C-N bond bridged bis-beta-carboline derivative as well as preparation method and application thereof

Abstract

The invention relates to a C-N bond bridged bis-beta-carboline derivative as well as a preparation method and application thereof. The invention discloses a novel compound, namely a C-N bond bridged bis-beta-carboline derivative, a preparation method of the C-N bond bridged bis-beta-carboline derivative, and application of the C-N bond bridged bis-beta-carboline derivative in preparation of antitumor drugs. The C-N bond bridged bis-beta-carboline 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 belongs to the field of biomedicine technology, and specifically relates to a CN bond bridged bis-β-carboline derivative and a preparation method and application thereof. Background Art

[0002] β-Carboline is a naturally occurring alkaloid that contains a pyridine ring and an indole ring. This type of compound is widely found in nature and has been found to have a variety of biological activities, including nervous system activity, antioxidant, anti-cancer, anti-inflammatory, and neurotransmitter regulation.

[0003] At present, the β-carboline compounds with anti-tumor effects reported in the prior art include β-carboline, dehydrogenated echinopsine and Eudistomin U (as shown below), but the types are not enough.

[0004]

[0005] In view of this, the present invention proposes a new β-carboline derivative, namely a CN bond-bridged bis-β-carboline derivative, which is of great significance for the synthesis and discovery of anti-tumor drugs. Summary of the invention

[0006] The first invention objective of the present invention is to provide a CN bond-bridged bis-β-carboline derivative, which is a β-carboline derivative with a novel structure and has important significance for the synthesis and discovery of anti-tumor drugs.

[0007] In order to achieve the above purpose, the technical solution adopted is:

[0008] A CN bond-bridged bis-β-carboline derivative, whose general chemical structure is:

[0009]

[0010] Furthermore, in the chemical structure formula of the CN bond-bridged bis-β-carboline derivative, R 1 , R 2 , R 2’ It is one of hydrogen, methyl, unsubstituted or substituted benzyl and phenylpropyl.

[0011] Furthermore, the R 1 , R 2 , R 2’ The substituent in the substituted benzyl group is C1-C3 alkyl or halogen.

[0012] The second object of the present invention is to provide a method for preparing the above-mentioned CN bond-bridged bis-β-carboline derivative, which has a simple process and a good yield.

[0013] In order to achieve the above purpose, the technical solution adopted is:

[0014] The preparation method of the above CN bond bridged bis-β-carboline derivative is:

[0015] Compound 4 is mixed with an aldehyde-β-carboline compound, a catalyst, and tetrahydrofuran, and subjected to a condensation reaction to obtain an imine intermediate; the aldehyde-β-carboline compound is 3-aldehyde-β-carboline or 1-aldehyde-β-carboline;

[0016] Methanol and NaBH4 are then added to carry out a reduction reaction to obtain a CN bond-bridged bis-β-carboline derivative.

[0017] Further, the molar ratio of the 1-amino-β-carboline to the aldehyde-β-carboline compound is 1:1.2-1.5;

[0018] The molar ratio of 1-amino-β-carboline to the catalyst is 1:2.5-3;

[0019] The molar ratio of 1-amino-β-carboline to NaBH4 is 1:3-4;

[0020] The catalyst is tetraisopropyl titanate (TIPT).

[0021] Furthermore, the molar ratio of the 1-amino-β-carboline to the aldehyde-β-carboline compound is 1:1.3-1.4; the molar ratio of the 1-amino-β-carboline to NaBH4 is 1:3.5;

[0022] The condensation reaction temperature is 23-27°C and the time is 2-3h;

[0023] The temperature of the reduction reaction is -1 to 3°C and the time is 10-20 minutes.

[0024] Furthermore, the condensation reaction temperature is 24-26°C and the time is 2.5h;

[0025] The reduction reaction is carried out at a temperature of -0.5 to 2°C and for 15 minutes.

[0026] The third invention objective of the present invention is to provide the use of the above-mentioned CN bond bridged bis-β-carboline derivatives in the preparation of anti-tumor drugs.

[0027] Furthermore, the anti-tumor drug comprises an active component and a pharmaceutically acceptable excipient;

[0028] The active component is the CN bond bridged bis-β-carboline derivative or the CN bond bridged bis-β-carboline derivative prepared by the above preparation method.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. The technical solution of the present invention obtains a series of novel structures of two bis-β-carboline derivatives bridged by CN bonds through condensation and reduction reactions, which have good anti-tumor activity against lung cancer, gastric cancer, colon cancer, liver cancer and breast cancer, and have good application prospects and potential in the preparation of anti-tumor drugs.

[0031] 2. The technical solution of the present invention provides a method for preparing a CN bond-bridged bis-β-carboline derivative, which has a simple process, simple operation, low production cost, is green and environmentally friendly, and is suitable for industrial production. DETAILED DESCRIPTION

[0032] In order to further illustrate a CN bond bridged bis-β-carboline derivative and its preparation method and application in the present invention and achieve the intended purpose of the invention, the following is a detailed description of a CN bond bridged bis-β-carboline derivative and its preparation method and application, its specific implementation, structure, characteristics and efficacy proposed in the present invention in combination with preferred embodiments. In the following description, different "embodiments" or "embodiments" do 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.

[0033] The following will further introduce in detail a CN bond bridged bis-β-carboline derivative of the present invention and its preparation method and application in conjunction with specific embodiments:

[0034] Unless otherwise specified, the materials and equipment used in the present invention are all commercially available products in the art.

[0035] The technical solution of the present invention mainly includes the following contents:

[0036] (1) CN bond-bridged bis-β-carboline derivatives

[0037] The present invention provides a CN bond-bridged bis-β-carboline derivative having a structure shown in Formula I:

[0038]

[0039] In the present invention, the R 1 , R 2 / R 2 ' is hydrogen, methyl, unsubstituted or substituted benzyl, or phenylpropyl.

[0040] Preferably, the substituent in the substituted benzyl group is a C1-C3 alkyl group or a halogen.

[0041] Further preferably, the halogen is one or more of fluorine, chlorine, bromine and iodine;

[0042] The C1-C3 alkyl group is preferably a methyl group, an ethyl group, or a propyl group;

[0043] (2) Preparation method of the above CN bond bridged bis-β-carboline derivative

[0044] ① In the present invention, the preparation method of the CN bond bridged bis-β-carboline derivative is: 1-amino-β-carboline (compound 4), aldehyde-β-carboline (3-aldehyde-β-carboline or 1-aldehyde-β-carboline), a catalyst and tetrahydrofuran are mixed to carry out a condensation reaction, and then methanol and NaBH4 are added to carry out a reduction reaction to obtain a CN bond bridged bis-β-carboline derivative. 1 With R in Formula I 1 The same, R 2 With R in Formula I 2 The same, 1-aldehyde β-carboline R 2’ With R in Formula I 2’ same.

[0045]

[0046] Preferably, the molar ratio of compound 4 to 3-formyl-β-carboline or 1-formyl-β-carboline is 1:1.2-1.5, and more preferably 1:1.3-1.4.

[0047] Preferably, the catalyst is tetraisopropyl titanate. Further preferably, the molar ratio of the compound 4 to tetraisopropyl titanate is 1:2.5-3.

[0048] Preferably, the molar ratio of compound 4 to reducing agent NaBH4 is 1:3-4. Further preferably, the molar ratio of compound 4 to reducing agent NaBH4 is 1:3.5.

[0049] Preferably, the temperature of the condensation reaction is 23-27°C and the time is 2-3 hours. Further preferably, the temperature of the first condensation reaction is 24-26°C and the time is 2.5 hours.

[0050] Preferably, the temperature of the reduction reaction is -1 to 3°C, and the time is 10-20 min. Further preferably, the temperature of the original reaction is -0.5 to 2°C, and the time is 15 min. In a specific embodiment of the present invention, the reaction progress is monitored by thin layer chromatography.

[0051] After the reduction reaction is completed, the present invention further comprises post-treatment, which comprises: separating the solid from the liquid reaction solution obtained by the reduction reaction, concentrating the organic phase of the filtrate, and then purifying by column chromatography to obtain a CN bond-bridged bis-β-carboline derivative.

[0052] The present invention has no particular 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.

[0053] Preferably, the eluent used in column chromatography purification is a dichloromethane-methanol mixed solvent for gradient elution, and the volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixed solvent is 30:1 to 20:1 to 10:1.

[0054] ② Preparation method of 1-amino-β-carboline (Compound 4)

[0055] In the present invention, the preparation method of 1-amino-β-carboline (compound 4) comprises the following steps:

[0056] (1) L-tryptophan, an inorganic strong base, formaldehyde and water are mixed, and a first substitution reaction and a first cyclization reaction are sequentially performed to obtain compound 2.

[0057] (2) Compound 2, an oxidant and water are mixed to carry out a first oxidation reaction, and then a sulfuric acid solution is added to carry out a second oxidation reaction to obtain Compound 3.

[0058] (3) Compound 3, NaNH2 and N,N-dimethylaniline are mixed and subjected to an amination reaction to obtain compound 4a.

[0059] (4) Compound 4a, NaH catalyst, R 1 X is mixed with anhydrous N,N-dimethylformamide to undergo a second substitution reaction to obtain compounds 4b-4e; the R 1 X in R 1 With the R 1 Same, X is halogen.

[0060] Wherein, the structural formulas of L-tryptophan and compound 1-4 are as follows:

[0061]

[0062] (3) Application of CN-bridged bis-β-carboline derivatives

[0063] The use of the CN bond bridged bis-β-carboline derivatives described in the above technical solution in the preparation of anti-tumor drugs. The tumor is one or more of lung cancer, gastric cancer, colon cancer, liver cancer and breast cancer.

[0064] Preferably, the anti-tumor drug comprises an active component and a pharmaceutically acceptable excipient, and the active component is the above-mentioned CN bond bridged bis-β-carboline derivative. The present invention has no special limitation on the content of the active component in the anti-tumor drug, 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.

[0065] Example 1.

[0066] The reaction formula is as follows:

[0067]

[0068] The specific steps are as follows:

[0069] Synthesis of compound 2: Weigh L-tryptophan (250mmol) and NaOH (250mmol) into a 1000mL round-bottom flask, then add solvent H2O (500mL), stir and dissolve evenly to obtain an orange-red solution, add 40wt% HCHO solution (19mL, 250mmol, solvent is water), stir at room temperature for 3.5h, and then heat to 100℃ and reflux for 2.5h; TLC monitors the reaction process. After the reaction is complete, cool the reaction solution to room temperature and pour it into ice water (400mL), adjust the pH value to 6 with HCl, and then place it in a refrigerator for 8h, filter it, wash the obtained solid product with water and acetone in turn, and dry it at 100℃ to constant weight to obtain compound 2 (0.246mmol, yield is 98.4%).

[0070] Synthesis of compound 3: Compound 2 (0.1 mol) and water (1000 mL) were fully stirred and heated to 100°C, MnO2 (0.3 mol) was added in 20 batches, and after reacting for 5 minutes, 2.5 mol / L sulfuric acid solution (200 mL) was slowly added dropwise, and reacted at 100°C for 1 hour. 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 3 (0.086 mmol, yield 86%).

[0071] Synthesis of compound 4a: Compound 3 (0.035 mol) and sodium amide (0.14 mol) were added to a round-bottom flask, 100 mL of N, N-dimethylaniline was added, the temperature was raised to 160 ° C, stirred and heated for 24 h, and the reaction was monitored by thin layer chromatography. After the reaction was completed, 5 wt% NaOH solution (50 mL) was added, the pH value was adjusted to 10, 100 mL of n-hexane was added and stirred for 10 min, filtered, and the filter cake was purified by column chromatography (gradient elution, the volume ratio of petroleum ether and ethyl acetate was 10: 1 to 5: 1 to 1: 1) to obtain compound 4a (0.026 mmol, yield 75%).

[0072] Synthesis of compounds 4b-4e: Compound 4a (10 mmol) was placed in a 250 mL eggplant-shaped bottle, and DMF solvent was added to completely dissolve it. A 60 wt% NaH solution (30 mmol, solvent: N,N-dimethylformamide) was slowly added at 0°C, and the reaction solution was heated to 25°C after stirring for 5 min. R 1 X (12mmol), then stirred at 25℃ for 5min; TLC monitored the reaction progress. After the reaction was complete, the reaction solution was poured into ice water to quench the reaction, then extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine for 3 times, the organic phases were combined, and anhydrous ethanol with 1 / 2 volume of the organic phase was added, the pH value was adjusted to 3 with HCl, and the mixture was concentrated under reduced pressure to constant weight, and then acetone was added and placed in a refrigerator, and recrystallized at -6℃ for 12h (the ratio of compound 4 to acetone was 1mol: 2L), and then filtered, the filter cake was dissolved with water, the pH value was adjusted to 9 with NaOH, and the mixture was extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine for 2 times, the organic phase was dried with a desiccant, concentrated under reduced pressure, and dried at 80℃ to constant weight to obtain compounds 4b-4e.

[0073] R 1 Methyl was added to afford compound 4b in 90% yield.

[0074] R 1 The compound 4c was obtained with a yield of 88%.

[0075] R 1 The compound 4d was obtained as p-fluorobenzyl with a yield of 85%.

[0076] R 1 The compound 4e was obtained with a yield of 79%.

[0077] Example 2.

[0078] The reaction formula is as follows:

[0079]

[0080]

[0081] The specific steps are as follows:

[0082] Compounds 4a-4e (0.1 mmol) and 3-formyl-β-carboline compound (0.13 mmol) were weighed into a reaction tube, 3 mL of anhydrous tetrahydrofuran was added, and then tetraisopropyl titanate (0.25 mmol) was added dropwise, and stirred at 25°C for 3 h. The reaction was monitored by thin layer chromatography. After the reaction was completed, 3 mL of methanol was added and the reaction tube was placed in an ice water bath and cooled to 0°C, and then NaBH4 (0.35 mmol) was added and reacted for 15 min, and then 0.5 mL of water was added and stirred for 15 min, and then the reaction solution was filtered, the organic phase of the filtrate was concentrated, and column chromatography was purified (gradient elution, the volume ratio of dichloromethane and methanol was 30:1 to 20:1 to 10:1) to obtain CN bond bridged bis-β-carboline derivatives (compounds Ⅰa-Ⅰy).

[0083] N-[(β-carboline-3-yl)methyl]-β-carboline-1-amine (Ia): white solid, yield 80.4%. mp 197.9-199.5℃. 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),11.33(s,1H),8.91(s,1H),8.20(d,J=7.6Hz,1H),8.19(s,1H)8.08(d,J=7.6Hz,1H),7.81(d,J=5.6Hz,1H),7 .60(t,J=8.0Hz,2H),7.55-7.50(m,1H),7.48-7.43(m,1H),7.33(d,J=5. 6Hz,1H),7.22-7.17(m,2H),7.02(t,J=5.6Hz,1H),5.02(d,J=5.2Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ148.33,146.44,141.47,139.38,136.75,135.60,133.52,128.85,128.57,126.99,12 6.34,123.67,122.24,121.57,121.05,119.62,119.45,112.77,112.44,112.41,105.10,46.89.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 364.1557, found 364.1561.

[0084] N-[(β-carboline-3-yl)methyl]-9-methyl-β-carboline-1-amine (Ib): white solid, yield 72.7%. mp 290.2-291.6℃. mp 204.1-205.6℃. 1 H NMR (400MHz, DMSO-d6) δ11.56(s,1H),8.90(s,1H),8.19(d,J=8.0Hz,1H),8.18(s,1H),8.11(d,J=8.0Hz,1H),7.79(d,J=5.6Hz,1H),7.70 (d,J=8.4Hz,1H),7.60-7.49(m,3H),7.41(d,J=5.6Hz,1H),7.26-7.15(m,2H),7.08(t,J=5.2Hz,1H),4.99(d,J=5.2Hz,2H),4.32(s,3H). 13 C NMR(100MHz,DMSO-d6)δ148.48,147.02,141.61,141.55,136.63,135.49,133.10,129.02,128.59,127.75,127.4 6,125.27,122.30,121.47,121.02,119.60,119.52,112.38,112.06,110.76,105.96,47.00,32.75.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 378.1713, found 378.1716.

[0085] N-[(β-carboline-3-yl)methyl]-9-benzyl-β-carboline-1-amine (Ic): white solid, yield 69.3%. mp 220.8-221.1℃. 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),8.79(s,1H),8.17(d,J=8.0Hz,1H),7.95(d,J=7.6Hz,1H),7.84(d,J=5.2z Hz,1H),7.76(d,J=7.6Hz,2H),7.57-7.48(m,3H),7.46(d,J=5.6Hz,1H),7.27-7.16( m,5H),7.11-7.05(m,2H),6.75(t,J=5.2Hz,1H),6.05(s,2H),4.90(d,J=5.2Hz,2H). 13C NMR(100MHz,DMSO-d6)δ148.23,146.60,141.67,141.43,139.04,137.35,135.43,133.09,129.04,128.75,128.65,128.50,127.73,12 7.71,126.62,124.58,122.02,121.99,121.62,120.90,120.12,119.45,112.38,111.53,111.27,106.00,47.98,46.86.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 454.2026, found 454.2027.

[0086] N-[(β-carboline-3-yl)methyl]-9-(4-fluorobenzyl)-β-carboline-1-amine (Id): white solid, yield 75.8%. mp 193.4-194.8℃. 1 H NMR (400MHz, DMSO-d6) δ11.49(s,1H),8.79(s,1H),8.17(d,J=8.0Hz,1H),7. 95(d,J=8.0Hz,1H),7.84(d,J=5.2Hz,1H),7.78(d,J=7.2Hz,2H),7.59-7.50 (m,3H),7.46(d,J=5.2Hz,1H),7.26(t,J=7.6Hz,1H),7.17(t,J=7.6Hz,1H), 7.14-7.05(m,4H),6.78(t,J=5.6Hz,1H),6.04(s,2H),4.92(d,J=5.2Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ163.02 (d, J = 241.0Hz), 148.28, 146.58, 141.59, 141. 44,137.45,135.43,135.21(d,J=3.0Hz),133.10,128.78,128.75,128.70(d, J=8.0Hz),128.52,127.79,124.43,122.04,121.93,121.66,120.90,120.20, 119.46, 115.96 (d, J = 21.0Hz), 112.38, 111.54, 111.24, 106.01, 47.25, 46.81. 19F NMR(376MHz,DMSO-d6)δ-115.36.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 472.1932, found 472.1938.

[0087] N-[(9-methyl-β-carbolin-3-yl)methyl]-9-(3-phenylpropyl)-β-carbolin-1-amine (Ie): white solid, yield 81.4%. mp 205.2-206.4℃. 1 H NMR (400MHz, DMSO-d6) δ11.53(s,1H),8.87(s,1H),8.13(d,J=8.8Hz,2H),8.00(d,J=7.6 Hz,1H),7.85(d,J=5.6Hz,1H),7.64(d,J=8.4Hz,1H),7.58(d,J=8.4Hz,1H),7.55-7.48( m,2H),7.44(d,J=5.6Hz,1H),7.22(t,J=7.6Hz,1H),7.20-7.07(m,6H),6.88(t,J=5.2Hz ,1H),5.00(d,J=4.8Hz,2H),4.79(t,J=7.6Hz,2H),2.75-2.66(m,2H),2.25-2.07(m,2H). 13 C NMR(100MHz,DMSO-d6)δ148.16,146.55,141.69,141.52,141.20,137.05 ,135.59,133.18,128.96,128.78,128.60,128.50,128.33,127.48,126. 31,124.35,122.07,121.72,121.56,120.93,119.74,119.56,112.38,11 2.05,110.79,105.95,49.08,46.94,44.77,33.43,32.75.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 482.2339, found 482.2346.

[0088] N-[(9-methyl-β-carbolin-3-yl)methyl]-β-carbolin-1-amine (IF): white solid, yield 74.5%. mp 206.1-207.5℃.1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),9.02(s,1H),8.28-8.17(m,2H),8.08(d,J=8.0Hz,1H),7.82(d,J=5.6Hz,1H),7.69-7.55(m ,3H),7.46(t,J=7.6Hz,1H),7.33(d,J=5.2Hz,1H),7.27-7.14(m,2H),7.06(t,J=5.6Hz,1H),5.04(d,J=5.6Hz,2H),3.97(s,3H). 13 C NMR(100MHz,DMSO-d6)δ148.67,146.39,142.22,139.40,136.63,136.31,132.09,128.72,128.44,127.03,126.39,12 3.67,122.31,122.23,121.59,120.68,119.76,119.48,112.61,112.44,110.41,105.16,46.86,29.78.HRMS(ESI)m / z calcd forC 30 H 26 N5 + (M+H) + 378.1713, found 378.1716.

[0089] N-[(9-methyl-β-carbolin-3-yl)methyl]-9-methyl-β-carbolin-1-amine (Ig): white solid, yield 77.8%. mp 208.5-209.7℃. 1 H NMR (400MHz, DMSO-d6) δ9.00 (s, 1H), 8.24-8.16 (m, 2H), 8.12-8.08 (m, 1H), 7.79 (d, J = 5.6Hz, 1H), 7.71-7.63 (m, 2H), 7.60-7 .52(m,2H),7.39(d,J=5.2Hz,1H),7.24-7.19(m,2H),7.05(t,J=5.6Hz,1H),5.00(d,J=5.2Hz,2H),4.32(s,3H),3.96(s,3H). 13C NMR(100MHz,DMSO-d6)δ149.04,147.06,142.23,141.56,136.89,136.24,131.79,128.66,128.49,127.71,127.40,125.31, 122.34,121.49,121.43,120.68,119.60,119.55,111.85,110.72,110.34,105.92,47.03,32.72,29.76.HRMS(ESI)m / zcalcd for C 30 H 26 N5 + (M+H) + 392.1870, found 392.1875.

[0090] N-[(9-methyl-β-carbolin-3-yl)methyl]-9-benzyl-β-carbolin-1-amine (Ih): white solid, yield 72.7%. mp 248.9-250.6℃. 1 H NMR (400MHz, DMSO-d6) δ8.93(d,J=1.0Hz,1H),8.16(d,J=8.0Hz,1H),7.98(d,J=8 .0Hz,1H),7.83(d,J=5.4Hz,1H),7.80-7.75(m,2H),7.65(d,J=8.0Hz,1H),7.61-7 .56(m,1H),7.55-7.50(m,1H),7.46(d,J=5.6Hz,1H),7.29-7.18(m,5H),7.12-7. 05(m,2H),6.77(t,J=5.2Hz,1H),6.05(s,2H),4.92(d,J=5.2Hz,2H),3.96(s,3H). 13 C NMR(100MHz,DMSO-d6)δ148.66,146.55,142.19,141.68,139.03,137.32,136.16,131.66,129.07,128.68,128.34,127.73,126.6 5,124.55,122.10,121.98,121.62,120.53,120.13,119.61,111.41,111.29,110.40,106.01,47.98,46.87,29.78.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) +468.2183, found 468.2189.

[0091] N-[(9-methyl-β-carbolin-3-yl)methyl]-9-(4-fluorobenzyl)-β-carbolin-1-amine (Ii): white solid, yield 69.3%. mp 232.8-233.8℃. 1 H NMR (400MHz, DMSO-d6) δ8.93(s,1H),8.16(d,J=7.6Hz,1H),7.97(m,1H),7.82-7.76(m,2H),7.65(d,J=8.3Hz,1H),7.61-7.51(m,2H) ,7.46(d,J=5.2Hz,1H),7.28-7.19(m,2H),7.14-7.05(m,4H),6.79(t,J=5.2Hz,1H),6.04(s,2H),4.93(d,J=5.2Hz,2H),3.96(s,3H). 13 C NMR(100MHz,DMSO-d6)δ163.03(d,J=244.0Hz),148.71,146.53,142.19,141.5 9,137.44,136.17,135.19(d,J=3.0Hz),131.69,128.80,128.74(d,J=8.2Hz),1 28.69,128.33,127.80,124.40,122.03,122.00,121.65,120.52,120.20,119.5 9,115.98(d,J=22.4Hz),111.42,111.25,110.39,106.01,47.25,46.82,29.77. 19 F NMR(376MHz,DMSO-d6)δ-115.35.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 486.2089, found 468.2092.

[0092] N-[(9-methyl-β-carbolin-3-yl)methyl]-9-(3-phenylpropyl)-β-carbolin-1-amine (Ij): white solid, yield 83.9%. mp 207.6-208.9℃. 1H NMR (400MHz, DMSO-d6) δ8.93(s,1H),8.16(d,J=7.6Hz,1H),7.97(d,J=8.0Hz,1H),7.82-7.76(m,2H),7.65(d,J=8.4Hz,1H),7.61-7.51(m ,2H),7.46(d,J=5.2Hz,1H),7.28-7.19(m,2H),7.14-7.05(m,4H),6.79(t,J=5.2Hz,1H),6.04(s,2H),4.93(d,J=5.2Hz,2H),3.96(s,3H). 13 C NMR(100MHz,DMSO-d6)δ148.62,146.51,142.27,141.69,141.24,136.99,136.28,131.71,128.77,128.53,128.50,128.38,127.50,126.30, 124.35,122.13,121.72,121.57,120.55,119.75,119.69,111.88,110 .82,110.40,105.96,46.89,44.75,33.30,32.73,29.78.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 496.2496, found 496.2501.

[0093] N-[(9-Benzyl-β-carboline-3-yl)methyl-β-carboline-1-amine (Ik): white solid, yield 65.1%. mp 191.1-193.2℃. 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),9.05(s,1H),8.27-8.24(m,2H),8.08(d,J=7.6Hz,1H),7.80(d,J=5.6Hz,1H),7.74(d,J=8.4Hz,1H), 7.61-7.55(m,2H),7.47-7.43(m,1H),7.32(d,J=5.6Hz,1H),7.31-7.14(m,8H),6.98(t,J=5.6Hz,1H),5.78(s,2H),5.00(d,J=5.6Hz,2H). 13C NMR(100MHz,DMSO-d6)δ149.01,146.38,141.77,139.36,137.96,136.74,135.86,132.49,129.15,128.93,128.83,127.92,127.29,12 7.00,126.35,123.64,122.50,122.22,121.58,120.97,120.11,119.46,112.85,112.43,110.88,105.16,46.88,46.39.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 454.2026, found 454.2031.

[0094] N-[(9-Benzyl-β-carbolin-3-yl)methyl]-9-methyl-β-carbolin-1-amine (I1): white solid, yield 71.3%. mp 226.1-227.2℃. 1 H NMR (400MHz, DMSO-d6) δ9.03(s,1H),8.25-8.20(m,2H),8.13-8.09(m,1H),7.79(d,J=5.6Hz,1H),7.72(d,J=8.4Hz,1H),7.69(d,J=8.4Hz ,1H),7.58-7.52(m,2H),7.40(d,J=5.6Hz,1H),7.29-7.18(m,7H),7.04(t,J=5.6Hz,1H),5.76(s,2H),4.99(d,J=5.2Hz,2H),4.31(s,3H). 13 C NMR(100MHz,DMSO-d6)δ149.48,147.06,141.78,141.57,138.00,136.88,135.78,132.13,129.14,128.89,128.87,127.91,127.72,127.4 1,127.29,125.31,122.52,121.49,121.45,120.98,119.96,119.55,112.00,110.80,110.73,105.95,47.01,46.39,32.74.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) +468.2183, found 468.2183.

[0095] N-[(9-Benzyl-β-carboline-3-yl)methyl]-9-benzyl-β-carboline-1-amine (Im): white solid, yield 79.9%. mp 251.4-253.1℃. 1 H NMR (400MHz, DMSO-d6) δ8.93(s,1H),8.16(d,J=7.6Hz,1H),8.00(d,J=8.0Hz,1 H),7.83(d,J=5.6Hz,1H),7.81(s,1H),7.76(d,J=8.4Hz,1H),7.72(d,J=8.4Hz ,1H),7.58-7.50(m,2H),7.46(d,J=5.6Hz,1H),7.31-7.15(m,10H),7.09-7.03 (m,2H),6.74(t,J=5.2Hz,1H),6.04(s,2H),5.76(s,2H),4.90(d,J=5.2Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ149.01,146.54,141.75,141.68,139.01,137.99,137 .35,135.68,132.07,129.14,129.03,128.87,128.72,128.67,127.92,127.7 4,127.69,127.29,126.63,124.55,122.25,121.97,121.62,120.81,120.12, 119.95,111.60,111.26,110.83,106.02,47.96,46.82,46.38.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 544.2496, found 544.2503.

[0096] N-[(9-Benzyl-β-carbolin-3-yl)methyl]-9-(4-fluorobenzyl)-β-carbolin-1-amine (In): white solid, yield 73.1%. mp 230.5-231.8℃. 1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.16(d,J=7.6Hz,1H),8.00(d,J=7.6Hz,1H),7 .84(d,J=5.6Hz,1H),7.82(s,1H),7.79(d,J=8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.5 9-7.50(m,2H),7.46(d,J=5.2Hz,1H),7.32-7.19(m,7H),7.16-7.09(m,2H),7.08-7 .01(m,2H),6.80(t,J=5.2Hz,1H),6.03(s,2H),5.76(s,2H),4.92(d,J=5.2Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ163.02 (d, J = 242.0Hz), 149.04, 146.51, 141.75, 141.60, 137. 98,137.40,135.71,135.18(d,J=3.0Hz),132.05,129.13,128.89(d,J=8.0Hz),128.7 4,128.66,127.92,127.81,127.30,124.39,122.16,122.03,121.66,120.81,120.21, 119.95,115.94(d,J=21.0Hz),111.59,111.25,110.85,106.04,47.24,46.78,46.39. 19 F NMR(376MHz,DMSO-d6)δ-115.31.HRMS(ESI)m / z calcd forC 30 H 26 N5 + (M+H) + 562.2402, found 562.2404.

[0097] N-[(9-Benzyl-β-carbolin-3-yl)methyl]-9-(3-phenylpropyl)-β-carbolin-1-amine (Io): white solid, yield 66.6%. mp 187.1-188.6℃. 1H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.18(s,1H),8.13(d,J=7.6Hz,1H),8.04(d,J=8.0H z,1H),7.85(d,J=5.2Hz,1H),7.72(d,J=8.4Hz,1H),7.64(d,J=8.4Hz,1H),7.59-7.49(m ,2H),7.44(d,J=5.6Hz,1H),7.28-7.07(m,12H),6.89(t,J=5.2Hz,1H),5.75(d,J=6.8Hz ,2H),5.01(d,J=5.2Hz,2H),4.78(t,J=6.8Hz,2H),2.72-2.64(m,2H),2.24-2.10(m,2H). 13 C NMR (100MHz, DMSO-d6) δ148.97,146.51,141.83,141.67,141.22,137.90,137. 01,135.86,132.06,129.11,128.94,128.75,128.47,128.37,127.89,127.49, 127.23,126.27,124.35,122.29,121.72,121.57,120.85,120.04,119.74,112 .03,110.83,110.80,105.99,46.89,46.39,44.75,33.33,32.73.HRMS(ESI)m / z calcdfor C 30 H 26 N5 + (M+H) + 572.2809, found 572.2812.

[0098] N-{[9-(4-fluorobenzyl)-β-carbolin-3-yl]methyl}-β-carbolin-1-amine (Ip): white solid, yield 78.4%. mp 170.4-172.7℃. 1H NMR (400MHz, DMSO-d6) δ11.27 (s, 1H), 9.07 (d, J = 1.2Hz, 1H), 8.27-8.23 (m, 2H), 8 .08(d,J=7.6Hz,1H),7.81(d,J=5.6Hz,1H),7.75(d,J=8.4Hz,1H),7.62-7.57(m, 2H),7.48-7.43(m,1H),7.33(d,J=5.6Hz,1H),7.29-7.24(m,3H),7.21-7.17(m,1 H),7.14-7.09(m,2H),6.99(t,J=5.6Hz,1H),5.77(s,2H),5.01(d,J=5.2Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ163.14 (d, J = 241.8Hz), 149.13, 146.38, 141.63, 139. 37,136.75,135.74,134.18(d,J=3.0Hz),132.46,129.43(d,J=8.0Hz),128.9 8,128.88,127.01,126.36,123.64,122.52,122.23,121.58,121.01,120.18, 119.47,116.07(d,J=21.5Hz),112.86,112.43,110.85,105.16,46.87,45.66. 19 F NMR(376MHz,DMSO-d6)δ-115.05.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 472.1932, found 472.1939.

[0099] N-{[9-(4-fluorobenzyl)-β-carbolin-3-yl]methyl}-9-methyl-β-carbolin-1-amine (Iq): white solid, yield 80.9%. mp 203.9-205.4℃. 1H NMR(400MHz,DMSO-d6)δ9.05(d,J=1.0Hz,1H),8.26-8.22(m,1H),8.21(d,J=1 .2Hz,1H),8.13-8.09(m,1H),7.78(d,J=5.6Hz,1zH),7.72(dd,J=17.2,8.4Hz, 2H),7.59-7.52(m,2H),7.40(d,J=5.2Hz,1H),7.29-7.20(m,4H),7.14-7.09( m,2H),7.05(t,J=5.6Hz,1H),5.76(s,2H),4.99(d,J=5.2Hz,2H),4.31(s,3H). 13 CNMR(100MHz,DMSO-d6)δ163.13(d,J=242.0Hz),149.54,147.02,141.66,141.5 8,136.79,135.66,134.21(d,J=3.0Hz),132.10,129.44(d,J=8.0Hz),128.95,1 28.93,127.73,127.43,125.29,122.56,121.47,121.45,121.01,120.03,119.5 7,116.06(d,J=22.0Hz),112.02,110.78,110.74,105.96,46.99,45.65,32.74. 19 F NMR(376MHz,DMSO-d6)δ-115.10.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 486.2089, found 486.2087.

[0100] N-{[9-(4-fluorobenzyl)-β-carbolin-3-yl]methyl}-9-benzyl-β-carbolin-1-amine (Ir): white solid, yield 82.0%. mp 230.1-231.5℃. 1H NMR (400MHz, DMSO-d6) δ8.95(s,1H),8.16(d,J=7.6Hz,1H),8.00(d,J=8.0Hz,1H),7.83(d,J=5.2Hz,1H),7.81(d,J=1.2Hz,1H),7.75(dd,J=10.8, 8.8Hz,2H),7.59-7.50(m,2H),7.46(d,J=5.2Hz,1H),7.29-7.05(m,11H) ,6.75(t,J=5.2Hz,1H),6.04(s,2H),5.75(s,2H),4.91(d,J=5.2Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ163.14(d,J=242.0Hz),149.13,146.54,141.69,141.62,139.0 2,137.34,135.56,134.21(d,J=3.0Hz),132.04,129.43,129.35,129.03,128.91,128.7 7,128.68,127.74(d,J=8.0Hz),126.64,124.55,122.28,121.97,121.62,120.85,120.1 2,120.01,116.05(d,J=21.0Hz),111.60,111.27,110.80,106.03,47.96,46.82,45.64. 19 F NMR(376MHz,DMSO-d6)δ-115.09.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 562.2402, found 562.2408.

[0101] N-{[9-(4-fluorobenzyl)-β-carbolin-3-yl]methyl}-9-(4-fluorobenzyl)-β-carbolin-1-amine (Is): white solid, yield 79.5%. mp 209.4-211.1℃. 1H NMR (400MHz, DMSO-d6) δ8.97(s,1H),8.16(d,J=7.6Hz,1H),7.99(d,J=7.6Hz,1 H),7.83(d,J=5.6Hz,1H),7.80(s,1H),7.79(d,J=8.4Hz,1H),7.74(d,J=3.6Hz ,1H),7.59-7.51(m,2H),7.46(d,J=5.2Hz,1H),7.28-7.20(m,4H),7.14-7.02( m,6H),6.79(t,J=5.2Hz,1H),6.03(s,2H),5.75(s,2H),4.91(d,J=5.2Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ163.14 (d, J = 242.0Hz), 163.02 (d, J = 242.0Hz), 149.18, 146.52, 141.63, 141. 59,137.45,135.59,135.19(d,J=3.0Hz),134.19(d,J=3.0Hz),132.04,129.43(d,J=8.0Hz),128.93,1 28.81,128.78(d,J=9.0Hz),128.76,127.80,124.40,122.18,122.04,121.66,120.85,120.20,120.0 0,116.05(d,J=22.0Hz),115.94(d,J=21.0Hz),111.59,111.25,110.81,106.04,47.24,46.78,45.65. 19 F NMR(376MHz,DMSO-d6)δ-115.07,-115.31.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 580.2307, found 580.2311.

[0102] N-{[9-(4-fluorobenzyl)-β-carbolin-3-yl]methyl}-9-(3-phenylpropyl)-β-carbolin-1-amine (It): white solid, yield 90.7%. mp 168.8-169.7℃. 1H NMR (400MHz, DMSO-d6) δ9.00(s,1H),8.17(s,1H),8.13(d,J=7.6Hz,1H),8.04(d,J=7.6Hz, 1H),7.84(d,J=5.2Hz,1H),7.74(d,J=8.4Hz,1H),7.64(d,J=8.4Hz,1H),7.59-7.49(m,2H) ,7.44(d,J=5.2Hz,1H),7.26-7.18(m,4H),7.16-7.03(m,7H),6.89(t,J=5.2Hz,1H),5.74( s,2H),5.00(d,J=4.8Hz,2H),4.78(t,J=7.6Hz,2H),2.71-2.64(m,2H),2.23-2.08(m,2H). 13 C NMR(100MHz,DMSO-d6)δ163.10(d,J=242.0Hz),149.08,146.51,141.71,141.67,141.2 2,137.02,135.74,134.11(d,J=3.0Hz),132.03,129.35(d,J=9.0Hz),129.00,128.74, 128.47,128.38,127.49,126.26,124.36,122.31,121.72,121.56,120.89,120.10,119 .74,116.02(d,J=21.0Hz),112.05,110.79,106.00,46.89,45.65,44.75,33.34,32.73. 19 F NMR(376MHz,DMSO-d6)δ-115.08.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 590.2715, found 590.2717.

[0103] N-{[9-(3-phenylpropyl)-β-carbolin-3-yl]methyl}-β-carbolin-1-amine (Iu): white solid, yield 74.6%. mp 126.4-127.8℃. 1H NMR (400MHz, DMSO-d6) δ11.31 (s, 1H), 9.02 (s, 1H), 8.26 (t, J = 4.0Hz, 2H), 8.1 1(d,J=8.0Hz,1H),7.85(d,J=4.0Hz,1H),7.68-7.59(m,3H),7.49(t,J=8.0Hz, 1H),7.36(d,J=8.0Hz,1H),7.32-7.19(m,7H),7.04(t,J=4.0Hz,1H),5.06(d, J=8.0Hz,2H),4.56(t,J=8.0Hz,2H),2.69(t,J=8.0Hz,2H),2.20-2.11(m,2H). 13 C NMR (100MHz, DMSO-d6) δ148.73,146.41,141.63,141.57,139.37,136.75,135.71,132.11,128.83,128.75,128.62,128.59,127.00,126. 37,123.66,122.44,122.24,121.58,120.81,119.80,119.46,112.78,112.43,110.51,105.14,46.88,42.77,32.91,30.82.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 482.2339, found 482.2346.

[0104] N-{[9-(3-phenylpropyl)-β-carbolin-3-yl]methyl}-9-methyl-β-carbolin-1-amine (Iv): white solid, yield 59.8%. mp 165.9-167.3℃. 1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.21(d,J=8.0Hz,2H),8.11(d,J=7.6Hz,1H),7 .80(d,J=5.6Hz,1H),7.69(d,J=8.4Hz,1H),7.62(d,J=8.4Hz,1H),7.59-7.52(m,2H ),7.40(d,J=5.2Hz,1H),7.30-7.15(m,7H),7.06(t,J=5.2Hz,1H),5.01(d,J=5.2Hz ,2H),4.51(t,J=7.2Hz,2H),4.32(s,3H),2.66(t,J=7.6Hz,2H),2.19-2.06(m,2H). 13 C NMR(100MHz,DMSO-d6)δ149.06,147.06,141.65,141.57,136.88,135.65,131.79,128.82,128.70,128.66,128.62,127.72,127.40,126.36, 125.31,122.47,121.49,121.44,120.82,119.64,119.55,111.97,110 .72,110.43,105.93,47.02,42.78,32.92,32.73,30.82.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 496.2496, found 496.2499.

[0105] N-{[9-(3-phenylpropyl)-β-carbolin-3-yl]methyl}-9-benzyl-β-carbolin-1-amine (Iw): white solid, yield 76.8%. mp 186.7-188.7℃. 1H NMR (400MHz, CDCl3) δ8.54(s,1H),8.10(dd,J=8.0,4.0Hz,2H),8.04(d,J=5.6Hz,1H ),7.86(s,1H),7.57(t,J=8.0Hz,1H),7.52(t,J=7.6Hz,1H),7.45-7.40(m,2H),7.37 (d,J=8.0Hz,1H),7.35-7.26(m,4H),7.25-7.13(m,8H),6.05(s,1H),5.88(s,2H),4. 94(d,J=4.4Hz,2H),4.39(t,J=7.2Hz,2H),2.75(t,J=7.6Hz,2H),2.31-2.23(m,2H). 13 C NMR (100MHz, CDCl3) δ146.54,141.79,141.61,140.63,137.62,135.70,130. 37,129.49,128.92,128.71,128.62,128.46,128.31,127.64,127.47,126.3 5,126.01,125.06,122.12,122.06,121.37,121.02,119.88,119.55,112.77 ,109.67,109.38,105.98,48.37,47.39,42.81,33.27,30.30.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 572.2809, found 572.2814.

[0106] N-{[9-(3-phenylpropyl)-β-carbolin-3-yl]methyl}-9-(4-fluorobenzyl)-β-carbolin-1-amine (IX): white solid, yield 70.4%. mp 194.5-195.6℃. 1H NMR (400MHz, DMSO-d6) δ8.89(s,1H),8.16(d,J=8.0Hz,1H),7.97(d,J=7.6Hz,1H),7.8 4(d,J=5.2Hz,1H),7.79(t,J=4.4Hz,2H),7.62(d,J=8.4Hz,1H),7.59-7.50(m,2H),7. 46(d,J=5.2Hz,1H),7.30-7.23(m,3H),7.23-7.04(m,8H),6.79(t,J=5.2Hz,1H),6.04 (s,2H),4.93(d,J=5.2Hz,2H),4.52(t,J=7.2Hz,2H),2.66(t,2H),2.19-2.04(m,2H). 13 C NMR(100MHz,DMSO-d6)δ163.01(d,J=241.7Hz),148.74,146.53,141.65,141.59,141.54,1 37.45,135.57,135.21(d,J=3.0Hz),131.69,128.83,128.81,128.75(d,J=8.1Hz),128.71, 128.62,128.48,127.79,126.38,124.40,122.11,122.04,121.66,120.65,120.20,119.63, 115.95(d,J=21.4Hz),111.53,111.25,110.50,106.01,47.24,46.79,42.77,32.92,30.82. 19 F NMR(376MHz,DMSO-d6)δ-115.34.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 590.2715, found 590.2717.

[0107] N-{[9-(3-phenylpropyl)-β-carbolin-3-yl]methyl}-9-(3-phenylpropyl)-β-carbolin-1-amine (Iy): white solid, yield 71.5%. mp 176.5-177.7℃. 1H NMR (400MHz, DMSO-d6) δ8.91(s,1H),8.16(s,1H),8.13(d,J=8.0Hz,1H),8.02(d,J=8.0Hz ,1H),7.85(d,J=5.6Hz,1H),7.64(t,J=8.4Hz,2H),7.57(t,J=7.6Hz,1H),7.52(t,J=7.6H z,1H),7.43(d,J=5.2Hz,1H),7.27-7.05(m,12H),6.89(t,J=5.2Hz,1H),5.01(d,J=4.8Hz ,2H),4.79(t,J=7.6Hz,2H),4.50(t,J=7.2Hz,2H),2.72-2.60(m,4H),2.23-2.03(m,4H). 13 C NMR(100MHz,DMSO-d6)δ148.57,146.52,141.68,141.64,141.60,141.22,137.0 2,135.70,131.69,128.80,128.73,128.71,128.59,128.46,128.35,127.49,126 .36,126.26,124.35,122.26,121.71,121.57,120.68,119.74,112.05,110.81, 110.50,105.97,46.88,44.77,42.78,33.33,32.91,32.73,30.78.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 600.3122, found 600.3130.

[0108] Example 3.

[0109] The reaction formula is as follows:

[0110]

[0111]

[0112] The specific steps are as follows:

[0113] Weigh compound 4a-4e (0.1mmol) and 1-formyl-β-carboline compound (0.13mmol) into a reaction tube, add 3mL of anhydrous tetrahydrofuran, then add tetraisopropyl titanate (0.25mmol) dropwise, stir at 25°C for 3h, and monitor the reaction by thin layer chromatography. After the reaction is completed, add 3mL of methanol and place the reaction tube in an ice water bath to cool to 0°C, then add NaBH4 (0.35mmol) and react for 15min, then add 0.5mL of water and stir for 15min, then filter the reaction solution, concentrate the organic phase of the filtrate, and purify by column chromatography (gradient elution, the volume ratio of dichloromethane and methanol is 30:1 to 20:1 to 10:1) to obtain CN bond bridged bis-β-carboline derivatives (compounds IIa-IIv).

[0114] N-[(β-carboline-1-yl)methyl]-β-carboline-1-amine (IIa): white solid, yield 89.3%. mp 264.2-266.5℃. 1 H NMR (400MHz, DMSO-d6) δ11.91 (s, 1H), 11.51 (s, 1H), 8.36 (d, J = 5.2Hz, 1H), 8. 25(d,J=7.6Hz,1H),8.14-8.02(m,2H),7.90(d,J=5.2Hz,1H),7.66(d,J=8.0Hz ,1H),7.62-7.51(m,2H),7.48-7.42(m,1H),7.38(d,J=5.2Hz,1H),7.25(t,J=4 .0Hz,1H),7.19(t,J=8.0Hz,1H),7.14(t,J=5.2Hz,1H),5.23(d,J=4.8Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ146.48,142.97,141.01,139.51,137.78,136.49,134.23,128.52,128.15,127.07,126.46 ,123.79,122.20,122.16,121.61,121.39,119.84,119.49,114.32,112.62,112.48,105.47,44.04.HRMS(ESI)m / z calcd for C 23 H 18 N5 + (M+H) + 364.1557, found 364.1558.

[0115] N-[(β-carboline-1-yl)methyl]-9-methyl-β-carboline-1-amine (IIb): pale yellow solid, yield 78.5%. mp 275.1-297.2℃. 1 H NMR (400MHz, DMSO-d6) δ11.90(s,1H),8.35(d,J=5.2Hz,1H),8.25(d,J=8.0H z,1H),8.13(d,J=7.6Hz,1H),8.07(d,J=5.2Hz,1H),7.89(d,J=5.6Hz,1H),7 .70(d,J=8.4Hz,1H),7.65(d,J=8.4Hz,1H),7.58-7.52(m,2H),7.46(d,J=5. 2Hz,1H),7.31(s,1H),7.27-7.21(m,2H),5.18(d,J=4.8Hz,2H),4.33(s,3H). 13 C NMR(100MHz,DMSO-d6)δ147.08,142.70,141.48,141.30,137.45,136.75,134.13,128.40,127.96,127.65,127.46,12 5.37,122.19,121.50,121.43,121.40,119.71,119.61,114.14,112.71,110.74,106.17,44.67,32.65.HRMS(ESI)m / z calcd for C 24 H 20 N5 + (M+H) + 378.1713, found 378.1718.

[0116] N-[(β-carboline-1-yl)methyl]-9-benzyl-β-carboline-1-amine (IIc): yellow solid, yield 81.1%. mp 218.9-219.8℃. 1H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.26(d,J=5.2Hz,1H),8.23(d,J=8.4Hz ,1H),8.18(d,J=8.4Hz,1H),8.04(d,J=5.3Hz,1H),7.94(d,J=5.4Hz,1H),7.74 (d,J=8.4Hz,1H),7.61(d,J=8.4Hz,1H),7.58-7.50(m,3H),7.30-7.20(m,4H) ,7.18-7.12(m,3H),6.98(t,J=4.0Hz,1H),6.03(s,2H),5.09(d,J=4.0Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ146.47,141.84,141.58,141.01,138.45,137.33,137.22,133.61,128.98,128.51,128.47,127.90,127.82,12 7.74,126.70,124.57,122.19,121.85,121.67,121.37,120.16,119.85,114.09,112.57,111.15,106.20,48.24,44.15.HRMS(ESI)m / z calcd forC 30 H 24 N5 + (M+H) + 454.2026, found 454.2022.

[0117] N-[(β-carboline-1-yl)methyl]-9-(4-fluorobenzyl)-β-carboline-1-amine (IId): white solid, yield 83.4%. mp 242.6-243.9℃. 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.30-8.21(m,2H),8.18(d,J=7.6Hz,1H),8.04(d,J=5.2Hz,1H),7.94(d,J=5.2Hz,1H),7.76(d,J=8.4Hz,1 H),7.61(d,J=8.4Hz,1H),7.59-7.49(m,3H),7.31-7.17(m,4H),7.06(t, J=8.8Hz,2H),6.97(d,J=4.4Hz,1H),6.01(s,2H),5.11(d,J=4.4Hz,2H). 13C NMR (100MHz, DMSO-d6) δ163.05 (d, J = 241.0Hz), 146.46, 141.94, 141.47, 141. 01,137.34,137.30,134.63(d,J=3.0Hz),133.63,128.85(d,J=8.0Hz),128.6 2,128.47,127.91,127.87,124.47,122.20,121.92,121.70,121.37,120.24, 119.85,115.88(d,J=21.0Hz),114.10,112.55,111.13,106.22,47.53,44.09. 19 F NMR(376MHz,DMSO-d6)δ-115.45.HRMS(ESI)m / z calcd forC 30 H 23 FN5 + (M+H) + 472.1932, found 472.1936.

[0118] N-[(β-carboline-1-yl)methyl]-9-(3-phenylpropyl)-β-carboline-1-amine (IIe): purple-black solid, yield 76.8%. mp 251.8-253.7℃. 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),8.35(d,J=5.2Hz,1H),8.26(d,J=7.6Hz, 1H),8.14(d,J=7.6Hz,1H),8.09(d,J=5.2Hz,1H),7.93(d,J=5.2Hz,1H),7.68- 7.60(m,2H),7.59-7.50(m,2H),7.48(d,J=5.2Hz,1H),7.30-7.09(m,8H),5.22 (d,J=4.0Hz,2H),4.78(t,J=7.6Hz,2H),2.89-2.78(m,2H),2.32-2.13(m,2H). 13C NMR(100MHz,DMSO-d6)δ146.32,142.04,141.70,141.09,141.00,137.41,136.89,133.69,128.78,128.57,128.54,128.10,128.00,127.56,1 26.31,124.33,122.27,121.61,121.59,121.38,119.93,119.78,114. 29,112.60,110.64,106.09,45.04,44.08,33.52,32.67.HRMS(ESI)m / z calcd for C 32 H 28 N5 + (M+H) + 482.2339, found 482.2344.

[0119] N-[(9-methyl-β-carboline-1-yl)methyl]-β-carboline-1-amine (IIf): yellow solid, yield 65.5%. mp 236.1-237.4℃. 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),8.40(d,J=5.2Hz,1H),8.30(d,J=8.0Hz,1H),8.18( d,J=5.2Hz,1H),8.09(d,J=8.0Hz,1H),7.88(d,J=5.6Hz,1H),7.71(d,J=8.4Hz,1H),7.65 -7.60(m,1H),7.55(d,J=8.4,1.0Hz,1H),7.47-7.41(m,1H),7.39(d,J=5.6Hz,1H),7.33- 7.28(m,1H),7.21-7.16(m,1H),7.06(t,J=4.8Hz,1H),5.41(d,J=4.8Hz,2H),4.20(s,3H). 13 C NMR(100MHz,DMSO-d6)δ145.91,142.41,142.25,139.41,137.72,136.67,135.41,129.07,128.83,127.08,126.49,12 3.67,122.15,121.97,121.60,120.76,120.03,119.52,114.69,112.44,110.70,105.54,45.74,32.20.HRMS(ESI)m / z calcd forC 24 H 20 N5+ (M+H) + 378.1713, found 378.1717.

[0120] N-[(9-methyl-β-carboline-1-yl)methyl]-9-methyl-β-carboline-1-amine (II g): white solid, yield 70.4%. mp 291.1-293.2℃. 1 H NMR (400MHz, CDCl3) δ8.42(d,J=5.2Hz,1H),8.14(d,J=8.0Hz,1H),8.05(d,J=8.0Hz,1H),8.02(d,J=5.6Hz,1H),7.93(d,J=5.2Hz,1H),7.67- 7.59(m,2H),7.56-7.45(m,3H),7.38(d,J=5.6Hz,1H),7.33-7.28(m,1 H),7.25-7.19(m,1H),5.49(d,J=3.6Hz,2H),4.38(s,3H),4.29(s,3H). 13 C NMR(100MHz,DMSO-d6)δ153.13,149.99,142.41,141.71,137.97,135.74,134.17,132.27,131.74,131.16,131.04,129.12,128.83,128.7 8,128.39,127.89,127.29,122.32,122.11,121.00,120.95,120.02,118.46,112.03,111.93,110.82,96.14,48.51,46.39.HRMS(ESI)m / z calcd for C 25 H 22 N5 + (M+H) + 392.1870, found 392.1873.

[0121] N-[(9-methyl-β-carboline-1-yl)methyl]-9-benzyl-β-carboline-1-amine (IIh): yellow solid, yield 81.8%. mp 219.3-220.9℃. 1H NMR (400MHz, CDCl3) δ8.16(d,J=5.2Hz,1H),8.11(t,J=7.2Hz,2H),8.06(d,J=5.6Hz,1H),7.86(d,J=5.2Hz,1H),7.63-7.57(m,1H),7.50 (t,J=8.0Hz,1H),7.45-7.39(m,3H),7.31-7.26(m,2H),7.13-7.01(m,5H),6.71(s,1H),5.87(s,2H),5.31(d,J=4.0Hz,2H),4.06(s,3H). 13 C NMR (100MHz, CDCl3) δ146.21,142.04,141.70,140.42,137.55,137.22,137.02,134.73,129.11,128.72,128.58,128.26,127.48,127.38 ,125.82,125.07,122.03,121.31,121.29,121.05,119.80,119.67,113.65,109.68,109.54,105.94,48.38,45.39,32.14.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 468.2183, found 468.2186.

[0122] N-[(9-methyl-β-carboline-1-yl)methyl]-9-(4-fluorobenzyl)-β-carboline-1-amine (IIi): white solid, yield 72.7%. mp 223.7-224.4℃. 1 H NMR (400MHz, DMSO-d6) δ8.29(d,J=7.2Hz,1H),8.27(d,J=5.2Hz,1H),8.20(d,J=7 .6Hz,1H),8.14(d,J=5.2Hz,1H),7.95(d,J=5.2Hz,1H),7.74(d,J=8.4Hz,1H),7.6 9(d,J=8.4Hz,1H),7.66-7.61(m,1H),7.58-7.51(m,2H),7.36-7.22(m,3H),7.08 -7.02(m,2H),6.98-6.92(m,2H),6.00(s,2H),5.37(d,J=4.0Hz,2H),4.10(s,3H). 13C NMR(100MHz,DMSO-d6)δ162.93(d,J=241.3Hz),146.01,142.20,141.57,14 1.31,136.71,136.69,134.72,134.70(d,J=3.1Hz),128.89,128.68,128.4 1(d,J=8.2Hz),128.05,124.40,122.04,121.78,120.65,120.37,120.07,1 15.85,115.64(d,J=21.6Hz),111.10,110.67,106.38,47.45,45.12,32.33. 19 F NMR(376MHz,DMSO-d6)δ-115.42.HRMS(ESI)m / z calcd for C 30 H 26 N5 + (M+H) + 486.2089, found 486.2092.

[0123] N-[(9-methyl-β-carboline-1-yl)methyl]-9-(3-phenylpropyl)-β-carboline-1-amine (IIj): purple-black solid, yield 78.5%. mp 229.9-232.1℃. 1 H NMR(400MHz, CDCl3)δ8.42(d,J=5.2Hz,1H),8.15(d,J=7.6Hz,1H),8.09-8.01 (m,2H),7.94(d,J=5.2Hz,1H),7.66-7.62(m,1H),7.53-7.46(m,2H),7.40(d,J =5.6Hz,1H),7.36-7.28(m,2H),7.27-7.22(m,4H),7.21-7.12(m,3H),5.56(s, 2H),4.81-4.70(m,2H),4.33(s,3H),2.94(t,J=7.6Hz,2H),2.47-2.37(m,2H). 13C NMR (100MHz, CDCl3) δ142.19,140.99,136.87,134.68,129.19,128.49,128.44,128.32,127.12,126.12,124.41,121.84,121.43,121 .25,121.06,119.85,119.46,113.89,109.66,109.53,105.71,77.33,77.02,76.70,45.13,45.03,33.06,32.67.HRMS(ESI)m / zcalcd for C 33 H 30 N5 + (M+H) + 496.2496, found 496.2501.

[0124] N-[(9-Benzyl-β-carboline-1-yl)methyl]-β-carboline-1-amine (IIk): yellow solid, yield 69.9%. mp 230.8-232.5℃. 1 H NMR (400MHz, CDCl3) δ11.50(s,1H),8.02(d,J=8.0Hz,1H),7.98(d,J=5.2Hz,1H),7.93-7.88(m,2H),7.68(t,J=8.0Hz,1H),7.48-7.41(m,2H),7.41- 7.36(m,3H),7.26(s,1H),7.23-7.19(m,1H),7.14(d,J=7.6Hz,2H),6.99( d,J=5.2Hz,1H),6.88-6.83(m,2H),6.25(s,1H),5.77(s,2H),5.14(s,2H). 13 C NMR (100MHz, CDCl3) δ144.92,142.47,140.72,139.86,137.44,136.42,135.88,134.80,130.63,129.46,128.80,127.55,127.44,126 .88,125.56,124.12,122.41,121.98,121.20,120.83,120.30,119.43,114.01,112.05,110.09,106.36,47.76,45.89.HRMS(ESI)m / z calcd for C 30 H 24 N5 + (M+H) +454.2046, found 454.2031.

[0125] N-[(9-Benzyl-β-carboline-1-yl)methyl]-9-methyl-β-carboline-1-amine (II1): white solid, yield 73.6%. mp 244.7-245.6℃. 1 H NMR (400MHz, CDCl3) δ8.39(d,J=5.2Hz,1H),8.14-8.10(m,1H),8.00-7.95(m,1H),7.94(d,J=5.2Hz,1H),7.89(d,J=5.6Hz,1H),7.51-7. 44(m,2H),7.38-7.33(m,2H),7.31-7.24(m,2H),7.18-7.04(m,5H),6.98-6.93(m,2H),5.91(s,2H),5.26(d,J=4.0Hz,2H),4.20(s,3H). 13 C NMR (100MHz, CDCl3) δ141.08,140.39,136.68,136.50,133.46,128.66,127.81,127.65,127.00,126.42,126.02,124.71,12 4.26,120.72,120.45,120.34,120.16,119.21,118.27,112.91,109.29,108.38,104.89,47.55,43.95,31.25.HRMS(ESI)m / z calcd for C 30 H 24 N5 + (M+H) + 468.2183, found 486.2192.

[0126] N-[(9-Benzyl-β-carbolin-1-yl)methyl]-9-(3-phenylpropyl)-β-carbolin-1-amine (IIm): white solid, yield 85.6%. mp 344.2-345.4℃. 1H NMR (400MHz, CDCl3) δ8.45(d,J=5.2Hz,1H),8.20(d,J=8.0Hz,1H),8.03(d,J=7.6H z,1H),8.01-7.95(m,2H),7.57(t,J=7.6Hz,1H),7.49-7.42(m,2H),7.39-7.31(m, 3H),7.30-7.26(m,2H),7.24-7.15(m,8H),7.08(d,J=7.6Hz,2H),5.97(s,2H),5.3 6(d,J=4.0Hz,2H),4.68(t,J=8.0Hz,2H),2.90(t,J=8.0Hz,2H),2.44-2.34(m,2H). 13 C NMR (100MHz, CDCl3) δ146.04,142.05,141.01,140.82,137.70,137.42,136.8 3,134.43,129.56,128.93,128.64,128.46,128.32,128.18,127.58,126.87,1 26.09,125.86,124.61,121.93,121.49,121.44,121.17,120.24,119.23,113. 86,110.32,109.44,105.69,48.78,45.04,44.71,33.08,32.97.HRMS(ESI)m / z calcd for C 39 H 33 N5 + (M+H) + 572.2809, found 572.2816.

[0127] N-{[9-(4-fluorobenzyl)-β-carboline-1-yl]methyl}-β-carboline-1-amine (IIn): purple-black solid, yield 72.5%. mp 259.3-260.6℃. 1H NMR (400MHz, DMSO-d6) δ11.15 (s, 1H), 8.45 (d, J = 5.6Hz, 1H), 8.38-8.34 (m, 1H), 8.26 ( d,J=5.2Hz,1H),8.08(d,J=7.6Hz,1H),7.84(d,J=5.6Hz,1H),7.63-7.57(m,2H),7.53 (d,J=8.0Hz,1H),7.46-7.41(m,1H),7.38(d,J=5.6Hz,1H),7.35-7.31(m,1H),7.20-7 .16(m,1H),7.05-6.98(m,3H),6.96-6.91(m,2H),5.93(s,2H),5.18(d,J=4.8Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ162.86(d,J=241.0Hz),145.63,142.15,142.02,13 9.37,138.34,136.45,134.93(d,J=3.0Hz),129.73,129.19,127.89(d,J=9. 0Hz),127.08,126.55,123.60,122.19,122.09,121.57,121.18,120.63,11 9.49,115.95(d,J=21.0Hz),115.01,112.38,111.04,105.63,47.12,45.59. 19 F NMR(376MHz,DMSO-d6)δ-115.83.HRMS(ESI)m / z calcd for C 30 H 23 FN5 + (M+H) + 472.1932, found 472.1937.

[0128] N-{[9-(4-fluorobenzyl)-β-carbolin-1-yl]methyl}-9-methyl-β-carbolin-1-amine (IIo): yellow solid, yield 75.8%. mp 260.7-261.1℃. 1H NMR (400MHz, CDCl3) δ8.47(d,J=5.2Hz,1H),8.20(d,J=8.0Hz,1H),8.04(d,J=7.6Hz,1H),8.00(d,J=5.2Hz,1H),7.96(d,J=5.6Hz,1H),7.60-7. 51(m,2H),7.46-7.32(m,4H),7.23(d,J=7.6Hz,2H),7.04-6.97(m,2H), 6.89(t,J=8.4Hz,2H),5.93(s,2H),5.32(d,J=4.0Hz,2H),4.29(s,3H). 13 C NMR (100MHz,CDCl3)δ

[0129] 163.33(d,J=244.4Hz),141.97,141.45,137.70,134.37,133.45(d,J=3.2Hz),129.77,128.77,128.11,127.46(d,J=8.0Hz),127. 13,121.73,121.56,121.43,121.22,120.37,119.38,115.89(d,J=21.6Hz),113.98,110.16,109.43,106.02,47.95,44.98,32.29. 19 F NMR(376MHz,CDCl3)δ-115.09.HRMS(ESI)m / z calcd for C 30 H 23 FN5 + (M+H) + 486.2098, found 486.2093.

[0130] N-{[9-(4-fluorobenzyl)-β-carbolin-1-yl]methyl}-9-(4-fluorobenzyl)-β-carbolin-1-amine (IIp): white solid, yield 87.2%. mp 285.7-286.8℃. 1H NMR (400MHz, DMSO-d6) δ8.98(d,J=1.0Hz,1H),8.16(d,J=7.6Hz,1H),7.99(d,J=8.0Hz, 1H),7.84(d,J=5.6Hz,1H),7.82-7.80(m,1H),7.79(d,J=8.4Hz,1H),7.74(d,J=8.3Hz, 1H),7.59-7.51(m,2H),7.46(d,J=5.4Hz,1H),7.29-7.20(m,4H),7.14-7.09(m,4H),7. 07-7.02(m,2H),6.80(t,J=5.2Hz,1H),6.03(s,2H),5.75(s,2H),4.92(d,J=5.2Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ163.14 (d, J = 242.0Hz), 163.01 (d, J = 241.0Hz), 149.19, 146.52, 141.62, 141. 59,137.44,135.59,135.20(d,J=3.0Hz),134.20(d,J=3.0Hz),132.04,129.43(d,J=8.0Hz),128.93,1 28.81,128.77,128.76(d,J=9.0Hz),127.80,124.39,122.17,122.03,121.66,120.85,120.20,120.0 0,116.05(d,J=22.0Hz),115.94(d,J=21.0Hz),111.58,111.25,110.81,106.03,47.24,46.77,45.65. 19 F NMR(376MHz,DMSO-d6)δ-115.08,-115.32.HRMS(ESI)m / zcalcd for C 37 H 28 N5 + (M+H) + 580.2307, found 580.2309.

[0131] N-{[9-(4-fluorobenzyl)-β-carbolin-1-yl]methyl}-9-(3-phenylpropyl)-β-carbolin-1-amine (IIq): yellow solid, yield 92.2%. mp 241.7-243.7℃. 1H NMR (400MHz, CDCl3) δ8.45(d,J=5.2Hz,1H),8.20(d,J=8.0Hz,1H),8.03(d,J=8.0Hz,1H ),7.99(m,2H),7.62-7.53(m,1H),7.48(t,J=7.6Hz,1H),7.42(d,J=8.4Hz,1H),7.39-7 .33(m,2H),7.28(d,J=8.4Hz,1H),7.26-7.11(m,7H),7.06(m,2H),6.92(t,J=8.8Hz,2H ),5.93(s,2H),5.35(s,2H),4.68(m,2H),2.90(t,J=8.0Hz,2H),2.38(p,J=8.0Hz,2H). 13 C NMR (100MHz, CDCl3) δ 163.39 (d, J = 245.0Hz), 141.96, 140.94, 137.52, 134.27, 133.46 (d, J = 3.0Hz), 129.69, 128.77, 128.48, 128.30, 127.57 (d, J=8.0Hz),126.13,121.58,121.45,121.23,120.39,115.97(d,J=21.0H z),113.95,110.17,109.49,105.80,48.08,45.05,44.78,33.06,32.97. 19 F NMR(376MHz,CDCl3)δ-114.91.HRMS(ESI)m / z calcd for C 39 H 33 N5 + (M+H) + 590.2715,found590.2717.

[0132] N-{[9-(3-phenylpropyl)-β-carbolin-1-yl]methyl}-β-carbolin-1-amine (IIr): white solid, yield 87.3%. mp 130.2-131.1℃. 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),8.42(d,J=5.2Hz,1H),8.30(d,J=8.0Hz,1H),8.20(d,J=5.2 Hz,1H),8.11(d,J=8.0Hz,1H),7.94(d,J=5.6Hz,1H),7.64-7.58(m,2H),7.56(d,J=8.0Hz,1H),7. 48-7.42(m,2H),7.32-7.27(m,1H),7.23-7.18(m,1H),7.08(t,J=5.2Hz,1H),7.05-6.99(m,3H),6 .93-6.88(m,2H),5.38(d,J=4.8Hz,2H),4.66-4.54(m,2H),2.49-2.41(m,2H),2.12-2.02(m,2H). 13 C NMR(100MHz,DMSO-d6)δ145.87,141.95,141.55,139.42,137.86,136.67,134.70 ,129.49,128.91,128.58,128.44,127.12,126.68,126.16,123.70,122.21,122. 06,121.63,121.07,120.19,119.55,114.91,112.45,110.82,105.73,45.98,44. 72,40.62,40.41,40.21,40.00,39.79,39.58,39.37,32.59,32.53.HRMS(ESI)m / z calcd for C 32 H 28 N5 + (M+H) + 482.2339, found 482.2343.

[0133] N-{[9-(3-phenylpropyl)-β-carbolin-1-yl]methyl}-9-methyl-β-carbolin-1-amine (IIs): purple-black solid, yield 78.6%. mp 201.2-202.0℃. 1H NMR (400MHz, CDCl3) δ8.43(d,J=5.2Hz,1H),8.13(d,J=7.6Hz,1H),8.09-8.02(m,2H),7.94(d,J=5.2Hz,1H),7.58-7.51(m,2H),7.49 -7.37(m,3H),7.36-7.16(m,8H),5.45(d,J=4.4Hz,2H),4.68(t,J=7.6Hz,2H),4.35(s,3H),2.81(t,J=8.0Hz,2H),2.31-2.21(m,2H). 13 C NMR (100MHz, CDCl3) δ146.62,141.53,141.43,140.87,140.51,137.23,136.89,134.10,129.54,128.47,128.34,128.06,126.99,12 6.10,125.45,121.84,121.46,121.36,121.20,119.84,119.27,113.79,109.90,109.43,105.98,44.98,33.05,32.34.HRMS(ESI)m / z calcd for C 33 H 30 N5 + (M+H) + 496.2496, found 496.2494.

[0134] N-{[9-(3-phenylpropyl)-β-carbolin-1-yl]methyl}-9-benzyl-β-carbolin-1-amine (IIt): yellow solid, yield 67.9%. mp 175.4-176.9℃. 1 H NMR(400MHz, CDCl3) δ8.19(d,J=5.2Hz,1H),8.15-8.11(m,2H),8.09(d,J=5.6Hz,1H),7.8 9(d,J=5.2Hz,1H),7.58-7.50(m,2H),7.48(d,J=5.5Hz,1H),7.43(d,J=8.2Hz,1H),7.34-7 .26(m,3H),7.18(dd,J=8.0,6.4Hz,2H),7.13(d,J=6.9Hz,1H),7.11-7.01(m,6H),6.46(s ,1H),5.86(s,2H),5.29(s,2H),4.46(s,2H),2.71(t,J=7.8Hz,2H),2.13(p,J=8.0Hz,2H). 13C NMR (100MHz, CDCl3) δ141.84,141.50,140.89,137.39,137.06,134.07,129.61,128.78,128.39,128.32,127.55,126.02,125.78,121 .96,121.38,121.30,119.77,113.78,109.88,109.71,106.09,77.33,77.01,76.69,48.41,45.53,44.65,32.95,32.20.HRMS(ESI)m / z calcd for C 39 H 34 N5 + (M+H) + 572.2809, found 572.2817.

[0135] N-{[9-(3-phenylpropyl)-β-carbolin-1-yl]methyl}-9-(4-fluorobenzyl)-β-carbolin-1-amine (IIu): white solid, yield 84.6%. mp 198.1-200.5℃. 1 H NMR(400MHz, CDCl3) δ8.18(d,J=5.2Hz,1H),8.15-8.08(m,3H),7.89(d,J=5.2Hz,1H),7.58 -7.50(m,2H),7.46(d,J=5.2Hz,1H),7.40(d,J=8.4Hz,1H),7.32-7.26(m,3H),7.22-7.17( m,2H),7.15-7.08(m,3H),7.08-7.03(m,2H),6.80(t,J=8.4Hz,2H),6.60(s,1H),5.82(s,2 H),5.29(d,J=4.0Hz,2H),4.52(t,J=7.8Hz,2H),2.74(t,J=8.0Hz,2H),2.20-2.11(m,2H). 13C NMR (100MHz, CDCl3) δ163.33 (d, J = 244.6Hz), 146.11, 141.64, 141.46, 140.82, 140.22, 137 .42,137.01,134.02,133.27(d,J=3.0Hz),129.55,128.79,128.43,128.35,128.30,127.63 (d,J=8.1Hz),127.50,126.08,125.02,122.14,121.43,121.39,121.30,119.96,119.83,1 15.80(d,J=21.5Hz),115.59,113.76,109.82,109.58,106.09,45.22,44.76,33.00,32.22. 19 F NMR(376MHz,CDCl3)δ-114.76.HRMS(ESI)m / z calcd for C 39 H 33 N5 + (M+H) + 590.2715, found 590.2718.

[0136] N-{[9-(3-phenylpropyl)-β-carboline-1-yl]methyl}-9-(3-phenylpropyl)-β-carboline-1-amine (IIv): white solid, yield 85.4%. mp 207.5-210.3℃. 1 H NMR(400MHz, CDCl3) δ8.43(d,J=5.2Hz,1H),8.15(d,J=8.4Hz,1H),8.11-8.00(m,2H),7.9 4(d,J=5.2Hz,1H),7.60-7.55(m,1H),7.54-7.44(m,2H),7.41(d,J=5.6Hz,1H),7.35(d,J= 8.4Hz,1H),7.30(d,J=7.6Hz,2H),7.26-7.14(m,11H),5.48(d,J=3.6Hz,2H),4.83-4.62( m,4H),2.93(t,J=7.6Hz,2H),2.85(t,J=7.6Hz,2H),2.48-2.37(m,2H),2.33-2.22(m,2H). 13C NMR (100MHz, CDCl3) δ146.17,141.55,141.03,140.87,140.84,140.48,137.11,136.98,134 .06,129.51,128.66,128.51,128.47,128.38,128.35,128.33,128.27,126.93,126.15,126 .09,124.67,121.97,121.49,121.41,121.21,119.97,119.89,119.29,113.81,109.93,109 .48,105.78,77.33,77.01,76.70,45.12,45.06,44.81,33.10,33.05,32.39.HRMS(ESI)m / z calcd for C 41 H 38 N5 + (M+H) + 600.3122, found 600.3124.

[0137] Example 4.

[0138] The specific steps are as follows:

[0139] Weigh compound 4a (0.1 mmol, R 1 is hydrogen) and 3-aldehyde-β-carboline compound (0.12 mmol, R 2 is hydrogen) in a reaction tube, 3 mL of anhydrous tetrahydrofuran is added, followed by dropwise addition of tetraisopropyl titanate (0.26 mmol), stirring at 23 ° C for 3 h, and monitoring the reaction by thin layer chromatography. After the reaction is completed, 3 mL of methanol is added and the reaction tube is placed in an ice water bath and cooled to -1 ° C, followed by addition of NaBH4 (0.3 mmol) and reaction for 20 min, followed by addition of 0.5 mL of water and stirring for 15 min, and then the reaction solution is filtered, the organic phase of the filtrate is concentrated, and column chromatography is purified (gradient elution, the volume ratio of dichloromethane and methanol is 30:1 to 20:1 to 10:1) to obtain a CN bond bridged bis-β-carboline derivative.

[0140] The product N-[(β-carboline-3-yl)methyl]-β-carboline-1-amine (Ia) was obtained by NMR analysis.

[0141] Example 5.

[0142] The specific steps are as follows:

[0143] Weigh compound 4a (0.1 mmol, R 1 is hydrogen) and 3-aldehyde-β-carboline compound (0.15 mmol, R2 is hydrogen) in a reaction tube, 3 mL of anhydrous tetrahydrofuran is added, followed by dropwise addition of tetraisopropyl titanate (0.3 mmol), stirring at 26°C for 2.5 h, and monitoring the reaction by thin layer chromatography. After the reaction is completed, 3 mL of methanol is added and the reaction tube is placed in an ice water bath and cooled to 2°C, followed by addition of NaBH4 (0.35 mmol) and reaction for 12 min, followed by addition of 0.5 mL of water and stirring for 15 min, and then the reaction solution is filtered, the organic phase of the filtrate is concentrated, and column chromatography is purified (gradient elution, the volume ratio of dichloromethane and methanol is 30:1 to 20:1 to 10:1) to obtain a CN bond bridged bis-β-carboline derivative.

[0144] The product N-[(β-carboline-3-yl)methyl]-β-carboline-1-amine (Ia) was obtained by NMR analysis.

[0145] Example 6.

[0146] The specific steps are as follows:

[0147] Weigh compound 4a (0.1 mmol, R 1 is hydrogen) and 1-aldehyde-β-carboline compound (0.14 mmol, R 2’ is hydrogen) in a reaction tube, 3 mL of anhydrous tetrahydrofuran is added, followed by dropwise addition of tetraisopropyl titanate (0.28 mmol), stirring at 24 ° C for 3 h, and monitoring the reaction by thin layer chromatography. After the reaction is completed, 3 mL of methanol is added and the reaction tube is placed in an ice water bath and cooled to -0.5 ° C, followed by addition of NaBH4 (0.35 mmol) and reaction for 18 min, followed by addition of 0.5 mL of water and stirring for 15 min, and then the reaction solution is filtered, the organic phase of the filtrate is concentrated, and column chromatography is purified (gradient elution, the volume ratio of dichloromethane and methanol is 30:1 to 20:1 to 10:1) to obtain CN bond bridged bis-β-carboline derivatives (compounds Ⅱa-Ⅱv).

[0148] The product N-[(β-carboline-1-yl)methyl]-β-carboline-1-amine (IIa) was obtained by NMR analysis.

[0149] Example 7.

[0150] The specific steps are as follows:

[0151] Weigh compound 4a (0.1 mmol, R 1 is hydrogen) and 1-aldehyde-β-carboline compound (0.15 mmol, R 2’is hydrogen) in a reaction tube, 4 mL of anhydrous tetrahydrofuran is added, followed by dropwise addition of tetraisopropyl titanate (0.3 mmol), stirring at 27 ° C for 2 h, and monitoring the reaction by thin layer chromatography. After the reaction is completed, 4 mL of methanol is added and the reaction tube is placed in an ice water bath and cooled to 3 ° C, followed by addition of NaBH4 (0.4 mmol) and reaction for 10 min, followed by addition of 0.5 mL of water and stirring for 15 min, and then the reaction solution is filtered, the organic phase of the filtrate is concentrated, and column chromatography is purified (gradient elution, the volume ratio of dichloromethane and methanol is 30:1 to 20:1 to 10:1) to obtain CN bond bridged bis-β-carboline derivatives (compounds Ⅱa-Ⅱv).

[0152] The product N-[(β-carboline-1-yl)methyl]-β-carboline-1-amine (IIa) was obtained by NMR analysis.

[0153] Example 8: Antitumor Activity Test

[0154] 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 the target compounds Ⅰa-Ⅰy and target compounds Ⅱa-Ⅱv on tumor cell lines using the MTT method. Cell lines with good growth status and in the 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.

[0155] Table 1 Antitumor activity of C-N bond bridged bis-β-carboline derivatives (n=47)

[0156]

[0157]

[0158]

[0159] As shown in Table 1, 25 compounds among the bis-β-carboline derivatives provided by the present invention have IC values ​​for lung cancer A549. 50 The IC values ​​of 24 compounds against gastric cancer BGC-823 were ≤10μM. 50The IC values ​​of 25 compounds against colon cancer CT-26 were ≤10μM. 50 The IC values ​​of 20 compounds against liver cancer Bel-7402 were ≤10μM. 50 The IC values ​​of 22 compounds against breast cancer MCF-7 cells were ≤10 μM. 50 The value is ≤10 μM. Therefore, the CN bond bridged bis-β-carboline derivative of the present invention has good anti-tumor activity against lung cancer, gastric cancer, colon cancer, liver cancer and breast cancer, and has good application prospects in the preparation of anti-tumor drugs.

[0160] 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 CN bond-bridged bis-β-carboline derivative, characterized in that: The chemical structure formula of the CN bond-bridged bis-β-carboline derivative is:

2. The CN bond-bridged bis-β-carboline derivative according to claim 1, characterized in that: In the chemical structure general formula of the CN bond-bridged bis-β-carboline derivative, R 1 , R 2 , R 2’ It is one of hydrogen, methyl, and unsubstituted or substituted benzyl.

3. The CN bond-bridged bis-β-carboline derivative according to claim 2, characterized in that: The R 1 , R 2 , R 2’ The substituent in the substituted benzyl group is C1-C3 alkyl or halogen.

4. The CN bond-bridged bis-β-carboline derivative according to claim 1, characterized in that: The CN bond-bridged bis-β-carboline derivative is any of the following compounds: N-[(β-carbolin-3-yl)methyl]-β-carbolin-1-amine, N-[(β-carbolin-3-yl)methyl]-9-methyl-β-carbolin-1-amine, N-[(β-carbolin-3-yl)methyl]-9-benzyl-β-carbolin-1-amine, N-[(β-carbolin-3-yl)methyl]-9-(4-fluorobenzyl)-β-carbolin-1-amine, N-[(9-methyl-β-carbolin-3-yl)methyl]-9-(3-phenylpropyl)-β-carbolin-1-amine, N-[(9-methyl-β-carbolin-3-yl)methyl]-β-carbolin-1-amine, N-[(9-methyl-β-carbolin-3-yl)methyl]-9-methyl-β-carbolin-1-amine, N-[(9-methyl-β-carbolin-3-yl)methyl]-9-methyl-β-carbolin-1-amine, N-[(9-methyl-β-carbolin-3-yl)methyl]-9-methyl-β-carbolin-1-amine, -3-yl)methyl]-9-benzyl-β-carbolin-1-amine, N-[(9-methyl-β-carbolin-3-yl)methyl]-9-(4-fluorobenzyl)-β-carbolin-1-amine, N-[(9-methyl-β-carbolin-3-yl)methyl]-9-(3-phenylpropyl)-β-carbolin-1-amine, N-[(9-benzyl-β-carbolin-3-yl)methyl-β-carbolin-1-amine, N-[(9-benzyl-β-carbolin-3-yl)methyl]-9-methyl-β-carbolin-1-amine, N-[(9-benzyl-β-carbolin-3-yl)methyl]-9-benzyl-β-carbolin-1-amine, N-[(9-benzyl-β-carbolin-3-yl)methyl]-9-(4-fluorobenzyl)-β-carbolin-1 -amine, N-[(9-benzyl-β-carbolin-3-yl)methyl]-9-(3-phenylpropyl)-β-carbolin-1-amine, N-{[9-(4-fluorobenzyl)-β-carbolin-3-yl]methyl}-β-carbolin-1-amine, N-{[9-(4-fluorobenzyl)-β-carbolin-3-yl]methyl}-9-methyl-β-carbolin-1-amine, N-{[9-(4-fluorobenzyl)-β-carbolin-3-yl]methyl}-9-methyl-β-carbolin-1-amine, N-{[9-(4-fluorobenzyl)-β-carbolin-3-yl]methyl}-9-benzyl-β-carbolin-1-amine, N-{[9-(4-fluorobenzyl)-β-carbolin-3-yl]methyl}-9-(4-fluorobenzyl)-β-carbolin-1-amine, N-{[9-(4-fluorobenzyl)-β-carbolin-3-yl]methyl}-9-(3-phenylpropyl)- β-carbolin-1-amine, N-{[9-(3-phenylpropyl)-β-carbolin-3-yl]methyl}-β-carbolin-1-amine, N-{[9-(3-phenylpropyl)-β-carbolin-3-yl]methyl}-9-methyl-β-carbolin-1-amine, N-{[9-(3-phenylpropyl)-β-carbolin-3-yl]methyl}-9-methyl-β-carbolin-1-amine, N-{[9-(3-phenylpropyl)-β-carbolin-3-yl]methyl}-9-benzyl-β-carbolin-1-amine, N-{[9-(3-phenylpropyl)-β-carbolin-3-yl]methyl}-9-(4-fluorobenzyl)-β-carbolin-1-amine, N-{[9-(3-phenylpropyl)-β-carbolin-3-yl]methyl}-9-(3-phenylpropyl)-β-carbolin-1-amine, N-[(β-carbolin-1-yl)methyl]-β-carbolin-1-amine,N-[(β-carbolin-1-yl)methyl]-9-methyl-β-carbolin-1-amine, N-[(β-carbolin-1-yl)methyl]-9-benzyl-β-carbolin-1-amine, N-[(β-carbolin-1-yl)methyl]-9-(4-fluorobenzyl)-β-carbolin-1-amine, N-[(β-carbolin-1-yl)methyl]-9-(3-phenylpropyl)-β-carbolin-1-amine, N-[(9-methyl-β-carbolin-1-yl)methyl]-β-carbolin-1-amine, N-[(9-methyl-β-carbolin-1-yl)methyl]-9-methyl-β-carbolin-1-amine, N-[(9-methyl-β-carbolin-1-yl)methyl]-9-benzyl-β-carbolin-1-amine, N-[(9-methyl-β-carbolin-1-yl)methyl]-9-(4-fluorobenzyl)-β-carbolin-1-amine, N-[(9-methyl-β-carbolin-1-yl)methyl]-9-(3-phenylpropyl)-β-carbolin-1-amine, N-[(9-benzyl-β-carbolin-1-yl)methyl]-β-carbolin-1-amine, N-[(9-benzyl-β-carbolin-1-yl)methyl]-9-methyl-β-carbolin-1-amine, N-[(9-benzyl-β-carbolin-1-yl)methyl]-9-methyl-β-carbolin-1-amine, N-[(9-benzyl-β-carbolin-1-yl)methyl]-9-methyl-β-carbolin-1-amine, β-carbolin-1-amine, N-{[9-(4-fluorobenzyl)-β-carbolin-1-yl]methyl}-9-methyl-β-carbolin-1-amine, N-{[9-(4-fluorobenzyl)-β-carbolin-1-yl]methyl}-9-methyl-β-carbolin-1-amine, N-{[9-(4-fluorobenzyl)-β-carbolin-1-yl]methyl}-9-(4-fluorobenzyl)-β-carbolin-1-amine, N-{[9-(4-fluorobenzyl)-β-carbolin-1-yl]methyl}-9-(3-phenylpropyl)-β-carbolin-1-amine, N-{[9-(4-fluorobenzyl)-β-carbolin-1-yl]methyl}-9-(3-phenylpropyl)-β-carbolin-1-amine, N-{[9-(4-fluorobenzyl)-β-carbolin-1-yl]methyl}-9-methyl-β-carbolin-1-amine 3-phenylpropyl)-β-carbolin-1-yl]methyl}-β-carbolin-1-amine, N-{9-(3-phenylpropyl)-β-carbolin-1-yl]methyl}-9-methyl-β-carbolin-1-amine, N-{[9-(3-phenylpropyl)-β-carbolin-1-yl]methyl}-9-benzyl-β-carbolin-1-amine, N-{[9-(3-phenylpropyl)-β-carbolin-1-yl]methyl}-9-(4-fluorobenzyl)-β-carbolin-1-amine, N-{[9-(3-phenylpropyl)-β-carbolin-1-yl]methyl}-9-(3-phenylpropyl)-β-carbolin-1-amine.

5. The method for preparing the CN bond bridged bis-β-carboline derivative according to any one of claims 1 to 4, characterized in that: The preparation method is: The 1-amino-β-carboline is mixed with an aldehyde-β-carboline compound, a catalyst and tetrahydrofuran, and then subjected to a condensation reaction to obtain an imine intermediate; the aldehyde-β-carboline compound is 3-aldehyde-β-carboline or 1-aldehyde-β-carboline; Methanol and NaBH4 are then added to carry out a reduction reaction to obtain a CN bond-bridged bis-β-carboline derivative.

6. The preparation method according to claim 5, characterized in that: The molar ratio of the 1-amino-β-carboline to the aldehyde-β-carboline compound is 1:1.2-1.5; The molar ratio of 1-amino-β-carboline to catalyst titanium is 1:2.5-3; The molar ratio of 1-amino-β-carboline to NaBH4 is 1:3-4; The catalyst is tetraisopropyl titanate.

7. The preparation method according to claim 6, characterized in that: The molar ratio of the 1-amino-β-carboline to the aldehyde-β-carboline compound is 1:1.3-1.4; The molar ratio of 1-amino-β-carboline to NaBH4 is 1:3.5; The condensation reaction temperature is 23-27°C and the time is 2-3h; The temperature of the reduction reaction is -1 to 3°C and the time is 10-20 minutes.

8. The preparation method according to claim 7, characterized in that: The condensation reaction temperature is 24-26°C and the time is 2.5h; The reduction reaction is carried out at a temperature of -0.5 to 2°C and for 15 minutes.

9. Use of the CN bond-bridged bis-β-carboline derivative according to any one of claims 1 to 4 or the CN bond-bridged bis-β-carboline 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 9, characterized in that: The anti-tumor drug comprises an active component and pharmaceutically acceptable excipients; The active component comprises the CN-bridged bis-β-carboline derivative according to any one of claims 1 to 4 or the CN-bridged bis-β-carboline derivative prepared by the preparation method according to any one of claims 5 to 8.

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