6-Carbohydrazonamidepurines: Convenient Precursors for 4,8-Disubstituted Pyrimido[5,4-d]pyrimidines

Abstract

A series of 4-arylamino-8-(alkyl or aryl)hydrazidepyr­imido[5,4-d]pyrimidines was obtained efficiently from 6-carbo­hydrazonamidepurines by reaction with piperidine. The 6-carbo-­hydrazonamidepurines were generated selectively by the reaction of 6-imidatopurine with hydrazides under acidic conditions.

Key words

rearrangement - ring opening - ring closure - substituent effects - fused-ring systems - heterocycles

• References and Notes

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• 13 Experimental Procedure for the Synthesis of 6-Carbo-hydrazonamidepurine 4a: The 6-imidatopurines 6a (0.19 g, 0.75 mmol) and hydrazide 7a (0.08g, 1.3 mmol, 1.5 equiv) were combined in a round-bottom flask using DMSO (1.2 mL) as solvent and sulfuric acid (25 μL) as catalyst. The reaction was stirred at r.t. until TLC analysis showed the absence of starting material (1 h) and H₂O (10 mL) was added to the reaction mixture. The yellow suspension was filtered, washed with H₂O, EtOH and Et₂O and identified as 6-carbohydrazonamidepurine 4a (0.12 g, 0.38 mmol, 51%); mp 235–237 °C. IR (nujol mull): 3459, 3363, 3203, 3057, 1680, 1655, 1590, 1576, 1567 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆–TFA): δ = 10.27 (s, 2 H, NH₂, D₂O exch.), 9.44 (s, 1 H, CH), 9.29 (s, 1 H, CH), 7.93 (d, J = 7.8 Hz, 2 H, Ar), 7.68 (t, J = 7.8 Hz, 2 H, Ar), 7.57 (t, J = 7.8 Hz, 1 H, Ar), 2.03 (s, 3 H, Me). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 168.7, 158.6, 153.4, 152.3, 149.4, 139.6, 133.6, 131.9, 129.8, 128.9, 124.0, 21.0. Anal. Calcd for C₁₄H₁₃N₇O: C, 56.94; H, 4.44; N, 33.20. Found: C, 56.77; H, 4.55; N, 33.02.
• 14 Experimental Procedure for the Synthesis of Pyrimido[5,4,-d]pyrimidine 3a: A solution of 6-carbo-hydrazonamidepurine 4a (0.35 g, 1.2 mmol) in EtOH (10 mL) and piperidine (0.6 mL) was heated to reflux for 24 h, when TLC showed the absence of starting material. The suspension was concentrated to dryness and H₂O was added to the residue. The resulting off-white solid was filtered, washed with H₂O and EtOH and identified as the pyrimido[5,4-d]pyrimidine 3a (0.22 g, 0.76 mmol, 63%); mp 181–182 °C. IR (nujol mull): 3360, 3225, 3048, 1610, 1590, 1551, 1528 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆–TFA): δ = 10.19 (br s, 1 H, NH, D₂O exch.), 10.16 (br s, 1 H, NH, D₂O exch.), 8.65 (s, 1 H, CH), 8.61 (s, 1 H, CH) 7.97 (d, J = 7.5 Hz, 2 H, Ar), 7.38 (t, J = 7.5 Hz, 2 H, Ar), 7.14 (t, J = 7.5 Hz, 1 H, Ar), 1.96 (s, 3 H, Me). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 168.4, 157.9, 156.5, 154.2, 153.5, 138.3, 131.8, 131.0, 128.6, 124.2, 121.9, 20.7. Anal. Calcd for C₁₄H₁₃N₇O: C, 56.94; H, 4.44; N, 33.20. Found: C, 56.77; H, 4.55; N, 33.57.
• 15 Analytical and spectroscopic data for compounds 3b–j and 4b–j: Compound 3b: yield: 76%; crème solid; mp 142–144 °C. IR (nujol mull): 3365, 3237, 1678, 1597, 1576, 1524 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆–TFA): δ = 10.11 (s, 1 H, NH, D₂O exch.), 10.08 (s, 1 H, NH, D₂O exch.), 8.64 (s, 1 H, CH), 8.58 (s, 1 H, CH), 7.99 (d, J = 7.5 Hz, 2 H, Ar), 7.38 (t, J = 7.5 Hz, 2 H, Ar), 7.13 (t, J = 7.5 Hz, 1 H, Ar), 2.21 (t, J = 7.2 Hz, 2 H), 1.55–1.58 (m, 2 H), 1.28 (m, 8 H), 0.84–0.86 (m, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 171.4, 158.3, 156.4, 154.1 (2 ×), 138.4, 131.9, 131.0, 128.6, 124.0, 121.9, 33.3, 31.3, 28.6, 28.5, 25.1, 22.1, 14.0. Anal. Calcd for C₂₀H₂₅N₇O: C, 63.30; H, 6.64; N, 25.84. Found: C, 63.33; H, 6.86; N, 25.85. Compound 3c: yield: 51%; yellow solid; mp >300 °C. IR (nujol mull): 3315, 3169, 1670, 1680, 1539, 1530 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 10.69 (br s, 1 H, NH, D₂O exch.), 10.41 (br s, 1 H, NH, D₂O exch.), 10.06 (s, 1 H, NH, D₂O exch.), 8.67 (s, 1 H, CH), 8.59 (s, 1 H, CH), 8.01 (d, J = 7.8 Hz, 2 H, Ar), 7.96 (d, J = 7.2 Hz, 2 H, Ar), 7.60 (t, J = 7.2 Hz, 1 H, Ar), 7.52 (t, J = 7.2 Hz, 2 H, Ar), 7.39 (t, J = 7.8 Hz, 2 H, Ar), 7.13 (t, J = 7.8 Hz, 1 H, Ar). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 165.4, 158.7, 156.3, 154.4, 154.1, 132.5, 132.1, 131.8, 131.1, 128.6, 128.5, 127.5, 123.3, 121.6. Anal. Calcd for C₁₉H₁₅N₇O: C, 63.86; H, 4.23; N, 27.44. Found: C, 63.58; H, 4.32; N, 27.53. Compound 3d: yield: 54%; yellow solid; mp 255–257 °C. IR (nujol mull): 3315, 3248, 3105, 1640, 1601, 1591, 1568, 1527 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆–TFA): δ = 10.95 (s, 1 H, NH, D₂O exch.), 10.10 (s, 1 H, NH, D₂O exch.), 9.14 (d, J = 1.6 Hz, 1 H), 8.81 (dd, J = 1.6, 5.2 Hz, 1 H, HetAr), 8.69 (s, 1 H, CH), 8.63 (s, 1 H, CH), 8.35 (dd, J = 1.6, 6.0 Hz, 1 H, HetAr), 8.01 (d, J = 7.6 Hz, 2 H, Ar), 7.64 (dd, J = 5.2, 6.0 Hz, 1 H, HetAr), 7.39 (t, J = 7.6 Hz, 2 H, Ar), 7.14 (t, J = 7.6 Hz, 1 H, Ar). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 164.4, 158.8, 156.5, 154.5, 154.3, 152.1, 148.1, 138.4, 136.0, 132.2, 131.1, 128.6, 128.4, 124.0 (2 ×), 121.7. Anal. Calcd for C₁₈H₁₄N₈O: C, 60.33; H, 3.94; N, 31.27. Found: C, 60.09; H, 4.00; N, 31.13. Compound 3e: yield: 75%; off-white solid; mp 165–167 °C. IR (nujol mull): 3357, 3251, 1679, 1654, 1615, 1603, 1595, 1569, 1547 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆–TFA): δ = 10.23 (s, 1 H, NH, D₂O exch.), 10.05 (s, 1 H, NH, D₂O exch.), 8.65 (s, 1 H, CH), 8.58 (s, 1 H, CH), 8.07 (d, J = 8.9 Hz, 2 H, Ar), 7.42 (d, J = 8.9 Hz, 2 H, Ar), 2.21 (t, J = 7.5 Hz, 2 H), 1.54–1.59 (m, 2 H), 1.26–1.29 (m, 8 H), 0.84–0.86 (m, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 171.4, 158.6, 156.4, 154.4, 153.9, 137.5, 132.0, 131.1, 128.4, 127.5, 123.2, 33.3, 31.2, 28.6, 28.5, 25.0, 22.1, 14.0. Anal. Calcd for C₂₀H₂₄ClN₇O: C, 58.04; H, 5.84; N, 23.69. Found: C, 58.15; H, 5.95; N, 23.43. Compound 3f: yield: 81%; orange solid; mp >300 °C. IR (nujol mull): 3310, 3218, 1693, 1666, 1604, 1594, 1570, 1537 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆–TFA): δ = 10.08 (s, 1 H, NH, D₂O exch.), 10.29 (s, 1 H, NH, D₂O exch.), 8.71 (s, 1 H, CH), 8.63 (s, 1 H, CH), 8.38 (d, J = 8.9 Hz, 2 H, Ar), 8.18 (d, J = 8.9 Hz, 2 H, Ar), 8.08 (d, J = 8.9 Hz, 2 H, Ar), 7.43 (d, J = 8.9 Hz, 2 H, Ar). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 164.1, 158.7, 156.5, 154.5, 154.2, 149.5, 138.1, 137.5, 132.2, 131.2, 129.1, 128.4, 127.6, 123.8, 123.3. Anal. Calcd for C₁₉H₁₃ClN₈O₃: C, 52.24; H, 3.00; N, 25.65. Found: C, 51.99; H, 3.27; N, 25.42. Compound 3g: yield 72%; light yellow solid; mp 282–284 °C. IR (nujol mull): 3347, 3209, 1684, 1642, 1614, 1580, 1544, 1505 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆–TFA): δ = 10.99 (br s, 1 H, NH, D₂O exch.), 10.27 (s, 1 H, NH, D₂O exch.), 9.14 (d, J = 1.6 Hz, 1 H, HetAr), 8.83 (s, 1 H, CH), 8.71 (s, 1 H, CH), 8.82 (dd, J = 2.0, 4.8 Hz, 1 H, HetAr), 8.37 (dt, J = 2.0, 8.0 Hz, 1 H, HetAr), 8.08 (d, J = 8.8 Hz, 2 H, Ar), 7.66 (dd, J = 4.8, 8.0 Hz, 1 H, HetAr), 7.43 (d, J = 8.8 Hz, 2 H, Ar). ¹³C NMR (100 MHz, DMSO-d ₆–TFA): δ = 163.9, 158.8, 156.5, 154.8, 154.1, 151.8, 147.8, 137.5, 136.3, 132.2, 131.2, 128.5, 128.4, 127.6, 124.2, 123.2. Anal. Calcd for C₁₈H₁₃ClN₈O: C, 55.04; H, 3.34; N, 28.53. Found: C, 55.14; H, 3.54; N, 28.74. Compound 3h: yield: 86%; yellow solid; mp 165–167 °C. IR (nujol mull): 3360, 3225, 1674, 1599, 1525 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆–TFA): δ = 10.10 (s, 1 H, NH, D₂O exch.), 10.07 (s, 1 H, NH, D₂O exch.), 8.68 (s, 1 H, CH), 8.58 (s, 1 H, CH), 8.24 (d, J = 1.5 Hz, 1 H, Ar), 7.84 (dd, J = 1.5, 8.1 Hz, 1 H, Ar), 7.31 (d, J = 8.1 Hz, 1 H, Ar), 2.30 (s, 3 H, Me), 2.26 (t, J = 7.2 Hz, 2 H), 1.54–1.58 (m, 2 H), 1.26–1.29 (m, 8 H), 0.84–0.86 (m, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆–TFA): δ = 171.4, 158.4, 156.4, 154.1, 154.0, 137.7, 132.8, 131.9, 131.0, 130.9, 130.6, 121.4, 120.3, 33.3, 31.1, 28.6, 28.5, 25.1, 22.1, 14.0. HRMS (ESI): m/z [M⁺ + 1] calcd for C₂₁H₂₇ClN₇O: 428.93838; found: 428.93840. Compound 3i: yield: 82%; orange solid; mp >300 °C. IR (nujol mull): 3311, 3215, 1665, 1591, 1533, 1522 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆–TFA): δ = 11.06 (s, 1 H, NH, D₂O exch.), 10.22 (s, 1 H, NH, D₂O exch.), 8.74 (s, 1 H, CH), 8.63 (s, 1 H, CH), 8.39 (d, J = 8.8 Hz, 2 H, Ar), 8.27 (d, J = 2.0 Hz, 1 H, Ar), 8.18 (d, J = 8.8 Hz, 2 H, Ar), 7.87 (dd, J = 2.0, 8.4 Hz, 1 H, Ar), 7.34 (d, J = 8.4 Hz, 1 H, Ar), 2.31 (s, 3 H, Me). ¹³C NMR (100 MHz, DMSO-d ₆–TFA): δ = 164.0, 158.8, 156.4, 154.6, 154.2, 149.5, 138.1, 137.7, 132.8 (2 ×), 131.1, 130.9, 130.4, 129.1, 123.8, 121.4, 120.3, 19.0. HRMS (ESI): m/z [M⁺ + 1] calcd for C₂₀H₁₆ClN₈O₃: 451.84584; found: 451.84583. Compound 3j: yield: 99%; yellow solid; mp 300–302 °C. IR (nujol mull): 3438, 3358, 3199, 1683, 1652, 1604, 1584, 1540 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆–TFA): δ = 11.05 (s, 1 H, NH, D₂O exch.), 10.23 (s, 1 H, NH, D₂O exch.), 9.18 (d, J = 1.6 Hz, 1 H, HetAr), 8.88 (dd, J = 1.6, 5.2 Hz, 1 H, HetAr), 8.74 (s, 1 H, CH), 8.62 (s, 1 H, CH), 8.48 (dd, J = 1.6, 8.0 Hz, 1 H, HetAr), 8.26 (d, J = 2.0 Hz, 1 H, Ar), 7.86 (dd, J = 2.0, 8.6 Hz, 1 H, Ar), 7.75 (dd, J = 5.2, 8.0 Hz, 1 H, HetAr), 7.34 (d, J = 8.6 Hz, 1 H, Ar), 2.31 (s, 3 H, Me). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.5, 159.0, 156.5, 154.4, 154.2, 150.8, 146.9, 137.6 (2 ×), 132.8, 132.2, 131.2, 130.9, 130.6, 128.9, 124.7, 121.5, 120.3, 19.0. Anal. Calcd for C₁₉H₁₅ClN₈O: C, 56.09; H, 3.72; N, 27.54. Found: C, 56.22; H, 3.82; N, 27.88. Compound 4b: yield: 97%; crème solid; mp 208–210 °C. IR (nujol mull): 3430, 3351, 3291, 3224, 3108, 3066, 3048, 1666, 1647, 1581, 1556, 1506 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆–TFA): δ = 10.80 (s, 1 H, NH, D₂O exch.), 10.24 (s, 2 H, NH₂, D₂O exch.), 9.46 (s, 1 H, CH), 9.31 (s, 1 H, CH), 7.94 (d, J = 7.6 Hz, 2 H, Ar), 7.69 (t, J = 7.6 Hz, 2 H, Ar), 7.58 (t, J = 7.6 Hz, 1 H, Ar), 2.30 (t, J = 7.2 Hz, 2 H), 1.58–1.60 (m, 2 H), 1.28–1.30 (m, 8 H), 0.86 (t, J = 6.8 Hz, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 171.5, 158.7, 153.3, 152.3, 149.3, 139.6, 133.6, 131.9, 129.8, 128.9, 124.0, 33.3, 31.2, 28.6, 28.5, 24.3, 22.1, 13.9. Anal. Calcd for C₂₀H₂₅N₇O: C, 63.30; H, 6.64; N, 25.84. Found: C, 63.27; H, 6.56; N, 25.74. Compound 4c: yield: 85%; yellow solid; mp 236–240 °C. IR (nujol mull): 3378, 3316, 3181, 3097, 1650, 1600, 1590, 1573, 1532, 1509 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆–TFA): δ = 9.63 (br s, 2 H, NH₂, D₂O exch.), 9.39 (s, 1 H, CH), 9.27 (s, 1 H, CH), 8.01 (d, J = 7.2 Hz, 2 H, Ar), 7.95 (d, J = 7.8 Hz, 2 H, Ar), 7.69 (t, J = 7.8 Hz, 2 H, Ar), 7.57 (m, 4 H, Ar). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 165.3, 157.3, 153.1, 152.2, 148.7, 141.5, 132.5, 132.1, 131.7, 128.4, 128.8, 128.0, 124.0. Anal. Calcd for C₁₉H₁₅N₇O: C, 63.86; H, 4.23; N, 27.44. Found: C, 63.55; H, 4.45; N, 27.17. Compound 4d: yield: 83%; orange solid; mp >300 °C. IR (nujol mull): δ = 3352, 3180, 1682, 1631, 1583, 1509 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆–TFA): δ = 9.77 (s, 2 H, NH₂, D₂O exch.), 9.43 (s, 1 H, CH), 9.28 (s, 1 H, CH), 9.24 (d, J = 1.2 Hz, 1 H, HetAr), 8.63 (dd, J = 1.2, 4.8 Hz, 1 H, HetAr), 8.46 (d, J = 8.0 Hz, 1 H, HetAr), 7.95 (d, J = 7.6 Hz, 2 H, Ar), 7.65–7.70 (m, 3 H, Ar + HetAr), 7.57 (t, J = 7.6 Hz, 1 H, Ar). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 151.0, 163.8, 154.7, 153.1, 151.9, 148.0, 147.3, 145.1, 136.8, 133.7, 131.5, 129.7, 129.6, 128.8, 123.9, 123.8. Anal. Calcd for C₁₈H₁₄N₈O: C, 60.33; H, 3.94; N, 31.27. Found: C, 60.49; H, 4.11; N, 30.98. Compound 4e: yield: 99%; off-white solid; mp 209–211 °C. IR (nujol mull): δ = 3420, 3345, 3283, 3225, 1668, 1646, 1603, 1575, 1553, 1518 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆–TFA): δ = 10.81 (s, 1 H, NH, D₂O exch.), 10.22 (s, 2 H, NH₂, D₂O exch.), 9.45 (s, 1 H, CH), 9.31 (s, 1 H, CH), 8.00 (d, J = 8.0 Hz, 2 H, Ar), 7.74 (d, J = 8.0 Hz, 2 H, Ar), 2.31 (t, J = 7.8 Hz, 2 H), 1.57–1.61 (m, 2 H), 1.24–1.30 (m, 8 H), 0.83–0.88 (m, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 171.7, 158.4, 153.3, 152.3, 149.1, 139.6, 133.3, 132.5, 131.9, 129.8, 125.6, 33.3, 31.2, 28.6, 28.5, 24.3, 22.1, 13.9. Anal. Calcd for C₂₀H₂₄ClN₇O: C, 58.04; H, 5.84; N, 23.69. Found: C, 57.95; H, 5.93; N, 23.44. Compound 4f: yield: 98%; orange solid; mp >300 °C. IR (nujol mull): 3405, 3355, 3298, 3258, 3241, 3210, 3040, 1686, 1671, 1650, 1620, 1590, 1573, 1547, 1509 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆–TFA): δ = 10.27 (s, 2 H, NH₂, D₂O exch.), 9.48 (s, 1 H, CH), 9.34 (s, 1 H, CH), 8.41 (d, J = 8.9 Hz, 2 H, Ar), 8.25 (d, J = 8.9 Hz, 2 H, Ar), 8.02 (d, J = 8.7 Hz, 2 H, Ar), 7.79 (d, J = 8.7 Hz, 2 H, Ar). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 157.2, 154.2, 153.3, 152.4, 149.6, 149.2, 139.7, 137.9, 133.3, 132.6, 131.8, 129.8, 129.6, 125.7, 123.6. Anal. Calcd for C₁₉H₁₃ClN₈O₃: C, 52.24; H, 3.00; N, 25.65. Found: C, 52.38; H, 3.28; N, 25.80. Compound 4g: yield: 94%; orange solid; mp >300 °C. IR (nujol mull): 3430, 1680, 1653, 1580 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆–TFA): δ = 9.77 (s, 2 H, NH₂, D₂O exch.), 9.47 (s, 1 H, CH), 9.34 (s, 1 H, CH), 9.24 (d, J = 1.5 Hz, 1 H, HetAr), 8.86 (dd, J = 1.5, 5.4 Hz, 1 H, HetAr), 8.63 (d, J = 8.1 Hz, 1 H, HetAr), 8.02 (d, J = 6.9 Hz, 2 H, Ar), 7.73–7.80 (m, 3 H, Ar + HetAr). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 163.7, 156.9, 153.3, 152.4, 150.8, 149.2, 147.5, 139.6, 137.7, 133.3, 132.6, 131.8, 129.8, 129.2, 125.7, 124.4. HRMS (ESI): m/z [M⁺ + 1] calcd for C₁₈H₁₄ClN₈O: 393.80976; found: 393.80975. Compound 4h: yield: 99%; white solid; mp 234–236 °C. IR (nujol mull): 3425, 3350, 3288, 3224, 3110, 3048, 1667, 1646, 1602, 1579, 1553, 1506 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆–TFA): δ = 10.81 (s, 1 H, NH, D₂O exch.), 10.20 (s, 2 H, NH₂, D₂O exch.), 9.46 (s, 1 H, CH), 9.32 (s, 1 H, CH), 8.12 (d, J = 2.1 Hz, 1 H, Ar), 7.87 (dd, J = 2.1, 8.4 Hz, 1 H, Ar), 7.67 (d, J = 8.4 Hz, 1 H, Ar), 2.25 (m, 5 H), 1.50–1.61 (m, 2 H), 1.24–1.29 (m, 8 H), 0.82–0.87 (m, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 171.7, 158.3, 153.3, 152.4, 149.1, 139.7, 136.3, 133.9, 132.6, 132.1, 131.8, 123.9, 122.4, 33.4, 31.2, 28.6, 28.5, 24.3, 22.1, 19.3, 13.9. Anal. Calcd for C₂₁H₂₆ClN₇O: C, 58.94; H, 6.12; N, 22.91. Found: C, 59.00; H, 5.98; N, 22.72. Compound 4i: yield: 83%; orange solid; mp >300 °C. IR (nujol mull): 3389, 3188, 1672, 1657, 1649, 1580, 1521, 1509 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆–TFA): δ = 9.59 (s, 2 H, NH₂, D₂O exch.), 9.38 (s, 1 H, CH), 9.28 (s, 1 H, CH), 8.35 (d, J = 8.4 Hz, 2 H, Ar), 8.28 (d, J = 8.4 Hz, 2 H, Ar), 8.11 (d, J = 2.0 Hz, 1 H, Ar), 7.87 (dd, J = 2.0, 8.4 Hz, 1 H, Ar), 7.65 (d, J = 8.4 Hz, 1 H, Ar), 2.45 (s, 3 H, Me). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 163.2, 156.3, 152.0, 149.4, 149.1, 140.3, 138.1, 136.0, 133.7, 132.4, 131.8, 131.3, 128.7, 124.5, 123.1, 122.1, 18.9. HRMS (ESI): m/z [M⁺ + 1] calcd for C₂₀H₁₆ClN₈O₃: 451.84584; found: 451.84583. Compound 4j: yield: 79%; orange solid; mp >300 °C. IR (nujol mull): 3438, 3358, 3199, 3041, 1683, 1652, 1604, 1584, 1540, 1510 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆–TFA): δ = 10.07 (s, 2 H, NH₂, D₂O exch.), 9.34 (s, 1 H, CH), 9.47 (s, 1 H, CH), 9.23 (d, J = 1.5 Hz, 1 H, HetAr), 8.85 (dd, J = 1.5, 4.8 Hz, 1 H, HetAr), 8.48 (d, J = 7.8 Hz, 1 H, HetAr), 8.13 (d, J = 2.1 Hz, 1 H, Ar), 7.89 (dd, J = 2.1, 2.4 Hz, 1 H, Ar), 7.66–7.73 (m, 2 H, Ar + HetAr), 2.49 (s, 3 H, Me). ¹³C NMR (75 MHz, DMSO-d ₆–TFA): δ = 163.8, 156.1, 153.2, 152.4, 151.0, 147.8, 139.9, 137.2, 136.3, 133.9, 132.6, 132.1, 131.6, 129.4, 124.2, 124.0, 122.4, 19.3. Anal. Calcd for C₁₉H₁₅ClN₈O: C, 56.09; H, 3.72; N, 27.54. Found: C, 56.31; H, 4.00; N, 27.72.