A spirocyclobutane indole ketone derivative, its preparation method and application

Abstract

This invention provides a spirocyclobutane indole ketone derivative, its preparation method, and its applications, belonging to the field of organic chemical synthesis technology. This invention utilizes a photocatalytic system to achieve a tandem cyclization coupling reaction between an N-iodoarylbicyclobutylamide compound and a vinylpyridine compound, for constructing a spirocyclobutane indole ketone derivative containing a pyridine structure. The spirocyclobutane indole ketone derivative synthesized in this invention exhibits inhibitory activity against H1975 human lung adenocarcinoma cells. The preparation method provided by this invention is mild, simple to operate, and economical, offering a convenient synthetic route for this complex bioactive molecule and showing promising application prospects.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and in particular to a spirocyclobutane indole ketone derivative, its preparation method, and its application. Background Technology

[0002] Spirocyclic indolones are an important class of spiroheterocyclic structures, widely found in numerous natural products and pharmaceutical active molecules, and possess significant biological activities (Bioorg. Med. Chem. 2015, 23, 7138; J. Am. Chem. Soc. 2008, 130, 17938; Angew. Chem., Int. Ed. 2004, 43, 1270). Studies have reported that compounds of this class, such as Horsflinee, Elacomine, and Mitraphylline, exhibit antitumor, anti-inflammatory, antibacterial, and antiviral pharmacological activities. Therefore, chemists have developed many efficient strategies for the synthesis of spirocyclic indolones over the past few decades (J. Heterocycl. Chem. 2018, 55, 1783–1790; Tetrahedron. 2018, 74, 955–9614; Synlett. 2019, 30, 82–88). Among these synthetic methods, relatively few are applicable to the synthesis of spirocyclobutane indolones due to limitations in substrate synthesis. For example, nucleophilic substitution reactions of indolones with alkyl dihalides and 1,5-hydrogen migration reactions of aryl halides are only applicable to the preparation of partially unsubstituted spirocyclobutane indolones (Journal of Medicinal Chemistry, 2013, 56, 9275-9295; Journal of Medicinal Chemistry, 2013, 56, 9275-9295). Intramolecular CH arylation of cyclobutane is also only applicable to the synthesis of spirocyclobenzocyclobutane indolones (Chem. Eur. J. 2013, 19, 11916). In recent years, bicyclobutane (BCB) structures have become star molecules for the preparation of functionalized strained ring molecules. The research groups of Hari, Maji, Li Jinheng, Tang Kewen, and Rong Liangce have achieved the synthesis of spirocyclobutane indolones with functional groups such as carbonyl, sulfone, selenide, and halogen by utilizing the radical cyclization strategy of aryl bicyclic butylamides (Chem. Sci. 2024, 15, 3182–3191; Org. Lett. 2024, 26, 6396-6401; Org. Lett. 2024, 26(10), 2073-2078; Org. Chem. Front. 2024, 11, 1982-1989; J. Org. Chem. 2024, 89, 15914-15923). Despite some progress, the functionalization types of spirocyclobutane indolones still need to be expanded, and more novel and green synthetic methods need to be developed to further broaden the structural diversity of this type of skeleton. Summary of the Invention

[0003] Based on the above, the present invention aims to provide a spirocyclobutane indole ketone derivative, its preparation method, and its applications. The present invention utilizes a photocatalytic system to achieve a tandem cyclization coupling reaction between an N-iodoarylbicyclobutylamide compound and a vinylpyridine compound, thereby constructing a spirocyclobutane indole ketone derivative containing a pyridine structure. Bioactivity evaluation revealed that the spirocyclobutane indole ketone derivative prepared by the method of the present invention has an inhibitory effect on H1975 human lung adenocarcinoma cells.

[0004] To achieve the above objectives, the present invention provides the following technical solution:

[0005] One of the technical solutions of this invention is a spirocyclobutane indole ketone derivative having the structure shown in Formula I:

[0006]

[0007] In Equation I, R 1 R is hydrogen, alkoxy, or alkyl. 2 It is alkyl or benzyl, R 3 It can be hydrogen or methyl.

[0008] In a preferred embodiment of the present invention, in formula I, R 1 R is hydrogen, methyl, or methoxy. 2 For methyl, benzyl, R 3 It can be hydrogen or methyl.

[0009] The second technical solution of the present invention is a method for preparing the above-mentioned spirocyclobutane indole ketone derivative, wherein an N-iodoarylbicyclobutylamide compound and a vinylpyridine compound are dissolved in an organic solvent, and then a catalyst and additives are added, and the reaction is carried out under blue light catalysis to obtain the spirocyclobutane indole ketone derivative.

[0010] The structural formula of the N-iodoarylbicyclobutylamide compound is:

[0011] The structural formula of the vinylpyridine compound is as follows:

[0012] Among them, in N-iodoarylbicyclobutylamide compounds and vinylpyridine compounds, R 1 R 2 R 3 With the above R 1 R 2 R 3 same.

[0013] In a preferred embodiment of the present invention, the catalyst is (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, tris(2-phenylpyridine)iridium, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile, or tris(2,2'-bipyridine)ruthenium di(hexafluorophosphate);

[0014] The additive is triethylamine, 8-diazabicycloundec-7-ene, or diisopropylamine;

[0015] The organic solvent is acetonitrile, N,N-dimethylformamide, dichloroethane, toluene, or N,N-dimethylacetamide.

[0016] In a preferred embodiment of the present invention, the molar ratio of the N-iodoarylbicyclobutylamide compound to the vinylpyridine compound is 1:2; the molar ratio of the N-iodoarylbicyclobutylamide compound to the catalyst is 1:0.01 to 0.2; the molar ratio of the N-iodoarylbicyclobutylamide compound to the additive is 1:10 to 15; and the molar ratio of the N-iodoarylbicyclobutylamide compound to the organic solvent is 0.1 mmol: 1 to 3 mL.

[0017] In a preferred embodiment of the present invention, the power of the blue light is 3 to 10 W, and the reaction time is 12 to 24 hours.

[0018] In a preferred embodiment of the present invention, after the reaction is completed, the product is further separated and purified.

[0019] The specific steps for separation and purification are as follows: After the reaction is completed, the resulting reaction solution is subjected to liquid phase extraction, and the extractant used for liquid phase extraction is ethyl acetate; after extraction, the supernatant is collected, dried with anhydrous sodium sulfate, and the ethyl acetate is evaporated to obtain crude crystals. After recrystallization, the crystals are subjected to silica gel column chromatography with a mesh size of 200-400. The eluent is a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1:1-10.

[0020] The third technical solution of the present invention is the application of the above-mentioned spirocyclobutane indoleone derivative in the preparation of a drug for treating H1975 human lung adenocarcinoma.

[0021] The fourth technical solution of the present invention is a drug for treating lung adenocarcinoma in H1975 patients, the raw materials of which include the above-mentioned spirocyclobutane indoleone derivative and pharmaceutically acceptable excipients.

[0022] The present invention discloses the following technical effects:

[0023] This invention utilizes N-iodoarylbicyclobutylamide compounds and vinylpyridine compounds to prepare spirocyclobutane indolone derivatives, thereby inhibiting H1975 human lung adenocarcinoma cells.

[0024] The preparation method of this invention is mild, low-cost, simple to operate, highly atom-economical, and environmentally friendly, providing a convenient synthetic route for this complex bioactive molecule and showing good prospects for industrial application. Detailed Implementation

[0025] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0026] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0027] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0028] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0029] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0030] The preparation method of the spirocyclobutane indole ketone derivative in this invention is as follows: N-iodoarylbicyclobutylamide compound and vinylpyridine compound are dissolved in an organic solvent, then a catalyst and additives are added, and the reaction is carried out under blue light catalysis. After the reaction is completed, the resulting reaction solution is subjected to liquid phase extraction; after extraction, the supernatant is collected, dried with anhydrous sodium sulfate, and ethyl acetate is evaporated to obtain crude crystals. After recrystallization, the crystals are subjected to silica gel column chromatography with a mesh size of 200-400. The eluent is a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1:1-10 to obtain the spirocyclobutane indole ketone derivative.

[0031]

[0032] The N-iodoarylbicyclobutylamide compounds used in the examples can be synthesized according to the literature (Org. Chem. Front. 2024, 11, 1982-1989).

[0033] In this invention, the additive is triethylamine, 8-diazabicycloundec-7-ene, or diisopropylamine;

[0034] The organic solvent is acetonitrile, N,N-dimethylformamide, dichloroethane, toluene, or N,N-dimethylacetamide;

[0035] The catalyst is (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III)hexafluorophosphate, tris(2-phenylpyridine)iridium, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile, or tris(2,2'-bipyridine)ruthenium di(hexafluorophosphate).

[0036] The extractant used in the liquid phase extraction is ethyl acetate.

[0037] Unless otherwise specified, the technical solutions described in this invention are all conventional solutions in the field, and the reagents or raw materials used are all purchased from commercial channels or are publicly available unless otherwise specified.

[0038] In this embodiment of the invention, the antitumor activity of spirocyclobutane indole ketone derivatives against tumor cells was evaluated by an in vitro cell proliferation and toxicity assay (CCK-8 assay), and compounds with good activity against tumor cells were screened out.

[0039] Cells were observed under a microscope. When the cells adhered and grew to 80%-90%, the culture dishes were sterilized and placed in a clean bench. The cells were washed twice with prepared PBS buffer and the central area was agitated with fresh culture medium. The cell suspension was then transferred to centrifuge tubes. Next, 10 μL of the cell suspension was pipetted into a cell counting chamber, and cell counting was performed using a cell counter. Cells were cultured in 96-well plates at a seeding density of 5000 cells per well (50000 cells / mL, 100 μL of cell suspension added). The plates were incubated in a CO2 cell culture incubator for 24 h until the cells adhered. The compounds to be tested were diluted with culture medium to the corresponding concentrations (5 μmol / L, 10 μmol / L, 20 μmol / L, 40 μmol / L, 60 μmol / L, 80 μmol / L) and added to 96-well plates already seeded with H1975 cells, 100 μL per well, with 6 replicates. The plates were then incubated in a cell culture incubator. After 24 hours, remove the samples, add 100 μL of CCK-8 reagent to each well, incubate for 2 hours, and then detect the results using a microplate reader. Calculate the IC50 using GraphPad. 50 .

[0040] To better understand the present invention, the following embodiments further illustrate the content of the present invention, but the content of the present invention is not limited to the following embodiments.

[0041] Example 1

[0042] Weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol), and acetonitrile (3 mL) were added sequentially to a 25 mL Shrek tube. The mixture was reacted under nitrogen atmosphere and 3 W blue light for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (15 mL × 3). The ethyl acetate layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-2 / 1) to give a yellow liquid with a yield of 82%.

[0043] The reaction equation is as follows:

[0044]

[0045] The structural characterization data of the obtained target product are shown below:

[0046] 1H NMR(400MHz,Chloroform-d)δ8.57–8.44(m,1H),7.67–7.44(m,1H),7.30(s,0 .3H),7.18–7.13(m,1.7H),7.11–7.05(m,1H),7.04–6.98(m,1H),6.69–6.53( m,1H),3.12(d,J=2.8Hz,3H),2.93–2.83(m,0.7H),2.80–2.67(m,2.3H),2.60 –2.50(m,2H),2.34(d,J=4.4Hz,3H),2.30–2.23(m,0.7H),2.10–1.91(m,3.3H)

[0047] 13 C NMR(100MHz,Chloroform-d)δ181.4,179.3,161.9,161.8,149.2(2C),140.7(2C),136.4(2C),135.1,133.6,132.1(2C),128.1,127.8 ,123.7,122.9(2C),122.8,121.1(2C),107.5,107.3,45.0(2C),37.6,37.4,37.2,36.6,35.8(2C),30.3,29.0,26.3,26.2,21.2(2C).

[0048] HRMS(ESI)m / z calcd for C 20 H 23 N₂O₁[M+H] + 307.1805, found 307.1797.

[0049] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0050]

[0051] This compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC50. 50 The value is 57.07 μM.

[0052] Example 2

[0053] Weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol), and acetonitrile (3 mL) were added sequentially to a 25 mL Shrek tube. The mixture was reacted under nitrogen atmosphere and 3 W blue light for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (15 mL × 3). The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-2 / 1) to give a yellow liquid with a yield of 84%.

[0054] The reaction equation is as follows:

[0055]

[0056] The structural characterization data of the obtained target product are shown below:

[0057] 1 H NMR(400MHz,Chloroform-d)δ8.50(t,J=5.3Hz,1H),7.65–7.48(m,1H),7.18–7.12(m,1H ),7.11–7.05(m,1.5H),6.95(d,J=2.5Hz,0.5H),6.77–6.71(m,1H),6.64(t,J=8.8Hz,1H ),3.80(d,3H),3.13(d,J=3.0Hz,3H),2.95–2.83(m,0.5H),2.80–2.74(m,2H),2.72–2.6 5(m,0.5H),2.61–2.52(m,1H),2.40–2.32(m,1H),2.31–2.23(m,1H),2.08–1.93(m,3H).

[0058] 13 C NMR(100MHz,Chloroform-d)δ181.1,179.0,161.9(2C),156.3(2C),149.4(2C),136.8(2C),136.61–136.4(3C),134.9,122.9(2C) ),121.1(2C),112.1,111.5,110.5,110.1,107.9(2C),56.0(2C),45.5(2C),37.8,37.4,37.3,36.6,35.9,30.3,29.1,26.5,26.3.

[0059] HRMS(ESI)m / z calcd for C 20 H 23 N₂O₂[M+H] + 323.1754, found 323.1748.

[0060] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0061]

[0062] This compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC50. 50 The value is 61.01 μM.

[0063] Example 3

[0064] Weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol), and acetonitrile (0.3 mL) were added sequentially to a 25 mL Shrek tube. The mixture was reacted under nitrogen atmosphere and 3 W blue light for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (15 mL × 3). The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-2 / 1) to give a yellow liquid with a yield of 81%.

[0065] The reaction equation is as follows:

[0066]

[0067] The structural characterization data of the obtained target product are shown below:

[0068] 1H NMR(400MHz,Chloroform-d)δ8.54(td,J=5.0,1.8Hz,1H),7.63–7.56(m,1H),7.51–7.48(m,0.4H) ,7.36(d,J=7.5Hz,0.6H),7.32–7.21(m,5H),7.20–7.16(m,1H),7.15–7.08(m,2H),7.04(t,J=7.5 Hz,1H),6.67(t,J=8.5Hz,1H),4.88(d,J=3.4Hz,2H),3.08–2.89(m,0.6H),2.84–2.72(m,2.4H),2 .70–2.62(m,1H),2.50–2.42(m,1H),2.40–2.33(m,1H),2.16–2.07(m,2H),2.03(q,J=7.7Hz,1H).

[0069] 13 C NMR(100MHz,Chloroform-d)δ181.5,179.5,161.9(2C),149.3(2C),142.2(2C),136.4(2C),136.2(2C),135.1,133.5,128.8(2C),127.9,127.6( 2C),127.4,122.9(2C),122.8,122.7(2C),122.2,121.1(2C),108.8,10 8.6,45.0(2C),43.9,43.7,37.9,37.4(2C),36.6,35.8(2C),30.2,29.2.

[0070] HRMS(ESI)m / z calcd for C 25 H 25 N₂O₁[M+H] + 369.1961, found 369.1953.

[0071] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0072]

[0073] This compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC50. 50 The value is 40.83 μM.

[0074] Example 4

[0075] Weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol), and acetonitrile (3 mL) were added sequentially to a 25 mL Shrek tube. The mixture was reacted under nitrogen atmosphere and 3 W blue light for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (15 mL × 3). The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-2 / 1) to give a yellow liquid with a yield of 57%.

[0076] The reaction equation is as follows:

[0077]

[0078] The structural characterization data are shown below:

[0079] 1 H NMR(400MHz,Chloroform-d)δ8.52(t,J=4.8Hz,1H),7.74–7.52(m,4.6H),7.48(d,J= 7.3Hz,0.4H),7.39–7.28(m,7H),7.23–7.13(m,2H),7.11–7.02(m,2H),6.81–6.68(m ,1H),4.15(q,J=5.9Hz,2H),3.75(q,J=6.8Hz,2H),3.26–3.07(m,2H),2.97–2.86(m, 2H),2.82–2.72(m,2H),2.64–2.54(m,1H),2.42–2.23(m,2.4H),2.12–1.93(m,5.6H).

[0080] 13C NMR(100MHz,Chloroform-d)δ181.4,179.3,172.0,161.9–161.7(3C),149.3(2C),145.5,1 42.3,142.2,136.4(2C),135.2(2C),133.6,132.5,129.0,128.7,128.6,128.5,128.1,128. 0,127.7,126.6,123.1,123.0,122.8,122.6(2C),122.3,121.1(2C),107.8,107.6,62.2(2 C),44.9(2C),37.8,37.4,37.3,37.0,36.8,36.5,35.8,31.1,30.2,29.8,29.1,26.7,23.6.

[0081] HRMS(ESI)m / z calcd for C 39 H 36 N3O4[MH] - 610.2711, found 610.2715.

[0082] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0083]

[0084] This compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC50. 50 The value is 42.34 μM.

[0085] Example 5

[0086] To a 25 mL Shrek tube, add the following compounds in sequence: N-iodoarylbicyclobutylamide (0.3 mmol), vinylpyridine (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III)hexafluorophosphate (0.003 mmol), triethylamine (3 mmol), and acetonitrile (3 mL). Under nitrogen atmosphere and blue light at 3 W, the mixture was reacted for 16 hours. After the reaction, the mixture was extracted with ethyl acetate (15 mL × 3). The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-2 / 1) to obtain a yellow liquid with a yield of 87%.

[0087] The reaction equation is as follows:

[0088]

[0089] The structural characterization data are shown below:

[0090] 1 H NMR(400MHz,Chloroform-d)δ8.51(t,J=5.4Hz,1H),8.06(d,J=8.0Hz,2H),7.83(d,J=7.9Hz,2H),7.58(t,J=7.4Hz,1H) ,7.48(d,J=7.3Hz,0.4H),7.34(d,J=7.0Hz,0.6H),7.24–7.18(m,1H),7.15(d,J=7.6Hz,1H),7.08(q,J=7.5Hz,2H),6.86 –6.66(m,1H),4.38(q,J=5.4Hz,2H),3.87(q,J=6.1Hz,2H),3.19–3.03(m,3H),2.94–2.83(m,0.8H),2.78–2.66(m,2.2H ),2.60–2.50(m,1H),2.39–2.22(m,2H),2.19–2.11(m,2H),2.08–1.91(m,4H),1.61–1.42(m,4H),0.86(t,J=7.3Hz,6H).

[0091] 13 C NMR(100MHz,Chloroform-d)δ181.5,179.4,165.2,161.8(2C),149.3(2C),144.3,14 2.2(2C),136.5(2C),135.2,133.7,133.4,130.3,128.0,127.8,127.1,123.2,123.0, 122.8–122.7(3C),122.4,121.2(2C),107.8,107.6,63.1,50.1,44.9,37.8,37.4,37. 2,37.1,36.9,36.5,35.8,34.0,30.2,29.4,29.1,27.3,26.8,25.7,25.0,22.1,11.3.

[0092] HRMS(ESI)m / z calcd for C 34 H 42 N3O5S1[M+H] + 604.2840, found 604.2825.

[0093] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0094]

[0095] This compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC50. 50 The value is 40.32 μM.

[0096] Example 6

[0097] Weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol), and acetonitrile (3 mL) were added sequentially to a 25 mL Shrek tube. The mixture was reacted under nitrogen atmosphere and 3 W blue light for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (15 mL × 3). The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-2 / 1) to give a yellow liquid with a yield of 87%.

[0098] The reaction equation is as follows:

[0099]

[0100] The structural characterization data are shown below:

[0101] 1 H NMR (400MHz, DMSO-d6) δ8.61–8.35(m,2H),7.54(d,J=7.2Hz,0.55H),7.48(d,J=7.2Hz,0.45H),7.31–7.20(m,3H),7.11–7.02(m,1H),6.99– 6.86(m,1H),3.09(s,3H),2.79–2.62(m,1H),2.61–2.52(m,2H),2.45– 2.33(m,1H),2.27–2.13(m,2H),2.09–2.00(m,1H),1.91–1.78(m,2H).

[0102] 13 C NMR(101MHz,DMSO-d6)δ180.0,178.1,150.8(2C),149.4(2C),142.9,142.8,134.2,132.7,127.9,127.7,123.9 (2C),122.8,122.3,122.2,121.9,108.1,107.8,44.1(2C),36.8(3C),36.6,31.8,31.7,29.1,28.3,26.0,25.8.

[0103] HRMS(ESI)m / z calcd for C 19 H 21 N₂O₁[M+H] + 293.1648, found 293.1641.

[0104] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0105]

[0106] This compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC50. 50 The value is 35.29 μM.

[0107] Example 7

[0108] Weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol), and acetonitrile (3 mL) were added sequentially to a 25 mL Shrek tube. The mixture was reacted under nitrogen atmosphere and 3 W blue light for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (15 mL × 3). The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-2 / 1) to give a yellow liquid with a yield of 94%.

[0109] The reaction equation is as follows:

[0110]

[0111] The structural characterization data are shown below:

[0112] 1 H NMR (400MHz, DMSO-d6) δ8.32(d,J=5.0Hz,1H),7.55(d,J=7.2Hz,0.45H),7.46(d,J=7.2Hz,0.55H),7.25(q,J=6.9Hz,1H),7.12–7.03(m,2H),7.00( d,J=4.6Hz,1H),6.97–6.86(m,1H),3.09(s,3H),2.83–2.57(m,3H),2.44– 2.35(m,1H),2.30–2.10(m,5H),2.08–1.98(m,1H),1.91(q,J=7.5Hz,2H).

[0113] 13 C NMR(100MHz,DMSO-d6)δ180.1,178.2,161.1,148.7,148.6,146.8,146.7,142.9,142.7,134.3,132.8,127.9,127.7,123.3(2C),12 3.2,122.7,122.4,122.3,122.0,121.9,108.1,107.8,44.1(2C),36.9,36.7,36.4,36.2,34.8,34.7,29.3,28.4,26.0,25.8,20.4.

[0114] HRMS(ESI)m / z calcd for C 20 H 23 N₂O[M+H] + 307.1805, found 307.1799.

[0115] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0116]

[0117] This compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC50. 50 The value is 32.82 μM.

[0118] Example 8

[0119] Weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol), and acetonitrile (3 mL) were added sequentially to a 25 mL Shrek tube. The mixture was reacted under nitrogen atmosphere and 3 W blue light for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (15 mL × 3). The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-2 / 1) to obtain a yellow liquid with a yield of 82%.

[0120] The reaction equation is as follows:

[0121]

[0122] The structural characterization data are shown below:

[0123] 1H NMR (400MHz, DMSO-d6) δ8.31(d,J=4.2Hz,1H),7.56(d,J=7.3Hz,0.4H),7.51–7.43(m,1.6H),7.25(q,J=7.3Hz,1H),7.14–7.02(m,2H ),6.98–6.85(m,1H),3.09(s,3H),2.87–2.56(m,3H),2.45–2.36(m,1H),2.31–2.12(m,5H),2.06–1.98(m,1H),1.91(q,J=7.5Hz,2H).

[0124] 13 C NMR(100MHz,DMSO-d6)δ180.1,178.2,159.5,146.3(2C),142.8(2C),137.3(2C),134.3,132.8,130.6(2C),127.9,127.6,122 .7,122.3,122.2,121.9,121.2(2C),108.0,107.8,44.1,37.0,36.7,35.1,34.8,32.0(2C),29.4,28.6,25.9(2C),18.2(2C).

[0125] HRMS(ESI)m / z calcd for C 20 H 23 N2O[M+H]+307.1805,found 307.1799.

[0126] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0127]

[0128] This compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC50. 50 The value is 35.47 μM.

[0129] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A spirocyclobutane indolone derivative, characterized in that, It has the structure shown in Equation I: In Equation I, R 1 R is hydrogen, methyl, or methoxy. 2 For methyl, benzyl, R 3 It can be hydrogen or methyl.

2. A method for preparing the spirocyclobutane indole ketone derivative of claim 1, characterized in that, The N-iodoarylbicyclobutylamide compound and the vinylpyridine compound were dissolved in an organic solvent, and then a catalyst and additives were added. The reaction was carried out under blue light catalysis to obtain the spirocyclobutane indolone derivative. The structural formula of the N-iodoarylbicyclobutylamide compound is: The structural formula of the vinylpyridine compound is as follows: Among them, in N-iodoarylbicyclobutylamide compounds and vinylpyridine compounds, R 1 R 2 R 3 With R in claim 1 1 R 2 R 3 same; The catalyst is (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate; The additive is triethylamine; The organic solvent is acetonitrile, N,N-dimethylformamide, dichloroethane, toluene, or N,N-dimethylacetamide.

3. The preparation method according to claim 2, characterized in that, The molar ratio of the N-iodoarylbicyclobutylamide compound to the vinylpyridine compound is 1:2; the molar ratio of the N-iodoarylbicyclobutylamide compound to the catalyst is 1:0.01-0.2; the molar ratio of the N-iodoarylbicyclobutylamide compound to the additive is 1:10-15; and the molar ratio of the N-iodoarylbicyclobutylamide compound to the organic solvent is 0.1 mmol:1 mL-3 mL.

4. The preparation method according to claim 2, characterized in that, The power of the blue light is 3-10W, and the reaction time is 12-24h.

5. The preparation method according to claim 2, characterized in that, After the reaction is complete, the steps also include separating and purifying the resulting product.

6. The use of the spirocyclobutane indolone derivative of claim 1 in the preparation of a drug for treating H1975 human lung adenocarcinoma.

7. A drug for treating lung adenocarcinoma in H1975 patients, characterized in that, The raw materials include the spirocyclobutane indole ketone derivative as described in claim 1, and pharmaceutically acceptable excipients.

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