CN104592116B - 1,3,5-trisubstituted pyrazole compounds, and preparation method and application thereof - Google Patents

Abstract

The invention discloses 1,3,5-trisubstituted pyrazole compounds, and a preparation method and application thereof. The structure of the compounds is shown as a general formula (I), and in the general formula (I), R1 is hydrogen, halogens, methyl or trifluoromethyl, R2 is methyl, ethyl, n-propyl, cyclopropyl, or C4-C8 aliphatic chain hydrocarbon or cyclohydrocarbon, R3, R4, R5, R6 or R7 is hydrogen, halogens, methyl, trifluoromethyl, methoxyl, trifluoromethoxyl, ethynyl, nitro or nitrile group, and X is carbonyl, amido, ureido or thioureido. The 1,3,5-trisubstituted pyrazole compounds, especially 8aM06, 8aM21, 8aM23, 8aM25, 8aM26, 8aE02, 8aE08, 8aE10, 8eE01 and 8cE01, all have relatively strong cell growth inhibiting activity on prostate cancer cells LNCaP and PC-3, and are applicable to prepare antitumor medicaments.

Description

1,3,5-trisubstituted pyrazole compounds and their preparation methods and applications

technical field

The invention relates to the field of organic compound synthesis and medical application, in particular to 1,3,5-trisubstituted pyrazole compounds and their preparation method and application.

Background technique

Prostate cancer (PCa) is a common tumor that threatens men's health. In the past decade, the incidence of PCa in my country has shown an obvious upward trend, and has become one of the fastest-growing tumors. Most prostate cancer cells need to grow and proliferate under the stimulation of androgen, so androgen deprivation therapy (ADT, also known as castration therapy) is currently the first-line treatment for prostate cancer in clinical practice. Androgen ablation therapy blocks the action of androgen on cancer cells by blocking the production of androgen and blocking the binding of endogenous androgen to the androgen receptor (AR) on the target organ (AR antagonist). inhibit its growth. However, after 12 to 18 months of treatment, almost all prostate cancer patients who initially respond to ADT will relapse. Even if the serum testosterone is at the castration level, the patient's tumor will still progress. This stage is called castration-resistant prostate cancer. (castration resistance prostate cancer, CRPC).

AR antagonists play an important role in the treatment of prostate cancer. AR antagonists compete with androgen receptors to inhibit the effect of androgen on target organs, thereby inhibiting the growth of tumor cells. At present, there are few types of AR antagonists used clinically, and they can be divided into steroids and non-steroids according to their chemical structures. Non-steroidal AR antagonists are widely used clinically because of their small side effects, including flutamide (Flutamide) , Nilutamide, Bicalutamide, Enzalutamide. Prostate cancer patients will develop resistance after taking the above drugs for a period of time, manifested as a continuous increase in the level of prostate-specific antigen (PSA) and tumor progression, which may be related to the similar chemical structures of the above drugs. Therefore, there is an urgent clinical need to research and develop non-steroidal androgen receptor antagonists with new chemical structures.

Contents of the invention

Aiming at the above-mentioned prior art, the present invention provides a kind of pyrazole non-steroidal androgen receptor antagonist with anti-prostate cancer activity—1,3,5-trisubstituted pyrazole compound, and the present invention also provides this kind of Process for the preparation of compounds and their use in pharmacy.

The present invention is achieved through the following technical solutions:

1,3,5-trisubstituted pyrazole compounds, the structure of which is shown in general formula (I):

Wherein, R is hydrogen, halogen, methyl or trifluoromethyl; R is methyl, ethyl, _{n -} propyl, isopropyl, cyclopropyl or an aliphatic hydrocarbon chain or ring with 4-8 carbons; R ₃ , R ₄ , R ₅ , R ₆ or R ₇ have the same or different structures and are all derived from the following groups: hydrogen, halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy, acetylene Base, nitro or nitrile; X is carbonyl, amido, urea, thiourea.

Preferably, R ₁ is para-position fluorine, chlorine, bromine, methyl or trifluoromethyl; R ₂ is methyl, ethyl; R ₃ , R ₄ , R ₅ , R ₆ or R ₇ have the same structure or Different, all derived from the following groups: hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, ethynyl, nitro or nitrile; X is carbonyl, amido .

Further preferably, the 1,3,5-trisubstituted pyrazole compounds of the present invention include but are not limited to one of the following compounds:

1-Methyl-3-(4-fluorophenyl)-1H-pyrazole-5-p-methylbenzophenone (7aM01);

1-methyl-3-(4-bromophenyl)-1H-pyrazole-5-p-methylbenzophenone (7cM01);

N-phenyl-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM01);

N-(2-bromophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM02);

N-(3-bromophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM03);

N-(4-bromophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM04);

N-(2-trifluoromethylphenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM05);

N-(3-(trifluoromethyl)phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM06);

N-(4-(trifluoromethyl)phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM07);

N-(2-cyanophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM08);

N-(3-cyanophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM09);

N-(4-cyanophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM10);

N,3-bis(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (8aM11);

N-(4-trifluoromethoxyphenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM12);

N-(p-tolyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM13);

N-(3-nitrophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM14);

N-(3-ethynylphenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM15);

N-(4-cyano-1-methyl-3-(trifluoromethyl)phenyl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM16);

N-(2,3,4-trifluorophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM17);

N-(3-chloro-4-fluorophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM18);

N-(3-chloro-2-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (8aM19);

N-(3-chloro-4-cyanophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM20);

N-(4-cyano-3-methoxy)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM21);

N-(3,4-dicyanophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM22);

N-(4-chloro-3-(trifluoromethyl)phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM23);

N-(2-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM24);

N-(4-bromo-3-(trifluoromethyl)phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM25);

N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM26);

N-(3-bromo-4-methylphenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM27);

N-(3-bromo-2-methylphenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM28);

N-(3-bromo-4-fluorophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM29);

N-(p-tolyl)-1-methyl-3-(4-chlorophenyl)-1H-pyrazole-5-carboxamide (8bM01);

N-(3-(trifluoromethyl)phenyl)-1-methyl-3-(4-chlorophenyl)-1H-pyrazole-5-carboxamide (8bM02);

N-(3-(trifluoromethyl)phenyl)-1-methyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxamide (8cM01);

N-(4-fluorophenyl)-1-methyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxamide (8cM02);

N-(3-bromophenyl)-3-(4-bromophenyl)-1-methyl-1H-pyrazole-5-carboxamide (8cM03);

N-(p-tolyl)-1-methyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxamide (8cM04);

N-phenyl-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE01);

N-(3-fluorophenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE02);

N,3-bis(4-fluorophenyl)-1-ethyl-1H-pyrazole-5-carboxamide (8aE03);

N-(4-chlorophenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE04);

N-(4-methylphenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE05);

N-(3-bromophenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE06);

N-(4-bromophenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE07);

N-(3-trifluoromethylphenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE08);

N-(4-trifluoromethylphenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE09);

N-(3-chlorophenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE10);

N-phenyl-1-ethyl-3-p-tolyl-1H-pyrazole-5-carboxamide (8dE01);

N-(3-bromophenyl)-1-ethyl-3-p-tolyl-1H-pyrazole-5-carboxamide (8dE02);

N-(4-bromophenyl)-1-ethyl-3-p-tolyl-1H-pyrazole-5-carboxamide (8dE03);

N-(4-chlorophenyl)-1-ethyl-3-p-tolyl-1H-pyrazole-5-carboxamide (8dE04);

N-(3-trifluoromethylphenyl)-1-ethyl-3-p-tolyl-1H-pyrazole-5-carboxamide (8dE05);

N-(4-trifluoromethylphenyl)-1-ethyl-3-p-tolyl-1H-pyrazole-5-carboxamide (8dE06);

N-(3-trifluoromethylphenyl)-1-ethyl-3-(4-trifluoromethylphenyl)-1H-pyrazole-5-carboxamide (8eE01);

N-(3-trifluoromethylphenyl)-1-ethyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxamide (8cE01).

The brackets behind the names of the above-mentioned preferred 55 compounds are their corresponding codes. For the convenience of narration, the codes in the above brackets will be directly used in the following contents of this description.

The preparation method of the above-mentioned 1,3,5-trisubstituted pyrazole compounds:

The preparation method of 1,3,5-trisubstituted pyrazole compounds of the present invention comprises the following steps (the synthetic route is as follows):

synthetic route:

Wherein, R is hydrogen, halogen, methyl or trifluoromethyl; R is methyl, ethyl, _{n -} propyl, isopropyl, cyclopropyl or an aliphatic hydrocarbon chain or ring with 4-8 carbons; R ₃ , R ₄ , R ₅ , R ₆ or R ₇ have the same or different structures and are all derived from the following groups: hydrogen, halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy, acetylene group, nitro group or nitrile group. Preferably, R ₁ is para-position fluorine, chlorine, bromine, methyl or trifluoromethyl; R ₂ is methyl, ethyl; R ₃ , R ₄ , R ₅ , R ₆ or R ₇ are hydrogen, Fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, ethynyl, nitro or nitrile.

Reagents and reaction conditions: (i) diethyl oxalate, EtOH, EtONa; (ii) hydrazine hydrate, EtOH, AcOH; (iii) dimethyl sulfate or diethyl sulfate, NaH, DMF; (iv) KOH, EtOH (v) SOCl ₂ , DMF, THF; (vi) AlCl ₃ , CH ₂ Cl ₂ , substituted benzene; (vii) pyridine, THF, substituted aniline.

Further, the specific steps are as follows:

(i) Preparation of sodium ethoxide: get 2.4～4.8g sodium hydride and add in 50～60ml dehydrated ethanol in portions, stir and reflux until the system is clarified to obtain the ethanol solution of sodium ethoxide, the mass of sodium hydride and dehydrated alcohol The ratio is (1～2):20;

Synthesis of β-diketoester: Weigh a certain amount of substituted acetophenone and diethyl oxalate, add them to absolute ethanol, then slowly add ethanol solution of sodium ethoxide dropwise to the solution, after adding, heat up to 70~ React at 80°C for 5 to 7 hours. When the unsubstituted acetophenone is detected by TLC, the reaction is complete, and the system is reddish brown at this time; stop heating, evaporate the solvent under reduced pressure, and obtain a dark reddish brown viscous substance, which is transferred to ice water , adjust the pH value to 1, stir for 30-40min, filter, and wash the filter cake with ice ethanol to obtain intermediate compound 2: β-diketonate, substituted acetophenone, sodium ethoxide, diethyl oxalate in molar ratio Is 1: (1～2): (1～2), the mass ratio of described diethyl oxalate, dehydrated alcohol, ice water is 1: (3～4): (9～12);

(ii) Weigh the intermediate compound 2: β-diketonate, add absolute ethanol to dissolve it, then add hydrazine hydrate and glacial acetic acid with a mass concentration of 80%, reflux at 90 to 95°C for 3 to 5 hours, and use When no intermediate compound 2 was detected by TLC, the reaction was complete; the system was evaporated to remove the solvent under reduced pressure to obtain a white yellowish solid; it was transferred to water, stirred, filtered, and dried to obtain a white solid, which was intermediate compound 3, intermediate The molar ratio of compound 2 to hydrazine hydrate is 1: (1-2), and the mass ratio of the hydrazine hydrate, absolute ethanol and glacial acetic acid is (6.3-12.6): (80-100): (1-1.5);

(iii) Weigh the intermediate compound 3, add DMF and stir until the solid is completely dissolved, add sodium hydride under ice bath, and stir for 10-15 minutes. After the suspension becomes clear, slowly add dimethyl sulfate or bisulphate Ethyl ester, reacted for 8-15 minutes, when no intermediate compound 3 was detected by TLC, the reaction was completed, the system was poured into ice water, and a white solid 2 was precipitated, extracted 3-4 times with ethyl acetate, the organic layers were combined, washed, and dried , evaporated the solvent under reduced pressure, separated and purified by column chromatography to obtain intermediate compound 4, the elution system was petroleum ether: ethyl acetate = 9: 1, intermediate compound 3: sodium hydride: dimethyl sulfate or diethyl sulfate The molar ratio of ester is 1: (1～1.5): (1～1.5), the mass ratio of described sodium hydride and DMF is 3～5:1000;

(iv) Weigh the intermediate compound 4, add ethanol with a mass concentration of 95%, stir well to dissolve the solid completely; add a KOH aqueous solution with a mass concentration of 10%, reflux at 90-95°C for 3-5 hours, and detect with TLC When there is no intermediate compound 4, the reaction is complete; the ethanol is evaporated under reduced pressure, the pH value is adjusted to 2, and a white solid 3 is precipitated, filtered, and the filter cake is washed with distilled water to obtain intermediate compound 5, the intermediate compound 4, ethanol, The mass ratio of KOH aqueous solution is (9～12): (3～5): (1～3);

(v) Weigh the intermediate compound 5, add DMF and anhydrous THF to dissolve it completely, slowly add thionyl chloride dropwise under ice-bath conditions, react at 50-60°C for 1-3 hours, after the reaction is completed, evaporate under reduced pressure Remove solvent to obtain intermediate compound 6, the mol ratio of described intermediate compound 5, thionyl chloride is 1: (1～2.5); The mass ratio of described thionyl chloride, DMF, anhydrous THF is (0.1- 0.4):(0.1～0.15):(10～15);

(vi) Dissolving the substituted benzene in redistilled CH ₂ Cl ₂ , adding AlCl ₃ in portions under ice-bath conditions, stirring evenly, dissolving the acid chloride intermediate compound 6 prepared in step (v) in redistilled CH ₂ Cl ₂ , Slowly drop into the reaction mixture, react at room temperature for 6 hours, after the reaction is completed, slowly pour the system into ice water, adjust the pH to 14, extract three times with ethyl acetate, combine the organic layers, wash, dry, filter, and evaporate the solvent under reduced pressure. The target compound 7 was separated and purified by silica gel column chromatography. The elution system was petroleum ether: ethyl acetate = (6-10): 1, and the molar ratio of acid chloride, substituted benzene and AlCl3 was ₁ : (0.5-1): (2-3), the mass ratio of AlCl ₃ , redistilled CH ₂ Cl ₂ and ice water is (0.2-0.4):(10-15):(50-80).

(vii) Take substituted aniline and redistilled pyridine, add heavy steamed THF until the solids are completely dissolved, and dissolve the acid chloride intermediate compound 6 prepared in step (v) with redistilled THF under stirring in an ice bath, and drop it into the reaction mixture , stirred for 2 to 2.5 hours, and when the unsubstituted aniline and redistilled pyridine were detected by TLC, the reaction was completed, and the solvent was evaporated under reduced pressure to obtain a reddish-brown viscous substance, which was added to a mixed solution of ethyl acetate and water, and then Extracted 3 times with ethyl acetate, combined the organic phases, washed, dried, filtered, the filtrate was evaporated to remove the solvent under reduced pressure, and the target compound 8 was separated and purified by silica gel column chromatography, and the elution system was petroleum ether: ethyl acetate=(6～ 10):1, the molar ratio of substituted aniline, acid chloride and pyridine is (0.8-1.5):1:1.

Preferably, in the above step (i), the substituted acetophenone is p-fluoroacetophenone, p-chloroacetophenone, p-bromoacetophenone, p-methylacetophenone, p-trifluoromethylacetophenone

Preferably, in the above step (ii), the β-diketonate intermediate compound 2 is ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate, 4-(4-chlorobenzene Base)-2,4-dioxobutanoic acid ethyl ester, 4-(4-bromophenyl)-2,4-dioxobutanoic acid ethyl ester, 4-(4-methylphenyl)-2, Ethyl 4-dioxobutyrate, ethyl 4-(4-trifluoromethylphenyl)-2,4-dioxobutyrate.

Preferably, in the above step (iii), the intermediate compound 3 is ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate, 3-(4-chlorophenyl)-1H-pyrazole -ethyl 5-carboxylate, ethyl 3-(4-bromophenyl)-1H-pyrazole-5-carboxylate, ethyl 3-(4-methylphenyl)-1H-pyrazole-5-carboxylate, 3-(4-Trifluoromethylphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester.

Preferably, in the above step (iv), the intermediate compound 4 is ethyl 1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate, 1-ethyl-3-(4 -Fluorophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester, 1-methyl-3-(4-chlorophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester, 1-methyl-3- (4-Bromophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester, 1-ethyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester, 1-ethyl- 3-(4-Methylphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester, 1-ethyl-3-(4-trifluoromethylphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester .

Preferably, in the above step (v), the intermediate compound 5 is 1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxylic acid, 1-ethyl-3-(4-fluoro Phenyl)-1H-pyrazole-5-carboxylic acid, 1-methyl-3-(4-chlorophenyl)-1H-pyrazole-5-carboxylic acid, 1-methyl-3-(4-bromophenyl )-1H-pyrazole-5-carboxylic acid, 1-ethyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxylic acid, 1-ethyl-3-(4-methylphenyl) -1H-pyrazole-5-carboxylic acid, 1-ethyl-3-(4-trifluoromethylphenyl)-1H-pyrazole-5-carboxylic acid.

Preferably, in the above step (vi), the intermediate compound 6 is 1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carbonyl chloride, 1-ethyl-3-(4- Bromophenyl)-1H-pyrazole-5-carbonyl chloride, substituting benzene with toluene.

Preferably, in the above step (vii), the intermediate compound 6 is 1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carbonyl chloride, 1-ethyl-3-(4- Fluorophenyl)-1H-pyrazole-5-carbonyl chloride, 1-methyl-3-(4-chlorophenyl)-1H-pyrazole-5-carbonyl chloride, 1-methyl-3-(4- Bromophenyl)-1H-pyrazole-5-formyl chloride, 1-ethyl-3-(4-bromophenyl)-1H-pyrazole-5-formyl chloride, 1-ethyl-3-p-tolyl -1H-pyrazole-5-formyl chloride, 1-ethyl-3-(4-trifluoromethylphenyl)-1H-pyrazole-5-formyl chloride, the substituted aniline is aniline, 2-bromoaniline, 3 -Bromoaniline, 4-bromoaniline, 2-trifluoromethylaniline, 3-trifluoromethylaniline, 4-trifluoromethylaniline, 2-cyanoaniline, 3-cyanoaniline, 4-cyanoaniline , 4-methylaniline, 3-fluoroaniline, 4-fluoroaniline, 3-chloroaniline, 4-chloroaniline, 4-trifluoromethoxyaniline, 3-nitroaniline, 3-ethynylaniline, 3- Trifluoromethyl-4-cyanoaniline, 3-chloro-4-fluoroaniline, 2-fluoro-3-chloroaniline, 3-chloro-4-cyanoaniline, 3-methoxy-4-cyanoaniline, 3,4-Dicyanoaniline, 3-trifluoromethyl-4-chloroaniline, 2-fluoro-5-trifluoromethylaniline, 3-trifluoromethyl-4-bromoaniline, 3-trifluoromethylaniline Base-4-fluoroaniline, 3-bromo-4-aniline, 2-methyl-3-bromoaniline, 3-bromo-4-fluoroaniline, 2,3,4-trifluoroaniline.

The 1,3,5-trisubstituted pyrazole compounds of the present invention, especially 8aM06, 8aM21, 8aM23, 8aM25, 8aM26, 8aE02, 8aE08, 8aE10, 8eE01 and 8cE01 have strong effects on prostate cancer cells LNCaP and PC-3 The cell growth inhibitory activity can be used to prepare antitumor drugs.

Compared with the prior art, the excellent effect of the present invention is: the present invention has synthesized 1,3,5-trisubstituted pyrazole compounds with different structures, and the innovation point is that it has the ability to antagonize the androgen receptor and prostatic cell growth Structurally novel pyrazole derivatives for inhibition. The growth inhibitory activity of prostate cancer cells was evaluated using the conventional tetramethylazolazolium blue colorimetric method (MTT method), and the antagonistic activity of the androgen receptor was determined by measuring the target gene prostate-specific antigen (PSA) in LNCaP cells. The percentage of down-regulated expression level was evaluated, and the results are shown in Table 1.

The results of activity experiments show that the 1,3,5-trisubstituted pyrazole compounds of the present invention have obvious cell growth inhibitory activity on prostate cancer cells LNCaP and PC-3, and have certain antagonistic activity on androgen receptor. The AR antagonistic activity of the compound whose linking chain X is a carbonyl group is better than that of the corresponding amide group as a linking chain compound, and when the meta-position of the benzene ring on the 5-position substituent of the pyrazole ring has bromine, trifluoromethyl, nitro or cyano group, AR The antagonistic activity is better. When the benzene ring at the 3-position of the pyrazole ring is para-fluorine, bromine or trifluoromethyl, it has AR antagonistic activity, and the trifluoromethyl activity is the best. Compounds 8aM06, 8aM21, 8aM23, 8aM25, 8aM26, 8aE02, 8aE08, 8aE10, 8eE01 and 8cE01 were significantly superior to the positive control drugs MDV3100 and Bicalutamide in inhibiting the growth of prostate cancer cells LNCaP and PC-3. In addition, the androgen receptor antagonistic activity of the above compounds is weaker than that of the positive control drugs, which suggests that 1,3,5-trisubstituted pyrazoles not only block AR by binding to AR competitively with endogenous androgen DHT Signaling pathways to inhibit the growth of prostate cancer cells, and also exert prostate cancer cell growth inhibitory activity through other signaling pathways.

Table 11, the number, structure and activity test results of 3,5-trisubstituted pyrazole compounds

detailed description

The present invention will be further described below in conjunction with the examples for a deeper understanding of the present invention and its advantages and effects, but the examples are only used to illustrate the present invention rather than limit the present invention.

Methods and reagents not described in detail in the examples are conventional methods and reagents in the field.

The synthesis of embodiment 1 intermediate compound β-diketonate 2a-2e

(1) Preparation of sodium ethylate

Add 50ml of absolute absolute ethanol into a 250ml two-necked flask connected with a reflux device, under stirring, add 4.8g (0.2mol, 2eq) of sodium hydride in portions, and stir until the system is clear.

(2) Synthesis of β-diketoesters

Weigh 0.1mol (1eq) of substituted acetophenone and 0.2mol (29.2g, 2eq) of diethyl oxalate in a 250ml three-necked flask, add 100ml of absolute absolute ethanol, and slowly add the newly prepared ethanol solution of sodium ethoxide dropwise, After the addition was completed, the temperature was raised to 70° C. for 5 hours of reaction. TLC detected that no raw material was substituted for acetophenone. After the reaction, the system was reddish brown. Heating was stopped, and the solvent was evaporated under reduced pressure to obtain a dark reddish-brown viscous substance, which was transferred to 200ml ice water with about 100ml of water, adjusted to pH 1 with 8ml of concentrated hydrochloric acid, stirred for 30min, filtered, and the filter cake was washed with ice ethanol.

The substituted acetophenone used is p-fluoroacetophenone, p-chloroacetophenone, p-bromoacetophenone, p-methylacetophenone and p-trifluoromethylacetophenone, correspondingly, the obtained β-diketonate (2a-2e) are ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate and ethyl 4-(4-chlorophenyl)-2,4-dioxobutyrate , 4-(4-bromophenyl)-2,4-dioxobutanoic acid ethyl ester, 4-(4-methylphenyl)-2,4-dioxobutanoic acid ethyl ester, 4-(4 -Ethyl trifluoromethylphenyl)-2,4-dioxobutyrate, specifically as follows:

Ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate (2a): yellow-white solid, Mp: 46.0-47.5℃, MS(ESI) m/z calcd for C ₁₂ H ₁₁ FO ₄ :238.1,found:239.3[M+H] ⁺ .

4-(4-Chlorophenyl)-2,4-dioxobutanoic acid ethyl ester (2b): yellow-white solid, Mp: 59.0-60.0℃, MS(ESI) m/zcalcd for C ₁₂ H ₁₁ ClO ₄ :254.0,found:255.3[M+H] ⁺ .

4-(4-Bromophenyl)-2,4-dioxobutanoic acid ethyl ester (2c): yellow-white solid, Mp: 65.0-66.0℃, MS(ESI) m/z calcd for C ₁₂ H ₁₁ BrO ₄ :298.1,found:299.4[M+H] ⁺ .

4-(4-Methylphenyl)-2,4-dioxobutanoic acid ethyl ester (2d): yellow-white solid, Mp: 47.0-48.0℃, MS(ESI) m/z calcd for C ₁₃ H ₁₄ O ₄ :234.1,found:235.3[M+H] ⁺ .

4-(4-Trifluoromethylphenyl)-2,4-dioxobutanoic acid ethyl ester (2e): yellow-white solid, Mp: 50.0-51.0℃, MS(ESI) m/z calcd for C ₁₃ H ₁₁ F ₃ O ₄ :288.1,found:289.2[M+H] ⁺ .

The preparation of embodiment 2 intermediate compound 3

Weigh 0.1mol (1eq) of intermediate compound β-diketone ester 2 in a 250ml round bottom flask, add 6.3g (1eq) of 80% hydrazine hydrate, add 100ml of absolute ethanol and 1ml of glacial acetic acid, and reflux at 90°C for 3 Hours, no intermediate 2 was detected by TLC, and the reaction was completed. The system was evaporated to remove the solvent under reduced pressure to obtain a white yellowish solid. The solid was transferred to water, stirred, filtered and dried to give a white solid.

The intermediate compound β-diketonate 2 used is ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate, 4-(4-chlorophenyl)-2,4-dioxo Ethyl butyrate, ethyl 4-(4-bromophenyl)-2,4-dioxobutyrate, ethyl 4-(4-methylphenyl)-2,4-dioxobutyrate , 4-(4-trifluoromethylphenyl)-2,4-dioxobutanoic acid ethyl ester, correspondingly, the obtained intermediate compound is one of the following five, specifically as follows:

3-(4-Fluorophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester (3a): white solid, 88% yield in two steps, Mp: 161.0-163.0°C, MS(ESI) m/z calcd for C ₁₂ H ₁₁ FN ₂ O ₂ : 234.1, found: 235.3 [M+H]+.

3-(4-Chlorophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester (3b): white solid, 90% yield in two steps, Mp: 179.0-181.0℃, MS(ESI) m/z calcd for C ₁₂ H ₁₁ ClN ₂ O ₂ : 250.1, found: 251.3 [M+H] ⁺ .

3-(4-Bromophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester (3c): white solid, 85% yield in two steps, Mp: 141.0-143.0°C, MS(ESI) m/z calcd for C ₁₂ H ₁₁ BrN ₂ O ₂ : 294.0, found: 295.3 [M+H]+.

3-(4-Methylphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester (3d): white solid, 87% yield in two steps, Mp: 166.0-168.0°C, MS(ESI) m/z calcd for C ₁₃ H ₁₄ ClN ₂ O ₂ : 230.3, found: 231.3 [M+H]+.

3-(4-Trifluoromethylphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester (3e): white solid, 85% yield over two steps, MS(ESI) m/ _zcalcd for _{C13H11F 3} N ₂ O ₂ : 284.1, found: 285.3 [M+H]+.

The preparation of embodiment 3 intermediate compound 4

Weigh 8.5mmol (1eq) of intermediate compound 3 in a 100ml two-neck flask, add 7ml of DMF and stir until the solid is completely dissolved, add 0.32g (12.7mmol, 1.5eq) of sodium hydride in an ice-salt bath, stir for 10min, and wait for the suspension After the liquid becomes clear, slowly add dimethyl sulfate or diethyl sulfate (1.5eq) dropwise with a needle tube, react for about 10min, detect by TLC, stop stirring after the reaction is complete, pour the system into 100ml ice water, and precipitate a white solid, use Extracted with ethyl acetate (100ml×3), combined the organic layers, washed with distilled water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure, separated and purified by column chromatography to obtain intermediate compound 4, and the elution system It is petroleum ether: ethyl acetate=9:1.

The intermediate compound 3 used is selected from the compounds involved in embodiment 2, and the corresponding intermediate compound 4 obtained by combined reaction with dimethyl sulfate or diethyl sulfate respectively is one of the following compounds, specifically as follows:

Ethyl 1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate (4aM): white solid, yield 76%, Mp: 54.0-56.0°C, MS (ESI) m/ z calcd for C ₁₃ H ₁₃ FN ₂ O ₂ :248.10,found:249.3[M+H] ⁺ , ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):7.900(dd,J ₁ =9.0Hz,J ₂ = 5.4Hz, 2H), 7.354(s, 1H), 7.247(t, J = 9.0Hz, 2H), 4.333(q, J = 7.2Hz, 2H), 4.132(s, 3H), 1.334(t, J=7.2Hz, 3H).

1-Ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester (4aE): white solid, yield 70%, MS(ESI) m/z calcd for C ₁₅ H ₁₈ N ₂ O ₂ :262.1,found:263.1[M+H] ⁺ , ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):7.913(dd,J ₁ =9.0Hz,J ₂ =5.4Hz,2H) ,7.350(s,1H),7.248(t,J=9.0Hz,2H),4.549(q,J=7.2Hz,2H),4.339(q,J=7.2Hz,2H),1.385(t,J= 7.2Hz, 3H), 1.337(t, J = 7.2Hz, 3H).

1-Methyl-3-(4-chlorophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester (4bM): yellow solid, yield 78%, Mp: 65.0-67.0°C, MS (ESI) m/ z calcd for C ₁₃ H ₁₃ ClN ₂ O ₂ :264.1,found:265.2[M+H] ⁺ , ¹ HNMR(400MHz,DMSO-d ₆ )δ(ppm):7.884(d,J＝8.4Hz,2H) ,7.473(d,J=8.4Hz,2H),7.391(s,1H),4.333(q,J=7.2Hz,2H),4.137(s,3H),1.335(t,J=7.2Hz,3H) .

1-Methyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester (4cM): white solid, yield 76%, Mp: 82.5-84.5°C, MS (ESI) m/ z calcd for C ₁₃ H ₁₃ BrN ₂ O ₂ :308.0,found:309.4[M+H] ⁺ , ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):7.820(d,J＝8.4Hz,2H) ,7.608(d,J=7.8Hz,2H),7.396(s,1H),4.332(q,J=7.2Hz,2H),4.135(s,3H),1.333(t,J=7.2Hz,3H) .

1-Ethyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester (4cE): white solid, 77% yield, MS (ESI) m/zcalcd for C ₁₂ H ₁₁ FO ₄ :322.0,found:323.4[M+H] ⁺ .

1-Ethyl-3-(4-methylphenyl)-1H-pyrazole-5-carboxylic acid ethyl ester (4dE): white solid, 73% yield, MS (ESI) m/zcalcd for C ₁₂ H ₁₁ FO ₄ :258.1,found:259.3[M+H] ⁺ .

Ethyl 1-ethyl-3-(4-trifluoromethylphenyl)-1H-pyrazole-5-carboxylate (4eE): white solid, 70% yield, MS (ESI) m/z calcd for C ₁₂ H ₁₁ FO ₄ :312.1,found:313.3[M+H] ⁺ .

The preparation of embodiment 4 hydrolyzate intermediate compound 5

Weigh 8.5mmol (1eq) of intermediate compound 4 into a 200ml two-neck flask, add 20ml of 95% ethanol and stir well to completely dissolve the solid. Add 10ml (2eq) of 10% (g/g) KOH aqueous solution, reflux at 90°C for 4 hours, detect by TLC, and the reaction is complete. The reaction was stopped, ethanol was distilled off under reduced pressure, the pH was adjusted to 2 with saturated citric acid, a white solid was precipitated, filtered, and the filter cake was washed with distilled water to obtain intermediate compound 5.

The intermediate compound 4 used is selected from the compounds involved in Example 3, and correspondingly, the obtained intermediate compound is one of the following 7 compounds, specifically as follows:

1-Methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxylic acid (5aM): white solid, 99% yield, Mp: 212.0-214.5°C, MS(ESI) m/z calcd for C ₁₁ H ₉ FN ₂ O ₂ :220.06,found:221.4[M+H] ⁺ , ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):13.473(s,1H),7.878(dd,J ₁ =9.0Hz, J ₂ =5.4Hz, 2H), 7.291(s, 1H), 7.243(t, J=9.0Hz, 2H), 4.119(s, 3H).

1-Ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxylic acid (5aE): white solid, yield 99%, Mp: 189.0-191.0℃, MS(ESI) m/z calcd for C ₁₂ H ₁₁ FN ₂ O ₂ :234.1,found:235.3[M+H] ⁺ , ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):13.481(s,1H),7.885(dd,J ₁ =9.0Hz, J ₂ =5.4Hz, 2H), 7.288(s, 1H), 7.243(t, J=9.0Hz, 2H), 4.549(q, J=6.6Hz, 2H), 1.373(t, J= 7.2Hz, 3H).

1-Methyl-3-(4-chlorophenyl)-1H-pyrazole-5-carboxylic acid (5bM): white solid, 100% yield, MS (ESI) m/zcalcdfor C ₁₁ H ₉ BrN ₂ O ₂ :236.0,found:237.3[M+H] ⁺ , ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):13.495(s,1H),7.865(d,J＝9.0Hz,2H),7.470(d ,J＝8.4Hz,2H),7.333(s,1H),4.126(s,3H).

1-Methyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxylic acid (5cM): white solid, yield 99%, Mp: 235.5-237.0°C, MS (ESI) m/z calcd for C ₁₁ H ₉ BrN ₂ O ₂ :280.0,found:281.3[M+H] ⁺ , ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):13.489(s,1H),7.802(d,J =8.4Hz, 2H), 7.604(d, J=9.0Hz, 2H), 7.331(s, 1H), 4.124(s, 3H).

1-Ethyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxylic acid (5cE): white solid, yield 99%, Mp: 219.0-221.0℃, MS(ESI) m/z calcd for C ₁₂ H ₁₁ BrN ₂ O ₂ :294.0,found:295.3[M+H] ⁺ , ¹ H-NMR(600MHz,DMSO-d ₆ )δ(ppm):13.486(s,1H),7.807(d, J=8.4Hz, 2H), 7.605(d, J=8.4Hz, 2H), 7.329(s, 1H), 4.556(q, J=7.2Hz, 2H), 1.375(t, J=7.2Hz, 3H) .

1-Ethyl-3-p-tolyl-1H-pyrazole-5-carboxylic acid (5dE): white solid, yield 98%, Mp: 187.0-189.0℃, MS(ESI) m/z calcd for C ₁₃ H ₁₄ N ₂ O ₂ :230.1,found:231.4[M+H] ⁺ , ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):13.400(s,1H),7.725(d,J＝8.4Hz,2H ), 7.225-7.212 (m, 3H), 6.540 (q, J = 6.6Hz, 2H), 2.320 (s, 3H), 1.368 (t, J = 7.2Hz, 3H).

1-Ethyl-3-(4-trifluoromethylphenyl)-1H-pyrazole-5-carboxylic acid (5eE): white solid, 98% yield, MS (ESI) m/ _zcalcd for _C12H11 FO ₄ :284.1,found:285.3[M+H] ⁺ .

The preparation of embodiment 5 intermediate compound 6

Weigh 1 mmol of intermediate 5 into a 50 ml eggplant-shaped bottle, add two drops of DMF and 10 ml of anhydrous THF to completely dissolve it, add 2 mmol of thionyl chloride, and react at 50°C for 2 hours. After the reaction is complete, evaporate the solvent under reduced pressure .

The intermediate compound 4 used is all selected from the compounds involved in Example 4 to obtain 7 corresponding acid chloride intermediate compounds, which are respectively 1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5- Formyl chloride, 1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carbonyl chloride, 1-methyl-3-(4-chlorophenyl)-1H-pyrazole-5- Formyl chloride, 1-methyl-3-(4-bromophenyl)-1H-pyrazole-5-formyl chloride, 1-ethyl-3-(4-bromophenyl)-1H-pyrazole-5- Formyl chloride, 1-ethyl-3-p-tolyl-1H-pyrazole-5-formyl chloride, 1-ethyl-3-(4-trifluoromethylphenyl)-1H-pyrazole-5-methanol acid chloride.

The preparation of embodiment 6 target compound 7

Dissolve 0.5 mmol of substituted benzene in 10 ml of redistilled CH ₂ Cl ₂ , add 0.264 g of AlCl ₃ in portions under ice-bath conditions, stir well, dissolve the prepared acid chloride (1 mmol) in 10 ml of redistilled CH ₂ Cl ₂ , drop slowly Add to the reaction mixture, the molar ratio of acid chloride, substituted benzene and AlCl3 is ₂ :1:4, react at room temperature for 6h, after the reaction is complete, slowly pour the system into 50ml of ice water, adjust the pH to 14 with 40% NaOH aqueous solution, Extract 50ml×3 with ethyl acetate, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, separate and purify the target compound 7 by silica gel column chromatography, and elute the system It is petroleum ether: ethyl acetate=6:1.

The intermediate compound 6 used is all selected from the acid chloride compounds involved in Example 5, which are respectively 1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-formyl chloride and 1-methyl-3 -(4-Bromophenyl)-1H-pyrazole-5-carbonyl chloride, substituted benzene with toluene.

1-Methyl-3-(4-fluorophenyl)-1H-pyrazole-5-p-methylbenzophenone (7aM01): white solid, yield 59%; Mp: 88.0-90.0°C; HPLC purity: 99.3%; HRMS (ESI) m/z for C ₁₈ H ₁₅ FN ₂ O [M+H] ⁺ : calculated 295.1241found 295.1243; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm): 7.926 (dd, J ₁ ＝9.0Hz, J ₂ ＝5.4Hz, 2H), 7.850(d, J＝8.4Hz, 2H), 7.415(d, J＝8.4Hz, 2H), 7.237-7.267(m, 3H), 4.127(s ,3H), 2.435(s,3H).

1-methyl-3-(4-bromophenyl)-1H-pyrazole-5-p-methylbenzophenone (7cM01): white solid, yield 63%; Mp: 133.0-134.0°C; HPLC purity: 97.1%; HRMS (ESI) m/z for C ₁₈ H ₁₅ BrN ₂ O [M+H] ⁺ : calculated 355.0441found 355.0439; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm): 7.848 (d, J =7.8Hz,4H),7.613(d,J=8.4Hz,2H),7.415(d,J=8.4Hz,2H),7.282(s,1H),4.131(s,3H),2.435(s,3H ).

The preparation of embodiment 7 target compound 8

Weigh 1 mmol of substituted aniline and 160 mg of re-distilled pyridine in an eggplant-shaped bottle, distill THF until the solids are completely dissolved, and dissolve the prepared acid chloride (1 mmol) in 10 ml of re-distilled THF under stirring in an ice bath, and slowly add it dropwise to the reaction mixture , stirred for 2 hours, TLC detection, after the reaction was completed, the solvent was evaporated under reduced pressure to obtain a reddish-brown viscous substance, which was transferred to a separatory funnel with ethyl acetate/water (30/30ml), and extracted with 30ml ethyl acetate ×3, combined organic phases, washed with 10% HCl (aq), 10% NaCO ₃ (aq), distilled water and NaCl (aq) successively, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure to remove solvent, silica gel column layer The target compound 8 was analyzed and purified, and the elution system was petroleum ether: ethyl acetate = 6:1.

The substituted anilines used are aniline, 2-bromoaniline, 3-bromoaniline, 4-bromoaniline, 2-trifluoromethylaniline, 3-trifluoromethylaniline, 4-trifluoromethylaniline, 2-cyanoaniline , 3-cyanoaniline, 4-cyanoaniline, 4-methylaniline, 3-fluoroaniline, 4-fluoroaniline, 3-chloroaniline, 4-chloroaniline, 4-trifluoromethoxyaniline, 3- Nitroaniline, 3-ethynylaniline, 3-trifluoromethyl-4-cyanoaniline, 3-chloro-4-fluoroaniline, 2-fluoro-3-chloroaniline, 3-chloro-4-cyanoaniline, 3-methoxy-4-cyanoaniline, 3,4-dicyanoaniline, 3-trifluoromethyl-4-chloroaniline, 2-fluoro-5-trifluoromethylaniline, 3-trifluoromethylaniline Base-4-bromoaniline, 3-trifluoromethyl-4-fluoroaniline, 3-bromo-4-aniline, 2-methyl-3-bromoaniline, 3-bromo-4-fluoroaniline, 2,3,4 -Trifluoroaniline, the intermediate compound 6 used is selected from the acid chloride compounds involved in Example 5, after the combination of different raw materials, the following 53 target compounds have been synthesized:

N-Phenyl-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM01): white solid, 65% yield; Mp: 139.5-141.0°C; HPLC purity :99.6%; HRMS(ESI)m/z for C ₁₇ H ₁₄ FN ₃ O[M+H] ⁺ :calculated296.1194found 296.1195; ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):10.328(s, 1H), 7.850(dd, J ₁ =9.0Hz, J ₂ =5.4Hz, 2H), 7.750(d, J=7.8Hz, 2H), 7.451(s, 1H), 7.380(t, J=7.8Hz, 2H), 7.293(t, J=9.0Hz, 2H), 7.138(t, J=7.8Hz, 1H), 4.129(s, 3H).

N-(2-Bromophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM02): white solid, 53% yield; Mp: 155.0- 157.5°C; HPLC purity: 99.2%; HRMS (ESI) m/z for C ₁₇ H ₁₃ BrFN ₃ O[M+H] ⁺ : calculated 374.0299found 374.0297; ¹ HNMR (400MHz, DMSO-d ₆ )δ(ppm) :10.122(s,1H),7.833(dd,J ₁ =8.6Hz,J ₂ =5.6Hz,2H),7.743(d,J=8.0Hz,1H),7.561(d,J=6.9Hz,1H) , 7.436-7.471 (m, 2H), 7.242-7.312 (m, 3H), 4.128 (s, 3H).

N-(3-bromophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM03): white solid, 63% yield; Mp: 148.5- 151.0°C; HPLC purity: 97.9%; HRMS (ESI) m/z for C ₁₇ H ₁₃ BrFN ₃ O[M+H] ⁺ : calculated 374.0299found 374.0299; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm) :10.464(s,1H),8.080(t,J=1.8Hz,1H),8.843(dd,J ₁ =9.0Hz,J ₂ =5.4Hz,2H),7.718(dt,J ₁ =7.8Hz,J ₂ = 1.8Hz, 1H), 7.455(s, 1H), 7.316-7.368(m, 2H), 7.297(t, J = 9.0Hz, 2H), 4.127(s, 3H).

N-(4-bromophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM04): white solid, 75% yield; Mp: 185.0- 187.0℃; HPLC purity: 93.5%; HRMS (ESI) m/z for C ₁₇ H ₁₃ BrFN ₃ O[M+H] ⁺ : calculated 374.0299found 374.0295; ¹ HNMR (400MHz, DMSO-d ₆ ) δ (ppm) :10.428(s,1H),7.840(dd,J ₁ ＝8.6Hz,J ₂ ＝5.5Hz,2H),7.731(d,J＝8.8Hz,2H),7.566(d,J＝8.8Hz,2H) , 7.439 (s, 1H), 7.287 (t, J=8.9Hz, 2H), 4.122 (s, 3H).

N-(2-Trifluoromethylphenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM05): white solid, 74% yield; Mp : 121.0-123.5°C; HPLC purity: 97.7%; HRMS (ESI) m/z for C ₁₈ H ₁₃ F ₄ N ₃ O[M+H] ⁺ : calculated 364.1068found 364.1069; ¹ HNMR (400MHz, DMSO-d ₆ )δ(ppm): 10.236(s, 1H), 7.808-7.843(m, 3H), 7.766(t, J＝7.6Hz, 1H), 7.576(t, J＝8.0Hz, 1H), 4.395(s, 1H), 7.287(t, J=8.8Hz, 2H), 4.105(s, 3H).

N-(3-(trifluoromethyl)phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM06): white solid, 52% yield ; Mp: 146.0-147.5°C; HPLC purity: 99.3%; HRMS (ESI) m/z for C ₁₈ H ₁₃ F ₄ N ₃ O[M+H] ⁺ : calculated 364.1068found 364.1068; ¹ HNMR (600MHz, DMSO- d ₆ )δ(ppm):10.622(s,1H),8.222(s,1H),8.015(d,J＝8.4Hz,1H),7.850(dd,J ₁ ＝9.0Hz,J ₂ ＝5.4Hz, 2H), 7.634(t, J=7.8Hz, 1H), 7.498(d, J=7.8Hz, 1H), 7.585(s, 1H), 7.301(t, J=9.0Hz, 2H), 4.142(s, 3H).

N-(4-(trifluoromethyl)phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM07): white solid, 68% yield ; Mp: 285.0-287.5°C; HPLC purity: 98.6%; HRMS (ESI) m/z for C ₁₈ H ₁₃ F ₄ N ₃ O[M+H] ⁺ : calculated 364.1068found 364.1066; ¹ HNMR (600MHz, DMSO- d ₆ )δ(ppm): 10.648(s,1H),7.987(d,J=9.0Hz,2H),7.854(dd,J ₁ =8.4Hz,J ₂ =6.0Hz,2H),7.761(d, J=8.4Hz, 2H), 7.495(s, 1H), 7.299(t, J=8.4Hz, 2H), 4.139(s, 3H).

N-(2-cyanophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM08): white solid, 30% yield; Mp: 162.0 -164.5°C; HPLC purity: 98.1%; HRMS (ESI) m/z for C ₁₈ H ₁₃ FN ₄ O[M+H] ⁺ : calculated 321.1146found 321.1148; ¹ HNMR (600MHz, DMSO-d ₆ )δ(ppm ): 10.747(s, 1H), 7.915(d, J=7.8Hz, 1H), 7.850(dd, J ₁ =8.4Hz, J ₂ =5.4Hz, 2H), 7.780(t, J=7.8Hz, 1H ), 7.582 (d, J = 7.8Hz, 1H), 7.469-7.487 (m, 2H), 7.300 (t, J = 8.4Hz, 2H), 4.134 (s, 3H).

N-(3-cyanophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM09): white solid, yield 68%; Mp: 198.0 -200.0°C; HPLC purity: 96.8%; HRMS (ESI) m/z for C ₁₈ H ₁₃ FN ₄ O[M+H] ⁺ : calculated 321.1146found 321.1149; ¹ HNMR (600MHz, DMSO-d ₆ )δ(ppm ):10.642(s,1H),8.227(s,1H),8.009(td,J ₁ =4.8Hz,J ₂ =2.4Hz,1H),7.850(dd,J ₁ =9.0Hz,J ₂ =5.4Hz , 2H), 7.615 (d, J1 ₌ 4.8Hz, 1H), 7.466 (s, 1H), 7.300 (t, J = 9.0Hz, 2H), 4.137 (s, 3H).

N-(4-cyanophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM10): white solid, yield 83%; Mp: 289.0 -291.0°C; HPLC purity: 99.2%; HRMS (ESI) m/z for C ₁₈ H ₁₃ FN ₄ O[M+H] ⁺ : calculated 321.1146found 321.1145; ¹ HNMR (400MHz, DMSO-d ₆ )δ(ppm ):10.690(s,1H),7.950(d,J=8.7Hz,2H),7.834-7.867(m,4H),7.474(s,1H),7.292(t,J=8.8Hz,2H),4.132 (s,3H).

N,3-bis(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (8aM11): white solid, yield 77%; Mp: 184.0-185.0°C; HPLC purity: 97.2 %; HRMS(ESI)m/z for C ₁₇ H ₁₃ F ₂ N ₃ O[M+H] ⁺ :calculated314.1099found 314.1100; ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):10.397(s, 1H), 7.845(dd, J ₁ =9.0Hz, J ₂ =5.4Hz, 2H), 7.765(dd, J ₁ =9.0Hz, J ₂ =5.4Hz, 2H), 7.430(s, 1H), 7.292( t, J=8.4Hz, 2H), 7.227(t, J=8.4Hz, 2H), 4.124(s, 3H).

N-(4-trifluoromethoxyphenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM12): white solid, yield 69%; Mp: 158.0-150.0℃; HPLC purity: 98.3%; HRMS (ESI) m/z for C ₁₈ H ₁₃ F ₄ N ₃ O ₂ [M+H] ⁺ : calculated 380.1017found 380.1016; ¹ HNMR (600MHz, DMSO- d ₆ )δ(ppm): 10.516(s,1H),7.867(d,J=9.0Hz,2H),7.848(dd,J ₁ =8.4Hz,J ₁ =5.4Hz,2H),7.452(s, 1H), 7.400(d, J=9.0Hz, 2H), 7.295(t, J=9.0Hz, 2H), 4.129(s, 3H).

N-(p-tolyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM13): white solid, yield 72%; Mp: 148.0-150.0°C ; HPLC purity: 98.9%; HRMS (ESI) m/z for C ₁₈ H ₁₆ FN ₃ O [M+H] ⁺ : calculated 310.1350found 310.1352; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm): 10.253 (s,1H),7.842(dd,J ₁ =9.0Hz,J ₂ =5.4Hz,2H),7.627(d,J=8.4Hz,2H),7.432(s,1H),7.292(t,J ₁ =9.0Hz, 2H), 7.180(d, J=7.8Hz, 2H), 4.121(s, 3H), 2.289(s, 3H).

N-(3-nitrophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM14): white solid, yield 52%; Mp: 212.0 -213.0°C; HPLC purity: 99.2%; HRMS (ESI) m/z for C ₁₇ H ₁₃ FN ₄ O ₃ [M+H] ⁺ : calculated 341.1044, found 341.1045; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm): 10.770 (s, 1H), 8.771 (t, J = 1.8Hz, 1H), 8.154-8.172 (m, 1H), 7.997-8.015 (m, 1H), 7.854 (dd, J ₁ = 9.0 Hz, J2 = 5.4Hz, 2H), _7.694 (t, J = 8.4Hz, 1H), 7.509 (s, 1H), 7.305 (t, J = 9.0Hz, 2H), 4.124 (s, 3H).

N-(3-ethynylphenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM15): white solid, yield 78%; Mp: 178.0 -179.0°C; HPLC purity: 96.3%; HRMS (ESI) m/z for C ₁₉ H ₁₄ FN ₃ O[M+H] ⁺ : calculated 320.1194found 320.1197; ¹ HNMR (600MHz, DMSO-d ₆ )δ(ppm ):10.413(s,1H),7.929(s,1H),7.842(dd,J ₁ =8.4Hz,J ₂ =5.4Hz,2H),7.765(d,J=7.8Hz,1H),7.453(s ,1H),7.401(t,J=7.8Hz,1H),7.297(t,J=8.4Hz,2H),7.248(d,J=7.8Hz,1H),4.230(s,1H),4.129(s ,3H).

N-(4-cyano-1-methyl-3-(trifluoromethyl)phenyl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM16): white solid , yield 72%; Mp: 259.5-261.0°C; HPLC purity: 97.8%; HRMS (ESI) m/z for C ₁₉ H ₁₂ F ₄ N ₄ O[M+H] ⁺ : calculated 389.1020found 389.1027; ¹ HNMR( 600MHz,DMSO-d ₆ )δ(ppm):10.989(s,1H),8.439(d,J=1.2Hz,1H),8.230(dd,J ₁ =9.0Hz,J ₂ =1.2Hz,1H), 8.188(d, J=9.0Hz, 1H), 7.852(dd, J ₁ =8.4Hz, J ₂ =5.4Hz, 2H), 7.516(s, 1H), 7.306(t, J=9.0Hz, 2H), 4.147(s,3H).

N-(2,3,4-Trifluorophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM17): white solid, 51% yield ; Mp: 167.0-169.0°C; HPLC purity: 98.3%; HRMS (ESI) m/z for C ₁₇ H ₁₁ F ₄ N ₃ O[M+H] ⁺ : calculated 350.0911found 359.0909; ¹ HNMR (600MHz, DMSO- d ₆ )δ(ppm):10.454(s,1H),7.838(dd,J ₁ =9.0Hz,J ₂ =5.4Hz,2H),7,472(s,1H),7.384-7.409(m,2H), 7.294 (t, J=9.0Hz, 2H), 4.119 (s, 3H).

N-(3-chloro-4-fluorophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM18): white solid, yield 55%; Mp: 165.0-167.5°C; HPLC purity: 92.4%; HRMS (ESI) m/z for C ₁₇ H ₁₂ ClF ₂ N ₃ O[M+H] ⁺ : calculated 348.0710found 348.0707; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm): 10.523 (s, 1H), 8.054 (dd, J ₁ = 6.6Hz, J ₂ = 3.0Hz, 1H), 7.843 (dd, J ₁ = 8.4Hz, J ₂ = 4.8Hz, 2H ), 7.679-7.693 (m, 1H), 7.458 (t, J = 9.0Hz, 1H), 7.436 (s, 1H), 7.296 (t, J = 8.4Hz, 2H), 4.126 (s, 3H).

N-(3-chloro-2-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (8aM19): white solid, yield 50%; Mp: 143.0-145.0°C; HPLC purity: 97.2%; HRMS (ESI) m/z for C ₁₇ H ₁₂ ClF ₂ N ₃ O[M+H] ⁺ : calculated 348.0710found 348.0709; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm): 10.411 (s, 1H), 7.841 (dd, J ₁ = 8.4Hz, J ₂ = 5.4Hz, 2H), 7.579 (t, J = 7.2Hz, 1H), 7.501 (t, J =7.2Hz, 1H), 7.485(s, 1H), 7.269-7.310(m, 3H), 4.123(s, 3H).

N-(3-Chloro-4-cyanophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM20): white solid, 68% yield ; Mp: 250.0-251.0°C; HPLC purity: 98.2%; HRMS (ESI) m/z for C ₁₈ H ₁₂ ClFN ₄ O[M+H] ⁺ : calculated 355.0756found 355.0756; ¹ HNMR (600MHz, DMSO-d ₆ )δ (ppm): 10.702 (s, 1H), 8.328 (d, J = 2.4Hz, 1H), 7.988 (dd, J ₁ = 9.0Hz, J ₂ = 2.4Hz, 1H), 7.906 (d, J = 9.0Hz, 1H), 7.846(dd, J ₁ =9.0Hz, J ₂ =5.4Hz, 2H), 7.475(s, 1H), 7.300(t, J = 9.0Hz, 2H), 4.137(s, 3H) .

N-(4-cyano-3-methoxy)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM21): white solid, 51% yield ; Mp: 251.0-253.0°C; HPLC purity: 99.4%; HRMS (ESI) m/z for C ₁₉ H ₁₅ FN ₄ O ₂ [M+H] ⁺ : calculated 351.1252found 351.1248; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm): 10.674 (s, 1H), 7.855 (dd, J ₁ = 8.4Hz, J ₂ = 5.4Hz, 2H), 7.743 (d, J = 1.2Hz, 1H), 7.726 (d, J =8.4Hz, 1H), 7.504(dd, J ₁ =8.4Hz, J ₂ =1.2Hz, 1H), 7.487(s, 1H), 7.299(t, J=8.4Hz, 2H), 4.137(s, 3H ), 3.921(s,3H).

N-(3,4-dicyanophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM22): white solid, yield 56%; Mp: 265.0-267.0℃; HPLC purity: 99.0%; HRMS (ESI) m/z for C ₁₉ H ₁₂ FN ₅ O[M+H] ⁺ : calculated 346.1099found 346.1100; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm): 10.990 (s, 1H), 8.446 (d, J = 1.8Hz, 1H), 8.172 (dd, J ₁ = 9.0Hz, J ₂ = 1.8Hz, 1H), 8.152 (d, J = 9.0 Hz, 1H), _7.852 (dd, J1 ₌ 8.4Hz, J2 = 5.4Hz, 2H), 7.498 (s, 1H), 7.305 (t, J = 8.4Hz, 2H), 4.142 (s, 3H).

N-(4-Chloro-3-(trifluoromethyl)phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM23): white solid, Yield 64%; Mp: 179.0-181.5°C; HPLC purity: 93.6%; HRMS (ESI) m/z for C ₁₈ H ₁₂ ClF ₄ N ₃ O[M+H] ⁺ : calculated 398.0678found 398.0680; ¹ HNMR (600MHz , DMSO-d ₆ ) δ (ppm): 10.712 (s, 1H), 8.337 (d, J = 2.4Hz, 1H), 8.066 (dd, J ₁ = 8.4Hz, J ₂ = 2.4Hz, 1H), 7.847 (dd, J ₁ =8.4Hz, J ₂ =6.0Hz, 2H), 7.756 (d, J = 9.0Hz, 1H), 7.474 (s, 1H), 7.300 (t, J = 9.0Hz, 2H), 4.138 (s,3H).

N-(2-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM24): white solid, Yield 66%; Mp: 185.5-186.5°C; HPLC purity: 99.3%; HRMS (ESI) m/zfor C ₁₈ H ₁₂ F ₅ N ₃ O[M+H] ⁺ : calculated 382.0973found 382.0972; ¹ HNMR (600MHz, DMSO-d ₆ )δ(ppm): 10.453(s, 1H), 8.107(d, J=4.8Hz, 1H), 7.845(dd, J ₁ =9.0Hz, J ₂ =5.4Hz, 2H), 7.130- 7.100 (m, 1H), 7.603 (t, J = 9.0Hz, 1H), 7.514 (s, 1H), 7.298 (t, J = 9.0Hz, 2H), 4.132 (s, 3H).

N-(4-Bromo-3-(trifluoromethyl)phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM25): white solid, Yield 80%; Mp: 188.0-189.5°C; HPLC purity: 96.8%; HRMS (ESI) m/z for C ₁₈ H ₁₂ BrF ₄ N ₃ O[M+H] ⁺ : calculated 442.0173found 442.0170; ¹ HNMR (600MHz , DMSO-d ₆ ) δ(ppm): 10.702(s, 1H), 8.328(d, J=2.4Hz, 1H), 7.988(dd, J ₁ =9.0Hz, J ₂ =2.4Hz, 1H), 7.905 (d, J = 9.0Hz, 1H), 7.846 (dd, J ₁ = 9.0Hz, J ₂ = 5.4Hz, 2H), 7.475 (s, 1H), 7.300 (t, J = 9.0Hz, 2H), 4.137 (s,3H).

N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM26): white solid, Yield 79%; Mp: 173.5-175.0°C; HPLC purity: 96.7%; HRMS (ESI) m/z for C ₁₈ H ₁₂ F ₅ N ₃ O[M+H] ⁺ : calculated 382.0973found 382.0973; ¹ HNMR (600MHz ,DMSO-d ₆ )δ(ppm):10.649(s,1H),8.236(dd,J ₁ =6.6Hz,J ₂ =2.4Hz,1H),8.051-8.070(m,1H),7.846(dd, J ₁ ＝8.4Hz, J ₂ ＝5.4Hz, 2H), 7.565(t, J＝10.2Hz, 1H), 7.458(s, 1H), 7.299(t, J＝8.4Hz, 2H), 4.137(s, 3H).

N-(3-bromo-4-methylphenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM27): white solid, 83% yield ; Mp: 173.5-175.0°C; HPLC purity: 97.7%; HRMS (ESI) m/z for C ₁₈ H ₁₅ BrFN ₃ O[M+H] ⁺ : calculated 388.0455found 388.0460; ¹ HNMR (600MHz, DMSO-d ₆ )δ (ppm): 10.386 (s, 1H), 8.090 (d, J = 1.8Hz, 1H), 7.838 (dd, J ₁ = 9.0Hz, J ₂ = 6.0Hz, 2H), 7.632 (dd, d, J ₁ ＝8.4Hz, J ₂ ＝1.8Hz, 1H), 7.443(s, 1H), 7.358(d, J＝9.0Hz, 1H), 7.293(t, J＝9.0Hz, 2H), 4.125(s, 3H), 2.327(s, 3H).

N-(3-Bromo-2-methylphenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM28): white solid, 78% yield ; Mp: 178.0-180.0°C; HPLC purity: 97.1%; HRMS (ESI) m/z for C ₁₈ H ₁₅ BrFN ₃ O[M+H] ⁺ : calculated 388.0455found 388.0450; ¹ HNMR (600MHz, DMSO-d ₆ )δ (ppm): 10.241 (s, 1H), 7.842 (dd, J ₁ = 8.4Hz, J ₂ = 5.4Hz, 2H), 7.566 (d, J = 7.8Hz, 1H), 7.448 (s, 1H) ,7.366(d,J=7.2Hz,1H),7.292(t,J=8.4Hz,2H),7.206(t,J=7.8Hz,1H),4.116(s,3H),2.308(s,3H) .

N-(3-bromo-4-fluorophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aM29): white solid, yield 87%; Mp: 176.0-177.5℃; HPLC purity: 98.7%; HRMS (ESI) m/z for C ₁₇ H ₁₂ BrF ₂ N ₃ O[M+H] ⁺ : calculated 392.0205found 392.0203; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm): 10.496 (s, 1H), 8.178 (dd, J ₁ = 6.6Hz, J ₂ = 2.4Hz, 1H), 7.842 (dd, J ₁ = 9.0Hz, J ₂ = 6.0Hz, 2H ), 7.745-7.719 (m, 1H), 7.436 (s, 1H), 7.421 (t, J=9.0Hz, 1H), 7.295 (t, J=9.0Hz, 2H), 4.128 (s, 3H).

N-(p-tolyl)-1-methyl-3-(4-chlorophenyl)-1H-pyrazole-5-carboxamide (8bM01): white solid, yield 84%; Mp: 202.0-204.0°C ; HPLC purity: 99.6%; HRMS (ESI) m/z for C ₁₈ H ₁₆ ClN ₃ O [M+H] ⁺ : calculated 326.1055 found 326.1055; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm): 10.259 (s,1H),7.824(d,J=7.8Hz,2H),7.623(d,J=7.8Hz,2H),7.518(d,J=9.0Hz,2H),7.468(s,1H),7.180 (d, J=8.4Hz, 2H), 4.1259(s, 3H), 2.288(s, 3H).

N-(3-(trifluoromethyl)phenyl)-1-methyl-3-(4-chlorophenyl)-1H-pyrazole-5-carboxamide (8bM02): white solid, 75% yield ; Mp: 168.5-170.5°C; HPLC purity: 97.1%; HRMS (ESI) m/z for C ₁₈ H ₁₃ ClF ₃ N ₃ O[M+H] ⁺ : calculated 380.0772found 380.0773; ¹ HNMR (600MHz, DMSO- d ₆ )δ(ppm):10.633(s,1H),8.221(s,1H),8.010(d,J＝7.8Hz,1H),7.834(d,J＝8.4Hz,2H),7.635(t, J＝7.8Hz,1H),7.493-7.537(m,4H),4.174(s,3H).

N-(3-(trifluoromethyl)phenyl)-1-methyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxamide (8cM01): white solid, 81% yield ; Mp: 182.0-183.0°C; HPLC purity: 97.5%; HRMS (ESI) m/z for C ₁₈ H ₁₃ BrF ₃ N ₃ O [M+H] ⁺ : calculated 424.0267found 424.0266; ¹ HNMR (600MHz, DMSO- d ₆ )δ(ppm):10.632(s,1H),8.221(s,1H),8.010(d,J＝8.4Hz,1H),7.771(d,J＝8.4Hz,2H),7.621-7.671( m, 3H), 7.528(s, 1H), 7.500(d, J=7.8Hz, 1H), 4.146(s, 3H).

N-(4-fluorophenyl)-1-methyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxamide (8cM02): white solid, 86% yield; Mp: 209.0- 209.5°C; HPLC purity: 97.2%; HRMS (ESI) m/z for C ₁₇ H ₁₃ BrFN ₃ O[M+H] ⁺ : calculated 374.0299found 374.0298; ¹ HNMR (600MHZ, DMSO-d ₆ )δ(ppm) :10.404(s,1H),7.750-7.772(m,4H),7.650(d,J=8.4Hz,2H),7.472(s,1H),7.227(t,J=9.0Hz,,2H),4.126 (s,3H).

N-(3-bromophenyl)-3-(4-bromophenyl)-1-methyl-1H-pyrazole-5-carboxamide (8cM03): white solid, 79% yield; Mp: 224.5- 226.0°C; HPLC purity: 93.0%; HRMS (ESI) m/z for C ₁₇ H ₁₃ Br ₂ N ₃ O [M+H] ⁺ : calculated 433.9498found 433.9494; ¹ HNMR (600MHz, DMSO-d ₆ ) δ( ppm): 10.473 (s, 1H), 8.079 (t, J = 1.8Hz, 1H), 7.765 (d, J = 8.4Hz, 2H), 7.717 (dt, J ₁ = 7.8Hz, J ₂ = 1.8Hz, 1H), 7.660 (d, J=8.4Hz, 2H), 7.499 (s, 1H), 7.324-7.369 (m, 2H), 4.132 (s, 3H).

N-(p-tolyl)-1-methyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxamide (8cM04): white solid, yield 90%; Mp: 214.0-215.0°C ; HPLC purity: 98.2%; HRMS (ESI) m/z for C ₁₈ H ₁₆ BrN ₃ O [M+H] ⁺ : calculated 370.0550found 370.0550; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm): 10.261 (s,1H),7.762(d,J=8.4Hz,2H),7.652(d,J=8.4Hz,2H),7.623(d,J=8.4Hz,2H),7.473(s,1H),7.180 (d, J=8.4Hz, 2H), 4.123(s, 3H), 2.288(s, 3H).

N-phenyl-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE01): white solid, yield 79%; Mp: 129.0-131.0°C; HRMS ( ESI)m/z for C ₁₈ H ₁₆ FN ₃ O[M+H] ⁺ :calculated 310.1350,found310.1353; ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):10.335(s,1H),7.857 (dd, J ₁ =7.8Hz, J ₂ =5.4Hz, 2H), 7.746(d, J=7.8Hz, 2H), 7.437(s, 1H), 7.385(, J=7.8Hz, 2H), 7.292( t, J = 9.0Hz, 2H), 7.138 (t, J = 7.8Hz, 1H), 4.540 (q, J = 7.2Hz, 2H), 1.401 (t, J = 7.2Hz, 3H).

N-(3-fluorophenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE02): white solid, yield 21.5%; Mp: 137.0- 139.0℃; HRMS(ESI)m/z for C ₁₈ H ₁₅ F ₂ N ₃ O[M+H] ⁺ :calculated328.1256,found328.1255; ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm): 10.519(s,1H),7.860(dd,J ₁ =9.0Hz,J ₂ =5.4Hz,2H),7.717(d,J=11.4Hz,1H),7.535(d,J=8.4Hz,1H), 7.456-7.400(m,3H),7.295(t,J＝9.0Hz,1H),6.977(t,J＝8.4Hz,1H),4.538(q,J＝6.6Hz,2H),1.416(t,J =7.2Hz, 3H).

N,3-bis(4-fluorophenyl)-1-ethyl-1H-pyrazole-5-carboxamide (8aE03): white solid, yield 16.8%; Mp: 174.0-180.0°C; HRMS (ESI) m/z for C ₁₈ H ₁₅ F ₂ N ₃ O[M+H] ⁺ :calculated 328.1256,found328.1258; ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):10.397(s,1H),7.851 (dd, J ₁ =8.4Hz, J ₂ =5.4Hz, 2H), 7.750(dd, J ₁ =8.4Hz, J ₂ =5.4Hz, 2H), 7.418(s, 1H), 7.290(t, J= 9.0Hz, 2H), 7.223 (t, J = 9.0Hz, 2H), 4.529 (q, J = 7.2Hz, 2H), 1.398 (t, J = 7.2Hz, 3H).

N-(4-chlorophenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE04): white solid, yield 21.8%; Mp: 182.0- 185.0℃; HRMS(ESI)m/z for C ₁₈ H ₁₅ ClFN ₃ O[M+H] ⁺ :calculated344.0960,found344.0963; ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):10.463( s, 1H), 7.851 (dd, J ₁ =9.0Hz, J ₂ =6.0Hz, 2H), 7.786 (d, J = 8.4Hz, 2H), 7.449 (d, J = 8.4Hz, 2H), 7.435 ( s, 1H), 7.292 (t, J = 9.0Hz, 2H), 4.533 (q, J = 7.2Hz, 2H), 1.398 (t, J = 7.2Hz, 3H).

N-(4-methylphenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE05): white solid, yield 31.5%; Mp: 146.0 -148.0℃; HRMS(ESI)m/z for C ₁₉ H ₁₈ FN ₃ O[M+H] ⁺ :calculated324.1507,found324.1508; ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):10.255 (s,1H),7.848(dd,J ₁ =9.0Hz,J ₂ =6.0Hz,2H),7.623(d,J=8.4Hz,2H),7.417(s,1H),7.287(t,J= 9.0Hz, 2H), 7.178 (d, J = 8.4Hz, 2H), 4.534 (q, J = 7.2Hz, 2H), 2.289 (s, 3H), 1.394 (t, J = 7.2Hz, 3H).

N-(3-bromophenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE06): white solid, yield 30.3%; Mp: 135.0- 137.0℃; HRMS(ESI)m/z for C ₁₈ H ₁₅ BrFN ₃ O[M+H] ⁺ :calculated388.0455,found388.0453; ¹ H NMR(600MHz,CDCl ₃ )δ(ppm):7.914(s ,1H),7.785(dd,J ₁ =8.4Hz,J ₂ =5.4Hz,2H),7.702(s,1H),7.497(d,J=8.4Hz,1H),7.321(d,J=9.0Hz ,1H),7.241(t,J=8.4Hz,1H),7.114(t,J=8.4Hz,2H),6.857(s,1H),4.648(q,J=7.2Hz,2H),1.522(t , J=7.2Hz, 3H).

N-(4-bromophenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE07): white solid, yield 52%; Mp: 192- 195℃; HRMS(ESI)m/z forC ₁₈ H ₁₅ BrFN ₃ O[M+H] ⁺ :calculated 388.0455,found388.0453; ¹ HNMR(600MHz,CDCl ₃ )δ(ppm):7.800-7.778(m, 3H), 7.540-7.500(m, 4H), 7.11(t, J=8.4Hz, 2H), 6.875(s, 1H), 4.634(q, J=7.2Hz, 2H), 1.523(t, J=7.2 Hz, 3H).

N-(3-Trifluoromethylphenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE08): white solid, yield 45%; Mp :130.0-135.0℃; HRMS(ESI)m/z for C ₁₉ H ₁₅ F ₄ N ₃ O[M+H] ⁺ :calculated378.1224,found378.1223; ¹ HNMR(600MHz,CDCl ₃ )δ(ppm) :7.938(s,1H),7.836-7.777(m,4H),7.521(t,J＝7.8Hz,1H),7.450(d,J＝7.8Hz,1H),7.120(t,J＝8.4Hz, 2H), 6.886(s, 1H), 4.673(q, J=6.6Hz, 2H), 1.528(t, J=6.6Hz, 3H).

N-(4-Trifluoromethylphenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE09): white solid, yield 43%; Mp :197.0-200.0℃; HRMS(ESI)m/z for C ₁₉ H ₁₅ F ₄ N ₃ O[M+H] ⁺ :calculated378.1224,found378.1220; ¹ HNMR(600MHz,DMSO-d ₆ )δ( ppm): 11.161(s, 1H), 7.938(J ₁ =8.4Hz, J ₂ =5.4Hz, 2H), 7.880(m, 3H), 7.780(d, J = 8.4Hz, 2H), 7.361(t, J=8.4Hz, 2H), 4.331(q, J=7.2Hz, 2H), 1.405(t, J=7.2Hz, 3H).

N-(3-chlorophenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (8aE10): white solid, yield 30.4%; Mp: 154.0- 156.0℃; HRMS(ESI)m/z for C ₁₈ H ₁₅ ClFN ₃ O[M+H] ⁺ :calculated344.0960,found344.0960; ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):10.474( s,1H),7.940(s,1H),7.853(dd,J ₁ =8.4Hz,J ₂ =5.4Hz,2H),7.671(d,J=8.4Hz,1H),7.444(s,1H), 7.412(t, J=8.4Hz, 1H), 7.292(t, J=8.4Hz, 2H), 7.203(d, J=7.8Hz, 1H), 4.538(q, J=7.2Hz, 2H), 1,404( t, J=7.2Hz, 3H).

N-phenyl-1-ethyl-3-p-tolyl-1H-pyrazole-5-carboxamide (8dE01): white solid, yield 18.0%; Mp: 150.0-152.0°C; HRMS (ESI) m/ z for C ₁₉ H ₁₉ N ₃ O[M+H] ⁺ :calculated 306.1601,found306.1600; ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):10.286(s,1H),7.748(d,J =7.8Hz, 2H), 7.713(d, J=8.4Hz, 2H), 7.413(s, 1H), 7.373(t, J=8.4Hz, 2H), 7.260(d, J=7.8Hz, 2H), 7.133 (t, J = 7.2Hz, 1H), 4.538 (q, J = 7.2Hz, 2H), 2.336 (s, 3H), 1.397 (t, J = 7.2Hz, 3H).

N-(3-bromophenyl)-1-ethyl-3-p-tolyl-1H-pyrazole-5-carboxamide (8dE02): white solid, yield 30%; Mp: 173.5-175.0°C; HRMS (ESI)m/z for C ₁₉ H ₁₈ BrN ₃ O[M+H] ⁺ :calculated 384.0706,found384.0706; ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):10.422(s,1H), 8.082(s, 1H), 7.730-7.704(m, 3H), 7.427(s 1H), 7.362-7.320(m, 2H), 7.275(d, J=7.8Hz, 2H), 4.535(q, J=6.6 Hz, 2H), 2.337(s, 3H), 1.41(t, J=7.2Hz, 3H).

N-(4-bromophenyl)-1-ethyl-3-p-tolyl-1H-pyrazole-5-carboxamide (8dE03): white solid, yield 40.3%; Mp: 144-146°C; HRMS (ESI)m/z for C ₁₉ H ₁₈ BrN ₃ O[M+H] ⁺ :calculated 384.0706,found384.0707; ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):10.428(s,1H), 7.739(d, J=9.0Hz, 2H), 7.712(d, J=8.4Hz 2H), 7.566(d, J=9.0Hz, 2H), 7.419(s, 1H), 7.262(d, J=8.4Hz , 2H). 4.530 (q, J = 7.2Hz, 2H), 2.336 (s, 3H), 1.394 (t, J = 7.2Hz, 3H).

N-(4-Chlorophenyl)-1-ethyl-3-p-tolyl-1H-pyrazole-5-carboxamide (8dE04): white solid, yield 21.7%; Mp: 158-161°C; HRMS (ESI)m/z for C ₁₉ H ₁₈ ClN ₃ O[M+H] ⁺ :calculated 340.1211,found340.1217; ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm):10.435(s,1H), 7.791(d, J=8.4Hz, 2H), 7.713(d, J=7.8Hz, 2H), 7.439(d, J=8.4Hz, 2H), 7.417(s, 1H), 7.263(d, J=7.8 Hz, 2H), 4.531 (q, J = 7.2Hz, 2H), 2.336 (s, 3H), 1.394 (t, J = 7.2Hz, 3H).

N-(3-trifluoromethylphenyl)-1-ethyl-3-p-tolyl-1H-pyrazole-5-carboxamide (8dE05): white solid, yield 20.4%; Mp: 158-162 ℃; HRMS (ESI) m/z for C ₂₀ H ₁₈ F ₃ N ₃ O[M+H] ⁺ : calculated374.1475, found374.1475; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm): 10.579 (s,1H),8.218(s,1H),8.021(d,J=7.8Hz,1H),7.716(d,J=8.4Hz,2H),7.627(t,J=7.8Hz,1H),7.491 (d, J=7.8Hz, 1H), 7.457(s, 1H), 7.268(d, J=7.8Hz, 2H), 4.550(q, J=7.2Hz, 2H), 2.339(s, 3H), 1.406 (t, J=7.2Hz, 3H).

N-(4-trifluoromethylphenyl)-1-ethyl-3-p-tolyl-1H-pyrazole-5-carboxamide (8dE06): white solid, yield 15.6%; Mp: 158-161 ℃; HRMS (ESI) m/z for C ₂₀ H ₁₈ F ₃ N ₃ O[M+H] ⁺ : calculated374.1475, found374.1474; ¹ HNMR (600MHz, DMSO-d ₆ ) δ (ppm): 10.625 (s,1H),7.991(d,J=8.4Hz,2H),7.755(d,J=8.4Hz,2H),7.721(d,J=8.4Hz,2H),7.469(s,1H),7.267 (d, J = 7.8Hz, 2H), 4.544 (q, J = 7.2Hz, 2H), 2.339 (s, 3H), 1.405 (t, J = 7.2Hz, 3H).

N-(3-trifluoromethylphenyl)-1-ethyl-3-(4-trifluoromethylphenyl)-1H-pyrazole-5-carboxamide (8eE01): white solid, yield 37 %; Mp: 170-173°C; HRMS(ESI) m/z for C ₂₀ H ₁₅ F ₆ N ₃ O[M+H] ⁺ : calculated 428.1192, found 428.1191; ¹ HNMR(600MHz, DMSO-d ₆ ) δ(ppm):10.688(s,1H),8.224(s,1H),8.047(d,J=7.8Hz,2H),8.018(d,J=8.4Hz,1H),7.840(d,J=7.8 Hz, 2H), 7.641(t, J=7.8Hz, 1H), 7.633(s, 1H), 7.509(d, J=7.2Hz, 1H), 4.594(q, J=7.2Hz, 2H), 1.432( t, J=7.2Hz, 3H).

N-(3-trifluoromethylphenyl)-1-ethyl-3-(4-bromophenyl)-1H-pyrazole-5-carboxamide (8cE01): white solid, yield 35%; Mp :147.0-152.0℃; HRMS(ESI)m/z for C ₁₉ H ₁₅ BrF ₃ N ₃ O[M+H] ⁺ :calculated438.0423,found 438.0423; ¹ HNMR(600MHz,DMSO-d ₆ )δ(ppm ):10.640(s,1H),8.217(s,1H),8.010(d,J=8.4Hz,1H),7.780(d,J=8.4Hz,2H),7.665(d,J=8.4Hz,2H ),7.633(d,J=8.4Hz,1H),7.522(s,1H),7.492(d,J=9.0Hz,1H),4.556(q,J=6.6Hz,2H),1.413(t,J =6.6Hz, 3H).

Although the specific implementation of the present invention has been described above, it does not limit the protection scope of the present invention. Those skilled in the art should understand that on the basis of the technical solution of the present invention, those skilled in the art can do it without creative work. Various modifications or deformations are still within the protection scope of the present invention.

Claims (7)

1.1,3,5-tri-substituted pyrazolecarboxylic compounds, it is characterised in that described 1, under 3,5-tri-substituted pyrazolecarboxylic compounds are State one of compound:

N-phenyl-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM01)；

N-(2-bromophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM02)；

N-(3-bromophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM03)；

N-(4-bromophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM04)；

N-(2-trifluoromethyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM05)；

N-(3-(trifluoromethyl) phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM06)；

N-(4-(trifluoromethyl) phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM07)；

N-(2-cyano-phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM08)；

N-(3-cyano-phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM09)；

N-(4-Trifluoromethoxyphen-l)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM12)；

N-(3-nitrobenzophenone)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM14)；

N-(3-ethynyl phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM15)；

N-(2,3,4-trifluorophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM17)；

N-(3-chloro-4-fluorophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM18)；

N-(3-chloro-2-fluorophenyl)-3-(4-fluorophenyl)-1-methyl isophthalic acidH-pyrazoles-5-Methanamide (8aM19)；

N-(4-cyano group-3-methoxyl group)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM21)；

N-(3,4-dicyano phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM22)；

N-(4-chloro-3-(trifluoromethyl) phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM23)；

N-(2-fluoro-5-(trifluoromethyl) phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM24)；

N-(4-bromo-3-(trifluoromethyl) phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM25)；

N-(4-fluoro-3-(trifluoromethyl) phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM26)；

N-(3-bromo-4-aminomethyl phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM27)；

N-(3-bromo-2-aminomethyl phenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM28)；

N-(3-bromo-4-fluorophenyl)-1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aM29)；

N-(p-methylphenyl)-1-methyl-3-(4-chlorphenyl)-1H-pyrazoles-5-Methanamide (8bM01)；

N-(3-(trifluoromethyl) phenyl)-1-methyl-3-(4-chlorphenyl)-1H-pyrazoles-5-Methanamide (8bM02)；

N-(3-(trifluoromethyl) phenyl)-1-methyl-3-(4-bromophenyl)-1H-pyrazoles-5-Methanamide (8cM01)；

N-(4-fluorophenyl)-1-methyl-3-(4-bromophenyl)-1H-pyrazoles-5-Methanamide (8cM02)；

N-(3-bromophenyl)-3-(4-bromophenyl)-1-methyl isophthalic acidH-pyrazoles-5-Methanamide (8cM03)；

N-(p-methylphenyl)-1-methyl-3-(4-bromophenyl)-1H-pyrazoles-5-Methanamide (8cM04)；

N-phenyl-1-ethyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aE01)；

N-(3-fluorophenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aE02)；

N, double (4-the fluorophenyl)-1-ethyl-1 of 3-H-pyrazoles-5-Methanamide (8aE03)；

N-(4-chlorphenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aE04)；

N-(4-aminomethyl phenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aE05)；

N-(3-bromophenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aE06)；

N-(4-bromophenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aE07)；

N-(3-trifluoromethyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aE08)；

N-(4-trifluoromethyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aE09)；

N-(3-chlorphenyl)-1-ethyl-3-(4-fluorophenyl)-1H-pyrazoles-5-Methanamide (8aE10)；

N-phenyl-1-ethyl-3-p-methylphenyl-1H-pyrazoles-5-Methanamide (8dE01)；

N-(3-bromophenyl)-1-ethyl-3-p-methylphenyl-1H-pyrazoles-5-Methanamide (8dE02)；

N-(4-bromophenyl)-1-ethyl-3-p-methylphenyl-1H-pyrazoles-5-Methanamide (8dE03)；

N-(4-chlorphenyl)-1-ethyl-3-p-methylphenyl-1H-pyrazoles-5-Methanamide (8dE04)；

N-(3-trifluoromethyl)-1-ethyl-3-p-methylphenyl-1H-pyrazoles-5-Methanamide (8dE05)；

N-(4-trifluoromethyl)-1-ethyl-3-p-methylphenyl-1H-pyrazoles-5-Methanamide (8dE06)；

N-(3-trifluoromethyl)-1-ethyl-3-(4-trifluoromethyl)-1H-pyrazoles-5-Methanamide (8eE01)；

N-(3-trifluoromethyl)-1-ethyl-3-(4-bromophenyl)-1H-pyrazoles-5-Methanamide (8cE01)；

It bracket after compound name is the code name of its correspondence.

2. 1 described in claim 1, the preparation method of 3,5-tri-substituted pyrazolecarboxylic compounds, it is characterised in that: including:

(i) the preparation of Sodium ethylate: take 2.4 ~ 4.8g sodium hydride and add in 50 ~ 60ml dehydrated alcohol by several times, be stirred at reflux to system Clarification, obtains the ethanol solution of Sodium ethylate, and the mass ratio of described sodium hydride and dehydrated alcohol is (1 ~ 2): 20；

The synthesis of beta-diketon acid esters: weigh a certain amount of substituted acetophenone and ethyl oxalate, adds in dehydrated alcohol, more molten to this Liquid is slowly added dropwise the ethanol solution of Sodium ethylate, finishes, be warming up to 70 ~ 80 ° of C and react 5 ~ 7 hours, detect unsubstituted benzene with TLC During ethyl ketone, reacting complete, now system is rufous；Stop heating, remove solvent under reduced pressure, obtain the thick thing of reddish brown, turn Move in frozen water, adjust pH value to 1, stir 30 ~ 40min, filter, filter cake ice washing with alcohol, obtain midbody compound 2: β- Diketonate, substituted acetophenone, Sodium ethylate, the mol ratio of ethyl oxalate are 1: (1 ~ 2): (1 ~ 2), described ethyl oxalate, Dehydrated alcohol, the mass ratio of frozen water are 1: (3 ~ 4): (9 ~ 12)；

(ii) weigh midbody compound 2: beta-diketon acid esters, addition dehydrated alcohol makes it dissolve, and adding mass concentration is 80% Hydrazine hydrate and glacial acetic acid, 90 ~ 95 ° of C reflux 3 ~ 5 hours, during with TLC detection without midbody compound 2, react complete；System Remove solvent under reduced pressure, obtain white light yellow complexion solid；Transfer them in water, stirring, filter, be dried, obtain white solid, be centre Body compound 3, midbody compound 2 is 1 with the mol ratio of hydrazine hydrate: (1 ~ 2), described hydrazine hydrate, dehydrated alcohol and glacial acetic acid Mass ratio be (6.3 ~ 12.6): (80 ~ 100): (1 ~ 1.5)；

(iii) weigh midbody compound 3, add DMF stirring and be completely dissolved to solid, under ice bath, add sodium hydride, stirring 10 ~ 15min, after suspension becomes clarification, is slowly added dropwise dimethyl sulfate or dithyl sulfate wherein, reacts 8 ~ 15min, use TLC When detection is without midbody compound 3, reacts complete, system is poured in frozen water, separate out white solid 2, be extracted with ethyl acetate 3 ~ 4 times, merge organic layer, washing, be dried, remove solvent, column chromatographic isolation and purification under reduced pressure, obtain midbody compound 4, eluting body System is petroleum ether: ethyl acetate=9: 1, midbody compound 3: sodium hydride: the mol ratio of dimethyl sulfate or dithyl sulfate is 1: (1 ~ 1.5): (1 ~ 1.5), the mass ratio of described sodium hydride and DMF is 3 ~ 5:1000；

(iv) weighing midbody compound 4, adding mass concentration is the ethanol of 95%, is sufficiently stirred for making solid be completely dissolved；Add Mass concentration is the KOH aqueous solution of 10%, refluxes 3 ~ 5 hours under 90 ~ 95 ° of C, during with TLC detection without midbody compound 4, and reaction Complete；Remove ethanol under reduced pressure, adjust pH value to 2, separate out white solid 3, filter, filter cake distilled water wash, obtain intermediate compound Thing 5, described midbody compound 4, ethanol, the mass ratio of KOH aqueous solution are (9 ~ 12): (3 ~ 5): (1 ~ 3)；

(v) weigh midbody compound 5, add DMF and anhydrous THF and be allowed to be completely dissolved, under condition of ice bath, be slowly dropped into chlorination Sulfoxide, reacts 1 ~ 3 hour under 50 ~ 60 ° of C, reacts complete, remove solvent under reduced pressure and obtain midbody compound 6, described intermediate compound Thing 5, the mol ratio of thionyl chloride are 1: (1 ~ 2.5)；Described thionyl chloride, DMF, the mass ratio of anhydrous THF are (0.1-0.4): (0.1 ~ 0.15): (10 ~ 15)；

(vii) take substituted aniline and heavily steam pyridine, increasing the weight of to steam THF the most molten to solid, under ice bath stirring, step (v) being prepared Acid chloride intermediate compound 6 dissolves with heavily steaming heavily steaming THF, instills in reaction mixture, stirs 2 ~ 2.5 hours, detect nothing with TLC When substituted aniline and heavily steaming pyridine, react complete, remove solvent under reduced pressure, obtain the thick thing of rufous, be added into ethyl acetate With in the mixed solution of water, then being extracted with ethyl acetate 3 times, merge organic facies, washing, be dried, filter, filtrate decompression is evaporated off molten Agent, the target compound 8 of silica gel column chromatography separating purification, eluent system is petroleum ether: ethyl acetate=(6 ~ 10): 1, substituted benzene Amine, acyl chlorides are (0.8 ~ 1.5) with the mol ratio of pyridine: 1: 1.

Preparation method the most according to claim 2, it is characterised in that: described step (i) in, described substituted acetophenone is right Fluoro acetophenone, parachloroacetophenone, parabromoacetophenone, melilotal or to trifluoromethyl acetophenone.

Preparation method the most according to claim 2, it is characterised in that: described step (ii) in, in described beta-diketon acid esters Intermediate compounds therefor 2 be 4-(4-fluorophenyl)-2,4-dioxobutyric acid ethyl ester, 4-(4-chlorphenyl)-2,4-dioxobutyric acid ethyl ester, 4-(4-bromophenyl)-2,4-dioxobutyric acid ethyl ester, 4-(4-aminomethyl phenyl)-2,4-dioxobutyric acid ethyl ester or 4-(4-trifluoro Aminomethyl phenyl)-2,4-dioxobutyric acid ethyl ester.

Preparation method the most according to claim 2, it is characterised in that: described step (iii) in, described midbody compound 3 is 3-(4-fluorophenyl)-1H-pyrazole-5-ethyl formate, 3-(4-chlorphenyl)-1H-pyrazole-5-ethyl formate, 3-(4-bromine Phenyl)-1H-pyrazole-5-ethyl formate, 3-(4-aminomethyl phenyl)-1H-pyrazole-5-ethyl formate or 3-(4-trifluoromethylbenzene Base)-1H-pyrazole-5-ethyl formate；

Described step (iv) in, described midbody compound 4 is 1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-formic acid second Ester, 1-ethyl-3-(4-fluorophenyl)-1H-pyrazole-5-ethyl formate, 1-methyl-3-(4-chlorphenyl)-1H-pyrazoles-5-first Acetoacetic ester, 1-methyl-3-(4-bromophenyl)-1H-pyrazole-5-ethyl formate, 1-ethyl-3-(4-bromophenyl)-1H-pyrazoles- 5-Ethyl formate, 1-ethyl-3-(4-aminomethyl phenyl)-1H-pyrazole-5-ethyl formate or 1-ethyl-3-(4-trifluoromethylbenzene Base)-1H-pyrazole-5-ethyl formate；

Described step (v) in, midbody compound 5 is 1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-formic acid, 1-ethyl- 3-(4-fluorophenyl)-1H-pyrazoles-5-formic acid, 1-methyl-3-(4-chlorphenyl)-1H-pyrazoles-5-formic acid, 1-methyl-3-(4- Bromophenyl)-1H-pyrazoles-5-formic acid, 1-ethyl-3-(4-bromophenyl)-1H-pyrazoles-5-formic acid, 1-ethyl-3-(4-methyl Phenyl)-1H-pyrazoles-5-formic acid, 1-ethyl-3-(4-trifluoromethyl)-1H-pyrazoles-5-formic acid.

Preparation method the most according to claim 2, it is characterised in that:

Described step (vii) in, midbody compound 6 is 1-methyl-3-(4-fluorophenyl)-1H-pyrazoles-5-formyl chloride, 1-second Base-3-(4-fluorophenyl)-1H-pyrazoles-5-formyl chloride, 1-methyl-3-(4-chlorphenyl)-1H-pyrazoles-5-formyl chloride, 1-first Base-3-(4-bromophenyl)-1H-pyrazoles-5-formyl chloride, 1-ethyl-3-(4-bromophenyl)-1H-pyrazoles-5-formyl chloride, 1-second Base-3-p-methylphenyl-1H-pyrazoles-5-formyl chloride, 1-ethyl-3-(4-trifluoromethyl)-1H-pyrazoles-5-formyl chloride, Substituted aniline is aniline, 2-bromaniline, 3-bromaniline, 4-bromaniline, 2-5-trifluoromethylaniline, 3-5-trifluoromethylaniline, 4-tri- Methyl fluoride aniline, 2-cyano-aniline, 3-cyano-aniline, 4-monomethylaniline., 3-fluoroaniline, 4-fluoroaniline, 3-chloroaniline, 4-chlorobenzene Amine, 4-trifluoro-methoxyaniline, 3-nitroaniline, 3-acetylenylaniline, 3-chloro-4-fluoroaniline 2-fluoro-3-chloroaniline, 3-first Epoxide-4-cyano-aniline, 3,4-dicyano aniline, 3-trifluoromethyl-4-chloroaniline, 2-fluoro-5-5-trifluoromethylaniline, 3-trifluoro Methyl-4-bromaniline, 3-trifluoromethyl-4-fluoroaniline, 3-bromo-4-aniline, 2-methyl-3-bromaniline, bromo-4 fluoroanilines of 3-, 2, 3,4-trifluoromethyl aniline.

7. the application in the medicine preparing anti-prostate cancer of the 1,3,5-tri-substituted pyrazolecarboxylic compounds described in claim 1.