Substituted Cyclic Urea-Based HIV-1 PR Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 11 2167
n yl]m eth yl]-2H-1,3-d ia za p in -2-on e (47): mp 189-
191 °C; NMR (CDCl3) δ 7.3 (m, 6 H), 7.2 (m, 4 H), 6.8
(d, J ) 7.5 Hz, 4 H), 6.6 (m, 2 H), 6.5 (d, J ) 7.5 Hz, 2
H), 6.0 (m, 4 H), 4.9 (d, J ) 13.0 Hz, 2 H), 3.6 (bs, 2 H),
3.5 (m, 2 H), 3.2 (d, J ) 13.0 Hz, 2 H), 2.9 (m, 4 H);
CIMS (NH3) m/ z 595 (M + H+, 100); HRMS calcd for
C35H35N2O7 (M + H+) 595.2444, found 595.2443. Anal.
(C35H34N2O7) C, H, N.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis-
(cyclopr opylm eth yl)-4,7-diisobu tyl-2H-1,3-diazapin -
2-on e (51): mp 137-139 °C; NMR (CDCl3) 3.94 (s, 2
H), 3.80 (dd, J ) 7.0, 7.0 Hz, 2 H), 3.47 (d, J ) 11.0 Hz,
2 H), 2.91 (bs, 2 H), 2.64 (dd, J ) 7.0, 7.0 Hz, 2 H), 1.98
(m, 2 H), 1.84 (m, 2 H), 1.42 (m, 2 H), 1.24 (s, 4 H), 1.20
(m, 2 H), 0.92 (d, J ) 7.0 Hz, 6 H), 0.88 (d, J ) 7.0 Hz,
6 H), 0.52 (m, 4 H), 0.21 (m, 4 H); CIMS (NH3) m/ z 367
(M + H+, 100); HRMS calcd for C21H39N2O3 (M + H+)
367.2961, found 367.2954.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis-
(cyclop r op ylm eth yl)-4,7-d iisop r op yl-2H-1,3-d ia za -
p in -2-on e (52): NMR (CDCl3) δ 4.2 (bs, 2 H), 3.72 (m,
2 H), 3.2 (m, 4 H), 2.66 (m, 4 H), 1.10 (d, J ) 7.0 Hz, 6
H), 0.91 (d, J ) 7.0 Hz, 6 H), 0.49 (m, 4 H), 0.18 (m, 4
H); CIMS (NH3) m/ z 339 (M + H+, 100); HRMS calcd
for C19H35N2O3 (M + H+) 339.2648, found 339.2653.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis-
(cyclop r op ylm eth yl)-4,7-bis[2-(m eth ylth io)eth yl]-
2H-1,3-d ia za p in -2-on e (53): NMR (CDCl3) δ 3.87 (s,
2 H), 3.65-3.79 (m, 4 H), 2.40-2.79 (m, 8 H), 2.26 (m,
2 H), 2.07 (s, 6 H), 1.01 (m, 2 H), 0.52 (m, 4 H), 0.13-
0.35 (m, 4 H); CIMS (NH3) m/ z 403 (M + H+, 100);
HRMS calcd for C19H35N2O3S2 (M + H+) 403.2089,
found 403.2085.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis-
(cyclop r op ylm et h yl)-4,7-b is[(4-flu or op h en yl)m e-
th yl]-2H-1,3-d ia za p in -2-on e (54): mp 193-194 °C;
NMR (CDCl3) δ 7.12 (m, 4 H), 6.97 (m, 4 H), 4.00 (bs, 2
H), 3.54 (dd, J ) 14.3, 6.6 Hz, 2 H), 3.08 (m, 4 H), 2.28
(bs, 2 H), 1.97 (dd, J ) 14.3, 6.6 Hz, 2 H), 0.88 (m, 2 H),
0.42 (m, 4 H), 0.06 (m, 4 H); CIMS (NH3) m/ z 471 (M +
H+, 100); HRMS calcd for C27H33N2O3F2 (M + H+)
471.2459, found 471.2441.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis-
(cyclop r op ylm et h yl)-4,7-b is[(2-m et h oxyp h en yl)-
m eth yl]-2H-1,3-d ia za p in -2-on e (55): mp 155-156 °C;
NMR (CDCl3) δ 7.2 (t, J ) 6.0 Hz, 2 H), 7.1 (d, J ) 6.0
Hz, 2 H), 6.85 (m, 4 H), 4.1 (bs, 2 H), 3.85 (s, 6 H), 3.5
(dd, J ) 7.0, 7.0 Hz, 2 H), 3.25 (dd, J ) 9.0, 2.0 Hz, 2
H), 3.0 (m, 2 H), 2.75 (bs, 2 H), 2.15 (dd, J ) 7.0, 7.0
Hz, 2 H), 0.9 (m, 2 H), 0.4 (m, 4 H), 0.1 (m, 4 H); CIMS
(NH3) m/ z 495 (M + H+, 100). Anal. (C29H38N2O5) C,
H, N.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis-
(cyclop r op ylm et h yl)-4,7-b is[(3-m et h oxyp h en yl)-
m eth yl]-2H-1,3-d ia za p in -2-on e (56): NMR (CDCl3) δ
7.2 (t, J ) 8.0 Hz, 2 H), 6.8 (m, 6 H), 4.1 (bs, 2 H), 3.8
(s, 6 H), 3.65 (m, 2 H), 3.6 (dd, J ) 7.0, 7.0 Hz, 2 H), 3.1
(m, 4 H), 2.75 (s, 2 H), 2.1 (dd, J ) 7.0, 7.0 Hz, 2 H), 0.9
(m, 2 H), 0.4 (m, 4 H), 0.1 (m, 4 H); CIMS (NH3) m/ z
495 (M + H+, 100); HRMS calcd for C29H39N2O5 (M +
H+) 495.2859, found 495.2867.
H), 3.5 (dd, J ) 7.0, 7.0 Hz, 2 H), 3.1 (m, 4 H), 2.75 (s,
2 H), 2.4 (dd, J ) 7.0, 7.0 Hz, 2 H), 0.9 (m, 2 H), 0.4 (m,
4 H), 0.1 (m, 4 H); CIMS (NH3) m/ z 467 (M + H+, 100);
HRMS calcd for C27H35N2O5 (M + H+) 467.2546, found
467.2532.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis-
(cyclop r op ylm et h yl)-4,7-b is[(4-m et h oxyp h en yl)-
m eth yl]-2H-1,3-d ia za p in -2-on e (58): mp 145-147 °C;
NMR (CDCl3) δ 7.11 (d, J ) 7.0 Hz, 4 H), 6.82 (d, J )
7.0 Hz, 4 H), 4.07 (bs, 2 H), 3.78 (s, 6 H), 3.66 (m, 4 H),
3.07 (m, 4 H), 2.08 (m, 2 H), 0.92 (m, 2 H), 0.43 (m, 4
H), 0.09 (m, 4 H); CIMS (NH3) m/ z 495 (M + H+, 100);
HRMS calcd for C29H39N2O5 (M + H+) 495.2859, found
495.2858.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis-
(cyclopr opylm eth yl)-4,7-bis(â-n aph th ylm eth yl)-2H-
1,3-diazapin -2-on e (59): mp 118-121 °C; NMR (CDCl3)
δ 7.8 (m, 6 H), 7.7 (s, 2 H), 7.4 (s, 6 H), 4.2 (s, 2 H), 3.8
(m, 2 H), 3.6 (m, 2 H), 3.3 (m, 4 H), 2.05 (m, 4 H), 0.95
(m, 2 H), 0.4 (m, 4 H), 0.05 (m, 4 H); CIMS (NH3) m/ z
535 (M + H+, 100). Anal. (C35H38N2O3) C, H, N.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis-
(cyclopr opylm eth yl)-4,7-bis[(3,5-dim eth oxyph en yl)-
m eth yl]-2H-1,3-d ia za p in -2-on e (60): NMR (CDCl3) δ
6.3 (s, 4 H), 6.2 (s, 2 H), 3.9 (bs, 2 H), 3.7 (bs, 2 H), 3.63
(s, 12 H), 3.58 (m, 2 H), 3.5 (dd, J ) 7.0, 7.0 Hz, 2 H),
3.0 (m, 4 H), 2.0 (dd, J ) 7.0, 7.0 Hz, 2 H), 0.9 (m, 2 H),
0.4 (m, 4 H), 0.1 (m, 4 H); CIMS (NH3) m/ z 555 (M +
H+, 100); HRMS calcd for C31H43N2O7 (M + H+)
555.3070, found 555.3068.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis-
(cyclop r op ylm eth yl)-4,7-bis(2-th ien ylm eth yl)-2H-
1,3-d ia za p in -2-on e (61): NMR (CDCl3) δ 7.15 (m, 2 H),
6.9 (m, 2 H), 6.8 (m, 2 H), 4.05 (bs, 2 H), 3.7 (m, 2 H),
3.7 (dd, J ) 7.0, 7.0 Hz, 2 H), 3.4 (m, 2 H), 3.35 (m, 2
H), 2.9 (s, 2 H), 2.2 (dd, J ) 7.0, 7.0 Hz, 2 H), 0.9 (m, 2
H), 0.4 (m, 4 H), 0.1 (m, 4 H); CIMS (NH3) m/ z 447 (M
+ H+, 100); HRMS calcd for C23H31N2O3S2 (M + H+)
447.1776, found 447.1770.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis-
[[4-(h yd r oxym eth yl)p h en yl]m eth yl]-4,7-bis[2-(m e-
t h ylt h io)et h yl]-2H -1,3-d ia za p in -2-on e (62): NMR
(CDCl3) 5.1 (d, J ) 14.0 Hz, 2 H), 4.7 (s, 4 H), 4.0 (d, J
) 14.0 Hz, 2 H), 3.6 (s, 2 H), 3.6 (m, 2 H), 3.4 (s, 2 H),
2.6 (m, 2 H), 2.4 (m, 2 H), 2.1 (s, 6 H), 1.9 (m, 4 H), 0.9
(m, 4 H); CIMS (NH3) m/ z 552 (M + NH4+, 100); HRMS
calcd for C27H39N2O5S2 (M + H+) 535.2300, found
535.2302.
(4R ,5S ,6S ,7R )-H e x a h y d r o -5,6-d ih y d r o x y -1,3-
bis[[4-(h yd r oxym eth yl)p h en yl]m eth yl]-4,7-bis(cy-
cloh exylm eth yl)-2H-1,3-d ia za p in -2-on e (63): NMR
(CD3OD) δ 7.4 (bs, 8 H), 5.1 (d, J ) 14.0 Hz, 2 H), 4.95
(s, 4 H), 4.7 (s, 2 H), 4.1 (d, J ) 14.0 Hz, 2 H), 3.5 (m, 4
H), 2.0-1.2 (m, 20 H), 0.9 (m, 2 H); ESIMS m/ z 579 (M
+ H+, 100); HRMS calcd for C35H51N2O5 (M + H+)
579.3798, found 579.3811.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis-
[[4-(h yd r oxym eth yl)p h en yl]m eth yl]-4,7-bis[(4-flu o-
r op h en yl)m eth yl]-2H-1,3-d ia za p in -2-on e (64): mp
174-175 °C; NMR (CDCl3) δ 7.28 (m, 4 H), 7.07 (m, 12
H), 4.82 (d, J ) 14.3 Hz, 2 H), 4.61 (bs, 4 H), 3.48 (m, 2
H), 3.41 (m, 2 H), 3.03 (d, J ) 14.3 Hz, 2 H), 2.92 (m, 4
H), 2.67 (bs, 1 H), 2.05 (bs, 1 H), 1.60 (bs, 2 H); CIMS
(NH3) m/ z 620 (M + NH4+, 100); HRMS calcd for
C35H37N2O5F2 (M + H+) 603.2671, found 603.2676.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis-
(cyclop r op ylm et h yl)-4,7-b is[(3-h yd r oxyp h en yl)-
m eth yl]-2H-1,3-d ia za p in -2-on e (57): NMR (methanol-
d4) δ 7.2 (m, 2 H), 6.75 (m, 6 H), 4.0 (m, 2 H), 3.6 (m, 2