Spirooxindole derivatives, diastereomers thereof, and methods of making and using the same

Abstract

The application discloses a spirocyclic indolinone derivative diastereomer and a preparation method and application thereof. The spirocyclic indolinone derivative diastereomer is obtained by one-step reaction of a tryptamine isonitrile compound and an unsaturated indolinone compound in the presence of an organic solvent. The preparation method is simple, does not need to use an expensive metal catalyst, and only needs to control reaction conditions such as the organic solvent and the reaction temperature, so that the diastereomeric dispersion synthesis of the spirocyclic indolinone derivative can be realized, and a green synthesis method for efficiently constructing the spirocyclic indolinone derivative diastereomer is provided. In addition, the spirocyclic indolinone derivative diastereomer shows inhibitory activity on various cancer cells in in-vitro cell experiments, and has a good application prospect in preparation of anticancer drugs.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a spirocyclic indole ketone derivative diastereomer, its preparation method, and its application. Background Technology

[0002] Spirinadinone skeletons are widely found in numerous natural products and drug molecules, such as Citridin A (1), Citridin B (2), and PF1270A-C (3-5). Citridin A and Citridin B are active against mouse leukemia L1210 and human epidermoid carcinoma KB cells; the alkaloid PF1270A-C shows sub-micromolar affinity for human H3 histamine receptors (J. Am. Chem. Soc. 2013, 135, 10886-10889; J. Am. Chem. Soc. 2014, 136, 14184-14192). Citridins and PF1270s share many structural features, the most significant difference being the relative stereochemistry of the spirocarbon atom in the spirindolone structure. Furthermore, in the development of MDM2 inhibitors, different diastereomers have been found, and the effects vary depending on the product configuration. The product MI-77301 / SAR405838, with a specific configuration, can significantly inhibit MDM2 and is currently in clinical trials for the treatment of malignant tumors. (J.Am.Chem.Soc.2013,135,7223-7234; Cancer RES.2014,74,5855-5865; Mol.Cancer.Ther.2016,15,2887-2893) Therefore, strategies for constructing spiroindolone compounds are frequently reported.

[0003]

[0004] Although there have been several reports of successful synthesis of the above compounds, the current preparation of these spiroindolone compounds requires the use of various additives and metal catalysts, and suffers from defects such as the inability to effectively control the product configuration, making it very inefficient in terms of process economy and atom economy. Summary of the Invention

[0005] To address the aforementioned problems, this invention provides a spirocyclic indolone derivative diastereosome, its preparation method, and its application. This type of spirocyclic indolone derivative diastereosome can be obtained using a one-pot reaction with simple starting materials. The operation is simple and does not require additional additives or catalysts. Furthermore, the precise synthesis of spirocyclic indolone derivative diastereosomes can be achieved by controlling the reaction conditions such as the reaction solvent and temperature.

[0006] A first aspect of the present invention provides a spirocyclic indolone derivative diastereomericensis having the structure shown in Formula III-a or Formula III-b:

[0007]

[0008] Among them, R 1 Selected from one of hydrogen, C1-C5 alkyl, halogen, and C1-C5 alkoxy;

[0009] R 2 Selected from one of hydrogen, alkyl, allyl, and benzyl;

[0010] R 3 Selected from one of hydrogen, halogen, C1-C5 alkoxy, and nitro;

[0011] R 4 Selected from C1-C5 alkyl, C1-C5 alkoxy, substituted or unsubstituted phenyl groups;

[0012] R 5 It is selected from one of C1-C5 alkyl, phenyl, p-toluenesulfonyl, benzoyl, and tert-butoxycarbonyl.

[0013] Furthermore, R 1 Preferably, one of hydrogen, chlorine, bromine, methyl, or methoxy; R 2 Preferably, it is one of hydrogen, methyl, allyl, or benzyl; R 3 Preferably, one of the following groups is selected: hydrogen, fluorine, chlorine, bromine, methoxy, or nitro; R 4 Preferably, one of the following is selected: methyl, ethoxy, phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, or nitro-substituted phenyl; R 5 Preferably, it is selected from methyl, phenyl, p-toluenesulfonyl, benzoyl, or tert-butoxycarbonyl.

[0014] Furthermore, the diastereomeric form of the spirocyclic indolone derivative is selected from one of the following structures:

[0015]

[0016] A second aspect of the present invention provides a method for preparing the diastereomeric form of the spirocyclic indole ketone derivative described in the first aspect, comprising the following steps:

[0017] The compound shown in Formula I was reacted with the compound shown in Formula II in the presence of an organic solvent to obtain the diastereomeric spirocyclic indolone derivative;

[0018] The structures of Equations I and II are shown below:

[0019]

[0020] Among them, R 1 Selected from one of hydrogen, C1-C5 alkyl, halogen, and C1-C5 alkoxy;

[0021] R 2 Selected from one of hydrogen, alkyl, allyl, and benzyl;

[0022] R 3 Selected from one of hydrogen, halogen, C1-C5 alkoxy, and nitro;

[0023] R 4 Selected from C1-C5 alkyl, C1-C5 alkoxy, substituted or unsubstituted phenyl groups;

[0024] R 5 It is selected from one of C1-C5 alkyl, phenyl, p-toluenesulfonyl, benzoyl, and tert-butoxycarbonyl.

[0025] Further, the compound represented by Formula I is selected from one of tryptamine isonitrile (1), 5-chlorotryptamine isonitrile (2), 5-bromotryptamine isonitrile (3), 5-methoxytryptamine isonitrile (4), 5-methyltryptamine isonitrile (5), 6-bromotryptamine isonitrile (6), N-methyltryptamine isonitrile (7), N-allyltryptamine isonitrile (8), and N-benzyltryptamine isonitrile (9). The specific structural formulas of the compounds represented by Formula I corresponding to the above numbers are as follows:

[0026]

[0027] Further, the compound represented by Formula II is selected from unsaturated indolones (10), 5-fluorounsaturated indolones (11), 5-chlorounsaturated indolones (11), 5-bromounsaturated indolones (13), 5-methoxyunsaturated indolones (14), 5-nitrounsaturated indolones (15), 6-fluorounsaturated indolones (16), 6-chlorounsaturated indolones (17), 6-bromounsaturated indolones (18), 6-methoxyunsaturated indolones (19), 4-chlorobenzoylunsaturated indolones (20), and 4-bromobenzoylunsaturated indolones (21). One of the following: 4-methoxybenzoyl unsaturated indole ketone (22), 4-nitrobenzoyl unsaturated indole ketone (23), 3-chlorobenzoyl unsaturated indole ketone (24), 3-bromobenzoyl unsaturated indole ketone (25), 3-methoxybenzoyl unsaturated indole ketone (26), acetyl unsaturated indole ketone (27), ethoxycarbonyl unsaturated indole ketone (28), N-phenyl unsaturated indole ketone (29), N-p-toluenesulfonyl unsaturated indole ketone (30), N-benzoyl unsaturated indole ketone (31), and N-tert-butoxycarbonyl unsaturated indole ketone (32). The specific structural formulas of the compounds represented by Formula II corresponding to the above numbers are as follows:

[0028]

[0029] Furthermore, the molar ratio of the compound represented by Formula I to the compound represented by Formula I is 1.2-1.5:1, for example 1.2:1, 1.3:1, 1.4:1, 1.5:1, etc., including but not limited to the molar ratios listed above.

[0030] Further, the organic solvent is selected from one or more of acetonitrile, methanol, ethanol, n-butanol, tetrahydrofuran, and 1,4-dioxane; when preparing the diastereomeric spirocyclic indole ketone derivative of formula III-a, the organic solvent is preferably tetrahydrofuran; when preparing the diastereomeric spirocyclic indole ketone derivative of formula III-b, the organic solvent is preferably n-butanol.

[0031] Further, the reaction temperature is 90-130℃, for example 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, 120℃, 125℃, 130℃, etc., and the reaction time is 14h-24h, for example 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, etc.; in some preferred embodiments, when preparing the diastereomeric spirocyclic indole ketone derivative shown in III-a, the reaction temperature is preferably 90-110℃.

[0032] Furthermore, the reaction is carried out in an air atmosphere.

[0033] Taking the reaction of tryptophan isonitrile, unsaturated indolone, and tetrahydrofuran and n-butanol as the raw materials as an example, the reaction principle for preparing the diastereomeric derivatives of spirocyclic indolone shown in Formula III-a and Formula III-b of the present invention is as follows:

[0034]

[0035] Tryptophan isonitrile undergoes a Michael addition reaction with an unsaturated indole ketone to generate intermediate A. Subsequently, a ring-closure reaction occurs at the 3-position of the indole to form the transition state B2-ts. After a double bond shift, the indole ketone undergoes a nucleophilic reaction with the indole at the 3-position, resulting in another ring-closure to product 3aa (the compound shown in Formula III-a). 3aa can undergo a reverse Mannich reaction to generate intermediate C2. Due to steric hindrance, C2 cannot be directly inverted to yield C. C undergoes a reversible reaction back to intermediate A, which then undergoes epimerization and ring-closure to generate the transition state B-ts. This is followed by another ring-closure to produce the diastereomer 4aa (the compound shown in Formula III-b). Calculations further demonstrate the existence of two transition states with different configurations during the reaction. The free energy barriers of these two transition states are different; B2-ts is lower than B-ts, making 3aa easier to form. However, since 4aa is more stable than 3aa, the configuration inverts to 4aa after the reverse Mannich ring-opening.

[0036] The third aspect of this invention provides the use of the diastereomeric spirocyclic indole ketone derivative described in the first aspect in the preparation of anticancer drugs.

[0037] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0038] 1. This invention utilizes tryptophan isonitriles and unsaturated indole ketone derivatives as reactants to achieve a one-step precise synthesis of diastereomeric spirocyclic indole ketone derivatives. Compared with existing technologies, the above preparation method has a wide substrate range, is simple to operate, and convenient for post-processing. It also boasts high step economy and atom economy. Furthermore, by controlling reaction conditions such as the type of reaction solvent and temperature, the diastereodispersive synthesis of spirocyclic indole ketone derivatives can be achieved in one step with a yield as high as 96%. This provides a simple and effective synthetic method for the diastereodispersive synthesis of spirocyclic indole ketone skeletons, suitable for industrial mass production.

[0039] 2. The series of spirocyclic indole ketone derivatives diastereomers provided by this invention exhibited good antitumor activity against one or more cancer cells in in vitro cancer cell toxicity tests, and have potential application prospects in the preparation of antitumor drugs. Detailed Implementation

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0041] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand and implement the present invention, but the embodiments are not intended to limit the present invention.

[0042] Example 1: Synthesis of the compound shown in formula III-1a

[0043] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of the compound corresponding to number (1)) and 0.1 mmol of unsaturated indolone (0.0263 g of the compound corresponding to number (10)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0305 g of reaction product.

[0044] The above reaction products were characterized by NMR, and the results are as follows:

[0045] 1 H NMR (400MHz, DMSO-d6) δ8.39 (s, 1H), 7.18 (d, J = 7.6Hz, 1H), 7.09-6.91 (m, 6H ),6.81(t,J=7.6Hz,1H),6.71(d,J=7.6Hz,2H),6.59(t,J=7.6Hz,1H),6.45(d ,J=8.0Hz,1H),6.40(d,J=8.0Hz,1H),6.17(s,1H),4.26-4.13(m,1H),4.11( s,1H),4.00-3.87(m,1H),2.86(s,3H),2.45-2.30(m,1H),1.95-1.80(m,1H).

[0046] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 70%.

[0047] Example 2: Synthesis of the compound shown in formula III-1b

[0048] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to number (1)) and 0.1 mmol of unsaturated indolone (0.0263 g of the compound corresponding to number (10)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0392 g of reaction product.

[0049] The above reaction products were characterized by NMR, and the results are as follows:

[0050] 1 H NMR (400MHz, DMSO-d6) δ7.97(s,1H),7.37-7.23(m,2H),7.19-7.00(m,4H),6.88-6.65(m,4H),6.52(t,J=7.6Hz,1H),6.22(d,J=8.0H z,1H),5.87(s,1H),5.81(d,J=7.6Hz,1H),4.19-4.03(m,2H),3.93-3.80(m,1H),2.79(s,3H),2.33-2.17(m,1H),1.96-1.83(m,1H).

[0051] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 90%.

[0052] Example 3: Synthesis of the compound shown in formula III-2a

[0053] Weigh 0.12 mmol of 5-chlorotryptamine isonitrile (the compound corresponding to number (2), 0.0245 g) and 0.1 mmol of unsaturated indolone (the compound corresponding to number (10), 0.0263 g) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0248 g of reaction product.

[0054] The above reaction products were characterized by NMR, and the results are as follows:

[0055] 1H NMR (400MHz, DMSO-d6) δ8.39 (s, 1H), 7.12 (s, 1H), 7.09-6.91 (m, 6H), 6.82 (t, = 7.6Hz, 1H), 6.71 (d, J = 7.6Hz, 2H), 6.47 (d, J=7.6Hz,1H),6.44-6.34(m,2H),4.24-4.09(m,2H),3.98-3.87(m,1H),2.86(s,3H),2.46-2.33(m,1H),1.96-1.86(m,1H).

[0056] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 53%.

[0057] Example 4: Synthetic compound shown in formula III-2b

[0058] Weigh 0.15 mmol of 5-chlorotryptamine isonitrile (the compound corresponding to number (2), 0.0306 g) and 0.1 mmol of unsaturated indolone (the compound corresponding to number (10), 0.0263 g) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0384 g of reaction product.

[0059] The above reaction products were characterized by NMR, and the results are as follows:

[0060] 1 H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.33-7.25(m,2H),7.22-7.11(m,3H), 7.11-7.03(m,1H),6.82(s,2H),6.75(d,J=8.0Hz,1H),6.60(t,J=7.6Hz,1H ),6.21(d,J=7.6Hz,1H),6.13(s,1H),5.91(d,J=7.6Hz,1H),4.20-4.06(m, 2H),3.93-3.80(m,1H),2.79(s,3H),2.32-2.17(m,1H),2.00-1.85(m,1H).

[0061] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield was calculated to be 82%.

[0062] Example 5: Synthesis of the compound shown in formula III-3a

[0063] Weigh 0.12 mmol of 5-bromotryptamine isonitrile (the compound corresponding to number (3), 0.0298 g) and 0.1 mmol of unsaturated indolone (the compound corresponding to number (10), 0.0263 g) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0302 g of reaction product.

[0064] The above reaction products were characterized by NMR, and the results are as follows:

[0065] 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),7.21(s,1H),7.12(d,J=8.4Hz,1H),7.09-6.91(m,5H),6.81(t,J=7.2Hz,1H),6.70(d,J=7.2Hz,2 H),6.50-6.41(m,2H),6.34(d,J=8.4Hz,1H),4.22-4.02(m,2H),3.97-3.88(m,1H),2.86(s,3H),2.45-2.33(m,1H),1.94-1.86(m,1H).

[0066] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 59%.

[0067] Example 6: Synthetic compound shown in formula III-3b

[0068] Weigh 0.15 mmol of 5-bromotryptamine isonitrile (the compound corresponding to number (3), 0.0372 g) and 0.1 mmol of unsaturated indolone (the compound corresponding to number (10), 0.0263 g) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0436 g of reaction product.

[0069] The above reaction products were characterized by NMR, and the results are as follows:

[0070] 1 H NMR (400MHz, DMSO-d6) δ7.96(s,1H),7.39(s,1H),7.34-7.23(m,1H),7.21-7.06(m,4H),6.80(s,2H),6.76-6.68(m,1H),6.61(t,J=7. 6Hz,1H),6.17(m,2H),5.92(d,J=7.6Hz,1H),4.23-4.01(m,2H),3.92-3.79(m,1H),2.79(s,3H),2.32-2.18(m,1H),2.00-1.86(m,1H).

[0071] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 85%.

[0072] Example 7: Synthetic compound shown in formula III-4b

[0073] Weigh 0.15 mmol of 5-methoxytryptamine isonitrile (the compound corresponding to number (4), 0.0300 g) and 0.1 mmol of unsaturated indolone (the compound corresponding to number (10), 0.0263 g) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0446 g of reaction product.

[0074] The above reaction products were characterized by NMR, and the results are as follows:

[0075] 1 H NMR (400MHz, DMSO-d6) δ7.98(s,1H),7.30–7.23(m,1H),7.16-7.07(m,3H),6.92-6.88(m,1H),6.78(s,2H),6.73-6.67(m,2H),6.55(t,J=7.6Hz 1H),6.16(d,J=8.8Hz,1H),5.85-5.77(m,1H),5.38(s,1H),4.20-4.09(m,1H),4.06(s, 1H),3.92-3.81(m,1H),3.76(s,3H),2.77(s,3H),2.31-2.19(m,1H),1.95-1.86(m,1H).

[0076] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 96%.

[0077] Example 8: Synthesis of the compound shown in formula III-5a

[0078] Weigh 0.12 mmol of 5-methyltryptamine isonitrile (the compound corresponding to number (5), 0.0221 g) and 0.1 mmol of unsaturated indolone (the compound corresponding to number (10), 0.0263 g) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0304 g of reaction product.

[0079] The above reaction products were characterized by NMR, and the results are as follows:

[0080] 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),7.10-6.89(m,6H),6.84-6.74(m,2H),6.73-6.64(m,2H),6.43(d,J=7.6Hz,1H),6.31(d,J=7.6Hz ,1H),5.92(s,1H),4.25-4.13(m,1H),4.08(s,1H),3.98-3.85(m,1H),2.84(s,3H),2.43-2.30(m,1H),2.24(s,3H),1.92-1.81(m,1H).

[0081] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 68%.

[0082] Example 9: Synthetic compound shown in formula III-5b

[0083] Weigh 0.15 mmol of 5-methyltryptamine isonitrile (the compound corresponding to number (5), 0.0276 g) and 0.1 mmol of unsaturated indolone (the compound corresponding to number (10), 0.0263 g) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0395 g of reaction product.

[0084] The above reaction products were characterized by NMR, and the results are as follows:

[0085] 1 H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.30-7.21(m,1H),7.19-7.07(m,4H),6.90-6 .84(m,1H),6.76(s,2H),6.69(d,J=7.6Hz,1H),6.54(t,J=7.6Hz,1H),6.13(d,J=7. 6Hz,1H),5.83(dd,J=7.2,1.2Hz,1H),5.60(s,1H),4.20-4.09(m,1H),4.07(s,1H), 3.92-3.81(m,1H),2.76(s,3H),2.30(s,3H),2.27-2.18(m,1H),1.94-1.85(m,1H).

[0086] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 88%.

[0087] Example 10: Synthesis of the compound shown in formula III-6a

[0088] Weigh 0.12 mmol of 6-bromotryptamine isonitrile (the compound corresponding to number (6), 0.0298 g) and 0.1 mmol of unsaturated indolone (the compound corresponding to number (10), 0.0263 g) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0256 g of reaction product.

[0089] The above reaction products were characterized by NMR, and the results are as follows:

[0090] 1H NMR (400MHz, DMSO-d6) δ8.36 (s, 1H), 7.13-7.04 (m, 2H), 7.04-6.94 (m, 4H), 6.82 (t, J = 7.2Hz, 1H), 6.71 (d, J = 7.2Hz, 3H), 6.56(s,1H),6.50-6.43(m,2H),4.20-4.09(m,2H),3.97-3.87(m,1H),2.87(s,3H),2.45-2.33(m,1H),1.93-1.83(m,1H).

[0091] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 50%.

[0092] Example 11: Synthesis of the compound shown in formula III-6b

[0093] Weigh 0.15 mmol of 6-bromotryptamine isonitrile (the compound corresponding to number (6), 0.0372 g) and 0.1 mmol of unsaturated indolone (the compound corresponding to number (10), 0.0263 g) into a 20 mL test tube reaction tube. Add 1 mL of n-butanol as solvent and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0435 g of reaction product.

[0094] The above reaction products were characterized by NMR, and the results are as follows:

[0095] 1 H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.33-7.22(m,2H),7.17-7.10(m,3H),6.89-6.73(m,4H),6.60(t,J=7.2Hz,1H),6.35(s,1H ),6.25(s,1H),5.93(d,J=7.2Hz,1H),4.14-4.03(m,2H),3.91-3.81(m,1H),2.80(s,3H),2.30-2.18(m,1H),1.94-1.85(m,1H).

[0096] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 85%.

[0097] Example 12: Synthesis of the compound shown in formula III-7a

[0098] Weigh 0.12 mmol of N-methyltryptamine isonitrile (the compound corresponding to number (7), 0.0221 g) and 0.1 mmol of unsaturated indolone (the compound corresponding to number (10), 0.0263 g) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0322 g of reaction product.

[0099] The reaction products were characterized, and the results are as follows:

[0100] 1 H NMR (400MHz, DMSO-d6) δ8.33(s,1H),7.17(d,J=7.2Hz,1H),7.13-6.94(m,6H),6.88(t,J=7.6Hz,1H),6.68(d, J=7.2Hz,2H),6.59(t,J=7.2Hz,1H),6.47(d,J=7.6Hz,1H),6.32-6.22(m,1H),4.28-4.10(m,2H),3.99-3.85(m 1H),2.86(s,3H),2.47-2.34(m,4H),1.95-1.84(m,1H).

[0101] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield was calculated to be 72%.

[0102] Example 13: Synthesis of the compound shown in formula III-8a

[0103] Weigh 0.12 mmol of N-allyl tryptamine isonitrile (the compound corresponding to number (8), 0.0252 g) and 0.1 mmol of unsaturated indolone (the compound corresponding to number (10), 0.0263 g) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0303 g of reaction product.

[0104] The above reaction products were characterized by NMR, and the results are as follows:

[0105] 1H NMR (400MHz, DMSO-d6) δ8.34 (s, 1H), 7.19 (d, J = 7.2Hz, 1H), 7.11-6.96 (m, 6H), 6.85 (t, J = 7.2Hz, 1H), 6. 73-6.65(m,2H),6.62(t,J=7.2Hz,1H),6.46(d,J=7.6Hz,1H),6.36(d,J=7.6Hz,1H),5.53-5.38(m,1H), 4.78(dd,J=17.2,2.0Hz,1H),4.62(dd,J=17.2,2.0Hz,1H),4.25-4.11(m,2H),3.98-3.86(m,1H),3.74( dd,J=15.8,5.8Hz,1H),3.10(dd,J=15.8,5.8Hz,1H),2.87(s,3H),2.46-2.37(m,1H),1.95-1.86(m,1H).

[0106] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 64%.

[0107] Example 14: Synthesis of the compound shown in formula III-9a

[0108] Weigh 0.12 mmol of N-benzyltryptamine isonitrile (0.0312 g of the compound corresponding to number (9)) and 0.1 mmol of unsaturated indolone (0.0263 g of the compound corresponding to number (10)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0268 g of reaction product.

[0109] The above reaction products were characterized by NMR, and the results are as follows:

[0110] 1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.23-7.19(m,1H),7.15-7.06(m,4H),7.06-6.95(m,5H) ,6.88-6.82(m,2H),6.80(t,J=7.2Hz,1H),6.73-6.66(m,2H),6.63(t,J=7.2Hz,1H),6.48(d, J=7.6Hz,1H),6.35(d,J=7.6Hz,1H),4.34(d,J=15.6Hz,1H),4.22(s,1H),4.21-4.12(m,1H), 3.96-3.87(m,1H),3.62(d,J=15.6Hz,1H),2.93(s,3H),2.42-2.32(m,1H),1.95-1.87(m,1H).

[0111] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 51%.

[0112] Example 15: Synthesis of the compound shown in formula III-10a

[0113] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g corresponding to compound (1)) and 0.1 mmol of 5-fluorounsaturated indolone (0.0281 g corresponding to compound (11)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0420 g of reaction product.

[0114] The above reaction products were characterized by NMR, and the results are as follows:

[0115] 1 H NMR(400MHz, DMSO-d6)δ8.41(s,1H),7.17(d,J=7.6Hz,1H),7.13-6.90(m,5H),6.83-6.68(m,3H),6.60(t,J=7.6Hz,1H),6.50-6.42( m,1H),6.39(d,J=7.6Hz,1H),6.20(s,1H),4.27-4.07(m,2H),3.97-3.83(m,1H),2.86(s,3H),2.49-2.38(m,1H),1.91-1.78(m,1H).

[0116] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 93%.

[0117] Example 16: Synthesis of the compound shown in formula III-10b

[0118] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to (1)) and 0.1 mmol of 5-fluorounsaturated indolone (0.0281 g of the compound corresponding to (11)) into a 20 mL test tube reaction tube. Add 1 mL of n-butanol as solvent and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0398 g of reaction product.

[0119] The above reaction products were characterized by NMR, and the results are as follows:

[0120] 1 H NMR (400MHz, DMSO-d6) δ7.96 (s, 1H), 7.43-7.25 (m, 2H), 7.25-7.12 (m, 2H), 7.08 (t, J = 7.6Hz, 1H), 7.00-6.80 (m, 3H), 6.80-6.67 (m, 2H), 6.2 7(d,J=8.0Hz,1H),5.99(s,1H),5.51-5.38(m,1H),4.23-4.00(m,2H), 3.95-3.77(m,1H),2.82(s,3H),2.35-2.17(m,1H),1.98-1.82(m,1H).

[0121] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 88%.

[0122] Example 17: Synthesis of the compound shown in formula III-11a

[0123] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of compound corresponding to number (1)) and 0.1 mmol of 5-chlorounsaturated indolone (0.0297 g of compound corresponding to number (12)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0421 g of reaction product.

[0124] The above reaction products were characterized by NMR, and the results are as follows:

[0125] 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),7.17(d,J=7.6Hz,1H),7.13-7.03(m,4H),7.02-6.95(m,2H),6.76(d,J=7.2Hz,2H),6.60(t,J=7.2Hz,1H),6.49 (d,J=8.0Hz,1H),6.39(d,J=7.6Hz,1H),6.22-6.16(m,1H),4.21-4.12(m, 2H),3.96-3.85(m,1H),2.86(s,3H),2.49-2.43(m,1H),1.87-1.79(m,1H).

[0126] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 90%.

[0127] Example 18: Synthesis of the compound shown in formula III-11b

[0128] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to (1)) and 0.1 mmol of 5-chlorounsaturated indolone (0.0297 g of the compound corresponding to (12)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0421 g of reaction product.

[0129] The above reaction products were characterized by NMR, and the results are as follows:

[0130] 1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.40-7.27(m,2H),7.27-7.17(m,2H),7.16-7.07(m,2H),6.90(s,2H),6.81-6.71(m,2H),6.26( d,J=8.0Hz,1H),5.98(s,1H),5.63(s,1H),4.24-4.01(m,2H),3.93-3.77(m,1H),2.83(s,3H),2.33-2.17(m,1H),1.97-1.83(m,1H).

[0131] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 90%.

[0132] Example 19: Synthesis of the compound shown in formula III-12a

[0133] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g corresponding to compound (1)) and 0.1 mmol of 5-bromounsaturated indolone (0.0341 g corresponding to compound (13)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0435 g of reaction product.

[0134] The above reaction products were characterized by NMR, and the results are as follows:

[0135] 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),7.24(s,1H),7.20-7.02(m,5H),6.99(t,J=7.6Hz,1H),6.76(d,J=7.2Hz,2H),6.60(t,J=7.2 Hz,1H),6.50-6.35(m,2H),6.20(s,1H),4.25-4.08(m,2H),3.98-3.83(m,1H),2.86(s,3H),2.49-2.42(m,1H),1.89-1.78(m,1H).

[0136] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 85%.

[0137] Example 20: Synthesis of the compound shown in formula III-12b

[0138] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to (1)) and 0.1 mmol of 5-bromounsaturated indolone (0.0341 g of the compound corresponding to (13)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0458 g of reaction product.

[0139] The above reaction products were characterized by NMR, and the results are as follows:

[0140] 1 H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.35-7.26(m,3H),7.25-7.15(m,2H) ,7.13-7.07(m,1H),6.91(s,2H),6.77(t,J=7.6Hz,1H),6.71(d,J=8.4Hz, 1H),6.26(d,J=7.6Hz,1H),5.97(s,1H),5.77-5.75(m,1H),4.18-4.03(m, 2H),3.92-3.80(m,1H),2.83(s,3H),2.32-2.19(m,1H),1.96-1.84(m,1H).

[0141] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 89%.

[0142] Example 21: Synthesis of the compound shown in formula III-13a

[0143] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of the compound corresponding to number (1)) and 0.1 mmol of 5-methoxyunsaturated indolone (0.0293 g of the compound corresponding to number (14)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0278 g of reaction product.

[0144] The above reaction products were characterized by NMR, and the results are as follows:

[0145] 1 H NMR(400MHz,DMSO-d6)δ8.38(s,1H),7.18(s,1H),7.12-6.90(m,4H),6.83-6.7(m,2H),6.67-6.49(m,3H),6.45-6.31(m, 2H),6.15(s,1H),4.28-4.05(m,2H),4.00-3.85(m,1H),3.66(s,3H),2.84(s,3H),2.46-2.35(m,1H),1.95-1.77(m,1H).

[0146] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 60%.

[0147] Example 22: Synthesis of the compound shown in formula III-13b

[0148] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to number (1)) and 0.1 mmol of 5-methoxyunsaturated indolone (0.0293 g of the compound corresponding to number (14)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0432 g of reaction product.

[0149] The above reaction products were characterized by NMR, and the results are as follows:

[0150] 1 H NMR (400MHz, DMSO-d6) δ8.07(s,1H),7.33(d,J=7.2Hz,1H),7.26(t,J=7.2,1H) ,7.18-7.08(m,2H),7.05(t,J=7.6,1H),6.84-6.69(m,3H),6.68-6.60(m,2H),6 .27(d,J=7.6Hz,1H),5.93(s,1H),5.55(d,J=2.4Hz,1H),4.18-4.03(m,2H),3.9 2-3.82(m,1H),3.29(s,3H),2.72(s,3H),2.31-2.19(m,1H),1.94-1.85(m,1H).

[0151] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 93%.

[0152] Example 23: Synthesis of the compound shown in formula III-14a

[0153] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of compound corresponding to number (1)) and 0.1 mmol of 5-methoxyunsaturated indolone (0.0308 g of compound corresponding to number (15)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0436 g of reaction product.

[0154] The above reaction products were characterized by NMR, and the results are as follows:

[0155] 1 H NMR(400MHz, DMSO-d6)δ8.46(s,1H),8.03-7.90(m,2H),7.20(d,J=7.6Hz,1H),7.14-6.94(m,4H),6.81-6.70(m,3H),6.62(t,J=7.6Hz,1H) ,6.40(d,J=7.6Hz,1H),6.28(s,1H),4.25(s,1H),4.23-4.13(m,1H), 3.99-3.90(m,1H),2.97(s,3H),2.63-2.52(m,1H),1.88-1.77(m,1H).

[0156] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 91%.

[0157] Example 24: Synthetic compound shown in formula III-14b

[0158] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of compound corresponding to number (1)) and 0.1 mmol of 5-nitrounsaturated indolone (0.0308 g of compound corresponding to number (15)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0446 g of reaction product.

[0159] The above reaction products were characterized by NMR, and the results are as follows:

[0160] 1 H NMR(400MHz, DMSO-d6)δ8.08(dd,J=8.8,2.4Hz,1H),7.91(s,1H),7.39(d,J=7.2 Hz,1H),7.34(t,J=7.2Hz,1H),7.28-7.17(m,2H),7.09-6.87(m,4H),6.79(t,J= 7.6Hz,1H),6.60(d,J=2.4Hz,1H),6.18(d,J=7.6Hz,1H),6.05(s,1H),4.20-4.0 6(m,2H),3.93-3.80(m,1H),2.98(s,3H),2.35-2.20(m,1H),1.96-1.86(m,1H).

[0161] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 93%.

[0162] Example 25: Synthesis of the compound shown in formula III-15a

[0163] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of compound corresponding to number (1)) and 0.1 mmol of 6-fluorounsaturated indolone (0.0281 g of compound corresponding to number (16)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0416 g of reaction product.

[0164] The above reaction products were characterized by NMR, and the results are as follows:

[0165] 1 H NMR (400MHz, DMSO-d6) δ8.42 (s, 1H), 7.17 (d, J = 7.6Hz, 1H), 7.13-7.08 (m, 1H),7.06-6.96(m,4H),6.71(s,1H),6.70-6.67(m,1H),6.62-6.54(m,2H) ,6.40(s,1H),6.39-6.36(m,1H),6.19(s,1H),4.23-4.13(m,1H),4.10(s, 1H),3.96-3.87(m,1H),2.85(s,3H),2.45-2.34(m,1H),1.91-1.83(m,1H).

[0166] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield was calculated to be 92%.

[0167] Example 26: Synthesis of the compound shown in formula III-15b

[0168] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to number (1)) and 0.1 mmol of 6-fluorounsaturated indolone (0.0281 g of the compound corresponding to number (16)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0385 g of reaction product.

[0169] The above reaction products were characterized by NMR, and the results are as follows:

[0170] 1 H NMR(400MHz, DMSO-d6)δ7.93(s,1H),7.38-7.25(m,2H),7.24-7.12(m,2H),7.06(t,J=7.6Hz,1H),6.86(s,2H),6.76-6.64(m,2H),6.34-6.17( m,2H),5.92(s,1H),5.74-5.64(m,1H),4.18-4.07(m,1H),4.05(s,1H) ,3.93-3.79(m,1H),2.81(s,3H),2.32-2.16(m,1H),1.96-1.83(m,1H).

[0171] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 85%.

[0172] Example 27: Synthesis of the compound shown in formula III-16a

[0173] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of compound corresponding to number (1)) and 0.1 mmol of 6-chlorounsaturated indolone (0.0297 g of compound corresponding to number (17)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0417 g of reaction product.

[0174] The above reaction products were characterized by NMR, and the results are as follows:

[0175] 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),7.23-6.93(m,6H),6.85(d,J=8.0Hz,1H),6.74(d,J=7.2Hz,2H),6.65-6.54(m,2H),6.41(d, J=8.0Hz,1H),6.20(s,1H),4.25-4.13(m,1H),4.11(s,1H),3.97-3.83(m,1H),2.86(s,3H),2.46-2.32(m,1H),1.92-1.78(m,1H).

[0176] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 89%.

[0177] Example 28: Synthetic compound shown in formula III-16b

[0178] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to number (1)) and 0.1 mmol of 6-chlorounsaturated indolone (0.0297 g of the compound corresponding to number (17)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0398 g of reaction product.

[0179] The above reaction products were characterized by NMR, and the results are as follows:

[0180] 1 H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.39-7.28(m,2H),7.27-7.14(m,2H),7.0 6(t,J=7.2Hz,1H),7.03-6.79(m,3H),6.74(t,J=7.2Hz,1H),6.53(dd,J=7.6,2 .0Hz,1H),6.25(d,J=8.0Hz,1H),5.96(s,1H),5.70(d,J=8.0Hz,1H),4.20-4.0 0(m,2H),3.93-3.75(m,1H),2.85(s,3H),2.32-2.16(m,1H),1.95-1.81(m,1H).

[0181] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 85%.

[0182] Example 29: Synthesis of the compound shown in formula III-17a

[0183] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g corresponding to compound (1)) and 0.1 mmol of 6-bromounsaturated indolone (0.0341 g corresponding to compound (18)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0440 g of reaction product.

[0184] The above reaction products were characterized by NMR, and the results are as follows:

[0185] 1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.21-7.10(m,2H),7.09-7.01(m,2H),7.01-6.91(m,3H),6.80-6.66(m,3H),6.59(s,1H),6.39( d,J=7.6Hz,1H),6.19(s,1H),4.24-4.12(m,1H),4.09(s,1H),3.97-3.83(m,1H),2.85(s,3H),2.45-2.32(m,1H),1.93-1.80(m,1H).

[0186] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 86%.

[0187] Example 30: Synthetic compound shown in formula III-17b

[0188] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to number (1)) and 0.1 mmol of 6-bromounsaturated indolone (0.0341 g of the compound corresponding to number (18)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0452 g of reaction product.

[0189] The above reaction products were characterized by NMR, and the results are as follows:

[0190] 1 H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.38-7.28(m,2H),7.27-7.15(m,2H),7.07 (t,J=7.6Hz,1H),7.00(s,1H),6.93(s,2H),6.74(t,J=7.6Hz,1H),6.67(dd,J=8. 0,1.6Hz,1H),6.26(d,J=8.0Hz,1H),5.97(s,1H),5.66(d,J=8.0Hz,1H),4.16-4. 03(m,2H),3.90-3.79(m,1H),2.86(s,3H),2.30-2.19(m,1H),1.94-1.84(m,1H).

[0191] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 88%.

[0192] Example 31: Synthetic compound shown in formula III-18b

[0193] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of compound corresponding to number (1)) and 0.1 mmol of 6-methoxyunsaturated indolone (0.0293 g of compound corresponding to number (19)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0302 g of reaction product.

[0194] The above reaction products were characterized by NMR, and the results are as follows:

[0195] 1 H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.34-7.23(m,2H),7.21-7.10(m,2H),7.05(t,J=7 .6Hz,1H),6.81(s,2H),6.71(t,J=7.6Hz,1H),6.36(s,1H),6.25(d,J=8.0Hz,1H),6.05 (dd,J=8.0,2.0Hz,1H),5.82(s,1H),5.64(d,J=8.0Hz,1H),4.17-4.05(m,1H),4.02(s, 1H),3.91-3.80(m,1H),3.69(s,3H),2.76(s,3H),2.30-2.17(m,1H),1.94-1.84(m,1H).

[0196] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 65%.

[0197] Example 32: Synthesis of the compound shown in formula III-19a

[0198] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g corresponding to compound (1)) and 0.1 mmol of 4-chlorobenzoyl unsaturated indolone (0.0297 g corresponding to compound (20)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0378 g of reaction product.

[0199] The above reaction products were characterized by NMR, and the results are as follows:

[0200] 1 H NMR (400MHz, DMSO-d6) δ8.42(s,1H),7.17(d,J=7.6Hz,1H),7.13-7.00(m,3H),7.00-6.92(m,2H),6.80-6.70(m,3H),6.60(t,J=7.6Hz,1H),6. 49-6.42(m,1H),6.40(d,J=7.6Hz,1H),6.20(s,1H),4.23-4.11(m,2H) ,3.96-3.85(m,1H),2.86(s,3H),2.49-2.42(m,1H),1.89-1.79(m,1H).

[0201] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield was calculated to be 81%.

[0202] Example 33: Compound shown in formula III-19b

[0203] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to (1)) and 0.1 mmol of 4-chlorobenzoyl unsaturated indolone (0.0297 g of the compound corresponding to (20)) into a 20 mL test tube reaction tube. Add 1 mL of n-butanol as solvent and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0412 g of reaction product.

[0204] The above reaction products were characterized by NMR, and the results are as follows:

[0205] 1H NMR(400MHz, DMSO-d6)δ8.00(s,1H),7.31(d,J=7.6Hz,1H),7.23(d,J=8.0Hz, 2H),7.12-7.02(m,2H),7.01-6.77(s,2H),6.77-6.66(m,2H),6.51(t,J=7.6H z,1H),6.22(d,J=8.0Hz,1H),5.89(s,1H),5.78(d,J=7.2Hz,1H),4.19-4.02( m,2H),3.92-3.79(m,1H),2.86(s,3H),2.32-2.16(m,1H),1.96-1.83(m,1H).

[0206] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 88%.

[0207] Example 34: Synthesis of the compound shown in formula III-20a

[0208] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of the compound corresponding to (1)) and 0.1 mmol of 4-bromobenzoyl unsaturated indolone (0.0341 g of the compound corresponding to (21)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0399 g of reaction product.

[0209] The reaction products were characterized by NMR and the results are as follows:

[0210] 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),7.28-7.10(m,3H),7.08-6.91(m,3H),6.83(t,J=7.6Hz,1H),6.71-6.55(m,3H),6.52(d,J=7.6Hz,1H) ,6.39(d,J=7.6Hz,1H),6.19(s,1H),4.26-4.13(m,1H),4.11(s,1H), 3.98-3.83(m,1H),2.87(s,3H),2.45-2.31(m,1H),1.84-1.79(m,1H).

[0211] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 78%.

[0212] Example 35: Compound shown in formula III-20b

[0213] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to (1)) and 0.1 mmol of 4-bromobenzoyl unsaturated indolone (0.0341 g of the compound corresponding to (21)) into a 20 mL test tube reaction tube. Add 1 mL of n-butanol as solvent and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0425 g of reaction product.

[0214] The above reaction products were characterized by NMR, and the results are as follows:

[0215] 1 H NMR(400MHz, DMSO-d6)δ8.00(s,1H),7.46-7.33(m,2H),7.31(d,J=7.6Hz,1H),7.15-7.00(m,2H),6.90-6.59(m,4H),6.51(t,J=7.6Hz,1H),6.2 1(d,J=7.6Hz,1H),5.89(s,1H),5.77(d,J=7.6Hz,1H),4.19-4.02(m,2H ),3.92-3.78(m,1H),2.86(s,3H),2.32-2.17(m,1H),1.95-1.84(m,1H).

[0216] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 83%.

[0217] Example 36: Synthetic compound shown in formula III-21a

[0218] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of the compound corresponding to (1)) and 0.1 mmol of 4-methoxybenzoyl unsaturated indolone (0.0293 g of the compound corresponding to (22)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0255 g of reaction product.

[0219] The above reaction products were characterized by NMR, and the results are as follows:

[0220] 1 H NMR (400MHz, DMSO-d6) δ8.07(s,1H),7.16(d,J=7.6Hz,1H),7.05-6.93(m,3H),6.87-6.76(m,3H),6.66-6.53(m,4H),6.40(d,J=7.6Hz ,1H),6.16(s,1H),4.20-4.09(m,1H),4.08(s,1H),3.95-3.85(m,1H),3.65(s,3H),2.93(s,3H),2.43-2.28(m,1H),1.92-1.81(m,1H).

[0221] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 55%.

[0222] Example 37: Compound shown in formula III-21b

[0223] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of compound corresponding to number (1)) and 0.1 mmol of 4-methoxybenzoyl unsaturated indoleone (0.0293 g of compound corresponding to number (22)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0371 g of reaction product.

[0224] The above reaction products were characterized by NMR, and the results are as follows:

[0225] 1H NMR (400MHz, DMSO-d6) δ7.55(s,1H),7.32(d,J=7.2Hz,1H),7.16-6.95(m,4H),6.83-6.71(m,4H),6.50(t,J=7.6Hz,1H),6.23(d,J=7 .6Hz,1H),5.87-5.75(m,2H),4.15-3.99(m,2H),3.85-3.78(m,1H),3.74(s,3H),2.96(s,3H),2.29-2.14(m,1H),1.94-1.82(m,1H).

[0226] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 80%.

[0227] Example 38: Synthetic compound shown in formula III-22a

[0228] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of the compound corresponding to number (1)) and 0.1 mmol of 4-nitrobenzoyl unsaturated indolone (0.0308 g of the compound corresponding to number (23)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0398 g of reaction product.

[0229] The above reaction products were characterized by NMR, and the results are as follows:

[0230] 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),7.85(d,J=8.0Hz,2H),7.18(d,J=7.2H z,1H),7.08(d,J=7.2Hz,1H),7.03-6.92(m,2H),6.91-6.72(m,3H),6.60(t ,J=7.2Hz,1H),6.49-6.29(m,2H),6.22(s,1H),4.32-4.18(m,1H),4.15(s, 1H),4.01-3.86(m,1H),2.83(s,3H),2.47-2.35(m,1H),1.97-1.83(m,1H).

[0231] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 83%.

[0232] Example 39: Compound shown in formula III-22b

[0233] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to number (1)) and 0.1 mmol of 4-nitrobenzyl unsaturated indolone (0.0308 g of the compound corresponding to number (23)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0374 g of reaction product.

[0234] The above reaction products were characterized by NMR, and the results are as follows:

[0235] 1 H NMR (400MHz, DMSO-d6) δ7.99 (s, 2H), 7.32 (d, J = 7.2Hz, 1H), 7.27-6.82 (m, 4H), 6.81-6.54 (m, 3H), 6.52 (d, J = 7.6Hz, 1H), 6.22 (d, J = 8. 0Hz,1H),5.93(s,1H),5.78(d,J=7.2Hz,1H),4.24-4.04(m,2H),3.96-3.79(m,1H),2.78(s,3H),2.34-2.21(m,1H),1.96-1.86(m,1H).

[0236] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 78%.

[0237] Example 40: Synthesis of the compound shown in formula III-23a

[0238] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of the compound corresponding to number (1)) and 0.1 mmol of 3-chlorobenzoyl unsaturated indolone (0.0297 g of the compound corresponding to number (24)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0370 g of reaction product.

[0239] The above reaction products were characterized by NMR, and the results are as follows:

[0240] 1 H NMR (400MHz, DMSO-d6) δ8.72(s,1H),7.18(d,J=7.6Hz,1H),7.21-7.14(m,1H),7.05-6.94(m,4H),6.84(t,J=7.6Hz,1H),6.67-6.55(m,3H),6.5 1(d,J=7.6Hz,1H),6.40(d,J=7.6Hz,1H),6.22(s,1H),4.28-4.16(m,1H ),4.13(s,1H),3.98-3.87(m,1H),2.46-2.32(m,1H),1.94-1.83(m,1H).

[0241] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 79%.

[0242] Example 41: Synthetic compound shown in formula III-23b

[0243] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to (1)) and 0.1 mmol of 3-chlorobenzoyl unsaturated indolone (0.0297 g of the compound corresponding to (24)) into a 20 mL test tube reaction tube. Add 1 mL of n-butanol as solvent and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0435 g of reaction product.

[0244] The above reaction products were characterized by NMR, and the results are as follows:

[0245] 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),7.31(d,J=7.2Hz,2H),7.23-7.07(m,2H),7.04(t,J=7.6Hz,1H),6.85-6.64(m,3H),6.53(t,J=7.6Hz,2H),6. 21(d,J=7.6Hz,1H),5.91(s,1H),5.80(d,J=7.2Hz,1H),4.23-4.06(m,2H ),3.99-3.81(m,1H),2.78(s,3H),2.37-2.17(m,1H),2.00-1.81(m,1H).

[0246] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 93%.

[0247] Example 42: Synthetic compound shown in formula III-24a

[0248] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of the compound corresponding to number (1)) and 0.1 mmol of 3-bromobenzoyl unsaturated indolone (0.0341 g of the compound corresponding to number (25)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0426 g of reaction product.

[0249] The above reaction products were characterized by NMR, and the results are as follows:

[0250] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),7.23(d,J=7.6Hz,1H),7.18(d,J=7.6Hz,1H),7.0 5-6.91(m,4H),6.84(t,J=7.2Hz,1H),6.73(s,1H),6.67(d,J=7.6Hz,1H),6.60(t,J=7 .2Hz,1H),6.51(d,J=7.6Hz,1H),6.40(d,J=7.6Hz,1H),6.21(s,1H),4.28-4.16(m,1H ),4.12(s,1H),3.99-3.89(m,1H),2.91(s,3H),2.46-2.32(m,1H),1.94-1.83(m,1H).

[0251] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 83%.

[0252] Example 43: Compound shown in formula III-24b

[0253] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of compound corresponding to number (1)) and 0.1 mmol of 3-bromobenzoyl unsaturated indolone (0.0341 g of compound corresponding to number (25)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0426 g of reaction product.

[0254] The above reaction products were characterized by NMR, and the results are as follows:

[0255] 1 H NMR(400MHz, DMSO-d6)δ8.41(s,1H),7.45(d,J=7.6Hz,1H),7.30(d,J=7.6Hz,1H), 7.14-7.06(m,2H),7.06-7.01(m,1H),6.89-6.57(m,4H),6.53(t,J=7.6Hz,1H),6. 20(d,J=7.6Hz,1H),5.91(s,1H),5.78(dd,J=7.2,1.2Hz,1H),4.23-4.11(m,1H),4 .09(s,1H),3.95-3.85(m,1H),2.79(s,3H),2.34-2.21(m,1H),1.96-1.86(m,1H).

[0256] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 83%.

[0257] Example 44: Synthesis of the compound shown in formula III-25a

[0258] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of compound corresponding to number (1)) and 0.1 mmol of 3-methoxybenzoyl unsaturated indolone (0.0293 g of compound corresponding to number (26)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0316 g of reaction product.

[0259] The above reaction products were characterized by NMR, and the results are as follows:

[0260] 1 H NMR (400MHz, DMSO-d6) δ8.39 (s, 1H), 7.17 (d, J = 7.2Hz, 1H), 7.08-6.93 (m, 3H) ,6.92-6.78(m,2H),6.67-6.53(m,2H),6.47(d,J=8.0Hz,1H),6.40(d,J=8.0H z,1H),6.32-6.20(m,2H),6.16(s,1H),4.27-4.13(m,1H),4.10(s,1H),3.99- 3.85(m,1H),3.57(s,3H),2.85(s,3H),2.45-2.30(m,1H),1.94-1.82(m,1H).

[0261] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 68%.

[0262] Example 45: Synthetic compound shown in formula III-25b

[0263] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of compound corresponding to number (1)) and 0.1 mmol of 3-methoxybenzoyl unsaturated indolone (0.0293 g of compound corresponding to number (26)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0399 g of reaction product.

[0264] The above reaction products were characterized by NMR, and the results are as follows:

[0265] 1H NMR (400MHz, DMSO-d6) δ7.93 (s, 1H), 7.30 (d, J = 7.2Hz, 1H), 7.10-7.01 (m, 3H), 6.84 (d,J=7.6Hz,1H),6.76-6.67(m,2H),6.51(t,J=7.2Hz,1H),6.39(s,2H),6.21(d,J=7 .6Hz,1H),5.85(s,1H),5.78(dd,J=7.2,1.2Hz,1H),4.18-4.09(m,1H),4.08(s,1H) ,3.92-3.80(m,1H),3.58(s,3H),2.83(s,3H),2.29-2.20(m,1H),1.95-1.84(m,1H).

[0266] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 86%.

[0267] Example 46: Synthetic compound shown in formula III-26a

[0268] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g corresponding to compound (1)) and 0.1 mmol of acetyl unsaturated indolone (0.0201 g corresponding to compound (27)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0235 g of reaction product.

[0269] The above reaction products were characterized by NMR, and the results are as follows:

[0270] 1 H NMR(400MHz, DMSO-d6)δ8.04(s,1H),7.28-7.21(m,1H),7.16-7.08(m,2H),7.01(t,J=7.6Hz,1H),6.97-6.90(m,2H),6.59-6.48(m,1H),6 .37(d,J=7.6Hz,1H),6.14(s,1H),4.17-4.05(m,2H),3.94-3.85(m,1H),3.03(s,3H),2.39-2.27(m,1H),1.89-1.81(m,1H),1.34(s,3H).

[0271] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 63%.

[0272] Example 47: Compound shown in formula III-26b

[0273] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to (1)) and 0.1 mmol of acetyl unsaturated indolone (0.0201 g of the compound corresponding to (27)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0279 g of reaction product.

[0274] The above reaction products were characterized by NMR, and the results are as follows:

[0275] 1 H NMR (400MHz, DMSO-d6) δ8.07(s,1H),7.22(d,J=7.6Hz,1H),7.08(t,J=7.6Hz,1H),6.9 9(t,J=7.6Hz,1H),6.87(d,J=7.6Hz,1H),6.67(t,J=7.2Hz,1H),6.45(t,J=7.2Hz,1H), 6.16(d,J=8.0Hz,1H),5.82(s,1H),5.61(d,J=7.2Hz,1H),4.18-4.07(m,1H),4.05(s,1 H),3.96-3.87(m,1H),3.13(s,3H),2.30-2.17(m,1H),1.92-1.81(m,1H),1.57(s,3H).

[0276] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 75%.

[0277] Example 48: Compound shown in formula III-27b

[0278] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to number (1)) and 0.1 mmol of ethoxycarbonyl unsaturated indolone (0.0231 g of the compound corresponding to number (28)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0375 g of reaction product.

[0279] The above reaction products were characterized by NMR, and the results are as follows:

[0280] 1 H NMR (400MHz, DMSO-d6) δ7.44(s,1H),7.22(d,J=7.2Hz,1H),7.07(t,J=7.6Hz,1H),7.01(t,J =7.6Hz,1H),6.84(d,J=8.0Hz,1H),6.67(t,J=7.6Hz,1H),6.46(t,J=7.6Hz,1H),6.20(d,J=8 .0Hz,1H),5.82(s,1H),5.63(d,J=7.2Hz,1H),4.12-4.01(m,2H),3.94-3.85(m,1H),3.82-3. 71(m,1H),3.71-358(m,1H),3.10(s,3H),2.28-2.14(m,1H),1.92-1.81(m,1H),0.93(s,3H).

[0281] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 93%.

[0282] Example 49: Synthetic compound shown in formula III-28a

[0283] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of the compound corresponding to number (1)) and 0.1 mmol of N-phenyl unsaturated indolone (0.0325 g of the compound corresponding to number (29)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0402 g of reaction product.

[0284] The above reaction products were characterized by NMR, and the results are as follows:

[0285] 1 H NMR(400MHz, DMSO-d6)δ8.45(s,1H),7.60-7.48(m,2H),7.39(t,J=7.6Hz,1H),7.32(d,J=7.6Hz,2H),7.20(d,J=7.6Hz,1H),7.16-7.03(m,4H),7.0 2-6.84(m,5H),6.59(t,J=7.6Hz,1H),6.49(s,1H),6.47-6.37(m,2H),4. 26-4.13(m,2H),4.00-3.88(m,1H),2.48-2.35(m,1H),1.95-1.84(m,1H).

[0286] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield was calculated to be 81%.

[0287] Example 50: Synthetic compound shown in formula III-28b

[0288] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to (1)) and 0.1 mmol of N-phenyl unsaturated indolone (0.0325 g of the compound corresponding to (29)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0431 g of reaction product.

[0289] The above reaction products were characterized by NMR, and the results are as follows:

[0290] 1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.59-7.46(m,2H),7.44-7.29(m,3H),7.28-7 .12(m,4H),7.12-6.90(m,4H),6.77(t,J=7.6Hz,1H),6.58(t,J=7.6Hz,1H),6.52( d,J=8.0Hz,1H),6.29(d,J=8.0Hz,1H),6.13(s,1H),5.92(d,J=7.6Hz,1H),4.19(s ,1H),4.17-4.06(m,1H),3.93-3.81(m,1H),2.35-2.20(m,1H),2.00-1.85(m,1H).

[0291] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 87%.

[0292] Example 51: Synthetic compound shown in formula III-29b

[0293] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of compound corresponding to number (1)) and 0.1 mmol of N-p-toluenesulfonyl unsaturated indolone (0.0403 g of compound corresponding to number (30)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0545 g of reaction product.

[0294] The above reaction products were characterized by NMR, and the results are as follows:

[0295] 1H NMR(400MHz, DMSO-d6)δ7.95(d,J=7.6Hz,2H),7.60(d,J=8.0Hz,1H),7.44(d,J=8.0Hz,2H), 7.38(d,J=7.2Hz,1H),7.35-7.26(m,4H),7.22-7.12(m,3H),7.11-7.03(m,1H),6.74(t,J=7. 2Hz,1H),6.66(t,J=7.2Hz,1H),6.28(d,J=7.6Hz,1H),6.12(s,1H),5.89(dd,J=7.6,1.2Hz,1 H),4.06-3.97(m,2H),3.80-3.70(m,1H),2.41(s,3H),2.24-2.12(m,1H),1.92-1.83(m,1H).

[0296] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield was calculated to be 95%.

[0297] Example 52: Compound shown in formula II-30a

[0298] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of the compound corresponding to number (1)) and 0.1 mmol of N-benzoyl unsaturated indolone (0.0353 g of the compound corresponding to number (31)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0445 g of reaction product.

[0299] The above reaction products were characterized by NMR, and the results are as follows:

[0300] 1H NMR (400MHz, DMSO-d6) δ7.80(d,J=7.6Hz,3H),7.62(d,J=8.0Hz,1H),7.57(t,J=7.6Hz,1H),7.51-7.43(m,2H),7.30-7.23(m,2H),7.22-7.09(m, 5H),7.09-6.97(m,3H),6.72(s,1H),6.68-6.58(m,2H),4.24(s,1H),4.1 7-4.04(m,1H),3.94-3.82(m,1H),2.47-2.34(m,1H),1.93-1.79(m,1H).

[0301] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 85%.

[0302] Example 53: Synthesis of the compound shown in formula III-31a

[0303] Weigh 0.12 mmol of tryptophan isonitrile (0.0204 g of the compound corresponding to number (1)) and 0.1 mmol of N-tert-butoxycarbonyl unsaturated indolone (0.0349 g of the compound corresponding to number (32)) into a 15 mL explosion-proof tube, add 0.5 mL of anhydrous tetrahydrofuran as solvent, and stir at 110 °C for 24 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:3) to obtain 0.0442 g of reaction product.

[0304] The above reaction products were characterized by NMR, and the results are as follows:

[0305] 1 H NMR (400MHz, DMSO-d6) δ8.06(s,1H),7.37(d,J=8.0Hz,1H),7.23-7.15(m,2H),7.14-6.97(m,6H),6.91(d,J=7.2H z,2H),6.63(t,J=7.2Hz,1H),6.50-6.35(m,2H),4.21-4.10(m,1H),4.10(s,1H),3.96-3.84(m,1H),2.46-2.31(m 1H),1.94-1.80(m,1H),1.54(s,9H).

[0306] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 85%.

[0307] Example 54: Compound shown in formula III-32b

[0308] Weigh 0.15 mmol of tryptophan isonitrile (0.0255 g of the compound corresponding to number (1)) and 0.1 mmol of N-benzoyl unsaturated indolone or N-tert-butoxycarbonyl unsaturated indolone (0.0353 g or 0.0349 g of the compounds corresponding to numbers (31, 32)) into a 20 mL test tube reaction tube, add 1 mL of n-butanol as solvent, and stir at 130 °C for 14 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is methanol (A) and dichloromethane (B), mobile phase change program (A:B) is 1:50) to obtain 0.0374 g-0.0378 g of reaction product.

[0309] The above reaction products were characterized by NMR, and the results are as follows:

[0310] 1 H NMR (400MHz, DMSO-d6) δ9.95 (s, 1H), 7.53 (s, 1H), 7.39-7.27 (m, 2H), 7.22 (t, J = 7.6 Hz,2H),7.09-7.00(m,3H),6.97(t,J=7.6Hz,1H),6.72(t,J=7.6Hz,1H),6.62(d,J=8 .0Hz,1H),6.42(t,J=7.6Hz,1H),6.23(d,J=7.6Hz,1H),5.85(s,1H),5.78(d,J=7.6 Hz,1H),4.10-4.00(m,2H),3.86-3.76(m,1H),2.26-2.14(m,1H),1.93-1.82(m,1H).

[0311] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 89-90%.

[0312] Test Example 1: Bioactivity Test

[0313] Based on relevant references (Cancer RES. 2014, 74, 5855-5865), this invention selected 10 compounds prepared in the above examples and conducted toxicity tests on three human cancer cells, SJSA-1, RS4;11, and LNCaP, using the MTT assay. The drug MI-77301 / SAR405808 was used as a control for toxicity testing. The test results are shown in Table 1 below:

[0314] Table 1. Cytotoxicity of different compounds (IC50)50 Test results (μM)

[0315] Compound SJSA-1 RS4;11 LNCaP III-10a 12.49 7.75 9.45 III-10b 1.64 1.34 1.74 III-13a 51.22 >100 41.28 III-13b 23.49 45.65 20.94 III-15a 7.84 10.46 9.83 III-15b 1.83 2.45 1.33 III-21a 60.5 >100 >100 III-21b 40.38 >100 34.55 III-26b 3.48 2.52 2.64 III-27b 4.87 3.98 2.3 MI-77301 / SAR405808 0.092±0.019 0.089±0.027 0.27±0.03

[0316] The results showed that the 10 diastereomers of spirocyclic indolone derivatives exhibited varying degrees of cytotoxicity against three types of cancer cells. For example, compounds represented by formulas III-10a, III-10b, III-15a, III-15b, III-26b, and III-27b all showed low micromolar cytotoxicity. Among them, spirocyclic indolone compounds III-10b, III-15b, III-26b, and III-27b showed stronger inhibitory effects against one or more human cancer cells. Therefore, the diastereomers of spirocyclic indolone derivatives synthesized in this invention possess antitumor activity and show promise for application in the preparation of antitumor drugs.

[0317] The above-described embodiments are merely preferred embodiments provided to fully illustrate the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims

1. A diastereomeric spirocyclic indole ketone derivative, characterized in that, The diastereomers of the spirocyclic indole ketone derivatives are selected from one of the following structures: ， 。 2. A method for preparing the diastereomeric form of the spirocyclic indole ketone derivative according to claim 1, characterized in that, Includes the following steps: The compound shown in Formula I was reacted with the compound shown in Formula II in the presence of an organic solvent to obtain the diastereomeric spirocyclic indolone derivative; The structure of the compound represented by Formula I is as follows: ； The compound represented by Formula II is selected from one of the following structures: ； When preparing the diastereomeric derivatives of spirocyclic indolones represented by formula III-10a, III-13a, III-15a or III-21a, the organic solvent is tetrahydrofuran. When preparing diastereomers of spirocyclic indolone derivatives of formula III-10b, III-13b, III-15b, III-21b, III-26b or III-27b, the organic solvent is n-butanol.

3. The preparation method according to claim 2, characterized in that, The molar ratio of the compound represented by Formula I to the compound represented by Formula I is 1.2-1.5:

1.

4. The preparation method according to claim 2, characterized in that, The reaction temperature is 90-130 °C, and the reaction time is 14 h-24 h.

5. The use of the diastereomeric spirocyclic indole ketone derivative of claim 1 in the preparation of an anticancer drug, said anticancer drug for the treatment of osteosarcoma, acute lymphoblastic leukemia or prostate cancer.

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