4.6. 4-Bromo-7-phenoxy[1,2,5]thiadiazolo[3,4-d]pyridazine (8b)
Sodium hydride (3 mg, 0.13 mmol) was added to a solution of phenol (12 mg, 0.13 mmol) in dry THF (3 mL) at 0 °C with stirring. The reaction mixture was stirred at 0 °C for 30 min, then 4,7-dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine (1, 40 mg, 0.13 mmol) was added. The mixture was stirred for 8 h at room temperature. On completion (monitored by TLC), the mixture was poured into water and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (CH2Cl2) to afford 32 mg (80%) of target compound 8b as a white solid, Rf = 0.7 (CH2Cl2). Mp = 106–108 °C. IR νmax (KBr, cm−1): 1590, 1416, 1361, 1344, 1326, 1257, 1193, 1052, 959, 865, 798, 757, 701, 516, 506. 1H-NMR (300 MHz, CDCl3): δ 7.32–7.40 (m, 3H), 7.48–7.53 (m, 2H). 13C-NMR (75 MHz, CDCl3): δ 121.4, 126.4, 129.9, 137.0, 143.3, 152.3, 152.32, 158.1. HRMS (ESI-TOF), m/z: calcd. for C10H679BrN4OS [M + H]+, 308.9440, found, 308.9448. MS (EI, 70 eV), m/z (I, %): 311 ([M + 2]+, 8), 310 ([M + 1]+, 75), 309 (M+, 72), 308 ([M − 1]+, 72), 307 ([M − 2]+, 12), 91 (100).
4.9. General Procedure for the Reaction of 4,7-dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine (1) with Thiols
Sodium hydride (8 mg, 0.34 mmol) was added to a solution of thiol (0.34 mmol) in dry THF (15 mL) at 0 °C with stirring. The reaction mixture was stirred at 0 °C for 30 min, then 4,7-dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine (1, 50 mg, 0.17 mmol) was added. The mixture was stirred for 3–4 h at room temperature. On completion (monitored by TLC), the mixture was poured into water (20 mL) and extracted with EtOAc (3 × 35 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography.
4.9.1. 4,7-Bis(phenylthio)[1,2,5]thiadiazolo[3,4-d]pyridazine (10a)
Yellow solid, 51 mg (85%), Rf = 0.8 (CH2Cl2). Mp = 186–188 °C. Eluent—CH2Cl2/hexane, 1:1 (v/v). IR νmax (KBr, cm−1): 3060, 3048, 1473, 1439, 1383, 1275, 1068, 1022, 978, 860, 750, 705, 688, 640, 564, 503. 1H-NMR (300 MHz, CDCl3): δ 7.42–7.45 (m, 6H), 7.68–7.71 (m, 4H). 13C-NMR (75 MHz, CDCl3): δ 126.4, 129.6, 129.9, 135.5, 147.9, 155.8. HRMS (ESI-TOF), m/z: calcd for C16H11N4S3 [M + H]+, 355.0140, found, 355.0138. MS (EI, 70 eV), m/z (I, %): 355 ([M + 1]+, 27), 354 (M+, 26), 353 ([M − 1]+, 98), 109(100).
4.9.2. 4,7-Bis(hexylthio)[1,2,5]thiadiazolo[3,4-d]pyridazine (10b)
Yellow solid, 56 mg (90%), Rf = 0.7 (CH2Cl2). Mp = 81–83 °C. Eluent—CH2Cl2/hexane, 1:1 (v/v). IR νmax (KBr, cm−1): 2954, 2925, 2858, 1468, 1395, 1286, 1258, 1208, 1042, 987, 852, 721, 644, 551, 511. 1H-NMR (300 MHz, CDCl3): δ 0.91 (t, J = 7.0 Hz, 6H), 1.32–1.38 (m, 8H), 1.51–1.57 (m, 4H), 1.86 (p, J = 7.4 Hz, 4H), 3.49 (t, J = 7.4 Hz, 4H). 13C-NMR (75 MHz, CDCl3): δ 14.0, 22.5, 28.5, 28.6, 29.7, 31.3, 148.0, 155.0. HRMS (ESI-TOF), m/z: calcd for C16H26N4S3Na [M + Na]+, 393.1212, found, 393.1221. MS (EI, 70 eV), m/z (I, %): 372 ([M + 2]+, 10), 371 ([M + 1]+, 48), 370 (M+, 65), 323 (68), 286 (98), 202 (100).
4.9.3. 4,7-Bis(dodecylthio)[1,2,5]thiadiazolo[3,4-d]pyridazine (10c)
Green solid, 80 mg (88%), Rf = 0.65 (CH2Cl2). Mp = 89–91 °C. Eluent—CH2Cl2/hexane, 1:1 (v/v). IR νmax (KBr, cm−1): 2955, 2921, 2852, 1471, 1396, 1286, 1270, 1242, 1215, 1192, 1033, 988, 852, 836, 717, 646, 552, 511. 1H-NMR (300 MHz, CDCl3): δ 0.87–0.92 (m, 6H), 1.28–1.34 (m, 32H), 1.39–1.62 (m, 6H), 1.84–1.89 (m, 2H), 2.50–2.58 (m, 2H), 3.47–3.53 (m, 2H). 13C-NMR (75 MHz, CDCl3): δ 14.2, 22.7, 24.7, 28.4, 29.1, 29.4, 29.6, 29.68, 29.7, 29.73, 32.0, 34.1, 148.1, 155.1. HRMS (ESI-TOF), m/z: calcd. for C28H51N4S3 [M + H]+, 539.3270, found, 539.3259. MS (EI, 70 eV), m/z (I, %): 540 ([M + 2]+, 10), 539 ([M + 1]+, 28), 538 (M+, 30), 370 (40), 337 (76), 43 (100).
4.10. General Procedure for the Preparation of Mono-Aminated Products 11
Amine (0.17 mmol) and Et3N (17mg, 0.17 mmol) were added to a solution of 4,7-dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine (1, 50 mg, 0.17 mmol) in dry CH2Cl2 (10 mL) at room temperature with stirring. The mixture was stirred at room temperature for 4 h. Then the mixture was poured into water (10 mL) and extracted with CH2Cl2 (3 × 35 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography.
4.10.1. 4-(7-Bromo[1,2,5]thiadiazolo[3,4-d]pyridazin-4-yl)morpholine (11a)
Orange solid, 44 mg (86%), Rf = 0.2 (CH2Cl2). Mp = 158–160 °C. Eluent—CH2Cl2/EtOAc, 1:1 (v/v). IR νmax (KBr, cm−1): 2972, 2924, 2868, 1541, 1463, 1445, 1422, 1299, 1276, 1253, 1113, 1028, 953, 892, 503. 1H-NMR (300 MHz, CDCl3): δ 3.91–3.94 (m, 4H), 4.34–4.38 (m, 4H). 13C-NMR (75 MHz, CDCl3): δ 47.0, 66.8, 130.7, 143.7, 151.2, 152.3. HRMS (ESI-TOF), m/z: calcd. for C8H979BrN5OS [M + H]+, 301.9706, found, 301.9704. MS (EI, 70 eV), m/z (I, %): 304([M + 2]+, 9), 303 ([M + 1]+, 45), 302 (M+, 8), 301 ([M − 1]+, 44), 222 (100), 137(30).
4.10.2. 4-Bromo-7-(piperidin-1-yl)[1,2,5]thiadiazolo[3,4-d]pyridazine (11b)
Yellow solid, 41 mg (82%), Rf = 0.2 (CH2Cl2). Mp = 116–118 °C. Eluent—CH2Cl2/EtOAc, 1:1 (v/v). IR νmax (KBr, cm−1): 2940, 2924, 2858, 1539, 1462, 1451, 1424, 1284, 1267, 1223, 1131, 1025, 952, 889, 848, 504. 1H-NMR (300 MHz, CDCl3): 1.76–1.80 (m, 6H), 4.29–4.32 (m, 4H). 13C-NMR (75 MHz, CDCl3): δ 24.6, 26.1, 48.0, 129.2, 143.8, 151.1, 152.3. HRMS (ESI-TOF), m/z: calcd. for C9H1179BrN5S [M + H]+, 299.9913, found, 299.9917. MS (EI, 70 eV), m/z (I, %): 302 ([M + 2]+, 6), 301 ([M + 1]+, 45), 300 (M+, 5). 299 ([M − 2]+, 44), 220 (100), 84 (43).
4.10.3. 4-Bromo-7-(pyrrolidin-1-yl)[1,2,5]thiadiazolo[3,4-d]pyridazine (11c)
Yellow solid, 39 mg (81%), Rf = 0.2 (CH2Cl2). Mp = 155–157 °C. Eluent—CH2Cl2/EtOAc, 1:1 (v/v). IR νmax (KBr, cm−1): 2953, 2923, 2863, 1548, 1454, 1420, 1292, 1230, 1154, 1057, 959, 903, 861, 840, 505. 1H-NMR (300 MHz, CDCl3): 2.04–2.23 (m, 4H), 3.83–4.36 (m, 4H). 13C-NMR (75 MHz, CDCl3): δ 29.7, 49.4, 128.0, 144.1, 150.8, 151.1. HRMS (ESI-TOF): calcd for C8H979BrN5S [M + H]+, 285.9757, found, 285.9759. MS (EI, 70 eV), m/z (I, %):286 ([M + 2]+, 8), 287 ([M + 1]+, 85), 286 (M+, 80). 208 (90), 137 (30), 70 (100).
4.10.4. 4-Bromo-7-(2,3,4,4a-hexahydro-1H-carbazol-9(9aH)-yl)[1,2,5]thiadiazolo[3,4-d]pyridazine (11d)
Red solid, 56 mg (85%), Rf = 0.4 (CH2Cl2). Mp = 196–198 °C. Eluent—CH2Cl2/hexane, 1:1 (v/v). IR νmax (KBr, cm−1): 2923, 2856, 1511, 1459, 1409, 1355, 1309, 1270, 1088, 880, 751, 506. 1H-NMR (300 MHz, CDCl3): δ 1.33–1.42 (m, 3H), 1.66–1.69 (m, 2H), 1.91–2.02 (m, 1H), 2.16–2.20 (m, 1H), 2.46 (d, J = 14.0 Hz, 1H), 3.66–3.71 (m, 1H), 5.73–5.81 (m, 1H), 7.17 (t, J = 7.3 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H). 7.33 (t, J = 8.1 Hz, 1H), 8.71 (d, J = 8.1 Hz, 1H). 13C-NMR (75 MHz, CDCl3): δ 20.9, 22.8, 24.2, 28.1, 40.2, 63.6, 120.4, 122.5, 124.5, 127.5, 130.8, 135.1, 142.7, 143.3, 149.8, 151.1. HRMS (ESI-TOF), m/z: calcd. for C16H1579BrN5S [M + H]+, 388.0226, found, 388.0229. MS (EI, 70 eV), m/z (I, %): 390 ([M + 2]+, 55), 389 ([M + 1]+, 70), 388 (M+, 55), 387 ([M − 1]+, 68), 308 (90), 172 (100), 130 (80).
4.10.5. 4-Bromo-7-(1,3,3a,8b-tetrahydrocyclopenta[b]indol-4(2H)-yl)[1,2,5]thiadiazolo[3,4-d]pyridazine (11e)
Red solid, 52 mg (82%), Rf = 0.4 (CH2Cl2). Mp = 178–180 °C. Eluent—CH2Cl2/hexane, 1:1 (v/v). IR νmax (KBr, cm−1): 2960, 2924, 2855, 1507, 1457, 1410, 1364, 1307, 1262, 1088, 884, 749, 509. 1H-NMR (300 MHz, CDCl3): 1.43–1.52 (m, 1H), 1.71–1.82 (m, 2H), 2.07–2.31 (m, 3H), 4.07–4.13 (m, 1H), 5.94–6.02 (m, 1H), 7.15 (t, J = 7.3 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 8.85 (d, J = 8.1 Hz, 1H). 13C-NMR (75 MHz, CDCl3): δ 23.7, 34.1, 36.7, 45.8, 67.6, 118.9, 124.0, 124.5, 127.6, 130.9, 136.2, 143.5, 143.7, 150.0, 151.0. HRMS (ESI-TOF), m/z: calcd for C15H1379BrN5S [M + H]+, 374.0070, found, 374.0063. MS (EI, 70 eV), m/z (I, %): 376 ([M + 2]+, 8), 375 ([M + 1]+, 26), 374 (M+, 10), 373 ([M − 1]+, 25), 294 (40), 277 (45), 155 (55). 130 (100).
4.10.6. 4-Bromo-7-(2,3,4,4a-tetrahydro-1H-1,4-methanocarbazol-9(9aH)-yl)-[1,2,5]thiadiazolo[3,4- d]pyridazine (11f)
Red solid, 53 mg (79%), Rf = 0.4 (CH2Cl2). Mp = 187–189 °C. Eluent—CH2Cl2/hexane, 1:1 (v/v). IR νmax (KBr, cm−1): 2949, 2871, 1505, 1459, 1409, 1366, 1303, 1250, 1163, 1089, 884, 774, 508. 1H-NMR (300 MHz, CDCl3): δ 1.08 (d, J = 10.3 Hz, 1H), 1.35 (d, J = 9.8 Hz, 1H), 1.53–1.76 (m, 4H), 2.41 (d, J = 26.5 Hz, 2H), 3.51 (d, J = 7.5 Hz, 1H), 5.35 (d, J = 7.1 Hz, 1H), 7.05 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 8.80 (d, J = 8.1 Hz, 1H). 13C-NMR (75 MHz, CDCl3): δ 25.4, 27.9, 31.8, 43.5, 43.6, 50.5, 69.4, 118.6, 124.2, 124.3, 127.7, 131.0, 135.2, 143.6, 144.8, 150.1, 150.9. HRMS (ESI-TOF), m/z: calcd for C17H1579BrN5S [M + H]+, 400.0226, found, 400.0232. MS (EI, 70 eV), m/z (I, %): 402 ([M + 2]+, 6), 401 ([M + 1]+, 24), 400 (M+, 5), 399 ([M − 1]+, 20), 320 (30), 184 (100), 143 (48), 116 (70).
4.10.7. 7-Bromo-N-methyl-N-phenyl[1,2,5]thiadiazolo[3,4-d]pyridazin-4-amine (11g)
Red solid, 43 mg (80%), Rf = 0.3 (CH2Cl2). Mp = 188–190 °C. Eluent—CH2Cl2/hexane, 1:1 (v/v). IR νmax (KBr, cm−1): 2955, 2924, 2852, 1538, 1524, 1494, 1422, 1391, 1361, 1345, 1311, 1282, 1198, 1064, 866, 777, 704, 564, 513. 1H-NMR (300 MHz, CDCl3): δ 3.76 (s, 3H), 7.20–7.33 (m, 2H), 7.43–7.46 (m, 3H). 13C-NMR (75 MHz, CDCl3): δ 41.9, 127.0, 127.7, 129.8, 131.4, 143.8, 145.8, 151.1, 152.5. HRMS (ESI-TOF), m/z: calcd for C11H979BrN5S [M + H]+, 321.9757, found, 321.9752. MS (EI, 70 eV), m/z (I, %): 323 ([M + 1]+, 18), 322 (M+, 98), 321 ([M − 1]+, 15), 320 ([M − 2]+, 100), 77 (6), 28 (8).
4.10.8. 7-Bromo-N-cyclohexyl[1,2,5]thiadiazolo[3,4-d]pyridazin-4-amine (11h)
Yellow solid, 45 mg (85%), Rf = 0.1 (CH2Cl2). Mp = 125–127 °C. Eluent—CH2Cl2/EtOAc, 1:1 (v/v). IR νmax (KBr, cm−1): 2933, 2852, 1568, 1522, 1448, 1415, 1386, 1314, 1143, 1091, 960, 864, 835, 510. 1H-NMR (300 MHz, CDCl3): 1.28–1.50 (m, 5H), 1.70–1.82 (m, 3H), 2.12–2.41 (m, 2H), 4.24–4.45 (m, 1H), 5.66–5.90 (m, 1H). 13C-NMR (75 MHz, CDCl3): δ 24.7, 25.5, 32.6, 50.3, 129.2, 143.6, 149.9, 150.8. HRMS (ESI-TOF), m/z: calcd for C10H1379BrN5S [M + H]+, 314.0070, found, 314.0067. MS (EI, 70 eV), m/z (I, %): 316 ([M + 2]+, 5), 315 ([M + 1]+, 45), 314 (M+, 44).234 (100), 137 (3), 55 (15), 18 (46).
4.10.9. 7-Bromo-N-phenyl[1,2,5]thiadiazolo[3,4-d]pyridazin-4-amine (11i)
Red solid, 41 mg (80%), Rf = 0.2 (CH2Cl2). Mp = 144–146 °C. Eluent—CH2Cl2/EtOAc, 1:1 (v/v). IR νmax (KBr, cm−1): 2924, 1601, 1569, 1531, 1485, 1419, 1338, 1130, 872, 758, 501. 1H-NMR (300 MHz, DMSO-d6): δ 7.12 (t, J = 7.2 Hz, 1H), 7.41 (dd, J = 7.7, 7.2 Hz, 2H), 8.07 (d, J = 7.7 Hz, 2H), 10.27 (s, 1H). 13C-NMR (75 MHz, DMSO-d6): δ 119.9, 121.7, 123.9, 129.0, 131.5, 139.5, 144.2, 150.7. HRMS (ESI-TOF), m/z: calcd for C10H779BrN5S [M + H]+, 307.9604, found, 307.9600. MS (EI, 70 eV), m/z (I, %): 309 ([M + 1]+, 24), 308 (M+, 100), 307 ([M − 1]+, 22), 306 ([M − 2]+, 90), 247 (46).
4.10.10. 7-Bromo-N-(tert-butyl)[1,2,5]thiadiazolo[3,4-d]pyridazin-4-amine (11j)
Yellow solid, 36 mg (75%), Rf = 0.2 (CH2Cl2). Mp = 119–121 °C. Eluent—CH2Cl2/EtOAc, 1:1 (v/v). IR νmax (KBr, cm−1): 2966, 2853, 1570, 1528, 1472, 1418, 1390, 1358, 1224, 1213, 1155, 1075, 957, 507. 1H-NMR (300 MHz, DMSO-d6): δ 1.65 (s, 9H), 5.80 (s, 1H). 13C-NMR (75 MHz, DMSO-d6): δ 28.6, 53.5, 129.5, 144.1, 149.8, 150.9. HRMS (ESI-TOF), m/z: calcd for C8H1179BrN5S [M + H]+, 287.9913, found, 287.9906. MS (EI, 70 eV), m/z (I, %): 290 ([M + 2]+, 25), 289 ([M + 1]+, 28), 288 (M+, 8), 287 ([M − 1]+, 40), 231 (100), 152 (60), 57 (80).
4.11. General Procedure for the Preparation of Di-Aminated Products 12
Amine (0.34 mmol) and Et3N (34 mg, 0.34 mmol) were added with stirring to a solution of 4,7-dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine (1, 50 mg, 0.17 mmol) in dry MeCN (15 mL). The mixture was stirred at reflux for 10–30 h. Then the mixture was poured into water (25 mL) and extracted with EtOAc (3 × 35 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography.
4.11.1. 4,7-Dimorpholino[1,2,5]thiadiazolo[3,4-d]pyridazine (12a)
Dark red solid, 45 mg (87%), Rf = 0.1 (CH2Cl2). Mp = 235–237 °C. Eluent—CH2Cl2/EtOAc, 1:2 (v/v). IR νmax (KBr, cm−1): 2967, 2927, 2853, 1469, 1445, 1363, 1315, 1276, 1264, 1113, 910, 891, 526, 503. 1H-NMR (300 MHz, CDCl3): δ 3.90–3.93 (m, 8H), 3.99–4.03 (m, 8H). 13C-NMR (75 MHz, CDCl3): δ 47.8, 66.8, 146.6, 150.4. HRMS (ESI-TOF), m/z: calcd for C12H17N6O2S [M + H]+, 309.1128, found, 309.1128. MS (EI, 70 eV), m/z (I, %): 309 ([M + 2]+, 23), 308 (M+, 100), 307 ([M − 1]+, 50), 251 (25), 147 (12), 73 (5).
4.11.2. 4,7-Di(piperidin-1-yl)[1,2,5]thiadiazolo[3,4-d]pyridazine (12b)
Dark red solid, 44 mg (85%), Rf = 0.1 (CH2Cl2). Mp = 104–106 °C. Eluent—CH2Cl2/EtOAc, 1:2 (v/v). IR νmax (KBr, cm−1): 2918, 2846, 1463, 1435, 1304, 1233, 990, 938, 871, 554. 1H-NMR (300 MHz, CDCl3): 1.69–1.83 (m, 12H), 3.86–4.01 (m, 8H). 13C-NMR (75 MHz, CDCl3): δ 24.9, 25.9, 48.8, 147.1, 150.7. HRMS (ESI-TOF), m/z: calcd for C14H21N6S [M + H]+, 305.1543, found, 305.1541. MS (EI, 70 eV), m/z (I, %): 306 ([M + 2]+, 20), 305 ([M + 1]+, 98), 304 (M+, 100), 228 (70), 84 (80).
4.11.3. 4,7-Bis(2,3,4,4a-tetrahydro-1H-carbazol-9(9aH)-yl)[1,2,5]thiadiazolo[3,4-d]pyridazine (12d)
Violet solid, 73 mg (90%), Rf = 0.6 (CH2Cl2). Mp = 239–241 °C. Eluent—CH2Cl2/Hexane, 1:1 (v/v). IR νmax (KBr, cm−1): 2927, 2853, 1526, 1475, 1435, 1270, 1164, 1132, 877, 752, 574. 1H-NMR (300 MHz, CDCl3): δ 1.36–1.54 (m, 6H), 1.61–1.64 (m, 4H), 1.91–2.00 (m, 2H), 2.08–2.14, 2.37 (d, J = 13.2 Hz, 2H), 3.63–3.67 (m, 2H), 5.50–5.59 (m, 2H), 7.05 (t, J = 7.3 Hz, 2H), 7.24–7.29 (m, 4H), 8.27 (d, J = 8.1 Hz, 2H). 13C-NMR (75 MHz, CDCl3): δ 21.3, 22.6, 24.9, 27.7, 40.3, 63.4, 117.2, 122.0, 122.3, 127.0, 134.3, 144.2, 146.1, 147.0. HRMS (ESI-TOF), m/z: calcd for C28H29N6S [M + H]+, 481.2169, found, 481.2150. MS (EI, 70 eV), m/z (I, %): 482 ([M + 2]+, 8), 481 ([M + 1]+, 30), 480 (M+, 100), 172 (60), 130 (50).
4.11.4. N4,N7-Diphenyl[1,2,5]thiadiazolo[3,4-d]pyridazine-4,7-diamine (12i)
Dark red solid, 42 mg (78%), Rf = 0.1 (CH2Cl2). Mp = 249–251 °C. Eluent—CH2Cl2/EtOAc, 1:2 (v/v). IR νmax (KBr, cm−1): 2916, 2852, 1594, 1544, 1497, 1457, 1434, 1261, 1243, 882, 751, 687, 499. 1H-NMR (300 MHz, DMSO-d6): δ 7. 13 (t, J = 7.2 Hz, 2H), 7.31 (s, 2H), 7.44 (dd, J = 7.2, 7.4 Hz, 5H), 7.98 (d, J = 7.4 Hz, 3H). 13C-NMR (75 MHz, DMSO-d6): δ 119.3, 122.8, 129.2, 139.2, 145.4, 145.6. HRMS (ESI-TOF), m/z: calcd. for C16H13N6S [M + H]+, 321.0917, found, 321.0917. MS (EI, 70 eV), m/z (I, %): 321 ([M + 1]+, 52), 320 (M+, 65), 319 ([M − 1]+, 100). 144 (26), 77 (52).
4.12. 4-(7-(Pyrrolidin-1-yl)[1,2,5]thiadiazolo[3,4-d]pyridazin-4-yl)morpholine (13)
Amine 10c (11.3 mg, 0.16 mmol) and Et3N (16.6 mg, 0.16 mmol) were added to a solution of 4-(7-bromo-[1,2,5]thiadiazolo[3,4-d]pyridazin-4-yl)morpholine (11a, 50 mg, 0.17 mmol) in dry MeCN (10 mL) at room temperature with stirring. The mixture was stirred at reflux for 16 h, then poured into water (20 mL) and extracted with CH2Cl2 (3 × 35 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (CH2Cl2/EtOAc, 1:1, v/v) to afford 40 mg (87%) of target compound 13 as a dark red solid, Rf = 0.1 (CH2Cl2). Mp = 199–201 °C. IR νmax (KBr, cm−1): 2977, 2919, 2862, 2821, 1551, 1472, 1445, 1342, 1330, 1261, 1243, 1117, 1024, 918, 890, 518. 1H-NMR (300 MHz, CDCl3): δ 2.04–2.09 (m, 4H), 3.83–3.86 (m, 4H), 3.91–3.94 (m, 4H), 3.98–4.03 (m, 4H). 13C-NMR (75 MHz, CDCl3): δ 25.5, 48.4, 48.9, 66.9, 146.7, 146.8, 148.9, 149.0. HRMS (ESI-TOF), m/z: calcd. for C12H17N6OS [M + H]+, 293.1179, found, 293.1171. MS (EI, 70 eV), m/z (I, %): 293 ([M + 1]+, 15), 292 (M+, 100), 291 ([M − 1]+, 48). 263 (43), 234 (48), 70 (80), 41 (60).
4.13. 4-(7-(Phenylthio)[1,2,5]thiadiazolo[3,4-d]pyridazin-4-yl)morpholine (14)
Sodium hydride (3.8 mg, 0.16 mmol) was added to a solution of thiol 8a (18 mg, 0.17 mmol) in dry THF (10 mL) at 0 °C with stirring. The reaction mixture was stirred at 0 °C for 30 min, then 4-(7-bromo-[1,2,5]thiadiazolo[3,4-d]pyridazin-4-yl)morpholine (11a, 50 mg, 0.16 mmol) was added. The mixture was stirred for 3 h at room temperature. On completion (monitored by TLC), the mixture was poured into water and extracted with EtOAc (3 × 35 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (CH2Cl2/Hexane, 2:1, v/v) to afford 43 mg (90%) of target compound 14 as a dark red solid, Rf = 0.3 (CH2Cl2). Mp = 142–144 °C. IR νmax (KBr, cm−1): 2957, 2923, 2871, 1520, 1442, 1421, 1305, 1277, 1263, 1112, 1065, 1028, 977, 896, 863, 757, 672, 504. 1H-NMR (300 MHz, CDCl3): δ 3.87–3.90 (m, 4H), 4.24–4.27 (m, 4H), 7.37–7.43 (m, 3H), 7.65–7.68 (m, 2H). 13C-NMR (75 MHz, CDCl3): δ 47.0, 66.8, 128.4, 129.1, 129.3, 134.7, 143.7, 148.3, 151.0, 151.5. HRMS (ESI-TOF), m/z: calcd for C14H14N5OS2 [M + H]+, 332.0634, found, 332.0629. MS (EI, 70 eV), m/z (I, %): 332 ([M + 1]+, 25), 331 (M+, 52), 330 ([M − 1]+, 100), 222 (65), 86 (77).
4.15. 4,7-Di(9H-carbazol-9-yl)[1,2,5]thiadiazolo[3,4-d]pyridazine (16)
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (74 mg, 0.32 mmol) was added to a solution of amine 12d (60 mg, 0.13 mmol) in toluene (12 mL). The mixture was refluxed for 7 h, diluted to with EtOAc (30 mL), washed with aq. NaHSO3, Na2CO3, water, and brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (CH2Cl2/Hexane, 2:1, v/v) to afford 46 mg (75%) of target compound 16 as a dark red solid, Rf = 0.4 (CH2Cl2). Mp > 260 °C. IR νmax (KBr, cm−1): 3044, 2921, 2851, 1599, 1490, 1479, 1446, 1332, 1264, 1223, 1151, 865, 739, 717, 511. 1H-NMR (300 MHz, CDCl3): δ 7.43–7.54 (m, 8H), 7.86 (d, J = 7.8 Hz, 4H), 8.20 (d, J = 7.2 Hz, 4H). 13C-NMR (75 MHz, CDCl3): δ 113.1, 120.7, 122.9, 125.8, 126.8, 140.0, 148.4, 148.5. HRMS (ESI-TOF), m/z: calcd for C28H17N6S [M + H]+, 469.1230, found, 469.1247. MS (EI, 70 eV), m/z (I, %): 470 ([M + 2]+, 10), 469 ([M + 1]+, 30), 468 (M+, 100), 387 ([M − 1]+, 12), 302 (80), 168 (45), 148 (28).