A 1-heteroaryl-3-sulfone bicyclo[1.1.1]pentane compound, and a preparation method and application thereof

Abstract

The application provides a 1-heteroaryl-3-sulfone group bicyclo[1.1.1]pentane compound and a preparation method and application thereof, and belongs to the technical field of synthesis of pharmaceutical intermediates. The compound provided by the application is a double-substituted bicyclo[1.1.1]pentane containing a sulfone group and a heteroaryl group and derivatives thereof, wherein the sulfone group is an important pharmacophore, plays a role in antitumor drugs by participating in hydrogen bond interaction, regulating cell signaling pathways and the like, and the series of compounds have antitumor activity. The application uses cheap and easily available sulfonic acid chlorides, [1.1.1]spiro propeller and heteroaromatic compounds as raw materials, and prepares a series of sulfone group and heteroaryl group double-substituted bicyclo[1.1.1]pentane under mild conditions through a three-component tandem reaction with high selectivity and high yield, and the preparation method is simple and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound, its preparation method, and its application. Background Technology

[0002] Bicyclic [1.1.1]pentane (BCP) is a class of small-ring systems with a three-dimensional rigid structure. Due to its unique spatial and electronic properties, it is often used as a bioisostere for para-substituted benzene rings in drug design. Compared to planar aromatic rings, the BCP skeleton usually exhibits better water solubility, metabolic stability, and membrane permeability, which is beneficial for improving the drug-likeness of candidate compounds. In recent years, polycyclic systems containing BCP have shown important bioisostere value in several drug discovery projects, becoming important structural units for constructing three-dimensional molecular libraries. Therefore, constructing more diverse BCP derivatives not only helps to enrich the three-dimensional molecular building block library, but also provides new chemical spaces and biological opportunities for the development of other therapeutic agents, and has become a cutting-edge research direction in the intersection of organic synthetic chemistry and medicinal chemistry. Summary of the Invention

[0003] The purpose of this invention is to provide a 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound, its preparation method and application. The bicyclic [1.1.1]pentane compound provided by this invention has both sulfonyl and heteroaryl structural units and can be used to prepare antitumor active drugs.

[0004] To achieve the objectives of this invention, the following technical solutions are provided: A 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound having the following chemical structure: ; Wherein, R1 is a heteroaryl group; R2 is an aryl, heteroaryl, or alkyl group.

[0005] Preferably, the heteroaryl group in R1 includes one of uracil, quinoxalone, pyrazinone, pyranone, cyclophosphinone, quinolinyl, and indole.

[0006] Preferably, the aryl group in R2 includes phenyl, substituted phenyl, or naphthyl; the substituent in the substituted phenyl group is one of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, and cyano. The heteroaryl group in R2 includes oxazolyl or piperidinyl.

[0007] Preferably, the 1-heteroaryl-3-sulfonylbicyclo[1.1.1]pentane has any of the following chemical structures: , , , , , , , , , , , , , , , , or .

[0008] The present invention also provides a method for preparing the 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound described in the above technical solution, comprising the following steps: R1-H, [1.1.1]spiroalkyl and sulfonyl chloride compounds were mixed and subjected to a multi-component radical coupling reaction under light, manganese-based catalyst, organic bisphosphine ligand and organic solvent conditions to obtain the 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound; The sulfonyl chloride compound has the following structure: ; R1 and R2 are defined as described in the above technical solution.

[0009] Preferably, the molar ratio of R1-H, [1.1.1]spiroalkyl and sulfonyl chloride compounds is 1:0.8~10:0.8~5.

[0010] Preferably, the manganese-based catalyst comprises one of manganese pentacarbonyl bromide, manganese acetate, and decacarbonyldimanganese; The molar ratio of R1-H to the manganese-based catalyst is 1:0.05~0.2.

[0011] Preferably, the organic bisphosphine ligand is one of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 1,2-bis(dimethylphosphine)ethane, 1,2-bis(diphenylphosphino)benzene, and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene; The molar ratio of the manganese-based catalyst to the organic bisphosphine ligand is 1:1~2.

[0012] Preferably, the wavelength of the light is 400~520nm; the reaction time is 8~24h.

[0013] The present invention also provides the application of the 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound described in the above technical solution or the 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound prepared by the preparation method described in the above technical solution in the preparation of antitumor drugs.

[0014] This invention provides a 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound with the following chemical structure; wherein R1 is a heteroaryl group; and R2 is an aryl, heteroaryl, or alkyl group. The compound provided by this invention is a sulfonyl-containing heteroaryl disubstituted BCP and its derivatives, representing a novel type of disubstituted BCP structure and a non-classical bioisosteric para-disubstituted benzene ring. In this compound, the sulfonyl group acts as an important pharmacophore, playing a role in antitumor drugs by participating in hydrogen bond interactions and regulating cell signaling pathways. The heteroaryl group in this compound exhibits structural diversity, target matching, and improved drug metabolism and pharmacokinetics, and some heteroaryl groups can directly participate in the antitumor mechanism. Furthermore, the sulfonyl group of this invention, as a strong hydrogen bond acceptor and polar group, can participate in the electrostatic interactions of target proteins and regulate cell signaling pathways; while the heteroaryl group provides hydrophobic interactions and π-system interactions. The synergistic effect of these two groups forms a "dual pharmacophore," simultaneously acting on multiple binding pockets of the target, significantly enhancing binding affinity and biological activity. While monosubstituted BCPs may have insufficient binding force or be metabolized too quickly due to their overly simple structure, this invention optimizes the balance of solubility and permeability by using disubstituted BCPs to balance the polarity (sulfone group increases hydrophilicity) and rigidity (heteroaryl group provides planarity), which is more in line with the five principles of drug-like formulations and improves the potential for drug development.

[0015] This invention also provides a method for preparing 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compounds. This invention uses inexpensive and readily available sulfonyl chloride compounds, [1,1,1]spiroane and heteroaryl compound R1-H as raw materials to prepare a series of sulfonyl and heteroaryl disubstituted bicyclic [1.1.1]pentanes with high selectivity and high yield through a three-component tandem reaction under mild conditions. The preparation method is simple and suitable for industrial production. Attached Figure Description

[0016] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 The graph shows the inhibitory effect of the 1-heteroaryl-3-sulfone bicyclic [1.1.1]pentane compounds obtained in Examples 9, 17 and 18 of this invention on HeLa cells; Figure 2~19 The above are the 1H NMR spectra of the 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compounds obtained in Examples 1-18 of this invention. Detailed Implementation

[0018] This invention provides a 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound having the following chemical structure: ; Wherein, R1 is a heteroaryl group; R2 is an aryl, heteroaryl, or alkyl group.

[0019] In this invention, the heteroaryl group in R1 includes one of uracil, quinoxalone, pyrazinone, pyranone, cenylone, quinolinyl, and indole, and can be one of the substituent-containing uracil, quinoxalone, pyrazinone, pyranone, cenylone, quinolinyl, and indole; the uracil group is 1,3-dimethylazauracil, ibuprofenazauracil, or gemfibrozilazauracil, and the ibuprofenazauracil is... The pyrimidinyl group can be ibuprofen 1-methyl-3-(2-hydroxyethyl)azauracil, and the gemfibrozil azauracil group can be gemfibrozil 1-methyl-3-(2-hydroxyethyl)azauracil; the quinoxalone group is N-methylquinoxalone; the pyrazinone includes diphenylpyrazinone; the pyranone group is coumarinyl or azacoumarin; the quinolinyl group is quinolinyl or isoquinoline; and the indole group is methyl indole-3-carboxylate. In the 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound R1 of this invention, the C atom in the heteroaryl group is bonded to the parent nucleus.

[0020] 1) In this invention, heteroaryl groups exhibit structural diversity and target matching. As common pharmacophores, their structures, electron distributions, and hydrogen-bonding abilities differ significantly from pure carbon aromatic rings. By introducing different heteroaryl groups, the spatial configuration, dipole moment, and electron cloud density of compounds can be precisely adjusted, thereby enhancing the matching with specific tumor target active sites (e.g., quinoline, indole, and uracil can utilize their planar hydrogen bond acceptor, electron-rich hydrogen bond donor, and nucleotide analog properties, respectively, to match and act on different types of tumor target active sites such as kinases, protein interfaces, and metabolic enzymes), improving binding affinity and selectivity. 2) Heteroaryl groups can improve drug metabolism and pharmacokinetic properties. The introduction of heteroaryl groups can optimize the compound's lipid-water partition coefficient (LogP), solubility, and metabolic stability. For example, nitrogen-containing heteroaryl groups may form additional hydrogen bonds or participate in π-π stacking interactions. Simultaneously, some heteroaryl rings can regulate cell membrane permeability, which is beneficial for oral bioavailability and tissue distribution. 3) Heteroaryl groups can also directly participate in antitumor mechanisms. Some heteroaryl groups (such as quinoline, indole, and uracil) have known antitumor activities in their skeletons, for example, as key binding units for kinase inhibitors. Introducing heteroaryl groups into the BCP skeleton may exert synergistic antitumor effects through multiple pathways, such as interfering with tumor cell proliferation signaling pathways, inducing apoptosis, or inhibiting angiogenesis.

[0021] In this invention, the aryl group in R2 includes phenyl, substituted phenyl, or naphthyl; the substituent in the substituted phenyl group is one of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, and cyano; the alkyl group in the alkyl and haloalkyl groups is a C1-C3 alkyl group, the haloalkyl group is a fluoroalkyl group, the fluoroalkyl group has 1-3 fluorine substitutions, and the substitution sites can be ortho, meta, or para; the alkyl group in the alkoxy and haloalkoxy groups is a C1-C3 alkoxy group, the haloalkoxy group is a fluoroC1-C3 alkoxy group, the fluoroalkoxy group has 1-3 fluorine substitutions, and the substitution sites can be ortho, meta, or para; the halogen includes F or Br, the halophenyl group has 1-3 halogen substitutions, and the substitution sites can be ortho, meta, or para.

[0022] In this invention, the alkyl group in R2 includes C1-C5 straight-chain alkyl, C1-C5 branched alkyl or C3-C5 cycloalkyl, specifically methyl, ethyl, propyl, butyl or pentyl, and in a specific embodiment it can be cyclopropyl.

[0023] In this invention, the heteroaryl group in R2 includes a substituted oxazolyl or piperidinyl group, which in a specific embodiment can be a 3,5-dimethylisoazolyl group.

[0024] In this invention, the 1-heteroaryl-3-sulfonylbicyclo[1.1.1]pentane has any of the following chemical structures: , , , , , , , , , , , , , , , , or .

[0025] The present invention also provides a method for preparing 1-heteroaryl-3-sulfonyl bicyclo[1.1.1]pentane as described in the above technical solution, comprising the following steps: R1-H, [1.1.1]spiroalkyl and sulfonyl chloride compounds were mixed and subjected to a multi-component radical coupling reaction under light, manganese-based catalyst, organic bisphosphine ligand and organic solvent conditions to obtain the 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound; The sulfonyl chloride compound has the following structure: ; R1 and R2 are defined as described in the above technical solution.

[0026] In this invention, unless otherwise specified, all raw materials used in the preparation are commercially available products known to those skilled in the art or prepared using conventional methods known to those skilled in the art.

[0027] In this invention, the heteroaryl compound R1-H is one of 1,3-dimethylazirauracil, N-methylquinoxalone, diphenylpyrazinone, coumarin, zolinone, azacoumarin, quinoline, isoquinoline, methyl indole-3-carboxylate, ibuprofen azauracil derivative, and gemfibrozil azauracil derivative; the ibuprofen azauracil derivative can be ibuprofen 1-methyl-3-(2-hydroxyethyl)azirauracil, and the gemfibrozil azauracil group can be gemfibrozil 1-methyl-3-(2-hydroxyethyl)azirauracil; the molar ratio of R1-H to [1.1.1]spiroalkyl is 1:0.8~10, and in specific embodiments it can be 1:1.0, 1:1.5, 1:2.2, 1:3.8, 1:4.5, 1:6, or 1:8.

[0028] In this invention, the sulfonyl chloride compound is one of p-methylbenzenesulfonyl chloride, p-trifluoromethoxybenzenesulfonyl chloride, p-cyanobenzenesulfonyl chloride, p-fluorobenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, 3,5-dimethylisozol-4-sulfonyl chloride, cyclopropylsulfonyl chloride, and piperidinesulfonyl chloride; the molar ratio of R1-H to the sulfonyl chloride compound is 1:0.8~5, and in specific embodiments it can be 1:1.0, 1:1.5, 1:2.5, 1:3.0, 1:4.0, or 1:4.5.

[0029] In this invention, the manganese-based catalyst includes one of manganese pentacarbonyl bromide, manganese acetate, and decacarbonyl dimanganese; the molar ratio of R1-H to the manganese-based catalyst is 1:0.05~0.2, and in specific embodiments it can be 1:0.08, 1:1.0, 1:1.5, 1:1.5 or 1:1.8.

[0030] In this invention, the organic bisphosphine ligand is one of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), 1,2-bis(dimethylphosphine)ethane, 1,2-bis(diphenylphosphino)benzene, and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (Xantphos); the molar ratio of R1-H to the organic bisphosphine ligand is 1:0.1~0.2, and in specific embodiments it can be 1:0.13 or 1:15.

[0031] In this invention, the organic solvent is one of dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, ethyl acetate, dimethyl sulfoxide, and N-methylpyrrolidone; the mass ratio of R1-H to the organic solvent is 1:10~100, and in specific embodiments it can be 1:15, 1:30, 1:50 or 1:80.

[0032] In this invention, the wavelength of the light is 400~520nm, and in a specific embodiment it can be 420, 455 or 470nm; the reaction time is 8~24h, and in a specific embodiment it can be 10h, 12h or 14h.

[0033] In this invention, the reaction is carried out in a protective atmosphere; the protective atmosphere may be nitrogen.

[0034] In this invention, after the reaction is completed, the reaction is quenched with a saturated ammonium chloride aqueous solution, and the resulting reaction system is extracted. The obtained organic phase is then dried, filtered, concentrated, and purified sequentially. The extractant used for extraction is ethyl acetate; the reagent used for drying is magnesium sulfate; the concentration is achieved by vacuum distillation of the solution using a rotary evaporator; the purification is performed by silica gel column chromatography, with ethyl acetate and petroleum ether as the eluent, the volume ratio of ethyl acetate to petroleum ether being 1:20~50, which can be 1:30 or 1:40 in specific embodiments; the elution program is gradient elution, from 1:100, 1:80, 1:60, 1:40 to 1:30; after gradient elution, the fraction containing the target compound is collected by TLC monitoring in the range of ethyl acetate / petroleum ether = 1:40 to 1:30. The fractions are combined and concentrated under reduced pressure to obtain the pure compound.

[0035] The present invention also provides the application of the 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound described in the above technical solution or the 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound prepared by the preparation method described in the above technical solution in the preparation of antitumor drugs.

[0036] In this invention, the cells can be small cell lung cancer cells or lymphoma cells, etc.

[0037] To further illustrate the present invention, the 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound, its preparation method, and its application provided by the present invention are described in detail below with reference to the accompanying drawings and embodiments, but these descriptions should not be construed as limiting the scope of protection of the present invention.

[0038] Example 1 ; 1,3-Dimethylazuracil (141 mg, 1 mmol), p-toluenesulfonyl chloride (287 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand for separation. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30, v / v) to obtain 325 mg of a yellow solid, with a yield of 90% and a melting point of 133 °C.

[0039] 1 H NMR (500 MHz, CDCl3) d 7.76 – 7.73 (m, 2H), 7.36 (d, J = 8.0 Hz,2H), 3.59 (s, 3H), 3.28 (s, 3H), 2.46 (s, 3H), 2.37 (s, 6H); 13 C NMR (126 MHz, CDCl3) d 155.6, 149.1, 144.9, 139.3, 133.6, 129.9, 128.7, 52.5, 52.0, 39.6, 37.8, 26.9, 21.7; HRMS-ESI: Theoretical Calculation C 17 H 19 N3O4SH: [M+H]+ 384.0988 , measured value 384.0989.

[0040] Example 2 ; N-methylquinoxalone (160 mg, 1 mmol), p-toluenesulfonyl chloride (287 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiropropane (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 323 mg of brown solid, with a yield of 85% and a melting point of 191 °C.

[0041] 1 H NMR (500 MHz, CDCl3) d 7.81 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.2Hz, 2H), 7.55 (t, J = 8.5 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.1Hz, 1H), 7.28 (d, J = 10.6 Hz, 1H), 3.63 (s, 3H), 2.53 (s, 6H), 2.46 (s, 3H); 13 C NMR (126 MHz, CDCl3) d 154.3, 154.2, 144.7, 133.8, 133.4, 132.7, 130.7, 130.2, 129.8, 128.7, 123.8, 113.7, 52.4, 52.3, 41.0, 28.6, 21.7; HRMS-ESI: Theoretical Calculation C 21 H 20 N₂O₃SH [M+H] + 403.1087, measured value 403.1075.

[0042] Example 3 Diphenylpyrazinone (262 mg, 1 mmol), p-toluenesulfonyl chloride (287 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiropropane (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 420 mg of a yellow solid, with a yield of 87% and a melting point of 206 °C.

[0043] 1 H NMR (500 MHz, CDCl3) d 7.78 (d, J = 8.2 Hz, 2H), 7.41 – 7.34 (m, 5H), 7.16 (d, J = 7.9 Hz, 2H), 7.12 – 7.05 (m, 5H), 3.25 (s, 3H), 2.52 (s, 6H), 2.45 (s, 3H); 13 C NMR (126 MHz, CDCl3) d 155.1, 150.8, 144.6, 138.2, 137.4, 133.9, 132.8, 132.3, 129.9, 129.8, 129.6, 129.2, 129.1, 128.7, 127.7, 127.1, 52.5, 52.1, 40.7, 33.7, 21.7; HRMS-ESI: Theoretical Calculation C 29 H 26 N₂O₃SH [M+H] + 483.1737, measured value 483.1737.

[0044] Example 4 Coumarin (146 mg, 1 mmol), p-toluenesulfonyl chloride (287 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 311 mg of a white solid, with a yield of 85% and a melting point of 138 °C.

[0045] 1 H NMR (500 MHz, CDCl3) d 7.75 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 7.7 Hz,1H), 7.43 (d, J = 7.6 Hz, 1H), 7.41 (s, 1H), 7.36 (d, J = 7.9 Hz, 2H), 7.28(d, J = 8.4 Hz, 1H), 7.24 (d, J = 6.0 Hz, 1H), 2.45 (s, 3H), 2.38 (s, 6H); 13 CNMR (126 MHz, CDCl3) d 159.8, 153.6, 144.9, 139.4, 133.6, 131.7, 129.9, 128.7, 127.7, 125.1, 124.6, 118.7, 116.6, 51.1, 51.8, 38.8, 21.7; HRMS-ESI: Theoretical Calculation C 21 H 18 O4SH [M+H] + 367.0999, measured value 367.1005. Example 5 Add 146 mg (1 mmol), p-toluenesulfonyl chloride (287 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) to a Schlenk reactor. After purging with nitrogen in a double-row tube, add 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol). React under 455 nm light for 12 h. After the reaction is complete, quench the reaction with 20 g of saturated ammonium chloride aqueous solution, add 20 g of ethyl acetate, stir thoroughly, and allow to stand for separation. The organic layer is dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product is purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 304 mg of brown solid, with a yield of 87% and a melting point of 211 °C.

[0046] 1 H NMR (500 MHz, CDCl3) d 11.15 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.67 (t, J = 7.7 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.37 (d, J =7.9 Hz, 3H), 2.55 (s, 6H), 2.47 (s, 3H); 13 C NMR (126 MHz, CDCl3) d 171.1, 145.5, 144.9, 141.2, 133.8, 133.5, 129.9, 128.6, 125.1, 124.9, 123.2, 115.8, 52.8, 52.2, 38.9, 21.7; HRMS-ESI: Theoretical Calculation C 20 H 18 N₂O₃SH [M+H] + 367.1111, measured value 367.1121.

[0047] Example 6 Azacoumarin (147 mg, 1 mmol), p-toluenesulfonyl chloride (287 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 305 mg of brown solid, with a yield of 87% and a melting point of 197 °C.

[0048] 1 H NMR (500 MHz, CDCl3) d 7.71 (d, J = 8.2 Hz, 2H), 7.65 (dd, J = 8.0,1.4 Hz, 1H), 7.45 – 7.40 (m, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.29 – 7.25 (m,1H), 7.20 – 7.18 (m, 1H), 2.44 (s, 6H), 2.40 (s, 3H); 13 C NMR (126 MHz, CDCl3) d 150.7, 150.6, 145.6, 143.9, 132.5, 130.6, 130.0, 128.9, 128.2, 127.7, 124.7, 115.4, 51.3, 51.2, 39.2, 20.7; HRMS-ESI: Theoretical Calculation C 20 H 17 NO4SH [M+H] + 368.0951, measured value 368.0950.

[0049] Example 7 Quinoline (128 mg, 1 mmol), p-toluenesulfonyl chloride (287 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 hours. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 304 mg of white solid, with a yield of 87% and a melting point of 127 °C.

[0050] 1 H NMR (500 MHz, CDCl3) d 8.10 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.1 Hz,1H), 7.81 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.1 Hz, 1H), 7.69 (t, J = 7.3 Hz,1H), 7.50 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.8 Hz, 1H), 2.49 (s, 6H), 2.46 (s, 3H); 13 C NMR (126 MHz, CDCl3) d 156.8, 144.8, 136.7, 133.8, 129.83, 129.80, 129.1, 128.73, 128.66, 127.6, 127.2, 126.5, 118.5, 52.3, 51.5, 42.1, 21.7; HRMS-ESI: Theoretical Calculation C 21 H 19 NO2SH [M+H] + 350.1209, measured value 350.1206.

[0051] Example 8 Isoquinoline (128 mg, 1 mmol), p-toluenesulfonyl chloride (287 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 hours. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 315 mg of a yellow solid, with a yield of 89% and a melting point of 153 °C.

[0052] 1 H NMR (500 MHz, CDCl3) d 8.43 (d, J = 5.7 Hz, 1H), 8.22 (d, J = 8.5 Hz,1H), 7.84 (dd, J = 8.3, 6.4 Hz, 3H), 7.73 – 7.67 (m, 1H), 7.62 – 7.57 (m,2H), 7.39 (d, J = 8.0 Hz, 2H), 2.70 (s, 6H), 2.47 (s, 3H); 13 C NMR (126 MHz, CDCl3) d 155.3, 144.8, 136.4, 133.8, 130.4, 129.9, 128.7, 127.7, 127.5, 127.0, 125.1, 120.9, 53.7, 52.6, 42.6, 21.7; HRMS-ESI: Theoretical Calculation C 21 H 19 NO2SH [M+H] + 350.1209, measured value 350.1213.

[0053] Example 9 Methyl indole-3-carboxylate (191 mg, 1 mmol), p-toluenesulfonyl chloride (287 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 341 mg of brown solid, with a yield of 83% and a melting point of 155 °C.

[0054] 1 H NMR (500 MHz, CDCl3) d 1H NMR (500 MHz, Chloroform-d) δ 8.03 (d, J =7.9 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.26 (d, J =9.2 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 2.76 (s, 6H), 2.46 (s, 3H); 13 C NMR (126 MHz, CDCl3) d 165.3, 144.9, 140.3, 136.6, 133.7, 130.0, 128.7, 126.2, 123.2, 122.1, 121.9, 109.3, 106.7, 54.1, 53.2, 51.0, 36.0, 31.2, 21.7; HRMS-ESI: Theoretical Calculation C 23 H 23 NO4SH [M+H] + 410,1421, measured value 410.1411.

[0055] Example 10 1,3-Dimethylazuracil (141 mg, 1 mmol), p-trifluoromethoxybenzenesulfonyl chloride (390 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 397 mg of a yellow solid, with a yield of 92% and a melting point of 153 °C.

[0056] 1 H NMR (500 MHz, CDCl3) d 7.93 (d, J = 8.8 Hz, 2H), 7.41 – 7.37 (m, 2H), 3.58 (s, 3H), 3.28 (s, 3H), 2.40 (s, 6H); 13 C NMR (126 MHz, CDCl3) d 155.6, 153.2, 149.1, 139.0, 134.9, 130.9, 120.9, 52.4, 52.1, 39.7, 38.0, 27.0; 19 F NMR (471 MHz, CDCl3) d -57.65(s); 19 F NMR (471 MHz, CDCl3) d -57.65; HRMS-ESI: Theoretical Calculation C 17 H 16 F3N3O5SH [M+H] + 432.0836, measured value 432.0825.

[0057] Example 11 1,3-Dimethylazuracil (141 mg, 1 mmol), p-cyanobenzenesulfonyl chloride (301 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 309 mg of a yellow solid, with a yield of 83% and a melting point of 128 °C.

[0058] 1 H NMR (500 MHz, CDCl3) d 8.00 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 3.61 – 3.55 (m, 3H), 3.27 (s, 3H), 2.40 (s, 6H); 13 C NMR (126 MHz, CDCl3) d 155.6, 149.0, 140.9, 138.7, 133.0, 129.4, 117.7, 117.0, 52.2, 39.7, 38.2, 30.9, 27.0; HRMS-ESI: Theoretical Calculation C 17 H 16 N4O4SH [M+H] + 373.0965, measured value 373.0958.

[0059] Example 12 1,3-Dimethylazuracil (141 mg, 1 mmol), p-fluorobenzenesulfonyl chloride (292 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 310 mg of a white solid, with a yield of 85% and a melting point of 199 °C.

[0060] 1 H NMR (500 MHz, CDCl3) δ 7.92 – 7.87 (m, 2H), 7.31 – 7.22 (m, 2H), 3.59 (s, 3H), 3.28 (s, 3H), 2.39 (s, 6H); 13 C NMR (126 MHz, CDCl3) d 166.99-164.95, 155.6, 149.1, 139.0, 132.68-132.66, 131.49-131.41, 116.7, 116.5, 52.5, 52.1, 39.6, 37.9, 26.9; 19 F NMR (471 MHz, CDCl3) d -103.18(s); HRMS-ESI: Theoretical Calculation C 16 H 16 FN3O4SH [M+H] + 366.0918, measured value 366.0922.

[0061] Example 13 1,3-Dimethylazuracil (141 mg, 1 mmol), 2-naphthalenesulfonyl chloride (340 mg, 2 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 318 mg of a yellow solid, with a yield of 80% and a melting point of 245 °C.

[0062] 1 H NMR (500 MHz, CDCl3) d 8.47 (d, J = 1.8 Hz, 1H), 8.01 (d, J = 8.6 Hz, 2H), 7.95 (d, J = 8.1 Hz, 1H), 7.84 (dd, J = 8.6, 1.9 Hz, 1H), 7.71 – 7.63 (m,2H), 3.58 (s, 3H), 3.27 (s, 3H), 2.42 (s, 6H).; 13 C NMR (126 MHz, CDCl3) d 155.6, 149.1, 139.2, 135.4, 133.6, 132.2, 130.5, 129.4, 129.4, 128.0, 127.7, 123.3, 52.6, 52.2, 39.6, 37.3, 26.9; HRMS-ESI: Theoretical Calculation C 20 H 19 N3O4SH [M+H] + 398.1169, measured value 398.1162.

[0063] Example 14 1,3-Dimethylazuracil (141 mg, 1 mmol), 3,5-dimethylisozol-4-sulfonyl chloride (293 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiropropane (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 318 mg of a white solid, with a yield of 80% and a melting point of 245 °C.

[0064] 1 H NMR (500 MHz, CDCl3) d 3.60 (s, 3H), 3.29 (s, 3H), 2.63 (s, 3H), 2.44 (s, 6H), 2.40 (s, 3H); 13 C NMR (126 MHz, CDCl3) d 175.5, 158.4, 155.6, 149.0, 138.8, 113.1, 53.3, 51.8, 39.7, 37.7, 27.0, 12.6, 10.9; HRMS-ESI: Theoretical Calculation C 15 H 18 N4O5SH [M+H] + 367.1071, measured value 367.1080.

[0065] Example 15 1,3-Dimethylazuracil (141 mg, 1 mmol), cyclopropylsulfonyl chloride (210 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiropropane (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 270 mg of a yellow solid, with a yield of 87% and a melting point of 215 °C.

[0066] 1 H NMR (500 MHz, CDCl3) d 3.63 (s, 3H), 3.33 (s, 3H), 2.58 (s, 6H), 2.36– 2.31 (m, 1H), 1.23 (dd, J = 4.7, 2.2 Hz, 2H), 1.05 (dd, J = 7.9, 2.2 Hz, 2H); 13 C NMR (126 MHz, CDCl3) d 155.7, 149.1, 139.2, 52.5, 51.3, 39.7, 37.9, 27.0, 26.5, 4.1; HRMS-ESI: Theoretical Calculation C 13 H 17 N3O4SH [M+H] + 312.1013, measured value 312.1013.

[0067] Example 16 1,3-Dimethylazuracil (141 mg, 1 mmol), piperidine-1-sulfonyl chloride (210 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. The mixture was stirred thoroughly and allowed to stand for separation. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:30) to obtain 270 mg of a yellow solid, with a yield of 89% and a melting point of 192 °C.

[0068] 1 HNMR (500 MHz, CDCl3) d 3.61 (s, 3H), 3.34 (d, J = 5.0 Hz, 3H), 3.32 (s,3H), 2.53 (s, 6H), 1.61 (ddt, J = 15.5, 8.3, 5.3 Hz, 7H); 13 C NMR (126 MHz, CDCl3) d 155.8, 149.2, 139.4, 53.3, 50.6, 47.1, 39.7, 38.4, 27.0, 26.0, 23.9; HRMS-ESI: Theoretical Calculation C 15 H 22 N4O4SH [M+H] + 355.1435, measured value 355.1435.

[0069] Example 17 1-Methyl-3-(2-hydroxyethyl)azauracil: A magnetic stir bar and reflux condenser were installed on a dry 100 mL three-necked round-bottom flask. The following were added sequentially to the reaction flask: N-methylazauracil (2.5 g, 20 mmol), 2-bromoethanol (2.5 g, 20 mmol), anhydrous potassium carbonate (4.2 g, 30 mmol), and anhydrous N,N-dimethylformamide (30 mL). The reaction system was heated to 80 ± 5°C and refluxed with stirring at this temperature for 12–18 hours. The reaction progress was monitored using thin-layer chromatography (TLC). After the reaction was complete, the reaction solution was cooled to room temperature and poured into 150 mL of water. The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed twice with saturated brine (50 mL) to remove DMF and residual inorganic salts. The organic phase was dried over anhydrous magnesium sulfate and filtered. The solvent was removed by rotary evaporation under reduced pressure to obtain crude 1-methyl-3-(2-hydroxyethyl)azuracil.

[0070] Esterification reaction: A magnetic stir bar was installed in a dry 50 mL round-bottom flask. Then, crude 1-methyl-3-(2-hydroxyethyl)azauracil (1.8 g, 10 mmol), gemfibrozil (10 mmol), 4-dimethylaminopyridine (0.12 g, 1 mmol), and anhydrous dichloromethane (20 mL) were added sequentially to the reaction flask. The flask was placed in an ice-water bath (0 ± 5°C), and N,N'-dicyclohexylcarbodiimide (2.3 g, 11 mmol) was slowly added in portions with stirring. After the addition was complete, the ice bath was removed, and the reaction mixture was allowed to rise naturally to room temperature (25–30°C). The mixture was stirred at this temperature for 24 h, and the reaction progress was monitored using thin-layer chromatography (TLC). After the reaction was complete, the reaction mixture was filtered to remove the precipitated dicyclohexylurea (DCU). The filtrate was washed once each with 5 wt.% dilute hydrochloric acid solution (20 mL), saturated sodium bicarbonate aqueous solution (20 mL), and saturated saline solution (20 mL). The resulting organic phase was dried over anhydrous magnesium sulfate and filtered. The solvent was removed by rotary evaporation under reduced pressure to obtain a viscous oily or solid crude product. The crude product was further purified by silica gel column chromatography. Using petroleum ether / ethyl acetate (1:10, v / v) as eluent, a single main fraction was collected, concentrated, and used to obtain gemfibrozil-azauracil derivatives.

[0071] Gemfibrozil aziridine derivative (403 mg, 1 mmol), p-toluenesulfonyl chloride (285 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:20) to obtain 499 mg of white solid, with a yield of 80% and a melting point of 181 °C.

[0072] 1 H NMR (500 MHz, CDCl3) d 7.74 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 1.4 Hz, 1H), 4.35 (t, J = 5.2 Hz, 2H), 4.19 (t, J = 5.2 Hz, 2H), 3.88 (t, J = 4.6 Hz, 2H), 3.26(s, 3H), 2.46 (s, 3H), 2.37 (s, 6H), 2.30 (s, 3H), 2.15 (s, 3H), 1.16 (s,6H); 13 C NMR (126 MHz, CDCl3) d 177.4, 156.8, 155.4, 148.9, 144.9, 139.7, 136.5, 133.6, 130.3, 129.9, 128.7, 123.5, 120.8, 112.0, 67.8, 61.1, 52.5, 52.1, 51.1, 42.1, 37.8, 36.9, 27.0, 25.1, 21.7, 21.4, 15.8; HRMS-ESI: Theoretical Calculation C 33 H 41N3O7SNa [M+Na] + 646.2557, measured value 646.2553.

[0073] Example 18 Ibuprofen azauracil derivatives were prepared according to the method described in Example 17, except that gemfibrozil was replaced with ibuprofen.

[0074] Ibuprofen-azauracil derivative (359 mg, 1 mmol), p-toluenesulfonyl chloride (285 mg, 1.5 mmol), decacarbonyldimanganese (10 mol%), and Xantphos (20 mol%) were added to a Schlenk reactor. After purging with nitrogen in a double-row tube, 20 mL of ethyl acetate solution containing [1.1.1]spiroalkyl (1.5 mmol) was added, and the reaction was carried out under 455 nm light for 12 h. After the reaction was completed, 20 g of saturated ammonium chloride aqueous solution was added to quench the reaction, followed by the addition of 20 g of ethyl acetate. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:20) to obtain 469 mg of a yellow liquid, with a yield of 81%.

[0075] 1 H NMR (500 MHz, CDCl3) d 7.76 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 4.41 – 4.36 (m, 1H), 4.30 (ddt, J = 11.5, 7.0, 3.7 Hz, 1H), 4.23 (ddd, J = 14.0, 7.0, 4.0 Hz, 1H),4.11 (ddd, J = 14.1, 6.0, 3.8 Hz, 1H), 3.62 (q, J = 7.2 Hz, 1H), 3.24 (s, 3H), 2.47 (s, 3H), 2.42 (d, J = 7.2 Hz, 2H), 2.35 (s, 6H), 1.82 (dq, J= 13.5, 6.8 Hz, 1H), 1.43 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.6 Hz, 6H); 13 C NMR (126 MHz, CDCl3) d 174.4, 155.2, 149.0, 144.9, 140.7, 139.7, 137.3, 133.6, 129.9, 129.3, 128.7, 127.0, 61.2, 52.4, 52.0, 50.4, 45.0, 45.0, 37.8, 30.1, 27.0, 22.4, 21.7, 18.5; HRMS-ESI: Theoretical Calculation C 31 H 37 N3O6SNa [M+Na] + 602.2295, measured value 602.2298.

[0076] Example 19 Prepared according to the method described in Example 1, the only difference being that the molar ratio of 1,3-dimethylazuracil, [1.1.1]spiroalkyl and p-toluenesulfonyl chloride was 1:1:1, yielding 217 mg of yellow solid with a yield of 60%.

[0077] Example 20 Prepared according to the method described in Example 1, the only difference being that the molar ratio of 1,3-dimethylazuracil, [1.1.1]spiroalkyl and p-toluenesulfonyl chloride was 1:2:2, the light wavelength was 405 nm, the reaction time was 24 h, and 260 mg of yellow solid was obtained, with a yield of 72%.

[0078] Example 21 Prepared according to the method described in Example 1, the only difference being that the equivalent amount of the decacarbonyl dimanganese catalyst was 5 mol%, the equivalent amount of the Xantphos ligand was 10 mol%, and the reaction solvent was acetonitrile, yielding 177 mg of yellow solid with a yield of 49%.

[0079] Example 22 Prepared according to the method described in Example 1, the only difference being that the manganese-based catalyst was manganese pentacarbonyl bromide and the light irradiation wavelength was 470 nm, yielding 126 mg of yellow solid with a yield of 35%.

[0080] Example 23 Prepared according to the method described in Example 1, the only difference being that the organophosphorus ligand was 1,2-bis(dimethylphosphine)ethane, the reaction time was 6 h, and the reaction solvent was N,N-dimethylformamide, yielding 119 mg of yellow solid with a yield of 33%.

[0081] Example 24 Prepared according to the method described in Example 1, the only difference being that the manganese-based catalyst was manganese acetate and the organophosphorus ligand was BINAP, yielding 83 mg of yellow solid with a yield of 23%.

[0082] Test Example 1 To evaluate the inhibitory effect of the compounds obtained in this invention on tumor cell proliferation, 1-sulfonyl-3-(hetero)arylbicyclo[1.1.1]pentane compounds obtained in Examples 9, 17, and 18 were selected and in vitro cytotoxicity tests were performed using the human cervical cancer HeLa cell line as a model, employing the classic MTT assay. The specific steps are as follows.

[0083] 1. Cell culture and seeding: Human cervical cancer HeLa cells were cultured in DMEM medium containing 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin in a humidified incubator at 37°C and 5% CO2. Cells in the logarithmic growth phase were harvested, digested with trypsin, resuspended in complete culture medium, and counted. The cell suspension was then divided into 5 × 10⁶ cells per well. 3 Cells were evenly seeded at a density of 100 μL in each well of a 96-well culture plate. The plate was then pre-cultured in an incubator for 24 hours to allow the cells to adhere fully.

[0084] 2. Compound treatment: The 1-sulfonyl-3-(hetero)arylbicyclo[1.1.1]pentane compounds obtained in Examples 9, 17, and 18 were prepared as stock solutions using dimethyl sulfoxide (DMSO) and serially diluted twofold with complete culture medium to establish eight concentration gradients: 1 µM, 2 µM, 4 µM, 8 µM, 16 µM, 32 µM, 64 µM, and 128 µM. The final concentration of DMSO in each well was ensured not to exceed 0.1% (v / v) to eliminate the influence of the solvent on cell viability. The old culture medium was removed from the 96-well plates, and 100 μL of fresh culture medium containing different concentrations of the test compounds was added. Five replicates were set up for each concentration. A negative control group (complete culture medium containing 0.1% DMSO) and a blank control group (culture medium only) were also set up.

[0085] 3. MTT testing and data analysis: Cells were cultured for another 48 hours after drug administration. Then, 20 μL of MTT solution (5 mg / mL) was added to each well, and incubation continued for another 4 hours. The supernatant was carefully aspirated from each well, and 150 μL of DMSO was added to each well. The cells were then shaken slowly for 10 min to fully dissolve the formazan crystals. The absorbance (OD value) of each well was measured at 570 nm using a microplate reader. Cell viability was calculated using the following formula: Survival rate (%) = [(OD_experimental group – OD_blank group) / (OD_negative control group – OD_blank group)] × 100%.

[0086] Subsequently, a dose-response curve was fitted with the logarithm of compound concentration on the x-axis and cell viability on the y-axis, and the half-maximal inhibitory concentration (IC50) was calculated. 50 The values ​​and their 95% confidence intervals. In vitro antitumor activity test results are as follows: Figure 1 As shown.

[0087] Depend on Figure 1 The results showed that all three compounds exhibited significant inhibitory effects on the proliferation of HeLa cells. The half-maximal inhibitory concentrations (IC50) of the compounds obtained in Examples 9, 17, and 18 were calculated. 50 The values ​​were 9.6±0.8 µM, 13.5±0.8 µM, and 11.2±0.6 µM, respectively. These data confirm that the 1-sulfonyl-3-(hetero)arylbicyclo[1.1.1]pentane compound provided by this invention exhibits excellent inhibitory activity against HeLa cells in in vitro experiments and can be considered as a candidate compound for antitumor drugs.

[0088] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A 1-heteroaryl-3-sulfone bicyclic [ 1.1.1] Pentane compounds, having the following chemical structures: ； in, R1 is a heteroaryl group; R2 is an aryl, heteroaryl, or alkyl group.

2. The 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound according to claim 1, characterized in that, The heteroaryl group in R1 includes one of uracil, quinoxalone, pyrazinone, pyranone, cyclophosphinone, quinolinyl, and indole.

3. The 1-heteroaryl-3-sulfone bicyclic [1.1.1]pentane compound according to claim 1, characterized in that, The aryl group in R2 includes phenyl, substituted phenyl, or naphthyl; the substituent in the substituted phenyl group is one of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, and cyano. The heteroaryl group in R2 includes oxazolyl or piperidinyl.

4. The 1-heteroaryl-3-sulfone bicyclic [according to claim 1] 1.1.1] Pentane compound, characterized in that, The 1-heteroaryl-3-sulfone bicyclic [ 1.1.1] Pentane has any of the following chemical structures: , , , , , , , , , , , , , , , , or .

5. The 1-heteroaryl-3-sulfone bicyclic [according to any one of claims 1 to 4] 1.1.1] A method for preparing pentane compounds, characterized by comprising the following steps: R1-H, [1.1.1]spiroalkyl and sulfonyl chloride compounds were mixed and subjected to a multi-component radical coupling reaction under light, manganese-based catalyst, organic bisphosphine ligand and organic solvent conditions to obtain the 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound; The sulfonyl chloride compound has the following structure: ； R1 and R2 are defined as in any one of claims 1 to 4.

6. The preparation method according to claim 5, wherein the molar ratio of R1-H, [1.1.1]spiroalkyl and sulfonyl chloride compound is 1:0.8~10:0.8~5.

7. The preparation method according to claim 5, characterized in that, The manganese-based catalyst includes one of manganese pentacarbonyl bromide, manganese acetate, and decacarbonyldimanganese; The molar ratio of R1-H to the manganese-based catalyst is 1:0.05~0.

2.

8. The preparation method according to claim 5, characterized in that, The organic bisphosphine ligand is one of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 1,2-bis(dimethylphosphine)ethane, 1,2-bis(diphenylphosphino)benzene, and 4,5-bis(diphenylphosphine)-9,9-dimethyloxane. The molar ratio of the manganese-based catalyst to the organic bisphosphine ligand is 1:1~2.

9. The preparation method according to claim 5, characterized in that, The wavelength of the light is 400~520nm; the reaction time is 8~24h.

10. The 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound according to any one of claims 1 to 4, or the 1-heteroaryl-3-sulfonyl bicyclic [1.1.1]pentane compound prepared by the preparation method according to any one of claims 5 to 9. 1.1.1] Application of pentane compounds in the preparation of antitumor drugs.

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