Structure–activity relationship of HIV-1 protease inhibitors containing α-hydroxy-β-amino acids. Detailed study of P1 site (original) (raw)

1999, Bioorganic & Medicinal Chemistry

Abstract

ÐThe structure±activity relationship of HIV-1 protease (HIV-1 PR) inhibitors containing a-hydroxy-b-amino acids is discussed. We demonstrated that substituent groups on the P 1 aromatic rings of the inhibitors exert signi®cant in¯uence on their biological activity. Inhibitors bearing an alkyl or a¯uorine atom at the meta and para position on their P 1 benzene ring were found to be good inhibitors. We also discovered that the substitution positions of the P 2 benzamides were crucial for good antiviral potency. In this study, inhibitor 48 was the most potent {IC 90 (CEM/HIV-1 IIIB) 27 nM} and showed good pharmacokinetics in rats.

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References (123)

  1. IR (KBr) 3325, 2969, 2931, 1648, 1586, 1526, 1455, 1367, 1282, 1225, 1208, 1176, 1112, 1093, 700 cm À1 . Anal. calcd for C 27 H 34 N 3 O 5 Cl . 1/2H 2 O: C, 61.77;
  2. H NMR (CDCl 3 ) d 1.30 (s, 9H), 2.02 (s, 3H), 2.32 (s, 3H), 2.63±
  3. Hz), 3.99±4.08 (m, 2H), 4.30±4.39 (m, 2H), 4.41±4.60 1H), 4.67±4.73 (m, 1H), 6.06 (d, 1H, J=8.1 Hz), 6.28 (s 1H), 6.69±6.84 (m, 5H), 7.00±7.17 (m, 5H); MS m/z 530 (M+H) + . (3-Hydroxy-2-methylbenzoyl)-(2(S)-hydroxy-3(S)-amino- 4-m-tolylbutanoyl)-4(S)-Cl-Pro-NH-t-Bu (11).
  4. H NMR (CDCl 3 ) d 1.31 (s, 9H), 2.02 (s, 3H), 2.27 (s, 3H), 2.62±
  5. Hz), 6.74 (s, 1H), 6.64±7.06 (m, 4H), 7.15±7.23 (m, 1H); MS m/z 530 (M+H) + .
  6. -Hydroxy-2-methylbenzoyl)-(2(S)-hydroxy-3(S)-amino- 4-o-tolylbutanoyl)-4(S)-Cl-Pro-NH-t-Bu (12).
  7. H NMR (CDCl 3 ) d 1.29 (s, 9H), 2.08 (s, 3H), 2.36 (s, 3H), 2.59±
  8. Hz), 6.33 (s, 1H), 6.62 (d, 1H, J=7.1 Hz), 6.76 (t, 1H, J=8.3 Hz), 6.97 (t, 1H, J=7.
  9. Hz), 7.04±7.26 (m, 4H); MS m/z 530 (M+H) + .
  10. -Hydroxy-2-methylbenzoyl)-{2(S)-hydroxy-3(S)-amino-
  11. H NMR (CDCl 3 ) d 1.31 (s, 9H), 2.03 (s, 3H), 2.53±
  12. F, 3.39. Found: C, 58.03; H, 6.02; N, 7.14; Cl, 6.03; F, 3.08; MS m/z 534 (M+H) + .
  13. -Hydroxy-2-methylbenzoyl)-{2(S)-hydroxy-3(S)-amino-
  14. H NMR (CDCl 3 ) d 1.31 (s, 9H), 2.06 (s, 3H), 2.61±
  15. -Hydroxy-2-methylbenzoyl)-{2(S)-hydroxy-3(S)-amino-
  16. H NMR (CDCl 3 ) d 1.31 (s, 9H), 2.04 (s, 3H), 2.60±
  17. 27±4.36 (m, 1H), 4.40±4.49 (m, m, 2H), 4.63±4.70 (m, 1H), 6.27 (s, 1H), 6.36 (s, 1H), 6.47 (s, 1H), 6.67±6.72 (m, 1H), 6.77±6.89 (m, 1H), 6.94±7.34 (m, 6H). Anal. calcd for C 27 H 33 N 3 O 5 ClF . 2/3H 2 O: C, 59.39; H, 6.34; N, 7.70; Cl, 6.49; F, 3.48. Found: C, 59.10; H, 6.48; N, 7.03; Cl, 6.06; F, 2.91; MS m/z 534 (M+H) + . (3-Hydroxy-2-methylbenzoyl)-{2(S)-hydroxy-3(S)-amino- 4-(3,4-di¯uoro)-phenylbutanoyl}-4(S)-Cl-Pro-NH-t-Bu (16).
  18. H NMR (CD 3 OD) d 1.34 (s, 9H), 2.01 (s, 3H), 2.67±2.81 (m, 2H), 3.03±3.09 (m, 1H), 3.84±3.91 (m, 1H), 4.06±4.17 (m, 1H), 4.32±4.58 (m, 5H), 6.95±7.01 (m, 1H), 7.14±7.19 (m, 3H), 7.26±7.36 (m, 2H); MS m/z 552 (M+H) + . (3-Hydroxy-2-methylbenzoyl)-{2(S)-hydroxy-3(S)-amino- 4-(3,5-di¯uoro)-phenylbutanoyl}-4(S)-Cl-Pro-NH-t-Bu (17).
  19. H NMR (CDCl 3 ) d 1.34 (s, 9H), 2.09 (s, 3H), 2.50±2.90 (m, 4H), 3.89±4.03 (m, 2H), 4.27±4.48 (m, 4H), 4.60±4.69 (m, 2H), 5.97 (s, 1H), 6.16 (d, 1H, J=8.
  20. H NMR (CDCl 3 ) d 1.31 (s, 9H), 2.06 (s, 3H),
  21. 28±4.47 (m, 3H), 4.59±4.67 (m, 2H), 5.83 (s, 1H), 6.15 (s, 1H), 6.33 (d, 1H, J=8.5 Hz), 6.76±6.89 (m, 3H), 6.98± 7.11 (s, 2H), 7.29±7.38 (m, 1H); MS m/z 552 (M+H) + . (3-Hydroxy-2-methylbenzoyl)-{2(S)-hydroxy-3(S)-amino- 4-(4-tri¯uoromethyl)-phenylbutanoyl}-4(S)-Cl-Pro-NH-t- Bu (19).
  22. H NMR (DMSO-d 6 ) d 1.24 (s, 9H), 1.72 (s, 3H), 1.91±2.00 (m, 1H), 2.69±2.92 (m,3H), 3.07±3.50 (m, 1H), 4.35±4.44 (m, 4H), 4.52±4.55 (m, 1H), 5.25 (d, 1H, J=6.
  23. Hz), 6.95 (t, 1H, 7.7 Hz), 7.55±7.62 (m, 5H), 8.27 (d, 1H, 8.4 Hz), 9.28 (s, 1H); MS m/z 584 (M+H) + . (3-Hydroxy-2-methylbenzoyl)-{2(S)-hydroxy-3(S)-amino- 4-(4-methoxy)-phenylbutanoyl}-4(S)-Cl-Pro-NH-t-Bu (20).
  24. H NMR (CD 3 OD) d 1.30 (s, 9H), 2.03 (s, 3H), 2.59±2.64 (m, 2H), 2.73±2.85 (m, 2H), 3.76 (s, 3H),
  25. H NMR (DMSO-d 6 ) d 1.26 (s, 9H), 1.81 (s, 3H), 1.81±2.03 (m, 1H), 2.70±2.92 (m, 3H), 3.71±3.77 (m, 1H), 4.28±4.59 (m, 5H), 5.11 (d, 1H, J=6.1 Hz), 6.57 (d, 1H, J=7.5 Hz), 6.79 (d, 1H, J=7.5 Hz), 6.95 (t, 1H, J=7.5 Hz), 7.52±7.61 (m, 3H), 7.75 (t, 1H, J= 5.7 Hz), 7.87 (s, 1H), 8.32 (d, 1H, J=9.5 Hz), 9.40 (s, 1H); MS m/z 584 (M+H) + . (3-Hydroxy-2-methylbenzoyl)-{2(S)-hydroxy-3(S)-amino- 4-(4-hydroxy)-phenylbutanoyl}-4(S)-Cl-Pro-NH-t-Bu (22).
  26. H NMR (CD 3 OD) d 1.33 (s, 9H), 1.89 (s, 3H), 2.60± 3.03 (m, 4H), 3.84±3.90 (m, 1H), 4.40±5.51 (m, 5H),
  27. -Hydroxy-2-methylbenzoyl)-{2(S)-hydroxy-3(S)-amino-
  28. H NMR (CDCl 3 ) d 1.31 (s, 9H), 2.05 (s, 3H), 2.61±
  29. -Hydroxy-2-methylbenzoyl)-2(S)-hydroxy-3(S)-amino-
  30. H NMR (CDCl 3 ) d 1.31 (s, 9H), 2.05 (s, 3H),
  31. -Hydroxy-2-methylbenzoyl)-2(S)-hydroxy-3(S)-amino-
  32. H NMR (CDCl 3 ) d 1.29 (s, 9H), 1.85±1.98 (m, 3H), 2.59±3.31 (m, 6H), 3.93±4.03 (m, 1H), 4.27±
  33. -Hydroxy-2-methylbenzoyl)-{2(S)-hydroxy-3(S)-amino-
  34. H NMR (CD 3 OD) d 1.33 (s, 9H), 1.72 (s, 3H), 2.11±2.18 (m, 1H), 2.69±2.70 (m, 1H), 3.11±3.17 (m, 1H), 3.57±
  35. 66 (m, 1H), 3.71±3.76 (m, 1H), 3.91 (dd, 1H, J 1 = 11.1, J 2 =7.6 Hz), 4.39±4.54 (m, 4H), 6.52 (d, 1H, J=7.0
  36. Hz), 6.72 (d, 1H, J=7.9 Hz), 6.89±6.93 (m, 1H),
  37. -Hydroxy-2-methylbenzoyl)-{2(S)-hydroxy-3(S)-amino-
  38. H NMR (CD 3 OD) d 1.34 (s, 9H), 1.66 (s, 3H), 2.10±2.17 (m, 1H), 2.71±2.78 (m, 1H), 2.91 (dd, 1H, J 1 =14.0, J 2 =11.5 Hz), 3.25±3.31 (m, 2H), 3.91 (dd, 1H, J 1 =10.8, J 2 =7.8 Hz), 4.36±4.55 (m, 4H), 4.66±4.88 (m, 1H), 6.55 (d, 1H, J=7.2 Hz), 6.71 (d, 1H, J=7.
  39. 9 Hz), 7.40±7.46 (m, 2H), 7.53 (dd, 1H, J 1 =8.2, J 2 =1.4 Hz), 7.71±7.83 (m, 4H); MS m/z 566 (M+H) + . (3-Hydroxy-2,4 -dimethylbenzoyl)-{2(S)-hydroxy -3(S)- amino-4-phenylbutanoyl}-4(S)-Cl-Pro-NH-t-Bu (28).
  40. H NMR (CDCl 3 ) d 1.30 (s, 9H), 2.11 (s, 3H), 2.22 (s, 3H),
  41. Hz), 6.26 (s, 1H), 6.61 (d, 1H, J=7.7 Hz), 6.90 (d, 1H, 7.7 Hz), 7.15±7.33 (m, 5H); MS m/z 530 (M+H) + .
  42. -Hydroxy -2,5 -dimethylbenzoyl) -(2(S) -hydroxy -3(S)- amino-4-phenylbutanoyl)-4(S)-Cl-Pro-NH-t-Bu (29).
  43. H NMR (CDCl 3 ) d 1.30 (s, 9H), 1.93 (s, 3H), 2.19 (s, 3H),
  44. 74 (m, 2H), 6.03 (d, 1H, J=8.2 Hz), 6.25 (s, 1H), 6.46 (s, 1H), 6.64 (s, 1H), 7.16±7.52 (m, 5H); MS m/z 530 (M+H) + . (5-Fluoro-3-hydroxy-2-methylbenzoyl)-(2(S)-hydroxy-3(S)- amino-4-phenylbutanoyl)-4(S)-Cl-Pro-NH-t-Bu (30).
  45. H NMR (CDCl 3 ) d 1.31 (s, 9H), 1.90 (s, 3H), 2.41±2.96 (m, 4H), 3.98 (d, 1H, J=4.0 Hz), 4.00±4.14 (m, 1H),
  46. 30±4.42 (m, 1H), 4.48±4.52 (m, 1H), 4.58±4.71 (m, 1H), 5.65 (br, 1H), 6.06 (d, 1H, J=8.4 Hz), 6.18 (br, 1H), 6.35±6.47 (m, 1H), 6.52±6.61 (m, 1H), 7.15±7.34 (m, 5H); MS m/z 534 (M+H) + . (3 -Hydroxy-2,6 -dimethylbenzoyl)-{2(S)-hydroxy -3(S)- amino-4-phenylbutanoyl}-4(S)-Cl-Pro-NH-t-Bu (31). Mp 134±136 C; H-NMR (CDCl 3 ) d 1.30 (s, 9H), 1.91 (s, 3H), 1.97 (s, 3H), 2.36±2.90 (m, 3H), 3.71±4.19 (m, 4H),
  47. IR (KBr) 3335, 2968, 1645, 1532, 1455, 1276, 1223, 1118, 872, 749, 700 cm À1 . Anal. calcd for C 28 H 36 N 3 O 5 Cl . 1.78H 2 O: C, 59.84; H, 7.09; N, 7.47; Cl, 6.31. Found: C, 60.07; H, 6.75; N, 7.09; Cl, 6.57; MS m/z 529 (M+) + . (3 -Hydroxy-2,4 -dimethylbenzoyl)-{2(S)-hydroxy -3(S)- amino -4 -(3 -tri¯uoromethyl) -phenylbutanoyl} -4(S) -Cl - Pro-NH-t-Bu (32).
  48. H NMR (CDCl 3 ) d 1.31 (s, 9H), 2.05 (s, 3H), 2.22 (s, 3H), 2.56±2.96 (m, 4H), 3.83 (d, 1H, J=6.1 Hz), 3.97±4.17 (m, 2H), 4.30±4.36 (m, 2H),
  49. 40±4.48 (m, 1H), 4.61±4.79 (m, 2H), 6.04 (s, 1H), 6.11 (d, 1H, 8.7 Hz), 6.63 (d, 1H, 7.6 Hz), 6.91 (d, 1H, 7.6
  50. Hz), 7.28±7.53 (m, 4H); MS m/z 598 (M+H) + . (3 -Hydroxy-2,5 -dimethylbenzoyl)-{2(S)-hydroxy -3(S)- amino -4 -(3 -tri¯uoromethyl) -phenylbutanoyl} -4(S) -Cl - Pro-NH-t-Bu (33).
  51. H NMR (CDCl 3 ) d 1.31 (s, 9H), 1.97 (s, 3H), 2.20 (s, 3H), 2.43±2.96 (m, 4H), 3.86 (d, 1H, J=6.40 Hz), 3.94±4.22 (m, 2H), 4.29±4.37 (m, 2H),
  52. 42±4.49 (m, 1H), 4.60±4.76 (m, 2H), 6.03 (br, 1H), 6.07 (d, 1H, J=8.8 Hz), 6.48 (s, 1H), 6.62 (s, 1H), 7.35± 7.55 (m, 4H); MS m/z 598 (M+H) + . (5-Fluoro-3-hydroxy-2-methylbenzoyl)-{2(S)-hydroxy- 3(S)-amino-4-(3-tri¯uoromethyl)-phenylbutanoyl}-4(S)- Cl-Pro-NH-t-Bu (34).
  53. H NMR (CDCl 3 ) d 1.31 (s, 9H), 1.91 (s, 3H), 2.45±2.96 (m, 4H), 3.87 (d, 1H, J=6.2 Hz), 3.94±4.06 (m, 1H), 4.07±4.37 (m, 2H), 4.44±4.48 (m, 1H), 4.62±4.71 (m, 2H), 5.48 (br, 1H), 5.97 (br, 1H), 6.11 (d, 1H, J=8.8 Hz), 6.41±6.46 (m, 1H), 6.54±6.62 (m, 1H), 7.35±7.54 (m, 4H); MS m/z 602 (M+H) + . (3 -Hydroxy-2,6 -dimethylbenzoyl)-{2(S)-hydroxy -3(S)- amino -4 -(3 -tri¯uoromethyl) -phenylbutanoyl} -4(S) -Cl - Pro-NH-t-Bu (35).
  54. H NMR (CDCl 3 ) d 1.31 (s, 9H), 1.85 (s, 3H), 1.92 (s, 3H), 2.42±3.09 (m, 4H), 3.77±3.80 (m, 1H), 4.00±4.20 (m, 2H), 4.29±4.44 (m, 2H), 4.46 (t, 1H, J=7.8 Hz), 4.54±4.88 (m, 3H), 6.01 (s, 1H), 6.65 (d, 1H, J=8.2 Hz), 6.78±6.87 (m, 1H), 7.30±7.54 (m, 4H);
  55. H NMR (CDCl 3 ) d 1.31 (s, 9H), 2.00 (s, 3H), 2.23 (s, 3H), 2.57±2.88 (m, 4H), 3.82 (d, 1H, 6.4 Hz), 3.92±4.18 (m, 2H), 4.30±4.36 (m, 2H),
  56. 41±4.51 (m, 1H), 4.64±4.79 (m, 2H), 6.03 (s, 1H), 6.06 (d, 1H, J=8.7 Hz), 6.64 (d, 1H, J=7.6 Hz), 6.92 (d, 1H, J=7.6
  57. Hz), 7.39 (d, 1H, 8.1 Hz), 7.56 (d, 1H, 8.1 Hz);
  58. MS m/z 598 (M+H) + .
  59. -Hydroxy-2,6 -dimethylbenzoyl)-{2(S)-hydroxy -3(S)- amino -4 -(4 -tri¯uoromethyl) -phenylbutanoyl} -4(S) -Cl - Pro-NH-t-Bu (37).
  60. H NMR (CDCl 3 ) d 1.31 (s, 9H),
  61. 82 (s, 3H), 1.90 (s, 3H), 2.44±2.96 (m, 4H), 3.79 (d, 1H, J=6.3 Hz), 4.00±4.19 (m, 1H), 4.31±4.39 (m, 2H),
  62. Hz), 6.81 (d, 1H, 8.2 Hz), 7.39 (d, 1H, J=8.1 Hz), 7.56 (d, 2H, J=8.1 Hz); MS m/z 598 (M+H) + .
  63. H NMR (CDCl 3 ) d 1.30 (s, 9H), 2.06 (s, 3H), 2.22 (s, 3H), 2.32 (s, 3H), 2.58±2.79 (m, 4H), 3.81 (d, 1H, J=7.4 Hz),
  64. 05 (m, 2H), 7.13±7.21 (m, 1H); MS m/z 544 (M+H) + . (3 -Hydroxy -2,5 -dimethylbenzoyl) -(2(S) -hydroxy -3(S)- amino-4-m-tolylbutanoyl)-4(S)-Cl-Pro-NH-t-Bu (39).
  65. H NMR (CDCl 3 ) d 1.31 (s, 9H), 1.96 (s, 3H), 2.19 (s, 3H), 2.31 (s, 3H), 2.41±2.96 (m, 4H), 3.87 (d, 1H, J=6.5 Hz),
  66. H NMR (CDCl 3 ) d 1.30 (s, 9H), 1.84 (s, 3H), 1.94 (s, 3H), 2.28 (s, 3H), 2.41±2.98 (m, 4H), 3.79 (d, 1H, J=6.3 Hz),
  67. 00±4.14 (m, 2H), 4.31±4.40 (m, 2H), 4.50±4.65 (m, 2H), 4.76±4.85 (m, 1H), 5.98 (d, 1H, J=8.1 Hz), 6.28 (s, H), 6.63±6.73 (m, 1H), 6.79±6.85 (m, 1H), 6.90±7.04 (m, 3H), 7.12±7.19 (m, 1H); MS m/z 544 (M+H) + .
  68. H NMR (CDCl 3 ) d 1.29 (s, 9H), 2.06 (s, 3H), 2.23 (s, 3H), 2.31 (s, 3H), 2.60±2.83 (m, 4H), 3.77 (d, 1H, J=6.6 Hz),
  69. H NMR (CDCl 3 ) d 1.30 (s, 9H), 1.84 (s, 3H), 1.94 (s, 3H), 2.31 (s, 3H), 2.59±2.88 (m, 4H), 3.76 (d, 1H, J=6.4 Hz),
  70. -Hydroxy -2,4 -dimethylbenzoyl) -(2(S) -hydroxy -3(S)- amino-4-o-tolylbutanoyl)-4(S)-Cl-Pro-NH-t-Bu (43).
  71. H NMR (CDCl 3 ) d 1.27 (s, 9H), 2.02 (s, 3H), 2.17 (s, 3H), 2.28 (s, 3H), 2.38±2.61 (m, 1H), 2.68±3.06 (m, 4H),
  72. Hz), 6.93 (dd, 1H, J 1 =26.0, J 2 =7.7 Hz) 7.01±7.07 (m, 2H), 7.08±7.15 (m, 2H); MS m/z 544 (M+H) + . (3 -Hydroxy -2,6 -dimethylbenzoyl) -(2(S) -hydroxy -3(S)- amino-4-o-tolylbutanoyl)-4(S)-Cl-Pro-NH-t-Bu (44).
  73. H NMR (CDCl 3 ) d 1.26±1.33 (m, 9H), 1.89 (s, 3H), 2.11 (s, 3H), 2.35 (s, 3H), 2.53±3.02 (m, 5H), 3.79±3.89 (m, 1H), 3.95±4.05 (m, 2H), 4.20±4.47 (m, 3H), 4.49±4.60 (m, H), 4.75±4.81 (m, 1H), 4.90 (t, 1H, J=7.5 Hz), 6.84± 6.92 (m, 1H), 7.04±7.14 (m, 5H); MS m/z 544 (M+H) + . (3 -Hydroxy-2,5 -dimethylbenzoyl)-{2(S)-hydroxy -3(S)- amino-4-(4-phenyl)-phenylbutanoyl}-4(S)-Cl-Pro-NH-t- Bu (45).
  74. H NMR (CDCl 3 ) d 1.31(s, 9H), 1.90 (s, 3H), 2.12 (s, 3H), 2.60±2.66 (m, 2H), 2.77±2.97 (m, 2H),
  75. 94±4.07 (m, 2H), 4.28±4.36 (m, 2H), 4.43±4.53 (m, 1H), 4.63±4.76 (m, 2H), 6.01 (s, 1H), 6.23 (s, 1H), 6.46± 6.64 (m, 1H), 7.21±7.57 (m, 11H); MS m/z 606 (M+H) + . (3 -Hydroxy-2,5 -dimethylbenzoyl)-{2(S)-hydroxy -3(S)- amino-4-(3,5-di¯uoro)-phenylbutanoyl}-4(S)-Cl-Pro-NH- t-Bu (46).
  76. H NMR (CDCl 3 ) d 1.34 (s, 9H), 1.87 (s, 3H), 2.05±2.16 (m, 1H), 2.20 (s, 3H), 2.70±2.81 (m, 2H), 3.08 (d, 1H, J=3.0 Hz), 3.88±3.89 (m, 1H), 4.40±4.58 (m, 5H), 6.46 (s, 1H), 6.61 (s, 1H), 6.74±6.83 (m, 1H), 7.00±7.07 (m, 2H); MS m/z 566(M+H) + . (3 -Hydroxy-2,4 -dimethylbenzoyl)-{2(S)-hydroxy -3(S)- amino-4-(-naphtyl)-butanoyl}-4(S)-Cl-Pro-NH-t-Bu (47).
  77. H NMR (CDCl 3 ) d 1.30 (s, 9H), 1.91 (s, 3H), 2.19 (s, 3H), 2.61±2.79 (m, 2H), 2.95±3.06 (m, 2H), 3.83 (d, 1H, J=6.5
  78. Hz), 3.92±4.07 (m, 2H), 4.33±4.45 (m, 2H), 4.54± 4.57 (m, 1H), 4.61±4.77 (m, 2H), 6.11 (d, 1H, J= 8.2 Hz), 6.29 (s, 1H), 6.59 (d, 1H, J=7.7 Hz), 6.84 (d, 1H, J=7.7 Hz), 7.29±7.49 (m, 3H), 7.60±8.02 (m, 4H);
  79. H NMR (CDCl 3 ) d 1.31 (s, 9H), 1.84 (s, 3H), 2.05 (s, 3H), 2.62±3.06 (m, 4H), 3.89 (d, 1H, J=6.5 Hz), 3.92±
  80. 29±7.52 (m, 4H), 7.61±7.83 (m, 4H); MS m/z 579 (M) + . (3 -Hydroxy-2,6 -dimethylbenzoyl)-{2(S)-hydroxy -3(S)- amino-4-(-naphtyl)-butanoyl}-4(S)-Cl-Pro-NH-t-Bu (49).
  81. H NMR (CDCl 3 ) d 1.30 (s, 9H), 1.70 (s, 3H), 1.83 (s, 3H), 2.63±3.02 (m, 4H), 3.79 (d, 1H, J=6.1 Hz), 4.02± 4.10 (m, 2H), 4.35±4.43 (m, 2H), 4.53±4.65 (m, 1H),
  82. 74±4.82 (m, 2H), 6.00 (d, 1H, J=8.2 Hz), 6.28 (s, 1H), 6.60±6.67 (m, 1H), 6.74±6.83 (m, 1H), 7.29±7.52 (m, 3H), 7.59±7.82 (m, 4H); MS m/z 580 (M+H) + . (5-Fluoro-3-hydroxy-2-methylbenzoyl)-{2(S)-hydroxy- 3(S)-amino-4-(-naphtyl)-butanoyl}-4(S)-Cl-Pro-NH-t- Bu (50).
  83. H NMR (CDCl 3 ) d 1.31 (s, 9H), 1.77 (s, 3H), 2.63±2.76 (m, 2H), 2.95±3.07 (m, 2H), 3.86±4.04 (m, 2H), 4.31±4.43 (m, 3H), 4.51±4.76 (m, 3H), 5.41 (s, 1H), 6.13±6.58 (m, 4H), 7.29±7.67 (m, 4H), 7.73±7.83 (m, 3H); MS m/z 584 (M+H) + .
  84. Wlodawer, A.; Erickson, J. W. Annu. Rev. Biochem. 1993, 62, 543.
  85. Meek, T. D. J. Enzyme Inhibition 1992, 6, 65.
  86. Barry, M.; Gibbons, S.; Back, D.; Mulcahy, F. Clin. Phar- macokinet. 1997, 32, 194.
  87. West, M. L.; Fairlie, D. P. Trends in Pharmacol. Sci. 1995, 16, 67.
  88. Boden, D.; Markowitz, M. Antimicrob. Agents Chemother. 1998, 42, 2775.
  89. Preston, B. D.; Dougherty, J. P. Trends in Microbiology 1996, 4, 16.
  90. Ala, P. J.; Huston, E. E.; Klabe, R. M.; McCabe, D. D.; Duke, J. L.; Rizzo, C. J.; Korant, B. D.; DeLoskey, R. J.; Lam, P. Y. S.; Hodge, C. N.; Chang, C.-H. Biochemistry 1997, 36, 1573.
  91. Ridky, T. W.; Kikonyogo, A.; Leis, J. Biochemistry 1998, 38, 13835.
  92. Molla, A.; Vasavanonda, S.; Kumar, G.; Sham, H. L.; Johnson, M.; Grabowski, B.; Denissen, J. F.; Kohlbrenner, W.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W.; Kempf, D. J. Virology 1998, 250, 255.
  93. Chen, X.; Kempf, D. J.; Sham, H. L.; Green, B. E.; Molla, A.; Korneyeva, M.; Vasavanonda, S.; Wideburg, N. E.; Saldi- var, A.; Marsh, K. C.; McDonard, E.; Norbeck, D. W.; Rod- gers, J. D.; Lam, P. Y.-S.; Johnson, B. L.; Wang, H.; Ko, S. S.; Seitz, S. P.; Trainor, G. L.; Anderson, P. S.; Klabe, R. M.; Bacheler, L. T.; Cordova, B.; Garber, S.; Reid, C.; Wright, M. R.; Chang, C.-H.; Erickson-Viitanen, S. Bioorg. Med. Chem. Lett. 1998, 8, 3531.
  94. Rodgers, J. D.; Lam, P. Y.-S.; Johnson, B. L.; Wang, H.; Ko, S. S.; Seitz, S. P.; Trainor, G. L.; Anderson, P. S.; Klabe, R. M.; Bacheler, L. T.; Cordova, B.; Garber, S.; Reid, C.; Wright, M. R.; Chang, C.-H.; Erickson-Viitanen, S. Chemistry and Biology 1998, 5, 597.
  95. Mimoto, T.; Imai, J.; Tanaka, S.; Hattori, N.; Takahashi, O.; Kisanuki, S.; Nagano, Y.; Shintani, M.; Hayashi, H.; Sakikawa, H.; Akaji, K.; Kiso, Y. Chem. Pharm. Bull. 1991, 39, 2465.
  96. Mimoto, T.; Imai, J.; Tanaka, S.; Hattori, N.; Kisanuki, S.; Akaji, K.; Kiso, Y. Chem. Pharm. Bull. 1991, 39, 3088.
  97. Mimoto, T.; Imai, J.; Kisanuki, S.; Enomoto, H.; Hattori, N.; Akaji, K.; Kiso, Y. Chem. Pharm. Bull. 1992, 40, 2251.
  98. Wang, Y.-X.; Freedberg, D. I.; Wing®eld, P. T.; Stahl, S. J.; Kaufman, J. D.; Kiso, Y.; Bhat, T. N.; Erickson, J. W.; Torchia, D. A. J. Am. Chem. Soc. 1996, 118, 12287.
  99. For chemistry of AHPBA, see: Sasai, H.; Kim, W.-S.; Suzuki, T.; Shibasaki, M.; Mitsuda, M.; Hasegawa, J.; Ohashi, T. Tetrahedron. Lett. 1994, 35, 6123 and references cited therein.
  100. Sakurai, M.; Higashida, S.; Sugano, M.; Komai, T.; Yagi, R.; Ozawa, Y.; Handa, H.; Nishigaki, T.; Yabe, Y. Bioorg. Med. Chem. 1994, 2, 807.
  101. Komai, T.; Higashida, S.; Sakurai, M.; Nitta, T.; Kasuya, A.; Miyamoto, S.; Yagi, R.; Ozawa, Y.; Handa, H.; Mohri, H.; Yasuoka, A.; Oka, S.; Nishigaki, T.; Kimura, S.; Shimada, K.; Yabe, Y. Bioorg. Med. Chem. 1996, 4, 1365.
  102. Takashiro, E.; Watanabe, T.; Nitta, T.; Kasuya, A.; Miyamoto, S.; Ozawa, Y.; Yagi, R.; Nishigaki, T.; Shibayama, T.; Nakagawa, A.; Iwatomo, A.; Yabe, Y. Bioorg. Med. Chem. 1998, 6, 595.
  103. Kaldor, S. W.; Kalish, V. J.; Davies II, J. F.; Shetty, B. V.; Fritz, J. E.; Appelt, K.; Burgess, J. A.; Campanale, K. M.; Chirgadze, N. Y.; Clawson, D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.; Kosa, M. B.; Lubbehusen, P. P.; Muesing, M. A.; Patick, A. M.; Reich, S. H.; Su, K. S.; Tatlock, J. H. J. Med. Chem. 1997, 40, 3979.
  104. For Nel®navir, see: Jarvis, B.; Faulds, D. Drugs 1998, 56, 147.
  105. Houbion, J. A.; Miles, J. A.; Paton, J. A. Org. Prep. Proc. Int. 1979, 11, 27.
  106. Agrawal, S. R.; Desai, V. B.; Kaushik, H. C.; Khan, M. S.; Merchant, J. R. J. Ind. Chem. Soc. 1962, 39, 759.
  107. Mandell, L.; Caine, D.; Kilpatrick, G. E. J. Am. Chem. Soc. 1961, 83, 4457.
  108. Charlesworth, E. H.; Levene, L. Can. J. Chem. 1963, 41, 1071.
  109. Reetz, M. T.; Drewes, M. W.; Harm, K.; Reif, W. Tetra- hedron Lett. 1988, 29, 3295.
  110. Shimizu, M.; Wakioka, I.; Fujisawa, T. Tetrahedron. Lett. 1997, 38, 6027.
  111. Ohba, T.; Ikeda, E.; Takei, H. Bioorg. Med. Chem. Lett. 1996, 6, 1875.
  112. Hanson, G. J.; Lindberg, T. J. Org. Chem. 1885, 50, 5399.
  113. Spaltenstein, A.; Leban, J. J.; Huang, J. J.; Reinhardt, K. R; Viveros, O. H.; Sigafoos, J.; Crouch, R. Tetrahedron. Lett. 1996, 37, 1343.
  114. Kim, B. M.; Guare, J. P.; Hani®n, C. M.; Arford-Bick- ersta, D. J.; Vacca, J. P.; Ball, R. G. Tetrahedron. Lett. 1994, 35, 5153.
  115. In this reaction, use of N-methoxy-N-methyl amide led to the formation of a side product, derived from Michael addition of magnesium N-methoxy-N-methyl amide to vinyl ketone. Use of diethyl amide completely suppressed this side reaction. 33. The absolute stereochemistry of hydroxyl groups was established as follows: treatment of these allyl alcohols with NaH in DMF gave oxazolidinones, which were analyzed by spectroscopic means: see ref 31.
  116. Lindgren, B. O.; Nilsson, T. Acta. Chem. Scand. 1973, 27, 888. 35. Dondoni, A.; Perrone, D. Synthesis 1993, 1162.
  117. Suzuki, T.; Honda, Y.; Izawa, K. EP 0 767 168 A2.
  118. Chenault, H. K.; Dahmer, J.; Whitesides, G. M. J. Am. Chem. Soc. 1989, 111, 6354.
  119. Chibata, I.; Ishikawa, T.; Yamada, S. Bull. Agr. Chem. Soc. Jpn. 1957, 21, 304.
  120. The details of preparing the l-amino acids and the corre- sponding a-hydroxy-b-amino acids will be reported elsewhere.
  121. Randad, R. S.; Lubkowska, L. L.; Bhat, T. N.; Munshi, S. M.; Gulnik, S. V.; Yu, B.; Erickson, J. W. Bioorg. Med. Chem. Lett. 1995, 5, 1707.
  122. Kempf, D. J.; Flentge, C. A.; Wideburg, N. E.; Saldivar, A.; Vasavanonda, S.; Norbeck, D. W. Bioorg. Med. Chem. Lett. 1995, 5, 2725.
  123. Kalish, V. J.; Tatlock, J. H.; Davies II, J. F.; Kaldor, S. W.; Dressmen, B. A.; Reich, S.; Pino, M.; Nyugen, D.; Appelt, K.; Musick, L.; Wu, B.-W. Bioorg. Med. Chem. Lett. 1995, 5, 727.