) merge organic phase, wash (120mL × 2) with the saturation NaCl solution of saturation；Anhydrous MgSO4 is dried, filtered, and is subtracted Pressure boils off solvent.Column chromatographic isolation and purification (40%EA/PE), obtains yellow solid 100mg.

(NB-4, P75)

Compound 10:¹H NMR (400MHz, CDCl3) δ 11.96 (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).

¹³C 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.

Embodiment 4

The preparation process of compound 11:

XM_A0002 293mg is weighed in 50mL round-bottomed flask, acetonitrile 12.5mL is added, stirs at room temperature；Adjacent ammonia is added 2- iodoxybenzoic acid 280mg is added after mixing evenly in base benzylamine 126mg, maintains 25 DEG C of reaction system, reacts 7h；Acetic acid is added Ethyl ester 60mL and water 60mL, shaking uniformly, separate organic phase, and water phase is extracted (30mL × 2) with ethyl acetate, merge organic Phase washs (60mL × 2) with the saturation NaCl solution of saturation；Anhydrous MgSO4 is dried, filtered, and decompression boils off solvent.Column chromatography point From purifying (30~80%EA/PE), yellow solid 62mg is obtained.

Compound 11:¹H NMR (400MHz, CDCl3) δ 9.65 (s, 1H), 8.81 (d, J=8.4Hz, 1H), 8.34 (d, J =8.4Hz, 1H), 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)

¹³C 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.

Embodiment 5

The preparation process of compound 14:

The preparation of S1.8- ((3-methoxybenzyl) oxy) quinolin-2 (1H)-one (QM08)

2,8- quinoline diol 5.0g is weighed in bis- mouthfuls of flasks of 500mL, 7.72g K is added₂CO₃With 300mL acetonitrile, room temperature Lower stirring；It is added 3- methoxybenzyl bromine 4.8mL (6.86g), is heated to flowing back, reaction is overnight.300mL acetic acid second is added in reaction solution Ester and 300mL water are uniformly mixed, and separate organic phase, and water phase extracts 2 times (100mL × 2) with ethyl acetate, merges organic phase, are used It is saturated NaCl solution washing (400mL × 2)；Anhydrous MgSO₄It dries, filters, decompression boils off solvent.Column chromatographic isolation and purification (75%EA/PE) obtains white solid 6.36g.

The preparation of S2.2-chloro-8- ((3-methoxybenzyl) oxy) quinoline (QM13)

QM08 2.53g is weighed in dry bis- mouthfuls of flasks of 250mL, under argon atmosphere protection, sequentially adds chlorobenzene 75mL, P DEG C of l₃4.8mL, anhydrous pyridine 0.25mL, anhydrous DMF 0.06mL are heated to flowing back, and reaction is overnight.TLC tracking is anti- It should finish, standing is cooled to room temperature；With oversaturated NaHCO₃PH to 8 is adjusted, 3 times (75mL × 3) is extracted with ethyl acetate, closes And organic phase, successively with the NaHCO of saturation₃Solution washs (150mL × 2), saturation NaCl solution washing (150mL × 2)；It is anhydrous MgSO₄It dries, filters, decompression boils off solvent.Column chromatographic isolation and purification (10%EA/PE), obtains white solid 1.38g.

The preparation of S3.2- (tributylstannyl) pyrimidine (QM17)

Under nitrogen atmosphere protection, 5mL lithium diisopropylamine (LDA, 2.0M inTHF/Hexane) and the anhydrous THF of 10mL - 2 DEG C are cooled under stirring, three n-butyltin hydride solution (2.91g in dry is slowly added dropwise by dropping funel THF10mL)；Drop finishes, and keeps thermotonus 1h；- 78 DEG C are cooled to, 2- chlorine pyrimidine solution is slowly added dropwise by dropping funel (1.15g in dry THF 10mL), drop finish, and keep thermotonus 2h；It is warming up to 0 DEG C, saturation NH is slowly added dropwise₄Cl solution 20mL is finished, and is moved to and is stirred 30min at room temperature；3 times (30mL × 3) are extracted with ethyl acetate, merge organic phase, with saturation It is saturated NaCl solution washing (50mL × 2)；Anhydrous MgSO₄It dries, filters, decompression boils off solvent.Rapid column chromatography isolates and purifies (5%EA/PE) obtains yellow solid 1.19g.

The preparation of S4 compound 14

QM13 0.967g is weighed in bis- mouthfuls of flasks of 100mL, Pd (PPh is added₃)₂Cl₂0.226g, confined reaction device, Replace argon gas protection；Anhydrous DMF 32mL is added, stirs 10min at room temperature, is added QM171.19g, 115 DEG C of oil bath heatings, instead It should stay overnight；It is cooled to room temperature, ethyl acetate 160mL and water 100mL is added, shaking uniformly, separates organic phase, and water phase is with using acetic acid Ethyl ester extracts (50mL × 2), merges organic phase, washs (150mL × 2) with the saturation NaCl solution of saturation；Anhydrous MgSO₄It is dry Dry, filtering, decompression boils off solvent.Rapid column chromatography isolates and purifies (80%EA/PE), obtains yellow oil；Grease is dissolved in 2M HCl/AcOEt solution is added in 20mL ethyl acetate, until yellow mercury oxide no longer generates；Filtering, is washed with appropriate ethyl acetate Precipitating is washed, is dried in vacuo, obtains yellow solid 448mg, as target compound 14.

Compound 14:Yield 448mg (33.4%), yellow solid.¹H 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)

¹³C NMR(125MHz,DMSO)δ161.8,159.3,158.0,154.6,152.2,138.6,138.4,138.1, 129.6,129.4,128.5,121.6,121.0,119.9,119.7,113.4,113.0,111.7,70.0,55.0.

The preparation process of compound 15~23 with compound 14 preparation process, the difference is that compound Q M08 is making During standby, replace 3- methoxybenzyl bromine that target product can be prepared using different raw materials.

Compound 12:¹H NMR (400MHz, Chloroform-d) δ 9.54 (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)

¹³C 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.

Compound 13:¹H NMR (400MHz, Chloroform-d) δ 9.34 (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)

¹³C NMR(100MHz,CDCl3)δ162.98,159.91,158.70,157.84,154.93,152.52, 140.35,138.69,137.18,130.32,129.66,128.05,120.12,119.27,119.12,118.26,113.41, 112.58,111.08,77.36,77.04,76.72,71.01,55.27.

Compound 15:¹H NMR (500MHz, CDCl3) δ 8.97 (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)

¹³C 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.

Compound 16:¹H NMR (500MHz, DMSO) δ 9.09 (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)

¹³C 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.

Compound 17:¹H NMR (400MHz, DMSO) δ 9.06 (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).

¹³C 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.

Compound 18:¹H NMR (400MHz, DMSO) δ 9.06 (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=2.2Hz, 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)

¹³C NMR(100MHz,DMSO)δ159.85,158.46,155.97,138.79,138.53,137.01,132.79, 130.10,122.66,121.78,120.36,118.87,114.08,113.68,112.21,70.79,55.50.

The preparation route of compound 19 are as follows:

It weighs respectively 5QL-04200mg (0.606mmol, 1.0eq), 2- (tri-n-butyl tin) pyrimidine 246.3mg (0.667mmol, 1.1eq) and Pd (PPh₃)₂Cl₂45mg (0.061mmol, 0.1eq) is in bis- mouthfuls of flasks of 25mL, confined reaction Device, displacement argon gas protection；Anhydrous DMF 3mL is added, 110 DEG C of oil bath heatings, reaction is overnight.It is cooled to room temperature, acetic acid is added Ethyl ester 30mL and water 100mL, shaking uniformly, separate organic phase, and water phase is extracted (30mL × 2) with ethyl acetate, merge organic Phase washs (150mL × 2) with the saturation NaCl solution of saturation；Anhydrous MgSO₄It dries, filters, decompression boils off solvent.Quick column Chromatography purifies (80%EA/PE+0.5%TEA), obtains yellow oil；Grease is dissolved in the anhydrous THF of 5mL, and 2M is added HCl/AcOEt solution, until yellow mercury oxide no longer generates；Filtration, washs precipitating with appropriate THF, is dried in vacuo, obtains red solid 55mg；Yield: 24.3%.

Compound 19:¹H NMR (400MHz, DMSO) δ 9.09 (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).

¹³C 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.

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

¹³C NMR(100MHz,DMSO)δ162.08,159.90,159.61,158.49,154.90,149.85,138.73, 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.

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

¹³C NMR(125MHz,DMSO)δ159.69,158.72,154.75,152.30,141.65,139.52,136.29, 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.

Compound 22:¹H NMR (500MHz, DMSO-d6) δ 9.14 (d, J=4.3Hz, 2H), 8.80 (d, J=8.2Hz, 1H), 8.49 (d, J=8.0Hz, 1H), 7.99 (d, J=8.7Hz, 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)

¹³C 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.

Compound 23:¹H NMR (400MHz, DMSO-d6) δ 9.21 (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), 7.36 (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).

¹³C 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.

Embodiment 6

The preparation process of compound 25:

S1. the preparation of (E) -3-ethoxy-N- (2-hydroxy-4-methylphenyl) acrylamide (LQM-01)

The 3- ethoxy-c olefin(e) acid (81.20mmol, 1.0eq) of 9.43g is weighed in dry 250mL round-bottomed flask, nitrogen Under atmosphere protection, the anhydrous DCM of 100mL is added；Then, be slowly dropped into 0 DEG C 60.90mL oxalyl chloride (121.80mmol, 1.5eq, 2.0M in DCM), reaction is stirred at room temperature overnight；Evaporated under reduced pressure solvent, obtains chloride compounds；Separately weigh 10g 2- amino-5-methylphenol (81.20mmol, 1.0eq) in dry bis- mouthfuls of bottles of 500mL, under nitrogen atmosphere protection, be added The anhydrous DCM of 150mL.The anhydrous DCM of 100mL is added in chloride compounds, chloride compounds are transferred to reaction in 0 DEG C In, it is eventually adding the anhydrous pyridine (162.40mmol, 2.0eq) of 13.07mL, reaction is stirred at room temperature overnight.TLC tracking is anti- Ying Hou pours into reaction solution in 250mL ice water, extracts (250mL × 2) with DCM, merges gained organic phase twice.Successively with 5% HCl solution (250mL × 2), saturation NaHCO₃(250mL × 2), saturation NaCl (250mL × 2) wash organic phase, anhydrous MgSO₄ Dry, filtration, evaporated under reduced pressure solvent obtains Tan solid.After a small amount of DCM dissolution, petroleum ether recrystallization is stood overnight. It filters, filter cake is sufficiently washed with petroleum ether, obtains yellow solid 10.97g；Yield: 61.0%, yellow solid.

The preparation of S2.8-hydroxy-6-methylquinolin-2 (1H)-one (LQM-02)

The LQM-01 (49.58mmol, 1.0eq) of 10.97g is weighed in dry 500mL round-bottomed flask, 150mL is added Anhydrous DCM, the trifluoromethanesulfonic acid of 24.79mL (49.58mmol, 1.0eq) is slowly dropped into reaction solution, is stirred at room temperature Reaction is overnight.After TLC tracking reaction, evaporated under reduced pressure solvent pours into reaction solution in 150mL ice water, DCM extraction (150mL × 3), merge gained organic phase.Successively with saturation NaHCO₃(150mL × 3), saturation NaCl (150mL × 3) washing, anhydrous MgSO₄ It is dry, filtration, evaporated under reduced pressure solvent.Obtain brown solid (mixture) 6.70g.

The preparation of S3.8- ((3-methoxybenzyl) oxy) -6-methylquinolin-2 (1H)-one (LQM-03)

LQM-02 (45.67mmol, the 1.0eq) mixture of 8.0g is weighed in dry bis- mouthfuls of bottles of 250mL, is added 12.62g K₂CO₃After (91.33mmol, 2.0eq) and the acetonitrile of 100mL, the 3- methoxybenzyl bromine of 7.03mL is injected After (50.23mmol, 1.1eq), 85 DEG C are heated to, reaction is overnight.After TLC tracking reaction, reaction solution is stood to room temperature.Filter silicon Diatomaceous earth, EA are rinsed, evaporated under reduced pressure solvent.Column chromatography isolates and purifies (80%EA/PE), obtains white solid 9.0g；Yield: 66.7%.

The preparation of S4.2-chloro-8- ((3-methoxybenzyl) oxy) -6-methylquinoline (LQM-04)

The LQM-03 (30.47mmol, 1.0eq) of 9.0g is weighed in dry bis- mouthfuls of bottles of 250mL, is added 100mL's The oxalyl chloride (60.95mmol, 2.0eq, 2.0M in DCM) of 30.47mL is slowly added to by DCE, then 2 drop anhydrous DMFs is taken to be added Wherein, 85 are heated to^℃, reaction is overnight.After TLC tracking reaction, reaction solution is stood to room temperature, the saturation NaHCO of 50mL is added₃It is molten Liquid stirring extracts (150mL × 2) with DCM, merges organic phase, washed with saturation NaCl solution (150mL × 2), anhydrous MgSO₄ It is dry, filtration, evaporated under reduced pressure solvent.Column chromatography isolates and purifies (10%EA/PE), obtains white solid 4.50g.Yield: 47.0%, white solid.

The preparation of S5.5-methoxy-2- (tributylstannyl) pyrimidine (LMD-01)

Weigh 2- chloro-5-methoxyl pyrimidine 3g (20.8mmol, 1.0eq) and Pd (PPh₃)₄1.2mg (1.08mmol, 0.05eq) in bis- mouthfuls of flasks of 100mL, under argon atmosphere protection, dry toluene 20mL is added, then six positive fourths are added in stirring Two tin 15mL (31.1mmol, 1.5eq) of base, is heated to flowing back, and reaction is overnight.Standing is cooled to room temperature, and 150mL is added in reaction solution Ethyl acetate and 250mL water are uniformly mixed, and separate organic phase, and water phase extracts (100mL × 2) with ethyl acetate, with saturation NaCl Solution washs (200mL × 2)；Anhydrous MgSO₄It dries, filters, decompression boils off solvent.Rapid column chromatography isolates and purifies (10%EA/ PE), colourless transparent liquid 2.9g is obtained；Yield 35.8%.

S6. the preparation of compound 25

It weighs respectively LQM-04 0.4g (1.0eq), LMD-01 0.56g (1.1eq) and Pd (PPh₃)₂Cl₂ 90mg (0.1eq) in bis- mouthfuls of flasks of 25mL, confined reaction device, displacement argon gas is protected；Anhydrous DMF 3mL is added, 110 DEG C of oil baths add Heat, reaction is overnight.It is cooled to room temperature, ethyl acetate 40mL and water 100mL is added, shaking uniformly, separates organic phase, and water phase is used Ethyl acetate extracts (30mL × 2), merges organic phase, washs (150mL × 2) with the saturation NaCl solution of saturation；Anhydrous MgSO₄ It dries, filters, decompression boils off solvent.Rapid column chromatography isolates and purifies (80%EA/PE+0.5%TEA), obtains yellow oil；Oil Shape object is dissolved in 5mL THF, and 2M HCl/AcOEt solution is added, until yellow mercury oxide no longer generates；Filtration, is washed with appropriate THF Precipitating, vacuum drying, obtains yellow solid 75mg；Yield 30.2%.

Compound 25:¹H NMR (500MHz, DMSO) δ 8.81 (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)

¹³C 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.

Compound 24,26-32 preparation process with compound 25 preparation process, the difference is that compound L QM-01 During the preparation process, replace 2- amino-5-methylphenol that target product can be prepared using different raw materials.

Compound 24:¹H NMR (500MHz, CDCl3) δ 8.62 (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)

¹³C 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.

Compound 26:¹H NMR (500MHz, DMSO) δ 8.76 (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)

¹³C NMR(125MHz,DMSO)δ161.90,159.85,156.65,156.07,153.37,152.86,144.36, 138.44,137.21,130.10,124.13,122.21,120.83,120.48,114.29,114.08,113.85,103.07, 102.43,70.89,55.52.

Compound 27:¹H NMR (400MHz, DMSO) δ 8.77 (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).

¹³C 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.

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

¹³C NMR(125MHz,DMSO)δ159.90,159.45,154.35,154.02,153.66,149.33,144.55, 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.

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

¹³C NMR(101MHz,MeOD)δ170.96,160.22,155.68,148.98,148.13,147.42,144.35, 136.87,129.74,129.67,129.55,121.66,119.67,115.27,114.49,113.79,113.15,99.31, 71.73,58.26,56.25,54.43,48.24,48.03,47.82,47.60,47.39,47.18,46.97.

Compound 30:1H NMR (400MHz, CDCl3) δ 8.65 (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).

HRMS (IT-TOF): C₂₂H₁₉N₃O₃For [M+H]+, calculated 374.1499, found 374.1493.

Compound 31:¹H NMR (500MHz, DMSO-d6) δ 8.82 (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).

¹³C 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.

Compound 32:¹H NMR (500MHz, Methanol-d4) δ 8.79 (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).

¹³C 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.

Embodiment 7

The preparation process of compound 66: step S1~S4 is the same as embodiment 6；

The preparation of S5.4-methyl-2- (tributylstannyl) pyrimidine (LMD-05)

Under argon atmosphere protection, 26mL lithium diisopropylamine (LDA, 52.5mmol, 1.5eq, 2.0M in THF/ Hexane it) and under the anhydrous THF stirring of 20mL is cooled to 0 DEG C, three n-butyltin hydride solution 14mL are then slowly added dropwise (52.5mmol, 1.5eq)；Drop finishes, and keeps thermotonus 1h；- 78 DEG C are cooled to, the chloro- 4- methylpyrimidine solution of 2- is slowly added dropwise (4.5g in dry THF10mL), drop finish, and keep thermotonus 2h；It is warming up to 0 DEG C the reaction was continued 1h.Saturation NH is added₄Cl is molten Liquid 50mL, finishes, and moves to and stirs 30min at room temperature；3 times (100mL × 3) are extracted with ethyl acetate, merge organic phase, with saturation Saturation NaCl solution wash (200mL × 2)；Anhydrous MgSO₄It dries, filters, decompression boils off solvent.Rapid column chromatography separation is pure Change (5%EA/PE), obtains colourless transparent liquid 4.05g；Yield 30.2%.

S6. the preparation of compound 34

It weighs respectively LQM-04 400mg (1.0eq), LMD-05 0.54g (1.1eq) and Pd (PPh₃)₂Cl₂ 90mg (0.1eq) in bis- mouthfuls of flasks of 25mL, confined reaction device, displacement argon gas is protected；Anhydrous DMF 3mL is added, 110 DEG C of oil baths add Heat, reaction is overnight.It is cooled to room temperature, ethyl acetate 30mL and water 100mL is added, shaking uniformly, separates organic phase, and water phase is used Ethyl acetate extracts (30mL × 2), merges organic phase, washs (150mL × 2) with the saturation NaCl solution of saturation；Anhydrous MgSO₄ It dries, filters, decompression boils off solvent.Rapid column chromatography isolates and purifies (80%EA/PE+0.5%TEA), obtains yellow oil；Oil Shape object is dissolved in 5mL THF, and 2M HCl/AcOEt solution is added, until yellow mercury oxide no longer generates；Filtration, is washed with appropriate THF Precipitating, vacuum drying, obtains yellow solid 95mg；Yield: 34.3%.

Compound 34:¹H NMR (500MHz, DMSO) δ 8.94 (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), 7.38-7.31 (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).

¹³C 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.

The preparation process of compound 33,35~40 with compound 34 preparation process, the difference is that compound L QM- 01 during the preparation process, replaces 2- amino-5-methylphenol that target product can be prepared using different raw materials.

Compound 33:¹H NMR (500MHz, CDCl3) δ 8.8 (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), 7.21 (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).

¹³C 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.

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

¹³C NMR(100MHz,DMSO)δ168.63,162.49,159.85,157.49,156.95,156.83,152.86, 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.

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

¹³C NMR(125MHz,DMSO)δ168.54,162.54,159.85,157.58,155.92,138.73,138.57, 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.

Compound 37:¹H NMR (500MHz, CDCl3) δ 8.72 (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)

Compound 38:¹H NMR (400MHz, DMSO) δ 8.95 (s, 2H), 8.63 (dd, J=8.7,1.7Hz, 1H), 8.55 (dd, J=8.6,1.7Hz, 1H), 7.47 (s, 1H), 7.39-7.29 (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)

¹³C 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.

Compound 39:¹H NMR (500MHz, DMSO) δ 8.90 (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).

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.

Compound 40:¹H NMR (500MHz, DMSO) δ 8.91 (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)

¹³C 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.

Embodiment 8

The preparation process of compound 42: step S1~S4 process is the same as embodiment 6；

The preparation of S5.4,6-dimethyl-2- (tributylstannyl) pyrimidine (LMD-02)

Under argon atmosphere protection, 15.24mL lithium diisopropylamine (LDA, 30.47mmol, 1.1eq, 2.0M in THF/ Hexane it) and under the anhydrous THF stirring of 20mL is cooled to 0 DEG C, three n-butyltin hydride solution 8.2mL are then slowly added dropwise (30.47mmol, 1.1eq)；Drop finishes, and keeps thermotonus 1h；- 78 DEG C are cooled to, chloro- 4, the 6- dimethyl pyrimidine of 2- is slowly added dropwise Solution (3.95g in dry THF10mL), drop finish, and keep thermotonus 2h；It is warming up to 0 DEG C the reaction was continued 1h.Saturation is added NH₄Cl solution 50mL, finishes, moves to and stir 30min at room temperature；3 times (100mL × 3) are extracted with ethyl acetate, are merged organic Phase washs (250mL × 2) with the saturation NaCl solution of saturation；Anhydrous MgSO₄It dries, filters, decompression boils off solvent.Quick column Chromatography purifies (5%EA/PE), obtains colourless transparent liquid 2.69g；Yield: 30.9%.

S6. the preparation of compound 42

It weighs respectively LQM-04 0.2g (1.0eq), LMD-02 0.28g (1.1eq) and Pd (PPh₃)₂Cl₂ 45mg (0.1eq) in bis- mouthfuls of flasks of 25mL, confined reaction device, displacement argon gas is protected；Anhydrous DMF 3mL is added, 110 DEG C of oil baths add Heat, reaction is overnight.It is cooled to room temperature, ethyl acetate 40mL and water 100mL is added, shaking uniformly, separates organic phase, and water phase is used Ethyl acetate extracts (30mL × 2), merges organic phase, washs (150mL × 2) with the saturation NaCl solution of saturation；Anhydrous MgSO₄ It dries, filters, decompression boils off solvent.Rapid column chromatography isolates and purifies (80%EA/PE+0.5%TEA), obtains yellow oil；Oil Shape object is dissolved in 5mL THF, and 2M HCl/AcOEt solution is added, until yellow mercury oxide no longer generates；Filtration, is washed with appropriate THF Precipitating, vacuum drying, obtains yellow solid 65mg；Yield 38.5%.

The preparation process of compound 41,43,44 with compound 42 preparation process, the difference is that compound L QM-01 During the preparation process, replace 2- amino-5-methylphenol that target product can be prepared using different raw materials.

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

¹³C NMR(125MHz,DMSO)δ168.19,159.88,158.98,149.36,140.84,140.30,138.60, 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.

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

¹³C NMR(100MHz,CDCl3)δ167.5,163.1,159.9,155.0,153.9,140.2,138.5,136.9, 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.

Compound 43:¹H NMR (500MHz, DMSO) δ 8.58-8.48 (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)

¹³C 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.

Compound 44:¹H NMR (400MHz, DMSO) δ 8.50 (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)

¹³C 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.

Embodiment 9

The preparation process of compound 63: step S1~S4 is the same as embodiment 6；

The preparation of S5.2-chloro-5- (ethoxymethoxy) pyrimidine (LMD-13-1)

Weigh the chloro- 5- hydroxy pyrimidine 5.0g (38.31mmol, 1.0eq) of 2- and K₂CO₃10.6g (76.61mmol, 2.0eq) In 100mL eggplant type bottle, under nitrogen atmosphere protection, anhydrous DMF 20mL is added, then chloromethyl ether 9mL is added in stirring (95.76mmol, 2.5eq), is stirred at room temperature, reacts 1h.About 60mL saturation NaHCO is injected into reaction₃Solution, stirring, instead Answer liquid that 150mL ethyl acetate and 150mL saturation NaHCO is added₃Solution is uniformly mixed, separates organic phase, water phase ethyl acetate 2 times (50mL × 2) are extracted, wash (200mL × 2) with the saturation NaCl solution of saturation；Anhydrous MgSO₄It dries, filters, decompression is steamed Remove solvent.Rapid column chromatography isolates and purifies (10%EA/PE), obtains colourless transparent liquid 2.23g；Yield 31.2%.

The preparation of S6.5- (ethoxymethoxy) -2- (tributylstannyl) pyrimidine (LMD-13-2)

Weigh LMD-13-1 2.23g (11.82mmol, 1.0eq) and Pd (PPh₃)₂Cl₂415mg (0.59mmol, 0.05eq) in bis- mouthfuls of flasks of 100mL, argon atmosphere protection under, anhydrous Isosorbide-5-Nitrae-dioxane 20mL is added, stir, then plus Enter six normal-butyls, two tin 6.57mL (13.01mmol, 1.1eq), be heated to flowing back, reaction is overnight.Standing is cooled to room temperature, reaction Liquid filtration over celite, decompression boil off solvent.Rapid column chromatography isolates and purifies (5%EA/PE), obtains colourless transparent liquid 1.1g；It produces Rate 30.1%.

S7. the preparation of compound 46

It weighs respectively LQM-04 0.2g (1.0eq), LMD-13-2 0.31g (1.1eq) and Pd (PPh₃)₂Cl₂ 45mg (0.1eq) in bis- mouthfuls of flasks of 25mL, confined reaction device, displacement argon gas is protected；Anhydrous DMF 3mL is added, 110 DEG C of oil baths add Heat, reaction is overnight.It is cooled to room temperature, ethyl acetate 40mL and water 100mL is added, shaking uniformly, separates organic phase, and water phase is used Ethyl acetate extracts (30mL × 2), merges organic phase, washs (150mL × 2) with the saturation NaCl solution of saturation；Anhydrous MgSO₄ It dries, filters, decompression boils off solvent.Rapid column chromatography isolates and purifies (40%EA/PE+0.5%TEA), obtains yellow oil；Oil Shape object is dissolved in 5mL THF, and 2M HCl/AcOEt solution is added, until yellow mercury oxide no longer generates；Filtration, is washed with appropriate THF Precipitating, vacuum drying, obtains yellow solid 55mg；Yield: 32.5%.

The preparation process of compound 45,47~50 with compound 45 preparation process, the difference is that compound L QM- 01 during the preparation process, replaces 2- amino-5-methylphenol that target product can be prepared using different raw materials.

Compound 45:¹H NMR (400MHz, DMSO) δ 8.66 (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).

¹³C 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.

Compound 46:¹H NMR (500MHz, DMSO) δ 11.54 (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)

¹³C 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.

Compound 47:¹H 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)

¹³C NMR(125MHz,DMSO)δ161.91,159.87,153.96,152.46,145.22,144.58,138.37, 138.00,136.44,130.11,129.48,122.06,120.36,114.12,113.73,103.19,103.01,102.73, 102.49,70.91,55.51.

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), 7.34 (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)

¹³C 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.

Compound 49:¹H NMR (500MHz, Methanol-d4) δ 9.10 (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)

¹³C 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.

Compound 50:¹H NMR (500MHz, Methanol-d4) δ 8.63 (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=8.0,2.4Hz, 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).

¹³C 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.

Embodiment 10

The preparation process of compound 52: step S1~S4 is the same as embodiment 6；

The preparation of S5.5-fluoro-2- (tributylstannyl) pyrimidine (LMD-11)

Weigh the chloro- 5-FU 5g (37.73mmol, 1.0eq) of 2- and Pd (PPh₃)₂Cl₂2.65g (3.77mmol, 0.1eq) in bis- mouthfuls of flasks of 250mL, under argon atmosphere protection, anhydrous Isosorbide-5-Nitrae-dioxane 40mL is added, stirs, is then added Six normal-butyls, two tin 26g (45.28mmol, 1.2eq), is heated to flowing back, and reaction is overnight.Standing is cooled to room temperature, reaction solution filter Diatomite is crossed, decompression boils off solvent.Rapid column chromatography isolates and purifies (10%EA/PE), obtains colourless transparent liquid 1.01g；Yield: 31.2%.

S6. the preparation of compound 52

It weighs respectively LQM-04 0.2g (1.0eq), LMD-02 0.27g (1.1eq) and Pd (PPh₃)₂Cl₂ 45mg (0.1eq) in bis- mouthfuls of flasks of 25mL, confined reaction device, displacement argon gas is protected；Anhydrous DMF 3mL is added, 110 DEG C of oil baths add Heat, reaction is overnight.It is cooled to room temperature, ethyl acetate 40mL and water 100mL is added, shaking uniformly, separates organic phase, and water phase is used Ethyl acetate extracts (30mL × 2), merges organic phase, washs (150mL × 2) with the saturation NaCl solution of saturation；Anhydrous MgSO₄ It dries, filters, decompression boils off solvent.Rapid column chromatography isolates and purifies (40%EA/PE+0.5%TEA), obtains yellow oil；Oil Shape object is dissolved in 5mL THF, and 2M HCl/AcOEt solution is added, until yellow mercury oxide no longer generates；Filtration, is washed with appropriate THF Precipitating, vacuum drying, obtains yellow solid 30mg；Yield: 30.1%.

The preparation process of compound 51,53,54 with compound 52 preparation process, the difference is that compound L QM-01 During the preparation process, replace 2- amino-5-methylphenol that target product can be prepared using different raw materials.

Compound 52:¹H NMR (400MHz, DMSO) δ 9.16 (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).

¹³C 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.

Compound 51:¹H NMR (400MHz, CDCl3) δ 8.82 (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)

¹³C 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.

Compound 53:¹H NMR (400MHz, DMSO) δ 9.17 (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).

¹³C NMR(100MHz,DMSO)δ159.87,154.71,146.37,146.16,139.14,138.67,138.47, 136.67,130.12,129.59,120.59,120.43,118.97,114.09,113.74,70.79,55.53.

Compound 54:HRMS (IT-TOF): C21H15N3O2F2for [M+H]+, calculated 380.1205, found380.1199.

Embodiment 11

The preparation process of compound 55:

Weigh respectively QM13200mg (0.667mmol, 1.0eq), LMD-13-2 0.325g (0.733mmol, 1.1eq) and Pd(PPh₃)₂Cl₂50mg (66.7umol, 0.1eq) is in bis- mouthfuls of flasks of 25mL, confined reaction device, displacement argon gas protection；Add Enter anhydrous DMF 3mL, 110 DEG C of oil bath heatings, reaction is overnight.It is cooled to room temperature, ethyl acetate 30mL and water 100mL, vibration is added It shakes uniformly, separates organic phase, water phase is extracted (20mL × 2) with ethyl acetate, merges organic phase, molten with the saturation NaCl of saturation Liquid washs (150mL × 2)；Anhydrous MgSO₄It dries, filters, decompression boils off solvent.Rapid column chromatography isolates and purifies (75%EA/ PE), yellow oil 92mg is obtained.Yield:33.1%.

Compound 55:¹H NMR (400MHz, CDCl3) δ 8.73 (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)

¹³C 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.

The bioactivity of 12 compound of embodiment

Compound is tested to the inhibiting effect of different cancer cells, specific test method is as follows:

(1) by the cell in logarithmic growth phase with 5x10³/ hole concentration kind in 96 orifice plates be placed on incubator (37 DEG C, 5%CO₂) culture；

(2) cell sucks former culture medium afterwards for 24 hours in incubator, and experiment is divided into blank control group, drug-treated group, blank Group culture medium changes full training, and medicine group is handled with experimental design drug concentration；

(3) will treated takes out after cell is placed in incubator 48h, 10 μ LCCK8 are added in every hole, and it is left to be put into incubator 2h It is taken out behind the right side and measures absorbance value (wavelength 450nm) in multi-function microplate reader, and cell survival feelings are calculated according to absorbance value Condition, every group of processing set 3 multiple holes；

(4) mapping analysis is carried out using GraphPad prism7 software.

The cancer cell type of test is as shown in table 2.

The cancer cell type that table 2 is tested

Cancer cell type is write a Chinese character in simplified form	Cancer cell type full name	Culture medium
			A549	People's non-small cell cancer cell	DMEM in high glucose+10%FBS
HCT116	Human colon cancer cell strain	DMEM in high glucose+10%FBS
			HeLa	Human cervical carcinoma cell	DMEM in high glucose+10%FBS
Kyse150	Human esophageal squamous cell cancer cell	DMEM in high glucose+10%FBS
			HL-60	People in loop	High sugar 1640+10%FBS

With cis-platinum (DDP) for positive control, each compound is measured for the IC of above-mentioned 5 kinds of cancer cells₅₀Value is such as 3 institute of table Show.

The activity of 3 compound of table

Note: " na " is " not available " in table 2, and expression is not tested.In table " ++++" indicate IC₅₀At 5 μM Below；" +++ " indicates IC₅₀At 5~10 μM；" ++ " indicates IC₅₀At 10~20 μM；"+" indicates IC₅₀At > 20 μM.

As can be known from Table 3, compound provided by the above embodiment shows significantly to inhibit to make to cancer cell in above-mentioned 5 With especially compound 1,2,5~9,13~17,23,24,26~28,30~35,38,39,42~44,51 and 55, to above-mentioned The IC of 5 kinds of cancer cells₅₀Value is lower than 10 μM；Especially compound 1,2,13,14,23,27,30~33,35,42,51 and 55, to upper State the IC of cancer cell₅₀Value is lower than 5 μM, and inhibiting effect is extremely significant, can be prepared as anticancer drug and is applied.

Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention The limitation of shield range can also be made on the basis of above description and thinking for those of ordinary skill in the art Other various forms of variations or variation, there is no necessity and possibility to exhaust all the enbodiments.It is all of the invention Made any modifications, equivalent replacements, and improvements etc., should be included in the protection of the claims in the present invention within spirit and principle Within the scope of.

Claims (10)

1. a kind of pyrimidine quinoline, which is characterized in that shown in the structure such as formula (I) of the pyrimidine quinoline:

Wherein, R₁For hydrogen, C_1~4Alkyl, C_1~4Halogenated alkyl, benzyl, substituted benzyl, C_4~7Heterocyclic aryl, C_4~7Substituted heterocycle virtue Base, glycosyl or amino acid；

R₂、R₃、R₄And R₅It is each independently hydrogen, halogen, C_1~4Alkyl, C_1~4Alkoxy, hydroxyl, amino, substituted-amino, C_1~4Halogen Substituted alkyl, glycosyl or amino acid；

R₆For substituted or non-substituted five-ring heterocycles, substituted or non-substituted hexa-member heterocycle, substituted or non-substituted C_8~12Thick and heterocycle；

The wherein substituted benzyl, C_4~7Substituted heterocycle aryl, substituted five-membered heterocycle, replaces hexa-member heterocycle and substitution at substituted-amino C_8~12Substituent group in thick and heterocycle is respectively hydroxyl, C_1~4Alkyl, C_1~4Alkoxy, C_1~4Halogenated alkyl or halogen；

Heterocycle therein is the ring containing N, O or S.

2. pyrimidine quinoline according to claim 1, which is characterized in that the R₁For hydrogen, C_1~2Alkyl, C_1~2Alkyl halide Base, benzyl, substituted benzyl, glycosyl or amino acid；

R₂、R₃、R₄And R₅It is each independently hydrogen, halogen, C_1~2Alkyl, C_1~2Alkoxy, C_1~2Halogenated alkyl, amino, takes hydroxyl For amino, glycosyl or amino acid；

R₆For pyrrole ring, substituted or non-substituted benzimidazole ring, substituted or non-substituted pyridine ring, substituted or non-substituted pyrimidine ring, take Generation or non-substituted quinazoline；

Wherein in substituted benzyl, substituted-amino, substituted pyridines ring, substituted benzimidazole ring, substituted pyrimidines ring and substituted quinazoline Substituent group be respectively hydroxyl, C_1~2Alkyl, C_1~2Alkoxy, C_1~2Halogenated alkyl or halogen.

3. pyrimidine quinoline according to claim 2, which is characterized in that the R₁For hydrogen, methyl, ethyl, methyl fluoride, Trifluoromethyl, trifluoroethyl, benzyl, 2- methylbenzyl, 3- methylbenzyl, 4- methylbenzyl, 2- trifluoromethyl benzyl, 3- trifluoro Methylbenzyl, 4- trifluoromethyl benzyl, 2- methoxy-benzyl, 3- methoxy-benzyl or 4- methoxy-benzyl.

4. pyrimidine quinoline according to claim 2, which is characterized in that work as R₆When for pyrrole ring, the pyrimidine quinoline spreads out Shown in the structure such as formula (II) of biology:

Work as R₆When for substituted or non-substituted benzimidazole ring, shown in the structure such as formula (III) of the pyrimidine quinoline:

R₇For hydrogen, C_1~2Alkyl, C_1~2Alkoxy, C_1~2Halogenated alkyl or halogen；

Work as R₆When for substituted or non-substituted pyridine ring, shown in the structure such as formula (IV) of the pyrimidine quinoline:

R₈For hydrogen, C_1~2Alkyl, C_1~2Alkoxy, C_1~2Halogenated alkyl or halogen；

Work as R₆When for substituted or non-substituted pyrimidine ring, shown in structure such as formula (V -1)~(V -3) of the pyrimidine quinoline:

R₉For hydrogen, C_1~2Alkyl, C_1~2Alkoxy, C_1~2Halogenated alkyl or halogen；

Work as R₆When for substituted or non-substituted quinazoline, shown in the structure such as formula (VI) of the pyrimidine quinoline:

R₁₀For hydrogen, C_1~2Alkyl, C_1~2Alkoxy, C_1~2Halogenated alkyl or halogen.

5. the preparation method of any pyrimidine quinoline of Claims 1-4, which is characterized in that work as R₅When for hydrogen, preparation Process are as follows:

S1. replace chloride compounds shown in 2- amino-5-methylphenol compound and formula (2) in inert gas atmosphere shown in formula (1) It is miscible in organic solvent under enclosing, pyridine is added, reacts to obtain formula (3) described intermediate；

S2. formula (3) intermediate and trifluoromethanesulfonic acid are miscible in organic solvent, and room temperature reaction obtains formula (4) described centre Body；

S3. formula (4) intermediate and R₁- Br heats reaction in the organic solvent dissolved with basic salt, obtains formula (5) described centre Body；

S4. formula (5) intermediate and oxalyl chloride are miscible in organic solvent, and DMF is added dropwise, and it is described to obtain formula (6) for heating reaction Intermediate；

S5. under atmosphere of inert gases, lithium diisopropylamine, tetrahydrofuran and the mixing of three n-butyltin hydride solution are simultaneously anti- It answers；To be cooled to -78~-20 DEG C after reaction；Addition formula (7) described compound, is warming up to room temperature reaction, obtains formula (8) institute State intermediate；

S6. formula (6) intermediate, formula (8) intermediate, Pd (PPh₃)₂Cl₂It is miscible in organic in atmosphere of inert gases In solvent, heating reaction, band can obtain target product after reaction；

Work as R₅For halogen, C_1~4Alkyl, C_1~4Alkoxy, hydroxyl, amino, substituted-amino, C_1~4Halogenated alkyl, glycosyl or amino acid When, preparation process are as follows:

S2-1. formula (2-1) compound and formula (2-2) compound are miscible in the organic solvent dissolved with basic salt, heating reaction, i.e., Formula (2-3) compound can be obtained；

S2-2. it formula (2-3) compound and is dissolved in anhydrous organic solvent, and m-CPBA reaction is added under condition of ice bath to obtain Formula (2-4) compound；

S2-3. formula (2-4) compound is miscible in organic solvent with triphenylphosphine under atmosphere of inert gases, and three chloroethenes are added Nitrile is heated to 100~130 DEG C of reactions, can obtain formula (2-5) compound；

S2-4. under atmosphere of inert gases, lithium diisopropylamine, tetrahydrofuran and the mixing of three n-butyltin hydride solution are simultaneously anti- It answers；To be cooled to -78 to -20 DEG C after reaction；Addition formula (7) described compound, is warming up to room temperature reaction, obtains formula (8) institute State intermediate；

S2-5. formula (2-5) intermediate, formula (8) intermediate, Pd (PPh₃)₂Cl₂In atmosphere of inert gases, it is miscible in In organic solvent, heating reaction, band can obtain target product after reaction.

6. the preparation method of pyrimidine quinoline according to claim 5, which is characterized in that the reaction anhydrous and It is carried out under oxygen free condition；The inert gas is nitrogen or argon gas.

7. the preparation method of pyrimidine quinoline according to claim 5, which is characterized in that the organic solvent of all reactions For one of tetrahydrofuran, methylene chloride, dimethyl methyl nitrosourea, dimethyl sulfoxide or acetonitrile or a variety of.

8. the preparation method of pyrimidine quinoline according to claim 5, which is characterized in that in step S1, reaction temperature It is -25~22 DEG C；In step S3 and S2-1, the basic salt is K₂CO₃Or Na₂CO₃；Step S3, the reaction of S4 and step S2-1 Temperature is 70~100 DEG C；The reaction temperature of step S5 is 22~25 DEG C；The reaction temperature of step S6 is 100~130 DEG C.

9. any pyrimidine quinoline of Claims 1-4 is preparing the application in anticancer drug.

10. applying according to claim 9, which is characterized in that the anticancer drug is anti-cervical cancer, colon cancer, non-small thin Born of the same parents' lung cancer, the drug for eating intestines squamous carcinoma, sdenocarcinoma of stomach, breast cancer, liver cancer or chronic myelogenous leukemia.