368
Z. Wang et al. / European Journal of Medicinal Chemistry 50 (2012) 361e369
5.21.3. 4-(4-Fluorobenzylcarbamoyl)-1-methyl-2-(2-(5-methyl-1,3,
4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyri-
midin-5-yl benzoate (25)
5.21.9. 2-(2-(2-(Diethylamino)-2-oxoacetamido)propan-2-yl)-4-
(4-fluorobenzylcarbamoyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-
5-yl acetate (33)
Treatment of 11 with benzoyl chloride at room temperature to
Treatment of 32 with acetylchloride at room temperature to
afford 25 in 89% yield, mp 79e81 ꢀC; 1H NMR (400 MHz, CDCl3):
afford 33 in 87% yield, mp 76e78 ꢀC; 1H NMR (400 MHz, CDCl3):
d
8.25 (d, J ¼ 7.1 Hz, 2H, AreH), 8.06 (s,1H, NH), 7.98 (s,1H, NH), 7.65
d 7.99 (s, 1H, NH), 7.96 (s, 1H, NH), 7.30 (s, 2H, AreH), 7.02 (s, 2H,
(t, J ¼ 5.9 Hz,1H, AreH), 7.48e7.56 (m, 2H, AreH), 7.30e7.34 (m, 2H,
AreH), 7.03 (t, J ¼ 7.2 Hz, 2H, AreH), 4.57 (d, J ¼ 4.8 Hz, 2H, CH2),
3.71 (s, 3H, NMe), 2.66 (s, 3H, CH3CNN), 1.91 (s, 6H, NHC(CH3)2);
HRMS (ESI) calcd for C27H25FN6NaO6 (M þ Na)þ 571.1712, found
571.1715.
AreH), 4.54 (s, 2H, CH2), 3.63 (s, 3H, NMe), 3.33e3.72 (m, 4H,
CH3CH2), 2.41 (s, 3H, CH3CO2), 1.75 (s, 6H, NHC(CH3)2), 1.13e1.23 (m,
6H, CH3CH2); HRMS (ESI) calcd for C24H30FN5NaO6 (M þ Na)þ
526.2072, found 526.2077.
5.21.10. 2-(2-(2-(Diethylamino)-2-oxoacetamido)propan-2-yl)-4-
(4-fluorobenzylcarbamoyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-
5-yl methanesulfonate (34)
5.21.4. 4-(4-Fluorobenzylcarbamoyl)-1-methyl-2-(2-(5-methyl-1,3,
4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyri-
midin-5-yl 2,4,6-trimethylbenzenesulfonate (26)
Treatment of 32 with methanesulfonyl chloride at room
Treatment of 11 with mesitylene sulfonyl chloride at reflux to
temperature to afford 34 in 90% yield, mp 203e205 ꢀC; 1H NMR
afford 26 in 92% yield, mp 224e226 ꢀC; 1H NMR (400 MHz, CDCl3):
(400 MHz, CDCl3):
d 7.89 (s, 1H, NH), 7.86 (s, 1H, NH), 7.33 (dd,
d
7.90 (s, 1H, CONHC(CH3)2), 7.64 (t, J ¼ 6.0 Hz, 1H, CONHCH2),
J ¼ 8.0, 13.2 Hz, 2H, AreH), 7.05 (dd, J ¼ 8.6, 15.1 Hz, 2H, AreH), 4.60
(d, J ¼ 5.9 Hz, 2H, CH2), 3.66 (s, 3H, NMe), 3.64e3.72 (m, 2H,
CH3CH2), 3.58 (s, 3H, CH3SO3), 3.36e3.44 (m, 2H, CH3CH2), 1.76 (s,
6H, NHC(CH3)2), 1.14e1.24 (m, 6H, CH3CH2); HRMS (ESI) calcd for
C23H30FN5NaO7S (M þ Na)þ 562.1742, found 562.1734.
7.33e7.36 (m, 2H, AreH), 6.98e7.04 (m, 4H, AreH), 4.57 (d,
J ¼ 6.0 Hz, 2H, Ar-CH2), 3.57 (s, 3H, NMe), 2.68 (s, 6H, Ar-CH3), 2.62
(s, 3H, CH3CNN), 2.31 (s, 3H, Ar-CH3), 1.85 (s, 6H, NHC(CH3)2); HRMS
(ESI) calcd for C29H30FN6O7S (MꢂH)ꢂ 625.1886, found 625.1880.
5.21.5. 4-(4-Fluorobenzylcarbamoyl)-6-methoxy-2-(2-(5-methyl-1,3,
4-oxadiazole-2-carboxamido)propan-2-yl)pyrimidin-5-yl acetate (27)
Treatment of 20 with acetylchloride at room temperature to
afford 27 in 91% yield, mp 133e135 ꢀC; 1H NMR (400 MHz, CDCl3):
5.21.11. 2-(2-(2-(Diethylamino)-2-oxoacetamido)propan-2-yl)-4-
(4-fluorobenzylcarbamoyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-
5-yl benzoate (35)
Treatment of 32 with benzoyl chloride at room temperature to
d
8.80 (s, 1H, NH), 8.07 (s, 1H, NH), 7.29 (s, 2H, AreH), 6.97 (s, 2H,
afford 35 in 82% yield, mp 101e103 ꢀC; 1H NMR (400 MHz, CDCl3):
AreH), 4.50 (d, J ¼ 3.3 Hz, 2H, CH2), 4.02 (s, 3H, OMe), 2.55 (s, 3H,
CH3CNN), 2.35 (s, 3H, CH3CO2), 1.80 (s, 6H, NHC(CH3)2); HRMS (ESI)
calcd for C22H23FN6NaO6 (M þ Na)þ 509.1555, found 509.1550.
d
8.22 (d, J ¼ 3.4 Hz, 2H, AreH), 8.04 (s, 1H, NH), 7.99 (s, 1H, NH),
7.57e7.63 (m, 1H, AreH), 7.44e7.52 (m, 2H, AreH), 7.24e7.31 (m,
2H, AreH), 6.94e7.03 (m, 2H, AreH), 4.51 (s, 2H, CH2), 3.65 (s, 3H,
NMe), 3.31e3.72 (m, 4H, CH3CH2), 1.75 (s, 6H, NHC(CH3)2), 1.11e1.28
(m, 6H, CH3CH2); HRMS (ESI) calcd for C29H32FN5NaO6 (M þ Na)þ
588.2229, found 588.2228.
5.21.6. 4-(4-Fluorobenzylcarbamoyl)-6-methoxy-2-(2-(5-methyl-1,3,
4-oxadiazole-2-carboxamido)propan-2-yl)pyrimidin-5-yl methane-
sulfonate (28)
Treatment of 20 with methanesulfonyl chloride at room
5.21.12. 2-(2-(2-(Diethylamino)-2-oxoacetamido)propan-2-yl)-4-
(4-fluorobenzylcarbamoyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-
5-yl 2,4,6-trimethylbenzenesulfonate (36)
temperature to afford 28 in 81% yield, mp 51e53 ꢀC; 1H NMR
(400 MHz, CDCl3):
d
8.74 (s, 1H, NH), 8.10 (t, J ¼ 2.2 Hz, 1H, NH), 7.38
(s, 2H, AreH), 7.06 (t, J ¼ 1.9 Hz, 2H, AreH), 4.62 (s, 2H, CH2), 4.18 (s,
3H, OMe), 3.54 (s, 3H, CH3SO3), 2.64 (s, 3H, CH3CNN), 1.88 (s, 6H,
NHC(CH3)2); HRMS (ESI) calcd for C21H23FN6NaO7S (M þ Na)þ
545.1225, found 545.1230.
Treatment of 32 with mesitylene sulfonyl chloride at reflux to
afford 36 in 22% yield, mp 243e245 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.89 (s, 1H, NH), 7.72 (t, J ¼ 1.4 Hz, 1H, NH), 7.34 (s, 2H, AreH),
6.95e7.06 (m, 4H, AreH), 4.58 (s, 2H, CH2), 3.54 (s, 3H, NMe),
3.33e3.71 (m, 4H, CH3CH2), 2.70 (s, 6H, AreCH3), 2.33 (s, 3H,
AreCH3), 1.74 (s, 6H, NHC(CH3)2), 1.11e1.22 (m, 6H, CH3CH2); HRMS
(ESI) calcd for C31H38FN5NaO7S (M þ Na)þ 666.2368, found
666.2372.
5.21.7. 4-(4-Fluorobenzylcarbamoyl)-6-methoxy-2-(2-(5-methyl-1,3,
4-oxadiazole-2-carboxamido)propan-2-yl)pyrimidin-5-yl benzoate
(29)
Treatment of 20 with benzoyl chloride at reflux to afford 29 in
85% yield, mp 55e57 ꢀC; 1H NMR (400 MHz, CDCl3):
d
8.91 (s, 1H,
5.21.13. 2-(2-(2-(Diethylamino)-2-oxoacetamido)propan-2-yl)-4-
(4-fluorobenzylcarbamoyl)-6-methoxypyrimidin-5-yl acetate (39)
Treatment of 38 with acetylchloride at room temperature to
afford 39 in 78% yield, mp 85e87 ꢀC; 1H NMR (400 MHz, CDCl3):
NeH), 8.15 (dd, J ¼ 7.4, 14.5 Hz, 2H, AreH), 7.74 (t, J ¼ 7.7 Hz, 1H,
NH), 7.61 (t, J ¼ 7.3 Hz, 2H, AreH), 7.51 (t, J ¼ 7.6 Hz, 1H, AreH), 7.44
(t, J ¼ 7.5 Hz, 2H, AreH), 7.34 (t, J ¼ 7.6 Hz, 1H, AreH), 6.93 (t,
J ¼ 8.5 Hz, 1H, AreH), 5.13 (s, 2H, Ar-CH2), 3.98 (s, 3H, OMe), 2.68 (s,
3H, CH3CNN), 1.80 (s, 6H, NHC(CH3)2); HRMS (ESI) calcd for
C27H24FN6O6 (MꢂH)ꢂ 547.1747, found 547.1750.
d
8.46 (s, 1H, NH), 8.41 (t, J ¼ 5.1 Hz, 1H, NH), 7.36 (dd, J ¼ 5.6, 7.8 Hz,
2H, AreH), 7.05 (t, J ¼ 8.6 Hz, 2H, AreH), 4.58 (d, J ¼ 6.0 Hz, 2H,
CH2), 4.09 (s, 3H, OMe), 3.71 (q, J ¼ 7.0, 14.0 Hz, 2H, NCH2CH3), 3.39
(q, J ¼ 7.0, 14.1 Hz, 2H, NCH2CH3), 2.44 (s, 3H, CH3CO2), 1.80 (s, 6H,
NHC(CH3)2), 1.25 (t, J ¼ 6.9 Hz, 3H, NCH2CH3), 1.18 (t, J ¼ 7.1 Hz, 3H,
NCH2CH3); HRMS (ESI) calcd for C24H31FN5O6 (M þ H)þ 504.2253,
found 504.2255.
5.21.8. 4-(4-Fluorobenzylcarbamoyl)-6-methoxy-2-(2-(5-methyl-1,3,
4-oxadiazole-2-carboxamido)propan-2-yl)pyrimidin-5-yl 2,4,6-
trimethylbenzenesulfonate (30)
Treatment of 20 with mesitylene sulfonyl chloride at reflux to
afford 30 in 74% yield, mp 183e185 ꢀC; 1H NMR (400 MHz, CDCl3):
5.21.14. 2-(2-(2-(Diethylamino)-2-oxoacetamido)propan-2-yl)-4-
(4-fluorobenzylcarbamoyl)-6-methoxypyrimidin-5-yl
methanesulfonate (40)
d
8.84 (s, 1H, NH), 7.72 (t, J ¼ 1.4 Hz, 1H, NH), 7.39 (dd, J ¼ 3.0, 6.1 Hz,
2H, AreH), 7.03e7.09 (m, 4H, AreH), 4.58 (d, J ¼ 5.6 Hz, 2H, CH2),
3.84 (s, 3H, OMe), 2.65 (s, 9H, AreCH3), 2.37 (s, 3H, CH3CNN),1.87 (s,
6H, NHC(CH3)2); HRMS (ESI) calcd for C29H31FN6NaO7S (M þ Na)þ
649.1851, found 649.1850.
Treatment of 38 with methanesulfonyl chloride at room
temperature to afford 40 in 98% yield, mp 45e47 ꢀC; 1H NMR
(400 MHz, CDCl3):
d 8.43 (s, 1H, NH), 8.21 (s, 1H, NH), 7.35 (d,