Bacteriostatic application of indole azepine-spiro-oxazolinone compound

Abstract

The invention discloses antibacterial application of an indole azepine-spiro-oxazolinone compound, and belongs to the technical field of medicinal chemistry. The indole azepine-spiro-oxazolinone compound provided by the invention has excellent inhibitory activity on four common pathogenic fungi: peanut root rot bacteria, strawberry botrytis cinerea, valsa mali and cucumber fusarium wilt bacteria, so that the indole azepine-spiro-oxazolinone compound has important application value in the field of agricultural germ control.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to the antibacterial use of indoleazepine-spiro-oxazolinone compounds. Background Art

[0002] Common pathogens in agriculture have brought many challenges to agricultural production. For example, apple rot bacteria seriously harm apple tree branches, fruits and seedlings, affecting the development of the apple industry; cucumber wilt bacteria infect cucumbers throughout their growth period, which can lead to a significant drop in yield or even a total crop failure; strawberry gray mold bacteria harm strawberry fruits, leaves and petioles, and are widely found in strawberry-growing areas; peanut root rot bacteria cause poor growth of peanut plants, rotten seeds, root rot and fruit rot, and are a worldwide peanut disease. These pathogens usually overwinter in soil, diseased remains and seeds, and spread through various channels, such as rain, air currents, and agricultural operations. Once they become ill, they will cause serious losses to crops, reduce the quality and yield of agricultural products, increase agricultural production costs, and pose a threat to the sustainable development of the agricultural economy.

[0003] Agricultural control, such as strengthening management, crop rotation, and cleaning up diseased and residual bodies, is difficult to implement and crop rotation is often limited by land resources; biological control using microorganisms and their metabolites is more environmentally friendly, but the effect is unstable and easily affected by environmental factors; among them, chemical control is the most commonly used means. Although it can quickly and effectively control diseases, its long-term use will cause pathogens to develop drug resistance, thereby reducing the control effect and even making some traditional agents ineffective. These defects make the prevention and control of agricultural pathogens challenging, and we need to continuously explore more effective prevention and control strategies. Therefore, it is urgent to find new active molecules in the field of chemical control to deal with the problem of drug resistance. Summary of the invention

[0004] The present invention provides the use of indoleazepine-spiro-oxazolinone compounds in the preparation of medicines with plant disease fungus inhibition activity.

[0005] In the present invention, the structural formula of the indole aza-spiro-oxazolinone compound is as follows:

[0006]

[0007] Among them, R 1 is selected from any one of acetyl, tert-butyloxycarbonyl, trifluoromethylsulfonyl, cyclopropylsulfonyl, n-butylsulfonyl, pyridylsulfonyl, thienylsulfonyl and morpholinylsulfonyl; X is selected from O or N; when X is O, R 2 Any one selected from phenyl, phenyl with an electron donating group (such as methoxy and methyl) or an electron withdrawing group (such as trifluoromethyl, nitro, fluorine, chlorine and bromine), furyl, thienyl, and R is absent3 ; When X is N, R 2 Any one selected from methyl, phenyl, phenyl with an electron donating group (methoxy and methyl) or an electron withdrawing group (trifluoromethyl, nitro, fluorine, chlorine and bromine), R 3 Any one selected from a phenyl group, a phenyl group with an electron donating group (methoxy and methyl) or an electron withdrawing group (chlorine and bromine).

[0008] The above-mentioned indole aza-spiro-oxazolinone compounds are prepared by the following method:

[0009] An indole-derived aldehyde compound is mixed with a phenyloxazolinone-derived compound, a solvent is added, the system temperature is controlled, and the reaction is stirred to obtain an indole aza-spiro-oxazolinone compound.

[0010] In the above preparation method, the structural formula of the indole-derived aldehyde compound is as follows:

[0011]

[0012] Among them, R 1 Any one selected from the group consisting of acetyl, tert-butyloxycarbonyl, trifluoromethylsulfonyl, cyclopropylsulfonyl, n-butylsulfonyl, pyridylsulfonyl, thienylsulfonyl and morpholinylsulfonyl.

[0013] In the above preparation method, the structural formula of the compound derived from phenyloxazolinone is as follows:

[0014]

[0015] Wherein, X is selected from O or N; when X is O, R 2 Any one selected from phenyl, phenyl with an electron donating group (such as methoxy and methyl) or an electron withdrawing group (such as trifluoromethyl, nitro, fluorine, chlorine and bromine), furyl, thienyl, and R is absent 3 ; When X is N, R 2 Any one selected from methyl, phenyl, phenyl with an electron donating group (methoxy and methyl) or an electron withdrawing group (trifluoromethyl, nitro, fluorine, chlorine and bromine), R 3 Any one selected from a phenyl group, a phenyl group with an electron donating group (methoxy and methyl) or an electron withdrawing group (chlorine and bromine).

[0016] In the above preparation method, the molar ratio of the indole-derived aldehyde compound to the phenyloxazolinone-derived compound is selected from 1:1.2 to 1:1.5. In a specific embodiment, the molar ratio of the two is 1:1.2.

[0017] In the above preparation method, the solvent is selected from any one of ethanol, methanol, isopropanol, water, toluene, ethyl acetate, hexane, and N,N-dimethylformamide. In a specific embodiment, the solvent is ethanol.

[0018] In the above preparation method, the amount of the solvent is selected from: adding 10 to 20 L of solvent per mole of indole-derived aldehyde compound. In a specific embodiment, the amount of the solvent is: adding 10 L of solvent per mole of indole-derived aldehyde compound.

[0019] In the above preparation method, the reaction temperature is selected from 60 to 80° C. In a specific embodiment, the reaction temperature is 60° C.

[0020] The above reaction was carried out under sealed conditions.

[0021] In a specific embodiment, the indole aza-spiro-oxazolinone compound can be specifically selected from the following structural formula:

[0022]

[0023] In the present invention, the plant pathogenic fungi are selected from one or more of apple rot pathogen, cucumber wilt pathogen, strawberry gray mold pathogen and peanut root rot pathogen.

[0024] The beneficial effects of the present invention are:

[0025] The indole azapine-spiro-oxazolinone compounds provided by the present invention have excellent inhibitory activity against four common pathogenic fungi: peanut root rot fungi, strawberry gray mold fungi, apple rot fungi and cucumber wilt fungi, and thus have important application value in the field of agricultural pathogen control. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the antibacterial graph of strawberry gray mold;

[0027] Figure 2 This is the antibacterial chart of apple rot bacteria;

[0028] Figure 3 This is the antibacterial diagram of peanut root rot pathogen;

[0029] Figure 4 This is the antibacterial chart of cucumber wilt bacteria. DETAILED DESCRIPTION

[0030] Other materials used in the present invention, if not otherwise stated, can be obtained through commercial channels. Other terms used in the present invention, unless otherwise specified, generally have the meanings commonly understood by those of ordinary skill in the art. The present invention is further described in detail below in conjunction with specific examples and with reference to data. The following examples are only for illustrating the present invention, and are not intended to limit the scope of the present invention in any way.

[0031] 1. Preparation of indole-aza-spiro-oxazolinone compounds

[0032] The preparation of indole azepine-spiro-oxazolinone compounds is as follows:

[0033] 0.2 mmol of indole-derived aldehyde compounds and 0.24 mmol of phenyloxazolinone-derived compounds were placed in a sealed tube, 2 mL of ethanol was added, the system temperature was controlled at 60°C, stirring was continued, and the reaction was tracked by spotting on a thin layer chromatography plate until the raw materials reacted completely. After completion, column chromatography technology was used for column separation and purification, and the purified product was distilled under reduced pressure to obtain indole aza-spiro-oxazolinone compounds.

[0034] The structural formula of the above-mentioned indole aza-spiro-oxazolinone compound is as follows:

[0035]

[0036] Among them, R 1 is selected from any one of acetyl, tert-butyloxycarbonyl, trifluoromethylsulfonyl, cyclopropylsulfonyl, n-butylsulfonyl, pyridylsulfonyl, thienylsulfonyl and morpholinylsulfonyl; X is selected from O or N; when X is O, R 2 Any one selected from phenyl, phenyl with an electron donating group (such as methoxy and methyl) or an electron withdrawing group (such as trifluoromethyl, nitro, fluorine, chlorine and bromine), furyl, thienyl, and R is absent 3 ; When X is N, R 2 Any one selected from methyl, phenyl, phenyl with an electron donating group (methoxy and methyl) or an electron withdrawing group (trifluoromethyl, nitro, fluorine, chlorine and bromine), R 3 Any one selected from a phenyl group, a phenyl group with an electron donating group (methoxy and methyl) or an electron withdrawing group (chlorine and bromine).

[0037] The structural formula of the above-mentioned indole-derived aldehyde compound is as follows:

[0038]

[0039] Among them, R 1Any one selected from the group consisting of acetyl, tert-butyloxycarbonyl, trifluoromethylsulfonyl, cyclopropylsulfonyl, n-butylsulfonyl, pyridylsulfonyl, thienylsulfonyl and morpholinylsulfonyl.

[0040] The structural formula of the above-mentioned phenyloxazolinone-derived compound is as follows:

[0041]

[0042] Wherein, X is selected from O or N; when X is O, R 2 Any one selected from phenyl, phenyl with an electron donating group (such as methoxy and methyl) or an electron withdrawing group (such as trifluoromethyl, nitro, fluorine, chlorine and bromine), furyl, thienyl, and R is absent 3 ; When X is N, R 2 Any one selected from methyl, phenyl, phenyl with an electron donating group (methoxy and methyl) or an electron withdrawing group (trifluoromethyl, nitro, fluorine, chlorine and bromine), R 3 Any one selected from a phenyl group, a phenyl group with an electron donating group (methoxy and methyl) or an electron withdrawing group (chlorine and bromine).

[0043] According to the above method, the present invention prepared 31 indole aza-spiro-oxazolinone compounds, and the specific preparation process thereof is referred to the following examples.

[0044] The chemical reaction formula is as follows:

[0045]

[0046] 0.2mmol 4-(pyrrolidin-1-yl)-1-p-toluenesulfonyl-1H-indole-3-carboxaldehyde and 0.24mmol 3-phenylisoxazol-5(4H)-one were placed in a sealed tube, 2mL ethanol was added, the system temperature was controlled at 60°C, stirring was continued, and the reaction of the raw materials was tracked by spotting on a thin layer chromatography plate until the reaction was complete. After completion, column chromatography technology was used for column separation and purification, and the purified product was distilled under reduced pressure to obtain the target product.

[0047] The NMR data of the 31 indoleazepine-spiro-oxazolinone compounds are as follows:

[0048] Example 1

[0049]

[0050] 3-phenyl-1'-tosyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]aze pino[4,3,2-cd]indol]-5-one:Light yellow solid;92.0mg,90%yield,1.2:1dr;mp 104-106℃;Rf=0.25(petroleum ether / EtOAc=5 / 1);eluent:petroleum ether / EtOAc=5 / 1; 1 H NMR(500MHz,CDCl3):for major diastereomer:δ7.93–7.88(m,2H),7.82–7.77(m,2H),7.49(d,J=5.8Hz,1H),7.38–7.32(m,2H),7.31–7.14(m,5H),6.44(d,J=7.9Hz,1H),4.13(dd,J=9.5,2.2Hz,1H),3.60(dd,J=16.3,1.9Hz,1H),3.28–3.10(m,3H),2.33(s,3H),2.10–1.98(m,1H),1.80–1.73(m,1H),1.65(ddd,J=9.7,6.7,4.5Hz,1H),1.62–1.52(m,1H);for minor diastereomer:δ7.77–7.74(m,2H),7.74–7.70(m,2H),7.51(d,J=5.9Hz,1H),7.47–7.43(m,1H),7.31–7.14(m,6H),6.52(d,J=7.9Hz,1H),4.16(dd,J=9.3,2.1Hz,1H),3.52(dd,J=16.3,1.9Hz,1H),3.45(dd,J=8.8,6.8Hz,1H),3.28–3.10(m,2H),2.36(s,3H),2.10–1.98(m,1H),1.96–1.84(m,2H),1.62–1.52(m,1H); 1313C NMR (126 MHz, CDCl3): for both major and minor diastereomers: δ 179.1, 178.9, 168.6, 168.1, 145.1, 145.05, 145.00, 144.6, 136.5, 136.4, 135.3, 135.2, 131.8, 131.4, 130.03, 130.01, 129.1, 128.7, 128.4, 127.9, 127.7, 127.1, 127.0, 126.9, 126.3, 125.9, 121.7, 121.1, 120.8, 120.5, 118.1, 116.9, 106.3, 106.1, 105.7, 105.3, 70.3, 68.3, 58.4, 57.1, 50.2, 49.5, 31.8, 31.2, 29.1, 29.0, 24.1, 23.7, 21.67, 21.66; HRMS (ESI-TOF) m / z: [M+H] + calcd for C 29 H 26 N3O4S, 512.1639; found, 512.1636.

[0051] Example 2

[0052]

[0053] 3-(4-methoxyphenyl)-1'-tosyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: Yellow solid; 90.9 mg, 84% yield, 1.4:1 dr; mp 165 - 167 °C; Rf = 0.32 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1H NMR(400MHz,CDCl3):for major diastereomer:δ8.01–7.93(m,2H),7.83–7.74(m,2H),7.52(d,J=8.2Hz,1H),7.33(d,J=1.8Hz,1H),7.287.17(m,3H),6.85–6.79(m,2H),6.51(d,J=8.5Hz,1H),4.19–4.10(m,1H),3.79(s,3H),3.58(dd,J=16.3,2.0Hz,1H),3.28–3.16(m,1H),3.10(d,J=16.3Hz,1H),2.34(s,3H),2.02–1.83(m,1H),1.80–1.72(m,1H),1.61–1.48(m,2H);for minor diastereomer:δ7.83–7.74(m,2H),7.70–7.64(m,2H),7.51(d,J=8.2Hz,1H),7.28–7.17(m,4H),6.79–6.73(m,2H),6.53(d,J=8.5Hz,1H),4.19–4.10(m,1H),3.83(s,3H),3.52(dd,J=16.3,2.0Hz,1H),3.48–3.41(m,1H),3.28–3.16(m,2H),2.37(s,3H),2.08(dt,J=10.9,7.1Hz,1H),2.02–1.83(m,2H),1.66–1.61(m,1H); 13 C NMR(101MHz,CDCl3):for both major and minordiastereomers:δ179.4,179.2,168.1,167.4,162.3,162.0,145.18,145.17,145.04,145.00,136.6,136.3,135.3,135.2,130.3,130.05,130.02,129.4,127.0,126.9,126.3,125.9,121.7,121.1,121.0,120.6,120.1,119.2,118.5,116.9,114.6,114.2,106.3,106.1,106.0,105.3,70.5,68.5,58.3,57.2,55.55,55.47,50.2,49.5,31.8,31.0,29.0,28.7,24.2,23.7,21.7;HRMS(ESI-TOF)m / z:[M+H] +Calculated for C 30 H 28 N3O5S, 542.1744; found, 542.1744.

[0054] Example 3

[0055]

[0056] 3-(p-tolyl)-1'-tosyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]

[0057] azepino[4,3,2-cd]indol]-5-one: Brown solid; 92.5 mg, 88% yield, 1.1:1 dr; mp 121 - 123 °C; Rf = 0.33 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1H NMR(500MHz,CDCl3):for major diastereomer:δ7.75–7.68(m,2H),7.55(d,J=7.9Hz,2H),7.45(d,J=8.2Hz,1H),7.21–7.09(m,4H),7.05–6.97(m,2H),6.47(d,J=7.9Hz,1H),4.13–4.03(m,1H),3.46(dd,J=16.3,2.0Hz,1H),3.39(t,J=7.8Hz,1H),3.22–3.08(m,2H),2.31(s,3H),2.30(s,3H),2.06–1.97(m,1H),1.88–1.87(m,1H),1.61–1.56(m,1H),1.55–1.42(m,1H);for minor diastereomer:δ7.79(d,J=8.0Hz,2H),7.75–7.68(m,2H),7.44(d,J=8.2Hz,1H),7.26(s,1H),7.21–7.09(m,3H),7.05–6.97(m,2H),6.41(d,J=7.9Hz,1H),4.13–4.03(m,1H),3.54(dd,J=16.3,1.9Hz,1H),3.22–3.08(m,2H),3.05(d,J=16.4Hz,1H),2.28(s,3H),2.25(s,3H),1.961.89(m,1H),1.88–1.87(m,1H),1.73–1.65(m,1H),1.55–1.42(m,1H); 1313C NMR(101MHz,CDCl3): for both major and minor diastereomers: δ 179.3, 179.1, 168.5, 167.9, 145.10, 145.06, 145.03, 144.9, 142.4, 142.0, 136.6, 136.4, 135.4, 135.3, 130.04, 130.02, 129.9, 129.5, 128.4, 127.6, 127.0, 126.9, 126.3, 125.9, 125.0, 124.2, 121.7, 121.1, 121.0, 120.6, 118.3, 116.9, 106.3, 106.1, 105.9, 105.3, 70.5, 68.4, 58.3, 57.2, 50.2, 49.5, 31.8, 31.1, 29.1, 28.8, 24.2, 23.7, 21.71, 21.67, 21.61, 21.57; HRMS(ESI-TOF) m / z: [M+H] + calcd for C 30 H 28 N3O4S, 526.1795; found, 526.1798.

[0058] Example 4

[0059]

[0060] 1'-tosyl-3-(4-(trifluoromethyl)phenyl)-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: Yellow solid; 92.7 mg, 80% yield, 1.6:1 dr; mp 104 - 106 °C; Rf = 0.35 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1HNMR(500MHz,CDCl3):for majordiastereomer:δ7.83–7.79(m,2H),7.77(d,J=8.2Hz,2H),7.50(d,J=8.3Hz,1H),7.38(d,J=1.3Hz,1H),7.31 7.21(m,4H),7.13(t,J=8.1Hz,1H),6.31(d,J=7.9Hz,1H),4.13(dd,J=8.9,3.1Hz,1H),3.56(dd,J=16.5,1.7Hz,1H),3.29(dd,J=16.5,1.1Hz,1H),3.27–3.17(m,1H),3.11–3.04(m,1H),2.36(s,3H),2.16–2.06(m,1H),1.93–1.79(m,1H),1.68–1.56(m,2H);for minor diastereomer:δ7.86(d,J=8.3Hz,2H),7.83–7.79(m,2H),7.58(d,J=8.3Hz,1H),7.47(d,J=8.4Hz,2H),7.31–7.21(m,4H),6.56(d,J=7.9Hz,1H),4.09(dd,J=9.4,2.2Hz,1H),3.61(dd,J=16.2,2.0Hz,1H),3.50–3.43(m,1H),3.27–3.17(m,2H),2.39(s,3H),2.16–2.06(m,1H),1.93–1.79(m,2H),1.68–1.56(m,1H); 1313C NMR(101MHz,CDCl3): for both major and minor diastereomers: δ 178.6, 178.5, 167.6, 167.7, 145.4, 145.3, 145.2, 143.6, 136.6, 136.4, 135.4, 135.1, 133.2(q, J = 33.0Hz), 132.4(q, J = 33.0Hz), 131.4(q, J = 1.1Hz), 130.5(q, J = 1.1Hz), 130.1, 130.0, 128.7, 128.2, 127.1, 126.9, 126.5, 126.1, 126.0(q, J = 3.8Hz), 125.2(q, J = 3.8Hz), 123.53(q, J = 273.7Hz), 123.50(q, J = 273.7Hz), 121.7, 121.1, 120.7, 120.2, 118.1, 116.7, 106.45, 106.38, 105.8, 105.4, 69.7, 68.3, 58.5, 57.2, 50.1, 49.8, 31.6, 29.5, 28.8, 23.9, 23.7, 21.6; 19 19F NMR(376MHz,CDCl3) δ –63.13(minor diastereomer), –63.19(major diastereomer); HRMS(ESI-TOF) m / z: [M+H] + calcd for C 30 H 25 F3N3O4S, 580.1512; found, 580.1513.

[0061] Example 5

[0062]

[0063] 3-(4-nitrophenyl)-1'-tosyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: Brown solid; 99.0 mg, 89% yield, 2.1:1 dr; mp 218 - 220 °C; Rf = 0.25(petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1H NMR(500MHz,CDCl3):for major diastereomer:δ7.85–7.79(m,2H),7.77(d,J=8.8Hz,2H),7.72(d,J=9.1Hz,2H),7.50(d,J=8.3Hz,1H),7.40(s,1H),7.32–7.27(m,2H),7.12(t,J=8.1Hz,1H),6.26(d,J=7.9Hz,1H),4.12(dd,J=8.9,3.2Hz,1H),3.56(dd,J=16.7,1.3Hz,1H),3.37(d,J=16.8Hz,1H),3.27–3.16(m,1H),3.02(ddt,J=9.4,7.3,2.9Hz,1H),2.39(s,3H),2.21–2.07(m,1H),1.93–1.82(m,1H),1.68–1.60(m,2H);for minor diastereomer:δ8.05–8.01(m,2H),7.93 7.90(m,2H),7.85–7.79(m,2H),7.59(d,J=8.3Hz,1H),7.36(d,J=8.2Hz,2H),7.32–7.27(m,1H),7.24(t,J=8.1Hz,1H),6.57(d,J=7.9Hz,1H),4.08–4.04(m,1H),3.65(d,J=16.2Hz,1H),3.48(dd,J=8.8,7.0Hz,1H),3.27–3.16(m,2H),2.43(s,3H),2.21–2.07(m,1H),1.93–1.82(m,2H),1.58–1.53(m,1H); 1313C NMR(101MHz,CDCl3): for both major and minor diastereomers: δ 178.4, 178.1, 167.6, 167.0, 149.4, 148.7, 145.8, 145.5, 145.2, 143.2, 136.6, 136.5, 135.4, 135.1, 134.1, 132.8, 130.3, 130.1, 129.3, 128.8, 127.1, 126.9, 126.6, 126.3, 124.1, 123.3, 121.9, 121.1, 120.7, 119.9, 117.9, 116.5, 106.54, 106.48, 106.0, 105.5, 69.4, 68.4, 58.7, 57.3, 50.1, 49.9, 31.9, 31.6, 29.8, 28.8, 23.8, 23.7, 21.75, 21.71; HRMS(ESI-TOF) m / z: [M+H] + calcd for C 29 H 25 N4O6S, 557.1489; found, 557.1489.

[0064] Example 6

[0065]

[0066] 3-(4-fluorophenyl)-1'-tosyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: Yellow solid; 94.3 mg, 89% yield, 1.5:1 dr; mp 183 - 185 °C; Rf = 0.40 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1H NMR(500MHz,CDCl3):for major diastereomer:δ7.92–7.87(m,2H),7.83–7.76(m,2H),7.52(d,J=8.3Hz,1H),7.35(d,J=1.7Hz,1H),7.297.16(m,3H),6.95–6.85(m,2H),6.44(d,J=7.9Hz,1H),4.16–4.08(m,2H),3.55(dd,J=10.3,2.0Hz,1H),3.28–3.10(m,3H),2.35(s,3H),2.16–2.01(m,1H),1.80(qd,J=7.8,7.4,3.0Hz,1H),1.64–1.53(m,2H);for minor diastereomer:δ7.83 7.76(m,2H),7.74–7.68(m,2H),7.54(d,J=8.2Hz,1H),7.29–7.16(m,4H),6.95–6.85(m,2H),6.55(d,J=7.9Hz,1H),4.16–4.08(m,2H),3.58(dd,J=10.1,2.0Hz,1H),3.46(t,J=7.9Hz,1H),3.28–3.10(m,2H),2.39(s,3H),2.16–2.01(m,1H),1.95–1.85(m,2H),1.64–1.53(m,1H); 13CNMR(101MHz,CDCl3): for both major and minor diastereomers: δ 179.0, 178.9, 167.7, 167.3, 165.6(d, J = 255.3Hz), 164.4(d, J = 254.9Hz), 145.3, 145.2, 145.1, 144.4, 136.6, 136.4, 135.5, 135.2, 130.8(d, J = 8.7Hz), 130.13, 130.06(d, J = 8.8Hz), 130.0, 127.0, 126.9, 126.0, 126.4, 124.2(d, J = 3.5Hz), 123.3(d, J = 3.5Hz), 121.8, 121.0, 120.7, 120.6, 118.2, 116.7, 116.4(d, J = 22.0Hz), 115.9(d, J = 22.1Hz), 106.4, 106.3, 105.9, 105.7, 70.2, 68.4, 58.3, 57.3, 50.2, 49.6, 31.7, 31.2, 29.0, 28.9, 24.1, 23.7, 21.7; 19 F NMR(376MHz,CDCl3) δ -106.52(minor diastereomer), -107.25(major diastereomer); HRMS(ESI-TOF) m / z: [M + H] + calcd for C 29 H 25 FN3O4S, 530.1544; found, 530.1541.

[0067] Example 7

[0068]

[0069] 3-(4-chlorophenyl)-1'-tosyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: Yellow solid; 95.0 mg, 87% yield, 1.5:1 dr; mp 142 - 144 °C; Rf = 0.38(petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1H NMR(500MHz,CDCl3):for major diastereomer:δ7.83–7.73(m,4H),7.51(d,J=8.3Hz,1H),7.34(s,1H),7.26–7.10(m,5H),6.42(d,J=7.9Hz,1H),4.11(dd,J=9.4,2.3Hz,1H),3.61–3.49(m,1H),3.27–3.08(m,3H),2.35(s,3H),2.12–2.00(m,1H),1.79(dq,J=11.6,5.8,4.3Hz,1H),1.62–1.51(m,2H);for minordiastereomer:δ7.83–7.73(m,2H),7.63(d,J=8.4Hz,2H),7.55(d,J=8.3Hz,1H),7.28(d,J=8.0Hz,2H),7.26–7.10(m,4H),6.54(d,J=7.9Hz,1H),4.09–4.02(m,1H),3.613.49(m,1H),3.44(t,J=7.9Hz,1H),3.27–3.08(m,3H),2.40(s,3H),2.12–2.00(m,1H),1.931.84(m,2H),1.62–1.51(m,1H); 13 C NMR(101MHz,CDCl3):for both major and minordiastereomers:δ178.8,178.7,167.7,167.4,145.3,145.2,145.1,144.2,138.0,137.5,136.5,136.3,135.5,135.1,130.1,130.0,129.7,129.4,129.0,128.9,127.0,126.9,126.41,126.36,126.0,125.4,121.8,121.0,120.61,120.59,118.2,116.7,106.4,106.3,105.8,105.7,70.1,68.3,58.3,57.2,50.1,49.6,31.6,31.2,29.1,28.9,24.0,23.7,21.7,21.6;HRMS(ESI-TOF)m / z:[M+H] + calcd for C 29 H 25 ClN3O4S,546.1249;found,546.1254.

[0070] Example 8

[0071]

[0072] 3-(4-bromophenyl)-1'-tosyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: Yellow solid; 99.2 mg, 84% yield, 1.4:1 dr; mp 160 - 162 °C; Rf = 0.38 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1 1H NMR (500 MHz, CDCl3): for major diastereomer: δ 7.82–7.76 (m, 2H), 7.71–7.66 (m, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 1.4 Hz, 1H), 7.33–7.23 (m, 4H), 7.17 (t, J = 8.1 Hz, 1H), 6.41 (d, J = 7.9 Hz, 1H), 4.11 (dd, J = 9.4, 2.4 Hz, 1H), 3.60–3.50 (m, 1H), 3.26–3.17 (m, 2H), 3.10 (ddd, J = 8.8, 6.4, 1.8 Hz, 1H), 2.35 (s, 3H), 2.13–2.00 (m, 1H), 1.83–1.76 (m, 1H), 1.62–1.51 (m, 2H); for minor diastereomer: δ 7.82–7.76 (m, 2H), 7.58–7.54 (m, 3H), 7.33–7.23 (m, 5H), 7.21 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 7.9 Hz, 1H), 4.06 (dd, J = 9.2, 2.3 Hz, 1H), 3.60–3.50 (m, 1H), 3.47–3.41 (m, 1H), 3.26–3.17 (m, 1H), 3.15 (d, J = 16.3 Hz, 1H), 2.40 (s, 3H), 2.13–2.00 (m, 1H), 1.92–1.83 (m, 2H), 1.62–1.51 (m, 1H); 1313C NMR (101 MHz, CDCl3): for both major and minor diastereomers: δ 178.8, 167.8, 167.5, 145.3, 145.2, 145.1, 144.2, 136.5, 136.3, 135.5, 135.1, 132.3, 131.8, 130.1, 130.0, 129.8, 129.2, 127.0, 126.9, 126.8, 126.5, 126.4, 126.1, 126.0, 125.9, 121.8, 121.0, 120.62, 120.56, 118.2, 116.7, 106.4, 106.3, 105.72, 105.70, 70.0, 68.3, 58.3, 57.2, 50.1, 49.6, 31.6, 31.2, 29.1, 28.8, 24.0, 23.7, 21.8, 21.7; HRMS (ESI-TOF) m / z: [M+H] + calcd for C 29 H 25 BrN3O4S, 590.0744; found, 590.1743.

[0073] Example 9

[0074]

[0075] 3-(furan-2-yl)-1'-tosyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: White solid; 94.2 mg, 94% yield, 1.2:1 dr; mp 117 - 119 °C; Rf = 0.26 (petroleum ether / EtOAc = 6 / 1); eluent: petroleum ether / EtOAc = 6 / 1; 1H NMR(500MHz,CDCl3):for major diastereomer:δ7.80–7.77(m,2H),7.55–7.45(m,2H),7.27–7.16(m,4H),6.69(d,J=3.5Hz,1H),6.56–6.51(m,1H),6.41(dd,J=3.6,1.8Hz,1H),4.18(dd,J=9.1,2.4Hz,1H),3.52(d,J=15.9,1H),3.45(ddd,J=8.6,6.4,1.7Hz,1H),3.27(ddd,J=10.3,8.9,6.1Hz,1H),3.21–3.13(m,1H),2.37(s,3H),2.08(tdd,J=11.3,6.9,4.3Hz,1H),1.89(tdd,J=11.5,5.4,3.6Hz,1H),1.67–1.50(m,2H);for minor diastereomer:δ7.77–7.73(m,2H),7.55 7.45(m,2H),7.32(d,J=1.8Hz,1H),7.27–7.16(m,3H),6.95(d,J=3.5Hz,1H),6.56–6.51(m,1H),6.43(dd,J=3.6,1.8Hz,1H),4.11(dd,J=9.7,1.6Hz,1H),3.52(d,J=15.9,1H),3.21–3.13(m,3H),2.35(s,3H),2.03–1.93(m,2H),1.81(ddd,J=11.9,8.2,3.7Hz,1H),1.67–1.50(m,1H); 13CNMR(101MHz, CDCl3): For both major and minor diastereomers: δ 178.3, 177.7, 160.3, 159.7, 146.1, 146.0, 145.12, 145.07, 145.06, 142.7, 142.1, 136.5, 136.3, 135.3, 135.2, 130.02, 130.01, 127.0, 126.9, 126.3, 126.0, 121.7, 121.2, 121.0, 120.6, 118.0, 117.9, 116.7, 116.1, 112.3, 112.2, 106.4, 106.2, 106.0, 105.4, 70.2, 68.5, 57.7, 56.8, 50.1, 49.6, 31.9, 31.3, 29.3, 28.7, 24.2, 23.6, 21.7; HRMS(ESI-TOF) m / z: [M+H] + Calcd for C 27 H 24 N3O5S, 502.1431; found, 502.1431.

[0076] Example 10

[0077]

[0078] 3-(Thiophen-2-yl)-1'-tosyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: Yellow solid; 90.0 mg, 87% yield, 2:1 dr; mp 165 - 167 °C; Rf = 0.33 (petroleum ether / EtOAc = 6 / 1); eluent: petroleum ether / EtOAc = 6 / 1; 1H NMR(500MHz,CDCl3):for major diastereomer:δ7.80–7.74(m,2H),7.65(dd,J=3.9,1.1Hz,1H),7.51(t,J=7.9Hz,1H),7.47(dd,J=5.0,1.0Hz,1H),7.32(d,J=1.8Hz,1H),7.26–7.18(m,3H),6.97(dd,J=5.1,3.8Hz,1H),6.56–6.51(m,1H),4.17–4.11(m,1H),3.60–3.54(m,1H),3.26–3.12(m,3H),2.34(s,3H),2.04–1.95(m,1H),1.78(tdd,J=10.2,5.9,4.0Hz,1H),1.60–1.56(m,1H),1.54 1.50(m,1H);forminor diastereomer:δ7.80–7.74(m,2H),7.51(t,J=7.9Hz,1H),7.47(dd,J=5.0,1.0Hz,1H),7.26–7.18(m,4H),7.16(dd,J=3.8,1.0Hz,1H),6.88(dd,J=5.1,3.8Hz,1H),6.56–6.51(m,1H),4.17–4.11(m,1H),3.60–3.54(m,1H),3.45(dd,J=8.8,6.8Hz,1H),3.26–3.12(m,2H),2.36(s,3H),2.14–2.05(m,1H),1.95–1.83(m,2H),1.65–1.60(m,1H); 1313C NMR (101 MHz, CDCl3): for both major and minor diastereomers: δ 178.7, 178.6, 164.4, 164.1, 145.4, 145.22, 145.19, 145.1, 136.6, 136.3, 135.3, 135.2, 133.3, 131.4, 130.7, 130.8, 130.1, 130.0, 129.2, 128.1, 127.9, 127.01, 127.97, 126.4, 126.0, 121.8, 121.29, 121.26, 120.7, 118.1, 116.7, 106.4, 106.3, 106.2, 105.6, 70.5, 68.9, 58.2, 57.5, 50.2, 49.7, 31.8, 31.2, 29.0, 28.6, 24.2, 23.7, 21.73, 21.71; HRMS (ESI-TOF) m / z: [M+H] + calcd for C 27 H 24 N3O4S2, 518.1203; found, 518.1203.

[0079] Example 11

[0080]

[0081] 3-methyl-1'-tosyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: White solid; 78.2 mg, 87% yield, 4.8:1 dr; mp 187 - 189 °C; Rf = 0.29 (petroleum ether / EtOAc = 6 / 1); eluent: petroleum ether / EtOAc = 6 / 1; 1H NMR(500MHz,CDCl3):for major diastereomer:δ7.75(dd,J=8.5,2.0Hz,2H),7.48(d,J=8.5Hz,1H),7.34(d,J=0.9Hz,1H),7.25–7.19(m,3H),6.43(d,J=8.0Hz,1H),3.94(dd,J=7.4,6.3Hz,1H),3.51–3.43(m,2H),3.33(dd,J=16.7,2.0Hz,1H),3.11(dd,J=16.6,0.9Hz,1H),2.34(s,3H),2.26(dq,J=12.9,7.3Hz,1H),1.99–1.87(m,2H),1.72–1.67(m,1H),1.64(s,3H);for minor diastereomer:δ7.75(dd,J=8.5,2.0Hz,2H),7.46(d,J=8.5Hz,1H),7.28(d,J=1.8Hz,1H),7.25–7.19(m,2H),7.18(t,J=8.1Hz,1H),6.54(d,J=7.9Hz,1H),3.76(dd,J=9.6,2.1Hz,1H),3.51–3.43(m,1H),3.41(dd,J=8.6,6.9Hz,1H),3.18(ddd,J=11.0,8.7,5.8Hz,1H),2.83(d,J=15.4Hz,1H),2.34(s,3H),2.18–2.09(m,1H),2.01(s,3H),1.99–1.87(m,2H),1.72–1.67(m,1H); 13 C NMR(101MHz,CDCl3):for major diastereomer:δ179.0,168.9,145.1,141.8,136.8,134.9,129.9,126.9,126.3,121.7,118.1,116.2,107.0,104.0,66.8,57.9,50.9,33.1,31.6,22.7,21.7,14.7;for minor diastereomer:δ178.7,169.0,145.8,136.3,135.1,130.0,126.9,126.3,121.3,120.8,117.4,106.4,105.7,67.5,57.4,49.7,30.9,28.7,23.8,12.6;HRMS(ESI-TOF)m / z:[M+H] + calcd for C24 H 24 N3O4S, 450.1482; found, 450.1482.

[0082] Example 12

[0083]

[0084] 3-phenyl-1'-((trifluoromethyl)sulfonyl)-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: White solid; 93.0 mg, 95% yield, 1.1:1 dr; mp 171 - 173 °C; Rf = 0.38 (petroleum ether / EtOAc = 10 / 1); eluent: petroleum ether / EtOAc = 10 / 1; 1 1H NMR (400 MHz, CDCl3): for major diastereomer: δ 8.04–7.93 (m, 2H), 7.46–7.25 (m, 5H), 7.15 (d, J = 1.9 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 4.22 (dd, J = 9.5, 2.1 Hz, 1H), 3.66 (dd, J = 16.3, 2.1 Hz, 1H), 3.37–3.23 (m, 2H), 3.18 (d, J = 16.4 Hz, 1H), 2.20–2.05 (m, 2H), 1.89–1.80 (m, 1H), 1.77–1.69 (m, 1H); for minor diastereomer: δ 7.76 (dt, J = 7.2, 1.3 Hz, 2H), 7.53–7.47 (m, 1H), 7.46–7.25 (m, 4H), 7.10 (d, J = 1.9 Hz, 1H), 6.68 (d, J = 7.9 Hz, 1H), 4.26 (dd, J = 9.0, 2.1 Hz, 1H), 3.62–3.50 (m, 2H), 3.37–3.23 (m, 2H), 2.05–1.91 (m, 2H), 1.69–1.57 (m, 2H); 1313C NMR(101MHz,CDCl3): for both major and minor diastereomers: δ 178.9, 178.6, 168.4, 167.7, 145.4, 145.1, 137.0, 136.9, 132.1, 131.6, 129.3, 128.9, 128.4, 127.8, 127.6, 127.5, 127.2, 127.0, 121.3, 121.0, 120.8, 120.7, 120.3, 119.8(q, J = 325.8Hz), 119.70, 119.69(q, J = 325.5Hz), 108.1, 107.9, 105.8, 105.3, 70.7, 68.5, 58.2, 57.0, 50.3, 49.7, 31.6, 30.9, 29.2, 29.0, 24.2, 23.7; 19F NMR(376MHz, CDCl3) δ -75.01; HRMS(ESI-TOF) m / z: [M+H]+ calcd for C 23 H 19 F3N3O4S, 490.1043; found, 490.1044.

[0085] Example 13

[0086]

[0087] 1'-(cyclopropylsulfonyl)-3-phenyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: White solid; 68.2 mg, 74% yield, 1.4:1 dr; mp 197 - 199 °C; Rf = 0.39 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1HNMR(500MHz,CDCl3):for majordiastereomer:δ8.04(d,J=7.2Hz,2H),7.47–7.33(m,4H),7.26–7.21(m,1H),7.18(d,J=1.8Hz,1H),6.56(d,J=7.9Hz,1H),4.33–4.24(m,1H),3.68(dd,J=16.2,1.9Hz,1H),3.37–3.22(m,2H),3.16(d,J=16.3Hz,1H),2.68–2.59(m,1H),2.17–2.05(m,1H),1.86–1.78(m,1H),1.67–1.61(m,1H),1.61–1.56(m,1H),1.43–1.31(m,2H),1.09–0.97(m,2H);for minordiastereomer:δ7.82–7.74(m,2H),7.49(d,J=8.1Hz,2H),7.47–7.33(m,2H),7.26–7.21(m,1H),7.12(d,J=1.7Hz,1H),6.60(d,J=7.9Hz,1H),4.33–4.24(m,1H),3.58(dd,J=16.2,1.9Hz,1H),3.53(t,J=7.8Hz,1H),3.37–3.22(m,2H),2.68–2.59(m,1H),2.17–2.05(m,1H),2.04–1.97(m,1H),1.94(ddd,J=13.2,11.0,5.6Hz,1H),1.73(dd,J=13.2,7.0Hz,1H),1.43–1.31(m,2H),1.09–0.97(m,2H); 1313C NMR (101 MHz, CDCl3): for both major and minor diastereomers: δ 179.3, 178.8, 168.6, 168.0, 145.02, 144.97, 136.9, 136.7, 131.9, 131.6, 129.2, 128.8, 128.5, 127.9, 127.7, 127.2, 126.3, 125.9, 122.0, 121.4, 121.0, 120.5, 117.2, 116.0, 106.2, 106.0, 105.8, 105.0, 70.6, 68.3, 58.4, 57.1, 50.3, 49.6, 31.9, 31.4, 31.2, 31.0, 29.4, 28.9, 24.2, 23.8, 6.23, 6.21, 6.13; HRMS (ESI-TOF) m / z: [M+H] + calcd for C 25 H 24 N3O4S, 462.1482; found, 462.1482.

[0088] Example 14

[0089]

[0090] 1'-(butylsulfonyl)-3-phenyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: Light yellow solid; 76.4 mg, 80% yield, 1.4:1 dr; mp 135 - 137 °C; Rf = 0.24 (petroleum ether / EtOAc = 10 / 1); eluent: petroleum ether / EtOAc = 10 / 1; 1HNMR(500MHz,CDCl3):for majordiastereomer:δ8.08–7.98(m,2H),7.45–7.32(m,4H),7.27–7.20(m,2H),6.56(d,J=7.9Hz,1H),4.25(dd,J=9.6,2.1Hz,1H),3.68(dd,J=16.2,2.0Hz,1H),3.38–3.22(m,4H),3.16(d,J=16.3Hz,1H),2.17–1.97(m,1H),1.86–1.79(m,1H),1.77–1.56(m,4H),1.41–1.32(m,2H),0.88(t,J=7.2Hz,3H);for minor diastereomer:δ7.82–7.74(m,2H),7.51–7.46(m,1H),7.45–7.32(m,3H),7.27–7.20(m,1H),7.15(d,J=1.6Hz,1H),6.59(d,J=7.9Hz,1H),4.29(dd,J=9.0,2.4Hz,1H),3.60–3.50(m,2H),3.38–3.22(m,4H),2.17–1.97(m,2H),1.94(tdd,J=11.6,5.2,3.3Hz,1H),1.77–1.56(m,3H),1.41–1.32(m,2H),0.87(t,J=7.2Hz,3H); 13 C NMR(101MHz,CDCl3):for both major and minor diastereomers:δ179.2,178.6,168.5,167.9,145.1,145.0,136.7,136.5,131.9,131.6,129.3,128.8,128.5,127.9,127.6,127.2,126.4,126.1,122.1,121.6,120.9,120.3,116.9,115.8,106.3,106.1,105.5,104.4,70.7,68.3,58.4,57.0,53.7,53.3,50.3,49.6,31.9,31.0,29.5,28.9,25.1,25.0,24.2,23.7,21.4,21.3,13.50,13.47;HRMS(ESI TOF)m / z:[M+H] + calcd for C 26 H 28N3O4S, 478.1795; found, 478.1796.

[0091] Example 15

[0092]

[0093] 3-phenyl-1'-(pyridin-3-ylsulfonyl)-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: Yellow solid; 87.7 mg, 88% yield, 1.2:1 dr; mp 198 - 200 °C; Rf = 0.40 (petroleum ether / EtOAc = 3 / 1); eluent: petroleum ether / EtOAc = 3 / 1; 1 1H NMR (500 MHz, CDCl3): for major diastereomer: δ 9.11 (d, J = 2.4 Hz, 1H), 8.76 (dd, J = 4.9, 1.7 Hz, 1H), 8.19–8.11 (m, 1H), 7.96–7.90 (m, 2H), 7.54–7.47 (m, 1H), 7.44–7.34 (m, 2H), 7.32 (d, J = 1.7 Hz, 1H), 7.30–7.18 (m, 3H), 6.50 (d, J = 7.9 Hz, 1H), 4.12 (dd, J = 9.5, 2.2 Hz, 1H), 3.62 (dd, J = 16.3, 1.9 Hz, 1H), 3.31 3.13 (m, 3H), 2.12–1.99 (m, 1H), 1.83–1.75 (m, 1H), 1.71–1.67 (m, 1H), 1.64 1.52 (m, 1H); for minor diastereomer: δ 9.09 (d, J = 2.4 Hz, 1H), 8.78 (dd, J = 4.8, 1.6 Hz, 1H), 8.19–8.11 (m, 1H), 7.74–7.70 (m, 2H), 7.54–7.47 (m, 2H), 7.44–7.34 (m, 3H), 7.30–7.18 (m, 2H), 6.56 (d, J = 8.0 Hz, 1H), 4.19 (dd, J = 9.1, 2.2 Hz, 1H), 3.54–3.45 (m, 2H), 3.31–3.13 (m, 2H), 2.12–1.99 (m, 1H), 1.99–1.86 (m, 2H), 1.64–1.52 (m, 1H);13 13C NMR (101 MHz, CDCl3): for both major and minor diastereomers: δ 179.0, 178.6, 168.4, 167.9, 154.4, 147.64, 147.62, 145.05, 144.98, 136.4, 136.3, 134.82, 134.77, 134.5, 134.4, 132.0, 131.5, 129.2, 128.8, 128.4, 127.8, 127.6, 127.0, 126.9, 126.5, 124.00, 123.97, 121.3, 120.9, 120.6, 120.5, 119.4, 118.3, 107.0, 106.9, 105.7, 105.0, 70.5, 68.3, 58.3, 56.9, 50.2, 49.6, 31.8, 31.0, 29.3, 28.9, 24.1, 23.7; HRMS (ESI-TOF) m / z: [M+H] + calcd for C 27 H 23 N4O4S, 499.1435; found, 499.1433.

[0094] Example 16

[0095]

[0096] 3-phenyl-1'-(thiophen-2-ylsulfonyl)-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: Light yellow solid; 90.5 mg, 90% yield, 1.2:1 dr; mp 198 - 200 °C; Rf = 0.30 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1HNMR(500MHz,CDCl3):for majordiastereomer:δ7.94–7.87(m,2H),7.71(dd,J=3.8,1.4Hz,1H),7.56(dd,J=5.0,1.4Hz,1H),7.55–7.51(m,1H),7.39 7.35(m,1H),7.35–7.30(m,1H),7.28–7.19(m,3H),7.04(dd,J=5.0,3.8Hz,1H),6.48(d,J=7.9Hz,1H),4.16(dd,J=9.5,2.2Hz,1H),3.63(dd,J=16.3,1.9Hz,1H),3.31–3.13(m,3H),2.15–2.02(m,1H),1.83–1.75(m,1H),1.65 1.57(m,2H);forminor diastereomer:δ7.76–7.73(m,2H),7.70(dd,J=3.8,1.4Hz,1H),7.58(dd,J=4.9,1.4Hz,1H),7.55–7.51(m,1H),7.49–7.45(m,1H),7.35–7.30(m,2H),7.28–7.19(m,2H),7.02(dd,J=5.0,3.8Hz,1H),6.58(d,J=7.9Hz,1H),4.20(dd,J=9.3,2.1Hz,1H),3.55(dd,J=16.2,2.0Hz,1H),3.51–3.46(m,1H),3.31–3.13(m,2H),2.15–2.02(m,1H),1.99–1.86(m,2H),1.72–1.65(m,1H); 1313C NMR (101 MHz, CDCl3): for both major and minor diastereomers: δ 179.1, 178.9, 168.6, 168.1, 145.1, 144.7, 138.17, 138.16, 136.5, 136.4, 133.7, 133.31, 133.27, 131.9, 131.4, 129.2, 128.7, 128.4, 127.9, 127.71, 127.68, 127.1, 126.6, 126.2, 121.5, 120.90, 120.87, 120.6, 119.1, 117.8, 106.8, 106.6, 106.0, 105.5, 70.4, 68.4, 58.4, 57.1, 50.2, 49.6, 31.9, 31.3, 29.2, 29.0, 24.2, 23.8; HRMS (ESI-TOF) m / z: [M+H] + calcd for C 26 H 22 N3O4S2, 504.1046; found, 504.1045.

[0097] Example 17

[0098]

[0099] 1'-(morpholinosulfonyl)-3-phenyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5-one: White solid; 88.0 mg, 87% yield, 1.5:1 dr; mp 142 - 144 °C; Rf = 0.25 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 11H NMR (500 MHz, CDCl3): for major diastereomer: δ 8.04 (dd, J = 7.4, 1.8 Hz, 2H), 7.50–7.34 (m, 4H), 7.23–7.17 (m, 2H), 6.54 (d, J = 7.8 Hz, 1H), 4.26 (dd, J = 9.7, 2.1 Hz, 1H), 3.71–3.58 (m, 5H), 3.36–3.12 (m, 7H), 2.19–2.06 (m, 1H), 1.87–1.79 (m, 1H), 1.68–1.56 (m, 2H); for minor diastereomer: δ 7.81–7.73 (m, 2H), 7.50–7.34 (m, 4H), 7.23–7.17 (m, 1H), 7.13 (d, J = 1.7 Hz, 1H), 6.57 (d, J = 7.9 Hz, 1H), 4.29 (dd, J = 9.2, 2.2 Hz, 1H), 3.71–3.58 (m, 5H), 3.53 (t, J = 7.8 Hz, 1H), 3.36 3.12 (m, 6H), 2.19–2.06 (m, 1H), 2.06–1.97 (m, 1H), 1.97–1.91 (m, 1H), 1.75–1.69 (m, 1H); 13 13C NMR (101 MHz, CDCl3): for both major and minor diastereomers: δ 179.2, 178.9, 168.6, 167.9, 145.13, 145.08, 137.1, 136.9, 131.9, 131.6, 129.2, 128.9, 128.5, 127.9, 127.7, 127.3, 126.1, 125.8, 122.6, 121.8, 120.6, 120.0, 116.2, 115.0, 106.4, 105.9, 105.8, 105.6, 70.8, 68.3, 65.94, 65.90, 58.4, 57.2, 50.3, 49.6, 46.8, 31.8, 31.0, 29.2, 28.9, 24.3, 23.8; HRMS (ESI-TOF) m / z: [M+H] + calcd for C 26 H 27 N4O5S, 507.1697; found, 507.1694.

[0100] Example 18

[0101]

[0102] 1'-acetyl-3-phenyl-1',3',4a',5',6',7'-hexahydro-5H-spiro[isoxazole-4,4'-pyrrolo[1',2':1,7]az epino[4,3,2-cd]indol]-5-one:Yellow solid;60.0mg,75%yield,2.1:1dr;mp 176-178℃;Rf=0.29(petroleum ether / EtOAc=6 / 1);eluent:petroleum ether / EtOAc=10 / 1; 1 H NMR(500MHz,CDCl3):for major diastereomer:δ8.14(d,J=7.3Hz,2H),7.98(d,J=8.3Hz,1H),7.51–7.44(m,1H),7.43–7.33(m,2H),7.30–7.11(m,2H),6.62(d,J=7.9Hz,1H),4.24(dd,J=9.8,1.8Hz,1H),3.70(dd,J=16.1,2.1Hz,1H),3.39–3.20(m,2H),3.10(d,J=16.2Hz,1H),2.61(s,3H),2.17–1.90(m,2H),1.82(ddt,J=11.5,7.9,4.5Hz,1H),1.62–1.54(m,1H);for minor diastereomer:δ7.91(s,1H),7.80(d,J=7.3Hz,2H),7.51–7.44(m,1H),7.43–7.33(m,2H),7.30–7.11(m,2H),6.63(d,J=8.0Hz,1H),4.28(dd,J=9.3,2.1Hz,1H),3.59(d,J=16.1Hz,1H),3.54(t,J=7.8Hz,1H),3.39–3.20(m,2H),2.60(s,3H),2.17–1.90(m,1H),1.74–1.69(m,1H),1.62–1.54(m,2H); 13CNMR(101MHz, CDCl3): for both major and minor diastereomers: δ 179.5, 179.0, 168.6, 168.4, 167.8, 144.8, 144.7, 137.23, 137.17, 131.9, 131.7, 129.2, 129.0, 128.6, 127.83, 127.76, 127.2, 126.9, 126.5, 121.0, 120.7, 120.3, 120.2, 118.2, 116.9, 109.4, 108.3, 107.1, 106.9, 71.2, 68.6, 58.6, 57.4, 50.3, 49.5, 32.0, 31.0, 29.3, 28.6, 24.4, 24.2, 23.8, 22.8; HRMS(ESI-TOF) m / z: [M+H] + calcd for C 24 H 22 N3O3, 400.1656; found, 400.1656.

[0103] Example 19

[0104] 5-oxo-3-phenyl-4a',5',6',7'-tetrahydro-5H-spiro[isoxazole-4,4'pyrrolo[1',2':1,7]azepino[4,3,2-cd]indole]-1'(3'H)-carboxylate: Yellow solid; 82.3 mg, 90% yield, 1.9:1 dr; mp 180 - 183 °C; Rf = 0.28 (petroleum ether / EtOAc = 10 / 1); eluent: petroleum ether / EtOAc = 10 / 1; 11H NMR (500 MHz, CDCl3): For the major diastereomer: δ 8.14 (d, J = 7.6 Hz, 2H), 7.73 (d, J = 6.5 Hz, 1H), 7.51–7.31 (m, 4H), 7.22 (t, J = 8.1 Hz, 1H), 6.63–6.50 (m, 1H), 4.33–4.19 (m, 1H), 3.69 (dd, J = 16.1, 2.1 Hz, 1H), 3.36–3.22 (m, 2H), 3.12 (d, J = 16.1 Hz, 1H), 2.18–2.01 (m, 1H), 1.83–1.78 (m, 1H), 1.73–1.64 (m, 9H), 1.61–1.53 (m, 2H); For the minor diastereomer: δ 7.82 (d, J = 7.6 Hz, 2H), 7.65 (d, J = 5.0 Hz, 1H), 7.51–7.31 (m, 4H), 7.22 (t, J = 8.1 Hz, 1H), 6.63–6.50 (m, 1H), 4.33–4.19 (m, 1H), 3.60 (dd, J = 16.2, 2.0 Hz, 1H), 3.54 (t, J = 7.8 Hz, 1H), 3.36–3.22 (m, 2H), 2.18–2.01 (m, 1H), 2.00–1.87 (m, 2H), 1.73–1.64 (m, 10H); 13 13C NMR (101 MHz, CDCl3): For both the major and minor diastereomers: δ 179.5, 179.2, 168.7, 167.9, 149.8, 149.6, 144.8, 136.8, 131.8, 131.6, 129.2, 128.9, 128.6, 127.9, 127.7, 127.2, 125.9, 125.6, 121.7, 121.1, 120.8, 120.3, 116.2, 114.8, 108.0, 107.1, 105.9, 105.7, 83.9, 83.7, 71.0, 68.5, 58.6, 57.3, 50.3, 49.5, 32.0, 31.0, 29.1, 28.7, 28.31, 28.27, 24.3, 23.8; HRMS (ESI-TOF) m / z: [M+H] + calcd for C 27 H 28 N3O4, 458.2074; found, 458.2077.

[0105] Example 20

[0106]

[0107] 1-methyl-3'-phenyl-6-tosyl-1,2,4,6-tetrahydro-5'H-spiro[azepino[4,3,2-cd]indole-3,4'-isoxazol]5'-one: Red solid; 74.8 mg, 77% yield; mp 195 - 197 °C; Rf = 0.33 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1 H NMR (500 MHz, CDCl3): δ 8.00–7.94 (m, 2H), 7.80–7.74 (m, 2H), 7.54 (d, J = 8.3 Hz, 1H), 7.51 7.46 (m, 1H), 7.39–7.33 (m, 2H), 7.30 (t, J = 1.2 Hz, 1H), 7.27–7.23 (m, 2H), 7.20 (t, J = 8.1 Hz, 1H), 6.57 (d, J = 7.8 Hz, 1H), 3.67 (d, J = 14.8 Hz, 1H), 3.64–3.58 (m, 2H), 3.26 (dd, J = 15.7, 1.1 Hz, 1H), 2.87 (s, 3H), 2.36 (s, 3H); 13 C NMR (126 MHz, CDCl3): 179.0, 168.4, 147.7, 145.1, 136.6, 135.4, 132.0, 130.1, 129.2, 127.9, 127.2, 127.0, 126.0, 122.0, 121.6, 117.3, 106.91, 106.87, 63.4, 53.7, 40.9, 30.6, 21.7; HRMS (ESI-TOF) m / z: [M + H] + calcd for C 27 H 24 N3O4S, 486.1482; found, 486.1482.

[0108] Example 21

[0109]

[0110] 3-methyl-1-phenyl-1'-tosyl-1',3',4a',5',6',7'-hexahydrospiro[pyrazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5(1H)-one: Yellow solid; 96.5 mg, 92% yield, >20:1 dr; mp 117 - 119 °C; Rf = 0.40 (petroleum ether / EtOAc = 6 / 1); eluent: petroleum ether / EtOAc = 6 / 1; 1 H NMR (500 MHz, CDCl3): δ 7.95 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.32 (s, 1H), 7.25–7.18 (m, 4H), 6.43 (d, J = 8.1 Hz, 1H), 3.99 (t, J = 7.1 Hz, 1H), 3.54–3.43 (m, 2H), 3.38 (dd, J = 16.7, 2.2 Hz, 1H), 3.04 (d, J = 16.7 Hz, 1H), 2.34 (s, 3H), 2.21 (dq, J = 13.4, 6.8 Hz, 1H), 1.92–1.81 (m, 2H), 1.70 (s, 3H), 1.57 (dt, J = 12.7, 7.4 Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 174.0, 162.7, 144.9, 142.2, 137.8, 136.9, 135.0, 129.8, 129.0, 1126.9, 126.2, 125.3, 121.2, 118.8, 118.2, 117.8, 106.8, 103.4, 66.9, 61.3, 50.8, 33.0, 31.1, 22.5, 21.6, 17.1; HRMS (ESI-TOF) m / z: [M+H] + calcd for C 30 H 29 N4O3S, 525.1955; found, 525.1951.

[0111] Example 22

[0112]

[0113] 1-(4-methoxyphenyl)-3-methyl-1'-tosyl-1',3',4a',5',6',7'-hexahydrospiro[pyrazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5(1H)-one: White solid; 104.3 mg, 94% yield, >20:1 dr; mp 176 - 178 °C; Rf = 0.38 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.31 (s, 1H), 7.25–7.14 (m, 3H), 6.95 (d, J = 8.6 Hz, 2H), 6.42 (d, J = 8.1 Hz, 1H), 3.98 (t, J = 7.1 Hz, 1H), 3.82 (s, 3H), 3.48 (dt, J = 11.4, 7.4 Hz, 2H), 3.37 (d, J = 16.7 Hz, 1H), 3.03 (d, J = 16.7 Hz, 1H), 2.34 (s, 3H), 2.21 (dq, J = 13.2, 6.7 Hz, 1H), 1.93–1.81 (m, 2H), 1.67 (s, 3H), 1.55 (dq, J = 14.8, 7.5 Hz, 1H); 13 13C NMR (101 MHz, CDCl3): δ 173.7, 162.6, 157.2, 145.0, 142.3, 137.0, 135.1, 131.1, 129.9, 126.9, 126.2, 121.2, 120.7, 118.2, 117.9, 114.2, 106.8, 103.5, 66.9, 61.1, 55.6, 50.9, 33.1, 31.2, 22.6, 21.7, 17.1; HRMS (ESI-TOF) m / z: [M+H] + calcd for C 31 H 31 N4O4S, 555.2061; found, 555.2061.

[0114] Example 23

[0115]

[0116] 3-methyl-1-(p-tolyl)-1'-tosyl-1',3',4a',5',6',7'-hexahydrospiro[pyrazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5(1H)-one: Yellow solid; 98.0 mg, 91% yield, >20:1 dr; mp 191 - 193 °C; Rf = 0.39 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1 H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 7.9 Hz, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.31 (s, 1H), 7.25–7.14 (m, 5H), 6.42 (d, J = 8.1 Hz, 1H), 3.98 (t, J = 7.1 Hz, 1H), 3.55–3.42 (m, 2H), 3.38 (dd, J = 16.7, 2.1 Hz, 1H), 3.03 (d, J = 16.7 Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H), 2.21 (dq, J = 13.3, 6.8 Hz, 1H), 1.92–1.80 (m, 2H), 1.68 (s, 3H), 1.55 (dq, J = 14.9, 7.7 Hz, 1H); 13 C NMR (101 MHz, CDCl3): δ 173.9, 162.6, 145.0, 142.3, 137.0, 135.4, 135.1, 129.9, 129.6, 126.9, 126.2, 121.3, 119.0, 118.2, 117.9, 106.8, 103.5, 67.0, 61.3, 50.9, 33.1, 31.2, 22.6, 21.7, 21.1, 17.1; HRMS (ESI-TOF) m / z: [M + H] + calcd for C 31 H 31 N4O3S, 539.2111; found, 539.2106.

[0117] Example 24

[0118]

[0119] 1-(4-chlorophenyl)-3-methyl-1'-tosyl-1',3',4a',5',6',7'-hexahydrospiro[pyrazole-4,4'-pyrro lo[1',2':1,7]azepino[4,3,2-cd]indol]-5(1H)-one: Yellow solid; 100.5 mg, 90% yield, >20:1 dr; mp 211 - 213 °C; Rf = 0.40 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1 1H NMR (400 MHz, CDCl3): δ 7.94–7.87 (m, 2H), 7.78–7.71 (m, 2H), 7.46 (d, J = 8.3 Hz, 1H), 7.40–7.35 (m, 2H), 7.31 (d, J = 1.8 Hz, 1H), 7.25–7.19 (m, 3H), 6.43 (d, J = 8.1 Hz, 1H), 3.99 (t, J = 7.1 Hz, 1H), 3.54–3.42 (m, 2H), 3.37 (dd, J = 16.7, 2.1 Hz, 1H), 3.04 (d, J = 16.7 Hz, 1H), 2.34 (s, 3H), 2.19 (dq, J = 13.2, 6.8 Hz, 1H), 1.91–1.83 (m, 2H), 1.69 (s, 3H), 1.52 (dq, J = 12.6, 7.6 Hz, 1H); 13 13C NMR (101 MHz, CDCl3): δ 174.1, 163.1, 145.0, 142.2, 137.0, 136.4, 135.1, 130.4, 129.9, 129.1, 126.9, 126.3, 121.3, 119.9, 118.2, 117.6, 106.9, 103.6, 67.0, 61.4, 50.9, 33.1, 31.2, 22.6, 21.7, 17.2; HRMS (ESI-TOF) m / z: [M+H] + calcd for C 30 H 28 ClN4O3S, 559.1565; found, 559.1566.

[0120] Example 25

[0121]

[0122] 1-(4-bromophenyl)-3-methyl-1'-tosyl-1',3',4a',5',6',7'-hexahydrospiro[pyrazole-4,4'-pyrro lo[1',2':1,7]azepino[4,3,2-cd]indol]-5(1H)-one: Yellow solid; 111.0 mg, 92% yield, >20:1 dr; mp 208 - 211 °C; Rf = 0.40 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1 1H NMR (400 MHz, CDCl3): δ 7.90–7.82 (m, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.55 7.49 (m, 2H), 7.46 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 1.9 Hz, 1H), 7.25–7.18 (m, 3H), 6.43 (d, J = 8.1 Hz, 1H), 3.98 (t, J = 7.1 Hz, 1H), 3.54–3.42 (m, 2H), 3.37 (dd, J = 16.7, 2.1 Hz, 1H), 3.04 (d, J = 16.7 Hz, 1H), 2.35 (s, 3H), 2.19 (dq, J = 13.3, 6.8 Hz, 1H), 1.92–1.82 (m, 2H), 1.69 (s, 3H), 1.52 (dq, J = 12.6, 7.6 Hz, 1H); 13 13C NMR (101 MHz, CDCl3): δ 174.1, 163.1, 145.0, 142.2, 137.0, 136.9, 135.1, 132.0, 129.9, 126.9, 126.3, 121.3, 120.2, 118.2, 118.1, 117.6, 106.9, 103.6, 67.0, 61.5, 50.9, 33.1, 31.2, 22.6, 21.7, 17.2; HRMS (ESI-TOF) m / z: [M+H] + calcd for C 30 H 28 BrN4O3S, 603.1060; found, 603.1062.

[0123] Example 26

[0124]

[0125] 3-methyl-1'-tosyl-1',3',4a',5',6',7'-hexahydrospiro[pyrazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2cd]indol]-5(1H)-one: White solid; 78.0 mg, 87% yield, >20:1 dr; mp 255 - 257 °C; Rf = 0.30 (petroleum ether / EtOAc = 1 / 1); eluent: petroleum ether / EtOAc = 1 / 1; 1 H NMR (500 MHz, CDCl3): δ 8.68 (s, 1H), 7.77–7.70 (m, 2H), 7.44 (d, J = 8.2 Hz, 1H), 7.32–7.28 (m, 1H), 7.23–7.17 (m, 3H), 6.41 (d, J = 8.0 Hz, 1H), 3.90 (t, J = 7.1 Hz, 1H), 3.53–3.41 (m, 2H), 3.27 (dd, J = 16.5, 2.1 Hz, 1H), 2.93 (dd, J = 16.5, 1.0 Hz, 1H), 2.34 (s, 3H), 2.24–2.17 (m, 1H), 1.93–1.82 (m, 2H), 1.60–1.51 (m, 4H); 13 C NMR (101 MHz, CDCl3): δ 178.3, 163.3, 145.0, 142.3, 137.0, 135.1, 129.9, 126.9, 126.2, 121.2, 118.2, 117.8, 106.8, 103.5, 66.4, 58.8, 50.9, 32.9, 31.3, 22.6, 21.7, 17.2; HRMS (ESI-TOF) m / z: [M + H] + calcd for C 24 H 25 N4O3S, 449.1642; found, 449.1642.

[0126] Example 27

[0127]

[0128] 3-cyclopropyl-1-phenyl-1'-tosyl-1',3',4a',5',6',7'-hexahydrospiro[pyrazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5(1H)-one: White solid; 100.2 mg, 91% yield, >20:1 dr; mp 186 - 188 °C; Rf = 0.30 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.44–7.35 (m, 2H), 7.27 (d, J = 1.9 Hz, 1H), 7.24–7.12 (m, 4H), 6.55 (d, J = 7.9 Hz, 1H), 4.04 (dd, J = 9.6, 2.0 Hz, 1H), 3.56 (dd, J = 15.3, 2.0 Hz, 1H), 3.45 (t, J = 7.6 Hz, 1H), 3.17 (ddd, J = 11.1, 8.7, 5.6 Hz, 1H), 2.87 (d, J = 15.2 Hz, 1H), 2.35 (s, 3H), 2.30–2.16 (m, 1H), 1.98–1.79 (m, 2H), 1.48–1.36 (m, 2H), 1.31 1.24 (m, 1H), 0.98–0.89 (m, 1H), 0.87–0.77 (m, 2H); 13 13C NMR (101 MHz, CDCl3): δ 174.1, 167.8, 146.7, 144.9, 138.2, 136.6, 135.3, 129.9, 128.9, 126.9, 126.2, 125.0, 121.8, 120.5, 119.7, 118.8, 106.1, 105.5, 68.8, 61.7, 49.8, 30.9, 28.5, 24.1, 21.7, 10.0, 9.1, 7.5; HRMS (ESI-TOF) m / z: [M+H] + calcd for C 32 H 31 N4O3S, 551.2111; found, 551.2111.

[0129] Example 28

[0130]

[0131] 1,3 - Diphenyl - 1'-tosyl - 1',3',4a',5',6',7'-hexahydrospiro[pyrazole - 4,4'-pyrrolo[1',2':1,7]azepino[4,3,2 - cd]indol]-5(1H)-one: White solid; 109.0 mg, 93% yield, >20:1 dr; mp 174 - 176 °C; Rf = 0.38 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1 1H NMR (500 MHz, CDCl3): δ 8.14 (d, J = 7.6 Hz, 2H), 8.06 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.3 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.36 - 7.27 (m, 4H), 7.26 - 7.16 (m, 4H), 6.50 (d, J = 7.9 Hz, 1H), 4.24 (dd, J = 9.8, 2.4 Hz, 1H), 3.61 (dd, J = 16.2, 2.0 Hz, 1H), 3.25 - 3.13 (m, 2H), 3.08 (d, J = 16.2 Hz, 1H), 2.33 (s, 3H), 1.99 - 1.85 (m, 1H), 1.75 - 1.65 (m, 1H), 1.62 - 1.51 (m, 1H), 1.38 (dd, J = 13.3, 7.0 Hz, 1H); 13 13C NMR (101 MHz, CDCl3): δ 174.8, 160.2, 145.5, 144.9, 138.1, 136.5, 135.5, 130.9, 130.2, 130.0, 129.1, 128.6, 128.3, 127.0, 125.7, 125.6, 121.4, 121.3, 119.2, 118.2, 105.9, 105.7, 70.6, 62.4, 49.5, 30.9, 28.5, 24.3, 21.7; HRMS (ESI - TOF) m / z: [M + H] + calcd for C 35 H 31 N4O3S, 587.2111; found, 587.2111.

[0132] Example 29

[0133]

[0134] 3-(4-Methoxyphenyl)-1-phenyl-1'-tosyl-1',3',4a',5',6',7'-hexahydrospiro[pyrazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5(1H)-one: White solid; 116.0 mg, 94% yield, >20:1 dr; mp 182 - 184 °C; Rf = 0.32 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 7.8 Hz, 2H), 7.86–7.76 (m, 4H), 7.52 (d, J = 8.3 Hz, 1H), 7.45 (t, J = 7.9 Hz, 2H), 7.32–7.18 (m, 5H), 6.81–6.74 (m, 2H), 6.54 (d, J = 7.9 Hz, 1H), 4.27–4.19 (m, 1H), 3.84 (s, 3H), 3.61 (dd, J = 16.1, 2.1 Hz, 1H), 3.50 (t, J = 7.8 Hz, 1H), 3.27–3.19 (m, 1H), 3.17 (d, J = 16.2 Hz, 1H), 2.38 (s, 3H), 2.16–2.02 (m, 1H), 1.86–1.74 (m, 2H), 1.52 (dd, J = 12.6, 7.9 Hz, 1H); 13 13C NMR (101 MHz, CDCl3): δ 174.6, 161.4, 160.8, 145.8, 145.0, 138.2, 136.8, 135.5, 130.0, 129.09, 129.06, 127.0, 126.2, 125.3, 122.7, 120.9, 120.8, 120.2, 119.1, 114.3, 106.0, 105.0, 69.2, 61.1, 55.5, 50.3, 31.4, 28.5, 24.0, 21.7; HRMS (ESI-TOF) m / z: [M + H] + calcd for C 36 H 36 N4O4S, 617.2217; found, 617.2216.

[0135] Example 30

[0136]

[0137] 3-(4-Chlorophenyl)-1-phenyl-1'-tosyl-1',3',4a',5',6',7'-hexahydrospiro[pyrazole-4,4'-pyrrolo[1',2':1,7]azepino[4,3,2-cd]indol]-5(1H)-one: Light yellow solid; 111.8 mg, 90% yield, >20:1 dr; mp 219 - 222 °C; Rf = 0.40 (petroleum ether / EtOAc = 5 / 1); eluent: petroleum ether / EtOAc = 5 / 1; 1 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.2 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.32–7.20 (m, 5H), 7.10 (d, J = 8.3 Hz, 2H), 6.55 (d, J = 7.9 Hz, 1H), 4.15 (d, J = 8.7 Hz, 1H), 3.64 (d, J = 16.0 Hz, 1H), 3.49 (t, J = 7.9 Hz, 1H), 3.21 (dt, J = 14.7, 7.1 Hz, 1H), 3.09 (d, J = 16.0 Hz, 1H), 2.41 (s, 3H), 2.18–2.02 (m, 1H), 1.86–1.70 (m, 2H), 1.45 (dd, J = 12.1, 7.3 Hz, 1H); 13 13C NMR (101 MHz, CDCl3): δ 174.5, 159.8, 145.8, 145.2, 137.9, 136.8, 136.5, 135.7, 130.1, 129.1, 129.0, 128.7, 128.5, 127.0, 126.4, 125.6, 120.9, 120.7, 119.9, 119.1, 106.1, 105.5, 69.1, 61.2, 50.2, 31.3, 28.4, 23.9, 21.8; HRMS (ESI-TOF) m / z: [M + H] + calcd for C 35 H 30 ClN4O3S, 621.1722; found, 621.1720.

[0138] Example 31

[0139]

[0140] 3-(4-bromophenyl)-1-phenyl-1'-tosyl-1',3',4a',5',6',7'-hexahydrospiro[pyrazole-4,4'-pyrro lo[1',2':1,7]azepino[4,3,2-cd]indol]-5(1H)-one:Lightyellow solid; 123.8mg, 93% yield, >20:1dr; mp 227-229℃; Rf=0.38(petroleum ether / EtOAc=5 / 1); eluent:petroleum ether / EtOAc=5 / 1; 1 H NMR (400MHz, CDCl3): δ8.05(d,J=8.0Hz,2H),7.82(d,J=8.0Hz,2H),7.68(d,J=8.3Hz,2H),7.58 (d,J=8.3Hz,1H),7.45(t,J=7.8Hz,2H),7.32–7.20(m,7H),6.55(d,J=7.9Hz,1H),4.14(d,J=8. 7Hz,1H),3.64(d,J=16.1Hz,1H),3.49(t,J=7.9Hz,1H),3.21(dt,J=14.6,6.5Hz,1H),3.09(d,J =16.1Hz,1H),2.43(s,3H),2.18–2.05(m,1H),1.83–1.71(m,2H),1.45(dd,J=12.2,7.4Hz,1H); 13 CNMR (101MHz, CDCl3): δ174.5,159.9,145.9,145.2,137.9,136.8,135.7,132.0,130.2,129.1,128.9,127.0,126.4,125 .6,124.9,121.0,120.8,119.9,119.1,106.1,105.5,69.1,61.2,50.2,31.3,28.4,23.9,21.8; HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 35 H 30 BrN4O3S,665.1217; found,665.1217.

[0141] 2. Antibacterial activity test of indoleazepine-spiro-oxazolinone compounds

[0142] The following four compounds (Example 1, Example 7, Example 28 and Example 30) were selected from the above examples for antibacterial testing.

[0143]

[0144] The test steps are as follows:

[0145] Four common pathogenic fungi in agricultural production were selected, including apple rot, peanut root rot, strawberry gray mold and cucumber wilt, and the mycelium growth rate method (Ann. Appl. Biol., 2008, 152, 369) was used to test the sterilization activity of the compounds. The above test strains were provided by Shandong Biopesticide Engineering Technology Research Center.

[0146] First, weigh a certain amount of PDA (potato dextrose agar) in a wide-mouth flask, add distilled water to make a culture medium and sterilize it in a 120℃ autoclave for half an hour. Weigh 1mg of the drug to be tested and dissolve it in 10mL of acetone to make a 100mg / L agent. Then take half of the agent and dilute it to 10mL with acetone to make a 50mg / L agent. By analogy, you can make 25mg / L and 12.5mg / L agents. Take 5mL of the agent and pour it into 50mL of potato dextrose agar to mix well, and then pour it into 5 high-temperature sterilized culture media respectively. After cooling, use an inoculation loop to inoculate the above four pathogens respectively, seal it with a sealing film, and transfer it to a suitable temperature for observation. When the colony in the control culture medium without adding the agent reaches 80%, the colony of the experimental group is measured by the cross method.

[0147] The antibacterial activity formula is as follows:

[0148] Inhibition rate = (colony diameter of control group - colony diameter of experimental group) / colony diameter of control group × 100%;

[0149] The test results are shown in Table 1:

[0150] Table 1 Antibacterial activity of each compound

[0151]

[0152] As shown in Table 1, compounds 1 to 4 showed good inhibitory activity against apple rot pathogen, strawberry gray mold pathogen, cucumber wilt pathogen and peanut root rot pathogen.

[0153] For the strawberry gray mold pathogen, when the lowest concentration of compounds 1 to 4 was 12.5 mg / L, the pathogen did not grow, and the inhibition rate of the compounds against the strawberry gray mold pathogen reached 100%, showing a high inhibition rate. Figure 1 As shown (the left picture is the blank control, and the right picture is the mycelial growth picture of the four compounds).

[0154] For apple rot pathogens, such as Figure 2 As shown, when the minimum inhibitory concentration of compound 1 and compound 4 was 12.5 mg / L, the mycelium did not grow and the inhibition rate reached 100%. When the concentration of compound 2 and compound 3 was 50 mg / L, they had good antibacterial performance. All four compounds showed good antibacterial activity.

[0155] For peanut root rot pathogens, such as Figure 3 As shown, compound 1, compound 2 and compound 3 have the best inhibitory effect, and the bacteria do not grow at the three concentrations. Compound 4 has an inhibition rate of 70% at 25 mg / L.

[0156] For cucumber wilt pathogens, such as Figure 4 As shown, compound 2 had an inhibition rate of 80% at a higher concentration (25 mg / L), and the remaining compounds did not cause mycelium growth at the other three concentrations, with an inhibition rate of 100%, showing excellent bactericidal activity.

[0157] In summary, in practical applications, the above-mentioned indole aza-spiro-oxazolinone compounds can be used to prepare bactericidal drugs, and can also be used as lead compounds and used for bactericidal purposes after modification.

[0158] The above is only a preferred embodiment of the present invention, and does not limit the present invention in other forms. Any technician familiar with the profession may use the above disclosed technical content to change or modify it into an equivalent embodiment with equivalent changes. However, any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the technical solution of the present invention still belongs to the protection scope of the technical solution of the present invention.

Claims

1. The use of indole azapine-spiro-oxazolinone compounds in the preparation of drugs with plant disease fungal inhibitory activity.

2. The use according to claim 1, characterized in that: The structural formula of the indole azepine-spiro-oxazolinone compound is as follows: Among them, R 1 is selected from any one of acetyl, tert-butyloxycarbonyl, trifluoromethylsulfonyl, cyclopropylsulfonyl, n-butylsulfonyl, pyridylsulfonyl, thienylsulfonyl and morpholinylsulfonyl; X is selected from O or N; when X is O, R 2 Any one selected from phenyl, phenyl with an electron donating group or an electron withdrawing group, furanyl, thienyl, and R is absent 3 ; When X is N, R 2 Any one selected from methyl, phenyl, phenyl with an electron donating group or an electron withdrawing group, R 3 Any one selected from a phenyl group, a phenyl group with an electron donating group or an electron withdrawing group.

3. The use according to claim 1, characterized in that: The indole azepine-spiro-oxazolinone compound is prepared by the following method: An indole-derived aldehyde compound is mixed with a phenyloxazolinone-derived compound, a solvent is added, the system temperature is controlled, and the reaction is stirred to obtain an indole aza-spiro-oxazolinone compound.

4. The use according to claim 3, characterized in that: The structural formula of the indole-derived aldehyde compound is as follows: Among them, R 1 Any one selected from acetyl, tert-butyloxycarbonyl, trifluoromethylsulfonyl, cyclopropylsulfonyl, n-butylsulfonyl, pyridylsulfonyl, thienylsulfonyl and morpholinylsulfonyl; The structural formula of the compound derived from the phenyloxazolinone is as follows: Wherein, X is selected from O or N; when X is O, R 2 Any one selected from phenyl, phenyl with an electron donating group or an electron withdrawing group, furanyl, thienyl, and R is absent 3 ; When X is N, R 2 Any one selected from methyl, phenyl, phenyl with an electron donating group or an electron withdrawing group, R 3 Any one selected from a phenyl group, a phenyl group with an electron donating group or an electron withdrawing group.

5. The use according to claim 3, characterized in that: The molar ratio of the indole-derived aldehyde compound to the phenyloxazolinone-derived compound is selected from 1:1.2 to 1:1.

5.

6. The use according to claim 3, characterized in that: The solvent is selected from any one of ethanol, methanol, isopropanol, water, toluene, ethyl acetate, hexane, and N,N-dimethylformamide.

7. The use according to claim 3, characterized in that: The amount of the solvent is selected from: adding 10 to 20 L of solvent per mole of indole-derived aldehyde compound.

8. The use according to claim 3, characterized in that: The reaction temperature is selected from 60 to 80°C.

9. The use according to claim 1, characterized in that: The indoleazepine-spiro-oxazolinone compound is specifically selected from one or more of the following structural formulas:

10. The use according to claim 1, characterized in that: The plant pathogenic fungi are selected from one or more of apple rot pathogen, cucumber wilt pathogen, strawberry gray mold pathogen and peanut root rot pathogen.

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