3.6. Data for All New Compounds
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3a)
[Reaction time: 4.0 h], 318 mg, 86%, a white solid, m.p. 214.5–216.5 °C; IR (thin film): νmax 3367, 3275, 3147, 3062, 3026, 2183, 1712, 1684, 1625, 1572, 1432, 1285, 1048, 752 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1 H), 7.74–7.71 (m, 3 H), 7.32 (d, J = 4.0 Hz, 1 H), 7.30 (td, J = 7.6, 0.8 Hz, 1 H), 7.18–7.11 (m, 4 H), 6.97 (brs, 2 H), 6.61 (d, J = 7.6 Hz, 1 H), 5.67 (d, J = 4.0 Hz, 1 H), 4.64 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.4, 150.2, 142.8, 142.6, 142.6, 134.7, 131.9, 130.1, 128.4, 128.2, 126.0, 123.1, 122.9, 119.6, 119.6, 110.6, 101.0, 67.4, 58.4, 46.6; HRMS (ESI): m/z calcd. for C21H15N5O2 [M + H]+ 370.1304 found 370.1380.
(±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-(o-tolyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′b)
[Reaction time: 2.0 h], 249 mg, 65%, a white solid, m.p. 210.3–212.1 °C; IR (thin film): νmax 3369, 3282, 3146, 3116, 3026, 2189, 1724, 1662, 1530, 1331, 1159, 1047, 758 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1 H), 7.73 (brs, 2 H), 7.39(d, J = 4.0 Hz, 1 H), 7.31 (td, J = 7.6, 0.8 Hz, 1 H), 7.21–7.10 (m, 2 H), 7.03 (d, J = 6.8 Hz, 1 H), 6.96 (d, J = 7.6 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 6.76 (ψt, J = 7.6 Hz, 1 H), 5.83 (d, J = 7.6 Hz, 1 H), 5.62 (d, J = 4.0 Hz, 1 H), 4.28 (s, 1 H), 1.71 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 172.1, 165.2, 149.8, 142.7, 142.4, 138.1, 135.7, 131.6, 130.4, 128.7, 128.4, 126.4, 126.0, 122.2, 121.7, 120.0, 111.0, 100.2, 66.6, 58.3, 40.9, 19.2; HRMS (ESI): m/z calcd. forC22H17N5O2 [M + H]+ 384.1460, found 384.1468.
(±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-(m-tolyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′c)
[Reaction time: 4.0 h], 228 mg, 59%,a white solid, m.p. 211.1–212.9 °C; IR (thin film): νmax 3481, 3321, 3252, 3147, 2185, 1735, 1686, 1604, 1560, 1466, 1426, 1286, 1200, 1175, 762 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1 H), 7.77–7.76 (m, 2 H), 7.62 (d, J = 4.0 Hz, 1 H), 7.24 (ψt, J = 7.6 Hz, 1 H), 7.06–7.02 (m, 2 H), 6.91 (ψt, J = 7.6 Hz, 1 H), 6.73 (d, J = 8.0 Hz, 1 H), 6.68 (brs, 2 H), 6.53 (d, J = 7.6 Hz, 1 H), 5.64 (d, J = 4.0 Hz, 1 H), 4.26 (s, 1 H), 2.13 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.4, 150.1, 142.8, 142.6, 137.1, 134.7, 131.8, 130.8, 129.1, 128.1, 127.2, 126.0, 123.1, 122.9, 119.6, 110.6, 100.9, 67.4, 58.6, 46.5, 21.4; HRMS (ESI): m/z calcd. for C22H17N5O2 [M + H]+ 384.1460, found 384.1464.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(p-tolyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3d)
[Reaction time: 4.0 h], 230 mg, 60%, a yellow solid, m.p. 210.5–212.5 °C; IR (thin film): νmax 3440, 3363, 3230, 3146, 2197, 1724, 1688, 1613, 1570, 1542, 1518, 1468, 1257, 1194, 752 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1 H), 7.72 (d, J = 7.2 Hz, 1 H), 7.68 (s, 2 H), 7.32–7.28 (m, 2 H), 7.16 (ψt, J = 7.4 Hz, 1 H), 6.94 (d, J = 7.6 Hz, 2 H), 6.85 (br s, 2 H), 6.62 (d, J = 8.0 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 4.61 (s, 1 H), 2.18 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.4, 150.1, 142.8, 142.5, 137.5, 131.8, 131.7, 130.0, 128.9, 126.0, 123.1, 123.0, 119.6, 110.7, 100.9, 67.4, 58.7, 46.2, 21.1; HRMS (ESI): m/z calcd. for C22H17N5O2 [M + H]+ 384.1460, found 384.1461.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2-methoxyphenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3e)
[Reaction time: 2.0 h], 275 mg, 69%, a white solid, m.p. 238.9–240.2 °C; IR (thin film): νmax 3369, 3270, 3136, 2186, 1714, 1677, 1620, 1569, 1509, 1471, 1426, 1253, 1189, 744 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1 H), 7.71 (d, J = 7.2 Hz, 1 H), 7.67 (s, 2 H), 7.31 (ψt, J = 7.6 Hz, 1 H), 7.30 (d, J = 4.0 Hz, 1 H), 7.16 (ψt, J = 7.6 Hz, 1 H), 6.87 (brs, 2 H), 6.69 (d, J = 8.0 Hz, 2 H), 6.63 (d, J = 7.6 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 4.60 (s, 1 H), 3.66 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 165.4, 159.2, 150.0, 142.9, 142.5, 131.2, 126.4, 126.0, 123.1, 123.0, 119.6, 113.6, 100.6, 100.9, 67.4, 58.9, 55.4, 45.8; HRMS (ESI): m/z calcd. for C22H17N5O3 [M + H]+ 400.1410, found 400.1405.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(3-methoxyphenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3f)
[Reaction time: 7.0 h], 171 mg, 43%, a white solid, m.p. 242.5–243.9 °C; IR (thin film): νmax 3440, 3363, 3230, 3146, 2197, 1724, 1688, 1613, 1570, 1542, 1518, 1468, 1257, 1194, 752 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.72 (s, 2 H), 7.34 (d, J = 4.0 Hz, 1 H), 7.32 (ψt, J = 7.6 Hz, 1 H), 7.18 (ψt, J = 7.6 Hz, 1 H), 7.06 (ψt, J = 7.6 Hz, 1 H), 6.73 (dd, J = 8.0, 2.0 Hz, 1 H), 6.63 (d, J = 7.6 Hz, 1 H), 6.53 (brs, 2 H), 5.67 (d, J = 4.0 Hz, 1 H), 4.64 (s, 1 H), 3.55 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.4, 158.8, 150.1, 142.9, 142.6, 136.2, 131.8, 129.2, 126.0, 123.1, 122.9, 122.3, 119.6, 115.8, 113.8, 110.6, 101.0, 67.3, 58.4, 55.2, 46.5; HRMS (ESI): m/z calcd. for C22H17N5O3 [M + H]+ 400.1410, found 400.1410.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(4-methoxyphenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3g)
[Reaction time: 2.0 h], 263 mg, 66%, a yellow solid, m.p. 245.2–247.1 °C; IR (thin film): νmax 3684, 3987, 1710, 1694, 1573, 1383, 1267, 1128, 761 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1 H), 7.71 (d, J = 7.6 Hz, 1 H), 7.67 (s, 2 H), 7.31 (ψt, J = 8.0 Hz, 1 H), 7.30 (d, J = 4.0 Hz, 1 H), 7.16 (ψt, J = 7.6 Hz, 1 H), 6.87 (brs, 2 H), 6.69 (d, J = 8.0 Hz, 2 H), 6.63 (d, J = 7.6 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 4.60 (s, 1 H), 3.65 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 165.4, 159.2, 150.0, 142.9, 142.6, 131.8, 131.2, 126.4, 126.0, 123.1, 123.0, 119.7, 113.6, 110.7, 100.9, 67.4, 58.8, 55.4, 45.7; HRMS (ESI): m/z calcd. for C22H17N5O3 [M + H]+ 400.1410, found 400.1419.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2-fluorophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3h)
[Reaction time: 1.0 h], 302 mg, 78%, a yellow solid, m.p. 192.7–193.2 °C; IR (thin film): νmax 3479, 3313, 2188, 1734, 1687, 1618, 1563, 1471, 1428, 1333, 1192, 1097, 758 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1 H), 7.78 (s, 2 H), 7.65 (d, J = 7.6 Hz, 1 H), 7.35 (td, J = 7.6, 1.6 Hz, 1 H), 7.33 (d, J = 4.0 Hz, 1 H), 7.31 (td, J = 7.6, 0.8 Hz, 1 H), 7.27–7.21 (m, 1 H), 7.17 (td, J = 7.6, 0.8 Hz, 1 H), 7.13 (ψt, J = 7.6 Hz, 1 H), 6.91 (ψt, J = 9.2 Hz, 1 H), 6.66 (d, J = 7.6 Hz, 1 H), 5.67 (d, J = 4.0 Hz, 1 H), 4.98 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 165.4, 150.5, 142.6, 142.4, 132.0, 131.2, 130.6 (d), 126.3, 124.8, 124.7, 123.1, 122.5, 121.9 (d), 119.4, 115.4 (d), 110.6, 100.9, 66.9, 57.5, 38.1; 19F NMR (376 MHz, DMSO-d6): δ −114.5; HRMS (ESI): m/z calcd. for C21H14FN5O2 [M + H]+ 388.1210, found 388.1216.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2-fluorophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3i)
[Reaction time: 2.0 h], 256 mg, 66%, a yellow solid, m.p. 246.3–248.1 °C; IR (thin film): νmax 3365, 3269, 3147, 2184, 1717, 1682, 1623, 1572, 1550, 1476, 1431, 1269, 1194, 893, 748 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.52 (s, 1 H), 7.76 (s, 2 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.36 (d, J = 4.0 Hz, 1 H), 7.33 (td, J = 7.6, 0.8 Hz, 1 H), 7.18 (ψt, J = 7.4 Hz, 2 H), 7.03 (td, J = 8.4, 2.4 Hz, 1 H), 6.78 (brs, 2 H), 6.65 (d, J = 7.6 Hz, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.73 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 165.4, 150.3, 142.8, 142.7, 137.8 (d), 132.0, 130.2 (d), 126.3, 126.0, 123.3, 122.6, 119.5, 116.7 (d), 115.5, 115.3, 110.8, 101.2, 66.7, 57.8, 46.1; 19F NMR (376 MHz, DMSO-d6): δ −113.5; HRMS (ESI): m/z calcd. for C21H14FN5O2 [M + H]+ 388.1210, found 388.1219.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2-fluorophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3j)
[Reaction time: 3.0 h], 225 mg, 58%, a yellow solid, m.p. 249.6–250.2 °C; IR (thin film): νmax 3375, 3271, 3146, 2184, 1716, 1678, 1623, 1572, 1541, 1507, 1474, 1278, 1068, 907, 742 cm−; 1H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1 H), 7.81 (s, 2 H), 7.64 (d, J = 4.0 Hz, 1 H), 7.25 (td, J = 7.6, 0.8 Hz, 1 H), 7.02 (ψt, J = 8.8 Hz, 1 H), 6.94 (ψt, J = 7.6 Hz, 3 H), 6.75 (d, J = 8.0 Hz, 1 H), 6.53 (d, J = 7.6 Hz, 1 H), 5.65 (d, J = 4.0 Hz, 1 H), 4.36 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 165.4, 150.2, 142.8, 142.7, 132.1, 132.0, 131.0 (d), 126.0, 123.2, 122.7, 119.6, 115.3, 115.1, 110.7, 101.0, 67.3, 58.2, 45.8; 19F NMR (376 MHz, DMSO-d6): δ −119.6; HRMS (ESI): m/z calcd. for C21H14FN5O2 [M + H]+ 388.1210, found 388.1217.
(±)-(3R,6′S)-8′-amino-6′-(2-chlorophenyl)-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′k)
[Reaction time:3.0 h], 360 mg, 89%, a white solid, m.p. 240.9–241.6 °C; IR (thin film): νmax 3402, 3271, 3136, 2183, 1736, 1683, 1626, 1575, 1540, 1473, 1257, 1042, 853, 752 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1 H), 7.85 (s, 2 H), 7.40–7.27 (m, 6 H), 6.90 (d, J = 8.0 Hz, 1 H), 6.74 (ψt, J = 7.4 Hz, 1 H), 5.65 (d, J = 4.0 Hz, 1 H), 4.40 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 172.0, 165.3, 150.0, 143.0, 142.5, 135.3, 131.8, 130.6, 130.4, 129.5, 128.0, 127.7, 125.8, 122.4, 121.0, 120.0, 111.2, 100.6, 65.9, 56.6, 41.7; HRMS (ESI): m/z calcd. for C21H14ClN5O2 [M + H]+ 404.0914, found 404.0914.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2-chlorophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3l)
[Reaction time:2.0 h], 239 mg, 59%, a yellow solid, m.p. 243.6–244.8 °C; IR (thin film): νmax 3488, 3324, 3243, 2186, 1734, 1687, 1614, 1565, 1469, 1428, 1333, 1197, 753, 697 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1 H), 7.77 (s, 2 H), 7.72 (d, J = 7.2 Hz, 1 H), 7.36 (d, J = 4.0 Hz, 1 H), 7.33 (td, J = 7.6, 1.2 Hz, 1 H), 7.27–7.24 (m, 1 H), 7.19 (td, J = 7.6, 0.8 Hz, 1 H), 7.01 (brs, 1 H), 6.90 (brs, 1 H), 6.65 (d, J = 8.0 Hz, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.73 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 165.4, 150.3, 142.9, 142.7, 137.4, 132.8, 132.0, 130.1, 129.9, 128.9, 128.5, 126.1, 123.3, 122.6, 119.5, 110.8, 101.2, 67.2, 57.7, 46.1; HRMS (ESI): m/z calcd. for C21H14ClN5O2 [M + H]+ 404.0914, found 404.0918.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2-chlorophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3m)
[Reaction time: 4.0 h], 219 mg, 54%, a yellow solid, m.p. 259.7–261.7 °C; IR (thin film): νmax 3452, 3240, 3136, 2192, 1725, 1685, 1613, 1570, 1536, 1489, 1465, 1282, 1206, 838, 759 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1 H), 7.77 (s, 2 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.36 (d, J = 4.0 Hz, 1 H), 7.33 (ψt, J = 7.6 Hz, 1 H), 7.25 (d, J = 7.6 Hz, 2 H), 7.18 (ψt, J = 7.6 Hz, 1 H), 6.97 (brs, 2 H), 6.66 (d, J = 8.0 Hz, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.72 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 165.4, 150.2, 142.8, 142.7, 133.9, 133.1, 132.0, 131.9, 128.4, 126.0, 123.3, 122.6, 119.6, 110.8, 101.1, 67.2, 57.9, 45.9; HRMS (ESI): m/z calcd. for C21H14ClN5O2 [M + H]+ 404.0914, found. 404.0915.
(±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-(2-bromophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′n)
[Reaction time: 3.0 h], 265 mg, 59%, a yellow solid, m.p. 259.7–261.2 °C; IR (thin film): νmax 3365, 3143, 2194, 1725, 1659, 1580, 1527, 1470, 1426, 1216, 1050, 745, 587 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 7.85 (s, 2 H), 7.49–7.44 (m, 2 H), 7.35–7.27 (m, 4 H), 6.91 (d, J = 8.0 Hz, 1 H), 6.73 (ψt, J = 7.6 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 5.64 (d, J = 8.8 Hz, 1 H), 4.36 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 172.0, 165.3, 150.0, 143.1, 142.4, 137.0, 132.7, 131.9, 130.7 (2C), 128.6, 126.9, 126.0, 122.4, 120.8, 120.0, 111.2, 100.5, 65.8, 56.7, 44.4; HRMS (ESI): m/z calcd. for C21H14BrN5O2 [M + H]+ 448.0409, found 448.0430.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(3-bromophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3o)
[Reaction time: 1.0 h], 319 mg, 71%, a yellow solid, m.p. 259.9–261.6 °C; IR (thin film): νmax 3362, 3268, 3146, 2182, 1718, 1682, 1624, 1570, 1542, 1473, 1281, 1189, 749, 591 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1 H), 7.77 (s, 2 H), 7.72 (d, J = 7.6 Hz, 1 H), 7.40–7.32 (m, 3 H), 7.21–7.12 (m, 3 H), 6.94 (brs, 1 H), 6.66 (d, J = 7.6 Hz, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.71 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 165.4, 150.3, 142.9, 142.7, 137.6, 132.8, 132.0, 131.4, 130.4, 129.2, 126.1, 123.3, 122.6, 121.4, 119.5, 110.8, 101.8, 101.2, 67.2, 57.7, 46.0; HRMS (ESI): m/z calcd. for C21H14BrN5O2 [M + H]+ 448.0409, found 448.0410.
(±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-(4-bromophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′p)
[Reaction time: 1.5 h], 319 mg, 71%, a yellow solid, m.p. 260.5–262.5 °C; IR (thin film): νmax 3361, 3269, 2189, 1720, 1681, 1626, 1570, 1535, 1476, 1279, 1105, 750, 608 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 7.85 (s, 2 H), 7.49–7.44 (m, 2 H), 7.35–7.27 (m, 4 H), 6.91 (d, J = 7.6 Hz, 1 H), 6.73 (ψt, J = 7.6 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 5.64 (d, J = 7.6 Hz, 1 H), 4.37 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 165.4, 150.2, 142.8, 142.7, 134.4, 132.2, 131.3, 126.0, 123.3, 122.6, 121.8, 119.6, 110.8, 101.8, 101.1, 67.2, 57.8, 45.9; HRMS (ESI): m/z calcd. for C21H14BrN5O2 [M + H]+ 448.0409, found 448.0425.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(4-nitrophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3q) and (±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-(4-nitrophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′q)
[Reaction time: 15.0 h], 108 mg, 26%, a yellow solid, m.p. 239.5–241.5 °C; IR (thin film): νmax 3442, 3351, 3262, 2193, 1726, 1679, 1622, 1570, 1521, 1471, 1344, 1110, 857 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 3q: 10.57 (s, 1 H), 8.08 (d, J = 8.8 Hz, 2 H), 7.85 (s, 2 H), 7.75 (d, J = 7.6 Hz, 1 H), 7.61 (d, J = 4.0 Hz, 1 H), 7.40 (d, J = 4.0 Hz, 1 H), 7.28–7.23 (m, 1 H), 7.20 (ψt, J = 7.6 Hz, 1 H), 6.90 (ψt, J = 7.6 Hz, 1 H), 6.66 (d, J = 8.0 Hz, 1 H), 5.72 (d, J = 4.0 Hz, 1 H), 4.92 (s, 1 H); 3′q: 10.97 (s, 1 H), 8.08 (d, J = 8.8 Hz, 2 H), 7.90 (s, 2 H), 7.34 (ψt, J = 7.6 Hz, 1 H), 7.28–7.23 (m, 4 H), 6.78 (d, J = 8.0 Hz, 1 H), 6.41 (d, J = 7.6 Hz, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.55 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 170.7, 165.4 (2C), 150.4, 150.0, 147.6, 144.1, 143.7, 143.0, 142.9, 142.5, 142.0, 132.2, 131.6, 126.0, 125.6, 123.5, 123.4, 122.6, 122.4, 122.0, 119.5 (2C), 111.3, 110.9, 101.4, 101.3, 67.3, 67.0, 57.3, 57.2, 46.2, 45.7; HRMS (ESI): m/z calcd. forC21H14N6O4 [M + H]+ 415.1155, found 415.12316.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(naphthalen-1-yl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3r)
[Reaction time: 4.0 h], 140 mg, 28%, a yellow solid, m.p. 248.8–250.8 °C; IR (thin film): νmax 3366, 3268, 3125, 2188, 1723, 1676, 1647, 1625, 1564, 1531, 1517, 1463, 1333, 1193, 743 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1 H), 7.84 (s, 4 H), 7.71 (s, 2 H), 7.54–7.20 (m, 7 H), 6.55 (d, J = 7.2 Hz, 1 H), 5.71 (s, 1 H), 4.89 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 165.4, 150.4, 142.7 (2C), 132.9, 132.8, 132.5, 131.9, 129.6, 128.2, 127.9, 127.7 (2C), 126.8, 126.7, 126.1, 123.2, 122.9, 119.7, 110.7, 101.0, 67.4, 58.5, 46.7; HRMS (ESI): m/z calcd. for C25H17N5O2 [M + H]+ 420.1460, found 420.15148.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(3,4-dimethylphenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3s)
[Reaction time: 2.5 h], 216 mg, 54%, a white solid, m.p. 236.6–237.9 °C; IR (thin film): νmax 3485, 3369, 3274, 3145, 2183, 1719, 1684, 1604, 1562, 1468, 1200, 752 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.69 (s, 2 H), 7.33–7.29 (m, 2 H), 7.17 (ψt, J = 7.6 Hz, 1 H), 6.88 (d, J = 6.8 Hz, 1 H), 6.75 (brs, 1 H), 6.64 (brs, 1 H), 6.63 (d, J = 8.0 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 4.58 (s, 1 H), 2.09 (s, 3 H), 2.03 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 165.4, 150.4, 142.9, 142.5, 136.2, 135.8, 132.1, 131.8, 131.2, 129.3, 127.6, 126.0, 123.1, 123.0, 119.7, 110.7, 101.0, 67.4, 58.9, 46.1, 19.9, 19.4; HRMS (ESI): m/z calcd. for C23H19N5O2 [M + H]+ 398.1617, found 398.1625.
(±)-(3R,6′S)-8′-amino-6′-(3,4-dimethoxyphenyl)-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′t)
[Reaction time: 7.0 h], 171 mg, 43%, a white solid, m.p. 242.5–243.9 °C; IR (thin film): νmax 3277, 3140, 2188, 1733, 1678, 1620, 1574, 1544, 1515, 1469, 1266, 1024, 755 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1 H), 7.79 (s, 2 H), 7.71 (d, J = 4.0 Hz, 1 H), 7.26 (d, J = 7.6 Hz, 1 H), 6.70 (ψt, J = 7.6 Hz, 1 H), 6.78–6.72 (m, 3 H), 6.56 (d, J = 7.6 Hz, 1 H), 6.20 (brs, 1 H), 5.64 (d, J = 4.0 Hz, 1 H), 4.30 (s, 1 H), 3.67 (s, 3 H), 3.34 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 165.3, 149.8, 148.9, 148.0, 143.9, 141.8, 131.1, 126.9, 124.9, 123.6, 122.8, 122.4, 119.4, 113.3, 111.2 (2C), 100.9, 68.4, 59.0, 55.7, 55.5, 46.5; HRMS (ESI): m/z calcd. for C23H20N5O4 [M + H]+ 430.1515, found 430.15274.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(2,4-dichloroxyphenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3u) and (±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-(2,4-dichloroxyphenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′u)
[Reaction time: 1.5 h], 382 mg, 87%, a yellow solid, m.p. 260.2–262.2 °C; IR (thin film): νmax 3450, 3304, 2150, 2192, 1719, 1685, 1617, 1565, 1473, 1433, 1280, 1105, 837, 752 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 3u: 10.84 (s, 1 H), 7.86 (d, J = 7.2 Hz, 2 H), 7.51–7.46 (m, 2 H), 7.43–7.41 (m, 1 H), 7.39–7.36 (m, 2 H), 7.34–7.30 (m, 2 H), 6.77 (d, J = 8.0 Hz, 1 H), 5.67 (d, J = 4.0 Hz, 1 H), 4.93 (s, 1 H); 3′u: 10.97 (s, 1 H), 7.86 (d, J = 7.2 Hz, 2 H), 7.56 (d, J = 7.2 Hz, 1 H), 7.51–7.46 (m, 2 H), 7.34–7.30 (m, 1 H), 7.11 (ψt, J = 7.6, 0.8 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 6.83 (ψt, J = 7.6, 0.8 Hz, 1 H), 5.86 (d, J = 7.2 Hz, 1 H), 5.68 (d, J = 4.0 Hz, 1 H), 4.38 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.8, 170.6, 165.4 (2C), 150.2, 150.1, 143.1, 142.9, 142.7, 142.0, 136.1, 135.4, 134.5, 124.0, 133.9, 132.7, 132.4, 132.1, 132.0, 131.9, 129.0, 128.8, 128.3, 128.0, 126.2, 125.7, 123.0, 122.9, 122.6, 120.9, 119.8, 119.3, 111.3, 110.9, 101.1, 100.8, 66.8, 65.8, 57.3, 56.2, 42.2, 41.5; HRMS (ESI): m/z calcd. for C21H13Cl2N5O2 [M + H]+ 438.0525, found 438.06128.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-(3,4-dichlorophenyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3v)
[Reaction time: 4.0 h], 183 mg, 42%, a yellow solid, m.p. 259.8–261.6 °C; IR (thin film): νmax 3358, 3176, 3150, 2191, 1736, 1655, 1627, 1580, 1536, 1469, 1429, 1295, 1030, 830, 750 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.61 (s, 1 H), 7.83 (s, 2 H), 7.71 (d, J = 6.4 Hz, 1 H), 7.48 (s, 1 H), 7.39–7.33 (m, 2 H), 7.19 (d, J = 6.4 Hz, 2 H), 6.94 (brs, 1 H), 6.70 (d, J = 6.8 Hz, 1 H), 5.71 (s, 1 H), 4.76 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.8, 165.4, 150.3, 143.0, 142.6, 136.2, 132.2, 132.0, 121.2, 130.9, 130.6, 126.0, 123.4, 122.4, 119.5, 110.9, 101.3, 67.0, 57.2, 45.5; HRMS (ESI): m/z calcd. for C21H13Cl2N5O2 [M + H]+ 438.0525, found 438.06011.
(±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-((E)-styryl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3w) and (±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-((E)-styry)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (3′w)
[Reaction time: 18 h], 246 mg, 62%, a yellow solid, m.p. 251.3–253.1 °C; IR (thin film): νmax 3354, 3273, 3229, 2188, 1724, 1689, 1626, 1566, 1541, 1515, 1472, 1206, 1170, 11003, 968, 747 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 3w: 10.40 (s, 1 H), 7.74–7.56 (m, 3 H), 7.57 (d, J = 7.2 Hz, 1 H), 7.39–7.16 (m, 7 H), 6.96 (brs, 2 H), 6.60 (d, J = 7.6 Hz, 1 H), 5.67–5.65 (m, 1 H), 4.07–4.02 (m, 1 H); 3′w: 10.78 (s, 1 H), 7.74–7.56 (m, 2 H), 7.39–7.16 (m, 9 H), 6.83 (d, J = 7.6 Hz, 1 H), 6.23 (d, J = 15.6 Hz, 1 H), 5.81–5.74 (m, 1 H), 5.67–5.65 (m, 1 H), 4.66 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 171.1, 165.4, 165.3, 150.2, 149.3, 142.8, 142.6 (2C), 136.2, 135.8, 134.7, 131.8 (2C), 130.1 (2C), 129.2, 128.6, 128.4, 128.2, 126.7 (2C), 126.0, 125.6, 123.6, 123.5, 123.3, 123.1, 122.9, 119.8, 119.6, 110.9, 110.6, 101.0, 100.9, 100.5, 67.4, 66.2, 58.5, 57.4, 46.5, 44.4, 14.2; HRMS (ESI): m/z calcd. for C23H17N5O2 [M + H]+ 396.1460, found 396.1524.
(±)-(3R,6′R)-8′-amino-5-methyl-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4a)
[Reaction time: 3.0 h], 307 mg, 80%, a white solid, m.p. 238.8–240.2 °C; IR (thin film): νmax 3364, 3306, 3279, 3155, 2185, 1715, 1681, 1625, 1579, 1550, 1494, 1284, 1163, 742 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1 H), 7.69 (s, 2 H), 7.56 (s, 1 H), 7.31 (d, J = 4.0 Hz, 1 H), 7.15–7.09 (m, 4 H), 6.98 (brs, 2 H), 6.49 (d, J = 8.0 Hz, 1 H), 5.66 (d, J = 4.0 Hz, 1 H), 4.61 (s, 1 H), 2.34 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.4, 150.1, 142.6, 140.4, 134.8, 132.1 (2C), 130.1, 128.4, 128.2, 126.4, 122.9, 119.6, 110.4, 100.9, 67.5, 58.5, 46.6, 21.3; HRMS (ESI): m/z calcd. for C22H17N5O2 [M+Na]+ 406.1280, found 406.13334.
(±)-(3R,6′R)-8′-amino-5-methoxy-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo [1,2-a]pyridazine]-7′-carbonitrile (4b) and (±)-(3R,6′S)-8′-amino-5-methoxy-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4′b)
[Reaction time: 7.0 h], 280 mg, 70%, a brown solid, m.p. 239.6–241.2 °C; IR (thin film): νmax 3363, 3245, 3214, 2172, 1732, 1683, 1624, 1576, 1539, 1494, 1431,1300, 1200, 781 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 4b: 10.21 (s, 1 H), 7.69 (s, 2 H), 7.44 (d, J = 2.4 Hz, 1 H), 7.36 (d, J = 4.0 Hz, 1 H), 7.28–7.20 (m, 2 H), 7.16–7.15 (m, 1H), 7.01 (brs, 2 H), 6.87–6.81 (m, 1 H), 6.52 (d, J = 8.4 Hz, 1 H), 5.67 (d, J = 4.0 Hz, 1 H), 4.70 (s, 1 H), 3.79 (s, 3 H); 4′b: 10.97 (s, 1 H), 7.77 (s, 2 H), 7.55 (d, J = 4.0 Hz, 1 H), 7.28–7.20 (m, 2 H), 7.16–7.15 (m, 1 H), 6.96 (d, J = 6.8 Hz, 2 H), 6.87–6.81 (m, 1 H), 6.69 (d, J = 8.8 Hz, 1 H), 5.83 (d, J = 1.6 Hz, 1 H), 5.64 (d, J = 4.0 Hz, 1 H), 4.22 (s, 1 H), 3.49 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 171.1, 165.4, 165.3, 155.9, 154.7, 150.1, 149.7, 143.4, 142.7, 136.5, 135.9, 135.2, 134.8, 130.1, 128.6, 128.4 (2C), 128.3, 123.9, 123.5, 119.8, 119.6, 117.1, 115.9, 112.4, 112.3, 111.6, 111.3, 100.9, 100.8, 67.8, 58.5, 56.5, 56.1, 55.7, 46.4; HRMS (ESI): m/z calcd. for C22H17N5O3 [M+K]+ 438.0968, found 438.10269.
(±)-(3R,6′R)-8′-amino-5-fluoro-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4c)
[Reaction time: 8.5 h], 237 mg, 61%, a white solid, m.p. 231.4–233.4 °C; IR (thin film): νmax 3431, 3270, 3146, 2189, 1727, 1658, 1622, 1574, 1543, 1488, 1428, 1275, 1175, 1071, 802 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1 H), 7.75–7.70 (m, 2 H), 7.48 (d, J = 4.0 Hz, 1 H), 7.18–7.12 (m, 4 H), 7.00 (brs, 2 H), 6.60 (dd, J = 8.8, 4.4 Hz, 1 H), 5.71 (d, J = 4.0 Hz, 1 H), 4.69 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.4, 150.1, 143.0, 139.1 (d), 134.5, 130.1, 128.5, 128.4, 124.4 (2C), 119.5, 118.4 (d), 114.2, 114.0, 111.7 (d), 101.2, 67.6, 58.3, 46.5; 19F NMR (376 MHz, DMSO-d6): δ -119.6; 19F NMR (376 MHz, DMSO-d6): δ −119.6; HRMS (ESI): m/z calcd. for C21H14FN5O2 [M+Na]+ 410.1029, found 410.10951.
(±)-(3R,6′R)-8′-amino-5-chloro-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4d)
[Reaction time: 6.0 h], 331 mg, 82%, a brown solid, m.p. 231.0–232.9 °C; IR (thin film): νmax 3435, 3270, 3141, 2191, 1722, 1654, 1627, 1559, 1527, 1477, 1427, 1276, 1211, 909, 703 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1 H), 7.90 (d, J = 1.6 Hz, 1 H), 7.70 (d, J = 5.6 Hz, 1 H), 7.51 (d, J = 4.0 Hz, 1 H), 7.36–7.33 (m, 1 H), 7.18–7.15 (m, 3 H), 6.98 (brs, 2 H), 6.61 (d, J = 7.6 Hz, 1 H), 5.57 (d, J = 4.0 Hz, 1 H), 4.71 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 165.4, 150.1, 143.0, 141.8, 134.5, 131.8, 130.1, 128.6, 128.4, 127.1, 126.4, 124.8, 119.5, 112.1, 101.2, 67.4, 58.3, 46.4; HRMS (ESI): m/z calcd. for C21H14ClN5O2 [M + H]+ 404.0914, found 404.09140.
(±)-(3R,6′R)-8′-amino-6-bromo-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4e)
[Reaction time: 12 h], 213 mg, 47%, a brown solid, m.p. 230.8–232.7 °C; IR (thin film): νmax 3426, 3395, 3365, 3138, 2188, 1733, 1682, 1655, 1618, 1577, 1543, 1482, 1455, 1278, 1175, 742, 593 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1 H), 7.71 (s, 2 H), 7.69 (s, 1 H), 7.48 (d, J = 4.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.19 (s, 3 H), 6.98 (brs, 2 H), 6.77 (s, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.68 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 165.4, 150.1, 143.0, 141.8, 134.5, 131.8, 130.1, 128.6, 128.4, 127.1, 126.4, 124.8, 119.5, 112.1, 101.2, 67.4, 58.3, 46.4; HRMS (ESI): m/z calcd. for C21H14BrN5O2 [M + H]+ 448.0409, found 448.04897.
(±)-(3R,6′R)-8′-amino-5-iodo-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2 -a]pyridazine]-7′-carbonitrile (4f)
[Reaction time: 8.0 h], 207 mg, 42%, a brown solid, m.p. 234.2–235.6 °C; IR (thin film): νmax 3144, 2190, 1735, 1687, 1616, 1568, 1544, 1468, 1427, 1319, 1206, 750, 527 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.51 (s, 1 H), 8.12 (d, J = 1.6 Hz, 1 H), 7.70 (s, 2 H), 7.63 (dd, J = 8.0, 1.6 Hz, 1 H), 7.47 (d, J = 4.0 Hz, 1 H), 7.18–7.16 (m, 3 H), 6.98 (brs, 2 H), 6.44 (d, J = 8.0 Hz, 1 H), 5.69 (d, J = 4.0 Hz, 1 H), 4.69 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 170.6, 165.3, 150.1, 143.0, 142.6, 140.3, 134.5, 134.4, 130.0, 128.5, 128.4, 125.3, 119.5, 112.9, 101.1, 85.8, 67.2, 58.3, 46.3; HRMS (ESI): m/z calcd. for C21H14IN5O2 [M + H]+ 496.0270, found 496.03396.
(±)-(3R,6′R)-8′-amino-5-nitro-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4g)
[Reaction time: 4.0 h], 83 mg, 20%, a yellow solid, m.p. 234.5–236.5 °C; IR (thin film): νmax 3466, 3376, 3344, 3134, 2193, 1745, 1683, 1622, 1560, 1526, 1481, 1427, 1279, 1176, 841 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1 H), 8.73 (d, J = 6.0 Hz, 1 H), 8.25 (dd, J = 8.8, 2.0 Hz, 1 H), 7.74 (s, 2 H), 6.98 (brs, 2 H), 6.79 (d, J = 8.8 Hz, 2 H), 5.76 (d, J = 4.0 Hz, 1 H), 4.87 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 171.5, 165.4, 150.1, 149.1, 143.4, 143.2, 134.1, 130.1, 128.8, 128.7, 128.5, 123.9, 122.6, 119.4, 111.0, 101.4, 67.1, 58.0, 46.3; HRMS (ESI): m/z calcd. for C21H14N6O4 [M + H]+ 415.1155, found 415.12022.
(±)-(3R,6′S)-8′-amino-1′,2-dioxo-6′-phenyl-7-(trifluoromethyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4′h) and (±)-(3R,6′R)-8′-amino-1′,2-dioxo-6′-phenyl-7-(trifluoromethyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (4h)
[Reaction time: 6.0 h], 324 mg, 74%, a yellow solid, m.p. 235.4–236.7 °C; IR (thin film): νmax 3456, 3280, 3121, 2187, 1736, 1H NMR (400 MHz, DMSO-d6): δ 4′h: 11.37 (s, 1 H), 7.83 (s, 2 H), 7.67 (d, J = 4.0 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.28–7.14 (m, 3 H), 7.05 (ψt, J = 8.0 Hz, 1 H), 6.92 (d, J = 6.4 Hz, 2 H), 6.56 (d, J = 7.6 Hz, 1 H), 5.74 (d, J = 4.0 Hz, 1 H), 4.35 (s, 1 H); 4h: 10.91 (s, 1 H), 8.03 (d, J = 7.6 Hz, 1 H), 7.77 (s, 2 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.36 (ψt, J = 7.6 Hz, 1 H), 7.28–7.14 (m, 3 H), 6.92 (d, J = 6.4 Hz, 2 H), 5.70 (d, J = 4.0 Hz, 1 H), 4.71 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 172.0, 171.6, 165.4, 165.3, 150.2, 149.7, 150.1, 143.7, 143.2, 139.5, 135.7, 134.0, 129.9, 129.4, 128.7, 128.6, 128.4, 128.3, 127.7, 124.9, 124.8, 124.5, 123.3, 122.5, 122.1, 119.6, 112.2, 111.9, 101.3, 101.1, 66.4, 66.3, 58.1, 58.0, 46.9, 46.3; 19F NMR (376 MHz, DMSO-d6): δ −60.2, −60.4; HRMS (ESI): m/z calcd. for C22H14F3N5O2 [M + H]+ 438.1178, found 438.1179.
(±)-(3R,6′R)-8′-amino-2′-methyl-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5a)
[Reaction time: 1.0 h], 299 mg, 78%, a yellow solid, m.p. 257.5–259.4 °C; IR (thin film): νmax 3465, 3276, 3095, 2189, 1733, 1679, 1614, 1575, 1468, 1425, 1245, 1160, 746 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.67 (s, 2 H), 7.30 (ψt, J = 7.6 Hz, 1 H), 7.18–7.12 (m, 4 H), 6.97 (brs, 2 H), 6.60 (d, J = 7.6 Hz, 1 H), 4.63 (s, 1 H), 1.69 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.2, 165.7, 150.8, 142.8, 139.6, 135.0, 131.7, 130.1, 128.3, 128.2, 125.9, 123.3, 123.0, 119.7, 110.2, 100.6, 67.3, 58.7, 46.7, 7.5; HRMS (ESI): m/z calcd. for C22H17N5O2 [M+Na]+ 406.1280, found 406.13367.
(±)-(3R,6′S)-8′-amino-2′-methyl-1′,2-dioxo-6′-(p-tolyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5′b) and (±)-(3R,6′R)-8′-amino-2′-methyl-1′,2-dioxo-6′-(p-tolyl)-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5b)
[Reaction time: 3.5 h], 346 mg, 87%, a white solid, m.p. 240.1–242.0 °C; IR (thin film): νmax 3376, 3210, 3101, 2193, 1717, 1673, 1624, 1570, 1515, 1473, 1427, 1250, 1161, 1047, 739 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 5′b: 10.84 (s, 1 H), 7.76 (s, 2 H), 7.43 (s, 1 H), 7.22 (ψt, J = 7.6 Hz, 1 H), 6.96–6.90 (m, 2 H), 6.85 (brs, 1 H), 6.78 (d, J = 7.2 Hz, 2 H), 6.71 (d, J = 7.6 Hz, 1 H), 6.57 (d, J = 7.6 Hz, 1 H), 4.27 (s, 1 H), 2.20 (s, 3 H), 1.65 (s, 3 H); 5b: 10.35 (s, 1 H), 7.72 (d, J = 7.6 Hz, 1 H), 7.65 (s, 2 H), 7.30 (ψt, J = 7.6 Hz, 1 H), 7.16 (ψt, J = 7.6 Hz, 1 H), 7.11 (s, 1 H), 6.96–6.90 (m, 4 H), 6.62 (d, J = 8.0 Hz, 1 H), 4.59 (s, 1 H), 2.18 (s, 3 H), 1.69 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.4, 171.2, 165.6, 150.0, 142.8, 141.8, 140.5, 139.5, 137.6, 137.4, 132.6, 131.9, 131.6, 131.0, 130.0, 128.8, 125.9, 125.2, 123.4, 123.0, 122.3, 119.7, 119.6, 111.2, 111.0 (2C), 110.6, 68.1, 67.3, 59.0, 58.9, 46.3, 46.2, 21.1 (2C), 19.0, 7.5; HRMS (ESI): m/z calcd. for C23H19N5O2 [M + H]+ 398.1617, found.398.16345.
(±)-(3R,6′R)-8′-amino-6′-(4-methoxylphenyl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5c) and (±)-(3R,6′S)-8′-amino-6′-(4-methoxylphenyl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazinee]-7′-carbonitrile (5′c)
[Reaction time: 4.0 h], 290 mg, 73%, a yellow solid, m.p. 241.5–242.7 °C; IR (thin film): νmax 3369, 3259, 3208, 2178, 1716, 1672, 1624, 1598, 1567, 1510, 1470, 1428, 1247, 1175, 738 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 5c: 10.35 (s, 1 H), 7.75 (s, 1 H), 7.65 (s, 2 H), 7.31 (ψt, J = 7.6 Hz, 1 H), 7.16 (ψt, J = 7.6 Hz, 1 H), 7.11 (s, 1 H), 6.94–6.80 (m, 3 H), 6.74–6.63 (m, 1 H), 6.63 (d, J = 7.6 Hz, 1 H), 4.58 (s, 1 H), 3.65 (s, 3 H), 1.69 (s, 3 H); 5′c: 10.84 (s, 1 H), 7.71 (d, J = 7.2 Hz, 2 H), 7.43 (s, 1 H), 7.23 (ψt, J = 7.6 Hz, 1 H), 6.94–6.80 (m, 3 H), 6.74–6.63 (m, 3 H), 6.56 (d, J = 7.2 Hz, 1 H), 4.25 (s, 1 H), 3.67 (s, 3 H), 1.65 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.3, 165.6, 159.1, 150.0 (2C), 142.8, 141.8, 140.5, 139.5, 131.6, 131.2, 131.0, 127.4, 126.6, 125.9, 125.2, 123.4, 123.0, 122.4, 119.8, 119.6, 113.6, 111.1, 111.0, 110.9, 110.6, 68.2, 67.3, 59.1 (2C), 55.4 (2C), 45.9, 45.8, 19.0, 7.5; HRMS (ESI): m/z calcd. for C23H19N5O3 [M + H]+ 414.1566, found 414.12751.
(±)-(3R,6′R)-8′-amino-6′-(4-fluorophenyl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5d)
[Reaction time: 2.0 h], 297 mg, 91%, a white solid, m.p. 260.8–262.4 °C; IR (thin film): νmax 3372, 3333, 3213, 3104, 2181, 1720, 1670, 1628, 1590, 1509, 1476, 1427, 1251, 1191, 737 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1 H), 7.71 (d, J = 7.2 Hz, 1 H), 7.69 (s, 2 H), 7.32 (ψt, J = 8.0, 1.2 Hz, 1 H), 7.17 (ψt, J = 8.8, 0.8 Hz, 1 H), 7.14 (d, J = 1.2 Hz, 1 H), 6.99 (d, J = 6.0 Hz, 4 H), 6.64 (d, J = 7.6 Hz, 1 H), 4.67 (s, 1 H), 1.69 (d, J = 0.8 Hz, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.7, 150.1, 142.7, 139.6, 132.1, 132.0, 131.8, 131.2, 125.9, 123.2 (2C), 119.7, 115.2, 115.0, 111.2, 110.6, 67.2, 58.4, 45.8, 7.5; 19F NMR (376 MHz, DMSO-d6): −114.3; HRMS (ESI): m/z calcd. for C22H16FN5O2 [M+K]+ 440.0925, found 440.09885.
(±)-(3R,6′R)-8′-amino-6′-(4-chlorophenyl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5e)
[Reaction time: 3.5 h], 243 mg, 58%, a yellow solid, m.p. 260.1–262.0 °C; IR (thin film): νmax 3472, 3373, 3344, 2182, 1725, 1652, 1624, 1567, 1471, 1427, 1277, 1161, 832, 742 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1 H), 7.72 (s, 1 H), 7.71 (s, 2 H), 7.32 (ψt, J = 7.6 Hz, 1 H), 7.24–7.14 (m, 4 H), 6.99 (brs, 2 H), 6.66 (d, J = 7.6 Hz, 1 H), 4.68 (s, 1 H), 1.69 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 165.7, 150.1, 142.7, 139.7, 134.2, 133.1, 131.9, 131.8, 128.3, 125.9, 123.2, 123.0, 119.7, 111.3, 110.7, 67.1, 58.1, 45.8, 7.5; HRMS (ESI): m/z calcd. for C22H16ClN5O2 [M + H]+ 418.1071, found 429.11331.
(±)-(3R,6′R)-8′-amino-6′-(4-bromophenyl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′ -pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5f)
[Reaction time: 1.5 h], 305 mg, 66%, a yellow solid, m.p. 263.7–265.7 °C; IR (thin film): νmax 3472, 3342, 3190, 3131, 3098, 2188, 1733, 1651, 1619, 1561, 1472, 1413, 1277, 1157, 744, 516 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1 H), 7.72 (s, 1 H), 7.70 (s, 1 H), 7.32 (ψt, J = 7.6 Hz, 1 H), 7.23 (d, J = 7.6 Hz, 1 H), 7.17 (ψt, J = 7.6 Hz, 1 H), 7.15 (s, 1 H), 6.97 (s, 2 H), 6.65 (d, J = 8.0 Hz, 1 H), 4.68 (s, 1 H), 1.69 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 165.7, 150.1, 142.7, 139.7, 134.6, 132.2, 131.8, 131.3, 125.9, 123.2, 123.0, 121.8, 119.7, 111.3, 110.7, 67.0, 58.0, 45.9, 7.5; HRMS (ESI): m/z calcd. for C22H16BrN5O2 [M + H]+ 462.0566, found 462.06279.
(±)-(3R,6′S)-8′-amino-6′-(4-nitrophenyl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5′g) and (±)-(3R,6′R)-8′-amino-6′-(4-nitrophen-yl)-2′-methyl-1′,2-dioxo-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (5g)
[Reaction time: 16.0 h], 301 mg, 70%, a yellow solid, m.p. 261.7–263.3 °C; IR (thin film): νmax 3368, 3260, 3217, 2188, 1722, 1675, 1619, 1571, 1521, 1473, 1428, 1251, 1165, 848, 748 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 5′g: 10.94 (s, 1 H), 8.09 (s, 2 H), 7.87 (s, 2 H), 7.38–7.19 (m, 4 H), 6.88 (ψt, J = 7.6 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 6.66 (d, J = 7.6 Hz, 1 H), 4.51 (s, 1 H), 1.66 (s, 3 H); 5g: 10.50 (s, 1 H), 8.07 (s, 2 H), 7.81 (s, 2 H), 7.74 (d, J = 7.6 Hz, 1 H), 7.38–7.19 (m, 5 H), 6.36 (d, J = 7.2 Hz, 1 H), 4.89 (s, 1 H), 1.70 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 171.3, 170.7, 165.7, 165.7, 150.3, 149.9, 147.6, 144.4, 143.2, 142.5, 142.0, 140.3, 139.8, 132.0, 131.5, 131.4, 125.9, 125.6, 123.4, 123.3, 122.8, 122.5, 122.0, 119.6, 111.6, 111.3, 111.2, 110.8, 67.2, 67.0, 57.5, 57.4, 46.2, 45.8, 21.2, 7.5; HRMS (ESI): m/z calcd. for C22H16N6O4 [M + H]+ 429.1311, found 429.13739.
(±)-Ethyl 2-(((3R,6′R)-8′-amino-7′-cyano-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazin]-1-yl)methyl)acrylate (6)
[Reaction time: 5.0 min], 73 mg, 76%, a white solid m.p. 206.0–207.3 °C; IR (thin film): νmax 3370, 2981, 2189, 1725, 1683, 1492, 1382, 1172, 1027, 754 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 7.85 (d, J = 7.2 Hz, 1 H), 7.72 (s, 2 H), 7.40 (td, J = 8.0–7.6, 0.8 Hz, 1 H), 7.32 (d, J = 4.0 Hz, 1 H), 7.28 (ψt, J = 7.6–7.2 Hz 1 H), 7.20–7.30 (m, 3 H), 6.91 (brs, 2 H), 6.77 (d, J = 7.8 Hz, 1 H), 5.76 (s, 1 H), 5.67 (d, J = 4.0 Hz, 1 H), 4.77 (s, 1 H), 4.20 (d, J = 16.8 Hz, B of AB, 1 H), 4.14–4.04 (m, 2 H), 1.18 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 169.3, 165.4, 165.0, 150.2, 143.3, 142.8, 134.4, 133.3, 132.0, 130.2, 128.6, 128.4, 126.0, 125.2, 124.1, 122.0, 119.5, 110.6, 101.4, 67.1, 61.2, 58.5, 46.4, 14.4; HRMS (ESI): m/z calcd. for C27H24N5O4 [M + H]+ 482.1828, found 482.1689.
(±)-tert-butyl (3R,6′R)-8′-(bis(tert-butoxycarbonyl)amino)-7′-cyano-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-1-carboxylate (7)
[Reaction time: 5.0 h], 95 mg, 71%, a white solid, m.p. 159.2–160.3 °C; IR (thin film): νmax 2980, 2926, 2855, 2221, 1775, 1741, 1708, 1647, 1551, 1465, 1043, 914, 857 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 7.81 (d, J = 7.6 Hz, 1 H), 7.57 (ψt, J = 7.6 Hz, 1 H), 7.53 (ψt, J = 7.6 Hz, 1 H), 7.47–7.43 (m, 2 H), 7.28–7.19 (m, 3 H), 6.83 (s, 2 H), 5.75 (d, J = 4.0 Hz, 1 H), 4.91 (s, 1 H), 1.60 (s, 9 H), 1.44 (s, 9 H), 1.38 (s, 9 H); 13C NMR (100 MHz, DMSO-d6): δ 1670.1, 162.3, 148.4, 147.8 (2C), 145.3, 140.4, 139.5, 132.5, 132.0, 129.8, 129.2, 128.6, 126.2, 125.9, 121.1, 115.4, 115.1, 103.7, 91.9, 84.5 (2C), 84.2, 67.2, 66.6, 48.9, 29.8, 28.2, 27.9, 27.8; HRMS (ESI): m/z calcd. for C36H39N5NaO8 [M+Na]+ 692.2696, found 692.2679.
(±)-(3R,6′S)-1′,2,8′-trioxo-6′-(o-tolyl)-7′,8′-dihydro-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (8)
[Reaction time: 5.0 h], 19 mg, 25%, a yellow solid, m.p. 270.7–272.7 °C; IR (thin film): νmax 3533, 3365, 3175, 2923, 2852, 2187, 1751, 1718, 1677, 1577, 1430, 1343, 1169, 1014, 887, 740 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1 H), 8.37 (s, 1 H), 7.34–7.30 (m, 2 H), 7.28–7.19 (m, 2 H), 7.08 (d, J = 6.4 Hz, 1 H), 7.01 (d, J = 6.8 Hz, 1 H), 6.90 (d, J = 7.6 Hz, 1 H), 6.72 (ψt, J = 7.2 Hz, 1 H), 5.74 (d, J = 7.2 Hz, 1 H), 5.64 (d, J = 4.0 Hz, 1 H), 4.44 (s, 1 H), 1.71 (s, 3 H), 1.70 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 172.3, 161.8, 143.8, 143.0, 138.8, 133.5, 131.8, 130.7, 130.1, 129.0, 128.4, 126.6, 126.2, 122.3, 121.2, 118.4, 111.0, 101.1, 89.2, 65.7, 41.9, 19.3; HRMS (ESI): m/z calcd. for C22H16N4NaO3 [M+Na]+ 407.1120, found 407.0876.
(±)-(3R,6′R)-1-acetyl-8′-amino-2′-methyl-1′,2-dioxo-6′-phenyl-1′H,6′H-spiro[indoline-3,5′-pyrazolo[1,2-a]pyridazine]-7′-carbonitrile (9)
[Reaction time: 5.0 h], 73 mg, 86%, a white solid, m.p. 252.5–254.4 °C; IR (thin film): νmax 3414, 3015, 2924, 2219, 1728, 1666, 1626, 1571, 1529, 1471, 1372, 1197, 897, 755 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 7.88–7.78 (m, 4 H), 7.51–7.48 (m, 2 H), 7.25 (s, 1 H), 7.20–7.16 (m, 3 H), 6.84 (brs, 2 H), 4.67 (s, 1 H), 2.29 (s, 3 H), 1.70 (s, 3 H); 13C NMR (100 MHz, DMSO-d6): δ 170.6, 169.6, 165.6, 150.1, 140.4, 140.1, 133.7, 129.6, 131.4, 125.9, 125.6, 123.4, 123.3, 122.8, 122.5, 122.0, 119.6, 111.6, 111.3, 111.2, 110.8, 67.2, 67.0, 57.5, 57.4, 46.2, 45.8, 21.2, 7.5; HRMS (ESI): m/z calcd. for C24H19N5NaO3 [M+Na]+ 448.1386, found 448.1376.