Synthesis of several furanopyrimidine-ibuprofen hybrid derivatives and their anti-tumor applications

Abstract

The application provides a synthesis method and antitumor application of several furanopyrimidine-ibuprofen hybrid derivatives, which are linked by aza-wittig reaction, intramolecular cyclization, substitution reaction, hydrolysis and acidification reaction and the like, and a fused triazole, a hydrazide, a bis-hydrazide and an oxadiazole are used as a bond bridge key, so that different series of furanopyrimidine-ibuprofen hybrid derivatives are synthesized in a simple and efficient manner. The CCK8 method in vitro pharmacodynamics test proves that the target compound has proliferation inhibition activity on A549 lung cancer cells and HepG2 liver cancer cell lines. Test results show that the target compound shows good proliferation inhibition activity on the two kinds of cells, and the structural formula is as follows:

Description

Technical Field

[0001] This invention relates to the design and synthesis of different series of furanopyrimidine-ibuprofen hybrid derivatives based on ibuprofen lead compounds and their antitumor activities. In vitro assays using the CCK8 assay to detect the inhibitory activity against the proliferation of A549 lung cancer cells and HepG2 liver cancer cell lines showed that the target compounds exhibited good inhibitory activity against both cell lines. Compounds 10h, 12a, and 13c showed the most superior activity against lung cancer cells (A549), with IC50 values ​​exceeding [value missing]. 50 The concentrations were 0.039 μM, 0.038 μM, and 0.068 μM, respectively. Compounds 10c, 13c, and 13i exhibited the best activity against hepatocellular carcinoma cells (HepG2), with IC50 values ​​of 0.039 μM, 0.038 μM, and 0.068 μM, respectively. 50 The concentrations were 0.021 μM, 0.144 μM, and 0.232 μM, respectively. All were superior to the antitumor control drug gefitinib. Background Technology

[0002] Cancer seriously threatens human health. According to statistics from the World Health Organization (WHO), there were 19.29 million new cancer cases and 9.96 million deaths worldwide in 2020. It is estimated that the number of people who die from cancer will reach 13.2 million by 2030 [1]. In the process of cancer treatment, in order to increase the efficacy of drugs or reduce the toxic side effects of drugs, combination therapy is usually adopted. Studies have shown that the development of cancer is closely related to inflammation. The continuous occurrence of inflammatory response plays an important role in the initiation, promotion and metastasis of cancer [2]. Therefore, anti-inflammatory therapy is often accompanied by cancer treatment. Anti-inflammatory drugs can reduce the incidence of tumors when administered as a preventive treatment and can slow down the progression of tumors and reduce mortality when administered as a treatment [3]. However, anti-inflammatory therapy cannot kill tumor cells and needs to be combined with anti-tumor drugs for conventional treatment [4]. Therefore, we want to design a new small molecule compound that combines anti-cancer drugs and anti-inflammatory drugs in order to achieve the effect of "1+1>2".

[0003] Ibuprofen, as a nonsteroidal anti-inflammatory drug, exhibits good anti-inflammatory and analgesic effects by non-selectively inhibiting cyclooxygenase (COX) and reducing prostaglandin synthesis. It is commonly used clinically to treat headaches, toothaches, etc. [5,6]. However, long-term use of ibuprofen can lead to serious gastrointestinal damage and renal insufficiency. These side effects are mainly related to the free carboxylic acid in the ibuprofen structure and its inhibitory effect on COX-1 [7]. In addition, studies have shown that COX-2 is overexpressed in gastric cancer, liver cancer, lung cancer, and prostate cancer, and its inhibition can reduce the risk of cancer development [8]. Therefore, in recent years, structural modification of ibuprofen lead compounds has received much attention. Modification of the carboxyl group of ibuprofen can improve the selectivity of ibuprofen for COX-2. The carboxyl group can be modified into ester or amide groups using the prodrug principle to reduce the irritation of the gastrointestinal tract by the carboxyl group, or ibuprofen can be linked to drugs with similar or different pharmacological effects by covalent bonds using the combination principle to enhance the anti-inflammatory activity of ibuprofen or generate new pharmacological activities [9-11].

[0004] In addition, furanopyrimidine, as an important class of heterocyclic compounds, is a biological isostere of purine in structure and is often used as a template for the design of antitumor drugs. It has a variety of biological activities such as anticancer, anti-inflammatory, antibacterial, antiviral, antioxidant and platelet aggregation inhibition [12-16], and plays an important role in different diseases. In recent years, it has attracted much attention for its antitumor effect.

[0005] Active substructure splicing, as an effective tool for the design of new entities of potent antitumor drugs, provides new ideas for the development of multi-target drugs

[17] . According to the splicing principle, two or more drug pharmacophores are connected by chemical bonds to obtain a new molecule. The spliced ​​molecule usually inherits the pharmacological activity of the pharmacophores involved in the splicing, while reducing the toxic side effects of the pharmacophores

[18] .

[0006] Based on the above reasons, we designed and synthesized three series of furanopyrimidine-ibuprofen hybrid derivatives based on ibuprofen lead compounds: furanopyrimidine-triazole-ibuprofen hybrid derivatives (10a-10h and 12a-12b); furanopyrimidine-hydrazide (diacylhydrazide)-ibuprofen hybrid derivatives (11a-11g and 13a-13m); and furano[2,3-d]pyrimidine-1,3,4-oxadiazole-ibuprofen hybrid derivatives (13a-13m). The inhibitory activity of these three target compounds against the proliferation of A549 lung cancer cells and HepG2 liver cancer cell lines was tested using the CCK8 assay. The results showed that the target compounds exhibited good inhibitory activity against both cell lines, with compounds 10h, 12a, and 13c showing the best activity against lung cancer cells (A549), with IC50 values ​​of [missing data]. 50The concentrations were 0.039 μM, 0.038 μM, and 0.068 μM, respectively. Compounds 10c, 13c, and 13i exhibited the best activity against hepatocellular carcinoma cells (HepG2), with IC50 values ​​of 0.039 μM, 0.038 μM, and 0.068 μM, respectively. 50 The effective concentrations were 0.021 μM, 0.144 μM, and 0.232 μM, respectively, all of which were superior to the control drug gefitinib.

[0007] References

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[0021]

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[0024]

[17] Kang Lu. Synthesis of coumarin-chalcone hybrid derivatives and their effects on cholinesterase [D]. Hunan University, 2018.

[0025]

[18] Liu Min, Zhang Wenjun, Gao Ning. The principle of combination and its application in new drug design [J]. Chemical Reagents, 2009, 31(10):795-797. Summary of the Invention

[0026] This invention provides a method for synthesizing several furanopyrimidine-ibuprofen hybrid derivatives and their antitumor applications. These compounds use ibuprofen as a lead compound and ethyl 2-amino-5-methyl-furan-3,4-dicarboxylate as starting materials. Using reactions such as the aza-Wittig reaction, under the catalysis of sodium ethoxide, phosphorus oxychloride, and potassium carbonate, furanopyrimidine-triazole-ibuprofen hybrid derivatives (10a-10h and 12a-12b) and furanopyrimidine-hydrazide (dihydrazide)-ibuprofen hybrid derivatives (11a-11g and 13a-13m) were designed and synthesized. In vitro pharmacodynamic experiments using the CCK8 method demonstrated the inhibitory activity of the target compounds on the proliferation of A549 lung cancer cells and HepG2 liver cancer cell lines.

[0027] 1. The different series of furanopyrimidine-ibuprofen hybrid derivatives of the present invention are characterized by the following structure of the compounds:

[0028] 1.1 Furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-ibuprofen heterozygous derivatives (10a-10h)

[0029]

[0030] 1.2 Furano[2,3-d]pyrimidine-ibuprofen-hydrazide hybrid derivatives (11a-11g)

[0031]

[0032]

[0033] 1.3 Furano[2,3-d]pyrimidine-ibuprofen-diazid hybrid derivatives (13a-13m)

[0034]

[0035] 1.4 Furano[2,3-d]pyrimidine-1,3,4-oxadiazole-ibuprofen compounds (14a-14e)

[0036]

[0037] in:

[0038] Compound 10a is ethyl 2-methyl-4-one-5-phenyl-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylate.

[0039] Compound 10b is ethyl 2-methyl-4-one-5-p-tolyl-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylate.

[0040] Compound 10c is ethyl 2-methyl-4-one-5-(4-fluorophenyl)-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylate.

[0041] Compound 10d is ethyl 2-methyl-4-one-5-(3,5-dimethylphenyl)-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylate.

[0042] Compound 10e is ethyl 2-methyl-4-one-5-m-tolyl-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylate.

[0043] Compound 10f is ethyl 2-methyl-4-one-5-(5-chloro-2-methylphenyl)-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylate.

[0044] Compound 10g is ethyl 2-methyl-4-one-5-(3-chloro-4-methylphenyl)-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylate.

[0045] Compound 10h is ethyl 2-methyl-4-one-5-(4-trifluoromethoxyphenyl)-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylate.

[0046] Compound 11a is ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(m-methylphenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate.

[0047] Compound 11b is ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(p-methylphenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate.

[0048] Compound 11c is ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(3,5-dimethylphenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate.

[0049] Compound 11d is ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(3,4-dichlorophenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate.

[0050] Compound 11e is ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(4-trifluoromethoxyphenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate.

[0051] Compound 11f is ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(4-chlorophenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate.

[0052] Compound 11g is ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(4-fluorophenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate.

[0053] Compound 12a is ethyl 8-methyl-5-(phenylamino)-3-(1-(4-isobutylphenyl)ethyl)furano[3,2-e][1,3,4]triazolo[1,5-c]pyrimidine-9-carboxylate.

[0054] Compound 12b is ethyl 8-methyl-5-(5-chloro-2-methylphenylamino)-3-(1-(4-isobutylphenyl)ethyl)furano[3,2-e][1,3,4]triazolo[1,5-c]pyrimidine-9-carboxylate.

[0055] Compound 13a is N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-morpholin-2-(phenylamino)furano[2,3-d]pyrimidine-5-carbazide

[0056] Compound 13b is N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-morpholino-2-(p-phenylamino)furano[2,3-d]pyrimidin-5-carbazide.

[0057] Compound 13c is N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-(4-methylpyrazin-1-yl)-2-(phenylamino)furano[2,3-d]pyrimidin-5-carbonylhydrazine

[0058] Compound 13d is N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-diethylamino-2-(p-phenylamino)furano[2,3-d]pyrimidine-5-carbazide.

[0059] Compound 13e is N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-(4-methylpyrazin-1-yl)-2-(4-(trifluoromethoxy)phenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine

[0060] Compound 13f is N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-di-n-propylamino-2-(p-phenylamino)furano[2,3-d]pyrimidine-5-carbazide.

[0061] Compound 13g is N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-diethylamino-2-(phenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine.

[0062] Compound 13h is N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-morpholino-2-(4-chlorophenylamino)furano[2,3-d]pyrimidine-5-carbazide.

[0063] Compound 13i is N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-(4-methylpyrazin-1-yl)-2-(5-chloro-2-methylphenylamino)furano[2,3-d]pyrimidin-5-carbonylhydrazine

[0064] Compound 13j is N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-morpholino-2-(3-chloro-4-methylphenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine

[0065] Compound 13k is N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-morpholino-2-(m-methylphenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine.

[0066] Compound 13l is N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-diethylamino-2-(5-chloro-2-methylphenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine

[0067] Compound 13m is N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-(4-methylpyrazin-1-yl)-2-(p-methylphenylamino)furano[2,3-d]pyrimidin-5-carbonylhydrazine

[0068] Compound 14a is 5-(5-(1-(4-isobutylphenyl)ethyl)-1,3,4-oxadiazolyl-2-yl)-6-methyl-4-morpholino-Np-p-phenylfurano[2,3-d]pyrimidin-2-amine

[0069] Compound 14b is N4,N4-diethyl-5-(5-(1-(4-isobutylphenyl)ethyl)-1,3,4-oxadiazolyl-2-yl)-6-methyl-N2-phenylfurano[2,3-d]pyrimidine-2,4-diamine

[0070] Compound 14c is 5-(5-(1-(4-isobutylphenyl)ethyl)-1,3,4-oxadiazolyl-2-yl)-6-methyl-4-morpholino-N-phenylfurano[2,3-d]pyrimidin-2-amine

[0071] Compound 14d is N-(4-chlorophenyl)-5-(5-(1-(4-isobutylphenyl)ethyl)-1,3,4-oxadiazolyl-2-yl)-6-methyl-4-morpholinylfurano[2,3-d]pyrimidin-2-amine

[0072] Compound 14e is N-(3-chloro-4-methylphenyl)-5-(5-(1-(4-isobutylphenyl)ethyl)-1,3,4-oxadiazolyl-2-yl)-6-methyl-4-morpholinylfurano[2,3-d]pyrimidin-2-amine

[0073] This invention also provides the antitumor application of several furanopyrimidine-ibuprofen hybrid derivatives, specifically: the application of three series of furanopyrimidine-ibuprofen hybrid derivatives 10a-10h, 11a-11g, 12a-12b, 13a-13m and 14a-14e in the preparation of antitumor drugs.

[0074] Furthermore, the compounds exhibited potential antitumor activity against A549 lung cancer cells and HepG2 liver cancer cells, with compounds 10h, 12a, and 13c showing the most excellent activity against lung cancer cells (A549), with an IC50 value of [missing value]. 50 The concentrations were 0.039 μM, 0.038 μM, and 0.068 μM, respectively. Compounds 10c, 13c, and 13i exhibited the best activity against hepatocellular carcinoma cells (HepG2), with IC50 values ​​of 0.039 μM, 0.038 μM, and 0.068 μM, respectively. 50 The concentrations were 0.021 μM, 0.144 μM, and 0.232 μM, respectively. All three concentrations showed superior antitumor activity compared to the control drug, gefitinib.

[0075] Beneficial effects:

[0076] This invention discloses a method for synthesizing several furanopyrimidine-ibuprofen hybrid derivatives and their antitumor applications. The method involves reactions based on an ibuprofen lead compound and a furanopyrimidine pharmacological skeleton, including aza-wittig reactions, intramolecular cyclization, substitution reactions, and hydrolysis-acidification reactions, linked by fused triazoles, acylhydrazides, diacylhydrazides, and oxadiazoles. The preparation method is simple and efficient, synthesizing different series of furanopyrimidine-ibuprofen hybrid derivatives. In vitro pharmacodynamic assays using the CCK8 assay demonstrated the inhibitory activity of the target compounds on the proliferation of A549 lung cancer cells and HepG2 liver cancer cell lines. The test results showed that the target compounds exhibited good inhibitory activity against both cell lines, with compounds 10h, 12a, and 13a showing the most excellent activity against lung cancer cells (A549), with an IC50 value of [missing value]. 50 The concentrations were 0.039 μM, 0.038 μM, and 0.068 μM, respectively. Compounds 10c, 13c, and 13i exhibited the best activity against hepatocellular carcinoma cells (HepG2), with IC50 values ​​of 0.039 μM, 0.038 μM, and 0.068 μM, respectively. 50 The effective concentrations were 0.021 μM, 0.144 μM, and 0.232 μM, respectively, all of which were superior to the control drug gefitinib. Detailed Implementation

[0077] The present invention will be further described in detail below through embodiments, but the scope of protection of the present invention is not limited to the contents described. Unless otherwise specified, the methods in the embodiments are conventional methods, and the reagents used are conventional commercial reagents or reagents prepared according to conventional methods.

[0078] The synthetic routes for the different series of furanopyrimidine-ibuprofen heterocyclic derivatives described in this invention are as follows:

[0079] 1. Synthesis of intermediates

[0080]

[0081]

[0082] 2. Synthesis of the target compound

[0083]

[0084] The different series of furanopyrimidine-ibuprofen hybrid derivatives and their uses described in this invention are mainly prepared by the following steps:

[0085] 1. Synthesis of intermediates

[0086] Preparation of intermediate ibuprofen hydrazide 2:

[0087] Following the method described in the reference, 4.12 g (20 mmol) of ibuprofen was weighed into a 100 mL round-bottom flask at room temperature. Thionyl chloride (SOCl2) was slowly added dropwise until the ibuprofen was completely dissolved. A drying tube containing soda lime was attached to the mouth of the flask to absorb the tail gas. The mixture was stirred for 24 h, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, unreacted SOCl2 was removed using a rotary evaporator to obtain a pale yellow oily liquid, ibuprofenformyl chloride 1. Product 1 was not purified. Under ice bath conditions, 30 mL of anhydrous methanol (CH3OH) was slowly added dropwise to the round-bottom flask using a separatory funnel. The mixture was stirred at room temperature for 4 h, and the reaction progress was monitored by TLC. After the reaction was complete, excess CH3OH was removed using a rotary evaporator to obtain a colorless oily liquid (i.e., ibuprofen methyl ester). Add 30 mL of anhydrous ethanol (EtOH) to the colorless liquid as a solvent, and add 5.01 g (100 mmol) of hydrazine hydrate (N2H4·H2O) dropwise while stirring. Reflux and stir in an oil bath at 70 °C for 8 h. The reaction progress is monitored by TLC. After the reaction is complete, pour the reaction system into ice water and stir. A white solid precipitates out. Filter the solid and recrystallize the filter cake with EtOH to obtain ibuprofen hydrazide 2, a white solid with a yield of 92% and mp: 82-83 °C (reference

[60] mp: 80-82 °C). Dry the solid for later use.

[0088] Preparation of intermediate 3:

[0089] Following the method described in the literature, 3.39 g (30 mmol) of ethyl cyanoacetate and 6.5 mL (45 mmol) of triethylamine were added to a 100 mL round-bottom flask, using 20 mL of ethanol as the solvent. Under ice bath conditions, 4.93 g (30 mmol) of ethyl 2-chloroacetoacetate was slowly added dropwise. After stirring for approximately 2 hours, a large amount of white solid precipitated. The reaction was continued until complete. The mixture was filtered, and the filter cake was recrystallized from EtOH:H2O (v:v = 1:1) to give ethyl 2-amino-5-methyl-furan-3,4-dicarboxylate 3, a white solid with a yield of 87%, mp: 83-84 °C (literature value: 85-86 °C). The solid was dried and stored for later use.

[0090] Preparation of intermediate 4:

[0091] Following the method described in the reference, 2.41 g (10 mmol) of ethyl 2-amino-5-methyl-furan-3,4-dicarboxylate (3), 3.93 g (15 mmol) of triphenylphosphine, and 3.56 g (15 mmol) of hexachloroethane were weighed into a 100 mL reaction flask, using 30 mL of dry acetonitrile as solvent. Under ice bath conditions, 4.2 mL (30 mmol) of triethylamine was slowly added dropwise. After the addition was complete, the reaction continued for 2 h. TLC was used to detect the complete reaction. The system was then poured into ice water and stirred, precipitating a solid. The solid was filtered, and the filter cake was recrystallized from EtOH:H2O (v:v = 2:1) to obtain phosphineimine 4, a white solid with a yield of 64%, mp: 133-135℃ (literature value: 169-170℃). The solid was dried and stored for later use.

[0092] Preparation of intermediates 5a-5j:

[0093] 5.01 g (10 mmol) of phosphine imine 4 was dissolved in 20 mL of dichloromethane, and 10 mmol of aromatic isocyanates with different substituents were added dropwise. The reaction was allowed to proceed at 0-5 °C for 20 h until complete. In a separate 100 mL flask, 15 mL of anhydrous ethanol and 1.75 g (20 mmol) of ammonia (NH3·H2O) were added. The reaction mixture was then transferred to this 100 mL flask with stirring. After a large amount of solid was produced, the mixture was filtered. The filter cake was washed with ethanol to obtain the intermediate furanopyrimidine-4-one derivative 5a-5j, a white solid, which could be used for the next reaction after drying without further purification.

[0094] Preparation of intermediates 6a-6j:

[0095] 10 mmol of the obtained intermediate furanopyrimidine derivative 5a-5j was weighed into a 50 mL round-bottom flask, and 2 mL of phosphorus oxychloride (POCl3) was added. The mixture was refluxed at 95 °C for 5 h and detected by TLC. After the reaction was complete, the reaction system was poured into ice water and stirred, producing a large amount of solid. The mixture was filtered, and the filter cake was neutralized with saturated sodium bicarbonate (NaHCO3) aqueous solution until it was weakly alkaline. The reaction was stirred for another 2 h and then filtered again. The filter cake was washed with water to obtain the intermediate 4-chloro-furanopyrimidine derivative 6a-6j, a white solid, which was dried and used in the next step of the reaction.

[0096] Preparation of intermediate 7a–7m:

[0097] In a 100 mL round-bottom flask, 10 mmol of the obtained intermediate 6a-6j and 2.76 g (20 mmol) of anhydrous potassium carbonate (K2CO3) were added. Using 30 mL of anhydrous acetonitrile as solvent, 15 mmol of a secondary amine (such as morpholine, N-methylpyrazine, diethylamine, di-n-propylamine, etc.) was added dropwise while stirring. The reaction was carried out at 75 °C for about 4 h. The reaction was monitored by TLC. After the reaction was complete, the reaction system was poured into ice water and stirred. A large amount of solid precipitated. After the ice was completely melted, the mixture was filtered. The filter cake was washed with water and ethanol to obtain intermediate 7a-7m, which was then dried for later use.

[0098] Preparation of intermediate 8a-8m:

[0099] In a 100 mL round-bottom flask, add 10 mmol of the obtained intermediate 7a-7m and 0.80 g (20 mmol) of sodium hydroxide (NaOH), and then add 50 mL of 70% ethanol solution (V). EtOH :V H2O Using a solvent of 7:3, the mixture was reacted at 75°C for about 6 hours. The reaction was monitored by TLC. After the reaction was complete, dilute hydrochloric acid was added dropwise to the system until a large amount of solid precipitated out, making the system acidic. The reaction was continued for 2 hours and then filtered. The filter cake was washed with water to obtain intermediate 8a-8m, which was then dried for later use.

[0100] 2. Synthesis of the target compound

[0101] Preparation of compound 10a-10h

[0102] Weigh out 1.00 g (2 mmol) of phosphonimine 4 and dissolve it in 10 mL of dichloromethane. Add 2 mmol of aromatic isocyanates with different substituents dropwise. Let the reaction stand at 0-5 °C for about 20 h until the reaction is complete. Add 0.44 g (2 mmol) of ibuprofen hydrazide 2 at room temperature and react for half an hour. Then, desolvate under reduced pressure until the system is oily. Add 20 mL of anhydrous ethanol to the mixture and add a few drops of anhydrous ethanol solution of sodium ethoxide (1 mol / L). Stir the reaction at room temperature until a solid precipitates. Filter to obtain a white solid. Recrystallize from CH2Cl2 / CH3CH2OH to obtain the target compound 10a-10h, a white solid.

[0103] Preparation of compound 11a

[0104] Weigh 3 mmol of the intermediate 4-chloro-furanopyrimidine derivative (6a) into a 50 mL round-bottom flask. Using 20 mL of anhydrous acetonitrile as solvent, add 1.00 g (15 mmol) of hydrazine hydrate (N2H4·H2O) dropwise while stirring. React at 60 °C for about 5 h. A large amount of white solid is generated in the system. Filter the solid and wash the filter cake with ethanol to obtain the intermediate 4-acylhydrazine-furanopyrimidine derivative 7n. Dry the solid for later use.

[0105] 0.41 g (2 mmol) of ibuprofen was weighed into a 50 mL round-bottom flask, and thionyl chloride (SOCl2) was slowly added dropwise to the ibuprofen. The mixture was stirred for 24 h, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, unreacted SOCl2 was removed by rotary evaporation to obtain a pale yellow oily liquid, ibuprofenformyl chloride 1. Without purification, 2 mmol of 4-hydrazino-furanopyrimidine derivative 7n was added, using 20 mL of dry CH2Cl2 as solvent. Anhydrous triethylamine ((C2H5)3N) was slowly added dropwise using a separatory funnel under ice bath conditions until the system became weakly alkaline. The mixture was then stirred at room temperature for about 24 h, and the reaction progress was monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation, and the solid residue was poured into ice water and stirred. A solid precipitated, which was filtered. The filter cake was recrystallized from EtOH:CH2Cl2 (V:V = 1:1) to obtain the target compound (11a), a white solid.

[0106] Preparation of compounds 11b-11g and 12a-12b

[0107] Weigh 3 mmol of the intermediate 4-chloro-furanopyrimidine derivative 6b-6i, 0.83 g (6 mmol) of anhydrous potassium carbonate (K2CO3), and 1.32 g (6 mmol) of ibuprofen hydrazide 2 into a 100 mL round-bottom flask. Use 30 mL of anhydrous acetonitrile as solvent and react at 75 °C for about 8 h. A large amount of solid precipitates out. Filter while hot and wash the filter cake with ethanol to obtain the target compounds 11b-11g and 12a-12b, which are white solids.

[0108] Preparation of compounds 13a-13m

[0109] 2 mmol of intermediate 8a-8m was weighed into a 50 mL round-bottom flask, and thionyl chloride (SOCl2) was slowly added dropwise. The mixture was stirred for about 20 h, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, excess thionyl chloride was removed, yielding intermediate furanopyrimidine formyl chloride 9a-9m. Without purification, 0.44 g (2 mmol) of ibuprofen hydrazide and 20 mL of dry CH2Cl2 were added as solvent. Anhydrous triethylamine ((C2H5)3N) was slowly added dropwise under ice bath conditions until the system became weakly alkaline. The mixture was stirred for about 4 h, and the reaction progress was monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation, and the mixture was poured into ice water and stirred. A solid precipitated, which was filtered. The filter cake was recrystallized from EtOH:CH2Cl2 (V:V = 1:1) to obtain the target compound 13a-13m.

[0110] Preparation of compounds 14a-14e

[0111] The obtained target compound 13a-13m (1 mmol) was weighed into a 50 mL round-bottom flask, and 2 mL of phosphorus oxychloride (POCl3) was added. The mixture was refluxed at 80 °C for 6 h, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction system was poured into ice water and stirred. A solid precipitated out and was filtered. The filter cake was neutralized with a saturated sodium bicarbonate (NaHCO3) aqueous solution until it was weakly alkaline. The reaction was stirred for another 2 h and then filtered again. The filter cake was washed with water, dried, and recrystallized from EtOH:CH2Cl2 (V:V = 1:1) to obtain the target compound 14a-14e, a white solid. Detailed Implementation

[0113] The present invention will be further described with reference to the embodiments, but the present invention is not limited to these embodiments;

[0114] Reagents: All reagents were commercially available analytical grade;

[0115] Example 4

[0116] Preparation of intermediates 5a-5j:

[0117] 5.01 g (10 mmol) of phosphineimine 4 obtained in Example 3 was dissolved in 20 mL of dichloromethane, and 10 mmol of aromatic isocyanates with different substituents were added dropwise. The reaction was allowed to proceed at 0-5 °C for 20 h until complete. In a separate 100 mL flask, 15 mL of anhydrous ethanol and 1.75 g (20 mmol) of ammonia (NH3·H2O) were added. The reaction mixture was then transferred to this 100 mL flask while stirring. After the reaction proceeded to produce a large amount of solid, the mixture was filtered. The filter cake was washed with ethanol to obtain the intermediate furanopyrimidine-4-one derivatives 5a-5j, a white solid.

[0118] Example 5

[0119] Preparation of intermediates 6a-6j:

[0120] 10 mmol of the intermediate furanopyrimidine derivative 5a-5j obtained in Example 4 was weighed into a 50 ml round-bottom flask, and 10 ml of phosphorus oxychloride was added. The mixture was refluxed at 95 °C for 5 h and detected by TLC. After the reaction was complete, the reaction system was poured into ice water and stirred. A large amount of solid was produced. After the ice was completely melted, the mixture was filtered. The filter cake was neutralized with saturated sodium bicarbonate solution until it was weakly alkaline. The reaction was stirred for another 2 h and then filtered. The filter cake was washed with water to obtain the intermediate 4-chloro-furanopyrimidine derivative 6a-6j, a white solid.

[0121] Example 6

[0122] Preparation of intermediate 7a-7m:

[0123] In a 100 mL round-bottom flask, 10 mmol of intermediate 6a-6j obtained in Example 5 and 2.76 g (20 mmol) of anhydrous potassium carbonate were added. Using 30 mL of anhydrous acetonitrile as solvent, 30 mmol of secondary amine (such as morpholine, N-methylpyrazine, diethylamine, di-n-propylamine, etc.) was added dropwise while stirring. The reaction was carried out at 75 °C for about 4 h. The reaction was monitored by TLC. After the reaction was complete, the reaction system was poured into ice water and stirred. A large amount of solid precipitated. After the ice was completely melted, the mixture was filtered. The filter cake was washed with water and ethanol to obtain intermediate 7a-7m.

[0124] Example 7

[0125] Preparation of intermediate 8a-8m:

[0126] In a 100 ml round-bottom flask, add 10 mmol of intermediate 7a-7m obtained in Example 6 and 0.80 g (20 mmol) of sodium hydroxide (NaOH), and then add 50 mL of 70% ethanol solution (V EtOH :V H2O Using a solvent of 7:3, the mixture was reacted at 75°C for about 6 hours. The reaction was monitored by TLC. After the reaction was complete, dilute hydrochloric acid was added dropwise to the system until a large amount of solid precipitated out, making the system acidic. The reaction was continued for 2 hours and then filtered. The filter cake was washed with water to obtain intermediate 8a-8m, a white solid.

[0127] Example 8

[0128] Preparation of target compound 10a

[0129] 1.00 g (2 mmol) of phosphonium imide 4 obtained in Example 3 was dissolved in 10 mL of dichloromethane. 0.24 g (2 mmol) of phenyl isocyanate was added dropwise. The mixture was allowed to stand at 0-5 °C for 20 h until the reaction was complete. Then, 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1 was added at room temperature. After reacting for half an hour at room temperature, the dichloromethane was removed under reduced pressure. 15 mL of anhydrous ethanol was then added as a solvent, followed by a few drops of anhydrous sodium ethoxide. The ethanol solution (1 mol / L) was stirred at room temperature until a solid precipitated. The solid was filtered to obtain a white solid. Recrystallization with CH2Cl2 / CH3CH2OH yielded the target compound 10a as ethyl 2-methyl-4-one-5-phenyl-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylate, yield: 93%, white solid, mp: 191-192℃.

[0130] 1H NMR (400MHz, CDCl3) δ (ppm): 0.85 (d, J=4.0Hz, 6H, 2×CH3), 1.21-1.30 (m, 3H, CH3), 1.51 (d, J=8.0Hz, 3H, CH3), 1.72-1.79 (m, 1H, CH), 2.34 (d, J=4.0Hz, 2H,CH2),2.45(s,3H,CH3),4.02(d,J=8.0Hz,1H,CH),4.20(q,J=8.0Hz,2H, OCH2),6.94-7.04(m,3H,ArH),7.13-7.16(m,4H,ArH),7.26(ds,s,2H,ArH). 13 C NMR (100MHz, CDCl3) δ (ppm): 14.14, 14.21, 17.44, 18.43, 22.41, 22.42, 30.12, 44.98, 58.44, 60.82, 97.11, 110.62, 120 .30,123.84,127.14,128.69,129.60,136.93,140.48,149.30,155.70,155.89,162.79,163.33.MS(m / z,%)Anal.Calcd for C 29 H 30 N4O4(498.2267),found:521.2173(M+Na)+.

[0131] Example 9

[0132] Preparation of target compound 10b

[0133] 1.00 g (2 mmol) of phosphine imine 4 obtained in Example 3 was dissolved in 10 mL of dichloromethane. 0.27 g (2 mmol) of p-methylphenyl isocyanate was added dropwise, and the mixture was allowed to stand at 0-5 °C for 20 h until the reaction was complete. Then, 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1 was added at room temperature. After reacting for half an hour at room temperature, the dichloromethane was removed under reduced pressure, and 15 mL of anhydrous ethanol was added as a solvent. A few drops of anhydrous sodium ethoxide solution were then added dropwise. The alcohol solution (1 mol / L) was stirred at room temperature until a solid precipitated. The solid was filtered to obtain a white solid, which was recrystallized from CH2Cl2 / CH3CH2OH to give the target compound (10b) 2-methyl-4-one-5-p-tolyl-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, yield: 87%, white solid, mp: 196-198℃.

[0134] 1H NMR (400MHz, CDCl3) δ (ppm): 0.89 (d, J=8.0Hz, 6H, 2×CH3), 1.22 (t, J=8.0Hz, 3H, CH3), 1 .54(d,J=4.0Hz,3H,CH3),1.79-1.86(m,1H,CH),2.29(s,3H,CH3),2.39-2.47(m,5H,CH2 and CH3),3.98(q,J=8.0Hz,1H,CH),4.13(q,J=8.0Hz,2H,OCH2),7.01-7.10(m,6H,ArH),7.26-7.35(m,2H,ArH). 13 C NMR (100MHz, CDCl3) δ (ppm): 13.92, 14.20, 18.06, 20.86, 22.42, 30.19, 44.62, 45.04, 60.67, 77.27, 96.93, 110.76, 120.74 ,127.25,129.29,129.72,133.94,134.18,138.49,140.78,149.72,155.45,155.64,162.61,163.61.MS(m / z,%)Anal.Calcd for C 30 H 32 N4O4(512.2424),found:535.2330(M+Na)+.

[0135] Example 10

[0136] Preparation of target compound 10c

[0137] 1.00 g (2 mmol) of phosphine 4 obtained in Example 3 was dissolved in 10 mL of dichloromethane. 0.27 g (2 mmol) of p-fluorophenyl isocyanate was added dropwise, and the mixture was allowed to stand at 0-5 °C for 20 h until the reaction was complete. Then, 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1 was added at room temperature. After reacting for half an hour at room temperature, the dichloromethane was removed under reduced pressure, and 15 mL of anhydrous ethanol was added as a solvent. A few drops of anhydrous ethanol containing sodium ethoxide were then added dropwise. The solution (1 mol / L) was stirred at room temperature until a solid precipitated. The solid was filtered to obtain a white solid, which was recrystallized from CH2Cl2 / CH3CH2OH to give the target compound (10c) 2-methyl-4-one-5-(4-fluorophenyl)-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, yield: 94%, white solid, mp: 167-169℃.

[0138] 1H NMR (400MHz, CDCl3) δ (ppm): 0.85 (d, J=8.0Hz, 6H, 2×CH3), 1.22-1.33 (m, 3H, CH3), 1.50 (d, J=8.0Hz, 3H, CH3), 1.73-1.76 (m, 1 H,CH),2.33(d,J=8.0Hz,2H,CH2),2.50(s,3H,CH3),4.02(bs,s,1H,CH),4.23(d,J=8.0Hz,2H,OCH2),6.84-7.26(m,8H,ArH). 13 CNMR(100MHz, CDCl3CDCl3)δ(ppm):14.21,18.44,22.38,28.60,30.15,42.29,44.29,44.96,46.02,60.89,66.32,74.24 ,84.44,97.12,115.20,115.42,122.19,123.72,126.24,127.14,129.57,149.40,155.72,162.80.MS(m / z,%)Anal.Calcd for C 29 H 29 FN4O4(516.2173),found:517.2249(M+H)+.

[0139] Example 11

[0140] Preparation of target compound 10d

[0141] 1.00 g (2 mmol) of phosphonium imide 4 obtained in Example 3 was dissolved in 10 mL of dichloromethane. 0.29 g (2 mmol) of 3,5-dimethylphenyl isocyanate was added dropwise, and the mixture was allowed to stand at 0-5 °C for 20 h until the reaction was complete. Then, 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1 was added at room temperature. After reacting for half an hour at room temperature, the dichloromethane was removed under reduced pressure, and 15 mL of anhydrous ethanol was added as a solvent. A few drops of anhydrous ethanol containing sodium ethoxide were then added dropwise. The solution (1 mol / L) was stirred at room temperature until a solid precipitated. The solid was filtered to obtain a white solid, which was recrystallized from CH2Cl2 / CH3CH2OH to give the target compound (10d) 2-methyl-4-one-5-(3,5-dimethylphenyl)-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, yield: 83%, white solid, mp: 180-181℃.

[0142] 1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (d, J=4.0Hz, 6H, 2×CH3), 1.25 (t, J=8.0Hz, 3H, CH3), 1. 55(d,J=8.0Hz,3H,CH3),1.78-1.85(m,1H,CH),2.25(s,6H,2×CH3),2.39-2.43(m,5H,CH2 and CH3),3.95-4.01(m,1H,CH),4.13-4.18(m,2H,OCH2),6.71(s,1H,ArH),6.85(s,2H,ArH),7.08-7.37(m,4H,ArH),7.26(ds,2H,ArH). 13 C NMR (100MHz, CDCl3) δ (ppm): 13.87, 14.21, 18.06, 21.40, 22.41, 30.23, 44.66, 45.14, 60.71, 77.27, 96.99, 110.73, 118.44 ,126.14,127.27,129.70,136.55,138.43,140.68,149.60,155.40,155.66,162.65,163.57,175.38.MS(m / z,%)Anal.Calcd for C 31 H 34 N4O4(526.2580),found:527.2652(M+H)+.

[0143] Example 12

[0144] Preparation of target compound 10e

[0145] 1.00 g (2 mmol) of phosphonium imide 4 obtained in Example 3 was weighed and dissolved in 10 mL of dichloromethane. 0.27 g (2 mmol) of m-methylphenyl isocyanate was added dropwise, and the mixture was allowed to stand at 0-5 °C for 20 h until the reaction was complete. Then, 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1 was added at room temperature. After reacting at room temperature for half an hour, the dichloromethane was removed under reduced pressure, and 15 mL of anhydrous ethanol was added as a solvent. A few drops of anhydrous sodium ethoxide were then added dropwise. The ethanol solution (1 mol / L) was stirred at room temperature until a solid precipitated. The solid was filtered to obtain a white solid, which was recrystallized from CH2Cl2 / CH3CH2OH to give the target compound (10e)2-methyl-4-one-5-m-tolyl-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, yield: 86%, white solid, mp: 131-133℃.

[0146] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.89 (d, J=8.0Hz, 6H, 2×CH3), 1.27 (t, J=8.0Hz, 3H, CH3), 1 .56(d,J=8.0Hz,3H,CH3),1.82-1.85(m,1H,CH),2.30(s,3H,CH3),2.41-2.45(m,5H,CH2 and CH3),3.98(q,J=8.0Hz,1H,CH),4.16-4.24(m,2H,OCH2),6.88-6.90(d,J=8.0Hz,1H,ArH),7 .01(s,1H,ArH),7.09-7.16(m,1H,ArH),7.01(s,1H,ArH),7.36-7.38(m,J=8.0Hz,2H,ArH). 13 C NMR (100MHz, CDCl3) δ (ppm): 13.84, 14.23, 17.98, 21.49, 22.41, 30.21, 44.87, 45.09, 60.73, 97.12, 110.79, 113.92, 117.78, 121.13 ,125.20,127.26,128.72,129.82,136.61,138.70,140.95,149.47,155.24,155.80,162.66,163.47,172.23.MS(m / z,%)Anal.Calcd for C 30 H 32 N4O4(512.2424),found:513.2507(M+H)+.

[0147] Example 13

[0148] Preparation of target compound 10f

[0149] 1.00 g (2 mmol) of phosphonium imide 4 obtained in Example 3 was dissolved in 10 mL of dichloromethane. 0.33 g (2 mmol) of 5-chloro-2-methylphenyl isocyanate was added dropwise. The mixture was allowed to stand at 0-5 °C for 20 h until the reaction was complete. Then, 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1 was added at room temperature. After reacting at room temperature for half an hour, the dichloromethane was removed under reduced pressure. 15 mL of anhydrous ethanol was then added as a solvent, followed by a few drops of anhydrous ethanol containing sodium ethoxide. The solution (1 mol / L) was stirred at room temperature until a solid precipitated. The solid was filtered to obtain a white solid, which was recrystallized from CH2Cl2 / CH3CH2OH to give the target compound (10f) 2-methyl-4-one-5-(5-chloro-2-methylphenyl)-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, yield: 92%, white solid, mp: 169-171℃.

[0150] 1 H NMR(400MHz, DMSO-d6)δ(ppm):0.85(d,J=4.0Hz,6H,2×CH3),1.29(s,3H,CH3),1.42(d,J=8.0Hz,3H,CH3),1.67-1.79(m,2H,CH2),2.11(s,1H,CH),2 .33-2.58(m,6H,2×CH3),3.84(d,J=8.0Hz,1H,CH),4.22-4.34(m,2H,OCH2 ),7.02(s,4H,ArH),7.35(d,J=4.0Hz,2H,ArH),7.56-7.79(m,1H,ArH).13C NMR (100MHz, DMSO-d6) δ (ppm): 13.69, 14.59, 17.27, 19.03, 22.65, 30.14, 44.80, 56.51, 60.48, 103.43, 110.47, 110.82, 119.63, 127. 86,128.99,130.42,131.49,137.30,139.27,139.60,140.27,141.79,143.83,155.04,155.36,163.12,169.82.MS(m / z,%)Anal.Calcd for C 30 H 31 ClN4O4(546.2034),found:547.2109(M+H)+.

[0151] Example 14

[0152] Preparation of 10g of the target compound

[0153] 1.00 g (2 mmol) of phosphonium imide 4 obtained in Example 3 was dissolved in 10 mL of dichloromethane. 0.33 g (2 mmol) of 3-chloro-4-methylphenyl isocyanate was added dropwise. The mixture was allowed to stand at 0-5 °C for 20 h until the reaction was complete. Then, 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1 was added at room temperature. After reacting for half an hour at room temperature, the dichloromethane was removed under reduced pressure. 15 mL of anhydrous ethanol was then added as a solvent, followed by a few drops of anhydrous ethanol containing sodium ethoxide. The solution (1 mol / L) was stirred at room temperature until a solid precipitated. The solid was filtered to obtain a white solid, which was recrystallized from CH2Cl2 / CH3CH2OH to give the target compound (10 g) 2-methyl-4-one-5-(3-chloro-4-methylphenyl)-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, yield: 74%, white solid, mp: 196-198℃.

[0154] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.83 (d, J=8.0Hz, 6H, 2×CH3), 1.18-1.24 (m, 3H, CH3), 1 .52(d,J=4.0Hz,3H,CH3),1.76-1.83(m,1H,CH),2.25(s,3H,CH3),2.37(s,3H,CH3) ,2.41(d,J=8.0Hz,2H,CH2),3.91(q,J=8.0Hz,1H,CH),4.11-4.19(m,2H,OCH2),7.0 2-7.11(m,4H,ArH),7.16(s,1H,ArH),7.19(s,1H,ArH),7.31(d,J=8.0Hz,2H,ArH). 13 C NMR (100MHz, CDCl3) δ (ppm): 14.03, 14.22, 17.74, 19.44, 22.41, 30.17, 43.35, 45.03, 60.88, 83.96, 97.36, 106.95, 110.71, 118.80 ,120.86,127.15,129.85,130.84,134.20,135.54,141.03,146.24,149.19,156.02,162.72,163.23,173.08.MS(m / z,%)Anal.Calcd forC 30 H 31 ClN4O4(546.2034),found:569.2234(M+Na)+.

[0155] Example 15

[0156] Preparation of target compound 10h

[0157] 1.00 g (2 mmol) of phosphine 4 obtained in Example 3 was weighed and dissolved in 10 mL of dichloromethane. 0.41 g (2 mmol) of 4-trifluoromethoxyphenyl isocyanate was added dropwise. The mixture was allowed to stand at 0-5 °C for 20 h until the reaction was complete. Then, 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1 was added at room temperature. After reacting at room temperature for half an hour, the mixture was desoluble under reduced pressure until the system was oily. Then, 20 mL of distilled ethanol was added as a solvent, and 10 drops of anhydrous ethanol solution of sodium ethoxide (1 mol / L) were added dropwise. The mixture was stirred at room temperature until a solid precipitated. After filtration, the white solid was recrystallized from CH2Cl2 / CH3CH2OH to give the target compound (10h) 2-methyl-4-one-5-(4-trifluoromethoxyphenyl)-8-(1-(4-isobutylphenyl)ethyl)-furano[3,2-e][1,3,4]triazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, yield: 87%, white solid, mp: 187-188℃.

[0158] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.90 (d, J = 4.0Hz, 6H, 2×CH3), 1.21 (t, J = 8.0Hz, 3H, CH3), 1.55 (d, J = 8.0Hz, 3H, CH3), 1.78-1.88 (m, 1H, CH), 2.41 (s, 3H, CH) 3),2.44(d,J=8.0Hz,2H,CH2),4.02(q,J=8.0Hz,1H,CH),4.06-4.11(m,2H, OCH2),7.09-7.12(m,4H,ArH),7.29(s,1H,ArH),7.38(d,J=8.0Hz,3H,ArH). 13 C NMR (100MHz, CDCl3) δ (ppm): 13.90, 14.10, 18.01, 22.34, 22.36, 30.24, 44.69, 45.03, 60.72, 97.59, 110.84, 121.56, 121.67, 12 1.75,127.32,129.80,135.47,138.25,141.04,145.30,149.43,155.34,155.99,162.41,163.28,175.23.MS(m / z,%)Anal.Calcd for C 30 H 29 F3N4O5(582.2090),found:583.2172(M+H)+.

[0159] Example 16

[0160] Preparation of target compound 11a

[0161] Weigh 1.04 g (3 mmol) of compound 6a into a 50 mL round-bottom flask, use 20 mL of anhydrous acetonitrile as solvent, and add 1.00 g (10 mmol) of hydrazine hydrate (N2H4·H2O) dropwise while stirring. React at 60 °C for about 5 h. A large amount of white solid is generated in the system. Filter and wash the filter cake with ethanol to obtain intermediate ethyl 2-(m-methylphenylamino)-4-hydrazino-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate 7n, which is dried for later use.

[0162] 0.41 g (2 mmol) of ibuprofen was weighed into a 50 mL round-bottom flask, and thionyl chloride (SOCl2) was slowly added dropwise. The mixture was stirred for 24 h, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, excess SOCl2 was removed by rotary evaporation to obtain a pale yellow oily liquid, which was ibuprofenformyl chloride 1. Without purification, 0.68 g (2 mmol) of intermediate 2-(m-methylphenylamino)-4-hydrazino-6-methyl-furano[2,3-d]pyrimidine-5-carboxylic acid ethyl ester 7n and 20 mL of dry CH2Cl2 were added. Under ice bath conditions, anhydrous triethylamine was slowly added dropwise using a separatory funnel until the system became weakly alkaline. The reaction was then stirred at room temperature, and the reaction progress was monitored by TLC. After the reaction was complete, the solvent was removed by rotary evaporation until the system was oily or a solid precipitated. Then, it was transferred to ice water and stirred to precipitate the solid. The solid was filtered, and the filter cake was recrystallized with EtOH:CH2Cl2 (V:V = 1:1) to give the target compound ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(m-methylphenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate 11a, yield: 64%, white solid, mp: 155-156℃.

[0163] 1H NMR (400MHz, CDCl3) δ (ppm): 0.90 (d, J=8.0Hz, 6H, 2×CH3), 1.37-1.44 (m, 3H, CH3), 1.58 (d, J=8.0Hz, 3H ,CH3),1.80-1.89(m,1H,CH),2.35(s,3H,CH3),2.48(d,J=4.0Hz,2H,CH2),2.62(s,3H,CH3),3.67-3.72 (m,1H,CH),4.35-4.40(m,2H,OCH2),6.68(s,1H,NH),6.81-6.85(m,1H,ArH),7.12-7.20(m,4H,ArH),7 .26-7.31(m,2H,ArH),7.44(d,J=8.0Hz,1H,ArH),8.17(d,J=4.0Hz,1H,NH),10.13(d,J=4.0Hz,1H,NH). 13 C NMR (100MHz, CDCl3) δ (ppm): 14.29, 14.59, 18.57, 21.62, 22.43, 30.26, 44.93, 45.14, 61.66, 92.09, 108.60, 116.57, 119.92, 123.25 ,127.56,128.67,129.56,137.87,138.54,139.37,140.90,154.91,157.04,157.09,165.00,166.78,171.36.MS(m / z,%)Anal.Calcd for C 30 H 35 N5O4(529.2689),found:530.2764(M+H)+.

[0164] Example 17

[0165] Preparation of target compound 11b

[0166] 1.04 g (3 mmol) of compound 6b obtained in Example 5, 0.83 g (6 mmol) of anhydrous potassium carbonate, and 1.32 g (6 mmol) of ibuprofen hydrazide 2 obtained in Example 1 were weighed into a 100 mL round-bottom flask. 30 mL of anhydrous acetonitrile was added, and the mixture was reacted at 75 °C for about 8 h. A large amount of solid precipitated. The solid was filtered while hot, and the filter cake was washed with ethanol and dried. Recrystallization from dichloromethane / ethanol (V:V = 1:1) yielded the target compound 11b as ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(p-methylphenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate, yield: 77%, white solid, mp: 222-224 °C.

[0167] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.90 (d, J=8.0Hz, 6H, 2×CH3), 1.38 (t, J=8.0Hz, 3H, CH3), 1.58 (d, J= 4.0Hz,3H,CH3),1.80-1.88(m,1H,CH),2.32(s,3H,CH3),2.46(d,J=4.0Hz,2H,CH2),2.60(s,3H,C H3),3.66-3.71(m,1H,CH),4.33-4.39(m,2H,OCH2),6.76(s,1H,NH),6.97-7.13(m,4H,ArH),7.2 6-7.30(m,2H,ArH),7.33-7.38(m,2H,ArH),8.20(d,J=4.0Hz,1H,NH),10.09(d,J=4.0Hz,1H,NH). 13 C NMR (100MHz, CDCl3) δ (ppm): 14.28, 14.58, 18.56, 20.83, 22.42, 30.23, 44.93, 45.09, 61.65, 91.90, 108.60, 119.70, 127.55 ,129.29,129.58,131.94,136.85,137.87,140.91,154.91,156.95,157.23,165.01,166.84,171.36.MS(m / z,%)Anal.Calcd for C 30 H 35 N5O4(529.2689),found:530.2759(M+H)+.

[0168] Example 18

[0169] Preparation of target compound 11c

[0170] 1.08 g (3 mmol) of compound 6c obtained in Example 5, 0.83 g (6 mmol) of anhydrous potassium carbonate, and 1.32 g (6 mmol) of ibuprofen hydrazide 2 obtained in Example 1 were weighed into a 100 mL round-bottom flask. The mixture was reacted at 75 °C for about 8 h with 30 mL of anhydrous acetonitrile as solvent. A large amount of solid precipitated. The mixture was filtered while hot, and the filter cake was washed with ethanol and dried. Recrystallization from dichloromethane / ethanol (V:V = 1:1) yielded the target compound 11c as ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(3,5-dimethylphenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate, yield: 62%, white solid, mp: 162-164 °C.

[0171] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.93 (d, J=8.0Hz, 6H, 2×CH3), 1.42-1.47 (m, 3H, CH3), 1.60 (d,J=8.0Hz,3H,CH3),1.85-1.91(m,1H,CH),2.34(s,6H,2×CH3),2.51(d,J=8.0Hz,2H, CH2),2.65(s,3H,CH3),3.71-3.76(m,1H,CH),4.38-4.44(m,2H,OCH2),6.70(s,1H,NH) ,7.11-7.16(m,4H,ArH),7.29-7.34(m,3H,ArH),8.28(s,1H,NH),10.21(s,1H,NH).13C NMR (100MHz, CDCl3) δ (ppm): 14.29, 14.60, 18.56, 21.55, 22.43, 30.18, 30.28, 44.87, 45.03, 45.17, 61.75, 91.91, 108.64, 117.25,124.47,127.59,129.20,129.55,137.87,138.43,140.89,157.18,164.96,166.70,171.40.MS(m / z,%)Anal.Calcd for C 31 H 37 N5O4(543.2846),found:544.2930(M+H)+.

[0172] Example 19

[0173] Preparation of target compound 11d

[0174] 1.20 g (3 mmol) of compound 6d obtained in Example 5, 0.83 g (6 mmol) of anhydrous potassium carbonate, and 1.32 g (6 mmol) of ibuprofen hydrazide 2 obtained in Example 1 were weighed into a 100 mL round-bottom flask. The mixture was reacted at 75 °C for about 8 h with 30 mL of anhydrous acetonitrile as solvent. A large amount of solid precipitated. The mixture was filtered while hot, and the filter cake was washed with ethanol and dried. The mixture was recrystallized from dichloromethane / ethanol (V:V = 1:1) to obtain the target compound 11d as ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(3,4-dichlorophenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate, yield: 71%, white solid, mp: 220-221 °C.

[0175] 1H NMR (400MHz, CDCl3) δ (ppm): 0.83 (d, J=8.0Hz, 6H, 2×CH3), 1.30-1.37 (m, 3H, CH3), 1.52(d,J=8.0Hz,3H,CH3),1.75-1.81(m,1H,CH),2.41(d,J=8.0Hz,2H,CH2),2.50 (s,3H,CH3),3.71-3.76(m,1H,CH),4.27(q,J=8.0Hz,2H,OCH2),6.85-7.11(m,4H, ArH),7.18-7.27(m,3H,ArH),7.55(s,1H,NH),8.32(s,1H,NH),9.93(s,1H,NH).13C NMR (100MHz, CDCl3) δ (ppm): 14.19, 14.59, 18.71, 22.45, 30.30, 44.78, 45.17, 61.87, 92.64, 108.43, 117.85, 119.66, 124.44, 12 7.52,127.64,129.23,129.53,129.97,132.03,138.08,139.05,140.87,157.62,164.79,166.00,172.65.MS(m / z,%)Anal.Calcd for C 29 H 31 ClN5O4(583.1753),found:584.1826(M+H)+.

[0176] Example 20

[0177] Preparation of target compound 11e

[0178] 1.25 g (3 mmol) of compound 6e obtained in Example 5, 0.83 g (6 mmol) of anhydrous potassium carbonate (K2CO3) and 1.32 g (6 mmol) of ibuprofen hydrazide 2 obtained in Example 1 were weighed into a 100 mL round-bottom flask. The mixture was reacted at 75 °C for about 8 h with 30 mL of anhydrous acetonitrile as solvent. A large amount of solid precipitated. The solid was filtered while hot, and the filter cake was washed with ethanol and dried. The solid was recrystallized from dichloromethane / ethanol (V:V = 1:1) to obtain the target compound 11e as ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(4-trifluoromethoxyphenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate, yield: 86%, white solid, mp: 228-229 °C.

[0179] 1H NMR (400MHz, CDCl3) δ (ppm): 0.90 (d, J = 8.0 Hz, 6H, 2 × CH3), 1.40 (t, J = 8.0 Hz, 3H, CH3), 1.59 (d, J =8.0Hz,3H,CH3),1.82-1.89(m,1H,CH),2.47(d,J=8.0Hz,2H,CH2),2.63(s,3H,CH3),3.67-3.7 3(m,1H,CH),4.39(q,J=8.0Hz,2H,OCH2),6.78(s,1H,NH),7.08-7.16(m,4H,ArH),7.30(d,J=8. 0Hz, 2H, ArH), 7.52 (d, J = 8.0Hz, 2H, ArH), 7.97 (d, J = 8.0Hz, 1H, NH), 10.16 (d, J = 4.0Hz, 1H, NH). 13 C NMR (100MHz, CDCl3) δ (ppm): 14.26, 14.61, 18.59, 22.39, 30.23, 44.98, 45.06, 61.76, 92.53, 108.66, 119.32, 120.22, 121.6 3,127.56,129.64,137.75,138.22,141.05,143.87,155.17,156.77,157.32,165.03,166.60,171.58.MS(m / z,%)Anal.Calcd for C 30 H 32 F3N5O5(599.2356),found:600.2430(M+H)+.

[0180] Example 21

[0181] Preparation of target compound 11f

[0182] 1.10 g (3 mmol) of compound 6f obtained in Example 5, 0.83 g (6 mmol) of anhydrous potassium carbonate (K2CO3) and 1.32 g (6 mmol) of ibuprofen hydrazide 2 obtained in Example 1 were weighed into a 100 mL round-bottom flask. The mixture was reacted at 75 °C for about 8 h with 30 mL of anhydrous acetonitrile as solvent. A large amount of solid precipitated. The mixture was filtered while hot, and the filter cake was washed with ethanol and dried. The mixture was recrystallized from dichloromethane / ethanol (V:V = 1:1) to obtain the target compound 11f, which is ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(4-chlorophenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate, yield: 83%, white solid, mp: 240-241 °C.

[0183] 1H NMR(400MHz,PY)δ(ppm):0.84(d,J=8.0Hz,6H,2×CH3),1.19(t,J=8.0Hz,3H,CH3),1.73(d,J=8.0Hz ,3H,CH3),1.77-1.84(m,1H,CH),2.43(d,J=8.0Hz,2H,CH2),2.47(s,3H,CH3),4.17-4.25(m,3H,CH and OCH2),7.45(d,J=8.0Hz,2H,ArH),7.59(s,2H,ArH),7.64(d,J=8.0Hz,2H,ArH),8.22 (d,J=8.0Hz,2H,ArH),10.36(s,1H,NH),10.49(d,J=8.0Hz,1H,NH),11.73(s,1H,NH. 13 C NMR(100MHz,PY)δ(ppm):13.85,14.21,19.58,22.18,22.21,30.12,44.63,44.85,48.52,61.52,92.55,108.77,120.95,1 25.88,127.67,128.69,129.53,139.61,140.33,140.54,156.94,158.06,165.06,167.16,173.47.MS(m / z,%)Anal.Calcd for C 29 H 32 ClN5O4(549.2143),found:550.2213(M+H)+.

[0184] Example 22

[0185] Preparation of 11g of target compound

[0186] 1.05 g (3 mmol) of compound 6 obtained in Example 5, 0.83 g (6 mmol) of anhydrous potassium carbonate (K2CO3) and 1.32 g (6 mmol) of ibuprofen hydrazide 2 obtained in Example 1 were weighed into a 100 mL round-bottom flask. The mixture was reacted at 75 °C for about 8 h with 30 mL of anhydrous acetonitrile as solvent. A large amount of solid precipitated. The mixture was filtered while hot, and the filter cake was washed with ethanol and dried. The mixture was recrystallized from dichloromethane / ethanol (V:V = 1:1) to give 11 g of the target compound, which was ethyl 4-((2-(4-isobutylphenyl)propionyl)hydrazino)-2-(4-fluorophenylamino)-6-methyl-furano[2,3-d]pyrimidine-5-carboxylate, yield: 85%, white solid, mp: 234-236 °C.

[0187] 1H NMR (400MHz, CDCl3), δ (ppm): 0.90 (d, J=8.0Hz, 6H, 2×CH3), 1.39 (t, J=8.0Hz, 3H, CH3), 1.58 (d, J=8.0 Hz,3H,CH3),1.81-1.88(m,1H,CH),2.46(d,J=8.0Hz,2H,CH2),2.60(s,3H,CH3),3.67-3.72(m,1H,CH ),4.37(q,J=8.0Hz,2H,OCH2),6.74(s,1H,NH),6.88-6.98(m,2H,ArH),7.13(d,J=8.0Hz,2H,ArH),7. 29(d,J=8.0Hz,2H,ArH),7.37-7.44(m,2H,ArH),8.13(d,J=4.0Hz,1H,NH),10.10(d,J=4.0Hz,1H,NH). 13 C NMR (100MHz, CDCl3), δ (ppm): 14.26, 14.57, 18.60, 22.40, 30.23, 44.92, 45.07, 61.69, 92.17, 108.61, 115.17, 115.39, 121.08, 1 21.16,127.56,129.58,135.45,137.82,140.95,155.15,157.05,157.10,159.60,165.00,166.70,171.60.MS(m / z,%)Anal.Calcd for C 29 H 32 FN5O4(533.2438),found:534.2515(M+H) + .

[0188] Example 23

[0189] Preparation of target compound 12a

[0190] 0.99 g (3 mmol) of compound 6h obtained in Example 5, 0.83 g (6 mmol) of anhydrous potassium carbonate (K2CO3), and 1.32 g (6 mmol) of ibuprofen hydrazide 2 obtained in Example 1 were weighed into a 100 mL round-bottom flask. The mixture was reacted at 75 °C for about 8 h with 30 mL of anhydrous acetonitrile as solvent. A large amount of solid precipitated. The mixture was filtered while hot, and the filter cake was washed with ethanol and dried. Recrystallization from dichloromethane / ethanol (V:V = 1:1) yielded the target compound 12a as ethyl 8-methyl-5-(phenylamino)-3-(1-(4-isobutylphenyl)ethyl)furano[3,2-e][1,3,4]triazolo[1,5-c]pyrimidine-9-carboxylate, yield: 79%, white solid, mp: 208-209 °C.

[0191] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.93 (d, J=4.0Hz, 6H, 2×CH3), 1.42 (d, J=8.0Hz, 3H, CH3), 1.63(d,J=8.0Hz,3H,CH3),1.85-1.91(m,1H,CH),2.49(d,J=4.0Hz,2H,CH2),2.66(s,3 H,CH3),3.82(d,J=4.0Hz,1H,CH),4.39-4.44(m,2H,OCH2),7.07(t,J=8.0Hz,1H,NH),7 .17(d,J=8.0Hz,2H,ArH),7.29-7.36(d,J=8.0Hz,5H,ArH),7.58(d,J=4.0Hz,2H,ArH). 13 C NMR (100MHz, CDCl3), δ (ppm): 14.27, 14.60, 18.47, 22.44, 30.23, 36.52, 44.90, 45.09, 61.97, 89.24, 103.67, 108.83, 11 9.63,122.96,127.62,128.86,129.64,137.74,140.97,141.56,154.49,164.87,167.29,172.31.MS(m / z,%)Anal.Calcd for C 29 H 31 N5O3(497.2427),found:520.3268(M+Na) + .

[0192] Example 24

[0193] Preparation of target compound 12b

[0194] 1.14 g (3 mmol) of compound 6i obtained in Example 5, 0.83 g (6 mmol) of anhydrous potassium carbonate (K2CO3) and 1.32 g (6 mmol) of ibuprofen hydrazide 2 obtained in Example 1 were weighed into a 100 mL round-bottom flask. The mixture was reacted at 75 °C for about 8 h with 30 mL of anhydrous acetonitrile as solvent. A large amount of solid precipitated. The mixture was filtered while hot, and the filter cake was washed with ethanol and dried. The mixture was recrystallized from dichloromethane / ethanol (V:V = 1:1) to obtain the target compound 12b, which is 8-methyl-5-(5-chloro-2-methylphenylamino)-3-(1-(4-isobutylphenyl)ethyl)furano[3,2-e][1,3,4]triazolo[1,5-c]pyrimidine-9-carboxylic acid ethyl ester, yield: 69%, white solid, mp: 223-225 °C.

[0195] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.91 (d, J=8.0Hz, 6H, 2×CH3), 1.43 (t, J=8.0Hz, 3H, CH3), 1.59 (d, J=8.0Hz, 3H, CH3), 1.82-1.91 (m, 1H, CH), 2.30 (s, 3H, CH3), 2.46(d,J=8.0Hz,2H,CH2),2.68(s,3H,CH3),3.81(s,1H,CH),4.43(q,J=8.0H z,2H,OCH2),6.95-7.03(m,1H,NH),7.14(d,J=4.0Hz,3H,ArH),7.29(s,1H,Ar H),7.32(d,J=8.0Hz,2H,ArH),8.18(s,1H,ArH). 13 C NMR(100MHz,CDCl3)δ(pp m):14.27,14.65,17.79,18.47,22.42,30.21,44.76,45.05,63.10,81.94,83.73,93.98,108.83,127.52,129.38,129 .63,131.31,131.74,132.11,137.71,140.92,154.96,156.49,164.93,174.81,179.84,197.64.MS(m / z,%)Anal.Calcd for C 30 H 32 ClN5O3(545.2194),found:546.2269(M+H) + .

[0196] Example 25

[0197] Preparation of target compound 13a

[0198] 0.71 g (2 mmol) of intermediate 8a obtained in Example 7 was weighed into a 50 mL round-bottom flask, and thionyl chloride (SOCl2) was slowly added dropwise. The mixture was stirred for 20–48 h, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the solvent was removed, and a solid precipitated, which was intermediate furanopyrimidine formyl chloride 9a. Without purification, 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1 was added to product 9a. Anhydrous triethylamine ((C2H5)3N) was slowly added dropwise using a separatory funnel under ice bath conditions until the system became weakly alkaline. The mixture was stirred for 4 h, and the reaction progress was monitored by TLC. After the reaction was complete, the solvent and solid residue were removed, and the mixture was poured into ice water and stirred to precipitate the solid. The solid was filtered, and the filter cake was dried and recrystallized from dichloromethane / ethanol (V:V = 1:1) to give the target compound 13a as N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-morpholino-2-(phenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine, yield: 62%, white solid, mp: 183-185℃.

[0199] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.84 (d, J=4.0Hz, 6H, 2×CH3), 1.58 (d, J=8.0Hz, 3H, CH3), 1.77-1.82 ( m,1H,CH),2.40(d,J=8.0Hz,2H,CH2),2.45(s,3H,CH3),3.17(s,4H,2×CH2),3.43(s,4H,2×CH2),3. 67-3.72(m,1H,CH),6.96(t,J=8.0Hz,1H,ArH),7.10(d,J=8.0Hz,2H,ArH),7.19(s,1H,NH),7.23- 7.28(m,4H,ArH),7.68(d,J=8.0Hz,2H,ArH),8.62(d,J=8.0Hz,1H,NH),10.86(d,J=8.0Hz,1H,NH). 13 C NMR (100MHz, CDCl3) δ (ppm): 13.44, 18.42, 22.39, 30.18, 44.99, 45.05, 49.74, 65.85, 95.34, 108.20, 118.94, 122.27, 12 7.26,128.85,129.90,137.10,139.82,141.36,155.09,156.14,159.27,160.84,167.66,170.33.MS(m / z,%)Anal.Calcd for C31 H 36 N6O4(556.2798),found:557.2878(M+H) + .

[0200] Example 26

[0201] Preparation of target compound 13b

[0202] Weigh 0.74 g (2 mmol) of intermediate 8b obtained in Example 7 into a 50 mL round-bottom flask, slowly add thionyl chloride (SOCl2), and stir the reaction for 20–48 h. Monitor the reaction progress by thin-layer chromatography (TLC). After the reaction is complete, remove the solvent and precipitate a solid, which is intermediate furanopyrimidineformyl chloride 9b. Without purification, add 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1, using 20 mL of dry CH2Cl2 as solvent. Under ice bath conditions, slowly add anhydrous triethylamine ((C2H5)3N) dropwise using a separatory funnel until the system becomes weakly alkaline. Stir the reaction for 4 h, and monitor the reaction progress by TLC. After the reaction was complete, the solvent and solid residue were removed, and the mixture was poured into ice water and stirred to precipitate a solid. The solid was filtered, and the filter cake was dried and recrystallized from dichloromethane / ethanol (V:V = 1:1) to give the target compound 13b as N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-morpholino-2-(p-phenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine, yield: 87%, white solid, mp: 243-246℃.

[0203] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 0.86 (d, J=4.0Hz, 6H, 2×CH3), 1.40 (d, J=4.0Hz, 3H, CH3), 1.77 -1.84(m,1H,CH),2.24(s,3H,CH3),2.42(d,J=4.0Hz,2H,CH2),2.46(s,3H,CH3),3.50(s,4H, 2×CH2),3.61(s,4H,2×CH2),3.68-3.74(m,1H,CH),7.09(q,J=8.0Hz,4H,ArH),7.29(d,J=8.0 Hz,2H,ArH),7.59(d,J=8.0Hz,2H,ArH),9.20(s,1H,NH),10.12(s,1H,NH),10.30(s,1H,NH). 13C NMR(100MHz,DMSO-d6)δ(ppm):12.95,18.44,20.34,22.16,29.61,42.67,44.23,47.71,65.93,93.38,111.09,118.74,127.0 8,128.80,128.83,129.72,138.21,138.63,139.48,148.64,155.95,158.50,162.67,168.00,173.03.MS(m / z,%)Anal.Calcd for C 32 H 38 N6O4(570.2955),found:571.3024(M+H) + .

[0204] Example 27

[0205] Preparation of target compound 13c

[0206] Weigh 0.73 g (2 mmol) of intermediate 8c obtained in Example 7 into a 50 mL round-bottom flask, slowly add thionyl chloride (SOCl2), and stir the reaction for 20–48 h. Monitor the reaction progress by thin-layer chromatography (TLC). After the reaction is complete, remove the solvent and precipitate a solid, which is intermediate furanopyrimidineformyl chloride 9c. Without purification, add 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1, using 20 mL of dry CH2Cl2 as solvent. Under ice bath conditions, slowly add anhydrous triethylamine ((C2H5)3N) dropwise using a separatory funnel until the system becomes weakly alkaline. Stir the reaction for 4 h, and monitor the reaction progress by TLC. After the reaction was complete, the solvent and solid residue were removed, and the mixture was poured into ice water and stirred to precipitate a solid. The solid was filtered, and the filter cake was dried and recrystallized from dichloromethane / ethanol (V:V = 1:1) to give the target compound 13c as N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-(4-methylpyrazin-1-yl)-2-(phenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine, yield: 46%, white solid, mp: 211-212℃.

[0207] 1H NMR (400MHz, CDCl3) δ (ppm): 0.91 (d, J=8.0Hz, 6H, 2×CH3), 1.63 (d, J=8.0Hz, 3H, CH3), 1.82-1.89 (m, 1H,CH),2.15(s,3H,CH3),2.33(s,4H,2×CH2),2.47(d,J=4.0Hz,2H,CH2),2.59(s,3H,CH3),3.32(d, J=4.0Hz,4H,2×CH2),3.70-3.75(m,1H,CH),7.02(t,J=8.0Hz,1H,ArH),7.15(d,J=8.0Hz,2H,ArH),7 .26(s,1H,NH),7.29-7.34(m,4H,ArH),7.71(d,J=8.0Hz,2H,ArH),7.88(s,1H,NH),8.58(s,1H,NH). 13 C NMR (100MHz, CDCl3) δ (ppm): 13.51, 18.56, 22.40, 30.19, 44.95, 45.04, 45.91, 49.57, 53.88, 95.58, 108.16, 118.92, 122.13 ,127.34,128.81,129.82,137.17,139.86,141.23,147.05,156.14,159.23,161.04,167.66,170.06.MS(m / z,%)Anal.Calcd for C 32 H 39 N7O3(569.3114),found:570.3183(M+H) + .

[0208] Example 28

[0209] Preparation of target compound 13d

[0210] 0.71 g (2 mmol) of intermediate 8d obtained in Example 7 was weighed into a 50 mL round-bottom flask, and thionyl chloride (SOCl2) was slowly added dropwise. The mixture was stirred for 20–48 h, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the solvent was removed, and a solid precipitated, which was intermediate furanopyrimidine formyl chloride 9d. Without purification, 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1 was added to product 9d. Anhydrous triethylamine ((C2H5)3N) was slowly added dropwise using a separatory funnel under ice bath conditions until the system became weakly alkaline. The mixture was stirred for 4 h, and the reaction progress was monitored by TLC. After the reaction was complete, the solvent and solid residue were removed, and the mixture was poured into ice water and stirred to precipitate the solid. The solid was filtered, and the filter cake was dried and recrystallized from dichloromethane / ethanol (V:V = 1:1) to give the target compound 13d as N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-diethylamino-2-(p-phenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine, yield: 72%, white solid, mp: 195-196℃.

[0211] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.90 (d, J=8.0Hz, 6H, 2×CH3), 0.98 (t, J=8.0Hz, 6H, 2×CH3), 1.61 ( d,J=4.0Hz,3H,CH3),1.82-1.89(m,1H,CH),2.33(s,3H,CH3),2.46(d,J=8.0Hz,2H,CH2),2.56( s,3H,CH3),3.24-3.33(m,4H,2×CH2),3.70-3.75(m,1H,CH),7.12(t,J=8.0Hz,4H,ArH),7.26-7 .29(m,2H,ArH),7.57(d,J=8.0Hz,2H,ArH),7.90(s,1H,NH),8.84(s,1H,NH),12.21(s,1H,NH). 13 C NMR (100MHz, CDCl3) δ (ppm): 11.99, 13.41, 18.51, 20.77, 22.39, 30.17, 44.87, 45.06, 45.52, 97.11, 99.99, 108.61, 118.86 ,127.26,129.20,129.72,131.29,137.47,137.55,141.05,156.22,159.52,160.34,167.67,169.82.MS(m / z,%)Anal.Calcd for C 32 H 40N6O3(556.3162),found:557.3238(M+H) + .

[0212] Example 29

[0213] Preparation of target compound 13e

[0214] Weigh 0.90 g (2 mmol) of intermediate 8e obtained in Example 7 into a 50 mL round-bottom flask, slowly add thionyl chloride (SOCl2), and stir the reaction for 20-48 h. Monitor the reaction progress by thin-layer chromatography (TLC). After the reaction is complete, remove the solvent and precipitate a solid, which is intermediate furanopyrimidineformyl chloride 9e. Without purification, add 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1, using 20 mL of dry CH2Cl2 as solvent. Under ice bath conditions, slowly add anhydrous triethylamine ((C2H5)3N) dropwise using a separatory funnel until the system becomes weakly alkaline. Stir the reaction for 4 h, and monitor the reaction progress by TLC. After the reaction was complete, the solvent and solid residue were removed, and the mixture was poured into ice water and stirred to precipitate a solid. The solid was filtered, and the filter cake was dried and recrystallized from dichloromethane / ethanol (V:V = 1:1) to give the target compound 13e as N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-(4-methylpyrazin-1-yl)-2-(4-(trifluoromethoxy)phenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine, yield: 54%, white solid, mp: 220-222℃.

[0215] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.91 (d, J=8.0Hz, 6H, 2×CH3), 1.65 (d, J=8.0Hz, 3H, CH3), 1.81-1.90 (m, 1H, CH), 2.13 (s, 3H, CH3), 2.23 (s, 4H, 2×C H2),2.47(d,J=8.0Hz,2H,CH2),2.53(s,3H,CH3),3.28(s,4H,2×CH2),3.72-3.78(m,1H,CH),7.16(d,J=8.0Hz,4H,ArH),7.26-7.32(m,3H,ArH and NH),7.77(d,J=8.0Hz,2H,ArH),8.49(s,1H,NH),8.69(s,1H,NH). 13C NMR (100MHz, CDCl3) δ (ppm): 13.26, 18.58, 22.39, 30.18, 44.92, 45.04, 45.86, 48.98, 53.92, 94.86, 108.58, 119.51, 121.57, 12 1.93,127.34,129.84,137.08,139.08,141.33,143.54,153.96,155.67,159.64,160.17,167.26,170.38.MS(m / z,%)Anal.Calcd for C 33 H 38 F3N7O4(653.2937),found:654.3014(M+H) + .

[0216] Example 30

[0217] Preparation of target compound 13f

[0218] Weigh 0.76 g (2 mmol) of intermediate 8f obtained in Example 7 into a 50 mL round-bottom flask, slowly add thionyl chloride (SOCl2), and stir the reaction for 20–48 h. Monitor the reaction progress using thin-layer chromatography (TLC). After the reaction is complete, remove the solvent to precipitate a solid, which is intermediate furanopyrimidineformyl chloride 9f. Without purification, add 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1, using 20 mL of dry CH2Cl2 as solvent. Under ice bath conditions, slowly add anhydrous triethylamine ((C2H5)3N) dropwise using a separatory funnel until the system becomes weakly alkaline. Stir the reaction for 4 h, and monitor the reaction progress using TLC. After the reaction was complete, the solvent and solid residue were removed, and the mixture was poured into ice water and stirred to precipitate the solid. The solid was filtered, and the filter cake was dried and recrystallized from dichloromethane / ethanol (V:V = 1:1) to give the target compound 13f as N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-di-n-propylamino-2-(p-phenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine, yield: 59%, white solid, mp: 200-202℃.

[0219] 1H NMR (400MHz, CDCl3) δ (ppm): 0.70 (t, J=8.0Hz, 6H, 2×CH3), 0.91 (d, J=8.0Hz, 6H, 2×CH3), 1.37-1.46 (m ,4H,2×CH2),1.62(d,J=8.0Hz,3H,CH3),1.83-1.89(m,1H,CH),2.33(s,3H,CH3),2.46-2.49(m,5H,CH2 and CH3),3.16(t,J=8.0Hz,4H,2×CH2),3.71-3.76(m,1H,CH),7.12(q,J=8.0Hz,4H,ArH),7.26-7. 30(m,2H,ArH),7.59(d,J=8.0Hz,2H,ArH),8.21(s,1H,NH),8.80(s,1H,NH),11.73(s,1H,NH). 13 C NMR (100MHz, CDCl3) δ (ppm): 11.34, 13.21, 18.62, 20.25, 20.76, 22.39, 30.19, 44.90, 45.07, 52.67, 97.19, 109.07, 118.73, 127 .32,129.09,129.71,130.94,137.41,137.95,141.10,152.70,155.92,159.81,160.16,167.46,169.99.MS(m / z,%)Anal.Calcd for C 34 H 44 N6O3(584.3475),found:585.3555(M+H) + .

[0220] Example 31

[0221] Preparation of 13g of target compound

[0222] Weigh 0.68 g (2 mmol) of the intermediate obtained in Example 7 (8 g) into a 50 mL round-bottom flask, slowly add thionyl chloride (SOCl2), and stir for 20-48 h. Monitor the reaction progress using thin-layer chromatography (TLC). After the reaction is complete, remove the solvent to precipitate a solid, which is 9 g of the intermediate furanopyrimidine formyl chloride. Without purification, add 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1, using 20 mL of dry CH2Cl2 as the solvent. Under ice bath conditions, slowly add anhydrous triethylamine ((C2H5)3N) dropwise using a separatory funnel until the system becomes weakly alkaline. Stir for 4 h, and monitor the reaction progress using TLC. After the reaction was complete, the solvent and solid residue were removed, and the mixture was poured into ice water and stirred to precipitate a solid. The solid was filtered, and the filter cake was dried and recrystallized from dichloromethane / ethanol (V:V = 1:1) to give 13g of the target compound, N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-diethylamino-2-(phenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine, yield: 82%, white solid, mp: 124-126℃.

[0223] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.90 (d, J=8.0Hz, 6H, 2×CH3), 0.95 (t, J=8.0Hz, 6H, 2×CH3), 1.62 (d, J=8. 0Hz,3H,CH3),1.78-1.89(m,1H,CH),2.46(d,J=8.0Hz,2H,CH2),2.51(s,3H,CH3),3.21-3.32(m,4H,2× CH2),3.71-3.76(m,1H,CH),6.99(t,J=8.0Hz,1H,ArH),7.13(d,J=8.0Hz,2H,ArH),7.26-7.31(m,4H,A rH),7.73(d,J=8.0Hz,2H,ArH),8.38(s,1H,NH),8.99(d,J=4.0Hz,1H,NH),12.15(d,J=4.0Hz,1H,NH). 13 C NMR (100MHz, CDCl3) δ (ppm): 12.06, 13.22, 18.55, 22.40, 30.21, 44.70, 44.77, 45.06, 58.45, 109.00, 118.57, 121.5 6,127.28,128.58,129.69,137.42,140.43,141.08,155.80,159.54,159.97,167.29,169.99.MS(m / z,%)Anal.Calcd for C 31 H 38N6O3(542.3005),found:543.3076(M+H) + .

[0224] Example 32

[0225] Preparation of target compound 13h

[0226] Weigh 0.78 g (2 mmol) of the intermediate 8h obtained in Example 7 into a 50 mL round-bottom flask, slowly add thionyl chloride (SOCl2), and stir the reaction for 20-48 h. Monitor the reaction progress by thin-layer chromatography (TLC). After the reaction is complete, remove the solvent and precipitate a solid, which is the intermediate furanopyrimidineformyl chloride 9h. Without purification, add 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1, using 20 mL of dry CH2Cl2 as solvent. Under ice bath conditions, slowly add anhydrous triethylamine ((C2H5)3N) dropwise using a separatory funnel until the system becomes weakly alkaline. Stir the reaction for 4 h, and monitor the reaction progress by TLC. After the reaction was complete, the solvent and solid residue were removed, and the mixture was poured into ice water and stirred to precipitate a solid. The solid was filtered, and the filter cake was dried and recrystallized from dichloromethane / ethanol (V:V = 1:1) to give the target compound N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-morpholino-2-(4-chlorophenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine, yield: 73%, white solid, mp: 265-266℃.

[0227] 1 H NMR (400MHz, DMSO-d6), δ (ppm): 0.86 (d, J=4.0Hz, 6H, 2×CH3), 1.40 (d, J=4.0Hz, 3H, CH3) ,1.77-1.84(m,1H,CH),2.41(d,J=8.0Hz,2H,CH2),2.48(s,3H,CH3),3.52(s,4H,2×CH2), 3.62(s,4H,2×CH2),3.69-3.74(m,1H,CH),7.11(d,J=8.0Hz,2H,ArH),7.30(t,J=8.0Hz,4 H, ArH), 7.77 (d, J = 12.0Hz, 2H, ArH), 9.51 (s, 1H, NH), 10.15 (s, 1H, NH), 10.35 (s, 1H, NH). 13C NMR(100MHz,DMSO-d6)δ(ppm):12.40,17.85,21.58,29.05,42.08,43.64,47.15,65.36,93.28,110.54,119.37,123.75,1 26.50,127.68,128.22,138.03,138.91,139.21,148.40,154.97,157.89,162.03,167.20,172.48.MS(m / z,%)Anal.Calcd for C 31 H 35 ClN6O4(590.2408),found:591.2494(M+H) + .

[0228] Example 33

[0229] Preparation of target compound 13i

[0230] Weigh 0.83 g (2 mmol) of intermediate 8i obtained in Example 7 into a 50 mL round-bottom flask, slowly add thionyl chloride (SOCl2), and stir the reaction for 20–48 h. Monitor the reaction progress using thin-layer chromatography (TLC). After the reaction is complete, remove the solvent to precipitate a solid, which is intermediate furanopyrimidineformyl chloride 9i. Without purification, add 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1, using 20 mL of dry CH2Cl2 as solvent. Under ice bath conditions, slowly add anhydrous triethylamine ((C2H5)3N) dropwise using a separatory funnel until the system becomes weakly alkaline. Stir the reaction for 4 h, and monitor the reaction progress using TLC. After the reaction was complete, the solvent and solid residue were removed, and the mixture was poured into ice water and stirred to precipitate the solid. The solid was filtered, and the filter cake was dried and recrystallized from dichloromethane / ethanol (V:V = 1:1) to give the target compound 13i as N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-(4-methylpyrazin-1-yl)-2-(5-chloro-2-methylphenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine, yield: 69%, white solid, mp: 250-256℃.

[0231] 1H NMR (400MHz, DMSO-d6) δ (ppm): 0.86 (d, J=8.0Hz, 6H, 2×CH3), 1.42 (d, J=8.0Hz, 3H, CH3), 1.77-1.84 (m, 1H, CH),2.23(s,3H,CH3),2.41(d,J=8.0Hz,2H,CH2),2.48(s,3H,CH3),2.74(d,J=4.0Hz,3H,CH3),3.36(s,8H ,4×CH2),3.71-3.76(m,1H,CH),7.05(d,J=8.0Hz,1H,ArH),7.13(d,J=8.0Hz,2H,ArH),7.21(d,J=8.0Hz,1 H, ArH), 7.31 (d, J = 8.0Hz, 2H, ArH), 7.78 (s, 1H, ArH), 8.70 (s, 1H, NH), 10.28 (s, 1H, NH), 10.41 (s, 1H, NH). 13 CNMR(100MHz,DMSO-d6)δ(ppm):13.63,18.04,18.84,22.67,30.12,42.61,43.17,44.70,44.79,52.63,94.76,111.22,123.50,123.66,1 27.60,129.35,129.91,130.20,132.04,139.02,139.89,140.02,150.10,156.85,158.49,163.08,168.69,173.86.MS(m / z,%)Anal.Calcd for C 33 H 40 ClN7O3(617.2881),found:618.2958(M+H) + .

[0232] Example 34

[0233] Preparation of target compound 13j

[0234] Weigh 0.80 g (2 mmol) of intermediate 8j obtained in Example 7 into a 50 mL round-bottom flask, slowly add thionyl chloride (SOCl2), and stir the reaction for 20-48 h. Monitor the reaction progress by thin-layer chromatography (TLC). After the reaction is complete, remove the solvent and precipitate a solid, which is intermediate furanopyrimidine formyl chloride 9j. Without purification, add 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1, using 20 mL of dry CH2Cl2 as solvent. Under ice bath conditions, slowly add anhydrous triethylamine ((C2H5)3N) dropwise using a separatory funnel until the system becomes weakly alkaline. Stir the reaction for 4 h, and monitor the reaction progress by TLC. After the reaction was complete, the solvent and solid residue were removed, and the mixture was poured into ice water and stirred to precipitate the solid. The solid was filtered, and the filter cake was dried and recrystallized from dichloromethane / ethanol (V:V = 1:1) to give the target compound 13j as N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-morpholino-2-(3-chloro-4-methylphenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine, yield: 89%, white solid, mp: 174-176℃.

[0235] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.84 (d, J=4.0Hz, 6H, 2×CH3), 1.59 (d, J=4.0Hz, 3H, CH3), 1.76-1.82 (m, 1H, CH), 2.28 (s, 3H, CH3), 2.39-2.42 (m, 5H, CH2 and CH3),3.19(s,4H,2×CH2),3.40(s,4H,2×CH2),3.67-3.73(m,1H,CH),7.08-7.11(m,3H,ArH),7. 19-7.25(m,3H,ArH),7.34-7.36(m,1H,ArH),7.93(s,1H,NH),8.66(s,1H,NH),10.86(s,1H,NH). 13 CNMR (100MHz, CDCl3) δ (ppm): 13.19, 18.53, 19.35, 22.40, 30.20, 44.88, 45.04, 49.15, 65.95, 94.24, 108.77, 117.20, 119.34, 127.28, 129.18,129.90,130.85,134.24,137.02,138.87,141.40,153.10,155.34,159.89,166.98,170.77,179.19.MS(m / z,%)Anal.Calcdfor C 32 H 37ClN6O4(604.2565),found:605.2641(M+H) + .

[0236] Example 35

[0237] Preparation of target compound 13k

[0238] Weigh 0.74 g (2 mmol) of intermediate 8k obtained in Example 7 into a 50 mL round-bottom flask, slowly add thionyl chloride (SOCl2), and stir the reaction for 20-48 h. Monitor the reaction progress by thin-layer chromatography (TLC). After the reaction is complete, remove the solvent and precipitate a solid, which is intermediate furanopyrimidineformyl chloride 9k. Without purification, add 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1, using 20 mL of dry CH2Cl2 as solvent. Under ice bath conditions, slowly add anhydrous triethylamine ((C2H5)3N) dropwise using a separatory funnel until the system becomes weakly alkaline. Stir the reaction for 4 h, and monitor the reaction progress by TLC. After the reaction was complete, the solvent and solid residue were removed, and the mixture was poured into ice water and stirred to precipitate a solid. The solid was filtered, and the filter cake was dried and recrystallized from dichloromethane / ethanol (V:V = 1:1) to give the target compound 13k as N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-morpholino-2-(m-methylphenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine, yield: 61%, white solid. mp: 205-206℃.

[0239] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.91 (d, J=4.0Hz, 6H, 2×CH3), 1.66 (d, J=4.0Hz, 3H, CH3), 1.83-1.89 (m, 1H, CH), 2.35(s,3H,CH3),2.47(d,J=8.0Hz,2H,CH2),2.51(s,3H,CH3),3.24(t,J=4.0Hz,4H,2×CH2),3.50(t,J=4.0H z,4H,2×CH2),3.71-3.80(m,1H,CH),6.84(d,J=8.0Hz,1H,ArH),7.15-7.22(m,3H,ArH),7.30(s,1H,ArH),7. 32(s,1H,ArH),7.55-7.60(m,2H,ArH),8.47(s,1H,NH),8.83(d,J=4.0Hz,1H,NH),10.97(d,J=4.0Hz,1H,NH). 13C NMR (100MHz, CDCl3) δ (ppm): 13.26, 18.44, 18.53, 21.70, 22.38, 30.18, 44.84, 45.03, 49.34, 65.88, 94.55, 108.46, 115.91, 119.51 ,122.80,127.24,128.61,129.84,137.15,138.38,140.02,141.31,155.98,159.60,160.30,167.38,170.40.MS(m / z,%)Anal.Calcd for C 32 H 38 N6O4(570.2955),found:571.3026(M+H) + .

[0240] Example 36

[0241] Preparation of target compound 13l

[0242] Weigh 0.78 g (2 mmol) of intermediate 8l obtained in Example 7 into a 50 mL round-bottom flask, slowly add thionyl chloride (SOCl2), and stir the reaction for 20-48 h. Monitor the reaction progress by thin-layer chromatography (TLC). After the reaction is complete, remove the solvent and precipitate a solid, which is intermediate furanopyrimidineformyl chloride 9l. Without purification, add 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1, using 20 mL of dry CH2Cl2 as solvent, and slowly add anhydrous triethylamine ((C2H5)3N) dropwise using a separatory funnel under ice bath conditions until the system is weakly alkaline. Stir the reaction for 4 h, and monitor the reaction progress by TLC. After the reaction was complete, the solvent and solid residue were removed, and the mixture was poured into ice water and stirred to precipitate the solid. The solid was filtered, and the filter cake was dried and recrystallized from dichloromethane / ethanol (V:V = 1:1) to give the target compound 13l as N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-diethylamino-2-(5-chloro-2-methylphenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine, yield: 86%, white solid, mp: 105-106℃.

[0243] 1H NMR (400MHz, CDCl3) δ (ppm): 0.91 (d, J=4.0Hz, 6H, 2×CH3), 1.07 (t, J=8.0Hz, 6H, 2×CH3), 1.59 (d, J=8.0 Hz,3H,CH3),1.82-1.89(m,1H,CH),2.30(s,3H,CH3),2.47(d,J=4.0Hz,2H,CH2),2.68(s,3H,CH3),3.35 -3.40(m,4H,2×CH2),3.67-3.74(m,1H,CH),6.92-6.96(m,2H,ArH),7.08-7.15(m,3H,ArH),7.25(s,1H, ArH), 7.27 (s, 1H, ArH), 8.40 (d, J = 4.0Hz, 1H, NH), 8.52 (d, J = 4.0Hz, 1H, NH), 11.85 (d, J = 4.0Hz, 1H, NH). 13 C NMR (100MHz, CDCl3) δ (ppm): 11.97, 13.78, 17.58, 18.44, 22.38, 30.19, 44.97, 45.04, 46.64, 99.56, 108.01, 119.84, 122.26, 124.55 ,127.24,129.80,131.06,132.01,137.35,138.70,141.14,156.09,157.48,158.60,161.36,168.00,169.61.MS(m / z,%)Anal.Calcd for C 32 H 39 ClN6O3(590.2772),found:591.2836(M+H) + .

[0244] Example 37

[0245] Preparation of target compound 13m

[0246] Weigh 0.76 g (2 mmol) of intermediate 8m obtained in Example 7 into a 50 mL round-bottom flask, slowly add thionyl chloride (SOCl2), and stir the reaction for 20-48 h. Monitor the reaction progress using thin-layer chromatography (TLC). After the reaction is complete, remove the solvent to precipitate a solid, which is intermediate furanopyrimidineformyl chloride 9m. Without purification, add 0.44 g (2 mmol) of ibuprofen hydrazide 2 obtained in Example 1, using 20 mL of dry CH2Cl2 as solvent. Under ice bath conditions, slowly add anhydrous triethylamine ((C2H5)3N) dropwise using a separatory funnel until the system becomes weakly alkaline. Stir the reaction for 4 h, and monitor the reaction progress using TLC. After the reaction was complete, the solvent and solid residue were removed, and the mixture was poured into ice water and stirred to precipitate a solid. The solid was filtered, and the filter cake was dried and recrystallized from dichloromethane / ethanol (V:V = 1:1) to give the target compound 13m as N'-(2-(4-isobutylphenyl)propionyl)-6-methyl-4-(4-methylpyrazin-1-yl)-2-(p-methylphenylamino)furano[2,3-d]pyrimidine-5-carbonylhydrazine, yield: 57%, white solid, mp: 226-228℃.

[0247] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 0.84 (d, J=8.0Hz, 6H, 2×CH3), 1.39 (d, J=8.0Hz, 3H, CH3), 1.76-1.82 (m, 1H, CH), 2.15 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.32(s,3H,CH3),2.40(d,J=4.0Hz,2H,CH2),2.45(s,3H,CH3),3.38(s,4H,4×CH2),3.51(s,4H,4×CH2),3.68-3.73(m,1H,CH),7.04-7.10(m,4H,NH and ArH),7.29(d,J=8.0Hz,2H,ArH),7.59(d,J=8.0Hz,2H,ArH),9.19(s,1H,ArH),10.16(s,1H,NH),10.33(s,1H,NH). 13C NMR(100MHz,DMSO-d6)δ(ppm):18.17,23.76,25.57,27.41,34.86,47.87,49.47,50.97,52.31,59.50,61.96,98.50,116.44,12 3.88,132.34,134.03,134.84,143.54,143.90,144.68,153.70,161.15,163.54,167.79,173.22,178.16.MS(m / z,%)Anal.Calcd for C 33 H 41 N7O3(583.3271), found:(M+H) + (Not done)

[0248] Example 38

[0249] Preparation of target compound 14a

[0250] Weigh 0.57 g (1 mmol) of target compound 13b obtained in Example 26 into a 50 mL round-bottom flask, add 2 mL of phosphorus oxychloride (POCl3), and reflux at 80 °C for 6 h. The reaction progress is monitored by TLC. After the reaction is complete, remove excess phosphorus oxychloride, pour the solid residue into ice water and stir, filter, neutralize the filter cake with saturated sodium bicarbonate (NaHCO3) aqueous solution until weakly alkaline, continue stirring for 2 h and filter, wash the filter cake with water, dry, and recrystallize with dichloromethane / ethanol (V:V = 1:1) to obtain target compound 14a, which is 5-(5-(1-(4-isobutylphenyl)ethyl)1,3,4-oxadiazol-2-yl)-6-methyl-4-morpholino-Np-p-phenylfurano[2,3-d]pyrimidin-2-amine, yield: 94%, white solid, mp: 168-169 °C.

[0251] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.91 (d, J=8.0Hz, 6H, 2×CH3), 1.82-1.90 (m, 4H, CH3and CH),2.32(s,3H,CH3),2.47(d,J=8.0Hz,2H,CH2),2.52(s,3H,CH3),3.10-3.22(m,4H,2×CH2),3.47(t,J=4.0Hz,4H,2×CH2), 4.39(q,J=8.0Hz,1H,CH),6.91(s,1H,NH),7.14(q,J=8.0Hz,4H,ArH),7.27(d,J=8.0Hz,2H,ArH),7.46(d,J=8.0Hz,2H,ArH).13 CNMR (100MHz, CDCl3) δ (ppm): 13.26, 19.12, 20.76, 22.38, 30.14, 37.17, 45.01, 48.31, 66.17, 94.29, 100.92, 119.42, 127.1 4,129.35,129.79,131.89,137.02,137.08,141.58,152.67,156.41,159.44,160.23,168.84,169.52.MS(m / z,%)Anal.Calcd for C 32 H 36 N6O3(552.2849),found:553.2933(M+H) + .

[0252] Example 39

[0253] Preparation of target compound 14b

[0254] Weigh 0.54 g (1 mmol) of the target compound 13 g obtained in Example 31 into a 50 ml round-bottom flask, add 2 ml of phosphorus oxychloride (POCl3), and reflux at 80 °C for 6 h. The reaction progress is monitored by TLC. After the reaction is complete, remove excess phosphorus oxychloride, pour the solid residue into ice water and stir, filter, neutralize the filter cake with saturated sodium bicarbonate (NaHCO3) aqueous solution until weakly alkaline, continue stirring for 2 h and filter, wash the filter cake with water, dry, and recrystallize with dichloromethane / ethanol (V:V = 1:1) to obtain the target compound 14b as N4,N4-diethyl-5-(5-(1-(4-isobutylphenyl)ethyl)1,3,4-oxadiazol-2-yl)-6-methyl-N2-phenylfurano[2,3-d]pyrimidine-2,4-diamine, yield: 87%, white solid, mp: 113-114 °C.

[0255] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.88-0.91 (m, 12H, 4×CH3), 1.80-1.86 (m, 4H, CH3and CH), 2.45-2.48 (m, 5H, CH2 and CH3),2.93-3.01(m,2H,CH2),3.09-3.16(m,2H,CH2),4.38(q,J=8.0Hz,1H,CH),6.98-7.01(m,2H,NH andArH),7.13(d,J=8.0Hz,2H,ArH),7.25-7.32(m,4H,ArH),7.62(d,J=8.0Hz,2H,ArH). 13C NMR (100MHz, CDCl3) δ (ppm): 12.89, 13.08, 19.05, 22.34, 30.23, 37.13, 43.26, 44.99, 94.26, 101.14, 118.87, 121.89, 12 7.13,128.78,129.66,137.20,140.05,141.29,152.14,156.04,158.65,160.68,168.56,169.62.MS(m / z,%)Anal.Calcd for C 31 H 36 N6O2(524.2900),found:525.2972(M+H) + .

[0256] Example 40

[0257] Preparation of target compound 14c

[0258] 0.56 g (1 mmol) of target compound 13a obtained in Example 25 was weighed into a 50 mL round-bottom flask, and 2 mL of phosphorus oxychloride (POCl3) was added. The mixture was refluxed at 80 °C for 6 h, and the reaction progress was monitored by TLC. After the reaction was complete, excess phosphorus oxychloride was removed, and the solid residue was poured into ice water and stirred. The mixture was then filtered, and the filter cake was neutralized with a saturated sodium bicarbonate (NaHCO3) aqueous solution until it was weakly alkaline. The mixture was stirred for another 2 h and then filtered again. The filter cake was washed with water, dried, and recrystallized from dichloromethane / ethanol (V:V = 1:1) to obtain target compound 14c, which is 5-(5-(1-(4-isobutylphenyl)ethyl)1,3,4-oxadiazol-2-yl)-6-methyl-4-morpholino-N-phenylfurano[2,3-d]pyrimidin-2-amine, yield: 89%, white solid, mp: 176-178 °C.

[0259] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.91 (d, J=4.0Hz, 6H, 2×CH3), 1.82-1.90 (m, 4H, CH3and CH),2.47(d,J=8.0Hz,2H,CH2),2.54(s,3H,CH3),3.11-3.23(m,4H,2×CH2),3.47(t,J=4.0Hz,4H,2×CH2),4.39(q,J=8.0Hz,1H,CH),7.02(t,2H,NH andArH),7.16(d,J=8.0Hz,2H,ArH),7.26-7.33(m,4H,ArH),7.59(d,J=8.0Hz,2H,ArH). 13C NMR (100MHz, CDCl3) δ (ppm): 13.30, 19.11, 22.40, 30.17, 37.17, 45.01, 48.31, 66.16, 94.46, 100.93, 119.11, 122.29, 12 7.15,128.86,129.80,136.99,139.68,141.60,152.83,156.18,159.39,160.19,168.72,169.53.MS(m / z,%)Anal.Calcd for C 31 H 34 N6O3(538.2692),found:539.2767(M+H) + .

[0260] Example 41

[0261] Preparation of target compound 14d

[0262] 0.59 g (1 mmol) of the target compound 13h obtained in Example 32 was weighed into a 50 mL round-bottom flask, and 2 mL of phosphorus oxychloride (POCl3) was added. The mixture was refluxed at 80 °C for 6 h, and the reaction progress was monitored by TLC. After the reaction was complete, excess phosphorus oxychloride was removed, and the solid residue was poured into ice water and stirred. The mixture was then filtered, and the filter cake was neutralized with saturated sodium bicarbonate (NaHCO3) aqueous solution until it was weakly alkaline. The mixture was stirred for another 2 h and then filtered again. The filter cake was washed with water, dried, and recrystallized from dichloromethane / ethanol (V:V = 1:1) to obtain the target compound 14d, which is N-(4-chlorophenyl)-5-(5-(1-(4-isobutylphenyl)ethyl)1,3,4-oxadiazol-2-yl)-6-methyl-4-morpholinylfurano[2,3-d]pyrimidin-2-amine, yield: 84%, white solid, mp: 188-190 °C.

[0263] 1 H NMR (400MHz, CDCl3) δ (ppm): 0.91 (d, J=8.0Hz, 6H, 2×CH3), 1.82-1.90 (m, 4H, CH3and CH),2.47(d,J=4.0Hz,2H,CH2),2.54(s,3H,CH3),3.09-3.22(m,4H,2×CH2),3.47(t,J=4.0Hz,4H,2×CH2),4.39(q ,J=8.0Hz,1H,CH),6.98(s,1H,NH),7.16(d,J=8.0Hz,2H,ArH),7.26-7.29(m,4H,ArH),7.54(d,J=8.0Hz,2H,ArH). 13C NMR (100MHz, CDCl3) δ (ppm): 13.29, 19.08, 22.38, 22.40, 30.16, 37.16, 44.99, 48.27, 66.13, 94.68, 100.94, 120.27, 127.05 ,127.13,128.79,129.80,136.96,138.27,141.62,153.00,155.90,159.35,160.09,168.61,169.56.MS(m / z,%)Anal.Calcd for C 31 H 33 ClN6O3(572.2303),found:573.2383(M+H) + .

[0264] Example 42

[0265] Preparation of target compound 14e

[0266] 0.60 g (1 mmol) of the target compound 13j obtained in Example 34 was weighed into a 50 mL round-bottom flask, and 2 mL of phosphorus oxychloride (POCl3) was added. The mixture was refluxed at 80 °C for 6 h, and the reaction progress was monitored by TLC. After the reaction was complete, excess phosphorus oxychloride was removed, and the solid residue was poured into ice water and stirred. The mixture was then filtered, and the filter cake was neutralized with a saturated sodium bicarbonate (NaHCO3) aqueous solution until it was weakly alkaline. The mixture was stirred for another 2 h and then filtered again. The filter cake was washed with water, dried, and recrystallized from dichloromethane / ethanol (V:V = 1:1) to obtain the target compound 14e, which is N-(3-chloro-4-methylphenyl)-5-(5-(1-(4-isobutylphenyl)ethyl)1,3,4-oxadiazol-2-yl)-6-methyl-4-morpholinylfurano[2,3-d]pyrimidin-2-amine, yield: 90%, white solid, mp: 197-198 °C.

[0267] 1H NMR (400MHz, CDCl3) δ (ppm): 0.91 (d, J=8.0Hz, 6H, 2×CH3), 1.82-1.90 (m, 4H, CH3and CH),2.33(s,3H,CH3),2.48(d,J=8.0Hz,2H,CH2),2.55(s,3H,CH3),3.10-3.23(m,4H,2×CH2),3.48(t,J=6.0Hz,4H,2×CH2),4. 40(q,J=8.0Hz,1H,CH),6.97(s,1H,NH),7.12-7.22(m,4H,ArH),7.27(s,1H,ArH),7.29(s,1H,ArH),7.87(d,J=2.0Hz,1H,ArH). 13 CNMR(100MHz, CDCl3)δ(ppm):13.30,19.06,19.32,22.39,22.41,30.17,37.16,44.99,48.33,66.19,94.55,100.90,117.33, 119.64,127.14,129.44,129.81,130.78,134.28,136.94,138.54,141.64,152.96,155.86,159.26,160.13,168.65,169.56.

[0268] Example 43

[0269] Screening assay for the antitumor activity of the furanopyrimidine-ibuprofen hybrid derivatives described in this invention:

[0270] CCK-8 assay for cell viability:

[0271] Tumor cells in the logarithmic growth phase were selected, the old culture medium was removed, and the cells were washed three times with PBS. They were then digested with 0.25% trypsin at room temperature or 37°C until the intercellular spaces widened. After digestion, complete culture medium containing 10% fetal bovine serum was added to stop the digestion, and the adherent cells were gently pipetted off into 15 ml centrifuge tubes. The tubes were centrifuged at 1000 rpm for 5 minutes, the supernatant was discarded, and 3 ml of complete culture medium was added to prepare a single-cell suspension. 10 μl of the single-cell suspension was used for cell counting on a cell counting plate. After counting, the cell concentration in the cell suspension was diluted to 5 × 10⁴ cells / ml with DMEM complete culture medium for later use.

[0272] Take a 96-well plate, add a ring of PBS around the outermost edge, and seed the above cell suspension at 5000 cells / well (i.e., 100 μl per well). After seeding, incubate statically at 37°C and 5% CO2 for 24 hours. Then remove the old culture medium, wash once with PBS, and add 100 μl of culture medium containing different concentrations of the test compound, setting up 5 replicates for each concentration. Use the culture medium without the drug as the control group and gefitinib as the positive control. After culturing for 48 hours, remove the old culture medium, wash once with PBS, and add 100 μl of culture medium containing 10 μl of enhanced CCK-8 solution to each well. Use wells with the corresponding amount of culture medium and enhanced CCK-8 solution but without cells as blank controls. Incubate in an incubator, and measure the absorbance (A) at 450 nm using a microplate reader at 1 hour, 2 hours, and 4 hours.

[0273] Calculation formula:

[0274] The inhibition rate of the test compound at a certain concentration is calculated as [1 - (Drug A - Blank A) / (Control A - Blank A)] × 100%. The IC50 value of the drug can be calculated by importing the concentration and inhibition rate data into SPSS software.

[0275] Sample preparation: The sample was dissolved in dimethyl sulfoxide (DMSO) and stored at low temperature. The concentration of DMSO in the final system was controlled within a range that would not affect the detection activity.

[0276] Data Processing and Results: This study investigated the inhibitory effects of all target compounds (10a-10h, 11a-11g, 12a-12b, 13a-13m, 14a-14e) on the proliferation of A549 lung cancer cells and HepG2 liver cancer cells using the CCK8 assay. The obtained IC50 values ​​were... 50 The values ​​are shown in the table below:

[0277] Table 1. Inhibitory activity of all target compounds against the proliferation of A549 and HepG2.

[0278]

[0279]

[0280] The table shows that 35 furanopyrimidine-ibuprofen hybrid derivatives exhibited good inhibitory effects on the proliferation of A549 lung cancer cells and HepG2 liver cancer cells. In both cell types, the target compounds generally showed better inhibitory effects on lung cancer cells (A549), with some compounds exhibiting activity superior to the positive control drug gefitinib. Preliminary comparisons of several different target compounds revealed that furanopyrimidine-triazole-ibuprofen compounds showed relatively good activity, followed by furanopyrimidine-hydrazide / diacylhydrazide-ibuprofen compounds, while furanopyrimidine-oxadiazole-ibuprofen compounds showed relatively low activity.

[0281] Among compounds 10a-10h, compounds 10a, 10f, and 10h showed relatively strong inhibitory effects on A549 (IC). 50 The values ​​were 0.106 μmol / L, 0.112 μmol / L, and 0.039 μmol / L, respectively. Compounds 10c, 10f, and 10h showed relatively strong inhibitory effects on HepG2, with IC50 values ​​of 0.106 μmol / L, 0.112 μmol / L, and 0.039 μmol / L. 50 The values ​​were 0.021 μmol / L, 0.604 μmol / L, and 0.314 μmol / L, respectively, all superior to the control drug gefitinib. Activity structure analysis showed a correlation with the substituent R; electron-withdrawing groups were beneficial for increased activity, i.e., electron-withdrawing R (-F, -OCF3) > H > electron-donating groups. Among compounds 11a-11g and 12a-12b, compounds 11a, 11g, and 12a showed relatively strong inhibitory activity against A549 (IC50). 50 The values ​​were 0.122 μmol / L, 0.096 μmol / L, and 0.038 μmol / L, respectively. Compound 11f showed a relatively strong inhibitory effect on HepG2, with an IC50 value of 0.122 μmol / L, 0.096 μmol / L, and 0.038 μmol / L. 50 The values ​​were 0.332 μmol / L, and all were superior to the control drug gefitinib. Among compounds 13a-13i, compounds 13a, 13c, 13e, and 13i showed relatively strong inhibitory effects on A549, with an IC50 value of 0.332 μmol / L. 50 The values ​​were 0.442 μmol / L, 0.068 μmol / L, 0.480 μmol / L, and 0.334 μmol / L, respectively. Compounds 13c, 13i, and 13l showed relatively strong inhibitory effects on HepG2, with IC50 values ​​of 0.442 μmol / L, 0.068 μmol / L, 0.480 μmol / L, and 0.334 μmol / L. 50 The values ​​were 0.144 μmol / L, 0.232 μmol / L, and 0.274 μmol / L, respectively, all superior to the control drug gefitinib. In compounds 13a-13i, activity structure analysis showed a correlation with substituent X; generally, X was more effective when substituted with a pyrazinyl group, and less effective when substituted with a di-n-propylamino group. In compounds 14a-14e, compound 14e showed relatively stronger inhibitory activity against A549, with an IC50 value of 0.144 μmol / L, 0.232 μmol / L, and 0.274 μmol / L. 50The value was 2.452 μmol / L; compound 14d showed a relatively strong inhibitory effect on HepG2, IC50. 50 The value was 1.231 μmol / L, which was comparable to the control drug gefitinib.

Claims

1. A furanopyrimidine-ibuprofen hybrid derivative as shown in Formula II: ###0001### Formula II wherein: R is selected from one or more substituents of H, halogen, CH3, NO2. is selected from any one of the following structures: ###0002### ###0003### ###0004### said tumor is lung cancer or liver cancer.

2. A furanopyrimidine-ibuprofen hybrid derivative, characterized in that ​ 3. Use of the furanopyrimidine-ibuprofen hybrid derivative according to claim 1 or 2 for the preparation of an antitumor medicament, characterized in that: ​

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