Design and Synthesis of HIV-1 Protease Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 18 4325
1.60 (m, 2H), 0.92 (d, J ) 6.8 Hz, 3H), 0.86 (d, J ) 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 170.27, 168.98, 156.99, 154.05,
138.48, 138.42, 137.54, 129.82 (2C), 129.62 (2C), 129.33 (2C),
128.44 (2C), 128.40 (2C), 126.38, 126.18, 124.84, 118.60 (2C),
71.23, 70.04, 63.53, 53.60, 48.75, 48.36, 42.06, 40.88, 40.28, 38.53,
31.81, 25.90, 21.81, 20.01, 18.97. HRMS (ESI) m/z calcd for
C37H46N5O6 [M + H]+, 656.3448; found, 656.3435.
(5S)-N-[(1S,2S,4S)-4-[[(2S)-3,3-Dimethyl-2-N-(methoxycarbo-
nyl)-1-oxo-butyl]amino]-2-hydroxy-5-phenyl-1-(phenylmethyl)-
pentyl]-2-oxo-3-phenyloxazolidine-5-carboxamide (15a). 1H NMR
(400 MHz, CDCl3) δ 7.47-7.38 (m, 4H), 7.28-7.24 (m, 2H),
7.20-7.17 (m, 2 H), 7.14-7.10 (m, 4 H), 7.03 (t, J ) 8.0 Hz, 2
H), 6.93 (m, 1H), 6.75 (d, J ) 12.0 Hz, 1H), 6.02 (d, J ) 8.0 Hz,
1H), 5.30 (br d, J ) 8.0 Hz, 1H), 4.77 (dd, J ) 12.0, 8.0 Hz, 1H),
4.25-4.16 (m, 2H), 4.08 (t, J ) 9.6 Hz, 1H), 3.78-3.73 (m, 2H),
3.69 (s, 3H), 3.48 (dd, J ) 9.2, 6.0 Hz, 1H), 2.88-2.78 (m, 4H),
1.73 (m, 1H), 1.60 (m 1H), 0.93 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 171.19, 168.97, 157.33, 153.27, 137.88, 137.61, 137.32,
129.51 (2C), 129.48 (2C), 129.36 (2C), 128.83 (2C), 128.56 (2C),
126.97, 126.64, 124.83, 118.53 (2C), 70.69, 69.95, 63.62, 54.91,
52.77, 49.33, 48.45, 41.66, 40.41, 38.69, 34.42, 26.78 (3C). HRMS
(ESI) m/z calcd for C36H45N4O7 [M + H]+, 645.3288; found,
645.3295.
(5R)-N-[(1S,3S,4S)-4-[(2,6-Dimethylphenoxyacetyl)]amino]-3-
hydroxy-5-phenyl-1-(phenylmethyl)pentyl]-2-oxo-3-phenylox-
1
azolidine-5-carboxamide (21a). H NMR (400 MHz, CDCl3) δ
7.50-7.48 (m, 2H), 7.39-7.35 (m, 2H), 7.28-7.23 (m, 2H), 7.21-
7.17 (m, 6H), 7.16-7.11 (m, 4H), 6.97-6.92 (m, 3H) 6.87 (d, J )
8.4 Hz, 1H), 4.83 (dd, J ) 9.6, 5.6 Hz, 1H), 4.22 (m, 1H), 4.20-
4.15 (m, 2H), 4.18 (s, overlapping signal, 2H), 4.08 (dd, J ) 9.2,
5.6 Hz, 1H), 3.69 (m, 1H), 3.19 (d, J ) 5.2 Hz, 1H), 2.91 (dd, J
) 7.6, 2.0 Hz, 2H), 2.86 (t, J ) 6.0 Hz, 2H), 2.13 (s, 6H), 1.76
(m, 1H), 1.69 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 169.38,
168.94, 154.43, 153.11, 138.06, 137.53, 137.18, 130.53, 129.45
(4C), 129.30 (2C), 128.86 (2C), 128.81 (2C), 127.09, 126.83,
125.05, 124.92, 118.26 (2C), 70.45, 70.27, 70.06, 54.84, 49.98,
48.35, 41.57, 39.61, 38.23, 16.42 (2C). HRMS (ESI) m/z calcd for
C38H42N3O6 [M + H]+, 636.3074; found, 636.3081.
(5S)-N-[(1S,3S,4S)-4-[(2,6-Dimethylphenoxyacetyl)]amino]-3-
hydroxy-5-phenyl-1-(phenylmethyl)pentyl]-2-oxo-3-phenylox-
1
azolidine-5-carboxamide (22a). H NMR (400 MHz, CDCl3) δ
7.46-7.38 (m, 4H), 7.32-7.24 (m, 4H), 7.22-7.17 (m, 2H), 7.06
(d, J ) 4.0 Hz, 4H), 7.01-6.92 (m, 4H), 6.61 (d, J ) 9.2 Hz, 1H),
4.76 (dd, J ) 10.4, 6.0 Hz, 1H), 4.34 (m, 1H), 4.28 (m, 1H), 4.26
(AB d, J ) 15.2 Hz, 1H), 4.19 (AB d, J ) 15.2 Hz, 1H), 4.12 (t,
J ) 9.6 Hz, 1H), 3.82 (m, 1H), 3.63 (dd, J ) 9.6, 6.0 Hz, 1H),
3.27 (d, J ) 5.2 Hz, 1H), 3.01 (d, J ) 8.0 Hz, 2H), 2.91 (dd, J )
13.6, 5.6 1H), 2.67 (dd, J ) 13.6, 8.4 Hz, 1H), 2.18 (s, 6H), 1.84-
1.70 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.38, 168.94,
154.43, 153.11, 138.06, 137.53, 137.18, 130.61, 129.52 (2C), 129.38
(4C), 129.35 (2C), 128.84 (2C), 128.73 (2C), 126.92, 126.85,
124.98, 124.91, 118.56 (2C), 70.47, 70.08, 69.93, 54.67, 49.33,
48.42, 41.87, 40.23, 38.28, 16.47 (2C). HRMS (ESI) m/z calcd for
C38H42N3O6 [M + H]+, 636.3074; found, 636.3120.
(5S)-N-[(1S,2S,4S)-4-[(2,6-Dimethylphenoxyacetyl)]amino]-3-
hydroxy-5-phenyl-1-(phenylmethyl)pentyl]-2-oxo-3-phenylox-
1
azolidine-5-carboxamide (16a). H NMR (400 MHz, CDCl3) δ
7.46 (m, 2H), 7.41 (m, 2H), 7.29 (m, 2H), 7.24-7.19 (m, 4H),
7.17-7.14 (m, 2H), 7.05 (t, J ) 7.2 Hz, 2H), 7.01-6.93 (m, 5H),
6.82 (d, J ) 9.6 Hz, 1H), 4.83 (dd, J ) 10.0, 6.0 Hz, 1H), 4.39 (m,
1H), 4.27 (m, 1H), 4.27 (d, J ) 15.2 Hz, 1H, overlapping signal),
4.12-4.07 (m, 2H), 3.86 (m, 1H), 3.73 (d, J ) 4.4 Hz, 1H), 3.50
(dd, J ) 9.6, 6.4 Hz, 1H), 3.01-2.83 (m, 4H), 2.13 (s, 6H), 1.85-
1.75 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.54, 168.99,
154.22, 153.23, 137.93, 137.64, 137.22, 130.67, 129.57 (2C), 129.43
(2C), 129.36 (2C), 129.34 (2C), 128.95 (2C), 128.57 (2C), 127.13,
126.63, 125.04, 124.79, 118.49 (2C), 70.79, 70.28, 69.97, 54.85,
48.95, 48.46, 41.83, 41.39, 38.84, 16.39 (2C). HRMS (ESI) m/z
calcd for C38H42N3O6 [M + H]+, 636.3074; found, 636.3094.
(5S)-3-(3-Acetylphenyl)-N-[(1S,2S,4S)-4-[(2,6-Dimethylphe-
noxyacetyl)]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pen-
tyl]-2-oxo-oxazolidine-5-carboxamide (16e). 1H NMR (400 MHz,
CDCl3) δ 7.92 (t, J ) 2.4 Hz, 1H), 7.84 (m, 1H), 7.76 (m, 1H),
7.52 (d, J ) 7.6 Hz, 1H), 7.31-7.27 (m, 2H), 7.24-7.19 (m, 3H),
7.15 (dd, J ) 8.8, 1.6 Hz, 2H), 7.04 (t, J ) 7.6 Hz, 2H), 7.01-
6.90 (m, 5H), 6.81 (d, J ) 10.0 Hz, 1H), 4.86 (dd, J ) 9.6, 6.4 Hz,
1H), 4.39 (m, 1H), 4.31 (m, 1H), 4.27 (d, J ) 15.2 Hz, 1H,
overlapping singal), 4.15-4.08 (m, 2H), 3.89-3.82 (m, 2H), 3.53
(dd, J ) 9.6, 6.4 Hz, 1H), 3.02-2.83 (m, 4H), 2.65 (s, 3H), 2.13
(s, 6H), 1.85-1.75 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 197.67,
169.59, 168.74, 154.21, 153.20, 138.22, 138.08, 137.94, 137.20,
130.66, 129.70, 129.60 (2C), 129.42 (2C), 129.34 (2C), 128.97 (2C),
128.55 (2C), 127.15, 126.62, 125.06, 124.66, 123.01, 117.59 70.76,
70.27, 70.04, 54.81, 48.95, 48.37, 41.77, 41.43, 38.84, 26.98, 16.39
(2C). HRMS (ESI) m/z calcd for C40H44N3O7 [M + H]+, 678.3179;
found, 678.3204.
(5S)-N-[(1S,3S,4S)-4-[(2,6-Dimethylphenoxyacetyl)]amino]-3-
hydroxy-5-phenyl-1-(phenylmethyl)pentyl]-2-oxo-3-[(3-trifluo-
romethyl)phenyl]oxazolidine-5-carboxamide (22d). 1H NMR
(400 MHz, CDCl3) δ 7.69 (m, 1H), 7.66 (d, J ) 8.4 Hz, 1H), 7.52
(t, J ) 7.2 Hz, 1H), 7.44 (d, J ) 7.6 Hz, 1H), 7.32-7.20 (m, 5H)
7.08-6.93 (m, 8H), 6.89 (t, J ) 7.2 Hz, 1H), 6.73 (d, J ) 8.8 Hz,
1H), 4.78 (dd, J ) 10.0, 5.6 Hz, 1H), 4.40 (m, 1H), 4.30 (m, 1H),
4.26 (AB d, J ) 14.8 Hz, 1H), 4.19 (AB d, J ) 14.8 Hz, 1H), 4.10
(t, J ) 9.6 Hz, 1H), 3.85 (m, 1H), 3.59 (dd, J ) 9.6, 6.0 Hz, 1H),
3.01 (d, J ) 8.0 Hz, 2H), 2.93 (dd, J ) 13.6, 5.6 Hz, 1H), 2.67
(dd, J ) 13.6, 9.6 Hz, 1H), 2.16 (s, 6H), 1.86-1.74 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 169.47, 168.59, 154.40, 152.96, 138.51,
138.07, 137.35, 131.86 (m), 130.60, 129.97, 129.52 (2C), 129.40
(2C), 129.35 (2C), 128.83 (2C), 128.64 (2C), 126.86, 126.78, 125.0,
121.38, 121.34 (m), 115.53 (m), 70.45, 70.04, 70.0, 54.72, 49.24,
48.23, 41.76, 40.17, 38.24, 16.45 (2C). HRMS (ESI) m/z calcd for
C39H41F3N3O6 [M + H]+, 704.2947; found, 704.2948.
(5S)-N-[(1S,3S,4S)-4-[[2-(Benzo[1,3]-dioxol-5-yl)]acetyl]amino]-
3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]-2-oxo-3-phenylox-
1
azolidine-5-carboxamide (23a). H NMR (400 MHz, CDCl3) δ
7.47-7.43 (m, 3H), 7.42-7.37 (m, 2H), 7.24-7.20 (m, 4H), 7.17-
7.11 (m, 3H), 7.05 (t, J ) 7.2 Hz, 2H), 6.94 (m, 3H), 6.90 (d, J )
10.0 Hz, 1H), 6.74 (d, J ) 8.0 Hz, 1H), 6.53 (s, 1H), 5.97 (dd, J
) 4.8, 1.6 Hz, 2H), 5.54 (d, J ) 8.4 Hz, 1H), 4.81 (dd, J ) 9.6,
6.0 Hz, 1H), 4.24-4.17 (m, 2H), 4.08 (m, 2H), 3.78 (m, 1H), 3.50
(dd, J ) 9.2, 6.4 Hz, 1H), 3.39 (s, 2H), 2.90-2.79 (m, 3H), 1.62
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 172.08, 168.98, 153.31,
148.33, 147.23, 138.05, 137.66, 137.09, 129.60 (2C), 129.39 (2C),
129.36 (2C), 128.82 (2C), 128.54 (2C), 128.0, 126.98, 126.60,
124.79, 123.02, 118.52 (2C), 110.11, 108.96, 101.41, 70.46, 70.02,
54.96, 49.15, 48.48, 43.52, 41.22, 40.91, 38.78. HRMS (ESI) m/z
calcd for C37H38N3O7 [M + H]+, 636.2710; found, 636.2743.
[(1S,2S,4S)-2-Hydroxy-4-[[(5R)-(2-oxo-3-phenyloxazolidine)-
5-carbonyl]amino]-5-phenyl-1-(phenylmethyl)pentyl]carbamic
Acid (3S)-Tetrahydro-3-furanyl Ester (24a). 1H NMR (400 MHz,
CDCl3) δ 7.52-7.48 (m, 2H), 7.40 (t, J ) 7.6 Hz, 2H), 7.28-7.24
(m, 2H), 7.22-7.16 (m, 5H), 7.14-7.10 (m, 4H), 7.02 (d, J ) 6.8
Hz, 1H), 6.91 (t, J ) 9.2 Hz, 1H), 5.13 (m, 1H), 5.0 (d, J ) 9.6
Hz, 1H), 4.81 (dd, J ) 9.6, 6.0 Hz, 1H), 4.24-4.17 (m, 2H), 4.13-
4.05 (m, 2H), 3.86-3.66 (m, 7H), 3.57 (br s, 1H), 2.91 (d, J ) 8.0
(5S)-3-(4-Acetylphenyl)-N-[(1S,2S,4S)-4-[(2,6-Dimethylphe-
noxyacetyl)]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pen-
tyl]-2-oxo-oxazolidine-5-carboxamide (16f). 1H NMR (400 MHz,
CDCl3) δ 8.01 (m, 2H), 7.57 (m, 2H), 7.29 (m, 2H), 7.24-7.19
(m, 3H), 7.14 (dd, J ) 8.0, 1.2 Hz, 2H), 7.03-6.94 (m, 6H), 6.88
(dt, J ) 8.4, 1.2 Hz, 1H), 6.79 (d, J ) 10.0 Hz, 1H), 4.85 (dd, J
) 9.6, 6.0 Hz, 1H), 4.39 (m, 1H), 4.30 (m, 1H), 4.27 (d, J ) 15.2
Hz, 1H), 4.14-4.09 (m, 2H), 3.38 (m, 1H), 3.84 (br s, 1H), 3.49
(dd, J ) 9.2, 6.4 Hz, 1H), 3.02-2.83 (m, 4H), 2.62 (s, 3H), 2.13
(s, 6H), 1.86-1.75 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 197.07,
169.59, 168.63, 154.21, 152.86, 141.69, 137.93, 137.19, 133.16,
130.65, 129.88 (2C), 129.59 (2C), 129.42 (2C), 129.36 (2C), 128.98
(2C), 128.50 (2C), 127.16, 126.61, 125.07, 117.61 (2C), 70.78,
70.27, 69.95, 54.84, 48.91, 48.16, 41.75, 41.43, 38.86, 26.75, 16.39
(2C). HRMS (ESI) m/z calcd for C40H44N3O7 [M + H]+, 678.3179;
found, 678.3206.