622 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 4
Hodous et al.
4-Methyl-3-(3-(4-(methylamino)-1,3,5-triazin-2-yl)pyridin-2-
yloxy)-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)benza-
mide (60). Following the procedure described for 15, 4-methyl-3-
(3-(4-(methylamino)-1,3,5-triazin-2-yl)pyridin-2-yloxy)benzoic acid
and 2-(piperidin-1-yl)-5-(trifluoromethyl)benzenamine provided the
title compound (51 mg, 40%): 1H NMR (400 MHz, two inseparable
isomers present in DMSO-d6) isomer 1, δ 9.52 (s, 1H), 8.68 (s,
1H), 8.37 (m, 1H), 8.24 (m, 1H), 8.08 (m, 1H), 7.72 (d, J ) 7.8
Hz, 1H), 7.56 (d, J ) 7.5 Hz, 1H), 7.50 (d, J ) 7.5 Hz, 1H), 7.44
(d, J ) 8.5 Hz, 1H), 7.33 (d, J ) 8.2 Hz, 1H), 7.29 (m, 1H), 2.85
(d, J ) 4.8 Hz, 3H), 2.79 (m, 4H), 2.20 (s, 3H), 1.50 (m, 4H), 1.41
(m, 2H); isomer 2, δ 9.50 (s, 1H), 8.58 (s, 1H), 8.37 (m, 1H), 8.24
(m, 1H), 8.08 (m, 1H), 7.72 (d, J ) 7.8 Hz, 1H), 7.56 (d, J ) 7.5
Hz, 1H), 7.50 (d, J ) 7.5 Hz, 1H), 7.44 (d, J ) 8.5 Hz, 1H), 7.33
(d, J ) 8.2 Hz, 1H), 7.29 (m, 1H), 2.79 (m, 4H), 2.78 (d, J ) 4.8
Hz, 3H), 2.23 (s, 3H), 1.50 (m, 4H), 1.41 (m, 2H). Anal.
(C29H28F3N7O2·0.33H2O) H, N. C: calcd 61.80, found 61.15.
N-(2-((3-(Dimethylamino)propyl)(methyl)amino)-5-(trifluo-
romethyl)phenyl)-4-methyl-3-(3-(4-(methylamino)-1,3,5-triazin-
2-yl)pyridin-2-yloxy)benzamide (61). Following the procedure
described for 15, 4-methyl-3-(3-(4-(methylamino)-1,3,5-triazin-2-
yl)pyridin-2-yloxy)benzoic acid and N1-(3-(dimethylamino)propyl)-
N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine provided the title
compound (87 mg, 27%): 1H NMR (400 MHz, two inseparable
isomers present in CDCl3) isomer 1, δ 9.25 (s, 1H), 8.81 (m, 1H),
8.62 (s, 1H), 8.40 (dd, J ) 2, 8 Hz, 1H), 8.26 (m, 1H), 7.66 (m,
2H), 7.43 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.16 (m, 1H), 3.03
(d, J ) 8 Hz, 3H), 2.71 (s, 3H), 2.63 (m, 2H), 2.43 (br s, 6H), 2.32
(s, 3H), 1.85 (m, 2H), 1.04 (m, 2H); isomer 2, δ 9.25 (s, 1H), 8.81
(m, 1H), 8.75 (s, 1H), 8.22 (dd, J ) 2, 8 Hz, 1H), 8.26 (m, 1H),
7.66 (m, 2H), 7.43 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.16 (m,
1H), 3.09 (d, J ) 8 Hz, 3H), 2.71 (s, 3H), 2.63 (m, 2H), 2.43 (br
s, 6H), 2.24 (s, 3H), 1.85 (m, 2H), 1.04 (m, 2H). Anal.
(C30H33F3N8O2·0.33H2O) H, N. C: calcd 60.60, found 59.99.
2-Fluoro-5-(3-(4-(methylamino)-1,3,5-triazin-2-yl)pyridin-2-
yloxy)-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)benza-
mide (62). Following the procedure described for 15, 2-fluoro-3-
(3-(4-(methylamino)-1,3,5-triazin-2-yl)pyridin-2-yloxy)benzoic acid
and 2-(piperidin-1-yl)-5-(trifluoromethyl)benzenamine provided the
title compound (10 mg, 7%): 1H NMR (400 MHz, two inseparable
isomers present in CDCl3) isomer 1, δ 10.05 (d, J ) 9 Hz, 1H),
8.91 (m, 1H), 8.77 (s, 1H), 8.42 (dd, J ) 2, 8 Hz, 1H), 8.27 (m,
1H), 8.01 (m, 1H), 7.42 (m, 1H), 7.36 (m, 1H), 7.27 (m, 1H), 7.18
(m, 1H), 3.08 (d, J ) 8 Hz, 3H), 2.84 (m, 4H), 1.77 (m, 4H), 1.63
(m, 2H); isomer 2, δ 10.05 (d, J ) 9 Hz, 1H), 8.91 (m, 1H), 8.63
(s, 1H), 8.27 (m, 2H), 8.01 (m, 1H), 7.42 (m, 1H), 7.36 (m, 1H),
7.27 (m, 1H), 7.18 (m, 1H), 3.04 (d, J ) 8 Hz, 3H), 2.84 (m, 4H),
1.77 (m, 4H), 1.63 (m, 2H); HPLC purity ) 96% (system A), 97%
(system C); HRMS (C30H29F3N6O2)+ calcd 563.23769, found
563.23706.
N-(2-((3-(Dimethylamino)propyl)(methyl)amino)-5-(trifluo-
romethyl)phenyl)-2-fluoro-5-(3-(4-(methylamino)-1,3,5-triazin-
2-yl)pyridin-2-yloxy)benzamide (63). Following the procedure
described for 15, 2-fluoro-5-(3-(4-(methylamino)-1,3,5-triazin-2-
yl)pyridin-2-yloxy)benzoic acid and N1-(3-(dimethylamino)propyl)-
N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine provided the title
compound (69 mg, 41%): 1H NMR (300 MHz, two inseparable
isomers present in DMSO-d6) isomer 1, δ 9.97 (d, J ) 6.9 Hz,
1H), 8.59 (s, 1H), 8.54 (m, 1H), 8.39 (d, J ) 4 Hz, 1H), 8.27 (m,
2H), 8.14 (m, 1H), 7.62 (m, 1H), 7.49 (m, 4H), 7.36 (m, 1H), 2.99
(m, 2H), 2.79 (d, J ) 3.3 Hz, 3H), 2.68 (s, 3H), 2.21 (m, 2H), 2.03
(s, 6H), 1.57 (m, 2H); isomer 2, δ 9.97 (d, J ) 6.9 Hz, 1H), 8.69
(s, 1H), 8.54 (m, 1H), 8.27 (m, 3H), 8.14 (m, 1H), 7.62 (m, 1H),
7.49 (m, 4H), 7.36 (m, 1H), 2.99 (m, 2H), 2.86 (d, J ) 3.3 Hz,
3H), 2.68 (s, 3H), 2.21 (m, 2H), 2.03 (s, 6H), 1.57 (m, 2H). Anal.
(C29H30F4N8O2·0.33H2O) H, N. C: calcd 58.19, found 57.67.
N-(2-((3-(Dimethylamino)propyl)(methyl)amino)-5-isopropy-
lphenyl)-2-fluoro-5-(3-(4-(methylamino)-1,3,5-triazin-2-yl)pyri-
din-2-yloxy)benzamide (64). Following the procedure described
for 15, 2-fluoro-5-(3-(4-(methylamino)-1,3,5-triazin-2-yl)pyridin-
2-yloxy)benzoic acid and N1-(3-(dimethylamino)propyl)-4-isopro-
pyl-N1-methylbenzene-1,2-diamine provided the title compound
(167 mg, 66%): 1H NMR (400 MHz, two inseparable isomers
present in DMSO-d6) isomer 1, δ 9.93 (d, J ) 8 Hz, 1H), 8.59 (s,
1H), 8.49 (d, J ) 2 Hz, 1H), 8.31 (m, 2H), 8.11 (m, 1H), 7.66 (m,
1H), 7.46 (m, 2H), 7.35 (m, 1H), 7.26 (d, J ) 8 Hz, 1H), 7.03 (d,
J ) 4 Hz, 1H), 2.88 (m, 4H), 2.80 (m, 2H), 2.58 (s, 3H), 2.38 (m,
2H), 2.17 (s, 6H), 1.57 (m, 2H), 1.20 (d, J ) 8 Hz, 6H); isomer 2,
δ 9.93 (d, J ) 8 Hz, 1H), 8.69 (s, 1H), 8.31 (m, 3H), 8.11 (m,
1H), 7.66 (m, 1H), 7.46 (m, 2H), 7.35 (m, 1H), 7.26 (d, J ) 8 Hz,
1H), 7.03 (d, J ) 4 Hz, 1H), 2.88 (m, 4H), 2.80 (m, 2H), 2.58 (s,
3H), 2.38 (m, 2H), 2.17 (s, 6H), 1.57 (m, 2H), 1.20 (d, J ) 8 Hz,
6H). Anal. (C31H37FN8O2·0.33H2O) H, N. C: calcd 65.02, found
64.34.
N-(5-Cyclopropyl-2-((3-(dimethylamino)propyl)(methyl)ami-
no)phenyl)-2-fluoro-5-(3-(4-(methylamino)-1,3,5-triazin-2-yl)py-
ridin-2-yloxy)benzamide (65). Following the procedure described
for 15, 2-fluoro-5-(3-(4-(methylamino)-1,3,5-triazin-2-yl)pyridin-
2-yloxy)benzoic acid and 4-cyclopropyl-N1-(3-(dimethylamino)-
propyl)-N1-methylbenzene-1,2-diamine provided the title compound
(97 mg, 35%): 1H NMR (400 MHz, two inseparable isomers
present in DMSO-d6) isomer 1, δ 9.98 (d, J ) 11.0 Hz, 1H), 8.69
(s, 1H), 8.40 (d, J ) 7.4, 1H), 8.27 (m, 1H), 8.12 (br s, 2H), 7.65
(br s, 1H), 7.46 (m, 2H), 7.36 (m, 1H), 7.21 (d, J ) 8.0 Hz, 1H),
6.86 (d, J ) 8.0 Hz, 1H), 2.86 (d, J ) 4.1 Hz, 3H), 2.84 (m, 2H),
2.55 (s, 3H), 2.17 (m, 2H), 1.99 (s, 6H), 1.88 (m, 1H), 1.48 (m,
2H), 0.91 (m, 2H), 0.61 (m, 2H); isomer 2, δ 9.98 (d, J ) 11.0 Hz,
1H), 8.59 (s, 1H), 8.32 (d, J ) 7.4, 1H), 8.27 (m, 1H), 8.12 (br s,
2H), 7.65 (br s, 1H), 7.46 (m, 2H), 7.36 (m, 1H), 7.21 (d, J ) 8.0
Hz, 1H), 6.86 (d, J ) 8.0 Hz, 1H), 2.84 (m, 2H), 2.79 (d, J ) 4.8
Hz, 3H), 2.55 (s, 3H), 2.17 (m, 2H), 1.99 (s, 6H), 1.88 (m, 1H),
1.48 (m, 2H), 0.91 (m, 2H), 0.61 (m, 2H). Anal. (C31H35FN8O2·
0.33H2O) H, N. C: calcd 65.25, found 64.57.
4-Methyl-3-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzoic Acid.
The title compound was synthesized following the procedure
described for 14: 1H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J )
1.1 Hz, 1H), 8.89 (d, J ) 5.4 Hz, 1H), 8.52 (dd, J ) 1.9, 7.4 Hz,
1H), 8.26 (dd, J ) 1.5, 5.4 Hz, 1H), 8.21 (dd, J ) 2.0, 5.1 Hz,
1H), 7.73 (dd, J ) 1.6, 7.8 Hz, 1H), 7.63 (d, J ) 2.0 Hz, 1H), 7.43
(d, J ) 7.8 Hz, 1H), 7.32 (dd, J ) 5.0, 7.8 Hz, 1H).
2-Fluoro-5-hydroxybenzoic Acid. To 2-fluoro-5-methoxyben-
zoic acid (15.0 g, 88.2 mmol) were added HBr (150 mL, 49%
aqueous) and glacial acetic acid (120 mL). A reflux condenser was
attached and the mixture was heated to 140 °C for 16 h. After
cooling the reaction to approximately 10 °C, the resulting solid
was filtered, washed with water, and dried to yield 13.6 g (99%)
of the title compound as a white solid: 1H NMR (300 MHz, DMSO-
d6) δ 9.71 (s, 1H), 7.18 (m, 1H), 7.11 (m, 1H), 6.96 (m, 1H).
2-Fluoro-5-(3-(4-(methylamino)-1,3,5-triazin-2-yl)pyridin-2-
yloxy)benzoic Acid. The title compound was synthesized following
the procedure described for 14: 1H NMR (300 MHz, DMSO-d6,
two inseparable isomers present in DMSO) isomer 1, δ 8.67 (s,
1H), 8.34 (m, 1H), 8.24 (m, 1H), 8.10 (br s, 1H), 7.48 (m, 1H),
7.35 (m, 3H), 2.85 (d, J ) 4.8 Hz, 3H); isomer 2, δ 8.56 (s, 1H),
8.24 (m, 2H), 8.10 (br s, 1H), 7.48 (m, 1H), 7.35 (m, 3H), 2.78 (d,
J ) 4.8 Hz, 3H).
N1-(3-(Dimethylamino)propyl)-N1-methyl-4-(trifluoromethyl)-
benzene-1,2-diamine. Step 1. N1,N1,N3-Trimethylpropane-1,3-
diamine (0.84 mL, 5.74 mmol) and sodium bicarbonate (1.1 g, 13
mmol) were added to 1-fluoro-2-nitro-4-(trifluoromethyl)benzene
(1.0 g, 4.8 mmol) in THF (25 mL). The mixture was stirred at
room temperature for 1 h, filtered, and concentrated. The crude
material was dissolved in CH2Cl2 and extracted with water. The
organic layer was dried over anhydrous sodium sulfate, filtered,
and concentrated to yield 1.42 g (97%) of N-(3-(dimethylamino)-
propyl)-N-methyl-2-nitro-4-(trifluoromethyl)benzenamine as an or-
ange oil: 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.55 (dd, J
) 2, 9 Hz, 1H), 7.16 (d, J ) 9 Hz, 1H), 3.39 (m, 2H), 2.86 (s,
3H), 2.31 (m, 2H), 2.22 (s, 6H), 1.83 (m, 2H).
Step 2. N-(3-(Dimethylamino)propyl)-N-methyl-2-nitro-4-(trif-
luoromethyl)benzenamine (1.42 g, 4.65 mmol) was dissolved in
MeOH (46 mL), and 10% Pd/C (0.493 g, 0.465 mmol) was added.