Beta-carboline bridged urea derivative as well as preparation method and application thereof

Abstract

The invention relates to a beta-carboline bridged urea derivative as well as a preparation method and application thereof. The invention discloses a novel compound-beta-carboline bridged urea derivative, a preparation method of the beta-carboline bridged urea derivative, and application of the beta-carboline bridged urea derivative in preparation of antitumor drugs. The beta-carboline bridged urea derivative disclosed by the invention is a novel compound, has relatively good anti-tumor activity, can be applied to anti-tumor drugs, and has important significance on synthesis and discovery of the anti-tumor drugs.

Description

Technical Field

[0001] The present invention specifically relates to a β-carboline bridged urea derivative and a preparation method and application thereof. Background Art

[0002] β-Carboline is a naturally occurring alkaloid with a pyridine ring and an indole ring in its structure. This type of compound is widely found in nature and has been found to have a variety of biological activities such as nervous system activity, antioxidant, anti-cancer, anti-inflammatory, and neurotransmitter regulation. The research on the anti-tumor activity of β-carboline compounds is very extensive, involving the modification of almost all sites of the β-carboline ring, among which the research on C1, N2, C3, and N9 is relatively rich, and active molecules with various types of substitutions (including polycyclic heterocycles, condensed rings, fatty amines, thioethers, carboxylates, amides, etc.) have been obtained.

[0003] Based on this, the present invention proposes a new β-carboline derivative, namely a β-carboline bridged urea derivative, which is of great significance for the synthesis and discovery of anti-tumor drugs. Summary of the invention

[0004] The first inventive object of the present invention is to provide a β-carboline bridged urea derivative, which is a β-carboline bridged urea derivative with a novel structure, which is a 6-urea substituted β-carboline derivative and has excellent anti-tumor activity.

[0005] In order to achieve the above purpose, the technical solution adopted is:

[0006] A β-carboline bridged urea derivative, the general chemical structure of which is:

[0007]

[0008] Furthermore, the R 9 is one of hydrogen, C1-C6 alkyl, unsubstituted or substituted benzyl;

[0009] The X is S or O;

[0010] The R 1 It is one of halogen, C1-C6 alkyl and C1-C6 haloalkyl.

[0011] Furthermore, the R 9 In the case of a substituted benzyl group, the substituent of the benzene ring is a C1-C6 alkyl group and / or a halogen group.

[0012] Furthermore, the β-carboline bridged urea derivative is any of the following compounds:

[0013] 1-(4-Fluorophenyl)-3-(1-methyl-β-carbolin-6-yl)thiourea, 1-(4-chlorophenyl)-3-(1-methyl-β-carbolin-6-yl)thiourea, 1-(1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea, 1-(1-methyl-β-carbolin-6-yl)-3-(p-tolyl)thiourea, 1-(1,9-dimethyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea, 1-(1,9-dimethyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(1,9-dimethyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea, 1-(9-butyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea, 1-(9-butyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(9- 1-(9-butyl-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)thiourea, 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea, 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea, 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)thiourea, 1-(9- (3-Chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea, 1-(9-(3-chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(9-(3-chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea, 1-(9-(4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea, 1-(9-((4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(9-(4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(4-fluorophenyl)-3-(1-methyl-β-carbolin-6-yl)urea, 1-(4-chlorophenyl)-3-(1-methyl-β-carbolin-6-yl)urea, 1-(1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(1-methyl-β-carbolin-6-yl)-3-(p-tolyl)urea, 1-(1,9-dimethyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea, 1-(1,9-dimethyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea, 1-(1,9-dimethyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)urea, 1-(9-butyl-1-methyl-β-carbolin-6-yl)- )-3-(4-fluorophenyl)urea, 1-(9-butyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea, 1-(9-butyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-butyl-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)urea, 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea, 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea, 1-(9-benzyl 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-(3-chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea, 1-(9-(3-chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea, 1-(9-(3-chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-(3 1-(9-(4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea, 1-(9-((4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea, 1-(9-(4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-((4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-((4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)urea,

[0014] The second object of the present invention is to provide a method for preparing the above-mentioned β-carboline bridged urea derivatives, which has a simple process and a good yield.

[0015] In order to achieve the above purpose, the technical solution adopted is:

[0016] The preparation method of the above-mentioned β-carboline bridged urea derivative is: 9-substituted-6-amino-1-methyl-β-carboline, phenyl isocyanate or phenyl isothiocyanate, and dichloromethane are mixed and subjected to nucleophilic addition reaction to obtain the β-carboline bridged urea derivative.

[0017] Furthermore, when X in the β-carboline bridged urea derivative is S, the molar ratio of 9-substituted-6-amino-1-methyl-β-carboline to phenyl isothiocyanate is 1:1.1-2.5;

[0018] When X in the β-carboline bridged urea derivative is O, the molar ratio of 9-substituted-6-amino-1-methyl-β-carboline to phenyl isocyanate is 1:1.1-2.

[0019] Furthermore, when X in the β-carboline bridged urea derivative is S, the molar ratio of 9-substituted-6-amino-1-methyl-β-carboline to phenyl isothiocyanate is 1:1.5-2.5;

[0020] When X in the β-carboline bridged urea derivative is O, the molar ratio of 9-substituted-6-amino-1-methyl-β-carboline to phenyl isocyanate is 1:1.5-2.

[0021] Furthermore, when X in the β-carboline bridged urea derivative is S, the temperature of the nucleophilic addition reaction is room temperature and the time is 6-10 hours.

[0022] When X in the β-carboline bridged urea derivative is O, the temperature of the nucleophilic addition reaction is room temperature and the time is 4-8 hours.

[0023] The third invention objective of the present invention is to provide the use of the above-mentioned β-carboline bridged urea derivatives in the preparation of anti-tumor drugs.

[0024] Furthermore, the anti-tumor drug comprises an active component and a pharmaceutically acceptable excipient;

[0025] The active component is the above-mentioned β-carboline bridged urea derivative.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] 1. The technical solution of the present invention combines a urea structure with good activity with a β-carboline structure with anti-tumor activity by using the active substructure splicing principle to obtain a β-carboline bridged urea derivative with high activity and low side effects, which is of great significance for the synthesis and discovery of anti-tumor drugs. It also has good anti-tumor activity against lung cancer, gastric cancer, colon cancer, liver cancer and breast cancer, and has good application prospects and potential in the preparation of anti-tumor drugs.

[0028] 2. The technical solution of the present invention provides a method for preparing β-carboline bridged urea derivatives, which has simple process, simple operation, low production cost, is green and environmentally friendly, and is suitable for industrial production. DETAILED DESCRIPTION

[0029] In order to further illustrate the β-carboline bridged urea derivatives and their preparation methods and applications of the present invention and achieve the intended purpose of the invention, the following is a detailed description of the β-carboline bridged urea derivatives and their preparation methods and applications, their specific implementation methods, structures, features and effects proposed in accordance with the present invention in combination with preferred embodiments. In the following description, different "one embodiment" or "embodiment" does not necessarily refer to the same embodiment. In addition, specific features, structures or characteristics in one or more embodiments may be combined in any suitable form.

[0030] The following will further introduce in detail a β-carboline bridged urea derivative of the present invention and its preparation method and application in conjunction with specific embodiments:

[0031] The technical solution of the present invention mainly includes the following contents:

[0032] (1) β-Carboline-bridged urea derivatives

[0033] The present invention provides a β-carboline bridged urea derivative having a structure shown in Formula I:

[0034]

[0035] Preferably, R 9 is one of hydrogen, C1-C6 alkyl, unsubstituted or substituted benzyl. The substituent in the substituted benzyl is C1-C6 alkyl and / or halogen; the halogen includes one or more of fluorine, chlorine, bromine and iodine.

[0036] Preferably, X is S or O. 1 It is one of halogen, C1-C6 alkyl and C1-C6 haloalkyl.

[0037] (2) Preparation method of the above-mentioned β-carboline bridged urea derivatives

[0038] ① The preparation method of β-carboline bridged urea derivatives is as follows: 9-substituted-6-amino-1-methyl-β-carboline, phenyl isothiocyanate or phenyl isocyanate, and dichloromethane are mixed and subjected to nucleophilic addition reaction to obtain β-carboline bridged urea derivatives; R in 9-substituted-6-amino-1-methyl-β-carboline 9 With R in Formula I 9 Same; R in phenyl isothiocyanate 1 With R in Formula I 1 The same, R 1 With R in Formula I1 same.

[0039]

[0040] Preferably, when X is S, the molar ratio of 9-substituted-6-amino-1-methyl-β-carboline to phenyl isothiocyanate is 1:1.1-2.5;

[0041] When X is O, the molar ratio of 9-substituted-6-amino-1-methyl-β-carboline to phenyl isocyanate is 1:1.1-2.

[0042] Further preferably, when X is S, the molar ratio of 9-substituted-6-amino-1-methyl-β-carboline to phenyl isothiocyanate is 1:1.5-2.5;

[0043] When X is O, the molar ratio of 9-substituted-6-amino-1-methyl-β-carboline to phenyl isocyanate is 1:1.5-2.

[0044] Preferably, when X is S, the temperature of the nucleophilic addition reaction is room temperature and the time is 6-10 hours. When X is O, the temperature of the nucleophilic addition reaction is room temperature and the time is 4-8 hours. In a specific embodiment of the present invention, the reaction progress is monitored by thin layer chromatography.

[0045] After completing the first nucleophilic addition reaction, the present invention also includes post-treatment, which is: concentrating the reaction solution obtained by the first nucleophilic addition reaction, filtering, and purifying by column chromatography to obtain a filter cake to obtain a β-carboline bridged urea derivative. The present invention has no special limitation on concentration, and the solvent can be removed by a concentration method well known to those skilled in the art, such as concentration under reduced pressure. Preferably, the eluent used for column chromatography purification is a dichloromethane-methanol mixed solvent, and the volume ratio of dichloromethane to methanol during gradient elution is 50:1 to 10:1.

[0046] ② A method for preparing 9-substituted-6-amino-1-methyl-β-carboline, comprising the following steps:

[0047] L-tryptophan and water are mixed, and then sulfuric acid solution and acetaldehyde are added to carry out a first cyclization reaction to obtain compound 1;

[0048] The compound 1, an oxidant and water are mixed to perform a first oxidation reaction, and then a sulfuric acid solution is added to perform a second oxidation reaction to obtain a compound 2;

[0049] The compound 2 is mixed with a nitric acid solution, and then a sulfuric acid solution is added to perform a first nitration reaction to obtain a compound 3;

[0050] The compound 3, the catalyst, R 9 X is mixed with a second organic solvent to undergo a first substitution reaction to obtain compound 4; the R9 X in R 9 With the R 9 Same, X is halogen;

[0051] The compound 4, a reducing agent, water and a third organic solvent are mixed, and then hydroiodic acid is added to carry out an amination reaction to obtain 9-substituted-6-amino-1-methyl-β-carboline (ie, compound 5).

[0052]

[0053] (3) Application of β-carboline bridged urea derivatives

[0054] The use of the above-mentioned β-carboline bridged urea derivatives in the preparation of anti-tumor drugs. Preferably, the tumor includes one or more of lung cancer, gastric cancer, colon cancer, liver cancer and breast cancer.

[0055] Preferably, the anti-tumor drug comprises an active ingredient and a pharmaceutically acceptable excipient, and the active ingredient is the above-mentioned β-carboline bridged urea derivative. The present invention has no special limitation on the content of the active ingredient in the pharmaceutical composition, and the content well known to those skilled in the art can be used. The present invention has no special limitation on the pharmaceutically acceptable excipient, and the pharmaceutically acceptable excipient well known to those skilled in the art can be used. The present invention has no special limitation on the dosage form of the pharmaceutical composition, and the pharmaceutically acceptable excipient well known to those skilled in the art can be used.

[0056] Example 1.

[0057] The reaction formula is as follows:

[0058]

[0059] The specific steps are as follows:

[0060] Synthesis of compound 1: L-tryptophan (250 mmol) was weighed and placed in a 2 L thick-walled conical flask, H2O (700 mL) was added, and 0.5 mol / L sulfuric acid (6 mL) solution and acetaldehyde (75 mL) were added in sequence under stirring. Stirring was continued at room temperature for about 8 hours. A large amount of white insoluble matter precipitated. After filtration, water washing, acetone rinsing, drying and other steps, compound 1 (225.4 mmol, yield 90.2%) was obtained.

[0061] Synthesis of compound 2: Compound 1 (100 mmol) and water (1000 mL) were fully stirred and heated to 100°C, MnO2 (300 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, and reacted at 100°C for 1 h. The reaction was monitored by thin layer chromatography. After the reaction was completed, the temperature was cooled to room temperature, the pH was adjusted to 9 with sodium hydroxide, and then extracted with ethyl acetate, and the organic phase was concentrated to constant weight to obtain compound 2 (86 mmol, yield 86%).

[0062] Synthesis of compound 3: In a 500 mL round-bottom flask under an ice bath, pre-refrigerated HNO3 (40 mL) was added, and then compound 2 (20 mmol) was weighed and added. After stirring for 10 min, H2SO4 (4 mL) was added and the reaction was allowed to react for 10 h. The reaction was monitored by thin layer chromatography. After the reaction was complete, if a precipitate was produced (if no precipitate was produced, water was added until a precipitate appeared and stirred for 10 min), it was filtered off with suction, and the filter cake was washed with a small amount of water (to remove by-products). The filter cake was dissolved in water and ammonia water was added to adjust the pH value to greater than 8. The mixture was stirred for 20 min, filtered off with suction, washed with water, and dried to obtain compound 3 (17.6 mmol, yield was 88%).

[0063] Synthesis of compound 4: Weigh compound 3 (30 mmol) and NaH (60 mmol), measure DMF (200 mL) into a 500 mL round-bottom flask, stir at room temperature for 15 min until all materials are evenly mixed and the solution is dark red, add halogenated hydrocarbon (36 mmol) dropwise to the mixed solution, monitor the reaction by TLC immediately after the addition is complete, prepare 150 mL of ice water into a 500 mL beaker, and after the reaction is complete, slowly pour the reaction solution into ice water to remove the remaining NaH to terminate the reaction, extract with ethyl acetate (200 mL × 3), collect the organic phase, wash with saturated brine to remove DMF, and then add 150 mL of ice water into a 500 mL beaker. F, concentrated HCl was added dropwise to the organic phase until no solid precipitated, 300 mL of anhydrous ethanol was added to remove the water introduced by hydrochloric acid later, ethyl acetate, water and anhydrous ethanol were distilled off under reduced pressure at 45°C, a small amount of acetone was added to the obtained solid to form a paste, which was placed in a refrigerator (-10-0°C) for 8 h, filtered, washed with a small amount of cold acetone to remove residual halogenated hydrocarbons and reaction by-products, the obtained solid was dissolved in water, NaHCO3 was added to adjust the pH value of the solution to alkaline, extracted with ethyl acetate (200 mL×3), ethyl acetate was distilled off under reduced pressure at 40°C, and the obtained oil was frozen for 1 h to obtain compound 4.

[0064] R 9 Hydrogen was added to give compound 4a with a yield of 83%. 9 Methyl was added to give compound 4b with a yield of 78%. 9 Ethyl group, to give compound 4c, yield 75%. 9Butyl group was added to obtain compound 4d with a yield of 80%. 9 The compound 4e was obtained with a yield of 85%. 9 The compound 4f was obtained with a yield of 79%. 9 The product is m-chlorobenzyl, and 4 g of compound is obtained with a yield of 76%.

[0065] Synthesis of 9-substituted-6-amino-1-methyl-β-carboline: Weigh SnCl2·2H2O (60 mmol) and compound 4 (10 mmol) in a 500 mL round-bottom flask, add methanol (100 mL) and water (100 mL) under stirring, stir at room temperature for 20 min, slowly add HI (20 mL), reflux for 1 h, monitor the reaction end point by TLC, and after the reaction is complete, cool the reaction solution to room temperature, add ammonia water to adjust the pH value to greater than 8, extract with ethyl acetate (400 mL×3), wash with saturated brine, dry with anhydrous Na2SO4, filter to remove solid impurities, concentrate the filtrate, and purify by column chromatography (gradient elution, the volume ratio of dichloromethane and methanol is 100:1 to 50:1) to obtain 9-substituted-6-amino-1-methyl-β-carboline.

[0066] R 9 Hydrogen was added to give compound 5a with a yield of 76%. 9 Methyl was used to obtain compound 5b with a yield of 68%. 9 Ethyl group, compound 5c was obtained with a yield of 75%. 9 Butyl to obtain compound 5d with a yield of 80%. 9 The compound 5e was obtained with a yield of 65%. 9 The compound 5f was obtained with a yield of 72%. 9 The product is m-chlorobenzyl, and 5 g of compound is obtained with a yield of 70%.

[0067] Example 2.

[0068] The reaction formula is as follows:

[0069]

[0070]

[0071] The specific steps are as follows:

[0072] Weigh 9-substituted-6-amino-1-methyl-β-carboline (1 mmol) and phenyl isothiocyanate (1.5 mmol) into a reaction tube, add 10 mL of dichloroethane, stir at room temperature for 8 h, monitor the reaction by thin layer chromatography, and after the reaction is completed, concentrate and filter to obtain a filter cake, which is purified by column chromatography (gradient elution, the volume ratio of dichloromethane to methanol is 50:1 to 10:1) to obtain β-carboline bridged urea derivatives (compounds 7a-7x).

[0073] 1-(4-Fluorophenyl)-3-(1-methyl-β-carbolin-6-yl)thiourea (7a): yellow solid, yield 71.8%. mp 185.8-187.5℃. 1 H NMR (400MHz, DMSO-d6) δ11.59(s,1H),9.81(s,1H),9.62(s,1H),8.20(d,J=5.2Hz,1H),8.17(s,1H), 7.92(d,J=5.2Hz,1H),7.57(d,J=8.4Hz,1H),7.54-7.44(m,3H),7.17(t,J=8.8Hz,2H),2.76(s,3H). 13 C NMR(100MHz,DMSO-d6)δ181.22,159.62(d,J=239.7Hz),142.69,138.76,137.93,136.44(d,J=2.6Hz),135.47 ,131.47,127.31,127.18,126.96(d,J=8.2Hz),121.47,119.01,115.41(d,J=22.3Hz),113.20,112.25,20.87. 19 F NMR(376MHz,DMSO-d6)δ-118.11.HRMS(ESI)m / z calcd for C 19 H 16 FN4S + (M+H) + 351.1074, found 351.1077.

[0074] 1-(4-Chlorophenyl)-3-(1-methyl-β-carbolin-6-yl)thiourea (7b): Off-white solid, yield 74.9%. mp 212.0-213.7℃. 1H NMR (400MHz, DMSO-d6) δ11.61(s,1H),9.90(s,1H),9.74(s,1H),8.20(d,J=5.2Hz,1H),8.18 (d,J=2.0Hz,1H),7.92(d,J=5.2Hz,1H),7.59-7.49(m,4H),7.40-7.36(m,2H),2.76(s,3H). 13 C NMR(100MHz,DMSO-d6)δ180.90,142.67,139.16,138.78,137.88,135.45,131.42,12 8.65,127.32,127.12,126.01,121.45,118.95,113.21,112.27,20.84.HRMS(ESI)m / z calcd for C 19 H 16 C1N4S + (M+H) + 367.0778, found 367.0778.

[0075] 1-(1-Methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (7c): light brown solid, yield 57.2%. mp 185.9-187.4℃. 1 H NMR (400MHz, DMSO-d6) δ11.67(s,1H),10.12(s,1H),10.06(s,1H),8.21(d,J=6.0Hz,2H),7.95 (d,J=5.4Hz,1H),7.80(d,J=8.4Hz,2H),7.68(d,J=8.4Hz,2H),7.63-7.50(m,2H),2.78(s,3H). 13 C NMR(100MHz,DMSO-d6)δ180.82,144.10,142.59,138.94,137.58,135.45,131.42,,127.50,127.15,125.95( q, J=3.8Hz), 124.90 (q, J=269.9Hz), 124.25 (q, J=31.8Hz), 123.47, 121.41, 118.91, 113.32, 112.35, 20.69. 19 F NMR(376MHz,DMSO-d6)δ-60.33.HRMS(ESI)m / z calcd for C 20 H 16 F3N4S + (M+H)+ 401.1042, found 401.1049.

[0076] 1-(1-Methyl-β-carbolin-6-yl)-3-(p-tolyl)thiourea (7d): yellow solid, yield 64.6%. mp 190.8-192.5℃. 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),9.71(s,1H),9.60(s,1H),8.19(d,J=5.4Hz,1H),8.17(d,J=2.0Hz,1H ),7.91(d,J=5.2Hz,1H),7.58-7.49(m,2H),7.39-7.34(m,2H),7.17-7.11(m,2H),2.76(s,3H),2.28(s,3H). 13 C NMR(100MHz,DMSO-d6)δ180.91,142.69,138.67,137.96,137.46,135.47,134.09,131.68,12 9.33,127.29,127.20,124.62,121.42,118.92,113.16,112.14,21.00,20.90.HRMS(ESI)m / z calcd for C 20 H 19 N4S + (M+H) + 347.1325, found 347.1328.

[0077] 1-(1,9-Dimethyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea (7e): gray solid, yield 66.8%. mp 179.7-181.6℃. 1 H NMR (400MHz, DMSO-d6) δ9.83(s,1H),9.66(s,1H),8.20(d,J=2.0Hz,1H),8.18(d,J=5.2Hz,1H),7.96(d,J=5.2Hz,1H) ,7.67(d,J=8.8Hz,1H),7.58(dd,J=8.8,2.0Hz,1H),7.52-7.46(m,2H),7.20-7.13(m,2H),4.15(s,3H),3.02(s,3H). 13CNMR(100MHz,DMSO-d6)δ181.24,159.63(d,J=239.8Hz),142.56,140.01,137.89,136.39(d,J=2.7Hz),136.12,13 1.69,127.95,127.27,126.93(d,J=8.3Hz),120.59,118.61,115.44(d,J=22.3Hz),113.42,110.54,32.62,23.71. 19 F NMR(376MHz,DMSO-d6)δ-118.08.HRMS(ESI)m / z calcd for C 20 H 18 FN4S + (M+H) + 365.1231, found 365.1239.

[0078] 1-(1,9-Dimethyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea (7f): yellow solid, yield 55.5%. mp 157.5-159.8℃. 1 H NMR (400MHz, DMSO-d6) δ9.93(s,1H),9.79(s,1H),8.22(d,J=2.0Hz,1H),8.19(d,J=5.2Hz,1H),7.98(d ,J=5.2Hz,1H),7.68(d,J=8.8Hz,1H),7.62-7.51(m,3H),7.40-7.36(m,2H),4.15(s,3H),3.03(s,3H). 13 C NMR(100MHz,DMSO-d6)δ180.95,142.48,140.11,139.14,137.61,136.08,131.69,128.70,12 8.67,128.08,127.31,125.97,120.54,118.58,113.50,110.59,32.64,23.54.HRMS(ESI)m / z calcd forC 20 H 18 C1N4S + (M+H) + 381.0935, found 381.0938.

[0079] 1-(1,9-Dimethyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (7 g): pale yellow solid, yield 64.8%. mp 183.3-184.5℃.1 H NMR (400MHz, DMSO-d6) δ10.10(s,1H),10.04(s,1H),8.24(s,1H),8.19(d,J=5.2Hz,1H),7.97(d,J=5 .2Hz,1H),7.79(d,J=8.4Hz,2H),7.72-7.65(m,3H),7.60(d,J=8.8Hz,1H),4.16(s,3H),3.03(s,3H). 13 C NMR(100MHz,DMSO-d6)δ180.86,144.06,142.57,140.11,137.83,136.12,131.53,127.98,127.13,126.24(q,J =269.8Hz), 125.98 (q, J = 3.9Hz), 124.29 (q, J = 31.9Hz), 123.49, 120.59, 118.53, 113.45, 110.62, 32.64, 23.64. 19 F NMR(376MHz,DMSO-d6)δ-60.33.HRMS(ESI)m / z calcd forC 21 H 18 F3N4S + (M+H) + 415.1199, found 415.1205.

[0080] 1-(9-Ethyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea (7h): yellow solid, yield 74.5%. mp 145.6-147.5℃. 1 H NMR (400MHz, DMSO-d6) δ9.83(s,1H),9.66(s,1H),8.21(dd,J=3.6,1.6Hz,2H),7.99(d,J=5.2Hz,1H),7.70(d,J=8.8Hz,1H), 7.58(dd,J=8.8,2.0Hz,1H),7.52-7.46(m,2H),7.20-7.14(m,2H),4.65(q,J=7.2Hz,2H),2.99(s,3H),1.35(t,J=7.2Hz,3H). 13C NMR (100MHz, DMSO-d6) δ181.24,159.64(d,J=239.7Hz),141.81,139.09,137.84,136.41(d,J=2.7Hz),135.08,131.8 7,128.46,127.44,126.97(d,J=8.3Hz),120.97,118.78,115.43(d,J=22.2Hz),113.57,110.57,60.23,23.46,16.12. 19 FNMR(376MHz,DMSO-d6)δ-118.08.HRMS(ESI)m / z calcd for C 21 H 20 FN4S + (M+H) + 379.1387, found 379.1384.

[0081] 1-(9-Ethyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea (7i): off-white solid, yield 82.3%. mp 161.0-161.4℃. 1 H NMR (400MHz, DMSO-d6) δ9.95 (s, 1H), 9.81 (s, 1H), 8.25-8.19 (m, 2H), 7.99 (d, J = 5.2Hz, 1H), 7.71 (d, J = 8. 8Hz,1H),7.62-7.52(m,3H),7.41-7.36(m,2H),4.66(q,J=7.2Hz,2H),2.99(s,3H),1.36(t,J=7.2Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ180.93,141.82,139.17,139.10,137.84,135.08,131.81,128.82,128.68,1 28.45,127.36,125.98,125.77,120.97,118.69,113.57,110.58,23.45,16.11.HRMS(ESI)m / zcalcd for C 21 H 20 C1N4S + (M+H) + 395.1092, found 395.1099.

[0082] 1-(9-Ethyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (7j): pale yellow solid, yield 89.2%. mp 165.6-166.3℃. 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),10.08(s,1H),8.25(d,J=2.0Hz,1H),8.22(d,J=5.2Hz,1H),7.99(d,J=5.2Hz,1H),7.8 1(d,J=8.4Hz,2H),7.74-7.67(m,3H),7.61(dd,J=8.8,2.0Hz,1H),4.66(q,J=7.2Hz,2H),2.99(s,3H),1.36(t,J=7.2Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ180.84,144.08,141.82,139.16,137.81,135.08,131.71,128.47,127.27,126.24(q,J=269 .8Hz), 125.96 (q, J = 3.7Hz), 124.29 (q, J = 31.8Hz), 123.50, 120.97, 118.65, 113.59, 113.44, 110.63, 23.41, 16.10. 19 F NMR(376MHz,DMSO-d6)δ-60.34.HRMS(ESI)m / z calcd for C 22 H 20 F3N4S + (M+H) + 429.1355, found 429.1358.

[0083] 1-(9-Butyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea (7k): yellow solid, yield 76.3%. mp 146.1-148.0℃. 1H NMR (400MHz, DMSO-d6) δ9.82(s,1H),9.66(s,1H),8.23-8.19(m,2H),7.99(d,J=5.2Hz,1H),7.69(d,J=8.8Hz,1H),7.57(dd,J=8.8,2.0Hz,1H ),7.51-7.46(m,2H),7.19-7.14(m,2H),4.58(t,J=7.6Hz,2H),2.98(s,3H),1.78-1.69(m,2H),1.39(h,J=7.4Hz,1H),0.93(t,J=7.2Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ181.22,159.64(d,J=239.9Hz),141.81,139.54,137.85,136.40(d,J=2.7Hz),135.30,131.82,128. 44,127.37,126.97(d,J=8.3Hz),120.82,118.68,115.43(d,J=22.2Hz),113.56,110.80,44.56,33.13,23.56,20.02,14.20. 19 F NMR(376MHz,DMSO-d6)δ-118.07.HRMS(ESI)m / z calcd for C 23 H 24 FN4S + (M+H) + 407.1700, found 407.1705.

[0084] 1-(9-Butyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea (7l): yellow solid, yield 52.1%. mp 148.4-150.7℃. 1 H NMR (400MHz, DMSO-d6) δ9.91 (s, 1H), 9.77 (s, 1H), 8.23-8.19 (m, 2H), 7.99 (d, J = 5.2Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.60-7.51 (m,3H),7.40-7.36(m,2H),4.58(t,J=7.6Hz,2H),2.98(s,3H),1.77-1.693(m,2H),1.44-1.34(m,2H),0.93(t,J=7.6Hz,3H). 13C NMR(100MHz,DMSO-d6)δ180.92,141.81,139.56,139.14,137.84,135.30,131.76,128.82,128.69,128.44, 127.30,126.02,125.81,120.81,118.62,113.56,110.82,44.56,33.13,23.54,20.02,14.20.HRMS(ESI)m / z calcd for C 23 H 24 C1N4S + (M+H) + 423.1405, found 423.1409.

[0085] 1-(9-Butyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (7m): off-white solid, yield 68.9%. mp 181.0-182.1℃. 1 H NMR (400MHz, DMSO-d6) δ10.12 (s, 1H), 10.07 (s, 1H), 8.25 (d, J = 2.0Hz, 1H), 8.22(d,J=5.2Hz,1H),7.99(d,J=5.2Hz,1H),7.81(d,J=8.4Hz,2H),7.71(d, J=8.8Hz,2H),7.68(s,1H),7.60(dd,J=8.8,2.0Hz,1H),4.58(t,J=7.6Hz,2H ), 2.98 (s, 3H), 1.77-1.70 (m, 1H), 1.44-1.35 (m, 1H), 0.93 (t, J = 7.2Hz, 3H). 13 CNMR(100MHz,DMSO-d6)δ180.81,144.07,141.84,139.54,137.96,135.31,131.62,128.35,127.12,126.23(q,J=269.8Hz) ,125.95(q,J=3.7Hz),124.28(q,J=31.7Hz),123.51,120.83,118.53,113.51,110.84,44.56,33.12,23.60,20.02,14.19. 19 F NMR(376MHz,DMSO-d6)δ-60.35.HRMS(ESI)m / z calcd for C 24 H 24 F3N4S + (M+H) +457.1668, found 457.1660.

[0086] 1-(9-Butyl-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)thiourea (7n): off-white solid, yield 54.2%. mp 172.0-173.8℃. 1 H NMR (400MHz, DMSO-d6) δ9.72(s,1H),9.62(s,1H),8.23-8.18(m,2H),7.97(d,J=5.2Hz,1H),7.68(d,J=8.8Hz,1H),7.57(dd,J=8.8,2.0Hz,1H),7. 40-7.32(m,2H),7.18-7.10(m,2H),4.58(t,J=7.6Hz,2H),2.97(s,3H),2 .28(s,3H),1.77-1.69(m,2H),1.43-1.34(m,2H),0.93(t,J=7.4Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ180.90,141.83,139.42,137.96,137.42,135.31,134.12,132.01,129.34,128.37, 127.35,124.63,120.78,118.59,113.50,110.67,44.55,33.13,23.64,21.00,20.03,14.21.HRMS(ESI)m / z calcd for C 24 H 27 N4S + (M+H) + 403.1951, found 403.1953.

[0087] 1-(9-Benzyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea (7o): Pale yellow solid, yield 54.5%. mp 197.2-198.4℃. 1H NMR (400MHz, DMSO-d6) δ9.85(s,1H),9.71(s,1H),8.28(d,J=2.0Hz,1H),8.24(d,J=5.2Hz,1H),8.05(d,J=5.2Hz,1H),7.64(d,J=8.8Hz, 1H),7.54(dd,J=8.8,2.1Hz,1H),7.52-7.46(m,2H),7.31-7.20(m,3H),7.20-7.13(m,2H),6.98-6.91(m,2H),5.92(s,2H),2.78(s,3H). 13 C NMR (100MHz, DMSO-d6) δ181.17,159.64(d,J=239.9Hz),142.04,139.88,139.39,138.38,136.40(d,J=2.6Hz),135.71,132.21,12 9.32,128.54,127.68,127.51,126.95(d,J=8.2Hz),125.77,120.93,118.70,115.43(d,J=22.3Hz),113.67,110.80,47.87,23.22. 19 F NMR(376MHz,DMSO-d6)δ-118.06.HRMS(ESI)m / zcalcd for C 26 H 22 FN4S + (M+H) + 441.1543, found 441.1545.

[0088] 1-(9-Benzyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea (7p): pale yellow solid, yield 57.3%. mp 197.8-198.9℃. 1 H NMR (400MHz, DMSO-d6) δ9.93(s,1H),9.81(s,1H),8.28(d,J=2.0Hz,1H),8.24(d,J=5.2Hz,1H),8.05(d,J=5.2Hz,1H),7.6 4(d,J=8.8Hz,1H),7.59-7.50(m,3H),7.43-7.34(m,2H),7.32-7.20(m,3H),6.99-6.92(m,2H),5.92(s,2H),2.79(s,3H). 13C NMR(100MHz,DMSO-d6)δ180.87,142.05,139.90,139.38,139.14,138.36,135.72,132.16,129.33,128.82,12 8.69,128.54,127.69,127.45,126.02,125.78,120.93,118.65,113.68,110.83,47.88,23.20.HRMS(ESI)m / z calcd for C 26 H 22 C1N4S + (M+H) + 457.1248, found 457.1259.

[0089] 1-(9-Benzyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (7q): white solid, yield 68.3%. mp 179.8-181.3℃. 1 H NMR (400MHz, DMSO-d6) δ10.09(d,J=12.4Hz,1H),8.31(d,J=2.0Hz,1H),8.24(d,J=5.2Hz,0H),8.05(d,J=5.2Hz,0H),7.79(d, J=8.4Hz,1H),7.70-7.63(m,2H),7.56(dd,J=8.8,2.1Hz,1H),7.34-7.19(m,3H),6.99-6.92(m,2H),5.93(s,1H),2.79(s,2H). 13 C NMR(100MHz,DMSO-d6)δ180.80,144.07,142.08,139.92,139.37,138.45,135.74,132.05,129.33,128.49,127.69,127.32,126 .24(q,J=269.8Hz),125.97(q,J=3.8Hz),125.78,124.31(q,J=31.9Hz),123.54,120.96,118.59,113.66,110.88,47.89,23.23. 19 F NMR(376MHz,DMSO-d6)δ-60.33.HRMS(ESI)m / z calcd forC 27 H 22 F3N4S + (M+H) + 491.1511, found 491.1519.

[0090] 1-(9-Benzyl-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)thiourea (7r): off-white solid, yield 64.6%. mp 181.1-183.9℃. 1 H NMR (400MHz, DMSO-d6) δ9.74(s,1H),9.66(s,1H),8.28(d,J=2.0Hz,1H),8.24(d,J=5.2Hz,1H),8.04(d,J=5.2Hz,1H),7.62(d,J=8.8Hz,1H),7 .55(dd,J=8.8,2.0Hz,1H),7.40-7.34(m,2H),7.32-7.20(m,3H),7.17- 7.10(m,2H),6.97-6.91(m,2H),5.91(s,2H),2.78(s,3H),2.28(s,3H). 13 C NMR(100MHz,DMSO-d6)δ180.87,142.02,139.81,139.40,138.34,137.41,135.71,134.15,132.44,129.35,129.3 2,128.55,127.68,127.57,125.77,124.63,120.87,118.64,113.65,110.69,47.87,23.21,21.00.HRMS(ESI)m / z calcd for C 27 H 25 N4S + (M+H) + 437.1794, found 437.1804.

[0091] 1-(9-(3-Chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea (7s): gray solid, yield 50.6%. mp 161.9-163.0℃. 1H NMR (400MHz, DMSO-d6) δ9.86(s,1H),9.72(s,1H),8.28(d,J=2.0Hz,1H),8.25(d,J=5.2Hz,1H),8.06(d,J=5.2Hz,1H),7.64(d,J=8.8Hz,1H),7.55(dd, J=8.8,2.0Hz,1H),7.52-7.46(m,2H),7.33-7.30(m,2H),7.21-7.14(m,2H) ,7.08(dd,J=2.0,1.0Hz,1H),6.83-6.81(m,1H),5.94(s,2H),2.78(s,3H). 13 C NMR (100MHz, DMSO-d6) δ181.17,159.65(d,J=240.0Hz),142.06,141.97,139.72,138.59,136.38(d,J=2.7Hz),135.59,133.97,132.39,13 1.33,128.62,127.74,127.63,126.96(d,J=8.2Hz),125.76,124.40,120.98,118.77,115.44(d,J=22.4Hz),113.74,110.72,47.36,23.21. 19 FNMR(376MHz,DMSO-d6)δ-118.04.HRMS(ESI)m / z calcd for C 26 H 21 ClFN4S + (M+H) + 475.1154, found 475.1152.

[0092] 1-(9-(3-Chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea (7t): white solid, yield 80.6%. mp 185.6-186.7℃. 1 H NMR (400MHz, DMSO-d6) δ9.93(s,1H),9.82(s,1H),8.29(d,J=2.0Hz,1H),8.26(d,J=5.2Hz,1H),8.07-8.04(m,1H),7.65(d,J=8.8 Hz,1H),7.58-7.52(m,3H),7.40-7.36(m,2H),7.34-7.29(m,2H),7.11-7.07(m,1H),6.85-6.79(m,1H),5.94(s,2H),2.78(s,3H). 13C NMR (100MHz, DMSO-d6) δ180.88,142.04,141.98,139.73,139.13,138.61,135.59,133.98,132.32,131.33,128.73,128. 70,128.60,127.74,127.56,126.05,125.77,124.40,120.99,118.73,113.73,110.74,47.37,23.22.HRMS(ESI)m / zcalcd for C 26 H 21 Cl2N4S + (M+H) + 491.0859, found 491.0859.

[0093] 1-(9-(3-Chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (7u): white solid, yield 54.7%. mp 171.4-172.9℃. 1 H NMR (400MHz, DMSO-d6) δ10.11(d,J=11.0Hz,2H),8.32(d,J=2.0Hz,1H),8.26(d,J=5.2Hz,1H),8.06(d,J=5.2Hz,1H),7.79(d,J=8.4Hz,2H), 7.70-7.64(m,3H),7.58(dd,J=8.8,2.0Hz,1H),7.33-7.30(m,2H),7.09(dd,J=2.0,1.0Hz,1H),6.85-6.80(m,1H),5.94(s,2H),2.78(s,3H). 13 C NMR(100MHz,DMSO-d6)δ180.79,144.06,142.04,142.01,139.77,138.63,135.61,133.98,132.23,131.34,128.59,127.75,127.45,126 .24(q,J=269.7Hz),125.98(q,J=3.8Hz),125.77,124.40,124.31(q,J=31.7Hz),123.53,121.00,118.66,113.74,110.80,47.38,23.22. 19 F NMR(376MHz,DMSO-d6)δ-60.34.HRMS(ESI)m / z calcd for C 27 H 21 ClF3N4S+ (M+H) + 525.1122, found 525.1123.

[0094] 1-(9-(4-Fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea (7v): off-white solid, yield 60.1%. mp 196.4-197.7℃. 1 H NMR (400MHz, DMSO-d6) δ9.84(s,1H),9.69(s,1H),8.28(d,J=2.0Hz,1H),8.24(d,J=5.2Hz,1H),8.05(d,J=5.2Hz,1H),7.64(d, J=8.8Hz,1H),7.55(dd,J=8.8,2.0Hz,1H),7.51-7.44(m,2H),7.20-7.10(m,4H),7.03-6.93(m,2H),5.90(s,2H),2.79(s,3H). 13 C NMR(100MHz,DMSO-d6)δ181.18,161.91(d,J=212.0Hz),159.50(d,J=210.5Hz) ,141.99,139.75,138.45,136.39(d,J=2.7Hz),135.60,135.50(d,J=2.9Hz),13 2.29,128.61,127.80(d,J=8.2Hz),127.57,126.97(d,J=8.2Hz),120.99,118. 74,116.15(d,J=21.5Hz),115.44(d,J=22.3Hz),113.70,110.78,47.24,23.22. 19 FNMR(376MHz,DMSO-d6)δ-115.57,-118.03.HRMS(ESI)m / z calcd for C 26 H 21 F2N4S + (M+H) + 459.1449, found 459.1458.

[0095] 1-(9-((4-Fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea (7w): brown solid, yield 65.6%. mp 156.5-157.4°C. 1H NMR (400MHz, DMSO-d6) δ9.93(s,1H),9.82(s,1H),8.28(d,J=2.0Hz,1H),8.24(d,J=5.2Hz,1H),8.04(d,J=5.2Hz,1H),7.64(d, J=8.8Hz,1H),7.55(dt,J=8.8,2.0Hz,3H),7.41-7.35(m,2H),7.18-7.08(m,2H),7.04-6.94(m,2H),5.90(s,2H),2.79(s,3H). 13 C NMR (100MHz, DMSO-d6) δ180.88,161.76(d,J=241.4Hz),142.01,139.75,139.14,138.49,135.61,135.49(d,J=3.0Hz),132.23,12 8.69,128.58,127.80(d,J=8.2Hz),127.48,126.01,125.78,120.99,118.67,116.16(d,J=21.5Hz),113.68,110.80,47.24,23.23. 19 F NMR(376MHz,DMSO-d6)δ-115.57.HRMS(ESI)m / z calcd forC 26 H 21 ClFN4S + (M+H) + 475.1154, found 475.1159.

[0096] 1-(9-(4-Fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (7x): white solid, yield 51.9%. mp 198.7-201.2°C. 1 H NMR (400MHz, DMSO-d6) δ10.11(d,J=11.8Hz,1H),8.31(d,J=2.0Hz,1H),8.25(d,J=5.2Hz,1H),8.05(d,J=5.2Hz,1H),7.79(d, J=8.4Hz,1H),7.71-7.64(m,2H),7.57(dd,J=8.8,2.0Hz,1H),7.16-7.10(m,1H),7.02-6.96(m,1H),5.91(s,1H),2.79(s,2H). 13C NMR (100MHz, DMSO-d6) δ 180.79, 161.77 (d, J = 241.4Hz), 144.07, 142.03, 139. 79,138.52,135.63,135.48(d,J=3.0Hz),132.14,128.56,127.81(d,J=8.1Hz) ,127.37,125.97(q,J=3.8Hz),124.89(q,J=269.7Hz),124.30(q,J=31.7Hz), 123.50,121.01,118.61,116.16(d,J=21.6Hz),113.68,110.84,47.25,23.23. 19 F NMR(376MHz,DMSO-d6)δ-60.34,-115.56.HRMS(ESI)m / z calcd for C 27 H 21 F4N4S + (M+H) + 509.1417, found 509.1419.

[0097] Example 3.

[0098] The reaction formula is as follows:

[0099]

[0100]

[0101] The specific steps are as follows:

[0102] 9-Substituted-6-amino-1-methyl-β-carboline (1 mmol) and phenyl isocyanate (1.2 mmol) were weighed into a reaction tube, 10 mL of dichloroethane was added, and the mixture was stirred at room temperature for 6 h. The reaction was monitored by thin layer chromatography. After the reaction was completed, the mixture was filtered to obtain a filter cake, which was purified by column chromatography (gradient elution, the volume ratio of dichloromethane to methanol was 50:1 to 10:1) to obtain β-carboline bridged urea derivatives (compounds 9a-9aa).

[0103] 1-(4-Fluorophenyl)-3-(1-methyl-β-carbolin-6-yl)urea (9a): light brown solid, yield 78.5%. mp 298.8-300.9℃. 1H NMR (400MHz, DMSO-d6) δ11.45(s,1H),8.73(s,1H),8.67(s,1H),8.33(d,J=2.0Hz,1H),8.18 (d,J=5.2Hz,1H),7.88(d,J=5.2Hz,1H),7.56-7.49(m,4H),7.17-7.10(m,2H),2.76(s,3H). 13 C NMR(100MHz,DMSO-d6)δ157.71(d,J=236.4Hz),153.62,142.62,137.63,136.93,136.81(d,J=2.3Hz),135.48 ,132.32,127.20,121.85,121.56,120.32(d,J=7.6Hz),115.72(d,J=22.1Hz),113.05,112.48,111.93,20.86. 19 FNMR(376MHz,DMSO-d6)δ-121.78.HRMS(ESI)m / z calcd for C 19 H 16 FN4O + (M+H) + 335.1303, found 335.1307.

[0104] 1-(4-Chlorophenyl)-3-(1-methyl-β-carbolin-6-yl)urea (9b): brown solid, yield 95.6%. mp 298.3-300.7℃. 1 H NMR (400MHz, DMSO-d6) δ11.47(s,1H),8.86(s,1H),8.74(s,1H),8.34(d,J=2.0Hz,1H),8.19 (d,J=5.2Hz,1H),7.89(d,J=5.2Hz,1H),7.58-7.50(m,4H),7.37-7.31(m,2H),2.77(s,3H). 13 C NMR(100MHz,DMSO-d6)δ153.41,142.60,139.50,137.56,137.01,135.48,132.17,129.07 ,127.24,125.57,121.90,121.56,120.09,113.07,112.51,112.03,20.83.HRMS(ESI)m / z calcd for C 19 H 16 ClN4O + (M+H)+ 351.1007, found 351.1009.

[0105] 1-(1-Methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea (9c): brown solid, yield 88.3%. mp 273.2-274.3℃. 1 H NMR (400MHz, DMSO-d6) δ11.48(s,1H),9.16(s,1H),8.84(s,1H),8.36(d,J=2.0Hz,1H),8.20(d,J=5.2Hz, 1H),7.90(d,J=5.2Hz,1H),7.73(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),7.59-7.52(m,2H),2.77(s,3H). 13 C NMR (100MHz, DMSO-d6) δ153.24,144.25,142.64,137.63,137.12,135.49,131.91,127.22,126.53(q,J=3.6 Hz), 125.09 (q, J = 269.1Hz), 121.99 (q, J = 31.7Hz), 121.96, 121.56, 118.20, 113.08, 112.53, 112.22, 20.84. 19 F NMR(376MHz,DMSO-d6)δ-60.00.HRMS(ESI)m / z calcd forC 20 H 16 F3N4O + (M+H) + 385.1271, found 385.1277.

[0106] 1-(1-Methyl-β-carbolin-6-yl)-3-(p-tolyl)urea (9d): white solid, yield 66.9%. mp318.1-320.4℃. 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),8.61(s,1H),8.55(s,1H),8.31(d,J=2.0Hz,1H),8.17(d,J=5.2Hz,1H ),7.87(d,J=5.2Hz,1H),7.56-7.45(m,2H),7.42-7.34(m,2H),7.13-7.05(m,2H),2.75(s,3H),2.25(s,3H). 13C NMR(100MHz,DMSO-d6)δ153.54,142.60,137.88,137.63,136.82,135.47,132.47,130.85,12 9.64,127.19,121.68,121.57,118.66,113.03,112.46,111.68,20.87,20.81.HRMS(ESI)m / z calcd for C 20 H 19 N4O + (M+H) + 331.1553, found 331.1553.

[0107] 1-(1,9-Dimethyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea (9e): Pale yellow solid, yield 83.7%. mp 334.1-336.3℃. 1 H NMR (400MHz, DMSO-d6) δ8.73(s,1H),8.69(s,1H),8.33(d,J=2.0Hz,1H),8.17(d,J=5.2Hz,1H),7.92(d,J=5.2Hz,1H) ,7.63(d,J=8.8Hz,1H),7.57(dd,J=8.8,2.0Hz,1H),7.54-7.47(m,2H),7.16-7.10(m,2H),4.13(s,3H),3.02(s,3H). 13 CNMR(100MHz,DMSO-d6)δ157.72(d,J=236.5Hz),153.59,142.44,138.31,137.46,136.77(d,J=2.4Hz),136.10,13 2.54,127.88,121.83,120.70,120.35(d,J=7.5Hz),115.72(d,J=22.0Hz),113.30,111.49,110.77,32.53,23.64. 19 F NMR(376MHz,DMSO-d6)δ-121.76.HRMS(ESI)m / z calcd for C 20 H 18 FN4O + (M+H) + 349.1459, found 349.1464.

[0108] 1-(1,9-Dimethyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea (9f): gray solid, yield 67.7%. mp 279.0-281.1℃. 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.86(s,1H),8.35(d,J=2.0Hz,1H),8.18(d,J=5.2Hz,1H),7.94(d,J=5.2Hz,1H), 7.63(d,J=8.8Hz,1H),7.58(dd,J=8.8,2.0Hz,1H),7.56-7.50(m,2H),7.34(d,J=8.8Hz,2H),4.13(s,3H),3.03(s,3H). 13 C NMR(100MHz,DMSO-d6)δ153.40,142.31,139.49,138.44,137.11,136.03,132.48,129.07,1 28.04,125.56,121.93,120.64,120.07,113.39,111.50,110.82,2.54,23.44.HRMS(ESI)m / z calcd for C 20 H 18 ClN4O + (M+H) + 365.1164, found 365.1169.

[0109] 1-(1,9-Dimethyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea (9 g): pale yellow solid, yield 64.2%. mp 317.5-319.1°C. 1 H NMR (400MHz, DMSO-d6) δ9.18(s,1H),8.87(s,1H),8.36(d,J=2.0Hz,1H),8.18(d,J=5.2Hz,1H),7.95(d,J=5 .2Hz,1H),7.71(d,J=8.4Hz,2H),7.67-7.63(m,3H),7.59(dd,J=8.8,2.0Hz,1H),4.14(s,3H),3.03(s,3H). 13C NMR (100MHz, DMSO-d6) δ153.21,144.21,142.39,138.54,137.28,136.08,132.16,127.98,126.54(q,J=4.0Hz) ,125.09(q,J=269.3Hz),122.01,122.00(q,J=31.8Hz),120.67,118.21,113.39,111.78,110.86,32.55,23.51. 19 F NMR(376MHz,DMSO-d6)δ-60.00.HRMS(ESI)m / z calcdfor C 21 H 18 F3N4O + (M+H) + 399.1427, found 399.1431.

[0110] 1-(9-Ethyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea (9h): white solid, yield 85.8%. mp 251.6-252.2℃. 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),8.70(s,1H),8.33(d,J=2.0Hz,1H),8.19(d,J=5.2Hz,1H),7.93(d,J=5.2Hz,1H),7.65(d,J=8.8 Hz,1H),7.57(dd,J=8.8,2.0Hz,1H),7.54-7.48(m,2H),7.17-7.09(m,2H),4.63(q,J=7.2Hz,2H),2.98(s,3H),1.34(t,J=7.2Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ157.72(d,J=236.5Hz),153.60,141.77,137.66,137.30,136.78(d,J=2.4Hz),135.11,13 2.67,128.31,121.97,121.13,120.34(d,J=7.7Hz),115.72(d,J=22.0Hz),113.37,111.69,110.79,23.53,16.08. 19 F NMR(376MHz,DMSO-d6)δ-121.77.HRMS(ESI)m / z calcd for C 21 H 20 FN4O + (M+H)+ 363.1616, found 363.1617.

[0111] 1-(9-Ethyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea (9i): pale yellow solid, yield 74.9%. mp 258.8-260.4℃. 1 H NMR (400MHz, DMSO-d6) δ8.86(s,1H),8.75(s,1H),8.34(d,J=2.0Hz,1H),8.20(d,J=5.2Hz,1H),7.94(d,J=5.2Hz,1H),7.66(d,J=8.8 Hz,1H),7.57(dd,J=8.8,2.0Hz,1H),7.56-7.51(m,2H),7.36-7.31(m,2H),4.63(q,J=7.2Hz,2H),2.98(s,3H),1.34(t,J=7.2Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ153.40,141.75,139.44,137.56,137.41,135.10,132.50,129.08,12 8.37,125.61,122.07,121.11,120.13,113.42,111.81,110.83,23.44,16.07.HRMS(ESI)m / z calcd for C 21 H 20 ClN4O + (M+H) + 379.1320, found 379.1323.

[0112] 1-(9-Ethyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea (9j): pale yellow solid, yield 81.9%. mp 244.1-245.5℃. 1 H NMR (400MHz, DMSO-d6) δ9.16(s,1H),8.86(s,1H),8.37(d,J=2.0Hz,1H),8.20(d,J=5.2Hz,1H),7.96(d,J=5.2Hz,1H),7.71 (d,J=8.4Hz,2H),7.69-7.63(m,3H),7.59(dd,J=8.8,2.0Hz,1H),4.64(q,J=7.2Hz,2H),2.98(s,3H),1.34(t,J=7.2Hz,3H). 13C NMR (100MHz, DMSO-d6) δ153.23,144.21,141.77,137.60,137.51,135.11,132.27,128.36,126.54(q,J=3.8Hz) ,125.09(q,J=269.3Hz),122.13,122.01(q,J=31.8Hz),121.12,118.22,113.43,112.00,110.85,23.46,16.07. 19 F NMR(376MHz,DMSO-d6)δ-60.00.HRMS(ESI)m / z calcd for C 22 H 20 F3N4O + (M+H) + 413.1584, found 413.1587.

[0113] 1-(9-Ethyl-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)urea (9k): pale yellow solid, yield 69.3%. mp 235.6-236.6℃. 1 H NMR (400MHz, DMSO-d6) δ8.65(s,1H),8.58(s,1H),8.34(d,J=2.0Hz,1H),8.19(d,J=5.2Hz,1H),7.93(d,J=5.2Hz,1H),7.65(d,J=8.8Hz,1H), 7.56(dd,J=8.8,2.0Hz,1H),7.40-7.37(m,2H),7.10(d,J=8.4Hz,2H),4.63(q,J=7.2Hz,2H),2.98(s,3H),2.25(s,3H),1.34(t,J=7.2Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ153.54,141.74,137.84,137.59,137.25,135.10,132.83,130.91,129.6 4,128.35,121.87,121.13,118.70,113.39,111.48,110.79,23.49,20.81,16.08.HRMS(ESI)m / z calcd for C 22 H 23 N4O + (M+H) + 359.1866, found 359.1868.

[0114] 1-(9-Butyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea (91): yellow solid, yield 83.8%. mp 224.7-226.5℃. 1 H NMR (400MHz, DMSO-d6) δ8.73 (s, 1H), 8.69 (s, 1H), 8.33 (d, J = 2.0Hz, 1H), 8. 19(d,J=5.2Hz,1H),7.94(d,J=5.2Hz,1H),7.66(d,J=8.8Hz,1H),7.56(dd,J =8.8,2.0Hz,1H),7.53-7.47(m,2H),7.16-7.09(m,2H),4.56(t,J=7.6Hz,2H ),2.97(s,3H),1.76-1.68(m,1H),1.41-1.32(m,1H),0.92(t,J=7.6Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ157.72 (d, J = 236.4Hz), 153.59, 141.72, 137.86, 137.47, 136.77 (d, J = 2.4Hz), 135.30, 132.65, 128. 39,122.03,120.93,120.33(d,J=7.7Hz),115.72(d,J=21.9Hz),113.42,111.62,111.08,44.50,33.13,23.52,20.03,14.20. 19 F NMR(376MHz,DMSO-d6)δ-121.77.HRMS(ESI)m / z calcd for C 23 H 24 FN4O + (M+H) + 391.1929, found 391.1931.

[0115] 1-(9-Butyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea (9m): white solid, yield 79.6%. mp 247.6-248.4℃. 1H NMR (400MHz, DMSO-d6) δ9.06(s,1H),8.92(s,1H),8.34(d,J=2.0Hz,1H),8.20(d,J=5.2Hz,1H),7.94(d,J=5.2Hz,1H),7.66(d,J=8.8Hz,1 H),7.58-7.52(m,3H),7.36-7.31(m,2H),4.57(t,J=7.6Hz,2H),2.97(s,3H),1.76-1.68(m,1H),1.41-1.32(m,1H),0.92(t,J=7.6Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ153.44,141.78,139.52,137.84,137.64,135.33,132.52,129.08,128.31,125. 51,121.89,120.95,120.01,113.37,111.57,111.08,44.49,33.13,23.62,20.03,14.20.HRMS(ESI)m / z calcd forC 23 H 24 ClN4O + (M+H) + 407.1633, found 407.1638.

[0116] 1-(9-Butyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea (9n): white solid, yield 70.6%. mp 222.5-223.3℃. 1 H NMR (400MHz, DMSO-d6) δ9.40(s,1H),9.09(s,1H),8.36(d,J=2.0Hz,1H),8.19(d,J=5.2Hz,1H),7.94(d,J=5.2Hz,1H),7.72(d,J=8.4Hz,2H),7 .67-7.62(m,3H),7.58(dd,J=8.8,2.0Hz,1H),4.57(t,J=7.6Hz,2H),2. 97(s,3H),1.76-1.68(m,1H),1.41-1.32(m,1H),0.92(t,J=7.6Hz,3H). 13C NMR (100MHz, DMSO-d6) δ153.30,144.34,141.81,137.92,137.72,135.34,132.32,128.29,126.51(q,J=4.0Hz),125.11(q ,J=269.5Hz),122.04,121.90(q,J=31.8Hz),120.95,118.20,113.37,111.84,111.07,44.49,33.13,23.65,20.03,14.20. 19 F NMR(376MHz,DMSO-d6)δ-59.97.HRMS(ESI)m / zcalcd for C 24 H 24 F3N4O + (M+H) + 441.1897, found 441.1907.

[0117] 1-(9-Butyl-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)urea (9o): yellow solid, yield 77.5%. mp 218.0-219.5℃. 1 H NMR (400MHz, DMSO-d6) δ8.65(s,1H),8.58(s,1H),8.33(d,J=2.0Hz,1H),8.19(d ,J=5.2Hz,1H),7.94(d,J=5.2Hz,1H),7.65(d,J=8.8Hz,1H),7.55(dd,J=8.8,2. 0Hz,1H),7.42-7.34(m,2H),7.09(d,J=8.0Hz,2H),4.56(t,J=7.6Hz,2H),2.97( s,3H),2.25(s,3H),1.75-1.68(m,1H),1.41-1.32(m,1H),0.92(t,J=7.6Hz,3H). 13 CNMR(100MHz,DMSO-d6)δ153.53,141.72,137.85,137.76,137.51,135.30,132.80,130.89,129.64,128.37 ,121.87,120.95,118.68,113.41,111.40,111.05,44.49,33.13,23.55,20.81,20.03,14.20.HRMS(ESI)m / z calcd for C 24 H 27 N4O + (M+H)+ 387.2179, found 387.2185.

[0118] 1-(9-Benzyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea (9p): white solid, yield 89.4%. mp 241.9-243.6℃. 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),8.70(s,1H),8.39(d,J=2.0Hz,1H),8.22(d,J=5.2Hz,1H),8.00(d,J=5.2Hz,1H),7.6 0(d,J=8.8Hz,1H),7.55-7.45(m,3H),7.31-7.20(m,3H),7.18-7.07(m,2H),6.96-6.88(m,2H),5.90(s,2H),2.78(s,3H). 13 C NMR(100MHz,DMSO-d6)δ157.72(d,J=236.4Hz),153.58,141.99,139.53,138.17,138.09,136.75(d,J=2.4Hz),135.71,132.99,12 9.30,128.45,127.62,125.74,122.17,121.07,120.33(d,J=7.6Hz),115.73(d,J=22.1Hz),113.52,111.75,111.08,47.82,23.24. 19 F NMR(376MHz,DMSO-d6)δ-121.75.HRMS(ESI)m / z calcd for C 26 H 22 FN4O + (M+H) + 425.1772, found 425.1785.

[0119] 1-(9-Benzyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea (9q): pale yellow solid, yield 95.2%. mp 245.2-247.5℃. 1H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.76(s,1H),8.41(d,J=2.0Hz,1H),8.22(d,J=5.2Hz,1H),8.01(d,J=5.2Hz,1H),7.61(d, J=8.8Hz,1H),7.53(dq,J=8.8,2.6Hz,3H),7.37-7.31(m,2H),7.31-7.20(m,3H),6.96-6.88(m,2H),5.90(s,2H),2.78(s,3H). 13 C NMR(100MHz,DMSO-d6)δ153.39,141.96,139.50,139.44,138.26,138.01,135.70,132.84,129.30,129.08,12 8.50,127.63,125.74,125.61,122.25,121.06,120.12,113.56,111.86,111.10,47.82,23.18.HRMS(ESI)m / z calcd for C 26 H 22 ClN4O + (M+H) + 441.1476, found 441.1471.

[0120] 1-(9-Benzyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea (9r): white solid, yield 87.2%. mp 211.6-213.2℃. 1 H NMR(400MHz, DMSO-d6)δ9.16(s,1H),8.86(s,1H),8.43(d,J=2.0Hz,1H),8.23(d,J=5.2Hz,1H),8.02(d,J=5.2Hz,1H),7 .71(d,J=8.6Hz,2H),7.68-7.59(m,3H),7.54(dd,J=8.8,2.0Hz,1H),7.33-7.18(m,3H),6.96-6.89(m,2H),2.78(s,3H). 13C NMR(100MHz,DMSO-d6)δ153.22,144.19,142.02,139.49,138.35,138.13,135.73,132.57,129.30,128.45,127.63,126.56(q,J =3.7Hz), 125.08 (q, J = 269.3Hz), 125.73, 122.30, 122.03 (q, J = 31.7Hz), 121.07, 118.23, 113.55, 112.06, 111.14, 47.83, 23.23. 19 F NMR(376MHz,DMSO-d6)δ-59.99.HRMS(ESI)m / z calcd for C 27 H 22 F3N4O + (M+H) + 475.1740, found 475.1747.

[0121] 1-(9-Benzyl-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)urea (9s): white solid, yield 80.0%. mp 229.3-231.7℃. 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.59(s,1H),8.40(d,J=2.0Hz,1H),8.22(d,J=5.2Hz,1H),7.99(d,J=5.2Hz,1H),7.59(d,J=8.8Hz,1H),7 .51(dd,J=8.8,2.0Hz,1H),7.42-7.34(m,2H),7.32-7.18(m,3H),7.13- 7.06(m,2H),6.96-6.88(m,2H),5.89(s,2H),2.78(s,3H),2.25(s,3H). 13 C NMR(100MHz,DMSO-d6)δ153.53,141.98,139.54,138.11,138.08,137.83,135.71,133.15,130.91,129.65,129.2 9,128.45,127.62,125.73,122.03,121.08,118.69,113.51,111.53,111.06,47.81,23.26,20.82.HRMS(ESI)m / z calcd for C 27 H 25 N4O + (M+H) +421.2023, found 421.2031.

[0122] 1-(9-(3-Chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea (9t): gray solid, yield 75.0%. mp 242.4-243.5℃. 1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.72(s,1H),8.41(d,J=2.0Hz,1H),8.24(d,J=5.2Hz,1H),8.01(d,J=5.2Hz,1H),7.61(d,J =8.8Hz,1H),7.56-7.46(m,3H),7.32-7.27(m,2H),7.16-7.10(m,2H),7.05(s,1H),6.82-6.77(m,1H),5.92(s,2H),2.77(s,3H). 13 C NMR(100MHz,DMSO-d6)δ157.73(d,J=236.4Hz),153.58,142.18,141.91,138.30,137.98,136.74(d,J=2.3Hz),135.58,133.94,133.17,13 1.31,128.54,127.68,125.71,124.38,122.25,121.12,120.35(d,J=7.5Hz),115.73(d,J=22.0Hz),113.58,111.79,111.00,47.30,23.23. 19 F NMR(376MHz,DMSO-d6)δ-121.73.HRMS(ESI)m / z calcd for C 26 H 21 ClFN4O + (M+H) + 459.1382, found 459.1389.

[0123] 1-(9-(3-Chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea (9u): light green solid, yield 84.6%. mp 235.3-236.6℃. 1H NMR (400MHz, DMSO-d6) δ8.89(s,1H),8.78(s,1H),8.42(d,J=2.0Hz,1H),8.24(d,J=5.2Hz,1H),8.02(d,J=5.2Hz,1H),7.61(d, J=8.8Hz,1H),7.55(dd,J=8.8,2.0Hz,3H),7.37-7.29(m,4H),7.06-7.05(m,1H),6.83-6.77(m,1H),5.92(s,2H),2.78(s,3H). 13 C NMR(100MHz,DMSO-d6)δ153.38,142.15,141.89,139.42,138.23,138.07,135.57,133.95,133.01,131.30,129.08,12 8.58,127.68,125.72,125.64,124.38,122.32,121.12,120.13,113.61,111.90,111.02,47.31,23.18.HRMS(ESI)m / z calcd forC 26 H 21 Cl2N4O + (M+H) + 475.1086, found 475.1085.

[0124] 1-(9-(3-Chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea (9v): white solid, yield 74.6%. mp 232.6-233.9°C. 1 H NMR (400MHz, DMSO-d6) δ9.17(s,1H),8.87(s,1H),8.44(d,J=2.0Hz,1H),8.25(d,J=5.2Hz,1H),8.04(d,J=5.2Hz,1H),7.71(d,J=8.8Hz, 2H),7.67-7.61(m,3H),7.55(dd,J=8.8,2.0Hz,1H),7.34-7.28(m,2H),7.06-7.05(m,1H),6.82-6.77(m,1H),5.93(s,2H),2.78(s,3H). 13C NMR(100MHz,DMSO-d6)δ153.21,144.17,142.13,141.89,138.22,138.18,135.58,133.95,132.77,131.32,128.62,127.70,126 .56(q,J=3.8Hz),125.08(q,J=269.4Hz),122.04(q,J=31.7Hz),122.44,121.10,118.24,113.67,112.10,111.08,47.32,23.14. 19 F NMR(376MHz,DMSO-d6)δ-59.99.HRMS(ESI)m / z calcd for C 27 H 21 ClF3N4O + (M+H) + 509.1351, found 509.1355.

[0125] 1-(9-(3-chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)urea (9w): brown solid, yield 64.4%. mp 193.1-194.9℃. 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.61(s,1H),8.42(d,J=2.0Hz,1H),8.24(d,J=5.2Hz,1H),8.01(d,J=5.2Hz,1H),7.60(d,J=8.8Hz,1H),7.53 (dd,J=8.8,2.0Hz,1H),7.41-7.36(m,2H),7.33-7.28(m,2H),7.12-7.08 (m,2H),7.06-7.05(m,1H),6.83-6.77(m,1H),5.91(s,2H),2.77(s,3H). 13 C NMR(100MHz,DMSO-d6)δ153.52,142.19,141.89,138.27,137.91,137.81,135.57,133.94,133.33,131.30,130.93,129.6 5,128.56,127.67,125.71,124.38,122.13,121.13,118.71,113.59,111.57,110.98,47.30,23.22,20.81.HRMS(ESI)m / z calcd for C 27 H 24 ClN4O+ (M+H) + 455.1633, found 455.1639.

[0126] 1-(9-(4-Fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea (9x): white solid, yield 52.3%. mp 243.8-245.1°C. 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.73(s,1H),8.40(d,J=2.0Hz,1H),8.22(d,J=5.2Hz,1H),7.99(d,J=5.2Hz,1H) ,7.60(d,J=8.8Hz,1H),7.54-7.48(m,3H),7.12(td,J=8.8,5.6Hz,4H),6.99-6.93(m,2H),5.88(s,2H),2.78(s,3H). 13 C NMR(100MHz,DMSO-d6)δ161.73(d,J=241.3Hz),157.73(d,J=236.4Hz),153.59 ,141.94,138.19,138.02,136.74(d,J=2.2Hz),135.62(d,J=3.3Hz),135.60,13 3.07,128.52,127.76(d,J=8.2Hz),122.20,121.13,120.34(d,J=7.7Hz),116. 12(d,J=21.5Hz),115.73(d,J=22.1Hz),113.53,111.75,111.05,47.18,23.24. 19 F NMR(376MHz,DMSO-d6)δ-115.66,-121.73.HRMS(ESI)m / z calcd for C 26 H 21 F2N4O + (M+H) + 443.1678, found 443.1683.

[0127] 1-(9-((4-Fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea (9y): brown solid, yield 79.9%. mp 228.6-229.4°C. 1H NMR (400MHz, DMSO-d6) δ9.65(s,1H),9.47(s,1H),8.43(d,J=2.0Hz,1H),8.23(d,J=5.2Hz,1H),8.00(d,J=5.2Hz,1H),7.62(d, J=8.8Hz,1H),7.58-7.53(m,3H),7.39-7.31(m,2H),7.17-7.07(m,2H),6.97(dd,J=8.8,5.6Hz,2H),5.88(s,2H),2.79(s,3H). 13 C NMR(100MHz,DMSO-d6)δ161.72(d,J=241.3Hz),153.57,141.91,139.66,138.12,137.99,135.63(d,J=2.8Hz),135.57,133.19,12 9.07,128.57,127.75(d,J=8.2Hz),125.35,121.88,121.12,119.76,116.11(d,J=21.4Hz),113.51,111.28,111.07,47.18,23.21. 19 F NMR(376MHz,DMSO-d6)δ-115.66.HRMS(ESI)m / z calcd forC 26 H 21 ClFN4O + (M+H) + 459.1382, found 459.1389.

[0128] 1-(9-(4-Fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea (9z): white solid, yield 62.8%. mp 209.7-211.2℃. 1 H NMR (400MHz, DMSO-d6) δ9.20(s,1H),8.90(s,1H),8.42(d,J=2.0Hz,1H),8.23(d,J=5.2Hz,1H),8.01(d,J=5.2Hz,1H),7.71(d, J=8.6Hz,2H),7.67-7.60(m,3H),7.54(dd,J=8.8,2.0Hz,1H),7.16-7.08(m,2H),7.00-6.93(m,2H),5.89(s,2H),2.79(s,3H). 13C NMR(100MHz,DMSO-d6)δ161.73(d,J=242.8Hz),153.23,144.19,141.98,138.24,1 38.20,135.61,135.60(d,J=3.3Hz),132.65,129.12,128.52,127.76(d,J=8.2Hz), 126.55(q,J=3.8Hz),126.43,123.73,122.50,122.31,122.18,121.86,121.54,121 .13,121.04,118.22,116.13(d,J=21.5Hz),113.56,112.04,111.11,47.19,23.24. 19 F NMR(376MHz,DMSO-d6)δ-59.99,-115.67.HRMS(ESI)m / z calcdfor C 27 H 21 F4N4O + (M+H) + 493.1646, found 493.1653.

[0129] 1-(9-((4-Fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)urea (9aa): brown solid, yield 68.8%. mp 194.9-196.1°C. 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.62(s,1H),8.40(d,J=2.0Hz,1H),8.22(d,J=5.2Hz,1H),8.00(d,J=5.2Hz,1H),7.60(d,J=8.8 Hz,1H),7.52(dd,J=8.8,2.0Hz,1H),7.43-7.34(m,2H),7.17-7.05(m,4H),7.00-6.92(m,2H),5.88(s,2H),2.78(s,3H),2.25(s,3H). 13C NMR(100MHz,DMSO-d6)δ161.73(d,J=241.4Hz),153.53,141.92,138.16,137.95,137.82,135.63(d,J=3.1Hz),135.59,133.24,130.9 2,129.64,128.54,127.76(d,J=8.1Hz),122.07,121.14,118.69,116.12(d,J=21.5Hz),113.54,111.53,111.04,47.17,23.23,20.81. 19 F NMR(376MHz,DMSO-d6)δ-115.67.HRMS(ESI)m / z calcd for C 27 H 24 FN4O + (M+H) + 439.1929, found 439.1936.

[0130] Example 4.

[0131] The operation steps are the same as those in Example 2. 9 is hydrogen, R 1 is hydrogen, and the differences are shown in Table 1.

[0132] Table 1

[0133]

[0134]

[0135] The product 6-(4-fluorophenyl)thiourea-1-methyl-β-carboline was obtained by NMR determination.

[0136] Example 5.

[0137] The operation steps are the same as those in Example 3. 9 is hydrogen, R 1 is hydrogen, and the differences are shown in Table 1.

[0138] Table 1

[0139] Compound 5 / mmol Phenyl isocyanate / mmol Stirring time / h 1 1 1.1 4 2 1 1.5 6 3 1 2.0 8 4 1 1.8 7

[0140] The product 6-(4-fluorophenyl)urea-1-methyl-β-carboline was obtained by NMR determination.

[0141] Example 6.

[0142] Antitumor activity test

[0143] 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) were used as the subjects to test the inhibitory activity of target compounds 7a-7x and target compounds 9a-9aa on tumor cell lines using the MTT method. Cell lines with good growth status and in logarithmic growth phase were respectively cultured at 1×10 4 The cells were inoculated into a 96-well plate at a concentration of 100 μL / mL and placed in a CO2 incubator at 37°C for 24 h. The old medium was discarded and replaced with fresh medium. The sterilized compound to be tested was added and cultured for 48 h. The medium was discarded and 20 μL of RPMI1640 medium containing 5 mg / mL MTT was added to each well. The culture was continued for 4 h. After the supernatant was removed, 100 μL of DMSO was added to each well. The plate was shaken for about 10 min to dissolve the precipitate. The OD value was then detected with an enzyme-labeled instrument at a wavelength of 490 nm. The IC value of each sample was calculated by plotting. 50 The specific results are shown in Table 1.

[0144] Table 1 Antitumor activity of β-carboline bridged urea derivatives

[0145]

[0146]

[0147]

[0148] As shown in Table 1, among the 51 β-carboline bridged urea derivatives provided by the present invention, 29 compounds have an IC of 50 Value ≤10μmol / L, IC values ​​of 25 compounds against BGC-823 (gastric cancer cells) 50 Value ≤10μmol / L, IC values ​​of 36 compounds against CT-26 (colon cancer cells) 50 Value ≤10μmol / L, IC values ​​of 26 compounds against Bel-7402 (liver cancer cells) 50 Value ≤10μmol / L, IC values ​​of 20 compounds against MCF-7 (breast cancer cells) 50 The value is ≤10 μmol / L. Therefore, the β-carboline bridged urea derivatives of the present invention have good anti-tumor activity against lung cancer, gastric cancer, colon cancer, liver cancer and breast cancer, and have good application prospects in the preparation of anti-tumor drugs.

[0149] The above is only a preferred embodiment of the embodiment of the present invention, and does not impose any form of limitation on the embodiment of the present invention. Any simple modification, equivalent changes and modifications made to the above embodiment based on the technical essence of the embodiment of the present invention are still within the scope of the technical solution of the embodiment of the present invention.

Claims

1. A β-carboline bridged urea derivative, characterized in that: The general chemical structure formula of the β-carboline bridged urea derivative is:

2. The β-carboline bridged urea derivative according to claim 1, characterized in that: The R 9 is one of hydrogen, C1-C6 alkyl, unsubstituted or substituted benzyl; The X is S or O; The R 1 It is one of halogen, C1-C6 alkyl and C1-C6 haloalkyl.

3. The β-carboline bridged urea derivative according to claim 2, characterized in that: The R 9 In the case of a substituted benzyl group, the substituent of the benzene ring is a C1-C6 alkyl group and / or a halogen group.

4. The β-carboline bridged urea derivative according to claim 1, characterized in that: The β-carboline bridged urea derivative is any of the following compounds: 1-(4-Fluorophenyl)-3-(1-methyl-β-carbolin-6-yl)thiourea, 1-(4-chlorophenyl)-3-(1-methyl-β-carbolin-6-yl)thiourea, 1-(1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea, 1-(1-methyl-β-carbolin-6-yl)-3-(p-tolyl)thiourea, 1-(1,9-dimethyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea, 1-(1,9-dimethyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(1,9-dimethyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea, 1-(9-butyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea, 1-(9-butyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(9- 1-(9-butyl-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)thiourea, 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea, 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea, 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)thiourea, 1-(9- (3-Chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea, 1-(9-(3-chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(9-(3-chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea, 1-(9-(4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)thiourea, 1-(9-((4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(9-(4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)thiourea, 1-(4-fluorophenyl)-3-(1-methyl-β-carbolin-6-yl)urea, 1-(4-chlorophenyl)-3-(1-methyl-β-carbolin-6-yl)urea, 1-(1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(1-methyl-β-carbolin-6-yl)-3-(p-tolyl)urea, 1-(1,9-dimethyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea, 1-(1,9-dimethyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea, 1-(1,9-dimethyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-ethyl-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)urea, 1-(9-butyl-1-methyl-β-carbolin-6-yl)- )-3-(4-fluorophenyl)urea, 1-(9-butyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea, 1-(9-butyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-butyl-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)urea, 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea, 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea, 1-(9-benzyl 1-(9-benzyl-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-(3-chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea, 1-(9-(3-chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea, 1-(9-(3-chlorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-(3 1-(9-(4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-fluorophenyl)urea, 1-(9-((4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-chlorophenyl)urea, 1-(9-(4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-((4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(9-((4-fluorobenzyl)-1-methyl-β-carbolin-6-yl)-3-(p-tolyl)urea, 5. The method for preparing the β-carboline bridged urea derivative according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: mixing 9-substituted-6-amino-1-methyl-β-carboline, phenyl isocyanate or phenyl isothiocyanate and dichloromethane, and performing a nucleophilic addition reaction to obtain a β-carboline bridged urea derivative.

6. The preparation method according to claim 5, characterized in that: When X in the β-carboline bridged urea derivative is S, the molar ratio of 9-substituted-6-amino-1-methyl-β-carboline to phenyl isothiocyanate is 1:1.1-2.5; When X in the β-carboline bridged urea derivative is O, the molar ratio of 9-substituted-6-amino-1-methyl-β-carboline to phenyl isocyanate is 1:1.1-2.

7. The preparation method according to claim 6, characterized in that: When X in the β-carboline bridged urea derivative is S, the molar ratio of 9-substituted-6-amino-1-methyl-β-carboline to phenyl isothiocyanate is 1:1.5-2.5; When X in the β-carboline bridged urea derivative is O, the molar ratio of 9-substituted-6-amino-1-methyl-β-carboline to phenyl isocyanate is 1:1.5-2.

8. The preparation method according to claim 5, characterized in that: When X in the β-carboline bridged urea derivative is S, the temperature of the nucleophilic addition reaction is room temperature and the time is 6-10 hours; When X in the β-carboline bridged urea derivative is O, the temperature of the nucleophilic addition reaction is room temperature and the time is 4-8 hours.

9. Use of the β-carboline bridged urea derivative according to any one of claims 1 to 4 or the β-carboline bridged urea derivative obtained by the preparation method according to any one of claims 5 to 8 in the preparation of antitumor drugs.

10. The use according to claim 1, characterized in that: The anti-tumor drug comprises an active component and pharmaceutically acceptable excipients; The active component is the β-carboline bridged urea derivative described in any one of claims 1 to 4 or the β-carboline bridged urea derivative prepared by the preparation method described in any one of claims 5 to 8.

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