Biarylether amide quinolines as liver X receptor agonists

Article abstract of DOI:10.1016/j.bmc.2008.12.048

A series of 4-(amido-biarylether)-quinolines was prepared as potential LXR agonists. Appropriate substitution with amide groups provided high affinity LXR ligands, some with excellent potency and efficacy in functional assays of LXR activity. Novel amide

Full text of DOI:10.1016/j.bmc.2008.12.048

Bioorganic & Medicinal Chemistry 17 (2009) 1663–1670
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Biarylether amide quinolines as liver X receptor agonists
a
a
a
a
Ronald C. Bernotas a, , Robert R. Singhaus , David H. Kaufman , John Ullrich , Horace Fletcher III ,
Elaine Quinet b, Ponnal Nambi b, Rayomand Unwalla a, Anna Wilhelmsson c, Annika Goos-Nilsson c,
Mathias Farnegardh c, Jay Wrobel a
*
a Chemical and Screening Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA
b Cardiovascular and Metabolic Diseases, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA
c 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:
A series of 4-(amido-biarylether)-quinolines was prepared as potential LXR agonists. Appropriate substi-
tution with amide groups provided high affinity LXR ligands, some with excellent potency and efficacy in
functional assays of LXR activity. Novel amide 4g had a binding IC50 = 1.9 nM for LXRb and EC50 = 34 nM
(96% efficacy relative to T0901317) in an ABCA1 gene expression assay in mouse J774 cells, demonstrat-
ing that 4-(biarylether)-quinolines with appropriate amide substitution are potent LXR agonists
Ó 2009 Elsevier Ltd. All rights reserved.
Received 7 November 2008
Revised 19 December 2008
Accepted 22 December 2008
Available online 27 December 2008
Keywords:
Liver X receptor
LXR
Agonist
Quinoline
ABCA1
1. Introduction
responsible for increases in triglyceride levels and ultimately hepa-
tic steatosis. Selective activation of the ABCA1 over SREBP1c may
Nuclear hormone receptors comprise a superfamily of gene
transcription factors that include estrogen receptors (ER), retinoid
X receptors (RXRs), and liver X receptors (LXRs). Among these
receptors, the LXRs are an increasingly important target since mod-
ulators of LXR function are potential therapeutic agents for the
have the desirable therapeutic profile of reducing lesion via reverse
cholesterol transport (RCT) while having minimal effects on tri-
glyceride production.5 Recent studies have supported the idea that
LXRb-selective agonists would likely lead to an increase in choles-
terol efflux from macrophages and other cell types, improving
most dyslipidemia measures, while not increasing triglyceride
levels.6
treatment of dyslipidemia.1 There are two subtypes of LXR: LXR
a
and LXRb. LXRa is principally expressed in the liver, kidney, intes-
tine, lung, spleen, and macrophages, with the highest levels found
in the liver. In contrast, LXRb is found in nearly all tissues and was
known as ubiquitous receptor (UR) prior to an understanding of its
The potential of LXR agonists to treat dyslipidemia has led to
the development of several high affinity LXR ligands with potent
agonism for both subtypes.7 Among the most studied are
T0901317 (1) from Tularik8 and GW3965 (2) from GlaxoSmithK-
line (Fig. 2).9
relationship to LXRa 2
. Both subtypes associate with RXR to form
functionally active heterodimers. Binding of an RXR agonist (e.g.,
9-cis-retinoic acid) to the RXR portion of the heterodimer or bind-
ing of an LXR agonist (e.g., oxysterols such as 24,25-epoxycholes-
terol) to the LXR portion activates the LXR response element
(LXRE) (Fig. 1). This activation leads to increased transcription of
mRNA encoding for various genes regulating lipids including
ATP-binding cassette transporters (e.g., ABCA1, ABCG1, ABCG5),3
and sterol regulatory element binding protein 1c (SREBP1c).4 Of
particular importance are ABCA1, which increases cholesterol ef-
flux from macrophages, and SREBP1c, which is believed to be
Oxysterols (e.g. 24,25-epoxycholesterol)
9-cis RA
Oxysterols (e.g. 24,2-5
GW-3965 (GSK)
)
GW-3965 (GSK)
T0901317 (Tularik)
T0901317 T( ularik)
RXR LXR
mRNA:
ABCA1
ABCG1
SREBP1c
LXRE
LXRE
* Corresponding author. Tel.: +1 1 484 865 2168.
E-mail address: bernotr@wyeth.com (R.C. Bernotas).
Figure 1. Either an LXR or RXR agonist at the RXR–LXR heterodimer activates the
LXR response element (LXRE).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.12.048

1664
R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 1663–1670
Ph
Ph
N
which may be associated with the PPAR activity, the acetic acid
was changed to a directly bonded amide (4 X = CONR1R2) and the
benzyl ether linkage replaced with an oxygen atom to form a biar-
ylether. To reduce molecular weight, the 3-benzyl group was also
replaced with a smaller and potentially more metabolically stable
methyl group. We describe in this paper the synthesis and biolog-
ical activity of compounds incorporating these modifications.
CO2H
F3C CF3
HO
O
O
O
S
N
Cl
F3C
1 T0901317 (Tularik)
CF3
2 GW3965 (GSK)
2. Chemistry
Figure 2. LXR agonists from Tularik and GlaxoSmithKline.
Preparation of the biarylethers was accomplished in two parts:
synthesis of the 4-(3-hydroxyphenyl)quinoline core structure fol-
lowed by elaboration of the core into the functionalized biaryle-
thers. Our approach to the core structure converted 2-fluoro-3-
trifluoromethylbenzoic acid 5 into the Weinreb amide 6 via the
acid chloride (Scheme 1). Addition of 3-methoxyphenylmagnesium
bromide provided 2-fluorophenone 7, which was converted to the
2-amino analog 8 using concentrated ammonium hydroxide under
pressure. The methoxy group was efficiently removed using a pyr-
idine hydrochloride melt at 200 °C to give 9. Transformation of the
2-aminophenone into 8-trifluoromethyl-4-(3-hydroxyphenyl)
quinoline (10a) using a Friedlander reaction13 employed hydrocin-
namaldehyde to afford the quinoline core.
Wyeth has identified a series of quinolines incorporating an
acid side chain.10 The acid group interacts with the Arg-319 resi-
due in the LXRb receptor while the quinoline nitrogen forms a
hydrogen bond with the His-435.11 Typical of this quinoline-acid
series is WAY-254011 (3), which reduced atherosclerotic lesion
in an 8-week model using LDL-KO mice fed a high fat (‘Western’)
diet.12 Unfortunately, 3 increased plasma triglycerides levels rela-
tive to control in several rodent species including hamster, an ef-
fect consistent with its lack of selectivity for the LXRb subtype.10
Compound 3 also was a PPAR agonist, activating all three subtypes
of the receptor. To further explore the SAR of the quinoline series,
and to address the issue of PPAR agonism, several modifications of
3 were targeted (Fig. 3). To eliminate the benzylacetic acid group,
An alternative shorter synthesis of the corresponding 8-chloro-
quinoline began with a Sugasawa reaction14 between 2-chloroani-
line
and
3-methoxy-benzonitrile,
which
afforded
the
2-aminophenone 11 directly. This reaction was generally accompa-
nied by small amounts of the demethylated product 12, with the
amount of 12 relative 11 increasing as the temperature and reac-
tion times were increased. We were able to combine the Sugasawa
reaction and the desired deprotection in one pot by prolonged
heating in chlorobenzene at reflux to directly give phenol 12, albeit
in modest yield. Phenol 12 was subjected to a Friedlander reaction
using propionaldehyde diethylacetal to prepare 3-methylquinoline
10b. While propionaldehyde could also be used in the Friedlander
reaction, its low boiling point required the sequential addition of
several equivalents and resulted in generally lower yields. Unfortu-
nately, this shorter approach to quinolines was not useful for 8-tri-
CO2H
O
O
Y
X
N
N
CF3
Z
3
4 X = CO2R, CONR1R2
Figure 3. Targeted modifications of WAY-254011 (3).
OH
OMe
O
F
O
OMe
a, b
c, d
e
O
OH
N
O
Me
NH2
F
R1
CF3
CF3
CF3
CF3
5
6
7 R1 = F
9
8 R1 = NH2
f
OR2
OH
Y
OMe
O
f
g
+
NH2
NH2
N
Cl
CN
Cl
Z
11 R2 = Me
12 R2 = H
10a Y = CH2Ph, Z = CF3
10b Y = Me, Z = Cl
Scheme 1. Reagents and conditions: (a) SOCl2, PhH; (b) HNMe(OMe)ÁHCl, pyridine, CHCl3, rt (95% for two steps); (c) 3-MeOPhMgBr, THF, À78 to 0 °C (88%); (d) concd NH4OH,
sealed tube, 140 °C, 8–10 h (70%); (e) pyridine hydrochloride, 200 °C, 2 h (91%); (f) PhCH2CHO or CH3CH2CH(OEt)2, cat. H2SO4, AcOH, 105 °C, 6–24 h (61–70%); (g) BCl3 in
xylenes, chlorobenzene, then 3-MeOPhCN, AlCl3, reflux, overnight (37%).

R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 1663–1670
1665
fluoromethyl analogs because of the instability of the group to
Sugasawa reaction conditions and workup.15
binding assays used recombinant human ligand binding domains
(LBDs) of the respective LXRa and LXRb subtypes and measured dis-
The second aromatic ring of the biaryl ether was incorporated
next. Copper-mediated coupling of the 4-(3-hydroxyphenyl)quino-
line cores with methyl 3-bromobenzoate16 installed the biaryle-
ther side chain (Scheme 2). Copper acetate-mediated coupling
placement of [3H]T0901317 from the LBD.10 4-(Biarylether)-quino-
lines incorporating a benzyl group at the 3-position of the
quinoline were examined first. The ester intermediate 4a had mod-
erate affinity for LXRb and was nearly fivefold selective over the
17
with 3-(EtO2C)PhB(OH)2 was also successful. Conversion of the
LXRa subtype. 1-Propylamide 4b had higher affinity and slightly
esters into amides, generally using Weinreb’s amidation proce-
improved binding selectivity, and was comparable to the 2-propyl
analog 4c. In general, the tertiary amides had higher affinity for both
subtypes. For example, diethylamide 4d had an LXRb binding IC50
value of 2.8 nM. Tying up the amide substituents into a ring, whether
a pyrrolidine (4e), piperidine (4f), or morpholine (4g), gave similar
LXR affinity to the unconstrained tertiary analogs. To reduce the
molecular weight we examined analogs in which the 3-benzyl group
was replaced with a methyl and the 8-trifluoromethyl with a chlo-
rine atom. Interestingly, these smaller analogs (4i–4l) still had good
LXRb affinity (binding IC50 6 100 nM). As before, the tertiary amides
had generallyhigher LXR affinitycompared to the secondaryamides.
The constrained analogs (4n–4p) had LXRb binding IC50 values
<10 nM. These results demonstrated that the smaller 8-chloro-3-
methyl-quinoline core was a suitable replacement for the 8-trifluo-
romethyl-3-benzyl-quinoline core for LXR ligands incorporating the
biarylether-amide motif.
dure,18 gave the final targets for testing.
3. Biological assays
The final targets and their ester intermediates were tested to
determine binding affinity for the two LXR subtypes (Table 1). The
OH
Y
O
Y
CO2R
Br
CO2Me
a
N
N
Z
Z
The compounds were also tested in Gal4b and Gal4a functional
10a Y = CH2Ph, Z = CF3
10b Y = Me, Z = Cl
4 X = ester
assays for LXR activity.10 These LXR transactivation assays used
Huh7 cells transfected with human LXR ligand binding domains
fused to Gal4 DNA binding domains. The most potent analogs in
both assays were the 3-benzylquinolines 4d–4g incorporating ter-
tiary amides, which had EC50 values <200 nM in the Gal4b assay
and comparable efficacy compared to 1. Comparison of the two
morpholine amides 4g and 4p suggested some loss in potency
and efficacy for the lower molecular weight compound. The com-
O
CONR1R2
Y
b
N
4 X = amide
Z
pounds tended to be less potent in the Gal4a assays but with sim-
ilar SAR to the Gal4b results.
In addition to the Gal4 assays, the functional activity of a
selected group of compounds was characterized in a J774 mouse
Scheme 2. Reagents and conditions: (a) CuO, K2CO3, pyridine, 110–120 °C (42–
43%); (b) Me3Al, HNR1R2, PhMe, 60–65 °C, 18–24 h (41–97%).
Table 1
Biarylether amide quinolines 4a
O
O
NR1R2
Y
3
N
8
Z
Compound
Y
Z
NR1R2
LXRb IC50 (nM)
LXR
a
IC50 (nM)
Gal4 LXRb EC50 (nM) (% ag)
Gal4 LXRa EC50 (nM) (% ag)
3
—
—
—
2.1
53
8.5
10
2.8
2.6
2.9
1.9
230
9
20
25
100
12
3
9.5
231
91
74
12
12
20
15
1002
125
272
280
357
108
34
93 (63%)
nt
1525 (107%)
nt
144 (83%)
98 (89%)
170 (85%)
138 (80%)
nt
800 (66%)
1272 (55%)
1180 (45%)
nt
238 (90%)
nt
2709 (43%)
nt
675 (73%)
435 (75%)
477 (99%)
345 (90%)
nt
1306 (37%)
2102 (28%)
1633 (8%)
nt
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
Me
Me
Me
Me
Me
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Cl
Cl
Cl
Cl
Cl
Methyl ester
NH(1-Pr)
NH(2-Pr)
NEt2
Pyrrolidine
Piperidine
Morpholine
Methyl ester
NHMe
NHEt
NH(1-Pr)
NH(2-Pr)
NEt2
Pyrrolidine
Piperidine
Morpholine
Me
Me
Me
Me
Cl
Cl
Cl
Cl
nt
nt
nt
nt
nt
nt
6
7
50
158
572 (46%)
1237 (33%)
a
Results are given as the mean of two independent experiments. The standard deviations for the binding assays were typically 30% of the 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.

1666
R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 1663–1670
Table 2
ABCA1 J774 activity for 4a
O
O
NR1R2
Y
3
N
8
Z
Compound
Y
Z
NR1R2
—
NH(1-Pr)
Morpholine
NH(1-Pr)
ABCA1 EC50 (lM) (% ag)
3
—
—
0.041 (114%)
0.420 (155%)
0.034 (96%)
1.60 (281%)
0.070 (102%)
4b
4g
4k
4p
CH2Ph
CH2Ph
Me
CF3
CF3
Cl
Me
Cl
Morpholine
a
Results are given as the mean of at least two independent experiments unless
otherwise indicated. The standard deviations for the binding assays were typically
50% of the mean or less. % of efficacy is relative to 1.
Figure 4. X-ray of LXRb cocrystallized with 4g.
itself typically forms homodimers. Each subunit of the homodi-
mer has very similar ligand–receptor interactions. With 4g, key
interactions within one subunit (Fig. 4) included interactions of
the quinoline nitrogen with the His-435, and a strong hydrogen
bond between the carbonyl oxygen of the amide with the back-
bone NH of the Leu-330. The 3-benzyl group on the quinoline is
located in a hydrophobic pocket defined by three phenylalanines
(Phe-329, Phe-340, and Phe-349), which is termed the ‘Phe pock-
et’. Interestingly, many of the compounds with a 3-methyl group
in place of the 3-benzyl group retained good affinity for the
LXRs, though reduced filling of the ‘Phe pocket’ may account
for the decrease in functional activity in both the Gal4 LXR
and ABCA1 gene expression assays.
macrophage cell line, testing for upregulation of ABCA1 mRNA
(Table 2).19 The ABCA1 protein is a transporter responsible for
removing cholesterol from various cells including macrophages.
When measuring mRNA induction relative to 3, the secondary
amides were relatively weak, with 4b about an order of magnitude
weaker than 3. In contrast to these results the morpholine amides,
which are tertiary, had good activity in the assay. This was true
even for smaller ligands such as 4p, in which a benzyl group was
replaced with a methyl. While compound 4p had about half the
potency of 3, it was still fully efficacious. However, compound 4g
was the most potent, with an EC50 value of 34 nM, potency compa-
rable to 3, and fully efficacious relative to the standard. Some min-
or differences in the potency of the compounds in the Gal4 assays
relative to the ABCA1 assays may be attributed to the differences in
species (human vs mouse), cell type (liver hepatocytes vs macro-
phages), and to the variations in the assay conditions.
To explore the nuclear hormone cross-reactivity of the biaryla-
mides relative to 3, PPAR functional activity in transiently transfec-
ted cell lines was examined. Lack of PPAR agonism was of
particular interest as PPAR activation can be associated with sev-
eral undesired effects. As indicated in Table 3, the biarylether
amides did not have significant agonist activity for any of the
PPARs examined, with the exception of 4b, which had very weak
5. Conclusion
In conclusion, a series of quinolines containing a biarylether
amide group at the 4-position of the quinoline, was prepared.
These were designed in part based on modifications of WAY-
254011, a previously reported LXR agonist. Several compounds in
the series had high affinity for the LXR receptors and exhibit potent
agonism both in a transiently transfected cell line, and in a J774
mouse cell line examining ABCA1 gene regulation. Among the
compounds tested, there was little or no PPAR agonist activity as
measured in transiently transfected cell lines. The most potent
compound for inducing ABCA1 gene expression was morpholine
amide 4g. This quinoline amide was cocrystallized with LXRb and
shown to have key hydrogen bonding interactions with His435
through the quinoline nitrogen and with Leu330 backbone amide
nitrogen. While these compounds had little functional selectivity
agonism and poor efficacy for PPARc. In contrast, 3 had weak par-
tial agonism for all three PPAR subtypes.
4. X-ray crystal structure
The most potent compound for upregulating ABCA1 mRNA,
4g, was cocrystallized with LXRb protein to determine its inter-
actions within the crystallized receptor. Unlike the functionally
active heterodimer that forms in the presence of RXR, LXRb by
for LXRb over LXR
a, the results presented here demonstrate that
4-(biarylether)-quinolines with appropriately positioned amide
substituents are potent LXR agonists with reduced or eliminated
PPAR agonist activity.
Table 3
PPAR activity for 3 and biarylether amide quinolines 4a
Compound
Y
Z
NR1R2
Gal4 PPAR
a
EC50
(
lM) (% ag)
Gal4 PPARd EC50
(l
M) (% ag)
Gal4 PPARc EC50 (lM) (% ag)
3
—
—
—
1.31 (19%)
No ag eff
No ag eff
No ag eff
No ag eff
0.68 (47%)
No ag eff
No ag eff
No ag eff
No ag eff
0.63 (24%)
3.8 (7%)
No ag eff
No ag eff
No ag eff
4b
4g
4k
4p
CH2Ph
CH2Ph
Me
CF3
CF3
Cl
NH(1-Pr)
Morpholine
NH(1-Pr)
Morpholine
Me
Cl
a
Results are for determinations in quadruplicate from a 12 concentration dose response curve, with the highest dose at 30
, [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14643); PPAR , 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]2-2,4-thiazo-
lidinone (Rosiglitazone); PPARd, 3-chloro-4-[[3-[(3-phenyl-7-propyl-6-benzofuranyl)oxy]propyl]thio]-phenylacetic acid (L796449).
lM. The % efficacy is relative to the following
references: PPAR
a
c

R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 1663–1670
1667
6.4. [2-Amino-3-(trifluoromethyl)phenyl](3-hydroxyphenyl)
methanone (9)
6. Experimental
General experimental: Solvents and chemicals were purchased
from EM Sciences, VWR, Oakwood, and Aldrich Chemical Co. and
used without further purification. High-resolution mass spectra
were obtained on a Waters LC-TOFMS instrument and were mea-
sured to within 5 ppm of calculated values. 1H NMR spectra were
taken on a Bruker DPX300 (300 MHz) or Varian (400 MHz) instru-
ments. NMR data are given as delta values (d) ppm using tetra-
methylsilane as an internal standard (d = 0 ppm). For the NMR
data peak appearance, app. means apparent and br means broad.
A stirred mixture of 8 (3.00 g, 10.0 mmol) and pyridine hydro-
chloride (40 g) was placed in a preheated bath at 190–200 °C. After
2 h, the reaction was cooled to near 20 °C and treated with aqueous
1 N HCl. The mixture was extracted with ethyl acetate and the
combined extracts washed sequentially with water and brine.
The organic layer was dried (Na2SO4), filtered, and concentrated
in vacuo to provide a semisolid material. This material was repeat-
edly stirred with portions of methylene chloride. The combined or-
ganic extracts were concentrated to provide crude product which
could be further purified by chromatography eluting with 1:99
methanol/methylene chloride to give 9 as a yellow solid (2.60 g,
91%). Mp: 106–107 °C; 1H NMR (DMSO-d6): d 9.82 (1H, s), 7.71
(1H, d, J = 7.7 Hz), 7.61 (1H, d, J = 7.9 Hz), 7.33 (1H, app. t,
J = 7.9 Hz), 7.13 (2H, br s), 7.01 (3H, m), 6.71 (1H, app. t,
J = 8.0 Hz); MS m/z 282; HRMS: calcd for C14H10F3NO2 + H+,
282.0736; found (ESI, [M+H]+), 282.0729.
6.1. 2-Fluoro-N-methoxy-N-methyl-3-trifluoromethyl-
benzamide (6)
To a stirred solution of 5 (15.0 g, 72 mmol) in benzene (150 mL) at
rt was added drop-wise a solution of SOCl2 (10.0 mL, 137 mmol) in
CH2Cl2 (30 mL) over 30 min. The resulting solution was heated at
reflux for 6 h, then cooled and concentrated in vacuo. The residue
was concentrated three times from toluene (50 mL). The crude acid
chloride was dissolved in CHCl3 (250 mL) and N,O-dimethylhydr-
oxylamine hydrochloride (10.0 g, 103 mmol) was added. The mix-
ture was cooled to 0 °C, slowly treated with pyridine (16 mL), then
stirred at 20 °C for 12 h. The reaction was concentrated in vacuo
and the residue dissolved in 1:1 CH2Cl2/Et2O (400 mL). The solution
was washed with water and brine. The organic layer was dried
(Na2SO4), filtered, and concentrated in vacuo to provide 17.0 g
(95%) of 6. 1H NMR (DMSO-d6): d 7.92–7.84 (2H, m), 7.51 (1H, app.
t, J = 7.8 Hz), 3.66 (3H, brs),3.32 (3H,brs);MS(ESI)m/z252.0;HRMS:
calcd for C10H9F4NO2 + H+, 252.0642; found (ESI, [M+H]+), 252.0651.
6.5. 3-[3-Benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol (10a)
A stirred mixture of 9 (3.00 g, 10.6 mmol) and 3-phenyl-pro-
pionaldehyde (2.11 g, 15.9 mmol) in glacial AcOH (20 mL) was
treated with a 1:19 v:v mixture of concd H2SO4/glacial AcOH
(1.5 mL) and then heated at 120 °C for 3 h. The reaction was
cooled and then concentrated in vacuo. The residue was dis-
solved in ethyl acetate and the organic layer washed with satu-
rated aqueous NaHCO3. The organic layer was dried (NaSO4) and
concentrated in vacuo. Purification of the oily residue by chro-
matography eluting with 2:98 methanol/CH2Cl2 gave 10a as a
light yellow solid from a foam (2.80 g, 70%). 1H NMR (DMSO-
d6): d 9.74 (1H, s), 8.98 (1H, s), 8.15 (1H, d, J = 6.9 Hz), 7.71–
7.63 (2H, m), 7.37 (1H, app. t, J = 7.9 Hz), 7.24 (2H, app. t,
J = 7.4 Hz), 7.17 (1H, app. t, J = 7.2 Hz), 7.03 (2H, d, J = 7.4 Hz),
6.94 (1H, dd, J = 1.8, 6.1 Hz), 6.71 (1H, d, J = 7.5 Hz), 6.69 (1H,
s), 4.00 (2H, s); MS (ES) m/z 378.2; HRMS: calcd for
C23H16F3NO + H+, 380.1257; found (ESI, [M+H]+), 380.1257.
6.2. [2-Fluoro-3-(trifluoromethyl)phenyl](3-methoxyphenyl)
methanone (7)
A stirred solution of 6 (17.0 g, 67.7 mmol) in THF (150 mL) at
À78 °C was treated with 1.0 M 3-methoxyphenylmagnesium bro-
mide in THF (97 mL, 97 mmol) over 1.5 h. After 1 h longer at
À78 °C, the reaction was brought to 0 °C. After 2 h, the reaction
was quenched by pouring into ice cold 1 M aqueous HCl. The product
was extracted with ethyl acetate and the extracts washed with
water, then brine, and then dried (Na2SO4). After concentration in
vacuo, the crude product was purified by chromatography eluting
with 90:10 methylene chloride/hexane to afford 7 as a colorless
liquid (17.8 g, 88%). 1H NMR (CDCl3): d 7.80 (1H, app. t, with addi-
tional fine coupling, J = 7.7 Hz), 7.72 (1H, app. t, with fine coupling,
J = 7.7 Hz), 7.42–7.36 (3H, m), 7.31 (1H, app. d, with fine coupling,
J = 7.5 Hz), 7.19 (1H, ddd, J = 1.1, 2.7, 8.1 Hz), 3.86 (3H, s); 19F NMR
(CDCl3): d À61.76 (s), À114.03 (m); MS (ES) m/z 299.1; HRMS: calcd
for C15H10F4O2 + H+, 299.0689; found (ESI, [M+H]+), 299.0693.
6.6. Methyl 3-{3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]
phenoxy}benzoate (4a)
A well-stirred mixture of 10a (2.65 g, 7.00 mmol), methyl 3-
bromobenzoate (3.01 g, 14.0 mmol), CuO (1.01 g, 12.6 mmol), and
K2CO3 (1.93 g, 14.0 mmol) was heated in pyridine at 120 °C under
nitrogen. After 48 h, the reaction was cooled, treated with water
(100 mL), and extracted with diethyl ether (2 Â 100 mL). The com-
bined extracts were dried over MgSO4, concentrated in vacuo with
heat to remove solvents. The dark residue was purified by chroma-
tography eluting with 20:80 ethyl acetate/hexanes to afford 4a as a
tacky glass (Rf ꢀ 0.3 in 20:80 ethyl acetate/hexanes) (1.53 g, 43%).
1H NMR (CDCl3): d 8.99 (1H, s), 8.02 (1H, d, J = 7 Hz), 7.79 (1H,
dt, J = 1.2, 7.8 Hz), 7.70 (2H, m), 7.49 (2H, app. t, J = 8.0 Hz), 7.40
(1H, app. t, J = 7.8 Hz), 7.23–7.13 (6H, m), 6.97 (2H, d, J = 7.5 Hz),
6.84 (1H, app. t, J = 1.0 Hz), 4.01 (2H, s), 3.88 (3H, s); MS (ESI) m/
z 514; HRMS: calcd for C31H22F3NO3 + H+, 514.1624; found (ESI,
[M+H]+), 514.1638.
6.3. [2-Amino-3-(trifluoromethyl)phenyl](3-methoxyphenyl)
methanone (8)
A mixture of 7 (7.00 g, 23.5 mmol), DME (50 mL) and concen-
trated NH4OH (150 mL) was heated in a steel bomb at 140 °C for
6 h. The vessel was cooled in ice, carefully opened, and the reaction
mixture concentrated in vacuo. The residue was dissolved in ethyl
acetate and the ethyl acetate layer washed with water, brine, and
dried (Na2SO4). After concentrating in vacuo, the crude aniline
was purified by chromatography with 98:2 methylene chloride/
methanol to afford 8 as a colorless liquid (4.80 g, 70%). 1H NMR
6.7. 3-{3-[3-Benzyl-8-(trifluoromethyl)quinolin-4-yl]phenoxy}-
N-propylbenzamide (4b)
(CDCl3 + DMSO-d6):
d 7.65–7.61 (2H, m), 7.39 (1H, app. t,
To a stirred mixture of 1-propylamine (59 mg, 1.00 mmol) in
toluene (2 mL) at ambient temperature under nitrogen was added
2.0 M trimethylaluminum in toluene (0.50 mL, 1.00 mmol). After
0.75 h, a solution of 4a (128 mg, 0.25 mmol) in toluene (7.0 mL)
was added and the reaction heated at 65 °C for 16 h. The cooled
J = 7.9 Hz), 7.15–7.09 (3H, m), 6.81 (2H, br s), 6.67 (1H, app. t,
J = 7.8 Hz), 3.85 (3H, s); 19F NMR (CDCl3 + DMSO-d6): d À63.60
(s); MS (ESI) m/z 296; HRMS: calcd for C15H12F3NO2 + H+,
296.0893; found (ESI, [M+H]+), 296.0887.

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R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 1663–1670
reaction was carefully treated with water (2 mL), then after 10 min
with 2 M aqueous HCl (1 mL) resulting in gas evolution. The reac-
tions were extracted with dichloromethane (5 mL, 2 mL) and the
combined extracts were dried (MgSO4). After concentrating in va-
cuo, the residues were chromatographed on silica gel using
25:75, then 50:50 ethyl acetate/hexane as eluent. Compound 4b
was isolated as a white solid-foam (121 mg, 89%). 1H NMR
(DMSO-d6): d 9.03 (1H, s), 8.49 (1H, t, J = 5.6 Hz), 8.16 (1H, d,
J = 7.0 Hz), 7.73–7.57 (6H), 7.46 (1H, app. t, J = 7.9 Hz), 7.23–7.10
(5H), 7.00 (2H, d, J = 6.8 Hz), 6.93 (1H, m), 4.02 (2H, s), 3.20 (2H,
q, J = 6.5 Hz), 1.51 (2H, m), 0.87 (3H, t, J = 7.4 Hz); MS (ESI) m/z
541; HRMS: calcd for C33H27F3N2O2 + H+, 541.2097; found (ESI,
[M+H]+), 541.2100.
6.12. 3-Benzyl-4-{3-[3-(morpholin-4-ylcarbonyl)
phenoxy]phenyl}-8-(trifluoromethyl)quinoline (4g)
Using essentially the same procedure as for 4b, except using
morpholine as the amine and using 50:50 ethyl acetate/hexane,
then ethyl acetate as eluent, 4g was obtained as a white solid-
foam (137 mg, 96%). 1H NMR (DMSO-d6): d 9.04 (1H, s), 8.16
(1H, dd, J = 1.0, 7.0 Hz), 7.73–7.65 (2H), 7.60 (1H, app. t,
J = 7.9 Hz), 7.44 (1H, app. t, J = 8.1 Hz), 7.24–7.09 (8H), 7.01–6.97
(3H), 4.03 (2H, m), 3.70–3.40 (8H, v. br peaks); MS (ESI) m/z
569; HRMS: calcd for C34H27F3N2O3 + H+, 569.2047; found (ESI,
[M+H]+), 569.2048.
6.13. (2-Amino-3-chlorophenyl)(3-hydroxyphenyl)methanone
(12)
6.8. 3-{3-[3-Benzyl-8-(trifluoromethyl)quinolin-4-yl]phenoxy}-
N-isopropylbenzamide (4c)
A stirred mixture of 1.0 M boron trichloride in dichloromethane
(202 mL, 202 mmol,) and chlorobenzene (350 mL) was treated
with 2-chloroaniline (32.7 mL, 311 mmol) in chlorobenzene
(150 mL) over ca. 15 min. The mixture was stirred for 5 min, then
3-methoxybenzonitrile (19.0 mL, 155 mmol) and aluminum chlo-
ride (26.93 g, 202 mmol) were added. The reaction was heated at
ca. 50 °C while removing the dichloromethane. The reaction was
then heated at reflux overnight. The mixture was cooled and trea-
ted with ice, followed by 2 N aqueous HCl (500 mL). This mixture
was then heated at 100 °C for 3 h, then cooled. The layers were sep-
arated and the aqueous layer was extracted with dichloromethane.
The combined organic extracts were dried over MgSO4 and concen-
trated in vacuo. The resulting material was triturated with 10:90
diethylether/hexane to give 12 as a tan solid (14.25 g, 37%). Mp:
126–127 °C; 1H NMR (DMSO-d6): d 9.80 (s, 1H), 7.56–7.53 (m,
1H), 7.34–7.29 (m, 2H), 7.00–6.97 (m, 5H), 6.60 (m, 1H); MS (ES)
m/z 248.1. Anal. calcd for C13H10ClNO2: C, 63.04; H, 4.07; N, 5.66.
Found: C, 63.23; H, 3.83; N, 5.57.
Using essentially the same procedure as for 4b, except using
isopropylamine as the amine, 4c was obtained as a white solid-
foam (120 mg, 89%). 1H NMR (DMSO-d6): d 9.03 (1H, s), 8.25 (1H,
d, J = 7.7 Hz), 8.16 (1H, dd, J = 1.2, 7.0 Hz), 7.73–7.58 (5H), 7.46
(1H, app. t, J = 7.9 Hz), 7.23–7.15 (5H), 7.10 (1H, app. d with addi-
tional fine coupling, J = 7.6 Hz), 7.00 (2H, app. d, J = 6.9 Hz), 6.92
(1H, dd, J = 1.5, 2.2 Hz), 4.07 (1H, s), 4.03 (2H, m) 1.14 (6H, d,
J = 6.5 Hz); MS (ESI) m/z 541; HRMS: calcd for C33H27F3N2O2 + H+,
541.2097; found (ESI, [M+H]+), 541.2088.
6.9. 3-{3-[3-Benzyl-8-(trifluoromethyl)quinolin-4-yl]phenoxy}-
N,N-diethylbenzamide (4d)
Using essentially the same procedure as for 4b, except using
diethylamine as the amine, 4d was obtained as an oil (60 mg,
43%). 1H NMR (DMSO-d6): d 9.04 (1H, s), 8.16 (1H, dd, J = 1.4,
7.0 Hz), 7.72–7.64 (2H), 7.60 (1H, app. t, J = 8.0 Hz), 7.44 (1H,
app. t, J = 7.9 Hz), 7.31–7.09 (9H), 6.99–6.95 (3H), 4.03 (2H, m),
3.39 (2H, v. br s), 3.12 (2H, v. br s), 1.10 (3H, v. br s), 0.93 (3H, v.
br s); MS (ESI) m/z 555; HRMS: calcd for C34H29F3N2O2 + H+,
555.2254; found (ESI, [M+H]+), 555.2251.
6.14. 3-(8-Chloro-3-methylquinolin-4-yl)phenol (10b)
A stirred mixture of 12 (2.47 g, 10.0 mmol) and propionalde-
hyde diethylacetal (4.90 mL, 30.0 mmol) in glacial acetic acid
(20 mL) was treated with concd H2SO4 (6 pipette drops) and then
heated at 105–110 °C for 18 h. The reaction was cooled and poured
carefully onto NaHCO3 (28 g) in water (100 mL) in a large beaker.
After further dilution with water (150 mL), the neutralized mixture
was extracted with ethyl acetate (2 Â 100 mL) and the extracts
dried with MgSO4. Concentration in vacuo afforded a brown oil-so-
lid which was triturated with 20:80 ethyl acetate/hexanes to give a
tan to slightly yellow solid, 10b (1.64 g, 61%). Mp: 241–243 °C; 1H
NMR (DMSO-d6): d 9.70 (1H, br s), 8.93 (1H, s), 7.84 (1H, dd, J = 1.3,
7.4 Hz), 7.43 (1H, dd, J = 7.5, 8.4 Hz), 7.34 (2H, m), 6.88 (1H, br d,
J = 8.4 Hz), 6.66 (1H, br d, J = 7.8 Hz), 6.62 (1H, m), 2.21 (3H, s);
MS (ESI) m/z 269.9; HRMS: calcd for C16H12ClNO + H+, 270.0680;
found (ESI, [M+H]+), 270.0683.
6.10. 3-Benzyl-4-{3-[3-(pyrrolidin-1-ylcarbonyl)phenoxy]phenyl}
-8-(trifluoromethyl)quinoline (4e)
Using essentially the same procedure as for 4b, except using
pyrrolidine as the amine and using 50:50 ethyl acetate/hexane,
then ethyl acetate as eluent, 4e was obtained as a white solid-foam
(126 mg, 91%). 1H NMR (DMSO-d6): d 9.04 (1H, s), 8.17 (1H, dd,
J = 1.3, 7.2 Hz), 7.73–7.65 (2H), 7.60 (1H, app. t, J = 7.9 Hz), 7.44
(1H, app. t, J = 7.9 Hz), 7.26 (1H, app. t with additional fine cou-
pling, J = 7.8 Hz), 7.24–7.11 (6H), 6.99 (2H, app. t, J = 6.8 Hz), 6.95
(1H, dd, J = 1.6, 2.2 Hz), 4.03 (2H, m), 3.42 (2H, t, J = 7.0 Hz), 3.28
(2H, t, J = 7.0 Hz), 1.82 (2H, m), 1.71 (2H, m); MS (ESI) m/z 553;
HRMS: calcd for C34H27F3N2O2 + H+, 553.2097; found (ESI,
[M+H]+), 553.2108.
6.15. Methyl 3-[3-(8-chloro-3-methylquinolin-4-yl)
phenoxy]benzoate (4h)
6.11. 3-Benzyl-4-{3-[3-(piperidin-1-ylcarbonyl)phenoxy]phenyl}
-8-(trifluoromethyl)quinoline (4f)
A well-stirred mixture of 10b (1.35 g, 5.00 mmol), methyl 3-
bromobenzoate (2.15 g, 10.0 mmol), CuO (0.72 g, 9.0 mmol), and
K2CO3 (1.38 g, 10.0 mmol) was heated in pyridine at 110 °C under
nitrogen. After 3 d, the reaction was cooled, treated with water
(100 mL), and extracted twice with CH2Cl2 (100 mL each). The
combined extracts were dried over MgSO4, concentrated in vacuo
with heat to remove solvents. The residue was purified by chroma-
tography eluting with 25:75 ethyl acetate/hexanes to afford a solid
which was triturated with a small volume of 20:80 ethyl acetate/
hexane to afford 4h as an off-white solid (0.86 g, 43%, Rf ꢀ 0.4 in
Using essentially the same procedure as for 4b, except using
piperidine as the amine and using 50:50 ethyl acetate/hexane, then
ethyl acetate as eluent, 4f was obtained as a white solid-foam
(121 mg, 85%). 1H NMR (DMSO-d6): d 9.04 (1H, s), 8.17 (1H, dd,
J = 1.3, 6.9 Hz), 7.73–7.65 (2H, m), 7.60 (1H, app. t, J = 7.9 Hz),
7.44 (1H, app. t, J = 8.0 Hz), 7.36–7.09 (7H), 7.01–6.96 (4H), 4.03
(2H, m), 3.32 (2H, v. br s), 3.18 (2H, v. br s), 1.52 (4H, v. br), 1.29
(2H, v. br s); MS (ESI) m/z 567; HRMS: calcd for C35H29F3N2O2 + H+,
567.2254; found (ESI, [M+H]+), 567.2275.

R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 1663–1670
1669
25:75 ethyl acetate/hexanes). Mp: 150–152 °C. 1H NMR (CDCl3): d
6.19. 3-[3-(8-Chloro-3-methylquinolin-4-yl)phenoxy]-N-
isopropylbenzamide (4l)
8.96 (1H, s), 7.80–7.73 (3H, m), 7.53 (1H, app. t, J = 7.9 Hz), 7.45–
7.41 (2H, m), 7.35 (1H, app. t, J = 7.8 Hz), 7.28 (1H, dd, J = 2.5,
8.0 Hz), 7.14 (1H, dd, J = 2.4, 8.2 Hz), 7.02 (1H, d, J = 7.5 Hz), 6.92
(1H, app. t, J = 1.9 Hz), 3.91 (3H, s), 2.32 (3H, s); MS (ES) m/z
404.2; HRMS: calcd for C24H18ClNO3 + H+, 404.1048; found (ESI,
[M+H]+), 404.1063.
Using essentially the same procedure as for 4k, except using
isopropylamine as the amine, 4l was obtained as a white solid-
foam (82 mg, 95%). 1H NMR (DMSO-d6): d 8.99 (1H, s), 8.26 (1H,
d, J = 7.8 Hz), 7.90 (1H, dd, J = 1.3, 7.4 Hz), 7.66–7.63 (2H), 7.60
(1H, m), 7.49 (1H, dt, J = 2.2, 7.4 Hz), 7.41 (1H, dd, J = 1.3, 8.4 Hz),
7.26 (1H, ddd, J = 1.0, 2.6, 8.1 Hz), 7.18 (1H, ddd, J = 0.9, 2.6,
8.3 Hz), 7.12 (1H, app. dt, J = 1.2, 7.6 Hz), 7.00 (1H, dd, J = 1.7,
2.4 Hz), 4.09 (1H, m), 2.28 (3H, s), 1.15 (6H, d, J = 6.5 Hz). MS
(ESI) m/z 431; HRMS: calcd for C26H23ClN2O2 + H+, 431.1521; found
(ESI, [M+H]+), 431.1501.
6.16. 3-[3-(8-Chloro-3-methylquinolin-4-yl)phenoxy]-N-
methylbenzamide (4i)
In essentially the same manner as described for 4j, except using
freshly dried methylamine hydrochloride as the amine, 4i was ob-
tained as a white solid (82 mg, 41%). 1H NMR (CDCl3): d 8.96 (1H,
s), 7.77 (1H, dd, J = 1.3, 7.3 Hz), 7.54–7.50 (2H), 7.45–7.34 (4H),
7.22 (1H, m), 7.14 (1H, ddd, J = 1.0, 2.6, 8.3 Hz), 7.02 (1H, ddd,
J = 1.0, 1.4, 7.5 Hz), 6.92 (1H, app. m), 6.06 (1H, v. br s), 3.02 (3H,
d, J = 4.9 Hz), 2.32 (3H, s). MS (ES) m/z 403.2; HRMS: calcd for
C24H19ClN2O2 + H+, 403.1208; found (ESI, [M+H]+), 403.1203.
6.20. 3-[3-(8-Chloro-3-methylquinolin-4-yl)phenoxy]-N,N-
diethylbenzamide (4m)
Using essentially the same procedure as for 4k, except using
diethylamine as the amine, 4m was obtained as an oil (42 mg,
47%). 1H NMR (DMSO-d6): d 8.99 (1H, s), 7.90 (1H, dd, J = 1.2,
7.4 Hz), 7.63 (1H, app. t, J = 7.8 Hz), 7.51–7.45 (2H), 7.39 (1H, dd,
J = 1.2, 8.5 Hz), 7.22 (1H, m), 7.17 (1H, m), 7.13 (1H, d, J = 7.7 Hz),
7.10 (1H, d, J = 7.5 Hz), 3.39 (2H, v. br s), 3.14 (2H, v. br s), 2.26
(3H, s), 1.11 (3H, v. br s), 0.95 (3H, v. br s); MS (ESI) m/z 445; HRMS:
calcd for C27H25ClN2O2 + H+, 445.1677; found (ESI, [M+H]+),
445.1694.
6.17. 3-[3-(8-Chloro-3-methylquinolin-4-yl)phenoxy]-N-
ethylbenzamide (4j)
To a stirred suspension of ethylamine hydrochloride (41 mg,
0.50 mmol) in toluene (2 mL) at ambient temperature under nitro-
gen was added 2.0 M trimethylaluminum in toluene (0.25 mL,
0.50 mmol). After 0.5 h, 4h (101 mg, 0.25 mmol) was added and
the reaction heated at 60–65 °C for 16 h. The cooled reaction was
carefully treated with water (2 mL), then 2 M aqueous HCl (1 mL)
and extracted with dichloromethane (2 Â 5 mL). The combined ex-
tracts were dried (MgSO4), concentrated in vacuo, and the resulting
oil was chromatographed on silica gel using 50:50, then 75:25
ethyl acetate/hexane as eluent. Compound 4j was isolated as a
glass (101 mg, 97%, Rf ꢀ 0.3 in 50:50 ethyl acetate/hexane). 1H
NMR (DMSO-d6): d 8.99 (1H, s), 8.51 (1H, br t, J = 5.5 Hz), 7.90
(1H, dd, J = 1.3, 7.4 Hz), 7.65–7.61 (2H), 7.58 (1H, app. t,
J = 2.0 Hz), 7.48 (1H, dd, J = 7.5, 8.4 Hz), 7.41 (1H, dd, J = 1.3,
8.5 Hz), 7.27 (1H, ddd, J = 1.0, 2.6, 8.1 Hz), 7.20 (1H, ddd, J = 0.9,
2.5, 8.5 Hz), 7.13 (1H, ddd, J = 1.0, 1.4, 8.0 Hz), 7.01 (1H, dd,
J = 1.6, 2.3 Hz), 3.27 (2H, m), 2.28 (3H, s), 1.11 (3H, t, J = 7.2 Hz);
MS (ES) m/z 417.2; HRMS: calcd for C25H21ClN2O2 + H+, 417.1364;
found (ESI, [M+H]+), 417.1357.
6.21. 8-Chloro-3-methyl-4-{3-[3-(pyrrolidin-1-ylcarbonyl)
phenoxy]phenyl}quinoline (4n)
Using essentially the same procedure as for 4k, except using
pyrrolidine as the amine and using ethyl acetate as the eluent,
4n was obtained as a white solid-foam (79 mg, 89%). 1H NMR
(DMSO-d6): d 8.99 (1H, s), 7.90 (1H, dd, J = 1.3, 7.4 Hz), 7.63 (1H,
app. t, J = 7.9 Hz), 7.51–7.44 (2H), 7.40 (1H, dd, J = 1.3, 8.4 Hz),
7.26 (1H, dt, J = 1.1, 7.7 Hz), 7.22–7.18 (2H), 7.13 (1H, app. dt,
J = 1.2, 7.5 Hz), 7.02 (1H, m), 3.43 (2H, t, J = 6.9 Hz), 3.30 (2H, app.
t, J = 6.5 Hz), 2.27 (3H, s), 1.83 (2H, m), 1.73 (2H, m); MS (ESI) m/
z 443; HRMS: calcd for C27H23ClN2O2 + H+, 443.1521; found (ESI,
[M+H]+), 443.1523.
6.22. 8-Chloro-3-methyl-4-{3-[3-(piperidin-1-ylcarbonyl)
phenoxy]phenyl}quinoline (4o)
6.18. 3-[3-(8-Chloro-3-methylquinolin-4-yl)phenoxy]-N-
propylbenzamide (4k)
Using essentially the same procedure as for 4k, except using
piperidine as the amine and using ethyl acetate as the eluent, 4o
was obtained as a white solid-foam (87 mg, 91%). 1H NMR
(DMSO-d6): d 8.99 (1H, s), 7.90 (1H, dd, J = 1.3, 7.5 Hz), 7.65 (1H,
app. t, J = 7.9 Hz), 7.51–7.45 (2H), 7.40 (1H, dd, J = 1.3, 8.6 Hz),
7.22 (1H, ddd, J = 0.9, 2.6, 8.3 Hz), 7.17 (1H, ddd, J = 1.9, 2.5,
7.8 Hz), 7.12 (1H, app. t, J = 8.4 Hz), 7.03 (1H, m), 3.54 (2H, v. br
s), 3.21 (2H, v. br s), 1.60–1.45 (2H, v. br), 1.32 (2H, v. br s); MS
(ESI) m/z 457; HRMS: calcd for C28H25ClN2O2 + H+, 457.1677; found
(ESI, [M+H]+), 457.1673.
To a stirred mixture of 1-propylamine (59 mg, 1.00 mmol) in
toluene (2.0 mL) at ambient temperature under nitrogen was
added 2.0 M trimethylaluminum in toluene (0.50 mL, 1.00 mmol).
After 45 min, a solution of 4h (82 mg, 0.20 mmol) in toluene
(7.0 mL) was added and the reaction heated at 65 °C for 16 h. The
cooled reaction was carefully treated with water (2 mL), then after
10 min with 2 M aqueous HCl (1 mL) resulting in gas evolution. The
reactions were extracted with dichloromethane (5 mL, 2 mL) and
the combined extracts were dried (MgSO4). After concentrating
in vacuo, the residues were chromatographed on silica gel using
50:50, then ethyl acetate as eluent. Compound 4k was isolated as
a white solid-foam (78 mg, 91%). 1H NMR (DMSO-d6): d 8.99 (1H,
s), 8.49 (1H, br t, J = 5.7 Hz), 7.90 (1H, dd, J = 1.3, 7.3 Hz), 7.65–
7.61 (2H), 7.58 (1H, app. t, J = 1.9 Hz), 7.49 (1H, dt, J = 1.4,
8.0 Hz), 7.41 (1H, dd, J = 1.3, 8.5 Hz), 7.27 (1H, ddd, J = 1.0, 2.5,
8.1 Hz), 7.20 (1H, ddd, J = 0.9, 2.5, 8.3 Hz), 7.13 (1H, ddd, J = 1.0,
2.5, 8.1 Hz), 7.01 (1H, dd, J = 1.6, 2.2 Hz), 3.20 (2H, q, J = 6.3 Hz),
2.28 (3H, s), 1.50 (2H, m), 0.89 (3H, t, J = 7.4 Hz), MS (ESI) m/z
431; HRMS: calcd for C26H23ClN2O2 + H+, 431.1521; found (ESI,
[M+H]+), 431.1519.
6.23. 8-Chloro-3-methyl-4-{3-[3-(morpholin-4-ylcarbonyl)
phenoxy]phenyl}quinoline (4p)
Using essentially the same procedure as for 4k, except using
morpholine as the amine and using ethyl acetate as the eluent,
4p was obtained as a white solid-foam (87 mg, 95%). 1H NMR
(DMSO-d6): d 8.99 (1H, s), 7.90 (1H, dd, J = 1.3, 7.4 Hz), 7.63 (1H,
app. t, J = 7.9 Hz), 7.52–7.46 (2H), 7.40 (1H, dd, J = 1.3, 8.4 Hz),
7.24–7.10 (5H), 7.04 (1H, m), 3.70–3.40 (8H, v. br peaks), 2.27
(3H, s); MS (ESI) m/z 459; HRMS: calcd for C27H23ClN2O3 + H+,
459.1470; found (ESI, [M+H]+), 459.1472.

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R. C. Bernotas et al. / Bioorg. Med. Chem. 17 (2009) 1663–1670
9. Collins, J. L. et al J. Med. Chem. 2002, 45, 1963.
Acknowledgments
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-
Nilsson, A.; Wilhelmsson, A.; Nambi, P.; Wrobel, J. J. Med. Chem. 2006, 49, 6151.
11. Hu, B.; Quinet, E.; Unwalla, R.; Collini, M.; Jetter, J.; Dooley, R.; Andraka, D.;
Nogle, L.; Savio, D.; Halpern, A.; Goos-Nilsson, A.; Wilhelmsson, A.; Nambi, P.;
Wrobel, J. Bioorg. Med. Chem. Lett. 2008, 18, 54.
We thank Anita Halpern, Dawn Savio, Ronald Magolda, and
Magid Abou-Gharbia for project support.
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