Journal of Medicinal Chemistry
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6H), 2.54 (dt, J = 2.60, 12.66 Hz, 1H), 2.74 (t, J = 11.60 Hz, 1H),
(s, 2H), 4.57 (m, 1H), 6.78 (m, 1H), 6.83 (m, 1H), 6.96 (m, 1H), 7.06
(m, 1H), 7.16 (d, 1H), 7.34 (m, 2H), 7.74 (s, 1H) ppm.
1
2.80−3.10 (m, 3H), 4.43−4.48 (m, 1H), 7.53 (s, 1H). H NMR (400
MHz, DMSO-d6): δ 1.60−1.68 (m, 1H), 1.76 (s, 3H), 1.78−1.85 (m,
3H), 2.54−2.60 (m, 1H), 2.85−2.94 (m, 3H), 2.98−3.06 (m,1H),
4.46−4.54 (m, 1H), 7.66 (s, 1H), 11.20 (br s, 1H) ppm.
(S)-1-(1-(3-(3-Chlorophenoxy)benzyl)piperidin-3-yl)-5-methylpyr-
imidine-2,4(1H,3H)-dione (22). LC-MS (Method 2) tR = 1.90 min, m/
1
z = 426.1 (M + 1). H NMR (300 MHz, CD3OD) δ 1.47−1.87 (m,
7H) 2.00−2.34 (m, 2H), 2.63 (br s, 1H), 2.68−2.84 (m, 1H), 3.47 (s,
2H), 4.45 (br s, 1H), 6.70−6.88 (m, 3H), 6.88−7.13 (m, 3H), 7.13−
7.32 (m, 2H), 7.64 (br s, 1H) ppm.
5-Methyl-1-(1-(3-phenoxybenzyl)piperidin-3-yl)pyrimidine-2,4-
(1H,3H)-dione (4). A mixture of 5-methyl-1-(piperidin-3-yl)-
pyrimidine-2,4(1H,3H)-dione (1, 100 mg, 0.48 mmol), 3-(phenoxy)-
benzaldehyde (285 mg, 1.44 mmol), and (polystyrylmethyl)-
trimethylammonium cyanoborohydride (200 mg, 0.8 mmol) in
dichloromethane/acetic acid (90:10 v/v, 4 mL) was stirred at room
temperature for 16 h. The reaction mixture was concentrated under
reduced pressure, and the crude product was purified by reverse phase
preparative HPLC to afford the title compound as a white solid (18
mg, 19%). LC-MS (Method 1) tR = 3.43 min, m/z = 392 (M + 1).
(S)-1-(1-(3-(3-Bromophenoxy)benzyl)piperidin-3-yl)-5-methylpyr-
imidine-2,4(1H,3H)-dione (23). LC-MS (Method 2) tR = 3.04 min, m/
z = 469.8 471.7 (M + 1, M + 3). HRMS calcd for C23H25BrN3O3
1
470.1074, found 470.1057. H NMR (400 MHz, DMSO-d6) δ 1.60
(m, 1H), 1.65−1.80 (s and m, 6H), 2.05 (t, 1H), 2.20 (t, 1H), 2.54
(m, 2H), 3.50 (s, 2H), 4.40 (m, 1H), 6.95 (m, 1H), 7.01 (m’s 2H),
7.15 (m’s, 2H), 7.33 (m, 2H), 7.37 (t, 1H), 7.71 (s, 1H), 11.2 (br s,
1H) ppm.
1
HRMS calcd for C23H26N3O3 392.1969, found 392.1969. H NMR
(400 MHz, DMSO-d6) δ 1.55 (m, 1H), 1.68−1.80 (s, 6H), 2.05 (t,
1H), 2.20 (t, 1H), 2.70 (m, 2H), 3.55 (m, 2H), 4.45 (m, 1H), 6.95 (d,
1H), 7.00−7.20 (m, 5H), 7.35−7.42 (m, 3H), 7.74 (m, 1H), 11.23 (s,
1H) ppm.
(S)-1-(1-(3-(3-Chloro-4-methylphenoxy)benzyl)piperidin-3-yl)-5-
methylpyrimidine-2,4(1H,3H)-dione (24). LC-MS (Method 2) tR
=
3.19 min, m/z = 439.95, 441.88 (M + 1, M + 3). HRMS calcd for
C24H27ClN3O3 440.1735, found 440.1723. 1H NMR (400 MHz,
CD3OD) δ 1.66−1.90 (s and m, 7H), 2.23 (m, 1H), 2.33 (m, 4H),
2.73 (m, 1H), 2.85 (m, 1H), 3.55 (s, 2H), 4.55 (m, 1H), 6.83 (m, 1H),
6.83 (m, 1H), 6.91 (m, 1H), 6.94 (d, 1H), 7.00 (m, 1H), 7.11 (d, J =
7.83, 1H), 7.24 (d, J = 8.34, 1H), 7.33 (d, J = 7.83, 1H) 7.75 (s, 1H)
ppm.
5-Methyl-1-(1-(3-phenoxybenzyl)piperidin-3-yl)pyrimidine-2,4-
(1H,3H)-dione (15). LC-MS (Method 1) tR = 3.43 min, m/z = 392 (M
1
+ 1). HRMS calcd for C23H26N3O3 392.1969, found 392.1969. H
NMR (400 MHz, DMSO-d6) δ 1.55 (m, 1H), 1.68−1.80 (s, 6H), 2.05
(t, 1H), 2.20 (t, 1H), 2.70 (m, 2H), 3.55 (m, 2H), 4.45 (m, 1H), 6.95
(d, 1H), 7.00−7.20 (m, 5H), 7.35−7.42 (m, 3H), 7.74 (s, 1H), 11.23
(s, 1H) ppm.
(S)-1-(1-(3-(3-Chloro-5-fluorophenoxy)benzyl)piperidin-3-yl)-5-
methylpyrimidine-2,4(1H,3H)-dione (25). LC-MS (Method 1) tR
=
5-Methyl-1-(1-(3-(3-(trifluoromethyl)phenoxy)benzyl)piperidin-3-
yl)pyrimidine-2,4(1H,3H)-dione (16). LC-MS (Method 1) tR = 3.86
min, m/z = 460 (M + 1), 458 (M − 1). HRMS calcd for
C24H25F3N3O3 460.1843, found 460.1842. 1H NMR (400 MHz,
DMSO-d6) δ 1.57 (m, 1H), 1.66−1.83 (m, 3H), 1.83 (s, 3H), 2.08 (t,
1H), 2.24 (t, 1H), 2.69−2.83 (m, 2H), 3.57 (s, 2H), 4.38−4.46 (m,
1H), 7.02 (dd, 1H), 7.08 (s, 1H), 7.19 (d, 1H), 7.32 (d, 2H), 7.43 (t,
1H), 7.51 (d, 1H), 7.65 (t, 1H), 7.74 (s, 1H), 11.22 (s, 1H) ppm.
5-Methyl-1-{1-[3-(4-methylphenoxy)benzyl]piperidin-3-yl}-
pyrimidine-2,4(1H,3H)-dione (17). LC-MS (Method 2) tR = 2.64 min,
m/z = 406.4 (M + 1). HRMS calcd for C24H28N3O3 406.2125, found
406.2130. 1H NMR (400 MHz, CDCl3): δ 1.68−1.74 (m, 3H), 1.80−
1.82 (m, 1H), 1.90 (s, 3H), 2.34 (m, 5H), 2.58 (m, 1H), 2.77−2.79
(m, 1H), 3.49 (q, J = 13.20 Hz, 2H), 4.58−4.60 (m, 1H), 6.86−7.02
(m, 5H), 7.14 (d, J = 8.40 Hz, 2H), 7.23−7.28 (m, 1H), 7.69 (s, 1H),
8.12 (s, 1H) ppm.
1-(1-(3-(4-Chlorophenoxy)benzyl)piperidin-3-yl)-5-methylpyrimi-
dine-2,4(1H,3H)-dione (18). LC-MS (Method 2) tR = 2.71 min, m/z =
426, 428 (M + 1, M + 2). HRMS calcd for C23H25ClN3O3 426.1583,
found 426.1577. 1H NMR (400 MHz, CDCl3): δ 1.69−1.86 (m, 4H),
1.91 (s, 3H), 2.35 (m, 2H), 2.62 (m, 1H), 2.79−2.81 (m, 1H), 3.51 (q,
J =13.20 Hz, 2H), 4.58−4.60 (m, 1H), 6.89−6.90 (m, 3H), 7.01 (s,
1H), 7.06−7.08 (m, 1H), 7.28−7.32 (m, 3H), 7.62 (m, 1H), 8.13 (s,
1H) ppm.
1-(1-(3-(4-Methoxyphenoxy)benzyl)piperidin-3-yl)-5-methylpyri-
midine-2,4(1H,3H)-dione (19). LC-MS (Method 2) tR = 2.50 min, m/
z = 422.1 (M + 1). HRMS calcd for C24H28N3O4 422.2074, found
422.2072. 1H NMR (400 MHz, CDCl3): δ 1.66−1.75 (m, 3H), 1.81−
1.83 (m, 1H), 1.91 (s, 3H), 2.37−2.42 (m, 2H), 2.59 (m, 1H), 2.78
(dd, J =3.68, 11.34 Hz, 1H), 3.49 (q, J =13.20 Hz, 2H), 3.82 (s, 3H),
4.57−4.60 (m, 1H), 6.82 (dd, J = 1.84, 8.12 Hz, 1H), 6.88−6.93 (m,
3H), 6.96−7.00 (m, 3H), 7.22−7.25 (m, 1H), 7.67 (s, 1H), 8.05 (s,
1H) ppm.
(S)-5-Methyl-1-(1-(3-(m-tolyloxy)benzyl)piperidin-3-yl)-
pyrimidine-2,4(1H,3H)-dione (20). LC-MS (Method 2) tR = 2.70 min,
m/z = 406.2 (M). HRMS calcd for C24H28N3O3 484.1634, found
406.2105. 1H NMR (300 MHz, DMSO-d6) δ 1.60 (m, 1H), 1.65−1.80
(s and m, 6H), 2.05 (t, 1H), 2.20 (t, 1H), 2.54 (m, 2H), 3.50 (s, 2H),
4.40 (m, 1H), 6.95 (m, 1H), 7.01 (m’s, 2H), 7.15 (m’s, 2H), 7.33 (m,
2H), 7.37 (t, 1H), 7.71 (s, 1H), 11.2 (br s, 1H) ppm.
1.86 min, m/z = 444.1 (M + 1), 442.3 (M − 1). HRMS calcd for
C23H24ClFN3O3 444.1485, found 444.1487. 1H NMR (300 MHz,
CD3OD) δ 1.48−1.81 (m, 7H), 2.13 (br s, 1H), 2.24 (t, J = 10.17 Hz,
1H), 2.65 (d, J = 11.30 Hz, 1H), 2.76 (dd, J = 10.55, 3.77 Hz, 1H),
3.49 (s, 2H), 4.36−4.55 (m, 1H), 6.56 (d, J = 10.55 Hz, 1 H), 6.66 (s,
1H), 6.81 (d, J = 8.29 Hz, 1H), 6.90 (d, J = 8.29 Hz, 1H), 6.99 (s, 1H),
7.11 (d, J = 7.54 Hz, 1H), 7.30 (t, J = 7.91 Hz, 1H), 7.65 (s, 1H) ppm.
(S)-1-(1-(3-(3,5-Dichlorophenoxy)benzyl)piperidin-3-yl)-5-methyl-
pyrimidine-2,4(1H,3H)-dione (26). LC-MS (Method 2) tR = 1.92 min,
m/z = 460.1, 462.5 (M, M + 2). HRMS calcd for C23H24Cl2N3O3
1
460.1189, found 460.1184. H NMR (300 MHz, CD3OD) δ 1.83 (m,
7H), 2.28 (dt, 2H), 2.8 (dm, 2H), 3.58 (s, 2H), 4.55 (m, 1H), 6.89 (m,
2H), 6.93 (d, 1H), 7.08 (s, 1H), 7.15 (s, 1H), 7.28 (m, 1H), 7.39 (m,
1H), 7.74 (s, 1H) ppm.
(S)-1-(1-(3-(4-Chlorophenoxy)benzyl)piperidin-3-yl)-5-methylpyr-
imidine-2,4(1H,3H)-dione (27). LC-MS (Method 2) tR = 1.96 min, m/
z = 426.1 (M + 1). HRMS calcd for C23H25ClN3O3 426.1579, found
1
426.1570. H NMR (300 MHz, DMSO-d6) δ 1.79 (m, 7H), 2.82 (s,
1H), 3.17 (m, 1H), 3.42 (t, 2H), 4.32 (m, 2H), 4.72 (br t, 1H), 7.08
(s, 1H), 7.10 (s, 1H), 7.20 (d, 1H), 7.24 (s, 1H), 7.37 (d, 1H), 7.43−
7.55 (m, 4H), 9.9 (br s, 1H), 11.4 (s, 1H) ppm.
(R)-1-(1-(3-(4-Chlorophenoxy)benzyl)piperidin-3-yl)-5-methylpyr-
imidine-2,4(1H,3H)-dione (28). LC-MS (Method 2) tR = 1.82 min, m/
z = 428.3 (M + 1). HRMS calcd for C23H25ClN3O3 426.1579, found
426.1583. 1H NMR (300 MHz, CD3OD) δ 1.54−1.93 (m, 7H), 2.05−
2.42 (m, 2H), 2.63−2.96 (m, 2H), 3.55 (br s, 2H), 4.55 (d, J = 3.77
Hz, 1H), 6.78−7.05 (m, 4H), 7.10 (d, J = 7.54 Hz, 1H), 7.33 (d, J =
4.52 Hz, 3H), 7.72 (br s, 1H) ppm.
(S)-1-(1-(3-(3,4-Dichlorophenoxy)benzyl)piperidin-3-yl)-5-methyl-
pyrimidine-2,4(1H,3H)-dione (29). LC-MS (Method 2) tR = 2.29 min,
m/z = 460.0, 461.9 (M + 1 M + 3). HRMS calcd for C23H24Cl2N3O3
460.1189, found 460.1190. 1H NMR (300 MHz, DMSO-d6) δ 1.75 (s,
3H), 1.90 (m, 4H), 2.85 (m, 1H), 3.20 (m, 1H), 3.45 (t, 2H), 4.30 (m,
2H), 4.75 (t, 1H), 7.07 (m, 1H), 7.20 (d, 1H), 7.35 (m’s, 3H), 7.55
(m’s, 2H), 7.85 (d, 1H), 10.6 (br s, 1H), 11.35 (s, 1H) ppm.
(R)-1-(1-(3-(3,4-Dichlorophenoxy)benzyl)piperidin-3-yl)-5-meth-
ylpyrimidine-2,4(1H,3H)-dione (30). LC-MS (Method 2) tR = 2.04
min, m/z = 461.9 (M + 1), 458.3 (M − 1). HRMS calcd for
C23H24Cl2N3O3 460.1189, found 460.1187. 1H NMR (300 MHz,
CD3OD) δ 1.54−1.94 (m, 7H), 2.10−2.40 (m, 2H), 2.75 (d, J = 11.30
Hz, 1H), 2.80−2.92 (m, 1H), 3.20−3.45 (m, 2H), 3.45−3.67 (m, 2H),
4.54 (br s, 1H), 6.76−7.00 (m, 2H), 7.00−7.26 (m, 3H), 7.26−7.58
(m, 2H), 7.72 (br s, 1H) ppm.
(S)-1-(1-(3-(3-Fluorophenoxy)benzyl)piperidin-3-yl)-5-methylpyri-
midine-2,4(1H,3H)-dione (21). LC-MS (Method 2) tR = 2.77 min, m/
z = 410.1 (M + 1). 1H NMR (400 MHz, CD3OD) δ 1.60−1.88 (s and
m, 7H), 2.23 (t, 1H), 2.35 (t, 1H), 2.75 (m, 1H), 2.83 (m, 1H), 3.57
10017
dx.doi.org/10.1021/jm3011806 | J. Med. Chem. 2012, 55, 10010−10021