A pyrazole hydrazide derivative containing diphenyl ether unit, and a preparation method and application thereof

Abstract

The application belongs to the field of medicine, and discloses a compound with the structure of formula I, a preparation method of the compound, and the compound is a pyrazole acylhydrazine derivative containing a diphenyl ether unit, which is obtained by substituting p-chloronitrobenzene with phenol, and then by reduction, diazotization, re-reduction, hydrochloric acid removal and hydrazide reaction; the pyrazole acylhydrazine derivative containing the diphenyl ether unit has obvious inhibitory effect on human pancreatic cancer cells, human breast cancer cells and human gastric cancer cells, and can be used as a potential new type of antitumor candidate drug molecule.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a pyrazole hydrazide derivative containing a diphenyl ether unit and a preparation method and application thereof. BACKGROUND

[0002] Cancer, as a widespread and deadly non-communicable disease, is an important factor leading to the death of global population. So far, chemotherapy is still the main strategy for treating malignant tumors. However, these chemical drugs often only act on tumors with low specificity, and can cause adverse side effects such as diarrhea, extreme fatigue and leukopenia in patients. Therefore, it is still a challenging task to develop new antitumor drugs with good efficacy and small side effects. SUMMARY

[0003] The first object of the present application is to provide a pyrazole hydrazide derivative containing a diphenyl ether unit with antitumor activity; the second object of the present application is to provide a preparation method of the pyrazole hydrazide derivative containing a diphenyl ether unit; and the third object of the present application is to provide an application of the pyrazole hydrazide derivative containing a diphenyl ether unit in resisting tumor cells.

[0004] Technical scheme: The pyrazole hydrazide derivative containing a diphenyl ether unit provided by the present application has a structure as shown in formula I:

[0005]

[0006] wherein R is selected from 3,5-dichloro, 2,4-dichloro, 3,5-dimethyl, 3-chloro, 4-methyl, 2,6-dichloro, 2-methyl-4-chloro, 4-fluoro, 2-fluoro, 2,3-dichloro, 3-methyl, 2,6-dimethyl, 2,3,6-trimethyl, 3,4-dimethyl, 2,3,5-trimethyl or 4-ethyl.

[0007] The preparation method of the pyrazole hydrazide derivative containing a diphenyl ether unit provided by the present application is as follows: after substitution reaction of p-chloronitrobenzene and phenol occurs in a DMF solution containing potassium carbonate, zinc powder reduction, nitrous acid oxidation and tin chloride reduction are performed, and then p-phenoxyphenylhydrazine molecules obtained after deacidification are subjected to hydrazide reaction with 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylic acid to obtain the pyrazole hydrazide derivative containing a diphenyl ether unit, and the synthetic route is as follows:

[0008]

[0009] The pyrazole hydrazide derivative containing a diphenyl ether unit provided by the present application is applied in resisting tumor cells.

[0010] The tumor cells are human pancreatic cancer cells, human breast cancer cells and human gastric cancer cells.

[0011] Beneficial effects: compared with the prior art, the pyrazole hydrazide derivative containing a diphenyl ether unit has the following advantages (1) the pyrazole hydrazide derivative containing a diphenyl ether unit has inhibitory effect on breast cancer cells, gastric cancer cells or pancreatic cancer cells; (2) the pyrazole hydrazide derivative containing a diphenyl ether unit has simple preparation method, raw materials are easy to obtain, and the reaction is novel and efficient; (3) the pyrazole hydrazide derivative containing a diphenyl ether unit has strong inhibitory activity on tumor cells, and the optimal inhibitory rate (84.5%) of the pyrazole hydrazide derivative containing a diphenyl ether unit on pancreatic cancer cells at a dose of 10 μM is higher than that (54.9%) of the control drug fluorouracil, so that the pyrazole hydrazide derivative containing a diphenyl ether unit can be used as a potential new anti-tumor candidate drug molecule. DETAILED DESCRIPTION

[0012] The technical solutions of the present application are further described below in combination with examples.

[0013] Example 1

[0014]

[0015] The pyrazole hydrazide derivative containing a diphenyl ether unit I1, R = 3,5-di-Cl, the chemical name is N'-(4-(3,5-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, the English name is N'-(4-(3,5-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, and the structural formula is as follows:

[0016] First step: synthesis of 1,3-dichloro-5-(4-nitrophenoxy)benzene (intermediate A1)

[0017]

[0018] In a 100 mL round-bottom flask, 3,5-dichlorophenol (40 mmol), potassium carbonate (96 mmol) and DMF (15 mL) were sequentially added, and after stirring at room temperature for about 10 min, p-chloronitrobenzene (32 mmol) dissolved in DMF (15 mL) was added to the reaction system by a constant pressure dropping funnel, and the reaction was carried out at 130°C for about 5 h. After the disappearance of the raw material was monitored by TLC, the above reaction liquid was added to 500 mL of water, and a large amount of yellow precipitate was precipitated after standing overnight. The filter cake was dried to obtain 1,3-dichloro-5-(4-nitrophenoxy)benzene (intermediate A1).

[0019] Second step: synthesis of 4-(3,5-dichlorophenoxy)aniline (intermediate B1)

[0020]

[0021] To a solution of 4-(3,5-dichlorophenoxy)aniline (12 mmol) in ethanol (20 mL) was added concentrated hydrochloric acid (10 mL) and stirred at room temperature for about 10 min. Sodium nitrite (24 mmol) dissolved in water (5 mL) was added dropwise to the reaction mixture under ice bath condition and stirred for about 5 h under ice bath condition. After the starting material was consumed as monitored by TLC, the ethanol was removed under reduced pressure and distilled water (30 mL) was added. The aqueous phase was washed with dichloromethane. The aqueous phase was collected and distilled under reduced pressure to remove excess dichloromethane to give a solution of 4-(3,5-dichlorophenoxy)phenyl diazonium salt (Intermediate Cl) in water.

[0022] Third step: Synthesis of 4-(3,5-dichlorophenoxy)phenyl diazonium salt (Intermediate Cl)

[0023]

[0024] To a solution of 4-(3,5-dichlorophenoxy)aniline (12 mmol) in ethanol (20 mL) was added concentrated hydrochloric acid (10 mL) and stirred at room temperature for about 10 min. Sodium nitrite (24 mmol) dissolved in water (5 mL) was added dropwise to the reaction mixture under ice bath condition and stirred for about 5 h under ice bath condition. After the starting material was consumed as monitored by TLC, the ethanol was removed under reduced pressure and distilled water (30 mL) was added. The aqueous phase was washed with dichloromethane. The aqueous phase was collected and distilled under reduced pressure to remove excess dichloromethane to give a solution of 4-(3,5-dichlorophenoxy)phenyl diazonium salt (Intermediate Cl) in water.

[0025] Fourth step: Synthesis of 4-(3,5-dichlorophenoxy)phenylhydrazine hydrochloride (Intermediate Dl)

[0026]

[0027] To a solution of 4-(3,5-dichlorophenoxy)aniline (12 mmol) in ethanol (20 mL) was added concentrated hydrochloric acid (10 mL) and stirred at room temperature for about 10 min. Sodium nitrite (24 mmol) dissolved in water (5 mL) was added dropwise to the reaction mixture under ice bath condition and stirred for about 5 h under ice bath condition. After the starting material was consumed as monitored by TLC, the ethanol was removed under reduced pressure and distilled water (30 mL) was added. The aqueous phase was washed with dichloromethane. The aqueous phase was collected and distilled under reduced pressure to remove excess dichloromethane to give a solution of 4-(3,5-dichlorophenoxy)phenyl diazonium salt (Intermediate Cl) in water.

[0028] Fifth step: Synthesis of 4-(3,5-dichlorophenoxy)phenylhydrazine (Intermediate El)

[0029]

[0030] To a solution of 4-(3,5-dichlorophenoxy)benzenamine hydrochloride (10 mmol) in water (30 mL), the pH of the system was adjusted to 8-9 with 5% NaOH solution, and the mixture was stirred at room temperature for about 30 min. Then, the mixture was extracted with dichloromethane, and the organic phase was combined and concentrated under reduced pressure to remove excess dichloromethane. The residue was separated by column chromatography to obtain 4-(3,5-dichlorophenoxy)benzenamine (intermediate El).

[0031] Step 6: Synthesis of N'-(4-(3,5-dichlorophenoxy)phenyl)-3-(difluoromethyl)-l- methyl-lH-pyrazole-4-carbohydrazide (target compound II)

[0032] In a 100 mL round-bottom flask, 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid (6 mmol), TBTU (7 mmol), triethylamine (18 mmol), and dichloromethane (30 mL) were sequentially added, and the mixture was stirred at room temperature for about 30 min. Then, 4-(3,5-dichlorophenoxy)benzenamine (9 mmol) was added to the above mixture, and the stirring was continued at room temperature. After the disappearance of the starting material was monitored by TLC, the excess solvent was removed under reduced pressure, and the residue was separated by column chromatography to obtain the target compound II.

[0033] The target compound II was a yellow oil; yield 45%; 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.04 (d, J = 1.7 Hz, 1H), 7.30 (t, J = 54.1 Hz, 1H), 7.26 (s, 1H), 7.00 (d, J = 8.6 Hz, 2H), 6.90 (s, 2H), 6.84 (d, J = 8.7 Hz, 2H), 3.97 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 161.83, 160.72, 147.46, 146.85, 145.40 (t, J = 23.3 Hz), 135.27, 132.87, 122.20, 121.63, 115.87, 114.41 (t, J = 3.3 Hz), 114.04, 110.09 (t, J = 234.7 Hz), 38.70; HRMS (ESI) m / z [M+H] + calcd for C 18 H 14 Cl2F2N4O2: 427.0535, found: 427.0539.

[0034] Example 2

[0035] The pyrazole hydrazide derivative I2 containing diphenyl ether unit according to the present application, R1=2,4-di-Cl, chemical name is N'-(4-(2,4-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, English name is N'-(4-(2,4-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, the structural formula is as follows:

[0036]

[0037] First step: synthesis of 2,4-dichloro-1-(4-nitrophenoxy)benzene (intermediate A2)

[0038]

[0039] As example 1 first step, the difference lies in using 2,4-dichlorophenol as a reactant.

[0040] Second step: synthesis of 4-(2,4-dichlorophenoxy)aniline (intermediate B2)

[0041]

[0042] As example 1 second step, the difference lies in using 2,4-dichloro-1-(4-nitrophenoxy)benzene as a reactant.

[0043] Third step: synthesis of 4-(2,4-dichlorophenoxy)phenyl diazonium salt (intermediate C2)

[0044]

[0045] As example 1 third step, the difference lies in using 4-(2,4-dichlorophenoxy)aniline as a reactant.

[0046] Fourth step: synthesis of 4-(2,4-dichlorophenoxy)phenylhydrazine hydrochloride (intermediate D2)

[0047]

[0048] As example 1 fourth step, the difference lies in using 4-(2,4-dichlorophenoxy)phenyl diazonium salt as a reactant.

[0049] Fifth step: synthesis of 4-(2,4-dichlorophenoxy)phenylhydrazine (intermediate E2)

[0050]

[0051] As in Example 1, Step 5, except using 4-(2,4-dichlorophenoxy)phenylhydrazine as the reactant.

[0052] Step 6: Synthesis of N'-(4-(2,4-dichlorophenoxy)phenyl)-3-(difluoromethyl)- 1 -methyl- 1 H-pyrazole-4-carbohydrazide (Target Compound I2)

[0053] As in Example 1, Step 6, except using 4-(2,4-dichlorophenoxy)phenylhydrazine as the reactant.

[0054] Target Compound I2 was a yellow oil; yield 47%; 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (d, J = 2.6 Hz, 1H), 8.39 (s, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 8.9, 2.6 Hz, 1H), 7.28 (t, J = 54.2 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.9 Hz, 1H), 6.81 (d, J = 8.9 Hz, 2H), 5.75 (s, 1H), 3.95 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) 161.81, 153.19, 148.08, 146.94, 145.38 (t, J = 23.3 Hz), 132.85, 130.28, 128.93, 127.19, 124.38, 120.34, 119.81, 114.42 (t, J = 3.2 Hz), 114.04, 110.08 (t, J = 234.6 Hz), 38.70; HRMS (ESI) m / z [M+H] + calcd for C 18 H 14 Cl2F2N4O2: 427.0535, found: 427.0535.

[0055] Example 3

[0056] The pyrazole carbohydrazide derivative I3 containing diphenyl ether unit described in the present application, R1=3,5-di-CH3, chemical name 3-(difluoromethyl)-N'-(4-(3,5-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, English name 3-(difluoromethyl)-N'-(4-(3,5-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, has the following structural formula:

[0057]

[0058] First Step: Synthesis of 1,3-Dimethyl-5-(4-nitrophenoxy)benzene (Intermediate A3)

[0059]

[0060] As in Example 1, First Step, except using 3,5-dimethylphenol as the reactant.

[0061] Second Step: Synthesis of 4-(3,5-Dimethylphenoxy)aniline (Intermediate B3)

[0062]

[0063] As in Example 1, Second Step, except using 1,3-dimethyl-5-(4-nitrophenoxy)benzene as the reactant.

[0064] Third Step: Synthesis of 4-(3,5-Dimethylphenoxy)phenyl Diazonium Salt (Intermediate C3)

[0065]

[0066] As in Example 1, Third Step, except using 4-(3,5-dimethylphenoxy)aniline as the reactant.

[0067] Fourth Step: Synthesis of 4-(3,5-Dimethylphenoxy)phenylhydrazine Hydrochloride (Intermediate D3)

[0068]

[0069] As in Example 1, Fourth Step, except using 4-(3,5-dimethylphenoxy)phenyl diazonium salt as the reactant.

[0070] Fifth Step: Synthesis of 4-(3,5-Dimethylphenoxy)phenylhydrazine (Intermediate E3)

[0071]

[0072] As in Example 1, Fifth Step, except using 4-(3,5-dimethylphenoxy)phenylhydrazine hydrochloride as the reactant.

[0073] Sixth Step: Synthesis of 3-(Difluoromethyl)-N'-(4-(3,5-dimethylphenoxy)phenyl)-1- methyl 11H-pyrazole-4-carbohydrazide (Target Compound I3)

[0074] As in Example 1, Sixth Step, except using 4-(3,5-dimethylphenoxy)phenylhydrazine as the reactant.

[0075] The target compound I3 is a yellow oil; yield 43%; 1 H NMR (500 MHz, DMSO-d6) δ 10.14 (d, J = 2.8 Hz, 1H), 8.39 (s, 1H), 7.89 (d, J = 2.7 Hz, 1H), 7.30 (t, J = 54.2 Hz, 1H), 6.87 (t, J = 6.0 Hz, 2H), 6.79 (d, J = 8.9 Hz, 2H), 6.67 (s, 1H), 6.50 (s, 2H), 3.96 (s, 3H), 2.70 (s, 6H); 13 CNMR (100 MHz, CDC13) δ 161.84, 158.28, 151.19, 143.90, 143.52, 139.45, 135.21, 124.26, 120.62, 115.42, 115.07, 113.93, 111.32 (t, J = 74.8 Hz), 39.59, 38.63; HRMS (ESI) m / z [M+H] + calcd for C 20 H 20 F2N4O2: 387.1627, found: 387.1625.

[0076] Example 4

[0077] The pyrazole hydrazide derivative I4 containing diphenyl ether unit according to the present application, R1=3-Cl, chemical name is N'-(4-(3-chlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, English name is N'-(4-(3-chlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, the structural formula is as follows:

[0078]

[0079] First step: synthesis of 1-chloro-3-(4-nitrophenoxy)benzene (intermediate A4)

[0080]

[0081] As the first step of example 1, the difference is that 3-chlorophenol is used as the reactant.

[0082] Second step: synthesis of 4-(3-chlorophenoxy)aniline (intermediate B4)

[0083]

[0084] As in Example 1, Step 2, except using 1-chloro-3-(4-nitrophenoxy)benzene as the reactant.

[0085] Step 3: Synthesis of 4-(3-chlorophenoxy)phenyl diazonium salt (Intermediate C4)

[0086]

[0087] As in Example 1, Step 3, except using 4-(3-chlorophenoxy)aniline as the reactant.

[0088] Step 4: Synthesis of 4-(3-chlorophenoxy)phenylhydrazine hydrochloride (Intermediate D4)

[0089]

[0090] As in Example 1, Step 4, except using 4-(3-chlorophenoxy)phenyl diazonium salt as the reactant.

[0091] Step 5: Synthesis of 4-(3-chlorophenoxy)phenylhydrazine (Intermediate E4)

[0092]

[0093] As in Example 1, Step 5, except using 4-(3-chlorophenoxy)phenylhydrazine hydrochloride as the reactant.

[0094] Step 6: Synthesis of N'-(4-(3-chlorophenoxy)phenyl)-3-(difluoromethyl)-l-methyl- lH-pyrazole-4-carbohydrazide (Target Compound I4)

[0095] As in Example 1, Step 6, except using 4-(3-chlorophenoxy)phenylhydrazine as the reactant.

[0096] Target Compound I4 was a yellow oil; yield 43%; 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (d, J = 2.6 Hz, 1H), 8.39 (s, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.30 (t, J = 54.1 Hz, 1H), 7.10 (dd, J = 8.0, 1.2 Hz, 1H), 6.95 (t, J = 6.0 Hz, 2H), 6.90 (t, J = 2.1 Hz, 1H), 6.86 (dd, J = 8.3, 1.9 Hz, 1H), 6.83 (d, J = 8.9 Hz, 2H), 3.96 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 161.82, 160.09, 147.59, 147.04, 145.39 (t, J = 23.4 Hz), 134.27, 132.85, 131.72, 122.48, 121.41, 116.93, 115.82, 114.43 (t, J = 3.2 Hz), 114.03, 110.09 (t, J = 234.3 Hz), 38.70. HRMS (ESI) m / z [M + H] + calcd for C 18 H 15 ClF2N4O2: 393.0924, found: 393.0927.

[0097] Example 5

[0098] The pyrazole carbohydrazide derivative I5, R1= 4-CH3, with diphenyl ether unit according to the present application, chemical name 3-(difluoromethyl)-1-methyl-N'-(4-(p-tolyloxy)phenyl)-1H-pyrazole-4-carbohydrazide, structure formula as follows:

[0099]

[0100] First step: synthesis of 1-methyl-4-(4-nitrophenoxy)benzene (intermediate A5)

[0101]

[0102] As example 1 first step, the difference is that p-methyl phenol as the reactant.

[0103] Second step: synthesis of 4-(p-methylphenoxy)aniline (intermediate B5)

[0104]

[0105] As example 1 second step, the difference is that 1-methyl-4-(4-nitrophenoxy)benzene as the reactant.

[0106] Third step: synthesis of 4-(p-methylphenoxy)phenyl diazonium salt (intermediate C5)

[0107]

[0108] As example 1 third step, the difference is that 4-(p-methylphenoxy)aniline as the reactant.

[0109] Fourth Step: Synthesis of 4-(p-methylphenoxy)phenylhydrazine hydrochloride (Intermediate D5)

[0110]

[0111] As in Example 1, Fourth Step, except using 4-(p-methylphenoxy)phenyldiazonium salt as the reactant.

[0112] Fifth Step: Synthesis of 4-(p-methylphenoxy)phenylhydrazine (Intermediate E5)

[0113]

[0114] As in Example 1, Fifth Step, except using 4-(p-methylphenoxy)phenylhydrazine hydrochloride as the reactant.

[0115] Sixth Step: Synthesis of 3-(difluoromethyl)-l-methyl-N'-(4-(p- tolyloxy)phenyl)-lH-pyrazole-4-carbohydrazide (Target Compound I5)

[0116] As in Example 1, Sixth Step, except using 4-(p-methylphenoxy)phenylhydrazine as the reactant.

[0117] Target Compound I5 was a yellow oil; yield 45%; 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.39 (s, 1H), 7.87 (s, 1H), 7.29 (t, J = 54.1 Hz, 1H), 7.12 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 6.79 (dd, J = 8.5, 6.4 Hz, 4H), 3.95 (s, 3H), 2.25 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 161.82, 156.48, 149.24, 146.20, 145.37 (t, J = 23.3 Hz), 132.82, 131.68, 130.57, 120.50, 117.57, 114.47 (t, J = 3.3 Hz), 114.01, 110.09 (t, J = 234.6 Hz), 38.69, 20.60. HRMS (ESI) m / z [M + H] + calcd for C 19 H 18 F2N4O2: 373.1471, found: 373.1474.

[0118] Example 6

[0119] The pyrazole hydrazide derivative I6 containing diphenyl ether unit described in the present application, R1=2,6-di-Cl, chemical name is N'-(4-(2,6-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, English name is N'-(4-(2,6-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, the structural formula is as follows:

[0120]

[0121] First step: synthesis of 1,3-dichloro-2-(4-nitrophenoxy)benzene (intermediate A6)

[0122]

[0123] As example 1 first step, the difference lies in using 2,6-dichlorophenol as the reactant.

[0124] Second step: synthesis of 4-(2,6-dichlorophenoxy)aniline (intermediate B6)

[0125]

[0126] As example 1 second step, the difference lies in using 1,3-dichloro-2-(4-nitrophenoxy)benzene as the reactant.

[0127] Third step: synthesis of 4-(2,6-dichlorophenoxy)phenyl diazonium salt (intermediate C6)

[0128]

[0129] As example 1 third step, the difference lies in using 4-(2,6-dichlorophenoxy)aniline as the reactant.

[0130] Fourth step: synthesis of 4-(2,6-dichlorophenoxy)phenylhydrazine hydrochloride (intermediate D6)

[0131]

[0132] As example 1 fourth step, the difference lies in using 4-(2,6-dichlorophenoxy)phenyl diazonium salt as the reactant.

[0133] Fifth step: synthesis of 4-(2,6-dichlorophenoxy)phenylhydrazine (intermediate E6)

[0134]

[0135] As in Example 1, Step 5, except using 4-(2,6-dichlorophenoxy)phenylhydrazine as the reactant.

[0136] Step 6: Synthesis of N'-(4-(2,6-dichlorophenoxy)phenyl)-3-(difluoromethyl)-l- methyl-lH-pyrazole-4-carbohydrazide (Target Compound I6)

[0137] As in Example 1, Step 6, except using 4-(2,6-dichlorophenoxy)phenylhydrazine as the reactant.

[0138] Target Compound I6 was a yellow oil; yield 47%; 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (d, J = 2.4 Hz, 1H), 8.36 (s, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.32 (t, J = 8.1 Hz, 1H), 7.27 (t, J = 54.1 Hz, 1H), 6.72 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.9 Hz, 2H), 3.94 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 165.06, 161.82, 150.07, 147.17, 145.39, 145.35 (t, J = 23.3 Hz), 132.79, 130.14, 129.43, 127.73, 115.48, 114.49 (t, J = 3.4 Hz), 114.03, 110.07 (t, J = 234.6 Hz), 38.70; HRMS (ESI) m / z [M+H]+calcd for C 18 H 14 Cl2F2N4O2: 427.0535, found: 427.0531.

[0139] Example 7

[0140] The pyrazole carbohydrazide derivative I7 containing diphenyl ether unit described in the present application, R1=2-CH3-4-Cl, chemical name is N'-(4-(4-chloro-2-methylphenoxy)phenyl)-3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carbohydrazide, English name is N'-(4-(4-chloro-2-methylphenoxy)phenyl)-3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carbohydrazide, the structural formula is as follows:

[0141]

[0142] First Step: Synthesis of 4-chloro-2-methyl-l-(4-nitrophenoxy)benzene (Intermediate A7)

[0143]

[0144] As in Example 1, First Step, except using 4-chloro-2-methylphenol as the reactant.

[0145] Second Step: Synthesis of 4-(4-chloro-2-methylphenoxy)aniline (Intermediate B7)

[0146]

[0147] As in Example 1, Second Step, except using 4-chloro-2-methyl-l-(4-nitrophenoxy)benzene as the reactant.

[0148] Third Step: Synthesis of 4-(4-chloro-2-methylphenoxy)phenyl diazonium salt (Intermediate C7)

[0149]

[0150] As in Example 1, Third Step, except using 4-(4-chloro-2-methylphenoxy)aniline as the reactant.

[0151] Fourth Step: Synthesis of 4-(4-chloro-2-methylphenoxy)phenylhydrazine hydrochloride (Intermediate D7)

[0152]

[0153] As in Example 1, Fourth Step, except using 4-(4-chloro-2-methylphenoxy)phenyl diazonium salt as the reactant.

[0154] Fifth Step: Synthesis of 4-(4-chloro-2-methylphenoxy)phenylhydrazine (Intermediate E7)

[0155]

[0156] As in Example 1, Fifth Step, except using 4-(4-chloro-2-methylphenoxy)phenylhydrazine hydrochloride as the reactant.

[0157] Sixth Step: Synthesis of N'-(4-(4-chloro-2-methylphenoxy)phenyl)-3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carbohydrazide (Target Compound I7)

[0158] As in Example 1, Sixth Step, except using 4-(4-chloro-2-methylphenoxy)phenylhydrazine as the reactant.

[0159] Target Compound I7 was a yellow oil; yield 48%; 1H NMR (400 MHz, DMSO-d6) δ 10.15 (d, J = 2.8 Hz, 1H), 8.39 (s, 1H), 7.90 (d, J = 2.7 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.41 - 7.15 (m, 1H), 6.84 (dd, J = 9.3, 2.5 Hz, 2H), 6.81 - 6.77 (m, 2H), 6.69 (d, J = 8.7 Hz, 1H), 3.96 (s, 3H), 2.23 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 161.80, 155.39, 149.08, 146.30, 145.37 (t, J = 23.4 Hz), 132.82, 131.07, 130.53, 127.26, 126.57, 114.47 (t, J = 3.3 Hz), 114.07, 110.08 (t, J = 234.6 Hz), 38.69, 16.16; HRMS (ESI) m / z [M+H] + calcd for C 19 H 17 ClF2N4O2: 407.1081, found: 407.1082.

[0160] Example 8

[0161] The pyrazole carbohydrazide derivative I8, R1= 4-F, containing diphenyl ether unit according to the present application, with chemical name 3-(difluoromethyl)-N'-(4-(4-fluorophenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, has the following structure:

[0162]

[0163] First step: synthesis of 1-fluoro-4-(4-nitrophenoxy)benzene (intermediate A8)

[0164]

[0165] As example 1, first step, except that 4-fluorophenol was used as reactant.

[0166] Second step: synthesis of 4-(4-fluorophenoxy)aniline (intermediate B8)

[0167]

[0168] As in Example 1, Step 2, except using 1-fluoro-4-(4-nitrophenoxy)benzene as the reactant.

[0169] Step 3: Synthesis of 4-(4-fluorophenoxy)phenyl diazonium salt (Intermediate C8)

[0170]

[0171] As in Example 1, Step 3, except using 4-(4-fluorophenoxy)aniline as the reactant.

[0172] Step 4: Synthesis of 4-(4-fluorophenoxy)phenylhydrazine hydrochloride (Intermediate D8)

[0173]

[0174] As in Example 1, Step 4, except using 4-(4-fluorophenoxy)phenyl diazonium salt as the reactant.

[0175] Step 5: Synthesis of 4-(4-fluorophenoxy)phenylhydrazine (Intermediate E8)

[0176]

[0177] As in Example 1, Step 5, except using 4-(4-fluorophenoxy)phenylhydrazine hydrochloride as the reactant.

[0178] Step 6: Synthesis of 3-(difluoromethyl)-N'-(4-(4-fluorophenoxy)phenyl)-l-methyl- lH-pyrazole-4-carbohydrazide (Target Compound I8)

[0179] As in Example 1, Step 6, except using 4-(4-fluorophenoxy)phenylhydrazine as the reactant.

[0180] Target Compound I8 was a yellow oil; yield 44%; 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.38 (s, 1H), 7.90 (s, 1H), 7.28 (t, J = 54.2 Hz, 1H), 7.17-7.13 (m, 2H), 6.94-6.91 (m, 2H), 6.90-6.87 (m, 2H), 6.80-6.78 (m, 2H), 3.95 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 161.81, 157.91 (d, J = 238.0 Hz), 154.91 (d, J = 2.0 Hz), 149.11, 146.47, 145.37 (t, J = 23.3 Hz), 132.84, 120.55, 119.13 (d, J = 8.3 Hz), 116.69 (d, J = 23.3 Hz), 114.47 (t, J = 3.3 Hz), 114.05, 110.09 (t, J = 234.5 Hz), 38.70. HRMS (ESI) m / z [M + H] + calcd for C 18 H 15 F3N4O2: 377.1220, found: 377.1223.

[0181] Example 9

[0182] The pyrazole carbohydrazide derivative I9, R1= 2-F, with diphenyl ether unit according to the present application, chemical name 3-(difluoromethyl)-N'-(4-(2- fluorophenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, structure as follows:

[0183]

[0184] First step: synthesis of 1-fluoro-2-(4-nitrophenoxy)benzene (intermediate A9)

[0185]

[0186] As example 1, first step, except that 2-fluorophenol was used as reactant.

[0187] Second step: synthesis of 4-(2-fluorophenoxy)aniline (intermediate B9)

[0188]

[0189] As example 1, second step, except that 1-fluoro-2-(4-nitrophenoxy)benzene was used as reactant.

[0190] Third step: synthesis of 4-(2-fluorophenoxy)phenyl diazonium salt (intermediate C9)

[0191]

[0192] As in Example 1, Step 3, except using 4-(2-fluorophenoxy)aniline as the reactant.

[0193] Fourth Step: Synthesis of 4-(2-fluorophenoxy)phenylhydrazine hydrochloride (Intermediate D9)

[0194]

[0195] As in Example 1, Step 4, except using 4-(2-fluorophenoxy)phenyl diazonium salt as the reactant.

[0196] Fifth Step: Synthesis of 4-(2-fluorophenoxy)phenylhydrazine (Intermediate E9)

[0197]

[0198] As in Example 1, Step 5, except using 4-(2-fluorophenoxy)phenylhydrazine hydrochloride as the reactant.

[0199] Sixth Step: Synthesis of 3-(difluoromethyl)-N'-(4-(2-fluorophenoxy)phenyl)-l- methyl-lH-pyrazole-4-carbohydrazide (Target Compound I9)

[0200] As in Example 1, Step 6, except using 4-(2-fluorophenoxy)phenylhydrazine as the reactant.

[0201] Target Compound I9 was a yellow oil; yield 40%; 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (d, J = 2.8 Hz, 1H), 8.39 (s, 1H), 7.91 (d, J = 2.7 Hz, 1H), 7.34-7.30 (m, 1H), 7.29 (t, J = 54.1 Hz, 1H) 7.15-7.10 (m, 2H), 6.96 (td, J = 8.4, 2.1 Hz, 1H), 6.88 (t, J = 6.0 Hz, 2H), 6.81-6.79 (m, 2H), 3.95 (s, 3H), 1.98 (s, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 161.83, 153.41 (d, J = 245.4 Hz), 149.12, 146.42, 145.39 (t, J = 23.4 Hz), 145.32 (d, J = 10.9 Hz), 132.83, 125.55 (d, J = 3.7 Hz), 124.37 (d, J = 7.0 Hz), 120.36, 119.43, 117.34 (d, J = 17.9 Hz), 114.48 (t, J = 3.3 Hz), 114.02, 110.09 (t, J = 234.6 Hz), 38.68; HRMS (ESI) m / z [M + H]+ calcd for C 18 H 15 F3N4O2: 377.1220, found: 377.1218.

[0202] Example 10

[0203] The pyrazole carbohydrazide derivative I containing diphenyl ether unit according to the present application 10 , R1= 2,3-di-Cl, chemical name N'-(4-(2,3-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, English name N'-(4-(2,3-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, structure as follows:

[0204]

[0205] First step: synthesis of 1,2-dichloro-3-(4-nitrophenoxy)benzene (intermediate A 10 )

[0206]

[0207] As example 1, step 1, the difference is that 2,3-dichlorophenol is used as the reactant.

[0208] Second step: synthesis of 4-(2,3-dichlorophenoxy)aniline (intermediate B 10 )

[0209]

[0210] As example 1, step 2, the difference is that 1,2-dichloro-3-(4-nitrophenoxy)benzene is used as the reactant.

[0211] Third step: synthesis of 4-(2,3-dichlorophenoxy)phenyl diazonium salt (intermediate C 10 )

[0212]

[0213] As example 1, step 3, the difference is that 4-(2,3-dichlorophenoxy)aniline is used as the reactant.

[0214] Fourth step: synthesis of 4-(2,3-dichlorophenoxy)phenylhydrazine hydrochloride (intermediate D 10 )

[0215]

[0216] As in Example 1, fourth step, except that 4-(2,3-dichlorophenoxy)benzenediazonium salt was the reactant.

[0217] Fifth step: synthesis of 4-(2,3-dichlorophenoxy)phenylhydrazine (Intermediate E 10 )

[0218]

[0219] As in Example 1, fifth step, except that 4-(2,3-dichlorophenoxy)phenylhydrazine hydrochloride was the reactant.

[0220] Sixth step: synthesis of N'-(4-(2,3-dichlorophenoxy)phenyl)-3-(difluoromethyl)-l- methyl-lH-pyrazole-4-carbohydrazide (Target Compound I 10 )

[0221] As in Example 1, sixth step, except that 4-(2,3-dichlorophenoxy)phenylhydrazine was the reactant.

[0222] Target Compound I 10 was a yellow oil; yield 42%; 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.40 (s, 1H), 7.99 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.30 (t, J = 54.1 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.81 (dd, J = 13.8, 5.0 Hz, 3H), 3.96 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 161.82, 155.73, 147.93, 147.06, 145.38 (t, J = 23.3 Hz), 133.20, 132.86, 129.11, 124.53, 122.09, 120.58, 116.84, 114.43 (t, J = 3.3 Hz), 114.03, 110.09 (t, J = 234.6 Hz), 38.70; HRMS (ESI) m / z [M + H] + calcd for C 18 H 14 Cl2F2N4O2: 427.0535, found: 427.0532.

[0223] Example 11

[0224] The pyrazole carbohydrazide derivative I containing diphenyl ether units according to the present application 11, R1= 3-CH3, chemical name 3-(difluoromethyl)-1-methyl-N'-(4-(m-tolyloxy)phenyl)-1H-pyrazole-4-carbohydrazide, English name 3-(difluoromethyl)-1-methyl-N'-(4-(m-tolyloxy)phenyl)-1H-pyrazole-4-carbohydrazide, structure as follows:

[0225]

[0226] First step: synthesis of 1-methyl-3-(4-nitrophenoxy)benzene (intermediate A 11 )

[0227]

[0228] As in Example 1, first step, except that m-methylphenol is the reactant.

[0229] Second step: synthesis of 4-(m-methylphenoxy)aniline (intermediate B 11 )

[0230]

[0231] As in Example 1, second step, except that 1-methyl-3-(4-nitrophenoxy)benzene is the reactant.

[0232] Third step: synthesis of 4-(m-methylphenoxy)phenyl diazonium salt (intermediate C 11 )

[0233]

[0234] As in Example 1, third step, except that 4-(m-methylphenoxy)aniline is the reactant.

[0235] Fourth step: synthesis of 4-(m-methylphenoxy)phenylhydrazine hydrochloride (intermediate D 11 )

[0236]

[0237] As in Example 1, fourth step, except that 4-(m-methylphenoxy)phenyl diazonium salt is the reactant.

[0238] Fifth step: synthesis of 4-(m-methylphenoxy)phenylhydrazine (intermediate E 11 )

[0239]

[0240] As in step 5 of Example 1, the difference is that 4-(m-methylphenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0241] Step 6: 3-(difluoromethyl)-1-methyl-N′-(4-(m-tolyloxy)phenyl)-1H-pyrazole-4-acylhydrazide (target compound I) 11 Synthesis of )

[0242] As in step 6 of Example 1, the difference is that 4-(m-methylphenoxy)phenylhydrazine is used as the reactant.

[0243] Target compound I 11 It is a yellow oily substance; yield 43%; 1 H NMR (400MHz, DMSO) δ10.15 (d, J=2.6Hz, 1H), 8.40 (s, 1H), 7.91 (d, J=2.5Hz, 1H), 7.31 (t, J=50.4Hz, 1H), 7.19 (d, J=7.9Hz, 1H), 6 .90 (d, J=8.8Hz, 2H), 6.85 (d, J=7.4Hz, 1H), 6.80 (d, J=8.8Hz, 2H), 6.72 (s, 1H), 6.69 (d, J=8.1Hz, 1H), 3.96 (s, 3H), 2.26 (s, 3H); 13 C NMR (100MHz, DMSO-d6) δ161.82, 158.88, 148.66, 146.41, 145.38 (t, J=23.4Hz), 139.84, 132.83, 129.9 5, 123.38, 120.96, 117.87, 114.47, 114.00, 110.09 (t, J=234.6Hz), 38.70, 21.45; HRMS (ESI) m / z [M+H] + calcdfor C 19 H 18 F2N4O2: 373.1471, found: 373.1474.

[0244] Example 12

[0245] The pyrazolylhydrazine derivative I containing a diphenyl ether unit described in this invention 12, R1= 2,6-di-CH3, chemical name 3-(difluoromethyl)-N'-(4-(2,6-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, English name 3-(difluoromethyl)-N'-(4-(2,6-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, structure as follows:

[0246]

[0247] First step: synthesis of 1,3-dimethyl-2-(4-nitrophenoxy)benzene (intermediate A 12 )

[0248]

[0249] As in Example 1, first step, except that 2,6-dimethylphenol is used as the reactant.

[0250] Second step: synthesis of 4-(2,6-dimethylphenoxy)aniline (intermediate B 12 )

[0251]

[0252] As in Example 1, second step, except that 1,3-dimethyl-2-(4-nitrophenoxy)benzene is used as the reactant.

[0253] Third step: synthesis of 4-(2,6-dimethylphenoxy)phenyl diazonium salt (intermediate C 12 )

[0254]

[0255] As in Example 1, third step, except that 4-(2,6-dimethylphenoxy)aniline is used as the reactant.

[0256] Fourth step: synthesis of 4-(2,6-dimethylphenoxy)phenylhydrazine hydrochloride (intermediate D 12 )

[0257]

[0258] As in Example 1, fourth step, except that 4-(2,6-dimethylphenoxy)phenyl diazonium salt is used as the reactant.

[0259] Fifth step: synthesis of 4-(2,6-dimethylphenoxy)phenylhydrazine (intermediate E 12 )

[0260]

[0261] As in Example 1, fifth step, except using 4-(2,6-dimethylphenoxy)phenylhydrazine hydrochloride as the reactant.

[0262] Sixth step: synthesis of 3-(difluoromethyl)-N'-(4-(2,6-dimethylphenoxy)phenyl)- 1 -methyl- 1 H-pyrazole-4-carbohydrazide (Target Compound I 12 )

[0263] As in Example 1, sixth step, except using 4-(2,6-dimethylphenoxy)phenylhydrazine as the reactant.

[0264] Target Compound I 12 was a yellow oil; yield 40%; 1 H NMR (400 MHz, DMSO) δ 10.09 (d, J = 2.0 Hz, 1H), 8.37 (s, 1H), 7.68 (s, 1H), 7.29 (t, J = 54.1 Hz, 1H), 7.13 (d, J = 7.5 Hz, 2H), 7.08 - 7.03 (m, 1H), 6.72 (d, J = 8.9 Hz, 2H), 6.57 (d, J = 8.9 Hz, 2H), 3.95 (s, 3H), 2.06 (s, 6H); 13 C NMR (100 MHz, DMSO-d6) δ 165.06, 161.80, 151.55, 151.08, 145.35 (t, J = 23.3 Hz), 144.38, 132.76, 131.26, 129.44, 125.31, 115.02, 114.56 (t, J = 3.2 Hz), 114.30, 110.07 (t, J = 234.6 Hz), 55.35, 40.48, 40.31, 40.15, 39.98, 39.87, 39.81, 39.64, 39.48, 38.69, 16.49; HRMS (ESI) m / z [M + H] + calcd for C 20 H 20 F2N4O2: 387.1627, found: 387.1631.

[0265] Example 13

[0266] The pyrazole carbohydrazide derivative I containing diphenyl ether units according to the present application 13, R1= 2,3,6-tri-CH3, chemical name 3-(difluoromethyl)-1-methyl-N'-(4-(2,3,6-trimethylphenoxy)phenyl)-1H-pyrazole-4-carbohydrazide, English name 3-(difluoromethyl)-1-methyl-N'-(4-(2,3,6-trimethylphenoxy)phenyl)-1H-pyrazole-4-carbohydrazide, structure as follows:

[0267]

[0268] First step: synthesis of 1,2,4-trimethyl-3-(4-nitrophenoxy)benzene (intermediate A 13 )

[0269]

[0270] As in Example 1, Step 1, except using 2,3,6-trimethylphenol as the reactant.

[0271] Second step: synthesis of 4-(2,3,6-trimethylphenoxy)aniline (intermediate B 13 )

[0272]

[0273] As in Example 1, Step 2, except using 1,2,4-trimethyl-3-(4-nitrophenoxy)benzene as the reactant.

[0274] Third step: synthesis of 4-(2,3,6-trimethylphenoxy)phenyl diazonium salt (intermediate C 13 )

[0275]

[0276] As in Example 1, Step 3, except using 4-(2,3,6-trimethylphenoxy)aniline as the reactant.

[0277] Fourth step: synthesis of 4-(2,3,6-trimethylphenoxy)phenylhydrazine hydrochloride (intermediate D 13 )

[0278]

[0279] As in Example 1, Step 4, except using 4-(2,3,6-trimethylphenoxy)phenyl diazonium salt as the reactant.

[0280] Fifth step: synthesis of 4-(2,3,6-trimethylphenoxy)phenylhydrazine (intermediate E 13 )

[0281]

[0282] As in step 5 of Example 1, the difference is that 4-(2,3,6-trimethylphenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0283] Step 6: 3-(difluoromethyl)-N′-(4-(2,3,6-trimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-acylhydrazide (target compound I) 13 Synthesis of )

[0284] As in step 6 of Example 1, the difference is that 4-(2,3,6-trimethylphenoxy)phenylhydrazine is used as the reactant.

[0285] Target compound I 13 It is a yellow oily substance; yield 42%; 1 H NMR (400MHz, DMSO-d6) δ10.08 (d, J=3.0Hz, 1H), 8.35 (s, 1H), 7.65 (d, J=2.9Hz, 1H), 7.28 (t, J=54.1Hz, 1H), 7.00 (d, J=7.7Hz, 1H), 6.95 (d, J=7.7Hz, 1H), 6.70 (d, J=8.9Hz, 2H), 6.54 (d, J=8.9Hz, 2H), 3.94 (s, 3H), 2.21 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H); 13 C NMR (100MHz, DMSO-d6) δ165.05, 161.79, 151.31, 145.33 (t, J=23.3Hz), 144.28, 136.23, 132.76, 129.88, 128.44, 128.41 , 126.59, 115.01, 114.56 (t, J=2.9Hz), 114.30, 110.07 (t, J=234.6Hz), 38.70, 19.93, 16.52, 12.81; HRMS (ESI) m / z [M+H] + calcd for C21H22F2N4O2: 401.1784, found: 401.1786.

[0286] Example 14

[0287] The pyrazolylhydrazine derivative I containing a diphenyl ether unit described in this invention 14, R1= 3,4-di-CH3, chemical name 3-(difluoromethyl)-N'-(4-(3,4-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, English name 3-(difluoromethyl)-N'-(4-(3,4-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, structure as follows:

[0288]

[0289] First step: synthesis of 1,2-dimethyl-4-(4-nitrophenoxy)benzene (intermediate A 14 )

[0290]

[0291] As in Example 1, first step, except that 3,4-dimethylphenol is used as the reactant.

[0292] Second step: synthesis of 4-(3,4-dimethylphenoxy)aniline (intermediate B 14 )

[0293]

[0294] As in Example 1, second step, except that 1,2-dimethyl-4-(4-nitrophenoxy)benzene is used as the reactant.

[0295] Third step: synthesis of 4-(3,4-dimethylphenoxy)phenyl diazonium salt (intermediate C 14 )

[0296]

[0297] As in Example 1, third step, except that 4-(3,4-dimethylphenoxy)aniline is used as the reactant.

[0298] Fourth step: synthesis of 4-(3,4-dimethylphenoxy)phenylhydrazine hydrochloride (intermediate D 14 )

[0299]

[0300] As in Example 1, fourth step, except that 4-(3,4-dimethylphenoxy)phenyl diazonium salt is used as the reactant.

[0301] Fifth step: synthesis of 4-(3,4-dimethylphenoxy)phenylhydrazine (intermediate E 14 )

[0302]

[0303] As in step 5 of Example 1, the difference is that 4-(3,4-dimethylphenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0304] Step 6: 3-(difluoromethyl)-N′-(4-(3,4-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-acylhydrazide (target compound I) 14 Synthesis of )

[0305] As in step 6 of Example 1, the difference is that 4-(3,4-dimethylphenoxy)phenylhydrazine is used as the reactant.

[0306] Target compound I 14 It is a yellow oily substance; yield 41%; 1 H NMR (400MHz, DMSO-d6) δ10.14 (d, J=2.6Hz, 1H), 8.36 (s, 1H), 7.83 (d, J=2.4Hz, 1H), 7.27 (t, J=54.1Hz, 1H), 7.05 (d, J=8.2Hz, 1H), 6 .84 (d, J=8.9Hz, 2H), 6.77 (d, J=8.9Hz, 2H), 6.70 (d, J=2.4Hz, 1H), 6.60 (dd, J=8.2, 2.5Hz, 1H), 3.94 (s, 3H), 2.14 (d, J=3.9Hz, 6H); 13 C NMR (100MHz, DMSO-d6) δ165.13, 161.85, 156.57, 149.43, 146.04, 145.36 (t, J=23.3 Hz), 138.19, 132.81, 130.90, 130.54, 120.41, 118.93, 114.97, 114.46 (t, J=3.4Hz) , 114.01, 110.08 (t, J=234.6Hz), 60.26, 55.29, 40.33, 40.26, 40.17, 40.09, 40.00, 39.83, 39.67, 39.50, 39.33, 38.67, 21.18, 19.96, 18.94, 14.50; HRMS(ESI)m / z[M+H] + calcd for C 20 H 20 F2N4O2: 387.1627, found: 387.1630.

[0307] Example 15

[0308] The pyrazolylhydrazine derivative I containing a diphenyl ether unit described in this invention 15, R1= 2,3,5-tri-CH3, chemical name 3-(difluoromethyl)-1-methyl-N'-(4-(2,3,5-trimethylphenoxy)phenyl)-1H-pyrazole-4-carbohydrazide, English name 3-(difluoromethyl)-1-methyl-N'-(4-(2,3,5-trimethylphenoxy)phenyl)-1H-pyrazole-4-carbohydrazide, structure as follows:

[0309]

[0310] First step: synthesis of 1,2,5-trimethyl-3-(4-nitrophenoxy)benzene (intermediate A 15 )

[0311]

[0312] As in Example 1, first step, except that 2,3,5-trimethylphenol is used as the reactant.

[0313] Second step: synthesis of 4-(2,3,5-trimethylphenoxy)aniline (intermediate B 15 )

[0314]

[0315] As in Example 1, second step, except that 1,2,5-trimethyl-3-(4-nitrophenoxy)benzene is used as the reactant.

[0316] Third step: synthesis of 4-(2,3,5-trimethylphenoxy)phenyl diazonium salt (intermediate C 15 )

[0317]

[0318] As in Example 1, third step, except that 4-(2,3,5-trimethylphenoxy)aniline is used as the reactant.

[0319] Fourth step: synthesis of 4-(2,3,5-trimethylphenoxy)phenylhydrazine hydrochloride (intermediate D 15 )

[0320]

[0321] As in Example 1, fourth step, except that 4-(2,3,5-trimethylphenoxy)phenyl diazonium salt is used as the reactant.

[0322] Fifth step: synthesis of 4-(2,3,5-trimethylphenoxy)phenylhydrazine (intermediate E 15 )

[0323]

[0324] As in Example 1, Step 5, except using 4-(2,3,5-trimethylphenoxy)benzenzenhydrazine hydrochloride as the reactant.

[0325] Step 6: Synthesis of 3-(difluoromethyl)-N'-(4-(2,3,5-trimethylphenoxy)phenyl)-l- methyl-lH-pyrazole-4-carbohydrazide (Target Compound I 15 )

[0326] As in Example 1, Step 6, except using 4-(2,3,5-trimethylphenoxy)benzenzenhydrazine as the reactant.

[0327] Target Compound I 15 was a yellow oil; yield 43%; 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (d, J = 2.2 Hz, 1H), 8.38 (s, 1H), 7.80 (s, 1H), 7.29 (t, J = 54.1 Hz, 1H), 6.76 (s, 4H), 6.72 (s, 1H), 6.41 (s, 1H), 3.95 (s, 3H), 2.21 (s, 3H), 2.14 (s, 3H), 2.06 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 165.08, 161.83, 155.63, 150.38, 145.29 (d, J = 23.3 Hz), 138.35, 135.78, 132.79, 125.75, 124.04, 119.14, 116.98, 116.44, 114.52 (t, J = 3.3 Hz), 114.08, 110.09 (t, J = 234.6 Hz), 60.22, 55.32, 40.43, 40.26, 40.18, 40.09, 39.93, 39.86, 39.76, 39.59, 39.42, 38.67, 21.17, 21.04, 20.06, 14.51, 11.97; HRMS (ESI) m / z [M + H] + calcd for C 21 H 22 F2N4O2: 401.1784, found: 401.1782.

[0328] Example 16

[0329] The pyrazole carbohydrazide derivative I containing diphenyl ether units according to the present application 16, R1= 4-Et, chemical name 3-(difluoromethyl)-N'-(4-(4-ethylphenoxy)phenyl)-1- methyl-1 H-pyrazole-4-carbohydrazide, English name 3-(difluoromethyl)-N'-(4-(4- ethylphenoxy)phenyl)-1-methyl-1 H-pyrazole-4-carbohydrazide, structure as follows:

[0330]

[0331] First step: synthesis of 1-ethyl-4-(4-nitrophenoxy)benzene (intermediate A 16 )

[0332]

[0333] As in example 1, first step, except that 4-ethylphenol is used as reactant.

[0334] Second step: synthesis of 4-(4-ethylphenoxy)aniline (intermediate B 16 )

[0335]

[0336] As in example 1, second step, except that 1-ethyl-4-(4-nitrophenoxy)benzene is used as reactant.

[0337] Third step: synthesis of 4-(4-ethylphenoxy)phenyl diazonium salt (intermediate C 16 )

[0338]

[0339] As in example 1, third step, except that 4-(4-ethylphenoxy)aniline is used as reactant.

[0340] Fourth step: synthesis of 4-(4-ethylphenoxy)phenylhydrazine hydrochloride (intermediate D 16 )

[0341]

[0342] As in example 1, fourth step, except that 4-(4-ethylphenoxy)phenyl diazonium salt is used as reactant.

[0343] Fifth step: synthesis of 4-(4-ethylphenoxy)phenylhydrazine (intermediate E 16 )

[0344]

[0345] As in Example 1, Step 5, except using 4-(4-ethylphenoxy)phenylhydrazine hydrochloride as the reactant.

[0346] Step 6: Synthesis of 3-(difluoromethyl)-l-methyl-N'-(4-(4- ethylphenoxy)phenyl)-lH-pyrazole-4-carbohydrazide (Target Compound I) 16

[0347] As in Example 1, Step 6, except using 4-(4-ethylphenoxy)phenylhydrazine as the reactant.

[0348] Target Compound I 16 was a yellow oil; yield 43%; 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (d, J = 2.4 Hz, 1H), 8.39 (s, 1H), 7.88 (d, J = 2.5 Hz, 1H), 7.30 (t, J = 54.2 Hz, 1H), 7.14 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.9 Hz, 2H), 6.82 (s, 1H), 6.80 (s, 2H), 6.78 (s, 1H), 3.95 (s, 3H), 2.53 (t, J = 7.3 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 165.08, 161.84, 156.71, 149.18, 146.26, 145.40 (t, J = 23.3 Hz), 138.10, 132.82, 129.38, 120.60, 117.51, 114.50 (t, J = 3.3 Hz), 114.03, 110.10 (t, J = 234.6 Hz), 107.46, 55.33, 40.43, 40.27, 40.10, 39.93, 39.87, 39.77, 39.60, 39.43, 38.67, 27.83, 16.23; HRMS (ESI) m / z [M + H] + calcd for C 20 H 20 F2N4O2: 387.1627, found: 387.1631.

[0349] Application Performance Testing

[0350] In vitro anti-tumor activity testing method:

[0351] ​The inhibitory effects of the target compound at concentrations of 100 μM and 10 μM on human pancreatic cancer cells, human breast cancer cells, and human gastric cancer cells were determined using the MTT assay. Stock solutions of the test compound and the standard compound (fluorouracil) were prepared using DMSO and then diluted to 100 μmol / L with DMEM (containing 10% serum). Logarithmic-phase cells were seeded into 96-well plates at a density of 5000 cells / well, with the edge wells filled with PBS. Cells were incubated for 24 h at 5% CO2, 37℃, and 90% humidity until a monolayer covered the bottom of the wells. 100 μL of the test compound was added to each well (three replicates), and the cells were incubated for 48 h. Then, 10 μL of CCK8 solution was added to each well, and the cells were cultured for another 2 h. The absorbance of each well was measured at 450 nm using a microplate reader. The cell inhibition rate was calculated based on the absorbance. Target molecules I1–I 16 The inhibitory effects of the drug on human pancreatic cancer cells, human breast cancer cells, and human gastric cancer cells at drug concentrations of 10 μm and 100 μm are shown in Table 1.

[0352] Table 1 Compounds I1~I 16 Inhibitory activity against tumor cells

[0353]

[0354] From Table 1, we can see that the target compounds I1 to I 16 At a concentration of 100 μm, the inhibitory effects on human pancreatic cancer cells (76.6%–92.8%), human breast cancer cells (73.2%–92.8%), and human gastric cancer cells (75.2%–97.9%) all exceeded those of the control drug fluorouracil (68.9%, 60.2%, and 58.3%, respectively). Notably, the target compounds I1–I... 16 At a concentration of 10 μm, the inhibition rate against human pancreatic cancer cells ranged from 69.4% to 84.5%, significantly superior to the control drug fluorouracil (54.9%). Simultaneously, the target compounds I1, I7-I... 10 and I 12 At a concentration of 10 μm, the inhibition rates against human breast cancer cells were 38.3%, 32.0%, 33.3%, 36.3%, 40.7%, and 30.6%, respectively, slightly better than the control drug fluorouracil (30.0%). Furthermore, target molecules I2, I4, and I7 also exhibited significant inhibitory activity against human gastric cancer cells at a concentration of 10 μm, with inhibition rates of 51.4%, 46.6%, and 47.1%, respectively, slightly better than the control drug fluorouracil (45.6%). These activity data indicate that the pyrazolyl hydrazine derivative containing a diphenyl ether unit has significant inhibitory activity against human pancreatic cancer cells, human breast cancer cells, and human gastric cancer cells, and can be developed as a candidate molecule for novel antitumor drugs.

Claims

1. A pyrazolylhydrazine derivative containing a diphenyl ether unit, characterized in that, The structural formula is shown in I: Wherein, R is selected from 3,5-dichloro, 2,4-dichloro, 3,5-dimethyl, 3-chloro, 4-methyl, 2,6-dichloro, 2-methyl-4-chloro, 4-fluoro, 2-fluoro, 2,3-dichloro, 3-methyl, 2,6-dimethyl, 2,3,6-trimethyl, 3,4-dimethyl, 2,3,5-trimethyl, or 4-ethyl.

2. The method for preparing the pyrazolyl hydrazine derivative containing a diphenyl ether unit according to claim 1, characterized in that, After a substitution reaction between p-chloronitrobenzene and phenol in a DMF solution containing potassium carbonate, the p-phenoxyphenylhydrazine molecule is obtained by reduction with zinc powder, oxidation with nitrous acid, and reduction with stannous chloride. This deacidified p-phenoxyphenylhydrazine then undergoes an acylation reaction with 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylic acid to yield the pyrazole hydrazine derivative I containing the diphenyl ether unit. The synthetic route is as follows:

3. The use of the pyrazolyl hydrazine derivative containing a diphenyl ether unit as described in claim 1 in the preparation of antitumor cell drugs.

4. The application according to claim 3, characterized in that, The tumor cells mentioned are breast cancer cells, gastric cancer cells, or pancreatic cancer cells.

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