Discovery of HIV-1 protease inhibitors with picomolar affinities incorporating N-aryl-oxazolidinone-5-carboxamides as novel P2 ligands

Article abstract of DOI:10.1021/jm060666p

Here, we describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors incorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino)sulfonamide scaffold as P2 ligands. Series of inhibitors with variations at the P2 phenyloxazolidinone and the P2′ phenylsulfonamide moieties were synthesized. Compounds with the (S)-enantiomer of substituted phenyloxazolidinones at P2 show highly potent inhibitory activities against HIV-1 protease. The inhibitors possessing 3-acetyl, 4-acetyl, and 3-trifluoromethyl groups at the phenyl ring of the oxazolidinone fragment are the most potent in each series, with K_i values in the low picomolar (pM) range. The electron-donating groups 4-methoxy and 1,3-dioxolane are preferred at P2′ phenyl ring, as compounds with other substitutions show lower binding affinities. Attempts to replace the isobutyl group at P1′ with small cyclic moieties caused significant loss of affinities in the resulting compounds. Crystal structure analysis of the two most potent inhibitors in complex with the HIV-1 protease provided valuable information on the interactions between the inhibitor and the protease enzyme. In both inhibitor-enzyme complexes, the carbonyl group of the oxazolidinone ring makes hydrogen-bond interactions with relatively conserved Asp29 residue of the protease. Potent inhibitors from each series incorporating various phenyloxazolidinone based P2 ligands were selected and their activities against a panel of multidrug-resistant (MDR) protease variants were determined. Interestingly, the most potent protease inhibitor starts out with extremely tight affinity for the wild-type enzyme (K_i = 0.8 pM), and even against the MDR variants it retains picomolar to low nanomolar K_i, which is highly comparable with the best FDA-approved protease inhibitors.

Full text of DOI:10.1021/jm060666p

7342
J. Med. Chem. 2006, 49, 7342-7356
Discovery of HIV-1 Protease Inhibitors with Picomolar Affinities Incorporating
N-Aryl-oxazolidinone-5-carboxamides as Novel P2 Ligands
Akbar Ali,†,‡ G. S. Kiran Kumar Reddy,†,‡ Hong Cao,†,‡ Saima Ghafoor Anjum,†,‡ Madhavi N. L. Nalam,‡
Celia A. Schiffer,‡ and Tariq M. Rana*,†,‡
Chemical Biology Program, Department of Biochemistry and Molecular Pharmacology, UniVersity of Massachusetts Medical School,
Worcester, Massachusetts 01605
ReceiVed June 2, 2006
Here, we describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors
incorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino)sulfonamide scaffold as
P2 ligands. Series of inhibitors with variations at the P2 phenyloxazolidinone and the P2′ phenylsulfonamide
moieties were synthesized. Compounds with the (S)-enantiomer of substituted phenyloxazolidinones at P2
show highly potent inhibitory activities against HIV-1 protease. The inhibitors possessing 3-acetyl, 4-acetyl,
and 3-trifluoromethyl groups at the phenyl ring of the oxazolidinone fragment are the most potent in each
series, with Ki values in the low picomolar (pM) range. The electron-donating groups 4-methoxy and 1,3-
dioxolane are preferred at P2′ phenyl ring, as compounds with other substitutions show lower binding affinities.
Attempts to replace the isobutyl group at P1′ with small cyclic moieties caused significant loss of affinities
in the resulting compounds. Crystal structure analysis of the two most potent inhibitors in complex with the
HIV-1 protease provided valuable information on the interactions between the inhibitor and the protease
enzyme. In both inhibitor-enzyme complexes, the carbonyl group of the oxazolidinone ring makes hydrogen-
bond interactions with relatively conserved Asp29 residue of the protease. Potent inhibitors from each series
incorporating various phenyloxazolidinone based P2 ligands were selected and their activities against a
panel of multidrug-resistant (MDR) protease variants were determined. Interestingly, the most potent protease
inhibitor starts out with extremely tight affinity for the wild-type enzyme (Ki ) 0.8 pM), and even against
the MDR variants it retains picomolar to low nanomolar Ki, which is highly comparable with the best FDA-
approved protease inhibitors.
Introduction
However, the emergence of HIV-1 mutants that are resistant to
current drug regimens is a critical factor in the clinical failure
of antiviral therapy. For most of the currently approved protease
inhibitors, the emergence of multidrug-resistant (MDR) protease
variants poses a great challenge to the efficacy of these
drugs.13,14 Development of next-generation HIV-1 protease
inhibitors active against MDR virus has been the focus of intense
research efforts in recent years.11,15 Thus, there is an increasing
need to discover new classes of protease inhibitors that possess
favorable pharmacological profiles and are less susceptible to
drug resistance with an emphasis on broad spectrum activity
against MDR variants.
One possible strategy to reduce the probability of drug
resistance is to design inhibitors that interact with the same
residues of HIV-1 protease that are necessary to recognize the
substrate.16,17 Analysis of the crystal structures of HIV-1 protease
in complex with substrate peptides suggests that substrate
specificity for HIV-1 protease is based not on a particular amino
acid sequence but on a conserved shape (“substrate envelope”).18
Comparison of the substrate structures with protease inhibitor
structures reveals critical differences between inhibitor and
substrate binding to the enzyme. In the case of substrates, most
of the conserved hydrogen bonds occur primarily between the
backbone of the protease and the backbone of the substrate.
Thus, it is important that the inhibitors are designed to form
hydrogen bonds with relatively conserved residues and prefer-
ably with the backbone atoms of the protease rather than the
side chain atoms. Among the approved protease inhibitors,
amprenavir (APV, 1; Figure 1) fits reasonably well within the
substrate envelope. It has been suggested that the inhibitors
designed on the APV template may be less susceptible to drug
Human immunodeficiency virus type 1 (HIV-1) protease
plays a critical role in the virus life cycle by processing the
viral Gag and Gag-Pol polyproteins into structural and functional
proteins essential for viral maturation. Inhibition of HIV-1
protease leads to the production of noninfectious virus particles
and hence is a promising therapeutic target for antiviral therapy
in AIDS patients. In fact, HIV-1 protease inhibitors represent
the most potent anti-AIDS drugs reported to date and are
essential components of highly active antiretroviral therapy
(HAART).1,2 In the past decade, structure-based drug design
has led to the discovery of nine FDA-approved drugs and several
others in advanced clinical trials. Currently marketed HIV-1
protease inhibitors, saquinavir,3 indinavir,4 ritonavir,5 nelfinavir,6
amprenavir,7 lopinavir,8 atazanavir,9 tipranavir,10 and darunavir
(TMC-114),11 are all competitive inhibitors that bind in the
active site of the enzyme. Except the newly approved drug
tipranavir, all approved inhibitors have been developed on the
basis of the transition state mimetic concept and contain various
noncleavable dipeptide isosteres as core scaffolds to mimic the
transition state of HIV-1 protease substrates. The development
and clinical introduction of anti-AIDS HIV-1 protease inhibitors
is regarded as a major success of structure-based drug design.12
Anti-AIDS chemotherapy based on HIV-1 protease and
reverse-transcriptase inhibitors has been remarkably successful
in decreasing the mortality rate in HIV-1-infected patients.
* To whom correspondence should be addressed. Tel: (508) 856-6216.
Fax: (508) 856-6696. E-mail: tariq.rana@umassmed.edu.
† Chemical Biology Program.
‡ Department of Biochemistry and Molecular Pharmacology.
10.1021/jm060666p CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/14/2006

Aryloxazolidinonecarboxamides as NoVel P2 Ligands
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7343
to make additional contacts with the protease. In addition, the
selected heterocyclic moiety can be linked to the (hydroxyethyl-
amino)sulfonamide isostere in a stereochemically defined man-
ner using either the (R)- or (S)-enantiomer of N-phenyloxazo-
lidinone-5-carboxylic acids.
The N-phenyloxazolidinone-based cyclic carbamate ligands
have not been utilized previously in protease inhibitors.
However, there are reports of inhibitors containing other cyclic
carbamate ligands, but with poor protease inhibitory activities.28
On the other hand, cyclic urea based ligands have been widely
used in protease inhibitors; approved drug lopinavir (LPV)
contains cyclic urea at the P3 position.8 Substituted imidazo-
lidines have been incorporated as cyclic P1-P2 scaffolds in
protease inhibitors based on hydroxyethylene and hydroxyethyl-
amine isosteres. These conformationally restricted molecules
displayed potent inhibitory activities against HIV-1 protease with
Ki values in the nanomolar range.29 Recently, potent oximi-
noarylsulfonamide-based HIV-1 protease inhibitors that contain
N-substituted five-membered cyclic urea moiety linked to the
hydroxyethylamine core analogous to the LPV P3 side chain
have been reported.30
Figure 1. Chemical structures of APV (1), DRV (2), and designed
inhibitors (3).
Herein, we report the synthesis and biological evaluation of
novel series of HIV-1 protease inhibitors incorporating N-phe-
nyloxazolidinone-5-carboxamides as P2 ligands. Preliminary
structure-activity relationship (SAR) studies with variations at
the P2, P2′, and P1′ positions resulted in the discovery of highly
potent inhibitors of HIV-1 protease. In addition to activities
against wild-type protease, we also report the inhibitory activities
of several new inhibitors against a panel of MDR variants of
HIV-1 protease. The crystal structures of the two most potent
new inhibitors in complex with wild-type HIV-1 protease are
also discussed.
resistance.19 Recently approved protease inhibitor darunavir
(DRV, 2), structurally similar to 1, has been shown to possess
very potent in vitro and in vivo antiviral activity against wild-
type as well as MDR variants. Compared to the THF moiety in
1, the additional interactions of the bis-THF moiety in 2 with
the backbone atoms of fairly conserved Asp29 and Asp30
residues in protease explains its potent and broad spectrum
activity against MDR variants.19,20
In an effort to discover new classes of HIV-1 protease
inhibitors that target ensembles of HIV-1 protease and exhibit
broad spectrum activity against MDR variants, we have designed
inhibitors based on the (R)-(hydroxyethylamino)sulfonamide
isostere present in 1 and 2. We envisioned that a small
heterocyclic moiety with multiple polar atoms located at the
P2 position would mimic the critical interactions of the THF/
bis-THF moieties present in APV/DRV. Since the oxygen atom
of the carbamate linking THF/bis-THF moieties to the hydroxy-
ethylamine core in 1 and 2 does not make any hydrogen-bond
contacts with the protease, we decided to attach the heterocyclic
moiety to the core isostere via an amide linkage. Previous reports
of inhibitors with heteroaryl and other polar heterocyclic groups
as P2 ligands directly linked to the (hydroxyethylamino)-
sulfonamide fragment did not show promising activities.21
However, inhibitors incorporating substituted hydroxybenza-
mides as P2 ligands have shown potent inhibitory activities
against HIV-1 protease.22,23 Recently, protease inhibitors in-
corporating 2,3-dihydroxybenzoic acid derived macrocyclic P1-
P2 ligands have been reported to exhibit low nanomolar protease
inhibitory activities.24
Among possible five-membered heterocyclic structures, we
selected N-phenyloxazolidinone-5-carboxamides to be utilized
as P2 ligands in HIV-1 protease inhibitors. The oxazolidinones
represent a class of synthetic antimicrobial agents that are highly
stable and exhibit exceptional bioavailability profiles.25 Linezolid
is an FDA-approved antibacterial drug that contains N-phenyl-
oxazolidinone nucleus.26 Recently, N-phenyloxazolidinone-5-
carboxamides have been reported to possess better antibacterial
activities compared to linezolid with enhanced solubility and
bioavailability properties.27 We reasoned that the carbonyl group
of the oxazolidinone ring would mimic critical hydrogen-bond
interactions of THF/bis-THF moieties of APV and DRV in the
S2 binding pocket of the protease active site. The phenyl group
at the ring nitrogen can be utilized to introduce functional groups
Chemistry
Chiral N-phenyloxazolidinone-5-carboxylic acids 9 and 10
used in the synthesis of designed inhibitors were prepared
following the literature procedure as outlined in Scheme 1.26,27,31
The intermediate chiral alcohols, 5-(hydroxymethyl)-3-arylox-
azolidine-2-ones 7 and 8, were obtained from substituted anilines
in two steps. The reaction of CBZ-protected anilines 4a-g with
either the (R)- or the (S)-enantiomer of glycidyl butyrate
promoted by n-BuLi provided chiral alcohols 7a and 8a-g. This
one-pot, three-step cascade reaction involves the initial ring
opening of chiral epoxide with N-lithium species followed by
an intramolecular cyclization and finally an in situ ester
hydrolysis.26 Oxidation of the resulting chiral alcohols using
catalytic ruthenium chloride provided the desired N-phenylox-
azolidinone-5-carboxylic acids 9a and 10a-g (Scheme 1). In
the case of the unsubstituted phenyloxazolidinones, both (R)-
and (S)-enantiomers, 9a and 10a, respectively, were prepared
from the corresponding chiral epoxide. All other compounds
with a substituted phenyl ring, 10b-g, were prepared only as
(S)-enantiomers.
The synthetic route applied for the preparation of designed
protease inhibitors is illustrated in Scheme 2. The Boc-protected
intermediate (R)-(hydroxyethylamino)sulfonamides 14-19 were
prepared following a literature procedure.11 Briefly, ring opening
of commercially available chiral epoxide (1S,2S)-(1-oxiranyl-
2-phenylethyl)carbamic acid tert-butyl ester (11) with isobutyl-
amine provided the amino alcohol 12. Reactions of substituted
phenylsulfonyl chlorides with 12 afforded the sulfonamides 14-
19 that were coupled with phenyloxazolidinone fragments.
Initially, four compounds were synthesized using either unsub-
stituted (R)- or (S)-3-phenyloxazolidinone-5-carboxylic acid 9a

7344 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25
Ali et al.
Scheme 1. Synthesis of Intermediates N-Phenyloxazolidinone-5-carboxylic Acids 9 and 10a
a (a) n-BuLi, THF, -78 °C to rt overnight; (b) NaIO4, RuCl3‚H2O, CH3CN-CCl4-H2O (2:2:3), 0 °C to rt 4-10 h.
Scheme 2. Synthesis of Designed Protease Inhibitors 20-29a
a (a) iBuNH2, EtOH, 80 °C, 3-4 h; (b) aq Na2CO3, CH2Cl2, 0 °C to rt, 4-8 h; (c) TFA, CH2Cl2, 1 h; (d) (COCl)2, rt, overnight; (e) Et3N, THF, 0 °C to
rt, 4-8 h; (f) SnCl2‚2H2O, EtOAc, 70 °C, 2 h.
or 10a attached to the (R)-(hydroxyethylamino)sulfonamide
isostere at the P2 position. The previously optimized phenyl-
sulfonamides 4-methoxyphenylsulfonamide and 4-aminophen-
ylsulfonamide were utilized as P2′ ligands. Thus, removal of
the Boc protection of sulfonamides 14 and 15 followed by the
reactions of the resulting amino alcohols with either the (R)- or
the (S)-enantiomer of the activated carboxylic acids 9a or 10a
provided the target compounds 20a-23a (Scheme 2). In the
case of compounds 22a and 23a, the nitro group was reduced
using tin chloride to afford the corresponding amino derivatives
24a and 25a. It has to be noted that attempts to use the standard
amide coupling conditions EDCI/HOBt/DIEA were not very
successful and resulted in poor yields, mainly because of very
slow reactions even with DMF as solvent. In all subsequent
reactions the carboxylic acids 9 and 10 were converted to the
corresponding acid chlorides using oxalyl chloride.
mediates 14-19, the resulting amines were reacted with (S)-
N-phenyloxazolidinone-5-carbonyl chlorides obtained by the
activation of the corresponding carboxylic acids 10b-g to afford
the target compounds 21 and 25-29 (Scheme 2). The com-
pounds 23b-f containing 4-nitrophenylsulfonamide group at
P2′ position were transformed to the corresponding 4-aminophen-
ylsulfonamide derivatives 25b-f by the reduction of the nitro
group.
In addition to the compounds described above, series of
compounds were prepared with variations at three different
positions. The isobutyl group at the P1′ position was replaced
with three cyclic primary amines. Again, starting from com-
mercially available chiral epoxide 11, the target compounds were
synthesized using an analogous synthetic route (Scheme 3). In
brief, ring opening of epoxide 11 with primary amines 30a-c
provided amino alcohols 31a-c. Reactions of various substituted
phenylsulfonyl chlorides with 31a-c provided sulfonamides
32-35. After deprotection of intermediate compounds 32-35,
the resulting amines were reacted with (S)-N-phenyloxazolidi-
none-5-carbonyl chlorides prepared from the corresponding
Series of inhibitors were synthesized using substituted (S)-
phenyloxazolidinones at P2 and different phenylsulfonamide
groups at the P2′ position for structure-activity relationship
(SAR) studies. Following the deprotection of sulfonamide inter-

Aryloxazolidinonecarboxamides as NoVel P2 Ligands
Scheme 3. Synthesis of Inhibitors 36-39a
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7345
a (a) iPrOH or EtOH, 80 °C, 3-4 h; (b) aq Na2CO3, CH2Cl2, 0 °C to rt, 4-8 h; (c) TFA, CH2Cl2, 1 h; (d) (COCl)2, rt, overnight; (e) Et3N, THF, 0 °C
to rt, 4-8 h.
carboxylic acids 10 to afford the target compounds 36-39
(Scheme 3).
Biological Evaluation of Inhibitors
HIV protease inhibitor activities were determined by the
fluorescence resonance energy transfer (FRET) method.32 Pro-
tease substrate [Arg-Glu(EDANS)-Ser-Gln-Asn-Tyr-Pro-Ile-Val-
Gln-Lys(DABCYL)-Arg] was labeled with the energy transfer
donor (EDANS) and acceptor (DABCYL) dyes at its two ends
to perform FRET. The inhibitor binding dissociation constant
(Ki value) was obtained by nonlinear regression fitting to the
plot of initial velocity as a function of inhibitor concentration.33
The activities of all the synthesized inhibitors against wild-type
HIV-1 protease (Q7K) were determined in triplicate. Chemical
structures of inhibitors and their inhibitory activities (Ki values)
are presented in Table 1. A small set of protease inhibitors with
potent activities against wild-type protease was studied against
a panel of MDR variants of HIV-1 protease each representing
different paradigms of resistance. The mutant variants were
selected by examining the Stanford HIV-1 Drug Resistance
Database (http://hivdb.stanford.edu), which contains sequences
of HIV-1 isolates from HIV-1-infected persons. The three
selected protease variants represent the pattern of resistance
mutations that occur under the selective pressure of three or
more currently prescribed protease inhibitors.34 These MDR
variants are L10I, G48V, I54V, L63P, V82A (M1); D30N,
L63P, N88D (M2); and L10I, L63P, A71V, G73S, I84V, L90M
(M3). The inhibitory activities of selected protease inhibitors
against M1-M3 mutant HIV-1 proteases were examined. For
comparison, two currently marketed drugs, APV and LPV, were
also studied against the selected panel of mutant proteases.
Figure 2. Structure and inhibitory activities of new protease inhibitors.
wild-type HIV-1 protease with Ki ) 10.7 and 37.4 nM,
respectively. When (5S)-10a was attached at the P2 position,
there was significant improvement in the inhibitory activities
with both phenylsulfonamide groups. Interestingly, the com-
pound 21a with 4-methoxybenzenesulfonamide as P2′ ligand
was more potent (Ki ) 0.1 nM) than the 4-aminobenzene-
sulfonamide analogue 25a (Ki ) 0.53 nM). The protease
inhibitory activities of compounds 21a and 25a are comparable
to that of structurally related drug APV (1) with Ki ) 0.10 nM
in our assay.
These results clearly show that hydroxyethylamine isostere
based inhibitors incorporating N-phenyloxazolidinone-5-car-
boxamides as P2 ligands exhibit potent HIV-1 protease inhibi-
tory activities. These studies also suggest that compounds
containing (5S)-N-phenyloxazolidinone-5-carboxamides are more
potent inhibitors of HIV-1 protease compared to the corre-
sponding (5R)-inhibitors. Thus, in subsequent SAR studies, only
(S)-N-phenyloxazolidinone-5-carboxylic acids 10a-g were used.
Structure-Activity Relationship Studies. To explore the
possibilities of enhancing the potency of 21a and 25a, we
synthesized and tested series of analogues with variations at
both the P2 and P2′ positions. The inhibitor series 21 and 25-
29 were prepared using a small set of mainly substituted (S)-
N-phenyloxazolidinone-5-carboxylic acids 10b-g linked to the
(R)-(hydroxyethylamino)sulfonamides 14-19 as P2 ligands
(Scheme 2). All the compounds were evaluated for their
activities against wild-type HIV-1 protease, and Ki values are
presented in Table 1, where the Ki values of 21a and 25a are
also included. The inhibitory activities of APV and LPV were
also determined using the same assay conditions, and Ki data
are included in Table 1 for comparison.
Results and Discussion
To test the design concept, protease inhibitors based on the
hydroxyethylamine isostere incorporating unsubstituted N-phe-
nyloxazolidinone-5-carboxamide were prepared and their inhibi-
tory activities against the wild-type HIV-1 protease were
determined. It was also critical to determine which stereoisomer
of phenyloxazolidinone-based P2 ligand will bind more favor-
ably to the protease. For these preliminary investigations, two
pairs of compounds containing either (R)- or (S)-N-phenylox-
azolidinone-5-carboxylic acid [(5R)-9a or (5S)-10a] and two
phenylsulfonamide groups, 4-methoxy- and 4-aminophenylsul-
fonamide, were prepared and tested (Figure 2). The inhibitors
20a and 24a containing (5R)-9a attached at P2 and both
4-methoxy- and 4-amino-substituted phenylsulfonamides at the
P2′ position exhibited nanomolar inhibitory activities against
In the first series of inhibitors, the 4-methoxybenzenesulfona-
mide group at P2′ was kept constant, and substituted N-
phenyloxazolidinones 10b-g were attached to the (R)-(hydroxy-
ethylamino)sulfonamide isostere 14 as P2 ligands. Compared
to 21a, all the compounds with a substituted phenyl ring (21b-

7346 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25
Ali et al.
Table 1. Inhibitory Activities of Compounds against Wild-type HIV-1
Table 2. Inhibitory Activities of Compounds against Wild-type HIV-1
Protease
Protease
compd
R1
R2
Ki (nM)
21a
21b
21c
21d
21e
21f
21g
25a
25b
25c
25d
25e
25f
26b
26c
26d
26e
26f
27b
27c
27d
27e
27f
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-NH2
4-NH2
4-NH2
4-NH2
4-NH2
H
3-F
0.10
0.083
0.066
0.006
0.0008
0.004
0.045
0.530
0.170
0.230
0.042
0.032
0.184
0.107
0.085
0.016
0.006
0.016
0.070
0.343
0.072
0.133
0.080
10.0
3,4-di-F
3-CF3
3-Ac
4-Ac
3-OCH3
H
3-F
3,4-di-F
3-CF3
3-Ac
4-Ac
3-F
3,4-di-F
3-CF3
3-Ac
4-Ac
3-F
3,4-di-F
3-CF3
3-Ac
4-Ac
3-CF3
3-Ac
H
4-NH2
3,4-OCH2O-
3,4-OCH2O-
3,4-OCH2O-
3,4-OCH2O-
3,4-OCH2O-
3-F, 4-OCH3
3-F, 4-OCH3
3-F, 4-OCH3
3-F, 4-OCH3
3-F, 4-OCH3
4-OCF3
28d
28e
29a
29f
substituted phenyloxazolidinones at P2. It appears that the
addition of a 3-fluoro group on the phenyl ring at P2′ is not
well tolerated. Relatively low Ki values were observed for
derivatives with 3-fluoro (27b, Ki ) 70 pM), 3-trifluoromethyl
(27d, Ki ) 72 pM), and 4-acetyl (27f, Ki ) 80 pM) groups
compared to derivatives with 3,4-difluoro (27c, Ki ) 343 pM)
and 3-acetyl (27e, Ki ) 133 pM) groups. The replacement of
4-methoxyphenyl with 4-trifluoromethoxyphenyl resulted in
substantial loss of activity (inhibitors 28d-e). Changing the
position of the methoxy group from the 4- to the 3-position in
29a and 29f also resulted in significant loss of protease inhibitory
activity (Table 1, entries 26 and 27). These results suggest that
inhibitors with the electron-donating substituents methoxy,
dioxolane, and amino at the P2′ phenylsulfonamide group exhibit
potent HIV-1 protease inhibitory activities. Other substitutions
and modifications are not well tolerated and could result in
significant loss of protease inhibitory activity.
4-OCF3
3-OCH3
3-OCH3
2.0
3.80
0.84
4-Ac
APV
LPV
0.10
0.005
g) exhibited improved inhibitory activities against HIV-1
protease (Table 1, entries 1-7). For the inhibitors with 3-fluoro
and 3,4-difluoro groups on the phenyl ring, 21b and 21c, the
improvement was relatively minor; Ki values of 21b and 21c
are 80 and 66 pM, respectively. Introduction of polar groups
trifluoromethyl, acetyl, and methoxy at positions 3 and 4 of
the phenyl ring resulted in a significant increase in the potency
of the inhibitors. The Ki value of compound 21d with a
3-trifluoromethyl group is 6 pM and the 3-methoxy analogue
21g showed a Ki value of 45 pM. Inhibitors 21e and 21f with
3- and 4-acetyl groups are the most potent HIV-1 protease
inhibitors discovered in our studies, with Ki values of 0.8 and
4 pM, respectively.
The protease inhibitors 25b-f with 4-aminobenzenesulfona-
mide at P2′ did not show much improvement in the protease
inhibitory activities, as was observed in the corresponding
4-methoxy analogues 21. Only the inhibitors with a 3-trifluo-
romethyl- and 3-acetyl-substituted phenyl ring, 25d (Ki ) 42
pM) and 25e (Ki ) 32 pM), exhibited a significant increase in
potency compared to the unsubstituted analogue 25a. Inhibitors
with 3-fluoro (25b), 3,4-difluoro (25c), and 4-acetyl (25f) groups
at the phenyl ring showed relatively small improvement in
activities compared to 25a (Table 1, entries 9, 10, and 13).
Compounds 26b-f with another commonly used P2′ ligand,
1,3-benzodioxolane sulfonamide, also showed very potent
inhibitory activities. Again, inhibitors with 3-trifluoromethyl
(26d), 3-acetyl (26e) and 4-acetyl (26f) groups at the phenyl
ring of oxazolidinone were the most potent against HIV-1
protease, with Ki values of 16, 6, and 16 pM, respectively.
The introduction of disubstituted 3-fluoro-4-methoxyphenyl-
sulfonamide at P2′ (27b-f) showed mixed results with different
In addition to the variations at the P2 and P2′ positions, the
SAR effort was extended to replace the isobutyl group at P1′
with cyclic groups. Selected primary amines 30a-c include a
small hydrophobic group, cyclopropylmethylamine, as well as
polar saturated (S)-(2-tetrahydrofuranyl)methylamine and un-
saturated 2-(thiophenyl)methylamine heterocyclic groups. Again,
sulfonyl chlorides utilized at the R1 position are all substituted
benzene derivatives containing functional groups at various
positions. A small set of compounds with variations at all three
R1, R2, and R3 positions, corresponding to P2′, P2, and P1′,
were prepared and tested (Table 2). To our surprise, replacing
the isobutyl group at P1′ with cyclopropylmethyl resulted in
significantly lower inhibitory activities. The Ki values of 36b
(257 pM), 36c (580 pM), and 36f (800 pM) are about 3-, 9-,
and 200-fold higher than the corresponding inhibitors with
isobutyl group at the P1′ position. Inhibitors 37-39 with (2-
thiophenyl)methyl and (S)-(2-tetrahydrofuranyl)methyl groups
at the P1′ position all showed very weak inhibitory activities
against HIV-1 protease (Table 2, entries 4-11).

Aryloxazolidinonecarboxamides as NoVel P2 Ligands
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7347
Table 3. X-ray Crystallographic Data Collection and Refinement
Statistics for Complexes of 21e and 21f with the Wild-type HIV-1
Protease
21e
1.95
21f
1.8
resolution (Å)
temperature (°C)
space group
a (Å)
b (Å)
c (Å)
-80
-80
P212121
50.78
58.31
61.69
4
P212121
50.77
57.65
61.89
4
Z
R
merge (%)
4.7
5.0
completeness (%)
95.3
95.6
total no. of reflections
no. of unique reflections
65 161
13 238
21.6
107 046
16 632
18.5
R
R
free (%)
factor (%)
16.6
16.0
RMSDa
bond length (Å)
0.008
1.294
159
0.007
1.232
174
bond angle (deg)
no. of crystallographic waters
PDB codeb
2I0D
2I0A
a RMSD, root-mean-square deviation. b PDB, Protein Data Bank.
Crystal Structures of HIV-1 Protease Complexes. Crystal
structures of the two most potent inhibitors, 21e and 21f, in
complex with wild-type HIV-1 protease have been determined
to a resolution of 1.95 and 1.8 Å, respectively.35 Both
compounds are similar except for the position of the acetyl group
on the phenyl ring attached to the oxazolidinone moiety at P2.
The refinement statistics are presented in Table 3. The high
resolution of the structures combined with the unambiguous
density for the inhibitors and the active site residues allow for
a detailed analysis of the intermolecular interactions present in
the complexes. The backbone atoms in the two structures
superimpose within 0.16 Å. The inhibitors also superimpose
well on each other in the crystal structures, and the inhibitor-
protease contacts are almost similar except at the substituted
phenyloxazolidinone moiety, where the position of the acetyl
group is different in 21e and 21f. Figure 3 shows the inhibitor-
protease hydrogen bonds in the 21e and 21f complexes,
including those mediated by water. Table 4 shows the hydrogen-
bond distances observed in the crystal structures. Except for
one hydrogen bond in 21f, the hydrogen-bonding pattern is
almost the same in both the structures. As observed with other
protease inhibitors, a water molecule tetrahedrally coordinated
the backbone nitrogen atoms in Ile50 of both monomers of the
protease at the tips of the flaps to the sulfonyl and carbonyl
groups of the inhibitors. The central hydroxyl group forms
hydrogen bonds with the carboxylate groups of the catalytic
aspartic acids of the protease, Asp25 and Asp25′, located in
the floor of the active site. The amide nitrogen of the inhibitors
forms a hydrogen bond with the main chain carbonyl of Gly27.
The central skeleton of 21e and 21f is similar to that of APV
(1) and DRV (2). All the hydrogen bonds mentioned above are
also observed in the crystal structures of 1 and 2.
Figure 3. Hydrogen bonds, shown as black lines, observed in the
protease complexes of (a) 21e and (b) 21f. The two monomers and the
inhibitor are shown in cyan, magenta, and gray, respectively. Nitrogen,
oxygen, and sulfur atoms are in blue, red, and yellow, respectively.
The carbonyl group of the oxazolidinone ring of both 21e
and 21f forms hydrogen bonds with the backbone nitrogen and
side chain oxygen atoms of Asp29. This carbonyl group also
forms a weak hydrogen bond (3.5 Å) with the side chain of
Arg8′ in 21f, whereas the Arg8′ in 21e points away from the
carbonyl group. This is one of the major differences between
the two structures. A water molecule bridges this carbonyl group
with the oxygen atom of the Gly27 at the bottom of the active
site through hydrogen bonds. The oxazolidinone ring in both
the structures forms VDW contacts with the residues Gly48 and
Gly49 in the upper region of the active site and with the residues
Gly27, Ala28, and Asp29 in the lower region of the active site.
In addition, it forms VDW contacts with Arg8′ in 21f. A water
molecule connects the nitrogen atom of the oxazolidinone ring
to the oxygen atom of Gly48 in the flap through hydrogen
bonding, and another water molecule connects the oxygen atom
in the oxazolidinone ring to the backbone nitrogen of Asp30 in
both the structures.
The methoxy group at the P2′ end of the inhibitors 21e/21f
forms a hydrogen bond with the backbone nitrogen of the
protease residue Asp30′ with a distance of 3.4/3.3 Å. The
4-acetyl group on the other end of the 21f does not form any
hydrogen bond with the protease but extends beyond the
protease into the solvent. The carbonyl of the 3-acetyl group in
21e forms van der Waals (VDW) contacts with the residues
Gly48, Gly49, and Pro81′ of the protease. The methyl group of
the acetyl moiety forms VDW contacts with the phenyl ring of
Phe53 in the flap region in both the structures. This interaction
pattern involving Phe53 has not been seen in other FDA-
approved protease inhibitors.
The protease inhibitors incorporating phenyloxazolidinones
as P2 ligands form many interesting hydrogen bonds, some

7348 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25
Ali et al.
Table 4. Hydrogen-Bonding Distances between Protease and Inhibitor
Atoms in the Crystal Structures of 21e and 21f
wild-type protease. However, the relative loss of activity is
different in different class of inhibitors. While LPV significantly
loses activity against protease variants M1 and M3, it still retains
high affinity against the M2 variant. In the case of APV, the
relative loss of activity is not that significant against all mutants,
but its Ki value for wild-type is also relatively high. The protease
inhibitors with N-phenyloxazolidinone at P2 showed some loss
of activities against M1 variant and significant loss against M3
variant but still retained potent inhibitory activities against M2
variant. These data are consistent with an analysis of the crystal
structures. The M1 and M3 variants are more severely drug
resistant, with M1 having the active site mutations V82A and
G48V and M3 having I84V and L90M, whereas M2 is more
representative of nelfinavir resistance with D30N. G48V could
potentially cause a van der Waals clash with the acetyl group
in 21e, while V82A and I84V would potentially cause a loss of
van der Waals contacts. As no group is making an ionic
interaction with the side chain of D30, the D30N mutation in
M2 should have minimal effect on the Ki, as is observed.
Interestingly, the most potent protease inhibitor, 21e, starts out
with extremely tight affinity for the wild-type enzyme (Ki )
0.8 pM), and even against the resistant variants it retains
picomolar to low nanomolar Ki, which is highly comparable
with the best FDA-approved protease inhibitors.
distance (Å)
protease
atom
inhibitor
atom
21e
21f
Asp 29 N
Asp 29 OD1
Asp 29 OD2
water
Arg 8′ NH2
Asp 29 N
water
Gly 27 O
water
water
Asp 25 OD1
Asp 25 OD2
Asp 25′ OD1
Asp 25′ OD2
flap water
flap water
Asp 30′ N
O27
O27
O27
O27
O27
O28
O28
N20
O45
N24
O18
O18
O18
O18
O22
O9
3.0
3.2
3.3
3.0
3.1
3.2
3.0 (W82)
3.5
3.6
3.1 (W88)
3.2
3.5 (W64)
3.3 (W47)
2.6
3.3
2.5
3.0 (W3)a
3.6
3.1 (W10)
3.1
2.8 (W152)
3.4 (W124)
2.5
3.3
2.5
2.9
2.9
2.7 (W12)
2.7 (W12)
3.4
2.7 (W17)
2.8 (W17)
3.3
Conclusions
O19
In summary, we have discovered novel and highly potent
HIV-1 protease inhibitors based on the (hydroxyethylamino)-
sulfonamide isostere incorporating N-phenyloxazolidinone-5-
carboxamides as P2 ligands. The inhibitors with the (S)-
enantiomer of N-phenyloxazolidinone-5-carboxylic acid attached
at P2 are significantly more potent compared to the correspond-
ing compounds with the (R)-enantiomer. Preliminary SAR
studies suggest that both electron-donating and -withdrawing
groups are well-tolerated on the phenyl ring of the oxazolidinone
fragment at P2 position. The addition of any functionality on
the phenyl ring results in significantly increased inhibitory
activities against HIV-1 protease. On the P2′ side, inhibitors
with electron-donating substituents at phenylsulfonamide group
exhibited highly potent HIV-1 protease inhibitory activities.
Other substitutions and modifications are not well tolerated and
result in significant loss of protease inhibitory activity. In current
SAR studies, only N-phenyloxazolidinone moieties with the
phenyl group substituted at various positions were used. The
structural knowledge obtained from the two crystal structures
of the drug-enzyme complexes in this series can be utilized to
design new protease inhibitors that may interact with relatively
conserved residues in the protease active site. A variety of
N-aryl-, heteroaryl-, acyl-, and alkyloxazolidinone derivatives
could be utilized as potential P2 ligands, thus vastly expanding
the possibilities of finding new potent inhibitors in future SARs.
Several new inhibitors exhibiting low picomolar inhibitory
activities against wild-type protease were evaluated for their
activity against a panel of MDR proteases. The most potent
protease inhibitor, 21e, with a Ki value of 0.8 pM against wild-
type HIV-1 protease, also showed potent activity against MDR
enzymes. In future studies, the bioavailability and antiviral
activities of these inhibitors will be investigated.
a The corresponding water number is in parentheses.
Table 5. Inhibitory Activities of Compounds against MDR Variants of
HIV-1 Proteasea
Ki (nM)
compd
Wt
M1
M2
M3
21b
21c
21e
21f
25a
25d
26e
APV
LPV
0.083
0.066
0.0008
0.004
0.53
0.042
0.006
0.10
3.56
1.18
0.16
0.78
2.08
4.42
0.72
0.15
6.10
0.080
0.152
0.039
0.179
0.92
0.36
0.235
0.21
4.94
8.69
3.36
1.94
10.3
12.3
3.51
1.40
0.90
0.005
0.04
a Wt: Q7K. M1: L10I, G48V, I54V, L63P, V82A. M2: D30N, L63P,
N88D. M3: L10I, L63P, A71V, G73S, I84V, L90M.
directly with the protease and some bridging through the water
molecules to the protease. The side chain of Asp30 near the
oxazolidinone ring does not participate in direct hydrogen
bonding with the inhibitor in both the structures. The structural
knowledge obtained from the two crystal structures can be
utilized to design new compounds of high binding affinity by
varying substituents on the phenyloxazolidinone ring so as to
form hydrogen bonds with Asp30.
Inhibitor Activities against MDR Variants. Selected inhibi-
tors that exhibited potent activities against wild-type HIV-1
protease were further evaluated for their activities against a panel
of MDR protease variants that represent different paradigms of
resistance found in HIV-1-infected persons.34 At least one
compound was selected from each of the series incorporating
different phenyloxazolidinone-based P2 ligands. In some cases,
different functional group variations on the benzenesulfonamide
fragment were selected in preference to compounds with the
lowest Ki values in that series. The Ki values of selected
inhibitors against M1-M3 MDR variants of protease are
presented in Table 5. Two known drugs, APV and LPV, were
also studied for comparisons. The data show that all protease
inhibitors lose affinity against mutant variants compared to the
Experimental Section
1
General. H and 13C NMR spectra were recorded on a Varian
1
400 MHz NMR spectrometer, operating at 400 MHz for H and
100 MHz for 13C. Chemical shifts are reported in ppm relative to
the solvent signal, and coupling constant (J) values are reported in
hertz (Hz). Thin-layer chromatography (TLC) was performed on

Aryloxazolidinonecarboxamides as NoVel P2 Ligands
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7349
E. Merck silica gel 60-F-254 plates, and spots were visualized with
UV light. Flash column chromatography was performed using 230-
400 mesh silica gels (E-Merck). High-resolution mass spectra
(HRMS) were recorded on a Waters Q-TOF Premier mass
spectrometer by direct infusion of solutions of each compound using
electrospray ionization (ESI) in positive mode. Low-resolution mass
spectra were obtained using a Waters Alliance HT/Micromass ZQ
system (ESI). Tetrahydrofuran (THF) was distilled from sodium/
benzophenone. Anhydrous dichloromethane, N,N-dimethylforma-
mide (DMF), benzene, and toluene were purchased from Aldrich
and used as such. All reagents and chemicals were purchased from
commercial vendors and used as received. Analytical reversed-phase
high performance liquid chromatography (HPLC) was performed
on a Waters Separation Module 2695 system equipped with an
autosampler and a Waters 996 photodiode array detector. Purity of
the final compounds was determined using two different chromato-
graphic systems. First system: column, Waters Nova-Pak RP-C18
(4 µm, 3.9 mm × 150 mm); mobile phase A, 10 mM ammonium
acetate in water; mobile phase B, acetonitrile; flow rate of 0.8 mL/
min, gradient elution was performed from 50% B to 100% B over
10 min. Second system: column, Agilent Zorbax 300SB-C8 (5 µm,
4.6 mm × 250 mm); mobile phase A, 0.1% trifluoroacetic acid
(TFA) in water; mobile phase B, 0.1% TFA in acetonitrile; gradient
elution was performed from 50% B to 100% B over 10 min at a
flow rate of 1 mL/min. A table containing the retention time and
purity of each final compound is in Supporting Information.
Synthesis of Designed Protease Inhibitors. General experi-
mental procedures for the synthesis of intermediates phenyloxazo-
lidinones (9 and 10) and (R)-(hydroxyethylamino)sulfonamides
(14-19 and 32-35) and for the coupling reactions to provide the
target compounds (20-29 and 36-39) are provided in the Sup-
porting Information.
(dd, J ) 13.2, 8.8 Hz, 1H), 2.97 (dd, J ) 15.2, 2.4 Hz, 1H), 2.81
(dd, J ) 13.6, 6.8 Hz, 1H), 2.73 (dd, J ) 14.0, 10.4 Hz, 1H), 1.84
(m, 1H), 0.96 (d, J ) 6.4 Hz, 3H), 0.90 (d, J ) 6.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 168.60, 163.29, 163.18 (d, J ) 244.2
Hz), 152.82, 138.98 (d, J ) 10.6 Hz), 137.48, 130.48 (d, J ) 9.1
Hz), 129.91, 129.70 (2C), 129.50 (2C), 128.49 (2C), 126.60, 114.58
(2C), 113.52 (d, J ) 2.3 Hz), 111.49 (d, J ) 21.2 Hz), 106.06 (d,
J ) 27.3 Hz), 72.47, 69.82, 58.95, 55.82, 53.79, 53.44, 48.20, 35.56,
27.46, 20.31, 20.08; HRMS (ESI) m/z C31H37FN3O7S (M + H)+
calcd 614.2336, found 614.2357.
(5S)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl[(4-methoxy-
phenyl)sulfonyl]amino]propyl]-3-(3,4-difluorophenyl)-2-oxooxazoli-
dinone5-carboxamide (21c): 1H NMR (400 MHz, CDCl3) δ 7.74
(m, 2H), 7.54-7.48 (m, 1H), 7.19 (dd, J ) 18.4, 8.8 Hz, 1H), 7.12
(d, J ) 6.8 Hz, 2H), 7.05-6.97 (m, 5H), 6.89 (t, J ) 7.6 Hz, 1H),
6.75 (d, J ) 10.0 Hz, 1H), 4.78 (dd, J ) 9.6, 5.6 Hz, 1H), 4.25 (m,
1H), 3.99 (t, J ) 9.2 Hz, 1H), 3.92 (m, 1H), 3.87 (s, 3H), 3.69 (d,
J ) 3.2 Hz, 1H), 3.31 (dd, J ) 9.2, 6.0 Hz, 1H), 3.22 (dd, J )
15.2, 9.6 Hz, 1H), 3.12-2.97 (m, 3H), 2.82 (dd, J ) 13.2, 6.8 Hz,
1H), 2.74 (dd, J ) 14.0, 11.2 Hz, 1H), 1.84 (m, 1H), 0.95 (d, J )
6.4 Hz, 3H), 0.90 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 168.45, 163.35, 152.78, 150.49 (dd, J ) 246.4, 13.6 Hz), 147.41
(dd, J ) 245.0, 12.1 Hz), 137.46, 134.03 (m), 129.87, 129.72 (2C),
129.55 (2C), 128.53 (2C), 126.61, 117.62 (d, J ) 18.2 Hz), 114.62
(2C), 113.85 (q, J ) 3.0 Hz), 108.37 (dd, J ) 22.8 Hz), 72.47,
69.70, 59.05, 55.84, 53.86, 53.39, 48.25, 35.51, 27.54, 20.34, 20.08;
HRMS (ESI) m/z C31H36F2N3O7S (M + H)+ calcd 632.2242, found
632.2251.
(5S)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl[(4-methoxy-
phenyl)sulfonyl]amino]propyl]-2-oxo-3-[(3-trifluoromethyl)phenyl]-
1
oxazolidine-5-carboxamide (21d): H NMR (400 MHz, CDCl3)
δ 7.74 (dd, J ) 10.0, 2.4 Hz, 2H), 7.70 (dd, J ) 8.8, 1.6 Hz, 1H),
7.64 (s, 1H), 7.54 (t, J ) 8.0 Hz, 1H), 7.46 (d, J ) 8.0 Hz, 1H),
7.12 (dd, J ) 8.4, 1.6 Hz, 2H), 7.01-6.96 (m, 4H), 6.83 (t, J )
7.2 Hz, 1H), 6.79 (d, J ) 10.0 Hz, 1H), 4.81 (dd, J ) 10.0, 6.0
Hz, 1H), 4.27 (m, 1H), 4.04 (t, J ) 9.6 Hz, 1H), 3.94 (m, 1H),
3.87 (s, 3H), 3.69 (br s, 1H), 3.33 (dd, J ) 9.2, 5.6 Hz, 1H), 3.22
(dd, J ) 15.6, 9.6 Hz, 1H), 3.10 (dd, J ) 14.0, 4.4 Hz, 1H), 3.04-
2.98 (m, 2H), 2.83 (dd, J ) 13.2, 6.8 Hz, 1H), 2.74 (dd, J ) 14.0,
10.8 Hz, 1H), 1.85 (m, 1H), 0.95 (d, J ) 6.4 Hz, 3H), 0.90 (d, J
) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.49, 163.34,
152.83, 138.19, 137.43, 131.76 (d, J ) 32.6 Hz), 129.93, 129.87,
129.72 (2C), 129.53 (2C), 128.52 (2C), 126.58, 121.40, 121.24 (q,
J ) 3.8 Hz), 115.02 (q, J ) 3.8 Hz), 114.61 (2C), 72.50, 69.86,
59.03, 55.83, 53.84, 53.36, 48.10, 35.56, 27.52, 20.34, 20.08; HRMS
(ESI) m/z C32H37F3N3O7S (M + H)+ calcd 664.2304, found
664.2316.
(5S)-3-(3-Acetylphenyl)-N-[(1S,2R)-1-benzyl-2-hydroxy-3-[isobu-
tyl[(4-methoxyphenyl)sulfonyl]amino]propyl]-2-oxooxazolidine-
5-carboxamide (21e): 1H NMR (400 MHz, CDCl3) δ 7.89 (t, J )
1.6 Hz, 1H), 7.80-7.74 (m, 2H), 7.71 (d, J ) 9.2 Hz, 2H), 7.50 (t,
J ) 8.0 Hz, 1H), 7.10 (d, J ) 7.2 Hz, 2H), 6.98 (m, 4H), 6.83 (m,
2H), 4.78 (dd, J ) 10.0, 6.0 Hz, 1H), 4.23 (m, 1H), 4.05 (t, J )
9.6 Hz, 1H), 3.93 (m, 1H), 3.84 (s, 3H), 3.46 (s, 1H), 3.36 (dd, J
) 9.2, 5.6 Hz, 1H), 3.19 (dd, J ) 15.2, 9.6 Hz, 1H), 3.09 (dd, J )
14.0, 4.4 Hz, 1H), 3.01-2.95 (m, 2H), 2.82 (dd, J ) 13.2, 6.8 Hz,
1H), 2.73 (dd, J ) 14.0, 10.8 Hz, 1H), 2.63 (s, 3H), 1.84 (m, 1H),
0.92 (d, J ) 6.4 Hz, 3H), 0.88 (d, J ) 6.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 197.59, 168.59, 163.31, 153.07, 138.10, 138.04,
137.52, 129.91, 129.71 (2C), 129.65, 129.55 (2C), 128.53 (2C),
126.62, 124.71, 123.01, 117.58, 114.60 (2C), 72.54, 69.93, 59.01,
55.82, 53.85, 53.44, 48.23, 35.63, 27.50, 26.90, 20.33, 20.08; HRMS
(ESI) m/z C33H40N3O8S (M + H)+ calcd 638.2536, found 638.2544.
(5S)-3-(4-Acetylphenyl)-N-[(1S,2R)-1-benzyl-2-hydroxy-3-[isobu-
tyl[(4-methoxyphenyl)sulfonyl]amino]propyl]-2-oxooxazolidine-
5-carboxamide (21f): 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J )
9.2 Hz, 2H), 7.72 (d, J ) 8.8 Hz, 2H), 7.53 (d, J ) 9.2 Hz, 2H),
7.10 (d, J ) 7.2 Hz, 2H), 6.98-6.93 (m, 4H), 6.86 (d, J ) 10.0
Hz, 1H), 6.80 (t, J ) 7.6 Hz, 1H), 4.80 (dd, J ) 10.0, 6.0 Hz, 1H),
4.24 (m, 1H), 4.05 (t, J ) 9.6 Hz, 1H), 3.95 (m, 1H), 3.85 (s, 3H),
3.33 (dd, J ) 9.6, 6.0 Hz, 1H), 3.19 (dd, J ) 14.8, 8.8 Hz, 1H),
(5R)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl[(4-methoxy-
phenyl)sulfonyl]amino]propyl]-2-oxo-3-phenyloxazolidine-5-
1
carboxamide (20a): H NMR (400 MHz, CDCl3) δ 7.67 (d, J )
8.8 Hz, 2H), 7.46 (d, J ) 8.4 Hz, 2H), 7.35 (t, J ) 7.6 Hz, 2H),
7.24-7.13 (m, 6H), 6.92 (d, J ) 8.8 Hz, 2H), 6.75 (d, J ) 8.4 Hz,
1H), 4.71 (dd, J ) 10.0, 6.0 Hz, 1H), 4.17 (m, 2H), 4.07 (dd, J )
9.2, 6.0 Hz, 1H), 3.91 (m, 1H), 3.84 (m, 1H), 3.82 (s, 3H), 3.10-
2.77 (m, 6H), 1.76 (m, 1H), 0.84 (d, J ) 6.4 Hz, 3H), 0.79 (d, J )
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.98, 163.23,
153.06, 137.49, 137.46, 129.91, 129.67 (2C), 129.44 (2C), 129.41
(2C), 128.79 (2C), 126.96, 124.95, 118.55 (2C), 114.54 (2C), 72.28,
70.03, 58.90, 55.80, 54.41, 53.56, 48.19, 35.05, 27.46 20.25, 20.11;
HRMS (ESI) m/z C31H38N3O7S (M + H)+ calcd 596.2430, found
596.2421.
(5S)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl[(4-methoxy-
phenyl)sulfonyl]amino]propyl]-2-oxo-3-phenyloxazolidine-5-carbox-
amide (21a): 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J ) 8.8 Hz,
2H), 7.45-7.38 (m, 4H), 7.19 (t, J ) 7.2 Hz, 1H), 7.12 (d, J ) 7.2
Hz, 2H), 7.04-6.98 (m, 4H), 6.89 (t, J ) 7.6 Hz, 1H), 6.69 (d, J
) 9.6 Hz, 1H), 4.77 (dd, J ) 9.6, 5.6 Hz, 1H), 4.22 (m, 1H), 4.04
(t, J ) 9.6 Hz, 1H), 3.90 (m, 1H), 3.87 (s, 3H), 3.78 (d, J ) 2.4
Hz, 1H), 3.36 (dd, J ) 9.2, 6.0 Hz, 1H), 3.23 (dd, J ) 15.2, 9.2
Hz, 1H), 3.11 (dd, J ) 13.6, 4.4 Hz, 1H), 3.02 (dd, J ) 13.6, 8.8
Hz, 1H), 2.96 (dd, J ) 15.2, 2.8 Hz, 1H), 2.81 (dd, J ) 13.6, 6.8
Hz, 1H), 2.73 (dd, J ) 14.0, 10.8 Hz, 1H), 1.84 (m, 1H), 0.96 (d,
J ) 6.8 Hz, 3H), 0.90 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 168.86, 163.25, 153.12, 137.52, 137.49, 129.94, 129.68
(2C), 129.50 (2C), 129.26 (2C), 128.50 (2C), 126.61, 124.76, 118.47
(2C), 114.56 (2C), 72.46, 69.87, 58.91, 55.79, 53.78, 53.52, 48.29,
35.64, 27.44, 20.31, 20.07; HRMS (ESI) m/z C31H38N3O7S (M +
H)+ calcd 596.2430, found 596.2438.
(5S)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl[(4-methoxy-
phenyl)sulfonyl]amino]propyl]-3-(3-fluorophenyl)-2-oxooxazolidine-5-
1
carboxamide (21b): H NMR (400 MHz, CDCl3) δ 7.74 (d, J )
8.8 Hz, 2H), 7.39-7.33 (m, 2H), 7.10 (m, 3H), 7.04-6.98 (m, 4H),
6.93-6.85 (m, 2H), 6.68 (d, J ) 9.6 Hz, 1H), 4.78 (dd, J ) 10.2,
6.0 Hz, 1H), 4.23 (m, 1H), 4.01 (t, J ) 9.6 Hz, 1H), 3.91 (m, 1H),
3.88 (s, 3H), 3.68 (br s, 1H), 3.32 (dd, J ) 9.2, 6.0 Hz, 1H), 3.23
(dd, J ) 14.8, 9.2 Hz, 1H), 3.10 (dd, J ) 13.6, 4.4 Hz, 1H), 3.03

7350 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25
Ali et al.
3.10-2.94 (m, 3H), 2.83 (dd, J ) 13.2, 6.4 Hz, 1H), 2.73 (dd, J )
14.0, 11.2 Hz, 1H), 2.60 (s, 3H), 1.84 (m, 1H), 0.92 (d, J ) 6.4
Hz, 3H), 0.88 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 196.99, 168.46, 163.29, 152.75, 141.55, 137.51, 133.13, 129.86,
129.78 (2C), 129.68 (2C), 129.52 (2C), 128.44 (2C), 126.58, 117.57
(2C), 114.58 (2C), 72.47, 69.85, 58.95, 55.81, 53.78, 53.43, 48.0,
35.49, 27.46, 26.65, 20.31, 20.07; HRMS (ESI) m/z C33H40N3O8S
(M + H)+ calcd 638.2536, found 638.2545.
48.17, 35.62, 27.58, 20.38, 20.10; HRMS (ESI) m/z C30H36FN4O6S
(M + H)+ calcd 599.2339, found 599.2340.
(5S)-N-[(1S,2R)-3-[[(4-Aminophenyl)sulfonyl](isobutyl)amino]-
1-benzyl-2-hydroxypropyl]-3-(3,4-difluorophenyl)-2-oxooxazo-
lidine-5-carboxamide (25c): 1H NMR (400 MHz, CDCl3) δ 7.56
(d, J ) 8.4 Hz, 2H), 7.54-7.48 (m, 1H), 7.19 (q, J ) 9.2 Hz, 1H),
7.11 (d, J ) 7.6 Hz, 2H), 7.02-6.96 (m, 3H), 6.90-6.85 (m, 2H),
6.68 (d, J ) 8.8 Hz, 2H), 4.78 (dd, J ) 10.0, 5.6 Hz, 1H), 4.28-
4.21 (m, 2H), 3.98 (t, J ) 9.6 Hz, 1H), 3.94 (m, 1H), 3.76 (br s,
1H), 3.27 (dd, J ) 9.2, 6.0 Hz, 1H), 3.17 (dd, J ) 15.2, 8.8 Hz,
1H), 3.08 (dd, J ) 14.0, 4.4 Hz, 1H), 2.99 (dd, J ) 14.8, 2.4 Hz,
1H), 2.95 (dd, J ) 13.6, 8.4 Hz, 1H), 2.81 (dd, J ) 13.2, 6.8 Hz,
1H), 2.73 (dd, J ) 14.0, 10.8 Hz, 1H), 1.83 (m, 1H), 0.92 (d, J )
6.4 Hz, 3H), 0.89 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 168.41, 152.92, 151.02, 150.44 (dd, J ) 246.5, 13.6 Hz), 147.36
(dd, J ) 245.0, 12.4 Hz), 137.59, 134.06 (m), 129.72 (2C), 129.55
(2C), 128.45 (2C), 126.52, 126.14, 117.59 (d, J ) 18.2 Hz), 114.32
(2C), 113.88 (q, J ) 3.8 Hz), 108.36 (d, J ) 22.0 Hz), 72.491,
69.75, 59.01, 53.81, 53.36, 48.27, 35.48, 27.48, 20.34, 20.10; HRMS
(ESI) m/z C30H35F2N4O6S (M + H)+ calcd 617.2245, found
617.2246.
(5S)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl[(4-methoxy-
phenyl)sulfonyl]amino]propyl]-3-(3-methoxyphenyl)-2-oxooxazoli-
1
dine-5-carboxamide (21g): H NMR (400 MHz, CDCl3) δ 7.73
(m, 2H), 7.29 (t, J ) 8.8 Hz, 1H), 7.14 (d, J ) 2 Hz, 1H), 7.11 (m,
2H), 7.03 (t, J ) 7.2 Hz, 2H), 6.98 (m, 2H), 6.92-6.88 (m, 2H),
6.73 (ddd, J ) 8.4, 2.8, 0.8 Hz, 1H), 6.70 (d, J ) 9.6 Hz, 1H),
4.75 (dd, J ) 10.4, 6.4 Hz, 1H), 4.21 (m, 1H), 4.01 (t, J ) 9.6 Hz,
1H), 3.89 (m, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.68 (br s, 1H), 3.32
(dd, J ) 9.6, 6.4 Hz, 1H), 3.21 (dd, J ) 15.2, 9.2 Hz, 1H), 3.10
(dd, J ) 14.0, 4.8 Hz, 1H), 3.01 (dd, J ) 13.2, 8.8 Hz, 1H), 2.96
(dd, J ) 15.2, 2.4 Hz, 1H), 2.80 (dd, J ) 13.6, 6.4 Hz, 1H), 2.73
(dd, J ) 13.6, 10.4 Hz, 1H), 1.83 (m, 1H), 0.95 (d, J ) 6.4 Hz,
3H), 0.89 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
168.86, 163.37, 160.45, 152.94, 138.72, 137.39, 130.08, 129.87,
129.76 (2C), 129.55 (2C), 128.65 (2C), 126.79, 114.66 (2C), 110.61,
110.33, 104.73, 72.49, 69.77, 59.12, 55.89, 55.65, 53.97, 53.52,
48.41, 35.76, 27.60, 20.40, 20.11; HRMS (ESI) m/z C32H40N3O8S
(M + H)+ calcd 626.2536, found 626.2546.
(5S)-N-[(1S,2R)-3-[[(4-Aminophenyl)sulfonyl](isobutyl)amino]-
1-benzyl-2-hydroxypropyl]-2-oxo-3-[(3-trifluoromethyl)phenyl]-
1
oxazolidine-5-carboxamide (25d): H NMR (400 MHz, CDCl3)
δ 7.68 (d, J ) 8.0 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J ) 8.8 Hz, 2H),
7.52 (t, J ) 8.0 Hz, 1H), 7.45 (d, J ) 7.6 Hz, 1H), 7.09 (d, J ) 7.2
Hz, 2H), 6.96 (t, J ) 7.6 Hz, 2H), 6.81 (t, J ) 7.6 Hz, 1H), 6.77
(d, J ) 10.4 Hz, 1H), 6.67 (d, J ) 8.8 Hz, 2H), 4.78 (dd, J ) 10.4,
6.0 Hz, 1H), 4.24 (m, 1H), 4.16 (br s, 1H), 4.02 (t, J ) 9.6 Hz,
1H), 3.91 (m, 1H), 3.73 (br s, 1H), 3.30 (dd, J ) 9.2, 6.0 Hz, 1H),
3.19 (dd, J ) 15.2, 9.2 Hz, 1H), 3.07 (dd, J ) 14.0, 4.4 Hz, 1H),
3.0-2.93 (m, 2H), 2.78 (dd, J ) 13.2, 6.8 Hz, 1H), 2.70 (dd, J )
13.6, 10.8 Hz, 1H), 1.82 (m, 1H), 0.93 (d, J ) 6.8 Hz, 3H), 0.88
(d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.44, 152.86,
150.98, 138.13, 137.50, 131.77 (d, J ) 32.6 Hz), 129.94, 129.77
(2C), 129.55 (2C), 128.50 (2C), 126.55, 126.24, 121.40, 121.23
(q, J ) 3.8 Hz), 115.02 (q, J ) 3.8 Hz), 114.35 (2C), 72.50, 69.85,
59.09, 53.89, 53.32, 51.06, 48.10, 35.57, 27.56, 20.37, 20.11; HRMS
(ESI) m/z C31H36F3N4O6S (M + H)+ calcd 649.2307, found
649.2291.
(5R)-N-[(1S,2R)-3-[[(4-Aminophenyl)sulfonyl](isobutyl)amino]-
1-benzyl-2-hydroxypropyl]-2-oxo-3-phenyloxazolidine-5-car-
1
boxamide (24a): H NMR (400 MHz, CDCl3) δ 7.52-7.47 (m,
4H), 7.38 (t, J ) 8.4 Hz, 2H), 7.24-7.15 (m, 7H), 6.86 (d, J ) 8.8
Hz, 1H), 6.61 (d, J ) 8.8 Hz, 2H), 4.72 (dd, J ) 9.6, 6.4 Hz, 1H),
4.23-4.11 (m, 2H), 4.05 (dd, J ) 9.2, 6.0 Hz, 1H), 3.95 (m, 1H),
3.87 (br s, 1H), 3.14-2.96 (m, 3H), 2.89-2.80 (m, 3H), 1.78 (m,
1H), 0.86 (d, J ) 6.8 Hz, 3H), 0.82 (d, J ) 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 168.79, 153.29, 150.81, 137.68, 137.56,
129.61 (2C), 129.43 (2C), 129.34 (2C), 128.65 (2C), 126.79, 126.20,
124.83, 118.61 (2C), 114.32 (2C), 72.29, 70.12, 58.80, 54.30, 53.53,
48.18, 35.19, 27.33, 20.23, 20.12; HRMS (ESI) m/z C30H37N4O6S
(M + H)+ calcd 581.2434, found 581.2430.
(5S)-N-[(1S,2R)-3-[[(4-Aminophenyl)sulfonyl](isobutyl)amino]-
(5S)-3-(3-Acetylphenyl)-N-[(1S,2R)-3-[[(4-aminophenyl)sulfo-
nyl](isobutyl)amino]-1-benzyl-2-hydroxypropyl]-2-oxooxazoli-
1-benzyl-2-hydroxypropyl]-2-oxo-3-phenyloxazolidine-5-car-
1
boxamide (25a): H NMR (400 MHz, CDCl3) δ 7.56 (d, J ) 8.4
1
dine-5-carboxamide (25e): H NMR (400 MHz, CDCl3) δ 7.91
Hz, 2H), 7.43-7.37 (m, 5H), 7.18 (t, J ) 6.8 Hz, 1H), 7.10 (d, J
) 7.6 Hz, 2H), 6.98 (m, 3H), 6.87 (t, J ) 7.6 Hz, 1H), 6.69 (d, J
) 8.0 Hz, 2H), 4.77 (dd, J ) 9.6, 6.0 Hz, 1H), 4.23 (m, 1H), 4.02
(t, J ) 9.6 Hz, 1H), 3.93 (m, 1H), 3.31 (dd, J ) 9.2, 6.4 Hz, 1H),
3.19-3.0 (m, 3H), 2.93 (dd, J ) 13.6, 8.8 Hz, 1H), 2.82 (dd, J )
13.2, 6.8 Hz, 1H), 2.71 (t, J ) 13.2 Hz, 1H), 1.83 (m, 1H), 0.91
(d, J ) 6.4 Hz, 3H), 0.88 (d, J ) 6.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 168.82, 153.25, 150.64, 137.60, 137.47, 129.68
(2C), 129.51 (2C), 129.26 (2C), 128.46 (2C), 126.55, 126.41,
124.77, 118.49 (2C), 114.57 (2C), 72.45, 69.91, 58.89, 53.74, 53.50,
48.32, 35.63, 27.42, 20.32, 20.10; HRMS (ESI) m/z C30H37N4O6S
(M + H)+ calcd 581.2434, found 581.2438.
(t, J ) 2.0 Hz, 1H), 7.80-7.74 (m, 2H), 7.54 (d, J ) 8.8 Hz, 2H),
7.50 (t, J ) 7.6 Hz, 1H), 7.10 (d, J ) 7.2 Hz, 2H), 6.97 (t, J ) 7.2
Hz, 2H), 6.92 (d, J ) 10.0 Hz, 1H), 6.83 (t, J ) 7.2 Hz, 1H), 6.65
(d, J ) 8.8 Hz, 2H), 4.78 (dd, J ) 10.0, 6.0 Hz, 1H), 4.22 (m,
2H), 4.03 (t, J ) 9.6 Hz, 1H), 3.94 (m, 1H), 3.79 (br s, 1H), 3.34
(dd, J ) 9.2, 6.0 Hz, 1H), 3.15 (dd, J ) 15.2, 9.2 Hz, 1H), 3.08
(dd, J ) 14.0, 4.4 Hz, 1H), 3.01-2.90 (m, 2H), 2.80 (dd, J )
13.6, 6.8 Hz, 1H), 2.72 (dd, J ) 13.6, 11.2 Hz, 1H), 2.62 (s, 3H),
1.82 (m, 1H), 0.91 (d, J ) 6.4 Hz, 3H), 0.87 (d, J ) 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 197.64, 168.54, 153.15, 151.03,
138.12, 138.01, 137.62, 129.72 (2C), 129.63, 129.56 (2C), 128.47
(2C), 126.55, 126.14, 124.69, 123.0, 117.61, 114.30 (2C), 72.55,
69.94, 59.02, 53.84, 53.41, 48.23, 35.65, 27.47, 26.90, 20.34, 20.10;
HRMS (ESI) m/z C32H39N4O7S (M + H)+ calcd 623.2539, found
623.2543.
(5S)-N-[(1S,2R)-3-[[(4-Aminophenyl)sulfonyl](isobutyl)amino]-
1-benzyl-2-hydroxypropyl]-3-(3-fluorophenyl)-2-oxooxazolidine-
1
5-carboxamide (25b): H NMR (400 MHz, CDCl3) δ 7.58 (d, J
) 8.8 Hz, 2H), 7.38-7.33 (m, 2H), 7.12-7.08 (m, 3H), 7.01 (t, J
) 8.0 Hz, 2H), 6.93-6.85 (m, 2H), 6.70 (d, J ) 8.8 Hz, 3H), 4.78
(dd, J ) 10.0, 6.0 Hz, 1H), 4.22 (m, 2H), 4.01 (t, J ) 9.2 Hz, 1H),
3.91 (m, 1H), 3.73 (br s, 1H), 3.30 (dd, J ) 9.2, 5.6 Hz, 1H), 3.22
(dd, J ) 14.8, 9.2 Hz, 1H), 3.07 (dd, J ) 13.6, 4.4 Hz, 1H), 3.0
(dd, J ) 13.6, 8.8 Hz, 1H), 2.95 (dd, J ) 14.8, 2.4 Hz, 1H), 2.79
(dd, J ) 13.6, 6.8 Hz, 1H), 2.72 (dd, J ) 14.0, 10.8 Hz, 1H), 1.83
(m, 1H), 1.60 (br s, 1H), 0.95 (d, J ) 6.4 Hz, 3H), 0.89 (d, J ) 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.51, 163.22 (d, J )
244.2 Hz), 152.72, 150.92, 139.0 (d, J ) 10.6 Hz), 137.43, 130.50
(d, J ) 9.10 Hz), 129.77 (2C), 129.53 (2C), 128.54 (2C), 126.64,
126.33, 114.37 (2C), 113.50 (d, J ) 3.0 Hz), 111.52 (d, J ) 21.2
Hz), 106.06 (d, J ) 27.3 Hz), 72.46, 69.75, 59.11, 53.92, 53.40,
(5S)-3-(4-Acetylphenyl)-N-[(1S,2R)-3-[[(4-aminophenyl)sulfo-
nyl](isobutyl)amino]-1-benzyl-2-hydroxypropyl]-2-oxooxazoli-
dine-5-carboxamide (25f): 1H NMR (400 MHz, CDCl3) δ 8.04-
8.01 (m, 2H), 7.59-7.53 (m, 4H), 7.11 (d, J ) 6.8 Hz, 2H), 6.98
(t, J ) 7.6 Hz, 2H), 6.81 (t, J ) 7.2 Hz, 1H), 6.72-6.66 (m, 3H),
4.80 (dd, J ) 9.6, 5.6 Hz, 1H), 4.24 (m, 1H), 4.16 (br s, 2H), 4.06
(t, J ) 9.6 Hz, 1H), 3.91 (m, 1H), 3.74 (br s, 1H), 3.35 (dd, J )
9.6, 6.4 Hz, 1H), 3.24 (dd, J ) 15.2, 9.6 Hz, 1H), 3.08 (dd, J )
14.0, 4.8 Hz, 1H), 3.01 (dd, J ) 13.6, 8.8 Hz, 1H), 2.94 (dd, J )
14.8, 2.4 Hz, 1H), 2.79 (dd, J ) 13.2, 6.0 Hz, 1H), 2.73 (dd, J )
14.0, 11.2 Hz, 1H), 2.63 (s, 3H), 1.83 (m, 1H), 0.96 (d, J ) 6.8
Hz, 3H), 0.90 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 197.0, 168.39, 152.73, 151.0, 141.58, 137.52, 133.17, 129.81-

Aryloxazolidinonecarboxamides as NoVel P2 Ligands
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7351
(2C), 129.75 (2C), 129.55 (2C), 128.46 (2C), 126.60, 126.22, 117.58
(2C), 114.34 (2C), 72.47, 69.84, 59.08, 53.88, 53.40, 48.0, 35.54,
27.55, 26.68, 20.37, 20.11; HRMS (ESI) m/z C32H39N4O7S (M +
H)+ calcd 623.2539, found 623.2532.
NMR (100 MHz, CDCl3) δ 197.64, 168.68, 153.16, 151.72, 148.52,
138.10, 138.01, 137.61, 131.59, 129.62, 129.54 (2C), 128.50 (2C),
126.58, 124.71, 123.33, 123.0, 117.64, 108.56, 107.72, 102.55,
72.65, 69.96, 59.02, 53.86, 53.49, 48.25, 35.67, 27.44, 26.89, 20.29,
20.08; HRMS (ESI) m/z C33H38N3O9S (M + H)+ calcd 652.2329,
found 652.2324.
(5S)-N-[(1S,2R)-3-[[(Benzo[1,3]dioxole-5-sulfonyl)](isobutyl)-
amino]-1-benzyl-2-hydroxypropyl]-3-(3-fluorophenyl)-2-oxoox-
1
azolidine-5-carboxamide (26b): H NMR (400 MHz, CDCl3) δ
(5S)-3-(4-Acetylphenyl)-N-[(1S,2R)-3-[[(benzo[1,3]dioxole-5-
sulfonyl)](isobutyl)amino]-1-benzyl-2-hydroxypropyl]-2-oxoox-
7.38-7.30 (m, 3H), 7.20 (s, 1H), 7.13-7.08 (m, 3H), 7.02 (t, J )
8.0 Hz, 2H), 6.92-6.86 (m, 3H), 6.75 (d, J ) 9.6 Hz, 1H), 6.09 (s,
2H), 4.78 (dd, J ) 10.0, 6.0 Hz, 1H), 4.23 (m, 1H), 4.02 (t, J )
9.6 Hz, 1H), 3.93 (m, 1H), 3.64 (br s, 1H), 3.32 (dd, J ) 8.8, 5.6
Hz, 1H), 3.20 (dd, J ) 15.2, 9.2 Hz, 1H), 3.10 (dd, J ) 14.0, 4.4
Hz, 1H), 3.03-2.98 (m, 2H), 2.83 (dd, J ) 13.6, 6.4 Hz, 1H),
2.74 (dd, J ) 14.0, 10.8 Hz, 1H), 1.85 (m, 1H), 0.96 (d, J ) 6.8
Hz, 3H), 0.91 (d, J ) 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 168.63, 163.19 (d, J ) 243.4 Hz), 152.81, 151.77, 148.56, 139.01
(d, J ) 10.6 Hz), 137.45, 131.57, 130.48 (d, J ) 9.1 Hz), 129.49
(2C), 128.52 (2C), 126.63, 123.35, 113.52 (d, J ) 3.1 Hz), 111.50
(d, J ) 21.3 Hz), 108.58, 107.71, 106.06 (d, J ) 27.3 Hz), 102.56,
72.52, 69.81, 59.04, 53.87, 53.47, 48.20, 35.58, 27.48, 20.31, 20.07;
HRMS (ESI) m/z C31H35FN3O8S (M + H)+ calcd 628.2129, found
628.2127.
1
azolidine-5-carboxamide (26f): H NMR (400 MHz, CDCl3) δ
8.01 (d, J ) 8.8 Hz, 2H), 7.54 (d, J ) 8.8 Hz, 2H), 7.36 (dd, J )
8.4, 2.0 Hz, 1H), 7.19 (d, J ) 1.6 Hz, 1H), 7.11 (d, J ) 7.2 Hz,
2H), 6.98 (t, J ) 7.6 Hz, 2H), 6.89 (d, J ) 8.0 Hz, 1H), 6.83-6.79
(m, 2H), 6.08 (s, 2H), 4.81 (dd, J ) 9.6, 5.6 Hz, 1H), 4.24 (m,
1H), 4.07 (t, J ) 9.6 Hz, 1H), 3.95 (m, 1H), 3.64 (br s, 1H), 3.35
(dd, J ) 9.2, 6.0 Hz, 1H), 3.19 (dd, J ) 15.2, 9.2 Hz, 1H), 3.10
(dd, J ) 13.6, 4.4 Hz, 1H), 3.05-2.96 (m, 2H), 2.84 (dd, J )
13.2, 6.4 Hz, 1H), 2.73 (dd, J ) 13.6, 10.8 Hz, 1H), 2.62 (s, 3H),
1.86 (m, 1H), 0.94 (d, J ) 6.8 Hz, 3H), 0.90 (d, J ) 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 196.97, 168.48, 152.71, 151.79,
148.57, 141.55, 137.46, 133.17, 131.53, 129.80 (2C), 129.52 (2C),
128.49 (2C), 126.64, 123.36, 117.58 (2C), 108.60, 107.71, 102.58,
72.53, 69.84, 59.09, 53.90, 53.46, 48.0, 35.53, 27.51, 26.66, 20.32,
20.08; HRMS (ESI) m/z C33H38N3O9S (M + H)+ calcd 652.2329,
found 652.2325.
(5S)-N-[(1S,2R)-3-[[(Benzo[1,3]dioxole-5-sulfonyl)](isobutyl)-
amino]-1-benzyl-2-hydroxypropyl]-3-(3,4-difluorophenyl)-2-
oxooxazolidine-5-carboxamide (26c): 1H NMR (400 MHz, CDCl3)
δ 7.54-7.48 (m. 1H), 7.36 (dd, J ) 8.0, 1.6 Hz, 1H), 7.22-7.11
(m, 4H), 7.04-6.98 (m, 3H), 6.89 (t, J ) 4.0 Hz, 2H), 6.81 (d, J
) 9.6 Hz, 1H), 6.08 (s, 2H), 4.79 (dd, J ) 10.0, 5.6 Hz, 1H), 4.25
(m, 1H), 4.0 (t, J ) 9.6 Hz, 1H), 3.95 (m, 1H), 3.64 (br s, 1H),
3.30 (dd, J ) 9.2, 6.0 Hz, 1H), 3.17 (dd, J ) 15.2, 9.2 Hz, 1H),
3.10 (dd, J ) 13.6, 4.4 Hz, 1H), 3.05-2.95 (m, 2H), 2.85 (dd, J )
13.6, 6.4 Hz, 1H), 2.74 (dd, J ) 13.6, 10.8 Hz, 1H), 1.85 (m, 1H),
0.94 (d, J ) 6.0 Hz, 3H), 0.90 (d, J ) 6.8 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 168.49, 152.84, 151.79, 150.45 (dd, J ) 246.3,
12.9 Hz), 148.57, 147.39 (dd, J ) 245.0, 12.9 Hz), 137.49, 134.05
(m), 131.53, 129.53 (2C), 128.51 (2C), 126.59, 123.36, 117.60 (d,
J ) 18.2 Hz), 113.86 (d, J ) 3.8 Hz), 108.59, 108.37 (d, J ) 22.0
Hz), 107.71, 102.58, 72.54, 69.74, 59.07, 53.87, 53.42, 48.26, 35.50,
27.49, 20.31, 20.07; HRMS (ESI) m/z C31H34F2N3O8S (M + H)+
calcd 646.2034, found 646.2037.
(5S)-N-[(1S,2R)-1-Benzyl-3-[[(3-fluoro-4-methoxyphenyl)sul-
fonyl](isobutyl)amino]-2-hydroxypropyl]-3-(3-fluorophenyl)-2-
oxooxazolidine-5-carboxamide (27b): 1H NMR (400 MHz, CDCl3)
δ 7.58 (m, 1H), 7.51 (dd, J ) 10.4, 2.4 Hz, 1H), 7.38-7.32 (m,
2H), 7.13-7.05 (m, 4H), 7.02 (t, J ) 7.6 Hz, 2H), 6.92-6.86 (m,
2H), 6.83 (d, J ) 10.0 Hz, 1H), 4.80 (dd, J ) 10.0, 6.0 Hz, 1H),
4.24 (m, 1H), 4.03 (t, J ) 9.6 Hz, 1H), 3.95 (s, 3H, overlapping
signal), 3.94 (m, 1H, overlapping signal), 3.61 (d, J ) 3.2 Hz, 1H),
3.32 (dd, J ) 9.6, 6.0 Hz, 1H), 3.20 (dd, J ) 15.2, 9.2 Hz, 1H),
3.11 (dd, J ) 13.6, 4.4 Hz, 1H), 3.05 (dd, J ) 15.2, 2.8 Hz, 1H),
2.99 (dd, J ) 13.2, 8.4 Hz, 1H), 2.86 (dd, J ) 13.2, 6.4 Hz, 1H),
2.74 (dd, J ) 14.0, 10.8 Hz, 1H), 1.86 (m, 1H), 0.93 (d, J ) 6.4
Hz, 3H), 0.90 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 168.67, 163. 21 (d, J ) 244.2 Hz), 152.80, 151.95 (d, J ) 250.2
Hz), 151.83 (d, J ) 9.8 Hz), 139.0 (d, J ) 10.6 Hz), 137.37, 130.51
(d, J ) 9.1 Hz), 130.34 (d, J ) 4.5 Hz), 129.49 (2C), 128.56 (2C),
126.69, 124.89 (d, J ) 3.8 Hz), 115.60 (d, J ) 20.5 Hz), 113.53
(d, J ) 3 Hz), 113.19, 111.54 (d, J ) 21.2 Hz), 106.08 (d, J )
26.6 Hz), 72.48, 69.81, 58.91, 56.63, 53.78, 53.50, 48.21, 35.59,
27.46, 20.29, 20.06; HRMS (ESI) m/z C31H36F2N3O7S (M + H)+
calcd 632.2242, found 632.2258.
(5S)-N-[(1S,2R)-1-Benzyl-3-[[(3-fluoro-4-methoxyphenyl)sul-
fonyl](isobutyl)amino]-2-hydroxypropyl]-3-(3,4-difluorophenyl)-
2-oxooxazolidine-5-carboxamide (27c): 1H NMR (400 MHz,
CDCl3) δ 7.59-7.55 (m, 1H), 7.54-7.48 (m, 2H), 7.18 (q, J )
9.2 Hz, 1H), 7.12 (d, J ) 7.2 Hz, 2H), 7.07-6.97 (m, 4H), 6.90 (t,
J ) 7.2 Hz, 1H), 6.86 (d, J ) 10.0 Hz, 1H), 4.80 (dd, J ) 10.0,
6.0 Hz, 1H), 4.26 (m, 1H), 4.0 (t, J ) 9.2 Hz, 1H), 3.96 (m, 1H,
overlapping signal), 3.95 (s, 3H), 3.62 (d, J ) 3.6 Hz, 1H), 3.31
(dd, J ) 9.2, 6.0 Hz, 1H), 3.18 (dd, J ) 15.2, 9.2 Hz, 1H), 3.21-
3.04 (m, 2H), 2.97 (dd, J ) 13.6, 8.0 Hz, 1H), 2.87 (dd, J ) 13.6,
6.8 Hz, 1H), 2.74 (dd, J ) 13.6, 10.8 Hz, 1H), 1.86 (m, 1H), 0.92
(d, J ) 6.4 Hz, 3H), 0.89 (d, J ) 6.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 168.55, 152.88, 151.92 (d, J ) 250.2 Hz), 151.82
(d, J ) 10.6 Hz), 150.45 (dd, J ) 246.4, 12.9 Hz), 147.39 (dd, J
) 245.7, 12.9 Hz), 137.46, 134.03 (m), 130.32 (d, J ) 3.8 Hz),
129.51 (2C), 128.52 (2C), 126.61, 124.88 (d, J ) 3.8 Hz), 117.61
(d, J ) 18.2 Hz), 115.58 (d, J ) 21.2 Hz), 113.88 (q, J ) 3.8 Hz),
113.18, 108.37 (d, J ) 22.0 Hz), 72.50, 69.76, 58.86, 56.62, 53.72,
53.47, 48.28, 35.49, 27.42, 20.27, 20.06; HRMS (ESI) m/z
C31H35F3N3O7S (M + H)+ calcd 650.2148, found 650.2151.
(5S)-N-[(1S,2R)-1-Benzyl-3-[[(3-fluoro-4-methoxyphenyl)-
sulfonyl](isobutyl)amino]-2-hydroxypropyl]-2-oxo-3-[(3-trifluoro-
methyl)phenyl)]oxazolidine-5-carboxamide (27d): 1H NMR (400
MHz, CDCl3) δ 7.69 (d, J ) 8 Hz, 1H), 7.64 (br s, 1H), 7.59-
7.49 (m 3H), 7.45 (d, J ) 7.6 Hz, 1H), 7.12 (d, J ) 6.8 Hz, 2H),
7.05 (t, J ) 8.4 Hz, 1H), 6.99 (t, J ) 7.6 Hz, 2H), 6.87-6.82 (m,
(5S)-N-[(1S,2R)-3-[[(Benzo[1,3]dioxole-5-sulfonyl)](isobutyl)-
amino]-1-benzyl-2-hydroxypropyl]-2-oxo-3-[(3-trifluoromethyl)-
1
phenyl]oxazolidine-5-carboxamide (26d): H NMR (400 MHz,
CDCl3) δ 7.70 (dd, J ) 8.0, 1.2 Hz, 1H), 7.63 (s, 1H), 7.54 (t, J )
8.4 Hz, 1H), 7.46 (d, J ) 7.6 Hz, 1H), 7.37 (dd, J ) 8.4, 2.0 Hz,
2H), 7.20 (d, J ) 2.0 Hz, 1H), 7.11 (dd, J ) 8.4, 1.6 Hz, 1H), 6.99
(t, J ) 7.2 Hz, 2H), 6.90 (d, J ) 8.0 Hz, 1H), 6.85-6.80 (m, 2H),
6.09 (s, 2H), 4.81 (dd, J ) 10.0, 5.6 Hz, 1H), 4.26 (m, 1H), 4.05
(t, J ) 9.6 Hz, 1H), 3.94 (m, 1H), 3.65 (br s, 1H), 3.34 (dd, J )
9.6, 6.4 Hz, 1H), 3.20 (dd, J ) 14.8, 8.8 Hz, 1H), 3.11 (dd, J )
13.6, 4.4 Hz, 1H), 3.04-2.97 (m, 2H), 2.84 (dd, J ) 13.6, 7.2 Hz,
1H), 2.73 (dd, J ) 13.6, 11.2 Hz, 1H), 1.86 (m, 1H), 0.95 (d, J )
6.8 Hz, 3H), 0.91 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 168.54, 152.83, 151.82, 148.60, 138.11, 137.42, 131.78 (d, J )
32.6 Hz), 131.52, 129.94, 129.52 (2C), 129.54 (2C), 126.61, 123.38,
121.40, 121.27 (q, J ) 3.8 Hz), 115.02 (q, J ) 3.8 Hz), 108.62,
107.73, 102.59, 72.57, 69.86, 59.14, 53.94, 53.39, 51.05, 48.11,
35.58, 27.54, 20.34, 20.08; HRMS (ESI) m/z C32H35F3N3O8S (M
+ H)+ calcd 678.2097, found 678.2101.
(5S)-3-(3-Acetylphenyl)-N-[(1S,2R)-3-[[(benzo[1,3]dioxole-5-
sulfonyl)](isobutyl)amino]-1-benzyl-2-hydroxypropyl]-2-oxoox-
azolidine-5-carboxamide (26e):1H NMR (400 MHz, CDCl3) δ 7.95
(s, 1H), 7.77 (dd, J ) 7.6, 1.6 Hz, 2H), 7.52 (t, J ) 8.0 Hz, 1H),
7.36 (dd, J ) 8.0, 2.0 Hz, 1H), 7.19 (d, J ) 2.0 Hz, 1H), 7.13 (d,
J ) 6.8 Hz, 2H), 6.99 (t, J ) 7.6 Hz, 3H), 6.89-6.83 (m, 2H),
6.07 (d, J ) 2 Hz, 2H), 4.82 (dd, J ) 10.0, 6.0 Hz, 1H), 4.24 (m,
1H), 4.07 (t, J ) 9.6 Hz, 1H), 3.98 (m, 1H), 3.77 (br s, 1H), 3.38
(dd, J ) 9.2, 6.4 Hz, 1H), 3.20-3.11 (m, 2H), 3.06 (dd, J ) 15.2,
4.6 Hz, 1H), 2.97 (dd, J ) 13.2, 8.0 Hz, 1H), 2.87 (dd, J ) 13.2,
6.8 Hz, 1H), 2.75 (dd, J ) 14.0, 11.0 Hz, 1H), 2.64 (s, 3H), 1.87
(m, 1H), 0.93 (d, J ) 6.8 Hz, 3H), 0.90 (d, J ) 6.4 Hz, 3H); 13C

7352 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25
Ali et al.
2H), 4.81 (dd, J ) 10.0, 5.6 Hz, 1H), 4.27 (m, 1H), 4.06 (t, J )
10.0 Hz, 1H), 3.96 (m, 1H, overlapping signal), 3.95 (s, 3H), 3.61
(br s, 1H), 3.35 (dd, J ) 9.2, 5.6 Hz, 1H), 3.20 (dd, J ) 15.2, 9.2
Hz, 1H), 3.11 (dd, J ) 14.0, 4.4 Hz, 1H), 3.05 (dd, J ) 15.2, 3.2
Hz, 1H), 2.98 (dd, J ) 13.2, 8.0 Hz, 1H), 2.87 (dd, J ) 13.2, 6.8
Hz, 1H), 2.74 (dd, J ) 14, 10.8 Hz, 1H), 1.87 (m, 1H), 0.94 (d, J
) 6.4 Hz, 3H), 0.90 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 168.59, 152.88, 151.95 (d, J ) 250.9 Hz), 151.84 (d, J
) 10.7 Hz), 138.09, 137.40, 131.76 (d, J ) 32.5 Hz), 130.30,
129.94, 129.50 (2C), 128.54 (2C), 126.62, 124.89 (d, J ) 3.8 Hz),
121.40, 121.25 (q, J ) 3.8 Hz), 115.60 (d, J ) 20.5 Hz), 115.04
(q, J ) 3.8 Hz), 113.19, 72.53, 69.88, 58.92, 56.63, 53.78, 53.43,
48.13, 35.56, 27.46, 20.29, 20.06; HRMS (ESI) m/z C32H36F4N3O7S
(M + H)+ calcd 682.2210, found 682.2203.
(S)-3-(3-Acetylphenyl)-N-[(1S,2R)-1-benzyl-3-[[(3-fluoro-4-
methoxyphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl]-2-
oxooxazolidine-5-carboxamide (27e): 1H NMR (400 MHz, CDCl3)
δ 7.96 (m, 1H), 7.78-7.73 (m, 2H), 7.59-7.48 (m, 3H), 7.13 (d,
J ) 7.2 Hz, 2H), 7.07-6.98 (m, 4H), 6.85 (t, J ) 8.0 Hz, 1H),
4.82 (dd, J ) 9.6, 5.6 Hz, 1H), 4.25 (m, 1H), 4.07 (t, J ) 9.6 Hz,
1H), 3.99 (br s, 1H), 3.94 (s, 3H), 3.75 (m, 1H), 3.41-3.37 (m,
1H), 3.21-3.06 (m, 3H), 3.0-2.86 (m, 2H), 2.76 (dd, J ) 14.0,
11.2 Hz, 1H), 2.64 (s, 3H), 1.88 (m, 1H), 0.92 (d, J ) 6.8 Hz,
3H), 0.89 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
197.65, 168.71, 153.18, 151.90 (d, J ) 251.0 Hz), 151.74 (d, J )
9.9 Hz), 138.09, 138.01, 137.59, 130.46 (d, J ) 4.5 Hz), 129.62,
129.53 (2C), 128.51 (2C), 126.61, 124.86 (d, J ) 3.8 Hz), 124.74,
122.98, 117.64, 115.58 (d, J ) 20.4 Hz), 113.17, 72.60, 69.98,
58.82, 56.60, 53.69, 53.55, 48.26, 35.68, 27.38, 26.88, 20.25, 20.06;
HRMS (ESI) m/z C33H39FN3O8S (M + H)+ calcd 656.2442, found
656.2441.
(S)-3-(4-Acetylphenyl)-N-[(1S,2R)-1-Benzyl-3-[[(3-fluoro-4-
methoxyphenyl)sulfonyl](isobutyl)amino]-2-hydroxypropyl]-2-
oxooxazolidine-5-carboxamide (27f): 1H NMR (400 MHz, CDCl3)
δ 8.01 (d, J ) 8.8 Hz, 2H), 7.58-7.52 (m, 3H), 7.50 (dd, J )
10.4, 2.4 Hz, 1H), 7.11 (d, J ) 8.0 Hz, 2H), 7.04 (t, J ) 8.4 Hz,
1H), 6.97 (t, J ) 7.6 Hz, 2H), 6.92 (d, J ) 9.6 Hz, 1H), 6.82 (t, J
) 7.2 Hz, 1H), 4.82 (dd, J ) 9.6, 5.6 Hz, 1H), 4.26 (m, 1H), 4.08
(t, J ) 10.0 Hz, 1H), 3.98 (m, 1H), 3.94 (s, 3H), 3.68 (br s, 1H),
3.35 (dd, J ) 9.6, 6.4 Hz, 1H), 3.18 (dd, J ) 15.2, 8.8 Hz, 1H),
3.13-3.06 (m, 2H), 2.97 (dd, J ) 13.2, 8.0 Hz, 1H), 2.89 (dd, J )
13.6, 6.8 Hz, 1H), 2.74 (dd, J ) 14.0, 11.2 Hz, 1H), 2.61 (s, 3H),
1.87 (m, 1H), 0.91 (d, J ) 6.4 Hz, 3H), 0.89 (d, J ) 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 197.0, 168.55, 152.78, 151.90 (d,
J ) 251.0 Hz), 151.78 (d, J ) 10.7 Hz), 141.54, 137.46, 133.15,
130.31, 129.78 (2C), 129.50 (2C), 128.47 (2C), 126.63, 124.86 (d,
J ) 3.0 Hz), 117.58 (2C), 115.56 (d, J ) 20.5 Hz), 113.18, 72.49,
69.88, 58.83, 56.60, 53.69, 53.50, 48.01, 35.49, 27.39, 26.64, 20.26,
20.06; HRMS (ESI) m/z C33H39FN3O8S (M + H)+ calcd 656.2442,
found 656.2448.
(5S)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl[[(4-trifluo-
romethoxy)phenyl]sulfonyl]amino]propyl]-2-oxo-3-[(3-trifluo-
romethyl)phenyl]oxazolidine-5-carboxamide (28d): 1H NMR
(400 MHz, CDCl3) δ 7.88-7.85 (m, 2H), 7.70 (d, J ) 8.0 Hz,
1H), 7.63 (s, 1H), 7.54 (dt, J ) 8.0, 2.4 Hz, 1H), 7.46 (d, J ) 8.0
Hz, 1H), 7.37 (dd, J ) 7.6, 1.2 Hz, 2H), 7.12 (dd, J ) 7.6, 1.2 Hz,
2H), 7.03-6.98 (m, 2H), 6.85 (dt, J ) 8.0, 2.4 Hz, 1H), 6.70 (d,
J ) 8.0 Hz, 1H), 4.81 (dd, J ) 9.6, 6.0 Hz, 1H), 4.26 (m, 1H),
4.06 (t, J ) 10.0 Hz, 1H), 3.94 (m, 1H), 3.54 (br s, 1H), 3.37 (dd,
J ) 10.0, 6.0 Hz, 1H), 3.25 (dd, J ) 15.6, 9.2 Hz, 1H), 3.13-3.02
(m, 3H), 2.87 (dd, J ) 13.6, 6.0 Hz, 1H), 2.71 (dd, J ) 13.6, 9.6
Hz, 1H), 1.87 (m, 1H), 0.96 (d, J ) 6.4 Hz, 3H), 0.91 (d, J ) 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.61, 152.78, 152.57,
138.06, 137.26, 136.82, 131.81 (d, J ) 32.6 Hz), 129.96 129.71
(2C), 129.48 (2C), 128.61 (2C), 126.69, 121.40, 121.33, 121.27
(2C), 115.02 (m), 72.50, 69.84, 58.90, 53.79, 53.47, 51.07, 48.10,
35.56, 27.49, 20.28, 20.02; HRMS (ESI) m/z C32H34F6N3O7S (M
+ H)+ calcd 718.2021, found 718.2028.
7.90-7.77 (m, 5H), 7.53 (t, J ) 8.0 Hz, 1H), 7.36 (d, J ) 8.8 Hz,
2H), 7.13 (d, J ) 8.0 Hz, 2H), 7.03 (t, J ) 8.0 Hz, 2H), 6.87 (t, J
) 7.6 Hz, 1H), 6.83 (d, J ) 9.6 Hz, 1H), 4.82 (dd, J ) 9.6, 5.6
Hz, 1H), 4.25 (m, 1H), 4.09 (t, J ) 10.0 Hz, 1H), 3.94 (m, 1H),
3.59 (d, J ) 3.2 Hz, 1H), 3.42 (dd, J ) 9.6, 6.0 Hz, 1H), 3.25 (dd,
J ) 15.2, 9.2 Hz, 1H), 3.13 (dd, J ) 14.4, 4.8 Hz, 1H), 3.07-3.02
(m, 2H), 2.88 (dd, J ) 13.2, 6.4 Hz, 1H), 2.75 (dd, J ) 13.6, 10.8
Hz, 1H), 2.65 (s, 3H), 1.87 (m, 1H), 0.95 (d, J ) 6.8 Hz, 3H),
0.90 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.53,
168.68, 152.95, 152.55, 138.06, 137.27, 136.85, 129.72 (2C),
129.68, 129.50 (2C), 128.65 (2C), 126.77, 124.79, 123.01, 121.27
(2C), 117.53, 72.52, 69.89, 58.93, 53.84, 53.54, 48.21, 35.65, 27.51,
26.90, 20.29, 20.03; HRMS (ESI) m/z C33H37F3N3O8S (M + H)+
calcd 692.2253, found 692.2244.
(5S)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl[(3-methoxy-
phenyl)sulfonyl]amino]propyl]-2-oxo-3-phenyloxazolidine-5-
1
carboxamide (29a): H NMR (400 MHz, CDCl3) δ 7.46-7.36
(m, 6H), 7.31 (t, J ) 2.8 Hz, 1H), 7.20 (m, 1H), 7.12 (m, 3H),
7.02 (t, J ) 7.2 Hz, 2H), 6.88 (t, J ) 7.6 Hz, 1H), 6.77 (d, J ) 10
Hz, 1H), 4.78 (dd, J ) 10.0, 6.0 Hz, 1H), 4.22 (m, 1H), 4.04 (t, J
) 9.6 Hz, 1H), 3.93 (m, 1H), 3.86 (s, 3H), 3.64 (br s, 1H), 3.36
(dd, J ) 8.8, 5.6 Hz, 1H), 3.25 (dd, J ) 15.6, 9.6 Hz, 1H), 3.12
(dd, J ) 14.0, 4.4 Hz, 1H), 3.07-3.01 (m, 2H), 2.87 (dd, J )
13.6, 6.4 Hz, 1H), 2.73 (dd, J ) 14.0, 10.8 Hz, 1H), 1.86 (m, 1H),
0.96 (d, J ) 6.4 Hz, 3H), 0.90 (d, J ) 6.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 168.89, 160.23, 153.02, 139.53, 137.49, 137.37,
130.51, 129.49 (2C), 129.31 (2C), 128.59 (2C), 126.71, 124.82,
119.65, 119.16, 118.47 (2C), 112.65, 72.47, 69.82, 59.03, 55.91,
53.91, 53.56, 48.29, 35.70, 27.53, 20.31, 20.06; HRMS (ESI) m/z
C31H38N3O7S (M + H)+ calcd 596.2430, found 596.2435.
(5S)-3-(4-Acetylphenyl)-N-[(1S,2R)-1-benzyl-2-hydroxy-3-[isobu-
tyl[(3-methoxyphenyl)sulfonyl]amino]propyl]-2-oxooxazolidine-
1
5-carboxamide (29f): H NMR (400 MHz, CDCl3) δ 8.0 (d, J )
8.8 Hz, 2H), 7.54 (d, J ) 8.8 Hz, 2H), 7.43 (t, J ) 7.6 Hz, 1H),
7.36 (d, J ) 8.8 Hz, 1H), 7.30 (t, J ) 2.4 Hz, 1H), 7.10 (d, J ) 7.6
Hz, 3H), 6.97 (t, J ) 7.6 Hz, 2H), 6.85 (d, J ) 10.0 Hz, 1H), 6.80
(t, J ) 7.6 Hz, 1H), 4.81 (dd, J ) 9.6, 5.6 Hz, 1H), 4.25 (m, 1H),
4.06 (t, J ) 9.6 Hz, 1H), 3.96 (m, 1H), 3.85 (s, 3H), 3.68 (br s,
1H), 3.34 (dd, J ) 9.2, 6.0 Hz, 1H), 3.23 (dd, J ) 15.4, 9.2 Hz,
1H), 3.12-3.05 (m, 2H), 3.02 (dd, J ) 13.6, 8.4 Hz, 1H), 2.89
(dd, J ) 13.6, 7.2 Hz, 1H), 2.74 (dd, J ) 14.0, 11.2 Hz, 1H), 2.61
(s, 3H), 1.87 (m, 1H), 0.93 (d, J ) 6.4 Hz, 3H), 0.90 (d, J ) 6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 196.97, 168.49, 160.19,
152.72, 141.54, 139.49, 137.46, 133.14, 130.50, 129.78 (2C), 129.50
(2C), 128.46 (2C), 126.61, 119.61, 119.06, 117.57 (2C), 112.70,
72.47, 69.84, 58.97, 55.89, 53.81, 53.47, 47.99, 35.49, 27.46, 26.65,
20.28, 20.05; HRMS (ESI) m/z C33H40N3O8S (M + H)+ calcd
638.2536, found 638.2538.
(5S)-N-[(1S,2R)-1-Benzyl-3-[(cyclopropylmethyl)[(3-methoxy-
phenyl)sulfonyl]amino]-2-hydroxypropyl]-3-(3-fluorophenyl)-2-
oxooxazolidine-5-carboxamide (36b): 1H NMR (400 MHz, CDCl3)
δ 7.74 (d, J ) 9.2 Hz, 2H), 7.38-7.32 (m, 1H), 7.13 (d, J ) 6.8
Hz, 2H), 7.09 (dd, J ) 8.8, 2.0 Hz, 1H), 7.04-6.97 (m, 4H), 6.92-
6.86 (m, 2H), 6.80 (d, J ) 10.0 Hz, 1H), 4.79 (dd, J ) 10.0, 5.6
Hz, 1H), 4.28 (m, 1H), 4.02 (t, J ) 9.2 Hz, 2H), 3.87 (s, 3H), 3.62
(br s, 1H), 3.36-3.10 (m, 5H), 2.96 (dd, J ) 14.0, 7.2 Hz, 1H),
2.78 (dd, J ) 14.0, 11.2 Hz, 1H), 0.87 (m, 1H), 0.56-0.53 (m,
2H), 0.18 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 168.63, 163.26,
163.20 (d, J ) 244.2 Hz), 152.77, 139.03 (d, J ) 10.6 Hz), 137.49,
130.53, 130.44, 129.57 (2C), 129.51 (2C), 128.54 (2C), 126.63,
114.61 (2C), 113.52 (d, J ) 3.1 Hz), 111.51 (d, J ) 21.2 Hz),
106.07 (d, J ) 27.3 Hz), 72.36, 69.81, 55.82, 55.04, 53.40, 52.15,
48.21, 35.57, 10.07, 4.72, 4.26; HRMS (ESI) m/z C31H35FN3O7S
(M + H)+ calcd 612.2179, found 612.2180.
(5S)-N-[(1S,2R)-1-Benzyl-3-[(cyclopropylmethyl)[(3-methoxy-
phenyl)sulfonyl]amino]-2-hydroxypropyl]-3-(3,4-difluorophenyl)-2-
oxooxazolidine-5-carboxamide (36c): 1H NMR (400 MHz, CDCl3)
δ 7.74 (d, J ) 8.8 Hz, 2H), 7.54-7.48 (m, 1H), 7.19 (q, J ) 9.6
Hz, 1H), 7.13 (d, J ) 7.6 Hz, 2H), 7.05-6.96 (m, 5H), 6.90 (t, J
) 7.6 Hz, 1H), 6.82 (d, J ) 10.0 Hz, 1H), 4.80 (dd, J ) 10.0, 5.6
Hz, 1H), 4.29 (m, 1H), 4.04 (m, 1H), 4.0 (t, J ) 9.2 Hz, 1H), 3.87
(5S)-3-(3-Acetylphenyl)-N-[(1S,2R)-1-benzyl-2-hydroxy-3-[isobu-
tyl[[(4-trifluoromethoxy)phenyl]sulfonyl]amino]propyl]-2-oxoox-
1
azolidine-5-carboxamide (28e): H NMR (400 MHz, CDCl3) δ

Aryloxazolidinonecarboxamides as NoVel P2 Ligands
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25 7353
(s, 3H), 3.60 (br s, 1H) 3.35-3.24 (m, 3H), 3.21-3.10 (m, 2H),
2.96 (dd, J ) 14.4, 7.6 Hz, 1H), 2.79 (dd, J ) 14.0, 10.8 Hz, 1H),
0.91-0.83 (m, 1H), 0.54 (m, 2H), 0.18 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 168.51, 163.27, 152.83, 150.46 (d, J ) 246.4 Hz),
147.38 (d, J ) 245.6 Hz), 137.57, 134.05 (m), 130.42, 129.56 (2C),
129.55 (2C), 128.51 (2C), 126.57, 117.59 (d, J ) 17.4 Hz), 114.60
(2C), 113.87 (d, J ) 3.8 Hz), 108.38 (d, J ) 22.7 Hz), 72.38, 69.76,
55.82, 55.03, 53.37, 52.12, 48.28, 35.48, 10.05, 4.71, 4.26; HRMS
(ESI) m/z C31H34F2N3O7S (M + H)+ calcd 630.2086, found
630.2077.
(5S)-3-(4-Acetylphenyl)-N-[(1S,2R)-1-Benzyl-3-[(cyclopropyl-
methyl)[(3-methoxyphenyl)sulfonyl]amino]-2-hydroxypropyl]-2-
oxooxazolidine-5-carboxamide (36f): 1H NMR (400 MHz, CDCl3)
δ 8.02 (d, J ) 9.2 Hz, 2H), 7.74 (d, J ) 8.8 Hz, 2H), 7.55 (d, J )
8.8 Hz, 2H), 7.12 (d, J ) 7.6 Hz, 2H), 7.02-6.97 (m, 4H), 6.83 (t,
J ) 6.8 Hz, 1H), 6.69 (d, J ) 9.6 Hz, 1H), 4.81 (dd, J ) 10.4, 6.0
Hz, 1H), 4.28 (m, 1H), 4.08 (t, J ) 9.6 Hz, 1H), 4.02 (m, 1H),
3.87 (s, 3H), 3.54 (d, J ) 2.4 Hz, 1H), 3.39 (dd, J ) 9.2, 5.6 Hz,
1H), 3.30 (dd, J ) 15.2, 8.8 Hz, 1H), 3.23-3.18 (m, 2H), 3.12
(dd, J ) 14.4, 4.8 Hz, 1H), 2.94 (dd, J ) 14.0, 7.2 Hz, 1H), 2.78
(dd, J ) 13.6, 10.4 Hz, 1H), 2.62 (s, 3H), 0.88 (m, 1H), 0.56 (d,
J ) 7.6 Hz, 2H), 0.23-0.15 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 196.97, 168.50, 163.24, 152.74, 141.57, 137.58, 133.13, 130.44,
129.78 (2C), 129.54 (4C), 128.46 (2C), 126.58, 117.58 (2C), 114.59
(2C), 72.38, 69.89, 55.80, 55.0, 53.40, 52.09, 48.01, 35.49, 26.65,
10.02, 4.69, 4.26; HRMS (ESI) m/z C33H38N3O8S (M + H)+ calcd
636.2379, found 636.2369.
J ) 13.6, 10.4, Hz, 1H), 2.62 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 196.98, 168.56, 160.31, 152.63, 141.54, 139.81, 138.25, 137.27,
133.20, 130.63, 129.84 (2C), 129.51 (2C), 128.52 (2C), 128.34,
127.22, 127.10, 126.66, 119.67, 119.58, 117.57 (2C), 112.41, 72.01,
69.75, 55.93, 53.28, 51.73, 48.29, 47.97, 35.58, 26.68; HRMS (ESI)
m/z C34H36N3O8S2 (M + H)+ calcd 678.1944, found 678.1953.
(5S)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[(2-thiophenylmethyl)-
[(2,4,5-trifluorophenyl)sulfonyl]amino]propyl]-2-oxo-3-
1
phenyloxazolidine-5-carboxamide (38a): H NMR (400 MHz,
CDCl3) δ 7.76-7.70 (m, 1H), 7.43-7.36 (m, 4H), 7.19-7.16 (m,
2H), 7.08-7.01 (m, 5H), 6.93-6.86 (m, 3H), 6.67 (d, J ) 9.2 Hz,
1H), 4.79-4.67 (m, 3H), 4.12 (m, 1H), 4.06 (t, J ) 9.6 Hz, 1H),
3.79 (m, 1H), 3.49-3.33 (m, 4H), 3.02 (dd, J ) 14.0, 4.4 Hz, 1H),
2.69 (dd, J ) 14.0, 10.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
169.21, 154.8 (dd, J ) 253.2, 10.6 Hz), 153.45 (dt, J ) 257.0,
13.6 Hz), 153.05, 146.48 (dd, J ) 253.2, 13.2 Hz), 137.57, 137.44,
137.14, 129.43 (2C), 129.34 (2C), 128.68 (2C), 127.20, 127.14,
126.81, 124.89, 119.64 (d, J ) 22.0 Hz), 118.51 (2C), 107.72 (dd,
J ) 27.3, 21.2 Hz), 72.10, 69.81, 53.78, 51.05, 51.02, 48.29, 47.63,
35.45, 29.88; HRMS (ESI) m/z C31H29F3N3O6S2 (M + H)+ calcd
660.1450, found 660.1462.
(5S)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[(2-thiophenylmethyl)-
[(2,4,5-trifluorophenyl)sulfonyl]amino]propyl]-3-(3-fluorophe-
nyl)-2-oxooxazolidine-5-carboxamide (38b): 1H NMR (400 MHz,
CDCl3): δ 7.78-7.72 (m, 1H), 7.39-7.32 (m, 2H), 7.22 (d, J )
4.8, 1.2 Hz, 1H), 7.11-7.03 (m, 6H), 6.95-6.87 (m, 4H), 6.55 (d,
J ) 9.2 Hz, 1H), 4.79-4.69 (m, 3H), 4.14 (m, 1H), 4.05 (t, J )
9.6 Hz, 1H), 3.78 (m, 1H), 3.47-3.35 (m, 3H), 3.18 (d, J ) 4.0
Hz, 1H), 3.04 (dd, J ) 14.0, 4.8 Hz, 1H), 2.72 (dd, J ) 14.0, 11.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.94, 164.42, 161.98,
154.75 (dd, J ) 250.0, 10.6 Hz), 153.43 (dt, J ) 248.0, 10.4 Hz)),
152.83, 146.32 (dd, J ) 248.2, 10.4 Hz), 138.97 (d, J ) 10.6 Hz),
137.51, 137.21, 130.52 (d, J ) 9.5 Hz), 129.43 (2C), 128.72, 128.62
(2C), 127.17, 127.09, 126.74, 119.61 (d, J ) 22.0 Hz), 113.55,
111.58 (d, J ) 21.2 Hz), 107.69 (dd, J ) 27.3, 21.3 Hz), 106.10
(d, J ) 27.3 Hz), 72.24, 69.81, 53.71, 50.94, 48.21, 47.55, 35.40;
HRMS (ESI) m/z C31H28F4N3O6S2 (M + H)+ calcd 678.1355, found
678.1377.
(S)-3-(4-Acetylphenyl)-N-[(2S,3R)-1-Benzyl-2-hydroxy-3-[(2-
thiophenylmethyl)[(2,4,5-trifluorophenyl)sulfonyl]amino]propyl]-
2-oxooxazolidine-5-carboxamide (38f): 1H NMR (400 MHz,
CDCl3) δ 8.02 (d, J ) 9.2 Hz, 2H), 7.78-7.72 (m, 1H), 7.55 (d,
J ) 9.2 Hz, 2H), 7.21 (dd, J ) 5.2, 1.2 Hz, 1H), 7.10-6.99 (m,
5H), 6.93-6.85 (m, 3H), 6.67 (d, J ) 8.8 Hz, 1H), 4.82-4.70 (m,
3H), 4.17 (m, 1H), 4.10 (t, J ) 10 Hz, 1H), 3.84 (m, 1H), 3.50-
3.36 (m, 3H), 3.30 (d, J ) 4.0 Hz, 1H), 3.04 (dd, J ) 14.0, 4.4 Hz,
1H), 2.71 (dd, J ) 14.0, 10.8 Hz, 1H), 2.62 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 196.97, 168.80, 154.50 (dd, J ) 252.3, 10.8
Hz), 153.4 (dt, J ) 255.6, 12.2 Hz), 152.68, 146.28 (dd, J ) 252.4,
10.5 Hz), 141.51, 137.53, 137.17, 133.25, 129.84 (2C), 129.45 (2C),
128.71, 128.62 (2C), 127.21, 127.16, 126.78, 119.76 (d, J ) 22.0
Hz), 117.61 (2C), 107.74 (dd, J ) 27.3, 21.2 Hz), 72.22, 69.81,
53.69, 51.09, 51.06, 48.0, 47.66, 35.43, 26.67; HRMS (ESI) m/z
C33H31F3N3O7S2 (M + H)+ calcd 702.1555, found 702.1561.
(5S)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[[(3-methoxyphenyl)-
sulfonyl][(R)-(tetrahydro-2-furanyl)methyl]amino]propyl]-2-
oxo-3-phenyloxazolidine-5-carboxamide (39a): 1H NMR (400
MHz, CDCl3) δ 7.47-7.38 (m, 5H), 7.35 (d, J ) 7.6 Hz, 1H),
7.29 (d, J ) 1.8 Hz, 1H), 7.19 (t, J ) 7.2 Hz, 2H), 7.11 (m, 3H),
7.0 (t, J ) 7.6 Hz, 2H), 6.89 (t, J ) 7.6 Hz, 1H), 6.83 (d, J ) 10
Hz, 1H), 5.27 (br s, 1H), 4.81 (dd, J ) 10.4, 6.0 Hz, 1H), 4.31-
4.18 (m, 2H), 4.05 (t, J ) 9.6 Hz, 1H), 4.0 (t, J ) 10.0 Hz, 1H),
3.92-3.80 (m, 2H, overlapping signal), 3.88 (s, 3H, overlapping
signal), 3.66 (dt, J ) 15.2, 2.4 Hz, 1H), 3.43 (dd, J ) 9.2, 6.0 Hz,
1H), 3.05 (dd, J ) 14.0, 4.4 Hz, 1H), 2.88 (dd, J ) 9.2, 4.8 Hz,
1H), 2.84 (dd, J ) 9.6, 4.8 Hz, 1H), 2.72 (dd, J ) 13.2, 10.0 Hz,
1H), 2.04 (m, 1H), 1.92 (m, 2H), 1.47 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 168.53, 160.22, 153.13, 139.78, 137.65, 137.57,
130.53, 129.67 (2C), 129.28 (2C), 128.44 (2C), 126.55, 124.67,
119.45, 119.02, 118.44 (2C), 112.68, 80.49, 73.81, 69.87, 68.48,
(5S)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[[(3-methoxyphenyl)-
sulfonyl](2-thiophenylmethyl)]amino]propyl]-2-oxo-3-phenylox-
1
azolidine-5-carboxamide (37a): H NMR (400 MHz, CDCl3) δ
7.45-7.38 (m, 6H), 7.32 (d, J ) 2.0 Hz, 1H), 7.22-7.17 (m, 2H),
7.13 (m, 1H), 7.08 (d, J ) 8.0 Hz, 2H), 7.02 (t, J ) 7.6 Hz, 2H),
6.93-6.88 (m, 3H), 6.57 (d, J ) 9.6 Hz, 1H), 4.72 (dd, J ) 10.0,
6.0 Hz, 1H), 4.65 (AB, d, J ) 15.6 Hz, 1H), 4.59 (AB, d, J ) 15.6
Hz, 1H), 4.10 (m, 1H), 4.05 (t, J ) 9.6 Hz, 1H), 3.85 (s, 3H), 3.66
(dd, J ) 11.2, 6.4 Hz, 1H), 3.48 (br s, 1H), 3.43 (dd, J ) 9.2, 6.0
Hz, 1H), 3.24 (m, 2H), 3.04 (dd, J ) 14.0, 4.0 Hz, 1H), 2.68 (dd,
J ) 14.0, 10.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.97,
160.30, 153.01, 139.91, 138.26, 137.49, 137.29, 130.59, 129.50
(2C), 129.31 (2C), 128.59 (2C), 128.34, 127.21, 127.07, 126.67,
124.82, 119.68, 119.59, 118.47 (2C), 112.34, 71.96, 69.78, 55.91,
53.36, 51.68, 48.27, 48.20, 35.61; HRMS (ESI) m/z C32H34N3O7S2
(M + H)+ calcd 636.1838, found 636.1864.
(5S)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[[(3-methoxyphenyl)-
sulfonyl](2-thiophenylmethyl)]amino]propyl]-3-(3-fluorophenyl)-
2-oxooxazolidine-5-carboxamide (37b): 1H NMR (400 MHz,
CDCl3) δ 7.47-7.34 (m, 4H), 7.32 (t, J ) 2.0 Hz, 1H), 7.24 (t, J
) 3.2 Hz, 1H), 7.14 (m, 1H), 7.10-7.01 (m, 5H), 6.93-6.87 (m,
4H), 6.43 (d, J ) 9.2 Hz, 1H), 4.72 (dd, J ) 10.0, 5.6 Hz, 1H),
4.65 (AB d, J ) 15.6 Hz, 1H), 4.58 (AB d, J ) 15.6 Hz, 1H), 4.11
(m, 1H), 4.02 (t, J ) 10.0 Hz, 1H), 3.86 (s, 3H), 3.63 (m, 1H),
3.38 (dd, J ) 9.2, 5.6 Hz, 1H), 3.29-3.17 (m, 2H), 3.04 (dd, J )
14.0, 4.4, Hz, 1H), 2.67 (dd, J ) 13.6, 10.4, Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 168.70, 163.19 (d, J ) 244.1 Hz), 160.28,
152.76, 139.91, 139.01 (d, J ) 10.6 Hz), 138.24, 137.32, 130.59,
130.51 (d, J ) 9.8 Hz), 129.49 (2C), 128.53 (2C), 128.35, 127.18,
127.04, 126.62, 119.66, 119.56, 113.51 (d, J ) 2.2 Hz), 112.37,
111.52 (d, J ) 21.3 Hz), 106.05 (d, J ) 26.5 Hz), 72.04, 69.74,
55.91, 53.30, 51.58, 48.16, 48.15, 35.56; HRMS (ESI) m/z C32H33-
FN3O7S2 (M + H)+ calcd 654.1744, found 654.1766.
(S)-3-(4-Acetylphenyl)-N-[(2S,3R)-1-benzyl-2-hydroxy-3-[[(3-
methoxyphenyl)sulfonyl](2-thiophenylmethyl)]amino]propyl]-2-
oxooxazolidine-5-carboxamide (37f): 1H NMR (400 MHz, CDCl3)
δ 8.02 (d, J ) 8.8 Hz, 2H), 7.55 (d, J ) 9.2 Hz, 2H), 7.45 (t, J )
7.6 Hz, 1H), 7.40 (d, J ) 7.6 Hz, 1H), 7.32 (t, J ) 2.4 Hz, 1H),
7.23 (dd, J ) 4.4, 2.8 Hz, 1H), 7.13 (m, 1H), 7.07 (d, J ) 7.2 Hz,
2H), 6.99 (t, J ) 7.6 Hz, 2H), 6.91 (m, 2H), 6.84 (t, J ) 7.6 Hz,
1H), 6.54 (d, J ) 9.6 Hz, 1H), 4.76 (dd, J ) 10.0, 6.0 Hz, 1H),
4.65 (AB d, J ) 15.2 Hz, 1H), 4.59 (AB d, J ) 15.2 Hz, 1H), 4.14
(m, 1H), 4.07 (t, J ) 9.6 Hz, 1H), 3.85 (s, 3H), 3.68 (m, 1H), 3.41
(m, 2H), 3.24 (m, 2H), 3.04 (dd, J ) 14.0, 4.4, Hz, 1H), 2.67 (dd,

7354 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 25
Ali et al.
56.48, 56.27, 55.91, 52.90, 48.29, 35.96, 29.22, 25.46; HRMS (ESI)
m/z C32H38N3O8S (M + H)+ calcd 624.2379, found 624.2390.
(5S)-N-[(1S,2R)-1-Benzyl-2-hydroxy-3-[[(3-methoxyphenyl)-
sulfonyl][(R)-(tetrahydro-2-furanyl)methyl]amino]propyl]-3-(3-
fluorophenyl)-2-oxooxazolidine-5-carboxamide (39b): 1H NMR
(400 MHz, CDCl3) δ 7.42 (t, J ) 7.6 Hz, 1H), 7.38-7.32 (m, 2H),
7.28 (t, J ) 2.4 Hz, 1H), 7.11 (m, 4H), 7.0 (t, J ) 7.2 Hz, 2H),
6.91-6.86 (m, 2H), 6.84 (d, J ) 9.6 Hz, 1H), 5.28 (d, J ) 2.8 Hz,
1H), 4.82 (dd, J ) 10.0, 5.6 Hz, 1H), 4.31-4.19 (m, 2H), 4.02 (m,
2H), 3.92-3.80 (m, 2H, overlapping signal), 3.85 (s, 3H, overlap-
ping signal), 3.69-3.64 (m, 2H), 3.39 (dd, J ) 9.2, 5.6 Hz, 1H),
3.05 (dd, J ) 14.0, 4.4 Hz, 1H), 2.89-2.82 (m, 2H), 2.71 (dd, J )
using Refmac544 was performed by incorporating Schomaker and
Trueblood tensor formulation of TLS (translation, libration, screw-
rotation) parameters.45-47 The working R (Rfactor) and its cross-
validation (Rfree) were monitored throughout the refinement. The
refinement statistics are also shown in Table 1. Figures were made
using MIDASPlus.48 The structures of 21e- and 21f-protease
complexes were deposited in the PDB with accession codes 2I0D
and 2I0A, respectively.
Acknowledgment. We thank Drs. Bruce Tidor, Michael K.
Gilson, Ronald Swanstrom, Robert Shafer, and members of the
Rana lab for helpful discussions. We also thank Kaneka USA
for the generous gift of chiral epoxides. This work was supported
in part by an NIH grant (GM66524).
14.0, 10.4 Hz, 1H), 2.04 (m, 1H), 1.92 (m, 2H), 1.46 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 168.29, 163.21 (d, J ) 243.4 Hz),
160.22, 152.86, 139.75, 139.17 (d, J ) 10.6 Hz), 137.59, 130.54,
130.46 (d, J ) 9.1 Hz), 129.67 (2C), 128.40 (2C), 126.50, 119.43,
118.99, 113.48 (d, J ) 3.1 Hz), 112.71, 111.38 (d, J ) 20.4 Hz),
106.03 (d, J ) 27.3 Hz), 80.51, 73.85, 69.84, 68.49, 56.53, 56.31,
55.90, 52.87, 48.20, 35.92, 29.23, 25.46; HRMS (ESI) m/z C32H37-
FN3O8S (M + H)+ calcd 642.2285, found 642.2289.
Supporting Information Available: Detailed experimental
procedures for the synthesis of intermediate and target compounds,
characterization data of intermediate compounds 7-10, and results
of HPLC analysis of final compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Biological Evaluation of HIV-1 Protease Inhibitors. HIV-1
protease inhibitor activities were determined by the fluorescence
resonance energy transfer (FRET) method.32 Protease substrate
[Arg-Glu(EDANS)-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Lys(DABCYL)-
Arg] was purchased from Molecular Probe. The energy transfer
donor (EDANS) and acceptor (DABCYL) were labeled at its two
ends respectively to perform FRET. Fluorescence measurements
were carried out on a PTI fluorescence spectrophotometer (Photon
Technology International) at 30 °C. Excitation and emission
wavelengths were set at 340 and 490 nm, respectively. Each reaction
was recorded for about 10 min. Wide-type HIV-1 protease (Q7K)
and its MDR variants M1 (L10I, G48V, I54V, L63P, V82A), M2
(D30N, L63P, N88D), and M3 (L10I, L63P, A71V, G73S, I84V,
L90M) were desalted through PD-10 columns (Amersham Bio-
sciences). Sodium acetate (20 mM, pH 5) was used as elution buffer.
Apparent protease concentrations were around 50 nM as estimated
by UV spectrophotometer (Shimadzu) at 280 nm. All inhibitors
were dissolved in DMSO and diluted to appropriate concentrations.
Protease (2 µL) and inhibitor (2 µL) or DMSO were mixed and
the solution incubated for 20-30 min at room temperature before
initializing the substrate cleavage reaction. Throughout this work,
150 µL of 1 µM substrate was used. Substrate buffer is a composite
of 0.1 M sodium acetate, 1 M sodium chloride, 1 mM ethylene-
diaminetetraacetic acid (EDTA), 1 mM dithiothreitol (DTT), 2%
dimethyl sulfoxide (DMSO), and 1 mg/mL bovine serum albumin
(BSA) with an adjusted pH 4.7. Inhibitor binding dissociation
constant (Ki) was obtained by nonlinear regression fitting (GraFit
5, Erithacus software) to the plot of initial velocity as a function
of inhibitor concentrations based on Morrison equation.33 The initial
velocities were derived from the linear range of reaction curves.
Protein Crystallography. Protein expression, isolation, and
purification were carried out as previously described.36 The protein
used for crystallizing 21e and 21f was further purified using a
Pharmacia Superdex 75 FPLC column. Crystals were set up with
a 3-5-fold molar excess of inhibitors to protease of 1-1.5 mg/
mL concentration. The hanging drop vapor diffusion method was
used for crystallization as previously described.17 The reservoir
solution consisted of 126 mM phosphate buffer at pH 6.2, 63 mM
sodium citrate, and 24-29% ammonium sulfate. Intensity data were
collected on an in-house Rigaku X-ray generator equipped with an
R-axis IV image plate system. Data were collected at -80 °C and
the data processing was carried out using the programs DENZO
and ScalePack, respectively.37,38 Data collection statistics are listed
in Table 3.
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The CCP4i interface to the CCP4 suite39 was used to refine the
structures. Structure solution was obtained with the molecular
replacement package AMoRe,40 with 1F7A41 as the starting model.
The molecular replacement phases were further improved using
ARP/wARP42 by building solvent molecules into the unaccounted
regions of electron density. Model building was performed using
the interactive graphics program O.43 Conjugate gradient refinement

Aryloxazolidinonecarboxamides as NoVel P2 Ligands
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