CN112679515A - Benzofuran derivative and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the field of medicines, and relates to a benzofuran derivative, and a preparation method and application thereof. The structural formula of the benzofuran derivative is shown as a formula I:

pharmacological studies show that the compound prepared by the invention can effectively inhibit the activity of AKT protein kinase, and can be used as an AKT protein kinase inhibitor to effectively prevent and/or treat hyperproliferative diseases such as cancers.

Description

Benzofuran derivative and preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, and relates to a benzofuran derivative, and a preparation method and application thereof.

Background

At present, malignant tumor is one of the diseases with the highest fatality rate in the world, and is second to cardiovascular and cerebrovascular diseases, so the research and development of anticancer drugs have very important clinical and social significance. Protein kinase signaling pathways have been shown to play an important role in the development of cancer. The phosphatidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signal transduction pathway is one of the important signal transduction pathways in mammalian cells, plays roles of inhibiting apoptosis and promoting proliferation by influencing the activation states of various downstream effector molecules, is over-activated in cancer patients and is one of the most frequently changed pathways in human cancers. Research shows that the PI3K/Akt/mTOR signal transduction pathway inhibits cancer cell autophagic death by regulating and controlling the transcription, translation and expression of cancer-promoting genes and various important proteins, and plays roles of promoting cancer cell proliferation, resisting apoptosis, promoting angiogenesis, transferring, resisting drug resistance and the like.

Some anti-tumor drugs play a therapeutic role by inhibiting the conduction of AKT signal pathway, and some Chinese herbal medicines such as curcumin, baicalin and the like are proved to inhibit cancer cell proliferation by inhibiting PI3K and AKT phosphorylation and promoting apoptosis-related protein expression. However, most of the AKT protein kinase inhibitors have high drug cost, poor absorption effect and easy drug resistance. Therefore, the development of a novel kinase inhibitor which has small toxic and side effects and is easy to absorb and targets abnormal regulation pathways and finally causes diseases has great ethical and commercial benefits for the medical field.

The benzofuran derivative is innovatively synthesized, has a good inhibition effect on the activity of AKT protein kinase, can inhibit the growth of abnormal tumor cells, has obvious antitumor activity, strong targeting effect and small toxic and side effects, so that a brand new compound for preparing the AKT protein kinase inhibitor can be obtained.

Disclosure of Invention

In view of the above problems, the present invention aims to provide a preparation method and an application of benzofuran derivatives, which can effectively inhibit the activity of AKT protein kinase, have strong anti-tumor activity, have good therapeutic effect on some hyperproliferative diseases such as cancer, and can be used for preparing anti-tumor drugs. In order to achieve the purpose, the invention adopts the following technical scheme.

A benzofuran derivative has a structural general formula I as follows:

wherein R ═

Another objective of the present invention is to provide a synthetic route of benzofuran derivatives of formula I:

further, the synthesis method of each step in the synthesis route is as follows:

1) in a proper solvent, 2, 3-bis (bromomethyl) benzene-1, 4-diol and triphenylphosphine are used as raw materials to react to obtain 2, 3-bis ((bromotriphenyl-lambda)⁵-phosphanyl) methyl) benzene-1, 4-diol;

2) with 2, 3-bis ((bromotriphenyl-lambda)⁵-phosphanyl) methyl) benzene-1, 4-diol as a raw material to obtain 2, 6-dibutylbenzo [1,2-b:5,4-b']Difurane;

3) 2, 6-dibutylbenzo [1,2-b:5,4-b '] difuran is used as a raw material to react to obtain (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4-methoxyphenyl) methanone);

4) taking (2, 6-dibutylbenzo [1,2-b:5,4-b '] difuran-3, 5-diyl) bis ((4-methoxyphenyl) methanone) as a raw material to react to obtain (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4-hydroxyphenyl) methanone);

5) under the alkaline condition, (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4-hydroxyphenyl) methanone) and corresponding chloride are used as raw materials to react to obtain the corresponding final product.

Of partial compounds¹H-NMR (400MHz) and¹³C-NMR (125MHz) was as follows:

intermediate (compound of structure 2):¹H-NMR(400MHz,CDCl₃)δ:2.60(d,4H),6.49(s,2H),7.15(m,12H),7.44-7.47(m,18H),9.68(s,2H).¹³C-NMR(125MHz,CDCl₃)δ:29.58,118.00,123.17,126.49,131.37,132.66,134.54,147.30.

intermediate (compound represented by structure 3):¹H-NMR(400MHz,CDCl₃)δ:0.90(t,6H),1.30(m,4H),1.59(m,4H),2.87(t,4H),6.72(s,2H),7.64(s,1H),7.97(s,1H).¹³C-NMR(125MHz,CDCl₃)δ:14.00,22.40,29.29,31.49,94.62,103.98,116.02,122.59,149.73,157.55.

intermediate (compound represented by structure 4):¹H-NMR(400MHz,CDCl₃)δ:0.90(t,6H),1.30(m,4H),1.59(m,4H),3.18(t,4H),3.79(s,6H),7.10(d,4H),7.54(s,1H),7.73-7.97(m,5H).¹³C-NMR(125MHz,CDCl₃)δ:14.00,22.40,27.95,29.26,56.08,96.39,114.40,117.53,118.58,118.69,129.77,134.06,159.33,164.47,172.69,193.50.

intermediate (compound of structure 5):¹H-NMR(400MHz,CDCl₃)δ:0.90(t,6H),1.30(m,4H),1.59(m,4H),2.91(t,4H),5.00(s,2H),6.88(d,4H),7.68(d,4H),7.78(s,1H),8.04(s,1H).¹³C-NMR(125MHz,CDCl₃)δ:14.00,22.40,27.95,29.26,96.39,115.77,117.53,118.58,118.69,129.41,133.29,159.33,163.59,172.69,193.50.

compound 1 (compound represented by structure 6):¹H-NMR(400MHz,CDCl₃)δ:0.87-0.94(m,18H),1.21-1.34(m,12H),1.35-1.48(m,8H),1.59(m,4H),1.83(m,4H),2.38(t,8H),2.48(t,4H),2.91(t,4H),4.05(t,4H),7.12(d,4H),7.76(s,2H),7.84(d,4H).¹³C-NMR(125MHz,CDCl₃)δ:14.00,20.75,22.40,27.95,28.13,29.25,29.26,51.76,56.45,67.16,96.39,115.25,117.53,118.58,118.69,129.90,134.17,159.33,165.76,172.69,193.50.

the benzofuran derivative disclosed by the invention can effectively inhibit the activity of AKT protein kinase, has strong anti-tumor activity and has a good treatment effect on some hyperproliferative diseases such as cancers. The benzofuran derivative has positive significance in treating or preventing tumors as an AKT protease inhibitor, and can be further researched.

The medicine for preventing or treating the tumor or the pharmaceutically acceptable salt or solvate thereof is applied to the development of the medicine for treating the AKT protein kinase inhibitor, and particularly provides the application of the benzofuran derivative in the treatment or prevention of the tumor.

Compared with the prior art, the invention has the following beneficial effects:

the benzofuran derivative disclosed by the invention has strong tumor inhibition activity, and shows good inhibition effect in a plurality of tumor cell strains; also has good AKT protein kinase inhibition effect, and has good development prospect for developing medicaments for treating AKT protein kinase pathway cancer.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

Drawings

FIG. 1: influence of benzofuran derivatives obtained by the invention on AKT enzyme activity

FIG. 2: influence of benzofuran derivatives on tumor cell proliferation

FIG. 3: influence of benzofuran derivatives on expression of PI3K/AKT/mTOR signal pathway protein (Western blot method)

Detailed Description

The following synthetic examples, biological test results, are used to further illustrate the invention, but are not meant to limit the invention.

Synthesis examples

Example 1 preparation of Compound 1

(1) Intermediate 2, 3-bis ((bromotriphenyl-lambda)⁵-synthesis of a phosphanyl) methyl) benzene-1, 4-diol (compound of formula 2):

2, 3-bis (bromomethyl) benzene-1, 4-diol (compound of formula 1) (100mmol) and triphenylphosphine (210mmol) were heated at reflux in 160.0mL chloroform for 0.5 h. The reaction mixture was then cooled and the white precipitate formed was filtered off. The filtrate was evaporated to dryness in vacuo and the resulting crude product was slurried in 50.0mL of toluene, filtered, washed with toluene and the resulting solids combined and dried in vacuo at 50 ℃ to give 66.46g of an off-white solid in 81% yield.

¹H-NMR(400MHz,CDCl₃)δ:2.60(d,4H),6.49(s,2H),7.15(m,12H),7.44-7.47(m,18H),9.68(s,2H).¹³C-NMR(125MHz,CDCl₃)δ:29.58,118.00,123.17,126.49,131.37,132.66,134.54,147.30.

(2) Synthesis of intermediate 2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran (compound shown in structural formula 3)

Valeryl chloride (110mmol) was slowly added to 2, 3-bis ((bromotriphenyl-. lamda.) with stirring⁵-Phosphoalkyl) methyl) benzene-1, 4-diol (compound of formula 2) (50mmol) and pyridine (200mmol) in chloroform (100 mL). The mixture was then heated to reflux for 2 hours. Toluene (280.0mL) was added and 140.0mL of solvent was distilled off. Triethylamine (225mmol) was then added and the mixture was heated under reflux for 3 hours. It was cooled and the triphenylphosphine oxide formed was filtered off and the solid was washed with ethyl acetate. The filtrate was concentrated to dryness in vacuo. The resulting oil was dissolved in acetonitrile, n-pentane was added dropwise to the solution to crystallize, filtered and dried at 50 ℃ in vacuo to give 10.54g of a tan solid in 78% yield.

¹H-NMR(400MHz,CDCl₃)δ:0.90(t,6H),1.30(m,4H),1.59(m,4H),2.87(t,4H),6.72(s,2H),7.64(s,1H),7.97(s,1H).¹³C-NMR(125MHz,CDCl₃)δ:14.00,22.40,29.29,31.49,94.62,103.98,116.02,122.59,149.73,157.55.LC-MS(ESI,pos,ion)m/z:271.15[M+H].

(3) Synthesis of intermediate (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4-methoxyphenyl) methanone) (compound represented by structural formula 4)

Tin tetrachloride (51mmol) was added to a stirred solution of 2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran (compound of formula 3) (50mmol) and 4-methoxybenzoyl chloride (110mmol) in dichloromethane (50mL) at 0-5 ℃. The mixture was stirred at the same temperature for 0.5 hour, and after returning to room temperature, stirring was continued for 2 hours. The temperature was again lowered to 0-5 ℃ and water (50mL) was added dropwise to the stirred mixture. The mixture was then extracted with dichloromethane (3X 30 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated. After purification by column chromatography (eluent: ethyl acetate/hexane 1:3 vol.%), 16.91g of a pale yellow solid were obtained, yield 62.8%.

¹H-NMR(400MHz,CDCl₃)δ:0.90(t,6H),1.30(m,4H),1.59(m,4H),3.18(t,4H),3.79(s,6H),7.10(d,4H),7.54(s,1H),7.73-7.97(m,5H).¹³C-NMR(125MHz,CDCl₃)δ:14.00,22.40,27.95,29.26,56.08,96.39,114.40,117.53,118.58,118.69,129.77,134.06,159.33,164.47,172.69,193.50.LC-MS(ESI,pos,ion)m/z:539.25[M+H].

(4) Synthesis of intermediate (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4-hydroxyphenyl) methanone) (compound represented by structural formula 5)

Intermediate (2, 6-dibutylbenzo [1,2-b:5,4-b']Difuran-3, 5-diyl) bis ((4-methoxyphenyl) methanone) (the compound represented by the formula 4) (50mmol) was added to a solution of HBr (10mmol) in AcOH (100mL), and the reaction was refluxed for 15 hours. The reaction mixture was cooled and slowly poured into cold water (80mL), kept at a temperature below 15 ℃ and extracted with DCM (100 mL). The resulting DCM layer was washed with water (80mL) and then with 5% NaHCO₃(100mL) solution wash. The organic phase was dried over anhydrous magnesium sulfate, concentrated to dryness to give the crude product, slurried with n-heptane (60mL), filtered, and dried to give 22.77g of a light brown solid in 89.2% yield.

¹H-NMR(400MHz,CDCl₃)δ:0.90(t,6H),1.30(m,4H),1.59(m,4H),2.91(t,4H),5.00(s,2H),6.88(d,4H),7.68(d,4H),7.78(s,1H),8.04(s,1H).¹³C-NMR(125MHz,CDCl₃)δ:14.00,22.40,27.95,29.26,96.39,115.77,117.53,118.58,118.69,129.41,133.29,159.33,163.59,172.69,193.50.LC-MS(ESI,pos,ion)m/z:511.22[M+H].

(5) Synthesis of (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4- (3- (dibutylamino) propoxy) phenyl) methanone) (compound represented by structural formula 6)

Potassium carbonate (20mmol) was added to a solution of (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4-hydroxyphenyl) methanone) (the compound represented by the formula 5) (20mmol) in toluene (80 mL). The mixture was then stirred at 25-30 ℃ for 0.5 h and heated to reflux, followed by addition of 1-chloro-3-di-n-butylaminopropane (45mmol) while maintaining the temperature. The reaction mixture was refluxed for 5 hours. The reaction mixture was then cooled to 25-30 ℃, filtered, and washed with toluene (50 mL). The filtrate was collected and concentrated under reduced pressure and flash column chromatography (eluent ethyl acetate) afforded 15.20g of an off-white solid in 89.5% yield.

¹H-NMR(400MHz,CDCl₃)δ:0.87-0.94(m,18H),1.21-1.34(m,12H),1.35-1.48(m,8H),1.59(m,4H),1.83(m,4H),2.38(t,8H),2.48(t,4H),2.91(t,4H),4.05(t,4H),7.12(d,4H),7.76(s,2H),7.84(d,4H).¹³C-NMR(125MHz,CDCl₃)δ:14.00,20.75,22.40,27.95,28.13,29.25,29.26,51.76,56.45,67.16,96.39,115.25,117.53,118.58,118.69,129.90,134.17,159.33,165.76,172.69,193.50.LC-MS(ESI,pos,ion)m/z:849.55[M+H].

Example 2 preparation of Compound 2 (Compound represented by chemical formula 7)

(1) Synthesis of (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4- ((2-methylpropenyl) oxy) phenyl) methanone) (compound represented by chemical formula 7):

potassium carbonate (20mmol) was added to a solution of (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4-hydroxyphenyl) methanone) (the compound represented by the formula 5) (20mmol) in toluene (80 mL). The mixture was then stirred at 25-30 ℃ for 0.5 h and heated to reflux, followed by addition of 3-chloro-3-methylpropene (45mmol) while maintaining the temperature. The reaction mixture was refluxed for 5 hours. The reaction mixture was then cooled to 25-30 ℃, and the inorganic solid was filtered and washed with toluene (50 mL). The filtrate was collected and concentrated under reduced pressure and flash column chromatography (eluent ethyl acetate) afforded 9.71g of an off-white solid in 78.5% yield.

¹H-NMR(400MHz,CDCl₃)δ:0.91(t,6H),1.28(m,4H),1.67(m,4H),1.87(s,6H),2.75(t,4H),4.39(s,4H),5.00(s,4H),7.02(m,4H),7.44(s,1H),7.82(m,5H).¹³C-NMR(125MHz,CDCl₃)δ:13.89,19.16,20.84,26.99,27.68,71.38,93.09,112.42,114.86,117.6,123.65,130.12,132.81,139.43,155.21,162.37,162.76,192.09.LC-MS(ESI,pos,ion)m/z:619.30[M+H].

Example 3 preparation of Compound 3 (Compound represented by formula 8)

(1) Synthesis of (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4- (2-methylbutoxy) phenyl) methanone) (compound represented by structural formula 8)

Potassium carbonate (20mmol) was added to a solution of (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4-hydroxyphenyl) methanone) (the compound represented by the formula 5) (20mmol) in toluene (80 mL). The mixture was then stirred at 25-30 ℃ for 0.5 h and heated to reflux, followed by addition of 1-chloro-2-methylbutane (45mmol) while maintaining the temperature. The reaction mixture was refluxed for 5 hours. The reaction mixture was then cooled to 25-30 ℃, and the inorganic solid was filtered and washed with toluene (50 mL). The filtrate was collected and concentrated under reduced pressure and flash column chromatography (eluent ethyl acetate) afforded 10.74g of an off-white solid in 82.5% yield.

¹H-NMR(400MHz,CDCl₃)δ:0.90(m,12H),1.05(d,6H),1.27(m,4H),1.51(m,4H),1.67(m,4H),1.97(m,2H),2.75(t,4H),3.94(m,4H),6.98(dt,4H),7.44(s,1H),7.83(m,5H).¹³C-NMR(125MHz,CDCl₃)δ:11.48,13.81,17.5,22.28,26.75,28,31.86,35.26,72.75,96.81,117.86,120.03,122.43,129.79,136.79,142.43,154.73,158.16,192.49.LC-MS(ESI,pos,ion)m/z:651.37[M+H].

Example 4 preparation of Compound 4 (Compound represented by formula 9)

(1) Synthesis of (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4- (cyclopentyloxy) phenyl) methanone) (compound represented by structural formula 9)

Potassium carbonate (20mmol) was added to a solution of (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4-hydroxyphenyl) methanone) (the compound represented by the formula 5) (20mmol) in toluene (80 mL). The mixture was then stirred at 25-30 ℃ for 0.5 h and heated to reflux, followed by addition of cyclopentyl chloride (45mmol) while maintaining the temperature. The reaction mixture was refluxed for 5 hours. The reaction mixture was then cooled to 25-30 ℃, and the inorganic solid was filtered and washed with toluene (50 mL). The filtrate was collected and concentrated under reduced pressure and flash column chromatography (eluent ethyl acetate) afforded 11.36g of an off-white solid in 87.8% yield. LC-MS (ESI, pos, ion) M/z 647.32[ M + H ].

Example 5 preparation of Compound 5 (Compound represented by formula 10)

(1) (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4- (phenylethoxy) phenyl) methanone) (structure

Synthesis of Compound represented by the formula 10)

Potassium carbonate (20mmol) was added to a solution of (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4-hydroxyphenyl) methanone) (the compound represented by the formula 5) (20mmol) in toluene (80 mL). The mixture was then stirred at 25-30 ℃ for 0.5 h and heated to reflux, followed by addition of 1-chloro-2-phenylethane (45mmol) while maintaining the temperature. The reaction mixture was refluxed for 5 hours. The reaction mixture was then cooled to 25-30 ℃, and the inorganic solid was filtered and washed with toluene (50 mL). The filtrate was collected and concentrated under reduced pressure and flash column chromatography (eluent ethyl acetate) afforded 11.44g of an off-white solid in 79.6% yield. LC-MS (ESI, pos, ion) M/z 719.33[ M + H ].

Biological example 1 Effect of the Compounds obtained according to the invention on AKT-1 kinase Activity

The influence of the compound on the activity of AKT kinase is determined by the following method: this method describes a kinase Assay that measures phosphorylation of fluorescently labeled skin by full-length human recombinant active AKT-1 by fluorescence polarization using a commercially available IMAP Kit (IMAP AKT Assay Bulk Kit, # R8059, Molecular Devices, Sunnyvale, Calif.). The AKT-1 kinase used was prepared from full-length human recombinant AKT-1 activated with PDK1 and MAP kinase 2. The assay procedure begins with the preparation of a 10mM stock of compound in DMSO. The assay was initiated by diluting the 2-fold gradient 9 times, mixing the compound and positive control (Akti-1/2) at different concentrations with the corresponding buffer substrate, adding 200nM fluorescently labeled peptide substrate and 4nM MAKT-1 to 384-well plates according to the kit protocol. After the plate was centrifuged at 100g for 1 minute, it was left at room temperature for 60 minutes. The reaction was then quenched by addition of binding solution, centrifuged again, held at room temperature for an additional 30 minutes, and read on a Victor 1420Mutilabel HTS counter to measure fluorescence polarization. As shown in FIG. 1, the compounds obtained by the present invention showed excellent AKT protein kinase inhibitory activity.

Biological example 2 Effect of the Compounds obtained according to the invention on tumor cell proliferation

The antitumor cell proliferation activity of the compound obtained by the present invention was measured by the MTT method. Ovarian cancer SKOV3 and human liver cancer SMMC-7721 cells were cultured in RPMI1640 medium containing 10% fetal bovine serum and 1% penicillin/streptomycin. The cells were cultured at 37 ℃ in 5% CO₂In a cell culture incubator. Cultured cells were trypsinized and transferred to 96-well plates (2000 cells/well). After further overnight incubation, the cells were treated with the compounds obtained according to the invention at the indicated working concentrations. After 48 hours of incubation, 20uL of MTT (5mg/ml) was added dropwise to the wells. After an additional 4 hours of incubation, the mixed media in the 96-well plate was removed and then 150uL of dimethyl sulfoxide (DMSO) was added. Next, the 96-well plate was shaken for about 15 minutes, and kept at room temperature to mix the contents. The OD was then measured at a wavelength of 490 nm. The results are shown in FIG. 2. The results show that the compound obtained by the invention has an inhibiting effect on the proliferation of ovarian cancer cells and liver cancer cells.

Biological example 3, effect of western immunoblotting on AKT kinase signaling pathway.

Cultured SKOV3 cells were trypsinized and transferred to 6-well plates (1X 10)⁶Cells/well). After further overnight incubation, the cells were treated with the compound obtained according to the invention at a working concentration of 100 uM. Treat 24 hoursAt this time, the cells were harvested. After the cultured cells are harvested, the cells are lysed by using Whole Cell Lysates (WCL), centrifuged, added with a sample buffer solution to boil, subjected to SDS-PAGE, proteins are transferred to a PVDF membrane after electrophoresis, primary antibodies AKT, p-AKT (Ser473) and p-AKT (Thr308) and internal reference protein (GAPDH)) are incubated overnight after 5% BSA blocking, HPR-labeled secondary antibodies are incubated for two hours at room temperature after washing, and an Enhanced chemiluminiscence detection system (ECL) is detected after washing. As shown in figure 3, the compound prepared by the invention plays a role in inducing apoptosis probably by inhibiting the activation of a PI3K/AKT signal path.

The above shows that the compound prepared by the invention can effectively inhibit the activity of AKT protein kinase, and can be used as an AKT protein kinase inhibitor to effectively prevent and/or treat hyperproliferative diseases such as cancers.

Claims (7)

1. A benzofuran derivative has a chemical structure formula shown in formula I,

wherein

2. The benzofuran derivative of claim 1, which is prepared by the following synthesis route:

3. a process for the preparation of benzofuran derivatives according to claim 1, comprising the steps of:

(1) in a proper solvent, 2, 3-bis (bromomethyl) benzene-1, 4-diol and triphenylphosphine are used as raw materials to react2, 3-bis ((bromotriphenyl-. lamda.) is obtained⁵-phosphanyl) methyl) benzene-1, 4-diol;

(2) with 2, 3-bis ((bromotriphenyl-lambda)⁵-phosphanyl) methyl) benzene-1, 4-diol as a raw material to obtain 2, 6-dibutylbenzo [1,2-b:5,4-b']Difurane;

(3) 2, 6-dibutylbenzo [1,2-b:5,4-b '] difuran is used as a raw material to react to obtain (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4-methoxyphenyl) methanone);

(4) taking (2, 6-dibutylbenzo [1,2-b:5,4-b '] difuran-3, 5-diyl) bis ((4-methoxyphenyl) methanone) as a raw material to react to obtain (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4-hydroxyphenyl) methanone);

(5) under the alkaline condition, (2, 6-dibutylbenzo [1,2-b:5,4-b' ] difuran-3, 5-diyl) bis ((4-hydroxyphenyl) methanone) and corresponding chloride are used as raw materials to react to obtain the corresponding final product.

4. The solvent of claim 3, wherein the solvent of step (1) is dichloromethane, chloroform or toluene, preferably chloroform.

5. The base of the synthesis step (5) according to claim 3 is preferably potassium carbonate.

6. The benzofuran derivative of claim 1, for use as an AKT protein kinase inhibitor.

7. Use according to claim 6, characterized in that the compounds obtained according to the invention are used as AKT protease inhibitors for the preparation of a medicament for the treatment of hyperproliferative diseases or inflammations, preferably ovarian, liver, colon, stomach and kidney cancers and the like.

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