2-pyridyl P1'-substituted symmetry-based human immunodeficiency virus protease inhibitors (A-792611 and A-790742) with potential for convenient dosing and reduced side effects

Article abstract of DOI:10.1021/jm900044w

A series of symmetry-based HIV protease inhibitors was designed and synthesized. Modification of the core regiochemistry and stereochemistry significantly affected the potency, metabolic stability, and oral bioavailability of the inhibitors, as did the variation of a pendent arylmethyl P3 group. Optimization led to the selection of two compounds, 10c (A-790742) and 9d (A-792611), for advancement to preclinical studies. Both compounds displayed low nanomolar potency against wild type HIV in the presence of human serum, low rates of metabolism in human liver microsomes, and high oral bioavailability in animal models. The compounds were examined in a preclinical model for the hyperbilirubinemia observed with some HIV PIs, and both exhibited less bilirubin elevation than comparator compounds. X-ray crystallographic analyses of the new cores were used to examine differences in their binding modes. The antiviral activity of the compounds against protease inhibitor resistant strains of HIV was also determined.

Full text of DOI:10.1021/jm900044w

J. Med. Chem. 2009, 52, 2571–2586
2571
2-Pyridyl P1′-Substituted Symmetry-Based Human Immunodeficiency Virus Protease Inhibitors
(A-792611 and A-790742) with Potential for Convenient Dosing and Reduced Side Effects†
David A. DeGoey,* David J. Grampovnik, Charles A. Flentge, William J. Flosi, Hui-ju Chen, Clinton M. Yeung,
John T. Randolph, Larry L. Klein, Tatyana Dekhtyar, Lynn Colletti, Kennan C. Marsh, Vincent Stoll, Mulugeta Mamo,
David C. Morfitt, Bach Nguyen, James M. Schmidt, Sue J. Swanson, Hongmei Mo, Warren M. Kati, Akhteruzzaman Molla, and
Dale J. Kempf
AntiViral Research, Global Pharmaceutical Research and DeVelopment, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, Illinois 60064
ReceiVed January 14, 2009
A series of symmetry-based HIV protease inhibitors was designed and synthesized. Modification of the
core regiochemistry and stereochemistry significantly affected the potency, metabolic stability, and oral
bioavailability of the inhibitors, as did the variation of a pendent arylmethyl P3 group. Optimization led to
the selection of two compounds, 10c (A-790742) and 9d (A-792611), for advancement to preclinical studies.
Both compounds displayed low nanomolar potency against wild type HIV in the presence of human serum,
low rates of metabolism in human liver microsomes, and high oral bioavailability in animal models. The
compounds were examined in a preclinical model for the hyperbilirubinemia observed with some HIV PIs,
and both exhibited less bilirubin elevation than comparator compounds. X-ray crystallographic analyses of
the new cores were used to examine differences in their binding modes. The antiviral activity of the compounds
against protease inhibitor resistant strains of HIV was also determined.
Introduction
Since the introduction of the first HIV protease inhibitors (PIa)
more than a decade ago, they have continued to play a
prominent role in highly active antiretroviral therapy (HAART),
used in combination with two nucleoside reverse transcriptase
inhibitors. Since that time, the efficacy and tolerability of
this class have improved. Pharmacokinetic enhancement of
protease inhibitors using low-dose ritonavir (RTV) is now
widely used to maintain drug plasma levels leading to
improved viral suppression while decreasing both the dosing
frequency and pill count.1 New HIV PIs with improved
potencies and pharmacokinetics, however, could allow for a
lower pill count using once-daily dosing. Drugs with
improved resistance profiles have also been discovered. A
long-term study of lopinavir (LPV)/RTV has demonstrated
durable viral suppression over 7 years of therapy.2 Tipranavir
(TPV) and darunavir (DRV) have potent antiviral activity
against drug resistant viruses harbored by PI-experienced
patients.3,4 Despite the advances, improvements are needed
Figure 1. Symmetry-based HIV PI cores.
in reducing the side effects associated with HIV PI therapy.
inhibition of human proteasome has been implicated as a
Indinavir (IDV) and atazanavir (ATV) cause elevations of
possible link and recent studies have provided a means to
unconjugated bilirubin (hyperbilirubinemia), leading to jaun-
screen compounds preclinically for this off-target activity.8
dice and scleral icterus in some patients, and we recently
It remains a challenge to identify protease inhibitors with
developed a preclinical model useful for screening new
compounds for this effect.5 Several PIs produce elevations
improved potencies and pharmacokinetics, along with im-
proved profiles for these off-target activities. We investigated
of serum triglycerides, cholesterol, and low-density lipopro-
compounds with 2-pyridyl P1′-substituted cores A, B, and
teins that may be associated with long-term cardiovascular
risk.6,7 While the exact mechanism(s) remain unclear, PI
C (Figure 1), which demonstrated higher potencies and higher
metabolic stabilities than the unsubstituted pseudo-C2-sym-
†
metric core of RTV. We also investigated additional cyclic-
urea-linked P3 groups, which have provided potent inhibitors
in several core series.9 The central hydroxyl regiochemistry
and P1′ stereochemistry as well as the P3 substituent affected
the potency, metabolic stability, and oral bioavailability of
the inhibitors. Herein, we report the optimization of the
antiviral activity and pharmacokinetics of these compounds
as well as the first use of our preclinical model for
X-ray coordinates have been deposited in the Protein Data Bank for
HIV protease complexed with 10a (PDB code 3GGX) and 11 (PDB code
3GGA).
* To whom correspondence should be addressed. Phone: (847) 937-7205.
Fax: (847) 938-2756. E-mail: David.DeGoey@abbott.com.
a Abbreviations: PI, protease inhibitor; HAART, highly active antiret-
roviral therapy; RTV, ritonavir; LPV, lopinavir; ATV, atazanavir; UGT,
UDP-glucuronosyltransferase; WT, wild type; HS, human serum; HLM,
human liver microsomes; DEPBT, 3-(diethoxyphosphoryloxy)-1,2,3-ben-
zotriazin-4(3H)-one.
10.1021/jm900044w CCC: $40.75
2009 American Chemical Society
Published on Web 03/26/2009

2572 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
Scheme 1. Synthesis of Core A and Core B Analoguesa
DeGoey et al.
a Reagents and conditions: (a) NaOH; (b) TBSCl, imidazole; (c) AcOH; (d) (i) DPPA, toluene, reflux, (ii) benzyl alcohol; (e) TBAF; (f) Pd(OH)2 on C,
H2; (g) DEPBT, MeO2C-t-Bu-Gly-OH; (h) TFA; (i) DEPBT; (j) Pd on C, H2.
hyperbilirubinemia to identify compounds with less potential
for this side effect.
as described previously)9b and the appropriate aryl aldehyde
(Scheme 3) by reductive amination with NaBH4, cyclization to
form the urea, and removal of the tert-butyl protecting group.
Acids 8c and 8r were prepared starting from 19 which was
prepared from methyl 6-formylpicolinate under the standard
conditions (Scheme 4). Reaction of 19 with excess methyl
Grignard reagent gave the tertiary alcohol 20, which was treated
with TFA to give 8c. Reaction of 19 with methyl Grignard
reagent at -78 °C gave ketone 21. Wittig olefination gave 22,
and the olefin was reduced to the isopropyl compound 23 by
hydrogenation. Treatment with TFA gave the acid 8r.
Chemistry
Core A and B compounds were prepared as shown in Scheme
1. The lactone 2 was prepared as described previously with the
stereochemistry favoring the (4S)-isomer (1.6:1, S/R).10 Opening
of the lactone with hydroxide gave a mixture of acids 3, which
was subjected to Curtius rearrangement and reaction with benzyl
alcohol. After treatment with TBAF, orthogonally protected
intermediates 4 and 5 were obtained as a mixture at C-5 (1.6:1,
respectively) and were separated by chromatography on silica
gel. Removal of the Cbz group through hydrogenolysis, coupling
with tert-butylglycine methyl carbamate, and removal of the
Boc protecting group gave intermediates 6b and 7b. Final
compounds (9a-g, 9j-p, 10a-i) were prepared by coupling
with the appropriate arylmethyl-substituted cyclic urea acids
8a-g, 8j-p, 8r, and 8s, respectively. Compounds 9h and 9i
were obtained through hydrogenation of the 2-nitrophenyl and
4-nitrophenyl intermediates, respectively.
Core C analogues were prepared starting from p-bromophe-
nylalanine (Scheme 2), which was benzylated using benzyl
chloride and potassium carbonate to give 12. Palladium
catalyzed coupling of 12 with 2-(tributylstannyl)pyridine gave
13. Reaction of 13 with sodioacetonitrile resulted in nitrile 14,
which was treated with benzyl Grignard reagent to give the
enaminone 15. A high degree of stereocontrol was observed
for the stepwise reduction of 15 by using the procedure reported
for a similar enaminone to give 16.11 Removal of the benzyl
protecting groups through hydrogenolysis gave the amine, which
was coupled with tert-butylglycine methyl carbamate to give
17a. Removal of the Boc protecting group gave intermediate
17b, and final compounds (18a-h) were prepared by coupling
with the appropriate arylmethyl-substituted cyclic urea acids
8a-g and 8q, respectively.
Results and Discussion
As mentioned, some HIV PIs elevate serum levels of
unconjugated bilirubin clinically, including IDV and ATV.12
Bilirubin is the major end-product of the catabolism of heme,
and 300-400 mg is formed daily in humans. The main
metabolic pathway for bilirubin excretion is glucuronidation
catalyzed by UDP-glucuronosyltransferase 1A1 (UGT1A1).
Bilirubin is highly protein bound, and unconjugated bilirubin
has toxic side effects in humans if the serum bilirubin
concentration exceeds the albumin concentration. Although the
mechanism has not been unequivocally established, the above
HIV PIs may elevate unconjugated bilirubin via direct inhibition
of UGT1A1. Previously, we reported an in vivo model for
assessing the potential for compounds to induce hyperbiliru-
binemia utilizing Gunn rats, which are heterozygous for an
inherited deficiency in hepatic-bilirubin conjugating activity and
are susceptible to bilirubin elevations.5 In contrast to in vitro
UGT1A1 inhibition measurements, the in vivo model data
correlated well with the clinical observations.
Five years ago, we evaluated exploratory HIV PI, 1a (A-
681799, Figure 2), as a potential drug candidate.13 Compound
1a demonstrated potent antiviral activity and high oral bioavail-
ability with coadministration of RTV. Since 1a shares the aza-
core structure with ATV, the effect of 1a on serum bilirubin
levels was evaluated in the Gunn rat assay. Observed elevations
Cyclic urea acids 8a, 8b, 8d-q, and 8s were prepared from
N-(2-aminoethyl)-(L)-tert-butylglycine tert-butyl ester (prepared

2-Pyridyl P1′-Substituted Symmetry-Based HIV P1s
Scheme 2. Synthesis of Core C Analoguesa
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 2573
a Reagents and conditions: (a) Pd(PPh3)4, LiCl, 2-(tributylstannyl)pyridine; (b) NaHMDS, CH3CN; (c) BzlMgCl; (d) (i) NaBH4, CH3SO3H, (ii) NaBH4,
TFA; (e) Pd(OH)2 on C, H2; (f) DEPBT, MeO2C-t-Bu-Gly-OH; (g) TFA; (h) DEPBT.
Scheme 3. General Synthesis of Cyclic Urea Acidsa
improved metabolic stability (see Table 1). In contrast to the
aza core, the all-carbon core allowed for variation of both
the position of the central hydroxyl group and the stereo-
chemistry at the P1′ position. Consequently, we focused our
structure-activity relationship (SAR) investigation on cores
A, B, and C (Figure 1).
Antiviral activity and metabolic stability data for new
compounds, along with reference compounds, are presented in
Table 1. Compounds were screened in cell culture against wild
type (WT) HIV-1 (pNL4-3 strain), both in the absence and
presence of 50% human serum (HS), since it is known that the
addition of serum reduces the potency of HIV PIs because of
protein binding.15 In addition, activity against a HIV PI resistant
strain, A17 (protease mutations L10F, V32I, M46I, I47V, Q58E,
I84V), which was generated by in vitro serial passage of LPV/
RTV, was routinely determined.16 The A17 mutant clone has
several mutations that confer cross-resistance to other HIV PIs17
and was highly resistant to LPV as well as other marketed PIs
including RTV, ATV, amprenavir (APV), saquinavir (SQV),
and DRV in antiviral assays. Consequently, the fold resistance
to this multiple PI resistant mutant was monitored to gauge the
potential effectiveness of new compounds in PI experienced
patients.
As shown in Table 1, each of the cores (A, B and C in Figure
1) was combined with a series of arylmethyl-substituted P3
substituents. While the initial compound in the series 9a lost
2-fold potency relative to 1a in the presence of 50% HS, core
B and C analogues 10a and 18a had 2-fold better potency than
9a and nearly identical potency to 1a. Generally, core B and C
analogues displayed higher potency than the core A analogues.
This trend was observed for the other P3 modifications, such
as the 2-methyl-4-thiazole analogues (9a, 10b, and 18b) and
6-(2-methyl-2-hydroxyethyl)-2-pyridyl analogues (9c, 10c, and
18c). An exception was the phenyl analogue series, in which
the core A and C compounds, 9d and 18d, respectively,
a Reagents and conditions: (a) (i) 50 °C, 16 h, (ii) NaBH4; (b) N,N-
disuccinimidyl carbonate, room temperature or bis(4-nitrophenyl)carbonate,
reflux in toluene; (c) TFA.
of serum bilirubin were significantly greater for 1a than those
for ATV or IDV, and development of this compound was
discontinued. In order to design a compound with lower potential
for this side effect, we ascertained the structural features of 1a
associated with hyperbilirubinemia by examining multiple
compounds in Gunn rats. Replacement of the P1′ pyridylbenzyl
side chain of 1a with an unsubstituted benzyl group as in 1b
did not significantly change the degree of bilirubin elevation
(Figure 2). In contrast, compounds in which the aza core of 1a
was replaced with the symmetry-based all-carbon core of RTV,14
such as 1c (Figure 2), elevated bilirubin to a significantly lower
extent, including compound 9a, with the same P1′ pyridylbenzyl
group contained in compound 1a. This data suggested that the
presence of the nitrogen atom in the aza core contributes to
the hyperbilirubinemia observed with compounds 1a and 1b.
In other screening assays, unsubstituted symmetry-based core
compounds, such as 1c, exhibited lower antiviral potency
and were less stable in human liver microsomes (HLM) than
1a, making them unlikely candidates for convenient dosing.
While compound 9a was less potent than 1a, it displayed

2574 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
Scheme 4. Preparation of Cyclic Urea Acids 8c and 8ra
DeGoey et al.
a Reagents and conditions: (a) excess MeMgBr, 0 °C; (b) TFA; (c) 1.2 equiv of MeMgBr, -78 °C; (d) Me(PPh3)Br, t-BuOK; (e) Pd on C, H2.
with a single active site, and the active site subsites (S1/S1′,
S2/S2′, and S3/S3′) are symmetrically disposed around the
symmetry axis that dissects the active site. The absolute
stereochemistry of the P1 and P1′ side chains of core A and C
analogues matches that of early C2-symmetric inhibitors18 and
the pseudo-C2-symmetry-based PIs exemplified by RTV and
LPV.14 Obtained as a side product from the synthesis of the
desired core A analogues, core B analogues are epimeric at the
P1′ (C-5) position. Because of the mismatch with the C2-
symmetric HIV protease binding site, these analogues were
expected to be significantly less potent. In order to determine
the binding mode, X-ray crystallographic analysis of core B
analogue 10a bound to HIV protease was conducted. Figure 3
depicts compound 10a (in purple) overlaid with core A analogue
11, which is capped at each end with tert-butylglycine methyl
carbamate (in brown). The C-3 hydroxyl groups of both cores
are similarly positioned to allow hydrogen-bonding interactions
with the catalytic Asp residues 25 and 25′. To accommodate
this binding mode, the conformations of the two cores differ
significantly. While the core A compound 11 binds in a gauche
conformation between C-3 and C-4, the core of 10a adopts an
all anti conformation. Both compounds form water mediated
hydrogen bonds between the P2 side chain carbonyls and Ile
50 and 50′ (water shown in red, Figure 3), a feature common
to all peptidomimetic inhibitors. To achieve this interaction, the
C5-N bond of 10a adopts a high energy conformation (the
carbonyl carbon is gauche to C-4 and C-6), whereas compound
11 is in a lower energy conformation with the carbonyl carbon
eclipsing the C-5 methine proton. Thus, both compounds require
Figure 2. (A) Structures of aza-core analogues (1a and 1b) and carbon-
core analogues (1c and 9a). (B) Mean change in serum bilirubin
a gauche conformation to form the key hydrogen bonds in the
center of the active site. The two cores project the pyridylbenzyl
groups into the S1′ subsite of the enzyme at different angles,
resulting in poor overlap between the P1′ pyridyl groups.
However, this site is sufficiently large to accommodate both
orientations. Overall, the crystal structures of both compounds
are therefore consistent with their similar potencies.
concentrations in the Gunn rat assay (error bars are standard deviation).
All compounds were dosed orally along with 50 mg/kg RTV for
pharmacokinetic enhancement.
displayed higher potencies than the core B analogue 10d. Larger
bicyclic heterocycles were also tolerated at the P3 position. For
example, the 4-quinoline analogues (9e, 10e, and 18e) were
uniformly potent against WT HIV, as were the 2-(pyridin-3-
yl)-4-thiazole analogues (9f, 10f, and 18f). The benzimidazole
analogue 9g, however, was markedly less potent than the above
bicyclic analogues. In general, the series of compounds (9a-g,
10a-g, 18a-g) demonstrated 5-fold to 10-fold reduction in
potency with the addition of 50% HS. The compounds retained
relatively high activity against the A17 mutant (<12-fold increase
in EC50, compared to WT HIV), with the core B analogues
generally exhibiting slightly lower potency (i.e., larger fold
change in EC50) than core A or C analogues.
In order to identify compounds with high potential for
convenient dosing, the metabolic stability of new analogues was
routinely screened in HLM by evaluating the disappearance of
parent compound. Stability was determined for the compounds
alone and in the presence of 0.4 µM RTV. The percentage
inhibition of the metabolism by RTV provided an estimate of
the potential effectiveness of PK enhancement by RTV.
Improved stability in the absence of RTV provided insight into
the potential for sustained plasma levels with a dose of RTV of
100 mg/day or less, in which inhibition of first pass metabolism
by RTV is likely but systemic metabolism is relatively minimal.
Such a compound might be advantageous in that lipid elevations
The potent antiviral activity of the core B analogues was
unexpected on the basis of previous SAR of symmetry-based
HIV PIs. HIV protease functions as a C2-symmetric homodimer

2-Pyridyl P1′-Substituted Symmetry-Based HIV P1s
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 2575
Table 1. In Vitro Cell Culture Potency and Metabolic Stability Data
a Wild type ) pNL4-3. b Fold resistance. c % Inh. ) percent inhibition of metabolism by RTV. d HS ) human serum.
As mentioned earlier, compound 9a, bearing the 2-pyridyl
substituted benzyl group, was substantially more stable to
microsomal metabolism than the unsubstituted version, 1c. With
only 24% disappearance under these conditions, compound 9a
was also more stable to metabolism than 1a. Compounds 10a
and 18a, the core B and core C analogues, however, were
considerably less stable than 9a to metabolism, exhibiting g70%
disappearance. This trend was generally observed, with the core
A analogues, 9a-9f, demonstrating higher metabolic stability
than the core B or C analogues. The phenyl analogue, 9d,
displayed the highest metabolic stability of the compound set
in the absence of RTV (11% disappearance), and it was
markedly more stable than core B and C analogues, 10d and
18d. The quinoline analogues (9e, 10e, and 18e) showed the
highest rate of metabolism among the P3 analogues tested. RTV
efficiently inhibited the metabolism of most of the compounds,
with less than 50% inhibition observed with only analogue 9d.
On the basis of their potencies and metabolic stabilities,
compounds 9d, 18b, and 10c were selected for additional P3
group SAR studies. The unadorned phenyl ring of 9d was a
potential liability in terms of metabolism and contributing to
low aqueous solubility. SAR studies were targeted toward P3
groups that could improve potency, metabolic stability, or
aqueous solubility. The 2-amino analogue 9h displayed similar
potency and metabolic stability to 9d, while the 4-amino isomer
Figure 3. X-ray crystal structures of core B analogue 10a (purple)
analogue overlaid with core A analogue 11, which is capped at each
end with MeO2C-tert-Bu-Gly (brown). Catalytic Asp 25 and Asp 25′
are highlighted, and water is shown in red.
by RTV are dose-dependent and relatively minimal at doses of
<100 mg, b.i.d. It has been demonstrated in healthy volunteers
that RTV (100 mg, b.i.d.) elevated LDL and HDL cholesterol
levels as well as triglycerides.19
Trends in metabolic stability that emerged on the basis of
the identity of the core and P3 groups are shown in Table 1.

2576 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
DeGoey et al.
Table 2. Pharmacokinetic Data in Rats (5 mg/kg)
Table 3. Pharmacokinetic Data in Dogs (5 mg/kg)
oral
compd data
RTV data
b
b
iv
no RTV
with RTVa
AUCd
compd
AUCa
Cmax
C12h
dosec
AUCa
b
10c
0.02
6.72
10.64
0.21
18.96
41.90
0.04
2.22
2.56
0.17
3.91
5.89
0.00
0
2.5
5
0
2.5
5
0
compd
t1/2
CLc
F (%)
AUCd
0.013
0.058
0.00
0.068
0.924
1.56
8.8
0
0.71
5.23
10b
18b
9c
10c
18c
9d
0.4
0.5
1.0
0.5
0.9
1.0
1.1
0.6
0.4
0.7
0.8
0.7
1.2
1.2
1.4
1.86
1.90
1.40
1.35
1.00
1.15
1.80
2.50
2.00
2.05
2.80
3.24
1.99
2.16
1.76
5.9
11.2
5.7
4.9
17.0
3.4
0.6
0.0
1.1
0.8
1.6
0.1
2.9
3.1
0.8
0.16
0.32
0.20
0.18
0.88
0.15
0.02
0.00
0.05
0.02
0.03
0.00
0.08
0.07
0.02
1.98
8.40
0.83
12.93
1.82
3.50
2.86
9.20
3.30
0.12
0.26
1.17
1.25
9.38
2.70
9d
a µg·h/mL. b µg/mL. c mg/kg.
9e
Table 4. Properties of 10c and 9d
10e
18e
9f
18f
10g
9h
assay
10c
9d
solubility (µg/mL)a
11.3
<0.15
99.66
moderate
>10
protein bindingb
98.2
moderate
>5
Caco-2 permeability
CYP1A2 IC50 (µM)c
CYP2C9 IC50 (µM)d
CYP2C19 IC50 (µM)e
CYP2D6 IC50 (µM)f
CYP3A4 Ki (nM)g
HIV protease Ki (nM)
pepsin Ki (µM)
9j
9p
>5
>5
>5
66
0.014
200
>20
0.54
>10
>10
>10
18
a Coadministered with 5 mg/kg RTV. b h. c L/(h·kg). d µg·h/mL.
0.015
177
9i was less potent. Similarly, the 2-methoxy analogue 9j, but
not the 3-methoxy analogue 9k, exhibited similar potency to
9d. Fluorinated analogues 9l, 9m, and 9n and methylated
analogues 9o and 9p were also similarly potent and comparably
stable to 9d. An analogue of compound 18b, 2-isopropyl-4-
thiazole 18h, had improved potency compared to 18b but was
significantly less stable in HLM, with 71% disappearance.
Analogues of compound 10c included the structurally simpler
analogues 10h and 10i, bearing 6-isopropyl and 6-tert-butyl
substituents, respectively. Both compounds were less active than
10c, and 10h demonstrated decreased metabolic stability. The
tertiary hydroxyl group of 10c contributed to both its potency
and metabolic stability.
Pharmacokinetic Evaluation. The pharmacokinetic profiles
for select compounds were examined both alone and with
coadministration of RTV. As shown in Table 2, all of the
compounds showed high rates of clearance when dosed intra-
venously in the rat. The plasma levels from oral dosing alone
were quite low, with oral bioavailability ranging from 0 to 17%.
At the extremes, compound 18c exhibited the highest plasma
concentrations and the lowest clearance, while compound 10e
showed no detectable plasma levels upon oral dosing. Consistent
with the predictions from the microsomal metabolism data, the
plasma levels of all of the compounds were substantially
enhanced upon oral coadministration with RTV, with AUCs
increasing by 2- to 143-fold. Notably, compound 10e, which
showed no detectable plasma levels when dosed alone, showed
high oral bioavailability upon coadministration with RTV.
Direct comparison of the effect of the core on the oral
bioavailability was possible with two sets of analogues: (1) 9c,
10c, 18c and (2) 9e, 10e, 18e. In both cases the core B
analogues, 10c and 10e, showed significantly higher plasma
levels when coadministered with RTV than the core A or C
analogues.
renin Ki (µM)
cathepsin D Ki (µM)
>4
4.3
a pH 7.4 at 25 °C. b % bound in human plasma by equilibrium dialysis.
c Phenacetin O-deethylation. d Tolbutamide hydroxylation. e S-Mephenytion
hydroxylation. f Dextromethorphan O-demethylation. g Midazolam 1′-
hydroxylation.
drug plasma levels of 9d in rats were moderate after oral dosing,
compound 9d possessed both the highest potency of the series
in the presence of 50% HS and the highest metabolic stability.
The measured aqueous solubility for 9d was quite low (see Table
4), suggesting the potential for improved oral exposure through
formulation efforts. Although substituents on the phenyl ring
of 9d were accommodated in terms of potency, metabolic
stability, and oral bioavailability (i.e., 9j and 9p), the analogues
prepared in the series (9h-p) did not provide a significant
advantage over 9d. Compound 10c was also selected for further
evaluation, since it had nearly equivalent potency and metabolic
stability compared to 9d, but produced higher plasma levels
upon oral administration with RTV. In addition, the structurally
distinct core and P3 substituent of 10c compared to 9d offered
the potential advantage of differentiated drug resistance and
safety profiles for the two compounds.
Oral administration of either 10c or 9d alone in dogs resulted
in low plasma levels and low oral bioavailability, similar to the
observations from rats (Table 3). Coadministration with RTV
(5 mg/kg), however, resulted in dramatic increases in the plasma
levels and oral bioavailability of both compounds, with 500-
and 200-fold increases in the AUC for 10c and 9d, respectively.
Plasma exposures (AUC) were 3- to 4-fold higher for compound
9d compared to compound 10c, and at the 12 h time point 9d
provided plasma levels of approximately 1 µg/mL, whereas the
concentrations of 10c were significantly lower. At a lower dose
of RTV (2.5 mg/kg), plasma levels of compound 9d exceeded
RTV levels by 27-fold, whereas the AUC of 10c was only 4-fold
higher than the RTV AUC. Compound 9d thus provided a
potential advantage in its sensitivity to pharmacokinetic en-
hancement by RTV, since a lower dose of RTV could be used
to obtain the high levels of 9d.
Several analogues of compound 9d with substitution of the
phenyl P3 group were also evaluated. Amino-substituted P3
analogue 9h showed poor plasma levels even with RTV
coadministration. The methoxy substituted analogue 9j, on the
other hand, showed 3-fold higher plasma levels than 9d. The
methyl-substituted analogue 9p displayed similar pharmacoki-
netics to 9d.
Characterization of 10c and 9d. On the basis of their
potencies, metabolic stabilities, and oral bioavailabilities in our
screening assays, two compounds, 10c and 9d, were selected
for further pharmacokinetic and drug safety evaluation. While
Further in vitro characteristics of compounds 10c and 9d are
shown in Table 4. Both compounds exhibited low aqueous
solubility at pH 7.4, with 10c displaying higher solubility than
9d. The compounds were highly protein bound in human
plasma, and the Caco-2 permeability model predicted moderate

2-Pyridyl P1′-Substituted Symmetry-Based HIV P1s
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 2577
Table 5. Activity Against LPV-Resistant Strains
than 1a. Consequently, dosing was continued on day 2 to
increase the plasma levels. Although the drug plasma levels of
9d were doubled on day 2, no accompanying increase in serum
bilirubin levels was observed. These results suggest that any
elevation of unconjugated bilirubin in humans by 10c and 9d
is likely to be clinically insignificant.
cell culture EC50 (nM)
PI
WTa
A17b
B26c
P25d
45
103
>10000
515
10c
9d
LPV
DRV
ATV
3
2
18
12
3
10
22
1057
338
250
25
140
3790
587
74
298
Conclusions
a pNL4-3. b A17: L10F, V32I, M46I, I47V, Q58E, and I84V. c B26:
L33F, K45I, M46I, I50V, I54V, A71V, and V82F. d P25: L10F, G16E,
V32I, M46I, I47A, H69Y, I84V, and T91S.
Investigation of HIV PI cores A, B, and C (Figure 1) revealed
that the potency, metabolic stability, and pharmacokinetics could
be modulated through the regiochemistry and stereochemistry
of the core as well as through variation of the arylmethyl
substituent appended to the cyclic urea P3 group. Through these
modifications, we were able to identify two compounds, 10c
(A-790742) and 9d (A-792611), for preclinical evaluation. Each
has potent activity against WT HIV in the presence of 50%
human serum and high oral bioavailability when coadministered
with RTV. Compound 10c retains potency against multiple PI-
resistant strains of HIV. Unlike LPV, which exhibits rapid
disappearance in HLM in the absence of RTV, both compounds
are more stable than LPV in HLM, potentially allowing for the
maintenance of high drug plasma levels using a lower dose of
RTV than required for LPV in humans (200 mg/day). Finally,
compounds 10c and 9d also demonstrated reduced potential for
the common side effects of HIV PIs (bilirubin elevations and
hyperlipidemia) in preclinical models.
Table 6. Changes in Biliburin and Drug Concentrations in Gunn Rats
change in bilirubin,
mg/dL (SD)b
serum drug concn,
µg/mL (SD)
compd dosea
day 1
day 2
day 1
day 2
1a
1b
9a
1c
10c
9d
100 0.536(0.216) 0.685(0.415) 8.87(6.86)
8.88(5.35)
NAc
250 0.429(0.212) NAc
250 0.233(0.124) NAc
250 0.195(0.029) NAc
125 0.125(0.045) NAc
13.28(2.99)
5.83(4.98)
NAc
18.68(10.04) NAc
9.37(3.93)
NAc
5.33(1.20)
125 0.144(0.107) 0.133(0.096) 2.45(0.71)
a mg/kg. All compounds were coadministered with 50 mg/kg RTV. b SD
) standard deviation. c NA ) not available.
permeability for the compounds. The potential for drug-drug
interactions for 10c and 9d was evaluated in vitro against a
panel of cytochrome P450 (CYP) isoforms. No significant
inhibition of CYP2C19, CYP1A2, CYP2C9, or CYP2D6 was
observed at the highest concentrations tested. Both compounds
exhibited potent inhibition of CYP3A4; however, the conse-
quence of this inhibition is unclear, since both compounds are
likely to require coadministration of RTV, a potent CYP3A4
inhibitor.
Compounds 10c and 9d demonstrated subnanomolar potency
against WT HIV protease. Greater than 11000-fold selectivity
for HIV protease inhibition was observed over the human
aspartic proteinases pepsin, renin, and cathepsin D. Potencies
of 10c and 9d against LPV resistant clones A17 (L10F, V32I,
M46I, I47V, Q58E, I84V), B26 (L33F, K45I, M46I, I50V, I54V,
A71V, V82F), and P25 (L10F, G16E, V32I, M46I, I47A, H69Y,
I84V, T91S) are provided in Table 5. Compound 10c maintained
double-digit nanomolar potency against these viruses and
displayed an advantage against these resistant mutant viruses
compared to compound 9d, LPV, ATV, or DRV. Additional
studies of the resistance profile of 10c including resistance
selection and activity against clinical isolates have been
described in detail elsewhere.20
Experimental Section
Chemistry. Unless otherwise noted, all materials were obtained
from commercial suppliers and used without further purification.
Anhydrous solvents were obtained from Aldrich (Milwaukee, WI)
and used directly. All reactions involving air- or moisture-sensitive
reagents were performed under a nitrogen or argon atmosphere.
All final compounds were purified to >95% purity as determined
by high-performance liquid chromatography (HPLC) by two
methods. Silica gel chromatography was performed using either
glass columns packed with silica gel 60 (230-400 mesh) or
prepacked silica gel cartridges (Biotage, 32-63 µM). Preparative
reverse phase HPLC was conducted on a Waters 600 system using
Waters Nova-Pak C18 (6 µM, 60Å) or Biotage KP-C18-HS
cartridges. NMR spectra were determined with a Bruker ARX 300
MHz, Varian Unity 400 MHz, or Varian Unity INOVA 500 MHz
spectrometer. Chemical shifts are reported in parts per million (ppm)
relative to tetramethylsilane internal standard. Low-resolution mass
spectral (MS) ESI and DCI data were determined on a Thermo-
Finnigan SSQ7000 instrument. Combustion analysis was performed
by Robertson Microlit Laboratories (Madison, NJ) or Quantitative
Technologies Inc. (Whitehouse, NJ), and data were within 0.4%
of calculated values.
tert-Butyl (1S)-1-((2S)-5-Oxo-4-(4-(pyridin-2-yl)benzyl)tet-
rahydrofuran-2-yl)-2-phenylethylcarbamate (2). tert-Butyl (1S)-
1-((2R)-oxiran-2-yl)-2-phenylethylcarbamate (10.0 g, 38.0 mmol)
and diethyl malonate (5.8 mL, 38.2 mmol) were dissolved in ethanol
(30 mL) and cooled at 0 °C as a solution of NaOEt (17 mL, 21%
in ethanol) was added over 10 min. The mixture was warmed to
room temperature and stirred for 2 h. At that time, additional diethyl
malonate (0.58 mL, 3.4 mmol) was added and the mixture was
stirred for 1 h. The mixture was recooled at 0 °C, and solid 2-(4-
(bromomethyl)phenyl)pyridine (9.43 g, 38.0 mmol) was added in
four increments over 10 min. To this suspension was added ethanol
(20 mL), and the mixture was warmed to room temperature for
16 h. LiOH monohydrate (4.6 g, 109.6 mmol) solution in water
(30 mL) was added followed by stirring at room temperature for
16 h. The mixture was cooled at 0 °C and then adjusted to pH 5 by
addition of 4 N HCl and then partitioned between dichloromethane
and water. The organic was washed with brine, dried over MgSO4,
filtered, and evaporated.
Compound 9d was examined in a gene microarray model
for HIV PI-induced hyperlipidemia. Few proteasome genes were
regulated by 9d, while RTV strongly induced the expression
of proteasome genes, and the results will be described
elsewhere.8d
Evaluation of 10c and 9d in the Gunn Rat Model for
Unconjugated Bilirubin. Compounds 10c and 9d were evalu-
ated for their potential to elevate serum levels of unconjugated
bilirubin in the Gunn rat assay. The results are presented in
Table 6 along with data for reference compounds 1a, 1b, 1c,
and 9a. The compounds were dosed in Gunn rats at 125 mg/kg
along with 50 mg/kg RTV to enhance their plasma concentra-
tions. Both compounds 10c and 9d caused only small increases
in serum bilirubin concentrations on day 1, of a magnitude that
is consistent with that caused by treatment with 50 mg of
ritonavir alone and significantly less than that caused by 1a,
1b, or ATV. While compound 10c achieved comparable plasma
levels to 1a on day 1, the plasma levels for 9d were 75% lower

2578 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
DeGoey et al.
A solution of the crude product from the first step dissolved in
toluene (100 mL) was then heated at reflux for 16 h. Evaporation
of the solvent gave crude product (21.4 g), which was obtained as
a 1.6:1 mixture of the (4S)- and (4R)-isomers, respectively, and
Methyl (S)-1-((2S,4S,5S)-5-(tert-Butoxycarbonyl)amino-4-hy-
droxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-
dimethyl-1-oxobutan-2-ylcarbamate (6a). To a solution containing
4 (4.2 g, 7.0 mmol) in a mixture of methanol (35 mL) and ethyl
acetate (35 mL) were added Pd(OH)2 on carbon (1.4 g, 20% Pd by
weight) and HCl solution (1.8 mL, 4 N in dioxane), and the mixture
was stirred under a hydrogen atmosphere (balloon pressure) for
16 h. The mixture was filtered through a bed of Celite and rinsed
with methanol. The solvent was evaporated to give the crude
product (3.7 g), which was used in the next step without further
purification.
To a solution containing the product from the first step (3.7 g)
in THF (75 mL) were added (S)-2-(methoxycarbonylamino)-3,3-
dimethylbutanoic acid (1.39 g, 7.4 mmol), DEPBT (3.3 g, 11.0
mmol), and N,N-diisopropylethylamine (6.4 mL, 36.7 mmol), and
the mixture was stirred at room temperature for 16 h. The mixture
was partitioned between ethyl acetate and 10% Na2CO3 solution.
The organic was washed with additional 10% Na2CO3 solution and
then brine, dried over MgSO4, filtered, and evaporated. The residue
was purified by chromatography on silica gel, eluting with a gradient
of 33-100% ethyl acetate in chloroform to give the product (3.5
g, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.81 (s, 9H),
1.28 (s, 9H), 1.51 (t, J ) 7.00 Hz, 2H), 2.55-2.80 (m, 4H), 3.49
(s, 3H), 3.55-3.65 (m, 1H), 3.71-3.79 (m, 1H), 3.83 (d, J ) 9.61
Hz, 1H), 4.09-4.24 (m, 1H), 4.57 (d, J ) 6.86 Hz, 1H), 6.26 (d,
J ) 9.47 Hz, 1H), 6.63 (d, J ) 9.88 Hz, 1H), 7.08-7.25 (m, 7H),
7.26-7.35 (m, 1H), 7.70-8.00 (m, 5H), 8.56-8.84 (m, 2H). MS
(ESI) m/z 633 (M + H)+.
Methyl (S)-1-((2S,4S,5S)-5-Amino-4-hydroxy-6-phenyl-1-(4-
(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-oxobutan-
2-ylcarbamate (6b). To a solution containing 6a (3.5 g, 5.5 mmol)
in dichloromethane (40 mL) was added TFA (20 mL), and the
mixture was stirred at room temperature for 1 h. The solvent was
evaporated, and the mixture was partitioned between ethyl acetate
and saturated NaHCO3 solution. The organic was washed with brine,
dried over MgSO4, filtered, and evaporated. The crude product (3.19
g) was used without further purification. 1H NMR (400 MHz,
CDCl3) δ ppm 0.99 (s, 9H), 1.54-1.67 (m, 1H), 1.70-1.80 (m,
1H), 2.48 (dd, J ) 13.38, 9.13 Hz, 1H), 2.74-2.91 (m, 3H), 3.10
(dd, J ) 13.45, 5.21 Hz, 1H), 3.38-3.50 (m, 1H), 3.66 (s, 3H),
3.85 (d, J ) 9.06 Hz, 1H), 4.17-4.27 (m, 1H), 5.45 (d, J ) 8.37
Hz, 1H), 6.66 (d, J ) 5.76 Hz, 1H), 7.09-7.32 (m, 8H), 7.64-7.79
(m, 2H), 7.86-7.92 (m, 2H), 8.64-8.71 (m, 1H). MS (ESI) m/z
533 (M + H)+.
Methyl (S)-1-((2R,4S,5S)-5-(tert-Butoxycarbonyl)amino-4-hy-
droxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-
dimethyl-1-oxobutan-2-ylcarbamate (7a). 7a was prepared ac-
cording to the procedure for 6a from 5 (74% yield). 1H NMR (400
MHz, DMSO-d6) δ ppm 0.75 (s, 9H), 1.28 (s, 9H), 1.36-1.61 (m,
2H), 2.57-2.87 (m, 4H), 3.45-3.64 (m, 2H), 3.56 (s, 3H),
3.73-3.85 (m, 1H), 4.04-4.27 (m, 1H), 4.55 (d, J ) 6.04 Hz,
1H), 6.31 (d, J ) 9.47 Hz, 1H), 6.86 (d, J ) 9.47 Hz, 1H),
7.05-7.41 (m, 8H), 7.76-8.00 (m, 5H), 8.51-8.69 (m, 1H). MS
(ESI) m/z 633 (M + H)+.
1
was used without further purification. (4S)-Isomer: H NMR (300
MHz, CDCl3) δ ppm 1.37 (s, 9H), 1.76-1.92 (m, 1H), 2.06-2.18
(m, 1H), 2.66-2.79 (m, 1H), 2.79-3.00 (m, 3H), 3.28-3.39 (m,
1H), 3.87-4.02 (m, 1H), 4.29-4.38 (m, 1H), 4.62 (d, J ) 9.83
Hz, 1H), 7.10-7.34 (m, 8H), 7.65-7.82 (m, 2H), 7.86-7.98 (m,
2H), 8.63-8.72 (m, 1 H). (4R)-Isomer: 1H NMR (300 MHz, CDCl3)
δ ppm 1.36 (s, 9H), 1.92-2.03 (m, 1H), 2.19-2.32 (m, 1H),
2.79-3.09 (m, 3H), 3.15 (dd, J ) 13.56, 4.41 Hz, 1H), 3.88-4.05
(m, 1H), 4.19-4.26 (m, 1H), 4.51 (d, J ) 9.49 Hz, 1H), 7.10-7.34
(m, 8H), 7.66-7.79 (m, 2H), 7.87-7.98 (m, 2H), 8.64-8.72 (m,
H). MS (ESI) m/z 473 (M + H)+.
(4S,5S)-5-(tert-Butoxycarbonylamino)-4-(tert-butyldimethyl-
silyloxy)-6-phenyl-2-(4-(pyridin-2-yl)benzyl)hexanoic Acid (3).
A solution containing 2 (21.4 g) in dioxane (100 mL) was treated
with sodium hydroxide solution (57 mL, 1 N) for 30 min at room
temperature. The dioxane was evaporated, the crude residue was
cooled at 0 °C, and the mixture was acidified to pH 5 using 4 N
HCl. The mixture was partitioned between dichloromethane and
water, and the organic layer was washed with brine and dried over
MgSO4, and the solvents were evaporated to give 38 g of crude
product.
The crude hydroxy acid from the first step was dissolved in DMF
(100 mL) and treated with imidazole (21 g, 308.5 mmol) and tert-
butyldimethylsilyl chloride (23 g, 152.6 mmol) at room temperature
for 16 h. The solvent was evaporated, and the residue was combined
with ice and acidified with 4 N HCl to pH 3. Ethyl acetate (50
mL) was added to permit stirring during the acidification. This
mixture was extracted with ethyl acetate, washed with brine, dried
over MgSO4, and filtered, and the solvents were evaporated. The
residue was purified by chromatography on silica gel, eluting with
a gradient of 20-100% ethyl acetate in chloroform, followed by
elution with 5% methanol in ethyl acetate to give the product as a
mixture of isomers (11.3 g, 49% yield). 1H NMR (300 MHz, CDCl3)
δ ppm 0.06-0.16 (m, 6H), 0.94 (s, 9H), 1.33-1.39 (m, 9H),
1.52-1.99 (m, 2H), 2.59-3.09 (m, 4H), 3.66-4.09 (m, 2H),
4.57-4.83 (m, 1H), 7.07-7.39 (m, 8H), 7.64-7.79 (m, 2H),
7.81-7.91 (m, 2H), 8.56-8.72 (m, 1H). MS (ESI) m/z 605 (M +
H)+.
Benzyl (2S,4S,5S)-5-(tert-Butoxycarbonyl)amino-4-hydroxy-
6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylcarbamate (4) and
Benzyl (2R,4S,5S)-5-(tert-Butoxycarbonyl)amino-4-hydroxy-6-
phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylcarbamate (5). To a
solution of 3 (11.3 g, 18.7 mmol) in toluene (190 mL) were added
diphenylphosphoryl azide (8.1 mL, 37.6 mmol) and triethylamine
(5.2 mL, 37.3 mmol), and the mixture was heated at reflux for 2 h.
Benzyl alcohol (5.8 mL, 56.0 mmol) was added, and the mixture
was heated at reflux for an additional 16 h. The solvent was
evaporated.
To the crude residue from the first step was added TBAF solution
in THF (94 mL, 1 N), and the mixture was stirred at room
temperature for 40 h. The THF was evaporated, and the mixture
was partitioned between ethyl acetate and water. The organic was
washed with brine, dried over MgSO4, filtered, and evaporated. The
residue was purified by chromatography on silica gel, eluting with
50% ethyl acetate in chloroform to give 2.6 g (23% yield) of the
higher Rf product 5 by TLC (35% ethyl acetate in dichloromethane)
Methyl (S)-1-((2R,4S,5S)-5-Amino-4-hydroxy-6-phenyl-1-(4-
(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-oxobutan-
2-ylcarbamate (7b). 7bwas prepared according to the procedure for
1
6b from 7a. H NMR (300 MHz, DMSO-d6) δ ppm 0.73 (s, 9H),
1.51 (t, J ) 10.85 Hz, 1H), 1.61-1.75 (m, 1H), 2.69-2.91 (m, 4H),
3.30-3.44 (m, 1H), 3.80 (d, J ) 9.56 Hz, 1H), 4.08-4.29 (m, 1H),
6.90 (d, J ) 9.56 Hz, 1H), 7.11-7.43 (m, 8H), 7.78-8.07 (m,
5H), 8.64 (d, J ) 4.78 Hz, 1H). MS (ESI) m/z 533 (M + H)+.
(S)-Benzyl 3-(4-bromophenyl)-2-(dibenzylamino)propanoate
(12). To a suspension of (S)-2-amino-3-(4-bromophenyl)propanoic
acid (5 g, 20.5 mmol) in a mixture of water and ethanol (2:1,
respectively, 20 mL) were added potassium carbonate (9.3 g, 67.3
mmol) and benzyl chloride (7.77 mL, 67.5 mmol), and the mixture
was heated at reflux for 16 h. The mixture was cooled to room
temperature, and a mixture of hexanes and THF (1:1, 100 mL) was
added followed by addition of water. The mixture was partitioned,
and the organic was washed two times with a mixture of water
1
and 4.2 g (38% yield) of the lower Rf product 4 by TLC. 4: H
NMR (300 MHz, DMSO-d6) δ ppm 1.30 (s, 9H), 1.46-1.66 (m,
2H), 2.56-2.83 (m, 4H), 3.50-3.70 (m, 1H), 3.74-3.90 (m, 1H),
3.89-4.06 (m, 1H), 4.61 (d, J ) 6.62 Hz, 1H), 4.85-5.00 (m,
2H), 6.32 (d, J ) 9.56 Hz, 1H), 7.05-7.45 (m, 13H), 7.80-8.01
(m, 4H), 8.66 (d, J ) 4.04 Hz, 1H). MS (ESI) m/z 596 (M + H)+.
5: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (s, 9H), 1.39-1.56
(m, 2H), 2.53-2.87 (m, 4H), 3.49-3.63 (m, 1H), 3.84-3.97 (m,
1H), 4.51 (d, J ) 6.25 Hz, 1H), 4.87-5.04 (m, 2H), 6.33 (d, J )
9.19 Hz, 1H), 7.10-7.37 (m, 13H), 7.77-8.04 (m, 4H), 8.65 (d, J
) 4.04 Hz, 1H). MS (ESI) m/z 596 (M + H)+.

2-Pyridyl P1′-Substituted Symmetry-Based HIV P1s
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 2579
and methanol (2:1, respectively) and then with brine, dried over
MgSO4, filtered, and evaporated. The crude product (11.23 g) was
used without further purification. H NMR (300 MHz, CDCl3) δ
ppm 2.84-2.98 (m, 1H), 2.99-3.17 (m, 1H), 3.47-3.56 (m, 2H),
3.61-3.69 (m, 1H), 3.90 (d, J ) 13.97 Hz, 2H), 5.10-5.28 (m,
2H), 6.84 (d, J ) 8.46 Hz, 2H), 7.06-7.15 (m, 4H), 7.17-7.44
(m, 13H). MS (ESI) m/z 516 (M + H)+.
0 °C, and the mixture was allowed to warm to room temperature
and stirred for 16 h. The reaction was cooled at 0 °C and quenched
cautiously by slow addition of NaOH solution (65 mL, 3 N),
followed by partitioning between tert-butyl methyl ether and water.
The organic was washed with NaOH solution (0.5 N), NH4Cl
solution, and brine, dried over MgSO4, filtered, and evaporated to
give the crude product, which was used without further purification.
To a solution containing the product from the second step (9.65
mmol) in tert-butyl methyl ether (50 mL) were added 10% K2CO3
(23 mL) and di-tert-butyl dicarbonate (3.5 g, 16.0 mmol), and the
mixture was stirred at room temperature for 1 h. The mixture was
diluted with tert-butyl methyl ether, and the organic layer was
washed with water and brine, dried over MgSO4, filtered, and
evaporated. The residue was purified by chromatography on silica
gel, eluting with a gradient of 0-50% ethyl acetate in hexanes to
give the product (2.7 g, 43% yield). 1H NMR (300 MHz, DMSO-
d6) δ ppm 1.22 (s, 9H), 1.50-1.62 (m, 1H), 1.66-1.85 (m, 1H),
2.38-2.68 (m, 2H), 2.86-3.11 (m, 2H), 3.45-3.60 (m, 3H),
3.95-4.12 (m, 2H), 4.69 (d, J ) 4.41 Hz, 1H), 6.43 (d, J ) 8.09
Hz, 1H), 6.96-7.45 (m, 18H), 7.76-8.11 (m, 4H), 8.64 (d, J )
4.41 Hz, 1H). MS (ESI) m/z 642 (M + H)+.
1
(S)-Benzyl 2-(Dibenzylamino)-3-(4-(pyridin-2-yl)phenyl)pro-
panoate (13). To a solution containing 12 (11.0 g, 20.5 mmol) in
DMF (90 mL) were added LiCl (8 g, 188.7 mmol), tetrakis(triph-
enylphosphine)palladium(0) (5 g, 4.3 mmol), and 2-(tributylstan-
nyl)pyridine (22 g, 59.8 mmol), and the mixture was heated to 80
°C for 16 h. The mixture was cooled, filtered, and evaporated. The
residue was partitioned between ethyl acetate and water, and the
organic was washed with brine and dried over MgSO4, filtered,
and evaporated. The mixture was purified by chromatography on
silica gel, eluting with a gradient of 0-25% ethyl acetate in hexanes
to give the product (7.6 g, 72% yield). 1H NMR (300 MHz, CDCl3)
δ ppm 2.99-3.11 (m, 1H), 3.12-3.27 (m, 1H), 3.55 (d, J ) 13.97
Hz, 2H), 3.75 (t, J ) 7.72 Hz, 1H), 3.94 (d, J ) 13.97 Hz, 2H),
5.07-5.17 (m, 1H), 5.20-5.32 (m, 1H), 7.05-7.28 (m, 14H),
7.32-7.42 (m, 4H), 7.67-7.81 (m, 2H), 7.85 (d, J ) 8.09 Hz,
2H), 8.70 (d, J ) 4.41 Hz, 1H). MS (ESI) m/z 513 (M + H)+.
(S)-4-(Dibenzylamino)-3-oxo-5-(4-(pyridin-2-yl)phenyl)pen-
tanenitrile (14). To a solution of sodium bis(trimethylsilyl)amide
(1 M in THF, 50 mL) at -45 °C was added a solution of acetonitrile
(2.81 mL, 53.4 mmol) in THF (10 mL) dropwise, and the mixture
was stirred for 15 min at -45 °C and then cooled at -78 °C. A
room temperature solution of 13 (7.6 g, 14.8 mmol) dissolved in
THF (20 mL) was then added dropwise to the sodioacetonitrile
solution above at -78 °C. After complete addition, the mixture
was stirred at -45 °C for 1 h. Solid NH4Cl (10 g) was added, and
the mixture was warmed to 5 °C, followed by the addition of water.
The mixture was allowed to warm to room temperature and was
partitioned between ethyl acetate and water. The organic was
washed with brine and dried over MgSO4, filtered, and evaporated
to give an oil. Precipitation from ethanol gave the product (4.3 g,
tert-Butyl (2S,4S,5S)-5-Amino-4-hydroxy-1-phenyl-6-(4-(py-
ridin-2-yl)phenyl)hexan-2-ylcarbamate (17a). 17a was prepared
according to the procedure for 6a from 16, except the hydrogenoly-
1
sis was heated to 60 °C for 6 h (28% yield). H NMR (300 MHz,
DMSO-d6) δ ppm 0.83 (s, 9H), 1.25 (s, 9H), 1.43-1.60 (m, 2H),
2.53-2.66 (m, 2H), 2.69-2.88 (m, 2H), 3.51 (s, 3H), 3.55-3.66
(m, 1H), 3.69-3.85 (m, 1H), 3.92 (d, J ) 9.19 Hz, 1H), 4.08-4.24
(m, 1H), 4.79 (d, J ) 5.52 Hz, 1H), 6.56 (d, J ) 8.46 Hz, 1H),
6.80 (d, J ) 9.93 Hz, 1H), 7.06-7.37 (m, 8H), 7.55 (d, J ) 8.82
Hz, 1H), 7.80-8.01 (m, 4H), 8.63 (d, J ) 4.04 Hz, 1H). MS (ESI)
m/z 633 (M + H)+.
Methyl (S)-1-((2S,3S,5S)-5-Amino-3-hydroxy-6-phenyl-1-(4-
(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-oxobutan-
2-ylcarbamate (17b). 17b was prepared according to the procedure
1
for 6b from 17a. H NMR (300 MHz, CD3OD) δ ppm 0.84 (s,
9H), 1.57-1.80 (m, 2H), 2.72-3.03 (m, 4H), 3.48-3.57 (m, 1H),
3.53 (s, 3H), 3.79-3.89 (m, 2H), 4.03-4.15 (m, 1H), 7.13-7.39
(m, 8H), 7.74-7.95 (m, 4H), 8.58 (d, J ) 5.15 Hz, 1 H). MS (ESI)
m/z 533 (M + H)+.
1
62% yield). H NMR (300 MHz, CDCl3) δ ppm 2.96-3.13 (m,
2H), 3.19-3.36 (m, 1H), 3.49-3.65 (m, 3H), 3.81-3.96 (m, 3H),
7.14-7.48 (m, 13H), 7.62-7.79 (m, 2H), 7.89 (d, J ) 8.46 Hz,
2H), 8.67 (d, J ) 4.41 Hz, 1H). MS (ESI) m/z 446 (M + H)+.
(S,E)-5-Amino-2-(dibenzylamino)-6-phenyl-1-(4-(pyridin-2-
yl)phenyl)hex-4-en-3-one (15). A solution containing 14 (4.3 g,
9.65 mmol) in THF (15 mL) was added dropwise to a solution of
benzylmagnesium chloride (30 mL, 1 M in ether) at 0 °C. The
mixture was allowed to warm to room temperature and was stirred
for 16 h. The reaction was cooled at 0 °C and quenched with 10%
citric acid, followed by partitioning between ethyl acetate and water.
The organic was washed with brine and dried over MgSO4, filtered,
and evaporated to give the crude product (6.18 g), which was used
General Procedure for the Preparation of Carboxylic Acids
8. To a solution containing N-(2-aminoethyl)-L-tert-butylglycine
tert-butyl ester (prepared as described previously)9b (0.230 g, 1.0
mmol) in a mixture of toluene (4.0 mL) and methanol (4.0 mL)
was added the arylaldehyde (1.05 mmol), and the mixture was
stirred at 50 °C for 16 h. The mixture was cooled to room
temperature. Sodium borohydride (0.075 g, 2.0 mmol) was added,
and the mixture was stirred at room temperature for 1 h. The
reaction was quenched with 1 M NaHCO3 and stirred for 1 h. The
mixture was partitioned between ethyl acetate and water, and
the organic was washed with brine and dried over MgSO4, filtered,
and evaporated to give the product, which was used without further
purification.
Urea Cyclization Method A. To a solution containing the crude
product from the first step in 1,2-dichloroethane (15 mL) were added
N,N-disuccinimidyl carbonate (0.308 g, 1.20 mmol) and triethy-
lamine (0.169 mL, 1.20 mmol), and the mixture was stirred at room
temperature for 16 h. The mixture was partitioned between 10%
Na2CO3 and dichloromethane. The organic layer was separated,
washed with brine, dried over MgSO4, and evaporated to give the
crude product.
Urea Cyclization Method B. To a solution containing the crude
product from the first step in toluene (5.7 mL) was added bis(4-
nitrophenyl)carbonate (0.365 g, 1.2 mmol), and the mixture was
heated at reflux for 16 h. The mixture was cooled and partitioned
between ethyl acetate and 10% K2CO3. The organic was washed
with brine, dried over MgSO4, filtered, and evaporated to give the
crude product.
To a solution containing the crude product from cyclization
method A or B in dichloromethane (2.5 mL) was added TFA (2.5
mL), and the mixture was stirred at room temperature for 2 h. The
1
without further purification. H NMR (300 MHz, CDCl3) δ ppm
3.00 (dd, J ) 13.42, 6.07 Hz, 1H), 3.20 (dd, J ) 13.60, 7.72 Hz,
1H), 3.48 (d, J ) 6.99 Hz, 2H), 3.51-3.56 (m, 1H), 3.61-3.70
(m, 2H), 3.77-3.85 (m, 2H), 5.04-5.13 (m, 1H), 7.12-7.44 (m,
18H), 7.66-7.77 (m, 2H), 7.85 (d, J ) 8.09 Hz, 2H), 8.65-8.79
(m, 1 H). MS (ESI) m/z 538 (M + H)+.
tert-Butyl (2S,4S,5S)-5-(Dibenzylamino)-4-hydroxy-1-phenyl-
6-(4-(pyridin-2-yl)phenyl)hexan-2-ylcarbamate (16). To a sus-
pension of NaBH4 (1.75 g, 46.3 mmol) in THF (45 mL) at -10 °C
was added methanesulfonic acid (7.46 mL, 114.9 mmol) dropwise
cautiously (gas evolution). After complete addition, a solution
containing 15 (6.18 g, 9.65 mmol) in a mixture of THF (16 mL)
and water (1.6 mL) was added and the mixture was stirred at -10
°C for 16 h.
To a suspension of NaBH4 (1.75 g, 46.3 mmol) in THF (45 mL)
at 0 °C was added TFA (4.4 mL, 57.1 mmol) dropwise cautiously
(gas evolution), and the mixture was stirred at 0 °C for 30 min.
The solution was then added to the mixture from the first step and
allowed to warm to room temperature and was stirred for 16 h.
NaBH4 (1.75 g, 46.3 mmol) and TFA (4.4 mL, 57.1 mmol) were
combined as described above and again added to the mixture at

2580 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
DeGoey et al.
solvent was evaporated and the product was purified by reversed
phase (C18) chromatography, eluting with a gradient starting with
water (0.1% TFA) and ending with acetonitrile to give the product.
(S)-3,3-Dimethyl-2-(3-((6-methylpyridin-2-yl)methyl)-2-ox-
oimidazolidin-1-yl)butanoic Acid (8a). 8a was prepared by the
general procedure starting from 6-methyl-2-pyridinecarboxaldehyde
using urea cyclization method A. 1H NMR (300 MHz, DMSO-d6)
δ ppm 1.04 (s, 9H), 2.57 (s, 3H), 3.33 (t, J ) 7.93 Hz, 2H),
3.51-3.82 (m, 2H), 4.21 (s, 1H), 4.46 (s, 2H), 7.30 (d, J ) 7.54
Hz, 1H), 7.43 (d, J ) 7.93 Hz, 1H), 7.99 (t, J ) 7.73 Hz, 1H). MS
(ESI) m/z 306 (M + H)+.
mixture was cooled to room temperature and evaporated. The
mixture was partitioned between chloroform and saturated NaHCO3,
and the organic was washed with brine and dried over MgSO4,
filtered, and evaporated. The residue was purified by chromatog-
raphy on silica gel, eluting with a gradient of 0-15% methanol in
chloroform containing 1% NH4OH to give the product (36.3 g, 71%
1
yield). H NMR (300 MHz, CDCl3) δ ppm 1.44 (t, J ) 7.17 Hz,
3H), 4.47 (q, J ) 7.35 Hz, 2H), 7.42 (dd, J ) 8.46, 4.41 Hz, 1H),
8.23 (s, 1H), 8.31-8.40 (m, 1H), 8.70 (dd, J ) 4.96, 1.65 Hz,
1H), 9.20 (d, J ) 1.47 Hz, 1H). MS (ESI) m/z 235 (M + H)+.
2-(Pyridin-3-yl)thiazole-4-carbaldehyde. To a solution contain-
ing ethyl 2-(pyridin-3-yl)thiazole-4-carboxylate (20 g, 85.5 mmol)
in dichloromethane (340 mL) was added DIBAL (86 mL, 1 M in
dichloromethane) dropwise at -78 °C, and the mixture was stirred
at -78 °C for 2 h. Additional DIBAL (43 mL, 1 M in dichlo-
romethane) was added, and the mixture was stirred at -78 °C for
1 h. Methanol (20 mL) was added at -78 °C, and the mixture was
warmed to room temperature. Dichloromethane (250 mL), a
saturated solution of aqueous sodium potassium tartrate (350 mL),
and pH 7 buffer (300 mL) were added, and the mixture was stirred
vigorously with a mechanical stirrer for 16 h. The mixture was
filtered through Celite, and the layers were separated. The aqueous
was washed with chloroform, and the combined organics were
washed with brine and dried over MgSO4, filtered, and evaporated.
The residue was purified by chromatography on silica gel, eluting
with a gradient of 0-4% methanol in chloroform to give the product
(S)-3,3-Dimethyl-2-(3-((2-methylthiazol-4-yl)methyl)-2-oxoim-
idazolidin-1-yl)butanoic Acid (8b). 8b was prepared by the general
procedure starting from 2-methylthiazole-4-carbaldehyde (prepara-
tion has been described previously)21 using urea cyclization method
1
B. H NMR (300 MHz, DMSO-d6) δ ppm 1.02 (s, 9H), 2.63 (s,
3H), 3.19-3.35 (m, 2H), 3.45-3.71 (m, 2H), 4.19 (s, 1H),
4.25-4.40 (m, 2H), 7.22 (s, 1H). MS (ESI) m/z 312 (M + H)+.
Preparation of 8c. (S)-Methyl 6-((3-(1-tert-Butoxy-3,3-dimeth-
yl-1-oxobutan-2-yl)-2-oxoimidazolidin-1-yl)methyl)picolinate (19).
19 was prepared by the general procedure (first two steps) from
methyl 6-formylpicolinate (preparation has been described previ-
ously)22 using urea cyclization method B (64% yield). H NMR
1
(300 MHz, CDCl3) δ ppm 1.10 (s, 9H), 1.48 (s, 9H), 3.30-3.38
(m, 2H), 3.53-3.68 (m, 1H), 3.90 (q, J ) 8.58 Hz, 1H), 4.00 (s,
3H), 4.42 (s, 1H), 4.64 (s, 2H), 7.52 (d, J ) 7.72 Hz, 1H), 7.81 (t,
J ) 7.72 Hz, 1H), 8.03 (d, J ) 7.72 Hz, 1H). MS (ESI) m/z 406
(M + H)+.
1
(11.61 g, 71% yield). H NMR (300 MHz, CDCl3) δ ppm 7.45
(dd, J ) 8.09, 4.78 Hz, 1H), 8.24 (s, 1H), 8.29-8.42 (m, 1H),
8.67-8.81 (m, 1H), 9.22 (d, J ) 2.57 Hz, 1H), 10.13 (s, 1H). MS
(ESI) m/z 191 (M + H)+.
(S)-tert-Butyl 2-(3-((6-(2-Hydroxypropan-2-yl)pyridin-2-yl)-
methyl)-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoate (20). A
solution of 19 (9 g, 22.2 mmol) in THF (200 mL) at 0 °C was
treated with 3 M methylmagnesium bromide in diethyl ether (37
mL, 111 mmol). The mixture was stirred for 1.5 h at 0 °C, quenched
with 10% citric acid (20 mL), and extracted with ethyl acetate.
The organic layer was decanted, evaporated, and the residue was
purified by chromatography on silica gel, eluting with a gradient
of 20-70% ethyl acetate in hexane give the product as a gummy
solid (7.2 g, 80% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.09
(s, 9H), 1.47 (s, 9H), 1.52 (s, 6H), 3.29-3.39 (m, 2H), 3.55-3.68
(m, 1H), 3.89 (q, J ) 8.46 Hz, 1H), 4.42 (s, 1H), 4.45-4.62 (m,
2H), 5.20 (s, 1H), 7.16-7.29 (m, 2H), 7.68 (t, J ) 7.72 Hz, 1H).
MS (ESI) m/z 406 (M + H)+.
(S)-2-(3-((6-(2-Hydroxypropan-2-yl)pyridin-2-yl)methyl)-2-
oxoimidazolidin-1-yl)-3,3-dimethylbutanoic Acid (8c). 20 (7.2 g,
17.8 mmol) was treated with 90% TFA in water (30 mL) at 25 °C
for 3 h. The solvent was evaporated and the residue was purified
by chromatography on silica gel, eluting with 5% methanol in
dichloromethane to give the product as a gummy solid (7.4 g, 90%
yield). 1H NMR (300 MHz, CD3OD) δ ppm 1.12 (s, 9H), 1.62 (s,
6H), 3.50 (t, J ) 8.09 Hz, 2H), 3.70-3.81 (m, 1H), 3.92 (q, J )
8.70 Hz, 1H), 4.38 (s, 1H), 4.70 (s, 2H), 7.65 (d, J ) 7.72 Hz,
1H), 7.87 (d, J ) 8.09 Hz, 1H), 8.29 (t, J ) 7.91 Hz, 1H). MS
(ESI) m/z 450 (M + H)+.
(S)-3,3-Dimethyl-2-(2-oxo-3-((2-(pyridin-3-yl)thiazol-4-yl)m-
ethyl)imidazolidin-1-yl)butanoic Acid (8f). 8f was prepared by
the general procedure starting from 2-(pyridin-3-yl)thiazole-4-
carbaldehyde using urea cyclization method B. 1H NMR (300 MHz,
DMSO-d6) δ ppm 1.04 (s, 9H), 3.31-3.44 (m, 2H), 3.50-3.76
(m, 2H), 4.22 (s, 1H), 4.48 (s, 2H), 7.65 (s, 1H), 7.74 (dd, J )
7.93, 5.16 Hz, 1H), 8.52 (d, J ) 7.93 Hz, 1H), 8.76 (d, J ) 5.16
Hz, 1H), 9.20 (d, J ) 1.98 Hz, 1H). MS (ESI) m/z 375 (M + H)+.
(S)-3,3-Dimethyl-2-(3-((1-methyl-1H-benzo[d]imidazol-2-yl)m-
ethyl)-2-oxoimidazolidin-1-yl)butanoic Acid (8g). 8g was pre-
pared by the general procedure from 1-methyl-2-formylbenzimi-
dazole using urea cyclization method A. 1H NMR (300 MHz,
DMSO-d6) δ ppm 0.35 (s, 9H), 2.66-2.80 (m, 2H), 2.89-3.00
(m, 1H), 3.01-3.12 (m, 1H), 3.27 (s, 3H), 3.53 (s, 1H), 4.11-4.27
(m, 2H), 6.83-6.96 (m, 2H), 7.09-7.17 (m, 1H), 7.21-7.30 (m,
1H). MS (ESI) m/z 345 (M + H)+.
(S)-3,3-Dimethyl-2-(3-(2-nitrobenzyl)-2-oxoimidazolidin-1-
yl)butanoic Acid (8h). 8h was prepared by the general procedure
starting from 2-nitrobenzaldehyde using urea cyclization method
1
A. H NMR (300 MHz, CDCl3) δ ppm 1.15 (s, 9H), 3.40-3.52
(m, 2H), 3.68-3.77 (m, 1H), 3.89-4.03 (m, 1H), 4.50 (s, 1H),
4.70-4.88 (m, 2H), 7.41-7.52 (m, 2H), 7.59-7.67 (m, 1H), 8.03
(d, J ) 8.09 Hz, 1H). MS (ESI) m/z 336 (M + H)+.
(S)-3,3-Dimethyl-2-(3-(4-nitrobenzyl)-2-oxoimidazolidin-1-
yl)butanoic Acid (8i). 8i was prepared by the general procedure
starting from 4-nitrobenzaldehyde using urea cyclization method
A. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 9H), 3.16-3.29
(m, 2H), 3.52-3.73 (m, 2H), 4.22 (s, 1H), 4.43 (s, 2H), 7.51 (d, J
) 8.72 Hz, 2H), 8.22 (d, J ) 8.72 Hz, 2H). MS (ESI) m/z 336 (M
+ H)+.
(S)-2-(3-(2-Methoxybenzyl)-2-oxoimidazolidin-1-yl)-3,3-dim-
ethylbutanoic Acid (8j). 8j was prepared by the general procedure
starting from o-anisaldehyde using urea cyclization method A. 1H
NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 9H), 3.04-3.28 (m,
2H), 3.47-3.68 (m, 2H), 4.20 (s, 1H), 4.27 (s, 2H), 6.91 (t, J )
7.54 Hz, 1H), 7.00 (d, J ) 8.46 Hz, 1H), 7.12 (d, J ) 7.35 Hz,
1H), 7.21-7.32 (m, 1H). MS (ESI) m/z 321 (M + H)+.
(S)-2-(3-(3-Methoxybenzyl)-2-oxoimidazolidin-1-yl)-3,3-dim-
ethylbutanoic Acid (8k). 8k was prepared by the general procedure
starting from m-anisaldehyde using urea cyclization method A. 1H
NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 9H), 3.02-3.25 (m,
(S)-2-(3-Benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutano-
ic Acid (8d). 8d was prepared by the general procedure starting
from benzaldehyde using urea cyclization method A. 1H NMR (300
MHz, DMSO-d6) δ ppm 1.03 (s, 9H), 3.06-3.22 (m, 2H),
3.47-3.67 (m, 2H), 4.22 (s, 1H), 4.23-4.36 (m, 2H), 7.18-7.42
(m, 5H). MS (ESI) m/z 291 (M + H)+.
(S)-3,3-Dimethyl-2-(2-oxo-3-(quinolin-4-ylmethyl)imidazoli-
din-1-yl)butanoic Acid (8e). 8e was prepared by the general
procedure starting from 4-quinolinecarboxaldehyde using urea
cyclization method B. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.06
(s, 9H), 3.30-3.42 (m, 2H), 3.56-3.78 (m, 2H), 4.26 (s, 1H), 5.03
(s, 2H), 7.83 (d, J ) 5.55 Hz, 1H), 7.89-7.96 (m, 1H), 8.06-8.14
(m, 1H), 8.39 (d, J ) 8.72 Hz, 1H), 8.47 (d, J ) 8.33 Hz, 1H),
9.21 (d, J ) 5.16 Hz, 1H). MS (ESI) m/z 342 (M + H)+.
Preparation of 8f. Ethyl 2-(Pyridin-3-yl)thiazole-4-carboxy-
late. To a solution containing thionicotinamide (30 g, 217.1 mmol)
in ethanol (540 mL) was added ethyl bromopyruvate (30.3 mL,
241.4 mmol), and the mixture was heated to 70 °C for 3 h. The

2-Pyridyl P1′-Substituted Symmetry-Based HIV P1s
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 2581
2H), 3.46-3.68 (m, 2H), 3.73 (s, 3H), 4.19-4.34 (m, 2H), 4.22
(s, 1H), 6.73-6.88 (m, 3H), 7.25 (t, J ) 7.93 Hz, 1H). MS (ESI)
m/z 321 (M + H)+.
3.34-3.43 (m, 2H), 3.55-3.67 (m, 1H), 3.88 (q, J ) 8.46 Hz,
1H), 4.43 (s, 1H), 4.46-4.62 (m, 2H), 5.24-5.31 (m, 1H),
5.86-5.92 (m, 1H), 7.15 (d, J ) 7.72 Hz, 1H), 7.34 (d, J ) 7.72
Hz, 1H), 7.61 (t, J ) 7.72 Hz, 1H). MS (ESI) m/z 388 (M + H)+.
(S)-tert-Butyl 2-(3-((6-isopropylpyridin-2-yl)methyl)-2-oxoimi-
dazolidin-1-yl)-3,3-dimethylbutanoate (23). To a solution contain-
ing 22 (0.038 g, 0.098 mmol) in methanol (1 mL) was added 10%
Pd on carbon (0.005 g), and the mixture was stirred under an
atmosphere of hydrogen (balloon pressure) for 2 h. The reaction
was filtered, and the solvent was evaporated to give the product,
(S)-2-(3-(2-Fluorobenzyl)-2-oxoimidazolidin-1-yl)-3,3-dimeth-
ylbutanoic Acid (8l). 8l was prepared by the general procedure
starting from 2-fluorobenzaldehyde using urea cyclization method
A. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02 (s, 9H), 3.12-3.26
(m, 2H), 3.47-3.69 (m, 2H), 4.20 (s, 1H), 4.35 (s, 2H), 7.11-7.25
(m, 2H), 7.25-7.41 (m, 2H). MS (ESI) m/z 309 (M + H)+.
(S)-2-(3-(3-Fluorobenzyl)-2-oxoimidazolidin-1-yl)-3,3-dimeth-
ylbutanoic Acid (8m). 8m was prepared by the general procedure
starting from 3-fluorobenzaldehyde using urea cyclization method
A. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 9H), 3.10-3.25
(m, 2H), 3.49-3.71 (m, 2H), 4.22 (s, 1H), 4.31 (s, 2H), 6.97-7.18
(m, 3H), 7.32-7.47 (m, 1H). MS (ESI) m/z 309 (M + H)+.
(S)-2-(3-(4-Fluorobenzyl)-2-oxoimidazolidin-1-yl)-3,3-dimeth-
ylbutanoic Acid (8n). 8n was prepared by the general procedure
starting from 4-fluorobenzaldehyde using urea cyclization method
A. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02 (s, 9H), 3.05-3.21
(m, 2H), 3.47-3.69 (m, 2H), 4.21 (s, 1H), 4.27 (s, 2H), 7.08-7.22
(m, 2H), 7.23-7.31 (m, 2H). MS (ESI) m/z 309 (M + H)+.
(S)-3,3-Dimethyl-2-(3-(2-methylbenzyl)-2-oxoimidazolidin-1-
yl)butanoic Acid (8o). 8o was prepared by the general procedure
1
which was used without further purification. H NMR (300 MHz,
CDCl3) δ ppm 1.09 (s, 9H), 1.28 (d, J ) 6.99 Hz, 6H), 1.47 (s,
9H), 2.95-3.10 (m, 1H), 3.32-3.40 (m, 2H), 3.56-3.65 (m, 1H),
3.87 (q, J ) 8.46 Hz, 1H), 4.43 (s, 1H), 4.44-4.58 (m, 2H), 7.04
(d, J ) 8.09 Hz, 1H), 7.07 (d, J ) 7.72 Hz, 1H), 7.56 (t, J ) 7.72
Hz, 1H). MS (ESI) m/z 390 (M + H)+.
(S)-2-(3-((6-Isopropylpyridin-2-yl)methyl)-2-oxoimidazolidin-
1-yl)-3,3-dimethylbutanoic Acid (8r). 8r was prepared from 23
by the general procedure for tert-butyl ester hydrolysis using TFA.
1H NMR (300 MHz, CDCl3) δ ppm 1.11 (s, 9H), 1.41 (d, J ) 6.99
Hz, 6H), 3.41-3.59 (m, 3H), 3.64-3.78 (m, 1H), 3.92 (q, J )
8.46 Hz, 1H), 4.39 (s, 1H), 4.70-4.93 (m, 2H), 7.64 (d, J ) 8.09
Hz, 1H), 7.74 (d, J ) 7.72 Hz, 1H), 8.32 (t, J ) 7.91 Hz, 1H). MS
(ESI) m/z 334 (M + H)+.
1
starting from o-tolualdehyde using urea cyclization method A. H
NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 9H), 2.24 (s, 3H),
3.03-3.23 (m, 2H), 3.44-3.71 (m, 2H), 4.22 (s, 1H), 4.28 (s, 2H),
7.14-7.21 (m, 4H). MS (ESI) m/z 305 (M + H)+.
(S)-3,3-Dimethyl-2-(3-(3-methylbenzyl)-2-oxoimidazolidin-1-
yl)butanoic Acid (8p). 8p was prepared by the general procedure
starting from m-tolualdehyde using urea cyclization method A. 1H
NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 9H), 2.28 (s, 3H),
3.04-3.25 (m, 2H), 3.45-3.67 (m, 2H), 4.22 (s, 1H), 4.25 (d, J )
2.38 Hz, 2H), 6.97-7.12 (m, 3H), 7.18-7.29 (m, 1H). MS (ESI)
m/z 305 (M + H)+.
(S)-2-(3-((6-tert-Butylpyridin-2-yl)methyl)-2-oxoimidazolidin-
1-yl)-3,3-dimethylbutanoic Acid (8s). 8s was prepared by the
general procedure starting from 6-tert-butylpicolinaldehyde (prepa-
ration has been described previously)23 using urea cyclization
1
method A. tert-Butyl ester: H NMR (300 MHz, CDCl3) δ ppm
1.08 (s, 9H), 1.33 (s, 9H), 1.47 (s, 9H), 3.40 (t, J ) 7.91 Hz, 2H),
3.54-3.67 (m, 1H), 3.86 (q, J ) 8.70 Hz, 1H), 4.39-4.56 (m,
2H), 4.42 (s, 1H), 7.04 (d, J ) 7.72 Hz, 1H), 7.18 (d, J ) 8.09 Hz,
1H), 7.54 (t, J ) 7.72 Hz, 1H). MS (ESI) m/z 404 (M + H)+.
General Procedure for Preparation of Compounds 9a-p,
10a-i, 18a-h. Preparation of Methyl (S)-1-((2S,4S,5S)-5-((S)-
3,3-Dimethyl-2-(3-((6-methylpyridin-2-yl)methyl)-2-oxoimidazo-
lidin-1-yl)butanamido)-4-hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phe-
nyl)hexan-2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate
(9a). To a solution containing 6b (1.0 g, 1.88 mmol) in THF (19
mL) were added 8a (0.83 g, 1.98 mmol), DEPBT (0.84 g, 2.8
mmol), and N,N-diisopropylethylamine (1.6 mL, 9.2 mmol), and
the mixture was stirred at room temperature for 16 h. The mixture
was partitioned between a mixture of dichloromethane and ethyl
acetate (2:1, respectively) and 10% Na2CO3 solution. The organic
was washed with additional 10% Na2CO3 solution and then brine,
dried over MgSO4, filtered, and evaporated. The residue was purified
by chromatography on silica gel, eluting with a gradient of 0-100%
ethyl acetate in dichloromethane, followed by elution with a gradient
of 0-5% methanol in ethyl acetate to give the product as a white
(S)-2-(3-((2-Isopropylthiazol-4-yl)methyl)-2-oxoimidazolidin-
1-yl)-3,3-dimethylbutanoic Acid (8q). 8q was prepared by the
general procedure starting from 2-isopropylthiazole-4-carbaldehyde
(preparation has been described previously)14 using urea cyclization
1
method B. H NMR (300 MHz, DMSO-d6) δ ppm 1.02 (s, 9H),
1.31 (d, J ) 6.99 Hz, 6H), 3.19-3.35 (m, 3H), 3.45-3.71 (m,
2H), 4.19 (s, 1H), 4.25-4.40 (m, 2H), 7.25 (s, 1H). MS (ESI) m/z
340 (M + H)+.
Preparation of 8r. (S)-tert-Butyl 2-(3-((6-Acetylpyridin-2-
yl)methyl)-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanoate (21).
A solution of 19 (1.95 g, 4.815 mmol) in THF (50 mL) at -78 °C
was treated with methylmagnesium bromide in butyl ether (5.7 mL,
1 M). The mixture was stirred for 0.5 h at -78 °C, quenched with
acetone (3 mL) and 10% citric acid. The mixture was partitioned
between ethyl acetate and 1 N NaHCO3, and the organic layer was
decanted and evaporated. The residue was purified by chromatog-
raphy on silica gel, eluting with a gradient of 25-50% ethyl acetate
1
solid (1.15 g, 75% yield). H NMR (300 MHz, DMSO-d6) δ 0.83
(s, 9H), 0.90 (s, 9H), 1.55 (m, 2H), 2.38 (q, J ) 9.44 Hz, 1H),
2.46 (s, 3H), 2.57 (m, 1H), 2.67 (d, J ) 7.35 Hz, 2H), 2.79 (m,
1H), 2.97 (m, 1H), 3.09 (q, J ) 8.95 Hz, 1H), 3.21 (m, 1H), 3.50
(s, 3H), 3.67 (m, 1H), 3.85 (d, J ) 9.93 Hz, 1H), 4.12 (m, 3H),
4.35 (m, 2H), 4.54 (d, J ) 7.72 Hz, 1H), 6.63 (d, J ) 9.56 Hz,
1H), 7.09 (m, 7H), 7.22 (d, J ) 8.09 Hz, 2H), 7.31 (m, 1H), 7.49
(d, J ) 9.56 Hz, 1H), 7.69 (t, J ) 7.54 Hz, 1H), 7.86 (m, 5H),
8.63 (d, J ) 4.78 Hz, 1H). MS (ESI) m/z 820 (M + H)+.
1
in hexane to give the product (1.6 g, 85% yield). H NMR (300
MHz, CDCl3) δ ppm 1.10 (s, 9H), 1.48 (s, 9H), 2.70 (s, 3H),
3.33-3.49 (m, 2H), 3.56-3.77 (m, 1H), 3.94 (q, J ) 8.46 Hz,
1H), 4.43 (s, 1H), 4.52-4.73 (m, 2H), 7.46 (d, J ) 7.72 Hz, 1H),
7.79 (t, J ) 7.54 Hz, 1H), 7.92 (d, J ) 7.72 Hz, 1H). MS (ESI)
m/z 390 (M + H)+.
(S)-tert-Butyl 3,3-Dimethyl-2-(2-oxo-3-((6-(prop-1-en-2-yl)py-
ridin-2-yl)methyl)imidazolidin-1-yl)butanoate (22). To a solution
of methyltriphenylphosphonium bromide (0.33 g, 0.923 mmol) in
THF (2.5 mL) was added a solution of potassium tert-butoxide in
THF (0.89 mL, 1 M) dropwise, and the mixture was stirred for 1 h
at room temperature. A solution of 21 (0.116 g, 0.298 mmol) in
THF (2 mL) was then added, and the mixture was stirred at room
temperature for 30 min. The reaction was quenched with saturated
NH4Cl solution and partitioned between ethyl acetate and water,
and the organic was washed with brine and dried over MgSO4,
filtered, and evaporated. The residue was purified by chromatog-
raphy on silica gel, eluting with a gradient of 15-25% ethyl acetate
in hexane to give the product (0.040 g, 35% yield). 1H NMR (300
MHz, CDCl3) δ ppm 1.09 (s, 9 H), 1.47 (s, 9H), 2.20 (s, 3H),
Compounds 9b-p, 10a-i, 18a-h were prepared by the above
procedure, substituting 7b and 17b for 6b as appropriate and
coupling with the appropriate carboxylic acid 8a-s.
Methyl (S)-1-((2S,3S,5S)-5-((S)-3,3-Dimethyl-2-(3-((6-meth-
ylpyridin-2-yl)methyl)-2-oxoimidazolidin-1-yl)butanamido)-3-
hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-
3,3-dimethyl-1-oxobutan-2-ylcarbamate (18a). Yield 54%, white
solid. 1H NMR (300 MHz, DMSO-d6) δ 0.83 (s, 9H), 0.86 (s, 9H),
1.25 (m, 1H), 1.53 (m, 2H), 2.41 (m, 1H), 2.46 (m, 3H), 2.66 (d,
J ) 10.66 Hz, 1H), 2.78 (d, J ) 6.99 Hz, 2H), 2.96 (m, 1H), 3.07
(q, J ) 8.70 Hz, 1H), 3.24 (m, 1H), 3.51 (s, 3H), 3.62 (m, 1H),
3.96 (m, 2H), 4.19 (m, 2H), 4.34 (m, 2H), 4.83 (d, J ) 5.52 Hz,
1H), 6.79 (d, J ) 9.56 Hz, 1H), 7.05 (m, 6H), 7.15 (d, J ) 7.35

2582 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
DeGoey et al.
Hz, 1H), 7.30 (m, 3H), 7.58 (d, J ) 9.19 Hz, 1H), 7.68 (t, J )
7.72 Hz, 1H), 7.86 (m, 5H), 8.63 (d, J ) 4.78 Hz, 1H). HRMS
(ESI) m/z calcd for C47H61N7O6 820.4756; found 820.4756 (∆ e
0.1 ppm). Anal. (C47H61N7O6) C, H, N.
J ) 7.72 Hz, 1H), 7.86 (m, 5H), 8.63 (d, J ) 4.04 Hz, 1H). MS
(ESI) m/z 864 (M + H)+.
Methyl (S)-1-((2R,4S,5S)-4-Hydroxy-5-((S)-2-(3-((6-(2-hydrox-
ypropan-2-yl)pyridin-2-yl)methyl)-2-oxoimidazolidin-1-yl)-3,3-
dimethylbutanamido)-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-
2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (10c). Yield
84%, white solid. 1H NMR (300 MHz, DMSO-d6) δ 0.80 (s, 9H),
0.88 (s, 9H), 1.39 (m, 10H), 2.64 (m, 3H), 2.83 (m, 1H), 3.01 (m,
1H), 3.20 (m, 2H), 3.54 (m, 4H), 3.83 (d, J ) 9.56 Hz, 1H), 3.93
(m, 1H), 4.02 (s, 1H), 4.17 (m, 1H), 4.39 (m, 3H), 6.87 (d, J )
10.30 Hz, 1H), 7.08 (m, 6H), 7.24 (d, J ) 8.46 Hz, 2H), 7.32 (m,
1H), 7.52 (m, 2H), 7.75 (t, J ) 7.72 Hz, 1H), 7.89 (m, 5H), 8.64
(d, J ) 4.78 Hz, 1H). MS (ESI) 864 m/z (M + H)+. Anal.
(C49H65N7O7) C, H, N.
Methyl (S)-1-((2S,4S,5S)-5-((S)-2-(3-Benzyl-2-oxoimidazoli-
din-1-yl)-3,3-dimethylbutanamido)-4-hydroxy-6-phenyl-1-(4-
(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-oxobutan-
2-ylcarbamate (9d). Yield 73%, white solid. 1H NMR (300 MHz,
DMSO-d6) δ 0.83 (s, 9H), 0.89 (s, 9H), 1.56 (m, 2H), 2.33 (q, J )
9.07 Hz, 1H), 2.82 (m, 5H), 3.19 (m, 2H), 3.50 (s, 3H), 3.67 (m,
1H), 3.85 (d, J ) 9.93 Hz, 1H), 4.09 (s, 1H), 4.19 (m, 2H), 4.31
(s, 2H), 4.55 (d, J ) 7.72 Hz, 1H), 6.63 (d, J ) 9.56 Hz, 1H), 7.07
(m, 5H), 7.31 (m, 8H), 7.47 (d, J ) 9.56 Hz, 1H), 7.87 (m, 5H),
8.63 (d, J ) 4.78 Hz, 1H). HRMS (ESI) m/z calcd for C47H60N6O6
805.4647; found 805.4646 (∆ ) 0.1 ppm). Anal. (C47H60N6O6) C,
H, N.
Methyl (S)-1-((2S,3S,5S)-5-((S)-2-(3-Benzyl-2-oxoimidazoli-
din-1-yl)-3,3-dimethylbutanamido)-3-hydroxy-6-phenyl-1-(4-
(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-oxobutan-
2-ylcarbamate (18d). Yield 30%, white solid. 1H NMR (300 MHz,
CDCl3) δ 0.96 (s, 9H), 1.00 (s, 9H), 1.27 (m, 1H), 2.62 (dd, J )
13.79, 8.64 Hz, 1H), 2.85 (m, 5H), 3.03 (q, J ) 8.58 Hz, 1H), 3.39
(m, 1H), 3.64 (m, 4H), 3.82 (d, J ) 9.19 Hz, 1H), 3.94 (m, 1H),
4.00 (s, 1H), 4.11 (m, 2H), 4.35 (m, 2H), 5.31 (m, 1H), 6.13 (m,
2H), 7.10 (m, 5H), 7.21 (m, 2H), 7.33 (m, 7H), 7.74 (m, 2H), 7.89
(d, J ) 8.46 Hz, 2H), 8.68 (d, J ) 4.78 Hz, 1H). MS (ESI) m/z
805 (M + H)+.
Methyl (S)-1-((2R,4S,5S)-5-((S)-2-(3-Benzyl-2-oxoimidazoli-
din-1-yl)-3,3-dimethylbutanamido)-4-hydroxy-6-phenyl-1-(4-
(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-oxobutan-
2-ylcarbamate (10d). Yield 73%, white solid. 1H NMR (300 MHz,
DMSO-d6) δ 0.80 (s, 9H), 0.87 (s, 9H), 1.38 (t, J ) 11.58 Hz,
1H), 1.54 (m, 1H), 2.41 (m, 1H), 2.64 (m, 3H), 2.87 (m, 3H), 3.19
(m, 1H), 3.53 (m, 4 H), 3.84 (d, J ) 9.56 Hz, 1H), 3.95 (m, 1H),
4.04 (s, 1H), 4.18 (m, 1H), 4.29 (m, 2H), 4.45 (d, J ) 7.35 Hz,
1H), 6.88 (d, J ) 9.56 Hz, 1H), 7.05 (m, 5H), 7.30 (m, 8H), 7.53
(d, J ) 9.56 Hz, 1H), 7.90 (m, 5H), 8.65 (d, J ) 4.41 Hz, 1H). MS
(ESI) m/z 805 (M + H)+.
Methyl (S)-1-((2R,4S,5S)-5-((S)-3,3-Dimethyl-2-(3-((6-meth-
ylpyridin-2-yl)methyl)-2-oxoimidazolidin-1-yl)butanamido)-4-
hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-
3,3-dimethyl-1-oxobutan-2-ylcarbamate (10a). Yield 65%, white
solid. 1H NMR (300 MHz, DMSO-d6) δ 0.80 (s, 9H), 0.88 (s, 9H),
1.29 (m, 2H), 1.53 (m, 1H), 2.45 (s, 3H), 2.66 (m, 3H), 2.83 (dd,
J ) 13.79, 6.07 Hz, 1H), 3.03 (m, 2H), 3.23 (m, 1H), 3.53 (m,
4H), 3.84 (d, J ) 9.56 Hz, 1H), 4.01 (m, 2H), 4.16 (m, 1H), 4.34
(m, 2H), 4.44 (d, J ) 6.99 Hz, 1H), 6.88 (d, J ) 9.56 Hz, 1H),
7.09 (m, 7H), 7.24 (d, J ) 8.09 Hz, 2H), 7.32 (m, 1H), 7.54 (d, J
) 9.56 Hz, 1H), 7.67 (t, J ) 7.72 Hz, 1H), 7.89 (m, 5H), 8.64 (d,
J ) 4.04 Hz, 1H). MS (ESI) m/z 820 (M + H)+.
Methyl (S)-1-((2S,4S,5S)-5-((S)-3,3-Dimethyl-2-(3-((2-meth-
ylthiazol-4-yl)methyl)-2-oxoimidazolidin-1-yl)butanamido)-4-hy-
droxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-
dimethyl-1-oxobutan-2-ylcarbamate (9b). Yield 83%, white solid.
1H NMR (300 MHz, DMSO-d6) δ 0.83 (s, 9H), 0.88 (s, 9H), 1.54
(m, 2H), 2.36 (q, J ) 9.31 Hz, 1H), 2.61 (m, 5H), 2.78 (m, 1H),
3.01 (m, 2H), 3.22 (m, 2H), 3.50 (s, 3H), 3.66 (m, 1H), 3.85 (d, J
) 9.56 Hz, 1H), 4.17 (m, 4H), 4.41 (m, 1H), 4.54 (d, J ) 7.35 Hz,
1H), 6.63 (d, J ) 9.56 Hz, 1H), 7.06 (m, 5H), 7.21 (s, 1H), 7.24
(s, 2H), 7.31 (m, 1H), 7.45 (d, J ) 9.56 Hz, 1H), 7.87 (m, 5H),
8.63 (d, J ) 4.41 Hz, 1H). MS (ESI) m/z 826 (M + H)+.
Methyl (S)-1-((2S,3S,5S)-5-((S)-3,3-Dimethyl-2-(3-((2-meth-
ylthiazol-4-yl)methyl)-2-oxoimidazolidin-1-yl)butanamido)-3-hy-
droxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-
dimethyl-1-oxobutan-2-ylcarbamate (18b). Yield 70%, white
solid. 1H NMR (300 MHz, DMSO-d6) δ 0.81 (s, 9H), 0.86 (s, 9H),
1.53 (m, 2H), 2.39 (m, 2H), 2.64 (m, 4H), 2.77 (d, J ) 6.62 Hz,
2H), 3.00 (m, 2H), 3.19 (m, 1H), 3.51 (s, 3H), 3.61 (m, 1H), 3.96
(m, 2H), 4.32 (m, 4H), 4.82 (d, J ) 5.52 Hz, 1H), 6.79 (d, J )
9.56 Hz, 1H), 7.04 (m, 5H), 7.21 (s, 1H), 7.30 (m, 3H), 7.58 (d, J
) 8.82 Hz, 1H), 7.87 (m, 5H), 8.63 (d, J ) 4.78 Hz, 1H). MS
(ESI) m/z 826 (M + H)+.
Methyl (S)-1-((2R,4S,5S)-5-((S)-3,3-Dimethyl-2-(3-((2-meth-
ylthiazol-4-yl)methyl)-2-oxoimidazolidin-1-yl)butanamido)-4-hy-
droxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-
dimethyl-1-oxobutan-2-ylcarbamate (10b). Yield 94%, white
solid. 1H NMR (300 MHz, DMSO-d6) δ 0.80 (s, 9H), 0.89 (s, 9H),
1.38 (m, 1H), 1.53 (m, 1H), 2.43 (m, 1H), 2.63 (m, 6H), 2.83 (m,
1H), 3.03 (m, 2H), 3.20 (m, 1H), 3.53 (m, 4H), 3.94 (m, 3H), 4.36
(m, 4H), 6.88 (d, J ) 9.56 Hz, 1H), 7.05 (m, 5H), 7.24 (m, 3H),
7.32 (m, 1H), 7.51 (d, J ) 9.56 Hz, 1H), 7.89 (m, 5H), 8.65 (d, J
) 4.78 Hz, 1H). MS (ESI) m/z 826 (M + H)+.
Methyl (S)-1-((2S,4S,5S)-5-((S)-3,3-Dimethyl-2-(2-oxo-3-(quin-
olin-4-ylmethyl)imidazolidin-1-yl)butanamido)-4-hydroxy-6-
phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-
1-oxobutan-2-ylcarbamate (9e). Yield 67%, white solid. 1H NMR
(500 MHz, DMSO-d6) δ ppm 0.82 (s, 9H), 0.90 (s, 9H), 1.45-1.64
(m, 2H), 2.16-2.32 (m, 1H), 2.54-2.69 (m, 3H), 2.78 (d, J )
10.25 Hz, 1H), 2.85 (dd, J ) 8.06, 5.62 Hz, 1H), 3.00 (q, J ) 8.30
Hz, 1H), 3.14-3.22 (m, 1H), 3.49 (s, 3H), 3.65 (d, J ) 6.35 Hz,
1H), 3.84 (d, J ) 8.79 Hz, 1H), 4.03-4.31 (m, 3H), 4.52 (d, J )
7.32 Hz, 1H), 4.64 (d, J ) 15.63 Hz, 1H), 4.94 (d, J ) 15.63 Hz,
1H), 6.58 (d, J ) 8.79 Hz, 1H), 6.76-6.85 (m, 2H), 6.90 (t, J )
7.08 Hz, 1H), 6.96 (d, J ) 7.32 Hz, 2H), 7.09-7.35 (m, 5H),
7.39-7.49 (m, 2H), 7.63 (t, J ) 7.57 Hz, 1H), 7.72-7.95 (m, 7H),
8.06 (d, J ) 7.81 Hz, 1H), 8.31 (d, J ) 8.30 Hz, 1H), 8.62 (d, J )
3.42 Hz, 1H), 8.90 (d, J ) 4.39 Hz, 1H). MS (ESI) m/z 856 (M +
H)+.
Methyl (S)-1-((2S,3S,5S)-5-((S)-3,3-Dimethyl-2-(2-oxo-3-(quin-
olin-4-ylmethyl)imidazolidin-1-yl)butanamido)-3-hydroxy-6-
phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-
1-oxobutan-2-ylcarbamate (18e). Yield 37%, white solid. 1H NMR
(500 MHz, DMSO-d6) δ 0.83 (s, 9H), 0.85 (s, 9H), 1.61-1.50 (m,
2H), 2.41-2.31 (m, 2H), 2.69-2.59 (m, 1H), 2.78 (bs, 2H), 2.88
(m, 1H), 3.03-2.95 (m, 1H), 3.23-3.14 (m, 1H), 3.50 (s, 3H),
Methyl (S)-1-((2S,4S,5S)-4-Hydroxy-5-((S)-2-(3-((6-(2-hydrox-
ypropan-2-yl)pyridin-2-yl)methyl)-2-oxoimidazolidin-1-yl)-3,3-
dimethylbutanamido)-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-
2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (9c). Yield
86%, white solid. 1H NMR (300 MHz, DMSO-d6) δ 0.83 (s, 9H),
0.90 (s, 9H), 1.43 (d, J ) 5.15 Hz, 6H), 1.53 (m, 2H), 2.36 (m,
1H), 2.65 (m, 3H), 2.79 (m, 1H), 2.99 (m, 1H), 3.20 (m, 3H), 3.50
(s, 3H), 3.65 (m, 1H), 3.85 (d, J ) 9.93 Hz, 1H), 4.05 (m, 3H),
4.45 (m, 3H), 6.63 (d, J ) 9.93 Hz, 1H), 7.08 (m, 6H), 7.22 (d, J
) 8.09 Hz, 2H), 7.31 (m, 1H), 7.46 (d, J ) 9.56 Hz, 1H), 7.54 (d,
J ) 7.72 Hz, 1H), 7.83 (m, 6H), 8.64 (d, J ) 4.78 Hz, 1H). MS
(ESI) m/z 864 (M + H)+.
Methyl (S)-1-((2S,3S,5S)-3-Hydroxy-5-((S)-2-(3-((6-(2-hydrox-
ypropan-2-yl)pyridin-2-yl)methyl)-2-oxoimidazolidin-1-yl)-3,3-
dimethylbutanamido)-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-
2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (18c). Yield
64%, white solid. 1H NMR (300 MHz, DMSO-d6) δ 0.82 (s, 9H),
0.86 (s, 9H), 1.42 (d, J ) 4.78 Hz, 6H), 1.55 (m, 2H), 2.39 (m,
2H), 2.65 (d, J ) 13.24 Hz, 1H), 2.78 (d, J ) 6.25 Hz, 2H), 2.98
(m, 1H), 3.20 (m, 3H), 3.51 (s, 3H), 3.61 (m, 1H), 3.98 (m, 2H),
4.19 (m, 2H), 4.39 (m, 2H), 4.82 (d, J ) 5.52 Hz, 1H), 6.78 (d, J
) 9.19 Hz, 1H), 7.06 (m, 6H), 7.31 (m, 3H), 7.55 (m, 2H), 7.76 (t,

2-Pyridyl P1′-Substituted Symmetry-Based HIV P1s
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 2583
3.61 (m, 1H), 3.94 (m, 1H), 4.00 (s, 1H), 4.18 (m, 2H), 4.65 (d, J
) 15.14 Hz, 1H), 4.81 (bs, 1H), 4.91 (d, J ) 15.63 Hz, 1H),
6.87-6.73 (m, 4H), 6.96 (m, 2H), 7.29 (m, 3 H), 7.41 (bs, 1H),
7.61-7.54 (m, 2H), 7.89-7.77 (m, 5H), 8.05 (d, J ) 7.81 Hz,
1H), 8.29 (d, J ) 7.32 Hz, 1H), 8.62 (bs, 1H), 8.89 (bs, 1H). MS
(ESI) m/z 856 (M + H)+.
Methyl (S)-1-((2R,4S,5S)-5-((S)-3,3-Dimethyl-2-(2-oxo-3-(quin-
olin-4-ylmethyl)imidazolidin-1-yl)butanamido)-4-hydroxy-6-
phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-
1-oxobutan-2-ylcarbamate (10e). Yield 65%, white solid. 1H NMR
(300 MHz, DMSO-d6) δ 0.81 (s, 9H), 0.89 (s, 9H), 1.26 (m, 1H),
1.37 (m, 1H), 1.53 (m, 1H), 2.30 (m, 1H), 2.65 (m, 2H), 2.85 (m,
2H), 3.00 (m, 1H), 3.18 (m, 1H), 3.53 (m, 4H), 3.84 (d, J ) 9.56
Hz, 1H), 3.94 (m, 1H), 4.05 (m, 1H), 4.19 (m, 1H), 4.44 (d, J )
7.35 Hz, 1H), 4.63 (d, J ) 15.44 Hz, 1H), 4.95 (d, J ) 15.44 Hz,
1H), 6.87 (m, 6H), 7.25 (d, J ) 8.46 Hz, 2H), 7.32 (m, 1H), 7.43
(d, J ) 4.41 Hz, 1H), 7.60 (m, 2H), 7.86 (m, 6H), 8.06 (d, J )
7.72 Hz, 1H), 8.30 (d, J ) 8.09 Hz, 1H), 8.65 (m, 1H), 8.90 (d, J
) 4.04 Hz, 1H). MS (ESI) m/z 856 (M + H)+.
Methyl (S)-1-((2S,4S,5S)-5-((S)-3,3-Dimethyl-2-(2-oxo-3-((2-
(pyridin-3-yl)thiazol-4-yl)methyl)imidazolidin-1-yl)butanamido)-
4-hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-
3,3-dimethyl-1-oxobutan-2-ylcarbamate (9f). Yield 70%, white
solid. 1H NMR (300 MHz, DMSO-d6) δ 0.83 (s, 9H), 0.89 (s, 9H),
1.54 (m, 2H), 2.34 (m, 1H), 2.63 (m, 2H), 2.79 (m, 1H), 3.16 (m,
4H), 3.50 (s, 3H), 3.65 (m, 1H), 3.85 (d, J ) 9.93 Hz, 1H), 4.14
(m, 3H), 4.50 (m, 3H), 6.63 (d, J ) 9.56 Hz, 1H), 6.98 (m, 1H),
7.06 (m, 4H), 7.22 (d, J ) 8.09 Hz, 2H), 7.31 (m, 1H), 7.52 (m,
2H), 7.61 (s, 1H), 7.87 (m, 5H), 8.31 (m, 1H), 8.65 (m, 2H), 9.14
(d, J ) 1.84 Hz, 1H). MS (ESI) m/z 889 (M + H)+.
(m, 1H), 3.80 (s, 3H), 3.93 (m, 2H), 4.16 (m, 2H), 4.60 (m, 2H),
4.83 (d, J ) 5.52 Hz, 1H), 6.91 (m, 4H), 7.02 (m, 2H), 7.20 (m,
2H), 7.29 (m, 3H), 7.58 (m, 3H), 7.87 (m, 5H), 8.63 (d, J ) 4.78
Hz, 1H). MS (ESI) m/z 859 (M + H)+.
Methyl (S)-1-((2R,4S,5S)-5-((S)-3,3-Dimethyl-2-(3-((1-methyl-
1H-benzo[d]imidazol-2-yl)methyl)-2-oxoimidazolidin-1-yl)bu-
tanamido)-4-hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-
2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (10g). Yield
50%, white solid. 1H NMR (300 MHz, DMSO-d6) δ 0.81 (s, 9H),
0.88 (s, 9H), 1.38 (m, 1H), 1.53 (m, 1H), 2.40 (m, 1H), 2.64 (m,
3H), 2.83 (m, 1H), 3.12 (m, 4H), 3.54 (m, 4H), 3.82 (m, 3H), 3.95
(m, 1H), 4.03 (s, 1H), 4.18 (m, 1H), 4.43 (d, J ) 6.99 Hz, 1H),
4.60 (m, 2H), 6.92 (m, 4H), 7.04 (m, 2H), 7.21 (m, 4H), 7.32 (m,
1H), 7.58 (m, 3H), 7.89 (m, 5H), 8.65 (d, J ) 4.41 Hz, 1H). MS
(ESI) m/z 859 (M + H)+.
Methyl (S)-1-((2S,4S,5S)-5-((S)-2-(3-(2-Aminobenzyl)-2-ox-
oimidazolidin-1-yl)-3,3-dimethylbutanamido)-4-hydroxy-6-phen-
yl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-
oxobutan-2-ylcarbamate (9h). Compounds 6b and 8hwere coupled
under the standard conditions to give the 2-nitro product (61% yield),
which was hydrogenated using the procedure for 23 to give 9h (0.014
g, 55% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.84 (s, 9H), 0.86
(s, 9H), 1.63-1.46 (m, 2H), 2.16-2.07 (m, 1H), 2.65-2.54 (m, 3H),
3.00-2.74 (m, 3H), 3.18-3.08 (m, 1H), 3.50 (s, 3H), 3.71-3.62 (m,
1H), 3.87-3.83 (d, J ) 9.56 Hz, 1H), 4.05 (s, 1H), 4.28-4.10 (m,
4H), 4.53-4.51 (d, J ) 7.72 Hz, 1H), 5.20 (s, 2H), 6.56-6.51 (t,
J ) 7.35 Hz, 1H), 6.68-6.64 (m, 2H), 7.08-6.92 (m, 7H),
7.24-7.21 (d, J ) 8.09 Hz, 2H), 7.33-7.29 (m, 1H), 7.43-7.40
(d, J ) 9.93 Hz, 1H), 7.91-7.82 (m, 5H), 8.64-8.63 (d, J ) 4.41
Hz, 1H). MS (ESI) m/z 820 (M + H)+.
Methyl (S)-1-((2S,3S,5S)-5-((S)-3,3-Dimethyl-2-(2-oxo-3-((2-
(pyridin-3-yl)thiazol-4-yl)methyl)imidazolidin-1-yl)butanamido)-
3-hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-
3,3-dimethyl-1-oxobutan-2-ylcarbamate (18f). Yield 50%, white
solid. 1H NMR (300 MHz, DMSO-d6) δ 0.82 (s, 9H), 0.86 (s, 9H),
1.53 (m, 2H), 2.40 (m, 1H), 2.64 (d, J ) 13.97 Hz, 1H), 2.77 (d,
J ) 6.62 Hz, 2H), 3.15 (m, 4H), 3.51 (s, 3H), 3.62 (m, 1H), 3.96
(m, 2H), 4.18 (m, 2H), 4.47 (m, 2H), 4.82 (d, J ) 5.52 Hz, 1H),
6.79 (d, J ) 9.56 Hz, 1H), 6.95 (m, 1H), 7.03 (m, 4H), 7.30 (m,
3H), 7.54 (m, 3H), 7.87 (m, 5H), 8.30 (m, 1H), 8.65 (m, 2H), 9.14
(d, J ) 1.47 Hz, 1H). MS (ESI) m/z 889 (M + H)+.
Methyl (S)-1-((2R,4S,5S)-5-((S)-3,3-Dimethyl-2-(2-oxo-3-((2-
(pyridin-3-yl)thiazol-4-yl)methyl)imidazolidin-1-yl)butanamido)-
4-hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-
3,3-dimethyl-1-oxobutan-2-ylcarbamate (10f). Yield 78%, white
solid. 1H NMR (300 MHz, DMSO-d6) δ 0.80 (s, 9H), 0.88 (s, 9H),
1.46 (m, 2H), 2.44 (d, J ) 8.82 Hz, 1H), 2.63 (m, 3H), 2.83 (m,
1H), 3.15 (m, 3H), 3.54 (m, 4H), 3.84 (d, J ) 9.56 Hz, 1H), 3.93
(m, 1H), 4.04 (s, 1H), 4.18 (m, 1H), 4.46 (m, 3H), 6.88 (d, J )
9.56 Hz, 1H), 6.96 (m, 1H), 7.06 (m, 4H), 7.24 (d, J ) 8.46 Hz,
2H), 7.32 (m, 1H), 7.53 (m, 2H), 7.60 (s, 1H), 7.89 (m, 5H), 8.29
(m, 1H), 8.65 (m, 2H), 9.13 (d, J ) 1.47 Hz, 1H). MS (ESI) m/z
889 (M + H)+.
Methyl (S)-1-((2S,4S,5S)-5-((S)-3,3-Dimethyl-2-(3-((1-methyl-
1H-benzo[d]imidazol-2-yl)methyl)-2-oxoimidazolidin-1-yl)bu-
tanamido)-4-hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-
2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (9g). Yield
14%, white solid. 1H NMR (300 MHz, DMSO-d6) δ 0.83 (s, 9H),
0.89 (s, 9H), 1.26 (m, 1H), 1.52 (m, 2H), 2.32 (m, 1H), 2.70 (m,
4H), 2.98 (m, 1H), 3.09 (m, 2H), 3.46 (s, 1H), 3.50 (s, 3H), 3.81
(s, 3H), 4.15 (m, 3H), 4.53 (dd, J ) 11.40, 3.68 Hz, 2H), 4.70 (d,
J ) 15.44 Hz, 1H), 6.63 (d, J ) 9.56 Hz, 1H), 6.93 (m, 3H), 7.07
(d, J ) 6.62 Hz, 2H), 7.24 (m, 6H), 7.59 (m, 3H), 7.88 (m, 4H),
8.63 (d, J ) 3.31 Hz, 1H). MS (ESI) m/z 859 (M + H)+.
Methyl (S)-1-((2S,3S,5S)-5-((S)-3,3-Dimethyl-2-(3-((1-methyl-
1H-benzo[d]imidazol-2-yl)methyl)-2-oxoimidazolidin-1-yl)bu-
tanamido)-3-hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-
2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (18g). Yield
51%, white solid. 1H NMR (300 MHz, DMSO-d6) δ 0.82 (s, 9H),
0.86 (s, 9H), 1.27 (m, 1H), 1.53 (m, 2H), 2.36 (m, 2H), 2.72 (m,
3H), 2.98 (m, 1H), 3.10 (m, 1H), 3.48 (d, J ) 13.97 Hz, 3H), 3.61
Methyl (S)-1-((2S,4S,5S)-5-((S)-2-(3-(4-Aminobenzyl)-2-ox-
oimidazolidin-1-yl)-3,3-dimethylbutanamido)-4-hydroxy-6-phen-
yl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-
oxobutan-2-ylcarbamate (9i). Compounds 6b and 8i were coupled
under the standard conditions to give the 4-nitro product (56%
yield), which was hydrogenated using the procedure for 23 to give
9i (0.024 g, 39% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.83 (s,
9H), 0.87 (s, 9H), 1.60-1.48 (m, 2H), 2.29-2.20 (m, 1H),
2.67-2.53 (m, 3H), 2.92-2.75 (m, 3H), 3.16-3.08 (m, 1H), 3.50
(s, 3H), 3.71-3.61 (m, 1H), 3.86-3.83 (d, J ) 9.93 Hz, 1H), 4.07
(s, 1H), 4.11 (s, 2H), 4.23-4.09 (m, 2H), 4.56-4.53 (d, J ) 7.72
Hz, 1H), 5.00 (s, 2H), 6.55-6.52 (d, J ) 8.46 Hz, 2H), 6.67-6.64
(d, J ) 9.93 Hz, 1H), 6.94-6.91 (d, J ) 8.46 Hz, 2H), 7.10-7.02
(m, 5H), 7.23-7.21 (d, J ) 8.46 Hz, 2H), 7.33-7.29 (m, 1H),
7.45-7.42 (d, J ) 9.56 Hz, 1H), 7.91-7.82 (m, 5H), 8.64-8.62
(m, 1H). MS (ESI) m/z 820 (M + H)+.
Methyl (S)-1-((2S,4S,5S)-4-Hydroxy-5-((S)-2-(3-(2-methoxy-
benzyl)-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanamido)-6-
phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-
1-oxobutan-2-ylcarbamate (9j). Yield 59%, white solid. 1H NMR
(300 MHz, DMSO-d6) δ 0.83 (s, 9H), 0.89 (s, 9H), 1.26 (m, 1H),
1.38 (m, 1H), 1.54 (m, 2H), 2.33 (m, 1H), 2.83 (m, 5H), 3.18 (m,
1H), 3.50 (s, 3H), 3.66 (m, 1H), 3.83 (m, 4H), 4.25 (m, 4H), 4.53
(d, J ) 7.72 Hz, 1H), 6.63 (d, J ) 9.93 Hz, 1H), 6.95 (t, J ) 6.99
Hz, 1H), 7.18 (m, 11H), 7.45 (d, J ) 9.19 Hz, 1H), 7.86 (m, 5H),
8.63 (d, J ) 4.41 Hz, 1H). MS (ESI) m/z 835 (M + H)+.
Methyl (S)-1-((2S,4S,5S)-4-Hydroxy-5-((S)-2-(3-(3-methoxy-
benzyl)-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanamido)-6-
phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-
1-oxobutan-2-ylcarbamate (9k). Yield 59%, white solid. 1H NMR
(300 MHz, DMSO-d6) δ 0.83 (s, 9H), 0.89 (s, 9H), 1.55 (m, 2H),
2.32 (m, 1H), 2.80 (m, 6H), 3.18 (m, 1H), 3.50 (s, 3H), 3.65 (m,
1H), 3.74 (s, 3H), 3.85 (d, J ) 9.93 Hz, 1H), 4.20 (m, 5H), 4.54
(d, J ) 7.72 Hz, 1H), 6.63 (d, J ) 9.93 Hz, 1H), 6.85 (m, 3H),
7.08 (m, 5H), 7.28 (m, 4H), 7.48 (d, J ) 9.56 Hz, 1H), 7.86 (m,
5H), 8.63 (d, J ) 4.78 Hz, 1H). MS (ESI) m/z 835 (M + H)+.
Methyl (S)-1-((2S,4S,5S)-5-((S)-2-(3-(2-Fluorobenzyl)-2-ox-
oimidazolidin-1-yl)-3,3-dimethylbutanamido)-4-hydroxy-6-phen-
yl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-
1
oxobutan-2-ylcarbamate (9l). Yield 61%, white solid. H NMR
(300 MHz, DMSO-d6) δ 0.83 (s, 9H), 0.88 (s, 9H), 1.58-1.49 (m,

2584 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
DeGoey et al.
2H), 2.35-2.27 (m, 1H), 2.61-2.54 (m, 1H), 2.67-2.65 (d, J )
6.99 Hz, 2H), 2.87-2.76 (m, 2H), 3.03-2.94 (q, J ) 8.70 Hz,
1H), 3.20-3.16 (m, 1H), 3.50 (s, 3H), 3.70-3.63 (m, 1H),
3.86-3.83 (d, J ) 9.93 Hz, 1H), 4.07 (s, 1H), 4.23-4.10 (m, 2H),
4.46-4.28 (m, 2H), 4.55-4.52 (d, J ) 7.35 Hz, 1H), 6.65-6.62
(d, J ) 9.56 Hz, 1H), 7.09-6.99 (m, 4H), 7.26-7.21 (m, 4H),
7.40-7.28 (m, 3H), 7.50-7.46 (d, J ) 9.56 Hz, 1H), 7.91-7.82
(m, 5H), 8.64-8.63 (m, 1H). MS (ESI) m/z 823 (M + H)+.
Methyl (S)-1-((2S,4S,5S)-5-((S)-2-(3-(3-Fluorobenzyl)-2-ox-
oimidazolidin-1-yl)-3,3-dimethylbutanamido)-4-hydroxy-6-phen-
yl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-
oxobutan-2-ylcarbamate (9m). Yield 61%, white solid. 1H NMR
(300 MHz, DMSO-d6) δ 0.83 (s, 9H), 0.89 (s, 9H), 1.58-1.49 (m,
2H), 2.39-2.30 (q, J ) 9.19 Hz, 1H), 2.62-2.54 (m, 1H),
2.69-2.66 (d, J ) 7.35 Hz, 2H), 2.90-2.77 (m, 2H), 3.02-2.93
(q, J ) 8.7 Hz, 1H), 3.27-3.18 (m, 1H), 3.50 (s, 3H), 3.70-3.63
(m, 1H), 3.87-3.83 (d, J ) 9.93 Hz, 1H), 4.09 (s, 1H), 4.19-4.14
(m, 2H), 4.39-4.27 (m, 2H), 4.56-4.54 (d, J ) 7.72 Hz, 1H),
6.65-6.62 (d, J ) 9.56 Hz, 1H), 7.15-7.04 (m, 8H), 7.24-7.21
(d, J ) 8.46 Hz, 2H), 7.33-7.29 (m, 1H), 7.46-7.39 (m, 1H),
7.53-7.50 (d, J ) 9.56 Hz, 1H), 7.91-7.82 (m, 4H), 8.65-8.62
(m, 1H). MS (ESI) m/z 823 (M + H)+.
7.24 (s, 1H), 7.30 (m, 3H), 7.58 (d, J ) 9.56 Hz, 1H), 7.87 (m,
5H), 8.63 (d, J ) 4.41 Hz, 1H). MS (ESI) m/z 854 (M + H)+.
Methyl (S)-1-((2R,4S,5S)-4-Hydroxy-5-((S)-2-(3-((6-isopropy-
lpyridin-2-yl)methyl)-2-oxoimidazolidin-1-yl)-3,3-dimethylbu-
tanamido)-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-
3,3-dimethyl-1-oxobutan-2-ylcarbamate (10h). Yield 62%, white
solid. 1H NMR (300 MHz, DMSO-d6) δ 0.80 (s, 9H), 0.88 (s, 9H),
1.27-1.25 (d, J ) 6.99 Hz, 6H), 1.42-1.23 (m, 1H), 1.58-1.47
(m, 1H), 2.70-2.53 (m, 3H), 2.87-2.78 (m, 1H), 3.31-2.98 (m,
4H), 3.57-3.50 (m, 1H), 3.57 (s, 3H), 3.85-3.82 (d, J ) 9.56 Hz,
1H), 3.99-3.87 (m, 1H), 4.03 (s, 1H), 4.23-4.13 (m, 2H), 4.45
(s, 2H), 6.91-6.87(d, J ) 9.93 Hz, 1H), 7.10-7.06 (m, 5H),
7.28-7.21 (m, 4H), 7.44-7.37 (m, 2H), 7.58-7.55 (d, J ) 9.19
Hz, 1H), 7.97-7.86 (m, 5H), 8.69-8.67 (m, 1H). MS (ESI) m/z
848 (M + H)+.
Methyl (S)-1-((2R,4S,5S)-5-((S)-2-(3-((6-tert-Butylpyridin-2-
yl)methyl)-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanamido)-4-
hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-
3,3-dimethyl-1-oxobutan-2-ylcarbamate (10i). Yield 39%, white
solid. 1H NMR (300 MHz, DMSO-d6) δ 0.80 (s, 9H), 0.88 (s, 9H),
1.30 (s, 9H), 1.42-1.23 (m, 1H), 1.58-1.47 (m, 1H), 2.47-2.42
(m, 1H), 2.73-2.55 (m, 2H), 2.87-2.78 (m, 1H), 3.05-2.99 (m,
1H), 3.31-3.18 (m, 1H), 3.57-3.50 (m, 1H), 3.57 (s, 3H),
3.85-3.82 (d, J ) 9.56 Hz, 1H), 3.99-3.87 (m, 1H), 4.02 (s, 1H),
4.23-4.13 (m, 1H), 4.44-4.32 (m, 2H), 4.44-4.42 (d, J ) 7.35
Hz, 1H), 6.90-6.87 (d, J ) 9.19 Hz, 1H), 7.09-7.04 (m, 6H),
7.25-7.22 (d, J ) 8.46 Hz, 2H), 7.34-7.29 (m, 2H), 7.54-7.51
(d, J ) 9.91 Hz, 1H), 7.73-7.68 (t, J ) 7.72 Hz, 1H), 7.90-7.83
(m, 3H), 7.97-7.94 (d, J ) 8.09 Hz, 2H), 8.65-8.64 (m, 1H). MS
(ESI) m/z 862 (M + H)+.
Methyl (S)-1-((2S,4S,5S)-5-((S)-2-(3-(4-Fluorobenzyl)-2-ox-
oimidazolidin-1-yl)-3,3-dimethylbutanamido)-4-hydroxy-6-phen-
yl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-
1
oxobutan-2-ylcarbamate (9n). Yield 62%, white solid. H NMR
(300 MHz, DMSO-d6) δ 0.83 (s, 9H), 0.88 (s, 9H), 1.58-1.49 (m,
2H), 2.37-2.28 (m, 1H), 2.61-2.54 (m, 1H), 2.68-2.66 (d, J )
7.35 Hz, 2H), 2.90-2.75 (m, 2H), 2.98-2.87 (q, J ) 8.46 Hz,
1H), 3.20-3.16 (m, 1H), 3.50 (s, 3H), 3.70-3.63 (m, 1H),
3.86-3.83 (d, J ) 9.93 Hz, 1H), 4.08 (s, 1H), 4.21-4.13 (m, 2H),
4.30 (s, 2H), 4.56-4.54 (d, J ) 7.35 Hz, 1H), 6.65-6.62 (d, J )
9.56 Hz, 1H), 7.12-7.03 (m, 4H), 7.24-7.18 (m, 4H), 7.34-7.29
(m, 3H), 7.49-7.46 (d, J ) 9.56 Hz, 1H), 7.91-7.82 (m, 5H),
8.64-8.63 (m, 1H). MS (ESI) m/z 823 (M + H)+.
Dimethyl (2S,2′S)-1,1′-((2S,3S,5S)-3-Hydroxy-1-phenyl-6-(4-
(pyridin-2-yl)phenyl)hexane-2,5-diyl)bis(azanediyl)bis(3,3-di-
methyl-1-oxobutane-2,1-diyl)dicarbamate (11). 11 was prepared
from 6b and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic
1
acid in 75% yield as a white solid. H NMR (300 MHz, DMSO-
Methyl (S)-1-((2S,4S,5S)-5-((S)-3,3-Dimethyl-2-(3-(2-methyl-
benzyl)-2-oxoimidazolidin-1-yl)butanamido)-4-hydroxy-6-phen-
yl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-
d6) δ ppm 0.79 (s, 9 H), 0.82 (s, 9 H), 1.51 (m, 2 H), 2.72 (m, 3
H), 3.49 (s, 3 H), 3.55 (s, 3 H), 3.63 (m, 1 H), 3.82 (d, J ) 9.93
Hz, 1 H), 3.90 (d, J ) 9.56 Hz, 1 H), 4.04 (m, 3 H), 4.86 (d, J )
5.88 Hz, 1 H), 6.60 (d, J ) 9.93 Hz, 1 H), 6.78 (d, J ) 9.19 Hz,
1 H), 7.16 (m, 7 H), 7.31 (m, 1 H), 7.54 (d, J ) 8.46 Hz, 1 H),
7.83 (m, 5 H), 8.63 (d, J ) 4.78 Hz, 1 H). MS (ESI) m/z 704 (M
+ H)+.
Biological Evaluation. Procedures for EC50 determination against
WT and mutant strains of HIV in MT-4 cells have been reported
previously.20
Pharmacokinetic Analysis. Compounds were formulated as 5
mg/mL solutions in 5% dextrose containing 20% ethanol, 30%
propylene glycol, and appropriate equivalents of methanesulfonic
acid, and Sprague-Dawley-derived rats (Charles River, male; n )
3) and beagle dogs (male and female; n ) 3) received doses by iv
or oral gavage. Plasma samples, obtained as a function of time after
dosing (rat, 10 time points over 8 h; dog, 12 time points over 12 h),
were extracted into mixtures of ethyl acetate and hexane, concen-
trated, and analyzed by reversed-phase HPLC with an internal
standard.
1
oxobutan-2-ylcarbamate (9o). Yield 49%, white solid. H NMR
(300 MHz, DMSO-d6) δ ppm 0.83 (m, 9H), 0.89 (m, 9H),
1.62-1.48 (m, 2H), 2.31 (s, 3H), 2.34-2.24 (m, 1H), 2.62-2.53
(m, 1H), 2.68-2.65 (m, 2H), 2.84-2.73 (m, 2H), 2.97-2.88 (m,
1H), 3.22-3.12 (m, 1H), 3.50 (s, 3H), 3.70-3.62 (m, 1H),
3.87-3.83 (d, J ) 9.93 Hz, 1H), 4.08 (s, 1H), 4.43-4.12 (m, 4H),
4.55-4.52 (d, J ) 7.72 Hz, 1H), 6.65-6.62 (d, J ) 9.56 Hz, 1H),
7.01-6.99 (m, 3H), 7.09-7.08 (m, 2H), 7.24-7.20 (m, 5H),
7.32-7.29 (m, 1H), 7.49-7.46 (d, J ) 9.56 Hz, 1H), 7.91-7.82
(m, 5H), 8.64-8.63 (d, J ) 4.41 Hz, 1H). MS (ESI) m/z 819 (M
+ H)+.
Methyl (S)-1-((2S,4S,5S)-5-((S)-3,3-Dimethyl-2-(3-(3-methyl-
benzyl)-2-oxoimidazolidin-1-yl)butanamido)-4-hydroxy-6-phen-
yl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-
1
oxobutan-2-ylcarbamate (9p). Yield 44%, white solid. H NMR
(300 MHz, DMSO-d6) δ 0.83 (m, 9H), 0.89 (m, 9H), 1.62-1.48
(m, 2H), 2.31 (s, 3H), 2.34-2.24 (m, 1H), 2.62-2.53 (m, 1H),
2.68-2.65 (m, 2H), 2.97-2.73 (m, 3H), 3.22-3.12 (m, 1H), 3.50
(s, 3H), 3.70-3.62 (m, 1H), 3.87-3.83 (d, J ) 9.93 Hz, 1H), 4.08
(s, 1H), 4.33-4.11 (m, 4H), 4.56-4.53 (d, J ) 7.72 Hz, 1H),
6.65-6.62 (d, J ) 9.56 Hz, 1H), 7.04-7.02 (m, 3H), 7.11-7.07
(m, 4H), 7.25-7.21 (m, 4H), 7.33-7.28 (m, 1H), 7.49-7.46 (d, J
) 9.56 Hz, 1H), 7.91-7.82 (m, 4H), 8.64-8.63 (d, J ) 4.04 Hz,
1H). MS (ESI) m/z 819 (M + H)+.
Methyl (S)-1-((2S,3S,5S)-3-Hydroxy-5-((S)-2-(3-((2-isopropy-
lthiazol-4-yl)methyl)-2-oxoimidazolidin-1-yl)-3,3-dimethylbu-
tanamido)-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-
3,3-dimethyl-1-oxobutan-2-ylcarbamate (18h). Yield 62%, white
solid. 1H NMR (300 MHz, DMSO-d6) δ 0.81 (s, 9H), 0.86 (s, 9H),
1.32 (d, J ) 6.99 Hz, 6H), 1.52 (m, 2H), 2.38 (m, 2H), 2.64 (d, J
) 9.93 Hz, 1H), 2.77 (d, J ) 6.99 Hz, 2H), 3.01 (m, 2H), 3.23 (m,
2H), 3.51 (s, 3H), 3.61 (m, 1H), 3.95 (m, 2H), 4.30 (m, 4H), 4.82
(d, J ) 5.52 Hz, 1H), 6.79 (d, J ) 9.19 Hz, 1H), 7.00 (m, 5H),
Metabolic Stability Screening. Inhibitors were incubated at 2
µM in a reaction mixture containing 100 mM potassium phosphate,
pH 7.4, 0.5 mg/mL of pooled (HLM), 1 mM NADPH, 0.5%
DMSO, and 0.5% acetonitrile in a final volume of 100 µL. Control
samples received water instead of NADPH to start the reaction,
and some samples received 0.4 µM RTV. All mixtures were
incubated at 37 °C for 20 min and then terminated with the addition
of cold acetonitrile/methanol (1:1) containing an internal standard
in order to denature the protein and extract the compound. The
extractions were allowed to progress to completion by storing the
samples overnight at 4 °C, and samples were then centrifuged at
15000g for 10 min at 4 °C. The supernatants were analyzed by
LC/MS/MS.
Hyperbilirubinemia Model. As described previously,5 com-
pounds for dosing in Gunn rats (n ) 8-10 (rats/arm)/experiment)
were formulated in 5% ethanol/95% propylene glycol with ap-

2-Pyridyl P1′-Substituted Symmetry-Based HIV P1s
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 2585
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propriate equivalents of p-toluenesulfonic acid. Plasma samples
were obtained 4 h after the first and second doses and were analyzed
for drug concentration as described above for pharmacokinetic
analysis and for bilirubin concentration to the nearest 0.01 mg/
mL.
(8) (a) Lum, P. Y.; He, Y. D.; Slatter, J. G.; Waring, J. F.; Zelinsky, N.;
Cavet, G.; Dai, X.; Fong, O.; Gum, R.; Jin, L.; Adamson, G. E.;
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expression profiling of rat liver reveals a mechanistic basis for
ritonavir-induced hyperlipidemia. Genomics 2007, 90, 464–473. (b)
Waring, J. F.; Ciurlionis, R.; Marsh, K.; Klein, L. L.; DeGoey, D. A.;
Randolph, J. T.; Spear, B.; Kempf, D. J. Identification of Proteasome
Gene Regulation in a Rat Model for HIV Protease Inhibitor-Induced
Hyperlipidemia Using Microarray Analysis. Presented at the 12th
Conference on Retroviruses and Opportunistic Infections, Boston, MA,
2005; Abstract 839. (c) Parker, R. A.; Flint, O. P.; Mulvey, R.; Elosua,
C.; Wang, F.; Fenderson, W.; Wang, S.; Yang, W.-P.; Noor, M. A.
Endoplasmic reticulum stress links dyslipidemia to inhibition of
proteasome activity and glucose transport by HIV protease inhibitors.
Mol. Pharmacol. 2005, 67, 1909–1919. (d) Waring, J. F.; Ciurlionis,
R.; Marsh, K.; Klein, L. L.; DeGoey, D. A.; Randolph, J. T.; Spear,
B.; Kempf, D. J. Identification of Proteasome Gene Regulation in a
Rat Model for HIV Protease Inhibitor-Induced Hyperlipidemia Using
Microarray Analysis. Unpublished results.
(9) (a) Flosi, W. J.; DeGoey, D. A.; Grampovnik, D. J.; Chen, H. J.; Klein,
L. L.; Dekhtyar, T.; Masse, S.; Marsh, K. C.; Mo, H. M.; Kempf,
D. J. Discovery of imidazolidine-2,4-dione-linked HIV protease
inhibitors with activity against lopinavir-resistant mutant HIV. Bioorg.
Med. Chem. 2006, 14, 6695–6712. (b) Randolph, J. T.; Huang, P. P.;
Flosi, W. J.; DeGoey, D. A.; Klein, L. L.; Yeung, C. M.; Flentge, C.;
Sun, M.; Zhao, C.; Dekhtyar, T.; Mo, H.; Colletti, L.; Kati, W.; Marsh,
K. C.; Molla, A.; Kempf, D. J. Synthesis, antiviral activity, and
pharmacokinetic evaluation of P3 pyridylmethyl analogs of oximi-
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14, 4035–4046. (c) Yeung, C. M.; Klein, L. L.; Flentge, C. A.;
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X-ray Crystallographic Analysis. HIV protease was purified
and crystallized in the presence of compounds according to
procedures previously described.18b Data were collected at the
Argonne National Laboratory synchrotron on the IMCA ID17
beamline using a Mar 165 CCD detector. Data were processed using
HKL2000. The crystals of 11 belong to the monoclinic space group
P2(1), with unit cell dimensions a ) 67.08 Å, b ) 61.50 Å, c )
87.68 Å, R ) 90.00°, ꢀ ) 111.12°, γ ) 90.00°. The final structure
of the HIV protease/11 inhibited complex was refined using
CNX,24,25 an Rfree set of 5.0%, and an R ) 22.70%, Rfree ) 28.66%,
at 2.5 Å resolution. The crystals of 10a belong to the monoclinic
space group P2(1), with unit cell dimensions a ) 42.65 Å, b )
195.57 Å, c ) 50.37 Å, R ) 90.00°, ꢀ ) 91.19°, γ ) 90.00°. The
final structure of the HIV protease/10a inhibited complex was
refined using CNX, an Rfree set of 5.0%, and an R ) 22.11%, Rfree
) 30.30%, at 2.7 Å resolution.
Acknowledgment. X-ray data were collected at beamline
17-ID in the facilities of the Industrial Macromolecular Crystal-
lography Association Collaborative Access Team (IMCA-CAT)
at the Advanced Photon Source. These facilities are supported
by the companies of the Industrial Macromolecular Crystal-
lography Association through a contract with Illinois Institute
of Technology (IIT), executed through IIT’s Center for Syn-
chrotron Radiation Research and Instrumentation. Use of the
Advanced Photon Source was supported by the U.S. Department
of Energy, Basic Energy Sciences, Office of Science, under
Contract No. W-31-109-Eng-38.
(10) Process improvement of our original synthetic route reported here for
the synthesis of core A compounds has been published: Engstrom,
K.; Henry, R.; Hollis, S.; Kotecki, B.; Marsden, I.; Pu, Y.; Wagaw,
S.; Wang, W. An efficient, stereoselective synthesis of the hydroxy-
ethylene dipeptide isostere core for the HIV protease inhibitor
A-792611. J. Org. Chem. 2006, 71, 5369–5372.
(11) Haight, A. R.; Stuk, T. L.; Allen, M. S.; Bhagavatula, L.; Fitzgerald,
M.; Hannick, S. M.; Kerdesky, F. A.; Menzia, J. A.; Parekh, S. I.;
Robbins, T. A.; Scarpetti, D.; Tien, J. Reduction of an enaminone:
synthesis of the diamino alcohol core of ritonavir. Org. Process Res.
DeV. 1999, 3, 94–100.
Supporting Information Available: HPLC purity data for
compounds 1b,c, 9a-p, 10a-i, 11, 18a-h and synthetic details
for preparation of 1b and 1c. This material is available free of charge
via the Internet at http://pubs.acs.org.
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