Journal of Medicinal Chemistry
Article
(4.00 mL) was added to the mixture and the resulting mixture heated at
110 °C for 16 h. The resulting solution was concentrated, and the
product was partitioned between CHCl3 and saturated aqueous
NaHCO3. The organic phase was then dried over Na2SO4, filtered,
and concentrated. The resulting solid was slurried twice with
dichloromethane and hexane, filtered, and dried under reduced pressure
to yield 9n as a light green solid (0.080 g). Mp: 231 °C dec. 1H NMR
(400 MHz, CD3OD): 8.50 (s, 1H), 7.38−7.37 (m, 4H), 7.24−7.19 (m,
1H), 7.08 (d, J = 8.8 Hz, 2H), 4.16−4.10 (m, 1H), 3.85 (t, J = 4.8 Hz,
4H), 3.76−3.59 (m, 3H), 3.20 (t, J = 4.8 Hz, 5H), 2.01−1.91 (m, 3H),
1.66−1.58 (m, 1H). HPLC−MS (ESI+): m/z 527.2 (100%). HRMS
(ESI+): m/z calcd for C27H31ClFN6O3 (M + H) 527.1968, found
527.1962.
(br s, 1H), 9.09 (s, 1H), 8.83 (br s, 1H), 8.72 (s, 1H), 7.49 (d, J =
8.4 Hz, 2H), 7.43−7.30 (m, 3H), 6.67 (d, J = 8.8 Hz, 2H), 4.02−3.98
(m, 1H), 3.76−3.71 (m, 1H), 3.62−3.57 (m, 2H), 3.42−3.37 (m, 1H),
1.93−1.87 (m, 1H), 1.84−1.75 (m, 2H), 1.56−1.47 (m, 1H). 19F
NMR (376 MHz, DMSO-d6): δ −116.15 to −116.19 (m). LC−MS
(ESI+): m/z 458.13 (M + H)+. HRMS (ESI+): m/z calcd for
C22H22ClFN5O3 (M + H)+ 458.1390, found 458.1390.
5-Fluoro-N2-[(4-hydroxy-3-fluorophenyl)amino]-N4-[(tetra-
hydrofuran-2-yl)methyl]pyrimidine-2,4-diamine Hydrochlor-
ide [( )-9s]. A mixture of pyrimidine 8d (0.116 g, 0.5 mmol) and
4-amino-2-fluorophenol (0.064 g, 0.5 mmol) in EtOH (2 mL) was
heated in a microwave reactor at 150 °C for 20 min. The solvent was
removed, and the resulting residue was slurried and sonicated with
EtOAc (3 mL). The mixture was filtered, and the precipitate was
washed with EtOAc (2 mL) and then dried under high vacuum to
afford the title compound as a dark brown solid (0.152 g, 84%). Mp:
201 °C dec. HPLC: 98.5% [tR = 7.72 min, 35% CH3OH in 0.1% TFA/
water, 20 min]. 1H NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 9.87
(br s, 1H), 10.18 (s, 1H), 9.19 (br s, 1H), 8.08 (d, J = 5.2 Hz, 1H),
7.43 (dd, J = 13.2, 2.0 Hz, 1H), 7.01 (dd, J = 8.8, 1.6 Hz, 1 H), 6.94 (t,
J = 9.6 Hz, 1H), 4.07−4.01 (m, 1H), 3.75−3.69 (m, 1H), 3.63−3.58
(m, 1H), 1.93−1.85 (m, 1H), 1.83−1.75 (m, 2H), 1.59−1.51 (m, 1H).
19F NMR (376 MHz, DMSO-d6): δ −134.70 (s), −163.23 (s). LC−
5-[(2-Chloro-6-fluorophenyl)carbamoyl]-N2-[(4-(piperidin-4-
yl)phenyl]-N4-[(tetrahydrofuran-2-yl)methyl]pyrimidine-2,4-di-
amine [( )-9o]. A mixture of chloropyrimidine 8c (0.062 g,
0.161 mmol) and 4-piperidinylaniline (0.028 g, 0.161 mmol) in
EtOH (1 mL) and HCl (1 mL of a 0.1 M aq solution) was heated in a
microwave reactor at 150 °C for 40 min. The solvent was removed,
and the resulting residue was slurried with DCM, filtered, and dried
under high vacuum to afford the title compound 9o as a solid
(0.032 mg, 36%). Mp: 186 °C dec. HPLC: 89.4% [tR = 10.37 min, 45%
CH3OH in 0.1% TFA/water, 20 min]. 1H NMR (400 MHz, CD3OD):
δ 8.60 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.40−7.38 (m,
3H),), 7.25−7.19 (m, 1H), 4.19−4.10 (m, 1H), 3.93−3.80 (m, 1H),
3.75−3.60 (m, 3H), 3.53−3.50 (d, J = 12.0 Hz, 2H), 3.16 (t, J =
10.4 Hz, 2H), 2.97 (t, J = 12.0 Hz, 1H), 2.11−1.89 (m, 6H), 1.67−1.60
(m, 1H). LC−MS (ESI+): m/z 525.2; (M + H)+. HRMS (ESI+): m/z
calcd for C27H31ClFN6O2 (M + H)+ 525.2176, found 525.2175.
5-[(2-Chloro-6-fluorophenyl)carbamoyl]-N2-[(3-fluoro-4-
hydroxyphenyl)amino]-N4-[(tetrahydrofuran-2-yl)methyl]-
pyrimidine-2,4-diamine [( )-9p]. This compound was synthesized
according to the procedure described for 9o using 8c (0.050 g,
0.130 mmol), 4-amino-2-fluorophenol (0.017 g, 0.130 mmol), and EtOH
(1 mL). A mixture of EtOAc/hexane was used for recrystallization to
afford the title compound as a brown solid (0.051 g, 76%). Mp: 183 °C
dec. HPLC: 99.4% [tR = 6.53 min, 55% CH3OH in 0.1% TFA/water,
20 min]. 1H NMR (400 MHz, CD3OD): δ 8.54 (s, 1H), 7.43−7.38 (m,
3H), 7.24−7.19 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 8.4 Hz,
1H), 4.15−4.09 (m, 1H), 3.90−3.85 (m, 1H), 3.77−3.59 (m, 3H),
2.05−1.99 (m, 1H), 1.96−1.88 (m, 1H), 1.67−1.58 (m, 1H). 19F NMR
(376 MHz, CD3OD): δ −118.25 (d). LC−MS (ESI+): m/z 476.12
(M + H)+. HRMS (ESI+): m/z calcd for C22H21F2N5O3 (M + H)+
476.1296, found 476.1290.
MS (ESI+): m/z 323.14 (M + H)+. HRMS (ESI+): m/z calcd for
C15H17F2N4O2 (M + H)+ 323.1314, found 323.1314.
5-Methyl-N2-[(4-hydroxy-3-fluorophenyl)amino]-N4-[(tetra-
hydrofuran-2-yl)methyl]pyrimidine-2,4-diamine Hydrochlor-
ide [( )-9t]. A suspension of pyrimidine 8e (0.114 g, 0.5 mmol)
and 4-amino-2-fluorophenol (0.064 g, 0.5 mmol) in EtOH (1 mL) was
heated in a microwave reactor at 150 °C for 20 min. The mixture was
concentrated, and the residue obtained was recrystallized with MeOH/
EtOAc, filtered, and washed with EtOAc (2 mL) to afford the title
compound 9t as a dark brown solid. The filtrate was concentrated and
recrystallized again with MeOH/EtOAc to afford a second crop of
solid. The solids were combined to afford the title compound 9t as a
dark brown solid (0.163 g, 92%). Mp: 199 °C dec. HPLC: 98.8% [tR =
12.26 min, 35% CH3OH in 0.1% TFA/water, 20 min]. 1H NMR (400
MHz, CD3OD): δ 7.45 (s, 1H), 7.29 (dd, J = 12.0, 1.6 Hz, 1H), 7.03−
6.93 (m, 2H), 4.20−4.13 (m, 1H), 3.88−3.83 (m, 1H), 3.78−3.72 (m,
1H), 3.64−3.51 (m, 2H), 2.04 (s, 3H), 1.96−1.87 (m, 2H), 1.66−1.57
(m, 1H). 19F NMR (376 MHz, CD3OD): δ −136.94 (s). LC−MS
(ESI+): m/z 319.16 (M + H)+. HRMS (ESI+): m/z calcd for
C16H20FN4O2 (M + H)+ 319.1565, found 319.1566.
5-Bromo-N2-[(4-hydroxy-3-fluorophenyl)amino]-N4-[(tetra-
hydrofuran-2-yl)methyl]pyrimidine-2,4-diamine [( )-13]. A
mixture of pyrimidine 8b (0.400 g, 1.4 mmol) and 4-amino-2-
fluorophenol (0.174 g, 1.4 mmol) in EtOH (3 mL) in a microwave vial
was heated to 150 °C for 20 min in a microwave reactor. The solvent
was evaporated, and the residue obtained was washed with ethyl
acetate, slurried with dichloromethane and hexane, and filtered to
afford 13 as a pure beige solid (0.580 g, 98%). Mp: 205−207 °C.
HPLC: 94% [tR = 6.33 min, 40% CH3OH in 0.1% TFA/water,
20 min]. 1H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.83 (br s,
1H), 8.34 (br s, 1H), 8.16 (s, 1H), 7.44 (dd, J = 12.8, 2.0 Hz, 1H),
7.02 (dd, J = 8.4, 1.2 Hz, 1H), 6.91 (t, J = 8.4 Hz, 1H), 4.07−4.01 (m,
1H), 3.72−3.67 (m, 1H), 3.60−3.55 (m, 1H), 3.42−3.37 (m, 2H),
1.88−1.71 (m, 3H), 1.56−1.48 (m, 1H). HPLC−MS (ESI+): m/z 383
and 385 for Br isotopes (M + H)+. HRMS (ESI+): m/z calcd for
C15H17BrFN4O2 (M + H)+ 383.0513, found 383.0513.
5-[(2-Chloro-6-fluorophenyl)carbamoyl]-N2 -[(4-
methoxyphenyl)amino]-N4-[(tetrahydrofuran-2-yl)methyl]-
pyrimidine-2,4-diamine [( )-9q]. A mixture of 8c (0.050 g, 0.130
mmol), 4-methoxyaniline (0.016 g, 0.132 mmol), and HCl (0.033 mL
of a 4 M solution in dioxane, 0.132 mmol) in dioxane (1 mL) was
heated in a microwave reactor at 180 °C for 30 min. The mixture was
evaporated to dryness, EtOAc was added (5 mL), and the resulting
mixture was sonicated. The resulting solid was filtered, washed with
satd NaHCO3 (5 mL × 2) and water (5 mL × 2), and dried under
vacuum to afford the title compound 9q as a pure white solid (0.051 g,
84%). Mp: 201 °C dec. HPLC: 99.5% [tR = 4.37 min, 65% CH3OH in
1
0.1% TFA/water, 20 min]. H NMR (400 MHz, DMSO-d6): δ 10.22
(s, 1H), 10.06 (br s, 1H), 9.27 (br s, 1H), 8.72 (s, 1H), 7.54 (app d,
J = 7.6 Hz, 2H), 7.45−7.32 (m, 3H), 6.93 (d, J = 8.8 Hz, 2H), 4.04−
3.98 (m, 1H), 3.75−3.70 (m, 4H), 3.61−3.55 (m, 3H), 1.95−1.87 (m,
1H), 1.82−1.76 (m, 2H), 1.56−1.48 (m, 1H). 19F NMR (376 MHz,
DMSO-d6): δ −116.16 to −116.19 (m). LC−MS (ESI+): m/z 472.14
(M + H)+. HRMS (ESI+): m/z calcd for C23H24ClFN5O3 (M + H)+
472.1546, found 472.1548.
5-[(2-Chloro-6-fluorophenyl)carbamoyl]-N2-(3-fluoro-4-hy-
droxyphenyl)-N4-[(tetrahydrofuran-2-yl)methyl]pyrimidine-
2,4-diamine Hydrochloride [( )-14]. This compound was
synthesized using the procedure described for 9t except using 8c
(0.050 g, 0.130 mmol), 4-amino-2-fluorophenol (0.017 g, 0.130 mmol),
and EtOH (1 mL). EtOAc/hexane was used for recrystallization to
afford the title compound as a brown solid (0.051 g, 76%). Mp: 183 °C
dec. HPLC: 99.4% [tR = 6.53 min, 55% CH3OH in 0.1% TFA/water,
20 min]. 1H NMR (400 MHz, CD3OD): δ 8.54 (s, 1H), 7.43−7.38 (m,
3H), 7.24−7.19 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 8.4 Hz,
1H), 4.15−4.09 (m, 1H), 3.90−3.85 (m, 1H), 3.77−3.59 (m, 3H),
5-[(2-Chloro-6-fluorophenyl)carbamoyl]-N2 -[(4-
hydroxyphenyl)amino]-N4-[(tetrahydrofuran-2-yl)methyl]-
pyrimidine-2,4-diamine [( )-9r]. This compound was synthesized
using the procedure described for 9q using pyrimidine 8c (0.050 g,
0.130 mmol) and 4-aminophenol (0.017 g, 0.156 mmol) to obtain the
title compound 9r as a beige solid (0.046 g, 78%). Mp: 263 °C dec.
HPLC: 99.4% [tR = 6.77 min, 55% CH3OH in 0.1% TFA/water,
20 min]. 1H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 9.41
2760
J. Med. Chem. 2015, 58, 2746−2763