An indenoazepine compound, a preparation method thereof and medical uses thereof

Abstract

This discovery relates to the fields of organic chemistry and medicinal chemistry, specifically to an indene-aza compound I, its preparation method, and its pharmaceutical applications. This invention uses an indene-oxaheptacyclic compound as a starting material, adding an amine compound under solvent-free and additive-free conditions. After this reaction, the intermediate product is directly added to a stoichiometric amount of thionyl chloride and acetonitrile without separation or pretreatment to continue the reaction. After the reaction is complete, a base is added again without separation or pretreatment, and the reaction temperature is controlled to finally obtain the indene-aza compound. This invention reports a class of novel compounds and develops a one-pot continuous synthesis method for these compounds. This method conforms to the principles of green chemistry and demonstrates significant advantages in chemical synthesis. Furthermore, these compounds exhibit certain inhibitory effects on human esophageal cancer cells and human bladder cancer cells.

Description

Technical Field

[0001] This invention relates to the fields of organic synthesis and medicinal chemistry, specifically to an indene-azapyridine. Compounds, their preparation methods, and pharmaceutical uses. Background Technology

[0002] Benzo[a]azine heterocyclic structures containing indanone structures exhibit good physiological activity. For example, indanone-isoquinolinone derivatives containing six-membered nitrogen heterocycles, as non-camptothecin topoisomerase 1 (TOP1) inhibitors, possess better pharmacological properties and chemical stability than camptothecin derivatives. For instance, LMP-400 and LMP-776 can be used as therapeutic drugs for various types of tumors. However, compounds containing seven-membered nitrogen heterocycles with an aromatic ring-[e]indo[1,2-b]azine heptane structures, their synthetic methods, and antitumor applications have not been reported.

[0003] Therefore, novel compounds with the aryl[e]indeno[1,2-b]azacycloheptane structure are of great significance for the development of new antitumor drugs, while the synthesis of this structure remains to be solved. Summary of the Invention

[0004] This invention discloses a novel class of indene-azapyridines. Compounds and their preparation method. This method is green, efficient, simple to operate, and has a high yield, and can be completed through a continuous one-pot reaction. Pharmacological experiments have demonstrated that these compounds possess certain antitumor activity.

[0005] The technical solution of this invention is: an indene-azapyridine... The chemical structure of the compound, which has the general formula I, is as follows:

[0006]

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

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

[0009]

[0010] An indene-azo dye The method for preparing the compound includes the following steps:

[0011] Step A: Indene-benzoxane-heptacyclic compound II is placed in a pressure-resistant tube as raw material. Amine compound III is added under solvent-free and additive-free conditions. The reaction temperature is maintained and the mixture is stirred to obtain mixture IV. The stirring method is magnetic stirring, specifically, a magnetic stir bar is installed in the pressure-resistant tube for stirring.

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

[0013] Step C: Add alkali directly to the mixture obtained in Step B, raise the temperature to the reaction temperature and maintain the temperature, and finally obtain indene-benzodiazepines by column chromatography. Compound; reaction equation as follows:

[0014]

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

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

[0017] Furthermore, in step C, the solvent used is the untreated acetonitrile from step B. The base can be selected from one of KOH, NaOH, NaH, Na2CO3, or Cs2CO3. The molar ratio of base to indenebenzoxoneheptacyclic compound III is 1-10:1. The reaction temperature is 20-80℃, and the reaction time is 2-4 hours. KOH is the optimal base.

[0018] Furthermore, the optimal molar ratio of base to indobenzoxoxane 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, meaning that the reaction mixture IV obtained in step A can be directly used for step B without pretreatment and separation.

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

[0021] The indoza The use of compounds or pharmaceutically acceptable salts thereof in the preparation of drugs for treating tumor diseases.

[0022] The beneficial effects of the present invention are: the indanoneza of the present invention described above The synthesis of this type of compound can be carried out using a one-pot continuous operation method, which involves pre-preparing indene-benzoxoxa-heptacyclic compounds with pre-functionalized groups and then obtaining indene-ketone-azacycloheptacyclic compounds through a one-pot three-step reaction. This type of compound currently lacks a synthetic method. Because this invention employs a continuous one-pot reaction, the system is simple, and intermediates do not require separation or pretreatment to obtain indanone and its derivatives. This method involves simple and convenient compound preparation, broad substrate applicability, tolerance to various functional groups, and good product yield. This discovery not only successfully solves the problem of indanone-aza compounds... The synthesis of this type of compound was addressed by employing a continuous one-pot reaction to achieve high yields of indanone and azazo. This class of compounds. This class of indanone-aza compounds... The structure is a type of skeletal structure with antitumor activity, exhibiting certain antitumor activity. This invention provides a new synthetic method for developing novel antitumor drugs, with economic practicality and promising industrial application prospects. Detailed Implementation

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

[0024] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 107 mg (1.0 mmol) of benzylamine (IIIa) were added to the reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-1, a red solid, was obtained by column chromatography with a 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]azacycloheptane-12(5H)-one (I-2)

[0026] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepane-12-one (IIa) and 121 mg (1.0 mmol) of 2-methylbenzylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-2, a red solid, was obtained by column chromatography with a yield of 86%; mp 217.2–217.9 °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]azacycloheptane-12(5H)-one (I-3)

[0028] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 121 mg (1.0 mmol) of 3-methylbenzylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-3, a red solid, was obtained by column chromatography with a yield of 84%; mp 130.4–132.4 °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]azacycloheptane-12(5H)-one (I-4)

[0030] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 121 mg (1.0 mmol) of 4-methylbenzylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-4, a red solid, was obtained by column chromatography with a 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]azacycloheptane-12(5H)-one (I-5)

[0032] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepane-12-one (IIa) and 135 mg (1.0 mmol) of 3,4-dimethylbenzylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-5, a red solid, was obtained by column chromatography with a 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]azacycloheptane-12(5H)-one (I-6)

[0034] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 137 mg (1.0 mmol) of 3-methoxybenzylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-6, a red solid, was obtained by column chromatography with a yield of 85%; mp 143.8–145.8 °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]azacycloheptane-12(5H)-one (I-7)

[0036] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepane-12-one (IIa) and 137 mg (1.0 mmol) of 4-methoxybenzylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-7, a red solid, was obtained by column chromatography with a 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]azacycloheptane-12(5H)-one (I-8)

[0038] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 167 mg (1.0 mmol) of 3,4-dimethoxybenzylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-8, a red solid, was obtained by column chromatography with a 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]dioxanol-5-ylmethyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azacycloheptane-12(5H)-one (I-9)

[0040] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 151 mg (1.0 mmol) of benzo[d][1,3]dioxo-5-ylmethylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-9, a red solid, was obtained by column chromatography with a yield of 84%; mp 152.7–154.7 °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]azacycloheptane-12(5H)-one (I-10)

[0042] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 125 mg (1.0 mmol) of 4-fluorobenzylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-10, a red solid, 86% (mp 186.7-188.7 °C), was obtained by column chromatography. 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 FNONa + (M+Na) + 378.12646, found 378.12643.

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

[0044] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepane-12-one (IIa) and 141 mg (1.0 mmol) of 2-chlorobenzylamine were added to the reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-11, a red solid, was obtained by column chromatography with a 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]azacycloheptane-12(5H)-one (I-12)

[0046] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 141 mg (1.0 mmol) of 4-chlorobenzylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-12, a red solid, was obtained by column chromatography with a yield of 84%; mp 124.3–126.3 °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]azacycloheptane-12(5H)-one (I-13)

[0048] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepane-12-one (IIa) and 174 mg (1.0 mmol) of 3,4-dichlorobenzylamine were added to the reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-13, a red solid, was obtained by column chromatography with a yield of 81%; mp 227.4–229.4 °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, found 428.05798.

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

[0050] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepane-12-one (IIa) and 186 mg (1.0 mmol) of 3-bromobenzylamine were added to the reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-14, a red solid, was obtained by column chromatography with a yield of 84%; mp 143.6–145.6 °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]azacycloheptane-12(5H)-one (I-15)

[0052] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepane-12-one (IIa) and 186 mg (1.0 mmol) of 4-bromobenzylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-15, a red solid, was obtained by column chromatography with a 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]azacycloheptane-12(5H)-one (I-16)

[0054] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 175 mg (1.0 mmol) of 4-trifluoromethylbenzylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product, I-16, was obtained as a red solid by column chromatography, with a yield of 82% and mp values ​​of 160.8–162.8 °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 F3NONa + (M+Na) + 428.12327, found 428.12326.

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

[0056] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 157 mg (1.0 mmol) of naphth-1-ylmethylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product, I-17, was obtained as a red solid by column chromatography, with a yield of 88% and mp values ​​of 195.6–197.6 °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-(thiophene-2-ylmethyl)-6,11-dihydrobenzo[e]indeno[1,2-b]azacycloheptane-12(5H)-one (I-18)

[0058] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 113 mg (1.0 mmol) of thiophene-2-methylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product, I-18, was obtained as a red solid by column chromatography, with a yield of 86% and mp values ​​of 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 NOSNa + (M+Na) + 366.09231, found 366.09222.

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

[0060] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 97 mg (1.0 mmol) of furan-2-methylamine were added to the reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-19, a red solid, was obtained by column chromatography with a yield of 85%; mp 181.3–183.3 °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]azacycloheptane-12(5H)-one (I-20)

[0062] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 59 mg (1.0 mmol) of propane-1-amine were added to the reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product, I-20, was obtained as a red solid by column chromatography, with a yield of 89% and an mp value of 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]azacycloheptane-12(5H)-one (I-21)

[0064] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 73 mg (1.0 mmol) of but-1-amine were added to the reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-21, a red solid, was obtained by column chromatography with a yield of 87% and mp values ​​of 118.4–120.4 °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]azacycloheptane-12(5H)-one (I-22)

[0066] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 87 mg (1.0 mmol) of penta-1-amine were added to the reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-22, a red solid, was obtained by column chromatography with a yield of 86%; mp 136.3–138.3 °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]azacycloheptane-12(5H)-one (I-23)

[0068] Add 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 101 mg (1.0 mmol) of hexyl-1-amine to a reaction flask, and stir the mixture in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-23, a red solid, was obtained by column chromatography with a yield of 84%; mp 132.5–134.5 °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]azacycloheptane-12(5H)-one (I-24)

[0070] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 89 mg (1.0 mmol) of 3-methoxypropyl-1-amine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-24, a red solid, was obtained by column chromatography with a 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]azacycloheptane-12(5H)-one (I-25)

[0072] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepane-12-one (IIa) and 85 mg (1.0 mmol) of cyclopentylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-25, a red solid, was obtained by column chromatography with a 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]azacycloheptane-12(5H)-one (I-26)

[0074] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepane-12-one (IIa) and 113 mg (1.0 mmol) of cyclohexylmethylamine were added to the reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-26, a red solid, was obtained by column chromatography with a 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]azacycloheptane-12(5H)-one (I-27)

[0076] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 101 mg (1.0 mmol) of (tetrahydrofuran-2-yl)methylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-27, a red solid, was obtained by column chromatography with a yield of 84%; mp 119.5–121.5 °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]azacycloheptane-12(5H)-one (I-28)

[0078] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 144 mg (1.0 mmol) of 3-morpholinopropane-1-amine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-28, a red solid, was obtained by column chromatography with a yield of 85%; mp 116.7–118.7 °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-phenylethyl-6,11-dihydrobenzo[e]indeno[1,2-b]azacycloheptane-12(5H)-one (I-29)

[0080] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 121 mg (1.0 mmol) of 2-phenylethyl-1-amine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-29, a red solid, was obtained by column chromatography with a yield of 84%; mp 123.6–125.6 °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]azacycloheptane-12(5H)-one (I-30)

[0082] 248 mg (1.0 mmol) of 6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxetane-12-one (IIa) and 135 mg (1.0 mmol) of 3-phenylprop-1-amine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIa, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-30, a red solid, was obtained by column chromatography with a yield of 83%; mp 135.2–137.2 °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]azacycloheptane-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]oxepane-12-one (IIb) and 121 mg (1.0 mmol) of 4-methylbenzylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIb, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-31, a red solid, was obtained by column chromatography with a 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]azacycloheptane-12(5H)-one (I-32)

[0086] Add 308 mg (1.0 mmol) of 8,9-dimethoxy-6,11-dihydro-12H-benzo[e]indo[1,2-b]oxepane-12-one (IIc) and 137 mg (1.0 mmol) of 3-methoxybenzylamine to a reaction flask, and stir the mixture in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of reactant IIc, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-32, a red solid, was obtained by column chromatography with a yield of 82%; mp 112.4–114.4 °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]azacycloheptane-12(5H)-one (I-33)

[0088] Add 403 mg (1.0 mmol) of 7,10-dibromo-6,11-dihydro-12H-benzo[e]indeno[1,2-b]oxepane-12-one (IId) and 107 mg (1.0 mmol) of benzylamine (IIIa) to a reaction flask, and stir the mixture in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of the reactant IId, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-33, a red solid, was obtained by column chromatography with a yield of 85%; mp 109.44–111.4 °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]azacycloheptane-12(5H)-one (I-34)

[0090] Add 403 mg (1.0 mmol) of 7,10-dibromo-6,11-dihydro-12H-benzo[e]indo[1,2-b]oxepane-12-one (IId) and 97 mg (1.0 mmol) of furan-2-methylamine to a reaction flask, and stir the mixture in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of the reactant IId, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-34, a red solid, was obtained by column chromatography with a 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]azacycloheptane-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]oxetane-12-one (IId) and 87 mg (1.0 mmol) of penta-1-amine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of the reactant IId, the reaction flask was removed from the metal bath and 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 flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-35, a red solid, was obtained by column chromatography with a 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] Preparation of 36:5-benzyl-1,3-dimethyl-5,11-dihydroinden[1,2-b]thieno[3,4-e]azacycloheptane-10(4H)-one (I-36)

[0094] Add 282 mg (1.0 mmol) of 1,3-dimethyl-4H-indeno[1,2-b]thieno[3,4-e]oxepane-10(11H)-one (IIe) and 107 mg (1.0 mmol) of benzylamine (IIIa) to a reaction flask, and stir the mixture in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of the reactant Ie, the reaction flask was removed from the metal bath and cooled to room temperature. 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl was slowly added dropwise to the flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product, I-36, was obtained as a red solid by column chromatography, with a yield of 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-(naphth-1-ylmethyl)-5,11-dihydroinden[1,2-b]thieno[3,4-e]azacycloheptane-10(4H)-one (I-37)

[0096] 282 mg (1.0 mmol) of 1,3-dimethyl-4H-indeno[1,2-b]thieno[3,4-e]oxepane-10(11H)-one (IIe) and 157 mg (1.0 mmol) of naphth-1-methylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of the reactant Ie, the reaction flask was removed from the metal bath and cooled to room temperature. 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl was slowly added dropwise to the flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product, I-37, was obtained as a red solid by column chromatography, with a 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]azacycloheptane-10(4H)-one (I-38)

[0098] 282 mg (1.0 mmol) of 1,3-dimethyl-4H-indeno[1,2-b]thieno[3,4-e]oxepane-10(11H)-one (IIe) and 87 mg (1.0 mmol) of penta-1-amine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of the reactant Ie, the reaction flask was removed from the metal bath and cooled to room temperature. 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl was slowly added dropwise to the flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product, I-38, was obtained as a red solid by column chromatography, with a yield of 87%; mp 110.9–112.9 °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]azacycloheptane-10(4H)-one (I-39)

[0100] 282 mg (1.0 mmol) of 1,3-dimethyl-4H-indeno[1,2-b]thieno[3,4-e]oxepane-10(11H)-one (IIe) and 101 mg (1.0 mmol) of (tetrahydrofuran-2-yl)methylamine were added to a reaction flask and stirred in a metal bath preheated to 40 °C for 2 hours. Thin-layer chromatography (TLC) was used to determine the reaction endpoint. Once the TLC plate showed complete disappearance of the reactant Ie, the reaction flask was removed from the metal bath and cooled to room temperature. 4 mL of MeCN was added as the reaction solvent, and 119 mg (1.0 mmol) of SOCl was slowly added dropwise to the flask. After stirring at room temperature for 2 hours, 560 mg (10.0 mmol) of KOH was added, and the flask was placed in a metal bath preheated to 80 °C. The reaction was stirred for another 2 hours, then quenched with 200 mL of saturated brine and extracted with EtOAc. The organic layer was dried with Na2SO4, and EtOAc was removed under reduced pressure. The target product I-39, a red solid, was obtained by column chromatography with a 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 of the pharmacological tests and results of the compounds of this invention.

[0102] The structural formulas of the compounds in the pharmacological testing section are as follows:

[0103]

[0104] Compound antitumor assay:

[0105] The assay was performed using the CCK-8 assay as standard. Compounds I-1, I-9, I-17, I-20, I-24, I-25, I-28, I-32, I-37, and I-38 were tested at a concentration of 20 μmol / L against common human tumor cells (human lung cancer cells (A549), human gastric cancer cells (MKN-45), and human colon cancer cells (HCT). 116) Inhibitory activity against human cervical cancer cells (HeLa), human chronic myeloid leukemia cells (K-562), human clear cell renal 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), and human rhabdomyosarcoma cells (A-673). This method has been widely used as a primary screening method for tumor cell proliferation inhibition activity. The positive control is doxorubicin hydrochloride (Dox), which is a widely used anti-tumor drug in clinical practice.

[0106] The assay was performed using the CCK-8 assay as standard, measuring the IC50 of compounds with an inhibition rate greater than or equal to 50% in the initial screening results against the corresponding tumor cells. 50 Value. This method has been widely used to inhibit the proliferation activity of tumor cells (IC). 50 The value was determined. The positive control was doxorubicin hydrochloride (Dox), which is a widely used anti-tumor drug in clinical practice.

[0107] Inhibition rate = (mean OD value of control group - mean OD value of treatment group) / mean OD value of control group × 100%. Initial screening results showed that compound I-37 at a concentration of 20 μmol / L had an inhibition rate of 60.28 ± 3.66% against human esophageal cancer cells (TE-1) and 54.93 ± 3.05% against human bladder cancer cells (5637) at the same concentration. Other compounds tested showed inhibition rates of less than 50% against the proliferation of other tumor cells.

[0108] The following describes the antitumor activity (IC50) of compound I-37. 50 Value (μmol / L)

[0109]

[0110] Note: IC50 was calculated only for compounds with a cell inhibition rate of 50% or higher in the initial screening results. 50 IC 50 Value unit: μmol; cell inhibition rate less than 50%, IC50 cannot be calculated. 50 value.

[0111] The above pharmacological tests show that the present invention possesses indanonezaza... Some compounds in the skeleton have certain tumor cell inhibitory activities.

[0112] The above description is merely a specific embodiment of the present invention, illustrating the general method for synthesizing compounds with the parent skeleton of compound I and the antitumor activity of such novel structures. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be within the protection scope of the present invention.

Claims

1. An indene-aza compound, characterized in that, The structural formula of the indene-azo compound .

2. The method for preparing an indene-aza compound according to claim 1, characterized in that, Includes the following steps: Step A: Using indene-benzoxane heptacyclic compound II as raw material, place it in a pressure-resistant tube, add amine compound III under solvent-free and additive-free conditions, maintain the reaction temperature and stir to obtain mixture IV; Step B: Cool the mixture obtained in Step A to room temperature, add the reaction solvent acetonitrile (MeCN) and the reaction reagent SOCl2 directly, maintain the reaction temperature and stir to obtain mixture V; Step C: Add alkali directly to the mixture obtained in Step B, raise the temperature to the reaction temperature and maintain it, and finally obtain the indene-benzo[a]aza compound by column chromatography; the reaction equation is as follows: The R 1 R 2 R 3 The group corresponds to compound I-37 as described in claim 1.

3. The method for preparing the indene-aza compound according to claim 2, characterized in that, In step A, the molar ratio of indene-benzoxoxaheptacyclic compound II to amine compound is 1:1-10, and the reaction temperature is 20-80°C. o C, the heat preservation time is 2-4 hours.

4. The method for preparing the indene-aza compound according to claim 2, characterized in that, In step B, the molar ratio of SOCl2 to indenebenzoxoxaheptacyclic compound II is 1:1, the reaction temperature is room temperature, and the reaction time is 2-4 hours.

5. The method for preparing the indene-aza compound according to claim 2, characterized in that, In step C, the molar ratio of base to indenebenzoxoxane II is 5-10:1, and the reaction temperature is 40-80°C. o C, the heat preservation time is 2-4 hours.

6. The method for preparing the indene-aza compound according to claim 2, characterized in that, The alkali is one of KOH, NaOH, NaH, Na2CO3, and Cs2CO3.

7. The method for preparing the indene-aza compound according to claim 2, characterized in that, The reaction from step A to step B is a one-pot reaction, meaning that the reaction mixture IV obtained in step A can be directly used for step B without pretreatment and separation.

8. The method for preparing the indene-aza compound according to claim 2, characterized in that, The reaction from step B to step C is a one-pot reaction, meaning that the reaction mixture V obtained in step B can be directly carried out in step C without pretreatment and separation.

9. The indene-aza compound according to claim 1, characterized in that, Application of compound I-37 in the preparation of drugs for human esophageal cancer and human bladder cancer.

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