A synthesis method and application of hydrogenated indole derivatives

Abstract

The present invention discloses a synthesis method and application of a hydrogenated indole derivative, and belongs to the technical field of chemical medicine and organic synthesis. The present invention provides a hydrogenated indole compound as shown in general formula III or IV, or a pharmaceutically acceptable salt or deuterated product thereof, which is prepared by reacting p-quinoneamine and nitroolefin as raw materials without adding any catalyst or under the action of a base as a catalyst; the synthesis method of the compound is simple, green and environmentally friendly, the substrate has a wide range of application and a high yield, and at the same time exhibits a certain anti-inflammatory effect, and has a broad application space in the field of anti-inflammatory drug preparation.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical medicine and organic synthesis, and specifically relates to a synthesis method and application of a hydrogenated indole derivative. Background Art

[0002] As a core synthetic intermediate in heterocyclic chemistry, hydroindole can not only be used to construct typical heterocyclic compounds such as pyrrole and pyrazine, but also frequently appears as a key transformation unit in the synthesis of natural products and drugs. It is worth noting that a large number of natural products and drug compounds with a wide range of diverse biological activities contain the hydroindole skeleton. For example, (1) Acutumine not only has anti-memory activity but also has selective T cell toxicity; (2) Perindopril is a long-acting angiotensin-converting enzyme (ACE) inhibitor that has significant blood pressure control effects in patients with hypertension; (3) Stenine is used as an anthelmintic for respiratory diseases in livestock and humans in China and Japan; (4) Mesembrine is a member of the Ezoicaceae alkaloids and is used in anti-anxiety treatment for its ability to inhibit serotonin reuptake; (5) Epicoccin G has shown an inhibitory effect on HIV in cell experiments; (6) Eburenine exhibits significant cytotoxicity to a variety of cancer cells; (7) Pretazettine is an Amaryllis alkaloid that can bind to DNA, inhibit protein synthesis, and bind to oncogenic viral reverse transcriptase, showing significant antiviral effects; (8) DhβE is a member of the Erythrina alkaloids that exhibits selectivity for the a4β2 subtype and is widely used as an important pharmacological tool. In summary, given the significant biological activity of hydroindoles and their broad prospects in drug development, seeking a rapid and efficient route to synthesize hydroindole compounds has become a research hotspot that has attracted much attention in the fields of organic chemistry and medicinal chemistry.

[0003]

[0004] In view of the fascinating biological properties of hydroindoles, many efficient synthetic methods have been developed in the past few decades to construct hydroindoles skeletons. At present, the strategies for constructing such structures are diversified, including the use of chemical transformation strategies such as classic Diels-Alder reaction, condensation reaction, reduction reaction and cyclization reaction to achieve the construction of hydroindoles skeletons. However, these methods often require the use of expensive reagents and catalysts, and the synthesis steps are cumbersome. In most cases, only 2-substituted or 3-substituted hydroindoles are obtained, and the resulting product structure is relatively simple. For 2,3-disubstituted hydroindoles with more diverse and complex spatial structures, the synthesis difficulty is significantly greater, and there are fewer synthetic directions reported so far, which greatly restricts the development of such skeleton drugs. The present invention develops a method to complete the efficient construction of a class of 2,3-disubstituted hydroindoles skeletons, further enriching the hydroindoles compound library, and at the same time, it is found that such compounds have good anti-inflammatory activity and have potential application value. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a novel 2,3-disubstituted hydrogenated indole compound, which exhibits good anti-inflammatory effect.

[0006] Another object of the present invention is to provide a method for synthesizing a class of 2,3-disubstituted hydroindole compounds, which is simple, has readily available starting materials, is green and environmentally friendly, has a wide range of substrate applications, has a high yield, does not use or uses low-cost organic catalysts, and has high atom economy.

[0007] Another object of the present invention is to provide a class of 2,3-disubstituted hydroindole compounds for use in the preparation of anti-inflammatory drugs.

[0008] To achieve the above object, the present invention adopts the following technical solution:

[0009] The present invention provides a hydroindole compound as shown in the general formula III or IV, or a pharmaceutically acceptable salt or deuterated product thereof;

[0010]

[0011] In the formula,

[0012] means Or n = 0;

[0013] R is selected from: C1-C8 straight or branched alkyl, C3-C6 cycloalkyl, substituted or unsubstituted aryl; the substitution on the aryl includes any one of mono- to tri-substitution, and the substituent is selected from halogen (F, Cl, Br, I), C1-C8 straight or branched alkyl, C1-C8 alkoxy;

[0014] R 1 Selected from: C1-C8 straight or branched alkyl containing 0-2 unsaturated double bonds, C3-C8 cycloalkyl, unsubstituted or substituted phenyl, naphthyl; the substituent includes any one of mono-substituted to tri-substituted, and the substituent is selected from halogen (F, Cl, Br, I), C1-C8 alkyl, phenyl;

[0015] R 2 Selected from: H, halogen (F, Cl, Br, I), C1-C6 straight chain or branched alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy;

[0016] R 3 Selected from: H, C1-C6 straight chain or branched alkyl, benzyl, -CO-R a 、-SO2R b ; R a R is selected from unsubstituted or halogen (F, Cl, Br) substituted C1-4 alkyl, unsubstituted or substituted phenyl, C1-C4 alkoxy; b Selected from unsubstituted or substituted phenyl groups; the substituents on the phenyl group are halogen (F, Cl, Br, I), C1-C6 straight chain or branched alkyl groups.

[0017] In one embodiment of the present invention, n=0, and the structure of the hydroindole compound represented by formula III or IV is as follows:

[0018]

[0019] In one embodiment of the present invention, the aryl group is selected from the group consisting of phenyl, naphthyl, thienyl, and furanyl.

[0020] In one embodiment of the present invention, R 1 Further selected from:

[0021] In one embodiment of the present invention, R 2 Further selected from: or

[0022] In one embodiment of the present invention, the R 3 Further selected from: H, C1-C6 straight chain or branched alkyl, benzyl, chloroacetyl, tert-butyloxycarbonyl, benzoyl, p-toluenesulfonyl.

[0023] In one embodiment of the present invention, R is specifically selected from:

[0024] In one embodiment of the present invention, R 1 Specific selection:

[0025] In one embodiment of the present invention, R 2 Specific selection: or

[0026] In one embodiment of the present invention, R 3 Specific selection: or

[0027] In one embodiment of the present invention, most preferably, the hydroindole compound is specifically selected from:

[0028]

[0029]

[0030] In one embodiment of the present invention, the pharmaceutically acceptable salt includes an inorganic salt or an organic salt; wherein the inorganic salt includes hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; the organic salt is selected from formates, acetates, trifluoroacetates, propionates, pyruvates, glycolates, oxalates, malonates, succinates, glutarates, fumarates, maleates, lactates, malates, citrates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, salicylates, p-toluenesulfonates, and ascorbates.

[0031] The present invention also provides a method for synthesizing the above-mentioned hydroindole derivative, which comprises:

[0032] Method A: Using p-quinoneamine and nitroolefin as raw materials, without adding any catalyst, a hydroindole compound as shown in formula III-a can be obtained;

[0033] Alternatively, method B: using p-quinoneamine and nitroolefin as raw materials, reacting in the presence of a base as a catalyst to obtain another configuration of a hydroindole compound as shown in formula IV-a;

[0034] Alternatively, method C: alkylating or acylating the nitrogen atom on III-a or IV-a to obtain a hydroindole compound of formula III-b or IV-b;

[0035]

[0036] Among them, n, R, R 1 , R 2 is as defined above; and, R 3’ Selected from C1-C6 straight or branched alkyl, benzyl, -CO-R a 、-SO2R b ; R a R is selected from unsubstituted or halogen (F, Cl, Br) substituted C1-4 alkyl, unsubstituted or substituted phenyl, C1-C4 alkoxy; b Selected from unsubstituted or substituted phenyl groups; the substituents on the phenyl group are halogen (F, Cl, Br, I), C1-C6 straight chain or branched alkyl groups.

[0037] In one embodiment of the present invention, in one embodiment of the present invention, the R 3’ Further selected from: C1-C6 straight chain or branched alkyl, benzyl, chloroacetyl, tert-butyloxycarbonyl, benzoyl, p-toluenesulfonyl.

[0038] In one embodiment of the present invention, the reactions are all carried out in an organic solvent; the organic solvent is any one or more of dichloromethane, toluene, methanol, acetonitrile, tetrahydrofuran, benzene, carbon tetrachloride, acetone, N,N-dimethylformamide and ethyl acetate; the organic solvent in method A is preferably dichloromethane, and the organic solvent in method B is preferably acetonitrile.

[0039] In one embodiment of the present invention, the catalyst described in method B includes any one or more of triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triphenylphosphine, 1,4-diazabicyclo[2.2.2]octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,8-diazabicyclo(5,4,0)undec-7-ene, potassium tert-butoxide, potassium carbonate, cesium carbonate and sodium carbonate. Preferably, 4-dimethylaminopyridine is used.

[0040] In one embodiment of the present invention, the reaction environment used in method C includes: a) formaldehyde, zinc chloride, sodium cyanoborohydride, methanol; or b) chloroacetyl chloride, sodium bicarbonate, dichloromethane; or c) di-tert-butyl dicarbonate, 1,4-dioxane; or d) benzoyl chloride, triethylamine, 4-dimethylaminopyridine, dichloromethane.

[0041] In one embodiment of the present invention, the molar ratio of the p-quinoneamine of formula I to the nitroalkene of formula II is 1.0:(1.2-3.0). The molar ratio of the two in method A is preferably 1.0:1.2 and 1.0:2.0, and the molar ratio of the two in method B is preferably 1.0:1.5.

[0042] In one embodiment of the present invention, the reaction temperature of method A is 25°C to 80°C, preferably 50°C, and the time is 24 to 72 hours. The reaction temperature of method B is 25°C to 80°C, preferably 25°C, and the time is 6 to 24 hours. The reaction temperature of method C is 0°C to 100°C, and the time is 0.5 to 12 hours.

[0043] In one embodiment of the present invention, the molar ratio of the p-quinoneamine represented by Formula I to the catalyst is 1:(0.05-1), preferably 1:0.1.

[0044] In one embodiment of the present invention, the amount of the organic solvent added is 1 to 10 mL / mmol based on the amount of the p-quinoneamine substance represented by Formula I, preferably 5 mL / mmol.

[0045] The present invention also provides an anti-inflammatory drug, which contains a hydroindole compound represented by general formula III or IV, or a pharmaceutically acceptable salt or deuterated product thereof.

[0046] The present invention also provides the use of the above-mentioned hydroindole derivatives in the preparation of drugs for preventing or treating diseases associated with inflammation.

[0047] The diseases associated with inflammation generally include enteritis, multiple sclerosis, obesity, type II diabetes, metabolic syndrome, non-alcoholic fatty liver disease, alcoholic liver disease, kidney disease, Behcet's disease, sepsis, gout, arthritis, viral inflammation such as viral hepatitis and pneumonia, acute and chronic tissue damage caused by infection, atherosclerosis, myocardial infarction, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, depression, asbestosis, silicosis and silicosis, asthma or acute respiratory distress syndrome, peritonitis, UV-induced skin sunburn, contact hypersensitivity, familial cold autoinflammatory syndrome, chronic infantile neurocutaneous joint syndrome, Mullen-Weigler syndrome and cold porphyrin-associated periodic syndrome (CAPS), as well as cytokine storm caused by tumor treatment such as CART therapy and immune checkpoint inhibitor therapy.

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] The reported methods for synthesizing hydroindole compounds have obvious disadvantages, some of which require the use of expensive ligands and metal catalysts, some of which require the use of toxic or dangerous reagents, and in most cases only 2-substituted or 3-substituted hydroindole products are obtained, and the resulting product structure is relatively simple, which seriously restricts the industrial production of hydroindole compounds. Compared with the prior art, the present invention has the following advantages: the construction of a 2,3-disubstituted hydroindole skeleton is successfully achieved, the synthetic operation is simple, the substrate trial range is wide, and no or low-cost catalysts are used. The content of this study has greatly enriched the types of compounds containing a hydroindole skeleton and promoted the drug development of such skeleton compounds.

[0050] Experiments have shown that the hydroindole compounds synthesized by the present invention can effectively inhibit the activation of NLRP3 inflammasome induced by Nigericin and ATP, and show good anti-inflammatory effects. Therefore, the hydroindole compounds provided by the present invention can be used as potential active lead compounds for in-depth research. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 The effects of hydrogenated indole derivatives on NLRP3 inflammasome activation and pyroptosis. A is a schematic diagram of the anti-inflammatory activity screening process for the selected compounds. B is a diagram of the ability of compounds to inhibit NLRP3 inflammasomes by analyzing the secretion of IL-1β using Elisa. C is the IC50 value of compound P44 on IL-1β produced by nigericin. D is a diagram verifying that compound P44 effectively inhibits the cleavage of caspase-1. E is a diagram verifying that compound P44 inhibits the secretion of IL-1β. F is a diagram verifying that compound P44 effectively inhibits cell pyroptosis. G is an experiment in which compound P44 inhibits the cleavage of caspase-1 induced by ATP. H is a diagram verifying that compound P44 inhibits the secretion of IL-1β induced by ATP.

[0052] Figure 2 This is the X-ray single crystal diffraction structure diagram of P29.

[0053] Figure 3 This is the X-ray single crystal diffraction structure diagram of P15. DETAILED DESCRIPTION

[0054] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments.

[0055] The present invention relates to the following chemical abbreviations: Me is methyl, Et is ethyl, Ph is phenyl, OMe is methoxy, n-Bu is n-butyl, n-Hexyl is n-hexyl, and Boc is tert-butyloxycarbonyl.

[0056] The para-quinoneamine represented by formula I (such as N1-N14 in the following embodiments) involved in the present invention can be prepared by itself according to existing literature, such as Organic Letters, 2021, 23(20): 7873-7877.

[0057] The nitroolefins represented by formula II of the present invention (such as S1-S14 in the following embodiments) can be prepared according to existing literature, such as Chemistry Select, 2017, 2(9): 2670-2676.

[0058] Example 1

[0059] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0060]

[0061] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 24 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the product P1 (47.9 mg, 88%) is obtained as a brown oil.

[0062] Characterization data: 1 H NMR (600MHz, CDCl3) δ7.41–7.29(m,5H),6.59(dd,J=10.3,1.7Hz,1H),6.13(d,J=10.3Hz,1H),4.96(dd,J=11.0,7.9Hz, 1H), 4.86 (d, J=7.9Hz, 1H), 3.10–3.01 (m, 1H), 2.70 (dd, J=18.2, 7.2Hz, 1H), 2.49 (dd, J=18.2, 0.9Hz, 1H), 1.54 (s, 3H). 13 CNMR(151MHz, CDCl3)δ193.8,153.2,138.4,129.5,128.8,128.5,126.4,94.2,64.8,59.6,46.2,33.8,25.6.HRMS(ESI)calculated for C 15 H 17 N2O3[M+H] + :273.1234,found273.1230.

[0063] Example 2

[0064] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0065]

[0066] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S2 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 60 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the product P2 (49.6 mg, 82%) is obtained as a yellow oil.

[0067] Characterization data: 1 H NMR (400MHz, CDCl3) δ7.26 (d, J = 8.7Hz, 2H), 6.86 (d, J = 8.7Hz, 2H), 6.58 (dd, J = 10.3, 1.7Hz, 1H), 6.12 (d, J = 10.3Hz, 1H), 4.92 (dd, J = 11.1, 8.0Hz,1H),4.77(d,J=8.0Hz,1H),3.78(s,3H),3.09–2.98(m,1H),2.68(dd,J=18.2,7.2Hz,1H),2.45(dd,J=18.2,1.2Hz,1H),1.52(s,3H). 13 C NMR(151MHz, CDCl3)δ193.7,159.8,153.1,130.3,129.7,127.7,114.3,94.3,64.6,59.5,55.3,46.3,33.9,25.8.HRMS(ESI)calculated forC 16 H 19 N2O4[M+H] + :303.1339, found 303.1335.

[0068] Example 3

[0069] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0070]

[0071] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S3 (0.24 mmol, 44.1 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 48 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 3:1), and the product P3 (49.7 mg, 81%) is obtained as a white solid.

[0072] Characterization data: mp: 167-169℃. 1 H NMR (500MHz, CDCl3) δ7.34–7.28(m,4H),6.57(dd,J=10.4,1.7Hz,1H),6.14(d,J=10.3Hz,1H),4.88(dd,J=10.5,7.9Hz, 1H),4.84(d,J=7.9Hz,1H),3.08–3.00(m,1H),2.69(dd,J=18.2,7.2Hz,1H),2.48(dd,J=18.3,1.3Hz,1H),1.54(s,3H). 13 C NMR(126MHz, CDCl3)δ193.5,152.7,137.1,134.5,129.8,129.1,127.9,94.0,64.0,59.5,46.0,33.8,25.9.HRMS(ESI)calculated for C 15 H 16 ClN2O3[M+H] + :307.0844,found307.0839.

[0073] Example 4

[0074] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0075]

[0076] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S4 (0.24 mmol, 47.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 48 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 3:1), and the product P4 (60.0 mg, 93%) is obtained as a yellow solid.

[0077] Characterization data: mp: 104-106℃. 1H NMR (400MHz, CDCl3) δ7.89–7.76(m,4H),7.51–7.47(m,2H),7.44(dd,J=8.5,1.8Hz,1H),6.60(dd,J=10.4,1.8Hz,1H),6.14(d, J=10.3Hz,1H),5.05–4.98(m,2H),3.13–2.99(m,1H),2.69(dd,J=18.2,7.1Hz,1H),2.47(dd,J=18.2,2.4Hz,1H),1.55(s,3H). 13 C NMR (101MHz, CDCl3) δ193.8,153.1,135.8,133.3,133.1,129.7,128.9,127.9,127.7, 126.5,126.4,125.8,123.9,94.1,64.9,59.6,46.2,33.9,25.7.HRMS(ESI)calculated for C 19 H 19 N2O3[M+H] + :323.1390, found 323.1390.

[0078] Example 5

[0079] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0080]

[0081] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S5 (0.24 mmol, 33.4 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 48 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the product P5 (39.3 mg, 75%) is obtained as a brown solid.

[0082] Characterization data: mp: 84-86℃. 1H NMR(600MHz, CDCl3) δ7.39(dd,J=1.7,0.8Hz,1H),6.60(dd,J=10.3,1.7Hz,1H),6.36–6.31(m,2H),6.08(dd,J=10.4,1.0Hz,1H),5.21(d d,J=10.8,7.4Hz,1H),4.93(d,J=7.4Hz,1H),3.11–3.03(m,1H),2.70(dd,J=18.2,7.2Hz,1H),2.57(dd,J=18.2,1.6Hz,1H),1.53(s,3H). 13 C NMR(101MHz, CDCl3)δ193.4,152.4,150.1,143.1,129.8,110.6,108.5,91.4,60.3,59.2,47.0,33.8,25.7.HRMS(ESI)calculated forC 13 H 15 N2O4[M+H] + :263.1026,found 263.1025.

[0083] Example 6

[0084] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0085]

[0086] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S6 (0.24 mmol, 37.2 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 36 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the product P6 (44.5 mg, 80%) is obtained as a yellow solid.

[0087] Characterization data: mp: 85-87℃. 1H NMR (400MHz, CDCl3) δ7.30–7.26(m,1H),7.02–6.93(m,2H),6.59(dd,J=10.3,1.8Hz,1H),6.12(dd,J=10.3,1.1Hz,1H),5.15(d,J=7 .5Hz,1H),5.01(dd,J=10.9,7.5Hz,1H),3.16–3.04(m,1H),2.70(dd,J=18.2,7.2Hz,1H),2.52(dd,J=18.2,1.3Hz,1H),1.54(s,3H). 13 C NMR(101MHz, CDCl3)δ193.5,152.5,142.3,129.7,127.2,125.5,125.2,94.2,60.9,59.8,46.1,33.8,25.9.HRMS(ESI)calculated forC 13 H 14 N2NaO3S[M+Na] + :301.0617, found 301.0621.

[0088] Example 7

[0089] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0090]

[0091] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S7 (0.4 mmol, 46.1 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 24 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the product P7 (38.1 mg, 80%) is obtained as a brown oil.

[0092] Characterization data: 1H NMR (400MHz, CDCl3) δ6.55(dd,J=10.4,1.7Hz,1H),6.04(d,J=10.4Hz,1H),4.70(dd,J=11.1,7.8Hz,1H),3. 68(q,J=6.9Hz,1H),2.96–2.81(m,1H),2.65(dd,J=18.3,7.3Hz,1H),2.43(dd,J=18.3,1.1Hz,1H),1.84(br s,1H),1.62–1.53(m,2H),1.43(s,3H),1.40–1.31(m,2H),0.90(t,J=7.3Hz,3H). 13 C NMR(151MHz, CDCl3)δ193.8,153.3,129.8,93.7,62.8,60.2,47.5,36.4,34.0,25.9,19.7,14.0.HRMS(ESI)calculated for C 12 H 19 N2O3[M+H] + :239.1390,found 239.1387.

[0093] Example 8

[0094] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0095]

[0096] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S8 (0.4 mmol, 51.7 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 60 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1), and the product P8 (37.3 mg, 74%) is obtained as a yellow solid.

[0097] Characterization data: mp: 67-69℃. 1H NMR(500MHz, CDCl3) δ6.55(dd,J=10.4,1.8Hz,1H),6.05(d,J=10.4Hz,1H),4.68(dd,J=11.1,7.8Hz,1H),3. 72(q,J=7.5Hz,1H),2.92–2.82(m,1H),2.65(dd,J=18.3,7.3Hz,1H),2.43(dd,J=18.4,1.9Hz,1H),1.78(br s,1H),1.67–1.61(m,1H),1.51–1.45(m,2H),1.43(s,3H),0.89(d,J=6.6Hz,6H). 13 C NMR(126MHz, CDCl3)δ193.6,153.2,129.7,94.1,61.2,60.1,47.4,43.5,33.8,25.7,25.6,22.9,22.2.HRMS(ESI)calculated for C 13 H 21 N2O3[M+H] + :253.1547,found 253.1543.

[0098] Example 9

[0099] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0100]

[0101] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S9 (0.24 mmol, 57.3 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 72 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1), and the product P9 (43.1 mg, 81%) is obtained as a yellow oil.

[0102] Characterization data: 1H NMR (400MHz, CDCl3) δ6.54(dd,J=10.4,1.7Hz,1H),6.05(d,J=10.4Hz,1H),4.70(dd,J=11.1,7.8Hz,1H),3.67(q,J=7.1Hz,1H),2.91–2.82 (m,1H),2.65(dd,J=18.3,7.3Hz,1H),2.44(dd,J=18.2,3.0Hz,1H),1.64–1.55(m,2H),1.44(s,3H),1.33–1.21(m,6H),0.88–0.84(m,3H). 13 C NMR(101MHz, CDCl3)δ193.7,153.2,129.7,93.6,62.9,60.0,47.4,34.2,33.8,31.6,26.0,25.8,22.3,13.9.HRMS(ESI)calculated forC 14 H 23 N2O3[M+H] + :267.1703,found 267.1700.

[0103] Example 10

[0104] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0105]

[0106] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S10 (0.4 mmol, 70.9 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 24 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:2), and the product P10 (46.9 mg, 78%) is obtained as a yellow oil.

[0107] Characterization data: 87-89℃. 1H NMR (400MHz, CDCl3) δ7.30–7.26(m,2H),7.22–7.14(m,3H),6.52(dd,J=10.3,1.7Hz,1H),6.04(d,J=10.3Hz,1H),4.75(dd,J=11.0,7.7Hz,1 H),3.78–3.69(m,1H),2.95–2.83(m,1H),2.76–2.66(m,2H),2.64–2.61(m,1H)2.46(dd,J=18.3,1.2Hz,1H),2.02–1.85(m,2H),1.44(s,3H). 13 C NMR(101MHz, CDCl3)δ193.6,153.0,140.6,129.7,128.6,128.1,126.3,93.3,62.4,60.0,47.3,35.9,33.8,32.6,25.9.HRMS(ESI)calculated for C 17 H 21 N2O3[M+H] + :301.1547, found 301.1542.

[0108] Embodiment 11

[0109] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0110]

[0111] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S11 (0.24 mmol, 27.2 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 72 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:2), and the product P11 (40.6 mg, 86%) is obtained as a yellow solid.

[0112] Characterization data: mp: 72-74°C. 1H NMR (400MHz, CDCl3) δ6.53(dd,J=10.3,1.8Hz,1H),6.00(d,J=10.3Hz,1H),4.82(dd,J=7.7,6.3Hz,1H),3.25–3.21(m,1H),2.7 7–2.64(m,2H),2.55(t,J=8.2Hz,1H),1.54(s,3H),0.71–0.58(m,2H),0.57–0.50(m,1H),0.34–0.28(m,1H),0.27–0.21(m,1H). 13 C NMR(101MHz, CDCl3)δ195.5,154.3,129.8,95.4,66.7,60.5,51.3,36.9,23.9,10.0,3.5,2.8.HRMS(ESI)calculated for C 12 H 17 N2O3[M+H] + :237.1234, found 237.1231.

[0113] Example 12

[0114] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0115]

[0116] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S12 (0.24 mmol, 33.9 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 72 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1), and the product P12 (51.3 mg, 97%) is obtained as a yellow solid.

[0117] Characterization data: mp: 66-68℃. 1H NMR (400MHz, CDCl3) δ6.56(dd,J=10.4,1.8Hz,1H),6.03(dd,J=10.3,1.0Hz,1H),4.79(dd,J=11.2,7.7Hz,1H),3.56(t,J=8.1Hz,1H),2.89–2 .84(m,1H),2.65(dd,J=18.4,7.3Hz,1H),2.40(dd,J=18.4,0.9Hz,1H),1.91–1.81(m,3H),1.72–1.50(m,5H),1.43(s,3H),1.14–1.04(m,1H). 13 C NMR(151MHz, CDCl3)δ193.6,153.4,129.6,93.1,67.4,59.8,47.5,44.9,33.8,30.5,28.8,25.7,25.0,24.9.HRMS(ESI)calculated for C 14 H 21 N2O3[M+H] + :265.1547,found 265.1542.

[0118] Example 13

[0119] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0120]

[0121] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S13 (0.24 mmol, 37.2 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 72 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the product P13 (53.4 mg, 96%) is obtained as a yellow solid.

[0122] Characterization data: 68-70℃. 1H NMR(600MHz, CDCl3) δ6.55(dd,J=10.4,1.8Hz,1H),6.02(d,J=10.3Hz,1H),4.82(dd,J =11.3,7.7Hz,1H),3.53(t,J=8.0Hz,1H),2.86–2.78(m,1H),2.64(dd,J=18.4,7.2Hz, 1H),2.42(dd,J=18.4,1.0Hz,1H),1.82(d,J=12.5Hz,2H),1.75–1.63(m,3H),1.57(d, J=12.6Hz,1H),1.42(s,3H),1.24–1.18(m,2H),1.16–1.11(m,1H),1.05–0.93(m,2H). 13 C NMR(101MHz, CDCl3)δ193.7,153.5,129.6,91.9,67.4,59.7,47.2,42.2,33.8,30.3,29.0,26.0,25.7,25.61,25.59.HRMS(ESI)calculated forC 15 H 23 N2O3[M+H] + :279.1703,found279.1701.

[0123] Embodiment 14

[0124] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0125]

[0126] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S14 (0.24 mmol, 30.5 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 96 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1), and the product P14 (37.5 mg, 75%) is obtained as a brown solid.

[0127] Characterization data: 98-100℃. 1H NMR (500MHz, CDCl3) δ6.39(dd,J=10.4,1.4Hz,1H),5.94(d,J=10.3Hz,1H),3.97(t,J=5.6Hz,1H),2.62–2.56(m,2H),2.56 –2.49(m,1H),2.41–2.36(m,1H),2.07–2.01(m,1H),1.87–1.81(m,1H),1.62–1.51(m,3H),1.47(s,3H),1.44–1.36(m,2H). 13 C NMR(126MHz, CDCl3)δ194.1,152.5,127.8,95.9,58.5,58.0,52.0,34.2,33.6,28.0,27.9,22.1,20.7.HRMS(ESI)calculated for C 13 H 19 N2O3[M+H] + :251.1390, found 251.1386.

[0128] Embodiment 15

[0129] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0130]

[0131] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S1 (0.3 mmol, 22.4 mg) are dissolved in CH3CN (1.0 mL) under air conditions, and DMAP (0.02 mmol, 2.4 mg) is added, and the mixture is reacted at room temperature for 6 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 4:1), and the product P15 (40.8 mg, 75%) is obtained as a yellow solid.

[0132] Characterization data: 136-138°C. 1H NMR (400MHz, CDCl3) δ7.36–7.26(m,5H),6.62(dd,J=10.3,1.8Hz,1H),6.13(dd,J=10.3,0.7Hz,1H),5.03(dd,J=7.9,6.0Hz,1H ), 4.58 (d, J = 7.9Hz, 1H), 3.35 (tt, J = 5.9, 2.2Hz, 1H), 2.79 (dd, J = 17.3, 5.9Hz, 1H), 2.70 (dd, J = 17.4, 1.4Hz, 1H), 1.65 (s, 3H). 13 C NMR(101MHz, CDCl3)δ195.6,154.2,135.0,130.0,128.7,128.5,126.7,95.9,64.5,60.1,49.9,37.0,24.1.HRMS(ESI)calculated for C 15 H 17 N2O3[M+H] + :273.1234,found 273.1230.

[0133] Example 16

[0134] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0135]

[0136] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S4 (0.3 mmol, 59.8 mg) are dissolved in CH3CN (1.0 mL) under air conditions, and DMAP (0.02 mmol, 2.4 mg) is added, and the mixture is reacted at room temperature for 6 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 3:1), and the product P16 (46.4 mg, 72%) is obtained as a yellow solid.

[0137] Characterization data: mp: 148-150℃. 1H NMR (400MHz, CDCl3) δ7.83–7.77(m,4H),7.51–7.45(m,2H),7.34(dd,J=8.6,1.7Hz,1H),6.65(dd,J=10.3,1.8Hz,1H),6.16(dd,J=10.3,1.0Hz ,1H),5.12(dd,J=7.9,5.9Hz,1H),4.74(d,J=7.9Hz,1H),3.41(tt,J=5.9,2.2Hz,1H),2.82(dd,J=17.4,5.9Hz,1H),2.76–2.71(m,1H),2.61(br s,1H),1.70(s,3H). 13 C NMR (101MHz, CDCl3) δ195.6,154.2,133.3,133.0,132.5,130.1,128.3,128.0,127.7,1 26.4,126.38,126.0,124.4,95.9,64.7,60.1,50.0,37.1,24.2.HRMS(ESI)calculated forC 19 H 19 N2O3[M+H] + :323.1390, found 323.1391.

[0138] Embodiment 17

[0139] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0140]

[0141] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S5 (0.3 mmol, 41.7 mg) are dissolved in CH3CN (1.0 mL) under air conditions, and DMAP (0.02 mmol, 2.4 mg) is added, and the mixture is reacted at room temperature for 6 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 4:1), and the product P17 (37.2 mg, 71%) is obtained as a yellow solid.

[0142] Characterization data: mp: 137-139℃. 1H NMR (400MHz, CDCl3) δ7.34(dd,J=1.7,0.8Hz,1H),6.61(dd,J=10.3,1.8Hz,1H),6.34–6.29(m,2H),6.08(dd,J=10.3,0.7Hz,1H),4.99(d d,J=7.8,6.8Hz,1H),4.62(d,J=7.8Hz,1H),3.44–3.33(m,1H),2.79(dd,J=17.5,5.7Hz,1H),2.71(dd,J=17.5,1.4Hz,1H),1.63(s,3H). 13 C NMR(101MHz, CDCl3)δ195.3,153.9,148.4,143.1,129.8,110.6,108.7,94.1,60.3,59.3,49.8,36.6,24.0.HRMS(ESI)calculated for C 13 H 15 N2O4[M+H] + :263.1026,found 263.1025.

[0143] Embodiment 18

[0144] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0145]

[0146] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S6 (0.3 mmol, 46.6 mg) are dissolved in CH3CN (1.0 mL) under air conditions, and DMAP (0.02 mmol, 2.4 mg) is added, and the mixture is reacted at room temperature for 6 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, and eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 4:1) to obtain the product P18 (38.4 mg, 90%), which is a yellow solid.

[0147] Characterization data: mp: 135-137℃. 1H NMR (600MHz, CDCl3) δ7.25(dd,J=5.0,1.3Hz,1H),6.98–6.94(m,2H),6.60(dd,J=10.3,1.9Hz,1H),6.10(d,J=10.3Hz,1H),5.00(dd, J=8.0,6.8Hz,1H),4.85(d,J=8.0Hz,1H),3.43–3.39(m,1H),2.78(dd,J=17.4,5.9Hz,1H),2.69(dd,J=17.4,1.1Hz,1H),1.64(s,3H). 13 C NMR(151MHz, CDCl3)δ195.4,154.0,138.8,129.6,127.2,125.6,125.6,94.8,60.1,59.8,48.9,36.7,24.2.HRMS(ESI)calculated forC 13 H 14 N2NaO3S[M+Na] + :301.0617, found 301.0620.

[0148] Embodiment 19

[0149] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0150]

[0151] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S8 (0.3 mmol, 38.8 mg) are dissolved in CH3CN (1.0 mL) under air conditions, and DMAP (0.3 mmol, 22.4 mg) is added, and the mixture is reacted at room temperature for 6 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 6:1), and the product P19 (35.8 mg, 71%) is obtained as a yellow solid.

[0152] Characterization data: mp: 78-80℃. 1H NMR (400MHz, CDCl3) δ6.57(dd,J=10.3,1.7Hz,1H),6.06(d,J=10.3Hz,1H),4.80(dd,J=7.2,5.3Hz,1H),3.30(q,J=7.0Hz,1H ),3.20–3.16(m,1H),2.78–2.66(m,2H),1.75–1.64(m,1H),1.54(s,3H),1.25(t,J=7.0Hz,2H),0.88(dd,J=13.2,6.6Hz,6H). 13 C NMR(101MHz, CDCl3)δ195.7,154.3,130.1,97.0,61.0,60.0,52.0,37.9,37.2,25.7,23.8,23.3,21.8.HRMS(ESI)calculated for C 13 H 21 N2O3[M+H] + :253.1547,found 253.1543.

[0153] Embodiment 20

[0154] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0155]

[0156] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S10 (0.3 mmol, 53.2 mg) are dissolved in CH3CN (1.0 mL) under air conditions, and DMAP (0.02 mmol, 2.4 mg) is added to react at room temperature for 6 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 5:1), and the product P20 (38.4 mg, 64%) is obtained, which is a yellow oil.

[0157] Characterization data: 1H NMR (400MHz, CDCl3) δ7.29–7.25(m,2H),7.21–7.13(m,3H),6.55(dd,J=10.3,1.7Hz,1H),6.02(d,J=10.3Hz,1H),4.81(dd,J=7.2,5.3Hz,1H),3. 27–3.22(m,1H),3.22–3.18(m,1H),2.81–2.74(m,1H),2.73–2.70(m,2H ),2.69–2.63(m,1H),1.77–1.72(m,1H),1.70–1.64(m,1H),1.56(s,3H). 13 C NMR(101MHz, CDCl3)δ195.6,154.2,140.5,130.0,128.5,128.3,126.3,96.4,61.1,60.9,52.0,37.1,33.1,31.2,23.9.HRMS(ESI)calculated for C 17 H 21 N2O3[M+H] + :301.1547, found 301.1541.

[0158] Embodiment 21

[0159] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0160]

[0161] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S11 (0.3 mmol, 33.9 mg) are dissolved in CH3CN (1.0 mL) under air conditions, and DMAP (0.02 mmol, 2.4 mg) is added, and the mixture is reacted at room temperature for 6 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, and eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain the product P21 (34.0 mg, 72%), which is a yellow solid.

[0162] Characterization data: mp: 79-81°C. 1H NMR (400MHz, CDCl3) δ6.53(dd,J=10.3,1.8Hz,1H),6.00(dd,J=10.3,0.8Hz,1H),4.82(dd,J=7.6,6.3Hz,1H),3.25–3.21(m,1H),2 .76–2.64(m,2H),2.54(t,J=8.2Hz,1H),1.54(s,3H),0.70–0.58(m,2H),0.56–0.49(m,1H),0.34–0.28(m,1H),0.27–0.21(m,1H). 13 C NMR(101MHz, CDCl3)δ195.6,154.3,129.8,95.4,66.7,60.5,51.3,36.9,23.9,10.0,3.6,2.8.HRMS(ESI)calculated for C 12 H 17 N2O3[M+H] + :237.1234,found237.1233.

[0163] Embodiment 22

[0164] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0165]

[0166] The preparation method is as follows: N1 (0.2 mmol, 24.6 mg) and S12 (0.3 mmol, 42.4 mg) are dissolved in CH3CN (1.0 mL) under air conditions, and DMAP (0.02 mmol, 2.4 mg) is added, and the mixture is reacted at room temperature for 6 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, and eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 3:1) to obtain the product P22 (39.6 mg, 75%), which is a yellow solid.

[0167] Characterization data: mp: 108-110℃. 1H NMR (400MHz, CDCl3) δ6.55 (dd, J=10.4, 2.0Hz, 1H), 6.06 (d, J=10.3Hz, 1H), 4.84–4.80 (m, 1H), 3.14–3.10 (m, 1H), 3.00–2.92 (m, 1H), 2.75–2 .68(m,2H),1.91–1.84(m,1H),1.79–1.68(m,2H),1.66–1.57(m,2H), 1.54(s,3H),1.49–1.43(m,1H),1.43–1.20(m,2H),1.20–1.09(m,1H). 13 C NMR(101MHz, CDCl3)δ195.8,154.4,130.0,96.3,68.8,60.7,53.0,39.8,37.4,32.1,30.0,25.3,25.2,23.9.HRMS(ESI)calculated for C 14 H 21 N2O3[M+H] + :265.1547,found 265.1543.

[0168] Embodiment 23

[0169] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0170]

[0171] The preparation method is as follows: N2 (0.2 mmol, 27.5 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 24 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 3:1), and the product P23 (48.1 mg, 84%) is obtained as a brown solid.

[0172] Characterization data: mp: 99-101℃. 1H NMR (400MHz, CDCl3) δ7.42–7.26(m,5H),6.61(dd,J=10.4,1.7Hz,1H),6.22(dd,J=10.4,0.8Hz,1H),4.93(dd,J=10.9,8.1Hz,1H),4.84(d,J=8.1H z,1H),3.15–3.06(m,1H),2.67(dd,J=18.3,7.4Hz,1H),2.44(dd,J=18.3 ,1.2Hz,1H),1.96–1.87(m,1H),1.85–1.76(m,1H),1.10(t,J=7.6Hz,3H). 13 C NMR(101MHz, CDCl3)δ194.0,152.0,138.5,130.5,128.9,128.7,126.6,94.3,64.3,62.4,44.1,34.4,32.8,8.6.HRMS(ESI)calculated for C 16 H 19 N2O3[M+H] + :287.1390,found 287.1386.

[0173] Embodiment 24

[0174] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0175]

[0176] The preparation method is as follows: N3 (0.2 mmol, 29.8 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 24 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 5:1), and the product P24 (48.9 mg, 82%) is obtained as a brown solid.

[0177] Characterization data: mp: 119-121℃. 1H NMR (400MHz, CDCl3) δ7.38–7.29(m,5H),6.46(dd,J=10.4,1.7Hz,1H),6.19(d,J=10.4Hz,1H),4.91(dd,J=10.8,7.9Hz,1H),4.85(d,J=7.9Hz,1H),3.2 8–3.17(m,1H),2.77(dd,J=18.2,7.3Hz,1H),2.46(dd,J=18.2,3.1Hz,1H), 1.22–1.11(m,1H),0.67–0.58(m,2H),0.58–0.50(m,1H),0.45–0.37(m,1H). 13 C NMR(151MHz, CDCl3)δ194.1,150.5,138.8,130.9,128.9,128.7,126.6,94.1,63.9,61.3,45.9,34.2,18.6,1.2,-0.23.HRMS(ESI)calculated for C 17 H 19 N2O3[M+H] + :299.1390,found299.1387.

[0178] Embodiment 25

[0179] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0180]

[0181] The preparation method is as follows: N4 (0.2 mmol, 33.1 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 84 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 8:1), and the product P25 (54.1 mg, 86%) is obtained as a yellow solid.

[0182] Characterization data: mp: 101-103℃. 1H NMR (400MHz, CDCl3) δ7.40–7.29 (m, 5H), 6.61 (dd, J=10.4, 1.6Hz, 1H), 6.21 (d, J= 10.4Hz,1H),4.93(dd,J=10.9,8.1Hz,1H),4.84(d,J=8.1Hz,1H),3.15–3.05(m,1 H),2.68(dd,J=18.3,7.4Hz,1H),2.44(dd,J=18.2,2.5Hz,1H),1.91–1.82(m,1H) ,1.77–1.70(m,1H),1.52–1.43(m,2H),1.42–1.36(m,2H),0.95(t,J=7.1Hz,3H). 13 C NMR(101MHz, CDCl3)δ193.9,152.2,138.5,130.4,129.0,128.7,126.6,94.3,64.4,62.2,44.6,40.1,34.4,26.4,23.2,13.9.HRMS(ESI)calculated for C 18 H 23 N2O3[M+H] + :315.1703, found 315.1699.

[0183] Embodiment 26

[0184] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0185]

[0186] The preparation method is as follows: N5 (0.2 mmol, 38.7 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 24 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 9:1), and the product P26 (62.3 mg, 91%) is obtained as a white solid.

[0187] Characterization data: mp: 69-71°C. 1H NMR (400MHz, CDCl3) δ7.38–7.30(m,5H),6.61(dd,J=10.4,1.7Hz,1H),6.20(dd,J=10.4,0.9Hz,1H),4.92(dd,J=11.0,8 .1Hz,1H),4.82(d,J=8.0Hz,1H),3.14–3.04(m,1H),2.68(dd,J=18.3,7.4Hz,1H),2.43(dd,J=18.3,1.2Hz,1H),1.97(br s,1H),1.90–1.83(m,1H),1.77–1.69(m,1H),1.52–1.42(m,2H),1.37–1.29(m,6H),0.90(t,J=7.0Hz,3H). 13 C NMR(101MHz, CDCl3)δ194.0,152.3,138.5,130.4,128.9,128.7,126.6,94.2,64.4,62.2,44.6,40.3,34.4,31.6,29.7,24.2,22.5,14.0.HRMS(ESI)calculated for C 20 H 27 N2O3[M+H] + :343.2016, found 343.2014.

[0188] Embodiment 27

[0189] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0190]

[0191] The preparation method is as follows: N6 (0.2 mmol, 32.7 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 24 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 5:1), and the product P27 (56.2 mg, 90%) is obtained as a brown solid.

[0192] Characterization data: mp: 91-93℃. 1H NMR (400MHz, CDCl3) δ7.43–7.28(m,5H),6.62(dd,J=10.4,1.7Hz,1H),6.21(d,J=10.4Hz, 1H),5.91–5.81(m,1H),5.11(dq,J=17.1,1.6Hz,1H),5.04(dq,J=10.2,1.4Hz,1H),4.91(d d,J=10.8,8.0Hz,1H),4.84(d,J=8.0Hz,1H),3.15–3.09(m,1H),2.69(dd,J=18.3,7.4Hz,1 H),2.45(dd,J=18.4,1.1Hz,1H),2.37–2.22(m,2H),2.01–1.95(m,1H),1.90–1.82(m,1H). 13 C NMR(101MHz, CDCl3)δ193.8,151.8,138.5,137.4,130.5,128.9,128.7,126.6,115.7,94.1,64.3,62.0,44.4,39.0,34.2,28.5.HRMS(ESI)calculated for C 18 H 21 N2O3[M+H] + :313.1547,found 313.1543.

[0193] Embodiment 28

[0194] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0195]

[0196] The preparation method is as follows: N7 (0.2 mmol, 37.1 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 48 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 9:1), and the product P28 (51.5 mg, 77%) is obtained as a brown solid.

[0197] Characterization data: mp: 153-155℃. 1H NMR (600MHz, CDCl3) δ7.71(d,J=7.4Hz,2H),7.52(d,J=7.0Hz,2H),7.46(t,J=7.6Hz,2H),7.43–7.33(m,4H),6.65(dd,J=10.3,1.8Hz,1H),6.48(d,J=1 0.3Hz,1H),5.04(d,J=8.2Hz,1H),4.98(dd,J=11.2,8.1Hz,1H),3.26–3.19 (m,1H),2.68(dd,J=18.2,7.0Hz,1H),2.39(dd,J=18.3,2.2Hz,1H),2.22(br s,1H). 13 CNMR(151MHz, CDCl3)δ193.8,150.2,140.9,138.7,131.5,129.1,129.0,128.9,128.6,126.8,125.9,93.4,64.5,64.2,47.6,33.5.HRMS(ESI)calculated for C 20 H 19 N2O3[M+H] + :335.1390, found 335.1386.

[0198] Embodiment 29

[0199] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0200]

[0201] The preparation method is as follows: N8 (0.2 mmol, 39.9 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 72 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 8:1), and the product P29 (58.5 mg, 84%) is obtained as a white solid.

[0202] Characterization data: mp: 139-141℃. 1H NMR (600MHz, CDCl3) δ7.57(d,J=8.2Hz,2H),7.51(d,J=7.1Hz,2H),7.41–7. 35(m,3H),7.25(d,J=7.7Hz,2H),6.63(dd,J=10.3,1.8Hz,1H),6.46(d,J=10 .3Hz,1H),5.02(d,J=8.2Hz,1H),4.97(dd,J=11.2,8.1Hz,1H),3.23–3.16(m ,1H),2.67(dd,J=18.2,7.0Hz,1H),2.39(s,3H),2.39–2.36(m,1H),2.20(br s,1H). 13 CNMR(151MHz, CDCl3)δ194.0,150.5,138.8,138.5,137.9,131.3,129.7,129.0,128.9,126.8,125.8,93.5,64.4,64.1,47.6,33.5,21.0.HRMS(ESI)calculated for C 21 H 21 N2O3[M+H] + :349.1547,found349.1544.

[0203] Embodiment 30

[0204] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0205]

[0206] The preparation method is as follows: N9 (0.2 mmol, 40.6 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 72 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 9:1), and the product P30 (59.9 mg, 85%) is obtained as a white solid.

[0207] Characterization data: mp: 47-49℃. 1H NMR (400MHz, CDCl3) δ7.74–7.64(m,2H),7.51(d,J=6.1Hz,2H),7.42–7.36(m,3H),7.13(t,J=8.6Hz,2H),6.62(dd,J=10.3,1.8Hz,1H ),6.47(d,J=10.2Hz,1H),5.05–4.95(m,2H),3.25–3.10(m,1H),2.64(dd,J=18.2,7.0Hz,1H),2.39(dd,J=18.2,2.8Hz,1H),2.23(br s,1H). 13 C NMR (101MHz, CDCl3) δ193.6, 162.8 (d, J = 246.0Hz), 149.9, 138.6, 136.7 (d, J = 3.0Hz), 131.6, 129.0, 127. 8(d,J=8.0Hz),126.8,125.9,116.0(d,J=22.0Hz),93.3,64.1,64.08,47.6,33.4.HRMS(ESI)calculated forC 20 H 18 FN2O3[M+H] + :353.1296,found 353.1296.

[0208] Embodiment 31

[0209] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0210]

[0211] The preparation method is as follows: N10 (0.2 mmol, 52.3 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 96 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 9:1), and the product P31 (69.0 mg, 84%) is obtained as a yellow solid.

[0212] Characterization data: mp: 93-95℃. 1H NMR (600MHz, CDCl3) δ7.77(d,J=8.3Hz,2H),7.67(d,J=8.4Hz,2H),7.61(d,J=7.2Hz,2 H),7.54(d,J=7.2Hz,2H),7.47(t,J=7.7Hz,2H),7.44–7.35(m,4H),6.68(dd,J=10.3,1 .8Hz,1H),6.50(d,J=10.3Hz,1H),5.06(d,J=8.2Hz,1H),5.01(dd,J=11.2,8.1Hz,1H), 3.31–3.22(m,1H),2.72(dd,J=18.3,7.0Hz,1H),2.42(dd,J=18.4,1.0Hz,1H),2.26(br s,1H). 13 C NMR (151MHz, CDCl3) δ193.8,150.2,141.6,140.2,139.9,138.7,131.5,129.0,128.92,128 .9,127.8,127.7,127.1,126.8,126.4,93.4,64.4,64.2,47.6,33.5.HRMS(ESI)calculated for C 26 H 23 N2O3[M+H] + :411.1703,found 411.1703.

[0213] Embodiment 32

[0214] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0215]

[0216] The preparation method is as follows: N11 (0.2 mmol, 47.1 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 72 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 8:1), and the product P32 (74.6 mg, 97%) is obtained as a white solid.

[0217] Characterization data: mp: 68-70℃. 1H NMR(600MHz, CDCl3)δ8.02(d,J=1.8Hz,1H),7.95(d,J=8.6Hz,1H),7.93–7.85(m,3H) ,7.57–7.52(m,4H),7.43(t,J=7.3Hz,2H),7.40–7.37(m,1H),6.72(dd,J=10.3,1.8H z,1H),6.54(d,J=10.3Hz,1H),5.08(d,J=8.2Hz,1H),5.02(dd,J=11.2,8.2Hz,1H),3 .33–3.26(m,1H),2.69(dd,J=18.3,7.0Hz,1H),2.40(dd,J=18.2,1.0Hz,1H),2.31(br s,1H). 13 C NMR (101MHz, CDCl3) δ193.9,150.2,138.7,138.2,133.2,133.0,131.6,129.2,129.0,128.9,128. 1,127.6,126.8,126.72,126.7,125.3,123.4,93.4,64.6,64.3,47.4,33.5.HRMS(ESI)calculated for C 24 H 21 N2O3[M+H] + :385.1547,found 385.1545.

[0218] Embodiment 33

[0219] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0220]

[0221] The preparation method is as follows: N12 (0.2 mmol, 27.4 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 48 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 5:1), and the product P33 (36.7 mg, 64%) is obtained as a yellow oil.

[0222] Characterization data: 1H NMR (400MHz, CDCl3) δ7.38–7.32(m,5H),6.03(d,J=2.5Hz,1H),4.94(dd,J=10.9,7.2Hz,1H),4.71(d,J=7.2Hz,1H) ,3.02–2.97(m,1H),2.74(dd,J=18.4,7.2Hz,1H),2.61(dd,J=18.4,1.2Hz,1H),2.05(d,J=1.4Hz,3H),1.54(s,3H). 13 C NMR(151MHz, CDCl3)δ193.4,161.6,138.9,129.1,129.0,128.6,126.4,94.2,64.5,62.3,48.2,34.0,25.1,18.1.HRMS(ESI)calculated for C 16 H 19 N2O3[M+H] + :287.1390,found287.1387.

[0223] Embodiment 34

[0224] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0225]

[0226] The preparation method is as follows: N13 (0.2 mmol, 40.1 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 48 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 5:1), and the product P34 (52.7 mg, 75%) is obtained as a brown oil.

[0227] Characterization data: 1 H NMR (400MHz, CDCl3) δ7.40–7.32(m,5H),7.06(d,J=1.6Hz,1H),4.95(dd,J=10.8,7.8Hz,1H),4.88(d,J= 7.8Hz,1H),3.13–3.01(m,1H),2.85(dd,J=18.1,6.9Hz,1H),2.72(dd,J=18.2,2.3Hz,1H),1.58(s,3H). 13C NMR(151MHz, CDCl3)δ185.6,153.3,138.2,129.0,128.8,126.5,124.3,93.9,65.1,62.7,46.3,34.0,25.5.HRMS(ESI)calculated for C 15 H 16 BrN2O3[M+H] + :351.0344, found 351.0345.

[0228] Embodiment 35

[0229] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0230]

[0231] The preparation method is as follows: N14 (0.2 mmol, 34.6 mg) and S1 (0.24 mmol, 35.8 mg) are dissolved in CH2Cl2 (1.0 mL) under air conditions, and the reaction is terminated at 50°C for 24 hours. The reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 8:1), and the product P35 (47.7 mg, 74%) is obtained as a black solid.

[0232] Characterization data: mp: 48-50℃. 1 H NMR(600MHz, CDCl3)δ8.05(dd,J=7.9,1.4Hz,1H),7.72–7.65(m,2H),7.47–7.39(m,1H),7.38–7.28(m,5H),5.06(dd,J=10.8, 7.3Hz,1H),4.58(d,J=7.3Hz,1H),3.14–3.10(m,1H),2.99(dd,J=18.4,7.2Hz,1H),2.88(dd,J=18.4,2.5Hz,1H),1.70(s,3H). 13 C NMR(151MHz, CDCl3)δ192.8,146.9,139.0,134.8,131.6,128.9,128.5,127.8,126.6,126.4,125.6,94.6,65.1,61.8,48.8,34.6,30.1.HRMS(ESI)calculated for C 19 H 19 N2O3[M+H] + :323.1390, found 323.1390.

[0233] Embodiment 36

[0234] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0235]

[0236] The preparation method is as follows: N2 (0.2 mmol, 27.5 mg) and S1 (0.3 mmol, 42.4 mg) are dissolved in CH3CN (1.0 mL) under air conditions, and DMAP (0.02 mmol, 2.4 mg) is added, and the mixture is reacted at room temperature for 6 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 8:1), and the product P36 (43.5 mg, 76%) is obtained as a yellow solid.

[0237] Characterization data: mp: 152-154℃. 1 H NMR (400MHz, CDCl3) δ7.34–7.26(m,5H),6.64(dd,J=10.3,1.7Hz,1H),6.20(dd,J=10.4,1.0Hz,1H),5.01(dd,J=7.8,5.6Hz,1H),4.57(d,J=7 .8Hz,1H),3.41(tt,J=5.9,2.1Hz,1H),2.77(dd,J=17.5,6.1Hz,1H),2.69(dd,J=17.5,1.5Hz,1H),2.06–1.93(m,2H),1.19(t,J=7.5Hz,3H). 13 C NMR(101MHz, CDCl3)δ195.9,153.5,135.1,130.7,128.7,128.5,126.8,96.3,64.2,62.8,47.6,37.7,31.0,8.6.HRMS(ESI)calculated for C 16 H 19 N2O3[M+H] + :287.1390,found 287.1386.

[0238] Embodiment 37

[0239] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0240]

[0241] The preparation method is as follows: N3 (0.2 mmol, 29.8 mg) and S1 (0.3 mmol, 42.4 mg) are dissolved in CH3CN (1.0 mL) under air conditions, and DMAP (0.02 mmol, 2.4 mg) is added, and the mixture is reacted at room temperature for 6 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, and eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 8:1) to obtain the product P37 (53.7 mg, 90%), which is a yellow solid.

[0242] Characterization data: mp: 177-179℃. 1 H NMR (400MHz, CDCl3) δ7.32–7.28(m,5H),6.50(dd,J=10.3,1.8Hz,1H),6.19(dd ,J=10.3,1.1Hz,1H),4.97(dd,J=8.2,6.3Hz,1H),4.58(d,J=8.3Hz,1H),3.51( tt,J=6.0,1.8Hz,1H),2.87(dd,J=17.4,6.1Hz,1H),2.67(dd,J=17.4,0.9Hz,1 H),1.35–1.25(m,2H),0.73–0.69(m,1H),0.66–0.61(m,1H),0.52–0.44(m,1H). 13 CNMR(101MHz,CDCl3)δ196.0,151.9,135.5,131.1,128.7,128.4,127.1,95.4,63.5,61.6,48.6,37.3,17.3,1.4,-0.09.HRMS(ESI)calculated for C 17 H 19 N2O3[M+H] + :299.1390,found 299.1387.

[0243] Embodiment 38

[0244] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0245]

[0246] The preparation method is as follows: N5 (0.2 mmol, 38.7 mg) and S1 (0.3 mmol, 42.4 mg) are dissolved in CH3CN (1.0 mL) under air conditions, and DMAP (0.02 mmol, 2.4 mg) is added, and the mixture is reacted at room temperature for 6 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 7:1), and the product P38 (62.3 mg, 91%) is obtained as a white solid.

[0247] Characterization data: mp: 79-81°C. 1 H NMR (400MHz, CDCl3) δ7.35–7.27(m,5H),6.65(dd,J=10.4,1.8Hz,1H),6.18(dd,J=10. 3,0.9Hz,1H),5.00(dd,J=7.8,5.6Hz,1H),4.56(d,J=7.8Hz,1H),3.39(tt,J=5.9,1.8H z,1H),2.78(dd,J=17.5,6.2Hz,1H),2.72–2.66(m,1H),2.02–1.94(m,1H),1.93–1.84( m,1H),1.61–1.53(m,2H),1.45–1.38(m,2H),1.37–1.32(m,4H),0.91(t,J=6.9Hz,3H). 13 C NMR(101MHz, CDCl3)δ195.9,153.7,135.1,130.5,128.6,128.5,126.8,96.3,64.3,62.7,48.2,38.5,37.6,31.6,29.8,24.3,22.6,14.0.HRMS(ESI)calculated for C 20 H 27 N2O3[M+H] + :343.2016, found 343.2014.

[0248] Embodiment 39

[0249] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0250]

[0251] The preparation method is as follows: N6 (0.2 mmol, 32.7 mg) and S1 (0.3 mmol, 42.4 mg) are dissolved in CH3CN (1.0 mL) under air conditions, and DMAP (0.02 mmol, 2.4 mg) is added, and the mixture is reacted at room temperature for 7 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, and eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 5:1) to obtain the product P39 (51.2 mg, 82%), which is a brown solid.

[0252] Characterization data: mp: 89-91℃. 1 H NMR(400MHz, CDCl3) δ7.36–7.29(m,5H),6.65(dd,J=10.3,1.8Hz,1H),6.19(dd,J=1 0.3,1.0Hz,1H),5.96–5.85(m,1H),5.15(dd,J=17.1,1.7Hz,1H),5.08(dd,J=10.2,1 .5Hz,1H),4.99(dd,J=7.9,5.7Hz,1H),4.57(d,J=7.9Hz,1H),3.47–3.43(m,1H),2. 78(dd,J=17.5,6.1Hz,1H),2.71–2.65(m,1H),2.44–2.37(m,2H),2.13–1.98(m,2H). 13 C NMR(101MHz, CDCl3)δ195.8,153.3,137.4,135.1,130.6,128.7,128.5,126.9,115.8,95.9,64.2,62.4,47.8,37.4,37.2,28.5.HRMS(ESI)calculated forC 18 H 21 N2O3[M+H] + :313.1547,found 313.1543.

[0253] Embodiment 40

[0254] The reaction formula for preparing the hydroindole compound in this embodiment is as follows:

[0255]

[0256] The preparation method is as follows: N13 (0.2 mmol, 24.6 mg) and S1 (0.3 mmol, 42.4 mg) are dissolved in CH3CN (1.0 mL) under air conditions, and DMAP (0.02 mmol, 2.4 mg) is added, and the mixture is reacted at room temperature for 7 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 3:1), and the product P40 (45.0 mg, 64%) is obtained as a brown solid.

[0257] Characterization data: mp: 162-164℃. 1 H NMR (400MHz, CDCl3) δ7.37–7.26(m,5H),7.08(d,J=1.6Hz,1H),5.02(dd,J=8.0,6.0Hz,1H),4.63(d,J=8.0H z,1H),3.41(tt,J=5.8,2.2Hz,1H),2.97(dd,J=17.2,2.5Hz,1H),2.89(dd,J=17.3,5.6Hz,1H),1.69(s,3H). 13 C NMR(101MHz, CDCl3)δ187.9,154.7,134.8,128.9,128.5,126.8,123.8,95.2,64.4,62.9,49.4,37.0,24.0.HRMS(ESI)calculated for C 15 H 16 BrN2O3[M+H] + :351.0339, found 351.0345.

[0258] Embodiment 41

[0259] The reaction formula for preparing the hydroindole derivatives in this embodiment is as follows:

[0260]

[0261] At room temperature, P1 (0.3mmol, 81.7mg), 37% aqueous formaldehyde solution (0.9mmol, 90ul), zinc chloride (0.18mmol, 24.5mg), sodium cyanoborohydride (0.45mmol, 28.3mg) and methanol (3mL) were added to the reaction bottle. The reactants were stirred for 30 minutes and quenched by adding 3.5mL 0.1M sodium hydroxide. Methanol was removed under reduced pressure, the reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate = 7: 1) to obtain a brown solid product P41 (63.6mg, 74%).

[0262] Characterization data: mp: 93-95℃. 1 H NMR (400MHz, CDCl3) δ7.38–7.28(m,5H),6.94(dd,J=10.7,1.9Hz,1H),6.21(dd,J=10.6,1.1Hz,1H),4.86(dd,J=11.3,7.5H z,1H),4.26(d,J=7.4Hz,1H),3.06–2.95(m,1H),2.75(dd,J=18.3,7.1Hz,1H),2.56–2.51(m,1H),2.26(s,3H),1.49(s,3H). 13 C NMR(101MHz, CDCl3)δ193.9,147.4,138.3,131.3,129.0,128.7,127.4,93.4,71.8,61.6,45.2,34.1,31.3,24.1.HRMS(EI)calculated for C 16 H 18 N2O3[M] + :286.1317,found286.1313.

[0263] Embodiment 42

[0264] The reaction formula for preparing the hydroindole derivatives in this embodiment is as follows:

[0265]

[0266] P1 (0.2mmol, 54.4mg), sodium bicarbonate (0.24mmol, 20.2mg) and dichloromethane (4mL) were added to the reaction bottle, cooled to 0°C, chloroacetyl chloride (0.24mmol, 27.1mg) was slowly added under stirring, and then the reaction system was moved to room temperature and stirred for 5 hours. After the reaction was completed, water was added to quench the reaction. The ethyl acetate was extracted, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was flash column chromatography on silica gel (petroleum ether: ethyl acetate = 3:1) to give a white solid product P42 (55.1mg, 79%).

[0267] Characterization data: mp: 56-58℃. 1 H NMR (400MHz, CDCl3) δ7.51–7.41(m,4H),7.31(d,J=7.2Hz,2H),6.00(s,1H),5.86(d,J=10.6Hz,1H),4.82(d,J=6.3Hz,1H),3.93(d, J=13.4Hz,1H),3.72(d,J=13.4Hz,1H),3.10–3.04(m,1H),3.00(dd,J=18.4,2.7Hz,1H),2.74(dd,J=18.4,7.2Hz,1H),2.02(s,3H). 13 C NMR(151MHz, CDCl3)δ192.0,165.9,147.1,136.9,130.1,129.5,127.4,125.4,91.1,64.0,63.0,45.1,42.9,32.9,25.0.HRMS(ESI)calculated for C 17 H 18 ClN2O4[M+H] + :349.0950, found 349.0948.

[0268] Embodiment 43

[0269] The reaction formula for preparing the hydroindole derivatives in this embodiment is as follows:

[0270]

[0271] P15 (0.1mmol, 27.2mg) was dissolved in 1,4-dioxane (1.0mL) solution, di-tert-butyl dicarbonate (0.50mmol, 109.1mg) was added, heated to 80°C and stirred for 12 hours. 1,4-dioxane was removed under reduced pressure, the reaction mixture was extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate = 8:1) to obtain a yellow solid product P43 (34.3mg, 92%).

[0272] Characterization data: mp: 123-125℃. 1 H NMR (400MHz, CDCl3) δ7.35–7.29(m,4H),7.20–7.16(m,2H),5.99(d,J=10.4Hz,1H),5.39(d,J=8.9Hz,1H),5.08(dd,J=12.2 ,9.2Hz,1H),3.46(dd,J=12.2,5.5Hz,1H),2.79(dd,J=18.1,5.6Hz,1H),2.56(d,J=18.0Hz,1H),2.04(s,3H),1.25(s,9H). 13 C NMR (101MHz, CDCl3) δ194.3,152.6,149.3,136.1,128.7,128.5,126.8,126.6,86.2,81.5,63.4,60.2,44.3,34.4,29.7,28.0.HRMS(ESI)calculated forC 20 H 25 N2O5[M+H] + :373.1758, found 373.1496.

[0273] Embodiment 44

[0274] The reaction formula for preparing the hydroindole derivatives in this embodiment is as follows:

[0275]

[0276] At room temperature, P15 (0.1mmol, 27.2mg) was dissolved in dichloromethane (0.5mL), followed by the addition of benzoyl chloride (0.15mmol, 21.1mg), triethylamine (0.15mmol, 15.2mg) and 4-dimethylaminopyridine (0.01mmol, 1.2mg), and stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate = 8:1) to obtain a yellow solid product P44 (17.1mg, 92%).

[0277] Characterization data: mp: 56-58℃. 1 H NMR (600MHz, CDCl3) δ7.69 (dd, J=10.5, 1.9Hz, 1H), 7.29 (t, J=7.4Hz, 1H), 7.24 (t ,J=7.7Hz,3H),7.11(t,J=7.8Hz,2H),6.91(d,J=7.1Hz,2H),6.84(d,J=7.1Hz,2H) ,6.07(d,J=10.4Hz,1H),5.21(d,J=8.7Hz,1H),5.15(dd,J=12.1,8.7Hz,1H),3.5 8–3.55(m,1H),2.86(dd,J=18.0,5.6Hz,1H),2.61(d,J=17.9Hz,1H),2.27(s,3H). 13 C NMR (151MHz, CDCl3) δ194.1,171.6,148.5,136.6,135.5,129.3,129.2,128.7,128 .1,127.3,127.1,125.3,86.1,65.0,62.5,43.7,34.2,23.4.HRMS(EI)calculated for C 22 H 20 N2O4[M] + :376.1423, found 376.1416.

[0278] Embodiment 45

[0279] The reaction formula for preparing the hydroindole derivatives in this embodiment is as follows:

[0280]

[0281] At room temperature, P15 (0.1mmol, 27.2mg), 37% aqueous formaldehyde solution (0.3mmol, 30ul), zinc chloride (0.06mmol, 8.2mg), sodium cyanoborohydride (0.15mmol, 9.4mg) and methanol (1.0mL) were added to the reaction bottle. The reactants were stirred for 30 minutes and quenched with 0.1N NaOH (1.2mL). Methanol was removed under reduced pressure, the reaction mixture was extracted with ethyl acetate, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate = 8:1) to obtain a white solid product P45 (22.6mg, 79%).

[0282] Characterization data: mp: 122-124℃. 1 H NMR (400MHz, CDCl3) δ7.35–7.28(m,5H),6.96(dd,J=10.5,2.0Hz,1H),6.18(d,J=10.5Hz,1H),4.91(dd,J=9.6,8.2Hz,1H),4. 01(d,J=9.5Hz,1H),3.45–3.40(m,1H),2.78(dd,J=17.5,5.4Hz,1H),2.60(dd,J=17.6,3.5Hz,1H),2.30(s,3H),1.57(s,3H). 13 C NMR(151MHz, CDCl3)δ195.9,149.1,135.2,130.9,128.9,128.4(two C),92.6,70.6,61.4,47.0,36.7,32.0,22.6.HRMS(ESI)calculated for C 16 H 18 N2O3[M+H] + :286.1317, found 286.1312.

[0283] Example 46: Amplification reaction

[0284] Referring to Example 1, the preparation method is as follows: N1 (2.0 mmol, 246.3 mg) and S1 (2.4 mmol, 358.0 mg) were dissolved in CH2Cl2 (5.0 mL) under air conditions, and the reaction was terminated at 50°C for 24 hours. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by flash column chromatography on silica gel, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the product P1 (435.7 mg, 80%) was obtained, which was a brown oil.

[0285] Referring to Example 15, the preparation method is as follows: N1 (2.0 mmol, 246.3 mg) and S1 (3.0 mmol, 447.4 mg) were dissolved in CH3CN (5 mL) under air conditions, and DMAP (0.2 mmol, 24.4 mg) was added to react at room temperature for 6 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the crude product was purified by flash column chromatography on silica gel, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 4:1), and the product P15 (386.7 mg, 71%) was obtained, which was a yellow solid.

[0286] Stereo configuration characterization of the above product:

[0287] ① Class III-a products prepared by method A, and Class III-b products prepared by further derivatization

[0288] Figure 2 The single crystal structure diagram of product P29 and the corresponding X-ray single crystal diffraction data are shown below:

[0289]

[0290]

[0291]

[0292] Correspondingly, other type III-a products P1~P14, P23~P28, P30~35, and type III-b products P41~P42 also have consistent configurations.

[0293] ② Class IV-a products obtained by method B, and Class IV-b products obtained by further derivatization

[0294] Figure 3 The single crystal structure diagram of product P15 and the corresponding X-ray single crystal diffraction data are shown below:

[0295]

[0296]

[0297]

[0298] Correspondingly, other type IV-a products P16~P22, P36~P40, and type IV-b products P43~P45 also have consistent configurations.

[0299] Example 47: Temperature Exploration and Comparison

[0300] Referring to Example 1, only the reaction temperature was replaced with other temperatures shown in Table 1, and the other conditions remained unchanged. The results of the corresponding reactions are shown in Table 1.

[0301] Table 1 Effect of temperature and catalyst on the preparation of hydroindole

[0302] temperature P1 yield (%) 50°C (Example 1) 88 25℃ 80

[0303] Example 48: Catalyst Exploration and Comparison

[0304] Referring to Example 15, only the catalyst was replaced with an equimolar amount of other catalysts shown in Table 2, and the other factors remained unchanged. The results of the corresponding reactions are shown in Table 2.

[0305] Table 2 Effect of catalyst on the preparation of hydroindole

[0306] catalyst P15 yield (%) Triethylamine 57 4-Dimethylaminopyridine (Example 15) 75 N,N-Diisopropylethylamine 63 Triphenylphosphine 62 1,4-Diazabicyclo[2.2.2]octane 70 Potassium tert-butoxide 60 Potassium carbonate 60 Cesium carbonate 15 Sodium carbonate 30

[0307] Example 49: Comparison of solvents

[0308] Referring to Example 1, only the solvent was replaced from dichloromethane to other solvents shown in Table 3, and the other conditions remained unchanged. The results of the corresponding reactions are shown in Table 3.

[0309] Table 3 Effect of solvent on the preparation of hydroindole

[0310]

[0311]

[0312] Referring to Example 15, only the solvent was replaced from acetonitrile to other solvents shown in Table 4, and the other conditions remained unchanged. The results of the corresponding reactions are shown in Table 4.

[0313] Table 4 Effect of solvent on the preparation of hydroindole

[0314] solvent P15 yield (%) Dichloromethane 55 Toluene 52 Acetonitrile (Example 15) 75 Tetrahydrofuran 53 acetone 53 N,N-Dimethylformamide 55 Methanol 62 Ethyl acetate 63

[0315] Example 50: Comparison of reaction substrate feed ratios

[0316] Referring to Example 1, only the reaction substrate feed ratio was replaced with the feed ratio shown in Table 5, and the other factors remained unchanged. The results of the corresponding reactions are shown in Table 5.

[0317] Table 5 Effect of reaction substrate feed ratio on the preparation of hydroindole

[0318] entry S1 / N1 P1 yield (%) 1 1:1.2 (Example 1) 88 2 1:1.5 88 3 1:2 87

[0319] Referring to Example 15, only the reaction substrate feed ratio was replaced with the feed ratio shown in Table 6, and the other factors remained unchanged. The results of the corresponding reactions are shown in Table 6.

[0320] Table 6 Effect of reaction substrate feed ratio on the preparation of hydroindole

[0321] entry 1a / 2a P15 yield (%) 1 1:1.2 72 2 1:1.5 (Example 15) 75 3 1:2 75

[0322] Example 51: Anti-inflammatory activity test of the compounds of the present invention

[0323] After pre-stimulating bone marrow-derived macrophages (BMDM) with LPS (100 ng / mL) for 3 hours, 10 μM of the test compounds (P1 to P45) were added to treat the cells for 30 minutes, and then Nigericin was added for 30 minutes to induce NLRP3 activation. The cell supernatant was collected and the secretion of IL-1β was detected by ELISA.

[0324] The ability of 14 compounds of the present invention to inhibit NLRP3 inflammasome activation was determined. Figure 1 As shown in Table 7:

[0325] Table 7 NLRP3 inhibitor screening ( n=3)

[0326] Group IL-1β secretion (pg / mL) Group IL-1β secretion (pg / mL) Mock 73.80±0 Nig+P19 1021.1±119.0 Nig 1479.4±5.9 Nig+P24 921.9±111.0 Nig+P1 915.0±32.3 Nig+P37 799.0±90.0 Nig+P15 1846.1±76.0 Nig+P27 798.6±48.2 Nig+P11 1460.5±24.8 Nig+P39 729.0±37.8 Nig+P21 1297.9±6.6 Nig+P42 107.3±2.9 Nig+P28 710.9±44.7 Nig+P43 273.3±10.6 Nig+P8 1345.2±293.7 Nig+P44 104.1±1.8

[0327] Among them, Mock refers to the blank control, and Nig refers to the positive control group in which Nigericin is added alone without the test compound.

[0328] Experimental results ( Figure 1 and Table 7) showed that compounds P42 and P44 could significantly inhibit NLRP3 inflammasome activation.

[0329] Compound P44 was selected to further explore its anti-inflammatory effect. After pre-stimulating BMDM cells with LPS (100 ng / mL) for 3 hours, different concentrations of compound P44 were added to treat the cells for 30 minutes, and Nigericin was used to induce NLRP3 activation. ELISA was used to detect the secretion of IL-1β, LDH was used to detect cell death, and Western blot was used to analyze the activated caspase-1 (P20) in the cell supernatant and pro-caspase-1 (Input) in the lysate. Mouse BMDM cells were pre-stimulated with LPS for 3 hours, and then compound P44 was added for 30 minutes. ATP was then used to induce NLRP3 inflammasome activation. Western blot was used to analyze the activated caspase-1 (P20) in the cell supernatant and pro-caspase-1 (Input) in the lysate, and ELISA was used to detect the secretion of IL-1β in the cell supernatant.

[0330] The experimental results showed that compound P44 inhibited the IC of NLRP3 inflammasome50 The compound P44 can inhibit Nigericin-induced cell pyroptosis, caspase-1 cleavage and IL-1β secretion, and can also effectively inhibit ATP-induced caspase-1 activation and 1L-1β secretion. Therefore, the compound of the present invention has potential application space in the development of anti-inflammatory drugs.

[0331] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present invention, which should be included in the scope of the claims of the present invention.

Claims

1. A hydroindole compound represented by the general formula III or IV, or a pharmaceutically acceptable salt thereof; In the formula, means Or n = 0; R is selected from: C1-C8 straight or branched alkyl, C3-C6 cycloalkyl, substituted or unsubstituted aryl; the substitution on the aryl includes any one of mono- to tri-substitution, and the substituent is selected from halogen, C1-C8 straight or branched alkyl, C1-C8 alkoxy; R 1 Selected from: C1-C8 straight or branched alkyl containing 0-2 unsaturated double bonds, C3-C8 cycloalkyl, unsubstituted or substituted phenyl, naphthyl; the substituent includes any one of mono-substituted to tri-substituted, and the substituent is selected from halogen, C1-C8 alkyl, phenyl; R 2 Selected from: H, halogen, C1-C6 straight or branched alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy; R 3 Selected from: H, C1-C6 straight chain or branched alkyl, benzyl, -CO-R a 、-SO2R b ; R a R is selected from unsubstituted or halogen-substituted C1-4 alkyl, unsubstituted or substituted phenyl, C1-C4 alkoxy; b is selected from unsubstituted or substituted phenyl groups; the substituent on the phenyl group is halogen, C1-C6 straight chain or branched alkyl; Aryl is selected from: phenyl, naphthyl, thienyl, furyl.

2. The hydroindole compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R is specifically selected from:

3. The hydroindole compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R 1 Specific selection:

4. The hydroindole compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R 2 Specific selection: or 5. The hydroindole compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R 3 Specific selection: H, or 6. The method for synthesizing the hydroindole compound according to claim 1, characterized in that: The method comprises: Method A: Using p-quinoneamine and nitroolefin as raw materials, without adding any catalyst, a hydroindole compound as shown in formula III-a can be obtained; Alternatively, method B: using p-quinoneamine and nitroolefin as raw materials, reacting in the presence of a base as a catalyst to obtain another configuration of a hydroindole compound as shown in formula IV-a; Alternatively, method C: alkylating or acylating the nitrogen atom on III-a or IV-a to obtain a hydroindole compound of formula III-b or IV-b; Among them, n, R, R 1 , R 2 has the same meaning as in claim 1; and R 3’ Selected from C1-C6 straight or branched alkyl, benzyl, -CO-R a 、-SO2R b ; R a R is selected from unsubstituted or halogen-substituted C1-4 alkyl, unsubstituted or substituted phenyl, C1-C4 alkoxy; b Selected from unsubstituted or substituted phenyl groups; the substituent on the phenyl group is halogen, C1-C6 straight chain or branched alkyl.

7. The method according to claim 6, characterized in that The molar ratio of the p-quinoneamine of formula I to the nitroalkene of formula II is 1.0:(1.2-3.0); The reaction is carried out in an organic solvent; the organic solvent is any one or more of dichloromethane, toluene, methanol, acetonitrile, tetrahydrofuran, benzene, carbon tetrachloride, acetone, N,N-dimethylformamide and ethyl acetate; the amount of the organic solvent added is 1 to 10 mL / mmol based on the amount of the p-quinoneamine substance shown in Formula I; The catalyst described in method B includes any one or more of triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triphenylphosphine, 1,4-diazabicyclo[2.2.2]octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,8-diazabicyclo(5,4,0)undec-7-ene, potassium tert-butoxide, potassium carbonate, cesium carbonate and sodium carbonate; the molar ratio of the p-quinoneamine to the catalyst shown in method B is 1:(0.05-1); The reaction temperature of method A is 25°C to 80°C and the reaction time is 24 to 72 hours, the reaction temperature of method B is 25°C to 80°C and the reaction time is 6 to 24 hours, and the reaction temperature of method C is 0°C to 100°C and the reaction time is 0.5 to 12 hours; The reaction environment used in method C includes: a) formaldehyde, zinc chloride, sodium cyanoborohydride, methanol; or b) chloroacetyl chloride, sodium bicarbonate, dichloromethane; or c) di-tert-butyl dicarbonate, 1,4-dioxane; or d) benzoyl chloride, triethylamine, 4-dimethylaminopyridine, dichloromethane.

8. An anti-inflammatory drug, characterized in that: It contains the hydroindole compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

9. Use of the hydroindole compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating diseases associated with inflammation.

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