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9
(dd, J = 9.0, 2.4 Hz, 1H), 7.63 (t, J = 7.5 Hz 1H), 7.13 (d, J = 8.4 Hz,
1H), 6.91 (d, J = 7.5 Hz, 1H), 6.81–6.74 (m, 2H), 6.64 (d, J = 9.0 Hz,
1H), 4.71 (s, 2H), 4.10–4.07 (m, 2H), 3.99–3.96 (m, 2H),3.89 (t,
J = 6.0 Hz, 2H), 2.94 (t, J = 6.0 Hz, 2H), 2.48 (s, 3H). 13C NMR
(125 MHz, DMSO-d6) d: 165.0, 159.8, 157.6, 156.9, 152.2, 149.4,
138.7, 137.6, 136.7, 127.9, 126.3, 119.1, 118.0, 114.0, 113.3,
112.0, 105.6, 69.9, 60.0, 46.2, 42.4, 28.7, 24.0. MS (ESI): m/z 405
(M+H)+, 403 (MÀH)À.
compound 7a (74 mg, 0.5 mmol) and compound 11a (125 mg,
0.5 mmol) in the presence of potassium carbonate (207 mg,
1.5 mmol) to afford compound 3b (146 mg, 41%) as a light yellow
solid purified by flash column chromatography (EtOAc/hex-
ane = 1:1). IR (cmÀ1): 1677 (CO). Mp 142–143 °C. 1H NMR
(300 MHz, CDCl3) d: 9.92 (s, 1H), 8.98 (s, 1H), 8.21 (d, J = 6.0 Hz,
1H), 8.04 (s, 1H), 7.63 (t, J = 9.0 Hz, 1H), 7.15–7.12 (m, 1H), 7.08–
7.04 (m, 2H), 6.91 (d, J = 6.0 Hz, 1H), 4.81 (s, 2H), 3.95 (t,
J = 6.0 Hz, 2H), 2.99 (t, J = 6.0 Hz, 2H), 2.50 (s, 3H), 3.35 (s, 3H).
13C NMR (125 MHz, CDCl3) d: 162.5, 156.9, 154.9, 150.7, 143.2,
138.5, 136.7, 134.6, 132.1, 129.8, 128.8, 127.4, 127.3, 126.4,
118.9, 110.6, 46.2, 42.3, 28.7, 24.1, 21.0. MS (ESI): m/z 360 (M+H)+.
5.2.1.7.
2-(5-((6-Methylpyridin-2-yl)carbamoyl)pyridin-2-yl)-
1,2,3,4-tetrahydroisoquinolin-6-yl 4-methylbenzenesulfonate
(1g). The procedure described for the synthesis of compound
1a was used with compound 8f (321 mg, 0.94 mmol) and com-
pound 6 (232 mg, 0.94 mmol) in the presence of potassium carbon-
ate (338 mg, 2.8 mmol) to afford compound 1g (93 mg, 19%) as a
yellow solid purified by flash column chromatography (EtOAc/hex-
ane = 1:2). IR (cmÀ1): 1673 (CO). Mp 150–152 °C. 1H NMR
(300 MHz, CDCl3) d: 8.80 (d, J = 3.0 Hz 1H), 8.38 (br s, 1H), 8.15
(d, J = 9.0 Hz 1H), 8.04 (dd, J = 9.0, 3.0 Hz, 1H), 7.74–7.72 (m, 2H),
7.62 (t, J = 6.0 Hz, 1H), 7.32 (d, J = 9.0 Hz, 2H),7.11 (d, J = 9.0 Hz,
1H), 6.90–6.88 (m, 2H), 6.78–6.75 (m, 1H), 6.67 (d, J = 9.0 Hz,
1H), 4.77 (s, 2H), 3.88 (t, J = 6.0 Hz, 2H), 2.93 (t, J = 6.0 Hz, 2H),
2.48 (s, 3H), 2.46 (s, 3H). 13C NMR (125 MHz, CDCl3) d: 164.2,
159.6, 156.7, 150.9, 148.3, 148.0, 145.3, 138.7, 136.6, 132.5,
129.7, 128.4, 127.6, 122.1, 120.2, 119.1, 118.1, 111.0, 105.3, 46.3,
42.1, 28.8, 23.9, 21.7. MS (ESI): m/z 515 (M+H)+.
5.2.2.3.
5-(6-Methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-(6-
methylpyridin-2-yl)pyrazine-2-carboxamide (3c). The proce-
dure described for the synthesis of compound 3a was used with
compound 7b (82 mg, 0.5 mmol) and compound 11a (125 mg,
0.5 mmol) in the presence of potassium carbonate (207 mg,
1.5 mmol) to afford compound 3c (84 mg, 21%) as a yellow solid
purified by flash column chromatography (EtOAc/hexane = 1:1).
IR (cmÀ1): 3371 (NH), 1670 (CO). Mp 143–144 °C. 1H NMR
(300 MHz, CDCl3) d: 9.92 (s, 1H), 8.99 (s, 1H), 8.20 (d, J = 6.0 Hz,
1H), 8.03 (s, 1H), 7.63 (t, J = 9.0 Hz, 1H), 7.13 (t, J = 3.0 Hz, 1H),
6.91 (d, J = 6.0 Hz, 1H), 6.83–6.75 (m, 2H), 4.78 (s, 2H), 3.95 (t,
J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.00 (t, J = 6.0 Hz, 2H), 2.50 (s, 3H).
13C NMR (125 MHz, CDCl3) d: 162.5, 158.5, 156.9, 154.9, 150.7,
143.2, 138.51, 136.0, 132.1, 127.5, 127.4, 125.3, 124.8, 118.9,
113.2, 112.6, 110.6, 55.3, 45.9, 42.2, 29.0, 24.1. MS (ESI): m/z 376
(M+H)+.
5.2.1.8.
6-(6-Hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-
methylpyridin-2-yl)nicotinamide (1h). The procedure described
for the synthesis of compound 1a was used with compound 24
(345 mg, 1.5 mmol) and compound 6 (372 mg, 1.5 mmol) in the
presence of potassium carbonate (622 mg, 4.5 mmol) to afford
compound 1h (172 mg, 32%) as a yellow solid purified by flash col-
umn chromatography (EtOAc/hexane = 1:2). IR (cmÀ1): 3386 (NH),
1672 (CO). Mp 213–215 °C. 1H NMR (300 MHz, CDCl3) d: 8.75 (d,
J = 2.4 Hz 1H), 8.47 (br s, 1H), 8.16 (d, J = 8.4 Hz 1H), 7.98 (dd,
J = 9.0, 2.4 Hz, 1H), 7.64 (t, J = 7.8 Hz 1H), 7.08 (d, J = 8.4 Hz, 1H),
6.92 (d, J = 7.5 Hz, 1H), 6.75–6.70 (m, 2H), 6.62 (d, J = 9.0 Hz, 1H),
4.70 (s, 2H), 3.86 (t, J = 6.0 Hz, 2H), 2.90 (t, J = 6.0 Hz, 2H), 2.49 (s,
3H). 13C NMR (125 MHz, DMSO-d6) d: 165.0, 162.8, 159.8, 156.9,
156.2, 152.2, 149.4, 138.6, 137.5, 136.6, 127.8, 124.6, 119.1,
117.9, 114.9, 113.8, 112.0, 105.6, 46.2, 42.5, 36.2, 31.2, 28.65,
24.0. MS (ESI): m/z 361 (M+H)+, 359 (MÀH)À.
5.2.2.4. 5-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-
(6-methylpyridin-2-yl)pyrazine-2-carboxamide (3d). The pro-
cedure described for the synthesis of compound 3a was used
with 6,7-dimethoxy-1,2,3,4-tetra-hydroisoquinoline hydrochloride
(115 mg, 0.5 mmol) and compound 11a (125 mg, 0.5 mmol) in the
presence of potassium carbonate (207 mg, 1.5 mmol) to afford
compound 3d (100 mg, 49%) as a yellow solid purified by flash col-
umn chromatography (EtOAc/hexane = 1:2). IR (cmÀ1): 3366 (NH),
1680 (CO). Mp 188–189 °C. 1H NMR (300 MHz, CDCl3) d: 9.93 (s,
1H), 8.98 (s, 1H), 8.21 (d, J = 6.0 Hz, 1H), 8.05 (s, 1H), 7.63 (t,
J = 6.0 Hz, 1H), 6.91 (d, J = 6.0 Hz, 1H), 6.73 (s, 1H), 6.70 (s, 1H),
4.78 (s, 2H), 3.97 (t, J = 6.0 Hz, 2H), 3.89 (s, 6H), 2.94 (t, J = 6.0 Hz,
2H), 2.50 (s, 3H). 13C NMR (125 MHz, CDCl3) d: 162.5, 156.9,
155.0, 150.7, 148.0, 147.9, 143.2, 138.5, 132.2, 127.3, 126.6,
124.5, 119.0, 111.2, 110.6, 109.3, 56.0, 56.03, 56.00, 46.2, 42.3,
28.1, 24.1. MS (ESI): m/z 406 (M+H)+.
5.2.2. Synthesis compounds 3a–l
5.2.2.1. 5-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-(6-methylpyri-
din-2-yl)pyrazine-2-carboxamide (3a). 1,2,3,4-Tetra-hydroiso-
quinoline (67 mg, 0.5 mmol), compound 11a (125 mg, 0.5 mmol),
and potassium carbonate (207 mg, 1.5 mmol) were added to N,N-
dimethylformamide, and the mixture was stirred at 100 °C for
12 h. After the reaction was completed, the mixture was extracted
with EtOAc, washed with water, brine, and dried over Na2SO4. The
organic phase was concentrated in vacuo. The residues were puri-
fied by flash column chromatography (EtOAc/hexane = 1:3) to give
compound 3a (90 mg, 52%) as a white solid. IR (cmÀ1): 1677 (CO).
Mp 173–174 °C. 1H NMR (300 MHz, CDCl3) d: 9.92 (s, 1H), 8.99 (s,
1H), 8.21 (d, J = 6.0 Hz, 1H), 8.05 (s, 1H), 7.63 (t, J = 9.0 Hz, 1H),
7.26–7.21 (m, 4H), 6.91 (d, J = 6.0 Hz, 1H), 4.85 (s, 2H), 3.97 (t,
J = 6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.50 (s, 3H). 13C NMR
(125 MHz, CDCl3) d: 162.5, 156.9, 154.9, 150.7, 143.2, 138.5,
134.8, 132.9, 132.2, 128.2, 127.3, 127.0, 126.7, 126.5, 119.0,
110.6, 46.4, 42.3, 28.7, 24.1. MS (ESI): m/z 346 (M+H)+.
5.2.2.5.
5-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-(pyridin-2-yl)
pyrazine-2-carboxamide (3e). The procedure described for the
synthesis of compound 3a was used with 1,2,3,4-tetra-hydroiso-
quinoline (40 mg, 0.3 mmol) and compound 11b (70 mg,
0.3 mmol) in the presence of potassium carbonate (124 mg,
0.9 mmol) to afford compound 3e (72 mg, 72%) as a white solid
purified by flash column chromatography (EtOAc/hexane = 1:1).
IR (cmÀ1): 3359 (NH), 1669 (CO). Mp 161–163 °C. 1H NMR
(300 MHz, CDCl3) d: 10.00 (s, 1H), 9.00 (s, 1H), 8.43–8.40 (m, 1H),
8.35–8.33 (m, 1H), 8.07 (s, 1H), 7.78–7.72 (m, 1H), 7.26–7.23 (m,
4H), 7.05–7.03 (m, 1H), 4.86 (s, 2H), 3.97 (t, J = 6.0 Hz, 2H), 3.04
(t, J = 6.0 Hz, 2H). 13C NMR (125 MHz, CDCl3) d: 162.6, 155.0,
151.4, 148.0, 143.2, 138.2, 134.8, 132.9, 132.1, 128.3, 127.4,
127.0, 126.7, 126.5, 119.5, 113.8, 46.4, 42.3, 28.7. MS (ESI): m/z
332 (M+H)+.
5.2.2.2.
5-(6-Methyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(6-
5.2.2.6. 5-(6-Methyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(pyri-
din-2-yl)pyrazine-2-carboxamide (3f). The procedure described
for the synthesis of compound 3a was used with compound 7a
methylpyridin-2-yl)pyrazine-2-carboxamide (3b). The proce-
dure described for the synthesis of compound 3a was used with