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G.R. Mathi et al. / European Journal of Medicinal Chemistry 126 (2017) 536e549
7.63 (t, J ¼ 7.8 Hz, 1H), 7.49 (s, 1H), 7.29e7.22 (m, 1H), 6.70 (s, 1H),
3.87 (s, 3H), 3.26 (sept, J ¼ 6.8 Hz,1H), 2.94 (t, J ¼ 6.8 Hz, 2H), 2.75 (t,
J ¼ 7.0 Hz, 2H), 2.18 (s, 5H), 1.31 (d, J ¼ 6.9 Hz, 6H); LC/MS m/z 489.8
[MþHþ]; HRMS (EI) m/z calcd for C23H28ClN5O3S [Mþ] 489.1601,
found 489.1601.
5.1.11. N2-(4-(1-Amino-2-methylpropan-2-yl)-2-methoxy-5-
methylphenyl)-5-chloro-N4-(2-(isopropylsulfonyl)phenyl)
pyrimidine-2,4-diamine (13)
To a solution of 8 (100 mg, 0.194 mmol), 1.0 M BH3$THF in THF
(0.972 mL, 0.972 mmol) was added at 0 ꢀC. The reaction mixture
was stirred at rt for 12 h, quenched with methanol, and concen-
trated to dryness. To the mixture was added 1.5 N HCl (aq) (25 mL)
and extracted with EtOAc. The aqueous layer was basified with
NaOH (aq) and extracted with EtOAc (2 ꢁ 50 mL). The combined
organic layers were dried over anhydrous Na2SO4, concentrated to
obtain the crude mixture which was purified by silica gel column
chromatography using MeOH/DCM (1/9) to afford the title com-
5.1.8. 5-Chloro-N2-(4-(2-(dimethylamino)ethyl)-2-methoxy-5-
methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-
diamine (10)
To a solution of 9 (25.0 mg, 0.051 mmol) in MeOH (2.0 mL) was
added acetic acid (catalytic), formalin (35%) (4.37 mg, 0.051 mmol)
at 0 ꢀC. After 30 min, NaBH3CN (4.80 mg, 0.076 mmol) was added to
the mixture and stirred at rt for 30 min. The reaction mixture was
quenched with NaHCO3 (aq) and extracted with EtOAc (2 ꢁ 15 mL).
The combined organic layers were dried over anhydrous Na2SO4,
concentrated to obtain the crude mixture which was purified by
silica gel column chromatography using MeOH/DCM (1/9) to afford
the title compound (20.0 mg, 0.039 mmol, 77%) as a white solid. Mp
pound (45.0 mg, 0.087 mmol, 45%) as
a
white solid. Mp
152.3e154.1 ꢀC; 1H NMR (300 MHz, CDCl3)
d 9.51 (s, 1H), 8.57 (d,
J ¼ 8.4 Hz, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 7.93 (dd, J ¼ 8.0, 1.4 Hz, 1H),
7.63 (t, J ¼ 7.8 Hz, 1H), 7.47 (s, 1H), 7.31e7.21 (m, 1H), 6.87 (s, 1H),
3.89 (s, 3H), 3.26 (sept, J ¼ 6.9 Hz, 1H), 2.97 (s, 2H), 2.34 (s, 3H), 1.40
(s, 6H), 1.32 (d, J ¼ 6.9 Hz, 6H), 1.26 (s, br, 2H); 13C NMR (125 MHz,
140.4e142.1 ꢀC; 1H NMR (500 MHz, CDCl3)
d
9.54 (s, 1H), 8.59 (d,
CDCl3) d 157.40, 155.36, 155.19, 146.08, 138.41, 136.19, 134.76, 131.29,
J ¼ 8.3 Hz, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.95 (dd, J ¼ 8.0, 1.5 Hz, 1H),
7.66 (t, J ¼ 8.5 Hz, 1H), 7.52 (s, 1H), 7.33e7.28 (m, 1H), 6.73 (s, 1H),
3.91 (s, 3H), 3.28 (sept, J ¼ 6.9 Hz, 1H), 2.86 (dd, J ¼ 10.2, 6.5 Hz, 2H),
2.68 (dd, J ¼ 10.2, 6.4 Hz, 2H), 2.52 (s, 6H), 2.20 (s, 3H), 1.34 (d,
128.14, 127.05, 124.80, 123.46, 123.33, 123.20, 110.49, 106.16, 55.82,
55.49, 50.43, 40.44, 27.35, 22.80, 15.37; LC/MS m/z 517.7 [MþHþ];
HRMS (EI) m/z calcd for C25H32ClN5O3S [Mþ] 517.1914, found
517.1916.
J ¼ 6.9 Hz, 6H); 13C NMR (125 MHz, CDCl3)
d 157.57, 155.33, 155.32,
146.49, 138.47, 134.68, 131.96, 131.25, 127.66, 126.68, 124.80, 123.62,
123.11, 120.78, 111.33, 105.87, 60.43, 55.87, 55.45, 45.43, 31.73, 18.91,
15.37; LC/MS m/z 518.0 [MþHþ]; HRMS (EI) m/z calcd for
5.1.12. 5-Chloro-N2-(4-(1-(dimethylamino)-2-methylpropan-2-yl)-
2-methoxy-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)
pyrimidine-2,4-diamine (14)
C
25H32ClN5O3S [Mþ] 517.1914, found 517.1909.
To a solution of 13 (40.0 mg, 0.077 mmol) in DMF (1.0 mL) was
added DIPEA (24.9 mg, 0.192 mmol) and CH3I (21.9 mg, 0.154 mmol)
at rt and the reaction mixture was heated under microwave at 80 ꢀC
for 10 min. The reaction was quenched with water (10 mL) and
extracted with EtOAc (2 ꢁ 15 mL). The combined organic layers
were washed with brine solution, concentrated to obtain the crude
mixture which was purified by silica gel column chromatography
using MeOH/DCM (1/9) to afford the title compound (20.0 mg,
0.036 mmol, 47%) as a pale yellow solid. Mp 134.2e136.4 ꢀC; 1H
5.1.9. N-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)
pyrimidin-2-yl)amino)-5-methoxy-2-methylphenethyl)formamide
(11)
A solution of 9 (250 mg, 0.510 mmol) in ethyl formate (10 mL)
was heated at 60 ꢀC for 4 h. The reaction mixture was concentrated
under reduced pressure to obtain the crude mixture which was
purified by silica gel column chromatography using MeOH/DCM (1/
9) to afford the title compound (200 mg, 0.386 mmol, 76%) as a
white solid. Mp 145.5e147.4 ꢀC; 1H NMR (300 MHz, CDCl3, rota-
NMR (300 MHz, CDCl3)
d
9.49 (s, 1H), 8.57 (d, J ¼ 8.3 Hz, 1H), 8.15 (s,
1H), 7.98e7.88 (m, 2H), 7.62 (t, J ¼ 7.8 Hz,1H), 7.47 (s, 1H), 7.32e7.21
(m, 1H), 6.94 (s, 1H), 3.89 (s, 3H), 3.26 (sept, J ¼ 6.9 Hz, 1H), 2.60 (s,
2H), 2.36 (s, 3H), 2.11 (s, 6H), 1.44 (s, 6H), 1.31 (d, J ¼ 6.9 Hz, 6H); LC/
MS m/z 545.6 [MþHþ]; HRMS (EI) m/z calcd for C27H36ClN5O3S [Mþ]
545.2227, found 545.2225.
meric mixture)
d
9.52 (s, 1H), 8.57 (d, J ¼ 8.4 Hz, 1H), 8.18 (s, 1H),
8.16 (s, 1H), 8.07 (s, 0.2H), 8.05 (s, 0.8H), 7.94 (dd, J ¼ 7.9, 1.3 Hz, 1H),
7.64 (t, J ¼ 7.8 Hz, 1H), 7.49 (s, 1H), 7.31e7.22 (m, 1H), 6.68 (s, 0.8H),
6.61 (s, 0.2H), 5.54 (s, br, 1H), 3.87 (s, 3H), 3.53 (q, J ¼ 6.8 Hz, 1.7H),
3.44e3.42 (m, 0.4H), 3.26 (sept, J ¼ 6.8 Hz, 1H), 2.82 (t, J ¼ 7.2 Hz,
2H), 2.18 (s, 3H), 1.32 (d, J ¼ 6.9 Hz, 6H); LC/MS m/z 517.7 [MþHþ];
HRMS (EI) m/z calcd for C24H28ClN5O4S [Mþ] 517.1551, found
517.1551.
5.1.13. N-(2-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)
pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)-2-
methylpropyl)formamide (15)
A solution of 13 (80.0 mg, 0.154 mmol) in ethyl formate (3.0 mL)
was heated at 60 ꢀC for 4 h. The reaction mixture was concentrated
under reduced pressure to obtain the crude mixture which was
purified by silica gel column chromatography using MeOH/DCM (1/
9) to afford the title compound (80.0 mg, 0.146 mmol, 94%) as a
white solid. Mp 89.4e91.3 ꢀC; 1H NMR (300 MHz, CDCl3, rotameric
5.1.10. 5-Chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-
5-methyl-4-(2-(methylamino)ethyl)phenyl)pyrimidine-2,4-diamine
(12)
To a solution of 11 (180 mg, 0.347 mmol) in THF (15 mL) was
added LiAlH4 (132 mg, 3.47 mmol) at 0 ꢀC. The reaction mixture was
stirred at 60 ꢀC for 12 h, quenched with water and NaOH (aq), and
filtered. The filtrate was extracted with EtOAc (2ꢁ) and the com-
bined organic layers were concentrated under reduced pressure to
obtain the crude mixture which was purified by silica gel column
chromatography using MeOH/DCM (1/9) to afford the title com-
pound (30.0 mg, 0.059 mmol, 17%) as a pale yellow solid. Mp
mixture)
d
9.54 (s, 0.7H), 9.50 (s, 0.2H), 8.56 (d, J ¼ 8.4 Hz, 1H), 8.17
(s, 1H), 8.12 (s, 1H), 8.05 (s, 1H), 7.93 (d, J ¼ 7.8 Hz, 1H), 7.64 (t,
J ¼ 7.9 Hz, 1H), 7.48 (s, 1H), 7.36e7.21 (m, 1H), 6.86 (s, 0.8H), 6.79 (s,
0.2H), 5.20 (s, 1H), 3.89 (s, 2H), 3.88 (s, 1H), 3.67 (d, J ¼ 5.9 Hz, 1.6H),
3.48 (d, J ¼ 6.6 Hz, 0.4H), 3.26 (sept, J ¼ 6.9 Hz, 1H), 2.37 (s, 2.3H),
2.34 (s, 0.7H), 1.44 (s, 6H), 1.32 (d, J ¼ 6.9 Hz, 6H); LC/MS m/z 546.2
[MþHþ]; HRMS (EI) m/z calcd for C26H32ClN5O4S [Mþ] 545.1864,
found 545.1866.
123.2e125.2 ꢀC; 1H NMR (300 MHz, CDCl3)
d 9.51 (s, 1H), 8.57 (d,
J ¼ 8.3 Hz, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 7.93 (d, J ¼ 7.9 Hz, 1H), 7.63
(t, J ¼ 7.9 Hz, 1H), 7.48 (s, 1H), 7.34e7.21 (m, 1H), 6.70 (s, 1H), 3.87 (s,
3H), 3.26 (sept, J ¼ 6.8 Hz, 1H), 2.80 (s, 4H), 2.48 (s, 3H), 2.18 (s, 3H),
1.78 (s, br, 1H), 1.32 (d, J ¼ 6.9 Hz, 6H); LC/MS m/z 504.0 [MþHþ];
HRMS (EI) m/z calcd for C24H30ClN5O3S [Mþ] 503.1758, found
503.1729.
5.1.14. 5-Chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-
5-methyl-4-(2-methyl-1-(methylamino)propan-2-yl)phenyl)
pyrimidine-2,4-diamine (16)
To a solution of 15 (54.0 mg, 0.098 mmol) in THF (5.0 mL) was