Pyrrolo [3, 2, 1-ij] quinoline compound containing alkynyl full-carbon quaternary carbon center as well as preparation method and application of pyrrolo [3, 2, 1-ij] quinoline compound

Abstract

The invention relates to the technical field of synthetic methods of heterocyclic skeletons, in particular to pyrrolo [3, 2, 1-ij] quinoline compounds containing alkynyl all-carbon quaternary carbon centers as well as a preparation method and application of the pyrrolo [3, 2, 1-ij] quinoline compounds. A preparation method of pyrrolo [3, 2, 1-ij] quinoline compounds containing alkynyl all-carbon quaternary carbon center comprises the following steps: placing an indole compound, an organic phosphine catalyst and potassium carbonate in a solvent to obtain a mixed solution, and reacting at the temperature of 60-80 DEG C for 1-2 hours to obtain the pyrrolo [3, 2, 1-ij] quinoline compounds. And then adding a beta '-acetoxymethyl allenoate compound into the mixed solution for cyclization reaction to obtain the pyrrolo [3, 2, 1-ij] quinoline compound containing the alkynyl full-carbon quaternary carbon center. The preparation method disclosed by the invention is simple to operate, the preparation cost is also remarkably reduced, and the use of a noble metal catalyst is effectively avoided, so that the application prospect of the pyrrolo [3, 2, 1-ij] quinoline compound in the field of medicines is widened.

Description

Technical Field

[0001] The invention relates to the technical field of synthesis methods of heterocyclic skeletons, and in particular to pyrrolo[3,2,1-ij]quinoline compounds containing an alkynyl full-carbon quaternary carbon center, and preparation methods and applications thereof. Background Art

[0002] Pyrrolo[3,2,1-ij]quinolines are a unique class of nitrogen-containing heterocyclic skeletons that are widely found in natural alkaloids, such as Murrayazoline with antiplatelet aggregation activity, and drug molecules, such as KC 11404 with antihistamine activity.

[0003] The current preparation methods of pyrrolo[3,2,1-ij]quinoline compounds are mainly prepared by CH activation on indole substrates and intramolecular coupling reaction; or by intermolecular cycloaddition reaction promoted by a catalyst.

[0004] However, the preparation of pyrrolo[3,2,1-ij]quinoline compounds currently faces multiple challenges. On the one hand, the preparation process often requires the introduction of precious metal catalysts such as palladium, nickel, indium, rhodium, and rubidium into the reaction system, and also requires harsh anhydrous and oxygen-free reaction conditions, which leads to high preparation costs. On the other hand, some methods require excess oxidants, such as diphenylquinone; or require the use of organic amine catalysis under high temperature conditions; or require the use of equivalent organic phosphine (such as tricyclohexylphosphine) to promote the reaction, that is, the molar amount of the organic phosphine is the same as or more than the molar amount of the indole substrate. In the most commonly used transition metal catalysis method, the precious metal catalyst is not only toxic, but also difficult to completely remove after the reaction is completed, which limits the application of pyrrolo[3,2,1-ij]quinoline compounds in the medical field. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl full carbon quaternary carbon center, a preparation method and an application thereof, and a series of pyrrolo[3,2,1-ij]quinoline compounds containing an alkynyl full carbon quaternary carbon center are obtained for the first time by a "one-pot method" by using a method of continuous catalysis with an organic phosphine catalyst. The preparation method of the present invention is not only simple to operate, but also significantly reduces the preparation cost, and effectively avoids the use of a noble metal catalyst, thereby broadening the application prospects of pyrrolo[3,2,1-ij]quinoline compounds in the field of medicine.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is:

[0007] The first object of the present invention is to provide a method for preparing a pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center, comprising the following steps:

[0008] An indole compound, an organic phosphine catalyst and potassium carbonate are placed in a solvent to obtain a mixed solution, and then a β'-acetoxymethyl allenoate compound is added to the mixed solution for a cyclization reaction to obtain a pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl full-carbon quaternary carbon center.

[0009] Preferably, the molar ratio of the indole compound, the organic phosphine catalyst and the bottom β'-acetoxymethyl allenoate compound is 1:1.5~3:1.5~2.4; among them, when the molar ratio of the indole compound, the organic phosphine catalyst and the bottom β'-acetoxymethyl allenoate compound is 1:2.4:2, the yield of the pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl full-carbon quaternary carbon center is the highest.

[0010] Preferably, the conditions of the cyclization reaction are: stirring the reaction at -10°C to 25°C for 12h to 60h; wherein, when the reaction temperature is 0°C and the stirring time is 48h, the yield of pyrrolo[3,2,1-ij]quinoline compounds containing an alkynyl all-carbon quaternary carbon center is the highest.

[0011] Preferably, the indole compound is selected from (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, (E)-3-(5-chloro-3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)-1-phenylprop-2-en-1-one, (E)-3-(5-bromo-3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)-1-phenylprop-2-en-1-one, (E)-3-(4-bromo-3 -(2,2,2-trifluoroacetyl)-1H-indol-7-yl)-1-phenylprop-2-en-1-one, (E)-1-(4-fluorophenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, (E)-1-(4-chlorophenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, (E)-1-(4-bromophenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one )-1H-indol-7-yl)prop-2-en-1-one, (E)-1-(p-tolyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, (E)-1-(4-methoxyphenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, (E)-1-(3-bromophenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one -1-one, (E)-1-(naphthalen-2-yl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, (E)-1-(benzo[d][1,3]dioxolan-5-yl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one or (E)-1-(furan-2-yl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one;

[0012] The β'-acetoxymethyl allenoate compound is selected from 2-(acetoxymethyl)but-2,3-dienoic acid benzyl ester, 2-(acetoxymethyl)but-2,3-dienoic acid methyl ester, 2-(acetoxymethyl)but-2,3-dienoic acid ethyl ester, 2-(acetoxymethyl)but-2,3-dienoic acid isopropyl ester, 2-(acetoxymethyl)but-2,3-dienoic acid tert-butyl ester, 2-(acetoxymethyl)-4-phenylbut-2,3-dienoic acid benzyl ester or 2-(acetoxymethyl)-4-phenylbut-2,3-dienoic acid benzyl ester.

[0013] Preferably, the organic phosphine catalyst is selected from triphenylphosphine, tri(4-methoxyphenyl)phosphine, tri(4-fluorophenyl)phosphine, tri(4-chlorophenyl)phosphine or tricyclohexylphosphine.

[0014] Preferably, the molar ratio of the organic phosphine catalyst to the indole compound is 0.1 to 0.4:1.

[0015] Preferably, the solvent of the mixed solution is selected from chloroform, tetrahydrofuran, ethyl acetate, toluene or acetone.

[0016] The synthesis technology route of the pyrrolo[3,2,1-ij]quinoline compounds containing an alkynyl all-carbon quaternary carbon center of the present invention is as follows:

[0017]

[0018] The second object of the present invention is to provide a pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center prepared by the above preparation method, wherein the structural formula of the pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center is:

[0019]

[0020] Among them, R 1 is hydrogen or halogen; Ar is aryl or furyl; R is C1-C4 alkyl or benzyl; R 2 is bromine, hydrogen or phenyl.

[0021] Preferably, the aryl group is phenyl, substituted phenyl or naphthyl, and the substituent of the substituted phenyl group is selected from halogen, methyl, methoxy or benzo[d]dioxol.

[0022] Preferably, the pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center is:

[0023] 5-Ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid benzyl ester, 5-Ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 5-Ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester, 5-Ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid 6-(2-oxo-2-phenylethyl)-5-(phenylethynyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid benzyl ester, 5-(bromoethynyl)-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid tert-butyl ester, 6-(2-oxo-2-phenylethyl)-5-(phenylethynyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid benzyl ester, 5-(bromoethynyl)-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline Quinoline-5-carboxylic acid benzyl ester, 8-chloro-5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 8-bromo-5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 9-bromo-5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid tert-butyl ester, 5-ethynyl-6-(2-( 6-(2-(4-chlorophenyl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 6-(2-(4-bromophenyl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 5-ethynyl-6-(2-oxo-2-(p-tolyl)ethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester, 5-ethynyl-6-(2-(4-methoxyphenyl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester, 6-(2-(3-bromophenyl)-2-oxoethyl)-5-ethynyl-1 -(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 5-ethynyl-6-(2-oxo-2-(m-tolyl)ethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 6-(2-([1,1'-biphenyl]-4-yl)-2-oxoethyl )-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 5-ethynyl-6-(2-(naphthalen-2-yl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester, 6-(2-(benzo[d][1,3 ]dioxol-5-yl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester or 5-ethynyl-6-(2-(furan-2-yl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester.

[0024] The third object of the present invention is to provide the use of the above-mentioned pyrrolo[3,2,1-ij]quinoline compounds containing an alkynyl all-carbon quaternary carbon center and pharmaceutically acceptable salts thereof in the preparation of tumor cell proliferation inhibitors.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] 1. The present invention provides a method for preparing a pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl full-carbon quaternary carbon center. The method adopts a continuous catalysis mode of an organic phosphine catalyst, places an indole compound, an organic phosphine catalyst and potassium carbonate in a solvent to obtain a mixed solution, and then adds a β'-acetoxymethyl allenoate compound to the mixed solution for cyclization reaction to obtain a pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl full-carbon quaternary carbon center.

[0027] First, an enyne intermediate is generated in situ from β'-acetoxymethyl allenoate under the action of an organic phosphine catalyst, and then the enyne intermediate undergoes a cyclization reaction with an indole compound under the action of an organic phosphine catalyst to obtain a pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl full-carbon quaternary carbon center. The generated enyne intermediate does not need to be separated and purified, but is directly involved in the organic phosphine catalytic cycle after being generated in situ, which simplifies the operation of the reaction; on the basis of the efficient synthesis of 1,7-fused indole heterocycles, an alkynyl quaternary carbon center is simultaneously generated in situ.

[0028] 2. Compared with the existing preparation technology of pyrrolo[3,2,1-ij]quinoline compounds, the preparation method of the present invention is insensitive to the presence of moisture and oxygen. Even if there is a trace amount of moisture and oxygen coexisting in the reaction system, the reaction can be ensured to proceed smoothly, avoiding the steps of dehydration and deoxygenation before the reaction, simplifying the operation process; at the same time, the preparation method of the present invention does not need to introduce an organic phosphine equivalent to the indole substrate to promote the reaction, nor does it need to introduce an excessive amount of oxidant and rely on a precious metal catalyst, reducing the production cost; in addition, the product prepared by the preparation method of the present invention has excellent diastereoselectivity.

[0029] 3. Compared with the prior art, the organophosphine used in the prior art is equivalent, that is, the molar amount of the organophosphine is the same as or even greater than the molar amount of the indole substrate, while the organophosphine used in the present invention is a catalytic amount, that is, the molar amount of the organophosphine is only 10% to 40% of the indole substrate to complete the cyclization reaction.

[0030] 4. The pyrrolo[3,2,1-ij]quinoline compounds containing an alkynyl all-carbon quaternary carbon center prepared by the present invention have an alkynyl all-carbon quaternary carbon center structure, which is widely present in medicines and biologically active molecules and has important synthetic value; in addition, the pyrrolo[3,2,1-ij]quinoline compounds containing an alkynyl all-carbon quaternary carbon center obtained by the present invention and pharmaceutically acceptable salts thereof have the effect of inhibiting tumor cell proliferation and can be used to prepare tumor cell proliferation inhibitors. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The synthetic technology roadmap of the pyrrolo[3,2,1-ij]quinoline compounds containing an alkynyl all-carbon quaternary carbon center of Examples 1 to 21 of the present invention;

[0032] Figure 2 This is a graph showing the test results of the proliferation inhibition activity of the compounds prepared in Example 1, Example 3 to Example 5, Example 9 and Example 17 to Example 19 of the present invention on PC3 cells;

[0033] Figure 3This is a graph showing the test results of the proliferation inhibition activity of the compounds prepared in Examples 1, 3 to 5, 9 and 18 of the present invention on TMD8 cells. DETAILED DESCRIPTION

[0034] The technical solution of the present invention will be clearly and completely described below in combination with the data in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0035] In the prior art, the preparation methods of pyrrolo[3,2,1-ij]quinoline compounds mainly rely on a variety of transition metal catalytic systems, such as transition metal palladium, nickel, indium, rhodium, and rubidium. These catalysts promote the activation of CH on indole, thereby initiating an intramolecular coupling reaction to achieve the synthesis of the target compound. In addition, there are also preparation methods that use organic amines, azacarbene catalysis and equivalent organic phosphines, such as tricyclohexylphosphine, to promote intermolecular cycloaddition reactions. However, the common problems of these methods are that, on the one hand, the preparation process often requires the introduction of precious metal catalysts, such as palladium, nickel, indium, rhodium, and rubidium, into the reaction system, and also requires harsh anhydrous and oxygen-free reaction conditions, which leads to high preparation costs. On the other hand, some methods require an excess of oxidants, such as diphenylquinone; or require the use of organic amine catalysis under high temperature conditions; or require the use of equivalent organic phosphine to promote the reaction, that is, the molar amount of the organic phosphine is the same as or more than the molar amount of the reaction substrate. In the most commonly used transition metal catalysis method, the precious metal catalyst is not only toxic but also difficult to remove completely after the reaction is completed, which limits the application of pyrrolo[3,2,1-ij]quinoline compounds in the medical field.

[0036] In view of the defects of the prior art, the present invention provides a method for preparing a pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl full-carbon quaternary carbon center, comprising the following steps: placing an indole compound, an organic phosphine catalyst and potassium carbonate in a solvent to obtain a mixed solution, and then adding a β'-acetoxymethyl allenoate compound to the mixed solution for a cyclization reaction to obtain a pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl full-carbon quaternary carbon center.

[0037] The present invention uses a mode of continuous catalysis of an organic phosphine catalyst to obtain a series of pyrrolo[3,2,1-ij]quinoline compounds containing an alkynyl full carbon quaternary carbon center for the first time through a "one-pot method". First, β'-acetoxymethyl allenoate is used to generate an enyne intermediate in situ under the action of an organic phosphine catalyst, and then the enyne intermediate and an indole compound are cyclized under the action of an organic phosphine catalyst to obtain a pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl full carbon quaternary carbon center. The synthetic route is as follows: Figure 1 As shown. Compared with the prior art, the preparation method of the present invention shows excellent insensitivity to moisture and oxygen, which greatly broadens the flexibility of the operating environment and reduces the complexity of controlling the reaction conditions. In particular, the preparation method of the present invention abandons the need to add an equimolar amount or excess of an organic phosphine to the indole reaction substrate to promote the reaction, and also avoids the safety hazards and cost burden caused by the use of excessive oxidants and reliance on precious metal catalysts.

[0038] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention is further explained using embodiments below, as shown below:

[0039] Example 1

[0040] A method for preparing benzyl 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate comprises the following steps:

[0041] At 0°C, 0.15 mmol (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, 0.03 mmol catalyst triphenylphosphine, 0.36 mmol potassium carbonate and 1.5 mL chloroform were sequentially added into a 10 mL round-bottom flask. After stirring evenly, 0.30 mmol 2-(acetoxymethyl)benzyl but-2,3-dienoate was added under stirring, and the reaction was continued at 0°C for 48 h.

[0042] The reaction was monitored by TLC. After the reaction was completed, column chromatography was performed on a silica gel column. The eluent was composed of petroleum ether and ethyl acetate in a volume ratio of 5:1 to obtain 54.0 mg of 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid benzyl ester, denoted as 3aa, as a white solid with a yield of 68%; its structural formula is as follows:

[0043]

[0044] The product data are characterized as follows:

[0045] Melting point 131℃~134℃;

[0046] 1 H NMR(400MHz, CDCl3)δ8.09(d,J=7.9Hz,1H),7.98-7.82(m,3H),7.56(t,J=7.4Hz,1H), 7.44(t,J=7.6Hz,2H),7.32-7.07(m,5H),6.97(d,J=7.1Hz,2H),5.07(d,J=12.1Hz,1H) ,4.96(d,J=12.1Hz,1H),4.88(d,J=12.8Hz,1H),4.71(dd,J=9.3,3.2Hz,1H),4.42(d,J =12.9Hz,1H),3.72(dd,J=17.4,3.1Hz,1H),3.36(dd,J=17.5,9.3Hz,1H),2.44(s,1H);

[0047] 13 C NMR(101MHz, CDCl3)δ196.8,175.0(q,J=35.0Hz),168.1,136.6,135.0(q,J=4.4Hz),134.4,133.5,132.1,128.7,128.6, 128.1,128.0,124.9,124.8,123.0,122.6,121.2,117.0(d,J=291.0Hz),110.7,78.9,75.9,68.4,49.4,46.8,41.7,37.4;

[0048] 19 F NMR (377MHz, CDCl3) δ-72.39 (s, 3F);

[0049] HRMS(ESI):m / z C 31 H 23 F3NO4([M+H] + ):Calculated value: 476.1704; Measured value: 476.1702.

[0050] Example 2

[0051] The preparation method of 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester is the same as the preparation steps of Example 1, except that 2-(acetoxymethyl)buta-2,3-dienoic acid benzyl ester is replaced with 2-(acetoxymethyl)buta-2,3-dienoic acid methyl ester to obtain 50.3 mg of the product 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, denoted as 3ab, as a white solid with a yield of 74%; its structural formula is as follows:

[0052]

[0053] The product data are characterized as follows:

[0054] Melting point 118℃~121℃;

[0055] 1 H NMR(400MHz, CDCl3)δ8.16(d,J=7.7Hz,1H),8.04-7.95(m,3H),7.61(t,J=7.4H z,1H),7.50(t,J=7.6Hz,2H),7.28(d,J=6.9Hz,1H),7.19(d,J=7.4Hz,1H),4.9 1(d,J=12.9Hz,1H),4.72(dd,J=8.6,3.5Hz,1H),4.48(d,J=12.8Hz,1H),3.80( dd,J=17.5,3.7Hz,1H),3.66(s,3H),3.45(dd,J=17.5,8.5Hz,1H),2.43(s,1H);

[0056] 13 C NMR (101MHz, CDCl3) δ196.9,175.0(q,J=35.0Hz),168.9,136.6,135.1(q,J=5.0Hz),133.5,132.2,128.8,1 28.1,125.0,124.7,122.6,122.5,121.2,121.4-112.5(m),110.7,78.9,75.6,53.8,49.7,46.7,41.5,37.4;

[0057] 19 F NMR (377MHz, CDCl3) δ-72.39 (s, 3F);

[0058] HRMS (ESI) m / z C25 H 19 F3NO4([M+H] + ):Calculated value: 454.1261; Measured value: 454.1258.

[0059] Example 3

[0060] The preparation method of 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester is the same as the preparation steps of Example 1, except that 2-(acetoxymethyl)buta-2,3-dienoic acid benzyl ester is replaced with 2-(acetoxymethyl)buta-2,3-dienoic acid ethyl ester to obtain the product 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester 51.9 mg, denoted as 3ac, white solid, yield 74%; its structural formula is as follows:

[0061]

[0062] The product data are characterized as follows:

[0063] Melting point 138℃~140℃;

[0064] 1 HNMR (400MHz, CDCl3) δ8.02(d,J=7.4Hz,1H),7.87(d,J=7.6Hz,3H),7.48(t,J=7.3H z,1H),7.37(t,J=7.6Hz,2H),7.23-7.05(m,2H),4.80(d,J=12.8Hz,1H),4.61(dd,J =9.1,3.2Hz,1H),4.36(d,J=12.9Hz,1H),3.97(qq,J=10.8,7.1Hz,2H),3.69(dd,J= 17.5,3.3Hz,1H),3.32(dd,J=17.5,9.1Hz,1H),2.34(s,1H),0.93(t,J=7.1Hz,3H);

[0065] 13C NMR(101MHz, CDCl3)δ196.8,175.0(q,J=35.1Hz),168.2,136.6,135.1(q,J=5.2Hz),133.5,132.2,128.8,128.1, 124.9,124.7,122.8,122.7,121.2,117.0(q,J=290.8Hz),110.7,79.1,75.6,62.9,49.5,46.8,41.6,37.4,13.6;

[0066] 19 F NMR (377MHz, CDCl3) δ-72.41 (s, 3F);

[0067] HRMS (ESI) m / z C 26 H 21 F3NO4([M+H] + ):Calculated value: 468.1417; Measured value: 468.1416.

[0068] Example 4

[0069] The preparation method of 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid isopropyl ester is the same as the preparation steps of Example 1, except that 2-(acetoxymethyl)buta-2,3-dienoic acid benzyl ester is replaced with 2-(acetoxymethyl)buta-2,3-dienoic acid isopropyl ester to obtain 47.6 mg of the product 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid isopropyl ester, denoted as 3ad, as a white solid with a yield of 66%; its structural formula is as follows:

[0070]

[0071] The product data are characterized as follows:

[0072] Melting point 119℃~122℃;

[0073] 1H NMR (400MHz, CDCl3) δ8.12 (dd, J=7.2, 1.8Hz, 1H), 8.02-7.91 (m, 3H), 7.63-7.55 (m, 1H ),7.47(t,J=7.7Hz,2H),7.32-7.14(m,2H),4.92(d,J=12.8Hz,1H),4.90-4.78(m,1H) ,4.71(dd,J=9.7,2.8Hz,1H),4.45(d,J=12.8Hz,1H),3.77(dd,J=17.3,2.8Hz,1H),3. 39(dd,J=17.4,9.7Hz,1H),2.47(s,1H),1.08(d,J=6.3Hz,3H),0.97(d,J=6.2Hz,3H).

[0074] 13 C NMR(101MHz, CDCl3)δ196.8,175.0(q,J=35.1Hz),167.5,136.7,135.1(q,J=4.8Hz),133.5,132.1,128.7,128.1, 124.9,124.7,123.1,122.8,121.2,117.0(q,J=290.7Hz),110.7,79.2,75.5,70.7,49.2,46.8,41.9,37.3,21.1.

[0075] 19 F NMR (377MHz, CDCl3) δ-72.40 (s, 3F).

[0076] HRMS (ESI) m / z C 27 H 23 F3NO4([M+H] + ):Calculated value: 482.1574; Measured value: 482.1572.

[0077] Example 5

[0078] The preparation method of tert-butyl 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate is the same as the preparation steps of Example 1, except that 2-(acetoxymethyl)but-2,3-dienoic acid benzyl ester is replaced with tert-butyl 2-(acetoxymethyl)but-2,3-dienoate to obtain 47.0 mg of the product tert-butyl 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate, recorded as 3ae, as a white solid with a yield of 63%; its structural formula is as follows:

[0079]

[0080] The product data are characterized as follows:

[0081] Melting point 112℃~115℃;

[0082] 1 H NMR (400MHz, CDCl3) δ8.02(d,J=7.4Hz,1H),7.86(d,J=8.4Hz,3H),7.48(t,J=7.3Hz,1H),7.37(t,J=7.6Hz,2H),7.23-7.07(m,2H),4.76(d,J=12.8 Hz,1H),4.56(dd,J=9.7,2.7Hz,1H),4.33(d,J=12.8Hz,1H),3.66(dd,J=17.3,2.7Hz,1H),3.27(dd,J=17.2,9.9Hz,1H),2.37(s,1H),1.08(s,9H);

[0083] 13 C NMR(101MHz, CDCl3)δ196.8,175.0(q,J=35.0Hz),167.0,136.7,135.1(q,J=5.0Hz),133.4,132.2,128.7,128.1, 124.9,124.6,123.2,123.1,121.1,117.0(q,J=290.9Hz),110.7,83.8,79.6,75.3,49.2,47.4,41.9,37.6,27.3;

[0084] 19 F NMR(377MHz, CDCl3)δ-72.37(s,3F);

[0085] HRMS (ESI) m / z C 28H 25 F3NO4([M+H] + ):Calculated value: 496.1730; Measured value: 496.1728.

[0086] Example 6

[0087] The preparation method of 6-(2-oxo-2-phenylethyl)-5-(phenylethynyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid benzyl ester is the same as the preparation steps of Example 1, except that 2-(acetoxymethyl)buta-2,3-dienoic acid benzyl ester is replaced with 2-(acetoxymethyl)-4-phenylbuta-2,3-dienoic acid benzyl ester to obtain 34.4 mg of the product 6-(2-oxo-2-phenylethyl)-5-(phenylethynyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid benzyl ester, recorded as 3af; white solid, yield 57%; its structural formula is as follows:

[0088]

[0089] The product data are characterized as follows:

[0090] Melting point 128℃~131℃;

[0091] 1 H NMR (400MHz, CDCl3) δ8.01(d,J=6.7Hz,1H),7.82(d,J=6.6Hz,3H),7.44(t,J= 7.4Hz,1H),7.31(t,J=7.6Hz,2H),7.27-7.01(m,9H),6.87(d,J=7.4Hz,2H),5 .00(d,J=12.2Hz,1H),4.89(dd,J=16.4,12.5Hz,2H),4.79-4.70(m,1H),4.39 (d,J=12.9Hz,1H),3.73(dd,J=17.2,3.5Hz,1H),3.25(dd,J=17.2,9.4Hz,1H);

[0092] 13C NMR (101MHz, CDCl3) δ196.9,175.7-174.3(m),168.4,136.7,135.1(q,J=6.5,5.4Hz),134.6,133.5,131.9,129.2,128.7,128.5,128.5, 128.4,128.2,127.9,125.0,124.8,123.3,122.9,121.3,121.2,117.0(d,J=290.1Hz),110.7,87.6,84.0,68.2,47.5,42.2,37.7,29.7;

[0093] 19 F NMR (377MHz, CDCl3) δ-72.36 (s, 3F);

[0094] HRMS (ESI) m / z C 37 H 26 F3NNaO4([M+Na] + ):Calculated value: 628.1706; Measured value: 628.1707.

[0095] Example 7

[0096] The preparation method of 5-(bromoethynyl)-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid benzyl ester is the same as the preparation steps of Example 1, except that 2-(acetoxymethyl)buta-2,3-dienoic acid benzyl ester is replaced with 2-(acetoxymethyl)-4-phenylbuta-2,3-dienoic acid benzyl ester to obtain 46.2 mg of the product 5-(bromoethynyl)-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid benzyl ester, recorded as 3ag; white solid, yield 76%; its structural formula is as follows:

[0097]

[0098] The product data are characterized as follows:

[0099] Melting point 118℃~120℃;

[0100] 1H NMR(400MHz, CDCl3)δ7.97(d,J=7.6Hz,1H),7.88-7.69(m,3H),7.45(t,J=7.4Hz,1H ),7.33(t,J=7.6Hz,2H),7.19-6.95(m,5H),6.83(d,J=7.3Hz,2H),4.95(d,J=12.1H z,1H),4.84(d,J=12.1Hz,1H),4.77(d,J=12.9Hz,1H),4.63(dd,J=9.3,3.2Hz,1H), 4.31(d,J=12.9Hz,1H), 3.57(dd,J=17.3,3.4Hz,1H), 3.24(dd,J=17.4,9.3Hz,1H).

[0101] 13 C NMR(101MHz, CDCl3)δ196.7,175.0(q,J=34.9Hz),167.7,136.6,135.1,134.4,133.5,132.0,128.8,128.6,128.2,127 .9,125.0,124.8,123.2,122.5(d,J=1.9Hz),121.3,121.9-111.9(m),110.8,75.2,68.4,48.9,47.9,41.9,37.5,29.7.

[0102] 19 F NMR (377MHz, CDCl3) δ-72.40 (s, 3F).

[0103] HRMS (ESI) m / z C 31 H 21 BrF3NNaO4([M+Na] + ):Calculated value: 630.0504; Measured value: 630.0504.

[0104] Example 8

[0105] The preparation method of 8-chloro-5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester is the same as the preparation steps of Example 2, except that (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced by (E)-3 -(5-chloro-3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)-1-phenylprop-2-en-1-one, to obtain the product 8-chloro-5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester 56.3 mg, recorded as 3ah, white solid, yield 77%; its structural formula is as follows:

[0106]

[0107] The product data are characterized as follows:

[0108] Melting point 144~147℃;

[0109] 1 H NMR (400MHz, CDCl3) δ8.12(dd,J=4.6,1.8Hz,1H),8.06-7.92(m,3H),7.61(t,J=7.4Hz,1H),7.50(t,J=7.6Hz,2H),7.22(s,1H),4.89(d,J=12 .9Hz,1H),4.68(dd,J=8.5,3.5Hz,1H),4.44(d,J=12.9Hz,1H),3.80(d,J=3.7Hz,1H),3.66(s,3H),3.42(dd,J=17.8,8.5Hz,1H),2.44(s,1H).

[0110] 13 C NMR(101MHz, CDCl3)δ196.4,174.9(q,J=35.5Hz),168.6,136.3,135.6(q,J=5.0Hz),133.7,130.6,128.8, 128.2,125.7,123.9,123.3,121.0,116.8(q,J=290.7Hz),110.3,78.5,75.9,53.9,46.7,41.3,37.1,29.7.

[0111] 19 F NMR (377MHz, CDCl3) δ-72.63 (s, 3F).

[0112] HRMS (ESI) m / z C 25 H 18 ClF3NO4([M+H] + ):Calculated value: 488.0871; Measured value: 488.0871.

[0113] Example 9

[0114] The preparation method of 8-bromo-5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester is the same as that in Example 2, except that (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced by (E)-3-( 5-bromo-3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)-1-phenylprop-2-en-1-one, to obtain the product 8-bromo-5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester 56.7 mg, recorded as 3ai, white solid, yield 71%; its structural formula is as follows:

[0115]

[0116] The product data are characterized as follows:

[0117] Melting point 190℃~192℃;

[0118] 1 HNMR(400MHz, CDCl3)δ8.18(s,1H),7.92-7.82(m,3H),7.50(t,J=7.4Hz,1H),7.39(t,J=7.6Hz,2H),7.24(s,1H),4.78(d,J=12.9Hz,1H), 4.57(dd,J=8.5,3.6Hz,1H),4.33(d,J=12.9Hz,1H),3.72(dd,J=17.8,3.6Hz,1H),3.55(s,3H),3.29(dd,J=17.8,8.3Hz,1H),2.32(s,1H);

[0119] 13C NMR (101MHz, CDCl3) δ196.3,174.9(q,J=35.9Hz),168.5,136.4,135.4(q,J=4.9Hz),133.7,131.0,128 .8,128.1,126.3,125.8,124.3,124.0,118.3,115.4,110.2,78.5,75.9,53.9,49.6,46.7,41.3,37.1;

[0120] 19 F NMR (377MHz, CDCl3) δ-72.63 (s, 3F);

[0121] HRMS (ESI) m / z C 25 H 18 BrF3NO4([M+H] + ):Calculated value: 532.0366; Measured value: 532.0362.

[0122] Example 10

[0123] The preparation method of tert-butyl 9-bromo-5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate is the same as that in Example 5, except that (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced by (E)-3-(4 -bromo-3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)-1-phenylprop-2-en-1-one to obtain 60.3 mg of product 9-bromo-5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid tert-butyl ester, recorded as 3aj, white solid, yield 70%; its structural formula is as follows:

[0124]

[0125] The product data are characterized as follows:

[0126] Melting point 183℃~186℃;

[0127] 1H NMR (400MHz, CDCl3) δ7.92(s,1H),7.85(d,J=7.8Hz,2H),7.48(t,J=7.3Hz,1H),7.42-7.25(m,3H),6.98(d,J=7.9Hz,1H),4.75(d,J= 12.8Hz,1H),4.58-4.43(m,1H),4.32(d,J=12.7Hz,1H),3.73-3.56(m,1H),3.23(dd,J=17.4,10.1Hz,1H),2.39(s,1H),1.10(s,9H);

[0128] 13 C NMR(101MHz, CDCl3)δ196.7,173.2(d,J=34.7Hz),166.7,136.8-136.5(m),136.5,133.8,133.6,129.6,128.8,1 28.1,124.5,124.4,122.5,117.3(d,J=292.3Hz),113.2,110.4,84.0,79.2,75.6,49.2,46.8,41.8,37.2,27.3;

[0129] 19 F NMR (377MHz, CDCl3) δ-71.26 (s, 3F);

[0130] HRMS (ESI) m / z C 28 H 24 BrF3NO4([M+H] + ):Calculated value: 574.0835; Measured value: 574.0838.

[0131] Embodiment 11

[0132] The preparation method of 5-ethynyl-6-(2-(4-fluorophenyl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester is the same as that in Example 2, except that (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced by (E)-1-(4-fluorophenyl)- -3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, and the rest was the same as in Example 2 to obtain 58.0 mg of the product 5-ethynyl-6-2-(4-fluorophenyl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, denoted as 3ba, as a white solid with a yield of 82%; its structural formula is as follows:

[0133]

[0134] The product data are characterized as follows:

[0135] Melting point 130℃~133℃;

[0136] 1 H NMR (400MHz, CDCl3) δ8.19-8.06(m,1H),8.06-7.91(m,3H),7.29-7.20(m,1H),7.16-7.09(m,3H),4.88(d,J=12.9Hz,1H),4.66(dd ,J=8.6,3.5Hz,1H),4.44(d,J=12.9Hz,1H),3.74(dd,J=17.5,3.7Hz,1H),3.63(s,3H),3.39(dd,J=17.5,8.6Hz,1H),2.40(s,1H);

[0137] 13 C NMR(101MHz, CDCl3)δ195.3,175.0(q,J=35.1Hz),168.8,167.2,164.7,135.1(q,J=4.9Hz),133.0(d,J=3.1Hz),132.2,130 .8(d,J=9.3Hz),124.7,122.3,121.3,121.7-112.2(m),116.0,115.8,110.8,78.8,75.7,53.8,46.7,50.5-10.2(m),37.4;

[0138] 19F NMR(377MHz, CDCl3)δ-72.43(s,3F),-104.22(s,1F);

[0139] HRMS (ESI) m / z C 25 H 18 F4NO4([M+H] + ):Calculated value: 472.1166; Measured value: 472.1163.

[0140] Example 12

[0141] The preparation method of methyl 6-(2-(4-chlorophenyl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate is the same as that in Example 2, except that (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced by (E)-1-(4 -chlorophenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one to obtain 52.6 mg of the product 6-(2-(4-chlorophenyl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, denoted as 3ca, a white solid with a yield of 72%; its structural formula is as follows:

[0142]

[0143] The product data are characterized as follows:

[0144] Melting point 151℃~153℃;

[0145] 1 H NMR (400MHz, CDCl3) δ8.11(d,J=7.9Hz,1H),7.97(s,1H),7.91(d,J=8.3Hz,2H),7.43(d,J=8.1Hz,2H),7.23(t,J=8.4Hz,1H),7.14(d,J=7.5Hz,1 H),4.88(d,J=12.9Hz,1H),4.71-4.61(m,1H),4.44(d,J=12.9Hz,1H),3. 79-3.69(m,1H),3.63(s,3H),3.38(dd,J=17.6,8.6Hz,1H),2.40(s,1H).

[0146] 13C NMR(101MHz, CDCl3)δ195.7,175.0(q,J=35.0Hz),168.8,140.1,135.1(q,J=5.0Hz),134.8,134.7,132.2,129.6, 129.1,125.0,124.7,122.5,122.3,121.3,117.0(d,J=291.1Hz),110.7,78.8,75.7,53.8,49.7,46.7,41.4,37.4.

[0147] 19 F NMR(377MHz, CDCl3)δ-72.43(s,3F).

[0148] HRMS (ESI) m / z C 31 H 22 ClF3NO4([M+H] + ):Calculated value: 488.0871; Measured value: 488.0868.

[0149] Example 13

[0150] The preparation method of methyl 6-(2-(4-bromophenyl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate is the same as that in Example 2, except that (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced by (E)-1-(4 -bromophenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one to obtain the product 6-(2-(4-bromophenyl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester 63.1 mg, recorded as 3da, white solid, yield 79%; its structural formula is as follows:

[0151]

[0152] The product data are characterized as follows:

[0153] Melting point 148℃~151℃;

[0154] 1H NMR (400MHz, CDCl3) δ8.11(d,J=7.7Hz,1H),7.96(s,1H),7.82(d,J=8.2Hz,2H ),7.60(d,J=8.1Hz,2H),7.23(t,J=7.6Hz,1H),7.13(d,J=7.4Hz,1H),4.87(d ,J=12.9Hz,1H),4.65(dd,J=8.5,3.6Hz,1H),4.44(d,J=12.9Hz,1H),3.73(dd ,J=17.8,3.5Hz,1H),3.63(s,3H),3.37(dd,J=17.6,8.5Hz,1H),2.40(s,1H);

[0155] 13 C NMR (101MHz, CDCl3) δ195.9, 175.0 (q, J = 35.1Hz), 168.8, 135.3, 135.1 (q, J = 4.7Hz), 132.1, 129.6, 128. 8,125.0,124.7,122.5,122.3,121.3,121.6-112.4(m),110.8,78.8,75.7,53.8,49.7,46.7,41.4,37.4;

[0156] 19 F NMR (377MHz, CDCl3) δ-72.43 (s, 3F);

[0157] HRMS (ESI) m / z C 25 H 18 BrF3NO4([M+H] + ):Calculated value: 532.0366; Measured value: 532.0362.

[0158] Embodiment 14

[0159] The preparation method of ethyl 5-ethynyl-6-(2-oxo-2-(p-tolyl)ethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate is the same as that in Example 3, except that (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced by (E)-1-( The product 5-ethynyl-6-(2-oxo-2-(p-tolyl)ethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester was obtained as 3ea, a white solid with a yield of 82%. The structural formula is as follows:

[0160]

[0161] The product data are characterized as follows:

[0162] Melting point 161℃~164℃;

[0163] 1 H NMR (400MHz, CDCl3) δ8.12 (dd, J=7.7, 1.1Hz, 1H), 7.99 (q, J=2.0Hz, 1H), 7.88 (d, J=8.0Hz, 2H ),7.27(dd,J=8.5,1.6Hz,3H),7.19(d,J=7.3Hz,1H),4.91(d,J=12.8Hz,1H),4.71(dd,J=9.2, 3.2Hz,1H),4.47(d,J=12.8Hz,1H),4.08(dddd,J=17.8,10.8,7.2,3.7Hz,2H),3.76(dd,J=17 .4,3.2Hz,1H),3.40(dd,J=17.4,9.1Hz,1H),2.44(s,1H),2.42(s,3H),1.04(t,J=7.1Hz,3H);

[0164] 13C NMR (101MHz, CDCl3) δ196.5,175.0(q,J=34.8Hz),168.2,144.4,135.1(q,J=4.7Hz),134.1,133.9,132.2,129.4,128. 3,124.9,124.7,122.8,121.1,122.0-111.8(m),110.7,79.1,75.5,62.8,46.8,41.5,37.4,51.8-19.6(m),21.7,13.7;

[0165] 19 F NMR (377MHz, CDCl3) δ-72.39 (s, 3F);

[0166] HRMS (ESI) m / z C 27 H 23 F3NO4([M+H] + ):Calculated value: 482.1574; Measured value: 482.1571.

[0167] Embodiment 15

[0168] The preparation method of ethyl 5-ethynyl-6-(2-(4-methoxyphenyl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate is the same as that in Example 3, except that (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced by (E)-1-(4- 5-ethynyl-6-(2-(4-methoxyphenyl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester 57.5 mg was obtained, which was recorded as 3fa as a white solid with a yield of 77%. Its structural formula is as follows:

[0169]

[0170] The product data are characterized as follows:

[0171] Melting point 91℃~94℃;

[0172] 1H NMR (400MHz, CDCl3) δ8.01 (d, J = 7.5Hz, 1H), 7.93-7.81 (m, 3H), 7.18-7.05 (m, 2H ),6.83(d,J=8.5Hz,2H),4.79(d,J=12.9Hz,1H),4.59(dd,J=9.2,3.1Hz,1H),4. 35(d,J=12.8Hz,1H),3.97(qd,J=10.6,5.2Hz,2H),3.77(s,3H),3.61(dd,J=17. 3,3.2Hz,1H),3.27(dd,J=17.2,9.1Hz,1H),2.33(s,1H),0.93(t,J=7.2Hz,3H);

[0173] 13 C NMR(101MHz, CDCl3)δ195.3,175.0(q,J=34.9Hz),168.2,163.8,135.1(q,J=4.9Hz),132.2,130.4,129.7,124.9,1 24.7,122.8,121.1,121.9-112.3(m),113.9,110.7,79.1,75.5,62.8,55.5,46.8,41.2,46.5-20.1(m),37.6,13.6;

[0174] 19 F NMR (377MHz, CDCl3) δ-72.39 (s, 3F);

[0175] HRMS (ESI) m / z C 27 H 23 F3NO5([M+H] + ):Calculated value: 498.1523; Measured value: 498.1520.

[0176] Example 16

[0177] The preparation method of methyl 6-(2-(3-bromophenyl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate is the same as that in Example 2, except that (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced by (E)-1-(3-bromophenyl)-2-oxoethyl -3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, and the rest was the same as in Example 2 to obtain 46.7 mg of the product 6-(2-(3-bromophenyl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, denoted as 3ga, as a white solid with a yield of 57%; its structural formula is as follows:

[0178]

[0179] The product data are characterized as follows:

[0180] Melting point 136℃~139℃;

[0181] 1 HNMR (400MHz, CDCl3) δ8.03(d,J=7.9Hz,1H),7.99(d,J=1.8Hz,1H),7.89(d,J=2.0Hz,1H),7.79(d ,J=7.9Hz,1H),7.61(d,J=7.9Hz,1H),7.25(t,J=7.9Hz,1H),7.19-7.13(m,1H),7.08(d,J=7.4Hz, 1H),4.81(d,J=12.9Hz,1H),4.59(dd,J=9.2,3.1Hz,1H),4.36(d,J=12.9Hz,1H),4.11-3.89(m,2H ),3.66(dd,J=17.6,3.2Hz,1H),3.27(dd,J=17.6,9.1Hz,1H),2.36(s,1H),0.94(t,J=7.1Hz,3H);

[0182] 13C NMR (101MHz, CDCl3) δ195.5,175.0(q,J=35.3Hz),168.1,138.3,136.3,135.1(q,J=4.8Hz),132.1,131.2,130.4,126. 6,125.0,124.7,123.1,122.8,122.4,121.3,121.2-111.8(m),110.8,79.0,75.7,62.9,49.4,46.7,41.8,37.2,13.7;

[0183] 19 F NMR (377MHz, CDCl3) δ-72.42 (s, 3F);

[0184] HRMS (ESI) m / z C 26 H 20 BrF3NO4([M+H] + ):Calculated value: 546.0522; Measured value: 546.0518.

[0185] Embodiment 17

[0186] The preparation method of methyl 5-ethynyl-6-(2-oxo-2-(m-tolyl)ethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate is the same as that in Example 2, except that (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced by (E)-1-(3 -methylphenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one to obtain 44.9 mg of 5-ethynyl-6-(2-oxo-2-(m-methylphenyl)ethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, recorded as 3ha, white solid, yield 64%; its structural formula is as follows:

[0187]

[0188] The product data are characterized as follows:

[0189] Melting point 141℃~144℃;

[0190] 1H NMR(400MHz, CDCl3)δ8.11(d,J=7.8Hz,1H),8.00-7.94(m,1H),7.76(d,J=9.5Hz ,2H),7.36(dt,J=14.9,7.5Hz,2H),7.22(d,J=7.8Hz,1H),7.16(d,J=7.4Hz,1H), 4.88(d,J=12.8Hz,1H),4.68(dd,J=8.7,3.5Hz,1H),4.45(d,J=12.9Hz,1H),3.75 (dd,J=17.8,3.6Hz,1H),3.63(s,3H),3.41(dd,J=17.6,8.6Hz,1H),2.40(s,4H);

[0191] 13 C NMR (101MHz, CDCl3) δ197.0,175.0(q,J=34.8Hz),168.9,138.6,136.6,135.1(q,J=5.0Hz),134.4,134.3,132.2,128.6,1 25.4,124.9,124.7,122.6,122.5,121.2,117.0(q,J=290.7Hz),110.7,78.9,75.6,53.8,46.7,54.2-28.7(m),41.5,37.4;

[0192] 19 F NMR (377MHz, CDCl3) δ-72.40 (s, 3F);

[0193] HRMS (ESI) m / z C 26 H 21 F3NO4([M+H] + ):Calculated value: 468.1417; Measured value: 468.1415.

[0194] Embodiment 18

[0195] The preparation method of methyl 6-(2-([1,1'-biphenyl]-4-yl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate is the same as that in Example 2, except that (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced by (E)- 1-(3-methylphenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, to obtain 63.5 mg of the product 5-ethynyl-6-(2-oxo-2-(m-methylphenyl)ethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, denoted as 3ia, as a white solid with a yield of 80%; its structural formula is as follows:

[0196]

[0197] The product data are characterized as follows:

[0198] Melting point 169℃~171℃;

[0199] 1 H NMR (400MHz, CDCl3) δ8.13 (dd, J=8.1, 4.1Hz, 1H), 8.03 (d, J=8.1Hz, 2H), 7.97 (s, 1H), 7.67 (d, J=8.1Hz,2H),7.60(d,J=7.6Hz,2H),7.45(t,J=7.5Hz,2H),7.39(t,J=7.3Hz,1H),7.30-7.21(m ,1H),7.17(d,J=7.3Hz,1H),4.87(d,J=12.9Hz,1H),4.70(dd,J=8.6,3.5Hz,1H),4.45(d,J=12. 9Hz,1H),3.79(dd,J=17.5,3.6Hz,1H),3.63(s,3H),3.45(dd,J=17.5,8.6Hz,1H),2.40(s,1H);

[0200] 13C NMR (101MHz, CDCl3) δ196.5,175.0(q,J=35.1Hz),168.9,146.2,139.7,135.3,135.1(q,J=5.3Hz),132.3,129.0,128.8,128.4,127. 4,127.3,125.0,124.8,122.6,122.5,121.3,117.0(q,J=290.9Hz),110.8,78.9,75.6,53.8,46.8,44.6(d,J=1041.8Hz),41.5,37.5;

[0201] 19 F NMR (377MHz, CDCl3) δ-72.35 (s, 3F);

[0202] HRMS (ESI) m / z C 31 H 23 F3NO4([M+H] + ):Calculated value: 530.1574; Measured value: 530.1574.

[0203] Embodiment 19

[0204] The preparation method of ethyl 5-ethynyl-6-(2-(naphthalen-2-yl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate is the same as that in Example 3, except that the raw material (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced with (E)-1-(naphthalen-2-yl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate. )-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, and the rest was the same as in Example 3 to obtain 41.9 mg of the product 5-ethynyl-6-(2-(naphthalen-2-yl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester, denoted as 3ja, as a white solid with a yield of 54%; its structural formula is as follows:

[0205]

[0206] The product data are characterized as follows:

[0207] Melting point 157℃~160℃;

[0208] 1H NMR (400MHz, CDCl3) δ8.40-8.32(m,1H),8.02(dd,J=6.3,2.6Hz,1H),7.96(dd,J=8.6,1.8Hz,1H),7.89(q,J=1 .8Hz,1H),7.80(td,J=10.7,7.9Hz,3H),7.51(ddd,J=8.2,6.9,1.4Hz,1H),7.45(ddd,J=8.2,6.8,1.3Hz,1H), 7.16-7.07(m,2H),4.82(d,J=12.9Hz,1H),4.67(dd,J=9.1,3.2Hz,1H),4.40(d,J=12.8Hz,1H),3.99(qq,J=10 .8,7.1Hz,2H),3.80(dd,J=17.3,3.3Hz,1H),3.46(dd,J=17.3,9.1Hz,1H),2.36(s,1H),0.93(t,J=7.1Hz,3H);

[0209] 13 C NMR (101MHz, CDCl3) δ196.8,175.0(q,J=34.9Hz),168.2,135.7,135.1(q,J=4.5Hz),133.9,132.4,132.2,129.9,129.6,128.8,128.7, 127.8,127.0,125.0,124.7,123.7,122.9,122.7,121.2,117.0(q,J=290.9Hz),110.7,79.1,75.6,62.9,49.5,46.8,41.7,37.5,13.7;

[0210] 19 F NMR (377MHz, CDCl3) δ-72.40 (s, 3F);

[0211] HRMS (ESI) m / z C 30 H 23 F3NO4([M+H] + ):Calculated value: 518.1574; Measured value: 518.1571.

[0212] Embodiment 20

[0213] The preparation method of the product 6-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester is the same as that in Example 3, except that (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced by (E)-1-(benzo[d][ 1,3]dioxolan-5-yl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one to obtain the product 6-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester 60.6 mg, recorded as 3ka, white solid, yield 79%; its structural formula is as follows:

[0214]

[0215] The product data are characterized as follows:

[0216] Melting point 95℃~98℃;

[0217] 1 H NMR (400MHz, CDCl3) δ8.10(d,J=7.7Hz,1H),7.99-7.92(m,1H),7.53(dd,J=8.2,1.8Hz,1H),7.45(d ,J=1.7Hz,1H),7.22(t,J=7.7Hz,1H),7.15(d,J=7.3Hz,1H),6.82(d,J=8.2Hz,1H),6.03(s,2H),4. 88(d,J=12.8Hz,1H),4.66(dd,J=9.2,3.2Hz,1H),4.43(d,J=12.8Hz,1H),4.06(qq,J=10.8,7.0Hz, 1H),3.67(dd,J=17.2,3.2Hz,1H),3.31(dd,J=17.2,9.1Hz,1H),2.42(s,1H),1.02(t,J=7.1Hz,2H);

[0218] 13C NMR (101MHz, CDCl3) δ194.8,175.0(q,J=35.0Hz),168.2,152.1,148.3,135.1(q,J=4.9Hz),132.2,131.5,124.9,124.7,124.5 ,122.8,122.7,121.1,117.0(d,J=291.0Hz),110.7,107.9(d,J=4.7Hz),102.0,79.0,75.5,62.8,49.5,46.8,41.3,37.6,13.7;

[0219] 19 F NMR (377MHz, CDCl3) δ-72.40 (s, 3F);

[0220] HRMS (ESI) m / z C 27 H 21 F3NO6([M+H] + ):Calculated value: 512.1315; Measured value: 512.1312.

[0221] Embodiment 21

[0222] The preparation method of the product 5-ethynyl-6-(2-(furan-2-yl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester is the same as the steps in Example 3, except that (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one is replaced by (E)-1- (Furan-2-yl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one to obtain 45.3 mg of 5-ethynyl-6-(2-(furan-2-yl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester, denoted as 31a, a light yellow oil with a yield of 66%; its structural formula is as follows:

[0223]

[0224] The product data are characterized as follows:

[0225] 1HNMR (400MHz, CDCl3) δ8.04(d,J=60.7Hz,2H),7.54(s,1H),7.23(d,J=28.9Hz,3H),6.52(s,1H),4.89(d,J=12.7Hz,1 H),4.52(dd,J=79.6,11.6Hz,2H),4.05(s,2H),3.62(d,J=17.1Hz,1H),3.47-3.14(m,1H),2.45(s,1H),1.01(s,3H);

[0226] 13 C NMR(101MHz, CDCl3)δ186.0,175.0(q,J=34.9Hz),168.1,152.5,146.6,135.1(q,J=4.8Hz),132.1 ,124.7,122.9,122.4,121.2,117.4,112.5,110.7,78.9,75.7,62.8,49.2,46.7,41.4,37.1,13.6;

[0227] 19 F NMR (377MHz, CDCl3) δ-72.41 (s, 3F);

[0228] HRMS (ESI) m / z C 24 H 19 F3NO5([M+H] + ):Calculated value: 458.1210; Measured value: 458.1206.

[0229] Embodiment 22

[0230] The preparation method of benzyl 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate is the same as the steps of Example 1, except that the molar ratio of the indole compound, potassium carbonate and β'-acetoxymethyl allenoate compound is 1:1.5:1.5, the molar amount of the organic phosphine catalyst is 10% of the molar amount of the indole compound, the reaction temperature is -10°C, and the reaction time is 12h, comprising the following steps:

[0231] At -10°C, 0.15 mmol (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, 0.015 mmol catalyst triphenylphosphine, 0.225 mmol potassium carbonate and 1.5 mL chloroform were sequentially added into a 10 mL round-bottom flask, stirred evenly, and then 0.225 mmol 2-(acetoxymethyl)but-2,3-dienoic acid benzyl ester was added under stirring, and then the reaction was continued at 0°C for 12 h to obtain 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid benzyl ester.

[0232] Embodiment 23

[0233] The preparation method of benzyl 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate is the same as the steps of Example 1, except that the molar ratio of the indole compound, potassium carbonate and β'-acetoxymethyl allenoate compound is 1:3:2.4, the molar amount of the organic phosphine catalyst is 40% of the molar amount of the indole compound, the reaction temperature is 25° C., and the reaction time is 60 h, comprising the following steps:

[0234] At 25°C, 0.15 mmol (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, 0.06 mmol catalyst triphenylphosphine, 0.45 mmol potassium carbonate and 1.5 mL chloroform were sequentially added into a 10 mL round-bottom flask and stirred evenly. Then, 0.36 mmol 2-(acetoxymethyl)but-2,3-dienoic acid benzyl ester was added under stirring, and the reaction was continued at 0°C for 60 h to obtain 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid benzyl ester.

[0235] The compounds prepared in the above Examples 1 to 23 are all single diastereomers.

[0236] Taking the compounds prepared in Examples 1, 3 to 5, 9 and 17 to 19 of the present invention as examples, the effects of the compounds on tumor cell activity were detected using the MTT cell proliferation inhibition assay. The specific methods and results are as follows:

[0237] The tumor cells used in the experiment, namely PC3 cells and TMD8 cells, were both from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

[0238] Take the three types of cells in logarithmic phase, digest the tumor cells with trypsin to obtain cell suspension, count and adjust the cell density to 2×10 4 / mL. 200μL cells were inoculated in each well of a 96-well plate, and after culturing in an incubator at 37°C and 5% CO2 for 24 hours, different example compounds with concentrations of 1μM, 2μM, 4μM, 8μM, 16μM, 32μM, and 64μM were added in sequence, with 3 replicates for each compound. The blank control group was only added with the corresponding volume of dimethyl sulfoxide solvent without adding the compound; then the cells were continued to be cultured in an incubator at 37°C and 5% CO2 for 48 hours. Then 20μL of 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyl tetrazolium bromide was added at a final concentration of 5mg / mL and cultured for 4 hours.

[0239] The absorbance of each well was detected at a wavelength of 490 nm using a Bio-Rad microplate reader.

[0240] Cell number (% blank group) = 100 × (absorbance value of compound treatment group - absorbance value of blank group) / (absorbance value of control group - absorbance value of blank group);

[0241] Each experiment was repeated three times, with compound concentration as the horizontal axis and cell survival rate as the vertical axis, and the graph was drawn using GraphPadPrism software.

[0242] Table 1 shows the results of the inhibition of proliferation activity of the compounds prepared in Example 1, Example 3 to Example 5, Example 9 and Example 17 to Example 19 on PC3 cells, as shown in Table 1.

[0243] Table 1 Data table of the inhibitory activity of the compounds prepared in Example 1, Example 3 to Example 5, Example 9 and Example 17 to Example 19 on PC3 cells

[0244] Compound No. PC3 cytotoxicity (cell survival rate) 3aa 107.35 3ac 109.81 3ad 78.92 3ae 105.77 3ai 103.41 3ha 91.55 3ia 106.18 3ja 111.26 Dimethyl sulfoxide solvent 100

[0245] Figure 2 This is a graph showing the test results of the proliferation inhibition activity of the compounds prepared in Example 1, Example 3 to Example 5, Example 9, and Example 17 to Example 19 on PC3 cells.

[0246] Depend on Figure 2 As shown in Table 1, compound 3ad showed a significant inhibitory effect on PC3 cells, indicating that compound 3ad has great potential value in preparing drugs for treating prostate cancer.

[0247] Table 2 shows the results of the inhibition of proliferation activity of the compounds prepared in Example 1, Example 3 to Example 5, Example 9 and Example 18 on TMD8 cells, as shown in Table 2.

[0248] Table 2 Data table of the inhibitory activity of the compounds prepared in Example 1, Example 3 to Example 5, Example 9 and Example 18 on TMD8 cells

[0249]

[0250]

[0251] Figure 3 The results of the test of the proliferation inhibition activity of the compounds prepared in Example 1, Example 3 to Example 5, Example 9 and Example 18 on TMD8 cells are shown in FIG. Figure 3 As can be seen from Table 2, compounds 3aa, 3ac, 3ad and 3ae showed significant inhibitory effects on PC3 cells, indicating that compounds 3aa, 3ac, 3ad and 3ae have potential value in preparing drugs for treating lymphoma.

[0252] It should be noted that when the present invention involves a numerical range, it should be understood that the two endpoints of each numerical range and any value between the two endpoints can be selected. Since the steps and methods used are the same as those in the embodiments, in order to avoid redundancy, the present invention describes a preferred embodiment. Although the preferred embodiments of the present invention have been described, those skilled in the art may make additional changes and modifications to these embodiments once they know the basic creative concept. Therefore, the attached claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0253] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A method for preparing a pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center, It is characterized in that The following steps are involved: An indole compound, an organic phosphine catalyst and potassium carbonate are placed in a solvent to obtain a mixed solution, and then a β'-acetoxymethyl allenoate compound is added to the mixed solution for a cyclization reaction to obtain a pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl full-carbon quaternary carbon center.

2. The method for preparing the pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center according to claim 1, It is characterized in that The molar ratio of the indole compound, potassium carbonate and β'-acetoxymethyl allenoate compound is 1:1.5-3:1.5-2.

4.

3. The method for preparing the pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center according to claim 1, It is characterized in that The conditions for the cyclization reaction are: stirring the reaction at -10°C to 25°C for 12h to 60h.

4. The method for preparing the pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center according to claim 1, It is characterized in that The indole compound is selected from (E)-1-phenyl-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, (E)-3-(5-chloro-3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)-1-phenylprop-2-en-1-one, (E)-3-(5-bromo-3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)-1-phenylprop-2-en-1-one, (E)-3-(4-bromo-3-(2, (E)-1-(4-fluorophenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, (E)-1-(4-chlorophenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, (E)-1-(4-bromophenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, H-indol-7-yl)prop-2-en-1-one, (E)-1-(p-tolyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, (E)-1-(4-methoxyphenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, (E)-1-(3-bromophenyl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one -one, (E)-1-(naphthalen-2-yl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one, (E)-1-(benzo[d][1,3]dioxolan-5-yl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one or (E)-1-(furan-2-yl)-3-(3-(2,2,2-trifluoroacetyl)-1H-indol-7-yl)prop-2-en-1-one; The β'-acetoxymethyl allenoate compound is selected from benzyl 2-(acetoxymethyl)buta-2,3-dienoate, methyl 2-(acetoxymethyl)buta-2,3-dienoate, ethyl 2-(acetoxymethyl)buta-2,3-dienoate, isopropyl 2-(acetoxymethyl)buta-2,3-dienoate, tert-butyl 2-(acetoxymethyl)buta-2,3-dienoate, benzyl 2-(acetoxymethyl)-4-phenylbuta-2,3-dienoate or benzyl 2-(acetoxymethyl)-4-phenylbuta-2,3-dienoate.

5. The method for preparing the pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center according to claim 1, It is characterized in that The organic phosphine catalyst is selected from triphenylphosphine, tri(4-methoxyphenyl)phosphine, tri(4-fluorophenyl)phosphine, tri(4-chlorophenyl)phosphine or tricyclohexylphosphine.

6. The method for preparing the pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center according to claim 1, It is characterized in that The molar ratio of the organic phosphine catalyst to the indole compound is 0.1-0.4:

1.

7. A pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center prepared by the preparation method of any one of claims 1 to 6, It is characterized in that The chemical structure of pyrrolo[3,2,1-ij]quinoline compounds containing an alkynyl all-carbon quaternary carbon center is: Among them, R 1 is hydrogen or halogen; Ar is aryl or furyl; R is C 1 ~C 4 Alkyl or benzyl; R 2 is bromine, hydrogen or phenyl.

8. The pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center according to claim 7, It is characterized in that Aryl is phenyl, substituted phenyl or naphthyl, and the substituent of substituted phenyl is selected from halogen, methyl, methoxy or benzo[d]dioxol.

9. The pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center according to claim 7, It is characterized in that The pyrrolo[3,2,1-ij]quinoline compounds containing an alkynyl all-carbon quaternary carbon center are: 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid benzyl ester, 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester , 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid isopropyl ester, 5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid tert-butyl ester, 6-(2-oxo-2-phenylethyl)-5-(phenylethynyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid benzyl ester, 5-(bromoethynyl)-6-(2-oxo-2-phenylethyl) Benzyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate, 8-chloro-5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate, methyl-8-bromo-5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate, methyl-9-bromo-5-ethynyl-6-(2-oxo-2-phenylethyl)-1-(2,2,2-trifluoroacetyl)-5, 6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid tert-butyl ester, 5-ethynyl-6-(2-(4-fluorophenyl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 6-(2-(4-chlorophenyl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 6-(2-(4-bromophenyl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester,1-ij]quinoline-5-carboxylic acid methyl ester, 5-ethynyl-6-(2-oxo-2-(p-tolyl)ethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester, 5-ethynyl-6-(2-(4-methoxyphenyl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline -5-carboxylic acid ethyl ester, 6-(2-(3-bromophenyl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 5-ethynyl-6-(2-oxo-2-(m-tolyl)ethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 6- (2-([1,1'-biphenyl]-4-yl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester, 5-ethynyl-6-(2-(naphthalen-2-yl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester, 6-( 2-(Benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)-5-ethynyl-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester or 5-ethynyl-6-(2-(furan-2-yl)-2-oxoethyl)-1-(2,2,2-trifluoroacetyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid ethyl ester. , 10. Use of the pyrrolo[3,2,1-ij]quinoline compound containing an alkynyl all-carbon quaternary carbon center and a pharmaceutically acceptable salt thereof as claimed in any one of claims 7 to 9 in the preparation of a tumor cell proliferation inhibitor.

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