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Synlett 2014; 25(3): 343-348
DOI: 10.1055/s-0033-1340344
DOI: 10.1055/s-0033-1340344
letter
6-Carbohydrazonamidepurines: Convenient Precursors for 4,8-Disubstituted Pyrimido[5,4-d]pyrimidines
Further Information
Publication History
Received: 25 September 2013
Accepted after revision: 09 November 2013
Publication Date:
19 December 2013 (online)
![](https://www.thieme-connect.de/media/synlett/201403/lookinside/thumbnails/10.1055-s-0033-1340344-1.jpg)
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.
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References and Notes
- 1a Dye C. Nat. Rev. Microbiol. 2009; 7: 81
- 1b Tomioka H, Tatano Y, Yasumoto K, Shimizu T. Expert Rev. Respir. Med. 2008; 2: 455
- 2a Chhabria M, Jani M, Patel S. Mini-Rev. Med. Chem. 2009; 401
- 2b Showalter HD, Denny W. Tuberculosis 2008; 88: S3
- 2c Goldman R, Plumley KV, Laughon BE. Infect. Disord. Drug Targets 2007; 7: 73
- 2d Nguyen L, Thompson CJ. Trends Microbiol. 2006; 14: 304
- 2e Shi R, Itagaki N, Sugawara I. Mini-Rev. Med. Chem. 2007; 7: 1177
- 3a Ballell L, Field RA, Duncan K, Young RJ. Antimicrob. Agents Chemother. 2005; 2153
- 3b Nayyar A, Jain R. Curr. Med. Chem. 2005; 12: 1873
- 3c Tangallapally RP, Yendapally R, Daniels AJ, Lee RE. B. Curr. Top. Med. Chem. 2007; 7: 509
- 4 Bacelar AH, Carvalho MA, Proença MF. Eur. J. Med. Chem. 2010; 3234
- 5a Rewcastle GW, Bridges AJ, Fry DW, Rubin JR, Denny WA. J. Med. Chem. 1997; 40: 1820
- 5b Rewcastle GW, Denny WA, Showalter DH. Curr. Org. Chem. 2000; 4: 679
- 5c Al-Azmi A. J. Chem. Res., Synop. 2005; 8: 530
- 6a Sanghvi YS, Larson SB, Matsumoto SS, Nord LD, Smee DF, Willis RC, Avery TL, Robins RK, Revankar GR. J. Med. Chem. 1989; 32: 629
- 6b Curtin NJ, Barlow HC, Bowman KJ, Calvert AH, Davison R, Golding BT, Huang B, Loughlin PJ, Newell DR, Smith PG, Griffin RJ. J. Med. Chem. 2004; 47: 4905
- 6c Northen JS, Boyle FT, Clegg W, Curtin NJ, Edwards AJ, Griffin RJ, Golding BT. J. Chem. Soc., Perkin Trans. 1 2002; 108
- 6d El-Araby M, Pottorf RS, Player MR. Comb. Chem. High Throughput Screening 2004; 7: 413
- 7a Srivastava PC, Revankar GR, Robins RK, Rousseau RJ. J. Med. Chem. 1981; 24: 393
- 7b Cook PD, Berry DA. US Patent US4801698, 1989 ; Chem. Abstr. 1989, 109: 110861h
- 7c Mabry TE, Jones CD, Chou TS, Colacino JM, Grindey GB, Worzalla JF, Pearce HL. Nucleosides Nucleotides 1994; 13: 1125
- 7d Berman HM, Rousseau RJ, Mancuso RW, Kreishman GP, Robins RK. Tetrahedron Lett. 1973; 3099
- 7e Westover JD, Revankar GR, Robins RK, Madsen RD, Ogden JR, North JA, Mancuso RW, Rousseau RJ, Stephen EL. J. Med. Chem. 1981; 24: 941
- 7f Rao TS, Revankar GR. Nucleosides Nucleotides 1995; 14: 1601
- 7g Al-Azmi A, Kumari KA. Heterocycles 2009; 78: 2245
- 8 Al-Azmi A, Booth BL, Carpenter RA, Carvalho MA, Marrelec E, Pritchard RG, Proença MF. J. Chem. Soc., Perkin Trans. 1 2001; 2532
- 9 Carvalho MA, Esperança S, Esteves T, Proença MF. Eur. J. Org. Chem. 2007; 1324
- 10 Ribeiro A, Carvalho MA, Proença MF. Eur. J. Org. Chem. 2009; 4867
- 11 Mechanisms of Molecular Migration . Vol. 1. Thyagarajan BS. Interscience Publishers; USA: 1968: 209
- 12 Carvalho MA, Esteves TM, Proença MF, Booth BL. Org. Biomol. Chem. 2004; 1019
- 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.