4-(2-(bis(4-methoxybenzyl)amino)pyrimidin-5-yl)-2-morpholino-N-phenyl-5,6-dihydro-7H-pyrrolo[2,3-d]p
yrimidine-7-carboxamide (33.7 mg, 51%). To a solution of this intermediate in TFA (1 mL) was added
conc. H2SO4 (0.53 μL, 10.0 μmol), and the mixture was stirred at 70 ˚C for 3 hours. After cooling to
ambient temperature, the mixture was diluted with H2O (1 mL) and neutralized by 5M NaOH. The
resulting filter cake was washed with MeOH to afford the titled compound as a light brown powder (17.1
mg, 82%). 1H-NMR (400 MHz, DMSO-d6) δ: 8.85 (2H, s), 7.53 (2H, d, J = 7.8 Hz), 7.36 (2H, t, J = 8.1 Hz),
7.19 (2H, s), 7.07 (1H, t, J =7.6 Hz), 4.05 (2H, t, J = 8.5 Hz), 3.79-3.73 (8H, m), 3.23 (2H, t, J = 8.5 Hz);
13C-NMR (400 MHz, DMSO-d6) δ: 164.1, 163.6, 159.9, 158.4, 155.0, 151.0, 138.7, 129.7, 123.6, 120.0,
119.4, 106.3, 66.4, 46.4, 45.0, 23.5 ; HRMS (ESI), m/z Calcd for C21H22N8O2+H: 419.1944, Found
419.1943.
5.1.2
4-(2-Amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic
acid methyl-phenyl-amide (4a)
To a solution of 3 (54.0 mg, 0.100 mmol) and pyridine (16 μL, 0.200 mmol) in DCM (1 mL) was added
triphosgene (59.4 mg, 0.200 mmol) at 0 ˚C. After stirring for 1 hour at an ambient temperature, DCM was
evaporated under reduced pressure. The residue was dissolved in DCM (1 mL) again and
N-methylaniline (13 μL, 0.120 mmol) was added to the mixture. After stirring for 4 hours, the mixture was
directly charged on silica gel and purified (DCM/MeOH, 1/0 to 95/5) to afford
4-[2-[bis(4-methoxybenzyl)amino]pyrimidin-5-yl]-N-methyl-2-morpholino-N-phenyl-5,6-dihydro-7H-pyrrol
o[2,3-d]pyrimidine-7-carboxamide (52.2 mg, 78% in 2 steps). This residue and NAC (25.2 mg, 0.155
mmol) was dissolved in TFA (1 mL) and the mixture was refluxed for 6 hours. After cooling to an ambient
temperature, H2O (1 mL) and 5M NaOH (1 mL) was added. The resulting filter cake was washed by
MeOH and purified by silica gel flash column chromatography (DCM/MeOH, 1/0 to 95/5) to afford titled
compound as a white powder (21.1 mg, 63%). 1H-NMR (270 MHz, DMSO-d6) δ: 8.71 (2H, s), 7.32-7.27
(4H, m), 7.14-7.11 (1H, m), 7.11-7.08 (2H, m), 3.87 (2H, t, J = 8.2 Hz), 3.64-3.59 (8H, brm), 3.35 (3H, s),
3.09 (2H, t, J =8.2 Hz); 13C-NMR (400 MHz, DMSO-d6) δ: 164.9, 163.9, 160.7, 158.1, 155.5, 153.5,
144.8, 129.1, 125.7, 125.0, 120.3, 105.1, 66.6, 48.4, 44.7, 38.8, 24.5 ; HRMS (ESI-TOF), m/z Calcd for
C22H24N8O2+H: 433.2100, Found 433.2094.
5.1.3
4-(2-Amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic
acid o-tolylamide (4b)
Compound 4b was prepared from 3 and 2-methylaniline by following the same procedure as
1
described for 4a (white powder, 68% in 3 steps). H-NMR (400 MHz, DMSO-d6) δ: 10.29 (1H, s), 8.84
(2H, s), 7.59 (1H, d, J = 8.1 Hz), 7.26 (1H, d, J = 7.0 Hz), 7.23-7.18 (3H, m), 7.09 (1H, t, J = 7.5 Hz), 4.05
(2H, t, J = 8.3 Hz), 3.74-3.65 (8H, m), 3.24 (2H, t, J = 8.3 Hz), 2.27 (3H, s); 13C-NMR (400 MHz,
DMSO-d6) δ: 164.1, 163.9, 160.1, 158.4, 154.8, 151.6, 136.3, 130.8, 130.4, 126.6, 125.1, 124.9, 120.0,
106.5, 66.4, 46.5, 45.1, 23.5, 18.1 ; HRMS (ESI-TOF), m/z Calcd for C22H24N8O2+H: 433.2100, Found
433.2097.
5.1.4
4-(2-Amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic
acid (2-ethyl-phenyl)-amide (4c)
Compound 4c was prepared from 3 and 2-ethylaniline by following the same procedure as
described for 4a (white powder, 56% in 3 steps). 1H-NMR (DMSO-d6) δ: 10.29 (1H, s), 8.85 (2H, s), 7.52
(1H, d, J = 7.5 Hz), 7.29 (1H, d, J = 7.5 Hz), 7.24-7.13 (4H, m), 4.05 (2H, t, J = 8.3 Hz), 3.72-3.65 (8H, m),
3.24 (2H, t, J = 8.3 Hz), 2.63 (2H, q, J = 7.5 Hz), 1.16 (3H, t, J = 7.5 Hz); 13C-NMR (400 MHz, DMSO-d6)
δ: 164.1, 163.9, 160.0, 158.4, 154.8, 151.9, 136.9, 135.5, 128.8, 126.6, 126.1, 125.8, 120.0, 106.5, 66.3,
46.5, 45.1, 24.1, 23.5, 14.5 ; HRMS (ESI-TOF), m/z Calcd for C23H26N8O2+H: 447.2257, Found
447.2255.
5.1.5
4-(2-Amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic
acid (2-isopropyl-phenyl)-amide (4d)
Compound 4d was prepared from 3 and 2-isopropylaniline by following the same procedure as
1
described for 4a (white powder, 57% in 3 steps). H-NMR (DMSO-d6) δ: 10.33 (1H, s), 8.85 (2H, s),
7.46-7.33 (2H, m), 7.24-7.17 (4H, m), 4.05 (2H, t, J = 8.3 Hz), 3.67 (8H, brs s), 3.24 (2H, t, J = 8.3 Hz),
3.18 (1H, q, J = 7.0 Hz), 1.17 (6H, d, J = 7.0 Hz); 13C-NMR (400 MHz, DMSO-d6) δ: 164.1, 163.9, 160.0,
158.4, 154.8, 152.1, 142.2, 134.5, 126.9, 126.4, 126.3, 126.1, 120.0, 106.5, 66.3, 46.5, 45.0, 28.0, 23.7,
23.5 ; HRMS (ESI-TOF), m/z Calcd for C24H28N8O2+H: 461.2413, Found. 461.2413