Journal of Medicinal Chemistry
Article
1
methylpiperazine (20 μL, 0.18 mmol). H NMR (400 MHz,
ybenzyl)-6-methyl-1,3,5-triazin-2-amine (106h) (110 mg, 63%)
as a viscous yellow oil. LC−MS m/z: 640 (M + H) .
+
CDCl ): δ 11.41 (br s, 1H), 8.51 (d, J = 2.93 Hz, 1H), 8.34 (d,
J = 2.54 Hz, 1H), 8.11 (d, J = 2.93 Hz, 1H), 8.11−8.07 (m,
H), 6.76 (d, J = 8.80 Hz, 1H), 5.34 (br s, 2H), 3.93 (s, 3H),
3
A solution of 106h (110 mg, 0.17 mmol) in TFA (265 μL,
3.44 mmol) was treated with TfOH (15 μL, 0.17 mmol), and
the mixture was heated at 80 °C for 16 h. The mixture was
concentrated and purified by silica gel column chromatography
(gradient: 0% → 3% 2 M NH in MeOH/CH Cl ) to give 61
1
3
.22 (br s, 4H), 2.71 (br s, 4H), 2.56 (s, 3H), 2.45 (br s, 3H).
5
-(4-Amino-6-methyl-1,3,5-triazin-2-yl)-N-(6-methox-
ypyridin-3-yl)-6′-methyl-3,3′-bipyridin-6-amine (42).
The title compound was synthesized as a yellow crystalline
solid (57 mg, 56%) following a similar two step procedure to
that described for 40 using 73j (144 mg, 0.25 mmol) and 6-
methylpyridin-3-ylboronic acid (40.5 mg, 0.30 mmol).
NMR (400 MHz, DMSO-d ): δ 11.85 (s, 1H), 9.03 (d, J = 2.7
Hz, 1H), 8.77 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.5 Hz, 1H),
.56 (d, J = 2.7 Hz, 1H), 8.20 (dd, J = 8.8, 2.7 Hz, 1H), 7.99
3
2
2
1
(15 mg, 22%) as a yellow solid. H NMR (400 MHz, DMSO-
d6): δ 11.68 (s, 1H), 8.61 (d, J = 2.15 Hz, 1H), 8.53 (d, J = 2.54
Hz, 1H), 8.23 (d, J = 2.15 Hz, 1H), 8.16 (dd, J = 8.80, 2.74 Hz,
1H), 7.83 (br s, 1H), 7.69 (br s, 1H), 7.11−7.45 (m, 5H), 6.81
(d, J = 8.80 Hz, 1H), 3.94 (s, 2H), 3.84 (s, 3H), 2.41 (s, 3H).
4-(5-((2-Methoxyethylamino)methyl)-2-(6-methoxy-
pyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-
amine (38). A solution of 103a (240 mg, 0.42 mmol) in
CH Cl (2 mL) and MeOH (2 mL) was treated with 2-
1
H
6
8
(
(
(
dd, J = 8.1, 2.2 Hz, 1H), 7.91 (br s, 1H), 7.77 (br s, 1H), 7.38
d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 3.86 (s, 3H), 2.52
s, 3H), 2.46 (s, 3H).
2
2
methoxyethanamine (54 μL, 0.62 mmol) and NaBH(OAc)3
(264 mg, 1.25 mmol). The mixture was stirred for 2 h,
concentrated, diluted with CH Cl (100 mL), washed with
4
-(2-(6-Methoxypyridin-3-ylamino)-5-(1-methyl-1H-
pyrazol-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-
amine (43). The title compound was synthesized as an orange
crystalline solid (72 mg, 83%) following a similar two step
procedure to that described for 40 using 73j (97 mg, 0.17
2
2
saturated aqueous NaHCO (2 × 100 mL), dried (Na SO ),
3
2
4
and concentrated to give N,N-bis(4-methoxybenzyl)-4-(5-(((2-
methoxyethyl)amino)methyl)-2-((6-methoxypyridin-3-yl)-
amino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (107a),
which was used without further purification.
mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
1
2
-yl)-1H-pyrazole (42 mg, 0.20 mmol). H NMR (400 MHz,
DMSO-d ): δ 11.69 (s, 1H), 8.87 (d, J = 2.5 Hz, 1H), 8.55 (t, J
The 107a thus obtained was deprotected using the procedure
6
=
(
3
3.1 Hz, 2H), 8.18 (dd, J = 8.8, 2.7 Hz, 1H), 8.12 (s, 1H), 7.90
s, 1H), 7.82 (s, 1H), 7.77 (s, 1H), 6.84 (d, J = 8.8 Hz, 1H),
.88 (s, 3H), 3.85 (s, 3H), 2.46 (s, 3H).
-(2-(6-Methoxypyridin-3-ylamino)-5-((4-methylpi-
perazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-
-amine (51). A mixture of 73j (160 mg, 0.27 mmol), X-Phos
13 mg, 0.03 mmol), Cs CO (268 mg, 0.82 mmol), potassium
described for 36 to give 38 (37 mg, 22%) as a yellow crystalline
1
solid. H NMR (400 MHz, CDCl ): δ 11.63 (s, 1H), 8.78 (d, J
3
= 2.54 Hz, 1H), 8.35 (d, J = 2.54 Hz, 1H), 8.24 (d, J = 2.54 Hz,
1H), 8.12 (dd, J = 8.80, 2.74 Hz, 1H), 6.77 (d, J = 8.80 Hz,
1H), 5.63 (s, 2H), 3.94 (s, 3H), 3.78 (s, 2H), 3.57−3.52 (m,
2H), 3.36 (s, 3H), 2.86−2.80 (m, 2H), 2.55 (s, 3H).
4
2
(
4-(5-(Azetidin-1-ylmethyl)-2-(6-methoxypyridin-3-
ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine
(44). The title compound was synthesized as a yellow
crystalline solid (11 mg, 7%) following the two step procedure
described for 38 using 103a (228 mg, 0.40 mmol) and
2
3
1
-methyl-4-trifluoroboratomethylpiperazine (66 mg, 0.30
mmol), and Pd(OAc) (3.1 mg, 0.014 mmol) in THF (1
mL) and H O (0.1 mL) was purged with Ar and heated in a
microwave reactor at 140 °C for 30 min. The mixture was
filtered through a short plug of diatomaceous earth, washing
with EtOAc, and the filtrate was concentrated and purified by
silica gel column chromatography (gradient: 0% → 5% MeOH/
CH Cl ) to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methox-
2
2
1
azetidine hydrochloride (48 mg, 0.51 mmol). H NMR (400
MHz, CDCl ): δ 11.75 (s, 1H), 8.90 (d, J = 2.35 Hz, 1H), 8.37
3
(d, J = 2.74 Hz, 1H), 8.17 (d, J = 2.35 Hz, 1H), 8.08 (dd, J =
8.90, 2.64 Hz, 1H), 6.77 (d, J = 8.80 Hz, 1H), 3.94 (s, 3H),
3.76 (s, 2H), 3.53 (t, J = 7.34 Hz, 4H), 2.53 (s, 3H), 2.28 (quin,
J = 7.38 Hz, 2H).
4-(2-(6-Methoxypyridin-3-ylamino)-5-(pyrrolidin-1-
ylmethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine
(45). The title compound was synthesized as a yellow
crystalline solid (81 mg, 46%) following the two step procedure
2
2
ypyridin-3-ylamino)-5-((4-methylpiperazin-1-yl)methyl)-
pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (106g) (161 mg,
+
8
9%) as a viscous yellow oil. LC−MS m/z: 662 (M + H) .
The title compound was synthesized from 106g (175 mg,
.28 mmol) as a yellow solid (98 mg, 96%) following an
0
analogous deprotection procedure to that described for
compound 36. H NMR (400 MHz, DMSO-d ): δ 11.74 (s,
1
described for 38 using 103a (257 mg, 0.45 mmol) and
6
1
1
8
=
H), 8.69 (d, J = 2.15 Hz, 1H), 8.54 (d, J = 2.74 Hz, 1H),
.33−8.00 (m, 2H), 7.86 (br s, 1H), 7.71 (br s, 1H), 6.82 (d, J
pyrrolidine (48 mg, 0.67 mmol). H NMR (400 MHz, CDCl ):
3
δ 11.64 (s, 1H), 8.71 (d, J = 2.35 Hz, 1H), 8.36 (d, J = 2.54 Hz,
1H), 8.20 (d, J = 2.35 Hz, 1H), 8.13 (dd, J = 8.80, 2.74 Hz,
1H), 6.76 (d, J = 8.80 Hz, 1H), 6.33 (br s, 2H), 3.94 (s, 3H),
3.58 (s, 2H), 2.57 (br s, 4H), 2.54 (s, 3H), 1.90−1.80 (m, 4H).
4-(2-(6-Methoxypyridin-3-ylamino)-5-(piperidin-1-
ylmethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine
(46). The title compound was synthesized as a yellow
crystalline solid (52 mg, 28%) following the two step procedure
8.80 Hz, 1H), 3.84 (s, 3H), 3.81−3.49 (m, 4H), 3.40 (s, 2H),
2
.44 (s, 3H), 2.35 (m, 4H), 2.14 (s, 3H).
-(5-Benzyl-2-(6-methoxypyridin-3-ylamino)pyridin-
-yl)-6-methyl-1,3,5-triazin-2-amine (61). A mixture of 2-
4
3
benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (90 mg, 0.41
mmol), 73j (160 mg, 0.27 mmol), Pd dba (12 mg, 0.014
mmol), X-Phos (13 mg, 0.027 mmol), and Na CO ·H O (73
mg, 0.69 mmol) in 1,4-dioxane (2.5 mL) and H O (0.25 mL)
2
3
2
3
2
described for 38 using 103a (264 mg, 0.46 mmol) and
2
1
was purged with Ar and heated in a microwave reactor at 140
piperidine (68 μL, 0.69 mmol). H NMR (400 MHz, CDCl ):
3
°
C for 30 min. The mixture was filtered through a short plug of
δ 11.64 (s, 1H), 8.72 (d, J = 2.35 Hz, 1H), 8.35 (d, J = 2.54 Hz,
1H), 8.21 (d, J = 2.35 Hz, 1H), 8.14 (dd, J = 8.90, 2.84 Hz,
1H), 6.77 (d, J = 9.00 Hz, 1H), 5.56 (br s, 2H), 3.94 (s, 3H),
3.45 (s, 2H), 2.56 (s, 3H), 2.41 (br s, 3H), 1.60 (dt, J = 10.95,
5.48 Hz, 5H), 1.46−1.39 (m, 2H).
diatomaceous earth, washing with EtOAc. The filtrate was
concentrated and purified by silica gel column chromatography
(
(
gradient: 0% → 30% EtOAc/hexanes) to give 4-(5-benzyl-2-
6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methox-
5
212
dx.doi.org/10.1021/jm300184s | J. Med. Chem. 2012, 55, 5188−5219