3.1. Chemistry
General procedure A: To a solution of halogenated derivative (1.0 eq.), in 1.2-dimethoxyethane was added boronic acid (1.5 eq.). An aqueous solution (1 M) of potassium carbonate (3.0 eq.) was then injected and the mixture was degassed by argon bubbling for 15 min. Pd(PPh3)4 (0.05 eq.) was added and the mixture was heated to 150 °C for 1 h by microwave irradiation. The solvent was removed in vacuo. The crude product was purified by flash chromatography.
General procedure B: A solution of halogenated derivative (1.0 eq.), potassium carbonate (3.0 eq.), 4.4.6-trimethyl-2-vinyl-1.3,2-dioxaborinane (2.0 eq.), in dry toluene/ethanol, (3/1 mL) was degassed by argon bubbling for 15 min. Pd(PPh3)4 (0.05 eq.) was added and the mixture was heated to 150 °C for 1 h by microwave irradiation. The solvent was removed in vacuo. The crude product was purified by flash chromatography.
General procedure C: To a solution of MOM protected compound (1.0 eq.), in dioxane was added a solution of HCl in dioxane, 4.0 M (6.0 eq.). The mixture was stirred at room temperature until completion monitored by TLC. The solvent was removed by filtration and the product was washed with diethyl ether prior to drying the solid under reduced pressure.
General procedure D: To a solution of aldehyde in dry CH2Cl2/DMF, 6/1 (6 mL), was added the secondary amine. After cooling the reaction to 0 °C, NaBH(OAc)3 (5.0 eq.) was added. After 10 min of stirring, four drops of acetic acid were added to the mixture. The reaction was stirred at room temperature for 5 h before adding water (5 mL) and extracting the product. The combined organic layers were washed with a solution of saturated NaHCO3 (2 × 10 mL) and dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product then underwent the reaction as described in general procedure C to afford the final compound.
2,4,7-Trichloropyrido[3,2-d]pyrimidine (2) [
21]. To a solution of
1 [
20] (1.0 g, 6.13 mmol) in phosphorus oxychloride (10 mL) was added phosphorus pentachloride (7.65 g, 36.78 mmol, 6.0 eq.). The mixture was heated by microwave irradiation at 160 °C for 2 h. The crude product was dissolved in CH
2Cl
2 (100 mL) and was then poured in ice. The mixture was stirred at room temperature for 6 h and then extracted. The combined organic layers were washed with water (2 × 20 mL) and dried over MgSO
4 and filtered. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (CH
2Cl
2/petroleum ether, 5/5) to afford
2 as a yellow solid (0.934 g, 65%).
1H NMR (400 MHz, CDCl
3) δ: 8.31 (d, 1H,
J = 2.2 Hz), 9.03 (d, 1H,
J = 2.2 Hz). HRMS (EI-MS):
m/z calculated for C
7H
3Cl
3N
3 [M + H]
+: 234.9314; found 234.9323.
2,7-Dichloro-4-morpholinylpyrido[3,2-d]pyrimidine (3). To a solution of 2 (0.755 g, 3.22 mmol) in THF (33 mL) were added successively morpholine (0.28 mL, 3.22 mmol, 1.0 eq.) and triethylamine (0.49 mL, 3.54 mmol, 1.1 eq.). The mixture was stirred at room temperature for 12 h and the solvent was removed under reduced pressure. The crude product was dissolved in CH2Cl2 (30 mL) and the organic layer was washed with a saturated solution of NaHCO3 (2 × 10 mL). The organic layer was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2/MeOH, 99/1) yielded 3 as a yellow solid (0.835 g, 91%). Rf (CH2Cl2/MeOH, 99/1): 0.11. Mp: 201–203 °C. IR (ATR diamond, cm−1) ν: 3043, 2966, 1546, 1411, 1334, 1254, 1108, 927, 865, 686. 1H NMR (250 MHz, CDCl3) δ: 3.87 (m, 4H, 2 × CH2(N)), 4.53 (m, 4H, 2 × CH2(O)), 7.99 (d, 1H, J = 2.5 Hz), 8.58 (d, 1H, J = 2.5 Hz). 13C NMR (62.5 MHz, CDCl3) δ: 47.8 (2 × CH2), 67.1 (2 × CH2), 130.7 (Cq), 133.7 (CH), 135.2 (Cq), 145.5 (CH), 149.4 (Cq), 159.2 (Cq), 168.2 (Cq) HRMS (EI-MS): m/z calculated for C11H11Cl2N4O [M + H]+: 286.0232; found 286.0302.
7-Chloro-2-(3-methoxymethoxyphenyl)-4-morpholinylpyrido[3,2-d]pyrimidine (4). The reaction was carried out as described in general procedure A using 3 and 3-methoxymethoxyphenylboronic acid as the boronic acid. Purification by flash chromatography on silica gel (petroleum ether/EtOAc, 8/2) yielded 4 as a yellow solid (193 mg, 71%). Rf (petroleum ether/EtOAc, 8/2): 0.10. Mp: 196–198 °C. IR (ATR diamond, cm−1) ν: 2950, 1516, 1454, 1344, 1307, 1266, 1148, 1074, 1009, 874, 731. 1H NMR (250 MHz, CDCl3) δ: 3.53 (s, 3H, CH3), 3.92 (m, 4H, 2 × CH2(N)), 4.57 (m, 4H, 2 × CH2(O)), 5.28 (s, 2H, CH2), 7.17 (ddd, 1H, J = 1.1 Hz, J = 2.4 Hz, J = 8.1 Hz), 7.40 (t, 1H, J = 8.1 Hz), 8.14 (m, 3H), 8.59 (d, 1H, J = 2.4 Hz). 13C NMR (62.5 MHz, CDCl3) δ: 48.3 (2 × CH2), 56.3 (CH3), 66.6 (CH2), 67.5 (CH2), 94.8 (CH2), 116.6 (CH), 118.7 (CH), 120.2 (Cq), 122.4 (CH), 129.6 (CH), 131.3 (Cq), 135.0 (CH), 139.8 (Cq), 145.2 (CH), 149.1 (Cq), 157.6 (Cq), 159.2 (Cq), 160.9 (Cq). HRMS (EI/MS): m/z calculated for C19H20ClN4O3 [M + H]+: 387.1146; found 387.1151.
7-Chloro-2-(3-hydroxyphenyl)-4-morpholinylpyrido[3,2-d]pyrimidine (5). The reaction was carried out as described in general procedure A using 3 (200 mg, 0.701 mmol) and 3-hydroxyphenylboronic acid as the boronic acid (116 mg, 0.842 mmol, 1.2 eq.). Purification by flash chromatography on silica gel (petroleum ether/EtOAc, 7/3) yielded 5 as a yellow solid (172 mg, 71%). Rf (petroleum ether/EtOAc, 7/3): 0.10. Mp: 230-232 °C. IR (ATR diamond, cm−1) ν: 3301, 2853, 1527, 1425, 1370, 1270, 1229, 1107, 1022, 948, 876, 737. 1H NMR (400 MHz, DMSO-d6) δ: 3.85 (m, 4H, 2 × CH2(N)), 4.50 (m, 4H, 2 × CH2(O)), 6.95 (d, 1H, J = 5.0 Hz), 7.32 (dd, 1H, J = 2.5 Hz, J = 5.0 Hz), 7.90 (d, 1H, J = 2.5 Hz), 7.91 (s, 1H), 8.29 (s, 1H), 8.75 (s, 1H), 9.61 (s, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ: 47.8 (2 × CH2), 66.8 (2 × CH2), 114.9 (CH), 117.8 (CH), 119.1 (CH), 129.3 (CH), 130.6 (Cq), 133.5 (Cq), 134.2 (CH), 138.6 (Cq), 144.9 (Cq), 148.2 (CH), 157.4 (Cq), 158.3 (Cq), 159.8 (Cq). HRMS (EI-MS): m/z calculated for C17H16ClN4O2 [M + H]+: 343.0884; found 343.0956.
3-(7-Methyl-4-morpholinylpyrido[3,2-d]pyrimidin-2-yl)phenol (6). To a solution of compound 5 (100 mg, 0.32 mmol) in THF (3.5 mL) under argon were added trimethylaluminium (2M in toluene, 0.35 mL, 0.70 mmol, 2.2 eq.) and Pd(PPh3)4 (36 mg, 0.032 mmol, 0.1 eq.). The mixture was refluxed for 16h, and after cooling, the solvent was evaporated. The crude residue was purified by column chromatography on silica gel (gradient CH2Cl2 100 to CH2Cl2/MeOH 99/1) to give the desired product 6 (65 mg, 70%) as a yellow solid. Rf (petroleum ether/EtOAc, 7/3): 0.10. Mp: 230–232 °C. IR (ATR diamond, cm−1) ν: 3301, 2853, 1527, 1425, 1370, 1270, 1229, 1107, 1022, 948, 876, 737. 1H NMR (400 MHz, CDCl3) δ 2.49 (d, J = 1.0 Hz, 3H, CH3), 3.85 (m, 4H, 2 × CH2(N)), 4.58 (m, 4H, 2 × CH2(O)), 6.94 (ddd, J = 8.1 Hz, J = 2.2 Hz, J = 1.0 Hz, 1H), 7.33 (t, J = 8.1 Hz, 1H), 7.94-8.04 (m, 4H), 8.51 (d, J = 2.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 18.9 (CH3), 48.2 (2 × CH2), 67.4 (2 × CH2), 115.5 (CH), 117.7 (CH), 121.1 (CH), 129.8 (CH), 131.1 (Cq), 135.1 (CH), 137.6 (Cq), 140.1 (Cq), 148.1 (CH+Cq), 156.2 (Cq), 159.4 (Cq), 160.1 (Cq). HRMS (EI-MS): m/z calculated for C18H19N4O2 [M + H]+: 323.1502; found 323.1503.
2-(3-Methoxymethoxyphenyl)-4-morpholinyl-7-vinylpyrido[3,2-d]pyrimidine (7). The reaction was carried out as described in general procedure B using 4 to afford 7 as a yellow solid (178 mg, 91%). Rf (petroleum ether/EtOAc, 8/2): 0.16. Mp: 105–107 °C. IR (ATR diamond, cm−1) ν: 2856, 1527, 1487, 1454, 1343, 1275, 1111, 1070, 1021, 956, 910, 739. 1H NMR (400 MHz, CDCl3) δ: 3.52 (s, 3H, CH3), 3.96–3.89 (m, 4H, 2 × CH2(N)), 4.58 (m, 4H, 2 × CH2(O)), 5.28 (s, 2H, CH2), 5.56 (d, 1H, J = 11.0 Hz, CH2alkene), 6.05 (d, 1H, J = 17.7 Hz, CH2alkene), 6.84 (dd, 1H, J = 11.0 Hz, J = 17.7 Hz, CHalkene), 7.20–7.13 (m, 1H), 7.40 (t, 1H, J = 7.9 Hz), 8.19–8.09 (m, 3H), 8.72 (d, 1H, J = 1.9 Hz). 13C NMR (101 MHz, CDCl3) δ: 48.3 (2 × CH2), 56.3 (CH3), 67.5 (2 × CH2), 94.7 (CH2), 116.5 (CH), 118.4 (CH), 119.0 (CH2), 122.3 (CH), 129.5 (CH), 132.6 (CH), 133.2 (CH), 136.2 (Cq), 139.8 (Cq), 140.2 (Cq), 144.9 (CH), 148.4 (Cq), 157.6 (Cq), 159.4 (Cq), 160.2 (Cq). HRMS (EI/MS): m/z calculated for C21H23ClN4O3 [M + H]+: 379.1765; found 379.1766.
7-(3-(Methoxymethoxy)phenyl)-4-morpholinylpyrido[3,2-d]pyrimidine-7-carbaldehyde (8). To a solution of 7 (400 mg, 1.06 mmol) in THF/H2O, 1/1 (30 mL) was added osmium tetroxide, 2.5% wt (0.76 mL, 0.053 mmol, 0.05 eq.). The mixture was stirred until it turned dark, then NaIO4 (680 mg, 3.18 mmol, 3.0 eq.) was added was added in three equal portions. The solution was stirred during 2 h at room temperature followed by the addition of an aqueous solution of Na2S2O3 10% wt. After filtration on celite, the filtrate was diluted in EtOAc (50 mL), the combined organic layers were washed with water (2 × 20 mL) and dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (petroleum ether/EtOAc, 8/2) to afford 8 as a yellow solid (395 mg, 98%). Rf (petroleum ether/EtOAc, 8/2): 0.20. Mp: 141–143 °C. IR (ATR diamond, cm−1) ν: 2911, 1701, 1508, 1461, 1426, 1268, 1154, 1116, 1071, 1008, 957, 739. 1H NMR (400 MHz, DMSO-d6) δ: 3.43 (s, 3H, CH3), 3.83 (m, 4H, 2 × CH2(N)), 4.52 (m, 4H, 2 × CH2(O)), 5.28 (s, 2H, CH2), 7.25–7.13 (m, 1H), 7.45 (t, 1H, J = 7.5 Hz), 8.10 (d, 2H, J = 7.4 Hz), 8.67 (s, 1H,), 9.09 (s, 1H), 10.28 (s, 1H, CHO). 13C NMR (101 MHz, DMSO-d6) δ: 47.8 (2 × CH2), 55.6 (CH3), 66.3 (2 × CH2), 94.0 (CH2), 115.7 (CH), 118.5 (CH), 121.7 (CH), 129.6 (CH), 133.3 (Cq), 135.1 (Cq), 138.9 (CH), 139.2 (Cq), 144.4 (CH), 147.4 (Cq), 157.0 (Cq), 158.5 (Cq), 159.7 (Cq), 192.4 (CH). HRMS (EI/MS): m/z calculated for C20H21ClN4O4 [M + H]+: 381.1557; found 381.1560.
2-(3-Hydroxyphenyl)-4-morpholinyl-7-vinylpyrido[3,2-d]pyrimidine (9). The reaction was carried out as described in general procedure C using 7 (150 mg, 0.396 mmol) to afford 9 as a white solid (130 mg, 98%). Rf (petroleum ether/EtOAc, 8/2): 0.08. Mp: 183–185 °C. IR (ATR diamond, cm−1) ν: 3338, 2856, 1597, 1531, 1483, 1438, 1230, 1107, 968, 858, 739. 1H NMR (400 MHz, CDCl3) δ: 3.89 (m, 4H, 2 × CH2(N)), 4.54 (m, 4H, 2 × CH2(O)), 5.51 (d, 1H, J = 11.0 Hz, CH2alkene), 5.99 (d, 1H, J = 17.6 Hz, CH2alkene), 6.77 (dd, 1H, J = 11.0 Hz, J = 17.6 Hz, CHalkene), 6.92 (d, 1H, J = 7.5 Hz), 7.29 (t, 1H, J = 7.5 Hz), 7.98 (s, 2H), 8.08 (m, 2H), 8.70 (d, 1H, J = 7.5 Hz). 13C NMR (101 MHz, CDCl3) δ: 48.3 (2 × CH2), 66.1 (CH2), 67.5 (CH2), 115.6 (CH), 118.0 (CH), 119.2 (CH2), 121.0 (CH), 129.8 (CH), 132.2 (CH), 132.3 (Cq), 133.1 (CH), 136.4 (Cq), 140.0 (Cq), 144.9 (CH), 148.2 (Cq), 156.4 (Cq), 159.3 (Cq), 160.5 (Cq). HRMS (EI/MS): m/z calculated for C19H19N4O2 [M + H]+: 335.1430; found 335.1504.
2-(3-Hydroxyphenyl)-4-morpholinylpyrido[3,2-d]pyrimidine-7-carbaldehyde (10). The reaction was carried out as described in general procedure G using 8 (200 mg, 0.526 mmol) to afford 10 as a yellow solid (159 mg, 90%). Rf (petroleum ether/EtOAc, 8/2): 0.05. Mp: 182–184 °C. IR (ATR diamond, cm−1) ν: 2852, 1695, 1556, 1516, 1426, 1377, 1283, 1107, 1025, 882, 743. 1H NMR (400 MHz, DMSO-d6) δ: 3.84 (m, 4H, 2 × CH2(N)), 4.52 (bs, 4H, 2 × CH2(O)), 6.92 (m, 1H), 7.30 (t, 1H, J = 8.1 Hz), 7.90 (m, 2H), 8.64 (d, 1H, J = 1.9 Hz), 9.09 (d, 1H, J = 1.9 Hz), 9.58 (s, 1H, OH), 10.28 (s, 1H, CHO). 13C NMR (101 MHz, DMSO-d6) δ: 48.1 (2 × CH2), 66.3 (2 × CH2), 114.9 (CH), 117.8 (CH), 119.1 (CH), 129.4 (CH), 133.3 (Cq), 136.1 (Cq), 138.8 (CH), 139.0 (Cq), 144.3 (CH), 147.4 (Cq), 157.5 (Cq), 158.4 (Cq), 159.7 (Cq), 192.4 (CH). HRMS (EI/MS) m/z calculated for C18H17N4O3 [M + H]+: 337.1563; found 337.1546.
3-(7-((Cyclopropylamino)methyl)-4-morpholinylpyrido[3,2-d]pyrimidin-2-yl)phenol hydrochloride salt (11). To a solution of 8 (70 mg, 0.184 mmol) in dry CH2Cl2 (6 mL), was added a small amount of MgSO4 and cyclopropylamine (12 µL, 0.184 mmol, 1.0 eq.). The reaction was stirred at room temperature for 12 h before filtering the MgSO4 and removing the solvent in vacuo. The crude product was diluted in methanol (6 mL) and NaBH3CN (60 mg, 0.92 mmol, 5.0 eq.) was added to the mixture. Once the reaction stopped bubbling (15 min), the crude product was extracted. The combined organic layers were washed with a solution of saturated NaHCO3 (2 × 10 mL) and dried over MgSO4 and filtered. The crude product was then subjected to the general procedure C to afford 11 as a white solid (28 mg, 40%). Rf (CH2Cl2/MeOH, 99/1): 0.05. Mp: 244–246 °C. IR (ATR diamond, cm−1) ν: 3351, 3047, 1613, 1552, 1517, 1428, 1385, 1310, 1114, 1024, 864, 732. 1H NMR (400 MHz, DMSO-d6) δ: 0.81 (s, 2H, 2xHcypro), 1.09 (s, 2H 2×Hcypro), 2.72 (s, 1H, Hcypro), 3.87 (m, 4H, 2 × CH2(N)), 4.48 (s, 2H, CH2), 4.64 (m, 4H, 2 × CH2(O)), 7.06 (s, 1H), 7.38 (s, 1H), 7.91 (d, 2H, J = 11.7 Hz), 8.70 (s, 1H), 9.10 (s, 1H), 9.38 (s, 1H, OH), 10.39 (s, 1H, NH). 13C DEPT NMR (101 MHz, DMSO-d6) δ 10.2 (2 × CH2), 28.3 (CH), 48.9 (2 × CH2), 51.6 (CH2), 66.7 (2 × CH2), 112.9 (CH), 116.9 (CH), 120.1 (CH), 131.6 (CH), 134.9 (CH), 150.1 (CH). HRMS (EI/MS): m/z calculated for C21H24N5O2 [M + H]+: 378.1852; found 378.1927.
3-(4-Morpholinyl-7-(morpholinylmethyl)pyrido[3,2-d]pyrimidin-2-yl)phenol hydrochloride salt (12). The reaction was carried out as described in general procedure D using 8 (80 mg, 0.21 mmol) and morpholine to afford 12 as a white solid (52 mg, 61%) Rf (CH2Cl2/MeOH, 99/1): 0.04. Mp: 239–141 °C. IR (ATR diamond, cm−1) ν: 3344, 3037, 1552, 1510, 1417, 1292, 1114, 1028, 864, 736. 1H NMR (400 MHz, DMSO-d6) δ: 3.26 (m, 4H, 2 × CH2(N)), 3.86 (m, 8H, 2 × CH2(N) and 2 × CH2(O)), 4.63 (m, 6H, CH2 and 2 × CH2(O)), 7.03 (s, 1H), 7.37 (s, 1H), 7.96 (m, 2H), 8.76 (s, 1H), 9.13 (s, 1H, H6), 12.35 (s, 1H, NH). 13C DEPT NMR (101 MHz, DMSO-d6) δ: 18.4 (2CH2), 54.4 (2CH2), 59.1 (2CH2), 66.4 (2CH2), 66.8 (2CH2), 114.1 (CH), 117.9 (CH), 119.9 (CH), 130.4 (CH), 136.2 (CH), 147.1 (CH) HRMS (EI/MS): m/z calculated for C22H26N5O3 [M + H]+: 408.1957; found 408.2020
2-(3-Hydroxyphenyl)-7-(4-methylpiperazin-1-ylmethyl)-4-morpholinylpyrido[3,2-d]pyrimidine hydrochloride salt (13). The reaction was carried out as described in general procedure D using 8 (100 mg, 0.21 mmol,) and N-methylpiperazine to afford 13 as a white solid (120 mg, 92%). Rf (CH2Cl2/MeOH, 99/1): 0.04. Mp: 243–245 °C. IR (ATR diamond, cm−1) ν: 2927, 1616, 1556, 1508, 1420, 1388, 1312, 1112, 881, 729. 1H NMR (400 MHz, DMSO-d6) δ: 2.81 (s, 3H, NCH3), 3.46 (m, 2H, CH2(N)), 3.88 (s, 5H), 4.86–4.45 (m, 6H, 3 × CH2(N)), 7.10 (d, 1H, J = 7.2 Hz), 7.40 (t, 1H, J = 8.2 Hz), 7.99–7.76 (m, 2H), 8.81 (s, 1H), 9.10 (s, 1H, H6), 9.76 (bs, 1H, OH), 11.91 (s, 1H, NH). 13C DEPT NMR (101 MHz, DMSO-d6) δ: 48.4 (2 × CH2), 50.1 (CH3), 54.7 (2 × CH2), 57.8 (2 × CH2), 60.1 (CH2), 66.4 (2 × CH2), 115.6 (CH), 119.7 (2 × CH), 129.9 (CH), 145.4 (CH), 146.5 (CH), 148.5 (CH). HRMS (EI/MS): m/z calculated for C23H28N6O2 [M + H]+: 421.2274; found 421.2361.
(2-(3-(Methoxymethoxy)phenyl)-4-morpholinylpyrido[3,2-d]pyrimidin-7-yl)methanol (14). To a solution of NaBH4 (60 mg, 1.58 mmol, 2.0 eq.) in MeOH (12 mL), was added 8 (300 mg, 0.79 mmol). The mixture was stirred at room temperature for two hours. The solvent was then removed under reduced pressure, the crude product was diluted in CH2Cl2 (30 mL), the organic layer was washed with brine (10 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure to afford 14 as a yellow solid (298 mg, 99%). Rf (petroleum ether/EtOAc, 7/3): 0.1. Mp: 134–136 °C. IR (ATR diamond, cm−1) ν: 3265, 2913, 1532, 1491, 1438, 1356, 1262, 1152, 1115, 1066, 1009, 915, 874, 739. 1H NMR (400 MHz, DMSO-d6) δ: 3.54 (s, 3H, CH3), 3.90 (m, 4H, 2 × CH2(N)), 4.55 (m, 4H, 2 × CH2(O)), 4.82 (s, 2H, CH2OH), 5.29 (s, 2H, CH2), 7.18 (dd, 1H, J = 2.3 Hz, J = 8.1 Hz), 7.41 (t, 1H, J = 7.9 Hz), 8.12 (m, 3H), 8.55 (d, 1H, J = 1.7 Hz), 9.54 (bs, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ: 48.3 (2 × CH2), 56.3 (CH3), 62.3 (2 × CH2), 67.4 (CH2), 94.7 (CH2), 116.5 (CH), 118.5 (CH), 122.3 (CH), 129.6 (CH), 132.2 (Cq), 133.4 (CH), 139.9 (Cq), 140.5 (Cq), 145.5 (CH), 148.0 (Cq), 157.6 (Cq), 159.3 (Cq), 160.0 (Cq). HRMS (EI/MS): m/z calculated for C20H23N4O4 [M + H]+: 383.1641; found 383.1715.
3-(7-(Hydroxymethyl)-4-morpholinylpyrido[3,2-d]pyrimidin-2-yl)phenol (15). The reaction was carried out as described in general procedure C using 14 (200 mg, 0.523 mmol) to afford 15 as a yellow solid (154 mg, 87%). Rf (CH2Cl2/MeOH, 97/3): 0.20. Mp: 229–231 °C. IR (ATR diamond, cm−1) ν: 3248, 2851, 1511, 1458, 1356, 1238, 1111, 1054, 886, 735. 1H NMR (400 MHz, DMSO-d6) δ: 3.82 (m, 4H, 2 × CH2(N)), 4.51 (m, 4H, 2 × CH2(O)), 4.73 (d, 2H, J = 5.6 Hz, CH2OH), 5.59 (t, 1H, OH), 6.89 (dd, 1H, J = 1.6 Hz, J = 7.9 Hz), 7.29 (t, 1H, J = 7.9 Hz), 7.89 (m, 2H), 8.04 (s, 1H), 8.70 (s, 1H), 9.54 (s, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ: 47.6 (2 × CH2), 60.3 (CH2), 66.4 (2 × CH2), 114.8 (CH), 117.5 (CH), 119.0 (CH), 129.3 (CH), 131.1 (Cq), 132.5 (CH), 139.3 (Cq), 142.2 (Cq), 145.8 (CH), 147.6 (Cq), 157.4 (Cq), 158.5 (Cq), 158.8 (Cq). HRMS (EI/MS): m/z calculated for C18H19N4O3 [M + H]+: 339.1379; found 339.1441.
3-(7-(Methoxymethyl)-4-morpholinylpyrido[3,2-d]pyrimidin-2-yl)methanol (16). To a solution of 8 (80 mg, 0.209 mmol) in THF (10 mL) at 0 °C, was added NaBH4 (8 mg, 0.23 mmol, 1.1 eq.) followed by the addition of MeI (13 µL, 0.209 mmol, 1.0 eq.). The solution was stirred at room temperature for 2 h 30 min before removing the solvent in vacuo. The crude product was diluted in CH2Cl2 (30 mL) and the organic layer was washed with brine (10 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude product directly underwent the reaction described in general procedure C to afford 16 as a yellow solid (54 mg, 74%). Rf (CH2Cl2/MeOH, 99/1): 0.13. Mp: 165–167 °C. IR (ATR diamond, cm−1) ν: 3273, 2852, 1540, 1491, 1438, 1352, 1270, 1103, 1021, 968, 878, 739, 678. 1H NMR (400 MHz, CDCl3) δ: 3.46 (s, 3H, CH3), 3.92 (m, 4H, 2 × CH2(N)), 4.58 (m, 4H, 2 × CH2(O)), 4.63 (s, 2H, CH2), 6.94 (dd, 1H, J = 2.2 Hz, J = 7.7 Hz), 7.38 (t, 1H, J = 7.9 Hz), 7.98 (m, 1H), 8.02 (d, 1H, J = 7.9 Hz), 8.10 (m, 1H), 8.65 (d, 1H, J = 2.1 Hz), 9.62 (s, 1H, OH). 13C NMR (101 MHz, CDCl3) δ: 48.3 (2 × CH2), 58.9 (CH3), 67.5 (2 × CH2), 72.0 (CH2), 115.5 (CH), 117.9 (CH), 121.1 (CH), 129.8 (CH), 132.5 (Cq), 134.5 (CH), 137.7 (Cq), 140.1 (Cq), 146.1 (CH), 148.1 (Cq), 156.2 (Cq), 159.4 (Cq), 160.3 (Cq). HRMS (EI/MS): m/z calculated for C19H21N4O3 [M + H]+: 353.1535; found 353.1609.
4-(7-(Iodomethyl)-2-(3-(methoxymethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (17). To a solution of triphenylphosphine (137 mg, 0.523 mmol, 2.0 eq.) in CH2Cl2 (5 mL) at 0 °C, was added iodine (199 mg, 0.784 mmol, 3.0 eq.) and imidazole (36 mg, 0.523 mmol, 2.0 eq.) and then 8 (100 mg, 0.262 mmol). The reaction was stirred at 0 °C for 7 h before adding an aqueous solution of Na2S2O3 10% (5 mL). After 15 min of stirring, the mixture was extracted and the organic layer was washed with water (5 mL), dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (petroleum ether/EtOAc, 1/9) to afford 17 as a yellow solid (89 mg, 69%). Rf (petroleum ether/EtOAc, 1/9): 0.14. Mp: 144–146 °C. IR (ATR diamond, cm−1) ν: 2921, 1732, 1663, 1532, 1491, 1430, 1270, 1234, 1148, 1107, 1021, 964, 874, 739. 1H NMR (400 MHz, CDCl3) δ: 3.53 (s, 3H, CH3), 3.92 (m, 4H, 2 × CH2(N)), 4.53 (s, 2H, CH2), 4.58 (m, 4H, 2 × CH2(O)), 5.28 (s, 2H, CH2), 7.17 (m, 1H), 7.40 (t, 1H, J = 7.9 Hz), 8.17–8.10 (m, 3H), 8.66 (d, 1H, J = 2.3 Hz). 13C NMR (101 MHz, CDCl3) δ: 48.3 (2 × CH2), 56.3 (CH3), 62.4 (CH2), 67.4 (2 × CH2), 94.8 (CH2), 116.5 (CH), 118.5 (CH), 122.4 (CH), 129.6 (CH), 132.2 (Cq), 133.4 (CH), 135.4 (Cq), 140.0 (Cq), 145.5 (CH), 148.0 (Cq), 157.6 (Cq), 159.3 (Cq), 160.0 (Cq). HRMS (EI/MS): m/z calculated for C20H22IN4O3 [M + H]+: 493.0658; found 493.0738.
4-(7-(Azidomethyl)-2-(3-(methoxymethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-yl) morpholine (18). To a solution of 17 (78 mg, 0.158 mmol) in DMF (5 mL) was added sodium azide (15 mg, 0.238 mmol, 1.5 eq.). The reaction was stirred at 65 °C for 6 h, before diluting the solution in CH2Cl2 (60 mL). The combined organic layers were washed with an aqueous solution of citric acid, 10% (10 mL), a saturated solution of NaHCO3 (10 mL) and then were washed twice with water (10 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 98/2) to afford 18 as a yellow solid (49 mg, 75%). Rf (CH2Cl2/MeOH, 98/2): 0.11. Mp: 143–145 °C. IR (ATR diamond, cm−1) ν: 2872, 2086, 1612, 1523, 1428, 1307, 1109, 1021, 862, 731. 1H NMR (400 MHz, CDCl3) δ: 3.53 (s, 3H, CH3), 3.88 (m, 4H, 2 × CH2(N)), 4.68 (m, 4H, 2 × CH2(O)), 4.90 (s, 2H, CH2N3), 5.28 (s, 2H, CH2), 7.08 (m, 1H), 7.41 (m, 1H), 7.87 (m, 2H), 8.46 (s, 1H), 8.91 (s, 1H). 13C NMR (101 MHz, CDCl3) δ: 48.4 (2 × CH2), 50.4 (CH2), 56.3 (CH3), 66.3 (2 × CH2), 94.7 (CH2), 115.5 (CH), 119.6 (2 × CH), 130.0 (CH), 132.2 (Cq), 134.8 (Cq), 137.8 (CH), 140.2 (Cq), 147.5 (CH), 149.2 (Cq), 157.8 (Cq), 159.5 (Cq), 160.3 (Cq). HRMS (EI/MS): m/z calculated for C20H22N7O3 [M + H]+: 408.1706; found 408.1803.
3-(7-(Azidomethyl)-4-morpholinylpyrido[3,2-d]pyrimidin-2-yl)phenol (19). The reaction was carried out as described in general procedure C using 18 (40 mg, 0.10 mmol) to afford 19 as a yellow solid (35 mg, 98%). Rf (CH2Cl2/MeOH, 99/1): 0.05. Mp: 169–171 °C. IR (ATR diamond, cm−1) ν: 3383, 3043, 2868, 2096, 1613, 1552, 1511, 1434, 1307, 1111, 1021, 862, 731, 670. 1H NMR (400 MHz, CDCl3) δ: 3.89 (m, 4H, 2 × CH2(O)), 4.70 (bs, 4H, 2 × CH2(N)), 4.89 (s, 2H, CH2N3), 7.12 (m, 1H), 7.43 (m, 1H), 7.87 (m, 2H), 8.49 (s, 1H), 8.87 (s, 1H), 10.06 (bs, 1H, OH). 13C NMR (101 MHz, CDCl3) δ: 48.4 (2 × CH2), 50.4 (CH2), 66.3 (2 × CH2), 115.4 (CH), 119.6 (2 × CH), 130.0 (CH), 132.7 (Cq), 133.8 (Cq), 137.4 (CH), 139.9 (Cq), 146.9 (CH), 148.8 (Cq), 157.8 (Cq), 159.1 (Cq), 160.0 (Cq). HRMS (EI/MS): m/z calculated for C18H18N7O2 [M + H]+: 364.1444; found 364.1517.
3-(7-((4-((Dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-morpholinylpyrido[3,2-d]pyrimidin-2-yl)phenol (20). To a solution of 19 (80 mg, 0.22 mmol) in MeCN (3 mL) were added CuOAc.H2O (25 µL, C = 0.4 M, 0.011 mmol, 0.05 eq.), 3-dimethylamino-1-propyne (26 µL, 0.22 mmol, 1.0 eq.) and a few drops of triethylamine until the products were soluble in the solvent. The reaction was stirred at room temperature for 12 h, before removing the solvent in vacuo. The crude product was dissolved in CH2Cl2 (30 mL) and the organic layer was washed with a saturated solution of NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was purified by precipitation with CH2Cl2 to afford 20 as a yellow solid (30 mg, 31%). Mp: 224–226 °C. IR (Diamond ATR, cm−1) ν: 3271, 2856, 1595, 1557, 1508, 1437, 1308, 1269, 1166, 1113, 1062, 1029, 968, 792, 739, 674, 1H NMR (400 MHz, DMSO-d6) δ: 2.18 (bs, 6H, 2 × CH3), 3.55 (bs, 2H, CH2), 3.83 (m, 4H, 2 × CH2(N)), 4.51 (m, 4H, 2 × CH2(O)), 5.89 (s, 2H, CH2OCH3), 6.90 (d, 1H, J = 7.8 Hz), 7.30 (t, 1H, J = 8.0 Hz), 7.87 (d, 2H, J = 6.6 Hz), 7.94 (s, 1H), 8.24 (s, 1H, CH), 8.73 (s, 1H, H6), 9.55 (s, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ: 45.0 (2 × CH3), 48.1 (2 × CH2), 50.4 (CH2), 55.4 (CH2), 66.8 (2 × CH2), 115.3 (CH), 118.1 (CH), 119.5 (CH), 124.8 (CH), 129.8 (CH), 132.3 (Cq), 135.0 (CH), 136.3 (Cq), 139.5 (Cq), 144.4 (Cq), 146.4 (CH), 147.8 (Cq), 157.9 (Cq), 158.8 (Cq), 159.6 (Cq). HRMS (EI-MS): m/z calculated for C23H27N8O2 [M + H]+, 447.2257 found 447.2251.
3-(7-((4-(Methoxymethyl)-1H-1.2.3-triazol-1-yl)methyl)-4-morpholinylpyrido[3,2-d]pyrimidin-2-yl)phenol (21). To a solution of 19 (80 mg, 0.22 mmol, 1.0) in MeCN (4 mL) were added CuI (3 mg, 0.01 mmol, 0.05 eq.), 3-methoxy-1-propyne (19 µL, 0.22 mmol, 1.0 eq.) and a few drops of triethylamine until the products were soluble in the solvent. The reaction was stirred at room temperature for 12 h, before removing the solvent in vacuo. The crude product was dissolved in EtOAc (30 mL) and the organic layer was washed with a saturated solution of NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 99/1) to afford 21 as a yellow solid (73 mg, 79%). Rf (CH2Cl2/MeOH, 99/1): 0.05. Mp: 241–243 °C. IR (ATR diamond, cm−1) ν: 3130, 2856, 1589, 1552, 1516, 1430, 1315, 1275, 1107, 1062, 1029, 968, 792, 739, 674. 1H NMR (400 MHz, DMSO-d6) δ: 3.28 (s, 3H, CH3), 3.81 (m, 4H, 2 × CH2(N)), 4.47 (m, 6H, CH2 and 2 × CH2(O)), 5.88 (s, 2H, CH2(O)), 6.89 (d, 1H, J = 7.8 Hz), 7.28 (t, 1H, J = 8.0 Hz), 7.87 (d, 2H, J = 6.6 Hz), 7.94 (s, 1H), 8.32 (s, 1H, CH), 8.72 (s, 1H), 9.53 (s, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ: 47.6 (2 × CH2), 49.9 (CH2), 57.4 (CH3), 64.9 (CH2), 66.4 (2 × CH2), 114.8 (CH), 117.6 (CH), 119.0 (CH), 124.5 (CH), 129.3 (CH), 131.8 (Cq), 134.5 (CH), 135.8 (Cq), 139.0 (Cq), 144.4 (Cq), 145.9 (CH), 147.3 (Cq), 157.4 (Cq), 158.4 (Cq), 159.2 (Cq). HRMS (EI/MS): m/z calculated for C22H24N7O3 [M + H]+: 434.1862; found 434.1939.
3-(7-((4-((Methoxymethoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-morpholinyl pyrido[3,2-d]pyrimidin-2-yl)phenol (22). To a solution of 19 (45 mg, 0.13 mmol) in MeCN (4 mL) were added CuI (1.2 mg, 0.006 mmol, 0.05 eq.), methoxy(prop-2-yn-1-yloxy)methane (14 mg, 0.14 mmol, 1.1 eq.) and a few drops of triethylamine until the products were soluble in the solvent. The reaction was stirred at room temperature for 12 h, before removing the solvent in vacuo. The crude product was dissolved in CH2Cl2 (30 mL) and the organic layer was washed with a saturated solution of NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 98/2) to afford 22 as a brown pale solid (15 mg, 25%). Mp: 218–220 °C. IR (Diamond ATR, cm−1) ν: 3204, 2937, 1618, 1589, 1552, 1516, 1430, 1315, 1275, 1107, 1062, 1029, 968, 792, 739, 674. 1H NMR (400 MHz, CDCl3) δ: 3.29 (s, 3H, CH3), 3.82 (m, 4H, 2 × CH2(N)), 4.47 (m, 4H, 2 × CH2(O)), 4.61 (s, 2H, CH2), 4.65 (s. 2H, CH2), 5.90 (s, 2H, CH2), 6.89 (d, 1H, J = 7.8 Hz), 7.30 (t, 1H, J = 8.0 Hz), 7.88 (d, 2H, J = 6.6 Hz), 7.96 (s, 1H), 8.35 (s, 1H, CH), 8.74 (s, 1H), 9.55 (s, 1H, OH). 13C NMR (101 MHz, CDCl3) δ: 47.6 (2 × CH2), 49.9 (CH2), 56.6 (CH3), 61.7 (CH2), 68.2 (2 × CH2), 95.5 (CH2), 115.4 (CH), 118.0 (CH), 119.7 (CH), 122.9 (CH), 125.3 (CH), 129.8 (CH), 135.0 (Cq), 136.0 (Cq), 139.1 (Cq), 144.8 (Cq), 146.4 (CH), 147.8 (Cq), 157.9 (Cq), 158.8 (Cq), 159.5 (Cq). HRMS (EI-MS): m/z calculated for C23H26N7O4 [M + H]+, 464.2046 found 464.2041.
3-(7-((4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-morpholinylpyrido[3,2-d]pyrimidin-2-yl)phenol (23). To a solution of 19 (82 mg, 0.23 mmol) in MeCN (4 mL) were added CuI (4 mg, 0.01 mmol, 0.05 eq.), 2-propyn-1-ol (16 µL, 0.25 mmol, 1.1 eq.) and a few drops of triethylamine until the products were soluble in the solvent. The reaction was stirred at room temperature for 12 h, before removing the solvent in vacuo. The crude product was dissolved in CH2Cl2 (30 mL) and the organic layer was washed with a saturated solution of NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 98/2) to afford 23 as a yellow solid (49 mg, 51%). Rf (CH2Cl2/MeOH, 98/2): 0.04. Mp: 238–240 °C. IR (ATR diamond, cm−1) ν: 3154, 2962, 2848, 1605, 1556, 1495, 1458, 1348, 1266, 1115, 1025, 886, 739, 678. 1H NMR (400 MHz, DMSO-d6) δ: 3.81 (m, 4H, 2 × CH2(N)), 4.50 (s, 4H, 2 × CH2(O)), 4.54 (d, 2H, J = 5.6 Hz, CH2), 4.64 (s. 2H, CH2), 5.20 (t, 1H, J = 5.6 Hz, OH), 5.87 (s, 1H, CH), 6.89 (d, 1H, J = 7.8 Hz), 7.28 (t, 1H, J = 8.0 Hz), 7.84 (m, 2H), 7.94 (d, 1H, J = 2.0 Hz), 8.72 (d, 1H, J = 2.0 Hz), 9.53 (s, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ: 47.6 (2 × CH2), 49.9 (CH2), 55.0 (CH2), 66.4 (2 × CH2), 114.8 (CH), 117.6 (CH), 119.0 (CH), 123.4 (Cq), 129.3 (CH), 131.8 (CH), 134.4 (Cq), 136.0 (Cq), 139.0 (CH), 145.9 (CH), 147.3 (Cq), 148.6 (Cq), 157.4 (Cq), 158.4 (Cq), 159.2 (Cq). HRMS (EI/MS): m/z calculated for C21H21N7O3 [M + H]+: 420.1706; found 420.1784.
3-(7-((4-(Fluoromethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-morpholinylpyrido[3,2-d]pyrimidin-2-yl)phenol (24). Derivative 18 (35 mg, 0.17 mmol) was subjected to the triazole formation using the same procedure as described for 23. The crude material was dissolved in dry CH2Cl2 (4 mL) and the mixture was cooled to 0 °C under inert atmosphere. A solution of DAST (11 µL, 0.083 mmol, 1.1 eq) was added slowly. After stirring at 0 °C, 22 µL of DAST (0.34 mmol, 2.0 eq) was added again. The mixture was stirred at 0 °C for 1 h. Hydrolysis was performed with a saturated solution of NaHCO3 (10 mL). The organic layer was extracted with CH2Cl2 (3 × 10 mL). The organic layer was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product directly underwent the reaction described in general procedure C to afford 24 as a yellow solid (44 mg, 62%). Mp: 168–170 °C. IR (Diamond ATR, cm−1) ν: 3354, 3046, 1620, 1562, 1506, 1425, 1314, 1266, 1115, 1025, 886, 739, 678. 1H NMR (400 MHz, DMSO-d6) δ: 3.86 (m, 4H, 2 × CH2(N)), 4.56 (s, 4H, 2 × CH2 (O)), 5.55 (d, 2H, J = 48.0 Hz, CH2 F), 5.92 (s, 1H, CH), 6.01 (s, 2H, CH2), 7.03 (m, 1H), 7.39 (t, 1H, J = 8.0 Hz), 7.77 (m, 1H), 7.83 (d, 1H, J = 2.0 Hz), 8.09 (s, 1H, CH), 8.56 (d, 1H, J = 2.0 Hz), 8.86 (s, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ: 47.6 (2 × CH2), 55.0 (CH2), 66.4 (2 × CH2), 76.4 (d, J = 159.0 Hz, CH2), 114.8 (CH), 117.6 (CH), 119.0 (CH), 123.4 (Cq), 129.3 (CH), 131.8 (CH), 134.4 (Cq), 136.0 (Cq), 139.0 (CH), 145.9 (CH), 147.3 (Cq), 148.6 (Cq), 157.4 (Cq), 158.4 (Cq), 159.2 (Cq). 19F NMR (376 MHz, DMSO-d6) δ: −202.6 (CH2F). HRMS (EI-MS): m/z calculated for C21H21FN7O2 [M + H]+, 422.1741 found 422.1735.
2-(2-(3-(Methoxymethoxy)phenyl)-4-morpholinylpyrido[3,2-d]pyrimidin-7-yl)aceto nitrile (25). To a solution of t-BuOK (108 mg, 0.962 mmol, 1.6 eq.) in dry DME (4 mL) at -50 °C, were added dropwise a solution of TosMIC (141 mg, 0.722 mmol, 1.2 eq.) in dry DME (4 mL) and after 10 min a solution of 8 (230 mg, 0.602 mmol). The reaction was stirred at −50 °C for 40 min, then MeOH (5mL) was added and the solution was refluxed for 1 h. The solvent was removed in vacuo, with the crude product diluted in EtOAc (30 mL). The organic layers were washed with water (2 × 10 mL) and dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 99.4/0.6) to afford 25 as a yellow solid (109 mg, 46%). Rf (CH2Cl2/MeOH, 99.4/0.6): 0.15. Mp: 158-160 °C. IR (ATR diamond, cm−1) ν: 2952, 2259, 1600, 1553, 1524, 1502, 1435, 1350, 1271, 1150, 1112, 1078, 1017, 967, 916, 875, 736, 685. 1H NMR (400 MHz, CDCl3) δ: 3.56 (s, 3H, CH3), 3.95 (m, 6H, CH2CN and 2 × CH2(N)), 4.61 (m, 4H, 2 × CH2(O)), 5.31 (s, 2H, CH2), 7.20 (ddd, 1H, J = 1.1 Hz, J = 2.5 Hz, J = 8.1 Hz), 7.43 (t, 1H, J = 7.9 Hz), 8.16 (m, 3H), 8.62 (d, 1H, J = 2.3 Hz, H6). 13C NMR (101 MHz, CDCl3) δ: 21.6 (CH2), 48.3 (2 × CH2), 56.3 (CH3), 67.4 (2 × CH2), 94.7 (CH2), 116.6 (CH), 118.6 (CH), 122.4 (CH), 129.5 (CH), 129.6 (Cq), 132.9 (Cq), 135.6 (CH), 139.8 (Cq), 145.0 (CH), 148.1 (Cq), 157.6 (Cq), 159.2 (Cq), 160.6 (Cq). HRMS (EI/MS): m/z calculated for C21H21N5O3 [M + H]+: 392.1644; found 392.1718.
2-(2-(3-Hydroxyphenyl)-4-morpholinylpyrido[3,2-d]pyrimidin-7-yl)acetonitrile (26). The reaction was carried out as described in general procedure C using 25 (100 mg, 0.255 mmol) to afford 26 as a yellow solid (74 mg, 84%). Rf (CH2Cl2/MeOH, 99/1): 0.12. Mp: 201–203 °C. IR (ATR diamond, cm−1) ν: 3402, 2930, 2246, 1616, 1556, 1505, 1439, 1385, 1318, 1245, 1116, 1024, 865, 732. 1H NMR (250 MHz, DMSO-d6) δ: 3.87 (m, 4H, 2 × CH2(N)), 4.44 (s, 2H, CH2), 4.66 (m, 4H, 2 × CH2(O)), 7.08 (d, 1H, J = 8.0 Hz), 7.41 (t, 1H, J = 7.9 Hz), 8.04-7.76 (m, 2H), 8.46 (s, 1H), 8.82 (d, 1H, J = 2.0 Hz, H6), 9.85 (s, 1H, OH). 13C DEPT NMR (101 MHz, DMSO-d6) δ: 21.5 (CH2), 48.9 (2 × CH2), 66.5 (2 × CH2), 112.7 (CH), 117.4 (CH), 121.2 (CH), 130.8 (CH), 134.8 (CH). HRMS (EI/MS): m/z calculated for C19H18N5O2 [M + H]+: 348.1382; found 348.1455.
4-(2-(3-(Methoxymethoxy)phenyl)-7-(2-methoxyvinyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (27). To a solution of methoxymethyltriphenylphosphonium chloride (665 mg, 1.94 mmol, 1.5 eq.) in dry THF (15 mL) at 0 °C was added dropwise a solution of tBuOK (1.94 mL, 1.94 mmol, 1.5 eq.). The mixture was stirred at 0 °C for 1h until a solution of 8 (490 mg, 1.29 mmol) in dry THF (15 mL) was dropwise added. The reaction was stirred at room temperature for 48 h, then H2O (30 mL) were added and the crude product diluted in EtOAc (30 mL). The organic layers were extracted with EtOAc (2 × 10 mL) and dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (petroleum ether/EtOAc, 8/2) to afford 27 as a colorless oil containing a mixture of two isomers (327 mg, 80%). IR (Diamond ATR, cm−1) ν: 3293, 2856, 1528, 1495, 1442, 1352, 1111, 1021, 861, 739. 1H NMR (400 MHz, CDCl3) δ: 3.55 (s, 3H, CH3), 3.80 (s, 3H, CH3 isomer E), 3.92 (s, 2H, CH3 isomer Z), 3.94 (m, 4H, 2 × CH2(N)), 4.48 (m, 4H, 2 × CH2(O)), 5.30 (s, 2H, CH2), 5.37 (d, 1H, J = 6.8 Hz, CH isomer Z), 5.90 (d, 1H, J = 13.0 Hz, CH isomer E), 6.45 (d, 1H, J = 6.8 Hz, CH isomer Z), 7.35 (d, 1H, J = 13.0 Hz, CH isomer E), 7.41 (t, 1H, J = 8.1 Hz), 7.95 (d, 1H, J = 1.9 Hz, isomer E), 8.17 (m, 2H), 8.42 (d, 1H, J = 1.9 Hz, isomer Z), 8.58 (d, 1H, J = 1.9 Hz, isomer E), 8.77 (d, 1H, isomer Z). 13C NMR (101 MHz, CDCl3) δ: 48.0 (2 × CH2), 56.0 (CH3), 57.2 (OCH3), 61.2 (OCH3), 67.3 (2 × CH2), 94.5 (2 × CH2), 100.9 (CH isomer E), 101.1 (CH isomer Z), 110.4 (Cq), 116.2 (CH), 116.3(CH), 117.9 (CH), 118.0 (CH), 119.8 (CH), 129.9 (CH), 130.4 (CH), 130.8 (Cq), 133.6 (CH), 135.4 (Cq), 135.9 (Cq) 147.8 (Cq), 148.4 (Cq), 148.2 (CH), 146.3 (CH) 152.1 (CH isomer Z), 152.2 (CH isomer E), 157.3 (Cq), 57.4 (Cq), 158.1 (Cq), 159.2 (Cq), 159.6 (Cq), 159.9 (Cq); HRMS (EI-MS): m/z calculated for C20H21N4O3 [M + H]+, 365.1676, found 365.1770.
2-(2-(3-(Methoxymethoxy)phenyl)-4-morpholinylpyrido[3,2-d]pyrimidin-7-yl) acetaldehyde oxime (28). To a solution of 27 (60 mg, 0.178 mmol) in 20 mL THF/H2O (3/1) was added mercury acetate (800 mg, 2.51 mmol, 3.0 eq.) at 0 °C. The reaction was stirred for 2 h at 0 °C and brine (5 mL) was added. The organic layers were extracted with EtOAc (3 × 10 mL) and dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude aldehyde was directly dissolved in CH2Cl2 (10 mL), hydroxylammonium chloride (112 mg, 1.62 mmol, 2.0 eq.) and next triethylamine (338 µL, 2.43 mmol, 4.0 eq.) were added. The reaction was stirred for 12 h at room temperature, and an aqueous solution of saturated NaHCO3 (5 mL) was then added. The organic layers were washed with water (2 × 5 mL) and dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (petroleum ether/EtOAc, 1/1) to afford 28 as yellow solid containing the two stereoisomers (154 mg, 45%). Mp: 154–156 °C. IR (Diamond ATR, cm−1) ν: 3200, 2911, 1701, 1640, 1508, 1461, 1426, 1268, 1154, 1116, 1071, 1008, 957, 739. 1H NMR (400 MHz, CDCl3) δ: 3.52 (s, 3H, CH3), 3.72 (d, J = 6.1 Hz, CH2 for E), 3.92 (m, 6H, CH2 for Z et 2 × CH2(N)), 4.60 (m, 4H, 2 × CH2(O)), 5.28 (s, 2H, CH2), 6.88 (t, J = 5.5 Hz, 1H, CHoxime), 7.18 (m, 1H), 7.40 (t, 1H, J = 7.5 Hz), 7.62 (t, J = 6.1 Hz, 1H, CHoxime), 8.12 (m, 4H,), 8.56 (d, J = 2.0 Hz, 1H, isomer Z), 8.58 (d, J = 2.0 Hz, 1H, isomer E), 8.85 (bs, 1H, OH). 13C NMR (101 MHz, CDCl3) δ: 28.8 (CH2 for Z), 33.3 (CH2 for E), 48.4 (2 × CH2), 55.9 (CH3), 66.6 (2 × CH2), 94.6 (CH2), 115.7 (CH), 118.5 (CH), 122.8 (CH), 129.6 (CH), 131.9 (Cq), 135.1 (CH), 136.2 (Cq), 139.8 (Cq), 146.9 (CH), 147.0 (Cq), 148.3 (CH for E), 148.7 (CH for Z), 157.4 (Cq), 159.2 (Cq), 160.2 (Cq). HRMS (EI-MS): m/z calculated for C21H24N5O4 [M + H]+, 410.1828, found 410.1823.
4-(2-(3-(Methoxymethoxy)phenyl)-7-((5-(methoxymethyl)isoxazol-3-yl)methyl)pyrido [3,2-d]pyrimidin-4-yl)morpholine (29). To a solution of 28 (60 mg, 0.178 mmol) in 4 mL of THF was added methyl propargyl ether (20 µL, 0.22 mmol, 1.1 eq.) and sodium hypochlorite (246 µL, 0.43 mmol, 2.0 eq.) at room temperature. The reaction was stirred for 12 h and H2O (5 mL) was added. The organic layers were extracted with EtOAc (3 × 10 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (EA/EP, 1/1) to afford 29 as a yellow oil (42 mg, 50%). IR (Diamond ATR, cm−1) ν: 2923, 2852, 1701, 1640, 1508, 1461, 1426, 1268, 1154, 1116, 1071, 1008, 957, 739; 1H NMR (400 MHz, CDCl3) δ: 3.41 (s, 3H, CH3), 3.52 (s, 3H, CH3), 3.92 (m, 4H, 2 × CH2(N)), 4.20 (s, 2H, CH2), 4.50 (s, 2H, CH2), 4.60 (m, 4H, 2 × CH2(O)), 5.28 (s, 2H, CH2), 6.88 (t, J = 5.5 Hz, 1H, CH), 7.18 (m, 1H), 7.40 (t, 1H, J = 7.5 Hz), 8.15 (m, 3H), 8.58 (d, J = 2.0 Hz, 1H, H6), 13C NMR (101 MHz, CDCl3) δ: 30.0 (CH2), 47.7 (2 × CH2), 56.2 (CH3), 59.1 (CH3), 65.7 (CH2), 67.4 (2 × CH2), 94.8 (CH2), 100.1 (Cq), 102.5 (CH), 116.5 (CH), 118.3 (CH), 122.1 (CH), 129.4 (CH), 135.4 (Cq), 136.5 (CH), 136.2 (Cq), 146.9 (CH), 157.2 (Cq), 157.7 (Cq), 159.2 (Cq), 161.2 (Cq), 170.1 (Cq). HRMS (EI-MS): m/z calculated for C25H28N5O5 [M + H]+, 478.2090, found 478.2085.
3-(7-((5-(Methoxymethyl)isoxazol-3-yl)methyl)-4-morpholinylpyrido[3,2-d]pyrimidin-2-yl)phenol (30). The reaction was carried out as described in general procedure C using 29 (50 mg, 0.123 mmol) to afford 30 as a yellow solid (52 mg, 98%). Mp: 169–171 °C; IR (Diamond ATR, cm−1) υ: 3200, 2911, 1701, 1640, 1508, 1461, 1426, 1268, 1154, 1116, 1071, 1008, 957, 739; 1H NMR (400 MHz, DMSO-d6) δ: 3.52 (s, 3H, CH3), 3.90 (m, 4H, 2 × CH2(N)), 4.37 (s, 2H, CH2), 4.54 (s, 2H, CH2), 4.69 (m, 4H, 2 × CH2(O)), 6.88 (s, 1H, CH), 7.18 (m, 1H), 7.40 (t, 1H, J = 7.5 Hz), 7.80 (m, 2H), 8.38 (m, 1H), 8.88 (d, J = 2.0 Hz, 1H), 10.0 (bs, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ: 30.0 (CH2), 47.7 (2 × CH2), 58.2 (CH3), 66.0 (CH2), 68.4 (2 × CH2), 104.5 (CH), 116.5 (CH), 118.3 (CH), 120.1 (CH), 130.6 (CH), 135.4 (Cq), 136.2 (CH), 136.5 (Cq), 139.8 (Cq), 146.9 (CH), 147.0 (Cq), 157.1 (Cq), 157.6 (Cq), 159.2 (Cq), 163.1 (Cq), 170.1 (Cq). HRMS (EI-MS): m/z calculated for C23H24N5O4 [M + H]+, 434.1828, found 434.1823.
2-(3-Hydroxyphenyl)-4-morpholinylpyrido[3,2-d]pyrimidine-7-carbaldehyde oxime (31). To a solution of 10 (66 mg, 0.196 mmol), in CH2Cl2 (10 mL) was added hydroxylammonium chloride (16 mg, 0.236 mmol, 1.2 eq.) and triethylamine (33 µL, 0.236 mmol, 1.2 eq.). The reaction was stirred for 12 h at room temperature, an aqueous solution of saturated NaHCO3 (5 mL) was added. The organic layers were washed with water (2 × 5 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 99/1) to afford 31 as a yellow solid (43 mg, 62%). Rf (CH2Cl2/MeOH, 99/1): 0.10. Mp: 231–233 °C. IR (ATR diamond, cm−1) ν: 3277, 2864, 1736, 1561, 1520, 1434, 1356, 1311, 1234, 1107, 972, 739, 678. 1H NMR (400 MHz, DMSO-d6) δ: 3.91–3.69 (m, 4H, 2 × CH2(N)), 4.50 (m, 4H, 2 × CH2(O)), 6.90 (dd, 1H, J = 1.8 Hz, J = 7.7 Hz), 7.30 (t, 1H, J = 8.0 Hz), 7.99–7.81 (m, 2H), 8.23 (d, 1H, J = 2.0 Hz), 8.40 (s, 1H), 9.00 (d, 1H, J = 2.0 Hz), 9.54 (d, 1H, J = 5.7 Hz, OH), 11.92 (s, 1H, CNH). 13C NMR (101 MHz, DMSO-d6) δ: 47.3 (2 × CH2), 66.4 (2 × CH2), 114.9 (CH), 117.6 (CH), 119.0 (CH), 129.3 (CH), 132.1 (Cq), 132.3 (Cq), 133.5 (CH), 139.1 (Cq), 143.5 (CH), 145.7 (CH), 147.6 (Cq), 157.4 (Cq), 158.4 (Cq), 159.3 (Cq). HRMS (EI/MS): m/z calculated for C18H18N5O3 [M + H]+: 352.1331; found 352.1407.
2-(3-Hydroxyphenyl)-4-morpholinylpyrido[3,2-d]pyrimidine-7-carbaldehyde O-methyl oxime (32). Compound 32 was obtained as described for 31 starting from 10 (60 mg, 0.178 mmol) and using methoxyammonium chloride (20 mg, 0.232 mmol, 1.2 eq.). The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 99/1) to afford 32 as a yellow solid (44 mg, 68%). Rf (CH2Cl2/MeOH, 99/1): 0.28. Mp: 244–246 °C. IR (ATR diamond, cm−1) ν: 3040, 2962, 1517, 1442, 1348, 1148, 1115, 1054, 927, 743, 674. 1H NMR (400 MHz, DMSO-d6) δ: 3.83 (m, 4H, 2 × CH2(N)), 4.00 (s, 3H, CH3), 4.50 (m, 4H, 2 × CH2(O)), 6.90 (d, 1H, J = 8.1 Hz), 7.30 (t, 1H, J = 8.1 Hz), 7.88 (s, 2H), 8.28 (s, 1H), 8.49 (s, 1H, Hoxime), 8.97 (s, 1H, H6), 9.55 (s, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ: 48.7 (2 × CH2), 62.3 (CH3), 66.3 (2 × CH2), 114.9 (CH), 117.7 (CH), 119.0 (CH), 121.1 (Cq), 129.3 (CH), 131.1 (Cq), 132.4 (Cq), 134.2 (Cq), 143.6 (CH), 146.2 (CH), 157.4 (Cq), 158.4 (Cq), 159.3 (Cq), 164.8 (CH). HRMS (EI/MS): m/z calculated for C19H20N5O3 [M + H]+: 366.1561; found 366.1564.