14
X. Zhao et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
(20 mL) was degassed with nitrogen for 5 min, followed by addi-
tion Na2CO3 (106 mg, 2 M in water) under continuous flow of
nitrogen. The reaction mixture was stirred at 100 °C for 2 h, and
the catalyst was removed by filtration through Celite. The filtrate
was concentrated to a residue and the residue product was purified
on a silica gel column using DCM/CH3OH (20:1, v/v) as eluent to
afford 16a (241 mg, 75.2%) as a gray solid. Mp:180.1–182.3 °C;
MS (ESI) m/z 648.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6): d 8.66
(d, J = 1.80 Hz, 1H), 8.53 (s, 1H), 8.06 (s, 1H), 7.61–7.48 (m, 3H),
7.44 (d, J = 7.60 Hz, 1H), 7.41–7.29 (m, 3H), 7.27–7.21 (m, 2H),
7.00–6.96 (d, J = 2.40 Hz, 1H), 6.58 (d, J = 7.44 Hz, 1H), 4.77 (dd,
J = 4.04 Hz, 4.16 Hz, 1H), 4.53 (t, J = 6.36 Hz, 2H), 4.43 (t,
J = 6.08 Hz, 2H), 4.39–4.29 (m, 1H), 4.25–4.17 (m, 1H), 3.59 (s,
3H), 2.77 (d, J = 7.24 Hz, 2H), 2.49–2.35 (m, 1H), 2.13–1.95 (m,
1H), 1.9–1.77 (m, 2H), 1.73–1.55 (m, 4H), 1.13–1.05 (m, 2H),
0.93–0.75 (m, 2H); 13C NMR (100 MHz, DMSO-d6): d 163.20,
160.60, 158.40, 156.51, 153.67, 151.75, 144.99, 141.53, 140.24,
140.77, 135.87, 135.79, 135.22, 132.51, 130.46, 130.26, 128.71,
127.89, 127.37, 118.30, 118.13, 117.90, 112.42, 110.75, 103.98,
74.72, 58.69, 56.91, 49.89, 37.45, 32.29, 15.40, 10.73, 10.70; HPLC
96.7%; HRMS (ESI) m/z calcd for C38H38FN5O4 [M+H]+ 648.2980,
found 648.2979.
4.1.66. 2-(3-(5-((5-(4-(Cyclopropanecarbonyl)piperazin-1-yl)
pyridin-2-yl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-
2-(hydroxymethyl)phenyl)-6-cyclopropyl-8-fluoroisoquinolin-
1(2H)-one (16d)
Using a method similar to that of 16a, compound 16d was syn-
thesized as a white solid (17 mg, 43.2%). Mp: 189.3–191.1 °C; MS
(ESI) m/z 661.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6): d 8.59–
8.58 (d, J = 2.12 Hz, 1H), 8.42 (s, 1H), 7.89–7.88 (d, J = 2.68 Hz,
1H), 7.54–7.52 (t, J = 7.88 Hz, 1H), 7.44–7.41 (m, 2H), 7.39–7.31
(m, 3H), 7.25–6.97 (m, 2H), 7.00–6.97 (d, J = 12.76 Hz, 1H), 6.60–
6.58 (d, J = 7.44 Hz, 1H), 4.78–4.76 (t, J = 8.48 Hz, 1H), 4.33–4.29
(dd, J = 4.24 Hz, J = 3.16 Hz, 1H), 4.21–4.11 (dd, J = 4.72 Hz,
J = 4.76 Hz, 1H), 3.79 (s, 4H), 3.58 (s, 3H), 3.07 (s, 4H), 2.08–2.00
(m, 2H), 1.11–1.08 (m, 2H), 0.93–0.83 (m, 2H), 0.74–0.70 (m,
4H); 13C NMR (100 MHz, DMSO-d6): d 171.01, 163.20, 160.60,
158.42, 156.54, 151.75, 149.05, 141.54, 140.62, 140.36, 140.17,
135.87, 135.22, 134.46, 130.58, 130.48, 128.68, 127.86, 127.66,
126.75, 118.30, 117.99, 116.78, 112.95, 111.94, 103.99, 56.89,
49.75, 49.12, 37.41, 15.40, 10.69, 10.19, 7.03; HPLC 95.7%; HRMS
(ESI) m/z calcd for C38H37FN6O4 [M+H]+ 661.2933, found 661.2938.
4.1.67. 1-Methyl-3-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)
amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-
2(1H)-one (16e)
4.1.64. 6-Cyclopropyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-
methyl-5-((5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)
amino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)isoquinolin-
1(2H)-one (16b)
Using a method similar to that of 16a, compound 16e was syn-
thesized as a white solid (63 mg, 57.1%). Mp: 170.4–173.2 °C; MS
(ESI) m/z 589.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6): d 8.58 (s,
1H), 8.36 (s, 1H), 8.12 (d, J = 8.40 Hz, 1H), 7.86 (s, 1H), 7.54 (dd,
J = 7.70 Hz, 7.80 Hz, 1H), 7.49–7.40 (d, 2H), 7.41–7.31 (m, 4H),
7.28 (d, J = 8.40 Hz, 1H), 7.22 (d, J = 9.00 Hz, 1H), 6.64 (d,
J = 7.40 Hz, 1H), 4.74 (s, 1H), 4.39–4.35 (m, 1H), 4.25–4.15 (m,
1H), 3.60 (s, 3H), 3.04 (s, 4H), 2.45 (s, 4H), 2.22 (s, 3H), 2.18–2.03
(m, 1H), 1.15–1.01 (m, 2H), 0.92–0.78 (m, 2H); 13C NMR
(100 MHz, DMSO-d6): d 161.80, 157.07, 149.93, 149.02, 142.29,
141.35, 140.93, 138.00, 136.32, 134.63, 134.39, 131.15, 130.96,
129.19, 128.20, 127.82, 127.46, 127.15, 125.09, 123.73, 122.58,
118.56, 117.06, 113.33, 105.19, 57.41, 54.92, 49.22, 46.13, 37.87,
15.93, 10.86, 10.82; HPLC 97.5%; HRMS (ESI) m/z calcd for
Using a method similar to that of 16a, compound 16b was
synthesized as
a white solid (98 mg, 63.2%). Mp: 179.5–
181.3 °C; MS (ESI) m/z 649.3 [M+H]+; 1H NMR (400 MHz,
DMSO-d6): d 8.57 (d, J = 1.48 Hz, 1H), 8.38 (s, 1H), 7.86 (d,
J = 2.44 Hz, 1H), 7.52–7.50 (m, 1H), 7.43 (d, J = 7.80 Hz, 1H),
7.38–7.24 (m, 4H), 7.26 (s, 1H), 7.22 (d, J = 9.04 Hz, 1H), 7.01 (d,
J = 13.08 Hz, 1H), 6.59 (d, J = 7.20 Hz, 1H), 4.77 (dd, J = 4.04 Hz,
4.48 Hz, 1H), 4.50 (dt, J = 6.28 Hz, 19.56 Hz, 2H), 4.31 (dd,
J = 3.84 Hz, 7.44 Hz, 2H), 4.20 (dd, J = 4.76 Hz, 11.20 Hz, 1H),
4.18 (dd, J = 4.76 Hz, 11.20 Hz, 1H), 3.59 (s, 3H), 3.51–3.40 (m,
1H), 3.06 (s, 4H), 2.38 (s, 4H), 2.15–2.03 (m, 1H), 1.20–1.01 (m,
2H), 0.92–0.81 (m, 2H); 13C NMR (100 MHz, DMSO-d6):
d
C
35H36N6O3 [M+H]+ 589.2849, found 589.2919.
163.18, 160.58, 158.45, 156.55, 151.80, 148.54, 141.51, 140.83,
140.33, 140.15, 135.83, 135.16, 133.86, 130.61, 130.48, 128.72,
127.82, 127.04, 126.66, 118.30, 118.09, 116.62, 112.85, 110.65,
104.06, 74.31, 58.40, 56.39, 48.86, 48.58, 37.42, 5.39, 10.72,
4.1.68. 2-Cyclopropyl-6-(2-(hydroxymethyl)-3-(1-methyl-5-((5-
(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-
dihydropyridin-3-yl)phenyl)-1,6-naphthyridin-5(6H)-one (16f)
Using a method similar to that of 16a, compound 16f was syn-
thesized as a white solid (33 mg, 65%). Mp: 167.3–170.8 °C; MS
(ESI) m/z 590.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6): d 8.59 (S,
1H), 8.41 (s, 1H), 8.38 (d, J = 3.10 Hz, 1H), 7.86 (d, J = 2.80 Hz,
1H), 7.65–7.50 (m, 2H), 7.51–7.42 (m, 2H), 7.41–7.31 (m, 3H),
7.22 (d, J = 9.00 Hz, 1H), 6.64 (d, J = 7.60 Hz, 1H), 4.81 (dd,
J = 4.10 Hz, 4.40 Hz, 1H), 4.33 (dd, J = 3.60 Hz, 11.10 Hz, 1H), 4.20
(dd, J = 4.60 Hz, 11.30 Hz, 1H), 3.60 (s, 3H), 3.05 (s, 4H), 2.45 (s,
4H), 2.40–2.27 (m, 1H), 2.22 (s, 3H), 1.20–1.05 (m, 4H); 13C NMR
(100 MHz, DMSO-d6): d 168.41, 161.40, 156.52, 150.25, 153.51,
148.56, 141.32, 140.81, 140.36, 137.82, 135.70, 135.44, 133.75,
130.62, 128.71, 127.76, 127.02, 126.64, 120.41, 119.02, 117.94,
116.52, 112.84, 106.11, 56.82, 54.41, 48.81, 45.64, 37.46, 17.52,
11.31, 11.22; HPLC 95.5%; HRMS (ESI) m/z calcd for C33H36N8O3
[M+H]+ 590.2801, found 590.2877.
10.70; HPLC 98.7%; HRMS (ESI) m/z calcd for
C37H37FN6O4
[M+H]+ 649.2933, found 649.2926.
4.1.65. 6-Cyclopropyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-
methyl-5-((5-(4-(1-methylazetidin-3-yl)piperazin-1-yl)pyridin-
2-yl)amino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)isoquinolin-
1(2H)-one (16c)
Using a method similar to that of 16a, compound 16c was syn-
thesized as a white solid (51 mg, 50.2%). Mp: 230.4–232 °C; MS
(ESI) m/z 662.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6): d 8.56
(s, 1H), 8.36 (s, 1H), 7.85 (s, 1H), 7.53 (t, J = 7.64 Hz, 1H), 7.43
(d, J = 7.24 Hz, 1H), 7.40–7.28 (m, 4H), 7.26 (s, 1H), 7.21 (d,
J = 9.12 Hz, 1H), 6.98 (d, J = 13.08 Hz, 1H), 6.60 (d, J = 7.00 Hz,
1H), 4.77 (s, 1H), 4.37–4.29 (m, 1H), 4.25–4.15 (m, 1H), 3.59 (s,
4H), 3.35 (m, 1H), 3.03 (s, 4H), 2.88 (s, 3H), 2.35 (s, 4H), 2.27
(s, 3H), 2.12–2.03 (m, 1H), 1.15–1.03 (m, 2H), 0.93–0.82 (m,
2H); 13C NMR (100 MHz, DMSO-d6): d 163.25, 161.13, 158.88,
157.08, 152.10, 149.08, 142.03, 141.39, 140.91, 140.71, 136.39,
135.71, 134.43, 131.21, 131.01, 129.22, 128.35, 127.53, 127.14,
118.82, 118.60, 117.10, 113.39, 111.08, 104.56, 60.54, 57.45,
54.90, 49.59, 49.12, 46.02, 37.90, 15.89, 11.13; HPLC 97.7%; HRMS
4.1.69. 6-Cyclopropyl-2-(2-(hydroxymethyl)-3-(1-methyl-5-((5-
(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-
dihydropyridin-3-yl)phenyl)-2,7-naphthyridin-1(2H)-one (16g)
Using a method similar to that of 16a, compound 16g was syn-
thesized as a white solid (63 mg, 58.0%). Mp: 149.6–151.3 °C; MS
(ESI) m/z 590.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6): d 9.20 (s,
1H), 8.59 (s, 1H), 8.40 (s, 1H), 7.84 (d, J = 2.20 Hz, 1H), 7.61–7.50
(ESI) m/z calcd for
C
38H40FN7O3 [M+H]+ 662.3177, found
662.3252.