Preparation of 1-dihydrobenzofuran-3-aryl-2-pyrazole-propenone and application of 1-dihydrobenzofuran-3-aryl-2-pyrazole-propenone as antitumor drug

Abstract

The invention relates to a novel compound as well as a preparation method and application thereof, in particular to (Z / E)-1-(2, 2-dimethyl-2, 3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propylene-1-ketone as well as a preparation method and application thereof in preparation of an anti-tumor drug, and discloses a preparation method of (Z / E)-1-(2, 2-dimethyl-2, 3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propylene-1-ketone. The structural formula of the compound 1-(2, 2-dimethyl-2, 3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propylene-1-ketone is as shown in a formula I or a formula II: # imgabs 0 #, and the structural formula of the compound 1-(2, 2-dimethyl-2, 3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propylene-1-ketone is as shown in a formula II. Wherein R1 is selected from a methoxy group, an ethyoxyl group or a propoxy group; r1 is selected from methyl, methoxy, ethyoxyl, nitro, iodine, bromine, chlorine, fluorine, 2, 4-difluoro, 2, 4-dichloro, 2, 3, 4-trichloro, 2, 4-dimethoxy and 2, 3, 4-trimethoxy, and R2 is selected from methyl, methoxy, ethyoxyl, nitro, iodine, bromine, chlorine, fluorine, 2, 4-difluoro, 2, 4-dichloro, 2, 3, 4-trichloro, 2, 4-dimethoxy and 2, 3, 4-trimethoxy.

Description

Technical Field

[0001] The present invention relates to a new class of compounds, their preparation methods and applications, specifically (Z / E)-1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one, its preparation method and its application as an anti-tumor drug. Background Art

[0002] Julie S. Bose et al. [J. Med. Chem., 2009, 52, 3184-3190] described that dihydrobenzofuran lignans (Compound 1) have potential anti-tumor effects, mainly causing G2 / M arrest and apoptosis through the mitochondrial control pathway. Umar Farooq et al. [Biol. Res., 2019, 52, 1] isolated 3 dihydrobenzofuran derivatives (Compounds 2-4) from Polygonum barbatum L. and tested their inhibitory activities against oral cancer cells (CAL-27) and human lung cancer cells (NCI-H460). Among them, Compounds 2 and 4 have inhibitory activities against oral cancer cells (CAL-27) and human lung cancer cells (NCI-H460). Liang Xuewu et al. [ACS Med. Chem. Lett., 2016, 7, 950-955] designed and synthesized a series of 4-amino-(1H)-pyrazole derivatives as JAK inhibitors for the treatment of cancer. Among them, Compound 5 showed strong anti-proliferative activities against human prostate cancer cells (PC-3) and human breast cancer (MCF-7).

[0003]

[0004] Chinese Patent CN102010405A discloses a 4-(benzofuran-5-yl)-2-benzylideneaminothiazole and its application as an anti-tumor drug; Chinese Patent CN102786515A discloses a 2-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)morpholine and its preparation method and application; Chinese Patent CN105585562A discloses a 1-(benzofuran-5-yl)-3-aryl-2-(triazol-1-yl)propenone and its application as an anti-cancer drug.

[0005] Therefore, it is of great significance to develop a new dihydrobenzofuran derivative and study its anti-tumor activity. Summary of the Invention

[0006] The object of the present invention is to provide 1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one shown in Chemical Structural Formula I or II:

[0007]

[0008] Among them, R1 is selected from: methoxy, ethoxy or propoxy; R2 is selected from: methyl, methoxy, ethoxy, nitro, iodine, bromine, chlorine, fluorine, 2,4-difluoro, 2,4-dichloro, 2,3,4-trichloro, 2,4-dimethoxy, 2,3,4-trimethoxy.

[0009] Preferably, the R1 is methoxy.

[0010] More preferably, the 1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one is selected from: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14 or A15; among them,

[0011] A1 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2-tolyl)-2-propen-1-one;

[0012] A2 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(3-tolyl)-2-propen-1-one;

[0013] A3 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-tolyl)-2-propen-1-one;

[0014] A4 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2-methoxyphenyl)-2-propen-1-one; A5 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(3-methoxyphenyl)-2-propen-1-one; A6 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-methoxyphenyl)-2-propen-1-one; A7 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(3-chlorophenyl)-2-propen-1-one;

[0015] A8 is 1-(dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-chlorophenyl)-2-propen-1-one;

[0016] A9 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(3-fluorophenyl)-2-propen-1-one;

[0017] A10 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-fluorophenyl)-2-propen-1-one;

[0018] A11 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2,4-dichlorophenyl)-2-propen-1-one; A12 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2-ethoxyphenyl)-2-propen-1-one;

[0019] A13 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-ethoxyphenyl)-2-propen-1-one;

[0020] A14 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2,4-dimethoxyphenyl)-2-propen-1-one;

[0021] A15 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2,3,4-trimethoxyphenyl)-2-propen-1-one.

[0022] The reaction formula of the above 1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one is as follows:

[0023]

[0024] Among them, R1 is selected from: methoxy, ethoxy or propoxy; R2 is selected from: methyl, methoxy, ethoxy, nitro, iodine, bromine, chlorine, fluorine, 2,4-difluoro, 2,4-dichloro, 2,3,4-trichloro, 2,4-dimethoxy, 2,3,4-trimethoxy.

[0025] The present invention also provides the use of any one of the above-mentioned 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one in the preparation of anti-tumor drugs.

[0026] Preferably, the tumor is human breast cancer cells, human gastric cancer cells, human colorectal cancer cells or human non-small cell lung cancer cells.

[0027] More preferably, the present invention provides the use of compounds (Z)-A1, A2, (Z)-A3, A5, (E)-A6, A7, A8, A9 or A10 in the preparation of drugs against human breast cancer cells, wherein the definitions of A1, A2, A3, A5, A6, A7, A8, A9, A10 are as described in claim 3.

[0028] More preferably, the present invention provides the use of compounds A1, A2, A3, A4, (E)-A5, (E)-A6, A7, A8, A9, A10, (Z)-A11, A12, A13 or A15 in the preparation of drugs against human gastric cancer cells; wherein the definitions of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A15 are as described in claim 3.

[0029] More preferably, the present invention provides the use of compounds (Z)-A1, A2, A3, (Z)-A4, (Z)-A5, (E)-A6, A7, A8, A9, A10, (Z)-A11, A12, (E)-A13, A14 or (Z)-A15 in the preparation of drugs against human colorectal cancer cells; wherein the definitions of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15 are as described in claim 3.

[0030] More preferably, the present invention provides the use of compounds (Z)-A3, (Z)-A5, (Z)-A7, (Z)-A8, (E)-A9 or (E)-A10 in the preparation of drugs against human non-small cell lung cancer cells; wherein the definitions of A3, A5, A7, A8, A9, A10 are as described in claim 3.

[0031] The present invention has the following advantages compared with the prior art:

[0032] The present invention provides a new class of compounds (Z / E)-1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one, its preparation method and its application as an anti-tumor drug. It is synthesized from furfuryl alcohol through multiple steps such as etherification and acylation. The compounds of the present invention especially have anti-tumor activity against human breast cancer cells (MCF-7), human gastric cancer cells (HGC-27), human colorectal cancer cells (HCT-116) and human non-small cell lung cancer cells (A549), which will provide more choices for the research and development of anti-tumor drugs. Detailed embodiments

[0033] The following examples are intended to illustrate the present invention rather than further limit the present invention.

[0034] Example 1

[0035] Synthesis of 7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran (B):

[0036]

[0037] 10 g (0.06 mol) of furanphenol, 0.4 g (0.002 mol) of potassium iodide, and 16.8 g (0.122 mol) of potassium carbonate were added to a two-necked flask. Anhydrous ethanol was used as the solvent. After stirring at 35 °C for about 0.5 h, 17.3 g (0.121 mol) of methyl iodide was added. The reaction was monitored by TLC until completion. The reaction solution was filtered to remove potassium carbonate, the solvent was removed by rotary evaporation, and the solution was poured into ice water to precipitate a large amount of solid. The solid was filtered and dried to obtain a grayish-brown solid B. The yield was 70%, m.p. 42.6 - 43.7 °C. HRMS: HR-MS(ESI): m / z calcd for C 11 H 15 O2([M+H] + ) 179.1067, found 179.1065.

[0038] Example 2

[0039] Synthesis of 1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-1-ethanone (C):

[0040]

[0041] Under ice bath conditions, 25 mL of 1,2-dichloroethane and 2.94 g (0.02 mol) of anhydrous zinc chloride were added to a three-necked flask. Then, 1.875 g (0.0237 mol) of acetyl chloride was added dropwise using a dropping funnel. After the addition, stirring was continued for about 0.5 h. A solution of 3 g (0.0169 mol) of compound B in dichloroethane was added dropwise using a dropping funnel. The initial color of the reaction solution was light blue, and then the solution gradually turned purple-black. The reaction time was about 6 h, and the reaction was monitored by TLC until completion. The mixture was poured into 0.1 mol / L ice hydrochloric acid while stirring, and the organic layer was separated, dried, and the solvent was evaporated. Finally, recrystallization from anhydrous ethanol gave a white solid. The yield was 50%, m.p. 98 - 105 °C. HRMS: HR-MS(ESI): m / z calcd for C 13 H 16 O3([M+Na] + ) 243.0997, found 243.0988.

[0042] Example 3

[0043] Synthesis of 2-bromo-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-1-ethanone (D):

[0044]

[0045] 0.5 g (2.27 mmol) of compound C and an appropriate amount of absolute ethanol were added to a three-necked flask, and the mixture was stirred and refluxed to raise the temperature to 60 °C. 1.014 g (4.54 mmol) of copper bromide was added in portions, and the reaction was monitored by TLC until completion. The cuprous bromide was removed by hot filtration while it was hot, the solvent was rotary evaporated, the resulting mixture was dissolved in ethyl acetate, washed with dilute hydrochloric acid, separated with a separatory funnel, the organic layer was dried over anhydrous sodium sulfate, the solvent was rotary evaporated, a viscous yellow substance was obtained, and the white product was obtained by separation on a silica gel chromatographic column with a yield of 40%, m.p. 78 - 90 °C. HRMS: HR-MS (ESI): m / z calcd for C 13 H 15 BrO3([M + Na] + ) 321.0097, found 321.0092.

[0046] Example 4

[0047] Synthesis of 1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-1-ethanone (E):

[0048]

[0049] 7.41 mmol of pyrazole, 29.64 mmol of potassium carbonate and 30 mL of acetone were added, the temperature was raised to 55 °C, and the mixture was refluxed for 0.5 h. 7.41 mmol of 2-bromo-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)ethanone (D) was added, the temperature was raised to 75 °C, and the mixture was refluxed for 8 h. After the reaction was monitored by TLC until completion, hot filtration was carried out while it was hot, the filtrate was rotary evaporated to dryness, and recrystallized with ethanol to obtain light yellow solid 1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-1-ethanone (E) with a yield of 47.2%, m.p. 143.8 - 148.6 °C. 11H NMR (600 MHz, CDCl3) δ 1.55 (s, 6H, 2×CH3), 3.09 (s, 2H, CH2), 3.91 (d, J = 8.8 Hz, 3H, OCH3), 5.53 (s, 2H, CH2), 6.38 (d, J = 25.8 Hz, 1H, pyrazole ring 4-H), 7.44 (s, 1H, pyrazole ring 3-H), 7.48 (s, 1H, C6H2 6-H), 7.51 (s, 1H, C6H2 4-H), 7.58 (s, 1H, pyrazole ring 5-H); 13 13C NMR (151 MHz, CDCl3) δ 188.14, 158.55, 152.98, 145.23, 139.72, 130.83, 128.21, 124.13, 110.90, 106.45, 89.98, 57.41, 56.02, 42.62, 28.25. HRMS: HR-MS (ESI): m / z calcd for C 16 H 19 N2O3 ([M + H] + ) 287.1390, found 287.1379.

[0050] Example 5

[0051] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2-methylphenyl)-2-propen-1-one was prepared as follows:

[0052]

[0053] 0.3495 mmol of 1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-1-ethanone (E), 0.4993 mmol of p-tolualdehyde and 30 mL of chloroform were stirred. A catalytic amount of piperidine was added, and the temperature was raised to 55 °C and refluxed for 10 h, monitored by TLC. After the reaction was completed, the reaction solution was washed with water, saturated brine, dried, concentrated by evaporation, and separated by column chromatography to obtain the product with a total yield of 55%.

[0054] (E)-A1: Melting point 92.2 - 95.4 °C, yield 18.33%, 11H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 1.4 Hz, 1H, pyrazole ring 4-H), 7.61 (d, J = 2.4 Hz, 1H, pyrazole ring 2-H), 7.50 (s, 1H, C=CH), 7.36 (s, 2H, C6H2 3,5-H), 7.15 (d, J = 7.7 Hz, 1H, C6H4), 7.11 - 7.05 (m, 2H, C6H4), 6.93 (t, J = 7.4 Hz, 1H, C6H4), 6.38 - 6.37 (m, 1H, pyrazole ring 3-H), 3.81 (s, 3H, OCH3), 2.91 (s, 2H, CH2), 2.40 (s, 3H, C6H4 2-CH3), 1.46 (s, 6H, 2×CH3); 13 13C NMR (151 MHz, CDCl3) δ 190.46, 153.07, 144.63, 141.44, 136.62, 136.33, 132.83, 129.97, 129.73, 129.09, 128.84, 128.48, 128.06, 126.02, 121.11, 120.24, 112.12, 107.41, 90.07, 55.93, 42.46, 28.28, 20.30. HRMS: HR-MS (ESI): m / z calcd for C 24 H 24 N2O3 ([M + H] + ) 389.1865, found 389.1853.

[0055] (Z)-A1: Melting point 100.1 - 110.5 °C, yield 36.67%, 1 1H NMR (600 MHz, CDCl3) δ 7.63 (d, J = 1.5 Hz, 1H, pyrazole ring 4-H), 7.37 (s, 1H, C=CH), 7.33 (s, 1H, C6H2 3-H), 7.29 (d, J = 2.4 Hz, 1H, pyrazole ring 2-H), 7.21 (s, 1H, C6H2 5-H), 7.21 - 7.20 (m, 1H, C6H4), 7.20 (d, J = 0.6 Hz, 1H, C6H4), 7.03 - 7.00 (m, 1H, C6H4), 6.70 (d, J = 7.8 Hz, 1H, C6H4), 6.29 - 6.28 (m, 1H, pyrazole ring 3-H), 3.82 (s, 3H, OCH3), 3.02 (s, 2H, CH2), 2.32 (s, 3H, C6H4 2-CH3), 1.52 (s, 6H, 2×CH3); 1313C NMR (151 MHz, CDCl3) δ 189.69, 152.32, 144.42, 141.19, 137.84, 137.18, 132.00, 131.53, 131.44, 130.54, 129.92, 129.57, 128.69, 128.01, 126.13, 120.79, 112.52, 107.29, 89.83, 56.05, 42.76, 28.37, 20.21. HRMS: HR-MS (ESI): m / z calcd for C 24 H 24 N2O3 ([M + H] + ) 389.1865, found 389.1855。

[0056] Example 6

[0057] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(3-methylphenyl)-2-propen-1-one Preparation:

[0058]

[0059] The preparation method is the same as that in Example 5, reacting for 10 h, with an overall yield of 54%.

[0060] (E)-A2: Yellow molten state, yield 18%, 1 1H NMR (600 MHz, CDCl3) δ 1.47 (s, 6H, 2×CH3), 2.23 (s, 3H, CH3), 2.93 (s, 2H, CH2), 3.84 (s, 3H, OCH3), 6.37 (m, 1H, C6H4), 6.98 (t, J = 3.6 Hz, 1H, pyrazole ring 3-H), 7.10 - 7.07 (m, 3H, C6H4), 7.34 (s, 1H, C6H2 5-H), 7.41 (s, 1H, C6H2 3-H), 7.47 (s, 1H, C=CH), 7.60 (d, J = 2.5 Hz, 1H, pyrazole ring 2-H), 7.67 (d, J = 1.6 Hz, 1H, pyrazole ring 4-H); 1313C NMR (151 MHz, CDCl3) δ 190.73, 153.33, 144.85, 141.40, 138.13, 135.65, 133.45, 129.85, 129.43, 129.03, 128.52, 128.31, 125.90, 121.48, 120.93, 112.22, 107.43, 90.17, 56.02, 42.51, 28.33, 21.40. HRMS: HR-MS (ESI): m / z calcd for C 24 H 24 N2O3 ([M + H] + ) 389.1860, found 389.1852.

[0061] (Z)-A2: Melting point 98.2 - 106.5 °C, yield 36%, 1 1H NMR (600 MHz, CDCl3) δ 1.52 (s, 6H, 2×CH3), 2.24 (s, 3H, CH3), 3.02 (s, 2H, CH2), 3.82 (s, 3H, OCH3), 6.40 (t, J = 2.1 Hz, 1H, pyrazole ring 3-H), 6.73 - 6.69 (m, 2H, C6H4 4,5-H), 7.16 - 7.12 (m, 2H, C6H4 2-H, C6H2 6-H), 7.19 (s, 1H, C6H2 5-H), 7.32 (s, 1H, C6H2 3-H), 7.38 (s, 1H, C=CH), 7.42 (d, J = 2.0 Hz, 1H, pyrazole ring 2-H), 7.73 (d, J = 1.4 Hz, 1H, pyrazole ring 4-H); 13 13C NMR (151 MHz, CDCl3) δ 189.97, 152.07, 144.33, 141.21, 138.37, 136.89, 136.04, 132.22, 131.61, 131.16, 131.00, 129.97, 128.62, 128.00, 127.24, 120.63, 112.53, 107.46, 89.72, 56.07, 42.77, 28.36, 21.39. HRMS: HR-MS (ESI): m / z calcd for C 24 H 24 N2O3 ([M + Na] + ) 411.1680, found 411.1623。

[0062] Example 7

[0063] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-methylphenyl)-2-propen-1-one Preparation:

[0064]

[0065] The preparation method is the same as that of Example 5, reacting for 10 h, with an overall yield of 58%.

[0066] (E)-A3: Yellow molten state, yield 19.33%, 1 H NMR(600MHz,CDCl3)δ1.48(s,6H,2×CH3),2.26(s,3H,CH3),2.93(s,2H,CH2),3.85(s,3H,OCH3),6.36(t,1H,pyrazole ring 3-H),7.02(d,J = 7.9Hz,2H,C6H4 3,5-H),7.18(d,J = 8.0Hz,2H,C6H4 2,6-H),7.33(s,1H,C6H2 5-H),7.43(s,1H,C6H23-H),7.49(s,1H,C=CH),7.59(d,J = 2.4Hz,1H,pyrazole ring 2-H),7.67(d,J = 1.6Hz,1H,pyrazole ring 4-H); 13 C NMR(151MHz,CDCl3)δ190.81,153.36,144.85,141.32,138.25,135.07,130.60,129.38,129.32,128.87,128.45,128.32,121.53,120.88,112.23,107.37,90.17,56.00,42.48,28.32,21.31.HRMS: HR-MS(ESI):m / z calcd for C 24 H 24 N2O3([M+H] + )389.1860,found 389.1864.

[0067] (Z)-A3: Melting point 126.8 - 135.6 °C, yield 38.67%, 11H NMR (600 MHz, CDCl3) δ 1.52 (s, 6H, 2×CH3), 2.31 (s, 3H, CH3), 3.02 (s, 2H, CH2), 3.81 (s, 3H, OCH3), 6.41 (t, J = 2.0 Hz, 1H, pyrazole ring 3-H), 6.80 (d, J = 8.1 Hz, 2H, C6H4 3,5-H), 7.06 (d, J = 8.0 Hz 2H, C6H4 2,6-H), 7.17 (s, 1H, C6H2 5-H), 7.31 (s, 1H, C6H2 3-H), 7.42 (s, 1H, C=CH), 7.43 (d, J = 2.3 Hz, 1H, pyrazole ring 2-H), 7.74 (d, J = 1.3 Hz, 1H, pyrazole ring 4-H); 13 13C NMR (151 MHz, CDCl3) δ 190.02, 151.93, 144.24, 141.24, 141.01, 137.35, 135.38, 131.60, 130.34, 130.01, 129.54, 129.43, 127.96, 120.52, 112.41, 107.52, 89.69, 56.03, 42.75, 28.35, 21.57. HRMS: HR-MS (ESI): m / z calcd for C 24 H 24 N2O3 ([M + H] + ) 389.1860, found 389.1864。

[0068] Example 8

[0069] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2-methoxyphenyl)-2-propen-1-one Preparation:

[0070]

[0071] The preparation method is the same as that of Example 5, reacting for 10 h, with an overall yield of 86%.

[0072] (E)-A4: Yellow molten state, yield 26.46%, 11H NMR (600 MHz, CDCl3) δ 1.47 (s, 6H, 2×CH3), 2.92 (s, 2H, CH2), 3.78 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 6.37 (t, J = 2.1 Hz, 1H, pyrazole ring 3-H), 6.72 (t, J = 7.5 Hz, 1H, C6H4 3-H), 6.77 (d, J = 8.2 Hz, 1H, C6H4 5-H), 7.16 (dd, J = 17.1, 7.9 Hz, 2H, C6H4 2,4-H), 7.42 (s, 1H, C6H2 5-H), 7.425 (s, 1H, C6H2 3-H), 7.54 (s, 1H, C=CH), 7.65 (d, J = 2.1 Hz, 1H, pyrazole ring 2-H), 7.67 (d, J = 1.5 Hz, 1H, pyrazole ring 4-H); 13 13C NMR (151 MHz, CDCl3) δ 190.60, 157.14, 152.92, 144.54, 141.33, 135.64, 129.98, 129.86, 129.72, 128.72, 128.10, 122.96, 121.10, 120.61, 117.61, 112.35, 110.37, 107.21, 90.00, 55.89, 55.32, 42.55, 28.31. HRMS: HR-MS (ESI): m / z calcd for C 24 H 24 N2O4 ([M + H] + ) 405.1809, found 405.1804.

[0073] (Z)-A4: melting point 145.0 - 147.3 °C, yield 59.54%, 1 1H NMR (600 MHz, CDCl3) δ 1.52 (s, 6H, 2×CH3), 3.02 (s, 2H, CH2), 3.80 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.34 (t, J = 2.1 Hz, 1H, pyrazole ring -3-H), 6.51 (dd, J = 7.8, 1.3 Hz, 1H), 6.74 (d, J = 7.5, 1H, C6H4 3-H), 6.87 (d, J = 8.3, 1H, C6H4 5-H), 7.22 (s, 1H, C6H2 5-H), 7.29 - 7.26 (m, 1H, C6H4 2-H), 7.34 (s, 1H, C6H2 3-H), 7.41 (d, J = 2.3, 1H, pyrazole ring 2-H), 7.67 (d, J = 1.6, 1H, pyrazole ring 4-H), 7.68 (s, 1H, C=CH); 1313C NMR(151MHz,CDCl3)δ189.97,158.30,151.95,144.22,141.02,136.07,131.55,131.52,130.61,130.15,129.59,127.90,121.51,120.73,120.60,112.65,110.77,107.15,89.62,56.00,55.61,42.76,28.32.HRMS:HR-MS(ESI):m / z calcd for C 24 H 24 N2O4([M+H] + )405.1809,found 405.1815。

[0074] Example 9

[0075] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(3-methoxyphenyl)-2-propen-1-one Preparation:

[0076]

[0077] The preparation method is the same as that of Example 5, reacting for 10 h, and the total yield is 85%.

[0078] (E)-A5: Melting point 95.2 - 98.4 °C, yield 26.25%, 1 1H NMR(600MHz,CDCl3)δ1.48(s,6H,2×CH3),2.94(s,2H,CH2),3.67(s,3H,OCH3),3.84(s,3H,OCH3),6.37 - 6.36(m,1H),6.72(dd,J = 8.2,2.0Hz,1H,C6H4 4-H),6.83(s,1H,C6H4 6-H),6.88(d,J = 7.7Hz,1H,C6H2 2-H),7.12(t,J = 8.0Hz,1H,C6H4 3-H),7.35(s,1H,C6H2 5-H),7.42(s,1H,C6H2 3-H),7.49(s,1H,C=CH),7.59(d,J = 2.3Hz,1H,pyrazole ring 2-H),7.68(d,J = 1.4Hz,1H,pyrazole ring 4-H); 1313C NMR (151 MHz, CDCl3) δ 190.65, 159.60, 153.46, 144.92, 141.50, 135.95, 134.84, 129.65, 129.35, 128.51, 128.38, 121.56, 121.53, 120.25, 114.33, 114.01, 112.14, 107.54, 90.27, 56.05, 55.20, 42.50, 28.36. HRMS: HR-MS(ESI): m / z calcd for C 24 H 24 N2O4 ([M+H] +) 405.1809, found 405.1804.

[0079] (Z)-A5: Melting point 103.3 - 107.4 °C, yield 59.84%, 1 1H NMR (600 MHz, CDCl3) δ 1.53 (s, 6H, 2×CH3), 3.03 (s, 2H, CH2), 3.63 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.35 (s, 1H, C6H4 6-H), 6.42 - 6.41 (m, 1H, pyrazole ring - 3-H), 6.65 (d, J = 7.6 Hz, 1H, C6H4 4-H), 6.87 (dd, J = 8.3, 1.9 Hz, 1H, C6H2 3-H), 7.18 (d, J = 8.0 Hz, 1H, C6H4 2-H), 7.20 (s, 1H, C6H2 5-H), 7.33 (s, 1H, C6H2 3-H), 7.39 (s, 1H, C=CH), 7.45 (d, J = 2.1 Hz, 1H, pyrazole ring 2-H), 7.74 (d, J = 1.3 Hz, 1H, pyrazole ring 4-H); 13 13C NMR (151 MHz, CDCl3) δ 189.87, 159.74, 152.20, 144.41, 141.33, 136.56, 136.33, 133.54, 131.78, 129.92, 129.70, 128.07, 123.37, 120.70, 117.20, 113.95, 112.63, 107.57, 89.77, 56.12, 55.26, 42.82, 28.39. HRMS: HR-MS(ESI): m / z calcd for C 24 H 24 N2O4 ([M+H] + )405.1809, found 405.1805。

[0080] Example 10

[0081] Preparation of (Z / E)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-methoxyphenyl)-2-propen-1-one:

[0082]

[0083] The preparation method is the same as that of Example 5, reacting for 10 h, and the total yield is 82%.

[0084] (E)-A6: Yellow molten state, yield 25.23%, 1 H NMR(600 MHz, CDCl3) δ 1.48(s, 6H, 2×CH3), 2.94(s, 2H, CH2), 3.75(s, 3H, OCH3), 3.85(s, 3H, OCH3), 6.36 - 6.35(m, 1H, pyrazole ring 3-H), 6.74(d, J = 8.8 Hz, 2H, C6H4 3,5-H), 7.23(d, J = 8.7 Hz, 2H, C6H4 2,6-H), 7.31(s, 1H C6H2 5-H), 7.43(s, 1H, C6H2 3-H), 7.49(s, 1H, C=CH), 7.58(d, J = 2.4 Hz, 1H, pyrazole ring 2-H), 7.66(d, J = 1.6 Hz, 1H, pyrazole ring 4-H); 13 C NMR(151 MHz, CDCl3) δ 190.98, 159.69, 153.39, 144.88, 141.27, 134.25, 130.44, 129.37, 128.42, 126.05, 121.54, 121.03, 114.17, 112.25, 107.33, 90.23, 56.04, 55.34, 42.53, 28.39. HRMS: HR-MS(ESI): m / z calcd for C 24 H 24 N2O4([M + H] +) 405.1809, found 405.1804.

[0085] (Z)-A6: Melting point 97.6 - 103.2 °C, yield 59.77%, 11H NMR (600 MHz, CDCl3) δ 1.52 (s, 6H, 2×CH3), 3.02 (s, 2H, CH2), 3.79 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 6.43 - 6.42 (m, 1H, pyrazole ring 3-H), 6.77 (d, J = 9.0 Hz, 2H, C6H4 3,5-H), 6.82 (d, J = 8.9 Hz, 2H, C6H4 2,6-H), 7.14 (s, 1H, C6H2 5-H), 7.28 (s, 1H, C6H2 3-H), 7.44 (d, J = 2.3 Hz, 1H, pyrazole ring 2-H), 7.47 (s, 1H, C=CH), 7.76 (d, J = 1.6 Hz, 1H, pyrazole ring 4-H); 13 13C NMR (151 MHz, CDCl3) δ 190.05, 161.57, 151.78, 144.21, 141.24, 138.01, 134.30, 132.45, 131.63, 130.23, 127.97, 124.82, 120.37, 114.34, 112.43, 107.58, 89.62, 56.07, 55.44, 42.82, 28.38. HRMS: HR-MS (ESI): m / z calcd for C 24 H 24 N2O4 ([M + H] +) 405.1809, found 405.1804.

[0086] Example 11

[0087] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(3-chlorophenyl)-2-propen-1-one Preparation:

[0088]

[0089] The preparation method is the same as that in Example 5, reacting for 10 h, with an overall yield of 40%.

[0090] (E)-A7: Yellow molten state, yield 10.12%, 11H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 1.6 Hz, 1H, pyrazole ring 4-H), 7.58 (d, J = 2.4 Hz, 1H, pyrazole ring 2-H), 7.46 (s, 1H, C=CH), 7.38 (s, 1H, C6H2 3-H), 7.34 (s, 1H, C6H2 5-H), 7.27 (d, J = 1.7 Hz, 1H, C6H4), 7.16 - 7.11 (m, 3H, C6H4), 6.39 - 6.38 (m, 1H, pyrazole ring 3-H), 3.86 (s, 3H, OCH3), 2.95 (s, 2H, CH2), 1.49 (s, 6H, 2×CH3); 13 13C NMR (151 MHz, CDCl3) δ 190.23, 153.69, 145.03, 141.75, 136.93, 135.52, 134.52, 129.88, 129.16, 128.97, 128.65, 128.47, 128.16, 126.82, 121.59, 118.57, 112.18, 107.82, 90.40, 56.11, 42.50, 28.37. HRMS: HR-MS (ESI): m / z calcd for C 23 H 21 N2O3Cl ([M + H] + ) 409.1313, found 409.1302.

[0091] (Z)-A7: Melting point 111.3 - 116.7 °C, yield 29.88%, 1 1H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 1.2 Hz, 1H, pyrazole ring 4-H), 7.43 (d, J = 2.1 Hz, 1H, pyrazole ring 2-H), 7.305 (s, 1H, C=CH), 7.30 (s, 1H, C6H2 3-H), 7.28 (s, 1H, C6H2 5-H), 7.19 (dd, J = 14.8, 6.8 Hz, 2H, C6H4), 6.89 (t, J = 1.8 Hz, 1H, C6H4), 6.82 (d, J = 7.8 Hz, 1H, C6H4), 6.42 (t, J = 2.1 Hz, 1H, pyrazole ring 3-H), 3.82 (s, 3H, OCH3), 3.02 (s, 2H, CH2), 1.53 (s, 6H, 2×CH3); 1313C NMR (151 MHz, CDCl3) δ 189.50, 152.38, 144.44, 141.61, 137.19, 134.73, 134.20, 134.18, 131.50, 130.16, 130.04, 129.95, 129.57, 128.18, 128.12, 120.71, 112.46, 107.95, 89.92, 56.10, 42.75, 28.40. HRMS: HR-MS (ESI): m / z calcd for C 23 H 21 N2O3F ([M + H] + ) 409.1313, found 409.1308。

[0092] Example 12

[0093] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-chlorophenyl)-2-propen-1-one Preparation:

[0094]

[0095] The preparation method is the same as that of Example 5, reacting for 10 h, and the yield is 42%.

[0096] (E)-A8: Melting point 110.7 - 115.4 °C, yield 11%, 1 1H NMR (600 MHz, CDCl3) δ 1.49 (s, 6H, 2×CH3), 2.94 (s, 2H, CH2), 3.85 (s, 3H, OCH3), 6.37 (t, J = 1.9 Hz, 1H, pyrazole ring 3-H), 7.18 (d, J = 8.6 Hz, 2H, C6H4 3,5-H), 7.22 (d, J = 8.5 Hz, 2H, C6H4 2,6-H), 7.33 (s, 1H, C6H2 5-H), 7.39 (s, 1H, C6H2 3-H), 7.47 (s, 1H, C = CH), 7.56 (d, J = 2.4 Hz, 1H, pyrazole ring -2-H), 7.68 (d, J = 1.6 Hz, 1H, pyrazole ring 4-H); 1313C NMR (151 MHz, CDCl3) δ 190.37, 153.74, 145.02, 141.63, 136.26, 134.04, 132.13, 130.10, 129.04, 128.91, 128.54, 128.50, 121.59, 118.87, 112.20, 107.72, 90.38, 56.08, 42.48, 28.37. HRMS: HR-MS (ESI): m / z calcd for C 23 H 21 N2O3Cl ([M+H] + ) 409.1313, found 409.1306.

[0097] (Z)-A8: Melting point 136.0 - 140.1 °C, yield 31%, 1 1H NMR (600 MHz, CDCl3) δ 1.51 (s, 6H, 2×CH3), 3.01 (s, 2H, CH2), 3.80 (s, 3H, OCH3), 6.40 (t, J = 2.1 Hz, 1H, pyrazole ring 3-H), 6.84 (d, J = 8.5 Hz, 2H, C6H4 3,5-H), 7.14 (s, 1H, C6H2 5-H), 7.22 (d, J = 8.6 Hz, 2H, C6H4 2,6-H), 7.28 (s, 1H, C6H2 3-H), 7.34 (s, 1H, C=CH), 7.41 (d, J = 2.3 Hz, 1H, pyrazole ring 2-H), 7.72 (d, J = 1.5 Hz, 1H, pyrazole ring 4-H); 13 13C NMR (151 MHz, CDCl3) δ 189.57, 152.29, 144.40, 141.54, 136.61, 136.36, 134.91, 131.52, 131.48, 130.90, 129.69, 129.09, 128.12, 120.60, 112.50, 107.89, 89.85, 56.10, 42.78, 28.39. HRMS: HR-MS (ESI): m / z calcd for C 23 H 21 N2O3Cl ([M+H] + ) 409.1313, found 409.1313。

[0098] Example 13

[0099] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(3-fluorophenyl)-2-propen-1-one Preparation:

[0100]

[0101] The preparation method was the same as that in Example 5, reacting for 10 h, and the yield was 32%.

[0102] (E)-A9: Yellow molten state, yield 7.9%, 1 H NMR(600MHz,CDCl3)δ7.69(d,J = 1.6Hz,1H,pyrazole ring 2-H),7.57(d,J = 2.5Hz,1H,pyrazole ring 4-H),7.48(s,1H,C=CH),7.40(s,1H,C6H2 3-H),7.35(s,1H,C6H2 5-H),7.17(td,J = 8.0,6.2Hz,1H),7.07(d,J = 7.9Hz,1H),6.99(d,J = 10.1Hz,1H),6.87(td,J = 8.3,2.2Hz,1H),6.37(t,J = 2.0Hz 1H,pyrazole ring 3-H),3.86(s,3H),2.95(s,2H),1.49(s,6H); 13 C NMR(151MHz,CDCl3)δ190.25,163.60,161.97,153.71,145.02,141.72,136.77,135.82,135.77,130.20,130.15,129.08,128.59,128.47,124.73,124.71,121.60,118.67,118.66,115.61,115.46,115.15,115.01,112.14,107.80,90.39,56.08,42.48,28.37.HRMS:HR-MS(ESI):m / z calcd for C 23 H 21 N2O3F([M+H] + )393.1609,found 393.1602.

[0103] (Z)-A9: Melting point 113.2 - 116.7 °C, yield 24.1%, 11H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 1.4 Hz, 1H, pyrazole ring 4-H), 7.43 (d, J = 2.2 Hz, 1H, pyrazole ring 2-H), 7.34 (s, 1H, C=CH), 7.31 (s, 1H, C6H23-H), 7.26 - 7.22 (m, 1H), 7.17 (s, 1H, C6H25-H), 7.02 (td, J = 8.3, 2.0 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.54 (d, J = 10.0 Hz, 1H), 6.42 (t, J = 2.0 Hz, 1H), 3.82 (s, 3H), 3.02 (s, 2H), 1.53 (s, 6H); 13 13C NMR (151 MHz, CDCl3) δ 189.53, 163.58, 161.95, 152.37, 144.43, 141.60, 137.11, 134.49, 134.47, 134.44, 131.51, 130.24, 130.19, 129.60, 128.13, 126.26, 126.24, 120.69, 117.30, 117.16, 116.59, 116.43, 112.51, 107.93, 89.88, 56.10, 42.76, 28.39. HRMS: HR-MS (ESI): m / z calcd for C 23 H 21 N2O3F ([M + H] + ) 393.1609, found 393.1603.

[0104] Example 14

[0105] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-fluorophenyl)-2-propen-1-one Preparation:

[0106]

[0107] The preparation method is the same as that of Example 5, reacting for 10 h, with an overall yield of 35%.

[0108] (E)-A10: Yellow molten state, yield 8.75%, 11H NMR (600 MHz, CDCl3) δ 7.66 (d, J = 1.4 Hz, 1H, pyrazole ring 4-H), 7.55 (d, J = 2.4 Hz, 1H, pyrazole ring 2-H), 7.45 (s, 1H, C=CH), 7.38 (s, 1H, C6H2 3-H), 7.33 (s, 1H, C6H2 5-H), 7.24 (dd, J = 5.4, 3.1 Hz, 2H, C6H4 2,6-H), 6.88 (t, J = 8.6 Hz, 2H, C6H4 3,5-H), 6.35 (t, J = 2.1 Hz, 1H, pyrazole ring 3-H), 3.83 (s, 3H), 2.92 (s, 2H), 1.47 (s, 6H); 13 13C NMR (151 MHz, CDCl3) δ 190.52, 163.36, 161.71, 153.65, 144.98, 141.53, 135.74, 130.70, 130.64, 129.76, 129.74, 129.13, 128.56, 128.46, 121.57, 119.45, 115.84, 115.70, 112.24, 107.62, 90.35, 56.08, 42.50, 28.38. HRMS: HR-MS(ESI): m / z calcd for C 23 H 21 N2O3F ([M + H] + ) 393.1609, found 393.1605.

[0109] (Z)-A10: Melting point 95.2~102.5 °C, yield 26.25%, 1 1H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 1.9 Hz, 1H, pyrazole ring 4-H), 7.43 (d, J = 2.2 Hz, 1H, pyrazole ring 2-H), 7.40 (s, 1H, C=CH), 7.29 (s, 1H, C6H2 3-H), 7.15 (s, 1H, C6H2 5-H), 6.95 (t, J = 8.6 Hz, 2H, C6H4 3,5-H), 6.90 (dd, J = 8.5, 5.6 Hz, 2H, C6H4 2,6-H), 6.42 (t, 1.9 Hz, 1H, pyrazole ring 3-H), 3.81 (s, 3H), 3.02 (s, 2H), 1.52 (s, 6H); 13CNMR(151MHz, CDCl3) δ 189.72, 164.61, 162.93, 152.18, 144.36, 141.49, 135.95, 135.58, 132.49, 132.43, 131.54, 129.79, 128.58, 128.56, 128.09, 120.56, 116.10, 115.95, 112.46, 107.85, 89.82, 56.10, 42.79, 28.40. HRMS: HR-MS(ESI): m / z calcd for C 23 H 21 N2O3F([M + H] + ) 393.1609, found 393.1605。

[0110] Example 15

[0111] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2,4-dichloro)-2-propen-1-one Preparation:

[0112]

[0113] The preparation method is the same as that in Example 5, reacting for 10 h, with an overall yield of 35%.

[0114] (E)-A11: Yellow molten state, yield 9.2%, 1 H NMR(600MHz, CDCl3) δ 7.71(d, J = 1.6Hz, 1H, pyrazole ring 4-H), 7.63(d, J = 2.5Hz, 1H, pyrazole ring 2-H), 7.50(s, 1H, C=CH), 7.41(s, 1H, C6H2 3-H), 7.37(s, 1H, C6H2 5-H), 7.34(d, J = 2.1Hz, 1H, C6H4 5-H), 7.21(d, J = 8.4Hz, 1H, C6H4 2-H), 7.01(dd, J = 8.4, 2.1Hz, 1H, C6H4 3-H), 6.41 - 6.40(m, 1H, pyrazole ring 3-H), 3.84(s, 3H, OCH3), 2.95(s, 2H, CH2), 1.49(s, 6H, 2×CH3); 1313C NMR (151 MHz, CDCl3) δ 189.89, 153.68, 144.86, 142.00, 137.56, 134.65, 134.61, 131.23, 131.19, 129.33, 129.26, 128.80, 128.51, 127.32, 121.33, 115.77, 112.19, 107.89, 90.44, 56.05, 42.47, 28.36. HRMS: HR-MS(ESI): m / z calcd for C 23 H 20 N2O3Cl2 ([M+H] + ) 443.0924, found 443.0918.

[0115] (Z)-A11: Melting point 128.5 - 132.6 °C, yield 25.8%, 1 1H NMR (600 MHz, CDCl3) δ 7.65 (d, J = 1.4 Hz, 1H, pyrazole ring 4-H), 7.43 (d, J = 2.0 Hz, 1H, C6H4 5-H), 7.42 (d, J = 2.3 Hz, 1H, pyrazole ring 2-H), 7.40 (s, 1H, C=CH), 7.33 (s, 1H, C6H2 3-H), 7.23 (s, 1H, C6H2 5-H), 7.05 (dd, J = 8.5, 2.0 Hz, 1H, C6H4 2-H), 6.57 (d, J = 8.5 Hz, 1H, C6H4 3-H), 6.35 (t, J = 1.8 Hz, 1H, pyrazole ring 3-H), 3.83 (s, 3H, OCH3), 3.02 (s, 2H, CH2), 1.52 (s, 6H, 2×CH3); 13 13C NMR (151 MHz, CDCl3) δ 189.16, 152.63, 144.51, 141.60, 138.08, 135.99, 135.83, 131.46, 130.87, 130.18, 129.72, 129.41, 128.54, 128.18, 127.35, 120.89, 112.66, 107.82, 89.98, 56.09, 42.74, 28.38. HRMS: HR-MS(ESI): m / z calcd for C 23 H 20 N2O3Cl2 ([M+H] + ) 443.0924, found 443.0917。

[0116] Example 16

[0117] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2-ethoxy)-2-propen-1-one Preparation:

[0118]

[0119] The preparation method is the same as that in Example 5, reacting for 10 h, with an overall yield of 62%.

[0120] (E)-A12: Melting point 131.5 - 135.7 °C, yield 20.67%, 1 H NMR(600MHz,CDCl3)δ7.67(d,J = 2.4Hz,2H, pyrazole ring 2,4-H),7.55(s,1H,C = CH),7.44(s,1H,C6H2 3-H),7.42(s,1H,C6H2 5-H),7.16(d,J = 7.6Hz,1H,C6H4),7.14 - 7.11(m,1H,C6H4),6.77(d,J = 8.2Hz,1H,C6H4),6.69(t,J = 7.5Hz,1H,C6H4),6.38(t,J = 2.1Hz,1H, pyrazole ring 3-H),4.05(q,J = 7.0Hz,2H,OC2H5),3.81(s,3H,OCH3),2.92(s,2H,CH2),1.47(s,6H,2×CH3),1.42(t,J = 7.0Hz,3H,OC2H5); 13 C NMR(151MHz,CDCl3)δ190.80,156.64,152.94,144.57,141.34,135.50,130.03,129.86,129.84,128.82,128.11,123.15,121.15,120.47,118.10,112.45,111.35,107.17,89.99,63.94,55.90,42.58,28.33,14.98.HRMS: HR-MS(ESI): m / z calcd for C 25 H 26 N2O4([M + H] + )419.1965,found 419.1963.

[0121] (Z)-A12: Melting point 123.4 - 127.6 °C, yield 41.33%, 11H NMR (600 MHz, CDCl3) δ 7.72 (s, 1H, C=CH), 7.68 (d, J = 1.7 Hz, 1H, pyrazole ring 4-H), 7.46 (d, J = 2.4 Hz, 1H, pyrazole ring 2-H), 7.37 (s, 1H, C6H2 3-H), 7.28 - 7.24 (m, 1H, C6H2 5-H), 7.24 (d, J = 1.4 Hz, 1H, C6H4), 6.86 (d, J = 8.2 Hz, 1H, C6H4), 6.73 (t, J = 7.6 Hz, 1H, C6H4), 6.49 (dd, J = 7.8, 1.5 Hz, 1H, C6H4), 6.37 - 6.35 (m, 1H, pyrazole ring 3-H), 4.05 (q, J = 7.0 Hz, 2H, OC2H5), 3.83 (s, 3H, OCH3), 3.03 (s, 2H, CH2), 1.53 (s, 6H, 2×CH3), 1.39 (t, J = 7.0 Hz, 3H, OC2H5); 13 13C NMR (151 MHz, CDCl3) δ 190.04, 157.80, 151.92, 144.26, 141.00, 135.86, 131.53, 131.49, 130.66, 130.15, 129.55, 127.80, 121.58, 120.71, 120.44, 112.57, 111.72, 107.17, 89.61, 64.04, 56.00, 42.76, 28.29, 14.84. HRMS: HR-MS (ESI): m / z calcd for C 25 H 26 N2O4 ([M + H] + ) 419.1965, found 419.1962.

[0122] Example 17

[0123] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-ethoxy)-2-propen-1-one Preparation:

[0124]

[0125] The preparation method is the same as that of Example 5, reacting for 10 h, with an overall yield of 65%.

[0126] (Z)-A13: Melting point 135.6 - 140.7 °C, yield 21.22%, 11H NMR (600 MHz, CDCl3) δ 7.66 (d, J = 1.6 Hz, 1H, pyrazole ring 4-H), 7.58 (d, J = 2.4 Hz, 1H, pyrazole ring 2-H), 7.48 (s, 1H, C=CH), 7.43 (s, 1H, C2H6 3-H), 7.30 (s, 1H, C2H6 5-H), 7.21 (d, J = 8.7 Hz, 2H, C6H4 2,6-H), 6.72 (d, J = 8.8 Hz, 2H, C6H4 3,5-H), 6.35 (t, J = 2.1 Hz, 1H, pyrazole ring 3-H), 3.96 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.84 (s, 3H, OCH3), 2.94 (s, 2H, CH2), 1.48 (s, 6H, 2×CH3), 1.36 (t, J = 7.0 Hz, 3H, OCH2CH3); 13 13C NMR (151 MHz, CDCl3) δ 191.02, 159.11, 153.37, 144.87, 141.25, 134.16, 130.45, 129.40, 128.50, 128.35, 125.89, 121.54, 121.22, 114.68, 112.31, 107.29, 90.20, 63.55, 56.05, 42.55, 28.38, 14.86. HRMS: HR-MS (ESI): m / z calcd for C 25 H 26 N2O4 ([M + H] + ) 419.1965, found 419.1957.

[0127] (Z)-A13: melting point 127.0~133.6 °C, yield 43.78%, 1 1H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 1.7 Hz, 1H, pyrazole ring 4-H), 7.46 (s, 1H, C=CH), 7.43 (d, J = 2.3 Hz, 1H, pyrazole ring 2-H), 7.27 (s, 1H, C2H6 3-H), 7.13 (s, 1H, C6H2 5-H), 6.80 (d, J = 8.9 Hz, 2H, C6H4 2,6-H), 6.74 (d, J = 8.9 Hz, 2H, C6H4 3,5-H), 6.41 (t, J = 2.1 Hz, 1H, pyrazole ring 3-H), 4.00 (q, J = 7.0 Hz, 2H, OC2H5), 3.80 (s, 3H, OCH3), 3.01 (s, 2H, CH2), 1.51 (s, 6H, 2×CH3), 1.38 (t, J = 7.0 Hz, 3H, OC2H5); 1313C NMR (151 MHz, CDCl3) δ 190.03, 160.97, 151.71, 144.17, 141.17, 138.14, 134.13, 132.43, 131.61, 130.24, 127.93, 124.57, 120.31, 114.77, 112.42, 107.51, 89.55, 63.65, 56.03, 42.78, 28.34, 14.74. HRMS: HR-MS (ESI): m / z calcd for C 25 H 26 N2O4 ([M + H] + ) 419.1965, found 419.1956。

[0128] Example 18

[0129] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2,4-dimethoxy)-2-propen-1-one Preparation:

[0130]

[0131] The preparation method is the same as that of Example 5, reacting for 10 h, with an overall yield of 90%,

[0132] (E)-A14: Yellow molten state, yield 36%, 1 1H NMR (600 MHz, CDCl3) δ 7.65 (d, J = 1.6 Hz, 1H, pyrazole ring 4-H), 7.63 (d, J = 2.4 Hz, 1H, pyrazole ring 2-H), 7.45 (s, 1H, C=CH), 7.432 (s, 1H, C6H2 3-H), 7.426 (s, 1H, C6H2 5-H), 7.10 (d, J = 8.5 Hz, 1H, C6H3 2-H), 6.35 (dd, J = 4.4, 2.3 Hz, 2H, C6H33-H, pyrazole ring 3-H), 6.26 (dd, J = 8.5, 2.3 Hz, 1H, C6H3 5-H), 3.81 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 2.93 (s, 2H, CH2), 1.47 (s, 6H, 2×CH3); 1313C NMR (151 MHz, CDCl3) δ 190.97, 161.42, 158.40, 152.85, 144.54, 141.16, 134.33, 130.75, 129.79, 128.72, 128.12, 121.07, 117.98, 115.82, 112.39, 107.03, 104.61, 98.32, 89.99, 55.90, 55.42, 55.37, 42.59, 28.33. HRMS: HR-MS(ESI): m / z calcd for C 25 H 26 N2O5 ([M+Na] + ) 457.1734, found 457.1702.

[0133] (Z)-A14: Yellow molten state, yield 54%, 1 1H NMR (600 MHz, CDCl3) δ 7.80 (s, 1H), 7.70 (d, J = 1.7 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 6.39 (d, J = 2.3 Hz, 1H), 6.37 (t, J = 2.1 Hz, 1H), 6.32 - 6.29 (m, 1H), 6.26 (dd, J = 8.8, 2.3 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.01 (s, 2H), 1.51 (s, 6H); 13 13C NMR (151 MHz, CDCl3) δ 190.19, 163.03, 160.16, 151.57, 144.05, 140.95, 134.14, 132.08, 131.62, 130.84, 130.47, 127.84, 120.46, 114.25, 112.54, 107.19, 105.40, 98.05, 89.50, 55.98, 55.68, 55.48, 42.80, 28.33. HRMS: HR-MS(ESI): m / z calcd for C 25 H 26 N2O5 ([M+Na] + ) 457.1734, found 457.1702。

[0134] Example 19

[0135] (Z / E)-1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2,3,4-trimethoxy)-2-propen-1-one Preparation:

[0136]

[0137] The preparation method is the same as that in Example 5, reacting for 10 h, with an overall yield of 92%.

[0138] (E)-A15: Yellow molten state, yield 36.8%, 1 H NMR(600MHz,CDCl3)δ7.67(d,J=1.7Hz,1H,pyrazole ring 4-H),7.64(d,J=2.5Hz,1H,pyrazole ring 2-H),7.44(s,2H,C=CH,C6H2 3-H),7.41(s,1H,C6H2 5-H),6.89(d,J=8.7Hz,1H,C6H2 3-H),6.43(d,J=8.7Hz,1H,C6H2 2-H),6.37(t,J=2.1Hz,1H,pyrazole ring 3-H),3.91(s,3H,OCH3),3.84(s,3H,OCH3),3.79(s,3H,OCH3),3.78(s,3H,OCH3),2.93(s,2H,CH2),1.47(s,6H,2×CH3); 13 C NMR(151MHz,CDCl3)δ190.85,154.23,153.02,152.09,144.70,142.13,141.35,135.14,129.80,128.68,128.12,124.40,121.26,120.76,117.17,112.27,107.28,107.26,90.08,61.30,60.95,56.03,56.02,42.60,28.36.HRMS: HR-MS(ESI): m / z calcd for C 26 H 28 N2O6([M+Na] + )487.1840,found 487.1805.

[0139] (Z)-A15: Yellow molten state, yield 55.2%, 11H NMR (600 MHz, CDCl3) δ 7.72 (s, 1H, C=CH), 7.72 (d, J = 1.7 Hz, 1H, pyrazole ring 4-H), 7.45 (d, J = 2.3 Hz, 1H, pyrazole ring 2-H), 7.31 (s, 1H, C6H2 3-H), 7.19 (s, 1H, C6H2 5-H), 6.46 (d, J = 9.0 Hz, 1H, C6H2 3-H), 6.40 (t, J = 2.0 Hz, 1H, pyrazole ring 3-H), 6.10 (d, J = 9.0 Hz, 1H, C6H2 2-H), 3.91 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.82 (s, 6H, 2×OCH3), 3.02 (s, 2H, CH2), 1.52 (s, 6H, 2×CH3); 13 13C NMR (151 MHz, CDCl3) δ 190.14, 155.81, 153.98, 151.83, 144.24, 141.93, 141.13, 135.01, 131.63, 130.23, 127.91, 124.70, 120.57, 119.19, 112.59, 107.63, 107.38, 89.64, 61.83, 60.97, 56.10, 56.05, 42.82, 28.36. HRMS: HR-MS (ESI): m / z calcd for C 26 H 28 N2O6 ([M+Na] + ) 487.1840, found 487.1806.

[0140] Example 20

[0141] Determination of the Anticancer Activity of 1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one

[0142] 1. Principle of Antitumor Activity

[0143] The MTT bioactivity test, also known as the MTT colorimetric assay, is a method for detecting cell survival and growth. The MTT analysis is based on the live cell metabolite reducing agent thiazolyl blue [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTT]. MTT is a dye that can accept hydrogen atoms. The dehydrogenase related to NADP in the mitochondria of live cells can convert yellow MTT into insoluble blue-violet formazan in the cell, while dead cells do not have this function. After dissolving formazan with DMSO, the optical density value is measured with an enzyme-linked immunosorbent assay (ELISA) reader at a certain wavelength, and the cell survival rate can be quantitatively measured. The inhibitory effect of the sample on tumor cells is observed according to the change of the optical density value.

[0144] 2. Antitumor Activity Experiment

[0145] Samples: (Z / E)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one:

[0146]

[0147] Among them, R2 is selected from: methyl, methoxy, chlorine, fluorine, 2,4-dichloro, ethoxy, 2,4-dimethoxy or 2,3,4-trimethoxy.

[0148] Cell lines: human breast cancer cells (MCF-7), human gastric cancer cells (HGC-27), human colon cancer cells (HCT-116), human non-small cell lung cancer cells (A549).

[0149] Reagents: thiazolyl blue (MTT), RPMI 1640 culture medium, DMEM culture medium, fetal bovine serum (Zhejiang Tianhang Biotechnology Co., Ltd.), antibiotics (Beijing Regene Biotechnology Co., Ltd.); trypsin (Vicente Biotechnology Co., Ltd.); 96-well culture plates (Guangzhou Jet Biological Filtration Co., Ltd.); dimethyl sulfoxide (Beyotime Biotechnology Co., Ltd.).

[0150] Instruments: Thermo 1300 series Class II Type A2 laminar flow hood, Thermo 371 CO2 incubator (Fuyue Biotechnology Shanghai Co., Ltd.); XSP-15C inverted microscope (Shanghai Changfang Optical Instrument Co., Ltd.); Multiskan MK3 microplate reader (Thermo, USA); ultrapure water purifier (Milli-Q, USA), DXY-4 constant temperature water bath, TDZ5-tabletop low-speed centrifuge (Huxi Instrument and Equipment Co., Ltd., Hunan), JL-D Vortex Mixer, WTL-4K mini centrifuge (Xiangyi Laboratory Instrument Development Co., Ltd., Hunan).

[0151] Experimental operations: Testing of samples against cancer cells. During one experimental process, each sample was serially diluted at concentrations of 0, 0.625, 1.25, 2.5, 5, 10, 20, 40, 80, 160 μM, and the experiment was repeated 2 times or more. Conclusions were drawn by comparing with the positive control group of doxorubicin. The OD values of each well were measured using a microplate reader at a detection wavelength of 450 nm.

[0152] 3. Anti-tumor activity evaluation

[0153] 1) Calculation of cell inhibition rate:

[0154]

[0155] 2) IC 50 value calculation

[0156] The logarithm of the sample concentration was linearly regressed against the cell inhibition rate, and the half-maximal inhibitory concentration IC 50 value of the sample on cells was calculated using the software GraphPad Prism 9. The IC 50 of (Z / E)-1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one against cancer cells is shown in Table 1 below.

[0157] Table 1 Half-maximal inhibitory activity of the compounds of the present invention against tumor cells

[0158]

[0159]

[0160] The above results indicate that the compounds of the present invention have anti-tumor activities against human breast cancer cells (MCF-7), human gastric cancer cells (HGC-27), human colon cancer cells (HCT-116), and human non-small cell lung cancer cells (A549). In terms of the trend of anti-tumor activities, generally, the activities of the "Z configuration" target compounds are superior to those of the "E configuration" target compounds. In terms of the activity magnitude, it shows that the activity of the "Z configuration" target compounds is about twice that of the "E configuration" target compounds, especially against HCT-116 cells. The compounds of the present invention can be made into a mixed preparation with a pharmaceutical adjuvant or used as a cell cycle blocker drug for anti-tumor applications.

Claims

1. 1-(7-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one shown in Chemical Structural Formula Ⅰ or Ⅱ: Among them, R1 is selected from: methoxy, ethoxy or propoxy; R2 is selected from: methyl, methoxy, ethoxy, nitro, iodine, bromine, chlorine, fluorine, 2,4-difluoro, 2,4-dichloro, 2,3,4-trichloro, 2,4-dimethoxy, 2,3,4-trimethoxy.

2. The 1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one according to claim 1, characterized in that, The said R1 is methoxy.

3. The 1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one according to claim 1, characterized in that, Selected from: A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14 or A15; wherein, A1 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2-methylphenyl)-2-propen-1-one; A2 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(3-methylphenyl)-2-propen-1-one; A3 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-methylphenyl)-2-propen-1-one; A4 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2-methoxyphenyl)-2-propen-1-one; A5 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(3-methoxyphenyl)-2-propen-1-one; A6 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-methoxyphenyl)-2-propen-1-one; A7 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(3-chlorophenyl)-2-propen-1-one; A8 is 1-(dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-chlorophenyl)-2-propen-1-one; A9 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(3-fluorophenyl)-2-propen-1-one; A10 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-fluorophenyl)-2-propen-1-one; A11 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2,4-dichlorophenyl)-2-propen-1-one; A12 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2-ethoxyphenyl)-2-propen-1-one; A13 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(4-ethoxyphenyl)-2-propen-1-one; A14 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2,4-dimethoxyphenyl)-2-propen-1-one; A15 is 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(1H-pyrazol-1-yl)-3-(2,3,4-trimethoxyphenyl)-2-propen-1-one.

4. The preparation method of 1-(7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one according to claim 1, characterized in that, The reaction formula is as follows: In the formula, R1 and R2 are defined as described in claim 1.

5. Use of 1-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-3-aryl-2-(1H-pyrazol-1-yl)-2-propen-1-one according to any one of claims 1-3 in the preparation of anti-tumor drugs.

6. The application according to claim 5, characterized in that, The tumor is human breast cancer cells, human gastric cancer cells, human colorectal cancer cells or human non-small cell lung cancer cells.

7. The application according to claim 6, characterized in that, Use of compounds (Z)-A1, A2, (Z)-A3, A5, (E)-A6, A7, A8, A9 or A10 in the preparation of drugs against human breast cancer cells, wherein A1, A2, A3, A5, A6, A7, A8, A9, A10 are defined as described in claim 3.

8. The application according to claim 6, characterized in that, Use of compounds A1, A2, A3, A4, (E)-A5, (E)-A6, A7, A8, A9, A10, (Z)-A11, A12, A13 or A15 in the preparation of drugs against human gastric cancer cells; wherein A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A15 are defined as described in claim 3.

9. The application according to claim 6, characterized in that Use of compounds (Z)-A1, A2, A3, (Z)-A4, (Z)-A5, (E)-A6, A7, A8, A9, A10, (Z)-A11, A12, (E)-A13, A14 or (Z)-A15 in the preparation of drugs against human colorectal cancer cells; wherein A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15 are defined as described in claim 3.

10. The application according to claim 6, wherein Use of compounds (Z)-A3, (Z)-A5, (Z)-A7, (Z)-A8, (E)-A9 or (E)-A10 in the preparation of drugs against human non-small cell lung cancer cells; wherein A3, A5, A7, A8, A9, A10 are defined as described in claim 3.

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