8-hydroxy uramil a derivatives, and preparation method and application thereof

Abstract

The application belongs to the field of pharmaceutical chemistry, and particularly relates to a kind of 8-position hydroxyl urolithin A derivatives and a preparation method and application thereof.2-bromo-5-hydroxybenzoic acid is prepared into 2-bromo-5-(benzyl methoxy)-benzoic acid by hydroxyl protection, then cyclization, etherification, deprotection reaction, reaction condition is more mild, reaction time is shorter and yield is higher, acid and base sensitive group and various substrates can be well tolerated to reaction condition, 8-position hydroxyl urolithin A derivative is prepared, and the obtained derivative is targeted to PDE2 small molecule, which has great potential for treating alzheimer's disease and other neurodegenerative diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry, in particular to derivatives as inhibitors of phosphodiesterase 2 (PDE2). BACKGROUND

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

[0003] Punica, blackberry, walnut, round leaf grape and other fruits or nuts are rich in ellagitannins, and urolithins are a series of products collectively referred to as the products of the multi-stage metabolism of ellagitannins by intestinal flora, including urolithins A-D. The good biological activity of polyphenolic compound urolithin A (UA) has made it a hot spot 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 intervention in neurodegenerative diseases. Due to individual metabolic differences, dietary absorption of UA is very limited. In addition, the low bioavailability and low blood-brain barrier permeability of UA are not conducive to its absorption and utilization. Therefore, the corresponding structural optimization of UA as a lead compound lays a theoretical basis 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. The UA-structure-based derivative targets PDE2 small molecules for the treatment of Alzheimer's disease and other neurodegenerative diseases has great potential, and the present application is based on the structure of UA to modify its structure in order to obtain an effective PDE2 inhibitor. SUMMARY

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

[0005] An 8-position hydroxyl urolithin A PDE2 inhibitor derivative, the general formula is as follows Compound I:

[0006]

[0007] In the formula, 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. The substituents on the substituted alkyl group are cycloalkyl or substituted cycloalkyl, heterocyclic or substituted heterocyclic, aromatic or substituted aromatic. Further, the cycloalkyl group is cyclopentyl or cyclohexyl; the heterocyclic group is a tetrahydrofuran ring, a tetrahydropyran ring, a 1,3-dioxolane ring, a 1,3-dioxane ring, a piperidine ring, a pyrazole ring or a pyrimidine ring; and 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 or hydroxymethyl.

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

[0009]

[0010]

[0011] A preparation method of a urolithin A PDE2 inhibitor derivative, the steps of which are as follows:

[0012] (1) Protecting hydroxyl group: To a solution of 2-bromo-5-hydroxybenzoic acid and anhydrous potassium carbonate in DMF was added dropwise 4-methoxybenzyl chloride and heated to 80 °C for 5 h. After the reaction was completed, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was concentrated to give the crude product which was used in the next step without purification. To a solution of the product, 2-bromo-5-(benzylmethoxy)-phenyl methyl benzoate, in a mixture of tetrahydrofuran and methanol at 0 °C was added dropwise aqueous LiOH solution. The reaction mixture was stirred at room temperature for 4 h. 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 mixture was washed twice with ethyl acetate. The aqueous phase was acidified with 1 M hydrochloric acid and the product, 2-bromo-5-(benzylmethoxy)-benzoic acid, was collected by suction filtration and dried.

[0013] (2) Cyclization: 2-bromo-5-(benzylmethoxy)-benzoic acid, m-dihydroxybenzene and NaOH were refluxed in water for 1 h. 5% aqueous CuSO4 solution was added dropwise and refluxing was continued for 30 min. After the reaction was completed, the mixture was cooled and the precipitate was filtered off. The precipitate was washed with 1 M HCl and dried. White crystals were obtained by recrystallization from a 1:1 mixture of methanol and ethyl acetate.

[0014] (3) Etherification: The product obtained in step (2) was dissolved in DMF and anhydrous K2CO3 was added. After stirring for 5 min, the bromide was added dropwise and the reaction mixture was heated to 70 °C for 3-24 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the mixture was poured into ice water and the product was collected by suction filtration. The product was recrystallized from methanol several times.

[0015] (4) Deprotection: The product obtained in step (3) was dissolved in 1,2-dichloroethane and oxalyl chloride (0.5 eq) was added at room temperature. The reaction mixture was stirred for 1-4 h. After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried and column chromatographed using methanol:dichloromethane = 1:30.

[0016] The synthetic route is shown in the following formula:

[0017]

[0018] wherein R-X is Cl, Br or I; and R is the same as defined above.

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

[0020] In step 2, the molar ratio of the compound 2-bromo-5-(benzylmethoxy)-benzoic acid, m-dihydroxybenzene 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 the 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 the step 3 to oxalyl chloride is 1:0.5-1.5.

[0023] Advantages of the present application:

[0024] The present application provides novel PDE2 inhibitor compounds, mainly including 29 novel compounds, 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 PDE2 activity inhibiting drugs. In addition, corresponding synthesis methods are given for the provided compound structures, and the synthesis method is simple. At the beginning of the synthesis reaction, two active hydrogens are protected by etherification, and then the carboxylic acid group is exposed by the characteristics of ester hydrolysis under alkaline conditions, which not only ensures the smooth progress of the subsequent cyclization reaction, but also ensures the maximum degree of single substitution reaction during etherification. The last step of deprotection uses oxalyl chloride as a catalyst, which has fast reaction speed and high selectivity. In addition, the removal of the p-methoxybenzyl group can be completed in the presence of benzyl. In addition, this method has milder conditions, shorter reaction time and higher yield, and can well tolerate reaction conditions for acid and base sensitive groups and various substrates. DETAILED DESCRIPTION

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

[0026] Example 1

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

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

[0029] C2: white solid (yield 81%), m.p. 162.1-164.7 °C, 1 HNMR (400 MHz, DMSO-d6) δ 13.47 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.42-7.36 (m, 2H), 7.35 (d, J = 3.1 Hz, 1H), 7.09 (dd, J = 8.8, 3.1 Hz, 1H), 7.00-6.92 (m, 2H), 5.07 (s, 2H), 3.77 (s, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 167.15, 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 (4.46 mmol, 1.5 g), resorcinol (13.38 mmol, 1.47 g) and NaOH (13.38 mmol, 0.53 g) were added to water 20 ml, heated to 100 °C and refluxed for 1 h, 5% CuSO4 (1.34 mmol, 0.08 g) aqueous solution was added dropwise, and refluxed for another 30 min. The reaction was monitored by TLC (petroleum spirit: ethyl acetate = 1:1), and after the reaction was completed, the precipitate was filtered off after cooling. The precipitate was washed with 1 M HCl several times and dried in an oven. White crystals were obtained by recrystallization in methanol and ethyl acetate 1:1, 3-hydroxy-8-((4-methoxybenzyl)oxy)-6H-benzo[c]chromen-6-one, in a yield of 41%.

[0032] C3: white needle-like crystals (yield 41%), m.p. 236.8-238.9 °C, 1HNMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 2.7 Hz, 1H), 7.53 (dd, J = 8.8, 2.8 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 6.96 (d, J = 8.2 Hz, 2H), 6.82 (dd, J = 8.5, 2.4 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 5.16 (s, 2H), 3.76 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.48, 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 (1.43 mmol, 0.5 g) was dissolved in DMF (10 mL) in a 50 ml round bottom flask, anhydrous K2CO3 (2.82 mmol, 0.39 g) was added and stirred for 5 min, halide R-Br / Cl (as shown in Table 1) (2.86 mmol) was added dropwise, and reacted at 70 °C for 3-24 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1), after the reaction was completed, it was poured into 100 mL ice water, stirred to make the reaction liquid fully mixed with ice water, a precipitate was separated out, and the product was filtered and dried. The product was recrystallized with methanol several times, and Z1-Z35 were collected respectively, with a yield of 67%-92%

[0036] Z1: 1 HNMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 9.0 Hz, 1H), 8.16 (d, J = 9.6 Hz, 1H), 7.69 (d, J = 2.8 Hz, 1H), 7.55 (dd, J = 8.8, 2.8 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.02 - 6.93 (m, 4H), 5.17 (s, 2H), 4.02 (t, J = 6.6 Hz, 2H), 3.77 (s, 3H), 1.77 (h, J = 7.1 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.42, 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 °C.

[0037] Z2: 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 9.0 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.53 (dd, J = 8.9, 2.8 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.00 - 6.90 (m, 4H), 5.16 (s, 2H), 4.74 (hept, J = 6.0 Hz, 1H), 3.77 (s, 3H), 1.31 (d, J = 6.0 Hz, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 160.42, 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 °C.

[0038] Z3: 1 H NMR (400 MHz, Chloroform-d) δ 7.91 - 7.76 (m, 2H), 7.38 (d, J = 7.9 Hz, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.90 - 6.77 (m, 1H), 5.06 (dd, J = 3.9, 1.9 Hz, 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 = 7.4 Hz, 2H). 13CNMR (101 MHz, Chloroform-d) δ 161.62, 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 °C.

[0039] Z4: 1 HNMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 8.9 Hz, 1H), 8.13 (d, J = 8.6 Hz, 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 = 8.6 Hz, 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) δ 160.42, 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 °C.

[0040] Z5: 1 H NMR (400 MHz, Chloroform-d) δ 7.89 (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, 6.7 Hz, 1H), 1.05 (d, J = 6.7 Hz, 6H).13 C NMR (101 MHz, Chloroform-d) δ 161.65, 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 °C. Z6: 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (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) δ 160.38, 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 °C.

[0041] Z7: 1 H NMR (400 MHz, Chloroform-d) δ 7.88 (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) δ 161.65, 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 °C.

[0042] Z8: 1 H NMR (400 MHz, DMSO-d6) δ 8.23 (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 C NMR (101 MHz, Chloroform-d) δ 161.65, 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 °C.

[0043] Z9: 1H NMR (400 MHz, Chloroform-d) δ 7.88 (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 = 2.5 Hz, 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 (101 MHz, Chloroform-d) δ 161.66, 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 °C.

[0044] Z10: 1 H NMR (400 MHz, Chloroform-d) δ 7.93-7.82 (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 (101 MHz, Chloroform-d) δ 161.51, 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 °C.

[0045] Z11: 1HNMR (400 MHz, Chloroform-d) δ 7.83 (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) δ 160.45, 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 °C.

[0046] Z12: 1 HNMR (400 MHz, Chloroform-d) δ 7.90 (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 (101 MHz, Chloroform-d) δ 161.53, 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 °C. Z13: 1HNMR (400 MHz, Chloroform-d) δ 7.90 (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) δ 163.06 (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 = 21.21 Hz), 114.30 (d, J = 21.21 Hz), 114.13, 113.03, 112.14, 111.78, 102.64, 70.27, 69.51, 55.35. m.p. 175.5-178.8 °C. Z14: 1 HNMR (400 MHz, Chloroform-d) δ 7.83 (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) δ 162.73 (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, 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 °C.

[0047] Z15: 1H NMR (400 MHz, Chloroform-d) δ 7.96-7.83 (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 C NMR (101 MHz, DMSO-d6) δ 160.38, 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, 102.28, 69.43, 68.45, 55.07, 18.47. m.p. 142.8-145.5 °C.

[0048] Z16: 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (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) δ 160.38, 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, 102.28, 69.43, 68.45, 55.07, 18.47. m.p. 142.8-145.5 °C.

[0049] Z17: 1H NMR (400 MHz, Chloroform-d) δ 7.88 (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 C NMR (101 MHz, Chloroform-d) δ 161.60, 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, 111.46, 102.65, 70.36, 70.26, 55.35, 21.27. m.p. 173.1-175.0 °C.

[0050] Z18: 1 H NMR (400 MHz, Chloroform-d) δ 7.89 (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 C NMR (101 MHz, Chloroform-d) δ 161.62, 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, 112.11, 111.46, 102.62, 70.31, 70.26, 55.35, 34.67, 31.36. m.p. 189.5-191.2 °C.

[0051] Z19: 1H NMR (400 MHz, Chloroform-d) δ 7.82 (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, CDC13) δ 160.40, 158.66, 158.22, 157.42, 150.52, 139.18, 129.35, 128.46, 127.48, 126.98, 126.41, 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 °C.

[0052] Z20: 1 H NMR (400 MHz, DMSO-d6) δ 8.23 (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) δ 160.36, 159.38, 159.10, 157.93, 151.01, 142.43, 134.77, 129.62, 128.27, 128.11, 127.71, 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 °C.

[0053] Z21: 1H NMR (400 MHz, DMSO-d6) δ 8.22 (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, 2.5 Hz, 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) δ 160.36, 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 °C.

[0054] Z22: 1 H NMR (400 MHz, Chloroform-d) δ 7.94 - 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). 13 C NMR (101 MHz, Chloroform-d) δ 161.43, 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 °C.

[0055] Z23: 1H NMR (400 MHz, Chloroform-d) δ 7.89 (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) δ 161.52, 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 °C.

[0056] Z24: 1 H NMR (400 MHz, Chloroform-d) δ 7.84 (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 = 2.5 Hz, 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) δ 160.55, 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 °C. Z25:1 H NMR (400 MHz, Chloroform-d) δ 7.89 (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, 2.6 Hz, 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). 13 C NMR (101 MHz, Chloroform-d) δ 161.47, 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 °C.

[0057] Z26: 1 H NMR (400 MHz, Chloroform-d) δ 7.89 (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, 2.6 Hz, 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 (101 MHz, Chloroform-d) δ 161.61, 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 °C

[0058] Z27: 1 HNMR (400 MHz, Chloroform-d) δ 7.90 (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) δ 161.61, 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 °C

[0059] Z28: 1HNMR (400 MHz, Chloroform-d) δ 7.91 (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). 13 C NMR (101 MHz, Chloroform-d) δ 161.64, 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 °C.

[0060] Z29: 1 HNMR (400 MHz, DMSO-d6) δ 8.70 (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 = 2.1 Hz, 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) δ 164.41, 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 °C.

[0061] Z30: 1HNMR (400 MHz, DMSO-d6) δ 8.25 (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, 2.6 Hz, 1H), 7.00 - 6.93 (m, 2H), 5.30 (s, 2H), 5.16 (s, 2H), 3.77 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.14, 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 °C.

[0062] Z31 : 1 H NMR (400 MHz, Chloroform-d) δ 7.90 (d, J = 8.9 Hz, 1H), 7.84 (dd, J = 5.8, 3.1 Hz, 2H), 7.40 (dq, J = 9.2, 3.0 Hz, 3H), 6.98 - 6.81 (m, 4H), 5.09 (s, 2H), 4.20 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H), 2.92 (t, J = 6.7 Hz, 2H), 2.24 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 161.51, 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 °C.

[0063] Z32 : 1H NMR (400 MHz, Chloroform-d) δ 7.89 (d, J = 8.9 Hz, 1H), 7.83 (dd, J = 5.8, 3.0 Hz, 2H), 7.39 (dd, J = 8.8, 3.4 Hz, 3H), 6.93 (dd, J = 8.9, 3.1 Hz, 3H), 6.86 (d, J = 2.5 Hz, 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). 13 C NMR (101 MHz, Chloroform-d) δ 161.58, 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 °C.

[0064] Z33: 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 9.0 Hz, 1H), 8.21 - 8.14 (m, 1H), 7.69 (d, J = 2.8 Hz, 1H), 7.55 (dd, J = 8.9, 2.8 Hz, 1H), 7.47 - 7.39 (m, 2H), 6.98 (ddd, J = 10.8, 6.2, 2.7 Hz, 4H), 5.17 (s, 2H), 4.91 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.38, 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, 102.22, 69.43, 64.87, 60.77, 55.06, 14.02. m.p. 133.8 - 136.2 °C.

[0065] Z34: 1H NMR (400 MHz, Chloroform-d) δ 7.89 (d, J = 8.9 Hz, 1H), 7.83 (dd, J = 5.8, 3.0 Hz, 2H), 7.43 - 7.35 (m, 3H), 6.96 - 6.88 (m, 3H), 6.85 (d, J = 2.5 Hz, 1H), 6.06 (ddt, J = 17.3, 10.6, 5.3 Hz, 1H), 5.45 (dq, J = 17.2, 1.6 Hz, 1H), 5.34 (dq, J = 10.6, 1.4 Hz, 1H), 5.08 (s, 2H), 4.58 (dt, J = 5.4, 1.5 Hz, 2H), 3.82 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 161.58, 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. m.p. 128.5 - 130.1 °C.

[0066] Z35: 1 H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 8.9 Hz, 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 = 2.4 Hz, 2H), 3.82 (s, 3H), 2.58 (t, J = 2.4 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 161.47, 159.71, 158.51, 158.45, 151.46, 129.55, 128.53, 128.06, 125.04, 123.26, 122.97, 121.10, 114.13, 112.93, 112.15, 112.12, 102.88, 77.78, 76.34, 70.27, 56.17, 55.35. m.p. 149.5 - 151.2 °C.

[0067] Example 4

[0068] Preparation of compounds F1-F35:

[0069] A solution of the substituted 3-hydroxy-8-((4-methoxybenzyl)oxy)-6H- benzo[c]chromen-6-one (Z1-Z35 compounds) (0.5 mmol) in 1,2-dichloroethane (10 mL) was reacted with oxalyl chloride (0.25 mmol, 0.03 g) at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the remaining solid was dissolved in 10 mL of ethyl acetate, washed with 20 mL of water, and separated. The organic layer was dried and purified by column chromatography (methanol: dichloromethane) to obtain a solid product F1-F35. The product was recrystallized with methanol, and the yield was 11-55%.

[0070] F1: 1 HNMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 9.5 Hz, 1H), 7.54 (d, J = 2.7 Hz, 1H), 7.34 (dd, J = 8.7, 2.7 Hz, 1H), 6.92 (dq, J = 5.0, 2.5 Hz, 2H), 3.99 (t, J = 6.5 Hz, 2H), 1.76 (h, J = 7.1 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 160.48, 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 °C.

[0071] F2: 1 HNMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 9.5 Hz, 1H), 7.54 (d, J = 2.7 Hz, 1H), 7.34 (dd, J = 8.7, 2.7 Hz, 1H), 6.92 (dq, J = 5.0, 2.5 Hz, 2H), 3.99 (t, J = 6.5 Hz, 2H), 1.76 (h, J = 7.1 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 160.48, 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 °C.

[0072] F3: 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 9.6 Hz, 1H), 7.54 (d, J = 2.7 Hz, 1H), 7.34 (dd, J = 8.7, 2.7 Hz, 1H), 6.93 (d, J = 7.5 Hz, 2H), 4.04 (t, J = 6.5 Hz, 2H), 1.78 - 1.66 (m, 2H), 1.45 (h, J = 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.48, 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 °C.

[0073] F4: 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.35 (dd, J = 8.7, 2.7 Hz, 1H), 6.99 - 6.90 (m, 2H), 4.52 (q, J = 6.0 Hz, 1H), 1.76 - 1.55 (m, 2H), 1.27 (d, J = 6.0 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.52, 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 °C.

[0074] F5: 1HNMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 9.5 Hz, 1H), 7.54 (d, J = 2.7 Hz, 1H), 7.35 (dd, J = 8.7, 2.7 Hz, 1H), 6.96 (dq, J = 4.4, 2.5 Hz, 2H), 3.84 (d, J = 6.5 Hz, 2H), 2.04 (dq, J = 12.8, 6.4 Hz, 1H), 1.00 (d, J = 6.7 Hz, 6H). 13 CNMR (101 MHz, DMSO-d6) δ 160.50, 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 °C.

[0075] F6: 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (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 CNMR (101 MHz, DMSO-d6) δ 160.49, 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 °C. F7: 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 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) δ 160.47, 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 °C.

[0076] F8: 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 9.5 Hz, 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, 2.6 Hz, 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) δ 160.48, 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 °C.

[0077] F9: 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 9.6 Hz, 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, 2.5 Hz, 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 = 12.2 Hz, 3H), 1.11 - 0.98 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.49, 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 °C.

[0078] F10: 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (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, 2.7 Hz, 1H), 7.09 - 7.01 (m, 2H), 5.23 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.42, 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 °C.

[0079] F11: 1H NMR (400 MHz, DMSO-d6) δ 10.31 (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, 2.6 Hz, 1H), 5.21 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.43, 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 °C.

[0080] F12: 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (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) δ 160.48 (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 °C.

[0081] F13: 1H NMR (400 MHz, DMSO-d6) δ 10.34 (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, 2.3 Hz, 1H), 7.06 - 7.01 (m, 2H), 5.23 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 162.19, 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 °C.

[0082] F14: 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (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 = 2.6 Hz, 1H), 7.03 (dd, J = 8.8, 2.6 Hz, 1H), 5.19 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 161.84 (d, J = 245.43 Hz), 160.45, 158.90, 157.35, 150.74, 132.78 130.21, 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 °C.

[0083] F15: 1H NMR (400 MHz, DMSO-d6) δ 10.33 (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 = 8.0 Hz, 2H), 5.23 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 163.64, 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 °C.

[0084] F16: 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (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 C NMR (101 MHz, DMSO-d6) δ 160.47, 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 °C.

[0085] F17: 1H NMR (400 MHz, DMSO-d6) δ 10.31 (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 (101 MHz, DMSO-d6) δ 160.45, 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 °C. F18: 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (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 (101 MHz, DMSO-d6) δ 160.45, 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 °C.

[0086] F19: 1HNMR (400 MHz, DMSO-d6) δ 10.34 (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, 2.7 Hz, 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 (101 MHz, DMSO-d6) δ 160.41, 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 °C.

[0087] F20: 1 HNMR (400 MHz, DMSO-d6) δ 10.32 (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) δ 160.46, 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 °C.

[0088] F21: 1H NMR (400 MHz, DMSO-d6) δ 10.30 (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, 3.6 Hz, 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) δ 160.47, 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 °C.

[0089] F22: 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (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, 2.5 Hz, 1H), 6.20 (s, 1H), 5.22 (s, 2H), 3.77 (s, 3H), 2.13 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.43, 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 °C.

[0090] F23: 1H NMR (400 MHz, DMSO-d6) δ 10.31 (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) δ 160.44, 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 °C.

[0091] F24: 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.19 - 8.08 (m, 2H), 7.54 (d, J = 2.7 Hz, 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) δ 160.48, 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 °C.

[0092] F25: 1H NMR (400 MHz, DMSO-d6) δ 10.33 (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) δ 160.44, 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 °C.

[0093] F26: 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (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, 2.5 Hz, 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 (101 MHz, DMSO-d6) δ 160.40, 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 °C.

[0094] F27: 1H NMR (400 MHz, DMSO-d6) δ 10.31 (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, 4.1 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 160.46, 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 °C.

[0095] F28: 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (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, 4.1 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 160.46, 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 °C.

[0096] F29: 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (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 = 2.4 Hz, 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) δ 164.45, 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 °C.

[0097] F30: 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (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, 2.6 Hz, 1H), 5.31 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.26, 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 °C.

[0098] F31: 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 2.7 Hz, 1H), 7.33 (dd, J = 8.7, 2.7 Hz, 1H), 6.99 - 6.90 (m, 2H), 4.22 (t, J = 6.6 Hz, 2H), 2.87 (t, J = 6.5 Hz, 2H), 2.18 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.44, 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 °C.

[0099] F32: 1 HNMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.10 (dd, J = 23.2, 8.6 Hz, 2H), 7.53 (d, J = 2.7 Hz, 1H), 7.33 (dd, J = 8.7, 2.7 Hz, 1H), 6.94 (d, J = 8.2 Hz, 2H), 4.20 - 4.13 (m, 2H), 3.71 - 3.67 (m, 2H), 3.32 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.44, 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 °C.

[0100] F33: 1 HNMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.15 (dd, J = 17.2, 9.2 Hz, 2H), 7.54 (d, J = 2.7 Hz, 1H), 7.35 (dd, J = 8.7, 2.7 Hz, 1H), 6.99 (dq, J = 5.1, 2.6 Hz, 2H), 4.91 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.44, 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 °C.

[0101] F34: 1HNMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.15 (d, J = 8.9 Hz, 1H), 8.13 - 8.07 (m, 1H), 7.54 (d, J = 2.7 Hz, 1H), 7.34 (dd, J = 8.7, 2.7 Hz, 1H), 6.97 (d, J = 7.6 Hz, 2H), 6.08 (ddt, J = 17.3, 10.5, 5.3 Hz, 1H), 5.46 (dq, J = 17.3, 1.7 Hz, 1H), 5.31 (dq, J = 10.5, 1.5 Hz, 1H), 4.66 (dt, J = 5.3, 1.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.44, 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 °C.

[0102] F35: 1 HNMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.14 (dd, J = 12.4, 8.8 Hz, 2H), 7.54 (d, J = 2.6 Hz, 1H), 7.34 (dd, J = 8.7, 2.7 Hz, 1H), 7.03 (d, J = 2.5 Hz, 1H), 7.00 (dd, J = 8.7, 2.6 Hz, 1H), 4.92 (d, J = 2.5 Hz, 2H), 3.66 (t, J = 2.3 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 160.38, 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. m.p. 231.1-233.2 °C.

[0103] Table 1 8-(4-methoxybenzyl)oxy)-6H-benzo[c]chromen-6-one derivatives

[0104]

[0105]

[0106]

[0107]

[0108]

[0109] Table 2 8-hydroxy-6H-benzo[c]chromen-6-one derivatives

[0110]

[0111]

[0112]

[0113]

[0114] Effect example

[0115] PDE2 enzyme inhibition activity study of F1-35 product obtained from Example 4

[0116] The recombinant plasmid pET15b-PDE2A was transformed into E. coli for expression, and PDE2 protein was obtained by culture and nickel column affinity chromatography purification. The AlphaScreen kit was used to measure the inhibition of PDE2 by the compound. When PDE2 is present, it will hydrolyze Biotinylated cAMP, making it difficult for the acceptor microbead to approach the donor microbead, resulting in a decrease in signal value. If there is a PDE2 inhibitor in the system, it will inhibit PDE2, so that Biotinylated cAMP cannot be hydrolyzed, and finally the signal value level increases.

[0117] Take 2 μL of compound diluent and 4 μL of PDE2 protein diluent, and react at constant temperature (25°C) for 0.5 h, then add 4 μL of Biotinylated cAMP and centrifuge (1000 r / min) for 1 min, react again at constant temperature (25°C) for 1 h, then add 15 μL of Acceptor and Donor Bead suspension, centrifuge (1000 r / min) for 1 min, react at constant temperature (25°C) for 1 h in the dark, and finally read the values with a multifunctional enzyme marker. Positive control (without compound and PDE2 protein) and negative control (without compound) are required for the experiment, and the parts not added are supplemented with 1 × Reaction buffer. The experiment is carried out in a 384 white well plate, with 3 parallel holes set for each group.

[0118] Further determination of IC 50Values, the potential compounds were diluted with 1 x Reaction buffer to 7 final concentrations of 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.5625 μM, the specific experimental steps refer to the above IC 50 determination method.

[0119] Table 3 IC values of 8-hydroxy-6H-benzo[c]chromen-6-one derivatives 50 values

[0120]

[0121]

[0122]

[0123] The present application provides 35 8-hydroxy-6H-benzo[c]chromen-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 PDE2 activity inhibiting drugs. The IC 50 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, F35 are all less than 50 μM, wherein the activities of F1, F2, F5, F7, F8, F9, F10, F11, F13, F16, F17, F18, F20, F201, F22, F25, F27, F28, F29, F32, F33, F35 are better 50 than the others. 50 The IC 50 values of F16 and F17 are 0.63 μM and 0.85 μM, respectively.

[0124] (1) When introducing alkyl by etherification of the hydroxyl group at position 3 of Urolithin A, it is found that increasing the chain length is not conducive to the inhibitory activity of the compound on PDE2, and the activity of branched alkyl is significantly higher than that of straight-chain alkyl, the IC 50 value of F2 is 3.16 μM when the substituent is isopropyl, the IC 50 value of F5 is 1.61 μM when the substituent is isobutyl, and the IC 5014.81 μM, thus the position of the alkyl branch also has a great influence on the activity, and the compound with a terminal branch has better activity. When a cycloalkane is introduced, the substituent is methylcyclopentane, and the IC 50 of compound F8 is 4.60 μM, while the IC 50 of compound F9 with a methylcyclohexane substituent is 6.68 μM.

[0125] (2) When a benzyl series is introduced by etherification of the 3-hydroxyl group of urolithin A, it is found that the activity of the compound is influenced by both the type and position of the substituent on the benzyl group. When the substituent is at the para position, the activity from high to low is para-methylbenzyl (F17) IC 50 = 0.85 μM, para-methylbenzyl alcohol (F20) IC 50 = 1.09 μM, para-tert-butylbenzyl (F18) IC 50 = 1.51 μM, para-Cl benzyl (F11) IC 50 = 8.55 μM, para-trifluoromethylbenzyl bromide (F19) IC 50 = 48.69 μM, para-F benzyl (F14) IC 50 > 50 μM. 2-F benzyl (F12) IC 50 = 22.85 μM, 3-F benzyl (F13) IC 50 = 5.73 μM, the activity of the meta substitution is 4 times higher than that of the ortho substitution. The IC 50 of compound F15 with 3,5-difluorobenzyl substitution is 26.91 μM, which is lower than that of the ortho and meta single substitution compounds but better than that of the para single substitution.

[0126] (3) When a heterocycle containing an oxygen atom is introduced by etherification of the 3-hydroxyl group of urolithin A, the compound F27 with a 2-(methyl)tetrahydro-2H-pyran substituent has the best inhibitory activity against PDE2, with an IC 50 of 1.51 μM. When a heterocycle containing a nitrogen atom is introduced by etherification of the 3-hydroxyl group of urolithin A, the compound has PDE2 inhibitory activity. When the substituent is methyl-1,3-dimethylpyrazole (F22), ethylpyrazole (F25), or 2-pyrimidine (F29), the IC 50 is 8.82 μM, 7.20 μM, and 9.59 μM, respectively.

[0127] (4) When an unsaturated or heteroatom-containing alkane is introduced by etherification of the 3-hydroxyl group of urolithin A, the etherification group is 2-ethylmethyl sulfide, and the IC 50 of compound F31 against PDE2 is greater than 50 μM, but when the sulfur atom is replaced by an oxygen atom, the IC 50 of compound F32 is 1.57 μM. The IC50 3.84 μM, which is better than 3-propenyl substituted compound (F34, IC 50 = 23.49 μM). Acetonitrile substitution is not conducive to the PDE2 inhibitory activity of Urolithin A, the IC 50 21.21 μM, which is lower than the inhibitory activity of Urolithin A. Ethyl acetate of Urolithin A derivative (F33) has a slight promotion effect on PDE2 inhibitory activity, the IC 50 12.81 μM.

[0128] The above examples are only used to illustrate the technical solutions of the present application, but not to limit it; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that the technical solutions recorded in the foregoing examples can still be modified, or some technical features can be replaced by equivalents; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

Claims

1. A class of 8-hydroxyurolithin A derivatives, characterized in that: The structural formula of the 8-hydroxyurolithin A derivative is as follows: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; 。 2. The method for preparing the 8-hydroxyurolithin A derivative according to claim 1, characterized in that: (1) Add 4-methoxybenzyl chloride dropwise to a DMF solution of 2-bromo-5-hydroxybenzoic acid and anhydrous potassium carbonate and heat the mixture to react. After the reaction is complete, collect the product. The product was added to a mixed solution of tetrahydrofuran and methanol, and then an aqueous solution of lithium hydroxide was added dropwise. After reacting at room temperature, the product was obtained. ; (2) Resorcinol and sodium hydroxide were refluxed in water for a period of time, and CuSO4 aqueous solution was added dropwise. The reflux reaction continued. After the reaction was completed, the mixture was cooled, the precipitate was filtered out, washed, dried, and recrystallized to obtain white crystals. (3) The white crystalline product obtained in step (2) was dissolved in DMF, anhydrous K2CO3 was added, and after stirring, the halogenated product was added dropwise. The reaction was carried out at 70℃ for 3-24 h. After the reaction was completed, the product was poured into ice water, filtered, and recrystallized to obtain the etherified product. (4) The etherified product obtained in step (3) is reacted with oxalyl chloride. After the reaction is completed, the product is separated and purified to obtain the 8-hydroxyurolithin A derivative as described in claim 1.

3. The method for preparing the 8-hydroxyurolithin A derivative according to claim 2, characterized in that: In step (1), the molar ratio of 2-bromo-5-hydroxybenzoic acid to 4-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 resorcinol to 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.

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

5.

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

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