4614 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 24
Barvian et al.
8-sec-Bu tyl-2-ph en yla m in o-8H-p yr id o[2,3-d ]p yr im idin -
7-on e (41): mp 155-156 °C; 1H NMR (DMSO-d6) δ 0.78 (br s,
3H), 1.50 (d, J ) 6.5 Hz, 3H), 2.15 (br s, 1H), 1.93 (dq, J )
6.7, 3.7 Hz, 1H), 5.54 (br s, 1H), 6.32 (d, J ) 8.4 Hz, 1H), 7.04
(t, J ) 7.2 Hz, 1H), 7.34 (t, J ) 7.5 Hz, 2H), 7.73 (d, J ) 8.0
Hz, 1H), 7.67 (d, J ) 9.4 Hz, 2H), 8.76 (s, 1H), 10.02 (br s,
1H); MS (CI) m/z ) 295 (M + 1). Anal. (C17H18N4O) C, H, N.
8-Bu t yl-2-p h en yla m in o-8H-p yr id o[2,3-d ]p yr im id in -7-
on e (42): mp 183-184 °C; 1H NMR (DMSO-d6) δ 0.94 (t, J )
7 Hz, 3H), 1.38-1.44 m, 2H), 1.63-1.67 (m, 2H), 4.25 (t, J )
8 Hz, 2H), 6.39 (d, J ) 9 Hz, 1H), 7.04 (t, J ) 7 Hz, 1H), 7.33
(t, J ) 7 Hz, 2H), 7.80-7.83 (m, 3H), 8.78 (s, 1H), 10.12 (s,
1H); MS (CI) m/z 295 (M + 1). Anal. (C17H18N4O‚0.25H2O) C,
H, N.
8-Isobu tyl-2-p h en yla m in o-8H-p yr id o[2,3-d ]p yr im id in -
7-on e (43): mp 170-171 °C; 1H NMR (DMSO-d6) δ 0.89 (d, J
) 7 Hz, 6H), 2.26-2.29 (m, 1H), 4.14 (d, J ) 7 Hz, 2H), 6.39
(d, J ) 9 Hz, 1H), 7.04 (t, J ) 7 Hz, 1H), 7.34 (t, J ) 7 Hz,
2H), 7.81-7.83 (m, 3H), 8.78 (s, 1H), 10.11 (s, 1H); MS (CI)
m/z 295 (M + 1). Anal. (C17H18N4O‚0.10EtOAc) C, H, N.
8-(1-Eth ylp r op yl)-2-p h en yla m in o-8H-p yr id o[2,3-d ]p y-
r im id in -7-on e (44): mp 116-118 °C; major conformer: 1H
NMR (DMSO-d6) δ 0.76 (t, J ) 7 Hz, 6H), 1.83-1.90 (m, 4H),
5.40-5.55 (m, 1H), 6.30 (d, J ) 9 Hz, 1H), 7.04 (t, J ) 7 Hz,
1H), 7.32-7.36 (m, 2H), 7.75-7.81 (m, 3H), 8.77 (s, 1H), 10.07
(s, 1H); MS (CI) m/z 309 (M + 1). Anal. (C18H20N4O‚0.2H2O)
C, H, N.
8-Cyclop en tyl-2-p h en yla m in o-8H-p yr id o[2,3-d ]p yr im i-
d in -7-on e (45): mp 188-192 °C; 1H NMR (DMSO-d6) δ 1.59-
1.64 (m, 2H), 1.73-1.78 (m, 2H), 1.81-1.92 (m, 2H), 2.22-
2.30 (m, 2H), 5.81-6.03 (m, 1H), 6.33 (d, J ) 9 Hz, 1H), 7.04
(t, J ) 7 Hz, 1H), 7.34 (t, J ) 7 Hz, 2H), 7.71 (d, J ) 8 Hz,
2H), 7.77 (d, J ) 9 Hz, 1H), 8.76 (s, 1H), 10.00 (s, 1H); MS
(CI) m/z 307.3 (M + 1). Anal. (C18H18N4O‚0.28H2O) C, H, N.
8-Cycloh exyl-2-p h en yla m in o-8H-p yr id o[2,3-d ]p yr im i-
d in -7-on e (46): mp 202-204 °C; 1H NMR (DMSO-d6) δ 1.21-
1.39 (m, 3H), 1.57-1.99 (m, 5H), 2.49-2.60 (m, 2H), 5.35 (br
s, 1H), 6.31 (d, J ) 9 Hz, 1H), 7.06 (t, J ) 7 Hz, 1H), 7.35 (t,
J ) 7 Hz, 2H), 7.59-7.77 (m, 3H), 8.75 (s, 1H), 10.04 (s, 1H);
MS (CI) m/z 321 (M + 1). Anal. (C19H20N4O‚0.20H2O) C, H, N.
8-Cycloh ep tyl-2-p h en yla m in o-8H-p yr id o[2,3-d ]p yr im i-
d in -7-on e (47): mp 156-158 °C; 1H NMR (DMSO-d6) δ 1.52-
1.77 (m, 10H), 2.41-2.43 (m, 2H), 5.59 (br s, 1H), 6.31 (d, J )
9 Hz, 1H), 7.06 (t, J ) 7 Hz, 1H), 7.34 (t, J ) 7 Hz, 2H), 7.74-
7.77 (m, 3H), 8.75 (s, 1H), 10.11 (s, 1H); MS (CI) m/z 335 (M
+ 1). Anal. (C20H22N4O) C, H, N.
brine. The organic layer was dried over magnesium sulfate,
filtered, and concentrated in vacuo.
8-Cycloh exylm eth yl-2-p h en yla m in o-8H-p yr id o[2,3-d ]-
p yr im id in -7-on e (50): mp 230-231 °C; 1.00-1.20 (m, 5H),
1.57-1.60 (m, 3H), 1.67 (br s, 2H), 1.97 (br s, 1H), 1.45 (d, J
) 7 Hz, 2H), 6.39 (d, J ) 9 Hz, 1H), 7.04 (t, J ) 7 Hz, 1H),
7.33 (t, J ) 8 Hz, 2H), 7.80-7.84 (m, 3H), 8.78 (s, 1H), 10.11
(s, 1H); MS (CI) m/z 335.2 (M + 1). Anal. (C20H22N4O) C, H,
N.
8-Ben zyl-2-p h en yla m in o-8H-p yr id o[2,3-d ]p yr im id in -7-
on e (51): mp 215-216 °C; 1H NMR (DMSO-d6) δ 5.49 (s, 2H),
6.48 (d, J ) 9.4 Hz, 1H), 6.99 (t, J ) 7.4 Hz, 1H), 7.20-7.31
(m, 7H), 7.60 (d, J ) 8.0 Hz, 2H), 7.90 (d, J ) 9.4 Hz, 1H),
8.82 (s, 1H), 10.09 (s, 1H); MS (CI) m/z ) 329 (M + 1). Anal.
(C20H16N4O1‚0.25H2O) C, H, N.
8-Meth oxym eth yl-2-p h en yla m in o-8H-p yr id o[2,3-d ]p y-
1
r im id in -7-on e (52): mp 173-174 °C; H NMR (DMSO-d6) δ
3.34 (s, 3H), 5.64 (s, 2H), 6.40 (d, J ) 9 Hz, 1H), 7.03 (t, J )
7 Hz, 1H), 7.34 (t, J ) 7 Hz, 2H), 7.81 (d, J ) 7 Hz, 2H), 7.86
(d, J ) 9 Hz, 1H), 8.80 (s, 1H), 8.83 (s, 1H), 10.14 (s, 1H); MS
(CI) m/z 283 (M + 1). Anal. (C15H14N4O2) C, H, N.
8-(2-Met h oxyet h yl)-2-p h en yla m in o-8H -p yr id o[2,3-d ]-
p yr im id in -7-on e (53): mp 179-180 °C; 1H NMR (DMSO-d6)
δ 3.26 (s, 3H), 3.62 (t, J ) 6.4 Hz, 2H), 4.47 (t, J ) 6.4 Hz,
2H), 6.39 (d, J ) 9.4 Hz, 2H), 7.03 (t, J ) 7.3 Hz, 1H), 7.33 (t,
J ) 7.8 Hz, 2H), 7.80 (d, J ) 6.8 Hz, 2H), 7.82 (d, J ) 9.2 Hz,
1H), 8.78 (s, 1H), 10.11 (s, 1H); MS (CI) m/z ) 297 (M + 1).
Anal. (C16H16N4O2‚0.12H2O) C, H, N.
8-(2-Eth oxyeth yl)-2-p h en yla m in o-8H-p yr id o[2,3-d ]p y-
1
r im id in -7-on e (54): mp 151-153 °C; H NMR (DMSO-d6) δ
0.99 (t, J ) 7.0 Hz, 3H), 3.40 (q, J ) 6.9 Hz, 2H), 3.58 (t, J )
6.7 Hz, 2H), 4.40 (t, J ) 6.7 Hz, 2H), 6.34 (d, J ) 9.3 Hz, 1H),
6.98 (t, J ) 7.3 Hz, 1H), 7.27 (t, J ) 7.8 Hz, 2H), 7.74-7.78
(m, 3 H), 8.73 (s, 1H), 10.06 (s, 1H); MS (CI) m/z ) 311.1 (M
+ 1). Anal. (C17H18N4O2) C, H, N.
8-Oxir a n ylm eth yl-2-p h en yla m in o-8H-p yr id o[2,3-d ]p y-
1
r im id in -7-on e (55): mp 163-165 °C; H NMR (DMSO-d6) δ
2.61-2.62 (m, 1H), 2.73-2.75 (m, 1H), 3.30-3.32 (m, 1H),
4.34-4.39 (m, 1H), 4.52-4.57 (m,1H), 6.42 (d, J ) 9 Hz, 1H),
7.04 (t, J ) 7 Hz, 1H), 7.35 (t, J ) 7 Hz, 2H), 7.79 (d, J ) 7
Hz, 2H), 7.86 (d, J ) 9 Hz, 1H), 8.80 (s, 1H), 10.13 (s, 1H); MS
(CI) m/z 295 (M + 1). Anal. (C16H14N4O2‚0.05EtOAc) C, H, N.
(7-Oxo-2-p h en yla m in o-7H -p yr id o[2,3-d ]p yr im id in -8-
yl)a cetic a cid m eth yl ester (56): mp 232-233 °C; 1H NMR
(DMSO-d6) δ 3.68 (s, 3H), 5.04 (s, 2H), 6.45 (d, J ) 9 Hz, 1H),
7.04 (t, J ) 7 Hz, 1H), 7.32 (t, J ) 7 Hz, 2H), 7.69 (d, J ) 7
Hz, 2H), 7.91 (d, J ) 9 Hz, 1H), 8.83 (s, 1H), 10.18 (s, 1H); MS
(CI) m/z 311 (M + 1). Anal. (C16H14N4O3) C, H, N.
8-Bicyclo[2.2.1]h ept-2-yl-2-ph en ylam in o-8H-pyr ido[2,3-
1
d ]p yr im id in -7-on e (48): mp 225-226 °C; H NMR (DMSO-
The following compounds were prepared from 2 via a similar
route to the one described for compound 1.
d6) δ 1.16 (d, J ) 9 Hz, 1H), 1.25-1.29 (m, 1H), 1.40 (t, J ) 9
Hz, 1H), 1.51-1.62 (m, 2H), 1.69 (t, J ) 10 Hz, 1H), 2.17-
2.20 (m, 1H), 2.37 (br s, 1H), 2.41 (br s, 1H), 2.62 (d, J ) 9 Hz,
1H), 5.32 (t, J ) 8 Hz, 1H), 6.28 (d, J ) 9 Hz, 1H), 7.05 (t, J
) 7 Hz, 1H), 7.33 (t, J ) 9 Hz, 2H), 7.73 (d, J ) 9 Hz, 1H),
7.77 (d, J ) 9 Hz, 2H), 8.74 (s, 1H), 10.06 (s, 1H). Anal.
(C20H20N4O1‚0.2H2O) C, H, N.
2-[4-(2-Dieth ylam in oeth oxy)ph en ylam in o]-8-isopr opyl-
8H -p yr id o[2,3-d ]p yr im id in -7-on e (57): mp 84-85 °C; 1H
NMR (DMSO-d6) δ 0.975 (t, J ) 7 Hz, 6H), 1.50 (d, J ) 6 Hz,
6H), 2.55 (q, J ) 7 Hz, 4H), 2.76 (t, J ) 6 Hz, 2H), 3.99 (t, J
) 6 Hz, 2H), 5.45 (b, 1H), 6.27 (d, J ) 9 Hz, 1H), 6.92 (d, J )
9 Hz, 2H), 7.58 (d, J ) 9 Hz, 2H), 7.72 (d, J ) 9 Hz, 1H), 8.70
(s, 1H), 9.82 (s, 1H); MS (CI) m/z 396 (M + 1). Anal.
(C22H29N5O2) C, H, N.
8-P h en yl-2-p h en yla m in o-8H-p yr id o[2,3-d ]p yr im id in -7-
on e (49): mp 300-302 °C; 1H NMR (DMSO-d6) δ 6.49 (d, J )
- 9 Hz, 1H), 6.84 (t, J ) 7 Hz, 1H), 6.96 (t, J ) 8 Hz, 2H), 7.29
(d, J ) 8 Hz, 2H), 7.35 (dd, J ) 1, 4 Hz, 2H), 7.55-7.63 (m,
3H), 7.94 (d, J ) 9 Hz, 1H), 8.83 (s, 1H), 10.01 (s, 1H). Anal.
(C19H14N4O1‚0.25H2O) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of 8-Su bsti-
t u t e d -2-p h e n y la m in o -8H -p y r id o [2,3-d ]p y r im id in -7-
on es fr om 2-P h en yla m in o-8H-p yr id o[2,3-d ]p yr im id in -7-
on e (7). To a suspension of NaH (1.0-1.5 equiv of a 60%
suspension of NaH in mineral oil) in 5 mL of dimethylforma-
mide was added 7 (1 equiv). The reaction mixture was heated
to 50-60 °C resulting in a yellow solution. The solution was
cooled slightly and the desired alkyl halide (1.1-2.0 equiv) was
added. The reaction mixture was heated at 50 °C, for a time
ranging from 5 min to 1 h, then cooled to room temperature
and partitioned between water and ethyl acetate. In some
cases, the organic layer was washed with additional water or
8-Cyclop en tyl-2-[4-(2-d ieth yla m in oeth oxy)p h en yla m i-
n o]-8H-p yr id o[2,3-d ]p yr im id in -7-on e (58): mp 105-107
1
°C; H NMR (DMSO-d6) δ 0.975 (t, J ) 7 Hz, 6H), 1.56-1.87
(m, 6H), 2.21-2.28 (m, 2H), 2.50 (q, J ) 7 Hz, 4H), 2.76 (t, J
) 6 Hz, 2H), 3.99 (t, J ) 6 Hz, 2H), 5.82 (br s, 1H), 6.29 (d, J
) 9 Hz, 1H), 6.92 (d, J ) 9 Hz, 2H), 7.55 (d, J ) 9 Hz, 2H),
7.74 (d, J ) 9 Hz, 1H), 8.70 (s, 1H), 9.81 (s, 1H); MS (CI) m/z
422 (M + 1). Anal. (C24H31N5O2‚0.25H2O) C, H, N.
8-Cycloh exyl-2-[4-(2-dieth ylam in oeth oxy)ph en ylam in o]-
8H-p yr id o[2,3-d ]p yr im id in -7-on e (59): mp 135-137 °C; 1H
NMR (DMSO-d6) δ 0.975 (t, J ) 7 Hz, 6H), 1.29-1.82 (m, 8H),
2.50 (q, J ) 7 Hz, 4H), 2.76 (t, J ) 6 Hz, 2H), 4.01 (t, J ) 6
Hz, 2H), 5.35 (br s, 1H), 6.27 (d, J ) 9 Hz, 1H), 6.92 (d, J ) 9
Hz, 2H), 7.59 (br s, 2H), 7.72 (d, J ) 9 Hz, 1H), 8.69 (s, 1H),
9.90 (s, 1H); MS (CI) m/z 436 (M + 1). Anal. (C25H33N5O2) C,
H, N.