C2-quaternary carbon indole-3-ketone compound as well as preparation method and application thereof

Abstract

The invention relates to a C2-quaternary carbon indole-3-ketone compound as well as a preparation method and application thereof, the structure of the compound is shown as a structural general formula (I-1) or (I-2), and the compound is prepared by taking an indole-3-ketone derivative or a 3, 3-gem-difluoroindole derivative as a reaction substrate and carrying out Mannich reaction. According to the present invention, the reaction conditions are mild, the atom economy is high, the highest yield of the synthesized C2-quaternary carbon indole-3-one compound can achieve 86%, and the prepared C2-quaternary carbon indole-3-one compound can inhibit NO released by LPS-induced mouse macrophages RAW264.7, and can be used for preparing drugs for treating NO-mediated inflammatory diseases. Or a product thereof

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and relates to an indole ketone compound, particularly a C2-quaternary carbon indole-3-one compound, as well as the preparation method of this type of compound and its application in pharmaceuticals. Background Technology

[0002] The C2-quaternary carbon indole-3-one skeleton is widely found in various natural products and pharmaceutical active molecules, serving as a key building block for constructing bioactive structures. For example, (-)-Isatisine A is one of the main components of the traditional Chinese medicine plant Isatis indigotica, and its derivatives exhibit cytotoxicity and anti-HIV-1 activity against C8166 cells. IIIB Activity. From the plant Cephalosporium orchid ( Cephalanceropsis slender Cephalinone B, extracted from [the fungicide], exhibits significant cytotoxicity against human breast cancer (MCF-7), lung cancer (NCI-H460), and central nervous system cancer (SF268) cell lines.

[0003] Due to the crucial value of such indole-based structures in drug development, researchers have conducted systematic and in-depth studies on the asymmetric construction of this scaffold. To date, significant progress has been made in the asymmetric synthesis of chiral indoles using indole-3-one or 2-substituted indoles as substrates.

[0004] Currently, the chemical community has reported various strategies for constructing C2-quaternary carbon indole-3-ones, including the acid-catalyzed Friedel-Crafts reaction with indole, the base-catalyzed Aza-Henry reaction with nitromethane, and the acid-catalyzed Morita-Baylis-Hillman reaction with alkenyl ketones. However, these methods generally suffer from drawbacks such as a narrow substrate applicability (e.g., difficulty in incorporating sterically hindered groups) and lengthy synthetic routes (requiring pre-functionalization of the indole substrate), which limit the preparation of structurally diverse derivatives.

[0005] In recent years, emerging catalytic technologies have attempted to overcome these limitations. Lu et al. (Highly enantioselective electrosynthesis of C2-quaternary indolin-3-ones). Chemical Communications(2020, 56(4), 623-626.) An electrochemical / organocatalytic synergistic system was developed to achieve the direct asymmetric conversion of 2-arylindole to C2-quaternary carbon indole-3-one via anodic oxidation. Although this method achieved moderate enantioselectivity, it was dependent on a Pt electrode, a constant current of 0.8 mA, and various additives (including 0.1 equivalent of TEMPO, 2.0 equivalent of benzoic acid, and 0.1 equivalent of TBPA), resulting in a complex reaction system, cumbersome post-processing, and poor atom economy.

[0006] Zhao et al. (One-Pot Asymmetric Oxidative Dearomatization of 2-Substituted Indoles by Merging Transition Metal Catalysis with Organocatalysis to AccessC2-Tetrasubstituted Indolin-3-Ones. Advanced Synthesis & Catalysis (2022, 364(7), 1277-1285.) Further proposed a copper / proline dual-catalyzed one-pot method to synthesize the corresponding C2-quaternary carbon indoline-3-one target molecules through oxidative dearomatization-Mannich tandem reaction. However, this method requires up to 20 mol% CuI and 20 mol% L-proline for synergistic catalysis, which significantly increases the cost due to the increased catalyst loading. Its representative compound 3s showed MICs of only 8 μg / mL and 16 μg / mL against Staphylococcus aureus standard strain (ATCC 25923) and clinical methicillin-resistant strain S. aureus (20151027077), respectively, indicating moderate antibacterial activity. However, its antibacterial activity against some representative ketone products was still insufficient, and its bioactivity still needs to be optimized.

[0007] In summary, although significant progress has been made in the asymmetric synthesis of chiral indole derivatives, the following three challenges remain:

[0008] 1) Harsh reaction conditions (such as complex electrodes and additives in electrochemical systems).

[0009] 2) High catalyst loading (e.g., a dual-catalyst system requires 20 mol% metal and organic catalysts).

[0010] 3) Insufficient product activity (e.g., key drug activity indicators do not reach ideal levels)

[0011] Therefore, developing universal synthetic methods that are easy to operate, require low amounts of catalysts, and can enhance pharmacological activity remains a critical technological bottleneck that needs to be overcome in this field. Summary of the Invention

[0012] The purpose of this invention is to provide a C2-quaternary carbon indole-3-one compound with a simple synthesis method and further enhanced pharmacological activity, as well as the preparation method and application of this type of compound.

[0013] The present invention first provides a novel C2-quaternary carbon indole-3-one compound having the structure shown in general formula (I-1) or (I-2): or

[0014] in: R1 is selected from halogen or C. 1-4 alkyl; R2 is selected from hydrogen or C. 1-4 alkyl; R3 is selected from hydrogen, halogens, and C. 1-4 Alkyl, C 1-4 Any one of the alkoxy groups; R4 is selected from hydrogen or C. 1-4 alkyl; R5 is selected from phenyl, thiophene, halophenyl, dihalophenyl, C 1-4 alkylphenyl or C 1-4 Any one of the alkoxyphenyl groups; X is selected from oxygen or carbon; n is an integer from 1 to 3.

[0015] The absolute configuration of the compound shown in general structural formula (I-2) is S,R-configuration.

[0016] Furthermore, for compounds represented by the general structural formula (I-1), R1 can preferably be chlorine or methyl; R2 can preferably be hydrogen or methyl.

[0017] Furthermore, for compounds represented by the general structural formula (I-2), R3 can preferably be any one of hydrogen, halogen, methyl, ethyl, or methoxy; R4 can preferably be any one of hydrogen or methyl; R5 can preferably be any one of phenyl, halophenyl, dihalophenyl, tolyl, or methoxyphenyl; X can preferably be any one of oxygen or carbon; and n is preferably an integer from 2 to 3.

[0018] Furthermore, in the compound represented by the general structural formula (I-2), R3 is preferably hydrogen or halogen, R4 is hydrogen or methyl, R5 is any one of phenyl, halophenyl or dihalophenyl, X is carbon, and n is an integer from 2 to 3.

[0019] More specifically, the C2-quaternary carbon indole-3-one compounds of the present invention can be any one of the following structural formulas:

[0020] , referred to as I-1-A;

[0021] Abbreviated as I-1-B;

[0022] Abbreviated as I-1-C;

[0023] Abbreviated as I-1-D;

[0024] , referred to as I-1-E;

[0025] , referred to as I-2-A;

[0026] Abbreviated as I-2-B;

[0027] Abbreviated as I-2-C;

[0028] Abbreviated as I-2-D;

[0029] , referred to as I-2-E;

[0030] Abbreviated as I-2-F;

[0031] Abbreviated as I-2-G;

[0032] Abbreviated as I-2-H;

[0033] , referred to as I-2-I;

[0034] Abbreviated as I-2-J;

[0035] Abbreviated as I-2-K;

[0036] Abbreviated as I-2-L;

[0037] Abbreviated as I-2-M;

[0038] Abbreviated as I-2-N;

[0039] , referred to as I-2-O.

[0040] Furthermore, the present invention also provides a typical method for preparing the C2-quaternary carbon indole-3-one compounds.

[0041] It should be noted that the preparation methods of C2-quaternary carbon indole-3-one compounds provided below are not the only synthetic routes for preparing such compounds. Other suitable synthetic routes can also be used to prepare the C2-quaternary carbon indole-3-one compounds described in this invention, and this invention does not impose any particular limitations on them.

[0042] First, the present invention can be prepared according to the following method, using the C2-quaternary carbon indole-3-one compound of general structural formula (I-1):

[0043] S1. Using the indole-3-one derivative of general formula (II) as a substrate, a Mannich reaction is carried out with the pyrazolinone derivative of general formula (III) under triethylamine catalysis to obtain the intermediate of general formula (IV):

[0044] ,

[0045] ,

[0046] ;

[0047] S2. Then, the intermediate described in general structural formula (IV) is subjected to an acylation reaction with acetic anhydride to prepare the C2-quaternary carbon indole-3-one compound described in general structural formula (I-1).

[0048] The substituents in the above raw materials and intermediates are the same as those in the compound with general structural formula (I-1), specifically R1 is selected from halogens or C. 1-4 Alkyl group, R2 is selected from hydrogen or C 1-4 alkyl.

[0049] Furthermore, in the above preparation method, the Mannich reaction is specifically carried out at room temperature for 12-24 hours; the acylation reaction is specifically carried out at room temperature in a solvent DCM in the presence of a triethylamine catalyst for 0.5-1 hour.

[0050] Secondly, the present invention can be used to prepare C2-quaternary carbon indole-3-one compounds of general structural formula (I-2) according to the following method:

[0051] Using the 3,3-genomicifluoroindole derivative of general formula (V) as a substrate, a Mannich reaction was carried out with the compound of general formula (VI) under chiral phosphoric acid catalysis to obtain the C2-quaternary carbon indole-3-one compound of general formula (I-2):

[0052] ,

[0053] .

[0054] Similarly, the substituents in the above general structural formulas are the same as those in compounds of general structural formula (I-2), specifically R3 is selected from hydrogen, halogen, C. 1-4 Alkyl, C 1-4 Any one of the alkoxy groups; R4 is selected from hydrogen or C. 1-4 Alkyl group; R5 is selected from phenyl, thiophene, halophenyl, dihalophenyl, C 1-4 alkylphenyl or C 1-4 Any one of alkoxyphenyl; X is selected from oxygen or carbon; n is an integer from 1 to 3.

[0055] Furthermore, in the above preparation method, the Mannich reaction is specifically carried out at 0°C for 12–24 h.

[0056] Experiments have demonstrated that the C2-quaternary carbon indole-3-one compounds prepared in this invention significantly inhibit the release of NO from LPS-induced mouse RAW264.7 macrophages. Therefore, the C2-quaternary carbon indole-3-one compounds of this invention can be used to prepare drugs for treating NO-mediated inflammatory diseases.

[0057] More specifically, the NO-mediated inflammatory diseases may include, but are not limited to, sepsis, rheumatoid arthritis, or inflammatory bowel disease.

[0058] The C2-quaternary carbon indole-3-one compounds described in this invention have advantages such as simple synthetic methods, high atom economy, and almost no byproducts. Furthermore, the reactants are easy to prepare, the reaction conditions are relatively mild, the yield is high, and the substrate applicability is broad. Preliminary activity evaluations have demonstrated that these compounds exhibit potential anti-inflammatory activity, and are expected to provide structurally diverse small molecule entities for subsequent systematic bioactivity studies, thus laying the material foundation for the discovery and optimization of related lead structures. Attached Figure Description

[0059] Figure 1 This is the 1H NMR spectrum of compound I-2-A.

[0060] Figure 2 This is the carbon NMR spectrum of compound I-2-A.

[0061] Figure 3 It is 10 μmol·L -1 The inhibition rate of various compounds on LPS-induced NO in RAW264.7 cells. Implementation

[0062] The specific embodiments of the present invention will be further described in detail below with reference to the accompanying drawings and examples. The following examples are only used to more clearly illustrate the technical solutions of the present invention, so that those skilled in the art can better understand and utilize the present invention, and are not intended to limit the scope of protection of the present invention.

[0063] Unless otherwise specified, the production processes, experimental methods, or testing methods involved in the embodiments of this invention are all conventional methods in the prior art, and their names and / or abbreviations are all conventional names in the field, which are very clear and distinct in the relevant application areas. Those skilled in the art can understand the conventional process steps based on the names and apply the corresponding equipment, and implement them according to conventional conditions or the conditions recommended by the manufacturer.

[0064] The various instruments, equipment, raw materials or reagents used in the embodiments of this invention are not subject to any special restrictions on their source. They are all conventional products that can be purchased through regular commercial channels and can be prepared according to conventional methods known to those skilled in the art. Example

[0065] Example 1: 2-Phenyl-3- H Synthesizing I-1-A from indole-3-one

[0066]

[0067] The reaction raw material 2-phenyl-3 H 2-Indole-3-one (0.1 mmol) was dissolved in dichloromethane, and 1-(2'-chlorophenyl)-3-methyl-5-pyrazolone (0.1 mmol) was added, followed by triethylamine (0.01 mmol). The mixture was stirred at room temperature for 12 h, concentrated by rotary evaporation, and separated by column chromatography to give the product 2-(1-(2-chlorophenyl)-3-methyl-5-oxo-4,5-dihydro-1- H -pyrazol-4-yl)-2-phenylindoline-3-one.

[0068] The product 2-(1-(2-chlorophenyl)-3-methyl-5-oxo-4,5-dihydro-1 H (-pyrazol-4-yl)-2-phenylindololin-3-one was dissolved in dichloromethane, and triethylamine (0.03 mmol) and acetic anhydride (0.1 mmol) were added. The mixture was stirred at room temperature for 0.5 h, and the solvent was removed by rotary evaporation. The product was purified by column chromatography to obtain 32.9 mg of the target product I-1-A, with a yield of 72%.

[0069] 1 H NMR (600 MHz, CDCl3) d 7.68 – 7.61 (m, 2H), 7.58 (d, J= 7.8 Hz,1H), 7.51 – 7.45 (m, 2H), 7.38 – 7.30 (m, 5H), 7.29 – 7.26 (m, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.83 (t, J = 7.4 Hz, 1H), 1.98 (s, 3H), 1.47 (s, 3H).

[0070] Example 2: Using 2-phenyl-3 H Synthesization of I-1-B from indole-3-one

[0071]

[0072] The reaction raw material 2-phenyl-3 H 2-(4'-chlorophenyl)-3-methyl-5-pyrazolone (0.1 mmol) was dissolved in dichloromethane, followed by the addition of 1-(4'-chlorophenyl)-3-methyl-5-pyrazolone (0.1 mmol), and then triethylamine (0.01 mmol). The mixture was stirred at room temperature for 12 h, concentrated by rotary evaporation, and separated by column chromatography to give the product 2-(1-(4-chlorophenyl)-3-methyl-5-oxo-4,5-dihydro-1-yl)-pyrazolone. H -pyrazol-4-yl)-2-phenylindoline-3-one.

[0073] The product 2-(1-(4-chlorophenyl)-3-methyl-5-oxo-4,5-dihydro-1 H (-pyrazol-4-yl)-2-phenylindololin-3-one was dissolved in dichloromethane, and triethylamine (0.03 mmol) and acetic anhydride (0.1 mmol) were added. The mixture was stirred at room temperature for 0.5 h, and the solvent was removed by rotary evaporation. The product was purified by column chromatography to obtain 39.3 mg of the target product I-1-B, with a yield of 86%.

[0074] 1 H NMR (600 MHz, CDCl3) d 7.65 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 7.7Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.40 – 7.29 (m, 7H), 6.93 (d, J = 8.2 Hz, 1H), 6.84 (t, J = 7.4 Hz, 1H), 1.93 (s, 3H), 1.61 (s, 3H).

[0075] Example 3: Using 2-phenyl-3 H Synthesizing I-1-C from indole-3-one as a starting material

[0076] The reaction raw material 2-phenyl-3 H 2-(1-(4-methylphenyl)-3-methyl-5-pyrazolone) (0.1 mmol) was dissolved in dichloromethane, followed by the addition of 1-(4'-methylphenyl)-3-methyl-5-pyrazolone (0.1 mmol), and then triethylamine (0.01 mmol). The mixture was stirred at room temperature for 12 h, concentrated by rotary evaporation, and separated by column chromatography to give the product 2-(1-(4-methylphenyl)-3-methyl-5-oxo-4,5-dihydro-1-yl)-pyrazolone. H -pyrazol-4-yl)-2-phenylindoline-3-one.

[0077] The product 2-(1-(4-methylphenyl)-3-methyl-5-oxo-4,5-dihydro-1 H (-pyrazol-4-yl)-2-phenylindololin-3-one was dissolved in dichloromethane, and triethylamine (0.03 mmol) and acetic anhydride (0.1 mmol) were added. The mixture was stirred at room temperature for 0.5 h, and the solvent was removed by rotary evaporation. The product was purified by column chromatography to obtain 34.5 mg of the target product I-1-C, with a yield of 79%.

[0078] 1 H NMR (600 MHz, CDCl3) d 7.70 – 7.62 (m, 2H), 7.59 (d, J = 7.8 Hz,1H), 7.48 (m, 1H), 7.35 – 7.31 (m, 2H), 7.31 – 7.26 (m, 3H), 7.18 (d, J = 8.3Hz, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.83 (t, J = 7.4 Hz, 1H), 2.35 (s, 3H), 1.93 (s, 3H), 1.58 (s, 3H).

[0079] Example 4: 2-[4-(p-methyl)phenyl]-3 H Synthesizing I-1-D from indole-3-one

[0080]

[0081] The reaction raw material 2-[4-(p-methyl)phenyl]-3 H2-Indole-3-one (0.1 mmol) was dissolved in dichloromethane, and 1-(2'-chlorophenyl)-3-methyl-5-pyrazolone (0.1 mmol) was added, followed by triethylamine (0.01 mmol). The mixture was stirred at room temperature for 12 h, concentrated by rotary evaporation, and separated by column chromatography to give the product 2-(1-(2-chlorophenyl)-3-methyl-5-oxo-4,5-dihydro-1- H -pyrazol-4-yl)-2-phenylindoline-3-one.

[0082] The product 2-(1-(2-chlorophenyl)-3-methyl-5-oxo-4,5-dihydro-1 H (-pyrazol-4-yl)-2-phenylindololin-3-one was dissolved in dichloromethane, and triethylamine (0.03 mmol) and acetic anhydride (0.1 mmol) were added. The mixture was stirred at room temperature for 0.5 h, and the solvent was removed by rotary evaporation. The product was purified by column chromatography to obtain 27.3 mg of the target product I-1-D, with a yield of 58%.

[0083] 1 H NMR (600 MHz, CDCl3) d 7.57 (d, J = 7.7 Hz, 1H), 7.52 – 7.49 (m,2H), 7.48 – 7.44 (m, 2H), 7.37 – 7.32 (m, 3H), 7.12 (d, J = 8.0 Hz, 2H), 6.92(d, J = 8.3 Hz, 1H), 6.81 (t, J = 7.4 Hz, 1H), 2.30 (s, 3H), 1.97 (s, 3H), 1.49 (s, 3H).

[0084] Example 5: 2-[4-(p-methyl)phenyl]-3 H Synthesizing I-1-E from indole-3-one

[0085]

[0086] The reaction raw material 2-[4-(p-methyl)phenyl]-3 H 2-(1-(4-chlorophenyl)-3-methyl-5-pyrazolone) (0.1 mmol) was dissolved in dichloromethane, followed by the addition of 1-(4'-chlorophenyl)-3-methyl-5-pyrazolone (0.1 mmol), and then triethylamine (0.01 mmol). The mixture was stirred at room temperature for 12 h, concentrated by rotary evaporation, and separated by column chromatography to give the product 2-(1-(4-chlorophenyl)-3-methyl-5-oxo-4,5-dihydro-1-yl)-5-methyl-5-oxo-4,5-dihydro-5-yl)-5-methyl ... H-pyrazol-4-yl)-2-[4-(p-methyl)phenyl]indoline-3-one.

[0087] The product 2-(1-(4-chlorophenyl)-3-methyl-5-oxo-4,5-dihydro-1 H (-pyrazol-4-yl)-2-[4-(p-methyl)phenyl]indoline-3-one was dissolved in dichloromethane, and triethylamine (0.03 mmol) and acetic anhydride (0.1 mmol) were added. The mixture was stirred at room temperature for 0.5 h, and the solvent was removed by rotary evaporation. The product was purified by column chromatography to obtain 28.7 mg of the target product I-1-E, with a yield of 61%.

[0088] 1 H NMR (600 MHz, CDCl3) d 7.56 (d, J = 7.7 Hz, 1H), 7.52 – 7.48 (m,2H), 7.37 – 7.32 (m, 5H), 7.13 (d, J = 8.0 Hz, 2H), 6.90 (dd, J = 15.3, 8.2Hz, 2H), 6.81 (t, J = 7.4 Hz, 1H), 2.31 (s, 3H), 1.92 (s, 3H), 1.62 (s, 3H).

[0089] Example 6: 2-(4-bromophenyl)-3,3-genomicifluoro-3 H - Synthesis of I-2-A from indole

[0090]

[0091] 2-(4-bromophenyl)-3,3-gesidifluoro-3 H -Indole (0.05 mmol) was dissolved in cyclohexanone (1.0 mL), and chiral phosphoric acid (0.005 mmol) was added. The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to obtain 16 mg of the target product I-2-A, with a yield of 86%.

[0092] 1 H NMR (600 MHz, CDCl3) d 7.49 – 7.45 (m, 2H), 7.43 – 7.39 (m, 4H), 6.93 (d, J = 8.5 Hz, 1H), 6.77 – 6.74 (m, 1H), 5.92 (s, 1H), 3.68 (dd,J =12.7, 5.1 Hz, 1H), 2.40 (m, 1H), 2.32 (d, J = 12.7 Hz, 1H), 2.12 (m, 1H), 2.01 (m, 1H), 1.77 (d, J = 13.0 Hz, 1H), 1.74 – 1.69 (m, 1H), 1.66 – 1.63 (m, 1H), 1.53 (m, 1H), see details. Figure 1 .

[0093] 13 C{ 1 H NMR (151 MHz, CDCl3) d 212.1, 200.3, 160.8, 138.2, 137.9, 131.6, 128.8, 126.9, 125.2, 121.5, 118.6, 111.2, 71.6, 57.8, 43.5, 29.8, 28.9, 25.0, as detailed below. Figure 2 .

[0094] IR vmax 3377, 2920, 2849, 1702, 1677, 1621, 1580, 1487, 1463, 1327,1278, 1125, 1098, 1084, 1009, 748 cm -1 .

[0095] HRMS (ESI) m / z calcd. for C 20 H 19 BrNO2 (M+H) + :384.0594, found 384.0597.

[0096] Example 7: 2-(3-chlorophenyl)-3,3-genomicifluoro-3 H - Synthesis of I-2-B from indole

[0097]

[0098] 2-(3-chlorophenyl)-3,3-genomicifluoroindole (0.05 mmol) was dissolved in cyclohexanone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to give 14 mg of the target product I-2-B, with a yield of 77%.

[0099] 1H NMR (600 MHz, CDCl3) d 7.53 – 7.52 (m, 1H), 7.49 – 7.46 (m, 2H), 7.44 – 7.42 (m, 1H), 7.23 – 7.18 (m, 2H), 6.95 (d, J = 8.2 Hz, 1H), 6.76 (t, J = 7.4 Hz, 1H), 5.92 (s, 1H), 3.70 (dd, J = 12.6, 5.0 Hz, 1H), 2.42 (m, 1H), 2.32 (dd, J = 12.7, 1.6 Hz, 1H), 2.16 – 2.11 (m, 1H), 2.03 – 1.99 (m, 1H), 1.88 – 1.77 (m, 2H), 1.74 – 1.64 (m, 2H).

[0100] 13 C{ 1 H NMR (151 MHz, CDCl3) d 212.0, 200.1, 160.8, 141.2, 137.9, 134.4, 129.7, 128.8, 127.5, 125.4, 125.2, 123.3, 118.7, 111.2, 71.6, 57.8, 43.5, 29.8, 28.9, 25.0.

[0101] IR v max 3383, 2919, 2849, 1726, 1690, 1620, 1608, 1590, 1490, 1466,1324, 1285, 1126, 1080, 1033, 748, 695 cm -1 .

[0102] HRMS (ESI) m / z calcd. for C 20 H 18 ClNNaO2 (M+Na) + :362.0918, found362.0920.

[0103] Example 8: 2-(4-methoxyphenyl)-3,3-genomicifluoro-3 H - Synthesis of I-2-C from indole as a starting material

[0104]

[0105] 2-(4-methoxyphenyl)-3,3-gesidifluoro-3 H -Indole (0.05 mmol) was dissolved in cyclohexanone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to obtain 19 mg of the I-2-C target product, with a yield of 90%.

[0106] 1 H NMR (600 MHz, CDCl3) d 7.48 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 9.0Hz, 3H), 6.92 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.9 Hz, 2H), 6.73 (t, J = 7.4Hz, 1H), 5.94 (s, 1H), 3.74 (s, 3H), 3.73 – 3.69 (m, 1H), 2.41 (m, 1H), 2.33– 2.29 (m, 1H), 2.15 – 2.09 (m, 1H), 2.04 – 1.99 (m, 1H), 1.83 – 1.74 (m, 2H), 1.70 – 1.58 (m, 2H).

[0107] 13 C{ 1 H NMR (151 MHz, CDCl3) d 212.3, 201.1, 160.9, 158.9, 137.6, 130.8, 126.1, 125.2, 119.0, 118.3, 114.0, 111.1, 71.6, 57.5, 55.2, 43.7, 30.0, 29.0, 25.1.

[0108] IR vmax 3389, 2925, 2856, 1686, 1618, 1508, 1486, 1465, 1321, 1248,1181, 1099, 829, 752 cm -1 .

[0109] HRMS (ESI) m / z calcd. for C21 H 22 NO3 (M+H) + :336.1594, found 336.1597.

[0110] Example 9: 2-Phenyl-3,3-genomicifluoro-3 H I-2-D was synthesized from indole.

[0111]

[0112] 2-Phenyl-3,3-gesidifluoro-3 H -Indole (0.05 mmol) was dissolved in cyclopentanone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to give 12 mg of the target product I-2-D, with a yield of 83%.

[0113] 1 H NMR (600 MHz, CDCl3) d 7.53 – 7.45 (m, 4H), 7.32 (t, J = 7.7 Hz,2H), 7.27 – 7.24 (m, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.80 (t, J = 7.4 Hz, 1H), 5.39 (s, 1H), 3.48 (dd, J = 12.6, 7.8 Hz, 1H), 2.41 – 2.27 (m, 1H), 2.17 –2.04 (m, 2H), 1.97 (m, 1H), 1.83 (m, 1H), 1.49 (m, 1H).

[0114] 13 C{ 1 H NMR (151 MHz, CDCl3) d 218.0, 200.1, 161.0, 137.8, 137.6, 128.7, 127.6, 125.5, 125.3, 119.4, 119.2, 111.6, 71.1, 54.4, 38.0, 25.3, 19.7.

[0115] IR vmax 3404, 2963, 2922, 1730, 1675, 1614, 1582, 1491, 1462, 1320,1294, 1277, 1141, 1098, 1074, 893, 751 cm -1 .

[0116] HRMS (ESI) m / z calcd. for C 19 H 18 NO2(M+H) + :292.1332, found 292.1331.

[0117] Example 10: 2-Thienyl-3,3-genomicifluoro-3 H Synthesis of I-2-E from indole as a starting material

[0118]

[0119] 2-Thienyl-3,3-gesidifluoro-3 H -Indole (0.05 mmol) was dissolved in cyclohexanone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to give 13 mg of the target product I-2-E, with a yield of 86%.

[0120] 1 H NMR (600 MHz, CDCl3) d 7.52 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 8.4Hz, 1H), 7.12 (d, J = 5.1 Hz, 1H), 7.04 (dd, J = 3.7, 1.3 Hz, 1H), 6.92 (dd, J = 8.1, 4.5 Hz, 2H), 6.78 (t, J = 7.4 Hz, 1H), 6.03 (s, 1H), 3.63 (dd, J =13.3, 4.5 Hz, 1H), 2.48 – 2.41 (m, 1H), 2.39 – 2.32 (m, 1H), 2.13 (m, 1H), 2.04 – 1.96 (m, 1H), 1.84 – 1.72 (m, 2H), 1.70 – 1.57 (m, 2H).

[0121] 13 C{ 1 H NMR (151 MHz, CDCl3) d 212.0, 199.4, 160.7, 144.0, 137.9, 127.3, 125.4, 124.1, 122.9, 118.8, 118.3, 111.3, 70.7, 58.5, 43.6, 29.9, 29.0, 25.0.

[0122] IR v max 3380, 2957, 2922, 2853, 1686, 1612, 1584, 1483, 1465, 1445,1319, 1291, 1236, 1126, 1080, 1038, 759, 704, 687 cm -1 .

[0123] HRMS (ESI) m / z calcd. for C 18 H 18 NO2S (M+H) + :312.1053, found 312.1066.

[0124] Example 11: 2-(3-bromophenyl)-3,3-genomicifluoro-3 H Synthesization of I-2-F from indole

[0125]

[0126] 2-(3-bromophenyl)-3,3-gesidifluoro-3 H -Indole (0.05 mmol) was dissolved in cyclohexanone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to give 16 mg of the target product I-2-F, with a yield of 86%.

[0127] 1 H NMR (600 MHz, CDCl3) d 7.69 (s, 1H), 7.47 (m, 3H), 7.36 – 7.32 (m,1H), 7.15 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.75 (t, J= 7.4 Hz,1H), 5.97 (s, 1H), 3.69 (dd, J = 12.6, 5.0 Hz, 1H), 2.41 (m, 1H), 2.34 – 2.30(m, 1H), 2.12 (dd, J = 10.2, 3.1 Hz, 1H), 2.03 – 1.96 (m, 1H), 1.83 – 1.73(m, 2H), 1.66 – 1.59 (m, 1H), 1.53 (dd, J = 12.7, 4.3 Hz, 1H).

[0128] 13 C{ 1 H NMR (151 MHz, CDCl3) d 212.0, 200.1, 160.8, 141.5, 137.9, 130.4, 130.0, 128.3, 125.2, 123.9, 122.7, 118.7, 118.6, 111.3, 71.5, 57.9, 43.5, 29.8, 28.9, 25.0.

[0129] IR v max 2917, 2849, 1694, 1619, 1487, 1466, 1323, 1289, 1260, 1129,1076, 749 cm -1 .

[0130] HRMS (ESI) m / z calcd. for C 20 H 19 BrNO2 (M+H) + :384.0594, found 384.0599.

[0131] Example 12: 2-Phenyl-3,3-genomicifluoro-3 H Synthesis of I-2-G from indole

[0132]

[0133] 2-Phenyl-3,3-gesidifluoro-3 H -Indole (0.05 mmol) was dissolved in 4-methylcyclohexanone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to give 12 mg of the target product I-2-G, with a yield of 80%.

[0134] 1 H NMR (600 MHz, CDCl3) d 7.52 – 7.44 (m, 4H), 7.28 (d, J = 7.7 Hz,2H), 7.22 – 7.18 (m, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.74 (t, J = 7.3 Hz, 1H), 5.98 (s, 1H), 3.84 (dd, J = 12.8, 4.9 Hz, 1H), 2.50-2.43 (m, 1H), 2.26 (m,1H), 2.12-2.02 (m, 2H), 1.95-1.90 (m, 1H), 1.42-1.24 (m, 3H), 0.89 (d, J = 6.5 Hz, 3H).

[0135] 13 C{ 1 H NMR (151 MHz, CDCl3) d 212.4, 200.8, 161.1, 138.9, 137.7, 128.6, 127.3, 125.3, 124.9, 118.9, 118.4, 111.2, 72.0, 56.3, 42.6, 37.5, 36.7, 31.9, 21.0.

[0136] IR v max 3391, 2956, 2926, 2861, 1685, 1618, 1583, 1489, 1464, 1325,1095, 906, 752, 726, 699, 648 cm -1 .

[0137] HRMS (ESI) m / z calcd. for C 21 H 22 NO2 (M+H) + :320.1645, found 320.1644.

[0138] Example 13: 2-Phenyl-3,3-genomicifluoro-3 H Synthesis of I-2-H from indole as a starting material

[0139]

[0140] 2-Phenyl-3,3-gesidifluoro-3 H -Indole (0.05 mmol) was dissolved in cycloheptanone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to give 12 mg of the target product I-2-H, with a yield of 74%.

[0141] 1 H NMR (600 MHz, CDCl3) d 7.59 (d, J = 7.8 Hz, 2H), 7.55 (d, J = 7.6Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.27 (d, J = 7.7Hz, 2H), 6.97 (d, J = 8.1 Hz, 1H), 6.82 (t, J = 7.4 Hz, 1H), 3.61 (dd, J =10.7, 2.6 Hz, 1H), 2.53 – 2.48 (m, 1H), 2.37 – 2.30 (m, 2H), 1.90 (dd, J =11.3, 6.1 Hz, 2H), 1.87 – 1.83 (m, 2H), 1.72 (dd, J = 7.6, 4.5 Hz, 1H), 1.68– 1.61 (m, 2H).

[0142] 13 C{ 1 H NMR (151 MHz, CDCl3) d 214.9, 200.9, 161.3, 138.7, 137.7, 128.6, 127.5, 125.2, 125.1, 118.7, 118.1, 111.1, 72.9, 56.6, 44.8, 28.9, 27.7, 27.1, 22.8.

[0143] IR v max3576, 3393, 2987, 2971, 2921, 1685, 1618, 1582, 1488, 1466,1405, 1325, 1273, 1141, 1065, 750, 727, 698, 486, 442 cm -1 .

[0144] HRMS (ESI) m / z calcd. for C 21 H 22 NO2(M+H) + :320.1645, found 320.1646.

[0145] Example 14: 2-Phenyl-3,3-genomicifluoro-3 H - Synthesis of I-2-I from indole as a raw material

[0146]

[0147] 2-Phenyl-3,3-gesidifluoro-3 H -Indole (0.05 mmol) was dissolved in tetrahydropyranone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to give 12 mg of the target product I-2-I, with a yield of 78%.

[0148] 1 H NMR (600 MHz, CDCl3) d 7.49 (d, J = 7.3 Hz, 4H), 7.30 (t, J = 7.8Hz, 2H), 7.23 (t, J = 7.3 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.78 (t, J = 7.4Hz, 1H), 5.83 (s, 1H), 4.35 – 4.19 (m, 2H), 4.03 (dd, J = 10.7, 6.0 Hz, 1H),3.61 (m, 1H), 3.44 (t, J = 10.7 Hz, 1H), 2.78 (m, 1H), 2.32 (m, 1H).

[0149] 13 C{ 1H NMR (151 MHz, CDCl3) d 207.2, 199.2, 160.5, 138.1, 137.9, 128.7, 127.6, 125.4, 124.7, 119.1, 118.7, 111.4, 70.4, 70.0, 69.2, 57.8, 44.5.

[0150] IR v max 3361, 2962, 2924, 2855, 1710, 1617, 1487, 1467, 1446, 1382,1321, 1121, 1129, 1095, 1030, 739, 709 cm -1 .

[0151] HRMS (ESI) m / z calcd. for C 19 H 18 NO3(M+H) + :308.1281, found 308.1281.

[0152] Example 15: 2-(4-fluorophenyl)-3,3-genomicifluoro-3 H - Synthesis of I-2-J from indole as a raw material

[0153]

[0154] 2-(4-fluorophenyl)-3,3-gesidifluoro-3 H -Indole (0.05 mmol) was dissolved in cyclohexanone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to obtain 15 mg of the target product I-2-J, with a yield of 86%.

[0155] 1 H NMR (600 MHz, CDCl3) d 7.51 (dd, J = 9.0, 5.1 Hz, 2H), 7.50 – 7.43(m, 2H), 6.96 (t, J = 8.7 Hz, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.75 (t, J = 7.4Hz, 1H), 5.98 (s, 1H), 3.70 (dd, J= 12.6, 5.0 Hz, 1H), 2.40 (m, 1H), 2.31(d, J = 10.1 Hz, 1H), 2.12 (m, 1H), 2.01 (dd, J = 7.8, 3.3 Hz, 1H), 1.84 –1.74 (m, 2H), 1.70 – 1.59 (m, 2H).

[0156] 13 C{ 1 H NMR (151 MHz, CDCl3) d 211.2, 199.7, 161.1 (d, J = 245.7 Hz),159.8, 136.8, 133.7, 125.8 (d, J = 7.8 Hz), 124.2, 117.7, 117.5, 114.3 (d, J = 21.5 Hz), 110.1, 70.5, 56.8, 42.6, 28.9, 27.9, 24.0.

[0157] 19 F NMR (565 MHz, CDCl3) d -115.75.

[0158] IR v max 3394, 2927, 1704, 1675, 1620, 1597, 1582, 1505, 1487, 1463,1328, 1272, 1223, 1083, 747 cm -1 .

[0159] HRMS (ESI) m / z calcd. for C 20 H 18 FNNaO2 (M+Na) + :346.1213, found 346.1213.

[0160] Example 16: Synthesis of I-2-K from 2-(3-bromo-4-fluorophenyl)-3,3-genomicifluoroindole

[0161]

[0162] 2-(3-bromo-4-fluorophenyl)-3,3-genomicifluoroindole (0.05 mmol) was dissolved in cyclohexanone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to give 17 mg of the target product I-2-K, with a yield of 87%.

[0163] 1 H NMR (600 MHz, CDCl3) d 7.75 (dd, J = 6.5, 2.4 Hz, 1H), 7.49 (d, J =7.7 Hz, 3H), 7.03 (t, J = 8.4 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.77 (t, J =7.4 Hz, 1H), 5.92 (s, 1H), 3.63 (dd, J = 12.6, 5.0 Hz, 1H), 2.41 (m, 1H), 2.36 – 2.30 (m, 1H), 2.13 (m, 1H), 2.00 (m, 1H), 1.88 – 1.67 (m, 3H), 1.67 –1.61 (m, 1H).

[0164] 13 C{ 1 H NMR (151 MHz, CDCl3) d 212.1, 200.1, 160.7, 158.4 (d, J =247.7 Hz), 138.0, 136.5, 136.5, 130.4, 128.8, 125.9 (d, J = 7.2 Hz), 125.2,118.8, 118.6, 116.3 (d, J = 22.4 Hz), 111.2, 70.9, 58.1, 43.5, 29.9, 28.9,25.0.

[0165] 19 F NMR (565 MHz, CDCl3) d -109.71.

[0166] IR v max3437, 2951, 2918, 1702, 1687, 1617, 1579, 1484, 1462, 1320,1239, 1080, 756 cm -1 .

[0167] HRMS (ESI) m / z calcd. for C 20 H 18 BrFNO2(M+H) + :402.0499, found 402.0503.

[0168] Example 17: Using 3,3-gesidifluoro-5-methyl-2-phenyl-3 H - Synthesis of I-2-L from indole as a raw material

[0169]

[0170] 3,3-gesidifluoro-5-methyl-2-phenyl-3 H -Indole (0.05 mmol) was dissolved in cyclohexanone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to give 13 mg of the target product I-2-L, with a yield of 84%.

[0171] 1 H NMR (600 MHz, CDCl3) d 7.50 (d, J = 7.8 Hz, 2H), 7.27 (q, J = 7.5Hz, 4H), 7.19 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 5.86 (s, 1H), 3.77 (dd, J = 12.7, 5.0 Hz, 1H), 2.42 – 2.36 (m, 1H), 2.30 (m, 1H), 2.23 (s,3H), 2.13 – 2.07 (m, 1H), 2.03 – 1.98 (m, 1H), 1.82 – 1.75 (m, 2H), 1.65 –1.52 (m, 2H).

[0172] 13 C{ 1 H NMR (151 MHz, CDCl3) d212.1, 200.8, 159.6, 139.1, 139.1, 128.5, 127.8, 127.2, 124.9, 124.5, 119.0, 111.1, 72.4, 57.4, 43.6, 29.8, 28.9, 25.1, 20.4.

[0173] IR v max 3402, 2927, 2859, 1685, 1626, 1582, 1496, 1445, 1431, 1378,1311, 1281, 1261, 1207, 1126, 1081, 1931, 944, 800, 751, 731, 698, 625, 539,516 cm -1 .

[0174] HRMS (ESI) m / z calcd. for C 21 H 22 NO2 (M+H) + :320.1645, found 320.1657.

[0175] Example 18: Using 3,3-genomicifluoro-5-fluoro-2-phenyl-3 H I-2-M was synthesized from indole.

[0176]

[0177] 3,3-gesidifluoro-5-fluoro-2-phenyl-3 H -Indole (0.05 mmol) was dissolved in cyclohexanone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to give 14 mg of the target product I-2-M, with a yield of 88%.

[0178] 1 H NMR (600 MHz, CDCl3) d 7.50 (d, J = 7.8 Hz, 2H), 7.29 (t, J = 7.7Hz, 2H), 7.22 (t, J = 7.3 Hz, 2H), 7.13 (d, J = 7.4 Hz, 1H), 6.89 (dd, J=8.9, 3.8 Hz, 1H), 5.91 (s, 1H), 3.76 (dd, J = 12.7, 4.9 Hz, 1H), 2.40 (dd, J = 13.3, 6.0 Hz, 1H), 2.31 (m, 1H), 2.16 – 2.09 (m, 1H), 2.01 (m, 1H), 1.87 –1.74 (m, 2H), 1.67 – 1.55 (m, 2H).

[0179] 13 C{ 1 H NMR (151 MHz, CDCl3) d 211.9, 200.5 (d, J = 3.4 Hz), 156.9, 156.1 (d, J = 239.2 Hz), 138.5, 128.6, 127.5, 125.7 (d, J = 25.7 Hz), 124.9,119.0 (d, J = 7.0 Hz), 112.1 (d, J = 7.5 Hz), 109.8 (d, J = 22.6 Hz). 73.2,57.6, 53.4, 43.6, 29.9, 28.9, 25.1.

[0180] IR v max 3388, 2923, 2853, 1804, 1698, 1628, 1491, 1453, 1376, 1277,1253, 1200, 1128, 1075, 1032, 957, 875, 818, 799, 784, 733, 698, 517cm -1 .

[0181] HRMS (ESI) m / z calcd. for C 20 H 19 FNO2 (M+H) + :324.1394, found 324.1398.

[0182] Example 19: 3,3-Genoderfluoro-7-ethyl-2-phenyl-3 H - Synthesis of I-2-N from indole

[0183]

[0184] 3,3-gesidifluoro-7-ethyl-2-phenyl-3 H -Indole (0.05 mmol) was dissolved in cyclohexanone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to give 14 mg of the target product I-2-N, with a yield of 85%.

[0185] 1 H NMR (600 MHz, CDCl3) d 7.49 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 7.8Hz, 1H), 7.33 – 7.26 (m, 3H), 7.21 (t, J = 7.3 Hz, 1H), 6.73 (t, J = 7.5 Hz,1H), 5.78 (s, 1H), 3.80 (dd, J = 12.6, 4.9 Hz, 1H), 2.71 (q, J = 7.6 Hz, 2H), 2.43 (m, 1H), 2.32 (m, 1H), 2.13 (dd, J = 10.2, 3.1 Hz, 1H), 2.03 (m, 1H), 1.80 (m, 2H), 1.72 – 1.56 (m, 2H), 1.36 (t, J = 7.5 Hz, 3H).

[0186] 13 C{ 1 H NMR (151 MHz, CDCl3) d 212.3, 201.0, 159.7, 139.0, 135.5, 128.6, 127.3, 126.2, 124.8, 122.5, 118.6, 118.4, 72.1, 57.6, 43.6, 30.0, 29.0, 25.1, 23.1, 13.1.

[0187] IR v max3434, 3365, 2970, 2940, 2877, 1692, 1605, 1594, 1499, 1463,1439, 1376, 1356, 1311, 1297, 1273, 1251, 1219, 1180, 1153, 1127, 1097, 1080,1042, 1030, 1010, 771, 747, 715, 698, 528, 514, 455 cm -1 .

[0188] HRMS (ESI) m / z calcd. for C 22 H 23 NO2 (M+H) + :334.1802, found 334.1812.

[0189] Example 20: 3,3-Gesdifluoro-6-methoxy-2-phenyl-3 H - Synthesis of I-2-O from indole as a raw material

[0190]

[0191] 3,3-gesidifluoro-6-methoxy-2-phenyl-3 H -Indole (0.05 mmol) was dissolved in cyclohexanone (1.0 mL), followed by the addition of chiral phosphoric acid (0.005 mmol). The mixture was stirred at 0 °C for 24 h, concentrated by rotary evaporation, and purified by column chromatography to give 11 mg of the target product I-2-O, with a yield of 65%.

[0192] 1 H NMR (600 MHz, CDCl3) d 7.50 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 7.6Hz, 2H), 7.20 (t, J = 7.3 Hz, 1H), 7.16 (m, 1H), 6.93 – 6.89 (m, 2H), 5.71(s, 1H), 3.76 (dd, J = 12.5, 4.8 Hz, 1H), 3.72 (s, 3H), 2.40 (m, 1H), 2.31(m, 1H), 2.14 – 2.10 (m, 1H), 2.06 – 1.98 (m, 2H), 1.81 (m, 3H).

[0193] 13 C{ 1 H NMR (151 MHz, CDCl3) d 210.9, 199.8, 156.0, 151.9, 138.0, 127.5, 127.4, 126.2, 123.9, 117.8, 111.6, 103.9, 72.0, 56.4, 54.7, 42.6, 28.8, 27.9, 24.1.

[0194] IR v max 3385, 2922, 2853, 1681, 1628, 1586, 1492, 1447, 1344, 1301,1263, 1222, 1180, 1147, 1127, 1082, 1027, 800, 780, 730, 699, 518cm -1 .

[0195] HRMS (ESI) m / z calcd. for C 21 H 21 NO3 (M+H) + :336.1594, found 336.1606.

[0196] Example 21

[0197] This embodiment tested the inhibitory effect of the C2-quaternary carbon indole-3-one compounds prepared in the above embodiments on the release of NO induced by LPS from mouse macrophages RAW264.7.

[0198] Lipopolysaccharide (LPS): Beijing Solarbio Science & Technology Co., Ltd.; NO reagent kit: Shanghai Beyotime Biotechnology Co., Ltd.

[0199] LPS-induced RAW264.7 cells were used as an inflammation model. Cells grown to the logarithmic growth phase were seeded into 96-well plates. The control group was given serum-free DMEM medium (containing 110 mg / L) for culture. -1 Sodium pyruvate, 4500 mg·L -1 Glucose (pH 7.0–7.4), the model group was given 1.0 μg / mL. -1 LPS, the drug group was given 1.0 μg / mL -1 LPS and 10 μmol·L -1 The solution of the compound to be tested.

[0200] Incubate at 37℃ for 24 h, then take 50 μL of the supernatant, add 50 μL of Griess A and Griess B reagents, measure the absorbance at 540 nm, and calculate the inhibition rate: Inhibition rate % = (A 模型 -A 药物 ) / (A 模型 -A 空白 ) × 100%. Specific test results are as follows: Figure 3 As shown.

[0201] In particular, compounds I-1-C and I-2-H exhibit the most prominent anti-inflammatory activity at a concentration of 10 μmol·L⁻¹. -1 The inhibition rates against NO reached 63.9% and 60.0%, respectively.

[0202] The above test results demonstrate that the C2-quaternary carbon indole-3-one compounds provided by this invention have a certain inhibitory effect on the release of NO from LPS-induced mouse macrophages RAW264.7, which can provide a basis for subsequent structural modification and development of novel anti-inflammatory drugs.

[0203] The above embodiments of the present invention do not describe all details exhaustively, nor do they limit the present invention to the embodiments described above. Various changes, modifications, substitutions, and variations made by those skilled in the art to these embodiments without departing from the principles and spirit of the present invention should be included within the scope of protection of the present invention.

Claims

1. A C2-quaternary carbon indole-3-one compound having the structure shown in general formula (I-1) or (I-2): or ; in: R1 is selected from halogen or C. 1-4 alkyl; R2 is selected from hydrogen or C. 1-4 alkyl; R3 is selected from hydrogen, halogens, and C. 1-4 Alkyl, C 1-4 Any one of the alkoxy groups; R4 is selected from hydrogen or C. 1-4 alkyl; R5 is selected from phenyl, thiophene, halophenyl, dihalophenyl, C 1-4 alkylphenyl or C 1-4 Any one of the alkoxyphenyl groups; X is selected from oxygen or carbon; n is an integer from 1 to 3.

2. The C2-quaternary carbon indole-3-one compound according to claim 1, wherein R1 is selected from chlorine or methyl; and R2 is selected from hydrogen or methyl.

3. The C2-quaternary carbon indole-3-one compound according to claim 1, wherein R3 is selected from any one of hydrogen, halogen, methyl, ethyl, and methoxy; R4 is selected from hydrogen or methyl; R5 is selected from any one of phenyl, halophenyl, dihalophenyl, tolyl, or methoxyphenyl; X is selected from oxygen or carbon; and n is an integer from 2 to 3.

4. The C2-quaternary carbon indole-3-one compound according to claim 1, wherein R3 is selected from hydrogen or halogen; R4 is selected from hydrogen or methyl; R5 is selected from any one of phenyl, halophenyl or dihalophenyl, X is carbon; and n is an integer from 2 to 3.

5. The method for preparing the C2-quaternary carbon indole-3-one compound according to claim 1, characterized in that: The compound of general formula (I-1) was prepared according to the following method: Using the indole-3-one derivative of general formula (II) as a substrate, a Mannich reaction was carried out with the pyrazolinone derivative of general formula (III) under triethylamine catalysis to obtain the intermediate of general formula (IV): ， ， ； in: R1 is selected from halogen or C. 1-4 alkyl; R2 is selected from hydrogen or C. 1-4 alkyl; The intermediate of the general structural formula (IV) is subjected to an acylation reaction with acetic anhydride to obtain the C2-quaternary carbon indole-3-one compound of the general structural formula (I-1).

6. The preparation method according to claim 5, characterized in that: The Mannich reaction was carried out at room temperature for 12–24 h; the acylation reaction was carried out at room temperature in DCM solvent in the presence of triethylamine catalyst for 0.5–1 h.

7. The method for preparing the C2-quaternary carbon indole-3-one compound according to claim 1, characterized in that: The compound of general formula (I-2) was prepared according to the following method: Using the 3,3-genomicifluoroindole derivative of general formula (V) as a substrate, a Mannich reaction was carried out with the compound of general formula (VI) under chiral phosphoric acid catalysis to obtain the C2-quaternary carbon indole-3-one compound of general formula (I-2): ， ； in: R3 is selected from hydrogen, halogens, and C. 1-4 Alkyl, C 1-4 Any one of the alkoxy groups; R4 is selected from hydrogen or C. 1-4 alkyl; R5 is selected from phenyl, thiophene, halophenyl, dihalophenyl, C 1-4 alkylphenyl or C 1-4 Any one of the alkoxyphenyl groups; X is selected from oxygen or carbon; n is an integer from 1 to 3.

8. The preparation method according to claim 7, characterized in that: The Mannich reaction was carried out at 0°C for 12–24 h.

9. The use of the C2-quaternary carbon indole-3-one compound according to any one of claims 1 to 4 in the preparation of a medicament for treating NO-mediated inflammatory diseases.

10. The application according to claim 9, wherein the NO-mediated inflammatory disease is sepsis, rheumatoid arthritis, or inflammatory bowel disease.

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