Synthesis and structure-activity relationship for new series of 4-phenoxyquinoline derivatives as specific inhibitors of platelet-derived growth factor receptor tyrosine kinase

Article abstract of DOI:10.1016/j.bmc.2003.08.020

We discovered a new series of 4-phenoxyquinoline derivatives as potent and selective inhibitors of the platelet-derived growth factor receptor (PDGFr) tyrosine kinase. We researched the highly potent and selective inhibitors on the basis of both PDGFr and epidermal growth factor receptor (EGFr) inhibitory activity. First, we found a compound, Ki6783 (1), which inhibited PDGFr autophosphorylation at 0.13 μM, but it did not inhibit EGFr autophosphorylation at 100 μM. After extensive explorations, we found the two desired compounds, Ki6896 (2) and Ki6945 (3), which are substituted by benzoyl and benzamide at the 4-position of the phenoxy group on 4-phenoxyquinoline, respectively. These inhibitory activities were 0.31 and 0.050 μM, respectively, but neither of them inhibited EGFr autophosphorylation at 100 μM. We further investigated the profile of both compounds toward various tyrosine and serine/threonine kinases. The three compounds specifically inhibited PDGFr rather than the other kinases.

Full text of DOI:10.1016/j.bmc.2003.08.020

Bioorganic & Medicinal Chemistry 11 (2003) 5117–5133
Synthesis and Structure–Activity Relationship for New Series of
4-Phenoxyquinoline Derivatives as Specific Inhibitors of
Platelet-Derived Growth Factor Receptor Tyrosine Kinase
Kazuo Kubo,* Shin-ichi Ohyama, Toshiyuki Shimizu, Atsuya Takami, Hideko Murooka,
Tsuyoshi Nishitoba, Shinichiro Kato, Mikio Yagi, Yoshiko Kobayashi, Noriko Iinuma,
Toshiyuki Isoe, Kazuhide Nakamura, Hiroshi Iijima, Tatsushi Osawa and Toshio Izawa
Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd., 3 Miyahara-cho, Takasaki-shi, Gunma 370-1295, Japan
Received 7 May 2002; accepted 19 August 2003
Abstract—We discovered a new series of 4-phenoxyquinoline derivatives as potent and selective inhibitors of the platelet-derived
growth factor receptor (PDGFr) tyrosine kinase. We researched the highly potent and selective inhibitors on the basis of both
PDGFr and epidermal growth factor receptor (EGFr) inhibitory activity. First, we found a compound, Ki6783 (1), which inhibited
PDGFr autophosphorylation at 0.13 mM, but it did not inhibit EGFr autophosphorylation at 100 mM. After extensive explorations,
we found the two desired compounds, Ki6896 (2) and Ki6945 (3), which are substituted by benzoyl and benzamide at the 4-position
of the phenoxy group on 4-phenoxyquinoline, respectively. These inhibitory activities were 0.31 and 0.050 mM, respectively, but
neither of them inhibited EGFr autophosphorylation at 100 mM. We further investigated the profile of both compounds toward
various tyrosine and serine/threonine kinases. The three compounds specifically inhibited PDGFr rather than the other kinases.
# 2003 Elsevier Ltd. All rights reserved.
Introduction
important roles as already described, specific inhibitor
toward a target kinase would be good for medicine. In
general, it seemed difficult to obtain specific inhibitors
for respective tyrosine kinases, because the three-
dimensional structure of kinase domain is highly con-
served.4 In fact, the first generation of synthetic tyrosine
kinase inhibitors, known as tyrphostins, gave wide
inhibitory activities against various receptor kinases.5
However, a potent and highly selective inhibitor of
EGFr tyrosine kinase was reported in 1994,6 many spe-
cific inhibitors of EGFr, PDGFr, and so on have
subsequently emerged.7
It has been elucidated that the intracellular signaling
pathway of biological events, such as cell growth, dif-
ferentiation and migration, are modulated by a variety
of transmembrane growth factor receptors and their
cytoplasmic protein tyrosine kinases. It has also been
clarified that abnormal signaling via tyrosine kinases
causes a number of diseases.1
PDGF receptors have transmembrane protein tyrosine
kinase domains, and participate in various physiological
processes like wound healing.2 An abnormal signal
transduction of PDGFr is known to play a central role
in the etiology of certain adverse pathophysiological
situations, such as cancer, atherosclerosis, restenosis,
pulmonary fibrosis, glomerulonephritis, and rheuma-
toid arthritis.3 Therefore, PDGFr tyrosine kinase inhi-
bitors are believed to be useful for the treatment of
many kinds of diseases. Because kinases play many
Until now, 3-substituted quinolines,8 3-substituted qui-
noxalines,9 2-phenylaminopyrimidines,10 3-substituted
indolinones11 and piperazinyl quinazolines12 were repor-
ted as small molecule PDGFr inhibitors. Recently, a
novel series of 4-phenoxyquinoline derivatives was found
in the screening with in-house compounds (Fig. 1).13,14 In
this report, we present the synthesis and structure–
activity relationships of 4-phenoxyquinoline derivatives
toward PDGFr and EGFr. We also report the inhibi-
tory effects of the selected compounds against several
kinases in order to determine the kinase selectivity.
*Corresponding author. Tel.: +81-27-346-9742; fax: +81-27-346-
8751; e-mail: ka-kubo@kirin.co.jp
0968-0896/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2003.08.020

5118
K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
Synthesis
the presence of palladium catalyst (method B).16 Pro-
tection of bromophenol (12) with the methoxymethyl
(MOM) group in ether obtained 13. This was followed
by the addition of magnesium ribbon and a catalytic
amount of iodine as an initiator in THF under reflux
that gave the corresponding Grignard reagent in situ.
The general synthetic route of the 4-phenoxyquinoline
derivatives was summarized in Scheme 1. 4-Chloro-6,7-
dimethoxyquinoline (7) synthesized from 3,4-dimethoxy-
aniline (4) was reacted with various substituted phenols
at 150–190 ꢀC to give 4-phenoxyquinoline derivatives (8)
in isolated yields of 5–100%. Most of the acylphenols
(11) were prepared by two methods as shown in Scheme
2. One was the Friedel–Clafts acylation using lantha-
nide triflate as the catalyst (method A).15 The reaction
of anisole (9) with various acid chlorides using a cata-
lytic amount of Yb(OTf)3 or Sc(OTf)3 at 60 ꢀC in nitro-
methane gave 4-acylated anisoles (10) in good yields.
Removal of the methyl group of 4 with NaSMe in
refluxing DMF or with BBr3 in ice-cooled CH2Cl2 gave
11 in excellent yields. Another method was the cross
coupling reaction of arylstannane with acyl chlorides in
n
The addition of Bu3SnCl to the Grignard reagent then
produced arylstannane 14. 14 was coupled with acid
chlorides by using Pd(PPh3)2Cl2 as a catalyst in CHCl3
under reflux. Subsequent acid treatment gave the corre-
sponding 11 in 36–74% yields. Finally, 11 was reacted
with 7 at the same method as described above to give
the desired 8. 11 was also coupling with 7 using 4-
dimethylaminopyridine in xylene under reflux to give 8
in isolated yields of 31–77%. 4-Dimethylaminopyridine
was the most effective base that we used to accelerate
the coupling reaction. The amide substituted 4-phenoxy-
quinoline derivatives (17) were synthesized as shown in
Figure 1. Representative structures of 4-phenoxyquinoline derivatives. A, B, C and D represents, the names of the ring system in this report.
Scheme 1. Synthesis of 4-phenoxyquinoline derivatives. Reagents and conditions: (a) diethyl ethoxymethylenemalonate, 120 ꢀC; (b) diphenylether,
280 ꢀC; (c) 10% aq NaOH/MeOH, reflux; (d) diphenylether, 280 ꢀC; (e) POCl3, reflux; (f) 150–190 ꢀC; (g) DMAP, xylene, reflux.
Scheme 2. Synthesis of 4-acylphenols. Reagents and conditions: (a) RCOCl, cat. Yb(OTf)3 or Sc(OTf)3, MeNO2, 60 ꢀC; (b) NaSMe, DMF, reflux;
(c) BBr3, THF, CHCl3, 0 ꢀC; (c) methoxymethylchloride, NaH, DMF, 0 ꢀC; (d) (1) Mg, cat. I2, THF, reflux to rt; (2) nBu3SnCl, THF, rt; (e) RCOCl,
cat. PdCl2 (PPh3)2, CHCl3, reflux.

K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
5119
Scheme 3. Synthesis of amide group substituted 4-phenoxyquinoline derivatives. Reagents and conditions: (a) nitrophenol, ethyleneglycol dime-
thylether, 180 ꢀC; (b) palladium hydroxide on carbon, H2, Et3N, DMF, rt; (c) RCOCl, Et3N, CH2Cl2, rt; (d) RCOOH, 1-ethyl-3-(30-
dimethylaminopropyl)carbodiimide, DMF, rt; (e) MeI, NaH, DMF, 0 ꢀC.
Table 1. Inhibitory activity of 4-phenoxyquinoline derivatives for
PDGFr and EGFr
Table 2. Inhibitory activity of acyl substituted 4-phenoxyquinoline
derivatives for PDGFr and EGFr
a
No.
R
IC50 (mM)
PDGFr
EGFr
14
a
No.
R
IC50 (mM)
8q
48
PDGFr
EGFr
8a
8b
8c
8d
8e
H
0.76
0.60
0.44
1.9
0.56
15
15
0.70
6.9
0.56
0.048
1.5
8.4
0.20
7.7
1.7
0.20
4.4
50
92
18
44
2-OMe
3-OMe
4-OMe
3-COMe
4-COMe
3-COOMe
3-NO2
3-Me
3-OH
4-OH
3-F
3-Br
4-Br
2-NH2
3-NH2
4-NH2
2,3-(OMe)2
2,6-(OMe)2
3,4-(OMe)2
3,5-(OMe)2
8r
37
89
>100
>100
>100
35
8f
8g
15b
8h
8i
8j
8k
8l
8m
16a
16b
16c
8n
8o
1
14
19
16
24
8s
8t
8u
8v
7.1
50
16
2.5
1.5
20
<10
40
>100
>100
81
0.48
>100
>100
69
0.13
5.5
>100
49
8p
40
aIC50 values were averaged values determined by at least two inde-
pendent experiments.
aIC50 values were averaged values determined by at least two inde-
pendent experiments.
Scheme 3. 7 was added to nitrophenols in diethyle-
neglycol dimethyl ether at 180 ꢀC to give the 4-nitro-
phenoxyquinoline (15). 15 was reduced by palladium
hydroxide on carbon under hydrogen and triethylamine
in DMF at room temperature to produce aminophe-
noxyquinoline 16. The desired quinoline 17 was
obtained in good yields by condensation of the amine 16
with various benzoic acids or benzoyl chlorides in the
usual manner. The amide 18 was prepared by N-
methylation of 17. Amide 19 was prepared by a con-
densation reaction between the corresponding car-
boxylic acid and 4-tert-butylaniline.9

5120
K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
Table 4. Inhibitory activity of amide substituted 4-phenoxyquinoline
derivatives for PDGFr and EGFr
Table 3. Inhibitory activity of benzoyl substituted 4-phenox-
yquinoline derivatives for PDGFr and EGFr
No.
R
IC50a (mM)
PDGFr
EGFr
a
No.
R
IC50 (mM)
3
0.050
>100
PDGFr
EGFr
8s
8w
8x
8y
H
2-Me
3-Me
4-Me
2-CF3
3-CF3
4-CF3
3-F
4-F
4-Cl
3,4-Cl2
4-Br
4-I
4-NO2
4-OCF3
4-CN
4-nBu
4-tBu
4-Ph
7.1
4.3
2.6
1.7
7.2
3.9
0.85
2.5
6.9
3.9
3.5
2.4
0.77
0.89
1.0
50
43
95
>100
21
>100
>100
28
75
>100
31
>100
>100
>100
>100
>100
>100
>100
>100
19
1.8
30
8z
8aa
8ab
8ac
8ad
8ae
8af
8ag
8ah
8ai
8aj
8ak
8al
2
18
0.33
0.044
6.0
17a
0.65
4.2
0.15
0.31
0.90
aIC50 values were averaged values determined by at least two inde-
pendent experiments.
8am
aIC50 values were averaged values determined by at least two inde-
pendent experiments.
Next, we surveyed the effect of substituents on the ben-
zoyl group of the benzoyl substituted 4-phenoxy-
quinolines (2, 8s, 8w–8am). These results are shown in
Table 3. The 4-substituted phenyl (ring D) enhanced the
inhibitory activity against PDGFr and reduced the
activity against EGFr as compared with the corre-
sponding 2- and 3-substituted compounds (8w–8y and
8z–8ab). We observed that the greater hydrophobicity at
the 4-substituent tended to provide greater inhibitory
activity toward PDGFr (8s<8y<8ab<8al and 2), but
the shape of butyl group did not affect the activity. No
effects on the 4-substituents were shown against EGFr.
These observations suggest that PDGFr has a high affi-
nity bind site for the hydrophobic substituent at the 4
position of the ring D.
Results and Discussion
The inhibitory activity of the 4-phenoxyquinolines was
measured by PDGF-BB stimulated autophos-
phorylation of the PDGFbr in rat glomerular mesangial
cells and also measured by EGF-stimulated autopho-
sphorylation of the EGFr in A431 cells as a reference of
selectivity as previously discribed.14 These result are
summarized in Tables 1–5.
The compounds substituted by typical functional
groups on the phenoxy ring (ring C) were estimated
(Table 1). We thought that the best compound in Table 1
was 1 in terms of its potent inhibitory activity and high
selectivity toward PDGFr. On the other hand, it seemed
that the carbonyl group reduced the inhibitory activity
for EGFr as 8e, 8f and 8g. Accordingly, we developed the
acyl group substituted 4-phenoxy-quinoline derivatives.
An amide moiety is sometimes used as a bioisoster
instead of the carbonyl group.17 Therefore, in order to
explore the importance of carbonyl group of 2, the cor-
responding amide group substituted 4-phenoxyquinolines
(3, 17a, 18 and 19) were investigated (Table 4). For-
tunately, 3 showed about 6 times more active than 2
toward PDGFr, and had high selectivity for PDGFr
over EGFr. However, its reverse amide 19 was 36 times
less active than 3, and showed a loss of selectivity. The
N-methylation of 3, compound 18, was decreased the
activity for PDGFr. The 3-substituted derivative (17a)
showed a similar inhibition to 3 toward PDGFr, but
lost selectivity toward EGFr. These results indicated
that configuration of the amide group was important for
the inhibitory activity and kinase selectivity. In this series,
3 seemed to be a most favorable form for inhibitory
activity and selectivity against PDGFr.
Table 2 shows the PDGFr and EGFr inhibitory activ-
ities of the acyl group substituted 4-phenoxyquinolines
and their analogues. In case of the benzoyl group sub-
stituted derivatives, the activity of PDGFr inhibition
decreased as compared with 8e, but still retained a good
potency toward para-substituted compound (8s).
Though the introduction of benzoyl or thiophene-
carbonyl moieties on the phenoxy ring greatly dimin-
ished their selectivity between PDGFr and EGFr (8q,
8r, 8s and 8t), the furoyl derivative still had good
selectivity (8u).

K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
5121
Table 5. Inhibitory activity of various amide substituted 4-phenoxyquinoline derivatives for PDGFr and EGFr
a
a
No.
R
IC50 (mM)
No.
R
IC50 (mM)
PDGFr
EGFr
48
PDGFr
EGFr
17b
17c
3
0.18
0.20
0.050
0.070
0.15
0.33
0.42
17h
17i
2.0
>100
93
>100
>100
>100
>100
>100
3.6
>100
>100
>100
>100
>100
>100
17j
1.8
17d
17e
17f
17g
17k
17l
5.1
Me
2.3
17m
17n
0.53
0.53
aIC50 values were averaged values determined by at least two independent experiments.
Table 6. Inhibitory activities for various kinases using intact-cell assays
a
No.
IC50 (mM)
PDGFr
EGFr
bFGFr
Insulinbr
1 (Ki6783)
2 (Ki6896)
3 (Ki6945)
CGP 53716
0.13
0.31
0.050
0.17
>100
>100
>100
>100
>100
3.8
>100
>100
>100
>100
>100
>100
aIC50 values were averaged values determined by at least two independent experiments.
We examined the effect of various substituted benza-
mides and other amide derivatives as shown in Table 5.
The benzamide derivatives showed potent inhibitory
activity toward PDGFr, but most of the compounds
were found to be inactive toward EGFr. Substitution of
more hydrophobic group at the 4-position resulted in a
moderate increase of inhibitory activity (3 and 17d) as
compared to the other substituents in the same way as the
benzoyl substituted 4-phenoxyquinolines. Alkyl amides
showed good inhibitory activity, but the heteroaromatic
Table 7. Inhibitory activities for various kinases by cell-free assays
IC50a (mM)
No.
PDGFbr EGFr c-Src PKA PKCa MAPK MEK1
1 (Ki6783)
2 (Ki6896)
3 (Ki6945)
0.03
0.59
0.64
>10 >10 >10 >10
>100 >10 >10 >10
>100 >10 >10 >10
>10
>10
>10
>10
>10
>10
aIC50 values were averaged values determined by at least two inde-
pendent experiments.

5122
K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
amides (17j and 17k) had lower activity toward PDGFr
than the benzamide derivatives.
(500 MHz). Chemical shifts (d) are given in ppm down-
field from tetramethylsilane as the internal standard.
MS spectra were collected with a Platform–LC (micro-
mass). Elemental analysis and high-resolution mass
spectra were performed by Toray Research Center, Inc.
Elemental analysis results are within ꢁ0.4% of the
theoretical values. Column chromatography was carried
out on silica gel 60 (70–230 mesh, Kanto Chemical) or
preparative thin layer chromatography (PLC plates;
Merck).
Finally, we evaluated three selected compounds, 1, 2
and 3, toward various tyrosine kinases by intact-cell
assays (Table 6), and tyrosine and serine/threonine
kinases by cell-free assays (Table 7).15 CGP 53716
known as one of the most specific inhibitors for PDGFr
was used the positive control.10 In intact-cell assays, 2
showed good potency toward PDGFr, weak potency
toward bFGFr, and no activity against EGFr and the
insulinb receptor. On the other hand, 1, 3 and CGP
53716 showed potent activity toward PDGFr but did
not show inhibitory activities toward the other three
kinases. In the cell-free assays, all of the compounds
also showed potent activity toward PDGFbr but did
not show potent activities for EGFr, c-Src, PKA, PKC,
MAPK and MEK1. Therefore, these compounds would
be significant specific inhibitors toward PDGFr. More-
over, since these three compounds showed similar inhi-
bitory activity toward PDGFr for both intact-cell assay
and cell-free assay, the permeability of them into the cell
membrane might be enough for further development.
Ethyl 6,7-dimethoxy-4-oxo-1,4-dihydro-3-quinolinecar-
boxylate (5). A mixture of 3,4-dimethoxyaniline (3.00 g,
19.6 mmol) and diethy ethoxymethylenemalonate (5.08
g, 23.50 mmol) was stirred at 120 ꢀC for 1 h. Diphenyl-
ether (30 mL) was then added and stirred at 280 ꢀC for 1
h. The reaction mixture was purified by column chro-
matography eluting with CHCl3/MeOH (100/1–10/1) to
obtain 3.58 g of 5 (66%). 1H NMR (DMSO-d6,
400 MHz): d 1.28 (t, J=7.1 Hz, 3H), 3.85 (s, 3H), 3.88
(s, 3H), 4.20 (q, J=7.1 Hz, 2H), 7.05 (s, 1H), 7.52 (s,
1H), 8.43 (d, J=6.6 Hz, 1H), 12.06 (d, J=6.6 Hz, 1H);
MS (ESI) m/z 278 (M++1).
It is interesting that the compounds which substituted
by carbonyl groups such as benzoyl and benzamide at
the 4-position on the C ring show potent and selective
biological activities, accordingly, we have been in inves-
tigation the docking model of 4-phenoxyquinoines and
some receptors to investigate the binding mode between
the compounds and the receptors. Furthermore, the
advanced research for new types of C ring substituted 4-
phenoxyquinolines has continuously carried out to
improve the inhibitory activity and some physicochemical
properties.
6,7-Dimethoxy-4-quinolone (6). To a solution of 5 (3.28
g, 11.84 mmol) in MeOH (30 mL) was added 10%
aqueous NaOH (45 mL) and heated under reflux for 1
h. The reaction mixture was acidified with 10% aqueous
HCl. The resulting solid was collected by filtration and
washed with CHCl3/MeOH (200 mL/40 mL) to obtain
2.85 g of crude 6,7-dimethoxy-4-oxo-1,4-dihydro-3-qui-
nolinecarboxylic acid. Then, a mixture of the acid (2.85
g) and diphenylether (90 mL) was stirred at 280 ꢀC for 1
h. The reaction mixture was purified by column chro-
matography eluting with CHCl3/MeOH (100/1–10/1) to
obtain 2.3 g of 6 (91%). 1H NMR (DMSO-d6,
400 MHz): d 3.82 (s, 3H), 3.86 (s, 3H), 5.95 (d, J=4.6
Hz, 1H), 6.69 (s, 1H), 7.43 (s, 1H), 7.78 (d, J=4.6 Hz,
1H), 8.13 (s, 1H); MS (ESI) m/z 206 (M++1).
Conclusion
We discovered a new series of 4-phenoxyquinoline deri-
vatives as potent and selective inhibitors of PDGFr tyr-
osine kinase. In particular, it was revealed that the
compounds with a benzoyl group and benzamide group
at the 4-position of the C ring showed high selectivity
for PDGFr over EGFr. Typical compounds 1 (Ki6783),
2 (Ki6896) and 3 (Ki6945) also showed high selectivity
for PDGFr over various tyrosine and serine/threoronine
kinases in intact-cell or cell-free assays.
4-Chloro-6,7-Dimethoxyquinoline (7). A mixture of 6
(2.13 g, 10.39 mmol) and POCl3 (1.45 mL, 15.59 mmol)
was heated under reflux for 0.5 h. The reaction mixture
was concentrated and extracted with CHCl3/MeOH (40
mL/10 mL). The organic layer was washed with 5%
aqueous NaOH and brine. The solution was dried over
Na2SO4 and concentrated. The resulting residue was
purified by column chromatography eluting with
1
CHCl3/MeOH (50/1) to obtain 1.98 g of 7 (8%). H
The 4-phenoxyquinolines are expected to be useful
pharmaceuticals with reduced side effects. We have
already reported that 2 improved glomerulosclerosis in
vivo without significant toxicity.18
NMR (CDCl3, 400 MHz): d 4.05 (s, 3H), 4.07 (s, 3H),
7.36 (d, J=4.9 Hz, 1H), 7.42 (s, 1H), 7.43 (s, 1H), 8.59
(d, J=4.6 Hz, 1H); MS (ESI) m/z 224 (M++1).
6,7-Dimethoxy-4-(3,4-dimethoxyphenoxy)quinoline
(1:
Ki6783). A mixture of 7 (200 mg, 0.9 mmol) and 3,4-
dimethoxyphenol (410 mg, 2.7 mmol) was heated at
170 ꢀC for 20 min. The reaction mixture was cooled and
treated with saturated NaHCO3 (10 mL). The solution
was extracted with AcOEt (10 mL). The organic layer
was washed with brine (10 mL), dried over Na2SO4 and
concentrated. The residue was purified by column
chromatography on silica gel eluting with hexane/ace-
tone (4/1) and CHCl3/MeOH (50/1) to obtain 200 mg
Experimental
General methods
Melting points were determined on a Yanaco micro-
1
melting point apparatus and are uncorrected. H NMR
spectra were recorded on a JEOL EX-90A (90 MHz),
JEOL JNM-LA400 (400 MHz) or JEOL JNM-A500

K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
5123
(62%). Mp: 188–189 ꢀC; 1H NMR (CDCl3, 500 MHz): d
3.87 (s, 3H), 3.93 (s, 3H), 4.05 (s, 3H), 4.06 (s, 3H), 6.45
(d, J=4.9 Hz, 1H), 6.75 (dd, J=2.4, 9.2 Hz, 1H), 6.75
(d, J=2.4 Hz, 1H), 6.93 (d, J=9.2 Hz, 1H), 7.42 (s,
1H), 7.57 (s, 1H), 8.48 (d, J=4.9 Hz, 1H); MS (FD) m/z
6,7-Dimethoxy-4-(4-acetylphenoxy)quinoline (8f). Com-
pound 8f was prepared as described for 1, except using
4-acetylyphenol. Purification was performed by column
chromatography on silica gel eluting with hexane/ace-
tone (4/1) and CHCl3/MeOH (50/1) to obtain 120 mg
(83%). Mp: 155–156 ꢀC; 1H NMR (CDCl3, 400 MHz): d
2.65 (s, 3H), 4.05 (s, 3H), 4.10 (s, 3H), 6.64 (d, J=5.6
Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.51 (s, 1H), 7.67 (s,
1H), 8.10 (d, J=8.8 Hz, 2H), 8.46 (d, J=5.6 Hz, 1H); MS
(ESI) m/z 324 (M++1). Anal. (C19H17NO4) C, H, N.
+
.
341 (M ). Anal. (C19H19NO5 H2O) C, H, N.
6,7-Dimethoxy-4-phenoxyquinoline (8a). Compound 8a
was prepared as described for 1, except using phenol.
Purified by column chromatography on silica gel eluting
with hexane/acetone (4/1) and CHCl3/MeOH (50/1) to
obtain 450 mg (97%). Mp: 130–131 ꢀC; 1H NMR
(CDCl3, 400MHz): d 4.08 (s, 3H), 4.12 (s, 3H), 6.59 (d,
J=6.1 Hz, 1H), 7.22 (d, J=7.6 Hz, 2H), 7.38 (t, J=7.6
Hz, 1H), 7.53 (t, J=7.6 Hz, 2H), 7.62 (s, 1H), 7.84 (s,
1H), 8.48 (d, J=6.1 Hz, 1H); MS (ESI) m/z 282
(M++1). Anal. (C17H15NO3) C, H, N.
Methyl 3-[(6,7-Dimethoxy-4-quinolyl)oxy]benzoate (8g).
Compound 8g was prepared as described for 1, except
using methyl 3-hydroxybenzoate. Purification was per-
formed by column chromatography on silica gel eluting
with hexane/acetone (4/1) and CHCl3/MeOH (50/1) to
1
obtain 460 mg (100%). H NMR (CDCl3, 400 MHz): d
3.93 (s, 3H), 4.04 (s, 3H), 4.06 (s, 3H), 6.47 (d, J=5.1
Hz, 1H), 7.40 (dd, J=1.5, 8.1 Hz, 1H), 7.44 (s, 1H), 7.54
(s, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.86 (t, J=2.0 Hz, 1H),
6,7-Dimethoxy-4-(2-methoxyphenoxy)quinoline
(8b).
Compound 8b was prepared as described for 1, except
using 2-methoxyphenol. Purification was performed by
column chromatography on silica gel eluting with hexane/
acetone (4/1) and CHCl3/MeOH (50/1) to obtain 76 mg
(54%). 1H NMR (CDCl3, 90MHz): d 3.78 (s, 3H), 4.05 (s,
3H), 4.05 (s, 3H), 6.31 (d, J=5.3 Hz, 1H), 6.9–7.4 (m, 4H),
7.42 (s, 1H), 7.63 (s, 1H), 8.45 (d, J=5.3 Hz, 1H); MS
(ESI) m/z 312 (M++1). Anal. (C18H17NO4) C, H, N.
7.97 (d, J=7.8 Hz, 1H), 8.51 (d, J=5.1 Hz, 1H); MS
+
.
(ESI) m/z 340 (M +1). Anal. (C19H17NO5 1.7H2O) C,
H; N: calcd, 3.79, found, 3.25.
6,7-Dimethoxy-4-(3-methylphenoxy)quinoline (8h). Com-
pound 8h was prepared as described for 1, except using
3-methylphenol. Purification was performed by column
chromatography on silica gel eluting with hexane/ace-
tone (4/1) and CHCl3/MeOH (50/1) to obtain 108 mg
(82%). 1H NMR (CDCl3, 400 MHz): d 2.41 (s, 3H), 4.06
(s, 3H), 4.08 (s, 3H), 6.52 (d, J=5.6 Hz, 1H), 6.99–7.02
(m, 2H), 7.13 (d, J=7.3 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H),
7.58 (s, 1H), 7.58 (s, 1H), 8.48 (d, J=5.6 Hz, 1H); MS
(ESI) m/z 296 (M++1). Anal. (C18H17NO3) C, H, N.
6,7-Dimethoxy-4-(3-methoxyphenoxy)quinoline
(8c).
Compound 8c was prepared as described for 1, except
using 3-methoxyphenol. Purification was performed by
column chromatography on silica gel eluting with hex-
ane/acetone (4/1) and CHCl3/MeOH (50/1) to obtain 29
mg (52%). Mp: 124–125 ꢀC; 1H NMR (CDCl3,
90 MHz): d 3.82 (s, 3H), 4.04 (s, 3H), 4.05 (s, 3H), 6.53
(d, J=5.3 Hz, 1H), 6.7–6.9 (m, 3H), 7.35 (t, J=7.0 Hz,
1H), 7.43 (s, 1H), 7.54 (s, 1H), 8.50 (d, J=5.3 Hz, 1H);
MS (FD) m/z 311 (M+); HRMS (ESI) (C18H18NO4)
(M+H+) calcd 312.1236, found 312.1255.
6,7-Dimethoxy-4-(3-hydroxyphenoxy)quinoline (8i). Pre-
paration as described for 1 starting from 3-acetoxy-
phenol obtained (173 mg, 0.51 mmol) of 6,7-
Dimethoxy-4-(3-acetoxyphenoxy)quinoline (38%); 1H
NMR (CDCl3, 400 MHz): d 2.30 (s, 3H), 4.04 (s, 3H),
4.05 (s, 3H), 6.58 (d, J=5.4 Hz, 1H), 6.98 (t, J=2.2 Hz,
1H), 7.02 (ddd, J=1.0, 2.2, 8.1 Hz, 1H), 7.07 (ddd,
J=1.0, 2.2, 8.1 Hz, 1H), 7.44 (s, 1H), 7.47 (d, J=8.1
Hz, 1H), 7.51 (s, 1H), 8.52 (d, J=5.4 Hz, 1H); MS (ESI)
m/z 340 (M++1). To a solution of 6,7-dimethoxy-4-(3-
acetoxyphenoxy)quinoline (173 mg, 0.51 mmol) in
CHCl3/MeOH (3 mL/3 mL) was added 10% aqueous
K2CO3 (2 mL) and stirred at room temperature for 3 h.
The reaction mixture was neutralized with 10% aqueous
HCl. The resulting solid was collected by filtration and
washed with CHCl3 to obtain 469 mg of 8i (92%). mp:
>231 ꢀC (decomposition); 1H NMR (DMSO-d6,
400 MHz): d 3.30 (s, 3H), 3.32 (s, 3H), 6.37 (d, J=5.4
Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz,
2H), 7.37 (s, 1H), 7.51 (s, 1H), 8.44 (d, J=5.1 Hz, 1H),
9.55 (s, 1H); MS (ESI) m/z 298 (M++1). Anal.
(C17H15NO4) C, H, N.
6,7-Dimethoxy-4-(4-methoxyphenoxy)quinoline
(8d).
Compound 8d was prepared as described for 1, except
using 4-methoxyphenol. Purification was performed by
column chromatography on silica gel eluting with hex-
ane/acetone (4/1) and CHCl3/MeOH (50/1) to obtain 2.2
g (88%). Mp: 126–127 ꢀC; 1H NMR (CDCl3, 90 MHz): d
3.85 (s, 3H), 4.05, (s, 3H), 4.05 (s, 3H), 6.41 (d, J=5.3 Hz,
1H), 6.97 (d, J=9.5 Hz, 2H), 7.14 (d, J=9.5 Hz, 2H),
7.43 (s, 1H), 7.58 (s, 1H), 8.46 (d, J=5.3 Hz, 1H); MS
(ESI) m/z 312 (M++1). Anal. (C18H17NO4) C, H, N.
6,7-Dimethoxy-4-(3-acetylphenoxy)quinoline (8e). Com-
pound 8e was prepared as described for 1, except using
3-acetylyphenol. Purification was performed by column
chromatography on silica gel eluting with hexane/ace-
tone (4/1) and CHCl3/MeOH (50/1) to obtain 91 mg
(63%). Mp: 135–136 ꢀC; 1H NMR (CDCl3, 400 MHz): d
2.64 (s, 3H), 4.06 (s, 3H), 4.10 (s, 3H), 6.52 (d, J=5.6
Hz, 1H), 7.42 (dd, J=2.4, 8.1 Hz, 1H), 7.57 (s, 1H), 7.61
(t, J=7.8 Hz, 1H), 7.65 (s, 1H), 7.80 (t, J=2.2 Hz, 1H),
7.92 (d, J=7.8 Hz, 1H), 8.51 (d, J=5.6 Hz, 1H); MS
(ESI) m/z 324 (M++1). Anal. (C19H17NO4) C; H:
calcd, 5.30; found, 5.74; N: calcd 4.33, found 3.84.
6,7-Dimethoxy-4-(4-hydroxyphenoxy)quinoline (8j). Pre-
paration as described for Ki6783 starting from 4-benzylox-
yphenol obtained 546 mg (32%) of 6,7-dimethoxy-4-(4-
benzyloxyphenoxy)quinoline. 1H NMR (CDCl3,
400 MHz): d 4.05 (s, 3H), 4.11 (s, 3H), 5.11 (s, 2H), 6.42

5124
K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
(d, J=5.4 Hz, 1H), 7.06 (d, J=9.0 Hz, 2H), 7.12 (d,
J=9.0 Hz, 2H), 7.34–7.48 (m, 6H), 7.57 (s, 1H), 8.47 (d,
J=5.1 Hz, 1H); MS (FAB) m/z 388 (M++1). To a
solution of 6,7-dimethoxy-4-(4-benzyloxyphenoxy)-
quinoline (420 mg, 1.09 mmol) in DMF/AcOEt (5 mL/
20 mL) was added palladium hydoroxide on carbon
(wet type, 50 mg) and stirred under hydrogen at room
temperature for 3.5 h. The suspension was filtered with
Celite and washed with AcOEt. The resulting solution
was concentrated and The residue was purified with
CHCl3/acetone (2/1) to obtain 259 mg of 8j (81%). Mp:
342 (M++1); HRMS (ESI) (C19H20NO5) (M+H+)
calcd 342.1341, found 342.1350.
6,7-Dimethoxy-4-(2,6-dimethoxyphenoxy)quinoline (8o).
Compound 8o was prepared as described for 1, except
using 2,6-dimethoxylphenol. Purification was performed
by column chromatography on silica gel eluting with
hexane/acetone (4/1) and CHCl3/MeOH (50/1) to
1
obtain 17 mg (11%). H NMR (CDCl3, 400 MHz): d
3.77 (s, 6H), 4.08 (s, 3H), 4.08 (s, 3H), 6.36 (d, J=5.6
Hz, 1H), 6.72 (d, J=8.3 Hz, 2H), 7.25 (t, J=8.3 Hz,
1H), 7.61 (s, 1H), 7.70 (s, 1H), 8.25 (d, J=5.6 Hz, 1H);
236–240 ꢀC; H NMR (DMSO-d6, 400 MHz): d 3.30 (s,
1
3H), 3.32 (s, 3H), 6.37 (d, J=5.4 Hz, 1H), 6.87 (d,
J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 7.37 (s, 1H),
MS
(ESI)
.
m/z
342
(C19H19NO5 0.8H2O) C, H, N.
(M++1).
Anal.
7.51 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 9.55 (s, 1H); MS
+
.
(ESI) m/z 298 (M +1). Anal. (C17H15NO4 0.3H2O) C,
H, N.
6,7-Dimethoxy-4-(3,5-dimethoxyphenoxy)quinoline (8p).
Compound 8p was prepared as described for 1, except
using 3,5-dimethoxylphenol. Purification was performed
by column chromatography on silica gel eluting with
hexane/acetone (4/1) and CHCl3/MeOH (50/1) to
6,7-Dimethoxy-4-(3-fluorophenoxy)quinoline (8k). Com-
pound 8k was prepared as described for 1, except using
3-fluorophenol. Purification was performed by column
chromatography on silica gel eluting with hexane/ace-
tone (4/1) and CHCl3/MeOH (50/1) to obtain 125 mg
1
obtain 96 mg (63%). H NMR (CDCl3, 400 MHz): d
3.79 (s, 3H), 3.80 (s, 3H), 4.05 (s, 6H), 6.35 (q, J=1.0
Hz, 2H), 6.38 (t, J=1.0 Hz, 1H), 6.59 (d, J=5.1 Hz,
1H), 7.43 (s, 1H), 7.53 (s, 1H), 8.51 (d, J=5.1 Hz, 1H);
MS (ESI) m/z 342 (M++1); HRMS (ESI) (C19H20NO5)
(M+H+) calcd 342.1341, found 342.1330.
(94%). Mp: 132 ꢀC; H NMR (CDCl3, 90 MHz): d 4.04
1
(s, 3H), 4.06 (s, 3H), 6.56 (d, J=4.9 Hz, 1H), 6.93 (d,
J=9.2 Hz, 1H), 6.95–7.05 (m, 2H), 7.39–7.45 (m, 1H),
7.47 (s, 1H), 7.50 (s, 1H), 8.53 (d, J=4.3 Hz, 1H); MS
(FD) m/z 299 (M+). Anal. (C17H14FNO3) C, H, N.
{2-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}phenylmetha-
none (8q). Compound 8q was prepared as described for
1, except using 2-hydroxybenzophenone. Purification
was performed by column chromatography on silica gel
eluting with hexane/acetone (4/1) and CHCl3/MeOH
(50/1) to obtain 14 mg (5%). 1H NMR (CDCl3,
400 MHz): d 3.83 (s, 3H), 3.99 (s, 3H), 6.43 (d, J=5.1
Hz, 1H), 6.93 (s, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.31 (s,
1H), 7.33 (t, J=7.6 Hz, 2H), 7.42–7.49 (m, 2H), 7.63
(td, J=1.7, 7.6 Hz, 1H), 7.68 (dd, J=1.7, 7.6 Hz, 1H),
7.69–7.72 (m, 2H), 8.44 (d, J=5.1 Hz, 1H); MS (ESI)
m/z 386 (M++1); HRMS (ESI) (C24H20NO4)
(M+H+) calcd 386.1392, found 386.1403.
6,7-Dimethoxy-4-(3-bromophenoxy)quinoline (8l). Com-
pound 8l was prepared as described for 1, except using
3-bromophenol. Purification was performed by column
chromatography on silica gel eluting with hexane/ace-
tone (4/1) and CHCl3/MeOH (50/1) to obtain 160 mg
(100%). Mp: 124–126 ꢀC; H NMR (CDCl3, 400 MHz):
1
d 4.05 (s, 3H), 4.09 (s, 3H), 6.57 (d, J=5.4 Hz, 1H), 7.15
(dd, J=2.2, 8.1 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.39
(t, J=2.2 Hz, 1H), 7.47 (d, J=7.1 Hz, 1H), 7.52 (s, 1H),
7.62 (s, 1H), 8.53 (d, J=5.6 Hz, 1H); MS (ESI) m/z 360
(M+), 362 (M++2). Anal. (C17H14BrNO3) C, H, N.
6,7-Dimethoxy-4-(4-bromophenoxy)quinoline (8m). Com-
pound 8m was prepared as described for 1, except using
4-bromophenol. Purification was performed by column
chromatography on silica gel eluting with hexane/
acetone (4/1) and CHCl3/MeOH (50/1) to obtain 1.2 g
{3-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}phenylmetha-
none (8r). Compound 8r was prepared as described for
1, except using 3-hydroxybenzophenone. Purification
was performed by thin layer chromatography on silica
gel eluting with hexane/acetone (2/1) to obtain 126 mg
of the title compound (65%). Mp 137 ꢀC; 1H NMR
(CDCl3, 400 MHz): d 4.05 (s, 3H), 4.07 (s, 3H), 6.53 (d,
J=5.4 Hz, 1H), 7.42–7.65 (m, 8H), 7.72 (dd, J=1.5, 6.3
Hz, 1H), 7.83 (dd, J=1.2, 8.3 Hz, 2H) 8.53 (d, J=5.1
Hz, 1H); MS (FD) m/z 385 (M+); HRMS (ESI)
(C24H20NO4) (M+H+) calcd 386.1392, found
386.1373.
(76%). Mp: 163–165 ꢀC; H NMR (CDCl3, 90 MHz):
1
d 4.04 (s, 3H), 4.05 (s, 3H), 6.48 (d, J=4.9 Hz, 1H),
7.08 (d, J=8.5 Hz, 2H), 7.43 (s, 1H), 7.51 (s, 1H),
7.58 (d, J=8.5 Hz, 2H), 8.51 (d, J=4.9 Hz, 1H); MS
(FD) m/z 359 (M+), 361 (M+ +2). Anal.
(C17H14BrNO3) C, H, N.
6,7-Dimethoxy-4-(2,3-dimethoxyphenoxy)quinoline (8n).
Compound 8n was prepared as described for 1, except
using 2,3-dimethoxylphenol. Purification was performed
by column chromatography on silica gel eluting with
hexane/acetone (4/1) and CHCl3/MeOH (50/1) to
{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}(phenyl)me-
thanone (8s). Compound 8s was prepared as described
for 1, except using 4-hydroxybenzophenone. Purifica-
tion was performed by column chromatography on
silica gel eluting with hexane/acetone (4/1) and CHCl3/
1
obtain 77 mg (51%). H NMR (CDCl3, 400 MHz): d
1
3.76 (s, 3H), 3.94 (s, 3H), 4.09 (s, 3H), 4.12 (s, 3H), 6.56
(d, J=6.1 Hz, 1H), 6.83 (dd, J=1.5, 8.3 Hz, 1H), 6.95
(dd, J=1.5, 8.3 Hz, 1H), 7.17 (t, J=8.3 Hz, 1H), 7.64 (s,
1H), 7.87 (s, 1H), 8.46 (d, J=6.1 Hz, 1H); MS (ESI) m/z
MeOH (50/1) to obtain 38 mg (24%). amorphous; H
NMR (CDCl3, 400 MHz): d 4.04 (s, 3H), 4.04 (s, 3H),
6.67 (d, J=5.1 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.46 (s,
1H), 7.51 (t, J=7.3 Hz, 2H), 7.54 (s, 1H), 7.62 (t, J=7.3

K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
5125
Hz, 1H), 7.83 (d, J=7.1 Hz, 2H), 7.95 (d, J=8.8 Hz,
2H), 8.58 (d, J=5.4 Hz, 1H); MS (ESI) m/z 386 (M+
+1); HRMS (ESI) (C24H20NO4) (M+H+) calcd
386.1392, found 386.1388.
(C17H17N2O3) (M+H+) calcd 297.1239, found
297.1207.
6,7-Dimethoxy-4-(3-nitrophenoxy)quinoline (15b). Com-
pound 15b was prepared as described for 15a, except
using 3-nitrophenol. Purification was performed by col-
umn chromatography on silica gel eluting with CHCl3/
AcOEt (5/1) to obtain 293 mg (67%). Mp: 145–146 ꢀC;
1H NMR (CDCl3, 400 MHz): d 4.11 (s, 3H), 4.18 (s,
3H), 6.69 (d, J=6.3 Hz, 1H), 7.61 (s, 1H), 7.63 (d,
J=8.1 Hz, 1H), 7.80 (t, J=8.3 Hz, 1H), 8.13 (s, 1H),
8.17 (m, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.55 (d, J=6.3
Hz, 1H); MS (ESI) m/z 327 (M++1); HRMS (ESI)
(C17H15N2O5) (M+H+) calcd 327.0981, found
327.0963.
(4-Fluorophenyl){4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-
methanone (8ad). Compound 8ad was prepared as
described for 1, except using 4-hydroxy-40-fluor-
obenzophenone. Purification was performed by column
chromatography on silica gel eluting with hexane/ace-
tone (4/1) and CHCl3/MeOH (50/1) to obtain 114 mg
(57%). 1H NMR (CDCl3, 400 MHz): d 4.05 (s, 3H), 4.05
(s, 3H), 6.67 (d, J=5.1 Hz, 1H), 7.20 (t, J=8.5 Hz, 2H),
7.29 (d, J=8.8 Hz, 2H), 7.46 (s, 1H), 7.50 (s, 1H), 7.87
(dd, J=5.4, 8.8 Hz, 2H), 7.91 (d, J=8.5 Hz, 2H), 8.58
(d, J=5.1 Hz, 1H); MS (ESI) m/z 404 (M+ +1);
HRMS (ESI) (C24H19FNO4) (M+H+) calcd 404.1298,
found 404.1267.
6,7-Dimethoxy-4-(3-aminophenoxy)quinoline (16b). Com-
pound 16b was prepared as described for 16a, except
using 15b. Purification was performed by column chro-
matography on silica gel eluting with CHCl3/MeOH
(50/1) to obtain 245 mg (92%). Mp: 165–167 ꢀC; amor-
(4-Chlorophenyl){4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-
methanone (8ae). Compound 8ae was prepared as
described for 1, except using 4-hydroxy-40-chloro-
benzophenone. Purification was performed by column
thin layer chromatography on silica gel eluting with
CHCl3/AcOEt (5/1) to obtain 26 mg (12%). Mp 169–
1
phaous substance; H NMR (CDCl3, 400 MHz): d 3.89
(br, 2H), 4.07 (s, 3H), 4.11 (s, 3H), 6.51 (t, J=2.2 Hz,
1H), 6.56 (dd, J=2.4 Hz, J=7.5 Hz, 1H), 6.65 (dd,
J=2.2, 7.3 Hz, 1H), 6.68 (d, J=5.9 Hz, 1H), 7.25 (s, 1H),
7.58 (s, 1H), 7.83 (s, 1H), 8.47 (d, J=6.1 Hz, 1H); MS
(ESI) m/z 297 (M++1); HRMS (ESI) (C17H17N2O3)
(M+H+) calcd 297.1239, found 297.1252.
ꢀ
1
171 C; H NMR (CDCl3, 400 MHz): d 4.03 (s, 3H),
4.07 (s, 3H), 6.66 (d, J=5.1 Hz, 1H), 7.28 (d, J=8.5 Hz,
2H), 7.46 (s, 1H), 7.47 (s, 1H), 7.49 (d, J=8.8 Hz, 2H),
7.78 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.8 Hz, 2H), 8.58
(d, J=5.1 Hz, 1H); MS (FD) m/z 419 (M+). Anal.
(C24H18ClNO4) C, H, N.
6,7-Dimethoxy-4-(2-nitrophenoxy)quinoline (15c). Com-
pound 15c as prepared as described for 15a, except
using 2-nitrophenol. Purification was performed by col-
umn chromatography on silica gel eluting with CHCl3/
AcOEt (5/1) to obtain 180 mg (61%). Mp: 145–146 ꢀC;
1H NMR (CDCl3, 400 MHz): d 4.04 (s, 3H), 4.06 (s,
3H), 6.49 (d, J=5.4 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H),
7.43 (t, J=8.3 Hz, 1H), 7.45 (s, 1H), 7.51 (s, 1H), 7.69
(td, J=1.7, 8.3 Hz, 1H), 8.11 (dd, J=1.7, 8.3 Hz, 1H),
8.54 (d, J=5.1 Hz, 1H); MS (ESI) m/z 327 (M++1);
HRMS (ESI) (C17H15N2O5) (M+H+) calcd 327.0981,
found 327.0944.
6,7-Dimethoxy-4-(4-nitrophenoxy)quinoline (15a). A solu-
tion of 4-chloro-6,7-dimethoxyquinoline (3.00 g, 13.4
mmol) and 4-nitrophenol (4.66 g, 33.6 mmol) in diethy-
leneglycol dimethylether (2 mL) was heated at 180 ꢀC
for 1 h. The reaction mixture was cooled and treated
with saturated NaHCO3 (30 mL) and extracted with
CHCl3 (30 mL). The organic layer was washed with
brine (10 mL), dried over Na2SO4 and concentrated.
Purification was performed by column chromatography
on silica gel eluting with hexane/acetone (5/1) to obtain
1
3.92 g of 15a (76%); H NMR (CDCl3, 400 MHz): d
6,7-Dimethoxy-4-(2-aminophenoxy)quinoline (16c). Com-
pound 16c was prepared as described for 16a, except
using 15c. Purification was performed by column chro-
matography on silica gel eluting with CHCl3/MeOH
(50/1) to obtain 134 mg (82%). Mp: 165–167 ꢀC; 1H
NMR (CDCl3, 400 MHz): d 3.84 (br, 2H), 4.11 (s, 3H),
4.11 (s, 3H), 6.61 (d, J=6.1 Hz, 1H), 6.86 (dt, J=1.5,
8.1 Hz, 1H), 6.94 (dd, J=1.5, 8.1 Hz, 1H), 7.05 (dd,
J=1.2, 8.1 Hz, 1H), 7.19 (dt, J=1.5, 8.1 Hz, 1H), 7.68
(s, 1H), 7.85 (s, 1H), 8.44 (d, J=6.1 Hz, 1H); MS (ESI)
m/z 297 (M++1); HRMS (ESI) (C17H17N2O3)
(M+H+) calcd 297.1239, found 297.1207.
4.01 (s, 3H), 4.06 (s, 3H), 6.69 (d, J=5.1 Hz, 1H), 7.26
(d, J=9.3 Hz, 2H), 7.37 (s, 1H), 7.47 (s, 1H), 8.33 (dd,
J=1.7, 8.3 Hz, 2H), 8.62 (d, J=5.1 Hz, 1H); MS (ESI)
m/z: 327 (M++1).
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (16a). To a
solution of 15a (1.35 g, 4.18 mmol) and triethylamine
(2.9 mL, 20.98 mmol) in DMF (100 mL) was added
palladium hydoroxide on carbon (wet type, 270 mg) and
stirred under hydrogen at room temperature for 3.5 h.
The suspension was filtered with Celite and washed with
AcOEt. The organic layer was washed with brine and
dried over Na2SO4. The resulting solution was con-
centrated and purified by column chromatography
eluting with CHCl3/MeOH (50/1) obtained 1.16 g of
16a (94%). Mp: 214 ꢀC; 1H NMR (CDCl3, 400 MHz): d
3.82 (br, 2H), 4.09 (s, 3H), 4.13 (s, 3H), 6.64 (d, J=6.3
Hz, 1H), 6.64 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz,
2H), 7.62 (s, 1H), 7.95 (s, 1H), 8.45 (d, J=6.3 Hz, 1H);
MS (ESI) m/z 297 (M++1); HRMS (ESI)
4-t-Butylphenyl 4-methoxyphenyl ketone (10a). To a
solution of anisole (541 mg, 5.0 mmol) and 4-t-butyl-
benzoyl chloride (983 mg, 5.0 mmol) in nitromethane
(5 mL) was added Sc(OTf)3 (506 mg, 1.0 mmol) stirred
at 60 ꢀC for 21 h. The reaction mixture was treated with
saturated aqueous NaHCO3 (10 mL) and extracted with
CHCl3. The organic layer was dried over Na2SO4 and
concentrated. The residue was purified by column

5126
K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
chromatography on silica gel eluting with hexane/
AcOEt (5/1) to obtain 862 mg of 10a (64%). MS (FD)
m/z 268 (M+).
{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}(2-thienyl)me-
thanone (8t). A mixture of 7 (112 mg, 0.50 mmol) and
11b (102 mg, 0.50 mmol) was heated at 160 ꢀC for 40
min. The reaction mixture was purified by thin layer
chromatography on silica gel eluting with hexane/ace-
tone (2/1) to obtain 34 mg of 8t (17%). 1H NMR
(CDCl3, 500 MHz): d 4.04 (s, 3H), 4.07 (s, 3H), 6.65 (d,
J=5.5 Hz, 1H), 7.20 (dd, J=3.7, 4.9 Hz, 1H), 7.29 (d,
J=8.5 Hz, 2H), 7.47 (s, 1H), 7.49 (s, 1H), 7.70 (d,
J=3.1 Hz, 1H), 7.75 (d, J=4.9 Hz, 1H), 8.00 (d, J=8.6
Hz, 2H), 8.58 (d, J=5.5 Hz, 1H); MS (ESI) m/z 392
(M++1); HRMS (ESI) (C22H18NO4S) (M+H+) calcd
392.0957, found 392.0964.
4-t-Butylphenyl 4-hydroxyphenyl ketone (11a). A solu-
tion of 10a (804 mg, 3.0 mmol) in DMF (30 mL) was
added sodium thiomethoxide (562 mg, 8.0 mmol). The
reaction mixture was refluxed under argon for 5 h. The
reaction mixture was cooled to room temperature and
partitioned between 10% aqueous phosphoric acid (30
mL) and AcOEt (30 mL). The organic layer was washed
with 0.5 N aqueous AgNO3 and dried over MgSO4. The
solution was concentrated and the resulting residue was
purified by column chromatography on silica gel elut-
1
ing with CHCl3 to obtain 862 mg of 11a (97%). H
4-Cyclohexylcarbonyl-1-methoxybenzene (10c). Com-
pound 10c was prepared as described for 10b, except
using cyclohexanecarbonyl chloride (51%). 1H NMR
(CDCl3, 500 MHz): d 1.21–1.88 (m, 10H), 3.19–3.25 (m,
1H), 3.87 (s, 3H), 6.93 (d, J=9.2 Hz, 2H), 7.94 (d,
J=9.2 Hz, 2H); MS (ESI) m/z 219 (M++1).
NMR (CDCl3, 500 MHz): d 1.36 (s, 9H), 6.92 (d,
J=8.5 Hz, 2H), 7.49 (d, J=8.6 Hz, 2H), 7.72 (d,
J=7.9 Hz, 2H), 7.79 (d, J=8.5 Hz, 2H); MS (FD) m/z
254 (M+).
(4-t-Butylphenyl){4-[(6,7-dimethoxy-4-quinolyl)oxy]phe-
nyl}methanone (2: Ki6896). A mixture of 7 (341 mg,
1.52 mmol) and 11a (775 mg, 3.05 mmol) was heated at
160 ꢀC for 40 min. The reaction mixture was purified by
thin layer chromatography on silica gel eluting with
hexane/acetone (2/1) to obtain 72 mg of 2 (11%). Mp:
173–174 ꢀC; 1H NMR (CDCl3, 500 MHz): d 1.38 (s,
9H), 4.04 (s, 3H), 4.06 (s, 3H), 6.65 (d, J=5.5 Hz, 1H),
7.27 (d, J=8.6 Hz, 2H), 7.45 (s, 1H), 7.50 (s, 1H), 7.52
(d, J=8.5 Hz, 2H), 7.78 (d, J=8.6 Hz, 2H), 7.94 (d,
J=8.6 Hz, 2H), 8.57 (d, J=4.9 Hz, 1H); MS (ESI) m/z
442 (M++1). Anal. (C28H27NO4) C, H, N.
4-Cyclohexylcarbonyl-1-hydroxybenzene (11b). Com-
pound 11b was prepared as described for 11a, except
using 10b (93%). H NMR (CDCl3, 500 MHz): d 1.23–
1.88 (m, 10H), 3.19–3.25 (m, 1H), 6.06 (brs, 1H) 6.89 (d,
J=8.6 Hz, 2H), 7.90 (d, J=8.6 Hz, 1H); MS (FD) m/z:
204 (M+).
1
4-Cyclohexylcarbonyl-1-[(6,7-dimethoxy-4-quinolyl)oxy]-
benzene (8v). Compound 8v was prepared as described
for 2, except using 11b. Purification was performed by
thin layer chromatography on silica gel eluting with
hexane/acetone (4/1) and then CHCl3/MeOH (50/1) to
obtain 65 mg (33%). Mp 125 ꢀC; 1H NMR (CDCl3,
500 MHz): d 1.21–1.93 (m, 10H), 3.24–3.29 (m, 1H),
4.03 (s, 3H), 4.06 (s, 3H), 6.60 (d, J=5.5 Hz, 1H), 7.24
(d, J=8.5 Hz, 2H), 7.45 (s, 1H), 7.47 (s, 1H), 8.05 (d,
J=8.5 Hz, 2H), 8.55 (d, J=5.5 Hz, 1H); MS (FD) m/z
392 (M+ +1); HRMS (ESI) (C24H26NO4) (M+H+)
calcd 392.1862, found 392.1837.
4-Methoxyphenyl 2-thienyl ketone (10b). To a solution
of anisole (1.1g, 10 mmol) and 2-thiophenecarbonyl
chloride (1.5 g, 10 mmol) in nitromethane (10 mL) was
added Yb(OTf)3 (620 mg, 1.0 mmol) stirred at 60 ꢀC for
8 h. The reaction mixture was treated with saturated
aqueous NaHCO3 (10 mL) and extracted with CHCl3.
The organic layer was dried over Na2SO4 and con-
centrated. The residue was purified by column chroma-
tography on silica gel eluting with hexane/AcOEt (5/1)
to obtain 965 mg of 10b (44%). 1H NMR (CDCl3,
500 MHz): d 3.89 (s, 3H), 6.98 (d, J=8.5 Hz, 2H), 7.16
(dd, J=3.7 Hz, 4.9 Hz, 1H), 7.64 (d, J=3.7 Hz, 1H),
7.68 (d, J=4.9 Hz, 1H), 7.90 (d, J=8.6 Hz, 2H); MS
(FD) m/z 218 (M+).
2-Trifluoromethylphenyl 4-methoxyphenyl ketone (10d).
Compound 10d was prepared as described for 10b, except
1
using 2-trifluoromethylbenzoyl chloride (50%). H NMR
(CDCl3, 500MHz): d 3.88 (s, 3H) 6.93 (d, J=9.2 Hz, 2H),
7.37–7.39 (m, 1H), 7.60–7.63 (m, 2H), 7.75 (d, J=9.2 Hz,
2H), 7.73–7.78 (m, 1H); MS (FD) m/z 280 (M+).
4-Hydroxyphenyl 2-thienyl ketone (11b). To a solution
of 10b (804 mg, 3.7 mmol) in DMF (30 mL) was added
sodium thiomethoxide (645 mg, 9.2 mmol). The reaction
mixture was refluxed under argon for 5 h. The reaction
mixture was cooled to room temperature and parti-
tioned between 10% aqueous phosphoric acid (30 mL)
and AcOEt (30 mL). The organic layer was washed with
0.5 N aqueous AgNO3 and dried over MgSO4. The
solution was concentrated and the resulting residue was
purified by column chromatography on silica gel eluting
2-Trifluoromethylphenyl 4-hydroxyphenyl ketone (11d).
Compound 11d was prepared as described for 11a,
except using 10d (74%). 1H NMR (CDCl3, 500 MHz): d
5.88 (s, 1H), 6.87 (d, J=8.5 Hz, 2H), 7.37–7.38 (m, 1H),
7.58–7.63 (m, 2H), 7.71 (d, J=9.2 Hz, 2H), 7.76–7.78
(m, 1H); MS (FD) m/z 266 (M+).
(2-Trifluoromethylphenyl){4-[(6,7-dimethoxy-4-quinolyl)-
oxy]phenyl}methanone (8z). Compound 8z was pre-
pared as described for 2, except using 11d. Purification
was performed by column chromatography on silica gel
eluting with hexane/AcOEt (4/1), CHCl3 and CHCl3/
AcOEt (5/1) to obtain 899 mg (55%). 1H NMR
(CDCl3, 500 MHz): d 4.01 (s, 3H), 4.06 (s, 3H), 6,67 (d,
J=5.5 Hz, 1H), 7.22 (d, J=9.2 Hz, 2H), 7.42 (s, 1H),
1
with chloroform to obtain 702 mg of 11b (93%). H
NMR (CDCl3, 500 MHz): d 6.84 (brs, 1H), 6.93 (d,
J=8.5 Hz, 2H), 7.14 (dd, J=3.7, 4.9 Hz, 1H), 7.64 (d,
J=3.7 Hz, 1H), 7.68 (d, J=4.9 Hz, 1H), 7.83 (d, J=8.5
Hz, 2H); MS (FD) m/z 204 (M+).

K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
5127
7.42–7.44 (m, 1H), 7.45 (s, 1H), 7.62–7.68 (m, 2H),
7.80–7.81 (m, 1H), 7.87 (d, J=8.6 Hz, 2H), 8.58 (d,
J=5.5 Hz, 1H); MS (FD) m/z 453 (M+); HRMS (ESI)
(C25H19F3NO4) (M+H+) calcd 454.1266, found
454.1260.
(d, J=5.5 Hz, 1H); MS (FD) m/z 440 (M+ꢂ1). Anal.
(C28H27NO4) H, N; C: calcd 76.17, found 75.73.
4-Biphenyl 4-methoxyphenyl ketone (10g). Compound
10g was prepared as described for 10b, except using 4-
phenylbenzoyl chloride. (34%). 1H NMR (CDCl3,
500 MHz): d 3.90 (s, 3H), 6.98 (d, J=8.5 Hz, 2H), 7.40
(t, J=7.3 Hz, 1H), 7.48 (t, J=7.3 Hz, 2H), 7.65 (d,
J=7.3 Hz, 2H), 7.76 (d, J=8.6 Hz, 2H), 7.85 (d, J=8.5
Hz, 2H), 7.87 (d, J=9.2 Hz, 2H); MS (FD) m/z 288
(M+).
3-Trifluoromethylphenyl 4-methoxyphenyl ketone (10e).
Compound 10e was prepared as described for 10b,
except using 3-(trifluoromethyl)benzoyl chloride (26%).
1H NMR (CDCl3, 500 MHz): d 3.91 (s, 3H), 6.99 (d,
J=9.2 Hz, 2H), 7.60–7.64 (m, 1H), 7.80–7.83 (m, 1H),
7.82 (d, J=8.5 Hz, 2H), 7.93–7.94 (m, 1H), 8.01 (s, 1H);
MS (FD) m/z 280 (M+).
4-Biphenyl 4-hydroxyphenyl ketone (11g). Compound
11g was prepared as described for 11a, except using 10g
1
3-Trifluoromethylphenyl 4-hydroxyphenyl ketone (11e).
Compound 11e was prepared as described for 11a,
except using 10e (73%). 1H NMR (CDCl3, 500 MHz): d
5.85 (s, 1H), 6.94 (d, J=9.2 Hz, 2H), 7.62 (t, J=7.3 Hz,
1H), 7.78 (d, J=9.2 Hz, 2H), 7.83 (d, J=7.3 Hz, 1H),
7.93 (d, J=7.3 Hz, 1H), 8.01 (s, 1H).
(82%). H NMR (CDCl3, 500 MHz): d 6.91 (d, J=8.5
Hz, 2H), 7.43 (t, J=7.3 Hz, 1H), 7.52 (dd, J=7.3 Hz,
7.9 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 7.75 (d, J=7.9 Hz,
2H) 7.77 (d, J=7.9 Hz, 2H), 7.83 (d, J=7.9 Hz, 2H);
MS (FD) m/z 274 (M+).
{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}(4-biphenyl)-
methanone (8am). Compound 8am was prepared as
described for 2, except using 11g. Purification was per-
formed by thin layer chromatography on silica gel elut-
ing with chloroform/ethyl acetate (10/1) to obtain 50 mg
(3-Trifluoromethylphenyl){4-[(6,7-dimethoxy-4-quinolyl)-
oxy]phenyl}methanone (8aa). Compound 8aa was pre-
pared as described for 2, except using 11e. Purification
was performed by column chromatography on silica gel
eluting with hexane/AcOEt (4/1) and CHCl3/AcOEt (5/
1) to obtain 204 mg (28%). 1H NMR (CDCl3,
500 MHz): d 4.03 (s, 3H) 4.07 (s, 3H), 6,69 (d, J=4.9
Hz, 1H), 7.30 (d, J=9.2 Hz, 2H), 7.47 (s, 2H), 7.66 (t,
J=7.9 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.92 (d, J=9.2
Hz, 2H), 8.00 (d, J=7.9 Hz, 1H), 8.08 (s, 1H), 8.60 (d,
J=4.9 Hz, 1H); MS (FD) m/z 453 (M+). Anal.
1
(37%). H NMR (CDCl3, 90 MHz): d 4.11 (s, 3H), 4.14
(s, 3H), 6.74 (d, J=5.3 Hz, 1H), 7.30–8.09 (m, 15H),
8.65 (d, J=5.3 Hz, 1H); MS (ESI) m/z 462 (M+). Anal.
.
(C30H23NO4 1.5H2O) C, H, N.
4-Methoxyphenyl 2-methylphenyl ketone (10h). Com-
pound 10h was prepared as described for 10b, except
using 2-methylbenzoyl chloride (74%). MS (FD) m/z
226 (M+).
.
(C25H18F3NO4 H2O) C, H, N.
4-n-Butylphenyl 4-methoxyphenyl ketone (10f). Com-
pound 10f was prepared as described for 10b, except
using 4-n-butylbenzoyl chloride (32%). 1H NMR
(CDCl3, 500 MHz): d 0.95 (t, J=7.3 Hz, 3H), 1.38 (tq,
J=7.3, 7.3 Hz, 2H), 1.64 (q, J=7.3 Hz, 2H), 2.69 (t,
J=7.3 Hz, 2H), 3.89 (s, 3H), 6.96 (d, J=9.2 Hz, 2H),
7.27 (d, J=8.6 Hz, 2H), 7.69 (d, J=8.6 Hz, 2H), 7.82
(d, J=9.2 Hz, 2H); MS (FD) m/z 268 (M+).
4-Hydroxyphenyl 2-methylphenyl ketone (11h). To a
solution of 10h (1.66 g, 7.35 mmol) in CHCl3 (10 mL)
was added a solution of 1.0 M BBr3 in CH2Cl2 (29 mL)
at 0 ꢀC and stirred at room temperature for 15 h. A
solution of 1.0 M BBr3 in CH2Cl2 (15 mL) was further
added and stirred at room temperature for 2 days. The
reaction mixture was then poured into ice water and
partitioned between water and CHCl3. The organic
layer was dried over MgSO4 and concentrated. The
resulting residue was purified by column chromato-
graphy on silica gel eluting with hexane/AcOEt (4/1) to
obtain 1.50 g of 11h (96%). 1H NMR (CDCl3,
500 MHz): d 2.30 (s, 3H), 6.87 (d, J=8.5 Hz, 2H), 7.22–
7.29 (m, 3H), 7.37 (td, J=1.2, 7.3 Hz, 1H), 7.73 (d,
J=8.5 Hz, 2H); MS (FD) m/z 212 (M+).
4-n-Butylphenyl 4-hydroxyphenyl ketone (11f). Com-
pound 11f was prepared as described for 11a, except
using 10f (96%). 1H NMR (CDCl3, 500 MHz): d 0.95 (t,
J=7.3 Hz, 3H), 1.38 (tq, J=7.3, 7.3 Hz, 2H), 1.64
(septet, J=7.3 Hz, 2H), 2.69 (t, J=7.9 Hz, 2H), 6.35 (s,
1H), 6.92 (d, J=8.5, 2H), 7.28 (d, J=7.9 Hz, 2H), 7.69
(d, J=8.6 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H); MS (FD)
m/z 254 (M+).
{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}(2-methylphe-
nyl)methanone (8w). To a solution of 11h (1.33 g, 6.29
mmol) in xylene (15 mL) was added 4-dimethylamino-
pyridine (845 mg, 6.92 mmol) and stirred at room tem-
perature for 1 h. Then 7 (1.41 g, 6.29 mmol) was added
and stirred under reflux for 23 h. The reaction mixture
was partitioned between saturated aqueous NaHCO3
and CHCl3. The organic layer was dried under MgSO4
and concentrated. The resulting residue was purified by
column chromatography on silica gel eluting with hex-
ane/AcOEt (4/1), CHCl3 and hexane/acetone (2/1) to
(4-n-Butylphenyl){4-[(6,7-dimethoxy-4-quinolyl)oxy]phe-
nyl}methanone (8al). Compound 8al was prepared as
described for 2, except using 11f. Purification was per-
formed by column chromatography on silica gel eluting
with hexane/AcOEt (4/1) and CHCl3/AcOEt (5/1) to
1
obtain 400 mg of (32%). H NMR (CDCl3, 500 MHz):
d 0.95 (t, J=7.3 Hz, 3H), 1.38 (tq, J=7.3, 7.3 Hz, 2H),
1.62–1.68 (m, 2H), 2.71 (t, J=7.3 Hz, 2H), 4.04 (s, 3H),
4.07 (s, 3H), 6.65 (d, J=4.9 Hz, 1H), 7.26 (d, J=8.5 Hz,
2H), 7.31 (d, J=7.9 Hz, 2H), 7.46 (s, 1H), 7.49 (s, 1H),
7.76 (d, J=7.9 Hz, 2H), 7.92 (d, J=8.5 Hz, 2H), 8.58
obtain 1.26 g of 8w (50%). Mp: 143–144 ꢀC; H NMR
1

5128
K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
(CDCl3, 500 MHz): d 2.37 (s, 3H), 4.02 (s, 3H), 4.06 (s,
3H), 6.65 (d, J=4.9 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H),
7.25–7.35 (m, 3H), 7.39–7.42 (m, 1H), 7.45 (s, 1H), 7.46
(s, 1H), 7.91 (d, J=8.5 Hz, 2H), 8.57 (d, J=5.5 Hz, 1H);
MS (FD) m/z 399 (M+). Anal. (C25H21NO4) C, H, N.
Hz, 1H), 7.28 (d, J=7.9 Hz, 2H), 7.31–7.33 (m, 1H),
1.46 (s, 1H), 7.47 (s, 1H), 7.48–7.53 (m, 2H), 7.59–7.61
(m, 1H), 7.93 (d, J=8.6 Hz. 2H), 8.59 (d, J=5.5 Hz, 1H);
MS (FD) m/z 403 (M+). Anal. (C24H18FNO4) C, H, N.
3,4-Dichlorophenyl 4-methoxyphenyl ketone (10k).
Compound 10k was prepared as described for 10b,
except using 3,4-dichlorobenzoyl chloride (10%). Mp:
133–134 ꢀC; 1H NMR (CDCl3, 500 MHz): d 3.90 (s,
3H), 6.98 (d, J=9.2 Hz, 2H), 7.56 (s, 1H), 7.58 (d,
J=1.8 Hz, 1H), 7.79 (d, J=9.2 Hz, 2H), 7.84 (d, J=1.8
Hz, 1H); MS (FD) m/z 280 (M+), 282 (M++2).
4-Methoxyphenyl 3-methylphenyl ketone (10i). Com-
pound 10i was prepared as described for 10b, except
using 3-methylbenzoyl chloride (56%). MS (FD) m/z
226 (M+).
4-Hydroxyphenyl 3-methylphenyl ketone (11i). Com-
pound 11i was prepared as described for 11a, except using
1
10i (56%). H NMR (DMSO-d6, 500 MHz): d 2.38 (s,
3H), 6.89 (d, J=8.6 Hz, 2H), 7.37–7.47 (m, 4H), 7.65 (d,
3,4-Dichlorophenyl 4-hydroxyphenyl ketone (11k). Com-
pound 11k was prepared as described for 11j, except
1
J=8.6 Hz, 2H), 10.42 (s, 1H); MS (FD) m/z 212 (M+).
using 10k (77%). H NMR (DMSO-d6, 500 MHz): d
6.91 (d, J=8.5 Hz, 2H), 7.62 (dd, J=1.8, 8.6 Hz, 1H),
7.68 (d, J=8.5 Hz, 2H), 7.80 (d, J=7.9 Hz, 1H), 7.85
(d, J=1.8 Hz, 1H), 10.55 (s, 1H); MS (FD) m/z 266
(M+), 268 (M++2).
{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}(3-methylphe-
nyl)methanone (8x). Compound 8x was prepared as
described for 8w except using 11i. Purification was per-
formed by column chromatography on silica gel eluting
with hexane/AcOEt (4/1), CHCl3 and hexane/acetone
(2/1) to obtain 262 mg (45%). 1H NMR (CDCl3,
500 MHz): d 2.44 (s, 3H), 4.03 (s, 3H), 4.06 (s, 3H), 6.66
(d, J=4.9 Hz, 1H), 7.27 (d, J=8.6 Hz, 2H), 7.38 (t,
J=7.3 Hz, 1H), 7.41 (d, J=7.3 Hz, 1H), 7.46 (s, 1H),
7.49 (s, 1H), 7.59 (d, J=7.3 Hz, 1H), 7.64 (s, 1H), 7.93
(d, J=8.6 Hz, 2H), 8.57 (d, J=5.5 Hz, 1H); MS (FD)
m/z 399 (M+). Anal. (C25H21NO4) C, H, N.
{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}(3,4-dichloro-
phenyl)methanone (8af). Compound 8af was prepared
as described for 8w, except using 11k. Purification was
performed by thin layer chromatography on silica gel
eluting with hexane/acetone (2/1) to obtain 81 mg
(31%). 1H NMR (CDCl3, 500 MHz): d 4.03 (s, 3H), 4.07
(s, 3H), 6.68 (d, J=5.5 Hz, 1H), 7.28 (d, J=8.5 Hz,
2H), 7.46 (s, 1H), 7.47 (s, 1H), 7.60 (d, J=8.5 Hz, 1H),
7.66 (dd, J=1.8, 8.6 Hz, 1H), 7.90 (d, J=9.2 Hz, 2H),
7.91 (d, J=1.8 Hz, 1H), 8.60 (d, J=4.9 Hz, 1H); MS
(FD) m/z 453 (M+), 455 (M+ +2). Anal.
3-Fluorophenyl 4-methoxyphenyl ketone (10j). To a
solution of anisole (541 mg, 5.0 mmol) and 3-fluor-
obenzoyl chloride (793 mg, 5.0 mmol) in nitromethane
(5 mL) was added Sc(OTf)3 (49 mg, 0.50 mmol) stirred
at 60 ꢀC for 3 days. The reaction mixture was treated
with saturated aqueous NaHCO3 (10 mL). The solution
was extracted with CHCl3. The organic layer was dried
over MgSO4 and concentrated. The residue was purified
by column chromatography on silica gel eluting with
hexane/acetone (5/1) to obtain 585 mg of 10j (51%). MS
(ESI) m/z 231 (M++1).
.
(C24H17Cl2NO4 H2O) C, H, N.
4-Methoxyphenyl 4-bromophenyl ketone (10l). Com-
pound 10l was prepared as described for 10b, except using
4-bromobenzoyl chloride (57%). 1H NMR (CDCl3,
500 MHz): d 3.89 (s, 3H), 6.97 (d, J=8.6 Hz, 2H), 7.62 (d,
J=1.8 Hz, 2H), 7.62 (d, J=1.8 Hz, 2H), 7.80 (d, J=9.2
Hz, 2H); MS (FD) m/z 290 (M+), 292 (M++2).
4-Hydroxyphenyl 4-bromophenyl ketone (11l). Com-
pound 11l was prepared as described for 11j, except
using 10l (85%). 1H NMR (DMSO-d6, 500 MHz): d
6.90 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.66
(d, J=8.6 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 10.46 (brs,
1H); MS (FD) m/z 276 (M+), 278(M++2).
4-Hydroxyphenyl 3-fluorophenyl ketone (11j). To a solu-
tion of 10j (580 mg) in CH2Cl2 (5 mL) was added a
solution of 1.0 M BBr3 in CH2Cl2 (23 mL) at 0 ꢀC and
stirred at room temperature for 3 days. The reaction
mixture was then poured into ice water and partitioned
between water and CHCl3. The organic layer was dried
over MgSO4 and concentrated. The resulting residue
was purified by column chromatography on silica gel
eluting with hexane/AcOEt (4/1) to obtain 402 mg of
{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}(4-bromophe-
nyl)methanone (8ag). Compound 8ag was prepared as
described for 8w, except using 11l. Purification was per-
formed by column chromatography on silica gel eluting
with CHCl3/AcOEt (5/1) to obtain 1.57 g (79%). Mp:
173–174 ꢀC; 1H NMR (CDCl3, 500 MHz): d 4.05 (s,
3H), 4.66 (s, 3H), 6.66 (d, J=4.9 Hz, 1H), 7.27 (d,
J=8.6 Hz, 2H), 7.46 (s, 1H), 7.47 (s, 1H), 7.65 (d,
J=7.9 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.6
Hz, 2H), 8.58 (d, J=5.5 Hz, 1H); MS (FD) m/z 463
(M+), 465 (M++2). Anal. (C24H18BrNO4) C, H, N.
1
11j (74%). H NMR (DMSO-d6, 500 MHz): d 6.91 (d,
J=8.5 Hz, 2H), 7.44–7.49 (m, 3H), 7.57–7.61 (m, 1H),
7.68 (d, J=8.5 Hz, 2H), 10.51 (brs, 1H); MS (ESI) m/z
217 (M++1).
{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl})(3-fluorophe-
nyl)methanone (8ac). Compound 8ac was prepared as
described for 8w, except using 11j. Purification was
performed by column chromatography on silica gel
eluting hexane/acetone, CHCl3 and CHCl3/AcOEt (5/1)
4-Methoxyphenyl 4-iodophenyl ketone (10m). Compound
10m was prepared as described for 10b, except using 4-
iodobenzoyl chloride (21%). MS (FD) m/z 338 (M+).
ꢀ
1
to obtain 484 mg (70%). Mp 144 C; H NMR (CDCl3,
500 MHz): d 4.04 (s, 3H), 4.07 (s, 3H), 6.67 (d, J=4.9

K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
5129
4-Hydroxyphenyl 4-iodophenyl ketone (11m). Com-
pound 11l was prepared as described for 11j, except
using 10l. Purification was performed by column chro-
matography on silica gel eluting with hexane/AcOEt (4/
1) to obtain 380 mg (55%). 1H NMR (DMSO-d6,
500 MHz): d 6.89 (d, J=8.6 Hz, 2H), 7.44 (d, J=8.5 Hz,
2H), 7.65 (d, J=8.6 Hz, 2H), 7.92 (d, J=8.5 Hz, 2H),
10.47 (s, 1H); MS (ESI) m/z 325 (M++1).
The organic layer was dried over MgSO4 and con-
centrated. The resulting residue was purified by column
chromatography on silica gel eluting with hexane/
1
AcOEt (5/1) to obtain 218 mg of 11n (39%). H NMR
(DMSO-d6, 500 MHz): d 6.76 (dd, J=1.2, 3.1 Hz, 1H),
6.91 (d, J=8.5 Hz, 2H), 7.33 (d, J=3.1 Hz, 1H), 7.87
(d, J=8.5 Hz, 2H), 8.06 (d, J=1.2 Hz, 1H), 10.39 (s,
1H); MS (FD) m/z 188 (M+).
{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}(4-iodophenyl)-
methanone (8ah). Compound 8ah was prepared as
described for 8w, except using 11m. Purification was
performed by column chromatography on silica gel
eluting with CHCl3/AcOEt (5/1) to obtain 459 mg
(77%). Mp: 163–165 ꢀC; 1H NMR (CDCl3, 500 MHz): d
4.03 (s, 3H), 4.07 (s, 3H), 6.66 (d, J=4.9 Hz, 1H), 7.27
(d, J=7.6 Hz, 2H), 7.46 (s, 1H), 7.47 (s, 1H), 7.54 (d,
J=8.6 Hz, 2H), 7.88 (d, J=7.9 Hz, 2H), 7.90 (d, J=8.6
Hz, 2H), 8.58 (d, J=5.5 Hz, 1H); MS (FD) m/z 511
(M+). Anal. (C24H18INO4) C, H, N.
2-Furoyl-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}me-
thanone (8u). To a solution of 11n (205 mg, 1.09 mmol)
in xylene (5 mL) was added 4-dimethylaminopyridine
(146 mg, 1.20 mmol) and stirred under argon at room
temperature for 1 h. Then 7 (244 mg, 1.09 mmol) was
added and heated under reflux for 20 h. The reaction
mixture was partitioned between saturated aqueous
NaHCO3 and CHCl3. The organic layer was dried over
MgSO4 and concentrated. The resulting residue was
purified by chromatography on silica gel eluting with
hexane/AcOEt (4/1), CHCl3 and CHCl3/AcOEt (5/1) to
obtain 192 mg of 8u (47%). Mp 126–127 ꢀC; H NMR
1
4-Bromo-1-methoxymethylphenol (13). To a solution of
4-bromophenol (17.3 g, 10.0 mmol) in DMF (90 mL)
was added NaH (60% in oil, 2.64 g, 66.0 mmol) at 0 ꢀC
for 1 h. After stirring at room temperature for 8 h,
chloromethyl methyl ether (8.85 g, 110 mmol) was
added and stirred for a further 1 h. The reaction mixture
was partitioned between water and AcOEt. The organic
layer was dried over MgSO4 and concentrated. The
resulting residue was purified by column chromatography
on silica gel eluting with hexane/acetone (4/1) to obtain
18.25 g of 13 (84%). 1H NMR (CDCl3, 90 MHz): d 3.46
(s, 3H), 5.13 (s, 2H), 6.91 (d, J=9.2 Hz, 2H), 7.38 (d,
J=9.2 Hz, 2H); MS (FD) m/z 216 (M+), 218 (M++2).
(CDCl3, 500 MHz): d 4.03 (s, 3H), 4.07 (s, 3H), 6.63 (dd,
J=1.8, 3.7 Hz, 1H), 6.65 (d, J=5.5 Hz, 1H), 7.28 (d,
J=8.5 Hz, 2H), 7.32 (d, J=3.7 Hz, 1H), 7.47 (s, 1H),
7.48 (s, 1H), 7.73 (d, J=1.8 Hz, 1H), 8.14 (d, J=9.2 Hz,
2H), 8.58 (d, J=5.5 Hz, 1H); MS (FD) m/z 375 (M+).
.
Anal. (C22H17NO5 0.3H2O) C, H, N.
4-Hydroxyphenyl 4-methylphenyl ketone (11o). Com-
pound 11o was prepared as described for 11n, except
using 4-toluoyl chloride. Purification was performed by
column chromatography on silica gel eluting with
CHCl3/AcOEt (5/1) to obtain 271 mg (34%). MS (FD)
m/z 212 (M+).
4-Tri-n-butyltin-1-methoxymethylphenol (14). To a solu-
tion of 13 (15.99 g, 73.69 mmol) in THF (20 mL) was
added Mg (1.97 g) and a drop of an iodine solution in
THF under argon at room temperature. The resulting
suspension was refluxed till magnesium disappeared,
and returned to room temperature. Then a solution of
nBu3SnCl (23.99 g, 73.70 mmol) dissolved in THF (10
mL) was added slowly dropwise to the suspension. The
reaction mixture was stirred at room temperature for 4
h and then partitioned between 5% aqueous NH4Cl and
CHCl3. The organic layer was dried over MgSO4 and
concentrated. The resulting residue was purified by col-
umn chromatography eluting with hexane/AcOEt (10/1)
to obtain 31.39 g of 14 (100%). 1H NMR (CDCl3,
90 MHz): d 0.80–1.65 (m, 27H), 3.48 (s, 3H), 5.17 (s,
2H), 6.91–7.42 (m, 4H); MS (FD) m/z 428 (M++1).
{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}(4-methylphe-
nyl)methanone (8y). Compound 8y was prepared as
described for 8w, except using 11o. Purification was
performed by column chromatography on silica gel
eluting with CHCl3/AcOEt (5/1) to obtain 118 mg
(74%). 1H NMR (CDCl3, 500 MHz): d 2.45 (s, 3H), 4.03
(s, 3H), 4.06 (s, 3H), 6.65 (d, J=5.5 Hz, 1H), 7.27 (d,
J=8.6 Hz, 2H), 7.30 (d, J=7.9 Hz, 2H), 7.46 (s, 1H),
7.49 (s, 1H), 7.74 (d, J=7.9 Hz, 2H), 7.91 (d, J=8.5 Hz,
2H), 8.57 (d, J=4.9 Hz, 1H); MS (FD) m/z 399(M+).
Anal. (C25H21NO4) C, H, N.
4-Hydroxyphenyl 4-trifluoromethylphenyl ketone (11p).
Compound 11p was prepared as described for 11n,
except using 4-(trifluoromethyl)benzoyl chloride. Puri-
fication was performed by column chromatography on
silica gel eluting with hexane/acetone (2/1) to obtain 348
mg (30%). MS (FD) m/z 266 (M+).
2-Furoyl 4-hydroxyphenyl ketone (11n). To a solution of
14 (1.28 g, 3.00 mmol) and 2-furoyl chloride (392 mg,
3.00 mmol) in CHCl3 (5 mL) was added PdCl2(PPh3)2 (8
mg, 0.01 mmol) and heated under reflux for 11 h. The
reaction mixture was partitioned between water and
ether and the organic layer was washed with saturated
aqueous KF and brine. The organic layer was dried
over MgSO4 and concentrated. The resulting residue
(662 mg) was dissolved in THF (2 mL) and added 6 N
aqueous HCl (12 mL). The mixture was heated under
reflux for 3 h and partitioned between brine and CHCl3.
(4-Trifluoromethylphenyl){4 - [(6,7 - dimethoxy - 4 - quino-
lyl)oxy]phenyl}methanone (8ab). Compound 8ab was
prepared as described for 8w, except using 11p. Pur-
ification was performed by column chromatography on
silica gel eluting with hexane/acetone (2/1) to obtain 98
mg (60%). Mp 144–146 ꢀC; 1H NMR (CDCl3,
500 MHz): d 4.03 (s, 3H), 4.06 (s, 3H), 6.68 (d, J=4.9
Hz, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.46 (s, 1H), 7.47 (s,
1H), 7.78 (d, J=7.9 Hz, 2H), 7.91 (d, J=7.9 Hz, 2H),

5130
K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
7.94 (d, J=9.2 Hz, 2H), 8.59 (d, J=4.9 Hz, 1H); MS
(FD) m/z 453 (M+). Anal. (C25H18F3NO4) C, H, N.
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}-(4-tert-bu-
tylphenyl)carboxamide (3: Ki6945). To a solution of 16a
(54 mg, 0.18 mmol) and 4-tert-butylbenzoic acid (102
mg, 0.57 mmol) in DMF (3 mL) was added 1-ethyl-3-
(30-dimethylaminopropyl)carbodiimide hydrochloride
(106 mg, 0.55 mmol) and stirred at room temperature
for 6 h. The reaction mixture was partitioned between
water and AcOEt. The organic layer was washed with
brine, dried over Na2SO4 and concentrated. The residue
was purified by column chromatography on silica gel
eluting CHCl3/acetone (10/1) to obtain 59 mg of the 3
4-Hydroxyphenyl 4-nitrophenyl ketone (11r). Compound
11r was prepared as described for 11n, except using 4-
nitrobenzoyl chloride. Purification was performed by
column chromatography on silica gel eluting with hex-
1
ane/acetone (2/1) to obtain 398 mg (55%). H NMR
(DMSO-d6, 500 MHz): d 6.92 (d, J=8.6 Hz, 2H), 7.69
(d, J=8.6 Hz, 2H), 7.89 (d, J=8.5 Hz, 2H), 8.36 (d,
J=8.5 Hz, 2H), 10.62 (s, 1H); MS (FD) m/z 243 (M+).
(72%). Mp 108–110 ꢀC; H NMR (CDCl3, 400 MHz): d
1
{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}(4-nitrophenyl)-
methanone (8ai). Compound 8ai was prepared as
described for 8w, except using 11r. Purification was
performed by column chromatography on silica gel
eluting with hexane/acetone (2/1) to obtain 238 mg
1.37 (s, 9H), 4.05 (s, 3H), 4.06 (s, 3H), 6.49 (d, J=5.4 Hz,
1H), 7.21 (d, J=9.0 Hz, 2H), 7.43 (s, 1H), 7.53 (d, J=8.3
Hz, 2H), 7.57 (s, 1H), 7.75 (d, J=9.0 Hz, 2H), 7.84 (d,
J=8.5 Hz, 2H), 7.90 (br, 1H), 8.49 (d, J=5.4 Hz, 1H);
MS (FD) m/z 456 (M+). Anal. (C28H28N2O4) C, H, N.
(36%). Mp 165–167 ꢀC; H NMR (CDCl3, 500 MHz): d
1
4.63 (s, 3H), 4.07 (s, 3H), 6.69 (d, J=4.9 Hz, 1H), 7.29
(d, J=8.5 Hz, 2H), 7.44 (s, 1H), 7.47 (s, 1H), 7.93 (d,
J=9.2 Hz, 2H), 7.96 (d, J=8.5 Hz, 2H), 8.37 (d, J=8.5
Hz, 2H), 8.60 (d, J=5.5 Hz, 1H); MS (FD) m/z 430
N-(4-t-Butylphenyl)-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-
phenyl}carboxamide (19). To a solution of 4-[6,7-dime-
thoxy-4-quinolyl]oxybenzoic acid (54 mg, 0.17 mmol)
and 4-tert-butylaniline (102 mg, 0.68 mmol) in DMF (3
mL) was added 1-ethyl-3-(30-dimethylaminopro-
pyl)carbodiimide hydrochloride (106 mg, 0.55 mmol)
and stirred at room temperature for 6 h. The reaction
mixture was partitioned between water and AcOEt. The
organic layer was washed with brine, dried over Na2SO4
and concentrated. The residue was purified by column
chromatography on silica gel eluting CHCl3/acetone (10/
+
.
(M ). Anal. (C24H18N2O6 0.5H2O) C, H, N.
4-Hydroxyphenyl 4-trifluoromethoxyphenyl ketone (11s).
Compound 11s was prepared as described for 11n,
except using 4-(trifluoromethoxy)benzoyl chloride. Pur-
ification was performed by column chromatography on
silica gel eluting with hexane/AcOEt (4/1) to obtain 2.1
g (25%). MS (FD) m/z 282 (M+).
1
1) to obtain 29 mg of the 19 (35%). H NMR (CDCl3,
90 MHz): d 1.34 (s, 9H), 4.03 (s, 3H), 4.06 (s, 3H), 6.57 (d,
J=5.3 Hz, 1H), 7.2–8.1 (m, 11H), 8.55 (d, J=5.3 Hz,
1H); MS (FD) m/z 456 (M+); HRMS (ESI)
(C28H29N2O4) (M+H+) calcd 457.2127, found 457.2140.
(4-Trifluoromethoxyphenyl){4-[(6,7-dimethoxy-4-quino-
lyl)oxy]phenyl}methanone (8aj). Compound 8aj was
prepared as described for 8w, except using 11s. Pur-
ification was performed by column chromatography on
silica gel eluting with hexane/AcOEt (4/1) then CHCl3/
AcOEt (5/1) to obtain 470 mg (49%). 1H NMR (CDCl3,
500 MHz): d 4.03 (s, 3H) 4.07 (s, 3H), 6.66 (d, J=4.5 Hz,
1H), 7.28 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.7 Hz, 2H),
7.46 (s, 1H), 7.47 (s, 1H), 7.89 (d, J=8.5 Hz, 2H), 7.92 (d,
N-(4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl)-N-methyl-
(4-t-butylphenyl)carboxamide (18). To a solution of 3
(100 mg) in DMF (3 mL) was added NaH (60% in oil,
10 mg, mmol) and stirred at 0 ꢀC for 1 h. Then, methyl
iodide (31 mg) was added and stirred for 3 h. The reac-
tion mixture was purified by column chromatography
on silica gel eluting CHCl3/acetone (10/1) to obtain 48
J=9.2 Hz, 2H), 8.59 (d, J=4.5 Hz, 1H); MS (FD) m/z
+
.
469 (M ). Anal. (C25H18F3NO5 1.5H2O) C, H, N.
mg of 18 (46%). Mp: 172–174 ꢀC; H NMR (CDCl3,
1
4-(4-Hydroxybenzoyl)benzonitrile (11t). Compound 11t
was prepared as described for 11n, except using 4-
cyanobenzoyl chloride. Purification was performed by
column chromatography on silica gel eluting with hex-
ane/AcOEt (4/1) to obtain 250 mg (37%). 1H NMR
(DMSO-d6, 500 MHz): d 6.91 (d, J=9.2 Hz, 2H), 7.67
(d, J=8.5 Hz, 2H), 7.80 (d, J=7.9 Hz, 2H), 8.01 (d,
J=8.6 Hz, 2H), 10.57 (s, 1H); MS (FD) m/z 223(M+).
90 MHz): d 1.28 (s, 9H), 3.54 (s, 3H), 4.04 (s, 3H), 4.05
(s, 3H), 6.32 (d, J=5.3 Hz, 1H), 7.0–7.3 (m, 8H), 7.42
(s, 1H), 7.50 (s, 1H), 8.47 (d, J=5, 3 Hz, 1H); MS (FD)
+
.
m/z 470 (M ). Anal. (C29H30N2O4 H2O) C, H, N.
N-{3-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}-(4-t-butyl-
phenyl)carboxamide (17a). To a solution of 16b (54 mg,
0.17 mmol) and 4-t-butyl benzoic acid (102 mg, 0.57
mmol) in DMF (3 mL) was added 1-ethyl-3-(30-dime-
thylaminopropyl)carbodiimide hydrochloride (106 mg,
0.55 mmol) and stirred at room temperature for 6 h.
The reaction mixture was purified by column chroma-
tography on silica gel eluting CHCl3/acetone (10/1) to
obtain 50 mg of 17a (61%). Mp: 93 ꢀC; 1H NMR
(CDCl3, 400 MHz): d 1.35 (s, 9H), 4.05 (s, 3H), 4.05 (s,
3H), 6.57 (d, J=5.4 Hz, 1H), 6.97 (ddd, J=1.2, 2.2, 7.8
Hz, 1H), 7.42–7.51 (m, 5H), 7.55(s, 1H), 7.70 (t, J=2.2
Hz, 1H), 7.81(d, J=8.3 Hz, 2H), 8.02 (s, 1H), 8.52 (d,
J=5.4 Hz, 1H); MS (ESI) m/z 457 (M+ +1). Anal.
4-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]benzoyl}benzonitrile
(8ak). Compound 8ak was prepared as described for
8w, except using 11t. Purification was performed by
column chromatography on silica gel eluting with hex-
ane/AcOEt (4/1) then CHCl3/AcOEt (5/1) to obtain 199
mg (47%). Mp 159–160 ꢀC; 1H NMR (CDCl3,
500 MHz): d 4.03 (s, 3H), 4.06 (s, 3H), 6.68 (d, J=5.5
Hz, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.45 (s, 1H), 7.46 (s,
1H), 7.82 (d, J=7.9 Hz, 2H), 7.90 (d, J=8.6 Hz, 2H),
7.91 (d, J=8.5 Hz, 2H), 8.60 (d, J=5.5 Hz, 1H); MS
(FD) m/z 410(M+). Anal. (C25H18N2O4) C, H, N.
.
(C28H28N2O4 H2O) C, H; N: calcd 5.90, found 5.48.

K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
5131
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}-(4-bromo-
phenyl)carboxamide (17b). Compound 17b was pre-
pared as described for 3, except using 4-bromobenzoic
acid. Purification was performed by column chromato-
graphy on silica gel eluting with hexane/AcOEt (4/1)
then CHCl3/AcOEt (5/1) to obtain 43 mg (52%). Mp:
224 ꢀC (decomposition); 1H NMR (CDCl3, 400 MHz): d
4.11 (s, 3H), 4.15 (s, 3H), 6.69 (d, J=6.8 Hz, 1H), 7.25 (d,
J=8.8 Hz, 2H), 7.65 (s, 1H), 7.66 (d, J=8.5 Hz, 2H), 7.85
(d, J=8.5 Hz, 2H), 7.95 (d, J=8.8 Hz, 2H), 8.11 (s, 1H),
8.37 (d, J=6.8 Hz, 1H), 8.39 (s, 1H); MS (ESI) m/z 479
(M+), 481 (M++2); HRMS (ESI) (C24H20BrN2O4)
(M+H+) calcd 479.0606, found 479.0637.
1.49–1.57 (m, 2H), 1.78–1.83 (m, 2H), 4.04 (t, J=6.3
Hz, 2H), 4.11 (s, 3H), 4.15 (s, 3H), 6.70 (d, J=6.6 Hz, 1H),
6.99 (d, J=8.8 Hz, 2H), 7.23 (d, J=9.0 Hz, 2H), 7.65 (s,
1H), 7.90 (d, J=8.8 Hz, 2H), 7.90 (d, J=8.8 Hz, 2H), 8.09
(s, 1H), 8.12 (s, 1H), 8.55 (d, J=6.6 Hz, 1H); ESI-MS (m/
+
.
z): 473 (M +1). Anal. (C24H28N2O5 H2O) C, H, N.
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}-(4-biphenyl)-
carboxamide (17g). To a solution of 6,7-dimethoxy-4-
(4-aminophenoxy)quinoline (52 mg, 0.18 mmol) and
triethylamine (3 mL) in CH2Cl2 (2 mL) was added 4-
biphenylcarbonyl chloride (80 mg, 0.37 mmol). The
mixture was stirred at room temperature for 6 h. The
reaction mixture was purified by column chromato-
graphy on silica gel eluting CHCl3/acetone (10/1) to
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}-(4-trifluoro-
methylphenyl)carboxamide (17c). Compound 17c was
prepared as described for 3, except using 4-tri-
fluoromethylbenzoic acid. Purification was performed
by column chromatography on silica gel eluting with
hexane/AcOEt (4/1) then CHCl3/AcOEt (5/1) to obtain
32 mg (38%). Mp: 240–242 ꢀC; 1H NMR (CDCl3,
400 MHz): d 4.09 (s, 3H), 4.09 (s, 3H), 6.58 (d, J=6.1
Hz, 1H), 7.23 (d, J=8.8 Hz, 2H), 7.61 (s, 1H), 7.78 (d,
J=8.1 Hz, 2H), 7.79 (s, 1H), 7.94 (d, J=8.8 Hz, 2H),
8.11 (d, J=8.3 Hz, 2H), 8.39 (d, J=6.1 Hz, 1H), 8.54 (s,
1H); MS (ESI) m/z 469 (M++1). Anal.
(C25H19F3N2O4) C, H, N.
ꢀ
1
obtain 9 mg of 17g (10%). Mp 235–237 C; H NMR
(CDCl3, 400 MHz): d 4.11 (s, 3H), 4.14 (s, 3H), 6.68 (d,
J=6.3 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H), 7.41–7.51 (m,
4H), 7.64 (d, J=8.5 Hz, 2H), 7.64 (s, 1H), 7.74 (d,
J=8.3 Hz, 2H), 7.94 (d, J=8.8 Hz, 2H), 8.03 (d, J=8.5
Hz, 2H), 8.30 (s, 1H), 8.42 (d, J=6.3 Hz, 1H); MS (ESI)
m/z 476 (M++1). Anal. (C30H24N2O4) C, H, N.
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}-(3,4-dime-
thoxyphenyl)carboxamide (17h). Compound 17h was pre-
pared as described for 3, except using 3,4-
dimethoxybenzoic acid. Purification was performed by
column chromatography on silica gel eluting with hex-
ane/AcOEt (4/1) then CHCl3/AcOEt (5/1) to obtain 7
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}-(4-n-butyl-
phenyl)carboxamide(17d). Compound 17d was prepared
as described for 3, except using 4-n-butylbenzoic acid.
Purification was performed by column chromatography
on silica gel eluting with hexane/AcOEt (4/1) then
CHCl3/AcOEt (5/1) to obtain 65 mg (78%). Mp: 135 ꢀC;
1H NMR (CDCl3, 400 MHz): d 0.95(t, J=7.3 Hz, 3H),
1.33–1.42 (m, 2H), 1.60–1.67 (m, 2H), 2.97 (t, J=7.6 Hz,
2H), 4.09 (s, 3H), 4.10 (s, 3H), 7.60 (d, J=6.1 Hz, 1H),
7.22 (d, J=9.0 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 7.61 (s,
1H), 7.78(s, 1H), 7.83 (d, J=9.0 Hz, 2H), 7.84 (d, J=8.3
Hz, 2H), 8.03 (s, 1H), 8.46 (d, J=5.9 Hz, 1H); MS (ESI)
m/z 457 (M++1). Anal. (C28H28N2O4) C, H, N.
1
mg (8%). H NMR (CDCl3, 400 MHz): d 3.96 (s, 3H),
3.97 (s, 3H), 4.06 (s, 3H), 4.07 (s, 3H), 6.52 (d, J=5.4
Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 7.21 (d, J=9.0 Hz,
2H), 7.47 (dd, J=2.0, 8.3 Hz, 1H), 7.54 (d, J=2.0 Hz,
1H), 7.58 (s, 1H), 7.80 (d, J=9.0 Hz, 2H), 8.01 (s, 1H),
8.19 (s, 1H), 8.47 (d, J=5.6 Hz, 1H); MS (ESI) m/z 461
(M++1). Anal. (C26H24N2O6) C, H, N.
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}-(4-acetyl-
phenyl)carboxamide (17i). Compound 17i was prepared
as described for 3, except using 4-acetylbenzoic acid.
Purification was performed by column chromatography
on silica gel eluting with hexane/AcOEt (4/1) then
CHCl3/AcOEt (5/1) to obtain 43 mg (53%). Mp: 210 ꢀC
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}-(4-nitrophe-
nyl)carboxamide (17e). Compound 17e was prepared as
described for 3, except using 4-nitrobenzoic acid. Puri-
fication was performed by column chromatography on
silica gel eluting with hexane/AcOEt (4/1) then CHCl3/
AcOEt (5/1) to obtain 60 mg (77%). Mp 253 ꢀC
(decomposition); 1H NMR (CDCl3, 400 MHz): d 4.09(s,
3H), 4.12 (s, 3H), 6.64 (d, J=5.9 Hz, 1H), 7.25 (d,
J=9.0 Hz, 2H), 7.33 (s, 1H), 7.63 (s, 1H), 7.65 (s, 1H),
7.90 (d, J=8.8 Hz, 2H), 8.15 (d, J=9.0 Hz, 2H), 8.35
(d, J=8.8 Hz, 2H), 8.51 (d, J=5.9 Hz, 1H); MS (ESI)
m/z 446 (M++1); HRMS (ESI) (C24H20N3O6)
(M+H+) calcd 446.1352, found 446.1340.
1
(decomposition); H NMR (CDCl3, 400 MHz): d 2.67
(s, 3H), 4.09 (s, 3H), 4.10 (s, 3H), 6.59 (d, J=5.9 Hz,
1H), 7.24 (d, J=8.8 Hz, 2H), 7.61 (s, 1H), 7.77 (s, 1H),
7.90 (d, J=8.5 Hz, 2H), 8.05 (d, J=8.8 Hz, 2H), 8.08
(d, J=8.5 Hz, 2H), 8.36 (s, 1H), 8.43 (d, J=5.9 Hz,
1H); MS (ESI) m/z 443 (M++1); HRMS (ESI)
(C26H23N2O5) (M+H+) calcd 443.1607, found
443.1606.
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}-2-thiophene-
carboxamide (17j). Compound 17j was prepared as
described for 3, except using 2-thiophenecaroboxylic
acid. Purification was performed by column chromato-
graphy on silica gel eluting with hexane/AcOEt (4/1)
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}-(4-n-butox-
yophenyl)carboxamide (17f). Compound 17f was pre-
pared as described for 3, except using 4-butoxybenzoic
acid. Purification was performed by column chromato-
graphy on silica gel eluting with hexane/AcOEt (4/1)
1
then CHCl3/AcOEt (5/1) to obtain 37 mg (54%). H
NMR (CDCl3, 400 MHz): d 4.09 (s, 3H), 4.09 (s, 3H),
6.58 (d, J=6.1 Hz, 1H), 7.16 (dd, J=3.9, 5.1 Hz, 1H), 7.20
(d, J=8.8 Hz, 2H), 7.58 (dd, J=1.2, 5.1 Hz, 1H), 7.61 (s,
1H), 7.81 (s, 1H), 7.84 (dd, J=1.2, 3.9 Hz, 1H), 7.87 (d,
J=8.8 Hz, 2H), 8.24 (s, 1H), 8.49 (d, J=5.9 Hz, 1H); MS
1
then CHCl3/AcOEt (5/1) to obtain 34 mg (41%). H
NMR (CDCl3, 400 MHz): d 1.00 (t, J=7.3 Hz, 3H),

5132
K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
(ESI) m/z 391 (M++1); HRMS (ESI) (C22H19N2O4S)
Growth arrested MCs were treated with various con-
centrations of compound in the medium containing
0.1% BSA at 37 ꢀC for 1 h. Then recombinant human
PDGF-BB [Upstate Biotechnology Inc. (UBI)], which
was adjusted to 50 ng/mL as a final concentration in the
medium, was added and incubated at 37 ꢀC for 10 min.
After removal of the medium, lysate of the cells was
prepared. Electrophoresis was carried out using 7.5%
polyacrylamide gel, and the separated proteins in the gel
were transferred to Immunobilon PVDF transfer mem-
brane (Daiichi Pure Chemical, Tokyo, Japan). Western
blot analysis was performed with anti-phosphotyrosine
monoclonal antibody (4G10, UBI). Bound antibodies
were visualized with using horseradish peroxidase-con-
jugated goat anti-mouse IgG (Amersham, UK) and the
enhanced chemiluminescene (ECL) detection system
(Amersham). The density of each protein band was
quantitated using a VIDAS Plus image analyzer (Carl
Zeiss, Oberkochen, Germany). After the analysis of tyr-
osine phosphorylation, bound antibodies on the blotting
membrane were removed. PDGFbr on the membrane
was detected by Western blot with rabbit anti-PDGFbr
antiserum (UBI) and confirmed corresponding bands.
Tyrosine phosphorylation assay of other receptors was
carried out by the same method as that of the PDGFbr.
A431 cells, NIH3T3 cells and HepG2 cells were used to
study autophosphorylation of the EGFr, bFGFr and
insulinbr induced by recombinant human EGF (UBI),
recombinant human bFGF (UBI) and recombinant
human insulin (Sigma Chemical Co.), respectively.
(M+H+) calcd 407.1066, found 407.1080.
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}-2-furamide
(17k). Compound 17k was prepared as described for 3,
except using 2-furoic acid. Purification was performed
by column chromatography on silica gel eluting with
hexane/AcOEt (4/1) then CHCl3/AcOEt (5/1) to obtain
1
35 mg (48%). H NMR (CDCl3, 400 MHz): d 4.08 (s,
3H), 4.10 (s, 3H), 6.58 (d, J=5.9 Hz, 1H), 6.60 (dd,
J=1.7, 3.4 Hz, 1H), 7.22 (d, J=9.0 Hz, 2H), 7.30 (dd,
J=0.7, 3.4 Hz, 1H), 7.55 (dd, J=0.7, 1.7 Hz, 1H), 7.60
(s, 1H), 7.70 (s, 1H), 7.80 (d, J=8.8 Hz, 2H), 8.19 (s,
1H), 8.49 (d, J=5.9 Hz, 1H); MS (ESI) m/z 391
(M++1); HRMS (ESI) (C22H19N2O5) (M+H+) calcd
391.1294, found 391.1274.
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}acetamide
(17l). Compound 17l was prepared as described for
17g, except using acetic anhydride. Purification was
performed by column chromatography on silica gel eluting
with hexane/AcOEt (4/1) then CHCl3/AcOEt (5/1) to
obtain 7 mg (10%). Mp: 105ꢀC; 1H NMR (CDCl3,
400 MHz): d 2.27 (s, 3H), 4.11 (s, 3H), 4.17 (s, 3H), 6.65 (d,
J=6.6 Hz, 1H), 7.17 (d, J=8.8 Hz, 2H), 7.64 (s, 1H), 7.81
(d, J=8.8 Hz, 2H), 7.90 (s, 1H), 8.12 (s, 1H), 8.39 (d,
J=6.3 Hz, 1H); MS (ESI) m/z 339 (M++1); HRMS (ESI)
(C19H19N2O4) (M+H+) calcd 339.1345, found 339.1367.
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}cyclopro-
panecarboxamide (17m). Compound 17m was prepared
as described for 3, except using cyclohexanecarboxylic
acid. Purification was performed by column chromato-
graphy on silica gel eluting with hexane/AcOEt (4/1)
Cell-free receptor tyrosine kinase assay
Tyrosine phosphorylation of PDGFbr was analyzed by
Western blot using anti-phosphotyrosine antibodies and
detected by ECL fluorography as previously published14
and the method was briefly described as follows.
1
then CHCl3/AcOEt (5/1) to obtain 45 mg (64%). H
NMR (CDCl3, 500 MHz): d 1.64 (m, 2H), 1.81 (m, 2H),
1.91 (m, 4H), 2.75 (m, 1H), 4.04 (s, 3H), 4.04 (s, 3H), 6.44
(d, J=4.9 Hz, 1H), 7.13 (d, J=9.2 Hz, 2H), 7.45 (s, 1H),
7.55 (m, 1H), 7.65 (d, J=8.6 Hz, 2H), 8.47 (d, J=5.5 Hz,
1H); MS (ESI) m/z 393 (M++1); HRMS (ESI)
(C23H25N2O4) (M+H+) calcd 393.1814, found 393.1794.
Lysate of quiescent NIH3T3 cells was prepared by
treatment of the detergent buffer (50 mM Hepes (pH
7.5), 1.5 mM MgCl2, 150 mM NaCl, 1 mM EGTA,
10% glycelol, and 1% Triton X-100). The lysate was
reduced with PDGF-BB (50 ng/mL) at 4 ꢀC for 30 min,
then PDGFbr antiserum at a 1:100 dilution as a final
concentration and with protein A-sepharose-beads
(Pharmacia Biotech). The immunoprecipitates were
washed with HNTG buffer [20 mM Hepes (pH 7.5), 150
mM NaCl, 0.1% Triton X-100 and 10 mM MgCl2]. The
mixture was incubated with compound at 4 ꢀC for 10
min. The reaction was started by the addition of 20 mM
ATP (disodium salt, Sigma), incubated at 4 ꢀC for 10
min and stopped by the addition of SDS sample buffer
(0.14 M Tris–HCl (pH 7.5), 22.4% glycelol, 6% SDS,
0.02% bromophenol blue, 10% 2-marcaptoethanol).
N-{4-[6,7-Dimethoxy-4-quinolyl]oxy}phenyl}cyclohexane-
carboxamide (17n). Compound 17n was prepared as
described for 3, except using cyclohexanecarboxylic
acid. Purification was performed by column chromato-
graphy on silica gel eluting with hexane/AcOEt (4/1)
then CHCl3/AcOEt (5/1) to obtain 45 mg (64%).
1
Amorphous substance; H NMR (CDCl3, 400 MHz): d
1.26–1.39 (m, 3H), 1.52–1.62 (m, 2H), 1.79–2.00 (m,
5H), 2.27–2.33 (m, 1H), 4.08 (s, 3H), 4.11 (s, 3H), 6.55
(d, J=6.1 Hz, 1H), 7.16 (d, J=9.0 Hz, 2H), 7.45 (s,
1H), 7.60 (s, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.78 (s, 1H),
8.45 (d, J=5.9 Hz, 1H); MS (ESI) m/z 407 (M++1).
.
Anal. (C24H26N2O4 H2O) C, H, N.
EGFr kinase assay was measured by Homogeneous
time resolved florescence (HTRF) techniques,19 it was
based on phosphorylation of biotinylated poly-Glu, Tyr
[CIS bio international (CIS)] by EGFr. Src kinase
activity was measured in ELISA system (Roche, Tyr-
oisine Kinase Assay Kit), it was based on phosphoryla-
tion of p34cdc2 substrate peptide, PKS-1, by Src. PKA
kinase activity was measured by PKA Assay Kit (UBI),
CGP 53716 was prepared by previous literatures.10
Receptor autophosphorylation assay in intact cells
The assay of PDGFbr autophosphorylation was carried
out by a method previously published,14 and the
method was briefly described as follows.

K. Kubo et al. / Bioorg. Med. Chem. 11 (2003) 5117–5133
5133
it was based on phosphorylation of a specific peptide,
Kemptide, using the transfer of [g-32P] ATP by PKA.
PKC kinase activity was measured by PKC Assay Kit
(UBI), it was based on phosphorylation of a specific
peptide, QKRPSQRSKYL, using the transfer of [g-32P]
ATP by PKC. MAP kinase activity was measured by
MAP Kinase Assay Kit (UBI), it was based on phos-
phorylation of a specific substrate, myelin basic protein
(MBP), using the transfer of [g-32P] ATP by MAP
kinase. MEK1 activity was measured by MEK1 Assay
Kit (UBI), it was based on phosphorylation of a specific
substrate, myelin basic protein (MBP), using the trans-
fer of [g-32P] ATP.
Faltynek, C. R.; Xie, W.; Sarup, J.; Bode, D. C.; Pagani, E. D.;
Silver, P. J. J. Med. Chem. 1994, 37, 2627.
9. (a) Kovalenko, M.; Gazit, A.; Bohmer, A.; Rorsman, C.;
Ronnstrand, L.; Heldin, C.-H.; Waltenberger, J.; Bohmer, F.-
D.; Levitzki, A. Cancer Res. 1994, 54, 6106. (b) Bilder, G.;
Wentz, T.; Leadley, R.; Leadley, R.; Amin, D.; Byan, L.;
O’Conner, B.; Needle, S. M.; Galczenski, H.; Bostwick, J.;
Kasiewski, C.; Myers, M.; Spada, A.; Merkel, L.; Ly, C.;
Persons, P.; Page, K.; Perrone, M.; Dunwiddie, C. Circulation
1999, 99, 3292.
10. (a) Buchdunger, E.; Zimmermann, J.; Mett, H.; Meyer, T.;
Muller, M.; Regenass, U.; Lydon, N. B. Proc. Natl. Acad. Sci.
U.S.A. 1995, 92, 2558. (b) Zimmermann, J.; Buchdunger, E.;
Mett, H.; Meyer, T.; Lydon, N. B.; Traxler, P. Bioorg. Med.
Chem. Lett. 1996, 6, 1221. (c) Zimmermann, J.; Buchdunger,
E.; Mett, H.; Meyer, T.; Lydon, N. B. Bioorg. Med. Chem.
Lett. 1997, 7, 187.
11. Sun, L.; Tran, N.; Liang, C.; Tang, F.; Rice, A.; Shreck,
R.; Waltz, K.; Shawver, L. K.; McMahon, G.; Tang, C. J.
Med. Chem. 1999, 42, 5120.
References and Notes
12. Yu, J.-C.; Lokker, N. A.; Hollenbach, S.; Apatira, M.; Li,
J.; Betz, A.; Sedlock, D.; Oda, S.; Nomoto, Y.; Matsuo, K.;
Ide, S.; Tsukuda, E.; Giese, N. A. J. Pharm. Exp. Ther. 2001,
298, 1172.
1. (a) Plowman, G. D.; Ullrich, A.; Shawver, L. K. Drug News
Perspect 1994, 7, 334. (b) Schlessinger, J.; Ullich, A. Neuron
1992, 9, 383.
2. (a) Yarden, Y.; Escobedo, J. A.; Kuang, W. J.; Yang-Feng,
T. L.; Daniel, T. O.; Tremble, P. M.; Chen, E. Y.; Ando,
M. E.; Harkins, R. N.; Francke, U.; Fried, V. A.; Ullich, A.;
Williams, L. T. Nature 1986, 323, 226. (b) Claesson-Welsh, L.;
Eriksson, A.; Westermark, B.; Popescu, N.; Rochelle, W. L.;
Kraus, M.; Pierce, J.; Aaronson, S. Proc. Natl. Acad. Sci.
U.S.A. 1989, 86, 4917. (c) Matsui, T.; Heidaran, M.; Miki, T.;
Popescu, N.; Rochelle, W.L.; Kraus, M.; Pieree, J.; Aaronson,
S. Science 1989, 243, 800. (d) Soriano, P. Genes Dev. 1994, 8,
1888.
3. (a) Heldin, C.-H.; Westermark, B. Transplan. Proc 1993,
25, 2074. (b) Heldin, C. H. EMBO J. 1992, 11, 4251.
4. Hubbard, S. R.; Till, J. H. Annu. Rev. Biochem. 2000, 69,
373.
5. Bilder, G. E.; Kasiewski, C. J.; Walczak, E. M.; Perrone,
M. H. Drug Dev. Res. 1993, 29, 158.
13. Kubo, K.; Shimizu, T.; Ohyama, S.; Murooka, H.; Nishi-
toba, T.; Kato, S.; Kobayashi, Y.; Yagi, M.; Isoe, T.; Naka-
mura, K.; Osawa, T.; Izawa, T. Bioorg. Med. Chem. Lett.
1997, 23, 2935.
14. Yagi, M.; Kato, S.; Kobayashi, Y.; Kubo, K.; Ohyama,
S.; Shimizu, T.; Nishitoba, T.; Isoe, T.; Nakamura, K.; Oha-
shi, H.; Kobayashi, N.; Iinuma, N.; Osawa, T.; Onose, R.;
Osada, H. Exp. Cell Res. 1997, 234, 285.
15. (a) Kawada, A.; Mitamura, S.; Kobayashi, S. J. Chem.
Soc., Chem. Commun 1993, 1157. (b) Kobayashi, S. Synlett
1994, 689.
16. Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem.
1983, 48, 4634.
17. Patani, G. A.; Lavoie, E. J. Chem. Rev. 1996, 96, 3147.
18. Yagi, M.; Kato, S.; Kobayashi, Y.; Kobayashi, N.;
Iinuma, N.; Nakamura, K.; Kubo, K.; Ohyama, S.; Murooka,
H.; Shimizu, T.; Nishitoba, T.; Osawa, T.; Nagano, N. Gen.
Pharmac 1998, 31, 765.
19. (a) Kolb, A. J.; Kaplita, P. V.; Hayes, D. J.; Park, Y. W.;
Pernell, C.; Major, J. S.; Mathis, G. Drug Discov. Today 1988,
3, 333. (b) Gaarde, W. A.; Hunter, T.; Brady, H.; Murray,
B. W.; Goldman, M. E. J Biomol Screen 1997, 2, 213. (c)
Ohmi, N.; Wingfield, J. M.; Yazawa, H.; Inagaki, O. J Biomol
Screen 2000, 5, 463.
6. Fry, D. W.; Kracker, A. J.; McMichael, A.; Ambroso,
L. A.; Nelson, J. M.; Leopold, W. R.; Connors, R. W.;
Bridges, A. J. Science 1994, 265, 1093.
7. Dumas, J. Exp.Opin, Ther. Pat 2001, 11, 405.
8. (a) Maguire, M. P.; Sheets, K. R.; McVety, K.; Spada,
A. P.; Zilberstein, A. J. Med. Chem. 1994, 37, 2129. (b) Dolle,
R. E.; Dunn, J. A.; Bobko, M.; Singh, B.; Kuster, J. E.; Baiz-
man, E.; Harris, A. L.; Sawutz, D. G.; Miller, D.; Wang, S.;