Compound with furo [3, 2-g] chromene structure and application thereof

Abstract

The invention firstly discloses a compound with a furo [3, 2-g] chromene structure and a preparation method thereof, the compound (namely the compound with the furo [3, 2-g] chromene structure) is designed and synthesized on the basis of a natural product Morunigrol C from black mulberry for the first time, the structural formula of the compound is shown as a formula I, R1 and R2 are independently selected from hydrogen atoms or organic substituent groups, and R1 is not equal to R2; the organic substituent is selected from any one of hydroxyl, amino, nitryl, methoxyl, cyano and dimethylamino; r3 is selected from a hydrogen atom; or when R1 is methoxy or hydroxyl, R3 can be further selected from the same group as R1. The ferroptosis inhibition activity / neuroprotection activity of the compound is remarkable and is not reported in literatures, and a brand-new treatment strategy is provided for nervous system diseases, reperfusion injury and other diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and mainly relates to preparation of a class of furan[3,2-g]chromene structure compounds and related medical uses thereof. BACKGROUND

[0002] Ferroptosis is an iron-dependent, lipid peroxide-driven cell death mode. Ferroptosis is mainly related to iron metabolism, active oxygen (ROS) accumulation and abnormal lipid metabolism. Iron participates in many physiological functions in cells, and imbalance in its uptake, distribution and transport can trigger ferroptosis. When ferroptosis occurs, iron metabolism in the body is disordered, Fe 2+ Fenton reaction occurs, causing intracellular ROS accumulation. Lipid peroxidation is a core feature of ferroptosis, mainly caused by oxidative damage of polyunsaturated fatty acids under the action of ROS, and accumulation of peroxides can damage cell membrane integrity and ultimately lead to cell death. The GPX4 / GSH pathway in cells is an important way to remove lipid peroxides: glutathione peroxidase 4 (GPX4) is a key enzyme for inhibiting lipid peroxidation, which reduces lipid peroxides to harmless lipid alcohols through glutathione (GSH), thereby inhibiting ferroptosis.

[0003] Ischemic stroke is a brain disease caused by insufficient blood flow, accounting for about 85% of all stroke events, and causing about 6.4 million deaths each year, which has become a serious medical and social challenge. At present, the "reperfusion" treatment represented by thrombolysis and thrombectomy can achieve blood recanalization for about 70%-90% of stroke patients, but only about half of the patients have good functional recovery, and a considerable proportion of patients still have varying degrees of disability after 90 days of treatment. Numerous studies have shown that the blood flow recovery after ischemia-reperfusion can cause an "explosion" of ROS and lipid peroxidation, leading to increased tissue damage and inflammatory response, and ferroptosis plays an important role in it. At present, there is still a lack of effective drug development for cerebral ischemia / reperfusion injury, and the development of new ferroptosis inhibitors is expected to provide new ideas and targets for the treatment of cerebral ischemia / reperfusion injury.

[0004] Current ferroptosis inhibitors mainly include iron chelators, GPX4 activators, specific inhibitors and enzyme inhibitors, but have the disadvantages of single mechanism, low bioavailability, lack of mechanism research, etc. In view of this, the present application proposes a class of furan[3,2-g]chromene structure compounds and uses thereof, which have relatively significant ferroptosis inhibition activity / neuroprotective activity. SUMMARY

[0005] Based on the above analysis, the present application aims to provide a completely new solution for ischemic stroke, nervous system diseases such as Alzheimer's disease, myocardial infarction and reperfusion injury caused by acute kidney injury.

[0006] In order to achieve the above technical effects, the present application adopts the following technical means:

[0007] The present application firstly discloses a class of compounds with furan[3,2-g]chromene structure, the structural formula of which is shown as formula I:

[0008] ; wherein:

[0009] R1 and R2 are each independently selected from a hydrogen atom or an organic substituent, and R1≠R2;

[0010] The organic substituent is selected from any one of hydroxyl, amino, nitro, methoxy, cyano, and dimethylamino;

[0011] The R3 is selected from a hydrogen atom; or when R1 is methoxy or hydroxyl, R3 can be further selected from the same group as R1.

[0012] Further, the structural formula of the compound with furan[3,2-g]chromene structure is shown as formula A-formula L:

[0013] .

[0014] The iron death inhibition activity of the compounds at the cell level is evaluated by using two different mechanisms of iron death inducers, and it is found that the iron death inhibition activity / neural cell protection activity of compound D is the best.

[0015] The present application also discloses a preparation method of the above-mentioned compound with furan[3,2-g]chromene structure, comprising the following steps:

[0016] (1) An aldehyde containing a benzene ring is used as a starting material, and an isopentenyl group is introduced on the benzene ring through a Friedel-Crafts reaction to obtain compound 2; compound 2 is cyclized through the isopentenyl group to form a six-membered heterocycle to obtain compound 3; then, a double bond is introduced at the six-membered heterocycle through a DDQ dehydrogenation reaction to obtain compound 4; then, compound 4 is prepared into a geminal dibromoalkene using a phosphorus ylide reagent to obtain compound 5; then, the geminal dibromo vinyl group of compound 5 is coupled with the ortho hydroxyl group under the catalysis of a base and a copper catalyst to form a benzofuran ring to obtain compound 6;

[0017] (2) A substituted bromobenzene with formula II (compound 7) is used as a raw material, and the substituted bromobenzene is prepared into a corresponding borate (compound 8) through a Miyaura boronation reaction;

[0018] ;

[0019] (3) Then, the compound 8 is introduced to the right side of the benzofuran of the compound 6 through Suzuki-Miyaura reaction to obtain the compound with furan[3, 2-g] chromene structure (such as the compounds A-L shown in Figure 4 ).

[0020] Further, in the structure of the formula II in the step (2), R1 and R2 are each independently selected from a hydrogen atom or an organic substituent, and R1≠R2; the organic substituent is selected from any one of a hydroxyl group, an amino group, a nitro group, a methoxyl group, a cyano group, and a dimethylamino group; and R3 is selected from a hydrogen atom; or when R1 is a methoxyl group or a hydroxyl group, R3 can be further selected from the same group as R1.

[0021] Further, the preparation method of the compound with furan[3, 2-g] chromene structure, specifically includes the following steps:

[0022] S1, mixing the aldehyde containing benzene ring and the acid catalyst at a molar ratio of 0.5-1.5:1.1-1.6, and reacting for 4-5 h to obtain the compound 2;

[0023] S2, mixing the compound 2 and the Lewis acid at a molar ratio of 1:1-1.2, and reacting for 0.5 h-2 h to obtain the compound 3;

[0024] S3, mixing the compound 3 and the DDQ at a molar ratio of 1:1-1.3, and reacting at 120°C for 14 h-18 h to obtain the compound 4;

[0025] S4, mixing the compound 4 and the phosphorus ylide reagent at a molar ratio of 1:2.5-3.5, and reacting for 1.5-2.5 h to obtain the compound 5;

[0026] S5, mixing the compound 5, the base and the copper catalyst at a molar ratio of 0.5-1.5:3-4:0.03-0.07, and reacting at 75-90°C for 4-5 h to obtain the compound 6;

[0027] S6, mixing the compound 7, the boronizing agent, the base and the palladium catalyst at a molar ratio of 0.5-1.5:1-2:1-2:0.03-0.07, and reacting at 90-100°C for 5-6 h to obtain the compound 8;

[0028] S7, mixing the compound 6, the compound 8, the base and the palladium catalyst at a molar ratio of 0.5-1.5:1-2:1.5-2.5:0.03-0.07, and reacting at 70-80°C for 5-6 h to obtain the compound with furan[3, 2-g] chromene structure (such as the compounds A-L shown in

[0029] ). Figure 4

[0030] ​Further, the benzene ring-containing aldehyde in step S1 is 2,4-dihydroxybenzaldehyde, and the acid catalyst is a mixture of boron trifluoride diethyl ether and 2-methyl-3-buten-2-ol in a molar ratio of 1-1.5:0.03-0.07.

[0031] Further, the compound 2 in step S1 is 2,4-dihydroxy-5-(3-methylbut-2-en-1-yl)benzaldehyde.

[0032] Furthermore, the Lewis acid mentioned in step S2 is boron trifluoride diethyl ether.

[0033] Further, the compound 3 in step S2 is 7-hydroxy-2,2-dimethylchroman-6-carboxaldehyde.

[0034] Further, the compound 4 in step S3 is 7-hydroxy-2,2-dimethyl-2H-chromene-6-carboxaldehyde.

[0035] Further, the phosphorus ylide reagent described in step S4 is prepared by mixing triphenylphosphine, carbon tetrabromide and triethylamine, and reacting at -5~5℃ for 10-15 minutes to obtain the reagent.

[0036] Further, the compound 5 in step S4 is 6-(2,2-dibromovinyl)-2,2-dimethyl-2H-chromene-7-ol.

[0037] Furthermore, the copper catalyst in step S5 is cuprous iodide.

[0038] Further, the compound 6 in step S5 is 2-bromo-7,7-dimethyl-7H-furano[3,2-g]chromene.

[0039] Further, the borizing agent in step S6 is selected from: pinacol diborate or pinacol borane; the palladium catalyst is 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride.

[0040] Further, the substituted bromobenzene of compound 7 in step S6 is selected from any one of the following: 3,5-dihydroxybromobenzene (7a), p-bromophenol (7b), 1-bromo-3,5-dimethoxybenzene (7c), p-bromoaniline (7d), m-bromophenol (7e), p-bromobenzonitrile (7f), m-bromobenzonitrile (7g), 1-bromo-4-nitrobenzene (7h), 1-bromo-3-nitrobenzene (7i), m-bromoaniline (7j), 3-bromo-N,N-dimethylaniline (7k), and 4-bromo-N,N-dimethylaniline (7l).

[0041] Further, the borate ester of compound 8 in step S7 is selected from: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzene-1,3-diol (8a), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (8b), 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboran (8c), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (8d), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (8e), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzene The following are all of the following: nitrile (8f), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzonitrile (8g), 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaboran (8h), 4,4,5,5-tetramethyl-2-(3-nitrophenyl)-1,3,2-dioxaboran (8i), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (8j), N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (8k), and N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (8l).

[0042] Furthermore, the alkali mentioned in step S7 is selected from any one of potassium carbonate, potassium phosphate, or potassium acetate.

[0043] The present invention also discloses a compound having a furano[3,2-g]chromene structure prepared according to any of the above preparation methods.

[0044] The present invention also discloses the use of any of the above-mentioned compounds having a furano[3,2-g]chromene structure in the preparation of drugs for treating ferroptosis inhibitors.

[0045] The beneficial effects of this invention are as follows:

[0046] This invention is the first to design and synthesize a class of compounds (i.e., compounds with furano[3,2-g]chromene structure) based on Morunigrol C, a natural product derived from black mulberry. These compounds exhibit significant ferroptosis inhibitory and neuroprotective activities, which have not been reported in the literature, providing a novel treatment strategy for diseases such as nervous system disorders and reperfusion injury. Attached Figure Description

[0047] Figure 1The diagram shows the protective effects of different derivatives against HT22 cell damage. (A) shows the protective effect of Morunigrol C derivative (5 μM, 24 h) against RSL3 (1.5 μM, 24 h)-induced HT22 cell damage; (B) shows the protective effect of Morunigrol C derivative (5 μM, 24 h) against Erastin (3 μM, 24 h)-induced HT22 cell damage; (C) shows the dose-response relationship of compound D inhibiting RSL3 (1.5 μM, 24 h)-induced HT22 cell death; and (D) shows the dose-response relationship of compound D inhibiting Erastin (3 μM, 24 h)-induced HT22 cell death.

[0048] Figure 2 The graph shows the cytotoxicity results of the Morunigrol C derivative (10 μM, 24 h).

[0049] Figure 3 Figures show the status of HT22 cells after different treatments. In the figures: A represents the malondialdehyde content in HT22 cells after different treatments, B represents the GPX4 specific activity in cells, C represents the ferrous ion content in cells, and D represents the glutathione content in cells.

[0050] Figure 4 This is a synthetic route diagram for the present invention. Detailed Implementation

[0051] This invention discloses the preparation of a class of compounds with a furano[3,2-g]chromene structure and their related pharmaceutical uses. Those skilled in the art can refer to the content of this document and appropriately modify the process parameters to achieve the desired results. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments, and those skilled in the art will clearly be able to modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0052] The present invention will be further described below with reference to the embodiments:

[0053] Example 1

[0054] S1, 2,4-Dihydroxy-5-(3-methylbut-2-en-1-yl)benzaldehyde (compound 2). 2,4-Dihydroxybenzaldehyde (21.7 mmol) was dissolved in dioxane (10 mL), and 2-methyl-3-buten-2-ol (28.2 mmol) and boron trifluoride diethyl ether (1.08 mmol) were added slowly simultaneously, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, ethyl acetate (10 mL) and water (30 mL) were added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL × 3). The mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography was used to purify and separate compound 2 (1.5 g), 32% yield, as a white solid. 1 H NMR (600 MHz, CDCl3) δ 11.18 (s, 1H), 9.61 (s, 1H), 7.16 (s, 1H), 6.30 (s, 1H), 5.23 (t, J = 7.1 Hz, 1H), 3.23 (d, J = 7.2 Hz, 2H), 1.72 (s, 3H), 1.69 (s, 3H).

[0055] S2,7-hydroxy-2,2-dimethylbenzodihydropyran-6-carboxaldehyde (compound 3). Boron trifluoride diethyl ether (2.3 mmol) was added to a solution of compound 2 (1.9 mmol) in dichloromethane (3 mL), and stirred at room temperature. After the starting material was exhausted, saturated sodium bicarbonate aqueous solution was added to adjust the pH to neutral. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with water (20 mL × 2), and then washed with saturated brine (20 mL × 2). The mixture was dried over anhydrous magnesium sulfate for 2 h, filtered, and concentrated under reduced pressure to obtain the crude product. Column chromatography was used to purify and separate compound 3 (0.32 g), 80% yield, as a white solid. 1 H NMR (400 MHz, CDCl3) δ 10.99 (s, 1H), 9.58 (s, 1H), 7.14 (s, 1H), 6.24 (s, 1H), 2.68 (t, J= 6.7 Hz, 2H), 1.76 (t, J = 6.7 Hz, 2H), 1.29 (s, 6H).

[0056] S3, 7-hydroxy-2,2-dimethyl-2H-methylene-6-carboxaldehyde (compound 4). 2,3-Dichloro-5,6-dicyanobenzoquinone (5.8 mmol) and 7-hydroxy-2,2-dimethylbenzodihydropyran-6-carboxaldehyde (compound 3) (4.9 mmol) were added to anhydrous toluene (10 mL), and the mixture was refluxed for 16 h. After the reaction, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain the crude product. Column chromatography was used to purify and separate compound 4 (0.71 g), 72% yield, as a white solid. 1 H NMR (400 MHz, CDCl3) δ11.35 (s, 1H), 9.59 (s, 1H), 7.04 (s, 1H), 6.26 (s, 1H), 6.22 (d, J = 10.0Hz, 1H), 5.52 (d, J = 9.9 Hz, 1H), 1.38 (s, 6H).

[0057] S4,6-(2,2-dibromovinyl)-2,2-dimethyl-2H-chromen-7-ol (compound 5): A solution of carbon tetrabromide (8.8 mmol) in dichloromethane (3 mL) was slowly added dropwise to a stirred solution of triphenylphosphine (17.6 mmol) in dichloromethane (10 mL). The reaction was carried out at 0 °C for 10 min. Triethylamine (17.6 mmol) was then slowly added and stirred for an additional 5 min. Compound 4 (2.9 mmol) was slowly added to the reaction solution, and the mixture was stirred at 10 °C for 30 min. The temperature was then slowly raised to room temperature until the starting material disappeared. After the reaction was complete, the pH was adjusted to neutral with a saturated ammonium chloride aqueous solution. The mixture was washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound 5 (0.53 g) was purified by column chromatography in 50% yield as a yellow oily liquid. This compound is unstable in the non-solution state, therefore, 1H NMR data are not provided.

[0058] S5,2-bromo-7,7-dimethyl-6,7-dihydro-5H-furano[3,2-g]chromene (compound 6). Compound 5 (0.6 mmol), tripotassium phosphate (2.2 mmol), and cuprous iodide (0.03 mmol) were added to a thick-walled sealed tube, followed by anhydrous tetrahydrofuran (3 mL). The mixture was stirred at 75 °C for 5 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure to obtain the crude product. Compound 6 (0.21 g) was purified by column chromatography in 87% yield as a colorless oily liquid. 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 6.80 (s, 1H), 6.48 (s, 1H), 2.79 (t, J = 6.8 Hz, 2H), 1.75 (t, J = 6.8 Hz, 2H), 1.27 (s, 6H).

[0059] S6,5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzene-1,3-diol (compound 8a). 3,5-Dihydroxybromobenzene (7.9 mmol), pinacol diboronate (11.9 mmol), potassium acetate (11.9 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.4 mmol) were added to 15 mL of dioxane, degassed for 30 min, and reacted at 100 °C for 6 h. After the reaction, the mixture was filtered through diatomaceous earth and ethyl acetate (20 mL) and water (30 mL) were added. The layers separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 8a.

[0060] S7,5-(7,7-dimethyl-6,7-dihydro-5H-furano[3,2-g]chromen-2-yl)benzene-1,3-diol (compound A). Compound 8a (0.38 mmol) and compound 6 (0.32 mmol), potassium phosphate (0.64 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.04 mmol) were added to N,N-dimethylformamide (3 mL) and water (1 mL). After degassing for 30 mins and stirring at 75 °C for 5 h, the reaction was cooled to room temperature, filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (10 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound A (0.088 g) was purified by column chromatography, yielding 90%, as a yellow oily liquid. 1H NMR (400 MHz, CDCl3) δ 7.14 (s, 1H), 6.84 (s, 1H), 6.80(d, J = 2.2 Hz, 2H), 6.75 (d, J = 0.9 Hz, 1H), 6.24 (t, J = 2.2 Hz, 1H), 2.82(t, J = 6.8 Hz, 2H), 1.77 (t, J = 6.8 Hz, 2H), 1.30 (s, 6H); 13 C NMR (151 MHz, DMSO -d6) δ 159.28, 154.84, 154.21, 152.36, 132.05, 122.24, 121.04, 117.86,103.22, 102.87, 101.61, 99.02, 74.78, 32.72, 27.07, 22.56; HRMS (ESI) m / zcalcd. for C 19 H 18 O4. [M+H] + 311.1278 found 311.1278; HPLC purity = 96.46%.

[0061] Example 2

[0062] Steps S1-S5 are the same as in Example 1.

[0063] S6,4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenol (compound 8b). p-Bromophenol (2.9 mmol), pinacol diboronate (4.3 mmol), potassium acetate (4.3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.14 mmol) were added to 15 mL of dioxane, degassed for 30 min, and reacted at 100 °C for 6 h. After the reaction, the mixture was filtered through diatomaceous earth and ethyl acetate (20 mL) and water (30 mL) were added. The layers separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 8b (0.53 g), 83% yield, as a white solid. 1 H NMR (600MHz, DMSO-d6) δ 9.78 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 1.27 (s, 12H).

[0064] S7,4-(7,7-dimethyl-7H-furano[3,2-g]chromen-2-yl)phenol (compound B). Compound 8b (0.20 mmol) and compound 6 (0.16 mmol), potassium phosphate (0.21 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.008 mmol) were added to N,N-dimethylformamide (3 mL) and water (1 mL). After degassing for 30 mins and stirring at 75 °C for 5 h, the reaction was cooled to room temperature, filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (10 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound B (32 mg) was purified by column chromatography, yield 76%, as a white solid. Melting point: 130–132 °C; 1 H NMR (600 MHz, CDCl3) δ 7.61 (d, J = 8.5 Hz, 2H), 7.04 (s, 1H), 6.87 (s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.67 (s, 1H), 6.34 (d, J = 9.8 Hz,1H), 5.55 (d, J = 9.8 Hz, 1H), 1.38 (s, 5H); 13 C NMR (151 MHz, CDCl3) δ 157.28,154.58, 154.24, 149.94, 128.88, 125.16, 122.72, 121.82, 117.14, 116.31,114.69, 113.81, 98.46, 82.73, 75.30, 26.73; HRMS (ESI) m / z calcd. for C 19 H 16 O3.[M+H] + 293.1172 found 293.1168; HPLC purity = 95.87%.

[0065] Example 3

[0066] Steps S1-S5 are the same as in Example 1.

[0067] S6, 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (compound 8c). 1-Bromo-3,5-dimethoxyphenyl (2.3 mmol), pinacol diborate (3.4 mmol), potassium acetate (3.4 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.11 mmol) were added to 15 mL of dioxane, degassed for 30 min, and reacted at 100 °C for 6 h. After the reaction, the mixture was filtered through diatomaceous earth and ethyl acetate (20 mL) and water (30 mL) were added. The layers separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 8c (0.53 g), 87% yield, as a white solid. 1 H NMR (600 MHz, DMSO-d6) δ 6.78 (d, J = 2.0 Hz, 1H), 6.74 (d, J = 1.8Hz, 1H), 3.75 (d, J = 2.6 Hz, 6H), 1.18 (s, 12H).

[0068] S7,2-(3,5-dimethoxyphenyl)-7,7-dimethyl-7H-furano[3,2-g]chromene (compound C). Compound 8c (0.2 mmol) and compound 6 (0.16 mmol), potassium phosphate (0.21 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.08 mmol) were added to N,N-dimethylformamide (3 mL) and water (1 mL). After degassing for 30 mins and stirring at 75 °C for 5 h, the reaction was cooled to room temperature, filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (10 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound C (43 mg) was purified by column chromatography, yield 71%, as a white solid. Melting point: 112-113 °C; 1H NMR (600 MHz, CDCl3) δ 7.06 (d, J = 4.3 Hz, 1H), 6.89 (d, J =5.5 Hz, 1H), 6.81 (d, J = 4.3 Hz, 1H), 6.37 (d, J = 6.3 Hz, 1H), 6.34 (d, J =9.4 Hz, 1H), 5.56 (dd, J = 9.8, 4.0 Hz, 1H), 3.79 (d, J = 4.3 Hz, 1H), 1.38(d, J = 4.4 Hz, 1H); 13 C NMR (151 MHz, CDCl3) δ 160.02, 154.45, 153.93, 150.55,131.31, 129.02, 121.72, 117.32, 116.61, 101.50, 100.67, 99.55, 98.49, 75.29,54.44, 26.78; HRMS (ESI) m / z calcd. for C 21 H 20 O4. [M+H] + 337.1434 found337.1433; HPLC purity = 97.88%.

[0069] Example 4

[0070] Steps S1-S5 are the same as in Example 1.

[0071] S6,4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (compound 8d). p-Bromoaniline (2.9 mmol), pinacol diboronate (4.4 mmol), potassium acetate (4.4 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.14 mmol) were added to 15 mL of dioxane, degassed for 30 min, and reacted at 100 °C for 6 h. After the reaction, the mixture was filtered through diatomaceous earth and ethyl acetate (20 mL) and water (30 mL) were added. The layers separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 8d (0.51 g), 80% yield, as a off-white solid. 1H NMR (600 MHz, DMSO-d6) δ 7.34 (d, J = 7.9 Hz, 2H), 6.52 (d, J = 7.9 Hz, 2H), 5.45 (s, 2H), 1.25 (s, 12H).

[0072] S7,4-(7,7-dimethyl-7H-furano[3,2-g]chromen-2-yl)aniline (compound D). Compound 8d (0.2 mmol) and compound 6 (0.16 mmol), potassium phosphate (0.21 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.008 mol%) were added to N,N-dimethylformamide (3 mL) and water (1 mL). After degassing for 30 mins and stirring at 75 °C for 5 h, the reaction was cooled to room temperature, filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (10 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound D (47 mg) was purified by column chromatography, yield 90%, as a pale yellow solid. Melting point: 120-124 °C; 1 H NMR (600 MHz, CDCl3) δ 7.53 (d, J = 8.5 Hz, 2H), 7.01 (s, 1H), 6.85 (s, 1H), 6.65 (d, J = 8.4 Hz, 2H), 6.60 (s, 1H), 6.34 (d, J = 9.8 Hz,1H), 5.54 (d, J = 9.8 Hz, 1H), 3.72 (s, 1H), 1.38 (s, 6H); 13 C NMR (151 MHz, CDCl3) δ 154.95, 154.14, 149.74, 145.50, 128.74, 124.91, 122.27, 121.89,120.30, 116.97, 116.04, 114.06, 98.40, 97.34, 75.13, 26.74; HRMS (ESI) m / zcalcd. for C 19 H 17 NO2. [M+H] + 292.1332 found 292.1330; HPLC purity = 97.33%.

[0073] Example 5

[0074] Steps S1-S5 are the same as in Example 1.

[0075] S6,3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenol (compound 8e). m-Bromophenol (2.9 mmol), pinacol diboronate (4.4 mmol), potassium acetate (4.4 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.14 mmol) were added to 15 mL of dioxane, degassed for 30 min, and reacted at 100 °C for 6 h. After the reaction, the mixture was filtered through diatomaceous earth and ethyl acetate (20 mL) and water (30 mL) were added. The layers separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 8e (0.5 g), 79% yield, as a white solid. 1 H NMR (600MHz, DMSO-d6) δ 9.32 (s, 1H), 7.19 (t, J = 7.7 Hz, 1H), 7.10 (s, 1H), 7.09 (d, J = 1.3 Hz, 1H), 6.89 – 6.86 (m, 1H), 1.29 (s, 12H).

[0076] S7,3-(7,7-dimethyl-7H-furano[3,2-g]chromen-2-yl)phenol (compound E). Compound 8e (0.1 mmol) and compound 6 (0.08 mmol), potassium phosphate (0.1 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.004 mmol) were added to N,N-dimethylformamide (3 mL) and water (1 mL). After degassing for 30 mins and stirring at 75 °C for 5 h, the reaction was cooled to room temperature, filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (10 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound E (29 mg) was purified by column chromatography, yield 86%, as a white solid. Melting point: 162–164 °C; 1H NMR (600 MHz, CDCl3) δ 7.29 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 13.2Hz, 2H), 7.05 (s, 1H), 6.88 (s, 1H), 6.79 (s, 1H), 6.71 (dd, J = 8.2, 2.5 Hz, 1H), 6.34 (d, J = 9.8 Hz, 1H), 5.56 (d, J = 9.8 Hz, 1H), 1.38 (s, 6H); 13 C NMR(151 MHz, CDCl3) δ 154.90, 154.49, 153.70, 150.50, 131.08, 129.04, 126.11,121.73, 119.99, 117.33, 116.64, 116.07, 114.07, 110.22, 100.55, 98.51, 75.35,26.79; HRMS (ESI) m / z calcd. for C 19 H 16 O3. [M+H] + 293.1172 found 293.1173;HPLCpurity = 99.81%.

[0077] Example 6

[0078] Steps S1-S5 are the same as in Example 1.

[0079] S6,4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzonitrile (compound 8f). p-Bromobenzonitrile (2.8 mmol), pinacol diboronate (4.2 mmol), potassium acetate (4.2 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.14 mmol) were added to 15 mL of dioxane, degassed for 30 min, and reacted at 100 °C for 6 h. After the reaction, the mixture was filtered through diatomaceous earth and ethyl acetate (20 mL) and water (30 mL) were added. The layers separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 8f (0.59 g), 94% yield, as a off-white solid. 1H NMR (600 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 1.28 (s, 12H).

[0080] S7,4-(7,7-dimethyl-7H-furano[3,2-g]chromen-2-yl)benzonitrile (compound F). Compound 8f (0.2 mmol) and compound 6 (0.16 mmol), potassium phosphate (0.21 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.008 mmol) were added to N,N-dimethylformamide (3 mL) and water (1 mL). After degassing for 30 mins and stirring at 75 °C for 5 h, the reaction was cooled to room temperature, filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (10 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound F (44 mg), a white solid, was purified by column chromatography with a yield of 81%. Melting point: 159–161 °C; 1 H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.61 (d, J= 8.2 Hz, 2H), 7.10 (s, 1H), 6.97 (s, 1H), 6.89 (s, 1H), 6.35 (d, J = 9.8 Hz,1H), 5.60 (d, J = 9.8 Hz, 1H), 1.39 (s, 6H); 13 C NMR (151 MHz, CDCl3) δ 154.98,151.76, 151.51, 133.53, 131.54, 129.48, 123.54, 121.46, 121.31, 117.89,117.84, 117.13, 109.69, 103.42, 98.49, 75.59, 26.88; HRMS (ESI) m / z calcd.for C 20 H 15 NO2. [M+H] + 302.1176 found 302.1176; HPLC purity = 98.92%.

[0081] Example 7

[0082] Steps S1-S5 are the same as in Example 1.

[0083] S6,3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzonitrile (8 g of compound). m-Bromobenzonitrile (2.7 mmol), pinacol diboronate (4.05 mmol), potassium acetate (4.05 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.14 mmol) were added to 15 mL of dioxane, degassed for 30 min, and reacted at 100 °C for 6 h. After the reaction, the mixture was filtered through diatomaceous earth and ethyl acetate (20 mL) and water (30 mL) were added. The layers separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain 8 g (0.57 g) of compound, 91% yield, as a creamy white solid. 1 H NMR (600 MHz, CDCl3) δ 8.11 (s, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 7.7Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 1.37 (s, 12H).

[0084] S7,3-(7,7-dimethyl-7H-furano[3,2-g]chromen-2-yl)benzonitrile (compound G). Compound 8 g (0.2 mmol) and compound 6 (0.16 mmol), potassium phosphate (0.21 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.008 mmol) were added to N,N-dimethylformamide (3 mL) and water (1 mL). The mixture was degassed for 30 mins and stirred at 75 °C for 5 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (10 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound G (40 mg) was purified by column chromatography, yield 74%, as a white solid. Melting point: 180–183 °C; 1H NMR (600 MHz, CDCl3) δ 7.99 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.09 (s, 1H), 6.90 (d, J= 9.5 Hz, 2H), 6.35 (d, J = 9.8 Hz, 1H), 5.59 (d, J = 9.8 Hz, 1H), 1.39 (s,6H); 13 C NMR (151 MHz, CDCl3) δ 154.76, 151.43, 151.23, 130.79, 129.90, 129.37,128.54, 127.17, 126.68, 121.51, 121.28, 117.73, 117.54, 116.98, 112.06,102.10, 98.53, 75.51, 26.85; HRMS (ESI) m / z calcd. for C 20 H 15 NO2. [M+H] + 302.1176 found 302.1175; HPLC purity = 99.65%.

[0085] Example 8

[0086] Steps S1-S5 are the same as in Example 1.

[0087] S6,4,4,5,5-Tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborane (compound 8h). 1-Bromo-4-nitrobenzene (2.5 mmol), pinacol diboronate (3.75 mmol), potassium acetate (3.75 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.13 mmol) were added to 15 mL of dioxane, degassed for 30 min, and reacted at 100 °C for 6 h. After the reaction, the mixture was filtered through diatomaceous earth and ethyl acetate (20 mL) and water (30 mL) were added. The layers separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 8h (0.58 g), 94% yield, as a pale yellow solid. 1HNMR (600 MHz, CDCl3) δ 8.12 (d, J = 8.1 Hz, 2H), 7.89 (d, J = 8.1 Hz, 2H), 1.29 (s, 12H).

[0088] S7,7,7-Dimethyl-2-(4-nitrophenyl)-7H-furano[3,2-g]chromene (compound H). Compound 8h (0.2 mmol) and compound 6 (0.16 mmol), potassium phosphate (0.21 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.008 mmol) were added to N,N-dimethylformamide (3 mL) and water (1 mL). After degassing for 30 mins and stirring at 75 °C for 5 h, the reaction was cooled to room temperature, filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (10 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound H (43 mg) was purified by column chromatography as an orange-yellow solid with a yield of 75%. Melting point: 166–167 °C; 1 H NMR (600 MHz, CDCl3) δ 8.19 (d, J = 8.8 Hz, 2H), 7.83 (d, J= 8.6 Hz, 2H), 7.11 (s, 1H), 7.03 (s, 1H), 6.89 (s, 1H), 6.35 (d, J = 9.9 Hz,1H), 5.60 (d, J = 9.8 Hz, 1H), 1.40 (s, 6H); 13 C NMR (151 MHz, CDCl3) δ 155.25,151.77, 151.50, 145.71, 135.37, 129.57, 127.30, 123.53, 123.28, 121.43,117.96, 117.20, 104.19, 98.56, 75.67, 26.90; HRMS (ESI) m / z calcd. forC 19 H 15 NO4. [M+H] + 322.1074 found 322.1076; HPLC purity = 97.10%.

[0089] Example 9

[0090] Steps S1-S5 are the same as in Example 1.

[0091] S6,4,4,5,5-Tetramethyl-2-(3-nitrophenyl)-1,3,2-dioxaborane (compound 8i). 1-Bromo-3-nitrobenzene (2.5 mmol), pinacol diboronate (3.8 mmol), potassium acetate (3.8 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.13 mmol) were added to 15 mL of dioxane, degassed for 30 min, and reacted at 100 °C for 6 h. After the reaction, the mixture was filtered through diatomaceous earth and ethyl acetate (20 mL) and water (30 mL) were added. The layers separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 8i (0.53 g), 86% yield, as a pale yellow solid. 1 HNMR (600 MHz, CDCl3) δ 8.57 (s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.03 (d, J =7.3 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 1.30 (s, 12H).

[0092] S7,7,7-Dimethyl-2-(4-nitrophenyl)-7H-furano[3,2-g]chromene (compound I). Compound 8i (0.2 mmol) and compound 6 (0.16 mmol), potassium phosphate (0.21 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.008 mmol) were added to N,N-dimethylformamide (3 mL) and water (1 mL). After degassing for 30 mins and stirring at 75 °C for 5 h, the reaction was cooled to room temperature, filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (10 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound I (40 mg) was purified by column chromatography, yield 69%, as a bright yellow solid. Melting point: 140–143 °C; 1H NMR (600 MHz, CDCl3) δ 8.54 (s, 1H), 8.06 (d, J = 7.3 Hz,1H), 8.01 (d, J = 7.5 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.11 (s, 1H), 6.98(s, 1H), 6.91 (s, 1H), 6.35 (d, J = 9.8 Hz, 1H), 5.60 (d, J = 9.8 Hz, 1H), 1.40 (s, 6H); 13 C NMR (151 MHz, CDCl3) δ 155.87, 152.41, 152.37, 148.78,132.28, 130.46, 129.77, 122.54, 122.32, 122.24, 119.13, 118.84, 118.06,103.54, 99.61, 76.58, 27.90; HRMS (ESI) m / z calcd. for C19H15NO4. [M+H] + 322.1074 found 322.1074; HPLC purity = 95.82%.

[0093] Example 10

[0094] Steps S1-S5 are the same as in Example 1.

[0095] S6,3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (compound 8j). m-Bromoaniline (2.9 mmol), pinacol diborate (4.4 mmol), potassium acetate (4.4 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.15 mmol) were added to 15 mL of dioxane, degassed for 30 min, and reacted at 100 °C for 6 h. After the reaction, the mixture was filtered through diatomaceous earth and ethyl acetate (20 mL) and water (30 mL) were added. The mixture separated into two phases, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 8j (0.46 g), 72% yield, as a creamy white solid. 1H NMR (600MHz, CDCl3) δ 7.14 (d, J = 7.2 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.06 (d, J= 1.3 Hz, 1H), 6.72 (dd, J = 7.7, 1.1 Hz, 1H), 3.56 (s, 2H), 1.26 (s, 12H).

[0096] S7,3-(7,7-dimethyl-7H-furano[3,2-g]chromen-2-yl)aniline (compound J). Compound 8j (0.2 mmol) and compound 6 (0.16 mmol), potassium phosphate (0.21 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.008 mmol) were added to N,N-dimethylformamide (3 mL) and water (1 mL). After degassing for 30 mins and stirring at 75 °C for 5 h, the reaction was cooled to room temperature, filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (10 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound J (43 mg) was purified by column chromatography, yield 82%, as a yellowish-brown solid. Melting point: 150–152 ℃; 1H NMR (600 MHz, CDCl3) δ 7.12 (s, 2H), 7.07 (s, 1H), 7.05 (s,1H), 6.87 (s, 1H), 6.77 (s, 1H), 6.57 (s, 1H), 6.34 (d, J = 9.8 Hz, 1H), 5.56(d, J = 9.6 Hz, 1H), 3.68 (s, 2H), 1.38 (s, 6H);13 C NMR (151 MHz, CDCl3) δ155.49, 155.41, 151.42, 146.74, 131.56, 130.00, 129.70, 122.91, 122.83,118.27, 117.61, 115.10, 114.96, 110.91, 101.17, 99.53, 76.32, 27.85; HRMS(ESI) m / z calcd. for C 19 H 17 NO2. [M+H] + 292.1332 found 292.1330; HPLC purity =98.87%.

[0097] Example 11

[0098] Steps S1-S5 are the same as in Example 1.

[0099] S6,N,N-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (compound 8k). 3-Bromo-N,N-dimethylaniline (2.5 mmol), pinacol diboronate (3.8 mmol), potassium acetate (3.8 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.13 mmol) were added to 15 mL of dioxane, degassed for 30 min, and reacted at 100 °C for 6 h. After the reaction, the mixture was filtered through diatomaceous earth and ethyl acetate (20 mL) and water (30 mL) were added. The layers separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 8k (0.55 g), 89% yield, as a creamy white solid. 1 H NMR (600 MHz, CDCl3) δ 7.62 (d, J = 8.2 Hz, 2H), 6.62 (d, J= 8.3 Hz, 2H), 2.91 (s, 6H), 1.25 (s, 12H).

[0100] S7,4-(7,7-dimethyl-7H-furano[3,2-g]chromen-2-yl)-N,N-dimethylaniline (compound K). Compound 8h (0.2 mmol) and compound 6 (0.16 mmol), potassium phosphate (0.21 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (5 mol%) were added to N,N-dimethylformamide (3 mL) and water (1 mL). After degassing for 30 mins and stirring at 75 °C for 5 h, the reaction was cooled to room temperature, filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (10 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound K (51 mg) was purified by column chromatography, yield 89%, as a light green solid. Melting point: 159–164 °C; 1 H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 8.6 Hz, 2H), 7.00 (s,1H), 6.86 (s, 1H), 6.69 (d, J = 8.4 Hz, 2H), 6.59 (s, 1H), 6.33 (d, J = 9.8Hz, 1H), 5.53 (d, J = 9.8 Hz, 1H), 2.93 (s, 6H), 1.37 (s, 6H); 13 C NMR (151MHz, CDCl3) δ 155.29, 154.15, 149.58, 149.25, 128.66, 124.69, 123.44, 122.46,121.94, 116.89, 115.88, 111.22, 98.40, 96.86, 75.08, 39.38, 26.72; HRMS (ESI)m / z calcd. for C 21 H 21 NO2. [M+H] + 320.1645 found 320.1642; HPLC purity = 96.75%.

[0101] Example 12

[0102] Steps S1-S5 are the same as in Example 1.

[0103] S6, N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (compound 8l). 4-Bromo-N,N-dimethylaniline (2.5 mmol), pinacol diboronate (3.8 mmol), potassium acetate (3.8 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.13 mmol) were added to 15 mL of dioxane, degassed for 30 min, and reacted at 100 °C for 6 h. After the reaction, the mixture was filtered through diatomaceous earth and ethyl acetate (20 mL) and water (30 mL) were added. The layers separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 8l (0.5 g), 81% yield, as a creamy white solid. 1 H NMR (600 MHz, CDCl3) δ 7.18 (t, J = 7.6 Hz, 1H), 7.14 – 7.09 (m,2H), 6.85 – 6.76 (m, 1H), 2.88 (s, 6H), 1.26 (s, 12H).

[0104] S7,3-(7,7-dimethyl-7H-furano[3,2-g]chromen-2-yl)-N,N-dimethylaniline (L). Compound 8l (0.2 mmol) and compound 6 (0.16 mmol), potassium phosphate (0.21 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.008 mmol) were added to N,N-dimethylformamide (3 mL) and water (1 mL). After degassing for 30 mins and stirring at 75 °C for 5 h, the reaction was cooled to room temperature, filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (10 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound L (54 mg) was purified by column chromatography, yield 94%, as a white solid. Melting point: 100–101 ℃; 1H NMR (600 MHz, CDCl3) δ 7.20 – 7.16 (m, 1H), 7.10 – 7.06 (m,2H), 6.89 (s, 1H), 6.86 (d, J = 6.1 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.63(d, J = 8.2 Hz, 1H), 6.34 (d, J = 9.8 Hz, 1H), 5.55 (d, J = 9.8 Hz, 1H), 2.94(s, 6H), 1.38 (s, 6H); 13 C NMR (151 MHz, CDCl3) δ 154.99, 154.42, 150.25,149.77, 130.20, 128.87, 128.34, 121.95, 121.81, 117.14, 116.45, 112.17,111.46, 107.36, 99.93, 98.51, 75.19, 39.62, 26.76; HRMS (ESI) m / z calcd. forC 21 H 21 NO2. [M+H] + 320.1645 found 320.1644; HPLC purity = 97.76%.

[0105] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

[0106] Study on the inhibition rate of ferroptosis by the compounds of this invention:

[0107] Experimental Methods: To investigate the inhibitory rate of the compounds of this invention on ferroptosis, a screening model for ferroptosis was constructed as follows: Cell viability was detected using the CCK-8 assay. First, mouse hippocampal neurons HT22 were cultured in culture dishes. Cells in a normal proliferating state were seeded at 5000 cells (100 μL) per well in 96-well plates and incubated at 37°C with 5% CO2 for 12 h. Subsequently, 10 μL of the compounds of this invention diluted with DMEM medium at various concentrations, along with the classic ferroptosis inhibitor ferrostatin-1 as a positive control, were added. Ferroptosis inducers RSL-3 (final concentration 1.5 μmol / L) or Erastin (final concentration 3 μmol / L) were also added. Each compound was tested in triplicate. A blank control group (containing an equal volume of culture medium and an equal volume of DMSO, but no cells) and a solvent control group (containing an equal volume of culture medium and an equal volume of DMSO, but containing cells) were also set up, with triplicate wells for each group to ensure accurate results. After adding the drug, the 96-well plate was placed in a CO2 incubator and cultured for another 24 h. After the drug effect was complete, the original culture medium was aspirated, and 100 μL of DMEM medium containing CCK-8 reagent (final concentration 10%) was added to each well. The plate was cultured for another 2 h, and then the absorbance value at 450 nm was measured using a microplate reader to calculate the inhibitory rate of the compound on ferroptosis.

[0108] The survival rate is calculated using the following formula:

[0109] Survival rate % = [(Experimental group absorbance - Blank control group) / (Solvent control group - Blank control group)] * 100%

[0110] All data are expressed as mean ± standard deviation. The inhibition rate curves were fitted using GraphPad Prism software (version 9.5.0), and the EC50 (half-maximum effective concentration) of some compounds was calculated. Experimental results are shown in Table 1 and... Figure 1 .

[0111] Studies on the cytotoxicity of the compounds of this invention:

[0112] Experimental Methods: To evaluate the cytotoxic effects of the compound of this invention on cells, a cytotoxicity screening model was established, as follows: Cell viability was detected using the CCK-8 assay. First, mouse hippocampal neurons HT22 were cultured in culture dishes. Cells in a normal proliferating state were seeded at a rate of 5000 cells (100 μL) per well in a 96-well plate and incubated at 37°C with 5% CO2 for 12 h. Subsequently, 10 μL of the compound of this invention diluted with DMEM medium was added to a final concentration of 10 μmol / L. Each compound was tested in triplicate. A blank control group (containing an equal volume of culture medium and an equal volume of DMSO, but no cells) and a solvent control group (containing an equal volume of culture medium and an equal volume of DMSO, but containing cells) were also set up, with triplicate wells for each group to ensure accurate results. After drug addition, the 96-well plates were incubated in a CO2 incubator for another 24 h. After the drug treatment ended, the original culture medium was aspirated, and 100 μL of DMEM medium containing CCK-8 reagent (final concentration of 10%) was added to each well. The cells were cultured for another 2 h, and then the absorbance value at 450 nm was detected by microplate reader to calculate the cell viability of the compound and assess its cytotoxicity.

[0113] The survival rate is calculated using the following formula:

[0114] Survival rate % = [(Experimental group absorbance - Blank control group) / (Solvent control group - Blank control group)] * 100%

[0115] All data are expressed as mean ± standard deviation. Statistical analysis and graphing were performed using GraphPad Prism software (version 9.5.0). The cytotoxicity of the compound of this invention to HT22 cells is shown in [see figure]. Figure 2 .

[0116] The effects of the compounds of this invention on key indicators of ferroptosis:

[0117] Experimental Methods: To evaluate the effect of the compounds of this invention on cellular lipid peroxidation levels, the Elabscience malondialdehyde (MDA) colorimetric assay kit was used for determination, as follows: HT22 cells were divided into groups of 1 × 10⁻⁶ cells per well. 6 Cells were seeded in 6-well plates and, when the cells reached 70%–80% confluence, were divided into the following groups (3 replicates per group): blank control group, RSL3 (1.5 µM) group, and RSL3 (1.5 µM) + compound D (5 µM) group. After 5 hours of treatment, cells were collected using a cell scraper, and each group was divided into 3 × 10⁶ cells. 6Add 500 µL of extraction buffer to each cell and sonicate on ice (90 W, 4 seconds on, 2 seconds off, total 10 minutes). Use a portion of the lysate for total protein concentration determination. Then, add the appropriate reagents sequentially according to the manufacturer's instructions, incubate at 100°C for 40 minutes, centrifuge at 7500 rpm for 10 minutes, and measure the absorbance of 250 µL of the supernatant at 532 nm. Determine the total protein concentration of the sample using the Elabscience Total Protein Assay Kit, and calculate the MDA content in the cells according to the formula provided in the kit.

[0118] To evaluate the effect of the compound of this invention on the GPX4 enzyme activity in cells, the Elabscience GPX4 colorimetric assay kit was used for determination, as follows: HT22 cells were divided into groups of 1×10⁶ cells per well. 6 Cells were seeded in 6-well plates (3 replicates per group). When the cells reached 70%–80% confluence, the following groups were established: blank control group, RSL3 (1.5 µM) group, and RSL3 (1.5 µM) + Compound D (5 µM) group. After 3 hours of treatment, cells were collected using a cell scraper, added to the kit's extraction buffer, and sonicated on ice (parameters as above). After centrifugation at 7500 rpm for 10 minutes, the supernatant was collected for total protein determination and enzyme activity analysis. 20 µL of sample supernatant was added to a 96-well plate, and the reaction system was prepared strictly according to the manufacturer's instructions. The absorbance was immediately measured at 340 nm. The total protein concentration was determined using the Elabscience Total Protein Assay Kit, and the enzyme activity of GPX4 in the cell samples was calculated based on the standard curve and the kit formula.

[0119] To evaluate the effect of the compound of this invention on intracellular Fe²⁺ levels, the Elabscience ferrous colorimetric assay kit was used for measurement, as follows: HT22 cells were divided into 5 × 10⁶ cells per well. 5 Cells were evenly seeded in 6-well plates. Once the cell confluence reached 70%–80%, cells were divided into groups (3 replicates per group): blank control group, RSL3 (1.5 µM) group, and RSL3 (1.5 µM) + compound D (5 µM) group. Cells were collected 5 hours after treatment, and each group was divided into 10 replicates. 6 Cells were lysed at low temperature with 0.2 mL of lysis buffer. After centrifugation at 7500 rpm for 10 minutes, the supernatant was collected and transferred in 80 µL to a 96-well plate for later use. Standard wells, assay wells, and sample wells were then set up according to the instructions. After adding the chromogenic reagent, the plates were incubated at 37°C in the dark for 10 minutes. The absorbance of each well was measured at 593 nm. The total Fe²⁺ content in the cells was calculated based on the standard curve and the formula provided in the kit.

[0120] To evaluate the effect of the compounds of this invention on intracellular antioxidant levels, the Elabscience Cellular Reduced Glutathione (GSH) Colorimetric Assay Kit was used for measurement, as follows: HT22 cells were divided into groups of 1 × 10⁶ cells per well. 6 Cells were seeded in 6-well plates and, after reaching 70%–80% confluence, were divided into three groups (three replicates per group): a blank control group, an RSL3 (1.5 µM) group, and an RSL3 (1.5 µM) + compound D (5 µM) group. After 5 hours of treatment, cells were collected by trypsin digestion, resuspended in 500 µL of phosphate-buffered saline, and sonicated on ice (90 W, 4 seconds on, 2 seconds off, 10 minutes total). The supernatant was collected after centrifugation at 7500 rpm for 10 minutes. 100 µL of the supernatant was transferred to a 96-well plate, and reagents were added sequentially according to the manufacturer's instructions. The plates were vortexed for 1 minute and allowed to stand for 5 minutes before the absorbance was measured at 405 nm. Total protein concentration was determined using the Elabscience Total Protein Assay Kit, and the intracellular reduced GSH content was calculated using the formula in the manufacturer's instructions based on the standard curve.

[0121] All data are expressed as mean ± standard deviation. Statistical analysis and graphing were performed using GraphPad Prism software (version 9.5.0). The key indicators of intracellular ferroptosis in HT22 cells by the compounds of this invention are described below. Figure 3 .

[0122] Table 1

[0123] Compound EC 50 (µM) (Erastin) EC 50 (µM) (RSL3) Compound D 0.4 ± 0.02 0.2 ± 0.04 Compound I > 5 2.1 ± 0.4 Compound J 1.1 ± 0.05 1.7 ± 0.2 Compound K 1.9 ± 0.9 1.6 ± 0.3

Claims

1. A class of compounds having a furano[3,2-g]chromene structure, the structural formula of which is shown in Formula I: ;in: R1 and R2 are each independently selected from hydrogen atoms or organic substituents, and R1≠R2; The organic substituent is selected from any one of the following: hydroxyl, amino, nitro, methoxy, cyano, and dimethylamino. R3 is selected from hydrogen atoms; or when R1 is methoxy or hydroxyl, R3 may be further selected from the same group as R1.

2. The compound having a furano[3,2-g]chromene structure according to claim 1, wherein: The structural formula of the compound is shown in formulas A-L below: 。 3. A method for preparing a compound having a furano[3,2-g]chromene structure according to claim 1 or 2, comprising the following steps: S1, aldehydes containing benzene rings are mixed with an acid catalyst at a molar ratio of 0.5-1.5:1.1-1.6 and reacted for 4-5 hours to obtain compound 2; S2, Compound 2 is mixed with a Lewis acid at a molar ratio of 1:1-1.2 and reacted for 0.5-2 hours to obtain Compound 3; S3, Compound 3 and DDQ were mixed and reacted at 120℃ for 14-18h in a molar ratio of 1:1-1.3 to obtain Compound 4; S4, Compound 4 was mixed with phosphorus ylide reagent at a molar ratio of 1:2.5-3.5 and reacted for 1.5-2.5 h to obtain Compound 5; S5, compound 5, base and copper catalyst are mixed in a molar ratio of 0.5-1.5:3-4:0.03-0.07 and reacted at 75-90℃ for 4-5 h to obtain compound 6; S6, Compound 7, boriding agent, base and palladium catalyst are mixed in a molar ratio of 0.5-1.5:1-2:1-2:0.03-0.07 and reacted at 90-100℃ for 5-6 h to obtain Compound 8; S7. Compound 6, compound 8, base and palladium catalyst are mixed in a molar ratio of 0.5-1.5:1-2:1.5-2.5:0.03-0.07 and reacted at 70-80℃ for 5-6 h to obtain a compound with a furano[3,2-g]chromene structure.

4. The preparation method according to claim 3, comprising: The benzene ring-containing aldehyde in step S1 is 2,4-dihydroxybenzaldehyde, and the acid catalyst is a mixture of boron trifluoride diethyl ether and 2-methyl-3-buten-2-ol in a molar ratio of 1-1.5:0.03-0.

07. Compound 2 is 2,4-dihydroxy-5-(3-methylbut-2-en-1-yl)benzaldehyde.

5. The preparation method according to claim 3, comprising: The Lewis acid in step S2 is boron trifluoride ethyl ether; the compound 3 is 7-hydroxy-2,2-dimethylchroman-6-carboxaldehyde; Compound 4 in step S3 is 7-hydroxy-2,2-dimethyl-2H-chromene-6-carboxaldehyde; The phosphorus ylide reagent in step S4 is prepared by the following method: triphenylphosphine, carbon tetrabromide and triethylamine are mixed and reacted at -5~5℃ for 10-15 min to obtain the reagent; the compound 5 is 6-(2,2-dibromoethenyl)-2,2-dimethyl-2H-chromene-7-ol.

6. The preparation method according to claim 3, comprising: The copper catalyst mentioned in step S5 is cuprous iodide; Compound 6 in S5 is 2-bromo-7,7-dimethyl-7H-furano[3,2-g]chromene.

7. The preparation method according to claim 3, comprising: The borate agent in step S6 is selected from: pinacol diborate or pinacol borane; the palladium catalyst is 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride; The substituted bromobenzene of compound 7 is selected from any one of the following: 3,5-dihydroxybromobenzene (7a), p-bromophenol (7b), 1-bromo-3,5-dimethoxybenzene (7c), p-bromoaniline (7d), m-bromophenol (7e), p-bromobenzonitrile (7f), m-bromobenzonitrile (7g), 1-bromo-4-nitrobenzene (7h), 1-bromo-3-nitrobenzene (7i), m-bromoaniline (7j), 3-bromo-N,N-dimethylaniline (7k), and 4-bromo-N,N-dimethylaniline (7l).

8. The preparation method according to claim 3, comprising: The borate ester of compound 8 in step S7 is selected from: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzene-1,3-diol (8a), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (8b), 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboran (8c), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (8d), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (8e), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzonitrile (8c), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzonitrile ...c), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzonitrile (8c), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzonitrile (8c), 4-(4,4,5,5-tetramethyl-1, 8f), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzonitrile (8g), 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaboran (8h), 4,4,5,5-tetramethyl-2-(3-nitrophenyl)-1,3,2-dioxaboran (8i), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (8j), N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (8k), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (8l); The alkali is selected from any one of potassium carbonate, potassium phosphate, or potassium acetate.

9. A compound having a furano[3,2-g]chromene structure prepared by any of the preparation methods according to claims 3 to 8.

10. The use of a compound having a furano[3,2-g]chromene structure according to any one of claims 1, 2 or 9 in the preparation of a medicament for treating ferroptosis inhibitors.

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