A method for preparing a heterocyclic bridged bisindole derivative by iodine-catalyzed cyclization-isomerization of a ynamine compound

Abstract

The application discloses a method for preparing a heterocyclic bridged double indole derivative through iodine-catalyzed cyclization isomerization of a ynamine compound. The method does not need to use a transition metal and an acid catalyst, and can be performed only under iodine catalysis, has high catalytic efficiency, does not need any anhydrous operation, has moderate reaction conditions, is simple, has moderate yield, has a wide substrate range, realizes chemoselectivity and controllable synthesis of a series of functionalized indole derivatives.

Description

Technical Field

[0001] This application belongs to the field of organic synthesis methodology technology, specifically relating to a method for preparing heterocyclic bridged bisindole derivatives by iodine-catalyzed cyclization and isomerization of acetyleneamine compounds. Background Technology

[0002] Bis(indole) motifs, comprising two indole motifs and an additional five- or six-membered heterocyclic unit, are widely distributed in various natural products and bioactive compounds, such as Nortopsentins, dragmacidins, and hamacanthins alkaloids (Formula 1). These compounds and their analogues have attracted considerable attention due to their broad pharmacological activities, including antibacterial, antiviral, and cytotoxic effects. Despite numerous strategies for their preparation, the development of practical and diverse multipurpose bis(indole) derivatives from readily available commercially available raw materials, particularly in an atom-economical and environmentally friendly manner, remains both promising and challenging.

[0003]

[0004] On the other hand, existing technologies have widely reported catalytic cyclization-isomerization reactions of alkynes to construct complex molecules, but these typical synthetic strategies are often limited by activated metals or Acid catalysts. Recently, the use of molecular iodine for the ring isomerization of alkynes has been explored to facilitate the construction of carbocyclic or heterocyclic rings in a convenient and practical manner. This has attracted considerable attention in organic synthesis because I2 has the advantages of transition metal-like activity, low toxicity, cost-effectiveness, commercial availability and ease of handling (Org. Biomol. Chem. 2016, 14, 7639; RSCAdv. 2013, 3, 7182; Chem. Rev. 2011, 111, 2937.). In particular, I2-mediated alkyne iodination has proven to be an efficient method for constructing various iodinated heterocycles. Due to the favorable alkyne affinity of molecular iodine, these iodinated heterocycles are considered useful intermediates in the synthesis of natural products and pharmaceuticals (J. Org. Chem. 2022, 87, 7531; Chem. Commun. 2020, 56, 1421; J. Org. Chem. 2020, 85, 2438; J. Org. Chem. 2019, 84, 9282; Chem. Commun. 2012, 48, 10748; Angew. Chem. Int. Ed. 2007, 46, 4764). Furthermore, iodine-catalyzed or promoted alkyne oxidative cyclization has been successfully applied to prepare valuable carbon or heterocycles, primarily derived from carbonyl intermediates from alkyne oxidation or radical species. Encouragingly, existing techniques have achieved catalytic regioselective cyclization isomerization of alkynes using molecular iodine as a π-acid catalyst. These synthetic strategies allow for simple one-step redox yielding of cyclized products without oxidants (Adv. Synth. Catal. 2012, 354, 2218; Org. Lett. 2017, 19, 6744; Chem. Commun. 2020, 56, 474; J. Org. Chem. 2021, 86, 8154). Despite these significant achievements, several limitations restrict further development, such as the use of excessive molecular iodine and oxidants. Furthermore, research on I2-catalyzed alkyne cyclization isomerization remains extremely rare, limited to simple one-step cyclizations, because iodine is a strong electrophile, more reactive than metals and... The acid has low reactivity. Developing I2-catalyzed dominoynylene cyclization isomerization to obtain complex molecules, especially synthetic pathways based on the sequential cleavage and formation of C-C bonds, is both challenging and attractive.

[0005] Alkynes, as highly useful building blocks, have attracted considerable attention over the past few decades. Numerous synthetic strategies based on alkynylamines as substrates for the preparation of various valuable heterocycles, particularly N-heterocycles, have been widely reported in existing techniques. In these synthetic strategies, transition metals or... Acid-catalyzed cyclization and isomerization of tryptamine-acetyleneamine substrates is particularly attractive because its high efficiency and atom economy enable the rapid assembly of a series of structurally complex indole derivatives. For example, multifunctional spiroindole products or polycyclic indole derivatives can be constructed via the 5-exo-dig cyclization reaction of tryptamine-acetyleneamine substrates (Org. Lett. 2005, 7, 1047; Chem. Asian). J. 2016, 11, 371; Chem.-Eur. J. 2018, 24, 4026; Adv. Synth. Catal. 2018, 360, 1483; Chem. Commun. 2019, 55, 14418; Adv. Synth. Catal. 2022, 364, 890), and the efficient and selective construction of azircono-[4,5-b]indole and spiro[4,4'-piperidine] compounds under non-noble metal catalyst conditions via 6-endo-dig cyclization reaction (ACS Catal. 2017, 7, 4004; Org. Biomol. Chem. 2019, 17, 2247; J. Org. Chem. 2020, 85, 3010; Chem. Commun. 2022, 58, 3051). Despite some progress, current synthetic strategies disclosed in existing technologies are limited to the 1,2-alkenyl migration or further substituent cyclization of spirocyclic intermediates. In stark contrast, a completely different approach based on spirocyclic intermediates, C(sp... 3 )-C(sp 3 The mechanism of alkyl bond cleavage remains immature and extremely challenging. More importantly, known catalytic cyclization and isomerization of indoleyl alkynylamine substrates are limited to the use of filtered metals or... Acids, but without metals and The cyclization and isomerization of acid-catalyzed indoleyl alkynylamine substrates remains to be explored.

[0006] Through extensive research on existing technologies and long-term in-depth studies by the inventors' research group, the inventors envisioned introducing an indole group into tryptamine-alkynylamine to achieve I2-catalyzed alkyne cyclization isomerization, involving a novel C(sp) group. 3 )-C(sp 3 By breaking and rearranging bonds, versatile indole derivatives can be synthesized with excellent chemoselectivity.

[0007] Therefore, this invention discloses a novel cyclization-isomerization reaction of indoleyl acetylamine substrates catalyzed by molecular iodine, leading to the chemoselective and controllable synthesis of a series of functionalized indole derivatives with moderate yields, a broad substrate range, and compatibility with known transition metals and... Compared to acid-catalyzed synthetic strategies, this provides a new pathway for catalyzing the cyclization and isomerization of alkynes. The synthetic strategy of this invention not only represents the first molecular iodine-catalyzed tandem cyclization and isomerization of alkynes—a complex process that is not a simple one-step cyclization—but also constitutes the first chemically selective cyclization and isomerization of tryptamine-alkynylamine compounds, involving a new C(sp...) 3 )-C(sp 3 This alkyl bond breaking / rearrangement process is significantly different from previous 1,2-olefin migrations or other cyclizations. In addition to achieving an excellent efficiency of 344 TON, I2 completely suppresses hydration, requiring no anhydrous operation. Furthermore, this I2-catalyzed indoleacetic amide cyclization likely involves a tandem 5-exo-dig cyclization / rearrangement process, which is strongly supported by control experiments and density functional theory (DFT) calculations. Summary of the Invention

[0008] The purpose of this invention is to enrich and develop existing synthetic strategies, providing a novel method for the iodine-catalyzed cyclization and isomerization of tryptamine-alkynylamine compounds to prepare heterocyclic bridged bisindole derivatives. This method does not require the use of transition metals and The acid catalyst can be used for the synthesis of a series of functionalized indole derivatives under iodine catalysis alone. It has high catalytic efficiency, requires no anhydrous operation, has mild and simple reaction conditions, moderate yield, and a wide substrate range.

[0009] According to the present invention, a method for preparing heterocyclic bridged bisindole derivatives by iodine-catalyzed cyclization and isomerization of alkynylamine compounds includes the following steps:

[0010] The acetylamine compound shown in Formula 1 was dissolved in an organic solvent, followed by the addition of iodine as a catalyst. The reaction mixture was stirred at a certain temperature until complete, and then purified to obtain the heterocyclic bridged bisindole derivative shown in Formula 2. The reaction formula is as follows:

[0011]

[0012] In the above reaction formula, n = 0 or 1; PG is an amino protecting group.

[0013] R1 is selected from substituted or unsubstituted C. 1-20 Alkyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted C 2-20 heteroaryl, substituted or unsubstituted C 3-20 cycloalkyl, substituted or unsubstituted C 2-20 alkenyl, substituted or unsubstituted C 2-20 alkynyl, tri(C) 1-20Alkyl)silyl; wherein the substituents in the substituted or unsubstituted form are selected from halogens, -OH, -SH, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkoxycarbonyl, C 1-6 Acyloxy group, C 1-6 Acyloxy-C 1-6 Alkyl, C 6-14 Aryl, C 6-14 Aryl-C 1-6 Alkyl, C 6-14 Aryl-C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 6-14 Aryloxy-C 1-6 alkyl,

[0014] R2,R 2’ They are independently selected from hydrogen, halogens, and carbon. 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 1-6 Halogenated alkoxy groups.

[0015] R3,R 3’ They are independently selected from hydrogen and C. 1-20 Alkyl, substituted or unsubstituted C 6-20 Aryl-C 1-20 Alkyl; wherein the substituents in the substituted or unsubstituted form are selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups.

[0016] R is selected from hydrogen, C 1-20 Alkyl, C 1-20 Haloalkyl, C 3-20 cycloalkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 6-20 Aryl, C 2-20 Mixed aromatic compounds.

[0017] Preferably, PG is selected from R4SO2- or p-methoxybenzyl, and R4 is selected from C 1-20 Alkyl, C 1-6 Halogenated alkyl, substituted or unsubstituted C 6-20Aryl; wherein the substituents in the substituted or unsubstituted form are selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl group.

[0018] R1 is selected from C 1-6 Alkyl, substituted or unsubstituted C 6-14 Aryl, C 2-12 heteroaryl, C 3-8 Cycloalkyl, phenyl-substituted C 2-6 alkenyl, phenyl substituted C 2-6 alkynyl, tri(C) 1-6 Alkyl)silyl; wherein the substituents in the substituted or unsubstituted form are selected from fluorine, chlorine, bromine, iodine, -OH, -SH, -CN, -NO2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetoxy, acetoxymethyl, phenyl, naphthyl, benzyl, benzyloxymethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, phenoxymethyl,

[0019] R2,R 2’ They are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, and trifluoromethoxy.

[0020] R3,R 3’ The C atoms are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, substituted or unsubstituted C atoms. 6-14 Aryl-C 1-6 Alkyl; wherein the substituents in the substituted or unsubstituted form are selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, and trifluoromethoxy.

[0021] R is selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-14 Aryl, C 2-12 Mixed aromatic compounds.

[0022] More preferably, PG is selected from methanesulfonyl, p-toluenesulfonyl, benzenesulfonyl, p-bromobenzenesulfonyl, and p-methoxybenzyl.

[0023] R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted phenyl, thiophene, furanyl, benzothiaphenyl, benzofuranyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, styryl, phenylethynyl, trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl; wherein the substituent in the substituted or unsubstituted group is selected from fluorine, chlorine, bromine, iodine, -OH, -SH, -CN, -NO2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetoxy, acetoxymethyl, phenyl, naphthyl, benzyl, benzyloxymethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, phenoxymethyl.

[0024] R2,R 2’ They are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, and trifluoromethoxy.

[0025] R3,R 3’ The substituents are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, substituted or unsubstituted benzyl; wherein the substituents in the substituted or unsubstituted are selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, trifluoromethoxy.

[0026] R is selected from hydrogen, methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, and phenyl.

[0027] Most preferably, when n = 0, the acetyleneamine compounds shown in Formula 1 are selected from compounds having the following structural formula:

[0028]

[0029] When n = 1, the acetylene amine compounds shown in Formula 1 are selected from compounds having the following structural formula:

[0030]

[0031] According to the aforementioned method of the present invention, the molar ratio of the acetylene amine compound shown in Formula 1 to the catalyst iodine is 1:0.001 to 1:0.2, preferably 1:0.0025 to 1:0.1, and most preferably 1:0.02 to 0.1.

[0032] According to the aforementioned method of the present invention, when n=0, the organic solvent is toluene, the specific temperature is room temperature to 80°C, and the reaction time to completion is 5 min to 48 h. The reaction temperature is room temperature, and the reaction time is preferably 10 min to 1 h, most preferably 10 min; when n=1, the organic solvent is acetonitrile, the specific temperature is 60-100°C, preferably 80°C; and the reaction time to completion is 6 h to 48 h, preferably 12 h to 24 h.

[0033] According to the aforementioned method of the present invention, the purification process is as follows: the reaction mixture is quenched with Na2S2O3 solution, extracted with ethyl acetate, dried, filtered and concentrated to obtain the residue, and the residue is separated by silica gel column chromatography to obtain the heterocyclic bridged bisindole derivative shown in Formula 2.

[0034] Furthermore, the compound shown in Formula 2 of the present invention, reacted in the presence of an oxidizing agent, can be used to prepare the compound shown in Formula X; the reaction formula is as follows:

[0035]

[0036] Where, R1, R2, R 2’ ,R3,R 3’ R and PG have the definitions described above; R" represents H or PG.

[0037] Furthermore, the compound shown in Formula 2 of the present invention, reacted in the presence of an oxidizing agent, can be used to prepare the compound shown in Formula Y; the reaction formula is as follows:

[0038]

[0039] Where n = 1, R1, R2, R 2’ ,R3,R 3’ R and PG have the characteristics defined above in this document.

[0040] Preferably, the oxidant is DDQ.

[0041] Compared with the prior art, the method of the present invention has the following significant advantages:

[0042] (1) This invention discloses for the first time a novel cyclization isomerization reaction of indole-based alkynylamine substrates under molecular iodine catalysis, which leads to the chemical selectivity and controllable synthesis of a series of functionalized indole derivatives with moderate yield and a wide substrate range.

[0043] (2) The method of the present invention does not require the use of transition metals and The acid catalyst has mild and simple reaction conditions, is easy to operate, and has a catalyst efficiency of up to 344 TON.

[0044] (3) The method of the present invention uses iodine as a catalyst. I2 completely inhibits hydration, eliminating the need for any anhydrous operation and making the reaction easier to implement.

[0045] (4) The mechanism of this invention involves a series of 5-exo-dig cyclication / rearrangement, involving a new C(sp) 3 )-C(sp 3 The (alkyl) bond breaking / rearrangement process provides a completely new reaction mechanism and synthetic route compared to the existing one-step cyclization reaction process. Attached Figure Description

[0046] Figure 1 Figure 1a and Figure 1b The image shows the X-ray diffraction pattern of compound 10.

[0047] Figure 2 The image shows the X-ray diffraction pattern of compound 43.

[0048] Figure 3 The image shows the X-ray diffraction pattern of compound 63. Detailed Implementation

[0049] The present invention will be further described in detail below with reference to specific embodiments.

[0050] Preparation of raw materials (Pure Appl. Chem. 2003, 75, 39; Acc. Chem. Res. 2022, 35, 984): The raw material compounds of this invention are prepared according to the following general formula. The reaction formula is as follows:

[0051]

[0052] The preparation steps are as follows:

[0053] Acetal compound S1 (20 mmol) was dissolved in acetonitrile (50 mL) at room temperature. Then, indole compound S2 (40 mmol) and diphenyl phosphate (DPP, 20 mmol, 5 g) were added. The mixture was heated to 80 °C and stirred for 5 hours. After the reaction was complete, it was cooled to room temperature, quenched with saturated sodium bicarbonate solution (80 mL), extracted with dichloromethane (80 mL * 3), dried over anhydrous magnesium sulfate, filtered, and the organic solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate) to give bisindole intermediate S3 (yield 80-90%).

[0054] The bisindole intermediate S3 (3 mmol) was dissolved in toluene (30 mL), followed by the addition of CuBr (3 mmol, 429 mg), K3PO4 (12 mmol, 2.54 g), alkynyl bromide (4.5 mmol), and DMEDA (3 mmol, 0.33 mL). The reaction mixture was heated to 60 °C and stirred until the reactants were completely consumed by TLC (approximately 4 h). The reaction mixture was filtered through a diatomaceous earth filter, and the organic solvent was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate) to obtain alkynylamine reactant S4 (yield 70-80%).

[0055] Examples 1-13: Optimization Experiments of Reaction Conditions

[0056] Using compound 1 as a template substrate, the effects of different synthetic conditions on the selectivity and yield of the target product were investigated. The results are shown in Table 1, and the reaction formulas are as follows:

[0057]

[0058] Table 1:

[0059]

[0060] [a] Reaction conditions: Compound 1 (0.05 mmol), catalyst (10 mol%), solvent (1.0 mL); air atmosphere.

[0061] [b]Yield was determined using 1,3,5-trimethoxybenzene as an internal standard. 1 Obtained by H NMR integral calculation.

[0062] Taking Example 11 as an example, the typical reaction operation is as follows:

[0063] Compound 1 (0.05 mmol) dissolved in toluene (1.0 mL) was added to an NMR tube reactor, followed by the addition of iodine (10 mol%, i.e., 0.005 mmol). The reaction was carried out at room temperature under air for 10 minutes. Then, a measured amount of 1,3,5-trimethoxybenzene was added as an internal standard. 1 H NMR integration calculations confirm the yield.

[0064] As shown in Table 1, using 10 mol% iodine as a catalyst, the target product 2 (Example 11) can be rapidly and selectively obtained by reacting in toluene solvent at room temperature for 10 minutes. Its yield and selectivity are far superior to those of transition metal catalysts used in existing synthesis methods. Acid catalysts (Examples 1-10). Iodine, as a catalyst, completely suppressed the formation of the hydrolysis byproduct (compound 4) without requiring any anhydrous treatment. The reaction could not proceed without the addition of a catalyst (Example 13). Surprisingly, compound 3 was selectively obtained in 85% yield with DCE as a solvent at 60°C for 10 hours (Example 12), which will be discussed in detail in other patent applications.

[0065] Example 14 General method for preparing the compound of the present invention (when n=0)

[0066] Taking the preparation of compound 2 as an example, the reaction formula is as follows:

[0067]

[0068] Procedure: Alkyne compound 1 (0.2 mmol) was dissolved in toluene (4 mL), followed by the addition of iodine (0.02 mmol, 5.1 mg) to the mixture. The reaction mixture was stirred at room temperature until the starting material was completely consumed by TLC (approximately 10 min). After the reaction was complete, the reaction mixture was quenched with Na₂S₂O₃ (aq., 5 mL), extracted with ethyl acetate (8 mL x 3), dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate) to give 125.5 mg of the target product shown in Formula 2, with a yield of 99%. 1 HNMR(400MHz, DMSO-d6)δ7.84(d,J=7.2Hz,1H),7.72(s,1H),7.44(d,J=7.6Hz,1H),7.40–7.35(m,3H),7.31–7.18(m,6H),7.14–6 .92(m,13H),5.47(s,2H),5.34(s,2H),5.05(dd,J=8.8,5.6Hz,1H),4.60–4.50(m,1H),4.00(dd,J=10.8,5.6Hz,1H),2.84(s,3H); 13C NMR (100MHz, DMSO-d6) δ138.3,138.1,136.5,135.8,135.2,132.2,131.1,128.5(1),128.4(8),127.8,127.7,127.6,127.5,127.3(1),127.2( 6),126.9,126.8,126.6,126.0,121.6,121.5,120.0,119.8,119.1,119.0,115.4,110.6,110.5,105.7,56.4,49.2,48.9,40.8,37.5; HRESIMS Calcd for[C 41 H 36 N3O2S] + (M+H + )634.2523,found 634.2525.

[0069] The following compounds were prepared according to the method of Example 14:

[0070]

[0071]

[0072] Structural characterization of the product:

[0073] Compound 5: 1 H NMR (400MHz, DMSO-d6) δ7.59(s,1H),7.52(d,J=7.6Hz,1H),7.46(d,J=7.6Hz,2H),7.39(d,J=8.0Hz,1H),7.33–7.19(m,1 2H),7.10–6.83(m,12H),5.47(s,2H),5.31–5.14(m,2H),4.58–4.43(m,2H),4.04(dd,J=15.2,12.0Hz,1H),2.39(s,3H).

[0074] Compound 6: 1 H NMR(400MHz,DMSO-d6)δ7.64(s,1H),7.58–7.52(m,3H),7.44–7.38(m,3H),7.33–7.17(m,10H),7.12–7.03(m, 3H),7.01–6.89(m,9H),5.51–5.39(m,2H),5.36–5.18(m,2H),4.66–4.53(m,2H),4.07(dd,J=9.2,5.2Hz,1H).

[0075] Compound 7: 1 H NMR (400MHz, DMSO-d6) δ7.74–6.69(m,1H),7.65(s,1H),7.61(d,J=7.6Hz,2H),7.52(d,J=7.6Hz,1H ),7.49–7.44(m,2H),7.41(d,J=8.4Hz,1H),7.35–7.27(m,4H),7.25(d,J=7.0Hz,1H),7.23–7.17(m, 5H),7.12–7.07(m,1H),7.07–7.02(m,1H),7.00–6.95(m,3H),6.93–6.84(m,7H),5.52–5.38(m,2H) ,5.30–7.12(m,2H),4.57(dd,J=11.2,10.0Hz,1H),4.48–4.41(m,1H),4.08(dd,J=11.2,7.6Hz,1H).

[0076] Compound 8: 1 H NMR (400MHz, DMSO-d6) δ7.84(d,J=6.8Hz,1H),7.72(s,1H),7.43(d,J=8.0Hz,1H),7.41–7.36(m,3H),7.30–7.19(m,6H),7.13–6.98(m,10H),6. 81–6.75(m,2H),5.47(s,2H),5.35(s,2H),5.07(dd,J=9.2,6.4Hz,1H),4.56(dd,J=11.6,9.2Hz,1H),4.00(dd,J=11.6,6.4Hz,1H),2.86(s,3H).

[0077] Compound 9: 1 H NMR (400MHz, DMSO-d6) δ7.84(dd,J=6.8,1.6Hz,1H),7.72(s,1H),7.46–7.36(m,4H),7.30–7.20(m,6H),7.14–7.06(m,5H),7.04–6.96( m,7H),5.48(s,2H),5.34(s,2H),5.09(dd,J=9.6,6.4Hz,1H),4.58(dd,J=11.2,9.6Hz,1H),4.02(dd,J=11.2,6.4Hz,1H),2.87(s,3H).

[0078] Compound 10: 1H NMR(400MHz, DMSO-d6)δ7.87(d,J=6.0Hz,1H),7.74(s,1H),7.50–7.38(m,4H),7.33–7.21(m,7H),7.17–7.10(m,7H),7.0 1–6.95(m,4H),5.50(s,2H),5.36(s,2H),5.16–5.09(m,1H),4.66–4.54(m,1H),4.05(dd,J=9.6,5.2Hz,1H),2.90(s,3H).

[0079] Compound 11: 1 H NMR(400MHz, DMSO-d6)δ7.86–7.82(m,1H),7.74(s,1H),7.44–7.36(m,4H),7.30–7.24(m,5H),7.21–7.16(m,5H),7.13–7.02 (m,6H),6.98–6.94(m,2H),5.48(s,2H),5.34(s,2H),5.19–5.10(m,1H),4.65–4.57(m,1H),4.05–3.95(m,1H),2.88(s,3H).

[0080] Compound 12: 1 H NMR(400MHz,DMSO-d6)δ7.86–7.82(m,1H),7.76(s,1H),7.51(d,J=8.8Hz,2H),7.42 (d,J=8.4Hz,2H),7.39–7.36(m,2H),7.29–7.23(m,3H),7.20–7.12(m,8H),7.11–7.0 6(m,2H),7.03–6.95(m,3H),5.48(s,2H),5.33(s,2H),5.17(dd,J=9.6,6.4Hz,1H),4 .62(dd,J=11.2,9.6Hz,1H),4.05(dd,J=11.2,6.4Hz,1H),3.74(s,3H),2.89(s,3H).

[0081] Compound 13: 1H NMR(400MHz,DMSO-d6)δ7.86(d,J=7.2Hz,1H),7.72(s,1H),7.48(d,J=7.6Hz,1H),7.42–7. 38(m,3H),7.33–7.27(m,3H),7.26–7.21(m,3H),7.17–7.09(m,5H),7.06–7.02(m,3H),6.9 7(d,J=8.0Hz,2H), 6.77(d,J=8.0Hz,2H), 5.49(s,2H), 5.36(s,2H), 5.06(dd,J=9.6,6.0Hz,1H), 4.56(dd,J=11.6,9.6Hz,1H), 4.01(dd,J=11.6,6.0Hz,1H), 2.85(s,3H), 2.11(s,3H)

[0082] More information: 14: 1 H NMR(400MHz,DMSO-d6)δ7.87–7.84(m,1H),7.72(s,1H),7.48(d,J=8.0Hz,1H), 7.41–7.36(m,3H),7.30–7.20(m,6H),7.15–7.08(m,5H),7.04–6.98(m,5H),6.5 2(d,J=8.8Hz,2H), 5.48(s,2H), 5.35(s,2H), 5.02(dd,J=9.6,6.0Hz,1H), 4.53(dd,J=11.2,9.6Hz,1H), 3.99(dd,J=11.2,6.0Hz,1H), 3.57(s,3H), 2.82(s,3H)

[0083] More information: 15: 1 H NMR(400MHz,DMSO-d6)δ7.86(d,J=7.2Hz,1H),7.76(s,1H),7.52(d,J=7.6Hz,1H) ,7.44–7.39(m,3H),7.32–7.19(m,6H),7.16(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2 H),7.10–6.94(m,8H),5.49(s,2H),5.41–5.30(m,2H),4.95(dd,J=9.6,4.8Hz,1H ),4.51(t,J=10.8Hz,1H),3.96(dd,J=11.2,4.8Hz,1H),2.78(s,3H),1.11(s,9H)。

[0084] More information: 16: 1H NMR(500MHz,DMSO-d6)δ7.85(d,J=7.5Hz,1H),7.74(s,1H),7.48(d,J=7.5Hz,1H) ,7.41–7.37(m,3H),7.32–7.28(m,2H),7.26–7.18(m,4H),7.14–7.00(m,10H),6. 95(d,J=8.0Hz,2H),5.48(s,2H),5.35(s,2H),5.07(dd,J=9.5,6.0Hz,1H),4.87( s,2H),4.58–4.52(m,1H),4.00(dd,J=11.0,6.0Hz,1H),2.84(s,3H),1.98(s,3H).

[0085] Compound 17: 1 H NMR(400MHz,acetone-d6)δ7.92–7.87(m,1H),7.62(s,1H),7.51(d,J=8.0Hz ,1H),7.36–7.31(m,3H),7.27–7.08(m,11H),7.03–6.98(m,3H),6.96–6.85( m,3H),6.69–6.63(m,1H),5.44(s,2H),5.29(s,2H),5.08(dd,J=9.6,6.0Hz, 1H), 4.62 (dd, J=11.6, 9.6Hz, 1H), 4.20 (dd, J=11.6, 6.0Hz, 1H), 2.71 (s, 3H).

[0086] Compound 18: 1 H NMR(400MHz, DMSO-d6)δ7.82(d,J=7.2Hz,1H),7.76(s,1H),7.44–7.41(m,2H),7.38(d,J=8.0Hz,2H),7.31–7.18(m,7H),7.13–7.06(m,6H),7.04 –6.98(m,4H),6.96(s,1H),5.49(s,2H),5.36(s,2H),5.09(dd,J=9.6,6 .4Hz, 1H), 4.59–4.52 (m, 1H), 3.99 (dd, J = 11.6, 6.4Hz, 1H), 2.86 (s, 3H).

[0087] Compound 19: 1H NMR (400MHz, acetone-d6) δ7.87(d,J=7.2Hz,1H),7.60(s,1H),7.48(d,J=7.6Hz,1H),7.35–7.25(m,6H),7.24–7.14(m,6H),7.11–7 .00(m,8H),6.83–6.75(m,1H),5.44(s,2H),5.29(s,2H),5.11–5.04(m,1H),4.61(t,J=10.0Hz,1H),4.24–4.15(m,1H),2.71(s,3H).

[0088] Compound 20: 1 H NMR(400MHz, DMSO-d6)δ7.83(d,J=6.8Hz,1H),7.72(s,1H),7.45–7.35(m,4H),7.30–7.19(m,5H),7.14–6.98(m,10H),6.83–6.74(m ,3H),5.47(s,2H),5.34(s,2H),5.07–5.00(m,1H),4.53(t,J=10.0Hz,1H),3.99(dd,J=10.4,5.6Hz,1H),2.83(s,3H),1.92(s,3H).

[0089] Compound 21: 1 H NMR(400MHz,acetone-d6)δ7.97–7.92(m,1H),7.65(s,1H),7.55(d,J=8.0Hz,1H),7.42–7.37(m,3 H),7.34–7.21(m,8H),7.18–7.11(m,3H),7.10–7.04(m,3H),6.91–6.86(m,1H),6.82–6.78(m,1H), 6.74–6.72(m,1H),6.54(dd,J=8.0,2.0Hz,1H),5.49(s,2H),5.35(d,J=4.0Hz,2H),5.09(dd,J=9.6 ,5.6Hz,1H),4.64(dd,J=11.6,9.6Hz,1H),4.23(dd,J=11.6,5.6Hz,1H),3.17(s,3H),2.74(s,3H).

[0090] Compound 22: 1H NMR(400MHz, DMSO-d6)δ7.83–7.79(m,1H),7.59(s,1H),7.43(d,J=8.0Hz,1H),7.32–7.29(m,3H),7.26–7.17(m,6H),7.05–6.87(m,11H), 6.75–6.70(m,1H),5.40(s,2H),5.30(s,2H),5.25–5.19(m,1H),4.65(dd,J=11.2,10.4Hz,1H),4.05(dd,J=11.2,9.2Hz,1H),3.05(s,3H).

[0091] Compound 23: 1 H NMR(400MHz,DMSO-d6)δ7.85–7.80(m,1H),7.71(s,1H),7.46(d,J=8.0Hz,1H),7.40–7.3 4(m,3H),7.28–7.24(m,3H),7.23–7.20(m,3H),7.13–7.07(m,5H),7.04–7.01(m,3H),6. 61–6.58(m,1H),6.55–6.50(m,2H),5.80(s,2H),5.48(s,2H),5.35(s,2H),5.00(dd,J=9 .6, 6.0Hz, 1H), 4.50 (dd, J=11.6, 9.6Hz, 1H), 3.95 (dd, J=11.6, 6.0Hz, 1H), 2.82 (s, 3H).

[0092] Compound 24: 1 H NMR (400MHz, DMSO-d6) δ7.81–7.77(m,2H),7.64(d,J=8.4Hz,1H),7.55(s,1H),7.51(d,J =7.6Hz,1H),7.38(s,1H),7.32–7.29(m,2H),7.22–7.15(m,8H),7.08–7.03(m,2H),7.01– 6.97(m,2H),6.95–6.87(m,3H),6.84–6.80(m,2H),5.32(s,2H),5.27(s,2H),5.21(dd,J= 9.6, 8.0Hz, 1H), 4.70 (dd, J=11.6, 9.6Hz, 1H), 4.11 (dd, J=11.6, 8.0Hz, 1H), 3.02 (s, 3H).

[0093] Compound 25: 11H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.36–7.24 (m, 6H), 7.23–7.16 (m, 6H), 7.15–7.12 (m, 3H), 7.10 (d, J = 7.5 Hz, 2H), 7.06–7.01 (m, 5H), 6.94 (d, J = 16.0 Hz, 1H), 6.39 (d, J = 16.0 Hz, 1H), 5.35 (s, 2H), 5.29 (d, J = 16.0 Hz, 1H), 5.17 (d, J = 16.0 Hz, 1H), 4.63 (dd, J = 9.0, 2.0 Hz, 1H), 4.50 (dd, J = 12.0, 9.0 Hz, 1H), 4.26 (dd, J = 12.0, 2.0 Hz, 1H), 2.35 (s, 3H).

[0094] Compound 26: 1 1H NMR (400 MHz, CDCl3) δ 8.06–7.98 (m, 1H), 7.80–7.72 (m, 2H), 7.36–7.28 (m, 6H), 7.25–7.17 (m, 10H), 7.14–7.09 (m, 4H), 6.94–6.89 (m, 2H), 5.43–5.31 (m, 4H), 4.71–4.60 (m, 2H), 4.29–4.21 (m, 1H), 2.65 (s, 3H).

[0095] Compound 27: 1 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.66–7.62 (m, 1H), 7.48–7.41 (m, 3H), 7.33–7.27 (m, 4H), 7.26–7.18 (m, 6H), 7.17–7.05 (m, 4H), 5.50 (s, 2H), 5.43 (s, 2H), 4.26 (dd, J = 11.2, 9.2 Hz, 1H), 4.15 (dd, J = 9.2, 3.6 Hz, 1H), 3.80 (dd, J = 11.2, 3.6 Hz, 1H), 2.62 (s, 3H), 1.50–1.40 (m, 1H), 0.50–0.30 (m, 3H), 0.20–0.12 (m, 1H).

[0096] Compound 28: 11H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.31–7.24 (m, 4H), 7.19–7.01 (m, 9H), 6.87–6.81 (m, 1H), 6.63 (d, J = 7.6 Hz, 2H), 6.09 (s, 1H), 5.38 (d, J = 15.6 Hz, 1H), 5.31 (d, J = 15.6 Hz, 1H), 5.26 (d, J = 16.8 Hz, 1H), 4.90 (dd, J = 10.4, 7.6 Hz, 1H), 4.78 (d, J = 16.8 Hz, 1H), 4.34 (dd, J = 14.8, 7.6 Hz, 1H), 3.54 (dd, J = 14.8, 10.4 Hz, 1H), 2.69 (s, 3H), 1.29 (s, 9H).

[0097] Compound 29: 1 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 7.5 Hz, 1H), 7.36–7.29 (m, 5H), 7.28–7.23 (m, 3H), 7.18–7.12 (m, 4H), 7.08–7.03 (m, 2H), 6.98–6.88 (m, 2H), 6.51 (d, J = 7.5 Hz, 2H), 6.35 (s, 1H), 5.31 (d, J = 15.0 Hz, 1H), 5.20 (d, J = 15.0 Hz, 1H), 5.15 (d, J = 16.5 Hz, 1H), 4.62 (d, J = 16.5 Hz, 1H), 4.45–4.30 (m, 2H), 3.85–3.65 (m, 1H), 2.46 (s, 3H), 1.49–1.39 (m, 3H), 1.16 (dd, J = 10.0, 7.5 Hz, 18H).

[0098] Compound 30: 1H NMR(400MHz, DMSO-d6)δ7.74–7.71(m,2H),7.66(d,J=8.0Hz,1H),7.50(s,1H),7.48–7.4 2(m,2H),7.29–7.22(m,6H),7.20–7.12(m,10H),7.10–7.03(m,3H),5.48(s,2H),5.41(d, J=2.8Hz,2H),4.65(dd,J=10.0,6.0Hz,1H),4.46(dd,J=11.6,10.0Hz,1H),4.27(d,J=12. 0Hz, 1H), 4.12 (d, J = 12.0Hz, 1H), 3.95 (dd, J = 11.6, 6.0Hz, 1H), 3.84 (s, 2H), 2.78 (s, 3H).

[0099] Compound 31: 1 H NMR(400MHz,DMSO-d6)δ7.66(s,1H),7.60(s,1H),7.32–7.30(m,2H),7.27–7.21( m,5H),7.20–7.16(m,3H),7.06(d,J=7.6Hz,2H),7.04–7.00(m,2H),6.98–6.90(m ,7H),5.42(s,2H),5.29(s,2H),5.00(dd,J=10.0,5.6Hz,1H),4.53(dd,J=11.2,1 0.0Hz, 1H), 3.96 (dd, J = 11.2, 5.6Hz, 1H), 2.85 (s, 3H), 2.42 (s, 3H), 2.32 (s, 3H).

[0100] Compound 32: 1 H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.73(s,1H),7.51–7.37(m,4H),7.30–7.17(m,6H),7.10–6.91(m, 11H),5.46(s,2H),5.32(s,2H),5.18–5.10(m,1H),4.66–4.52(m,1H),4.01–3.92(m,1H),2.95(s,3H).

[0101] Compound 33: 1H NMR(400MHz,DMSO-d6)δ8.08(d,J=2.0Hz,1H),7.70(s,1H),7.66–7.63(m,1H), 7.43(s,1H),7.38–7.32(m,2H),7.30–7.18(m,8H),7.08–7.05(m,2H),7.04–6. 96(m,5H),6.94–6.90(m,2H),5.45(s,2H),5.32(s,2H),5.14(dd,J=9.6,6.4Hz , 1H), 4.60 (dd, J = 11.6, 10.4Hz, 1H), 3.95 (dd, J = 11.6, 6.8Hz, 1H), 2.96 (s, 3H).

[0102] Compound 34: 1 H NMR(400MHz, DMSO-d6)δ7.81(dd,J=8.8,6.0Hz,1H),7.71(s,1H),7.42–7.36(m,2H),7.31–7.19(m,8H),7.11(d,J=6.8Hz,2H),7.04–6.8 6(m,9H),5.44(s,2H),5.31(s,2H),5.06(dd,J=8.8,6.0Hz,1H),4.54(dd,J=11.2,8.8Hz,1H),3.96(dd,J=11.2,6.0Hz,1H),2.87(s,3H).

[0103] Compound 35: 1 H NMR (400MHz, DMSO-d6) δ7.84(d,J=8.4Hz,1H),7.76(s,1H),7.52(dd,J=6.8,1.2Hz,2H),7.45–7.41(m,2H),7.32–7.18(m,7H),7.14 –6.95(m,10H),5.48(s,2H),5.35(s,2H),5.10(dd,J=9.2,6.4Hz,1H),4.61–4.53(m,1H),3.98(dd,J=11.6,6.4Hz,1H),2.90(s,3H).

[0104] Compound 36: 11H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.64 (dd, J = 6.4, 1.2 Hz, 2H), 7.40 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.32–7.25 (m, 3H), 7.22–7.18 (m, 4H), 7.13 (dd, J = 8.4, 1.2 Hz, 1H), 7.09 (d, J = 7.2 Hz, 2H), 7.02–6.93 (m, 7H), 5.47 (s, 2H), 5.35 (s, 2H), 5.09 (dd, J = 9.6, 6.8 Hz, 1H), 4.54 (dd, J = 11.6, 9.6 Hz, 1H), 3.95 (dd, J = 11.6, 6.8 Hz, 1H), 2.89 (s, 3H).

[0105] Compound 37: 1 1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.34–7.27 (m, 4H), 7.25–7.19 (m, 4H), 7.18–7.16 (m, 2H), 7.12–7.08 (m, 2H), 7.07–7.03 (m, 2H), 6.99–6.93 (m, 5H), 6.89 (dd, J = 8.0, 0.8 Hz, 1H), 6.84 (dd, J = 8.4, 0.8 Hz, 1H), 5.43 (s, 2H), 5.30 (s, 2H), 5.00 (dd, J = 9.6, 6.0 Hz, 1H), 4.52 (dd, J = 11.6, 9.6 Hz, 1H), 3.97 (dd, J = 11.6, 6.0 Hz, 1H), 2.82 (s, 3H), 2.35 (s, 3H), 2.34 (s, 3H).

[0106] Compound 38: 11H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.31–7.15 (m, 8H), 7.12–7.08 (m, 2H), 7.00–6.96 (m, 3H), 6.92–6.88 (m, 3H), 6.80 (d, J = 7.2 Hz, 2H), 6.70–6.66 (m, 2H), 5.66 (s, 2H), 5.55 (s, 2H), 5.09 (dd, J = 9.6, 6.4 Hz, 1H), 4.58 (dd, J = 11.2, 9.6 Hz, 1H), 4.03 (dd, J = 11.2, 6.0 Hz, 1H), 2.91 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H).

[0107] Compound 39: 1 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 0.4 Hz, 1H), 7.87–7.81 (m, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H), 7.38–7.34 (m, 2H), 7.26–7.22 (m, 1H), 7.21–7.15 (m, 4H), 7.13 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 7.03–6.97 (m, 3H), 6.92–6.84 (m, 3H), 6.54 (d, J = 2.0 Hz, 1H), 4.61 (dd, J = 11.6, 8.8 Hz, 1H), 4.44 (dd, J = 8.8, 4.4 Hz, 1H), 4.32 (dd, J = 11.6, 4.4 Hz, 1H).

[0108] Compound 40: 1 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.45–7.35 (m, 4H), 7.13–7.05 (m, 7H), 7.03–6.94 (m, 6H), 6.86 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 8.0 Hz, 2H), 5.39 (s, 2H), 5.26 (s, 2H), 5.04 (dd, J = 8.8, 6.8 Hz, 1H), 4.61–4.50 (m, 1H), 4.05–3.95 (m, 1H), 3.71 (s, 3H), 3.68 (s, 3H), 2.83 (s, 3H).

[0109] Compound 41: 1H NMR (500MHz, DMSO-d6) δ8.10(d,J=8.0Hz,2H),7.90(d,J=8.0Hz,2H),7.86(d,J=7.0Hz,1H),7.77 (s,1H),7.49(d,J=7.5Hz,1H),7.44–7.36(m,3H),7.27–7.15(m,5H),7.13–7.06(m,10H),7.04–6. 98(m,3H),5.48(s,2H),5.35(s,2H),5.20(s,2H),5.10–5.03(m,1H),4.60–4.51(m,1H),4.00(dd, J=10.5,5.0Hz,1H),3.02(t,J=6.5Hz,4H),2.85(s,3H),1.49–1.40(m,4H),0.78(t,J=7.0Hz,6H).

[0110] Compound 42: 1 H NMR(500MHz,DMSO-d6)δ7.85(d,J=7.0Hz,1H),7.74(s,1H),7.45(d,J=6.0Hz,1H),7.41–7.36(m,3H),7.32–7 .27(m,2H),7.24–7.16(m,4H),7.15–7.06(m,5H),7.05–6.98(m,5H),6.89(d,J=7.5Hz,2H),5.48(s,2H),5.34 (s,2H),5.28–5.23(m,1H),5.11–5.02(m,2H),4.56(t,J=10.5Hz,1H),4.23(s,2H),4.01(dd,J=9.5,6.5Hz,1 H),3.87(d,J=5.5Hz,2H),2.85(s,3H),2.06–2.00(m,2H),1.99–1.93(m,2H),1.59(s,3H),1.55–1.50(m,6H).

[0111] Example 15 General method for preparing the compound of the present invention (when n=1)

[0112] Taking the preparation of compound 43 as an example, the reaction formula is as follows:

[0113]

[0114] Procedure: Alkyne compound A (0.2 mmol) was dissolved in acetonitrile (5.7 mL), followed by the addition of iodine (0.02 mmol, 5.1 mg) to the mixture. The reaction mixture was stirred at 80 °C until the starting material was completely consumed by TLC (approximately 24 h). After the reaction was complete, the reaction mixture was quenched with Na₂S₂O₃ (aq., 5 mL), extracted with ethyl acetate (8 mL x 3), dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate) to give 58.3 mg of the target product shown in Formula 43, with a yield of 45%. 1 HNMR (500MHz, CDCl3) δ7.86 (s, 1H), 7.71 (d, J = 4.0Hz, 1H), 7.23–7.14 (m, 12H), 6.96–6.84 (m, 9H) ,6.75–6.69(m,2H),5.22(s,2H),5.15(s,2H),4.69–3.37(m,3H),2.61–2.49(m,2H),2.46(s,3H); 13 C NMR (125MHz, CDCl3) δ141.4,137.5,136.9,136.6,135.3,131.3,130.1,129.1,128.5(3),128.4(7),127.7,127.3(2),127.2(6),127.2,127 .1,126.3(4),126.2(5),125.4,121.8,121.7,120.1,119.5,119.1,117.0,111.1,110.1,109.6,49.9,49.6,43.3,43.2,31.9,29.6; HRESIMS Calcd for[C 42 H 38 N3O2S] + (M+H + )648.2679,found648.2677.

[0115] The following compounds were prepared according to the method of Example 15:

[0116]

[0117] Product structure characterization:

[0118] Compound 44: 1H NMR(400MHz, CDCl3)δ7.78(d,J=6.0Hz,1H),7.30(d,J=7.2Hz,1H),7.24–7.20(m,8H),7.19–7.13(m,3H),7.02–6.93(m,2H),6.91 –6.83(m,9H),6.80–6.70(m,5H),5.21(s,2H),5.08(s,2H),4.50–4.26(m,2H),4.05–3.75(m,1H),2.49–2.34(m,2H),2.21(s,3H).

[0119] Compound 45: 1 H NMR(400MHz, CDCl3)δ7.83(s,1H),7.24–7.15(m,10H),7.09–7.02(m,3H),7.00–6.93(m,2H),6.92–6.83( m,10H),6.81–6.77(m,2H),6.70(s,1H),5.22(s,2H),5.07(s,2H),4.68–3.65(m,3H),2.60–2.40(m,2H).

[0120] Compound 46: 1 H NMR(400MHz,DMSO-d6)δ7.69(d,J=7.6Hz,1H),7.30–7.14(m,14H),7.10–6.97(m,4H),6.95 –6.76(m,8H),6.72–6.68(m,1H),5.32–5.20(m,4H),4.56–3.54(m,3H),2.30–2.13(m,2H).

[0121] Compound 47: 1 H NMR(400MHz, DMSO-d6)δ7.69(d,J=7.6Hz,2H),7.32–7.13(m,13H),7.10–6.96(m, 5H),6.95–6.79(m,9H),5.36–5.17(m,4H),4.70–3.60(m,3H),2.36–2.10(m,2H).

[0122] Compound 48: 1H NMR (400MHz, DMSO-d6) δ7.69 (d, J=6.8Hz, 1H), 7.30–7.14 (m, 14H), 7.10–7.00 (m, 5H), 6.96–6. 90(m,4H),6.87–6.76(m,4H),5.31(s,2H),5.24(s,2H),4.63–3.95(m,3H),2.33–2.05(m,2H).

[0123] Compound 49: 1 H NMR(400MHz,acetone-d6)δ7.84(s,1H),7.30–7.10(m,15H),7.09–7.01(m,3H),6.97–6.90(m,3H),6.89–6. 81(m,3H),6.80–6.67(m,3H),5.29(s,2H),5.21(s,2H),4.75–3.85(m,3H),2.57–2.25(m,2H),1.88(s,3H).

[0124] Compound 50: 1 H NMR(400MHz, CDCl3)δ7.79(s,2H),7.22–7.08(m,11H),7.05–6.93(m,3H),6.92–6.79(m,7H),6.77–6.66(m,4H) ,6.53–6.37(m,2H),6.33(s,1H),5.17(s,2H),5.03(s,2H),4.80–3.41(m,3H),3.04(s,3H),2.62–2.14(m,2H).

[0125] Compound 51: 1 H NMR (400MHz, CDCl3) δ7.82(s,1H),7.24–7.19(m,8H),7.18–7.13(m,3H),7.07–7.02(m,3H),6.99(d,J=8.0Hz,1H),6.92(d,J=8.4Hz,2H) ,6.89–6.81(m,4H),6.80–6.75(m,3H),6.67(s,1H),6.52–6.46(m,2H),5.21(s,2H),5.07(s,2H),4.65–3.53(m,3H),2.61–2.27(m,2H).

[0126] Compound 52: 1H NMR(400MHz, DMSO-d6)δ7.69(d,J=7.2Hz,1H),7.28(d,J=7.6Hz,2H),7.24–7.15(m,12H),7.09–6.98(m,4H) ,6.93–6.85(m,7H),6.82(d,J=5.6Hz,2H),5.28(s,2H),5.24(s,2H),4.63–3.54(m,3H),2.35–1.89(m,2H).

[0127] Compound 53: 1 H NMR(500MHz,DMSO-d6)δ7.69(d,J=5.5Hz,1H),7.31–7.14(m,12H),7.10–6.98(m,6H) ,6.95–6.75(m,9H),5.28(s,2H),5.24(s,2H),4.60–3.75(m,3H),2.31–2.03(m,2H).

[0128] Compound 54: 1 H NMR(400MHz,DMSO-d6)δ7.80–7.68(m,1H),7.31–7.11(m,18H),7.07–6.99(m,3H),6.96– 6.91(m,1H),6.89–6.76(m,5H),5.34–5.19(m,4H),4.70–3.53(m,2H),2.35–2.09(m,1H).

[0129] Compound 55: 1 H NMR (400MHz, DMSO-d6) δ7.71(d,J=7.2Hz,1H),7.28(d,J=8.0Hz,2H),7.22–7.16(m,10H),7.05(d,J=8.0Hz,2H),7.03–6.97(m,2H),6.9 5–6.88(m,4H),6.86–6.78(m,5H),6.66(d,J=8.0Hz,2H),5.29(s,2H),5.22(s,2H),4.50–3.65(m,3H),2.34–2.13(m,2H),2.06(s,3H).

[0130] Compound 56: 1H NMR (400MHz, DMSO-d6) δ7.72(d,J=6.8Hz,1H),7.29(d,J=8.0Hz,2H),7.23–7.17(m,10H),7.13(d,J=8 .4Hz,2H),7.02–6.80(m,13H),5.33–5.19(m,4H),4.51–3.54(m,3H),2.35–1.95(m,2H),1.06(s,9H).

[0131] Compound 57: 1 H NMR(400MHz,DMSO-d6)δ7.72(d,J=6.4Hz,1H),7.33–7.15(m,13H),7.12–6.97(m,6H) ,6.96–6.75(m,8H),5.30(s,2H),5.23(s,2H),4.59–3.55(m,3H),2.39–2.10(m,2H).

[0132] Compound 58: 1 H NMR(400MHz,acetone-d6)δ7.86(d,J=6.8Hz,1H),7.32–7.14(m,10H),7.12–6.90(m,12H),6.87–6.78( m,2H),6.74(s,1H),6.43(d,J=5.2Hz,1H),5.29(d,J=8.4Hz,4H),4.52–3.84(m,3H),2.49–2.23(m,2H).

[0133] Compound 59: 1 H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.20–7.12(m,9H),7.10–7.03(m,3H),6.94–6.84(m,10H),6.82–6.79(m,2H),6.7 1(d,J=8.4Hz,1H),5.27(d,J=16.8Hz,2H),5.15(d,J=16.4Hz,2H),4.65–3.66(m,2H),2.38(m,3H),2.37–2.24(m,5H).

[0134] Compound 60: 1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.35–7.27(m,2H),7.26–6.99(m,15H), 6.94–6.79(m,10H),5.34–5.18(m,4H),4.61–3.64(m,3H),2.38–2.03(m,2H).

[0135] Compound 61: 1 H NMR(400MHz, DMSO-d6)δ7.59(d,J=8.0Hz,1H),7.23–7.11(m,11H),7.06(s,1H),7.02(s,1H),6.92–6.81(m,10H),6.79–6.7 4(m,2H),6.62(d,J=7.2Hz,1H),5.24(s,2H),5.17(s,2H),4.44–3.82(m,3H),2.32(s,3H),2.30(s,3H),2.27–2.07(m,2H).

[0136] Compound 62: 1 H NMR (400MHz, DMSO-d6) δ7.62(d,J=8.4Hz,1H),7.54(d,J=0.8Hz,1H),7.33–7.13(m,14H),7.11(dd,J=8.4,0.8Hz ,1H),6.94–6.83(m,8H),6.78(d,J=5.2Hz,2H),5.30(s,2H),5.23(s,2H),4.64–3.70(m,3H),2.35–2.03(m,2H).

[0137] Example 16 General method for preparing enantiomers (n=1) of the compounds of the present invention

[0138] Taking compound 63 as an example, the reaction formula is as follows:

[0139]

[0140] The operation steps are as follows:

[0141] Alkyne compound B (0.15 mmol) was dissolved in acetonitrile (4.3 mL), followed by the addition of iodine (0.015 mmol) to the mixture. The reaction mixture was stirred at 40 °C until the starting material was completely consumed by TLC (approximately 10 h). After the reaction was complete, the reaction mixture was quenched with Na₂S₂O₃ (aq., 5 mL), extracted with ethyl acetate (8 mL x 3), dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluting solvent: petroleum ether / ethyl acetate) to give 73.3 mg of the target product shown in Formula 63, with a yield of 61% and dr = 5:1.

[0142] Compound 63: [α] D 20 = -142° (c = 1.0, CHCl3). 99% ee (HPLC determination conditions: Chiralpak IA Column, 40 / 60i-PrOH / hexane, 1.0 mL / min, 254 nm, 25 °C; TR = 7.71 min (minor), 9.13 min (major)); 1 H NMR(500MHz, CDCl3)δ8.00–7.94(m,1H),7.25–7.15(m,8H),7.14–7.10(m,3H), 7.07(d,J=8.5Hz,2H),6.97–6.85(m,8H),6.82–6.72(m,4H),6.65–6.58(m,3H) ,5.25(d,J=16.0Hz,1H),5.20(d,J=16.0Hz,1H),5.10–4.95(m,3H),3.98(dd,J =10.5,7.0Hz,1H),2.94–2.82(m,1H),2.26–2.15(m,1H),1.78(d,J=6.5Hz,3H); 13 C NMR (125MHz, CDCl3) δ141.3,139.9,137.8,137.0(4),136.9(5),134.9,132.6, 131.4,130.5,129.1,128.6,128.5,128.1,127.5(0),127.4(5),127.3(0),127 .2(8),127.0,126.8,126.4,126.3,125.9,125.6,121.7,121.4,120.2,119.5, 119.3,115.0,111.0,109.8,109.3,50.7,49.7,49.6,37.8,36.0,19.1; HRESIMS Calcd for[C 48 H 41BrN3O2S] + (M+H + )802.2097,found802.2099.

[0143] Compound 63': [α] D 20 = -137° (c = 1.0, CHCl3). 96% ee (HPLC determination conditions: Chiralpak IA Column, 40 / 60i-PrOH / hexane, 1.0 mL / min, 254 nm, 25°C; TR = 9.71 min (major), 11.14 min (minor)). Colourless solid (mp 92-94°C). 1 H NMR (400MHz, CDCl3) δ7.44–7.37(m,2H),7.27–7.23(m,3H),7.22–7.18(m,2H),7.17–7.06(m,8H),7.04–6.98(m,2H),6.92–6.87(m,1H),6.86–6. 76(m,7H),6.63–6.58(m,3H),6.48(s,1H),5.05–4.94(m,5H),4.10(t,J= 6.0Hz,1H),2.76–7.68(m,1H),2.37–2.30(m,1H),1.66(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3) δ140.6,139.2,137.4,136.9,135.7,135.2,134.4,131.2, 130.9,129.1,128.5(2),128.4(5),128.3,128.2,128.1,127.8,127.5,127.4, 127.3,127.2,126.6,126.5,126.2,125.4,121.5(4),121.4(7),119.8,119.7, 119.1,118.7,116.7,111.8,109.5,51.3,49.8,49.6,39.6,33.0,21.6; HRESIMS Calcd for[C 48 H 41 BrN3O2S] + (M+H + )802.2097,found802.2098.

[0144] The following compounds were prepared according to the method of Example 16:

[0145]

[0146]

[0147] b This indicates that the iodine dosage is 20 mol%. c This indicates that ent-alkynylamine is used as a raw material.

[0148] Example 17

[0149] To further demonstrate the application value of the synthesis strategy of this invention, the following exemplary application experiments were conducted: (1) Process scale-up test and catalytic efficiency test

[0150]

[0151] (a) By scaling up the substrate dosage to the gram scale, the target product 2 can still be obtained in near-equivalent yield even when the catalyst dosage is reduced to 2 mol%.

[0152] (b) The catalyst dosage was further reduced to 0.25 mol%, and the reaction was carried out at 80 °C for 48 hours. The yield was still as high as 86%, and the catalyst efficiency was as high as 344 TON.

[0153] (2) Further derivatization of the compound to prepare relevant valuable products.

[0154]

[0155] Compound 2 was prepared under DDQ oxidation conditions to obtain pyrrole-bridged bisindole compound 93, which could then be further prepared under NBS conditions to obtain brominated product 94.

[0156] Compound 93: 1 H NMR (500MHz, CDCl3) δ7.78 (d, J = 7.5Hz, 1H), 7.72 (s, 1H), 7.35–7.31 (m, 2H), 7.27–7.19 (m, 8H), 7. 18–7.07(m,6H),7.02–6.96(m,7H),6.60(s,1H),5.30(d,J=8.0Hz,2H),5.14(s,2H),2.89(s,3H); 1313C NMR (125 MHz, CDCl3) δ 137.1(9), 137.1(5), 136.3, 135.7, 134.5, 132.0, 130.1, 130.0, 129.3, 128.7, 128.6, 127.6, 127.5, 127.4, 127.2, 126.8, 126.5, 126.4, 124.3, 122.0, 121.9, 120.2, 120.1(4), 120.1(2), 119.9, 119.8, 119.1, 109.9, 109.7, 108.3, 104.2, 50.2, 50.0, 42.1; HRESIMS Calcd for [C 41 H 34 N3O2S] + (M + H + ) 632.2366, found 632.2365。

[0157] Compound 94: 1 1H NMR (400 MHz, acetone-d6) δ 7.48 (d, J = 8.0 Hz, 1H), 7.46–7.41 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.30–7.21 (m, 7H), 7.16 (s, 1H), 7.11–6.92 (m, 13H), 5.49–5.37 (m, 4H), 3.37 (s, 3H); 13 13C NMR (100 MHz, acetone-d6) δ 138.8, 136.9, 136.6, 134.9, 132.1, 13'1.7, 130.9, 130.5, 130.1, 129.5, 129.3, 129.2(3), 129.1(8), 128.4, 128.1, 128.0, 127.9, 127.4, 127.2, 127.0, 125.6, 122.3, 122.2, 立21.2, 120.6, 120.4, 120.1, 110.9, 110.8, 108.0, 106.9, 103.2, 50.1(6), 50.1(5), 42.8; HRESIMS Calcd for [C 41 H 33 BrN3O2S] + (M + H + ) 710.1471, found 710.1472。

[0158]

[0159] Compound 40 was prepared under DDQ oxidation conditions to obtain pyrrole-bridged bisindole compound 95, which was then prepared by a two-step deprotection reaction to obtain compound 96.

[0160] Compound 95: 1 H NMR(400MHz,acetone-d6)δ7.71–7.64(m,2H),7.57(s,1H),7.42(d,J=8.0Hz,1H),7.36–7.30(m,2H),7.17–7.11(m ,3H),7.09–7.02(m,9H),6.97–6.91(m,1H),6.88–6.79(m,5H),5.38(s,2H),5.20(s,2H),3.75(s,6H),3.07(s,3H); 13 C NMR(100MHz,acetone-d6)δ159.9(3),159.8(5),137.0,136.4,135.7,133.1,130.7,130.6,130.5(2),130.4(5),129.2,128.7,128.4,128.0,1 27.1,125.3,122.3(3),122.2(9),120.6,120.5,120.2,119.5,114.6,1 11.0,110.8,108.7,104.7,55.3(6),55.3(5),49.9,49.6,42.3; HRESIMS Calcd for[C 43 H 38 N3O4S] + (M+H + )692.2578,found 692.2580.

[0161] Compound 96: 1 H NMR (400MHz, acetone-d6) δ10.25–9.91(m,2H),7.64(d,J=8.0Hz,1H),7.44(d,J=8.0Hz,1H),7.42–7.36(m,2H),7.26–7.2 2(m,2H),7.20(d,J=2.8Hz,1H),7.15–7.05(m,6H),6.99–6.95(m,1H),6.95–6.90(m,1H),6.81–6.78(m,1H),2.90(s,1H); 13CNMR(100MHz,acetone-d6)δ138.8,137.3,137.2,131.4,128.4,128.0,127.2,125.9,125.1,124.2,124 .0,123.0,122.9,122.1,121.7,120.7,119.8,119.4,118.1,116.4,116.2,112.0,111.8,110.0; HRESIMS Calcd for[C 26 H 20 N3] + (M+H + )374.1652,found374.1648.

[0162]

[0163] Compound 44 can also be prepared under DDQ oxidation conditions to obtain pyridine-bridged bisindole compound 99.

[0164] Compound 99: 1 H NMR (400MHz, CDCl3) δ8.77(d,J=5.2Hz,1H),8.36(d,J=7.6Hz,1H),7.87–7.81(m,1H),7.55(d,J=5.2Hz,1H),7 .22–7.14(m,12H),7.11–7.07(m,5H),6.87–6.78(m,4H),6.32(s,1H),6.23(s,1H),5.00(s,2H),4.97(s,2H); 13 C NMR (100MHz, CDCl3) δ153.9,148.0,142.6,140.0,136.8,136.5,135.8(1),135.8(0),1 33.8,130.8,130.2,129.5,128.6,128.5,128.2,128.1,127.5,127.4,127.3,126.8(2),

[0165] 126.7(6),122.0,121.9,121.5,120.4,120.3,119.7,115.3,113.1,109.8,109.3,49.8(9),49.8(6); HRESIMS

[0166] Calcd for [C 41 H 32 N3] + (M+H +)566.2591,found 566.2579。

Claims

1. A method for preparing heterocyclic bridged bisindole derivatives by iodine-catalyzed cyclization and isomerization of alkynylamine compounds, characterized in that, Includes the following steps: The acetylamine compound shown in Formula 1 was dissolved in an organic solvent, followed by the addition of iodine as a catalyst. The reaction mixture was stirred at a certain temperature until complete, and then purified to obtain the heterocyclic bridged bisindole derivative shown in Formula 2. The reaction formula is as follows: In the above reaction formula, n = 0 or 1; PG is selected from methanesulfonyl, p-toluenesulfonyl, benzenesulfonyl, p-bromobenzenesulfonyl, and p-methoxybenzyl. R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, substituted or unsubstituted phenyl, thiophene, furanyl, benzothiaphenyl, benzofuranyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, styryl, phenylethynyl, trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl; wherein the substituent in the substituted or unsubstituted group is selected from fluorine, chlorine, bromine, iodine, -OH, -SH, -CN, -NO2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetoxy, acetoxymethyl, phenyl, naphthyl, benzyl, benzyloxymethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, phenoxymethyl. , , ; R2 and R2' are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, and trifluoromethoxy. R3, R3' are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, substituted or unsubstituted benzyl; wherein the substituent in the substituted or unsubstituted group is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, trifluoromethoxy; R is selected from hydrogen, methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, and phenyl.

2. The method according to claim 1, characterized in that, When n=0, the acetylene amine compounds shown in Equation 1 are selected from compounds having the following structural formula: ； When n=1, the acetylene amine compounds shown in Formula 1 are selected from compounds having the following structural formula: , 。 3. The method according to any one of claims 1-2, characterized in that, The molar ratio of the acetylene amine compound shown in Formula 1 to the catalyst iodine is 1:0.001 to 1:0.

2.

4. The method according to any one of claims 1-2, characterized in that, When n=0, the organic solvent is toluene, the specific temperature is room temperature to 80℃, and the reaction time to completion is 5 min to 48 h.

5. The method according to any one of claims 1-2, characterized in that, When n=1, the organic solvent is acetonitrile, the specific temperature is 60-100℃, and the reaction time to completion is 6h~48h.

6. The method according to any one of claims 1-2, characterized in that, The purification process is as follows: the reaction mixture is quenched with Na2S2O3 solution, extracted with ethyl acetate, dried, filtered and concentrated to obtain the residue, and the residue is separated by silica gel column chromatography to obtain the heterocyclic bridged bisindole derivative shown in Formula 2.

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