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X. Xu et al. / European Journal of Medicinal Chemistry 192 (2020) 112196
1H), 7.71 (d, J ¼ 6.8 Hz, 1H), 7.56 (d, J ¼ 11.2 Hz, 1H), 5.29 (s, 2H),
(t, J ¼ 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, DMSO‑d6):
d 178.3, 172.2,
3.26-3.24 (m, 2H), 1.54-1.48 (m, 2H), 1.38-1.33 (m, 2H), 0.93 (t,
165.8, 153.9, 135.9, 134.4,133.8, 133.6, 131.1, 129.6,129.2,129.1, 127.1,
126.2, 123.8, 114.7, 57.9, 56.3, 54.4, 46.0, 34.5, 29.6, 15.2 ppm. HRMS
(ESI): m/z, calcd for C21H16F3N5O2S [M - H]-, 458.0977; found:
458.0956. HPLC: tR ¼ 18.549 min, 96.2% purity.
J ¼ 10.7 Hz, 3H) ppm. 13C NMR (75 MHz, DMSO‑d6):
d 177.8, 171.6,
162.3, 159.2, 155.9, 153.4, 135.4, 135.3, 135.2, 133.1, 129.0, 128.7,
126.6, 123.6, 119.6, 116.3, 114.2, 57.1, 48.2, 45.0, 32.1, 29.0, 25.1,
24.6 ppm. HRMS (ESI): m/z, calcd for C25H21F4N5O2S [M - H]-,
530.1302; found: 530.1310. HPLC: tR ¼ 21.362 min, 99.2% purity.
5.1.23.10. 2-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-N-propyl-1-
oxo–3-thioxo-1,2,3,5,10,10a-hexahydroimidazo [1,5-b]isoquinoline-7-
carboxamide (30e). The title compound was prepared using 30b,
propylamine and following the general method. The crude material
was purified on a silica gel column, PE/EtOAc ¼ 6:1, affording yel-
low powder, 54% yield. m.p. 234e237 ꢀC. 1H NMR (300 MHz,
5.1.23.6. 2-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-fluoro-N-(2-
hydroxyethyl)-1-oxo-3-thioxo-1,2,3,5,10,10a-hexahydroimidazo [1,5-
b]isoquinoline-7-carboxamide (29h). The title compound was pre-
pared using 29b, 2-aminoethanol and following the general
method. The crude material was purified on a silica gel column, PE/
EtOAc ¼ 6:1, affording yellow powder, 65% yield. m.p. 247e251 ꢀC.
DMSO‑d6):
d 9.19 (s, 1H), 8.73 (s, 1H), 8.42 (s, 1H), 7.85 (s, 1H), 7.74
(d, J ¼ 7.9 Hz, 1H), 7.43 (d, J ¼ 8.0 Hz, 1H), 5.45 (d, J ¼ 17.6 Hz, 1H),
4.82 (dd, J ¼ 25.9, 12.2 Hz, 2H), 3.45-3.31 (m, 2H), 3.23 (d, J ¼ 6.1 Hz,
2H),1.6-1.46 (m, 2H), 0.91 (d, J ¼ 7.3 Hz, 3H) ppm. 13C NMR (75 MHz,
1H NMR (300 MHz, DMSO‑d6):
d 9.18 (s, 1H), 8.71 (s, 1H), 8.23 (s,
1H), 7.69 (d, J ¼ 6.8 Hz, 1H), 7.34 (d, J ¼ 11.2 Hz, 1H), 5.40 (d,
J ¼ 18.5 Hz, 1H), 4.77 (t, J ¼ 25.0 Hz, 3H), 3.50 (s, 2H), 3.34 (s, 4H)
DMSO‑d6):
d 178.2, 172.2, 166.0, 153.9, 135.9, 134.4, 133.9, 133.6,
ppm. 13C NMR (75 MHz, DMSO‑d6):
d
178.3,172.1,163.6,159.8,156.5,
131.1, 129.8, 129.6, 129.5, 129.2, 126.7, 126.2, 123.8, 120.1, 114.7, 57.9,
153.9, 136.4, 136.3, 135.9, 133.6, 129.5, 127.3, 123.2, 116.9, 114.7, 60.0,
57.5, 45.5, 42.5, 29.5 ppm. HRMS (ESI): m/z, calcd for C21H15F4N5O3S
[M - H]-, 492.0749; found: 492.0743. HPLC: tR ¼ 19.061 min, 99.5%
purity.
46.0, 41.4, 29.6, 22.8, 11.9 ppm. HRMS (ESI): m/z, calcd for
C
tR ¼ 18.552 min, 96.2% purity.
22H18F3N5O2S [M -
H]-, 472.1061; found: 472.1051. HPLC:
5.1.23.11. 2-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-N-butyl-1-
oxo-3-thioxo-1,2,3,5,10,10a-hexahydroimidazo [1,5-b]isoquinoline-7-
carboxamide (30f). The title compound was prepared using 30b,
butylamine and following the general method. The crude material
was purified on a silica gel column, eluant PE/EtOAc ¼ 6:1, affording
yellow powder, 63% yield. m.p. 191e194 ꢀC. 1H NMR (300 MHz,
5.1.23.7. 2-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-fluoro-N-(1-
hydroxypropan-2-yl)-1-oxo-3-thioxo-1,2,3,5,10,10a-hexahy-
droimidazo [1,5-b]isoquinoline-7-carboxamide (29i). The title com-
pound was prepared using 29b, 1-amino-2-propanol and following
the general method. The crude material was purified on a silica gel
column, PE/EtOAc ¼ 6:1, affording yellow powder, 62% yield. m.p.
DMSO‑d6):
d
9.19 (d, J ¼ 1.6 Hz, 1H), 8.73 (d, J ¼ 1.6 Hz, 1H), 8.40 (d,
188e193 ꢀC. 1H NMR (300 MHz, DMSO‑d6):
d
9.18 (s, 1H), 8.72 (s,
J ¼ 5.4 Hz, 1H), 7.85 (s, 1H), 7.74 (d, J ¼ 7.9 Hz, 1H), 7.43 (d, J ¼ 8.1 Hz,
1H), 5.45 (d, J ¼ 17.8 Hz, 1H), 4.95-4.66 (m, 2H), 3.47-3.31 (m, 4H),
1.52 (d, J ¼ 7.1 Hz, 2H),1.37-1.25 (m, 2H), 0.91 (t, J ¼ 7.3 Hz, 3H) ppm.
1H), 8.17 (s, 1H), 7.70 (d, J ¼ 6.9 Hz, 1H), 7.34 (d, J ¼ 11.3 Hz, 1H), 5.40
(d, J ¼ 17.7 Hz, 1H), 4.94-4.82 (m, 1H), 4.73 (d, J ¼ 17.6 Hz, 2H), 3.84-
3.69 (m, 2H), 3.22 (s, 3H), 1.09 (d, J ¼ 5.8 Hz, 3H) ppm. 13C NMR
13C NMR (75 MHz, DMSO‑d6):
d 177.7, 171.7, 165.5, 153.4, 135.4,
(75 MHz, DMSO‑d6):
d
171.6, 163.1, 159.3, 156.0, 153.4, 135.8, 135.7,
135.3, 133.9, 133.4, 131.1, 129.4, 129.2, 129.1, 127.1, 126.2, 123.8, 114.7,
135.4, 135.3, 133.1, 129.4, 128.8, 126.9, 123.3, 119.6, 116.4, 114.2, 64.9,
57.9, 56.3, 54.4, 46.0, 34.5, 29.6,15.2 ppm. HRMS (ESI): m/z, calcd for
57.1, 48.0, 46.8, 45.0, 29.0, 21.0 ppm. HRMS (ESI): m/z, calcd for
C23H20F3N5O2S [M -
H]-, 486.1217; found: 486.1227. HPLC:
C
22H17F4N5O3S [M
-
H]-, 506.0915; found: 506.0937. HPLC:
tR ¼ 18.565 min, 97.3% purity.
tR ¼ 19.507 min, 99.1% purity.
5.1.23.12. 2-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-N-cyclo-
5.1.23.8. 2-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-N-methyl-1-
oxo-3-thioxo-1,2,3,5,10,10a-hexahydroimidazo [1,5-b]isoquinoline-7-
carboxamide (30c). The title compound was prepared using 30b,
methylamine and following the general method. The crude mate-
rial was purified on a silica gel column, PE/EtOAc ¼ 6:1, affording
yellow powder, 80% yield. m.p. 228e233 ꢀC. 1H NMR (300 MHz,
hexyl-1-oxo-3-thioxo-1,2,3,5,10,10a-hexahydroimidazo
[1,5-b]iso-
quinoline-7-carboxamide (30g). The title compound was prepared
using 30b, cyclohexylamine and following the general method. The
crude material was purified on a silica gel column, PE/EtOAc ¼ 6:1,
affording yellow powder, 68% yield. m.p. 136e138 ꢀC. 1H NMR
(300 MHz, DMSO‑d6):
d
9.19 (d, J ¼ 1.4 Hz, 1H), 8.73 (d, J ¼ 1.5 Hz,
DMSO‑d6):
d
9.19 (d, J ¼ 1.6 Hz, 1H), 8.73 (d, J ¼ 1.6 Hz, 1H), 8.42 (d,
1H), 8.15 (d, J ¼ 7.9 Hz, 1H), 7.86 (s, 1H), 7.74 (d, J ¼ 7.6 Hz, 1H), 7.42
(d, J ¼ 8.1 Hz, 1H), 5.45 (d, J ¼ 17.7 Hz, 1H), 4.93-4.67 (m, 2H), 3.81
(d, J ¼ 2.9 Hz, 1H), 3.42-3.33 (m, 2H), 1.78 (m, 8H), 1.31 (s, 2H) ppm.
J ¼ 4.5 Hz, 1H), 7.84 (s, 1H), 7.73 (d, J ¼ 7.7 Hz, 1H), 7.43 (d, J ¼ 8.1 Hz,
1H), 5.44 (d, J ¼ 17.8 Hz, 1H), 4.96-4.72 (m, 2H), 3.82 (d, J ¼ 11.2 Hz,
2H), 2.79 (dd, J ¼ 4.5, 2.1 Hz, 3H) ppm. 13C NMR (75 MHz, DMSO‑d6):
13C NMR (75 MHz, DMSO‑d6):
d 177.8, 171.7, 166.6, 164.7, 153.4,
d
178.3, 172.2, 166.5, 153.9, 135.9, 134.4, 133.7, 133.6, 131.1, 129.6,
135.4, 133.8, 133.5, 133.1, 130.5, 129.4, 129.3, 129.0, 128.7, 126.8,
125.8, 114.2, 57.4, 53.9, 49.2, 45.5, 32.4, 29.1, 25.2, 24.8 ppm. HRMS
(ESI): m/z, calcd for C25H22F3N5O2S [M - H]-, 512.1446; found:
512.1415. HPLC: tR ¼ 18.470 min, 97.7% purity.
126.1, 114.7, 57.9, 54.4, 46.0, 29.6, 27.6, 26.7 ppm. HRMS (ESI): m/z,
calcd for C20H14F3N5O2S [M - H]-, 444.0720; found: 444.0761. HPLC:
tR ¼ 18.537 min, 96.3% purity.
5.1.23.9. 2-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-N-ethyl-1-
oxo-3-thioxo-1,2,3,5,10,10a-hexahydroimidazo [1,5-b]isoquinoline-7-
carboxamide (30d). The title compound was prepared using 30b,
ethylamine and following the general method. The crude material
was purified on a silica gel column, PE/EtOAc ¼ 6:1, affording yel-
low powder, 72% yield. m.p. 223e226 ꢀC. 1H NMR (300 MHz,
5.1.23.13. 2-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(2-
hydroxyethyl)-1-oxo-3-thioxo-1,2,3,5,10,10a-hexahydroimidazo [1,5-
b]isoquinoline-7-carboxamide (30h). The title compound was pre-
pared using 30b, 2-aminoethanol and following the general
method. The crude material was purified on a silica gel column, PE/
EtOAc ¼ 6:1, affording yellow powder, 71% yield. m.p. 122e125 ꢀC.
DMSO‑d6):
d
9.19 (s, 1H), 8.73 (s, 1H), 8.43 (s, 1H), 7.85 (s, 1H), 7.74
1H NMR (300 MHz, DMSO‑d6):
d 9.19 (s, 1H), 8.73 (s, 1H), 8.40 (t,
(d, J ¼ 7.9 Hz, 1H), 7.43 (d, J ¼ 7.9 Hz, 1H), 5.45 (d, J ¼ 17.7 Hz, 1H),
J ¼ 5.2 Hz,1H), 7.87 (s, 1H), 7.76 (d, J ¼ 8.1 Hz, 1H), 7.44 (d, J ¼ 8.0 Hz,
4.96-4.64 (m, 2H), 3.93 (d, J ¼ 25.4 Hz, 2H), 3.43-3.34 (m, 2H), 1.14
1H), 5.45 (d, J ¼ 17.6 Hz, 1H), 4.89 (dd, J ¼ 9.9, 6.7 Hz, 1H), 4.83-4.68