W. Chen, X. Chen, D. Li et al.
European Journal of Medicinal Chemistry 223 (2021) 113677
with saturated sodium chloride solution (3 ꢀ 30 mL). The organic
phase was then separated, dried (Na2SO4), filtered, and concen-
trated to provide crude product. Then purified by column chro-
matography on silica gel using a common 2e10% MeOH/DCM
gradient to afford compounds 20-26.
54.34, 53.16, 50.61, 45.74, 45.01, 40.35, 40.08, 37.41, 36.37, 28.93,
25.43, 11.97, 11.91. HRMS (ESI): calcd. for m/z C29H38ClFN9O3 [M þ
H]þ 614.2765, found 614.2787. HPLC (80% methanol in water):
tR ¼ 4.383 min, 99.54%. Yield: 94.2%. m.p. 135e138 ꢂC.
4.1.5.6. 5-amino-2-chloro-4-fluoro-3-methyl-N-(2-(4-
methylpiperazin-1-yl)-5-(4-(4-methylpiperazine-1-carbonyl)-1H-
1,2,3-triazol-1-yl) phenyl) benzamide (25). 1H NMR (300 MHz,
4.1.5.1. 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-
methylpiperazin-1-yl) phenyl)-N,N-dimethyl-1H-1,2,3-triazole-4-
carboxamide (20). 1H NMR (300 MHz, DMSO‑d6)
d
9.59 (s, 1H),
DMSO‑d6)
d
9.50 (s,1H), 9.19 (s,1H), 8.64 (d, J ¼ 2.6 Hz,1H), 7.70 (dd,
9.18 (s, 1H), 8.63 (d, J ¼ 2.5 Hz, 1H), 7.71 (dd, J ¼ 8.6, 2.6 Hz, 1H), 7.42
J ¼ 8.7, 2.6 Hz, 1H), 7.43 (d, J ¼ 8.7 Hz, 1H), 6.89 (d, J ¼ 9.2 Hz, 1H),
5.54 (s, 2H), 4.02 (s, 2H), 3.68 (s, 2H), 2.95 (t, J ¼ 4.5 Hz, 4H), 2.55 (s,
4H), 2.41 (t, J ¼ 5.1 Hz, 4H), 2.32e2.24 (m, 6H), 2.24 (s, 3H). HRMS
(ESI): calcd. for m/z C27H34ClFN9O2 [M þ H]þ 570.2502, found
570.2505. HPLC (80% methanol in water): tR ¼ 4.415 min, 99.46%.
Yield: 70.2%. m.p. 117e120 ꢂC.
(d, J ¼ 8.6 Hz, 1H), 6.83 (d, J ¼ 9.2 Hz, 1H), 5.50 (s, 2H), 3.11 (br s,
10H), 3.02 (s, 3H), 2.70e2.69 (m, 4H), 2.24 (d, J ¼ 2.5 Hz, 3H). 13
C
NMR (75 MHz, DMSO‑d6)
d 165.45, 160.61, 150.76, 147.56, 143.96,
143.30, 135.56, 135.37, 133.06, 132.47, 132.42, 132.27, 126.02, 123.31,
123.08, 121.71, 117.04, 115.59, 114.72, 112.78, 112.70, 53.54, 49.40,
43.72, 38.19, 35.50, 28.94, 11.97, 11.91. HRMS (ESI): calcd. for m/z
C
24H29ClFN8O2 [M þ H]þ 515.2080, found 515.2103. HPLC (80%
4.1.5.7. 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-
methanol in water): tR ¼ 5.053 min, 99.06%. Yield: 78.4%. m.p. >
methylpiperazin-1-yl) phenyl)-N-(2-morpholinoethyl)-1H-1,2,3-
250 ꢂC.
triazole-4-carboxamide (26). 1H NMR (300 MHz, DMSO‑d6)
d 9.51
(s, 1H), 9.24 (s, 1H), 8.66 (d, J ¼ 2.4 Hz, 1H), 8.56 (t, J ¼ 5.8 Hz, 1H),
7.71 (dd, J ¼ 8.7, 2.6 Hz, 1H), 7.43 (d, J ¼ 8.7 Hz, 1H), 6.89 (d,
J ¼ 9.2 Hz, 1H), 5.54 (s, 2H), 3.58 (t, J ¼ 4.6 Hz, 4H), 3.44 (s, 2H), 2.96
(t, J ¼ 4.8 Hz, 4H), 2.59 (s, 4H), 2.54 (s, 2H), 2.44 (s, 4H), 2.30 (s, 3H),
4.1.5.2. 5-amino-2-chloro-4-fluoro-3-methyl-N-(2-(4-
methylpiperazin-1-yl)-5-(4-(morpholine-4-carbonyl)-1H-1,2,3-
triazol-1-yl) phenyl) benzamide (21). 1H NMR (300 MHz, DMSO‑d6)
d
9.61 (s, 1H), 9.24 (s, 1H), 8.64 (d, J ¼ 2.5 Hz, 1H), 7.73 (dd, J ¼ 8.6,
2.26 (d, J ¼ 2.6 Hz, 3H). 13C NMR (75 MHz, DMSO‑d6)
d 165.15,
2.6 Hz, 1H), 7.44 (d, J ¼ 8.7 Hz, 1H), 6.86 (d, J ¼ 9.2 Hz, 1H), 5.52 (s,
2H), 4.06 (s, 2H), 3.68 (s, 6H), 3.12 (br s, 8H), 2.69 (s, 3H), 2.26 (d,
J ¼ 2.6 Hz, 3H). HRMS (ESI): calcd. for m/z C26H31ClFN8O3 [M þ H]þ
557.2186, found 557.2198. HPLC (100% methanol): tR ¼ 3.193 min,
95.82%. Yield: 67.5%. m.p. > 250 ꢂC.
159.24, 150.85, 147.65, 143.78, 143.60, 135.60, 135.41, 133.17, 132.24,
124.49, 123.39, 123.17, 121.17, 116.85, 115.58, 114.02, 112.95, 112.87,
66.10, 57.14, 54.41, 53.13, 50.71, 45.11, 36.39, 35.61, 28.94, 11.97,
11.91. HRMS (ESI): calcd. for m/z C28H36ClFN9O3 [M þ H]þ 600.2608,
found 600.2619. HPLC (80% methanol in water): tR ¼ 4.441 min,
99.07%. Yield: 72.5%. m.p. 195e197 ꢂC.
4.1.5.3. 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-
methylpiperazin-1-yl)
1,2,3-triazole-4-carboxamide (22). Brown oil. 1H NMR (300 MHz,
DMSO‑d6) 9.52 (s, 1H), 9.26e9.24 (m, 1H), 8.65 (s, 2H), 7.71 (d,
J ¼ 8.7 Hz, 1H), 7.42 (d, J ¼ 9.4 Hz, 1H), 6.89 (s, 1H), 5.53 (s, 2H), 4.06
(s, 1H), 3.9e3.86 (m, 2H), 2.99 (s, 6H), 2.71 (s, 4H), 2.38 (s, 3H), 2.25
(s, 3H), 1.71 (s, 4H). HRMS (ESI): calcd. for m/z C27H33ClFN8O3 [M þ
H]þ 571.2343, found 571.2358. HPLC (80% methanol in water):
tR ¼ 4.286 min, 99.60%. Yield: 82.9%.
phenyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-
4.1.6. Methyl-3'-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-
4'-(4-methylpiper-azin-1-yl)-[1, 10-biphenyl]-4-carboxylate (27)
To a solution of compounds 49 (0.55 mmol) in EA (50 mL) at
room temperature was added SnCl2.2H2O (0.5 g, 2.2 mmol). The
mixture was refluxed with vigorous stirring for 5 h, and subse-
quently cooled to room temperature. Following dilution with EA
(100 mL) and the mixture was neutralized with saturated sodium
bicarbonate solution. Then filtered and washed residue with EA
(5 ꢀ 40 mL), and the organic phase was dried (Na2SO4), filtered, and
concentrated to afford compounds 27. 1H NMR (300 MHz,
d
4.1.5.4. 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-
methylpiperazin-1-yl) phenyl)-N-(1-methylpiperidin-4-yl)-1H-1,2,3-
DMSO‑d6)
d
9.33 (s, 1H), 8.39 (s, 1H), 8.04 (d, J ¼ 8.4 Hz, 2H), 7.76 (d,
triazole-4-carboxamide (23). 1H NMR (300 MHz, DMSO‑d6)
d
9.48
J ¼ 8.3 Hz, 2H), 7.52 ((dd, J ¼ 8.3, 2.0 Hz, 1H), 7.32 (d, J ¼ 8.4 Hz, 1H),
6.88 (d, J ¼ 9.3 Hz, 1H), 5.50 (s, 2H), 3.87 (s, 3H), 2.89 (t, J ¼ 4.4 Hz,
4H), 2.49 (t, J ¼ 4.4 Hz, 4H), 2.25 (d, J ¼ 2.2 Hz, 3H), 2.19 (s, 3H).
HRMS (ESI): calcd. for m/z C27H29ClFN4O3 [M þ H]þ 511.1907, found
511.1913. HPLC (90% methanol in water): tR ¼ 6.036 min, 95.06%.
m.p. > 250 ꢂC.
(s, 1H), 9.22 (s, 1H), 8.65 (d, J ¼ 2.6 Hz, 1H), 8.52 (d, J ¼ 8.2 Hz, 1H),
7.70 (dd, J ¼ 8.5, 2.7 Hz, 1H), 7.42 (d, J ¼ 8.6 Hz, 1H), 6.89 (d,
J ¼ 9.2 Hz, 1H), 5.54 (s, 2H), 3.78 (s, 1H), 2.92 (t, J ¼ 4.6 Hz, 4H),
2.82e2.78 (m, 2H), 2.26 (d, J ¼ 2.7 Hz, 3H), 2.22 (s, 3H), 2.19 (s, 3H),
2.07e1.86 (m, 4H), 1.75e1.66 (m, 4H). 13C NMR (75 MHz, DMSO‑d6)
d
165.16, 158.86, 150.81, 147.61, 143.97, 143.51, 135.62, 135.44, 133.13,
132.16, 124.67, 123.66, 123.25, 121.69, 116.84, 113.93, 112.89, 54.52,
53.07, 50.91, 45.38, 44.42, 43.81, 40.32, 29.50, 12.00, 11.94. HRMS
(ESI): calcd. for m/z C28H36ClFN9O2 [M þ H]þ 584.2659, found
584.2665. HPLC (100% methanol): tR ¼ 3.221 min, 98.28%. Yield:
49.9%. m.p. 240e243 ꢂC.
4.1.6.1. Methyl-40-fluoro-30-nitro-[1, 10-biphenyl]-4-carboxylate (46).
Boronic acid (4.3 g, 24.1 mmol) was added to a solution of 4-bromo-
1-fluoro-2-nitrobenzene (4.4 g, 20.1 mmol) in dioxane (150 mL).
Then Cs2CO3 (13.1 g, 40.2 mmol) in water (15 mL) was added into
the mixture, follow by a small amount of Pd(PPh3)2Cl2. Removing
the gas in the reaction bottle and protected with N2, then the re-
action was heated to reflux for 20 h. The mixture was filtered to
remove catalytic agent and Cs2CO3, then purified by column chro-
matography on silica gel using a common 1e5% MeOH/DCM
gradient to afford compounds 46. 1H NMR (300 MHz, CDCl3)
4.1.5.5. 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-
methylpiperazin-1-yl) phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-
triazole-4-carboxamide (24). 1H NMR (300 MHz, DMSO‑d6)
d 9.51
(s, 1H), 9.22 (s, 1H), 8.85 (t, J ¼ 5.8 Hz, 1H), 8.66 (s, 1H), 7.71 (dd,
J ¼ 8.6, 2.7 Hz, 1H), 7.43 (d, J ¼ 8.8 Hz, 1H), 6.89 (d, J ¼ 9.2 Hz, 1H),
5.53 (s, 2H), 3.62 (t, J ¼ 4.6 Hz, 4H), 2.98e2.97 (m, 4H), 2.63 (s, 4H),
2.54 (s, 2H), 2.46e2.36 (m, 6H), 2.33 (s, 3H), 2.26 (d, J ¼ 2.6 Hz, 3H),
d
8.31e8.13 (m, 3H), 7.88e7.59 (m, 1H), 8.28 (m, 3H), 7.42e7.36 (m,
1H), 3.94 (s, 3H). m/z (EI-MS): 276.2 [M]þ. Yield: 74.2%. m.p.
145e147 ꢂC.
1.74e1.70 (m, 2H). 13C NMR (75 MHz, DMSO‑d6)
d 165.18, 159.22,
150.84, 147.64, 143.74, 135.59, 135.40, 133.16, 132.26, 124.41, 123.38,
123.16, 121.71, 116.82, 115.58, 114.02, 112.93, 112.85, 65.90, 56.22,
4.1.6.2. Methyl-4'-(4-methylpiperazin-1-yl)-30-nitro-[1, 10-biphenyl]-
4-carboxylate (47). To a solution of compounds 46 (13.8 mmol) in
14