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C.M. Grombein et al. / European Journal of Medicinal Chemistry 90 (2015) 788e796
126.2, 131.5, 133.3, 135.3, 135.7, 147.0, 147.7, 165.8. MS m/z 226.15
2H), 7.98 (d, 3J ¼ 8.2 Hz, 1H), 8.49 (dd, 3J ¼ 4.4 Hz, 4J ¼ 1.3 Hz, 1H),
8.82 (d, 4J ¼ 1.9 Hz, 1H), 9.14 (s, 1H). 13C NMR (125 MHz, DMSO-d6):
(MHþ).
d
¼ 42.5, 114.1, 118.9, 123.7, 124.2, 126.1, 129.6, 133.2, 135.1, 138.2,
4.1.9. 4-Methyl-6-(pyridin-3-yl)-3,4-dihydroquinoxalin-2(1H)-one
(6)
147.0, 147.7, 154.3. MS m/z 226.16 (MHþ).
Compound 6 was obtained according to general procedure A
using 6a (342 mg, 1.42 mmol) and 3-pyridineboronic acid (229 mg,
1.86 mmol) after flash chromatography (CH2Cl2/methanol 97/3)
and crystallization from acetone as pale yellow solid (55 mg,
0.23 mmol, 16%), mp > 300 ꢀC. 1H NMR (500 MHz, DMSO-d6):
4.1.14. 6-(Isoquinolin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (11)
Compound 11 was obtained according to general procedure B
using 10a (454 mg, 2.00 mmol) and 4-isoquinolineboronic acid
(450 mg, 2.60 mmol) after flash chromatography (CH2Cl2/methanol
95/5) and crystallization from ethanol as yellow solid (345 mg,
1.25 mmol, 63%), mp (decomp.) 221 ꢀC. 1H NMR (500 MHz, DMSO-
d
¼ 2.87 (s, 3H), 3.70 (s, 2H), 6.90 (d, 3J ¼ 7.9 Hz, 1H), 6.98 (s, 1H),
7.06 (d, 3J ¼ 7.9 Hz, 1H), 7.43 (dd, 3J ¼ 7.6 Hz, 3J ¼ 5.0 Hz, 1H), 8.02
(dd, 3J ¼ 7.6 Hz, 4J ¼ 1.6 Hz, 1H), 8.51 (d, 3J ¼ 4.7 Hz, 1H), 8.86 (d,
4J ¼ 2.2 Hz, 1H), 10.52 (s, 1H). 13C NMR (125 MHz, DMSO-d6):
d6):
d
¼ 4.41 (s, 2H), 6.88 (s, 1H), 6.96 (d, 3J ¼ 8.2 Hz, 1H), 7.29e7.30
(m, 2H), 7.72 (dd, 3J ¼ 3J ¼ 7.4 Hz, 1H), 7.79 (dd, 3J ¼ 3J ¼ 7.4 Hz, 1H),
7.90 (d, 3J ¼ 8.5 Hz, 1H), 8.20 (d, 3J ¼ 8.2 Hz, 1H), 8.40 (s, 1H), 9.20 (s,
d
¼ 36.8, 54.0, 109.7, 115.1, 117.0, 123.6, 127.4, 131.9, 133.6, 135.8,
1H), 9.30 (s, 1H). 13C NMR (125 MHz, DMSO-d6):
d
¼ 42.4, 113.7,
136.7, 147.3, 147.7, 165.9. MS m/z 240.0 (MHþ).
118.6, 124.1, 127.1, 127.3, 127.9, 128.0, 129.2, 133.2, 138.0, 141.4, 142.2,
147.0, 151.4, 151.5, 154.4. MS m/z 276.05 (MHþ).
4.1.10. 6-(Isoquinolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (7)
Compound 7 was obtained according to general procedure A
using 5a (340 mg, 1.5 mmol) and 4-isoquinolineboronic acid
(337 mg, 1.95 mmol) after flash chromatography (CH2Cl2/methanol
95/5) and crystallization from ethanol as yellow solid (148 mg,
0.54 mmol, 36%), mp > 300 ꢀC. 1H NMR (500 MHz, DMSO-d6):
4.1.15. 6-(Pyridin-3-yl)-1H-4,2,1-benzoxathiazine-2,2-dioxide (12)
Compound 12 was obtained according to general procedure B
using 12a (154 mg, 0.58 mmol) and 3-pyridineboronic acid (93 mg,
0.76 mmol) after flash chromatography (CH2Cl2/methanol 98/2) as
colorless solid (53 mg, 0.20 mmol, 35%), mp (decomp.) 214 ꢀC. 1H
d
¼ 3.82 (d, 4J ¼ 1.8 Hz, 2H), 6.14 (s, 1H), 6.75 (dd, 3J ¼ 7.9 Hz,
NMR (500 MHz, DMSO-d6):
d
¼ 5.23 (s, 2H), 6.95 (d, 3J ¼ 8.5 Hz,1H),
4J ¼ 1.6 Hz, 1H), 6.82 (d, 4J ¼ 1.8 Hz, 1H), 6.90 (d, 3J ¼ 7.9 Hz, 1H),
7.69e7.73 (m, 1H), 7.76e7.80 (m, 1H), 7.93 (d, 3J ¼ 8.5 Hz, 1H), 8.19
(d, 3J ¼ 8.2 Hz, 1H), 8.37 (s, 1H), 9.28 (s, 1H), 10.42 (s, 1H). 13C NMR
7.41e7.46 (m, 2H), 8.03 (d, 3J ¼ 7.9 Hz, 1H), 8.53 (dd, 3J ¼ 4.8 Hz,
4J ¼ 1.4 Hz, 1H), 8.85 (d, 4J ¼ 2.1 Hz, 1H). 13C NMR (125 MHz, DMSO-
d6):
d
¼ 76.6, 116.5, 120.5, 122.1, 123.9, 127.4, 132.6, 133.9, 134.5,
(125 MHz, DMSO-d6):
d
¼ 46.1, 114.4, 115.0, 119.2, 124.2, 126.0, 127.3,
142.5, 147.4, 148.4. MS m/z 262.92 (MHþ).
127.9, 127.9, 130.7, 130.7, 132.7, 133.2, 134.9, 142.0, 151.4, 165.9. MS
m/z 276.0 (MHþ).
4.1.16. 1-Methyl-6-(pyridin-3-yl)-1H-4,2,1-benzoxathiazine-2,2-
dioxide (13)
4.1.11. 6-(Pyridin-3-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one (8)
Compound 8 was obtained according to general procedure B
using 8a (342 mg, 1.50 mmol) and 3-pyridineboronic acid (240 mg,
1.95 mmol) after flash chromatography (CH2Cl2/methanol 97/3)
and crystallization from acetone as colorless solid (85 mg,
0.38 mmol, 25%), mp 211 ꢀC. Anal. C13H10N2O2 (C, H, N, O). 1H NMR
Compound 13 was obtained according to general procedure B
using 13a (46 mg, 0.52 mmol) and 3-pyridineboronic acid (84 mg,
0.68 mmol) after flash chromatography (CH2Cl2/methanol 99/1) as
off-white solid (103 mg, 0.37 mmol, 72%), mp 128 ꢀC. 1H NMR
(500 MHz, CDCl3):
d
¼ 3.34 (s, 3H), 5.01 (s, 2H), 7.06 (d, 3J ¼ 8.2 Hz,
1H), 7.29 (d, 4J ¼ 2.1 Hz, 1H), 7.33 (dd, 3J ¼ 8.4 Hz, 4J ¼ 2.0 Hz, 1H),
7.36 (ddd, 3J ¼ 7.9 Hz, 3J ¼ 4.9 Hz, 5J ¼ 0.6 Hz,1H), 7.82 (d, 3J ¼ 7.9 Hz,
1H), 8.59 (dd, 3J ¼ 4.8 Hz, 4J ¼ 1.5 Hz, 1H), 8.80 (d, 4J ¼ 1.8 Hz, 1H).
(500 MHz, DMSO-d6):
d
¼ 5.35 (s, 2H), 7.00 (d, 3J ¼ 8.2 Hz, 1H), 7.46
(dd, J ¼ 8.2 Hz, 3J ¼ 4.7 Hz, 1H), 7.61 (s, 1H), 7.64 (dd, 3J ¼ 8.0 Hz,
4J ¼ 2.0 Hz, 1H), 8.00e8.02 (m, 1H), 8.53 (dd, 3J ¼ 4.7 Hz, 4J ¼ 1.6 Hz,
1H), 8.85 (d, 4J ¼ 1.9 Hz, 1H), 10.29 (s, 1H). 13C NMR (125 MHz,
3
13C NMR (125 MHz, CDCl3):
d
¼ 31.6, 76.6, 117.1, 118.7, 122.5, 123.6,
129.9, 134.0, 134.2, 134.8, 143.4, 148.0, 148.8. MS m/z 276.93 (MHþ).
DMSO-d6):
d
¼ 67.4, 114.2, 119.2, 122.9, 123.7, 125.1, 127.2, 131.0,
133.4, 136.4, 147.1, 148.0, 151.5. MS m/z 227.32 (MHþ).
4.1.17. 6-(Isoquinolin-4-yl)-1H-4,2,1-benzoxathiazine-2,2-dioxide
(14)
4.1.12. 6-(Isoquinolin-4-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one (9)
Compound 9 was obtained according to general procedure B
using 8a (255 mg, 1.12 mmol) and 4-isoquinolineboronic acid
(232 mg, 1.34 mmol) after flash chromatography (CH2Cl2/methanol
98/2) and crystallization from acetone as colorless solid (74 mg,
0.27 mmol, 24%), mp 215 ꢀC. Anal. C17H12N2O2 (C, H, N, O). 1H NMR
Compound 14 was obtained according to general procedure B
using 12a (169 mg, 0.64 mmol) and 4-isoquinolineboronic acid
(144 mg, 0.83 mmol) after flash chromatography (CH2Cl2/methanol
98/2) as off-white solid (30 mg, 0.10 mmol, 15%), mp (decomp.)
213 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d
¼ 5.30 (s, 2H), 7.02 (d,
3J ¼ 8.2 Hz, 1H), 7.23 (dd, 3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz, 1H), 7.27 (d,
4J ¼ 1.6 Hz,1H), 7.74 (ddd, 3J ¼ 3J ¼ 7.5 Hz, 4J ¼ 1.2 Hz, 1H), 7.81 (ddd,
3J ¼ 3J ¼ 7.6 Hz, 4J ¼ 1.5 Hz,1H), 7.87 (dd, 3J ¼ 8.5 Hz, 4J ¼ 0.9 Hz,1H),
(500 MHz, DMSO-d6):
d
¼ 5.38 (s, 2H), 7.08 (d, 3J ¼ 8.2 Hz, 1H), 7.41
(s, 1H), 7.44 (dd, 3J ¼ 8.2 Hz, 4J ¼ 1.9 Hz, 1H), 7.72e7.75 (m, 1H),
7.78e7.81 (m, 1H), 7.88 (d, 3J ¼ 8.5 Hz, 1H), 8.21 (d, 3J ¼ 8.2 Hz, 1H),
8.41 (s, 1H), 9.32 (s, 1H), 10.34 (s, 1H). 13C NMR (125 MHz, DMSO-
8.22 (d, 3J ¼ 8.2 Hz, 1H), 8.42 (s, 1H), 9.34 (s, 1H), 10.84 (s, 1H). 13
C
NMR (125 MHz, DMSO-d6):
d
¼ 76.4, 119.3, 119.9, 123.8, 125.1, 127.0,
d6):
d
¼ 67.4, 113.8, 118.9, 124.0, 125.9, 127.4, 127.9, 128.0, 130.2,
127.4, 127.9, 128.0, 131.1, 131.2, 131.6, 133.0, 141.9, 142.3, 151.9. MS m/
130.2, 131.0, 131.8, 133.1, 136.3, 142.3, 151.6, 151.7. MS m/z 277.18
z 313.01 (MHþ).
(MHþ).
4.1.18. 6-(Pyridin-3-yl)-3,4-dihydrobenzothiazin-4-one-2,2-dioxide
(15)
4.1.13. 6-(Pyridin-3-yl)-3,4-dihydroquinazolin-2(1H)-one (10)
Compound 10 was obtained according to general procedure B
using 10a (341 mg,1.50 mmol) and 3-pyridineboronic acid (221 mg,
1.80 mmol) after flash chromatography (CH2Cl2/methanol 93/7) as
colorless solid (331 mg, 1.47 mmol, 98%), mp (decomp.) 170 ꢀC. 1H
Compound 15a (273 mg, 0.75 mmol) and 10% Pd/C (273 mg)
were refluxed in 10 ml methanol overnight under a hydrogen at-
mosphere. The suspension was filtered over charcoal and the sol-
vent evaporated. Purification by flash chromatography (CH2Cl2/
methanol 97/3) afforded 15 as colorless solid (33 mg, 0.12 mmol,
NMR (500 MHz, DMSO-d6):
d
¼ 4.39 (s, 2H), 6.86 (s, 1H), 6.88 (d,
3J ¼ 8.8 Hz, 1H), 7.43 (dd, 3J ¼ 7.7 Hz, 3J ¼ 4.9 Hz, 1H), 7.49e7.51 (m,
16%), mp (decomp.) 172 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d
¼ 4.85