8-site hydroxyurolithin A derivative as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to an 8-position hydroxyurolithin A derivative as well as a preparation method and application thereof. According to the method, 2-bromo-5-(benzyl methoxy)-benzoic acid is prepared from 2-bromo-5-hydroxybenzoic acid through hydroxyl protection, then cyclization, etherification and deprotection reaction are carried out, the reaction conditions are milder, the reaction time is shorter, the yield is higher, groups sensitive to acid and alkali and various substrates can well tolerate the reaction conditions, and the method is suitable for industrial production. The 8-site hydroxyurolithin A derivative is prepared, the obtained derivative is targeted to PDE2 small molecules, and the 8-site hydroxyurolithin A derivative has huge potential for treating neurodegenerative diseases such as Alzheimer's disease.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to inhibitor derivatives of phosphodiesterase 2 (PDE2). Background Art

[0002] Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play an important regulatory role in cell activities and are second messengers in cells. They regulate the enzyme activity of the intracellular metabolic system, control the uptake and utilization of glucose, the storage and movement of fat, the secretion of cell products, and the proliferation, differentiation and survival of cells, and participate in the regulation of gene transcription. Regulating the concentration of cAMP and cGMP in the body to a normal level is of great significance for the treatment of many diseases, and the regulation of their concentration is mainly determined by the balance between the synthesis of adenylate cyclase and the hydrolysis of phosphodiesterase (PDEs). PDEs include 11 types and more than 30 phosphodiesterase isozymes with different substrate specificity and enzyme kinetic characteristics. Among them, PDE2 is a dual-substrate enzyme that can hydrolyze both cAMP and cGMP. It is expressed in both the peripheral and central nervous systems, but its expression is highest in brain regions such as the cortex, hippocampus and striatum. Inhibiting the activity of PDE increases the concentration of cAMP and cGMP in the body, further activating phosphokinase, increasing membrane permeability, increasing metabolic rate and cell activity, and thus playing a wide range of positive roles. Selective phosphodiesterase inhibitors have been widely used in diseases such as heart failure, asthma, impotence, anti-inflammatory, and anti-thrombotic. Studies have shown that selective PDE2 inhibitors can improve mild cognitive impairment and memory disorders related to age and aging. PDE2 inhibitors have a pro-cognitive effect in memory tests and can also prevent cognitive deficits in various cognitive impairment models. In addition, PDE2 inhibitors can prevent many different forms of stress-induced anxiety-like and depression-like behaviors. At present, new therapies for the treatment of mood and cognitive disorders and other neurodegenerative diseases are urgently needed, and PDE2 is becoming a viable target for future drug development for the treatment of many of these diseases.

[0003] Fruits or nuts such as pomegranates, blackberries, walnuts, and muscadines are rich in ellagitannins. Urolithin is a general term for a series of products of ellagitannins after multi-level metabolism by intestinal flora, including urolithin A to D. The good biological activity of the polyphenolic compound urolithin A (UA) has made it a hot topic in recent years. Its antioxidant, anti-inflammatory, anti-atherosclerotic, and neuroprotective effects have been widely studied, and it is a potential active small molecule for intervening in neurodegenerative diseases. Due to individual metabolic differences, the absorption of UA through diet alone is very limited. UA has low bioavailability and low blood-brain barrier permeability, which is not conducive to its absorption and utilization. Therefore, using UA as a lead compound for corresponding structural optimization has laid a theoretical and experimental foundation for the research and development of PDE2 inhibitors, and it is expected that a new type of PDE2 inhibitor can be found through this method. Derivatives based on the structure of urolithin A target PDE2 small molecules and have great potential for the treatment of neurodegenerative diseases such as Alzheimer's disease. This patent uses the structure of UA as the basis to structurally modify it in order to obtain an effective PDE2 inhibitor. Summary of the invention

[0004] In order to achieve the purpose of the present invention, the technical solution adopted by the present invention is as follows:

[0005] An 8-hydroxy urolithin APDE2 inhibitor derivative, the general formula of which is as follows:

[0006]

[0007] Wherein, R is an alkyl group, an olefin group, a substituted alkyl group, an alkoxy group, an alkylthio group, an ester group, a cyano group or a cyanoalkyl group. Wherein the substituent on the substituted alkyl group is a cycloalkyl group or a substituted cycloalkyl group, a heterocyclic group or a substituted heterocyclic group, an aromatic group or a substituted aromatic group. Further, the cycloalkyl group is: cyclopentyl, cyclohexyl; the heterocyclic group is a tetrahydrofuran ring, a tetrahydropyran ring, a 1,3-dioxolane ring, a 1,3-dioxane, a piperidine ring, a pyrazole ring and a pyrimidine ring; the aromatic group is a phenyl group or a naphthyl group. The substituents in the substituted cycloalkyl group, the substituted heterocyclic group and the substituted aromatic group are halogen, methyl, tert-butyl and hydroxymethyl.

[0008] The compound I is selected from the compounds represented by formula F1-F35:

[0009]

[0010]

[0011] A method for preparing a urolithin APDE2 inhibitor derivative, comprising the following steps:

[0012] (1) Protecting hydroxyl groups: 4-methoxybenzyl chloride was added dropwise to a DMF solution of 2-bromo-5-hydroxybenzoic acid and anhydrous potassium carbonate and heated to 80°C for 5 hours. After the reaction was completed, it was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated to obtain a preliminary product. The product did not need to be purified and was directly subjected to the next step of reaction. At 0°C, the product 2-bromo-5-(benzylmethoxy)-phenylmethyl ester benzoic acid was added to a mixed solution of tetrahydrofuran and methanol, and a LiOH aqueous solution was added dropwise, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, the organic solvents methanol and tetrahydrofuran were evaporated under reduced pressure, a small amount of water was added, and the reaction solution was washed twice with ethyl acetate. The aqueous phase was acidified with 1M hydrochloric acid, and the product 2-bromo-5-(benzylmethoxy)-benzoic acid was obtained by suction filtration and drying.

[0013] (2) Cyclization: 2-bromo-5-(benzylmethoxy)-benzoic acid, resorcinol and NaOH were refluxed in water for 1 h, 5% CuSO4 aqueous solution was added dropwise, and reflux was continued for 30 min. After the reaction was completed, the mixture was cooled and the precipitate was filtered out. The precipitate was washed with 1M HCl and dried. Recrystallization with methanol and ethyl acetate in a ratio of 1:1 gave white crystals.

[0014] (3) Etherification: The product obtained in step (2) was dissolved in DMF, anhydrous K2CO3 was added, stirred for 5 min, and the bromide was added dropwise, and the reaction was carried out at 70°C for 3-24 h. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was poured into ice water and filtered. The product was recrystallized several times with methanol.

[0015] (4) Deprotection: The 1,2-dichloroethane solution of the etherified product was reacted with oxalyl chloride (0.5 eq) at room temperature for 1-4 h. After the reaction, the solvent was evaporated under reduced pressure, and the remaining solid was dissolved in ethyl acetate. The solution was washed with water and then separated. The organic layer was spin-dried and subjected to column chromatography using methanol: dichloromethane = 1:30.

[0016] The synthetic route is shown below:

[0017]

[0018] Wherein, RX is Cl, Br or I; R has the same definition as above.

[0019] In the step 1, the molar ratio of the compound 2-bromo-5-hydroxybenzoic acid to p-methoxybenzyl chloride, potassium carbonate and lithium hydroxide is 1:2.0-2.5:2.2-4.0:2.0-3.0;

[0020] In the step 2, the molar ratio of the compound 2-bromo-5-(benzylmethoxy)-benzoic acid to resorcinol and sodium hydroxide is 1:1.0-3.0:3.0-7.1;

[0021] In the step 3, the molar ratio of the product obtained in step 2 to the bromide and potassium carbonate is 1:2.0-2.4:2.0-2.4;

[0022] In the step 4, the molar ratio of the etherification product obtained in step 3 to oxalyl chloride is 1:0.5-1.5.

[0023] Beneficial effects of the present invention:

[0024] The present invention provides novel PDE2 inhibitor compounds, mainly including 29 new compounds, all of which have good PDE2 inhibitory activity, have the potential to treat central nervous system diseases, such as memory deficiency, cognitive impairment, anxiety and depression, etc., and can be used as active ingredients to prepare drugs that inhibit PDE2 activity. In addition, according to the provided compound structure, a corresponding synthesis method is provided, and the synthesis method is simple. At the beginning of the synthesis reaction, two active hydrogens are first protected by an etherification reaction, and then the carboxylic acid group is exposed by the characteristics of ester hydrolysis under alkaline conditions, which not only ensures that the subsequent cyclization reaction proceeds smoothly, but also ensures that the single substitution reaction during the subsequent etherification proceeds to the maximum extent. The last step of deprotection uses oxalyl chloride as a catalyst, which has a fast reaction speed and high selectivity. And the removal of p-methoxybenzyl can be completed in the presence of benzyl. In addition, the method has milder conditions, shorter reaction time and higher yield, and can well tolerate the reaction conditions for acid- and alkali-sensitive groups and a variety of substrates. DETAILED DESCRIPTION

[0025] The present invention is further described below in conjunction with the embodiments. The following embodiments are only used to more clearly illustrate the technical solution of the present invention, and cannot be used to limit the protection scope of the present invention.

[0026] Example 1

[0027] 2-Bromo-5-hydroxybenzoic acid (11.5mmol, 2.5g) and anhydrous K2CO3 (27.6mmol, 3.8g) in anhydrous DMF (20mL) were added dropwise with 4-methoxybenzyl chloride (24.1mmol, 3.78g) and heated to 60°C for 5h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, the reaction solution was poured into 200mL of saturated ammonium chloride aqueous solution, stirred with a glass rod to fully mix, left to stand for 30min, extracted with ethyl acetate, and the organic phase was concentrated to obtain a brown-yellow viscous liquid.

[0028] The obtained product was added with THF (25 mL) and MeOH (12.5 mL) and stirred at 0°C for 10 min, and LiOH (25 mmol, 0.6 g) aqueous solution (12.5 mL) was added dropwise, and the reaction was allowed to react at room temperature for 4 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1) after sampling and acidification. After the reaction was completed, the organic solvent in the reaction solution was removed by rotation, a small amount of water was added and the reaction solution was washed with ethyl acetate (2×20 mL), the organic phase was discarded, the aqueous phase was acidified to pH=1 with 1M hydrochloric acid, the reaction solution was stirred and allowed to stand for 30 min, and the white precipitate produced was filtered and dried to obtain 2-bromo-5-(benzylmethoxy)-benzoic acid with a yield of 81%.

[0029] C2: white solid (yield 81%), mp 162.1-164.7°C, 1 HNMR(400MHz,DMSO-d6)δ13.47(s,1H),7.59(d,J=8.8Hz,1H),7.42-7.36(m,2H),7.35(d ,J=3.1Hz,1H),7.09(dd,J=8.8,3.1Hz,1H),7.00-6.92(m,2H),5.07(s,2H),3.77(s,3H). 13 CNMR(101MHz,DMSO-d6)δ167.15,159.09,157.43,134.63,134.53,129.61,128.26,119.26,116.55,113.82,110.13,69.42,55.06.

[0030] Example 2

[0031] 2-Bromo-5-(benzylmethoxy)-benzoic acid (4.46mmol, 1.5g), resorcinol (13.38mmol, 1.47g) and NaOH (13.38mmol, 0.53g) were added with 20ml of water, heated to 100℃ and refluxed for 1h, 5% CuSO4 (1.34mmol, 0.08g) aqueous solution was added dropwise, and refluxed for 30min. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction was completed, the mixture was cooled and the precipitate was filtered out by suction. The precipitate was rinsed with 1M HCl several times and dried in an oven. Recrystallization from methanol and ethyl acetate 1:1 gave white crystals, 3-hydroxy-8-((4-methoxybenzyl)oxy)-6H-benzo[c]chromen-6-one, with a yield of 41%.

[0032] C3: white needle-like crystals (yield 41%), mp 236.8-238.9°C, 1HNMR (300MHz, DMSO-d6) δ10.26(s,1H),8.19(d,J=8.9Hz,1H),8.08(d,J=8.8Hz,1H),7.67(d,J=2.7Hz,1H),7.53(dd,J=8.8,2.8H z,1H),7.42(d,J=8.3Hz,2H),6.96(d,J=8.2Hz,2H),6.82(dd,J=8.5,2.4Hz,1H),6.74(d,J=2.3Hz,1H),5.16(s,2H),3.76(s,3H). 13 C NMR(101MHz,DMSO-d6)δ160.48,159.09,158.94,157.56,151.15,129.61,128.54,128.30 ,124.43,124.10,123.48,119.93,113.82,113.06,111.91,109.46,102.81,69.38,55.05.

[0033] Example 3

[0034] Preparation of compounds Z1-Z35

[0035] 3-Hydroxy-8-((4-methoxybenzyl)oxy)-6H-benzo[c]chromen-6-one (1.43mmol, 0.5g) was dissolved in a 50ml round-bottom flask with DMF (10mL), anhydrous K2CO3 (2.82mmol, 0.39g) was added and stirred for 5min, and a halide R-Br / Cl (as shown in Table 1) (2.86mmol) was added dropwise, and the reaction was carried out at 70°C for 3-24h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, it was poured into 100mL of ice water, stirred to make the reaction solution fully mixed with ice water, and the precipitate was precipitated, and the product was filtered and dried. The product was recrystallized with methanol several times, and Z1-Z35 was collected separately, with a yield of 67%-92%

[0036] Z1: 1 HNMR (400MHz, DMSO-d6) δ8.25(d,J=9.0Hz,1H),8.16(d,J=9.6Hz,1H),7.69(d,J=2.8Hz,1H),7.55(dd,J=8.8,2.8Hz,1H),7.48 -7.39(m,2H),7.02-6.93(m,4H),5.17(s,2H),4.02(t,J=6.6Hz,2H),3.77(s,3H),1.77(h,J=7.1Hz,2H),1.00(t,J=7.4Hz,3H). 13C NMR(101MHz,DMSO-d6)δ160.42,159.81,159.09,157.88,151.11,129.63,128.28,128.20,124.51,124.08,123.87,120.26,113.85,112.60,112.03,101.78,69.48,69.41,55.07,21.87,10.34.m.p.132.0-132.7℃.

[0037] Z2: 1 HNMR(400MHz,DMSO-d6)δ8.21(d,J=9.0Hz,1H),8.12(d,J=8.7Hz,1H),7.67(d,J=2.8Hz,1H),7.53(dd,J=8.9,2.8Hz,1H),7.47-7.39(m,2H),7.00-6.90(m,4H),5.16(s,2H),4.74(hept,J=6.0Hz,1H),3.77(s,3H),1.31(d,J=6.0Hz,6H). 13 CNMR(101MHz,DMSO-d6)δ160.40,159.09,158.58,157.83,151.15,129.62,128.27,128.19,124.43,124.09,123.79,120.23,113.83,113.32,111.98,110.49,102.71,69.83,69.40,55.06,21.64.m.p.127.5-129.5℃

[0038] Z3: 1 HNMR(400MHz,Chloroform-d)δ7.91-7.76(m,2H),7.38(d,J=7.9Hz,2H),6.93(d,J=8.3Hz,1H),6.90-6.77(m,1H),5.06(dd,J=3.9,1.9Hz,1H),4.03-3.94(m,1H),3.81(s,2H),1.85-1.75(m,1H),1.56-1.44(m,1H),0.99(t,J=7.4Hz,2H). 13CNMR(101MHz,Chloroform-d)δ161.62,160.28,159.68,158.24,151.64,129.51,128.83,128.14,124.95,123.09,122.81,120.86,114.11,112.78,112.06,111.06,102.04,77.31,70.21,68.18,55.34,31.14,19.25,13.90.m.p.129.8-133.7℃.

[0039] Z4: 1 HNMR(400MHz,DMSO-d6)δ8.22(d,J=8.9Hz,1H),8.13(d,J=8.6Hz,1H),7.68(d,J=2.8 Hz,1H),7.53(dd,J=8.8,2.8 Hz,1H),7.43(d,J=8.2 Hz,2H),6.97(d,J=8.6Hz,4H),5.16(s,2H),4.52(h,J=6.0 Hz,1H),3.77(s,3H),1.64(dtt,J=27.8,13.8,7.0 Hz,2H),1.27(d,J=6.0 Hz,3H),0.94(t,J=7.4 Hz,3H). 13 C NMR(101 MHz,DMSO-d6)δ160.42,159.09,158.93,157.84,151.16,129.62,128.27,128.20,124.45,124.12,123.81,120.23,113.83,113.36,111.99,110.51,102.73,74.67,69.40,55.06,28.39,18.87,9.45.m.p.85.6-86.5℃.

[0040] Z5: 1 H NMR(400 MHz,Chloroform-d)δ7.89(dt,J=9.0,1.7 Hz,1H),7.85-7.78(m,2H),7.43-7.35(m,3H),6.97-6.91(m,2H),6.88(ddd,J=8.8,2.5,1.0 Hz,1H),6.82(dd,J=2.6,1.3 Hz,1H),5.07(s,2H),3.82(s,3H),3.76(d,J=6.5 Hz,2H),2.13(dq,J=13.3,6.7Hz,1H),1.05(d,J=6.7 Hz,6H).13 C NMR(101 MHz,Chloroform-d)δ161.65,160.40,159.69,158.26,151.67,129.52,128.87,128.14,124.99,123.08,122.83,120.89,114.12,112.82,112.09,111.08,102.12,74.80,70.24,55.35,28.20,19.25.m.p.128.5-130.8℃.Z6: 1 H NMR(400 MHz,DMSO-d6)δ8.22(d,J=9.0 Hz,1H),8.12(d,J=9.6 Hz,1H),7.67(d,J=2.8 Hz,1H),7.53(dd,J=8.9,2.8 Hz,1H),7.46-7.38(m,2H),7.01-6.90(m,4H),5.15(s,2H),4.03(t,J=6.5 Hz,2H),3.76(s,3H),1.73(p,J=6.6 Hz,2H),1.37(ttd,J=14.8,7.7,7.3,2.6 Hz,4H),0.90(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO-d6)δ160.38,159.80,159.10,157.86,151.09,129.58,128.28,128.19,124.44,124.02,123.82,120.25,113.84,112.56,112.03,110.61,101.75,69.42,68.01,55.07,28.21,27.63,21.87,13.89.m.p.108.3-110.2℃.

[0041] Z7: 1 H NMR(400 MHz,Chloroform-d)δ7.88(dd,J=9.1,2.1 Hz,1H),7.85-7.78(m,2H),7.43-7.35(m,3H),6.97-6.90(m,2H),6.90-6.80(m,2H),5.10-5.05(m,2H),4.03(td,J=6.7,1.0 Hz,2H),3.82(s,3H),1.85(dp,J=13.3,6.7 Hz,1H),1.72(t,J=6.7 Hz,2H),0.98(d,J=6.6 Hz,6H). 13C NMR(101 MHz,Chloroform-d)δ161.65,160.27,159.69,158.26,151.66,129.53,128.86,128.13,125.01,123.11,122.83,120.88,114.12,112.82,112.06,111.09,102.05,70.23,66.89,55.35,37.76,25.06,22.62.m.p.133.9-135.9℃.

[0042] Z8: 1 H NMR(400 MHz,DMSO-d6)δ8.23(d,J=8.9 Hz,1H),8.14(d,J=9.5 Hz,1H),7.68(d,J=2.7 Hz,1H),7.53(dd,J=8.9,2.8 Hz,1H),7.46-7.38(m,2H),6.96(td,J=5.7,4.9,2.1 Hz,4H),5.16(s,2H),3.92(d,J=7.0 Hz,2H),3.76(s,3H),2.32(hept,J=7.5 Hz,1H),1.78(h,J=6.7 Hz,2H),1.68-1.49(m,4H),1.35(dt,J=12.4,6.0 Hz,2H). 13 CNMR(101MHz,DMSO-d6)δ160.40,159.94,159.10,157.87,151.10,129.60,128.29,128.20,124.47,124.04,123.86,120.25,113.84,112.62,112.04,110.63,101.81,72.10,69.41,55.07,38.37,28.94,24.92.m.p.137.5-139.8℃.

[0043] Z9: 1H NMR(400 MHz,Chloroform-d)δ7.88(d,J=8.9 Hz,1H),7.85-7.77(m,2H),7.38(dd,J=8.9,2.6 Hz,3H),6.97-6.90(m,2H),6.87(dd,J=8.8,2.5 Hz,1H),6.81(d,J=2.5Hz,1H),5.07(s,2H),3.80(d,J=17.1 Hz,5H),1.93-1.85(m,2H),1.84-1.68(m,4H),1.27(dddd,J=24.6,15.5,12.4,6.2 Hz,3H),1.07(qd,J=12.2,3.3 Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ161.66,160.44,159.69,158.23,151.66,129.52,128.88,128.14,124.99,123.07,122.82,120.86,114.11,112.80,112.06,111.02,102.09,73.90,70.23,55.35,37.56,29.86,26.49,25.80.m.p.151.7-153.8℃.

[0044] Z10: 1 H NMR(400 MHz,Chloroform-d)δ7.93-7.82(m,3H),7.45(s,1H),7.43-7.37(m,3H),7.32(d,J=1.6 Hz,3H),6.98-6.87(m,4H),5.08(s,4H),3.82(s,3H). 13 C NMR(101MHz,Chloroform-d)δ161.51,159.72,159.40,158.46,151.59,138.25,134.70,130.04,129.53,128.61,128.43,128.08,127.48,125.44,125.06,123.32,122.94,121.04,114.13,113.02,112.15,111.81,102.64,70.27,69.50,55.35.m.p.168.3-171.2℃.

[0045] Z11: 1HNMR(400 MHz,Chloroform-d)δ7.83(d,J=8.9 Hz,1H),7.80-7.74(m,2H),7.31(d,J=9.4 Hz,7H),6.89-6.83(m,3H),6.81(d,J=2.5 Hz,1H),5.01(s,2H),5.00(s,2H),3.75(s,3H). 13 C NMR(101 MHz,Chloroform-d)δ160.45,158.66,158.41,157.39,150.53,133.62,133.07,128.47,127.88,127.82,127.56,127.02,124.00,122.22,121.86,119.98,113.08,111.96,111.11,110.70,101.59,69.22,68.53,54.29.m.p.169.1-170.6℃.

[0046] Z12: 1 HNMR(400 MHz,Chloroform-d)δ7.90(d,J=8.9 Hz,1H),7.88-7.82(m,2H),7.50(td,J=7.5,1.8 Hz,1H),7.42-7.30(m,4H),7.18(td,J=7.5,1.2 Hz,1H),7.11(ddd,J=9.7,8.2,1.2 Hz,1H),6.99-6.92(m,4H),5.18(s,2H),5.08(s,2H),3.82(s,3H). 13 C NMR(101MHz,Chloroform-d)δ161.53,160.54(d,J=248.46 Hz),159.72,159.52,158.43,151.62,130.12(d,J=8.08 Hz),129.79(d,J=4.04 Hz),129.53,128.67,128.10,125.04,124.40(d,J=3.03 Hz),123.37(d,J=14.14 Hz),123.27,122.93,121.05,115.57(d,J=21.21 Hz),114.13,112.88,112.16,111.77,102.74,77.27,70.28,64.16,64.12,55.35.m.p.169.6-170℃.Z13: 1HNMR(400 MHz,Chloroform-d)δ7.90(d,J=8.9 Hz,1H),7.88-7.81(m,2H),7.44-7.39(m,2H),7.39-7.32(m,2H),7.24-7.13(m,2H),7.03(td,J=8.5,2.6 Hz,1H),6.99-6.90(m,3H),6.88(d,J=2.5 Hz,1H),5.09(d,J=10.1 Hz,4H),3.82(s,3H). 13 C NMR(101 MHz,Chloroform-d)δ163.06(d,J=246.44 Hz),161.52,159.72,159.42,158.45,151.59,138.77(d,J=8.08 Hz),130.35(d,J=9.09 Hz),129.53,128.62,128.08,125.06,123.30,122.93,122.82(d,J=3.03 Hz),121.03,115.18(d,J=21.21Hz),114.30(d,J=21.21Hz),114.13,113.03,112.14,111.78,102.64,70.27,69.51,55.35.m.p.175.5-178.8℃.Z14: 1 HNMR(400 MHz,Chloroform-d)δ7.83(d,J=8.9 Hz,1H),7.81-7.75(m,2H),7.38-7.29(m,5H),7.02(td,J=8.7,2.5 Hz,2H),6.90-6.82(m,4H),5.00(d,J=6.1 Hz,4H),3.75(s,3H). 13 C NMR(101 MHz,CDCl3)δ162.73(d,J=236.37 Hz),159.72,159.57,158.43,151.60,131.94,129.54,129.45,128.67,128.08,125.08,123.28,122.93,121.02,115.81,

[0047] 115.60,114.14,113.06,112.14,111.69,102.61,77.39,77.07,76.75,70.28,69.72,55.35.m.p.179.9-181.6℃.

[0048] Z15:1 H NMR(400 MHz,Chloroform-d)δ7.96-7.83(m,3H),7.46-7.35(m,3H),7.02-6.87(m,6H),6.78(tt,J=8.9,2.4 Hz,1H),5.10(d,J=1.8 Hz,4H),3.83(s,3H). 13 CNMR(101 MHz,DMSO-d6)δ159.11,158.88,158.02,151.01,129.63,128.27,128.02,124.49,

[0049] 124.24,124.00,120.43,113.85,112.83,112.09,111.31,110.67,110.42,102.44,69.44,68.21,55.07.m.p.208.0-209.6℃.

[0050] Z16: 1 H NMR(400 MHz,DMSO-d6)δ8.26(d,J=8.9 Hz,1H),8.19(d,J=8.9 Hz,1H),7.70(d,J=2.8 Hz,1H),7.56(dd,J=8.9,2.8 Hz,1H),7.45(t,J=7.7 Hz,3H),7.25(tdd,J=9.0,7.1,4.2 Hz,3H),7.13(d,J=2.5 Hz,1H),7.07(dd,J=8.8,2.5 Hz,1H),7.02-6.94(m,2H),5.19(d,J=8.8 Hz,4H),3.77(s,3H),2.36(s,3H). 13 C NMR(101 MHz,DMSO-d6)δ160.38,159.53,159.11,157.95,151.07,136.73,134.41,130.18,129.62,128.64,128.28,128.24,128.14,125.82,124.48,124.13,123.93,120.35,113.85,112.85,112.07,111.00,

[0052] 102.28,69.43,68.45,55.07,18.47.m.p.142.8-145.5℃.

[0053] Z17: 1H NMR(400 MHz,Chloroform-d)δ7.88(d,J=8.9 Hz,1H),7.85-7.79(m,2H),7.43-7.36(m,3H),7.33(d,J=7.8 Hz,2H),7.20(d,J=7.8 Hz,2H),6.94(td,J=6.0,2.7 Hz,3H),6.89(d,J=2.5 Hz,1H),5.06(d,J=3.8 Hz,4H),3.82(s,3H),2.36(s,3H). 13 CNMR(101 MHz,Chloroform-d)δ161.60,159.84,159.71,158.35,151.59,138.16,133.12,129.54,129.45,128.76,128.12,127.74,125.02,123.17,122.88,120.97,114.13,113.12,112.10,

[0054] 111.46,102.65,70.36,70.26,55.35,21.27.m.p.173.1-175.0℃.

[0055] Z18: 1 H NMR(400 MHz,Chloroform-d)δ7.89(d,J=8.9 Hz,1H),7.83(dd,J=5.8,3.1 Hz,2H),7.45-7.36(m,7H),6.98-6.90(m,4H),5.08(s,4H),3.82(s,3H),1.33(s,9H). 13 CNMR(101 MHz,Chloroform-d)δ161.62,159.91,159.71,158.36,151.61,151.41,133.10,129.54,128.77,128.12,127.54,125.73,125.05,123.18,122.89,120.97,114.13,113.11,

[0057] 112.11,111.46,102.62,70.31,70.26,55.35,34.67,31.36.m.p.189.5-191.2℃.

[0058] Z19: 1H NMR(400 MHz,Chloroform-d)δ7.82(d,J=8.9 Hz,1H),7.80-7.73(m,2H),7.58(d,J=8.1 Hz,2H),7.49(d,J=8.1 Hz,2H),7.37-7.27(m,3H),6.91-6.82(m,3H),6.80(d,J=2.5 Hz,1H),5.09(s,2H),5.00(s,2H),3.74(s,3H). 13 C NMR(101 MHz,CDCl3)δ160.40,158.66,158.22,157.42,150.52,139.18,129.35,128.46,127.48,126.98,126.41,

[0059] 124.65,123.99,122.98,122.29,121.87,119.99,113.07,111.88,111.09,110.83,101.58,76.32,76.00,75.69,69.21,68.38,54.28.m.p.174.8-176.8℃.

[0060] Z20: 1 H NMR(400 MHz,DMSO-d6)δ8.23(d,J=9.0 Hz,1H),8.16(d,J=8.8 Hz,1H),7.68(d,J=2.8 Hz,1H),7.54(dd,J=8.8,2.8 Hz,1H),7.44(dd,J=8.4,6.9 Hz,4H),7.36(d,J=7.9 Hz,2H),7.08-7.00(m,2H),7.00-6.93(m,2H),5.24(t,J=5.7 Hz,1H),5.19(s,2H),5.16(s,2H),4.52(d,J=5.7 Hz,2H),3.77(s,3H). 13 C NMR(101 MHz,DMSO-d6)δ160.36,159.38,159.10,157.93,151.01,142.43,134.77,129.62,128.27,128.11,127.71,

[0061] 126.52,124.45,124.08,123.89,120.33,113.84,112.91,112.04,110.93,102.31,69.61,69.42,62.62,55.07.m.p.185.0-187.6℃.

[0062] Z21: 1 H NMR(400 MHz,DMSO-d6)δ8.22(d,J=9.0 Hz,1H),8.18-8.10(m,1H),7.67(d,J=2.8 Hz,1H),7.52(dd,J=8.8,2.8 Hz,1H),7.47-7.39(m,2H),6.97(td,J=4.9,2.5Hz,4H),5.15(s,2H),4.18(qd,J=6.8,3.7 Hz,1H),4.09-3.95(m,2H),3.80(dt,J=8.0,6.6 Hz,1H),3.77(s,3H),3.69(td,J=7.7,6.2 Hz,1H),2.08-1.96(m,1H),1.96-1.76(m,2H),1.68(ddt,J=11.9,8.6,6.9 Hz,1H). 13 C NMR(101 MHz,DMSO-d6)δ160.36,159.65,159.09,157.88,151.03,129.61,128.27,128.12,124.42,124.04,123.85,120.27,113.83,112.58,111.99,110.79,101.85,76.30,70.56,69.40,67.47,55.06,27.56,25.17.m.p.136.4-139.2℃.

[0067] Z22: 1 H NMR(400 MHz,Chloroform-d)δ7.94-7.82(m,3H),7.45-7.36(m,3H),6.97-6.90(m,4H),6.15(s,1H),5.07(d,J=17.8 Hz,4H),3.84(d,J=16.2 Hz,6H),2.26(s,3H). 13C NMR(101 MHz,Chloroform-d)δ161.43,159.72,158.95,158.53,151.52,147.46,137.10,129.54,128.48,128.03,125.07,123.38,122.96,121.08,114.14,112.94,112.18,112.06,107.11,102.53,70.28,60.84,55.35,36.54,13.45.m.p.186.4-187.8℃.

[0070] Z23: 1 H NMR(400 MHz,Chloroform-d)δ7.89(d,J=9.0 Hz,1H),7.86-7.80(m,2H),7.43-7.35(m,3H),6.97-6.90(m,3H),6.87(d,J=2.6 Hz,1H),5.32(t,J=3.9 Hz,1H),5.08(s,2H),4.10-4.02(m,4H),4.02-3.95(m,2H),3.82(s,3H). 13 C NMR(101 MHz,Chloroform-d)δ161.52,159.70,159.52,158.41,151.52,129.53,128.62,128.09,125.01,123.22,122.93,121.03,114.12,112.72,112.12,111.79,102.47,101.72,70.25,69.03,65.41,55.35.m.p.140.4-142.5℃.

[0072] Z24: 1H NMR(400 MHz,Chloroform-d)δ7.84(d,J=9.0 Hz,1H),7.77(dd,J=5.8,3.1 Hz,2H),7.37-7.29(m,3H),6.91-6.84(m,2H),6.81(dd,J=8.8,2.5 Hz,1H),6.76(d,J=2.5Hz,1H),5.02(s,2H),3.97(ddd,J=11.4,5.0,1.7 Hz,2H),3.78(d,J=6.4 Hz,2H),3.75(s,3H),3.38(td,J=11.9,2.1 Hz,2H),2.08-1.98(m,1H),1.70(ddd,J=13.1,4.1,2.0 Hz,2H),1.42(dtd,J=13.4,12.0,4.6 Hz,2H). 13 C NMR(101 MHz,Chloroform-d)δ160.55,159.04,158.64,157.29,150.61,128.47,127.72,127.04,124.00,122.13,121.82,119.90,113.07,111.64,111.07,110.27,101.09,71.86,69.21,66.56,54.29,33.95,28.61.m.p.211.4-212.6℃.Z25: 1 H NMR(400 MHz,Chloroform-d)δ7.89(d,J=8.9 Hz,1H),7.86-7.79(m,2H),7.56(d,J=2.1 Hz,2H),7.40(dq,J=9.3,2.9 Hz,3H),6.98-6.90(m,2H),6.84(dd,J=8.8,2.6Hz,1H),6.80(d,J=2.5 Hz,1H),6.28(t,J=2.0 Hz,1H),5.08(s,2H),4.56(t,J=5.1 Hz,2H),4.39(t,J=5.1 Hz,2H),3.82(s,3H). 13C NMR(101MHz,Chloroform-d)δ161.47,159.71,159.24,158.46,151.55,139.97,130.34,129.54,128.55,128.06,125.05,123.28,122.94,121.06,114.13,112.44,112.15,111.90,105.87,102.57,70.27,67.14,55.35,51.31.m.p.171.8-172.9℃.

[0074] Z26: 1 HNMR(400 MHz,Chloroform-d)δ7.90(d,J=8.9 Hz,1H),7.86-7.80(m,2H),7.39(dq,J=9.7,2.8 Hz,3H),6.94(d,J=2.0 Hz,1H),6.94-6.87(m,2H),6.85(d,J=2.5Hz,1H),5.08(s,2H),4.15(t,J=6.0 Hz,2H),3.82(s,3H),2.80(t,J=6.0 Hz,2H),2.52(t,J=5.4 Hz,4H),1.62(p,J=5.6 Hz,4H),1.46(dq,J=12.6,7.4,6.0 Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ161.61,159.97,159.70,158.33,151.63,129.53,128.79,128.11,125.02,123.13,122.87,120.95,114.12,112.85,112.11,111.33,102.30,70.26,66.47,57.77,55.35,55.14,25.95,24.18.m.p.113.4-116.7℃

[0075] Z27: 1HNMR(400 MHz,Chloroform-d)δ7.90(d,J=8.9 Hz,1H),7.86-7.80(m,2H),7.44-7.36(m,3H),6.93(dd,J=8.7,2.3 Hz,3H),6.87(d,J=2.5 Hz,1H),5.08(s,2H),4.12-3.97(m,2H),3.94(dd,J=9.9,3.6 Hz,1H),3.82(s,3H),3.75(dtd,J=8.3,5.1,4.2,2.3 Hz,1H),3.53(td,J=11.6,2.4 Hz,1H),1.93(dt,J=10.1,2.9 Hz,1H),1.73-1.54(m,4H),1.54-1.43(m,1H). 13 C NMR(101 MHz,Chloroform-d)δ161.63,160.01,159.70,158.33,151.57,129.53,128.78,128.12,125.02,123.12,122.89,120.97,114.12,112.93,112.11,111.43,102.34,75.76,71.87,70.25,68.64,55.35,28.12,25.84,23.06.m.p.172.5-175.9℃.

[0077] Z28: 1 HNMR(400 MHz,Chloroform-d)δ7.91(d,J=8.9 Hz,1H),7.87-7.82(m,2H),7.44-7.37(m,3H),6.97-6.85(m,4H),5.09(s,2H),4.80(t,J=5.2 Hz,1H),4.16-4.10(m,4H),3.85-3.76(m,5H),2.12(td,J=6.4,5.1 Hz,3H),1.38(dtt,J=13.5,2.6,1.3 Hz,1H). 13C NMR(101 MHz,Chloroform-d)δ161.64,160.05,159.70,158.32,151.66,129.54,128.83,128.12,125.04,123.13,122.88,120.96,114.13,112.66,112.11,111.30,102.36,99.32,70.26,66.97,63.83,55.35,34.91,25.80.m.p.151.2-153.9℃.

[0078] Z29: 1 HNMR(400 MHz,DMSO-d6)δ8.70(d,J=4.8 Hz,2H),8.37(t,J=8.3 Hz,2H),7.76(d,J=2.8 Hz,1H),7.63(dd,J=8.8,2.8 Hz,1H),7.45(d,J=8.2 Hz,2H),7.39(d,J=2.1Hz,1H),7.34(t,J=4.8 Hz,1H),7.28(dd,J=8.8,2.3 Hz,1H),6.99(d,J=8.2 Hz,2H),5.22(s,2H),3.78(s,3H). 13 C NMR(101 MHz,DMSO-d6)δ164.41,160.17,160.08,159.15,158.68,153.32,150.49,129.68,128.23,127.41,124.61,124.43,124.16,121.28,118.56,117.37,115.16,113.88,112.30,110.42,69.53,55.09.m.p.201.1-203.7℃.

[0079] Z30: 1 HNMR(400 MHz,DMSO-d6)δ8.25(t,J=9.0 Hz,2H),7.69(d,J=2.9 Hz,1H),7.55(dd,J=8.9,2.8 Hz,1H),7.46-7.40(m,2H),7.17(d,J=2.6 Hz,1H),7.10(dd,J=8.9,2.6Hz,1H),7.00-6.93(m,2H),5.30(s,2H),5.16(s,2H),3.77(s,3H). 13C NMR(101MHz,DMSO-d6)δ160.14,159.10,158.24,157.10,150.86,129.63,128.22,127.63,124.48,124.40,124.14,120.67,116.36,113.84,112.50,112.45,112.10,102.70,69.45,55.06,53.80.m.p.182.1-184.7℃.

[0080] Z31: 1 H NMR(400MHz,Chloroform-d)δ7.90(d,J=8.9Hz,1H),7.84(dd,J=5.8,3.1Hz,2H),7.40(dq,J=9.2,3.0Hz,3H),6.98-6.81(m,4H),5.09(s,2H),4.20(t,J=6.7Hz,2H),3.82(s,3H),2.92(t,J=6.7Hz,2H),2.24(s,3H). 13 C NMR(101MHz,Chloroform-d)δ161.51,159.71,159.57,158.40,151.63,129.52,128.67,128.10,125.02,123.26,122.90,121.01,114.13,112.70,112.16,111.60,102.29,70.27,67.81,55.35,32.93,16.32.m.p.140.0-141.1℃.

[0084] Z32: 1 H NMR(400MHz,Chloroform-d)δ7.89(d,J=8.9Hz,1H),7.83(dd,J=5.8,3.0Hz,2H),7.39(dd,J=8.8,3.4Hz,3H),6.93(dd,J=8.9,3.1Hz,3H),6.86(d,J=2.5Hz,1H),5.08(s,2H),4.20-4.13(m,2H),3.82(s,3H),3.81-3.77(m,2H),3.47(s,3H). 13C NMR(101MHz,Chloroform-d)δ161.58,159.86,159.70,158.35,151.57,129.52,128.72,128.11,125.01,123.17,122.89,120.98,114.12,112.87,112.12,111.50,102.24,70.81,70.25,67.71,59.33,55.35.m.p.124.6-125.7℃.

[0085] Z33: 1 HNMR(400MHz,DMSO-d6)δ8.24(d,J=9.0Hz,1H),8.21-8.14(m,1H),7.69(d,J=2.8Hz,1H),7.55(dd,J=8.9,2.8Hz,1H),7.47-7.39(m,2H),6.98(ddd,J=10.8,6.2,2.7Hz,4H),5.17(s,2H),4.91(s,2H),4.20(q,J=7.1Hz,2H),3.77(s,3H),1.24(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ168.38,160.30,159.10,158.61,158.03,150.91,129.63,128.25,127.94,124.45,124.14,123.97,120.42,113.84,112.50,112.04,111.42,

[0086] 102.22,69.43,64.87,60.77,55.06,14.02.m.p.133.8-136.2℃.

[0087] Z34: 1 H NMR(400MHz,Chloroform-d)δ7.89(d,J=8.9Hz,1H),7.83(dd,J=5.8,3.0Hz,2H),7.43-7.35(m,3H),6.96-6.88(m,3H),6.85(d,J=2.5Hz,1H),6.06(ddt,J=17.3,10.6,5.3Hz,1H),5.45(dq,J=17.2,1.6Hz,1H),5.34(dq,J=10.6,1.4Hz,1H),5.08(s,2H),4.58(dt,J=5.4,1.5Hz,2H),3.82(s,3H). 13C NMR(101MHz,Chloroform-d)δ161.58,159.70,159.63,158.35,151.59,132.54,129.53,128.73,128.11,125.01, 123.17,122.88,120.97,118.38,114.13,112.95,112.11,111.44,102.46,70.25,69.18,55.35.mp128.5-130.1℃.

[0091] Z35: 1 HNMR(400MHz,Chloroform-d)δ7.91(d,J=8.9Hz,1H),7.88-7.81(m,2H),7.45-7.35(m,3H) ,6.99-6.90(m,4H),5.08(s,2H),4.75(d,J=2.4Hz,2H),3.82(s,3H),2.58(t,J=2.4Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ161.47,159.71,158.51,158.45,

[0092] 151.46,129.55,128.53,128.06,125.04,123.26,122.97,121.10,114.13,112.9 3,112.15,112.12,102.88,77.78,76.34,70.27,56.17,55.35.mp149.5-151.2℃.

[0094] Example 4

[0095] Preparation of Compounds F1-F35:

[0096] A solution of substituted 3-hydroxy-8-((4-methoxybenzyl)oxy)-6H-benzo[c]chromene-6-one (Z1-Z35 compound) (0.5mmol) in 1,2-dichloroethane (10mL) was reacted with oxalyl chloride (0.25mmol, 0.03g) at room temperature for 3 hours. After the reaction, the solvent was evaporated under reduced pressure, and the remaining solid was dissolved in 10ml of ethyl acetate, washed with 20ml of water and separated. The organic layer was dried by spin drying and subjected to column chromatography (methanol: dichloromethane) to obtain solid products F1-F35. The product was recrystallized from methanol with a yield of 11%-55%.

[0097] F1: 1HNMR(400MHz,DMSO-d6)δ10.30(s,1H),8.14(d,J=8.8Hz,1H),8.07(d,J=9.5Hz,1H),7.54(d,J=2.7Hz,1H),7.34(dd,J=8.7,2.7Hz,1H),6.92(dq,J=5.0,2.5Hz,2H),3.99(t,J=6.5Hz,2H),1.76(h,J=7.1Hz,2H),1.00(t,J=7.4Hz,3H). 13 CNMR(101MHz,DMSO-d6)δ160.48,159.39,157.24,150.78,126.52,124.05,123.79,123.61,120.41,113.53,112.40,110.93,101.72,69.40,21.89,10.33.m.p.188.7-190.2℃.

[0098] F2: 1 HNMR(400MHz,DMSO-d6)δ10.30(s,1H),8.13(dd,J=24.6,8.8Hz,2H),7.54(d,J=2.7Hz,1H),7.34(dd,J=8.7,2.7Hz,1H),6.98-6.89(m,2H),4.74(hept,J=6.0Hz,1H),1.31(d,J=6.0Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ160.52,158.20,157.21,150.86,126.54,124.09,123.80,123.72,120.41,113.53,113.26,110.83,102.75,69.77,21.64.m.p.198.2-200.0℃.

[0099] F3: 1 H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.15(d,J=8.8Hz,1H),8.09(d,J=9.6Hz,1H),7.54(d,J=2.7Hz,1H),7.34(dd,J=8.7,2.7Hz,1H),6.93(d,J=7.5Hz,2H),4.04(t,J=6.5Hz,2H),1.78-1.66(m,2H),1.45(h,J=7.4Hz,2H),0.95(t,J=7.4Hz,3H). 13C NMR(101MHz,DMSO-d6)δ160.48,159.43,157.25,150.81,126.54,124.08,123.82,123.65,120.42,113.54,112.46,110.95,101.76,67.68,30.57,18.68,13.66.m.p.172.8-174.2℃.

[0100] F4: 1 HNMR(400MHz,DMSO-d6)δ10.31(s,1H),8.15(d,J=8.8Hz,1H),8.09(d,J=8.8Hz,1H),7.55(d,J=2.6Hz,1H),7.35(dd,J=8.7,2.7Hz,1H),6.99-6.90(m,2H),4.52(q,J=6.0Hz,1H),1.76-1.55(m,2H),1.27(d,J=6.0Hz,3H),0.95(t,J=7.4Hz,3H). 13 CNMR(101MHz,DMSO-d6)δ160.52,158.55,157.23,150.88,126.56,124.08,123.80,123.73,120.42,113.55,113.28,110.86,102.77,74.62,28.41,18.89,9.47.m.p.145.5-147.3℃.

[0101] F5: 1 HNMR(400MHz,DMSO-d6)δ10.31(s,1H),8.17(d,J=8.8Hz,1H),8.11(d,J=9.5Hz,1H),7.54(d,J=2.7Hz,1H),7.35(dd,J=8.7,2.7Hz,1H),6.96(dq,J=4.4,2.5Hz,2H),3.84(d,J=6.5Hz,2H),2.04(dq,J=12.8,6.4Hz,1H),1.00(d,J=6.7Hz,6H). 13 CNMR(101 MHz,DMSO-d6)δ160.50,159.50,157.24,150.80,126.54,124.10,123.85,123.68,120.42,113.53,112.50,110.97,101.82,74.11,27.59,19.06,18.97.m.p.167.9-169.1℃.

[0102] F6: 1 H NMR(400 MHz,DMSO-d6)δ10.29(s,1H),8.13(dd,J=24.2,9.2 Hz,2H),7.54(d,J=2.7 Hz,1H),7.34(dd,J=8.8,2.7 Hz,1H),6.99-6.89(m,2H),4.03(t,J=6.5 Hz,2H),1.73(dt,J=14.5,6.7 Hz,2H),1.45-1.30(m,4H),0.90(t,J=6.9 Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ160.49,159.44,157.25,150.81,126.55,124.10,123.85,123.67,120.43,113.54,112.49,110.96,101.77,67.97,28.21,27.64,21.87,13.89.m.p.177.8-179.6℃.F7: 1 H NMR(400 MHz,DMSO-d6)δ10.31(s,1H),8.18(d,J=8.8 Hz,1H),8.12(d,J=8.8Hz,1H),7.54(d,J=2.7 Hz,1H),7.35(dd,J=8.8,2.7 Hz,1H),7.01-6.92(m,2H),4.08(t,J=6.6 Hz,2H),1.80(dp,J=13.3,6.7 Hz,1H),1.64(q,J=6.7 Hz,2H),0.95(d,J=6.6 Hz,6H). 13 C NMR(101 MHz,DMSO-d6)δ160.47,159.39,157.24,150.79,126.53,124.05,123.79,123.60,120.41,113.53,112.46,110.94,101.74,66.43,37.23,24.53,22.37.m.p.177.1-179.6℃.

[0103] F8: 1H NMR(400 MHz,DMSO-d6)δ10.29(s,1H),8.14(d,J=8.8 Hz,1H),8.07(d,J=9.5Hz,1H),7.54(d,J=2.7 Hz,1H),7.34(dd,J=8.7,2.7 Hz,1H),6.93(dq,J=5.7,2.6Hz,2H),3.90(d,J=7.0 Hz,2H),2.32(hept,J=7.4 Hz,1H),1.84-1.72(m,2H),1.66-1.49(m,4H),1.34(tdd,J=12.0,10.8,9.1,4.0 Hz,2H). 13 C NMR(101 MHz,DMSO-d6)δ160.48,159.53,157.24,150.78,126.53,124.06,123.80,123.60,120.41,113.53,112.46,110.94,101.77,72.03,38.37,28.93,24.90.m.p.174.1-176.0℃.

[0104] F9: 1 H NMR(400 MHz,DMSO-d6)δ10.28(s,1H),8.15(d,J=8.8 Hz,1H),8.09(d,J=9.6Hz,1H),7.53(d,J=2.7 Hz,1H),7.34(dd,J=8.8,2.7 Hz,1H),6.93(dq,J=4.2,2.5Hz,2H),3.84(d,J=6.2 Hz,2H),1.81(d,J=12.6 Hz,2H),1.76-1.62(m,4H),1.23(h,J=12.2Hz,3H),1.11-0.98(m,2H). 13 C NMR(101 MHz,DMSO-d6)δ160.49,159.55,157.24,150.80,126.55,124.08,123.82,123.65,120.42,113.54,112.47,110.94,101.80,73.12,36.93,29.15,25.99,25.20.m.p.199.3-201.1℃.

[0105] F10: 1H NMR(400 MHz,DMSO-d6)δ10.31(s,1H),8.14(dd,J=14.2,8.8 Hz,2H),7.56(dd,J=8.7,2.3 Hz,2H),7.50-7.44(m,2H),7.44-7.40(m,1H),7.35(dd,J=8.7,2.7Hz,1H),7.09-7.01(m,2H),5.23(s,2H). 13 C NMR(101 MHz,DMSO-d6)δ160.42,158.72,157.37,150.72,139.15,133.15,130.41,127.90,127.43,126.39,126.30,124.08,123.92,123.78,120.55,113.58,112.73,111.49,102.38,68.68.m.p.217.1-218.7℃.

[0106] F11: 1 H NMR(400 MHz,DMSO-d6)δ10.31(s,1H),8.15(dd,J=15.8,8.8 Hz,2H),7.57-7.44(m,5H),7.34(dd,J=8.8,2.7 Hz,1H),7.06(d,J=2.5 Hz,1H),7.03(dd,J=8.7,2.6Hz,1H),5.21(s,2H). 13 C NMR(101 MHz,DMSO-d6)δ160.43,158.80,157.36,150.73,135.62,132.57,129.65,128.49,126.41,124.10,123.94,123.78,120.53,113.57,112.78,111.43,102.38,68.78.m.p.242.7-244.1℃.

[0107] F12: 1H NMR(400 MHz,DMSO-d6)δ10.33(s,1H),8.16(dd,J=15.1,8.8 Hz,2H),7.61(t,J=7.7 Hz,1H),7.55(d,J=2.7 Hz,1H),7.46(q,J=7.2 Hz,1H),7.35(dd,J=8.6,2.7 Hz,1H),7.28(q,J=8.5,7.2 Hz,2H),7.12(d,J=2.5 Hz,1H),7.05(dd,J=8.7,2.6 Hz,1H),5.24(s,2H). 13 C NMR(101 MHz,DMSO-d6)δ160.48(d,J=247.45 Hz),160.44,158.83,157.37,150.75,130.95,130.65,126.40,124.58,124.09,123.95,123.80,123.31,120.55,115.46,113.56,112.63,111.50,102.25,64.05.m.p.255.8-257.5℃.

[0108] F13: 1 H NMR(400 MHz,DMSO-d6)δ10.34(s,1H),8.12(dd,J=16.4,8.7 Hz,2H),7.56(d,J=2.7 Hz,1H),7.48(td,J=8.0,6.0 Hz,1H),7.38-7.32(m,3H),7.20(td,J=8.8,8.3,2.3Hz,1H),7.06-7.01(m,2H),5.23(s,2H). 13 C NMR(101 MHz,DMSO-d6)δ162.19,160.41,158.70,157.34,150.68,139.46,130.50,126.36,124.02,123.85,123.70,123.63,120.51,114.72,114.34,113.55,112.66,111.43,102.30,68.72.m.p.199.7-201.5℃.

[0109] F14: 1H NMR(400 MHz,DMSO-d6)δ10.31(s,1H),8.15(dd,J=16.7,8.8 Hz,2H),7.55(td,J=5.7,2.5 Hz,3H),7.34(dd,J=8.7,2.7 Hz,1H),7.30-7.19(m,2H),7.07(d,J=2.6Hz,1H),7.03(dd,J=8.8,2.6 Hz,1H),5.19(s,2H). 13 C NMR(101 MHz,DMSO-d6)δ161.84(d,J=245.43 Hz),160.45,158.90,157.35,150.74,132.78130.21,130.13,126.44,124.10,123.93,123.76,120.52,115.42,115.21,113.57,112.78,111.37,102.34,68.93.m.p.234.8-235.9℃.

[0110] F15: 1 H NMR(400 MHz,DMSO-d6)δ10.33(s,1H),8.14(dd,J=12.2,8.7 Hz,2H),7.54(d,J=2.7 Hz,1H),7.34(dd,J=8.7,2.7 Hz,1H),7.22(qd,J=6.5,2.9 Hz,3H),7.04(d,J=8.0Hz,2H),5.23(s,2H). 13 C NMR(101 MHz,DMSO-d6)δ163.64,161.19,160.40,158.48,157.37,150.70,141.25,126.34,124.05,123.94,123.81,120.56,113.55,112.69,111.62,110.63,110.38,103.29,102.41,68.17.m.p.221.1-222.8℃.

[0111] F16: 1HNMR(400 MHz,DMSO-d6)δ10.31(s,1H),8.16(dd,J=15.4,8.9 Hz,2H),7.55(d,J=2.7 Hz,1H),7.45(dd,J=7.2,1.4 Hz,1H),7.35(dd,J=8.7,2.7 Hz,1H),7.31-7.18(m,3H),7.12(d,J=2.5 Hz,1H),7.05(dd,J=8.8,2.6 Hz,1H),5.19(s,2H),2.35(s,3H). 13 CNMR(101 MHz,DMSO-d6)δ160.47,159.16,157.33,150.78,136.73,134.45,130.17,128.65,128.22,126.49,125.81,124.10,123.93,123.76,120.51,113.56,112.77,111.33,102.29,68.42,18.47.m.p.243.2-244.8℃.

[0112] F17: 1 H NMR(400 MHz,DMSO-d6)δ10.31(s,1H),8.16(d,J=8.8 Hz,1H),8.11(d,J=8.8 Hz,1H),7.54(d,J=2.7 Hz,1H),7.40-7.32(m,3H),7.21(d,J=7.6 Hz,2H),7.04(d,J=2.6 Hz,1H),7.01(dd,J=8.7,2.5 Hz,1H),5.15(s,2H),2.31(s,3H). 13 C NMR(101MHz,DMSO-d6)δ160.45,159.03,157.31,150.73,137.26,133.49,129.02,127.95,126.47,124.08,123.89,123.70,120.49,113.55,112.82,111.23,102.30,69.57,20.76.m.p.256.9-258.1℃.F18: 1HNMR(400 MHz,DMSO-d6)δ10.31(s,1H),8.13(dd,J=18.0,8.9 Hz,2H),7.54(d,J=2.7 Hz,1H),7.41(s,4H),7.34(dd,J=8.7,2.7 Hz,1H),7.05(d,J=2.5 Hz,1H),7.01(dd,J=8.7,2.6 Hz,1H),5.15(s,2H),1.28(s,9H). 13 C NMR(101 MHz,DMSO-d6)δ160.45,159.06,157.31,150.74,150.46,133.52,127.76,126.46,125.21,124.09,123.88,123.71,120.48,113.56,112.76,111.23,102.25,69.46,34.26,31.06.m.p.225.3-226.5℃.

[0113] F19: 1 HNMR(400 MHz,DMSO-d6)δ10.34(s,1H),8.17(dd,J=11.2,8.8 Hz,2H),7.79(d,J=8.2 Hz,2H),7.71(d,J=8.1 Hz,2H),7.54(d,J=2.7 Hz,1H),7.35(dd,J=8.7,2.7Hz,1H),7.09(d,J=2.5 Hz,1H),7.06(dd,J=8.7,2.6 Hz,1H),5.34(s,2H). 13 C NMR(101MHz,DMSO-d6)δ160.41,158.66,157.38,150.72,141.46,128.41,128.11,126.36,125.37,124.19,124.08,123.94,123.82,120.55,113.57,112.73,111.55,102.40,68.67,40.08,39.87,39.66,39.45,39.24,39.03,38.82.m.p.247.6-249.1℃.

[0114] F20: 1HNMR(400 MHz,DMSO-d6)δ10.32(s,1H),8.15(dd,J=17.8,8.7 Hz,2H),7.54(s,1H),7.45(d,J=7.6 Hz,2H),7.36(d,J=7.1 Hz,3H),7.04(d,J=15.5 Hz,2H),5.23(t,J=5.4 Hz,1H),5.19(s,2H),4.52(d,J=5.5 Hz,2H). 13 C NMR(101 MHz,DMSO-d6)δ160.46,159.02,157.32,150.73,142.40,134.82,127.72,126.52,124.10,123.93,123.74,120.50,113.56,112.85,111.26,102.34,69.57,62.61.m.p.231.8-233.6℃.

[0115] F21: 1 HNMR(400 MHz,DMSO-d6)δ10.30(s,1H),8.13(dd,J=23.6,8.6 Hz,2H),7.54(d,J=2.7 Hz,1H),7.34(dd,J=8.7,2.7 Hz,1H),6.96(d,J=8.4 Hz,2H),4.18(qd,J=6.8,3.6Hz,1H),4.10-3.95(m,2H),3.75(dq,J=43.3,7.3 Hz,2H),2.08-1.97(m,1H),1.87(qd,J=12.6,7.1 Hz,2H),1.69(dt,J=18.7,7.2 Hz,1H). 13 C NMR(101 MHz,DMSO-d6)δ160.47,159.29,157.29,150.76,126.49,124.08,123.86,123.68,120.46,113.55,112.50,111.13,101.89,76.32,70.54,67.47,27.56,25.17.m.p.173.5-174.6℃.

[0116] F22: 1H NMR(400 MHz,DMSO-d6)δ10.35(s,1H),8.17(dd,J=16.5,8.9 Hz,2H),7.55(d,J=2.7 Hz,1H),7.35(dd,J=8.7,2.7 Hz,1H),7.13(d,J=2.5 Hz,1H),7.05(dd,J=8.8,2.5Hz,1H),6.20(s,1H),5.22(s,2H),3.77(s,3H),2.13(s,3H). 13 C NMR(101 MHz,DMSO-d6)δ160.43,158.47,157.41,150.68,145.61,137.59,126.38,124.10,123.97,123.75,120.56,113.58,112.78,111.61,106.63,102.47,60.37,36.08,13.10.m.p.269.8-271.1℃.

[0117] F23: 1 H NMR(400 MHz,DMSO-d6)δ10.31(s,1H),8.17(d,J=8.8 Hz,1H),8.12(d,J=8.8 Hz,1H),7.54(d,J=2.6 Hz,1H),7.34(dd,J=8.7,2.7 Hz,1H),7.03-6.95(m,2H),5.24(t,J=3.9 Hz,1H),4.11(d,J=4.0 Hz,2H),4.03-3.84(m,4H). 13 C NMR(101 MHz,DMSO-d6)δ160.44,158.88,157.35,150.72,126.41,124.10,123.95,123.75,120.53,113.56,112.49,111.44,102.10,101.09,68.48,64.53.m.p.238.1-239.6℃.

[0118] F24: 1H NMR(400 MHz,DMSO-d6)δ10.30(s,1H),8.19-8.08(m,2H),7.54(d,J=2.7Hz,1H),7.34(dd,J=8.7,2.7 Hz,1H),6.95(d,J=7.5 Hz,2H),3.93-3.86(m,4H),3.37-3.29(m,2H),2.02(ddt,J=11.4,8.5,4.4 Hz,1H),1.69(ddd,J=12.6,4.1,1.9 Hz,2H),1.40-1.29(m,2H). 13 C NMR(101 MHz,DMSO-d6)δ160.48,159.41,157.27,150.80,126.53,124.10,123.87,123.70,120.45,113.55,112.50,111.06,101.88,72.43,66.57,34.29,29.12.m.p.192.7-194.2℃.

[0119] F25: 1 H NMR(400 MHz,DMSO-d6)δ10.33(s,1H),8.15(d,J=8.8 Hz,1H),8.09(d,J=8.9 Hz,1H),7.83(d,J=2.2 Hz,1H),7.54(d,J=2.7 Hz,1H),7.50(d,J=1.8 Hz,1H),7.34(dd,J=8.7,2.7 Hz,1H),6.97(d,J=2.5 Hz,1H),6.92(dd,J=8.8,2.6 Hz,1H),6.28(t,J=2.1 Hz,1H),4.55(t,J=5.1 Hz,2H),4.44(t,J=5.1 Hz,2H).13C NMR(101 MHz,DMSO-d6)δ160.44,158.71,157.35,150.72,138.91,130.61,126.39,124.08,123.91,123.74,120.51,113.55,112.49,111.41,105.24,102.01,66.99,50.47.m.p.217.6-219.4℃.

[0120] F26: 1H NMR(400 MHz,DMSO-d6)δ10.48(s,1H),8.18(dd,J=10.4,8.8 Hz,2H),7.57(d,J=2.7 Hz,1H),7.39(dd,J=8.7,2.7 Hz,1H),7.07(d,J=2.6 Hz,1H),7.03(dd,J=8.8,2.5Hz,1H),4.54(t,J=5.1 Hz,2H),3.51(q,J=7.8,4.7 Hz,4H),3.02(q,J=11.7,11.0 Hz,2H),1.91-1.76(m,4H),1.71(d,J=12.5 Hz,1H),1.46-1.33(m,1H). 13 C NMR(101MHz,DMSO-d6)δ160.40,158.10,157.57,150.69,126.23,124.17,123.97,123.86,120.55,113.64,112.58,111.82,102.35,62.76,54.42,52.55,22.28,21.17.m.p.279.2-280.8℃.

[0121] F27: 1 H NMR(400 MHz,DMSO-d6)δ10.31(s,1H),8.14(d,J=8.8 Hz,1H),8.11-8.04(m,1H),7.54(d,J=2.7 Hz,1H),7.34(dd,J=8.7,2.7 Hz,1H),6.95(q,J=3.3 Hz,2H),4.01-3.95(m,2H),3.94-3.88(m,1H),3.69-3.59(m,1H),3.42-3.34(m,1H),1.83(dd,J=9.0,3.9 Hz,1H),1.69-1.61(m,1H),1.49(dt,J=7.9,3.0 Hz,3H),1.34(qd,J=12.4,11.9,4.1Hz,1H). 13 C NMR(101 MHz,DMSO-d6)δ160.46,159.25,157.26,150.73,126.47,124.05,123.81,123.63,120.43,113.53,112.42,111.07,101.82,75.19,71.34,67.24,27.45,25.45,22.52.m.p.184.6-185.9℃.

[0122] F28:1 HNMR(400 MHz,DMSO-d6)δ10.31(s,1H),8.15(d,J=8.9 Hz,1H),8.12-8.07(m,1H),7.54(d,J=2.7 Hz,1H),7.34(dd,J=8.7,2.7 Hz,1H),6.97-6.92(m,2H),4.76(t,J=5.2 Hz,1H),4.10(t,J=6.5 Hz,2H),4.03(dd,J=10.5,5.0 Hz,2H),3.74(td,J=12.3,2.5Hz,2H),1.98(q,J=6.2 Hz,2H),1.94-1.84(m,1H),1.36(dq,J=12.3,2.0,1.5Hz,1H). 13 C NMR(101 MHz,DMSO-d6)δ160.46,159.12,157.28,150.77,126.47,124.07,123.85,123.69,120.47,113.54,112.35,111.14,101.87,98.63,66.06,63.67,34.43,25.34.m.p.221.9-223.5℃.

[0123] F29: 1 H NMR(400 MHz,DMSO-d6)δ10.46(s,1H),8.69(d,J=4.8 Hz,2H),8.29(dd,J=8.9,5.1 Hz,2H),7.59(d,J=2.6 Hz,1H),7.40(dd,J=8.7,2.7 Hz,1H),7.37(d,J=2.4Hz,1H),7.33(t,J=4.8 Hz,1H),7.25(dd,J=8.7,2.4 Hz,1H). 13 C NMR(101 MHz,DMSO-d6)δ164.45,160.15,158.10,152.91,150.20,125.75,124.62,124.07,123.76,121.38,118.48,117.31,115.47,113.75,110.42.m.p.278.6-280.2℃.

[0124] F30: 1H NMR(400 MHz,DMSO-d6)δ10.40(s,1H),8.21(dd,J=9.0,2.2 Hz,2H),7.56(d,J=2.7 Hz,1H),7.37(dd,J=8.7,2.7 Hz,1H),7.18(d,J=2.6 Hz,1H),7.10(dd,J=8.9,2.6Hz,1H),5.31(s,2H). 13 C NMR(101 MHz,DMSO-d6)δ160.26,157.67,156.74,150.59,126.00,124.19,124.12,124.07,120.83,116.40,113.63,112.85,112.39,102.71,53.79.m.p.250.0-252.5℃.

[0125] F31: 1 H NMR(400 MHz,DMSO-d6)δ10.31(s,1H),8.13(d,J=8.8 Hz,1H),8.07(d,J=8.7Hz,1H),7.53(d,J=2.7Hz,1H),7.33(dd,J=8.7,2.7Hz,1H),6.99-6.90(m,2H),4.22(t,J=6.6Hz,2H),2.87(t,J=6.5Hz,2H),2.18(s,3H). 13 C NMR(101MHz,DMSO-d6)δ160.44,158.90,157.29,150.74,126.43,124.05,123.84,123.68,120.46,113.54,112.44,111.21,101.91,67.37,32.01,15.19.m.p.172.6-174.6℃.

[0126] F32: 1 HNMR(400MHz,DMSO-d6)δ10.30(s,1H),8.10(dd,J=23.2,8.6Hz,2H),7.53(d,J=2.7Hz,1H),7.33(dd,J=8.7,2.7Hz,1H),6.94(d,J=8.2Hz,2H),4.20-4.13(m,2H),3.71-3.67(m,2H),3.32(s,3H). 13C NMR(101MHz,DMSO-d6)δ160.46,159.17,157.27,150.75,126.46,124.06,123.81,123.65,120.45,113.54,112.44,111.11,101.81,70.19,67.39,58.14.m.p.174.2-175.8℃.

[0127] F33: 1 HNMR(400MHz,DMSO-d6)δ10.34(s,1H),8.15(dd,J=17.2,9.2Hz,2H),7.54(d,J=2.7Hz,1H),7.35(dd,J=8.7,2.7Hz,1H),6.99(dq,J=5.1,2.6Hz,2H),4.91(s,2H),4.20(q,J=7.1Hz,2H),1.24(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ168.40,160.39,158.24,157.42,150.62,126.29,124.08,123.97,123.75,120.58,113.57,112.41,111.75,102.22,64.86,60.75,14.02.m.p.158.0-161.2℃.

[0128] F34: 1 HNMR(400MHz,DMSO-d6)δ10.31(s,1H),8.15(d,J=8.9Hz,1H),8.13-8.07(m,1H),7.54(d,J=2.7Hz,1H),7.34(dd,J=8.7,2.7Hz,1H),6.97(d,J=7.6Hz,2H),6.08(ddt,J=17.3,10.5,5.3Hz,1H),5.46(dq,J=17.3,1.7Hz,1H),5.31(dq,J=10.5,1.5Hz,1H),4.66(dt,J=5.3,1.6Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ160.44,158.83,157.29,150.72,133.24,126.45,124.06,123.85,123.67,120.47,117.88,113.55,112.59,111.20,102.11,68.60.m.p.203.2-204.7℃.

[0129] F35: 1 HNMR (400MHz, DMSO-d6) δ10.33(s,1H),8.14(dd,J=12.4,8.8Hz,2H),7.54(d,J=2.6Hz,1H),7.34(dd,J=8.7, 2.7Hz, 1H), 7.03 (d, J = 2.5Hz, 1H), 7.00 (dd, J = 8.7, 2.6Hz, 1H), 4.92 (d, J = 2.5Hz, 2H), 3.66 (t, J = 2.3Hz, 1H). 13 C NMR(101MHz,DMSO-d6)δ160.38,157.78,157.42,150.59,126.30,124.07,123.96,123 .72,120.60,113.58,112.66,111.76,102.47,78.79,78.70,55.88.mp231.1-233.2℃.

[0130] Table 1 8-(4-methoxybenzyl)oxy)-6H-benzo[c]chromen-6-one derivatives

[0131]

[0132]

[0133]

[0134]

[0135]

[0136] Table 2 8-Hydroxy-6H-benzo[c]chromene-6-one derivatives

[0137]

[0138]

[0139]

[0140]

[0141] Effect example

[0142] The PDE2 enzyme inhibitory activity of the F1-35 product obtained in Example 4 was studied

[0143] The recombinant plasmid pET15b-PDE2A was transformed into Escherichia coli for expression, and the PDE2 protein was obtained by culture and nickel column affinity chromatography purification. The AlphaScreen kit was used to measure the inhibitory effect of the compound on PDE2. When PDE2 was present, it would hydrolyze Biotinylated cAMP, making it difficult for the acceptor microbeads and donor microbeads to be brought close, resulting in a decrease in the signal value. If a PDE2 inhibitor was present in the system, it would inhibit PDE2 so that Biotinylated cAMP could not be hydrolyzed, and ultimately manifested as an increase in the signal value level.

[0144] Take 2μL of compound dilution and 4μL of PDE2 protein dilution, react at constant temperature (25℃) for 0.5h, then add 4μL of Biotinylated cAMP and centrifuge (1000r / min) for 1min, react at constant temperature (25℃) for 1h again, then add 15μL of Acceptor and Donor Bead suspension, centrifuge (1000r / min) for 1min, react at constant temperature (25℃) for 1h under light-proof conditions, and finally read the value with a multifunctional microplate reader. The experiment needs to configure positive control (no compound and PDE2 protein) and negative control (no compound), and the unadded part is supplemented with an equal amount of 1×Reaction buffer. The experiment is carried out in a 384-well plate, and 3 parallel wells are set for each group.

[0145] The IC values ​​of the synthesized compounds were further determined. 50 The potential compound was diluted with 1× Reaction buffer to 7 final concentrations of 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, and 1.5625 μM. The specific experimental steps refer to the IC value of BAY60-7550 mentioned above. 50 Determination method.

[0146] Table 3 IC of 8-hydroxy-6H-benzo[c]chromene-6-one derivatives 50 value

[0147]

[0148]

[0149]

[0150] The present invention provides 35 8-hydroxy-6H-benzo[c]chromene-6-one derivatives, all of which have good PDE2 inhibitory activity and have the potential to treat central nervous system diseases, such as memory deficiency, cognitive impairment, anxiety and depression, etc., and can be used as active ingredients to prepare drugs for inhibiting PDE2 activity. Among them, the IC values ​​of F1, F2, F4, F5, F6, F7, F8, F9, F10, F11, F12, F13, F15, F16, F17, F18, F19, F20, F21, F22, F25, F27, F28, F29, F30, F32, F33, F34, and F35 are 50 Less than 50 μM, among which F1, F2, F5, F7, F8, F9, F10, F11, F13, F16, F17, F18, F20, F201, F22, F25, F27, F28, F29, F32, F33, and F35 have better activity IC 50 Less than urolithin A (IC 50 =14.16μM), IC of F16 and F17 50 They are 0.63μM and 0.85μM respectively.

[0151] (1) When introducing alkanes by etherifying the 3-hydroxyl group of urolithin A, it was found that the increase in chain length was not conducive to the inhibitory activity of the compound against PDE2. The activity of branched alkanes was significantly higher than that of straight-chain alkanes. When the substituent was isopropyl, the IC 50 The IC of F5 is 3.16 μM when the substituent is isobutyl. 50 The IC of F4 is 1.61 μM when the substituent is sec-butyl. 50 The IC value of compound F8 is 14.81 μM, which shows that the position of the alkane branch chain also has a great influence on its activity, and the compounds with terminal branches have better activity. When the cycloalkane is introduced, the substituent is methylcyclopentane. 50 is 4.60 μM, while the IC of compound F9 with methylcyclohexane as the substituent is 50 It is 6.68μM.

[0152] (2) When the benzyl series was introduced by etherification of the 3-hydroxyl group of urolithin A, it was found that the activity of the compound was affected by both the type and position of the substituent when the benzyl group was substituted. When the substituent position was para, the activity was as follows: para-methylbenzyl (F17) IC 50 =0.85μM, p-methylbenzyl alcohol (F20) IC 50 =1.09μM, p-tert-butylbenzyl (F18) IC 50 =1.51μM, p-Cl benzyl (F11) IC 50 =8.55μM, p-Trifluoromethylbenzyl bromide (F19) IC 50=48.69μM, IC for F-benzyl (F14) 50 >50μM. 2-F benzyl (F12) IC 50 =22.85μM, 3-F benzyl (F13) IC 50 =5.73μM, the activity of the meta-position substitution was 4 times higher than that of the ortho-position substitution. IC of F15 compound substituted with 3,5-difluorobenzyl 50 The activity was 26.91 μM, which was lower than that of the ortho- and meta-monosubstituted compounds but better than that of the para-monosubstituted compounds.

[0153] (3) When a heterocyclic ring containing an oxygen atom was introduced by etherifying the 3-hydroxyl group of urolithin A, when the substituent was 2-(methyl)tetrahydro-2H-pyran, compound F27 had the best inhibitory activity against PDE2, IC 50 The IC value is 1.51 μM. When the 3-hydroxyl group of urolithin A is etherified to introduce a nitrogen-containing heterocyclic ring, the compound has PDE2 inhibitory activity. When the substituent is methyl-1,3-dimethylpyrazole (F22), ethylpyrazole (F25), or 2-pyrimidine (F29), the IC value is 1.51 μM. 50 They are 8.82μM, 7.20μM and 9.59μM respectively.

[0154] (4) When an unsaturated or heteroatom-containing alkane is introduced by etherifying the 3-hydroxyl group of urolithin A, and the etherified group is 2-ethylmethyl sulfide, the IC of compound F31 for PDE2 is 50 greater than 50 μM, but when the sulfur atom was replaced by an oxygen atom, the IC of compound F32 50 The IC value of the compound with 3-propyne (F35) as the substituent is 1.57 μM. 50 The inhibitory activity against PDE2 was 3.84 μM, which was superior to that of 3-propylene-substituted compounds (F34, IC 50 =23.49 μM). Acetonitrile substitution is not conducive to the PDE2 inhibitory activity of urolithin A. The IC 50 The inhibitory activity of urolithin A was 21.21 μM, which was lower than that of urolithin A. The ethyl acetate urolithin A derivative (F33) had a slight promoting effect on the PDE2 inhibitory activity, and its IC 50 It is 12.81μM.

[0155] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A class of 8-hydroxy urolithin A derivatives, characterized in that: The general formula of the 8-hydroxy urolithin A derivative is as shown in Compound I: R is an alkyl group, an alkene group, a substituted alkyl group, an alkoxy group, an alkylthio group, an ester group, a cyano group, or a cyanoalkyl group; the substituent on the substituted alkyl group is a cycloalkyl group or a substituted cycloalkyl group, a heterocyclic group or a substituted heterocyclic group, an aromatic group or a substituted aromatic group.

2. The method for preparing the 8-hydroxy urolithin A derivative according to claim 1, characterized in that: (1) adding 4-methoxybenzyl chloride dropwise to a DMF solution of 2-bromo-5-hydroxybenzoic acid and anhydrous potassium carbonate and heating for reaction, collecting the product 2-bromo-5-(benzylmethoxy)-phenylmethyl ester benzoic acid after the reaction is completed, adding the product to a mixed solution of tetrahydrofuran and methanol, and dropping a lithium hydroxide aqueous solution into the solution, reacting at room temperature to obtain the product 2-bromo-5-(benzylmethoxy)-benzoic acid; (2) 2-bromo-5-(benzylmethoxy)-benzoic acid, resorcinol and sodium hydroxide are refluxed in water for a period of time, and a CuSO4 aqueous solution is added dropwise, and the reflux reaction is continued. After the reaction is completed, the reaction is cooled, the precipitate is filtered out, washed, dried, and recrystallized to obtain white crystals; (3) The white crystalline product obtained in step (2) is dissolved in DMF, anhydrous K2CO3 is added, and the halogenated compound is added dropwise after stirring. The reaction is carried out at 70°C for 3-24 hours. After the reaction is completed, the mixture is poured into ice water, filtered, and recrystallized to obtain an etherified product. (4) reacting the etherified product obtained in step (3) with oxalyl chloride, separating and purifying after the reaction to obtain an 8-hydroxy urolithin A derivative.

3. The method for preparing the 8-hydroxy urolithin A derivative according to claim 2, characterized in that: In step (1), the molar ratio of 2-bromo-5-hydroxybenzoic acid to p-methoxybenzyl chloride, potassium carbonate and lithium hydroxide is 1:2.0-2.5:2.2-4.0:2.0-3.

0.

4. The method for preparing the 8-hydroxyurolithin A derivative according to claim 2, characterized in that: In step (2), the molar ratio of 2-bromo-5-(benzylmethoxy)-benzoic acid to resorcinol and sodium hydroxide is 1:1.0-3.0:3.0-7.

1.

5. The method for preparing the 8-hydroxyurolithin A derivative according to claim 2, characterized in that: In step (3), the molar ratio of the white crystalline product to the halide and potassium carbonate is 1:2.0-2.4:2.0-2.4; the halide has a structural formula of RX, wherein X is Cl, Br or I, and R is an alkyl group, an olefin group, a substituted alkyl group, an alkoxy group, an alkylthio group, an ester group, a cyano group, or a cyanoalkyl group; and the substituent on the substituted alkyl group is a cycloalkyl group or a substituted cycloalkyl group, a heterocyclic group or a substituted heterocyclic group, an aromatic group or a substituted aromatic group.

6. The method for preparing the 8-hydroxy urolithin A derivative according to claim 2, characterized in that: In step 4, the molar ratio of the etherification product to oxalyl chloride is 1:0.5-1.

5.

7. Use of the 8-hydroxyurolithin A derivative according to claim 1 in the preparation of PDE2 inhibitor drugs.

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