A beta-carboline fused [1',2':1,2] imidazole derivative, a preparation method and application thereof, and a pharmaceutical composition

Abstract

The present application relates to the technical field of biological medicine, in particular to a kind of β-quinoline and [1',2':1,2] imidazole derivative and its preparation method and application, pharmaceutical composition. The β-quinoline and [1',2':1,2] imidazole derivative of the present application has good antitumor activity to lung cancer, gastric cancer, colon cancer, liver cancer and breast cancer, and has good application prospect in the preparation of antitumor drugs. As shown in the test results of example, 22 compounds in the compound provided by the present application have IC 50 Value ≤10 μM, 20 compounds have IC 50 Value ≤10 μM, 19 compounds have IC 50 Value ≤10 μM, 22 compounds have IC 50 Value ≤10 μM, 11 compounds have IC 50 Value ≤10 μM.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to a β-carbazo[1',2':1,2]imidazole derivative, its preparation method and application, and pharmaceutical compositions. Background Technology

[0002] β-Carboline is a naturally occurring alkaloid containing a pyridine ring and an indole ring in its structure. These compounds are widely found in nature and have been discovered to possess a variety of biological activities, including nervous system activity, antioxidant activity, anticancer activity, anti-inflammatory activity, and neurotransmitter regulation.

[0003] Currently, existing technologies report β-carboline compounds with anti-tumor properties, including β-carboline, dehydrocamellia alkaloid, and Eudistomin U, but the variety is still insufficient.

[0004] Summary of the Invention

[0005] In view of this, the object of the present invention is to provide a β-carbazo[1',2':1,2]imidazol derivative, its preparation method and application, and a pharmaceutical composition thereof. The β-carbazo[1',2':1,2]imidazol derivative provided by the present invention exhibits excellent antitumor activity.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a β-carbazo[1',2':1,2]imidazol derivative having the structure shown in Formula I: Formula I; The R 3 Including hydrogen, C1-C6 alkyl groups, and unsubstituted or substituted phenyl groups; When the R 2 When it is hydrogen, the R 1 Including C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, unsubstituted or substituted phenyl; When the R 1 When it is hydrogen, the R 2 This includes C1-C6 alkyl groups, C1-C6 haloalkyl groups, and unsubstituted or substituted phenyl groups.

[0007] Preferably, the R 3 The substituents in the substituted phenyl group include C1-C6 alkyl groups and / or halogens.

[0008] Preferably, the R 1 The substituents in the substituted phenyl group include one or more of halogens, C1-C6 haloalkyl groups, and C1-C6 alkoxy groups.

[0009] Preferably, the R 2 The substituents in the substituted phenyl group include halogens and / or C1~C6 alkoxy groups.

[0010] This invention provides a method for preparing the β-carbazo[1',2':1,2]imidazol derivative described in the above technical solution. When R 2 When the hydrogen is present, the preparation method includes the following steps: mixing compound 4, a haloketone, and a first organic solvent, and performing a first cyclization reaction to obtain a β-carbazo[1',2':1,2]imidazolium derivative; wherein X in the haloketone is a halogen; When R 1 When hydrogen is used, the preparation method includes the following steps: mixing compound 4, aldehyde compound, organic amine, S8 and second organic solvent, and carrying out a second cyclization reaction to obtain β-carbazo[1',2':1,2]imidazol derivative; .

[0011] Preferably, the molar ratio of compound 4 to the haloketone is 1:1.1~2; The first organic solvent includes alcohol solvents; The temperature of the first cyclization reaction is 60~100℃, and the time is 2~4h.

[0012] Preferably, the molar ratio of compound 4 to the aldehyde compound is 1:1.1~2; The molar ratio of compound 4 to the organic amine is 1:0.05~0.5; The molar ratio of compound 4 to S8 is 1:0.1~0.4; The second organic solvent includes a mixed solvent of highly polar solvents and less polar solvents, wherein the highly polar solvents include sulfone solvents and / or amide solvents, and the less polar solvents include cycloalkanes solvents and / or ether solvents; The second cyclization reaction is carried out at a temperature of 120-160°C for 1-5 hours.

[0013] The present invention also provides the application of the β-carbazo[1',2':1,2]imidazol derivatives described in the above technical solutions or the β-carbazo[1',2':1,2]imidazol derivatives prepared by the above technical solutions in the preparation of drugs.

[0014] Preferably, the drug includes an antitumor drug.

[0015] The present invention provides a pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises the β-carbazo[1',2':1,2]imidazol derivative described in the above-described technical solution or the β-carbazo[1',2':1,2]imidazol derivative prepared by the preparation method described in the above-described technical solution.

[0016] The β-carbazo[1',2':1,2]imidazol derivative of the present invention, having the structure shown in Formula I, exhibits excellent antitumor activity against lung cancer, gastric cancer, colon cancer, liver cancer, and breast cancer, indicating that the fused imidazolium ring at the 1,2-position of β-carbazoline can significantly enhance the activity of this type of compound. It shows great promise for application in the preparation of antitumor drugs. As shown in the test results of the examples, the average IC50 of the β-carbazo[1',2':1,2]imidazol derivative provided by the present invention against A549 (lung cancer cells) is... 50 Value ≤56.2 μmol / L, average IC50 against BGC-823 (gastric cancer cells) 50 Value ≤67.9 μmol / L, average IC50 against CT-26 (colon cancer cells) 50 Value ≤48.7 μmol / L, average IC50 against Bel-7402 (liver cancer cells) 50 Value ≤48.2 μmol / L, average IC50 against MCF-7 (breast cancer cells) 50 Value ≤68.4 μmol / L; among them, 22 compounds showed an IC50 value of ≤68.4 μmol / L for lung cancer A549. 50 With a value ≤10 μM, 20 compounds showed an IC50 value against gastric cancer BGC-823. 50 With a value ≤10μM, 19 compounds showed an IC50 value against CT-26 colon cancer. 50 With a value ≤10 μM, 22 compounds showed an IC50 value against Bel-7402 hepatocellular carcinoma. 50 With a value ≤10 μM, 11 compounds showed an IC50 value against breast cancer MCF-7. 50 Value ≤10μM.

[0017] The method for preparing β-carbazo[1',2':1,2]imidazol derivatives provided by this invention is simple in process, easy to operate, low in production cost, green and environmentally friendly, and suitable for industrial production. Detailed Implementation

[0018] This invention provides a β-carbazo[1',2':1,2]imidazol derivative having the structure shown in Formula I: Formula I.

[0019] In this invention, the R 3Including hydrogen, C1-C6 alkyl, unsubstituted or substituted phenyl groups; the substituents in the substituted phenyl groups preferably include C1-C6 alkyl groups and / or halogens; the halogens preferably include one or more of fluorine, chlorine, bromine and iodine; the C1-C6 alkyl groups preferably include methyl, ethyl, propyl, butyl, pentyl or hexyl; the R 3 Specifically, preferred groups include hydrogen, methyl, benzyl, p-fluorobenzyl, or phenylpropyl.

[0020] In this invention, when the R 2 When it is hydrogen, the R 1 This includes C1-C6 alkyl groups, C1-C6 haloalkyl groups, cycloalkyl groups, and unsubstituted or substituted phenyl groups; the substituents in the substituted phenyl groups preferably include one or more of halogens, C1-C6 haloalkyl groups, and C1-C6 alkoxy groups; the alkyl groups in the C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C1-C6 alkoxy groups preferably independently include methyl, ethyl, propyl, butyl, pentyl, or hexyl; the halogens in the C1-C6 haloalkyl groups preferably include one or more of fluorine, chlorine, bromine, and iodine, and the C1-C6 haloalkyl groups specifically preferably include trifluoromethyl; the C1-C6 alkoxy groups preferably include methoxy groups; the cycloalkyl groups preferably include cyclopropane groups; the R 1 Specifically, preferred compounds include phenyl, p-fluorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-methoxyphenyl, methyl, trifluoromethyl, or cyclopropane.

[0021] In this invention, when the R 1 When it is hydrogen, the R 2 Includes C1-C6 alkyl groups, C1-C6 haloalkyl groups, and unsubstituted or substituted phenyl groups; the substituents in the substituted phenyl groups preferably include halogens and / or C1-C6 alkoxy groups; the alkyl groups in the C1-C6 alkyl groups, C1-C6 haloalkyl groups, and C1-C6 alkoxy groups independently preferably include methyl, ethyl, propyl, butyl, pentyl, or hexyl; the halogens in the C1-C6 haloalkyl groups independently preferably include one or more of fluorine, chlorine, bromine, and iodine; the R 2 Specifically, preferred compounds include phenyl, p-fluorophenyl, p-bromophenyl, p-methoxyphenyl, ethyl, or trifluoromethyl.

[0022] In this invention, when the R 2 When hydrogen is present, the β-carbazo[1',2':1,2]imidazol derivative (compound 6) has the structure shown in formulas 6aa~6eh; when the R 1 When hydrogen is present, the β-carbazo[1',2':1,2]imidazol derivative (compound 8) has the structure shown in formulas 8aa~8ef: .

[0023] This invention provides a method for preparing the β-carbazo[1',2':1,2]imidazol derivative described in the above-mentioned technical solution. In this invention, when R 2 When the hydrogen content is 1, the preparation method of the β-carbazo[1',2':1,2]imidazol derivative includes the following steps: mixing compound 4, a haloketone, and a first organic solvent, and carrying out a first cyclization reaction to obtain the β-carbazo[1',2':1,2]imidazol derivative; wherein R in compound 4 3 With R in Equation I 3 Same; R in the haloketone 1 With R in Equation I 1 Same, X is a halogen.

[0024] .

[0025] Unless otherwise specified, the materials and equipment used in this invention are all commercially available products in the field.

[0026] In this invention, the molar ratio of compound 4 to the haloketone is preferably 1:1.1~2, more preferably 1:1.5~2; the X (halogen) in the haloketone preferably includes fluorine, chlorine, bromine or iodine, more preferably chlorine or bromine.

[0027] In this invention, the first organic solvent preferably includes an alcohol solvent, more preferably anhydrous methanol and / or anhydrous ethanol. In this invention, the ratio of compound 4 to the first organic solvent is preferably 1 mol: 2-3 L, more preferably 1 mol: 2.5-3 L.

[0028] In this invention, the temperature of the first cyclization reaction is preferably 60~100℃, more preferably 80~90℃, and the time is preferably 2~4h, more preferably 3h. In a specific embodiment of this invention, the reaction process is preferably monitored by thin-layer chromatography.

[0029] After the first cyclization reaction is completed, the present invention preferably further includes post-treatment, which preferably includes: cooling the reaction solution obtained from the first cyclization reaction to room temperature, adjusting the pH value to alkaline, extracting with an organic solvent, concentrating the obtained organic phase, and purifying by column chromatography to obtain the β-carbazo[1',2':1,2]imidazol derivative. In the present invention, the alkaline pH value is preferably 8-10, more preferably 8-9; the alkaline solution used to adjust the pH value to alkaline preferably includes a saturated NaHCO3 solution. In the present invention, the organic solvent used for extraction preferably includes ethyl acetate and / or dichloromethane. The present invention does not have a special limitation on the concentration, and the solvent can be removed by a concentration method well known to those skilled in the art, such as vacuum concentration. In the present invention, the eluent used for column chromatography purification is preferably a petroleum ether-ethyl acetate mixed solvent, and the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate mixed solvent is preferably 10:1 to 1:1; the elution method is preferably gradient elution, and the volume ratio of petroleum ether to ethyl acetate in the gradient elution process is preferably 10:1, 5:1, and 1:1 respectively.

[0030] In this invention, when R 1 When the hydrogen content is 1, the preparation method of the β-carbazo[1',2':1,2]imidazol derivative includes the following steps: mixing compound 4, an aldehyde compound, an organic amine, and a second organic solvent, and carrying out a second cyclization reaction to obtain the β-carbazo[1',2':1,2]imidazol derivative; wherein R in compound 4 3 With R in Equation I 3 Same; R in the aldehyde compounds 2 With R in Equation I 2 same; .

[0031] In this invention, the molar ratio of compound 4 to aldehyde compound is preferably 1:1.1~2, more preferably 1:1.5~2.

[0032] In this invention, the second organic solvent preferably comprises a mixture of a highly polar solvent and a less polar solvent. The highly polar solvent preferably comprises sulfone solvents and / or amide solvents, and the less polar solvent preferably comprises cycloalkane solvents and / or ether solvents. The sulfone solvent preferably comprises dimethyl sulfoxide (DMSO); the amide solvent preferably comprises dimethylformamide (DMF); the cycloalkane solvent preferably comprises cyclohexane; and the ether solvent preferably comprises petroleum ether. The volume ratio of the highly polar solvent to the less polar solvent in the second organic solvent is preferably 1:1.5~3, more preferably 1:2~2.5. In this invention, the molar ratio of compound 4 to the second organic solvent is preferably 1 mol:5~7 L, more preferably 1 mol:2.5~3 L.

[0033] In this invention, the organic amine preferably includes triethylamine and / or formamide. In this invention, the molar ratio of compound 4 to the organic amine is preferably 1:0.05 to 0.5, more preferably 1:0.1 to 0.3, and even more preferably 1:0.1 to 0.2.

[0034] In this invention, the molar ratio of compound 4 to S8 is preferably 1:0.1 to 0.4, more preferably 1:0.2 to 0.35, and even more preferably 1:0.25 to 0.3.

[0035] In this invention, the mixing preferably includes: dissolving compound 4 and the aldehyde compound in a second organic solvent, adding an organic amine and mixing, and then adding S8 and mixing.

[0036] In this invention, the temperature of the second cyclization reaction is preferably 120~160℃, more preferably 120~150℃, and even more preferably 120~130℃; the time of the second cyclization reaction is preferably 1~5h, more preferably 2~4h, and even more preferably 3h.

[0037] After the second cyclization reaction is completed, the present invention preferably further includes post-treatment, which preferably includes: cooling the reaction solution obtained from the second cyclization reaction, extracting with an organic solvent, concentrating the obtained organic phase, and then purifying it by column chromatography to obtain the β-carbazo[1',2':1,2]imidazol derivative. In the present invention, the organic solvent used for extraction preferably includes ethyl acetate and / or dichloromethane. The present invention does not have a special limitation on the concentration; any concentration method well known to those skilled in the art can be used to remove the solvent, such as vacuum concentration. In the present invention, the eluent used for column chromatography purification is preferably a petroleum ether-ethyl acetate mixed solvent, wherein the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate mixed solvent is preferably 10:1 to 1:1; the elution method is preferably gradient elution, wherein the volume ratio of petroleum ether to ethyl acetate during the gradient elution process is preferably 10:1, 5:1, and 1:1 respectively.

[0038] In this invention, the preparation method of compound 4 preferably includes the following steps: L-tryptophan, an inorganic strong base, formaldehyde, and water were mixed and subjected to a first substitution reaction and a third cyclization reaction in sequence to obtain compound 1. Compound 1, an oxidant, and water were mixed to carry out a first oxidation reaction, and then sulfuric acid solution was added to carry out a second oxidation reaction to obtain compound 2. Compound 2, NaNH2, and a third organic solvent were mixed and subjected to an amination reaction to obtain compound 3. Compound 3, catalyst, and R 3X is mixed with a fourth organic solvent to carry out a second substitution reaction, yielding compound 4; R 3 X in R 3 With R in Equation I 3 Same, X is a halogen; .

[0039] In this invention, L-tryptophan, an inorganic strong base, formaldehyde, and water are mixed and subjected to a first substitution reaction and a third cyclization reaction in sequence to obtain compound 1.

[0040] In this invention, the inorganic strong base preferably comprises an alkali metal hydroxide, more preferably NaOH and / or KOH. In this invention, the molar ratio of L-tryptophan to the inorganic strong base is preferably 1:1 to 1.2, more preferably 1:1.05 to 1.1.

[0041] In this invention, the molar ratio of L-tryptophan to formaldehyde (HCHO) is preferably 1:1 to 1.2, more preferably 1:1.05 to 1.1. In this invention, the formaldehyde is preferably used in the form of an aqueous solution, and the concentration of the aqueous solution is preferably 35 to 40 wt%, more preferably 38 to 40 wt%.

[0042] In this invention, the ratio of L-tryptophan to water is 1 mol: 0.6~1 L, more preferably 1 mol: 0.7~0.8 L.

[0043] In this invention, the mixing preferably includes: mixing L-tryptophan, an inorganic strong base and water, and then adding formaldehyde to mix.

[0044] In this invention, the temperature of the first substitution reaction is preferably room temperature, and the time is preferably 1 to 6 hours, more preferably 2 to 4 hours.

[0045] In this invention, the temperature of the third cyclization reaction is preferably 80~100℃, more preferably 90~100℃, and the time of the third cyclization reaction is preferably 1~4h, more preferably 2~3h.

[0046] After completing the third cyclization reaction, the present invention preferably further includes post-treatment, which preferably includes: cooling the reaction solution obtained from the third cyclization reaction to room temperature, adding ice water to quench the reaction, adjusting the pH value to acidic, allowing it to stand, separating the solid and liquid, washing the obtained solid product, and drying it to obtain compound 1. In the present invention, the acidic pH value is preferably 1-6, more preferably 4-6, and the acid used to adjust the pH value to acidic preferably includes hydrochloric acid solution and / or sulfuric acid solution. In the present invention, the standing temperature is preferably 0-10℃, more preferably 4-5℃, the standing time is preferably 5-10h, more preferably 6-8h, and the standing is preferably refrigerated in a refrigerator. The present invention does not have a special limitation on the solid-liquid separation, and any solid-liquid separation method well known to those skilled in the art can be used, such as vacuum filtration, filtration, or centrifugation. In the present invention, the washing preferably includes sequential washing with water and washing with acetone. In this invention, the drying temperature is preferably 70~120℃, more preferably 80~100℃. This invention does not have a special limitation on the drying time; drying to a constant weight is sufficient.

[0047] After obtaining compound 1, the present invention mixes compound 1, an oxidant and water to carry out a first oxidation reaction, and then adds sulfuric acid solution to carry out a second oxidation reaction to obtain compound 2.

[0048] In this invention, the oxidant preferably includes one or more of MnO2, K2Cr2O7, and KMnO4. In this invention, the molar ratio of compound 1 to the oxidant is preferably 1:1 to 5, more preferably 1:2 to 3.

[0049] In this invention, the preferred ratio of compound 1 to water is 1 mol: 1.5~4 L, more preferably 1 mol: 2.5~3 L.

[0050] In this invention, the temperature of the first oxidation reaction is preferably 80~100℃, more preferably 90~100℃; the time of the first oxidation reaction is preferably 5~30min, more preferably 10~20min.

[0051] In this invention, the molar ratio of compound 1 to sulfuric acid in the sulfuric acid solution is preferably 1:1 to 5, more preferably 1:3 to 5. In this invention, the concentration of the sulfuric acid solution is preferably 2 to 4 mol / L, more preferably 2.5 to 3 mol / L.

[0052] In this invention, the temperature of the second oxidation reaction is preferably 80~100℃, more preferably 90~100℃; the time of the first oxidation reaction is preferably 0.5~4h, more preferably 1~2h.

[0053] After the second oxidation reaction is completed, the present invention preferably further includes post-treatment, which preferably includes: cooling the reaction solution obtained from the second oxidation reaction to room temperature, adjusting the pH value to alkaline, extracting with an organic solvent, and concentrating the obtained organic phase to constant weight to obtain compound 2. In the present invention, the alkaline pH value is preferably 8-11, more preferably 9-10; the base used to adjust the pH value to alkaline preferably includes alkali metal hydroxides, more preferably including NaOH and / or KOH. In the present invention, the organic solvent used for extraction preferably includes ethyl acetate and / or dichloromethane. The present invention does not have a special limitation on the concentration, and concentration methods well known to those skilled in the art can be used, such as vacuum concentration.

[0054] After obtaining compound 2, the present invention mixes compound 2, NaNH2 and a third organic solvent to carry out an amination reaction to obtain compound 3.

[0055] In this invention, the molar ratio of compound 2 to NaNH2 is preferably 1:3 to 5, more preferably 1:4.

[0056] In this invention, the third organic solvent preferably includes N,N-dimethylaniline and / or aniline. In this invention, the ratio of compound 2 to the third organic solvent is preferably 1 mol: 2-4 L, more preferably 1 mol: 3 L.

[0057] In this invention, the temperature of the amination reaction is preferably 100~200℃, more preferably 150~180℃; the time of the amination reaction is preferably 5~12h, more preferably 6~8h.

[0058] After the amination reaction is completed, the present invention preferably includes post-treatment, which preferably includes: cooling the reaction solution obtained from the amination reaction, adjusting the pH value to alkaline, extracting with an organic solvent, washing the obtained organic phase with a saturated NaCl solution, drying with a desiccant, concentrating the obtained liquid component, and purifying by column chromatography to obtain compound 3. In the present invention, the alkaline pH value is preferably 8-11, more preferably 9-10; the alkaline solution used to adjust the pH value to alkaline preferably includes an alkali metal hydroxide solution, more preferably NaOH solution and / or KOH solution; the concentration of the alkali metal hydroxide solution is preferably 2-10 wt%, more preferably 4-5 wt%. In the present invention, the organic solvent used for extraction preferably includes ethyl acetate and / or dichloromethane. In the present invention, the number of times the saturated NaCl solution is washed is preferably 1-3 times, more preferably 2-3 times. In the present invention, the desiccant preferably includes anhydrous sodium sulfate and / or anhydrous magnesium sulfate. The present invention does not have a special limitation on the concentration, and concentration methods well known to those skilled in the art can be used, such as vacuum concentration. In this invention, the eluent used for column chromatography purification is preferably a petroleum ether-ethyl acetate mixed solvent, wherein the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate mixed solvent is preferably 10:1 to 1:1; the elution method is preferably gradient elution, wherein the volume ratio of petroleum ether to ethyl acetate during the gradient elution process is preferably 10:1, 5:1 and 1:1 respectively.

[0059] After obtaining compound 3, the present invention combines compound 3, catalyst, and R 3 X and a fourth organic solvent are mixed to carry out a second substitution reaction, yielding compound 4.

[0060] In this invention, compound 3 and R 3 The molar ratio of X is preferably 1:1.1~2, more preferably 1:1.5~2. In this invention, the R... 3 X in X preferably includes fluorine, chlorine, bromine or iodine, more preferably bromine or iodine.

[0061] In this invention, the molar ratio of compound 3 to the catalyst is preferably 1:2 to 4, more preferably 1:2.5 to 3. In this invention, the catalyst preferably comprises one or more of NaH, K3PO4, and CsCO3. In this invention, the NaH is preferably used in the form of a NaH solution, the concentration of which is preferably 50 to 90 wt%, more preferably 60 wt%; the solvent in the NaH solution preferably comprises anhydrous dimethylformamide (DMF).

[0062] In this invention, the fourth organic solvent preferably includes anhydrous dimethylformamide.

[0063] In this invention, the temperature of the second substitution reaction is preferably 0~20℃, more preferably 0~10℃; the time of the second substitution reaction is preferably 5~30min, more preferably 10~15min.

[0064] After the second substitution reaction is completed, the present invention preferably further includes a post-treatment, which preferably includes: adding water to the reaction solution obtained from the second substitution reaction to quench the reaction, extracting with an organic solvent, adding an anhydrous lower alcohol to the obtained organic phase, adjusting the pH to acidic, concentrating, recrystallizing, separating the solid and liquid, washing the obtained solid product, redissolving it in water, adjusting the pH to alkaline, extracting with an organic solvent, washing the obtained organic phase with NaCl solution, drying with a drying agent, concentrating, and drying to obtain compound 4. In the present invention, the organic solvents used for the two organic solvent extractions preferably include ethyl acetate and / or dichloromethane. In the present invention, the anhydrous lower alcohol preferably includes anhydrous methanol and / or anhydrous ethanol. In the present invention, the acidic pH is preferably 2-3, more preferably 2.5; the acid used to adjust the pH to acidic is preferably hydrochloric acid. In the present invention, the concentration (two concentrations) is not particularly limited, and concentration methods well known to those skilled in the art can be used, such as vacuum concentration. In this invention, the solvent for recrystallization preferably includes acetone and / or anhydrous ethanol; the ratio of compound 3 to the recrystallization solvent is preferably 1 mol: 2~2.5 L, more preferably 1 mol: 2~2.2 L; the recrystallization temperature is preferably -20~10℃, more preferably -10~0℃; in a specific embodiment of this invention, the recrystallization is preferably carried out in a refrigerator. This invention does not have any particular limitation on the solid-liquid separation; any solid-liquid separation method well known to those skilled in the art can be used, such as vacuum filtration, filtration, or centrifugation. In this invention, the washing preferably includes acetone washing and / or petroleum ether washing. In this invention, the alkaline pH value is preferably 8~11, more preferably 9~10; the alkali used to adjust the pH value to alkalinity preferably includes alkali metal hydroxides, more preferably NaOH and / or KOH. In this invention, the number of times the saturated NaCl solution is washed is preferably 1~3 times, more preferably 2~3 times. In this invention, the drying agent preferably includes anhydrous sodium sulfate and / or anhydrous magnesium sulfate. In this invention, the drying temperature is preferably 40~80℃, more preferably 50~70℃. This invention does not have a special limitation on the drying time; drying to constant weight is sufficient.

[0065] This invention provides the application of the β-carbazo[1',2':1,2]imidazole derivatives described in the above-described technical solutions, or the β-carbazo[1',2':1,2]imidazole derivatives prepared by the above-described technical solutions, in the preparation of pharmaceuticals. In this invention, the pharmaceuticals preferably include antitumor drugs. In this invention, the tumors preferably include one or more of lung cancer, gastric cancer, colon cancer, liver cancer, and breast cancer.

[0066] This invention also provides a pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients. The active ingredient comprises the β-carbazo[1',2':1,2]imidazole derivative described in the above-described technical solutions or the β-carbazo[1',2':1,2]imidazole derivative prepared by the preparation method described in the above-described technical solutions. This invention does not impose any particular limitation on the content of the active ingredient in the pharmaceutical composition; any content well-known to those skilled in the art can be used. This invention does not impose any particular limitation on the pharmaceutically acceptable excipients; any pharmaceutically acceptable excipient well-known to those skilled in the art can be used. This invention does not impose any particular limitation on the dosage form of the pharmaceutical composition; any pharmaceutically acceptable excipient well-known to those skilled in the art can be used.

[0067] To further illustrate the present invention, the following detailed descriptions of β-carbazo[1',2':1,2]imidazole derivatives, their preparation methods and applications, and pharmaceutical compositions are provided in conjunction with examples, but these should not be construed as limiting the scope of protection of the present invention.

[0068] Example 1 Synthesis of Compound 1: L-tryptophan (250 mmol) and NaOH (250 mmol) were weighed and added to a 1000 mL round-bottom flask, and H2O (500 mL) solvent was added. The mixture was stirred thoroughly to dissolve the compounds evenly, resulting in an orange-red solution. A 40 wt% HCHO aqueous solution (19 mL, 250 mmol) was added, and the mixture was stirred at room temperature for 3.5 h. The mixture was then heated to 100 °C and refluxed for 2.5 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was cooled to room temperature and poured into ice water (400 mL). The pH was adjusted to 6 with HCl and stored in a refrigerator (5 °C) for 8 h. The mixture was then filtered, and the resulting solid product was washed with water and acetone, and dried at 100 °C to constant weight to obtain Compound 1 (0.246 mmol, yield 98.4%).

[0069] Synthesis of Compound 2: Compound 1 (0.1 mol) and water (300 mL) were stirred thoroughly and heated to 100 °C. MnO2 (0.3 mol) was added in 20 batches, and after reacting for 5 min, 2.5 mol / L sulfuric acid solution (200 mL) was slowly added dropwise. The reaction was carried out at 100 °C for 1 h, and the reaction was monitored by thin-layer chromatography. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 9 with sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to constant weight to give Compound 2 (0.086 mmol, yield 86%).

[0070] Synthesis of Compound 3: Compound 2 (0.035 mol) and sodium amide (0.14 mol) were added to a round-bottom flask, followed by 100 mL of N,N-dimethylaniline. The mixture was heated to 160 °C and stirred for 8 h. The reaction was monitored by thin-layer chromatography. After the reaction was complete, 50 mL of 5 wt% NaOH solution was added, and the mixture was filtered. The filter cake was purified by column chromatography (gradient elution, with petroleum ether and ethyl acetate in volume ratios of 10:1, 5:1, and 1:1, respectively), yielding compound 3 (0.026 mmol, yield 75%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.12 (s, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 5.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.32 (d, J = 5.6 Hz, 1H), 7.19(t, J = 7.5 Hz, 1H), 6.19 (s, 2H).

[0071] Synthesis of compound 4: Compound 3 (10 mmol) was added to a 250 mL round-bottom flask, and DMF was added to dissolve it completely. Then, 30 mmol of 60 wt% NaH solution (DMF) was slowly added, and the mixture was stirred for 5 min. Finally, R was slowly added dropwise. 3I (12 mmol) was stirred thoroughly at 0 °C for 10 min; the reaction progress was monitored by TLC; after the reaction was complete, the reaction solution was poured into ice water to quench the reaction, and then extracted with ethyl acetate. The obtained organic phase was washed with saturated brine, the organic phases were combined, and 1 / 2 volume of anhydrous ethanol was added. The pH was adjusted to 3 with HCl, and the mixture was concentrated under reduced pressure to constant weight. The mixture was recrystallized from acetone at -10 °C (the ratio of compound 3 to acetone was 1 mol: 2 L). The mixture was filtered, the resulting filter cake was dissolved in water, the pH was adjusted to 9 with NaOH, and the mixture was extracted with ethyl acetate. The obtained organic phase was concentrated under reduced pressure and dried at 80 °C to constant weight to obtain compound 4.

[0072] R 3 Methyl group was removed to give compound 4b in 90% yield. 1 H NMR (400 MHz, DMSO- d 6) d 8.09 (dt, J = 7.9, 1.0 Hz, 1H), 7.74 (d, J = 5.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.52 (ddd, J =8.3, 7.0, 1.2 Hz, 1H), 7.40 (d, J = 5.4 Hz, 1H), 7.20 (ddd, J = 7.9, 7.0, 1.0 Hz,1H), 5.90 (s, 2H), 4.12 (s, 3H). R 3 The compound was benzyl, yielding compound 4c in 88% yield. 1 H NMR (400 MHz, DMSO- d 6) d 8.13 (d, J = 7.8Hz, 1H), 7.79 (d, J = 5.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.52 – 7.43 (m, 2H), 7.21 (ddt, J = 14.5, 10.8, 5.1 Hz, 4H), 7.07 – 7.01 (m, 2H), 5.88 (s, 2H), 5.83(s, 2H). R 3 To obtain p-fluorobenzyl, compound 4d was given with a yield of 85%. 1H NMR (400 MHz, DMSO- d 6) d 8.12 (d, J =7.8 Hz, 1H), 7.80 (d, J = 5.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.50 (ddd, J =8.3, 7.0, 1.3 Hz, 1H), 7.46 (d, J = 5.4 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.10 –7.06 (m, 4H), 5.88 (s, 2H), 5.86 (s, 2H). R 3 The compound was phenylpropyl, yielding compound 4e in 79% yield. 1 H NMR (400 MHz, DMSO- d 6) d 8.10 (d, J =7.8 Hz, 1H), 7.77 (d, J = 5.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.49 (ddd, J =8.3, 6.8, 1.2 Hz, 1H), 7.43 (d, J = 5.4 Hz, 1H), 7.28 – 7.09 (m, 6H), 5.87 (s,2H), 4.63 (t, J = 7.4 Hz, 2H), 2.57 (t, J = 7.4 Hz, 2H), 2.04 – 1.92 (m, 2H). Example 2 Compound 4 (1 mmol) and bromoketone (2 mmol) were weighed into a reaction tube, 3 mL of anhydrous ethanol was added, and the mixture was refluxed at 90 °C for 3 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 8 with saturated NaHCO3 solution, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (gradient elution, with the volume ratios of petroleum ether and ethyl acetate being 10:1, 5:1, and 1:1, respectively), to obtain β-carbazo[1',2':1,2]imidazol derivatives (compounds 6aa~6eh, R). 2 (For hydrogen).

[0073] 2-Phenyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6aa): White solid, yield 77.5%. mp 292.6 - 293.2℃. 1 H NMR (400 MHz, DMSO- d 6) d 12.47 (s, 1H), 8.52 (s, 1H), 8.27 (d, J = 6.8 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.06 - 8.00 (m, 2H), 7.66 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.39(ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.36 - 7.30 (m, 1H), 7.26 - 7.21 (m, 1H). 13 CNMR (100 MHz, DMSO- d 6) d 143.37, 139.24, 137.40, 134.69, 129.24, 127.85, 126.83, 125.88, 125.15, 123.30, 120.30, 120.27, 119.26, 115.26, 112.53, 111.08, 107.23. 2-(4-Fluorophenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6ab): White solid, yield 86.7%. mp 290.2 - 291.6℃. 1 H NMR (400 MHz, DMSO- d 6) d 12.46 (s, 1H), 8.50 (s, 1H), 8.27 (d, J = 6.8 Hz, 1H), 8.13 - 8.02 (m, 3H), 7.66 (d, J= 6.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.39 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.36 - 7.28 (m,2H), 7.27 - 7.20 (m, 1H). 13 C NMR (100 MHz, DMSO- d 6) d 160.90 (d, J = 242.4 Hz),142.48, 139.24, 137.41, 131.25 (d, J = 3.0 Hz), 127.73 (d, J = 8.1 Hz), 126.79,125.19, 123.28, 120.32, 120.29, 119.26, 116.01 (d, J = 21.5 Hz), 115.33,112.53, 110.90, 107.27. 19 F NMR (376 MHz, DMSO- d 6) d -114.96. 2-(4-Bromophenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6ac): White solid, yield 80.3%. mp 280.7 - 282.6℃. 1 H NMR (400 MHz, DMSO- d 6) d 12.49 (s, 1H), 8.58 -8.53 (m, 1H), 8.27 (dd, J = 7.2, 1.2 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.01 -7.95 (m, 2H), 7.69 - 7.65 (m, 3H), 7.58 (d, J = 8.0 Hz, 1H), 7.39 (ddd, J = 8.0,6.8, 1.2 Hz, 1H), 7.26 - 7.20 (m, 1H). 13 C NMR (100 MHz, DMSO- d 6) d 142.21, 139.25, 137.52, 134.00, 132.19, 127.85, 126.77, 125.24, 123.27, 120.76, 120.35, 120.32, 119.29, 115.40, 112.54, 111.48, 107.43. 2-(4-(trifluoromethyl)phenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6ad): White solid, yield 85.8%. mp 266.8 - 267.4℃. 1 H NMR (400 MHz, CDCl3) d 10.92 (s, 1H),8.16 - 8.10 (m, 2H), 8.09 (s, 1H), 7.99 (d, J = 6.8 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 6.8 Hz, 1H), 7.34 - 7.22 (m, 3H). 13 CNMR (100 MHz, CDCl3) d 142.16, 138.69, 137.76, 136.89, 129.47 (q, J = 32.1 Hz),126.37, 125.97, 125.82 (q, J = 3.9 Hz), 125.51, 123.10, 122.87 (q, J = 270.2 Hz),120.58, 119.77, 118.13, 116.62, 111.99, 110.56, 107.81. 19 F NMR (376 MHz, CDCl3) d -62.49. 2-(4-Methoxyphenyl)-11 H -imidazo[1,2':1,2]pyrido[3,4- b Indole (6ae): White solid, yield 83.4%. mp 264.8 - 265.9℃. 1 H NMR (400 MHz, DMSO-d 6) d 12.44 (s, 1H), 8.39 (s, 1H), 8.25 (d, J = 6.8 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.98 - 7.92 (m, 2H), 7.63 (d, J = 7.2 Hz, 1H), 7.58 (dt, J = 8.4, 0.8 Hz, 1H), 7.38 (ddd, J = 8.4, 6.8,1.2 Hz, 1H), 7.23 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.08 - 7.02 (m, 2H), 3.82(s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 159.26, 143.42, 139.23, 137.22, 127.33, 127.16, 126.82, 125.08, 123.32, 120.26, 120.22, 119.16, 115.15, 114.67, 112.49, 109.97, 106.96, 55.61. 2-Methyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6af): White solid, yield 56.5%. mp 203.5 - 204.7℃. 1 H NMR (400 MHz, DMSO- d 6) d 12.28 (s, 1H), 8.19 (d, J =7.2 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 1.2 Hz, 1H), 7.57 (d, J = 7.2Hz, 1H), 7.56 - 7.49 (m, 1H), 7.36 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H), 7.21 (ddd, J= 8.0, 7.2, 1.2 Hz, 1H), 2.41 (d, J = 1.2 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 140.44, 139.09, 136.26, 126.62, 124.99, 123.31, 120.23, 120.12, 118.93, 114.85, 112.40, 111.69, 106.33, 14.54. 2-(trifluoromethyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6 ag): White solid, yield 70.8%. mp 280.3 - 281.0 °C. 1 H NMR (400 MHz, DMSO- d 6) d 12.72 (s, 1H), 8.67 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 6.8 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H), 7.83 (d, J =6.8 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.43 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.27(ddd, J = 8.4, 7.2, 1.2 Hz, 1H). 13 C NMR (100 MHz, DMSO- d 6) d 139.26, 137.73, 132.41 (q, J = 37.5 Hz), 126.56, 125.80, 122.99, 121.40 (q, J = 265.9 Hz),120.66, 120.61, 119.67, 116.27, 114.84 (q, J = 4.0 Hz), 112.68, 108.93. 19 F NMR (376 MHz, CDCl3) d-60.80. 2-Cyclopropyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6ah): White solid, yield 75.7%. mp 182.6 - 183.4℃. 1 H NMR (400 MHz, DMSO- d 6) d 12.22 (s, 1H), 8.20 (d, J =6.8 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.37 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.22 (ddd, J = 8.0,7.2, 1.2 Hz, 1H), 2.14 - 2.07 (m, 1H), 1.01 - 0.88 (m, 4H). 13 C NMR (100 MHz, DMSO- d 6) d 145.92, 139.25, 135.73, 126.01, 125.27, 123.14, 120.33, 120.25, 118.96, 115.59, 112.52, 110.61, 106.76, 9.57, 8.49. 11-Methyl-2-phenyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6ba): White solid, yield 79.3%. mp 211.7 - 212.9℃. 1 H NMR (400 MHz, CDCl3) d 8.07 - 8.02 (m, 2H), 7.99 (dt, J = 7.9, 1.0 Hz, 1H), 7.94 (s, 1H), 7.88 (d, J = 6.9 Hz, 1H), 7.52 (dt, J = 8.3, 1.0 Hz, 1H), 7.47 (qd,J = 6.6, 1.4 Hz, 3H), 7.41 (d, J = 6.9 Hz, 1H), 7.36 - 7.28 (m, 2H), 4.58 (s, 3H). 13 C NMR (100 MHz, CDCl3) d 143.93, 139.97, 137.92, 134.15, 128.71, 127.96, 127.59, 125.84, 124.78, 122.87, 120.13, 119.70, 117.78, 114.48, 109.71, 109.11, 106.78, 31.98. 2-(4-Fluorophenyl)-11-methyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6bb): White solid, yield 80.9%. mp 209.8 - 211.4℃. 1 H NMR (400 MHz, CDCl3) d 8.06 - 7.94 (m, 3H), 7.87 (t, J = 3.4 Hz, 2H), 7.54 - 7.44 (m, 2H), 7.41 (d, J = 7.0 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.19 - 7.09 (m, 2H), 4.56 (s, 3H). 13 C NMR (100 MHz, CDCl3) d 161.31 (d, J = 244.6 Hz), 143.06, 139.98, 137.90, 130.36 (d, J = 2.9 Hz), 127.86, 127.43 (d, J = 8.0 Hz), 124.87, 122.84, 120.18, 119.73, 117.74, 115.50(d, J = 21.5 Hz), 114.61, 109.72, 108.76, 106.86, 31.96. 19 F NMR (376 MHz, CDCl3) d -114.76. 2-(4-bromophenyl)-11-methyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6bc): White solid, yield 83.1%. mp 204.8 - 206.6℃. 1 H NMR (400 MHz, CDCl3) d 7.99 (d, J = 8.0Hz, 1H), 7.95 - 7.84 (m, 4H), 7.61 - 7.55 (m, 2H), 7.53 (dt, J = 8.0, 1.2 Hz,1H), 7.51 - 7.46 (m, 1H), 7.42 (d, J = 6.8 Hz, 1H), 7.33 - 7.29 (m, 1H), 4.56(s, 3H). 13 C NMR (100 MHz, CDCl3) d 142.82, 139.99, 138.00, 133.16, 131.79, 127.84, 127.36, 124.92, 122.82, 121.38, 120.22, 119.74, 117.74, 114.66, 109.74, 109.22, 107.02, 31.97. 11-Methyl-2-(4-(trifluoromethyl)phenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6bd): White solid, yield 78.3%. mp 212.3 - 213.8℃. 1 H NMR (400 MHz, CDCl3) d 8.12(d, J = 8.0 Hz, 2H), 7.99 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J = 6.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.54 - 7.45 (m, 2H), 7.42 (d, J = 6.8 Hz, 1H), 7.34 - 7.29 (m, 1H), 4.55 (s, 3H). 13C NMR (100 MHz, CDCl3) d 142.37, 139.99,138.14, 137.64, 129.42 (q, J = 32.1 Hz), 127.79, 125.87, 125.66 (q, J = 3.8 Hz), 125.00, 123.03 (q, J = 270.4 Hz), 122.77, 120.28, 119.76, 117.75, 114.75,110.00, 109.77, 107.24, 31.96. 19 F NMR (376 MHz, CDCl3) d -62.35. 2-(4-methoxyphenyl)-11-methyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6be): White solid, yield 79.9%. mp 222.6 - 223.7℃. 1 H NMR (400 MHz, CDCl3) d 7.97 (t, J =8.0 Hz, 3H), 7.86 (d, J = 6.8 Hz, 1H), 7.83 (s, 1H), 7.55 - 7.43 (m, 2H), 7.38(d, J = 6.8 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.00 (d, J = 8.4 Hz, 2H), 4.56 (s, 3H), 3.86 (s, 3H). 13 C NMR (100 MHz, CDCl3) d 159.32, 143.86, 139.96, 137.77, 127.92, 127.09, 126.98, 124.72, 122.89, 120.07, 119.67, 117.74, 114.41, 114.13, 109.67, 108.22, 106.54, 55.34, 31.96. 2,11-Dimethyl-11 H -imidazo[1',2':1,2]pyrido[3,4- bIndole (6bf): White solid, yield 55.1%. mp 169.6 - 171.2℃. 1 H NMR (400 MHz, CDCl3) d 7.97 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.40 (s, 1H), 7.35 (d, J = 6.8 Hz,1H), 7.31 - 7.26 (m, 1H), 4.48 (s, 3H), 2.53 (s, 3H). 13 C NMR (100 MHz, CDCl3) d 141.25, 139.82, 137.24, 127.73, 124.64, 122.84, 119.99, 119.63, 117.55, 114.28, 110.61, 109.59, 106.00, 32.00, 14.51. 11-Methyl-2-(trifluoromethyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6 bg): White solid, yield 72.6%. mp 192.8 - 193.6℃. 1 H NMR (400 MHz, CDCl3) d 8.00 (dt, J = 8.0, 1.2 Hz, 1H), 7.96 (q, J = 1.2 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.56 - 7.48 (m,3H), 7.33 (ddd, J = 8.0, 6.0, 2.1 Hz, 1H), 4.48 (s, 3H). 13 C NMR (100 MHz, CDCl3) d 139.98, 138.14, 134.45 (q, J = 38.4 Hz), 127.68, 125.44, 123.26 (q, J= 266.2Hz), 122.47, 120.54, 119.91, 117.84, 115.32, 112.64 (q, J = 4.0 Hz), 109.95,108.43, 32.05. 19 F NMR (376 MHz, CDCl3) d -62.47. 2-Cyclopropyl-11-methyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6bh): White solid, yield 70.4%. mp 118.6 - 120.4℃. 1 H NMR (400 MHz, CDCl3) d 7.96 (dt, J = 8.0, 1.2 Hz, 1H), 7.77 (d, J = 6.8 Hz, 1H), 7.50 - 7.42 (m, 2H), 7.37 (s, 1H), 7.33(d, J = 6.8 Hz, 1H), 7.30 - 7.25 (m, 1H), 4.47 (s, 3H), 2.11 (tt, J = 8.4, 5.2Hz, 1H), 1.03 - 0.92 (m, 4H). 13 C NMR (100 MHz, CDCl3) d 147.74, 139.83, 137.12, 127.77, 124.54, 122.88, 119.93, 119.61, 117.52, 114.13, 109.57, 108.60, 105.95, 31.94, 9.70, 8.04. 11-Benzyl-2-phenyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6ca): White solid, yield 83.9%. mp 214.3 - 214.6℃. 1 H NMR (400 MHz, CDCl3) d 8.03 - 7.99 (m, 2H), 7.97 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 7.88 (d, J= 6.8 Hz, 1H), 7.48 (d, J = 8.4Hz, 1H), 7.45 - 7.35 (m, 6H), 7.33 - 7.26 (m, 2H), 7.25 - 7.16 (m, 3H), 6.37(s, 2H). 13 C NMR (100 MHz, CDCl3) d 144.00, 139.34, 138.20, 137.71, 134.24, 128.69, 128.61, 127.67, 127.65, 127.58, 127.36, 125.88, 124.87, 123.37, 120.33, 119.78, 118.10, 114.77, 110.76, 109.11, 106.66, 48.82. 11-Benzyl-2-(4-Fluorophenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6Cb): White solid, yield 83.0%. mp 206.3 - 206.9℃. 1 H NMR (400 MHz, CDCl3) d 8.00 - 7.91 (m, 3H), 7.86 (d, J = 6.8 Hz, 1H), 7.84 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.41 -7.35 (m, 4H), 7.29 - 7.26 (m, 1H), 7.25 - 7.16 (m, 3H), 7.14 - 7.06 (m, 2H), 6.35 (s, 2H). 13 C NMR (100 MHz, CDCl3) d 161.25 (d, J = 244.7 Hz), 143.09, 139.32,138.13, 137.65, 130.39 (d, J = 2.7 Hz), 128.59, 127.53, 127.39 (d, J = 8.0 Hz),127.34, 124.92, 123.28, 120.34, 119.76, 118.02, 115.42 (d, J= 21.4 Hz),114.85, 110.72, 108.70, 106.70, 48.76. 19 F NMR (376 MHz, CDCl3) d -114.77. 11-Benzyl-2-(4-bromophenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6cc): White solid, yield 80.5%. mp 208.1 - 210.3℃. 1 H NMR (400 MHz, CDCl3) d 7.98 (dt, J = 8.0,0.8 Hz, 1H), 7.91 - 7.81 (m, 4H), 7.56 - 7.50 (m, 2H), 7.47 (d, J = 8.0 Hz,1H), 7.43 - 7.35 (m, 4H), 7.30 - 7.26 (m, 1H), 7.25 - 7.17 (m, 3H), 6.34 (s,2H). 13 C NMR (100 MHz, CDCl3) d 142.84, 139.33, 138.09, 137.72, 133.17, 131.72, 128.59, 127.54, 127.48, 127.36, 127.35, 124.97, 123.25, 121.31, 120.38, 119.78, 118.02, 114.91, 110.73, 109.17, 106.86, 48.77. 11-Benzyl-2-(4-(trifluoromethyl)phenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6Cd): White solid, yield 86.7%. mp 205.4 - 206.8℃. 1 H NMR (400 MHz, CDCl3) d 8.05(d, J = 8.0 Hz, 2H), 7.97 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.64 (d,J = 8.0 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.41 - 7.36 (m, 4H), 7.31 - 7.15 (m, 4H), 6.32 (s, 2H). 13 C NMR (100 MHz, CDCl3) d 142.45, 139.37,138.06, 137.93, 137.68, 129.36 (q, J = 32.1 Hz), 128.62, 127.52, 127.49,127.41, 125.86, 125.72 (q, J = 270.2 Hz), 125.61 (q, J = 3.8 Hz), 125.08, 123.23,120.46, 119.83, 118.07, 115.03, 110.75, 109.98, 107.11, 48.78. 19 F NMR (376MHz, CDCl3) d -62.36. 11-Benzyl-2-(4-methoxyphenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6ce): White solid, yield 84.3%. mp 229.4 - 230.3℃. 1 H NMR (400 MHz, CDCl3) d 7.99 (d, J =7.6 Hz, 1H), 7.97 - 7.88 (m, 3H), 7.86 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.45- 7.34 (m, 4H), 7.28 (d, J = 7.2 Hz, 1H), 7.24 - 7.16 (m, 2H), 7.00 - 6.93 (m,2H), 6.38 (s, 2H), 3.85 (s, 3H). 13 C NMR (100 MHz, CDCl3) d159.31, 143.90, 139.32, 138.20, 137.53, 128.57, 127.62, 127.30, 127.10, 124.80, 123.36, 120.26, 119.73, 118.04, 114.71, 114.09, 110.71, 108.16, 106.45, 55.33, 48.79. 11-Benzyl-2-methyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6cf): White solid, yield 59.8%. mp 160.8 - 162.4℃. 1 H NMR (400 MHz, CDCl3) d 7.90 (dt, J = 8.0, 1.2Hz, 1H), 7.77 (d, J = 6.8 Hz, 1H), 7.35 - 7.28 (m, 3H), 7.26 (ddd, J = 8.0, 6.8,1.2 Hz, 1H), 7.21 - 7.08 (m, 6H), 6.24 (s, 2H), 2.41 (s, 3H). 13 C NMR (100 MHz, CDCl3) d 140.33, 138.09, 137.04, 135.93, 127.49, 126.49, 126.27, 126.17, 123.63, 122.36, 119.15, 118.62, 116.80, 113.45, 109.79, 109.53, 104.85, 47.77, 13.48. 11-Benzyl-2-(trifluoromethyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6 cg): White solid, yield 70.3%. mp 159.3 - 159.8 °C. 1 H NMR (400 MHz, CDCl3) d 7.98 (d, J = 7.6Hz, 1H), 7.92 (s, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.48 (dd, J= 7.6, 2.8 Hz, 2H), 7.44 - 7.38 (m, 1H), 7.35 - 7.26 (m, 3H), 7.24 - 7.15 (m, 3H), 6.22 (s, 2H). 13 C NMR (100 MHz, CDCl3) d 139.36, 137.84, 137.67, 134.49 (q, J = 38.4 Hz),128.58, 127.60, 127.48, 127.37, 125.51, 123.25 (q, J = 266.2 Hz), 122.96,120.71, 119.98, 118.16, 115.63, 112.64 (q, J = 4.1 Hz), 111.03, 108.30,48.80. 19 F NMR (376 MHz, CDCl3) d -62.43. 11-Benzyl-2-cyclopropyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6 ch): White solid, yield 73.2%. mp 174.8 - 175.6 °C. 1 H NMR (400 MHz, CDCl3) d 7.95 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.37 - 7.31 (m, 4H), 7.25 -7.13 (m, 4H), 6.24 (s, 2H), 2.09 - 1.99 (m, 1H), 0.96 (d, J = 4.8 Hz, 4H). 13 CNMR (100 MHz, CDCl3) d 147.63, 139.21, 138.29, 136.89, 128.49, 127.64, 127.48, 127.24, 124.61, 123.40, 120.12, 119.68, 117.79, 114.38, 110.64, 108.84, 105.79, 48.71, 9.67, 8.23. 11-(4-Fluorobenzyl)-2-Phenylacetyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6da): White solid, yield 75.5%. mp 220.2 - 220.8℃. 1 H NMR (400 MHz, CDCl3) d 8.05 - 7.93 (m, 4H), 7.91 (d, J = 6.8 Hz, 1H), 7.49 - 7.38 (m, 7H), 7.34 - 7.26 (m, 2H), 6.93(t, J = 8.8 Hz, 2H), 6.32 (s, 2H). 13 C NMR (100 MHz, CDCl3) d 160.88 (d, J = 244.1Hz), 144.02, 139.14, 137.61, 134.15, 133.90 (d, J = 2.9 Hz), 129.35 (d, J = 8.0Hz), 128.69, 127.62, 127.44, 125.81, 124.92, 123.37, 120.41, 119.85, 118.17,115.33 (d, J = 21.4 Hz), 114.83, 110.51, 109.13, 106.64, 48.02. 19 F NMR (376 MHz, CDCl3) d -115.25. 11-(4-Fluorobenzyl)-2-(4-Fluorophenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6 dB): White solid, yield 80.8%. mp 231.2 - 232.0 °C. 1 H NMR (400 MHz, CDCl3) d 8.06 -7.92 (m, 4H), 7.91 (s, 1H), 7.51 - 7.35 (m, 5H), 7.29 (ddd, J= 8.0, 6.8, 0.8Hz, 1H), 7.16 - 7.09 (m, 2H), 6.98 - 6.88 (m, 2H), 6.33 (s, 2H). 13 C NMR (100MHz, CDCl3) d 161.32 (d, J = 244.9 Hz), 160.89 (d, J = 244.0 Hz), 143.16, 139.20,137.61, 133.84 (d, J = 3.2 Hz), 130.26 (d, J = 4.2 Hz), 129.24 (d, J = 8.0 Hz), 127.42 (d, J = 8.0 Hz), 125.05, 123.33, 120.49, 119.90, 118.17, 115.50 (d, J =21.5 Hz), 115.37 (d, J = 21.3 Hz), 114.98, 110.54, 108.80, 106.79, 48.04. 19 F NMR (376 MHz, CDCl3) d -114.66, -115.20. 2-(4-bromophenyl)-11-(4-fluorobenzyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6dc): White solid, yield 81.4%. mp 232.8 - 233.8℃. 1 H NMR (400 MHz, CDCl3) d 8.00(dt, J = 8.0, 0.8 Hz, 1H), 7.96 (s, 1H), 7.93 (d, J = 6.8 Hz, 1H), 7.87 (d, J = 8.4Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.46 (d, J= 6.8 Hz,1H), 7.44 - 7.36 (m, 3H), 7.30 (ddd, J = 8.0, 6.8, 0.8 Hz, 1H), 6.98 - 6.89 (m,2H), 6.33 (s, 2H). 13 C NMR (100 MHz, CDCl3) d 160.90 (d, J = 244.1 Hz), 142.86,139.26, 137.55, 133.79 (d, J = 3.2 Hz), 132.84, 131.80, 129.23 (d, J = 8.0 Hz),127.40, 127.26, 125.16, 123.28, 121.49, 120.55, 119.93, 118.17, 115.38 (d, J =21.4 Hz), 110.56, 109.29, 107.01, 48.03. 19 F NMR (376 MHz, CDCl3) d -115.13. 11-(4-Fluorobenzyl)-2-(4-(trifluoromethyl)phenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6dd): White solid, yield 80.1%. mp 236.4 - 238.8℃. 1 H NMR (400 MHz, CDCl3) d 8.10 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 7.6 Hz, 2H), 7.94 (d, J = 6.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.51 - 7.45 (m, 2H), 7.45 - 7.36 (m, 3H), 7.30 (ddd, J =8.0, 6.8, 0.8 Hz, 1H), 6.98 - 6.88 (m, 2H), 6.32 (s, 2H). 13 C NMR (100 MHz, CDCl3) d 160.91 (d,J = 244.3 Hz), 142.53, 139.24, 137.88, 137.61, 133.77 (d, J =3.1 Hz), 129.22 (d, J = 8.1 Hz), 129.17 (q, J = 32.2 Hz), 127.33, 125.88, 125.64(q, J = 4.0 Hz), 125.20, 123.28, 122.99 (q, J = 270.4 Hz), 120.60, 119.95,118.20, 115.40 (d, J = 21.4 Hz), 115.20, 110.57, 110.06, 107.19, 48.05. 19 F NMR (376 MHz, CDCl3) d -62.40, -115.08. 11-(4-Fluorobenzyl)-2-(4-Methoxyphenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6de): White solid, yield 78.9%. mp 236.5 - 238.3℃. 1 H NMR (400 MHz, CDCl3) d 7.99(dt, J = 8.0, 0.8 Hz, 1H), 7.96 - 7.88 (m, 3H), 7.86 (s, 1H), 7.47 (d, J = 8.0Hz, 1H), 7.45 - 7.37 (m, 4H), 7.28 (ddd, J = 8.0, 6.8, 0.8 Hz, 1H), 7.01 - 6.95(m, 2H), 6.95 - 6.88 (m, 2H), 6.32 (s, 2H), 3.85 (s, 3H). 13 C NMR (100 MHz, CDCl3) d 160.87 (d, J = 244.0 Hz), 159.35, 143.95, 139.15, 137.48, 133.93 (d, J=3.3 Hz), 129.34 (d, J = 8.0 Hz), 127.41, 127.07, 126.96, 124.87, 123.40,120.37, 119.83, 118.13, 115.32 (d, J = 21.5 Hz), 114.77, 114.13, 110.48,108.21, 106.43, 55.34, 48.01. 19 F NMR (376 MHz, CDCl3) d -115.29. 11-(4-Fluorobenzyl)-2-methyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6df): White solid, yield 50.0%. mp 136.1 - 137.9℃. 1 H NMR (400 MHz, CDCl3) d 7.97 (dt, J = 8.0, 0.8 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 0.8 Hz, 1H), 7.40 - 7.33 (m,3H), 7.30 - 7.23 (m, 3H), 6.95 - 6.87 (m, 2H), 6.26 (s, 2H), 2.49 (s, 3H). 13 CNMR (100 MHz, CDCl3) d 160.83 (d, J = 243.8 Hz), 141.44, 138.95, 136.92, 133.80(d, J = 3.1 Hz), 129.06 (d, J = 8.0 Hz), 127.35, 124.72, 123.45, 120.28, 119.75,117.93, 115.28 (d, J = 21.3 Hz), 114.53, 110.62, 110.60, 105.86, 48.05,14.53. 19 F NMR (376 MHz, CDCl3) d -115.49. 11-(4-Fluorobenzyl)-2-(Trifluoromethyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6 dg): Yellow-green solid, yield 69.1%. mp 173.7 - 174.9℃. 1 H NMR (400 MHz, CDCl3) d 8.01(dt, J = 8.0, 0.8 Hz, 1H), 7.97 (q, J = 1.2 Hz, 1H), 7.92 (d, J = 6.8 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.51 (dt, J = 8.4, 0.8 Hz, 1H), 7.45 (ddd, J = 8.4, 6.8, 1.2Hz, 1H), 7.37 - 7.29 (m, 3H), 6.96 - 6.88 (m, 2H), 6.20 (s, 2H). 13 C NMR (100MHz, CDCl3) d 160.95 (d, J = 244.3 Hz), 139.22, 137.78, 134.16 (q, J = 38.3 Hz), 133.39 (d, J = 3.2 Hz), 129.36 (d, J = 8.2 Hz), 127.21, 125.60, 122.99, 120.81,120.53 (q, J = 266.2 Hz), 120.09, 118.28, 115.74, 115.34 (d, J = 21.3 Hz), 112.63(q, J = 4.0 Hz), 110.78, 108.34, 48.04. 19 F NMR (376 MHz, CDCl3) d -62.52, -114.99. 2-Cyclopropyl-11-(4-Fluorobenzyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- bIndole (6dh): White solid, yield 68.9%. mp 148.7 - 149.3℃. 1 H NMR (400 MHz, CDCl3) d 7.94 (d, J = 8.0Hz, 1H), 7.77 (d, J = 6.8 Hz, 1H), 7.45 - 7.28 (m, 6H), 7.27 - 7.21 (m, 1H), 6.89 (t, J = 8.8 Hz, 2H), 2.05 (p, J = 6.8 Hz, 1H), 0.96 (d, J = 6.4 Hz, 4H). 13 C NMR (100 MHz, CDCl3) d 160.81 (d, J = 243.8 Hz), 147.62, 138.99, 136.75, 133.99 (d, J =3.1 Hz), 129.31 (d, J = 8.0 Hz), 127.23, 124.64, 123.38, 120.18, 119.73,117.83, 115.18 (d, J = 21.3 Hz), 114.40, 110.35, 108.88, 105.71, 47.86, 9.62,8.20. 19 F NMR (376 MHz, CDCl3) d -115.40. 2-Phenylacetyl-11-(3-Phenylacetyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6ea): White solid, yield 73.1%. mp 174.2 - 175.2℃. 1 H NMR (400 MHz, CDCl3) d 8.06 - 8.02 (m, 2H), 8.00 (dt, J = 7.6, 1.2 Hz, 1H), 7.96 (s, 1H), 7.92 (d, J= 7.2 Hz, 1H),7.50 - 7.41 (m, 5H), 7.37 - 7.26 (m, 3H), 7.25 - 7.14 (m, 4H), 5.15 (t, J = 7.6Hz, 2H), 2.87 (t, J = 7.6 Hz, 2H), 2.44 - 2.35 (m, 2H). 13 C NMR (100 MHz, CDCl3) d 141.54, 139.20, 128.70, 128.40, 128.36, 127.68, 125.93, 125.87, 124.83, 122.96, 120.10, 119.83, 117.88, 110.00, 109.14, 106.87, 44.96, 33.31, 31.69. 2-(4-Fluorophenyl)-11-(3-Phenylacetyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6eb): White solid, yield 78.7%. mp 160.1 - 161.0℃. 1 H NMR (400 MHz, CDCl3) d 8.02 -7.95 (m, 3H), 7.90 (d, J = 6.8 Hz, 2H), 7.47 - 7.40 (m, 3H), 7.31 - 7.26 (m,2H), 7.25 - 7.11 (m, 6H), 5.11 (t, J = 7.6 Hz, 2H), 2.86 (t, J = 7.6 Hz, 2H),2.43 - 2.35 (m, 2H). 13 C NMR (100 MHz, CDCl3) d 161.30 (d, J = 244.9 Hz), 143.02,141.50, 139.16, 137.50, 130.37, 128.40, 128.38, 127.43 (d, J = 8.2 Hz), 125.90,124.81, 122.97, 120.10, 119.83, 117.82, 115.48 (d, J= 21.6 Hz), 114.85,109.98, 108.71, 106.82, 44.93, 33.32, 31.64. 19 F NMR (376 MHz, CDCl3) d -114.80. 2-(4-bromophenyl)-11-(3-phenylpropyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6ec): White solid, yield 79.2%. mp 179.1 - 180.3℃. 1 H NMR (400 MHz, CDCl3) d 8.00(d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.91 - 7.84 (m, 3H), 7.60 - 7.54 (m, 2H), 7.48 - 7.40 (m, 3H), 7.32 - 7.26 (m, 2H), 7.25 - 7.16 (m, 4H), 5.11 (t, J = 7.2Hz, 2H), 2.85 (t, J = 7.6 Hz, 2H), 2.42 - 2.34 (m, 2H). 13 C NMR (100 MHz, CDCl3) d 142.78, 141.46, 139.15, 137.59, 133.15, 131.78, 128.39, 127.39, 125.91, 124.85, 122.95, 121.37, 120.13, 119.84, 117.84, 114.88, 109.99, 109.20, 106.97, 44.93, 33.33, 31.63. 11-(3-phenylpropyl)-2-(4-(trifluoromethyl)phenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6ed): White solid, yield 72.5%. mp 160.9 - 162.3℃. 1 H NMR (400 MHz, CDCl3) d 8.09 (d, J = 8.0 Hz, 2H), 8.00 (t, J= 4.0 Hz, 2H), 7.90 (d, J = 7.2 Hz, 1H), 7.70(d, J = 8.0 Hz, 2H), 7.48 - 7.41 (m, 3H), 7.33 - 7.25 (m, 2H), 7.25 - 7.15 (m,4H), 5.11 (t, J = 7.6 Hz, 2H), 2.86 (t, J = 7.6 Hz, 2H), 2.44 - 2.34 (m, 2H). 13 CNMR (100 MHz, CDCl3) d 142.45, 141.44, 139.15, 137.86, 137.74, 129.06 (q, J =32.2 Hz), 128.40, 128.38, 127.41, 125.94, 125.88, 125.62 (q, J = 3.9 Hz), 124.90, 123.05 (q, J = 270.1 Hz), 122.94, 120.19, 119.86, 117.88, 114.88,110.01, 107.17, 44.95, 33.35, 31.64. 19 F NMR (376 MHz, CDCl3) d -62.34. 2-(4-methoxyphenyl)-11-(3-phenylpropyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6ee): White solid, yield 73.7%. mp 168.4 - 169.9℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.41 (s, 1H), 8.26 (d, J = 6.8 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.95 - 7.90 (m,2H), 7.70 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.45 (ddd, J= 8.4, 7.2,1.2 Hz, 1H), 7.31 - 7.17 (m, 6H), 7.07 - 7.02 (m, 2H), 5.07 (t, J = 7.2 Hz,2H), 3.83 (s, 3H), 2.80 (t, J = 7.6 Hz, 2H), 2.31 - 2.21 (m, 2H). 13 C NMR (100MHz, DMSO- d 6) d 159.33, 143.39, 141.85, 139.15, 136.96, 128.81, 128.69, 127.12, 126.93, 126.29, 125.16, 122.98, 120.52, 120.45, 119.34, 114.63, 114.46, 110.73, 109.68, 106.85, 55.63, 44.87, 33.12, 32.04. 2-Methyl-11-(3-phenylpropyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6ef): a purplish-black solid, yield 55.4%. mp 84.3 - 86.2℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.18 (d, J =6.8 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 1.2 Hz, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.54 (d, J = 6.8 Hz, 1H), 7.39 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.25 -7.17 (m, 3H), 7.15 - 7.10 (m, 3H), 4.97 (t, J = 7.2 Hz, 2H), 2.64 (t, J = 7.2 Hz, 2H), 2.41 (s, 3H), 2.22 - 2.13 (m, 2H). 13C NMR (100 MHz, DMSO- d 6) d 141.75, 140.95, 139.03, 136.35, 128.67, 128.59, 126.90, 126.19, 124.93, 123.00, 120.37, 120.28, 119.06, 114.10, 111.58, 110.60, 106.06, 44.53, 32.75, 31.86, 14.84. 11-(3-Phenylacetyl)-2-(Trifluoromethyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6eg): White solid, yield 67.9%. mp 118.3 - 120.2℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.70(d, J = 1.2 Hz, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.84 (d, J =7.2 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.49 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.32(t, J = 7.6 Hz, 1H), 7.26 - 7.19 (m, 2H), 7.18 - 7.12 (m, 3H), 4.97 (t, J = 7.2Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.26 - 2.17 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d 141.59, 139.27, 137.55, 132.58 (q, J = 37.5 Hz), 128.69, 128.53, 126.59,126.24, 125.85, 122.59, 121.31 (q, J= 265.7 Hz), 120.85, 120.83, 119.88,115.78, 114.81 (q, J = 4.2 Hz), 111.02, 108.78, 44.79, 32.76, 31.76. 19 F NMR (376MHz, CDCl3) d -60.80. 2-Cyclopropyl-11-(3-Phenypropyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (6eh): White solid, yield 70.0%. mp 101.6 - 102.9℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.17 (d, J =7.2 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 6.8 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.29 - 7.22 (m, 3H), 7.20 - 7.13(m, 3H), 4.95 (t, J = 7.2 Hz, 2H), 2.70 (t, J = 8.0 Hz, 2H), 2.21 - 2.13 (m, 2H), 2.12 - 2.05 (m, 1H), 1.00 - 0.87 (m, 4H). 13 C NMR (100 MHz, DMSO- d 6) d 147.12, 141.82, 139.01, 136.19, 128.77, 128.55, 126.84, 126.25, 124.95, 122.97, 120.41, 120.29, 119.02, 114.06, 110.60, 110.07, 106.09, 44.67, 32.94, 32.02, 9.90, 8.59. Example 3 Weigh compound 4 (1 mmol) and aldehyde compound 7 (2 mmol) into a reaction tube, and add 6 mL of DMSO / cyclohexane (V) DMSO :V 环己烷 =1:2), add catalytic amount of triethylamine (0.2 mmol) with stirring, then add S8 (0.25 mmol), stir and reflux at 120 °C for 3 h, and monitor the reaction by TLC. After the reaction is complete, cool to room temperature, extract with ethyl acetate, concentrate the organic phase under reduced pressure to remove the solvent, and purify by column chromatography (gradient elution, volume ratio of petroleum ether to ethyl acetate is 10:1, 5:1 and 1:1 respectively) to give the compound β-carbamo[1',2':1,2]imidazol derivative (compound 8aa~8ef, R 1 (For hydrogen).

[0074] 3-Phenylon-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8aa): White solid, yield 72.3%. mp 310.2 - 311.0℃. 1 H NMR (400 MHz, DMSO- d 6) d 12.46 (s, 1H), 8.27 (d, J =7.2 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.80 - 7.68 (m, 4H), 7.64 - 7.55 (m,3H), 7.48 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H). 13 C NMR (100 MHz, DMSO- d 6) d 139.31, 137.90, 131.22, 129.83, 129.79, 128.46, 128.24, 127.51, 127.02, 125.23, 123.15, 120.39, 120.33, 116.47, 114.97, 112.52, 107.64. 3-(4-Fluorophenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8ab): Yellow solid, yield 78.5%. mp 298.5 - 299.6℃.1 H NMR (400 MHz, DMSO- d 6) d 12.47 (s, 1H), 8.21 (d, J = 7.2 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.74 (s, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.27 - 7.22 (m, 1H). 13 C NMR (100 MHz, DMSO-) d 6) d 161.04 (d, J = 243.8 Hz), 139.31, 137.83, 131.23, 130.57 (d, J = 8.1 Hz), 127.46, 126.28 (d, J = 3.2 Hz), 126.04, 125.25, 123.14, 120.40,120.34, 116.63 (d, J = 21.5 Hz), 116.38, 114.98, 112.52, 107.66. 19 F NMR (376MHz, DMSO- d 6) d -113.53. 3-(4-Bromophenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8ac): Yellow solid, yield 82.1%. mp 348.7 - 349.9℃. 1 H NMR (400 MHz, DMSO- d 6) d 12.47 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.83 - 7.74 (m, 3H), 7.74 - 7.67(m, 3H), 7.60 (d, J= 8.0 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.24 (t, J = 7.6 Hz, 1H). 13 C NMR (100 MHz, DMSO- d 6) d 139.35, 138.15, 132.70, 131.67, 130.13, 129.08, 127.45, 125.90, 125.33, 123.11, 121.39, 120.46, 120.37, 116.52, 115.15, 112.54, 107.81. 3-(4-Methoxyphenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8ad): White solid, yield 83.9%. mp 313.5 - 314.0℃. 1 H NMR (400 MHz, DMSO- d 6) d 12.43 (s, 1H), 8.17 (d, J = 7.2 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.66- 7.61 (m, 3H), 7.59 (d, J = 8.0 Hz, 1H), 7.39 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H),7.23 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H), 7.18 - 7.13 (m, 2H), 3.85 (s, 3H). 13 C NMR (100 MHz, DMSO-) d 6) d 159.59, 139.24, 137.53, 130.56, 129.92, 127.58, 126.86, 125.10, 123.20, 122.04, 120.31, 120.28, 116.36, 115.23, 114.67, 112.48, 107.41, 55.77. 3-Ethyl-11 H-imidazo[1',2':1,2]pyrido[3,4- b Indole (8ae): a purplish-black solid in 66.8% yield. mp 327.3 - 328.0℃. 1 H NMR (400 MHz, DMSO- d 6) d 12.31 (s, 1H), 8.09 (d, J =8.0 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 8.0Hz, 1H), 7.40 - 7.33 (m, 2H), 7.22 (t, J = 7.6 Hz, 1H), 2.93 (q, J = 7.6 Hz, 2H), 1.38 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 139.03, 136.73, 128.10, 127.81, 127.40, 124.89, 123.27, 120.23, 120.15, 116.67, 114.27, 112.40, 106.68, 17.48, 12.17. 11-Methyl-3-phenyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8ba): Yellow solid, yield 75.5%. mp 182.3 - 184.2℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.27 (d, J = 7.2 Hz, 1H), 8.16 (dt, J = 8.0, 0.8 Hz, 1H), 7.78 (s, 1H), 7.76 - 7.69 (m, 4H), 7.63 -7.57 (m, 2H), 7.51 - 7.46 (m, 2H), 7.30 (ddd, J = 8.0, 7.2, 0.8 Hz, 1H), 4.47(s, 3H).13 C NMR (100 MHz, DMSO- d 6) d 140.15, 137.97, 131.30, 129.81, 129.68, 128.58, 128.31, 127.93, 126.81, 125.34, 122.66, 120.64, 120.51, 116.52, 114.25, 110.70, 107.60, 32.14. 3-(4-Fluorophenyl)-11-methyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8bb): White solid, yield 80.4%. mp 222.0 - 222.8℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.20 (d, J = 7.2Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.80 - 7.74 (m, 3H), 7.71 (d, J = 7.2 Hz, 2H), 7.49 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.33 - 7.27 (m, 1H), 4.47 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 161.10 (d, J = 244.1 Hz), 140.15,137.90, 131.33, 130.67 (d, J = 8.2 Hz), 127.89, 126.13 (d, J = 3.1 Hz), 125.83,125.36, 122.65, 120.66, 120.52, 116.67 (d, J = 21.4 Hz), 116.45, 114.25,110.71, 107.63, 32.14. 19 F NMR (376 MHz, DMSO- d 6) d -113.38. 3-(4-bromophenyl)-11-methyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8bc): Yellow solid, yield 80.8%. mp 211.2 - 211.8℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.26 (d, J = 7.2Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.80 - 7.75 (m, 2H), 7.74 -7.66 (m, 4H), 7.49 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.33 - 7.27 (m, 1H), 4.46(s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 140.19, 138.22, 132.72, 131.74, 130.22, 128.94, 127.87, 125.69, 125.44, 122.62, 121.52, 120.68, 120.58, 116.58, 114.42, 110.73, 107.77, 32.15. 3-(4-methoxyphenyl)-11-methyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8bd): White solid, yield 82.7%. mp 143.0 - 143.6℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.17 (d, J =7.2 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.73 - 7.66 (m, 3H), 7.65 - 7.61 (m,2H), 7.48 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.29 (ddd, J= 8.0, 7.2, 0.8 Hz, 1H), 7.18 - 7.13 (m, 2H), 4.47 (s, 3H), 3.85 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 159.67, 140.09, 137.59, 130.64, 130.00, 127.99, 126.66, 125.21, 122.72, 121.86, 120.60, 120.43, 116.43, 115.26, 113.96, 110.67, 107.39, 55.78, 32.12. 3-Ethyl-11-methyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8be): a purplish-black solid in 68.5% yield. mp 147.1 - 147.8℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.12 (d, J = 8.0Hz, 1H), 8.01 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.45 (ddd, J = 8.0,7.2, 1.2 Hz, 1H), 7.39 (s, 1H), 7.28 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H), 4.43 (s,3H), 2.93 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 139.83, 136.90, 128.39, 127.96, 127.60, 124.94, 122.83, 120.43, 120.32, 116.69, 113.37, 110.52, 106.59, 32.04, 17.45, 12.13. 11-Methyl-3-(trifluoromethyl)-11 H-imidazo[1',2':1,2]pyrido[3,4- b Indole (8bf): Yellow solid, yield 59.9%. mp 155.6 - 157.4℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.28 - 8.20 (m, 3H), 7.97 (d, J = 6.8 Hz, 1H), 7.77 (dt, J = 8.4, 0.8 Hz, 1H), 7.56 (ddd, J =8.4, 7.2, 1.2 Hz, 1H), 7.35 (ddd, J = 8.0, 7.2, 0.8 Hz, 1H), 4.45 (s, 3H). 13 CNMR (100 MHz, DMSO- d 6) d 140.43, 139.79, 134.24 (q, J = 3.0 Hz), 127.06, 126.40,122.13, 121.08, 121.05, 120.88 (q, J = 264.3 Hz), 117.24 (q, J = 2.3 Hz), 116.16,113.97 (q, J = 39.9 Hz), 111.01, 109.63, 32.25. 19 F NMR (376 MHz, DMSO- d 6) d -60.29. 11-Benzyl-3-phenyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8ca): White solid, yield 83.6%. mp 172.6 - 173.1℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.32 (d, J = 7.2 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.80 - 7.72 (m, 4H), 7.67 (d, J= 8.4 Hz, 1H),7.62 - 7.58 (m, 2H), 7.51 - 7.46 (m, 1H), 7.41 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.31 - 7.23 (m, 5H), 7.23 - 7.17 (m, 1H), 6.34 (s, 2H). 13 C NMR (100 MHz, DMSO- d 6) d 139.38, 138.66, 137.80, 131.41, 129.81, 129.61, 129.01, 128.63, 128.39, 127.69, 127.55, 127.51, 126.90, 125.48, 123.10, 120.90, 120.70, 116.95, 114.67, 111.37, 107.60, 48.03. 11-Benzyl-3-(4-Fluorophenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8cb): White solid, yield 88.7%. mp 196.2 - 197.5℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.26 (d, J = 7.2Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.82 - 7.74 (m, 4H), 7.67 (d, J = 8.4 Hz, 1H), 7.47 - 7.39 (m, 3H), 7.31 - 7.18 (m, 6H), 6.34 (s, 2H). 13 C NMR (100 MHz, DMSO- d 6) d 161.14 (d, J = 244.2 Hz), 139.38, 138.64, 137.69, 131.37, 130.75 (d, J = 8.3Hz), 129.00, 127.69, 127.49, 126.04 (d, J= 3.2 Hz), 125.93, 125.50, 123.08,120.72 (d, J = 20.9 Hz), 116.87, 116.66, 114.71, 111.36, 107.63, 48.03. 19 F NMR (376 MHz, DMSO- d 6) d -113.30. 11-Benzyl-3-(4-bromophenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8cc): Yellow solid, yield 90.0%. mp 177.9 - 178.2℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.32 (d, J = 7.2Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.80 - 7.75 (m, 3H), 7.73 -7.69 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.42 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.31 - 7.19 (m, 6H), 6.33 (s, 2H). 13 C NMR (100 MHz, DMSO- d 6) d 139.41, 138.62, 138.03, 132.71, 131.82, 130.29, 129.01, 128.86, 127.69, 127.49, 125.78, 125.57, 123.05, 121.60, 120.93, 120.76, 116.99, 114.85, 111.38, 107.75, 48.03. 11-Benzyl-3-(4-methoxyphenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8Cd): White solid, yield 86.6%. mp 179.6 - 180.9℃. 1 H NMR (400 MHz, DMSO-d 6) d 8.22 (d, J =7.2 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.71 - 7.62 (m,4H), 7.40 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.31 - 7.23 (m, 5H), 7.22 - 7.14 (m,3H), 6.34 (s, 2H), 3.85 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 159.71, 139.31, 138.68, 137.40, 130.73, 130.08, 129.00, 127.68, 127.59, 127.52, 126.75, 125.36, 123.15, 121.77, 120.86, 120.63, 116.86, 115.26, 114.40, 111.34, 107.40, 55.78, 48.02. 11-Benzyl-3-ethyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8ce): a purplish-black solid in 70.5% yield. mp 154.0 - 155.1℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.15 (dt, J = 8.0, 0.8 Hz, 1H), 8.08 (d, J = 7.2 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 8.4Hz, 1H), 7.42 - 7.34 (m, 2H), 7.28 - 7.16 (m, 6H), 6.29 (s, 2H), 2.94 (q, J =7.6 Hz, 2H), 1.38 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6) d 139.04, 138.70, 136.72, 128.95, 128.46, 127.74, 127.64, 127.56, 125.10, 123.28, 120.69, 120.53, 117.15, 113.86, 111.25, 106.64, 47.97, 17.47, 12.07. 11-Benzyl-3-(trifluoromethyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8cf): Yellow solid, yield 65.8%. mp 160.8 - 161.7℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.29 (dd, J =11.2, 7.4 Hz, 2H), 8.24 (s, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.49 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.27 - 7.18(m, 5H), 6.31 (s, 2H). 13 C NMR (100 MHz, DMSO- d 6) d 139.68, 139.60, 138.26,134.34 (q, J = 3.0 Hz), 129.05, 127.79, 127.43, 126.70, 126.56, 123.48 (q, J =264.3 Hz), 122.57, 121.31, 121.29, 117.70 (q, J = 2.3 Hz), 116.63, 114.49 (q, J =40.1 Hz), 111.63, 109.66, 48.16. 19 F NMR (376 MHz, DMSO- d 6) d -60.28. 11-(4-Fluorobenzyl)-3-phenyl-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8da): Yellow solid, yield 88.7%. mp 194.1 - 195.4℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.32 (d, J = 7.2Hz, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.78 - 7.73 (m, 3H), 7.71 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 8.4, 6.8 Hz, 2H), 7.52 - 7.47 (m, 1H), 7.43 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.29 (dt, J = 7.6, 0.8 Hz, 1H), 7.13 - 7.07 (m, 2H), 6.32 (s, 2H). 13 C NMR (100 MHz, DMSO- d 6) d 160.62 (d, J =241.5 Hz), 139.25, 137.76, 134.83 (d, J = 3.0 Hz), 131.45, 129.82, 129.66 (d, J =8.2 Hz), 129.59, 128.64, 128.39, 127.38, 126.94, 125.54, 123.12, 120.96,120.74, 117.01, 115.72 (d, J = 21.2 Hz), 114.74, 111.32, 107.60, 47.28. 19 F NMR (376 MHz, DMSO- d 6) d -115.33. 11-(4-Fluorobenzyl)-3-(4-Fluorophenyl)-11 H-imidazo[1',2':1,2]pyrido[3,4- b Indole (8 dB): White solid, yield 87.2%. mp 246.4 - 247.8 °C. 1 H NMR (400 MHz, DMSO- d 6) d 8.26(d, J = 6.8 Hz, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.82 - 7.74 (m, 4H), 7.71 (d, J =8.0 Hz, 1H), 7.47 - 7.40 (m, 3H), 7.39 - 7.34 (m, 2H), 7.29 (t, J = 7.2 Hz,1H), 7.13 - 7.06 (m, 2H), 6.31 (s, 2H). 13 C NMR (100 MHz, DMSO- d 6) d 161.16 (d, J =244.2 Hz), 160.62 (d, J = 241.6 Hz), 139.26, 137.64, 134.81 (d, J = 3.0 Hz), 131.38, 130.78 (d, J = 8.4 Hz), 129.65 (d, J = 8.2 Hz), 127.30, 126.01 (d, J = 3.0Hz), 125.97, 125.58, 123.10, 120.98, 120.77, 116.97, 116.67 (d, J = 21.4 Hz), 115.72 (d, J = 21.2 Hz), 114.81, 111.33, 107.65, 47.28. 19 F NMR (376 MHz, DMSO- d 6) d -113.28, -115.32. 3-(4-bromophenyl)-11-(4-fluorobenzyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- bIndole (8dc): Yellow solid, yield 91.2%. mp 222.3 - 222.8℃. 1 H NMR (400 MHz, DMSO- d 6) δ8.32 (d, J = 7.2 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.78 (dt, J =7.2, 2.0 Hz, 3H), 7.74 - 7.68 (m, 3H), 7.43 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.32 - 7.26 (m, 1H), 7.13 - 7.06 (m, 2H), 6.31 (s, 2H). 13 C NMR (100 MHz, DMSO- d 6) d 160.62 (d, J = 241.6 Hz), 139.29, 137.98, 134.79 (d, J = 3.0 Hz), 132.73, 131.82, 130.31, 129.64 (d, J = 8.3 Hz), 128.83, 127.29,125.83, 125.64, 123.07, 121.63, 121.00, 120.81, 117.07, 115.72 (d, J = 21.3Hz), 114.95, 111.34, 107.77, 47.28. 19 F NMR (376 MHz, DMSO- d 6) d -115.31. 11-(4-Fluorobenzyl)-3-(4-Methoxyphenyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8dd): White solid, yield 88.3%. mp 175.5 - 176.9℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.22(d, J= 7.2 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.72 -7.68 (m, 2H), 7.68 - 7.63 (m, 2H), 7.42 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.39 -7.34 (m, 2H), 7.28 (ddd, J = 8.0, 7.2, 0.8 Hz, 1H), 7.18 - 7.14 (m, 2H), 7.13 -7.07 (m, 2H), 6.31 (s, 2H), 3.86 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 160.62 (d, J = 241.7 Hz), 159.72, 139.19, 137.35, 134.85 (d, J = 3.0 Hz), 130.73, 130.08,129.67 (d, J = 8.2 Hz), 127.40, 126.79, 125.43, 123.17, 121.74, 120.93, 120.67,116.92, 115.71 (d, J = 21.4 Hz), 115.26, 114.50, 111.29, 107.41, 55.78,47.27. 19 F NMR (376 MHz, DMSO- d 6) d -60.27, -115.34. 3-Ethyl-11-(4-Fluorobenzyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8de): a purplish-black solid, in 77.6% yield. mp 150.8 - 151.5℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.15 (d, J =8.0 Hz, 1H), 8.09 (d, J= 7.2 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 8.4Hz, 1H), 7.43 - 7.37 (m, 2H), 7.37 - 7.31 (m, 2H), 7.26 (td, J = 7.6, 7.2, 0.8Hz, 1H), 7.10 - 7.04 (m, 2H), 6.27 (s, 2H), 2.95 (q, J = 7.6 Hz, 2H), 1.39 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 160.59 (d, J = 241.5 Hz), 138.91,136.71, 134.87 (d, J = 3.0 Hz), 129.71 (d, J = 8.2 Hz), 128.54, 127.78, 127.38,125.15, 123.30, 120.75, 120.56, 117.21, 115.65 (d, J = 21.3 Hz), 113.91,111.20, 106.61, 47.20, 17.47, 12.06. 19 F NMR (376 MHz, DMSO- d 6) d -115.38. 11-(4-Fluorobenzyl)-3-(Trifluoromethyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8df): Yellow solid, yield 66.9%. mp 149.8 - 151.1℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.30(d, J = 6.8 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 1.2 Hz, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.50 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.37- 7.31 (m, 3H), 7.11 - 7.05 (m, 2H), 6.28 (s, 2H). 13 C NMR (100 MHz, DMSO- d 6) d 160.66 (d, J = 241.7 Hz), 139.58, 139.56, 134.43 (d, J = 3.1 Hz), 134.37 (q, J =3.0 Hz), 129.61 (d, J = 8.3 Hz), 126.62, 126.55, 123.46 (q, J = 264.3 Hz),122.60, 121.38, 121.33, 117.78 (q, J = 2.4 Hz), 116.72, 115.76 (d, J = 21.4 Hz), 114.13 (q, J = 40.0 Hz), 111.59, 109.67, 47.42. 19 F NMR (376 MHz, DMSO- d 6) d -60.27, -115.17. 3-Phenylacetyl-11-(3-Phenylacetyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8ea): White solid, yield 84.0%. mp 109.8 - 110.7℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.28 (d, J =7.2 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.71 (m, 3H), 7.68(d, J= 8.0 Hz, 1H), 7.62 - 7.58 (m, 2H), 7.51 - 7.43 (m, 2H), 7.31 - 7.22 (m,3H), 7.20 - 7.13 (m, 3H), 5.07 (t, J = 7.2 Hz, 2H), 2.72 (t, J = 7.2 Hz, 2H),2.29 - 2.18 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d 141.78, 139.37, 137.72, 131.48, 129.79, 129.69, 128.76, 128.59, 128.57, 128.36, 127.46, 126.80, 126.28, 125.33, 122.78, 120.64, 120.59, 116.63, 114.51, 110.75, 107.54, 44.70, 32.81, 32.08. 3-(4-Fluorophenyl)-11-(3-Phenylacetyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8eb): White solid, yield 86.4%. mp 122.9 - 123.4℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.21(d, J = 7.2 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.81 - 7.74 (m, 3H), 7.72 (d, J =7.2 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.48 - 7.40 (m, 3H), 7.31 - 7.21 (m,3H), 7.20 - 7.13 (m, 3H), 5.06 (t, J = 7.2 Hz, 2H), 2.71 (t, J = 7.2 Hz, 2H),2.29 - 2.18 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d 161.11 (d, J = 244.1 Hz), 141.77,139.37, 137.65, 131.50, 130.71 (d, J = 8.1 Hz), 128.77, 128.59, 127.41, 126.28,126.15 (d, J = 3.2 Hz), 125.82, 125.34, 122.77, 120.66, 120.60, 116.65 (d, J =21.5 Hz), 116.56, 114.51, 110.76, 107.57, 44.70, 32.80, 32.08. 19 F NMR (376MHz, DMSO- d 6) d -113.38. 3-(4-bromophenyl)-11-(3-phenylpropyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8ec): White solid, yield 89.9%. mp 161.8 - 162.9℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.27(d, J = 7.2 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.79 - 7.75 (m, 2H), 7.73 (d, J = 7.2 Hz, 1H), 7.71 - 7.64 (m, 3H), 7.46 (ddd, J = 8.4, 7.2, 1.2 Hz,1H), 7.29 (t, J = 7.6 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.16 (d, J = 7.6 Hz, 3H), 5.05 (t, J = 7.2 Hz, 2H), 2.74 - 2.67 (t, J = 8.0 Hz, 2H), 2.27 - 2.18 (m, 2H). 13 CNMR (100 MHz, DMSO-d 6) d 141.76, 139.40, 137.97, 132.70, 131.91, 130.24, 128.95, 128.76, 128.58, 127.39, 126.28, 125.67, 125.41, 122.74, 121.52, 120.70, 120.61, 116.66, 114.67, 110.76, 107.69, 44.70, 32.80, 32.07. 3-(-Methoxyphenyl)-11-(3-Phenylacetyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8ed): White solid, yield 85.2%. mp 113.9 - 114.5℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.18 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.73 - 7.68 (m, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.65 - 7.61 (m, 2H), 7.45 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.31- 7.22 (m, 3H), 7.17 (ddd, J = 8.8, 5.6, 2.4 Hz, 5H), 5.06 (t, J = 7.2 Hz, 2H),3.85 (s, 3H), 2.68 (t, J = 7.2 Hz, 2H), 2.27 - 2.19 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d159.68, 141.80, 139.32, 137.33, 130.81, 130.05, 128.77, 128.59, 127.51, 126.66, 126.28, 125.22, 122.83, 121.87, 120.58, 120.56, 116.55, 115.25, 114.23, 110.73, 107.35, 55.78, 44.69, 32.81, 32.09. 3-Ethyl-11-(3-Phenylacetyl)-11 H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8ee): a purplish-black solid in 70.8% yield. mp 97.3 - 98.9℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.14 (dt, J =8.0, 0.8 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.63 (d, J =8.0 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.29 - 7.20 (m, 3H), 7.17 - 7.12 (m, 3H), 5.03 (t, J = 7.2 Hz, 2H), 2.93 (q, J = 7.6 Hz, 2H), 2.71 - 2.64 (m, 2H), 2.23 -2.15 (m, 2H), 1.38 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 141.81, 139.05, 136.69, 128.75, 128.60, 128.56, 127.59, 127.52, 126.25, 124.94, 122.96, 120.47, 120.38, 116.83, 113.63, 110.61, 106.55, 44.62, 32.78, 32.05, 17.48, 12.11. 11-(3-Phenylacetyl)-3-(trifluoromethyl)-11H -imidazo[1',2':1,2]pyrido[3,4- b Indole (8ef): Yellow solid, yield 70.5%. mp 90.8 - 92.4℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.29 -8.21 (m, 3H), 7.98 (d, J = 7.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.53 (ddd, J =8.4, 7.2, 1.2 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.25 - 7.19 (m, 2H), 7.17 - 7.11(m, 3H), 5.04 (t, J = 7.2 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 2.26 - 2.17 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d 141.62, 139.68, 139.57, 134.38 (q, J = 3.2 Hz),128.72, 128.55, 126.60, 126.40, 126.27, 122.27, 121.22, 121.01, 120.88 (q, J =264.2 Hz), 117.36 (q, J = 2.2 Hz), 116.44, 113.97 (q, J = 39.9 Hz), 111.06,109.59, 44.84, 32.73, 31.91. 19 F NMR (376 MHz, DMSO- d 6) d -60.29. Test Example 1 Antitumor activity test Using A549 (lung cancer cells), BGC-823 (gastric cancer cells), CT-26 (colon cancer cells), Bel-7402 (liver cancer cells), and MCF-7 (breast cancer cells) as subjects, the inhibitory activity of target compounds 6aa~6eh and 8aa~8ef against tumor cell lines was tested using the MTT assay. Cell lines in good growth condition and in logarithmic growth phase were respectively subjected to MTT assays at a concentration of 1×10⁻⁶ cells / cells. 4 Inoculate 96-well plates with a concentration of 1 / mL and incubate at 37°C in a CO2 incubator for 24 hours. Discard the old medium and replace with fresh medium. Add the sterilized test compound and continue incubation for 48 hours. Discard the medium and add 20 μL of RPMI 1640 medium containing 5 mg / mL MTT to each well. Continue incubation for 4 hours. After removing the supernatant, add 100 μL of DMSO to each well and shake for about 10 minutes to dissolve the precipitate. Then, detect the OD value using a microplate reader at a wavelength of 490 nm and calculate the IC50 for each sample using a graphical method. 50 Values. See Table 1 for specific results.

[0075] Table 1. Antitumor activity of β-carbazo[1',2':1,2]imidazol derivatives (n=3)

[0076] As shown in Table 1, the β-carbazo[1',2':1,2]imidazol derivative of the present invention has good antitumor activity against lung cancer, gastric cancer, colon cancer, liver cancer and breast cancer, and has good application prospects in the preparation of antitumor drugs.

[0077] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, not all embodiments. People can obtain other embodiments based on the present invention without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A β-carbazo[1',2':1,2]imidazol derivative, characterized in that, It has the structure shown in Equation I: Equation I; Where R 2 For hydrogen, R 3 When it is hydrogen, R 1 It is phenyl, 4-fluorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, methyl, trifluoromethyl or cyclopropane; When R 2 For hydrogen, R 3 When it is methyl, R 1 It is phenyl, 4-fluorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, methyl, trifluoromethyl or cyclopropane; When R 2 For hydrogen, R 3 When it is benzyl, R 1 It is phenyl, 4-fluorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, methyl, trifluoromethyl or cyclopropane; When R 2 For hydrogen, R 3 When it is 4-fluorobenzyl, R 1 It is phenyl, 4-fluorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, methyl, trifluoromethyl or cyclopropane; When R 2 For hydrogen, R 3 When it is phenylpropyl, R 1 It is phenyl, 4-fluorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, methyl, trifluoromethyl or cyclopropane; When R 1 For hydrogen, R 3 When it is hydrogen, R 2 It is phenyl, 4-fluorophenyl, 4-bromophenyl, 4-methoxyphenyl, or ethyl; When R 1 For hydrogen, R 3 When it is methyl, R 2 It is phenyl, 4-fluorophenyl, 4-bromophenyl, 4-methoxyphenyl, ethyl or trifluoromethyl; When R 1 For hydrogen, R 3 When it is benzyl, R 2 It is phenyl, 4-fluorophenyl, 4-bromophenyl, 4-methoxyphenyl, ethyl or trifluoromethyl; When R 1 For hydrogen, R 3 When it is 4-fluorobenzyl, R 2 It is phenyl, 4-fluorophenyl, 4-bromophenyl, 4-methoxyphenyl, ethyl or trifluoromethyl; When R 1 For hydrogen, R 3 When it is 3-phenylpropyl, R 2 It can be phenyl, 4-fluorophenyl, 4-bromophenyl, 4-methoxyphenyl, ethyl or trifluoromethyl.

2. The method for preparing the β-carbazo[1',2':1,2]imidazol derivative according to claim 1, When R 2 When the hydrogen is used, the preparation method includes the following steps: Compound 4, the haloketone, and the first organic solvent were mixed and subjected to a first cyclization reaction to obtain a β-carbazo[1',2':1,2]imidazol derivative; in the haloketone, X is a halogen. When R 1 When hydrogen is used, the preparation method includes the following steps: mixing compound 4, aldehyde compound, organic amine, S8 and second organic solvent, and carrying out a second cyclization reaction to obtain β-carbazo[1',2':1,2]imidazol derivative; 。 3. The preparation method according to claim 2, characterized in that, The molar ratio of compound 4 to the haloketone is 1:1.1~2; The first organic solvent is selected from alcohol solvents; The temperature of the first cyclization reaction is 60~100℃, and the time is 2~4h.

4. The preparation method according to claim 2, characterized in that, The molar ratio of compound 4 to the aldehyde compound is 1:1.1~2; The molar ratio of compound 4 to the organic amine is 1:0.05~0.5; The molar ratio of compound 4 to S8 is 1:0.1~0.4; The second organic solvent is selected from a mixture of highly polar solvents and less polar solvents, wherein the highly polar solvent is selected from sulfone solvents and / or amide solvents, and the less polar solvent is selected from cycloalkanes solvents and / or ether solvents; The second cyclization reaction is carried out at a temperature of 120-160°C for 1-5 hours.

5. The use of the β-carbazo[1',2':1,2]imidazol derivative according to claim 1 or the β-carbazo[1',2':1,2]imidazol derivative prepared by any one of claims 2 to 4 in the preparation of antitumor drugs.

6. A pharmaceutical composition, characterized in that, It includes an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient is selected from the β-carbazo[1',2':1,2]imidazol derivative of claim 1 or the β-carbazo[1',2':1,2]imidazol derivative prepared by any one of claims 2 to 4.

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