Further modification on phenyl acetic acid based quinolines as liver X receptor modulators

Article abstract of DOI:10.1016/j.bmc.2007.03.013

A series of phenyl acetic acid based quinolines was prepared as LXR modulators. An SAR study in which the C-3 and C-8 positions of the quinoline core were varied led to the identification of two potent LXR agonists 23 and 27. Both compounds displayed good binding affinity for LXRβ and LXRα, and increased expression of ABCA1 in THP-1 cells. These two compounds also had desirable pharmacokinetic profiles in mice and displayed in vivo efficacy in a 12-week Apo E knockout mouse lesion model.

Full text of DOI:10.1016/j.bmc.2007.03.013

Bioorganic & Medicinal Chemistry 15 (2007) 3321–3333
Further modification on phenyl acetic acid based quinolines
as liver X receptor modulators
Baihua Hu,a,* James Jetter,a David Kaufman,a Robert Singhaus,a Ronald Bernotas,a
Rayomand Unwalla,a Elaine Quinet,b Dawn Savio,b Anita Halpern,b Michael Basso,b
James Keith,b Valerie Clerin,b Liang Chen,b Qiang-Yuan Liu,b Irene Feingold,c
Christine Huselton,c Farooq Azam,c Annika Goos-Nilsson,d Anna Wilhelmsson,d
Ponnal Nambib and Jay Wrobela
aChemical and Screening Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA
bCardiovascular and Metabolic Diseases, Wyeth Pharmaceuticals, Collegeville, PA, USA
cBio Transformation and Disposition, Wyeth Pharmaceuticals, Collegeville, PA, USA
dKaro-Bio, Huddinge, Sweden
Received 30 January 2007; revised 1 March 2007; accepted 8 March 2007
Available online 12 March 2007
Abstract—A series of phenyl acetic acid based quinolines was prepared as LXR modulators. An SAR study in which the C-3 and
C-8 positions of the quinoline core were varied led to the identification of two potent LXR agonists 23 and 27. Both compounds
displayed good binding affinity for LXRb and LXRa, and increased expression of ABCA1 in THP-1 cells. These two compounds
also had desirable pharmacokinetic profiles in mice and displayed in vivo efficacy in a 12-week Apo E knockout mouse lesion model.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
gate heterodimers with retinoid X receptors (RXRs).
Several LXR agonists (Fig. 1), such as a natural ligand
24(S), 25-epoxycholesterol (1, EPC)4 as well as two
structurally distinct synthetic non-steroidal ligands 2
(GW3965)5 and 3 (TO901317),6 have been shown to in-
crease expression of several genes involved in lipid
metabolism and reverse cholesterol transport including
ABCA1, ABCG1, and ApoE. These compounds
reduced or even reversed atherosclerotic processes in
Coronary heart disease (CHD) is the leading cause of
mortality in the western world, and accounting for
nearly 50% of all deaths.1 Major risk factors for the
development of CHD are hypercholesterolemia and
dyslipoproteinemia. Numerous studies have identified
decreased high-density lipoprotein (HDL) and increased
low-density lipoprotein (LDL) cholesterol as major con-
tributors to CHD. As a result, many current therapies
for the treatment of CHD, including the statins, are
aimed at lowering LDL or increasing HDL. Liver X
receptors (LXRa and LXRb) are members of the nucle-
ar hormone receptor super-family and are involved in
the regulation of cholesterol and lipid metabolism.2,3
The a-subtype is expressed primarily in liver, while the
b-subtype is ubiquitously expressed. They are ligand-
activated transcription factors and bind to DNA as obli-
H
O
CO2H
O
N
Cl
HO
CF3
1
2
CO2H
H
N
O
N
S
F3C
F3C
HO
O
N
Keywords: Liver X receptor (LXR); LXR agonists; Quinoline; Phenyl
acetic acid.
F3C
CF3
3
4
*
Corresponding author. Tel.: +1 484 865 7867; fax: +1 484 865
9399; e-mail: hub@wyeth.com
Figure 1. LXR agonists.
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.03.013

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B. Hu et al. / Bioorg. Med. Chem. 15 (2007) 3321–3333
X Y
mouse models of atherosclerosis. Currently available
synthetic LXR agonists, however, also activated triglyc-
eride (TG) synthesis in the liver by the upregulation of
SREBP-1c and FAS which limits the utility of these
LXR synthetic agonists. Thus, there is a clear need for
new LXR modulators which retain the antiatheroscle-
rotic activity while avoiding the undesired lipogenic
activity.
X Y
a
OH
O
Me or Et
Me
21-94%
O
O
R3
11 X, Y = H, Me, OH, F
b
25%
O
NH2
R3
H
N
O
O
12
O
CN
R1
c
NH2
28%
13
N
O
O
CF3
10
OH
d
Recently, we reported the identification and optimiza-
tion of phenyl acetic acid substituted quinolines as po-
tent LXR agonists.7 These quinolines displayed good
binding affinity for LXRb and LXRa, and were potent
agonists in Gal4 transactivation assays. We also
reported in vivo efficacy (inhibition of lesion progres-
sion) of quinoline 4 in LDLr knockout mouse. We pres-
ent here additional phenyl acetic acid substituted
quinoline analogs, varying the substituents on the quin-
oline core at the C-3 and C-8 positions. Some carboxylic
acid replacements were also evaluated.
R1
30%
14
e
37-51%
15
Scheme 2. Reagents: (a) LiOH, THF/MeOH/water; (b) NH4OH,
MeOH; (c) H2O2, NaOH, EtOH; (d) NaBH4, MeOH; (e) N2H4, KOH,
ethane-1,2-diol.
The C-3 benzyl analog 15 was obtained by hydrazine
reduction of 10.
3. Results and discussion
2. Synthetic chemistry
The LXR binding activity of the newly synthesized com-
poundswas evaluated (Table 1) in binding assays using re-
combinant human LXRa or LXRb ligand binding
domains (LBD) with [3H]T0901317 as a tracer. A CHO-
cell based reporter assay employing a stably transfected
hLXRb reporter cell line (LAFb) was next used to deter-
mine agonist potency and efficacy.7 As seen earlier,7 the
removal of the C-3 carbonyl (16 vs 4) did not have a large
effect on the binding affinity or on the agonist activity in
the LAFb assay (Table 1). Compared to 16, similar bind-
ing affinities were observed for C-3 methyl analog 17 and
C-3 phenyl analog 18, which had binding hLXRb IC50
values of 4.3 nM and 3.7 nM, respectively. Both com-
pounds also showed good potency (EC50 6100 nM) in
the LAFb assay. However, replacement of the C-3 car-
bonyl group with the more polar hydroxyl methyl group
caused a 24-fold reduction in hLXRb binding affinity
(19 vs 16). Likewise, replacement of the C-3 carbonyl with
the more polar nitrile group resulted in a 14-fold loss of
hLXRb binding affinity (20 vs 16). C-3 amide analog 21
was essentially inactive with an hLXRb IC50 value of
>10 lM. These results suggested that lipophilic groups
are preferred for the C-3 substituents.
Our initial research efforts focused on variations of sub-
stituents at position 3 and 8 of the quinoline nucleus.
The general approach for the syntheses of these kinds
of molecules is depicted in Scheme 1. Condensation of
acrylates 5 with various anilines followed by thermal
cyclization provided 4-hydroxyquinoline 6. Conversion
of 6 to bromide or chloride 7 was accomplished readily
with phosphorus oxybromide or phosphorus oxychlo-
ride, respectively. Reaction of 7 with 3-aminophenylbo-
ronic acid under Suzuki conditions provided 8.
Alkylation with benzyl bromides or reductive amination
with benzaldehydes gave key intermediate 9. Further
functional transformations were carried out as illus-
trated in Scheme 2. Carboxylic acids 11 were obtained
by hydrolysis of the corresponding esters. Conversion
of the esters into amides 12 was easily achieved with
ammonium hydroxide in methanol. A base catalyzed
conversion of nitrile by hydrogen peroxide afforded
amide 13. Reduction of the quinoline C-3 carbonyl with
sodium borohydride gave the corresponding alcohol 14.
OH
Br or Cl
R1 CO2Et
R1
R1
c or d
a, b
+
62-99%
22-95%
H2N
N
N
R2
7
OR
Several sterically small replacements for the C-8 trifluo-
romethyl substituent were also evaluated (Table 1). Com-
pared to C-8 trifluoromethyl analog 16, a small loss of
binding activity was seen in the C-8 methyl analog 22.
Replacing the trifluoromethyl with a fluorine (24) resulted
in reduced affinity in the binding assays (hLXRb
IC50 = 17 nM) and reduced potency in the LAFb assay
(EC50 = 700 nM). C-8 hydrogen analog 25 lost substan-
tial potency but maintained its full agonist efficacy
(110%) in LAFb. Chlorine proved to be a good replace-
ment for trifluoromethyl since the 8-chloro quinoline 26
had essentially the same binding affinity and LAFb activ-
ity as the trifluoromethyl substituted quinoline 16.
Removal of the C-3 carbonyl had minimal effect on the
agonist activity (22 vs 23, and 26 vs 27).
R2
R2
5 R = H, Et
6
e
R1 = Me, Ph, C(O)Ph,
Bn, CN
R2 = H, F, Cl, CF3
R3 = H, CO2R4,
CH2CO2R4,
CH(Me)CO2R4,
C(Me)2CO2R4,
CH(OH)CO2R4,
CF2CO2R4, and acid
mimics
20-95%
R3
H
N
NH2
R1
R1
f or g
52-95%
N
N
R2
R2
8
9
R
4 = H, Me, or Et
Scheme 1. Reagents: (a) Toluene; (b) Dowtherm; (c) POBr3, DMF; (d)
POCl3, DMF; (e) 3-aminophenylboronic acid, K3PO4, Pd(PPh3)4,
dioxane; (f) benzyl bromides, K2CO3; (g) benzaldehydes, NaBH(OAc)3,
DMF.

B. Hu et al. / Bioorg. Med. Chem. 15 (2007) 3321–3333
Table 1. Modification at the C-3 and C-8 positionsa,b
3323
CO2H
H
N
X
3
N
8
Y
Compound
X
Y
LXRb IC50 (nM)
LXRa IC50 (nM)
LAFb EC50 (nM) (% ag)
47
16
17
18
19
20
21
22
23
24
25
26
27
Ph–CH2–
Ph–CO–
Me
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CH3
CH3
F
1.9
2.4
7.6
7.0
33 (85%)
29 (100%)
100 (89%)
44 (101%)
812 (68%)
450 (89%)
4.3
3.7
16
8.0
Ph
Ph–CH(OH)–
–CN
56.4
33.8
>10,000
5.5
384
150
>10,000
18
–CONH2
Ph–CO–
Ph–CH2–
Ph–CO–
Ph–CO–
Ph–CO–
Ph–CH2–
61 (75%)
90 (97%)
5.0
21.0
104
650
9.0
17.0
154
2.7
700 (142%)
1650 (110%)
39 (101%)
23 (107%)
H
Cl
Cl
1.4
5.0
a Results are given as means of two independent experiments. The standard deviations for these assays were typically 30% of mean or less.
b % of efficacy is relative to 3.
Compounds 23 and 27 were also tested in Gal4 func-
tional transactivation assays (Table 2, for assay condi-
tion, see reference ). Both compounds showed greater
greater variation in activity upon replacing the acetic acid
group was observed in the LAFb assay than in the binding
assays. The meta-acetic acid isomer 28 and oxyacetic acid
29 had reduced activity in hLXRb binding assay, while the
acrylic acid analog 30 had very poor activity (hLXRb
binding IC50 >10 lM). We had earlier reported that trun-
cation of the acetic acid to the benzoic acid reduced both
binding affinity and functional potency.7 This same effect
was also seen in the benzylamine linker based quinoline
series (16 vs 31). A few a-substituted acetic acid analog,
with a mono-methyl (32), di-methyl (33), mono-hydroxy
(34), and di-fluoro (35) group in the a-position, were
synthesized and all showed potent affinity (binding IC50
<10 nM) in the hLXRb binding assay. Although small
alkyl groups at the a-position were tolerated in the LAFb
assay, introduction of a hydroxyl or di-fluoro group
resulted in a dramatic reduction of LAFb potency with
EC50 of 4 lM for 34 and 2.4 lM for 35, possibly due to
decreased permeability resulting from decreased pKa
relative to 16. Likewise, the primary amide 36 and the
ethanol analog 37 had potent hLXRb binding affinity
(hLXRb IC50 = 1.4 nM for 36 and 5.4 nM for 37), but
compared to 16 both of them showed more than 10-fold
reduction of LAFb potency. Replacing the acid
7
potency in LXRb vs hLXRa, however they were slightly
more efficacious against LXRa. In addition, 23 and 27
up-regulated ABCA1 in THP-1 cells with an EC50 of
438 nM and 81 nM, respectively, and an efficacy of
139% and 162% relative to 3, respectively.8 On the other
hand, in a liver cell line (Huh-7) 23 and 27 also increased
expression of SREBP-1c with an EC50 value of 51 nM
and 75 nM, and an efficacy of 114% and 137% relative
to 3, respectively, showing that these two compounds
did not have the desired gene selectivity. Quinoline 23
and 27 had >140-fold receptor binding selectivity
against a few closely related nuclear receptors (such as
PXR and RXR, data not shown) but were shown to
be PPAR agonists (particularly against PPARc and
PPARd) in human Gal4-PPAR transactivation assays
(Table 2). The PPAR activity for these two compounds
may complicate the significance of the LXR agonist
effect in vivo.
The contribution of the acetic acid to the LXR agonist
activity was then investigated (Table 3). In general a
Table 2. Gene expression activity and selectivity in Gal4 human transactivation assays (EC50 nM, % eff.)9–11
Compound
ABCA1a
SREBP1cb
Gal4 hLXRbc
Gal4 hLXRac
Gal4 PPARad
Gal4 PPARcd
Gal4 PPARdd
23
27
438 (139%)
81 (162%)
51.4 (114%)
75 (137%)
267 (75%)
54 (67%)
467 (101%)
121 (89%)
1772 (7.5%)
2053 (12%)
1030 (46.6%)
506 (50.6%)
1975 (46.7%)
631 (40.8%)
a THP cell line. Results are given as means of two independent experiments. The standard deviations for these assays were typically 50% of mean or
less. % of efficacy is relative to 3.
b Huh-7 cell line. Results are given as means of two independent experiments. The standard deviations for these assays were typically 50% of mean
or less. % of efficacy is relative to 3.
c Transient transfection assays in Huh-7 cell line. Human LXR LBDs were fused to GAL4 DBD. The standard deviations for these assays were
typically 50% of mean or less. % efficacy is relative to 3.
d Results are given as means of two independent experiments. % of efficacy is relative to references: PPARa: [4-chloro-6-(2,3-xylidino)-2-pyrimidi-
nylthio]acetic acid (WY-14643); PPARc: 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy] phenyl]methyl]-2,4-thiazolidinedione (Rosiglitazone); PPARd:
3-chloro-4-[[3-[(3-phenyl-7-propyl-6-benzofuranyl)oxy]propyl]thio]-phenylacetic acid (L-796449).

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B. Hu et al. / Bioorg. Med. Chem. 15 (2007) 3321–3333
Table 3. Acetic acid modificationsa,b
p
S
O
R
NH
NH
m
O
O
a
O
S
N
S
CF3
NH
b
Compound
R
LXRb IC50 (nM)
LXRa IC50 (nM)
LAFb EC50 (nM) (% ag)
16
28
29
30
31
32
33
34
35
36
37
38
39
40
41
p-CH2CO2H
m-CH2CO2H
p-OCH2CO2H
p-CH@CHCO2H
p-CO2H
2.4
6.0
7.0
29 (100%)
141 (88%)
1271 (70%)
33.6
63.9
>10,000
420
12.0
>10,000
138
2.6
365 (34%)
58 (97%)
78 (86%)
p-CH(Me)CO2H
p-C(Me)2CO2H
p-CH(OH)CO2H
p-CF2CO2H
p-CH2CONH2
p-CH2CH2OH
H
15.2
17.2
33.6
30.2
11.0
34
3.8
8.5
4003 (91%)
2395 (124%)
316 (85%)
795 (102%)
770 (26%)
2304 (105%)
369 (16%)
286 (12%)
7.8
1.4
5.4
45
241
p-CH2OH
para-a
para-b
12.8
276
310
90.5
456
479
a Results are given as the mean of two independent experiments. The standard deviations for these assays were typically 30% of mean or less.
b % of efficacy is relative to 3.
Table 4. C57 mouse pharmacokinetic parameters for 23 and 27a
Compound
IV t1/2 (h)
Cl (mL/min/kg)
Vss (L/kg)
PO t1/2 (h)
Cmax (ng mL)
Tmax (h)
AUC inf (h ng/mL)
%F
23
27
1.6
1.8
25
37
1.2
1.8
1.2
1.2
4191
2505
0.25
0.25
3576
2581
53
57
a 1 mg/kg IV, 10 mg/kg PO.
Table 5. In vivo activity dosed at 10 mg/kg/day for 12 weeks
Compound
Number of ApoE
knockout mice
% of aortic arch
lesion area
% of aortic arch
lesion reduction
Difference of plasma
triglyceride levels (mg/dL)a
Control
2
10
8
9.55 0.45
1.99 0.54
4.09 1.25
4.47 0.53
79
6
2.95
15.20
64.56
23
27
8
57 13
53 11
8
a Difference = mean of control-mean of sample.
functionality with hydrogen (38), methyl alcohol (39), and
an acid mimic such as thiazolidine-2,4-dione (40) or rho-
danine (41) all resulted in reduced agonist potency. The
loss of agonist potency upon deletion of the acetic acid
suggested that the acetic acid is necessary for LXR agonist
activity.
in a western diet (0.21% cholesterol)-fed ApoE knock-
out mouse model. Administration of quinoline 23 and
27 for 12 weeks at 10 mg/kg/day orally resulted in a sig-
nificant reduction in lesion burden by 57% and 53%,
respectively, compared to the control group (Table 5).
In the same experiment, the literature standard 2 also
significantly reduced the lesion burden by 79%. How-
ever, these two agonists (23 and 27) also caused a mean
increase of plasma triglyceride levels.
To select compounds for in vivo efficacy studies, the
pharmacokinetic (PK) profiles of 23 and 27 were evalu-
ated in mice (Table 4). These two compounds were cho-
sen because they were among the most potent in the
in vitro assays and also they were stable against mouse
and human liver microsomes. Following a single dose
of 1 mg/kg iv and 10 mg/kg oral in mouse both com-
pounds displayed moderate volume of distribution,
moderate clearance, and good bioavailability (%F
>50%). An atherosclerotic lesion study was conducted
4. Conclusion
In summary, modifications on previously reported com-
pound 4 via SAR study produced two additional quino-
line leads 23 and 27 with good potency and efficacy
in vitro. The compounds also had good oral bioavail-

B. Hu et al. / Bioorg. Med. Chem. 15 (2007) 3321–3333
3325
ability in mice and displayed in vivo efficacy in a 12-week
Apo E knockout mouse lesion model. However, both
compounds increased plasma triglyceride levels. The
identification of novel LXR agonists without increasing
the triglycerides is a great challenge in the pursuit of
LXR modulators. It might be possible to develop
LXR modulators free of TG liabilities through the
development of LXRb isoform selective agonist or tis-
sue/gene selective agonist. To achieve this goal, we are
continuing to investigate the SAR and biological prop-
erties of this new series of LXR agonists.
alcohol produced during the reaction. After cooling to
ꢀ100 ꢁC, the reaction mixture was poured into hexane
(600 mL) and allowed to stand overnight. A solid pre-
cipitated which was filtered off and dried to yield 6a as
an off-white solid (18.13 g, 65%); 1H NMR (DMSO-
d6): d 11.08 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.04 (d,
J = 7.5 Hz, 1H), 7.82 (s, 1H), 7.45 (t, J = 7.6 Hz, 1H),
2.01 (s, 3H); MS (ESI) m/z 228.
The following compounds (6b–6e) were prepared following
essentially the same procedure as used for compound 6a.
5.2. 4-Hydroxy-8-(trifluoromethyl)quinoline-3-carbonitri-
le (6b)
5. Experimental
General Solvents and chemicals were purchased from
VWR and Aldrich Chemical Co. and were used without
further purification. Anhydrous and deuterated solvents
as well as fine chemicals were purchased from Aldrich
Chemical Co. and used without further treatment. CHN
analysis was performed by Robertson Microlit Labs
(Madison, NJ). High-resolution mass spectra were
recorded on a Waters LC-TOFMS instrument and were
The title compound was prepared from 2-(trifluorom-
ethyl)aniline and 2-cyano-3-ethoxy-acrylic acid ethyl
ester as a white solid (11.0 g, 46%); H NMR (DMSO-
d6): d 12.10 (s, 1H), 9.37 (s, 1H), 8.64 (d, J = 8.6 Hz,
1H), 8.50 (d, J = 9.5 Hz, 1H), 8.04 (t, J = 7.8 Hz, 1H);
MS (ESI) m/z 239; HRMS calcd for C11H6F3N2O[M+H]:
239.0427; found (ESI, [M+H]+): 239.0424.
1
1
5.3. (4-Hydroxy-8-methylquinolin-3-yl)(phenyl)methanone
(6c)
measured to within 5 ppm of the calculated values. H
NMR spectra were recorded on a Bruker DPX300
(300 MHz) instrument and delta values (d) were measured
in ppm using tetramethylsilane as an internal standard
(d = 0 ppm). High-performance liquid chromatography
(HPLC) was performed with an Agilent 1100F series
instrument with auto sampler and a diode array detector
(Xterra RP18, 3.5u, 150 · 4.6 mm column, 1.2 mL/min,
85/15-5/95 solvent A-solvent B for 10 min, hold 4 min,
solvent A: ammonium formate buffer (pH 3.5), solvent
B: ACN/MeOH 1:1). Appropriate safety practices were
observed during all laboratory functions.
The title compound was prepared from 2-methylaniline
and 2-benzoyl-3-ethoxy-acrylic acid ethyl ester as a
white solid (1.88 g, 74%); 1H NMR (DMSO-d6): d
11.60 (s, 1H), 8.20 (s, 1H), 8.12 (d, J = 10.7 Hz, 1H),
7.87 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 7.4 Hz, 2H), 7.42
(t, J = 7.3 Hz, 2H), 7.28 (t, J = 7.8 Hz, 1H), 2.58 (s,
3H); MS (ESI) m/z 264; HPLC purity = 98.3% at
7.2 min; HRMS calcd for C18H13NO2 [M+H]:
264.1019; found (ESI, [M+H]+): 264.1017; Anal. Calcd
for C17H13NO2ÆH2O: C, 76.50; H, 5.06; N, 5.25. Found:
C, 76.67; H, 4.77; N, 5.14.
5.1. 3-Methyl-8-(trifluoromethyl)quinolin-4-ol (6a)
5.4. (8-Fluoro-4-hydroxyquinolin-3-yl)(phenyl)methanone
(6d)
To ethyl propionate (65.0 mL, 566 mmol) in ethyl for-
mate (150 ml) at 0 ꢁC, under nitrogen atmosphere, was
added sodium hydride (27.2 g, 680 mmol) in equal por-
tions over 1.5 h. The resulting gray mixture was stirred
at room temperature overnight, then quenched with 2 N
aqueous HCl (dropwise at first, 600 mL total), and ex-
tracted with ether. The combined extracts were dried over
MgSO4, filtered, and concentrated in vacuo. The crude
material was used without further purification.
The title compound was prepared from 2-fluoroaniline
and 2-benzoyl-3-ethoxy-acrylic acid ethyl ester as a
white solid (2.08 g, 98%); 1H NMR (DMSO-d6): d
12.15 (s, 1H), 8.20 (d, J = 6.3 Hz, 1H), 8.07 (d,
J = 8.1 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.60–7.25
(m, 4H), 6.98 (d, J = 7.7 Hz, 1H); MS (ES) m/z 266.1;
HPLC purity 93.7%; HRMS calcd for C16H9FNO2
[MÀH]: 266.0623; found (ESI, [MÀH]À): 266.0626.
2-(Trifluoromethyl)aniline (26.8 mL, 216 mmol) was
added to a mixture of the crude material (60.96 g) in
dichloromethane (250 mL) at room temperature. The
mixture was stirred at room temperature overnight
and concentrated in vacuo to yield a yellow oil. This
oil was purified by silica gel chromatography (5:95 ethyl
acetate–hexane) to afford ethyl 2-methyl-3-{[2-(trifluo-
romethyl)phenyl]amino}acrylate as a 3:1 E/Z mixture
(33.76 g, 22% yield); MS (ESI) m/z 274.
5.5. (4-Hydroxyquinolin-3-yl)(phenyl)methanone (6e)
The title compound was prepared from aniline and
2-benzoyl-3-ethoxy-acrylic acid ethyl ester as a white
solid (0.93 g, 83%); 1H NMR (DMSO-d6): d 12.12
(s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.6 Hz,
2H), 7.60–7.30 (m, 6H), 6.98 (d, J = 9.0 Hz, 1H); MS
(ES) m/z 248.1; HRMS calcd for C16H10NO2 [MÀH]:
248.0717; found (ESI, [MÀH]À): 248.0702.
The E/Z mixture of ethyl 2-methyl-3-{[2-(trifluorometh-
yl)phenyl]amino}acrylate (33.76 g, 123.6 mmol) and
Dowtherm-A (200 ml) under a nitrogen atmosphere
was heated at reflux for 1 h. The reaction vessel was
equipped with a Dean-Stark adapter to remove the ethyl
5.6. 3-Phenyl-8-(trifluoromethyl)quinolin-4-ol (6f)
Step 1: 8-Trifluoromethyl-quinolin-4-ol (9.12 g, 42.8 mmol)
was dissolved in acetic acid (300 mL). Bromine (2.20 mL

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B. Hu et al. / Bioorg. Med. Chem. 15 (2007) 3321–3333
42.8 mmol) was dissolved in acetic acid (30 mL) and
then added dropwise to the reaction mixture over
20 min. After 0.5 h, the solution was poured into
500 mL of 2 N aqueous NaOH and stirred. The result-
ing white precipitate was filtered off and dried in vacuo
yielding 3-bromo-8-(trifluoromethyl)quinolin-4-ol as a
white solid (10.3 g, 83%); mp 297–299 ꢁC; 1H NMR
(DMSO-d6): d 11.67 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H),
8.26 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.57 (t,
J = 7.5 Hz, 1H); MS (ESI) m/z 292; MS (ESI) m/z
290; HRMS calcd for C10H6BrNF3O [M+H] 291.9585;
found (ESI, [M+H]+): 291.9585.
5.9. 4-Chloro-8-(trifluoromethyl)quinoline-3-carbonitrile (7c)
The title compound was prepared from 6b and POCl3 as
an off-white solid (6.70 g, 62%); 1H NMR (DMSO-d6): d
9.19 (s, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.36 (d,
J = 7.1 Hz, 1H), 7.97 (t, J = 8.1 Hz, 1H); MS (ES) m/z
256.9; HRMS calcd for C11H5ClF3N2 [M+H]:
257.0088; found (ESI, [M+H]+): 257.0095.
5.10. (4-Chloro-8-methylquinolin-3-yl)(phenyl)methanone
(7d)
The title compound was prepared from 6c and POCl3 as
1
an off-white solid (1.68 g, 99%); H NMR (CDCl3): d
Step 2: A solution of 3-bromo-8-(trifluoromethyl)quino-
lin-4-ol (3.20 g, 10.95 mmol) and phenyl boronic acid
(2.67 g, 21.9 mmol) in 2:1 toluene–methanol (120 mL)
and saturated aqueous NaHCO3 (40 mL) was treated
with Pd(PPh3)4 (760 mg) and heated at reflux overnight.
The reaction mixture was poured into water and ex-
tracted with ethyl acetate. The combined extracts were
washed sequentially with 2 N aqueous NaOH, water,
and brine, then dried with magnesium sulfate. The ex-
tracts were concentrated and the residue was chromato-
graphed with 1:4 ethyl acetate–hexanes to afford 6f as a
8.85 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.86 (d,
J = 7.0 Hz, 2H), 7.72 (d, J = 7.0 Hz, 1H), 7.70–7.60
(m, 2H), 7.50 (t, J = 7.8 Hz, 2H); MS (ESI) m/z 282;
HPLC purity 97.6% at 10.8 min; Anal. Calcd for
C17H12ClNO: C, 72.47; H, 4.29; N, 4.97. Found: C,
72.38; H, 3.93; N, 4.86.1
5.11. (4-Chloro-8-fluoroquinolin-3-yl)(phenyl)methanone (7e)
The title compound was prepared from 6d and POCl3 as
1
1
yellow solid (6.40 g, 59%); mp 272–275 ꢁC; H NMR
an off-white solid (1.98 g, 92%); H NMR (CDCl3): d
(DMSO-d6): d 11.47 (s, 1H), 8.55 (d, J = 7.2 Hz, 1H),
8.11 (d, J = 7.4 Hz, 1H), 7.98 (s, 1H), 7.68 (d,
J = 8.1 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.43 (t,
J = 7.6 Hz, 2H), 7.34 (d, J = 7.4 Hz, 1H); MS (ESI)
m/z 290; HRMS calcd for C16H11NF3O [M+H]:
290.0793; found (ESI, [M+H]+), 290.0782.
8.88 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.86 (d,
J = 8.2 Hz, 2H), 7.75–7.48 (m, 5H); MS (ESI) m/z 286;
HPLC purity 97.1% at 9.7 min; HRMS calcd for
C16H10ClFNO [M+H]: 286.0429; found (ESI,
[M+H]+): 286.0421.
5.12. (4-Chloroquinolin-3-yl)(phenyl)methanone (7f)
5.7. 4-Bromo-3-methyl-8-(trifluoromethyl)quinoline (7a)
Thetitlecompoundwaspreparedfrom6eandPOCl3 asan
off-white solid (2.18 g, 97%); 1H NMR (CDCl3): d 8.84 (s,
1H), 8.35 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H),
7.95–7.85 (m, 2H), 7.80–7.70 (m, 1H), 7.70–7.60 (m, 1H),
7.55–7.45 (m, 2H), 7.40–7.30 (m, 1H); HPLC purity
91.2% at 9.8 min; HRMS calcd for C16H10ClNO [M+H]:
268.0524; found (ESI, [M+H]+): 268.0518.
Phosphorus oxybromide (12.4 g, 43.3 mmol) was added
to a mixture of 6a (7.02 g, 30.9 mmol) in DMF (160 ml)
at room temperature. The mixture was heated at 80 ꢁC
for 1 h and then allowed to cool to room temperature.
The reaction mixture was poured into aqueous ethyl
acetate and solid Na2CO3 was added until pH >8. The
layers were separated and the aqueous layer was ex-
tracted with ethyl acetate. The combined ethyl acetate
layers were washed with brine and dried over MgSO4.
After concentrating in vacuo, the resulting material
was purified by silica gel chromatography (5:95 ethyl
acetate–hexanes) to afford 7a as a white solid (7.89 g,
88%); 1H NMR (CDCl3): d 8.85 (s, 1H), 8.45 (d,
J = 8.6 Hz, 1H), 8.07 (d, J = 7.3 Hz, 1H), 7.67 (t,
J = 7.9 Hz, 1H), 2.04 (s, 3H); MS (ESI) m/z 290.
5.13. (4,8-Dichloroquinolin-3-yl)(phenyl)methanone (7g)
The title compound was prepared from 2-chloroaniline
and 2-benzoyl-3-ethoxy-acrylic acid ethyl ester accord-
ing to the procedure of 6a followed by the procedure
1
of 7a with POCl3 (0.97 g, 72%); H NMR (CDCl3): d
8.95 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 8.01 (d,
J = 7.5 Hz, 1H), 7.86 (d, J = 9.6 Hz, 2H), 7.70–7.65
(m, 2H), 7.55–7.45 (m, 2H); MS (ESI) m/z 302; HRMS
calcd for C16H10Cl2NO [M+H]: 302.0134; found (ESI,
[M+H]+): 302.0125.
The following compounds (7b–7g) were prepared fol-
lowing the procedure of compound 7a.
5.8. 4-Bromo-3-phenyl-8-(trifluoromethyl)quinoline (7b)
5.14. {3-[3-Methyl-8-(trifluoromethyl)quinolin-4-yl]-
phenyl}amine (8a)
The title compound was prepared from 6f and POBr3
(0.17 g, 86%); mp 75–77 ꢁC; H NMR (DMSO-d6): d
1
9.19 (s, 1H), 8.63(d, J = 8.4 Hz, 1H), 8.34 (d,
J = 6.9 Hz, 1H), 7.96 (t, J = 8.1 Hz, 1H), 7.60–7.50 (m,
5H); HRMS calcd for C16H10BrF3N [M+H]: 351.9943;
found (ESI, [M+H]+): 351.9948; Anal. Calcd for
C16H9BrF3NÆ0. 3H2O: C, 53.75; H, 2.71; N, 3.92.
Found: C, 53.60; H, 2.64; N, 3.82.
Compound 7a (5.00 g, 17.2 mmol) was taken into
toluene–ethanol–water (300 mL:75 mL:130 mL). Then
3-aminophenylboronic acid (5.34 g, 34.5 mmol) was
added followed by Na2CO3 (5.48 g, 51.7 mmol) and
Pd(PPh3)4 (1.99 g, 1.72 mmol). The reaction mixture
was heated at 90 ꢁC overnight. The solvent was removed

B. Hu et al. / Bioorg. Med. Chem. 15 (2007) 3321–3333
3327
and the resulting material was purified via silica gel chro-
matography eluting with 20:80 ethyl acetate–hexane to af-
ford 4.8 g (92%) of 8a as a tan solid; 1H NMR (CDCl3): d
8.98 (s, 1H), 7.98 (d, J = 7.3 Hz, 1H), 7.74 (d, J = 8.4 Hz,
1H), 7.43 (t, J = 7.9 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 6.81
(dd, J = 8.2, 1.5 Hz, 1H), 6.61 (d, J = 7.4 Hz, 1H), 6.54 (br
s, 1H), 3.80 (br s, 2H), 2.31(s, 3H); HPLC purity 99.4% at
9.6 min; HRMS calcd for C17H14F3N2 [M+H]: 303.1104;
found (ESI, [M+H]+): 303.1117.
NMR (CDCl3): d 8.98 (s, 1H), 7.72 (d, J = 7.8 Hz,
1H), 7.68–7.60 (m, 3H), 7.50–7.40 (m, 2H), 7.30 (t,
J = 7.6 Hz, 2H), 7.03 (t, J = 8.7 Hz, 1H), 6.62 (d,
J = 6.3 Hz, 1 H), 6.54–6.56 (m, 2H), 3.65 (br s, 2H),
2.90 (s, 3H); MS (ESI) m/z 339; HPLC purity 99.5% at
9.7 min; HRMS calcd for C23H19N2O [M+H]:
339.1492; found (ESI, [M+H]+): 339.1487; Anal. Calcd
for C23H18N2OÆH2O: C, 79.52; H, 5.51; N, 8.06. Found:
C, 79.54; H, 5.46; N, 7.66.
The following compounds (8b, 8c, 8e–8h) were prepared
following the procedure of compound 8a.
5.19. [4-(3-Aminophenyl)-8-fluoroquinolin-3-yl](phenyl)-
methanone (8f)
5.15. {3-[3-Phenyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}-
amine (8b)
The title compound was prepared from 7e and 3-amin-
ophenylboronic acid as a white solid (0.71 g, 59%); H
1
NMR (CDCl3): d 9.02 (s, 1H), 7.70–7.60 (m, 3H),
7.55–7.45 (m, 3H), 7.33 (t, J = 8.2 Hz, 2H), 7.06 (d,
J = 7.5 Hz, 1H), 7.64 (d, J = 7.3 Hz, 1H), 6.59–6.57
(m, 2H), 3.70 (br s, 2H); HPLC purity 100% at
8.9 min; HRMS calcd for C22H16FN2O [M+H]:
343.12412; found (ESI, [M+H]+): 343.1241.
The title compound was prepared from 7b and 3-amin-
ophenylboronic acid as a white solid (0.171 g, 69%);
mp 163–165 ꢁC; H NMR (DMSO-d6): d 9.07 (s, 1H),
8.21 (d, J = 7.1 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.72
(t, J = 7.6 Hz, 1H), 7.40–7.25 (m, 5H), 7.05 (t,
J = 7.7 Hz, 1H), 6.60–6.55 (m, 1H), 6.45–6.40 (m, 1H),
6.37 (d, J = 8.3 Hz, 1H), 5.17 (s, 2H); MS (ES) m/z
365.1; HRMS calcd for C22H16N2F3 [M+H]: 365.1266;
found (ESI, [M+H]+): 365.1276.
1
5.20. [4-(3-Aminophenyl)quinolin-3-yl](phenyl)methanone
(8g)
The title compound was prepared from 7f and 3-amin-
ophenylboronic acid as a white solid (0.49 g, 70%); H
1
5.16. 4-(3-Aminophenyl)-8-(trifluoromethyl)quinoline-3-
carbonitrile (8c)
NMR (CDCl3): d 8.97 (s, 1H), 8.23 (d, J = 8.4 Hz,
1H), 7.90 (d, J = 7.7 Hz, 1H), 7.80 (t, J = 8.5 Hz, 1H),
7.75–7.25 (m, 6H), 7.04 (t, J = 7.3 Hz, 1H), 6.65 (d,
J = 7.8 Hz, 1H), 6.60–6.55 (m, 2H), 3.70 (br s, 2H);
HPLC purity 100% at 6.3 min.
The title compound was prepared from 7c and 3-amin-
ophenylboronic acid as a white solid (0.35 g, 22%); H
1
NMR (DMSO-d6): d 9.37 (s, 1H), 8.40 (d, J = 6.9 Hz,
1H), 8.07 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H),
7.28 (t, J = 7.8 Hz, 1H), 6.84–6.80 (m, 1H), 6.69–6.65
(m, 1H), 6.64 (d, J = 7.4 Hz, 1H), 5.47 (s, 2H); MS (ES)
m/z 314.0; HPLC purity 100% at 9.3 min; HRMS calcd
for C17H11F3N3 [M+H]: 314.0900; found (ESI,
[M+H]+): 314.0905.
5.21. [4-(3-Aminophenyl)-8-chloroquinolin-3-yl](phenyl)
methanone (8h)
The title compound was prepared from 7g and 3-amin-
ophenylboronic acid as a white solid (0.93 g, 83%); H
1
NMR (CDCl3): d 9.07 (s, 1H), 7.93 (d, J = 7.5 Hz,
1H), 7.81 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H),
7.52–7.45(m, 2H), 7.31 (t, J = 7.9 Hz, 2H), 7.05 (t,
J = 7.8 Hz, 1H), 6.65–6.55 (m, 3H), 1.63(br s, 2H); MS
(ES) m/z 359.2; HRMS: calcd for C22H16ClN2O
[M+H]: 359.0946; found (ESI, [M+H]+): 359.0965.
5.17. 4-(3-Aminophenyl)-8-(trifluoromethyl)quinoline-3-
carboxamide (8d)
A mixture of 8c (0.50 g, 1.6 mmol), NaOH (0.50 g,
12.5 mmol), and 30% aqueous H2O2 (5.0 mL) in ethanol
(15 mL) was heated to 40 ꢁC for 3 h. The reaction mixture
was poured into water and the pH was adjusted to ꢀ6
using dilute aqueous HCl. The aqueous solution was ex-
tracted with ethyl acetate and the residue from concentra-
tion was purified by reverse phase semi-preparative
5.22. Methyl {4-[({3-[3-methyl-8-(trifluoromethyl)quino-
lin-4-yl]phenyl}amino) methyl]phenyl}acetate (9a)
Compound 8a (0.10 g, 0.33 mmol) and (4-formyl-phe-
nyl)-acetic acid methyl ester (0.117 g, 0.66 mmol) were
mixed in acetonitrile (4.0 mL) and then treated with NaB-
H(OAc)3 (0.28 g, 1.32 mmol) and acetic acid (0.5 mL).
After stirring at 45 ꢁC under a N2 atmosphere for 1 h,
the mixture was quenched with water and then extracted
with ethyl acetate. The organic residue was purified by re-
verse phase semi-preparative HPLC to provide 9a as a yel-
1
HPLC to afford 8d as a white solid (0.15 g, 28%); H
NMR (DMSO-d6): d 9.04 (s, 1H), 8.23 (d, J = 6.9 Hz,
1H), 7.93 (d, J = 7.7 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H),
7.64 (br s, 1H), 7.56 (br s, 1H), 7.16 (t, J = 7.7 Hz, 1H),
6.70–6.68 (m, 1H), 6.56–6.53 (m, 1H), 6.51 (d,
J = 7.6 Hz, 1H), 5.29 (s, 2H); MS (ESI) m/z 332; HPLC
purity 100% at 7.3 min; HRMS calcd for C17H13F3N3O
[M+H]: 332.1005; found (ESI, [M+H]+): 332.0994.
1
low oil (0.14 g, 91%); H NMR (CDCl3): d 8.97 (s, 1H),
7.98 (d, J = 6.5 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.50–
7.25 (m, 6H), 6.76 (d, J = 8.2 Hz, 1H), 6.57 (d,
J = 6.9 Hz, 1H), 6.45 (s, 1H), 4.34 (s, 2H), 3.70 (s, 3H),
3.63 (s, 2H), 2.27 (s, 3H); HPLC purity 99.1% at
11.2 min; HRMS calcd for C27H24F3N2O2 [M+H]:
465.1784; found (ESI, [M+H]+): 465.1797.
5.18. [4-(3-Aminophenyl)-8-methylquinolin-3-yl](phenyl)
methanone (8e)
The title compound was prepared from 7d and 3-amino-
phenyl-boronic acid as a white solid (1.12 g, 58%); H
1

3328
B. Hu et al. / Bioorg. Med. Chem. 15 (2007) 3321–3333
5.23. Methyl {4-[({3-[3-phenyl-8-(trifluoromethyl)quino-
lin-4-yl]phenyl}amino) methyl] phenyl}acetate (9b)
Step 2: Difluoro-(4-formyl-phenyl)-acetic acid ethyl es-
ter was prepared from (4-cyano-phenyl)-difluoro-acetic
acid ethyl ester by Raney nickel reduction as described
in step 1 of 9c.
To a solution of {3-[3-phenyl-8-(trifluoromethyl)quino-
lin-4-yl]phenyl}amine (0.163 g, 0.45 mmol) and potas-
sium carbonate (0.068 g, 0.49 mmol) in DMF at 80 ꢁC
was added 4-bromomethylphenylacetic acid ethyl ester
(0.204 g, 0.89 mmol) dropwise over 5 min. After an
additional 4 h, the cooled reaction mixture was poured
into 2 N aqueous HCl and extracted with ethyl acetate.
The combined extracts were washed with saturated
aqueous NaHCO3, water, and brine, and dried with
magnesium sulfate. The extracts were concentrated
and the residue was chromatographed with 1:9 ethyl
Step 3: Compound 9d was prepared from [4-(3-amino-
phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl- metha-
none7 and difluoro-(4-formyl-phenyl)-acetic acid ethyl
ester according to the procedure of 9a as a gummy yel-
low solid (0.20 g, 81%); 1H NMR (DMSO-d6): d 9.07 (s,
1H), 8.30 (d, J = 7.3 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H),
7.70 (t, J = 8.2 Hz, 1H), 7.60–7.50 (m, 5H), 7.41 (d,
J = 8.1 Hz, 2H), 7.33 (t, J = 8.2 Hz, 3H), 6.98 (t,
J = 7.6 Hz, 1H), 6.60–6.35 (m, 4H), 4.29 (q,
J = 7.1 Hz, 2H), 4.22 (br s, 2H), 1.21 (t, J = 7.1 Hz,
3H); MS (ES) m/z 605.3.
acetate–hexanes to afford 9b as
a yellow syrup
1
(0.127 g, 52%); H NMR (DMSO-d6): d 9.05 (s, 1H),
8.19 (d, J = 7.1 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.65
(t, J = 7.7 Hz, 1H), 7.30–7.15 (m, 8H), 7.05 (t,
J = 7.0 Hz, 1H), 6.65–6.60 (m, 1H), 6.44 (s, 1H), 6.40–
6.30 (m, 2H), 4.18 (d, J = 6.2 Hz, 2H), 3.65 (s, 2H),
3.59 (s, 3H); MS (ES) m/z 527.0; HRMS calcd for
C32H26F3N2O2 [M+H]: 527.1941; found (ESI,
[M+H]+): 527.1966.
5.26. {4-[({3-[3-Benzoyl-8-(trifluoromethyl)quinolin-4-yl]-
phenyl}amino)methyl]-phenyl}acetic acid (16)
Step 1: [4-(3-Aminophenyl)-8-(trifluoromethyl)quinolin-
3-yl](phenyl)methanone7 (0.39 g, 1.0 mmol) and (4-
formyl-phenyl)-acetic acid methyl ester12 (0.17 g,
0.96 mmol) were mixed in THF (15 mL) and then trea-
ted with NaBH(OAc)3 (0.43 g, 2.0 mmol) and acetic acid
(0.50 mL). After stirring at 40 ꢁC under an N2 atmo-
sphere for 2 h, the mixture was quenched with water
and then extracted with ethyl acetate. The organic resi-
due was purified by silica gel chromatography eluting
with a 5:95–50:50 ethyl acetate–hexane gradient to give
methyl {4-[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-
4- yl]phenyl}amino)methyl]phenyl}acetate as an orange
solid (0.30 g, 54%): 1H NMR (DMSO-d6): d 9.08 (s, 1H),
8.30 (d, J = 7.3 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.72 (t,
J = 8.6 Hz, 1H), 7.59 (d, J = 9.0 Hz, 2H), 7.55 (t,
J = 7.4 Hz, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.22–7.18 (m,
4H), 6.98 (t, J = 7.7 Hz, 1H), 6.49 (d, J = 6.8 Hz, 2H),
6.40 (d, J = 6.8 Hz, 2H), 4.12 (d, J = 6.0 Hz, 2H), 3.66
(s, 2H), 3.61 (s, 3H); MS (EI) m/z 555.3 (M+H)+.
5.24. Ethyl {4-[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-
4-yl]phenyl}amino) methyl]phenyl}(hydroxy)acetate (9c)
Step 1: A mixture of (4-cyano-phenyl)-oxo-acetic acid
ethyl ester (0.41 g, 2.0 mmol) in 25 mL of 90% formic
acid and a large excess of Raney nickel (50% slurry in
water) was refluxed for 1 h. The solid was filtered off
and the filtrate was concentrated. The crude material
was purified by silica gel chromatography eluting with
a 5:95–100:0 ethyl acetate–hexane gradient to give
0.35 g of (4-formyl-phenyl)-hydroxy-acetic acid ethyl
ester as an oil. This material was used in the next step.
Step 2: Compound 9c was prepared from [4-(3-amino-
phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl- metha-
none7 and (4-formyl-phenyl)-hydroxy-acetic acid ethyl
ester according to the procedure of compound 9a
Step 2: To a stirred solution of methyl {4-[({3-[3-benzoyl-
8-(trifluoromethyl)quinolin-4-yl]phenyl}amino)methyl]-
phenyl}acetate (0.06 g, 0.11 mmol) in THF–methanol–
water (2:1:1, 10 mL) was added lithium hydroxide mono-
hydrate (0.060 g, 1.40 mmol). The reaction mixture was
stirred at 40 ꢁC for 1 h. The reaction mixture was made
acidic (pH 6) with glacial acetic acid, and the solid was col-
lected and dried over P2O5 to give 16 as an orange solid
(0.05 g, 93%); 1H NMR (DMSO-d6): d 9.08 (s, 1H), 8.29
(d, J = 7.1 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.72 (t,
J = 8.0 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.36 (t,
J = 7.8 Hz, 2H), 7.22–7.15 (m, 4H), 6.97 (t, J = 7.4 Hz,
1H), 6.55–6.35 (m, 4H), 4.12 (d, J = 5.8 Hz, 2H), 3.53 (s,
2H); MS (ESI) m/z 541; HPLC purity 94.3% at
10.6 min; HRMS calcd for C32H24F3N2O3 [M+H]:
541.1734; found (ESI, [M+H]+): 541.1720.
1
(0.21 g, 95%); H NMR (CDCl3): d 9.08 (s, 1H), 8.15
(d, J = 7.0 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.61 (d,
J = 8.1 Hz, 2H), 7.55 (t, J = 7.9 Hz, 1H), 7.47 (t,
J = 7.3 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.35–7.25
(m, 4H), 7.06 (t, J = 7.8 Hz, 1H), 6.56 (d, J = 8.5 Hz,
1H), 6.51 (d, J = 7.5 Hz, 1H), 6.46 (s, 1H), 5.16 (d,
J = 4.4 Hz, 1H), 4.2 5(q, J = 7.1 Hz, 2H), 3.48 (d,
J = 7.0 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H); MS (ES) m/z
585.3.
5.25. Ethyl {4-[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-
4-yl]phenyl}amino) methyl]phenyl}(difluoro)acetate (9d)
Step 1: A mixture of (4-cyano-phenyl)-oxo-acetic acid
ethyl ester (1.00 g, 4.9 mmol) in dichloromethane
(20 mL) and (diethylamino)sulfur trifluoride (DAST)
(1.0 g, 6.2 mmol) was stirred at room temperature for
3 h. The mixture was poured into iced water and ex-
tracted with ethyl acetate. The organics were dried over
MgSO4 and concentrated to give crude (4-cyano-phe-
nyl)-difluoro-acetic acid ethyl ester, which was used for
the next reaction.
5.27. {4-[({3-[3-Methyl-8-(trifluoromethyl)quinolin-4-yl]-
phenyl}amino)methyl]-phenyl}acetic acid (17)
The title compound was prepared from 9a following the
procedure of step 2 for compound 16 (0.119 g, 85%); 1H
NMR (DMSO-d6): d 8.96 (s, 1H), 8.08 (d, J = 7.2 Hz,

B. Hu et al. / Bioorg. Med. Chem. 15 (2007) 3321–3333
3329
1H), 7.66 (d, J = 7.9 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H),
7.30–7.15 (m, 5H), 6.73 (d, J = 8.2 Hz, 1H), 6.50–6.38
(m, 4H), 4.23 (d, J = 5.6 Hz, 2H), 3.42 (s, 2H), 2.20 (s,
3H); HPLC purity 97.8% at 10.6 min.; HRMS calcd
for C26H22F3N2O2 [M+H]: 451.1628; found (ESI,
[M+H]+): 451.1609.
cedure of compound 16 as a pale yellow solid (0.034 g,
59%); H NMR (DMSO-d6): d 12.15 (br s, 1H), 9.02
1
(s, 1H), 8.20 (d, J = 6.6 Hz, 1H), 7.80 (d, J = 8.7 Hz,
1H), 7.70–7.60 (m, 2H), 7.54 (br s, 1H), 7.30 (d,
J = 8.1 Hz, 2H), 7.25–7.15 (m, 3H), 6.73 (dd, J = 8.2,
1.6 Hz, 1H), 6.60 (s, 1H), 6.55 (d, J = 7.5 Hz, 1H),
6.47 (t, J = 5.8 Hz, 1H), 4.25 (d, J = 4.2 Hz, 2H), 3.54
(s, 2H); MS (ESI) m/z 480; HPLC purity 100% at
8.9 min; HRMS calcd for C26H21F3N3O3 [M+H]:
480.1530; found (ESI, [M+H]+): 480.1516.
5.28. {4-[({3-[3-Phenyl-8-(trifluoromethyl)quinolin-4-yl]-
phenyl}amino)methyl]-phenyl}acetic acid (18)
The title compound was prepared from 9b following the
procedure of step 2 for compound 16 as a tan tacky solid
(0.021 g, 31%); mp 71–73 ꢁC; H NMR (DMSO-d6): d
5.32. [4-({[3-(3-Benzoyl-8-methylquinolin-4-yl)phenyl]-
amino}methyl)phenyl]acetic acid (22)
1
12.15 (br s, 1H), 9.05 (s, 1H), 8.19 (d, J = 7.1 Hz, 1H),
7.82 (d, J = 8.5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.30–
7.15 (m, 8H), 7.05 (t, J = 7.6 Hz, 1H), 6.61 (dd,
J = 8.2, 1.5 Hz, 1H), 6.45 (s, 1H), 6.40–6.30 (m, 3H),
4.17 (d, J = 6.1 Hz, 2H), 3.53 (s, 2H); MS (ESI) m/z
513; HPLC purity 90.2% at 11.0 min; HRMS calcd for
C31H24F3N2O2 [M+H]: 513.1784; found (ESI,
[M+H]+): 513.1795.
[4-({[3-(3-Benzoyl-8-methylquinolin-4-yl)phenyl]amino}-
methyl)phenyl] acetic acid methyl ester was prepared
from 8e and (4-formyl-phenyl)-acetic acid methyl ester12
according to the procedure of step 1 of compound 16.
Basic hydrolysis of the methyl ester following the proce-
dure of step 2 of compound 16 gave 22 as a yellow solid
1
(0.2 g, 82%); H NMR (DMSO-d6): d 12.15 (br s, 1H),
8.92(s, 1H), 7.72 (d, J = 6.8 Hz, 1H), 7.60–7.45 (m,
5H), 7.40–7.30 (m, 2H), 7.22–7.15 (m, 4H), 6.94 (t,
J = 7.6 Hz, 1H), 6.46–6.44 (m, 2H), 6.36–6.30 (m, 2H),
4.12 (d, J = 5.8 Hz, 2H), 3.54 (s, 2H), 2.80 (s, 3H); MS
(ESI) m/z 487; HPLC purity 100% at 10.5 min; HRMS
calcd for C32H27N2O3 [M+H]: 487.2016; found (ESI,
[M+H]+): 487.2029; Anal. Calcd for C32H26N2O3Æ
0.3H2O: C, 78.12; H, 5.45; N, 5.69. Found: C, 77.90;
H, 5.22; N, 5.56.
5.29. {4-[({3-[3-[Hydroxy(phenyl)methyl]-8-(trifluorometh-
yl)quinolin-4-yl]phenyl}amino)methyl]phenyl}acetic acid
(19)
Step 1: Phenyl[4-(3-aminophenyl)-8-(trifluoromethyl)-
quinolin-3-yl]methanone7 (0.39 g, 1.0 mmol) was dis-
solved in MeOH (20 mL), cooled to 0 ꢁC, and treated
with NaBH4 (0.060 g, 1.5 mmol). The ice bath was re-
moved and the reaction mixture was allowed to stir at
room temperature overnight. The MeOH was removed
and water was added to the resulting material, and the
mixture was extracted with ethyl acetate. The combined
extracts were dried over sodium sulfate and concentrated
in vacuo. The crude product was used for the next step.
5.33. [4-({[3-(3-Benzyl-8-methylquinolin-4-yl)phenyl]amino}-
methyl)phenyl]acetic acid (23)
A solution of [4-({[3-(3-benzoyl-8-methylquinolin-4-yl)-
phenyl]amino}methyl)phenyl] acetic acid methyl ester
(0.50 g, 1.00 mmol), hydrazine (0.50 mL), and KOH
(0.20 g, 3.6 mmol) in ethyleneglycol (8.0 ml) was heated
to 160 ꢁC. After 3 h, the reaction mixture was cooled,
poured into water mixture and acidified with acetic acid.
The solution was extracted with ethyl acetate, concen-
trated, and the residue was purified by reverse phase
semi-preparative HPLC to give 23 as a pale brown solid
(0.035 g, 37%); 1H NMR (DMSO-d6): d 12.27 (br s, 1H),
8.73 (s, 1H), 7.54 (d, J = 6.7 Hz, 1H), 7.34 (t, J = 8.4 Hz,
1H), 7.30–7.10 (m, 9H), 6.98 (d, J = 6.9 Hz, 2H), 6.72
(dd, J = 8.2, 1.5 Hz, 1H), 6.45–6.35 (m, 3H), 4.19 (d,
J = 5.7 Hz, 2H), 3.52 (s, 2H), 2.71 (s, 3H); MS (ES)
m/z 473.3; HPLC purity 100% at 11.1 min; HRMS calcd
for C32H29N2O2 [M+H]: 473.2224; found (ESI,
[M+H]+): 473.2224.
Step 2: Compound 19 was prepared according to the
procedure of step 2 of 16 as a ꢀ1:1 mixture of rotomers,
isolated as an off-white solid, (0.15 g, 28%); MS (ES) m/z
541.2; HRMS calcd for C32H26F3N2O3 [M+H]:
543.1890; found (ESI, [M+H]+): 543.1870.
5.30. {4-[({3-[3-Cyano-8-(trifluoromethyl)quinolin-4-yl]-
phenyl}amino)methyl]-phenyl}acetic acid (20)
The title compound was prepared from 8c and (4-for-
myl-phenyl)-acetic acid methyl ester12 following the pro-
cedure of compound 16 as a yellow solid (0.015 g, 21%);
1H NMR (DMSO-d6): d 12.15 (br s, 1H), 9.36 (s, 1H),
8.37 (d, J = 7.3 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.76
(t, J = 7.7 Hz, 1H), 7.35–7.27 (m, 3H), 7.22 (d,
J = 8.2 Hz, 2H), 6.84 (dd, J = 8.5, 1.6 Hz, 1H), 6.75–
6.60 (m, 3H), 4.29 (d, J = 5.9 Hz, 2H), 3.55 (s, 2H);
MS (ES) m/z 459.9; HPLC purity 100% at 10.2 min;
HRMS calcd for C26H19F3N3O2 [M+H]: 462.1424;
found (ESI, [M+H]+): 462.1408.
5.34. [4-({[3-(3-Benzoyl-8-fluoroquinolin-4-yl)phenyl]amino}-
methyl)phenyl]acetic acid (24)
The title compound was prepared from 8f and 3-(4-for-
myl-phenyl)-acetic acid methyl ester12 according to the
procedure of compound 16 as a yellow solid (0.029 g,
40%); 1H NMR (CDCl3): d 9.00 (s, 1H), 7.65 (d,
J = 7.7 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.50–7.40
(m, 3H), 7.34–7.24 (m, 5H), 7.05 (t, J = 7.6 Hz, 1H),
6.59 (d, J = 7.6 Hz, 1H), 6.51–6.49 (m, 3H), 4.20 (s,
2H), 3.67 (s, 2H); HPLC purity 99.5% at 9.9 min;
5.31. {4-[({3-[3-(Aminocarbonyl)-8-(trifluoromethyl)quin-
olin-4-yl]phenyl}-amino)methyl]phenyl}acetic acid (21)
The title compound was prepared from 8d and (4-for-
myl-phenyl)-acetic acid methyl ester12 following the pro-

3330
B. Hu et al. / Bioorg. Med. Chem. 15 (2007) 3321–3333
HRMS calcd for C31H24FN2O3 [M+H]: 491.1766; found
(ESI, [M+H]+): 491.1758.
541; HPLC purity 98.5 % at 10.4 min; HRMS calcd for
C32H24F3N2O3 [M+H]: 541.1734; found (ESI, [M+H]+):
541.1732.
5.35. [4-({[3-(3-Benzoylquinolin-4-yl)phenyl]amino}methyl)-
phenyl]acetic acid (25)
5.39. {4-[({3-[3-Benzoyl-8-(trifluoromethyl)quinolin-4-yl]-
phenyl}amino)methyl]-phenoxy} acetic acid (29)
The title compound was prepared from 8g and 3-(4-for-
myl-phenyl)-acetic acid methyl ester12 according to the
procedure of compound 16 as a yellow solid (0.016 g,
33%); 1H NMR (CDCl3): d 8.96 (s, 1H), 8.22 (d,
J = 8.3 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.79 (t, J =
6.9 Hz, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.52 (t, J = 7.3 Hz,
1H), 7.45 (t, J = 7.4 Hz, 1H), 7.32–7.20 (m, 5H), 7.05 (t,
J = 7.5 Hz, 1H), 6.61 (d, J = 7.4 Hz, 1H), 6.50–6.45 (m,
3H), 4.20 (s, 2H), 3.68 (s, 2H); MS (ES) m/z 471.1; HPLC
purity 100% at 9.9 min; HRMS calcd for C31H25N2O3
[M+H]: 473.1860; found (ESI, [M+H]+): 473.1867.
The title compound was prepared from [4-(3-amino-
phenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)meth-
anone7 and (4-formyl-phenoxy)-acetic acid according
to the procedure of step 1 of 16 as a pale brown solid
1
(0.095 g, 65%); H NMR (DMSO-d6): d 12.97 (s, 1H),
9.08 (s, 1H), 8.30 (d, J = 7.1 Hz, 1H), 7.98 (d,
J = 8.6 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.61 (d,
J = 7.5 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.42–7.30
(m, 2H), 7.15 (d, J = 8.3 Hz, 2H), 6.97 (t, J = 7.7 Hz,
1H), 6.85 (d, J = 8.2 Hz, 2H), 6.55–6.30 (m, 4H), 4.65
(s, 2H), 4.06 (s, 2H); MS (ESI) m/z 557; HPLC purity
100% at 10.0 min; HRMS calcd for C32H24F3N2O4
[M+H]: 557.1683; found (ESI, [M+H]+): 557.1681.
5.36. [4-({[3-(3-Benzoyl-8-chloroquinolin-4-yl)phenyl]amino}-
methyl)phenyl]acetic acid (26)
The title compound was prepared from 8h and (4-for-
myl-phenyl)-acetic acid methyl ester12 according to the
procedure of compound 16 as a yellow solid (0.18 g,
85%); H NMR (DMSO-d6): d 12.28 (s, 1H), 9.03 (s,
1H), 8.06 (d, J = 7.4 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H),
7.60–7.53 (m, 4H), 7.36 (t, J = 7.8 Hz, 2H), 7.21–7.15
(m, 4H), 6.96 (t, J = 8.1 Hz, 1H), 6.50–6.45 (m, 2H),
6.37 (d, J = 7.4 Hz, 2H), 4.12 (s, 2H), 3.54 (s, 2H); MS
(ESI) m/z 507; HPLC purity 100% at 11.1 min; HRMS
calcd for C31H24ClN2O3[M+H]: 507.1470; found (ESI,
[M+H]+): 507.1497.
5.40. (2E)-3-{4-[({3-[3-Benzoyl-8-(trifluoromethyl)quino-
lin-4-yl]phenyl}amino)-methyl]phenyl}acrylic acid (30)
The title compound was prepared from [4-(3-aminophe-
nyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone7
and 3-(4-formyl-phenyl)-acrylic acid according to the pro-
cedure of step 1 of 16 as a yellow solid (0.060 g, 41%); 1H
NMR (DMSO-d6): d 12.35 (br s, 1H), 9.07 (s, 1H), 8.29
(d, J = 6.9 Hz, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.70 (t,
J = 7.7 Hz, 1H), 7.68–7.52 (m, 6H), 7.37 (t, J = 7.5 Hz,
2H), 7.27 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 7.8 Hz, 1H),
6.55–6.45 (m, 4H), 6.41 (d, J = 7.6 Hz, 1H), 4.19 (br s,
2H); MS (ESI) m/z 553; HPLC purity 100% at 10.7 min;
HRMS calcd for C33H24F3N2O3 [M+H]: 553.1734; found
(ESI, [M+H]+): 553.1728.
5.37. [4-({[3-(3-Benzyl-8-chloroquinolin-4-yl)phenyl]amino}-
methyl)phenyl]acetic acid (27)
The title compound was prepared from [4-({[3-(3-ben-
zoyl-8-chloroquinolin-4-yl)phenyl]amino}methyl)phenyl]-
acetic acid methyl ester following the procedure of
5.41. 4-[({3-[3-Benzoyl-8-(trifluoromethyl)quinolin-4-yl]-
phenyl}amino)methyl]-benzoic acid (31)
1
compound 23 as a pale yellow solid (0.15 g, 51%); H
NMR (CDCl3): d 8.95 (s, 1H), 7.75 (d, J = 7.3 Hz, 1H),
7.46 (d, J = 8.4 Hz, 1H), 7.35–7.22 (m, 6H), 7.20–7.10
(m, 3H), 6.96 (d, J = 6.9 Hz, 2H), 6.72 (dd, J = 8.2,
1.4 Hz, 1H), 6.53 (d, J = 7.4 Hz, 1H), 6.34 (s, 1H), 4.24
(d, J = 4.4 Hz, 1H), 4.20 (d, J = 4.4 Hz, 1H), 3.98 (d,
J = 5.5 Hz, 1H), 3.93 (d, J = 5.5 Hz, 1H), 3.65 (s, 2 H);
MS (ESI) m/z 493; HPLC purity 100% at 11.1 min;
HRMS calcd for C31H24ClN2O2 [MÀH]: 491.1532; found
(ESI, [MÀH]À): 491.1519.
The title compound was prepared from [4-(3-amino-
phenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)meth-
anone7 and 4-formyl-benzoic acid methyl ester
according to the procedure of compound 16 as a yellow
1
solid (0.125 g, 63%); H NMR (DMSO-d6): d 9.07 (s,
1H), 8.29 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 7.5 Hz,
1H), 7.89 (d, J = 8.1 Hz, 2H), 7.70 (t, J = 7.8 Hz, 1H),
7.59 (d, J = 8.1 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H),
7.40–7.30 (m, 4H), 6.98 (t, J = 7.8 Hz, 1H), 6.55–6.46
(m, 3H), 6.41 (d, J = 7.4 Hz, 1H), 4.23 (t, J = 5.2 Hz,
2H); MS (ESI) m/z 527; HPLC purity 100% at 10.8
min, HRMS calcd for C31H22F3N2O3 [M+H]:
527.1577; found (ESI, [M+H]+): 527.1581. Anal. Calcd
for C31H21F3N2O3Æ0.75H2O: C, 68.94; H, 4.20; N, 5.19.
Found: C, 68.93; H, 3.81; N, 5.17.
5.38. {3-[({3-[3-Benzoyl-8-(trifluoromethyl)quinolin-4-yl]-
phenyl}amino)methyl]-phenyl} acetic acid (28)
The title compound was prepared from [4-(3-aminophe-
nyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone7
and (3-formyl-phenoxy)-acetic acid according to the pro-
cedure of step 1 of 16 as a pale brown solid (0.079 g,
94%); 1H NMR (CDCl3): d 9.08 (s, 1H), 8.14 (d,
J = 7.3 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.63 (d,
J = 8.3 Hz, 2H), 7.54 (t, J = 7.9 Hz, 1H), 7.46 (t,
J = 7.4 Hz, 1H), 7.35–7.15 (m, 6H), 7.06 (t, J = 7.8 Hz,
1H), 6.57 (d, J = 7.1 Hz, 1H), 6.53 (dd, J = 8.3, 1.6 Hz,
1H), 6.47 (s, 1H), 4.20 (s, 2H), 3.65 (s, 2H); MS (ESI) m/z
5.42. 2-{4-[({3-[3-Benzoyl-8-(trifluoromethyl)quinolin-4-
yl]phenyl}amino)-methyl]phenyl}propanoic acid (32)
The title compound was prepared from [4-(3-amino-
phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-meth-
anone7 and 2-(4-formyl-phenyl)-propionic acid methyl
ester12 according to the procedure of compound 16 as

B. Hu et al. / Bioorg. Med. Chem. 15 (2007) 3321–3333
3331
1
a yellow solid (0.10 g, 65%); H NMR (DMSO-d6): d
(0.060 g, 0.110 mmol) in concentrated ammonium
hydroxide (25 mL) and methanol (5.0 mL) was stirred
at room temperature for 2 d. Removal of solvent under
reduced pressure gave crude product that was purified
by reverse phase semi-preparative HPLC to give 36
(0.015 g, 25%) as a pale yellow solid; 1H NMR (CDCl3):
d 9.06 (s, 1H), 8.15 (d, J = 7.3 Hz, 1H), 8.08 (d,
J = 8.6 Hz, 1H), 7.60–7.51 (m, 3H), 7.47 (t, J = 7.4 Hz,
1H), 7.35–7.25 (m, 6H), 7.05 (t, J = 7.7 Hz, 1H), 6.57
(d, J = 7.5 Hz, 1H), 6.52 (dd, J = 7.4, 1.4 Hz, 1H), 6.43
(s, 1H), 5.60 (br s, 1H), 5.35 (br s, 1H), 4.21 (d,
J = 9.5 Hz, 1H), 4.17 (d, J = 9.5 Hz, 1H), 3.61 (s, 2H);
MS (ESI) m/z 540; HPLC purity 100% at 10.2 min;
HRMS calcd for C32H25F3N3O2 [M+H]: 540.1893;
found (ESI, [M+H]+): 540.1881.
12.35 (br s, 1H), 9.08 (s, 1H), 8.30 (d, J = 7.1 Hz, 1H),
7.99 (d, J = 8.7 Hz, 1H), 7.71 (t, J = 7.0 Hz, 1H), 7.60
(d, J = 8.1 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.35 (t,
J = 7.7 Hz, 2H), 7.30–7.15 (m, 1H), 6.98 (t, J = 7.4 Hz,
1H), 6.52–6.46 (m, 2H), 6.38 (d, J = 7.5 Hz, 2H), 4.11
(d, J = 5.8 Hz, 2H), 3.64 (q, J = 7.0 Hz, 1H), 1.35 (d,
J = 7.0 Hz, 3H); MS (ESI) m/z 555; HPLC purity
96.1% at 10.9 min; HRMS calcd for C33H26F3N2O3
[M+H]: 555.1890; found (ESI, [M+H]+): 555.1895.
5.43. 2-{4-[({3-[3-Benzoyl-8-(trifluoromethyl)quinolin-4-yl]-
phenyl}amino)methyl]-phenyl}-2-methylpropanoic acid (33)
The title compound was prepared from [4-(3-amino-phe-
nyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone7
and 2-(4-formyl-phenyl)-2-methyl-propionic acid methyl
ester13 according to the procedure of compound 16 as an
5.47. [4-(3-{[4-(2-Hydroxyethyl)benzyl]amino}phenyl)-8-
(trifluoromethyl) quinolin-3-yl](phenyl)methanone (37)
1
orange solid (0.16 g, 56%); H NMR (CDCl3): d 9.07 (s,
1H), 8.13 (d, J = 7.3 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H),
7.59 (d, J = 8.5 Hz, 2H), 7.53 (t, J = 7.7 Hz, 1H), 7.45 (t,
J = 7.4 Hz, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.32–7.22 (m,
3H), 7.21 (d, J = 8.1 Hz, 2H), 7.04 (t, J = 7.8 Hz, 1H),
6.56 (d, J = 7.4 Hz, 1H), 6.50 (dd, J = 8.3, 1.7 Hz, 1H),
6.44 (s, 1H), 4.20–4.10 (m, 2H), 1.58 (s, 6H); MS m/z
569; HPLC purity 100% at 11.1 min; HRMS calcd for
C34H28F3N2O3 [M+H]: 569.2047; found (ESI, [M+H]+):
569.2047.
The title compound was prepared from [4-(3-amino-
phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-meth-
anone7 and 4-(2-hydroxyethyl)-phenyl-carbaldehyde14
according to the procedure of compound 9a (0.044 g,
32%); 1H NMR (CDCl3): d 9.08 (s, 1H), 8.15 (d,
J = 6.9 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.58 (d,
J = 8.4 Hz, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.32–7.20 (m,
4H), 7.04 (t, J = 7.8 Hz, 1H), 6.56 (d, J = 6.5 Hz, 1H),
6.52 (dd, J = 8.2, 1.6 Hz, 1H), 6.44 (s, 1H), 4.17 (d,
J = 4.3 Hz, 1H), 4.14 (d, J = 4.3 Hz, 1H), 3.89 (t,
J = 6.3 Hz, 2H), 2.88 (t, J = 6.3 Hz, 2H); MS (ESI) m/z
527; HPLC purity 96.0% at 10.8 min; HRMS calcd for
C32H26F3N2O2 [M+H]: 527.1941; found (ESI,
[M+H]+): 527.1954.
5.44. {4-[({3-[3-Benzoyl-8-(trifluoromethyl)quinolin-4-yl]-
phenyl}amino)-methyl]phenyl} (hydroxy)acetic acid (34)
The title compound was prepared from 9c according to
the procedure of step 2 of 16 as a yellow solid (0.16 g,
1
76%); H NMR (DMSO-d6): d 9.07 (s, 1H), 8.28 (d,
5.48. [4-[3-(Benzylamino)phenyl]-8-(trifluoromethyl)quin-
olin-3-yl](phenyl)-methanone (38)
J = 7.3 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.72 (td,
J = 7.8, 2.1 Hz, 1H), 7.61 (d, J = 7.8 Hz, 2H), 7.52 (t,
J = 7.8 Hz, 1H), 7.40–7.30 (m, 4H), 7.19 (d,
J = 8.1 Hz, 2H), 6.97 (t, J = 7.5 Hz, 1H), 6.50–6.46 (m,
2H), 6.42–6.37 (m, 2H), 4.93 (s, 1H), 4.12 (d,
J = 5.7 Hz, 2H); MS (ES) m/z 555.2; HPLC purity
100% at 9.9 min; HRMS calcd for C32H24F3N2O4
[M+H]: 557.1683; found (ESI, [M+H]+): 557.1665.
The title compound was prepared from [4-(3-amino-
phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-meth-
anone7 and benzaldehyde according to the procedure of
compound 9a as a yellow solid (0.056 g, 46%); 1H NMR
(DMSO-d6): d 9.08 (s, 1H), 8.30 (d, J = 7.0 Hz, 1H), 7.99
(d, J = 7.7 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.60 (t,
J = 8.3 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.40–7.37 (m,
5H), 7.24 (d, J = 7.3 Hz, 2H), 6.98 (t, J = 7.6 Hz, 1H),
6.52–6.45 (m, 2H), 6.43–6.39 (m, 2H), 4.16 (br s, 2H);
MS (ESI) m/z 483; HPLC purity 100% at 11.4 min;
HRMS: calcd for C30H22F3N2O [M+H]: 483.1679;
found (ESI, [M+H]+): 483.1664.
5.45. {4-[({3-[3-Benzoyl-8-(trifluoromethyl)quinolin-4-yl]-
phenyl}amino)methyl]-phenyl} (difluoro)acetic acid (35)
The title compound was prepared from 9d according to
the procedure of step 2 of 16 as a pale yellow solid
(0.11 g, 52%); 1H NMR (CDCl3): d 9.07 (s, 1H), 8.29 (d,
J = 7.1 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.68 (t,
J = 7.7 Hz, 1H), 7.58 (d, J = 7.0 Hz, 2H), 7.57–7.52 (m,
4H), 7.39 (d, J = 8.2 Hz, 2H), 7.32 (t, J = 8.0 Hz, 2H),
6.98 (t, J = 7.8 Hz, 1H), 6.51–6.47 (m, 2H), 6.40 (d,
J = 7.4 Hz, 1H), 4.23 (br s, 2H); MS (ES) m/z575.2; HPLC
purity 100% at 9.6 min; HRMS: calcd for C32H22F5N2O3
[M+H]: 577.1545; found (ESI, [M+H]+): 577.1524.
5.49. [4-(3-{[4-(Hydroxymethyl)benzyl]amino}phenyl)-8-
(trifluoromethyl)-quinolin-3-yl](phenyl)methanone (39)
The title compound was prepared from 4-(3-amino-
phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-meth-
anone7 and 4-hydroxymethylbenzaldehyde according
1
to the procedure of compound 9a (0.014 g, 41%); H
NMR (CDCl3): d 9.08 (s, 1H), 8.15(d, J = 7.3 Hz, 1H),
8.06 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.55
(t, J = 8.0 Hz, 1H), 7.48 (t, J = 6.8 Hz, 1H), 7.35–7.25
(m, 7H), 7.06 (t, J = 8.0 Hz, 1H), 6.57 (d, J = 7.4 Hz,
1H), 6.52 (dd, J = 7.4, 1.5 Hz, 1H), 6.46 (s, 1H), 4.70
(s, 2H), 4.21 (s, 2H), 1.70 (br s, 1H); MS (ES) m/z
5.46. 2-{4-[({3-[3-Benzoyl-8-(trifluoromethyl)quinolin-4-yl]-
phenyl}amino)methyl]-phenyl} acetamide (36)
A mixture of methyl {4-[({3-[3-benzoyl-8-(trifluorom-
ethyl)quinolin-4-yl]phenyl}amino)methyl]phenyl}acetate7

3332
B. Hu et al. / Bioorg. Med. Chem. 15 (2007) 3321–3333
513.2; HPLC purity 100% at 10.6 min; HRMS calcd for
C31H24F3N2O2 [M+H]: 513.1784; found (ESI, [M+H]+):
513.1772.
lowed by 10% neutral buffered formalin. The aortas
were carefully excised down to the diaphragm and
placed in a vial containing 10% neutral buffered forma-
lin until time of analysis.
5.50. (5Z)-5-{4-[({3-[3-Benzoyl-8-(trifluoromethyl)quino-
lin-4-yl]phenyl} amino)methyl] benzylidene}-1,3-thiazoli-
dine-2,4-dione (40)
5.52.2. Quantification of atherosclerotic lesions. Quanti-
tative analysis of atherosclerotic lesion was performed
in the thoracic aorta by an observer blinded to the
experimental protocol. Images of the aorta used for
the analysis were processed using Adobe Photoshop
6.0 and Scion Imaging software (Scion Image Beta
4.02). The thoracic aorta was collected and adventitial
tissue was carefully removed. The aorta was then
opened longitudinally, pinned out on a black wax sur-
face, and stained for lipid deposition with Oil Red-O.
Images of the open luminal surface of the aorta were
captured using a dissecting microscope (Nikon SMZ
800) equipped with a digital video camera (Nikon
DXM 1200). Oil Red-O stained atherosclerotic plaque
area was quantified and expressed as a percentage of to-
tal luminal surface area of the aorta.
The title compound was prepared from [4-(3-amino-phe-
nyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone7
and 4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzalde-
hyde according to the procedure of compound 9a as a yel-
lowsolid(0.063 g, 52%);1H NMR(DMSO-d6):d 12.60(br
s, 1H), 9.07 (s, 1H), 8.29 (d, J = 7.2 Hz, 1H), 7.96 (d,
J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.68 (t, J = 7.8 Hz, 1H),
7.60–7.50 (m, 4H), 7.40–7.30 (m 4H), 6.98 (t, J = 7.8 Hz,
1H), 6.53 (t, J = 5.9 Hz, 1H), 6.50–6.40 (m, 2H), 6.41 (d,
J = 7.5 Hz, 1H), 4.30–4.15 (m, 2H); MS (ES) m/z 607.8;
HPLC purity 98.4% at 11.4 min; HRRMS calcd for
C34H23F3N3O3S [M+H]: 610.1407; found (ESI,
[M+H]+): 610.1407.
5.51. 5-{4-[({3-[3-Benzoyl-8-(trifluoromethyl)quinolin-4-
yl]phenyl}amino)methyl] benzylidene}-2-thioxo-1,3-thiaz-
olidin-4-one (41)
Acknowledgments
We thank the Wyeth Discovery Analytic Chemistry
Department for the analytical data. We also thank
Drs. Ron Magolda, Magid Abou-Gharbia, Steve Gar-
dell, and George Vlasuk for their support of this work.
The title compound was prepared from [4-(3-amino-phe-
nyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone7
and 4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-ben-
zaldehyde according to the procedure of compound 9a
as an orange solid (0.10 g, 63%); 1H NMR (DMSO-
d6): d 13.81 (br s, 1H), 9.07 (s, 1H), 8.29 (d,
J = 6.8 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.68 (t,
J = 8.1 Hz, 1H), 7.65–7.50 (m, 6H), 7.40–7.30 (m 4H),
6.98 (t, J = 7.8 Hz, 1H), 6.54 (t, J = 6.0 Hz, 1H), 6.50–
6.40 (m, 2H), 6.41 (d, J = 7.7 Hz, 1H), 4.29–4.17 (m,
2H); MS (ES) m/z 623.8; HPLC purity 94.9% at 11.9
min; HRMS calcd for C34H23F3N3O2S2 [M+H]:
626.1178; found (ESI, [M+H]+): 626.1185.
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