A class of N 1 aryl-3-fluoroalkyl-5-fluoropyrazole compounds, their preparation methods and applications

Abstract

The application provides a kind of N 1 -Aryl-3-fluoroalkyl-5-fluoropyrazoles, its preparation method and application;The N 1 -Aryl-3-fluoroalkyl-5-fluoropyrazoles are as formula (I);Wherein, R is difluoromethyl or trifluoromethyl;R 1 Selected from substituted or unsubstituted C6-C30 aryl;R 2 Selected from substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C5-C30 heterocyclic group, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C20 alkenyl.The N 1 -Aryl-3-fluoroalkyl-5-fluoropyrazoles contain fluoralkyl, fluorine atom and pyrazole heterocyclic structure simultaneously, which can not only be used as drugs, but also be used as core structural unit for drug synthesis, for drug activity screening, and the synthesis method has higher conversion rate, superior regioselectivity and wide substrate application range and other advantages.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and particularly relates to a class of N 1 3-Aryl-3-fluoroalkyl-5-fluoropyrazole compounds, their preparation methods and applications. Background Technology

[0002] In medicinal chemistry research, fluoroalkylpyrazoles are the core structure of many drug molecules and functional materials, and occupy a pivotal position in the field of medicinal chemistry.

[0003] In the 1990s, Pfizer successfully developed celecoxib, the world's first selective nonsteroidal anti-inflammatory drug (NSAID). Compared to other NSAIDs, it did not damage the patient's gastrointestinal function and had a certain degree of safety and controllability, marking a milestone in drug synthesis. This sparked research interest in fluroxypyrazole compounds. Soon after, structurally similar anti-inflammatory veterinary drugs, deracoxib and mavacoxib, were also developed. More recently, Novartis developed a Crizanib, a VEGFR-2 inhibitor, which has been shown to treat neovascular age-related macular degeneration. Gilead Sciences reported a novel HIV drug, lenapavir, which, with an interval of up to six months between doses, effectively reduces the viral load in patients. All of these common drugs are fluroxypyrazole compounds. Fluroxypyrazole compounds are also widely used in pesticides and fungicides. For example, the fungicides successively promoted by Bayer, BASF, and Zenith are all difluoromethyl substituted pyrazole drugs (Pavel). These include Bixafen, Iso-Pyrazam, Sedaxane, Fluxapyroxad, and Benzodiflupyr. K.Mykhailiuk,Chem.Rev.,2021,121,1670-1715;JCSloop,C.Holder,M.Hanary,Eur.J.Org.Chem.,2015,3405-3422;SPChandrasekharan,A.Dhami,S.Kumar , K. Mohanan, Org. Biomol. Chem., 2015, 13, 3438-3445; F. Giornal, S. Pazenok, L. Rodefeld, N. Lui, J.-P. Vos, FRLeroux, J. Fluorine Chem., 2013, 152, 2-11).

[0004] Organic synthesizers have developed various synthetic methods to introduce a single fluorine atom or a fluorinated alkyl group into the pyrazole ring. However, synthetic methods for pyrazole molecules containing two different fluorinated groups are still very rare. Currently, methods involving the introduction of fluorine atoms into the fluoroalkylpyrazole skeleton mainly involve the cycloaddition of ethyl-4,4-difluoro-3-oxobutyrate with methylhydrazine, followed by halogen exchange (KF), and finally, late-stage CH functionalization of the pyrazole to achieve this (G.Wei,M.-W.Huang,W.-J.Wang,Y.Wu,S.-F.Mei,L.-M.Zhou,L.-C.Mei,X.-L.Zhu,G.-F.Yang,J.Agri.Food Chem.,2021,69,3965-3931;H.Li,Y.-X.Wang,X.-L.Zhu,G.-F.Yang,J.Agric.Food Chem.,2021,69,13227-13234). Existing methods suffer from cumbersome synthetic steps, demanding reaction conditions, and limited substrate scope. Furthermore, regarding N... 1 Arylfluoroalkyl fluoropyrazoles have not yet been reported. Therefore, developing a direct and efficient method for the preparation of novel fluoropyrazoles is of great significance and application potential in organic synthesis and medicinal chemistry. Summary of the Invention

[0005] In view of this, the technical problem to be solved by the present invention is to provide a novel N 1 Aryl-3-fluoroalkyl-5-fluoropyrazole compounds, their preparation methods, and applications. This preparation method offers advantages such as readily available and simple raw materials, metal-free reaction process, excellent regioselectivity, good substrate versatility, and high one-pot reaction efficiency. The resulting novel difluoromethyl or trifluoromethyl fluoropyrazole heterocyclic structures exhibit significant biological activity compared to traditional fluoroalkylpyrazole compounds. Besides their potential as pharmaceuticals, they can also serve as core structural units in drug synthesis for innovative drug development. This invention provides a more efficient strategy for constructing novel, multi-fluorosubstituted pyrazoles to meet the demands of drug development for structurally diverse and complex pyrazoles.

[0006] This invention provides an N 1 -Aryl-3-fluoroalkyl-5-fluoropyrazole compounds, as shown in formula (I):

[0007]

[0008] Wherein, R is difluoromethyl or trifluoromethyl;

[0009] R1 is selected from substituted or unsubstituted aryl groups of C6 to C30;

[0010] R2 is selected from substituted or unsubstituted aryl groups of C6 to C30, substituted or unsubstituted heterocyclic groups of C5 to C30, substituted or unsubstituted alkyl groups of C1 to C10, and substituted or unsubstituted alkenyl groups of C2 to C20.

[0011] The substituents of the substituted C6-C30 aryl group, the substituted C5-C30 heterocyclic group, the substituted C1-C10 alkyl group, and the substituted C2-C20 alkenyl group are selected from one or more of halogen, hydroxyl, nitro, amino, sulfonamide, azide, cyano, tert-butoxycarbonylamino, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, phenyl, and C2-C10 ester group; the substituents of the substituted C1-C10 alkyl and substituted C1-C10 alkoxy groups are selected from one or more of halogen, hydroxyl, nitro, amino, sulfonamide, azide, and phenyl.

[0012] R1 is selected from one of formulas (1) to (28); R2 is selected from one of formulas (1) to (25):

[0013]

[0014] The N1-aryl-3-fluoroalkyl-5-fluoropyrazole compound is one of the following: Formula L-1 to Formula L-67:

[0015]

[0016]

[0017]

[0018]

[0019] The N1-aryl-3-fluoroalkyl-5-fluoropyrazole compound is preferably from formula L-54 to L-67:

[0020]

[0021]

[0022] The present invention discloses a method for preparing N1-aryl-3-fluoroalkyl-5-fluoropyrazole compounds, wherein the compound N1-arylacetylhydrazide chloride shown in formula (II) is reacted with the compound (Z)-(2-fluoro-2-nitrovinyl)benzene derivative shown in formula (III) under alkaline conditions to obtain the N1-aryl-3-fluoroalkyl-5-fluoropyrazole compound shown in formula (I);

[0023]

[0024] Wherein, R is difluoromethyl or trifluoromethyl;

[0025] R1 is selected from substituted or unsubstituted aryl groups of C6 to C30;

[0026] R2 is selected from substituted or unsubstituted C6-C30 aryl groups, substituted or unsubstituted C5-C30 heterocyclic groups, substituted or unsubstituted C1-C10 alkyl groups, and substituted or unsubstituted C2-C20 alkenyl groups.

[0027] X is a halogen or -OSO2Ph.

[0028] The molar ratio of the compound represented by formula (II) and the compound represented by formula (III) to the base is 2:1:(2-4).

[0029] The base is selected from one or more inorganic bases selected from potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate, potassium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium fluoride, cesium fluoride, cesium carbonate, potassium tert-butoxide, and lithium tert-butoxide.

[0030] The reaction is carried out in an organic solvent; the organic solvent is selected from one or more of toluene, tetrahydrofuran, acetone, ethyl acetate, dichloromethane, 1,4-dioxane, acetonitrile, and 1,2-dichloroethane; the reaction temperature is 0℃ to 100℃; and the reaction time is 1 to 48 h.

[0031] The present invention also provides the application of the above-mentioned N1-aryl-3-fluoroalkyl-5-fluoropyrazole compounds in the preparation of anti-inflammatory drugs.

[0032] The present invention also provides the above-mentioned N 1 Application of aryl-3-fluoroalkyl-5-fluoropyrazole compounds in the preparation of drugs that inhibit COX2 protein.

[0033] Compared with the prior art, the N provided by the present invention 1 -aryl-3-fluoroalkyl-5-fluoropyrazole compounds contain two different pyrazole heterocyclic structures with different fluorine groups and have significant biological activity. They can be used as drugs themselves or as core structural units for drug synthesis in innovative drug development.

[0034] Furthermore, the N provided by this invention 1 The preparation method of -aryl-3-fluoroalkyl-5-fluoropyrazole compounds has the advantages of simple and readily available raw materials, no metal involvement in the reaction process, excellent regioselectivity, good substrate versatility, and high one-pot reaction efficiency; this invention provides a more efficient strategy for constructing novel multi-fluorinated pyrazoles, and the obtained N 1-aryl-3-fluoroalkyl-5-fluoropyrazole compounds have excellent anti-inflammatory activity and can be used as anti-inflammatory and analgesic drugs in drug development. Attached Figure Description

[0035] Figure 1 Example: Polymer activity test diagram Detailed Implementation

[0036] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0037] This invention provides an N 1 -Aryl-3-fluoroalkyl-5-fluoro compounds, as shown in formula (I):

[0038]

[0039] Wherein, R is difluoromethyl or trifluoromethyl;

[0040] R 1 Selected from substituted or unsubstituted aryl groups of C6–C30;

[0041] R 2 Selected from substituted or unsubstituted C6-C30 aryl groups, substituted or unsubstituted C5-C30 heterocyclic groups, substituted or unsubstituted C1-C10 alkyl groups, and substituted or unsubstituted C2-C20 alkenyl groups.

[0042] In this invention, the substituents of the substituted C6-C30 aryl group, the substituted C5-C30 heterocyclic group, the substituted C1-C10 alkyl group, and the substituted C2-C20 alkenyl group are selected from one or more of halogen, hydroxyl, nitro, amino, sulfonamide, cyano, tert-butoxycarbonylamino, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, phenyl, and C2-C10 ester group; the substituents of the substituted C1-C10 alkyl and substituted C1-C10 alkoxy groups are selected from one or more of halogen, hydroxyl, nitro, amino, sulfonamide, and phenyl.

[0043] According to the present invention, most preferably, the R 1 Selected from one of formulas (1) to (28); the R 2 Choose one of equations (1) to (25):

[0044]

[0045] More preferably, the N 1 -Aryl-3-fluoroalkyl-5-fluoropyrazole compounds are one of those shown in formulas L-1 to L-67:

[0046]

[0047]

[0048]

[0049] More preferably, the N 1 -Aryl-3-fluoroalkyl-5-fluoropyrazole compounds are one of those shown in formulas L-54 to L-67:

[0050]

[0051]

[0052] Compared with the prior art, the N provided by the present invention 1 -aryl-3-fluoroalkyl-5-fluoropyrazole compounds contain two different pyrazole heterocyclic structures with different fluorine groups and have significant biological activity. They can be used as drugs themselves or as core structural units for drug synthesis in innovative drug development.

[0053] This invention provides an N 1 A method for preparing aryl-3-fluoroalkyl-5-fluoropyrazole compounds, comprising: reacting the compound shown in formula (II) with the compound shown in formula (III) under alkaline conditions to obtain N shown in formula (I). 1 aryl-3-fluoroalkyl-5-fluoropyrazole compounds;

[0054]

[0055] Wherein, R is difluoromethyl or trifluoromethyl;

[0056] R 1 Selected from substituted or unsubstituted aryl groups of C6–C30;

[0057] R 2 Selected from substituted or unsubstituted C6-C30 aryl groups, substituted or unsubstituted C5-C30 heterocyclic groups, substituted or unsubstituted C1-C10 alkyl groups, and substituted or unsubstituted C2-C20 alkenyl groups.

[0058] X is a halogen or -OSO2Ph.

[0059] This invention does not impose any special restrictions on the source of any raw materials; commercially available materials are acceptable. The R, R... 1With R 2 As mentioned above, there will be no further explanation here.

[0060] In this invention, the alkali is preferably one or more of the following inorganic alkalis: potassium phosphate, dipotassium hydrogen phosphate, potassium carbonate, potassium bicarbonate, sodium phosphate, disodium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium fluoride, cesium fluoride, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, etc.; the organic solvent is preferably one or more of the following: toluene, tetrahydrofuran, acetone, ethyl acetate, dichloromethane, 1,4-dioxane, acetonitrile, 1,2-dichloroethane; the molar ratio of the compound represented by formula (II) and the compound represented by formula (III) to the alkali is preferably (1-2):(1-2):(2-4), more preferably (1.5-2):(1-1.5):(2-4), and even more preferably 2:1:(2-4).

[0061] In this invention, the reaction is preferably carried out in an organic solvent; the organic solvent is selected from one or more of toluene, tetrahydrofuran, acetone, ethyl acetate, dichloromethane, 1,4-dioxane, acetonitrile, and 1,2-dichloroethane; the reaction temperature is preferably 0℃ to 100℃; and the reaction time is preferably 1 to 48 hours. The reaction formula is shown below:

[0062]

[0063] After the reaction is complete, the solvent is preferably removed, and the residue is purified by rapid silica gel chromatography to obtain N. 1 -Aryl-3-fluoroalkyl-5-fluoropyrazole compounds; the mobile phase used for the rapid silica gel chromatography purification is preferably petroleum ether or petroleum ether and ethyl acetate; the rapid silica gel chromatography purification is preferably performed using gradient elution, with the elution program increasing the volume ratio of petroleum ether or petroleum ether and ethyl acetate from 100:1 to 3:1 within 1 to 2 hours.

[0064] The present invention also provides the above-mentioned N 1 Application of aryl-3-fluoroalkyl-5-fluoropyrazole compounds in the preparation of anti-inflammatory drugs.

[0065] The present invention also provides the above-mentioned N 1 Application of aryl-3-fluoroalkyl-5-fluoropyrazole compounds in the preparation of drugs that inhibit COX2 protein.

[0066] The N provided by this invention 1 -aryl-3-fluoroalkyl-5-fluoropyrazole compounds exhibit good inhibitory effects on COX2 protein, a key protein in rheumatoid arthritis models, and possess excellent anti-inflammatory activity, making them suitable for drug development as anti-inflammatory and analgesic agents.

[0067] To further illustrate the present invention, the following embodiments demonstrate an N provided by the present invention.1 This paper provides a detailed description of aryl-3-fluoroalkyl-5-fluoropyrazole compounds, their preparation methods, and applications.

[0068] All reagents used in the following examples are commercially available and used directly without further purification, unless otherwise specified. All parts and percentages are by mass, and temperatures are in Celsius, unless otherwise specified. Rapid column chromatography used 200-300 mesh standard silica gel from Qingdao Ocean Chemical Co., Ltd.; thin-layer chromatography used 0.20 mm standard plates from Qingdao Ocean Chemical Co., Ltd.; nuclear magnetic resonance (NMR) data were obtained using a Bruker 400 MHz NMR spectrometer, with tetramethylsilane as the internal standard and deuterated chloroform as the solvent (s represents singlet, d represents doublet, t represents triplet, q represents quartet, and m represents multiplet).

[0069] Example 1: (Z)-2,2-difluoro-N 1 Preparation of phenylacetylhydrazine chloride

[0070]

[0071] Step 1: Add phenylhydrazine hydrochloride (2.00 g, 12.4 mmol), dichloromethane (20 mL), triethylamine (3.5 mL, 2.0 equiv.), and difluoroacetic anhydride (1.6 mL, 1.0 equiv.) dissolved in dichloromethane (20 mL) to a 100 mL round-bottom flask. Stir the mixture at room temperature for 14 h. Then, wash the resulting mixture with saturated sodium bicarbonate (NaHCO3) aqueous solution, concentrate it, and purify it by silica gel column chromatography to obtain a pale yellow solid, 2,2-difluoro-N'-phenylacetylhydrazine.

[0072] Step 2: At room temperature, benzenesulfonyl chloride (1.4 mL, 10.5 mmol) was added dropwise to a solution of 2,2-difluoro-N'-phenylacetylhydrazine (1.90 g, 10 mmol) in ethyl acetate (30 mL). The resulting mixture was then cooled to 0 °C, and N,N-diisopropylethylamine (DIPEA, 1.8 mL, 10.5 mmol) was slowly added dropwise. After stirring the resulting mixture overnight at room temperature, the mixture was diluted with ethyl acetate, and the organic layer was then washed with water (3 × 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to give a yellow liquid 2,2-difluoro-N'-phenylacetylhydrazine chloride (1.30 g, 64%). The remainder was (Z)-2,2-difluoromethyl-N 1 -Arylacetylhydrazide chloride 1b–1l were also prepared by this method, with yields ranging from 10% to 77%.

[0073] Example 2: (Z)-2,2-difluoro-N 1Preparation of 1-(2-methylphenyl)acetylhydrazine chloride (1b)

[0074]

[0075] Compound 1b was prepared from 2-methylphenylhydrazine according to the preparation method in Example 1. After column chromatography (petroleum ether / ethyl acetate = 100:1, Rf = 0.7), 721.5 mg of a yellow liquid was obtained, yield: 33%. 1 H NMR(400MHz, CDCl3) δ7.90(s,1H),7.35(dd,J=8.1,1.3Hz,1H),7.19(td,J=7.8,1.7Hz,1 H),7.14–7.03(m,1H),6.91(td,J=7.4,1.3Hz,1H),6.31(t,J=53.9Hz,1H),2.23(s,3H). 19 FNMR (376MHz, CDCl3) δ-115.30 (d, J=54.0Hz). 13 C NMR(101MHz, CDCl3)δ139.8,130.8,127.4,122.2,121.7,118.8(t,J=33.3Hz),113.6,111.3(t,J=238.3Hz),16.7.HRMS(ESI)m / z[M+Na] + calcd.for C9H9N2F2NaCl + 241.0320; found 241.0318.

[0076] Example 3: (Z)-2,2-difluoro-N 1 Preparation of 3-(3-methylphenyl)acetylhydrazine chloride (1c)

[0077]

[0078] Compound 1c was prepared from 3-methylphenylhydrazine according to the preparation method in Example 1. After column chromatography (petroleum ether / ethyl acetate = 100:1, Rf = 0.5), 524.7 mg of a yellow liquid was obtained, yield: 24%. 1 H NMR (400MHz, CDCl3) δ7.83(s,1H),7.06(t,J=7.8Hz,1H),6.85–6.64(m,3H),6.18(t,J=54.0Hz,1H),2.21(s,3H). 19 F NMR (565MHz, CDCl3) δ-115.07 (d, J=54.1Hz). 13C NMR(101MHz, CDCl3)δ142.0,139.6,129.3,123.4,117.6(t,J=33.3Hz),114.5,111.4(t,J=238.1Hz),111.0,21.5.HRMS(ESI)m / z[M+Na] + calcd.for C9H9N2F2NaCl + 241.0320; found 241.0319.

[0079] Example 4: (Z)-2,2-difluoro-N 1 Preparation of 1-(2,5-dimethylphenyl)acetylhydrazine chloride (1d)

[0080]

[0081] Compound 1d was prepared from 2,5-dimethylphenylhydrazine according to the preparation method in Example 1. After column chromatography (petroleum ether / ethyl acetate = 100:1, Rf = 0.7), 767.8 mg of a yellow liquid was obtained, yield: 33%. 1 H NMR (400MHz, CDCl3) δ7.77(s,1H),7.13(d,J=1.8Hz,1H),6.91(d,J=7.6Hz,1H) ,6.67(dd,J=7.7,1.8Hz,1H),6.26(t,J=54.0Hz,1H),2.27(s,3H),2.08(s,3H). 19 F NMR (565MHz, CDCl3) δ-114.83 (d, J=53.8Hz). 13 C NMR (101MHz, CDCl3) δ139.6, 137.2, 130.7, 123.1, 118.9, 118.5 (t, J = 33.3Hz), 114.3, 111.5 (t, J = 238.2Hz), 21.3, 16.1.HRMS (ESI) m / z [M+H] + calcd.for C 10 H 12 N2F2Cl + 233.0657; found 233.0663.

[0082] Example 5: (Z)-2,2-difluoro-N 1 Preparation of 1-(4-isopropylphenyl)acetylhydrazine chloride (1e)

[0083]

[0084] Compound 1e was prepared from 4-isopropylphenylhydrazine according to the preparation method in Example 1. After column chromatography (petroleum ether, Rf = 0.7), 246.7 mg of a yellow liquid was obtained, yield: 10%. 1 H NMR (400MHz, CDCl3) δ7.95 (s, 1H), 7.15 (d, J = 8.5Hz, 2H), 7.00 (d, J = 8.6Hz, 2H), 6.29 (t, J = 54.0Hz, 1H), 2.85 (p, J = 6.9Hz, 1H), 1.22 (d, J = 6.9Hz, 6H). 19 F NMR (376MHz, CDCl3) δ-115.18 (d, J=54.0Hz). 13 C NMR(101MHz, CDCl3)δ143.3,139.9,127.4,117.3(t,J=33.4Hz),113.8,111.4(t,J=238.0Hz),33.5,24.1.HRMS(ESI)m / z[M+H] + calcd.for C 11 H 14 N2F2Cl + 247.0814; found 247.0819.

[0085] Example 6: (Z)-2,2-difluoro-N 1 Preparation of 1-(4-tert-butylphenyl)acetylhydrazine chloride (1f)

[0086]

[0087] Compound 1f was prepared from 4-tert-butylphenylhydrazine according to the preparation method in Example 1. After column chromatography (petroleum ether, Rf = 0.5), 521.4 mg of a pink solid was obtained, with a melting point of 20% and a melting point of 76–78 °C. 1 H NMR (400MHz, CDCl3) δ7.99 (s, 1H), 7.43–7.31 (m, 2H), 7.18–6.90 (m, 2H), 6.32 (t, J = 54.0Hz, 1H), 1.31 (s, 9H). 19 F NMR (376MHz, CDCl3) δ-115.33 (d, J=54.1Hz). 13 C NMR(101MHz, CDCl3)δ145.5,139.5,126.3,117.4(t,J=33.2Hz),113.5,111.3(t,J=238.0Hz),31.4.HRMS(ESI)m / z[M+H] + calcd.for C12 H 16 N2F2Cl + 261.0970; found 261.0977.

[0088] Example 7: (Z)-2,2-difluoro-N 1 Preparation of 1 g of (2-bromophenyl)acetylhydrazine chloride

[0089]

[0090] 1 g of the compound was prepared from 2-bromophenylhydrazine according to the preparation method in Example 1. The compound was then subjected to column chromatography (petroleum ether, R...) f =0.6) After that, 1.10 g of white liquid was obtained, yield: 40%. 1 H NMR (400MHz, CDCl3) δ8.51(s,1H),7.44(dd,J=8.0,1.4Hz,1H),7.37(dd,J=8.2,1 .6Hz,1H),7.30–7.15(m,1H),6.83(td,J=7.7,1.6Hz,1H),6.30(t,J=53.9Hz,1H). 19 F NMR (376MHz, CDCl3) δ-115.57 (d, J=53.9Hz). 13 CNMR(101MHz, CDCl3)δ138.9,132.6,128.7,123.1,120.5(t,J=33.3Hz),115.1,111.1(t,J=239.1Hz),108.2.HRMS(ESI)m / z[M+H] + calcd.for C8H7N2F2BrCl + 282.9449; found 282.9448.

[0091] Example 8: (Z)-2,2-difluoro-N 1 Preparation of 3-(bromophenyl)acetylhydrazine chloride (1h)

[0092]

[0093] The compound was prepared by following the preparation method in Example 1 using 3-bromophenylhydrazine as a starting material for 1 hour. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.3) yielded 992.2 mg of orange solid, yield: 35%, melting point: 70–72 °C. 1H NMR (400MHz, CDCl3) δ8.04(s,1H),7.31(t,J=2.0Hz,1H),7.20–7.03(m,2H),7.02–6.86(m,1H),6.31(t,J=53.9Hz,1H). 19 F NMR (376MHz, CDCl3) δ-115.67 (d, J=53.9Hz). 13 C NMR(101MHz, CDCl3)δ143.1,130.8,125.3,123.4,119.2(t,J=33.5Hz),116.8,112.4,111.0(t,J=238.9Hz).HRMS(ESI)m / z[M+H] + calcd.for C8H7N2F2BrCl + 282.9449; found 282.9456.

[0094] Example 9: (Z)-2,2-difluoro-N 1 Preparation of -(2,4-dichlorophenyl)acetylhydrazine chloride (1i)

[0095]

[0096] Compound 1i was prepared from 2,4-dichlorophenylhydrazine according to the preparation method in Example 1. The compound was then subjected to column chromatography (petroleum ether / ethyl acetate = 10:1, R...). f =0.3) yielded 2.10g of orange liquid, yield: 77%. 1 H NMR (400MHz, CDCl3) δ8.09 (s, 1H), 7.00–6.91 (m, 2H), 6.88 (dd, J = 8.8, 2.2Hz, 1H), 6.11 (t, J = 53.8Hz, 1H). 19 FNMR (376MHz, CDCl3) δ-115.49 (d, J=53.8Hz). 13 C NMR (101MHz, CDCl3) δ136.6, 128.8, 128.1, 126.9, 118.6, 115.3, 111.0 (t, J = 239.4Hz). HRMS (ESI) m / z [M+Na] + calcd.forC8H5N2F2Cl3Na + 294.9384; found 293.9486.

[0097] Example 10: (Z)-2,2-difluoro-N 1 Preparation of 1-(4-nitrophenyl)acetylhydrazine chloride (1j)

[0098]

[0099] Compound 1j was prepared from 4-nitrophenylhydrazine using the method described in Example 1. The compound was then subjected to column chromatography (petroleum ether / ethyl acetate = 20:1, R...). f =0.3) yielded 502.9 mg of orange solid, yield: 23%. 1 H NMR (400MHz, CDCl3) δ8.37 (s, 1H), 8.23 ​​(d, J = 9.1Hz, 2H), 7.20 (d, J = 9.1Hz, 2H), 6.34 (t, J = 53.8Hz, 1H). 19 FNMR (376MHz, CDCl3) δ-116.16 (d, J=53.8Hz). 13 C NMR (101MHz, CDCl3) δ146.9, 142.6, 126.0, 122.2 (t, J = 33.6Hz), 113.4, 110.6 (t, J = 240.3Hz). HRMS (ESI) m / z [M+H] + calcd.for C8H7N3O2F2Cl + 250.0195; found 250.0200.

[0100] Example 11: (Z)-2,2-difluoro-N 1 Preparation of -((4-tert-butoxycarbonylamino)phenyl)acetylhydrazine chloride (1k)

[0101]

[0102] Step 1: N-(4-nitrocyclohexyl-1,5-dien-1-yl)acetylhydrazine chloride (10 mmol) was dissolved in MeOH:AcOH (V:V = 2:1). Then, reduced zinc powder (100 mmol) was added to the solution, and the mixture was heated at 50 °C for 4 hours. The reaction mixture was diluted with ethyl acetate, and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE / EA = 3:1) to give 4-(amino)phenylhydrazine chloride.

[0103] Step 2: Add Boc₂O (11 mmol) to a solution of EtOH (20 mL) containing 10 mmol of 4-(amino)phenylhydrazine chloride. Stir the reaction mixture at 30 °C until the starting material is completely converted as monitored by TLC. Extract the resulting organic phase with ethyl acetate, concentrate under vacuum, and purify the residue by rapid chromatography on silica gel (eluting with petroleum ether / ethyl acetate) to give 84.7 mg of a white solid, yield: 53%, melting point: 95–97 °C. 1 H NMR (400MHz, CDCl3) δ7.99 (s, 1H), 7.30 (d, J = 8.4Hz, 2H), 7.06–6.98 (m, 2H), 6.48 (s, 1H), 6.30 (t, J = 54.0Hz, 1H), 1.51 (s, 9H). 19 FNMR (376MHz, CDCl3) δ-115.29 (d, J=53.9Hz). 13 C NMR(101MHz, CDCl3)δ153.1,137.7,133.2,120.2,117.4(t,J=33.2Hz),114.3,111.3(t,J=238.1Hz),80.5,28.4.HRMS(ESI)m / z[M+Na] + calcd.for C 13 H 16 N3O2F2ClNa + 342.0797; found 342.0794.

[0104] Example 12: (Z)-2,2,2-trifluoro-N 1 Preparation of -((4-tert-butoxycarbonylamino)phenyl)acetylhydrazine chloride (1l)

[0105]

[0106] (Z)-2,2,2-trifluoro-N 1 Compound 11 was prepared from (4-nitrophenyl)acetylhydrazide chloride according to the preparation method in Example 11. The compound was then subjected to column chromatography (petroleum ether / ethyl acetate = 10:1, R...). f =0.2) yielded 1.50 g of yellow solid, yield: 45%, melting point: 95–97 °C. 1 H NMR (400MHz, CDCl3) δ8.00 (s, 1H), 7.31 (d, J = 8.5Hz, 2H), 7.06 (d, J = 8.5Hz, 2H), 6.50 (s, 1H), 1.51 (s, 9H). 19 F NMR (376MHz, CDCl3) δ -67.66.13 C NMR(101MHz, CDCl3)δ153.0,137.4,133.6,120.2,118.4(q,J=272.0Hz),114.6,110.9(q,J=43.6Hz),80.5,28.4.HRMS(ESI)m / z[M+Na] + calcd.for C 13 H 15 N3O2F3ClNa + 360.0703; found 360.0697.

[0107] Example 13: (Z)-2,2-difluoro-N 1 Preparation of 1-(4-aminosulfonylphenyl)acetylhydrazine chloride (1m)

[0108]

[0109] Step 1: A suspension of 10 mmol of 4-sulfonylphenylhydrazine hydrochloride was prepared in 15 mL of acetonitrile and cooled to 5–10 °C. 15 mmol of difluoroacetic anhydride was added dropwise, and the reaction mixture was heated at room temperature for 4 hours. The suspension was concentrated to approximately one-third of its original volume under reduced pressure, and hexane was added to precipitate the product. The suspension was cooled to 0–5 °C and allowed to stand for 1 hour. The mixture was filtered and washed with hexane. The filter cake was collected and dried under reduced pressure at 50 °C.

[0110] Step 2: A suspension of 4-(2-(2,2-difluoroacetyl)hydrazino)benzenesulfonamide (2.7 g, 10 mmol) was prepared in ethyl acetate (20 mL) and cooled to 0 °C in an ice bath. Benzenesulfonyl chloride (1.5 mL, 12 mmol) was added, followed by dropwise addition of N-methylmorphine (1.2 mL, 10.5 mmol). The reaction mixture was allowed to stand at 5–10 °C for 1 hour, then water (10 mL) was added and the mixture was stirred for 0.5 hours. The organic layer was separated and washed with saturated brine (10 mL). The organic extract was dried over magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give a white solid (1 mL, 1.30 g), yield: 45%, melting point: 154–156 °C. 1 HNMR (400MHz, DMSO) δ10.73(s,1H),7.77(d,J=8.8Hz,2H),7.40(d,J=8.7Hz,2H),7.23(s,2H),6.85(t,J=53.4Hz,1H). 19 F NMR (376MHz, DMSO) δ-115.32 (d, J = 53.5Hz). 13C NMR(101MHz, DMSO)δ146.2,137.2,127.8,117.9(t,J=33.0Hz),114.5–108.9(m).HRMS(ESI)m / z[M+Na] + calcd.for C8H8N3O2F2SClNa + 305.9892; found 305.9881.

[0111] Example 14: (Z)-2,2,2-trifluoro-N 1 Preparation of 1-(4-aminosulfonylphenyl)acetylhydrazine chloride (1n)

[0112]

[0113] The compound was prepared according to the preparation method in Example 13, yielding 1.50 g of a white solid 1n, with a yield of 49% and a melting point of 150–152 °C. 1 H NMR (400MHz, DMSO) δ11.00 (s, 1H), 7.79 (d, J = 8.8Hz, 2H), 7.41 (d, J = 8.5Hz, 2H), 7.26 (s, 2H). 19 F NMR (376MHz, DMSO) δ -66.75. 13 C NMR(101MHz, DMSO)δ145.7,137.9,127.9,119.0(q,J=270.9Hz),114.3,110.6(q,J=42.2Hz).HRMS(ESI)m / z[M+Na] + calcd.for C8H7N3O2F3SClNa + 323.9797; found 323.9789.

[0114] Example 15: Preparation of (Z)-2-fluoro-4-(2-fluoro-2-nitrovinyl)-1-methoxybenzene (2a)

[0115]

[0116] Step 1: PPh3 (7 mmol) and CFBr3 (6.1 mmol) were placed in a 50 mL round-bottom flask. The resulting mixture was dissolved in THF (5 mL) and refluxed at 70 °C for 15 min. The reaction mixture was then cooled to room temperature, and the aldehyde (4.7 mmol) and the remaining PPh3 (7 mmol) were added. The reaction mixture was then heated at 70 °C. After the reaction was complete, the crude reaction mixture was poured into cold water and extracted with petroleum ether (4 × 20 mL). All organic fractions were then dried over anhydrous Na2SO4 and concentrated under vacuum. Finally, the crude reaction mixture was purified by rapid column chromatography using petroleum ether as the eluent.

[0117] Step 2: 2-Bromo-2-fluoroolefin was placed in a 50 mL round-bottom flask and dissolved in MeCN (5 mL / 1 mmol), followed by the addition of AgNO3 (1.3 equiv.). The reaction mixture was heated and stirred at 65 °C (oil bath) for 45–60 min (TLC monitoring). The mixture was cooled to room temperature and filtered through diatomaceous earth. The diatomaceous earth was then washed with EtOAc. The filtrate was evaporated and the crude product was purified by column chromatography to obtain a yellow solid (Z)-2-fluoro-4-(2-fluoro-2-nitrovinyl)-1-methoxybenzene (2a) 1.20 g, yield: 53%, melting point: 94–96 °C. 1 H NMR (400MHz, CDCl3) δ7.45 (dd, J=11.9, 2.2Hz, 1H), 7.42–7.31 (m, 2H), 7.04 (t, J=8.5Hz, 1H), 3.97 (s, 3H). 19 F NMR (376MHz, CDCl3) δ-112.97 (d, J = 26.2Hz), -132.82 (t, J = 10.1Hz). 13 C NMR (101MHz, CDCl3) δ 153.6, 128.5 (dd, J = 7.0, 3.5Hz), 118.0, 117.9, 117.8, 117.7, 113.5 (d, J = 2.3Hz), 109.3 (dd, J = 6.4, 2.6Hz), 56.3. HRMS (ESI) m / z [M+H] + calcd.for C9H8NO3F2 + 216.0472; found 216.0479.

[0118] Example 16: Preparation method of 3-difluoromethyl-5-flupyrazole-1,4-diphenyl-1H-pyrazole (L-1)

[0119]

[0120] After drying the 10mL pressure tube with a sealed screw cap and a stir bar in an oven, add (Z)-2,2-difluoro-N to the tube. 1 -Phenylacetylhydrazyl chloride (1, 0.15 mmol), (Z)-(2-fluoro-2-nitrovinyl)benzene (2, 0.1 mmol), and Na3PO4 (32.8 mg, 0.2 mmol). 1,2-Dichloroethane (1.0 mL) was transferred to a reaction tube using a syringe. The resulting mixture was stirred at 85 °C for 24 hours. The reaction mixture was extracted with ethyl acetate. The combined organic phases were concentrated under vacuum, and the residue was purified by rapid silica gel chromatography (petroleum ether, R). f =0.2), yielding 24.0 mmg of 3-difluoromethyl-5-fluoropyrazole-1,4-diphenyl-1H-pyrazole (L-1), yield: 83%, melting point: 59–61 °C. 1 H NMR (400MHz, CDCl3) δ7.63–7.56(m,2H),7.53–7.46(m,2H),7.45–7.38(m,2H),7.39–7.31(m,2H),7.32–7.23(m,2H),6.62(t,J=53.7Hz,1H). 19 F NMR (376MHz, CDCl3) δ-111.24 (d, J=53.8Hz), -131.17. 13 C NMR (101MHz, CDCl3) δ149.8 (d, J = 285.5Hz), 142.9 (td, J = 28.6, 8.7Hz), 136.5 (d, J = 2.9Hz), 129.5, 128.8 (d, J = 2.8Hz), 128.3,127.9,127.8(d,J=4.2Hz),121.9(d,J=3.9Hz),112.2(t,J=235.0Hz),103.2(d,J=11.1Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 12 N2F3 + 289.0953; found 289.0955.

[0121] Example 17: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(4-methylphenyl)-1H-pyrazole (L-2)

[0122]

[0123] (Z)-2,2-difluoro-N 1Compound L-2 was prepared from (4-methylphenyl)acetylhydrazide chloride and (Z)-(2-fluoro-2-nitrovinyl)benzene according to the preparation method in Example 16. The compound was then subjected to column chromatography (diethyl ether / petroleum ether = 1:50, R... f =0.4) yielded 19.4 mg of a yellow solid, yield: 64%, melting point: 58–60 °C. 1 H NMR (400MHz, CDCl3) δ7.54–7.45(m,4H),7.43–7.34(m,2H),7.34–7.25(m,1H),7.25(d,J=8.3Hz,2H),6.63(t,J=53.7Hz,1H),2.35(s,3H). 19 F NMR (376MHz, CDCl3) δ-111.18 (d, J=53.8Hz), -131.52. 13 C NMR (101MHz, CDCl3) δ148.7 (d, J = 284.6Hz), 141.6 (td, J = 28.3, 8.1Hz), 137.3, 133.0 (d, J = 2.8Hz), 129.0, 127.7 (d, J = 2.3 Hz),126.8(d,J=4.3Hz),126.7,120.9(d,J=3.6Hz),111.2(t,J=235.0Hz),101.9(d,J=11.2Hz),20.1.HRMS(ESI)m / z[M+H] + calcd.forC 17 H 14 N2F3 + 303.1109; found 303.1106.

[0124] Example 18: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(2-methylphenyl)-1H-pyrazole (L-3)

[0125]

[0126] (Z)-2,2-difluoro-N 1 Compound L-3 was prepared from (2-methylphenyl)acetylhydrazide chloride and (Z)-(2-fluoro-2-nitrovinyl) as starting materials, following the preparation method described in Example 16. The compound was then prepared by column chromatography (diethyl ether / petroleum ether = 1:50, R...). f After adding 0.4 g of solution, 21.8 mg of orange liquid was obtained, yield: 72%. 1H NMR (400MHz, CDCl3) δ7.54–7.47(m,2H),7.44(s,1H),7.39(td,J=7.8,7.1,3.6Hz, 3H),7.35–7.28(m,2H),7.16(d,J=7.6Hz,1H),6.64(t,J=54.3Hz,1H),2.38(s,3H). 19 F NMR (376MHz, CDCl3) δ-111.23 (d, J=53.8Hz), -131.17. 13 CNMR(101MHz, CDCl3)δ149.3(d,J=282.6Hz),141.8(td,J=28.3,8.1Hz),134.2,133.7(d,J=2.1Hz),130.3,129.1,127.7,1 27.6(q,J=2.0Hz),126.7,126.1,125.9,111.2(t,J=235.2Hz),100.7(d,J=10.7Hz),16.5(d,J=2.1Hz).HRMS(ESI)m / z[M+H] + calcd.forC 17 H 14 N2F3 + 303.1109; found 303.1110.

[0127] Example 19: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(3-methylphenyl)-1H-pyrazole (L-4)

[0128]

[0129] (Z)-2,2-difluoro-N 1 Compound L-4 was prepared from (3-methylphenyl)acetylhydrazide chloride and (Z)-(2-fluoro-2-nitrovinyl) as starting materials, following the preparation method described in Example 16. The compound was then subjected to column chromatography (diethyl ether / petroleum ether = 1:50, R... f After adding 0.2 g of solution, 23.6 mg of orange liquid was obtained, yield: 78%. 1 H NMR (400MHz, CDCl3) δ7.56–7.51(m,2H),7.42–7.34(m,3H),7.32–7.25(tt,J=7.7,1.5Hz,4H),6.63(t,J=53.7Hz,1H),2.19(s,3H). 19 FNMR (376MHz, CDCl3) δ-111.03 (d, J=53.8Hz), -131.66. 13C NMR (101MHz, CDCl3) δ148.7 (d, J = 285.1Hz), 141.7 (td, J = 28.4, 8.5Hz), 138.7, 135.3 (d, J = 3.0Hz), 128.2, 128.0, 127.7 (d, J = 2.7Hz),126.8,121.6(d,J=3.3Hz),117.9(d,J=4.3Hz),111.1(t,J=235.6Hz),102.0(d,J=11.4Hz),20.4.HRMS(ESI)m / z[M+H] + calcd.for C 17 H 14 N2F3 + 303.1109; found 303.1115.

[0130] Example 20: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(2,5-dimethylphenyl)-1H-pyrazole (L-5)

[0131]

[0132] (Z)-2,2-difluoro-N 1 Compound L-5 was prepared from (2,5-dimethylphenyl)acetylhydrazide chloride and (Z)-(2-fluoro-2-nitrovinyl) as starting materials, following the preparation method in Example 16. Column chromatography (diethyl ether / petroleum ether = 1:50, R) was then performed. f =0.3) yielded 22.8 mg of orange liquid, 72% yield. 1 H NMR(400MHz, CDCl3)δ7.55–7.50(m,2H),7.38(dd,J=8.5,6.8Hz,2H),7.32–7.2 6(m,1H),7.18–7.10(m,3H),6.62(t,J=53.7Hz,1H),2.31(s,3H),2.13(s,3H). 19 F NMR (376MHz, CDCl3) δ-110.96 (d, J=52.8Hz), -131.62. 13CNMR (101MHz, CDCl3) δ149.3 (d, J = 282.3Hz), 141.7 (td, J = 28.4, 8.3Hz), 135.9, 133.4 (d, J = 2.1Hz), 130.8, 129.9 (d, J = 16.0Hz), 127.7, 127.6 ( q,J=2.0Hz),126.9(d,J=4.3Hz),126.6(d,J=8.4Hz),111.3(t,J=235.3Hz),100.6(d,J=10.9Hz),19.7,15.9(d,J=2.1Hz).HRMS(ESI)m / z[M+H] + calcd.for C 18 H 16 N2F3 + 317.1266; found 317.1265.

[0133] Example 21: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(4-tert-butylphenyl)-1H-pyrazole (L-6)

[0134]

[0135] (Z)-2,2-difluoro-N 1 Compound L-6 was prepared from (4-tert-butylphenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl) as starting materials, following the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.2) yielded 28.9 mg of orange solid, yield: 84%, melting point: 64–66 °C. 1 H NMR (400MHz, CDCl3) δ7.51(td,J=4.2,2.4Hz,4H),7.45(d,J=8.8Hz,2H),7.38(t,J=7.8Hz,2H),7.31–7.26(m,1H),6.63(t,J=53.7Hz,1H),1.29(s,9H). 19 F NMR (376MHz, CDCl3) δ-111.11 (d, J=53.8Hz), -131.56. 13C NMR (101MHz, CDCl3) δ151.6, 149.7 (d, J = 284.5Hz), 142.7 (td, J = 27.9, 8.6Hz), 133.9 (d, J = 2.9Hz), 128.8, 127.9 (d, J = 4.2Hz),127.8,126.4,121.7(d,J=3.6Hz),112.3(t,J=235.2Hz),102.9(d,J=11.2Hz),34.8,31.3.HRMS(ESI)m / z[M+H] + calcd.for C 20 H 20 N2F3 + 345.1579; found 345.1582.

[0136] Example 22: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(4-isopropylphenyl)-1H-pyrazole (L-7)

[0137]

[0138] (Z)-2,2-difluoro-N 1 Compound L-7 was prepared from (4-isopropylphenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl) as starting materials, following the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f After adding 0.2 mg of the solution, 20.2 mg of orange solid was obtained, yield: 61%. 1 H NMR (400MHz, CDCl3) δ7.54–7.47(m,4H),7.37(t,J=7.7Hz,2H),7.31–7.25(m,3H),6.62(t,J=53.8Hz,1H),2.90(p,J=6.9Hz,1H),1.21(d,J=6.9Hz,6H). 19 F NMR (376MHz, CDCl3) δ-111.12 (d, J=53.8Hz), -131.56. 13 C NMR (101MHz, CDCl3) δ149.7 (d, J = 284.9Hz), 149.3, 142.6 (td, J = 28.4, 8.1Hz), 134.2 (d, J = 2.9Hz), 129.5, 128.7 (d, J = 2.5Hz), 12 7.9(d,J=4.3Hz),127.8,127.5,122.0(d,J=3.6Hz),112.3(t,J=235.3Hz),102.9(d,J=11.4Hz),33.8,23.9.HRMS(ESI)m / z[M+H]+ calcd.for C 19 H 18 N2F3 + 331.1422; found 331.1424.

[0139] Example 23: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(2,4-dichlorophenyl)-1H-pyrazole (L-8)

[0140]

[0141] (Z)-2,2-difluoro-N 1 Compound L-8 was prepared from (2,4-dichlorophenyl)acetylhydrazide chloride and (Z)-(2-fluoro-2-nitrovinyl) as starting materials, following the preparation method described in Example 16. Column chromatography (petroleum ether / ethyl acetate = 20:1, R) was then performed. f =0.7) yielded 20.0 mg of orange solid, yield: 56%, melting point: 66–68 °C. 1 HNMR (400MHz, CDCl3) δ7.57–7.47(m,3H),7.44–7.40(m,1H),7.40–7.34(m,3H),7.33–7.28(m,1H),6.61(t,J=53.6Hz,1H). 19 F NMR (376MHz, CDCl3) δ-111.61 (d, J=53.7Hz), -129.26. 13 C NMR (101MHz, CDCl3) δ149.5 (d, J = 285.2Hz), 143.1 (td, J = 28.5, 7.2Hz), 135.9, 131.4, 129.4, 128.8, 12 7.8,127.7(d,J=2.0Hz),127.2,126.9,110.9(t,J=235.8Hz),101.3(d,J=9.8Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 10 N2F3Cl2 + 357.0173; found 357.0176.

[0142] Example 24: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(4-fluorophenyl)-1H-pyrazole (L-9)

[0143]

[0144] (Z)-2,2-difluoro-N1 Compound L-9 was prepared from (4-fluorophenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl) as starting materials, following the preparation method in Example 20. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.2) yielded 15.3 mg of a yellow solid, yield: 50%, melting point: 52–54 °C. 1 H NMR (400MHz, CDCl3) δ7.62–7.56(m,2H),7.49(d,J=7.6Hz,2H),7.38(t,J=7.6Hz ,2H),7.30(t,J=7.4Hz,1H),7.15(q,J=8.4,7.8Hz,2H),6.62(t,J=53.7Hz,1H). 19 F NMR (376MHz, CDCl3) δ-111.42 (d, J=53.6Hz), -112.58 (tt, J=8.1, 4.6Hz), -131.56. 13 CNMR(101MHz, CDCl3)δ162.1(d,J=248.9Hz),149.7(d,J=285.0Hz),142.9(td,J=28.5,9.5Hz),133.9–131.0(m),128.80,128.7 5(d,J=2.6Hz),127.9,123.9(dd,J=8.6,3.8Hz),116.6,116.4,112.0(t,J=235.5Hz),103.2(d,J=11.0Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 11 N2F4 + 307.0858; found 307.0866.

[0145] Example 25: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(4-chlorophenyl)-1H-pyrazole (L-10)

[0146]

[0147] (Z)-2,2-difluoro-N 1 Compound L-10 was prepared from (4-chlorophenyl)acetylhydrazidochloride and (Z)-(2-fluoro-2-nitrovinyl) as starting materials, following the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.2) yielded 20.3 mg of orange solid, yield: 63%, melting point: 53–55 °C. 1H NMR (400MHz, CDCl3) δ7.57 (d, J = 8.4Hz, 2H), 7.48 (d, J = 7.6Hz, 2H), 7.39 (dd, J = 17.0, 8.3Hz, 4H), 7.30 (t, J = 7.2Hz, 1H), 6.61 (t, J = 53.6Hz, 1H). 19 F NMR (376MHz, CDCl3) δ-111.52 (d, J=53.5Hz), -130.87. 13 C NMR (101MHz, CDCl3) δ149.7 (d, J = 286.0Hz), 143.2 (td, J = 28.5, 9.5Hz), 135.1 (d, J = 2.9Hz), 133.9, 129.7, 128.8 ,128.7(d,J=1.9Hz),127.9,122.9(d,J=4.2Hz),111.9(t,J=236.1Hz),103.5(d,J=11.2Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 11 N2F3Cl + 323.0563; found 323.0562.

[0148] Example 26: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(4-bromophenyl)-1H-pyrazole (L-11)

[0149]

[0150] (Z)-2,2-difluoro-N 1 Compound L-11 was prepared from (4-bromophenyl)acetylhydrazidochloride and (Z)-(2-fluoro-2-nitrovinyl) as starting materials, following the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f After adding 0.2 g of the solution, 22.1 mg of red liquid was obtained, yield: 60%. 1 H NMR (400MHz, CDCl3) δ7.60–7.55(m,2H),7.52(dd,J=9.0,1.8Hz,2H),7.50–7.46(m,2H),7.37(m,2H),7.33–7.27(m,1H),6.62(t,J=53.7Hz,1H). 19 FNMR (376MHz, CDCl3) δ-111.56 (d, J=53.6Hz), -130.78. 13C NMR (101MHz, CDCl3) δ148.7 (d, J = 285.8Hz), 142.2 (td, J = 28.3, 8.6Hz), 134.6 (d, J = 2.9Hz), 131.7, 127.8, 127.7 (d, J = 1 .9Hz),126.9,126.4(d,J=4.3Hz),122.1(d,J=4.4Hz),110.9(t,J=235.5Hz),102.5(d,J=11.4Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 11 N2F3Br + 367.0058; found 367.0067.

[0151] Example 27: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(2-bromophenyl)-1H-pyrazole (L-12)

[0152]

[0153] (Z)-2,2-difluoro-N 1 Compound L-12 was prepared from (2-bromophenyl)acetylhydrazidochloride and (Z)-(2-fluoro-2-nitrovinyl) as starting materials, following the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 12.5 mg of yellow liquid, yield: 34%. 1 H NMR(400MHz, CDCl3)δ7.92(q,J=1.8Hz,1H),7.68–7.64(m,1H),7.58–7.52(m ,3H),7.46(dd,J=8.3,6.6Hz,2H),7.42–7.35(m,2H),6.70(t,J=53.6Hz,1H). 19 F NMR (376MHz, CDCl3) δ-111.61 (d, J=53.8Hz), -130.45. 13 C NMR (101MHz, CDCl3) δ149.8 (d, J = 286.0Hz), 143.4 (td, J = 27.6, 8.5Hz), 137.6 (d, J = 3.3Hz), 131.2, 130.8, 128.81, 128.77 (d, J =1.9Hz),128.0,127.4(d,J=4.4Hz),124.8(d,J=4.2Hz),123.1,119.9(d,J=4.8Hz),111.9(t,J=235.7Hz).HRMS(ESI)m / z[M+H]+ calcd.for C 16 H 11 N2F3Br + 367.0058; found 367.0059.

[0154] Example 28: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(3-bromophenyl)-1H-pyrazole (L-13)

[0155]

[0156] (Z)-2,2-difluoro-N 1 Compound L-13 was prepared from (3-bromophenyl)acetylhydrazidochloride and (Z)-(2-fluoro-2-nitrovinyl) as starting materials, following the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 27.5 mg of orange liquid, yield: 75%. 1 H NMR (400MHz, CDCl3) δ7.92 (q, J=1.8Hz, 1H), 7.66 (dd, J=8.1, 1.0Hz, 1H), 7.6 0–7.50(m,3H),7.51–7.43(m,2H),7.42–7.34(m,2H),6.70(t,J=53.6Hz,1H). 19 F NMR (376MHz, CDCl3) δ-111.60 (d, J=53.7Hz), -130.45. 13 C NMR (101MHz, CDCl3) δ149.8 (d, J = 286.5Hz), 143.4 (td, J = 28.5, 8.5Hz), 137.5 (d, J = 3.0Hz), 131.2, 130.8, 128.82, 128.77 (d, J = 2.1Hz), 12 8.0,127.4(d,J=4.3Hz),124.75(d,J=4.0Hz),123.1,119.9(d,J=5.0Hz),111.9(t,J=235.8Hz),103.6(d,J=11.3Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 11 N2F3Br + 367.0058; found 367.0062.

[0157] Example 29: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(4-trifluoromethylphenyl)-1H-pyrazole (L-14)

[0158]

[0159] (Z)-2,2-difluoro-N 1 Compound L-14 was prepared from (4-trifluoromethylphenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl) as starting materials, following the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.2) yielded 22.1 mg of orange solid, yield: 62%, melting point: 38–40 °C. 1 H NMR (400MHz, CDCl3) δ7.88(d,J=8.4Hz,2H),7.79(d,J=8.6Hz,2H),7.57(d,J= 7.6Hz,2H),7.47(t,J=7.6Hz,2H),7.44–7.37(m,1H),6.71(t,J=53.6Hz,1H). 19 F NMR (376MHz, CDCl3) δ-62.57, -111.78 (d, J=53.6Hz), -130.12. 13 C NMR (101MHz, CDCl3) δ149.9 (d, J = 287.1Hz), 143.8 (td, J = 28.5, 8.6Hz), 139.3, 130.2, 129.8, 128.9, 128.8 (d, J = 2.3Hz), 128.1 ,127.2(d,J=4.3Hz),126.8(q,J=3.8Hz),121.4(d,J=5.1Hz),111.9(t,J=235.9Hz),103.9(d,J=11.7Hz).HRMS(ESI)m / z[M+H] + calcd.for C 17 H 11 N2F6 + 357.0826; found 357.0823.

[0160] Example 30: Preparation of 3-difluoromethyl-5-fluoro-4-phenyl-1-(naphth-2-yl)-1H-pyrazole (L-15)

[0161]

[0162] (Z)-2,2-difluoro-N 1 Compound L-15 was prepared from (naphthyl-2-yl)acetylhydrazide chloride and (Z)-(2-fluoro-2-nitrovinyl) as starting materials, following the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f=0.1) yielded 27.1 mg of orange solid, yield: 80%, melting point: 90–92 °C. Main configuration: 1 H NMR(400MHz, CDCl3)δ8.05(d,J=2.2Hz,1H),7.91(d,J=8.9Hz,1H),7.86–7.81(m,2H),7.76(dt,J=8.9, 2.0Hz,1H),7.55–7.45(m,3H),7.39(t,J=7.6Hz,2H),7.33–7.05(m,2H),6.70(td,J=53.8,18.9Hz,1H). 19 F NMR (376MHz, CDCl3) δ -111.27 (d, J = 53.8Hz), -113.78 (dd, J = 53.8, 4.9Hz), -130.77, -172.80 (t, J = 5.1Hz). 13 C NMR(101MHz, CDCl3)δ148.9(d,J=285.5Hz),141.9(td,J=28.4,8.5Hz),132.8(d,J=2.9Hz),132.1,131.4,128.6,128.1–127.9(m),127.7(d,J=2.9Hz ),127.2,126.8,126.7(d,J=4.3Hz),126.2,125.9,125.1,123.4,118.9(d, J=4.0Hz),111.1(t,J=235.4Hz),102.3(d,J=11.4Hz).HRMS(ESI)m / z[M+H] + calcd.for C 20 H 14 N2F3 + 339.1109; found 339.1107.

[0163] Example 31: Preparation of 3-difluoromethyl-5-fluoro-1-phenyl-4-(4-methylphenyl)-1H-pyrazole (L-16)

[0164]

[0165] (Z)-2,2-difluoro-N 1 Using phenylacetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-2-methylbenzene as starting materials, compound L-16 was prepared according to the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 17.2 mg of orange solid, yield: 57%, melting point: 58–60 °C. 1H NMR (400MHz, CDCl3) δ7.61(d,J=7.9Hz,2H),7.47–7.36(m,4H),7.35–7.29(m,1H),7.19(d,J=8.0Hz,2H),6.62(t,J=53.7Hz,1H),2.32(s,3H). 19 F NMR (376MHz, CDCl3) δ-111.33 (d, J=53.8Hz), -131.45. 13 C NMR (101MHz, CDCl3) δ148.7 (d, J = 285.0Hz), 141.8 (td, J = 28.2, 8.5Hz), 136.7, 135.5 (d, J = 2.9Hz), 128.4, 127.6 (q, J = 2.0 Hz),127.1,123.7(d,J=4.3Hz),120.8(d,J=4.0Hz),111.1(t,J=235.3Hz),102.1(d,J=11.5Hz),20.2.HRMS(ESI)m / z[M+H] + calcd.for C 17 H 14 N2F3 + 303.1109; found 303.1106.

[0166] Example 32: Preparation of 3-difluoromethyl-5-fluoro-1-phenyl-4-(3-methylphenyl)-1H-pyrazole (L-17)

[0167]

[0168] (Z)-2,2-difluoro-N 1 Using phenylacetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-3-methylbenzene as starting materials, compound L-17 was prepared according to the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether r, R). f =0.1) yielded 21.8 mg of orange liquid, yield: 72%. 1 H NMR (400MHz, CDCl3) δ7.64–7.56(m,2H),7.44(t,J=7.9Hz,2H),7.37–7.22(m,4H),7.11(d,J=7.0Hz,1H),6.63(t,J=53.9Hz,1H),2.34(s,3H). 19 FNMR (376MHz, CDCl3) δ-111.38 (d, J=53.8Hz), -131.21. 13C NMR (101MHz, CDCl3) δ149.8 (d, J = 285.1Hz), 142.9 (td, J = 28.0, 8.3Hz), 138.4, 136.6 (d, J = 2.8Hz), 129.5, 129.4 (q, J = 2.1Hz), 128.7, 12 8.2,127.6(d,J=4.4Hz),125.9(q,J=1.9Hz),121.9(d,J=4.0Hz),112.1(t,J=235.4Hz),103.3(d,J=11.3Hz),21.5.HRMS(ESI)m / z[M+H] + calcd.forC 17 H 14 N2F3 + 303.1109; found 303.1099.

[0169] Example 33: Preparation of 3-difluoromethyl-5-fluoro-1-phenyl-4-(4-methoxyphenyl)-1H-pyrazole (L-18)

[0170]

[0171] (Z)-2,2-difluoro-N 1 Compound L-18 was prepared from phenylacetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-4-methoxybenzene according to the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f After adding 0.1%, 21.6 mg of orange liquid was obtained, yield: 68%. 1 H NMR (400MHz, CDCl3) δ7.69 (d, J=7.8Hz, 2H), 7.52 (td, J=9.7, 8.7, 3.4Hz, 4H), 7. 42(d,J=7.4Hz,1H),6.99(d,J=8.8Hz,2H),6.69(t,J=53.7Hz,1H),3.85(s,3H). 19 F NMR (376MHz, CDCl3) δ-111.31 (d, J=53.8Hz), -131.84. 13C NMR (101MHz, CDCl3) δ159.3, 149.6 (d, J = 284.1Hz), 142.8 (td, J = 28.0, 9.5Hz), 136.6 (d, J = 2.6Hz), 132.9, 130.0 (d,J=2.4Hz),129.5,128.2,124.5,123.9,121.8(d,J=4.0Hz),112.3(t,J=236.8Hz),55.3.HRMS(ESI)m / z[M+H] + calcd.for C 17 H 13 N2F3O + 319.1047; found 319.1053.

[0172] Example 34: Preparation of 3-difluoromethyl-5-fluoro-1-phenyl-4-(4-tert-butylphenyl)-1H-pyrazole (L-19)

[0173]

[0174] (Z)-2,2-difluoro-N 1 Compound L-19 was prepared from phenylacetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-4-tert-butylbenzene according to the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f After adding 0.1%, 21.4 mg of white liquid was obtained, yield: 62%. 1 H NMR (400MHz, CDCl3) δ7.62 (d, J = 7.8Hz, 2H), 7.43 (p, J = 8.6, 8.0Hz, 6H), 7.34 (t, J = 7.5Hz, 1H), 6.64 (t, J = 53.7Hz, 1H), 1.29 (s, 9H). 19 FNMR (376MHz, CDCl3) δ-111.44 (d, J=53.7Hz), -131.27. 13 C NMR (101MHz, CDCl3) δ148.7 (d, J = 284.1Hz), 149.8, 141.8 (td, J = 28.6, 8.6Hz), 135.5 (d, J = 2.4Hz), 129.9 (d, J = 2.8Hz), 128.5, 127.3 (d, J = 2.2Hz),127.1,124.7,123.7(d,J=4.4Hz),120.8(d,J=4.1Hz),111.1(t,J=235.6Hz),102.0(d,J=11.3Hz),33.6,30.3.HRMS(ESI)m / z[M+H]+ calcd.forC 20 H 20 N2F3 + 345.1579; found 345.1587.

[0175] Example 35: Preparation of 3-difluoromethyl-5-fluoro-1-phenyl-4-(naphth-2-yl)-1H-pyrazole (L-20)

[0176]

[0177] (Z)-2,2-difluoro-N 1 Compound L-20 was prepared from phenylacetylhydrazidochloro and (Z)-2-(2-fluoro-2-nitrovinyl)naphthalene according to the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f After adding 0.1%, 23.7 mg of yellow liquid was obtained, yield: 70%. 1 H NMR (400MHz, CDCl3) δ8.01–7.89(m,2H),7.82–7.70(m,3H),7.61–7.48(m,6H),7.43(t,J=7.4Hz,1H),6.60(t,J=53.7Hz,1H). 19 F NMR (376MHz, CDCl3) δ-112.61 (dd, J=275.2, 54.0Hz), -128.67. 13 C NMR (101MHz, CDCl3) δ150.2 (d, J = 285.1Hz), 144.3 (td, J = 27.4, 8.6Hz), 136.7 (d, J = 3.0Hz), 135.3, 133.7, 132.2, 129.6, 129.3, 129.2, 128.5 ,128.2,126.6,126.2,125.3,125.2,124.7(d,J=3.3Hz),121.8(d,J=4.1Hz),111.3(t,J=236.2Hz),101.1(d,J=14.2Hz).HRMS(ESI)m / z[M+H] + calcd.forC 20 H 14 N2F3 + 339.1109; found 339.1102.

[0178] Example 36: Preparation of 3-difluoromethyl-5-fluoro-1-phenyl-4-(3-cyanophenyl)-1H-pyrazole (L-21)

[0179]

[0180] (Z)-2,2-difluoro-N 1 Compound L-21 was prepared from phenylacetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-3-cyanobenzene according to the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 10.3 mg of a yellow solid, yield: 33%, melting point: 70–72 °C. 1 H NMR (400MHz, CDCl3) δ7.84–7.74(m,2H),7.64–7.55(m,3H),7.52–7.43(m,3H),7.41–7.33(m,1H),6.64(t,J=53.4Hz,1H). 19 FNMR (376MHz, CDCl3) δ-110.40 (d, J=53.7Hz), -129.99. 13 C NMR (101MHz, CDCl3) δ148.9 (d, J = 286.7Hz), 141.8 (td, J = 29.4, 8.2Hz), 135.1 (d, J = 2.9Hz), 131.9 (q, J = 2.2Hz), 130.9 (q, J = 2.3Hz), 130 .2,128.6,128.3(d,J=4.4Hz),127.6,120.8(d,J=3.7Hz),117.5,112.1,111.4(t,J=235.0Hz),100.0(d,J=11.0Hz).HRMS(ESI)m / z[M+H] + calcd.for C 17 H 11 N3F3 + 314.0905; found 314.0908.

[0181] Example 37: Preparation of 3-difluoromethyl-5-fluoro-1-phenyl-4-(4-trifluoromethylphenyl)-1H-pyrazole (L-22)

[0182]

[0183] (Z)-2,2-difluoro-N 1 Compound L-22 was prepared from phenylacetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-4-trifluoromethylbenzene according to the preparation method in Example 16. Petroleum ether was then subjected to column chromatography. f =0.1) yielded 26.7 mg of a yellow solid, yield: 75%, melting point: 60–62 °C. 1H NMR (400MHz, CDCl3) δ7.74–7.66(m,6H),7.57–7.51(m,2H),7.47–7.42(m,1H),6.72(t,J=53.7Hz,1H). 19 F NMR (376MHz, CDCl3) δ-62.67, -110.76 (d, J=53.8Hz), -130.07. 13 C NMR (101MHz, CDCl3) δ150.0 (d, J = 286.5Hz), 142.9 (td, J = 29.5, 7.6Hz), 136.2 (d, J = 2.9Hz), 131.6 (d, J = 5.2Hz), 129.6, 128.9 (d,J=2.3Hz),128.5,125.7(q,J=3.9Hz),121.9(d,J=3.9Hz),112.4(t,J=235.0Hz),101.8(d,J=10.8Hz).HRMS(ESI)m / z[M+H] + calcd.for C 17 H 11 N2F6 + 357.0826; found 357.0826.

[0184] Example 38: Preparation of 3-difluoromethyl-5-fluoro-1-phenyl-4-(4-fluorophenyl)-1H-pyrazole (L-23)

[0185]

[0186] (Z)-2,2-difluoro-N 1 Using phenylacetylhydrazidoyl chloride and (Z)-1-(2-fluoro-2-nitrovinyl)-4-fluorobenzene as starting materials, compound L-23 was prepared according to the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f After reacting with 0.1%, 23.9 mg of a yellow solid was obtained, yield: 78%, melting point: 59–61 °C. 1 H NMR (400MHz, CDCl3) δ7.68(d,J=7.9Hz,2H),7.54(q,J=8.3Hz,4H),7.43(t,J=7.4Hz,1H),7.15(t,J=8.7Hz,2H),6.69(t,J=53.7Hz,1H). 19 F NMR (376MHz, CDCl3) δ-111.01 (d, J=53.8Hz), -113.79 (ddd, J=13.8, 8.7, 5.1Hz), -131.43. 13CNMR (101MHz, CDCl3) δ161.3 (d, J = 247.6Hz), 148.7 (d, J = 285.0Hz), 141.8 (td ,J=28.9,8.6Hz),135.4(d,J=2.6Hz),132.0(t,J=8.4Hz),129.5(dd,J=8.2,2 .2Hz),128.5,127.3,120.8(d,J=3.9Hz),115.9,115.6,114.9,114.6,111.3( t,J=235.2Hz),107.8(d,J=6.3Hz),101.1(d,J=11.4Hz).HRMS(ESI)m / z[M+H] + calcd.forC 16 H 11 N2F4 + 307.0858; found 307.0860.

[0187] Example 39: Synthesis of 3-difluoromethyl-5-fluoro-1-phenyl-4-(4-chlorophenyl)-1H-pyrazole (L-24)

[0188]

[0189] (Z)-2,2-difluoro-N 1 Using phenylacetylhydrazidoyl chloride and (Z)-1-(2-fluoro-2-nitrovinyl)-4-chlorobenzene as starting materials, compound L-24 was prepared according to the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.2) yielded 17.4 mg of orange solid, yield: 54%, melting point: 90–92 °C. 1 H NMR (400MHz, CDCl3) δ7.68 (d, J = 7.7Hz, 2H), 7.53 (dd, J = 8.2, 6.2Hz, 4H), 7.46–7.39 (m, 3H), 6.70 (t, J = 53.7Hz, 1H). 19 FNMR (376MHz, CDCl3) δ-110.94 (d, J=53.5Hz), -130.77. 13C NMR (101MHz, CDCl3) δ149.8 (d, J = 285.8Hz), 142.9 (td, J = 28.9, 8.0Hz), 136.4 (d, J = 2.9Hz), 133.9, 130.0 (q, J = 2.2Hz), 129 .6,129.0,128.4,126.3(d,J=4.4Hz),121.9(d,J=3.9Hz),112.4(t,J=235.2Hz),102.0(d,J=11.3Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 11 N2F3Cl + 323.0563; found 323.0571.

[0190] Example 40: Preparation of 3-difluoromethyl-5-fluoro-1-phenyl-4-(4-bromophenyl)-1H-pyrazole (L-25)

[0191]

[0192] (Z)-2,2-difluoro-N 1 Using phenylacetylhydrazidoyl chloride and (Z)-1-(2-fluoro-2-nitrovinyl)-4-bromobenzene as starting materials, compound L-25 was prepared according to the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.2) yielded 27.5 mg of white solid, yield: 75%, melting point: 79–81 °C. 1 H NMR (400MHz, CDCl3) δ7.64–7.57(m,2H),7.55–7.47(m,2H),7.46(dd,J=8.7,7.1Hz,2H),7.37(dd,J=15.7,7.9Hz,3H),6.62(t,J=53.9Hz,1H). 19 F NMR (376MHz, CDCl3) δ-110.91 (d, J=53.8Hz), -130.67. 13 C NMR (101MHz, CDCl3) δ148.7 (d, J = 286.5Hz), 141.7 (td, J = 29.6, 8.6Hz), 135.3 (d, J = 2.9Hz), 130.9, 129.2 (d, J = 2.2Hz), 128 .5,127.4,125.7(d,J=4.3Hz),120.9,120.8(d,J=3.9Hz),111.3(t,J=235.2Hz),101.0(d,J=11.2Hz).HRMS(ESI)m / z[M+H]+ calcd.for C 16 H 11 N2F3Br + 367.0058; found 367.0066.

[0193] Example 41: Preparation of 3-difluoromethyl-5-fluoro-1-phenyl-4-(2-bromophenyl)-1H-pyrazole (L-26)

[0194]

[0195] (Z)-2,2-difluoro-N 1 Using phenylacetylhydrazidoyl chloride and (Z)-1-(2-fluoro-2-nitrovinyl)-2-bromobenzene as starting materials, compound L-26 was prepared according to the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f After adding 0.1%, 25.7 mg of white liquid was obtained, yield: 70%. 1 H NMR (400MHz, CDCl3) δ7.79–7.65(m,3H),7.53(t,J=7.9Hz,2H),7.48–7.37(m,3H),7.32–7.24(m,1H),6.64(t,J=53.8Hz,1H). 19 F NMR (376MHz, CDCl3) δ-117.42 (d, J=52.5Hz), -126.02. 13 C NMR (101MHz, CDCl3) δ149.6 (d, J = 285.8Hz), 143.6 (td, J = 27.6, 8.7Hz), 136.5 (d, J = 3.0Hz), 132.9 (d, J = 3.4Hz), 130.2, 129.5, 129.1, 128.8(d,J=3.9Hz),128.3,127.4,124.8,123.8,121.9(d,J=4.0Hz),111.5(t,J=235.9Hz),102.3(d,J=13.7Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 11 N2F3Br + 367.0058; found 367.0065.

[0196] Example 42: Preparation of 3-difluoromethyl-5-fluoro-1-phenyl-4-(thien-2-yl)-1H-pyrazole (L-27)

[0197]

[0198] (Z)-2,2-difluoro-N 1 Compound L-27 was prepared from phenylacetylhydrazide chloride and (Z)-2-(2-fluoro-2-nitrovinyl)thiophene according to the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 7.9 mg of orange solid, yield: 27%, melting point: 83–85 °C. 1 H NMR (400MHz, CDCl3) δ7.74–7.64(m,2H),7.54(d,J=7.5Hz,2H),7.47–7.40(m ,1H),7.40–7.33(m,2H),7.12(dd,J=5.1,3.6Hz,1H),6.73(t,J=53.6Hz,1H). 19 F NMR (376MHz, CDCl3) δ-112.64 (d, J=53.4Hz), -127.91. 13 C NMR (101MHz, CDCl3) δ147.9 (d, J = 288.2Hz), 141.4 (d, J = 5.7Hz), 141.2, 140.4 (td, J = 28.0, 8.0Hz), 135.2, 128.46, 128.51 (d, J =2.3Hz),127.4,120.9(d,J=3.8Hz),110.4(t,J=235.8Hz),110.3,107.1(q,J=2.5Hz),94.1(d,J=12.6Hz).HRMS(ESI)m / z[M+H] + calcd.forC 14 H 10 N2F3S + 295.0517; found 295.0524.

[0199] Example 43: Preparation of 3-difluoromethyl-5-fluoro-1-phenyl-4-(furan-2-yl)-1H-pyrazole (L-27)(L-28)

[0200]

[0201] (Z)-2,2-difluoro-N 1 Compound L-28 was prepared from phenylacetylhydrazidochloro and (Z)-2-(2-fluoro-2-nitrovinyl)furan according to the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 10.0 mg of a yellow solid, yield: 36%, melting point: 52–54 °C. 1H NMR(400MHz, CDCl3)δ7.60(d,J=8.3Hz,2H),7.51–7.42(m,3H),7.36(q,J=7.4,6 .0Hz,1H),6.76(t,J=53.6Hz,1H),6.56(d,J=3.4Hz,1H),6.44(d,J=2.6Hz,1H). 19 F NMR (376MHz, CDCl3) δ-114.69 (d, J=53.7Hz), -127.19. 13 CNMR(101MHz, CDCl3)δ144.1(d,J=257.5Hz),138.9,133.5(td,J=29.9,8.2Hz),129.4,129.3,128.6(d,J=3.2Hz),1 27.9(d,J=1.9Hz),127.4,126.2(d,J=5.1Hz),126.1,125.3,125.1,110.4(td,J=236.0,2.8Hz).HRMS(ESI)m / z[M+H] + calcd.for C 14 H 10 N2F3O + 279.0745; found 279.0743.

[0202] Example 44: Preparation of 3-trifluoromethyl-4-(2,6-dimethylhept-5-en-1-yl)-5-fluoro-1-phenyl-1H-pyrazole (L-29)

[0203]

[0204] (Z)-2,2-difluoro-N 1 Using phenylacetylhydrazidoyl chloride and (Z)-1-fluoro-4,8-dimethyl-1-nitronon-1,7-diene as starting materials, compound L-29 was prepared according to the preparation method in Example 16. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 5.1 mg of orange liquid, yield: 15%. 1H NMR (400MHz, CDCl3) δ7.63(d,J=7.7Hz,2H),7.48(t,J=8.0Hz,2H),7.37(t,J =7.4Hz,1H),6.60(t,J=54.0Hz,1H),5.10(td,J=6.8,3.3Hz,1H),2.58(dd,J =14.4,6.2Hz,1H),2.35(dd,J=14.4,8.4Hz,1H),2.03(ddt,J=30.0,14.9,7. 6Hz,2H),1.68(s,3H),1.61(s,3H),1.49–1.36(m,2H),0.93(d,J=6.6Hz,3H). 19 F NMR (376MHz, CDCl3) δ-112.23 (dd, J=54.0, 36.3Hz), -131.82. 13 C NMR (101MHz, CDCl3) δ151.2 (d, J = 281.3Hz), 144.4 (td, J = 29.0, 10.3Hz), 136.8 (d, J = 2.9Hz), 131.4, 129.4, 127.8, 124.6, 121.5 (d, J = 4.1 Hz),112.7(t,J=234.0Hz),100.2(d,J=14.4Hz),36.8,33.3,29.7,28.6(d,J=3.6Hz),25.6(d,J=16.9Hz),19.4,17.7.HRMS(ESI)m / z[M+H] + calcd.forC 19 H 24 N2F3 + 337.1892; found 337.1897.

[0205] Example 45: Preparation of 5-fluoro-1,4-diphenyl-3-trifluoromethyl-1H-pyrazole (L-30)

[0206]

[0207] After drying the 10mL pressure tube with a sealed screw cap and a stir bar in an oven, add (Z)-2,2,2-trifluoro-N to the tube. 1-Phenylacetylhydrazyl chloride (0.3 mmol), (Z)-(2-fluoro-2-nitrovinyl)benzene (0.1 mmol), and K₂CO₃ (55.3 mg, 0.4 mmol). 1,2-Dichloroethane (1.0 mL) was transferred to a tube using a syringe. The resulting mixture was stirred at 85 °C for 24 hours. The reaction mixture was extracted with ethyl acetate. The combined organic phases were concentrated under vacuum and subjected to column chromatography (petroleum ether, R) f After adding 0.1%, compound L-30 was obtained as a yellow liquid, 25.7 mg, yield: 84%. 1 H NMR (400MHz, CDCl3) δ7.61 (d, J = 7.9 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.39 (td, J = 10.0, 3.2 Hz, 4H), 7.33 (dd, J = 12.2, 4.8 Hz, 2H). 19 F NMR (376MHz, CDCl3) δ-61.04,-130.83. 13 C NMR (101MHz, CDCl3) δ 148.6 (d, J = 285.5Hz), 137.9 (qd, J = 37.4, 8.6Hz), 135.2 (d, J = 2.9Hz), 128.5, 128.0 (t, J = 1.5Hz), 127. 7,127.5,127.2,125.9(d,J=3.9Hz),121.0(d,J=3.7Hz),119.7(qd,J=271.1,1.2Hz),104.3–100.7(m).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 11 N2F4 + 307.0858; found 307.0854.

[0208] Example 46: Preparation of 5-fluoro-4-phenyl-1-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazole (L-31)

[0209]

[0210] (Z)-2,2,2-trifluoro-N 1 Compound L-31 was prepared from (4-methylphenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl)benzene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 25.0 mg of a yellow solid, yield: 78%, melting point: 56–58 °C. 1H NMR (400MHz, CDCl3) δ7.62–7.54(m,2H),7.46(d,J=6.7Hz,4H),7.41(dd,J=5.6,2.8Hz,1H),7.32(d,J=8.0Hz,2H),2.43(s,3H). 19 F NMR(376MHz, CDCl3)δ-60.99,-131.14. 13 C NMR (101MHz, CDCl3) δ149.6 (d, J = 284.9Hz), 138.76, 138.75 (qd, J = 38.1, 8.3Hz), 133.9 (d, J = 3.0Hz), 130.9 (d, J = 7.9Hz), 130.1, 12 9.1,128.7,128.2,127.2(d,J=4.1Hz),122.1(d,J=3.5Hz),120.9(qd,J=269.5,1.7Hz),103.6–102.3(m),21.1.HRMS(ESI)m / z[M+H] + calcd.for C 17 H 13 N2F4 + 321.1015; found 321.1022.

[0211] Example 46: Preparation of 5-fluoro-4-phenyl-1-(2-methylphenyl)-3-trifluoromethyl-1H-pyrazole (L-32)

[0212]

[0213] (Z)-2,2,2-trifluoro-N 1 Compound L-32 was prepared from (2-methylphenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl)benzene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 22.4 mg of a yellow solid, yield: 70%, melting point: 54–56 °C. 1 H NMR (400MHz, CDCl3) δ7.53 (s, 2H), 7.47 (d, J = 6.0Hz, 5H), 7.43–7.37 (m, 2H), 2.45 (s, 3H). 19 F NMR(376MHz, CDCl3)δ-61.02,-130.80. 13CNMR(101MHz, CDCl3)δ150.3(d,J=282.6Hz),139.0(qd,J=37.1,8.1Hz),135.4,135.3,134.5(d,J=2.1Hz),131.4,131.3,130.4,129.9,1 29.2,129.0,128.8,128.7,128.1,127.9,127.2,126.9,120.8(qd,J=271.6,1.2Hz),105.6–96.3(m),21.8–13.4(m).HRMS(ESI)m / z[M+H] + calcd.for C 17 H 13 N2F4 + 321.1015; found 321.1007.

[0214] Example 47: Synthesis of 5-fluoro-4-phenyl-1-(3-methylphenyl)-3-trifluoromethyl-1H-pyrazole (L-33)

[0215]

[0216] (Z)-2,2,2-trifluoro-N 1 Compound L-33 was prepared from (3-methylphenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl)benzene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 25.6 mg of yellow liquid, yield: 80%. 1 H NMR (400MHz, CDCl3) δ7.54–7.44(m,5H),7.43–7.35(m,3H),7.32–7.29(m,1H),2.27(s,3H). 19 F NMR (376MHz, CDCl3) δ-60.97 -131.25. 13 CNMR (101MHz, CDCl3) δ149.7 (d, J = 285.2Hz), 139.8, 138.9 (qd, J = 37.8, 9.0Hz), 136.2 (d, J = 2.8Hz), 130.9 (d, J = 7.7Hz), 129.4, 129.3, 129.1, 12 8.7,128.2,127.1(d,J=4.0Hz),122.8(d,J=3.2Hz),120.9(qd,J=271.1,1.9Hz),119.2(d,J=4.2Hz),104.9–102.0(m),21.4.HRMS(ESI)m / z[M+H]+ calcd.for C 17 H 13 N2F4 + 321.1015; found 321.1013.

[0217] Example 48: Preparation of 5-fluoro-4-phenyl-1-(2,5-dimethylphenyl)-3-trifluoromethyl-1H-pyrazole (L-34)

[0218]

[0219] (Z)-2,2,2-trifluoro-N 1 Compound L-34 was prepared from (2,5-dimethylphenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl)benzene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f After adding 0.1%, 23.7 mg of yellow liquid was obtained, yield: 71%. 1 H NMR (400MHz, CDCl3) δ7.54–7.42(m,3H),7.42–7.26(m,2H),7.26–7.05(m,3H),2.51–1.64(m,6H). 19 F NMR (376MHz, CDCl3) δ-60.94,-131.27. 13 CNMR(101MHz,CDCl3)δ150.3(d,J=282.5Hz),138.9(qd,J=37.6,8.6Hz),138.1,136 .9,134.3,132.0,131.9,131.1(d,J=2.7Hz),131.0,130.8,129.2,129.0,128.8,12 8.7,128.3,128.13,128.08(d,J=2.7Hz),127.7,127.3(d,J=4.3Hz),124.2(qd,J=2 70.7,1.4Hz),103.7–99.1(m),20.7(d,J=3.4Hz),19.6–9.9(m).HRMS(ESI)m / z[M+H] + calcd.forC 18 H 15 N2F4 + 335.1171; found 335.1180.

[0220] Example 49: Preparation of 5-fluoro-4-phenyl-1-(4-tert-butylphenyl)-3-trifluoromethyl-1H-pyrazole (L-35)

[0221]

[0222] (Z)-2,2,2-trifluoro-N 1 Compound L-35 was prepared from (4-tert-butylphenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl)benzene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f After reacting with 0.1%, a yellow solid of 29.4 mg was obtained, yield: 81%, melting point: 60–62 °C. 1 H NMR (400MHz, CDCl3) δ7.60(dt,J=8.8,2.0Hz,2H),7.53(dd,J=8.7,2.0Hz,2H),7.46(dt,J=13.1,4.2Hz,4H),7.41–7.36(m,1H),1.36(d,J=2.0Hz,9H). 19 F NMR (376MHz, CDCl3) δ-61.00,-131.25. 13 C NMR (101MHz, CDCl3) δ 151.9, 149.6 (d, J = 285.1Hz), 138.8 (qd, J = 38.0, 9.4Hz), 133.7 (d, J = 2.9Hz), 129.1, 128.7, 128.2, 127. 2(d,J=4.0Hz),126.5,121.9(d,J=3.6Hz),120.8(qd,J=271.0,1.5Hz),103.3(d,J=14.6Hz),34.8,31.3.HRMS(ESI)m / z[M+H] + calcd.for C 20 H 19 N2F4 + 363.1484; found 363.1492.

[0223] Example 50: Preparation of 5-fluoro-4-phenyl-1-(4-methoxyphenyl)-3-trifluoromethyl-1H-pyrazole (L-36)

[0224]

[0225] (Z)-2,2,2-trifluoro-N 1 Compound L-36 was prepared from (4-methoxyphenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl)benzene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f After adding 0.1%, 22.9 mg of yellow liquid was obtained, yield: 68%. 1H NMR (400MHz, CDCl3) δ7.60–7.47(m,2H),7.39(d,J=6.7Hz,3H),7.34–7.27(m,1H),7.20–7.09(m,1H),7.05–6.74(m,2H),3.77(d,J=21.9Hz,3H). 19 F NMR (376MHz, CDCl3) δ-60.95,-131.63. 13 C NMR(101MHz, CDCl3)δ158.7,148.5(d,J=283.9Hz),137.5(qd,J=38.0,9.4Hz),128.7,128.5,128.2,128.0,127.8,127.7,127.1 ,126.2(d,J=4.0Hz),125.6,122.9(d,J=3.2Hz),119.9(qd,J=271.1,2.0Hz),113.6,104.8–99.8(m),54.6.HRMS(ESI)m / z[M+H] + calcd.for C 17 H 13 N2F4O + 337.0964; found 337.0971.

[0226] Example 51: Preparation of 5-fluoro-4-phenyl-1-(4-trifluoromethylphenyl)-3-trifluoromethyl-1H-pyrazole (L-37)

[0227]

[0228] (Z)-2,2,2-trifluoro-N 1 Compound L-37 was prepared from (4-trifluoromethylphenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl)benzene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 17.6 mg of white solid, yield: 47%, melting point: 53–55 °C. 1 H NMR (400MHz, CDCl3) δ7.69 (ddd, J=9.0, 4.7, 1.7Hz, 2H), 7.47 (d, J=4.5Hz, 4H), 7.43–7.38 (m, 1H), 7.23 (t, J=8.1Hz, 2H). 19 FNMR(376MHz, CDCl3)δ-61.20,-67.80,-130.50. 13C NMR (101MHz, CDCl3) δ 149.88 (d, J = 286.7Hz), 139.9 (qd, J = 37.7, 8.7Hz), 139.0, 129.2, 129.1, 128.8, 128.5, 126.9 (q, J = 3.8Hz), 126.5 (dd, J = 7.8, 4.0Hz), 124.9 (d, J = 2.2Hz), 121.7 (d, J = 4.7Hz), 120.7 (qd, J = 271.4, 1.2Hz), 119.4 (q, J = 277.6Hz), 106.8–102.5 (m). HRMS (ESI) m / z [M+H] + calcd.forC 17 H 10 N2F7 + 375.0732; found 375.0725.

[0229] Example 52: Preparation of 5-fluoro-4-phenyl-1-(4-fluorophenyl)-3-trifluoromethyl-1H-pyrazole (L-38)

[0230]

[0231] (Z)-2,2,2-trifluoro-N 1 Compound L-38 was prepared from (4-fluorophenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl)benzene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 13.0 mg of orange liquid, yield: 40%. 1 H NMR (400MHz, CDCl3) δ7.69 (ddd, J=9.0, 4.5, 2.1Hz, 2H), 7.51–7.43 (m, 4H), 7.40 (dq, J=5.3, 2.7Hz, 1H), 7.23 (ddt, J=10.9, 8.8, 2.3Hz, 2H). 19 FNMR (376MHz, CDCl3) δ-61.13, -112.04 (q, J=6.0Hz), -131.13. 13C NMR (101MHz, CDCl3) δ162.3 (d, J = 249.3Hz), 149.6 (d, J = 285.1Hz), 139.2 (qd, J = 37.4, 9.0Hz), 135.8, 132.4, 129.1, 128.8, 128. 4,126.9,124.1(dd,J=8.6,3.8Hz),120.8(qd,J=271.1,1.4Hz),116.6(d,J=23.3Hz),103.6(d,J=13.2Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 10 N2F5 + 325.0764; found 325.0771.

[0232] Example 53: Preparation of 5-fluoro-4-phenyl-1-(4-chlorophenyl)-3-trifluoromethyl-1H-pyrazole (L-39)

[0233]

[0234] (Z)-2,2,2-trifluoro-N 1 Compound L-39 was prepared from (4-chlorophenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl)benzene according to the preparation method in Example 50. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 31.3 mg of white liquid, yield: 92%. 1 H NMR (400MHz, CDCl3) δ7.60 (d, J = 8.4Hz, 2H), 7.48–7.30 (m, 6H), 7.28–7.14 (m, 1H). 19 F NMR(376MHz, CDCl3)δ-61.18,-130.45. 13 C NMR (101MHz, CDCl3) δ149.6 (d, J = 285.6Hz), 139.4 (qd, J = 37.4, 9.0Hz), 134.8 (d, J = 3.0Hz), 134.4, 12 9.8,129.1,128.8,128.4,123.1(d,J=4.1Hz),120.8(qd,J=270.2,2.0Hz),109.9.HRMS(ESI)m / z[M+H] + calcd.for C 16 H 10 N2F4Cl + 341.0469; found 341.0475.

[0235] Example 54: Preparation of 5-fluoro-4-phenyl-1-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole (L-40)

[0236]

[0237] (Z)-2,2,2-trifluoro-N 1 Compound L-40 was prepared from (4-bromophenyl)acetylhydrazidochloro and (Z)-(2-fluoro-2-nitrovinyl)benzene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f After adding 0.1%, 23.5 mg of brown liquid was obtained, yield: 61%. 1 H NMR (400MHz, CDCl3) δ7.69–7.64(m,2H),7.61(dd,J=8.9,1.8Hz,2H),7.46(d,J=4.4Hz,4H),7.42(dd,J=8.2,4.3Hz,1H). 19 F NMR(376MHz, CDCl3)δ-61.20,-130.34. 13 C NMR(101MHz, CDCl3)δ149.6(d,J=286.1Hz),139.8–139.4(qd,J=37.8,9.3Hz),135.3(d,J=3.0Hz),132.8,129.4,12 9.1,128.8,128.4,123.3(d,J=4.3Hz),122.3,120.8(qd,J=270.5,1.5Hz),103.9(d,J=13.1Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 10 N2F4Br + 384.9963; found 384.9957.

[0238] Example 55: Preparation of 5-fluoro-1-phenyl-4-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazole (L-41)

[0239]

[0240] (Z)-2,2,2-trifluoro-N 1 Using phenylacetylhydrazidoyl chloride and (Z)-1-(2-fluoro-2-nitrovinyl)-4-methylbenzene as starting materials, compound L-41 was prepared according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). fAfter adding 0.2 g of solution, 25.6 mg of orange liquid was obtained, yield: 80%. 1 H NMR (400MHz, CDCl3) δ7.67–7.60(m,2H),7.45(td,J=8.0,3.8Hz,2H),7.38–7.32(m,1H),7.29(d,J=7.8Hz,2H),7.23–7.15(m,2H),2.33(s,3H). 19 F NMR(376MHz, CDCl3)δ-61.12,-131.03. 13 C NMR (101MHz, CDCl3) δ149.7 (d, J = 284.6Hz), 139.1 (qd, J = 37.5, 9.0Hz), 138.2, 136.3 (d, J = 2.9Hz), 130.9 (d, J = 7.7Hz), 130.2, 129.6, 129.5, 129.1–128.8(m),128.5,124.0(d,J=4.0Hz),122.1(d,J=3.8Hz),120.9(qd,J=271.1,1.7Hz),103.5(d,J=12.5Hz),21.3.HRMS(ESI)m / z[M+H] + calcd.forC 17 H 13 N2F4 + 321.1015; found 321.1021.

[0241] Example 56: Preparation of 5-fluoro-1-phenyl-4-(3-methylphenyl)-3-trifluoromethyl-1H-pyrazole (L-42)

[0242]

[0243] (Z)-2,2,2-trifluoro-N 1 Using phenylacetylhydrazidoyl chloride and (Z)-1-(2-fluoro-2-nitrovinyl)-3-methylbenzene as starting materials, compound L-42 was prepared according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f After adding 0.1%, 22.4 mg of orange liquid was obtained, yield: 70%. 1 H NMR (400MHz, CDCl3) δ7.69–7.60(m,2H),7.46(t,J=7.7Hz,2H),7.36(t,J=7.4Hz,1H),7.30–7.12(m,4H),2.34(s,3H). 19 F NMR(376MHz, CDCl3)δ-61.06,-130.81. 13C NMR (101MHz, CDCl3) δ149.7 (d, J = 285.2Hz), 139.1 (qd, J = 37.3, 8.8Hz), 138.4, 136.3 (d, J = 2.9Hz), 129.8, 129.6, 129.1, 128.6 (d, J = 7.3Hz),126.9(d,J=4.0Hz),126.2,123.6(qd,J=272.5,1.6Hz),122.1(d,J=3.9Hz),103.7(d,J=13.0Hz),21.5.HRMS(ESI)m / z[M+H] + calcd.for C 17 H 13 N2F4 + 321.1015; found 321.1015.

[0244] Example 57: Preparation of 5-fluoro-1-phenyl-4-(4-tert-butylphenyl)-3-trifluoromethyl-1H-pyrazole (L-43)

[0245]

[0246] (Z)-2,2,2-trifluoro-N 1 Using phenylacetylhydrazidoyl chloride and (Z)-1-(2-fluoro-2-nitrovinyl)-4-tert-butylbenzene as starting materials, compound L-43 was prepared according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 31.9 mg of orange solid, yield: 88%, melting point: 87–89 °C. 1 H NMR (400MHz, CDCl3) δ7.61 (d, J = 7.9 Hz, 2H), 7.42 (dd, J = 20.8, 7.9 Hz, 4H), 7.33 (d, J = 7.9 Hz, 3H), 1.28 (s, 9H). 19 F NMR (376MHz, CDCl3) δ-61.05,-130.81. 13 C NMR (101MHz, CDCl3) δ151.3, 149.7 (d, J = 285.0Hz), 139.0 (qd, J = 37.3, 9.0Hz), 136.4 (d, J = 2.9Hz), 129.6, 128.7, 128.5, 125. 7,124.0(d,J=4.0Hz),122.1(d,J=4.0Hz),121.0(qd,J=270.1,1.2Hz),103.5(d,J=13.2Hz),34.7,31.3.HRMS(ESI)m / z[M+H] +calcd.for C 20 H 19 N2F4 + 363.1484; found 364.1475.

[0247] Example 58: Preparation of 5-fluoro-1-phenyl-4-(4-methoxyphenyl)-3-trifluoromethyl-1H-pyrazole (L-44)

[0248]

[0249] (Z)-2,2,2-trifluoro-N 1 Compound L-44 was prepared from phenylacetylhydrazide chloride and (Z)-1-(2-fluoro-2-nitrovinyl)-4-methoxybenzene according to the preparation method in Example 45. Column chromatography (petroleum ether / ethyl acetate = 100:1, R...) f =0.4) yielded 13.5 mg of brown liquid, yield: 40%. 1 H NMR (400MHz, CDCl3) δ7.68–7.59(m,2H),7.46(td,J=8.1,6.6,1.9Hz,2H),7.35(dd,J=15.9,8.0Hz,3H),7.00–6.88(m,2H),3.79(s,3H). 19 F NMR(376MHz, CDCl3)δ-61.19,-131.32. 13 C NMR (101MHz, CDCl3) δ159.6,149.6(d,J=283.9Hz),139.0(qd,J=37.9,9.5Hz),136.4(d,J=2.6Hz),130.3,129.6,128.5,1 22.1(d,J=3.9Hz),121.0(qd,J=274.7,1.7Hz),119.2(d,J=4.0Hz),114.2,103.3(d,J=14.2Hz),55.3.HRMS(ESI)m / z[M+H] + calcd.for C 17 H 19 N2OF4 + 337.0964; found 337.0972.

[0250] Example 59: Preparation of 5-fluoro-4-(naphth-2-yl)-1-phenyl-3-trifluoromethyl-1H-pyrazole (L-45)

[0251]

[0252] (Z)-2,2,2-trifluoro-N 1 Using phenylacetylhydrazidochloro and (Z)-2-(2-fluoro-2-nitrovinyl)naphthalene as starting materials, compound L-45 was prepared according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f After reacting with 0.1), 28.5 mg of a yellow solid was obtained, yield: 80%, melting point: 53–55 °C. Regioisomer ratio: 5q:5q' = 2.5:1. Major configuration: 1 HNMR (400MHz, CDCl3) δ7.93(ddd,J=9.1,6.6,3.4Hz,2H),7.81–7.72(m,2H),7.53(tq,J=6.3,3.4,2.8Hz,6H),7.46–7.41(m,1H),7.18(d,J=1.7Hz,1H). 19 F NMR (376MHz, CDCl3) δ -61.35 (d, J = 6.9Hz), -61.59, -127.95, -168.12 (q, J = 7.2Hz). 13 C NMR (101MHz, CDCl3) δ 150.2 (d, J = 285.4Hz), 144.8 (d, J = 257.2Hz), 140.7 (qd, J = 37.4, 9.6Hz), 139. 1,136.4(d,J=2.9Hz),133.7,132.3,131.4,130.7,129.8,129.6,129.5,129.3,129.1,128.7,128.6 (d,J=5.2Hz),128.3,127.5,126.72,126.69,126.2,125.3,125.2,125.1,124.7,124.2(d,J=3.3Hz ),123.9,120.6(qd,J=257.3,2.2Hz),122.0(d,J=4.0Hz),101.4(d,J=15.2Hz).HRMS(ESI)m / z[M+H] + calcd.for C 20 H 13 N2F4 + 357.1015; found 357.1006.

[0253] Example 60: Preparation of 5-fluoro-1-phenyl-4-(4-cyanophenyl)-3-trifluoromethyl-1H-pyrazole (L-46)

[0254]

[0255] (Z)-2,2,2-trifluoro-N 1Compound L-46 was prepared from phenylacetylhydrazide chloride and (Z)-1-(2-fluoro-2-nitrovinyl)-4-cyanobenzene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether / ethyl acetate = 5:1, R... f After adding 0.2 g of the mixture, 20.2 mg of a white solid was obtained, yield: 61%, melting point: 104–106 °C. 1 H NMR (400MHz, CDCl3) δ7.69(d,J=8.1Hz,2H),7.62(dd,J=8.0,1.9Hz,2H),7.54(d,J=8.1Hz,2H),7.48(t,J=7.8Hz,2H),7.40(t,J=7.4Hz,1H). 19 F NMR (376MHz, CDCl3) δ-61.03,-129.28. 13 C NMR (101MHz, CDCl3) δ149.8 (d, J = 287.3Hz), 138.9 (qd, J = 38.8, 9.5Hz), 135.9 (d, J = 2.8Hz), 132.6, 131.9 (d, J = 4.3Hz), 129 .7,129.5,129.0,122.2(d,J=3.7Hz),120.7(qd,J=270.2,1.8Hz),118.4,112.1,101.9(d,J=11.4Hz).HRMS(ESI)m / z[M+H] + calcd.forC 17 H 10 N3F4 + 332.0811; found 332.0802.

[0256] Example 61: Preparation of 5-fluoro-1-phenyl-4-(3-cyanophenyl)-3-trifluoromethyl-1H-pyrazole (L-47)

[0257]

[0258] (Z)-2,2,2-trifluoro-N 1 Compound L-47 was prepared from phenylacetylhydrazide chloride and (Z)-1-(2-fluoro-2-nitrovinyl)-3-cyanobenzene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether / ethyl acetate = 5:1, R... f After adding 0.2 g of solution, 19.9 mg of orange liquid was obtained, yield: 60%. 1H NMR (400MHz, CDCl3) δ7.77 (s, 1H), 7.75–7.66 (m, 4H), 7.63–7.52 (m, 3H), 7.47 (dd, J = 8.4, 6.4Hz, 1H). 19 F NMR(376MHz, CDCl3)δ-61.03,-129.89. 13 C NMR (101MHz, CDCl3) δ149.8 (d, J = 286.4Hz), 141.6, 138.8 (qd, J = 37.9, 8.8Hz), 135.9 (d, J = 3.0Hz), 133.4, 132.4, 131.8, 129.8, 129.7, 129.5 ,128.9,128.6(d,J=4.3Hz),122.2(d,J=3.7Hz),120.7(qd,J=271.4,2.0Hz),118.3,113.9,113.2,101.5(d,J=12.3Hz).HRMS(ESI)m / z[M+H] + calcd.for C 17 H 10 N3F4 + 332.0811; found 332.0819.

[0259] Example 62: Preparation of 5-fluoro-1-phenyl-4-(3-trifluoromethylphenyl)-3-trifluoromethyl-1H-pyrazole (L-48)

[0260]

[0261] (Z)-2,2,2-trifluoro-N 1 Using phenylacetylhydrazidoyl chloride and (Z)-1-(2-fluoro-2-nitrovinyl)-4-trifluoromethylbenzene as starting materials, compound L-48 was prepared according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 26.6 mg of orange solid, yield: 71%, melting point: 90–92 °C. 1 H NMR (400MHz, CDCl3) δ7.64(t,J=7.7Hz,4H),7.54(d,J=7.9Hz,2H),7.47(t,J=7.7Hz,2H),7.39(t,J=7.3Hz,1H). 19 FNMR(376MHz, CDCl3)δ-61.06,-62.74,-130.00. 13C NMR(101MHz, CDCl3)δ149.9(d,J=286.5Hz),142.9,138.9(qd,J=38.0,8.8H z),136.1(d,J=2.9Hz),130.8,130.5(d,J=6.4Hz),130.2,129.5(d,J=33.0H z),128.9,125.7(q,J=3.8Hz),124.0(q,J=272.2Hz),122.1(d,J=3.7Hz),1 21.0(qd,J=270.3,2.1Hz),113.6,102.3(d,J=12.8Hz).HRMS(ESI)m / z[M+H] + calcd.for C 17 H 10 N2F7 + 375.0732; found 375.0730.

[0262] Example 63: Preparation of 5-fluoro-1-phenyl-4-(4-fluorophenyl)-3-trifluoromethyl-1H-pyrazole (L-49)

[0263]

[0264] (Z)-2,2,2-trifluoro-N 1 Compound L-49 was prepared from phenylacetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-4-fluorobenzene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 16.5 mg of brown solid, yield: 51%, melting point: 50–53 °C. 1 H NMR (400MHz, CDCl3) δ7.62(dd,J=8.1,1.9Hz,2H),7.46(t,J=7.8Hz,2H),7.37(dd,J=8.3,5.4Hz,3H),7.08(t,J=8.7Hz,2H). 19 FNMR (376MHz, CDCl3) δ -61.16, -113.09 (td, J = 8.5, 4.3Hz), -130.99. 13C NMR (101MHz, CDCl3) δ162.7 (d, J = 248.2Hz), 149.7 (d, J = 285.1Hz), 139.0 (qd ,J=37.6,9.0Hz),136.2(d,J=2.8Hz),130.9(dt,J=8.3,1.5Hz),129.9,129. 7,129.6,129.2(d,J=35.0Hz), 128.7,122.1(d,J=3.8Hz), 120.9(qd,J=270. 1,2.0Hz),115.9(d,J=21.7Hz),113.6,105.9–97.3(m).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 10 N2F5 + 325.0764; found 325.0771.

[0265] Example 64: Preparation of 5-fluoro-1-phenyl-4-(4-chlorophenyl)-3-trifluoromethyl-1H-pyrazole (L-50)

[0266]

[0267] (Z)-2,2,2-trifluoro-N 1 Using phenylacetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-4-chlorobenzene as starting materials, compound L-50 was prepared according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 22.1 mg of orange solid, yield: 65%, melting point: 55–57 °C. 1 H NMR (400MHz, CDCl3) δ7.62 (d, J = 7.8Hz, 2H), 7.46 (t, J = 7.9Hz, 2H), 7.42–7.32 (m, 5H). 19 F NMR(376MHz, CDCl3)δ-61.12,-130.50. 13 C NMR (101MHz, CDCl3) δ149.7 (d, J = 285.7Hz), 142.9, 138.9 (qd, J = 37.9, 8.9Hz), 136.2 (d, J = 2.9Hz), 134.4, 130.3, 129.6, 129.1 ,128.7,125.5(d,J=4.1Hz),122.1(d,J=3.8Hz),120.4(qd,J=270.0,1.8Hz),113.6,102.5(d,J=12.6Hz).HRMS(ESI)m / z[M+H]+ calcd.for C 16 H 10 N2F4Cl + 341.0469; found 341.0476.

[0268] Example 65: Preparation of 5-fluoro-1-phenyl-4-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole (L-51)

[0269]

[0270] (Z)-2,2,2-trifluoro-N 1 Compound L-51 was prepared from phenylacetylhydrazide chloride and (Z)-1-(2-fluoro-2-nitrovinyl)-4-bromobenzene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.2) yielded 33.9 mg of red solid, yield: 88%, melting point: 85–87 °C. 1 H NMR (400MHz, CDCl3) δ7.69(d,J=7.9Hz,2H),7.61(dd,J=11.6,8.3Hz,2H),7.57–7.49(m,2H),7.45(t,J=7.4Hz,1H),7.36(t,J=9.1Hz,2H). 19 F NMR (376MHz, CDCl3) δ-61.09,-130.41. 13 C NMR (101MHz, CDCl3) δ149.6 (d, J = 285.4Hz), 138.9 (qd, J = 37.3, 8.9Hz), 136.1 (d, J = 2.9Hz), 132.8, 132.0, 130.6, 129.6, 128.7, 124. 2(qd,J=288.9,1.0Hz),126.0(d,J=4.1Hz),122.6,122.1(d,J=3.8Hz),108.9(d,J=6.2Hz),102.5(d,J=12.7Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 10 N2F4Br + 384.9963; found 384.9956.

[0271] Example 66: Preparation of 5-fluoro-1-phenyl-4-(thien-2-yl)-3-trifluoromethyl-1H-pyrazole (L-52)

[0272]

[0273] (Z)-2,2,2-trifluoro-N 1 Compound L-52 was prepared from phenylacetylhydrazide chloride and (Z)-2-(2-fluoro-2-nitrovinyl)thiophene according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 10.3 mg of orange liquid, yield: 33%. 1 H NMR (400MHz, CDCl3) δ7.74–7.63(m,2H),7.60–7.48(m,2H),7.48–7.37(m,2H),7.26(s,1H),7.13(dd,J=5.2,3.6Hz,1H). 19 F NMR(376MHz, CDCl3)δ-62.14,-127.39. 13 C NMR(101MHz, CDCl3)δ148.3(d,J=536.9Hz),138.6(qd,J=43.7,10.5Hz),136.1(d,J=2.7Hz),129.9,129.6,128.7,127.8–127.6(m),1 27.5,126.8(d,J=5.5Hz),126.4(d,J=1.4Hz),122.1(d,J=3.8Hz),121.2(qd,J=301.8,3.0Hz),97.4(d,J=3.6Hz).HRMS(ESI)m / z[M+H] + calcd.for C 14 H9N2F4S + 313.0423; found 313.0432.

[0274] Example 67: Preparation of 5-fluoro-1-phenyl-4-(2,6-dimethylhept-5-en-1-yl)-3-trifluoromethyl-1H-pyrazole (L-53)

[0275]

[0276] (Z)-2,2,2-trifluoro-N 1 Using phenylacetylhydrazidoyl chloride and (Z)-1-fluoro-4,8-dimethyl-1-nitronon-1,7-diene as starting materials, compound L-53 was prepared according to the preparation method in Example 45. The compound was then subjected to column chromatography (petroleum ether, R...). f =0.1) yielded 5.0 mg of orange liquid, yield: 14%. 1H NMR (400MHz, CDCl3) δ7.65(d,J=7.9Hz,2H),7.49(t,J=7.7Hz,2H),7.39(t,J=7.4Hz,1H),5.09(t,J=7.2Hz,1H),2.55(dd,J=14.5 ,6.2Hz,1H),2.32(dd,J=14.6,8.5Hz,1H),2.17–1.89(m,2H),1.68(s,3H),1.61(s,3H),1.45–1.26(m,2H),0.92(d,J=6.6Hz,3H). 19 F NMR(376MHz, CDCl3)δ-62.18,-131.08. 13 C NMR (101MHz, CDCl3) δ150.9 (d, J = 281.8Hz), 140.3 (qd, J = 36.9, 10.4Hz), 136.6 (d, J = 2.9Hz), 131.5, 129.4, 128.2, 124.4, 121.8 (d, J = 4.0Hz) ,121.1(qd,J=271.5,1.6Hz),100.7(d,J=15.3Hz),36.7,33.2,29.7,28.7(d,J=3.5Hz),25.6(d,J=20.7Hz),19.3,17.7.HRMS(ESI)m / z[M+H] + calcd.for C 19 H 23 N2F4 + 355.1797; found 355.1800.

[0277] Example 68: Preparation of 4-(3-difluoromethyl-5-fluoro-4-phenyl-1H-pyrrole-1-yl)aniline (L-54)

[0278]

[0279] Step 1: Add (Z)-2,2-difluoro-N to a dry, sealed tube. 1-(N-Boc-aminophenyl)acetylhydrazine chloride (0.15 mmol), (Z)-(2-fluoro-2-nitrovinyl)benzene (0.1 mmol), and Na3PO4 (32.8 mg, 0.2 mmol). 1,2-Dichloroethane (1.0 mL) was transferred into a tube using a syringe. The mixture was stirred at 85 °C for 24 hours. The reaction mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under vacuum, and the residue was subjected to column chromatography (petroleum ether / ethyl acetate = 10:1) to give 5-fluoro-1-(4-N-Boc-aminophenyl)-4-phenyl-3-difluoromethyl-1H-pyrazole.

[0280] Step 2: 10 mmol of 5-fluoro-1-(4-N-Boc-aminophenyl)-4-phenyl-3-difluoromethyl-1H-pyrazole was dissolved in a mixture of hydrochloric acid and ethyl acetate (volume ratio 1:2) and stirred at room temperature for 4 hours. A saturated sodium bicarbonate solution (5 mL) was added, and the solution was diluted with ethyl acetate (EtOAc). The aqueous layer was then extracted three times with ethyl acetate. The organic layers were combined, the mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (petroleum ether / ethyl acetate = 3:1, Rf = 0.5) yielded compound L-5417.3 mg, yield: 57%, melting point: 75–77 °C. 1 H NMR (400MHz, CDCl3) δ7.57(d,J=7.7Hz,2H),7.49–7.38(m,4H),7.35(dd,J=8.4,6.3Hz,1H),6.85–6.53(m,3H),3.87(s,2H). 19 F NMR (376MHz, CDCl3) δ-110.95 (d, J=53.8Hz), -132.19. 13 C NMR (101MHz, CDCl3) δ149.6 (d, J = 283.5Hz), 146.8, 141.9 (td, J = 28.3, 8.6Hz), 128.72, 128.69, 128.1 (d, J = 4.4Hz), 1 27.6,127.5(d,J=2.7Hz),123.9(d,J=2.9Hz),115.2,112.3(t,J=235.1Hz),102.5(d,J=10.8Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 13 N3F3 + 304.1062; found 304.1054.

[0281] Example 69: Preparation of 4-(3-trifluoromethyl-5-fluoro-4-phenyl-1H-pyrrole-1-yl)aniline (L-55)

[0282]

[0283] (Z)-2,2,2-trifluoro-N 1 Using (N-Boc-aminophenyl)acetylhydrazide chloride and (Z)-(2-fluoro-2-nitrovinyl)benzene as starting materials and K₂CO₃ as a base, compound L-55 was prepared according to the preparation method in Example 68. Column chromatography (petroleum ether / ethyl acetate = 3:1, R) was then performed. f =0.3) yielded 10.9 mg of white solid, yield: 34%, melting point: 77–79 °C. 1 H NMR (400MHz, CDCl3) δ7.52–7.34 (m, 7H), 6.75 (d, J = 8.4Hz, 2H), 3.88 (s, 2H). 19 F NMR (376MHz, CDCl3) δ-60.82,-131.81. 13 C NMR (101MHz, CDCl3) δ149.5 (d, J = 283.3Hz), 147.1, 138.2 (qd, J = 37.4, 9.2Hz), 129.1 (t, J = 1.5Hz), 128.7, 128.1, 127.4 (d, J = 4.0Hz),127.2(d,J=2.8Hz),124.1(d,J=2.9Hz),121.0(qd,J=271.0,2.0Hz),115.2,102.9(d,J=13.3Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 12 N3F4 + 322.0967; found 322.0968.

[0284] Example 70: Preparation of 4-(3-difluoromethyl-5-fluoro-4-(4-methylphenyl)-1H-pyrrolo-1-yl)aniline (L-56)

[0285]

[0286] (Z)-2,2-difluoro-N 1 Compound L-56 was prepared from (N-Boc-aminophenyl)acetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-4-methylbenzene according to the preparation method in Example 68. Column chromatography (petroleum ether / ethyl acetate = 3:1, R...) f=0.6) yielded 10.8 mg of white solid, yield: 34%, melting point: 74–76 °C. 1 H NMR (400MHz, CDCl3) δ7.50–7.36(m,4H),7.29–7.22(m,2H),6.83–6.54(m,3H),3.86(s,2H),2.39(s,3H). 19 F NMR (376MHz, CDCl3) δ-111.00 (d, J=53.7Hz), -132.45. 13 C NMR (101MHz, CDCl3) δ149.5 (d, J = 282.7Hz), 146.7, 142.2 (td, J = 28.2, 8.6Hz), 137.5, 129.5, 128.6 (d, J = 1.9Hz), 127.6 (d, J = 2.5Hz),125.1(d,J=4.2Hz),123.9(d,J=2.9Hz),115.2,112.3(t,J=235.2Hz),102.5(d,J=11.5Hz),21.3.HRMS(ESI)m / z[M+H] + calcd.for C 17 H 15 N3F3 + 318.1218; found 318.1224.

[0287] Example 71: Preparation of 4-(3-trifluoromethyl-5-fluoro-4-(4-methylphenyl)-1H-pyrrolo-1-yl)aniline (L-57)

[0288]

[0289] (Z)-2,2,2-trifluoro-N 1 Using α-(N-Boc-aminophenyl)acetylhydrazidochlorochloride and (Z)-1-(2-fluoro-2-nitrovinyl)-4-methylbenzene as starting materials and K2CO3 as a base, compound L-57 was prepared according to the preparation method in Example 68. Column chromatography (petroleum ether / ethyl acetate = 3:1, R...) f =0.3) yielded 15.1 mg of white solid, yield: 45%, melting point: 70–72 °C. 1 HNMR (400MHz, CDCl3) δ7.45–7.39(m,2H),7.36(d,J=7.8Hz,2H),7.29–7.22(m,2H),6.78–6.74(m,2H),3.89(s,2H),2.40(s,3H). 19F NMR(376MHz, CDCl3)δ-60.89,-132.02. 13 C NMR (101MHz, CDCl3) δ149.4(d,J=282.4Hz),146.9,138.2(qd,J=37.3,9.4Hz),137.9,130.9,129.4,128.9,127.3(d,J=2.7Hz ),124.4(d,J=4.0Hz),124.1(d,J=2.9Hz),124.3(qd,J=270.9,1.7Hz),115.2,102.9(d,J=12.8Hz),21.3.HRMS(ESI)m / z[M+H] + calcd.forC 17 H 14 N3F4 + 336.1124; found 336.1132.

[0290] Example 72: Preparation of 4-(3-difluoromethyl-5-fluoro-4-(3-fluoro-4-methoxyphenyl)-1H-pyrrolo-1-yl)aniline (L-58)

[0291]

[0292] (Z)-2,2-difluoro-N 1 Compound L-58 was prepared from (N-Boc-aminophenyl)acetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-3-fluoro-4-methoxybenzene, following the preparation method described in Example 68. The compound was then subjected to column chromatography (petroleum ether / ethyl acetate = 3:1, R... f =0.4) yielded 13.0 mg of white solid, yield: 37%, melting point: 72–74 °C. 1 H NMR (400MHz, CDCl3) δ7.39(d,J=7.1Hz,2H),7.36–7.28(m,2H),7.03(t,J=8.9Hz,1H),6.82–6.52(m,3H),3.93(s,3H),3.75(s,2H). 19 F NMR (376MHz, CDCl3) δ-110.75 (d, J = 53.8Hz), -132.05, -134.78 (dd, J = 11.7, 8.8Hz). 13C NMR (101MHz, CDCl3) δ152.2 (d, J = 245.7Hz), 149.5 (d, J = 283.4Hz), 147.2, 147.1, 146.8, 141.8 (td, J = 28.5, 8.3Hz), 127.4, 124.7, 123.9 (d, J=2.9Hz),121.3–120.5(m),116.6,116.4,115.2,113.5(d,J=2.4Hz),112.5(t,J=234.7Hz),101.2(d,J=10.7Hz),56.3.HRMS(ESI)m / z[M+H] + calcd.for C 17 H 14 N3F4O + 352.1073; found 352.1064.

[0293] Example 73: Preparation of 4-(3-trifluoromethyl-5-fluoro-4-(3-fluoro-4-methoxyphenyl)-1H-pyrrolo-1-yl)aniline (L-59)

[0294]

[0295] (Z)-2,2,2-trifluoro-N 1 Compound L-59 was prepared from (N-Boc-aminophenyl)acetylhydrazyl chloride and (Z)-1-(2-fluoro-2-nitrovinyl)-3-fluoro-4-methoxybenzene using K₂CO₃ as a base, following the preparation method described in Example 68. The compound was then subjected to column chromatography (petroleum ether / ethyl acetate = 3:1, R... f =0.4) yielded 19.9 mg of white solid, yield: 54%, melting point: 71–73 °C. 1 H NMR (400MHz, CDCl3) δ7.32(d,J=8.2Hz,2H),7.14(q,J=11.0,8.2Hz,2H),6.95(t,J=8.7Hz,1H),6.68(d,J=8.2Hz,2H),4.04(s,2H),3.85(s,3H). 19 F NMR(376MHz, CDCl3)δ-60.99,-131.67,-133.61–-136.31(m). 13C NMR (101MHz, CDCl3) δ152.2 (d, J = 246.1Hz), 149.4 (d, J = 283.2Hz), 147.6 (d, J = 10. 5Hz),147.1,139.0,138.0(qd,J=37.2,9.1Hz),127.1(d,J=2.9Hz),125.1,124.1( d, J=2.8Hz), 121.0 (qd, J=271.0, 1.6Hz), 120.1 (dd, J=7.6, 4.2Hz), 116.9 (d, J=19 .7Hz),115.1,113.5(d,J=2.4Hz),101.7(d,J=12.6Hz),56.3.HRMS(ESI)m / z[M+H] + calcd.for C 17 H 13 N3F5O + 370.0979; found 370.0978.

[0296] Example 74: Preparation of 4-(3-difluoromethyl-5-fluoro-4-(4-fluorophenyl)-1H-pyrrolo-1-yl)aniline (L-60)

[0297]

[0298] (Z)-2,2-difluoro-N 1 Compound L-60 was prepared from -(N-Boc-aminophenyl)acetylhydrazidochlorochloride and (Z)-1-(2-fluoro-2-nitrovinyl)-4-fluorobenzene according to the preparation method in Example 68. Column chromatography (petroleum ether / ethyl acetate = 3:1, R...) f =0.3) yielded 11.2 mg of red solid, yield: 35%, melting point: 70–72 °C. 1 H NMR (400MHz, CDCl3) δ7.54(dd,J=8.4,5.4Hz,2H),7.39(d,J=8.2Hz,2H),7.13(t,J=8.4Hz,2H),6.85–6.50(m,3H),3.88(s,2H). 19 F NMR (376MHz, CDCl3) δ-110.69 (d, J=53.8Hz), -114.16 (tt, J=8.6, 5.3Hz), -132.42. 13C NMR (101MHz, CDCl3) δ 162.3 (d, J = 247.3Hz), 149.5 (d, J = 283.0Hz), 146.8, 141.9 (td, J = 28.3, 8.1Hz), 130.5 (dd, J = 8.1, 2.3Hz), 128.7 ,127.6,127.4(d,J=2.6Hz),123.9(d,J=3.0Hz),115.8,115.6,115.2,112.5(t,J=234.7Hz),101.5(d,J=11.5Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 12 N3F4 + 322.0967; found 322.0967.

[0299] Example 75: Preparation of 4-(3-trifluoromethyl-5-fluoro-4-(4-fluorophenyl)-1H-pyrrolo-1-yl)aniline (L-61)

[0300]

[0301] (Z)-2,2-difluoro-N 1 Using α-(N-Boc-aminophenyl)acetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-4-fluorobenzene as raw materials and K2CO3 as base, compound L-61 was prepared according to the preparation method in Example 68. The compound was then subjected to column chromatography (petroleum ether / ethyl acetate = 3:1, R...) f =0.3) yielded 15.9 mg, yield: 47% yield, melting point: 74–76℃. 1 H NMR (400MHz, CDCl3) δ7.50–7.36(m,3H),7.25–7.00(m,3H),6.68(dd,J=56.1,8.7Hz,2H),3.83(s,2H). 19 F NMR(376MHz, CDCl3)δ-60.91,-61.47(d,J=7.1Hz),-110.85(ddd,J=13.7,8.6 ,5.2Hz),-113.44(ddd,J=13.8,8.8,5.3Hz),-131.97,-171.41(q,J=7.0Hz). 13C NMR (101MHz, CDCl3) δ162.5 (d, J = 248.0Hz), 149.4 (d, J = 283.0Hz), 147.1, 138.1 (qd, J = 37.5, 9.1Hz), 130.9 (d, J = 8.8Hz), 127.1 (d ,J=2.7Hz),126.6,124.1(d,J=2.9Hz),123.4(qd,J=284.9,2.8Hz),115.9,115.7,115.2,101.9(d,J=12.8Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 11 N3F5 + 340.0873; found 340.0878.

[0302] Example 76: Preparation of 4-(3-(difluoromethyl)-5-fluoro-4-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide (L-62)

[0303]

[0304] Add (Z)-2,2-difluoro-N to a 10 mL dry, sealed tube 1 -(4-aminosulfonylphenyl)acetylhydrazine chloride (0.15 mmol), (Z)-1-(2-fluoro-2-nitrovinyl)-3-fluoro-4-methoxybenzene (0.1 mmol), and K3PO4 (42.5 mg, 0.2 mmol). DCE (1.0 mL) was added to the tube using a syringe. The mixture was stirred at 85 °C for 24 hours. The combined organic phases were concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether / ethyl acetate = 3:1, R... f =0.2) yielded a white solid L-628.3 mg, yield: 20%, melting point: 100–102℃. 1 H NMR (600MHz, DMSO) δ8.02–7.97(m,2H),7.90(dd,J=8.7,1.4Hz,2H),7.71–7.61(m,1H),7.49(s ,2H),7.35(dd,J=12.2,2.0Hz,1H),7.29(d,J=2.1Hz,1H),7.14(t,J=52.9Hz,1H),3.85(s,3H). 19 F NMR(376MHz, DMSO)δ-112.70(d,J=53.1Hz),-129.08,-132.90–-137.01(m). 13C NMR (101MHz, DMSO) δ151.7 (d, J = 244.3Hz), 150.0 (d, J = 286.6Hz), 147.5 (td, J = 26.9, 10.1Hz), 146.2, 137.2, 127.8 (d, J = 8.9 Hz),122.6(d,J=4.1Hz),117.9(t,J=33.0Hz),113.9,111.8(t,J=236.7Hz),102.1(d,J=11.5Hz),56.6.HRMS(ESI)m / z[M+H] + calcd.for C 17 H 14 N3F4O3S + 416.0692; found 416.0693.

[0305] Example 77: Preparation of 4-(3-(trifluoromethyl)-5-fluoro-4-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide (L-63)

[0306]

[0307] (Z)-2,2,2-trifluoro-N 1 -(4-aminosulfonylphenyl)acetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-3-fluoro-4-methoxybenzene, with K2CO3 as a base, were used to prepare compound L-63 according to the preparation method in Example 76. The residue was subjected to column chromatography (petroleum ether / ethyl acetate = 3:1, R) f =0.2) gave 17.3 mg of yellow solid, yield: 40%, melting point: 55–57 °C. 1 H NMR(400MHz, CDCl3)δ8.10(d,J=8.7Hz,1H),8.00–7.87(m,2H),7.47(d,J=8.6Hz ,1H),7.24–7.13(m,1H),7.11–6.88(m,2H),4.93(d,J=12.3Hz,2H),3.95(s,3H). 19 F NMR (376MHz, CDCl3) δ-61.53, -128.99, -134.24 (dd, J=12.3, 8.4Hz). 13C NMR (101MHz, CDCl3) δ151.4 (d, J = 222.7Hz), 151.1 (d, J = 246.8Hz), 140.9 (d, J = 11.4Hz), 1 40.6,139.0(qd,J=37.7,8.8Hz),138.4(d,J=3.3Hz),127.1,126.8,124.1,120.7(d,J=5.1 Hz),119,5(qd,J=271.8,1.7Hz),117.9–117.7(m),116.8–116.3(m),115.8(d,J=19.8Hz) ,112.8(d,J=2.5Hz),112.5(d,J=2.4Hz),102.2(d,J=15.4Hz),55.2.HRMS(ESI)m / z[M+Na] + calcd.for C 17 H 12 N3O3F5SNa + 456.0417; found 456.0411.

[0308] Example 78: Preparation of 4-(3-(difluoromethyl)-5-fluoro-4-(4-tolyl)-1H-pyrazole-1-yl)benzenesulfonamide (L-64)

[0309]

[0310] (Z)-2,2-difluoro-N 1 Using (4-aminosulfonylphenyl)acetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-4-methylbenzene as starting materials, compound L-64 was prepared according to the preparation method in Example 76. The residue was then subjected to column chromatography (petroleum ether / ethyl acetate = 3:1, R...). f =0.3) to obtain 15.3 mg of solid, yield: 40%, melting point: 96–98 °C. 1 H NMR (400MHz, DMSO) δ7.84(dd,J=7.7,1.8Hz,3H),7.62–7.53(m,5H),7.37(s,2H),7.16(t,J=51.7Hz,1H),2.35(d,J=9.0Hz,3H). 19 F NMR (376MHz, DMSO) δ -112.53 (d, J = 52.9Hz), -129.63. 13C NMR (101MHz, DMSO) δ150.1(d,J=285.4Hz),144.6,144.0,143.4(td,J=26.6,7.6Hz),138.7(d,J=2.9Hz),138.0,132.3,129.9,129 .4,128.9,128.1,127.8,126.0,122.6(d,J=4.0Hz),119.9,112.3(t,J=234.1Hz),103.3(d,J=11.1Hz),21.3.HRMS(ESI)m / z[M+H] + calcd.for C 17 H 15 N3F3O2S + 382.0837; found 382.0831.

[0311] Example 79: Preparation of 4-(3-(trifluoromethyl)-5-fluoro-4-(4-tolyl)-1H-pyrazole-1-yl)benzenesulfonamide (L-65)

[0312]

[0313] (Z)-2,2,2-trifluoro-N 1 -(4-aminosulfonylphenyl)acetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-4-methylbenzene were used as a base, and compound L-64 was prepared according to the preparation method in Example 76. The residue was subjected to column chromatography (petroleum ether / ethyl acetate = 4:1, R) f =0.2) gave 17.6 mg of solid, yield: 24%, melting point: 90–92 °C. 1 H NMR (400MHz, DMSO) δ8.06(d,J=8.7Hz,4H),7.98(d,J=8.3Hz,4H),7.57(s,4H),7.45–7.31(m,8H),2.37(s,6H). 19 F NMR(376MHz,DMSO)δ-60.10,-128.51. 13C NMR (101MHz, DMSO) δ155.2 (d, J = 297.7Hz), 147.1, 144.5 (d, J = 9.2Hz), 142.2 (d, J = 46.6Hz), 138.2 (qd, J = 34.6, 4.2Hz), 133.5, 132.3 (d, J = 5.2Hz), 130.2 (d, J = 48.7Hz), 129.4, 126.1, 123.0 (d, J = 3.9Hz), 121.8, 119.9, 122.3 (qd, J = 296.4, 3.7Hz), 103.7 (d, J = 2.2Hz), 21.3, 21.2.

[0314] Example 80: Preparation of 4-(2-(difluoromethyl)-5-fluoro-4-(4-fluorophenyl)-1H-pyrazol-1-yl)benzenesulfonamide (L-66)

[0315]

[0316] (Z)-2,2-difluoro-N 1 Using (4-aminosulfonylphenyl)acetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-4-fluorobenzene as starting materials, compound L-66 was prepared according to the preparation method in Example 76. The residue was subjected to column chromatography (petroleum ether / ethyl acetate = 3:1, R...) f =0.3) gave 11.6 mg of solid, yield: 30%, melting point: 102–104 °C. 1 H NMR (400MHz, DMSO) δ8.05 (d, J=8.4Hz, 1H), 7.96 (dd, J=8.8, 1.6Hz, 1H), 7.83 (dd, J= 7.6,1.9Hz,4H),7.64–7.51(m,10H),7.37(d,J=4.8Hz,4H),7.19(t,J=53.0Hz,2H). 19 F NMR (376MHz, DMSO) δ -110.55, -112.45 (d, J = 52.8Hz), -113.51, -114.33 (d, J = 53.0Hz), -129.35, -173.30. 13C NMR (101MHz, DMSO) δ162.3 (d, J = 245.5Hz), 150.2 (d, J = 285.4Hz), 144.6, 144.1, 143.3 (qd, J = 28.1, 8.1Hz), 138.6 (d, J = 2.8Hz), 132.3, 131.2 (d,J=8.3Hz),129.4,127.9,126.1,122.6(d,J=4.0Hz),116.4(d,J=21.7Hz),112.4(t,J=234.1Hz),102.3(d,J=11.4Hz).HRMS(ESI)m / z[M+H] + calcd.for C 16 H 12 N3O2F4S + 386.0586; found 386.0592.

[0317] Example 81: Preparation of 4-(2-(difluoromethyl)-5-fluoro-4-(4-fluorophenyl)-1H-pyrazol-1-yl)benzenesulfonamide (L-66)

[0318]

[0319] (Z)-2,2,2-trifluoro-N 1 Using (4-aminosulfonylphenyl)acetylhydrazidochloro and (Z)-1-(2-fluoro-2-nitrovinyl)-4-fluorobenzene as raw materials and K2CO3 as base, compound L-67 was prepared according to the preparation method in Example 76. The residue was subjected to column chromatography (petroleum ether / ethyl acetate = 4:1, R...) f =0.2) 12.9 mg of solid was obtained, yield: 30%, melting point: 89–90 °C. 1 H NMR (400MHz, DMSO) δ8.06(d,J=8.7Hz,4H),7.98(d,J=8.3Hz,4H),7.57(s,4H),7.45–7.31(m,8H),2.37(s,6H). 19 F NMR(376MHz,DMSO)δ-60.10,-128.51. 13C NMR (101MHz, DMSO) δ155.2 (d, J = 297.7Hz), 147.1, 144.5 (d, J = 9.2Hz), 142.2 (d, J = 46.6Hz), 138.2 (qd, J = 34.6, 4.2Hz), 133.5, 132.3 (d, J = 5.2Hz), 130.2 (d, J = 48.7Hz), 129.4, 126.1, 123.0 (d, J = 3.9Hz), 121.8, 119.9, 122.3 (qd, J = 296.4, 3.7Hz), 103.7 (d, J = 2.2Hz), 21.3, 21.2.

[0320] Example 82: N 1 Applications of aryl-3-fluoroalkyl-5-fluoropyrazole compounds - Anti-inflammatory activity experiments

[0321] Compounds L56 to L67 from the examples were selected for anti-inflammatory activity testing.

[0322] 1) Cell culture: RAW264.7 cells were cultured in high-glucose DMEM complete medium containing 10% FBS. When the cell density reached 80% to 90%, the cells were scraped off with a disposable cell scraper and passaged at a density of 1:3.

[0323] 2) Cell plating: Cells were laid at a density of 4 × 10⁻⁶. 7 Add each sample to a six-well plate and incubate overnight at 37°C with 5% CO2.

[0324] 3) Cell modeling and drug administration: Prepare a culture medium containing 1 μg / mL LPS (lipopolysaccharide) as a stock solution. Dissolve the compounds in DMSO to prepare a 1 mM stock solution. Using the LPS-containing stock solution as a diluent, dissolve compounds L56-L67 from the examples and the positive control Celebrex at specific concentrations. The final concentration of both Celebrex and the examples compounds was 10 μM.

[0325] Add the prepared solutions to the corresponding well plates and incubate them in a 37°C incubator with 5% CO2 for 48 hours.

[0326] 4) Protein extraction and Western blotting: Remove the plate, wash once with PBS, add 200 μL of protein lysis buffer RIPA, react at low temperature for 30 minutes, aspirate and transfer to a centrifuge tube, centrifuge at 14000 rpm for 10 minutes, aspirate the supernatant, perform protein quantification, adjust the protein concentration, prepare the protein to the corresponding loading volume, add loading buffer, boil the sample, and place in a 4℃ refrigerator for later use.

[0327] Prepare the appropriate lower gel according to protein size. Add freshly prepared electrophoresis buffer to the inner layer and recycled electrophoresis buffer to the outer layer. Run the gel at 90V for 20 minutes, then switch to 120V for 90 minutes. Transfer conditions are 240mA for 120 minutes. Remove the membrane and place it in 5% skim milk powder. Shake for 1 hour, then add the corresponding antibody. Incubate overnight at 4°C. Afterward, remove the membrane and wash it three times with TBST for 15 minutes each time. Add secondary antibody and shake at room temperature for 1 hour, then remove the membrane and wash it three times with TBST for 15 minutes each time.

[0328] Activity test results:

[0329] Test results are as follows Figure 1 As shown, COX-2 protein expression was significantly upregulated in the model group, proving the successful establishment of the cellular inflammation model (###, P<0.001). After administration of equal concentrations of the positive control drug Celebrex and compounds L56-L67 from the examples, COX-2 protein expression in each treatment group was significantly downregulated compared to the model group, proving that the compounds from the examples have significant anti-inflammatory activity (***, P<0.001). Among them, compared with the positive control drug Celebrex, compounds L56, L57, L58, L61, L62, L63, L64, L65, and L66 from the examples showed more significant COX-2 protein inhibitory activity (Δ, P<0.05).

[0330] The above results show that the obtained N 1 Preliminary anti-inflammatory activity tests of aryl-3-fluoroalkyl-5-fluoropyrazole compounds revealed that they exhibited good inhibitory effects on COX2, a key protein in a rheumatoid arthritis model. Furthermore, several tested compounds showed better efficacy than the positive control drug Celebrex, indicating good potential for further drug development.

[0331] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A kind of N 1 -aryl-3-fluoroalkyl-5-fluoropyrazole compound, characterized in that The structural formulas are selected from formulas L-56, L-57, L-58, L-61, L-62, L-63, L-65, and L-66: 。 2. The N according to claim 1 1 Application of aryl-3-fluoroalkyl-5-fluoropyrazole compounds in the preparation of anti-inflammatory drugs.

3. The N according to claim 1 1 Application of aryl-3-fluoroalkyl-5-fluoropyrazole compounds in the preparation of drugs that inhibit COX2 protein.

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