3, 8-dyhydroxyl-6H-benzo [c] chromene-6-ketone 8-hydroxyl etherified derivative of phosphodiesterase 2 inhibitor and application of 3, 8-dyhydroxyl-6H-benzo [c] chromene-6-ketone 8-hydroxyl etherified derivative

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a 3, 8-dyhydroxyl-6H-benzo [c] chromene-6-ketone 8-site hydroxyl etherified derivative of a phosphodiesterase 2 inhibitor and application of the 3, 8-dyhydroxyl-6H-benzo [c] chromene-6-ketone 8-site hydroxyl etherified derivative. The 3, 8-dyhydroxyl-6H-benzo [c] chromene-6-ketone 8-position hydroxyl etherified derivative is shown in the specification. According to the invention, 2-bromo-5-hydroxy-benzoic acid is used as a raw material, and etherification, hydrolysis and cyclization are carried out to obtain a final product. The purposes of reducing the reaction time, improving the product purity and improving the reaction yield are achieved by improving the reaction temperature, adjusting the catalyst concentration and optimizing the purification method. Meanwhile, the compound obtained by the invention has good PDE2 inhibitory activity. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to an 8-hydroxyl etherified derivative of 3,8-dihydroxy-6H-benzo[c]chromene-6-one as an inhibitor of phosphodiesterase 2 (PDE2), and a preparation method and application thereof. Background Art

[0002] There are various receptors distributed on the cell surface. After receiving external signal stimulation, the nervous system transmits the information to the corresponding effector after a series of information integration and enhancement, producing specific physiological or pathological effects. In this process, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play an irreplaceable role as second messengers. The action mode of the second messenger is divided into direct action and indirect action, among which indirect action is the main action mode of the second messenger. The concentration levels of cAMP and cGMP are jointly regulated by the generation of nucleotide cyclase and the hydrolysis of phosphodiesterase, maintaining a dynamic balance in the cell microdomain. Phosphodiesterase (PDEs) catalyzes the hydrolysis and ring opening of cAMP and cGMP, which is the only way to degrade cAMP and cGMP in cells.

[0003] The PDEs family has 11 subtypes (PDE1-11), and most subtypes have more than one gene product. The main difference between the subtypes is the degree of affinity with two different cyclic nucleotides. For example, PDE5, 6, and 9 are cGMP-specific enzymes, PDE4, 7, and 8 are cAMP-specific enzymes, and PDE1, 2, 3, 10, and 11 are dual-substrate PDEs enzymes that can act on cAMP and cGMP at the same time. PDEs regulate the cAMP (cG MP) / protein kinase B (PKA) [protein kinase G (PKG)] / cAMP response element binding protein (cAMP-responsive element binding protein, CREB) cell signaling pathway, thereby affecting the CREB phosphorylation process and its downstream gene expression levels, and producing various biological effects, including anti-inflammation, anti-depression, memory enhancement, and improvement of cognitive function.

[0004] PDE2 hydrolyzes intracellular cAMP or cGMP, and then terminates the corresponding physiological effects. Overexpression of PDE2 will cause the levels of cAMP and cGMP to be lower than the minimum catalytic activity threshold, resulting in neurological pathological phenomena such as memory loss and depression. Inhibiting overexpressed PDE2 and increasing the level of cyclic nucleotides are effective targets for treating central nervous system diseases. PDE2 inhibitors (PDE2 inhibitors) inhibit the activity of PDE, causing local enrichment of cAMP and cGMP to exert physiological effects. So far, there are no PDE2 inhibitor drugs on the market. The present invention provides a novel structure of 3,8-dihydroxy-6H-benzo[c]chromene-6-one PDE2 inhibitors and a preparation method thereof. Summary of the invention

[0005] The present invention provides a novel structure of 3,8-dihydroxy-6H-benzo[c]chromene-6-one PDE2 inhibitor. At the same time, the present invention also provides a preparation method of the compound, which is scientific, reasonable, simple and easy to operate.

[0006] In order to achieve the purpose of the present invention, the technical solution adopted by the present invention is as follows:

[0007] The 3,8-dihydroxy-6H-benzo[c]chromene-6-one compounds used as PDE2 inhibitors of the present invention have the general formula (I):

[0008]

[0009] Wherein, R is one of C2-C5 alkyl, C3-C5 olefin, C2-C6 alkoxy, C2-C6 alkylthio, cycloalkyl-substituted C2-C3 alkyl, heterocyclic-substituted C2-C3 alkyl, aromatic or substituted aromatic-substituted C2 alkyl; wherein "cycloalkyl-substituted C2 alkyl" means that R is C2 alkyl, but the terminal C of C2 alkyl is replaced by cycloalkyl; "heterocyclic-substituted C2 alkyl" means that R is C2 alkyl, but the terminal C of C2 alkyl is replaced by heterocyclic; "aromatic or substituted aromatic-substituted C2 alkyl" means that R is C2 alkyl, but the terminal C of C2 alkyl is replaced by aromatic or substituted heterocyclic.

[0010] Furthermore, the heterocyclic group is a substituted or unsubstituted five-membered or six-membered heterocyclic group, and the heterocyclic group contains 1 to 2 heteroatoms selected from N, O or S.

[0011] Furthermore, the aromatic group is selected from at least one of phenyl, naphthyl, phenanthrenyl, anthracenyl, acenaphthenyl, acenaphthenyl, fluorenyl, pyrene and fluoranthenyl; and the substituents on the substituted aromatic group are independently selected from one of fluorine, chlorine, bromine, cyano, alkyl, haloalkyl, alkoxy and alkylthio.

[0012] The preparation method of 3,8-dihydroxy-6H-benzo[c]chromene-6-one derivatives as PDE2 inhibitors of the present invention comprises the following steps:

[0013]

[0014] The preferred steps are as follows:

[0015] (1) Etherification: 2-bromo-5-hydroxy-benzoic acid was dissolved in DMF, anhydrous K2CO3 was added, stirred evenly, and the halogenated compound was added dropwise, and the reaction was carried out at 80°C for 3-24 hours. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was poured into a saturated NH4Cl solution, extracted with ethyl acetate three times, and the organic layer was taken, dried over anhydrous Na2SO4, and then rotary evaporated to obtain a white solid.

[0016] (2) Hydrolysis: The product obtained in step (1) was added to a mixed solution of THF and MeOH, and a 5% sodium hydroxide solution was added, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure, and the mixture was washed twice with ethyl acetate. The aqueous phase was acidified with 1M hydrochloric acid, and the residue was filtered and dried to obtain the hydroxy etherification product of 2-bromo-5-hydroxy-benzoic acid.

[0017] (3) Cyclization: The product obtained in step (2), resorcinol and NaOH were refluxed in water for 1 hour, 5% CuSO4 aqueous solution was added dropwise, and reflux was continued for 30 minutes. After the reaction was completed, the mixture was cooled and the precipitate was filtered out. The precipitate was washed with 1M hydrochloric acid and dried. Recrystallization from methanol gave white crystals.

[0018] In the step (1), the molar ratio of the raw materials 2-bromo-5-hydroxy-benzoic acid to anhydrous potassium carbonate and halide is 1:1.05:1.05.

[0019] In the step (2), the volume ratio of the solvent THF to MeOH to 5% sodium hydroxide solution is 10:5:30.

[0020] In the step (3), the molar ratio of the product obtained in the step (2) to resorcinol and NaOH is 1:3:3.3.

[0021] In the step (3), the molar ratio of the product obtained in the step (2) to the copper sulfate in the 5% CuSO4 aqueous solution of the catalyst is 5:3.

[0022] The reagents and raw materials used in the synthesis steps of the present invention are available on the market.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention provides novel PDE2 inhibitor compounds, mainly including 34 compounds of 3,8-dihydroxy-6H-benzo[c]chromene-6-one 8-hydroxy ether derivatives, all of which have good PDE2 inhibitory activity. These compounds have the potential to treat central nervous system diseases, such as memory deficiency, cognitive impairment, anxiety and depression, and can be used as active ingredients to prepare drugs for inhibiting PDE2 activity.

[0025] In addition, for the compound structure provided, a corresponding synthesis method is given, the synthesis method is simple and has a high yield. Among them, in the cyclization step, when the reaction temperature is increased and stabilized at 100°C, the reaction time is effectively shortened to 1h. In terms of catalytic conditions, copper sulfate plays a catalytic role in the system. When a large amount of copper sulfate solution is added, copper ions are freed and attached to the surface of the product, making the derivative properties reddish, while affecting the purity and physicochemical properties. The copper sulfate solution is adjusted to react, which are 30%, 20%, 10%, and 5%, respectively. It is found that 5% has the best reaction properties and the highest purity. In the post-processing method, when column chromatography is used, the processing time is long and the yield is low. Therefore, the present invention adopts a recrystallization method, tries various different recrystallization solvents, and finally determines that continuous recrystallization of solvent methanol can effectively reduce losses. Continuous recrystallization changes the reaction solution from a yellow suspension to a green, clear and transparent one, with pure white solid precipitation, and the final yield is increased by 20-40% compared with column chromatography. DETAILED DESCRIPTION

[0026] The technical scheme of the present invention will be described in detail below with reference to the examples. The following examples are used to illustrate but not to limit the synthesis method of the compound of formula I. In the embodiment, the 3,8-dihydroxy-6H-benzo[c]chromene-6-one compound includes the following compounds:

[0027]

[0028] Example 1

[0029] 2-Bromo-5-hydroxybenzoic acid (5mmol 1.08g) and anhydrous potassium carbonate (6.5mmol 0.90g) were added to the solvent DMF (15mL) and halogenated 2-bromobutane (13mmol 1.77g) was added dropwise, heated to 80°C, and reacted for 8h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1: 1). After the reaction was completed, it was poured into a saturated NH4Cl solution, extracted three times with ethyl acetate (15mL), and the organic layer was taken. After drying with anhydrous Na2SO4, it was rotary evaporated to obtain 1.49g (yield 91%) of 2-bromo-5-(sec-butoxy)benzoate sec-butyl ester as a white solid.

[0030] Example 2

[0031] At 0°C, the product of Example 1 was added to a mixed solution of THF (10 mL) and MeOH (5 mL), and a 5% sodium hydroxide (30 mL) solution was added, and the reaction was carried out at room temperature for 4 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1: 1). After the reaction was completed, the organic solvent was evaporated under reduced pressure, washed twice with ethyl acetate (10 mL), the aqueous phase was acidified with 1M hydrochloric acid (20 mL), filtered and dried to obtain 0.87 g (yield 70%) of 2-bromo-5-(sec-butoxy)benzoic acid as a white solid.

[0032] Example 3

[0033] The product of Example 2 (2mmol 0.54g), resorcinol (6mmol 0.66g) and NaOH (6.6mmol 0.26g) were refluxed in water for 1h, 2mL of 5% CuSO4 (0.6mmol 0.10g) aqueous solution was added dropwise, and reflux was continued for 30min. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, the mixture was cooled and the precipitate was filtered out. The precipitate was washed with 1M hydrochloric acid (20mL) and dried. The solid product 8-(sec-butoxy)-3-hydroxy-6H-benzo[c]chromene-6-one (1f) 0.47g (yield 82%) was obtained by recrystallization from methanol, with a comprehensive yield of 53%.

[0034] 1f: white solid (53% yield), mp 497.2-517.3°C. 1 HNMR (400MHz, DMSO-d6) δ10.23(s,1H),8.16(d,J=8.9Hz,1H),8.05(d,J=8.8Hz,1H),7.56(d,J=2.8Hz,1H),7.45(dd,J=8.8,2.8Hz,1H) ,6.82(dd,J=8.7,2.4Hz,1H),6.75(d,J=2.4Hz,1H),4.57-4.50(m,1H),1.74-1.57(m,2H),1.28(d,J=6.0Hz,3H),0.95(t,J=7.4Hz,3H). 13 CNMR(101MHz,DMSO-d6)δ160.50,158.86,156.96,151.10,128.16,124.95,124. 05,123.64,120.06,113.04,112.72,109.50,102.80,74.77,28.39,18.76,9.45.

[0035] Example 4

[0036] 2-Bromo-5-hydroxybenzoic acid (5mmol 1.08g) and anhydrous potassium carbonate (6.5mmol 0.90g) were added to the solvent DMF (15mL) and halogenated 2-(bromomethyl)tetrahydrofuran (13mmol 2.13g) was added dropwise, heated to 80°C, and reacted for 8h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction was completed, it was poured into a saturated NH4Cl solution, extracted three times with 15mL of ethyl acetate, and the organic layer was taken. After drying over anhydrous Na2SO4, rotary evaporation was performed to obtain 1.77g (yield 92%) of white solid (tetrahydrofuran-2-yl)methyl 2-bromo-5-((tetrahydrofuran-2-yl)methoxy)benzoate.

[0037] Example 5

[0038] At 0°C, the product of Example 4 was added to a mixed solution of THF (10 mL) and MeOH (5 mL), and a 5% sodium hydroxide (30 mL) solution was added, and the reaction was carried out at room temperature for 4 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1: 1). After the reaction was completed, the organic solvent was evaporated under reduced pressure, washed twice with ethyl acetate (10 mL), the aqueous phase was acidified with 1M hydrochloric acid (20 mL), filtered and dried to obtain 0.91 g (yield 66%) of 2-bromo-5-(tetrahydrofuran-2-yl)methoxy)benzoic acid as a white solid.

[0039] Example 6

[0040] The product of Example 5 (2mmol 0.54g), resorcinol (6mmol 0.66g) and NaOH (6.6mmol 0.26g) were refluxed in water for 1h, 2mL of 5% CuSO4 (0.6mmol 0.10g) aqueous solution was added dropwise, and reflux was continued for 30min. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, the mixture was cooled and the precipitate was filtered out. The precipitate was washed with 1M hydrochloric acid (20mL) and dried. The solid product 3-hydroxy-8-((tetrahydrofuran-2-yl)methoxy)-6H-benzo[c]chromene-6-one (1q) 0.52g (yield 84%) was obtained by recrystallization from methanol, with a comprehensive yield of 51%.

[0041] 1q: white solid (51% yield), mp 512.4-527.4°C. 1HNMR (400MHz, DMSO-d6) δ10.24(s,1H),8.17(d,J=9.0Hz,1H),8.06(d,J=8.8Hz,1H),7.58 (d,J=2.8Hz,1H),7.47(dd,J=8.9,2.8Hz,1H),6.83(dd,J=8.7,2.4Hz,1H),6.74(d,J=2.4H z,1H),4.23-4.17(m,1H),4.10(dd,J=10.2,3.7Hz,1H),4.03(dd,J=10.1,6.5Hz,1H),3.83 -3.78(m,1H),3.73-3.67(m,1H),2.09-1.96(m,1H),1.96-1.79(m,2H),1.76-1.68(m,1H). 13 C NMR(101MHz,DMSO-d6)δ160.46,158.91,157.76,151.13,128.49,124.19,124.11,1 23.52,119.94,113.05,111.45,109.46,102.79,76.30,70.48,67.48,27.52,25.19.

[0042] Example 7

[0043] 2-Bromo-5-hydroxybenzoic acid (5mmol 1.08g) and anhydrous potassium carbonate (6.5mmol 0.90g) were added to the solvent DMF (15mL) and the halogenated compound 1-(bromomethyl)-3,5-dimethoxybenzene (13mmol 2.99g) was added dropwise, heated to 80°C, and reacted for 8h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction was completed, it was poured into a saturated NH4Cl solution, extracted three times with ethyl acetate (15mL), and the organic layer was taken, dried over anhydrous Na2SO4, and then rotary evaporated to obtain 2.27g (yield 88%) of white solid 3,5-dimethoxybenzyl 2-bromo-5-((3,5-dimethoxybenzyl)oxy)benzoate.

[0044] Example 8

[0045] At 0°C, the product of Example 7 was added to a mixed solution of THF (10 mL) and MeOH (5 mL), and a 5% sodium hydroxide (30 mL) solution was added, and the mixture was reacted at room temperature for 4 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1: 1). After the reaction was completed, the organic solvent was evaporated under reduced pressure, washed twice with ethyl acetate (10 mL), the aqueous phase was acidified with 1M hydrochloric acid (20 mL), filtered and dried to obtain 0.87 g (yield 54%) of 2-bromo-5-((3,5-dimethoxybenzyl)oxy)benzoic acid as a white solid.

[0046] Example 9

[0047] The product of Example 8 (2mmol 0.54g), resorcinol (6mmol 0.66g) and NaOH (6.6mmol 0.26g) were refluxed in water for 1h, 2mL of 5% CuSO4 (0.6mmol 0.10g) aqueous solution was added dropwise, and reflux was continued for 30min. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, the mixture was cooled and the precipitate was filtered out. The precipitate was washed with 1M hydrochloric acid (20mL) and dried. The solid product 8-((3,5-dimethoxybenzyl)oxy)-3-hydroxy-6H-benzo[c]chromene-6-one (2d) 0.62g (yield 82%) was obtained by recrystallization from methanol, with a comprehensive yield of 39%.

[0048] 2d: white solid (39% yield), mp 535.4-551.7°C. 1 HNMR (400MHz, DMSO-d6) δ10.24(s,1H),8.19(d,J=8.9Hz,1H),8.07(d,J=8.7Hz,1H),7.67(d,J=2.8Hz,1H),7.55(dd,J=8.9,2.8H z,1H),6.83(dd,J=8.8,2.4Hz,1H),6.75(d,J=2.3Hz,1H),6.66(d,J=2.3Hz,2H),6.47(d,J=2.4Hz,1H),5.19(s,2H),3.76(s,6H). 13 C NMR(101MHz,DMSO-d6)δ160.53,160.46,158.95,157.41,151.17,138.82,128.67,124.41 ,124.15,123.58,119.96,113.06,112.03,109.45,105.41,102.80,99.47,69.41,55.15.

[0049] Example 10

[0050] 2-Bromo-5-hydroxybenzoic acid (5mmol 1.08g) and anhydrous potassium carbonate (6.5mmol 0.90g) were added to the solvent DMF (15mL) and the halogenated compound 1-(bromomethyl)-4-methylbenzene (13mmol 2.39g) was added dropwise, heated to 80°C, and reacted for 8h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1: 1). After the reaction was completed, it was poured into a saturated NH4Cl solution, extracted three times with ethyl acetate (15mL), and the organic layer was taken. After drying with anhydrous Na2SO4, it was rotary evaporated to obtain a white solid (4-methylbenzyl 2-bromo-5-((4-methylbenzyl)oxy)benzoate 1.99g (yield 94%).

[0051] Embodiment 11

[0052] At 0°C, the product of Example 10 was added to a mixed solution of THF (10 mL) and MeOH (5 mL), and a 5% sodium hydroxide (30 mL) solution was added, and the reaction was carried out at room temperature for 4 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1: 1). After the reaction was completed, the organic solvent was evaporated under reduced pressure, washed twice with ethyl acetate (10 mL), the aqueous phase was acidified with 1M hydrochloric acid (20 mL), filtered and dried to obtain 1.16 g of 2-bromo-5-((4-methylbenzyl)oxy)benzoic acid as a white solid (yield 77%).

[0053] Example 12

[0054] The product of Example 11 (2mmol 0.54g), resorcinol (6mmol 0.66g) and NaOH (6.6mmol 0.26g) were refluxed in water for 1h, and 2mL of 5% CuSO4 (0.6mmol 0.10g) aqueous solution was added dropwise, and refluxed for 30min. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, the mixture was cooled and the precipitate was filtered out. The precipitate was washed with 1M hydrochloric acid (20mL) and dried. The solid product 3-hydroxy-8-((4-methylbenzyl)oxy)-6H-benzo[c]chromene-6-one (2j) 0.56g (yield 84%) was obtained by recrystallization from methanol, with a comprehensive yield of 61%.

[0055] 2j: white solid (61% yield), mp 521.4-535.7°C. 1H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.18(d,J=9.0Hz,1H),8.06(d,J=8.8Hz,1H),7.66(d,J=2.8Hz,1H),7.53(dd,J=8.9,2.8 Hz,1H),7.41-7.35(m,2H),7.22(d,J=7.8Hz,2H),6.83(dd,J=8.7,2.4Hz,1H),6.74(d,J=2.4Hz,1H),5.19(s,2H),2.31(s,3H).

[0056] Embodiment 13

[0057] Compared with Examples 1-3, Example 13 differs in that the halide in Example 1 is replaced by ethyl bromide, and other operations are the same as those in Examples 1-3, to obtain a solid product 1a with a yield of 58%.

[0058] 1a: white solid (58% yield), mp 397.4-438.6°C. 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),8.05(d,J=8.9Hz,1H),7.98(d,J=8.7Hz,1H),7.46(d,J=2.8Hz,1H),7.36(dd, J=8.8,2.8Hz,1H),6.81(dd,J=8.7,2.4Hz,1H),6.71(d,J=2.4Hz,1H),4.07(q,J=6.9Hz,2H),1.36(t,J=6.9Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ160.50,158.85,157.69,151.08,128.31,124.14,124.05,123.48,119.92,113.04,111.18,109.47,102.78,63.57,14.46.

[0059] Embodiment 14

[0060] Compared with Example 1-3, Example 14 differs in that the halide in Example 1 is replaced by 1-bromopropane, and other operations are the same as those in Example 1-3, to obtain a solid product 1b with a yield of 47%.

[0061] 1b: white solid (47% yield), mp 467.4-498.6°C. 1H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.14(d,J=9.0Hz,1H),8.04(d,J=8.9Hz,1H),7.53(d,J=2.8Hz,1H),7.44(dd,J=8.8,2. 8Hz,1H),6.83(dd,J=8.7,2.5Hz,1H),6.74(d,J=2.4Hz,1H),4.02(d,J=13.1Hz,2H),1.82-1.73(m,2H),1.01(t,J=7.4Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ160.49,158.85,157.82,151.07,128.29,124.12,12 4.04,123.46,119.91,113.03,111.22,109.47,102.77,69.34,21.88,10.29.

[0062] Embodiment 15

[0063] Compared with Example 1-3, Example 15 differs in that the halide in Example 1 is replaced by 2-bromopropane, and other operations are the same as Example 1-3, to obtain a solid product 1c with a yield of 61%.

[0064] 1c: white solid (61% yield), mp 478.3-502.6°C. 1 H NMR (300 MHz, DMSO-d6) δ 10.26-

[0065] 10.20(m,1H),8.18(d,J=8.9Hz,1H),8.07(d,J=8.7Hz,1H),7.57(d,J=2.7Hz,1H),7.46(dd,J=8.7,2. 8Hz,1H),6.83(dd,J=8.7,2.4Hz,1H),6.75(d,J=2.3Hz,1H),4.81-4.73(m,1H),1.32(d,J=5.9Hz,6H). 13 C NMR (75MHz, DMSO-d6) δ160.50,158.85,156.64,151.10,128.15,124.94,124.03,123.60,120.04,113.05,112.70,109.49,102.81,69.92,21.58.

[0066] Example 16

[0067] Compared with Example 1-3, Example 16 differs in that the halide in Example 1 is replaced by 1-bromobutane, and other operations are the same as those in Example 1-3, to obtain a solid product 1d with a yield of 56%.

[0068] 1d: white solid (56% yield), mp 493.2-508.3°C. 1 HNMR (400MHz, DMSO-d6) δ10.27(s,1H),8.17(d,J=9.0Hz,1H),8.07(d,J=8.8Hz,1H),7.56(d,J=2.8Hz,1H),7.46(dd,J=8.8,2.8Hz,1H) ,6.83(dd,J=8.7,2.4Hz,1H),6.75(d,J=2.4Hz,1H),4.08(t,J=6.5Hz,2H),1.79-1.68(m,2H),1.53-1.41(m,2H),0.95(t,J=7.4Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ160.53,158.87,157.88,151.10,128.34,124.22,124.1 0,123.54,119.95,113.07,111.29,109.50,102.79,67.63,30.56,18.66,13.67.

[0069] Embodiment 17

[0070] Compared with Example 1-3, Example 17 differs in that the halide in Example 1 is replaced by 1-bromo-2-methylpropane, and other operations are the same as those in Example 1-3, to obtain a solid product 1e with a yield of 47%.

[0071] 1e: white solid (47% yield), mp501.4-525.3°C. 1 HNMR (400MHz, DMSO-d6) δ10.26(s,1H),8.12(d,J=9.0Hz,1H),8.03(d,J=8.8Hz,1H),7.52(d,J=2.8Hz,1H),7.42(dd,J=8.8,2 .8Hz,1H),6.81(dd,J=8.7,2.4Hz,1H),6.73(d,J=2.4Hz,1H),3.82(d,J=6.5Hz,2H),2.12-1.97(m,1H),1.00(d,J=6.7Hz,6H). 13C NMR(101MHz,DMSO-d6)δ160.48,158.85,157.90,151.07,128.30,124.11,12 4.03,123.45,119.90,113.03,111.28,109.47,102.77,74.02,27.61,18.94.

[0072] Embodiment 18

[0073] Compared with Example 1-3, Example 18 differs in that the halide in Example 1 is replaced by 1-bromopentane, and other operations are the same as Example 1-3, to obtain 1 g of solid product with a yield of 62%.

[0074] 1g: white solid (62% yield), mp 527.6-534.2°C. 1 HNMR (400MHz, DMSO-d6) δ10.25(s,1H),8.15(d,J=9.0Hz,1H),8.05(d,J=8.8Hz,1H),7.53(d,J=2.8Hz,1H),7.43(dd,J=8.9,2.8Hz,1H) ,6.82(dd,J=8.7,2.4Hz,1H),6.74(d,J=2.4Hz,1H),4.05(t,J=6.5Hz,2H),1.80-1.69(m,2H),1.47-1.28(m,4H),0.91(t,J=7.0Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ160.48,158.86,157.83,151.09,128.30,124.14,124.05,1 23.46,119.92,113.03,111.22,109.47,102.77,67.87,28.21,27.60,21.88,13.89.

[0075] Embodiment 19

[0076] Compared with Example 1-3, Example 19 differs in that the halide in Example 1 is replaced by 1-bromo-3-methylpentane, and other operations are the same as those in Example 1-3, to obtain a solid product 1h with a yield of 57%.

[0077] 1h: white solid (57% yield), mp 517.3-527.7°C. 1HNMR (400MHz, DMSO-d6) δ10.23(s,1H),8.14(d,J=9.0Hz,1H),8.04(d,J=8.8Hz,1H),7.54(d,J=2.8Hz,1H),7.43(dd,J=8.9,2.8Hz,1H),6 .82(dd,J=8.7,2.4Hz,1H),6.73(d,J=2.4Hz,1H),4.08(t,J=6.7Hz,2H),1.83-1.75(m,1H),1.64(q,J=6.7Hz,2H),0.94(d,J=6.6Hz,6H). 13 CNMR(101MHz,DMSO-d6)δ160.48,158.87,157.82,151.09,128.32,124.14,124.0 4,123.45,119.94,113.03,111.30,109.48,102.78,66.37,37.23,24.54,22.39.

[0078] Embodiment 20

[0079] Compared with Examples 1-3, Example 20 differs in that the halide in Example 1 is replaced by 2-chloroethyl methyl sulfide, and other operations are the same as those in Examples 1-3, to obtain a solid product 1i with a yield of 42%.

[0080] 1i: white solid (42% yield), mp 482.3-497.3°C. 1 HNMR(400MHz,DMSO-d6)δ10.25(s,

[0081] 1H),8.16(d,J=8.9Hz,1H),8.06(d,J=8.7Hz,1H),7.57(d,J=2.8Hz,1H),7.47(dd,J=8.9,2.8Hz,1H),6.83(dd,J =8.7,2.3Hz,1H),6.74(d,J=2.3Hz,1H),4.27(t,J=6.5Hz,2H),3.41(s,2H),2.90(t,J=6.5Hz,2H),2.19(s,3H). 13 C NMR (101MHz, DMSO-d6) δ160.44,158.93,157.40,151.14,128.58,124.12,123.56,119.96,113.05,111.54,109.43,102.79,67.35,32.03,15.23.

[0082] Embodiment 21

[0083] Compared with Examples 1-3, Example 21 differs in that the halide in Example 1 is replaced by 2-bromoethyl methyl ether, and other operations are the same as Examples 1-3, to obtain a solid product 1j with a yield of 64%.

[0084] 1j: white solid (64% yield), mp 485.3-512.4°C. 1 HNMR(400MHz,DMSO-d6)δ10.24(s,

[0085] 1H),8.17(d,J=8.9Hz,1H),8.06(d,J=8.7Hz,1H),7.58(d,J=2.8Hz,1H),7.48(dd,J=8.9,2.7Hz,1H), 6.83(dd,J=8.7,2.4Hz,1H),6.74(d,J=2.3Hz,1H),4.26-4.19(m,2H),3.76-3.68(m,2H),3.34(s,3H). 13 C NMR(101MHz,DMSO-d6)δ160.47,158.92,157.69,151.14,128.52,124.24,12 4.11,123.56,119.96,113.07,111.39,109.45,102.80,70.18,67.37,58.15.

[0086] Embodiment 22

[0087] Compared with Example 1-3, Example 22 differs in that the halide in Example 1 is replaced by 4-bromo-2-methyl-2-butene, and other operations are the same as Example 1-3, to obtain a solid product 1k with a yield of 35%.

[0088] 1k: white solid (35% yield), mp 523.4-538.2°C. 1 HNMR(400MHz,DMSO-d6)δ10.23(s,

[0089] 1H),8.16(d,J=8.9Hz,1H),8.06(d,J=8.7Hz,1H),7.59(d,J=2.8Hz,1H),7.45(dd,J=8.8,2.8Hz,1H),6.83 (dd,J=8.7,2.4Hz,1H),6.74(d,J=2.4Hz,1H),5.50-5.37(m,1H),4.65(d,J=6.7Hz,2H),1.83-1.71(m,6H). 13C NMR(101MHz,DMSO-d6)δ160.49,158.87,157.60,151.11,137.74,128.34,124.36,12 4.07,123.45,119.91,119.37,113.03,111.60,109.49,102.79,64.76,25.43,18.04.

[0090] Embodiment 23

[0091] Compared with Example 1-3, Example 23 differs in that the halide in Example 1 is replaced by 3-bromo-1-propylene, and other operations are the same as those in Example 1-3, to obtain a solid product 11 with a yield of 67%.

[0092] 1l: white solid (67% yield), mp 479.3-493.2°C. 1 HNMR(400MHz,DMSO-d6)δ10.24(s,

[0093] 1H),8.17(d,J=8.9Hz,1H),8.06(d,J=8.7Hz,1H),7.59(d,J=2.8Hz,1H),7.49(dd,J=8.8,2.8Hz,1H),6.83(dd,J=8.7,2.4Hz,1H),6.74( d,J=2.4Hz,1H),6.09(ddt,J=17.4,10.4,5.1Hz,1H),5.46(dd,J=17.3,1.7Hz,1H),5.32(dd,J=10.6,1.6Hz,1H),4.71(d,J=5.2Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ160.45,158.93,157.32,151.14,133.17,128.54,124.25,12 4.10,123.52,119.94,117.78,113.05,111.81,109.43,102.79,68.52.HRMS(ESI)m / z calcd for C 16H11 O4 - [MH] - :267.0663; found:267.0667.

[0094] Embodiment 24

[0095] Compared with Example 1-3, Example 24 differs in that the halide in Example 1 is replaced by bromomethylcyclopropane, and other operations are the same as Example 1-3, to obtain a solid product 1m with a yield of 32%.

[0096] 1m: white solid (32% yield), mp 482.5-497.3°C. 1 H NMR (400MHz, DMSO-d6) δ10.05(s,1H),7.96(d,J=9.0Hz,1H),7.86(d,J=8.8Hz,1H),7.34(d,J=2.8Hz,1H),7.27(dd,J=8.8,2.8Hz,1H ),6.63(dd,J=8.7,2.4Hz,1H),6.55(d,J=2.4Hz,1H),3.74(d,J=7.0Hz,2H),1.16-1.01(m,1H),0.47-0.35(m,2H),0.27-0.11(m,2H). 13 C NMR(101MHz,DMSO-d6)δ160.48,158.83,157.80,151.09,128.30,124.28,1 24.06,123.46,119.91,113.02,111.22,109.49,102.77,72.49,9.97,3.13.

[0097] Embodiment 25

[0098] Compared with Example 1-3, Example 25 differs in that the halide in Example 1 is replaced by bromomethylcyclobutane, and other operations are the same as Example 1-3, to obtain a solid product 1n with a yield of 48%.

[0099] 1n: white solid (48% yield), mp 492.4-498.4°C. 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),8.15(d,J=9.0Hz,1H),8.05(d,J=8.7Hz,1H),7.55(d,J=2.8Hz,1H),7.44(dd,J=8.8,2.8Hz,1H ),6.82(dd,J=8.7,2.4Hz,1H),6.74(d,J=2.4Hz,1H),4.05(d,J=6.7Hz,2H),2.78-2.71(m,1H),2.17-2.03(m,2H),1.97-1.80(m,4H). 13C NMR (101MHz, DMSO-d6) δ160.48,158.82,157.96,151.10,128.35,124.22,124.08,123. 48,119.93,113.03,111.29,109.49,102.77,71.82,33.78,24.30,18.09.HRMS(ESI)m / z calcd for C 18 H 15 O4 - [MH] - :295.0976; found:295.0982.

[0100] Embodiment 26

[0101] Compared with Example 1-3, Example 26 differs in that the halide in Example 1 is replaced by bromomethylcyclopentane, and other operations are the same as Example 1-3, to obtain a solid product 1o with a yield of 36%.

[0102] 1o: white solid (36% yield), mp 502.4-509.3°C. 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),7.55(d,J=2.3Hz,1H),7.45(dd,J=8.9,2.5Hz,1H),6.82(dd,J=8.7,2.4Hz,1H),6.74 (d,J=2.3Hz,1H),3.94(dd,J=7.0,1.7Hz,2H),2.39-2.28(m,1H),1.85-1.74(m,2H),1.68-1.49(m,4H),1.42-1.30(m,2H). 13 C NMR(101MHz,DMSO-d6)δ160.50,158.86,157.97,151.09,128.32,124.20,124.0 7,123.48,119.92,113.05,111.29,109.48,102.78,71.97,38.37,28.92,24.90.

[0103] Embodiment 27

[0104] Compared with Example 1-3, Example 27 differs in that the halide in Example 1 is replaced by bromomethylcyclohexane, and other operations are the same as Example 1-3, to obtain a solid product 1p with a yield of 42%.

[0105] 1p: white solid (42% yield), mp 514.2-527.4°C. 1HNMR (400MHz, DMSO-d6) δ10.26(s,1H),8.14(d,J=8.9Hz,1H),8.04(d,J=8.8Hz,1H),7.51(d,J=2.7Hz,1H),7.43(dd,J=8.8,2.8Hz,1H ),6.82(dd,J=8.6,2.4Hz,1H),6.74(d,J=2.3Hz,1H),3.85(d,J=6.3Hz,2H),1.86-1.61(m,6H),1.34-1.14(m,3H),1.10-1.01(m,2H). 13 CNMR(101MHz,DMSO-d6)δ160.49,158.86,157.95,151.08,128.29,124.15,124.04,1 23.44,119.90,113.04,111.21,109.48,102.77,73.03,36.94,29.11,25.97,25.20.

[0106] Embodiment 28

[0107] Compared with Example 1-3, Example 28 differs in that the halide in Example 1 is replaced by 2-bromomethyl-1,3-dioxolane, and other operations are the same as Example 1-3, to obtain a solid product 1r with a yield of 38%.

[0108] 1r: white solid (38% yield), mp 528.9-528.4°C. 1 HNMR (400MHz, DMSO-d6) δ10.25(s,1H),8.17(d,J=8.9Hz,1H),8.06(d,J=8.7Hz,1H),7.59(d,J=2.8Hz,1H),7.50(dd,J=8.8,2.8Hz,1H) ,6.83(dd,J=8.6,2.4Hz,1H),6.74(d,J=2.3Hz,1H),5.27(t,J=3.8Hz,1H),4.15(d,J=3.9Hz,2H),4.06-3.94(m,2H),3.94-3.83(m,2H). 13 CNMR(101MHz,DMSO-d6)δ160.40,158.98,157.39,151.17,128.75,124.15,12 4.09,123.56,119.96,113.06,111.79,109.39,102.80,101.06,68.39,64.54.

[0109] Embodiment 29

[0110] Compared with Example 1-3, Example 29 differs in that the halide in Example 1 is replaced by 2-bromoethyl-1,3-dioxolane, and other operations are the same as Example 1-3, to obtain a solid product 1s with a yield of 41%.

[0111] 1s: white solid (41% yield), mp 525.4-541.9°C. 1 HNMR (400MHz, DMSO-d6) δ10.23(s,1H),8.18(d,J=9.2Hz,1H),8.07(d,J=8.5Hz,1H),7.57(s,1H),7.47(d,J=8.8Hz,1H),6.83(d,J =8.9Hz,1H),6.75(s,1H),5.03(t,J=5.4Hz,1H),4.20(t,J=6.8Hz,2H),3.94(s,2H),3.85-3.79(m,2H),2.09(q,J=6.9,6.5Hz,2H). 13 CNMR(101MHz,DMSO-d6)δ160.44,158.91,157.54,151.13,128.51,124.08,12 3.53,119.96,113.04,111.35,109.43,102.79,101.08,64.27,63.96,33.08.

[0112] Embodiment 30

[0113] Compared with Example 1-3, Example 30 differs in that the halide in Example 1 is replaced by 4-bromomethyltetrahydropyran, and other operations are the same as those in Example 1-3, to obtain 1t of solid product with a yield of 15%.

[0114] 1t: white solid (15% yield), mp 535.7-549.7°C. 1 HNMR (400MHz, DMSO-d6) δ10.23(s,1H),8.15(d,J=9.0Hz,1H),8.05(d,J=8.8Hz,1H),7.54(d,J=2.8Hz,1H),7.44(dd,J=8.8,2.8Hz,1H),6.82(dd,J =8.7,2.4Hz,1H),6.74(d,J=2.4Hz,1H),3.95-3.87(m,4H),3.38-3.31(m ,3H),2.07-1.97(m,1H),1.70(dd,J=12.6,2.2Hz,2H),1.41-1.31(m,2H). 13CNMR(101MHz,DMSO-d6)δ160.47,158.89,157.84,151.11,128.40,124.14 ,124.08,123.49,119.94,113.04,111.33,109.47,102.79,72.34,66.57.

[0115] Embodiment 31

[0116] Compared with Example 1-3, Example 31 differs in that the halide in Example 1 is replaced by 2-(2-bromoethyl)-1,3-dioxane, and other operations are the same as those in Example 1-3, to obtain a solid product 1u with a yield of 52%.

[0117] 1u: white solid (52% yield), mp 534.9-542.8°C. 1 HNMR(400MHz,DMSO-d6)δ10.23(s,1H),8.16(d,J=9.0Hz,1H),8.06(d,J=8.8Hz,1 H),7.54(d,J=2.8Hz,1H),7.46(dd,J=8.8,2.8Hz,1H),6.82(dd,J=8.7,2.4Hz,1H) ,6.74(d,J=2.4Hz,1H),4.77(t,J=5.2Hz,1H),4.13(t,J=6.6Hz,2H),4.05-4.01(m ,2H),3.78-3.71(m,2H),2.02-1.95(m,2H),1.94-1.85(m,1H),1.39-1.34(m,1H). 13 C NMR(101MHz,DMSO-d6)δ160.46,158.92,157.60,151.13,128.49,124.10,123.5 5,119.97,113.05,111.35,109.45,102.80,98.63,66.07,63.63,34.38,25.33.

[0118] Embodiment 32

[0119] Compared with Example 1-3, Example 32 differs in that the halide in Example 1 is replaced by benzyl bromide, and other operations are the same as those in Example 1-3, to obtain a solid product 2a with a yield of 35%.

[0120] 2a: white solid (35% yield), mp 537.4-568.6°C. 1HNMR (400MHz, DMSO-d6) δ10.28(s,1H),8.19(d,J=9.0Hz,1H),8.07(d,J=8.8Hz,1H),7.68(d,J=2.8Hz,1H),7.58-7.52(m,1H ),7.52-7.47(m,2H),7.47-7.39(m,2H),7.39-7.32(m,1H),6.83(dd,J=8.7,2.4Hz,1H),6.75(d,J=2.4Hz,1H),5.25(s,2H). 13 CNMR(101MHz,DMSO-d6)δ160.47,158.95,157.50,151.15,136.48,128.65,128.48,127 .99,127.77,124.46,124.16,123.58,119.95,113.07,111.91,109.44,102.80,69.56.

[0121] Embodiment 33

[0122] Compared with Example 1-3, Example 33 differs in that the halide in Example 1 is replaced by 4-methoxybenzyl bromide, and other operations are the same as Example 1-3, to obtain a solid product 2b with a yield of 39%.

[0123] 2b: white solid (39% yield), mp 528.4-558.6°C. 1 HNMR (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=8.9,2.8H 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(75MHz,DMSO-d6)δ160.46,159.07,158.93,157.55,151.14,129.59,128.53,128.29, 124.42,124.09,123.47,119.92,113.81,113.05,111.91,109.45,102.80,69.38,55.04.

[0124] Embodiment 34

[0125] Compared with Example 1-3, Example 34 differs in that the halide in Example 1 is replaced by 3-methoxybenzyl bromide, and other operations are the same as Example 1-3, to obtain a solid product 2c with a yield of 28%.

[0126] 2c: white solid (28% yield), mp 525.4-542.8°C. 1 HNMR(400MHz,DMSO-d6)δ10.26(s,

[0127] 1H),8.18(d,J=8.9Hz,1H),8.06(d,J=8.8Hz,1H),7.67(d,J=2.8Hz,1H),7.55(dd,J=8.9,2.8Hz,1H),7.33(t,J=8.1Hz,1H), 7.10-7.04(m,2H),6.92(dd,J=8.3,2.5Hz,1H),6.83(dd,J=8.7,2.4Hz,1H),6.75(d,J=2.3Hz,1H),5.22(s,2H),3.78(s,3H). 13 CNMR(101MHz,DMSO-d6)δ160.46,159.33,158.95,157.46,151.16,138.05,129.60,128.66,124.42 ,124.13,123.56,119.96,119.74,113.36,113.17,113.08,112.02,109.44,102.81,69.42,55.02.

[0128] Embodiment 35

[0129] Compared with Example 1-3, Example 35 differs in that the halide in Example 1 is replaced by 2-cyanobenzyl bromide, and the other operations are the same as those in Example 1-3, to obtain a solid product 2e with a yield of 54%.

[0130] 2e: white solid (54% yield), mp 524.8-543.5°C. 1 HNMR(400MHz,DMSO-d6)δ10.28(s,

[0131] 1H),8.24(d,J=8.8Hz,1H),8.10(d,J=8.4Hz,1H),7.95(d,J=7.5Hz,1H),7.81-7.78(m,2H) ,7.75(d,J=2.6Hz,1H),7.63-7.58(m,2H),6.84(d,J=8.4Hz,1H),6.76(s,1H),5.41(s,2H).13 C NMR(101MHz,DMSO-d6)δ160.42,159.08,157.22,151.25,139.49,133.47,133.36,129.71,129.24, 129.13,124.38,124.25,123.74,120.02,117.19,113.12,112.07,111.37,109.37,102.83,67.98.

[0132] Embodiment 36

[0133] Compared with Example 1-3, Example 36 differs in that the halide in Example 1 is replaced by 2-trifluoromethylbenzyl bromide, and other operations are the same as Example 1-3, to obtain a solid product 2f with a yield of 43%.

[0134] 2f: white solid (43% yield), mp 542.8-574.9°C. 1 HNMR(400MHz,DMSO-d6)δ10.26(s,

[0135] 1H),8.21(d,J=8.9Hz,1H),8.07(d,J=8.7Hz,1H),7.82(dd,J=7.8,4.8Hz,2H),7.74(t,J=7. 6Hz,1H),7.71-7.52(m,3H),6.84(dd,J=8.7,2.4Hz,1H),6.75(d,J=2.4Hz,1H),5.38(s,2H). 13 C NMR(101MHz,DMSO-d6)δ160.41,159.05,157.13,151.22,134.33,132.86,130.48,129.01,128.90,127 .07,126.77,126.24,126.18,124.33,124.20,123.73,120.02,113.09,111.83,109.37,102.81,66.57.

[0136] Embodiment 37

[0137] Compared with Example 1-3, Example 37 differs in that the halide in Example 1 is replaced by 3-trifluoromethylbenzyl bromide, and other operations are the same as Example 1-3, to obtain 2 g of solid product with a yield of 26%.

[0138] 2g: white solid (26% yield), mp 556.8-567.4°C. 1HNMR(400MHz,DMSO-d6)δ10.27(s,

[0139] 1H),8.20(d,J=8.9Hz,1H),8.08(d,J=8.8Hz,1H),7.89(s,1H),7.83(d,J=7.6Hz,1H),7.77-7.70(m,2H),7.68 (t,J=7.7Hz,1H),7.58(dd,J=8.9,2.8Hz,1H),6.84(dd,J=8.7,2.4Hz,1H),6.75(d,J=2.3Hz,1H),5.36(s,2H). 13 CNMR(101MHz,DMSO-d6)δ160.44,159.01,157.27,151.20,138.03,131.71,129.59,129.20(d,J=32.32Hz),128.88 ,124.69,124.43,124.18,124.11(d,J=4.04Hz),123.63,122.79,119.98,113.09,111.97,109.40,102.81,68.69.

[0140] Embodiment 38

[0141] Compared with Example 1-3, Example 38 differs in that the halide in Example 1 is replaced by 4-trifluoromethylbenzyl bromide, and other operations are the same as Example 1-3, to obtain a solid product 2h with a yield of 11%.

[0142] 2h: white solid (11% yield), mp 546.8-564.2°C. 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.21(d,J=9.0Hz,1H),8.08(d,J=8.7Hz,1H),7.82-7.67(m, 5H), 7.58 (dd, J=8.9, 2.8Hz, 1H), 6.83 (dd, J=8.7, 2.4Hz, 1H), 6.75 (d, J=2.4Hz, 1H), 5.38 (s, 2H). 13 C NMR(101MHz,DMSO-d6)δ160.44,159.03,157.23,151.20,141.42,128.89,128.55,128.03, 125.38,125.34,124.42,124.20,123.69,120.00,113.10,112.04,109.39,102.81,68.65.

[0143] Embodiment 39

[0144] Compared with Example 1-3, Example 39 differs in that the halide in Example 1 is replaced by 2-methylbenzyl bromide, and other operations are the same as Example 1-3, to obtain a solid product 2i with a yield of 44%.

[0145] 2i: white solid (44% yield), mp 515.7-524.8°C. 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.21(d,J=9.0Hz,1H),8.09(d,J=8.8Hz,1H),7.73(d,J=2.8Hz,1H),7.57(dd,J=8.8,2.8 Hz,1H),7.46(d,J=7.3Hz,1H),7.32-7.18(m,3H),6.84(dd,J=8.7,2.4Hz,1H),6.76(d,J=2.4Hz,1H),5.23(s,2H),2.36(s,3H). 13 C NMR(101MHz,DMSO-d6)δ160.49,158.96,157.65,151.17,136.73,134.41,130.16,128.69,128.64 ,128.23,125.81,124.45,124.18,123.61,119.98,113.07,111.85,109.47,102.81,68.31,18.49.

[0146] Embodiment 40

[0147] Compared with Example 1-3, Example 40 differs in that the halide in Example 1 is replaced by 2-fluorobenzyl bromide, and other operations are the same as Example 1-3, to obtain a solid product 2k with a yield of 54%.

[0148] 2k: white solid (54% yield), mp 534.7-548.4°C. 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.20(d,J=9.0Hz,1H),8.08(d,J=8.8Hz,1H),7.72(d,J=2.8Hz,1H),7.66-7 .52(m,2H),7.49-7.43(m,1H),7.34-7.23(m,2H),6.84(dd,J=8.7,2.4Hz,1H),6.76(d,J=2.4Hz,1H),5.29(s,2H). 13C NMR (101MHz, DMSO-d6) δ161.66,160.43,159.01,157.33,151.20,130.79(d,J=4.04Hz),130.59(d,J=8.08Hz),128.86,124.56(d,J =3.03Hz),124.36,124.19,123.65,123.30(d,J=15.15Hz),120.00,115.44(d,J=21.21Hz),113.08,111.88,109.41,102.82,63.97.

[0149] Embodiment 41

[0150] Compared with Example 1-3, Example 41 differs in that the halide in Example 1 is replaced by 2-bromobenzyl bromide, and other operations are the same as those in Example 1-3, to obtain a solid product 21 with a yield of 47%.

[0151] 2l: white solid (47% yield), mp 541.5-546.7°C. 1 HNMR(400MHz, DMSO-d6)δ10.27(s,1H),8.21(d,J=8.9Hz,1H),8.08(d,J=8.7Hz,1H),7.74-7.66(m,2H),7.64(dd,J=7.7,1.7Hz,1H),7 .57(dd,J=8.9,2.8Hz,1H),7.45(t,J=7.5Hz,1H),7.36-7.32(m,1H),6.84(dd,J=8.7,2.4Hz,1H),6.75(d,J=2.3Hz,1H),5.26(s,2H). 13 CNMR(101MHz,DMSO-d6)δ160.44,159.02,157.30,151.21,135.34,132.67,130.30,130.28,128 .95,127.94,124.40,124.20,123.70,122.91,120.00,113.11,111.90,109.40,102.83,69.45.

[0152] Embodiment 42

[0153] Compared with Example 1-3, Example 42 differs in that the halide in Example 1 is replaced by 3-chlorobenzyl bromide, and other operations are the same as Example 1-3, to obtain a solid product 2m with a yield of 45%.

[0154] 2m: white solid (45% yield), mp 537.8-548.5°C.1 HNMR (400MHz, DMSO-d6) δ10.26(s,1H),8.20(d,J=8.9Hz,1H),8.07(d,J=8.7Hz,1H),7.67(d,J=2.8Hz,1H ),7.60-7.49(m,2H),7.49-7.38(m,3H),6.83(dd,J=8.6,2.4Hz,1H),6.74(d,J=2.3Hz,1H),5.26(s,2H). 13 CNMR(101MHz,DMSO-d6)δ160.45,158.99,157.26,151.18,139.08,133.13,130.40,128.82,127 .88,127.36,126.23,124.45,124.19,123.64,119.96,113.07,111.90,109.41,102.80,68.60.

[0155] Effect example: The obtained products 1a-1u and 2a-2m were subjected to phosphodiesterase inhibition activity study. Experimental method: 1 μL of compound dilution and 1.5 μL of PDE2 protein dilution were placed at room temperature for 30 minutes, then 2.5 μL of cAMP or cGMP was added and centrifuged for 1 minute, then shaken, incubated at room temperature for 20 minutes, and then centrifuged with 2.5 μL of terminator for 1 minute, immediately added 2.5 μL of detection solution for centrifugation, and then incubated at room temperature for 20 minutes. Finally, Kinase Reagent buffer was added and placed in a cool place for reaction for 10 minutes. The reading was performed using a multifunctional microplate reader. In this test, there is no need to add compounds to the positive control, and there is no need to add compounds and PDE2 protein to the negative control, and the volume is supplemented with 1x reaction buffer. The experiment was performed in a 384-well plate, with 3 parallel wells in each group.

[0156] The PDE2 protein was diluted in a double gradient to prepare PDE2 protein solutions with concentrations of 1.0, 0.5, 0.2, 0.12, 0.062, and 0.031 mg / mL, respectively; 1x reaction buffer, PDE2 protein solutions of different concentrations, cAMP or cGMP, stop solution, detection solution, and Kinase Reagent buffer were added to the positive control wells. After the reaction was completed, data was recorded using a multifunctional microplate reader.

[0157] Dimethyl sulfoxide was added to make the concentration of BAY60-7550 10mM, and BAY60-7550 was further diluted with 1× reaction buffer to a final concentration of 100, 50, 25, 12.5, 6.25, 3.125, 1.562, and 0.781nM in the system; PDE2 protein solution, cAMP or cGMP, stop solution, detection solution, and Kinase Reagent buffer were added to the positive compound wells. After the reaction, the data was read by a microplate reader and the fitted IC was calculated using GraphPad Prism. 50 Positive and negative controls were designed for each screening plate.

[0158] The IC values ​​of the 34 synthesized compounds were further determined. 50 The potential compound was diluted with 1× reaction buffer to 7 final concentrations of 200μM, 100μM, 50μM, 25μM, 12.5μM, 6.25μM, and 3.125μM. The specific experimental steps refer to the IC value of BAY60-7550 mentioned above. 50 Determination method.

[0159] Table 1

[0160]

[0161] From the specific IC in the table above 50 The data show that the compounds of the general formula 3,8-dihydroxy-6H-benzo[c]chromene-6-one exhibit a strong inhibitory effect on PDE2 and have the potential to treat central nervous system diseases such as memory deficits, cognitive impairment, anxiety and depression, and can be used as active ingredients to prepare drugs that inhibit PDE2 activity. Among them, the IC values ​​of compounds 1a, 1e, 1f, 1i, 1p, 1q, 1s, 2c, 2d, 2f, 2g, 2h, 2i, 2j, 2k, 2l, and 2m are 50 All <50 and IC of 1q and 2d 50 The breakthrough reaches the nanomolar level. Although the present invention is described by the specific examples above, it should not be construed as being limited thereto; rather, the present invention encompasses the general aspects disclosed above. Various modifications and various embodiments may be made without departing from the spirit and scope of the present invention.

[0162] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical solutions and concepts of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A class of 3,8-dihydroxy-6H-benzo[c]chromene-6-one 8-hydroxyl etherified derivatives as phosphodiesterase 2 inhibitors, characterized in that: The structural formula of the 8-hydroxyl etherified derivative of 3,8-dihydroxy-6H-benzo[c]chromene-6-one is as follows: Wherein, R is one of C2-C5 alkyl, C3-C5 olefin, C2-C6 alkoxy, C2-C6 alkylthio, cycloalkyl-substituted C2-C3 alkyl, heterocyclic-substituted C2-C3 alkyl, aromatic or substituted aromatic-substituted C2 alkyl.

2. The 8-hydroxyl-etherified derivative of 3,8-dihydroxy-6H-benzo[c]chromene-6-one as a phosphodiesterase 2 inhibitor according to claim 1, characterized in that: The 8-hydroxyl etherified derivative of 3,8-dihydroxy-6H-benzo[c]chromene-6-one is one of the following structural formulas:

3. Use of the 8-hydroxyl etherified derivative of 3,8-dihydroxy-6H-benzo[c]chromene-6-one according to claim 1 in the preparation of phosphodiesterase 2 inhibitor drugs.

4. A pharmaceutical preparation, characterized in that: It comprises the 8-hydroxyl etherified derivative of 3,8-dihydroxy-6H-benzo[c]chromene-6-one according to claim 1, and one or more pharmaceutically acceptable carriers or excipients.

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