Cyclic HIV protease inhibitors: Design and synthesis of orally bioavailable, pyrazole P2/P2' cyclic ureas with improved potency

Article abstract of DOI:10.1021/jm9704199

Highly potent HIV-1 protease (HIVPR) inhibitors have been designed and synthesized by introducing bidentate hydrogen-bonding oxime and pyrazole groups at the meta-position of the phenyl ring on the P2/P2' substituents of cyclic ureas. Nonsymmetrical cyclic ureas incorporating 3(1H)-pyrazolylbenzyl as P2 and hydrophilic functionalities as P2' show potent protease inhibition and antiviral activities against HIV and have good oral bioavailabilities. The X-ray structure of HIVPR-10A complex confirms that the two pyrazole rings of 10A form bidentate hydrogen bonds with the side-chain oxygen (C=O) and backbone nitrogen (N-H) of Asp30/30' of HIVPR.

Full text of DOI:10.1021/jm9704199

J . Med. Chem. 1998, 41, 2019-2028
2019
Cyclic HIV P r otea se In h ibitor s: Design a n d Syn th esis of Or a lly Bioa va ila ble,
P yr a zole P 2/P 2′ Cyclic Ur ea s w ith Im p r oved P oten cy
Qi Han,* Chong-Hwan Chang, Renhua Li, Yu Ru, Prabhakar K. J adhav, and Patrick Y. S. Lam*
Chemical and Physical Sciences, The DuPont Merck Pharmaceutical Company, Experimental Station, P.O. Box 80500,
Wilmington, Delaware 19880-0500
Received J une 26, 1997
Highly potent HIV-1 protease (HIVPR) inhibitors have been designed and synthesized by
introducing bidentate hydrogen-bonding oxime and pyrazole groups at the meta-position of
the phenyl ring on the P2/P2′ substituents of cyclic ureas. Nonsymmetrical cyclic ureas
incorporating 3(1H)-pyrazolylbenzyl as P2 and hydrophilic functionalities as P2′ show potent
protease inhibition and antiviral activities against HIV and have good oral bioavailabilities.
The X-ray structure of HIVPR‚10A complex confirms that the two pyrazole rings of 10A form
bidentate hydrogen bonds with the side-chain oxygen (CdO) and backbone nitrogen (N-H) of
Asp30/30′ of HIVPR.
In tr od u ction
The RNA genome of the human immunodeficiency
virus (HIV), the causative agent of acquired immuno-
deficiency syndrome (AIDS), encodes an essential as-
partic protease (PR)1 that processes the viral gag and
gag-pol polyproteins into structural and functional
proteins. Inhibition of HIVPR in vitro results in the
production of progeny virions which are immature and
noninfectious.2 In clinical settings, four HIVPR inhibi-
tors, recently approved by the FDA for AIDS therapy
in combination with reverse transcriptase inhibitors,
have been shown to reduce the viral load and increase
the number of CD4+ lymphocytes in HIV-infected
F igu r e 1. Structures of first clinical candidate DMP323 and
second clinical candidate DMP450
individuals.3 In addition, the large abundance of struc-
tural information on HIVPR has made the enzyme an
attractive target for computer-aided drug design strate-
gies.4 Consequently, HIVPR inhibitors have become a
prime focus for the development of HIV therapeutics.5
However, the daunting ability of the virus to rapidly
generate resistant mutants3e-f,6 suggests that there is
an ongoing need for new HIVPR inhibitors with superior
pharmacokinetic and efficacy profiles.
ketones, oximes, pyrazoles, imidazoles, triazoles, and
tetrazoles substituted at the meta-position of the phenyl
ring on P2/P2′. These compounds have improved po-
tency and oral bioavailability.
Resu lts a n d Discu ssion
Syn th esis. Synthesis of cyclic ureas has been re-
ported recently.9 The synthesis of aldehyde, ketone, and
oxime derivatives of the cyclic ureas is illustrated in
Scheme 1. Alkylation of the parent cyclic urea 2 with
m-cyanobenzyl bromide (3A) and m-iodobenzyl bromide
(3B) in the presence of NaH in DMF gave 4A,B,
respectively. Reduction of 4A with DIBAL-H (diisobu-
tylaluminum hydride), followed by deprotection of the
methoxyethoxymethyl (MEM) groups with HCl, pro-
vided aldehyde 5A. Treatment of 4A with Grignard
reagents gave ketone derivatives 5B-D after hydrolysis
and deprotection of the MEM groups. Metalation of 4B
with t-BuLi followed by quenching of the organolithium
with N,N-dimethyltrifluoroacetamide and then depro-
tection of the MEM groups provided 5E. Metalation of
4A with t-BuLi followed by hydrolysis and deprotection
of the MEM groups provided 5F . Reactions of 5A-E
with excess hydroxylamine in refluxing pyridine af-
forded the corresponding aldoxime and ketoximes 6A-E
in high yields.
We have recently reported the rational design and
discovery of a novel class of orally bioavailable, non-
peptidal cyclic ureas as potent HIVPR inhibitors.7 The
design strategy incorporates the unique structural
water, commonly found in the X-ray complexes of linear
peptidal mimetic inhibitors and HIVPR, in a preorga-
nized cyclic urea scaffold. Structure-based optimization
rapidly led to the first clinical candidate, DMP3237
(Figure 1). However, the clinical trial was terminated
due to highly variable oral bioavailability as a result of
low aqueous solubility (6 µg/mL) and metabolic instabil-
ity of the benzylic hydroxymethylene groups in DMP323.
The second clinical candidate, DMP4508 (Figure 1),
which has excellent water solubility (>130 mg/mL),
exhibited high oral bioavailability in humans with a
Cmax of 6.5 µM when dosed at 750 mg as a neat powder.
In our continuing search for the second generation of
cyclic inhibitors using structure-based design tech-
niques, we have synthesized cyclic ureas containing
S0022-2623(97)00419-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/13/1998

2020 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Han et al.
Sch em e 1. Synthetic Sequence for Making Ketones and Oximesa
a
Reagents: (a) 6 equiv of NaH, DMF; (b) for 5A, DIBAL-H; for 5E, n-BuLi, N,N-dimethyltrifluoroacetamide; for 5F , t-BuLi; for the
rest, RMgBr; (c) 4 M HCl in dioxane and MeOH; (d) NH2OH, pyridine.
Sch em e 2. Synthetic Sequence for Making Pyrazoles
methylsilyl)ethoxy]methyl]pyrazolyl-5-boronic acid (9A),
1-[(dimethylamino)sulfonyl]pyrazolyl-4-trimethyltin (9B),
1-[(dimethylamino)sulfonyl]imidazolyl-2-zinc chloride
(9C), and 1-[[(2-(trimethylsilyl)ethoxy]methyl]imidazolyl-
5-boronic acid (9D), followed by treatment with HCl.
The structure of 10A was further confirmed by X-ray
diffraction as illustrated in Figure 2.
and Imidazolesa
The preparation of cyclic urea derivatives with m-
triazolylbenzyl and m-tetrazolylbenzyl as P2/P2′ sub-
stituents is described in Schemes 3 and 4. Aldol
condensation of MEM-protected 5A with nitromethane
afforded intermediate 7. Treatment of 7 with NaN3 in
DMSO, followed by deprotection of the MEM groups,
provided 1,2,3-triazole derivative 10E. Oxidation of 4A
with H2O2 in basic DMSO gave an amide, which reacted
with N,N-dimethylformamide diethyl acetal to form 8.
Cyclization of 8 with hydrazine followed by deprotection
of MEM groups provided 1,2,4-triazole derivative 10F .
5-Tetrazolylbenzyl-substituted derivative 10G was pre-
pared by the reaction of 4A with NaN3 and then
treatment with HCl.
a
Reagents: (a) 9, Pd(PPh3)4; (b) 4 M HCl in dioxane and MeOH.
The synthesis of cyclic urea derivatives with m-
pyrazolylbenzyl and m-imidazolylbenzyl as P2/P2′ sub-
stituents is described in Scheme 2. The pyrazole and
imidazole derivatives 10A-D were obtained respec-
tively from coupling reactions of 4B with 1-[[(2-(tri-
Sch em e 3. Synthetic Sequence for Making Triazolesa
a
Reagents: (a) DIBAL-H; (b) CH3NO2, NH4OAc, HOAc; (c) NaN3, DMSO; (d) 4 M HCl in dioxane and MeOH; (e) H2O2, K2CO3; (f)
Me2NCH(OEt)2; (g) NH2NH2, HOAc.

Cyclic HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2021
Ta ble 1. SAR of Ketones and Oximes
*0.51 µM in gelucire.
bonding network of the inhibitors with the protease at
the S2/S2′ subsites. Molecular modeling suggests that
the S2/S2′ subsites are essentially lipophilic except
toward the edge of the pockets near the entrance to the
active site where there are numerous hydrogen-bonding
donors and acceptors comprised of the side chains and
backbone amides of Asp29/29′, Asp30/30′, and Gly48/
48′. In addition, there is sufficient space available
around the meta-positions of the phenyl ring on P2/P2′
benzyl for attachment of functional groups.
Our initial objective was to introduce ketone groups
at the meta-positions of the phenyl ring on P2/P2′
substituents since oxygen of the carbonyl group of
ketone can be a good hydrogen bond acceptor. In
addition, ketones can be readily elaborated into other
derivatives. All ketone derivatives exhibit very potent
activities against HIVPR (Table 1). The methyl ketone
5B and trifluoromethyl ketone 5E are more potent than
DMP450. The affinity of the ketone derivatives is
decreased as the size of the R-group increases from
methyl (5B) to ethyl (5C), n-propyl (5D), and tert-butyl
(5F ). Interestingly, although a trifluoromethyl group
is bulkier than a methyl group, 5E has a lower Ki than
5B. That is probably due to the existence of a hydrated
form of trifluoromethyl ketone, which is capable of
forming more hydrogen bonds. To further increase the
number of potential hydrogen bond donors/acceptors, we
introduced oxime functional groups. The oximes 6A-D
have lower Ki’s than DMP450 (Table 1). Methyl ke-
toxime 6B has the lowest Ki (0.018 nM) and IC90 (2 nM).
The trifluoromethyl ketoxime 6E is a weak binder
probably because of steric reasons. The methyl ke-
toxime derivative 6B is stable in weak acid solutions
but decomposes under strong acidic conditions. Al-
though the chemical instability of 6B may limit its
usefulness as a drug candidate, the extremely potent
Ki and IC90 provide a very important lead for further
design.
F igu r e 2. Crystal structure of pyrazole 10A.
Sch em e 4. Synthetic Sequence for Making Tetrazolea
a
Reagents: (a) NH4Cl, NaN3, DMF; (b) 4 M HCl in dioxane
and MeOH.
The nonsymmetrical cyclic ureas 12A-G were pre-
pared as shown in Scheme 5. Monoalkylation of 2 with
3 equiv of KOH and 2 equiv of m-iodobenzyl bromide
(3B) in toluene in the presence of 10% PEG gave
monoalkylated intermediate. Suzuki coupling reaction
of the intermediate with boronic acid 9A in the presence
of palladium catalyst afforded 11. Deprotection of 11
with HCl provided mono-3(1H)-pyrazolylbenzyl alky-
lated cyclic urea 12A. Further alkylation of 11 with
substituted benzyl bromides in the presence of NaH in
DMF, followed by deprotection of MEM groups, formed
nonsymmetrical cyclic ureas 12B-G.
To understand the nature of the increased binding of
oxime analogues, we have obtained the low-resolution
X-ray structure10 of 6A/HIV-1 PR. Each oxime hydroxyl
group donates a hydrogen bond to the carboxylate of
Asp30/30′, identical to the amino group of DMP450. In
addition, each oxime nitrogen accepts a hydrogen bond
from the backbone amide N-H of Asp30/30′. The two
additional hydrogen bonds as part of the new bidentate
interactions provide 1 order of magnitude increase in
Str u ctu r e-Ba sed Design a n d Op tim iza tion of
Cyclic Ur ea s. To design more potent HIVPR inhibitors
than DMP450, we decided to increase the hydrogen-

2022 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Han et al.
Sch em e 5. Synthetic Sequence for Making Nonsymmetric Cyclic Ureasa
a
Reagents: (a) 3 equiv of KOH, toluene; (b) 9A, Pd(PPh3)4; (c) NaH, ArCH2Br, DMF; (d) 4 M HCl in dioxane and MeOH.
Ta ble 2. SAR of Heterocyclic Ring Compounds
F igu r e 3. Hydrogen-bonding interactions of pyrazole 10A
with HIV-1 PR based on X-ray.
of P2 being 6° and P2′ being 15°. The inhibitor molecule
binds symmetrically to the active site of the enzyme
with two symmetric portions being related to each other
by the pseudo-2-fold axis of symmetry that relates one
monomer of the protease to the other. Details of the
inhibitor binding model are shown in Figures 3 and 4.
*For po in rat: Cl is 5.3 L/kg/h, t1/2 is 0.2 h. For iv in dog: Cl is
1.2 L/kg/h, t1/2 is 1.7 h, Vss is 1.1 L/kg.
binding of the oximes 6A-D over DMP450. To utilize
this new bidentate hydrogen-bonding feature and sta-
bilize the oxime functional group, we replaced the
oximes with heterocycles which mimic the hydrogen
bond donor/acceptor arrays of the extremely potent
oxime. Table 2 shows a series of heterocycles capable
of donating and accepting hydrogen bonds. Pyrazole
(10A,B)-, imidazole (10C,D)-, and triazole (10E,F )-
substituted cyclic urea derivatives are all tight binders
of HIVPR except tetrazole (10G). The reason 10G is
not active is not clear. The tightest binder is 3-pyrazole
10A with a similar Ki as oximes 6A,B.
The three-dimensional structure of the complex of
HIV-1 PR and 10A with 2.0-Å diffraction data has been
determined. The overall conformation of the structure
is similar to the previously reported one for DMP3239
and DMP450.8 The urea oxygen atom interacts with
the backbone nitrogen atom of Ile50/50′ at the flap. The
diols in the seven-membered ring participate in an
extensive hydrogen-bonding network with the catalytic
Asp 25/25′ at the base of the pocket. Two benzyl groups
attached at the 4R,7R positions of the cyclic urea ring
occupy S1/S1′ pockets. The pyrazolylbenzyl groups
attached to the urea nitrogens are located within the
S2/S2′ pockets. The pyrazole ring forms bidentate
hydrogen bonds with the side-chain oxygen and back-
bone nitrogen of Asp30/30′. The bonding distances are
between 3.3 and 3.5 Å. The benzyl and pyrazole rings
are nearly coplanar with the angle between two rings
Unfortunately, all these heterocycle-substituted com-
pounds, despite the excellent chemical stability, have
low oral bioavailablity probably due to low aqueous
solubilities. For example, pyrazole 10A has an aqueous
solubility at pH 7.4 of less than 0.0001 mg/mL, com-
pared with DMP450 (bis-myslate salt) which is >130
mg/mL. Nonsymmetric cyclic ureas should have the
advantage of better solubility due to lower crystal-
packing energy. This can result in improvement of oral
bioavailability. We therefore decided to synthesize
nonsymmetric cyclic urea derivatives (Table 3). Since
3-pyrazole derivative 10A has the best Ki and IC90
among the heterocycles 10A-G, it was chosen for
nonsymmetric cyclic ureas. Three of the nonsymmetric
cyclic ureas (12D,F ,G) have similar low Ki values as the
symmetric 10A, and 12D has the lowest IC90 of 27 nM.
The nonsymmetric cyclic ureas in general have better
oral bioavailability than the symmetric cyclic ureas. The
dog oral bioavailability of 12D is 0.85 µM in Cmax at a
dose of 2.5 mg/kg. This is quite good considering the
low dose. Monopyrazole 12A shows a relatively good
Cmax of 0.78 µM in rats at 10 mg/kg po, probably due to
its relatively small size. In general, smaller size
compounds tend to show better pharmacokinetics.11

Cyclic HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2023
F igu r e 4. Stereoview of X-ray of the 10A and HIVPR complex. Residues 24-30 at the active site and 46-54 at the flap are
shown. The hydrogen bond is the yellow dotted line. Two of the eight possible hydrogen bonds between the hydroxyls of CU and
catalytic aspartates (Asp25/25′) are shown. The two pyrazole rings of 10A form bidentate hydrogen bonds with the side-chain
oxygen (CdO) and backbone nitrogen (N-H) of Asp30/30′ of HIVPR.
Ta ble 3. SAR of Nonsymmetric Cyclic Ureas
Exp er im en ta l Section
Biologica l Meth od s. Inhibition of HIV protease was
measured by assaying the cleavage of a fluorescent peptide
substrate using HPLC.12 The antiviral 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.13 Uninfected cells were incubated in microtiter
plate wells with serial dilutions of test compound in cell culture
medium for 30 min; then virus was added. After 3 days of
culture at 37 °C and 5% CO2, infected cell cultures were lysed
and the levels of HIV RNA determined using a microtiter
plate-based hybridization assay. 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 the IC90. The cytotoxity of the com-
pounds (TC50) as determined by a 50% reduction in the number
of viable cells as determined by the metabolism of a tetrazo-
lium dye was at least 20-fold greater than the antiviral RNA
IC90
.
Oral bioavailability was measured as previously
described.7-9
Ch em ica l Meth od s. All procedures were carried out under
inert gas in oven-dried glassware unless otherwise indicated.
Proton and carbon NMR spectra were obtained on VXR or
Unity 300- or 400-MHz instruments (Varian Instruments, Palo
Alto) with TMS as an internal reference standard. Mass
spectra were measured with a HP5988A mass spectrometer
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. Melting points were determined on a Mettler SP61
apparatus and are uncorrected. Separation of isomers was
performed using supercritical fluid chromatography with a
Chiracel OD (Diacel Chemical Ind. Ltd.) and 20% methanol-
modified CO2 mobile phase. Solvents and reagents were
obtained from commercial vendors in the appropriate grade
and used without further purification unless otherwise indi-
cated. All compounds were determined to be homogeneous by
TLC, elemental analysis, and/or HPLC. Elemental analyses
were performed by Quantitative Technologies, Inc., Bound
Brook, NJ . Purity values were obtained by reverse-phase
analytic HPLC using a J asco system equipped with a UV
detector. Combustion analyses are within (0.4% of the
calculated value. Compounds for elemental analysis are
further purified by HPLC with a reverse-phase preparative
*@2.5 mg/kg in dog.
Con clu sion
In conclusion, with the help of X-ray structures, we
have designed and synthesized more potent HIVPR
inhibitors relative to our first-generation candidates
DMP323 and DMP450 by introducing bidentate hydro-
gen-bonding groups on the P2/P2′ benzyl of cyclic urea.
The best inhibitor combining potent antiviral activity
and metabolic stability is 10A (Ki ) 0.027 nM; IC90
)
20 nM). Nonsymmetric cyclic urea 12D, hybrid of 10A
and DMP450, also combines good potency and stability.
The IC90 of 12D is 5-fold better than that of DMP450
(IC90 ) 130 nM). Importantly, 12D has good dog oral
bioavailability with a plasma Cmax of 0.85 µM at a low
dose of 2.5 mg/kg. These inhibitors have potential for
further development in the search of a second-genera-
tion drug candidate. Further work awaits to be done
in this m-heterocyclic benzyl P2/P2′ CU area.

2024 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Han et al.
column by using gradient solvents (H2O-CH3CN-0.05% TFA)
2H-1,3-d ia zep in -2-on e (6B). A solution of 5B (84 mg, 0.142
mmol) and hydroxylamine hydrochloride (59.4 mg, 0.854
mmol) in pyridine and ethanol (6 mL, 1:1) was refluxed for 16
h. Evaporation of all solvents under full vacuum gave a
residue, which was purified by TLC with ethyl acetate,
methylene chloride, and methanol (50:50:2) to give 6B (71 mg,
83%) as a solid: mp 200-202 °C; DCIMS m/z 621 (M + H)+;
HRMS (M + H)+ 621.3070 (calcd 621.3077); 1H NMR (CD3-
OD) δ 7.47 (d, J ) 7.8 Hz, 2H), 7.39 (s, 2H), 7.27-7.17 (m,
8H), 7.09 (d, J ) 7.6 Hz, 2H), 7.06 (d, J ) 6.8 Hz, 4H), 4.74 (d,
J ) 13.9 Hz, 2H), 3.64-3.62 (m, 4H), 3.09-2.89 (m, 6H), 2.17
(s, 6H); 13C NMR (CD3OD) δ 163.94, 155.43, 141.23, 139.46,
138.97, 130.77, 130.65, 129.69, 129.37, 128.10, 127.47, 126.32,
72.02, 67.16, 57.08, 33.62, 11.96. Anal. (C37H40N4O5‚H2O) C,
H, N.
as a mobile phase.
Rep r esen ta tive P r oced u r es for Keton e Der iva tives:
(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-b is [(3-
a cet ylp h en yl)m et h yl]-4,7-b is(p h en ylm et h yl)-2H -1,3-d i-
a zep in -2-on e (5B). To a solution of 4A (750 mg, 1.02 mmol)
in THF (20 mL) was added methylmagnesium bromide (3 M
in Et2O, 3 mL), and the resulting mixture was allowed to reflux
for 2 h. After all solvents were removed on a rotary evapora-
tor, the resulting residue was dissolved in MeOH (15 mL),
followed by carefully treating with 4 M HCl in dioxane (15
mL) and stirring for 16 h. The reaction mixture was concen-
trated and then partitioned in ethyl acetate and water (200
mL, 4:1). The organic layer was washed with 10% NaHCO3
and brine, dried over MgSO4, filtered, and concentrated. The
resulting crude residue was purified by thin-layer chromatog-
raphy (TLC) with 40% EtOAc in CH2Cl2 to give 5B (600 mg,
90%) as a white solid: mp 158-159 °C; DCIMS m/z 608 (M +
1-N-[[2-(Tr im eth ylsilyl)eth oxy]m eth yl]p yr a zolyl-5-bo-
r on ic Acid (9A). To a solution of 1-N-SEM-protected pyrazole
(1.98 g, 10 mmol) in THF (40 mL) at -78 °C was added
dropwise n-BuLi (1.6 M, 7.5 mL, 12 mmol), and the resulting
solution was stirred for an additional 30 min. After triisopro-
pyl borate (9.4 g, 50 mmol) was added, the mixture was allowed
to warm to room temperature over 2 h. The reaction mixture
was acidified to pH 6 with 2 N HCl, extracted with ethyl
acetate, washed with water and brine, and dried over MgSO4.
After filtration, concentration, and purification by column
chromatography with gradient solvents (CH2Cl2-EtOAc-
MeOH), 9A was obtained in almost quantitative yield: 1H
NMR (CD3OD) δ 7.57 (s, 1H), 6.80 (s, 1H), 5.70 (s, 2H), 3.57
1
NH4)+; HRMS (M + H)+ 591.2849 (calcd 591.2859); H NMR
(CDCl3) δ 7.82 (dd, J ) 6.6 Hz, J ) 3.8 Hz, 2H), 7.78 (s, 2H),
7.72 (bs, 4H), 7.43-7.23 (m, 6H), 7.06 (d, J ) 6.6 Hz, 4H),
4.87 (d, J ) 14.3 Hz, 2H), 3.70 (s, 2H), 3.57 (d, J ) 11.0 Hz,
2H), 3.18 (d, J ) 14.3 Hz, 2H), 3.09 (dd, J ) 13.2 Hz, J ) 2.1
Hz, 2H), 2.91 (dd, J ) 11.4 Hz, J ) 1.8 Hz, 2H), 2.58 (b, 2H),
2.53 (s, 6H); 13C NMR (CDCl3) δ 198.03, 161.83, 139.40, 138.78,
137.12, 133.87, 129.29, 129.04, 128.74, 128.52, 127.36, 126.46,
71.25, 65.32, 55.82, 30.73, 26.51. Anal. (C37H38N2O5‚0.5H2O)
C, H, N.
(t, J ) 7.8.0 Hz, 2H), 0.89 (t, J ) 8.0 Hz, 2H), 0.00 (s, 9H); 13
C
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis[[3-(tr i-
flu or oa cetyl)p h en yl]m eth yl]-4,7-bis(p h en ylm eth yl)-2H-
1,3-d ia zep in -2-on e (5E). To a solution of 4B (980 mg, 1.07
mmol) in THF (10 mL) at -78 °C was added t-BuLi (2.64 mL
of 1.7 M in hexane, 4.5 mmol), and the resulting solution was
stirred for an additional 30 min. Then N,N-dimethyltrifluo-
roacetamide (560 mg, 4 mmol) was added, and the resulting
mixture was warmed to room temperature over 2.5 h. The
mixture was diluted with ether and acidified to pH 6 with 2
N HCl. The ether layer was washed with water and brine,
dried over MgSO4, and concentrated. The residue was purified
by column chromatography with gradient solvents (0-20%
ethyl acetate in CH2Cl2) to give an oil (350 mg). The oil was
dissolved in CHCl3 (5 mL) and treated with 4 M HCl in dioxane
(5 mL) for 16 h. General workup and purification by TLC with
40% EtOAc in CH2Cl2 gave 5E (300 mg, 40.2% for two steps):
CIMS m/z 699.4 (M + H)+; HRMS (M + H)+ 699.2286 (calcd
699.2294); 1H NMR (CD3COCD3) δ 7.97 (bs, 4H), 7.73 (s, 2H),
7.70-7.59 (m, 2H), 7.30-7.21 (m, 6H), 7.98-6.96 (m, 4H), 4.75
(d, J ) 13.9 Hz, 2H), 4.41 (s, 2H), 3.72-3.63 (m, 4H), 3.32 (d,
J ) 14.3 Hz, 2H), 3.18-3.13 (m, 2H), 2.95-2.79 (m, 2H); 19F
NMR (CD3COCD3) δ -72.54; 13C NMR (CD3COCD3) δ 180.83
(q, J ) 34.3 Hz), 162.39, 141.27, 141.06, 137.90, 131.60, 130.43,
130.35, 130.23, 129.73, 129.16, 127.05, 117.62 (q, J ) 291.4
Hz), 71.83, 67.40, 56.55, 33.59.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis[(3-p iv-
a loylp h en yl)m et h yl]-4,7-b is(p h en ylm et h yl)-2H -1,3-d i-
a zep in -2-on e (5F ). To a solution of 4A (366 mg, 0.5 mmol)
in THF (15 mL) at -78 °C was added dropwise t-BuLi (2.59
mL of 1.7 M in hexane, 4.4 mmol), and the resulting solution
was allowed to warm to room temperature. The mixture was
diluted with ether, washed with saturated NH4Cl and water,
and dried over MgSO4. A concentrated residue was depro-
tected by general de-MEM procedure and was then purified
by TLC with 10% EtOAc in CH2Cl2 to give 5F (287 mg, 85%):
CIMS m/z 675.5 (M + H)+; HRMS (M + H)+ 675.3805 (calcd
675.3798); 1H NMR (CDCl3) δ 7.56-7.54 (m, 2H), 7.05 (s, 2H),
7.43-7.25 (m, 12H), 7.08-7.06 (m, 2H), 4.88 (d, J ) 14.3 Hz,
2H), 3.64 (s, 2H), 3.53 (d, J ) 11.0, Hz, 2H), 3.09-2.87 (m,
6H), 2.58 (b, 2H), 1.29 (s, 18H); 13C NMR (CDCl3) δ 209.24,
161.87, 139.35, 139.05, 138.23, 131.66, 129.43, 128.70, 128.36,
126.96, 126.62, 71.58, 64.76, 55.80, 44.21, 32.89, 27.94. Anal.
(C43H50N2O5‚0.29TFA‚0.4H2O) C, H, N, F.
NMR (CD3OD) δ 138.54, 115.65, 78.98, 65.98, 17.31, -2.30.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis[[3-(1H-
p yr a zol-3-yl)p h en yl]m et h yl]-4,7-bis(p h en ylm et h yl)-2H-
1,3-d ia zep in -2-on e (10A). To a solution of 4B (932 mg, 1
mmol) in THF (5 mL) were added 9A (968 mg, 4 mmol), Pd-
(PPh3)4 (57.8 mg, 0.05 mmol), and Na2CO3 (1.7 g in 4 mL of
H2O), and the resultant mixture was allowed to reflux under
nitrogen over 48 h. General workup gave a residue, which
was purified by column chromatography with gradient solvents
(CH2Cl2-EtOAc) to give a MEM-protected intermediate.
A
solution of the intermediate in MeOH (15 mL) was treated with
4 M HCl in dioxane (15 mL) and stirred for 16 h. General
workup followed by purification by thin-layer chromatography
with 20% EtOH in hexane gave 10A (560 mg, 87.8%) as a
solid: CIMS m/z 639 (M + H)+; HRMS (M + H)+ 639.3081
(calcd 639.3083); 1H NMR (CD3OD) δ 8.32 (d, J ) 1.6 Hz, 2H),
7.74 (d, J ) 6.9 Hz, 2H), 7.66 (s, 2H), 7.49 (d, J ) 6.9 Hz, 4H),
7.15-7.09 (m, 8H), 6.89-6.87 (m, 4H), 4.68 (d, J ) 13.9 Hz,
2H), 3.87 (b, 2H), 3.80 (d, J ) 11.3 Hz, 2H), 3.33 (dd, J ) 10.2
Hz, J ) 1.1 Hz, 2H), 3.06 (d, J ) 12.8 Hz, 2H), 2.78-2.69 (m,
2H); 13C NMR (CD3OD) δ 162.82, 140.19, 139.01, 129.67,
129.22, 128.96, 128.59, 127.06, 126.49, 125.03, 102.41, 71.02,
66.69, 56.37, 32.65. Anal. (C39H38N6O3‚2.0TFA‚0.12HCl‚
1.0H2O) C, H, N, F, Cl. The single crystal of 10A was obtained
from recrystallization in CD3OD.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis[[3-(1H-
p r a zol-4-yl)p h en yl]m et h yl]-4,7-b is(p h en ylm et h yl)-2H -
1,3-d ia zep in -2-on e (10B). A solution of 4-iodopyrazole (1.54
g, 8 mmol) in THF (20 mL) was treated with NaH (0.43 g,
10.6 mmol) at room temperature, followed by slowly quenching
with dimethylsulfamoyl chloride (1.38 g, 9.6 mmol). General
workup provided N-[(dimethylamino)sulfonyl]pyrazole (2.4 g,
92%). The N-protected intermediate (1.5 g, 5 mmol) in THF
(25 mL) was reacted with hexamethylditin (1.8 g, 5.5 mmol)
in the presence of Pd(Ph3P)4 (0.115 g, 0.1 mmol) under nitrogen
at 78 °C for 16 h and then cooled to room temperature. To
the solution (9B) were added 4B (0.932 g, 1.0 mmol) and
another portion of Pd(Ph3P)4 (0.18 g, 0.16 mmol) under
nitrogen, and the resulting mixture was stirred under nitrogen
at 80 °C for 18 h. General workup followed by deprotection
by general de-MEM procedure gave a residue, which was
purified by reverse-phase thin-layer chromatography with 85%
MeOH in water to give 10B (516 mg, 81%) as a solid: DCIMS
m/z 639 (M + H)+; HRMS (M + H)+ 639.3100 (calcd 639.3083);
1H NMR (CD3OD) δ 7.77-7.12 (m, 4H), 7.38-6.95 (m, 18H),
Rep r esen ta tive P r oced u r es for Oxim e Der iva tives:
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis[[3-[1-(h y-
dr oxyim in o)eth yl]ph en yl]m eth yl]-4,7-bis(ph en ylm eth yl)-

Cyclic HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2025
4.72 (d, J ) 14.3 Hz, 2H), 3.59-3.55 (m, 4H), 3.02-2.88 (m,
6H); 13C NMR (CD3OD) δ 163.36, 140.63, 139.40, 133.75,
130.19, 129.83, 129.18, 127.87, 127.38, 127.12, 125.47, 122.79,
71.64, 66.46, 56.76, 33.23. Anal. (C39H38N6O3‚1.2TFA‚0.16HCl‚
2.0H2O) C, H, N, F, Cl.
in toluene (150 mL) at -78 °C was added dropwise DIBAL-H
(1.5 M in toluene, 27 mL, 40.9 mmol), and the mixture stirred
for an additional 2.5 h. After slowly warming to room
temperature and stirring for 16 h, the mixture was cooled to
-20 °C, quenched with methanol, and then poured into 5%
HCl (50 mL) and ether (200 mL). The organic layer was
separated, washed with saturated sodium bicarbonate (100
mL), water (3 × 100 mL), and brine (80 mL), dried over MgSO4,
filtered, and concentrated. Flash chromatography (50% ethyl
acetate in hexane) purification of the residue gave an aldehyde
intermediate (6.3 g, 63%). To a solution of the aldehyde (2.0
g, 2.7 mmol) in acetic acid (15 mL) was added ammonium
acetate (0.17 g, 2.16 mmol) followed by addition of ni-
tromethane (0.42 g, 7.04 mmol). After the mixture was
refluxed for 3 h, another portion of nitromethane (0.33 g, 5.4
mmol) was added and the resulting mixture was refluxed for
16 h. The reaction mixture was cooled to room temperature
and diluted with ethyl acetate (30 mL) and water (20 mL).
The organic phase was separated, washed with saturated
sodium bicarbonate (2 × 15 mL), water (15 mL), and brine
(15 mL), dried over MgSO4, filtered, and concentrated. Flash
chromatographic (30% ethyl acetate in hexane) purification
gave nitrostyrene 7 (0.6 g, 30%). To a solution of 7 (0.21 g,
0.25 mmol) in DMSO (5 mL) was added NaN3 (0.10 g, 6 mmol),
and the mixture stirred at room temperature for 16 h and then
was poured into water (20 mL). A yellow precipitate was
collected, washed with water, and air-dried to give a residue
(0.2 g), which was treated with 4 M HCl (in dioxane, 1.5 mL)
in methanol (10 mL) at room temperature for 16 h. After
solvents and reagent were removed under reduced pressure,
a residue was purified by flash column chromatograph (10%
methanol in chloroform) to give 10E (0.12 g, 78%) as yellow
crystals: mp 224-226 °C; HRMS (M + H)+ 641.2999 (calcd
641.2989); 1H NMR (CD3OD) δ 8.06 (bs, 2H), 7.90 (s, 2H), 7.74
(d, J ) 7.7 Hz, 2H), 7.69 (s, 2H), 7.39-7.43 (m, 2H), 7.21-
7.27 (m, 10H), 7.07 (d, J ) 6.2 Hz, 2H), 4.78 (d, J ) 14.3 Hz,
2H), 3.69-3.61 (m, 4H), 3.10-2.85 (m, 6H). Anal. (C37H36N8O3)
C, H, N.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis[[3-(1H-
im id a zol-2-yl)p h en yl]m eth yl]-4,7-bis(p h en ylm eth yl)-2H-
1,3-d ia zep in -2-on e (10C). N-(Dimethylsulfamoyl)imidazolyl-
2-zinc chloride (9C) was made in situ by lithiation of
N-(dimethylsulfamoyl)imidazole (0.97 g, 5.5 mmol) in THF (20
mL) with t-BuLi (1.7 M, 6.7 mL) at -78 °C for 20 min, followed
by quenching with a solution of zinc chloride (1.87 g, 13.75
mmol) in THF (15 mL) at the same temperature and then
warming to room temperature over 1 h. A coupling reaction
of the crude 9C and 4B (0.932 g, 1.0 mmol) in the presence of
Pd(Ph3P)4 (0.12 g, 0.1 mmol) was carried out under nitrogen
and refluxed for 16 h. After being cooled to room temperature,
the reaction mixture was poured into EtOAc-H2O (250 mL,
1:1). The organic layer was dried over MgSO4 and concen-
trated to give a residue. The residue was dissolved in MeOH
and treated with 4 M HCl in dioxane under reflux for 2 h.
The resulting mixture was worked up and purified on reverse-
phase TLC plate with 80% MeOH in water to give 10C (370
mg, 50%) as a solid: mp 178-180 °C; CIMS m/z 639.4 (M +
H)+; HRMS (M+ H)+ 639.3069 (calcd 639.3084); 1H NMR (CD3-
OD) δ 7.75-7.70 (m, 4H), 7.42-7.33 (m, 2H), 7.28-7.12 (m,
12H), 7.00-6.94 (m, 4H), 4.73 (d, J ) 14.3 Hz, 2H), 3.71 (bs,
4H), 3.14 (d, J ) 13.9 Hz, 2H), 3.04-2.99 (m, 2H), 2.85-2.77
(m, 2H); 13C NMR (CD3OD) δ 162.00, 146.27, 139.58, 138.87,
130.23, 129.36, 129.11, 128.80, 128.00, 126.20, 125.89, 124.36,
122.64, 70.39, 67.14, 56.29, 32.22. Anal. (C39H38N6O3‚
2.1TFA‚0.23HCl‚2.5H2O) C, H, N, F, Cl.
1-[[2-(Tr im et h ylsilyl)et h oxy]m et h yl]im id a zolyl-5-b o-
r on ic Acid (9D). To a solution of N-[[(trimethylsilyl)ethoxy]-
methyl](SEM)-imidazole (2 g, 10 mmol) in THF (20 mL) was
added t-BuLi (1.7 M, 6.9 mL) at -78 °C, and the mixture
stirred for an additional 20 min. After TMSCl (1.25 g) was
added, the mixture was allowed to warm to 0 °C over 2 h and
then cooled to -78 °C again. The mixture was treated with
t-BuLi (1.7 M, 6.9 mL) at the same temperature over 30 min,
followed by quenching with B(OMe)3 (10.4 g, 100 mmol). After
the resulting mixture was warmed to room temperature and
stirred for 16 h, it was poured into EtOAc-H2O (250 mL, 4:1),
and the organic layer was acidified to pH 7 with 1 N HCl, dried
over MgSO4, and purified by column chromatography with
gradient solvents (CH2Cl2-MeOH) to give pure 9D (2.3 g, 95%)
as a solid: 1H NMR (CD3OD) δ 7.63 (d, J ) 0.74 Hz, 1H), 6.87
(d, J ) 1.1 Hz, 1H), 5.47 (s, 2H), 3.55 (t, J ) 8.4 Hz, 2H), 0.93
(t, J ) 8.4 Hz, 2H), 0.00 (s, 9H); 13C NMR (CD3OD) δ 138.97,
134.54, 77.89, 68.00, 20.19, 0.00.
(4R,5S,6S,7R)-Hexah ydr o-5,6-dih ydr oxy-1,3-bis[[3-(1,2,4-
tr ia zolyl)p h en yl]m eth yl]-4,7-bis(p h en ylm eth yl)-2H-1,3-
d ia zep in -2-on e (10F ). To a slurry solution of 4A (3.0 g, 4.09
mmol) and K2CO3 (4.5 g, 32.7 mmol) in DMSO (10 mL) at 0
°C was added dropwise H2O2 (30%, 18 mL), and the mixture
stirred for 0.5 h. After slowly warming to room temperature
and stirring for an additional 2 h, the reaction mixture was
poured into water (80 mL) and extracted with ethyl acetate.
The organic phase was separated, washed with water (3 × 40
mL) and brine (2 × 30 mL), dried over MgSO4, filtered, and
concentrated. A residue was purified by flash chromatography
(40% ethyl acetate in hexane) to give an amide intermediate
(1.6 g, 51%). A mixture of the amide (300 mg, 0.39 mmol) and
N,N-dimethylformaldehyde diethyl acetal (500 mg, 3.4 mmol)
was stirred at 100 °C for 2 h, followed by removing excess of
N,N-dimethylformaldehyde diethyl acetal under reduced pres-
sure, to give compound 8 (320 mg, 93%). A solution of 8 (320
mg, 0.36 mmol) in acetic acid (3 mL) was treated with
anhydrous hydrazine (70 mg, 2 mmol) at 90 °C for 2.5 h. After
excess hydrazine and acetic acid were removed under reduced
pressure, a residue was partitioned between water (10 mL)
and ethyl acetate (10 mL). The organic phase was separated,
washed with water (2 × 5 mL) and saturated sodium bicar-
bonate (5 mL), dried over MgSO4, and concentrated to leave
the MEM-protected intermediate. The intermediate was
deprotected by general de-MEM procedure and workup, fol-
lowed by flash chromatographic (15% methanol in chloroform)
purification to give 10F (100 mg, 64%) as a pale-yellow solid:
mp 190-192 °C; HRMS (M + H)+ 641.2990 (calcd 641.2989);
1H NMR (CD3OD) δ 9.58 (s, 2H), 8.00 (s, 2H), 7.98 (d, J ) 6.6
Mz, 2H), 7.70-7.60 (m, 4H), 7.30-7.20 (m, 8H), 7.06-7.01 (m,
4H), 4.75 (d, J ) 14.3, 2H), 3.90 (s, 2H), 3.84 (d, J ) 10.6,
2H), 3.44-3.40 (m, 4H), 3.18 (d, J ) 12.8, 2H), 2.98-2.88 (m,
2H). Anal. (C37H36N8O3) C, H, N.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-bis[[3-(1H-
im id a zol-4-yl)p h en yl]m eth yl]-4,7-bis(p h en ylm eth yl)-2H-
1,3-d ia zep in -2-on e (10D). A solution of 9D (1.3 g, 5.37
mmol), 4B (0.937 g, 1.01 mmol), Pd(Ph3P)4 (0.18 g, 0.16 mmol),
and K2CO3 (7.5 g) in THF (20 mL) and H2O (20 mL) was
degassed and then heated to reflux under nitrogen for 16 h.
The reaction mixture was cooled to room temperature and
partitioned in EtOAc-H2O (250 mL, 4:1). The organic layer
was dried over MgSO4 and concentrated to give a residue,
which was treated with 4 M HCl in dioxane under reflux for
16 h. The mixture was concentrated, and the resulting residue
was purified on reverse-phase TLC plate with 80% MeOH in
water to give 10D (0.24 g, 37%) as a solid: mp 171-175 °C;
CIMS m/z 639.4 (M + H)+; HRMS (M + H)+ 639.3089 (calcd
1
639.3084); H NMR (CD3OD) δ 7.71 (bs, 2H), 7.61 (d, J ) 7.7
Hz, 2H), 7.52 (s, 2H), 7.35-7.19 (m, 10H), 7.10-7.08 (m, 6H),
4.78 (d, J ) 13.9 Hz, 2H), 3.71-3.65 (m, 4H), 3.32-3.00 (m,
4H), 2.96-2.87 (m, 2H); 13C NMR (CD3OD) δ 163.80, 141.26,
139.94, 137.20, 134.78, 130.67, 130.11, 129.52, 128.88, 127.40,
127.08, 125.22, 72.00, 67.72, 57.38, 33.60. Anal. (C39H38N6O3‚
2.2TFA‚0.13HCl‚3.0H2O) C, H, N, F, Cl.
(4R,5S,6S,7R)-Hexah ydr o-5,6-dih ydr oxy-1,3-bis[[3-(1,2,3-
tr ia zolyl)p h en yl]m eth yl]-4,7-bis(p h en ylm eth yl)-2H-1,3-
d ia zep in -2-on e (10E). To a solution of 4A (10.0 g, 13.6 mmol)
(4R,5S,6S,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3-b is[[3-(5-
tetr a zolyl)p h en yl]m eth yl]-4,7-bis(p h en ylm eth yl)-2H-1,3-

2026 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Han et al.
d ia zep in -2-on e (10G). A solution of 4A in DMF (10 mL) was
treated with ammonium chloride (214 mg, 4 mmol) and sodium
azide (260 mg, 4 mmol) at 100 °C for 48 h. The mixture was
diluted with water (50 mL) and extracted with ether (2 × 25
mL). The aqueous layer was acidified and extracted with ethyl
acetate (2 × 25 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated to afford MEM-protected
intermediate (808 mg), which was treated with 4 M HCl in
dioxane and methanol (1:1, 8 mL) at room temperature for 18
h. The mixture was diluted with water (50 mL) and extracted
with ethyl acetate (2 × 25 mL). The combined organic extracts
were dried (MgSO4), filtered, concentrated, and purified by
reverse-phase (C18) preparative HPLC using gradient solvents
(H2O-CH3CN-0.05% TFA) as a mobile phase to afford 10G
(548 mg, 85.3% for the two steps) as a white solid: 1H NMR
(CD3OD) δ 2.75-2.86 (m, 2H), 3.00-3.08 (m, 2H), 3.16-3.25
(d, 2H), 3.62-3.8 (m, 4H), 4.6-4.7 (d, 2H), 6.85-6.97 (m, 4H),
7.05-7.19 (m, 6H), 7.37-7.5 (m, 4H), 7.8-7.9 (m, 4H); 13C
NMR (CD3OD) δ 33.93, 57.54, 68.53, 72.00, 127.46, 129.47,
129.54, 130.55, 130.78, 133.51, 141.06, 157.87, 163.69; HRMS
(M+ + H) 643.2898 (calcd for C35H35N10O3 643.2893).
(4R,5S,6S,7R)-Hexah ydr o-5,6-dih ydr oxy-1-[[3-[1-N-[[(tr i-
m eth ylsilyl)eth oxy]m eth yl]p yr a zol-5-yl]p h en yl]m eth yl]-
4,7-bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (11). A mix-
ture of 2 (5.2 g, 10.4 mmol), 85% KOH (2 g, 31 mmol), and
PEG1000 (0.5 g) in toluene (80 mL) was refluxed for 3 h to
remove water. After cooling to room temperature, to the
formed potassium salt was added m-iodobenzyl bromide (6.1
g, 20.7 mmol), and the resulting mixture was stirred at 75 °C
for 18 h. The mixture was then poured into ice-cold NH4Cl
(aq) and extracted with ethyl acetate. The organic layer was
washed with water and brine, dried over MgSO4, filtered, and
concentrated to give a residue. The residue was purified by
column chromatography with ethyl acetate and hexane (4:6)
to give a monoalkylated cyclic urea (2.9 g, 40%). The mono-
m-iodobenzyl cyclic urea (2.9 g, 4 mmol) in THF (15 mL) was
coupled with 9A (3.87 g, 16 mmol) by the same procedure to
make and purify 10A to provide pure coupled product 11 (2.4
g, 75%): ESMS m/z 6812.2 (M + Na)+; 1H NMR (CDCl3) δ 7.62
(d, J ) 7.7 Hz, 1H), 7.58 (d, J ) 1.8 Hz, 1H), 7.45-7.18 (m,
13H), 6.43 (d, J ) 1.8 Hz, 1H), 5.42 (s, 2H), 4.94-4.64 (m,
4H), 4.68 (dd, J ) 18.3 Hz, J ) 7.0 Hz, 2H), 4.02-3.98 (m,
1H), 3.92-3.80 (m, 1H), 3.74 (t, J ) 8.3 Hz, 2H), 3.85-3.43
(m, 11H), 3.41 (s, 3H), 3.35 (s, 3H), 3.28 (d, J ) 10.6 Hz, 1H),
3.09 (dd, J ) 10.4 Hz, J ) 2.5 Hz, 2H), 2.78 (t, J ) 10.7 Hz,
1H), 0.93 (t, J ) 8.4 Hz, 2H), 0.00 (s, 9H).
nitrobenzyl chloride (0.360 g, 2.13 mmol). After the resulting
mixture was stirred at room temperature for 18 h, it was
partitioned in EtOAc and water. The organic layer was
washed with water and brine, dried over MgSO4, filtered, and
concentrated to give a residue. The residue was purified by
column chromatography with a gradient solvent system (ethyl
acetate and hexane) to give the desired nonsymmetric cyclic
urea. The urea was deprotected by general de-MEM and de-
SEM procedures with 4 M HCl, followed by purification on
TLC plates with EtOAc to give the pure nitro intermediate
(230 mg, 52.5% for the two steps). Hydrogenation of the nitro
intermediate (210 mg, 0.34 mmol) in MeOH (5 mL) and 1 N
HCl (1 mL) in the presence of 10% Pd on C (10% w/w) was
carried out at room temperature for 16 h. After the reaction
mixture was filtered, the filtrate was concentrated to give a
residue, which was purified on TLC plates with EtOAc to give
12D (140 mg, 61%) as a solid: mp 136-138 °C; 1H NMR (CD3-
OD) δ 8.31 (s, 1H), 7.81-6.88 (m, 19H), 4.60 (d, J ) 13.6 Hz,
2H), 3.80-3.57 (m, 4H), 3.16-2.68 (m, 6H); 13C NMR (CD3-
OD) δ 163.99, 149.09, 141.38, 141.23, 140.01, 130.73, 130.65,
130.35, 130.15, 129.93, 129.55, 129.46, 128.04, 127.42, 127.35,
125.97, 120.06, 117.33, 115.81, 103.32, 72.11, 71.99, 66.39,
57.28, 56.97, 33.66, 33.53; MS 605 (M+ + NH4, 100%); HRMS
(M + H)+ 588.2983 (calcd for C36H38N5O3 588.2975).
(4R,5S,6S,7R)-Hexah ydr o-5,6-dih ydr oxy-1-[[3-(1H-pyr a-
zol-3-yl)p h en yl]m eth yl]-3-[[3-(m eth oxyca r bon yl)p h en yl]-
m 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
(12B): mp 127-130 °C; CIMS m/z 631.4 (M + H)+; HRMS (M
1
+ H)+ 631.2916 (calcd 631.2920); H NMR (CD3OD) δ 7.85-
7.82 (m, 2H), 7.66-7.57 (m, 4H), 7.35-7.01 (m, 13H), 6.56 (s,
1H), 4.76 (d, J ) 14.3 Hz, 1H), 4.69 (d, J ) 14.3 Hz, 1H), 3.77
(s, 3H), 3.72-3.58 (m, 4H), 3.11-3.02 (m, 4H), 2.94-2.84 (m,
2H); 13C NMR (CD3OD) δ 166.79, 162.24, 139.69, 139.59,
138.56, 138.50, 133.63, 130.09, 129.16, 128.78, 128.61, 128.46,
128.29, 128.16, 126.59, 126.08, 124.60, 102.00, 70.50, 66.36,
66.31, 55.99, 55.63, 51.32, 32.23, 32.15. Anal. (C38H38N4O5‚
1.5TFA‚0.18HCl‚0.8H2O) C, H, N, F, Cl.
(4R,5S,6S,7R)-Hexah ydr o-5,6-dih ydr oxy-1-[[3-(1H-pyr a-
zol-3-yl)ph en yl]m eth yl]-3-[[3-(h ydr oxym eth ylen e)ph en yl]-
m 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
(12C). To a solution of compound 12B (63 mg, 0.1 mmol) in
THF (1 mL) were added LiBH4 (2 M in THF, 0.3 mL) and
MeOH (57.6 mg, 1.8 mmol), and the resulting mixture was
stirred at room temperature for 16 h. The mixture was
acidified to pH 1 with 2 N HCl and extracted with EtOAc. The
organic layer was washed with H2O brine, dried over MgSO4,
and concentrated to give a residue. The residue was purified
on TLC plate with EtOAc to give compound 12C (46 mg,
76.3%): 1H NMR (CD3OD) δ 7.78-7.60 (m, 4H), 7.50-7.07 (m,
15H), 6.68 (d, J ) 2.2 Hz, 1H), 4.90-4.81 (m, 2H), 4.66 (bs,
2H), 3.79-3.63 (m, 4H), 3.18-3.00 (m, 6H); 13C NMR (CD3-
OD) δ 163.92, 143.24, 141.32, 141.23, 139.41, 130.67, 130.17,
129.93, 129.69, 129.57, 129.53, 129.30, 129.04, 128.04, 127.45,
127.41, 127.25, 126.01, 103.33, 72.02, 71.96, 67.04, 64.97,
57.30, 57.07, 33.63, 33.57; MS m/z 603.2 (M + H)+; HRMS (M
+ H)+ 603.2968 (calcd for C37H39N4O4 603.2971).
(4R,5S,6S,7R)-Hexah ydr o-5,6-dih ydr oxy-1-[[3-(1H-pyr a-
zol-3-yl)p h en yl]m eth yl]-4,7-bis(p h en ylm eth yl)-2H-1,3-d i-
a zep in -2-on e (12A). Compound 11 (0.45 g, 0.57 mmol) was
treated with 4 M HCl in dioxane (5 mL) and methanol (5 mL)
at room temperature for 18 h. The mixture was neutralized
to pH 6 with saturated sodium bicarbonate and extracted with
ethyl acetate. The organic extracts were dried (MgSO4),
filtered, and concentrated to give a crude. The crude was
purified on prepared TLC plate with EtOAc, followed by
acidification with HCl (gas) in methanol and then concentra-
tion to afford 12A (207 mg, 70%) as a white solid: mp 152-
154 °C; aqueous solubility at pH 7.4 is 0.047 mg/mL; 1H NMR
(CD3OD) δ 7.67-7.05 (M, 15H), 6.58 (d, J ) 4.0 Hz, 1H), 4.80
(d, J ) 14.7 Hz, 1H), 3.86-3.82 (m, 1H), 3.71-3.62 (m, 2H),
(4R,5S,6S,7R)-Hexah ydr o-5,6-dih ydr oxy-1-[[3-(1H-pyr a-
zol-3-yl)p h en yl]m et h yl]-3-[(4-h yd r oxyp 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 (12F ). A so-
lution of 11 (220 mg, 0.28 mmol) in DMF (3 mL) was treated
with NaH (0.045 g, 1.12 mmol, 60% in mineral oil), followed
by quenching with p-(benzyloxy)benzyl chloride (0.13 g, 0.56
mmol). After the mixture stirred at room temperature for over
18 h, general workup and purification gave the desired
asymmetric cyclic urea, which was deprotected by general de-
MEM procedure to give a benzyl-protected intermediate. The
intermediate was hydrogenated in MeOH in the presence of
10% (w/w) Pd on C, followed by purification by thin-layer
chromatography with EtOAc-CH2Cl2 (3:1) to produce 12F (109
3.51-3.48 (m, 1H), 3.18-2.99 (m, 4H), 2.80-2.72 (m, 1H); 13
C
NMR (CD3OD) δ 163.90, 141.47, 140.89, 130.63, 130.49,
130.09, 130.01, 129.64, 129.49, 129.27, 127.52, 127.25, 125.85,
103.33, 72.99, 72.55, 66.50, 66.47, 55.27, 35.13, 34.32; CIMS
m/z 483.2 (M + H)+; HRMS (M + H)+ 483.2401 (calcd for
C29H31N4O3 483.2400). Anal. (C29H30N4O3‚1.25TFA‚0.09HCl‚
1.0H2O) C, H, N, F, Cl.
Rep r esen ta tive P r oced u r es for Non sym m etr ic Cyclic
Ur ea Der iva tives: Meth od C, (4R,5S,6S,7R)-Hexa h yd r o-
5,6-d ih yd r oxy-1-[[3-(1H -p yr a zol-3-yl)p h en yl]m et h yl]-3-
[(3-a m in op h en yl)m eth yl]-4,7-bis(p h en ylm eth yl)-2H-1,3-
d ia zep in -2-on e (12D). A solution of 11 (560 mg, 0.71 mmol)
in DMF (10 mL) at 0 °C was treated with NaH (0.114 g, 2.84
mmol, 60% in mineral oil), followed by quenching with m-
1
mg, 66% for the two steps): mp 150-153 °C; H NMR (CD3-
OD) δ 7.68-7.58 (m, 3H), 7.39-7.05 (m, 12H), 6.98 (d, J )
8.4 Hz, 2H), 6.73 (d, J ) 8.4 Hz, 2H), 6.58 (d, J ) 2.2 Hz, 1H),
4.78 (d, J ) 14.3 Hz, 1H), 4.66 (d, J ) 13.9 Hz, 1H), 3.68-
3.50 (m, 4H), 3.08-2.83 (m, 6H); 13C NMR (CD3OD) δ 163.94,

Cyclic HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2027
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M. S.; Shaw, G. M. Viral Dynamics in Human Immunodeficiency
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Pinching, A. J .; Weber, J . N. Safety and Acitivity of Saquinavir
in HIV Infection. Lancet 1995, 345, 952-955. (h) Reich, S. H.;
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K.; Wu, B.; Musick, L.; Kalish, V.; Kaldor, S.; Reich, S.; Ho, D.;
Webber, S. Antiviral and Resistance Studies of AG1343, an
Orally Bioavailable Inhibitors of Human Immunodeficiency
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plexes. Perspect. Drug Discovery Des. 1993, 1, 23-48.
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Capable of Displacing the Active-Site Structural Water Molecule.
Drug Discovery Today 1997, 2, 6-18. (c) Sham, H. L.; Zhao, C.;
Stewart, K. D.; Betebenner, D. A.; Lin, S.; Park, C. H.; Kong,
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vanonda, S.; Lyons, N.; Molla, A.; Saldivar, A.; Marsh, K. C.;
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Inhibitor of Human Immunodeficiency Virus Type 1 Protease.
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K. C.; Betebenner, D. A.; Lin, S.; Rosenbrook, W., J r., Herrin,
T.; Li, L.; Madigan, D.; Vasavanonda, S.; Molla, A.; Saldivar,
A.; McDonald, E.; Wideburg, N. E.; Kempf, D. J .; Norbeck, D.
W.; Plattner, J . J . Novel Azacyclic Ureas That Are Potent
Inhibitors of HIV-1 Protease. Biochem. Biophys. Res. Commun.
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K. C.; Lee, A.; Yu, B.; Gulnik, S.; Erickson, J . W. New Series of
Potent, Orally Bioavailable, Non-Peptidic Cyclic Sulfones as
HIV-1 Protease Inhibitors. J . Med. Chem. 1996, 39, 3431.
(6) (a) J acobsen, H.; Yasargil, K.; Winslow, D. L.; Craig, J . C.; Krohn,
A.; Duncan, I. B.; Mous, J . Characterization of Human Immu-
nodeficiency Virus Type 1 Mutants with Decreased Sensitivity
to Proteinase Inhibitor Ro 31-8959. Virology 1995, 206, 527-
534. (b) Markowitz, M. M.; Mo, H.; Kempf, D. J .; Norbeck, D.
W.; Bhat, T. N.; Erickson, J . W.; Ho, D. Selection and Analysis
158.15, 141.31, 140.11, 131.73, 130.69, 130.65, 130.16, 129.96,
129.56, 129.48, 128.04, 127.46, 127.35, 125.98, 116.39, 103.32,
72.10, 72.02, 66.42, 57.22, 56.37, 33.56; LRMS 589.3 (M + H)+;
HRMS (M + H)+ 589.2811 (calcd for C36H37N4O4 589.2815).
Anal. (C36H36N4O4‚1.5H2O) C, H, N.
(4R,5S,6S,7R)-Hexah ydr o-5,6-dih ydr oxy-1-[[3-(1H-pyr a-
zol-3-yl)p h en yl]m et h yl]-3-[[3-[[2-(4-m or p h olin yl)et h y-
la m in o]ca r bon yl]p h en yl]m eth yl]-4,7-bis(p h en ylm eth yl)-
2H-1,3-d ia zep in -2-on e (12G). To compound 12B (63 mg, 0.1
mmol) was added 4-(2-aminoethyl)morpholine (0.13 g, 1 mmol),
and the resulting mixture was stirred at 110 °C for 16 h. The
mixture was evaporated under full vacuum to remove excess
of 4-(2-aminoethyl)morpholine, and the residue was purified
on TLC plate with 10% MeOH in EtOAc to give pure 12G (44
mg, 60.4%): 1H NMR (CD3OD) δ 8.04 (s, 1H), 7.73-6.99 (m,
18H), 6.59 (d, J ) 2.2 Hz, 1H), 4.72 (d, J ) 14.4 Hz, 2H), 3.69-
3.64 (m, 8H), 3.36 (t, J ) 6.6 Hz, 2H), 3.14 (J ) 14.2 Hz, 2H),
3.08-2.85 (m, 4H), 2.54 (t, J ) 6.6 Hz, 2H), 2.51-2.45 (m, 4H);
13C NMR (CD3OD) δ 169.84, 163.68, 141.25, 141.12, 140.09,
136.07, 133.65, 130.63, 129.87, 129.56, 129.51, 128.02, 127.44,
103.31, 71.98, 71.91, 68.26, 67.75, 58.62, 58.37, 58.45, 54.68,
37.76, 35.76, 33.69, 33.62; CIMS m/z 729.5 (M + H)+; HRMS
(M + H)+ 729.3753 (calcd for C43H49N6O5 729.3764).
Cr ysta llogr a p h y. The complex of 10A and HIV protease
was crystallized as described previously.14 The unit cell
dimensions of the complex are a ) b ) 63.3 Å and c ) 83.6 Å.
The diffraction data were collected with an R-AXIS II imaging
plate mounted on a RU200 Rigaku rotating anode generator
operating at 50 kV and 100 mA. The crystal diffracts up to
2.0 Å with a total of 50 870 reflections of which 10 694 were
unique reflections; the completeness of data was 82% and the
Rsym was 10.5%. Difference maps calculated with the protein
coordinate of XK2637 revealed the corresponding inhibitor
position. The structure was refined using the simulated
annealing method XPLOR.15 The final R-factor16 was 0.186
without addition of any water molecules. No constraints were
applied to maintain an identity between two monomers of the
protease. Standard geometry of the inhibitor was based on
the single-crystal structure of a cyclic urea.
Ack n ow led gm en t. We would like to thank Dr.
J oseph C. Calabrese for solving the small-molecule
crystal structures, Dr. Gilbert N. Lam for pharmacoki-
netic studies, Ronald M. Klabe for Ki measurements,
and Dr. Lee Bacheler, Marlene M. Rayner, and Beverly
C. Cordova for RNA cell assays. We also thank Drs. Soo
Ko, Steve Seitz, George L. Trainor, and Paul S. Ander-
son and the HIVPR working group for their valuable
contributions to the HIVPR program.
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J M9704199