A 3-hydroxy-oxidized indole derivative containing Z-type 1,4-dicarbonyl olefin, its preparation method and application

Abstract

This invention belongs to the field of medicinal chemistry, specifically relating to a 3-hydroxy-oxidized indole derivative containing a Z-form 1,4-dicarbonyl olefin, its preparation method, and its applications. The 3-hydroxy-oxidized indole derivative containing a Z-form 1,4-dicarbonyl olefin provided by this invention has a novel structure and exhibits inhibitory activity against PTP1B protein, showing broad application prospects in the treatment of type II diabetes and cancer. Furthermore, this invention provides a method for preparing the aforementioned 3-hydroxy-oxidized indole derivative containing a Z-form 1,4-dicarbonyl olefin, which is prepared by a two-step reaction in an organic solvent using cyclopropene carboxylate and indigo as raw materials under the catalysis of a metal catalyst. The preparation method of this invention involves fewer reaction steps, uses inexpensive and readily available raw materials, is simple and safe to operate, has low cost, generates little waste, and features high atomic efficiency, good stereoselectivity, mild conditions, scalability, and high product value.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a 3-hydroxy-oxidized indole derivative containing a Z-type 1,4-dicarbonyl olefin, its preparation method, and its application. Background Technology

[0002] Protein tyrosine phosphatase 1B (PTP1B) is a member of the PTP family. It can inhibit or terminate insulin signaling pathways by binding to the insulin receptor (IR) or insulin receptor substrate (IRS) and dephosphorylating the aromatic phosphates of tyrosine residues, leading to insulin resistance and type II diabetes. Furthermore, PTP1B can dephosphorylate the negative regulator amino acid residue Y530 on the non-receptor tyrosine kinase Src protein, thereby activating Src and promoting tumor growth by affecting tumor cell proliferation, adhesion, migration, invasion, and metastasis. Src dysregulation is present in various tumor types, such as breast cancer, lung cancer, and colon cancer. For example, in breast cancer, overexpression of PTP1B has been reported in multiple breast cancer samples, playing a crucial role in cancer progression.

[0003] The role of PTP1B in disease progression has driven the discovery of numerous PTP1B inhibitors. For example, ISIS-113715 and ISIS-PTP1BRx, developed by ISI Pharmaceuticals, have entered Phase II clinical trials, primarily for the treatment of diabetes. Ertiporotafib, developed by Pfizer, has also entered Phase II clinical trials. However, regrettably, no PTP1B inhibitor has yet been approved by the FDA. Therefore, the development of novel small-molecule PTP1B inhibitors remains of great significance.

[0004] 3-Hydroxyindole structures are widely found in natural products and pharmaceutical active molecules, with many natural compounds containing this structure. Furthermore, many complex natural products can be synthesized from 3-hydroxyindole derivatives, and these derivatives have wide applications in materials science, agriculture, biology, and medicine. Given the advantages of the 3-hydroxyindole structure, developing efficient synthetic methods for these compounds has become a research hotspot in synthetic chemistry. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention proposes a 3-hydroxy-oxidized indole derivative containing a Z-type 1,4-dicarbonyl olefin, its preparation method, and its application.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0007] In a first aspect, the present invention provides a 3-hydroxy-oxidized indole derivative containing a Z-form 1,4-dicarbonyl olefin, wherein the structure of the 3-hydroxy-oxidized indole derivative containing the Z-form 1,4-dicarbonyl olefin is shown in general formula (I).

[0008]

[0009] Among them, R 1 Selected from hydrogen atom, benzyl, tert-butoxycarbonyl, acetyl, methyl; R 2 Selected from alkyl groups; Ar 1 Selected from aryl or substituted aryl; Ar 2 It is selected from aryl or substituted aryl; the substituted aryl is selected from alkyl, alkoxy or halogen-substituted aryl.

[0010] Preferably, the R 2 Selected from methyl, ethyl; Ar 1 Selected from phenyl, 4-chlorophenyl, 5-chlorophenyl, 6-chlorophenyl, 7-chlorophenyl, 5-fluorophenyl, 5-methoxyphenyl, 6-methoxyphenyl; Ar 2 It is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, and 3,4,5-trimethoxyphenyl.

[0011] Preferably, the 3-hydroxy-oxidized indole derivative containing a Z-type 1,4-dicarbonyl olefin is selected from at least one of compounds 6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6i, 6j, 6k, 6l, 6m, 6n, 6o, 6p, 6q, 6r, 6s, 6t, 6u, and 6v, and the chemical formulas of compounds 6a to 6v are as follows:

[0012]

[0013] Secondly, the present invention provides a method for preparing the above-mentioned 3-hydroxy-oxidized indole derivatives containing Z-type 1,4-dicarbonyl olefins, the method being as follows:

[0014] Indigo is mixed with a metal catalyst and an organic acid in an anhydrous organic solvent. Cyclopropene carboxylic acid ester is added to the mixture, and the mixture is reacted under nitrogen for a period of time. Then, the mixture is irradiated with visible light in air for a certain period of time to obtain hydroxyindole derivatives represented by general formula (Ⅰ).

[0015] Preferably, the molar ratio of indigo, metal catalyst, organic acid, and cyclopropene carboxylate is 1.0:(0.01-0.05):(0.1-2.0):(1.0-3.0); the reaction temperature under nitrogen is 20-80℃, the reaction time is 8-20h, and then the reaction is carried out under sunlight at 25℃ for 8-12h.

[0016] Preferably, the organic solvent includes, but is not limited to, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, toluene, xylene, or ethyl acetate; the metal catalyst includes, but is not limited to, rhodium acetate, bis[(A,A,A′,A′-tetramethyl-1,3-phenylenediol)rhodium], rhodium(II) octoate, tetracaprolactam dirhodium, and rhodium trifluoroacetate dimer; the organic acid includes, but is not limited to, acetic acid, benzoic acid, naphthol phosphoric acid, and p-toluenesulfonamide.

[0017] Thirdly, the present invention provides the application of the above-mentioned 3-hydroxy-oxidized indole derivatives containing Z-type 1,4-dicarbonyl olefins in the preparation of PTP1B small molecule inhibitors.

[0018] Fourthly, the present invention provides the use of the above-mentioned 3-hydroxy-oxidized indole derivatives containing Z-type 1,4-dicarbonyl olefins in the preparation of drugs for treating type II diabetes.

[0019] Preferably, in the application of preparing PTP1B small molecule inhibitors or type II diabetes drugs, the 3-hydroxy-oxidized indole derivative containing Z-type 1,4-dicarbonyl olefin is selected from at least one of compounds 6a, 6b, 6g, 6h, 6i, 6m, 6n, 6r, and 6u.

[0020] The beneficial effects of this invention are:

[0021] This novel 3-hydroxy-oxidized indole derivative containing a Z-form 1,4-dicarbonyl olefin exhibits excellent inhibitory activity against PTP1B protein, demonstrating significant application value in the treatment of type II diabetes and anti-tumor effects. It holds promise for development into drugs for treating type II diabetes or inhibiting tumor cell proliferation. Furthermore, the preparation method for this Z-form 1,4-dicarbonyl olefin-containing 3-hydroxy-oxidized indole derivative involves a two-step reaction in an organic solvent using indigo and cyclopropene carboxylate as raw materials, catalyzed by a metal catalyst. This method utilizes inexpensive and readily available raw materials, involves few reaction steps, is simple and safe to operate, has low cost, generates minimal waste, and boasts advantages such as high atom economy, high selectivity, and high yield. Detailed Implementation

[0022] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0023] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.

[0024] Example 1

[0025] Preparation of 3-hydroxy-oxidized indole derivatives containing Z-type 1,4-dicarbonyl alkenes

[0026] The 3-hydroxy-oxidized indole derivatives containing Z-form 1,4-dicarbonyl olefins have structures as shown in general formula (I):

[0027]

[0028] The synthetic reaction formula for the 3-hydroxy-oxidized indole derivative containing Z-form 1,4-dicarbonyl olefin is as follows:

[0029]

[0030] According to the above reaction equation, the specific preparation method of the 3-hydroxy-oxidized indole derivative containing Z-form 1,4-dicarbonyl olefin is as follows:

[0031] S1. Dissolve indigo (0.20 mmol), rhodium (0.004 mmol, metal catalyst), and acetic acid (0.30 mmol) as shown in Formula II in 3.0 mL of organic solvent ethyl acetate; then add cyclopropene carboxylate (0.30 mmol) as shown in Formula III to the mixed solution, replace the gas in the reaction system with nitrogen, and stir the reaction at 35 °C for 16 hours.

[0032] S2. After stirring, place the reaction solution under visible light and continue stirring in air at 25°C for 8 hours. After the reaction is completed, monitor by thin-layer chromatography, filter the reaction solution, concentrate under reduced pressure, and then separate and purify by column chromatography to prepare the target product shown in Formula I, a 3-hydroxy-oxidized indole derivative containing a Z-form 1,4-dicarbonyl olefin. The yields of the target products were all between 68% and 85%, and the Z / E selectivity was greater than 20:1, indicating high selectivity.

[0033] In equation (Ⅰ) and the reaction equation, R 1 Selected from hydrogen atom, benzyl, tert-butoxycarbonyl, acetyl, methyl; R 2 Selected from alkyl groups; Ar1 Selected from aryl or substituted aryl; Ar 2 Selected from aryl or substituted aryl; substituted aryl is selected from alkyl, alkoxy or halogen-substituted aryl.

[0034] Specifically, R 2 Selected from methyl, ethyl; Ar 1 Selected from phenyl, 4-chlorophenyl, 5-chlorophenyl, 6-chlorophenyl, 7-chlorophenyl, 5-fluorophenyl, 5-methoxyphenyl, 6-methoxyphenyl; Ar 2 It is selected from phenyl, 2-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, and 3,4,5-trimethoxyphenyl.

[0035] To further illustrate the preparation method of 3-hydroxy-oxidized indole derivatives containing Z-type 1,4-dicarbonyl alkenes, the following explanation uses compound 6a-6v as an example:

[0036] (1) Preparation of methyl 4-(1-benzyl-3-hydroxy-2-oxoindoline-3-yl)-2-phenyl-4-carbonyl-2(Z)-butenoate (compound 6a)

[0037] Compound 6a is R 1 benzyl, R 2 Methyl, Ar 1 For phenyl, Ar 2 The structure of compound 6a, a 3-hydroxy-oxidized indole derivative of a phenyl-containing 1,4-dicarbonyl olefin, is shown in formula (6a):

[0038]

[0039] The specific preparation method includes the following steps:

[0040] (1) Dissolve 1-(benzyl)indigo (0.20 mmol), bis[(A,A,A′,A′-tetramethyl-1,3-phenylpropionic acid)rhodium] (0.004 mmol, metal catalyst), and acetic acid (0.30 mmol) in 3.0 mL of ethyl acetate; then add methyl 2-phenyl-2-cyclopropenyl-1-acetate (0.30 mmol) to the mixed solution, replace the gas in the reaction system with nitrogen, and stir the reaction at 35 °C for 16 hours;

[0041] (2) After stirring, the reaction solution was placed under visible light and stirred in air at 25°C for 8 hours. After the reaction was monitored by thin-layer chromatography, the reaction solution was filtered, concentrated under reduced pressure, and then purified by column chromatography (using petroleum ether:ethyl acetate = 10:1 as eluent) to obtain the pure product. The product yield was 81%. The mass spectrometry information of this compound is as follows:

[0042] 1 H NMR(500MHz,Chloroform-d)δ7.43-7.38(m,3H),7.35-

[0043] 7.27(m,6H),7.22(d,J=7.5Hz,1H),7.14(d,J=7.8Hz,2H),7.09(t,J=7.6Hz,1H),6.93(d,J=7.9 Hz,1H),6.09(s,1H),5.27(d,J=15.3Hz,1H),5.08(s,1H),4.65(d,J=15.3Hz,1H),3.98(s,3H).

[0044] 13 C NMR(126MHz,Chloroform-d)δ189.96,172.60,167.99,150.94,143.88,135.46,132.38,131.61,131.14, 129.11,129.08,128.06,127.75,127.21,125.63,124.91,124.08,115.86,109.90,83.17,53.05,44.55.

[0045] HRMS(ESI)calcd for C 26 H 21 NO5Na[M+Na] + :450.1312,found450.1313.

[0046] (2) Preparation of methyl 4-(3-hydroxy-2-oxoindoline-3-yl)-2-phenyl-4-carbonyl-2(Z)-butenoate (compound 6b)

[0047] Compound 6b is R 1 For hydrogen atoms, R 2 Methyl, Ar 1 For phenyl, Ar 2 The structure of compound 6b is shown in formula (6b), which is a 3-hydroxy-oxidized indole derivative of a phenyl-containing 1,4-dicarbonyl olefin.

[0048]

[0049] The specific preparation method includes the following steps:

[0050] The preparation process of this compound is the same as that of compound 6a, except that 1-(benzyl)indigo in step (1) is replaced with indigo, which yields compound 6b with a product separation yield of 76%. The mass spectrometry information of this compound is as follows:

[0051] 1 H NMR(500MHz,Chloroform-d)δ8.65(s,1H),7.44-7.30(m,6H),7.22(d,J=7.5Hz,1H), 7.11(t,J=7.6Hz,1H),7.02(d,J=7.9Hz,1H),6.32(s,1H),5.10(s,1H),3.98(s,3H).

[0052] 13 C NMR(126MHz,Chloroform-d)δ189.85,174.75,168.07,151.27,141.78,132.47,131. 70,131.29,129.14,127.31,126.12,125.16,124.13,115.75,111.02,83.46,53.06.

[0053] HRMS(ESI)calcd for C 19 H 15 NO5Na[M+Na] + :360.0842,found360.0844.

[0054] (3) Preparation of methyl 4-(1-tert-butoxycarbonyl-3-hydroxy-2-oxoindoline-3-yl)-2-phenyl-4-carbonyl-2(Z)-butenoate (compound 6c)

[0055] Compound 6c is R 1 It is tert-butyloxycarbonyl, R 2 Methyl, Ar 1 For phenyl, Ar 2 The structure of compound 6c is shown in formula (6c), which is a 3-hydroxy-oxidized indole derivative of a phenyl-containing 1,4-dicarbonyl olefin.

[0056]

[0057] The specific preparation method includes the following steps:

[0058] The preparation process of this compound is the same as that of compound 6a, except that 1-(benzyl)indigo in step (1) is replaced with 1-(tert-butyloxycarbonyl)indigo, which yields compound 6c with a product separation yield of 71%. The mass spectrometry information of this compound is as follows:

[0059] 1 H NMR(500MHz,Chloroform-d)δ8.00(d,J=8.2Hz,1H),7.48(td,J=8.6,7.9,2.0Hz,1H),7.44(t,J=7.2Hz,1H),7.36(t,J=7.7Hz ,2H),7.31(d,J=7.6Hz,2H),7.26(d,J=5.7Hz,1H),7.24(t,J=7.3Hz,1H),6.21(s,1H),5.10(s,1H),3.97(s,3H),1.65(s,9H).

[0060] 13 C NMR(126MHz,Chloroform-d)δ189.41,170.49,167.92,151.50,148.76,141.05,132.50,131 .80,131.46,129.18,127.37,125.72,124.72,115.93,115.91,85.45,82.67,53.08,28.04.

[0061] HRMS(ESI)calcd for C 24 H 23 NO7Na[M+Na] + :460.1367,found460.1367.

[0062] (4) Preparation of methyl 4-(1-acetyl-3-hydroxy-2-oxoindoline-3-yl)-2-phenyl-4-carbonyl-2(Z)-butenoate (compound 6d)

[0063] Compound 6d is R 1 Acetyl, R 2 Methyl, Ar 1 For phenyl, Ar 2 The structure of compound 6d, a 3-hydroxy-oxidized indole derivative of a phenyl-containing 1,4-dicarbonyl olefin, is shown in formula (6d):

[0064]

[0065] The specific preparation method includes the following steps:

[0066] The preparation process of this compound is the same as that of compound 6a, except that 1-(benzyl)indigo in step (1) is replaced with 1-acetylindigo, which yields compound 6d with a product separation yield of 70%. The mass spectrometry information of this compound is as follows:

[0067] 1 H NMR(400MHz,Chloroform-d)δ8.35(d,J=8.3Hz,1H),7.54-7.39(m,3H),7.36(t,J= 7.6Hz,2H),7.33-7.27(m,3H),6.20(s,1H),5.15(s,1H),3.98(s,3H),2.70(s,3H).

[0068] 13 C NMR(126MHz,Chloroform-d)δ189.23,173.10,170.49,167.82,151.99,141.28,132.27,132 .00,131.60,129.26,127.35,126.48,125.03,124.50,117.37,115.37,82.87,53.12,26.58.

[0069] HRMS(ESI)calcd for C 21 H 17 NO6Na[M+Na] + :402.0948,found402.0948.

[0070] (5) Preparation of methyl 4-(1-methyl-3-hydroxy-2-oxoindoline-3-yl)-2-phenyl-4-carbonyl-2(Z)-butenoate (compound 6e)

[0071] Compound 6e is R 1 Methyl, R 2 Methyl, Ar 1 For phenyl, Ar 2 The structure of compound 6e, a 3-hydroxy-oxidized indole derivative of a phenyl-containing 1,4-dicarbonyl olefin, is shown in formula (6e):

[0072]

[0073] The specific preparation method includes the following steps:

[0074] The preparation process of this compound is the same as that of compound 6a, except that 1-(benzyl)indigo in step (1) is replaced with 1-methylindigo, which yields compound 6e with a product separation yield of 68%. The mass spectrometry information of this compound is as follows:

[0075] 1H NMR(400MHz,Chloroform-d)δ7.43(q,J=7.4Hz,2H),7.34(t,J=7.6Hz,2H),7.32-7.27(m,2H),7.25(d,J=7. 4Hz,1H),7.13(t,J=7.5Hz,1H),6.97(d,J=7.8Hz,1H),6.19(s,1H),5.03(s,1H),3.96(s,3H),3.31(s,3H).

[0076] 13 C NMR(101MHz,Chloroform-d)δ190.35,172.69,168.04,150.95,144.86,132.73,131.56, 131.27,129.12,127.24,125.71,124.86,124.08,116.23,109.09,83.07,53.04,27.06.

[0077] HRMS(ESI)calcd for C 20 H 17 NO5Na[M+Na] + :374.0999,found 374.0999.

[0078] (6) Preparation of methyl 4-(1-benzyl-3-hydroxy-4-chloro-2-oxoindoline-3-yl)-2-phenyl-4-carbonyl-2(Z)-butenoate (compound 6f)

[0079] Compound 6f is R 1 benzyl, R 2 Methyl, Ar 1 It is 4-chlorophenyl, Ar 2 The structure of compound 6f, a 3-hydroxy-oxidized indole derivative of a phenyl-containing 1,4-dicarbonyl olefin, is shown in formula (6f):

[0080]

[0081] The specific preparation method includes the following steps:

[0082] The preparation process of this compound is the same as that of compound 6a, except that 1-(benzyl)indigo in step (1) is replaced with 1-benzyl-4-chloro-indigo, which yields compound 6f with a product separation yield of 78%. The mass spectrometry information of this compound is as follows:

[0083] 1H NMR(500MHz,Chloroform-d)δ7.43(t,J=7.4Hz,1H),7.37(dd,J=7.3,2.1Hz,2H),7.33-7.26(m,6H),7.18(d,J=7.7Hz,2H),7.02 (d,J=8.2Hz,1H),6.82(d,J=7.9Hz,1H),6.08(s,1H),5.23(d,J=15.4Hz,1H),5.13(s,1H),4.67(d,J=15.3Hz,1H),3.99(s,3H).

[0084] 13 C NMR(126MHz,Chloroform-d)δ188.48,171.44,167.76,151.42,145.49,135.09,132.38,132.36,132.25, 131.73,129.18,129.10,128.22,127.67,127.30,124.68,122.95,115.43,108.25,82.89,53.09,44.73.

[0085] HRMS(ESI)calcd for C 26 H 20 NO5ClNa[M+Na] + :484.0922,found484.0922.

[0086] (7) Preparation of methyl 4-(1-benzyl-3-hydroxy-5-chloro-2-oxoindoline-3-yl)-2-phenyl-4-carbonyl-2(Z)-butenoate (compound 6 g)

[0087] Compound 6g is R 1 benzyl, R 2 Methyl, Ar 1 It is 5-chlorophenyl, Ar 2 The structure of compound 6g is shown in formula (6g), which is a 3-hydroxy-oxidized indole derivative of a phenyl-containing 1,4-dicarbonyl olefin.

[0088]

[0089] The specific preparation method includes the following steps:

[0090] The preparation process of this compound is the same as that of compound 6a, except that 1-(benzyl)indigo in step (1) is replaced with 1-benzyl-5-chloro-indigo, which yields compound 6g with a product separation yield of 68%. The mass spectrometry information of this compound is as follows:

[0091] 1 H NMR(400MHz,Chloroform-d)δ7.43(t,J=7.4Hz,1H),7.37(dd,J=7.3,2.1Hz,2H),7.34-7.26(m,6H),7.21(d,J=2.1Hz,1H),7.17 (d,J=7.7Hz,2H),6.84(d,J=8.4Hz,1H),6.08(s,1H),5.26(d,J=15.3Hz,1H),5.08(s,1H),4.62(d,J=15.3Hz,1H),3.98(s,3H).

[0092] 13 C NMR(126MHz,Chloroform-d)δ189.19,172.18,167.81,151.62,142.37,135.04,132.26,131.84,131.09, 129.55,129.21,129.14,128.25,127.72,127.32,127.25,125.35,115.36,110.91,82.92,53.12,44.69.

[0093] HRMS(ESI)calcd for C 26 H 20 NO5ClNa[M+Na] + :484.0922,found 484.0922.

[0094] (8) Preparation of methyl 4-(1-benzyl-3-hydroxy-6-chloro-2-oxoindoline-3-yl)-2-phenyl-4-carbonyl-2(Z)-butenoate (compound 6h)

[0095] Compound 6h is R 1 benzyl, R 2 Methyl, Ar 1 It is 6-chlorophenyl, Ar 2 The structure of compound 6h, a 3-hydroxy-oxidized indole derivative of a phenyl-containing 1,4-dicarbonyl olefin, is shown in formula (6h):

[0096]

[0097] The specific preparation method includes the following steps:

[0098] The preparation process of this compound is the same as that of compound 6a, except that 1-(benzyl)indigo in step (1) is replaced with 1-benzyl-6-chloro-indigo, which yields compound 6h with a product separation yield of 73%. The mass spectrometry information of this compound is as follows:

[0099] 1 H NMR(400MHz,Chloroform-d)δ7.43(t,J=7.4Hz,1H),7.38(dd,J=7.2,2.3Hz,2H),7.36-7.27(m,5H),7.20-7.11(m,3H),7 .07(d,J=8.0Hz,1H),6.92(s,1H),6.07(s,1H),5.25(d,J=15.4Hz,1H),5.06(s,1H),4.60(d,J=15.4Hz,1H),3.97(s,3H).

[0100] 13 C NMR(126MHz,Chloroform-d)δ189.37,172.56,167.88,151.49,145.06,137.03,134.95,132.23,131.82, 129.27,129.15,128.30,127.71,127.29,125.88,124.08,124.00,115.42,110.59,82.61,53.10,44.67.

[0101] HRMS(ESI)calcd for C 26 H 20 NO5ClNa[M+Na] + :484.0922,found484.0922.

[0102] (9) Preparation of methyl 4-(1-benzyl-3-hydroxy-7-chloro-2-oxoindoline-3-yl)-2-phenyl-4-carbonyl-2(Z)-butenoate (compound 6i)

[0103] Compound 6i is R 1 benzyl, R 2 Methyl, Ar 1 It is 7-chlorophenyl, Ar 2 The structure of compound 6i, a 3-hydroxy-oxidized indole derivative of a phenyl-containing 1,4-dicarbonyl olefin, is shown in formula (6i):

[0104]

[0105] The specific preparation method includes the following steps:

[0106] The preparation process of this compound is the same as that of compound 6a, except that 1-(benzyl)indigo in step (1) is replaced with 1-benzyl-7-chloro-indigo, which yields compound 6i with a product separation yield of 70%. The mass spectrometry information of this compound is as follows:

[0107] 1 H NMR(400MHz,Chloroform-d)δ7.44(t,J=7.4Hz,1H),7.41-7.28(m,6H),7.27-7.25(m,2H),7.19(d,J=7.6Hz,2H),7.14(d,J =7.3Hz,1H),7.04(t,J=8.0Hz,1H),6.12(s,1H),5.45(d,J=15.8Hz,1H),5.38(d,J=15.8Hz,1H),5.09(s,1H),3.97(s,3H).

[0108] 13 C NMR(126MHz,Chloroform-d)δ189.30,173.23,167.89,151.62,140.00,136.87,133.77,132.32,131.80, 129.16,128.85,128.51,127.65,127.36,127.17,124.96,123.63,116.18,115.65,82.16,53.08,45.49.

[0109] HRMS(ESI)calcd for C 26 H 20 NO5ClNa[M+Na] + :484.0922,found484.0922.

[0110] (10) Preparation of methyl 4-(1-benzyl-3-hydroxy-5-fluoro-2-oxoindoline-3-yl)-2-phenyl-4-carbonyl-2(Z)-butenoate (compound 6j)

[0111] Compound 6j is R 1 benzyl, R 2 Methyl, Ar 1 It is 5-fluorophenyl, Ar 2 The structure of compound 6j, a 3-hydroxy-oxidized indole derivative of a phenyl-containing 1,4-dicarbonyl olefin, is shown in formula (6j):

[0112]

[0113] The specific preparation method includes the following steps:

[0114] The preparation process of this compound is the same as that of compound 6a, except that 1-(benzyl)indigo in step (1) is replaced with 1-benzyl-5-fluoro-indigo, which yields compound 6j with a product separation yield of 82%. The mass spectrometry information of this compound is as follows:

[0115] 1 H NMR(400MHz,Chloroform-d)δ7.43(t,J=7.4Hz,1H),7.37(dd,J=7.3,2.2Hz,2H),7.35-7.26(m,5H),7.16(d,J=7.5Hz,2H),7.03(td,J=8.7,2.6Hz,1 H),6.98(dd,J=7.2,2.6Hz,1H),6.85(dd,J=8.6,3.9Hz,1H),6.09(s,1H), 5.26(d,J=15.3Hz,1H),5.07(s,1H),4.62(d,J=15.4Hz,1H),3.98(s,3H).

[0116] 13 C NMR(126MHz,Chloroform-d)δ189.31,172.35,167.83,160.66,158.72,151.52,139.79,135.15,132.26,131.81,129.20,129 .14,128.21,127.72,127.28,117.59(d,J=23.6Hz),115.41,113.03(d,J=25.4Hz),110.70(d,J=7.9Hz),83.15,53.12,44.72.

[0117] 19 F NMR(376MHz,Chloroform-d)δ-117.80.

[0118] HRMS(ESI)calcd for C 26 H 20 NO5FNa[M+Na] + :468.1218,found 468.1218.

[0119] (11) Preparation of methyl 4-(1-benzyl-3-hydroxy-5-methyl-2-oxoindoline-3-yl)-2-phenyl-4-carbonyl-2(Z)-butenoate (compound 6k)

[0120] Compound 6k is R1 benzyl, R 2 Methyl, Ar 1 5-Methylphenyl, Ar 2 The structure of compound 6k, a 3-hydroxy-oxidized indole derivative of a phenyl-containing 1,4-dicarbonyl olefin, is shown in formula (6k):

[0121]

[0122] The specific preparation method includes the following steps:

[0123] The preparation process of this compound is the same as that of compound 6a, except that 1-(benzyl)indigo in step (1) is replaced with 1-benzyl-5-methyl-indigo, which yields compound 6k with a product separation yield of 80%. The mass spectrometry information of this compound is as follows:

[0124] 1 H NMR(400MHz,Chloroform-d)δ7.45-7.35(m,3H),7.32-

[0125] 7.24(m,5H),7.14(d,J=7.8Hz,2H),7.11(d,J=7.8Hz,1H),7.03(s,1H),6.81(d,J=8.0Hz,1H),6. 09(s,1H),5.25(d,J=15.3Hz,1H),5.03(s,1H),4.62(d,J=15.3Hz,1H),3.98(s,3H),2.27(s,3H).

[0126] 13 C NMR(101MHz,Chloroform-d)δ190.03,172.50,168.05,150.86,141.46,135.61,133.91,132.40,131 .59,131.43,129.08,128.01,127.78,127.23,125.57,115.85,109.67,83.29,53.05,44.58,20.97.

[0127] HRMS(ESI)calcd for C 27 H 23 NO5Na[M+Na] + :464.1468,found 464.1468.

[0128] (12) Preparation of methyl 4-(1-benzyl-3-hydroxy-5-methoxy-2-oxoindoline-3-yl)-2-phenyl-4-carbonyl-2(Z)-butenoate (compound 6l)

[0129] Compound 6l is R 1 benzyl, R 2 Methyl, Ar 1 It is 5-methoxyphenyl, Ar 2 The structure of compound 6l is shown in formula (6l), which is a 3-hydroxy-oxidized indole derivative of a phenyl-containing 1,4-dicarbonyl olefin.

[0130]

[0131] The specific preparation method includes the following steps:

[0132] The preparation process of this compound is the same as that of compound 6a, except that 1-(benzyl)indigo in step (1) is replaced with 1-benzyl-5-methoxy-indigo, which yields compound 6l with a product separation yield of 78%. The mass spectrometry information of this compound is as follows:

[0133] 1 H NMR(500MHz,Chloroform-d)δ7.42(t,J=7.4Hz,1H),7.39(dd,J=7.4,2.1Hz,2H),7.32-7.26(m,5H),7.15(dd,J=8.4,1.3Hz, 2H),6.89-6.78(m,3H),6.10(s,1H),5.26(d,J=15.3Hz,1H),5.08(s,1H),4.61(d,J=15.3Hz,1H),3.98(s,3H),3.73(s,3H).

[0134] 13 C NMR(126MHz,Chloroform-d)δ189.93,172.27,168.02,156.86,151.03,137.05,135.55,132.36,131.65 ,129.10,128.04,127.76,127.25,126.70,116.32,115.74,111.09,110.62,83.52,55.79,53.07,44.66.

[0135] HRMS(ESI)calcd for C 27 H 23 NO6Na[M+Na] + :480.1418,found480.1418.

[0136] (13) Preparation of methyl 4-(1-benzyl-3-hydroxy-6-methoxy-2-oxoindoline-3-yl)-2-phenyl-4-carbonyl-2(Z)-butenoate (compound 6m)

[0137] Compound 6m is R 1 benzyl, R 2 Methyl, Ar 1 It is 6-methoxyphenyl, Ar 2 The structure of compound 6m, a 3-hydroxy-oxidized indole derivative of a phenyl-containing 1,4-dicarbonyl olefin, is shown in formula (6m):

[0138]

[0139] The specific preparation method includes the following steps:

[0140] The preparation process of this compound is the same as that of compound 6a, except that 1-(benzyl)indigo in step (1) is replaced with 1-benzyl-6-methoxy-indigo, which yields compound 6m with a product separation yield of 77%. The mass spectrometry information of this compound is as follows:

[0141] 1 H NMR(500MHz,Chloroform-d)δ7.44-7.37(m,3H),7.35-

[0142] 7.26(m,5H),7.15(d,J=7.3Hz,2H),7.12(d,J=8.3Hz,1H),6.55(dd,J=8.3,2.3Hz,1H),6.49(d,J=2.3Hz,1H),6.08(s,1H),5.24(d,J=

[0143] 15.3Hz,1H),5.00(s,1H),4.60(d,J=15.3Hz,1H),3.97(s,3H),3.78(s,3H).

[0144] 13 C NMR(126MHz,Chloroform-d)δ190.20,173.04,168.07,162.22,150.72,145.31,135.49,132.44,131.56,12 9.13,129.07,128.07,127.77,127.21,125.92,117.34,116.01,107.35,98.32,82.76,55.58,53.03,44.55.

[0145] HRMS(ESI)calcd for C 27 H 23 NO6Na[M+Na] + :480.1418,found480.1417.

[0146] (14) Preparation of methyl 4-(1-benzyl-3-hydroxy-2-oxoindoline-3-yl)-2-(4-chlorophenyl)-4-carbonyl-2(Z)-butenoate (compound 6n)

[0147] Compound 6n is R 1 benzyl, R 2 Methyl, Ar 1 For phenyl, Ar 2 The 3-hydroxy-oxidized indole derivative of a 4-chlorophenyl olefin containing a Z-form 1,4-dicarbonyl olefin, has the structure shown in formula (6n):

[0148]

[0149] The specific preparation method includes the following steps:

[0150] The preparation process of this compound is the same as that of compound 6a, except that methyl 2-phenyl-2-cyclopropenyl-1-acetate in step (1) is replaced with methyl 2-(4-chlorophenyl)-2-cyclopropenyl-1-acetate, which yields compound 6n with a product separation yield of 79%. The mass spectrometry information of this compound is as follows:

[0151] 1 H NMR(500MHz,Chloroform-d)δ7.41(d,J=7.2Hz,2H),7.38-7.26(m,5H),7.25-7.20(m,2H),7.09(t,J=7.6Hz,1H),7.03(d,J =8.6Hz,2H),6.95(d,J=7.9Hz,1H),6.02(s,1H),5.27(d,J=15.2Hz,1H),5.02(s,1H),4.64(d,J=15.2Hz,1H),3.97(s,3H).

[0152] 13C NMR(126MHz,Chloroform-d)δ189.89,172.45,167.64,149.56,143.84,137.88,135.51,131.22,130.85, 129.36,129.13,128.45,128.15,127.88,125.49,124.95,124.14,116.27,109.88,83.20,53.18,44.55.

[0153] HRMS(ESI)calcd for C 26 H 20 NO5ClNa[M+Na] + :484.0922,found484.0920.

[0154] (15) Preparation of methyl 4-(1-benzyl-3-hydroxy-2-oxoindoline-3-yl)-2-(3-chlorophenyl)-4-carbonyl-2(Z)-butenoate (compound 6o)

[0155] Compound 6o is R 1 benzyl, R 2 Methyl, Ar 1 For phenyl, Ar 2 The structure of compound 6o is shown in formula (6o), which is a 3-hydroxy-oxidized indole derivative of a 1,4-dicarbonyl olefin of the Z-form, which is a 3-chlorophenyl group.

[0156]

[0157] The specific preparation method includes the following steps:

[0158] The preparation process of this compound is the same as that of compound 6a, except that methyl 2-phenyl-2-cyclopropenyl-1-acetate in step (1) is replaced with methyl 2-(3-chlorophenyl)-2-cyclopropenyl-1-acetate, which yields compound 6o with a product separation yield of 80%. The mass spectrometry information of this compound is as follows:

[0159] 1 H NMR(500MHz,Chloroform-d)δ7.40-7.27(m,7H),7.25-

[0160] 7.20(m,2H),7.16(s,1H),7.10(t,J=7.5Hz,1H),7.01(d,J=7.9Hz,1H),6.93(d,J=7.9Hz,1 H), 6.06 (s, 1H), 5.26 (d, J = 15.3Hz, 1H), 4.99 (s, 1H), 4.65 (d, J = 15.3Hz, 1H), 3.97 (s, 3H).

[0161] 13 C NMR(126MHz,Chloroform-d)δ190.08,172.38,167.45,149.40,143.89,135.34,135.19,134.30,131.46,131.30, 130.30,129.14,128.21,127.62,127.07,125.37,125.33,124.94,124.15,117.36,110.03,83.21,53.24,44.60.

[0162] HRMS(ESI)calcd for C 26 H 20 NO5ClNa[M+Na] + :484.0922,found 484.0920.

[0163] (16) Preparation of methyl 4-(1-benzyl-3-hydroxy-2-oxoindoline-3-yl)-2-(2-fluorophenyl)-4-carbonyl-2(Z)-butenoate (compound 6p)

[0164] Compound 6p is R 1 benzyl, R 2 Methyl, Ar 1 For phenyl, Ar 2 The 3-hydroxy-oxidized indole derivative of a 2-fluorophenyl olefin containing a Z-form 1,4-dicarbonyl olefin, has the structure shown in formula (6p):

[0165]

[0166] The specific preparation method includes the following steps:

[0167] The preparation process of this compound is the same as that of compound 6a, except that methyl 2-phenyl-2-cyclopropenyl-1-acetate in step (1) is replaced with methyl 2-(2-fluorophenyl)-2-cyclopropenyl-1-acetate, which yields compound 6p with a product separation yield of 82%. The mass spectrometry information of this compound is as follows:

[0168] 1H NMR(500MHz,Chloroform-d)δ7.38(tdd,J=6.9,5.0,1.9Hz,1H),7.36-7.29(m,3H),7.27-7.22(m,4H),7.15(td,J=7.7,1.9Hz,1H),7.10(q,J=7.2H z,2H),7.03(dd,J=11.6,8.4Hz,1H),6.86(d,J=7.9Hz,1H),6.34(s,1H), 5.17(d,J=15.2Hz,1H),5.01(s,1H),4.73(d,J=15.5Hz,1H),3.95(s,3H).

[0169] 13 C NMR(126MHz,Chloroform-d)δ190.73,172.45,167.41,160.82(d,J=255.6Hz) ,144.64,143.94,135.16,132.83(d,J=9.3Hz),131.15,130.10,128.93,127. 95,127.51,125.45,124.89,124.76(d,J=3.6Hz),124.03,121.24(d,J=10.7H z), 120.90 (d, J = 9.7Hz), 116.72 (d, J = 22.7Hz), 110.03, 83.37, 53.17, 44.57.

[0170] 19 F NMR (376MHz, Chloroform-d) δ-110.05 (dt, J = 12.2, 6.3Hz).

[0171] HRMS(ESI)calcd for C 26 H 20 NO5FNa[M+Na] + :468.1218, found 468.1216.

[0172] (17) Preparation of methyl 4-(1-benzyl-3-hydroxy-2-oxoindoline-3-yl)-2-(4-methylphenyl)-4-carbonyl-2(Z)-butenoate (compound 6q)

[0173] Compound 6q is R 1 benzyl, R 2 Methyl, Ar 1 For phenyl, Ar 2The 3-hydroxy-oxidized indole derivative of a 4-methylphenyl olefin containing a Z-form 1,4-dicarbonyl olefin, has the structure shown in formula (6q):

[0174]

[0175] The specific preparation method includes the following steps:

[0176] The preparation process of this compound is the same as that of compound 6a, except that methyl 2-phenyl-2-cyclopropenyl-1-acetate in step (1) is replaced with methyl 2-(4-methylphenyl)-2-cyclopropenyl-1-acetate, which yields compound 6q with a product separation yield of 81%. The mass spectrometry information of this compound is as follows:

[0177] 1 H NMR(500MHz,Chloroform-d)δ7.43-7.37(m,2H),7.36-

[0178] 7.27(m,4H),7.21(d,J=7.4Hz,1H),7.15-6.98(m,5H),6.92(d,J=7.9Hz,1H),6.05(s,1H ),5.27(d,J=15.2Hz,1H),5.08(s,1H),4.64(d,J=15.3Hz,1H),3.97(s,3H),2.35(s,3H).

[0179] 13 C NMR(126MHz,Chloroform-d)δ189.81,172.65,168.19,151.07,143.90,142.57,135.53,131.06,129.81,129 .52,129.12,128.04,127.76,127.25,125.78,124.90,124.06,114.53,109.85,83.06,53.00,44.55,21.52.

[0180] HRMS(ESI)calcd for C 27 H 23 NO5Na[M+Na] + :464.1468,found 464.1464.

[0181] (18) Preparation of methyl 4-(1-benzyl-3-hydroxy-2-oxoindoline-3-yl)-2-(4-methoxyphenyl)-4-carbonyl-2(Z)-butenoate (compound 6r)

[0182] Compound 6r is R1 benzyl, R 2 Methyl, Ar 1 For phenyl, Ar 2 The structure of compound 6r is shown in formula (6r), which is a 3-hydroxy-oxidized indole derivative of a 4-methoxyphenyl olefin containing a Z-form 1,4-dicarbonyl olefin:

[0183]

[0184] The specific preparation method includes the following steps:

[0185] The preparation process of this compound is the same as that of compound 6a, except that methyl 2-phenyl-2-cyclopropenyl-1-acetate in step (1) is replaced with methyl 2-(4-methoxyphenyl)-2-cyclopropenyl-1-acetate, which yields compound 6r with a product separation yield of 80%. The mass spectrometry information of this compound is as follows:

[0186] 1 H NMR(500MHz,Chloroform-d)δ7.41(dd,J=6.9,2.8Hz,2H),7.35-7.27(m,4H),7.21(d,J=7.4Hz,1H),7.12-7.02(m,3H),6.93(d,J=7. 9Hz,1H),6.78(d,J=8.8Hz,2H),5.98(s,1H),5.28(d,J=15.3Hz,1H),5.11(s,1H),4.63(d,J=15.3Hz,1H),3.98(s,3H),3.82(s,3H).

[0187] 13 C NMR(126MHz,Chloroform-d)δ189.54,172.75,168.37,162.59,150.73,143.88,135.61,131.00,129.25,129 .13,128.04,127.81,125.96,124.87,124.57,124.04,114.55,112.81,109.80,82.97,55.53,53.03,44.52.

[0188] HRMS(ESI)calcd for C 27 H 23 NO6Na[M+Na] + :480.1418,found480.1420.

[0189] (19) Preparation of methyl 4-(1-benzyl-3-hydroxy-2-oxoindoline-3-yl)-2-(4-trifluoromethylphenyl)-4-carbonyl-2(Z)-butenoate (compound 6S)

[0190] Compound 6s is R 1 benzyl, R 2 Methyl, Ar 1 For phenyl, Ar 2 The 3-hydroxy-oxidized indole derivative of a 4-trifluoromethylphenyl olefin containing a Z-form 1,4-dicarbonyl olefin has the structure shown in formula (6s):

[0191]

[0192] The specific preparation method includes the following steps:

[0193] The preparation process of this compound is the same as that of compound 6a, except that methyl 2-phenyl-2-cyclopropenyl-1-acetate in step (1) is replaced with methyl 2-(4-trifluoromethylphenyl)-2-cyclopropenyl-1-acetate, which yields compound 6s with a product separation yield of 77%. The mass spectrometry information of this compound is as follows:

[0194] 1 H NMR(400MHz,Chloroform-d)δ7.66(d,J=7.8Hz,1H),7.45-7.40(m,2H),7.39-7.33(m,3H),7.27(d,J=6.3Hz,1H),7.26-7.20(m,4H),7. 11(td,J=7.6,1.0Hz,1H),6.93(d,J=7.9Hz,1H),6.10(s,1H),5.22(d,J=15.3Hz,1H),4.96(s,1H),4.68(d,J=15.3Hz,1H),3.98(s,3H).

[0195] 13 C NMR(126MHz,Chloroform-d)δ190.21,172.34,167.28,149.04,143.87,135.27,133.57,131.67(q,J=32.8Hz),131.32,130.17,129.68,129.03,1 28.13,127.85(q,J=3.6Hz),127.64,125.32,124.96,124.17,123.95(q, J=3.9Hz),123.35(q,J=272.7Hz),118.32,110.02,83.29,53.29,44.60.

[0196] 19 F NMR(376MHz,Chloroform-d)δ-62.91.

[0197] HRMS(ESI)calcd for C 27 H 20 NO5F3Na[M+Na] + :518.1186,found 518.1184.

[0198] (20) Preparation of methyl 4-(1-benzyl-3-hydroxy-2-oxoindoline-3-yl)-2-(3,4,5-trimethoxyphenyl)-4-carbonyl-2(Z)-butenoate (compound 6t)

[0199] Compound 6t is R 1 benzyl, R 2 Methyl, Ar 1 For phenyl, Ar 2 The 3-hydroxy-oxidized indole derivative of a 3,4,5-trimethoxyphenyl olefin containing a Z-form 1,4-dicarbonyl olefin, has the structure shown in formula (6t):

[0200]

[0201] The specific preparation method includes the following steps:

[0202] The preparation process of this compound is the same as that of compound 6a, except that methyl 2-phenyl-2-cyclopropenyl-1-acetate in step (1) is replaced with methyl 2-(3,4,5-trimethoxyphenyl)-2-cyclopropenyl-1-acetate, which yields compound 6t with a product separation yield of 76%. The mass spectrometry information of this compound is as follows:

[0203] 1 H NMR(500MHz,Chloroform-d)δ7.34-7.29(m,3H),7.25(d,J=7.5Hz,1H),7.23-7.14(m,3H),7.10(t,J=7.6Hz,1H),6.87(d,J=7.9Hz, 1H),6.35(s,2H),6.04(s,1H),5.26(d,J=15.4Hz,1H),5.04(s,1H),4.64(d,J=15.4Hz,1H),3.97(s,3H),3.86(s,3H),3.64(s,6H).

[0204] 13C NMR(126MHz,Chloroform-d)δ189.78,172.62,167.85,153.38,150.64,143.93,141.38,135.27,130.94,129.02 ,128.04,127.94,127.45,125.87,124.94,124.11,116.09,109.80,104.72,83.28,60.99,56.14,53.15,44.60.

[0205] HRMS(ESI)calcd for C 29 H 27 NO8Na[M+Na] + :540.1629,found540.1630.

[0206] (21) Preparation of methyl 4-(1-methyl-3-hydroxy-2-oxoindoline-3-yl)-2-(3,4,5-trimethoxyphenyl)-4-carbonyl-2(Z)-butenoate (compound 6u)

[0207] Compound 6u is R 1 Methyl, R 2 Methyl, Ar 1 For phenyl, Ar 2 The 3-hydroxy-oxidized indole derivative of a 3,4,5-trimethoxyphenyl olefin containing a Z-form 1,4-dicarbonyl olefin, compound 6u has the structure shown in formula (6u):

[0208]

[0209] The specific preparation method includes the following steps:

[0210] The preparation process of this compound is the same as that of compound 6a, except that 1-(benzyl)indigo in step (1) is replaced with 1-methylindigo, and methyl 2-phenyl-2-cyclopropenyl-1-acetate in step (1) is replaced with methyl 2-(3,4,5-trimethoxyphenyl)-2-cyclopropenyl-1-acetate. Compound 6u can be prepared with a product separation yield of 75%. The mass spectrometry information of this compound is as follows:

[0211] 1H NMR(500MHz,Chloroform-d)δ7.43(td,J=7.8,1.3Hz,1H),7.25(d,J=6.5Hz,1H),7.14(t,J=7.6Hz,1H),6.95(d ,J=7.8Hz,1H),6.48(s,2H),6.06(s,1H),4.95(br.s,1H),3.95(s,3H),3.84(s,3H),3.78(s,6H),3.30(s,3H).

[0212] 13 C NMR(126MHz,Chloroform-d)δ190.10,172.64,167.91,153.45,150.85,144.84,141.34,131.19 ,128.27,125.85,124.90,124.08,116.23,108.94,104.80,83.07,60.99,56.25,53.11,27.03.

[0213] HRMS(ESI)calcd for C 23 H 23 NO8Na[M+Na] + :464.1316,found 464.1317.

[0214] (22) Preparation of ethyl 4-(1-benzyl-3-hydroxy-2-oxoindoline-3-yl)-2-(4-chlorophenyl)-4-carbonyl-2(Z)-butenoate (compound 6v)

[0215] Compound 6v is R 1 benzyl, R 2 Ethyl, Ar 1 For phenyl, Ar 2 The 3-hydroxy-oxidized indole derivative of a 4-chlorophenyl-containing Z-form 1,4-dicarbonyl olefin, compound 6v has the structure shown in formula (6v):

[0216]

[0217] The specific preparation method includes the following steps:

[0218] The preparation process of this compound is the same as that of compound 6a, except that methyl 2-phenyl-2-cyclopropenyl-1-acetate in step (1) is replaced with ethyl 2-(4-chlorophenyl)-2-cyclopropenyl-1-acetate, which yields compound 6v with a product separation yield of 79%. The mass spectrometry information of this compound is as follows:

[0219] 1 H NMR(400MHz,Chloroform-d)δ7.40(dd,J=7.6,1.9Hz,2H),7.36-7.27(m,4H),7.24(d,J=8.6Hz,2H),7.21(d,J=7.4Hz,1H),7.11-7.03(m,3H),6. 94(d,J=7.9Hz,1H),6.03(s,1H),5.25(d,J=15.3Hz,1H),5.07(s,1H),4. 63(d,J=15.3Hz,1H), 4.44(qq,J=6.9,3.6Hz,2H), 1.39(t,J=7.2Hz,3H).

[0220] 13 C NMR(126MHz,Chloroform-d)δ189.86,172.55,167.13,149.81,143.82,137.76,135.52,131.18,131.04,129 .33,129.11,128.44,128.12,127.86,125.58,124.90,124.10,116.13,109.88,83.18,62.41,44.52,13.91.

[0221] HRMS(ESI)calcd for C 27 H 22 NO5ClNa[M+Na] + :498.1079,found498.1079.

[0222] Example 2

[0223] Application of 3-hydroxy-oxidized indole derivatives containing Z-type 1,4-dicarbonyl alkenes in inhibiting PTP1B protein activity:

[0224] This embodiment provides 3-hydroxyoxyindole derivatives containing Z-form 1,4-dicarbonyl olefins as PTP1B inhibitors for the preparation of drugs for type II diabetes. This embodiment uses nine 3-hydroxyoxyindole derivatives containing Z-form 1,4-dicarbonyl olefins (compounds 6a, 6b, 6g, 6h, 6i, 6m, 6n, 6r, and 6u) as examples to explore their inhibitory effects on PTP1B protein. Studies have demonstrated that these compounds (3-hydroxyoxyindole derivatives containing Z-form 1,4-dicarbonyl olefins) have significant inhibitory effects on PTP1B protein and possess potential for the treatment of type II diabetes.

[0225] The specific experimental method is as follows:

[0226] (1) Prepare phosphatase buffer (25M Bis-Tris propane pH7.5, 50mM NaCl, 2mM EDTA, 2mM DTT) and perform DiFMUP assay in a 96-well plate.

[0227] (2) 1 nM recombinant PTP1B protein (extracted in the laboratory; BL21 DE3 competent cells and PTP1B-NdeI-XhoI-pET-28a(+) plasmid purchased from Changzhou Jiyu Biotechnology Co., Ltd.) and positive control Na3VO4 or test compounds 6a, 6b, 6g, 6h, 6i, 6m, 6n, 6r, 6u (compound concentration range 0-50 μM, DMSO final concentration 0.5%) were incubated in reaction buffer (phosphatase buffer) at 37°C for 10 minutes, with a total volume of 90 μL. Then, 10 μL of substrate buffer (phosphatase buffer) containing DiFMUP (final concentration 10 μM) was added to the above reaction buffer, and incubated at 37°C for 10 minutes. Finally, the fluorescence intensity at 455 nm was read using a multi-function reader with 358 nm excitation light. The inhibition rate of the sample on PTP1B protein activity was calculated as the ratio of the fluorescence value of the test compound to the fluorescence value of the control well.

[0228] (3) Data processing: Import the fluorescence value data into Excel and use the following formula to calculate the inhibition value;

[0229] inhibition[%] = 100 - (F 455 control-F 455 compound) / (F 455 control-F 455 (blank) × 100;

[0230] The inhibition rates at different compound concentrations were imported into Graphpad Prism 9.0, and the IC50 was calculated by nonlinearly fitting the inhibition rate to the inhibitor concentration. 50 .

[0231] (4) Experimental results:

[0232] As shown in Table 1, the 3-hydroxy oxidized indole derivatives containing Z-form 1,4-dicarbonyl olefins of the present invention (compounds 6a, 6b, 6g, 6h, 6i, 6m, 6n, 6r, and 6u) all exhibit certain inhibitory activity against PTP1B protein. In particular, compound 6g shows significantly better inhibitory activity against PTP1B protein than the positive control Na3VO4. This indicates that the 3-hydroxy oxidized indole derivatives containing Z-form 1,4-dicarbonyl olefins (compounds 6a, 6b, 6g, 6h, 6i, 6m, 6n, 6r, and 6u) can serve as small molecule inhibitors of PTP1B and possess significant potential application value.

[0233] Table 1. Inhibitory activity of 3-hydroxy-oxidized indole derivatives containing Z-type 1,4-dicarbonyl olefins against PTP1B protein.

[0234] Compound numbering <![CDATA[IC 50 / uM[PTP1B:1nM]]]> 6a 4.63±0.42 6b 3.56±0.24 6g 0.28±0.04 6h 1.45±0.19 6i 4.56±0.24 6m 7.21±0.52 6n 5.87±0.53 6r 3.75±0.39 6u 1.06±0.16 <![CDATA[Na3VO4]]> 1.50±0.11

[0235] The preferred embodiments of this utility model disclosed above are merely illustrative of the present utility model. These preferred embodiments do not describe all details exhaustively, nor do they limit the utility model to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification.

Claims

1. A 3-hydroxyoxindole derivative containing a Z 1,4-dicarbonyl olefin of formula 1, characterized in that, ###00001### 1 The indole derivatives include compounds 6a, 6b, 6g, 6h, 6i, 6m, 6n, 6r, and 6u, with the following chemical formulas:

2. A process for the preparation of a 3-hydroxyoxindole derivative containing a Z 1,4-dicarbonyl olefin of formula 1 as claimed in claim 1, characterized in that, The specific steps are as follows: Indigo (as shown in Formula II) is mixed with a rhodium catalyst and acetic acid in the organic solvent ethyl acetate. Cyclopropylene carboxylate (as shown in Formula III) is then added to the mixture. The mixture is stirred under nitrogen atmosphere for a period of time, followed by stirring under visible light in air for a certain period of time to obtain the derivative of claim 1. Formulas II and III are as follows: Wherein, the indigo shown in Formula II is selected from 1-benzyl indigo, indigo, 1-benzyl-5-chloroindigo, 1-benzyl-6-chloroindigo, 1-benzyl-7-chloroindigo, 1-benzyl-6-methoxyindigo, or 1-methylindigo; The cyclopropene carboxylate shown in Formula III is selected from methyl 2-phenyl-2-cyclopropene-1-acetate, methyl 2-(4-chlorophenyl)-2-cyclopropene-1-acetate, methyl 2-(4-methoxyphenyl)-2-cyclopropene-1-acetate or methyl 2-(3,4,5-trimethoxyphenyl)-2-cyclopropene-1-acetate; The correspondence between indigo and cyclopropene carboxylic acid ester is as follows: When preparing compound 6a, the indigo used was 1-benzyl indigo, and the cyclopropene carboxylic acid ester used was methyl 2-phenyl-2-cyclopropene-1-acetate; In preparing compound 6b, the indigo used was indigo, and the cyclopropene carboxylic acid ester used was methyl 2-phenyl-2-cyclopropene-1-acetate; When preparing 6g of the compound, the indigo used was 1-benzyl-5-chloroindigo, and the cyclopropene carboxylic acid ester used was methyl 2-phenyl-2-cyclopropene-1-acetate; When preparing the compound for 6 hours, the indigo used was 1-benzyl-6-chloroindigo, and the cyclopropene carboxylic acid ester used was methyl 2-phenyl-2-cyclopropene-1-acetate; When preparing compound 6i, the indigo used was 1-benzyl-7-chloroindigo, and the cyclopropene carboxylic acid ester used was methyl 2-phenyl-2-cyclopropene-1-acetate; When preparing compound 6m, the indigo used was 1-benzyl-6-methoxyindigo, and the cyclopropene carboxylic acid ester used was methyl 2-phenyl-2-cyclopropene-1-acetate; When preparing compound 6n, the indigo used is 1-benzyl indigo, and the cyclopropene carboxylic acid ester used is methyl 2-(4-chlorophenyl)-2-cyclopropene-1-acetate; When preparing compound 6r, the indigo used is 1-benzyl indigo, and the cyclopropene carboxylic acid ester used is methyl 2-(4-methoxyphenyl)-2-cyclopropene-1-acetate; When preparing compound 6u, the indigo used was 1-methyl indigo, and the cyclopropene carboxylic acid ester used was methyl 2-(3,4,5-trimethoxyphenyl)-2-cyclopropene-1-acetate.

3. The method of preparing a Z-containing 1,4-dicarbonyl olefinic 3-hydroxyoxindole derivative according to claim 2, characterized in that, The molar ratio of indigo, rhodium catalyst, acetic acid, and cyclopropene carboxylate is 1.0:(0.01-0.05):(0.1-2.0):(1.0-3.0); the reaction is carried out under nitrogen at a temperature of 20-80℃ for 8-20 hours, followed by irradiation with sunlight at 25℃ for 8-12 hours.

4. The method for preparing 3-hydroxy-oxidized indole derivatives containing Z-type 1,4-dicarbonyl olefins according to claim 2, characterized in that, The rhodium catalysts include, but are not limited to, rhodium acetate, bis[(A,A,A′,A′-tetramethyl-1,3-phenylenedipropionic acid)rhodium], rhodium(II) octoate, tetracaprolactam dirhodium, and rhodium trifluoroacetate dimer.

5. The application of the 3-hydroxy-oxidized indole derivative containing Z-type 1,4-dicarbonyl olefin as described in claim 1 in the preparation of PTP1B small molecule inhibitors.

6. The use of the 3-hydroxy-oxidized indole derivative containing a Z-type 1,4-dicarbonyl olefin as described in claim 1 in the preparation of a drug for treating type II diabetes.

7. The application according to claim 5 or 6, characterized in that, The derivative is selected from at least one of compounds 6a, 6b, 6g, 6h, 6i, 6m, 6n, 6r and 6u.

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