3.2. Synthesis
7-Chloro-3-iodo-1
H-pyrrolo[2,3-
c]pyridine (
7): This compound is mentioned in a patent [
41]; here, we provide the methodology and identification data. To a solution of
6 (1.40 g, 9.15 mmol) in anhydrous methanol (50 mL),
N-iodosuccinimide (2.80 g, 12.4 mmol) was added, and the mixture was stirred at rt for 1 h. Then, the organic solvent was evaporated under vacuo, and the residue was extracted with ethyl acetate. The organic layer was washed with a 10% sodium thiosulfate aqueous solution, dried (Na
2SO
4) and evaporated to dryness to result in
7 (2.56 g, 99%), m.p. 278–279 °C (CH
2Cl
2/Et
2O).
1H NMR (600 MHz, DMSO-
d6) δ 12.56-12.40 (brs, 1H, NH), 8.00 (d,
J = 5.4Hz, 1H, H-5), 7.89 (s, 1H, H-2), 7.31 (d,
J = 5.4 Hz, 1H, H-4).
13C NMR (151 MHz, DMSO-
d6) δ 137.95 (C-5), 136.50 (C-3a), 134.66 (C-2), 133.72 (C-7), 129.68 (C-7a), 114.63 (C-4), 56.54 (C-3). HR-MS (ESI)
m/
z: Calcd for C
7H
5ClIN
2: [M + H]
+ = 278.9181, found 278.9193.
7-Chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-c]pyridine (8): To a solution of 7 (2.40 g, 8.62 mmol) in anhydrous N,N-dimethylformamide (10 mL), sodium hydride (300 mg, 60% in hexanes) was added under cooling in an argon atmosphere, and the resulting solution was stirred at rt for 15 min. Then, 4-methoxybenzyl chloride (1.40 mL, 10.4 mmol) was added, and the solution was stirred at rt for 90 min. The solvent was vacuum-evaporated, ice-water was added to the residue and the precipitate was filtered and air-dried to provide pure 8 (3.40 g, 99%), m.p. 98–99 °C (CH2Cl2/Et2O). 1H NMR (600 MHz, DMSO-d6) δ 8.06 (s, 1H, H-2), 8.02 (d, J = 5.3 Hz, 1H, H-5), 7.34 (d, J = 5.3 Hz, 1H, H-4), 7.04 (d, J = 8.6 Hz, 2H, methoxybenzyl H-2,6), 6.87 (d, J = 8.6 Hz, 2H, methoxybenzyl H-3,5), 5.72 (s, 2H, CH2), 3.69 (s, 3H, CH3O). 13C NMR (151 MHz, DMSO-d6) δ 158.63 (methoxybenzyl C-4), 139.37 (C-2), 138.56 (C-5), 138.22 (C-3a), 132.76 (C-7), 130.14 (methoxybenzyl C-1), 128.39 (C-7a), 127.66 (methoxybenzyl C-2,6), 115.34 (C-4), 114.08 (methoxybenzyl C-3,5), 56.36 (C-3), 55.03 (CH3O), 50.60 (CH2). HR-MS (ESI) m/z: Calcd for C15H13ClIN2O: [M + H]+ = 398.9756, found 398.9766.
7-Chloro-1-(4-methoxybenzyl)-3-phenyl-1H-pyrrolo[2,3-c]pyridine (9a): To a solution of 8 (1.00 g, 2.51 mmol) in toluene (40 mL) and absolute ethanol (5 mL), phenylboronic acid (360 mg, 2.95 mmol), potassium carbonate (700 mg, 5.07 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 60.6 μmol) were added sequentially, and the solution was heated at reflux for 3 h. The solvents were evaporated under vacuo, water was added to the residue and it was extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to dryness, and the residue was purified by silica gel column chromatography (cyclohexane/ethyl acetate: 4/1) to give 9a (770 mg, 88%), m.p. 85–86 °C (CHCl3/n-hexane). 1H NMR (600 MHz, CDCl3) δ 8.08 (d, J = 5.5 Hz, 1H, H-5), 7.78 (d, J = 5.5 Hz, 1H, H-4), 7.55 (d, J = 7.4 Hz, 2H, phenyl H-2,6), 7.47-7.44 (m, 3H, H-2, phenyl H-3,5), 7.34 (t, J = 7.4 Hz, 1H, phenyl H-4), 7.11 (d, J = 8.7 Hz, 2H, methoxybenzyl H-2,6), 6.87 (d, J = 8.7 Hz, 2H, methoxybenzyl H-3,5), 5.78 (s, 2H, CH2), 3.78 (s, 3H, CH3O). 13C NMR (151 MHz, CDCl3) δ 159.62 (methoxybenzyl C-4), 137.03 (C-5), 135.24 (C-7), 133.57 (phenyl C-1), 133.25 (C-3a), 132.74 (C-2), 129.42 (methoxybenzyl C-1), 129.21 (phenyl C-3,5), 129.13 (C-7a), 128.45 (methoxybenzyl C-2,6), 127.73 (phenyl C-2,6), 127.23 (phenyl C-4), 118.25 (C-3), 114.57 (methoxybenzyl C-3,5), 114.55 (C-4), 55.46 (CH3O), 51.80 (CH2). HR-MS (ESI) m/z: Calcd for C21H18ClN2O: [M + H]+ = 349.1103, found 349.1115.
7-Chloro-3-(3-fluorophenyl)-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-c]pyridine (9b): This compound was synthesized using a procedure analogous to that of 9a, starting from 8. Purification was carried out by silica gel column chromatography (cyclohexane/ethyl acetate: 7/3). Oil, yield: 98%. 1H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 5.5 Hz, 1H, H-5), 7.75 (d, J = 5.5 Hz, 1H, H-4), 7.45-7.41 (m, 2H, H-2, fluorophenyl H-5), 7.38-7.34 (m, 1H, fluorophenyl H-6), 7.29-7.26 (m, 1H, fluorophenyl H-2), 7.14 (d, J = 8.9 Hz, 2H, methoxybenzyl H-2,6), 7.06-7.01 (m, 1H, fluorophenyl H-4), 6.90 (d, J= 8.9 Hz, 2H, methoxybenzyl H-3,5), 5.80 (s, 2H, CH2), 3.82 (s, 3H, CH3O). 13C NMR (151 MHz, CDCl3) δ 164.20, 162.57 (fluorophenyl C-3), 159.55 (methoxybenzyl C-4), 138.61 (C-5), 134.48, 134.41 (fluorophenyl C-1), 134.24 (C-7), 131.72 (C-2), 130.64, 130.58 (fluorophenyl C-5), 129.64 (C-7a), 129.37 (methoxybenzyl C-1), 128.55 (C-3a), 128.44 (methoxybenzyl C-2,6), 123.20 (fluorophenyl C-6), 116.70 (C-3), 114.53 (methoxybenzyl C-3,5), 114.43, 114.29 (fluorophenyl C-2), 114.15 (C-4), 113.78, 113.64 (fluorophenyl C-4), 55.44 (CH3O), 51.68 (CH2). HR-MS (ESI) m/z: Calcd for C21H17ClFN2O: [M + H]+ = 367.1008, found 367.0995.
1-(4-Methoxybenzyl)-Ν,3-diphenyl-1H-pyrrolo[2,3-c]pyridin-7-amine (10a): To a solution of 9a (120 mg, 0.34 mmol) in anhydrous toluene (2 mL), tris(dibenzylideneacetone)dipalladium(0) (8.0 mg, 8.7 μmol), 2,2′-bis(diphenylphosphino)-1,1′-dinapthalene (16 mg, 0.26 mmol), potassium tert-butoxide (60 mg, 0.50 mmol) and aniline (46 μL, 0.50 mmol) were added sequentially, and the solution was heated at reflux for 3.5 h. It was then extracted with ethyl acetate,the organic layer was dried (Na2SO4) and concentrated to dryness, and the residue was purified by silica gel column chromatography (cyclohexane/ethyl acetate: 1/1) to give 10a in 87% yield, m.p. 180–181 °C (EtOAc/Et2O). 1H NMR (600 MHz, Acetone-d6) δ 7.87 (d, J = 5.3 Hz, 1H, H-5), 7.81 (s, 1H, H-2), 7.70 (d, J = 7.5 Hz, 2H, 3-phenyl H-2,6), 7.49-7.44 (m, 3H, H-4, 3-phenyl H-3,5), 7.29 (t, J = 7.4 Hz, 1H, 3-phenyl H-4), 7.25-7.18 (m, 6H, N7-phenyl H-2,6, methoxybenzyl H-2,6, N7-phenyl H-3,5), 7.16 (brs, 1H, ΝH), 6.92 (d, J = 8.7 Hz, 2H, methoxybenzyl H-3,5), 6.87 (t, J = 7.0 Hz, 1H, N7-phenyl H-4), 5.69 (s, 2H, CH2), 3.75 (s, 3H, CH3O). 13C NMR (151 MHz, Acetone-d6) δ 160.62 (methoxybenzyl C-4), 144.01 (N7-phenyl C-1), 143.60 (C-7), 138.19 (C-5), 135.83 (3-phenyl C-1), 134.39 (C-3a), 131.95 (C-2), 131.25 (methoxybenzyl C-1), 129.81 (3-phenyl C-3,5), 129.52 (N7-phenyl C-3,5), 128.94 (methoxybenzyl C-2,6), 128.02 (3-phenyl C-2,6), 126.99 (3-phenyl C-4), 124.93 (C-7a), 121.51 (N7-phenyl C-4), 119.09 (N7-phenyl C-2,6), 117.51 (C-3), 115.41 (methoxybenzyl C-3,5), 110.05 (C-4), 55.68 (CH3O), 52.53 (CH2). HR-MS (ESI) m/z: Calcd for C27H24N3O: [M + H]+ = 406.1914, found 406.1900. Anal. Calcd for C27H23N3O: C, 79.97; H, 5.72; N, 10.36. Found: C, 80.06; H, 5.77; N, 10.21.
3-(3-Fluorophenyl)-1-(4-methoxybenzyl)-Ν-phenyl-1H-pyrrolo[2,3-c]pyridin-7-amine (10b): This compound was synthesized using a procedure analogous to that of 10a, starting from 9b. Purification was carried out by silica gel column chromatography (dichloromethane/ethyl acetate: 9/1). Yield: 91%, m.p. 165–166 °C (CH2Cl2/n-pentane). 1H NMR (600 MHz, Acetone-d6) δ 7.91 (s, 1H, H-2), 7.89 (d, J = 5.4 Hz, 1H, H-5), 7.58-7.55 (m, 1H, fluorophenyl H-6), 7.51-7.48 (m, 2H, H-4, fluorophenyl H-5), 7.47-7.43 (m, 1H, fluorophenyl H-2), 7.25-7.16 (m, 7H, phenyl H-2,6, methoxybenzyl H-2,6, phenyl H-3,5,NH), 7.07-7.03 (m, 1H, fluorophenyl H-4), 6.92 (d, J = 8.2 Hz, 2H, methoxybenzyl H-3,5), 6.88 (t, J = 7.0 Hz, 1H, phenyl H-4), 5.71 (s, 2H, CH2), 3.76 (s, 3H, CH3O). 13C NMR (151 MHz, Acetone-d6) δ 165.09, 163.48 (fluorophenyl C-3), 160.67 (methoxybenzyl C-4), 143.89 (phenyl C-1), 143.70 (C-7), 138.51 (C-5), 138.32 (fluorophenyl C-1), 134.16 (C-3a), 132.59 (C-2), 131.65, 131.59 (fluorophenyl C-5), 131.07 (methoxybenzyl C-1), 129.52 (phenyl C-3,5), 128.96 (methoxybenzyl C-2,6), 124.90 (C-7a), 123.80 (fluorophenyl C-6), 121.61 (phenyl C-4), 119.18 (phenyl C-2,6), 116.21 (C-3), 115.44 (methoxybenzyl C-3,5), 114.35, 114.21 (fluorophenyl C-2), 113.52, 113.38 (fluorophenyl C-4), 109.81 (C-4), 55.69 (CH3O), 52.65 (CH2). HR-MS (ESI) m/z: Calcd for C27H23FN3O: [M + H]+ = 424.1820, found 424.1804. Anal. Calcd for C27H22FN3O: C, 76.58; H, 5.24; N, 9.92. Found: C, 76.73; H, 5.29; N, 9.66.
1-(4-Methoxybenzyl)-Ν-(3,4,5-trimethoxyphenyl)-3-phenyl-1H-pyrrolo[2,3-c]pyridin-7-amine (10c): This compound was synthesized using a procedure analogous to that of 10a, starting from 9a. Purification was carried out by silica gel column chromatography (cyclohexane/ethyl acetate: 1/1). Yield: 60%, m.p. 136–137 °C (EtOAc/Et2O). 1H NMR (600 MHz, DMSO-d6) δ 7.99 (s, 1H, H-2), 7.89 (s, 1H, NH), 7.82 (d, J = 5.5 Hz, 1H, H-5), 7.66 (d, J = 7.5 Hz, 2H, phenyl H-2,6), 7.46 (t, J = 7.6 Hz, 2H, phenyl H-3,5), 7.42 (d, J = 5.5 Hz, 1H, H-4), 7.28 (t, J = 7.3 Hz, 1H, phenyl H-4), 7.10 (d, J = 8.5 Hz, 2H, methoxybenzyl H-2,6), 6.83 (d, J = 8.5 Hz, 2H, methoxybenzyl H-3,5), 6.54 (s, 2H, trimethoxyphenyl H-2,6), 5.65 (s, 2H, CH2), 3.69 (s, 6H, trimethoxyphenyl CH3O-3,5), 3.66 (s, 3H, methoxybenzyl CH3O), 3.61 (s, 3H, trimethoxyphenyl CH3O-4). 13C NMR (151 MHz, DMSO-d6) δ 158.66 (methoxybenzyl C-4), 152.75 (trimethoxyphenyl C-3,5), 142.70 (C-7), 138.92 (trimethoxyphenyl C-1), 137.02 (C-5), 134.34 (phenyl C-1), 132.77 (C-3a), 131.59 (trimethoxyphenyl C-4), 131.46 (C-2), 130.23 (methoxybenzyl C-1), 128.92 (phenyl C-3,5), 128.13 (methoxybenzyl C-2,6), 126.59 (phenyl C-2,6), 125.92 (phenyl C-4), 123.40 (C-7a), 115.51 (C-3), 114.07 (methoxybenzyl C-3,5), 108.67 (C-4), 96.24 (trimethoxyphenyl C-2,6), 60.12 (trimethoxyphenyl CH3O-4), 55.64 (trimethoxyphenyl CH3O-3,5), 55.00 (methoxybenzyl CH3O), 51.06 (CH2). HR-MS (ESI) m/z: Calcd for C30H30N3O4: [M + H]+ = 496.2231, found 496.2224. Anal. Calcd for C30H29N3O4: C, 72.71; H, 5.90; N, 8.48. Found: C, 72.80; H, 5.94; N, 8.34.
3-(3-Fluorophenyl)-1-(4-methoxybenzyl)-Ν-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-c]pyridin-7-amine (10d): This compound was synthesized using a procedure analogous to that of 10a, starting from 9b.The reaction was completed at 20 h. Purification was carried out by silica gel column chromatography (cyclohexane/ethyl acetate: 1/1). Yield: 60%, m.p. 93–94 °C (CH2Cl2/n-pentane). 1H NMR (600 MHz, Acetone-d6) δ 7.91 (s, 1H, H-2), 7.87 (d, J = 5.2 Hz, 1H, H-5), 7.56-7.54 (m, 1H, fluorophenyl H-6), 7.49-7.46 (m, 1H, fluorophenyl H-5), 7.45-7.42 (m, 2H, H-4, fluorophenyl H-2), 7.26 (d, J = 8.8 Hz, 2H, methoxybenzyl H-2,6), 7.07-7.02 (m, 1H, fluorophenyl H-4), 6.98 (d, J = 8.8 Hz, 2H, methoxybenzyl H-3,5), 6.58 (s, 2H, trimethoxyphenyl H-2,6), 5.74 (s, 2H, CH2), 3.77 (s, 3H, methoxybenzyl CH3O), 3.73 (s, 6H, trimethoxyphenyl CH3O-3,5), 3.66 (s, 3H, trimethoxyphenyl CH3O-4). 13C NMR (151 MHz, Acetone-d6) δ 165.08, 163.47 (fluorophenyl C-3), 160.76 (methoxybenzyl C-4), 154.40 (trimethoxyphenyl C-3,5), 143.99 (C-7), 139.50 (trimethoxyphenyl C-1), 138.38, 138.32 (fluorophenyl C-1), 133.95 (trimethoxyphenyl C-4), 133.86 (C-3a), 132.64 (C-2), 131.65, 131.59 (fluorophenyl C-5), 131.01 (methoxybenzyl C-1), 128.92 (methoxybenzyl C-2,6), 124.30 (C-7a), 123.79 (fluorophenyl C-6), 116.18(C-3), 115.56 (methoxybenzyl C-3,5), 114.34, 114.20 (fluorophenyl C-2), 113.51, 113.37 (fluorophenyl C-4), 109.16 (C-4), 97.69 (trimethoxyphenyl C-2,6), 60.71 (trimethoxyphenyl CH3O-4), 56.40 (trimethoxyphenyl CH3O-3,5), 55.72 (methoxybenzyl CH3O), 52.77 (CH2). HR-MS (ESI) m/z: Calcd for C30H29FN3O4: [M + H]+ = 514.2137, found 514.2114. Anal. Calcd for C30H28FN3O4: C, 70.16; H, 5.50; N, 8.18. Found: C, 70.01; H, 5.44; N, 8.37.
7-Chloro-1-(4-methoxybenzyl)-3-phenyl-1H-pyrrolo[2,3-c]pyridin-6-oxide (11a): To a solution of 9a (240 mg, 0.69 mmol) in dichloromethane (5 mL), m-chloroperoxybenzoic acid (180 mg, 1.04 mmol) was added, and the solution was stirred at rt for 72h. The solvent was then vacuum-evaporated, and a saturated sodium bicarbonate solution was added to the residue and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol: 95/5) to yield 11a (220 mg, 88%), m.p. 160–161 °C (EtOAc/n-pentane). 1H NMR (600 MHz, CDCl3) δ 8.16 (d, J = 6.8 Hz, 1H, H-5), 7.60 (d, J = 6.8 Hz, 1H, H-4), 7.49 (d, J = 7.6 Hz, 2H, phenyl H-2,6), 7.43 (t, J = 7,5 Hz, 2H, phenyl H-3,5), 7.37 (s, 1H, H-2), 7.33 (t, J = 7.3 Hz, 1H, phenyl H-4), 7.04 (d, J = 7.8 Hz, 2H, methoxybenzyl H-2,6), 6.84 (d, J = 7.8 Hz, 2H, methoxybenzyl H-3,5), 5.66 (s, 2H, CH2), 3.76 (s, 3H, CH3O). 13C NMR (151 MHz, CDCl3) δ 159.68 (methoxybenzyl C-4), 133.45 (C-5), 132.65 (C-2), 132.11 (phenyl C-4), 130.45 (C-7a), 129.28 (phenyl C-1), 128.79 (phenyl C-3,5), 128.23 (methoxybenzyl C-2,6), 127.67 (phenyl C-2,6), 127.50 (C-7), 126.04 (C-3a), 118.83 (C-3), 114.65 (methoxybenzyl C-3,5), 114.47 (methoxybenzyl C-1), 114.03 (C-4), 55.47 (CH3O), 51.83 (CH2). HR-MS (ESI) m/z: Calcd for C21H18ClN2O2: [M + H]+ = 365.1052, found 365.1036.
7-Chloro-3-(3-fluorophenyl)-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-c]pyridin-6-oxide (11b): This compound was synthesized using a procedure analogous to that of 11a, starting from 9b. Purification was carried out by silica gel column chromatography (ethyl acetate/methanol: 9/1). Yield: 88%, m.p. 124–125 °C (EtOAc/n-pentane). 1H NMR (600 MHz, Acetone-d6) δ 8.23 (d, J = 6.7 Hz, 1H, H-5), 7.63 (d, J = 6.7 Hz, 1H, H-4), 7.51 (td, J = 7.9, 4.2 Hz, 1H, fluorophenyl H-5), 7.41 (s, 1H, H-2), 7.37 (dt, J = 7.8, 1.2 Hz, 1H, fluorophenyl H-6), 7.28 (ddd, J = 10.0, 2.5, 1.7 Hz, 1H, fluorophenyl H-2), 7.17 (tdd, J = 8.4, 2.7, 0.9 Hz, 1H, fluorophenyl H-4), 7.07 (d, J = 8.1 Hz, 2H, methoxybenzyl H-2,6), 6.87 (d, J = 8.1 Hz, 2H, methoxybenzyl H-3,5), 5.68 (s, 2H, CH2), 3.78 (s, 3H, CH3O). 13C NMR (151 MHz, Acetone-d6) δ 163.73, 162.11 (fluorophenyl C-3), 159.84 (methoxybenzyl C-4), 136.00, 135.94 (fluorophenyl C-1), 134.63 (C-7), 133.21 (C-5), 132.27 (C-2), 130.23 (C-7a), 130.05, 129.99 (fluorophenyl C-5), 128.24 (methoxybenzyl C-2,6), 125.57 (C-3a), 123.33 (fluorophenyl C-6), 119.10 (C-3), 114.77 (methoxybenzyl C-3,5), 114.47 (methoxybenzyl C-1), 114.43, 114.29 (fluorophenyl C-2), 114.25 (C-4), 114.04, 113.90 (fluorophenyl C-4), 55.48 (CH3O), 52.08 (CH2). HR-MS (ESI) m/z: Calcd for C21H17ClFN2O2: [M + H]+ = 383.0958, found 383.0967.
1-(4-Methoxybenzyl)-7-(4-methylpiperazin-1-yl)-3-phenyl-1H-pyrrolo[2,3-c]pyridine-6-oxide (12a): To a solution of 11a (120 mg, 0.33 mmol) in absolute ethanol (5 mL), 1-methylpiperazine (0.20 mL, 2.00 mmol) was added, and the solution was heated in an autoclave at 120 °C for 24 h. The mixture was extracted with ethyl acetate, the organic phase was dried (Na2SO4) and concentrated to dryness and the residue was purified by silica gel column chromatography (dichloromethane/methanol: 8/2) to give 12a (40 mg, 50%), m.p. 127–128 °C (EtOAc/n-pentane). 1H NMR (600 MHz, CD3OD) 8.00 (d, J = 6.9 Hz, 1H, H-5), 7.85 (d, J = 6.9 Hz, 1H, H-4), 7.79 (s, 1H, H-2), 7.62 (d, J = 7.7 Hz, 2H, phenyl H-2,6), 7.46 (t, J = 7.4 Hz, 2H, phenyl H-3,5), 7.32 (t, J = 7.4 Hz, 1H, phenyl H-4), 6.90 (m, 4H, methoxybenzyl H-2,3,5,6), 5.89 (s, 2H, CH2), 4.17-4.14 (m, 2H, methylpiperazine H), 3.75 (s, 3H, CH3O), 2.89-2.85 (m, 2H, methylpiperazine H), 2.80-2.75 (m, 2H, methylpiperazine H), 2.40 (s, 3H, methylpiperazine CH3), 2.24-2.18 (m, 2H, methylpiperazine H). 13C NMR (600 MHz, CD3OD) 160.65 (methoxybenzyl C-4), 142.92 (C-7), 135.49 (C-2), 134.34 (phenyl C-1), 134.17 (C-5), 131.90 (methoxybenzyl C-1), 131.56 (C-3a), 130.43 (C-7a), 130.14 (phenyl C-3,5), 128.41 (phenyl C-2,6), 128.09 (phenyl C-4), 127.62 (methoxybenzyl C-2,6), 119.51 (C-3), 115.69 (C-4), 115.40 (methoxybenzyl C-3,5), 55.78 (CH3O), 55.11 (methylpiperazine C-3,5), 52.30 (CH2), 47.81 (methylpiperazine C-2,6), 45.67 (methylpiperazine CH3). HR-MS (ESI) m/z: Calcd for C26H29N4O2: [M + H]+ = 429.2286, found 429.2273.
3-(3-Fluorophenyl)-1-(4-methoxybenzyl)-7-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-6-oxide (12b): This compound was synthesized using a procedure analogous to that of 12a, starting from 11b. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 85/15). Yield: 50%, m.p. 91–92 °C (EtOAc/n-pentane). 1H NMR (600 MHz, CD3OD) δ 8.01 (d, J = 6.9 Hz, 1H, H-5), 7.85 (d, J = 6.9 Hz, 1H, H-4), 7.84 (s, 1H, H-2), 7.49-7.45 (m, 1H, fluorophenyl H-5), 7.48-7.44 (m, 1H, fluorophenyl H-6), 7.39-7.34 (m, 1H, fluorophenyl H-2), 7.07-7.01 (m, 1H, fluorophenyl H-4), 6.90-6.88 (m, 4H, methoxybenzyl H-2,3,5,6), 5.91 (s, 2H, CH2), 4.14-4.10 (m, 2H, methylpiperazine H), 3.75 (s, 3H, CH3O), 2.77-2.72 (m, 4H, methylpiperazine H), 2.29 (s, 3H, methylpiperazine CH3), 2.10-2.06 (m, 2H, methylpiperazine H). 13C NMR (151 MHz, CD3OD) δ 165.55, 163.93 (fluorophenyl C-3), 160.63 (methoxybenzyl C-4), 143.34 (C-7), 136.81, 136.76 (fluorophenyl C-1), 135.89 (C-2), 134.46 (C-5), 131.95, 131.89 (fluorophenyl C-5), 131.75 (C-7a), 131.69 (C-3a), 129.72 (methoxybenzyl C-1), 127.66 (methoxybenzyl C-2,6), 124.16 (fluorophenyl C-6), 118.20 (C-3), 115.44 (C-4), 115.37 (methoxybenzyl C-3,5), 114.92, 114.77 (fluorophenyl C-2), 114.66, 114.52 (fluorophenyl C-4), 55.78 (CH3O), 55.26 (methylpiperazine C-3,5), 52.31 (CH2), 48.13 (methylpiperazine C-2,6), 46.10 (methylpiperazine CH3). HR-MS (ESI) m/z: Calcd for C26H28FN4O2: [M + H]+ = 447.2191, found 447.2176.
1-(4-Methoxybenzyl)-7-(4-methylpiperazin-1-yl)-3-phenyl-1H-pyrrolo[2,3-c]pyridine (13a): To a solution of 12a (70 mg, 0.16 mmol) in chloroform (3 mL), phosphorus trichloride (0.10 mL, 0.67 mmol) was added, and the solution was stirred at rt for 20 h. The solvent was then vacuum-evaporated and the mixture was neutralized with a sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated to dryness, and the residue was purified by silica gel column chromatography (dichloromethane/methanol: 9/1) to give 13a (50 mg, 72%), m.p. 88–89 °C (Et2O/n-pentane). 1H NMR (600 MHz, CDCl3) 8.04 (d, J = 5.5 Hz, 1H, H-5), 7.59-7.54 (m, 3H, H-4, phenyl H-2,6), 7.42 (t, J = 7.8 Hz, 2H, phenyl H-3,5), 7.30-7.27 (m, 2H, H-2, phenyl H-4), 7.08 (d, J = 8.7 Hz, 2H, methoxybenzyl H-2,6), 6.83 (d, J = 8.7 Hz, 2H, methoxybenzyl H-3,5), 5.70 (s, 2H, CH2), 3.78 (s, 3H, CH3O), 3.32-3.25 (brs, 4H, methylpiperazine H-2,6), 3.02-2.57 (brs, 4H, methylpiperazine H-3,5), 2.38 (s, 3H, methylpiperazine CH3). 13C NMR (600 MHz, CDCl3) 159.25 (methoxybenzyl C-4), 150.88 (C-7), 137.69 (C-5), 134.75 (phenyl C-1), 133.87 (C-3a), 130.62 (methoxybenzyl C-1), 129.77 (C-2), 129.02 (phenyl C-3,5), 128.45 (methoxybenzyl C-2,6), 127.51 (phenyl C-2,6), 126.56 (phenyl C-4), 126.49 (C-7a), 118.30 (C-3), 114.37 (methoxybenzyl C-3,5), 111.55 (C-4), 55.47 (CH3O), 55.26 (methylpiperazine C-3,5), 51.14 (methylpiperazine C-2,6), 50.38 (CH2), 46.38 (methylpiperazine CH3). HR-MS (ESI) m/z: Calcd for C26H29N4O: [M + H]+ = 413.2336, found 413.2319. Anal. Calcd for C26H28N4O: C, 75.70; H, 6.84; N, 13.58. Found: C, 75.52; H, 6.69; N, 13.66.
3-(3-Fluorophenyl)-1-(4-methoxybenzyl)-7-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine (13b): This compound was synthesized using a procedure analogous to that of 13a, starting from 12b. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 9/1). Oil, yield: 99%. 1H NMR (600 MHz, Acetone-d6) δ 7.98 (d, J = 5.6 Hz, 1H, H-5), 7.85 (s, 1H, H-2), 7.57 (d, J = 5.5 Hz, 1H, H-4), 7.52-7.50 (m, 1H, fluorophenyl H-6), 7.47-7.45 (m, 1H, fluorophenyl H-5), 7.41-7.37 (m, 1H, fluorophenyl H-2), 7.21 (d, J = 8.5 Hz, 2H, methoxybenzyl H-2,6), 7.06-7.02 (m, 1H, fluorophenyl H-4), 6.83 (d, J = 8.5 Hz, 2H, methoxybenzyl H-3,5), 5.76 (s, 2H, CH2), 3.72 (s, 3H, CH3O), 3.27-3.20 (brs, 4H, methylpiperazine H-2,6), 2.75-2.50 (brs, 4H, methylpiperazine H-3,5), 2.32 (s, 3H, methylpiperazine CH3). 13C NMR (151 MHz, Acetone-d6) δ 165.04, 163.43 (fluorophenyl C-3), 160.16 (methoxybenzyl C-4), 151.99 (C-7), 138.71 (C-5), 138.32, 138.26 (fluorophenyl C-1), 134.31 (C-3a), 132.02 (C-2), 131.91 (methoxybenzyl C-1), 131.61, 131.55 (fluorophenyl C-5), 129.48 (methoxybenzyl C-2,6), 127.07 (C-7a), 123.70, 123.69 (fluorophenyl C-6), 117.01 (C-3), 114.85 (methoxybenzyl C-3,5), 114.25, 114.10 (fluorophenyl C-2), 113.50, 113.36 (fluorophenyl C-4), 111.79 (C-4), 55.83 (CH3O), 55.55 (methylpiperazine C-3,5), 51.88 (methylpiperazine C-2,6), 51.15 (CH2), 46.44 (methylpiperazine CH3). HR-MS (ESI) m/z: Calcd for C26H28FN4O: [M + H]+ = 431.2242, found 431.2231. Anal. Calcd for C26H27FN4O: C, 72.54; H, 6.32; N, 13.01. Found: C, 72.33; H, 6.19; N, 13.26.
Ν,3-Diphenyl-1H-pyrrolo[2,3-c]pyridin-7-amine (14a): A solution of 10a (50 mg, 0.12 mmol) in trifluoroacetic acid (2mL) was heated at 60 °C for 20h. The mixture was then vacuum-evaporated, neutralized with a sodium bicarbonate solution, extracted with ethyl acetate, dried (Na2SO4) and concentrated to dryness. The residue was purified by silica gel column chromatography (dichloromethane/methanol: 9/1) to give 14a (yield 99%), m.p. 139-140 °C (EtOAc/Et2O). 1H NMR (600 MHz, Acetone-d6) δ 11.69-11.18 (brs, 1H, pyrrole NH), 9.45-8.50 (brs, 1H, pyridinamine NH), 7.89 (d, J = 8.0 Hz, 2H, N7-phenyl H-2,6), 7.82 (d, J = 5.8 Hz, 1H, H-5), 7.77 (s, 1H, H-2), 7.69 (d, J = 7.8 Hz, 2H, 3-phenyl H-2,6), 7.45 (t, J = 7.5 Hz, 2H, 3-phenyl H-3,5), 7.39 (d, J = 5.8 Hz, 1H, H-4), 7.31 (t, J = 7.5 Hz, 2H, N7-phenyl H-3,5), 7.28 (t, J = 7.4 Hz, 1H, 3-phenyl H-4), 6.99 (t, J = 7.4 Hz, 1H, N7-phenyl H-4). 13C NMR (151 MHz, Acetone-d6) δ 143.78 (C-7), 141.86 (N7-phenyl C-1), 136.08 (C-5), 135.36 (3-phenyl C-1), 131.38 (C-3a), 129.79 (3-phenyl C-3,5), 129.76 (N7-phenyl C-3,5), 127.93 (3-phenyl C-2,6), 126.95 (3-phenyl C-4), 126.12 (N7-phenyl C-4), 122.84 (C-2), 122.52 (C-7a), 120.55 (N7-phenyl C-2,6), 118.92 (C-3), 108.00 (C-4). HR-MS (ESI) m/z: Calcd for C19H16N3: [M + H]+ = 286.1339, found 286.1340. Anal. Calcd for C19H15N3: C, 79.98; H, 5.30; N, 14.72. Found: C, 79.77; H, 5.16; N, 14.89.
3-(3-Fluorophenyl)-Ν-phenyl-1H-pyrrolo[2,3-c]pyridin-7-amine (14b): This compound was synthesized using a procedure analogous to that of 14a, starting from 10b. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 9/1). Yield: 99%, m.p. 168–169 °C (EtOAc/Et2O). 1H NMR (600 MHz, Acetone-d6) δ 11.66-11.23 (brs, 1H, pyrrole NH), 8.94-8.58 (brs, 1H, pyridinamine NH), 7.90-7.85 (m, 4H, H-5, H-2, phenyl H-2,6), 7.57-7.54 (m, 1H, fluorophenyl H-6), 7.51-7.48 (m, 1H, fluorophenyl H-5), 7.46-7.43 (m, 1H, fluorophenyl H-2), 7.40 (d, J = 5.6 Hz, 1H, H-4), 7.31 (t, J = 7.5 Hz, 2H, phenyl H-3,5), 7.06-7.02 (m, 1H, fluorophenyl H-4), 6.98 (t, J = 7.1 Hz, 1H, phenyl H-4). 13C NMR (151 MHz, Acetone-d6) δ 165.10, 163.48 (fluorophenyl C-3), 143.94 (C-5, C-7), 142.19 (phenyl C-1), 138.76, 138.70 (fluorophenyl C-1), 136.40 (C-3a), 131.62, 131.56 (fluorophenyl C-5), 131.14 (C-2), 129.69 (phenyl C-3,5), 126.49 (C-7a), 123.69 (phenyl C-4), 122.72, 122.55 (fluorophenyl C-6), 120.22 (phenyl C-2,6), 117.57 (C-3), 114.24, 114.09 (fluorophenyl C-2), 113.44, 113.30 (fluorophenyl C-4), 107.82 (C-4). HR-MS (ESI) m/z: Calcd for C19H15FN3: [M + H]+ = 304.1245, found 304.1245. Anal. Calcd for C19H14FN3: C, 75.23; H, 4.65; N, 13.85. Found: C, 75.40; H, 4.71; N, 13.69.
N-(3,4,5-trimethoxyphenyl)-3-phenyl-1H-pyrrolo[2,3-c]pyridin-7-amine (14c): This compound was synthesized using a procedure analogous to that of 14a, starting from 10c. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 95/5).Yield: 99%, m.p. 153–154 °C (EtOAc/n-pentane). 1H NMR (600 MHz, DMSO-d6) δ 11.56-11.49 (brs, 1H, pyrrole NH), 8.73-8.65 (brs, 1H, pyridinamine NH), 7.90 (s, 1H, H-2), 7.80 (d, J = 5.7 Hz, 1H, H-5), 7.68 (d, J = 7.6 Hz, 2H, phenyl H-2,6), 7.45 (t, J = 7.6Hz, 2H, phenyl H-3,5), 7.30 (d, J = 5.7Hz, 1H, H-4), 7.28-7.25 (m, 3H, trimethoxyphenyl H-2,6, phenyl H-4), 3.81 (s, 6H, trimethoxyphenyl CH3O-3,5), 3.64 (s, 3H, trimethoxyphenyl CH3O-4).13C NMR (151 MHz, DMSO-d6) δ 152.83 (trimethoxyphenyl C-3,5), 142.93 (C-7), 137.89 (trimethoxyphenyl C-1), 136.24 (C-5), 135.06 (phenyl C-1), 131.83 (trimethoxyphenyl C-4), 129.21 (C-3a), 128.91 (phenyl C-3,5), 126.41 (phenyl C-2,6), 125.70 (phenyl C-4), 124.75 (C-2), 121.31 (C-7a), 116.39 (C-3), 106.62 (C-4), 96.13 (trimethoxyphenyl C-2,6), 60.18 (trimethoxyphenyl CH3O-4), 55.76 (trimethoxyphenyl CH3O-3,5). HR-MS (ESI) m/z: Calcd for C22H20N3O3: [M-H]- = 374.1510, found 374.1508. Anal. Calcd for C22H21N3O3: C, 70.38; H, 5.64; N, 11.19. Found: C, 70.44; H, 5.68; N, 11.11.
3-(3-Fluorophenyl)-N-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-c]pyridin-7-amine (14d): This compound was synthesized using a procedure analogous to that of 14a, starting from 10d. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 95/5).Yield: 99%, m.p. 149–150 °C (EtOAc/n-pentane). 1H NMR (600 MHz, Acetone-d6) δ 11.52-10,85 (brs, 1H, pyrrole NH), 8.90-8.14 (brs, 1H, pyridinamine NH), 7.87 (d, J = 5.7 Hz, 1H, H-5), 7.82 (s, 1H, H-2), 7.56-7.53 (m, 1H, fluorophenyl H-6), 7.50-7.47 (m, 1H, fluorophenyl H-5), 7.46-7.42 (m, 1H, fluorophenyl H-2), 7.37 (d, J = 5.7 Hz, 1H, H-4), 7.27 (s, 2H, trimethoxyphenyl H-2,6), 7.06-7.02 (m, 1H, fluorophenyl H-4), 3.78 (s, 6H, trimethoxyphenyl CH3O-3,5), 3.67 (s, 3H, trimethoxyphenyl CH3O-4). 13C NMR (151 MHz, Acetone-d6) δ 165.08, 163.47 (fluorophenyl C-3), 154.49 (trimethoxyphenyl C-3,5), 144.26 (C-6), 138.81, 138.75 (fluorophenyl C-1), 138.31 (trimethoxyphenyl C-1), 136.86 (C-5), 134.33 (trimethoxyphenyl C-4), 131.59, 131.54 (fluorophenyl C-5), 131.03 (C-3a), 126.22 (C-2), 123.65 (fluorophenyl C-6), 122.64 (C-7a), 117.47 (C-3), 114.18, 114.04 (fluorophenyl C-2), 113.38, 113.24 (fluorophenyl C-4), 107.61 (C-4), 98.40 (trimethoxyphenyl C-2,6), 60.73 (trimethoxyphenyl CH3O-4), 56.40 (trimethoxyphenyl CH3O-3,5). HR-MS (ESI) m/z: Calcd for C22H21FN3O3: [M + H]+ = 394.1562, found 394.1561. Anal. Calcd for C22H20FN3O3: C, 67.17; H, 5.12; N, 10.68. Found: C, 67.33; H, 5.24; N, 10.59.
7-(4-Methylpiperazin-1-yl)-3-phenyl-1H-pyrrolo[2,3-c]pyridine (14e): This compound was synthesized using a procedure analogous to that of 14a, starting from 13a. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 85/15). Yield: 91%, m.p. 220–221 °C (EtOAc/Et2O). 1H NMR (600 MHz, Acetone-d6) δ 10.80-10.70 (brs, 1H, ΝH), 7.88 (d, J = 5.6 Hz, 1H, H-5), 7.70-7.65 (m, 3H, phenyl H-2,6, H-2), 7.47-7.40 (m, 3H, phenyl H-3,5, H-4), 7.26 (t, J = 7.7 Hz, 1H, phenyl H-4), 3.52-3.46 (m, 4H, methylpiperazine H-2,6), 2.64-2.60 (m, 4H, methylpiperazine H-3,5), 2.32 (s, 3H, methylpiperazine CH3). 13C NMR (600 MHz, Acetone-d6) δ 150.27 (C-7), 137.95 (C-5), 136.39 (phenyl C-1), 132.33 (C-3a), 129.72 (phenyl C-3,5), 127.91 (phenyl C-2,6), 126.76 (phenyl C-4), 125.24 (C-7a), 125.08 (C-2), 118.36 (C-3), 109.71 (C-4), 55.98 (methylpiperazine C-3,5), 49.52 (methylpiperazine C-2,6), 46.44 (methylpiperazine CH3). HR-MS (ESI) m/z: Calcd for C18H19N4: [M-H]- =291.1615, found 291.1612. Anal. Calcd for C18H20N4: C, 73.94; H, 6.89; N, 19.17. Found: C, 74.03; H, 6.92; N, 19.02.
3-(3-Fluorophenyl)-7-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine (14f): This compound was synthesized using a procedure analogous to that of 14a, starting from 13b. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 85/15). Yield: 93%, m.p. 209–210 °C (EtOAc/n-pentane). 1H NMR (600 MHz, Acetone-d6) δ 11.08-10.87 (brs, 1H, NH), 7.90 (d, J = 5.7 Hz, 1H, H-5), 7.77 (s, 1H, H-2), 7.56-7.52 (m, 1H, fluorophenyl H-6), 7.50-7.40 (m, 3H, fluorophenyl H-5, H-4, fluorophenyl H-2), 7.05-6.98 (m, 1H, fluorophenyl H-4), 3.55-3.48 (m, 4H, methylpiperazine H-2,6), 2.72-2.65 (m, 4H, methylpiperazine H-3,5), 2.36 (s, 3H, methylpiperazine CH3). 13C NMR (151 MHz, Acetone-d6) δ 165.07, 163.46 (fluorophenyl C-3), 150.10 (C-7), 138.92, 138.87 (fluorophenyl C-1), 138.21 (C-5), 132.12 (C-3a), 131.54, 131.48 (fluorophenyl C-5), 125.93 (C-7a), 125.33 (C-2), 123.67 (fluorophenyl C-6), 117.06 (C-3), 114.20, 114.05 (fluorophenyl C-2), 113.28, 113.14 (fluorophenyl C-4), 109.62 (C-4), 55.65 (methylpiperazine C-3,5), 49.14 (methylpiperazine C-2,6), 46.02 (methylpiperazine CH3). HR-MS (ESI) m/z: Calcd for C18H20FN4: [M + H]+ = 311.1667, found 311.1670. Anal. Calcd for C18H19FN4: C, 69.66; H, 6.17; N, 18.05. Found: C, 69.43; H, 6.14; N, 18.21.
4-Chloro-7-iodo-5-(4-methoxybenzyl)-5H-pyrrolo[3,2-d]pyrimidine (22): This compound was synthesized using a procedure analogous to that of 8, starting from 21. Yield: 99%, m.p. 180–181 °C (CH2Cl2/Et2O). 1H NMR (600 MHz, CDCl3) δ 8.78 (s, 1H, H-2), 7.52 (s, 1H, H-6), 7.08 (d, J = 8.6 Hz, 2H, methoxybenzyl H-2,6), 6.88 (d, J = 8.6 Hz, 2H, methoxybenzyl H-3,5), 5.64 (s, 2H, methoxybenzyl CH2), 3.79 (s, 3H, methoxybenzyl CH3O). 13C NMR (151 MHz, CDCl3) δ 159.88 (methoxybenzyl C-4), 152.65 (C-7a), 150.64 (C-2), 142.62 (C-4), 140.09 (C-6), 128.76 (methoxybenzyl C-2,6), 127.81 (methoxybenzyl C-1), 124.45 (C-4a), 114.69 (methoxybenzyl C-3,5), 57.91 (C-7), 55.45 (CH3O), 52.29 (CH2). HR-MS (ESI) m/z: Calcd for C14H12ClIN3O: [M + H]+ = 399.9709, found 399.9718.
4-Chloro-5-(4-methoxybenzyl)-7-phenyl-5H-pyrrolo[3,2-d]pyrimidine (23a): This compound was synthesized using a procedure analogous to that of 9a, starting from 22. Purification was carried out by silica gel column chromatography (cyclohexane/ethyl acetate: 9/1). Yield: 94%, m.p. 93–94 °C (CHCl3/n-hexane). 1H NMR (600 MHz, CDCl3) δ 8.80 (s, 1H, H-2), 8.00 (d, J = 7.4 Hz, 2H, phenyl H-2,6), 7.71 (s, 1H, H-6), 7.45 (t, J = 7.7 Hz, 2H, phenyl H-3,5), 7.31 (t, J = 7.7 Hz, 1H, phenyl H-4), 7.11 (d, J = 8.7 Hz, 2H, methoxybenzyl H-2,6), 6.88 (d, J = 8.7 Hz, 2H, methoxybenzyl H-3,5), 5.70 (s, 2H, CH2), 3.79 (s, 3H, CH3O). 13C NMR (151 MHz, CDCl3) δ 159.76 (methoxybenzyl C-4), 150.17 (C-2), 149.91 (C-7a), 142.67 (C-4), 133.65 (C-6), 132.13 (phenyl C-1), 128.97 (phenyl C-3,5), 128.53 (methoxybenzyl C-2,6), 127.12 (phenyl C-4), 127.10 (phenyl C-2,6), 124.91 (C-4a), 117.21 (C-7), 114.75 (methoxybenzyl C-1), 114.65 (methoxybenzyl C-3,5), 55.47 (CH3O), 51.89 (CH2). HR-MS (ESI) m/z: Calcd for C20H17ClN3O: [M + H]+ = 350.1055, found 350.1065.
4-Chloro-7-(3-fluorophenyl)-5-(4-methoxybenzyl)-5H-pyrrolo[3,2-d]pyrimidine (23b): This compound was synthesized using a procedure analogous to that of 9a, starting from 22. Purification was carried out by silica gel column chromatography (cyclohexane/ethyl acetate: 8/2). Yield: 90%, m.p. 88–89 °C (CHCl3/n-hexane). 1H NMR (600 MHz, CDCl3) δ 8.81 (s, 1H, H-2), 7.82-7.79 (m, 1H fluorophenyl H-2), 7.79-7.76 (m, 1H, fluorophenyl H-6), 7.71 (s, 1H, H-6), 7.40-7.37 (m, 1H, fluorophenyl H-5), 7.12 (d, J = 8.5 Hz, 2H, methoxybenzyl H-2,6), 7.00-6.96 (m, 1H, fluorophenyl H-4), 6.89 (d, J = 8.6 Hz, 2H, methoxybenzyl H-3,5), 5.70 (s, 2H, CH2), 3.80 (s, 3H, CH3O). 13C NMR (151 MHz, CDCl3) δ 164.10, 162.48 (fluorophenyl C-3), 159.81 (methoxybenzyl C-4), 150.28 (C-2), 149.73 (C-7a), 142.80 (C-4), 134.28, 134.23 (fluorophenyl C-1) 133.77 (C-6), 130.37, 130.31 (fluorophenyl C-5), 128.59 (methoxybenzyl C-2,6), 124.96 (C-4a), 122.44 (fluorophenyl C-6), 115.92 (C-7), 114.75 (methoxybenzyl C-1), 114.69 (methoxybenzyl C-3,5), 113.94, 113.87 (fluorophenyl C-2), 113.79, 113.73 (fluorophenyl C-4), 55.46 (CH3O), 51.96 (CH2). HR-MS (ESI) m/z: Calcd for C20H16ClFN3O: [M + H]+ = 368.0961, found 368.0970.
5-(4-Methoxybenzyl)-Ν,7-diphenyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine (24a): This compound was synthesized using a procedure analogous to that of 10a, starting from 23a. Purification was carried out by silica gel column chromatography (cyclohexane/ethyl acetate: 7/3).Yield: 87%, m.p. 57–58 °C (CH2Cl2/Et2O). 1H NMR (600 MHz, Acetone-d6) δ 8.44 (s, 1H, H-2), 8.28 (d, J = 7.6 Hz, 2H, 7-phenyl H-2,6), 8.16 (s, 1H, H-6), 7.49 (d, J = 7.9 Hz, 2H, N4-phenyl H-2,6), 7.41 (t, J = 7.7 Hz, 2H, 7-phenyl H-3,5), 7.33 (brs, 1H, NH), 7.30-7.19 (m, 5H, N4-phenyl H-3,5, methoxybenzyl H-2,6, 7-phenyl H-4), 7.06-6.97 (m, 3H, N4-phenyl H-4, methoxybenzyl H-3,5), 5.81 (s, 2H, CH2), 3.77 (s, 3H, CH3O). 13C NMR (151 MHz, Acetone-d6) δ 160.91 (methoxybenzyl C-4), 151.09 (C-2), 149.36 (C-4), 148.44 (C-7a), 140.77 (N4-phenyl C-1), 134.92 (7-phenyl C-1), 132.90 (C-6), 130.46 (methoxybenzyl C-1), 129.43 (7-phenyl C-3,5), 129.28 (N4-phenyl C-3,5), 128.81 (methoxybenzyl C-2,6), 127.39 (7-phenyl C-2,6), 126.74 (7-phenyl C-4), 123.61 (N4-phenyl C-4), 121.63 (N4-phenyl C-2,6), 117.03 (C-4a), 116.11 (C-7), 115.71 (methoxybenzyl C-3,5), 55.75 (CH3O), 53.24 (CH2). HR-MS (ESI) m/z: Calcd for C26H23N4O: [M + H]+ = 407.1867, found 407.1864. Anal. Calcd for C26H22N4O: C, 76.83; H, 5.46; N, 13.78. Found: C, 76.99; H, 5.45; N, 13.60.
7-(3-Fluorophenyl)-5-(4-methoxybenzyl)-Ν-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine (24b): This compound was synthesized using a procedure analogous to that of 10a, starting from 23b. Purification was carried out by silica gel column chromatography (cyclohexane/ethyl acetate: 8/2). Yield: 85%, m.p. 131–132 °C (CH2Cl2/Et2O). 1H NMR (600 MHz, Acetone-d6) δ 8.46 (s, 1H, H-2), 8.26-8.22 (m, 2H, fluorophenyl H-2, H-6), 8.06-8.02 (m, 1H, fluorophenyl H-6), 7.48 (d, J = 7.9 Hz, 2H, phenyl H-2,6), 7.46-7.42 (m, 1H, fluorophenyl H-5), 7.33 (brs, 1H, NH), 7.31-7.24 (m, 4H, phenyl H-3,5, methoxybenzyl H-2,6), 7.05-6.96 (m, 4H, phenyl H-4, methoxybenzyl H-3,5, fluorophenyl H-4), 5.80 (s, 2H, CH2), 3.77 (s, 3H, CH3O). 13C NMR (151 MHz, Acetone-d6) δ 164.92, 163.32 (fluorophenyl C-3), 160.95 (methoxybenzyl C-4), 151.30 (C-2), 149.25 (C-4), 148.51 (C-7a), 140.63 (phenyl C-1), 137.44, 137.38 (fluorophenyl C-1), 133.43 (C-6), 131.01, 130.95 (fluorophenyl C-5), 130.26 (methoxybenzyl C-1), 129.44 (phenyl C-3,5), 128.84 (methoxybenzyl C-2,6), 123.74 (phenyl C-4), 122.79 (fluorophenyl C-6), 121.74 (phenyl C-2,6), 117.06 (C-4a), 115.74 (methoxybenzyl C-3,5), 114.69 (C-7), 113.93, 113.78 (fluorophenyl C-2), 113.14, 113.00 (fluorophenyl C-4), 55.75 (CH3O), 53.34 (CH2). HR-MS (ESI) m/z: Calcd for C26H22FN4O: [M + H]+ = 425.1773, found 425.1767. Anal. Calcd for C26H21FN4O: C, 73.57; H, 4.99; N, 13.20. Found: C, 73.73; H, 5.08; N, 13.02.
5-(4-Methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)-7-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine (24c): This compound was synthesized using a procedure analogous to that of 10a, starting from 23a. Purification was carried out by silica gel column chromatography (cyclohexane/ethyl acetate: 7/3). Yield: 60%, m.p. 187–188 °C (CH2Cl2/Et2O). 1H NMR (600 MHz, Acetone-d6) δ 8.45 (s, 1H, H-2), 8.28 (d, J = 8.1 Hz, 2H, phenyl H-2,6), 8.15 (s, 1H, H-6), 7.41 (t, J = 7.8 Hz, 2H, phenyl H-3,5), 7.31 (d, J = 8.7 Hz, 2H, methoxybenzyl H-2,6), 7.23 (t, J = 7.4 Hz, 1H, phenyl H-4), 7.12 (brs, 1H, NH), 7.05 (d, J = 8.7 Hz, 2H, methoxybenzyl H-3,5), 6.78 (s, 2H, trimethoxyphenyl H-2,6), 5.80 (s, 2H, CH2), 3.79 (s, 3H, methoxybenzyl CH3O), 3.78 (s, 6H, trimethoxyphenyl CH3O-3,5), 3.68 (s, 3H, trimethoxyphenyl CH3O-4). 13C NMR (151 MHz, Acetone-d6) δ 161.00 (methoxybenzyl C-4), 154.22 (trimethoxyphenyl C-3,5), 151.16 (C-2), 149.17 (C-4), 148.48 (C-7a), 136.56 (trimethoxyphenyl C-1), 135.08 (trimethoxyphenyl C-4), 134.93 (phenyl C-1), 132.94 (C-6), 130.45 (methoxybenzyl C-1), 129.28 (phenyl C-3,5), 128.84 (methoxybenzyl C-2,6), 127.39 (phenyl C-2,6), 126.74 (phenyl C-4), 116.91 (C-4a), 116.07 (C-7), 115.83 (methoxybenzyl C-3,5), 99.69 (trimethoxyphenyl C-2,6), 60.71 (trimethoxyphenyl CH3O-4), 56.51 (trimethoxyphenyl CH3O-3,5), 55.77 (methoxybenzyl CH3O), 53.29 (CH2). HR-MS (ESI) m/z: Calcd for C29H29N4O4: [M + H]+ = 497.2184, found 497.2165. Anal. Calcd for C29H28N4O4: C, 70.15; H, 5.68; N, 11.28. Found: C, 69.99; H, 5.51; N, 11.44.
7-(3-Fluorophenyl)-5-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (24d): This compound was synthesized using a procedure analogous to that of 10a, starting from 23b. Purification was carried out by silica gel column chromatography (cyclohexane/ethyl acetate: 6/4). Yield: 63%, m.p. 96–97 °C (CH2Cl2/n-pentane). 1H NMR (600 MHz, Acetone-d6) δ 8.47 (s, 1H, H-2), 8.26-8.20 (m, 2H, H-6, fluorophenyl H-2), 8.07-8.03 (m, 1H, fluorophenyl H-6), 7.47-7.40 (m, 1H, fluorophenyl H-5), 7.30 (d, J = 8.7 Hz, 2H, methoxybenzyl H-2,6), 7.15 (brs, 1H, NH), 7.05 (d, J = 8.7 Hz, 2H, methoxybenzyl H-3,5), 7.02-6.97 (m, 1H, fluorophenyl H-4), 6.77 (s, 2H, trimethoxyphenyl H-2,6), 5.81 (s, 2H, CH2), 3.79 (s, 3H, methoxybenzyl CH3O), 3.78 (s, 6H, trimethoxyphenyl CH3O-3,5), 3.67 (s, 3H, trimethoxyphenyl CH3O-4). 13C NMR (151 MHz, Acetone-d6) δ 164.92, 163.32 (fluorophenyl C-3), 161.05 (methoxybenzyl C-4), 154.23 (trimethoxyphenyl C-3,5), 151.39 (C-2), 149.07 (C-4), 148.53 (C-7a), 137.46, 137.40 (fluorophenyl C-1), 136.41 (trimethoxyphenyl C-1), 135.17 (trimethoxyphenyl C-4), 133.47 (C-6), 131.02, 130.96 (fluorophenyl C-5), 130.24 (methoxybenzyl C-1), 128.86 (methoxybenzyl C-2,6), 122.78 (fluorophenyl C-6), 116.94 (C-4a), 115.87 (methoxybenzyl C-3,5), 114.65 (C-7), 11393, 113.78 (fluorophenyl C-2), 113.15, 113.01 (fluorophenyl C-4), 99.78 (trimethoxyphenyl C-2,6), 60.71 (trimethoxyphenyl CH3O-4), 56.51 (trimethoxyphenyl CH3O-3,5), 55.78 (methoxybenzyl CH3O), 53.39 (CH2). HR-MS (ESI) m/z: Calcd for C29H28FN4O4: [M + H]+ = 515.2090, found 515.2075. Anal. Calcd for C29H27FN4O4: C, 67.69; H, 5.29; N, 10.89. Found: C, 67.48; H, 5.16; N, 11.03.
5-(4-Methoxybenzyl)-4-(4-methylpiperazin-1-yl)-7-phenyl-5H-pyrrolo[3,2-d]pyrimidine (25a): To a solution of 23a (30 mg, 0.09 mmol) in dimethylsulfoxide (1 mL), 1-methylpiperazine (0.1 mL, 0.90 mmol) was added, and the solution was heated at 120 °C for 20 h. Then, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol: 8/2) to give 25a in almost quantitative yield. M.p. 150–151 °C (CH2Cl2/n-pentane). 1H NMR (600 MHz, Acetone-d6) δ 8.57 (s, 1H, H-2), 8.22 (d, J = 7.6 Hz, 2H, phenyl H-2,6), 8.11 (s, 1H, H-6), 7.37 (t, J = 7.7 Hz, 2H, phenyl H-3,5), 7.23-7.19 (m, 3H, phenyl H-4, methoxybenzyl H-2,6), 6.82 (d, J = 8.6 Hz, 2H, methoxybenzyl H-3,5), 5.52 (s, 2H, CH2), 3.71 (s, 3H, CH3O), 3.46-3.37 (brs, 4H, methylpiperazine H-2,6), 2.68-2.60 (brs, 4H, methylpiperazine H-3,5), 2.32 (s, 3H, methylpiperazine CH3). 13C NMR (151 MHz, Acetone-d6) δ 160.31 (methoxybenzyl C-4), 156.02 (C-4), 151.09 (C-2), 150.79 (C-7a), 134.67 (phenyl C-1), 132.92 (C-6), 131.00 (methoxybenzyl C-1), 129.67 (phenyl C-3,5), 129.25 (methoxybenzyl C-2,6), 127.29 (phenyl C-2,6), 126.86 (phenyl C-4), 120.77 (C-4a), 117.66 (C-7), 114.90 (methoxybenzyl C-3,5), 55.53 (CH3O), 55.46 (methylpiperazine C-3,5), 51.63 (methylpiperazine C-2,6), 50.90 (CH2), 46.42 (methylpiperazine CH3). HR-MS (ESI) m/z: Calcd for C25H28N5O: [M + H]+ = 414.2289, found 414.2286. Anal. Calcd for C25H27N5O: C, 72.61; H, 6.58; N, 16.94. Found: C, 72.90; H, 6.69; N, 16.63.
7-(3-Fluorophenyl)-5-(4-methoxybenzyl)-4-(4-methylpiperazin-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (25b): This compound was synthesized using a procedure analogous to that of 25a, starting from 23b. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 9/1). Yield: 97%, m.p. 151–152 °C (CH2Cl2/n-pentane). 1H NMR (600 MHz, Acetone-d6) δ 8.58 (s, 1H, H-2), 8.20 (s, 1H, H-6), 8.18-8.14 (m, 1H, fluorophenyl H-2), 8.02-7.97 (m, 1H, fluorophenyl H-6), 7.42-7.35 (m, 1H, fluorophenyl H-5), 7.20 (d, J = 8.6 Hz, 2H, methoxybenzyl H-2,6), 6.98-6.93 (m, 1H, fluorophenyl H-4), 6.82 (d, J = 8.6 Hz, 2H, methoxybenzyl H-3,5), 5.53 (s, 2H, CH2), 3.71 (s, 3H,CH3O), 3.50-3.38 (brs, 4H, methylpiperazine H-2,6), 2.67-2.58 (brs, 4H, methylpiperazine, H-3,5), 2.30 (s, 3H, methylpiperazine CH3). 13C NMR (151 MHz, Acetone-d6) δ 164.86, 163.26 (fluorophenyl C-3), 160.38 (methoxybenzyl C-4), 156.14 (C-4), 151.28 (C-2), 150.65 (C-7a), 137.18, 137.12 (fluorophenyl C-1), 133.49 (C-6), 131.01, 130.95 (fluorophenyl C-5), 130.85 (methoxybenzyl C-1), 129.69 (methoxybenzyl C-2,6), 122.77 (fluorophenyl C-6), 121.89 (C-7), 116.27 (C-4a), 114.96 (methoxybenzyl C-3,5), 113.84, 113.69 (fluorophenyl C-2), 113.29, 113.15 (fluorophenyl C-4), 55.55 (CH3O, methylpiperazine C-3,5), 51.79 (CH2), 50.96 (methylpiperazine C-2,6), 46.46 (methylpiperazine CH3). HR-MS (ESI) m/z: Calcd for C25H27FN5O: [M + H]+ = 432.2195, found 432.2181. Anal. Calcd for C25H26FN5O: C, 69.59; H, 6.07; N, 16.23. Found: C, 69.80; H, 6.11; N, 16.00.
Ν,7-Diphenyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine (26a): This compound was synthesized using a procedure analogous to that of 14a, starting from 24a. Purification was carried out by silica gel column chromatography (dichloromethane/ethyl acetate: 7/3). Yield: 99%, m.p. > 250 °C (EtOAc). 1H NMR (600 MHz, Acetone-d6) δ 10.76-10.67 (brs, 1H, pyrrole NH), 8.64-8.58 (brs, 1H, pyrimidinamine NH), 8.54 (s, 1H, H-2), 8.26 (dd, J = 8.2, 1.1 Hz, 2H, 7-phenyl H-2,6), 8.02 (s, 1H, H-6), 7.93 (dd, J = 7.7, 1.0 Hz, 2H, N-phenyl H-2,6), 7.39 (t, J = 7.8 Hz, 2H, 7-phenyl H-3,5), 7.35 (t, J = 7.5 Hz, 2H, N-phenyl H-3,5), 7.21 (t, J = 7.4 Hz, 1H, 7-phenyl H-4), 7.05 (t, J = 7.3 Hz, 1H, N-phenyl H-4). 13C NMR (151 MHz, Acetone-d6) δ 151.09 (C-2), 148.19 (C-4), 147.05 (C-7a), 141.33 (N-phenyl C-1), 135.34 (7-phenyl C-1), 129.64 (7-phenyl C-3,5), 129.24 (N-phenyl C-3,5), 127.27 (7-phenyl C-2,6), 126.63 (7-phenyl C-4), 126.42 (C-6), 123.32 (N-phenyl C-4), 120.81 (N-phenyl C-2,6), 117.10 (C-4a), 116.53 (C-7). HR-MS (ESI) m/z: Calcd for C18H15N4: [M + H]+ =287.1292, found 287.1296. Anal. Calcd for C18H14N4: C, 75.50; H, 4.93; N, 19.57. Found: C, 75.36; H, 4.90; N, 19.69.
7-(3-Fluorophenyl)-Ν-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine (26b): This compound was synthesized using a procedure analogous to that of 14a, starting from 24b. Purification was carried out by silica gel column chromatography (dichloromethane/ethyl acetate: 75/25). Yield: 96%, m.p. > 250 °C (EtOAc). 1H NMR (600 MHz, Acetone-d6) δ 10.87-10.71 (brs, 1H, pyrrole NH), 8.63-8.58 (brs, 1H, pyrimidinamine NH), 8.55 (s, 1H, H-2), 8.24-8.20 (m, 1H, fluorophenyl H-2), 8.12 (s, 1H, H-6), 8.06-8.02 (m, 1H, fluorophenyl H-6), 7.93 (d, J = 7.7 Hz, 2H, phenyl H-2,6), 7.39-7.36 (m, 1H, fluorophenyl H-5), 7.34 (t, J = 7.5 Hz, 2H, phenyl H-3,5), 7.06 (t, J = 7.3 Hz, 1H, phenyl H-4), 6.99-6.93 (m 1H, fluorophenyl H-4). 13C NMR (151 MHz, Acetone-d6) δ 164.93, 163.33 (fluorophenyl C-3), 151.35 (C-2), 148.25 (C-4), 147.07 (C-7a), 141.23 (phenyl C-2,6), 137.90, 137.84 (fluorophenyl C-1), 130.97, 130.91 (fluorophenyl C-5), 129.67 (phenyl C-3,5), 127.06 (C-6), 123.44 (phenyl C-4), 122.69 (fluorophenyl C-6), 120.88 (phenyl C-2,6), 116.58 (C-4a), 115.74 (C-7), 113.79, 113.64 (fluorophenyl C-2), 113.03, 112.89 (fluorophenyl C-4). HR-MS (ESI) m/z: Calcd for C18H14FN4: [M + H]+ = 305.1197, found 305.1192. Anal. Calcd for C18H13FN4: C, 71.04; H, 4.31; N, 18.41. Found: C, 70.79; H, 4.22; N, 18.60.
N-(3,4,5-Trimethoxyphenyl)-7-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine (26c): This compound was synthesized using a procedure analogous to that of 14a, starting from 24c. Purification was carried out by silica gel column chromatography (cyclohexane/ethyl acetate: 3/7). Yield: 97%, m.p. > 250 °C (EtOAc). 1H NMR (600 MHz, Acetone-d6) δ 10.85-10.79 (brs, 1H, pyrrole NH), 8.70-8.63 (brs, 1H, pyrimidinamine NH), 8.53 (s, 1H, H-2), 8.26 (d, J = 7.9 Hz, 2H, phenyl H-2,6), 8.01 (s, 1H, H-6), 7.39 (t, J = 7.5 Hz, 2H, phenyl H-3,5), 7.31 (s, 2H, trimethoxyphenyl H-2,6), 7.21 (t, J = 7.2 Hz, 1H, phenyl H-4), 3.84 (s, 6H, trimethoxyphenyl CH3O-3,5), 3.71 (s, 3H, CH3O-4). 13C NMR (151 MHz, Acetone-d6) δ 154.46 (trimethoxyphenyl C-3,5), 151.17 (C-2), 148.32 (C-4), 147.07 (C-7a), 137.37 (trimethoxyphenyl C-1), 135.43 (phenyl C-1), 134.98 (trimethoxyphenyl C-4), 129.24 (phenyl C-3,5), 127.27 (phenyl C-2,6), 126.59 (phenyl C-4), 126.29 (C-6), 117.05 (C-4a), 116.48 (C-7), 99.14 (trimethoxyphenyl C-2,6), 60.75 (trimethoxyphenyl CH3O-4), 56.52 (trimethoxyphenyl CH3O-3,5). HR-MS (ESI) m/z: Calcd for C21H19N4O3: [M-H]- =375.1462, found 375.1456. Anal. Calcd for C21H20N4O3: C, 67.01; H, 5.36; N, 14.88. Found: C, 66.84; H, 5.29; N, 15.09.
7-(3-Fluorophenyl)-N-(3,4,5-trimethoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (26d): This compound was synthesized using a procedure analogous to that of 14a, starting from 24d. Purification was carried out by silica gel column chromatography (chloroform/ethyl acetate: 4/6). Yield: 93%, m.p. 139–140 °C (EtOAc/Et2O). 1H NMR (600 MHz, Acetone-d6) δ 10.82-10.66 (brs, 1H, pyrrole NH), 8.58-8.54 (m, 2H, pyrimidinamine NH, H-2), 8.25-8.19 (m, 1H, fluorophenyl H-2), 8.11 (s, 1H, H-6), 8.06-8.02 (m, 1H, fluorophenyl H-6), 7.44-7.38 (m, 1H, fluorophenyl H-5), 7.28 (s, 2H, trimethoxyphenyl H-2,6), 7.00-6.93 (m, 1H, fluorophenyl H-4), 3.84 (s, 6H, trimethoxyphenyl CH3O-3,5), 3.71 (s, 3H, CH3O-4). 13C NMR (151 MHz, Acetone-d6) δ 164.92, 163.32 (fluorophenyl C-3), 154.46 (trimethoxyphenyl C-3,5), 151.38 (C-2), 148.34 (C-4), 146.94 (C-7a), 137.91, 137.85 (fluorophenyl C-1), 137.16 (trimethoxyphenyl C-1), 135.07 (trimethoxyphenyl C-4), 130.97, 130.91 (fluorophenyl C-5), 126.97 (C-6), 122.68 (fluorophenyl C-6), 116.48 (C-4a), 115.69 (C-7), 113.77, 113.62 (fluorophenyl C-2), 113.02, 112.87 (fluorophenyl C-4), 99.19 (trimethoxyphenyl C-2,6), 60.75 (trimethoxyphenyl CH3O-4), 56.52 (trimethoxyphenyl CH3O-3,5). HR-MS (ESI) m/z: Calcd for C21H18FN4O3: [M-H]- = 393.1368, found 393.1370. Anal. Calcd for C21H19FN4O3: C, 63.95; H, 4.86; N, 14.21. Found: C, 64.12; H, 4.89; N, 14.05.
4-(4-Methylpiperazin-1-yl)-7-phenyl-5H-pyrrolo[3,2-d]pyrimidine (26e): This compound was synthesized using a procedure analogous to that of 14a, starting from 25a. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 85/15). Yield: 92%, m.p. > 250 °C (EtOAc/Et2O). 1H NMR (600 MHz, Acetone-d6) δ 11.18-10.91 (brs, 1H, NH), 8.44 (s, 1H, H-2), 8.25 (d, J = 7.5 Hz, 2H, phenyl H-2,6), 7.96 (s, 1H, H-6), 7.37 (t, J = 7.7 Hz, 2H, phenyl H-3,5), 7.19 (t, J = 7.4 Hz, 1H, phenyl H-4), 3.96-3.90 (m, 4H, methylpiperazine H-2,6), 2.82-2.76 (m, 4H, methylpiperazine H-3,5), 2.47 (s, 3H, methylpiperazine CH3). 13C NMR (151 MHz, Acetone-d6) δ 151.98 (C-2), 150.94 (C-4), 148.69 (C-7a), 135.32 (phenyl C-1), 129.17 (phenyl C-3,5), 127.38 (phenyl C-2,6), 126.79 (C-6), 126.54 (phenyl C-4), 116.95 (C-4a), 116.67 (C-7), 55.05 (methylpiperazine C-3,5), 46.24 (methylpiperazine C-2,6), 45.45 (methylpiperazine CH3). HR-MS (ESI) m/z: Calcd for C17H20N5: [M + H]+ = 294.1714, found 294.1715. Anal. Calcd for C17H19N5: C, 69.60; H, 6.53; N, 23.87. Found: C, 69.82; H, 6.58; N, 23.57.
7-(3-Fluorophenyl)-4-(4-methylpiperazin-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (26f): This compound was synthesized using a procedure analogous to that of 14a, starting from 25b. Oil purification was carried out by silica gel column chromatography (dichloromethane/methanol: 7/3). Yield: 91%. 1H NMR (600 MHz, Acetone-d6) δ 11.78-11.05 (brs, 1H, NH), 8.44 (s, 1H, H-2), 8.22-8.16 (m, 1H, fluorophenyl H-2), 8.02 (s, 1H, H-6), 8.00-7.96 (m, 1H, fluorophenyl H-6), 7.42-7.34 (m, 1H, fluorophenyl H-5), 6.97-6.89 (m, 1H, fluorophenyl H-4), 3.98-3.87 (m, 4H, methylpiperazine H-2,6), 2.75-2.67 (m, 4H, methylpiperazine H-3,5), 2.39 (s, 3H, methylpiperazine CH3). 13C NMR (151 MHz, Acetone-d6) δ 164.86, 163.26 (fluorophenyl C-3), 152.03 (C-4), 151.14 (C-2), 148.55 (C-7a), 137.89, 137.83 (fluorophenyl C-1), 130.84, 130.78 (fluorophenyl C-5), 127.27 (C-6), 122.76 (fluorophenyl C-6), 116.85 (C-4a), 115.21 (C-7), 113.87, 113.72 (fluorophenyl C-2), 112.89, 112.75 (fluorophenyl C-4), 55.21 (methylpiperazine C-3,5), 46.38 (methylpiperazine C-2,6), 45.68 (methylpiperazine CH3). HR-MS (ESI) m/z: Calcd for C17H19FN5: [M + H]+ = 312.1619, found 312.1610. Anal. Calcd for C17H18FN5: C, 65.58; H, 5.83; N, 22.49. Found: C, 65.66; H, 5.87; N, 22.34.
Ethyl 4-(3-fluorophenyl)-3-(hydroxyimino)-2,4-dioxobutanoate (31b): To a solution of 30b (1.28 g, 5.36 mmol) in glacial acetic acid (10 mL), a sodium nitrite solution (3.5 mL, 3.80 M) was added at 10 °C, under the surface of the solution with a flow rate of 0.15 mL/min via a controlled infusion device. The solution was stirred at rt for 1 h and then was neutralized with 25% ammonia solution and extracted with ethyl acetate; the solvent was dried (Na2SO4) and concentrated to dryness to give pure 31b that corresponded practically to a sole isomer. Yield: 85%. Amorphous solid. 1H NMR (600 MHz, DMSO-d6) δ 12.59 (s, 1H, OH), 7.81-7.78 (m, 1H, fluorophenyl H-6), 7.67-7.63 (m, 1H, fluorophenyl H-2), 7.58-7.55 (m, 1H, fluorophenyl H-5), 7.50-7.45 (m, 1H, fluorophenyl H-4), 4.38 (q, J = 7.2 Hz, 2H, ethylester H-1), 1.26 (t, J = 7.2 Hz, 3H, ethylester H-2). 13C NMR (151 MHz, DMSO-d6) δ 192.03 (C-4), 166.20 (C-2), 164.47 (C-1), 162.79, 161.17 (fluorophenyl C-3), 152.09 (C-3), 133.28, 133.23 (fluorophenyl C-1), 130.84, 130.78 (fluorophenyl C-5), 125.44, 125.42 (fluorophenyl C-6), 119.94, 119.80 (fluorophenyl C-4), 115.81, 115.66 (fluorophenyl C-2), 62.76 (ethylester C-1), 13.72 (ethylester C-2). HR-MS (ESI) m/z: Calcd for C12H9FNO5: [M-H]- =266.0470, found 266.0469.
Ethyl 4-amino-3-(3-fluorophenyl)-1H-pyrazole-5-carboxylate (32b): To a solution of 31b (1.22 g, 4.57 mmol) in absolute ethanol (8 mL), hydrazine hydrate (0.5 mL, 9.14 mmol) was added dropwise, under cooling, and the resulting solution was heated at 45 °C for 2 h. The solvent was then vacuum evaporated ethyl acetate was added to the residue and it was washed with a 3N hydrochloric acid solution. The aqueous phase was neutralized with a 2N sodium hydroxide solution and extracted with ethyl acetate; the organic phase was dried (Na2SO4) and concentrated to dryness to give pure 32b as an amorphous solid. Yield: 40%. 1H NMR (600 MHz, DMSO-d6) δ 13.50–13.15 (brs, 1H, NH), 7.62-7.58 (m, 1H, fluorophenyl H-6), 7.55-7.51 (m, 1H, fluorophenyl H-2), 7.49-7.45 (m, 1H, fluorophenyl H-5), 7.14-7.09 (m, 1H, fluorophenyl H-4), 5.15-4.90 (brs, 2H, NH2), 4.32 (q, J = 7.2 Hz, 2H, ethylester H-1), 1.33 (t, J = 7.2 Hz, 3H, ethylester H-2). 13C NMR (151 MHz, DMSO-d6) δ 163.23, 161.62 (fluorophenyl C-3), 160.32 (C=O), 136.90 (C-5), 135.21 (C-3), 133.44 (fluorophenyl C-1), 130.58, 130.53 (fluorophenyl C-5), 121.49 (fluorophenyl C-6), 118.59 (C-4), 113.46, 113.32 (fluorophenyl C-4), 112.08, 111.93 (fluorophenyl C-2), 59.88 (ethylester C-1), 14.28 (ethylester C-2). HR-MS (ESI) m/z: Calcd for C12H11FN3O2: [M-H]- = 248.0840, found 248.0836.
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (33b): To a solution of 32b (540 mg, 2.16 mmol) in butanol (8 mL), formamidine acetate (500 mg, 4.80 mmol) was added, and the solution was refluxed for 20 h. Upon completion of the reaction, chloroform (10 mL) was added into the flask, and the precipitate was filtered and dried to give pure 33b. Yield: 61%, m.p. > 250 °C (MeOH). 1H NMR (600 MHz, DMSO-d6) δ 14.70–14.24 (brs, 1H, pyrazole NH), 12.67–12.30 (brs, 1H, pyrimidinone NH), 8.15-8.13 (m, 1H, fluorophenyl H-6), 8.11-8.07 (m, 1H, fluorophenyl H-2), 8.00 (s, 1H, H-5), 7.56-7.51 (m, 1H, fluorophenyl H-5), 7.23-7.18 (m, 1H, fluorophenyl H-4). 13C NMR (151 MHz, DMSO-d6) δ 163.15, 161.54 (fluorophenyl C-3), 153.49 (C-7), 143.65 (C-5), 140.13 (C-3), 136.50 (C-3a), 133.91 (fluorophenyl C-1), 130.75, 130.69 (fluorophenyl C-5), 129.55 (C-7a), 121.86 (fluorophenyl C-6), 114.73, 114.59 (fluorophenyl C-4), 112.43, 112.27 (fluorophenyl C-2). HR-MS (ESI) m/z: Calcd for C11H6FN4O: [M-H]- = 229.0531, found 229.0540.
7-Chloro-3-phenyl-1H-pyrazolo[4,3-d]pyrimidine (34a): Compound 33a (100 mg, 0.47 mmol) was added under cooling to phosphorous oxychloride (1.5 mL). Then, N,N-diisopropylethylamine (122 µL, 0.71 mmol) was added, and the mixture was refluxed for 3 h under argon. The bulk of the volatile material was then vacuum-evaporated, water was added into the flask and the pH was adjusted to 5 upon addition of a saturated sodium bicarbonate solution. The precipitate was filtered, washed with water and air-dried. The residue was purified by silica gel column chromatography (cyclohexane/ethyl acetate: 7/3) to result in 34a (85 mg, 80%), m.p. 220–221 °C (acetone). 1H NMR (600 MHz, DMSO-d6) δ 14.80–14.55 (brs, 1H, NH), 8.94 (s, 1H, H-5), 8.43 (d, J = 7.7 Hz, 2H, phenyl H-2,6), 7.56 (t, J = 7.2 Hz, 2H, phenyl H-3,5), 7.46 (t, J = 7.5 Hz, 1H, phenyl H-4). 13C NMR (151 MHz, DMSO-d6) δ 150.43 (C-5), 143.94 (C-7), 143.02 (C-3), 142.28 (C-3a), 131.03 (C-7a), 130.65 (phenyl C-1), 128.79 (phenyl C-3,5), 128.76 (phenyl C-4), 126.28 (phenyl C-2,6). HR-MS (ESI) m/z: Calcd for C11H6ClN4: [M-H]- = 229.0286, found 229.0301.
7-Chloro-3-(3-fluorophenyl)-1H-pyrazolo[4,3-d]pyrimidine (34b): This compound was synthesized using a procedure analogous to that of 34a, starting from 33b. Purification was carried out by silica gel column chromatography (cyclohexane/ethyl acetate: 7/3). Yield: 80%, m.p. > 250 °C (EtOAc). 1H NMR (600 MHz, DMSO-d6) δ 13.80–13.54 (brs, 1H, NH), 8.96 (s, 1H, H-5), 8.30-8.27 (m, 1H, fluorophenyl H-6), 8.22-8.18 (m, 1H, fluorophenyl H-2), 7.65-7.59 (m, 1H, fluorophenyl H-5), 7.33-7.27 (m, 1H, fluorophenyl H-4). 13C NMR (151 MHz, DMSO-d6) δ 163.19, 161.58 (fluorophenyl C-3), 150.76 (C-5), 144.41 (C-7), 142.10 (C-3a), 141.52 (C-3), 133.18 (fluorophenyl C-1), 131.29 (C-7a), 131.08, 131.02 (fluorophenyl C-5), 122.27 (fluorophenyl C-6), 115.62, 115.48 (fluorophenyl C-4), 112.74, 112.58 (fluorophenyl C-2). HR-MS (ESI) m/z: Calcd for C11H5ClFN4: [M-H]- = 247.0192, found 247.1002.
N,3-Diphenyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine (35a): Aniline (0.1 mL, 0.85 mmol) was added into a solution of the chloride 34a (80 mg, 0.34 mmol) in absolute ethanol (5 mL), and the mixture was refluxed under argon for 2 hrs. Upon completion of the reaction, water (20 mL) was added, and the precipitate was filtered under vacuum, washed with water and air-dried. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 9/1). Yield: 61%, m.p. 247–248 °C (EtOAc). 1H NMR (600 MHz, DMSO-d6) δ 13.20-12.90 (brs, 1H, pyrazole NH), 9.80-9.55 (brs, 1H, pyrimidinamine NH), 8.53 (brs, 1H, H-5), 8.44 (brs, 2H, 3-phenyl H-2,6), 7.93 (brs, 2H, N-phenyl H-2,6), 7.53 (t, J = 7.5 Hz, 2H, 3-phenyl H-3,5), 7.45-7.38 (m, 3H, N-phenyl H-3,5, 3-phenyl H-4), 7.13 (t, J = 7.4 Hz, 1H, N-phenyl H-4). 13C NMR (151 MHz, DMSO-d6) δ 151.42 (C-5), 146.78 (C-7), 142.13 (C-3), 139.74 (C-3a), 138.91 (N-phenyl C-1), 132.16 (3-phenyl C-1), 128.89 (N-phenyl C-3,5), 128.62 (3-phenyl C-3,5), 128.08 (3-phenyl C-4), 126.15 (3-phenyl C-2,6), 123.23 (N-phenyl C-4), 122.78 (C-7a), 120.10 (N-phenyl C-2,6). HR-MS (ESI) m/z: Calcd for C17H12N5: [M-H]- = 286.1098, found 286.1095. Anal. Calcd for C17H13N5: C, 71.06; H, 4.56; N, 24.38. Found: C, 70.88; H, 4.65; N, 24.44.
3-(3-Fluorophenyl)-Ν-phenyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine (35b): This compound was synthesized using a procedure analogous to that of 35a starting from 34b. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 98/2). Yield: 65%, m.p. 237–238 °C (EtOAc). 1H NMR (600 MHz, DMSO-d6) δ 13.35-12.95 (brs, 1H, pyrazole NH), 9.85-9.60 (brs, 1H, pyrimidinamine NH), 8.55 (s, 1H, H-5), 8.30-8.26 (m, 1H, fluorophenyl H-6), 8.25-8.21 (m, 1H, fluorophenyl H-2), 7.93 (brs, 2H, phenyl H-2,6), 7.61-7.55 (m, 1H, fluorophenyl H-5), 7.43 (t, J = 7.4 Hz, 2H, phenyl H-3,5), 7.26-7.21 (m, 1H, fluorophenyl H-4), 7.13 (t, J = 7.4 Hz, 1H, phenyl H-4). 13C NMR (151 MHz, DMSO-d6) δ 163.18, 161.57 (fluorophenyl C-3), 151.65 (C-5), 146.79 (C-7), 140.81 (C-3), 139.73 (C-3a), 138.83 (phenyl C-1), 134.43 (fluorophenyl C-1), 130.65 (fluorophenyl C-5), 128.86 (phenyl C-3,5), 123.27 (phenyl C-4), 122.87 (C-7a), 121.99 (fluorophenyl C-6), 120.13 (phenyl C-2,6), 114.75, 114.61 (fluorophenyl C-4), 112.57, 112.42 (fluorophenyl C-2). HR-MS (ESI) m/z: Calcd for C17H11FN5: [M-H]- = 304.1003, found 304.0998. Anal. Calcd for C17H12FN5: C, 66.88; H, 3.96; N, 22.94. Found: C, 66.61; H, 4.02; N, 23.09.
3-Phenyl-N-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (35c): This compound was synthesized using a procedure analogous to that of 35a starting from 34a. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 95/5). Yield: 68%, m.p. > 250 °C (EtOAc). 1H NMR (600 MHz, DMSO-d6) δ 13.10-12.80 (brs, 1H, pyrazole NH), 9.70-9.50 (brs, 1H, pyrimidinamine NH), 8.53 (s, 1H, H-5), 8.43 (brs, 2H, phenyl H-2,6), 7.53 (t, J = 7.1 Hz, 2H, phenyl H-3,5), 7.40 (t, J = 7.4 Hz, 1H, phenyl H-4), 7.35-7.20 (brs, 2H, trimethoxyphenyl H-2,6), 3.83 (s, 6H, trimethoxyphenyl CH3O-3,5), 3.68 (s, 3H, trimethoxyphenyl CH3O-4). 13C NMR (151 MHz, DMSO-d6) δ 152.88 (trimethoxyphenyl C-3,5), 151.44 (C-5), 146.79 (C-7), 142.13 (C-3), 139.67 (C-3a), 134.96 (C-7a), 133.70 (trimethoxyphenyl C-4), 132.18 (phenyl C-1), 128.62 (phenyl C-3,5), 128.08 (phenyl C-4), 126.18 (phenyl C-2,6), 122.75 (trimethoxyphenyl C-1), 98.25 (trimethoxyphenyl C-2,6), 60.13 (trimethoxyphenyl CH3O-4), 55.88 (trimethoxyphenyl CH3O-3,5). HR-MS (ESI) m/z: Calcd for C20H18N5O3: [M-H]- =376.1415, found 376.1408. Anal. Calcd for C20H19N5O3: C, 63.65; H, 5.07; N, 18.56. Found: C, 63.90; H, 5.01; N, 18.69.
3-(3-Fluorophenyl)-N-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (35d): This compound was synthesized using a procedure analogous to that of 35a starting from 34b. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 98/2). Yield: 57%, m.p. > 250 °C (EtOAc). 1H NMR (600 MHz, DMSO-d6) δ 13.12-12.96 (brs, 1H, pyrazole NH), 9.66-9.54 (brs, 1H, pyrimidinamine NH), 8.54 (s, 1H, H-5), 8.30-8.19 (m, 2H, fluorophenyl H-6, fluorophenyl H-2), 7.60-7.53 (m, 1H, fluorophenyl H-5), 7.30-7.19 (m, 3H, trimethoxyphenyl H-2,6, fluorophenyl H-4), 3.83 (s, 6H, trimethoxyphenyl CH3O-3,5), 3.68 (s, 3H, trimethoxyphenyl CH3O-4). 13C NMR (151 MHz, DMSO-d6) δ 163.19, 161.58 (fluorophenyl C-3), 152.85 (C-5), 151.73 (trimethoxyphenyl C-3,5), 146.79 (C-7), 140.82 (C-3), 139.65 (C-3a), 134.85 (C-7a), 133.78 (trimethoxyphenyl C-4), 130.76 (trimethoxyphenyl C-1, fluorophenyl C-5), 122.80 (fluorophenyl C-1), 121.97 (fluorophenyl C-6), 114.81, 114.67 (fluorophenyl C-4), 112.52, 112.36 (fluorophenyl C-2), 98.36 (trimethoxyphenyl C-2,6), 60.12 (trimethoxyphenyl CH3O-4), 55.88 (trimethoxyphenyl CH3O-3,5). HR-MS (ESI) m/z: Calcd for C20H19FN5O3: [M + H]+ = 396.1467, found 396.1455. Anal. Calcd for C20H18FN5O3: C, 60.75; H, 4.59; N, 17.71. Found: C, 60.94; H, 4.46; N, 17.59.
7-(4-Methylpiperazin-1-yl)-3-phenyl-1H-pyrazolo[4,3-d]pyrimidine (35e): This compound was synthesized using a procedure analogous to that of 35a starting from 34a. Upon completion of the reaction, the solvent was evaporated and water (20 mL) was added into the flask, followed by extraction with ethyl acetate (3 × 20 mL). The combined organic layers were dried (Na2SO4) and evaporated to dryness. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 9/1). Yield: 80%, m.p. 184–185 °C (EtOAc). 1H NMR (600 MHz, DMSO-d6) δ 8.35 (d, J = 7.9 Hz, 2H, phenyl H-2,6), 8.30 (s, 1H, H-5), 7.52 (t, J = 7.2 Hz, 2H, phenyl H-3,5), 7.38 (t, J = 7.5Hz, 1H, phenyl H-4), 4.25-4.10 (brs, 4H, methylpiperazine H-2,6), 2.49-2.46 (m, 4H, methylpiperazine H-3,5), 2.24 (s, 3H, methylpiperazine CH3). 13C NMR (151 MHz, DMSO-d6) δ 152.80 (C-7), 151.80 (C-5), 138.33 (C-3a), 134.43 (C-3), 129.56 (C-7a, phenyl C-1), 128.76 (phenyl C-3,5), 128.01 (phenyl C-4), 125.73 (phenyl C-2,6), 54.53 (methylpiperazine C-3,5), 45.59 (methylpiperazine CH3), 44.89 (methylpiperazine C-2,6). HR-MS (ESI) m/z: Calcd for C16H17N6: [M-H]- =293.1520, found 293.1499. Anal. Calcd for C16H18N6: C, 65.29; H, 6.16; N, 28.55. Found: C, 65.44; H, 6.08; N, 28.31.
3-(3-Fluorophenyl)-7-(4-methylpiperazin-1-yl)-1H-pyrazolo[4,3-d]pyrimidine (35f): This compound was synthesized using a procedure analogous to that of 35a starting from 34b. The work-up procedure was similar to that of the derivative 35e. Purification was carried out by silica gel column chromatography (dichloromethane/methanol: 93/7). Yield: 80%, m.p. 212–213 °C (EtOAc). 1H NMR (600 MHz, DMSO-d6) δ 8.32 (s, 1H, H-5), 8.22-8.19 (m, 2H, fluorophenyl H-2, fluorophenyl H-6), 7.58-7.53 (m, 1H, fluorophenyl H-5), 7.22-7.18 (m, 1H, fluorophenyl H-4), 4.18-4.12 (brs, 4H, methylpiperazine H-2,6), 2.48-2.45 (m, 4H, methylpiperazine H-3,5), 2.23 (s, 3H, methylpiperazine CH3). 13C NMR (151 MHz, DMSO-d6) δ 163.17, 161.56 (fluorophenyl C-3), 152.52 (C-7), 152.03 (C-5), 138.82 (C-3a), 133.93 (C-3), 132.01, 131.96 (fluorophenyl C-5), 130.84, 130.78 (fluorophenyl C-1), 129.23 (C-7a), 121.58 (fluorophenyl C-6), 114.64, 114.50 (fluorophenyl C-4), 112.21, 112.06 (fluorophenyl C-2), 54.48 (methylpiperazine C-3,5), 45.55 (methylpiperazine CH3), 44.92 (methylpiperazine C-2,6). HR-MS (ESI) m/z: Calcd for C16H16FN6: [M-H]- =311.1425, found 311.1455. Anal. Calcd for C16H17FN6: C, 61.53; H, 5.49; N, 26.91. Found: C, 61.61; H, 5.36; N, 27.00.