Article
2-(2-Chloro-5-methoxy-6-oxo-6H-pyrimidin-1-ylmethyl)ben-
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2 519
3H), 7.95 (s, 1H), 7.90 (dd, 1H, J = 7.6, 1.2 Hz), 7.75 (t, 1H, J =
7.6Hz), 7.56(t, 1H,J= 7.6 Hz), 7.45 (d, 1H, J=7.6Hz), 5.28(AB
q, 2H, J = 46.8, 15.6 Hz), 3.50-3.55 (m, 1H), 3.24-3.35 (m, 2H),
2.83-3.00 (m, 2H), 1.92-2.02 (s, 1H), 1.76-1.84 (m, 1H), 1.50-
1.64 (m, 2H). MS (ES) [M þ H] calcd for C17H18BrN5O, 388, 390;
found 388, 390.
zonitrile (9i) was prepared in 33% yield from 2-chloro-5-meth-
oxy-3H-pyrimidin-4-one (8i) according to the general procedure
outlined for 2-(5-bromo-2-chloro-6-oxo-6H-pyrimidin-1-ylmethyl)-
benzonitrile (9c). 1H NMR (400 MHz, CDCl3): δ 7.71 (d, 1H, J =
7.2 Hz), 7.55 (t, 1H, J = 7.2 Hz), 7.42 (t, 1H, J = 7.2 Hz), 7.34 (s,
1H), 7.12 (d, 1H, J = 7.2 Hz), 5.66 (s, 2H), 3.89 (s, 3H). MS (ES)
[M þ H] calcd for C13H10ClN3O2, 276, 278; found 276, 278.
13i was prepared in 49% yield from 2-(2-chloro-5-methoxy-6-
oxo-6H-pyrimidin-1-ylmethyl)benzonitrile (9i) according to the
general procedure outlined for 13c and was isolated as the TFA
salt. 1H NMR (400 MHz, CD3OD): δ 7.71 (d, 1H, J = 7.2 Hz),
7.59 (t, 1H, J = 7.2 Hz), 7.47 (s, 1H), 7.42 (t, 1H, J = 7.2 Hz), 7.19
(d, 1H, J = 7.2 Hz), 5.46 (s, 2H), 3.79 (s, 3H), 3.31-3.40 (m, 1H),
3.02-3.21 (m, 2H), 2.72-2.85 (m, 2H), 1.92-2.02 (m, 1H),
1.61-1.82 (m, 2H), 1.38-1.48 (m, 1H). MS (ES) [M þ H] calcd
for C18H21N5O2, 340; found 340.
2-[2-(3-(R)-Aminopiperidin-1-yl)-6-oxo-4-phenyl-6H-pyrimidin-
1-ylmethyl]benzonitrile, TFA salt (13j). 2-(2-Chloro-6-oxo-4-phenyl-
6H-pyrimidin-1-ylmethyl)benzonitrile (9j) was prepared in 49%
yield from 2-chloro-4-phenyl-3H-pyrimidin-4-one29 according to
the procedure for 2-(5-bromo-2-chloro-6-oxo-6H-pyrimidin-1-yl-
methyl)benzonitrile (9c). 1H NMR (400 MHz, CDCl3): δ 7.96 (d,
2H, J = 7.6 Hz), 7.73 (d, 1H, J = 7.6 Hz), 7.41-7.60 (m, 5H), 7.21
(d, 1H, J = 7.6 Hz), 6.92 (s, 1H), 5.69 (s, 2H). MS (ES) [M þ H]
calcd for C18H12ClN3O, 322, 324; found 322, 324.
2-[2-(3-(R)-Aminopiperidin-1-yl)-6-oxo-5-phenyl-6H-pyrimidin-
1-ylmethyl]benzonitrile, TFA salt (15a). 2-[2-(3-(R)-Aminopiper-
idin-1-yl)-5-bromo-6-oxo-6H-pyrimidin-1-ylmethyl]benzonitrile
(13c, 70 mg, 0.18 mmol), phenylboronic acid (33 mg, 0.27 mmol),
and sodium carbonate (57 mg, 0.54 mmol) were stirred in DME
(2 mL)/ H2O (0.3 mL) in a flask purged with nitrogen. Tetrakis-
(triphenylphosphine)palladium(0) (31 mg, 0.03 mmol) was added,
and the mixture was stirred at 88 °C for 2 h. The mixture was
diluted with EtOAc, washed with brine, dried (MgSO4), and
concentrated in vacuo. Purification by silica gel chromatography
(5% MeOH/CHCl3) followed by conversion to the TFA salt with
TFA/CH2Cl2 gave 76 mg (85%) of the title compound as a white
solid. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.93 (br s,
3H), 7.82 (d, 1H, J = 7.2 Hz), 7.63 (dt, 1H, J = 7.6, 1.2 Hz), 7.56
(d, 2H, J = 8.4 Hz), 7.45 (t, 1H, J = 7.6 Hz), 7.24-7.37 (m, 4H),
5.34 (AB q, 2H, J = 40.0, 15.2 Hz), 3.53-3.59 (m, 1H), 3.36-3.45
(m, 1H), 3.18-3.25 (m, 1H), 2.80-3.08 (m, 2H), 1.92-2.00 (m,
1H), 1.79-1.85 (m, 1H), 1.51-1.67 (m, 2H). MS (ES) [M þ H]
calcd for C23H23N5O, 386; found 386.
2-[2-(3-(R)-Aminopiperidin-1-yl)-4-methyl-6-oxo-5-phenyl-6H-
pyrimidin-1-ylmethyl]benzonitrile, TFA salt (15b). 15b was pre-
pared in 64% yield from phenylboronic acid and 2-[2-(3-(R)-
aminopiperidin-1-yl)-5-bromo-4-methyl-6-oxo-6H-pyrimidin-1-
ylmethyl]benzonitrile (13d) according to the general procedure
outlined for 15a. 1H NMR (400 MHz, DMSO-d6): δ 8.09 (br s,
3H), 7.81 (d, 1H, J = 7.6 Hz), 7.64 (dt, 1H, J = 7.6, 1.2 Hz), 7.44
(t, 1H, J = 7.6 Hz), 7.14-7.37 (m, 6H), 5.30 (AB q, 2H, J = 43.2,
15.2 Hz), 3.51-3.57 (m, 1H), 3.33-3.42 (m, 1H), 3.12-3.20 (m,
1H), 3.10-3.19 (m, 1H), 2.85-2.93 (m, 1H), 2.08 (s, 3H),
1.92-2.00 (m, 1H), 1.79-1.85 (m, 1H), 1.51-1.67 (m, 2H). MS
(ES) [M þ H] calcd for C24H25N5O, 400; found 400.
Also obtained from the reaction were impure fractions of the
less polar O-alkylated isomer (10j).
13j was prepared in 72% yield from 2-(2-chloro-6-oxo-4-
phenyl-6H-pyrimidin-1-ylmethyl)benzonitrile (9j) according to
the general procedure outlined for 13c and was isolated as the
HCl salt. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 3H), 8.06-
8.14 (m, 2H), 7.81 (d, 1H, J = 7.6 Hz), 7.62 (t, 1H, J = 7.6 Hz),
7.39-7.51 (m, 4H), 7.23 (d, 1H, J=7.6Hz), 6.69(s,1H), 5.33(AB
q, 2H, J = 36.8, 15.2 Hz), 3.67-3.76 (m, 1H), 3.35-3.45 (m, 1H),
3.15-3.26 (m, 2H), 2.90-3.00 (m, 1H), 1.95-2.05 (m, 1H), 1.78-
1.88 (m, 1H), 1.53-1.70 (m, 2H). MS (ES) [M þ H] calcd for
C23H23N5O, 386; found 386.
(R)-2-{[2-(3-Aminopiperidin-1-yl)-4-oxo-5,6,7,8-tetrahydro-
quinazoline-3(4H)-yl]methyl}benzonitrile, TFA salt (13k). 2-
Chloro-5,6,7,8-tetrahydroquinazoline-4(3H)-one (8k) was
prepared in 47% yield from 5,6,7,8-tetrahydroquinazoline-
2,4(1H,3H)-dione30 (6k) utilizing a method analogous to the
preparation of 2-chloro-5,6-dimethyl-3H-pyrimidin-4-one.27
1H NMR (400 MHz, DMSO-d6): δ 13.20 (br s, 1H), 2.58-2.72
(m, 4H), 1.75-1.92 (m, 4H). MS (ES) [M þ H] calcd for
C8H9ClN2O 185, 187; found 185, 187.
2-[2-(3-(R)-Aminopiperidin-1-yl)-5-(2-fluorophenyl)-6-oxo-6H-
pyrimidin-1-ylmethyl]benzonitrile, TFA salt (15c). 15c was pre-
pared in 48%yield from2-fluorophenylboronic acid according to
the procedure outlined for 15a. 1H NMR (400 MHz, DMSO-d6):
δ 7.92(brs, 3H), 7.85 (s, 1H), 7.71(d, 1H, J = 7.2Hz), 7.54 (t, 1H,
J = 7.6 Hz), 7.35 (t, 1H, J = 7.6 Hz), 7.06-7.27 (m, 5H), 5.23
(AB q, 2H, J = 40.4, 15.2 Hz), 3.47-3.54 (m, 1H), 3.36-3.45 (m,
1H), 3.12-3.20 (m, 1H), 2.93-3.02 (m, 1H), 2.83-2.90 (m, 1H),
1.22-1.90 (m, 1H), 1.70-1.78 (m, 1H), 1.42-1.58 (m, 2H). MS
(ES) [M þ H] calcd for C23H22FN5O, 404; found 404.
2-[(2-Chloro-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)-
methyl]benzonitrile (9k) was prepared in 59% yield from 2-chloro-
5,6,7,8-tetrahydroquinazoline-4(3H)-one (8k) according to the
procedure outlined for 2-(5-bromo-2-chloro-6-oxo-6H-pyrimi-
2-[2-(3-(R)-Aminopiperidin-1-yl)-5-(2-methoxyphenyl)-6-oxo-
6H-pyrimidin-1-ylmethyl]benzonitrile, TFA salt (15d). 15d was
prepared in 42% yield from 2-methoxyphenylboronic acid accord-
ing to the procedure outlined for 15a. 1H NMR (400 MHz, DMSO-
d6): δ 8.02 (br s, 3H), 7.80-7.84 (m, 2H), 7.66 (t, 1H, J = 7.6 Hz),
7.46 (t, 1H, J= 7.6 Hz), 7.12-7.31 (m, 3H), 6.99 (d, 1H, J=8.4Hz),
6.91 (t, 1H, J = 7.6 Hz), 5.33 (AB q, 2H, J = 43.2, 15.2 Hz), 3.58
(s, 3H), 3.49-3.56 (m, 1H), 3.36-3.45 (m, 1H), 3.15-3.21 (m, 1H),
3.01-3.09 (m, 1H), 2.89-2.96 (m, 1H), 1.92-1.99 (m, 1H),
1.75-1.84 (m, 1H), 1.50-1.65 (m, 2H). MS (ES) [M þ H] calcd
for C24H25N5O2, 416; found 416.
1
din-1-ylmethyl)benzonitrile (9c). H NMR (400 MHz, CDCl3):
δ 7.70 (dd, 1H, J = 7.6, 1.2 Hz), 7.55 (td, 1H, J = 7.6, 1.2 Hz), 7.41
(t, 1H, J = 7.6 Hz), 7.14 (d, 1H, J = 7.6 Hz), 5.62 (s, 2H), 2.59-
2.65 (m, 2H), 2.50-2.58 (m, 2H), 1.71-1.87 (m, 4H). MS (ES)
[M þ H] calcd for C16H14ClN3O 300, 302; found 300, 302.
13k was prepared in 68% yield from 2-[(2-chloro-4-oxo-
5,6,7,8-tetrahydroquinazolin-3(4H)-yl)methyl]benzonitrile (9k)
according to the procedure outlined for 13c. 1H NMR (400 MHz,
DMSO-d6): δ 8.01 (br s, 3H), 7.82 (d, 1H, J = 7.6 Hz), 7.61 (t, 1H,
J= 7.6Hz), 7.44(t, 1H, J =7.6Hz), 7.09(d, 1H, J= 7.6Hz), 5.26
(qAB, 2H, J = 44.8, 15.2 Hz), 3.25-3.40 (m, 2H), 2.90-3.08 (m,
2H), 2.70-2.80 (m, 1H), 2.48 (br s, 2H), 2.23 (br s, 2H), 1.89-1.98
(m, 1H), 1.42-1.80 (m, 7H). MS (ES) [M þ H] calcd for
C21H25N5O 364; found 364.
2-[2-(3-(R)-Aminopiperidin-1-yl)-5-furan-3-yl-6-oxo-6H-pyri-
midin-1-ylmethyl]benzonitrile, TFA salt (15e). 15e was prepared
in 64% yield from 3-furanylboronic acid according to the
1
procedure outlined for 15a. H NMR (400 MHz, DMSO-d6):
δ 8.29 (s, 1H), 8.16 (s, 1H), 8.05 (br s, 3H), 7.82 (d, 1H, J =7.2 Hz),
7.68 (s, 1H), 7.62 (t, 1H, J = 7.6 Hz), 7.44 (t, 1H, J = 7.6 Hz),
7.19 (d, 1H, J = 7.6 Hz), 7.01 (s, 1H), 5.36 (AB q, 2H, J = 41.6,
15.2 Hz), 3.49-3.56 (m, 1H), 3.36-3.45 (m, 1H), 3.13-3.21 (m,
1H), 3.01-3.09 (m, 1H), 2.86-2.93 (m, 1H), 1.92-1.99 (m, 1H),
1.76-1.84 (m, 1H), 1.50-1.65 (m, 2H). MS (ES) [M þ H] calcd
for C21H21N5O2, 376; found 376.
2-{[2-(3-(R)-Aminopiperidin-1yl)-5-bromo-4-oxopyrimidine-
1(4H)-yl]methyl}benzonitrile, TFA salt (14). 14 was prepared in
58% yield from 2-[(5-bromo-2-chloro-4-oxopyrimidin-1(4H)-
yl)methyl]benzonitrile (11c) according to the procedure out-
1
lined for 13c. H NMR (400 MHz, DMSO-d6): δ 8.24 (br s,