A compound containing a seven-membered lactam and pyranone skeleton and construction and application thereof

Abstract

The application belongs to the field of compound synthesis, and discloses a kind of compound containing seven-membered lactam and pyrone skeleton and its construction and application, and the chemical structure is shown in the following, wherein R1 is selected from any one of hydrogen, alkyl, halogen;R2 is selected from any one of alkyl, aryl;R3 is selected from any one of hydrogen, phenyl.The seven-membered lactam and pyrone skeleton has good drug activity, and can be used for preparing antitumor drugs.The application also discloses a construction method of the seven-membered lactam and pyrone skeleton.The construction method of the seven-membered lactam and pyrone skeleton has the advantages that raw materials and catalysts are cheap and easy to obtain, operation is simple and convenient, and the universality of substrates is wide.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis, and specifically relates to a compound containing a seven-membered lactam and pyranone skeleton, its construction and application. Background Technology

[0002] Seven-membered cyclic lactams are important skeletons containing oxygen and nitrogen heterocycles, possessing significant biological activity and medicinal value. For example, benazepril, an angiotensin-converting enzyme inhibitor, can be used to treat diabetes, kidney disease, hypertension, and heart failure. Kenpaullone (A), as a biological adjuvant, has been shown to have antitumor and anticancer activities, and different substituted alsterpaullones have also been shown to have similar anticancer activities and cyclin-dependent kinase inhibitory activities. Benzodiazepines are a class of psychoactive drugs with various psychoactive activities such as sedation and anxiolytics. Clonazepam, in particular, has anticonvulsant and anxiolytic effects and can be used to treat acute mania, while lorazepam, as an adjunct to antipsychotics, can treat insomnia and anxiety.

[0003]

[0004] Research shows that seven-membered cyclic lactams possess high pharmacological activity in anti-inflammatory, antiviral, antidepressant, and antitumor effects. The existing synthetic methods mainly include the following two:

[0005]

[0006] Existing synthesis methods all require multiple steps, are inefficient, and require many reaction conditions such as high temperature, light, and precious metal catalysts. Summary of the Invention

[0007] In order to overcome the shortcomings and deficiencies of the prior art, the primary objective of this invention is to provide a class of compounds containing a seven-membered lactam and pyranone skeleton.

[0008] Another object of the present invention is to provide a method for constructing the above-mentioned compound containing a seven-membered lactam-pyranone skeleton. The raw materials for this method are simple and readily available, and the compound containing a seven-membered lactam-pyranone skeleton can be obtained in only one step.

[0009] Another object of the present invention is to provide the application of the above-mentioned compounds containing a heptapram-pyranone skeleton.

[0010] The objective of this invention is achieved through the following solution:

[0011] A class of compounds containing a seven-membered lactam and pyranone skeleton have the general chemical structure shown in Formula I:

[0012]

[0013] Wherein, R1 is selected from any one of hydrogen, alkyl, and halogen; R2 is selected from any one of alkyl and aryl; and R3 is selected from any one of hydrogen and phenyl.

[0014] Preferably, the compound containing a seven-membered lactam-pyranone skeleton has a chemical structure selected from one of the following structural formulas:

[0015]

[0016] More preferably, the compound containing a seven-membered lactam-pyranone skeleton has a chemical structure selected from one of the following structural formulas:

[0017]

[0018] A method for constructing the above-mentioned compound containing a seven-membered lactam and pyranone skeleton includes the following steps: under nitrogen or inert gas protection, a base, the compound shown in Formula II, the compound shown in Formula III, and a solvent are mixed evenly, and the mixture is stirred at 0-100°C until the reaction is complete, and the compound shown in Formula I is separated.

[0019] The specific reaction route is shown below:

[0020]

[0021] Wherein, R1 is selected from any one of hydrogen, alkyl, and halogen; R2 is selected from any one of alkyl and aryl; and R3 is selected from any one of hydrogen and phenyl.

[0022] The compound shown in Formula II is an indole-derived 1,3-dicarbonyl compound, which can be synthesized according to the following literature method [J. Rodriguez, K. Mohanan, M. Presset, D. Maihol, Y. Coquerel, Chem. Eur. J., 2012, 18, 9217-9220].

[0023] The compound shown in Formula III is an enone imine, which can be synthesized according to the following literature method [(a)P]. Acta Chem. Scand., Ser. B, 1974, 28, 586-588; (b) I. Fernández, FP Cossío, MA Sierra, Organometallics, 2007, 26, 3010-3017].

[0024] The alkali is triethylamine (Et3N), sodium methoxide (MeONa), cesium carbonate (Cs2CO3), potassium hydroxide (KOH), triethylenediamine (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium hydroxide (NaOH), sodium tert-butoxide ( t BuONa), potassium tert-butoxide ( t At least one of BuOK and potassium carbonate (K2CO3).

[0025] The amount of alkali used is x% of the amount of the compound shown in Formula II, where x = 0.1 to 100, and x is preferably 50.

[0026] The amount of substance of the compound shown in Formula III is y times the amount of substance of the compound shown in Formula II, where y = 0.5 to 120, preferably 4 times.

[0027] The solvent is at least one selected from diethyl ether, methanol, ethanol, toluene, acetone, acetonitrile, 1,1,2-trichloroethane, ethyl acetate, dichloromethane, tetrahydrofuran, dimethyl sulfoxide, isopropanol, 1,2-dichloroethane, and nitromethane.

[0028] The solvent is used only as a reaction medium, so there is no need to limit its amount. It is preferred to use 0.5 mL to 40 mL per millimole (mmol) of the compound represented by Formula II.

[0029] The preferred reaction temperature is 0–100°C, and the preferred reaction time is 0.5–10 h.

[0030] The method for constructing compounds containing a seven-membered lactam-pyranone skeleton described in this invention is a simple and efficient method for synthesizing a seven-membered lactam-pyranone skeleton; the raw materials of this method are readily available, the conditions are mild, and the substrates have broad applicability.

[0031] The above-mentioned compounds containing a seven-membered lactampyranone skeleton are used in the preparation of antitumor drugs, especially in the preparation of drugs for gastrointestinal stromal tumors.

[0032] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0033] The compounds containing indole-derived seven-membered ring lactam structures described in this invention exhibit good pharmaceutical activity and are expected to become a new type of pharmaceutical intermediate. The method for constructing the seven-membered lactam-pyranone skeleton described in this invention has the following advantages: the raw materials and catalysts are inexpensive and readily available; the operation is simple and convenient; the substrate has broad applicability, and high yields can be obtained for the construction of a series of seven-membered lactam-pyranone skeletons. Detailed Implementation

[0034] The present invention will be further described in detail below with reference to embodiments, but the implementation of the present invention is not limited thereto. Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments used, unless otherwise specified, are all commercially available products.

[0035] The compound shown in Formula II is an indole-derived 1,3-dicarbonyl compound, which can be synthesized according to the following literature method [J. Rodriguez, K. Mohanan, M. Presset, D. Maihol, Y. Coquerel, Chem. Eur. J., 2012, 18, 9217-9220]. The compound shown in Formula III is an enone imine, which can be synthesized according to the following literature method [(a) P]. ActaChem.Scand.,Ser.B,1974,28,586-588; (b)I. FP MA Sierra, Organometallics, 2007, 26, 3010-3017].

[0036] Example 1

[0037] Synthesis of compounds containing a seven-membered lactam-pyranone skeleton as shown in Formula I-1:

[0038]

[0039] Under nitrogen protection, 2-(1-methyl-1H-indole-3-carbonyl)cyclopentan-1-one (compound shown in Formula II-1) (24.11 mg, 0.10 mmol), methyl 2-phenyl-3-(p-tolueneimino)acrylate (compound shown in Formula III-1) (106.04 mg, 0.40 mmol), base [K₂CO₃] (6.91 mg, 0.05 mmol), and solvent CH₃CN (3.0 mL) were added sequentially to a 10 mL Schlenk tube. The reaction mixture was stirred at 60 °C for 3 h. TLC analysis showed that the starting material had largely reacted, and the reaction was stopped. The reaction mixture was concentrated by rotary evaporation and then subjected to column chromatography with petroleum ether / ethyl acetate as eluent (3 / 1) to give product I-1, a yellow solid, 43.62 mg, with a yield of 92%.

[0040] Analytical data for compounds containing a seven-membered lactam-pyranone skeleton, as shown in Formula I-1: 1H NMR (400MHz, CDCl3): δ2.03-2.13(m,1H),2.20(s,3H),2.32-2.39(m,1H),2.70-2.94(m,3H),3.19(dd,J=14.4,5.6Hz,1H),3.89(s,3H),6 .51(d,J=8.4Hz,2H),6.79(d,J=8.4Hz,2H),6.91-6.93(m,2H),7.14-7.19(m,3H),7.28-7.42(m,3H),7.45(s,1H),8.09(d,J=7.2Hz,1H); 13 C NMR (100MHz, CDCl3): δ171.53,162.90,155.93,153.92,137.28,136.83,135.86,132.59,130.17,129.54,128.50,128.06,127.76 ,126.26,125.97,123.21,121.52,121.40,118.53,111.85,109.79,107.50,34.00,33.41,25.95,24.81,20.92.HRMS(ESI):Exact mass calcdfor C 31 H 27 N₂O₃[M+H] + :475.2016,Found:475.2009.

[0041] Example 2

[0042] Synthesis of compounds containing a seven-membered lactam-pyranone skeleton as shown in Formula I-2:

[0043]

[0044] Under nitrogen protection, 2-(5-chloro-1-methyl-1H-indole-3-carbonyl)cyclopentan-1-one (compound shown in Formula II-2) (27.51 mg, 0.10 mmol), methyl 2-phenyl-3-(p-tolueneimino)acrylate (compound shown in Formula III-1) (29.15 mg, 0.11 mmol), base [DBU] (1.52 mg, 0.01 mmol), and solvent ethyl acetate (EA) (3.0 mL) were added sequentially to a 10 mL Schlenk tube. The reaction mixture was stirred at 40 °C for 5 h. TLC analysis showed that the starting material had largely reacted, and the reaction was stopped. The reaction mixture was concentrated by rotary evaporation and then subjected to column chromatography with petroleum ether / ethyl acetate as eluent (1 / 1) to give product I-2, a yellow solid, 41.66 mg, with a yield of 82%.

[0045] Analytical data for compounds containing a seven-membered lactam-pyranone skeleton, as shown in Formula I-2: 1 H NMR (400MHz, CDCl3): δ1.99-2.11(m,1H),2.20(s,3H),2.31-2.46(m,1H),2.71-2.83(m,2H),2.85-2.94(m,1H),3.12(dd,J=14.8,7.5Hz,1H),3. 89(s,3H),6.50(d,J=8.4Hz,2H),6.79(d,J=8.0Hz,2H),6.90-6.93(m,2H ),7.13-7.19(m,3H),7.28-7.33(m,2H),7.43(s,1H),8.02-8.03(m,1H); 13 C NMR (100MHz, CDCl3): δ171.44,162.72,155.80,153.07,137.24,135.96,135.27,132.47,130.99,129.50,128.55,128.11,127.88,12 7.51,127.22,127.14,125.99,123.71,120.76,118.98,112.27,110.88,107.19,34.00,33.64,25.99,24.84,20.94.HRMS(ESI):Exact mass calcd for C 31 H 26 ClN2O3[M+H] + :509.1626,Found:509.1618.

[0046] Example 3

[0047] Synthesis of compounds containing a seven-membered lactam-pyranone skeleton as shown in Formula I-3:

[0048]

[0049] Under nitrogen protection, 2-(1,7-dimethyl-1H-indole-3-carbonyl)cyclopentan-1-one (compound shown in formula II-3) (25.51 mg, 0.10 mmol), methyl 2-phenyl-3-(p-tolueneimino)acrylate (compound shown in formula III-1) (79.53 mg, 0.30 mmol), alkali [NaOH] (2.00 mg, 0.05 mmol), and solvent dichloroethane (DCE) (4.0 mL) were added sequentially to a 10 mL Schlenk tube. The reaction mixture was stirred at 75 °C for 4 h. TLC analysis showed that the starting material had largely reacted, and the reaction was stopped. The reaction mixture was concentrated by rotary evaporation and then subjected to column chromatography with petroleum ether / ethyl acetate as eluent (3 / 1) to give product I-3, a yellow solid, in 38.07 mg, with a yield of 78%.

[0050] Analytical data for compounds containing a seven-membered lactam-pyranone skeleton, as shown in Formula I-3: 1 H NMR (400MHz, CDCl3): δ2.00-2.10(m,1H),2.21(s,3H),2.27-2.36(m,1H),2.6 8-2.77(m,2H),2.80(s,3H),2.85-2.93(m,1H),3.14(dd,J=14.4,6.0Hz,1H), 4.14(s,3H),6.51(d,J=8.4Hz,2H),6.79(d,J=8.0Hz,2H),6.91-6.93(m,2H), 7.04(d,J=7.2Hz,1H),7.12-7.19(m,4H),7.32(s,1H),7.86(d,J=7.6Hz,1H); 13 C NMR (100MHz, CDCl3): δ171.49,162.92,155.88,153.81,137.27,135.83,135.56,132.59,131.81,129.51,128.48,128.04,127.74,12 7.38,125.96,125.82,121.73,121.60,119.22,118.65,112.16,107.12,37.52,33.97,25.99,24.79,20.91,19.68.HRMS(ESI):Exact mass calcd for C 32 H 29 N₂O₃[M+H] + :489.2173,Found:489.2162.

[0051] Example 4

[0052] Synthesis of compounds containing a seven-membered lactam-pyranone skeleton as shown in Formula I-4:

[0053]

[0054] Under nitrogen protection, 2-(1-methyl-1H-indole-3-carbonyl)cyclopentan-1-one (compound shown in Formula II-1) (24.11 mg, 0.10 mmol), methyl 2-phenyl-3-(m-tolueneimino)acrylate (compound shown in Formula III-2) (53.02 mg, 0.20 mmol), alkali [KOH] (2.81 mg, 0.05 mmol), and solvent DMSO (2.0 mL) were added sequentially to a 10 mL Schlenk tube. The reaction mixture was stirred at 80 °C for 3 h. TLC analysis showed that the starting material had largely reacted, and the reaction was stopped. The reaction mixture was concentrated by rotary evaporation and then subjected to column chromatography with petroleum ether / ethyl acetate as eluent (2 / 1) to give product I-4, a yellow solid, 35.09 mg, with a yield of 74%.

[0055] Analytical data for compounds containing a seven-membered lactam-pyranone skeleton, as shown in Formula I-4: 1 H NMR (400MHz, CDCl3): δ2.04-2.14(m,1H),2.09(s,3H),2.31-2.40(m,1H),2.70-2.94(m,3H),3.20(dd,J=14.4,6.0Hz,1H),3.89(s,3H),6.38(s ,1H),6.45(d,J=8.0Hz,1H),6.80(d,J=7.6Hz,1H),6.88-6.92(m,3H),7 .14-7.21(m,3H),7.28-7.42(m,3H),7.45(s,1H),8.11(d,J=8.0Hz,1H); 13 C NMR (125MHz, CDCl3): δ171.48,162.88,156.04,153.97,139.77,137.75,136.83,132.54,130.15,129.58,128.06,127.78,127.67,127.52 ,126.93,126.26,123.24,123.10,121.55,121.42,118.60,111.80,109.80,107.50,34.07,33.43,25.97,24.82,20.92.HRMS(ESI):Exact mass calcd for C 31 H 27 N₂O₃[M+H] +:475.2016,Found:475.2009.

[0056] Example 5

[0057] Synthesis of compounds containing a seven-membered lactam-pyranone skeleton as shown in Formula I-5:

[0058]

[0059] Under nitrogen protection, 2-(1-methyl-1H-indole-3-carbonyl)cyclopentan-1-one (compound shown in Formula II-1) (24.11 mg, 0.10 mmol), methyl 3-[(4-ethylphenyl)imino]-2-phenylacrylate (compound shown in Formula III-3) (69.78 mg, 0.25 mmol), base [Et3N] (3.54 mg, 0.035 mmol), and solvent dichloromethane (DCM) (4.0 mL) were added sequentially to a 10 mL Schlenk tube. The reaction mixture was stirred at 40 °C for 6 h. TLC analysis showed that the starting material had largely reacted, and the reaction was stopped. The reaction mixture was concentrated by rotary evaporation and then subjected to column chromatography with petroleum ether / ethyl acetate as eluent (2 / 1) to give product I-5, a yellow solid, 37.10 mg, with a yield of 76%.

[0060] Analytical data for compounds containing a seven-membered lactam-pyranone skeleton, as shown in Formula I-5: 1 H NMR(400MHz, CDCl3):1.13(t,J=7.6Hz,3H),2.04-2.14(m,1H),2.30-2.40(m, 1H),2.49(dd,J=14.8,7.6Hz,2H),2.70-2.94(m,3H),3.19(dd,J=14.8,6.0Hz, 1H),3.89(s,3H),6.54(d,J=8.4Hz,2H),6.80(d,J=8.4Hz,2H),6.89-6.91(m, 2H),7.12-7.20(m,3H),7.28-7.42(m,3H),7.45(s,1H),8.09(d,J=8.0Hz,1H); 13CNMR (100MHz, CDCl3): δ171.49,162.90,156.04,153.92,142.22,137.50,136.82,132.63,130.16,129.49,128.04,127.69,127.33,1 26.25,126.03,123.20,121.51,121.39,118.47,111.82,109.78,107.48,34.04,33.40,28.33,25.95,24.82,15.67.HRMS(ESI):Exact mass calcd for C 32 H 29 N₂O₃[M+H] + :489.2173,Found:489.2161.

[0061] Example 6

[0062] Synthesis of compounds containing a seven-membered lactam-pyranone skeleton as shown in Formula I-6:

[0063]

[0064] Under nitrogen protection, 2-(1-methyl-1H-indole-3-carbonyl)cyclopentan-1-one (compound shown in Formula II-1) (24.11 mg, 0.10 mmol), methyl 3-[(4-phenoxyphenyl)imino]-2-phenylacrylate (compound shown in Formula III-4) (68.62 mg, 0.20 mmol), base [Cs₂CO₃] (9.77 mg, 0.03 mmol), and solvent tetrahydrofuran (THF) (3.0 mL) were added sequentially to a 10 mL Schlenk tube. The reaction mixture was stirred at 80 °C for 6 h. TLC analysis showed that the starting material had largely reacted, and the reaction was stopped. The reaction mixture was concentrated by rotary evaporation and then subjected to column chromatography with petroleum ether / ethyl acetate as eluent (3 / 1) to give product I-6, a yellow solid, 45.83 mg, with a yield of 83%.

[0065] Analytical data for compounds containing a seven-membered lactam-pyranone skeleton, as shown in Formula I-6: 1H NMR (400MHz, CDCl3): δ2.08-2.14(m,1H),2.32-2.41(m,1H),2.72-2.83(m,2H) ,2.87-2.95(m,1H),3.20(dd,J=14.4,6.0Hz,1H),3.89(s,3H),6.62-6.66(m,4H ),6.91(d,J=7.6Hz,2H),6.99-7.01(m,2H),7.09(t,J=7.6Hz,1H),7.22-7.24(m ,3H),7.31-7.35(m,3H),7.37-7.42(m,2H),7.45(s,1H),8.10(d,J=8.0Hz,1H); 13 C NMR (100MHz, CDCl3): δ171.53,162.81,157.22,155.83,154.62,154.15,136.85,135.26,132.68,130.19,129.62,128.21,127.94,127.60 ,126.24,123.27,123.14,121.59,121.41,118.62,118.37,118.30,111.64,109.81,107.46,34.03,33.44,25.95,24.84.HRMS(ESI):Exact mass calcd for C 36 H 29 N₂O₄[M+H] + :553.2122,Found:553.2122.

[0066] Example 7

[0067] Synthesis of compounds containing a seven-membered lactam-pyranone skeleton, as shown in Formula I-7:

[0068]

[0069] Under nitrogen protection, 2-(1-methyl-1H-indole-3-carbonyl)cyclopentan-1-one (compound shown in Formula II-1) (24.11 mg, 0.10 mmol), methyl 3-(cyclohexylimino)-2-phenylacrylate (compound shown in Formula III-5) (89.99 mg, 0.35 mmol), base [DABCO] (3.37 mg, 0.03 mmol), and solvent toluene (3.0 mL) were added sequentially to a 10 mL Schlenk tube. The reaction mixture was stirred at 100 °C for 6 h. TLC analysis showed that the starting material had largely reacted, and the reaction was stopped. The reaction mixture was concentrated by rotary evaporation and then subjected to column chromatography with petroleum ether / ethyl acetate as eluent to give product I-7, a yellow solid, 41.96 mg, with a yield of 90%.

[0070] Analytical data for compounds containing a seven-membered lactam-pyranone skeleton, as shown in Formula I-7: 1 H NMR (400MHz, CDCl3): δ0.47 (d, J = 11.2Hz, 1H), 0.62-0.74 (m, 1H), 0.86-1.01 (m, 1H), 1.05-1 .10(m,1H),1.41-1.43(m,2H),1.55-1.62(m,3H),1.83-2.00(m,2H),2.17-2.26(m,1H),2.45 (dd,J=12.4,6.4Hz,1H),2.52-2.68(m,2H),3.02(d,J=14.4,6.0Hz,1H),3.07-3.14(m,1H), 3.86(s,3H),7.25-7.29(m,1H),7.31-7.39(m,6H),7.42-7.46(m,2H),7.94(d,J=7.6Hz,1H); 13 CNMR (100MHz, CDCl3): δ172.53,162.98,156.88,153.00,136.71,133.24,130.27,128.65,128.53,126.17,123.01,121.31,121 .11,118.76,112.61,109.77,107.48,65.86,34.73,33.31,29.66,29.40,26.60,26.34,25.54,25.10,24.42.HRMS(ESI):Exact mass calcdfor C 30 H 31 N₂O₃[M+H] + :467.2329,Found:467.2323.

[0071] Example 8

[0072] Synthesis of compounds containing a seven-membered lactam-pyranone skeleton, as shown in Formula I-8:

[0073]

[0074] Under nitrogen protection, 2-(1-methyl-1H-indole-3-carbonyl)cyclopentan-1-one (compound shown in Formula II-1) (24.11 mg, 0.10 mmol), 3-[(3,4-dimethoxyphenethyl)imino]-2-phenylacrylate methyl ester (compound shown in Formula III-6) (67.82 mg, 0.20 mmol), and a base were added sequentially to a 10 mL Schlenk tube. t BuONa (4.81 mg, 0.05 mmol) and acetone (3.0 mL) were added as solvent. The reaction mixture was stirred at 65 °C for 6 h. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction mixture was concentrated by rotary evaporation and then subjected to column chromatography with petroleum ether / ethyl acetate as eluent (2 / 1) to give product I-8, a yellow solid, 34.54 mg, with a yield of 63%.

[0075] Analytical data for compounds containing a seven-membered lactam-pyranone skeleton, as shown in Formula I-8: 1 H NMR (400MHz, CDCl3): δ1.83-1.91(m,1H),2.09-2.19(m,2H),2.55-2.65(m,4H),2 .66-2.74(m,1H),2.79-2.83(m,1H),3.75(s,3H),3.76(s,3H),3.85(s,3H),4.02- 4.11(m,1H),6.54(s,1H),6.58(dd,J=8.0,1.5Hz,1H),6.68(d,J=8.5Hz,1H),7.28 (d,J=7.5Hz,1H),7.31-7.38(m,4H),7.44(d,J=4.5Hz,4H),7.93(d,J=8.0Hz,1H); 13C NMR (125MHz, CDCl3): δ172.29,162.73,154.09,153.41,148.71,147.58, 136.73,132.70,130.48,130.24,129.40,128.83,128.59,126.19,123.1 1,121.41,121.19,120.46,116.32,112.46,111.76,111.15,109.74,107 .38,55.74,46.38,33.57,33.35,33.32,25.28,23.99.HRMS(ESI):Exact mass calcd forC 34 H 33 N₂O₅[M+H] + :549.2384,Found:549.2371.

[0076] Example 9

[0077] Synthesis of compounds containing a seven-membered lactam-pyranone skeleton, as shown in Formula I-9:

[0078]

[0079] Under nitrogen protection, in a 10 mL Schlenk tube, 2-(1-methyl-2-phenyl-1H-indole-3-carbonyl)cyclopentan-1-one (compound shown in formula II-3) (31.71 mg, 0.10 mmol), methyl 2-phenyl-3-(p-tolueneimino)acrylate (compound shown in formula III-1) (159.06 mg, 0.60 mmol), and alkali [ t [BuOK] (1.12 mg, 0.01 mmol) and solvent ethyl acetate (EA) (4.0 mL). The reaction mixture was stirred at 90 °C for 8 h. TLC showed that the starting material had basically reacted completely, and the reaction was stopped. The reaction mixture was concentrated by rotary evaporation and then subjected to column chromatography with petroleum ether / ethyl acetate = 3 / 1 as eluent to give product I-9, a yellow solid, 47.87 mg, with a yield of 87%.

[0080] Analytical data for compounds containing a seven-membered lactam-pyranone skeleton, as shown in Formula I-9: 1H NMR (400MHz, CDCl3): δ1.61(brs,1H),1.73-1.83(m,1H),2.00-2.16(m,1H),2. 20(s,3H),2.38-2.43(m,1H),2.53(dd,J=14.4,6.4Hz,2H),3.80(s,3H),6.33( d,J=8.0Hz,2H),6.77(d,J=8.0Hz,2H),6.92-6.94(m,2H),7.14-7.20(m,3H),7 .28-7.32(m,1H),7.36-7.40(m,1H),7.46-7.57(m,6H),7.78(d,J=8.0Hz,1H); 13 C NMR (100MHz, CDCl3): δ171.26,163.41,155.58,153.12,141.07,137.27,137.17,135.87,132.35,130.79,130.46,129.43,129.18,128.46 ,128.10,127.93,127.19,125.87,123.13,121.37,120.62,119.82,115.32,109.99,106.33,33.69,31.42,24.22,20.92.HRMS(ESI):Exact mass calcd for C 37 H 31 N₂O₃[M+H] + :551.2329,Found:551.2309.

[0081] Example 10

[0082] Antitumor activity assay of compounds containing a heptalactamopyranone skeleton:

[0083] Given that the seven-membered lactam-pyranone skeleton we synthesized contains important elements for anti-cell proliferation, we then performed MTT assays on the anti-proliferative activity of the compounds mentioned in the above examples. The background above introduces Kenpaullone (A), which has anti-tumor activity. The compounds synthesized using the method of this invention have similar seven-membered cyclic amide structures. All nine compounds reported in this paper underwent MTT assays for anti-proliferative activity.

[0084] The MTT assay for cell antiproliferative activity used human gastrointestinal stromal tumor (GIST) cells (Shanghai Enzyme-Link Biotechnology Co., Ltd.) as the test cell line. The specific steps were as follows: After thawing the GIST-882 cells from liquid nitrogen cryopreservation, the cells were transferred to 2 mL cryovials, centrifuged, and then resuspended in 1 mL of fetal bovine serum culture medium (Wuhan Shangen Biotechnology Co., Ltd.). The cells were then transferred to culture dishes and cultured routinely at 37°C in a 5% CO2 incubator. After rinsing with 3 mL of PBS buffer, the cells were treated with 0.6 mL of 0.25% trypsin. Two days later, 3 mL of culture medium containing fetal bovine serum (Sijiqing Bioengineering Materials Co., Ltd.) was added to terminate the digestion. The cells were then cultured at 8 × 10⁻⁶ cells / mL. 5 / mL, add 100μL of cell suspension to a 96-well plate and incubate overnight in a cell culture incubator. Weigh the positive control drug and the target compound into centrifuge tubes, add DMSO and a solubilizer (Tween 80, castor oil) to prepare a 100μM / L stock solution. Dilute the stock solution to different gradients and add it to the 96 wells in sequence. Incubate at 37℃ and 5% CO2 for 72h, then add MTT solution and continue incubation for 4h. Discard the supernatant, add DMSO solution, and measure the OD value of each well at 490nm and perform data processing.

[0085] Table 1. Inhibitory effects of Kenpaullone (A) and compounds from Examples 1-9 on the proliferation of GIST-882 cells.

[0086]

[0087]

[0088] The results showed that compounds I-1 to I-9 could effectively inhibit the proliferation of GIST-882 cells, thereby inhibiting tumor formation. Among them, compounds I-2, I-6, and I-9 exhibited significant antitumor activity, with IC50 values ​​of [missing information]. 50 The values ​​were 3.24±0.42μM, 3.57±0.02μM, and 4.13±0.75μM, respectively, compared with the reference drug kenparone A (IC50). 50 =4.71±0.02μM) compared to IC 50 The lower values ​​indicate that compounds I-2, I-6, and I-9 possess superior antitumor activity. Overall, the antitumor activity test data in Table 1 demonstrate that the compounds containing a seven-membered lactam-pyranone skeleton described in this invention exhibit high antitumor activity, providing an important basis for further research on such compounds and the development of novel antitumor drugs, and thus possessing significant research value.

[0089] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A class of compounds containing a seven-membered lactam and pyrone skeleton, characterized in that Its chemical structure is selected from one of the following structural formulas: 。 2. The compound containing a seven-membered lactam and pyranone skeleton according to claim 1, characterized by Its chemical structure is selected from one of the following structural formulas: 。 3. The use of the compound containing a heptapramopyranone skeleton according to any one of claims 1-2 in the preparation of an anti-gastrointestinal stromal tumor drug.

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