Pyrazole hydrazide derivative containing diphenyl ether unit as well as preparation method and application of pyrazole hydrazide derivative

Abstract

The invention belongs to the field of medicines, and discloses a compound with a structure shown as a formula I. A preparation method of the compound comprises the following steps: substituting parachloronitrobenzene with phenol, and then carrying out reduction, diazotization, re-reduction, hydrochloric acid removal and hydrazide reaction to obtain a pyrazole hydrazide derivative containing a diphenyl ether unit, the pyrazole hydrazide derivative containing the diphenyl ether unit has an obvious inhibition effect on human pancreatic cancer cells, human breast cancer cells and human gastric cancer cells, and can be used as a potential novel antitumor candidate drug molecule. # imgabs0 #

Description

Technical Field

[0001] The invention 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 Art

[0002] Cancer, as a widespread and fatal non-communicable disease, is an important factor leading to death in the global population. To date, chemotherapy remains 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, the development of new anti-tumor drugs with good efficacy and few toxic side effects remains a challenging task. Summary of the invention

[0003] Purpose of the invention: The first purpose of the present invention is to provide a pyrazole hydrazide derivative containing a diphenyl ether unit having anti-tumor activity; the second purpose of the present invention is to provide a method for preparing the pyrazole hydrazide derivative containing a diphenyl ether unit; the third purpose of the present invention is to provide the application of the pyrazole hydrazide derivative containing a diphenyl ether unit in anti-tumor cells.

[0004] Technical solution: The pyrazole hydrazide derivative containing a diphenyl ether unit described in the present invention has a structural formula as shown in 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 of the present invention comprises the following steps: p-chloronitrobenzene and phenol undergo a substitution reaction in a DMF solution containing potassium carbonate, followed by zinc powder reduction, nitrous acid oxidation and tin chloride reduction, and the p-phenoxyphenylhydrazine molecules obtained after deacidification undergo a hydrazide reaction with 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylic acid to obtain the pyrazole hydrazide derivative containing a diphenyl ether unit. The synthesis route is as follows:

[0008]

[0009] The invention discloses an application of the pyrazole hydrazide derivative containing a diphenyl ether unit in anti-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 present invention has the following significant advantages: (1) the pyrazole hydrazide derivative containing a diphenyl ether unit of the present invention has an inhibitory effect on breast cancer cells, gastric cancer cells or pancreatic cancer cells; (2) the preparation method of the pyrazole hydrazide derivative containing a diphenyl ether unit of the present invention is simple, the raw materials are easily available, and the reaction is novel and efficient; (3) the pyrazole hydrazide derivative containing a diphenyl ether unit of the present invention has a strong inhibitory activity on tumor cells, and its optimal inhibition rate (84.5%) on pancreatic cancer cells at a dose of 10 μM exceeds that of the control agent fluorouracil (54.9%), and can be used as a potential new anti-tumor candidate drug molecule. DETAILED DESCRIPTION

[0012] The technical solution of the present invention is further described below in conjunction with embodiments.

[0013] Example 1

[0014]

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

[0016] Step 1: 1,3-dichloro-5-(4-nitrophenoxy)benzene (Intermediate A 1 )

[0017]

[0018] 3,5-Dichlorophenol (40mmol), potassium carbonate (96mmol) and DMF (15mL) were added to a 100mL round-bottomed bottle in sequence. After stirring at room temperature for about 10 minutes, p-chloronitrobenzene (32mmol) dissolved in DMF (15mL) was added to the reaction system using a constant pressure dropping funnel and reacted at 130°C for about 5 hours. After TLC monitoring of the disappearance of the raw materials, the above reaction solution was added to 500mL of water and allowed to stand overnight to precipitate a large amount of yellow precipitate. Filter and dry the resulting filter cake to obtain 1,3-dichloro-5-(4-nitrophenoxy)benzene (intermediate A 1 ).

[0019] Step 2: 4-(3,5-dichlorophenoxy)aniline (Intermediate B 1 )

[0020]

[0021] 1,3-Dichloro-5-(4-nitrophenoxy)benzene (21mmol) and zinc powder (211mmol) were added to ethanol (50mL), heated under reflux for 30min, and then 2-3mL saturated ammonium chloride was added. The reaction was continued for about 4-5h. After TLC monitoring, the reaction raw materials disappeared, the excess ethanol was removed by vacuum distillation, 50mL water was added, and the pH of the system was adjusted to 8-9 with 5% NaOH solution. Subsequently, ethyl acetate was used for extraction three times, the solvent was removed by vacuum distillation, and column chromatography was used to obtain 4-(3,5-dichlorophenoxy)aniline (intermediate B 1 ).

[0022] Step 3: 4-(3,5-dichlorophenoxy)phenyl diazonium salt (Intermediate C 1 )

[0023]

[0024] Dissolve 4-(3,5-dichlorophenoxy)aniline (12mmol) in ethanol (20mL), add concentrated hydrochloric acid (10mL) after complete dissolution, and stir at room temperature for about 10min. Sodium nitrite (24mmol) dissolved in water (5mL) was slowly dripped into the reaction system under ice bath conditions, and continued to stir under ice bath conditions for about 5h. After TLC monitoring of the disappearance of the reaction raw materials, ethanol was removed by vacuum distillation, distilled water (30mL) was added, and the aqueous phase was washed with dichloromethane. The collected aqueous phase was distilled under reduced pressure to remove excess dichloromethane to obtain 4-(3,5-dichlorophenoxy)phenyl diazonium salt (intermediate C 1 ) in an aqueous solution.

[0025] Step 4: 4-(3,5-dichlorophenoxy)phenylhydrazine hydrochloride (Intermediate D 1 )

[0026]

[0027] The 4-(3,5-dichlorophenoxy)phenyldiazonium salt solution (12 mmol) obtained in the third step was added to ethanol (20 mL). After it was completely dissolved, a hydrochloric acid solution (10 mL) containing tin chloride (35 mmol) was added to the reaction system. The mixture was stirred for about 4 to 5 h in an ice bath. A large amount of solid precipitated. 4-(3,5-dichlorophenoxy)phenylhydrazine hydrochloride (intermediate D) was obtained by suction filtration. 1 ).

[0028] Step 5: 4-(3,5-dichlorophenoxy)phenylhydrazine (Intermediate E 1 )

[0029]

[0030] After dissolving 4-(3,5-dichlorophenoxy)phenylhydrazine hydrochloride (10 mmol) in water (30 mL), the pH of the system was adjusted to 8-9 with 5% NaOH solution and stirred at room temperature for about 30 min. Then, the mixture was extracted with dichloromethane, the organic phases were combined, and the excess dichloromethane was removed by vacuum distillation. The residue was separated by column chromatography to obtain 4-(3,5-dichlorophenoxy)phenylhydrazine (Intermediate E 1 ).

[0031] Step 6: N′-(4-(3,5-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-hydrazide (target compound I 1 )

[0032] 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-acid (6mmol), TBTU (7mmol), triethylamine (18mmol) and dichloromethane (30mL) were added to a 100mL round-bottom bottle in sequence and stirred at room temperature for about 30min. Subsequently, 4-(3,5-dichlorophenoxy)phenylhydrazine (9mmol) was added to the above mixture and stirred at room temperature. After the reaction raw materials disappeared under TLC monitoring, the excess solvent was removed by vacuum distillation, and the residue was separated by column chromatography to obtain the target compound I 1 .

[0033] Target compound I 1 Yellow oil; yield 45%; 1 H NMR (400 MHz, DMSO-d 6 ) δ10.17 (d, J=1.6Hz, 1H), 8.40 (s, 1H), 8.04 (d, J=1.7Hz, 1H), 7.30 (t, J=54.1Hz, 1H) , 7.26 (s, 1H), 7.00 (d, J=8.6Hz, 2H), 6.90 (s, 2H), 6.84 (d, J=8.7Hz, 2H), 3.97 (s, 3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.83, 160.72, 147.46, 146.85, 145.40 (t, J=23.3Hz), 135.27, 132.87, 122.20, 121.63 , 115.87, 114.41 (t, J=3.3Hz), 114.04, 110.09 (t, J=234.7Hz), 38.70; HRMS (ESI) m / z [M+H] + Calculate for C 18 H14 Cl 2 F 2 N 4 O 2 :427.0535, found:427.0539.

[0034] Example 2

[0035] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 2 , R 1 =2,4-di-Cl, chemical name is N′-(4-(2,4-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-hydrazide, English name is N′-(4-(2,4-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, structural formula is as follows:

[0036]

[0037] Step 1: 2,4-dichloro-1-(4-nitrophenoxy)benzene (Intermediate A 2 )

[0038]

[0039] The same as the first step of Example 1, except that 2,4-dichlorophenol is used as the reactant.

[0040] Step 2: 4-(2,4-dichlorophenoxy)aniline (Intermediate B 2 )

[0041]

[0042] The same as the second step of Example 1, except that 2,4-dichloro-1-(4-nitrophenoxy)benzene is used as the reactant.

[0043] Step 3: 4-(2,4-dichlorophenoxy)phenyl diazonium salt (Intermediate C 2 )

[0044]

[0045] The process is the same as the third step of Example 1, except that 4-(2,4-dichlorophenoxy)aniline is used as the reactant.

[0046] Step 4: 4-(2,4-dichlorophenoxy)phenylhydrazine hydrochloride (Intermediate D 2 )

[0047]

[0048] The process is the same as the fourth step of Example 1, except that 4-(2,4-dichlorophenoxy)phenyl diazonium salt is used as the reactant.

[0049] Step 5: 4-(2,4-dichlorophenoxy)phenylhydrazine (Intermediate E 2 )

[0050]

[0051] The process is as in the fifth step of Example 1, except that 4-(2,4-dichlorophenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0052] Step 6: N′-(4-(2,4-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-hydrazide (target compound I 2 )

[0053] As in the sixth step of Example 1, the difference is that 4-(2,4-dichlorophenoxy)phenylhydrazine is used as the reactant.

[0054] Target compound I 2 Yellow oil; yield 47%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.15 (d, J = 2.6Hz, 1H), 8.39 (s, 1H), 7.96 (d, J = 2.5Hz, 1H), 7.69 (d, J = 2.5Hz, 1H), 7.34 (dd, J = 8.9, 2.6Hz, 1H), 7. 28 (t, J=54.2Hz, 1H), 6.91 (d, J=8.9Hz, 2H), 6.85 (d, J=8.9Hz, 1H), 6.81 (d, J=8.9Hz, 2H), 5.75 (s, 1H), 3.95 (s, 3H); 13 C NMR (100 MHz, DMSO-d 6 )161.81, 153.19, 148.08, 146.94, 145.38 (t, J=23.3Hz), 132.85, 130.28, 128.93, 127.19, 124.38 , 120.34, 119.81, 114.42 (t, J=3.2Hz), 114.04, 110.08 (t, J=234.6Hz), 38.70; HRMS (ESI) m / z [M+H] + Calculate for C 18 H 14 Cl 2 F 2 N 4O 2 :427.0535, found:427.0535.

[0055] Example 3

[0056] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 3 , R 1 =3,5-di-CH 3 , the chemical name is 3-(difluoromethyl)-N′-(4-(3,5-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-hydrazide, the English name is 3-(difluoromethyl)-N'-(4-(3,5-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, and the structural formula is as follows:

[0057]

[0058] Step 1: 1,3-dimethyl-5-(4-nitrophenoxy)benzene (Intermediate A 3 )

[0059]

[0060] The same as the first step of Example 1, except that 3,5-dimethylphenol is used as the reactant.

[0061] Step 2: 4-(3,5-dimethylphenoxy)aniline (Intermediate B 3 )

[0062]

[0063] The same as the second step of Example 1, except that 1,3-dimethyl-5-(4-nitrophenoxy)benzene is used as the reactant.

[0064] Step 3: 4-(3,5-dimethylphenoxy)phenyl diazonium salt (intermediate C 3 )

[0065]

[0066] The process is the same as the third step of Example 1, except that 4-(3,5-dimethylphenoxy)aniline is used as the reactant.

[0067] Step 4: 4-(3,5-dimethylphenoxy)phenylhydrazine hydrochloride (Intermediate D 3 )

[0068]

[0069] The process is the same as the fourth step of Example 1, except that 4-(3,5-dimethylphenoxy)phenyl diazonium salt is used as the reactant.

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

[0071]

[0072] The process is as in the fifth step of Example 1, except that 4-(3,5-dimethylphenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0073] Step 6: 3-(difluoromethyl)-N′-(4-(3,5-dimethylphenoxy)phenyl)-1-methyl 11H-pyrazole-4-hydrazide (target compound I 3 )

[0074] As in the sixth step of Example 1, the difference is that 4-(3,5-dimethylphenoxy)phenylhydrazine is used as the reactant.

[0075] Target compound I 3 Yellow oil; yield 43%; 1 H NMR (500 MHz, DMSO-d 6 )δ10.14(d, J=2.8Hz, 1H), 8.39(s, 1H), 7.89(d, J=2.7Hz, 1H), 7.30(t, J=54.2Hz, 1H), 6.87( t, J=6.0Hz, 2H), 6.79 (d, J=8.9Hz, 2H), 6.67 (s, 1H), 6.50 (s, 2H), 3.96 (s, 3H), 2.70 (s, 6H); 13 CNMR (100MHz, CDCl 3 )δ161.84, 158.28, 151.19, 143.90, 143.52, 139.45, 135.21, 124.26, 120.62, 11 5.42, 115.07, 113.93, 111.32 (t, J=74.8Hz), 39.59, 38.63; HRMS (ESI) m / z [M+H] + Calculate for C 20 H 20 F 2 N 4 O 2 :387.1627, found:387.1625.

[0076] Example 4

[0077] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention4 , R 1 =3-Cl, chemical name is N′-(4-(3-chlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-hydrazide, English name is N′-(4-(3-chlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, structural formula is as follows:

[0078]

[0079] Step 1: 1-Chloro-3-(4-nitrophenoxy)benzene (Intermediate A 4 )

[0080]

[0081] The same as the first step of Example 1, except that 3-chlorophenol is used as the reactant.

[0082] Step 2: 4-(3-chlorophenoxy)aniline (Intermediate B 4 )

[0083]

[0084] The same as the second step of Example 1, except that 1-chloro-3-(4-nitrophenoxy)benzene is used as the reactant.

[0085] Step 3: 4-(3-chlorophenoxy)phenyl diazonium salt (intermediate C 4 )

[0086]

[0087] The process is the same as the third step of Example 1, except that 4-(3-chlorophenoxy)aniline is used as the reactant.

[0088] Step 4: 4-(3-chlorophenoxy)phenylhydrazine hydrochloride (Intermediate D 4 )

[0089]

[0090] The process is the same as the fourth step of Example 1, except that 4-(3-chlorophenoxy)phenyl diazonium salt is used as the reactant.

[0091] Step 5: 4-(3-chlorophenoxy)phenylhydrazine (Intermediate E 4 )

[0092]

[0093] The process is as in step 5 of Example 1, except that 4-(3-chlorophenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0094] Step 6: N′-(4-(3-chlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-hydrazide (target compound I 4 )

[0095] As in the sixth step of Example 1, the difference is that 4-(3-chlorophenoxy)phenylhydrazine is used as the reactant.

[0096] Target compound I 4 Yellow oil; yield 43%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.16 (d, J=2.6Hz, 1H), 8.39 (s, 1H), 7.98 (d, J=2.5Hz, 1H), 7.35 (t, J=8.1Hz, 1H), 7.30 (t, J=54.1Hz, 1H), 7.10 (dd, J=8. 0, 1.2Hz, 1H), 6.95 (t, J=6.0Hz, 2H), 6.90 (t, J=2.1Hz, 1H), 6.86 (dd, J=8.3, 1.9Hz, 1H), 6.83 (d, J=8.9Hz, 2H), 3.96 (s, 3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.82, 160.09, 147.59, 147.04, 145.39 (t, J=23.4Hz), 134.27, 132.85, 131.72, 122.48, 121.41 , 116.93, 115.82, 114.43 (t, J=3.2Hz), 114.03, 110.09 (t, J=234.3Hz), 38.70.HRMS (ESI) m / z [M+H] + Calculate for C 18 H 15 CIF 2 N 4 O 2 :393.0924, found:393.0927.

[0097] Example 5

[0098] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 5 , R 1 =4-CH 3, the chemical name is 3-(difluoromethyl)-1-methyl-N'-(4-(p-tolyloxy)phenyl)-1H-pyrazole-4-hydrazide, the English name is 3-(difluoromethyl)-1-methyl-N′-(4-(p-tolyloxy)phenyl)-1H-pyrazole-4-carbohydrazide, and the structural formula is as follows:

[0099]

[0100] Step 1: 1-Methyl-4-(4-nitrophenoxy)benzene (Intermediate A 5 )

[0101]

[0102] The process is the same as the first step in Example 1, except that p-methylphenol is used as the reactant.

[0103] Step 2: 4-(p-methylphenoxy)aniline (Intermediate B 5 )

[0104]

[0105] The same as the second step of Example 1, except that 1-methyl-4-(4-nitrophenoxy)benzene is used as the reactant.

[0106] Step 3: 4-(p-methylphenoxy)phenyldiazonium salt (intermediate C 5 )

[0107]

[0108] The process is the same as the third step of Example 1, except that 4-(p-methylphenoxy)aniline is used as the reactant.

[0109] Step 4: 4-(p-methylphenoxy)phenylhydrazine hydrochloride (Intermediate D 5 )

[0110]

[0111] The process is as in the fourth step of Example 1, except that 4-(p-methylphenoxy)phenyl diazonium salt is used as the reactant.

[0112] Step 5: 4-(p-methylphenoxy)phenylhydrazine (Intermediate E 5 )

[0113]

[0114] The process is as in the fifth step of Example 1, except that 4-(p-methylphenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0115] Step 6: 3-(difluoromethyl)-1-methyl-N′-(4-(p-tolyloxy)phenyl)-1H-pyrazole-4-hydrazide (target compound I 5 )

[0116] As in the sixth step of Example 1, the difference is that 4-(p-methylphenoxy)phenylhydrazine is used as the reactant.

[0117] Target compound I 5 Yellow oil; yield 45%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.15(s, 1H), 8.39(s, 1H), 7.87(s, 1H), 7.29(t, J=54.1Hz, 1H), 7.12(d, J=8.3Hz , 2H), 6.86 (d, J=8.8Hz, 2H), 6.79 (dd, J=8.5, 6.4Hz, 4H), 3.95 (s, 3H), 2.25 (s, 3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.82, 156.48, 149.24, 146.20, 145.37 (t, J=23.3Hz), 132.82, 131.68, 130.57, 120.50, 11 7.57, 114.47 (t, J=3.3Hz), 114.01, 110.09 (t, J=234.6Hz), 38.69, 20.60. HRMS (ESI) m / z [M+H] + Calculate for C 19 H 18 F 2 N 4 O 2 :373.1471, found:373.1474.

[0118] Example 6

[0119] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 6 , R 1=2,6-di-Cl, chemical name is N′-(4-(2,6-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-hydrazide, English name is N′-(4-(2,6-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, structural formula is as follows:

[0120]

[0121] Step 1: 1,3-dichloro-2-(4-nitrophenoxy)benzene (Intermediate A 6 )

[0122]

[0123] The same as the first step of Example 1, except that 2,6-dichlorophenol is used as the reactant.

[0124] Step 2: 4-(2,6-dichlorophenoxy)aniline (Intermediate B 6 )

[0125]

[0126] The same as the second step of Example 1, except that 1,3-dichloro-2-(4-nitrophenoxy)benzene is used as the reactant.

[0127] Step 3: 4-(2,6-dichlorophenoxy)phenyl diazonium salt (Intermediate C 6 )

[0128]

[0129] The process is the same as the third step of Example 1, except that 4-(2,6-dichlorophenoxy)aniline is used as the reactant.

[0130] Step 4: 4-(2,6-dichlorophenoxy)phenylhydrazine hydrochloride (Intermediate D 6 )

[0131]

[0132] The process is the same as the fourth step of Example 1, except that 4-(2,6-dichlorophenoxy)phenyl diazonium salt is used as the reactant.

[0133] Step 5: 4-(2,6-dichlorophenoxy)phenylhydrazine (Intermediate E 6 )

[0134]

[0135] The process is as in the fifth step of Example 1, except that 4-(2,6-dichlorophenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0136] Step 6: N′-(4-(2,6-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-hydrazide (target compound I 6 )

[0137] The process is the same as step 6 of Example 1, except that 4-(2,6-dichlorophenoxy)phenylhydrazine is used as the reactant.

[0138] Target compound I 6 Yellow oil; yield 47%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.10 (d, J=2.4Hz, 1H), 8.36 (s, 1H), 7.77 (d, J=1.9Hz, 1H), 7.60 (d, J=8.1Hz, 2H), 7.32 (t, J =8.1Hz, 1H), 7.27 (t, J = 54.1Hz, 1H), 6.72 (d, J = 8.8Hz, 2H), 6.64 (d, J = 8.9Hz, 2H), 3.94 (s, 3H); 13 C NMR (100 MHz, DMSO-d 6 )δ165.06, 161.82, 150.07, 147.17, 145.39, 145.35 (t, J=23.3Hz), 132.79, 130.14, 129.43, 127.7 3, 115.48, 114.49 (t, J = 3.4Hz), 114.03, 110.07 (t, J = 234.6Hz), 38.70; HRMS (ESI) m / z [M + H] + calcd for C 18 H 14 Cl 2 F 2 N 4 O 2 :427.0535, found:427.0531.

[0139] Example 7

[0140] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 7 , R 1 =2-CH 3-4-Cl, chemical name is N′-(4-(4-chloro-2-methylphenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-hydrazide, English name is N′-(4-(4-chloro-2-methylphenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, the structural formula is as follows:

[0141]

[0142] Step 1: 4-Chloro-2-methyl-1-(4-nitrophenoxy)benzene (Intermediate A 7 )

[0143]

[0144] The same as the first step of Example 1, except that 4-chloro-2-methylphenol is used as the reactant.

[0145] Step 2: 4-(4-chloro-2-methylphenoxy)aniline (Intermediate B 7 )

[0146]

[0147] The same as the second step of Example 1, except that 4-chloro-2-methyl-1-(4-nitrophenoxy)benzene is used as the reactant.

[0148] Step 3: 4-(4-chloro-2-methylphenoxy)phenyldiazonium salt (Intermediate C 7 )

[0149]

[0150] The process is the same as the third step of Example 1, except that 4-(4-chloro-2-methylphenoxy)aniline is used as the reactant.

[0151] Step 4: 4-(4-chloro-2-methylphenoxy)phenylhydrazine hydrochloride (Intermediate D 7 )

[0152]

[0153] The same as the fourth step of Example 1, except that 4-(4-chloro-2-methylphenoxy)phenyl diazonium salt is used as the reactant.

[0154] Step 5: 4-(4-chloro-2-methylphenoxy)phenylhydrazine (Intermediate E 7 )

[0155]

[0156] The process is as in the fifth step of Example 1, except that 4-(4-chloro-2-methylphenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0157] Step 6: N′-(4-(4-chloro-2-methylphenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-hydrazide (target compound I 7 )

[0158] As in the sixth step of Example 1, the difference is that 4-(4-chloro-2-methylphenoxy)phenylhydrazine is used as the reactant.

[0159] Target compound I 7 Yellow oil; yield 48%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.15 (d, J=2.8Hz, 1H), 8.39 (s, 1H), 7.90 (d, J=2.7Hz, 1H), 7.35 (d, J=2.3Hz, 1H), 7.41-7.15 (m, 1 H), 6.84 (dd, J=9.3, 2.5Hz, 2H), 6.81-6.77 (m, 2H), 6.69 (d, J=8.7Hz, 1H), 3.96 (s, 3H), 2.23 (s, 3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.80, 155.39, 149.08, 146.30, 145.37 (t, J=23.4Hz), 132.82, 131.07, 130.53, 127.26, 12 6.57, 114.47 (t, J=3.3Hz), 114.07, 110.08 (t, J=234.6Hz), 38.69, 16.16; HRMS (ESI) m / z [M+H] + Calculate for C 19 H 17 CIF 2 N 4 O 2 :407.1081, found:407.1082.

[0160] Example 8

[0161] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 8 , R 1=4-F, chemical name is 3-(difluoromethyl)-N′-(4-(4-fluorophenoxy)phenyl)-1-methyl-1H-pyrazole-4-hydrazide, English name is 3-(difluoromethyl)-N′-(4-(4-fluorophenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, structural formula is as follows:

[0162]

[0163] Step 1: 1-Fluoro-4-(4-nitrophenoxy)benzene (Intermediate A 8 )

[0164]

[0165] The same as the first step of Example 1, except that 4-fluorophenol is used as the reactant.

[0166] Step 2: 4-(4-fluorophenoxy)aniline (Intermediate B 8 )

[0167]

[0168] The same as the second step of Example 1, except that 1-fluoro-4-(4-nitrophenoxy)benzene is used as the reactant.

[0169] Step 3: 4-(4-fluorophenoxy)phenyl diazonium salt (intermediate C 8 )

[0170]

[0171] The process is the same as the third step of Example 1, except that 4-(4-fluorophenoxy)aniline is used as the reactant.

[0172] Step 4: 4-(4-fluorophenoxy)phenylhydrazine hydrochloride (Intermediate D 8 )

[0173]

[0174] The same as the fourth step of Example 1, except that 4-(4-fluorophenoxy)phenyl diazonium salt is used as the reactant.

[0175] Step 5: 4-(4-fluorophenoxy)phenylhydrazine (Intermediate E 8 )

[0176]

[0177] The process is as in the fifth step of Example 1, except that 4-(4-fluorophenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0178] Step 6: 3-(difluoromethyl)-N′-(4-(4-fluorophenoxy)phenyl)-1-methyl-1H-pyrazole-4-hydrazide (target compound I 8 )

[0179] As in the sixth step of Example 1, the difference is that 4-(4-fluorophenoxy)phenylhydrazine is used as the reactant.

[0180] Target compound I 8 Yellow oil; yield 44%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.14(s, 1H), 8.38(s, 1H), 7.90(s, 1H), 7.28(t, J=54.2Hz, 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); 13 C NMR (100 MHz, DMSO-d 6 ) δ161.81, 157.91 (d, J = 238.0Hz), 154.91 (d, J = 2.0Hz), 149.11, 146.47, 145.37 (t, J = 23.3Hz), 132.84, 120.55, 119.1 3 (d, J=8.3Hz), 116.69 (d, J=23.3Hz), 114.47 (t, J=3.3Hz), 114.05, 110.09 (t, J=234.5Hz), 38.70.HRMS (ESI) m / z [M+H] + Calculate for C 18 H 15 F 3 N 4 O 2 :377.1220, found:377.1223.

[0181] Example 9

[0182] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 9 , R 1=2-F, chemical name is 3-(difluoromethyl)-N′-(4-(2-fluorophenoxy)phenyl)-1-methyl-1H-pyrazole-4-hydrazide, English name is 3-(difluoromethyl)-N′-(4-(2-fluorophenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, structural formula is as follows:

[0183]

[0184] Step 1: 1-Fluoro-2-(4-nitrophenoxy)benzene (Intermediate A 9 )

[0185]

[0186] The same as the first step of Example 1, except that 2-fluorophenol is used as the reactant.

[0187] Step 2: 4-(2-fluorophenoxy)aniline (Intermediate B 9 )

[0188]

[0189] The same as the second step of Example 1, except that 1-fluoro-2-(4-nitrophenoxy)benzene is used as the reactant.

[0190] Step 3: 4-(2-fluorophenoxy)phenyl diazonium salt (intermediate C 9 )

[0191]

[0192] The process is the same as the third step of Example 1, except that 4-(2-fluorophenoxy)aniline is used as the reactant.

[0193] Step 4: 4-(2-fluorophenoxy)phenylhydrazine hydrochloride (Intermediate D 9 )

[0194]

[0195] The same as the fourth step of Example 1, except that 4-(2-fluorophenoxy)phenyl diazonium salt is used as the reactant.

[0196] Step 5: 4-(2-fluorophenoxy)phenylhydrazine (Intermediate E 9 )

[0197]

[0198] The process is as in the fifth step of Example 1, except that 4-(2-fluorophenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0199] Step 6: 3-(difluoromethyl)-N′-(4-(2-fluorophenoxy)phenyl)-1-methyl-1H-pyrazole-4-hydrazide (target compound I 9 )

[0200] The process is the same as step 6 of Example 1, except that 4-(2-fluorophenoxy)phenylhydrazine is used as the reactant.

[0201] Target compound I 9 Yellow oil; yield 40%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.15 (d, J=2.8Hz, 1H), 8.39 (s, 1H), 7.91 (d, J=2.7Hz, 1H), 7.34-7.30 (m, 1H), 7.29 (t, J=54.1Hz, 1H) 7.15- 7.10 (m, 2H), 6.96 (td, J=8.4, 2.1Hz, 1H), 6.88 (t, J=6.0Hz, 2H), 6.81-6.79 (m, 2H), 3.95 (s, 3H), 1.98 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 161.83, 153.41 (d, J = 245.4Hz), 149.12, 146.42, 145.39 (t, J = 23.4Hz), 145.32 (d, J = 10.9Hz), 132.83, 125.55 (d, J = 3.7Hz), 124.37 (d, J=7.0Hz), 120.36, 119.43, 117.34 (d, J=17.9Hz), 114.48 (t, J=3.3Hz), 114.02, 110.09 (t, J=234.6Hz), 38.68; HRMS (ESI) m / z [M+H] + Calculate for C 18 H 15 F 3 N 4 O 2 :377.1220, found:377.1218.

[0202] Example 10

[0203] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 10 , R 1=2,3-di-Cl, chemical name is N′-(4-(2,3-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-hydrazide, English name is N′-(4-(2,3-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbohydrazide, structural formula is as follows:

[0204]

[0205] Step 1: 1,2-dichloro-3-(4-nitrophenoxy)benzene (Intermediate A 10 )

[0206]

[0207] The first step is the same as in Example 1, except that 2,3-dichlorophenol is used as the reactant.

[0208] Step 2: 4-(2,3-dichlorophenoxy)aniline (Intermediate B 10 )

[0209]

[0210] The same as the second step of Example 1, except that 1,2-dichloro-3-(4-nitrophenoxy)benzene is used as the reactant.

[0211] Step 3: 4-(2,3-dichlorophenoxy)phenyl diazonium salt (intermediate C 10 )

[0212]

[0213] The process is the same as the third step of Example 1, except that 4-(2,3-dichlorophenoxy)aniline is used as the reactant.

[0214] Step 4: 4-(2,3-dichlorophenoxy)phenylhydrazine hydrochloride (Intermediate D 10 )

[0215]

[0216] The process is the same as the fourth step of Example 1, except that 4-(2,3-dichlorophenoxy)phenyl diazonium salt is used as the reactant.

[0217] Step 5: 4-(2,3-dichlorophenoxy)phenylhydrazine (Intermediate E 10 )

[0218]

[0219] The process is as in the fifth step of Example 1, except that 4-(2,3-dichlorophenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0220] Step 6: N′-(4-(2,3-dichlorophenoxy)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-hydrazide (target compound I 10 )

[0221] As in the sixth step of Example 1, the difference is that 4-(2,3-dichlorophenoxy)phenylhydrazine is used as the reactant.

[0222] Target compound I 10 Yellow oil; yield 42%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.17(s, 1H), 8.40(s, 1H), 7.99(s, 1H), 7.34(d, J=8.1Hz, 1H), 7.30(t, J=5 4.1Hz, 1H), 6.94 (d, J=8.8Hz, 2H), 6.81 (dd, J=13.8, 5.0Hz, 3H), 3.96 (s, 3H); 13 C NMR (100 MHz, DMSO-d 6 )δ161.82, 155.73, 147.93, 147.06, 145.38 (t, J=23.3Hz), 133.20, 132.86, 129.11, 124.53, 122.09 , 120.58, 116.84, 114.43 (t, J=3.3Hz), 114.03, 110.09 (t, J=234.6Hz), 38.70; HRMS (ESI) m / z [M+H] + Calculate for C 18 H 14 Cl 2 F 2 N 4 O 2 :427.0535, found:427.0532.

[0223] Embodiment 11

[0224] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 11 , R 1 =3-CH 3, the chemical name is 3-(difluoromethyl)-1-methyl-N′-(4-(m-tolyloxy)phenyl)-1H-pyrazole-4-hydrazide, the English name is 3-(difluoromethyl)-1-methyl-N′-(4-(m-tolyloxy)phenyl)-1H-pyrazole-4-carbohydrazide, and the structural formula is as follows:

[0225]

[0226] Step 1: 1-Methyl-3-(4-nitrophenoxy)benzene (Intermediate A 11 )

[0227]

[0228] The process is the same as the first step in Example 1, except that m-methylphenol is used as the reactant.

[0229] Step 2: 4-(m-methylphenoxy)aniline (Intermediate B 11 )

[0230]

[0231] The same as the second step of Example 1, except that 1-methyl-3-(4-nitrophenoxy)benzene is used as the reactant.

[0232] Step 3: 4-(m-methylphenoxy)phenyldiazonium salt (intermediate C 11 )

[0233]

[0234] The process is the same as the third step of Example 1, except that 4-(m-methylphenoxy)aniline is used as the reactant.

[0235] Step 4: 4-(m-methylphenoxy)phenylhydrazine hydrochloride (Intermediate D 11 )

[0236]

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

[0238] Step 5: 4-(m-methylphenoxy)phenylhydrazine (Intermediate E 11 )

[0239]

[0240] The process is as in the fifth step of Example 1, except 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-hydrazide (target compound I 11 )

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

[0243] Target compound I 11 Yellow oil; 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 (100 MHz, DMSO-d 6 )δ161.82, 158.88, 148.66, 146.41, 145.38 (t, J=23.4Hz), 139.84, 132.83, 129.95, 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 F 2 N 4 O 2 :373.1471, found:373.1474.

[0244] Example 12

[0245] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 12 , R 1 =2,6-di-CH 3, the chemical name is 3-(difluoromethyl)-N′-(4-(2,6-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-hydrazide, the English name is 3-(difluoromethyl)-N'-(4-(2,6-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, and the structural formula is as follows:

[0246]

[0247] Step 1: 1,3-Dimethyl-2-(4-nitrophenoxy)benzene (Intermediate A 12 )

[0248]

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

[0250] Step 2: 4-(2,6-dimethylphenoxy)aniline (Intermediate B 12 )

[0251]

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

[0253] Step 3: 4-(2,6-dimethylphenoxy)phenyldiazonium salt (Intermediate C 12 )

[0254]

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

[0256] Step 4: 4-(2,6-dimethylphenoxy)phenylhydrazine hydrochloride (Intermediate D 12 )

[0257]

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

[0259] Step 5: 4-(2,6-dimethylphenoxy)phenylhydrazine (Intermediate E 12 )

[0260]

[0261] The process is as in the fifth step of Example 1, except that 4-(2,6-dimethylphenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0262] Step 6: 3-(difluoromethyl)-N′-(4-(2,6-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-hydrazide (target compound I 12 )

[0263] As in the sixth step of Example 1, the difference is that 4-(2,6-dimethylphenoxy)phenylhydrazine is used as the reactant.

[0264] Target compound I 12 Yellow oil; yield 40%; 1 H NMR (400MHz, DMSO) δ10.09 (d, J=2.0Hz, 1H), 8.37 (s, 1H), 7.68 (s, 1H), 7.29 (t, J=54.1Hz, 1H), 7.13 (d, J =7.5Hz, 2H), 7.08-7.03 (m, 1H), 6.72 (d, J = 8.9Hz, 2H), 6.57 (d, J = 8.9Hz, 2H), 3.95 (s, 3H), 2.06 (s, 6H); 13 C NMR (100 MHz, DMSO-d 6 ) δ165.06, 161.80, 151.55, 151.08, 145.35 (t, J = 23.3Hz), 144.38, 132.76, 131.26, 129.44, 125.31, 115.02, 114.56 (t, J = 3.2Hz), 114.30, 110.07 (t, J=234.6Hz), 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] + Calculate for C 20 H 20 F 2 N 4 O 2 :387.1627, found:387.1631.

[0265] Embodiment 13

[0266] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 13 , R 1 =2,3,6-tri-CH 3, the chemical name is 3-(difluoromethyl)-1-methyl-N′-(4-(2,3,6-trimethylphenoxy)phenyl)-1H-pyrazole-4-hydrazide, the English name is 3-(difluoromethyl)-1-methyl-N′-(4-(2,3,6-trimethylphenoxy)phenyl)-1H-pyrazole-4-carbohydrazide, and the structural formula is as follows:

[0267]

[0268] Step 1: 1,2,4-trimethyl-3-(4-nitrophenoxy)benzene (Intermediate A 13 )

[0269]

[0270] The same as the first step of Example 1, except that 2,3,6-trimethylphenol is used as the reactant.

[0271] Step 2: 4-(2,3,6-trimethylphenoxy)aniline (Intermediate B 13 )

[0272]

[0273] The same as the second step of Example 1, except that 1,2,4-trimethyl-3-(4-nitrophenoxy)benzene is used as the reactant.

[0274] Step 3: 4-(2,3,6-trimethylphenoxy)phenyl diazonium salt (intermediate C 13 )

[0275]

[0276] The process is the same as the third step of Example 1, except that 4-(2,3,6-trimethylphenoxy)aniline is used as the reactant.

[0277] Step 4: 4-(2,3,6-trimethylphenoxy)phenylhydrazine hydrochloride (Intermediate D 13 )

[0278]

[0279] The process is the same as the fourth step of Example 1, except that 4-(2,3,6-trimethylphenoxy)phenyl diazonium salt is used as the reactant.

[0280] Step 5: 4-(2,3,6-trimethylphenoxy)phenylhydrazine (Intermediate E 13 )

[0281]

[0282] The process is as in the fifth step of Example 1, except 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-hydrazide (target compound I 13 )

[0284] The process is the same as step 6 of Example 1, except that 4-(2,3,6-trimethylphenoxy)phenylhydrazine is used as the reactant.

[0285] Target compound I 13 Yellow oil; yield 42%; 1 H NMR (400 MHz, DMSO-d 6 )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 (100 MHz, DMSO-d 6 )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, 1 15.01, 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] Embodiment 14

[0287] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 14 , R 1 =3,4-di-CH 3, the chemical name is 3-(difluoromethyl)-N'-(4-(3,4-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-hydrazide, the English name is 3-(difluoromethyl)-N′-(4-(3,4-dimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, and the structural formula is as follows:

[0288]

[0289] Step 1: 1,2-dimethyl-4-(4-nitrophenoxy)benzene (Intermediate A 14 )

[0290]

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

[0292] Step 2: 4-(3,4-dimethylphenoxy)aniline (Intermediate B 14 )

[0293]

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

[0295] Step 3: 4-(3,4-dimethylphenoxy)phenyl diazonium salt (Intermediate C 14 )

[0296]

[0297] The process is the same as the third step of Example 1, except that 4-(3,4-dimethylphenoxy)aniline is used as the reactant.

[0298] Step 4: 4-(3,4-dimethylphenoxy)phenylhydrazine hydrochloride (Intermediate D 14 )

[0299]

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

[0301] Step 5: 4-(3,4-dimethylphenoxy)phenylhydrazine (Intermediate E 14 )

[0302]

[0303] The process is as in the fifth step of Example 1, except 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-hydrazide (target compound I 14 )

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

[0306] Target compound I 14 Yellow oil; yield 41%; 1 H NMR (400 MHz, DMSO-d 6 )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 (100 MHz, DMSO-d 6 )δ165.13, 161.85, 156.57, 149.43, 146.04, 145.36 (t, J=23.3Hz), 138.19, 13 2.81, 130.90, 130.54, 120.41, 118.93, 114.97, 114.46 (t, J=3.4Hz), 114.01, 1 10.08 (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] + Calculate for C 20 H 20 F 2 N 4 O 2 :387.1627, found:387.1630.

[0307] Embodiment 15

[0308] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 15 , R 1 =2,3,5-tri-CH 3 , the chemical name is 3-(difluoromethyl)-1-methyl-N′-(4-(2,3,5-trimethylphenoxy)phenyl)-1H-pyrazole-4-hydrazide, the English name is 3-(difluoromethyl)-1-methyl-N′-(4-(2,3,5-trimethylphenoxy)phenyl)-1H-pyrazole-4-carbohydrazide, and the structural formula is as follows:

[0309]

[0310] Step 1: 1,2,5-trimethyl-3-(4-nitrophenoxy)benzene (Intermediate A 15 )

[0311]

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

[0313] Step 2: 4-(2,3,5-trimethylphenoxy)aniline (Intermediate B 15 )

[0314]

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

[0316] Step 3: 4-(2,3,5-trimethylphenoxy)phenyl diazonium salt (Intermediate C 15 )

[0317]

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

[0319] Step 4: 4-(2,3,5-trimethylphenoxy)phenylhydrazine hydrochloride (Intermediate D 15 )

[0320]

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

[0322] Step 5: 4-(2,3,5-trimethylphenoxy)phenylhydrazine (Intermediate E 15 )

[0323]

[0324] The process is as in the fifth step of Example 1, except that 4-(2,3,5-trimethylphenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0325] Step 6: 3-(difluoromethyl)-N′-(4-(2,3,5-trimethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-hydrazide (target compound I 15 )

[0326] As in the sixth step of Example 1, the difference is that 4-(2,3,5-trimethylphenoxy)phenylhydrazine is used as the reactant.

[0327] Target compound I 15 Yellow oil; yield 43%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.13 (d, J=2.2Hz, 1H), 8.38 (s, 1H), 7.80 (s, 1H), 7.29 (t, J=54.1Hz, 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-d 6 ) δ165.08, 161.83, 155.63, 150.38, 145.29 (d, J=23.3Hz), 138.35, 135.78, 132. 79, 125.75, 124.04, 119.14, 116.98, 116.44, 114.52 (t, J=3.3Hz), 114.08, 110. 09 (t, J=234.6Hz), 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] + Calculate for C 21 H 22 F 2 N 4 O 2 :401.1784, found:401.1782.

[0328] Example 16

[0329] The pyrazole hydrazide derivative I containing diphenyl ether unit of the present invention 16 , R 1 =4-Et, chemical name is 3-(difluoromethyl)-N′-(4-(4-ethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-hydrazide, English name is 3-(difluoromethyl)-N′-(4-(4-ethylphenoxy)phenyl)-1-methyl-1H-pyrazole-4-carbohydrazide, structural formula is as follows:

[0330]

[0331] Step 1: 1-ethyl-4-(4-nitrophenoxy)benzene (Intermediate A 16 )

[0332]

[0333] The process is the same as the first step in Example 1, except that 4-ethylphenol is used as the reactant.

[0334] Step 2: 4-(4-ethylphenoxy)aniline (Intermediate B 16 )

[0335]

[0336] The same as the second step of Example 1, except that 1-ethyl-4-(4-nitrophenoxy)benzene is used as the reactant.

[0337] Step 3: 4-(4-ethylphenoxy)phenyldiazonium salt (Intermediate C 16 )

[0338]

[0339] The process is the same as the third step of Example 1, except that 4-(4-ethylphenoxy)aniline is used as the reactant.

[0340] Step 4: 4-(4-ethylphenoxy)phenylhydrazine hydrochloride (Intermediate D 16 )

[0341]

[0342] The process is the same as the fourth step of Example 1, except that 4-(4-ethylphenoxy)phenyl diazonium salt is used as the reactant.

[0343] Step 5: 4-(4-ethylphenoxy)phenylhydrazine (Intermediate E16 )

[0344]

[0345] The process is as in the fifth step of Example 1, except that 4-(4-ethylphenoxy)phenylhydrazine hydrochloride is used as the reactant.

[0346] Step 6: 3-(difluoromethyl)-1-methyl-N′-(4-(4-ethylphenoxy)phenyl)-1H-pyrazole-4-hydrazide (target compound I 16 )

[0347] As in the sixth step of Example 1, the difference is that 4-(4-ethylphenoxy)phenylhydrazine is used as the reactant.

[0348] Target compound I 16 Yellow oil; yield 43%; 1 H NMR (400 MHz, DMSO-d 6 )δ10.15(d, J=2.4Hz, 1H), 8.39(s, 1H), 7.88(d, J=2.5Hz, 1H), 7.30(t, J=54.2Hz, 1H), 7.14(d, J=8.5Hz, 2H), 6.87( d, J=8.9Hz, 2H), 6.82 (s, 1H), 6.80 (s, 2H), 6.78 (s, 1H), 3.95 (s, 3H), 2.53 (t, J=7.3Hz, 2H), 1.14 (t, J=7.6Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ165.08, 161.84, 156.71, 149.18, 146.26, 145.40 (t, J=23.3Hz), 138.10, 132.82, 129.38, 120.60, 117.51, 114.50 (t, J=3.3Hz), 114.03, 110.10 (t, J=234.6Hz), 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] + calcdfor C 20 H 20 F 2 N 4 O 2 :387.1627, found:387.1631.

[0349] Application performance testing

[0350] In vitro antitumor activity test method:

[0351] The inhibitory effect of the target compound on human pancreatic cancer cells, human breast cancer cells and human gastric cancer cells at 100μM and 10μM concentrations was determined by MTT method. The stock solutions of the test compound and the standard compound (fluorouracil) were first prepared with DMSO, and then diluted to 100μmol / L with DMEM (10% serum was added). The cells in the logarithmic phase were collected and inoculated in a 96-well plate at a density of 5000 cells / well, and the edge wells of the 96-well plate were filled with PBS. Incubate at 5% CO 2 , 37°C, 90% humidity conditions for 24h, until the cell monolayer covers the bottom of the 96-well plate. Add the test compound, 100μL per well, set up 3 replicates, incubate for 48h, add 10μL CCK8 solution to each well, and continue to culture for 2h. Measure the absorbance of each well at 450nm with an enzyme reader. Calculate the cell inhibition rate based on the absorbance. Target molecule I 1 ~I 16 The inhibitory effects 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 Compound I 1 ~I 16 Inhibitory activity against tumor cells

[0353]

[0354] From Table 1, we can see that target compound I 1 ~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% to 92.8%), and human gastric cancer cells (75.2% to 97.9%) were all higher than those of the control agent fluorouracil (68.9%, 60.2%, and 58.3%). It is worth noting that the target compound I 1 ~I 16 The inhibition rate of human pancreatic cancer cells at a concentration of 10 μM was between 69.4% and 84.5%, significantly better than the control drug fluorouracil (54.9%). 1 ,I 7 ~I 10 and I 12 The inhibition rates of human breast cancer cells at a concentration of 10 μM were 38.3%, 32.0%, 33.3%, 36.3%, 40.7% and 30.6%, respectively, which were slightly better than the control agent fluorouracil (30.0%). 2 ,I 4 and I7 At a concentration of 10 μM, it also showed significant inhibitory activity against human gastric cancer cells, with inhibition rates of 51.4%, 46.6% and 47.1%, respectively, slightly better than the control agent fluorouracil (45.6%). The above activity data show that pyrazole hydrazide derivatives containing diphenyl ether units have significant inhibitory activity against human pancreatic cancer cells, human breast cancer cells and human gastric cancer cells, and can be developed as new anti-tumor drug candidate molecules.

Claims

1. A pyrazole hydrazide derivative containing a diphenyl ether unit and a preparation method and application thereof, 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 pyrazole hydrazide derivative containing 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 molecules obtained after deacidification are subjected to a hydrazide reaction with 3-(difluoromethyl)-1-methyl-pyrazole-4-carboxylic acid to obtain the pyrazole hydrazide derivative I containing a diphenyl ether unit. The synthetic route is as follows:

3. Use of the pyrazole hydrazide derivatives containing diphenyl ether units according to claim 1 in anti-tumor cells.

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

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