CN103497146A - 2-(N-alkyl piperidinol-4-amino)-4-(substituent phenol) benzene ring derivative as well as preparation method and application thereof - Google Patents

Abstract

The invention relates to a 2-(N-alkyl piperidinol-4-amino)-4-(substituent phenol) benzene ring derivative and pharmaceutically acceptable salts thereof. The series of compounds have a general structure formula (I); the invention also relates to a pharmaceutical composition containing the compound with a structure shown in the formula (I), and pharmaceutical application thereof.

Description

2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol)benzene ring derivatives and their preparation methods and applications

technical field

The present invention relates to a derivative and its preparation method and application, in particular to 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) benzene ring derivatives and its preparation method and application, belonging to Organic synthesis and medical application technology field.

Background technique

AIDS (AIDS) is one of the world's top ten fatal diseases caused by the human immunodeficiency virus (HIV), which seriously threatens human life and health. In the past two decades, although the number of HIV infections is still increasing sharply, with the clinical popularization of highly active antiretroviral therapy (HAART), the mortality rate caused by HIV infection has been effectively reduced. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have become an essential part of HAART therapy because of their high efficiency and low toxicity. However, since the amino acids at the binding sites of NNRTIs are prone to mutations, with the widespread clinical application of NNRTIs, drug-resistant mutant strains have begun to spread in recent years, causing the drugs to rapidly lose their clinical efficacy. Therefore, the development of new NNRTIs with high efficiency and resistance to drug resistance has become an urgent task in this field.

Through research, it was found that diarylpyrimidines (DAPY) not only exhibited excellent activity against wild strains, but also had significant inhibitory activity against a series of mutant strains. Among them, etravirine (TMC125) and rilpivirine (TMC278) have been successfully approved by the FDA for marketing, and dapivirine (TMC120) is in clinical research as a vaginal HIV inhibitor. However, most DAPY compounds have low oral bioavailability due to water solubility. Therefore, it is necessary to use DAPYs as the structural skeleton to conduct further research to improve their bioavailability and expand their antibacterial spectrum.

J.Q.Hang,G.M.Heilek,K.Klumpp,Discoveryof piperidin-4-yl-aminopyrimidines as HIV-1reverse transcriptase inhibitors.N-Benzyl derivativeswith broad potency against resistant mutant viruses,Bioorg.Med.Chem.Lett.,20(2010)4215–4218.②X.Chen,P.Zhan,X.Liu,Z.Cheng,C.Meng,S.Shao,C.Pannecouque,E.De Clercq,X.Liu,Design,synthesis,anti-HIV evaluation and molecular modeling of piperidine-linked amino-triazinederivatives as potent non-nucleoside reverse transcriptase inhibitors,Bioorganic&medicinalchemistry,20(2012)3856–3864.）。通过对DAPY类药物运用生物电子等排体原理进行改造，发现了二芳基苯胺类衍生物，对野生株和常见突变株保持了很好的HIV抑制活性，该结构骨架具有较大开发价值。（参考文献：B.Qin,X.Jiang,H.Lu,X.Tian,F.Barbault,L.Huang,K.Qian,C.-H.Chen,R.Huang,S.Jiang,K.-H.Lee,L.Xie,Diarylaniline Derivatives as a Distinct Class of HIV-1Non-nucleoside Reverse Transcriptase Inhibitors,J.Med.Chem.,53(2010)4906–4916.）In the study of DAPY-like NNRTIs, through molecular hybridization with benzophenone-like NNRTIs, piperidine-linked aminopyrimidine derivatives and piperidine-linked triazine derivatives were found, which were effective for wild strains and several common mutant strains. They all show activity at nanomolar level and improve the defect of low water solubility of the lead compound DAPY, which has the value of further research. (References: ① D.J. Kertesz, C. Brotherton-Pleiss, M. Yang, Z. Wang, X. Lin, Z. Qiu, DR Hirschfeld, S. Gleason, T. Mirzadegan, PW Dunten, SF Harris, AG

JQ Hang, GM Heilek, K. Klumpp, Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Benzyl derivatives with broad potency against resistant mutant viruses, Bioorg. Med. Chem. Lett., 20(2010) 4215–4218 .②X.Chen,P.Zhan,X.Liu,Z.Cheng,C.Meng,S.Shao,C.Pannecouque,E.De Clercq,X.Liu,Design,synthesis,anti-HIV evaluation and molecular modeling of piperidine-linked amino-triazine derivatives as potent non-nucleotide reverse transcriptase inhibitors, Bioorganic & Medicinal Chemistry, 20(2012) 3856–3864.). Through the transformation of DAPY drugs using the principle of bioelectronic isosteres, diarylaniline derivatives have been discovered, which maintain good HIV inhibitory activity against wild strains and common mutant strains, and this structural framework has great development value. (References: B. Qin, X. Jiang, H. Lu, X. Tian, F. Barbault, L. Huang, K. Qian, C.-H. Chen, R. Huang, S. Jiang, K.- H. Lee, L. Xie, Diarylaniline Derivatives as a Distinct Class of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors, J. Med. Chem., 53(2010) 4906–4916.)

Therefore, taking the above-mentioned piperidine-linked heterocyclic derivatives and diarylaniline derivatives as the forerunner, using the effective information of their structure-activity relationship, using the principle of skeleton transition to combine and carry out extensive structural modification, the discovery of broad-spectrum New NNRTIs with high efficiency, high bioavailability and independent intellectual property rights are of great significance.

Contents of the invention

Aiming at the deficiencies in the prior art, the invention provides 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) benzene ring derivatives and a preparation method thereof, and the invention also provides the above-mentioned compounds Activity Screening Results and Their Use.

Technical scheme of the present invention is as follows:

1. 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) benzene ring derivatives

2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) benzene ring derivatives of the present invention have general structural formula I as follows:

in,

R ₁ is: cyano or methyl;

R ₂ is: nitro, amino or acetamido;

Ar is phenyl, 4-pyridyl, 4-nitrophenyl, 4-aminosulfonylphenyl, 4-methylsulfonylphenyl, 4-aminoacylphenyl, 4-acetylphenyl, 4-hydroxy Methylphenyl, 4-carboxyphenyl or 4-methoxycarbonylphenyl.

Preferably, the above general formula I is one of the compounds of the following structures:

Two, the preparation method of 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) benzene ring derivatives

1. When _R is nitro or amino, the synthetic route of 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) benzene ring derivatives is as follows:

Reagents and conditions: (i) N-Boc piperidinamine, sodium carbonate, N,N-dimethylformamide; (ii) substituted phenols, potassium carbonate, tetrabutylammonium bromide, potassium iodide, N,N-dimethylformamide Methylformamide; (iii) trifluoroacetic acid, dichloromethane; (iv) potassium carbonate, N,N-dimethylformamide; (v) palladium carbon, hydrogen, tetrahydrofuran, ethanol; (ⅵ) concentrated hydrochloric acid, dichloromethane.

Wherein, R ₁ and Ar are the same as those described in general formula I.

The preparation steps are as follows:

When R ₂ is nitro, the preparation method of 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) nitrobenzene derivatives:

(1) Dissolve 4-chloro-2-fluoro-1-nitrobenzene (1), N-Boc piperidinamine, and sodium carbonate in N,N-dimethylformamide, and stir at 80°C for 1 hour; N,N-dimethylformamide was distilled off under reduced pressure, the resulting solid was dissolved in dichloromethane, washed with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by dry loading column A yellow solid was obtained, tert-butyl 4-(5-chloro-2-nitroanilino)piperidine-1-carboxylate (2);

(2) tert-butyl 4-(5-chloro-2-nitroanilino)piperidine-1-carboxylate (2), 4-cyano-3,5-dimethylphenol, potassium carbonate, Dissolve tetrabutylammonium bromide and potassium iodide in N,N-dimethylformamide, heat to 120-130°C for 12 hours; distill off N,N-dimethylformamide under reduced pressure, and dissolve the residue in Dichloromethane was washed with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, separated and purified by dry loading column to obtain a yellow solid, tert-butyl 4-(5-(4-cyano-2 ,6-Dimethylphenol)-2-nitroanilino)piperidine-1-carboxylate (3a);

(3) tert-butyl 4-(5-chloro-2-nitroanilino)piperidine-1-carboxylate (2), 2,4,6-trimethylphenol, potassium carbonate, tetrabutyl Ammonium bromide and potassium iodide were dissolved in N,N-dimethylformamide, heated to 120-130°C and stirred for 6h. The reactant was poured into water, the aqueous solution was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, separated and purified by dry loading column to obtain a yellow solid, tert-butyl 4-(5-(2, 4,6-trimethylphenoxy)-2-nitroanilino)piperidine-1-carboxylate (3b);

(4) Under the condition of water bath at 15°C, to tert-butyl 4-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitroanilino)piperidine-1-carboxylate Dichloride of ester (3a) or tert-butyl 4-(5-(2,4,6-trimethylphenoxy)-2-nitroanilino)piperidine-1-carboxylate (3b) Trifluoroacetic acid was added dropwise to the methane solution. The reactants continued to react under ice-bath conditions. A saturated sodium carbonate solution was added dropwise to the reactant. Filtration, the resulting precipitate was dried in a vacuum desiccator to give N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a ) or N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl) piperidin-4-amine (4b), directly used in the next step reaction;

(5) N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a) or N-(5-( 2,4,6-Trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b), substituted arylmethyl halides and potassium carbonate in N,N-dimethylformaldehyde Amides react at room temperature. The reactant was poured into excess water and filtered through celite. The filter cake was redissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol)nitro Benzene derivatives.

The substituted arylmethyl halide is selected from: 4-nitrobenzyl bromide, 4-chloromethylpyridine hydrochloride, 4-acetyl benzyl bromide, 4-hydroxymethyl benzyl chloride, 4-carboxybenzyl chloride, 4-Methanesulfonyl benzyl bromide, 4-carbamoyl benzyl chloride, 4-aminosulfonyl benzyl bromide, 4-methoxycarbonyl benzyl chloride, benzyl chloride. The structures of the obtained target compounds 5a1-5a10, 5b1-5b10 are shown in Table 1.

When R ₂ is amino, the preparation method of 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) aniline derivative hydrochloride:

Slowly add absolute ethanol to 10% palladium carbon catalyst, and add 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol)nitrobenzene derivatives (5a-b) to the resulting suspension ) in THF solution. The reaction solution was stirred and reacted under hydrogen at 30°C; filtered, purified, and the resulting pink solid was quickly dissolved in dichloromethane, and concentrated hydrochloric acid was added drop by drop under ice bath conditions, and the reaction was stirred; spin under reduced pressure After drying, a white solid 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) aniline derivative hydrochloride was obtained. The structure of the obtained target compound 7a1 is shown in Table 1.

2. When R _is acetylamino, the synthetic route of 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) benzene ring derivatives is as follows:

Reagents and conditions: (i) palladium on carbon, hydrogen, tetrahydrofuran, ethanol; (ii) acetyl chloride, triethylamine, dichloromethane; (iii) trifluoroacetic acid, dichloromethane; (iv) potassium carbonate, N,N -dimethylformamide.

Wherein, R ₁ and Ar are the same as those described in general formula I.

The preparation steps are as follows:

(1) Slowly add absolute ethanol to 10% palladium carbon catalyst, add tert-butyl 4-(5-(substituted phenoxy)-2-nitroanilino)piperidine-1-carboxylate to the resulting suspension tetrahydrofuran solution of acid ester (3a-b); the reaction solution was stirred and reacted under hydrogen at 30°C; filtered, spin-dried under reduced pressure, and the resulting pink solid was quickly dissolved in dichloromethane; triethylamine and acetyl chloride were dissolved in ice The above solution was added sequentially under bath conditions, and the stirring reaction was continued; the reaction solution was washed with water, the organic phase was collected, dried over anhydrous sodium sulfate, separated and purified by silica gel column chromatography, and recrystallized with ether to obtain a milky white solid, intermediate 9;

(2) Under the condition of a water bath at 15°C, add trifluoroacetic acid dropwise to the dichloromethane solution of intermediate 9; the reactants continue to react under ice bath conditions; add saturated sodium carbonate solution dropwise to the reactants ; Filtration, the resulting precipitate was dried in a vacuum drier to give a white solid, intermediate N-(4-(substituted phenoxy)-2-(piperidin-4-ylamino)phenyl)acetamide (10), directly used in the next reaction;

(3) Dissolve N-(4-(substituted phenoxy)-2-(piperidin-4-ylamino)phenyl)acetamide (10), substituted arylmethyl halide and potassium carbonate in N,N -Dimethylformamide was reacted at room temperature; the reactant was poured into excess water, and filtered with diatomaceous earth; the filter cake was redissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography Purification gave 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol)anilinoacetyl derivatives.

The substituted arylmethyl halide is selected from: 4-nitrobenzyl bromide, 4-chloromethylpyridine hydrochloride, 4-acetyl benzyl bromide, 4-hydroxymethyl benzyl chloride, 4-carboxybenzyl chloride, 4-Methanesulfonyl benzyl bromide, 4-carbamoyl benzyl chloride, 4-aminosulfonyl benzyl bromide, 4-methoxycarbonyl benzyl chloride, benzyl chloride. The structure of the obtained target compound 11 is shown in Table 1.

The structural formula of table 1 target compound

Three, the pharmaceutical composition containing the compound of the present invention

A pharmaceutical composition, comprising the compound described in the present invention and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition of the present invention can be prepared into various dosage forms according to conventional methods in the art, including but not limited to tablets, capsules, solutions, suspensions, granules or injections, etc., for oral or parenteral administration.

4. Application of 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) benzene ring derivatives

The 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) benzene ring derivatives provided by the invention can be used as HIV-1 non-nucleoside reverse transcriptase inhibitors. Specifically, it is used as an HIV-1 non-nucleoside reverse transcriptase inhibitor for the preparation of anti-AIDS drugs.

The present invention synthesizes a series of 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) benzene ring derivatives. The series of compounds have strong HIV-1 inhibitory activity and low cytotoxicity, and have further medicinal development value.

Application of the compound described in the present invention in the preparation of drugs for preventing and treating HIV infection.

Experimental example: activity and toxicity of 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) benzene ring derivatives

Compound anti-HIV activity test, thiazolyl blue method (MTT method): Add 50 μL of culture medium containing 1×10 ⁴ MT-4 cells (human acute lymphoblastoid cells) to a 96-well cell culture plate, and then add 20 μL of infected HIV- 1 (III _B ) or HIV-2 (ROD) MT-4 cell suspension (per milliliter containing 100 times the half infectious dose of cell culture CCID ₅₀ ), and then add different concentrations of the test compound solution, 3 for each concentration After culturing at 37°C for a certain period of time (5 days), add 20 μL (5 mg/ml) MTT solution to each well, continue to incubate for 2 hours, then add the dissolving solution dimethyl sulfoxide, and put it on a microplate reader , the absorbance was measured at 540nm, and the cell proliferation rate P% at different concentrations of the compound was calculated. At the same time, a blank group was set up, and the concentration required for the compound to protect 50% of the cells from HIV-induced cytopathy (EC ₅₀ ) was calculated.

Toxicity determination of the compound: In uninfected MT-4 cells, in parallel with the anti-HIV activity test of the compound, the concentration of the compound causing 50% of the uninfected cells to undergo cytopathic changes (CC ₅₀ ) was determined by the MTT method.

The 22 compounds shown in Table 1 were screened for anti-HIV activity, and their HIV inhibitory activity and toxicity data are shown in Table 2. Terminology explanation: The Chinese names of AZT, DDI, EFV, and DLV are zidovudine, didanosine, efavirenz, and delavirdine, respectively. Both were used as positive control drugs in this experiment.

Table 2 HIV inhibitory activity and toxicity of target compounds in MT-4 cells

^a EC ₅₀ : the concentration of compound that protects 50% of HIV-infected cells from cytopathic changes.

^b CC50: the concentration of the compound that protects 50% of HIV-uninfected cells from cytopathic changes.

^c SI: selectivity index, ie the ratio of CC ₅₀ /EC ₅₀ .

As shown in Table 2, except compound 11, all target compounds showed significant activity against wild-type HIV-1, and their EC ₅₀ values were all in the range of 0.022-2.09 μM, which was superior to the control drug didanosine, Half of the compounds outperformed the comparator delavirdine. The compound 5a6 with the best activity (EC ₅₀ =0.022±0.0091μM, SI>10770), its EC ₅₀ value is in the same order of magnitude as the control drugs zidovudine and efavirenz, and the SI value is in the same order of magnitude as zidovudine , far superior to Efavirenz. In addition, compound 7a1 not only has significant activity against HIV-1 wild strain, but also shows good activity against double mutant strain K103N+Y181C.

Activity test results show that 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol) benzene ring derivatives are a series of novel non-nucleoside HIV-1 inhibitors, most of which exhibit Significant HIV-1 inhibitory activity, among which compound 5a6 has the highest activity and the best selectivity, indicating that this type of compound has further research value and can be used as a lead compound against HIV-1.

Detailed ways

The present invention will be further described below in conjunction with embodiment, and the numbering of all target compounds is identical with table 1, and described percentage number is mass percentage.

Embodiment 1: Preparation of intermediate tert-butyl 4-(5-chloro-2-nitroanilino)piperidine-1-carboxylate (2)

Dissolve 0.09g (0.5mmol) 4-chloro-2-fluoro-1-nitrobenzene (1), 0.1g (0.5mmol) N-Boc piperidinamine, 0.15g (1.4mmol) sodium carbonate in 5mlN,N -Dimethylformamide (N,N-dimethylformamide), stirred and reacted at 80°C for 1 hour. N,N-dimethylformamide was distilled off under reduced pressure, and the resulting solid was dissolved in 10ml of dichloromethane (dichloromethane), washed with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and dried 0.18 g of tert-butyl 4-(5-chloro-2-nitroanilino)piperidine-1-carboxylate (2) was obtained by separation and purification on a column using the method. Yellow solid, yield: 100%, melting point: 93-95°C.

Product spectral analysis data:

ESI-MS: m/z 373.3(M+18), 375.4(M+2+18), 378.4(M+23).C ₁₆ H ₂₂ ClN ₃ O ₄ [355.13].;

Example 2: Intermediate tert-butyl 4-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitroanilino)piperidine-1-carboxylate (3a) preparation of

0.1g (0.28mmol) tert-butyl 4-(5-chloro-2-nitroanilino)piperidine-1-carboxylate (2), 0.04g (0.27mmol) 4-cyano-3,5 -Dimethylphenol, 0.08g (0.58mmol) potassium carbonate, 0.02g (0.062mmol) tetrabutylammonium bromide, 0.01g (0.060mmol) potassium iodide dissolved in 5ml N,N-dimethylformamide, heated to 120 React at -130°C for 12 hours. Evaporate N,N-dimethylformamide under reduced pressure, dissolve the residue in 10ml of dichloromethane, wash with saturated brine, collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate, and apply to the column by dry method Separation and purification gave 0.11 g of tert-butyl 4-(5-(4-cyano-2,6-dimethylphenol)-2-nitroanilino)piperidine-1-carboxylate (3a). Yellow solid, yield: 84.62%, melting point: 125-127°C.

Product spectral analysis data:

ESI-MS: m/z 467.5(M+1), 484.5(M+18), 489.5(M+23). C ₂₅ H ₃₀ N ₄ O ₅ [466.22].

Example 3: Preparation of intermediate tert-butyl 4-(5-(2,4,6-trimethylphenoxy)-2-nitroanilino)piperidine-1-carboxylate (3b)

0.05g (0.14mmol) tert-butyl 4-(5-chloro-2-nitroanilino) piperidine-1-carboxylate (2), 0.04g (0.29mmol) 2,4,6-trimethyl Base phenol, 0.08g (0.58mmol) potassium carbonate, 0.01g (0.03mmol) tetrabutylammonium bromide and 0.005g (0.03mmol) potassium iodide were dissolved in N,N-dimethylformamide and heated to 120-130 The reaction was stirred at ℃ for 6h. The reactant was poured into water, the aqueous solution was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, separated and purified by dry loading column to obtain 63.5 mg tert-butyl 4-(5-(2,4 ,6-trimethylphenoxy)-2-nitroanilino)piperidine-1-carboxylate (3b). Yellow solid, yield: 99.22%.

Product spectral analysis data:

ESI-MS: m/z 456.5(M+1), 473.3(M+18), 478.4(M+23).C25H33N3O5[455.24].

Example 4: Preparation of intermediate N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a)

Under the condition of water bath at 15°C, to 4.00g (8.58mmol) tert-butyl 4-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitroanilino)piperidine- 13ml of trifluoroacetic acid was added dropwise to a dichloromethane solution (13ml) of 1-carboxylate (3a) for 0.5h. The reactants continued to react for 0.5 h under ice bath conditions. 90 ml of saturated sodium carbonate solution was added dropwise to the reactant. Filtration, the resulting precipitate was dried in a vacuum dryer to give 3.09g N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a), directly used in the next reaction. Orange solid, yield: 98.41%.

Product spectral analysis data:

ESI-MS: m/z 367.3(M+1), 389.4(M+23).C ₂₀ H ₂₂ N ₄ O ₃ [366.17].

Example 5: Preparation of intermediate N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b)

The preparation method is the same as in Example 4, except that the reaction raw material is tert-butyl 4-(5-(2,4,6-trimethylphenoxy)-2-nitroanilino)piperidine-1-carboxylate acid ester (3b), and the product obtained is N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b). Yellow solid, yield: 99.53% Melting point: 152-154°C.

Product spectral analysis data:

ESI-MS: m/z 356.4(M+1), 378.4(M+23).C ₂₀ H ₂₅ N ₃ O ₃ [355.19].

Example 6: Preparation of 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol)benzene ring derivatives (5a1-5a10and5b1-5b10)

1eq N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a) or N-(5-(2, 4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b), 0.99eq-1.56eq substituted arylmethyl halide, 2.11eq-3.22eq potassium carbonate dissolved in N,N-dimethylformamide reacted at room temperature for 1.5h-12h. The reactant was poured into excess water and filtered through celite. The filter cake was redissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, separated and purified by column chromatography to obtain 2-(N-arylmethylpiperidine-4-amino)-4-(substituted phenol)benzene ring derivative. The substituted arylmethyl halide is selected from: 4-nitrobenzyl bromide, 4-chloromethylpyridine hydrochloride, 4-acetyl benzyl bromide, 4-hydroxymethyl benzyl chloride, 4-carboxybenzyl chloride, 4-methanesulfonyl benyl bromide, 4-carbamoyl benyl chloride, 4-aminosulfonyl benyl bromide, 4-methoxycarbonyl benyl chloride, benne chloride, the structures of the obtained target compounds 5a1-5a10, 5b1-5b10 are shown in Table 1.

Piperidinamine is selected from N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a), substituted arylmethyl halide Select 4-nitrobenzyl bromide to obtain 3,5-dimethyl-4-(4-nitro-3-(1-(4-nitrophenyl)piperidin-4-ylamino)phenoxy ) benzonitrile (5a1). Orange solid, yield: 100%, melting point: 208-210°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.28(d,1H,J=7.1Hz,NH),8.19(d,2H,J=8.6Hz,C ₃ ,C ₅ -Ph'-H),8.14 (d,1H,J=9.5Hz,C ₆ -Ph-H),7.53(d,2H,J=8.5Hz,C ₂ ,C ₆ -Ph'-H),7.46(s,2H,C ₃ , C ₅ -Ph''-H),6.13(d,1H,J=2.4Hz,C ₃ -Ph-H),5.97(dd,1H,J ₁ =2.5Hz,J ₂ =9.5Hz,C ₅ - Ph-H), 3.63(s,2H,CH ₂ ), 3.36(m,1H,C ₁ -Pi-H), 2.78(t,2H,Pi-CH ₂ ), 2.25(t,2H,Pi-CH ₂ ),2.17(s,6H,2×CH ₃ ),2.00(m,2H,Pi-CH ₂ ),1.68(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,CDCl ₃ ,ppm )δ:162.84(Ph-C ₄ ),153.77(Ph''-C ₁ ),147.21,146.49,146.43,133.05,133.01,130.22,129.35,127.77,123.59,118.39(C≡N),109.79,103.13, 97.66(Ph-C ₃ ), 62.07(Pi-CH ₂ -Py), 51.61, 48.96, 31.52, 16.16(2×CH ₃ ).ESI-MS: m/z502.3(M+1), 524.4(M +23),540.4(M+39).C ₂₇ H ₂₇ N ₅ O ₅ [501.20].

Piperidinamine is selected from N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a), substituted arylmethyl halide Select 4-chloromethylpyridine hydrochloride to obtain 3,5-dimethyl-4-(4-nitro-3-(1-(pyridin-4-ylmethyl)piperidin-4-ylamino )phenoxy)benzonitrile (5a2). Yellow solid, yield: 71.00%, melting point: 169-171°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,ppm)δ:8.56(dd,2H,J ₁ =1.4Hz,J ₂ =4.5Hz,C ₃ ,C ₅ -Py-H),8.28(d,J=7.1Hz, 1H,NH),8.15(d,1H,J=9.5Hz,C ₆ -Ph-H),7.46(s,2H,C ₃ ,C ₅ -Ph'-H),7.30(d,2H,J= 5.7Hz, C ₂ , C ₆ -Py-H), 6.12(d,1H, J=2.4Hz, C ₃ -Ph-H), 5.97(dd,1H, J ₁ =2.5Hz, J ₂ =9.5Hz ,C ₅ -Ph-H),3.55(s,2H,CH ₂ ),3.36(m,1H,C ₁ -Pi-H),2.79(t,2H,Pi-CH ₂ ),2.25(t,2H ,Pi-CH ₂ ), 2.17(s,6H,2×CH ₃ ), 2.01(m,2H,Pi-CH ₂ ),1.69(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz, CDCl ₃ ,ppm)δ:162.84(Ph-C ₄ ),153.75(Ph''-C ₁ ),149.88,146.49,133.04,133.01,130.24,127.76,123.76,118.39(C≡N),109.79,103.11, 97.65(Ph-C ₃ ), 61.63(Pi-CH ₂ -Py), 51.57, 31.41, 16.18(2×CH ₃ ).ESI-MS: m/z 458.5(M+1).C ₂₆ H ₂₇ N ₅ O ₃ [457.21].

Piperidinamine is selected from N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a), substituted arylmethyl halide Select 4-acetyl benzyl bromide to obtain 4-(3-(1-(4-acetylbenzyl)piperidin-4-ylamino)-4-nitrophenoxy)-3,5-dimethyl benzonitrile (5a3). Yellow solid, yield: 66.18%, melting point: 110-112°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,ppm)δ:8.28(d,1H,J=7.2Hz,NH),8.14(d,1H,J=9.4Hz,C ₆ -Ph-H),7.93(d,2H ,J=8.2Hz,C ₃ ,C ₅ -Ph'-H),7.45(s,2H,C ₃ ,C ₅ -Ph''-H),7.44(d,2H,J=9.3Hz,C ₂ ,C ₆ -Ph'-H),6.12(d,1H,J=2.5Hz,C ₃ -Ph-H),5.96(dd,1H,J ₁ =2.5Hz,J ₂ =9.5Hz,C ₅ - Ph-H), 3.59(s,2H,CH ₂ ), 3.34(m,1H,C ₁ -Pi-H), 2.79(t,2H,Pi-CH ₂ ), 2.61(s,3H,CO-CH ₃ ),2.22(t,2H,Pi-CH ₂ ),2.17(s,6H,2×CH ₃ ),1.99(m,2H,Pi-CH ₂ ),1.68(m,2H,Pi-CH ₂ ) . ¹³ C-NMR (100MHz, CDCl ₃ , ppm) δ: 197.86 (C=O), 162.81 (Ph-C ₄ ), 153.76 (Ph''-C ₁ ), 146.53, 144.11, 136.17, 133.04, 133.00, 130.21, 128.96, 128.44, 127.72, 118.40 (C≡N), 109.77, 103.05, 97.66 (Ph-C ₃ ), 62.53 (Pi-CH ₂ -Py), 51.58, 49.10, 31.54, 26.65 (CO-CH ₃ ) ,16.17(2×CH ₃ ).ESI-MS: m/z 499.4(M+1),521.4(M+23).C ₂₉ H ₃₀ N ₄ O ₄ [498.23].

Piperidinamine is selected from N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a), substituted arylmethyl halide Select 4-hydroxymethyl benzyl chloride to obtain 4-(3-(1-(4-(hydroxymethyl)benzyl)piperidin-4-ylamino)-4-nitrophenoxy)-3, 5-Dimethylbenzonitrile (5a4). Orange solid, yield: 38.46%, melting point: 163-165°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.25(d,1H,J=7.2Hz,NH),8.13(d,1H,J=9.4Hz,C ₆ -Ph-H),7.45(s,2H ,C ₃ ,C ₅ -Ph''-H),7.34(d,4H,C ₂ ,C ₃ ,C ₅ ,C ₆ -Ph'-H),6.10(d,1H,J=2.5Hz,C ₃ -Ph-H),5.96(dd,1H,J ₁ =2.5Hz,J ₂ =9.5Hz,C ₅ -Ph-H),4.69(s,2H,Ph'-CH ₂ -O),3.56( s,2H,Pi-CH ₂ -Ph'),3.32(m,1H,C ₁ -Pi-H),2.81(t,2H,Pi-CH ₂ ),2.23(m,2H,Pi-CH ₂ ) ,2.16(s,6H,2×CH ₃ ),1.99(t,2H,Pi-CH ₂ ),1.67(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,CDCl ₃ ,ppm)δ :162.81(Ph-C ₄ ),153.79(Ph''-C ₁ ),146.51,140.08,133.04,132.99,130.18,129.38,127.80,127.03,118.33(C≡N),109.81,103.10,97.68(Ph- C ₃ ), 65.06(CH ₂ ), 62.52(CH ₂ ), 51.24, 49.08, 31.36, 16.12(2×CH ₃ ).ESI-MS: m/z 487.5(M+1), 509.4(M+23 ).C ₂₈ H ₃₀ N ₄ O ₄ [486.23].

Piperidinamine is selected from N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a), substituted arylmethyl halide Select 4-carboxybenyl chloride to obtain 4-((4-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenylamino)piperidin-1-yl ) methyl) benzoic acid (5a5). Yellow solid, yield: 39.24%, mp: 230-232°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,ppm)δ:8.29(d,1H,J=6.2Hz,NH),8.14(d,1H,J=9.4Hz,C ₆ -Ph-H),8.05(d,2H ,J=7.7Hz,C ₃ ,C ₅ -Ph'-H),7.47(d,2H,C ₂ ,C ₆ -Ph'-H),7.45(s,2H,C ₃ ,C ₅ -Ph''-H),6.13(d,1H,J=1.3Hz,C ₃ -Ph-H),5.96(dd,1H,J ₁ =1.8Hz,J ₂ =9.4Hz,C ₅ -Ph-H), 3.77(s,2H,CH ₂ ),3.43(m,1H,C1-Pi-H),2.97(t,2H,Pi-CH ₂ ),2.49(t,2H,Pi-CH ₂ ),2.15(s ,6H,2×CH ₃ ), 2.09(m,2H,Pi-CH ₂ ),1.79(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,CDCl ₃ ,ppm)δ:162.87(Ph -C ₄ ),153.72(Ph''-C ₁ ),146.41,133.03,130.25,130.16,129.62,127.83,118.37(C≡N),109.82,103.17,97.70(Ph-C ₃ ),62.00(Pi- CH ₂ -Py), 53.44, 51.07, 30.56, 16.18 (2×CH ₃ ). ESI-MS: m/z 499.5 (M-1). C ₂₈ H ₂₈ N ₄ O ₅ [500.21].

Piperidinamine is selected from N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a), substituted arylmethyl halide Select 4-methylsulfonyl bromide to obtain 3,5-dimethyl-4-(3-(1-(4-(methylsulfonyl)benzyl)piperidin-4-ylamino)-4-nitro phenoxy)benzonitrile (5a6). Yellow solid, yield: 78.08%, melting point: 164-166°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.28(d,1H,J=7.0Hz,NH),8.14(d,1H,J=9.5Hz,C ₆ -Ph-H),7.91(d,2H ,J=8.2Hz,C ₃ ,C ₅ -Ph'-H),7.58(d,2H,J=7.2Hz,C ₂ ,C ₆ -Ph'-H),7.46(s,2H,C ₃ , C ₅ -Ph''-H),6.13(d,1H,J=2.4Hz,C ₃ -Ph-H),5.97(dd,1H,J ₁ =2.5Hz,J ₂ =9.5Hz,C ₅ - Ph-H), 3.64(s,2H,CH ₂ ), 3.37(m,1H,C ₁ -Pi-H), 3.07(s,3H,SO ₂ -CH ₃ ), 2.79(t,2H,Pi- CH ₂ ), 2.26(t,2H,Pi-CH ₂ ),2.17(s,6H,2×CH ₃ ),2.00(m,2H,Pi-CH ₂ ),1.70(m,2H,Pi-CH ₂ ⁽ _{_ _ _} C≡N),109.79,103.15,97.66(Ph-C ₃ ),62.15(Pi-CH ₂ -Py),51.54,44.53(SO ₂ -CH ₃ ),31.42,16.18(2×CH ₃ ).ESI- MS: m/z535.3(M+1),557.2(M+23).C ₂₈ H ₃₀ N ₄ O ₅ S[534.19].

Piperidinamine is selected from N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a), substituted arylmethyl halide Select 4-carbamoyl chloride to obtain 4-((4-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenylamino)piperidine-1 -yl)methyl)benzamide (5a7). Yellow solid, yield: 88.24%, melting point: 198-200°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.26(d,1H,J=7.1Hz,NH),8.14(d,1H,J=9.4Hz,C ₆ -Ph-H),7.80(d,2H ,J=8.1Hz,C ₃ ,C ₅ -Ph'-H),7.45(s,2H,C ₃ ,C ₅ -Ph''-H),7.43(d,2H,J=8.3Hz,C ₂ ,C ₆ -Ph'-H),6.10(br,2H,NH ₂ ),6.10(d,1H,J=2.4Hz,C ₃ -Ph-H),5.98(dd,1H,J ₁ =2.4Hz ,J ₂ =9.5Hz,C ₅ -Ph-H),3.61(s,2H,CH ₂ ),3.31(m,1H,C ₁ -Pi-H),2.80(t,2H,Pi-CH ₂ ) ,2.24(t,2H,Pi-CH ₂ ),2.16(s,6H,2×CH ₃ ),1.99(m,2H,Pi-CH ₂ ),1.67(m,2H,Pi-CH ₂ ). ¹³ C-NMR (100MHz, CDCl ₃ , ppm) δ: 169.22 (C=O), 162.83 (Ph-C ₄ ), 153.77 (Ph''-C ₁ ), 146.50, 133.05, 133.01, 132.33, 130.23, 129.20, 127.73,127.49,118.41(C≡N),109.75,103.16,97.61(Ph-C ₃ ),62.37(Pi-CH2-Py),51.39,31.39,16.17(2×CH ₃ ).ESI-MS:m/ z500.3(M+1),522.4(M+23).C ₂₈ H ₂₉ N ₅ O ₄ [499.22].

Piperidinamine is selected from N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a), substituted arylmethyl halide Select 4-aminosulfonyl bromide to obtain 4-((4-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenylamino)piperidine-1 -yl)methyl)benzenesulfonamide (5a8). Yellow solid, yield: 65.63%, melting point: 147-149°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.26(d,1H,J=7.0Hz,NH),8.14(d,1H,J=9.5Hz,C ₆ -Ph-H),7.90(d,2H ,J=8.0Hz,C ₃ ,C ₅ -Ph'-H),7.50(d,2H,J=8.0Hz,C ₂ ,C ₆ -Ph'-H),7.46(s,2H,C ₃ , C ₅ -Ph''-H),6.10(d,1H,C ₃ -Ph-H),5.99(dd,1H,J ₁ =1.6Hz,J ₂ =9.4Hz,C ₅ -Ph-H), 5.20(s,2H,NH ₂ ),3.62(s,2H,CH ₂ ),3.35(m,1H,C ₁ -Pi-H),2.78(t,2H,Pi-CH ₂ ),2.24(t, 2H,Pi-CH ₂ ),2.16(s,6H,2×CH ₃ ),1.99(m,2H,Pi-CH ₂ ),1.67(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz , CDCl ₃ , ppm) δ: 162.87 (Ph-C ₄ ), 153.78 (Ph''-C ₁ ), 146.51, 140.86, 133.05, 133.03, 130.23, 129.54, 127.70, 126.49, 118.43 (C≡N), 109.73 ,103.25,97.62(Ph-C ₃ ),62.15(Pi-CH ₂ -Py),51.35,31.37,16.17(2×CH ₃ ).ESI-MS: m/z536.4(M+1),558.4( M+23).C ₂₇ H ₂₉ N ₅ O ₅ S[535.19].

Piperidinamine is selected from N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a), substituted arylmethyl halide Select 4-methoxycarbonyl chloride to obtain methyl 4-((4-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenylamino)piperidine -1-yl)methyl)benzoate (5a9). Yellow solid, yield: 71.43%, melting point: 182-184°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,ppm)δ:8.27(d,1H,J=7.2Hz,NH),8.14(d,1H,J=9.5Hz,C ₆ -Ph-H),8.00(d,2H ,J=8.3Hz,C ₃ ,C ₅ -Ph'-H),7.45(s,2H,C ₃ ,C ₅ -Ph''-H),7.42(d,2H,J=8.1Hz,C ₂ ,C ₆ -Ph'-H),6.13(d,1H,J=2.5Hz,C ₃ -Ph-H),5.96(dd,1H,J ₁ =2.5Hz,J ₂ =9.5Hz,C ₅ - Ph-H), 3.92(s,3H,COO-CH ₃ ), 3.59(s,2H,CH ₂ ), 3.34(m,1H,C ₁ -Pi-H), 2.79(t,2H,Pi-CH ₂ ),2.22(t,2H,Pi-CH ₂ ),2.16(s,6H,2×CH ₃ ),1.99(m,2H,Pi-CH ₂ ),1.67(m,2H,Pi-CH ₂ ) . ¹³ C-NMR (100MHz, CDCl ₃ , ppm) δ: 167.01 (C=O), 162.82 (Ph-C ₄ ), 153.77 (Ph''-C ₁ ), 146.53, 133.04, 133.01, 130.22, 129.66, 129.11, 128.84, 127.74, 118.40 (C≡N), 109.78, 103.04, 97.70 (Ph-C ₃ ), 62.53 (Pi-CH ₂ -Py), 52.09 (O-CH ₃ ), 51.54, 31.47, 16.18 (2 ×CH ₃ ).ESI-MS: m/z 515.5(M+1), 537.4(M+23).C ₂₉ H ₃₀ N ₄ O ₅ [514.22].

Piperidinamine is selected from N-(5-(4-cyano-2,6-dimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4a), substituted arylmethyl halide Select Bian chlorine to obtain 4-(3-(1-benzylpiperidin-4-ylamino)-4-nitrophenoxy)-3,5-dimethylbenzonitrile (5a10). Yellow solid, yield: 72.00%, melting point: 156-158°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,ppm)δ:8.26(d,1H,J=7.2Hz,NH),8.14(d,1H,J=9.5Hz,C ₆ -Ph-H),7.45(s,2H ,C ₃ ,C ₅ -Ph''-H),7.33(m,4H,C ₂ ,C ₃ ,C ₅ ,C ₆ -Ph'-H),7.26(m,1H,C ₄ -Ph'- H),6.12(d,1H,J=2.5Hz,C ₃ -Ph-H),5.95(dd,1H,J ₁ =2.5Hz,J ₂ =9.5Hz,C ₅ -Ph-H),3.53( s,2H,CH ₂ ),3.32(m,1H,C ₁ -Pi-H),2.80(t,2H,Pi-CH ₂ ),2.20(t,2H,Pi-CH ₂ ),2.16(s, 6H,2×CH ₃ ), 1.97(m,2H,Pi-CH ₂ ),1.65(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,CDCl ₃ ,ppm)δ:162.80(Ph- C ₄ ),153.79(Ph''-C ₁ ),146.59,138.21,133.05,133.01,130.21,129.07,128.30,127.70,127.14,118.42(C≡N),109.77,103.00,97.70(Ph-C ₃ ) ,63.00(Pi-CH ₂ -Py),51.50,49.30,31.59,16.19(2×CH ₃ ).ESI-MS: m/z 457.5(M+1).C ₂₇ H ₂₈ N ₄ O ₃ [456.22 ].

N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b) is selected for piperidinamine, and 4- Nitrobenzyl bromide, N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)-1-(4-nitrobenzyl)piperidine-4- Amine (5b1). Orange solid, yield: 98.58%, melting point: 178-180°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.28(d,1H,J=7.2Hz,NH),8.19(d,2H,J=8.6Hz,C ₃ ,C ₅ -Ph'-H),8.11 (d,1H,J=9.5Hz,C ₆ -Ph-H),7.52(d,2H,J=8.6Hz,C ₂ ,C ₆ -Ph'-H),6.91(s,2H,C ₃ , C ₅ -Ph''-H),6.15(d,1H,J=2.4Hz,C ₃ -Ph-H),6.01(dd,1H,J ₁ =2.4Hz,J ₂ =9.5Hz,C ₅ - Ph-H),3.61(s,2H,CH ₂ ),3.38(m,1H,C ₁ -Pi-H),2.76(t,2H,Pi-CH ₂ ),2.31(s,3H,C ₄ - Ph''-CH ₃ ),2.25(t,2H,Pi-CH ₂ ),2.07(s,6H,C ₂ ,C ₆ -Ph''-CH ₃ ),2.00(m,2H,Pi-CH ₂ ),1.67(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,CDCl ₃ ,ppm)δ:164.41(Ph-C ₄ ),147.93,147.20,146.64,146.49,135.36,130.47,129.89, 129.70,129.34,127.21,123.59,103.75(Ph-C ₅ ),97.53(Ph-C ₃ ),62.12(Pi-CH ₂ -Py),51.61,48.78,31.48,20.80(Ph''-C ₄ -CH ₃ ), 16.09 (2×CH ₃ ). ESI-MS: m/z 491.4 (M+1), 513.4 (M+23). C ₂₇ H ₃₀ N ₄ O ₅ [490.22].

N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b) is selected for piperidinamine, and 4- Chloromethylpyridine hydrochloride, N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)-1-(pyridin-4-ylmethyl)piper Pyridine-4-amine (5b2). Yellow solid, yield: 47.62%, melting point: 105-107°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.56(dd,2H,J ₁ =1.4Hz,J ₂ =4.6Hz,C ₃ ,C ₅ -P _y -H),8.28(d,1H,J= 7.0Hz,NH),8.11(d,1H,J=9.5Hz,C ₆ -Ph-H),7.30(d,2H,J=5.5Hz,C ₂ ,C ₆ -Py-H),6.91(s ,2H,C ₃ ,C ₅ -Ph'-H),6.13(d,1H,J=2.3Hz,C ₃ -Ph-H),6.02(dd,1H,J ₁ =2.4Hz,J ₂ =9.5 Hz,C ₅ -Ph-H),3.55(s,2H,CH ₂ ),3.38(m,1H,C ₁ -Pi-H),2.78(t,2H,Pi-CH ₂ ),2.31(s, 3H,C ₄ -Ph'-CH ₃ ),2.28(t,2H,Pi-CH ₂ ),2.07(s,6H,C ₂ ,C ₆ -Ph'-CH ₃ ),2.03(m,2H,Pi -CH ₂ ),1.69(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,CDCl ₃ ,ppm)δ:164.42(Ph-C ₄ ),149.88,147.91,146.62,135.37,130.45,129.89 ,129.70,127.21,123.80,103.84(Ph-C ₅ ),97.48(Ph-C ₃ ),61.61(Pi-CH ₂ -Py),51.50,31.27,20.80(Ph''-C ₄ -CH ₃ ), 16.09(2×CH ₃ ).ESI-MS: m/z 447.5(M+1), 469.5(M+23).C ₂₆ H ₃₀ N ₄ O ₃ [446.23].

N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b) is selected for piperidinamine, and 4- Acetyl benzoyl bromide, resulting in 1-(4-((4-(5-(2,4,6-trimethylphenoxy)-2-nitrophenylamino)piperidin-1-yl)methanol yl)phenyl)acetyl (5b3). Yellow solid, yield: 87.21%, melting point: 138-140°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,ppm)δ:8.27(d,1H,J=6.9Hz,NH),8.10(d,1H,J=9.5Hz,C ₆ -Ph-H),7.93(d,2H ,J=8.1Hz,C ₃ ,C ₅ -Ph'-H),7.44(d,2H,J=7.8Hz,C ₂ ,C ₆ -Ph'-H),6.91(s,2H,C ₃ , C ₅ -Ph''-H),6.13(d,1H,J=1.9Hz,C ₃ -Ph-H),6.02(dd,1H,J ₁ =2.0Hz,J ₂ =9.4Hz,C ₅ - Ph-H), 3.59(s,2H,CH ₂ ), 3.36(m,1H,C ₁ -Pi-H), 2.78(t,2H,Pi-CH ₂ ), 2.60(s,3H,CO-CH ₃ ),2.31(s,3H,C ₄ -Ph''-CH ₃ ),2.23(t,2H,Pi-CH ₂ ),2.07(s,6H,C ₂ ,C ₆ -Ph''-CH ₃ ),2.00(m,2H,Pi-CH ₂ ),1.67(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,CDCl ₃ ,ppm)δ:197.80(C=O),164.40(Ph -C ₄ ),147.94,146.65,136.26,135.35,130.46,129.87,129.69,129.03,128.45,127.21,103.79(Ph-C ₅ ),97.50(Ph-C ₃ ),62.50(Pi-CH ₂ -Py) ,51.52,48.88,31.58,31.41,26.62(CO-CH ₃ ),20.79(Ph''-C ₄ -CH ₃ ),16.07(2×CH ₃ ).ESI-MS:m/z488.4(M+ 1),510.4(M+23).C ₂₉ H ₃₃ N ₃ O ₄ [487.25].

N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b) is selected for piperidinamine, and 4- Hydroxymethyl benzyl chloride, resulting in (4-((4-(5-(2,4,6-trimethylphenoxy)-2-nitrophenylamino)piperidin-1-yl)methyl ) phenyl) methanol (5b4). Yellow solid, yield: 62.69%, melting point: 68-70°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.26(d,1H,J=6.9Hz,NH),8.10(d,1H,J=9.5Hz,C ₆ -Ph-H),7.33(d,4H ,C ₂ ,C ₃ ,C ₅ ,C ₆ -Ph'-H),6.91(s,2H,C ₃ ,C ₅ -Ph''-H),6.12(d,1H,J=1.9Hz,C ₃ -Ph-H),6.01(dd,1H,J ₁ =2.1Hz,J ₂ =9.5Hz,C ₅ -Ph-H),4.69(s,2H,Ph'-CH ₂ -O),3.54( s,2H,Pi-CH ₂ -Ph'),3.34(m,1H,C ₁ -Pi-H),2.78(t,2H,Pi-CH ₂ ),2.31(s,3H,C ₄ -Ph''-CH ₃ ),2.22(t,2H,Pi-CH ₂ ),2.07(s,6H,C ₂ ,C ₆ -Ph''-CH ₃ ),2.01(m,2H,Pi-CH ₂ ), 1.66(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,CDCl ₃ ,ppm)δ:164.40(Ph-C ₄ ),147.93,146.68,139.99,135.36,130.47,129.87,129.70,129.41, 127.16,127.06,103.79(Ph-C ₅ ),97.50(Ph-C ₃ ),65.12(CH ₂ ),62.61(CH ₂ ),51.34,31.60,31.29,20.80(Ph''-C ₄ -CH ₃ ) ,16.09(2×CH ₃ ).ESI-MS: m/z 476.3(M+1),498.4(M+23).C ₂₈ H ₃₃ N ₃ O ₄ [475.25].

N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b) is selected for piperidinamine, and 4- Carboxybenzoic acid, resulting in 4-((4-(5-(2,4,6-trimethylphenoxy)-2-nitrophenylamino)piperidin-1-yl)methyl)benzoic acid (5b5). Yellow solid, yield: 78.26%, melting point: 133-135°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.28(d,1H,J=6.2Hz,NH),8.10(d,1H,J=9.5Hz,C ₆ -Ph-H),8.04(d,2H ,J=7.5Hz,C ₃ ,C ₅ -Ph'-H),7.44(d,2H,J=7.7Hz,C ₂ ,C ₆ -Ph'-H),6.90(s,2H,C ₃ , C ₅ -Ph''-H),6.11(d,1H,C ₃ -Ph-H),6.03(dd,1H,J ₁ =1.4Hz,J ₂ =9.5Hz,C ₅ -Ph-H), 3.84(s,2H,CH ₂ ),3.44(m,1H,C ₁ -Pi-H),3.01(t,2H,Pi-CH2),2.56(t,2H,Pi-CH ₂ ),2.30(s ,3H,C ₄ -Ph''-CH ₃ ),2.06(m,2H,Pi-CH ₂ ),2.06(s,6H,C ₂ ,C ₆ -Ph''-CH ₃ ),1.80((m ,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,DMSO-d ₆ ,ppm)δ:167.97(COOH),164.30(Ph-C ₄ ),147.91,146.72,143.62,135.44,131.98,131.00, 130.39,130.09,129.68,129.07,128.92,126.91,103.96(Ph-C ₅ ),98.26(Ph-C ₃ ),62.02(Pi-CH ₂ -Py),51.50,31.43,30.47,20.81(Ph''- C ₄ -CH ₃ ), 16.12 (2×CH ₃ ). ESI-MS: m/z 490.4 (M+1), 512.5 (M+23). C ₂₈ H ₃₁ N ₃ O ₅ [489.23].

N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b) is selected for piperidinamine, and 4- Methanesulfonyl benzyl bromide, N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)-1-(4-(methylsulfonyl)benzyl)piper Pyridine-4-amine (5b6). Yellow solid, yield: 73.97%, melting point: 136-138°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.28(d,1H,J=7.0Hz,NH),8.10(d,1H,J=9.5Hz,C ₆ -Ph-H),7.90(d,2H ,J=8.2Hz,C ₃ ,C ₅ -Ph'-H),7.56(d,2H,J=7.9Hz,C ₂ ,C ₆ -Ph'-H),6.91(s,2H,C ₃ , C ₅ -Ph''-H),6.14(d,1H,J=1.9Hz,C ₃ -Ph-H),6.01(dd,1H,J ₁ =2.0Hz,J ₂ =9.4Hz,C ₅ - Ph-H), 3.61(s,2H,CH ₂ ), 3.38(m,1H,C ₁ -Pi-H), 3.07(s,3H,SO ₂ -CH ₃ ), 2.77(t,2H,Pi- CH ₂ ), 2.31(s,3H,C ₄ -Ph''-CH3), 2.24(t,2H,Pi-CH ₂ ), 2.07(s,6H,C ₂ ,C ₆ -Ph''-CH ₃ ),2.00(m,2H,Pi-CH ₂ ),1.67(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,CDCl ₃ ,ppm)δ:164.42(Ph-C ₄ ),147.91, 146.64,139.32,135.37,130.46,129.90,129.71,129.63,127.46,127.19,103.78(Ph-C ₅ ),97.51(Ph- _{C 3 )} ,62.23(Pi- _CH -CH ₃ ), 31.42, 20.82(Ph''-C ₄ -CH ₃ ), 16.10(2×CH ₃ ).ESI-MS: m/z524.5(M+1), 541.5(M+18), 546.4(M+23).C ₂₈ H ₃₃ N ₃ O ₅ S[523.21].

N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b) is selected for piperidinamine, and 4- Carbamoyl benzyl chloride to give 4-((4-(5-(2,4,6-trimethylphenoxy)-2-nitrophenylamino)piperidin-1-yl)methyl) Benzamide (5b7). Yellow solid, yield: 92.75%, melting point: 92-94°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.27(d,1H,J=6.8Hz,NH),8.10(d,1H,J=9.5Hz,C ₆ -Ph-H),7.79(d,2H ,J=8.0Hz,C ₃ ,C ₅ -Ph'-H),7.43(d,2H,J=7.9Hz,C ₂ ,C ₆ -Ph'-H),6.91(s,2H,C ₃ , C ₅ -Ph''-H),6.13(d,1H,C ₃ -Ph-H),6.06(br,2H,NH ₂ ),6.01(dd,1H,J ₁ =1.6Hz,J ₂ =9.4 Hz,C ₅ -Ph-H),3.58(s,2H,CH ₂ ),3.36(m,1H,C ₁ -Pi-H),2.77(t,2H,Pi-CH ₂ ),2.31(s, 3H,C ₄ -Ph''-CH ₃ ),2.23(t,2H,Pi-CH ₂ ),2.07(s,6H,C ₂ ,C ₆ -Ph''-CH ₃ ),2.01(m,2H ,Pi-CH ₂ ),1.66(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,CDCl ₃ ,ppm)δ:169.25(C=O),164.42(Ph-C ₄ ),147.91, 146.68,135.36,132.25,130.46,129.88,129.70,129.13,127.46,127.15,103.78(Ph-C ₅ ),97.51(Ph-C ₃ ),62.47(Pi-CH ₂ -Py),51.49,31.60,31.40, 20.81(Ph''-C ₄ -CH ₃ ), 16.10(2×CH ₃ ).ESI-MS: m/z 489.6(M+1), 511.5(M+23).C ₂₈ H ₃₂ N ₄ O ₄ [488.24].

N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b) is selected for piperidinamine, and 4- Aminosulfonyl bromide to give 4-((4-(5-(2,4,6-trimethylphenoxy)-2-nitrophenylamino)piperidin-1-yl)methyl) Benzenesulfonamide (5b8). Yellow solid, yield: 75.34%, melting point: 128-130°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.27(d,1H,J=6.4Hz,NH),8.10(d,1H,J=9.4Hz,C ₆ -Ph-H),7.89(d,2H ,J=7.8Hz,C ₃ ,C ₅ -Ph'-H),7.49(d,2H,J=7.8Hz,C ₂ ,C ₆ -Ph'-H),6.91(s,2H,C ₃ , C ₅ -Ph''-H),6.14(d,1H,C3 -Ph _- H),6.01(dd,1H,J=9.2Hz,C ₅ -Ph-H),5.14(s,2H,NH ₂ ),3.59(s,2H,CH ₂ ),3.37(m,1H,C1-Pi-H),2.74(t,2H,Pi-CH ₂ ),2.31(s,3H,C ₄ -Ph''- CH ₃ ), 2.24(t,2H,Pi-CH ₂ ),2.07(s,6H,C ₂ ,C ₆ -Ph''-CH ₃ ),1.98(m,2H,Pi-CH ₂ ),1.66( m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,CDCl ₃ ,ppm)δ:164.45(Ph-C ₄ ),147.90,146.66,140.83,135.38,130.45,129.90,129.71,129.55,127.16, 126.51, 103.84 (Ph-C ₅ ), 97.52 (Ph-C ₃ ), 62.18 (Pi-CH ₂ -Py), 60.44, 51.31, 31.27, 20.81 (Ph''-C ₄ -CH ₃ ), 16.10 (2 ×CH ₃ ).ESI-MS:m/z525.6(M+1),547.2(M+23).C ₂₇ H ₃₂ N ₄ O ₅ S[524.21].

N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b) is selected for piperidinamine, and 4- Methoxycarbonyl benzyl chloride, resulting in methyl 4-((4-(5-(2,4,6-trimethylphenoxy)-2-nitrophenylamino)piperidin-1-yl)methyl base) benzoate (5b9). Yellow solid, yield: 81.48%, melting point: 168-170°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.27(d,1H,J=7.0Hz,NH),8.10(d,1H,J=9.5Hz,C ₆ -Ph-H),8.00(d,2H ,J=8.2Hz,C ₃ ,C ₅ -Ph'-H),7.42(d,2H,J=7.9Hz,C ₂ ,C ₆ -Ph'-H),6.91(s,2H,C ₃ , C ₅ -Ph''-H),6.13(d,1H,J=2.1Hz,C ₃ -Ph-H),6.01(dd,1H,J ₁ =2.2Hz,J ₂ =9.5Hz,C5-Ph -H), 3.92(s,3H,COO-CH ₃ ), 3.58(s,2H,CH ₂ ), 3.35(m,1H,C ₁ -Pi-H), 2.77(t,2H,Pi-CH ₂ ),2.31(s,3H,C ₄ -Ph''-CH ₃ ),2.23(t,2H,Pi-CH ₂ ),2.07(s,6H,C ₂ ,C ₆ -Ph''-CH3), 2.01(m,2H,Pi-CH ₂ ),1.66(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,CDCl ₃ ,ppm)δ:167.02(C=O),164.40(Ph-C ₄ ), 147.92, 146.67, 135.36, 130.47, 129.89, 129.70, 129.67, 129.09, 128.88, 127.16, 103.77 (Ph-C ₅ ), 97.50 (Ph-C ₃ ), 62.56 (Pi-CH ₂ -Py), 52.10 (O-CH ₃ ),51.57,31.42,20.82(Ph''-C ₄ -CH ₃ ),16.10(2×CH ₃ ).ESI-MS: m/z504.4(M+1),526.4(M +23).C ₂₉ H ₃₃ N ₃ O ₅ [503.24].

Use N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (4b) for piperidinamine, and use benzyl chloride for substituted arylmethyl halide , to obtain 1-benzyl-N-(5-(2,4,6-trimethylphenoxy)-2-nitrophenyl)piperidin-4-amine (5b10). Yellow solid, yield: 84.00%, melting point: 95-97°C.

Product spectral analysis data:

¹ H-NMR(CDCl ₃ ,400MHz)δ:8.27(d,1H,J=7.0Hz,NH),8.10(d,1H,J=9.5Hz,C ₆ -Ph-H),7.32(m,4H ,C ₂ ,C ₃ ,C ₅ ,C ₆ -Ph'-H),7.25(m,1H,C ₄ -Ph'-H),6.91(s,2H,C ₃ ,C5-Ph''-H ),6.12(d,1H,J=2.4Hz,C ₃ -Ph-H),6.01(dd,1H,J ₁ =2.4Hz,J ₂ =9.5Hz,C ₅ -Ph-H),3.53(s ,2H,CH ₂ ),3.33(m,1H,C ₁ -Pi-H),2.79(t,2H,Pi-CH ₂ ),2.31(s,3H,C ₄ -Ph''-CH ₃ ), 2.19(t,2H,Pi-CH ₂ ),2.07(s,6H,C ₂ ,C ₆ -Ph''-CH ₃ ),1.98(m,2H,Pi-CH ₂ ),1.64(m,2H, Pi-CH ₂ ). ¹³ C-NMR (100MHz, CDCl ₃ , ppm) δ: 164.38 (Ph-C ₄ ), 147.95, 146.73, 138.21, 135.35, 130.49, 129.87, 129.70, 129.10, 128.30, 127.16, 127.14, 103.74(Ph-C ₅ ), 97.51(Ph-C ₃ ), 63.01(Pi-CH ₂ -Py), 51.50, 49.32, 31.51, 20.82(Ph''-C ₄ -CH ₃ ), 16.11(2×CH ₃ ).ESI-MS: m/z 446.5(M+1).C ₂₇ H ₃₁ N ₃ O ₃ [445.24].

Example 7: 4-((4-(2-amino-5-(4-cyano-2,6-dimethylphenoxy)phenylamino)piperidin-1-yl)methyl)benzenesulfonate Preparation of amide hydrochloride (7a1)

Slowly add 1ml of absolute ethanol to 0.014g (10%) palladium carbon catalyst, add 0.07g of 4-((4-(5-(4-cyano-2,6-dimethylphenoxy )-2-nitrophenylamino)piperidin-1-yl)methyl)benzenesulfonamide (5a8) in tetrahydrofuran (0.5ml). The reaction solution was stirred and reacted for 36 h at 30° C. under hydrogen atmosphere. After filtration and purification, the resulting pink solid was quickly dissolved in 0.5ml of dichloromethane, and concentrated hydrochloric acid (4 drops) was added dropwise to it under ice-bath conditions, and the reaction was stirred for 0.5h. Spin dry under reduced pressure, recrystallize from ethanol to get 4-((4-(2-amino-5-(4-cyano-2,6-dimethylphenoxy)phenylamino)piperidine-1- base) methyl) benzenesulfonamide hydrochloride (7a1). White solid, yield: 56.34%, melting point: 207-209°C.

Product spectral analysis data:

¹ H-NMR(D ₂ O,400MHz)δ:7.94(d,2H,J=8.0Hz,C ₃ ,C ₅ -Ph'-H),7.66(d,2H,J=8.1Hz,C ₂ , C ₆ -Ph'-H),7.47(s,2H,C ₃ ,C ₅ -Ph''-H),7.09(d,1H,J=8.7Hz,C ₆ -Ph-H),6.40(d ,1H,J=2.1Hz,C ₃ -Ph-H),6.01(d,1H,J=8.6Hz,C ₅ -Ph-H),4.37(s,2H,CH ₂ ),3.53(t,2H ,Pi-CH ₂ ),3.31(m,1H,C ₁ -Pi-H),3.08(m,2H,Pi-CH ₂ ),2.21(t,2H,Pi-CH ₂ ),2.01(s,6H ,2×CH ₃ ), 1.65(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,D ₂ O,ppm)δ:158.15(Ph''-C ₁ ),154.62(Ph-C ₄ ),143.01(Ph'-C ₄ ),141.70(Ph'-C ₁ ),133.81,133.63,133.52,133.33,132.38,132.20,126.78,125.75,119.72(C≡N),111.65,108.08,103.917,10 _{C 27 H 31} N ₅ O ₃ S[505.21].

Example 8: Intermediate tert-butyl 4-(2-acetamido-5-(4-cyano-2,6-dimethylphenoxy)phenylamino)piperidine-1-carboxylate (9 ) preparation

Slowly add 8ml of absolute ethanol to 0.05g (10%) palladium carbon catalyst, add 0.5g (1.07mmol) tert-butyl 4-(5-(4-cyano-2,6-dimethyl phenoxy)-2-nitroanilino)piperidine-1-carboxylate (3a) in tetrahydrofuran (2ml). The reaction solution was stirred and reacted for 6 h at 30° C. under hydrogen atmosphere. Filter, spin dry under reduced pressure, and quickly dissolve the resulting pink solid in dichloromethane. 0.16g (1.6mmol) triethylamine and 0.1g (1.28mmol) acetyl chloride were added to the above solution sequentially under ice-bath conditions, and the reaction was stirred for 1h. The reaction liquid was washed with water, the organic phase was collected, dried over anhydrous sodium sulfate, separated and purified by silica gel column chromatography, and recrystallized from diethyl ether to obtain intermediate 9. Milky white solid, yield: 80.39%.

Product spectral analysis data:

ESI-MS: m/z 479.4(M+1), 501.4(M+23).C ₂₇ H ₃₄ N ₄ O ₄ [478.26].

Example 9: Preparation of intermediate N-(4-(4-cyano-2,6-dimethylphenoxy)-2-(piperidin-4-ylamino)phenyl)acetamide (10)

The preparation method is the same as in Example 4, except that the reaction raw material selects intermediate 9, and the resulting product is intermediate N-(4-(4-cyano-2,6-dimethylphenoxy)-2-(piper Pyridin-4-ylamino)phenyl)acetamide (10). White solid, yield: 96.88%.

Example 10: N-(4-(4-cyano-2,6-dimethylphenoxy)-2-(1-(4-sulfamoylbenzyl)piperidin-4-ylamino)benzene base) the preparation of acetamide (11)

The preparation method is the same as in Example 6, and the piperidinamine is selected from the intermediate N-(4-(4-cyano-2,6-dimethylphenoxy)-2-(piperidin-4-ylamino)phenyl) Acetamide (10), substituted arylmethyl halide selects 4-aminosulfonyl Bian bromide to obtain N-(4-(4-cyano-2,6-dimethylphenoxy)-2-(1 -(4-sulfamoylbenzyl)piperidin-4-ylamino)phenyl)acetamide (11). Off-white solid, yield: 62.22%.

Product spectral analysis data:

¹ H-NMR(DMSO-d ₆ ,400MHz)δ:9.00(s,1H,Ph-NH-CO),7.80(d,2H,J=8.2Hz,C ₃ ,C ₅ -Ph'-H), 7.67(s,2H,C ₃ ,C ₅ -Ph''-H),7.50(d,2H,J=8.2Hz,C ₂ ,C ₆ -Ph'-H),7.32(s,2H,NH ₂ ),6.97(d,1H,J=8.6Hz,C ₆ -Ph-H),6.20(d,1H,J=2.3Hz,C ₃ -Ph-H),5.71(dd,1H,J ₁ =2.4 Hz,J ₂ =8.5Hz,C ₅ -Ph-H),4.80(d,1H,J=7.5Hz,Pi-NH),3.55(s,2H,CH ₂ ),3.41(t,2H,Pi- CH ₂ ), 3.17(m,1H,C1-Pi-H),2.75(t,2H,Pi-CH ₂ ),2.11(s,6H,2×CH ₃ ),2.07(s,3H,CO-CH ₃ ),1.87(m,2H,Pi-CH ₂ ),1.44(m,2H,Pi-CH ₂ ). ¹³ C-NMR(100MHz,DMSO-d ₆ ,ppm)δ:169.21(C=O), 155.81, 155.24, 143.66, 143.17, 133.52, 133.36, 129.38, 127.97, 126.08, 119.14, 118.89 (C≡N), 108.18, 100.59, 98.63 (Ph-C ₃ ), 61.85 (Pi-CH ₂ -Py), ,49.44,31.97,23.67(CO-CH ₃ ),16.14(2×CH ₃ ).ESI-MS:m/z548.5(M+1).C ₂₉ H ₃₃ N ₅ O ₄ S[547.23].

Claims (9)

1. A2- (N-arylmethylpiperidine-4-amino) -4- (substituted phenol) benzene ring derivative having a structure represented by the following general formula I:

   

   wherein,

   R₁comprises the following steps: cyano or methyl;

   R₂comprises the following steps: nitro, amino or acetylamino;

   ar is phenyl, 4-pyridyl, 4-nitrophenyl, 4-aminosulfonylphenyl, 4-methanesulfonylphenyl, 4-aminoacylphenyl, 4-acetylphenyl, 4-hydroxymethylphenyl, 4-carboxyphenyl or 4-methoxycarbonylphenyl.
2. 2. The compound of claim 1, which is one of the following compounds:

   

   

   
3. 3. a process for the preparation of a compound according to claim 1, characterized in that: when R is₂In the case of nitro or amino, the synthetic route of the compound is as follows:

   

   reagents and conditions: N-Boc piperidinamine, sodium carbonate, N, N-dimethylformamide; (ii) substituted phenol, potassium carbonate, tetrabutylammonium bromide, potassium iodide, N, N-dimethylformamide; (iii) trifluoroacetic acid, dichloromethane; (iv) potassium carbonate, N, N-dimethylformamide; (v) palladium on carbon, hydrogen, tetrahydrofuran, ethanol; (vi) concentrated hydrochloric acid, dichloromethane;

   wherein R is₁Ar is the same as the structural general formula I.
4. 4. A process for the preparation of a compound according to claim 1, characterized in that: when R is₂In the case of acetamido, the synthetic route for the compound is as follows:

   

   reagents and conditions: palladium on carbon, hydrogen, tetrahydrofuran and ethanol; (ii) acetyl chloride, triethylamine, dichloromethane; (iii) trifluoroacetic acid, dichloromethane; (iv) potassium carbonate, N, N-dimethylformamide;

   wherein R is₁Ar is the same as the structural general formula I.
5. 5. A process for the preparation of a compound according to claim 3, characterized in that: when R is₂When the nitro group is adopted, the preparation steps are as follows:

   (1) dissolving 4-chloro-2-fluoro-1-nitrobenzene (1), N-Boc piperidine amine and sodium carbonate in N, N-dimethylformamide, and stirring at 80 ℃ for reaction for 1 hour; evaporating N, N-dimethylformamide under reduced pressure, dissolving the obtained solid in dichloromethane, washing with saturated saline, collecting the organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by a dry loading column to obtain yellow solid, namely tert-butyl 4- (5-chloro-2-nitroanilino) piperidine-1-carboxylate (2);

   (2) dissolving tert-butyl 4- (5-chloro-2-nitroanilino) piperidine-1-carboxylate (2), 4-cyano-3, 5-dimethylphenol, potassium carbonate, tetrabutylammonium bromide and potassium iodide in N, N-dimethylformamide, and heating to 120 ℃ and 130 ℃ for reaction for 12 hours; evaporating N, N-dimethylformamide under reduced pressure, dissolving the residue in dichloromethane, washing with saturated brine, collecting the organic phase, drying over anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by a dry loading column to obtain a yellow solid, namely tert-butyl 4- (5- (4-cyano-2, 6-dimethylphenol) -2-nitroanilino) piperidine-1-carboxylate (3 a);

   (3) dissolving tert-butyl 4- (5-chloro-2-nitroanilino) piperidine-1-carboxylate (2), 2,4, 6-trimethylphenol, potassium carbonate, tetrabutylammonium bromide and potassium iodide in N, N-dimethylformamide, heating to 120 ℃ and 130 ℃, and stirring for reacting for 6 hours; pouring the reactant into water, extracting the aqueous solution with ethyl acetate, collecting an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, separating and purifying by a dry-method sample loading column to obtain a yellow solid, namely tert-butyl 4- (5- (2,4, 6-trimethylphenoxy) -2-nitroanilino) piperidine-1-carboxylic ester (3 b);

   (4) trifluoroacetic acid is dropwise added into a dichloromethane solution of tert-butyl 4- (5- (4-cyano-2, 6-dimethylphenoxy) -2-nitroanilino) piperidine-1-carboxylate (3a) or tert-butyl 4- (5- (2,4, 6-trimethylphenoxy) -2-nitroanilino) piperidine-1-carboxylate (3b) under the condition of water bath at 15 ℃; the reaction is continued to react under the ice-bath condition; dropwise adding saturated sodium carbonate solution into the reaction product; filtering, drying the obtained precipitate in a vacuum drier to obtain N- (5- (4-cyano-2, 6-dimethylphenoxy) -2-nitrophenyl) piperidine-4-amine (4a) or N- (5- (2,4, 6-trimethylphenoxy) -2-nitrophenyl) piperidine-4-amine (4b), and directly using the precipitate in the next reaction;

   (5) dissolving N- (5- (4-cyano-2, 6-dimethylphenoxy) -2-nitrophenyl) piperidine-4-amine (4a) or N- (5- (2,4, 6-trimethylphenoxy) -2-nitrophenyl) piperidine-4-amine (4b), substituted arylmethyl halide and potassium carbonate in N, N-dimethylformamide to react at room temperature; the reaction was poured into excess water and filtered through celite; dissolving the filter cake in dichloromethane again, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain 2- (N-arylmethylpiperidine-4-amino) -4- (substituted phenol) nitrobenzene derivatives;

   the substituted arylmethyl halide is selected from: 4-nitrobenzyl bromide, 4-chloromethyl pyridine hydrochloride, 4-acetyl benzyl bromide, 4-hydroxymethyl benzyl chloride, 4-carboxyl benzyl chloride, 4-methylsulfonyl benzyl bromide, 4-carbamoyl benzyl chloride, 4-aminosulfonyl benzyl bromide, 4-methoxycarbonyl benzyl chloride and benzyl chloride.
6. 6. A process for the preparation of a compound according to claim 3, characterized in that: when R is₂When the amino group is adopted, the preparation steps are as follows:

   slowly adding anhydrous ethanol into 10% palladium-carbon catalyst, and adding the obtained suspension into tetrahydrofuran solution of 2- (N-arylmethylpiperidine-4-amino) -4- (substituted phenol) nitrobenzene derivative (5 a-b); the reaction solution is stirred and reacts under the condition of hydrogen gas at the temperature of 30 ℃; filtering, purifying, quickly dissolving the pink solid in dichloromethane, dropwise adding concentrated hydrochloric acid under an ice bath condition, and stirring for reaction; and spin-drying under reduced pressure to obtain white solid 2- (N-arylmethylpiperidine-4-amino) -4- (substituted phenol) aniline derivative hydrochloride.
7. 7. A process for the preparation of a compound according to claim 4, characterized in that: when R is₂In the case of acetylamino, the preparation steps are as follows:

   (1) slowly adding anhydrous ethanol into 10% palladium-carbon catalyst, and adding the obtained suspension into tetrahydrofuran solution of tert-butyl 4- (5- (substituted phenoxy) -2-nitroanilino) piperidine-1-carboxylic ester (3 a-b); the reaction solution is stirred and reacts under the condition of hydrogen gas at the temperature of 30 ℃; filtering, performing rotary drying under reduced pressure, and quickly dissolving the obtained pink solid in dichloromethane; sequentially adding triethylamine and acetyl chloride into the solution under the ice bath condition, and continuously stirring for reaction; washing the reaction solution with water, collecting an organic phase, drying with anhydrous sodium sulfate, separating and purifying by silica gel column chromatography, and recrystallizing with diethyl ether to obtain a milky white solid, namely an intermediate 9;

   (2) under the condition of water bath at 15 ℃, dropwise adding trifluoroacetic acid into the dichloromethane solution of the intermediate 9; the reaction is continued to react under the ice-bath condition; dropwise adding saturated sodium carbonate solution into the reaction product; filtering, drying the obtained precipitate in a vacuum drier to obtain a white solid, and directly using the intermediate N- (4- (substituted phenoxy) -2- (piperidine-4-ylamino) phenyl) acetamide (10) in the next reaction;

   (3) dissolving N- (4- (substituted phenoxy) -2- (piperidine-4-ylamino) phenyl) acetamide (10), substituted arylmethyl halide and potassium carbonate in N, N-dimethylformamide to react at room temperature; the reaction was poured into excess water and filtered through celite; dissolving the filter cake in dichloromethane again, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain 2- (N-arylmethylpiperidine-4-amino) -4- (substituted phenol) aniline acetyl derivative;

   the substituted arylmethyl halide is selected from: 4-nitrobenzyl bromide, 4-chloromethyl pyridine hydrochloride, 4-acetyl benzyl bromide, 4-hydroxymethyl benzyl chloride, 4-carboxyl benzyl chloride, 4-methylsulfonyl benzyl bromide, 4-carbamoyl benzyl chloride, 4-aminosulfonyl benzyl bromide, 4-methoxycarbonyl benzyl chloride and benzyl chloride.
8. 8. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for an HIV-1 inhibitor.
9. 9. An anti-HIV pharmaceutical composition characterized by comprising a compound according to claim 1 or 2 and one or more pharmaceutically acceptable carriers or excipients.