M. Zhu, et al.
Bioorganic&MedicinalChemistry28(2020)115719
J = 7.3 Hz, 2H), 2.33 (br s, 4H), 1.56 (br s, 4H), 1.16 (d,
J = 6.8 Hz, 6H); 13C NMR (101 MHz, DMSO–d6) δ 157.41, 155.72,
155.63, 149.13, 138.13, 135.39, 133.70, 133.10, 125.76, 125.00,
124.66, 120.93, 119.79, 110.08, 106.76, 99.98, 56.78, 55.26, 54.34,
53.53 (2C), 49.01, 23.55 (2C), 15.30 (2C).
5.1.10.3. 5-chloro-N2-(4-((2-((2-(dimethylamino)ethyl)(methyl)amino)
ethylsulfonyl)-2-methoxyphenyl)-N4
-(2-(isopropylsulfonyl)
phenyl)
pyrimidine-2,4-diamine(X-3). The product was isolated as a yellow
solid (63.6 mg, 57% yield). M.p.: 108–110 °C; MS (ESI) m/z: 625.3
[M + H]+;1H NMR (600 MHz, DMSO–d6) δ 9.56 (s, 1H), 8.50 (s, 1H),
8.49 (br d, 1H), 8.37 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.87 (dd,
J = 7.9, 1.4 Hz, 1H), 7.80–7.77 (m, 1H), 7.46 (d, J = 1.9 Hz, 2H),
7.45–7.42 (m, 1H), 7.39 (dd, J = 8.5, 1.8 Hz, 1H), 3.95 (s, 3H),
3.50–3.47 (m, 7H), 2.50–2.48 (m, 3H), 2.40–2.36 (m, 2H), 2.33 (br s,
2H), 2.17 (s, 6H), 2.10 (s, 3H), 1.16 (d, J = 6.8 Hz, 6H); 13C NMR
(151 MHz, DMSO–d6) δ 157.29, 155.64, 155.52, 149.06, 138.03,
135.32, 133.68, 132.85, 131.37, 125.67, 124.94, 124.60, 120.82,
119.67, 109.89, 106.70, 56.71, 56.63, 55.16, 53.81, 52.36, 50.69,
45.32 (2C), 41.99, 15.21 (2C).
5.1.10.8. 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)–N2-(2-methoxy-4-
((2-thiomorpholinoethyl)sulfonyl)phenyl)pyrimidine-2,4-diamine(X-
8). The product was isolated as a white solid (84.9 mg, 77% yield).
M.p.: 177–180 °C; MS (ESI) m/z: 626.3[M + H]+;1H NMR (600 MHz,
DMSO–d6) δ 9.55 (s, 1H), 8.50 (s, 1H), 8.50 (d, J = 9.8 Hz, 1H), 8.37 (s,
1H), 8.19 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.79 (t,
J = 7.8 Hz, 1H), 7.46–7.45 (m, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.49 (br
d, 1H), 3.53 (t, J = 7.0 Hz, 2H), 3.48–3.44 (m, 1H), 3.34 (br s, 4H),
2.58 (t, J = 7.0 Hz,2H), 2.24 (s, 4H), 1.16 (d, J = 6.8 Hz, 6H); 13C NMR
(151 MHz, DMSO–d6) δ 157.33, 155.63, 155.54, 149.05, 138.02,
135.33, 133.55, 133.33, 131.35, 125.64, 124.92, 124.58, 120.84,
119.69, 109.99, 106.65, 66.24, 56.70 (2C), 55.15, 53.03, 52.40 (2C),
51.85, 15.21 (2C).
5.1.10.4. 2-((2-((4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)
pyrimidin-2-yl)amino)-3-methoxyphenyl) Sulfonyl)ethyl)amino)acetamide
(X-4). The product was isolated as a white solid (42.8 mg, 40%
yield). M.p.: 102–105 °C; MS (ESI) m/z: 597.2 [M + H]+; 1H NMR
(600 MHz, DMSO–d6) δ 9.55 (s, 1H), 8.50 (s, 1H), 8.49 (d, J = 8.4 Hz,
1H), 8.37 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.87 (dd, J = 8.0, 1.5 Hz,
1H), 7.79–7.77 (m, 1H), 7.46–7.42 (m, 2H), 7.37 (dd, J = 8.5, 1.9 Hz,
1H), 7.25 (s, 1H), 7.03 (s, 1H), 3.95 (s, 3H), 3.49–3.44 (m, 3H), 3.01 (s,
2H), 2.75 (t, J = 6.9 Hz, 2H), 1.16 (d, J = 6.8 Hz, 6H); 13C NMR
(151 MHz, DMSO–d6) δ 173.48, 157.29, 155.64, 155.53, 149.12,
138.01, 135.33, 133.73, 132.62, 131.36, 125.69, 124.97, 124.64,
120.78, 119.80, 109.86, 106.69, 56.69, 55.43, 55.15, 51.79, 43.16,
15.22 (2C).
5.1.10.9. 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)–N2-(2-methoxy-4-
((2-(4-methylpiperazin-1-yl)ethyl)sulfonyl)phenyl)pyrimidine-2,4-diamine
(X-9). The product was isolated as a white solid (82.3 mg, 74% yield).
M.p.: 84–87 °C; MS (ESI) m/z: 623.7 [M + H]+;1H NMR (600 MHz,
DMSO–d6) δ 9.55 (s, 1H), 8.49 (d, J = 7.4 Hz, 1H), 8.49 (s, 1H), 8.37 (s,
1H), 8.19 (d, J = 8.5 Hz, 1H), 7.87 (dd, J = 7.9, 1.4 Hz, 1H), 7.87 (br t,
1H), 7.45 (s, 1H), 7.43 (br t, 1H), 7.38 (dd, J = 8.5, 1.8 Hz, 1H), 3.94
(s, 3H), 3.50 (t, J = 7.0 Hz, 2H), 3.48–3.43 (m, 1H), 2.57 (t,
J = 7.0 Hz,2H), 2.26 (br s, 4H), 2.13 (br s, 4H), 1.16 (d, J = 6.8 Hz,
6H); 13C NMR (151 MHz, DMSO–d6) δ 157.31, 155.62, 155.55, 149.01,
138.03, 135.32, 133.57, 133.18, 131.37, 125.63, 124.91, 124.58,
120.83, 119.62, 109.97, 106.65, 56.69, 55.16, 54.71 (2C), 52.69,
52.41 (2C), 51.40, 45.94, 15.22 (2C).
5.1.10.5. 2-((2-((4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)
pyrimidin-2-yl)amino)-3-methoxyphenyl)sulfonyl)ethyl)(methyl)amino)
ethan-1-ol(X-5). The product was isolated as an off-white solid
(42.8 mg, 40% yield). M.p.: 128–130 °C; MS (ESI) m/z: 598.6
[M + H]+;1H NMR (400 MHz, DMSO–d6) δ 9.55 (s, 1H), 8.49 (br d,
1H), 8.48 (s, 1H), 8.37 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.87 (dd,
J = 8.0, 1.4 Hz, 1H), 7.78 (br t, 1H), 7.46–7.42 (m, 2H), 7.38 (dd,
J = 8.5, 1.8 Hz, 1H), 4.29 (t, J = 5.3 Hz, 1H), 3.95 (s, 3H), 3.49–3.42
(m, 3H), 3.37 (q, J = 6.0 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.36 (t,
J = 6.1 Hz, 2H), 2.11 (s, 3H), 1.16 (d, J = 6.8 Hz, 6H); 13C NMR
(101 MHz, DMSO–d6) δ 157.39, 155.74, 155.63, 149.14, 138.12,
135.40, 133.75, 133.04, 131.45, 125.80, 125.04, 124.69, 120.86,
119.76, 109.98, 106.79, 59.20, 59.09, 56.81, 55.26, 52.73, 50.93,
42.27, 15.30 (2C).
5.1.10.10. 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)–N2-(2-methoxy-4-
((2-(4-methylpiperidin-1-yl)ethyl)sulfonyl)phenyl)pyrimidine-2,4-diamine
(X-10). The product was isolated as a white solid (90.3 mg, 81% yield).
M.p.: 197–200 °C; MS (ESI) m/z: 622.3 [M + H]+;1H NMR (400 MHz,
DMSO–d6) δ 9.55 (s, 1H), 8.49 (d, J = 8.3 Hz, 1H), 8.48 (s, 1H), 8.36 (s,
1H), 8.19 (d, J = 8.5 Hz, 1H), 7.87 (dd, J = 7.9, 1.4 Hz, 1H), 7.81–7.76
(m, 1H), 7.46–7.41 (m, 2H), 7.37 (dd, J = 8.5, 1.8 Hz, 1H), 3.94 (s,
40H), 3.50–3.43 (m, 3H), 2.64 (d, J = 11.3 Hz, 2H), 2.55 (t,
J = 7.3 Hz, 2H), 1.79 (br t, J = 10.6 Hz, 2H), 1.42 (d, J = 11.3 Hz,
2H), 1.23 (br s, 1H), 1.16 (d, J = 6.8 Hz, 6H), 0.92–0.82 (qd, J = 12.0,
11.6, 2.8 Hz, 46H), 0.77 (d, J = 6.5 Hz, 3H).
5.1.10.6. 2-((2-((4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)
pyrimidin-2-yl)amino)-3-methoxyphenyl)sulfonyl)ethyl)amino)ethan-1-ol
(X-6). The product was isolated as an off-white solid (74.3 mg, 71%
yield). M.p.: 180–185 °C; MS (ESI) m/z: 584.6 [M + H]+;1H NMR
(400 MHz, DMSO–d6) δ 9.55 (br s, 1H), 8.50 (s, 1H), 8.49 (d,
J = 9.0 Hz, 1H), 8.37 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.87 (dd,
J = 7.9, 1.4 Hz, 1H), 7.78 (br t, 1H), 7.46–7.43 (m, 2H), 7.38 (dd,
J = 8.5, 1.8 Hz, 1H), 4.47 (br s, 1H), 3.95 (s, 3H), 3.50–3.42 (m, 3H),
3.38 (t, J = 5.5 Hz, 2H), 2.79 (t, J = 7.0 Hz, 2H), 2.51 (t, J = 5.5 Hz,
2H), 1.16 (d, J = 6.8 Hz, 6H); 13C NMR (101 MHz, DMSO–d6) δ 157.39,
155.73, 155.61, 149.23, 138.14, 135.39, 133.81, 132.81, 131.44,
125.78, 125.02, 124.68, 120.87, 119.89, 109.95, 106.80, 60.67,
56.79, 55.58, 55.26, 51.61, 43.33, 15.30 (2C).
5.1.10.11. 5-chloro-N2-(4-((2-(4-ethylpiperazin-1-yl)ethyl)sulfonyl)-2-
methoxyphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine
(X-11). The product was isolated as an off-white solid (46.7 mg, 41%
yield). M.p.: 81–85 °C; MS (ESI) m/z: 637.7[M + H]+;1H NMR
(400 MHz, DMSO–d6) δ δ 9.55 (s, 1H), 8.49 (d, J = 9.8 Hz, 1H),
8.48 (s, 1H), 8.37 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.87 (dd, J = 7.9,
1.4 Hz, 1H), 7.81–7.77 (m, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.38 (dd,
J = 8.5, 1.6 Hz, 1H), 3.94 (s, 1H), 3.43–3.51 (m, 2H), 2.57 (t,
J = 7.1 Hz, 1H), 2.33–2.08 (m, 10H), 1.16 (d, J = 6.8 Hz, 6H), 0.90
(t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, DMSO–d6) δ 157.42, 155.72,
155.64, 149.11, 138.13, 135.41, 133.68, 133.31, 131.46, 125.74,
124.98, 124.67, 120.92, 119.71, 110.09, 106.77, 56.80, 55.28, 52.82,
52.68 (2C), 52.45 (2C), 51.93, 51.53, 15.31 (2C), 12.27.
5.1.10.7. 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)–N2-(2-methoxy-4-
((2-(pyrrolidin-1-yl)ethyl)sulfonyl)phenyl)pyrimidine-2,4-diamine(X-
7). The product was isolated as a white solid (61.7 mg, 58% yield).
M.p.: 153–155 °C; MS (ESI) m/z: 594.6 [M + H]+;1H NMR (400 MHz,
DMSO–d6) δ 9.56 (s, 1H), 8.51 (s, 1H), 8.49 (d, J = 9.0 Hz, 1H), 8.37 (s,
1H), 8.19 (d, J = 8.5 Hz, 1H), 7.87 (dd, J = 8.0, 1.4 Hz, 1H), 7.81–7.77
(m, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.46–7.42 (m, 1H), 7.39 (dd,
J = 8.5, 1.8 Hz, 1H), 3.94 (s, 3H), 3.52–3.43 (m, 3H), 2.67 (t,
5.1.11. Ethyl 2-((3-methoxy-4-nitrophenyl)thio)acetate(12)
Using intermediate 5-fluoro-2-nitroanisole (17.1 g, 0.1 mol) and
ethyl mercaptoacetate (50 mL) as starting materials, a light yellow solid
was obtained according to the preparation method of intermediate 7
(21.1 g, 78% yield).
8