Indazole nitrogen oxide as well as synthesis method and anticancer activity application thereof

Abstract

The invention discloses indazole nitrogen oxide as well as a synthesis method and anticancer activity application thereof, and belongs to the technical field of organic synthesis and drug discovery. An N-nitrosoaniline compound 1, a diazoindane diketone compound 2, a catalyst, an additive and hexafluoroisopropanol are mixed and subjected to a heating reaction, the indazole nitrogen oxide is prepared, the chemical structural general formula of the indazole nitrogen oxide is # imgabs0 #, and research shows that the indazole nitrogen oxide has the activity of inhibiting proliferation of three cancer cells of Hela, A549 and HCT-116 and has potential medicinal value; meanwhile, the synthesis method provided by the invention is completed by adopting a one-pot multi-step cascade reaction, and the process is simple and efficient; and the method has the remarkable characteristics of cheap and easily available raw materials, valuable products, high step economy, high atom economy and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and drug discovery, and specifically relates to an indazole nitrogen oxide and a synthesis method and anticancer activity application thereof. Background Art

[0002] Indazole compounds often have significant biological activity and unique physical / chemical properties, so they play an important role in synthetic chemistry, medicinal chemistry, and material chemistry. On the other hand, organic molecules with nitrogen-oxygen structural units have received increasing attention in drug development because nitrogen-oxygen structural units can increase the water solubility of the parent compound or reduce its membrane permeability.

[0003] Indazole N-oxides obtained by introducing N-oxide structural units into the indazole ring have been found to have strong antiprotozoal activity and show potential application value. In addition, the N-oxide structural unit in indazole N-oxides can also be used as a directing group to assist in the regioselective installation of the required functional groups onto the indazole ring, thereby obtaining target molecules that cannot be synthesized by other methods.

[0004] Given its importance, several methods for synthesizing indazole nitrogen oxides have been developed in the existing literature. Although these methods are relatively reliable, they still have problems such as difficult to obtain raw materials, cumbersome steps, poor atom economy, low efficiency and harsh reaction conditions.

[0005] Therefore, it is of great theoretical significance and application value to synthesize new indazole N-oxides, study their biological activity and medicinal value, and develop a simple, efficient and sustainable new atom-economical method to synthesize these new indazole N-oxides from simple and readily available raw materials under mild reaction conditions. Summary of the invention

[0006] In order to solve the problems existing in the prior art, one of the purposes of the present invention is to provide a new class of indazole nitrogen oxides. Studies have shown that this class of compounds has good anti-cancer activity.

[0007] The second object of the present invention is to provide the use of indazole nitrogen oxide in the preparation of anticancer drugs.

[0008] The third object of the present invention is to provide a pharmaceutical composition for treating cervical cancer, lung cancer and colon cancer, wherein the active ingredient is the indazole nitrogen oxide provided by the present invention.

[0009] A fourth object of the present invention is to provide a method for synthesizing indazole nitrogen oxides.

[0010] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0011] Indazole nitrogen oxide, its chemical structure formula is:

[0012]

[0013] Where: R 1 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxycarbonyl, phenyl, benzyl, trifluoromethyl or halogen, R 1 Selected from mono- or poly-substituted; R 2 C 1-6 Chain alkyl, C 3-6 Cycloalkyl or benzyl; R 3 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 3 Select from mono- or poly-substituted.

[0014] Furthermore, in the above general structure, in the most preferred case, the following specific structures are selected:

[0015]

[0016] The use of the above-mentioned indazole nitrogen oxide in the preparation of anti-cancer active drugs, wherein the anti-cancer is anti-cervical cancer, lung cancer and colon cancer.

[0017] Studies have shown that the indazole nitrogen oxide provided by the present invention has the activity of inhibiting the proliferation of three cancer cells, Hela, A549 and HCT-116, indicating that the compounds of the present invention can be used as active ingredients of drugs for treating cancers such as cervical cancer, lung cancer and colon cancer. In particular, the above-mentioned preferred compounds can significantly inhibit the growth and proliferation of Hela, A549 and HCT-116, indicating that such compounds as active ingredients of anticancer drugs have the effects of preventing, treating and inhibiting the progression of cervical cancer, lung cancer and colon cancer.

[0018] A pharmaceutical composition for treating cervical cancer, lung cancer and colon cancer, wherein the active ingredient is the aforementioned indazole nitrogen oxide.

[0019] The above-mentioned synthesis method of indazole nitrogen oxide is prepared by using N-nitrosoaniline compounds and indole dione compounds as raw materials; it comprises the following steps: mixing N-nitrosoaniline compound 1, indole dione compound 2, catalyst, additive and hexafluoroisopropanol (HFIP), and heating the mixture to obtain indazole nitrogen oxide 3, and the reaction equation is:

[0020]

[0021] Where: R 1 For hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Alkoxycarbonyl, phenyl, benzyl, trifluoromethyl or halogen, R 1 is a single or multiple substitution; R 2 C 1-6 Chain alkyl, C 3-6 Cycloalkyl or benzyl; R 3 For hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 3 It is a one- or multiple-element replacement.

[0022] Furthermore, in the above technical solution, the additive is cupric acetate or a mixture of cupric acetate and one or more of 2,2,6,6-tetramethylpiperidinyl oxide, silver acetate, silver oxide, silver carbonate or silver nitrate.

[0023] Furthermore, in the above technical scheme, the catalyst is dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer ([RhCp*Cl2]2) or tris(acetonitrile)(pentamethylcyclopentadienyl)rhodium(III) di(hexafluoroantimonate) ([RhCp*(MeCN)3](SbF6)2).

[0024] Furthermore, in the above technical solution, the molar ratio of the N-nitrosoaniline compound 1, the indanedione compound 2, the catalyst and the additive is 1:1-1.5:0.04-0.06:1-5.

[0025] Furthermore, in the above technical solution, the reaction temperature is 60-100°C.

[0026] Furthermore, in the above technical solution, the reaction is carried out in an atmosphere of air, oxygen or an inert gas.

[0027] Beneficial effects of the invention:

[0028] (1) The indazole nitrogen oxide provided by the present invention is screened for compounds having various substituents and verified by anticancer activity tests. The compounds provided by the present invention have the activity of significantly inhibiting the proliferation of three cancer cells, namely Hela, A549 and HCT-116, indicating that the compounds of the present invention have anticancer activity against cervical cancer, lung cancer and colon cancer, and have potential medicinal value;

[0029] (2) The synthesis method provided by the present invention is completed by a one-pot multi-step cascade reaction of N-nitrosoaniline compounds, indanedione compounds and hexafluoroisopropanol, and the process is simple and efficient;

[0030] (3) The synthesis method provided by the present invention has the remarkable characteristics of cheap and readily available raw materials, valuable products, high step economy and atom economy. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is the X-ray single crystal diffraction pattern of compound 3u in Example 3. DETAILED DESCRIPTION

[0032] The above contents of the present invention are further described in detail below through examples, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples, and all technologies implemented based on the above contents of the present invention belong to the scope of the present invention.

[0033] Example 1

[0034]

[0035] Compounds 1a, 2a, catalyst, additives and hexafluoroisopropanol were added to a 15 mL reaction tube in sequence, the reaction tube was sealed, and the mixture was placed in an oil bath and heated and stirred for reaction. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, the filtrate was concentrated, and separated through a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to obtain a yellow solid product 3a.

[0036] By changing the reaction conditions such as the catalyst, additives, material ratio, temperature and gas atmosphere, a series of results were obtained, as shown in Table 1.

[0037] Table 1 Synthesis of 3a under different conditions a

[0038]

[0039]

[0040] a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst (5 mol%), additive 1 (0.4

[0041] mmol), additive 2 (0.1 mmol), additive 3 (0.2 mmol), hexafluoroisopropanol (2 mL), 80 ° C, oxygen atmosphere, 0.5 h; b Isolation yield; c Air atmosphere; d Argon atmosphere; e Additive 1 (0.2 mmol); f Additive 1 (0.6 mmol), Additive 2 (0.2 mmol), Additive 3 (0.2 mmol); g 60℃;

[0042] h 100℃; i 2a (0.2 mmol);j 2a (0.3 mmol).

[0043] Example 2

[0044]

[0045] 1a (27.2 mg, 0.2 mmol), 2a (41.3 mg, 0.24 mmol), [RhCp*Cl2]2 (6.2 mg, 0.01 mmol), copper acetate (72.7 mg, 0.4 mmol), 2,2,6,6-tetramethylpiperidinoxide (15.6 mg, 0.1 mmol), silver oxide (46.3 mg, 0.2 mmol) and hexafluoroisopropanol (2 mL) were added to a 15 mL pressure tube in sequence, and then the reaction tube was sealed and placed in an 80 ° C oil bath for 0.5 h. After the reaction was completed, the reaction system was cooled to room temperature, filtered through diatomaceous earth, the filtrate was concentrated, and separated by a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to obtain a yellow solid product 3a (66.6 mg, 75%). The characterization data of this compound are: 1 H NMR (400MHz, CDCl3): δ8.38(d,J=8.0Hz,1H),8.16(dd,J1=7.6Hz,J2=0.4Hz,1H),7.76(td,J1=7.2Hz,J2=0.8Hz,1H),7.62( td,J1=8.0Hz, J2=1.2Hz,1H),7.50-7.46(m,2H),7.42-7.38(m,1H),7.19(d,J=8.4Hz,1H),5.86-5.80(m,1H),3.74(s,3H). 13 C{ 1 H}NMR (150MHz, CDCl3): δ186.0,162.8,143.0,134.5,130.7,130.0,129.8,127.7,127.0,125.5,124.9,122.0,121.3,120.4(q, 1 J C-F =278.0Hz),118.0,107.1,67.5-66.6(m),28.7. 19 F NMR (376MHz, CDCl3): δ-73.07 (d, J = 6.8Hz). HRMS (ESI) m / z: [M+Na] + Calcd for C 19 H 12 F6N2NaO4 + 469.0593;Found 469.0601.

[0046] Example 3

[0047] According to the method and steps of Example 2 a,b By changing reactant 1 and reactant 2, various indazole nitrogen oxides 3 can be synthesized. The specific results are as follows:

[0048]

[0049] a Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), [RhCp*Cl2]2 (0.01 mmol), copper acetate (0.4 mmol), 2,2,6,6-tetramethylpiperidinyl oxide (0.1 mmol), silver oxide (0.2 mmol), hexafluoroisopropanol (2 mL), 80 °C, 0.5 h, oxygen atmosphere; b Isolated yield.

[0050] Characterization data of representative products are as follows: 1-Ethyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1H-inda zole 2-oxide(3b)

[0051] 1 H NMR (600 MHz, CDCl3): δ8.39 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 7.2 Hz, 1H), 7.76 (td, J1 = 7.2 Hz, J2 = 0.6 Hz, 1H), 7.62 (td, J1 = 7.8 Hz, J2 = 1.2 Hz,1H),7.48-7.46(m,2H),7.40(t,J=7.2 Hz,1H),7.21(d,J=8.4 Hz,1H),5.84-5.80(m,1H),4.31(q,J=7.2Hz,2H),1.31(t,J=7.8 Hz,3H). 13 C{ 1 H}NMR (150 MHz, CDCl3): δ186.2,162.8,143.3,134.6,130.1,130.0,129.8,127.6,126.9,125.3,124.8,122.0,121.3,120.4(q, 1 J C-F =276.8 Hz),118.2,107.0,67.5-66.6(m),37.7,12.7. 19F NMR(565MHz,CDCl3):δ-73.08(d,J=6.2 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 14 F6N2NaO4 + 483.0750;Found 483.0748.

[0052] 3-(2-(((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1-propyl-1H-indazole 2-oxide(3c)

[0053] 1 H NMR(400 MHz,CDCl3):δ8.40(d,J=7.6 Hz,1H),8.18-8.16(m,1H),7.76.(td,J1=7.6 Hz,J2=1.2 Hz,1H),7.62(td,J1=8.0 Hz,J2=1.2 Hz,1H),7.49-7.45(m,2H),7.40(t,J=7.6 Hz,1H),7.21(d,J=8.0 Hz,1H),5.85-5.78(m,1H),4.21(t,J=7.2 Hz,2H),1.81-1.72(m,2H),0.91(t,J=7.2 Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ186.3,162.7,143.3,134.6,130.5,130.1,129.8,127.6,126.9,125.2,124.7,121.9,121.2,120.4(q, 1 J C-F =281.1 Hz),118.0,107.2,67.5-66.6(m),44.3,21.2,11.1. 19 F NMR(565 MHz,CDCl3):δ-73.08(d,J=6.2 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 21 H 16 F6N2NaO4 + 497.0906;Found 497.0902.

[0054] 1-Butyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1H-indazole 2-oxide(3d)

[0055] 1 H NMR(400 MHz,CDCl3):δ8.40(d,J=8.0 Hz,1H),8.17(d,J=7.6 Hz,1H),7.76.(td,J1=7.6 Hz,J2=1.2 Hz,1H),7.62(td,J1=8.0 Hz,J2=1.2 Hz,1H),7.49-7.45(m,2H),7.41-7.38(m,1H),7.21(d,J=8.0 Hz,1H),5.85-5.79(m,1H),4.24(t,J=7.2Hz,2H),1.74-1.66(m,2H),1.38-1.28(m,2H),0.90(t,J=7.2 Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ186.2,162.8,143.4,134.6,130.4,130.1,129.8,127.6,126.9,125.2,124.7,121.9,121.2,120.4(q, 1 J C-F =281.1 Hz),118.0,107.2,67.5-66.6(m),42.7,29.8,20.0,13.5. 19 F NMR(565 MHz,CDCl3):δ-73.08(d,J=6.2 Hz).HRMS(ESI)m / z:[M+Na] + Calcd forC 22 H 18 F6N2NaO4 + 511.1063;Found 511.1060.1-Benzyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1H-indazole 2-oxide(3e)

[0056] 1H NMR(600 MHz,CDCl3):δ8.40(dd,J1=7.2 Hz,J2=1.2 Hz,1H),8.16(dd,J1=7.8 Hz,J2=0.6 Hz,1H),7.77.(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.63(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.49(dd,J1=7.8 Hz,J2=1.2 Hz,1H),7.43-7.37(m,2H),7.30-7.25(m,3H),7.19-7.17(m,2H),7.14-7.13(m,1H),5.80-5.76(m,1H),5.44(s,2H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ186.3,162.8,143.2,134.6,133.9,130.6,130.1,129.9,129.0,128.4,127.7,127.5,127.1,125.3,124.9,121.9,121.4,120.4(q, 1 J C-F =284.4 Hz),118.1,107.6,67.5-66.6(m),45.7. 19 F NMR(565 MHz,CDCl3):δ-73.04(d,J=6.2 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 25 H 16 F6N2NaO4 + 545.0906;Found 545.0910.

[0057] 1-Cyclohexyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1H-indazole 2-oxide(3f)

[0058] 1H NMR(600 MHz,CDCl3):δ8.44(d,J=8.4 Hz,1H),8.16(dd,J1=7.8 Hz,J2=0.6Hz,1H),7.76.(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.62(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.47-7.42(m,3H),7.39-7.37(m,1H),5.84-5.80(m,1H),5.02-4.97(m,1H),2.08(qd,J1=12.6 Hz,J2=3.0 Hz,2H),1.93-1.75(m,5H),1.45-1.37(m,2H),1.31-1.23(m,1H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ186.5,162.8,143.4,134.6,130.0,129.7,127.6,126.5,125.3,124.3,121.7,121.4,120.4(q, 1 J C-F =281.1 Hz),118.2,108.6,67.5-66.6(m),54.2,30.0,25.9,25.1. 19 F NMR(565 MHz,CDCl3):δ-73.07(d,J=5.7 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 24 H 20 F6N2NaO4 + 537.1219;Found 537.1209.

[0059] 1-Ethyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-5-methyl-1H-indazole 2-oxide(3g)

[0060] 1H NMR(600 MHz,CDCl3):δ8.22(s,1H),8.16(dd,J1=7.8 Hz,J2=0.6 Hz,1H),7.76(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.62(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.46(dd,J1=7.8 Hz,J2=1.2 Hz,1H),7.30(dd,J1=8.4 Hz,J2=1.2 Hz,1H),7.11(d,J=7.8 Hz,1H),5.84-5.80(m,1H),4.29(q,J=7.2 Hz,2H),2.51(s,3H),1.29(t,J=7.2Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ186.3,162.8,143.4,134.9,134.6,130.0,129.7,128.5,128.3,127.6,125.3,121.8,120.7,120.4(q, 1 J C-F =282.3 Hz),118.3,106.8,67.5-66.5(m),37.7,21.6,12.7. 19 F NMR(565 MHz,CDCl3):δ-73.07(d,J=6.2 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 21 H 16 F6N2NaO4 + 497.0906;Found 497.0909.

[0061] 5-(tert-Butyl)-1-ethyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1H-indazole 2-oxide(3h)

[0062] 1H NMR(600 MHz,CDCl3):δ8.38(d,J=1.2 Hz,1H),8.16(dd,J1=7.8 Hz,J2=0.6Hz,1H),7.76(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.62(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.56(dd,J1=8.4 Hz,J2=1.8 Hz,1H),7.47(dd,J1=7.2 Hz,J2=0.6 Hz,1H),7.16(d,J=8.4 Hz,1H),5.85-5.81(m,1H),4.30(q,J=6.6 Hz,2H),1.42(s,9H),1.30(t,J=7.2 Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ186.3,162.8,148.3,143.5,134.6,130.0,129.7,128.2,127.6,125.3,125.2,122.1,120.4(q, 1 J C-F =278.9Hz),118.0,117.2,106.7,67.5-66.6(m),37.7,35.1,31.6,12.8. 19 F NMR(565 MHz,CDCl3):δ-73.06(d,J=6.2 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 24 H 22 F6N2NaO4 + 539.1376;Found 539.1374.

[0063] 5-Benzyl-1-ethyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1H-indazole 2-oxide(3i)

[0064] 1H NMR(600 MHz,CDCl3):δ8.29(d,J=0.6 Hz,1H),8.15(dd,J1=7.8 Hz,J2=0.6Hz,1H),7.75(td,J1=7.2 Hz,J2=1.2 Hz,1H),7.61(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.45(dd,J1=7.2 Hz,J2=0.6 Hz,1H),7.31-7.28(m,3H),7.24-7.20(m,3H),7.11(d,J=8.4 Hz,1H),5.85-5.80(m,1H),4.27(q,J=7.2 Hz,2H),4.12(s,2H),1.28(t,J=7.2 Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ186.3,162.8,143.3,141.1,138.2,134.6,130.0,129.8,128.9,128.6,128.3,127.6,126.3,125.3,121.9,121.0,120.4(q, 1 J C-F =283.4Hz),118.3,107.3,67.5-66.6(m),42.1,37.8,12.8. 19 FNMR(565 MHz,CDCl3):δ-73.04(d,J=5.7 Hz).HRMS(ESI)m / z:[M+Na] + Calcdfor C 27 H 20 F6N2NaO4 + 573.1219;Found 573.1214.

[0065] 1-Ethyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-5-phenyl-1H-indazole 2-oxide(3j)

[0066] 1H NMR(600 MHz,CDCl3):δ8.64(d,J=1.2 Hz,1H),8.18(d,J=8.4 Hz,1H),7.78(td,J1=7.2 Hz,J2=0.6 Hz,1H),7.73(dd,J1=8.4 Hz,J2=1.2 Hz,1H),7.69(d,J=7.2Hz,2H),7.65-7.62(m,1H),7.50-7.47(m,3H),7.39(t,J=7.2 Hz,1H),7.29(d,J=8.4 Hz,1H),5.85-5.81(m,1H),4.34(q,J=7.2 Hz,2H),1.34(t,J=7.2 Hz,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ186.2,162.8,143.2,140.8,138.5,134.6,130.0,129.8,129.3,128.9,127.7,127.5,127.4,126.7,125.3,122.2,120.4(q, 1 J C-F =282.2Hz),119.5,118.7,107.4,67.5-66.6(m),37.9,12.8. 19 F NMR(565 MHz,CDCl3):δ-73.04(d,J=6.2 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 26 H 18 F6N2NaO4 + 559.1063;Found 559.1060.

[0067] 5-Chloro-1-ethyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1H-indazole 2-oxide(3k)

[0068] 1H NMR(400 MHz,CDCl3):δ8.44(d,J=1.2 Hz,1H),8.17(d,J=8.0 Hz,1H),7.79-7.75(m,1H),7.66-7.62(m,1H),7.47-7.43(m,2H),7.15(d,J=8.8 Hz,1H),5.84-5.78(m,1H),4.29(q,J=7.2 Hz,2H),1.30(t,J=7.2 Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ186.0,162.8,142.8,134.7,130.8,130.1,130.0,128.2,127.7,127.4,125.3,121.6,120.8,120.4(q, 1 J C-F =281.1 Hz),119.1,108.2,67.5-66.6(m),38.0,12.7. 19 F NMR(565MHz,CDCl3):δ-73.08(d,J=6.2 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 13 ClF6N2NaO4 + 517.0360;Found 517.0373.

[0069] 1-Ethyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-5-(methoxycarbonyl)-1H-indazole 2-oxide(3l)

[0070] 1 H NMR(600 MHz,CDCl3):δ9.10(d,J=1.2 Hz,1H),8.20-8.17(m,2H),7.78(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.65(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.48(dd,J1=7.2 Hz,J2=0.6 Hz,1H),7.26(d,J=8.4 Hz,1H),5.84-5.80(m,1H),4.33(q,J=7.2Hz,2H),3.98(s,3H),1.33(t,J=7.8 Hz,3H). 13 C{1 H}NMR(150 MHz,CDCl3):δ186.0,166.8,162.8,142.8,134.7,132.2,130.1,130.0,128.3,127.7,126.8,125.3,123.8,122.3,120.3(q, 1 J C-F =281.1 Hz),117.7,106.9,67.5-66.6(m),52.3,38.0,12.8. 19 F NMR(565 MHz,CDCl3):δ-73.09(d,J=5.7 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 22 H 16 F6N2NaO6 + 541.0805;Found541.0807.

[0071] 1-Ethyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-6-methyl-1H-indazole 2-oxide(3m)

[0072] 1 H NMR(600 MHz,CDCl3):δ8.25(d,J=8.4 Hz,1H),8.16(dd,J1=8.4 Hz,J2=0.6Hz,1H),7.76(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.62(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.46(dd,J1=7.8 Hz,J2=0.6 Hz,1H),7.23(d,J=7.8 Hz,1H),7.01(s,1H),5.84-5.80(m,1H),4.28(q,J=7.8 Hz,2H),2.51(s,3H),1.30(t,J=6.6 Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ186.2,162.8,143.3,137.5,134.6,130.3,130.1,129.7,127.6,126.5,125.3,122.0,121.0,120.4(q, 1 J C-F=282.2 Hz),115.9,106.9,67.5-66.5(m),37.6,22.0,12.7. 19 F NMR(565 MHz,CDCl3):δ-73.07(d,J=6.2 Hz).HRMS(ESI)m / z:[M+Na] + Calcd forC 21 H 16 F6N2NaO4 + 497.0906;Found 497.0903.6-Chloro-1-ethyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1H-indazole 2-oxide(3n)

[0073] 1 H NMR(600 MHz,CDCl3):δ8.33(d,J=8.4 Hz,1H),8.17(d,J=7.2 Hz,1H),7.79-7.76(m,1H),7.65-7.63(m,1H),7.46(d,J=7.8 Hz,1H),7.37(dd,J1=8.4 Hz,J2=1.2 Hz,1H),7.23(d,J=1.2 Hz,1H),5.83-5.79(m,1H),4.27(q,J=7.2 Hz,2H),1.31(t,J=7.2Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ186.0,162.7,142.8,134.7,133.4,130.4,130.1,130.0,127.7,125.5,125.3,122.5,122.0,120.3(q, 1 J C-F =280.1 Hz),116.6,107.0,67.5-66.6(m),37.9,12.7. 19 F NMR(376 MHz,CDCl3):δ-73.08(d,J=5.6 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 13 ClF6N2NaO4 + 517.0360;Found 517.0364.

[0074] 4-Chloro-1-ethyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1H-indazole 2-oxide(3o)

[0075] 1 H NMR(400 MHz,CDCl3):δ8.03(d,J=7.6 Hz,1H),7.74(t,J=7.2 Hz,1H),7.66-7.61(m,2H),7.40-7.34(m,2H),7.12(dd,J1=7.2 Hz,J2=1.6 Hz,1H),5.85-5.79(m,1H),4.34(q,J=7.6 Hz,2H),1.31(t,J=7.6 Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ184.4,163.1,142.7,134.0,131.5,130.7,130.1,128.8,127.3,126.3,126.1,125.8,122.2,120.4(q, 1 J C-F =281.1 Hz),116.3,105.6,67.5-66.6(m),38.0,12.7. 19 F NMR(376 MHz,CDCl3):δ-73.09(d,J=5.3 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 13 ClF6N2NaO4 + 517.0360;Found 517.0359.

[0076] 1-Ethyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-7-methyl-1H-indazole 2-oxide(3p)

[0077] 1H NMR(600 MHz,CDCl3):δ8.30(d,J=7.8 Hz,1H),8.16(d,J=7.8 Hz,1H),7.78-7.75.(m,1H),7.64-7.61(m,1H),7.46(d,J=7.2 Hz,1H),7.29(t,J=7.2 Hz,1H),7.22(d,J=7.2 Hz,1H),5.84-5.80(m,1H),4.51(q,J=7.2 Hz,2H),2.67(s,3H),1.28(t,J=7.2Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ186.4,162.7,143.5,134.6,130.0,129.7,129.5,129.4,127.6,125.2,124.6,121.9,120.4(q, 1 J C-F =282.2 Hz),119.1,118.7,117.9,67.5-66.5(m),39.4,18.8,14.3. 19 F NMR(565 MHz,CDCl3):δ-73.06(d,J=6.2 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 21 H 16 F6N2NaO4 + 497.0906;Found 497.0907.

[0078] 5-Bromo-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1-isobutyl-1H-indazole 2-oxide(3q)

[0079] 1H NMR(600 MHz,CDCl3):δ8.60(d,J=1.8 Hz,1H),8.17(dd,J1=7.8 Hz,J2=1.2Hz,1H),7.77.(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.64(td,J1=7.2 Hz,J2=0.6 Hz,1H),7.57(dd,J1=8.4 Hz,J2=1.8 Hz,1H),7.45(dd,J1=7.8 Hz,J2=1.2 Hz,1H),7.08(d,J=8.4 Hz,1H),5.82-5.78(m,1H),4.01(d,J=7.2 Hz,2H),2.23-2.18(m,1H),0.89(d,J=6.6Hz,6H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ186.1,162.7,143.0,134.7,130.2,130.0,129.9,129.5,127.6,125.1,123.6,121.2,120.3(q, 1 J C-F =283.4 Hz),119.3,118.1,111.2,108.9,67.5-66.6(m),50.2,27.8,19.9. 19 F NMR(565MHz,CDCl3):δ-73.06(d,J=6.2 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 22 H 17 BrF6N2NaO4 + 589.0168;Found 589.0164.

[0080] 3-(2-(((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1,5-dimethyl-1H-indazole 2-oxide(3r)

[0081] 1H NMR(600 MHz,CDCl3):δ8.21(s,1H),8.15(d,J=7.8 Hz,1H),7.75(td,J1=7.8Hz,J2=1.2 Hz,1H),7.61(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.46(d,J=7.2 Hz,1H),7.29(dd,J1=8.4 Hz,J2=1.2 Hz,1H),7.08(d,J=8.4 Hz,1H),5.85-5.80(m,1H),3.71(s,3H),2.50(s,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ186.2,162.8,143.2,135.0,134.5,130.0,129.8,129.1,128.6,127.6,125.5,121.7,120.4(q, 1 J C-F =278.9 Hz),120.6,118.2,106.9,67.5-66.6(m),28.8,21.6. 19 F NMR(565 MHz,CDCl3):δ-73.06(d,J=4.5 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 14 F6N2NaO4 + 483.0750;Found 483.0766.

[0082] 3-(2-(((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1-methyl-5-(trifluoromethyl)-1H-indazole 2-oxide(3s)

[0083] 1H NMR(600 MHz,CDCl3):δ8.73(s,1H),8.17(dd,J1=8.4 Hz,J2=1.2 Hz,1H),7.78(td,J1=7.8 Hz,J2=1.8 Hz,1H),7.71(dd,J1=8.4 Hz,J2=1.2 Hz,1H),7.66(td,J1=7.8 Hz,J2=1.2 Hz,1H),7.47(dd,J1=7.8 Hz,J2=0.6 Hz,1H),7.30(d,J=8.4 Hz,1H),5.83-5.79(m,1H),3.77(s,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ185.9,162.8,142.4,134.7,131.9,130.2,130.0,127.8,127.3(q, 2 J C-F =32.7 Hz),125.5,124.2(q, 1 J C-F =271.4Hz),123.7(q, 3 J C-F =3.3 Hz),122.1,120.3(q, 1 J C-F =280.1 Hz),119.2(q, 3 J C-F =4.4 Hz),117.6,107.6,67.6-66.6(m),29.0. 19 F NMR(565MHz,CDCl3):δ-61.41(s),-73.10(d,J=6.2Hz).HRMS(ESI)m / z:[M+Na] + Calcdfor C 20 H 11 F9N2NaO4 + 537.0467;Found 537.0471.

[0084] 1-Ethyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-4,5-dimethoxybenzoyl)-1H-indazole 2-oxide(3t)

[0085] 1H NMR(600 MHz,CDCl3):δ8.37(d,J=7.8 Hz,1H),7.60(s,1H),7.48-7.46(m,1H),7.41-7.38(m,1H),7.21(d,J=7.8 Hz,1H),6.93(s,1H),5.84-5.80(m,1H),4.33(q,J=7.2 Hz,2H),4.01(s,3H),3.95(s,3H),1.32(t,J=7.2 Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ185.9,162.4,154.0,149.3,137.5,129.9,126.9,124.7,122.1,121.3,120.4(q, 1 J C-F =283.4 Hz),118.2,117.4,112.1,110.4,107.0,67.3-66.4(m),56.3,56.1,37.7,12.7. 19 F NMR(565 MHz,CDCl3):δ-73.14(d,J=5.7 Hz).HRMS(ESI)m / z:[M+Na] + Calcd forC 22 H 18 F6N2NaO6 + 543.0961;Found 543.0976.3-(4,5-Difluoro-2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1-ethyl-1H-indazole 2-oxide(3u)

[0086] 1 H NMR(400 MHz,CDCl3):δ8.38(d,J=8.0 Hz,1H),7.97(dd,J1=10.4 Hz,J2=7.6 Hz,1H),7.52-7.48(m,1H),7.44-7.40(m,1H),7.31-7.22(m,2H),5.81-5.75(m,1H),4.33(q,J=7.2 Hz,2H),1.33(t,J=6.8 Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ183.3,161.1,154.1(dd, 1 JC-F =260.4 Hz, 2 J C-F =13.2 Hz),150.2(dd, 1 J C-F =252.8 Hz, 2 J C-F =13.2 Hz),140.8-140.7(m),129.9,127.2,125.1,122.41-122.35(m),121.7,121.2,120.2(q, 1 J C-F =280.1 Hz),119.8(d, 2 J C-F =19.8 Hz),118.0,117.7(d, 2 J C-F =19.8 Hz),107.1,67.8-66.9(m),37.9,12.7. 19 F NMR(376 MHz,CDCl3):δ-73.09(d,J=5.3 Hz),-125.90--126.00(m),-133.31--133.41(m).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 12 F8N2NaO4 + 519.0562;Found 519.0574.

[0087] 3-(4,5-Dichloro-2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1-ethyl-1H-indazole 2-oxide(3v)

[0088] 1 H NMR(600 MHz,CDCl3):δ8.39(d,J=7.8 Hz,1H),8.19(s,1H),7.55(s,1H),7.51-7.49(m,1H),7.44-7.41(m,1H),7.23(d,J=8.4 Hz,1H),5.80-5.77(m,1H),4.33(q,J=7.2 Hz,2H),1.33(t,J=6.6 Hz,3H). 13 C{ 1H}NMR(150 MHz,CDCl3):δ183.4,161.3,142.1,139.5,134.3,131.6,130.0,129.9,127.2,125.10,125.07,121.8,121.2,120.2(q, 1 J C-F =279.9 Hz),117.9,107.2,67.8-66.8(m),37.9,12.7. 19 F NMR(565 MHz,CDCl3):δ-73.02(d,J=6.2 Hz).HRMS(ESI)m / z:[M+Na] + Calcd forC 20 H 12 Cl2F6N2NaO4 + 550.9971;Found550.9977.

[0089] 3-(2-(((1,1,1,3,3,3-Hexafluoropropan-2-yl)oxy)carbonyl)-4,5-dimethoxybenzoyl)-5-methoxy-1-methyl-1H-indazole 2-oxide(3w)

[0090] 1 H NMR(600 MHz,CDCl3):δ7.86(s,1H),7.59(s,1H),7.13-7.10(m,2H),6.92(s,1H),5.85-5.81(m,1H),4.01(s,3H),3.95-3.94(m,6H),3.73(s,3H). 13 C{ 1 H}NMR(100 MHz,CDCl3):δ186.0,162.4,158.0,153.9,149.3,137.4,125.4,122.3,120.4(q, 1 J C-F =279.5Hz),119.0,118.0,117.5,112.0,110.3,108.4,101.6,67.6-66.2(m),56.3,56.2,55.9,28.9. 19 F NMR(376 MHz,CDCl3):δ-73.10(d,J=5.6 Hz).HRMS(ESI)m / z:[M+Na] + Calcd forC 22 H18 F6N2NaO7 + 559.0910;Found 559.0922.3-(4,5-Difluoro-2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-5-methoxy-1-methyl-1H-indazole 2-oxide(3x)

[0091] 1 H NMR(400 MHz,CDCl3):δ7.96(dd,J1=10.0 Hz,J2=7.2 Hz,1H),7.82(s,1H),7.30-7.26(m,1H),7.130-7.127(m,2H),5.82-5.76(m,1H),3.94(s,3H),3.73(s,3H). 13 C{ 1 H}NMR(100 MHz,CDCl3):δ183.4,161.1,158.3,154.0(dd, 1 J C-F =259.3 Hz, 2 J C-F =13.0Hz),150.2(dd, 1 J C-F =252.8 Hz, 2 J C-F =13.0 Hz),140.6(dd, 3 J C-F =5.8Hz, 4 J C-F =4.4 Hz),125.4,122.5(dd, 3 J C-F =5.7 Hz, 4 J C-F =4.3 Hz),121.8,120.2(q, 1 J C-F =281.0 Hz),119.7(d, 2 J C-F =20.2 Hz),118.8,118.3,117.7(d, 2 J C-F =19.5 Hz),108.6,101.5,68.0-66.6(m),55.9,29.0. 19F NMR(376 MHz,CDCl3):δ-73.05(d,J=6.8 Hz),-126.07--126.17(m),-133.34--133.44(m).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 12 F8N2NaO5 + 535.0511;Found535.0514.

[0092] 3-(3,6-Dichloro-2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-1-ethyl-1H-indazole 2-oxide(3y)

[0093] 1 H NMR(400 MHz,CDCl3):δ8.29(d,J=8.0 Hz,1H),7.55-7.52(m,2H),7.50-7.47(m,1H),7.41(t,J=7.6 Hz,1H),7.25(d,J=8.0 Hz,1H),5.82-5.76(m,1H),4.43-4.37(m,2H),1.35(t,J=7.2 Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ181.4,161.6,141.5,133.5,132.2,132.0,129.94,129.85,127.9,127.1,125.0,122.3,121.0,120.0(q, 1 J C-F =281.1Hz),117.9,107.2,67.9-66.9(m),38.0,12.6. 19 F NMR(376 MHz,CDCl3):δ-72.56(d,J=5.6Hz),-72.85(d,J=5.6 Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 12 Cl2F6N2NaO4 + 550.9971;Found 550.9973.

[0094] 1-Ethyl-3-(2-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)benzoyl)-5-(2-(2-isopropyl-5-methylphenoxy)-2-oxoethyl)-1H-indazole 2-oxide(3z)

[0095] 1 H NMR(600MHz,CDCl3):δ8.46(d,J=0.6Hz,1H),8.17(dd,J1=7.8Hz,J2=0.6Hz,1H),7.76.(td,J1=7.8Hz,J2=1.2Hz,1H),7.62(td,J1=7.8Hz,J2=1.2Hz,1H),7.54(dd,J1=8.4Hz,J2=1.8Hz,1H),7.46(dd,J1=7.2Hz,J2=0.6Hz,1H),7.23(d,J=8.4Hz,1H),7.17(d,J=7.8Hz,1H),7.01(dd,J1=8.4Hz,J2=0.6Hz,1H),6.82(d,J=0.6Hz,1H),5.84-5.80(m,1H),4.31(q,J=7.2Hz,2H),4.04(s,2H),2.91-2.86(m,1H),2.29(s,3H),1.30(t,J=7.2Hz,3H),1.12(d,J=6.6Hz,6H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ186.2,170.2,162.8,147.9,143.2,137.0,136.6,134.6,130.5,130.0,129.8,129.2,128.4,127.6,127.2,126.4,125.3,122.6,122.0,121.9,120.4(q, 1 J C-F =283.2Hz),118.4,107.4,67.5-66.6(m),41.4,37.8,27.0,22.9,20.8,12.7. 19 F NMR(565MHz,CDCl3):δ-73.05(d,J=6.2Hz).HRMS(ESI)m / z:[M+Na] + Calcd for C 32 H 28 F6N2NaO6 +Found 673.1743.

[0096] Example 4

[0097] The anticancer activity of the compounds provided by the present invention was evaluated by studying the cell antiproliferative activity using CCK-8 assay.

[0098] The specific method is as follows: First, Hela, A549 or HCT-116 cells were inoculated into 96-well plates with 100 μL of culture medium in each well at a density of 4000 cells per well, and incubated overnight at 37°C and 5% CO2. On the second day, 100 μL of the compound to be tested prepared in culture medium at different concentrations was added to each well according to the plate map. Next, the cells were incubated for 48 hours at 37°C and 5% CO2. After the 96-well plate was equilibrated to room temperature, 10 μL of CCK-8 was added to each well and shaken on an orbital shaker for 2 minutes to induce cell lysis. After incubation for 1.5 hours at 37°C and 5% CO2, the absorbance at 450 nm was measured using a multi-function microplate reader (Perkin Elmer), and the IC was calculated using GraphPad Prism 6.0 software. 50 All experiments were performed with two parallel samples and repeated twice. 5-Fluorouracil (5-FU) was used as a positive control for the drug.

[0099] The anticancer activity results of some compounds are as follows:

[0100]

[0101]

[0102] The activity results show that the indazole nitrogen oxide 3 provided by the present invention can inhibit the proliferation activity of three cancer cells, Hela, A549 and HCT-116, among which 3b, 3c, 3d, 3e, 3m and 3p have significant effects on the three cancer cells; compounds 3g and 3h can significantly inhibit the proliferation of Hela cancer cells; compound 3i has significant anti-proliferation activity against both Hela and A-549 cancer cells; and compound 3j has a stronger effect on inhibiting the proliferation of HCT-116 cancer cells. This activity result suggests that this type of compound has a medicinal value for preventing / treating / inhibiting the progression of cancer, especially cervical cancer, lung cancer and colon cancer.

[0103] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. Indazole nitrogen oxide, characterized in that The general chemical structure is: Where: R 1 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxycarbonyl, phenyl, benzyl, trifluoromethyl or halogen, R 1 Selected from mono- or poly-substituted; R 2 Selected from C 1-6 Chain alkyl, C 3-6 Cycloalkyl or benzyl; R 3 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 3 Select from mono- or poly-substituted.

2. The indazole nitrogen oxide according to claim 1, characterized in that: The compound is selected from the following specific structures:

3. Use of the indazole nitrogen oxide according to claim 1 or 2 in the preparation of anticancer active drugs.

4. The use of indazole nitrogen oxide according to claim 3 in the preparation of anticancer active drugs, characterized in that: The anti-cancer effect is against cervical cancer, lung cancer and colon cancer.

5. The use of indazole nitrogen oxide according to claim 4 in the preparation of anticancer active drugs, characterized in that: The anti-cervical cancer effect is to inhibit the proliferation of Hela cancer cells, the anti-lung cancer effect is to inhibit the proliferation of A549 cancer cells, and the anti-colon cancer effect is to inhibit the proliferation of HCT-116 cancer cells.

6. A pharmaceutical composition for treating cervical cancer, lung cancer and colon cancer, wherein the active ingredient comprises the indazole nitrogen oxide according to claim 1 or 2.

7. The method for synthesizing indazole nitrogen oxide according to claim 1, characterized in that: The method comprises the following steps: mixing an N-nitrosoaniline compound 1, an indane dione compound 2, a catalyst, an additive and hexafluoroisopropanol, and heating the mixture to obtain an indazole nitrogen oxide compound 3. The reaction equation is: Where: R 1 For hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxycarbonyl, phenyl, benzyl, trifluoromethyl or halogen, R 1 is a single or multiple substitution; R 2 C 1-6 Chain alkyl, C 3-6 Cycloalkyl or benzyl; R 3 For hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 3 It is a one- or multiple-element replacement.

8. The method for synthesizing indazole nitrogen oxide according to claim 7, characterized in that: The additive is selected from copper acetate or a mixture of copper acetate and one or more of 2,2,6,6-tetramethylpiperidinium oxide, silver acetate, silver oxide, silver carbonate or silver nitrate; the catalyst is dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer or tris(acetonitrile)(pentamethylcyclopentadienyl)rhodium(III) di(hexafluoroantimonate).

9. The method for synthesizing indazole nitrogen oxide according to claim 7, characterized in that: The molar ratio of the N-nitrosoaniline compound 1, the indanedione compound 2, the catalyst and the additive is 1:1-1.5:0.04-0.06:1-5.

10. The method for synthesizing indazole nitrogen oxide according to any one of claims 7 to 9, characterized in that: The reaction temperature is 60-100°C; the reaction is carried out in air, oxygen or an inert gas atmosphere.

Images