B. Kuppast et al. / European Journal of Medicinal Chemistry 78 (2014) 1e9
7
4.1.6.12. N4-(2-bromo-4-isopropylphenyl)-N6,N6-diethyl-2-methyl-5-
(methylthio)pyrimidine-4,6-diamine (12). Yield: semisolid (76.7%);
J ¼ 8.6 Hz, 1H), 7.41 (d, J ¼ 2.0 Hz, 1H), 7.19 (dd, J ¼ 2.0, 8.6 Hz, 1H),
3.95 (t, J ¼ 6.0 Hz, 4H), 3.63 (t, J ¼ 6.0 Hz, 4H), 3.36 (s, 6H), 2.86 (spt,
J ¼ 6.8 Hz,1H), 2.67 (q, J ¼ 7.4 Hz, 2H), 2.42 (s, 3H),1.24 (d, J ¼ 6.8 Hz,
1H NMR (400 MHz, CDCl3)
d
8.88 (s, 1H), 8.55 (d, J ¼ 8.6 Hz, 1H), 7.41
(d, J ¼ 2.0 Hz,1H), 7.19 (dd, J ¼ 2.0, 8.6 Hz,1H), 3.69 (q, J ¼ 7.1 Hz, 4H),
6H),1.19 (t, J ¼ 7.4 Hz, 3H); 13C NMR (400 MHz, CDCl3)
d 164.9,164.6,
2.86 (spt, J ¼ 6.9 Hz, 1H), 2.42 (s, 3H), 2.20 (s, 3H), 1.26 (t, J ¼ 7.0 Hz,
162.4, 144.0, 135.5, 130.0, 126.0, 121.4, 113.9, 90.1, 71.2, 58.8, 51.0,
33.3, 29.2, 26.1, 23.9, 14.1; ESIeMS m/z: 497.23 (MHþ), 499.19
(MH þ 2þ).
6H) 1.20 (t, J ¼ 7.1 Hz, 6H); 13C NMR (400 MHz, CDCl3)
d 164.9,164.0,
161.8,143.9,135.7,130.0,126.0,121.5,114.1, 91.3, 44.7, 33.3, 26.1, 24.0,
18.6, 13.6; ESIeMS m/z: 423.19 (MHþ), 425.17 (MH þ 2þ).
4.1.6.19. N4-(2-bromo-4-isopropylphenyl)-N6-(cyclopropylmethyl)-
4.1.6.13. N4 -(2-bromo-4-isopropylphenyl)-N6 ,N6 -bis(2-
5-(ethylthio)-2-methyl-N6-propylpyrimidine-4,6-diamine
(19).
methoxyethyl)-2-methyl-5-(methylthio)pyrimidine-4,6-diamine (13).
Yield: semisolid (59.6%); 1H NMR (400 MHz, CDCl3)
d
8.91 (s, 1H),
Yield: semisolid (56%); 1H NMR (400 MHz, CDCl3)
d
8.90 (s, 1H),
8.59 (d, J ¼ 8.6 Hz, 1H), 7.41 (d, J ¼ 2.0 Hz, 1H), 7.19 (dd, J ¼ 1.8,
8.6 Hz, 1H), 3.74 (t, J ¼ 7.5 Hz, 2H), 3.53 (d, J ¼ 6.5 Hz, 2H), 2.86 (spt,
J ¼ 6.9 Hz, 1H), 2.66 (q, J ¼ 7.3 Hz, 2H), 2.43 (s, 3H), 1.67 (sxt,
J ¼ 7.5 Hz, 2H),1.25 (d, J ¼ 7.1 Hz, 6H), 1.17 (tquin, J ¼ 5.0, 6.8 Hz,1H),
1.19 (t, J ¼ 7.4 Hz, 3H), 0.90 (t, J ¼ 7.3 Hz, 3H), 0.51 (dt, J ¼ 2.0, 5.0 Hz,
8.53 (d, J ¼ 8.6 Hz, 1H), 7.41 (d, J ¼ 2.0 Hz, 1H), 7.19 (dd, J ¼ 2.0,
8.6 Hz, 1H), 3.96 (t, J ¼ 6.0 Hz, 4H), 3.65 (t, J ¼ 6.0 Hz, 4H), 3.37 (s,
6H), 2.87 (spt, J ¼ 6.9 Hz, 1H), 2.41 (s, 3H), 2.21 (s, 3H), 1.25 (d,
J ¼ 6.9 Hz, 6H); 13C NMR (400 MHz, CDCl3)
d 165.0, 163.9, 162.0,
144.1, 135.5, 130.0, 126.0, 121.6, 114.1, 91.7, 71.4, 58.8, 51.0, 33.3, 26.1,
2H), 0.25 (dt, J ¼ 2.0, 5.0 Hz, 2H); 13C NMR (400 MHz, CDCl3)
d 165.4,
23.9, 18.3; ESIeMS m/z: 483.2 (MHþ), 485.17 (MH þ 2þ).
164.8, 162.3, 143.8, 135.7, 130.0, 126.0, 121.3, 113.8, 90.2, 55.2, 52.4,
33.3, 29.2, 26.2, 24.0, 21.3, 14.2, 11.3, 10.2, 3.7; ESIeMS m/z: 477.27
(MHþ), 479.21 (MH þ 2þ).
4.1.6.14. N4-(2-bromo-4-isopropylphenyl)-N6-(cyclopropylmethyl)-
2-methyl-5-(methylthio)-N6-propylpyrimidine-4,6-diamine
(14).
8.88 (s, 1H),
Yield: semisolid (68.4%); 1H NMR (400 MHz, CDCl3)
d
4.1.6.20. N4-(2-bromo-4-isopropylphenyl)-N6-butyl-N6-ethyl-5-(eth-
8.56 (d, J ¼ 8.6 Hz, 1H), 7.41 (d, J ¼ 2.0 Hz, 1H), 7.19 (dd, J ¼ 2.0,
8.6 Hz, 1H), 3.70 (t, J ¼ 7.5 Hz, 2H), 3.53 (d, J ¼ 6.8 Hz, 2H), 2.87 (spt,
J ¼ 6.9 Hz,1H), 2.42 (s, 3H), 2.21 (s, 3H),1.68 (sxt, J ¼ 7.5 Hz, 2H),1.25
(d, J ¼ 6.9 Hz, 6H), 1.17 (tquint, J ¼ 5.0, 6.8 Hz, 1H), 0.91 (t, J ¼ 7.4 Hz,
3H), 0.51 (dt, J ¼ 2.0, 5.0 Hz, 2H), 0.25 (dt, J ¼ 2.0, 5.0 Hz, 2H); 13C
ylthio)-2-methylpyrimidine-4,6-diamine
(20). Yield: semisolid
8.92 (s, 1H), 8.58 (d, J ¼ 8.6 Hz,
(59.6%); 1H NMR (400 MHz, CDCl3)
d
1H), 7.41 (d, J ¼ 2.0 Hz, 1H), 7.19 (dd, J ¼ 2.0, 8.6 Hz, 1H), 3.70 (q,
J ¼ 7.1 Hz, 2H), 3.60 (t, J ¼ 7.2 Hz, 2H), 2.86 (spt, J ¼ 6.9 Hz, 1H), 2.64
(q, J ¼ 7.3 Hz, 2H), 2.42 (s, 3H), 1.63 (quin, J ¼ 7.2 Hz, 2H), 1.34 (sxt,
J ¼ 7.3 Hz, 2H), 1.25 (d, J ¼ 6.9 Hz, 6H), 1.20 (t, J ¼ 7.1 Hz, 3H), 0.96
NMR (400 MHz, CDCl3)
d 164.9, 164.7, 161.9, 143.9, 135.7, 130.0,
126.0, 121.5, 114.0, 92.0, 55.2, 52.3, 33.3, 26.1, 23.9, 21.4, 18.4, 11.3,
(m, 6H); 13C NMR (400 MHz, CDCl3)
d 164.8, 164.8, 162.3, 143.7,
10.3, 3.7; ESIeMS m/z: 463.23 (MHþ), 465.19 (MH þ 2þ).
135.7, 130.0,126.0,121.3, 113.8, 89.7, 50.0, 45.5, 33.3, 30.4, 29.4, 26.2,
24.0, 20.2, 14.2, 14.0, 13.5; ESIeMS m/z: 465.25 (MHþ), 467.21
(MH þ 2þ).
4.1.6.15. N4-(2-bromo-4-isopropylphenyl)-N6-butyl-N6-ethyl-2-
methyl-5-(methylthio)pyrimidine-4,6-diamine (15). Yield: semisolid
(72%); 1H NMR (400 MHz, CDCl3)
d
8.88 (s, 1H), 8.54 (d, J ¼ 8.6 Hz,
4.1.6.21. N4-mesityl-5-(methylthio)-N6,N6-dipropylpyrimidine-4,6-
1H), 7.40 (d, J ¼ 2.0 Hz, 1H), 7.18 (dd, J ¼ 2.0, 8.6 Hz, 1H), 3.69 (q,
J ¼ 7.0 Hz, 2H), 3.60 (t, J ¼ 7.2 Hz, 2H), 2.85 (spt, J ¼ 6.9 Hz, 1H), 2.40
(s, 3H), 2.18 (s, 3H), 1.63 (quin, J ¼ 7.4 Hz, 2H), 1.34 (sxt, J ¼ 7.3 Hz,
2H), 1.25 (d, J ¼ 6.9 Hz, 6H), 1.18 (t, J ¼ 7.0 Hz, 3H), 0.95 (t, J ¼ 7.3 Hz,
diamine (21). Yield: off white solid (67.2%); MP: 83 ꢂC; 1H NMR
(400 MHz, CDCl3)
d 8.09 (s, 1H), 7.58 (s, 1H), 6.94 (s, 2H), 3.63 (t,
J ¼ 7.4 Hz, 4H), 2.29 (s, 3H), 2.26 (s, 3H), 2.19 (s, 6H), 1.70 (sxt,
J ¼ 7.5 Hz, 4H), 0.93 (t, J ¼ 7.4 Hz, 6H); 13C NMR (400 MHz, CDCl3)
3H); 13C NMR (400 MHz, CDCl3)
d
164.9, 164.1, 161.9, 143.8, 135.7,
d 163.8, 156.6, 136.4, 135.9, 133.6, 128.9, 91.6, 52.7, 21.4, 21.0, 18.6,
130.0, 126.0, 121.5, 114.0, 91.3, 49.9, 45.4, 33.3, 30.5, 26.1, 24.0, 20.2,
18.2, 11.3; ESIeMS m/z: 459.25 (MHþ).
18.6, 14.0, 13.6; ESIeMS m/z: 451.23 (MHþ), 453.20 (MH þ 2þ).
4.1.6.22. N4-mesityl-N6,N6-bis(2-methoxyethyl)-5-(methylthio)py-
4.1.6.16. N4-(2-bromo-4-isopropylphenyl)-5-(ethylthio)-2-methyl-
rimidine-4,6-diamine (22). Yield: light yellow solid (60.9%); MP:
N6,N6-dipropylpyrimidine-4,6-diamine
(16). Yield:
semisolid
89 ꢂC; 1H NMR (400 MHz, CDCl3)
d
8.08 (s, 1H), 7.59 (s, 1H), 6.94 (s,
2H), 3.96 (t, J ¼ 6.0 Hz, 4H), 3.66 (t, J ¼ 6.0 Hz, 4H), 3.37 (s, 6H), 2.29
(s, 3H), 2.27 (s, 3H), 2.18 (s, 6H); 13C NMR (400 MHz, CDCl3)
163.9,
(66.4%); 1H NMR (400 MHz, CDCl3)
d
8.93 (s, 1H), 8.58 (d, J ¼ 8.6 Hz,
1H), 7.40 (d, J ¼ 2.0 Hz, 1H), 7.18 (dd, J ¼ 2.0, 8.6 Hz, 1H), 3.59 (t,
J ¼ 7.3 Hz, 4H), 2.86 (spt, J ¼ 6.9 Hz,1H), 2.64 (q, J ¼ 7.5 Hz, 2H), 2.42 (s,
3H),1.66 (sxt, J ¼ 7.3 Hz, 4H),1.24 (d, J ¼ 6.9 Hz, 6H),1.18 (t, J ¼ 7.4 Hz,
d
163.6, 156.6, 136.6, 135.9, 129.0, 92.0, 71.4, 58.9, 51.0, 21.0, 18.5; ESIe
MS m/z: 391.54 (MHþ).
3H), 0.90 (t, J ¼ 7.3 Hz, 6H); 13C NMR (400 MHz, CDCl3)
d 164.8,164.8,
162.3,143.7,135.8,130.0,126.0,121.2,113.8, 89.6, 52.8, 33.3, 29.5, 26.2,
4.1.6.23. N4-(cyclopropylmethyl)-N6-mesityl-5-(methylthio)-N4-pro-
24.0, 21.4, 14.1, 11.3; ESIeMS m/z: 465.24 (MHþ), 467.20 (MH þ 2þ).
pylpyrimidine-4,6-diamine (23). Yield: white solid (75.4%); MP:
85 ꢂC; 1H NMR (400 MHz, CDCl3)
d 8.12 (s, 1H), 7.56 (s, 1H), 6.94 (s,
4.1.6.17. N4-(2-bromo-4-isopropylphenyl)-N6,N6-diethyl-5-(ethyl-
thio)-2-methylpyrimidine-4,6-diamine (17). Yield: semisolid (54%);
1H NMR (400 MHz, CDCl3) d d 8.91 (s, 1H), 8.57 (d, J ¼ 8.6 Hz, 1H),
7.41 (d, J ¼ 2.0 Hz, 1H), 7.19 (dd, J ¼ 2.0, 8.6 Hz, 1H), 3.68 (q,
J ¼ 7.1 Hz, 4H), 2.86 (spt, J ¼ 6.9, 1H), 2.65 (q, J ¼ 7.4 Hz, 2H), 2.43 (s,
3H), 1.28 (d, J ¼ 6.9 Hz, 6H), 1.26 (t, J ¼ 7.1 Hz, 6H), 1.18 (t, J ¼ 7.4 Hz,
2H), 3.70 (t, J ¼ 7.3 Hz, 2H), 3.53 (d, J ¼ 6.5 Hz, 2H), 2.30 (s, 3H), 2.27
(s, 3H), 2.20 (s, 6H),1.71 (sxt, J ¼ 7.4, 2H),1.20 (tquin, J ¼ 12.5, 6.5 Hz,
1H), 0.94 (t, J ¼ 7.3 Hz, 3H), 0.52 (dt, J ¼ 6.5, 12.6 Hz, 2H), 0.26 (dt,
J ¼ 6.5, 12.6 Hz, 2H); 13C NMR (400 MHz, CDCl3)
d 164.4, 163.8,
156.6, 136.5, 135.9, 133.5, 129.0, 92.3, 55.2, 52.2, 21.3, 21.0, 18.6, 17.9,
11.3, 10.2, 3.7; ESIeMS m/z: 371.29 (MHþ).
3H); 13C NMR (400 MHz, CDCl3)
d 164.9, 162.3, 143.8, 135.7, 130.0,
126.0, 121.3, 113.9, 89.7, 44.8, 33.3, 29.4, 26.2, 24.0, 14.2, 13.5; ESIe
4.1.6.24. N4-butyl-N4-ethyl-N6-mesityl-5-(methylthio)pyrimidine-
MS m/z: 437.4 (MHþ), 439.20 (MH þ 2þ).
4,6-diamine (24). Yield: off white solid (73.8%); MP: 57 ꢂC; 1H NMR
(400 MHz, CDCl3)
d 8.10 (s, 1H), 7.57 (s, 1H), 6.94 (s, 2H), 3.70 (q,
4.1.6.18. N4-(2-bromo-4-isopropylphenyl)-5-(ethylthio)-N6,N6-bis(2-
J ¼ 7.1 Hz, 2H), 3.60 (t, J ¼ 7.5 Hz, 2H), 2.31 (s, 3H), 2.23 (s, 3H), 2.20
(s, 6H), 1.67 (quin, J ¼ 7.5 Hz, 2H), 1.36 (sxt, J ¼ 7.5 Hz, 2H), 1.24 (t,
J ¼ 7.1 Hz, 3H), 0.97 (t, J ¼ 7.4 Hz, 3H); 13C NMR (400 MHz, CDCl3)
methoxyethyl)-2-methylpyrimidine-4,6-diamine (18). Yield: semi-
solid (69.4%); 1H NMR (400 MHz, CDCl3)
d 8.92 (s, 1H), 8.56 (d,