Spirocyclic oxidized indole derivatives spliced ​​with MOMIPP skeleton, preparation method and application thereof

Abstract

The invention discloses a spirocyclic oxidized indole derivative spliced ​​with a MOMIPP skeleton, a preparation method and an application thereof. The invention obtains a spirocyclic oxidized indole derivative spliced ​​with a MOMIPP skeleton by reacting compound 1, compound 2 and compound 3 in an organic solvent at a molar ratio of 1:4:4 to produce a 1,3-dipole 3+2 cycloaddition reaction. The compound is an important class of drug molecule analogs, among which 26 compounds have better in vitro inhibitory activity on A549 cells than the positive control drug cisplatin, 32 compounds have better in vitro inhibitory activity on A549 / DDP cells than the positive control drug cisplatin, and 21 compounds such as compounds 4cl and 4al show very good selectivity on drug-resistant strain A549 / DDP cells, laying a foundation for the research on the development of highly efficient, low-toxic and highly selective anti-lung cancer drug resistance agents.

Description

Technical Field

[0001] The invention relates to the field of chemical technology, in particular to a MOMIPP skeleton-joined spirocyclic oxidized indole derivative and a preparation method and application thereof. Background Art

[0002] 3-(5-methoxy, 2-methyl-1H indol-3-yl)-1-(4-pyridyl)-2-propene-1-one (MOMIPP) has good anti-tumor activity, can cause giant vesicular death in glioblastoma U251 and human breast cancer cells MCF-7, and also has a good inhibitory effect on drug-resistant tumor cells. At the same time, spirocyclic indole compounds also have good anti-tumor activity. The structural mother core is widely present in many anti-tumor active molecules, such as MI-63, MI-219, MI-77301, etc., and its mechanism of action is different from that of MOMIPP. Its mechanism of action is mainly to inhibit the binding of p53-MDM2. Based on the fact that the MOMIPP active skeleton has the potential to be developed into a giant vesicular death inducer, and the spirocyclic oxidized indole structure is the basic skeleton of the p53-MDM2 inhibitor, we used the 1,3-dipole 3+2 cycloaddition reaction according to the drug splicing principle to splice the MOMIPP active skeleton with the spirocyclic oxidized indole structure, and then tested its in vitro anti-lung cancer activity, in order to obtain MOMIPP skeleton-spliced ​​spirocyclic oxidized indole derivatives with good anti-lung cancer activity and anti-drug resistance. Summary of the invention

[0003] The purpose of the present invention is to provide a spirocyclic oxidized indole derivative spliced ​​with a MOMIPP skeleton and a preparation method and application thereof. This type of compound is an important class of drug molecule analogs, has excellent in vitro anti-lung cancer activity, and also has excellent anti-drug resistance. It also has excellent selectivity for drug-resistant lung cancer cells, and is of great significance to the research on anti-lung cancer drugs and anti-lung cancer resistance drugs. The synthesis method is simple, the post-processing is simple, and the raw materials are cheap and easy to obtain.

[0004] The present invention also finds the anti-tumor drug resistance effect of the compound and the application in preparing drugs for preventing and treating tumor diseases.

[0005] The present invention is achieved by: a spirocyclic oxidized indole derivative spliced ​​with a MOMIPP skeleton, the compound having the following structure:

[0006]

[0007] The structure is specifically one of the following structural formulas:

[0008]

[0009] The preparation method of the spirocyclic oxidized indole derivatives spliced ​​with the MOMIPP skeleton is to subject compound 1 (MOMIPP skeleton derivative), compound 2 (isatin or substituted isatin), and compound 3 (amino acid or its derivative) to a 1,3-dipole 3+2 cycloaddition reaction in an organic solvent at a molar ratio of 1:4:4 to obtain a spirocyclic oxidized indole derivative spliced ​​with the MOMIPP skeleton, as shown in the following route:

[0010]

[0011] Wherein: the amino acid or its derivative is sarcosyl or proline or thioproline, etc., and the structural formula of compound 4 is consistent with the structural formula in (I).

[0012] The preparation method of the spirocyclic oxidized indole derivatives spliced ​​with a MOMIPP skeleton, wherein the organic solvent is acetonitrile, dichloromethane, anhydrous ethanol, methanol, acetone, N,N'-dimethylformamide, toluene, chloroform or ether.

[0013] The preparation method of the MOMIPP skeleton spliced ​​spirocyclic oxidized indole derivatives has a reaction time of 0.5 to 36.0 hours and a reaction temperature of 25 to 100°C.

[0014] The MOMIPP skeleton-spliced ​​spirocyclic oxidized indole derivatives are used in the preparation of drugs for preventing and treating tumor diseases, wherein the tumor diseases are tumors caused by non-small cell lung cancer cells A549 or human lung adenocarcinoma cisplatin-resistant strains A549 / DDP.

[0015] By adopting the above technical scheme, compound 1 (MOMIPP skeleton derivative), compound 2 (isatin or substituted isatin), and compound 3 (amino acid or its derivative) are subjected to a 1,3-dipole 3+2 cycloaddition reaction in an organic solvent at a molar ratio of 1:4:4 to obtain spirocyclic oxidized indole derivatives spliced ​​with a MOMIPP skeleton. This type of compound is an important class of drug molecule analogs, has excellent in vitro anti-lung cancer activity, and has excellent anti-drug resistance. It also has excellent selectivity for resistant lung cancer cells, and is of great significance for the research on anti-lung cancer drugs and anti-lung cancer resistance drugs. It has the advantages of simple synthesis method, simple post-processing, and cheap and readily available raw materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Attached Figure 1 The hydrogen spectrum and carbon spectrum of compound 4aa in the embodiment of the present invention;

[0017] Attached Figure 2 The hydrogen and carbon spectra of compound 4ba according to the embodiment of the present invention;

[0018] Attached Figure 3The hydrogen and carbon spectra of compound 4ca of the embodiment of the present invention; DETAILED DESCRIPTION

[0019] Embodiment 1 of the present invention:

[0020] Synthesis of compound 4aa: 32.6 mg of compound 1 (3-(5-bromo-1H indol-3-yl)-1-(4-pyridyl)-2-propene-1-one) (1 eq), 64.4 mg of 5-methyl isatin (4 eq), and 35.6 mg of sarcosine (4 eq) were weighed into a reaction tube, a magnetic stirrer was added, and finally 4 mL of acetonitrile solution was added to react at 80°C. The reaction was basically complete when detected by TLC. The spirocyclic oxidized indole derivative 4aa with MOMIPP skeleton splicing was obtained by silica gel column chromatography as a yellow solid with a melting point of 147.2-148.1°C and a yield of 88.9%. The high-resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 27 H 23 BrN4NaO2[M+Na] + :537.0902; Found:537.0899. The results of the MRI test are as follows: 1 H NMR (CDCl3, 600MHz) δ: 8.55 (s, 1H), 8.48 (s, 1H), 8.42 (d, J = 6.0Hz, 2H), 8.2 9(s,1H),7.20(d,J=8.6Hz,1H),7.13(d,J=6.1Hz,2H),6.91(s,1H),6.80(dd ,J=7.9,1.8Hz,1H),6.36(d,J=7.8Hz,1H),4.75–4.71(m,1H),4.61(d,J=9.3 Hz, 1H), 3.80 (t, J = 9.4Hz, 1H), 3.48–3.42 (m, 1H), 2.26 (s, 3H), 2.24 (s, 3H). 13 C NMR(CDCl3,151MHz)δ:197.73,180.05,150.05,143.33,138.29,135.20,132.74,129.81,128.31,127.31,126.7 9,125.02,123.45,122.46,120.70,115.23,113.02,112.78,109.36,73.28,61.96,59.17,36.13,34.93,21.01.

[0021] The preparation method of compounds 4ab to 4am is the same as that of compound 4aa, and the feed ratio is the same as that of compound 4aa, and compounds 4ab to 4am can be obtained. The detailed reaction is shown in Table 1, but it should be emphasized that the compounds of the present invention are not limited to the contents shown in Table 1.

[0022] Table 1 Synthesis route of spirocyclic oxidized indole derivatives spliced ​​with MOMIPP skeleton 1

[0023]

[0024] Compound 4ab prepared in this example: brown solid, melting point: 154.8-155.7°C, yield: 80.0%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 27 H 23 BrN4NaO3[M+Na] + :553.0851; Found:553.0852. The results of the MRI test are as follows: 1 H NMR(CDCl3,600MHz)δ:8.60(s,1H),8.49(s,1H),8.42(d,J=4.4Hz,2H),8.28(s,1H),7.20(d,J=8.5Hz,1H),7.18–7.15(m,2H),6.69(s,1H),6.55– 6.52(m,1H),6.38(d,J=8.4Hz,1H),4.74–4.70(m,1H),4.61(d,J=9.3Hz, 1H), 3.75 (s, 3H), 3.68–3.63 (m, 1H), 3.45 (t, J = 8.2Hz, 1H), 2.25 (s, 3H). 13 C NMR(CDCl3,151MHz)δ:197.60,180.11,156.19,150.12,143.13,135.18,134.04,128.28,127.93,125.00,123.4 7,122.42,120.67,115.21,115.07,113.00,112.78,112.62,110.20,73.64,61.89,59.09,55.92,36.16,34.89.

[0025] Compound 4ac prepared in this example: yellow solid, melting point: 149.6-150.5°C, yield: 76.8%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 26 H 20 BrClN4NaO2[M+Na] +:557.0356; Found:557.0348. The results of the MRI test are as follows: 1 H NMR(CDCl3,600MHz)δ:8.87(s,1H),8.49–8.44(m,3H),8.26(d,J=1.9Hz,1H),7.20(d,J=8.7Hz,1H),7.19–7.15(m,2H),7.04(d,J=8.0Hz,1H ), 6.94(dd,J=8.0,1.9Hz,1H),6.53(s,1H),4.73–4.66(m,1H),4.63(d,J=9.4Hz,1H),3.79(t,J=9.3Hz,1H),3.46–3.41(m,1H),2.23(s,3H). 13 C NMR(CDCl3,151MHz)δ:197.48,180.13,150.18,143.14,141.94,135.34,135.23,128.16,127.78,125.25,12 5.14,123.44,123.14,122.40,120.74,114.90,113.12,112.83,110.30,73.02,61.92,59.05,36.37,34.85.

[0026] This example prepares compound 4ad: yellow solid, melting point: 147.6-148.4°C, yield: 80.9

[0027] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 28 H 23 BrN4NaO2[M+Na] + :553.0851; Found:553.0856. The results of the MRI test are as follows: 1 H NMR (CDCl3, 600MHz) δ: 8.75 (s, 1H), 8.63 (s, 1H), 8.44 (d, J = 5.8Hz, 2H), 8.2 6(s,1H),7.24(d,J=10.4Hz,1H),7.20–7.15(m,2H),6.99(d,J=8.3Hz,1H), 6.45(dd,J=8.3,2.3Hz,1H),6.08(s,1H),4.75–4.67(m,1H),4.61(d,J=9.2 Hz, 1H), 3.76 (t, J = 9.4Hz, 1H), 3.66 (s, 3H), 3.46–3.40 (m, 1H), 2.22 (s, 3H). 13C NMR(CDCl3,151MHz)δ:197.81,180.65,160.98,150.04,143.31,142.11,135.21,127.62,125.00,123.41,1 22.41,120.77,118.20,115.42,112.99,112.81,107.80,96.93,73.12,61.75,59.12,55.47,36.00,34.79.

[0028] This example prepares compound 4ae: yellow solid, melting point: 171.5-172.4°C, yield: 87.2

[0029] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 28 H 23 BrN4NaO2[M+Na] + :537.0902; Found:537.0899. The results of the MRI test are as follows: 1 H NMR (CDCl3, 600MHz) δ: 8.90 (s, 1H), 8.53 (s, 1H), 8.43 (d, J = 6.1Hz, 2H), 8.28 (s, 1H), 7.20 (d, J = 8.5Hz, 1H), 7.12–7.08 (m, 2H), 6.94 (d, J = 7.2Hz, 1H),6.85(dd,J=14.1,7.4Hz,2H),4.76–4.68(m,1H),4.62(d,J=9.3Hz, 1H), 3.80 (t, J = 9.3Hz, 1H), 3.49–3.43 (m, 1H), 2.24 (s, 3H), 1.99 (s, 3H). 13 C NMR(CDCl3,151MHz)δ:197.68,180.58,149.86,143.32,139.43,135.22,130.74,128.25,126.37,125.05,124.0 6,123.48,123.09,122.42,120.68,118.89,115.33,113.03,112.79,73.78,62.29,59.25,36.01,35.01,15.96.

[0030] Compound 4af prepared in this example: brown solid, melting point: 171.1-171.8°C, yield: 88.6%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 26 H 21BrN4NaO2[M+Na] + :523.0746; Found:523.0743. The results of the MRI test are as follows: 1 H NMR (CDCl3, 600MHz) δ: 8.94 (s, 1H), 8.78 (s, 1H), 8.37 (d, J = 5.0Hz, 2H), 8.26 (s ,1H),7.22(d,J=8.9Hz,1H),7.18(d,J=8.4Hz,1H),7.12–7.06(m,2H),6.98(d,J =7.9Hz,1H),6.92(t,J=7.7Hz,1H),6.45(d,J=7.8Hz,1H),4.74-4.70(m,1H),4 .62(d,J=9.3Hz,1H), 3.77(t,J=9.4Hz,1H), 3.45(t,J=8.4Hz,1H), 2.21(s,3H). 13 C NMR(CDCl3,151MHz)δ:197.67,180.09,149.97,143.28,140.83,135.22,129.54,128.30,126.74,125.0 1,123.49,123.11,122.41,120.77,115.21,113.00,112.85,109.68,73.32,62.05,59.23,36.10,34.92.

[0031] Compound 4ag prepared in this example: brown solid, melting point: 139.9-140.8°C, yield: 76.8%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 26 H 20 BrClN4NaO2[M+Na] + :557.0356; Found:557.0355. The results of the MRI test are as follows: 1 H NMR (CD3OD, 600MHz) δ: 8.45 (d, J = 5.1Hz, 2H), 8.17 (d, J = 2.0Hz, 1H), 8.08 (d, J = 7.0Hz, 1H), 7.33 (s, 1H), 7.25 (s, 1H), 7.18 (d, J = 8.6Hz, 1H), 7. 05(d,J=6.3Hz,2H),6.93(d,J=6.9Hz,1H),6.47(d,J=9.7Hz,1H),4.70 –4.65(m,2H),3.80–3.74(m,1H),3.44–3.39(m,1H),2.24–2.20(m,3H). 13C NMR(CD3OD,151MHz)δ:198.79,181.06,151.11,142.06,137.06,130.63,129.43,129.04,127.94,125.3 8,125.24,122.86,122.28,114.80,114.15,113.27,111.95,108.20,74.67,63.29,60.20,37.72,35.20.

[0032] This example prepared compound 4ah: brown solid, melting point: 163.2-163.9°C, yield: 76.5

[0033] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 26 H 19 BrF2N4NaO2[M+Na] + :559.0557; Found:559.0559. The results of the MRI test are as follows: 1 H NMR(DMS O-d6,600MHz)δ:11.11(s,1H),10.61(s,1H),8.51(d,J=6.1Hz,2H),8.04(d,J=1 .9Hz,1H),7.34(d,J=2.6Hz,1H),7.24(d,J=8.5Hz,1H),7.18–7.15(m,2H),7.11 (dd,J=8.5,2.0Hz,1H),7.01(dd,J=9.6,7.9Hz,1H),6.44(dd,J=10.3,6.5Hz,1H ),4.54(d,J=9.9Hz,1H),4.51–4.46(m,1H),3.40(t,J=9.1Hz,2H),2.02(s,3H). 13 C NMR(DMSO-d6,151MHz)δ:197.93,178.75,150.60,142.33,135.26,128.19,124.32,123.72, 121.33,120.33,113.68,113.38,111.38,99.38,99.23,72.46,60.98,58.80,35.63,34.51.

[0034] Compound 4ai prepared in this example: yellow solid, melting point: 173.4-174.3°C, yield: 80.3%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 26 H 20Br2N4NaO2[M+Na] + :600.9851; Found:600.9853. The results of the MRI test are as follows: 1 H NMR(CDCl3,600MHz)δ:8.87(s,1H),8.57(s,1H),8.44(d,J=5.6Hz,2H),8.29(s,1H),7.23–7.19(m,2H),7.17(d,J=5.6Hz,2H),7.13(dd,J =8.2, 2.0Hz, 1H), 6.35 (d, J = 8.2Hz, 1H), 4.72–4.67 (m, 1H), 4.62 (d, J = 9.4Hz, 1H), 3.80 (t, J = 9.5Hz, 1H), 3.46–3.40 (m, 1H), 2.24 (s, 3H). 13 C NMR(CD Cl3,151MHz)δ:197.41,179.76,150.16,143.25,139.89,135.26,132.36,129.72,129.16,128.13,125.0 6,123.65,122.40,120.75,115.74,114.67,113.05,112.87,111.15,73.25,61.96,58.99,36.31,34.93.

[0035] Compound 4aj prepared in this example: brown solid, melting point: 156.8-157.7°C, yield: 77.9%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 26 H 20 BrN5NaO4[M+Na] + :568.0596; Found:568.0599. The results of the MRI test are as follows: 1 H NMR(DMSO-d6,600MHz)δ:11.21(s,1H),11.16(s,1H),8.49(d,J=5.0Hz,2H),8.07(s,1H),7.97(dd,J=8.6,2.5Hz,1H),7.74(s,1H),7.41(s,1H) ,7.29(d,J=8.5Hz,1H),7.16(d,J=5.0Hz,3H),6.63(d,J=8.7Hz,1H),4. 63(d,J=9.8Hz,1H),4.60–4.54(m,1H),3.51–3.45(m,2H),2.09(s,3H). 13CNMR(DMSO-d6,151MHz)δ:198.40,179.72,151.07,148.91,142.82,142.66,135.69,128.56,128.44,127.00, 124.94,124.15,121.83,121.70,120.69,114.11,113.39,111.84,110.19,72.45,61.46,59.23,36.39,34.98.

[0036] Compound 4ak prepared in this example: yellow solid, melting point: 139.9-140.7°C, yield: 85.5%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 26 H 20 BrFN4NaO2[M+Na] + :541.0651; Found:541.0657. The results of the MRI test are as follows: 1 H NMR (DMSO-d6, 600MHz) δ: 11.15 (s, 1H), 10.65 (s, 1H), 8.53 (d, J = 5.0Hz, 2H) ,8.09(s,1H),7.39(s,1H),7.30(d,J=8.5Hz,1H),7.18–7.16(m,3H),6.98– 6.96(m,1H),6.68(t,J=9.1Hz,1H),6.25(d,J=9.0Hz,1H),4.57(d,J=9.7Hz ,1H),4.54–4.50(m,1H),3.51–3.48(m,1H),3.41–3.38(m,1H),2.07(s,3H). 13 C NMR(DMSO-d6,151MHz)δ:198.40,179.56,150.86,142.82,135.70,128.54,124.83,124.10,121.73, 120.68,114.09,113.88,111.78,108.71,108.57,97.96,97.78,72.39,61.23,59.06,36.08,34.83.

[0037] Compound 4a1 prepared in this example: brown solid, melting point: 158.8-159.5°C, yield: 73.7%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 26 H 20 Br2N4NaO2[M+Na] +:600.9851; Found:600.9853. The results of the MRI test are as follows: 1 H NMR (DMSO-d6, 600MHz) δ: 11.16 (s, 1H), 10.80 (s, 1H), 8.50 (d, J = 4.8Hz, 2H), 8. 11(s,1H),7.41(s,1H),7.31(d,J=8.5Hz,1H),7.18(t,J=7.4Hz,2H),7.10(d,J =5.1Hz,2H),6.97(d,J=7.4Hz,1H),6.83(t,J=7.7Hz,1H),4.59(d,J=9.7Hz,1H ), 4.54–4.49 (m, 1H), 3.50 (t, J = 9.2Hz, 1H), 3.43 (t, J = 7.9Hz, 1H), 2.09 (s, 3H). 13 C NMR(DMSO-d6,151MHz)δ:198.23,179.29,150.67,142.76,141.85,135.69,132.52,129.22,128.57,125.50,1 24.87,124.11,124.00,121.73,120.54,114.09,113.76,111.80,102.39,73.71,61.91,59.24,36.03,35.01.

[0038] Compound 4am prepared in this example: brown solid, melting point: 166.2-166.8°C, yield: 83.9%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 26 H 20 BrClN4NaO2[M+Na] + :557.0356; Found:557.0355. The results of the MRI test are as follows: 1H NMR(DMS O-d6,400MHz)δ:11.19(s,1H),10.96(s,1H),8.56–8.50(m,2H),8.13(d,J=1.9Hz,1H), 7.43(d,J=2.5Hz,1H),7.33(d,J=8.6Hz,1H),7.20(dd,J=8.6,1.9Hz,1H),7.16–7.10(m, 2H),7.09(dd,J=7.9,1.4Hz,1H),6.97(d,J=6.1Hz,1H),6.92(t,J=7.6Hz,1H),4.62(d, J=9.8Hz,1H),4.60–4.49(m,1H),3.53(t,J=9.1Hz,1H),3.49–3.41(m,1H),2.12(s,3H). 13 C NMR(DMSO-d6,101MHz)δ:198.25,179.33,150.71,142.78,140.16,135.71,129.63,129.20,128.59,125.08,1 24.88,124.12,123.66,121.74,120.59,114.21,114.11,113.79,111.80,73.48,61.81,59.24,36.05,35.01.

[0039] The preparation method of compounds 4ba to 4bg is the same as that of compound 4aa, and the feed ratio is the same as that of compound 4aa. Compounds 4ba to 4bg can be obtained by simply replacing the reactant 3 sarcosine with proline. The detailed reaction is shown in Table 2, but it should be emphasized that the compounds of the present invention are not limited to the contents shown in Table 2.

[0040] Table 2 Synthesis route of spirocyclic oxidized indole derivatives spliced ​​with MOMIPP skeleton 2

[0041]

[0042] This example prepares compound 4ba: brown solid, melting point: 149.1-149.7°C, yield: 91.4

[0043] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 29 H 25 BrN4NaO2[M+Na] + :563.1059; Found:563.1051. The results of the MRI test are as follows: 1H NMR (CDCl3, 600MHz) δ: 8.74 (s, 1H), 8.64 (s, 1H), 8.41 (d, J = 5.1Hz, 2H), 8.2 1(s,1H),7.21(d,J=8.5Hz,1H),7.12(d,J=5.2Hz,2H),7.01(s,1H),6.92(d ,J=7.9Hz,1H),6.45(d,J=7.8Hz,1H),4.99(d,J=11.3Hz,1H),4.38–4.34(m ,1H),2.75–2.71(m,1H),2.63–2.59(m,1H),2.37(s,3H),2.05–1.83(m,5H). 13 C NMR(CDCl3,151MHz)δ:197.34,180.93,149.97,143.34,138.38,135.17,131.98,130.15,128.41,128.03,124.97, 124.81,123.34,122.02,120.95,113.85,112.91,110.13,73.58,70.96,64.33,48.17,44.29,31.15,27.27,21.26.

[0044] This example prepares compound 4bb: brown solid, melting point: 160.1-160.9°C, yield: 73.5

[0045] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 28 H 22 Br2N4NaO2[M+Na] + :627.0007; Found:627.0013. The results of the MRI test are as follows: 1 H NMR(CDCl3,600MHz)δ:8.65(s,1H),8.56(d,J=5.1Hz,3H),8.17(s,1H),7.32(d,J=8.2Hz,1H),7.23–7.19(m,2H),7.07(d, J=5.0Hz,2H),6.98(t,J=7.8Hz,1H),5.01(d,J=11.4Hz,1H),4.40–4.36(m,1H),2.65(t,J=6.5Hz,2H),2.07–1.88(m,5H). 13C NMR(CDCl3,151MHz)δ:197.36,179.51,150.20,143.39,140.27,135.13,132.43,128.41,126.61,126.20,125.19,1 23.63,123.21,122.01,120.76,113.67,113.10,112.91,103.76,74.86,71.23,65.25,48.05,44.12,31.50,27.67.

[0046] This example prepared compound 4bc: brown solid, melting point: 163.6-164.3°C, yield: 92.7

[0047] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 28 H 22 BrClN4NaO2[M+Na] + :583.0512; Found:583.0508. The results of the MRI test are as follows: 1 H NMR(CDCl3,600MHz)δ:9.26(s,1H),8.65(s,1H),8.54(d,J=5.2Hz,2H),8.16(s,1H),7.22–7.15(m,3H),7.07(d,J=5.1Hz,2H ),7.02(d,J=7.9Hz,1H),5.02(d,J=11.4Hz,1H),4.37–4.33(m,1H),2.65–2.63(m,2H),2.08–1.82(m,4H),1.74–1.69(m,1H). 13 C NMR(CDCl3,151MHz)δ:197.43,179.77,149.93,143.63,139.01,135.14,129.66,128.48,126.67,125.61,125.14,1 23.19,123.15,121.96,120.88,115.77,113.69,113.05,112.95,74.67,71.41,65.36,48.04,43.96,31.65,27.77.

[0048] Compound 4bd prepared in this example: yellow solid, melting point: 174.6-175.2°C, yield: 87.5%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 29 H 25BrN4NaO2[M+Na] + :563.1059; Found:563.1066. The results of the MRI test are as follows: 1 H NMR (CDCl3, 600MHz) δ: 8.87 (s, 1H), 8.62 (s, 1H), 8.46 (d, J = 6.1Hz, 2H), 8. 20(s,1H),7.21(d,J=8.5Hz,1H),7.08–7.05(m,3H),6.98–6.97(m,2H),4. 99(d,J=11.4Hz,1H),4.39–4.35(m,1H),2.74–2.70(m,1H),2.64–2.61(m, 1H),2.05–2.00(m,2H),1.99(s,3H),1.95–1.85(m,2H),1.76–1.71(m,1H). 13 C NMR(CDCl3,151MHz)δ:197.60,181.03,149.82,143.67,139.65,135.17,130.96,128.45,125.07,124.87,124.48,123. 32,122.42,122.07,120.98,119.49,113.98,113.00,112.90,74.01,71.16,64.93,48.24,44.15,31.36,27.41,16.20.

[0049] This example prepares compound 4be: brown solid, melting point: 168.2-168.7°C, yield: 85.0

[0050] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 28 H 23 BrN4NaO2[M+Na] + :549.0902; Found:549.0900. The results of the MRI test are as follows: 1 H NMR(CDCl3,400MHz)δ:8.49–8.44(m,2H),8.39(s,1H),8.22(s,2H),7.29(d,J=2.3Hz,1H),7.24–7.22(m,1H),7.18–7.12(m,3H ),7.07–7.03(m,1H),6.57(d,J=7.57Hz,1H),5.00(d,J=11.4Hz,1H),4.46–4.37(m,1H),2.76–2.59(m,2H),1.98–1.85(m,5H).13 C NMR(CDCl3,101MHz)δ:197.29,180.62,150.16,143.21,140.73,135.17,129.85,128.43,127.62,125.19,124.84,1 23.27,122.58,122.16,120.96,113.93,113.11,112.87,110.34,73.50,70.92,64.35,48.27,44.50,31.17,27.28.

[0051] Compound 4bf prepared in this example: brown solid, melting point: 156.7-157.2°C, yield: 85.8%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 29 H 25 BrN4NaO3[M+Na] + :579.1008; Found:579.1011. The results of the MRI test are as follows: 1 H NMR (DMSO-d6, 600MHz) δ: 11.11 (s, 1H), 10.12 (s, 1H), 8.49 (d, J = 5.2Hz, 2H), 8.07 (d, J = 1.9Hz, 1H), 7.4 5(d,J=2.5Hz,1H),7.24(d,J=8.6Hz,1H),7.16(d,J=8.3Hz,1H),7.13–7.09(m,3H),6.44(dd,J=8.3,2.4 Hz,1H),5.99(d,J=2.3Hz,1H),4.86(d,J=11.2Hz,1H),3.99(t,J=10.6Hz,1H),3.96–3.92(m,1H),3.61 (s,3H),2.54–2.50(m,1H),2.28–2.24(m,1H),1.84–1.76(m,2H),1.73–1.69(m,1H),1.65–1.60(m,1H). 13 C NMR(DMSO-d6,151MHz)δ:197.74,179.94,160.40,150.33,143.34,142.80,135.09,128.59,128.47,124.05,123.58,12 1.26,120.52,116.33,113.60,112.98,111.29,106.41,96.27,72.24,70.92,63.15,55.20,47.47,43.47,30.23,26.74.

[0052] This example prepares compound 4bg: brown solid, melting point: 157.6-158.5°C, yield: 83.9

[0053] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 28 H 21 BrF2N4NaO2[M+Na] + :585.0714; Found:585.0713. The results of the MRI test are as follows: 1 H NMR(DMS O-d6,600MHz)δ:11.10(s,1H),10.29(s,1H),8.55(d,J=4.3Hz,2H),8.14(s,1H),7.60(t,J=8.9 Hz,1H),7.48(s,1H),7.24(dd,J=8.6,1.7Hz,1H),7.20(d,J=4.3Hz,2H),7.13(d,J=8.5Hz,1H), 6.53–6.49(m,1H),4.95(dd,J=11.8,1.6Hz,1H),4.10(t,J=10.7Hz,1H),3.86–3.90(m,1H),2.4 7–2.44(m,1H),2.29–2.32(m,1H),1.91–1.82(m,2H),1.77(t,J=6.2Hz,1H),1.69–1.65(m,1H). 13 C NMR(DMSO-d6,151MHz)δ:197.93,179.80,150.92,143.03,135.39,129.26,124.10,124.04,121.92 ,121.04,113.90,113.38,111.71,99.92,99.77,72.93,72.18,63.84,47.58,43.24,30.58,27.75.

[0054] The preparation method of compounds 4ca to 4cn is the same as that of compound 4aa, and the feed ratio is the same as that of compound 4aa. Compounds 4ca to 4cn can be obtained by replacing the reactant 3 sarcosine with thioproline. The detailed reaction is shown in Table 3, but it should be emphasized that the compounds of the present invention are not limited to the contents shown in Table 3.

[0055] Table 3 Synthesis route of spirocyclic oxidized indole derivatives spliced ​​with MOMIPP skeleton 3

[0056]

[0057] This example prepares compound 4ca: black solid, melting point: 146.9-147.6°C, yield: 82.4

[0058] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 28 H 23 BrN4NaO2S[M+Na] + :581.0623; Found:581.0621. The results of the MRI test are as follows: 1 H NMR (CDCl3, 600MHz) δ: 8.61 (s, 1H), 8.48–8.42 (m, 2H), 8.24 (d, J = 1.8Hz, 1H), 7.62 (dd, J = 7.6, 1.2 Hz,1H),7.35(d,J=2.5Hz,1H),7.29(dd,J=8.6,1.8Hz,1H),7.24(d,J=8.6Hz,2H),7.09(t,J=7.5H z,1H),6.95–6.91(m,2H),6.39(d,J=7.7Hz,1H),4.81(d,J=11.6Hz,1H),4.62–4.56(m,1H),3.91( d,J=10.9Hz,1H),3.55–3.43(m,2H),3.09(dd,J=11.9,6.4Hz,1H),3.05–3.00(m,1H),2.80(s,3H). 13 C NMR(CDCl3,151MHz)δ:196.72,178.01,150.07,143.29,142.98,135.22,130.38,128.27,128.08,125.34,124.13,1 22.85,122.55,121.96,120.64,113.31,113.04,113.00,108.16,74.25,73.69,62.57,55.44,43.22,37.42,26.17.

[0059] Compound 4cb prepared in this example: brown solid, melting point: 151.3-152.1°C, yield: 85.1

[0060] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 28 H 23 BrN4NaO2S[M+Na] + :581.0623; Found:581.0618. The results of the MRI test are as follows: 1H NMR(CDCl3,600MHz)δ:8.73(s,1H),8.67(s,1H),8.41(s,2H),8.23(s,1H),7.3 6(d,J=20.9Hz,1H),7.23(d,J=8.6Hz,1H),7.06(d,J=5.0Hz,2H),6.95(d,J=7. 9Hz,1H),6.40(d,J=7.9Hz,1H),4.86(d,J=11.6Hz,1H),4.55(t,J=8.1Hz,1H), 3.89(d,J=10.7Hz,1H), 3.55(d,J=10.7Hz,1H), 3.09–2.98(m,2H), 2.38(s,3H). 13 C NMR(CDCl3,151MHz)δ:196.77,180.13,149.89,143.32,138.36,135.23,132.30,130.70,129.19,128.06,125. 32,124.12,123.02,121.94,120.97,113.28,113.07,109.80,74.40,73.64,62.26,54.93,43.22,37.18,21.23.

[0061] Compound 4cc prepared in this example: black solid, melting point: 185.3-186.1°C, yield: 86.9%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 28 H 23 BrN4NaO2S[M+Na] + :581.0623; Found:581.0617. The results of the MRI test are as follows: 1 H NMR (CDCl3, 600MHz) δ: 9.03 (s, 1H), 8.60 (s, 1H), 8.42 (d, J = 5.0Hz, 2H), 8.22 (s, 1 H),7.43(dd,J=6.0,2.8Hz,1H),7.36(d,J=2.5Hz,1H),7.23(d,J=8.6Hz,1H),6.99 –6.96(m,4H),4.87(d,J=11.6Hz,1H),4.57(t,J=8.3Hz,1H),3.91(d,J=10.7Hz,1H ),3.58(d,J=10.7Hz,1H),3.10–3.03(m,1H),3.01(d,J=11.6Hz,1H),1.94(s,3H). 13C NMR(CDCl3,151MHz)δ:197.04,180.56,149.71,143.67,139.65,135.24,131.50,128.07,125.99,125.30,124. 26,122.68,122.64,121.90,120.89,113.27,113.10,112.94,74.90,73.71,62.68,55.22,43.10,37.26,16.12.

[0062] This example prepares compound 4cd: black solid, melting point: 146.1-146.9°C, yield: 80.4

[0063] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 27 H 20 BrClN4NaO2S[M+Na] + :601.0077; Found:601.0071. The results of the NMR test are as follows: 1 H NMR(CD3OD,600MHz)δ:8.48(d,J=5.5Hz,2H),8.16(d,J=1.9Hz,1H),7.59(s,1H),7.46(s,1H),7.27(d,J=8.6Hz,1H),7.23–7.16(m,4H),6.53(d ,J=8.2Hz,1H),4.91(d,J=11.7Hz,1H),4.57–4.51(m,1H),4.13–4.07(m ,1H),3.83(d,J=10.6Hz,1H),3.46(d,J=10.6Hz,1H),3.10–2.99(m,2H). 13 CNMR(CD3OD,151MHz)δ:197.67,181.38,151.07,144.75,141.79,131.33,129.83,129.12,128.49,126.36,1 26.28,125.47,122.38,122.35,114.35,113.41,112.68,112.29,75.76,74.59,63.30,55.09,45.11,37.69.

[0064] Compound 4ce prepared in this example: brown solid, melting point: 163.1-163.9°C, yield: 80.1%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 27 H 20BrFN4NaO2S[M+Na] + :585.0372; Found:585.0371. The results of the MRI test are as follows: 1 H NMR (CD3OD, 600MHz) δ: 8.48 (d, J = 6.2Hz, 2H), 8.17 (s, 1H), 7.46 (s, 1H), 7.39 (d d,J=8.4,2.6Hz,1H),7.27(d,J=8.6Hz,1H),7.23–7.17(m,3H),7.01–6.93(m,2H ),6.53(dd,J=8.5,4.2Hz,1H),4.91(d,J=11.7Hz,1H),4.57–4.51(m,1H),4.13– 4.09(m,1H),3.85(d,J=10.7Hz,1H),3.47(d,J=10.7Hz,1H),3.10–3.01(m,2H). 13 C NMR(CD3OD,151MHz)δ:196.30 180.39,155.61,149.74,143.43,140.11,137.79,135.68,127.85,124.88,124.13,121.03,116. 45,116.05,115.88,112.99,112.06,111.41,110.55,74.76,73.34,62.00,53.76,43.68,36.36.

[0065] Compound 4cf prepared in this example: brown solid, melting point: 160.3-160.9°C, yield: 78.4%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 27 H 19 BrF2N4NaO2S[M+Na] + :603.0278; Found:603.0273. The results of the MRI test are as follows: 1H NMR (DMSO-d6, 600MHz) δ: 11.25 (s, 1H), 10.47 (s, 1H), 8.58 (d, J = 5.1Hz, 2H), 8.08 (s, 1H), 7.6 3(s,1H),7.59(dd,J=10.1,7.9Hz,1H),7.29(d,J=8.5Hz,1H),7.20–7.16(m,3H),6.54(dd,J= 10.2,6.5Hz,1H),4.88(d,J=11.7Hz,1H),4.26–4.20(m,1H),4.14–4.08(m,1H),3.71(d,J=10 .5Hz,1H),3.39(d,J=10.5Hz,1H),3.06(dd,J=11.3,3.1Hz,1H),3.01(dd,J=11.3,6.6Hz,1H). 13 C NMR(DMSO-d6,151MHz)δ:197.48,178.57,151.00,142.69,135.50,128.69,125.51,124.20,121 .42,120.96,114.18,112.32,111.98,99.94,99.79,74.39,73.90,62.05,53.94,42.84,37.00.

[0066] This example prepared compound 4cg: black solid, melting point: 179.5-180.4°C, yield: 78.8

[0067] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 27 H 20 Br2N4NaO2S[M+Na] + :644.9571; Found:644.9571. The results of the MRI test are as follows: 1H NMR(DMS O-d6,600MHz)δ:11.25(s,1H),10.49(s,1H),8.54(d,J=5.0Hz,2H),8.01(s,1H),7.6 2(s,1H),7.57(s,1H),7.31(dd,J=12.9,8.3Hz,2H),7.18(d,J=8.3Hz,1H),7.10(d,J= 5.0Hz,2H),6.44(d,J=8.2Hz,1H),4.87(d,J=11.5Hz,1H),4.28(dd,J=9.6,4.7Hz,1H ), 4.04 (t, J = 10.5Hz, 1H), 3.70 (d, J = 10.3Hz, 1H), 3.36 (s, 1H), 3.01 (d, J = 4.8Hz, 2H). 13 CNMR(DMSO-d6,151MHz)δ:197.50,178.21,150.96,142.66,141.86,135.62,133.26,130.92,128.45,125.85,125 .78,124.20,121.24,120.87,114.30,113.49,112.08,112.03,111.97,73.96,73.76,62.04,54.01,43.11,36.86.

[0068] This example prepared compound 4ch: black solid, melting point: 162.9 ~ 163.7 ° C, yield: 87.1

[0069] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 28 H 23 BrN4NaO3S[M+Na] + :597.0572; Found:597.0569. The results of the MRI test are as follows: 1H NMR (DMSO-d6, 600MHz) δ: 11.22 (s, 1H), 10.15 (s, 1H), 8.49 (d, J = 5.2Hz, 2H), 7.98 (s, 1H) ,7.56(d,J=2.7Hz,1H),7.27(d,J=8.6Hz,1H),7.15–7.13(m,1H),7.06(d,J=5.1Hz,2H), 6.98(s,1H),6.68(dd,J=8.5,2.6Hz,1H),6.35(d,J=8.4Hz,1H),4.81(d,J=11.5Hz,1H), 4.27–4.23(m,1H),4.01(t,J=10.5Hz,1H),3.67(s,4H),3.35(s,1H),2.98–2.91(m,2H). 13 C NMR(DMSO-d6,151MHz)δ:197.44,178.65,154.71,150.81,142.79,135.76,135.62,128.54,125.71,124.62,124.18, 121.25,120.90,115.46,114.99,114.29,112.28,111.95,110.42,74.03,73.98,62.12,56.06,53.95,42.89,36.80.

[0070] Compound 4ci prepared in this example: black solid, melting point: 159.6-160.5°C, yield: 77.9%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 27 H 20 BrClN4NaO2S[M+Na] + :601.0077; Found:601.0073. The results of the NMR test are as follows: 1H NMR (DMSO-d6, 600MHz) δ: 11.26 (s, 1H), 10.49 (s, 1H), 8.56 (d, J = 5.0Hz, 2H), 8.01 (s, 1H) ,7.62(s,1H),7.47(d,J=8.0Hz,1H),7.30(d,J=8.5Hz,1H),7.18(d,J=8.6Hz,1H),7.12(d ,J=5.1Hz,2H),7.04(d,J=8.0Hz,1H),6.50(s,1H),4.86(d,J=11.5Hz,1H),4.25(t,J=6. 3Hz, 1H), 4.07 (t, J = 10.4Hz, 1H), 3.71 (d, J = 10.3Hz, 1H), 3.37 (s, 1H), 3.07–2.95 (m, 2H). 13 C NMR(DMSO-d6,151MHz)δ:197.44,178.61,150.92,144.05,142.70,135.52,134.78,129.96,128.70,125.55,124. 19,122.23,121.52,121.22,120.90,114.24,112.27,111.97,110.15,74.28,73.49,62.05,54.06,42.94,36.97.

[0071] Compound 4cj prepared in this example: black solid, melting point: 136.6-137.3°C, yield: 84.5%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 27 H 20 BrFN4NaO2S[M+Na] + :585.0372;585.0371Found:585.0371. The results of the NMR test are as follows: 1H NMR (DMSO-d6, 600MHz) δ: 11.25 (s, 1H), 10.47 (s, 1H), 8.54 (d, J = 5.0Hz, 2H), 8.01 (s, 1 H),7.61(s,1H),7.45(t,J=7.0Hz,1H),7.29(d,J=8.6Hz,1H),7.17(d,J=8.6Hz,1H),7 .09(d,J=5.1Hz,2H),6.81–6.75(m,1H),6.29(d,J=8.8Hz,1H),4.84(d,J=11.6Hz,1H) ,4.25(t,J=6.2Hz,1H),4.09–3.97(m,2H),3.70(d,J=10.4Hz,1H),3.11–2.89(m,2H). 13 C NMR(DMSO-d6,151MHz)δ:197.60,179.04,150.88,142.83,135.54,128.71,125.54,124.18,121. 24,120.88,114.24,112.36,111.96,108.18,108.03,74.27,73.34,62.09,54.00,42.79,36.97.

[0072] Compound 4ck prepared in this example: black solid, melting point: 152.1-152.9°C, yield: 81.9%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 28 H 23 BrN4NaO3S[M+Na] + :597.0572; Found:597.0570. The results of the NMR test are as follows: 1 H NMR (DMSO-d6, 600MHz) δ: 11.22 (s, 1H), 10.23 (s, 1H), 8.51 (d, J = 4.9Hz, 2H), 7.98 (s, 1H) ,7.57(s,1H),7.31–7.25(m,2H),7.16(d,J=8.5Hz,1H),7.05(d,J=4.9Hz,2H),6.50(d,J= 8.4Hz,1H),5.98(s,1H),4.79(d,J=11.4Hz,1H),4.24–4.18(m,1H),4.01(t,J=10.5Hz,1 H), 3.66 (d, J = 10.4Hz, 2H), 3.64 (s, 3H), 2.98 (dd, J = 11.6, 6.4Hz, 1H), 2.94–2.89 (m, 1H). 13C NMR(DMSO-d6,151MHz)δ:197.62,179.32,161.21,150.78,143.97,142.94,135.54,129.44,128.68,125.53,124.16 ,121.22,120.87,114.84,114.26,112.53,111.92,106.86,96.66,74.19,73.57,61.87,55.69,54.11,42.83,37.07.

[0073] Compound 4cl prepared in this example: black solid, melting point: 162.5-163.4°C, yield: 73.2%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 27 H 20 Br2N4NaO2S[M+Na] + :644.9571; Found:644.9573. The results of the MRI test are as follows: 1 H NMR (DMSO-d6, 600MHz) δ: 11.26 (s, 1H), 10.57 (s, 1H), 8.52 (d, J = 4.9Hz, 2H), 8.02 (s, 1H), 7. 62(d,J=2.6Hz,1H),7.44(d,J=7.5Hz,1H),7.34(d,J=8.2Hz,1H),7.30(d,J=8.6Hz,1H),7.18 (d,J=8.8Hz,1H),7.00(d,J=4.3Hz,2H),6.94(t,J=7.8Hz,1H),4.85(d,J=11.5Hz,1H),4.29– 4.22(m,1H),4.05(t,J=10.4Hz,1H),3.71(d,J=10.2Hz,1H),3.40(s,1H),3.12–2.95(m,2H). 13 C NMR(DMSO-d6,151MHz)δ:197.67,178.67,150.72,142.97,141.83,135.51,133.29,128.73,127.28,125.53, 124.19,123.43,121.23,120.69,114.24,112.29,111.95,102.94,74.47,74.37,62.95,53.83,42.54,36.79.

[0074] Compound 4cm prepared in this example: black solid, melting point: 168.6-169.4°C, yield: 82.2%. High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 27 H 20 BrClN4NaO2S[M+Na] + :601.0077; Found:601.0078. The results of the NMR test are as follows: 1 H NMR(DMS O-d6,600MHz)δ:11.26(s,1H),10.71(s,1H),8.51(s,2H),8.01(s,1H), 7.62(s,1H),7.40(d,J=7.5Hz,1H),7.30(d,J=8.7Hz,1H),7.23–7.15(m, 2H),7.01(s,3H),4.86(d,J=11.5Hz,1H),4.25(s,1H),4.06(t,J=10.5Hz ,1H),3.71(d,J=10.3Hz,1H),3.38(d,J=11.8Hz,1H),3.06–2.96(m,2H). 13 C NMR(DMSO-d6,151MHz)δ:197.62,178.72,150.73,142.95,140.20,135.52,130.34,128.73,126.87,125.54,125. 48,124.20,123.03,121.24,120.73,114.70,114.23,112.28,111.97,74.37,74.27,62.82,53.87,42.59,36.82.

[0075] This example prepares compound 4cn: brown solid, melting point: 169.3-170.2°C, yield: 80.0

[0076] % High resolution mass spectrometry results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 27 H 21 BrN4NaO2S[M+Na] + :567.0466; Found:567.0467. The results of the MRI test are as follows: 1H NMR(DMSO-d6,600MHz)δ:11.25(s,1H),10.32(s,1H),8.51(s,2H),8.02(s,1H),7.60(s ,1H),7.41(d,J=7.4Hz,1H),7.30(d,J=8.6Hz,1H),7.18(d,J=8.4Hz,1H),7.12(d,J=8.1 Hz,1H),7.04(s,2H),6.96(d,J=9.2Hz,1H),6.46(d,J=7.5Hz,1H),4.84(d,J=11.4Hz,1 H), 4.34–4.22 (m, 1H), 4.08 (t, J = 10.8Hz, 1H), 3.70 (d, J = 9.9Hz, 1H), 3.11–2.90 (m, 2H). 13 C NMR(DMSO-d6,151MHz)δ:197.57,178.71,150.75,142.88,142.52,135.56,130.48,128.67,128.35,125.56,124. 17,123.39,121.76,121.24,120.87,114.25,112.45,111.94,110.12,74.20,73.60,62.21,53.85,42.79,36.86.

[0077] The compound of formula (I) of the present invention may have anti-tumor activity. Its in vitro anti-tumor activity on A549 cell line (human non-small cell lung cancer cell) and A549 / DDP cell line (human lung adenocarcinoma cisplatin-resistant cell) was tested by CCK-8 method. The results showed that the spirocyclic oxidized indole derivatives with MOMIPP skeleton splicing of the structure shown in formula (I) have excellent in vitro anti-tumor activity and anti-tumor drug resistance activity, and have excellent selectivity for drug-resistant tumor cells.

[0078] Pharmacological Example: The CCK-8 method was used to test the in vitro anti-proliferative activity of compounds 4aa to 4cn against A549 / DDP cell lines and A549 cell lines, taking the A549 / DDP cell line as an example.

[0079] A549 / DDP cells were collected and counted, and the cell suspension was adjusted to 1×10 4 / mL, 100μL per well was inoculated in a 96-well plate, cultured for 24 hours, and the prepared different concentration gradient compound 4aa~4cn solution (the final concentration of the compound in the well was 0μmol / L, 0.01μmol / L, 0.1μmol / L, 1μmol / L, 10μmol / L and 100μmol / L), and a cisplatin positive control group, a blank control group, and a culture medium control group were set up at the same time. Each group had 3 replicates. After continuing to culture for 72 hours, the cell culture plate was taken out, 10μL CCK-8 solution was added to each well, and cultured for 0.5 hours. The absorbance value (OD value) of each well was measured at a wavelength of 450nm using an enzyme marker. Cell survival rate (%) = [OD (experimental group) - OD (culture medium control group)] / [OD (blank control group) - OD (culture medium control group)] × 100, A549 / DDP cell half-inhibitory concentration IC 50 The data were analyzed by GraphPad Prism software.

[0080] The in vitro antitumor activity test of compounds 4aa~4cn is shown in Table 4. They have excellent in vitro antitumor activity and antitumor drug resistance activity, and have excellent selectivity for drug-resistant cells. The 26 target compounds showed good in vitro inhibitory activity against A549 cells, which was better than the positive control drug cisplatin. Among them, compound 4ce showed the best in vitro inhibitory activity against A549 (0.007±0.001μmol·L -1 ); 32 target compounds showed good in vitro inhibitory activity against A549 / DDP cells, which was better than the positive control drug cisplatin and showed good selectivity. Among them, compound 4cg showed the best in vitro inhibitory activity against A549 / DDP (0.023±0.001μmol·L -1 ); 21 compounds including compounds 4cl, 4al, 4cc, 4bg, 4cb, 4ah, 4aj, and 4cj showed very good selectivity for the resistant strain A549 / DDP cells.

[0081] Table 4 In vitro antitumor activity test results of compounds 4aa to 4cn

[0082]

[0083] a Data are expressed as IC 50 ±SD (μmol / L);

[0084] b The resistance factor is IC 50 (A549 / DDP) / IC 50 (A549)

[0085] Experimental conclusion: Non-small cell lung cancer cells (A549) and A549 / DDP cell lines (cisplatin-resistant human lung adenocarcinoma lines) are effective tools and evaluation indicators for testing the cytotoxicity of compounds to tumor cells in vitro, and are also important indicators for evaluating the cytotoxicity of compounds to drug-resistant tumor cells. This experiment shows that the spirocyclic oxidized indole derivatives with MOMIPP skeleton splicing shown in formula (I) have excellent in vitro antitumor activity and antitumor drug resistance activity, and have excellent selectivity for drug-resistant tumor cells. The 26 target compounds showed good in vitro inhibitory activity against A549 cells, which was better than the positive control drug cisplatin. Among them, compound 4ce showed the best in vitro inhibitory activity against A549 (0.007±0.001μmol·L -1 ); 32 target compounds showed good in vitro inhibitory activity against A549 / DDP cells, which was better than the positive control drug cisplatin and showed good selectivity. Among them, compound 4cg showed the best in vitro inhibitory activity against A549 / DDP (0.023±0.001μmol·L -1 ). 21 compounds including compounds 4cl, 4al, 4cc, 4bg, 4cb, 4ah, 4aj, and 4cj showed very good selectivity against drug-resistant strain A549 / DDP cells. After a series of mechanism studies in the later stage, it is very likely that they will be further developed into new drugs for preventing and treating tumors, which have certain economic value.

Claims

1. A spirocyclic oxidized indole derivative spliced ​​with a MOMIPP skeleton, characterized in that: The compound has the following structure: The structure is specifically one of the following structural formulas:

2. A method for preparing the spirocyclic oxidized indole derivatives spliced ​​with a MOMIPP skeleton as claimed in claim 1, characterized in that: Compound 1-MOMIPP skeleton derivative, compound 2-isatin or substituted isatin, and compound 3-amino acid or its derivative, in a molar ratio of 1:4:4, undergo 1,3-dipole 3+2 cycloaddition reaction in an organic solvent to obtain a spirocyclic oxidized indole derivative spliced ​​with a MOMIPP skeleton, as shown in the following route: Wherein: the amino acid or its derivative is sarcosamine or proline or thioproline, and the structural formula of compound 4 is consistent with the structural formula in claim 1.

3. The method for preparing the spirocyclic oxidized indole derivatives spliced ​​with a MOMIPP skeleton according to claim 2, characterized in that: The organic solvent is acetonitrile, dichloromethane, anhydrous ethanol, methanol, acetone, N,N'-dimethylformamide, toluene, chloroform or ether.

4. The method for preparing the MOMIPP skeleton spliced ​​spirocyclic oxidized indole derivatives according to claim 2, characterized in that: The reaction time is 0.5 to 36.0 hours, and the reaction temperature is 25 to 100°C.

5. A use of the MOMIPP skeleton-joined spirocyclic oxidized indole derivatives as claimed in claim 1 in the preparation of drugs for preventing and treating tumor diseases, characterized in that: The tumor disease is a tumor caused by non-small cell lung cancer cells A549 or human lung adenocarcinoma cisplatin-resistant strain A549 / DDP.

Images