Y. Chen et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
7
4.2.3. General procedure for the synthesis of 7a–j
A mixture of 6 (0.65 mmol), ( )-2,20-bis(diphenylphosphino)-
1,10-binaphthyl
(41 mg, 0.065 mmol), Pd(OAc)2 (8 mg,
(151 MHz, DMSO)
d
158.01, 150.52, 147.28, 136.83, 131.96,
131.88, 130.88, 129.33, 129.14, 128.88, 127.80, 124.81, 122.28,
111.69, 111.56, 106.00, 105.83, 105.65, 96.93, 81.00, 67.73, 59.53,
58.29, 53.61, 46.92, 42.56, 20.46. HRMS (ESI): [M+H]+: 539.3100.
HPLC: (Method B) tR = 5.61 min.
0.0325 mmol), K2CO3 (0.18 g, 1.30 mmol) and corresponding
propargyl amino compound (0.78 mmol) in anhydrous DMF
(10 mL) was heated at 100 °C under argon for 16 h. The reaction
mixture was cooled to room temperature, filtered, and quenched
with water (100 mL). The mixture was extracted with EtOAc
(4 ꢀ 50 mL), the organic layer was combined and washed with
brine (15 mL). The organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated. The resulting mixture was purified by
MPLC (ISCO CombiFlash purification system) (MeOH/DCM, eluted
from 0% to 10%). The fractions were collected, concentrated to
afford 7a–7k.
4.2.3.5. N-(5-(4-(3-(Dicyclohexylamino)prop-1-yn-1-yl)quinolin-
6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
(7e). The compound 7e was obtained according to general proce-
dure using 6b and N-cyclohexyl-N-(prop-2-yn-1-yl)cyclohex-
anamine. Yellow solid; mp > 226 °C. 1H NMR (600 MHz, CDCl3) d
8.86 (d, J = 4.1 Hz, 1H), 8.35 (d, J = 1.0 Hz, 1H), 8.23 (d, J = 2.3 Hz,
1H), 8.17 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.92–7.80 (m,
2H), 7.48 (d, J = 4.1 Hz, 1H), 7.05–6.77 (m, 2H), 3. 96 (s, 3H), 3.89
(s, 2H), 2.88 (d, J = 6.3 Hz, 2H), 1.94 (d, J = 10.9 Hz, 4H), 1.76 (d,
J = 11.0 Hz, 4H), 1.63–1.48 (m, 2H), 1.42–1.35 (m, 4H), 1.30–1.23
(m, 4H), 1.17–1.08 (m, 2H). 13C NMR (151 MHz, CDCl3) d 154.48,
149.97, 147.49, 141.12, 135.79, 132.52, 130.63, 130.48, 130.29,
128.86, 128.24, 127.57, 124.24, 123.72, 120.39, 111.91, 111.76,
105.85, 105.68, 105.51, 93.69, 79.36, 57.78, 54.07, 35.99, 31.27,
26.17, 26.06. HRMS (ESI): [M+H]+: 645.2724. HPLC: (Method A)
tR = 10.15 min.
4.2.3.1.
N-(5-(4-(3-(Dimethylamino)prop-1-yn-1-yl)quinolin-
6-yl)-2-methoxypyridin-3-yl)-4-fluorobenzenesulfonamide
(7a). The compound 7a was obtained according to general proce-
dure using 6a and N,N-dimethylprop-2-yn-1-amine. White solid;
mp: 158–162 °C. 1H NMR (300 MHz, CDCl3) d 8.88 (d, J = 4.4 Hz,
1H), 8.41 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.22–8.11 (m,
2H), 7.90 (dd, J = 8.7, 1.8 Hz, 1H), 7.84 (dd, J = 8.7, 5.0 Hz, 2H),
7.54 (d, J = 4.4 Hz, 1H), 7.14 (m, 2H), 3.89 (s, 3H), 3.71 (s, 2H),
2.49 (s, 6H). 13C NMR (151 MHz, CDCl3) d 167.13, 163.73, 154.40,
150.01, 147.57, 140.88, 135.79, 135.12, 130.81, 130.19, 130.00,
129.87, 128.83, 128.11, 127.43, 124.59, 123.47, 120.99, 116.56,
116.26, 95.21, 81.21, 54.10, 48.81, 44.40. HRMS (ESI): [M+H]+:
491.1555. HPLC: (Method A) tR = 7.12 min.
4.2.3.6. 2,4-Difluoro-N-(2-methoxy-5-(4-(3-(piperidin-1-yl)-
prop-1-yn-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide
(7f). The compound 7f was obtained according to general proce-
dure using 6b and 1-(prop-2-yn-1-yl)piperidine. White solid; mp:
200–204 °C. 1H NMR (300 MHz, CDCl3) d 8.87 (d, J = 4.5 Hz, 1H),
8.39 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 8.7 Hz,
1H), 8.12 (d, J = 2.2 Hz, 1H), 7.93–7.82 (m, 2H), 7.53 (d, J = 4.5 Hz,
1H), 7.01–6.89 (m, 2H), 3.96 (s, 3H), 3.72 (s, 2H), 2.77–2.61 (m,
4H), 1.74–1.65 (m, 4H), 1.53–1.42 (m, 2H). 13C NMR (151 MHz,
CDCl3) d 154.53, 149.97, 147.51, 141.02, 135.72, 132.52, 130.71,
130.14, 129.95, 128.74, 128.12, 127.54, 124.44, 123.58, 120.48,
111.97, 111.83, 105.87, 105.70, 105.54, 95.82, 80.95, 54.09, 53.59,
48.67, 25.89, 23.82. HRMS (ESI): [M+H]+: 549.1772. HPLC: (Method
A) tR = 7.72 min.
4.2.3.2. N-(5-(4-(3-(Dimethylamino)prop-1-yn-1-yl)quinolin-6-
yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
(7b). The compound 7b was obtained according to general pro-
cedure using 6b and N,N-dimethylprop-2-yn-1-amine. White
solid; mp: 153–161 °C. 1H NMR (300 MHz, CDCl3) d 8.89 (d,
J = 4.5 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H),
8.20 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.97–7.84 (m, 2H),
7.56 (d, J = 4.5 Hz, 1H), 7.02–6.91 (m, 2H), 3.99 (s, 3H), 3.73 (s,
2H), 2.51 (s, 6H). 13C NMR (151 MHz, CDCl3) d 154.43, 149.98,
147.54, 140.92, 135.79, 132.56, 130.77, 130.13, 129.81, 128.82,
128.08, 127.29, 124.56, 123.45, 120.55, 112.10, 111.75, 106.08,
105.75, 105.40, 95.16, 81.21, 54.15, 48.81, 44.39. HRMS (ESI): [M
+H]+: 509.1460. HPLC: (Method B) tR = 5.69 min.
4.2.3.7. 2,4-Difluoro-N-(2-methoxy-5-(4-(3-(4-methylpiperidin-
1-yl)prop-1-yn-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfon-
amide (7g). The compound 7g was obtained according to
general procedure using 6b and 4-methyl-1-(prop-2-yn-1-yl)
piperidine. White solid; mp: 186–188 °C. 1H NMR (300 MHz,
CDCl3) d 8.87 (d, J = 4.5 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.25 (d,
J = 2.2 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H),
7.94–7.82 (m, 2H), 7.53 (d, J = 4.5 Hz, 1H), 7.01–6.89 (m, 2H),
3.97 (s, 3H), 3.75 (s, 2H), 3.05 (d, J = 11.2 Hz, 2H), 2.42 (t,
J = 10.6 Hz, 2H), 1.74 (d, J = 9.5 Hz, 2H), 1.36 (m, 3H), 0.95 (d,
J = 5.7 Hz, 3H). 13C NMR (151 MHz, CDCl3) d 154.58, 149.95,
147.49, 141.06, 135.70, 132.52, 130.69, 130.12, 129.95, 128.73,
128.11, 127.64, 124.38, 123.57, 120.47, 111.95, 111.81, 105.86,
105.69, 105.52, 95.88, 80.96, 54.06, 53.03, 48.30, 34.21, 30.27,
21.80. HRMS (ESI): [M+H]+: 563.1931. HPLC: (Method A)
tR = 8.91 min.
4.2.3.3.
N-(5-(4-(3-(Diethylamino)prop-1-yn-1-yl)quinolin-6-
yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
(7c). The compound 7c was obtained according to general proce-
dure using 6b and N,N-diethylprop-2-yn-1-amine. White solid;
mp: 103–109 °C. 1H NMR (300 MHz, CDCl3) d 8.81 (d, J = 4.4 Hz,
1H), 8.32 (br s, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.96–7.69 (m, 3H),
7.47 (d, J = 4.4 Hz, 1H), 6.81 (br s, 2H), 3.91 (s, 3H), 3.82 (s, 2H),
2.69 (q, J = 7.1 Hz, 4H), 1.14 (t, J = 7.1 Hz, 6H). 13C NMR (151 MHz,
CDCl3) d 160.55, 158.93, 155.10, 149.66, 147.27, 136.24, 132.20,
132.14, 130.42, 130.20, 129.99, 128.88, 128.09, 124.36, 123.21,
111.57, 111.43, 105.60, 105.43, 105.25, 95.37, 80.87, 53.97, 47.57,
41.74, 12.65. HRMS (ESI): [M+H]+: 537.1780. HPLC: (Method A)
tR = 7.71 min.
4.2.3.8. 2,4-Difluoro-N-(2-methoxy-5-(4-(3-(2-methylpiperidin-
1-yl)prop-1-yn-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfon-
amide (7h). The compound 7h was obtained according to
general procedure using 6b and 2-(methyl(prop-2-yn-1-yl)
amino)ethanol. White solid; mp: 192–196 °C. 1H NMR (300 MHz,
CDCl3) d 8.87 (d, J = 4.5 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.25 (d,
J = 2.3 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H),
7.91–7.80 (m, 2H), 7.53 (d, J = 4.5 Hz, 1H), 7.00–6.89 (m, 2H),
4.11 (d, J = 17.8 Hz, 1H), 3.96 (s, 3H), 3.74 (d, J = 17.8 Hz, 1H),
2.98 (d, J = 11.9 Hz, 1H), 2.74–2.49 (m, 2H), 1.81–1.60 (m, 4H),
1.33 (dd, J = 20.6, 12.1 Hz, 2H), 1.22 (d, J = 6.2 Hz, 3H). 13C NMR
4.2.3.4.
2,4-Difluoro-N-(5-(4-(3-((2-hydroxyethyl)(methyl)-
amino)prop-1-yn-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)
benzenesulfonamide (7d). The compound 7d was obtained
according to general procedure using 6b and N-cyclohexyl-N-
(prop-2-yn-1-yl)cyclohexanamine. White solid; mp: 102–108 °C.
1H NMR (300 MHz, CDCl3) d 8.85 (d, J = 4.0 Hz, 1H), 8.36 (s, 1H),
8.22–8.13 (m, 2H), 8.07 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.50 (d,
J = 3.5 Hz, 1H), 6.91 (dd, J = 9.6, 4.2 Hz, 2H), 3.95 (s, 3H), 3.81 (s,
2H), 3.77–3.68 (m, 2H), 2.88–2.74 (m, 2H), 2.51 (s, 3H). 13C NMR