Design of Novel HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 12 2407
N-[3-[Cyclop r op yl[4-h yd r oxy-2-oxo-6-(2-p h en yleth yl)-
2H-p yr a n -3-yl]m eth yl]p h en yl]-1-m eth yl-1H-im id a zole-4-
su lfon a m id e (XIII): 1H NMR δ 0.21 (m, 2H), 0.45 (m, 1H),
0.63 (m, 1H), 1.80 (m, 1H), 2.69 (m, 2H), 2.92 (m, 2H), 3.30 (d,
J ) 10.3 Hz, 1H), 3.59 (s, 3H), 5.89 (s, 1H), 6.9 (m, 1H), 7.08
(t, 1H), 7.1-7.4 (m, 9H); HRMS (EI) m/z 505.1672 found (calcd
505.1671 for C27H27N3O5S); TLC Rf 0.27 (5% methanol in
dichloromethane).
N-[3-[Cyclop r op yl[6-[3-(2-m et h oxyet h oxy)p r op yl]-4-
h yd r oxy-2-oxo-2H-p yr a n -3-yl]m eth yl]p h en yl]-1-m eth yl-
1H-im id a zole-4-su lfon a m id e (XIV): 1H NMR (CDCl3) δ 0.10
(m, 1H), 0.26 (m, 1H), 0.44 (m, 1H), 0.60 (m, 1H), 1.75 (m,
1H), 1.86 (quintet, J ) 7.5 Hz, 2H), 2.47 (t, J ) 7.5 Hz, 2H),
3.32 (d, J ) 10.2 Hz, 1H), 3.35 (s, 3H), 3.4-3.6 (m, 4H), 3.59
(s, 3H), 5.96 (s, 1H), 6.98 (m, 1H), 7.11 (t, J ) 7.8 Hz, 1H), 7.2
(m, 2H), 7.28 (s, 1H), 7.44 (s, 1H); HRMS (EI) m/z 517.1874
found (calcd 517.1883 for C25H31N3O7S); TLC Rf 0.20 (5%
methanol in dichloromethane).
N-[3-[Cyclop r op yl[6-(1-eth ylp r op yl)-4-h yd r oxy-2-oxo-
2H-p yr a n -3-yl]m eth yl]p h en yl]-1-m eth yl-1H-im id a zole-4-
su lfon a m id e (XV): 1H NMR (CDCl3) δ 0.14 (m, 2H), 0.39 (m,
1H), 0.58 (m, 1H), 0.79 (t, J ) 7.3 Hz, 6H), 1.55 (m, 4H), 1.75
(m, 1H), 2.1 (m, 1H), 3.22 (d, J ) 10.3 Hz, 1H), 3.58 (s, 3H),
5.85 (s, 1H), 6.85 (m, 1H), 7.02 (t, J ) 7.8 Hz, 1H), 7.15 (m,
2H), 7.29 (s, 1H), 7.38 (s, 1H); HRMS (FAB) 472.1924 found
(calcd 472.1906 for C24H30N3O5S); TLC Rf 0.76 (20% methanol
in dichloromethane).
XVIII): 1H NMR δ 0.17 (m, 2H), 0.43 (m, 1H), 0.62 (m, 1H),
0.83 (t, J ) 7.4 Hz, 3H), 1.6 (m, 2H), 1.75 (m, 1H), 2.49 (m,
1H), 2.78 (dd, J ) 7.0 Hz, J ) 13.5 Hz, 1H), 2.90 (dd, J ) 8.0
Hz, J ) 13.5 Hz, 1H), 3.28 (d, J ) 10.2 Hz, 1H), 3.55 (s, 3H),
5.75 (s, 1H), 6.9-7.4 (m, 11H); HRMS (EI) m/z 533.1983 found
(calcd 533.1984 for C29H31N3O5S); TLc f 0.32 (5% methanol in
dichloromethane).
N-[3-[[S or R]-Cyclop r op yl[4-h yd r oxy-2-oxo-6-[1(R)-
(p h en ylm eth yl)p r op yl]-2H-p yr a n -3-yl]m eth yl]p h en yl]-1-
m et h yl-1H -im id a zole-4-su lfon a m id e (diastereomer 2 of
XVIII): 1H NMR δ 0.19 (m, 2H), 0.42 (m, 1H), 0.62 (m, 1H),
0.84 (t, J ) 7.4 Hz, 3H), 1.6 (m, 2H), 1.75 (m, 1H), 2.50 (m,
1H), 2.78 (dd, J ) 7.0 Hz, J ) 13.5 Hz, 1H), 2.91 (dd, J ) 7.9
Hz, J ) 13.5 Hz, 1H), 3.28 (d, J ) 10.2 Hz, 1H), 3.55 (s, 3H),
5.74 (s, 1H), 6.9-7.4 (m, 11H); HRMS (EI) m/z 533.1993 found
(calcd 533.1984 for C29H31N3O5S); TLC Rf 0.30 (5% methanol
in dichloromethane).
N-[3-[[R or S]-Cyclop r op yl[4-h yd r oxy-2-oxo-6-[1(S)-
(p h en ylm eth yl)p r op yl]-2H-p yr a n -3-yl]m eth yl]p h en yl]-1-
m et h yl-1H -im id a zole-4-su lfon a m id e (diastereomer 3 of
XVIII): 1H NMR δ 0.19 (m, 2H), 0.43 (m, 1H), 0.62 (m, 1H),
0.84 (t, J ) 7.4 Hz, 3H), 1.6 (m, 2H), 1.75 (m, 1H), 2.50 (m,
1H), 2.78 (dd, J ) 7.0 Hz, J ) 13.5 Hz, 1H), 2.91 (dd, J ) 7.9
Hz, J ) 13.5 Hz, 1H), 3.28 (d, J ) 10.2 Hz, 1H), 3.58 (s, 3H),
5.74 (s, 1H), 6.9-7.4 (m, 11H); HRMS (EI) m/z 533.1993 found
(calcd 533.1984 for C29H31N3O5S); TLC Rf 0.30 (5% methanol
in dichloromethane).
N -[3-[Cyclop r op yl[6-[2-cyclop r op yl-1-(cyclop r op yl-
m et h yl)et h yl]-4-h yd r oxy-2-oxo-2H -p yr a n -3-yl]m et h yl]-
p h en yl]-1-m eth yl-1H-im id a zole-4-su lfon a m id e (XVI): 1H
NMR (CDCl3-CD3OD) δ -0.02 (m, 4H), 0.21 (m, 2H), 0.4 (m,
5H), 0.65 (m, 3H), 1.4 (m, 2H), 1.6 (m, 2H), 1.8 (m, 1H), 2.6
(m, 1H), 3.31 (d, J ) 10.8 Hz, 1H), 3.67 (s, 3H), 6.02 (s, 1H),
6.89 (m, 1H), 7.07 (t, J ) 7.7 Hz, 1H), 7.12 (m, 1H), 7.25 (s,
1H), 7.44 (s, 1H), 7.57 (s, 1H); HRMS (EI) 523.2142 found
(calcd 523.2141 for C28H33N3O5S); TLC Rf 0.32 (5% methanol
in dichloromethane).
N-[3-[[S or R]-Cyclop r op yl[4-h yd r oxy-2-oxo-6-[1(S)-
(p h en ylm eth yl)p r op yl]-2H-p yr a n -3-yl]m eth yl]p h en yl]-1-
m et h yl-1H -im id a zole-4-su lfon a m id e (diastereomer 4 of
XVIII): 1H NMR δ 0.19 (m, 2H), 0.44 (m, 1H), 0.62 (m, 1H),
0.83 (t, J ) 7.4 Hz, 3H), 1.6 (m, 2H), 1.75 (m, 1H), 2.50 (m,
1H), 2.79 (dd, J ) 7.0 Hz, J ) 13.5 Hz, 1H), 2.91 (dd, J ) 7.9
Hz, J ) 13.5 Hz, 1H), 3.30 (d, J ) 10.2 Hz, 1H), 3.53 (s, 3H),
5.80 (s, 1H), 6.9-7.4 (m, 11H); HRMS (EI) m/z 533.1990 found
(calcd 533.1984 for C29H31N3O5S).
N-[3-[Cyclop r op yl[4-h yd r oxy-2-oxo-6-[1-[(tetr a h yd r o-
2H -p yr a n -4-yl)m et h yl]p r op yl]-2H -p yr a n -3-yl]m et h yl]-
p h en yl]-1-m eth yl-1H-im id a zole-4-su lfon a m id e (XIX): 1H
NMR δ 0.12 (m, 1H), 0.26 (m, 1H), 0.45 (m, 1H), 0.60 (m, 1H),
0.82 (t, J ) 7.4 Hz, 3H), 1.1-1.7 (m, 9H), 1.77 (m, 1H), 2.35
(m, 1H), 3.3 (m, 3H), 3.58 (s, 3H), 3.86 (m, 2H), 6.00 (s, 1H),
6.9-7.5 (m, 5H), 7.59 (m, 1H); HRMS (EI) m/z 541.2238 found
(calcd 541.2246 for C28H35N3O6S); TLC Rf 0.24 (5% methanol
in dichloromethane).
N-[3-[Cyclop r op yl[6-[1-eth yl-3-(2-m eth oxyeth oxy)p r o-
p yl]-4-h yd r oxy-2-oxo-2H -p yr a n -3-yl]m et h yl]p h en yl]-1-
m eth yl-1H-im idazole-4-su lfon am ide (XX): 1H NMR (CDCl3)
δ 0.05 (m, 1H), 0.3 (m, 1H), 0.5 (m, 1H), 0.6 (m, 1H), 0.83 (t,
J ) 7.3 Hz, 3H), 1.5-1.9 (m, 5H), 2.45 (m, 1H), 3.31 and 3.33
(2 s, 3H total), 3.3-3.6 (m, 7H), 3.62 (s, 3H), 6.01 (s, 1H), 6.98
(m, 1H), 7.1-7.3 (m, 4H), 7.48 (s, 1H); HRMS (EI) m/z 545.2186
found (calcd 545.2196 for C27H35N3O7S); TLC Rf 0.24 (5%
methanol in dichloromethane); Anal. (C27H35N3O7S) C, H, N.
N -[3-[Cyclop r op yl[6-[2-cyclop r op yl-1-(cyclop r op yl-
m et h yl)et h yl]-4-h yd r oxy-2-oxo-2H -p yr a n -3-yl]m et h yl]-
p h en yl]ben zen esu lfon a m id e (XXI): 1H NMR (CDCl3) δ
-0.06 (m, 4H), 0.11 (m, 1H), 0.3-0.7 (m, 9H), 1.3 (m, 2H), 1.4
(m, 2H), 1.65 (m, 1H), 2.55 (m, 1H), 3.43 (d, J ) 9.7 Hz, 1H),
6.06 (s, 1H), 6.9 (m, 1H), 7.1-7.5 (m, 7H), 7.72 (m, 2H); HRMS
(EI) 519.2078 found (calcd 519.2079 for C30H33NO5S); TLC Rf
The two individual enantiomers of compound XVI were
obtained via chiral HPLC preparative work; their physical data
are summarized as follows.
N-[3-[[R or S]-Cyclop r op yl[6-[2-cyclop r op yl-1-(cyclo-
p r op ylm e t h yl)e t h yl]-4-h yd r oxy-2-oxo-2H -p yr a n -3-yl]-
m et h yl]p h en yl]-1-m et h yl-1H -im id a zole-4-su lfon a m id e
(enantiomer 1 of XVI): 1H NMR (CDCl3-CD3OD) δ -0.07 (m,
4H), 0.15 (m, 2H), 0.35 (m, 5H), 0.57 (m, 3H), 1.35 (m, 2H),
1.55 (m, 2H), 1.75 (m, 1H), 2.52 (m, 1H), 3.24 (d, J ) 10.2 Hz,
1H), 3.60 (s, 3H), 5.88 (s, 1H), 6.85 (m, 1H), 7.04 (t, J ) 7.9
Hz, 1H), 7.15 (m, 2H), 7.27 (s, 1H), 7.37 (s, 1H); HRMS (EI)
523.2149 found (calcd 523.2141 for C28H33N3O5S); TLC Rf 0.32
(5% methanol in dichloromethane).
N-[3-[[S or R]-Cyclop r op yl[6-[2-cyclop r op yl-1-(cyclo-
p r op ylm e t h yl)e t h yl]-4-h yd r oxy-2-oxo-2H -p yr a n -3-yl]-
m et h yl]p h en yl]-1-m et h yl-1H -im id a zole-4-su lfon a m id e
(enantiomer 2 of XVI): 1H NMR (CDCl3-CD3OD) δ -0.07 (m,
4H), 0.15 (m, 2H), 0.35 (m, 5H), 0.57 (m, 3H), 1.35 (m, 2H),
1.55 (m, 2H), 1.75 (m, 1H), 2.52 (m, 1H), 3.24 (d, J ) 10.3 Hz,
1H), 3.60 (s, 3H), 5.88 (s, 1H), 6.85 (m, 1H), 7.04 (t, J ) 8.0
Hz, 1H), 7.15 (m, 2H), 7.27 (s, 1H), 7.37 (s, 1H); HRMS (EI)
523.2137 found (calcd 523.2141 for C28H33N3O5S); TLC Rf 0.32
(5% methanol in dichloromethane).
N-[3-[Cyclop r op yl[6-[1-[2-(m eth oxyeth oxy)eth yl]-3-(2-
m eth oxyeth oxy)p r op yl]-4-h yd r oxy-2-oxo-2H-p yr a n -3-yl]-
m et h yl]p h en yl]-1-m et h yl-1H -im id a zole-4-su lfon a m id e
(XVII): 1H NMR (CDCl3) δ 0.07 (m, 1H), 0.29 (m, 1H), 0.46
(m, 1H), 0.61 (m, 1H), 1.7-2.0 (m, 5H), 2.72 (m, 1H), 3.32 (s,
3H), 3.33 (s, 3H), 3.3-3.6 (m, 13H), 3.64 (s, 3H), 6.03 (s, 1H),
6.98 (m, 1H), 7.1-7.3 (m, 4H), 7.51 (s, 1H); HRMS (EI) m/z
619.2578 found (calcd 619.2563 for C30H41N3O9S); TLC Rf 0.21
(5% methanol in dichloromethane). Anal. (C30H41N3O9S) C,
H, N.
0.36 (5% ethyl acetate in dichloromethane). Anal. (C30H33
NO5S) C, H, N.
-
N -[3-[Cyclop r op yl[6-[2-cyclop r op yl-1-(cyclop r op yl-
m et h yl)et h yl]-4-h yd r oxy-2-oxo-2H -p yr a n -3-yl]m et h yl]-
p h en yl]-4-flu or oben zen esu lfon a m id e (XXII): 1H NMR
(CDCl3) δ -0.08 (m, 4H), 0.1-0.6 (m, 10H), 1.4-1.6 (m, 4H),
1.65 (m, 1H), 2.55 (m, 1H), 3.39 (d, J ) 9.9 Hz, 1H), 6.11 (s,
1H), 6.9-7.3 (m, 7H), 7.72 (m, 2H), 9.7 (br s, 1H); HRMS (EI)
537.1977 found (calcd 537.1985 for C30H32NO5SF); TLC Rf 0.39
(10% ethyl acetate in dichloromethane).
N -[3-[Cyclop r op yl[6-[2-cyclop r op yl-1-(cyclop r op yl-
m et h yl)et h yl]-4-h yd r oxy-2-oxo-2H -p yr a n -3-yl]m et h yl]-
p h en yl]-4-cya n ob en zen esu lfon a m id e (XIII): 1H NMR
(CDCl3) δ -0.03 (m, 4H), 0.1-0.7 (m, 10H), 1.4 (m, 2H), 1.6
The four individual diastereomers of compound XVIII were
obtained via chiral HPLC preparative work; their physical data
are summarized as follows.
N-[3-[[R or S]-Cyclop r op yl[4h h yd r oxy-2-oxo-6-[1(R)-
(p h en ylm eth yl)p r op yl]-2H-p yr a n -3-yl]m eth yl]p h en yl]-1-
m et h yl-1H -im id a zole-4-su lfon a m id e (diastereomer 1 of