Journal of Medicinal Chemistry
Article
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with vacuum and nitrogen. Tetrahydrofuran (1.0 mL) and water (0.26
mL) were added, and the reaction mixture was then heated for 24
hours at 85 °C before drying in vacuo. The crude product was then
purified by automated flash column chromatography (silica, 0−8%
methanol in dichloromethane) yielding the desired compound as an
HRMS-ESI (m/z): [M + H]+ calculated for C20H13N6 , 337.1196;
found, 337.1211.
4-(6-((5-Ethynylpyridin-3-yl)Ethynyl)-1H-Benzo[d]Imidazol-
1-yl)Pyrimidin-2-Amine (15). 4-(6-((5-((Triisopropylsilyl)-
ethynyl)pyridin-3-yl)ethynyl)-1H-benzo[d]imidazol-1-yl)pyrimidin-2-
amine 66 (80.0 mg and 0.162 mmol) in THF (1.8 mL) at 0 °C was
added, and TBAF (1 M in THF, 0.180 mL, and 0.180 mmol) was
reacted under the conditions described in general procedure A. The
remaining solid was purified by automated flash column chromatog-
raphy (silica, 0−10% methanol in dichloromethane) to yield the
desired compound as a white solid (22.0 mg, 65.4 μmol, and 41%);
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off-white solid (20.0 mg, 59.1 μmol, 23%), m.p.: 190−192 °C. H-
NMR (500 MHz, CDCl3): δ 5.55 (dd, J = 1.5, 10.7 Hz, 1H), 6.34
(dd, J = 1.5, 17.4 Hz, 1H), 6.81−6.91 (m, 1H), 7.19 (d, J = 5.6 Hz,
2H), 7.22 (s, 1H), 7.32 (d, J = 5.5 Hz, 1H), 7.47 (dd, J = 1.5, 5.0 Hz,
1H), 7.72 (t, J = 1.2 Hz, 1H), 7.84 (dd, J = 0.7, 8.3 Hz, 1H), 8.40 (d, J
= 5.5 Hz, 1H), 8.62 (dd, J = 0.8, 4.9 Hz, 1H), 8.92 (dd, J = 0.7, 1.7
Hz, 1H), 9.20 (s, 1H) ppm. 13C-NMR (126 MHz, DMSO-d6): δ 86.9,
95.1, 98.4, 117.4, 119.7, 120.4, 120.8, 123.5, 124.6, 127.8, 131.6,
132.0, 136.8, 144.3, 145.5, 150.3, 155.8, 157.2, 161.0, 164.0 ppm.
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m.p. 248−249 °C. H-NMR (500 MHz, DMSO-d6): δ 4.56 (s, 1H),
7.14 (s, 2H), 7.18 (d, J = 5.6, 1H), 7.57 (dd, J = 1.6, 8.3 Hz, 1H), 7.83
(dd, J = 0.7, 8.3 Hz, 1H), 8.15 (t, J = 2.0 Hz, 1H), 8.40 (d, J = 5.5 Hz,
1H), 8.70 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.90 (dd, J =
0.7, 1.6 Hz, 1H), 9.18 (s, 1H) ppm. 13C-NMR (126 MHz, DMSO-
d6): δ 80.0, 85.2, 85.5, 94.8, 98.3, 117.6, 119.2, 120.1, 120.3, 120.8,
127.6, 132.0, 141.3, 144.2, 145.4, 147.8, 151.6, 157.2, 161.0, 164.0
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HRMS-ESI (m/z): [M + H]+ calculated for C20H15N6 , 339.1353;
found, 339.1379.
4-(6-((4-Vinylpyridin-2-yl)Ethynyl)-1H-Benzo[d]Imidazol-1-
yl)Pyrimidin-2-Amine (12). 2-Chloro-4-vinylpyridine 59 (40.0 mg,
0.287 mmol), 4-(6-ethynyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-
amine 4 (50.0 mg and 0.213 mmol), bis(triphenylphosphine)-
palladium(II) dichloride (18.0 mg and 28.7 μmol), and copper(I)
iodide (4.60 mg and 28.7 μmol) were reacted under similar
conditions to those described in general procedure B. The crude
product was then purified by automated flash column chromatog-
raphy (silica, 0−10% methanol in dichloromethane) yielding the
desired compound as an off-white solid (22.0 mg, 65.0 μmol, and
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ppm. HRMS-ESI (m/z): [M + H]+ calculated for C20H13N6 ,
337.1196; found, 337.1186.
4-(6-((4-Ethynylpyrimidin-2-yl)Ethynyl)-1H-Benzo[d]-
Imidazol-1-yl)Pyrimidin-2-Amine (16). 4-(6-((4-
((Trimethylsilyl)ethynyl)pyridin-2-yl)ethynyl)-1H-benzo[d]imidazol-
1-yl)pyrimidin-2-amine 68 (80.0 mg, 0.196 mmol) was stirred in
methanol (2.30 mL) at 25 °C, and potassium carbonate (3.30 mg and
23.9 μmol) was stirred at 25 °C for 5 h. The solvent was then
removed in vacuo, and the crude product was purified using
automated flash column chromatography (silica, 0−10% methanol
in dichloromethane) to yield the desired product as an off-white solid
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23%), m.p.: 182−184 °C. H-NMR (500 MHz, CDCl3): δ 5.62 (d, J
= 11.2 Hz, 1H), 6.26 (d, J = 17.6 Hz, 1H), 6.79 (dd, J = 10.9, 17.6 Hz,
1H), 7.18 (d, J = 5.6 Hz, 1H), 7.21 (d, J = 13.2 Hz, 2H), 7.51 (dd, J =
1.7, 5.1 Hz, 1H), 7.59 (dd, J = 1.6, 8.3 Hz, 1H), 7.82 (dd, J = 1.2, 3.2
Hz, 1H), 7.84 (d, J = 0.6 Hz, 1H), 8.35−8.44 (m, 1H), 8.59 (dd, J =
0.8, 5.0 Hz, 1H), 8.85−8.94 (m, 1H), 9.19 (s, 1H) ppm. 13C-NMR
(126 MHz, CDCl3): δ 89.1, 90.05, 98.4, 117.11, 120.1, 120.8,
120.9124.7, 127.8, 132.0, 134.4, 142.92, 143.80, 144.3, 145.3, 151.0,
157.25, 157.45, 161.0, 164.0 ppm. HRMS-ESI (m/z): [M + H]+
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(16.0 mg, 47.6 μmol, and 24%), m.p.: 157−159 °C. H-NMR (500
MHz, CDCl3): δ 3.28 (s, 1H), 5.36 (s, 2H), 6.81 (d, J = 5.5 Hz, 1H),
7.25 (dd, J = 1.5, 5.1 Hz, 1H), 7.53 (dd, J = 1.5, 8.3 Hz, 1H), 7.57 (d,
J = 1.3 Hz, 1H), 7.76 (dd, J = 8.3, 0.7 Hz, 1H), 8.37 (d, J = 5.5 Hz,
1H), 8.46 (dd, J = 0.7, 1.5 Hz, 1H), 8.54 (dd, J = 0.9, 5.2 Hz, 1H),
8.58 (s, 1H) ppm. 13C-NMR (126 MHz, CDCl3): δ 80.3, 82.6, 83.3,
90.8, 99.6, 118.2, 118.6, 120.9, 125.0, 128.1, 129.4, 130.9, 131.05,
131.71, 142.1, 150.1, 156.9, 157.15, 160.5, 163.1 ppm. HRMS-ESI
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calculated for C20H15N6 , 339.1353; found, 339.1560.
4-(6-((6-Ethynylpyridin-2-yl)Ethynyl)-1H-Benzo[d]Imidazol-
1-yl)Pyrimidin-2-Amine (13). To a solution of 4-(6-((6-
((triisopropylsilyl)ethynyl)pyridin-2-yl)ethynyl)-1H-benzo[d]-
imidazol-1-yl)pyrimidin-2-amine 67 (92.0 mg and 0.187 mmol) in
THF (2.0 mL) at 0 °C was added TBAF (1 M in THF, 0.200 mL,
0.200 mmol), and the reaction was carried out according to general
procedure A. The resulting solid was purified directly by flash column
chromatography (silica, 0−10% methanol in dichloromethane) to
yield the desired product as a white solid (41.0 mg, 0.122 mmol,
65%); m.p. 234−236 °C. 1H-NMR (500 MHz, DMSO-d6): δ 4.43 (s,
1H), 7.17 (d, J = 5.6 Hz, 1H), 7.20 (s, 2H), 7.59 (dt, J = 1.4, 7.9 Hz,
2H), 7.72 (dd, J = 1.0, 7.9 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.90 (t, J
= 7.8 Hz, 1H), 8.39 (d, J = 5.5 Hz, 1H), 8.88 (d, J = 1.5 Hz, 1H), 9.17
(s, 1H) ppm. 13C-NMR (126 MHz, DMSO-d6): δ 81.2, 82.9, 88.3,
90.6, 98.4, 117.3, 120.2, 120.9, 127.3, 127.7, 128.0, 132.0, 138.1,
142.6, 143.4, 144.4, 145.5, 157.2, 161.0, 164.1 ppm. HRMS-ESI (m/
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(m/z): [M + H]+ calculated for C20H13N6 , 336.1196; found,
337.1211.
4-(6-((4-Vinylpyrimidin-2-yl)Ethynyl)-1H-Benzo[d]Imidazol-
1-yl)Pyrimidin-2-Amine (17). 4-(6-Ethynyl-1H-benzo[d]imidazol-
1-yl)pyrimidin-2-amine 4 (50.0 mg and 0.212 mmol) was reacted
with 2-chloro-4-vinylpyrimidine 60 (39.0 mg and 0.276 mmol) under
similar conditions to those described in procedure B. The crude
product was purified by automated flash column chromatography
twice (silica, 0−50% ethyl acetate in petroleum ether; C18 reversed-
phase flash cartridge, 0−65% methanol in dichloromethane) to yield
the title compound as a white solid (15.0 mg, 44.2 μmol, 16%); m.p.
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212−214 °C. H-NMR (500 MHz, CDCl3): δ 5.43 (s br, 2H), 5.78
(d, J = 10.9 Hz, 1H), 6.50 (d, J = 17.4 Hz, 1H), 6.77 (dd, J = 10.7,
17.4 Hz, 1H), 7.27 (d, J = 5.1 Hz, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.82
(d, J = 9.2 Hz, 1H), 8.42 (d, J = 4.5 Hz, 1H), 8.59−8.71 (m, 3H)
ppm. 13C-NMR (126 MHz, CDCl3): δ 87.0, 87.2, 98.6, 115.0, 116.6,
118.2, 119.9, 123.2, 127.7, 133.8, 141.2, 152.3, 155.9, 156.7, 159.4,
162.0, 162.1 ppm. HRMS-ESI (m/z): [M + H]+ calculated for
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z): [M + H]+ calculated for C20H13N6 , 337.1196; found, 337.1183.
4-(6-((2-Ethynylpyridin-4-yl)Ethynyl)-1H-Benzo[d]Imidazol-
1-yl)Pyrimidin-2-Amine (14). A stirred solution of 4-(6-((2-
((trimethylsilyl)ethynyl)pyridin-4-yl)ethynyl)-1H-benzo[d]imidazol-
1-yl)pyrimidin-2-amine 54 (120 mg and 0.294 mmol) in methanol
(3.0 mL) at 25 °C and potassium carbonate (5.00 mg and 36.2 μmol)
was stirred at room temperature for 5 h. The solvent was then
removed in vacuo, and purification by automated flash column
chromatography (silica, 0−10% methanol in dichloromethane)
yielded the desired product as an off-white solid (80.0 mg, 0.238
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C19H14N7 , 340.1305; found 340.1308.
4-(6-((4-Ethynylpyrimidin-2-yl)Ethynyl)-1H-Benzo[d]-
Imidazol-1-yl)Pyrimidin-2-Amine (18). 4-(6-((4-
((Triisopropylsilyl)ethynyl)pyrimidin-2-yl)ethynyl)-1H-benzo[d]-
imidazol-1-yl)pyrimidin-2-amine 69 (30.0 mg and 60.8 μmol) in THF
(0.79 mL) and TBAF (1.0 M in THF, 73.0 μL, and 73.0 μmol) at 0
°C were reacted under similar conditions to those described in
general procedure A. The solvent was then removed in vacuo, and
purification by automated flash column chromatography (silica, 0−
10% methanol in dichloromethane) yielded the desired product as an
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mmol, and 83%), m.p.: 187−189 °C. H-NMR (500 MHz, DMSO-
d6): δ 4.46 (s, 1H), 7.17−7.21 (m, 2H), 7.57−7.58 (m, 1H), 7.62−
7.64 (m, 2H), 7.76 (dd, J = 0.9, 1.7 Hz, 1H), 7.84 (dd, J = 0.7, 8.3 Hz,
1H), 8.40 (d, J = 5.5 Hz, 1H), 8.64 (dd, J = 0.9, 5.2 Hz, 1H), 8.93
(dd, J = 0.7, 1.6 Hz, 1H), 9.20 (s, 1H) ppm. 13C-NMR (DMSO-d6): δ
81.6, 82.9, 86.1, 96.2, 98.3, 117.1, 120.6, 120.9, 125.6, 127.8, 129.1,
131.7, 132.0, 142.6, 144.4, 145.6, 151.0, 157.2, 161.0, 164.0 ppm.
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off-white solid (8.00 mg, 23.7 μmol, 39%), m.p.: 183−185 °C. H-
NMR (500 MHz, DMSO-d6): δ 4.90 (s, 1H), 7.18 (d, J = 5.5 Hz,
1H), 7.24 (bs, 1H), 7.64 (dd, J = 1.7, 8.4 Hz, 1H), 7.68 (d, J = 5.2 Hz,
2H), 7.86 (d, J = 8.2 Hz, 1H), 8.40 (d, J = 5.5 Hz, 1H), 8.96−8.87
(m, 2H), 9.21 (s, 1H) ppm. 13C-NMR (126 MHz, DMSO-d6): δ 80.9,
10009
J. Med. Chem. 2021, 64, 10001−10018