Furo[3',2':3,4]naphtho[1,2-d]imidazole Derivatives

Supporting Information

Identification of Furo[3',2':3,4]naphtho[1,2-d]imidazole Derivatives as Orally Active and Selective Inhibitors of Microsomal Prostablandin E2Synthase-1 (mPGES-1)

Chih-Hua Tseng,a Cherng-Chyi Tzeng,a Pin-Keng Shih,bChia-Ning Yang,c You-Chung Chuang,cShin-I Peng,aChang-Sheng Lin,b Jih-Pyang Wang,d Chih-Mei Cheng,*, b and Yeh-Long Chen,*, a

aDepartment of Medicinal and Applied Chemistry, bDepartment of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan

cInstitute of Biotechnology, National University of Kaohsiung, 700 Kaohsiung University Rd, Kaohsiung City 811, Taiwan

dDepartment of Education and Research, Taichung Veterans General Hospital, Taichung 407, Taiwan

Contents:

ChemistryS2-S9

Chemistry

General

Melting points were determined on a Electrothermal IA9100 melting point apparatus and are uncorrected. Nuclear magnetic resonance (1H and13C) spectra were recorded on a Varian-Unity-400 spectrometer. Chemical shifts were expressed in parts per million () with tetramethylsilane (TMS) as an internal standard. Thin-layer chromatography was performed on silica gel 60 F-254 plates purchased from E. Merck and Co. High-resolution mass spectroscopic (HRMS) data were provided by the JointCenter for High Valued Instruments at NationalSunYat-senUniversity using Bruker APEX II (ESI) mass spectrometer. The elemental analyses were performed in the Instrument Center of National Science Council at NationalCheng-KungUniversity and NationalChung-HsingUniversity using Heraeus CHN-O Rapid EA.Purity of tested compounds was greater than 95%.

2-(2-Chloro-6-fluorophenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (3). The crude material was purified by FC (MeOH/ CH2Cl2 = 1/50) and recrystallized from EtOH to give a pale-brown solid (52%).Mp = 195-196oC. 1H-NMR (400 MHz, DMSO-d6+ TFA-d): 7.42 (d, 1H, J = 2.0 Hz, 4-H), 7.68-7.72 (m, 1H, Ar-H), 7.78 (d, 2H, J = 8.0 Hz, Ar-H), 7.82-7.87 (m, 1H, Ar-H), 7.91-7.97 (m, 1H, Ar-H), 8.33 (d, 1H, J = 2.0 Hz, 5-H), 8.43-8.48 (m, 1H, 7-H), 8.60-8.64 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 105.81, 111.60, 113.24 (J = 17.5 Hz), 116.01 (J = 20.5 Hz), 119.06, 120.12, 121.40, 122.75, 124.54, 125.58, 127.05 (J = 3.0 Hz), 127.67, 128.08, 135.03, 136.28 (J = 9.1 Hz), 137.81, 147.13, 149.83, 161.22 (J = 252.4 Hz). HRMS (ESI): m/z calcd for C19H11ClFN2O [M+H]+ 337.0544, found 337.0541. Anal. calcd for C19H10ClFN2O: C 67.77, H 2.99, N 8.32; found: C 67.83, H 2.97, N 8.30.

2-(4-Fluorophenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (5). Gray solid (42%). Mp =128-129oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 7.31 (d, 1H, J = 2.4 Hz, 4-H), 7.62-7.68 (m, 2H, Ar-H), 7.71-7.78 (m, 2H, 8- and 9-H),8.25 (d, 1H, J = 2.0 Hz, 5-H), 8.29-8.35 (m, 3H, Ar-H), 8.55-8.60 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 105.63, 111.22, 117.38 (2C, J = 21.9 Hz), 118.66, 119.66, 120.23 (J = 3.0 Hz), 121.21, 122.69, 123.60, 124.61, 127.31, 127.69, 130.96 (2C, J = 9.1 Hz), 145.70, 146.98, 149.54, 165.20 (J = 250.9 Hz). HRMS (ESI): m/z calcd for C19H12FN2O [M+H]+ 303.0934, found 303.0932.Anal. calcd for C19H11FN2O．1.0 H2O: C 71.23, H 4.10, N 8.75; found: C 71.06, H 4.45, N 8.80.

2-(4-Chlorophenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (6).Gray solid (41%). Mp = 287-288oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 7.34 (d, 1H, J = 2.0 Hz, 4-H), 7.73-7.80 (m, 2H, 8- and 9-H),7.86 (d, 2H, J = 8.8 Hz, Ar-H),8.26 (d, 2H, J = 8.8 Hz, Ar-H), 8.30 (d, 1H, J = 2.0 Hz, 5-H), 8.32-8.34 (m, 1H, 7-H), 8.59-8.61 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 105.44, 111.27, 118.68, 119.28, 120.92, 122.45, 122.94, 124.14, 125.14, 127.01, 127.33, 129.37 (2C), 129.87 (2C), 137.53, 145.53, 146.75, 149.07.HRMS (ESI): m/z calcd for C19H12ClN2O [M+H]+ 319.0638, found 319.0636.Anal. calcd for C19H11ClN2O: C 71.59, H 3.48, N 8.79; found: C 71.20, H 3.53, N 8.66.

2-(4-Cyanophenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (7). Brown solid (51%). Mp = 289-290oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 7.31 (d, 1H, J = 2.0 Hz, 4-H), 7.72-7.78 (m, 2H, 8- and 9-H),8.21-8.24 (m, 3H, Ar-H), 8.30-8.34 (m, 1H, 7-H), 8.40-8.42 (m, 2H, Ar-H), 8.56-8.60 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 105.81, 111.45, 115.25, 118.41, 118.98, 120.04, 121.38, 122.94, 124.64, 125.72, 127.48, 127.99, 128.08, 128.64 (2C), 133.87 (2C), 144.73, 147.07, 149.88.HRMS (ESI): m/z calcd for C20H12N3O [M+H]+ 310.0980, found 310.0977.Anal. calcd for C20H11N3O．0.7 H2O: C 74.61, H 3.89, N 13.05; found: C 74.64, H 3.81, N 12.92.

2-(4-Trifluoromethylphenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (8). White solid (71%). Mp = 276-277oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 7.35 (d, 1H, J = 2.4 Hz, 4-H), 7.75-7.81 (m, 2H, 8- and 9-H),8.15 (d, 2H, J = 8.0 Hz, Ar-H),8.25 (d, 1H, J = 2.0 Hz, 5-H), 8.34-8.38 (m, 1H, 7-H), 8.48 (d, 2H, J = 8.4 Hz, Ar-H), 8.63-8.67 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 105.89, 111.48, 119.02, 120.15, 121.49, 123.04, 124.24 (CF3, J = 270.6 Hz), 124.39, 125.44, 127.10 (2C, J = 3.8 Hz), 127.59, 127.69, 128.09, 129.00 (2C), 133.15 (J = 32.6 Hz), 145.09, 147.18, 150.01. HRMS (ESI): m/z calcd for C20H12F3N2O [M+H]+ 353.0902, found 353.0904.Anal. calcd for C20H11F3N2O．0.8 H2O．0.5 AcOH: C 63.58, H 3.71, N 7.06; found: C 63.77, H 4.03, N 6.87.

N-(4-(furo[3',2':3,4]naphtho[1,2-d]imidazol-2-yl)phenyl)acetamide (9). Brown solid (0.22 g, 69%); m.p.: 335-336oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 2.15 (s, 3H, Me), 7.19 (d, 1H, J = 2.0 Hz, 4-H), 7.58-7.65 (m, 2H, 8- and 9-H),7.89 (d, 2H, J = 8.8 Hz, Ar-H),7.99 (d, 1H, J = 2.0 Hz, 5-H), 8.04 (d, 2H, J = 8.8 Hz, Ar-H), 8.15-8.20 (m, 1H, 7-H), 8.43-8.47 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 24.96, 106.42, 112.03, 118.07, 119.57, 120.63 (2C), 122.13, 123.53, 124.24, 125.24, 127.95, 128.30, 129.68 (2C), 130.70, 145.01, 147.23, 150.71, 170.85.HRMS (ESI): m/z calcd for C21H16N3O2 [M+H]+ 342.1242, found 342.1241.Anal. calcd for C21H15N3O2: C 70.88, H 4.71, N 11.81; found: C 70.81, H 5.05, N 12.27.

2-(4-Methylphenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (10). Off-white solid (51%). Mp = 277-278oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 2.48 (s, 3H, Me), 7.31 (d, 1H, J = 2.0 Hz, 4-H), 7.56 (d, 2H, J = 8.0 Hz, Ar-H), 7.70-7.76 (m, 2H, 8- and 9-H),8.13 (d, 2H, J = 8.0 Hz, Ar-H), 8.23 (d, 1H, J = 2.0 Hz, 5-H), 8.29-8.32 (m, 1H, 7-H), 8.58-8.61 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 21.44, 105.68, 111.23, 118.68, 119.65, 120.66, 121.21, 122.75, 123.47, 124.46, 127.27, 127.62, 128.01 (2C), 130.60 (2C), 144.06, 146.65, 146.93, 149.56. HRMS (ESI): m/z calcd for C20H15N2O [M+H]+299.1184, found 299.1183.Anal. calcd for C20H14N2O．0.2 H2O: C 79.55, H 4.82, N 9.28; found: C 79.47, H 4.81, N 9.20.

2-(4-Hydroxyphenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (11). White solid (41%). Mp =320-321oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 7.15-7.19 (m, 2H, Ar-H), 7.31 (d, 1H, J = 2.0 Hz,4-H), 7.69-7.76 (m, 2H, 8- and 9-H), 8.11-8.15 (m, 2H, Ar-H), 8.24 (d, 1H, J = 2.0 Hz, 5-H), 8.29-8.32 (m, 1H, 7-H), 8.57-8.60 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 105.60, 111.20, 113.93, 116.90 (2C), 118.60, 119.37, 121.12, 122.62, 123.17, 124.13, 127.14, 127.36, 130.21 (2C), 146.84, 147.19, 149.30, 162.34.HRMS (ESI):m/z calcd for C19H13N2O2 [M+H]+ 301.0977, found 301.0975.Anal. calcd for C19H12N2O2．1.2 H2O．0.6 AcOH: C 67.78, H 4.73, N 7.83; found: C 67.75, H 4.87, N 7.50.

2-(4-Methoxyphenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (12). Beige solid (57%). Mp =294-296oC.(Dec)1H-NMR (400 MHz, DMSO-d6+ TFA-d): 3.95 (s, 3H, OMe), 7.28-7.32 (m, 3H, 4- and Ar-H), 7.67-7.74 (m, 2H, 8- and 9-H), 8.18-8.21 (m, 3H, 5- and Ar-H), 8.26-8.30 (m, 1H, 7-H), 8.53-8.58 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 56.09, 105.74, 115.61, 115.67 (2C),117.04, 118.78, 119.70, 121.33, 122.81, 123.41, 124.39, 127.30, 127.59, 130.13 (2C), 146.78, 146.94, 149.64, 163.68. HRMS (ESI): m/z calcd for C20H15N2O2 [M+H]+ 315.1133, found 315.1131.Anal. calcd for C20H14N2O2．0.5 H2O: C 74.28, H 4.69, N 8.66; found: C 74.47, H 4.44, N 8.55.Salt formation was performed bysuspending the free base (100 mg) in EtOH (20 mL)followed by the addition of concentrated HCl (1 mL). Theresulting salt precipitated out and afforded the HCl salt of 12(110 mg)as an off-white solid. Mp = 328-330oC.(Dec). 1H-NMR (400 MHz, DMSO-d6): 3.86 (s, 3H, OMe), 7.19-7.23 (m, 2H, Ar-H), 7.34 (d, 1H, J = 2.0 Hz, 4-H), 7.68-7.73 (m, 2H, Ar-H), 8.13-8.16 (m, 2H), 8.19 (d, 1H, J = 2.0 Hz, 5-H), 8.29-8.36 (m, 1H, Ar-H), 8.56-8.60 (m, 1H, Ar-H). 13C-NMR (100 MHz, DMSO-d6): 56.20, 106.01, 112.60, 115.55 (2C), 118.44, 119.25, 119.78, 121.29, 122.78, 126.07, 126.74, 127.13, 127.17, 129.55 (2C), 146.70, 148.22, 148.94, 162.48. Anal. calcd for C20H14N2O2．1.5 HCl: C 65.08, H 4.24, N 7.59; found: C 64.88, H 4.16, N 7.46.

2-(4-Methylthiophenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (13). Off-white solid (71%). Mp = 305-306oC.(Dec)1H-NMR (400 MHz, DMSO-d6+ TFA-d): 2.62 (s, 3H, SMe), 7.24 (d, 1H, J = 1.6 Hz, 4-H), 7.55 (d, 2H, J = 8.4 Hz, Ar-H), 7.66-7.68 (m, 2H, 8- and 9-H), 8.10 (d, 2H, J = 8.4 Hz, Ar-H), 8.14 (d, 1H, J = 1.6 Hz, 5-H), 8.22-8.24 (m, 1H, 7-H), 8.49-8.51 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 14.40, 105.84, 111.37, 118.84, 119.23, 119.91, 121.44, 122.91, 123.65, 124.63, 126.35 (2C), 127.39, 127.77, 128.35 (2C), 146.42, 146.61, 146.97, 149.88. HRMS (ESI): m/z calcd for C20H15N2OS [M+H]+ 331.0905, found 331.0903.Anal. calcd for C20H14N2OS．0.75 H2O: C 69.84, H 4.55, N 8.15; found: C 69.75, H 4.24, N 7.97.

2-(2-Methylphenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (14). Off-white solid (51%). Mp = 228-229oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 2.61 (s, 3H, Me), 7.39 (d, 1H, J = 2.0 Hz, 4-H), 7.56-7.62 (m, 2H, Ar-H), 7.69-7.72 (m, 1H, Ar-H), 7.79-7.82 (m, 2H, 8 and 9-H),7.88 (d, 1H, J = 7.6 Hz, Ar-H), 8.19 (d, 1H, J = 2.0 Hz, 5-H), 8.46-8.48 (m, 1H, 7-H), 8.66-8.68 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 20.35, 106.37, 112.26, 119.86, 120.87, 122.11, 123.51, 124.44, 124.70, 125.54, 127.61, 128.13, 128.46, 132.22, 132.52, 133.69, 139.33, 147.41, 150.70.HRMS (ESI): m/z calcd for C20H15N2O [M+H]+299.1184, found 299.1186.Anal. calcd for C20H14N2O．0.15 H2O: C 79.78, H 4.80, N 9.31; found: C 79.99, H 4.90, N 8.96.

2-(2-Hydroxyphenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (15). White solid (39%). Mp =274-275oC. 1H-NMR (400 MHz, DMSO-d6+ TFA-d): 7.19-7.23 (m, 1H, Ar-H), 7.33 (d, 1H, J = 8.0 Hz, Ar-H), 7.55 (d, 1H, J = 2.0 Hz, 4-H), 7.59-7.64 (m, 1H, Ar-H), 7.72-7.79 (m, 2H, 8- and 9-H), 8.10 (dd, 1H, J = 1.2, 7.6 Hz, Ar-H),8.20 (d, 1H, J = 2.0 Hz, 5-H), 8.34-8.38 (m, 1H, 7-H), 8.72-8.76 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 106.54, 110.52, 111.65, 117.52, 118.86, 120.44, 121.30, 123.13, 123.48, 124.23, 127.30, 127.67, 130.58, 134.91, 144.71, 146.60, 149.71, 156.90. HRMS (ESI): m/z calcd for C19H13N2O2 [M+H]+301.0977, found 301.0975.Anal. calcd for C19H12F6N2O2: C 75.98, H 4.04, N 9.33; found: C 75.58, H 4.07, N 9.12.

2-(2-Methoxyphenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (16). White solid (49%). Mp = 238-239oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 7.33-7.37 (m, 1H, Ar-H), 7.43 (d, 1H, J = 8.4 Hz, Ar-H), 7.50 (d, 1H, J = 2.0 Hz, 4-H),7.52-7.82 (m, 3H, 8-, 9-, and Ar-H), 8.14 (dd, 1H, J = 1.6, 8.0 Hz, Ar-H), 8.24 (d, 1H, J = 2.0 Hz, 5-H), 8.38-8.42 (m, 1H, 7-H), 8.74-8.78 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 56.79, 106.36, 111.57, 112.16, 113.14, 118.91, 120.00, 121.40, 121.69, 123.19, 123.55, 124.40, 127.44, 127.86, 131.27, 135.31, 144.08, 146.84, 149.86, 157.96.HRMS (ESI): m/z calcd for C20H15N2O2 [M+H]+ 315.1133, found 315.1135.Anal. calcd for C20H14N2O2: C 76.42, H 4.49, N 8.91; found: C 76.38, H 4.65, N 8.51.

2-(2,5-Dihydroxyphenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (17). Gray solid (34%). Mp = 319-320oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 7.12-7.19 (m, 2H, Ar-H), 7.54 (d, 1H, J = 2.4 Hz,4-H), 7.56 (d, 1H, J = 2.8 Hz,Ar-H), 7.69-7.73 (m, 2H, 8- and 9-H), 8.05 (d, 1H, J = 2.4 Hz, 5-H), 8.32-8.37 (m, 1H, 7-H), 8.71-8.75 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 107.31, 111.08, 112.42, 116.13, 119.33, 119.70, 120.84, 122.09, 123.45, 123.91, 124.23, 124.92, 127.92, 128.33, 145.56, 146.89, 150.61, 150.75, 151.96.HRMS (ESI): m/z calcd for C19H13N2O3 [M+H]+ 317.0926, found 317.0927.Anal. calcd for C19H12N2O3．0.25 H2O: C 71.12, H 3.94, N 8.73; found: C 70.91, H 3.85, N 8.42.

2-(2-Hydroxy-5-nitrophenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (18). Yellow solid (61%). Mp > 350oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 7.35 (d, 1H, J = 9.2 Hz, Ar-H), 7.45 (d, 1H, J = 2.4 Hz,4-H), 7.64-7.69 (m, 2H, 8- and 9-H), 8.09 (d, 1H, J = 2.4 Hz, 5-H), 8.26-8.28 (m, 1H, 7-H), 8.33 (dd, 1H, J = 2.8, 9.2 Hz, Ar-H), 8.58-8.60 (m, 1H, 10-H), 8.99 (d, 1H, J = 2.8 Hz, Ar-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 106.78, 111.32, 111.95, 118.40, 119.21, 120.28, 121.55, 123.31, 124.26, 125.14, 126.36, 127.34, 127.92, 129.55, 140.89, 142.90, 146.61, 150.13, 162.66.HRMS (ESI): m/z calcd for C19H12N3O4 [M+H]+ 346.0828, found 346.0827.Anal. calcd for C19H11N3O4．0.1 AcOH: C 65.63, H 3.28, N 11.96; found: C65.87, H 3.21, N 11.63.

2-(2-Methoxy-5-nitrophenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (19). Yellow solid (73%). Mp = 273-274oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 4.24 (s, 3H, OMe), 7.50 (d, 1H, J = 2.0 Hz,4-H), 7.56 (d, 1H, J = 9.2 Hz, Ar-H), 7.72-7.82 (m, 2H, 8- and 9-H), 8.21 (d, 1H, J = 2.0 Hz, 5-H), 8.38-8.42 (m, 1H, 7-H), 8.55 (dd, 1H, J = 2.8, 9.2 Hz, Ar-H), 8.73-8.77 (m, 1H, 10-H), 9.07 (d, 1H, J = 2.8 Hz, Ar-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 58.16, 106.44, 111.58, 112.94, 114.03, 118.98, 120.38, 121.57, 123.34, 123.99, 124.89, 126.83, 127.58, 128.21, 130.15, 141.74 (2C), 146.91, 150.23, 162.44.HRMS (ESI): m/z calcd for C20H14N3O4 [M+H]+ 360.0984, found 360.0981.Anal. calcd for C20H13N3O4．1.0 H2O: C 63.65, H 4.01, N 11.14; found: C 63.50, H 4.04, N 11.10.

2-(3-Nitro-4-methoxyphenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (20). Brown solid (54%). Mp = 257-258oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 4.15 (s, 3H, OMe), 7.38 (d, 1H, J = 2.0 Hz,4-H), 7.78-7.85 (m, 3H, 8-, 9-, and Ar-H), 8.28 (d, 1H, J = 2.0 Hz, 5-H), 8.42-8.45 (m, 1H, 7-H), 8.58 (dd, 1H, J = 2.4, 8.8 Hz, Ar-H), 7.66-8.68 (m, 1H, 10-H), 8.91 (d, 1H, J = 2.4 Hz, Ar-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 57.96, 105.90, 111.58, 116.09, 116.49, 119.09, 120.18, 121.66, 123.04, 124.07, 125.10, 125.54, 127.68, 128.10, 134.28, 140.04, 144.96, 147.32, 150.07, 156.11.HRMS (ESI): m/z calcd for C20H14N3O4 [M+H]+ 360.0984, found 360.0981.Anal. calcd for C20H13N3O4．0.75 H2O: C 64.42, H 3.93, N 11.27; found: C 64.02, H 4.05, N 11.22.

2-(3,4,5-Trimethoxyphenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (21). Off-white solid (55%). Mp = 283-284oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 3.85 (s, 3H, OMe), 3.98 (s, 6H, 2 X OMe), 7.39 (d, 1H, J = 2.0 Hz, 4-H), 7.60 (s, 2H, Ar-H), 7.75-7.81 (m, 2H, 8- and 9-H), 8.33-8.38 (m, 2H, 5- and 7-H), 8.61-8.65 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 56.48 (2C), 60.44, 105.43, 105.52 (2C), 111.09, 118.32, 1184.2, 119.23, 120.97, 122.47, 123.54, 124.51, 126.94, 127.39, 141.37, 146.39, 146.84, 149.10, 153.67 (2C).HRMS (ESI): m/z calcd for C22H19N2O4 [M+H]+ 375.1345, found 375.1343.Anal. calcd for C22H18N2O4: C 70.58, H 4.85, N 7.48; found: C 70.33, H 4.89, N 7.58.

2-(4-Methylsulfinylphenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (22). Mp = 155-156oC. 1H-NMR (400 MHz, DMSO-d6+ TFA-d): 2.92 (s, 3H, Me), 7.33 (d, 1H, J = 2.0 Hz, 4-H), 7.72-7.77 (m, 2H, 8- and 9-H), 8.10 (d, 2H, J = 8.4 Hz, Ar-H), 8.21 (d, 1H, J = 2.0 Hz, 5-H), 8.32-8.34 (m, 1H, 7-H), 8.44 (d, 2H, J = 8.4 Hz, Ar-H), 8.61-8.63 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 43.61, 105.94, 111.49, 119.00, 120.20, 121.55, 123.09, 124.20, 125.23, 125.60 (2C), 127.61, 128.11, 128.51, 129.02 (2C), 145.62, 147.17, 150.09, 152.08. HRMS (ESI): m/z calcd for C20H15N2O2S [M+H]+ 347.0854, found 347.0851.Anal. calcd for C20H14N2O2S．2.0 H2O: C 62.80, H 4.75, N 7.33; found: C 62.64, H 4.76, N 7.12.

2-(4-Methylsulfonylphenyl)furo[3',2':3,4]naphtho[1,2-d]imidazole (23). Mp = 268-269 oC.1H-NMR (400 MHz, DMSO-d6+ TFA-d): 3.38 (s, 3H, Me), 7.30 (d, 1H, J = 2.0 Hz, 4-H), 7.71-7.75 (m, 2H, 8- and 9-H), 8.18 (d, 1H, J = 2.0 Hz, 5-H), 8.28-8.31 (m, 1H, 7-H), 8.36-8.39 (m, 2H, Ar-H), 8.49-8.52 (m, 2H, Ar-H), 8.57-8.59 (m, 1H, 10-H). 13C-NMR (100 MHz, DMSO-d6+ TFA-d): 44.08, 106.06, 111.60, 119.15, 120.44, 121.69, 123.23, 124.66, 125.72, 127.76, 128.33, 128.58, 129.16 (2C), 129.26 (2C), 144.79, 144.89, 147.25, 150.33. HRMS (ESI): m/z calcd for C20H15N2O3S [M+H]+ 363.0803, found 363.0804. Anal. calcd for C20H14N2O3S: C 66.28, H 3.89, N 7.73; found: C 66.13, H 4.03, N 7.64.

Naphtho[1,2-b]furan-4,5-dione dioxime (24). Mp = 198-199oC.1H-NMR (400 MHz, DMSO-d6): 7.32 (d, 1H, J = 2.0 Hz, 3-H), 7.43-7.47 (m, 1H, 7-H), 7.54-7.58 (m, 1H, 8-H), 7.78 (dd,1H, J = 0.8, 7.6 Hz, 9-H), 7.96 (d,1H, J = 2.0 Hz, 2-H), 8.17 (dd,1H, J = 0.8, 8.4 Hz, 6-H), 12.72 (s, 1H, NOH), 14.71 (s, 1H, NOH). 13C-NMR (100 MHz, DMSO-d6):111.46, 113.05, 120.49, 123.10, 124.21, 128.59, 128.80, 129.67, 140.75, 143.85, 144.26, 151.64.HRMS (ESI): m/z calcd for C12H9N2O3 [M+H]+229.0613, found 229.0612.Anal. calcd for C12H8N2O3: C 63.16, H 3.53, N 12.28; found: C 63.03, H 3.60, N 12.10.

Furo[3',2':3,4]naphtho[1,2-c][1,2,5]oxadiazole (25).Mp =154-155oC.1H-NMR (400 MHz, CDCl3):7.23 (d, 1H, J = 2.0 Hz, 4-H), 7.63-7.67 (m, 1H, 8-H), 7.75 -7.79 (m, 1H, 7-H), 7.80 (d, 1H, J = 2.0 Hz, 5-H), 8.16 -8.19 (m, 1H, 6-H), 8.57-8.59 (m, 1H, 9-H). 13C-NMR (100 MHz, CDCl3):107.75, 108.95, 119.40, 121.61, 124.70, 126.26, 128.24, 131.00, 144.24, 145.25, 147.91, 153.06.HRMS (ESI): m/z calcd for C12H7N2O2 [M+H]+211.0508, found 211.0510.Anal. calcd for C12H6N2O2: C 68.57, H 2.88, N 13.33; found: C 68.54, H 2.98, N 13.25.

Benzo[f]furo[2,3-h]quinoxaline (26).Off-white solid (38%). Mp = 184-185oC. 1H-NMR (400 MHz, DMSO-d6): 7.58 (d, 1H, J = 2.0 Hz, 3-H), 7.80-7.84 (m, 1H, 10-H), 7.90-7.94 (m, 1H, 9-H), 8.32-8.34 (m, 2H, 2- and 8-H), 9.03 -9.05 (m, 2H, 5- and 6-H), 9.14-9.16 (m, 1H, 11-H). 13C-NMR (100 MHz, DMSO-d6): 107.03, 119.94, 119.99, 122.75, 125.07, 127.06, 128.29, 129.86, 138.41, 139.08, 142.55, 144.55, 146.33, 150.49.HRMS (ESI): m/z calcd for C14H9N2O [M+H]+221.0715, found 221.0716.Anal. calcd for C14H8N2O: C 76.35, H 3.66, N 12.72; found: C 76.40, H 3.70, N 12.78.

Benzo[a]furo[2,3-c]phenazine (27). Yellow solid (81%). Mp =195-196oC.1H-NMR (400 MHz, CDCl3): 7.62 (d, 1H, J = 2.0 Hz, 1-H),7.74-7.90 (m, 5H, Ar-H), 8.28-8.38 (m, 3H, Ar-H), 9.40-9.43 (m, 1H, 4-H).13C-NMR (100 MHz, CDCl3): 107.74, 120.08, 120.50, 124.83, 126.43, 127.17, 128.80, 129.07, 129.52, 129.85, 130.02, 130.15, 140.44, 140.98, 141.92, 142.13, 144.56, 152.68. HRMS (ESI): m/z calcd for C18H11N2O [M+H]+271.0871, found 271.0869.Anal. calcd forC18H10N2O: C 79.99, H 3.73, N 10.36; found: C 80.01, H 3.74, N 10.37.

10,11-Dimethylbenzo[a]furo[2,3-c]phenazine (28). Brown solid (88%). Mp = 230-231oC.1H-NMR (400 MHz, CDCl3): 2.55 (s, 6H, 2 X Me), 7.58 (d, 1H, J = 2.0 Hz, 1-H),7.70-7.81 (m, 2H, 5- and 6-H), 7.83 (d, 1H, J = 2.0 Hz, 2-H), 8.00 and 8.04 (two s, 2H, 9- and 12-H), 8.25-8.27 (m, 1H, 7-H), 9.33-9.36 (m, 1H, 4-H). 13C-NMR (100 MHz, CDCl3): 20.42, 20.56, 107.63, 120.16, 120.35, 124.50, 126.13, 126.92, 127.52, 128.52, 129.64, 129.67, 129.97, 139.83, 140.11, 140.95, 141.08, 144.36, 148.56, 152.22.HRMS (ESI): m/z calcd for C20H15N2O [M+H]+299.1184, found 299.1186.Anal. calcd for C20H14N2O．0.2 EtOH: C 79.66, H 4.99, N9.11; found: C80.06, H 4.66, N8.71.

10,11-Dichlorobenzo[a]furo[2,3-c]phenazine (29). Yellow solid (75%). Mp = 251-252oC. 1H-NMR (400 MHz, CDCl3): 7.50 (d, 1H, J = 2.0 Hz, 1-H), 7.71-7.84 (m, 3H, 2-, 5-, and 6-H), 8.23 (d, 1H, J = 8.0 Hz, 7-H), 8.34 and 8.37 (two s, 2H, 9- and 12-H), 9.23 (d, 1H, J = 8.0 Hz, 4-H). 13C-NMR (100 MHz, CDCl3): 107.67, 119.77, 120.62, 124.95, 126.54, 127.45, 129.04, 129.20, 130.10, 130.70, 133.52, 134.54, 139.38, 140.59, 140.97, 142.53, 144.79, 153.10.HRMS (ESI): m/z calcd for C18H9Cl2N2O [M+H]+ 339.0092, found 339.0090.Anal. calcd for C18H8Cl2N2O．0.1 H2O: C 63.38, H 2.43, N 8.22; found: C 62.98, H 2.45, N 8.06.

Dibenzo[a,i]furo[2,3-c]phenazine (30). Brown solid (72%). Mp = 246-247oC. 1H-NMR (400 MHz, CDCl3): 7.54-7.59 (m, 3H, 1-, 10-, and 13-H), 7.71-7.82 (m, 3H, 2, 5-, and 6-H), 8.13-8.21 (m, 3H, 7-, 11-, and 12-H), 8.42 and 8.91 (two s, 2H, 9- and 14-H), 9.35 (d, 1H, J = 8.0 Hz, 4-H). 13C-NMR (100 MHz, CDCl3): 107.92, 120.06, 120.63, 125.32, 126.26, 126.51, 126.64, 126.68, 127.45, 127.98, 128.38, 128.50, 129.71, 130.56, 133.47, 134.11, 137.88, 138.66, 141.56, 143.42, 144.56, 153.17.HRMS (ESI): m/z calcd for C22H13N2O [M+H]+ 321.1028, found 321.1027.Anal. calcd for C22H12N2O．0.1 H2O: C 82.01, H 3.82, N 8.70; found: C 81.95, H 3.84, N 8.68.

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