5-amino substituted indole compounds, processes for their preparation and use in anti-acetylcholinesterase drugs

Abstract

The present application relates to the technical field of biological medicine, and discloses a 5-amino-substituted indole compound, a preparation method thereof and application thereof in anti-acetylcholinesterase drugs. The 5-amino-substituted indole compound is prepared from a 4-iodo-substituted indole raw material through a palladium-catalyzed Catellani reaction. The reaction yield can reach medium to excellent, the chemical selectivity and the regioselectivity of the reaction are excellent, the reaction condition is mild, the applicable range of the substrate is wide, the operation is simple, the cost is low, the side reaction is less, the product purity is high, the product is easy to separate and purify, and the preparation is suitable for a large scale. The obtained product has a very good application prospect in the field of biological medicine, and has a good anti-acetylcholinesterase activity.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and more specifically, to 5-amino-substituted indole compounds, their preparation methods, and their application in anti-acetylcholinesterase drugs. Background Technology

[0002] Indole is an important core skeleton that is ubiquitous in many natural products and drug molecules with important physiological and pharmacological activities (Z). K.Poulíková,S.Mani,Eur.J.Med.Chem.2021,215,113231;Y.Han,W.Dong,Q.Guo,X.Li,L.Huang,Eur.J.Med.Chem.2020,203,112506;Y.Wan,Y.Li,C.Yan,M.Yan,Z.Ta ng,Eur.J.Med.Chem.2019,183,111691;PVThanikachalam,RKMaurya,V.Garg,V.Monga,Eur.J.Med.Chem.2019,180,111691;562-612;A.Kumari,RKSingh,Bioorganic Chemistry, 2019, 89, 103021; ​​N. Chadha, O. Silakari, European Journal of Medicinal Chemistry, 2017, 134, 159-184; AJ Kochanowska-Karamyan, M. T. Hamann, Chem. Rev. 2010, 110, 4489-4497; R. J. Jundberg, Indoles, Academic Press, San Diego, 1996. Among the many indole derivatives, 3,5-disubstituted indoles are a special class of structures that constitute the core components of many commercially available drugs (Y. Wu, Top Heterocycl. Chem. 2010, 26, 1-29). For example, sumatriptan, brand name Inminex, is a new type of anti-migraine drug. It is a highly selective serotonin receptor (5-HT) agonist that reverses intracranial vasodilation during migraines, reduces plasma protein extravasation, thereby improving cerebral blood flow and relieving migraine symptoms. It exerts its analgesic effect by constricting cerebral blood vessels and inhibiting the transmission of nerve pain signals in peripheral nerves and the second-order neurons of the trigeminal cervical complex. It is used to treat acute migraine attacks (with or without aura symptoms). Oral administration is faster than ergotamine caffeine, with an efficacy rate of up to 66%; it can also be used to treat cluster headaches, with an efficacy rate of 74%–77% within 15–30 minutes. Amotriptan, also a selective serotonin receptor agonist, works by constricting blood vessels in the brain, preventing pain signals from being sent to the brain, and stopping the release of certain natural substances that cause pain, nausea, and migraine symptoms, but it does not prevent migraine attacks. Zolmitriptan is very effective in treating true menstrual migraines, and patients tolerate it well. Naratriptan exhibits similar in vitro pharmacological effects to sumatriptan, but with greater potency.Verazorone is a selective serotonin reuptake inhibitor and a partial agonist of the 5-HT1A receptor, developed by Trovis Pharmaceuticals LLC in the United States. It is primarily used to treat moderate-to-severe depression in adults. Zafirlukast is an oral leukotriene receptor antagonist (LTRA) used for maintenance therapy of asthma, usually in combination with inhaled steroids and / or long-acting bronchodilators. It blocks the action of cysteine ​​leukotrienes on CysLT1 receptors, thereby reducing airway constriction, pulmonary mucus buildup, and respiratory inflammation. It is an orally effective serotonin receptor 4 (HTR4; 5-HT4R) agonist and a 5-HT2B receptor antagonist. Tegaserod, also known as Zemarco, has pKis values ​​of 7.5, 8.4, and 7.0 for recombinant human 5-HT2A, 5-HT2B, and 5-HT2C receptors, respectively. It stimulates gastrointestinal motility and secretion by activating gastrointestinal 5-HT4 receptors and is used for short-term symptom relief in women with constipation-predominant irritable bowel syndrome (IBS-C). It also possesses antitumor activity, effectively attenuating PI3K / Akt / mTOR signaling and reducing S6 phosphorylation, leading to tumor cell apoptosis.

[0003] Given the major pharmaceutical applications of 3,5-disubstituted indoles, organic synthetic chemists and pharmaceutical chemists have devoted considerable time and effort to seeking simple and efficient synthetic methods. There are generally two approaches to constructing 3,5-disubstituted indoles: one involves selecting suitable starting materials and introducing desired substituents during indole ring construction, but the influence of these substituents often leads to reduced cyclization efficiency and selectivity; the other involves direct functionalization of C-H bonds for later modification, selectively introducing desired functional groups at specific positions. Thanks to advancements in C-H bond activation over the past two decades, pre-activation of the reaction substrate is no longer required, offering advantages such as high selectivity and efficiency. The C-H activation strategy significantly improves the atom economy and step economy of the reaction, greatly enhancing its practical application in organic synthesis and medicinal chemistry (PHDixneuf, H. Doucet (Eds.), C–H Bond Activation and Catalytic Functionalization, Topics in Current Chemistry, Springer, Heidelberg, Germany, 2016; JQYu, ZJShi (Eds.), C–H Activation, Topics in Current Chemistry, Springer, Heidelberg, Germany, 2010). A well-established system has been developed, enabling selective functionalization at positions 2 and 7 via an indole 1-position directing group, and selective functionalization at positions 2 and 4 via an indole 1-position directing group. The indole 3-position exhibits high reactivity due to its electronegativity, facilitating derivatization reactions. In contrast, there is a lack of systematic and mature derivatization strategies for indole at the 5 and 6 positions (J. Wen, Z. Shi, Acc. Chem. Res. 2021, 54, 1723-1736; B. Prabagar, Youqing Yang, Z. Shi, Chem. Soc. Rev. 2021, 50, 11249-11269; J. A. Leitch, Y. Bhonoah, C. G. Frost, ACS Catal. 2017, 7, 5618-5627). Only a few examples have achieved the selective functionalization of indole at the 5-position. For instance, Professor Shuming Li's research group at the University of Marburg, Germany, used enzyme catalysis to achieve the 5-position benzylation of L-tryptophan and its analogues (M. Liebhold, S. Li, Org. Lett. 2013, 15, 5834-5837); and Professor Zhuangzhi Shi's research group at Nanjing University used a copper catalytic system assisted by a sterically hindered ketone at the 4-position to achieve the 5-position arylation of indole-3-one substrates (Y. Yang, P. Gao, Y. Zhao, Z. Shi, Angew. Chem. Int. Ed. 2017, 56, 3966-3971).Another indirect approach is to first hydrogenate indole to indoline, then functionalize it using the electron-rich para-position of aniline, and finally re-oxidize and aromatize it back to the indole structure. However, these reactions are limited to the formation of carbon-carbon bonds, and there are no reports on the formation of carbon-nitrogen bonds. Furthermore, the redundant redox steps, low atom economy, and limitations imposed by the electrophilic nature undoubtedly hinder the practicality of this method. Therefore, there is an urgent need to develop new methods for the selective modification of the 5-position of the indole ring to efficiently synthesize 5-amino-substituted indole compounds.

[0004] The inventors of this application have long been engaged in the research of indole heterocyclic chemistry and have previously developed several efficient methods for constructing indole heterocycles. For example, the inventors of this application developed a copper-catalyzed one-pot method for synthesizing 2-carboxylic acid ester-substituted indole compounds from o-bromobenzaldehyde and glycine ester hydrochloride, obtaining moderate to excellent yields under mild reaction conditions (Z. Zhu, J. Yuan, Y. Zhou, Q. Yang, J. Xu, Y. Peng, Eur. J. Org. Chem. 2014, 511-514); starting from acetanilide and trifluoromethyl-substituted phenylacetylene, trifluoromethyl-substituted indole compounds can be efficiently prepared through a rhodium-catalyzed one-step hydrocarbon-activated oxidative cyclization (Y. Zhou, C. Zhang, J. Yuan, Q. Yang, Q. Xiao, Y. Peng, Tetrahedron Lett. 2016, 57, 3222-3225). In addition, the inventors of this application also adopted a temporary directing group strategy to achieve the halogenation reaction at the 4-position of indole through palladium catalysis, which can successfully introduce three halogen atoms, namely chlorine, bromine and iodine, into the indole benzene ring skeleton under unified standard conditions (G.Kuang,D.Liu,X.Chen,G.Liu,Y.Fu,Y.Peng,H.Li,Y.Zhou,Org.Lett.2021,23,8402-8406). Summary of the Invention

[0005] Building upon the previous research, the inventors of this application further utilized a palladium and norbornene co-catalytic strategy to successfully synthesize 5-amino-substituted indole compounds via a Catellani reaction of 4-iodo- or bromo-indole with amine oxide. Further bioactivity tests showed that the synthesized 5-amino-substituted indole compounds exhibited good anti-acetylcholinesterase activity, and hold promise for the development of novel anti-acetylcholinesterase drugs.

[0006] Therefore, the purpose of this invention is to provide a 5-amino-substituted indole compound, a novel method for preparing a 5-amino-substituted indole compound, and to evaluate the anti-acetylcholinesterase activity of the 5-amino-substituted indole compound through activity screening, structure-activity relationship analysis, and in-depth study of its effects and mechanisms.

[0007] One aspect of the present invention provides 5-amino-substituted indole compounds represented by Formula I or Formula II:

[0008]

[0009] in,

[0010] R 1 R 2 Independently selected from C1-C7 alkyl, phenyl, naphthyl, and benzyl groups;

[0011] R 3 Selected from aldehyde, amide, ester, hydroxymethyl, and ester methyl groups;

[0012] R 4 Selected from arylsulfonyl groups;

[0013] Ring A is selected from morpholine, thiomorpholine, piperazine, pyrrolidine, piperidine, and hexamethyleneimine;

[0014] R 5 It is selected from hydrogen, C1-C7 alkyl, aryl, aryl, benzyloxycarbonyl, alkoxycarbonyl, benzoisoxazole, benzoisothiazolyl, pyrimidinyl, and benzothiaphenyl.

[0015] Preferably, R 1 R 2 Independently selected from methyl, ethyl, phenyl, naphthyl, benzyl; R 3 Selected from formaldehyde group, N,N-diethylformamido group, ethoxycarbonyl group, hydroxymethyl group, ethyl ester methyl group; R 4 Selected from benzenesulfonyl, 4-fluorobenzenesulfonyl, 4-chlorobenzenesulfonyl, 4-bromobenzenesulfonyl, 4-tert-butylbenzenesulfonyl, 4-methoxybenzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 3-chlorobenzenesulfonyl; R 5 Selected from hydrogen, methyl, ethyl, phenyl, naphthyl, benzoyl, benzyloxycarbonyl, tert-butoxycarbonyl, ethoxycarbonylmethyl, benzoisoxazolyl, benzoisothiazolyl, pyrimidinyl, and benzothiophene.

[0016] Preferably, the 5-amino-substituted indole compound represented by Formula I or Formula II is specifically one of the following compounds:

[0017]

[0018]

[0019] Among them, TJ-1 is [5-morpholine-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0020] TJ-2 is [5-thiomorpholine-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0021] TJ-3 is [5-(4-benzoylpiperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0022] TJ-4 is [4-(3-formyl-1-toluenesulfonyl-1H-indol-5-yl)piperazine-1-carboxylic acid benzyl ester]; TJ-5 is [4-(3-formyl-1-toluenesulfonyl-1H-indol-5-yl)piperazine-1-carboxylic acid tert-butyl ester]; TJ-6 is [4-(3-formyl-1-toluenesulfonyl-1H-indol-5-yl)piperazine-1-carboxylic acid ethyl ester]; TJ-7 is [5-(pyrrolidine-1-yl)-1-toluenesulfonyl-1H-indol-3-carboxaldehyde];

[0023] TJ-8 is [5-(piperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0024] TJ-9 is [5-(hexamethyleneimine-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0025] TJ-10 is [5-(4-methylpiperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde]; TJ-11 is [5-(4-phenylpiperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde]; TJ-12 is [1-(3-formyl-1-toluenesulfonyl-1H-indole-5-yl)piperidin-4-carboxylic acid ethyl ester];

[0026] TJ-13 is [5-(1,4-dioxo-8-azaspiro[4.5]dec-8-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0027] TJ-14 is [5-(3,4-dihydroisoquinoline-2(1H)-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0028] TJ-15 is [5-(diethylamino)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0029] TJ-16 is [5-(benzyl(methyl)amino)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0030] TJ-17 is [5-(4-((bis(phenyl)methyl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde]; TJ-18 is [5-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0031] TJ-19 is [5-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde]; TJ-20 is [5-(4-(8-chloro-5H-benzo[5,6]cycloheptane[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0032] TJ-21 is [5-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde]; TJ-22 is [5-(4-(benzo[d]isothiazo-3-yl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0033] TJ-23 is [5-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0034] TJ-24 is [5-(4-(pyrimidin-2-yl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0035] TJ-25 is [5-(4-(benzothiophene-4-yl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde];

[0036] TJ-26 is [5-morpholine-1-(phenylsulfonyl)-1H-indole-3-carboxaldehyde];

[0037] TJ-27 is [1-((4-fluorophenyl)sulfonyl)-5-morpholinyl-1H-indole-3-carboxaldehyde];

[0038] TJ-28 is [1-((4-chlorophenyl)sulfonyl)-5-morpholinyl-1H-indole-3-carboxaldehyde];

[0039] TJ-29 is [1-((4-bromophenyl)sulfonyl)-5-morpholinyl-1H-indole-3-carboxaldehyde];

[0040] TJ-30 is [1-((4-(tert-butyl)phenyl)sulfonyl)-5-morpholinyl-1H-indole-3-carboxaldehyde];

[0041] TJ-31 is [1-(4-methoxyphenyl)sulfonyl)-5-morpholinyl-1H-indole-3-carboxaldehyde];

[0042] TJ-32 is [5-morpholine-1-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-indole-3-carboxaldehyde];

[0043] TJ-33 is [5-morpholine-1-((4-nitrophenyl)sulfonyl)-1H-indole-3-carboxaldehyde];

[0044] TJ-34 is [1-((3-chlorophenyl)sulfonyl)-5-morpholinyl-1H-indole-3-carboxaldehyde];

[0045] TJ-35 is [N,N-diethyl-5-morpholino-1-toluenesulfonyl-1H-indole-3-carboxamide];

[0046] TJ-36 is [5-morpholine-1-toluenesulfonyl-1H-indole-3-carboxylic acid ethyl ester];

[0047] TJ-37 is [(5-morpholino-1-toluenesulfonyl-1H-indol-3-yl)methanol];

[0048] TJ-38 is [(5-morpholino-1-toluenesulfonyl-1H-indol-3-yl)methyl acetate].

[0049] Another aspect of the present invention provides a method for preparing the 5-amino-substituted indole compound, the method comprising the following steps:

[0050] In an organic solvent, under conditions involving a catalyst, ligand, base, and additive, the 4-position halogenated indole of Formula III is reacted with the amine oxide of Formula IV or V to obtain the 5-position amino-substituted indole compound of Formula I or II.

[0051]

[0052] in,

[0053] R 1 R 2 Independently selected from C1-C7 alkyl, phenyl, naphthyl, and benzyl groups;

[0054] R 3 Selected from aldehyde, amide, ester, hydroxymethyl, and ester methyl groups;

[0055] R 4 Selected from arylsulfonyl groups;

[0056] Ring A is selected from morpholine, thiomorpholine, piperazine, pyrrolidine, piperidine, and hexamethyleneimine;

[0057] R 5 Selected from hydrogen, C1-C7 alkyl, aryl, aryl, benzyloxycarbonyl, alkoxycarbonyl, benzoisoxazolyl, benzoisothiazolyl, pyrimidinyl, and benzothiaphenyl;

[0058] X is a halogen.

[0059] In the above method, the molar ratio of the 4-position haloindole represented by Formula III to the amine oxide represented by Formula V can be 1:1.2.

[0060] In the above method, the organic solvent can be toluene or dioxane.

[0061] In the above method, the catalyst can be palladium acetate or palladium chloride.

[0062] In the above method, the ligands can be triarylphosphine and norbornene.

[0063] In the above method, the alkali can be cesium carbonate or potassium carbonate.

[0064] In the above method, the additive can be p-trifluoromethylbenzyl alcohol.

[0065] In the above method, the reaction temperature can be 80–100℃.

[0066] In the above method, the reaction time can be 24 hours.

[0067] A third aspect of the invention provides the use of the 5-amino-substituted indole compound in anti-acetylcholinesterase drugs. The 5-amino-substituted indole compound possesses anti-acetylcholinesterase activity and can be used to prepare anti-acetylcholinesterase drugs.

[0068] Compared with the prior art, the advantages of the present invention include:

[0069] Firstly, this invention is the first to prepare an amino-substituted indole compound at the 5-position, successfully introducing an amino group selectively into the 5-position of indole.

[0070] Secondly, the preparation method of the present invention does not require pre-activation of the substrate, but directly involves the Catellani reaction; the reaction yield can reach good to excellent, the chemoselectivity and regioselectivity of the reaction are very high, no side reactions occur at other sites, the reaction conditions are mild, the substrate range is wide, the functional group compatibility is good, the operation is simple, the cost is low, there are few by-products, the product purity is high, it is easy to separate and purify, and it is suitable for large-scale preparation.

[0071] Third, the 5-amino-substituted indole compound of the present invention has potential biological and pharmaceutical activities, especially good anti-acetylcholinesterase activity, and therefore can be applied in the biomedical field, especially in the field of anti-acetylcholinesterase drugs, which has very good application prospects. Attached Figure Description

[0072] Figure 1 X-ray single-crystal diffraction structure of 5-morpholine-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-1.

[0073] Figure 2The molecular structure diagram of the compound corresponding to the single crystal structure of 5-morpholine-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-1.

[0074] Figure 3 The bar chart shows the inhibition rate of acetylcholinesterase activity by compounds TJ-1 to TJ-38. Detailed Implementation

[0075] To better understand the above-described objects, features, and advantages of the present invention, the invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. Many specific details are set forth in the following description to provide a thorough understanding of the invention; however, the invention may be practiced in other ways different from those described herein, and therefore, the invention is not limited to the specific embodiments disclosed below.

[0076] Some embodiments of the present invention provide a method for preparing 5-amino-substituted indole compounds, using 4-iodoindole as a reaction substrate, which reacts with amine oxide under palladium catalysis to undergo a Catellani reaction to prepare 5-amino-substituted indole compounds; and the structure is identified to confirm that it is the desired target product.

[0077]

[0078] The specific steps for preparing the 5-amino-substituted indole compound are as follows: 4-iodoindole, amine oxide, palladium acetate catalyst, tris(3-chlorophenyl)phosphine ligand, norbornene, cesium carbonate, and p-trifluoromethylbenzyl alcohol are added sequentially to a reaction tube. Finally, toluene solvent is added, and the reaction tube is sealed with a rubber stopper. The tube is then placed in an oil bath at 80–100°C and heated with stirring for 24 hours. The reaction is monitored by TLC until complete. For post-processing, the solvent is first evaporated, and the product (the compound shown in Formula I or Formula II) is directly separated by silica gel column chromatography.

[0079] Some embodiments of the present invention provide experimental data on the inhibitory activity of 5-amino-substituted indole compounds on acetylcholinesterase (AChE).

[0080] Example 1

[0081] 4-Iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde (0.2 mmol), morpholinobenzoate (0.24 mmol), palladium acetate catalyst (5 mol%), tris(3-chlorophenyl)phosphine ligand (25 mol%), norbornene (0.2 mmol), cesium carbonate alkali (0.4 mmol), and p-trifluoromethylbenzyl alcohol additive (0.24 mmol) were added sequentially to a reaction tube. Finally, toluene solvent (4 mL) was added, and the reaction tube was sealed with a rubber stopper. The tube was placed in an oil bath at 100 °C and heated with stirring for approximately 24 hours. The reaction was monitored by TLC until complete. For post-processing, the solvent was first evaporated to dryness, and the purified product 5-morpholino-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-1 was obtained by direct silica gel column chromatography.

[0082]

[0083] 5-morpholine-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-1, yield: 86%; yellow solid; melting point 126-128℃; 1 HNMR (400MHz, CDCl3) δ10.04 (s, 1H), 8.14 (s, 1H), 7.84-7.81 (m, 3H), 7.71 (d, J = 2.4Hz, 1H), 7.27 (d,J=8.8Hz,2H),7.05(dd,J=9.2,2.4Hz,1H),3.89–3.81(m,4H),3.29–3.08(m,4H),2.36(s,3H); 13 C NMR (100MHz, CDCl3) δ185.7,149.8,146.2,136.91,134.7,130.5,129.9,127.6, 127.3,122.5,116.8,114.0,108.2,67.1,50.4,21.9; HRMS(pos.ESI):m / z[M+Na] + for C 20 H 20 N2O4NaS calcd:407.1036,found:407.1037.

[0084] By changing only the corresponding reactants, Examples 2 to 38 were obtained using essentially the same method as Example 1.

[0085] Example 2

[0086] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and thiomorpholine benzoate, and the product is 5-thiomorpholine-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-2.

[0087]

[0088] 5-Thiomorpholine-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-2, yield: 65%; yellow solid; melting point 154-156℃; 1 H NMR (400MHz, CDCl3) δ10.03(s,1H),8.14(s,1H),7.81(m,3H),7.71(d,J=2.4Hz,1H),7.28(d, J=8.4Hz,2H),7.02(dd,J=9.2,2.4Hz,1H),3.60-3.42(m,4H),2.91-2.66(m,4H),2.37(s,3H); 13 C NMR (100MHz, CDCl3) δ186.0,150.4,146.5,137.2,135.0,130.8,130.1,127.9,1 27.7,122.8,118.75,114.4,110.1,53.5,27.6,22.2; HRMS(pos.ESI):m / z[M+Na] + for C 20 H 20 N2O3NaS2calcd:423.0808,found:423.0803.

[0089] Example 3

[0090] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-benzoylpiperazine-1-ylbenzoate, and the product is 5-(4-benzoylpiperazine-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-3.

[0091]

[0092] 5-(4-benzoylpiperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-3, yield: 61%; yellow solid; melting point 93-95℃; 1 H NMR (400MHz, CDCl3) δ10.03(s,1H),8.15(s,1H),7.89-7.78(m,3H),7.74(d,J=2.4Hz,1H),7.47-7.36(m,5 H),7.28(d,J=8.4Hz,2H),7.07(dd,J=9.2,2.4Hz,1H),4.05-3.56(m,4H),3.30-3.05(m,4H),2.36(s,3H); 13C NMR (100MHz, CDCl3) δ185.7,170.6,149.5,146.3,136.9,135.7,134.6,130.5,130.2,130.1,1 28.7,127.5,127.3,127.3,122.4,118.0,114.1,109.3,50.8,21.8; HRMS(pos.ESI):m / z[M+Na] + forC 27 H 25 N3O4NaS calcd:510.1458,found:510.1462.

[0093] Example 4

[0094] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-(benzoyloxy)piperazine-1-carboxylic acid benzyl ester, and the product is 4-(3-formyl-1-toluenesulfonyl-1H-indole-5-yl)piperazine-1-carboxylic acid benzyl ester TJ-4.

[0095]

[0096] 4-(3-formyl-1-toluenesulfonyl-1H-indol-5-yl)piperazine-1-carboxylic acid benzyl ester TJ-4, yield: 63%; yellow solid; melting point 78-79℃; 1 H NMR (400MHz, CDCl3) δ9.93 (s, 1H), 8.04 (s, 1H), 7.78-7.67 (m, 3H), 7.63 (d, J = 1.2Hz, 1H), 7.31-7.24 (m, 3H) ,7.24-7.12(m,4H),6.96(d,J=8.4Hz,1H),5.05(s,2H),3.62-3.42(m,4H),3.20-2.87(m,4H),2.26(s,3H); 13 C NMR (100MHz, CDCl3) δ185.3,155.1,146.0,136.6,136.5,134.3,130.2,129.9,128.4,128.0,127 .8,127.3,127.0,122.1,117.7,113.8,109.1,67.2,50.2,43.6,21.5; HRMS(pos.ESI):m / z[M+Na] + forC 28 H 27 N3O5NaS calcd:540.1564,found:540.1564.

[0097] Example 5

[0098] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-(benzoyloxy)piperazine-1-carboxylic acid tert-butyl ester, and the product is 4-(3-formyl-1-toluenesulfonyl-1H-indole-5-yl)piperazine-1-carboxylic acid tert-butyl ester TJ-5.

[0099]

[0100] 4-(3-formyl-1-toluenesulfonyl-1H-indol-5-yl)piperazine-1-carboxylic acid tert-butyl ester TJ-5, yield: 61%; yellow solid; melting point 176-177℃; 1 H NMR (400MHz, CDCl3) δ10.01(s,1H),8.11(s,1H),7.79(d,J=8.4Hz,3H),7.70(d,J=1.6Hz,1H),7.25(d,J= 8.4Hz,2H),7.04(dd,J=8.8,0.8Hz,1H),3.74-3.37(m,4H),3.31-2.93(m,4H),2.34(s,3H),1.45(s,9H); 13 C NMR (100MHz, CDCl3) δ185.7,154.9,149.8,146.2,136.9,134.7,130.5,123.0,127.6,127 .3,122.5,117.9,114.0,109.1,80.1,50.5,44.0,28.6,21.9; HRMS(pos.ESI):m / z[M+Na] + forC 25 H 29 N3O5NaScalcd:506.1720,found:506.1728.

[0101] Example 6

[0102] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and ethyl 4-(benzoyloxy)piperazine-1-carboxylate, and the product is ethyl 4-(3-formyl-1-toluenesulfonyl-1H-indole-5-yl)piperazine-1-carboxylate TJ-6.

[0103]

[0104] 4-(3-formyl-1-toluenesulfonyl-1H-indol-5-yl)piperazine-1-carboxylic acid ethyl ester TJ-6, yield: 62%; yellow solid; melting point 119-120℃; 1H NMR (400MHz, CDCl3) δ10.01(s,1H),8.12(s,1H),7.85-7.75(m,3H),7.71(d,J=2.4Hz,1H),7.25(d,J=8.4Hz,2H),7.04( dd,J=9.2,2.0Hz,1H),4.14(q,J=7.2Hz,2H),3.82-3.46(m,4H),3.30-3.02(m,4H),2.34(s,3H),1.25(t,J=7.1Hz,3H); 13 C NMR (100MHz, CDCl3) δ185.7,155.7,149.7,146.2,136.9,134.6,130.5,130.1,127.6,127 .3,122.5,117.9,114.0,109.3,61.7,50.4,43.9,21.8,14.9; HRMS(pos.ESI):m / z[M+Na] + for C 23 H 25 N3O5NaS calcd:477.1407,found:477.1399.

[0105] Example 7

[0106] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and pyrrolidine-1-ylbenzoate, and the product is 5-(pyrrolidine-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-7.

[0107]

[0108] 5-(pyrrolidone-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-7, yield: 40%; yellow solid; melting point 158-160℃; 1 H NMR (400MHz, CDCl3) δ10.03(s,1H),8.08(s,1H),7.80(d,J=8.4Hz,2H),7.76(d,J=9.2Hz,1H),7.29(d,J=2.4H z,1H),7.25(d,J=8.0Hz,2H),6.68(dd,J=9.2,2.4Hz,1H),3.51-3.01(m,4H),2.35(s,3H),2.07-1.94(m,4H); 13C NMR (100MHz, CDCl3) δ185.8,146.5,145.9,136.7,134.9,130.34,128.0,127.3, 127.2,122.6,114.0,112.3,102.9,48.3,25.7,21.8; HRMS(pos.ESI):m / z[M+Na] + for C 20 H 20 N2O3NaScalcd:391.1087,found:391.1083.

[0109] Example 8

[0110] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and piperidine-1-ylbenzoate, and the product is 5-(piperidine-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-8.

[0111]

[0112] 5-(piperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-8, yield: 75%; yellow solid; melting point 147-149℃; 1 H NMR (400MHz, CDCl3) δ10.02 (s, 1H), 8.10 (s, 1H), 7.87-7.74 (m, 3H), 7.70 (d, J = 2.4Hz, 1H), 7.32-7.17 (m,2H),7.07(dd,J=9.2,2.4Hz,1H),3.30-2.91(m,4H),2.34(s,3H),1.80-1.63(m,4H),1.55(m,2H); 13 C NMR (100MHz, CDCl3) δ185.7,150.9,146.1,136.7,134.7,130.4,129.4,127.6,127 .3,122.6,118.1,113.8,108.6,51.8,26.1,24.4,21.8; HRMS(pos.ESI):m / z[M+Na] + for C 21 H 22 N2O3NaScalcd:405.1243,found:405.1237.

[0113] Example 9

[0114] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and benzoic acid nitric acid-1-ester, and the product is 5-(hexamethyleneimine-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-9.

[0115]

[0116] 5-(hexamethyleneimine-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-9, yield: 52%; yellow solid; melting point 170-172℃; 1 H NMR (400MHz, CDCl3) δ10.01(s,1H),8.05(s,1H),7.80(d,J=8.4Hz,2H),7.72(d,J=9.2Hz,1H),7.43(d,J=2.4Hz,1H), 7.30-7.18(m,2H),6.79(dd,J=9.2,2.4Hz,1H),3.71-3.13(m,4H),2.34(s,3H),1.96-1.64(m,4H),1.60-1.36(m,4H); 13 CNMR (100MHz, CDCl3) δ185.8,147.6,145.9,136.6,134.9,130.4,128.2,127.3,127 .1,122.6,114.0,111.9,102.7,49.8,27.9,27.3,21.8; HRMS(pos.ESI):m / z[M+Na] + forC 22 H 24 N2O3NaScalcd:419.1400,found:419.1403.

[0117] Example 10

[0118] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-methylpiperidin-1-ylbenzoate, and the product is 5-(4-methylpiperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-10.

[0119]

[0120] 5-(4-methylpiperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-10, yield: 76%; yellow solid; melting point 130-132℃; 1H NMR (400MHz, CDCl3) δ10.02(s,1H),8.10(s,1H),7.85-7.74(m,3H),7.71(d,J=2.4Hz,1H),7.31-7.16(m,2H),7.08(d,J=8.4Hz,1H),3.6 3(d,J=12.4Hz,2H),2.77-2.59(m,2H),2.35(s,3H),1.73(d,J=13.2Hz,2H),1.56-1.43(m,1H),1.42-1.29(m,2H),0.96(d,J=6.4Hz,3H); 13 C NMR (100MHz, CDCl3) δ185.4,150.2,145.8,136.4,134.4,130.1,129.2,127.3,127.0, 122.3,117.8,113.5,108.4,50.8,34.0,30.5,21.7,21.5; HRMS(pos.ESI):m / z[M+Na] + for C 22 H 24 N2O3NaScalcd:419.1400,found:419.1396.

[0121] Example 11

[0122] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-phenylpiperidin-1-ylbenzoate, and the product is 5-(4-phenylpiperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-11.

[0123]

[0124] 5-(4-Phenylopiridin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-11, yield: 71%; yellow solid; melting point 163-164℃; 1 H NMR (400MHz, CDCl3) δ10.04(s,1H),8.13(s,1H),7.88-7.79(m,3H),7.77(d,J=2.0Hz,1H),7.38-7.17(m,7H),7.1 3(dd,J=9.2,2.4Hz,1H),3.99-3.55(m,2H),2.94-2.74(m,2H),2.72-2.55(m,1H),2.36(s,3H),2.10-1.78(m,4H); 13C NMR (100MHz, CDCl3) δ185.7,150.4,146.2,146.1,136.8,134.7,130.4,129.6,128.7,127.6,127 .4,127.0,126.5,122.6,118.1,113.9,108.8,51.6,42.6,33.6,21.8; HRMS(pos.ESI):m / z[M+Na] + for C 27 H 26 N2O3NaS calcd:481.1556,found:481.1549.

[0125] Example 12

[0126] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and ethyl 1-(benzoyloxy)piperidine-4-carboxylate, and the product is ethyl 1-(3-formyl-1-toluenesulfonyl-1H-indole-5-yl)piperidine-4-carboxylate TJ-12.

[0127]

[0128] 1-(3-formyl-1-toluenesulfonyl-1H-indol-5-yl)piperidine-4-carboxylic acid ethyl ester TJ-12, yield: 65%; yellow solid; melting point 110-112℃; 1 H NMR (400MHz, CDCl3) δ10.03(s,1H),8.13(s,1H),7.91-7.74(m,3H),7.72(d,J=2.0Hz,1H),7.27(d,J=7.6Hz,2H),7.07(dd,J=9.2,2.4Hz,1H),4.15( q,J=7.2Hz,2H),3.70-3.59(m,2H),2.91-2.66(m,2H),2.46-2.39(m,1H), 2.36(s,3H),2.08-1.97(m,2H),1.94-1.77(m,2H),1.26(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ185.7,175.0,150.2,146.1,136.8,134.7,130.4,129.6,127.6,127.3 ,122.6,118.1,113.9,108.9,60.6,50.3,41.1,28.3,21.8,14.4; HRMS(pos.ESI):m / z[M+Na] + forC 24 H 26N2O5NaScalcd:477.1455,found:477.1459.

[0129] Example 13

[0130] The reactants were 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 1,4-dioxo-8-azaspiro[4.5]dec-8-ylbenzoate, and the product was 5-(1,4-dioxo-8-azaspiro[4.5]dec-8-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-13.

[0131]

[0132] 5-(1,4-dioxo-8-azaspiro[4.5]dec-8-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-13, yield: 84%; yellow solid; melting point 156-158℃; 1 H NMR (400MHz, CDCl3) δ10.03(s,1H),8.11(s,1H),7.86-7.76(m,3H),7.74(d,J=2.0Hz,1H),7.27(d,J=8 .8Hz,2H),7.07(dd,J=9.2,2.4Hz,1H),3.98(s,4H),3.44-3.22(m,4H),2.37(s,3H),1.93-1.79(m,4H); 13 C NMR (100MHz, CDCl3) δ186.0,149.9,146.5,137.1,135.0,130.8,129.8,127.9,127.7, 122.9,118.1,114.2,109.3,107.6,64.9,49.1,35.1,22.2; HRMS(pos.ESI):m / z[M+Na] + forC 23 H 24 N2O5NaScalcd:463.1298,found:463.1304.

[0133] Example 14

[0134] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 3,4-dihydroisoquinoline-2(1H)-benzoate, and the product is 5-(3,4-dihydroisoquinoline-2(1H)-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-14.

[0135]

[0136] 5-(3,4-dihydroisoquinoline-2(1H)-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-14, yield: 70%; yellow solid; melting point 161-163℃; 1 H NMR (400MHz, CDCl3) δ10.14(s,1H),8.21(s,1H),8.04-7.75(m,4H),7.53-7 .03(m,7H),4.50(s,2H),3.79-3.53(m,2H),3.25-2.90(m,2H),2.45(s,3H); 13 C NMR (100MHz, CDCl3) δ185.8,149.2,146.1,136.9,134.9,134.7,134.5,130.5,129.1,128.7,127.8,127 .3,126.8,126.6,126.3,122.6,116.3,114.0,107.2,51.6,47.6,29.5,21.9; HRMS(pos.ESI):m / z[M+Na] + for C 25 H 22 N2O3NaScalcd:453.1243,found:453.1248.

[0137] Example 15

[0138] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and O-benzoyl-N,N-diethylhydroxylamine, and the product is 5-(diethylamino)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-15.

[0139]

[0140] 5-(diethylamino)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-15, yield: 35%; yellow solid; melting point 124-126℃; 1 H NMR (400MHz, CDCl3) δ10.01(s,1H),8.05(s,1H),7.80(d,J=8.4Hz,2H),7.72(d,J=9.2Hz,1H),7.45(d,J=2.0Hz,1 H),7.25(d,J=8.4Hz,2H),6.80(dd,J=9.2,2.0Hz,1H),3.36(q,J=7.2Hz,4H),2.35(s,3H),1.14(t,J=7.2Hz,6H); 13C NMR (100MHz, CDCl3) δ186.1,146.9,146.2,136.9,135.2,130.7,128.5,127.7,1 22.9,114.4,113.4,104.2,100.5,45.4,22.2,13.0; HRMS(pos.ESI):m / z[M+Na] + for C 20 H 22 N2O3NaScalcd:393.1243,found:393.1237.

[0141] Example 16

[0142] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and O-benzoyl-N-benzyl-N-methylhydroxylamine, and the product is 5-(benzyl(methyl)amino)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-16.

[0143]

[0144] 5-(benzyl(methyl)amino)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-16, yield: 53%; yellow solid; melting point 119-121℃; 1 H NMR (400MHz, CDCl3) δ10.03(s,1H),8.10(s,1H),7.88-7.77(m,2H),7.74(d,J=9.2Hz,1H),7.58(d,J =2.4Hz,1H),7.36-7.17(m,7H),6.87(dd,J=9.2,2.6Hz,1H),4.56(s,2H),3.05(s,3H),2.37(s,3H); 13 C NMR (100MHz, CDCl3) δ185.7,148.4,146.0,138.9,136.6,134.8,130.4,128.8,127.9,127.9,1 27.3,127.2,127.1,122.5,114.0,113.5,104.2,57.4,39.3,21.8; HRMS(pos.ESI):m / z[M+Na] + for C 24 H 22 N2O3NaScalcd:441.1243,found:441.1239.

[0145] Example 17

[0146] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-((bisphenyl)methyl)piperazin-1-ylbenzoate, and the product is 5-(4-((bisphenyl)methyl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-17.

[0147]

[0148] 5-(4-((bisphenyl)methyl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-17, yield: 56%; yellow solid; melting point 171-173℃; 1 H NMR (400MHz, CDCl3) δ10.00(s,1H),8.09(s,1H),7.85-7.73(m,3H),7.67(d,J=2.0Hz,1H),7.46-7.38(m,4H),7.30-7.21 (m,6H),7.20-7.13(m,2H),7.01(dd,J=9.2,2.4Hz,1H),4.25(s,1H),3.27-3.11(m,4H),2.59-2.46(m,4H),2.34(s,3H); 13 C NMR (100MHz, CDCl3) δ185.7,149.9,146.1,142.8,136.7,134.7,130.4,129.6,128.8,128.1,127 .6,127.3,127.2,122.6,117.2,113.9,108.2,76.3,52.1,50.3,21.8; HRMS(pos.ESI):m / z[M+H] + for C 33 H 32 N3O3Scalcd:550.2159,found:550.2157.

[0149] Example 18

[0150] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-(bis(4-fluorophenyl)methyl)piperazin-1-ylbenzoate, and the product is 5-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-18.

[0151]

[0152] 5-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-18, yield: 53%; yellow solid; melting point 210-213℃; 1 H NMR (400MHz, CDCl3) δ10.03(s,1H),8.12(s,1H),7.89-7.74(m,3H),7.70(d,J=2.4Hz,1H),7.44-7.32(m,4 H),7.31-7.23(m,2H),7.09-6.91(m,5H),4.27(s,1H),3.26-3.10(m,4H),2.58-2.43(m,4H),2.36(s,3H); 13 C NMR(100MHz,CDCl3)δ185.67,162.1(d,J C-F =244.1Hz),149.79,146.15,138.3(d,J C-F =2.9Hz),136.78,134.71,130.43,129.66,129.5(d,J C-F =7.8Hz),127.59,127.33,122.58,117.19,115.7(d,J C-F =21.1Hz),113.90,108.27,74.60,51.94,50.30,21.83; 19 F NMR(565MHz, CDCl3)δ-115.51; HRMS(pos.ESI):m / z[M+H] + for C 33 H 30 F2N3O3Scalcd:589.1970,found:589.1966.

[0153] Example 19

[0154] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-(bis(4-fluorophenyl)methyl)piperazin-1-ylbenzoate, and the product is 5-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-19.

[0155]

[0156] 5-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-19, yield: 72%; yellow solid; melting point 126-128℃; 1HNMR (400MHz, CDCl3) δ10.02(s,1H),8.42(d,J=3.6Hz,1H),8.11(s,1H),7.81(m,3H),7.69(d,J=2.0Hz,1H),7.45(d,J=6.8Hz,1H),7.33-7 .22(m,2H),7.21-7.01(m,5H),3.59-.46(m,2H),3.45-3.30(m,2H),3 .01-2.89(m,2H),2.89-2.74(m,2H),2.72-2.42(m,4H),2.36(s,3H); 13 C NMR (100MHz, CDCl3) δ185.4,157.1,149.5,146.5,145.8,139.4,138.1,137.6,137.4,136.4,134.4,133.4,133.1,132.7,130.6,130.1,12 9.3,128.9,127.3,127.0,126.0,122.3,122.2,117.7,113.6,108.5,51.8,51.6,31.7,31.4,30.7,30.5,21.5; HRMS(pos.ESI):m / z[M+Na] + for C 35 H 30 ClN3O3NaScalcd:630.1589,found:630.1584.

[0157] Example 20

[0158] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-ylbenzoate, and the product is 5-(4-(8-chloro-5H-benzo[5,6]cycloheptane[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-20.

[0159]

[0160] 5-(4-(8-chloro-5H-benzo[5,6]cycloheptane[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-20, yield: 60%; yellow solid; melting point 160-162℃; 1HNMR (400MHz, CDCl3) δ10.02 (s, 1H), 8.11 (s, 1H), 7.88-7.73 (m, 3H), 7.69 (d, J = 2.0Hz, 1H), 7.44-7.33 (m, 4H), 7.34-7.16(m,7H),7.03(dd,J=9.2,2.4Hz,1H),4.25(s,1H),3.26-3.12(m,4H),2.62-2.46(m,4H),2.35(s,3H); 13 C NMR (100MHz, CDCl3) δ185.7,149.8,146.1,142.2,141.4,136.8,134.7,132.9,130.4,129.6,129.4,128.9,128 .9,128.0,127.6,127.5,127.3,122.6,117.2,113.9,108.3,75.6,52.0,50.3,21.8; HRMS(pos.ESI):m / z[M+Na] + forC 33 H 30 ClN3O3NaScalcd:606.1589,found:606.1588.

[0161] Example 21

[0162] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-(6-fluorobenzo[d]isoxazole-3-yl)piperidin-1-ylbenzoate, and the product is 5-(4-(6-fluorobenzo[d]isoxazole-3-yl)piperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-21.

[0163]

[0164] 5-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-21, yield: 70%; yellow solid; melting point 136-138℃; 1H NMR (400MHz, CDCl3) δ10.02(s,1H),8.11(s,1H),7.80(d,J=8.4Hz,3H),7.76(d,J=2.0Hz,1H),7.66(dd,J=8.4,5.2Hz,1H),7.32-7.17(m,3H),7. 10(dd,J=9.2,2.0Hz,1H),7.03(td,J=8.8,1.6Hz,1H),3.91-3.63(m,2H ),3.33-3.09(m,1H),3.00-2.83(m,2H),2.34(s,3H),2.23-2.08(m,4H); 13 C NMR(100MHz,CDCl3)δ186.05,164.7(d,J C-F =249.2Hz), 164.4(d,J C-F =13.4Hz),161.34,150.42,146.51,137.17,135.01,130.78,130.10,127.92,127.66,123.0(d,J C-F =11.1Hz),122.88,118.53,117.9(d,J C-F =0.9Hz), 114.28, 113.0 (d, J) C-F =25.2Hz), 109.41, 98.0(d,J) C-F =26.6Hz),51.26,34.82,30.92,22.16; 19 F NMR(565MHz, CDCl3)δ-109.41; HRMS(pos.ESI):m / z[M+Na] + for C 28 H 24 FN3O4NaS calcd:540.1364,found:540.1364.

[0165] Example 22

[0166] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-(benzo[d]isothiazo-3-yl)piperazin-1-ylbenzoate, and the product is 5-(4-(benzo[d]isothiazo-3-yl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-22.

[0167]

[0168] 5-(4-(benzo[d]isothiazo-3-yl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-22, yield: 80%; yellow solid; melting point 103-105℃; 1 HNMR (400MHz, CDCl3) δ10.06 (s, 1H), 8.15 (s, 1H), 7.95 (d, J = 8.0Hz, 1H), 7.89-7.76 (m, 5H), 7.48 (t, J = 7.6Hz, 1H), 7.38 (t,J=7.6Hz,1H),7.28(d,J=8.4Hz,2H),7.15(dd,J=9.2,2.0Hz,1H),3.81-3.58(m,4H),3.55-3.33(m,4H),2.37(s,3H); 13 CNMR (100MHz, CDCl3) δ185.7,164.0,153.0,149.8,146.2,136.9,134.7,130.5,129.9,128.2,127.9,127 .6,127.3,124.2,124.0,122.6,120.8,117.6,114.0,108.7,50.3,50.2,21.8; HRMS(pos.ESI):m / z[M+Na] + for C 27 H 24 N4O3NaS2calcd:539.1182,found:539.1179.

[0169] Example 23

[0170] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-(4-chlorophenyl)-4-hydroxypiperidin-1-ylbenzoate, and the product is 5-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-23.

[0171]

[0172] 5-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-23, yield: 62%; yellow solid; melting point 120-122℃; 1H NMR(400MHz, CDCl3)δ9.96(s,1H),8.06(s,1H),7.83-7.68(m,4H),7.45-7.32(m,2H),7.30-7.14(m,4H),7.05(dd,J=9 .2,2.4Hz,1H),3.63-3.41(m,2H),3.25-3.07(m,2H),2.30(s,3H),2.22-2.08(m,2H),1.83-1.70(m,2H),1.64(s,1H); 13 C NMR (100MHz, CDCl3) δ185.8,150.0,146.9,146.2,136.9,134.7,133.2,130.5,129.7,128.7,127 .6,127.4,126.3,122.6,117.9,113.9,109.0,71.2,46.8,38.4,21.9; HRMS(pos.ESI):m / z[M+Na] + for C 27 H 25 ClN2O4NaScalcd:531.1116,found:531.1123.

[0173] Example 24

[0174] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-(pyrimidin-2-yl)piperazin-1-ylbenzoate, and the product is 5-(4-(pyrimidin-2-yl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-24.

[0175]

[0176] 5-(4-(pyrimidin-2-yl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-24, yield: 60%; yellow solid; melting point 138-140℃; 1 HNMR (400MHz, CDCl3) δ10.04(s,1H),8.33(d,J=4.8Hz,2H),8.14(s,1H),7.88-7.79(m,3H),7.77(d,J=2.4Hz,1H),7.27 (d,J=8.4Hz,2H),7.12(dd,J=9.2,1.6Hz,1H),6.51(t,J=4.8Hz,1H),4.13-3.85(m,4H),3.32-3.08(m,4H),2.36(s,3H); 13C NMR (100MHz, CDCl3) δ185.7,161.8,157.9,149.8,146.2,136.9,134.7,130.5,130.0127. 6,127.3,122.5,117.7,114.0,110.4,109.0,50.4,43.9,21.8; HRMS(pos.ESI):m / z[M+Na] + for C 24 H 23 N5O3NaScalcd:484.1414,found:484.1410.

[0177] Example 25

[0178] The reactants are 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxaldehyde and 4-(benzothiophene-4-yl)piperazin-1-ylbenzoate, and the product is 5-(4-(benzothiophene-4-yl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-25.

[0179]

[0180] 5-(4-(benzothiophene-4-yl)piperazin-1-yl)-1-toluenesulfonyl-1H-indole-3-carboxaldehyde TJ-25, yield: 80%; yellow solid; melting point 103-105℃; 1 H NMR (400MHz, CDCl3) δ10.06(s,1H),8.15(s,1H),7.95(d,J=8.0Hz,1H),7.89-7.76(m,5H),7.48(t,J=7.6Hz,1H),7.38( t,J=7.6Hz,1H),7.28(d,J=8.4Hz,2H),7.15(dd,J=9.2,2.0Hz,1H),3.81-3.58(m,4H),3.55-3.33(m,4H),2.37(s,3H); 13 CNMR (100MHz, CDCl3) δ185.7,164.0,153.0,149.8,146.2,136.9,134.7,130.5,129.9,128.2,127.9,127 .6,127.3,124.2,124.0,122.6,120.8,117.6,114.0,108.7,50.3,50.2,21.8; HRMS(pos.ESI):m / z[M+Na] + for C 27 H 24N4O3NaS2calcd:539.1182,found:539.1179.

[0181] Example 26

[0182] The reactants are 4-iodo-1-(phenylsulfonyl)-1H-indole-3-carboxaldehyde and morpholinobenzoate, and the product is 5-morpholino-1-(phenylsulfonyl)-1H-indole-3-carboxaldehyde TJ-26.

[0183]

[0184] 5-Morpholine-1-(phenylsulfonyl)-1H-indole-3-carboxaldehyde TJ-26, yield: 70%; yellow solid; melting point 153-155℃; 1 H NMR (400MHz, CDCl3) δ10.03(s,1H),8.13(s,1H),7.92(d,J=7.6Hz,2H),7.82(d,J=9.2Hz,1H),7.71(d,J=1.2H z,1H),7.59(t,J=7.6Hz,1H),7.54-7.43(m,2H),7.05(d,J=7.6Hz,1H),3.98-3.73(m,4H),3.26-3.06(m,4H); 13 C NMR (100MHz, CDCl3) δ185.7,149.8,137.7,136.8,134.8,129.9,129.9,127.6,127.3,122.7,117.0,114.0,108.2,67.1,50.4; HRMS (pos.ESI): m / z[M+Na] + for C 19 H 18 N2O4NaScalcd:393.0879,found:393.0880.

[0185] Example 27

[0186] The reactants are 1-((4-fluorophenyl)sulfonyl)-4-iodo-1H-indole-3-carboxaldehyde and morpholinobenzoic acid ester, and the product is 1-((4-fluorophenyl)sulfonyl)-5-morpholino-1H-indole-3-carboxaldehyde TJ-27.

[0187]

[0188] 1-((4-fluorophenyl)sulfonyl)-5-morpholino-1H-indole-3-carboxaldehyde TJ-27, yield: 74%; yellow solid; melting point 149-151℃; 1H NMR (400MHz, CDCl3) δ10.12(s,1H),8.19(s,1H),8.10-7.99(m,2H),7.88(d,J=9.2Hz,1H),7.80( d,J=2.0Hz,1H),7.29-7.19(m,2H),7.15(d,J=8.8Hz,1H),4.07-3.84(m,4H),3.37-3.16(m,4H); 13 C NMR(100MHz,CDCl3)δ185.65,166.3(d,J C-F =257.3Hz),149.91,136.65,133.6(d,J C-F =3.2Hz), 130.2(d,J C-F =9.8Hz),129.69,127.67,122.86,117.3(d,J C-F =22.9Hz),116.97,113.85,108.29,67.06,50.29; HRMS(pos.ESI):m / z[M+Na] + for C 19 H 17 FN2O4NaS calcd:411.0785,found:411.0779.

[0189] Example 28

[0190] The reactants were 1-((4-chlorophenyl)sulfonyl)-4-iodo-1H-indole-3-carboxaldehyde and morpholinobenzoic acid ester, and the product was 1-((4-chlorophenyl)sulfonyl)-5-morpholino-1H-indole-3-carboxaldehyde TJ-28.

[0191]

[0192] 1-((4-chlorophenyl)sulfonyl)-5-morpholino-1H-indole-3-carboxaldehyde TJ-28, yield: 68%; yellow solid; melting point 126-128℃; 1 H NMR (400MHz, CDCl3) δ10.05(s,1H),8.11(s,1H),7.86(d,J=8.4Hz,2H),7.80(d,J=9.2Hz,1H),7.72(d, J=1.2Hz,1H),7.46(d,J=8.4Hz,2H),7.06(dd,J=8.8,1.2Hz,1H),4.09-3.64(m,4H),3.44-2.90(m,4H); 13C NMR (100MHz, CDCl3) δ185.9,150.3,142.0,136.9,136.3,130.5,123.0,129.0,128.0,123.3,117.3,114.2,108.6,67.4,50.6; HRMS (pos.ESI): m / z[M+Na] + for C 19 H 17 ClN2O4NaScalcd:427.0490,found:427.0493.

[0193] Example 29

[0194] The reactants are 1-((4-bromophenyl)sulfonyl)-4-iodo-1H-indole-3-carboxaldehyde and morpholinobenzoate, and the product is 1-((4-bromophenyl)sulfonyl)-5-morpholino-1H-indole-3-carboxaldehyde TJ-29.

[0195]

[0196] 1-((4-bromophenyl)sulfonyl)-5-morpholinyl-1H-indole-3-carboxaldehyde TJ-29; Yield: 58%; Yellow solid; Melting point 110-112℃; 1 H NMR (400MHz, CDCl3) δ10.03(s,1H),8.09(s,1H),7.84-7.74(m,3H),7.71(d,J=2.4Hz,1H ),7.64-7.57(m,2H),7.04(dd,J=9.2,2.4Hz,1H),3.91-3.76(m,4H),3.24-3.09(m,4H); 13 C NMR (100MHz, CDCl3) δ185.6,149.9,136.6,136.6,133.2,130.4,129.8,128.6,127.7,123.0,117.1,113.9,108.4,67.0,50.4; HRMS (pos.ESI): m / z[M+Na] + for C 19 H 17 BrN2O4NaS calcd:470.9985,found:470.9978.

[0197] Example 30

[0198] The reactants were 1-((4-(tert-butyl)phenyl)sulfonyl)-4-iodo-1H-indole-3-carboxaldehyde and morpholinobenzoic acid ester, and the product was 1-((4-(tert-butyl)phenyl)sulfonyl)-5-morpholino-1H-indole-3-carboxaldehyde TJ-30.

[0199]

[0200] 1-((4-(tert-butyl)phenyl)sulfonyl)-5-morpholinyl-1H-indole-3-carboxaldehyde TJ-30; Yield: 85%; Yellow solid; Melting point 99-101℃; 1 HNMR (400MHz, DMSO) δ10.04(s,1H),8.78(s,1H),8.00(d,J=7.6Hz,2H),7.83(d,J=9.2Hz,1H),7.65(d ,J=7.6Hz,2H),7.55(s,1H),7.17(d,J=8.4Hz,1H),3.88-3.51(m,4H),3.18-2.95(m,4H),1.22(s,9H); 13 C NMR (100MHz, DMSO) δ187.3,159.1,149.8,139.1,134.1,128.9,127.6,127.5,127. 3,122.1,116.7,114.1,106.8,66.6,49.6,35.6,31.0; HRMS(pos.ESI):m / z[M+Na] + for C 23 H 26 N2O4NaScalcd:449.1505,found:449.1504.

[0201] Example 31

[0202] The reactants are 4-iodo-1-((4-methoxyphenyl)sulfonyl)-1H-indole-3-carboxaldehyde and morpholinobenzoic acid ester, and the product is 1-(4-methoxyphenyl)sulfonyl)-5-morpholino-1H-indole-3-carboxaldehyde TJ-31.

[0203]

[0204] 1-(4-methoxyphenyl)sulfonyl)-5-morpholinyl-1H-indole-3-carboxaldehyde TJ-31; Yield: 72%; Yellow solid; Melting point 93-95℃; 1H NMR (400MHz, CDCl3) δ10.02(s,1H),8.12(s,1H),7.86(d,J=8.8Hz,2H),7.80(d,J=9.2Hz,1H),7.71( s,1H),7.04(d,J=9.2Hz,1H),6.97-6.86(m,2H),3.95-3.81(m,4H),3.80(s,3H),3.25-3.02(m,4H); 13 C NMR (100MHz, CDCl3) δ185.7,164.6,149.7,136.9,129.8,129.7,128.9,127.6,1 22.4,116.8,115.1,114.0,108.2,67.1,56.0,50.4; HRMS(pos.ESI):m / z[M+Na] + for C 20 H 20 N2O5NaScalcd:423.0985,found:423.0990.

[0205] Example 32

[0206] The reactants are 4-iodo-1-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-indole-3-carboxaldehyde and morpholinobenzoic acid ester, and the product is 5-morpholino-1-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-indole-3-carboxaldehyde TJ-32.

[0207]

[0208] 5-Morpholine-1-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-indole-3-carboxaldehyde TJ-32; Yield: 70%; Yellow solid; Melting point 156-158℃; 1 H NMR (400MHz, CDCl3) δ10.07(s,1H),8.13(s,1H),8.06(d,J=8.4Hz,2H),7.83(d,J=9.2Hz, 1H),7.81-7.65(m,3H),7.08(dd,J=9.2,2.0Hz,1H),3.90-3.77(m,4H),3.28-3.08(m,4H); 13 C NMR (100MHz, CDCl3) δ185.6,150.1,141.0,136.4((q,J C-F =33.2Hz)),136.4,129.6,127.8,127.8,127.1(q,J C-F =3.7Hz), 123.3, 122.9(q,J)C-F =271.7Hz),117.1,113.9,108.4,67.1,50.2; HRMS(pos.ESI):m / z[M+Na] + for C 20 H 17 F3N2O4NaScalcd:461.0753,found:461.0746.

[0209] Example 33

[0210] The reactants are 4-iodo-1-((4-nitrophenyl)sulfonyl)-1H-indole-3-carboxaldehyde and morpholinobenzoate, and the product is 5-morpholino-1-((4-nitrophenyl)sulfonyl)-1H-indole-3-carboxaldehyde TJ-33.

[0211]

[0212] 5-Morpholine-1-((4-nitrophenyl)sulfonyl)-1H-indole-3-carboxaldehyde TJ-33; Yield: 50%; Yellow solid; Melting point 83-85℃; 1 H NMR (400MHz, CDCl3) δ10.07 (s, 1H), 8.37-8.26 (m, 2H), 8.16-8.05 (m, 3H), 7.83 (d, J = 9.2Hz, 1 H),7.72(d,J=2.4Hz,1H),7.08(dd,J=9.2,2.4Hz,1H),4.05-3.65(m,4H),3.37-2.97(m,4H); 13 C NMR (100MHz, CDCl3) δ185.5,151.3,150.2,142.9,136.2,129.5,128.6,127.9,125.1,123.7,117.2,113.8,108.5,67.0,50.2; HRMS (pos.ESI): m / z[M+Na] + for C 19 H 17 N3O6NaScalcd:438.0730,found:438.0720.

[0213] Example 34

[0214] The reactants were 1-((3-chlorophenyl)sulfonyl)-4-iodo-1H-indole-3-carboxaldehyde and morpholinobenzoate, and the product was 1-((3-chlorophenyl)sulfonyl)-5-morpholino-1H-indole-3-carboxaldehyde TJ-34.

[0215]

[0216] 1-((3-chlorophenyl)sulfonyl)-5-morpholinyl-1H-indole-3-carboxaldehyde TJ-34; Yield: 60%; Yellow solid; Melting point 108-110℃; 1 H NMR (400MHz, CDCl3) δ10.07(s,1H),8.12(s,1H),7.92(t,J=1.6Hz,1H),7.85-7.78(m,2H),7.73(d,J=2.4Hz,1H),7. 57(dd,J=8.0,0.8Hz,1H),7.44(t,J=8.0Hz,1H),7.09(dd,J=9.2,2.4Hz,1H),4.02-3.76(m,4H),3.40-2.97(m,4H); 13 C NMR (100MHz, CDCl3) δ185.6,150.0,139.3,136.6,136.2,135.0,131.1,129.7,127. 7,127.3,125.3,123.1,117.1,113.9,108.3,67.1,50.3; HRMS(pos.ESI):m / z[M+Na] + for C 19 H 17 ClN2O4NaScalcd:427.0490,found:427.0498.

[0217] Example 35

[0218] The reactants are N,N-diethyl-4-iodo-1-toluenesulfonyl-1H-indole-3-carboxamide and morpholinobenzoate, and the product is N,N-diethyl-5-morpholino-1-toluenesulfonyl-1H-indole-3-carboxamide TJ-35.

[0219]

[0220] N,N-Diethyl-5-morpholine-1-toluenesulfonyl-1H-indole-3-carboxamide TJ-35; Yield: 30%; White solid; Melting point 88-90℃; 1H NMR (400MHz, CDCl3) δ7.86(d,J=8.8Hz,1H),7.74(d,J=8.4Hz,2H),7.60(s,1H),7.21(d,J=8.4Hz,2H),7.15(s,1H), 7.10-7.00(m,1H),3.93-3.75(m,4H),3.50(q,J=1.2Hz,4H),3.19-3.05(m,4H),2.34(s,3H),1.22(t,J=6.8Hz,6H); 13 C NMR (100MHz, CDCl3) δ164.9,145.6,135.1,130.4,130.2,127.3,127.1,125.1,117.8 ,116.8,116.7,114.3,107.4,67.0,50.9,29.9,21.8,14.0; HRMS(pos.ESI):m / z[M+H] + forC 24 H 29 N3O4NaS calcd:478.1771,found:478.1774.

[0221] Example 36

[0222] The reactants were ethyl 4-iodo-1-toluenesulfonyl-1H-indole-3-carboxylate and morpholinobenzoate, and the product was ethyl 5-morpholino-1-toluenesulfonyl-1H-indole-3-carboxylate TJ-36.

[0223]

[0224] 5-morpholine-1-toluenesulfonyl-1H-indole-3-carboxylic acid ethyl ester TJ-36; yield: 40%; white solid; melting point 92-94℃; 1 H NMR (400MHz, CDCl3) δ8.18(s,1H),7.91-7.75(m,3H),7.63(s,1H),7.34-7.19(m,2H),7.04(d,J=6.4Hz ,1H),4.37(q,J=7.2Hz,2H),4.00-3.79(m,4H),3.24-3.13(m,4H),2.35(s,3H),1.41(t,J=7.2Hz,3H); 13C NMR (100MHz, CDCl3) δ164.0,145.8,135.0,132.4,130.4,130.3,129.2,127.5,127.3 ,116.4,114.1,113.6,107.9,67.1,60.7,50.6,21.8,14.6; HRMS(pos.ESI):m / z[M+H] + for C 22 H 24 N2O5NaScalcd:451.1298,found:451.1304.

[0225] Example 37

[0226] The reactants were (4-iodo-1-toluenesulfonyl-1H-indol-3-yl)methanol and morpholinobenzoate, and the product was (5-morpholino-1-toluenesulfonyl-1H-indol-3-yl)methanol TJ-37.

[0227]

[0228] (5-morpholino-1-toluenesulfonyl-1H-indol-3-yl)methanol TJ-37; Yield: 45%; White solid; Melting point: 72-75℃; 1 H NMR (400MHz, CDCl3) δ7.87(d,J=9.2Hz,1H),7.73(d,J=8.4Hz,2H),7.45(s,1H),7.19(d,J=8.0Hz,2H),7.05(d,J=2. 0Hz,1H),7.00(dd,J=9.2,2.4Hz,1H),4.76(s,2H),3.92–3.75(m,4H),3.17–3.03(m,4H),2.33(s,3H),1.72(s,1H).; 13 C NMR (100MHz, CDCl3) δ148.5,145.1,135.5,130.7,130.4,130.0,127.0,124.6, 122.6,116.1,114.6,106.1,67.2,57.3,50.8,21.7; HRMS(pos.ESI):m / z[M+Na] + for C 20 H 22 N2O4NaScalcd:409.1192,found:409.1185.

[0229] Example 38

[0230] The reactants were methyl (4-iodo-1-toluenesulfonyl-1H-indol-3-yl)acetate and morpholinobenzoate, and the product was methyl (5-morpholino-1-toluenesulfonyl-1H-indol-3-yl)acetate TJ-38.

[0231]

[0232] (5-morpholino-1-toluenesulfonyl-1H-indol-3-yl)methyl acetate TJ-38; yield: 52%; white solid; melting point 127-129℃; 1 H NMR (400MHz, CDCl3) δ7.87(d,J=8.8Hz,1H),7.74(d,J=8.4Hz,2H),7.55(s,1H),7.21(d,J=8.0Hz,2 H),7.07-6.89(m,2H),5.19(s,2H),4.00-3.70(m,4H),3.38-2.96(m,4H),2.33(s,3H),2.07(s,3H); 13 C NMR (100MHz, CDCl3) δ171.1,148.6,145.1,135.4,130.6,130.1,127.0,126.5,117 .6,116.1,114.6,105.7,67.3,57.9,50.8,21.7,21.2; HRMS(pos.ESI):m / z[M+Na] + for C 22 H 24 N2O5NaScalcd:451.1298,found:451.1291.

[0233] Example 39

[0234] Evaluation of the anti-acetylcholinesterase activity of compounds TJ-1 to TJ-38. Acetylcholinesterase (AChE) catalyzes the breakdown of acetylcholine, directly causing neural or transmission failure, thus triggering Alzheimer's disease (dementia AD). Acetylcholinesterase inhibitors can be used to treat Alzheimer's disease; currently, more than 40 anti-acetylcholinesterase drugs are under development worldwide, making it an important research area in Alzheimer's disease treatment. In this experiment, PBS solutions containing acetylcholinesterase were treated with different concentrations of compounds TJ-1 to TJ-38, and an equal volume of TDNB was added. After preheating for 2 min, thioacetylcholine was added, and the reaction was incubated at 37°C for 0.5 h. The reaction was then terminated with SDS. The absorbance of the resulting solutions was measured at 412 nm, and the absorbance was calculated according to the following formula.

[0235] Inhibition rate (%) = [Control A - (Sample A - Blank A)] / Control A × 100

[0236] The results of the anti-acetylcholinesterase activity assay showed that various compounds of the present invention (such as TJ-6, TJ-22, TJ-24, and TJ-35) exhibited good inhibitory activity against acetylcholinesterase activity compared to the positive control drug berberine, with the highest inhibition rate reaching 82%. This revealed that the specific amino group at the 5-position of the indole ring and the amide group at the 3-position are the key pharmacophores for drug efficacy. All experimental data are expressed as mean ± standard error, with the blank solvent control group (inhibition rate 0%) serving as the reference group.

[0237] Table 1 shows the inhibition rates of compounds TJ-1 to TJ-38 on acetylcholinesterase activity.

[0238] Table 1. Inhibition rate of compounds TJ-1 to TJ-38 on acetylcholinesterase activity.

[0239] compound Inhibition rate compound Inhibition rate compound Inhibition rate TJ-1 15％ TJ-14 23％ TJ-27 45％ TJ-2 24％ TJ-15 33％ TJ-28 -11％ TJ-3 20％ TJ-16 43％ TJ-29 27％ TJ-4 -12％ TJ-17 26％ TJ-30 21％ TJ-5 44％ TJ-18 37％ TJ-31 35％ TJ-6 62％ TJ-19 51％ TJ-32 18％ TJ-7 37％ TJ-20 50％ TJ-33 26％ TJ-8 28％ TJ-21 47％ TJ-34 42％ TJ-9 39％ TJ-22 68％ TJ-35 82％ TJ-10 30％ TJ-23 23％ TJ-36 53％ TJ-11 43％ TJ-24 75％ TJ-37 55％ TJ-12 18％ TJ-25 39％ TJ-38 48％ TJ-13 22％ TJ-26 45％ Berberine 61％

[0240] From the table above and the instruction manual attached Figure 3 It can be seen that among the 38 screened compounds, 4 (TJ-6, TJ-22, TJ-24, TJ-35) had inhibition rates exceeding those of the positive control drug berberine. Among them, compound TJ-35 showed the strongest inhibitory activity, reaching 82%, and is expected to be developed into a novel anti-acetylcholinesterase drug.

[0241] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for preparing a 5-amino-substituted indole compound of Formula I or Formula II, comprising the following steps: In an organic solvent, under conditions involving a catalyst, ligand, base, and additive, the 4-position halogenated indole of Formula III is reacted with the amine oxide of Formula IV or V to obtain the 5-position amino-substituted indole compound of Formula I or II. ； Among them, R 1 R 2 Independently selected from C1-C7 alkyl, phenyl, naphthyl, and benzyl groups; R 3 Selected from aldehyde, N,N-diethylformamido, ethoxycarbonyl, hydroxymethyl, and ethyl ester methyl groups; R 4 Selected from benzenesulfonyl, 4-fluorobenzenesulfonyl, 4-chlorobenzenesulfonyl, 4-bromobenzenesulfonyl, 4-tert-butylbenzenesulfonyl, 4-methoxybenzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 3-chlorobenzenesulfonyl; Ring A is selected from morpholine, thiomorpholine, piperazine, pyrrolidine, piperidine, and hexamethyleneimine; R 5 Selected from hydrogen, C1~C7 alkyl, phenyl, naphthyl, benzoyl, benzyloxycarbonyl, tert-butoxycarbonyl, ethoxycarbonylmethyl, benzoisoxazolyl, benzoisothiazolyl, pyrimidinyl, benzothiophene; X represents iodine; The catalyst is palladium acetate or palladium chloride; the ligands are triarylphosphine and norbornene; the base is cesium carbonate or potassium carbonate; the additive is p-trifluoromethylbenzyl alcohol; and the organic solvent is toluene or dioxane.

2. The method according to claim 1, characterized in that, R 1 R 2 It is independently selected from methyl and ethyl.

3. The method according to claim 1, characterized in that, R 3 It is a formaldehyde group.

4. The method according to claim 1, characterized in that, R 5 Selected from methyl and ethyl.

5. The method according to claim 1, characterized in that, The molar ratio of the 4-position haloindole shown in Formula III to the amine oxide shown in Formula V is 1:1.

2.

6. The method according to claim 1, characterized in that, The reaction temperature is 80~100℃; the reaction time is 24 hours.

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