CN114605408B

CN114605408B - 5-hydroxy-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound and preparation method and application thereof

Info

Publication number: CN114605408B
Application number: CN202210322319.0A
Authority: CN
Inventors: 胡春; 谢倩; 李乐瑢; 王宇航; 文杰; 杨小力; 黄二芳; 彭子俊; 姚语桐; 林柔嘉; 金逸丹; 邓杰元
Original assignee: Shenyang Pharmaceutical University
Current assignee: Shenyang Pharmaceutical University
Priority date: 2022-03-30
Filing date: 2022-03-30
Publication date: 2023-06-16
Anticipated expiration: 2042-03-30
Also published as: CN114605408A

Abstract

The 5-hydroxy-1, 3-disubstituted phenylpyrido [2,3-d ] of the present invention]Pyrimidine compounds, a preparation method and application thereof, and belongs to the technical field of medicines. In particular 5-hydroxy-1, 3-disubstituted phenylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione compounds have the structural general formula shown in formula (I): r is R ₁ Independently selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy; r is R ₂ Independently selected from hydrogen, methyl, butyl, cyclopropyl, 3-morpholinopropyl; r is R ₃ Independently selected from hydrogen, methyl, benzyl, 2-methylbenzyl. The synthesis method of the compound is simple and convenient, is suitable for industrial production, and biological activity tests show that the compound has anti-tumor activity and can be applied to preparation of anti-tumor drugs.

Description

5-hydroxy-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a 5-hydroxy-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound, a preparation method and application thereof.

Background

Malignant tumor is a serious disease, seriously threatens human health, has plagued human for many years, and is a big factor for preventing human life from increasing. With the discovery of oncogenes and cancer suppressor genes and elucidation of cell signaling pathways, the understanding of the canceration mechanism of cells by humans is greatly enriched, and by analyzing the functions of oncogene products, many oncoproteins are found at different sites of normal cell signaling pathways, which play an important role in promoting cell division and proliferation (Klein G.science,1987 (4833): 1539-1545).

The mitogen-activated protein kinase MAPK signaling pathway is a very important information transfer chain in cells. The MAPK pathway has three signaling processes: MAPK, MAPK kinase (MEK or MKK), and MAPK kinase (MEKK or MKK). These three kinases are activated in sequence and together regulate a variety of important physiological/pathological effects such as cell growth, differentiation, stress, inflammatory response, etc., which are the disaster areas (Orton RJ, sturm OE, vyshemirsky V, calder M, gilbert DR, kolch W.the Biochemical journal 2005,392 (2): 249-61) that induce tumor production. The common MAPK signal pathways in human body mainly comprise an extracellular signal kinase (ERK 1/2) signal pathway, a c-Jun-N-terminal kinase (JNK)/Stress Activated Protein (SAPK) signal pathway, a p38MAPK signal pathway, mitogen activated extracellular signal regulated kinase (MEK) and the like, and the MAPK pathway inhibitor small-molecule drugs on the market at present mainly comprise:

trametinib (Trametinib) is a MEK inhibitor drug with anticancer activity, which can inhibit the activity of MEK1 and MEK2 kinases. Trametinib has achieved good results in phase III clinical trials on metastatic melanoma harboring the BRAF V600E mutation. In this mutation, the valine amino acid at position 600 of the BRAF protein has been replaced by glutamic acid, thus rendering the mutant BRAF protein constitutively active (Flaherty KT, inanth JR, daud A, gonzalez R, kefford RF, sosman J, et al, the New England Journal of medicine.2012,367 (18): 1694-703).

Bimetainib (binimeinib) is a selective inhibitor of MEK and was developed by Array Biopharma for the treatment of a variety of cancers. Binimeinib is, MEK is a central kinase in the pro-tumor MAPK pathway. Inappropriate activation of this pathway has been shown to occur in many cancers. Month 6 of 2018, it was approved by the FDA in combination with encouraging for the treatment of unresectable or metastatic BRAF V600E or V600K mutation positive melanoma patients (Koelblinger P, dornbierer J, dummer R.Fuure oncology.2017,13 (20): 1755-1766).

Sorafenib (Sorafenib) is an orally available Raf kinase inhibitor that directly inhibits Raf kinase activity, blocks signaling of the Ras pathway, and also acts on platelet-derived growth factor receptors and vascular endothelial growth factor receptors to down-regulate the expression level of p-MEK, thereby blocking the downstream Ras-Raf-MEK-ERK pathway. The incidence of sorafenib-induced lethal adverse reactions such as gastrointestinal distress, skin toxicity, etc. is extremely low (Wilhelm SM, carter C, tang L, et al cancer research 2004,64 (19): 7099-7109).

Dabrafenib (Dabrafenib) is a drug for treating non-operable or metastatic melanoma, and can specifically act on B-Raf ^V600E Domain, blocking MAPK pathway, inhibiting tumor cell growth and proliferation, and promoting apoptosis. And researches show that the combination of the B-Raf kinase inhibitor and the MEK inhibitor can regulate parallel channels causing adverse reactions of the B-Raf inhibitor, and the combination of the B-Raf kinase inhibitor and the MEK inhibitor can improve response speed and reduce toxicity. Patients often develop resistance to dabrafenib faster, and thus this problem can be solved by co-administration with the MEK inhibitor trimetinib (Khoja L, hogg d. Expert Review of Anticancer therapy.2015,112 (6): 536-545).

Disclosure of Invention

The invention aims to provide 5-hydroxy-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compounds, in particular to 5-hydroxy-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione compounds, prodrugs and pharmaceutically acceptable salts thereof, a preparation method thereof and application thereof in preparing medicaments for treating or/and preventing tumor diseases related to MAPK (primary tumor diseases) such as B-Raf kinase, ras/Raf/MEK/ERK signal channels, p38MAPK signal channels, JNK-SAPK signal channels and the like, including application as multi-target inhibitors.

5-hydroxy-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidines, prodrugs and pharmaceutically active metabolites thereof, and pharmaceutically acceptable salts thereof, as shown in formula I;

R ₁ Independently selected from hydrogen, halogen, C1-C4 alkyl, halogen substituted C1-C4 alkyl, C1-C4 alkoxy, halogen substituted C1-C4 alkoxy;

R ₂ independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, morpholinyl substituted C1-C4 alkyl;

R ₃ independently selected from hydrogen, C1-C6 alkyl, benzyl, C1-C4 alkyl substituted benzyl.

Further, the compounds of formula I, prodrugs and pharmaceutically active metabolites thereof, and pharmaceutically acceptable salts thereof, as described herein:

R ₁ independently selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy;

R ₂ independently selected from hydrogen, methyl, butyl, cyclopropyl, 3-morpholinopropyl;

R ₃ independently selected from hydrogen, methyl, benzyl, 2-methylbenzyl.

Further, the present invention is preferably the following compounds:

6-benzyl-8-butyl-5-hydroxy-1, 3-bis (4-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 01);

6-benzyl-5-hydroxy-8-methyl-1, 3-bis (4-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 02);

5-hydroxy-8- (3-morpholinopropyl) -1, 3-bis (4-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 03);

6-benzyl-5-hydroxy-1, 3-bis (3-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA);

6-benzyl-5-hydroxy-8- (3-morpholinopropyl) -1, 3-bis (3-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA);

6-benzyl-5-hydroxy-8-methyl-1, 3-bis (3-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 06);

6-benzyl-5-hydroxy-8-methyl-1, 3-bis [4- (trifluoromethyl) phenyl ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 07);

6-benzyl-5-hydroxy-8-methyl-1, 3-bis [3- (trifluoromethyl) phenyl ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 08);

6-benzyl-5-hydroxy-1, 3-bis [4- (trifluoromethoxy) phenyl ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 09);

6-benzyl-1, 3-bis (4-chlorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 10);

6-benzyl-5-hydroxy-1, 3-bis (4-methoxyphenyl) -8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 11);

6-benzyl-5-hydroxy-8-methyl-1, 3-bis (2-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 12);

6-benzyl-1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 13);

6-benzyl-8-butyl-1, 3-bis (4-fluorophenyl) -5-hydroxypyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 14);

6-benzyl-8-cyclopropyl-1, 3-bis (4-fluorophenyl) -5-hydroxypyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 15);

6-benzyl-1, 3-bis (4-fluorophenyl) -5-hydroxy-8- (3-morpholinopropyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA);

1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 17);

8-cyclopropyl-1, 3-bis (4-fluorophenyl) -5-hydroxy-6- (2-methylbenzyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA);

1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methyl-6- (2-methylbenzyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA);

6-benzyl-8-cyclopropyl-5-hydroxy-1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA);

8-cyclopropyl-5-hydroxy-6- (2-methylbenzyl) -1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 21);

5-hydroxy-8-methyl-6- (2-methylbenzyl) -1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA).

A pharmaceutical composition comprising as active ingredient a compound of the invention, a prodrug thereof and a pharmaceutically active metabolite thereof, and any one of its pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier or diluent.

"pharmaceutically acceptable salts" refer to conventional acid or base addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed with non-toxic organic or inorganic acids or organic or inorganic bases. The acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, sulfate, perchlorate, thiocyanate, bisulfate, persulfate, borate, formate, acetate, propionate, valerate, pivalate, caproate, enanthate, caprylate, isooctanoate, undecanoate, laurate, palmitate, stearate, oleate, cyclopropanoate, oxalate, malonate, succinate, maleate, fumarate, adipate, azelate, acrylate, strawberry, crotonate, tiglate, itaconic acid, sorbate, cinnamate, glycolate, lactate, malate, tartrate, citrate, bitartrate, mandelate, dibenzoglycolate, tropinate, ascorbate, gluconate, glucoheptonate glucose di-, mannose-, lactose-, benzoate-, phthalate-, terephthalic-, furcate-, nicotinate-, isonicotinate-, salicylate-, acetylsalicylate-, caseinate-, gallate-, cafte-, ferulate-, picrate-, camphorate-, camphorsulfonate-, ethanesulfonate-, propanesulfonate-, phenylsulfonate-, p-toluenesulfonate-, sulfanilate-, sulfamate-, taurate-, 2-hydroxyethanesulfonate-, glycinate-, alaninate-, valine-, leucine-, isoleucine-, phenylalanine-, tryptophan-, tyrosine-, aspartic-, asparagine-, glutamic-, lysine-, glutamine-, methionine-, serine-, threonine-, cysteine-, proline-, histidine-, arginine-, proline-, and, edetate, pyruvate, alpha-ketoglutarate, alginate, cyclopentane propionate, 3-phenylpropionate, 3-cyclohexylpropionic acid, 2-naphthoate, 2-naphthalenesulfonate, pamoate, lauryl sulfate, glycerophosphate, lauryl sulfate, pectate. Preferred acids for use in forming the acid addition salts include hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid, malic acid, picric acid, citric acid, and sulfanilic acid. Base addition salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts of organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine salts, and basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides, such as benzyl and phenethyl bromides.

The invention also relates to a pharmaceutical composition for inhibiting MEK kinase and B-RAF kinase, which comprises a compound shown as a formula I or a derivative thereof or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.

"pharmaceutically acceptable" such as pharmaceutically acceptable carriers, excipients, prodrugs, refers to those that are pharmacologically acceptable and substantially non-toxic to the patient to whom the particular compound is administered.

"pharmaceutically active metabolite" refers to a metabolite of a compound of formula I that is pharmaceutically acceptable and effective.

The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.

The compounds of the invention may be administered to a patient by various methods, including oral administration in capsules or tablets, in sterile solutions or suspensions, and in some cases, may be administered intravenously in solution. The free base compounds of the present invention may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts.

The compound is used as a novel structural type small molecule inhibitor related to MAPK signal paths such as a B-Raf kinase, a Ras/Raf/MEK/ERK signal path, a p38MAPK signal path, a JNK-SAPK signal path and the like, has the characteristics of novel structural type, can act on a plurality of targets and the like, and can be used for preparing a novel pharmaceutical composition for treating or preventing cancer diseases related to MAPK paths such as a B-Raf kinase, a Ras/Raf/MEK/ERK signal path, a p38MAPK signal path, a JNK-SAPK signal path and the like; such as lung cancer, liver cancer, melanoma, colon cancer, rectal cancer, breast cancer, ovarian cancer, cervical cancer and renal cancer, has good application value and development and application prospect.

The preparation route of the compound of the invention comprises the following steps:

the compound XQA-XQA, pharmaceutically acceptable salts and prodrugs thereof have the functions of acting on Ras/Raf/MEK/ERK signal paths and inhibiting the phosphorylation of ERK1/2, thereby achieving the purpose of inhibiting tumor cell proliferation.

The invention has the beneficial effects that:

the invention provides a novel structure of an anti-tumor compound, which has potential patent drug value, simple preparation route, easy synthesis and low cost. Compared with the medicines on the market, the preparation has more remarkable anti-tumor cell proliferation activity.

Detailed Description

The invention will be described in detail with the following examples. However, it should be understood that the invention is not limited to the following examples specifically recited. Example 1: preparation of 6-benzyl-8-butyl-5-hydroxy-1, 3-bis (4-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 01)

Step I: 40mL of methylene chloride-dissolved solid phosgene (9.5 g,32 mmol) was weighed into a 500mL round bottom flask, p-toluidine (8.57 g,80 mmol) was weighed into 40mL of methylene chloride, and was dropped into the flask with a dropping funnel at room temperature over 30min, triethylamine (20.24 g,0.2 mol) was then weighed into 50mL of methylene chloride, and was dropped into the flask over 30min, p-toluidine (8.57 g,80 mmol) was again weighed into 40mL of methylene chloride, and was dropped into the flask again as described above. After the completion of the dripping, the reaction was stirred for 30min to monitor that the reaction of the p-toluidine was complete. About 3/4 of the volume of the methylene chloride was distilled off under reduced pressure, and a large amount of solid was produced after stirring with 5% HCl solution for 5-10min, and the solid was filtered off, repeatedly washed with diethyl ether, and dried to give 1, 3-di-p-toluurea as a white solid in a yield of 18.25g and a yield of 94.93%.

Step II: 1, 3-Di-p-toluurea (4.81 g,20 mmol), malonic acid (2.7 g,26 mmol), phosphorus oxychloride (3.4 g,22 mmol) and 15mL acetonitrile were weighed into a 35mL sealed tube. Sealing and heating to 120 ℃ for reaction for 1h, monitoring that the reaction of the raw material 1, 3-di-p-tolueneurea is complete, pouring the reaction liquid in the sealed tube into an eggplant-shaped bottle, distilling under reduced pressure to remove all solvents, adding 50mL of 2mol/L NaOH and 20mL of ethyl acetate, stirring and dissolving. The organic phases were extracted three more times with 2mol/L aqueous NaOH, the aqueous layers were combined, the aqueous layer was extracted once with a small amount of ethyl acetate, and the remaining aqueous layer was pH-adjusted with hydrochloric acid to yield a large amount of solids. The solid was filtered off, the filter cake was washed with water and dried to give 3.89g of 1, 3-bis (4-methylphenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione as an off-white solid in 63.08% yield.

Step III: 1, 3-bis (4-methylphenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione (4.99 g,16.2 mmol), phosphorus oxychloride (4.92 g,32.4 mmol) and 20mL acetonitrile were weighed into a 125mL sealed tube. Sealing and heating to 120 ℃ for reaction for 3 hours, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in a sealed tube into a eggplant-shaped bottle, decompressing and distilling to remove all solvents, adding a small amount of ethanol to dissolve the mixture, adding water to separate out solids, filtering out the solids, washing a filter cake with water, and drying to obtain 4.86g of yellow solid 6-chloro-1, 3-bis (4-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione with the yield of 91.80%.

Step IV: 6-chloro-1, 3-bis (4-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.26 g,10 mmol), n-butylamine (1.09 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask and stirred to reflux for 8h to complete the reaction. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6- (butylamino) -1, 3-bis (4-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 3.46g, 95.20%.

Step V: weighing 6- (butylamine group) -1, 3-bis (4-methylphenyl) pyrimidine-2, 4 (1H, 3H) -diketone (1.82 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether in a 100mL three-neck round bottom flask, heating to 256 ℃ on a heating sleeve, refluxing for 40min, after TLC monitoring the complete reaction of the raw materials, pouring the reaction solution into 30mL petroleum ether, precipitating a large amount of solid, suction filtering, drying and purifying by column chromatography to obtain pure 6-benzyl-8-butyl-5-hydroxy-1, 3-bis (4-methylphenyl) pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA), a white solid, 1.30g yield, 49.85% yield; m.p.:85.5-88.9 ℃; MS 522.23676[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.53(s,1H),7.40(d,J＝8.1Hz,2H),7.34(d,J＝8.2Hz,2H),7.29(d,J＝8.4Hz,3H),7.25(d,J＝2.9Hz,3H),7.22(d,J＝7.6Hz,2H),7.13(t,J＝6.9Hz,1H),3.47(t,J＝7.6Hz,2H),3.30(s,2H),2.36(d,J＝6.5Hz,6H),1.05(dq,J＝30.8,7.4Hz,2H),0.89–0.83(m,2H),0.68(t,J＝7.2Hz,3H)。

Example 2: preparation of 6-benzyl-5-hydroxy-8-methyl-1, 3-bis (4-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione (XQA 02):

The compound 6-chloro-1, 3-bis (4-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione was prepared by the method of example 1.

Step IV: 6-chloro-1, 3-bis (4-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.26 g,10 mmol), 40% aqueous methylamine (1.28 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask, stirred and refluxed for 8 hours, and then the reaction was complete. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid is filtered off, washed with diethyl ether and dried to obtain yellow solid 6- (methylamino) -1, 3-bis (4-methyl)Phenyl) pyrimidine-2, 4 (1H, 3H) -dione, yield 3.16g, 98.33%. m.p.:121.8-128.4 ℃; MS 480.18939[ M+H ]] ⁺ ；

Step V: weighing 6- (methylamino) -1, 3-bis (4-methylphenyl) pyrimidine-2, 4 (1H, 3H) -diketone (1.61 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating jacket, refluxing for 40min, after TLC monitoring the reaction completion, pouring the reaction solution into 30mL petroleum ether, precipitating a large amount of solid, suction filtering, drying, and purifying by column chromatography to obtain pure 6-benzyl-5-hydroxy-8-methyl-1, 3-bis (4-methylphenyl) pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 02), a white solid, 1.42g yield, 59.22%; m.p.:121.8-128.4 ℃; MS 480.18939[ M+H ] ] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.43(s,1H),7.36(d,J＝8.5Hz,2H),7.32(d,J＝8.1Hz,3H),7.28(d,J＝2.9Hz,2H),7.25(d,J＝6.6Hz,2H),7.22(d,J＝7.9Hz,3H),7.16–7.11(m,1H),3.73(s,2H),2.73(s,3H),2.36(d,J＝1.9Hz,6H)。

Example 3: preparation of 5-hydroxy-8- (3-morpholinopropyl) -1, 3-bis (4-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 03)

Step IV: 6-chloro-1, 3-bis (4-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.26 g,10 mmol), N-aminopropylmorpholine (2.16 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask and stirred to reflux for 8 hours to complete the reaction. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6- [ (3-morpholinopropyl) amino ] -1, 3-bis (4-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 3.16g, 72.72%.

Step V: weighing 6- [ (3-morpholinopropyl) amino group]1, 3-bis (4-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione (2.17 g,5 mmol), diethyl malonate (0.96 g,6 mmol) and 15g diphenyl ether were reacted in a 100mL three-necked round bottom flask, heated to 256℃on a heating mantle and then refluxed for 40min, and TLC monitored the completion of the starting material reactionThen pouring the reaction solution into 30mL of petroleum ether, precipitating a large amount of solid, suction filtering, drying and purifying by column chromatography to obtain a pure product of 5-hydroxy-8- (3-morpholinopropyl) -1, 3-bis (4-methylphenyl) pyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 03), a white solid, 0.98g yield 39.00%; m.p.:209.0-212.2 ℃; MS 503.12516[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ11.96(s,1H),7.35–7.23(m,8H),6.06(s,1H),3.93(t,J＝6.8Hz,2H),3.53(t,J＝4.5Hz,4H),2.37(d,J＝3.9Hz,6H),2.24(t,J＝4.5Hz,4H),2.10(t,J＝7.2Hz,2H),1.59(p,J＝7.0Hz,2H)。

Example 4: preparation of 6-benzyl-5-hydroxy-1, 3-bis (3-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 04)

Step I: 40mL of methylene chloride-dissolved solid phosgene (9.5 g,32 mmol) was weighed into a 500mL round bottom flask, m-toluidine (8.57 g,80 mmol) was weighed into 40mL of methylene chloride, and it was dropped into the flask with a dropping funnel at room temperature over 30min, triethylamine (20.24 g,0.2 mol) was then weighed into 50mL of methylene chloride, and it was dropped into the flask over 30min, and m-toluidine (8.57 g,80 mmol) was again weighed into 40mL of methylene chloride, and it was dropped into the flask again as described above. After the completion of the dripping, the reaction was stirred for 30min to monitor that the reaction of m-toluidine was complete. About 3/4 of the volume of methylene chloride was distilled off under reduced pressure, and after stirring with 5% HCl solution for 5-10min, a large amount of solids was produced, the solids were filtered off, repeatedly washed with diethyl ether, and dried to give 1, 3-dimethyl-phenylurea as a white solid in a yield of 18.25g and a yield of 94.93%.

Step II: 1, 3-Di-m-toluurea (4.81 g,20 mmol), malonic acid (2.7 g,26 mmol), phosphorus oxychloride (3.4 g,22 mmol) and 15mL acetonitrile were weighed into a 35mL sealed tube. Sealing and heating to 120 ℃ for reaction for 1h, monitoring that the reaction of the raw material 1, 3-di-p-tolueneurea is complete, pouring the reaction liquid in the sealed tube into an eggplant-shaped bottle, distilling under reduced pressure to remove all solvents, adding 50mL of 2mol/L NaOH and 20mL of ethyl acetate, stirring and dissolving. The organic phases were extracted three more times with 2mol/L aqueous NaOH, the aqueous layers were combined, the aqueous layer was extracted once with a small amount of ethyl acetate, and the remaining aqueous layer was pH-adjusted with hydrochloric acid to yield a large amount of solids. The solid was filtered off, the filter cake was washed with water and dried to give 3.91g of 1, 3-bis (3-methylphenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione as an off-white solid in 63.40% yield.

Step III: 1, 3-bis (3-methylphenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione (4.99 g,16.2 mmol), phosphorus oxychloride (4.92 g,32.4 mmol) and 20mL acetonitrile were weighed into a 125mL sealed tube. Sealing and heating to 120 ℃ for reaction for 3 hours, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in a sealed tube into a eggplant-shaped bottle, decompressing and distilling to remove all solvents, adding a small amount of ethanol to dissolve the mixture, adding water to separate out solids, filtering out the solids, washing a filter cake with water, and drying to obtain 4.92g of yellow solid 6-chloro-1, 3-bis (3-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione with the yield of 92.94%.

Step IV: 6-chloro-1, 3-bis (3-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.26 g,10 mmol), 25% aqueous ammonia (2.1 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask, stirred and refluxed for 8 hours, and then the reaction was complete. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-amino-1, 3-bis (3-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 2.93g, 95.23%.

Step V: weighing 6-amino-1, 3-bis (3-methylphenyl) pyrimidine-2, 4 (1H, 3H) -diketone (1.54 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating sleeve, refluxing for 40min, after TLC monitoring the reaction completion, pouring the reaction solution into 30mL petroleum ether, precipitating a large amount of solid, filtering, drying, and purifying by column chromatography to obtain pure 6-benzyl-5-hydroxy-1, 3-bis (3-methylphenyl) pyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 04), a white solid, 0.70g yield, 30.07% yield; m.p.:134.7-138.4 ℃; MS 466.17416[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.36(s,1H),11.71(s,1H),7.34–7.40(m,2H),7.26–7.13(m,11H),3.77(s,2H),2.34(s,6H)。

Example 5: preparation of 6-benzyl-5-hydroxy-8- (3-morpholinopropyl) -1, 3-bis (3-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 05)

The compound 6-chloro-1, 3-bis (3-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione was prepared by the method of example 4.

Step IV: 6-chloro-1, 3-bis (3-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.26 g,10 mmol), N-aminopropylmorpholine (2.16 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask and stirred to reflux for 8 hours to complete the reaction. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6- [ (3-morpholinopropyl) amino ] -1, 3-bis (3-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 3.67g, 84.46%.

Step V: weighing 6- [ (3-morpholinopropyl) amino group]-1, 3-bis (3-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione (2.17 g,5 mmol), diethyl benzylmalonate (1.50 g,6 mmol) and 15g diphenyl ether are placed in a 100mL three-neck round bottom flask, the mixture is heated to 256 ℃ on a heating sleeve and then is refluxed for 40min, after TLC monitoring the reaction of the raw materials is complete, the reaction solution is poured into 30mL petroleum ether, a large amount of solids are separated out, suction filtration and column chromatography purification are carried out after drying, thus obtaining the pure 6-benzyl-5-hydroxy-8- (3-morpholinopropyl) -1, 3-bis (3-methylphenyl) pyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 05), a white solid, produced in 0.64g, 21.60% yield; m.p.:109.5-110.4 ℃; MS 593.27572[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.24(s,1H),7.36–7.40(m,2H),7.27–7.15(m,11H),3.92(t,J＝6.3Hz,2H),3.79(s,2H),3.51(t,J＝4.5Hz,4H),2.35(d,J＝3.3Hz,6H),2.18(s,4H),2.03(d,J＝7.4Hz,2H),1.54(p,J＝6.8Hz,2H)。

Example 6: preparation of 6-benzyl-5-hydroxy-8-methyl-1, 3-bis (3-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 06)

Step IV: 6-chloro-1, 3-bis (3-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.26 g,10 mmol), 40% aqueous methylamine (1.28 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask, stirred and refluxed for 8 hours, and then the reaction was complete. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6- (methylamino) -1, 3-bis (3-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 3.06g, 95.23%.

Step V: weighing 6- (methylamino) -1, 3-bis (3-methylphenyl) pyrimidine-2, 4 (1H, 3H) -diketone (1.61 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating jacket, refluxing for 40min, after TLC monitoring the reaction completion, pouring the reaction solution into 30mL petroleum ether, precipitating a large amount of solid, suction filtering, drying, and purifying by column chromatography to obtain pure 6-benzyl-5-hydroxy-8-methyl-1, 3-bis (3-methylphenyl) pyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 06), a white solid, 1.30g yield, 54.22%; m.p.:111.6-118.3 ℃; MS 480.18945[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.41(s,1H),7.377.42(m,2H),7.20–7.35(m,9H),7.17–7.13(m,2H),3.72(d,J＝10.0Hz,2H),2.75(s,3H),2.34(s,6H)。

Example 7: preparation of 6-benzyl-5-hydroxy-8-methyl-1, 3-bis [4- (trifluoromethyl) phenyl ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 07)

Step I: 40mL of methylene chloride-dissolved solid phosgene (9.5 g,32 mmol) was weighed into a 500mL round bottom flask, para-trifluoromethylaniline (12.88 g,80 mmol) was weighed into 40mL of methylene chloride, and was dropped into the flask with a dropping funnel at room temperature over 30min, and then triethylamine (20.24 g,0.2 mol) was weighed into 50mL of methylene chloride, and was dropped into the flask over 30min, and para-trifluoromethylaniline (12.88 g,80 mmol) was weighed into 40mL of methylene chloride again, and was dropped into the flask again as described above. After the completion of the dripping, the reaction was stirred for 30min to monitor that the reaction of the p-fluoroaniline was complete. About 3/4 of the volume of methylene chloride was distilled off under reduced pressure, and after stirring with 5% HCl solution for 5-10min, a large amount of solids was produced, the solids were filtered off, repeatedly washed with diethyl ether, and dried to give 1, 3-di-p-trifluoromethylphenylurea as a white solid in a yield of 26.25g and a yield of 94.22%.

Step II: 1, 3-Di-p-trifluoromethylphenylurea (6.96 g,20 mmol), malonic acid (2.7 g,26 mmol), phosphorus oxychloride (3.4 g,22 mmol) and 15mL acetonitrile were weighed into a 35mL sealed tube. Sealing and heating to 120 ℃ for reaction for 1h, monitoring that the reaction of the raw material 1, 3-di-p-tolueneurea is complete, pouring the reaction liquid in the sealed tube into an eggplant-shaped bottle, distilling under reduced pressure to remove all solvents, adding 50mL of 2mol/L NaOH and 20mL of ethyl acetate, stirring and dissolving. The organic phases were extracted three more times with 2mol/L aqueous NaOH, the aqueous layers were combined, the aqueous layer was extracted once with a small amount of ethyl acetate, and the remaining aqueous layer was pH-adjusted with hydrochloric acid to yield a large amount of solids. The solid was filtered off, the filter cake was washed with water and dried to give 1, 3-bis [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4,6 (1H, 3H, 5H) -trione as an off-white solid, 6.41g, 76.99% yield.

Step III: 1, 3-bis [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4,6 (1H, 3H, 5H) -trione (6.74 g,16.2 mmol), phosphorus oxychloride (4.92 g,32.4 mmol) and 20mL acetonitrile were weighed into a 125mL sealed tube. Sealing and heating to 120 ℃ for reaction for 3 hours, monitoring that the raw materials are completely reacted, pouring the reaction liquid in a sealed tube into a eggplant-shaped bottle, decompressing and distilling to remove all solvents, adding a small amount of ethanol to dissolve the mixture, adding water to separate out solids, filtering out the solids, washing a filter cake with water, and drying to obtain yellow solid 6-chloro-1, 3-bis [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4 (1H, 3H) -dione 6.92g, wherein the yield is 98.26%.

Step IV: 6-chloro-1, 3-bis [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4 (1H, 3H) -dione (4.35 g,10 mmol), 40% aqueous methylamine (1.28 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask and stirred to reflux for 8 hours before reaction was complete. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-methylamino-1, 3-bis [4- (trifluoromethyl) phenyl ] pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 4.09g, 95.23%.

Step V: weighing 6-methylamino-1, 3-bis [4- (trifluoromethyl) phenyl ] ]Pyrimidine-2, 4 (1H, 3H) -diketone (2.14 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether are placed in a 100mL three-neck round bottom flask, heated to 256 ℃ on a heating sleeve and then reflux reacted for 40min, after TLC monitoring that the raw materials are completely reacted, the reaction solution is poured into 30mL petroleum ether, a large amount of solid is separated out, suction filtration and drying are carried out, and then column chromatography purification is carried out to obtain the pure product 6-benzyl-5-hydroxy-8-methyl-1, 3-bis [4- (trifluoromethyl) phenyl ]]Pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 07), a white solid,yield 1.70g, 57.87%; m.p.:123.2-128.3 ℃; MS 593.27572[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.24(s,1H),7.36–7.40(m,2H),7.27–7.15(m,11H),3.92(t,J＝6.3Hz,2H),3.79(s,2H),3.51(t,J＝4.5Hz,4H),2.35(d,J＝3.3Hz,6H),2.18(s,4H),2.03(d,J＝7.4Hz,2H),1.54(p,J＝6.8Hz,2H)。

Example 8: preparation of 6-benzyl-5-hydroxy-8-methyl-1, 3-bis [3- (trifluoromethyl) phenyl ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 08)

Step I: 40mL of methylene chloride-dissolved solid phosgene (9.5 g,32 mmol) was weighed into a 500mL round bottom flask, m-trifluoromethylaniline (12.88 g,80 mmol) was weighed into 40mL of methylene chloride, and was dropped into the flask at room temperature using a dropping funnel over 30min, triethylamine (20.24 g,0.2 mol) was then weighed into 50mL of methylene chloride, and was dropped into the flask over 30min, and m-trifluoromethylaniline (12.88 g,80 mmol) was again weighed into 40mL of methylene chloride, and was dropped into the flask again as described above. After the completion of the dripping, the reaction was stirred for 30min to monitor that the reaction of the p-fluoroaniline was complete. About 3/4 of the volume of methylene chloride was distilled off under reduced pressure, and after stirring with 5% HCl solution for 5-10min, a large amount of solids were produced, the solids were filtered off, repeatedly washed with diethyl ether, and dried to give 1, 3-di-m-trifluoromethylphenylurea as a white solid in a yield of 26.78g and 96.12%.

Step II: 1, 3-Di-m-trifluoromethylphenylurea (6.96 g,20 mmol), malonic acid (2.7 g,26 mmol), phosphorus oxychloride (3.4 g,22 mmol) and 15mL acetonitrile were weighed into a 35mL sealed tube. Sealing and heating to 120 ℃ for reaction for 1h, monitoring that the reaction of the raw material 1, 3-di-p-tolueneurea is complete, pouring the reaction liquid in the sealed tube into an eggplant-shaped bottle, distilling under reduced pressure to remove all solvents, adding 50mL of 2mol/L NaOH and 20mL of ethyl acetate, stirring and dissolving. The organic phases were extracted three more times with 2mol/L aqueous NaOH, the aqueous layers were combined, the aqueous layer was extracted once with a small amount of ethyl acetate, and the remaining aqueous layer was pH-adjusted with hydrochloric acid to yield a large amount of solids. The solid was filtered off, the filter cake was washed with water and dried to give 1, 3-bis [3- (trifluoromethyl) phenyl ] pyrimidine-2, 4,6 (1H, 3H, 5H) -trione as an off-white solid in a yield of 6.53g, 78.43%.

Step III: 1, 3-bis [3- (trifluoromethyl) phenyl ] pyrimidine-2, 4,6 (1H, 3H, 5H) -trione (6.74 g,16.2 mmol), phosphorus oxychloride (4.92 g,32.4 mmol) and 20mL acetonitrile were weighed into a 125mL sealed tube. Sealing and heating to 120 ℃ for reaction for 3 hours, monitoring that the raw materials are completely reacted, pouring the reaction liquid in a sealed tube into a eggplant-shaped bottle, decompressing and distilling to remove all solvents, adding a small amount of ethanol to dissolve the mixture, adding water to separate out solids, filtering out the solids, washing a filter cake with water, and drying to obtain yellow solid 6-chloro-1, 3-bis [3- (trifluoromethyl) phenyl ] pyrimidine-2, 4 (1H, 3H) -dione 6.62g with the yield of 94.00%.

Step IV: 6-chloro-1, 3-bis [3- (trifluoromethyl) phenyl ] pyrimidine-2, 4 (1H, 3H) -dione (4.35 g,10 mmol), 40% aqueous methylamine (1.28 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask and stirred to reflux for 8 hours before reaction was complete. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-amino-1, 3-bis [3- (trifluoromethyl) phenyl ] pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 4.09g, 95.35%.

Step V: weighing 6-methylamino-1, 3-bis [3- (trifluoromethyl) phenyl ]]Pyrimidine-2, 4 (1H, 3H) -diketone (2.15 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether are placed in a 100mL three-neck round bottom flask, heated to 256 ℃ on a heating sleeve and then reflux reacted for 40min, after TLC monitoring that the raw materials are completely reacted, the reaction solution is poured into 30mL petroleum ether, a large amount of solid is separated out, suction filtration and drying are carried out, and then column chromatography purification is carried out to obtain the pure product 6-benzyl-5-hydroxy-8-methyl-1, 3-bis [3- (trifluoromethyl) phenyl ]]Pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA) as a white solid in 1.56g yield 53.10%; m.p.:104.2-110.3 ℃; MS 588.13263[ M+H ] ] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.10(s,1H),7.93–7.67(m,8H),7.21–7.31(m,4H),7.17–7.11(m,1H),3.76(s,2H),2.76(s,3H)。

Example 9: preparation of 6-benzyl-5-hydroxy-1, 3-bis [4- (trifluoromethoxy) phenyl ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 09)

Step I: 40mL of methylene chloride-dissolved solid phosgene (9.5 g,32 mmol) was weighed into a 500mL round bottom flask, para-trifluoromethoxy aniline (14.17 g,80 mmol) was weighed into 40mL of methylene chloride, and was dropped into the flask with a dropping funnel at room temperature over 30min, triethylamine (20.24 g,0.2 mol) was then weighed into 50mL of methylene chloride, and was dropped into the flask over 30min, and para-trifluoromethoxy aniline 14.17g,80mmol was again weighed into 40mL of methylene chloride, and was dropped into the flask again as described above. After the completion of the dripping, the reaction was stirred for 30min to monitor that the reaction of the p-fluoroaniline was complete. About 3/4 of the volume of the methylene chloride was distilled off under reduced pressure, and then a large amount of solid was produced after stirring with 5% HCl solution for 5-10min, the solid was filtered off, repeatedly washed with diethyl ether, and dried to obtain 1, 3-di-p-trifluoromethoxybenzourea as a white solid in a yield of 16.25g and a yield of 53.42%.

Step II: 1, 3-Di-p-trifluoromethoxybenzourea (7.60 g,20 mmol), malonic acid (2.7 g,26 mmol), phosphorus oxychloride (3.4 g,22 mmol) and 15mL acetonitrile were weighed into a 35mL sealed tube. After the reaction is carried out for 1 hour after the sealing heating to 120 ℃, monitoring that the reaction of the raw materials is complete, pouring the reaction liquid in the sealed tube into a eggplant-shaped bottle, removing all the solvent by reduced pressure distillation, adding 50mL of 2mol/LNaOH and 20mL of ethyl acetate, stirring and dissolving. The organic phases were extracted three more times with 2mol/L aqueous NaOH, the aqueous layers were combined, the aqueous layer was extracted once with a small amount of ethyl acetate, and the remaining aqueous layer was pH-adjusted with hydrochloric acid to yield a large amount of solids. The solid was filtered off, the filter cake was washed with water and dried to give 1, 3-bis [4- (trifluoromethoxy) phenyl ] pyrimidine-2, 4,6 (1H, 3H, 5H) -trione as an off-white solid 6.91g in 77.07% yield.

Step III: 1, 3-bis [4- (trifluoromethoxy) phenyl ] pyrimidine-2, 4,6 (1H, 3H, 5H) -trione (7.26 g,16.2 mmol), phosphorus oxychloride (4.92 g,32.4 mmol) and 20mL acetonitrile were weighed into a 125mL sealed tube. Sealing and heating to 120 ℃ for reaction for 3 hours, monitoring that the raw materials are completely reacted, pouring the reaction liquid in a sealed tube into a eggplant-shaped bottle, removing all solvents by reduced pressure distillation, adding a small amount of ethanol to dissolve the mixture, adding water to separate out solids, filtering out the solids, washing a filter cake with water, and drying to obtain 7.04g of yellow solid 6-chloro-1, 3-bis [4- (trifluoromethoxy) phenyl ] pyrimidine-2, 4 (1H, 3H) -dione with the yield of 93.11%.

Step IV: 6-chloro-1, 3-bis [4- (trifluoromethoxy) phenyl ] pyrimidine-2, 4 (1H, 3H) -dione (4.67 g,10 mmol), 25% aqueous ammonia (2.1 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask and reacted completely under reflux with stirring for 8 hours. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-amino-1, 3-bis [4- (trifluoromethoxy) phenyl ] pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 4.26g, 95.23%.

Step V: weighing 6-amino-1, 3-bis [4- (trifluoromethoxy) phenyl ] ]Pyrimidine-2, 4 (1H, 3H) -diketone (2.24 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether are placed in a 100mL three-necked round bottom flask, heated to 256 ℃ on a heating sleeve and then reflux reacted for 40min, after TLC monitoring that the raw materials are completely reacted, the reaction solution is poured into 30mL petroleum ether, a large amount of solid is separated out, suction filtration and drying are carried out, and then column chromatography purification is carried out to obtain the pure product 6-benzyl-5-hydroxy-1, 3-bis [4- (trifluoromethoxy) phenyl ]]Pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 09), as a white solid, 0.86g in 28.41% yield; m.p.:116.9-21.9 ℃; MS 606.10614[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.16(s,1H),11.76(s,1H),7.56–7.49(m,8H),7.20–7.25(m,4H),7.11–7.17(m,1H),3.78(s,2H)。

Example 10: preparation of 6-benzyl-1, 3-bis (4-chlorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 10)

Step I: 40mL of methylene chloride-dissolved solid phosgene (9.5 g,32 mmol) was weighed into a 500mL round bottom flask, p-chloroaniline (10.21 g,80 mmol) was weighed into 40mL of methylene chloride, and was dropped into the flask with a dropping funnel at room temperature over 30min, triethylamine (20.24 g,0.2 mol) was then weighed into 50mL of methylene chloride, and was dropped into the flask over 30min, p-chloroaniline (10.21 g,80 mmol) was again weighed into 40mL of methylene chloride, and was dropped into the flask again as described above. After the completion of the dripping, the reaction was stirred for 30min to monitor that the reaction of the p-fluoroaniline was complete. About 3/4 of the volume of the methylene chloride was distilled off under reduced pressure, and a large amount of solid was produced after stirring with 5% HCl solution for 5-10min, and the solid was filtered off, repeatedly washed with diethyl ether, and dried to give 1, 3-di-p-chlorobenzourea as a white solid in a yield of 10.12g and 45.00%.

Step II: 1, 3-Di-p-chlorobenzourea (5.62 g,20 mmol), malonic acid (2.7 g,26 mmol), phosphorus oxychloride (3.4 g,22 mmol) and 15mL acetonitrile were weighed into a 35mL sealed tube. Sealing and heating to 120 ℃ for reaction for 1h, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in the sealed tube into a eggplant-shaped bottle, distilling under reduced pressure to remove all solvents, adding 50mL of 2mol/L NaOH and 20mL of ethyl acetate, stirring and dissolving. The organic phases were extracted three more times with 2mol/L aqueous NaOH, the aqueous layers were combined, the aqueous layer was extracted once with a small amount of ethyl acetate, and the remaining aqueous layer was pH-adjusted with hydrochloric acid to yield a large amount of solids. The solid was filtered off, the filter cake was washed with water and dried to give 5.99g of 1, 3-bis (4-chlorophenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione as an off-white solid in 85.78% yield.

Step III: 1, 3-bis (4-chlorophenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione (6.43 g,16.2 mmol), phosphorus oxychloride (4.92 g,32.4 mmol) and 20mL acetonitrile were weighed into a 125mL sealed tube. Sealing and heating to 120 ℃ for reaction for 3 hours, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in a sealed tube into a eggplant-shaped bottle, decompressing and distilling to remove all solvents, adding a small amount of ethanol to dissolve the mixture, adding water to separate out solids, filtering out the solids, washing a filter cake with water, and drying to obtain yellow solid of 5.54g of 6-chloro-1, 3-bis (4-chlorophenyl) pyrimidine-2, 4 (1H, 3H) -dione with the yield of 93.11 percent.

Step IV: 6-chloro-1, 3-bis (4-chlorophenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.68 g,10 mmol), 40% aqueous methylamine solution (1.28 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask, stirred and refluxed for 8 hours, and then the reaction was complete. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-methylamino-1, 3-bis (4-chlorophenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 3.46g, 95.52%.

Step V: weighing 6-methylamino-1, 3-bis (4-chlorophenyl) pyrimidine-2, 4 (1H, 3H) -dione (1.81 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating jacket, refluxing for 40min, after TLC monitoring the reaction of the raw materials, pouring the reaction solution into 30mL petroleum ether to separate out a large amount of solid, suction filtering, drying, and purifying by column chromatography to obtain pure 6-benzyl-1, 3-bis (4-chlorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 10), whiteColor solid, yield 0.86g, yield 33.05%; m.p.:131.3-150.4 ℃; MS 520.08032[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.23(s,1H),7.58–7.61(m,4H),7.52(d,J＝8.5Hz,2H),7.40(d,J＝8.6Hz,2H),7.30–7.20(m,4H),7.17–7.11(m,1H),3.74(s,2H),2.77(s,3H)。

Example 11: preparation of 6-benzyl-5-hydroxy-1, 3-bis (4-methoxyphenyl) -8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 11)

Step I: 40mL of methylene chloride-dissolved solid phosgene (9.5 g,32 mmol) was weighed into a 500mL round bottom flask, p-methoxyaniline (9.82 g,80 mmol) was weighed into 40mL of methylene chloride, and was dropped into the flask with a dropping funnel at room temperature over 30min, triethylamine (20.24 g,0.2 mol) was then weighed into 50mL of methylene chloride, and was dropped into the flask over 30min, p-methoxyaniline (9.82 g,80 mmol) was again weighed into 40mL of methylene chloride, and was dropped into the flask again as described above. After the completion of the dripping, the reaction was stirred for 30min to monitor that the reaction of the p-fluoroaniline was complete. About 3/4 of the volume of methylene chloride was distilled off under reduced pressure, and after stirring with 5% HCl solution for 5-10min, a large amount of solids were produced, and the solids were filtered off, repeatedly washed with diethyl ether, and dried to give 1, 3-di-p-methoxyphenylurea as a white solid in a yield of 10.57g and a yield of 48.52%.

Step II: 1, 3-Di-p-methoxyphenylurea (5.45 g,20 mmol), malonic acid (2.7 g,26 mmol), phosphorus oxychloride (3.4 g,22 mmol) and 15mL acetonitrile were placed in a 35mL sealed tube. Sealing and heating to 120 ℃ for reaction for 1h, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in the sealed tube into a eggplant-shaped bottle, distilling under reduced pressure to remove all solvents, adding 50mL of 2mol/L NaOH and 20mL of ethyl acetate, stirring and dissolving. The organic phases were extracted three more times with 2mol/L aqueous NaOH, the aqueous layers were combined, the aqueous layer was extracted once with a small amount of ethyl acetate, and the remaining aqueous layer was pH-adjusted with hydrochloric acid to yield a large amount of solids. The solid was filtered off, the filter cake was washed with water and dried to give 5.01g of 1, 3-bis (4-methoxyphenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione as an off-white solid in 73.60% yield.

Step III: 1, 3-bis (4-methoxyphenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione (5.51 g,16.2 mmol), phosphorus oxychloride (4.92 g,32.4 mmol) and 20mL acetonitrile were weighed into a 125mL sealed tube. Sealing and heating to 120 ℃ for reaction for 3 hours, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in a sealed tube into a eggplant-shaped bottle, decompressing and distilling to remove all solvents, adding a small amount of ethanol to dissolve the mixture, adding water to separate out solids, filtering out the solids, washing a filter cake with water, and drying to obtain yellow solid of 5.41g of 6-chloro-1, 3-bis (4-methoxyphenyl) pyrimidine-2, 4 (1H, 3H) -dione with the yield of 93.11 percent.

Step IV: 6-chloro-1, 3-bis (4-methoxyphenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.59 g,10 mmol), 40% aqueous methylamine (1.28 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask, stirred and refluxed for 8 hours, and then the reaction was completed. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-methylamino-1, 3-bis (4-methoxyphenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 3.37g, 95.23%.

Step V: weighing 6-methylamino-1, 3-bis (4-methoxyphenyl) pyrimidine-2, 4 (1H, 3H) -dione (1.77 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating jacket, refluxing for 40min, after TLC monitoring the reaction completion, pouring the reaction solution into 30mL petroleum ether, precipitating a large amount of solid, suction filtering, drying, and purifying by column chromatography to obtain pure 6-benzyl-5-hydroxy-1, 3-bis (4-methoxyphenyl) -8-methylpyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 11), a white solid, 1.02g yield, 39.88% yield; m.p.:104.1-111.2 ℃; MS 512.17969[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.47(s,1H),7.42–7.37(m,2H),7.30–7.22(m,6H),7.16–7.11(m,1H),7.08–7.01(m,4H),3.80(s,3H),3.80(s,3H),3.73(s,2H),2.75(s,3H)。

Example 12: preparation of 6-benzyl-5-hydroxy-8-methyl-1, 3-di-o-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA)

Step I: 40mL of methylene chloride-dissolved solid phosgene (9.5 g,32 mmol) was weighed into a 500mL round bottom flask, o-toluidine (8.57 g,80 mmol) was weighed into 40mL of methylene chloride, and was dropped into the flask with a dropping funnel at room temperature over 30min, triethylamine (20.24 g,0.2 mol) was then weighed into 50mL of methylene chloride, and was dropped into the flask over 30min, o-toluidine (8.57 g,80 mmol) was again weighed into 40mL of methylene chloride, and was dropped into the flask again as described above. After the completion of the dripping, the reaction was stirred for 30min to monitor that the o-toluidine was completely reacted. About 3/4 of the volume of the methylene chloride was distilled off under reduced pressure, and a large amount of solid was produced after stirring with 5% HCl solution for 5 to 10 minutes, and the solid was filtered off, repeatedly washed with diethyl ether, and dried to obtain 1, 3-diphthalic urea as a white solid in a yield of 10.57g and a yield of 54.98%.

Step II: 1, 3-Di-O-tolylurea (4.81 g,20 mmol), malonic acid (2.7 g,26 mmol), phosphorus oxychloride (3.4 g,22 mmol) and 15mL acetonitrile were weighed into a 35mL sealed tube. Sealing and heating to 120 ℃ for reaction for 1h, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in the sealed tube into a eggplant-shaped bottle, distilling under reduced pressure to remove all solvents, adding 50mL of 2mol/L NaOH and 20mL of ethyl acetate, stirring and dissolving. The organic phases were extracted three more times with 2mol/L aqueous NaOH, the aqueous layers were combined, the aqueous layer was extracted once with a small amount of ethyl acetate, and the remaining aqueous layer was pH-adjusted with hydrochloric acid to yield a large amount of solids. The solid was filtered off, the filter cake was washed with water and dried to give 5.01g of 1, 3-bis (2-methylphenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione as an off-white solid in 81.24% yield.

Step III: 1, 3-bis (2-methylphenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione (5.00 g,16.2 mmol), phosphorus oxychloride (4.92 g,32.4 mmol) and 20mL acetonitrile were weighed into a 125mL sealed tube. Sealing and heating to 120 ℃ for reaction for 3 hours, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in a sealed tube into a eggplant-shaped bottle, decompressing and distilling to remove all solvents, adding a small amount of ethanol to dissolve the mixture, adding water to separate out solids, filtering out the solids, washing a filter cake with water, and drying to obtain 4.93g of yellow solid 6-chloro-1, 3-bis (2-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione with the yield of 93.11%.

Step IV: 6-chloro-1, 3-bis (2-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.27 g,10 mmol), 40% aqueous methylamine (1.28 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask, stirred and refluxed for 8 hours, and then the reaction was complete. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-methylamino-1, 3-bis (2-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 3.06g, 95.23%.

Step V: weighing 6-methylamino-1, 3-bis (2-methylphenyl) pyrimidine-2, 4 (1H, 3H) -dione (1.61 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating jacket, refluxing for 40min, after TLC monitoring the reaction completion, pouring the reaction solution into 30mL petroleum ether, precipitating a large amount of solid, suction filtering, drying, and purifying by column chromatography to obtain pure 6-benzyl-5-hydroxy-8-methyl-1, 3-bis (2-methylphenyl) pyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA), a white solid, 1.02g yield 42.54%; m.p.:97.0-108.4 ℃; MS 480.18936[ M+H ]] ⁺ ； ¹ H NMR(400MHz,)δ12.51(s,1H),7.47(d,J＝7.8Hz,1H),7.35-7.44m,4H),7.23(dd,J＝8.4,6.6Hz,5H),7.13–7.15(m,2H),2.66(s,2H),2.64(s,3H),2.30(s,6H)。

Example 13: preparation of 6-benzyl-1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 13)

Step I: 40mL of methylene chloride-dissolved solid phosgene (9.5 g,32 mmol) was weighed into a 500mL round bottom flask, p-fluoroaniline (8.89 g, 80 mmol) was weighed into 40mL of methylene chloride, and was dropped into the flask with a dropping funnel at room temperature over 30 minutes, triethylamine (20.24 g,0.2 mol) was then weighed into 50mL of methylene chloride, and was dropped into the flask over 30 minutes, p-fluoroaniline (8.89 g, 80 mmol) was again weighed into 40mL of methylene chloride, and was dropped into the flask again as described above. After the completion of the dripping, the reaction was stirred for 30min to monitor that the reaction of the p-fluoroaniline was complete. About 3/4 of the volume of methylene chloride was distilled off under reduced pressure, and after stirring with 5% HCl solution for 5-10min, a large amount of solids were produced, the solids were filtered off, repeatedly washed with diethyl ether, and dried to give 1, 3-di-p-fluorobenzourea as a white solid in a yield of 18.5g, 93.16%.

Step II: 1, 3-Di-p-fluorobenzourea (4.96 g,20 mmol), malonic acid (2.7 g,26 mmol), phosphorus oxychloride (3.4 g,22 mmol) and 15mL acetonitrile were weighed into a 35mL sealed tube. Sealing and heating to 120 ℃ for reaction for 1h, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in the sealed tube into a eggplant-shaped bottle, distilling under reduced pressure to remove all solvents, adding 50mL of 2mol/L NaOH and 20mL of ethyl acetate, stirring and dissolving. The organic phases were extracted three more times with 2mol/L aqueous NaOH, the aqueous layers were combined, the aqueous layer was extracted once with a small amount of ethyl acetate, and the remaining aqueous layer was pH-adjusted with hydrochloric acid to yield a large amount of solids. The solid was filtered off, the filter cake was washed with water and dried to give 3.87g of 1, 3-bis (4-fluorophenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione as an off-white solid in 61.18% yield.

Step III: 1, 3-bis (4-fluorophenyl) pyrimidine-2, 4,6 (1H, 3H, 5H) -trione (5.12 g,16.2 mmol), phosphorus oxychloride (4.92 g,32.4 mmol) and 20mL acetonitrile were weighed into a 125mL sealed tube. Sealing and heating to 120 ℃ for reaction for 3 hours, after monitoring that the raw materials are reacted completely, pouring the reaction liquid in a sealed tube into a eggplant-shaped bottle, decompressing and distilling to remove all solvents, adding a small amount of ethanol to dissolve the mixture, adding water to separate out solids, filtering out the solids, washing a filter cake with water, and drying to obtain yellow solid of 5.12g of 6-chloro-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione with the yield of 94.43 percent.

Step IV: 6-chloro-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.35 g,10 mmol), 40% aqueous methylamine (1.28 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask, stirred and refluxed for 8 hours, and then the reaction was complete. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-methylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 3.28g, 99.60%.

Step V: weighing 6-methylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -diketone (1.65 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating jacket, refluxing for 40min, after TLC monitoring the reaction of the raw materials, pouring the reaction solution into 30mL petroleum ether to separate a large amount of solids, suction filtering, drying, and purifying by column chromatography to obtain pure 6-benzyl-1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 16), a white solid, 1.21g yield, 49.64% yield; m.p.:136.4-148.7 ℃; MS 510.12143[ M+Na ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.31(s,1H),7.59–7.52(m,2H),7.44–7.32(m,6H),7.29–7.20(m,4H),7.17–7.11(m,1H),3.74(s,2H),2.76(s,3H)。

Example 14: preparation of 6-benzyl-8-butyl-1, 3-bis (4-fluorophenyl) -5-hydroxypyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 14)

The compound 6-chloro-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione was prepared by the method of example 13.

Step IV: 6-chloro-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.35 g,10 mmol), n-butylamine (1.09 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask and stirred to reflux for 8 hours to complete the reaction. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-butylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 2.48g, 82.66%.

Step V: weighing 6-butylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -diketone (1.86 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating sleeve, refluxing for 40min, after TLC monitoring the reaction of the raw materials, pouring the reaction solution into 30mL petroleum ether to separate a large amount of solids, suction filtering, drying and purifying by column chromatography to obtain a pure product of 6-benzyl-8-butyl-1, 3-bis (4-fluorophenyl) -5-hydroxypyrido [2,3-d ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 17), a white solid, 1.03g yield, 38.90%; m.p.:104.8-107.1 ℃; MS 530.18634[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.42(s,1H),7.64–7.56(m,2H),7.47–7.38(m,4H),7.37–7.31(m,2H),7.27–7.21(m,4H),7.17–7.10(m,1H),3.75(s,2H),3.48(t,J＝7.6Hz,2H),1.10–1.03(m,2H),0.89–0.93(m,2H),0.70(t,J＝7.2Hz,3H)。

Example 15: preparation of 6-benzyl-8-cyclopropyl-1, 3-bis (4-fluorophenyl) -5-hydroxypyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 15)

Step IV: 6-chloro-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.35 g,10 mmol), cyclopropylamine (0.85 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask and stirred to reflux for 8 hours to complete the reaction. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-cyclopropylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 2.77g, 77.95%.

Step V: weighing 6-cyclopropylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -diketone (1.78 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating sleeve, refluxing for 40min, after TLC monitoring the reaction of the raw materials, pouring the reaction solution into 30mL petroleum ether, precipitating a large amount of solid, suction filtering, drying and purifying by column chromatography to obtain a pure product of 6-benzyl-8-cyclopropyl-1, 3-bis (4-fluorophenyl) -5-hydroxypyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA), a white solid, 0.89g yield 34.66%; m.p.:225.9-28.2 ℃; MS 514.15637[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.17(s,1H),7.54(dd,J＝8.8,4.8Hz,2H),7.42(dd,J＝8.8,5.1Hz,2H),7.39–7.18(m,8H),7.14(dd,J＝8.0,5.0Hz,1H),3.71(s,2H),1.64(p,J＝5.4Hz,1H),0.80(d,J＝6.0Hz,4H)。

Example 16: preparation of 6-benzyl-1, 3-bis (4-fluorophenyl) -5-hydroxy-8- (3-morpholinopropyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA)

Step IV: 6-chloro-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.35 g,10 mmol), N-aminopropyl morpholine (2.16 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask and stirred to reflux for 8 hours before reaction was complete. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-morpholinopropionylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 2.32g, 54.15%.

Step V: weighing 6-morpholinopropionyl-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -diketone (2.14 g,5 mmol), diethyl benzyl malonate (1.50 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating sleeve, refluxing for 40min, after TLC monitoring the reaction of the raw materials, pouring the reaction solution into 30mL petroleum ether, precipitating a large amount of solid, suction filtering, drying, and purifying by column chromatography to obtain a pure product of 6-benzyl-1, 3-bis (4-fluorophenyl) -5-hydroxy-8- (3-morpholinopropyl) pyrido [2,3-d ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 19), a white solid, 1.03g yield 34.30%; m.p.:181.3-181.6 ℃; MS 601.22611[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.14(s,1H),7.41–7.55(m,4H),7.29–7.40(m,4H),7.17–7.27(m,4H),7.11–7.17(m,1H),3.93(t,J＝6.5Hz,2H),3.80(s,2H),3.51(t,J＝4.5Hz,4H),2.18(t,J＝4.6Hz,4H),2.05(t,J＝7.2Hz,2H),1.56(p,J＝6.8Hz,2H)。

Example 17: preparation of 1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 17)

The compound 6-methylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione was prepared by the method of example 13.

Step V: weighing 6-methylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -diketone (1.65 g,5 mmol), diethyl malonate (0.96 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating jacket, refluxing for 40min, after TLC monitoring the reaction completion, pouring the reaction solution into 30mL petroleum ether, precipitating a large amount of solid, suction filtering, drying, and purifying by column chromatography to obtain pure 1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA), a white solid, 1.39g yield, 69.97% yield; m.p.:246.3-253.6 ℃; MS 398.09290[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.00(s,1H),7.60–7.54(m,2H),7.43–7.34(m,6H),5.63(s,1H),2.73(s,3H)。

Example 18: preparation of 8-cyclopropyl-1, 3-bis (4-fluorophenyl) -5-hydroxy-6- (2-methylbenzyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA)

Step IV: 6-chloro-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione (3.34 g,10 mmol), cyclopropylamine (0.85 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask and stirred to reflux for 8 hours to complete the reaction. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-cyclopropylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 2.77g, 77.95%.

Step V: weighing 6-cyclopropylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione (1.78 g,5 mmol), diethyl 2- (2-methylbenzyl) malonate (1.58 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating sleeve, refluxing for 40min, pouring the reaction solution into 30mL petroleum ether after TLC monitoring the reaction completion, precipitating a large amount of solid, suction filtering, drying and purifying by column chromatography to obtain a pure product of 8-cyclopropyl-1, 3-bis (4-fluorophenyl) -5-hydroxy-6- (2-methylbenzyl) pyrido [2, 3-d)]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 21), a white solid, 0.95g yield 36.02%; m.p.:133.2-140.6 ℃; MS 528.17218[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.16(s,1H),7.62–7.51(m,2H),7.48–7.40(m,2H),7.39–7.28(m,4H),7.16–7.09(m,1H),7.09–6.95(m,3H),3.65(s,2H),2.36(s,3H),1.63-1.67(m,1H),0.81(dd,J＝12.1,6.0Hz,4H)。

Example 19: preparation of 1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methyl-6- (2-methylbenzyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 19)

Step V: weighing 6-methylamino-1, 3-bis (4-fluorophenyl) pyrimidine-2, 4 (1H, 3H) -dione (1.65 g,5 mmol), diethyl 2- (2-methylbenzyl) malonate (1.58 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating sleeve, refluxing for 40min, after TLC monitoring the reaction completion, pouring the reaction solution into 30mL petroleum ether, precipitating a large amount of solid, suction filtering, drying, and purifying by column chromatography to obtain a pure product of 1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methyl-6- (2-methylbenzyl) pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA), a white solid, 0.85g yield, 33.90%; m.p.:118.8-125.3 ℃; MS 502.15601[ M+H ] ] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.30(s,1H),7.62–7.54(m,2H),7.46–7.32(m,6H),7.08–7.16(m,1H),7.07–7.01(m,3H),3.69(s,2H),2.77(s,3H),2.37(s,3H)。

Example 20: preparation of 6-benzyl-8-cyclopropyl-5-hydroxy-1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 20)

Step I: 40mL of methylene chloride-dissolved solid phosgene (9.5 g,32 mmol) was weighed into a 500mL round bottom flask, aniline (7.45 g,80 mmol) was weighed into 40mL of methylene chloride, and it was dropped into the bottle with a dropping funnel at room temperature over 30min, triethylamine (20.24 g,0.2 mol) was then weighed into 50mL of methylene chloride, and it was dropped into the bottle over 30min, aniline (7.4 g,80 mmol) was again weighed into 40mL of methylene chloride, and it was dropped into the bottle again as described above. After the completion of the dripping, the reaction was stirred for 30min to monitor that the reaction of the p-fluoroaniline was complete. About 3/4 of the volume of the methylene chloride was distilled off under reduced pressure, and a large amount of solid was produced after stirring with 5% HCl solution for 5-10min, and the solid was filtered off, repeatedly washed with diethyl ether, and dried to give 1, 3-diphenylurea as a white solid in a yield of 16.17g and a yield of 93.25%.

Step II: 1, 3-diphenylurea (4.25 g,20 mmol), malonic acid (2.7 g,26 mmol), phosphorus oxychloride (3.4 g,22 mmol) and 15mL acetonitrile were weighed into a 35mL sealed tube. Sealing and heating to 120 ℃ for reaction for 1h, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in the sealed tube into a eggplant-shaped bottle, distilling under reduced pressure to remove all solvents, adding 50mL of 2mol/L NaOH and 20mL of ethyl acetate, stirring and dissolving. The organic phases were extracted three more times with 2mol/L aqueous NaOH, the aqueous layers were combined, the aqueous layer was extracted once with a small amount of ethyl acetate, and the remaining aqueous layer was pH-adjusted with hydrochloric acid to yield a large amount of solids. The solid was filtered off, the filter cake was washed with water and dried to give 3.75g of 1, 3-diphenylpyrimidine-2, 4,6 (1H, 3H, 5H) -trione as an off-white solid in 66.90% yield.

Step III: 1, 3-Diphenyl pyrimidine-2, 4,6 (1H, 3H, 5H) -trione (4.54 g,16.2 mmol), phosphorus oxychloride (4.92 g,32.4 mmol) and 20mL acetonitrile were weighed into a 125mL sealed tube. Sealing and heating to 120 ℃ for reaction for 3 hours, after monitoring that the raw materials are completely reacted, pouring the reaction liquid in a sealed tube into a eggplant-shaped bottle, decompressing and distilling to remove all solvents, adding a small amount of ethanol to dissolve the mixture, adding water to separate out solids, filtering out the solids, washing a filter cake with water, and drying to obtain 4.58g of yellow solid 6-chloro-1, 3-diphenyl pyrimidine-2, 4 (1H, 3H) -diketone, wherein the yield is 94.64%.

Step IV: 6-chloro-1, 3-diphenylpyrimidine-2, 4 (1H, 3H) -dione (2.99 g,10 mmol), cyclopropylamine (1.10 g,15 mmol), triethylamine (2.22 g,20 mmol) and 20mL ethanol were weighed into a 50mL round bottom flask and reacted completely after stirring and refluxing for 8 hours. Most of the ethanol was distilled off under reduced pressure, and diethyl ether was added to stir out a solid. The solid was filtered off, washed with diethyl ether and dried to give 6-cyclopropylamino-1, 3-diphenylpyrimidine-2, 4 (1H, 3H) -dione as a yellow solid in a yield of 2.54g, 79.53%.

Step V: weighing 6-cyclopropylamino-1, 3-diphenyl pyrimidine-2, 4 (1H, 3H) -diketone (1.60 g,5 mmol), diethyl benzylmalonate (1.50 g,6 mmol) and 15g diphenyl ether in a 100mL three-neck round bottom flask, heating to 256 ℃ on a heating sleeve, refluxing for 40min, after TLC monitoring the reaction of the raw materials, pouring the reaction solution into 30mL petroleum ether to separate a large amount of solid, suction filtering, drying, and purifying by column chromatography to obtain pure 6-benzyl-8-cyclopropyl-5-hydroxy-1, 3-diphenyl pyrido [2,3-d ] ]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA), a white solid, 0.85g yield, 35.60% yield; m.p.:238.2-241.3 ℃; MS:478.17505[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.24(s,1H),7.53–7.43(m,8H),7.40–7.35(m,2H),7.27–7.21(m,4H),7.17–7.11(m,1H),3.71(s,2H),1.58–1.49(m,1H),0.84–0.73(m,4H)。

Example 21: preparation of 8-cyclopropyl-5-hydroxy-6- (2-methylbenzyl) -1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA 21)

The compound 6-cyclopropylamino-1, 3-diphenylpyrimidine-2, 4 (1H, 3H) -dione was prepared by the method of example 35.

Step V: weighing 6-cyclopropylamino-1, 3-diphenyl pyrimidine-2, 4 (1H, 3H) -diketone (1.60 g,5 mmol), diethyl 2- (2-methylbenzyl) malonate (1.58 g,6 mmol) and 15g diphenyl ether in a 100mL three-neck round bottom flask, heating to 256 ℃ on a heating sleeve, refluxing for 40min, after TLC monitoring the reaction of the raw materials, pouring the reaction solution into 30mL petroleum ether, precipitating a large amount of solid, suction filtering, drying and purifying by column chromatography to obtain a pure product of 8-cyclopropyl-5-hydroxy-6- (2-methylbenzyl) -1, 3-diphenyl pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA), a white solid, 0.92g yield 37.43%; m.p.:276.6-279.3 ℃; MS 492.19162[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.24(s,1H),7.55–7.43(m,8H),7.41–7.37(m,2H),7.16–7.09(m,1H),7.08–6.96(m,3H),3.66(s,2H),2.36(s,3H),1.55(tt,J＝7.0,4.0Hz,1H),0.92–0.82(m,2H),0.80–0.68(m,2H)。

Example 22: preparation of 5-hydroxy-8-methyl-6- (2-methylbenzyl) -1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione (XQA)

The compound 6-methylamino-1, 3-diphenylpyrimidine-2, 4 (1H, 3H) -dione was prepared by the method of example 30.

Step V: weighing 6-methylamino-1, 3-diphenyl pyrimidine-2, 4 (1H, 3H) -diketone (1.47 g,5 mmol), diethyl 2- (2-methylbenzyl) malonate (1.58 g,6 mmol) and 15g diphenyl ether in a 100mL three-necked round bottom flask, heating to 256 ℃ on a heating jacket, refluxing for 40min, after TLC monitoring the reaction completion, pouring the reaction solution into 30mL petroleum ether to separate a large amount of solid, suction filtering, drying, and purifying by column chromatography to obtain pure 5-hydroxy-8-methyl-6- (2-methylbenzyl) -1, 3-diphenyl pyrido [2,3-d ]]Pyrimidine-2, 4,7 (1H, 3H, 8H) -trionesXQA 37), white solid, yield 1.01g, yield 43.39%; m.p.:113.9-140.3 ℃; MS 466.17529[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ12.38(s,1H),7.57–7.43(m,8H),7.41–7.35(m,2H),7.15–7.09(m,1H),7.07–7.01(m,3H),3.69(s,2H),2.73(s,3H),2.37(s,3H)。

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Pharmacological examples

Example 23: inhibitory Activity of test Compounds on MCF7, A375, SK-Mel-2 cell proliferation

(1) Experimental materials

Cell line: MCF7, A375, SK-Mel-2 cells were plated in 96-well plates at densities of 4000, 5000, 4000 per well, 200ul per well, 24h later.

Target compounds numbered XQA 01-XQA: dissolving in DMSO, diluting with culture solution to obtain six different concentrations of 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, and 3.125 μM, and storing at-20deg.C until the final concentration of DMSO in culture solution is lower than 0.1%.

Positive control drug: 5-Fluorouracil (5-Fu, fluoraracil).

MTT: the solution was dissolved at 2mg/mL in PBS and stored at-20 ℃.

(2) Experimental method

MCF7, A375 and SK-Mel-2 cells are selected to evaluate the antitumor proliferation activity of the samples for test by MTT method. MCF7, A375The SK-Mel-2 cell line was cultured on DMEM medium containing 10% calf serum (FBS). Cells were pooled when they had proliferated to 80-90% and then subcultured for no more than 20 passages, and then allowed to acclimate for 24 hours before the next treatment. These cells were plated onto 96-well plates and then plated onto plates containing 5% CO ₂ Culturing in incubator at 37 deg.c until the cell adhesion is complete. After 24 hours, various concentrations of the inventive representative compound were added. After further culture for 24 hours, MTT (2 mg/mL) was added thereto and the culture was continued for 4 hours. The culture medium was removed, the crystals were dissolved in DMSO and absorbance was measured at 570nm wavelength using a microplate reader (Thermo Multiskan GO, thermo Fisher, usa). According to the formula: cell growth inhibition ratio= (1-drug group OD value/control group OD value) ×100%, calculating cell growth inhibition ratio at corresponding concentration, calculating IC corresponding to the test compound according to different concentrations of the test compound and inhibition ratio log curve to cells ₅₀ Values. Representative compounds of the present invention were determined as described above.

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Of the 22 compounds obtained above, most showed moderate tumor cell proliferation inhibition activity against MCF-7, A375 and SK-MEL-2 cell lines, wherein XQA09 showed proliferation inhibition activity against both malignant melanoma cells A375 and SK-MEL-2 superior to that of the positive control, IC ₅₀ As low as 9.92.+ -. 0.52. Mu.M and 8.80.+ -. 0.53. Mu.M.

Formulation examples

The following formulation examples merely illustrate the scope of the invention, but are not to be construed as limiting in any way. The active compounds described in the examples below refer to the compounds XQA to XQA22 prepared in the examples above.

Example 24: tablet formulation

25-1000mg of active compound, 45mg of starch, 35mg of microcrystalline cellulose, 4mL of polyvinylpyrrolidone (10% aqueous solution), 4.5mg of sodium carboxymethylcellulose, 0.5mg of magnesium stearate and 1mg of talcum.

Example 25: suspending agent formula

Active compound 0.1-1000mg, sodium carboxymethylcellulose 50mg, syrup 1.25mg, sodium benzoate 0.1mg, flavoring agent 25mg, colorant 5mg, and pure water to 5mL.

Example 26: aerosol formulation

0.25mg of active compound, 25-75mL of ethanol, and 70mg of propellant 22 (chlorodifluoromethane).

Example 27: suppository formula

250mg of active compound and 2000mL of saturated fatty acid glyceride.

Example 28: injectable formulation

50mg of active compound, 1000mL of isotonic saline solution.

Example 29: ointment formula

Micronizing active compound 0.025g, liquid paraffin 10g, and softening white wax to 100g.

Example 30: ointment formula

0.025g of active compound, 5g of propylene glycol, 5g of sorbitan sesquioleate, 10g of liquid paraffin and adding white wax to 100g.

Example 31: oil-in-water cream formulation

Active compound 0.025g, hexadecanol 5g, glyceryl monostearate 5g, liquid paraffin 10g, cetyl polyoxyethylene ether 2g, citric acid 0.1g, sodium citrate 0.2g, propylene glycol 35g, and water to 100g.

Example 32: oil-in-water cream formulation

Micronizing active compound 0.025g, soft white wax 15g, liquid paraffin 5g, hexadecanol 5g,Sorbimacrogol stearate (Tween 65 of specific pharmaceutical adjuvant grade) 2g, sorbitan monostearate 0.5g, sorbic acid 0.2g, citric acid 0.1g, sodium citrate 0.2g, and water to 100g.

Example 33: water-in-oil cream formulation

Active compound 0.025g, white soft wax 35g, liquid paraffin 5g, sorbitan sesquioleate 5g, sorbic acid 0.2g, citric acid 0.1g, sodium citrate 0.2g, and water to 100g.

Example 34: lotion formulation

Active compound 0.25g, isopropanol 0.5mL, carboxyvinyl polymer 3mg, naOH 2mg, add water to 1g.

Example 35: suspension formulations for injection

10mg of active compound, 7mg of sodium carboxymethyl cellulose, 7mg of NaCl, 0.5mg of polyoxyethylene (20) sorbitan monooleate, 8mg of benzyl alcohol and 1mL of sterile water.

Example 36: aerosol formulation for oral and nasal inhalation

0.1% w/w active compound, 0.7% w/w sorbitan trioleate, 24.8% w/w trichlorofluoromethane, 24.8% w/w dichlorotetrafluoroethane and 49.6% w/w dichlorodifluoromethane.

Example 37: atomized solution formulation

7mg of active compound, 5mg of propylene glycol and 10g of water are added.

Example 38: powder formulations for inhalation

The following mixture of ingredients was filled into a gelatin capsule, 0.1mg of micronized active compound and 20mg of lactose, and the powder was inhaled by inhalation device.

Example 39: powder formulations for inhalation

The spheroidized powder is loaded into a multi-dose powder inhaler, each dose containing 0.1mg of micronized active compound.

Example 40: powder formulations for inhalation

The spheroidized powder was loaded into a multi-dose powder inhaler, each dose containing 0.1mg of micronized active compound and 1mg of micronized lactose.

Example 41: capsule formulation

1.0mg of active compound, 321mg,Aquacoat ECD 30 6.6mg mg of small sugar ball, 0.5mg of acetyl tributyl citrate, 1.8mg of tween-80 0.1mg,Eudragit L100-55.5 mg of triethyl citrate, 8.8mg of talcum powder and 0.lmg of defoamer MMS.

Example 42: capsule seedling formula

2.0mg of active compound, 305mg,Aquocoat ECD 30 5.0mg mg of small sugar ball, 0.4mg of acetyl tributyl citrate, 80 0.14mg,Eudragit NE30D 12.6mg,Eudragit S100 12.6mg of tween and 0.6 mg of talcum powder.

Example 43: enema formula

2mg of active compound, 25mg of sodium carboxymethyl cellulose, 0.5mg of disodium ethylenediamine tetraacetate, 0.8mg of methylparaben, 0.2mg of propylparaben, 7mg of sodium chloride, 1.8mg of citric acid, 0.01mg of tween-80 and 1mL of pure water are added.

Example 44: liposome-containing formulations

A. The preparation of the instillation formula:

dipalmitoyl lecithin (45 mg), dimyristoyl lecithin (7 mg), dipalmitoyl phosphatidylglycerol (1 mg) and active compound (5 mg) were placed in a glass tube, all components were dissolved in chloroform, and N was used ₂ After evaporating most of the solvent, a lipid film was formed on the surface of the glass tube, an aqueous solution (0.9% NaCl) was added to the lipid, and liposomes were formed at a temperature higher than the inversion temperature of the lipid, and the resulting suspension contained liposomes ranging in size from very small vesicles to 2. Mu.m.

B. Preparation of the formulation for inhalation:

liposomes were prepared as in example A, wherein the aqueous solution contained 10% lactose at a lactose to lipid ratio of 7:3. The liposome suspension was frozen with dry ice and freeze-dried, and the dried product was micronised, the mass average aerodynamic diameter (MMAD) of the resulting particles being about 2 μm.

Claims

A 5-hydroxy-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the following compounds:

6-benzyl-8-butyl-5-hydroxy-1, 3-bis (4-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-5-hydroxy-8-methyl-1, 3-bis (4-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

5-hydroxy-8- (3-morpholinopropyl) -1, 3-bis (4-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-5-hydroxy-1, 3-bis (3-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-5-hydroxy-8- (3-morpholinopropyl) -1, 3-bis (3-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-5-hydroxy-8-methyl-1, 3-bis (3-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-5-hydroxy-8-methyl-1, 3-bis [4- (trifluoromethyl) phenyl ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-5-hydroxy-8-methyl-1, 3-bis [3- (trifluoromethyl) phenyl ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-5-hydroxy-1, 3-bis [4- (trifluoromethoxy) phenyl ] pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-1, 3-bis (4-chlorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-5-hydroxy-1, 3-bis (4-methoxyphenyl) -8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-5-hydroxy-8-methyl-1, 3-bis (2-methylphenyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-8-butyl-1, 3-bis (4-fluorophenyl) -5-hydroxypyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-8-cyclopropyl-1, 3-bis (4-fluorophenyl) -5-hydroxypyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-1, 3-bis (4-fluorophenyl) -5-hydroxy-8- (3-morpholinopropyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

8-cyclopropyl-1, 3-bis (4-fluorophenyl) -5-hydroxy-6- (2-methylbenzyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

1, 3-bis (4-fluorophenyl) -5-hydroxy-8-methyl-6- (2-methylbenzyl) pyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

6-benzyl-8-cyclopropyl-5-hydroxy-1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

8-cyclopropyl-5-hydroxy-6- (2-methylbenzyl) -1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1 h,3h,8 h) -trione;

5-hydroxy-8-methyl-6- (2-methylbenzyl) -1, 3-diphenylpyrido [2,3-d ] pyrimidine-2, 4,7 (1H, 3H, 8H) -trione.
2. A pharmaceutical composition comprising as an active ingredient a compound of any one of the 5-hydroxy-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidines according to claim 1 and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or diluent.
3. Use of a 5-hydroxy-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting MCF-7, a375, SK-MEL-2 tumor cell growth.
4. Use of a pharmaceutical composition according to claim 2 for the preparation of a medicament for inhibiting MCF-7, a375, SK-MEL-2 tumor cell growth.
5. Use of a 5-hydroxy-1, 3-disubstituted phenylpyrido [2,3-d ] pyrimidine compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer.
6. Use of a pharmaceutical composition according to claim 2 for the preparation of a medicament for the treatment of cancer.
7. The use according to claim 5 or 6, wherein the cancer is lung cancer, liver cancer, melanoma, colon cancer, rectal cancer, breast cancer, ovarian cancer, cervical cancer or renal cancer.