Indeno-aza compound as well as preparation method and medical application thereof

Abstract

The invention relates to the field of organic chemistry and medicinal chemistry, in particular to an indeno-aza compound I as well as a preparation method and medical application thereof. The method comprises the following steps: adding an amine compound into an indeno-oxa-heptacyclic compound serving as a raw material under solvent-free and additive-free conditions, directly adding stoichiometric thionyl chloride and a solvent acetonitrile into an intermediate product obtained after the reaction without separation and pretreatment to continue the reaction, adding alkali again without separation and pretreatment after the reaction is completed, and separating and purifying to obtain the product. And controlling the reaction temperature to finally prepare the indeno-aza compound. The invention reports a compound with a novel structure, and develops a one-pot continuous operation synthesis method of the compound. The synthesis operation of the method conforms to the concept of green chemistry, and the obvious advantages of chemical synthesis means are embodied. Meanwhile, the compound has a certain inhibition effect on human esophageal cancer cells and human bladder cancer cells.

Description

Technical Field

[0001] The present invention relates to the fields of organic synthesis and medicinal chemistry, and in particular to an indene azepine Compounds, preparation methods and medical uses thereof. Background Art

[0002] Benzazine heterocyclic structures containing indone structures have good physiological activity. For example, indone-isoquinolinone derivatives containing six-membered nitrogen heterocyclic rings are non-camptothecin topoisomerase 1 (TOP1) inhibitors with better pharmacological properties and chemical stability than camptothecin derivatives. For example, LMP-400 and LMP-776 can be used as therapeutic drugs for multiple types of tumors. However, there are no reports on compounds containing seven-membered nitrogen heterocyclic rings and aromatic rings and [e] indeno [1,2-b] azepane structures, their synthesis methods, and anti-tumor applications.

[0003] Therefore, novel compounds with an aromatic ring and [e] indeno [1,2-b] azepane structure are of great significance for the development of new anti-tumor drugs, and the synthesis problem of this structure needs to be solved. Summary of the invention

[0004] The invention discloses a novel indenozapine Compounds and preparation methods thereof. The method is green, efficient, simple to operate, has a high yield, and can be completed through a one-pot reaction with continuous operation. Pharmacological experiments have shown that the compounds have certain anti-tumor activity.

[0005] The technical solution of the present invention is: an indenozapine The compound has the following chemical structure:

[0006]

[0007] Among them, R 1 The group represents a substituted or unsubstituted aryl, cyclopentyl, C1-C5 alkyl, (CH2)2OCH3 cyclohexyl, tetrahydrofuranylmethyl, morpholinoethyl, benzyl, phenethyl; the Ar ... 2 , R 3 Substituents of benzene ring or 2,5-dimethylthiophene; R 2 The group represents one of hydrogen and bromine; R 3 The group represents one of hydrogen, methyl, and methoxy.

[0008] Further, the specific chemical formula of the compound includes:

[0009]

[0010] An indenoazepine The preparation method of the compound comprises the following steps:

[0011] Step A: placing an indenobenzooxaphenacyclic compound II as a raw material in a pressure tube, adding an amine compound III in the absence of solvents and additives, maintaining the reaction temperature and stirring to obtain a mixture IV, wherein the stirring method is magnetic stirring, specifically, a magnetic stirring bar is placed in the pressure tube for stirring;

[0012] Step B: Cool the mixture obtained in step A to room temperature, directly add the reaction solvent acetonitrile MeCN and the reaction reagent SOCl2, maintain the reaction temperature and stir to obtain a mixture V;

[0013] Step C: directly add a base to the mixture obtained in step B, raise the temperature to the reaction temperature and keep it warm, and finally obtain indenobenzazepine by column chromatography. Compound; the reaction equation is as follows:

[0014]

[0015] Furthermore, in step A, the molar ratio of indenobenzooxaphene ring compound II: amine compound is 1:1-10, the reaction temperature is 20-80°C, the reaction time is 2-4 hours, the optimal reaction temperature is 40°C, and the optimal reaction time is 2 hours.

[0016] Furthermore, in step B, the molar ratio of SOCl2 to indenobenzooxaphene ring compound II is 1:1, the reaction temperature is room temperature, and the reaction time is 2-4 hours, wherein the optimal reaction time is 2 hours.

[0017] Further, in step C, the solvent used is acetonitrile not treated in step B, the base can be selected from one of KOH, NaOH, NaH, Na2CO3, and Cs2CO3, the molar ratio of base: indenobenzooxaphenoxa compound III is 1-10:1, the reaction temperature is 20-80°C, and the reaction time is 2-4 hours. The best base is KOH.

[0018] Furthermore, the optimal molar ratio of base: indenobenzooxaphene ring compound II is 10:1, the optimal reaction temperature is 80° C., and the optimal reaction time is 2 hours.

[0019] Furthermore, the reaction from step A to step B is a one-pot reaction, that is, the reaction mixture IV obtained in step A can be directly subjected to the operation of step B without pretreatment and separation.

[0020] Furthermore, the reaction from step B to step C is a one-pot reaction, that is, the reaction mixture V obtained in step B can be directly subjected to the operation of step C without pretreatment and separation.

[0021] The indenozepine Use of the compound or its pharmaceutically acceptable salt in preparing medicine for treating tumor diseases.

[0022] The beneficial effects of the present invention are: The synthesis method of the compound can adopt a one-pot continuous operation synthesis method to prepare the indenobenzooxa seven-ring compound with a functional group, and obtain the indenobenzooxa seven-ring compound through a one-pot three-step reaction. Since the present invention adopts a one-pot reaction with continuous operation, the system is simple and the intermediate can be obtained without separation and pretreatment. The compounds are simple, easy to operate, have wide substrate applicability, can tolerate a variety of functional groups, and have good product yields. The synthesis of indanolide and azepine was solved by continuous one-pot reaction with high yield. This type of indanone azepine The structure is a kind of skeleton structure with anti-tumor activity, showing certain anti-tumor activity. The invention provides a new synthesis method for developing new anti-tumor drugs, and has economical practicality and industrial application prospects. DETAILED DESCRIPTION

[0023] Example 1: Preparation of 5-benzyl-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-1)

[0024] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 107 mg (1.0 mmol) of benzylamine (IIIa) were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-1 was separated by column chromatography as a red solid, with a product yield of 87%; mp 126.1-128.1°C. 1H NMR (400MHz, CDCl3) δ7.50-7.35(m,8H),7.28-7.25(m,2H),7.08(dt,J=7.6 ,4.0Hz,2H),6.94(d,J=7.6Hz,1H),4.76(s,2H),4.45(s,2H),3.88(s,2H). 13 C NMR (100MHz, CDCl3) δ192.1,164.5,141.0,138.6,136.3,134.8,134.6,131.1,129.3,129.1,1 28.8,128.7,128.3,127.9,126.8,126.6,120.5,119.8,107.7,54.5,54.4,27.4.HRMS(ESI)m / z calcd for C 24 H 19 NONa + (M+Na) + 360.13589, found 360.13586.

[0025] Example 2: Preparation of 5-(2-methylbenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-2)

[0026] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 121 mg (1.0 mmol) of 2-methylbenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-2 was separated by column chromatography as a red solid, with a product yield of 86%; mp217.2-217.9°C. 1H NMR (400MHz, CDCl3) δ7.50(m,1H),7.40(d,J=7.2Hz,1H),7.32(d,J=3.2Hz,1H),7.30(d,J=4.4Hz,4H),7.21(dd,J=7.6,4.0Hz, 1H),7.18-7.14(m,1H),7.04(dd,J=6.8,4.8Hz,2H),6.75(d,J=7.2Hz,1H),4.73(s,2H),4.52(s,2H),3.91(s,2H),2.29(s,3H). 13 C NMR (100MHz, CDCl3) δ191.9,164.8,141.1,138.6,135.3,134.9,134.7,134.2,131.0,130.7,129.3,128. 9,128.7,128.2,127.7,126.8,126.6,126.1,120.5,119.9,107.2,55.2,53.0,27.4,19.0.HRMS(ESI)m / z calcd forC 25 H 21 NONa + (M+Na) + 374.15154, found 374.15137.

[0027] Example 3: Preparation of 5-(3-methylbenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-3)

[0028] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 121 mg (1.0 mmol) of 3-methylbenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-3 was separated as a red solid by column chromatography. The yield of the product was 84%; mp130.4-132.4°C. 1H NMR (400MHz, CDCl3) δ7.40(d,J=6.8Hz,1H),7.34(d,J=8.0Hz,1H),7.29(d,J=3.6Hz,2H),7.24-7.16(m ,5H),7.09(t,J=7.2Hz,2H),6.96(d,J=7.2Hz,1H),4.75(s,2H),4.46(s,2H),3.89(s,2H),2.41(s,3H). 13 C NMR (100MHz, CDCl3) δ192.1,164.6,141.1,139.0,138.7,136.3,134.9,134.6,131.1,129.3,129.1,128.8 ,128.73,128.68,128.3,127.4,126.5,123.9,120.5,119.8,107.6,54.5,54.4,27.4,21.5.HRMS(ESI)m / z calcd for C 25 H 21 NONa + (M+Na) + 374.15154, found 374.15143.

[0029] Example 4: Preparation of 5-(4-methylbenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-4)

[0030] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 121 mg (1.0 mmol) of 4-methylbenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-4 was separated by column chromatography as a red solid, with a product yield of 85%; mp 173.7-175.7°C. 1H NMR (400MHz, CDCl3) δ7.41(d,J=7.2Hz,1H),7.34(s,1H),7.32(s,1H),7.28(s,3H),7.26(d,J=2.8Hz,1H),7.23-7.20(m,1H ),7.18(d,J=7.6Hz,1H),7.09(t,J=7.2Hz,2H),6.97(d,J=7.6Hz,1H),4.74(s,2H),4.45(s,2H),3.89(s,2H),2.42(s,3H). 13 C NMR (100MHz, CDCl3) δ192.1,164.6,141.1,138.7,137.7,134.9,134.7,133.3,131.1,129.8,129. 3,128.8,128.7,128.3,126.8,126.6,120.5,119.8,107.6,54.4,54.2,27.4,21.1.HRMS(ESI)m / z calcd for C 25 H 21 NONa + (M+Na) + 374.15154, found 374.15134.

[0031] Example 5: Preparation of 5-(3,4-dimethylbenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-5)

[0032] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 135 mg (1.0 mmol) of 3,4-dimethylbenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-5 was separated by column chromatography as a red solid, with a product yield of 83%; mp 187.6-189.6°C. 1H NMR (400MHz, CDCl3) δ7.40(d,J=6.8Hz,1H),7.27(d,J=3.2Hz,2H),7.24(d,J=4.8Hz,1H),7.19-7.15(m ,4H),7.08(t,J=3.6Hz,2H),6.97(d,J=7.2Hz,1H),4.70(s,2H),4.45(s,2H),3.88(s,2H),2.32(s,6H). 13 C NMR (100MHz, CDCl3) δ192.0,164.6,141.1,138.7,137.5,136.3,134.9,134.7,133.6,131.0,130.3,129.3, 128.8,128.7,128.3,128.0,126.5,124.2,120.4,119.8,107.4,54.4,54.2,27.4,19.9,19.4.HRMS(ESI)m / z calcd for C 26 H 23 NONa + (M+Na) + 388.16719, found 388.16702.

[0033] Example 6: Preparation of 5-(3-methoxybenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-6)

[0034] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 137 mg (1.0 mmol) of 3-methoxybenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by thin layer chromatography (TLC) spot plate. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C, and then 200 mL of saturated brine was added to quench, and extracted with EtOAc. The organic layer was dried with Na2SO4 and EtOAc was evaporated under reduced pressure. The target product I-6 was separated by column chromatography as a red solid with a product yield of 85%; mp143.8-145.8°C. 1H NMR (400MHz, CDCl3) δ7.36(d,J=5.2Hz,2H),7.24(s,2H),7.20-7.11(m,3H),7.06(d,J=8.0Hz,2H),6.99(d,J= 7.2Hz,1H),6.93(d,J=4.4Hz,1H),6.91(d,J=6.8Hz,1H),4.70(s,2H),4.43(s,2H),3.85(s,2H),3.80(s,3H). 13 CNMR (100MHz, CDCl3) δ191.9,164.4,160.2,140.9,138.5,138.0,134.7,134.5,131.0,130.1,129.2,128 .7,128.5,128.3,126.5,120.4,119.7,118.9,112.9,112.4,107.5,55.2,54.5,54.3,27.2.HRMS(ESI)m / z calcd for C 25 H 21 NO2Na + (M+Na) + 390.14645, found 390.14627.

[0035] Example 7: Preparation of 5-(4-methoxybenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-7)

[0036] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 137 mg (1.0 mmol) of 4-methoxybenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-7 was separated by column chromatography as a red solid with a product yield of 87%; mp 94.7-96.7°C. 1H NMR (400MHz, CDCl3) δ7.37(d,J=6.8Hz,1H),7.31(d,J=7.6Hz,2H),7.24(s,2H),7.19-7.12(m,2H) ,7.05(d,J=7.2Hz,2H),6.96(t,J=8.4Hz,3H),4.66(s,2H),4.40(s,2H),3.84(s,2H),3.83(s,3H). 13 C NMR (100MHz, CDCl3) δ191.8,164.3,159.2,140.9,138.5,134.8,134.5,130.9,129.2,128.7,128.5,1 28.2,127.97,127.95,126.4,120.3,119.7,114.4,107.3,55.2,54.2,53.8,27.2.HRMS(ESI)m / zcalcd for C 25 H 21 NO2Na + (M+Na) + 390.14645, found 390.14679.

[0037] Example 8: Preparation of 5-(3,4-dimethoxybenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-8)

[0038] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 167 mg (1.0 mmol) of 3,4-dimethoxybenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-8 was separated by column chromatography as a red solid with a product yield of 82%; mp 93.6-95.6°C. 1H NMR (400MHz, CDCl3) δ7.38 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 10.8 Hz, 2H), 7.21-7.13 (m, 2H), 7.11-7. 05(m,2H),7.00-6.92(m,3H),6.87(s,1H),4.71(s,2H),4.45(s,2H),3.91(s,3H),3.85(s,5H). 13 C NMR (100MHz, CDCl3) δ191.8,164.3,149.5,148.6,140.9,138.5,134.8,134.5,130.9,129.2,128.7,128.54,1 28.46,128.3,126.4,120.3,119.8,118.9,111.5,109.6,107.4,55.84,55.82,54.4,54.2,27.2.HRMS(ESI)m / z calcd for C 26 H 23 NO3Na + (M+Na) + 420.15701, found 420.15717.

[0039] Example 9: Preparation of 5-(Benzo[d][1,3]dioxolane-5-ylmethyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-9)

[0040] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 151 mg (1.0 mmol) of benzo[d][1,3]dioxol-5-ylmethylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40°C and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-9 was separated by column chromatography as a red solid with a product yield of 84%; mp152.7-154.7°C. 1H NMR (400MHz, CDCl3) δ7.39(d,J=6.8Hz,1H),7.26(t,J=6.0Hz,2H),7.23-7.19(m,1H),7.13-7.07(m,2H),7.17(d,J=7.2Hz ,1H),7.13-7.07(m,2H),6.97(d,J=7.2Hz,1H),6.89(d,J=8.4Hz,3H),6.00(s,2H),4.64(s,2H),4.42(s,2H),3.86(s,2H). 13 C NMR (100MHz, CDCl3) δ192.1,164.3,148.5,147.3,141.0,138.6,134.8,134.6,131.1,130.1,129.3,128. 8,128.7,128.3,126.5,120.5,120.1,119.7,108.7,107.8,107.2,101.3,54.2,54.0,27.3.HRMS(ESI)m / z calcdfor C 25 H 19 NO3Na + (M+Na) + 404.12571, found 404.12561.

[0041] Example 10: Preparation of 5-(4-fluorobenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-10)

[0042] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 125 mg (1.0 mmol) of 4-fluorobenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4 and the EtOAc was removed under reduced pressure. The target product I-10 was separated by column chromatography as a red solid, 86%; mp186.7-188.7°C. 1H NMR (400MHz, CDCl3) δ7.38 (d, J=6.0Hz, 3H), 7.25 (s, 2H), 7.15 (dd, J=16.8, 10.0Hz, 4H), 7 .07(dd,J=14.0,7.2Hz,2H),6.89(d,J=7.2Hz,1H),4.70(s,2H),4.40(s,2H),3.85(s,2H). 13 C NMR (100MHz, CDCl3) δ192.0,164.2,163.6,161.1,140.9,138.6,134.7,134.4,132.3,132.0,131.1,1 29.3,128.8,128.6,128.5,128.4,128.3,126.5,120.5,119.5,116.1,115.9,107.9,54.3,53.7,27.2. 19 F NMR(376MHz,CDCl3)δ-114.23.HRMS(ESI)m / z calcd for C 24 H 18 F + (M+Na) + 378.12646, found 378.12643.

[0043] Example 11: Preparation of 5-(2-chlorobenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-11)

[0044] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 141 mg (1.0 mmol) of 2-chlorobenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-11 was separated by column chromatography as a red solid, with a product yield of 85%; mp 192.8-194.8°C. 1H NMR (400MHz, CDCl3) δ7.52(dd,J=16.8,5.6Hz,2H),7.41-7.32(m,4H),7.26-7.11(m,2H),7.17(d,J=7.6Hz,1H ),7.13(t,J=6.4Hz,1H),7.05(t,J=7.6Hz,1H),6.71(d,J=7.2Hz,1H),4.84(s,2H),4.50(s,2H),3.90(s,2H). 13 CNMR (100MHz, CDCl3) δ192.1,164.4,141.0,138.5,134.7,134.4,134.0,132.7,131.1,129.9,129.3,1 29.1,129.0,128.7,128.4,127.8,127.5,126.7,120.6,119.7,107.5,55.5,53.0,27.3.HRMS(ESI)m / z calcd for C 24 H 18 ClNONa + (M+Na) + 394.09691, found 394.09686.

[0045] Example 12: Preparation of 5-(4-chlorobenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-12)

[0046] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 141 mg (1.0 mmol) of 4-chlorobenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-12 was separated as a red solid by column chromatography. The yield of the product was 84%; mp124.3-126.3°C. 1H NMR (400MHz, CDCl3) δ7.43 (d, J = 7.2Hz, 2H), 7.38 (s, 4H), 7.23-7.15 (m, 3H), 7.0 8(d,J=5.6Hz,2H),6.87(d,J=6.8Hz,1H),4.71(s,2H),4.42(s,2H),3.86(s,2H). 13 C NMR (100MHz, CDCl3) δ192.2,164.3,141.0,138.6,134.9,134.6,134.4,133.8,131.2,129.4,1 29.3,128.9,128.7,128.3,128.2,126.6,120.7,119.5,108.1,54.5,53.8,27.3.HRMS(ESI)m / z calcd for C 24 H 18 ClNONa + (M+Na) + 394.09691, found 394.09738.

[0047] Example 13: Preparation of 5-(3,4-dichlorobenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-13)

[0048] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 174 mg (1.0 mmol) of 3,4-dichlorobenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-13 was separated by column chromatography as a red solid with a product yield of 81%; mp227.4-229.4°C. 1H NMR (400MHz, CDCl3) δ7.55(d,J=6.4Hz,2H),7.41(d,J=6.8Hz,1H),7.28(t,J=7.6Hz,3H),7.23-7.17(m,2H) ,7.13(d,J=7.6Hz,1H),7.08(t,J=7.6Hz,1H),6.84(d,J=7.2Hz,1H),4.67(s,2H),4.42(s,2H),3.87(s,2H). 13 CNMR (100MHz, CDCl3) δ192.3,164.0,141.0,138.8,137.0,134.4,134.3,133.5,132.1,131.3,131.2,1 29.4,129.0,128.9,128.7,128.4,126.7,126.1,120.8,119.3,108.9,54.5,53.2,27.3.HRMS(ESI)m / z calcd for C 24 H 17 Cl2NONa + (M+Na) + 428.05794,found428.05798.

[0049] Example 14: Preparation of 5-(3-bromobenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-14)

[0050] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 186 mg (1.0 mmol) of 3-bromobenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-14 was separated by column chromatography as a red solid, with a product yield of 84%; mp143.6-145.6°C. 1H NMR (400MHz, CDCl3) δ7.57(s,1H),7.49(d,J=6.8Hz,1H),7.34(dd,J=13.2,8.0Hz,3H),7.24(d,J=7.6Hz,2 H),7.21-7.11(m,2H),7.05(d,J=6.0Hz,2H),6.83(d,J=7.2Hz,1H),4.66(s,2H),4.39(s,2H),3.83(s,2H). 13 C NMR (100MHz, CDCl3) δ192.0,164.0,140.8,138.9,138.5,134.4,134.3,131.1,130.9,130.7,129.6,1 29.2,128.8,128.6,128.3,126.5,125.3,123.3,120.5,119.4,108.2,54.4,53.5,27.2.HRMS(ESI)m / z calcd for C 24 H 18 BrNONa + (M+Na) + 438.04640, found 438.04654.

[0051] Example 15: Preparation of 5-(4-bromobenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-15)

[0052] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 186 mg (1.0 mmol) of 4-bromobenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-15 was separated by column chromatography as a red solid, with a product yield of 85%; mp 165.7-167.7°C. 1H NMR(400MHz, CDCl3)δ7.60(d,J=8.4Hz,2H),7.41(d,J=6.8Hz,1H),7.34-7.26(m,4H),7.24-7 .17(m,2H),7.13-7.06(m,2H),6.88(d,J=7.6Hz,1H),4.70(s,2H),4.43(s,2H),3.88(s,2H). 13 C NMR (100MHz, CDCl3) δ192.3,164.3,141.0,138.8,135.6,134.6,134.4,132.3,131.2,129.4,1 28.9,128.8,128.5,128.4,126.6,121.8,120.7,119.5,108.3,54.6,53.8,27.3.HRMS(ESI)m / z calcd forC 24 H 18 BrNONa + (M+Na) + 438.04640, found 438.04654.

[0053] Example 16: Preparation of 5-(4-trifluoromethylbenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-16)

[0054] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 175 mg (1.0 mmol) of 4-trifluoromethylbenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-16 was separated by column chromatography to obtain a red solid. The yield of the product was 82%; mp160.8-162.8°C. 1H NMR (400MHz, CDCl3) δ7.74(d,J=8.4Hz,2H),7.58(d,J=8.0Hz,2H),7.42(d,J=7.2Hz,1H),7.32-7.28(m,2H),7.24-7 .21(m,1H),7.21(d,J=7.2Hz,1H),7.13-7.06(m,2H),6.85(d,J=7.6Hz,1H),4.80(s,2H),4.45(s,2H),3.90(s,2H). 13 C NMR (100MHz, CDCl3) δ192.4,164.2,141.0,140.8,138.8,134.5,134.3,131.3,130.5,130.2,129.4,12 9.0,128.9,128.4,127.2,126.7,126.20,126.16,125.3,122.6,120.8,119.4,108.7,54.7,53.9,27.3. 19 F NMR(376MHz,CDCl3)δ-62.47.HRMS(ESI)m / z calcd for C 25 H 18 F3NO + (M+Na) + 428.12327, found 428.12326.

[0055] Example 17: Preparation of 5-(naphthalen-1-ylmethyl)6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-17)

[0056] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 157 mg (1.0 mmol) of naphthalene-1-ylmethylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-17 was separated by column chromatography to obtain a red solid. The yield of the product was 88%; mp195.6-197.6°C. 1 H NMR(400MHz, CDCl3)δ8.01-7.95(m,1H),7.89(d,J=8.0Hz,1H),7.86-7.83(m,1H),7 .67(d,J=7.2Hz,1H),7.60-7.56(m,2H),7.54(d,J=7.6Hz,1H),7.38(d,J=6.8Hz,1H) ,7.31-7.27(m,2H),7.21-7.16(m,1H),7.10(t,J=7.2Hz,1H),7.04(d,J=7.2Hz,1H), 6.87(t,J=7.6Hz,1H),6.69(d,J=7.2Hz,1H),5.21(s,2H),4.58(s,2H),3.93(s,2H). 13 C NMR (100MHz, CDCl3) δ192.0,164.8,141.1,138.4,134.8,134.7,133.8,131.4,131.0,130.4,129.3,129.1,128.9,1 28.7,128.3,126.7,126.6,126.2,125.8,123.8,121.9,120.5,119.9,107.3,55.7,53.0,27.4.HRMS(ESI)m / zcalcd for C 28 H 21 NONa + (M+Na) + 410.15154, found 410.15143.

[0057] Example 18: Preparation of 5-(thiophen-2-ylmethyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-18)

[0058] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 113 mg (1.0 mmol) of thiophen-2-ylmethylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-18 was separated by column chromatography as a red solid, with a yield of 86%; mp 109.2-111.2°C. 1 H NMR (400MHz, CDCl3) δ7.41 (dd, J=5.6, 2.0Hz, 1H), 7.39-7.36 (m, 1H), 7.27 (dd, J=7.2, 5.6Hz, 2H), 7.22 ( m,1H),7.22-7.18(m,2H),7.17-7.13(m,3H),7.12-7.08(m,1H),4.81(s,2H),4.48(s,2H),3.86(s,2H). 13 C NMR (100MHz, CDCl3) δ192.6,163.8,141.0,140.4,138.9,134.5,134.4,131.3,129.3,128.8,1 28.5,127.5,126.6,125.8,125.7,120.7,119.6,109.0,53.7,49.5,27.3.HRMS(ESI)m / zcalcd for C 22 H 17 NOS + (M+Na) + 366.09231, found 366.09222.

[0059] Example 19: Preparation of 5-(furan-2-ylmethyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-19)

[0060] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 97 mg (1.0 mmol) of furan-2-ylmethylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-19 was separated by column chromatography as a red solid with a product yield of 85%; mp181.3-183.3°C. 1 H NMR (400MHz, CDCl3) δ7.51 (s, 1H), 7.42-7.39 (m, 1H), 7.34-7.30 (m, 1H), 7.27 (d, J = 7.6Hz, 2H) ,7.24-7.19(m,3H),7.15(d,J=7.2Hz,1H),6.46(s,2H),4.58(s,2H),4.46(s,2H),3.84(s,2H). 13 C NMR (100MHz, CDCl3) δ192.5,163.9,150.0,143.1,141.0,138.9,134.49,134.46,131.2,129.2,1 28.78,128.76,128.4,126.5,120.6,120.0,110.6,109.1,108.9,53.6,47.3,27.3.HRMS(ESI)m / z calcd for C 22 H 17 NO2Na + (M+Na) + 350.11515, found 350.11502.

[0061] Example 20: Preparation of 5-propyl-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-20)

[0062] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 59 mg (1.0 mmol) of propan-1-amine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-20 was separated by column chromatography as a red solid, with a yield of 89%; mp 145.3-147.3°C. 1 H NMR (400MHz, CDCl3) δ7.41-7.37(m,1H),7.26(d,J=4.4Hz,2H),7.22-7.18(m,4H),7.08-7.04(m ,1H),4.54(s,2H),3.83(s,2H),3.54(d,J=8.0Hz,2H),1.94-1.83(m,2H),1.03(t,J=7.6Hz,3H). 13 C NMR (100MHz, CDCl3) δ191.2,163.8,141.0,138.3,135.6,134.9,130.7,129.3,128.8, 128.4,128.0,126.6,120.3,120.2,105.5,55.7,54.0,27.4,22.7,10.9.HRMS(ESI)m / z calcd for C 20 H 19 NONa + (M+Na) + 312.13589, found 312.13556.

[0063] Example 21: Preparation of 5-butyl-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-21)

[0064] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 73 mg (1.0 mmol) of butan-1-amine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-21 was separated by column chromatography as a red solid, with a yield of 87%; mp118.4-120.4°C. 1 H NMR (400MHz, CDCl3) δ7.35(dd,J=4.8,3.2Hz,1H),7.22-7.18(m,2H),7.18-7.13(m,4H),7.03-6.99(m,1H),4.46(s,2H),3.78(s,2H),3.49(t,J=8.0Hz 2H),1.83-1.74(m,2H),1.39(dt,J=14.8,7.6Hz,2H),1.00(t,J=7.6Hz,3H). 13 C NMR (100MHz, CDCl3) δ190.8,163.6,140.7,138.1,135.4,134.7,130.5,129.0,128.5,128 .1,127.9,126.4,120.1,119.9,105.2,55.4,52.1,31.3,27.1,19.6,13.7.HRMS(ESI)m / z calcd for C 21 H 21 NONa + (M+Na) + 326.15154, found 326.15091.

[0065] Example 22: Preparation of 5-pentyl-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-22)

[0066] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 87 mg (1.0 mmol) of pentan-1-amine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-22 was separated by column chromatography as a red solid with a product yield of 86%; mp136.3-138.3°C. 1 H NMR (400MHz, CDCl3) δ7.40-7.37(m,1H),7.25(s,2H),7.22-7.19(m,4H),7.09-7.06(m,1H),4.54(s, 2H),3.84(s,2H),3.56(t,J=8.0Hz,2H),1.90-1.82(m,2H),1.46-1.37(m,4H),0.97(t,J=6.8Hz,3H). 13 C NMR (100MHz, CDCl3) δ191.2,163.8,141.0,138.4,135.6,134.9,130.7,129.3,128.8,128.4 ,128.0,126.5,120.3,120.2,105.5,55.6,52.4,29.2,28.8,27.4,22.5,14.0.HRMS(ESI)m / z calcd forC 22 H 23 NONa + (M+Na) + 340.16719, found 340.16742.

[0067] Example 23: Preparation of 5-hexyl-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-23)

[0068] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 101 mg (1.0 mmol) of hexan-1-amine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40°C and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-23 was separated by column chromatography as a red solid, with a product yield of 84%; mp132.5-134.5°C. 1 H NMR (400MHz, CDCl3) δ7.35-7.30(m,1H),7.16-7.11(m,6H),7.00-6.94(m,1H),4.43(s ,2H),3.79-3.70(m,2H),3.46(s,2H),1.77(s,2H),1.34(s,6H),0.91(d,J=3.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ190.6,163.4,140.6,137.9,135.3,134.7,130.4,128.9,128.4,127.9,12 7.8,126.3,120.0,119.8,104.9,55.3,52.3,31.2,29.2,27.1,25.9,22.3,13.7.HRMS(ESI)m / z calcd for C 23 H 25 NONa + (M+Na) + 354.18284, found 354.18262.

[0069] Example 24: Preparation of 5-(3-methoxypropyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-24)

[0070] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 89 mg (1.0 mmol) of 3-methoxypropan-1-amine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed by distillation under reduced pressure. The target product I-24 was separated by column chromatography as a red solid, with a product yield of 86%; mp 106.7-108.7°C. 1 H NMR (400MHz, CDCl3) δ7.39-7.35(m,1H),7.27(dd,J=5.6,2.8Hz,2H),7.24(s,1H),7.22-7.17(m,4H),4.54( s,2H),3.83(s,2H),3.72(t,J=7.6Hz,2H),3.49(t,J=5.6Hz,2H),3.37(s,3H),2.08(dt,J=12.0,5.6Hz,2H). 13 C NMR (100MHz, CDCl3) δ191.3,163.9,141.0,138.3,135.4,134.8,130.8,129.2,128.8,128.3 ,128.0,126.5,120.7,120.1,105.7,69.2,58.8,55.4,49.5,29.8,27.3.HRMS(ESI)m / zcalcd for C 21 H 21 NO2Na + (M+Na) + 342.14645, found 342.14655.

[0071] Example 25: Preparation of 5-cyclopentyl-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-25)

[0072] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 85 mg (1.0 mmol) of cyclopentylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-25 was separated by column chromatography as a red solid, with a product yield of 86%; mp 176.7-178.7°C. 1 H NMR (400MHz, CDCl3) δ7.39 (d, J = 2.8Hz, 1H), 7.26-7.16 (m, 7H), 4.88-4.78 ( m,1H),4.51(s,2H),3.85(s,2H),1.96-1.84(m,6H),1.67(d,J=6.0Hz,2H). 13 C NMR (100MHz, CDCl3) δ190.7,164.0,141.3,138.3,135.89,135.87,130.4,129.2,128.4 ,128.3,128.1,126.4,120.9,120.1,105.2,61.9,49.5,30.3,27.6,23.8.HRMS(ESI)m / z calcd for C 22 H 21 NONa + (M+Na) + 338.15154, found 338.15137.

[0073] Example 26: Preparation of 5-(cyclohexylmethyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-26)

[0074] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 113 mg (1.0 mmol) of cyclohexylmethylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-26 was separated by column chromatography as a red solid, with a product yield of 81%; mp 127.3-129.3°C. 1 H NMR (400MHz, CDCl3) δ7.38-7.34(m,1H),7.25-7.14(m,6H),7.12-7.08(m,1H),4.54(s,2H),3.81(s,2H) ,3.47(d,J=7.6Hz,2H),1.86(t,J=7.2Hz,1H),1.76-1.64(m,5H),1.27-1.13(m,3H),1.03-0.92(m,2H). 13 C NMR (100MHz, CDCl3) δ190.7,163.8,140.8,138.2,135.6,134.6,130.4,128.9,128.5,128.1 ,127.9,126.3,120.8,119.9,105.2,58.9,56.9,38.4,30.5,27.3,26.0,25.6.HRMS(ESI)m / z calcdfor C 24 H 25 NONa + (M+Na) + 366.18284, found 366.18280.

[0075] Example 27: Preparation of 5-((tetrahydrofuran-2-yl)methyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-27)

[0076] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 101 mg (1.0 mmol) of (tetrahydrofuran-2-yl)methylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C, and then 200 mL of saturated brine was added to quench, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4 and the EtOAc was evaporated under reduced pressure. The target product I-27 was separated by column chromatography as a red solid with a product yield of 84%; mp119.5-121.5°C. 1 H NMR (400MHz, CDCl3) δ7.37(s,1H),7.23(s,3H),7.18(d,J=10.0Hz,3H),7.12(s,1H),4.71(s,2H),4.27(d,J=6.8Hz,1H),3.99(q,J=7.2Hz,1H) ,3.88-3.80(m,3H),3.72(d,J=15.2Hz,1H),3.59(dd,J=15.2,7.6Hz,1H),2.15-2.04(m,1H),2.02-1.93(m,2H),1.61(dt,J=18.8,9.6Hz,1H). 13 C NMR (100MHz, CDCl3) δ191.5,164.1,141.0,138.6,135.2,134.8,130.6,129.1,128.6,128.4 ,128.2,126.4,120.6,120.3,106.5,79.0,68.1,55.7,55.3,29.3,27.3,25.5.HRMS(ESI)m / z calcdfor C 22 H 21 NO2Na + (M+Na) + 354.14645, found 354.14636.

[0077] Example 28: Preparation of 5-(3-morpholinopropyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-28)

[0078] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 144 mg (1.0 mmol) of 3-morpholinopropane-1-amine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-28 was separated by column chromatography as a red solid, with a product yield of 85%; mp116.7-118.7°C. 1 H NMR (400MHz, CDCl3) δ7.35-7.30(m,1H),7.23-7.10(m,7H),4.47(d,J=10.8Hz,2H),3.76(d,J=10.0H z,2H),3.70-3.65(m,4H),3.63-3.58(m,2H),2.41(s,4H),2.37-3.31(m,2H),1.91(d,J=5.6Hz,2H). 13 C NMR (100MHz, CDCl3) δ190.7,163.5,140.5,137.9,135.1,134.6,130.3,128.8,128.4,127.9,12 7.7,126.2,120.4,119.7,105.2,66.5,55.0,54.9,53.4,50.0,27.0,26.1.HRMS(ESI)m / zcalcd for C 24 H 27 N2O2 + (M+H) + 375.20670, found 375.20718.

[0079] Example 29: Preparation of 5-phenethyl-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-29)

[0080] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 121 mg (1.0 mmol) of 2-phenylethyl-1-amine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-29 was separated by column chromatography as a red solid with a product yield of 84%; mp123.6-125.6°C. 1 H NMR (400MHz, CDCl3) δ7.39-7.34(m,2H),7.33(d,J=7.6Hz,2H),7.25(s,2H),7.24-7.19(m,2H),7.19-7. 17(m,2H),7.16-7.12(m,2H),7.08-7.05(m,1H),4.46(s,2H),3.83-3.78(m,4H),3.09(d,J=8.0Hz,2H). 13 C NMR (100MHz, CDCl3) δ191.4,163.7,140.8,138.3,137.5,135.2,134.7,130.7,129.2,128.82,128. 75,128.6,128.3,128.0,126.9,126.5,120.3,120.2,106.2,55.9,53.5,35.9,27.2.HRMS(ESI)m / z calcd for C 25 H 21 NONa + (M+Na) + 374.15154, found 374.15158.

[0081] Example 30: Preparation of 5-(3-phenylpropyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-30)

[0082] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIa) and 135 mg (1.0 mmol) of 3-phenylpropan-1-amine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40°C and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIa completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-30 was separated by column chromatography as a red solid, with a product yield of 83%; mp135.2-137.2°C. 1 H NMR (400MHz, CDCl3) δ7.32(t,J=7.6Hz,3H),7.25-7.20(m,2H),7.20-7.14(m,4H),7.09(dd,J=15.6,7.6Hz,2H),6.94(t,J =7.6Hz,1H),6.56(d,J=7.2Hz,1H),4.43(s,2H),3.77(s,2H),3.52-3.45(m,2H),2.69(t,J=7.2Hz,2H),2.17-2.07(m,2H). 13 C NMR (100MHz, CDCl3) δ191.2,163.7,140.8,140.3,138.0,135.2,134.7,130.6,129.0,128.7,128.51, 128.46,128.2,127.9,126.5,126.3,120.2,120.0,105.5,55.3,51.3,32.6,30.6,27.2.HRMS(ESI)m / z calcd for C 26 H 23 NONa + (M+Na) + 388.16719, found 388.16699.

[0083] Example 31: Preparation of 8,9-dimethyl-5-(4-methylbenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-31)

[0084] 276 mg (1.0 mmol) of 8,9-dimethyl-6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIb) and 121 mg (1.0 mmol) of 4-methylbenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40°C and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIb completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-31 was separated by column chromatography as a red solid with a product yield of 84%; mp 163.4-165.4°C. 1 H NMR (400MHz, CDCl3) δ7.38(d,J=7.2Hz,1H),7.31(d,J=8.0Hz,2H),7.26(d,J=8.0Hz,2H),7.15(d,J=7.2Hz,1H),7.06( d,J=10.4Hz,2H),6.93(d,J=7.6Hz,1H),6.84(s,1H),4.73(s,2H),4.37(s,2H),3.80(s,2H),2.41(s,3H),2.22(s,6H). 13 C NMR (100MHz, CDCl3) δ192.0,164.5,138.7,138.2,137.6,137.0,135.0,134.5,133.3,132.0,130.9,130. 0,129.7,129.6,129.2,126.7,120.3,119.7,107.7,54.23,54.16,26.8,21.1,19.3,19.2.HRMS(ESI)m / z calcd for C 27 H 26 NO + (M+H) + 380.20089, found 380.20120.

[0085] Example 32: Preparation of 8,9-dimethoxy-5-(4-methoxybenzyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-32)

[0086] 308 mg (1.0 mmol) of 8,9-dimethoxy-6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IIc) and 137 mg (1.0 mmol) of 3-methoxybenzylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIc completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-32 was separated by column chromatography as a red solid with a product yield of 82%; mp112.4-114.4°C. 1 H NMR (400MHz, CDCl3) δ7.93(d,J=31.6Hz,1H),7.41(d,J=6.8Hz,1H),7.34(d,J=8.0Hz,2H),7.19(d,J=7.2Hz,1H),7.111(d,J=7.2Hz, 1H),6.99(d,J=8.0Hz,2H),6.84(s,1H),6.57(s,1H),4.77(s,2H),4.41(s,2H),3.88(s,3H),3.86(s,3H),3.84(s,3H),3.81(s,2H). 13 C NMR (100MHz, CDCl3) δ192.0,164.4,159.3,148.8,146.9,138.7,135.0,133.7,131.0,129.3,128.14,128 .10,126.7,120.5,119.9,114.5,112.4,112.2,107.8,56.2,55.9,55.4,54.3,54.2,27.0.HRMS(ESI)m / z calcd for C 27 H 26 NO4 + (M+H) + 428.18563, found 428.18591.

[0087] Example 33: Preparation of 7,10-dibromo-5-benzyl-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-33)

[0088] 403 mg (1.0 mmol) of 7,10-dibromo-6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IId) and 107 mg (1.0 mmol) of benzylamine (IIIa) were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40°C and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IId completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C, and then 200 mL of saturated brine was added to quench, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4 and the EtOAc was evaporated under reduced pressure. The target product I-33 was separated by column chromatography as a red solid with a product yield of 85%; mp109.44-111.4°C. 1 H NMR (400MHz, CDCl3) δ7.59(d,J=7.6Hz,2H),7.53(t,J=7.6Hz,2H),7.40(t,J=7.2Hz,1H),7.31(t,J=7.6Hz,2H),7.17(d,J=8.4Hz,1H),7.1 2(t,J=7.2Hz,1H),7.03(t,J=7.2Hz,1H),6.93(d,7.2Hz,1H),6.88(d,15.2Hz,1H),5.28(t,J=7.6Hz,2H),5.01-4.91(m,2H),1.26(s,2H). 13 C NMR (100MHz, CDCl3) δ192.4,165.0,141.9,137.8,137.5,136.3,135.2,133.4,132.3,131.0,1 29.4,129.2,127.7,126.7,124.9,124.0,120.8,120.5,105.1,55.7,53.8,46.6.HRMS(ESI)m / z calcd for C 24 H 16 Br2NO + (M+H) + 493.95727, found 493.95728.

[0089] Example 34: Preparation of 7,10-dibromo-5-(furan-2-ylmethyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-34)

[0090] 403 mg (1.0 mmol) of 7,10-dibromo-6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IId) and 97 mg (1.0 mmol) of furan-2-ylmethylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40°C and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IId completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-34 was separated by column chromatography as a red solid with a product yield of 82%; mp 186.8-188.8°C. 1 H NMR (400MHz, CDCl3) δ7.51 (s, 1H), 7.40-7.33 (m, 3H), 7.28 (d, J = 8.8Hz, 1H), 7.19 (dd, J = 4.8, 2.8Hz, 2H), 6.54 (d, J = 2.8Hz, 1H), 6.45 (d, J = 1.6Hz, 1H), 4.84 (s, 2H), 4.77 (s, 2H), 4.09 (d, J = 16.4Hz, 2H). 13 CNMR (100MHz, CDCl3) δ191.3,163.4,149.6,143.2,142.4,137.9,136.2,134.5,133.8,131.7,1 31.1,129.4,122.7,122.5,120.7,120.4,110.5,109.3,105.3,52.4,47.9,27.1.HRMS(ESI)m / z calcd for C 22 H 16 Br2NO2 + (M+H) + 485.95218, found 485.95227.

[0091] Example 35: Preparation of 7,10-dibromo-5-propyl-6,11-dihydrobenzo[e]indeno[1,2-b]azepan-12(5H)-one (I-35)

[0092] 403 mg (1.0 mmol) of 7,10-dibromo-6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepan-12-one (IId) and 87 mg (1.0 mmol) of pentan-1-amine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40°C and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IId completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-35 was separated by column chromatography as a red solid, with a product yield of 86%; mp 148.8-168.8°C. 1 H NMR (400MHz, CDCl3) δ7.32-7.16(m,5H),6.81(d,J=15.2Hz,1H),5.18-4.97(m,2H),3. 83(s,2H),2.00(d,J=39.2Hz,2H),1.72(s,1H),1.44(s,4H),1.26(s,1H),0.98(s,3H). 13 C NMR (100MHz, CDCl3) δ192.0,164.5,141.9,138.0,137.7,135.7,133.3,132.1,130.7,129.3 ,124.8,123.9,121.0,120.3,104.3,54.3,53.5,46.7,29.6,28.9,22.4,14.1.HRMS(ESI)m / z calcd for C 22 H 20 Br2NO + (M+H) + 473.98857, found 473.98877.

[0093] Example 36: Preparation of 5-benzyl-1,3-dimethyl-5,11-dihydroindeno[1,2-b]thieno[3,4-e]azepan-10(4H)-one (I-36)

[0094] 282 mg (1.0 mmol) of 1,3-dimethyl-4H-indeno[1,2-b]thieno[3,4-e]oxepan-10(11H)-one (IIe) and 107 mg (1.0 mmol) of benzylamine (IIIa) were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40°C and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIe completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-36 was separated by column chromatography as a red solid. The yield of the product was 85%; mp 116.3-118.3°C. 1 H NMR (400MHz, CDCl3) δ7.49-7.43(m,4H),7.41(d,J=6.8Hz,2H),7.18(t,J=7.2Hz,1H),7.10(t,J=7 .6Hz,1H),6.97(d,J=7.2Hz,1H),4.71(s,2H),4.26(s,2H),3.66(s,2H),2.35(s,3H),2.25(s,3H). 13 CNMR (100MHz, CDCl3) δ192.6,164.5,139.3,136.6,135.5,134.6,131.72,131.65,131.2,12 9.2,128.8,127.9,126.8,120.6,119.6,108.7,54.7,47.6,20.8,12.6,12.5.HRMS(ESI)m / z calcd for C 24 H 22 NOS + (M+H) + 372.14166, found 372.14157.

[0095] Example 37: Preparation of 1,3-dimethyl-5-(naphthalen-1-ylmethyl)-5,11-dihydroindeno[1,2-b]thieno[3,4-e]azepan-10(4H)-one (I-37)

[0096] 282 mg (1.0 mmol) of 1,3-dimethyl-4H-indeno[1,2-b]thieno[3,4-e]oxepan-10(11H)-one (IIe) and 157 mg (1.0 mmol) of naphthalene-1-ylmethylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40°C and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIe completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-37 was separated by column chromatography as a red solid with a product yield of 86%; mp 208.7-210.7°C. 1 H NMR (400MHz, CDCl3) δ8.00-7.94(m,1H),7.91-7.84(m,2H),7.71(d,J=6.8Hz,1H),7.61-7.52(m,3H),7.38(d,J=6.8Hz,1H),7.10 (t,J=7.2Hz,1H),6.89(t,J=7.6Hz,1H),6.71(d,J=7.6Hz,1H),5.18(s,2H),4.40(s,2H),3.71(s,2H),2.38(s,3H),2.18(s,3H). 13 C NMR (100MHz, CDCl3) δ192.4,164.9,139.1,135.6,134.6,133.8,131.8,131.7,131.4,131.2,130.5,129.1,128 .8,128.3,126.7,126.2,125.8,123.8,121.7,120.5,119.8,108.3,53.2,48.8,20.7,12.7,12.5.HRMS(ESI)m / z calcd for C 28 H 24 NOS + (M+H) + 422.15731, found 422.15717.

[0097] Example 38: Preparation of 1,3-dimethyl-5-pentyl-5,11-dihydroindeno[1,2-b]thieno[3,4-e]azepan-10(4H)-one (I-38)

[0098] 282 mg (1.0 mmol) of 1,3-dimethyl-4H-indeno[1,2-b]thieno[3,4-e]oxepan-10(11H)-one (IIe) and 87 mg (1.0 mmol) of pentan-1-amine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40°C and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIe completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was evaporated under reduced pressure. The target product I-38 was separated by column chromatography as a red solid, with a product yield of 87%; mp110.9-112.9°C. 1 H NMR (400MHz, CDCl3) δ7.39-7.33(m,1H),7.24-7.17(m,2H),7.06(d,J=7.6Hz,1H),4.34(s,2H),3.58(s,2H),3.49(t J=7.6Hz,2H),2.43(s,3H),2.32(s,3H),1.91-1.82(m,2H),1.45-1.38(m,4H),0.97(t,J=6.8Hz,3H). 13 C NMR (100MHz, CDCl3) δ191.8,164.1,138.9,135.5,135.2,132.0,130.9,130.8,129.1,128. 4,120.2,120.1,106.5,52.4,48.3,29.1,28.8,22.4,20.8,13.9,12.7,12.4.HRMS(ESI)m / z calcd for C 22 H 26 NOS + (M+H) + 352.17296, found 352.17331.

[0099] Example 39: Preparation of 1,3-dimethyl-5-((tetrahydrofuran-2-yl)methyl)-5,11-dihydroindeno[1,2-b]thieno[3,4-e]azepan-10(4H)-one (I-39)

[0100] 282 mg (1.0 mmol) of 1,3-dimethyl-4H-indeno[1,2-b]thieno[3,4-e]oxepan-10(11H)-one (IIe) and 101 mg (1.0 mmol) of (tetrahydrofuran-2-yl)methylamine were added to the reaction bottle, and the mixture was placed in a metal bath preheated to 40° C. and stirred for reaction for 2 hours. The reaction endpoint was determined by TLC. When the TLC plate showed that the reaction raw material IIe completely disappeared, the reaction bottle was lifted from the metal bath, cooled to room temperature, 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl2 was slowly added dropwise to the reaction bottle. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added to the reaction bottle, and the reaction was continued to stir for 2 hours in a metal bath preheated to 80°C. Then, 200 mL of saturated brine was added to quench the reaction, and the reaction was extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed by distillation under reduced pressure. The target product I-39 was separated by column chromatography as a red solid, with a product yield of 84%; mp 104.6-106.6°C. 1 H NMR(400MHz, CDCl3) δ7.89(d,J=23.6Hz,1H),7.38(s,1H),7.17(d,J=28.4Hz,2H),4. 64(d,J=14.8Hz,1H),4.48(d,J=14.4Hz,1H),4.32(s,1H),4.01(d,J=6.4Hz,1H),3.88 (d,J=6.0Hz,1H),3.70(d,J=15.2Hz,1H),3.60(s,2H),3.52-3.43(m,1H),2.46(s,3H) ,2.33(s,3H),2.17(s,1H),2.00(s,1H),1.89(s,1H),1.61(s,1H).1.64-1.58(s,2H). 13 C NMR (100MHz, CDCl3) δ192.4,164.6,139.4,135.6,134.9,132.1,131.5,130.9,129.0,128. 5,120.5,120.4,107.9,79.2,68.3,55.3,48.5,29.5,25.5,20.8,12.8,12.5.HRMS(ESI)m / z calcd for C 22 H 24NO2S + (M+H) + 366.15223, found 366.15222.

[0101] The following are some pharmacological tests and results of the compounds of the present invention.

[0102] The structural formula of the compound in the pharmacological test section is as follows:

[0103]

[0104] Anti-tumor test of compounds:

[0105] The CCK-8 method was used as usual to test the compounds I-1, I-9, I-17, I-20, I-24, I-25, I-28, I-32, I-37, and I-38 at a concentration of 20 μmol / L in common human tumor cells (human lung cancer cells (A549), human gastric cancer cells (MKN-45), human colon cancer cells (HCT 116), human cervical cancer cells (HeLa), human chronic myeloid leukemia cells (K-562), human renal clear cell adenocarcinoma cells (786-O), human esophageal cancer cells (TE-1), human bladder cancer cells (5637), human gallbladder cancer cells (GBC-SD), human breast cancer cells (MCF7), human liver cancer cells (HepG2), human brain tumor cells (SF126), human prostate cancer cells (DU145), human thyroid cancer cells (CAL-62), human pancreatic cancer cells (PATU8988T), human osteosarcoma cells (HOS), human malignant melanoma cells (A-375), human rhabdomyosarcoma cells (A-673). This method has been widely used in the initial screening of tumor cell proliferation inhibition activity. The positive control is doxorubicin hydrochloride (Dox), which is an anti-tumor drug widely used in clinical practice.

[0106] The CCK-8 method was routinely used to determine the IC values ​​of the compounds with an inhibition rate of 50% or more on the corresponding tumor cells in the initial screening results. 50 This method has been widely used to determine the IC value of tumor cell proliferation inhibition activity. 50 The positive control was Doxorubicin (Dox), which is an anti-tumor drug widely used in clinical practice.

[0107] Inhibition rate = (average OD value of the control group - average OD value of the drug administration group) / average OD value of the control group × 100%. The initial screening results showed that the inhibition rate of compound I-37 on human esophageal cancer cells (TE-1) at a concentration of 20 μmol / L was 60.28±3.66%, and the inhibition rate of compound I-37 on human bladder cancer cells (5637) at a concentration of 20 μmol / L was 54.93±3.05%. The proliferation inhibition rates of other compounds tested on other tumor cells were less than 50%.

[0108] The following is the antitumor activity (IC 50 Value, μmol / L)

[0109]

[0110] Note: IC is calculated only for compounds with cell inhibition rate greater than or equal to 50% in the initial screening results. 50 IC 50 Value unit: μmol, cell inhibition rate is less than 50%, IC cannot be calculated 50 value.

[0111] The above pharmacological tests show that the indanoazepine Some compounds of the skeleton have certain tumor cell inhibitory activity.

[0112] The above description is only a specific embodiment of the present invention, which describes the general method for synthesizing compounds having the mother core skeleton of Compound I and the anti-tumor activity of this type of novel structure. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be within the scope of protection of the present invention.

Claims

1. An indenoazepine A compound, characterized in that The chemical structure of its general formula I is as follows: Among them, R 1 The group represents a substituted or unsubstituted aryl, cyclopentyl, C1-C5 alkyl, (CH2)2OCH3 cyclohexyl, tetrahydrofuranylmethyl, morpholinoethyl, benzyl, phenethyl; the Ar ... 2 , R 3 Substituents of benzene ring or 2,5-dimethylthiophene; R 2 The group represents one of hydrogen and bromine; R 3 The group represents one of hydrogen, methyl, and methoxy.

2. An indenoazepine according to claim 1 A compound, characterized in that Specific chemical formulas for compounds include:

3. An indenoazepine A method for preparing a compound, characterized in that: The steps include: Step A: placing an indenobenzooxaphenacyclic compound II as a raw material in a pressure-resistant tube, adding an amine compound III in the absence of solvents or additives, maintaining the reaction temperature and stirring to obtain a mixture IV; Step B: Cool the mixture obtained in step A to room temperature, directly add the reaction solvent acetonitrile MeCN and the reaction reagent SOCl2, maintain the reaction temperature and stir to obtain a mixture V; Step C: directly add a base to the mixture obtained in step B, raise the temperature to the reaction temperature and keep it warm, and finally obtain indenobenzazepine by column chromatography. Compound; the reaction equation is as follows:

4. The indenozepine according to claim 3 A method for preparing a compound, characterized in that: In the step A, the molar ratio of the indenobenzooxaphene ring compound II to the amine compound is 1:1-10, the reaction temperature is 20-80° C., and the insulation time is 2-4 hours.

5. The indenozepine according to claim 3 A method for preparing a compound, characterized in that: In step B, the molar ratio of SOCl2 to indenobenzooxaphene ring compound II is 1:1, the reaction temperature is room temperature, and the reaction time is 2-4 hours.

6. The indenozepine according to claim 3 A method for preparing a compound, characterized in that: In step C, the molar ratio of the base to the indenobenzooxaphene ring compound II is 5-10:1, the reaction temperature is 40-80° C., and the insulation time is 2-4 hours.

7. The indenozepine according to claim 3 A method for preparing a compound, characterized in that: The base is one of KOH, NaOH, NaH, Na2CO3, and Cs2CO3.

8. The indenozepine according to claim 3 A method for preparing a compound, characterized in that: The reaction from step A to step B is a one-pot reaction, that is, the reaction mixture IV obtained in step A can be directly subjected to the operation of step B without pretreatment and separation.

9. The indenozepine according to claim 3 A method for preparing a compound, characterized in that: The reaction from step B to step C is a one-pot reaction, that is, the reaction mixture V obtained in step B can be directly subjected to the operation of step C without pretreatment and separation.

10. The indenozepine according to any one of claims 1 to 9. Use of the compound or its pharmaceutically acceptable salt in preparing medicine for treating tumor diseases.

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