3-(3-Aryloxyaryl)imidazo[1,2-a]pyridine sulfones as liver X receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2009.11.098

Replacement of a quinoline with an imidazo[1,2-a]pyridine in a series of liver X receptor (LXR) agonists incorporating a [3-(sulfonyl)aryloxyphenyl] side chain provided high affinity LXR ligands 7. In functional assays of LXR activity, good agonist potency and efficacy were found for several analogs.

Full text of DOI:10.1016/j.bmcl.2009.11.098

Bioorganic & Medicinal Chemistry Letters 20 (2010) 521–525
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
3-(3-Aryloxyaryl)imidazo[1,2-a]pyridine sulfones as liver X receptor agonists
a
a
a
b
Robert R. Singhaus a, , Ronald C. Bernotas , Robert Steffan , Edward Matelan , Elaine Quinet ,
Ponnal Nambi b, Irene Feingold c, Christine Huselton c, Anna Wilhelmsson d,
Annika Goos-Nilsson d, Jay Wrobel a
*
a Chemical Sciences, Wyeth Pharmaceuticals, 500 Arcola Rd., Collegeville, PA 19426, USA
b Cardiovascular and Metabolic Diseases, Wyeth Pharmaceuticals, 500 Arcola Rd., Collegeville, PA 19426, USA
c Drug Safety and Metabolism, Wyeth Pharmaceuticals, 500 Arcola Rd., Collegeville, PA 19426, USA
d Karo Bio AB, Novum S-141, 57 Huddinge, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Replacement of a quinoline with an imidazo[1,2-a]pyridine in a series of liver X receptor (LXR) agonists
incorporating a [3-(sulfonyl)aryloxyphenyl] side chain provided high affinity LXR ligands 7. In functional
assays of LXR activity, good agonist potency and efficacy were found for several analogs.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 15 October 2009
Revised 18 November 2009
Accepted 19 November 2009
Available online 23 November 2009
Keywords:
Imidazo[1,2-a]pyridine
Liver X receptor
LXR
Atherosclerosis
Sulfone
ABCA1
Cholesterol
Triglycerides
Liver X receptors (LXRs) are members of the nuclear receptor
superfamily.1 LXRs act as ligand activated transcription factors
which increase the expression of several genes when turned on
by agonists including oxysterols, the endogenous agonists. The
activation requires the formation of an LXR-RXR (retinoid X recep-
tor) heterodimer. Among the key genes activated by LXR-RXR het-
erodimers are those corresponding to the ATP-binding cassette
proteins (ABCs), a group of lipid transporters partly responsible
for controlling lipid homeostasis.2 Increasing the expression of
ABCs and in particular ABCA1, an important transporter in macro-
phages and other cells, may increase reverse cholesterol transport
(RCT). Enhancing RCT could have the effect of slowing the develop-
ment of atherosclerosis. However activation of undesired genes,
especially sterol regulatory element-binding protein-1c (SREBP-
1c) and fatty acid synthetase (FAS), also under the control of LXRs,
may lead to increases in triglycerides (TGs) and to steatosis in the
liver.3 To minimize the potential for undesired effects, agonism of
the LXRb subtype (present in macrophages and independently able
in liver than LXRb and the site of TG synthesis) has been the focus
for several groups.4
As an alternative or addition to statin therapy, several compa-
nies have targeted LXR agonists for dislipidemia. These include
T0901317 (1)5 from Tularik and GW3965 (2)6 from GlaxoSmithK-
line (Fig. 1). These compounds are high affinity LXR ligands with
potent LXR agonism. An indazole-based LXR agonist, WAY-
252623 (3),7 has been shown to upregulate ABCA1 in whole blood
of cynomolgus monkeys8 and like wise in humans in a phase I clin-
ical trial (Fig. 2).9 A quinoline-based series also developed by
Wyeth is exemplified by WAY-254011 (4).10
Ph
Ph
N
CO2H
F3C CF3
HO
O
O
O
S
to upregulate ABCA1) rather than of the a-subtype (more prevalent
N
Cl
F3C
1 T0901317 (Tularik)
CF3
2 GW3965 (GSK)
* Corresponding author.
E-mail address: Singhar@wyeth.com (R.R. Singhaus).
Figure 1. LXR Agonists from Tularik and GlaxoSmithKline.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.098

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R. R. Singhaus et al. / Bioorg. Med. Chem. Lett. 20 (2010) 521–525
F
preparation of PhCH2C(O)CH2Cl (9, Y = benzyl) was problematic,
CO2H
imidazo[1,2-a]pyridine 10b (Y = CH2Ph, Z = CF3) was made from
10a by standard Suzuki coupling with phenylboronic acid (Scheme
2).17 Direct arylation of compounds 10 with 3-iodophenol
O
18
using Pd(OAc)2 or more conveniently with Pd(OH)2 on carbon19
N
Cl
F
N
gave phenols 11 in good yield. Introduction of the sulfone or sul-
fonamide side chains by reaction with arylhalide 1220 was accom-
plished either through copper-mediated coupling with aryliodides
and arylbromides21 or by aromatic substitution for arylfluorides
and arylchlorides.22 Incorporation of amines and azacycles on a
methylene group at the 2-position required bromination of 2-
methyl analog 7a to give 7j followed by displacement reactions
to give 7k–7o (Scheme 3). When sulfonamides were prepared,
para-methoxybenzyl protection23 was employed to provide 7s
and 7t which were deprotected with trifluoroacetic acid to give
primary and secondary sulfonamides 7u and 7v, respectively.
Alternative approaches to 7 were used to explore the structure–
activity relationships, especially for various linkers between the
aromatic rings of the side chain other than oxygen (Scheme 4).
For example, synthesis of compounds with biaryl side chains in
which the aromatic rings were connected by other linkers (L)
including methylene (7x) and oxymethylene (7y) was accom-
plished by making arylbromides such as 1424 and 17 for use in
the direct arylation. Ultimately, coupling a preformed biarylether
(L = O) to a 3-H-imidazo[1,2-a]pyridine was even used to effi-
ciently prepare biarylethers 7 (L = O). Compounds 7z and 7aa were
made by alkylation with benzyl bromides 15. Finally, two biaryl-
sulfones were prepared by coupling of 4-bromo-1-iodobenzene
to imidazo[1,2-a]pyridine 10c (Y = 2-Pr, Z = CF3) to give 18 fol-
lowed by Suzuki coupling with methylsulfonylbenzeneboronic
acids to provide 19a and 19b (Scheme 5).
CF3
N
CF3
3 WAY-252623
4 WAY-254011
O
Y
SO2R
O
SO2R
N
Y
N
N
Z
Z
5
6
L
SO2R
N
Y
N
Z
7
Figure 2. LXR Agonists from Wyeth.
The moderate peroxisome proliferator-activated receptor
(PPAR) agonism of quinoline 4, which activated all three subtypes
of the receptor,11 led us to target quinolines with a biarylether sub-
stituent and to identify non-carboxylic acid hydrogen bond accep-
tors,12 leading to 4-[(3-sulfone-phenoxy)phenyl]quinolines 5.13
These compounds were essentially devoid of PPAR agonism. To fur-
ther develop the SAR, we explored replacements for the quinoline
such as benzimidazole which maintained a key sp2 nitrogen and
trifluoromethyl (Z = CF3) on the core heterocycle (6).14 As an exten-
sion of this approach, we describe here the synthesis and struc-
ture–activity relationships of a series of imidazo[1,2-a]pyridines 7.
The first approach to targets 7 involved ether bond formation
between a 3-(3-hydroxyphenyl)imidazo[1,2-a]pyridine core 11
and an arylhalide 12 (Scheme 1). The phenols were typically pre-
To determine the affinity of imidazo[1,2-a]pyridines for the two
LXR subtypes, binding assays were run using recombinant human
ligand binding domains (LBDs) of the respective LXR
a and LXRb
subtypes, measuring displacement of [3H]T0901317 from the LBD
(Table 1).25 Comparing the simpler analogs 5a, 6a, and 7a from
the quinoline, benzimidazole, and imidazo[1,2-a]pyridine series,
respectively, there was a significant loss in affinity (almost 50-fold
vs 5a for LXRb). The affinity did not improve with larger sulfones as
the analogs 7b–7d had similar affinity relative to 7a. However,
extensive exploration of the 2-substituent (Y) indicated it played
an important role in LXR affinity in the series. While slightly larger
groups like ethyl (7e), isopropyl (7f), and t-butyl (7g) and even lar-
ger phenyl (7h) had comparable affinity for LXRb, enlarging to a
benzyl group (7i) provided essentially the same affinity as seen
with 5a. While introduction of dimethylamine at the 2-position
pared by reaction of 2-aminopyridines 8 with
a-haloketones 9 to
give imidazo[1,2-a]pyridines 1015 in which substituents Y and Z
were varied by appropriate choice of starting materials.16 Since
OH
I
OH
O
N
N
a
Y
N
+
Br,Cl
Y
Y
N
NH2
N
b or c
Z
Z
Z
8 Z = CF3, Cl, CN
9
10
11
X
O
O
Hal
X
SO2NHR3
f
W
Me
Me
12
N
N
N
Y
d or e
N
Z
Cl
7u R3 = H
7
7v R3 = Me
Scheme 1. Reagents and conditions: (a) EtOH, reflux, 16–24 h; (b) Pd(OAc)2 (0.02 equiv), Ph3P (0.04 equiv), Cs2CO3 (1.0 equiv), dioxane, reflux, 16–24 h; (c) 20% Pd(OH)2 on
carbon (0.1 equiv), KOAc (3.0 equiv), DMA, 145 °C, 16–24 h; d) 12 (Hal = Br, I,) (1.0–2.0 equiv), CuI (0.1 equiv), Me2NCH2CO2H hydrochloride (0.375 equiv), Cs2CO3 (3.0 equiv),
dioxane, 100–110 °C, 16–24 h; (e) 12 (Hal = F, Cl) (1.0–2.0 equiv), K2CO3 (1.0–2.0 equiv), DMF, 120–150 °C, 16–24 h; (f) TFA, CH2Cl2, 20 °C, 18–24 h.

R. R. Singhaus et al. / Bioorg. Med. Chem. Lett. 20 (2010) 521–525
523
p
N
N
N
SO2Me
m
CH2Cl
a
N
CF3
CF3
10b
10a
R2
Scheme 2. Reagents and conditions: (a) PhB(OH)2 (2.0 equiv), K2CO3 (3.0 equiv),
Pd(PPh3)4 (0.03 equiv), dioxane, water, reflux, 1.5 h (51%).
Me
Me
Me
Me
N
N
b
N
N
CF3
CF3
10c R2 = H
19a meta-SO2Me
19b para-SO2Me
O
O
a
SO2Me
b
SO2Me
18
2 = 4-BrPh
R
N
N
CH2R2
CH2R2
Scheme 5. Reagents and conditions: (a) 4-BrPhI, Pd(OAc)2 (0.02 equiv), Ph3P
(0.04 equiv), Cs2CO3 (1.0 equiv), dioxane, reflux, 16–24 h; (b) MeSO2PhB(OH)2
(1.3 equiv), Pd(PPh3)4 (0.15 equiv), Na2CO3 (2.3 equiv), aqueous diglyme, 80 °C,
18–24 h.
N
N
CF3
CF3
7a R2 = H
7j R2 = Br
7k R2 = NMe2
a
7l R2 = 1-pyrrolidine
7m R2 = 3-thiazolidine
7n R2 = 1-imidazole
7o R2 = 1-piperidine
as shown by 7v which had similar binding affinity to 7p, its closest
analog. A methylene linker in place of oxygen lost sixfold in affinity
(7e vs 7x) while other linkers provided even weaker LXR ligands
(7y–7aa). para-Biarylsulfones 19a and 19b had moderate and very
weak LXR affinity, respectively.
Scheme 3. Reagents and conditions: (a) N-bromosuccinimide (1.1 equiv),
azobisisobutyronitrile (0.1 equiv), MeCN, reflux, 3 h (79%); (b) azacycle
(3.0–5.0 equiv), DMSO or ethanol, rt, 1–24 h (37–68%).
a,a-
Binding selectivity for LXRb over LXR
erate, though 7e, 7h, and 7p showed selectivity (LXR
a
subtypes was only mod-
IC50/LXRb
a
CH2Br
IC50) of greater than tenfold. However, the in vivo functional impli-
cations of this level of binding selectivity are unclear. Essentially
none of compounds had PPAR agonism when tested in PPAR func-
tional assays reported earlier.12a
SO2Me
a
Br
13
Br
14
LXR functional activity was first examined in Gal4 assays,10
transient transactivation assays in Huh7 cells transfected with hu-
man LXR ligand binding domains (LBDs) fused to Gal4 DNA binding
d
domains. The assays were performed for both LXRa and LXRb LBDs.
L
As in the binding affinity, the potency in the Gal4 assays for 7a was
weaker compared to the analogous benzimidazole 6a and much
weaker compared to quinoline 5a. Efficacy was also reduced, espe-
cially compared to 7a. Larger sulfone groups gave comparable or
weaker potency (7b–7d) while more lipophilic Y groups had little
impact until a benzyl group was used (7i). Compound 7i was the
most potent analog in this assay (Gal4b EC50 = 20 nM) and was
essentially as efficacious as 1. Saturated azacycles 7m and particu-
larly 7n demonstrated good activity in the assay, with 7n being
nearly as potent and efficacious as 7i. Both were more potent than
1. Sulfonamides 7t and 7v were good agonists in the assay while
the methylene (7x) and oxymethylene (7z) spacers were much
weaker compared to the biarylether analogs. Rather modest func-
Br
SO2Me
b
SO2Me
N
Y
N
15a meta
15b para
Z
7x - 7aa
d
CH2Br
O
SO2Me
c
Br
Br
16
17
tional selectivity for LXRb over LXR
a was seen for a few com-
Scheme 4. Reagents and conditions: (a) 3-(MeSO2)PhB(OH)2 (1 equiv), Pd(PPh3)4
(0.03 equiv), 1 M aqueous Na2CO3 (0.12 equiv), EtOH, PhMe, 80 °C, 18–24 h (8%); (b)
11a (Y = 2-Pr, Z = CF3, 0.83 equiv), Cs2CO3 (1.16 equiv), DMF, 40 °C, 20 h (96–99%);
(c) 3-HO–PhSO2Me, K2CO3, DMF, 80 °C, 24 h (82%); (d) 10b (Y = Et, Z = CF3), 20%
Pd(OH)2 on carbon (0.1 equiv), KOAc (3.0 equiv), DMA, 145 °C, 24 h (67–87%).
pounds particularly 7i and 7m, about sevenfold and fivefold
selective, respectively. As noted above, none of the biarylethers
tested had any PPAR activity.
Additional cell based assays tested for upregulation of ABCA1
mRNA in a THP1 human macrophage cell line25 and for an increase
in cellular triglyceride levels in a HepG2 (human liver) cell line
(Table 2), with increases in ABCA1 mRNA and in TG levels using 1 ta-
ken as 100% efficacy. Ideally, good candidates for antiatherosclerotic
agents would show an ABCA1 mRNA increase with no increase in TG
accumulation. Most of imidazo[1,2-a]pyridines 7 were about 10-
fold weaker at increasing ABCA1 levels compared to 5a, with the
exception of 7n which was essentially equipotent. However, little
selectivity for ABCA1 mRNA increases relative to TG accumulation
was observed. About a fourfold selectivity in potency was found
for 7n, but this was less than seen for 5a. Higher concentrations
via a methylene linker gave much weaker affinity (7k), larger, more
lipophilic azacycles (7l, 7m) trended toward better binding. The
much more weakly basic amine found in thiazolidine gave a com-
pound with excellent affinity (7n, hLXRb IC50 = 2.0 nM). However,
imidazole in place of phenyl lost 30-fold in affinity (7o). Returning
to a 2-isopropyl group and varying the Z-substituent, affinity de-
creased slightly in a chloro for trifluoromethyl exchange (7f vs
7p) while cyano fared much worse (7q). The importance of the
hydrogen bond accepting ability of the sulfone can be inferred
from the dramatic reduction in affinity (over 50-fold) seen with
the trifluoromethylsulfone 7r compared to methylsulfone 7f, sug-
gesting the importance of more electron rich sulfone oxygens.
The receptors were more tolerant of large lipophilic groups over
primary sulfonamides as seen in a comparison of 7t–7u. Interest-
ingly, a secondary sulfonamide could also substitute for a sulfone
(3 lM and 10 lM) of both 7a and 7b led to decreases in TG levels,
an effect possibly related to cell toxicity affecting TG synthesis.
In an assay testing for stability in mouse, rat and human micro-
somes, compounds with smaller sulfones and 2-substituents
(7a, 7b, 7e) had good stability while larger 2-substituents

524
R. R. Singhaus et al. / Bioorg. Med. Chem. Lett. 20 (2010) 521–525
Table 1
Biarylether sulfone imidazo[1,2-a]pyridines 7, 19a
X
L
X
3
N
2
N
Y
Y
N
N
1
7a-7aa
19a-b
Z
Z
L
X
Y
Z
LXRb IC50 (nM)
LXR
a
IC50 (nM)
Gal4b EC50
(l
M) (% ag)
Gal4a EC50 (lM) (% ag)
1
—
—
Me
Me
Me
Me
Me
Me
Et
—
9
13
2.4
0.170 (100%)
0.031 (78%)
0.162 (49%)
0.84 (37%)
0.68 (39%)
0.70 (25%)
1.42 (17%)
0.42 (62%)
0.95 (68%)
0.71 (71%)
0.57 (64%)
0.020 (88%)
nt
0.135 (100%)
0.183 (75%)
0.64 (42%)
2.54 (25%)
2.28 (26%)
4.1 (17%)
6.0 (8%)
1.22 (58%)
1.86 (44%)
2.18 (55%)
1.11 (54%)
0.144 (62%)
nt
5a
6a
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
—
—
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
m-SO2Me
m-SO2Me
m-SO2Me
m-SO2Et
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Cl
1.0
7.0
49
30
33
128
799
561
960
>1000
217
137
222
91
5.9
m-SO2(i-Pr)
m-SO2(CH2)3OH
m-SO2Me
m-SO2Me
m-SO2Me
m-SO2Me
m-SO2Me
m-SO2Me
m-SO2Me
m-SO2Me
m-SO2Me
m-SO2Me
m-SO2Me
m-SO2Me
m-SO2Me
m-SO2CF3
m-SO2N(PMB)2
m-SO2NMe(PMB)
m-SO2NH2
m-SO2NHMe
m-CH2SO2Me
m-SO2Me
m-SO2Me
m-SO2Me
p-SO2Me
188
14
i-Pr
t-Bu
Ph
CH2Ph
CH2Br
CH2NMe2
CH2-1-pyrrolidine
CH2-1-piperidine
CH2-3-thiazolidine
CH2-1-imidazole
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Et
3.5
6.5
7.2
0.81
nt
>1000
279
69
2.0
30
10
43
194
nt
nt
>1000
>1000
>1000
9
365
304
>1000
>1000
nt
71
>1000
239
>1000
>1000
>1000
>1000
>1000
>1000
>1000
nt
nt
nt
nt
0.204 (56%)
0.032 (62%)
0.85 (81%)
0.54 (50%)
1.68 (44%)
nt
0.92 (45%)
0.170 (64%)
1.7 (79%)
1.66 (53%)
3.9 (20%)
nt
CN
CF3
Cl
Cl
Cl
7s
7t
nt
nt
24
0.89 (48%)
nt
0.53 (61%)
nt
1.57 (48%)
nt
3.24 (26%)
nt
0.93 (47%)
nt
1.61 (46%)
nt
3.2 (30%)
nt
6.5 (9%)
nt
7u
7v
7w
7x
7y
7z
7aa
19ª
19b
136
7.5
187
79
292
89
>1000
166
>1000
Cl
O
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CH2
CH2O
OCH2
OCH2
—
Et
i-Pr
i-Pr
i-Pr
i-Pr
m-SO2Me
p-SO2Me
na
na
na
na
—
a
Results are given as the mean of two independent experiments. The standard deviations for binding assays were typically 30% of mean or less. The standard deviations
for the Gal4 assays were typically 30% of the mean or less. % of efficacy is relative to 1. nt = not tested na = inactive. PMB = 4-MeOPhCH2.
Table 2
Cell-based assays, solubility and microsomal stability
O
SO2R
N
Y
N
CF3
a
c
c
R
Y
ABCA1 THP1 EC50
M) (% eff)
Hepatocyte TG accum assay
Solubility
g/mL)
Microsomal stability, t1/2
m, r, h, (min)
Cmax (ng/mL)/AUC0-
tmax (h)/
a
(
l
EC50
(
lM) (% eff)
(
l
(ng h/mL)
t1/2 (h)
last
1
—
—
0.044 (100%)
0.010 (82%)
0.42 (126%)
0.125 (99%)
0.130 (100%)
0.243 (65%)
0.12 (105%)
0.044 (100%)
0.137 (100%)
0.147 (69%)
0.270 (37%)
0.072 (8%)b
ndb
0.227 (38%)
0.065 (81%)
0.128 (26%)
—
<1
30, 30, 30
30, 30, 30
30, 30, 30
30, 30, 30
30, 30, 21
20, 30, 30
2, 7, 19
—
—
5a
6a
7a
7b
7e
7i
Me Me
Me Me
Me Me
Et
Me Et
457/1690
614/8938
1136/4667
1421/7792
—
2/nd
2/13.5
0.25/4.5
1.0/6.1
—
214
>100
68
228
3
Me
Me CH2Ph
—
—
—
—
7m Me CH2-1-
piperidine
Me CH2-3-
thiazolidine
73
2, 5, 3
7n
0.010 (98%)
0.042 (36%)
1
3, 23, 6
—
—
a
Results are given as the mean of at least two independent experiments. The EC50 values for the assays were typically 50% of mean or less (variability for 7i was higher). %
efficacy is relative to 1.
b
TG levels decreased at higher concentrations. nd = not determined.
C57 mouse PK dosing: 10 mg/kg po (gavage) in 0.5% methylcellulose/2% Tween in water, except 5a dosed at 2.5 mg/kg po (gavage).
c

R. R. Singhaus et al. / Bioorg. Med. Chem. Lett. 20 (2010) 521–525
525
Goos-Nilsson, A.; Wilhelmsson, A.; Zamaratski, E.; Evans, M. J. J. Med. Chem.
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8. Quinet, E.; Basso, M. D.; Halpern, A. R.; Steffan, R. J.; Yates, D. W.; DiBlasio-
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(7i, 7m, 7n) significantly reduced the half-life (Table 2). Solubility
followed the same trends, increasing for smaller, less lipophilic
compounds. In mice dosed orally (gavage) with several com-
pounds, two imidazo[1,2-a]pyridines, 7a and 7b, gave comparable
or slightly better Cmax and exposure compared to representative
examples from earlier series.
9. Katz, A.; Udata, C.; Ott, E.; Hickey, L.; Burczynski, M. E.; Burghart, P.;
Vesterqvist, O.; Meng, X. J. Clin. Pharmacol. 2009, 49, 643.
Compounds 7 in which an imidazo[1,2-a]pyridine replaced a
quinoline or benzimidazole found in earlier biarylether sulfones
led to a new series of LXR agonists. Efficient routes to synthesize
7 were developed, highlighted by a direct arylation reaction of imi-
dazo[1,2-a]pyridines 10 with an arylbromide or aryliodide. A lipo-
philic 2-substituent was important for both good affinity and
functional activity in Gal4 and ABCA1 mRNA gene expression as-
says. Little selectivity for desired increases in ABCA1 lipid trans-
porter relative to undesired TG accumulation was found.
10. Hu, B.; Collini, M.; Unwalla, R.; Miller, C.; Singhaus, R.; Quinet, E.; Savio, D.;
Halpern, A.; Basso, M.; Keith, J.; Clerin, V.; Chen, L.; Resmini, C.; Liu, Q.-Y.;
Feingold, I.; Huselton, C.; Azam, F.; Farnegardh, M.; Enroth, C.; Bonn, T.; Goos-
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Nambi, P.; Unwalla, R.; Savio, D.; Wilhelmsson, A.; Goos-Nilsson, A.;
Farnegardh, M.; Wrobel, J. Bioorg. Med. Chem. 2009, 17, 1663; (b) Bernotas,
R.; Kaufman, D.; Singhaus, R.; Ullrich, J.; Unwalla, R.; Quinet, E.; Nambi, P.;
Wilhelmsson, A.; Goos-Nilsson, A.; Wrobel, J. Bioorg. Med. Chem. 2009, 17, 8086.
13. Bernotas, R. C.; Singhaus, R. R.; Kaufman, D. H.; Travins, J. T.; Ullrich, J. W.;
Unwalla, R. J.; Quinet, E.; Evans, M.; Nambi, P.; Olland, A.; Kauppi, B.;
Wilhelmsson, A.; Goos-Nilsson, A.; Wrobel, J. Bioorg. Med. Chem. Lett., in press.
doi:10.1016/j.bmcl.2009.10.132.
Acknowledgments
14. Bernotas, R. C.; Travins, J. M.; Wrobel, J. E.; Kaufman, D. H. Patent WO
2009086138 A1 and Travins, J. M.; Bernotas, R. C.; Kaufman, D. H.; Quinet, E.;
Nambi, P.; Feingold, I.; Huselton, C.; Wilhelmsson, A.; Goos-Nilsson, A.; Wrobel,
J. Bioorg. Med. Chem. Lett., in press. doi:10.1016/j.bmcl.2009.11.099.
15. New compounds gave satisfactory 1H NMR, MS, and HRMS data. Compounds
were generally >95% pure by HPLC analysis. Further experimental details are
given in patent application WO 2009086123.
16. Barlin, G. B.; Davies, L. P.; Harrison, P. W. Aust. J. Chem. 1995, 48, 1031.
17. Chowdhury, S.; Georghiou, P. E. Tetrahedron Lett. 1999, 40, 7599.
18. Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G.
Synlett 2006, 3237.
We thank the Wyeth Discovery Analytical Chemistry Depart-
ment for analytical data and Anita Halpern and Dawn Savio for bio-
logical assay data. We acknowledge the contributions and support
of Drs. Li Di, Jeremy Travins, Ronald Magolda (deceased June 1,
2008), Tarek Mansour, Steven Gardell, and George Vlasuk.
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