Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19 7213
5.54-5.59 (m,1H), 5.90-6.03 (m, 1H), 7.14-7.18 (m, 3H),
7.33-7.37 (m, 2H), 7.49 (t,1H), 11.45 (s, 1H); MS, m/e 515.95
(M þ 1)þ; 1052.82 (2M þ 23)þ. HRMS, calcd for C21H28-
FN3O9P (Mþ þ H), 516.1542; found, 516.1526.
1-[(S)-[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimi-
din-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl-
methoxy]-(4-fluorophenoxy)phosphorylamino]cyclopropane-
carboxylic Acid Methyl Ester (39). Yield: 40%. 1H NMR
(DMSO-d6) δ 0.97-0.99 (m, 1H), 1.06-1.12 (m, 1H), 1.21-
1.29 (m, 5H), 3.55 (s, 3H), 3.73-3.90 (m, 1H), 4.01 (s, 1H),
4.25-4.29 (m, 1H), 4.38-4.43 (m, 1H), 5.56-5.60 (m, 1H), 5.88
(s, 1H), 5.92-6.10 (m, 1H), 6.59 (t, J = 16 Hz, 1H), 7.21-7.23
(m, 4H), 7.56 (dd, J = 8.0, 28.0 Hz, 1H), 11.55 (s, 1H); MS, m/e
532.00 (M þ 1)þ. HRMS, calcd for C21H25F2N3O9P (Mþ þ H),
532.1291; found, 532.1280.
(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-
1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy]-
phenoxyphosphorylamino}-3-methylbutyric Acid Methyl Ester
1
(33). Yield: 20%. H NMR (DMSO-d6) δ 0.75-0.85 (m, 6H),
1.21-1.29 (m, 3H), 1.89-1.94 (m, 1H), 3.51-3.55 (m, 1H), 3.58
(d, J = 10.4 Hz, 3H), 3.72-3.95 (m, 1H), 4.03-4.05 (m, 1H),
4.23-4.37 (m, 2H), 5.56 (t, J = 16.0 Hz, 1H), 5.85-5.92 (m,
1H), 6.01-6.07 (m, 1H), 7.16-7.21 (m, 3H), 7.37 (t, J = 8 Hz,
2H), 7.55-7.60 (m, 1H), 11.52 (s, 1H); MS, m/e 530 (M þ 1)þ.
HRMS, calcd for C22H30FN3O9P (Mþ þ H), 530.1698; found,
530.1684.
(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimi-
din-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl-
methoxy]phenoxyphosphorylamino}propionic Acid Isopropyl
1
Ester (40). Yield: 8.57%. H NMR (DMSO-d6) δ 1.19-1.29
(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimi-
din-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl-
methoxy]phenoxyphosphorylamino}-4-methylpentanoic Acid Methyl
(m, 12H), 3.65-3.75 (m, 2H), 3.95-4.05 (m, 1H), 4.24-4.25
(m, 1H), 4.35-4.37 (m, 1H), 4.84-4.86 (m, 1H), 5.53-5.61 (m,
1H), 5.88 (m, 1H), 6.01-6.14 (m, 2H), 7.14-7.39 (m, 5H),
7.48-7.60 (m, 1H), 11.53 (s, 1H); MS, m/e 529.96 (M þ 1)þ.
HRMS, calcd for C22H30FN3O9P (Mþ þ H), 530.1698; found,
530.1684.
1
Ester (34). Yield: 21%. H NMR (DMSO-d6) δ 0.68-0.89 (m,
6H), 1.26 (d, J = 7.2 Hz, 3H), 1.41-1.64 (m, 3H), 3.70 (s, 3H),
3.73-3.79 (m, 2H), 3.99-4.04 (m, 1H), 4.19-4.27 (m, 1H),
4.34-4.38 (m, 1H), 5.55 (t, J = 9.0 Hz, 1H), 5.86-5.92 (m, 1H),
5.99-6.12(m, 2H), 7.15-7.20 (m, 3H), 7.34-7.39 (m, 2H), 7.55 (s,
1H), 11.53 (s, 1H); MS, m/e 543.99 (M þ 1)þ. HRMS, calcd for
C23H32FN3O9P (Mþ þ H), 544.1855; found, 544.1841.
(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimi-
din-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl-
methoxy]-(4-fluorophenoxy)phosphorylamino]propionic Acid Ethyl
Ester (41). Yield: 15.4%. 1H NMR (DMSO-d6) δ 1.13-1.28
(m, 9H), 3.72-3.94(m, 2H), 3.98-4.10 (m, 3H), 4.21-4.42 (m,
2H), 5.56-5.61 (m, 1H), 5.85-6.20 (m, 3H), 7.21-7.24 (m, 4H),
7.55-7.58 (d, 1H), 11.50 (s, 1H); 13C NMR (DMSO-d6) δ 174.01,
173.97, 173.87, 163.60, 160.87, 158.48, 151.32, 147.65, 140.34,
130.52, 122.73, 122.68, 122.65, 120.92, 117.14, 116.90, 103.21,
102.10, 100.29, 89.53, 80.32, 72.40, 72.22, 65.41, 61.46, 61.43,
50.72, 50.60, 20.70, 20.63, 20.56, 20.49, 17.53, 17.28, 14.82;
MS, m/e 533.90 (M þ 1)þ; HRMS, calcd for C21H27F2N3O9P
(Mþ þ H), 534.1453; found, 534.1434.
(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimi-
din-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl-
methoxy]phenoxyphosphorylamino}-4-methylsulfanylbutyric Acid
1
Methyl Ester (35). Yield: 27.4%. HNMR (DMSO-d6): δ 1.25
(dd, J = 22.8 Hz, 5.6 Hz, 3H), 1.77-1.85 (m, 2H), 1.95 (d, J =
10.0 Hz, 3H), 2.31-2.36 (m, 1H), 2.40-2.44 (m, 1H), 3.59-3.64
(m, 3H), 3.88-3.91 (m, 2H), 4.05 (m, 1H), 4.25-4.26 (m, 1H),
4.29-4.40 (m, 1H), 5.56 (t, J = 8.0 Hz, 1H), 5.90-5.92 (m, 1H),
6.13-6.16 (m, 2H), 7.16-7.23 (m, 3H), 7.36-7.40 (m, 2H), 7.55
(d, J = 8.4 Hz, 1H), 11.51 (s, 1H); MS, m/e 562.52(M þ 1)þ.
HRMS, calcd for C22H30FN3O9PS (Mþ þ H), 562.1419; found,
562.1406.
(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimi-
din-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl-
methoxy]phenoxyphosphorylamino}-3-phenylpropionic Acid
Methyl Ester (36). Yield: 6.6%. 1H NMR (DMSO-d6) δ
1.19-1.34 (m, 3H), 2.79-2.97 (m, 2H), 3.51-3.57 (m, 3H),
3.60-3.85 (m, 1H), 3.91-4.13 (m, 4H), 5.50-5.52 (m, 1H),
5.80-6.10 (m, 2H), 6.20-6.35 (m, 1H), 7.01-7.05 (m, 2H),
7.14-7.32 (m, 8H), 7.47 (s, 1H), 11.50 (s.1H); MS, m/e 578.2
(M þ 1)þ. HRMS, calcd for C26H30FN3O9P (Mþ þ H),
578.1698; found, 578.1687.
(S)-2-{(4-Chlorophenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-
dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetra-
hydrofuran-2-ylmethoxy]phosphorylamino}propionic Acid Ethyl
Ester (42). Yield: 30.17%. 1H NMR (DMSO-d6) δ 1.14 (t, J =
7.0 Hz, 3H), 1.21-1.28 (m, 6H),3.77-3.89 (m, 2H), 4.00-4.08
(m, 3H), 4.24-4.27 (m, 1H), 4.34-4.43 (m, 1H), 5.56-5.61 (m,
1H), 5.86-6.13 (m, 2H), 6.17-6.24 (m, 1H), 7.21-7.26 (m, 2H),
7.44 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.6 Hz, 1H), 11.55 (s, 1H);
MS, m/e 549.11 (M þ 1)þ; HRMS, calcd for C21H27ClFN3O9P
(Mþ þ H), 550.1157; found, 550.1141.
(S)-2-{(4-Bromophenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-
dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetra-
hydrofuran-2-ylmethoxy]phosphorylamino}propionic Acid Ethyl
Ester (43). Yield: 35.86%. 1H NMR (DMSO-d6) δ 1.13 (t, J =
7.2 Hz, 3H), 1.16-1.28 (m, 6H), 3.78-3.86 (m, 2H), 4.01-4.07
(m, 3H), 4.24-4.28 (m, 1H), 4.39-4.40 (m, 1H), 5.56-5.61 (m,
1H), 5.82-5.90 (m, 1H), 5.93-6.07 (m, 1H), 6.14-6.19 (m, 1H),
7.18 (dd, J = 11.2, 8.8 Hz, 2H), 7.53-7.58 (m, 3H), 11.53 (s, 1H);
MS, m/e 593.90(M þ 1)þ. HRMS, calcd for C21H27BrFN3O9P
(Mþ þ H), 594.0652; found, 594.0640.
(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimi-
din-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl-
methoxy]phenoxyphosphorylamino}-3-(1H-indol-3-yl)propionic
1
Acid Methyl Ester (37). Yield: 8.1%. H NMR (DMSO-d6) δ
0.96 (d, J = 22.8 Hz, 3H), 2.90-2.94 (m, 1H), 3.03-3.08 (m,
1H), 3.42-3.48 (m, 3H) 3.60-3.65 (m, 1H), 3.92-3.94 (m, 2H),
4.17-4.19 (m, 2H), 5.48 (d, J = 8.4 Hz, 1H), 5.87 (d, J = 6.4
Hz, 1H), 5.95-6.00 (m, 1H), 6.21 (t, J = 11.4 Hz, 1H), 6.87-
6.91 (m, 1H), 6.99-7.03 (m, 4H), 7.07-7.11 (m, 1H), 7.22-7.30
(m, 3H), 7.37 (d, J = 8 Hz 1H), 7.45 (d, J = 8 Hz, 1H), 10.80 (s,
1H), 11.48 (s, 1H); MS, m/e 616.96 (M þ 1)þ; 1254.84 (2M þ
23)þ. HRMS, calcd for C28H31FN4O9P (Mþ þ H), 617.1807;
found, 617.1799.
2-[(S)-[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimi-
din-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl-
methoxy]-(4-fluorophenoxy)phosphorylamino]-2-methylpropio-
nic Acid Methyl Ester (38). Yield: 22%. 1H NMR (DMSO-d6)
δ 1.19-1.36 (m, 9H), 3.54 (s, 3H), 3.56-3.89 (m, 1H), 4.00
(s, 1H), 4.22-4.26 (m, 1H), 4.35-4.38 (m, 1H), 5.52-5.55
(m, 1H), 5.87-6.04 (m, 3H), 7.17-7.23 (m, 4H), 7.58-7.60
(m, 1H), 11.55 (s, 1H); MS, m/e 534.01 (M þ 1)þ. HRMS,
calcd for C21H27F2N3O9P (Mþ þ H), 534.1447; found,
534.1435.
(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimi-
din-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl-
methoxy]-(4-fluorophenoxy)phosphorylamino]propionic Acid Iso-
propyl Ester (44). Yield: 11.3%. 1H NMR (DMSO-d6) δ
1.14-1.28 (m, 12H), 3.74-3.84 (m,2H), 3.99-4.06 (m, 1H),
4.23-4.39 (m, 2H), 4.83-4.86 (m, 1H), 5.56-5.60 (t, 1H),
5.85-6.12 (m, 3H), 7.19-7.24 (m, 4H), 7.56-7.57 (d, 1H),
11.50 (s, 1H); MS, m/e 547.91 (M þ 1)þ. HRMS, calcd for
C22H29F2N3O9P (Mþ þ H), 548.1604; found, 548.1591.
(S)-2-{(4-Chlorophenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-
dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetra-
hydrofuran-2-ylmethoxy]phosphorylamino}propionic Acid Isopro-
1
pyl Ester (45). Yield: 24%. H NMR (DMSO-d6) δ 1.05-1.19
(m, 12H), 3.76-3.80 (m, 2H), 3.98-4.08 (m, 1H), 4.31 (m, 2H),
4.73-4.77 (m, 1H), 5.49-5.54 (m, 1H), 5.80-6.20 (m, 3H), 7.20-
7.2 5 (m, 2H), 7.43 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8 Hz, 1H), 11.51