Pyrrolyl heteroaromatic ring compound as well as synthesis method and application thereof

Abstract

The invention relates to a pyrrolyl heteroaromatic ring compound as well as a preparation method and application thereof. The preparation method comprises the following steps: under the irradiation of visible light, reacting an amine compound as shown in a formula 1, an alkyne compound as shown in a formula 2 and a difluorobromo aryl ketone compound as shown in a formula 3 under the action of organic alkali to obtain the pyrrolyl heteroaromatic ring compound as shown in a formula (I), or under the irradiation of visible light, the enamine compound as shown in the formula 4 and the difluorobromo aryl ketone compound as shown in the formula 3 react under the action of organic alkali to obtain the pyrrolyl heteroaromatic ring compound as shown in the formula (I), the organic base is tertiary amine. The reaction formula is as follows. The method has the advantages of high yield, economy, high efficiency, mild reaction conditions, simplicity in operation and the like. The pyrrolyl heteroaromatic ring compound prepared by the invention has certain anti-tumor activity, and part of the compound has excellent anti-tumor activity. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and medicine, and specifically relates to a pyrrolyl heteroaromatic ring compound and a synthesis method and application thereof. Background Art

[0002] As one of the most important heterocyclic frameworks, pyrrole is frequently found in a large number of drugs and natural products. Therefore, efforts have been devoted to developing efficient methods for assembling pyrrole groups, including transition metal catalysis, metal-free catalysis, or photoredox catalysis in the presence of transition metal photocatalysts or organic dyes.

[0003] Although the synthetic methods for pyrrole are very complex, these methods still have some disadvantages, such as harsh reaction conditions, complex operation, low sustainability, poor atom economy, difficulty in obtaining starting materials, and potential toxicity. In order to overcome these limitations, it is still very necessary to develop more economical, more efficient, milder reaction conditions, and simpler operation methods to prepare pyrrole skeletons with more diverse structures. Summary of the invention

[0004] Based on this, the purpose of the present invention is to provide a new synthesis method of pyrrolyl heteroaromatic ring compounds, which has the advantages of high yield, economic efficiency, mild reaction conditions, simple operation, etc.

[0005] The technical solution for achieving the above-mentioned invention object is as follows.

[0006] A method for synthesizing a pyrrolyl heteroaromatic ring compound comprises the following steps:

[0007] Under the irradiation of visible light, the amine compound represented by Formula 1, the alkyne compound represented by Formula 2 and the difluorobromoaryl ketone compound represented by Formula 3 react under the action of an organic base to obtain a pyrrolyl heteroaromatic ring compound represented by Formula (I); the organic base is a tertiary amine;

[0008] The reaction formula is as follows:

[0009]

[0010] Wherein, Ring A is selected from: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0011] E is selected from: electron-withdrawing substituents;

[0012] R 1 is hydrogen, or R 1 Connected to ring A to form a 5-12 membered heterocyclic or heteroaromatic ring structure;

[0013] R is selected from: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0014] In some embodiments, the structure of the amine compound is shown in Formula 1-a, the structure of the pyrrolyl heteroaromatic compound is shown in Formula (Ia), and the reaction is carried out under the protection of an inert gas, and the reaction formula is as follows:

[0015]

[0016] Alternatively, the structure of the amine compound is as shown in Formula 1-b, the structure of the pyrrolyl heteroaromatic compound is as shown in Formula (Ib), and the reaction is carried out under the protection of an inert gas, and the reaction formula is as follows:

[0017]

[0018] Among them, n is selected from: 0, 1, 2, 3.

[0019] In some embodiments, the reaction time is 8 hours to 56 hours, preferably 40 hours to 56 hours.

[0020] In some embodiments, the structure of the amine compound is shown in Formula 1-c, the structure of the pyrrolyl heteroaromatic compound is shown in Formula (Ic), the reaction is carried out under the protection of an inert gas for 8 hours to 56 hours, and then under an air atmosphere for 8 hours to 16 hours, and the reaction formula is as follows:

[0021]

[0022] In some embodiments, the reaction is carried out under the protection of an inert gas for 40 to 56 hours, and then under an air atmosphere for 10 to 14 hours.

[0023] A method for synthesizing a pyrrolyl heteroaromatic ring compound comprises the following steps:

[0024] Under the irradiation of visible light, the enamine compound shown in Formula 4 and the difluorobromoaryl ketone compound shown in Formula 3 react under the action of an organic base to obtain a pyrrolyl heteroaromatic ring compound shown in Formula (I); the organic base is a tertiary amine;

[0025] The reaction formula is as follows:

[0026]

[0027] Wherein, Ring A is selected from: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0028] E is selected from: electron-withdrawing substituents;

[0029] R 1 is hydrogen, or R 1 Connected to ring A to form a 5-12 membered heterocyclic or heteroaromatic ring structure;

[0030] R is selected from: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0031] In some embodiments, the structure of the enamine compound is shown in Formula 4-a, the structure of the pyrrolyl heteroaromatic compound is shown in Formula (Ia), and the reaction is carried out under the protection of an inert gas, and the reaction formula is as follows:

[0032]

[0033] Alternatively, the structure of the enamine compound is shown in Formula 4-b, the structure of the pyrrolyl heteroaromatic ring compound is shown in Formula (Ib), and the reaction is carried out under the protection of an inert gas, and the reaction formula is as follows:

[0034]

[0035] Among them, n is selected from: 0, 1, 2, 3.

[0036] In some embodiments, the reaction time is 8 hours to 56 hours, preferably 40 hours to 56 hours.

[0037] In some embodiments, Ring A is selected from: 1 or more R 2 Substituted or unsubstituted C 6 -C 10 Aryl, 1 or more R 2 a substituted or unsubstituted 5-10 membered heteroaryl group;

[0038] Each R 2 are independently selected from: hydrogen, halogen, C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkoxy, cyano, C 1 -C 6 Alkylamine, C 1 -C 6 Alkylthio, halogen-substituted C 1 -C 6 Alkylthio, or two adjacent R 2 Together with the carbon atoms in ring A, they form a 5-8 membered heterocyclic group.

[0039] In some embodiments, Ring A is selected from: 1 or more R 2 Substituted or unsubstituted phenyl, 1 or more R 2substituted or unsubstituted furanyl, 1 or more R 2 Substituted or unsubstituted thienyl, 1 or more R 2 substituted or unsubstituted pyridyl, 1 or more R 2 Substituted or unsubstituted indolyl.

[0040] In some embodiments, each R 2 Each independently: hydrogen, chlorine, fluorine, bromine, C 1 -C 4 Alkyl, trifluoromethyl, C 1 -C 3 Alkoxy, trifluoromethoxy, cyano, C 1 -C 3 Alkylamine, C 1 -C 3 Alkylthio, or two adjacent R 2 Together with the carbon atoms on ring A, it forms a 5-6 membered oxygen-containing heterocyclic group.

[0041] In some embodiments, the amine compound is selected from:

[0042]

[0043] In some embodiments, E is selected from: -C(=O)R 3 , trifluoromethyl, trifluoroethyl; wherein R 3 Selected from: C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio.

[0044] In some embodiments, R 3 Selected from: C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylthio.

[0045] In some embodiments, the alkyne compound is

[0046] In some embodiments, the structure of the enamine compound is shown in Formula 4-c,

[0047]

[0048] In some embodiments, the structure of the enamine compound is as shown in Formula 4-ca or Formula 4-cb,

[0049]

[0050] n is selected from: 0, 1, 2, 3.

[0051] In some embodiments, the enamine compound is selected from:

[0052]

[0053] In some embodiments, R is selected from: 1 or more R 4 Substituted or unsubstituted C 6 -C 10 Aryl, 1 or more R 4 a substituted or unsubstituted 5-10 membered heteroaryl group;

[0054] Each R 4 are independently selected from: hydrogen, halogen, C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkoxy, cyano, C 1 -C 6 Alkylamine, C 1 -C 6 Alkylthio, halogen-substituted C 1 -C 6 Alkylthio, or two adjacent R 2 Together with the carbon atom on R, it forms a 5-8 membered heterocyclic group.

[0055] In some embodiments, R is selected from: 1 or more R 4 Substituted or unsubstituted phenyl, 1 or more R 4 substituted or unsubstituted furanyl, 1 or more R 4 Substituted or unsubstituted thienyl, 1 or more R 4 substituted or unsubstituted pyridyl, 1 or more R 4 Substituted or unsubstituted indolyl.

[0056] In some embodiments, each R 4 are independently selected from: hydrogen, chlorine, fluorine, bromine, C 1 -C 4 Alkyl, trifluoromethyl, C 1 -C 3 Alkoxy, trifluoromethoxy, cyano, C 1 -C3 Alkylamine, C 1 -C 3 Alkylthio, or two adjacent R 4 Together with the carbon atom on R, it forms a 5-6 membered oxygen-containing heterocyclic group.

[0057] In some embodiments, the difluorobromoaryl ketone compound is selected from:

[0058]

[0059] In some embodiments, the pyrrolyl heteroaromatic compound is selected from:

[0060]

[0061] In some embodiments, the tertiary amine is selected from N,N-diisopropylethylamine (DIPEA), triethylamine (Et 3 At least one of N, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and N,N,N',N'-tetramethylethylenediamine (TMEDA), preferably triethylamine.

[0062] In some of the embodiments, the reaction is carried out in an organic solvent, and the organic solvent is selected from at least one of MeCN, dichloromethane (DCM), N,N-dimethylacetamide (DMA) and methyl tert-butyl ether (MTBE), preferably methyl tert-butyl ether.

[0063] In some embodiments, the visible light is blue light, and the wavelength of the blue light is preferably 430nm to 460nm.

[0064] In some of the embodiments, the wavelength of the blue light is 450nm-456nm.

[0065] In some embodiments, the reaction temperature is 15°C to 40°C.

[0066] In some embodiments, the reaction temperature is 20°C-30°C.

[0067] In some embodiments, the molar ratio of the organic base, the amine compound, the alkyne compound and the difluorobromoaryl ketone compound is 1.5-3:1:1:1.2-2.

[0068] In some embodiments, the molar ratio of the organic base, the enamine compound and the difluorobromoaryl ketone compound is 1.5-3:1:1.2-2.

[0069] The present invention also provides the use of the pyrrolyl heteroaromatic ring compound, including the use of the pyrrolyl heteroaromatic ring compound or its stereoisomer or its pharmaceutically acceptable salt in the preparation of a drug for preventing and / or treating tumors. The tumor is preferably colon cancer, liver cancer, prostate cancer, lung cancer, pancreatic cancer, and more preferably colon cancer, liver cancer, and pancreatic cancer.

[0070] The present invention also provides a drug for preventing and / or treating tumors, which is prepared from active ingredients and pharmaceutically acceptable excipients, wherein the active ingredient comprises the pyrrolyl heteroaromatic ring compound or its stereoisomer or a pharmaceutically acceptable salt thereof described in the present invention.

[0071] The present invention has the following beneficial effects:

[0072] The present invention uses amine compounds, alkyne compounds and difluorobromoaryl ketone compounds as raw materials, or uses enamine compounds and difluorobromoaryl ketone compounds as raw materials, and reacts under the irradiation of visible light and in the presence of tertiary amines to prepare pyrrolyl heteroaromatic ring compounds. The synthesis method uses green and sustainable visible light as reaction energy, without the need to use additives such as transition metal catalysts and photosensitive catalysts, and the raw materials used are cheap and readily available, such as benzylamine, tetrahydroisoquinoline, diethyl butadiynoate, etc., which are all cheap and readily available bulk chemical raw materials, and difluorobromoaryl ketone is also easy to synthesize. The synthesis method of the present invention can modularly synthesize a variety of pyrrolyl-containing aromatic heterocyclic products, with many advantages such as simplicity, high efficiency, high chemical selectivity, high yield, mild reaction conditions, green environmental protection, and low synthesis cost.

[0073] Pyrrolyl heteroaromatic rings are widely present in biologically active molecules such as natural products and drugs, and have important pharmaceutical activities. The synthesis method of the present invention can prepare a series of pyrrolyl heteroaromatic rings with high efficiency and high yield, providing a simple and effective synthesis strategy and method for developing more biologically active drug molecules, which plays an important role in the development and discovery of new drugs.

[0074] The pyrrole heteroaromatic ring compounds prepared by the present invention have certain anti-tumor activity, and some compounds have excellent anti-tumor activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] Figure 1 This is the X-ray single crystal diffraction crystal structure of compound 8-1.

[0076] Figure 2 The inhibitory activity of compounds 8-1 to 8-15 on tumor cells.

[0077] Figure 3 is the inhibition rate of compound 8-14 on colon cancer HCT116 cells.

[0078] Figure 4 is the inhibition rate of compound 8-14 on liver cancer HepG2 cells.

[0079] Figure 5 is the inhibition rate of compound 8-14 on pancreatic cancer BxPC3 cells. DETAILED DESCRIPTION

[0080] In order to facilitate the understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0081] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0082] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used in the present invention includes any and all combinations of one or more of the related listed items.

[0083] In addition, as used in the present invention, the term "or" is an inclusive "or" symbol and is equivalent to the term "and / or", unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for being based on other factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meanings of "a", "an", and "the" include plural referents. The meaning of "in..." includes "in..." and "on...".

[0084] In the compounds described in the present invention, when any variable (such as R 2 If a (, etc.) compound occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Likewise, combinations of substituents and variables are permitted so long as such combinations render the compound stable. A line drawn from a substituent into a ring system or carbon chain indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds are attached only to any suitable carbon atom of an adjacent ring. It is to be understood that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the invention to provide compounds that are chemically stable and that can be readily synthesized from readily available raw materials by techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is to be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0085] The term "alkyl" as used herein is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. 1 -C 6 "C" in "alkyl" 1 -C 6 The definition of " includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain. For example, "C 1 -C 6 The "alkyl group" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl and hexyl.

[0086] The term "alkoxy" as used herein refers to a group having an -O-alkyl structure, such as -OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 2 CH 3 、-O-CH 2 CH(CH 3 ) 2 、-OCH 2 CH 2 CH 2 CH 3 、-O-CH(CH 3 ) 2 wait.

[0087] The term "halogen" as used herein refers to chlorine, fluorine, bromine and iodine.

[0088] The room temperature described in the present invention refers to 23°C-25°C.

[0089] The present invention is further described in detail below with reference to specific embodiments.

[0090] The starting materials and reagents used in the following examples are all commercially available conventional materials and reagents, or can be synthesized by known methods reported in the literature.

[0091] Example 1 Synthesis of Compound 8-1

[0092]

[0093] Et 3N (56 μL, 0.4 mmol, 2.0 equiv), tetrahydroisoquinoline derivative 1-1 (0.2 mmol, 1.0 equiv), electron-deficient alkyne 2-1 (0.2 mmol, 1.0 equiv) and α-bromodifluoroacyl arene 3-1 (0.3 mmol, 1.5 equiv) were added to a flame-dried Schlenk flask equipped with a stirring bar, and the flask was evacuated and heated with N 2 Backfill three times to purge and replace the air in the flask with nitrogen. In the absence of light, anhydrous methyl tert-butyl ether (MTBE) (1 ml, 0.2 M) was added and the flask was sealed. The mixture was then stirred at room temperature and nitrogen atmosphere under irradiation of a 10 W blue LED (with a wavelength of 454 nm). After 48 hours, the crude product was purified by silica gel column chromatography using hexane / EtOAc as eluent to obtain compound 8-1 (yield 88%). The product structure of the product by X-ray single crystal diffraction is as follows Figure 1 shown.

[0094] 1 H NMR (400 MHz, CDCl 3 ): δ7.88(d,J=7.3Hz,2H),7.58-7.46(m,1H),7.39(t,J=7.7Hz,2H),7.29(d,J=7.9Hz,1H),7.19(dt,J=14.4,7.3Hz,2H),7.03(t,J=7.1Hz,1 H),4.63-4.44(m,2H),4.35(q,J=7.1Hz,2H),3.95(q,J=7.1Hz,2H),3.09(t,J=6.6Hz,2H),1.35(t,J=7.1Hz,3H),1.05(t,J=7.1Hz,3H)ppm;

[0095] 13 C NMR (100 MHz, CDCl 3 ): δ193.1,164.3,160.5,138.2,133.2,133.1,129.7,129.6,129.0,128.5,128.4,127 .8,127.2,126.6,126.5,123.3,121.7,119.9,61.4,61.1,42.8,29.1,14.0,13.7ppm;

[0096] HRMS(ESI):exact mass calculated for[M+H] + (C 25 H 24 NO 5 +)requires m / z418.1649,found m / z418.1652.

[0097] Example 2 Synthesis of Compounds 8-1 to 8-5

[0098] Compounds 8-1 to 8-5 were prepared by replacing compound 3-1 in Example 1 with compounds 3-2, 3-3, 3-4 and 3-5 respectively.

[0099]

[0100] 1. According to the synthesis steps of Example 1, a yellow solid product 8-2 (yield 93%) was obtained, and its structure is as follows:

[0101]

[0102] 1 H NMR (400 MHz, CDCl 3 ): δ7.73(d,J=9.0Hz,2H),7.35-7.26(m,1H),7.15-7.04(m,2H),7.02-6.93(m,1H),6.51(d,J=9.1Hz,2H),4.43(dd,J=8.2,5.1Hz, 2H),4.27(q,J=7.1Hz,2H),3.94(q,J=7.1Hz,2H),3.06-2.96(m,3H),2.95(s,6H),1.27(t,J=7.1Hz,3H),0.99(t,J=7.1Hz,3H)ppm;

[0103] 13 C NMR (100 MHz, CDCl 3 ): δ191.3,164.4,160.8,153.6,132.8,132.1,131.8,128.0,127.7,127.3,126.9,12 6.2,126.0,122.8,121.3,121.1,110.6,61.2,60.9,42.7,40.0,29.1,14.0,13.8ppm;

[0104] HRMS(ESI):exact mass calculated for[M+H] + (C 27 H 29 N 2 O 5 + ) requires m / z

[0105] 461.2071, found m / z 461.2070.

[0106] 2. According to the synthesis steps of the embodiment, a yellow solid product 8-3 (yield 91%) was obtained, and its structure is as follows:

[0107]

[0108] 1 H NMR (400 MHz, CDCl 3 ): δ7.72(d,J=8.5Hz,2H),7.21-7.17(m,1H),7.16-7.06(m,4H),6.97(dd,J=10.8,4.2Hz,1H),4.52-4.37(m,2H),4.27(q, J=7.1Hz,2H),3.92(q,J=7.1Hz,2H),3.01(t,J=6.5Hz,2H),2.40(s,3H),1.27(t,J=7.1Hz,3H),1.00(t,J=7.1Hz,3H)ppm;

[0109] 13 C NMR (100 MHz, CDCl 3 ): δ192.1,164.2,160.6,146.2,134.4,133.0,132.6,130.1,128.4,127.8,127.3,12 6.5,126.4,124.8,122.9,121.8,120.0,61.4,61.1,42.8,29.1,14.7,14.0,13.8ppm;

[0110] HRMS(ESI):exact mass calculated for[M+H] + (C 26 H 26 NO 5 S + )requires m / z464.1526, found m / z 464.1533.

[0111] 3. According to the synthesis steps of Example 1, a yellow solid product 8-4 (yield 89%) was obtained, and its structure is as follows:

[0112]

[0113] 1 H NMR (400 MHz, CDCl 3): δ7.36(dd,J=10.7,9.0Hz,2H),7.15(ddd,J=19.0,11.5,6.1Hz,3H),6.98(t,J= 7.4Hz,1H),6.66(dd,J=8.1,1.9Hz,1H),5.94(d,J=1.9Hz,2H),4.42(dd,J=9.1,3. 9Hz,2H),4.27(ddd,J=14.1,7.1,1.8Hz,2H),3.97(ddd,J=14.1,7.1,1.8Hz,2H),3 .01(t,J=6.3Hz,2H),1.28(td,J=7.1,1.9Hz,3H),1.04(td,J=7.1,1.9Hz,3H)ppm;

[0114] 13 C NMR (100 MHz, CDCl 3 ): δ191.4,164.2,160.6,152.0,148.2,133.0,132.9,132.3,128.4,127.8,127.3,126.9,126 .5,126.3,122.7,121.8,120.1,108.8,107.8,101.9,61.4,61.1,42.8,29.1,14.0,13.8ppm;

[0115] HRMS(ESI):exact mass calculated for[M+H] + (C 26 H 24 NO 7 + )requires m / z462.1547, found m / z 462.1544.

[0116] 4. According to the synthesis steps of the embodiment, a yellow solid product 8-5 (yield 87%) was obtained, and its structure is as follows:

[0117]

[0118] 1 H NMR (400 MHz, CDCl 3): δ7.57(d,J=4.9Hz,1H),7.40(d,J=3.7Hz,1H),7.34(d,J=7.8Hz,1H),7.13(q,J=7.7Hz,2H),7.06-6.98(m,1H),6.97-6.89(m,1H),4 .54-4.37(m,2H),4.28(q,J=7.1Hz,2H),3.99(q,J=7.1Hz,2H),3.01(t,J=6.6Hz,2H),1.28(t,J=7.1Hz,3H),1.04(t,J=7.1Hz,3H)ppm;

[0119] 13 C NMR (100 MHz, CDCl 3 ): δ185.0,164.1,160.5,145.3,134.9,134.6,133.0,132.5,128.5,128.0,127.8, 127.4,126.5,126.4,122.8,121.8,119.8,61.4,61.2,42.8,29.1,14.0,13.7ppm;

[0120] HRMS(ESI):exact mass calculated for[M+H] + (C 23 H 22 NO 5 S + )requires m / z424.1213,found m / z 424.1213.

[0121] Example 3

[0122] Compound 1-2 was used to replace compound 1-1 in Example 1, and compound 3-6 was used to replace compound 3-1 in Example 1. Compound 8-6 was prepared according to the method and conditions of Example 1 as a yellow solid with a yield of 96%.

[0123] The structure of compound 1-2 is:

[0124] The structure of compound 3-6 is:

[0125] The structure of compound 8-6 is:

[0126]

[0127] 1 H NMR (400 MHz, CDCl 3): δ7.67(d,J=8.5Hz,2H),7.35(d,J=8.4Hz,2H),7.19(d,J=4.9Hz,1H),6.87(d,J=5.0Hz,1H),4.56(t,J=7.1Hz,2H) ,4.24(q,J=7.1Hz,2H),3.59(q,J=7.1Hz,2H),3.02(t,J=7.1Hz,2H),1.37-1.11(m,12H),0.87(t,J=7.1Hz,3H)ppm;

[0128] 13 C NMR (100 MHz, CDCl 3 ): δ191.5,164.6,160.6,156.3,136.3,136.2,133.2,129.3,127.4,126.2,126.0 ,125.1,123.9,121.0,117.8,61.3,61.1,43.1,35.1,31.1,24.8,13.9,13.5ppm;

[0129] HRMS(ESI):exact mass calculated for[M+H] + (C 27 H 30 NO 5 S + )requires m / z480.1839, found m / z 480.1843.

[0130] Example 4 Synthesis of Compound 8-7

[0131]

[0132] Et 3 N (56 μL, 0.4 mmol, 2.0 equiv), tetrahydro-1H-pyrido[3,4-b]indole derivative 1-7 (0.2 mmol, 1.0 equiv), electron-deficient alkyne 2-1 (0.2 mmol, 1.0 equiv) and α-bromodifluoroacyl arene 3-6 (0.3 mmol, 1.5 equiv) were added to a flame-dried Schlenk flask equipped with a stir bar and the flask was evacuated and heated with N 2Backfill three times to purge and replace the air in the flask with nitrogen. In the absence of light, anhydrous MTBE (1 ml, 0.2 M) was added and the flask was sealed. The mixture was then stirred at room temperature and nitrogen atmosphere under the irradiation of a 10 W blue LED (whose wavelength is 454 nm). After 48 hours of reaction, the reaction was left open overnight (12 hours), and the crude product was purified by silica gel column chromatography using hexane / EtOAc as eluent the next day to obtain 8-15 as a yellow solid in a yield of 73%.

[0133] 1 H NMR (400 MHz, CDCl 3 ): δ10.36(s,1H),7.63(d,J=8.4Hz,2H),7.51(d,J=7.9Hz,1H),7.38(dd,J=14.0,5.5Hz,3H),7.21-7.14(m,1H),7.07(t,J=7.5Hz,1H),4 .68(t,J=7.3Hz,2H),4.25(q,J=7.1Hz,2H),3.49(q,J=7.2Hz,2H),3.19(t,J=7.3Hz,2H),1.32-1.08(m,12H),0.89(t,J=7.2Hz,3H)ppm;

[0134] 13 C NMR (100 MHz, CDCl 3 ): δ193.3,164.7,160.5,156.2,137.1,136.3,133.4,128.9,125.6,125.5,125.1,124.9,123.8,1 22.4,120.2,118.8,117.2,112.2,110.9,61.3,61.2,44.3,35.1,31.1,31.0,20.4,13.9,13.6ppm;

[0135] HRMS(ESI):exact mass calculated for[M+H] + (C 31 H 31 N 2 O 5 + )requires m / z511.2227, found m / z 511.2223.

[0136] Example 5

[0137] Replace compound 3-1 in Example 1 with compound 3-6, and replace compound 1-1 in Example 1 with compounds 1-3, 1-4, 1-5, and 1-6, respectively, and prepare compounds 8-8 to 8-11 according to the method and conditions of Example 1.

[0138]

[0139] 1. According to the synthesis steps of Example 1, a yellow solid product 8-8 (yield 53%) was obtained, and its structure is as follows:

[0140]

[0141] 1 H NMR (400 MHz, CDCl 3 ): δ9.55(d,J=119.5Hz,1H),7.65(d,J=8.4Hz,2H),7.32(d,J=8.4Hz,2H),6.88(d,J=7.2Hz,2H),6.70(d,J=8.5Hz,1H), 5.92(s,2H),4.34(q,J=7.1Hz,2H),4.00(q,J=7.1Hz,2H),1.35(t,J=7.0Hz,3H),1.28(s,9H),1.06(t,J=7.1Hz,3H)ppm;

[0142] 13 C NMR (100 MHz, CDCl 3 ): δ191.5,164.1,160.2,156.4,148.3,147.8,136.9,135.7,129.4,125.1,123.8,123 .3,122.7,122.2,120.6,108.9,108.5,101.4,61.6,61.3,35.0,31.1,14.2,13.7ppm;

[0143] HRMS(ESI):exact mass calculated for[M+H] + (C 28 H 30 NO 7 + )requires m / z492.2017, found m / z 492.2024.

[0144] 2. According to the synthesis steps of Example 1, a yellow solid product 8-9 (yield 61%) was obtained, and its structure is as follows:

[0145]

[0146] 1 H NMR (400 MHz, CDCl 3 ): δ9.84(s,1H),7.55(d,J=8.4Hz,2H),7.30(ddd,J=8.5,5.9,3.1Hz,2H),7.23(d,J=8.4Hz,2H),6.88(t,J=8.6Hz ,2H),4.22(q,J=7.1Hz,2H),3.94(q,J=7.1Hz,2H),1.27(d,J=7.0Hz,3H),1.20(s,9H),1.00(t,J=7.1Hz,3H)ppm;

[0147] 13 C NMR (100 MHz, CDCl 3 ): δ191.3,164.1(d,J=21.9Hz),161.8,160.2,156.5,136.2,135.5,130.5(d,J=8.4Hz),129.4,126.7-1 25.5(m),125.1,123.4,122.6,121.1,115.7(d,J=21.9Hz),61.6,61.3,35.0,31.2,31.0,14.1,13.7ppm;

[0148] 19 F NMR (376 MHz, CDCl 3 )δ-85.38--145.22(m)ppm;

[0149] HRMS(ESI):exact mass calculated for[M+H] + (C 27 H 29 FNO 5 + )requires m / z466.2024, found m / z 466.2021.

[0150] 3. According to the synthesis steps of Example 1, a yellow solid product 8-10 (yield 62%) was obtained, and its structure is as follows:

[0151]

[0152] 1 H NMR (400 MHz, CDCl 3)δ10.05(s,1H),7.64(d,J=8.4Hz,2H),7.52(s,4H),7.30(d,J=8.4Hz,2H),4.28(q,J=7.1 Hz,2H),4.02(q,J=7.1Hz,2H),1.38-1.26(m,3H),1.26(s,9H),1.07(t,J=7.1Hz,3H)ppm;

[0153] 13 CNMR (100MHz, CDCl 3 )δ191.1,163.8,160.2,156.9,135.3,133.4,131.7-130.0(m),129.4,128.8,125.6,1 25.5(q,J=3.7Hz),123.4(d,J=4.1Hz),121.8,61.8,61.4,35.1,31.0,14.1,13.6ppm;

[0154] 19 F NMR (376 MHz, CDCl 3 ):δ-62.9(s)ppm;

[0155] HRMS(ESI):exact mass calculated for[M+H] + (C 28 H 29 F 3 NO 5 + )requires m / z516.1992, found m / z 516.1990.

[0156] 4. According to the synthesis steps of Example 1, a white solid product 8-11 (yield 69%) was obtained, and its structure is as follows:

[0157]

[0158] 1 H NMR (400 MHz, CDCl 3 )δ10.04(s,1H),7.66(d,J=8.3Hz,2H),7.55(q,J=8.4Hz,4H),7.34(d,J=8.4Hz,2H),4.34(q,J =7.1Hz,2H),3.98(q,J=7.1Hz,2H),1.46-1.32(m,3H),1.29(s,9H),1.03(t,J=7.1Hz,3H)ppm;

[0159] 13 CNMR (100MHz, CDCl 3 )δ191.2,163.5,160.1,157.2,135.2,134.2,134.2,132.4,129.4,128.8,125 .3,123.9,123.3,122.3,118.2,112.4,61.9,61.5,35.1,31.0,14.1,13.6ppm;

[0160] HRMS(ESI):exact mass calculated for[M+H] + (C 28 H 29 N 2 O 5 + )requires m / z473.2071, found m / z 473.2079.

[0161] Example 6 Preparation of Compounds 8-12

[0162]

[0163] Et 3 N (56 μL, 0.4 mmol, 2.0 equiv), trifluoromethyl substituted enamine derivative 4-1 (0.2 mmol, 1.0 equiv) and α-bromodifluoroacyl arene 3-6 (0.3 mmol, 1.5 equiv) were added to a flame-dried Schlenk flask equipped with a stir bar and the flask was evacuated and heated with N 2 Backfill three times to purge the air in the flask with nitrogen. In the absence of light, anhydrous MTBE (1 ml, 0.2 M) was added and the flask was sealed. The mixture was then stirred at room temperature and nitrogen atmosphere under the irradiation of a 10 W blue LED (whose wavelength is 454 nm). After 48 hours, the crude product was purified by silica gel column chromatography using hexane / EtOAc as eluent to obtain compound 8-12 (yield 74%).

[0164] 1 H NMR (400 MHz, CDCl 3 )δ7.84(d,J=8.4Hz,2H),7.43(d,J=8.3Hz,3H),7.21(q,J=7.4Hz,2H),7.12-7.00(m,1H),4.27(t, J=6.5Hz,2H),3.91(q,J=7.1Hz,2H),3.13(t,J=6.5Hz,2H),1.31(s,9H),0.94(t,J=7.1Hz,3H)ppm;

[0165] 13 CNMR (100MHz, CDCl 3 )δ193.0,162.6,157.2,135.6,132.2,131.5,129.5,128.5,127.8,127.6,126. 4,126.1,125.5,123.5-118.1(m),61.2,43.4,43.4,35.2,31.1,29.0,13.4ppm;

[0166] 19 F NMR (376 MHz, CDCl 3 ):δ-55.6(s)ppm;

[0167] HRMS(ESI):exact mass calculated for[M+H] + (C 27 H 27 F 3 NO 3 + )requires m / z470.1938, found m / z 470.1944.

[0168] Example 7

[0169] Compounds 8-13 to 8-15 were prepared by replacing compound 4-1 in Example 5 with compounds 4-2, 4-3 and 4-4 respectively, according to the method and conditions of Example 4.

[0170]

[0171] 1. According to the synthesis steps of Example 5, a yellow solid product 8-13 (yield 86%) was obtained, and its structure is as follows:

[0172]

[0173] 1 H NMR (400 MHz, CDCl 3 )δ9.89(d,J=20.7Hz,1H),7.75(d,J=8.4Hz,2H),7.40(d,J=8.4Hz,2H),6.50(d,J=1.6Hz,2H),4 .03(q,J=7.1Hz,2H),3.76(s,3H),3.63(d,J=1.7Hz,6H),1.30(s,9H),0.95(t,J=7.1Hz,3H)ppm;

[0174] 13 CNMR (100MHz, CDCl 3 )δ192.8,161.8,157.1,153.0,137.8,135.9,132.7,129.3,125.5,125.3,123.2 ,122.6-121.5(m),118.9,116.7,105.2,60.9,60.9,55.7,35.1,31.0,13.4ppm;

[0175] 19 F NMR (376 MHz, CDCl 3 ):δ-58.8(s)ppm;

[0176] HRMS(ESI):exact mass calculated for[M+H] + (C 28 H 31 F 3 NO 6 + )requires m / z534.2098, found m / z 534.2103.

[0177] 2. According to the synthesis steps of Example 5, a yellow solid product 8-14 (yield 86%) was obtained, and its structure is as follows:

[0178]

[0179] 1 H NMR (400 MHz, CDCl 3 )δ10.13(s,1H),7.73(d,J=8.4Hz,2H),7.48(s,4H),7.41(d,J=8.5Hz,2H),4.00(q,J=7.1Hz,2H),1.30(s,9H),0.93(t,J=7.1Hz,3H)ppm;

[0180] 13 CNMR (100MHz, CDCl 3 )δ192.8,161.6,157.6,135.3,132.8,131.0,130.4(t,J=32.8Hz),129.3,127.7,125.8(q,J=3.7Hz), 125.6,125.1,124.2,122.5(dd,J=135.7,74.6Hz),117.2(t,J=134.6Hz).61.1,35.2,31.0,13.2ppm;

[0181] 19 F NMR (376 MHz, CDCl 3 ):δ-58.9(s),-62.9(s)ppm;

[0182] HRMS(ESI):exact mass calculated for[M+H] + (C 26 H 24 F 6 NO 3 + )requires m / z512.1655,found m / z 512.1658.

[0183] 3. According to the synthesis steps of Example 5, a yellow solid product 8-15 (yield 82%) was obtained, and its structure is as follows:

[0184]

[0185] 1 H NMR (400 MHz, CDCl 3 )δ9.48(s,1H),7.77(d,J=8.4Hz,2H),7.42(d,J=8.4Hz,2H),7.24(dd,J=14.7,3.9Hz, 2H), 6.96 (dd, J = 5.0, 3.8Hz, 1H), 3.99 (q, J = 7.1Hz, 2H), 1.31 (s, 9H), 0.89 (s, 3H) ppm;

[0186] 13 CNMR (100MHz, CDCl 3 )δ192.0,161.5,157.1,135.6,130.3,129.3,127.8,127.4,126.9,125.5,122.3 (dd,J=118.4,78.4Hz),117.3(dd,J=135.5,133.4Hz)61.0,35.1,31.0,13.3ppm;

[0187] 19 F NMR (376 MHz, CDCl 3 ):δ-58.9(s)ppm;

[0188] HRMS(ESI):exact mass calculated for[M+H] + (C 23 H 23 F 3 NO 3 S+ )requires m / z450.1345, found m / z 450.1346.

[0189] Example 8 Synthesis of Compound 8-1 under Different Reaction Conditions

[0190] Compound 8-1 was prepared by the method of Example 1 under the conditions shown in Table 1 below. The yield is shown in Table 1.

[0191] The preparation method and reaction conditions of this example are the same as those of Example 1 except for the differences shown in Table 1.

[0192]

[0193] Table 1

[0194]

[0195]

[0196] [a] Reaction in the dark; [b] 80°C and no light.

[0197] Example 9 Antitumor Activity Test

[0198] 1. Inhibitory activity of compounds on different tumor cells

[0199] Compounds 8-1 to 8-15 were tested for anti-tumor activity. Human colon cancer cells HCT116, liver cancer cells HepG2, prostate cancer cells DU145, lung cancer cells A549 and pancreatic cancer cells BxpC3 were selected. These cell lines were purchased from the American Type Culture Collection (ATCC). HepG2 and DU145 were cultured in DMEM medium, HCT116 was cultured in McCoy's 5A medium, A549 was cultured in F12K medium, and BxpC3 was cultured in RPMI1640 medium. All culture media were supplemented with 10% fetal bovine serum (FBS) to provide growth factors required for cell growth. The cell culture conditions were 37°C and 5% CO 2 The culture steps are as follows:

[0200] (1) Tumor cells in the logarithmic growth phase were digested with trypsin and resuspended in complete medium. The cell concentration was measured using a cell counter and the cells were diluted to 3×10 4 Pieces / mL;

[0201] (2) Inoculate 100 μL of cell suspension in each well of a 96-well plate and incubate overnight in a cell culture incubator;

[0202] (3) Compounds 8-1 to 8-15 were diluted to 20 μM with the complete culture medium of the corresponding cells, and 100 μL of the compound dilution was added to each well of a 96-well plate to make the final concentration of the compound 10 μM. Each compound was added to 3 replicates, and the control group was DMSO with the same volume as the compound. The cells were returned to the cell culture incubator and cultured for 72 hours;

[0203] (4) The inhibitory effects of compounds 8-1 to 8-15 on the survival of various tumor cells were detected by MTT assay. After the tumor cells were treated with the compounds for 72 hours, 20 μL of 5 mg / mL MTT solution was added to each well and incubated at 37°C for another 4 hours;

[0204] (5) Discard the cell culture medium, add 150 μL DMSO to dissolve the cells, and measure the OD value at 570 nm (OD570) using a microplate reader;

[0205] (6) Data processing: relative survival rate was calculated based on OD570 of the compound-treated group and the control-treated group. Cell survival rate = OD570 化合物 / OD570 DMSO .

[0206] The experimental results are as follows Figure 2 As shown: the pyrrolyl heteroaromatic ring compounds prepared by the present invention have certain anti-tumor effects, and most of the compounds have a certain degree of inhibitory effect on the proliferation of BxPC3 cells, especially compounds 8-14 have good inhibitory effects on the growth of colon cancer cells HCT116, liver cancer cells HepG2, prostate cancer cells DU145, lung cancer cells A549 and pancreatic cancer cells BxpC3, especially have excellent inhibitory effects on colon cancer cells, liver cancer cells and pancreatic cancer cells.

[0207] 2. Effects of different concentrations of compounds 8-14 on the survival of colon cancer, liver cancer, and pancreatic cancer cells

[0208] HCT116, HepG2 and BxPC3 cells were diluted with McCoy's 5A medium, DMEM and RPMI1640 medium containing 10% FBS, respectively, to a final cell concentration of 2×10 4 / mL, and then inoculate 100 μL of cell suspension into 96-well plates respectively. After the cells adhered, compounds 8-14 were added to make the final concentrations of 0 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM, and 20 μM, with 5 replicates for each concentration. After 72 hours of compound treatment, the MTT method was used to detect the effects of different concentrations of compounds 8-14 on the viability of HCT116, HepG2 and BxPC3 cells.

[0209] The experimental results are as follows Figure 3-Figure 5 As shown, with the increase of compound concentration, the survival ability of the three cancer cells decreased significantly, indicating that compounds 8-14 have considerable inhibitory activity against the three tumor cells. The half lethal concentrations of compounds 8-14 for colon cancer HCT116, liver cancer HepG2, and pancreatic cancer BxPC3 are 6.5μM, 8.2 and 7.2μM, respectively.

[0210] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for synthesizing a pyrrolyl heteroaromatic compound, characterized in that: The steps include: Under the irradiation of visible light, the amine compound represented by Formula 1, the alkyne compound represented by Formula 2 and the difluorobromoaryl ketone compound represented by Formula 3 react under the action of an organic base to obtain a pyrrolyl heteroaromatic ring compound represented by Formula (I); the organic base is a tertiary amine; The reaction formula is as follows: Wherein, Ring A is selected from: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; E is selected from: electron-withdrawing substituents; R1 is hydrogen, or R1 is connected to ring A to form a 5-12 membered heterocyclic or heteroaromatic ring structure; R is selected from: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

2. The method for synthesizing a pyrrolyl heteroaromatic compound according to claim 1, wherein The structure of the amine compound is shown in Formula 1-a, the structure of the pyrrolyl heteroaromatic compound is shown in Formula (Ia), and the reaction is carried out under the protection of an inert gas, and the reaction formula is as follows: Alternatively, the structure of the amine compound is as shown in Formula 1-b, the structure of the pyrrolyl heteroaromatic compound is as shown in Formula (Ib), and the reaction is carried out under the protection of an inert gas, and the reaction formula is as follows: Wherein, n is selected from: 0, 1, 2, 3; Preferably, the reaction time is 8 hours to 56 hours, preferably 40 hours to 56 hours.

3. The method for synthesizing a pyrrolyl heteroaromatic ring compound according to claim 1, characterized in that: The structure of the amine compound is shown in Formula 1-c, the structure of the pyrrolyl heteroaromatic compound is shown in Formula (Ic), the reaction is carried out under the protection of an inert gas for 8 to 56 hours, and then under an air atmosphere for 8 to 16 hours, and the reaction formula is as follows: Preferably, the reaction is carried out under the protection of an inert gas for 40 to 56 hours, and then under an air atmosphere for 10 to 14 hours.

4. A method for synthesizing a pyrrolyl heteroaromatic ring compound, characterized in that: The steps include: Under the irradiation of visible light, the enamine compound shown in Formula 4 and the difluorobromoaryl ketone compound shown in Formula 3 react under the action of an organic base to obtain a pyrrolyl heteroaromatic ring compound shown in Formula (I); the organic base is a tertiary amine; The reaction formula is as follows: Wherein, Ring A is selected from: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; E is selected from: electron-withdrawing substituents; R1 is hydrogen, or R1 is connected to ring A to form a 5-12 membered heterocyclic or heteroaromatic ring structure; R is selected from: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

5. The method for synthesizing a pyrrolyl heteroaromatic compound according to claim 4, characterized in that: The structure of the enamine compound is shown in Formula 4-a, the structure of the pyrrolyl heteroaromatic ring compound is shown in Formula (Ia), and the reaction is carried out under the protection of an inert gas, and the reaction formula is as follows: Alternatively, the structure of the enamine compound is shown in Formula 4-b, the structure of the pyrrolyl heteroaromatic ring compound is shown in Formula (Ib), and the reaction is carried out under the protection of an inert gas, and the reaction formula is as follows: Wherein, n is selected from: 0, 1, 2, 3; Preferably, the reaction time is 8 hours to 56 hours, preferably 40 hours to 56 hours.

6. The method for synthesizing a pyrrolyl heteroaromatic compound according to any one of claims 1 to 5, characterized in that: Ring A is selected from: 1 or more R2 substituted or unsubstituted C6-C 10 Aryl, 1 or more R2 substituted or unsubstituted 5-10 membered heteroaryl; Each R2 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, cyano, C1-C6 alkylamino, C1-C6 alkylthio, halogen-substituted C1-C6 alkylthio, or two adjacent R2 together with the carbon atoms on ring A form a 5-8 membered heterocyclic group; Preferably, Ring A is selected from: 1 or more R2 substituted or unsubstituted phenyl groups, 1 or more R2 substituted or unsubstituted furyl groups, 1 or more R2 substituted or unsubstituted thienyl groups, 1 or more R2 substituted or unsubstituted pyridyl groups, 1 or more R2 substituted or unsubstituted indolyl groups; Preferably, each R2 is independently: hydrogen, chlorine, fluorine, bromine, C1-C4 alkyl, trifluoromethyl, C1-C3 alkoxy, trifluoromethoxy, cyano, C1-C3 alkylamino, C1-C3 alkylthio, or two adjacent R2 and the carbon atoms on ring A together form a 5-6 membered oxygen-containing heterocyclic group; Preferably, the amine compound is selected from: E is selected from: -C(=O)R3, trifluoromethyl, trifluoroethyl; wherein R3 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio; preferably, R3 is selected from: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio; Preferably, the alkyne compound is Preferably, the structure of the enamine compound is as shown in Formula 4-c, Preferably, the structure of the enamine compound is as shown in Formula 4-ca or Formula 4-cb, n is selected from: 0, 1, 2, 3; Preferably, the enamine compound is selected from: R is selected from: 1 or more R4 substituted or unsubstituted C6-C 10 Aryl, 1 or more R4 substituted or unsubstituted 5-10 membered heteroaryl; Each R4 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, cyano, C1-C6 alkylamino, C1-C6 alkylthio, halogen-substituted C1-C6 alkylthio, or two adjacent R2s and the carbon atom on R together form a 5-8 membered heterocyclic group; Preferably, R is selected from: one or more R4 substituted or unsubstituted phenyl groups, one or more R4 substituted or unsubstituted furyl groups, one or more R4 substituted or unsubstituted thienyl groups, one or more R4 substituted or unsubstituted pyridyl groups, one or more R4 substituted or unsubstituted indolyl groups; Preferably, each R4 is independently selected from: hydrogen, chlorine, fluorine, bromine, C1-C4 alkyl, trifluoromethyl, C1-C3 alkoxy, trifluoromethoxy, cyano, C1-C3 alkylamino, C1-C3 alkylthio, or two adjacent R4 and the carbon atom on R together form a 5-6 membered oxygen-containing heterocyclic group; Preferably, the difluorobromoaryl ketone compound is selected from: Preferably, the pyrrolyl heteroaromatic compound is selected from:

7. The method for synthesizing a pyrrolyl heteroaromatic compound according to any one of claims 1 to 5, characterized in that: The tertiary amine is at least one selected from N,N-diisopropylethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and N,N,N',N'-tetramethylethylenediamine, preferably triethylamine; and / or, The reaction is carried out in an organic solvent, wherein the organic solvent is selected from at least one of MeCN, dichloromethane, N,N-dimethylacetamide and methyl tert-butyl ether, preferably methyl tert-butyl ether; and / or, The visible light is blue light, and the wavelength of the blue light is preferably 430nm to 460nm; and / or, The reaction temperature is 15°C to 40°C, preferably 20°C to 30°C; and / or, The molar ratio of the organic base, the amine compound, the alkyne compound and the difluorobromoaryl ketone compound is 1.5-3:1:1:1.2-2; or, The molar ratio of the organic base, the enamine compound and the difluorobromoaryl ketone compound is 1.5-3:1:1.2-2.

8. The pyrrolyl heteroaromatic ring compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

9. Use of the pyrrolyl heteroaromatic ring compound or its stereoisomer or its pharmaceutically acceptable salt as claimed in any one of claims 1 to 6 in the preparation of a drug for preventing and / or treating tumors, wherein the tumor is preferably colon cancer, liver cancer, prostate cancer, lung cancer, pancreatic cancer, more preferably colon cancer, liver cancer, pancreatic cancer.

10. A drug for preventing and / or treating tumors, characterized in that: The invention is prepared from active ingredients and pharmaceutically acceptable excipients, wherein the active ingredient comprises the pyrrolyl heteroaromatic ring compound or its stereoisomer or pharmaceutically acceptable salt as described in any one of claims 1 to 6.

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