M. G. Brasca et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
11
J = 5.7, 7.2 Hz, 2H), 2.11 (s, 3H), 1.02 (t, J = 7.2 Hz, 3H); LC–MS (ESI):
m/z 356 [M+H]+; HRMS (ESI): m/z calcd for C18H18ClN5O+H+
356.1273, found 356.1277.
5.1.26. 5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-
N-phenyl-1H-pyrrole-3-carboxamide (16)
1H NMR (400 MHz, DMSO-d6) d 12.05 (br s, 1H), 9.74 (s, 1H),
8.23 (d, J = 5.2 Hz, 1H), 7.65 (dd, J = 1.0, 8.6 Hz, 2H), 7.57 (d,
J = 1.3 Hz, 1H), 7.37 (dd, J = 2.3, 8.0 Hz, 1H), 7.34 (d, J = 2.3 Hz,
1H), 7.30 (d, J = 8.0 Hz, 1H), 7.26 (m, 2H), 7.00 (m, 1H), 6.99 (d,
J = 5.2 Hz, 1H), 6.37 (br s, 2H), 2.14 (s, 3H); LC–MS (ESI): m/z 404
[M+H]+; HRMS (ESI): m/z calcd for C22H18ClN5O+H+ 404.1273,
found 404.1274.
5.1.20. 5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-
N-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide (10)
1H NMR (400 MHz, DMSO-d6) d 11.86 (br s, 1H), 8.20 (d,
J = 5.4 Hz, 1H), 7.71 (t, J = 5.8 Hz, 1H), 7.32–7.38 (m, 2H),
7.23–7.30 (m, 2H), 6.94 (d, J = 5.2 Hz, 1H), 6.34 (br s, 2H), 4.61 (t,
J = 5.4 Hz, 1H), 3.38–3.44 (m, 2H), 3.17 (q, J = 6.1 Hz, 2H), 2.10 (s,
3H); LC–MS (ESI): m/z 372 [M+H]+; HRMS (ESI): m/z calcd for
5.1.27. 5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-
N-(1-methylpiperidin-4-yl)-1H-pyrrole-3-carboxamide (17)
1H NMR (400 MHz, DMSO-d6) d 11.85 (br s, 1H), 8.19 (d,
J = 5.2 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.33–7.38 (m, 2H), 7.29 (d,
J = 2.0 Hz, 1H), 7.28 (d, J = 8. 7 Hz, 1H), 6.94 (d, J = 5.2 Hz, 1H),
6.32 (br s, 2H), 3.55 (m, 1H), 2.63 (m, 2H), 2.12 (s, 3H), 2.10 (s,
3H), 1.88 (dt, J = 2.1, 11.4 Hz, 2H), 1.65 (m, 2H), 1.45 (dq, J = 3.9,
11.6 Hz, 2H); LC–MS (ESI): m/z 425 [M+H]+; HRMS (ESI): m/z calcd
for C22H25ClN6O+H+ 425.1851, found 425.1846.
C
18H18ClN5O2+H+ 372.1222, found 372.1230.
5.1.21. 5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-
N-[2-(methylamino)ethyl]-1H-pyrrole-3-carboxamide (11)
Compound 11 was obtained from tert-butyl [2-({[5-(2-amino-
pyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrol-3-yl]car-
bonyl}amino)ethyl]methylcarbamate (prepared according to the
method described above) after treatment with 50% CF3COOH in
DCM.
1H NMR (400 MHz, DMSO-d6) d 11.86 (br s, 1H), 8.19 (d,
J = 5.2 Hz, 1H), 7.66 (t, J = 5.7 Hz, 1H), 7.36 (dd, J = 2.2, 8.2 Hz,
1H), 7.33 (s, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H),
6.94 (d, J = 5.2 Hz, 1H), 6.33 (br s, 2H), 3.18 (q, J = 6.3 Hz, 2H),
2.54 (t, J = 6.5 Hz, 2H), 2.26 (s, 3H), 2.11 (s, 3H); LC–MS (ESI): m/z
385 [M+H]+; HRMS (ESI): m/z calcd for C19H21ClN6O+H+
385.1538, found 385.1541.
5.1.28. 5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-
1-methyl-1H-pyrrole-3-carboxamide (18)
To a solution of 38e (105.2 mg, 0.295 mmol) in DMF (2 mL),
Cs2CO3 (101 mg, 0.31 mmol) and MeI (28 lL, 0.43 mmol) were
added. The mixture was stirred at room temperature for 3 h, the
solvent was then removed. EtOAc and water were added to the res-
idue, the layers were separated, the aqueous layer was extracted
with EtOAc and the combined organic layers were washed with
water, dried over sodium sulfate, filtered and concentrated. The
crude material was purified by flash chromatography (DCM/MeOH
98:2) affording ethyl 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-
methylphenyl)-1-methyl-1H-pyrrole-3-carboxylate (40a, 74 mg,
68%). 1H NMR (400 MHz, DMSO-d6) d 8.20 (d, J = 5.2 Hz, 1H), 7.45
(dd, J = 2.3, 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 2.3 Hz,
1H), 7.24 (s, 1H), 6.97 (d, J = 5.2 Hz, 1H), 6.58 (s, 2H), 3.98 (q,
J = 7.1 Hz, 2H), 3.67 (s, 3H), 2.00 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H);
LC–MS (ESI): m/z 371 [M+H]+; HRMS (ESI): m/z calcd for
5.1.22. 5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-
N-(2-fluoroethyl)-1H-pyrrole-3-carboxamide (12)
1H NMR (400 MHz, DMSO-d6) d 11.90 (br s, 1H), 8.20 (d,
J = 5.2 Hz, 1H), 8.03 (t, J = 5.5 Hz, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.35
(dd, J = 2.3, 8.3 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.28 (d, J = 8.3 Hz,
1H), 6.94 (d, J = 5.2 Hz, 1H), 6.33 (br s, 1H), 4.43 (td, J = 5.2,
47.5 Hz, 2H), 3.44 (q, J = 5.2 Hz, 2H), 2.10 (s, 3H); LC–MS (ESI): m/
z
374 [M+H]+; HRMS (ESI): m/z calcd for C18H17ClFN5O+H+
374.1179, found 374.1185.
C
19H19ClN4O2+H+ 371.1270, found 371.1268.
5.1.23. 5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-
N-(2-methoxyethyl)-1H-pyrrole-3-carboxamide (13)
The intermediate 40a (70 mg, 0.19 mmol) was treated with 2 N
NaOH (1.0 mL) in EtOH (1 mL) under reflux for 3 h. After cooling, a
solution of citric acid was added. The resultant precipitate was col-
lected by filtration to give 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-
2-methylphenyl)-1-methyl-1H-pyrrole-3-carboxylic acid (41a,
62 mg, 95%). 1H NMR (400 MHz, DMSO-d6) d 8.15 (d, J = 5.2 Hz,
1H), 7.36 (dd, J = 2.2, 8.2 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.20 (d,
J = 2.1 Hz, 1H), 7.10 (s, 1H), 6.88 (d, J = 5.4 Hz, 1H), 6.47 (s, 2H),
3.61 (s, 3H), 2.02 (s, 3H); LC–MS (ESI): m/z 343 [M+H]+; HRMS
(ESI): m/z calcd for C17H15ClN4O2+H+ 343.0957, found 343.0966.
To a solution of 41a (34 mg, 0.1 mmol) in DMF/THF (1:1, 2 mL)
1H NMR (400 MHz, DMSO-d6) d 11.87 (br s, 1H), 8.19 (d,
J = 5.2 Hz, 1H), 7.69 (t, J = 5.5 Hz, 1H), 7.36 (dd, J = 2.2, 8.2 Hz,
1H), 7.34 (d, J = 2.6 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.29 (d,
J = 7.9 Hz, 1H), 6.94 (d, J = 5.2 Hz, 1H), 6.33 (br s, 2H), 3.22 (s,
3H), 2.10 (s, 3H); LC–MS (ESI): m/z 386 [M+H]+; HRMS (ESI): m/z
calcd for C19H20ClN5O2+H+ 386.1379, found 386.1384.
5.1.24. 5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-
N-(2-methylpropyl)-1H-pyrrole-3-carboxamide (14)
1H NMR (400 MHz, DMSO-d6) d 11.84 (br s, 1H), 8.19 (d,
J = 5.2 Hz, 1H), 7.72 (t, J = 5.9 Hz, 1H), 7.35 (dd, J = 2.3, 8.3 Hz,
1H), 7.35 (d, J = 2.3 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.28 (d,
J = 8.3 Hz, 1H), 6.95 (d, J = 5.2 Hz, 1H), 6.33 (br s, 2H), 2.92 (t,
J = 6.4 Hz, 2H), 2.11 (s, 3H), 1.71 (spt, J = 6.8 Hz, 1H), 0.81 (d,
J = 6.7 Hz, 6H); LC–MS (ESI): m/z 384 [M+H]+; HRMS (ESI): m/z
calcd for C20H22ClN5O+H+ 384.1586, found 384.1592).
and DIPEA (36 lL, 0.2 mmol) was added. EDCI (29 mg, 0.15 mmol)
and HOBTꢁNH3 (23 mg, 0.15 mmol) were added and the reaction
mixture was stirred for 3 h at room temperature. The mixture
was dropped into a saturated solution of NaHCO3 and ice and
extracted with DCM. The combined organic layers were washed
with water, dried over sodium sulfate, filtered and concentrated.
The crude material was purified by flash chromatography (DCM/
MeOH 95:5) affording 18 (21 mg, 63%). 1H NMR (400 MHz,
DMSO-d6) d 8.21 (d, J = 5.4 Hz, 1H), 7.40 (dd, J = 2.2, 8.2 Hz, 1H),
7.33 (s, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 2.2 Hz, 1H), 7.04
(br s, 1H), 6.81 (d, J = 5.4 Hz, 1H), 6.71 (br s, 1H), 6.54 (s, 2H),
3.61 (s, 3H), 2.00 (s, 3H); LC–MS (ESI): m/z 342 [M+H]+; HRMS
(ESI): m/z calcd for C17H16ClN5O+H+ 342.1116, found 342.1122.
The following compound 19 was prepared according to the
method described above using ethyl bromide instead of methyl
iodide.
5.1.25. 5-(2-Aminopyrimidin-4-yl)-N-benzyl-2-(5-chloro-2-
methylphenyl)-1H-pyrrole-3-carboxamide (15)
1H NMR (400 MHz, DMSO-d6) d 11.89 (br s, 1H), 8.38 (t,
J = 6.0 Hz, 1H), 8.20 (d, J = 5.2 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H),
7.34 (m, 1H), 7.17–7.32 (m, 7H), 6.94 (d, J = 5.2 Hz, 1H), 6.33 (br
s, 2H), 4.32 (d, J = 6.1 Hz, 2H), 2.09 (s, 3H); LC–MS (ESI): m/z 418
[M+H]+; HRMS (ESI): m/z calcd for C23H20ClN5O+H+ 418.1429,
found 418.1429.