CN102477009A - Substitutive (S)-benaldehyde sulfonyl pyrrolidine-3-amino derivative, and preparation method and application thereof - Google Patents

Abstract

The invention discloses a class of substituted (S)-phenylmethylsulfonylpyrrolidine-3-amino derivatives, a preparation method and application thereof. The structural formula of the compound is shown in Formula I. The preparation method is as follows: react differently substituted benzylsulfonyl chlorides with (S)-3-tert-butoxycarbonylaminopyrrolidine, and the product is deprotected to generate an important intermediate; another intermediate is made of differently substituted benzyl Piperazine can be prepared by 2-chloroacetylation reaction. The two intermediates react overnight in tetrahydrofuran under reflux, and then the structure of formula I is obtained through thin chromatography. The compound provided by the invention has good antitumor activity effect, and has important practical value and application prospect in the field of preparing antitumor drugs.

Description

Substituted (S)-phenylmethylsulfonylpyrrolidine-3-amino derivatives and their preparation methods and applications

technical field

The invention relates to a substituted (S)-phenylmethylsulfonylpyrrolidine-3-amino derivative and its preparation method and application. the

Background technique

Protein tyrosine kinases (PTK) are extremely important substances in the process of cell signal transduction, and have a variety of cellular functions. Overexpression of protein tyrosine kinases activates their downstream signaling pathways, leading to cell transformation, proliferation, resistance to apoptosis, promotion of cell survival, and ultimately tumor formation. Molecular design targeting tyrosine kinase ABL has promoted the successful marketing of drugs such as Imatinib, but clinical drug resistance has always existed. Studies have shown that the compensatory effect of the PI3K/AKT/mTOR signaling pathway is one of the mechanisms leading to Imatinib resistance; preclinical studies have found that the combined use of tyrosine kinase inhibitors and PI3K inhibitors can achieve very good therapeutic effects, so for Designing multi-target inhibitors of tyrosine kinases ABL and PI3K may overcome the drug resistance of Imatinib and obtain good anti-tumor activity in clinic. the

Since the tyrosine kinase and PI3K protein families belong to different protein families and showed structural differences in the early stages of evolution, the two family proteins lack significant sequence similarity. This makes it difficult to find dual inhibitors among known tyrosine kinase inhibitors and PI3K inhibitors. But they also have some similarities in structure and function, for example: the DFG structure sequence of coordination Mg ²⁺ -ATP is similar; the kinase structure region has a similar two-protrusion structure; they all use similar residues to catalyze the reaction, etc. .

Apsel, B et al. found that PP121 and PP487 exhibited excellent inhibitory activity on PI3K family proteins and tyrosine kinase family proteins such as ABL, SRC, and epidermal growth factor receptor through high-throughput screening. Further experiments proved that these two compounds showed similar inhibitory activity to 200 protein kinases as Dasatinib and Sunitinib, and also showed high selectivity to the serine-threonine kinase family, so these two compounds can simultaneously inhibit The protein tyrosine family and the PI3K protein family provide new ideas for solving the problem of Imatinib resistance due to the compensatory effect of the PI3K/AKT signaling pathway. the

Contents of the invention

The object of the present invention is to provide a class of substituted (S)-phenylmethylsulfonylpyrrolidine-3-amino derivatives and a preparation method thereof. the

The substituted (S)-phenylmethylsulfonylpyrrolidine-3-amino derivative provided by the present invention has a general structural formula as shown in formula I:

(formula I)

In formula I, R ₁ is hydrogen, or R ₁ is one or more of the following groups with single or multiple substitutions on the benzene ring: -F, -Cl, -Br, -CH ₃ , -OCH ₃ , -CF ₃ and -CN; R ₂ is hydrogen, or R ₂ is one or more of the following groups with single or multiple substitutions on the benzene ring: -F, -Cl, -Br, -CH ₃ , -OCH ₃ , -CF ₃ , and -CN.

The multi _- substitution of R refers to 2,4-disubstituted, 2,5-disubstituted, 2,6-disubstituted, 3,4-disubstituted, 3,5-disubstituted; or 2,4,6- Three substitutions, 3,4,5-three substitutions; or 2,3,5,6-four substitutions;

The R ₂ multi-substitution refers to 2,4-disubstituted, 2,5-disubstituted, 2,6-disubstituted, 3,4-disubstituted, 3,5-disubstituted; or 2,4,6- Trisubstitution, 3,4,5-trisubstitution; or 2,3,5,6-tetrasubstitution.

Preferably, R is _hydrogen , 2-fluoro, 2-chloro, 2-bromo, 2-methyl, 2-methoxy, 2-cyano, 2-trifluoromethyl, 3-fluoro, 3-chloro , 3-bromo, 3-methyl, 3-methoxy, 3-cyano, 3-trifluoromethyl, 4-fluoro, 4-chloro, 4-bromo, 4-methyl, 4-methoxy , 4-cyano, 4-trifluoromethyl, 2,5-difluoro, 3,5-difluoro, 2,6-dichloro, 2,4-dichloro, 3,4-dichloro, 3, 5-di-trifluoromethyl, 3,4,5-trifluoro, 3,4,5-trichloro, 2-chloro-6-fluoro, 3,5-dimethoxy, 2,4,6- Trimethoxy, 3,4,5-trimethoxy, 2,4,6-trimethyl, 2,3,5,6-tetramethyl.

R ₂ is hydrogen, 2-fluoro, 2-chloro, 2-bromo, 2-methyl, 2-methoxy, 2-cyano, 2-trifluoromethyl, 3-fluoro, 3-chloro, 3- Bromine, 3-methyl, 3-methoxy, 3-cyano, 3-trifluoromethyl, 4-fluoro, 4-chloro, 4-bromo, 4-methyl, 4-methoxy, 4- Cyano, 4-trifluoromethyl, 2,5-difluoro, 3,5-difluoro, 2,6-dichloro, 2,4-dichloro, 3,4-dichloro, 3,5-dichloro -Trifluoromethyl, 3,4,5-trifluoro, 3,4,5-trichloro, 2-chloro-6-fluoro, 3,5-dimethoxy, 2,4,6-trimethoxy , 3,4,5-trimethoxy, 2,4,6-trimethyl, 2,3,5,6-tetramethyl.

The method for preparing the above-mentioned compound provided by the invention comprises the following steps:

Step (1): make substituted or unsubstituted: phenylmethylsulfonyl chloride or phenylmethylsulfonyl bromide react with (S)-3-Boc-aminopyrrolidine under basic conditions to obtain the compound shown in formula II ;

(式II) 

(Formula II)

Wherein, R in formula II _is the same as R in formula _I ;

Step (2): the compound shown in the formula II is removed from the tert-butoxycarbonyl group to obtain the amino hydrochloride shown in the formula III;

(Formula III)

Step (3): acetylation of unsubstituted or substituted benzylpiperazine with chloroacetyl chloride or bromoacetyl bromide to obtain the compound shown in formula IV;

(式IV) 

(Formula IV)

Wherein, R in formula IV _is the _same as R in formula I;

Step (4): reacting the compounds represented by formula III and formula IV under basic conditions to obtain the target compound represented by formula I. the

The alkaline condition described in the above method step (1) is provided by any one of the following bases: triethylamine, N-methylmorpholine, diisopropylethylamine, salt of wormwood, cesium carbonate, potassium hydroxide and Sodium hydroxide; the reaction medium of the reaction is: a mixed solvent of ethyl acetate and tetrahydrofuran in a volume ratio of 1:1, dioxane, ethyl acetate or water; the reaction temperature of the reaction is room temperature. the

The deprotection reagent for removing the tert-butoxycarbonyl group in step (2) can be: 1.5-3M hydrochloric acid aqueous solution, trifluoroacetic acid or hydrochloric acid in dioxane solution. the

The alkaline condition described in the step (4) is provided by any one of the following bases: triethylamine, N-methylmorpholine, diisopropylethylamine, salt of wormwood, cesium carbonate, potassium hydroxide and hydroxide sodium; the reaction medium of the reaction is: tetrahydrofuran, ethanol, methyl alcohol or dioxane; the molar ratio of the compound shown in the formula III and the compound shown in the formula IV in the reaction is 1.05-2.5: 1; the reaction is in under reflux conditions. the

In order to increase the yield of the target substance in step (4), the reaction can be carried out under the catalysis of KI. the

The pharmaceutically acceptable salts, esters or solvates of the compound of formula I of the present invention also belong to the protection scope of the present invention. the

Another object of the present invention is to provide the application of the compound of formula I. the

The compound of formula I of the present invention or its pharmaceutically acceptable salts, esters and solvates can be used to prepare eukaryotic tumor cell inhibitors. the

The eukaryote is a mammal; the tumor cell is a cancer cell; the cancer cell is a leukemia cancer cell, a breast cancer cell or a liver cancer cell; the leukemia cancer cell can specifically be a leukemia cell K562, and the breast cancer cell It is breast cancer cell MCF-7, and the liver cancer cell is human liver cancer cell HepG-2. the

The compound of formula I of the present invention or its pharmaceutically acceptable salts, esters, and solvates can also be used for the preparation of medicaments for the prevention and/or treatment of tumors. the

The tumor is cancer; the cancer is leukemia, breast cancer or liver cancer. the

Drugs for preventing and/or treating tumors prepared with compounds represented by formula I or pharmaceutically acceptable salts, esters, and solvates thereof as active ingredients also fall within the protection scope of the present invention. the

The drug for preventing and/or treating tumors can be introduced into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated methods; Other substances are mixed or encapsulated and introduced into the body. the

When necessary, one or more pharmaceutically acceptable carriers can also be added to the above drugs. The carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and the like in the pharmaceutical field. the

Drugs for the prevention and/or treatment of tumors prepared with compounds of formula I or pharmaceutically acceptable salts, esters, and solvates thereof can be made into injections, tablets, powders, granules, capsules, oral liquids, ointments, and creams and many other forms. The above-mentioned medicines in various dosage forms can be prepared according to conventional methods in the field of pharmacy. the

The series of compounds provided by the present invention have correct structures through instrumental analysis and testing. The method for preparing the derivatives of the above-mentioned series of compounds provided by the present invention has easy-to-obtain raw materials, simple reaction, simple synthesis steps and easy operation. The compound has very good effect of inhibiting tumor activity, and has important practical value and application prospect in the field of preparing antitumor drugs. the

Description of drawings

Fig. 1 is the flowchart of synthesizing the compound of formula I of the present invention. the

Detailed ways

The present invention will be described below through specific examples, but the present invention is not limited thereto. the

The experimental methods described in the following examples, unless otherwise specified, are conventional methods; the reagents and materials, unless otherwise specified, can be obtained from commercial sources. the

Example 1, (S)-2-[(1-benzylsulfonyl)pyrrolidine-3-amino]-1-(4-benzylpiperazine)ethanone (in formula I, R1 is H, R2 is Synthesis of compounds of H)

Step (1): Dissolve 60 mmol potassium carbonate in 20 mL water and stir until completely dissolved, add 30.6 mmol (S)-Boc-3-aminopyrrolidine in ethyl acetate (70 mL), and stir at room temperature for 25 minutes. 33mmol of benzylsulfonyl chloride was dissolved in 60mL of ethyl acetate and tetrahydrofuran (1:1, v/v), added dropwise under an ice-water bath, and reacted at room temperature for one day after dropping. The reaction solution was concentrated under reduced pressure, then diluted with 30 mL of water and 50 mL of ethyl acetate, and then the organic phase was separated and collected, washed successively with saturated sodium bicarbonate solution, water, and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain Yellow solid (S)-tert-butyl-1-benzylsulfonylpyrrolidine-3-carbamate. the

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.38-7.41 (m, 5H), δ4.56 (br s, 1H), δ4.28 (s, 2H), δ4.13 (br s , 1H), δ3.34(dd, J=10.0, 6.4Hz, 1H), δ3.26(dd, J=16.2, 7.6Hz, 1H), δ3.15(br s, 1H), δ3.07( br s, 1H), δ2.04 (dt, J=18.8, 7.6Hz, 1H), δ1.61-1.78 (m, 1H), δ1.44 (s, 9H); δ ¹³ C NMR (100.6MHz, CDCl ₃ ) δ155.05, 130.59, 129.27, 128.87, 79.96, 57.19, 53.65, 50.59, 46.13, 32.15, 28.36.

Step (2): 14.4mmol (S)-tert-butyl-1-benzylsulfonylpyrrolidine-3-carbamate was placed in a 250mL round bottom flask, and 70mL of saturated hydrogen chloride in dioxane was quickly poured into solution, sealed. Stir at room temperature until the reaction solution becomes white and viscous, and concentrate under reduced pressure to obtain (S)-1-benzylsulfonyl-3-aminopyrrolidine hydrochloride as a brown solid. the

The structure confirmation data are as follows: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.57(br s, 3H), δ7.43-7.45(m, 2H), δ7.35-7.41(m, 3H), δ4. 51(s, 2H), δ3.75-3.81(m, 1H), δ3.52(dd, J=10.8, 6.8Hz, 1H), δ3.41(dd, J=16.6, 7.2Hz, 1H), δ3.39-3.46(m, 1H), δ3.23-3.29(m, 1H), δ2.17(dt, J=20.0, 6.8Hz, 1H), δ1.99(dt, J=20.0, 6.0Hz , 1H); δ ¹³ C NMR (100.6MHz, DMSO-d ₆ ) δ 131.38, 130.07, 128.88, 128.64, 54.34, 51.11, 49.76, 46.26, 29.97.

Step (3): 17.2 mmol of benzylpiperazine was dissolved in 10 mL of dichloromethane, and 20.64 mmol of chloroacetyl chloride in dichloromethane (10 mL) was added dropwise in an ice-water bath, and reacted at room temperature for about 30 minutes. The reaction solution was poured into 50 mL of cold water, adjusted to neutrality with 10% sodium bicarbonate solution, separated, and dried over anhydrous sodium sulfate. Evaporate to dryness under reduced pressure to obtain yellow oil 2-chloro-1-(4-benzylpiperazine)ethanone. the

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.30-7.35 (m, 4H), δ7.26-7.29 (m, 1H), δ4.05 (s, 2H), δ3.63 (t , J=4.8Hz, 2H), δ3.51 (m, 4H), δ2.47 (dt, J=12.8, 5.2Hz, 4H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ165.00, 137.50, 129.09, 128.37, 127.35, 62.78, 52.88, 52.48, 46.32, 42.20, 40.89.

Step (4): Dissolve 1.2 mmol (S)-1-benzylsulfonyl-3-aminopyrrolidine hydrochloride in tetrahydrofuran, add 0.56 mL triethylamine and stir at room temperature until completely dissolved. Add 0.498g potassium iodide (catalyst), 1mmol 1-(4 benzylpiperazine)-2 chloroethanone, and reflux for 20 hours. Concentrate under reduced pressure to remove THF, dilute with 50 mL ethyl acetate and 30 mL water, then separate the organic phase, wash the organic phase with water and saturated brine successively, and dry over anhydrous sodium sulfate overnight. Concentration under reduced pressure, thin layer chromatography (developing solvent: ethyl acetate: methanol = 20:1, v/v); the yellow target product (S)-2-[(1-benzylsulfonyl)pyrrolidine-3 was obtained -Amino]-1-(4-benzylpiperazine)ethanone 0.236 g. the

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.41-7.43 (m, 2H), δ7.35-7.39 (m, 3H), δ7.29-7.35 (m, 4H), δ7.26 -7.28(m, 1H), δ4.25(s, 2H), δ3.64(t, J=4.8Hz 2H), δ3.53(s, 2H), δ3.34-3.38(m, 1H), δ3.34-3.37(m, 3H), δ3.32(br s, 1H), δ3.31(br s, 1H), δ3.25-3.29(m, 3H), δ2.96(dd, J= 9.0, 4.8Hz, 4H), δ2.44(t, J=4.4Hz, 4H), δ2.00(dt, J=18.0, 6.0Hz, 1H), δ1.84(br s, 1H), δ1. 74 (dt, J=18.8, 6.4Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.81, 137.36, 130.78, 129.39, 129.14, 128.72, 128.57, 128.39, 127.40, 62.84, 57.82, 56.55, 53.58, 53.43, 52.71, 48.60, 46.58, 44.41, 41.99, 32.41.

Embodiment 2, preparation of differently substituted (S)-phenylmethylsulfonylpyrrolidine-3-amino derivatives

According to the method of Example 1, "benzylsulfonyl chloride" in step 1) is replaced with "substituted benzylsulfonyl chloride", and "benzylpiperazine" in step 3) is replaced with "substituted benzyl Piperazine", the following correspondingly substituted (S)-benzenemethylsulfonylpyrrolidine-3-amino derivatives can be obtained. the

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(2-methylbenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.41-7.43 (m, 2H), δ7.35-7.39 (m, 3H), δ7.30 (d, J=7.2Hz, 2H), δ7.14-7.21(m, 3H), δ4.25(s, 2H), δ3.61(br s, 2H), δ3.48(s, 2H), δ3.34-3.38(m, 1H), δ3.31-3.33(m, 4H), δ3.28(d, J=6.0Hz, 2H), δ3.27(br s, 1H), δ2.96-3.00(m, 1H), δ2.44( t, J=4.8Hz, 4H), δ2.37(s, 3H), δ1.96-2.04(m, 2H), δ1.73(dt, J=18.0, 6.4Hz, 1H); ¹³ C NMR ( 100.6MHz，CDCl ₃ )δ168.75，137.60，135.58，130.77，130.43，129.91，129.39，128.71，128.57，127.41，125.60，60.74，57.81，56.53，53.56，52.92，52.71，48.57，46.58，44.50，42.11， 32.38, 19.23.

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(3-methylbenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.41-7.43 (m, 2H), δ7.19 (dt, J=8.0, 2.0Hz, 2H), δ7.22 (t, J=7.6 Hz, 2H), δ7.08-7.12(m, 3H), δ4.25(s, 2H), δ3.64(t, J=4.8Hz, 2H), δ3.49(s, 2H), δ3. 34-3.38(m, 3H), δ3.32(d, J=6.0Hz, 2H), δ3.26-3.31(m, 3H), δ2.95-2.99(m, 1H), δ2.44(t , J=4.8Hz, 4H), δ2.35(s, 3H), δ2.04(s, 1H), δ1.96-2.03(m, 1H), δ1.70-1.77(m, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.77, 138.02, 137.19, 130.76, 129.89, 12938, 128.71, 128.56, 128.25, 128.13, 126.24, 62.86, 57.79, 56.50, 53.56, 53.84, 48.52 , 41.96, 32.38, 21.39.

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(4-methylbenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.35-7.43 (m, 5H), δ7.19 (d, J=8.0Hz, 2H), δ7.14 (d, J=8.0Hz, 2H), δ4.25(s, 2H), δ3.63(br s, 2H), δ3.49(s, 2H), δ3.34-3.37(m, 3H), δ3.31(s, 1H) , δ3.30(s, 1H), δ3.25-3.29(m, 3H), δ2.42(br s, 4H), δ2.34(s, 3H), δ2.00(dt, J=18.8, 7.2Hz, 1H), δ1.85 (br s, 1H), δ1.72 (dt, J=19.2, 6.4Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ164.79, 137.08, 130.78, 130.70, 129, 39, 129.14, 129.07, 128.71, 128.57, 62.56, 57.82, 56.54, 53.59, 52.80, 52.54, 48.60, 46.58, 44.39, 41.97, 32.41, 21.11.

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(2-chlorobenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.39-7.46 (m, 3H), δ7.36-7.38 (m, 4H), δ7.19-7.25 (m, 2H), δ4.25 (s, 2H), δ3.65 (s, 4H), δ3.37 (t, J=4.8Hz, 2H), δ3.34 (brs, 2H), δ3.33 (s, 1H), δ3.32 (br s, 1H), δ3.26-3.29(m, 3H), δ3.00(dd, J=9.8, 4.8Hz, 1H), δ2.50(t, J=4.4Hz, 4H), δ1. 97-2.04 (m, 1H), δ1.93 (br s, 1H), δ1.75 (dt, J=19.2, 6.4Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.77, 135.12 , 134.47, 130.78, 130.70, 129.63, 129.38, 128.78, 128.72, 128.58, 128.52, 126.70, 59.11, 57.81, 56.55, 53.55, 52.87, 52.63, 48.56, 46.58, 224.45,

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(3-chlorobenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.41-7.43 (m, 2H), δ7.35-7.39 (m, 3H), δ7.34 (br s, 1H), δ7.25 ( d, J=5.6Hz, 2H), δ7.19-7.20(m, 1H), δ4.25(s, 2H), δ3.64(br s, 2H), δ3.50(s, 2H), δ3 .34-3.38(m, 4H), δ3.31(br s, 1H), δ3.23-3.29(m, 3H), δ2.97(dd, J=9.8, 4.4Hz, 1H), δ2.43 (t, J=4.4Hz, 4H), δ1.96-2.04 (m, 2H), δ1.73 (dt, J=19.2, 6.4Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168. 81, 139.74, 134.36, 130.77, 129.65, 129.39, 128.98, 128.72, 128.58, 127.56, 127.10, 62.19, 57.80, 56.57, 53.56, 53.43, 52.86, 52.63, 48.53, 446.97

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(4-chlorobenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.39-7.42 (m, 2H), δ7.35-7.38 (m, 3H), δ7.35 (d, J=8.4Hz, 2H), δ7.25(d, J=8.4Hz, 2H), δ4.27(s, 2H), δ3.63(br s, 2H), δ3.48(s, 2H), δ3.33-3.37(m, 4H), δ3.31(br s, 1H), δ3.22-3.29(m, 3H), δ2.97(dd, J=9.6, 4.8Hz, 1H), δ2.40(br s, 4H), δ1.98 (dt, J=19.6, 6.0Hz, 1H), δ1.93 (br s, 1H), 1.73 (dt, J=19.2, 6.0Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.84，136.08，133.08，130.76，130.69，130.32，129.38，128.71，128.66，128.56，128.54，62.03，57.79，56.65，56.51，53.57，52.83，52.58，48.59，46.57，44.39，44.97，32.40.

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(2-fluorobenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.40-7.43 (m, 2H), δ7.34-7.39 (m, 4H), δ7.26-7.29 (m, 1H), δ7.13 (t, J=7.6Hz 1H), δ7.04(t, J=8.8Hz, 1H), δ4.25(s, 2H), δ3.60-3.65(m, 4H), δ3.34-3.37( m, 3H), δ3.31(d, J=6.4Hz, 2H), δ3.23-3.29(m, 3H), δ2.96(dd, J=9.8, 4.4Hz, 1H), δ2.47( t, J=4.4Hz, 4H), δ1.95-2.04 (m, 2H), δ1.72 (dt, J=18.0, 6.4Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.81 , 161.41, 131.5, 130.73, 129.40, 129.20, 129.11, 128.71, 128.56, 124.00, 123.87, 115.52, 115.30, 56.60, 55.17, 52.36, 48.57,46,46,46,46,46,46,46,46,46,46.4.4.46,46.4.4.4.46,46,46.4.4.

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(3-fluorobenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.40-7.43 (m, 2H), δ7.35-7.39 (m, 3H), δ7.26-7.31 (m, 1H), δ7.06 -7.09(m, 2H), δ6.95(dt, J=7.6, 1.6Hz, 1H), δ4.25(s, 2H), δ3.64(t, J=4.4Hz, 2H), δ3.37 (t, J=4.8Hz, 2H), δ3.36(br s, 1H), δ3.34(br s, 1H), δ3.25-3.30(m, 3H), δ2.98(dd, J= 10.4, 4.8Hz, 1H), δ2.44 (br s, 4H), δ1.96-2.05 (m, 2H), δ1.74 (dt, J=19.6, 6.0Hz, 1H); ¹³ C NMR (100.6 MHz，CDCl ₃ )δ168.78，163.00，140.22，130.77，129.60，129.38，128.64，124.48，115.68，114.39，114.18，62.19，57.81，56.56，53.54，52.86，52.61，48.59，46.58，44.40，41.97，32.37 .

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(4-fluorobenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.41-7.43 (m, 2H), δ7.35-7.40 (m, 3H), δ7.26-7.30 (m, 2H), δ7.00 (t, J=8.4Hz 2H), δ4.25(s, 2H), δ3.64(t, J=4.4Hz, 2H), δ3.58(br s, 1H), δ3.46-3.49(m , 3H), δ3.33-3.37(m, 3H), δ3.31(br s, 1H), δ3.26-3.29(m, 2H), δ2.97(dd, J=9.6, 4.8Hz, 1H ), δ2.42 (br s, 4H), δ1.98-2.05 (m, 1H), δ1.70-1.77 (m, 2H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.71, 162.16, 133.13, 130.77, 130.61, 130.53, 129.38, 128.72, 128.58, 115.32, 115.11, 62.01, 57.81, 56.58, 53.56, 52.94, 52.80, 52.54, 48.60, 46.57, 44.4970, 41.

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(3-trifluoromethylbenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.60 (br s, 1H), δ7.30 (t, J=8.0Hz, 2H), δ7.41-7.47 (m, 3H), δ7 .36-7.38(m, 3H), δ4.26(s, 2H), δ3.65(br s, 2H), δ3.47-3.57(m, 3H), δ3.36-3.38(m, 2H) , δ3.35(s, 1H), δ3.33(s, 1H), δ3.29(s, 1H), δ3.27-3.28(m, 1H), δ2.99(dd, J=9.6, 4.4 Hz, 1H), δ2.43(br s, 4H), δ2.15(br s, 2H), δ2.00(dt, J=18.8, 7.2Hz, 1H), δ1.74(dt, J=19.0 , 6.0Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.79, 138.72, 132.23, 130.99, 130.76, 130.70, 129.39, 128.75, 125.54, 124.24, 122.79, 62.23, 57.80, 536.61, , 52.65, 48.56, 46.56, 44.39, 41.95, 32.34.

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(2,4,6-trimethylbenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.36-7.43 (m, 5H), δ6.84 (s, 2H), δ4.25 (s, 2H), δ3.56 (br s, 2H), δ3.47(s, 2H), δ3.36(dd, J=9.6, 6.0Hz, 2H), δ3.31(d, J=7.2Hz, 2H), δ3.24-3.29(m, 5H), δ2.97(dd, J=9.6, 4.8Hz, 1H), δ2.42(br s, 4H), δ2.33(s, 6H), δ2.27(s, 3H), δ2.00 (dt, J=19.2, 6.8Hz, 1H), δ1.89(s, 1H), δ1.73 (dt, J=18.8, 6.4Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168. 73, 138.06, 136.73, 131.01, 130.78, 129.40, 129.00, 128.71, 128.56, 57.82, 56.52, 55.69, 53, 59, 52, 50, 52.28, 48.56, 46.58, 44.70, 42.32, 30.9040, 2

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(2-,6-dichlorobenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.39-7.42 (m, 2H), δ7.36 (d, J=5.2Hz, 3H), 7.32 (d, J=8.0Hz, 2H) , δ7.17(t, J=8.0Hz, 1H), δ4.25(s, 2H), δ3.78(br s, 2H), δ3.60(br s, 2H), δ3.36-3.39( m, 1H), δ3.30-3.35(m, 4H), δ3.26-3.27(m, 3H), δ2.97(dd, J=9.6, 4.8Hz, 1H), δ2.54-2.58(m , 4H), δ2.00(dt, J=18.8, 6.8Hz, 1H), δ1.91(s, 1H), δ1.74(dt, J=18.8, 6.4Hz, 1H); ¹³ C NMR (100.6 MHz, CDCl ₃ ) δ168.73, 136.96, 133.71, 130.78, 129.40, 129.13, 128.71, 128.57, 128.46, 57.82, 56.52, 56.27, 53.60, 53.43, 52.74, 52.55, 44.56, 44.05, 1

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(2,4-dichlorobenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.41-7.45 (m, 2H), δ7.39 (br s, 2H), δ7.35-7.37 (m, 3H), δ7.23 ( dd, J=8.2, 1.6Hz, 1H), δ4.25(s, 2H), δ3.64(br s, 2H), δ3.63(s, 2H), δ3.36-3.60(m, 3H) , δ3.34(s, 1H), δ3.32(s, 1H), δ3.26-3.30(m, 1H), δ2.98(dd, J=9.8, 4.8Hz, 1H), δ2.48( t, J=4.8Hz, 4H), δ2.01(dt, J=18.8, 6.8Hz, 1H), δ1.90(s, 1H), δ1.74(dt, J=19.2, 6.4Hz, 1H) ; ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.85, 135.01, 133.91, 133.53, 131.49, 130.77, 130.70, 129.39, 128.78, 128.72, 128.57, 127.05, 58.55, 56, 80, 56.577, 5.5 , 46.58, 44.43, 42.01, 32.41.

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(2-chloro-6-fluorobenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.40-7.42 (m, 2H), δ7.35-7.39 (m, 3H), 7.22-7.23 (m, 2H), δ6.98-7.02 (m, 1H), δ4.25(s, 2H), δ3.73(br s, 2H), δ3.61(brs, 2H), δ3.36-3.38(m, 1H), δ3.31-3.34 (m, 4H), δ3.24-3.29 (m, 3H), δ2.96 (dd, J=9.8, 4.8Hz, 1H), δ2.54 (br s, 4H), δ2.00 (dt, J =18.8, 6.8Hz, 1H), δ1.89 (s, 1H), δ1.72 (dt, J=19.2, 6.0Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.68, 162.07, 136.64, 130.78, 129.45, 128.71, 128.57, 125.55, 123.35, 123.17, 114.08, 57.81, 56.53, 53.58, 52.55, 52.33, 52.27, 48.53, 46.58, 42.03, 32.38.

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(3-methoxybenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.39-7.41 (m, 2H), δ7.35-7.38 (m, 3H), 7.24 (t, J=8.0Hz, 1H), δ6. 90(d, J=5.6Hz, 2H), δ6.82(dd, J=8.0, 2.4Hz, 1H), δ4.25(s, 2H), δ3.81(s, 3H), δ3.64( br s, 2H), δ3.51(s, 2H), δ3.41-3.38(m, 3H), δ3.33(s, 1H), δ3.31(s, 1H), δ3.25-3.29( m, 3H), δ2.43(d, J=4.8Hz, 4H), δ2.01(dt, J=18.8, 6.8Hz, 4H), δ1.84(br s, 1H), δ1.73(dt , J=18.8, 6.4Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.82, 159.75, 130.78, 129.40, 129.35, 128.71, 128.57, 121.39, 114.70, 112.64, 62.76, 57.82, 56.54, , 53.60, 52.87, 52.64, 48.60, 46.58, 44.42, 42.01, 32.42.

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(4-methoxybenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.40-7.43 (m, 2H), δ7.35-7.39 (m, 3H), δ7.22 (d, J=8.4Hz, 2H), δ6.86(d, J=8.4Hz, 2H), δ4.25(s, 2H), δ3.81(s, 3H), δ3.63(br s, 2H), δ3.47(s, 2H) , δ3.34-3.38(m, 3H), δ3.32(s, 1H), δ3.29(s, 1H), δ3.25-3.30(m, 3H), δ2.96(dd, J=9.8 , 4.4Hz, 1H), δ2.41(d, J=4.0Hz, 4H), δ2.00(dt, J=18.8, 6.8Hz, 1H), δ1.86(br s, 1H), 1.72(dt , J=18.8, 6.4Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.80, 158.95, 130.77, 130.32, 129.38, 128.71, 128.56, 113.74, 62.23, 57.80, 56.511, 55.28, 53.59, 5 , 52.49, 48.58, 46.58, 44.41, 41.99, 32.41.

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(3,5-dimethoxybenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.38-7.42(m, 2H), δ7.36-7.37(m, 3H), 6.49(s, 2H), δ6.38(s, 2H ), δ4.25(s, 2H), δ3.79(s, 6H), δ3.64(br s, 2H), δ3.47(s, 2H), δ3.34-3.37(m, 3H), δ3.32(s, 1H), δ3.31(s, 1H), δ3.26-3.29(m, 3H), δ2.97(dd, J=9.8, 4.4Hz, 1H), δ2.43(d , J=4.4, 4H), δ2.00(dt, J=18.8, 6.8Hz, 1H), δ1.80(br s, 1H), δ1.73(dt, J=19.2, 6.4Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.82, 160.85, 139.96, 130.78, 129.39, 128.72, 128.58, 106.93, 99.11, 62.89, 57.82, 56.54, 55.35, 53.60, 53.43, 52.866, 52.8 44.42, 42.00, 32.42.

(S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(2,4,6-trimethoxybenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.41-7.42(m, 2H), δ7.36-7.40(m, 3H), 6.56(s, 2H), δ4.25(s, 2H ), δ3.86(s, 6H), δ3.84(s, 3H), δ3.65(br s, 2H), δ3.46(s, 2H), δ3.35-3.38(m, 3H), δ3.31-3.34(m, 2H), δ3.29(br s, 2H), δ3.27(br s, 1H), δ3.23-3.26(m, 1H), δ2.98(dd, J= 9.8, 4.4Hz, 1H), δ2.40(d, J=4.4, 4H), δ2.00(dt, J=18.8, 6.8Hz, 1H), δ1.73(dt, J=19.6, 6.0Hz, 2H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.85, 153.22, 137.18, 133.24, 130.77, 130.69, 129.37, 128.72, 128.67, 128.58, 63.09, 60.87, 57.80, 56.61, 56.16, 5 , 48.61, 46.53, 44.42, 41.99, 34.82, 32.42.

(S)-2-[1-(2-Chlorobenzylsulfonyl)pyrrolidine-3-amino]-1-[4-(3-trifluoromethylbenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.40-7.42 (m, 2H), δ7.35-7.39 (m, 3H), 7.22-7.23 (m, 2H), δ6.98-7.02 (m, 1H), δ4.25(s, 2H), δ3.73(br s, 2H), δ3.61(brs, 2H), δ3.36-3.38(m, 1H), δ3.31-3.34 (m, 4H), δ3.24-3.29 (m, 3H), δ2.96 (dd, J=9.8, 4.8Hz, 1H), δ2.54 (br s, 4H), δ2.00 (dt, J =18.8, 6.8Hz, 1H), δ1.89 (s, 1H), δ1.72 (dt, J=19.2, 6.0Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.68, 162.07, 136.64, 130.78, 129.45, 128.71, 128.57, 125.55, 123.35, 123.17, 114.08, 57.81, 56.53, 53.58, 52.55, 52.33, 52.27, 48.53, 46.58, 42.03, 32.38.

(S)-2-[1-(3-Chlorobenzylsulfonyl)pyrrolidine-3-amino]-1-[4-(3-trifluoromethylbenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.59 (s, 1H), δ7.52 (t, J=7.2Hz, 2H), δ7.43-7.47 (m, 2H), δ7. 30-7.33(m, 3H), δ4.22(s, 2H), δ3.62-3.65(m, 1H), δ3.55-3.58(m, 4H), δ3.48(br s, 1H), δ3.36-3.42(m, 3H), δ3.30-3.34(m, 2H), δ3.05-3.14(m, 3H), δ2.41-2.46(m, 2H), δ2.03-2.08( m, 1H), δ1.76-1.86 (m, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.67, 168.65, 138.69, 138.66, 134.46, 134.44, 132.29, 131.30, 131.23, 130.79, 130.69, 130.03, 129.96, 129.03, 128.96, 128.86, 128.81, 128.74, 125.60, 125.56, 124.24, 62.21, 57.79, 55.67, 53.63, 52.74, 48.41, 46.62, 45.82, 42.39, 32

(S)-2-[1-(4-Chlorobenzylsulfonyl)pyrrolidine-3-amino]-1-[4-(3-trifluoromethylbenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.60(s, 1H), δ7.52(t, J=8.0Hz, 2H), δ7.43-7.47(t, J=7.6Hz, 1H), δ7.35(d, J=8.4Hz, 4H), δ4.2(s, 2H), δ3.66(br s, 2H), δ3.58(br s, 2H), δ3.36- 3.39(m, 3H), δ3.29-3.34(m, 3H), δ2.99-3.13(m, 2H), δ2.45(s, 4H), δ1.99-2.09(m, 2H), δ1 .78 (dt, J=18.3, 6.0Hz, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.73, 138.70, 134.69, 132.62, 132.12, 130.95, 130.63, 128.93, 128.86, 127.91, 125.57, 125.5 , 124.28, 124.24, 122.79, 62.63, 57.83, 55.65, 53.65, 52.87, 52.63, 48.53, 46.57, 44.35, 41.96, 32.40

(S)-2-[1-(4-trifluoromethylbenzylsulfonyl)pyrrolidine-3-amino]-1-[4-(3-trifluoromethylbenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.40-7.42 (m, 2H), δ7.35-7.39 (m, 3H), 7.22-7.23 (m, 2H), δ6.98-7.02 (m, 1H), δ4.25(s, 2H), δ3.73(br s, 2H), δ3.61(br s, 2H), δ3.36-3.38(m, 1H), δ3.31- 3.34(m, 4H), δ3.24-3.29(m, 3H), δ2.96(dd, J=9.8, 4.8Hz, 1H), δ2.54(br s, 4H), δ2.00(dt, J=18.8, 6.8Hz, 1H), δ1.89(s, 1H), δ1.72(dt, J=19.2, 6.0Hz, 1H); ¹³ C NMIR (100.6MHz, CDCl ₃ ) δ168.68, 162.07 .

(S)-2-[1-(2,4-dichlorobenzylsulfonyl)pyrrolidine-3-amino]-1-[4-(3-trifluoromethylbenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.59 (s, 1H), δ7.50-7.55 (m, 3H), δ7.43-7.47 (m, 2H), δ7.27-7.30 (m, 1H), δ4.43(s, 2H), δ3.65(br s, 2H), δ3.56(br s, 3H), δ3.37-3.43(m, 4H), δ3.28- 3.34(m, 2H), δ3.03-3.13(m, 2H), δ2.43-2.45(m, 4H), δ2.02-2.11(m, 1H), δ1.97(br s, 1H), δ1.76-1.84 (m, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.79, 138.73, 135.51, 135.33, 133.73, 132.25, 129.58, 128.85, 127.59, 126.35, 125.59, 125.525, 124.5 , 57.75, 53.55, 52.89, 52.75, 52.64, 48.57, 46.59, 45.74, 44.38, 41.94, 32.55.

(S)-2-[1-(2,6-dichlorobenzylsulfonyl)pyrrolidine-3-amino]-1-[4-(3-trifluoromethylbenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.59 (s, 1H), δ7.52 (t, J=7.6Hz, 1H), δ7.37 (d, J=8.0Hz 2H), δ7.21-7.25(m, 1H), δ4.74(s, 2H), δ3.64(br s, 2H), δ3.55-3.57(br s, 3H), δ3.48-3.53(m, 3H), δ3.33-3.44(m, 5H), δ3.31-3.38(m, 1H), δ2.42-2.45(m, 4H), δ2.12(dt, J=19.65, 6.0Hz, 1H ), δ1.90 ((m, 1H); ¹³ C NMR (100.6MHz, CDCl ₃ ) δ168.81, 168.58, 138.72, 136.94, 132.25, 130.96, 130.15, 128.85, 128.75, 126.82, 125.56, 124.23, 62.24, 57.74, 53.41, 52.89, 52.64, 52.00, 48.62, 46.56, 45.79, 44.40, 41.93, 32.63.

(S)-2-[1-(2-Chloro-6-fluorobenzylsulfonyl)pyrrolidine-3-amino]-1-[4-(3-trifluoromethylbenzyl)piperazine]ethanone

The structure confirmation data are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ7.59(s, 1H), δ7.52(t, J=8.0Hz, 2H), δ7.44(t, J=7.6Hz, 1H) , δ7.25-7.32(m, 3H), δ7.04-7.09(m, 1H), δ4.56(m, 2H), δ3.64(br s, 2H), δ3.55-3.57(br s , 3H), δ3.44-3.50(m, 3H), δ3.40(br s, 1H), δ3.33-3.39(m, 3H), δ3.09-3.14(m, 1H), δ2.43 (t, J=4.8Hz, 4H), δ2.10 (dt, J=19.5, 6.4Hz, 1H), δ1.94 (br s, 1H), δ1.83 (dt, J=19.5, 6.0Hz, 1H)； ¹³ C NMR(100.6MHz，CDCl ₃ )δ168.85，168.59，163.24，160.73，138.75，136.34，136.30，132.25，130.63，130.58，130.48，128.85，125.78，125.75，125.58，125.55，124.26，124.22 .

Example 3, MTT method cell proliferation inhibitory activity screening

Human liver cancer cell HepG-2 (catalogue number: TChu 72), breast cancer cell MCF-7 (catalogue number: TCHu 74) and leukemia cell K562 (catalogue number: TCHu191) in logarithmic growth phase were taken, (the above cells were purchased from Inoculated in 96-well plates at a density of 2× ¹⁰⁵ cells/mL in the cell bank of the Type Culture Collection Committee of the Chinese Academy of Sciences and the Cell Resource Center of the Shanghai Institutes for Biological Sciences of the Chinese Academy of Sciences, 99 μL/well, at 37°C, 5% CO _2. After culturing in the incubator for 4 hours, add the compound prepared in the embodiment of the present invention to each well to make the final concentration 50 μmol/L, 25 μmol/L, 10 μmol/L, 5 μmol/L, 2.5 μmol/L, 1 μmol/L , 0.5μmol/L, 0.25μmol/L, 0.1μmol/L, 0.05μmol/L 10 concentration gradients. Three replicate wells were set up for each compound, and both negative and positive controls were set up, wherein the negative control was 1% DMSO solution by volume. After 48 hours of action, add MTT (5mg/ml) solution, 10μL/well, continue to cultivate for 4-6 hours, centrifuge at 2000rpm, 4°C for 5 minutes, absorb the supernatant, add DMSO, 100μL/well, and incubate at 37°C for about 10 minutes, and vibrated with a micro-oscillator for about 5 minutes to completely dissolve the crystals, measure the OD value at 495 nm with a microplate reader, and calculate the cell proliferation inhibition rate (Inhibition Rate, IR%) according to the following formula:

IR%=(blank control OD-sample OD)/blank control OD×100%

After calculation, the _IC50 values of the half-major inhibitory doses of the compounds prepared in the examples of the present invention for in vitro experiments on HepG-2, MCF-7 and K562 tumor cell lines are shown in Table 1; as can be seen from Table 1, the series of derivatives provided by the present invention It has a good inhibitory effect on inhibiting the growth of tumor cells, especially has certain selectivity on K562 cells.

Table 1. _{The half-major} inhibitory dose IC value of substituted (S)-phenylmethylsulfonylpyrrolidine-3-amino derivatives to HepG-2, MCF-7 and K562 tumor cell lines in vitro experiments

Claims (10)

1. The compound shown in formula I, or its pharmaceutically acceptable salt, ester or solvate;

(Formula I); In formula I, R ₁ is hydrogen, or R ₁ is one or more of the following groups with single or multiple substitutions on the benzene ring: -F, -Cl, -Br, -CH ₃ , -OCH ₃ , -CF ₃ and -CN; R ₂ is hydrogen, or R ₂ is one or more of the following groups with single or multiple substitutions on the benzene ring: -F, -Cl, -Br, -CH ₃ , -OCH ₃ , -CF ₃ , and -CN. 2. The compound according to claim ₁ , characterized in that: the R multi-substitution refers to 2,4-disubstituted, 2,5-disubstituted, 2,6-disubstituted, 3,4-disubstituted , 3,5-disubstituted; or 2,4,6-trisubstituted, 3,4,5-trisubstituted; or 2,3,5,6-tetrasubstituted; the R2 multi-substituted refers to 2,4- Disubstituted, 2,5-disubstituted, 2,6-disubstituted, 3,4-disubstituted, 3,5-disubstituted; or 2,4,6-trisubstituted, 3,4,5-trisubstituted; Or 2,3,5,6-tetrasubstitution. 3. The compound according to claim 2, characterized in that: in formula I, _R is hydrogen, 2-fluoro, 2-chloro, 2-bromo, 2-methyl, 2-methoxy, 2-cyano Base, 2-trifluoromethyl, 3-fluoro, 3-chloro, 3-bromo, 3-methyl, 3-methoxy, 3-cyano, 3-trifluoromethyl, 4-fluoro, 4- Chlorine, 4-bromo, 4-methyl, 4-methoxy, 4-cyano, 4-trifluoromethyl, 2,5-difluoro, 3,5-difluoro, 2,6-dichloro, 2,4-dichloro, 3,4-dichloro, 3,5-di-trifluoromethyl, 3,4,5-trifluoro, 3,4,5-trichloro, 2-chloro-6-fluoro , 3,5-dimethoxy, 2,4,6-trimethoxy, 3,4,5-trimethoxy, 2,4,6-trimethyl or 2,3,5,6-tetramethyl base; R ₂ is hydrogen, 2-fluoro, 2-chloro, 2-bromo, 2-methyl, 2-methoxy, 2-cyano, 2-trifluoromethyl, 3-fluoro, 3-chloro, 3- Bromine, 3-methyl, 3-methoxy, 3-cyano, 3-trifluoromethyl, 4-fluoro, 4-chloro, 4-bromo, 4-methyl, 4-methoxy, 4- Cyano, 4-trifluoromethyl, 2,5-difluoro, 3,5-difluoro, 2,6-dichloro, 2,4-dichloro, 3,4-dichloro, 3,5-dichloro -Trifluoromethyl, 3,4,5-trifluoro, 3,4,5-trichloro, 2-chloro-6-fluoro, 3,5-dimethoxy, 2,4,6-trimethoxy , 3,4,5-trimethoxy, 2,4,6-trimethyl or 2,3,5,6-tetramethyl. 4. The method for preparing the compound described in any one of claims 1-3, comprising the steps of: 1) reacting substituted or unsubstituted: phenylmethylsulfonyl chloride or phenylmethylsulfonyl bromide with (S)-3-Boc-aminopyrrolidine under alkaline conditions to obtain the compound shown in formula II; (Formula II) Wherein, R in formula II _is the same as R in formula _I ; 2) removing the tert-butoxycarbonyl group from the compound shown in formula II to obtain amino hydrochloride shown in formula III; (Formula III) 3) Acetylation of unsubstituted or substituted benzylpiperazine with chloroacetyl chloride or bromoacetyl bromide to obtain the compound shown in formula IV;

(Formula IV) Wherein, R in formula IV _is the _same as R in formula I; 4) reacting the compounds represented by formula III and formula IV under basic conditions to obtain the compound represented by formula I. 5. The method according to claim 4, characterized in that: the alkaline condition described in the step (1) is provided by any one of the following bases: triethylamine, N-methylmorpholine, diisopropyl ethyl base amine, potassium carbonate, cesium carbonate, potassium hydroxide and sodium hydroxide; the reaction medium of the reaction is: a mixed solvent of ethyl acetate and tetrahydrofuran with a volume ratio of 1:1, dioxane, ethyl acetate or Water; The reaction temperature of described reaction is room temperature; The deprotection reagent for removing the tert-butoxycarbonyl group described in step (2) is: 1.5-3M hydrochloric acid aqueous solution, trifluoroacetic acid or hydrochloric acid dioxane solution; The alkaline condition described in the step (4) is provided by any one of the following bases: triethylamine, N-methylmorpholine, diisopropylethylamine, salt of wormwood, cesium carbonate, potassium hydroxide and hydroxide Sodium; the reaction is carried out under the catalysis of potassium iodide; the reaction medium of the reaction is: tetrahydrofuran, ethanol, methanol or dioxane; the molar ratio of the compound shown in the formula III and the compound shown in the formula IV in the reaction is 1.05-2.5:1; the reaction is carried out under reflux conditions. 6. Use of any one of the compounds according to claims 1-3 or pharmaceutically acceptable salts, esters, solvates thereof in the preparation of eukaryotic tumor cell inhibitors. 7. The application according to claim 6, characterized in that: the eukaryote is a mammal; the tumor cell is a cancer cell; and the cancer cell is a leukemia cell, a breast cancer cell or a liver cancer cell. 8. Use of the compound according to any one of claims 1-3 or a pharmaceutically acceptable salt, ester, solvate thereof in the preparation of a drug for preventing and/or treating tumors. 9. The application according to claim 8, characterized in that: the tumor is cancer; the cancer is leukemia, breast cancer or liver cancer. 10. A drug for preventing and/or treating tumors, the active ingredient of which is the compound according to any one of claims 1-3 or a pharmaceutically acceptable salt, ester, solvate thereof.

Images