Nonsymmetric P2/P2' cyclic urea HIV protease inhibitors. Structure- activity relationship, bioavailability, and resistance profile of monoindazole-substituted P2 analogues

Article abstract of DOI:10.1021/jm980103g

Using the structural information gathered from the X-ray structures of various cyclic urea/HIVPR complexes, we designed and synthesized many nonsymmetrical P2/P2'-substituted cyclic urea analogues. Our efforts concentrated on using an indazole as one of t

Full text of DOI:10.1021/jm980103g

J . Med. Chem. 1998, 41, 2411-2423
2411
Non sym m etr ic P 2/P 2′ Cyclic Ur ea HIV P r otea se In h ibitor s. Str u ctu r e-Activity
Rela tion sh ip , Bioa va ila bility, a n d Resista n ce P r ofile of
Mon oin d a zole-Su bstitu ted P 2 An a logu es
George V. De Lucca,* Ui T. Kim, J ing Liang, Beverly Cordova, Ronald M. Klabe, Sena Garber, Lee T. Bacheler,
Gilbert N. Lam, Matthew R. Wright, Kelly A. Logue, Susan Erickson-Viitanen, Soo S. Ko, and George L. Trainor
Dupont Merck Pharmaceutical Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500
Received February 16, 1998
Using the structural information gathered from the X-ray structures of various cyclic urea/
HIVPR complexes, we designed and synthesized many nonsymmetrical P2/P2′-substituted cyclic
urea analogues. Our efforts concentrated on using an indazole as one of the P2 substituents
since this group imparted enzyme (Ki) potency as well as translation into excellent antiviral
(IC90) potency. The second P2 substituent was used to adjust the physical and chemical
properties in order to maximize oral bioavailability. Using this approach several very potent
(IC90 11 nM) and orally bioavailable (F% 93-100%) compounds were discovered (21, 22).
However, the resistance profiles of these compounds were inadequate, especially against the
double (I84V/V82F) and ritonavir-selected mutant viruses. Further modification of the second
P2 substituent in order to increase H-bonding interactions with the backbone atoms of residues
Asp 29, Asp 30, and Gly 48 led to analogues with much better resistance profiles. However,
these larger analogues were incompatible with the apparent molecular weight requirements
for good oral bioavailability of the cyclic urea class of HIVPR inhibitors (MW < 610).
In tr od u ction
metabolism of DMP 323 was both rapid and extensive.7
Thus, further development of DMP 323 was discontin-
ued.
The identification of HIV as the causative agent of
AIDS has prompted an intense international research
effort to find effective therapies for this disease. One
of the prime targets of research has been the effort to
find inhibitors of the essential aspartic protease (PR)
of HIV.1 Several HIVPR inhibitors have been shown
to reduce the viral load and increase the number of
CD4+ lymphocytes in HIV infected patients.2 Saquinavir,
ritonavir, indinavir, and nelfinavir have been approved
by the FDA and are being used in AIDS therapy in
combination with reverse transcriptase (RT) inhibitors.
However, the ability of the virus to generate resistant
mutants3 suggests that there is an ongoing need for
new, structurally diverse HIVPR inhibitors.
The second clinical candidate, DMP 450, was taken
to phase I clinical studies in HIV seronegative male
volunteers and showed substantial blood levels. With
a single dose of 11 mg/kg the Cmax was 6.5 µM and the
level at 6 h remained above 1 µM. The measured half-
life in humans (5.7 h) is consistent with some degree of
potential accumulation with multiple dosing every 6-8
h. A multiple dose study using 1000 mg QID showed
an increase in trough level from 1.73 µM on day 2 to
3.2 µM by day 4. DMP 450 was well tolerated with no
adverse effects noted in these studies.6
Early clinical trial results of other protease inhibitors
identified the potential for rebound in plasma RNA
levels with concomitant emergence of HIV mutations,3
probably due to inadequate blood levels at trough to
cover wild-type or mutant virus strains. The impor-
tance of adequate blood levels and in particular free
drug concentration was accentuated by the clinical
failure of SC-52151,8 which was ascribed to high plasma
protein binding. These clinical results suggested that
it was the relationship between the plasma level of free
drug and the inherent drug potency against wild-type
and mutant viruses that were the likely predictors of
clinical efficacy.
Lam and co-workers at Dupont Merck recently de-
scribed the rational design of a novel class of cyclic urea
HIVPR inhibitors.4 This work resulted in the identifi-
cation of two clinical candidates in this series, DMP
3235 and DMP 450.6 The first clinical candidate, DMP
323, was examined in seronegative male volunteers with
single doses ranging from 60 to 1200 mg. Disappoint-
ingly, blood levels at each dose were low and showed a
high degree of intersubject variation.5
At least two factors contributed to the variable and
low plasma levels observed. First, the poor solubility
(6 µg/mL) of DMP 323 in aqueous media; second,
To assess the binding of DMP 450 to human plasma
protein, equilibrium dialysis experiments using 14C-
labeled compound were conducted. These showed that
* Email: George.V.DeLucca@usa.dupont.com.
S0022-2623(98)00103-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/03/1998

2412 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
De Lucca et al.
Ta ble 1. Enzyme and Antiviral Potency of Selected Cyclic
DMP 450 was 90-93% protein bound. The effect of this
plasma protein binding on the antiviral potency of DMP
450 was examined by conducting antiviral assays in the
presence of human serum proteins. In the presence of
45 mg/mL serum albumin plus 1 mg/mL R-1-acid
glycoprotein, the apparent antiviral potency (IC90)
decreased 4.5-8.4-fold.6
The plasma levels obtained using the dosing regimen
of 1000 mg QID would be sufficient to provide for 90%
inhibition of wild-type HIV, but would not be high
enough to provide for adequate inhibition of mutant
variants (when adjusted for protein binding).6 Further
development of DMP 450 was discontinued.
To discover superior inhibitors of HIVPR, we focused
on the simultaneous optimization of multiple proper-
ties: potency, oral bioavailability, and resistance profile.
Our goal was to design an inhibitor 10 times more
potent than DMP 450 which could provide sufficient
free drug at trough to inhibit both wild-type and mutant
variants of HIV with BID or TID dosing.
Urea Analogues
b
inhibitor
Kia (nM)
IC90 (nM)
reference
DMP 323
DMP 450
1
2
3
4
5
6
7
8
9
10
11
12
13
0.34
0.28
0.31
0.039
0.066
0.21
0.043
0.027
0.024
0.014
0.018
<0.010
0.088
0.023
0.018
57
130
3900
709
81
138
2.8
4.2
5.1
60
7
300
35
6
49
5
6
4
10
10
10
10
9a
9a
9a
11
this work
12a
this work
12a
a
Values were measured by cleavage of a fluorescent substrate
using HPLC as described previously.5,13 Values were measured
b
by a sensitive viral RNA-based detection system described previ-
ously.5,14
amides 2-8,9a,10 which show increasingly better trans-
lation as lipophilicity increases (Table 1). Several more
lipophilic heterocyclic amides were synthesized and
evaluated and showed exceptionally potent antiviral
activity.9a
P oten cy
In order to increase the potency of cyclic ureas, we
needed to design compounds with stronger interactions
with HIVPR. Examination of the large amount of
structural data obtained from the X-ray structures of
various cyclic urea analogues complexed with HIVPR
revealed several trends, which were useful in designing
more potent compounds. First it became obvious that
the cyclic urea is a very rigid scaffold, complementary
to the enzyme, that always binds to HIVPR in the same
mode. This makes the cyclic urea an ideal scaffold for
structure-based design. Thus, it was possible to design
P2 N-benzyl substituents and be confident that the
resulting compound would interact with the enzyme
with the same binding mode. For example, the X-ray
structures of DMP 323,5 DMP 450,6 the naphthyl
analogue 1,4 and the amide 79a were found to be super-
imposable in their common structural features (i.e., the
four benzyl groups).
The X-ray structures of cyclic ureas complexed with
HIVPR also revealed that the N-benzyl group serves two
very important functions. First, it provides an impor-
tant hydrophobic interaction with the lipophilic S2
enzyme pocket. Second, it serves as a scaffold for
directing substituents from the meta or the para posi-
tion toward the S2/S3 subsites where there are several
H-bond donors/acceptors, primarily the side chains and/
or backbone amides of residues Asp 29, Asp 30, and Gly
48.
An alternative approach to improving the translation
of some of these more polar P2 substituents was the use
of a more lipophilic scaffold. We recently described the
discovery of tetrahydropyrimidinones as another class
of very potent HIVPR inhibitors.12a The tetrahydro-
pyrimidinones are more lipophilic than the seven-
membered ring cyclic ureas (mono-ol vs diol). They have
a better translation of protease inhibition (Ki) to anti-
viral potency (IC90) for the more polar P2 groups that
in general give more potent enzyme inhibitors. For
example the amide 11 and amidoxime 13 analogues12a
are more potent (IC90) than the corresponding 7-mem-
bered cyclic ureas 210 and 10 (Figure 1, Table 1).
Besides heterocyclic amides and tetrahydropyrimidi-
nones, other compounds with the ability to translate
enzyme potency into excellent antiviral potency were
lipophilic heterocycles such as the indazole analogues
12 and 9,11 which had antiviral potencies of 6 and 7 nM
(Table 1).
Bioa va ila bility
Unfortunately, because of low solubility, the sym-
metrical amides (such as 7) and indazole (9) analogues
showed low oral bioavailability. While symmetric cyclic
ureas provided synthetic and cost advantages, they also
had significant limitations. The major disadvantage
was their inherent crystallinity and subsequently low
solubility.
Using the N-benzyl group as a scaffold for directing
substituents toward the S2/S3 residues, inhibitors were
designed to H-bond to these residues in order to increase
potency. While compounds with P2/P2′ functional
groups having multiple H-bond donor and acceptor
possibilities were more potent enzyme inhibitors (Ki),
many of them were polar and their translation to
antiviral potency (IC90) was poor. For example, the
amide 2 and the amidoxime 10 were extremely potent
inhibitors of the enzyme but showed only low to modest
antiviral activity (Table 1).
On the other hand, nonsymmetric cyclic ureas offered
the advantages of better solubility, flexibility in adjust-
ing the physical and chemical properties, and greater
versatility in designing enzyme interactions. These
potential benefits prompted us to concentrate our
synthesis efforts on nonsymmetrical analogues. In this
way we could better address the often conflicting issues
of solubility, potency, protein binding, resistance profile,
and oral bioavailability.
However, adjusting the lipophilicity of some of these
compounds resulted in better translation and more
potent antiviral activity. Of particular note are the

Nonsymmetric P2/ P2′ Cyclic Urea HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2413
F igu r e 1. Structures of compounds discussed in the text.
Thus, we focused our efforts on the synthesis of
7-membered cyclic urea analogues containing an inda-
zole as one of the P2 groups, since this substituent
showed excellent enzyme and antiviral potency (ex-
ample 9 Table 1). We planned to use the second P2
group to adjust the physical and chemical properties of
the compound in order to optimize oral bioavailability.
Many nonsymmetrical monoindazole-substituted ana-
logues were prepared, and the results are summarized
in Table 2. The N-monosubstituted cyclic urea 14 (R )
H Table 2), while having a sub-nanomolar Ki, did not
have adequate antiviral potency. Thus, nonsymmetrical
analogues that have both P2/P2′ substituents were
prepared. The second P2 groups contained H-bonding
substituents to increase enzyme potency, but they were
chosen from groups that were not too polar in order to
maintain good translation into antiviral potency (IC90).
The penalty for disregarding this strategy was exempli-
fied by the polar acid analogue 15, which had an
excellent Ki of 0.049 nM but had an IC90 of 750 nM.
Several analogues with nonpolar H-bonding substitu-
ents were examined; all of them displayed potent
enzyme inhibition activity (Ki) and several showed very
good antiviral potency (Table 2; entries 14-28).
Several of the more potent analogues were tested for
oral bioavailability in dogs at a dose of 10 mg/kg. The
anilines, 21 and 22, showed potent antiviral activity
(IC90 11 nM) and excellent oral bioavailability in the
dog (F% 93-100%). On the other hand the methyl
ketone analogue 19 and the N-methyl-4-fluoroaniline
28 had lower oral bioavailability (F% 25-14%). This
was probably due to poor solubility properties. While
the anilines 21 and 22 had good water solubility (0.040
mg/mL) and excellent acid solubility (1 N HCl: 60 mg/
mL), the ketone 19 had low aqueous (0.006 mg/mL) and
acid (1 N HCl: 0.014 mg/mL) solubility. Likewise, 28
also had low aqueous (<0.001 mg/mL) and acid (1 N
HCl: 0.446 mg/mL) solubility compared to 21 and 22.
As previously noted, plasma protein binding of HIVPR
inhibitors is an important parameter in determining
clinical efficacy. To examine the effect of plasma protein
binding on the antiviral potency of 21 and 22, the
antiviral assays were repeated in the presence of
quantities of human serum albumin and R-1-acid gly-
coprotein that approximate those found in the blood of
AIDS patients (45 mg/mL serum albumin plus 1 mg/
mL R-1-acid glycoprotein). Under these conditions the
apparent antiviral potency (IC90) of 21 or 22 decreased
5-fold, similar to the decrease found for DMP 450.
Resista n ce P r ofile
Since our goal was to discover an inhibitor 10 times
more potent than DMP 450 which could provide suf-
ficient free drug at trough to inhibit not only wild-type
but also mutant variants of HIV, we next examined 21
and 22 against a panel of mutant viruses as previously
described.6,9a This included mutant strains with single
amino acid substitutions (I84V),6 double amino acid
substitutions (I84V/V82F),6,23 and multiple amino acid
changes (corresponding to mutations observed in clinical
isolates of patients treated with ritonavir and indinavir).9a
The results are summarized in Table 3. Unfortunately,
both 21 and 22 had very poor resistance profiles,
especially against the double mutant (I84V/V82F) and
the related ritonavir-selected virus mutants (Table 3).
There is a very strong correlation between the number
of H-bonds to the backbone atoms of residues Asp 29,
Asp 30, and Gly 48 and the resistance profile of cyclic
urea HIVPR inhibitors.9a For example, the heterocyclic
benzamides 7 and 8, which have H-bonding interactions9b
with the backbone of residues Gly 48 and Asp 30, retain
their antiviral potency against the double mutant (I84V/
V82F) and the ritonavir- and indinavir-selected viruses
which also contain amino acid substitutions at positions
82 and 84 of the protease (Table 3). The amidoximes
10 and 13, which have the same H-bonding inter-
actions12b as the heterocyclic benzamides 7 and 8, also
have an excellent resistance profile as shown in Table
3.

2414 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
De Lucca et al.
Ta ble 2. P2/P2′ SAR of Nonsymmetric Cyclic Urea Inhibitors of HIV Protease
b
compd no.
R
Kia (nM)
IC90 (nM)
po bioavailabilityc Cmax (µM) (F%)
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
H
0.32
550
750
36
17
32
15
14
11
11
14
7
3-carboxybenzyl
3-hydroxybenzyl
3-(2-hydroxyethyl)benzyl
3-(carbomethoxymethyl)benzyl
3-acetylbenzyl
4-fluoro-3-carboxamidobenzyl
3-aminobenzyl
4-aminobenzyl
3-amino-4-fluorobenzyl
4-amino-3-fluorobenzyl
3-amino-4-methylbenzyl
3-(N,N-dimethylamino)benzyl
3-(N-methylamino)benzyl
3-(N-methylamino)-4-fluorobenzyl
3-((pyrazol-1-yl)methyl)benzyl
3-(1,2,4-triazol-1-yl)methyl)benzyl
3-(1,2,3-triazol-1-yl)methyl)benzyl
3-(1,2,3-triazol-2-yl)methyl)benzyl
3-(pyrazol-1-yl)-4-aminobenzyl
3-(1,2,4-triazol-1-yl)-4-aminobenzyl
3-(1,2,3-triazol-2-yl)-4-aminobenzyl
3-(1,2,3-triazol-1-yl)-4-aminobenzyl
3-(1,2,4-triazol-3-yl)benzyl
3-(pyrazol-3-yl)-4-aminobenzyl
3-(N-(5-methylpyrid-2-yl)carboxamido)benzyl
3-(N-pyrid-2-ylcarboxamido)benzyl
3-(N-(6-methylpyrid-2-yl)carboxamido)benzyl
3-(N-thiazol-2-ylcarboxamido)benzyl
3-(pyrid-2-ylacetyl)benzyl
0.049
0.045
0.05
0.11
0.036
0.018
0.03
1.3 (25)
7.2 (93)
10.6 (100)
0.03
0.018
0.036
0.05
15
39
8
0.23
0.039
0.027
0.17
0.054
0.11
0.081
0.045
0.029
0.059
0.034
0.041
0.025
0.048
0.051
0.04
0.016
0.073
0.23
0.063
0.021
0.046
0.022
0.016
0.028
0.059
8.0 (92)
0.67 (14)
7
46
35
30
32
6
35
12
38
24
22
4
0.5
<0.05
5
3
8
15
18
15
30
15
51
63
30
5
0.7
3-(thien-2-ylacetyl)benzyl
3-(pyrazol-1-ylacetyl)benzyl
3-(1,2,3-triazol-1-ylacetyl)benzyl
3-(1,2,3-triazol-2-ylacetyl)benzyl
3-(1,2,4-triazol-1-ylacetyl)benzyl
3-(N-(benzimidazol-2-ylmethyl)amino)benzyl
3-(N-(benzimidazol-2-ylmethyl)amino)-4-fluorobenzyl
3-(N-(benzthiazol-2-ylmethyl)amino)benzyl
0.15
a
b
Values were measured by cleavage of a fluorescent substrate using HPLC as described previously.5,13 Values were measured by a
sensitive viral RNA-based detection system described previously.5,14 c Bioavailability was determined in dogs (n ) 3 per group), dosed
with compound in formulations containing propylene glycol, polyethylene glycol 400, water at 10 mg/kg. The maximum plasma concentration
(Cmax) is the observed peak plasma concentration after an oral dose. Oral bioavailability (F%) was determined by the ratio AUC po/AUC
iv, where AUC is the area under the plasma concentration-time curve from time zero to infinity for oral and intravenous administration
of compound and is normalized for dose.
In order to improve the resistance profiles of 7-mem-
bered cyclic ureas containing an indazole as one of the
P2 groups, we synthesized analogues in which the
second P2 substituent was designed to maximize H-
bonding interaction with the backbone of residues Gly
48 and Asp 30. We chose to explore heterocycle-
containing substituents since these had a better prob-
ability of having the right combination of H-bonding
ability and lipophilicity needed to improve the resistance
profile while maintaining antiviral potency. The results
are summarized in Tables 2 and 3 (entries 29-51).
We examined a variety of methods to connect hetero-
cyclic substituents to the 3-position of the second P2
N-benzyl group. This included attaching the heterocycle
to the benzyl group directly (33-38) and via a methyl-
ene (29-32), an amide (39-42), or a ketone (43-
48) linkage. We also alkylated the aniline of 21 with a
heterocyclic-alkyl group (49-51). Several compounds
gave good to excellent antiviral potency and were
examined against the panel of mutant viruses. Many
showed an improvement, and a few gave significantly
better resistance profiles when compared to 21 (Table
3). For example, the ketone 43 had only a 5-fold loss
against the double mutant (I84V/V82F), compared to the
200-fold loss in potency for 21.
However, while some of the more lipophilic hetero-
cycles assisted in the translation to antiviral potency,
they had a detrimental effect on protein binding. For
example, in the presence of 45 mg/mL serum albumin
plus 1 mg/mL R-1-acid glycoprotein, the potent pyridine-
containing analogues 40 and 43, and the potent benz-

Nonsymmetric P2/ P2′ Cyclic Urea HIV Protease Inhibitors
Ta ble 3. Resistance of Mutant Viruses to Cyclic Urea Analogues
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2415
resistance of mutant viruses (IC90 mutant/IC90 WT)
inhibitor
Ki (nM)a
IC90 (nM)b
84Vc
84V/82Fc
ritonavird virus
indinavird virus
DMP 323
DMP 450
7
8
0.34
0.28
57
130
5.1
60
300
49
11
11
32
35
24
22
8
28
10
97
100
1.0
0.7
0.7
0.4
200
240
50
20
18
20
22
93
49
1.2
0.2
18
27
0.7
0.4
0.024
0.014
<0.01
0.018
0.030
0.030
0.081
0.029
0.041
0.025
0.016
0.073
0.016
0.059
0.6
0.7
1.0
1.0
6.8
31
3.3
1.0
3.3
2.2
2.0
1.0
1.0
3.3
10
13
21
22
33
34
37
38
42
43
49
51
75
170
70
9.0
3.8
2.1
9.0
10
20
7.3
15
63
5
5.0
3.0
20
25
a
b
Values were measured by cleavage of a fluorescent substrate using HPLC as described previously.5,13 Values were measured by a
sensitive viral RNA-based detection system described previously.5,14 c Values were measured using the yield reduction assay described
previously.6,22,23 The viruses were constructed and the IC90 values were measured using the viral p24 readout as described previously.6,9a
d
The ritonavir virus contains five mutations, 46I/63P/71V/82F/84V, and is named for its significant resistance to ritonavir. The indinavir
virus also contains five mutations, 10R/63P/71V/82T/84V, and is named for its resistance to indinavir.
F igu r e 2. Oral bioavailability of indazole containing P2 substituents in dog at a dose of 10 mg/kg.
thiazole-containing analogue 51, had 19-, 28-, and 25-
fold losses, respectively, in their antiviral potency.
Several of these analogues (34, 39, 43, 48) were tested
for oral bioavailability in dogs at a dose of 10 mg/kg.
Unfortunately, none of these compounds had good oral
bioavailability. A major factor contributing to the low
oral bioavailability of these compounds appeared to be
their high molecular weights. The dog oral bioavail-
ability of cyclic urea analogues have been examined, and
the results are summarized as a scatter plot of Cmax as
a function of molecular weight (Figure 2). The use of
the Cmax as an approximate surrogate for oral bioavail-
ability is used for convenience since the determination
of F% is not always possible for many poorly bioavail-
able compounds due to detection difficulties. Our
experience with cyclic ureas has shown that Cmax is an
adequate surrogate for F%. The data shows an appar-
ent cutoff of oral bioavailability at a molecular weight
(MW) of about 610. Most of the compounds with low
bioavailability, that have a MW below 610, are either
symmetrical or have low aqueous solubility. To improve
the resistance profile, analogues need to be larger in
order to have the multiple H-bonding interactions with
residues Asp 29, Asp 30, and Gly 48. However, in doing
so, the molecular weight of the resulting analogues often
exceeds the 610 MW limit that seems to be important
for oral bioavailability of HIVPR inhibitors in the cyclic
urea class.
Con clu sion s
Using the structural information gathered from the
X-ray structures of various cyclic urea/HIVPR com-
plexes, we designed and synthesized many nonsym-
metrical P2/P2′-substituted cyclic urea analogues. Our
efforts concentrated on using an indazole as one of the
P2 substituents since this group imparted enzyme (Ki)
potency as well as translation into excellent antiviral
(IC90) potency. The second P2 substituent was used to
adjust physical-chemical properties in order to maxi-
mize oral bioavailability. Through this approach several

2416 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
De Lucca et al.
pounds where analysis was not obtained, HPLC analysis was
used, and purity was determined to be >98%.
very potent (IC90 11 nM) and orally bioavailable (F%
93-100%) compounds were discovered (21, 22). How-
ever, the resistance profiles of these compounds were
inadequate, especially against the double (I84V/V82F)
and ritonavir-selected mutant viruses. Further modi-
fication of the second P2 substituent in order to increase
H-bonding interactions with the backbone atoms of
residues Asp 29, Asp 30, and Gly 48 led to analogues
with much better resistance profiles. However, these
larger analogues were incompatible with the apparent
molecular weight requirements for good oral bioavail-
ability in the cyclic urea class of HIVPR inhibitors (MW
< 610). Thus we were not able to overcome the
conflicting requirements needed for good oral bioavail-
ability (low MW, aqueous solubility) and potency/
resistance profile (large size, H-bonding, lipophilicity),
using nonsymmetrical monoindazole-substituted P2/P2′
cyclic urea analogues.
Synthesis of nonsymmetrical monoindazole-containing P2/
P2′ cyclic ureas was accomplished by using the monoalkylation
methods previously described,5,9a starting with the N,N-
unsubstituted cyclic urea acetonide 53.16 Alternatively, the
isourea 5417 was alkylated with 5-(bromomethyl)-1-SEM-
indazole11 to give the isourea 55 which was alkylated directly
a second time as previously described17 or converted to urea
56, which was then alkylated a second time using the standard
alkylating procedures.5 The synthesis of the tetrahydropyri-
midinone analogue was accomplished, starting with the 7-mem-
bered ring cyclic urea analogue 9,11 by the rearrangement,
ring-contraction reaction previously reported.12a
Exp er im en ta l Section
Biologica l Meth od s. Inhibition of HIVPR (Ki) was mea-
sured by the assay of the cleavage of a fluorescent substrate
using HPLC as described previously.5,13 The antiviral activity
potency of compounds was assessed by measuring their effect
on the accumulation of viral RNA transcripts 3 days after
infection of MT-2 cells with HIV-1 RF as described previ-
ously.5,14 The concentration of test compound which reduced
the concentration of HIV viral RNA by 90% from the level
measured in an untreated infected culture was designated IC90.
The cellular toxicity of compounds was assessed by measuring
the extent of MTT dye reduction in uninfected MT-2 cell
cultures grown for 3 days in the presence of various concentra-
tions of test compound as previously described. The compound
concentration which decreased the level of MTT dye reduction
[4R-(4r,5â,6â)]-Tetr a h yd r o-5-h yd r oxy-1,3-bis(1H-in d a -
zol-5-ylm eth yl)-4-(2-ph en yleth yl)-6-(ph en ylm eth yl)-2(1H)-
p yr im id in on e (12). From 7-membered cyclic urea: To a
solution of (4R,5S,6S,7R)-hexahydro-5,6-dihydroxy-1,3-bis[1-
SEM-indazol-5-ylmethyl]-4,7-bis-[phenylmethyl]-2H-1,3-diaza-
pin-2-one11 (0.38 g, 0.45 mmol) in CH2Cl2 (20 mL) at room
temperature was added 2-acetoxyisobutyryl bromide (0.40 g,
1.9 mmol), and the solution was stirred at room temperature
for 3 h at which time TLC showed complete conversion. The
solution was quenched with saturated NaHCO3, and the
organic layer was separated and washed with water and brine,
dried, and concentrated. The residue was chromatographed
(MPLC silica gel 25-50% EtOAc/hexane) to give 0.25 g of the
rearranged bromo acetate as a foam. The bromo acetate was
dissolved in 50 mL of acetic acid, treated with 5 g of Zn (dust),
and vigorously stirred at room temperature until TLC analysis
showed complete conversion. The mixture was filtered, and
the solid was washed thoroughly with EtOAc. The filtrate was
washed with water, saturated NaHCO3, and brine, dried, and
evaporated to give the acetate. The crude acetate was chro-
matographed (MPLC silica gel 40-60% EtOAc/hexane) to give
125 mg of pure acetate as an oil. The acetate (125 mg, 0.68
mol) was dissolved in MeOH, treated with concentrated HCl
(1 mL), and heated at reflux for 2 h. The mixture was
concentrated, and the residue was partitioned between 1 N
NaOH and EtOAc. The organic extract was washed with
water and brine, dried, and concentrated. The resulting
residue was chromatographed (MPLC, silica gel, EtOAc) to
give 40 mg of 12 as a foam: mp 130-134 °C; 1H NMR (CDCl3)
δ 10.95 (bs, 1H), 10.87 (bs, 1 H), 7.84 (s, 1 H), 7.72 (s, 1 H),
7.50 (s, 1 H), 7.47 (s, 1 H), 7.35-7.15 (m, 10 H), 7.07 (2
overlapping d, J ) 7 Hz, 2 H), 6.95 (2 overlapping d, J ) 7
Hz, 2 H), 5.51 (d, J ) 15 Hz, 1 H), 5.48 (d, J ) 15 Hz, 1 H),
4.10 (d, J ) 16 Hz, 1 H), 3.94 (d, J ) 15 Hz, 1 H), 3.53 (m, 1
H), 3.42 (m, 1 H), 3.32 (m, 1 H), 2.94 (m, 2 H), 2.42 (m, 2 H),
by 50% was designated the TC50
. Only compounds which
displayed an antiviral IC90 concentration which was at least
3-fold less than the TC50 concentration were considered to have
a specific antiviral effect. The single (I84V) and double (I84V/
V82F) mutant virus were obtained from in vitro selection
experiments in the presence of cyclic urea analogue DMP 323
as previously described.6,23 The IC90 of the single (I84V) and
double (I84V/V82F) mutant virus were measured using the
yield reduction assay as previously described.6,22 The con-
struction of the ritonavir and indinavir mutant viruses and
the measurement of the IC90 values using the viral p24 readout
was accomplished as previously described.6,9a,21 The ritonavir
virus contains five mutations, 46I/63P/71V/82F/84V, and is
named for its significant resistance to ritonavir. The indinavir
virus also contains five mutations, 10R/63P/71V/82T/84V, and
is named for its resistance to indinavir. Oral bioavailability
of compounds were determined as previously reported.5,15
Gen er a l. All reactions were carried out under an atmo-
sphere of dry nitrogen. Commercial reagents were used
without further purification. 1H NMR (300 MHz) spectra were
recorded using tetramethylsilane as an internal standard. TLC
was performed on E. Merck 15710 silica gel plates. Medium-
pressure liquid chromatography (MPLC) was carried out using
EM Science silica gel 60 (230-400 mesh). HPLC chromatog-
raphy was carried out using J asco PV-987 pumps, J asco UV-
975 detectors, and Dupont Zorbax Sil or Zorbax NH2 1-in.
preparative columns. All final targets were obtained as
noncrystalline amorphous solids unless specified otherwise.
Mass spectra were measured with a HP5988A mass spectrom-
eter with particle beam interface using NH3 for chemical
ionization or a Finnigan MAT 8230 mass spectrometer with
NH3-DCI or VG TRIO 2000 for ESI. High-resolution mass
spectra were measured on a VG 70-VSE instrument with NH3
chemical ionization. Elemental analysis was performed by
Quantitative Technologies, Inc., Bound Brook, NJ . For com-

Nonsymmetric P2/ P2′ Cyclic Urea HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2417
1.90 (m, 1 H), 1.76 (m, 1 H), 1.62 (bs, H); CIMS (NH3) m/ z
571 (M + H+, 100). Anal. (C35H34N6O2) C, H, N.
[4R-(4r,5r,6â,7â)]-3,3′-[[Tet r a h yd r o-5,6-d ih yd r oxy-2-
oxo-4,7-bis(ph en ylm eth yl)-1H-1,3-diazepin e-1,3(2H)-diyl]-
b is (m e t h y le n e )]b is [N -h y d r o x y b e n ze n e c a r b o x im id -
a m id e] (10). A solution of (4R,5S,6S,7R)-hexahydro-5,6-
dihydroxy-1,3-bis[3-cyanophenylmethyl]-4,7-bis[phenylmethyl]-
2H-1,3-diazapin-2-one5 in ethanol was treated with excess
NH2OH‚HCl and Et3N and heated to reflux for 4 h. The
solution was concentrated to dryness and the residue parti-
tioned between ethyl acetate and water. The ethyl acetate
solution was washed with water and brine and dried over
MgSO4. The solution was filtered and concentrated to give a
white solid. The solid was recrystallized from EtOAc/MeOH
to give the amidoxime 10: mp 142-145 °C; 1H NMR (DMSO-
d6) δ 9.65 (s, 1 H), 7.57 (m, 4 H), 7.37-7.14 (m, 10 H), 6.98 (d,
J ) 7 Hz, 4 H), 5.78 (bs, 4 H), 5.10 (bs, 2 H), 4.51 (d, J ) 15
Hz, 2 H), 3.45 (m, 4 H), 2.85 (d, J ) 15 Hz, 1 H), 2.80 (m, 4 H,
abx); ESIMS m/ z 623 (M + H)+, 100; HRMS calcd for
C
35H39N6O5 (M + H+) 623.2982, found 623.2954. Anal.
(C35H38N6O5‚0.5H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-Hexa h yd r o-5,6-d ih yd r oxy-1-(1H-in -
dazol-5-ylm eth yl)-4,7-bis(ph en ylm eth yl)-2H-1,3-diazepin -
2-on e (14). A solution of 5316 (0.26 g, 0.7 mmol) in DMF was
treated with NaH (0.12 g; 60% oil dispersion) and stirred at
room temperature for 30 min. Then the alkylating agent
5-(bromomethyl)-1-BOC-indazole11 was added and stirred
overnight. The reaction mixture was diluted with water and
extracted into ethyl acetate. The organic extract was washed
with water and brine, dried, and concentrated. The resulting
residue was chromatographed (MPLC silica gel, 25-50%
EtOAc/hexane) to give 170 mg of the monoalkylated product.
This was dissolved in a saturated solution of HCl(g)/MeOH and
stirred at room temperature for 1 h. The solution was
concentrated to dryness on a rotary evaporator, and the
residue was partitioned between aqueous Na2CO3 and ethyl
acetate. The organic layer was then washed with water and
brine, dried, and concentrated. The residue was chromato-
graphed (MPLC silica gel 5% MeOH/CH2Cl2) to give 45 mg of
14: mp 143-145 °C; 1H NMR (CDCl3/CD3OD) δ 7.91 (s, 1 H),
7.43-7.15 (m, 13 H), 5.91 (d, J ) 7 Hz, 1 H), 4.97 (d, J ) 15
Hz, 1 H), 3.85 (m, 1 H), 3.61-3.39 (m, 3 H), 3.10 (m, 4 H),
2.77 (m, 1 H); CI-MS m/ z 457 (M + H)+, 100. Anal.
(C27H28N4O3‚0.25H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-Meth yl 3-[[Hexa h yd r o-5,6-d ih yr oxy-
3-(1H -in d a zol-5-ylm et h yl)-2-oxo-4,7-b is(p h en ylm et h yl)-
1H-1,3-d ia zep in -1-yl]m eth yl]ben zen ea ceta te (18). A so-
lution of isourea 55 (2.0 g, 3.0 mmol) and 3-(carbomethoxy)-
benzyl bromide (1.4 g, 6.0 mmol) in acetonitrile was treated
with KI (1.0 g, 6.0 mmol) and heated at reflux for 6 h. The
mixture was diluted with water and extracted into ethyl
acetate. The organic extract was washed with water, sodium
bisulfite, and brine. The solution was concentrated, and the
resulting residue was chromatographed (MPLC silica gel, 20%
EtOAc/hexane) to give 1.2 g of the ester product.
The ester was dissolved in ether, cooled to 0 °C, treated with
LAH (0.17 g, 4.5 mmol), and stirred at room temperature for
2 h. The solution was cooled at 0 °C and quenched with
saturated aqueous NH4Cl. The organic layer was washed with
water and brine, dried, filtered, and concentrated to give 1.1
g of the benzyl alcohol 57 (R ) OH) as a white foam. The
benzyl alcohol 57 (1.1 g, 1.4 mmol) was then dissolved in CH2-
Cl2, cooled to 0 °C, and treated with CBr4 (0.6 g, 1.8 mmol).
To the resulting solution was added a solution of triphen-
ylphosphine (0.47 g, 1.8 mmol) in CH2Cl2, dropwise via an
addition funnel. After the addition was complete, the mixture
was allowed to warm to room temperature (4 h). The reaction
mixture was evaporated to dryness, and the residue was
chromatographed (MPLC silica gel, 20% EtOAc/hexane) to give
[4R-(4r,5r,6â,7â)]-H exa h yd r o-5,6-d ih yd r oxy-1-[(3-h y-
d r oxyp h en yl)m eth yl]-3-(1H-in d a zol-5-ylm eth yl)-4,7-bis-
(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (16). A solution of
urea 56 (0.40 g, 0.6 mmol) and 3-(benzyloxy)benzyl bromide
(0.23 g, 0.8 mmol) in THF was treated with KO-t-Bu (1.2 mL;
1 M THF solution) and stirred at room temperature overnight.
The solution was poured into water and extracted into ethyl
acetate. The organic layer was washed with water and brine
and then concentrated on a rotary evaporator. The residue
was chromatographed (MPLC silica gel 20% EtOAc/hexane)
to give the dialkylated urea product. The dialkylated urea (300
mg, 0.36 mmol) was dissolved in THF and was treated with
10% Pd/C (100 mg) and hydrogenated at 50 psi for 3 days.
The mixture was filtered (Celite) and the filtrate concentrated.
The residue was chromatographed (MPLC silica gel EtOAc)
to give 200 mg of the phenol as an oil. The protecting groups
(acetonide and SEM) were removed by dissolving the oil in
MeOH (10 mL), treating with concentrated HCl (5 mL), and
heating at reflux for 2 h. The solution was concentrated to
dryness on a rotary evaporator and the residue partitioned
was between aqueous Na2CO3 and ethyl acetate. The organic
layer was washed with water and brine, dried, and concen-
0.6 g of the corresponding benzyl bromide 57 (R ) Br).
A
solution of the benzyl bromide 57 (0.6 g, 0.7 mmol) in aqueous
dioxane was treated with KCN (0.24 g, 3.6 mmol) and warmed
to 60 °C overnight. The solution was diluted with water and
extracted into ethyl acetate. The organic layer was washed
with water and brine, dried, filtered, and concentrated to give
0.55 g of the benzyl cyanide 57 (R ) CN) as a white foam.
Using Katritzky’s procedure18 a solution of the benzyl cyanide
57 (0.55 g, 0.7 mmol) and K2CO3 in DMSO was treated with
2 mL of 30% H2O2 at 0 °C and then allowed to warm to room
temperature (2 h). The solution was dilluted with water and
extracted into ethyl acetate. The organic layer was washed
with water and brine, dried, filtered, and concentrated to give
0.55 g of the corresponding carboxamide 57 (R ) CONH2) as
a white foam. A solution of the carboxamide 57 (0.3 g, 0.38
mmol) in methanol (15 mL) was treated with 1 mL of H2SO4
and heated at reflux overnight. The solution was made basic
with 1 N NaOH and was extracted into ethyl acetate. The
organic layer was washed with water and brine, dried, filtered,
and concentrated to give 0.2 g of a white foam. This was
chromatographed (HPLC silica gel, 6% MeOH/EtOAc) to give
1
trated to give 16 as a white solid: mp 152-155 °C; H NMR
(CDCl3/CD3OD) δ 7.92 (s, 1 H), 7.39-7.20 (m, 10 H), 7.12-
7.08 (m, 4 H), 6.71-6.61 (m, 3 H), 4.91 (d, J ) 16 Hz, 1 H),
4.79 (d, J ) 16 Hz, 1 H), 3.59-3.46 (m, 4 H), 3.09 (d, J ) 16
Hz, 1 H), 3.00 (m, 4 H), 2.90 (d, J ) 16 Hz, 1 H); ESIMS m/ z
563 (M + H)+, 100. Anal. (C34H34N4O4‚H2O) C, H, N.

2418 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
De Lucca et al.
150 mg of 18 as a white foam: mp 99-101 °C; 1H NMR (CDCl3)
δ 7.85 (s, 1 H), 7.39-7.02 (m, 17 H), 4.98 (d, J ) 14 Hz, 1 H),
4.79 (d, J ) 16 Hz, 1 H), 3.59-3.46 (m, 4 H), 3.09 (d, J ) 16
Hz, 1 H), 3.00 (m, 4 H), 2.90 (d, J ) 16 Hz, 1 H); ESIMS (M +
H+, 100) 619; HRMS calcd for C37H39N4O5 (M + H+) 619.2920,
found 619.2943. Anal. (C37H38N4O5) C, H, N.
[4R-(4r,5r,6â,7â)]-H exa h yd r o-5,6-d ih yd r oxy-1-[[3-(2-
h yd r oxyeth yl)p h en yl]m eth yl]-3-(1H-in d a zol-5-ylm eth yl)-
4,7-bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (17). A so-
lution of the ester 18 in THF was reduced with LAH. This
was chromatographed (MPLC silica gel, 6% MeOH/CHCl3) to
give the ethyl alcohol 17 as a white solid: mp 102-105 °C;
ESIMS (M + H+, 100) 591; HRMS calcd for C36H39N4O4 (M +
H+) 619.2920, found 619.2943. Anal. (C36H38N4O4‚0.66CHCl3‚
0.33CH3OH) C, H, N.
H), 8.05 (s, 1 H), 7.51 (d, J ) 8 Hz, 2 H), 7.36-7.19 (m, 8 H),
7.13 (d, J ) 8 Hz, 2 H), 7.01 (d, J ) 8 Hz, 2 H), 6.94 (t, J ) 8
Hz, 1 H), 6.42 (d, J ) 8 Hz, 1 H), 6.33 (s, 1 H), 6.23 (d, J ) 8
Hz, 1 H), 5.07 (bs, 2 H), 5.00 (bs, 2 H), 4.79 (d, J ) 14 Hz, 1
H), 4.61 (d, J ) 14 Hz, 1 H), 3.55-3.35 (m, 4 H), 3.00-2.80
(m, 5 H), 2.59 (d, J ) 14 Hz, 1 H); ESIMS m/ z 562 (M + H+,
100); HRMS calcd for C34H36N5O3 (M + H+) 562.2818, found
562.2807. Anal. (C34H35N5O3‚H2O) C, H, N.
[4R -(4r,5r,6â,7â)]-1-[(4-Am in op h e n yl)m e t h yl]h e xa -
h yd r o-5,6-d ih yd r oxy-3-(1H -in d a zol-5-ylm et h yl)-4,7-b is-
(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (22). Similar pro-
cedure as detailed for 23 was used except alkylating with
1
4-azidobenzyl or 4-nitrobenzyl bromide: mp 137-140 °C; H
NMR (DMSO-d6) δ 13.02 (bs, 1 H), 8.04 (s, 1 H), 7.49 (d, J )
8 Hz, 1 H), 7.36-7.19 (m, 8 H), 7.11 (d, J ) 7 Hz, 2 H), 7.01
(d, J ) 7 Hz, 2 H), 6.75 (d, J ) 8 Hz, 2 H), 6.49 (d, J ) 8 Hz,
2 H), 5.00 (bs, 2 H), 4.95 (bs, 2 H), 4.79 (d, J ) 14 Hz, 1 H),
4.59 (d, J ) 14 Hz, 1 H), 3.55-3.21 (m, 4 H), 3.00-2.80 (m, 5
H), 2.62 (d, J ) 14 Hz, 1 H); ESIMS m/ z 562 (M + H+, 100);
HRMS calcd for C34H36N5O3 (M + H+) 562.2818, found
562.2834. Anal. (C34H35N5O3‚0.75H2O) C, H, N.
[4R -(4r,5r,6â,7â)]-1-[(3-Ace t ylp h e n yl)m e t h yl]h e xa -
h yd r o-5,6-d ih yd r oxy-3-(1H -in d a zol-5-ylm et h yl)-4,7-b is-
(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (19). The urea 56
was alkylated with 3-(2-methyl-1,3-dioxolan-2-yl)benzyl bro-
mide in THF using 1 M KO-t-Bu/THF, and the protecting
groups were removed using HCl/MeOH as described above for
16: mp 120-122 °C; 1H NMR (CDCl3) δ 7.93 (s, 1 H), 7.82 (d,
J ) 7 Hz, 1 H), 7.72 (s, 1 H), 7.45-7.24 (m, 11 H), 7.13-7.07
[4R-(4r,5r,6â,7â)]-1-[(3-Am in o-4-m eth ylph en yl)m eth yl]-
h exa h yd r o-5,6-d ih yd r oxy-3-(1H-in d a zol-5-ylm eth yl)-4,7-
bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (25). Similar
procedure as detailed for 23 was used except alkylating with
3-nitro-4-methylbenzyl bromide: mp 151-153 °C; 1H NMR
(DMSO-d6) δ 13.03 (bs, 1 H), 8.05 (s, 1 H), 7.49 (d, J ) 8 Hz,
1 H), 7.36-7.19 (m, 8 H), 7.16 (d, J ) 8 Hz, 2 H), 7.05 (d, J )
8 Hz, 2 H), 6.82 (d, J ) 8 Hz, 1 H), 6.36 (s, 1 H), 6.17 (d, J )
8 Hz, 1 H), 5.07 (bs, 2 H), 5.00 (bs, 2 H), 4.79 (d, J ) 14 Hz, 1
H), 4.58 (d, J ) 14 Hz, 1 H), 3.55-3.35 (m, 4 H), 3.00-2.80
(m, 5 H), 2.59 (d, J ) 14 Hz, 1 H); ESIMS m/ z 576 (M + H+,
100); HRMS calcd for C35H38N5O3 (M + H+) 576.2975, found
576.2982.
[4R-(4r,5r,6â,7â)]-Hexa h yd r o-5,6-d ih yd r oxy-1-(1H-in -
d a zol-5-ylm et h yl)-3-[[3-(m et h yla m in o)p h en yl]m et h yl]-
4,7-bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (27). The
urea 56 was alkylated with 3-nitrobenzyl bromide in THF
using 1 M KO-t-Bu/THF. The nitro group was hydrogenated
(10% Pd/C, THF, 30 psi) to give the aniline. The aniline was
converted to the trifluoroacetamide (trifluoroacetic anhydride/
CH2Cl2/Et3N/room temp) and then alkylated with MeI (NaH/
DMF/rt) to give the N-methyltrifluoroacetamide intermediate.
All the protecting groups were then removed (concentrated
HCl/MeOH/reflux) to give 27: mp 210 °C; 1H NMR (CDCl3/
CD3OD) δ 7.92 (s, 1 H), 7.46-7.08 (m, 14 H), 6.51 (m, 2 H),
6.37 (bs, 1 H), 4.95 (d, J ) 14 Hz, 1 H), 4.82 (d, J ) 14 Hz, 1
H), 3.62-3.33 (m, 4 H), 3.12 (d, J ) 14 Hz, 1 H), 3.05 (m, 4
H), 2.85 (d, J ) 14 Hz, 1 H), 2.75 (s, 3 H); ESIMS m/ z 288.8
(M + 2H2+, 100). Anal. (C35H37N5O3‚0.5H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-1-[[3-(Dim eth yla m in o)p h en yl]m eth -
yl]h exa h yd r o-5,6-d ih yd r oxy-3-(1H-in d a zol-5-ylm et h yl)-
4,7-bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (26). The
urea 56 was alkylated with 3-nitrobenzyl bromide in THF
using 1 M KO-t-Bu/THF. The nitro group was hydrogenated
(10% Pd/C, THF, 30 psi) to give the aniline. The aniline was
converted to the trifluoroacetamide (trifluoroacetic anhydride/
CH2Cl2 Et3N/room temperature) and then alkylated with MeI
(NaH/DMF/room temperature) to give the N-methyltrifluoro-
acetamide intermediate. The trifluoroacetamide was hydro-
lyzed (1 N NaOH/DMF) and was alkylated with MeI (NaH/
DMF/room temperature to give the N,N-dimethyl analogue.
All the protecting groups were then removed (concentrated
HCl/MeOH/reflux) to give 26: mp 190-191 °C; 1H NMR
(CDCl3) δ 7.92 (s, 1 H), 7.46-7.12 (m, 14 H), 6.62 (d, J ) 8
Hz, 1 H), 6.50 (d, J ) 8 Hz, 1 H), 6.46 (bs, 1 H), 4.95 (d, J )
14 Hz, 1 H), 4.87 (d, J ) 14 Hz, 1 H), 3.62-3.33 (m, 6 H), 3.12
(d, J ) 14 Hz, 1 H), 3.10-2.90 (m, 4 H), 2.93 (d, J ) 14 Hz, 1
H), 2.87 (s, 6 H); ESIMS m/ z 590 (M + H+, 100). Anal.
(C36H39N5O3‚0.5H2O) C, H, N.
(m, 4 H), 4.95 (d, J ) 14 Hz, 1 H), 4.91 (d, J ) 14 Hz, 1 H),
+
3.65-3.40 (m, 6 H), 3.19-2.93 (m, 6 H); CIMS (M + NH4
,
100) 606; HRMS calcd for C36H37N4O4 (M + H+) 589.2815,
found 589.2811. Anal. (C36H36N4O4‚0.5H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-2-Flu or o-5-[[h exah ydr o-5,6-dih ydr oxy-
3-(1H -in d a zol-5-ylm et h yl)-2-oxo-4,7-b is(p h en ylm et h yl)-
1H-1,3-d ia zep in -1-yl]m eth yl]ben za m id e (20). The urea 56
was alkylated with 4-fluoro-3-cyanobenzyl bromide in THF
using 1 M KO-t-Bu/THF, and the protecting groups were
removed using HCl/MeOH as described above for 16. Finally
the cyano group was then converted to the amide using 30%
H2O2 in DMSO as described for 18 to give 20 as a white solid:
mp 143-146 °C; 1H NMR (CDCl3/CD3OD) δ 7.92 (s, 1 H), 7.76
(dd, J ) 2 Hz, 7 Hz, 1 H), 7.46-7.20 (m, 11 H), 7.12-7.08 (m,
4 H), 4.88 (d, J ) 14 Hz, 1 H), 4.72 (d, J ) 14 Hz, 1 H), 3.69-
3.46 (m, 3 H), 3.59 (d, J ) 14 Hz, 1 H), 3.35 (m, 1 H), 3.18 (d,
J ) 14 Hz, 1 H), 3.06 (m, 2 H), 3.05-2.75 (m, 2 H); ESIMS
m/ z 608 (M + H+, 100). Anal. (C35H34N5O4F) C, H, N.
[4R-(4r,5r,6â,7â)]-1-[(3-Am in o-4-flu or op h en yl)m eth yl]-
h exa h yd r o-5,6-d ih yd r oxy-3-[(1H-in d a zol-5-ylm eth yl)-4,7-
bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (23). The urea
56 was alkylated with 4-fluoro-3-nitrobenzyl bromide in THF
using 1 M KO-t-Bu/THF. The nitro group was hydrogenated
(10% Pd/C, THF, 30 psi) to give the aniline, and the protecting
groups were removed using HCl/MeOH to give a white solid.
This was chromatographed (MPLC silica gel, EtOAc) to give
23. This was recrystallized from chloroform: mp 183-184 °C;
1H NMR (CDCl3/CD3OD) δ 7.87 (s, 1 H), 7.39-7.14 (m, 13 H),
6.84 (dd, J ) 11 Hz, 8 Hz, 1 H), 6.64-6.36 (m, 2 H), 4.93 (d,
J ) 14 Hz, 1 H), 4.72 (d, J ) 14 Hz, 1 H), 3.65-3.40 (m, 4 H),
3.19-2.93 (m, 6 H); ESIMS m/ z 580 (M + H+, 100). Anal.
(C34H34N5O3F‚0.20CHCl3) C, H, N.
[4R-(4r,5r,6â,7â)]-1-[(4-a m in o-3-flu or op h en yl)m eth yl]-
h exa h yd r o-5,6-d ih yd r oxy-3-(1H-in d a zol-5-ylm eth yl)-4,7-
bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (24). The urea
56 was alkylated with 4-azido-3-fluorobenzyl bromide in THF
using 1 M KO-t-Bu/THF. The azido was reduced to the aniline
with LAH in THF at room temperature, and the protecting
groups were removed using HCl/MeOH to give a white solid.
This was chromatographed (HPLC Zorbax Sil, 6% MeOH/
1
CHCl3) to give 24: mp 125-130 °C; H NMR (CDCl3) δ 7.83
(s, 1 H), 7.39-7.24 (m, 9 H), 7.18 (d, J ) 7 Hz, 2 H), 7.12 (d,
J ) 7 Hz, 2 H), 6.77-6.61 (m, 3 H), 4.98 (d, J ) 14 Hz, 1 H),
4.77 (d, J ) 14 Hz, 1 H), 3.65-3.40 (m, H), 3.19-2.93 (m, 6
H); ESIMS m/ z 580 (M + H+, 100). Anal. (C34H34N5O3F‚
0.25CHCl3) C, H, N.
[4R-(4r,5r,6â,7â)]-1-[(3-Am in op h en yl)m eth yl]h exa h y-
d r o-5,6-d ih yd r oxy-3-(1H -in d a zol-5-ylm e t h yl)-4,7-b is-
(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (21). Procedure de-
tailed for 23 was used except alkylating with 3-nitrobenzyl
bromide: mp 134-136 °C; 1H NMR (DMSO-d6) δ 13.03 (bs, 1
[4R-(4r,5r,6â,7â)]-1-[[4-Flu or o-3-(m eth ylam in o)ph en yl]-
m eth yl]h exa h yd r o-5,6-d ih yd r oxy-3-(1H-in d a zol-5-ylm e-
t h yl)-4,7-b is(p h en ylm et h yl)-2H-1,3-d ia zep in -2-on e (28).
The urea 56 was alkylated with 3-(N-methyl-N-trifluoroacetyl)-

Nonsymmetric P2/ P2′ Cyclic Urea HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2419
4-fluorobenzyl bromide in THF using 1 M KO-t-Bu/THF. All
the protecting groups were then removed (concentrated HCl/
MeOH/reflux) to give 28. Recrystallized from chloroform: mp
191-193 °C; 1H NMR (CDCl3/CD3OD) δ 7.87 (s, 1 H), 7.32 (d,
J ) 8 Hz, 1 H), 7.29-7.15 (m, 8 H), 7.10 (d, J ) 7 Hz, 2 H),
7.05 (d, J ) 7 Hz, 2 H), 6.77 (dd, J ) 11 Hz, 8 Hz, 1 H), 6.36
(dd, J ) 8 Hz, 2 Hz, 1 H), 6.24 (m, 1 H), 4.84 (d, J ) 14 Hz, 1
H), 4.70 (d, J ) 14 Hz, 1 H), 3.55-3.25 (m, 4 H), 3.00 (d, J )
14 Hz, 1 H), 2.96-2.84 (m, 4 H), 2.78 (d, J ) 14 Hz, 1 H), 2.66
(s, 3 H); ESIMS m/ z 297.8 (M + 2H+2, 100). Anal. (C35H36
N5O3F‚0.5H2O) C, H, N.
-
[4R-(4r,5r,6â,7â)]-Hexa h yd r o-5,6-d ih yd r oxy-1-(1H-in -
d a zol-5-ylm eth yl)-4,7-bis(p h en ylm eth yl)-3-[[3-(1H-p yr a -
zol-1-ylm eth yl)ph en yl]m eth yl]-2H-1,3-diazepin -2-on e (29).
A solution of pyrazole (0.16 g, 2.4 mmol) in DMF was treated
with NaH (0.1 g, 2.4 mmol, 60% oil dispersion), and the
mixture is stirred at room temperature for 30 min. Then a
solution of the benzyl bromide 57 (R ) Br) (0.2 g, 0.24 mmol)
in DMF was added, and the mixture was stirred at room
temperature for 30 min. The solution was diluted with water,
made acidic with 1 N HCl, and extracted into ethyl acetate.
The organic layer is washed with water and brine, dried over
MgSO4, filtered, and then concentrated on a rotary evaporator.
The residue was dissolved in MeOH (10 mL), treated with
concentrated HCl (5 mL), and heated at reflux for 2 h. The
solution was concentrated on a rotary evaporator and the
residue partitioned between aqueous Na2CO3 and ethyl ac-
etate. The organic layer was washed with water and brine,
dried, and concentrated. The residue was chromatographed
(MPLC silica gel EtOAc) to give 29 as a white solid: mp 118-
122 °C; 1H NMR (CDCl3) δ 11.0 (bs, 1 H), 7.77 (s, 1 H), 7.39-
6.9 (m, 18 H), 6.71 (bs, 1 H), 6.16 (dd, J ) 2 Hz, 2 Hz, 1 H),
5.07 (dd, J ) 15 Hz, 2 Hz, 2 H), 4.96 (d, J ) 14 Hz, 1 H), 4.83
(d, J ) 14 Hz, 1 H), 4.40 (bs, 1 H), 3.90 (bs, 1 H), 3.59-3.13
(m, 4 H), 3.10 (d, J ) 14 Hz, 1 H), 3.09-2.76 (m, 4 H), 2.95 (d,
J ) 14 Hz, 1 H); ESIMS m/ z 314 (M + 2H+2, 100); HRMS
calcd for C38H39N6O3 (M + H+) 627.3084, found 627.3108.
Anal. (C38H38N6O3‚0.75H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-1-[[4-Am in o-3-(1H-1,2,4-tr ia zol-1-yl)-
p h en yl]m eth yl]h exa h yd r o-5,6-d ih yd r oxy-3-(1H-in d a zol-
5-ylm e t h yl)-4,7-b is(p h e n ylm e t h yl)-2H -1,3-d ia ze p in -2-
on e (34). The urea 56 was alkylated with 4-nitro-3-fluoroben-
zyl bromide in THF using 1 M KO-t-Bu/THF to give the
dialkylated urea. A solution of triazole (0.16 g, 2.3 mmol) in
DMF was treated with NaH (0.1 g, 2.4 mmol, 60% oil
dispersion), and the mixture is stirred at room temperature
for 30 min. This solution was cooled to 0 °C, and the
dialkylated urea (containing the 4-nitro-3-fluorobenzyl group)
(0.2 g, 0.26 mmol) was added. The resulting dark mixture
stirred at 0 °C for 30 min and then warmed to room temper-
ature and stirred for 2 h. The solution was diluted with water,
acidified with 1 N HCl, and extracted into ethyl acetate. The
organic layer was washed with water and brine, dried, filtered,
and concentrated. The residue was chromatographed (MPLC
silica gel, 50% EtOAc/hexane) to give 0.1 g of the corresponding
3-(1,2,4-triazol-1-yl)-4-nitrobenzyl compound. This was dis-
solved in THF, treated with 100 mg of 10% Pd/C, and
hydrogenated at 50 psi for 5 h. The mixture was filtered
(Celite), and the residue was chromatographed (MPLC silica
gel, 60% EtOAc/hexane) to give 70 mg of the corresponding
3-(1,2,4-triazol-1-yl)-4-aminobenzyl compound. Finally the
protecting groups were removed by dissolving in MeOH (20
mL), treating with concentrated HCl (5 mL), and heating at
reflux for 2 h. The mixture was concentrated, and the residue
was partitioned between 1 N NaOH and EtOAc. The organic
extract was washed with water and brine and dried over
MgSO4. Solution was filtered and concentrated and the
residue was triturated with ethyl acetate/hexane to give 40
[4R-(4r,5r,6â,7â)]-Hexa h yd r o-5,6-d ih yd r oxy-1-(1H-in -
d a zol-5-ylm eth yl)-4,7-bis(p h en ylm eth yl)-3-[[3-(1H-1,2,4-
t r ia zol-1-ylm e t h yl)p h e n yl]m e t h yl]-2H -1,3-d ia ze p in -2-
on e (30). The procedure detailed for 29 was used except
starting with 1,2,4-triazole: mp 120-124 °C; 1H NMR (CDCl3)
δ 11.3 (bs, 1 H), 7.77 (s, 1 H), 7.73 (s, 1 H), 7.68 (s, 1 H), 7.60
(s, 1 H), 7.31-7.03 (m, 16 H), 6.96 (bs, 1 H), 5.13 (dd, J ) 15
Hz, 22 Hz, 2 H), 4.96 (d, J ) 14 Hz, 1 H), 4.85 (d, J ) 14 Hz,
1 H), 4.45 (bs, 2 H), 3.59-3.43 (m, 4 H), 3.07 (d, J ) 14 Hz, 1
H), 3.08-3.02 (m, 4 H), 3.02 (d, J ) 14 Hz, 1 H), 2.80 (m, 1
H); ESIMS m/ z 314.8 (M + 2H+2, 100); HRMS calcd for
C
37H38N7O3 (M + H+) 628.3036, found 628.3030. Anal.
(C37H37N7O3‚0.75H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-Hexa h yd r o-5,6-d ih yd r oxy-1-(1H-in -
d a zol-5-ylm eth yl)-4,7-bis(p h en ylm eth yl)-3-[[3-(1H-1,2,3-
t r ia zol-1-ylm e t h yl)p h e n yl]m e t h yl]-2H -1,3-d ia ze p in -2-
on e (31). The procedure detailed for 29 was used except
starting with 1,2,3-triazole. Two isomers were obtained. The
1
1
more polar isomer is 31: mp 114-118 °C; H NMR (CDCl3/
mg of 34 as a white solid: mp 144-148 °C; H NMR (CDCl3)
CD3OD) δ 7.77 (s, 1 H), 7.73 (s, 1 H), 7.56 (s, 1 H), 7.48 (s, 1
H), 7.38-6.99 (m, 17 H), 5.46 (dd, J ) 15 Hz, 22 Hz, 2 H),
4.91 (d, J ) 15 Hz, 1 H), 4.80 (d, J ) 15 Hz, 1 H), 3.59-3.43
(m, 4 H), 3.05 (d, J ) 15 Hz, 1 H), 3.07-2.90 (m, 3 H), 3.01 (d,
δ 12.13 (bs, 1 H), 8.31 (s, 1 H), 8.15 (s, 1 H), 7.82 (s, 1 H),
7.31-6.33 (m, 16 H), 4.96 (d, J ) 14 Hz, 1 H), 4.75 (d, J ) 14
Hz, 1 H), 4.75 (bs, 2 H), 4.12 (bs, 2 H), 3.59-3.33 (m, 4 H),
3.05-2.80 (m, 6 H); ESIMS m/ z 315.3 (M + 2H+2, 100); HRMS
calcd for C36H37N8O3 (M + H+) 629.2989, found 629.2971.
Anal. (C36H36N8O3‚0.5EtOAc‚0.1hexane‚0.75H2O) C, H, N.
[4R -(4r,5r,6â,7â)]-1-[[4-Am in o-3-(1H -p yr a zol-1-yl)-
p h en yl]m eth yl]h exa h yd r o-5,6-d ih yd r oxy-3-(1H-in d a zol-
5-ylm e t h yl)-4,7-b is(p h e n ylm e t h yl)-2H -1,3-d ia ze p in -2-
on e (33). The procedure detailed for 34 was used except
starting with pyrazole: recrystallized from ethyl acetate; mp
139-141 °C; 1H NMR (CDCl3/CD3OD) δ 7.95 (s, 1 H), 7.74 (d,
J ) 2 Hz, 1 H), 7.64 (d, J ) 2 Hz, 1 H), 7.42-6.47 (m, 17 H),
4.96 (d, J ) 14 Hz, 1 H), 4.83 (d, J ) 14 Hz, 1 H), 3.59-3.33
(m, 4 H), 3.19-2.80 (m, 6 H); ESIMS m/ z 628.5 (M + H+, 100);
J ) 15 Hz, 1 H), 2.66 (m, 1 H); ESIMS m/ z 314.9 (M + 2H+2
,
100); HRMS calcd for C37H38N7O3 (M + H+) 628.3036, found
628.3017. Anal. (C37H37N7O3‚0.66H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-Hexa h yd r o-5,6-d ih yd r oxy-1-(1H-in -
d a zol-5-ylm eth yl)-4,7-bis(p h en ylm eth yl)-3-[[3-(2H-1,2,3-
t r ia zol-2-ylm e t h yl)p h e n yl]m e t h yl]-2H -1,3-d ia ze p in -2-
on e (32). The procedure detailed for 29 was used except
starting with 1,2,3-triazole. Two isomers were obtained. The
less polar isomer is 32: mp 112-116 °C; 1H NMR (CDCl3/CD3-
OD) δ 7.77 (s, 1 H), 7.45 (s, 2 H), 7.38-6.99 (m, 17 H), 5.43 (s,
2 H), 4.98 (d, J ) 14 Hz, 1 H), 4.84 (d, J ) 14 Hz, 1 H), 3.59-
3.33 (m, 4 H), 3.07-2.80 (m, 6 H); ESIMS m/ z 628.5 (M +
H+, 100). Anal. (C37H37N7O3‚0.66H2O) C, H, N.
HRMS calcd for
628.3031. Anal. (C37H37N7O3‚0.66EtOAc‚0.66H2O) C, H, N.
C
37H38N7O3 (M + H+) 628.3036, found

2420 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
De Lucca et al.
[4R-(4r,5r,6â,7â)]-1-[[4-Am in o-3-(2H-1,2,3-tr ia zol-2-yl)-
p h en yl]m eth yl]h exa h yd r o-5,6-d ih yd r oxy-3-(1H-in d a zol-
5-ylm e t h yl)-4,7-b is(p h e n ylm e t h yl)-2H -1,3-d ia ze p in -2-
on e (35). The procedure detailed for 34 was used except
starting with 1,2,3-triazole to give 2 isomers. The less polar
isomer is 35: recrystallized from ethyl acetate; mp 139-142
°C; 1H NMR (CDCl3/DMSO-d6) δ 12.41 (bs, 1 H), 7.95 (s, 1 H),
7.79 (s, 2 H), 7.62-6.77 (m, 16 H), 5.50 (bs, 2 H), 4.96 (d, J )
14 Hz, 1 H), 4.77 (d, J ) 14 Hz, 1 H), 4.31 (bs, 1 H), 4.25 (bs,
1 H), 3.59-3.33 (m, 4 H), 3.19-2.80 (m, 6 H); ESIMS m/ z
315.3 (M + 2H+2, 100); HRMS calcd for C36H37N8O3 (M + H+)
629.2989, found 629.2979. Anal. (C36H36N8O3‚0.5EtOAc‚
0.25H2O) C, H, N.
s, 2 H), 3.18-2.97 (m, 4 H); ESIMS m/ z 628 (M + H+, 100);
HRMS calcd for
628.3034.
C
37H38N7O3 (M + H+) 628.3036, found
[4R-(4r,5r,6â,7â)]-3-[[Hexa h yd r o-5,6-d ih yd r oxy-3-(1H-
in d a zol-5-ylm eth yl)-2-oxo-4,7-bis(p h en ylm eth yl)-1H-1,3-
d ia zep in -1-yl]m eth yl]ben zoic Acid (15). The urea 56 (0.20
g, 0.3 mmol) was alkylated with 3-carbomethoxybenzyl bro-
mide (0.27 g, 1.2 mmol) under the standard conditions5 (DMF/
NaH (0.06 g, 1.5 mmol, 60% oil dispersion). The protecting
groups (acetonide and SEM) were removed by dissolving in
MeOH (10 mL) and 4 N HCl/dioxane (5 mL) and heating at
reflux for 3 h. The solution was evaporated to dryness, and
the residue was redissolved in dioxane, treated with 50%
aqueous NaOH (0.34 g), and stirred at room temperature for
24 h. The solution was acidified with 1 N HCl and extracted
into ethyl acetate. The organic layer was washed with water
and brine, dried, and concentrated on a rotary evaporator. The
residue was triturated with hot water and then with hot
methylene chloride to give 80 mg of 15 as a white solid: mp
[4R-(4r,5r,6â,7â)]-1-[[4-Am in o-3-(1H-1,2,3-tr ia zol-1-yl)-
p h en yl]m eth yl]h exa h yd r o-5,6-d ih yd r oxy-3-(1H-in d a zol-
5-ylm e t h yl)-4,7-b is(p h e n ylm e t h yl)-2H -1,3-d ia ze p in -2-
on e (36). The procedure detailed for 34 was used except
starting with 1,2,3-triazole to give two isomers. The more
polar isomer is 36: recrystallized from ethyl acetate; mp 142-
1
1
151-153 °C; H NMR (DMSO-d6) δ 13.07 (bs, 1 H), 8.04 (s, 1
148 °C; H NMR (CDCl3/DMSO-d6) δ 12.41 (bs, 1 H), 7.95 (s,
H), 7.84 (bs, 1 H), 7.50 (d, J ) 7 Hz, 1 H), 7.37-6.99 (m, 16
H), 5.22 (bs, 2 H), 4.76 (d, J ) 14 Hz, 1 H), 4.72 (bs, 2 H), 4.77
(d, J ) 14 Hz, 1 H), 3.59-3.30 (m, 4 H), 2.95-2.49 (m, 6 H);
ESIMS m/ z 591 (M + H+, 100); HRMS calcd for C35H35N4O5
(M + H+) 591.2607, found 591.2612. Anal. (C35H34N4O5‚
0.75CH2Cl2‚0.25H2O) C, H, N.
1 H), 7.84 (s, 1 H), 7.80 (s, 1 H), 7.47-6.87 (m, 16 H), 4.96 (d,
J ) 14 Hz, 1 H), 4.86 (bs, 2 H), 4.77 (d, J ) 14 Hz, 1 H), 4.31
(bs, 1 H), 4.25 (bs, 1 H), 3.59-3.33 (m, 4 H), 3.19-2.80 (m, 6
H); ESIMS m/ z 315.3 (M + 2H+2, 100); HRMS calcd for
C36H37N8O3 (M + H+) 629.2989, found 629.2983. Anal.
(C36H36N8O3‚0.25EtOAc‚0.5H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-3-[[Hexa h yd r o-5,6-d ih yd r oxy-3-(1H-
in d a zol-5-ylm eth yl)-2-oxo-4,7-bis(p h en ylm eth yl)-1H-1,3-
d ia zep in -1-yl]m eth yl]-N-(2-th ia zolyl)ben za m id e (42). A
solution of the acid 15 (60 mg, 0.1 mmol) in CH2Cl2/CH3CN
was treated with 2-aminothiazole (300 mg, 3.0 mmol) and 1-(3-
(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (58
mg, 0.3 mmol) and stirred at room temperature for 24 h. The
solution was diluted with water and extracted into ethyl
acetate. The organic layer was washed with water and brine,
dried, and concentrated on a rotary evaporator. The residue
was chromatographed (HPLC Zorbax Sil, 10% MeOH/CH2Cl2)
[4R-(4r,5r,6â,7â)]-Hexa h yd r o-5,6-d ih yd r oxy-1-(1H-in -
d a zol-5-ylm eth yl)-4,7-bis(p h en ylm eth yl)-3-[[3-(4H-1,2,4-
tr ia zol-3-yl)p h en yl]m eth yl]-2H-1,3-d ia zep in -2-on e (37).
The urea 56 was alkylated with 3-cyanobenzyl bromide in THF
using 1 M KO-t-Bu/THF. The 3-cyanobenzyl group was
converted to the corresponding carboxamide (30% H2O2 and
K2CO3 in DMSO).18 The 1,2,4-triazole group was obtained from
the carboxamide using the literature24 procedure by first
heating with N,N-dimethylformamide dimethyl acetal (90 °C)
for 2 h to obtain the corresponding N′-acyl-N,N-dimethylami-
dine. The N′-acyl-N,N-dimethylamidine intermediate is cy-
clized by heating with hydrazine in AcOH (90 °C) for 2 h to
give the triazole ring. Finally the protecting groups were
removed using HCl/MeOH, and the product was chromato-
graphed (MPLC silica gel, 5% MeOH/CHCl3) to give 37: mp
1
to give 30 mg of 42: mp 167-169 °C; H NMR (CDCl3/CD3-
OD) δ 7.95 (s, 1 H), 7.87 (d, J ) 7 Hz, 1 H), 7.76 (s, 1 H), 7.50
(d, J ) 3.6 Hz, 1 H), 7.47-7.22 (m, 12 H), 7.11 (d, J ) 7 Hz,
2 H), 7.04 (d, J ) 3.6 Hz, 1 H), 6.91 (d, J ) 7 Hz, 2 H), 4.90 (d,
J ) 14 Hz, 1 H), 4.77 (d, J ) 14 Hz, 1 H), 3.59-3.33 (m, 4 H),
3.25 (d, J ) 14 Hz, 1 H), 3.19-2.80 (m, 5 H); CIMS m/ z 673
(M + H+, 100); HRMS calcd for C38H37N6O4S (M + H+)
673.2597, found 673.2615. Anal. (C38H36N6O4S‚1.25H2O) C,
H, N.
1
166-168 °C; H NMR (DMSO-d6) δ 13.04 (s, 1 H), 8.05 (s, 1
H), 7.93 (br s, 1 H), 7.53-7.01 (m, 16 H), 5.05 (dd, J ) 16 Hz,
4 Hz, 2 H), 4.76 (t, J ) 14 Hz, 2 H), 3.52-3.35 (m, 4 H), 2.99-
2.73 (m, 6 H); ESIMS m/ z 614 (M + H+, 100); HRMS calcd
for C36H36N7O3 (M + H+) 614.2879, found 614.2852. Anal.
(C36H35N7O3) C, H, N.
[4R-(4r,5r,6â,7â)]-3-[[Hexa h yd r o-5,6-d ih yd r oxy-3-(1H-
in d a zol-5-ylm eth yl)-2-oxo-4,7-bis(p h en ylm eth yl)-1H-1,3-
d ia zep in -1-yl]m et h yl]-N-(5-m et h yl-2-p yr id in yl)b en za -
m id e (39). The procedure detailed for 42 was used except
using 2-amino-5-methylpyridine: mp 141-143 °; 1H NMR
(CDCl3/CD3OD) δ 8.23 (d, J ) 8 Hz, 1 H), 8.13 (d, J ) 2 Hz, 1
H), 7.95 (s, 1 H), 7.85-7.04 (m, 19 H), 4.90 (m, 2 H), 3.62-
3.38 (m, 4 H), 3.19-2.80 (m, 6 H); CIMS m/ z 681 (M + H+,
100); HRMS calcd for C41H41N6O4 (M + H+) 681.3189, found
681.3192. Anal. C41H40N6O4‚H2O C, H, N.
[4R -(4r,5r,6â,7â)]-1-[[4-Am in o-3-(1H -p yr a zol-3-yl)-
p h en yl]m eth yl]h exa h yd r o-5,6-d ih yd r oxy-3-(1H-in d a zol-
5-ylm e t h yl)-4,7-b is(p h e n ylm e t h yl)-2H -1,3-d ia ze p in -2-
on e (38). Isourea 55 was alkylated with 3-carbomethoxy-4-
fluorobenzyl bromide using the procedure detailed for 18. This
was converted to the Weinreb amide using the procedure
detailed for 43. The amide was treated with methylmagne-
sium bromide to give the 3-acetyl-4-fluorobenzyl group.
A
suspension of the 3-acetyl-4-fluorobenzyl analogue (0.3 g, 0.39
mmol) and NaN3 (1.0 g, 15.3 mmol) in DMF was stirred at 90
°C for 3 days. After being cooled to room temperature, the
suspension was diluted with H2O and extracted into EtOAc.
The organic layer was washed with water and brine, dried,
filtered, and concentrated in vacuo. The residue was chro-
matographed (MPLC silica gel, 30% EtOAc/hexane) to give 0.1
g of the corresponding 3-acetyl-4-azidobenzyl group. The
3-acetyl group was treated with N,N-dimethylformamide dim-
ethyl acetal (90 °C) for 4 h. After being cooled to room
temperature, the suspension was diluted with H2O and
extracted into EtOAc. The residue was then heated with
hydrazine in refluxing EtOH for 2 h to give the 3-(pyrazol-3-
yl)-4-aminophenylmethyl analogue. Finally the protecting
groups were removed using the HCl/MeOH procedure, and the
product was chromatographed (MPLC silica gel, 9:95:1 MeOH:
CHCl3:aqueous NH3) to give 38: mp 147-151 °C; 1H NMR
(CDCl3/CD3OD) δ 7.94 (s, 1 H), 7.60-7.07 (m, 17 H), 6.53 (br
s, 1 H), 4.93 (d, J ) 14 Hz, 2 H), 3.64-3.53 (m, 4 H), 3.39 (br
[4R-(4r,5r,6â,7â)]-3-[[Hexa h yd r o-5,6-d ih yd r oxy-3-(1H-
in d a zol-5-ylm eth yl)-2-oxo-4,7-bis(p h en ylm eth yl)-1H-1,3-
diazepin -1-yl]m eth yl]-N-(2-pyr idin yl)ben zam ide (40). The
procedure detailed for 42 was used except using 2-aminopy-
ridine: mp 150-152 °C; 1H NMR (DMSO-d6) δ 13.07 (bs, 1
H), 10.77 (s, 1 H), 8.39 (dd, J ) 2 Hz, 2 Hz, 1 H), 8.17 (d, J )
8 Hz, 1 H), 8.04 (s, 1 H), 7.94 (d, J ) 7 Hz, 1 H), 7.87-7.80
(m, 3 H), 7.50-6.99 (m, 11 H), 7.02 (d, J ) 8 Hz, 2 H), 6.97 (d,
J ) 8 Hz, 2 H), 5.09 (bs, 1 H), 5.03 (bs, 1 H), 4.76 (d, J ) 14
Hz, 1 H), 4.71 (d, J ) 14 Hz, 1 H), 3.59-3.30 (m, 4 H), 3.05-
2.59 (m, 6 H); ESIMS m/ z 667 (M + H+, 100); HRMS calcd
for C40H39N6O4 (M + H+) 667.3033, found 667.3045.
[4R-(4r,5r,6â,7â)]-3-[[Hexa h yd r o-5,6-d ih yd r oxy-3-(1H-
in d a zol-5-ylm eth yl)-2-oxo-4,7-bis(p h en ylm eth yl)-1H-1,3-
d ia zep in -1-yl]m et h yl]-N-(6-m et h yl-2-p yr id in yl)b en za -
m id e (41). A similar procedure as detailed for 42 was used
1
except using 2-amino-6-methylpyridine: mp 147-149 °C; H
NMR (CDCl3/CD3OD) δ 8.13 (d, 8 Hz, 1 H), 7.80 (s, 1 H), 7.71

Nonsymmetric P2/ P2′ Cyclic Urea HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2421
(d, J ) 7 Hz, 1 H), 7.63-7.56 (m, 2 H), 7.39-7.20 (m, 11 H),
7.11 (d, J ) 7 Hz, 2 H), 7.04 (d, J ) 7 Hz, 2 H), 6.88 (d, J ) 7
Hz, 1 H), 4.95 (d, J ) 16 Hz, 1 H), 4.81 (d, J ) 16 Hz, 1 H),
3.69-3.48 (m, 4 H), 3.19-2.80 (m, 6 H), 2.32 (s, 3 H); CIMS
m/ z 681 (M + H+, 100); HRMS calcd for C41H41N6O4 (M +
H+) 681.3189, found 681.3174. Anal. (C41H40N6O4‚H2O) C, H,
N.
keto-enol forms: mp 119-121 °C; 1H NMR (DMSO-d6) δ 13.07
(bs, 1 H), 8.39 (m, 1 H), 8.04 (s, 1 H), 7.95-6.80 (m, 20 H),
6.02 (s, 1 H, enol), 5.09 (vbs, 3 H), 4.86 (d, J ) 14 Hz, 1 H),
4.61 (d, J ) 14 Hz, 1 H), 4.42 (s, 1 H, keto form), 3.59-3.30
(m, 4 H), 3.05-2.59 (m, 6 H); ESIMS m/ z 666 (M + H+, 100);
HRMS calcd for
C
41H40N5O4 (M + H+) 666.3080, found
666.3098. Anal. (C41H39N5O4‚H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-Hexa h yd r o-5,6-d ih yd r oxy-1-(1H-in -
d a zol-5-ylm et h yl)-4,7-b is(p h en ylm et h yl)-3-[[3-(2-t h ien -
yla cetyl)p h en yl]m eth yl]-2H-1,3-d ia zep in -2-on e (44).
A
solution of isourea 55 (0.2 g, 0.3 mmol) and 3-(thien-2-ylacetyl)-
benzyl bromide (0.28 g, 0.94 mmol) in acetonitrile was heated
at reflux for 20 h. The mixture was concentrated, and the
resulting residue was chromatographed (MPLC silica gel, 10-
30% EtOAc/hexane) to give the dialkylated urea (0.10 g). The
protecting groups were removed by dissolving in MeOH (20
mL), treating with concentrated HCl (5 mL), and heating at
reflux for 2 h. The mixture was concentrated, and the residue
was partitioned between 1 N NaOH and EtOAc. The organic
extract was washed with water and brine, and dried over
MgSO4. Solution was filtered and concentrated and the
residue was chromatographed (MPLC silica gel, 5% MeOH/
CH2Cl2) to give 40 mg of 44: mp 121-123 °C; 1H NMR (CDCl3/
CD3OD) δ 7.96 (s, 1 H), 7.90 (d, J ) 7 Hz, 1 H), 7.78 (s, 1 H),
7.45-7.21 (m, 12 H), 7.12 (d, J ) 7 Hz, 2 H), 7.07 (d, J ) 7
Hz, 2 H), 6.94 (m, 1 H), 6.88 (m, 1 H), 4.93 (d, J ) 14 Hz, 1 H),
4.82 (d, J ) 14 Hz, 1 H), 4.45 (s, 2 H), 3.63-3.30 (m, 4 H),
3.15-2.81 (m, 6 H); ESIMS m/ z 671 (M + H+, 100); HRMS
calcd for C40H39N4O4S (M + H+) 671.2692, found 671.2684.
Anal. (C40H38N4O4S‚0.33H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-Hexa h yd r o-5,6-d ih yd r oxy-1-(1H-in -
d a zol-5-ylm et h yl)-4,7-b is(p h en ylm et h yl)-3-[[3-(2-p yr i-
d in yla cetyl)p h en yl]m eth yl]-2H-1,3-d ia zep in -2-on e (43).
The urea 56 was alkylated with 3-carbomethoxybenzyl bro-
mide under the standard conditions5 (DMF/NaH (60% oil
dispersion). The ester (1.7 g, 2.2 mmol) was dissolved in
dioxane (30 mL), treated with 1 N NaOH (7 mL), and stirred
at room temperature for 24 h. The solution was acidified with
1 N HCl and extracted into ethyl acetate. The organic layer
was washed with water and brine, dried, and concentrated on
a rotary evaporator. The acid formed was converted to the
Weinreb19 amide using the Ph3P/CBr4 procedure.20 A suspen-
sion of acid (0.83 g, 1.1 mmol), CBr4 (1.42 g, 1.3 mmol),
N-methoxy-N-methylamine hydrochloride (0.14 g, 1.3 mmol),
and pyridine (0.12 g, 1.4 mmol) in methylene chloride was
treated portionwise with Ph3P (0.37 g, 1.4 mmol) and was
stirred at room temperature for 1 h until homogeneous. The
solution was concentrated to dryness and the residue tritu-
rated with 50% EtOAc/hexane (100 mL). The solid was
removed by filtration and the filtrate concentrated on a rotary
evaporator. The residue is chromatographed (MPLC silica gel,
3% MeOH/CH2Cl2) to give 0.70 g of the N-methoxy-N-methyl-
amide. A solution of 2-picoline (46 mg, 0.49 mmol) in THF
was treated with phenyllithium (0.25 mL, 0.45 mmol, 1.8 M
solution) and stirred for 1 h at room temperature. The solution
was cooled to -78 °C, and the above N-methoxy-N-methyla-
mide (0.18 g, 0.22 mmol) was added. The mixture was allowed
to warm to room temperature, and the reaction was quenched
with saturated NH4Cl. The mixture was extracted into ethyl
acetate, and the organic layer was washed with water and
brine, dried, and concentrated on a rotary evaporator. The
residue was chromatographed (MPLC silica gel, 50% ETOAc/
hexane) to give 0.16 g of ketone as a yellow solid. The
protecting groups (acetonide and SEM) were removed by
dissolving in MeOH (10 mL) and 4 N HCl/dioxane (5 mL) and
heating at reflux for 8 h. The solution was evaporated to
dryness, and the residue was chromatographed (MPLC silica
gel, 7% MeOH/CH2Cl2) to give 80 mg of 43 as a mixture of
[4R-(4r,5r,6â,7â)]-Hexa h yd r o-5,6-d ih yd r oxy-1-(1H-in -
d a zol-5-ylm eth yl)-4,7-bis(p h en ylm eth yl)-3-[[3-(1H-p yr a -
zol-1-yla cetyl)p h en yl]m eth yl]-2H-1,3-d ia zep in -2-on e (45).
The urea 56 was alkylated with 3-cyanobenzyl bromide in THF
using 1 M KO-t-Bu/THF. The 3-cyanobenzyl group was
converted to the 3-acetylbenzyl group with methylmagnesium
bromide (THF, reflux). The acetyl group was brominated by
treating a solution of the methyl ketone (1.29 g, 1.7 mmol) in
ether with a solution of 2,4,4,6-tetrabromocyclohexa-2,5-di-
enone (1.44 g, 3.44 mmol) in ether (containing 1 M HCl) and
stirred at room temperature overnight. The mixture was
concentrated to dryness, and the residue was chromatographed
(MPLC silica gel, 30-50% EtOAc/hexane) to give 0.4 g of the
bromoacetyl product as the free diol. The diol was then re-
protected as the acetonide under standard conditions to give
58 (R ) Br). A solution of pyrazole (13 mg, 0.19 mmol) in THF
was treated with NaH (8 mg, 0.2 mmol, 60% oil dispersion),
and the mixture was stirred at room temperature for 30 min.

2422 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
De Lucca et al.
Then a solution of the bromoacetylacetonide 58 (0.1 g, 0.13
mmol) in THF was added, and the mixture was stirred at room
temperature for 30 min. The solution was diluted with
aqueous NH4Cl and extracted into ethyl acetate. The organic
layer was washed with water and brine, dried over MgSO4,
filtered, and concentrated on a rotary evaporator. The residue
was chromatographed (MPLC silica gel, 50% EtOAc/hexane)
to give 80 mg of pyrazole-substituted product 58. This was
dissolved in MeOH (10 mL) and concentrated HCl (5 mL) and
heated at reflux for 2 h. The solution was concentrated on a
rotary evaporator, and the residue was partitioned between
aqueous Na2CO3 and ethyl acetate. The organic layer was
then washed with water and brine, dried, and concentrated.
The residue was chromatographed (MPLC silica gel 9:1:90
MeOH:NH3:CHCl3) to give 45 as a white solid: mp 125-127
°C; 1H NMR (CDCl3/CD3OD) δ 7.94 (s, 1 H), 7.85 (m, 1 H),
7.73 (s, 1 H), 7.58 (d, J ) 2 Hz, 1 H), 7.49-7.21 (m, 8 H), 7.14-
7.07 (m, 4 H), 6.39 (t, J ) 2 Hz, 1 H), 5.55 (bs, 2 H), 4.94 (d,
J ) 14 Hz, 1 H), 4.86 (d, J ) 14 Hz, 1 H), 3.63-3.30 (m, 4 H),
3.15-2.81 (m, 6 H); ESIMS m/ z 328 (M + 2H+2, 100); HRMS
calcd for C39H39N6O4 (M + H+) 655.3033, found 655.3014.
on a rotary evaporator, and the residue was partitioned
between aqueous Na2CO3 and ethyl acetate. The organic layer
was then washed with water and brine, dried, and concen-
trated. The residue was chromatographed (HPLC Zorbax Sil,
10% MeOH/CHCl3) to give 49: mp 162-164 °C; 1H NMR
(DMSO-d6) δ 13.02 (s, 1 H), 12.30 (s, 1 H), 8.04 (s, 1 H), 7.48-
6.93 (m, 18 H), 6.52 (bs, 1 H), 6.41-6.35 (m, 2 H), 4.98 (bs, 2
H), 4.78 (d, J ) 14 Hz, 1 H), 4.61 (d, J ) 14 Hz, 1 H), 4.42 (s,
2 H), 3.53-3.30 (m, 4 H), 2.97-2.60 (m, 6 H); ESIMS m/ z 692
(M + H+, 100); HRMS calcd for C42H42N7O3 (M + H+) 692.3349,
found 692.3368. Anal. (C42H41N7O3‚1.5H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-1-[[3-[(1H-Ben zim id a zol-2-ylm eth yl)-
am in o]-4-flu or oph en yl]m eth yl]h exah ydr o-5,6-dih ydr oxy-
3-(1H-in d a zol-5-ylm eth yl)-4,7-bis(p h en ylm eth yl)-2H-1,3-
d ia zep in -2-on e (50). The procedure detailed for 49 was used
to give 50: mp 175-177 °C; 1H NMR (DMSO-d6) δ 13.02 (s, 1
H), 12.20 (s, 1 H), 8.04 (s, 1 H), 7.54-7.00 (m, 15 H), 6.82 (bs,
2 H), 6.41-6.33 (m, 2 H), 6.17 (bs, 1 H), 5.04 (d, J ) 3 Hz, 1
H), 4.95 (d, J ) 3 Hz, 1 H), 4.75 (d, J ) 14 Hz, 1 H), 4.55-
4.42 (m, 3 H), 3.52-3.31 (m, 5 H), 2.97-2.72 (m, 5 H), 2.54 (d,
J ) 14 Hz, 1 H); ESIMS m/ z 710 (M + H+, 100); HRMS calcd
for C42H41N7O3F (M + H+) 710.3254, found 710.3240. Anal.
(C42H40N7O3F‚H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-1-[[3-[(2-Ben zoth ia zolylm eth yl)a m i-
n o]p h en yl]m eth yl]h exa h yd r o-5,6-d ih yd r oxy-3-(1H-in d a -
zol-5-ylm eth yl)-4,7-bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-
on e (51). The procedure detailed for 49 was used in order to
obtain the protected aniline. A solution of the aniline (0.3 g,
0.45 mmol) in MeOH was treated with benzothiazole-2-
carboxaldehyde (0.33 g, 2.0 mmol), NaBH3CN (0.12 g, 1.9
mmol), and AcOH (0.1 mL, 1.74 mmol) and stirred at room
temperature for 20 h. The reaction was quenched with
saturated aqueous NaHCO3 and extracted into EtOAc. The
organic layer was washed with brine, dried, filtered, and
concentrated in vacuo. The residue was chromatographed
(MPLC silica gel, 50% EtOAc/hexane) to give 0.08 g of the
corresponding N-alkylaniline. The protecting groups were
removed using HCl/MeOH, and the product was chromato-
graphed (MPLC silica gel, 7% MeOH/CHCl3) to give 51: mp
125-128 °C; 1H NMR (CDCl3/CD3OD) δ 7.78 (s, 1 H), 7.69 (d,
J ) 7 Hz, 1 H), 7.61 (d, J ) 7 Hz, 1 H), 7.30-6.86 (m, 16 H),
6.43-6.34 (m, 2 H), 6.28 (bs, 1 H), 4.71 (d, J ) 14 Hz, 1 H),
4.58 (d, J ) 14 Hz, 1 H), 4.53 (s, 2 H), 3.41-3.26 (m, 4 H),
3.19 (bs, 1 H), 2.90-2.66 (m, 6 H); ESIMS m/ z 709 (M + H+,
100); HRMS calcd for C42H41N6O3S (M + H+) 709.2961, found
709.2948. Anal. (C42H40N6O3S‚0.5H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-Hexa h yd r o-5,6-d ih yd r oxy-1-(1H-in -
d a zol-5-ylm et h yl)-4,7-b is(p h en ylm et h yl)-3-[[3-(1-1,2,3-
t r ia zol-1-yla ce t yl)p h e n yl]m e t h yl]-2H -1,3-d ia ze p in -2-
on e (46). A similar procedure as detailed for 45 was used
except using 1,2,3-triazole to give two isomers. The more polar
isomer is 46: mp 140-142 °C; 1H NMR (DMSO-d6) δ 13.00 (s,
1 H), 8.09-8.00 (m, 3 H), 7.80 (m, 3 H), 7.57-7.50 (m, 3 H),
7.35-7.23 (m, 8H), 7.00 (m, 4 H), 6.16 (bs, 2 H), 5.05 (bs, 2
H), 4.77 (d, J ) 14 Hz, 1 H), 4.69 (d, J ) 14 Hz, 1 H), 3.51-
3.44 (m, 3 H), 3.14-2.74 (m, 7 H); ESIMS m/ z 328 (M + 2H+2
,
100); HRMS calcd for C38H38N7O4 (M + H+) 656.2985, found
656.2985. Anal. (C38H37N7O4) C, H, N.
[4R-(4r,5r,6â,7â)]-Hexa h yd r o-5,6-d ih yd r oxy-1-(1H-in -
d a zol-5-ylm eth yl)-4,7-bis(p h en ylm eth yl)-3-[[3-(2H-1,2,3-
t r ia zol-2-yla ce t yl)p h e n yl]m e t h yl]-2H -1,3-d ia ze p in -2-
on e (47). A similar procedure as detailed for 45 was used
except using 1,2,3-triazole to give two isomers. The less polar
isomer is 47: mp 125-128 °C; 1H NMR (DMSO-d6) δ 13.00 (s,
1 H), 8.01 (d, J ) 8 Hz, 1 H), 7.92 (m, 1 H), 7.83 (s, 2 H), 7.74
(s, 1H), 7.53-7.45 (m, 3 H), 7.31-7.18 (m, 8 H), 6.92 (bs, 4 H),
6.16 (s, 2 H), 5.05 (bs, 2 H), 4.72 (d, J ) 14 Hz, 1 H), 4.62 (d,
J ) 14 Hz, 1 H), 3.56-3.48 (m, 3 H), 3.15-2.68 (m, 7 H);
ESIMS m/ z 656 (M + H+, 100); HRMS calcd for C38H38N7O4
(M + H+) 656.2985, found 656.2977. Anal. (C38H37N7O4‚
0.33EtOAc) C, H, N.
[4R-(4r,5r,6â,7â)]-Hexa h yd r o-5,6-d ih yd r oxy-1-(1H-in -
d a zol-5-ylm eth yl)-4,7-bis(p h en ylm eth yl)-3-[[3-(1H-1,2,4-
t r ia zol-1-yla ce t yl)p h e n yl]m e t h yl]-2H -1,3-d ia ze p in -2-
on e (48). The procedure detailed for 45 was used except using
1,2,4-triazole to give 48: mp 142-145 °C; 1H NMR (CDCl3/
CD3OD) δ 8.21 (s, 1 H), 7.99 (s, 1 H), 7.93 (s, 1 H), 7.85 (d, J
) 7 Hz, 1 H), 7.76 (s, 1 H), 7.54-7.02 (m, 13 H), 5.65 (s, 2 H),
4.92 (d, J ) 14 Hz, 1 H), 4.80 (d, J ) 14 Hz, 1 H), 3.69-3.26
(m, 4 H), 3.11-2.79 (m, 6 H); ESIMS m/ z 328 (M + 2H+2, 100);
HRMS calcd for C38H38N7O4 (M + H+) 656.2985, found
656.2975. Anal. (C38H37N7O4‚0.5H2O) C, H, N.
[4R-(4r,5r,6â,7â)]-1-[[3-[(1H-Ben zim id a zol-2-ylm eth yl)-
a m in o]p h en yl]m et h yl]h exa h yd r o-5,6-d ih yd r oxy-3-(1H -
in d a zol-5-ylm et h yl)-4,7-b is(p h en ylm et h yl)-2H -1,3-d ia z-
epin -2-on e (49). The urea 56 was alkylated with 3-nitrobenzyl
bromide in THF using 1 M KO-t-Bu/THF, and the nitro group
was hydrogenated (10% Pd/C, THF, 40 psi). The resulting
aniline (0.3 g, 0.44 mmol) was dissolved in MeCN, treated with
2-(chloromethyl)benzimidazole (0.12 g, 0.72 mmol) and N-
diisopropylethylamine (0.08 mL, 0.44 mmol), and stirred at
room temperature for 2 days. The solution was concentrated
under vacuum and the residue extracted into EtOAc. The
organic layer was washed with saturated aqueous NaHCO3
and brine, dried, filtered, and concentrated in vacuo. The
residue was chromatographed (MPLC silica gel, 60:35:5 EtOAc:
hexane:MeOH) to give 0.04 g of the corresponding N-alkyla-
niline. This was dissolved in MeOH (10 mL) and HCl (5 mL)
and heated at reflux for 2 h. The solution was concentrated
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