Methods S1. Synthesis of Compounds, Related to STAR Methods

Methods S1. Synthesis of compounds, Related to STAR methods.

Information regarding chemistry can be found in STAR methods.

Compound synthesis.

Compounds ARS-806, ARS-869, ARS-917, and ARS-1116were synthesized according to Synthetic Scheme 1.

Synthetic Scheme 1

7-bromo-6-chloroquinazolin-4-ol. To a solution of 2-amino-4-bromo-5-chlorobenzoic acid (500 mg, 2mmol) in ethanol (20 mL) at room temperature, formamidine acetate (620 mg, 6 mmol) was added and the resulting mixture was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. Theresidue was washed with saturated NaHCO3 aqueous solution followed by a mixture of ethyl acetate and petroleum ether (1:2). The solid was dried in vacuoto afford the desired product (520 mg, 100% yield). ESI-MS m/z: 259.0 [M+H]+. The product was used directly in the next step without purification.

7-bromo-4,6-dichloroquinazoline. To a solution of 7-bromo-6-chloroquinazolin-4-ol (520 mg, 2 mmol) in thionyl chloride (15 mL), one drop of N,N-dimethylformamide was added and the resulting mixture was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo to afford the crude product. The crude product was used directly in the next step without purification.

tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate. To a solution of7-bromo-4,6-dichloroquinazoline (556 mg, 2 mmol) in dichloromethane (20 mL) at 0 °C, triethylamine (607 mg, 6 mmol) and tert-butyl piperazine-1-carboxylate (447 mg, 2.4 mmol) were added and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel to afford the desired product.

tert-butyl 4-(6-chloro-7-(2-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate. To a solution oftert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate (150 mg, 0.35 mmol) and (2-methoxyphenyl)boronic acid (64 mg, 0.42 mmol) in 1,4-dioxane (15 mL) and water (3 mL) under argon atmosphere, Pd(PPh3)4 (40 mg) and Na2CO3 (111 mg, 1.05 mmol) were added and the resulting mixture was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product (120 mg, 75% yield).

1-(4-(6-chloro-7-(2-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one. To a solution oftert-butyl 4-(6-chloro-7-(2-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate (120 mg, 0.26 mmol) in dichloromethane (2 mL) at room temperature, HCl in MeOH (10 mL) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL) and triethylamine (186 mg, 1.84 mmol) and then cooled to 0 °C. Acryloyl chloride (36 mg, 0.39 mmol) was added to the mixture and the resulting mixture was stirred at 0 °C for 30 min. The mixture was partitioned between dichloromethane and saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product (50 mg, 46% yield).

1-(4-(6-chloro-7-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one. To a solution of1-(4-(6-chloro-7-(2-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (50 mg, 0.12 mmol) in dichloromethane (10 mL) at -78 °C under argon atmosphere, BBr3 (306 mg, 1.22 mmol) was added and the resulting mixture was stirred from -78 °C to room temperature for 2 h. The mixture was poured into ice-water and basified with saturated NaHCO3 aqueous solution to adjust the pH to 8. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product ARS-869 (20 mg, 41% yield).1HNMR(400 MHz, DMSO-d6)δ: 9.7 (s, 1H), 8.7 (s, 1H), 8.1 (s, 1H), 7.8 (s, 1H), 7.3-7.2 (m, 1H), 7.2 (dd, J = 1.2, 7.2 Hz, 1H ), 7.0 (d, J = 7.6 Hz, 1H ), 6.9 (t, J = 7.2 Hz, 1H ), 6.8 (dd, J = 10.4, 16.8 Hz, 1H), 6.2(dd, J = 2.4, 16.4 Hz, 1H), 5.75(dd, J = 2.4, 10.4 Hz, 1H), 3.9-3.7(m, 8H); ESI-MS m/z: 395.70 [M+H]+.

ARS-1116 was prepared from tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate according to the following procedure.

tert-butyl 4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate. To a solution oftert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate (300 mg, 0.7 mmol) and 2-fluoro-6-methoxyphenylboronic acid (719 mg, 4.2 mmol) in tetrahydrofuran (15 mL) under argon atmosphere, S-Phos(144 mg, 0.35 mmol), Pd(OAc)2 (78.8 mg, 0.35 mmol) and potassium fluoride (203 mg, 3.5 mmol) were added and the resulting mixture was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product (200 mg, 60% yield).

1-(4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one. To a solution oftert-butyl 4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate (200 mg, 0.42 mmol) in methanol (2 mL) at room temperature, HCl in MeOH (10 mL) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL) and triethylamine (0.6 mL, 4 mmol) and cooled to 0 °C. Acryloyl chloride (58 mg, 0.6 mmol) was added to the mixture and the resulting mixture was stirred at 0 °C for 30 min. The mixture was partitioned between dichloromethane and saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product (101 mg, 56% yield).

1-(4-(6-chloro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one. To a solution of11-(4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (101 mg, 0.24 mmol) in dichloromethane (10 mL) at -78 °C under argon atmosphere, BBr3 (300 mg, 1.2 mmol) was added and the resulting mixture was stirred from -78 °C to room tempearture for 2 h. The mixture was poured into ice-water and basified with saturated NaHCO3 aqueous solution to adjust the pH to 8. The mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel to afford the desired product ARS-1116 (22 mg, 23% yield).1HNMR(400 MHz, DMSO-d6): δ10.15 (s,1H), 8.68 (s,1H), 8.18 (s,1H), 7.77 (s,1H), 7.31 (dd, J = 8.4, 15.6 Hz,1H), 6.88~6.83 (m, 2H), 6.81-6.76 (m, 1H), 6.18 (dd, J = 2.0,16.4 Hz,1H), 5.60 (dd, J = 2.4,10.8 Hz,1H), 3.87 (d, J = 13.6 Hz, 6H), 3.77 (bs, 2H); ESI-MS m/z: 413.25 [M+H]+.

ARS-917 was prepared from tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate according to the following procedure.

tert-butyl 4-(6-chloro-7-(2-fluorophenyl)quinazolin-4-yl)piperazine-1-carboxylate. To a solution oftert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate (200 mg, 0.47 mmol) and 2-fluorophenylboronic acid (79 mg, 0.56 mmol) in 1,4-dioxane (15 mL) and H2O (5 mL) under argon, Pd(PPh3)4 (54.3 mg, 0.047 mmol) and Na2CO3 (150 mg, 1.14 mmol) were added and the resulting mixture was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product (290 mg, 100% yield).

1-(4-(6-chloro-7-(2-fluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one. To a solution oftert-butyl 4-(6-chloro-7-(2-fluorophenyl)quinazolin-4-yl)piperazine-1-carboxylate (290 mg, 0.66 mmol) in methanol (2 mL) at room temperature, HCl in MeOH (10 mL) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL) and triethylamine (668 mg, 6.6 mmol) and cooled to 0 °C. Acryloyl chloride (178 mg, 1.97 mmol) was added to the mixture and the resulting mixture was stirred at 0 °C for 30 min. The mixture was partitioned between dichloromethane and saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product (37 mg, 14% yield). 1H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.49-7.44 (m, 1H), 7.39-7.36 (m, 1H), 7.30-7.28 (m, 1H), 7.23-7.19 (m, 1H), 6.62(dd, J = 10.4, 16.4 Hz, 1H), 6.38(dd, J = 1.6, 16.8 Hz, 1H), 5.78(dd, J = 1.2, 10.4 Hz, 1H), 3.92-3.87 (m, 8H); ESI-MS m/z: 397.25 [M+H]+.

ARS-806 was prepared from tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate according to the above described procedure for ARS-917.

1-(4-(6-chloro-7-phenylquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one.1H NMR(400 MHz, DMSO-d6):δ 8.7 (s, 1H), 8.2 (s, 1H), 7.8 (s, 1H), 7.6-7.4 (m, 5H), 6.85 (dd, J = 10.8, 16.8 Hz, 1H ), 6.2(d, J = 16.8 Hz, 1H), 5.75(d, J = 10 Hz, 1H), 3.9-3.7(m, 8H); ESI-MS m/z : 379.30 [M+H]+.

Compounds ARS-1323, ARS-1620, ARS-1630 and saturated version analog (ARS-1372) were synthesized according to Synthetic Scheme 2.

SyntheticScheme 2

2-amino-4-bromo-5-chloro-3-fluorobenzoic acid. To a solution of 2-amino-4-bromo-3-fluorobenzoic acid(234 mg, 1.0 mmol) in N,N-dimethylformamide (10 mL) at room temperature, N-chlorosuccinimide (134 mg, 1.0 mmol) was added and the resulting mixture was stirred at 70 oC for 16 h. The mixture was poured into ice-water. The precipitate was collected by filtration, rinsed with water and dried to afford the desired product (209 mg, 78% yield) as a white solid.ESI-MSm/z: 269.8 [M+H]+.

7-bromo-6-chloro-8-fluoroquinazolin-4(3H)-one. To a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid(1.07 g, 3.98 mmol) in ethanol (15 mL)at room temperature, formamidine acetate(4.92 g, 47.76 mmol) was added and the resulting mixture was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 100:1 to 50:1) to afford the desired product (600 mg, 55% yield) as a white solid.ESI-MS m/z: 278.9 [M+H]+.

7-bromo-4,6-dichloro-8-fluoroquinazoline. A mixture of 7-bromo-6-chloro-8-fluoroquinazolin-4(3H)-one (600 mg, 2.16 mmol), thionyl chloride(30 mL) and N,N-dimethylformamide (3 drops) was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo to afford the crude product (639 mg), which was used directly in the next step.

tert-butyl 4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate. To a solution of 7-bromo-4,6-dichloro-8-fluoroquinazoline (639 mg, 2.16 mmol ) in 1,4-dioxane (20 mL) at room temperature, tert-butyl piperazine-1-carboxylate (1.21 g, 6.48 mmol) and N,N-diisopropylethylamine (1.39 g, 10.8 mmol) were added and the resulting mixture was stirred at 50 oC for 3 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated NaHCO3 aqueous solution. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 100:1) to afford the desired product (950 mg, 98% yield) as a yellow solid. ESI-MS m/z: 446.1 [M+H]+.

tert-butyl 4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate. A mixture of tert-butyl 4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (5 g, 11.2mmol), 2-fluoro-6-hydroxyphenylboronic acid (8.7 g, 56.1 mmol), Pd(PPh3)4 (1.3 g, 1.12 mmol) and Na2CO3 (3.56 g, 33.6mmol ) in 1,4-dioxane and water (160 mL/ 40 mL) was stirred at 90oC under argon for 16 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to afford the desired product (4.2 g, 79% yield) as a yellow solid. ESI-MSm/z: 477.1 [M+H]+.

1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one. To a solution of tert-butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate (7.4 g, 15.5 mmol) in dichloromethane (60 mL), 2,2,2-trifluoroacetic acid (20 mL) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The residue was suspended in saturated NaHCO3 solution, and then extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The above obtained crude was dissolved in trimethylamine (7.8 g, 77.5 mmol) and dichloromethane (80 mL) and cooled to -50°C. To this mixture, acryloyl chloride (4.2 g, 46.5 mmol) was added and the resulting mixture was stirred at -40 oC for 30 min. The reaction mixture was quenched with saturated NaHCO3 aqueous solution, and then extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 80:1) to yield the desired product (4.6 g, 61% yield).

To a stirred mixture of 2-(4-(4-acryloylpiperazin-1-yl)-6-chloro-8-fluoroquinazolin-7-yl)-3-fluorophenyl acrylateof (4.6 g, 9.5 mmol) in tetrahydrofuran/water (30 mL/5 mL) at room temperature, lithium hydroxide monohydrate (1.6 g, 38 mmol) was added and the resulting mixture was stirred for 1 h. The mixture was acidified with 1N HCl to adjust the pH to 6-7. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 50:1) to yield the desired product ARS-1323 (4 g, 97% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 8.70 (s, 1H), 8.04 (s, 1H), 7.34-7.40 (m, 1H), 6.80-6.87 (m, 3H), 6.16-6.20 (m, 1H), 5.73-5.76 (m, 1H), 3.77-3.93 (m, 8H).ESI-MS m/z: 431.15 [M+H]+.

(S)-1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (ARS-1620). The atropisomers were separated by chiral separation using a CHIRALPAK AD-H column (50 × 250 mm, 5 μm) on preparative SFC-200 (Thar, Waters) instrument eluting with CO2/methanol (50:50) at a flow rate of 130 g/min to afford ARS-1620 and ARS-1630 respectively. For ARS-1620, 1H NMR(400 MHz,DMSO-d6):δ10.28 (brs, 1H), 8.69 (s, 1H), 8.04 (s, 1H), 7.39-7.33 (m, 1H), 6.86-6.78 (m, 3H), 6.18 (dd, J = 2.6, 16.7 Hz, 1H), 5.75 (dd, J = 1.8, 10.1 Hz, 1H), 3.92-3.76 (m, 8 H). ESI-MS m/z: 431.15 [M+H]+.

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)propan-1-one. To a solution of 6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-(piperazin-1-yl)quinazoline (1.4 g, 3.58 mmol) in DCM (30 mL) at room temperature, TEA (1.08 g, 10.74 mmol) was added followed by propionyl chloride (364 mg, 3.94 mmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was poured to ice water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purifiedby flash column chromatography on silica gel (dichloromethane/methanol = 100:1) to afford the desired product (1.07 g, 66.9% yield).

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)propan-1-one (ARS-1372). To a solution of 1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)propan-1-one (507 mg, 1.13 mmol) in dichloromethane (20 mL) at -78 °C under nitrogen atmosphere, boron tribromide (2.84 g, 11.34 mmol) was added and the resulting mixture was stirred at room temperature for 3 h. The mixture was poured to ice water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC plate (dichloromethane/methanol = 20:1) to afford 1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)propan-1-one (ARS-1372) (273 mg, 55.6% yield) as a white solid. 1HNMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.34-7.40 (m, 1H), 6.80-6.87 (m, 2H), 3.87-3.92 (m, 4H), 3.69 (m, 4H), 2.35-2.40 (m, 2H), 1.00-1.04 (m, 3H); ESI-MS m/z: 433.6 [M+H]+.

Compound ARS-1170 was synthesized according to Synthetic Scheme 3.

SyntheticScheme 3

methyl 3-amino-6-chloro-2,2'-difluoro-[1,1'-biphenyl]-4-carboxylate. A mixture of methyl 2-amino-4-bromo-5-chloro-3-fluorobenzoate (136 mg, 0.48 mmol), 2-fluoro-phenylboronic acid (81 mg, 0.58 mmol), Pd(PPh3)4 (55 mg, 0.048 mmol) and 2N Na2CO3 solution (0.72 mL, 1.44 mmol ) in 1,4-dioxane (6 mL) was stirred at 80 oC under nitrogen for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product (105 mg, 73 % yield).

6-chloro-8-fluoro-7-(2-fluorophenyl)quinazolin-4(3H)-one. A mixture of methyl 3-amino-6-chloro-2,2'-difluoro-[1,1'-biphenyl]-4-carboxylate (105 mg, 0.35 mmol) and formamide (10 mL) was stirred at 200 oC for 3 h. The mixture was allowed to cool to room temperature and then water was added. The precipitate was collected by filtration and dried to afford the desired product (95 mg, 93% yield).

tert-butyl 4-(6-chloro-8-fluoro-7-(2-fluorophenyl)quinazolin-4-yl)piperazine-1-carboxylate. A mixture of 6-chloro-8-fluoro-7-(2-fluorophenyl)quinazolin-4(3H)-one(95 mg, 0.33 mmol), thionyl chloride (15 mL) and N.N-dimethylformamide (2 mg, 0.033 mmol) was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL) at room temperature, tert-butyl piperazine-1-carboxylate (614 mg, 3.3 mmol) and triethylamine (0.91 mL, 6.6 mmol) were added. The resulting mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated NaHCO3 aqueous solution. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol = 5:1) to afford the desired product (150 mg, 100 % yield in 2 steps).

1-(4-(6-chloro-8-fluoro-7-(2-fluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one. A mixture of tert-butyl 4-(6-chloro-8-fluoro-7-(2-fluorophenyl)quinazolin-4-yl)piperazine-1-carboxylate (150 mg, 0.33 mmol) and HCl in methanol (2.8 M, 10 mL) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The residue was dissolved in triethylamine (133 mg, 1.32 mmol) and dichloromethane (10 mL) and cooled to 0°C. Acryloyl chloride (90 mg, 0.99 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and then extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Pre-HPLC to afford the desired product (6 mg, 4.4% yield). 1H NMR (400 MHz, CDCl3): δ 8.82 (s, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.51-7.22 (m, 4H), 6.62 (dd, J = 10.8, 16.8 Hz, 1H), 6.38 (dd, J = 2.0, 16.8 Hz, 1H), 5.79 (dd, J = 2.0, 10.4 Hz, 1H), 3.92-3.85 (m, 8H); ESI-MS m/z: 415.25 [M+H]+.