Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors

Article abstract of DOI:10.1016/j.bmc.2013.04.013

A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure-activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC₅₀ value of 0.59 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor.

Full text of DOI:10.1016/j.bmc.2013.04.013

Bioorganic & Medicinal Chemistry 21 (2013) 2843–2855
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing
4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase
inhibitors
⇑
Sai Li, Yanfang Zhao, Kewen Wang, Yali Gao, Jianming Han, Bingbing Cui, Ping Gong
Key Lab of New Drug Design and Discovery of Liaoning Province, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 110016 Shenyang, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 February 2013
Revised 1 April 2013
Accepted 4 April 2013
Available online 16 April 2013
A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-car-
boxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against
c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All
the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of
their structure–activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl
group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a prom-
ising compound 33, with a c-Met IC50 value of 0.59 nM, was identified as a multitargeted receptor tyro-
sine kinase inhibitor.
Keywords:
Receptor tyrosine kinase
c-Met
4-(2-Fluorophenoxy)quinoline derivatives
4-Oxo-1,4-dihydrocinnoline-3-carboxamide
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
inhibitors, foretinib, which is currently undergoing phase II studies
for different cancer types, is a novel oral multikinase inhibitor tar-
c-Met is a receptor tyrosine kinase that is normally activated by
binding its natural ligand hepatocyte growth factor, also known as
scatter factor (HGF/SF). The binding of HGF to c-Met induces sev-
eral complex signaling pathways and results in cell proliferation,
motility, migration, and survival.1–3 These cellular activities are
important during normal development and wound healing but
can lead to cancer when the pathway is deregulated. For example,
c-Met has been found to be overexpressed or mutated in human
cancers, and in many instances, the overexpression of c-Met has
been correlated with advanced disease stage and poor progno-
sis.4–7 As a result, c-Met has attracted considerable attention as a
potential target for cancer treatment.8–10
geting c-Met, VEGFR2, RON, KDR, and Flt-1.28 On account of its
advantage of multi-targets effects and satisfactory clinical results,
great attentions were attracted to the construction of 4-(2-fluoro-
phenoxy)quinoline derivatives and a variety of analogs have been
reported as small-molecule c-Met inhibitors.
As shown in Figure 2, these quinoline analogs28–33 have two
obvious structural characteristics in their linkers between moiety
A and moiety B. One is ‘five atoms regulation’, which means six
chemical bonds distance existing between moiety A and moiety
B; the other is the linker containing both hydrogen-bond donor
or acceptor and at least one amide group. In addition, the modifi-
cations of A moiety usually occurs at 7-position of quinoline, where
the methoxy group is replaced by a water-soluble fragment, such
as 3-morpholinopropoxy group, etc. However, there is little change
to moiety B except phenyl ring or substituted phenyl ring.
To our knowledge, compounds bearing 4-oxo-1,4-dihydrocinn-
oline-3-carboxa-mide fragment have been reported to exhibit a
large field of biological activities, including antitumor,34 antibacte-
rial,35 and anti-inflammatory activities,36 etc. Remarkably, this
framework conformed to the characteristics mentioned above, so
it was introduced to the target compounds as the linker.
To date, a variety of strategies have been employed to interrupt
the c-Met signalling pathway. These include antibody-based ther-
apies,11–14 truncated HGF fragments,15–17 decoy receptors,18 ribo-
zymebased
treatment,19,20
and
small-molecule
kinase
inhibitors.21–27 Recently, significant progress has been made on
the development of c-Met inhibitors resulting in more than ten
candidates have been in clinical trials, including foretinib (1, Phase
II),28 cabozantinib (2, Phase III),29 as well as several newly devel-
oped compounds bearing thienopyridine (MGCD265, 3, Phase
II),30 pyridine (BMS-777607, 4, Phase I)31 frameworks (Fig. 1),
et al., as the primary pharmacophoric scaffolds. Among these
Taking foretinib as the leading compound, a series of novel
4-(2-fluorophenoxy)quinoline derivatives (I, Fig. 3) were designed,
in which the moiety A was preserved and the 4-oxo-1-phenyl-1,4-
dihydrocinnoline-3-carboxamide fragment was attached to the C-
40 positon. Meanwhile, the morpholinyl group at 7-position of
⇑
Corresponding author. Tel./fax: +86 24 23986426.
E-mail address: gongpinggp@126.com (P. Gong).
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.04.013

2844
S. Li et al. / Bioorg. Med. Chem. 21 (2013) 2843–2855
Figure 1. Structures of foretinib and other c-Met inhibitors in clinical trials.
Figure 2. Structures of several 4-(2-fluorophenoxy)quinoline derivatives.
quinoline scaffold was replaced by several water-soluble groups
including piperidinyl, pyrrolidinyl and 4-methyl piperidinyl
groups. Additionally, various R3 substituted phenyl rings were
introduced to the 1-position of 4-oxo-1,4-dihydrocinnoline moiety
and a fluorine atom was as well added to the 7-position to inves-
tigate their effects on activity. In this paper, the synthesis of these
quinoline derivatives was reported and their c-Met kinase activity,
as well as cytotoxicity against six human cancer cell lines were
evaluated.
2. Chemistry
The synthetic route of the key intermediates 8a–e was illus-
trated in Scheme 1. The commercially available starting material
Figure 3. General structure of the target compounds.

S. Li et al. / Bioorg. Med. Chem. 21 (2013) 2843–2855
2845
Scheme 1. Reagents and conditions: (a) Br(CH2)3Cl, (CH3)2CO, K2CO3, rt; (b) fuming HNO3, CH2Cl2, ꢀ20 °C; (c) DMF–DMA, PhMe, 110 °C; (d) Fe, HOAc, 85 °C; (e) amine,
CH3CN, reflux; (f) POCl3, CH3CN, 85 °C; (g) 2-fluoro-4-nitrophenol, PhCl, reflux; (h) Fe, NH4Cl, EtOH, reflux.
1-(4-hydroxy-3-methoxyphenyl) ethanone was alkylated with 1-
bromo-3-chloropropane in acetone under basic condition to pro-
vide compound 1, which was converted to nitro compound 2 using
fuming nitric acid as nitration reagent in dichloromethane at
ꢀ20 °C for 6 h with 70% yield.37 Next, condensation of 2 with di-
methyl formamide dimethyl acetal (DMF–DMA) in refluxing tolu-
ene afforded yellow solid 3, which was reduced and cyclized
using glacial acetic acid and iron powder to provide hydroxy-quin-
oline 4 with a high yield and purity in a single step.38 Substitution
of 4 with excessive secondary amines (piperidine, 4-methyl piper-
idine, morpholine, and pyrrolidine) in acetonitrile at reflux pro-
vided intermediates 5a–d, which were treated with phosphorus
oxychloride to afford chloro-quinoline 6a–d,39 respectively. Fur-
ther, the obtained compounds 6a–d were etherified with 2-flu-
oro-4-nitrophenol in chlorobenzene to obtain purified
compounds 7a–d, which were reduced using iron powder and cat-
alytic amounts of ammonium chloride in ethanol to obtain amides
8a–d.40
The synthesis of target compounds 17–49 was summarized in
Scheme 2. The starting material, 2-fluorobenzoic acid or 2,4-diflu-
orobenzoic acid, were separately treated with dichlorosulfoxide
(SOCl2) in the presence of a catalytic amount of DMF and then acyl-
ated with meldrum’s acid and 4-dimethyl aminopyridine (DMAP)
in dichloromethane at 0 °C for 5–6 h to give compounds 9a and
9b.41 Refluxing in ethanol, 9a and 9b yielded esters 10a and 10b.
Subsequently, the condensation of 10a or 10b with different
substituted diazotized anilines in the presence of sodium acetate
in ethanol/water mixed solution obtained esters 11a–t and 12a–
Scheme 2. Reagents and conditions: (a) (1) SOCl2, PhMe, reflux, (2) DMAP, Meldrum’s acid, CH2Cl2, ꢀ10 °C; (b) EtOH, reflux; (c) NaNO2, HCl, phenylamine, C2H5COONa, 0–
25 °C; (d) 5% NaOH/EtOH, 50 °C; (e) SOCl2, reflux; (f) Et3N, CH2Cl2, 25 °C.

2846
S. Li et al. / Bioorg. Med. Chem. 21 (2013) 2843–2855
b,42 which could be converted to acids 13a–t and 14a–b in the 5%
sodium hydroxide solution at 50 °C for 2 h, respectively.43 Next,
the acids 13a–t and 14a–b separately refluxed in SOCl2 for 8 h to
provide acyl chlorides 15a–t and 16a–b, which were condensed
with intermediates 8a–d in the presence of triethylamine in
dichloromethane at room temperature overnight to obtain the tar-
get compounds 17–49, respectively.
Table 1
c-Met enzymatic activity of the target compounds 17–49
ID
R1
R2
R3
IC50 (nM)
c-Met
17
18
2-Cl
2-CF3
3-F
3-CF3
4-Cl
4-Br
2,4-(Cl)2
2,6-(Cl)2
2,4-(CH3)2
1.65 0.11
1.22 0.23
N
19
20
21
22
23
24
25
3.02 0.69
3.13 0.47
2.72 0.51
2.76 0.31
8.42 1.6
5.23 1.1
14.5 2.10
H
3. Biology
3.1. HTRF kinase assay
26
27
2-F
2-Br
3-CF3
4-F
4-CH3
2,6-(Cl)2
4-Cl-3-CF3
2.64 0.32
5.08 0.84
N
N
The c-Met kinase activity of all compounds was evaluated using
homogeneous time-resolved fluorescence (HTRF) assay as previ-
ously reported.44,45 In addition, the most promising compound
33 was further evaluated against other five tyrosine kinase (c-Kit,
Flt-3, VEGFR-2, EGFR, and PDGFR) using the same screening meth-
28
29
30
31
32
5.05 0.65
3.40 0.31
18.4 2.30
5.92 1.04
4.12 0.75
H
od. Briefly, 20
lg/mL poly (Glu, Tyr) 4:1 (Sigma) was precoated as a
33
34
2-CF3
3-CF3
3,4-(F)2
2,6-(Cl)2
2-Cl-5-CF3
2,5-(CH3)2
2-Br-4-F
0.59 0.07
11.9 1.65
substrate in 384-well plates. Then 50
lL of 10 mM ATP (Invitrogen)
35
36
37
38
39
3.55 0.74
6.68 1.00
4.50 0.80
10.4 1.25
13.5 2.37
solution diluted in kinase reaction buffer (50 mM HEPES, Ph 7.0,
1 M DTT, 1 M MgCl2, 1 M MnCl2, and 0.1% NaN3) was added to each
well. Various concentrations of compounds diluted in 10 lL of 1%
DMSO (v/v) were used as the negative control. The kinase reaction
H
H
F
40
41
42
43
44
45
H
2-Cl
2-CF3
2-OCF3
4-Br
3.64 1.02
1.05 0.17
1.03 0.27
4.80 1.00
7.54 1.05
10.24 1.75
was initiated by the addition of purified tyrosine kinase proteins
N
O
O
diluted in 39
time for the reactions was 30 min at 25 °C and stopped by the addi-
tion of 5 L of Streptavidin-XL665 and 5 L Tk Antibody Cryptate
lL of kinase reaction buffer solution. The incubation
l
l
2,5-(CH3)2
working solution to all of wells. The plates were read using Envi-
sion (PerkinElmer) at 320 and 615 nM. The inhibition rate (%)
46
47
2-F
2-Cl
24.35 4.20
21.12 3.35
N
N
N
was calculated using the following equation:
%
inhibi-
tion = 100 ꢀ [(Activity of enzyme with tested compounds ꢀ Min)/
(Max ꢀ Min)] ꢁ 100 (Max: the observed enzyme activity measured
in the presence of enzyme, substrates, and cofactors; Min: the ob-
served enzyme activity in the presence of substrates, cofactors and
in the absence of enzyme). IC50 values were calculated from the
inhibition curves.
48
2-F
27.49 5.10
49
2-Cl
20.57 3.61
1.16 0.17
Foretinib
were evaluated for their inhibitory activity toward c-Met enzyme
using a homogeneous time-resolved fluorescence (HTRF) assay.
Taking foretinib as the positive control, the results expressed as
IC50 were summarized in Table 1. The IC50 values are the average
of at least three independent experiments.
As illustrated in Table 1, all the tested compounds displayed po-
tent c-Met enzymatic activity with IC50 values ranging from 0.59 to
27.50 nM. Compared with foretinib (IC50 = 1.16 nM), five of them
(17, 18, 33, 41, 42) exhibited equivalent or higher potency with
IC50 values less than 2 nM, which indicated that replacement of
the N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide frame-
work with 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety
maintained the c-Met inhibitory efficacy. In addition, the activity
of compounds 17–45 (R2 = H) was significantly higher than com-
pounds 46–49 (R2 = F), suggesting that the introduction of a 7-flu-
oro group to the 4-oxo-1,4-hydrocinnoline ring led to an obvious
decline in efficiency.
Further analysis revealed that the introduction of different
water-soluble R1 groups had a slight influence on activity, which
suggested that the R1 group contributed little to their potency.
For example, compounds 18, 33 and 42 exhibited comparable
c-Met kinase activity with IC50 values of 1.22, 0.59 and 1.03 nM,
respectively. However, different biological properties were ob-
served when various R3 groups were introduced to the phenyl ring
(B moiety). Compound 40, with no substituent on the phenyl ring,
displayed strong enzymatic activity with an IC50 of 3.64 nM. The
addition of mono-EWGs, especially the halogen atoms and trifluo-
romethyl group led to an obvious improvement in activity such as
compound 41 (R3 = 2-chloro, IC50 = 1.05 nM) and 42 (R3 = 2-trifluo-
3.2. Cell proliferation assay
The antiproliferative activities of compounds 17–49 were eval-
uated against five c-Met-dependent cancer cell lines (A549, HT-29,
MKN-45, U87MG, and SMMC-7721) and one c-Met-independent
cancer cell line (H460) using the standard MTT assay in vitro, with
foretinib as the positive control.46–49 The cancer cell lines were cul-
tured in minimum essential medium (MEM) supplemented with
10% fetal bovine serum (FBS). Approximate 4 ꢁ 103 cells, sus-
pended in MEM medium, were plated onto each well of a 96-well
plate and incubated in 5% CO2 at 37 °C for 24 h. The compounds
tested at the indicated final concentrations were added to the cul-
ture medium and the cell cultures were continued for 72 h. Fresh
MTT was added to each well at a terminal concentration of 5 lg/
mL, and incubated with cells at 37 °C for 4 h. The formazan crystals
were dissolved in 100 mL of DMSO each well, and the absorbency
at 492 nM (for absorbance of MTT formazan) and 630 nM (for the
reference wavelength) was measured with an ELISA reader. All of
the compounds were tested three times in each cell line. The re-
sults expressed as IC50 (inhibitory concentration 50%) were the
averages of three determinations and calculated by using the Bacus
Laboratories Incorporated Slide Scanner (Bliss) sofeware.
4. Results and discussion
4.1. In vitro enzymatic assays
All the newly synthesized 4-(2-fluorophenoxy)quinoline deriv-
atives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety

S. Li et al. / Bioorg. Med. Chem. 21 (2013) 2843–2855
2847
romethyl, IC50 = 1.03 nM). However, the introduction of double-
electron-withdrawing groups (double-EWGs) (23, R3 = 2,4-di-
chloro, IC50 = 8.42 nM) or electron-donating groups (EDGs)
The data listed in Table 2 revealed that compounds 17–49 pos-
sessed moderate to strong cytotoxicity against the five tested cell
lines in the single-digit
lM range, and high selectivity for inhibi-
(30, R3 = 4-methyl, IC50 = 18.4 nM; 45, R3 = 2,5-dimethyl, IC50
=
tion A549, H460 and MKN-45 cells. The promising compound 33
10.24 nM) caused the potency reduce by 2.3-, 5.0- and 2.8-fold,
respectively. This could be demonstrated that mono-EWGs had a
positive effect on c-Met kinase activity, but double-EWGs and
EDGs showed negative results. Moreover, it was worth noting that
the position of R3 group was closely related to c-Met inhibitory
efficiency as well. Compounds with 2-substituted phenyl group
(26, R3 = 2-F, IC50 = 2.64 nM) displayed higher potency than those
with 3- (19, R3 = 3-F, IC50 = 3.02 nM) or 4-substituted phenyl group
(29, R3 = 4-F, IC50 = 3.40 nM). Among them, 2-chloro and 2-trifluo-
romethyl groups were the most favorable for activity.
was more active than foretinib against these tested cell lines with
IC50 values of 0.035, 0.055, 0.11, 0.022, 0.35 and 0.25 lM, respec-
tively. The study of structure–activity relationships (SARs) indi-
cated that these analogs showed similar SARs as summarized in
the c-Met kinase level: (a) compounds with the same R1 but differ-
ent R3 groups showed marked difference in cytotoxicity, while
compounds with the same R3 but different R1 exhibited equivalent
activity; (b) compounds bearing mono-EWGs were generally more
active than those with double-EWGs or EDGs; (c) the cytotoxicity
of compounds with substituent at 2-position of phenyl ring was
higher than those with substituents at other positions.
4.2. In vitro cell assays
4.3. Enzymatic selectivity assays
All the target compounds were evaluated for their antitumor
activity against A549 (non-small cell lung cancer), H460 (human
lung cancer), HT-29 (human colon cancer) and MKN-45 (human
gastric cancer cancer) cancer cell lines together with foretinib as
the positive control by a MTT assay. Furthermore, some potent
compounds were further evaluated against U87MG (human glio-
blastoma) and SMMC-7721 (human liver cancer) cell lines. The re-
sults expressed as IC50 were summarized in Table 2. The IC50 values
are the average of at least three independent experiments.
To examine whether compound 33 is a selective c-Met inhibi-
tor, 33 was screened against other 5 tyrosine kinases (Table 3).
Compared with its high potency against c-Met (IC50 = 0.59 nM),
33 also exhibited inhibitory effects against VEGFR-2, c-Kit, Flt-3,
PDGFR-
against c-Met. Moreover, this compound showed little or no kinase
inhibition activity against EGFR kinase (IC50 >10 M). These data
a although the potency was 6.5- to 45-fold lower than that
l
suggested that compound 33 is a promising selective multitarget
kinase inhibitor.
Table 2
In vitro growth inhibitory effects of compounds with 1,4-dihydrocinnolinone fragment
ID
R1
R2
R3
IC50 SEM (lM)
A549
H460
HT29
MKN-45
U87MG
SMMC-7721
17
18
2-Cl
2-CF3
0.043 0.0080
0.055 0.010
0.073 0.010
0.081 0.010
0.26 0.040
0.56 0.10
0.05 0.010
0.027 0.0042
0.49 0.090
1.16 0.15
0.42 0.090
1.35 0.20
N
19
20
21
22
23
24
25
3-F
3- CF3
4-Cl
0.11 0.013
0.31 0.040
0.20 0.031
0.53 0.10
0.47 0.10
0.41 0.071
1.28 0.19
0.91 0.12
1.03 0.13
0.64 0.10
0.40 0.072
1.03 0.17
0.77 0.15
1.57 0.25
1.88 0.22
0.56 0.083
2.12 0.33
1.14 0.10
0.99 0.12
1.15 0.20
3.56 0.65
0.14 0.030
0.27 0.021
0.23 0.40
0.45 0.085
0.59 0.083
0.39 0.060
1.85 0.37
2.46 0.35
1.62 0.30
1.62 0.28
1.60 0.32
ND
2.02 0.26
0.33 0.051
0.33 0.050
0.84 0.12
ND
H
4-Br
2,4-(Cl)2
2,6-(Cl)2
2,4-(CH3)2
1.36 0.27
ND
ND
ND
26
27
2-F
2-Br
3-CF3
4-F
4-CH3
2,6-(Cl)2
4-Cl-3-CF3
0.33 0.042
0.35 0.066
0.29 0.031
0.83 0.17
0.78 0.080
1.34 0.22
0.58 0.10
0.28 0.055
1.21 0.16
2.16 0.36
0.73 0.018
1.12 0.20
ND
0.95 0.15
ND
ND
0.93 0.15
ND
0.82 0.11
0.37 0.088
N
N
28
29
30
31
32
0.21 0.040
0.15 0.012
1.05 0.12
0.40 0.071
0.24 0.046
0.55 0.10
0.89 0.11
1.99 0.25
0.65 0.11
0.11 0.010
1.02 0.16
0.46 0.094
2.85 0.51
0.92 0.10
0.49 0.050
0.16 0.010
0.17 0.021
1.22 0.16
0.36 0.051
0.14 0.030
H
1.04 0.10
0.54 0.012
33
34
2-CF3
3-CF3
0.035 0.0042
0.30 0.025
0.055 0.010
1.04 0.25
0.11 0.016
0.78 0.21
0.022 0.0035
0.19 0.040
0.35 0.060
0.85 0.15
0.25 0.072
0.63 0.10
35
36
37
38
39
3,4-(F)2
0.26 0.48
0.35 0.045
0.20 0.021
1.15 0.20
1.03 0.44
0.64 0.12
0.37 0.045
0.61 0.06
2.03 0.35
3.65 0.65
1.12 0.15
1.05 0.17
1.12 0.19
3.05 0.47
2.91 0.30
0.35 0.060
0.35 0.050
0.17 0.023
0.42 0.070
1.72 0.22
1.06 0.40
1.25 0.40
1.42 0.33
2.47 0.42
ND
0.59 0.11
0.84 0.16
ND
ND
ND
2,6-(Cl)2
2-Cl-5-CF3
2,5-(CH3)2
2-Br-4-F
H
H
F
40
41
42
43
44
45
H
2-Cl
2-CF3
2-OCF3
4-Br
0.57 0.11
0.03 0.004
0.06 0.010
0.48 0.10
1.10 0.043
0.75 0.12
0.69 0.072
0.01 0.001
0.08 0.01
0.62 0.11
2.1 0.30
0.59 0.10
1.17 0.18
0.24 0.032
0.51 0.01
1.12 0.13
3.2 0.30
0.96 0.17
0.01 0.0017
0.02 0.003
0.76 0.11
0.68 0.10
0.03 0.0025
1.46 0.20
1.69 0.32
1.48 0.27
1.04 0.16
1.97 0.25
1.36 0.21
1.13 0.15
0.92 0.11
0.84 0.18
ND
ND
ND
N
O
O
2,5-(CH3)2
1.15 0.18
46
47
2-F
2-Cl
3.27 0.40
1.82 0.34
3.28 0.51
1.51 0.30
5.07 0.64
2.47 0.41
2.79 0.45
1.62 0.21
ND
ND
ND
ND
N
N
N
48
2-F
2.04 0.33
2.25 0.45
2.95 0.39
1.54 0.27
ND
ND
49
2-Cl
1.05 0.15
0.08 0.01
1.25 0.15
0.18 0.03
1.37 0.20
1.56 0.23
ND
ND
Foretinib
0.15 0.023
0.03 0.0055
0.90 0.13
0.44 0.062
ND = not determined.

2848
S. Li et al. / Bioorg. Med. Chem. 21 (2013) 2843–2855
Table 3
in activity. Preliminary biochemical selectivity screening revealed
Inhibition of tyrosine kinases by compound 33
that compound 33 is a multitarget kinase inhibitor. Further studies
on the structural optimization about these derivatives are still
underway in our laboratory.
Kinase
Enzyme IC50 (nM)
c-Kit
3.9
Flt-3
8.5
7. Experimental
VEGFR-2
PDGFR
EGFR
15.37
27.3
>10,000
All melting points were obtained on a Büchi Melting Point B-
540 apparatus (Büchi Labortechnik, Flawil, Switzerland) and were
uncorrected. Mass spectra (MS) were taken in ESI mode on Agilent
1100 LC–MS (Agilent, Palo Alto, CA, USA). Proton (1H) nuclear mag-
netic resonance spectroscopy was performed using Bruker ARX-
300, 300 MHz spectrometers (Bruker Bioscience, Billerica, MA,
USA) with TMS as an internal standard. Column chromatography
was run on silica gel (200–300 mesh) from Qingdao Ocean Chem-
icals (Qingdao, Shandong, China). Unless otherwise noted, all mate-
rials were obtained from commercially available sources and were
used without further purification.
7.1. 1-(4-(3-Chloropropoxy)-3-methoxyphenyl)ethanone (1)
A stirred solution of 1-(4-hydroxy-3-methoxyphenyl) ethanone
(24.9 g, 0.15 mol) and anhydrous potassium carbonate (57.9 g,
0.21 mol) in acetone was added dropwise with an acetone solution
of 1-bromo-3-chloropropane (66.1 g, 4.2 mol, in 200 mL acetone)
while maintaining the temperature below 25 °C. Upon completion
of the addition, the reaction mixture was stirred at room tempera-
ture for a whole night. The solid was removed by filtration, and the
filtrate was poured slowly into 1 L ice water, which is stirred vig-
orously. A lot of precipitated white solid was filtered and dried in
vacuo at 40 °C for 24 h to afford the target compound (69.5 g, yield:
92.5%). Mp 115–117 °C; MS (ESI) m/z (%): 264.8 [M+Na]+.
Figure 4. Binding poses of compound 33 with c-Met.
5. Binding model analysis
7.2. 1-(4-(3-Chloropropoxy)-5-methoxy-2-
nitrophenyl)ethanone (2)
To further elucidate the binding mode of the novel 4-(2-fluoro-
phenoxy)quinoline scaffold with c-Met, a detail docking analysis
was performed. In our study, the co-crystal structure of foretinib
(GSK1363089) with c-Met was selected as the docking model
(PDB ID code: 3LQ8). The conformations was conducted using
AutoDock 4.2 due to its powerful conformational search capabili-
ties.46 Lamarckian Genetic Algorithm (LGA) was used as a search
paparmeter with default setting. AutoDock was run several times
to give several docked conformations and analysis of the predicted
energy. Meanwhile, the consistency of results was combined to
identify the best solution. The image files were generated using
Accelrys DS visualizer 2.5 system. The binding model was exempli-
fied by the interaction of compound 33 with c-Met. As shown in
Figure 4, the nitrogen atom of the quinoline ring and the oxygen
atom of carbonyl group in compound 33 H-bond well with the pro-
tein residues Met108 and Lys58. In addition, the nitrogen atoms of
amido bond and position 2 of cinnoline ring formed two hydrogen
bonds with residue Asp170.
To a solution of 1-(4-(3-chloropropoxy)-3-methoxyphenyl)eth-
anone 1 (35 g, 0.14 mol) in dichloromethane (150 mL), fuming ni-
tric acid (10 mL, 0.28 mol) was added dropwise at a rate to
maintain the reaction temperature below 0 °C. Upon the comple-
tion of addition, the mixture was stirred at 0 °C for another 4 h.
The reaction mixture was poured slowly into the mixed solution
of cold water (200 mL) and dichloromethane (100 mL). The organic
layer was separated and washed with brine (600 mL ꢁ 5), dried
with anhydrous sodium sulfate and evaporated. The residue was
cooled and dried at room temperature to give a light yellow solid
(360 g, yield 86.7%). Mp 60–61 °C; MS (ESI) m/z (%): 288.0
[M+H]+, 310.0 [M+Na]+.
7.3. (E)-1-(4-(3-Chloropropoxy)-5-methoxy-2-nitrophenyl)-3-
(dimethylamino)prop-2-en-1-one (3)
1-(4-(3-Chloropropoxy)-5-methoxy-2-nitrophenyl)ethanone
2
(36 g, 0.125 mol) was added to toluene (100 mL) and heated to
110 °C. When the mixture became clear, N,N-dimethylformamide
dimethyl acetal (90 mL, 6.25 mol) was poured into the solution
and kept reacting for more 10 h. The resulting precipitate from
the cooled reaction mixture was filterd to obtain the target com-
pound as a yellow powder (31 g, yield 72.4%). Mp 127–129 °C;
MS (ESI) m/z (%): 343.4 [M+H]+, 355.3 [M+Na]+.
6. Conclusions
In conclusion, a series of 4-(2-fluorophenoxy)quinoline deriva-
tives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety
were designed, synthesized and evaluated as novel c-Met inhibi-
tors. Furthermore, six human cancer cell lines were used to evalu-
ate their cytotoxic activity. The preliminary investigation showed
that most compounds displayed good to excellent potency against
c-Met and the six tested cell lines. The analysis of SARs indicated
that compounds with a 2-chloro or 2-trifluoromethyl group on
the phenyl ring were more active than those with other substitu-
ents. On the other hand, the introduction of a fluorine atom to 7-
position of 4-oxo-1,4-dihydrocinnoline ring led to a sharply loss
7.4. 7-(3-Chloropropoxy)-6-methoxyquinolin-4-ol (4)
(E)-1-(4-(3-Chloropropoxy)-5-methoxy-2-nitrophenyl)-3-(dimeth-
ylamino)prop-2-en-1-one 3 (14.5 g, 0.05 mol) was dissolved in glacial
acetic acid (110 mL), and stirred at room temperature. Iron powder

S. Li et al. / Bioorg. Med. Chem. 21 (2013) 2843–2855
2849
was added slowly to keep the temperature below 60 °C. Upon the
completion of addition, the reaction mixture was heated to 80 °C for
2 h, and then filtered immediately to remove iron powder. The precip-
itate was filtered and the filter cake was washed to be colourless with
water, and dried at room temperature to obtain a white solid (10.5 g,
yield 78.4%). Mp 232–233 °C; MS (ESI) m/z (%): 268.1 [M+H]+, 290.2
[M+Na]+, 557.3 [2M+Na]+.
7.6.4. 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline
(6d)
White solid; yield: 82.4%; mp 174–175 °C; 1H NMR (300 MHz,
CDCl3) d 8.57 (d, J = 4.8 Hz, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 7.34 (d,
J = 4.8 Hz, 1H), 4.27 (t, J = 6.7 Hz, 2H), 4.04 (s, 3H), 3.72 (m, 4H),
2.57 (t, J = 7.1 Hz, 2H), 2.48 (m, 4H), 2.12 (m, 2H); MS (ESI) m/z
(%): 337.4 [M+H]+, 359.4 [M+Na]+.
7.5. General procedure for preparation of 4-hydroxyquinolines
(5a–5d)
7.7. General procedure for preparation of nitro compounds (7a–
7d)
To a stirring solution of 7-(3-chloropropoxy)-6-methoxyquino-
lin-4-ol (4) (10.15 g, 0.032 mol) in acetonitrile (80 mL) at 25 °C was
added appropriately secondary amines (0.3 mol), and the resulting
reaction mixture was heated to 85 °C for 10 h, then cooled to room
temperature and filtered. The light yellow filter cake was kept, and
the filtrate was concentrated in vacuum. Ethyl acetate (100 mL)
was added to the residue and stirred fully. The turbid fluid was fil-
tered and the cake was combined with the earlier one and recrys-
tallized with ethanol and acetone (2:5) to give the corresponding
4-hydroxyquinolines 5a–5d.
A stirring mixture of an appropriate 4-chloroquinoline (0.2 mol)
and 2-fluoro-4-nitrophenol (0.4 mol) in chlorobenzene (450 mL, 5
v/w) was heated to 140 °C for 30 h. The resulting mixture was
cooled, and filtered. The filter cake was washed with saturated
K2CO3 solution, and recrystallized with ethanol to give the corre-
sponding nitro compounds 7a–7d.
7.7.1. 4-(2-Fluoro-4-nitrophenoxy)-6-methoxy-7-(3-(piperidin-
1-yl)propoxy) quinoline (7a)
Yellowish-white solid; yield: 90.4%; mp 137–138 °C; MS (ESI)
m/z (%): 456.4 [M+H]+.
7.5.1. 6-Methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-ol
(5a)
7.7.2. 4-(2-Fluoro-4-nitrophenoxy)-6-methoxy-7-(3-(4-
methylpiperidin-1-yl)propoxy)quinoline (7b)
Yellow solid; yield: 88.7%; mp 133–134 °C; MS (ESI) m/z (%):
470.6 [M+H]+.
White solid; yield: 85.5%; mp 205–206 °C; MS (ESI) m/z (%):
317.4 [M+H]+.
7.5.2. 6-Methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-ol (5b)
7.7.3. 4-(2-Fluoro-4-nitrophenoxy)-6-methoxy-7-(3-
(pyrrolidin-1-yl)propoxy) quinoline (7c)
Yellow solid; yield: 86.3%; mp 140–141 °C; MS (ESI) m/z (%):
442.2 [M+H]+.
Sallow solid; yield: 93.4%; mp 202–203 °C; MS (ESI) m/z (%):
331.5 [M+H]+.
7.5.3. 6-Methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-ol
(5c)
7.7.4. 4-(3-(4-(2-Fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-
yloxy)propyl) morpholine (7d)
Light yellow solid; yield: 85.5%; mp 201–202 °C; MS (ESI) m/z
(%): 303.2 [M+H]+.
Light yellow solid; yield: 82.5%; mp 135–136 °C; MS (ESI) m/z
(%): 458.4 [M+1]+, 480.4 [M+23]+.
7.5.4. 6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-ol (5d)
White solid; yield: 97.6%; mp 207–208 °C; MS (ESI) m/z (%):
319.1 [M+H]+, 659.3 [2M+Na]+.
7.8. General procedure for preparation of anilines (8a–8d)
7.6. General procedure for preparation of 4-chloroquinolines
(6a–6d)
To a refluxing solution of an appropriate nitro compound
(0.1 mol) in EtOH (450 mL, 10 v/w) was added saturation NH4Cl
solution (450 mL) and Fe Powder in batches. The mixture was kept
at this temperature for more 5 h. After completion of the reaction
as indicated by TLC, the mixture was filtered immediately, and
the filtrate was cooled, filtered to obtain the corresponding anilines
(8a–8d)
To a solution of an appropriate 4-hydroxyquinoline (0.05 mol)
in acetonitrile (80 mL) at 85 °C was dropped POCl3 (80 mL), and
the resulting mixture was kept at this temperature for 6 h. The sol-
vent was concentrated in vacuum and the residue was poured into
stirring ice-water (200 mL), basified with potassium hydroxide to
pH 12, and extracted with CH2Cl2 (3 ꢁ 500 mL). The combined ex-
tracts were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuum to give the corresponding 4-chloroquino-
lines 6a–6d.
7.8.1. 3-Fluoro-4-(6-methoxy-7-(3-(piperdine-1-yl)
propoxy)quinolin-4-yloxy) aniline (8a)
Gray solid; yield: 85.5%; mp 196–197 °C; IR (KBr) cmꢀ1: 3482.2,
3387.0, 2946.5, 2835.1, 2788.1, 1621.1, 1587.8, 1512.8, 1483.4,
1252.9, 1215.4, 853.5; 1H NMR (300 MHz, CDCl3) d 8.46 (d,
J = 5.3 Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 7.03 (t, J = 8.7 Hz, 1H),
6.56 (dd, J = 11.8, 2.6 Hz, 1H), 6.50 (m, 1H), 6.39 (dd, J = 5.3,
1.1 Hz, 1H), 4.24 (t, J = 6.8 Hz, 2H), 4.04 (d, J = 3.8 Hz, 3H), 3.81 (s,
2H), 2.54 (m, 2H), 2.43 (s, 4H), 2.14 (m, 2H), 1.60 (m, 4H), 1.45
(d, J = 5.2 Hz, 2H); MS m/z (ESI): 426.3 [M+H]+.
7.6.1. 4-Chloro-6-methoxy-7-(3-(piperidin-1-yl)propoxy)
quinoline (6a)
White solid; yield: 85.4%; mp 187–188 °C; MS (ESI) m/z (%):
335.3 [M+H]+.
7.6.2. 4-Chloro-6-methoxy-7-(3-(4-methylpiperidin-1-yl)
propoxy)quinoline (6b)
7.8.2. 3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperdine-1-yl)
propoxy)quinolin-4-yloxy)aniline (8b)
White solid; yield: 79.7%; mp 179–180 °C; MS (ESI) m/z (%):
349.4 [M+H]+.
White solid; yield: 77.4%; mp 193–194 °C; 1H NMR (300 MHz,
CDCl3) d 8.46 (d, J = 5.3 Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 7.03 (t,
J = 8.7 Hz, 1H), 6.56 (dd, J = 11.8, 2.6 Hz, 1H), 6.50 (dd, J = 9.0,
2.9 Hz, 1H), 6.39 (dd, J = 5.3, 0.8 Hz, 1H), 4.25 (t, J = 6.7 Hz, 2H),
4.03 (s, 3H), 3.82 (s, 2H), 2.94 (d, J = 11.5 Hz, 2H), 2.57 (m, 2H),
7.6.3. 4-Chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)
quinoline (6c)
Yellow solid; yield: 78.2%; mp 177–178 °C; MS (ESI) m/z (%):
321.2 [M+H]+.

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S. Li et al. / Bioorg. Med. Chem. 21 (2013) 2843–2855
2.15 (m, 2H), 1.98 (t, J = 10.9 Hz, 2H), 1.63 (d, J = 10.4 Hz, 2H), 1.28
(m, 3H), 0.93 (d, J = 6.0 Hz, 3H); MS (ESI) m/z (%): 440.3 [M+H]+.
dropped into the mixture of appropriate intermediate (10a or
10b) (0.047 mol), sodium acetate anhydrous (10.2 g, 0.124 mol),
EtOH (200 mL) at 0 °C. Upon completing the addition, the mixture
was filtered and the cake was dried to give light yellow to white
solid (11a–t, 12a and 12b) yielded 75–80%.
7.8.3. 3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy)quinolin-4-yloxy) aniline (8c)
Light yellow solid; yield: 72.3%; mp 208–209 °C; 1H NMR
(300 MHz, DMSO-d6) d 8.49 (d, J = 5.2 Hz, 1H), 7.55 (s, 1H), 7.44
(s, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.57 (d, J = 14.1 Hz, 1H), 6.46 (m,
J = 12.8, 7.1 Hz, 2H), 4.28 (t, J = 5.7 Hz, 2H), 3.96 (s, 3H), 3.59 (s,
2H), 3.04 (m, 9H), 2.28 (m, 2H), 1.96 (d, J = 28.0 Hz, 4H); MS (ESI)
m/z (%): 412.5 [M+H]+.
To a solution of an appropriate intermediate (11a–t or 12a, or
12b) (0.04 mol) dissolved in EtOH (100 mL), was added drop-wise
10% NaOH (50 mL) at room temperature. After the completion of
addition, the mixture was heated to 50 °C for 2 h, evaporated most
solvent, the residue was poured into H2O (200 mL) and extracted
with ethyl acetate (100 mL ꢁ 1). The aqueous layer was separated
and acidified (HCl, 6 N) to yield substituted acids 13a–t, 14a and
14b as white precipitate, respectively.
7.8.4. 3-Fluoro-4-(6-methoxy-7-(3-
morpholinopropoxy)quinolin-4-yloxy) aniline (8d)
White solid; yield: 81.8%; mp 217–218 °C; 1H NMR (300 MHz,
CDCl3) d 8.47 (d, J = 5.2 Hz, 1H), 7.58 (s, 1H), 7.44 (s, 1H), 7.04 (t,
J = 8.7 Hz, 1H), 6.57 (dd, J = 11.9, 2.6 Hz, 1H), 6.50 (m, 1H), 6.41
(d, J = 5.3 Hz, 1H), 4.27 (t, J = 6.6 Hz, 2H), 4.04 (s, 3H), 3.82 (s,
2H), 3.74 (m, 4H), 2.60 (t, J = 7.1 Hz, 2H), 2.51 (d, J = 4.2 Hz, 4H),
2.13 (m, 2H); MS m/z (ESI): 428.2 [M+H]+, 450.1 [M+Na]+.
7.11.1. 1-Phenyl-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid
(13a)
Mp 274–275 °C; 1H NMR (300 MHz, DMSO-d6) d 14.18 (s, 1H),
8.34 (d, J = 7.9 Hz, 1H), 7.90 (t, J = 7.3 Hz, 1H), 7.72 (s, 6H), 7.30
(d, J = 8.7 Hz, 1H); MS m/z (ESI): 267.1 [M+H]+, 289.1 [M+Na]+,
555.1 [2M+Na]+.
7.9. General procedure for preparation of dones (9a and 9b)
7.11.2. 1-(2-Chlorophenyl)-4-oxo-1,4-dihydrocinnoline-3-
carboxylic acid (13b)
2-Fluorobenzoic acid and 2,4-difluorobenzoic acid (0.7 mol)
were added to the mixed solvent of toluene (200 mL) and SOCl2
(400 mL) and heated to 80 °C for 8 h, respectively. Evaporate the
solvent in vacuum and the residue were used to the next step reac-
tion directly.
To a mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (82.6 g,
0.574 mol), DMAP (87.5 g, 0.717 mol) and CH2Cl2 (600 mL), an
appropriate benzoyl chloride in CH2Cl2 was added drop-wise at
0 °C. Upon the completion of addition, the reaction mixture was
kept stirring at this temperature for more 6 h, and then poured into
HCl (1 mol/L). The organic phase was separated, washed with
brine, dried (MgSO4), filtered and concentrated to give substituted
dones 9a and 9b.
Mp 285–286 °C; MS m/z (ESI): 323.0 [M+Na]+.
7.11.3. 1-(2-Fluorophenyl)-4-oxo-1,4-dihydrocinnoline-3-
carboxylic acid (13c)
Mp 262–263 °C; MS m/z (ESI): 307.0 [M+Na]+, 313.0 [M+K]+.
7.11.4. 1-(2-Bromophenyl)-4-oxo-1,4-dihydrocinnoline-3-
carboxylic acid (13d)
Mp 280–281 °C; MS m/z (ESI): 345.1 [M+H]+, 367.0 [M+Na]+.
7.11.5. 1-(2-(Trifluoromethyl)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxylic acid (13e)
Mp 182–183 °C; IR (KBr) cmꢀ1: 3412.9, 1640.8, 1605.0, 1478.3,
1323.4, 1261.4, 1124.1, 1037.1, 906.4, 774.7, 757.3, 667.7; 1H NMR
(300 MHz, DMSO-d6) d 13.86 (s, 1H), 8.31 (m, 1H), 8.13 (d,
J = 7.4 Hz, 1H), 8.06 (m, 1H), 7.97 (m, 2H), 7.86 (m, 1H), 7.67 (t,
J = 7.6 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H); MS m/z (ESI): 335.2
[M+H]+, 691.3 [2M+Na]+.
7.9.1. 5-(2-Fluorobenzoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(9a)
Light yellow solid; yield: 50%; mp 232–233 °C; MS m/z (ESI):
264.9 [MꢀH]ꢀ.
7.9.2. 5-(2,4-Fluorobenzoyl)-2,2-dimethyl-1,3-dioxane-4,6-
dione (9b)
7.11.6. 1-(2-(Trifluoromethoxy)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxylic acid (13f)
White solid; yield: 53%; Mp 236–238 °C; MS m/z (ESI): 283.1
[MꢀH]ꢀ.
Mp 243–244 °C; MS m/z (ESI): 351.0 [M+H]+, 373.1 [M+Na]+.
7.10. General procedure for preparation of esters (10a and 10b)
7.11.7. 1-(3-Fluorophenyl)-4-oxo-1,4-dihydrocinnoline-3-
carboxylic acid (13g)
A mixture of an appropriate dione (9a or 9b) (0.3 mol) and EtOH
(500 mL) was heated to 80 °C refluxing for 5 h. Upon cooling to
room temperature, evaporated the solvent to give the esters 10a
or 10b as red oil.
Mp 239–240 °C; MS m/z (ESI): 285.3 [M+H]+, 307.2 [M+Na]+.
7.11.8. 1-(3-(Trifluoromethyl)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxylic acid (13h)
Mp 241–242 °C; MS m/z (ESI): 335.2 [M+H]+, 357.1 [M+Na]+,
373.1 [M+K]+.
7.10.1. Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (10a)
Red oil; yield: 85%; MS m/z (ESI): 233.1 [M+Na]+, 443.1
[2M+Na]+.
7.11.9. 1-(4-Chlorophenyl)-4-oxo-1,4-dihydrocinnoline-3-
carboxylic acid (13i)
7.10.2. Ethyl 3-(2,4-fluorophenyl)-3-oxopropanoate (10b)
Red oil; yield: 90%; MS m/z (ESI): 251.1 [M+Na]+.
Mp 286–287 °C; MS m/z (ESI): 301.1 [M+H]+, 323.1 [M+Na]+.
7.11. General procedure for preparation of acids (13a–t, 14a and
14b)
7.11.10. 1-(4-Fluorophenyl)-4-oxo-1,4-dihydrocinnoline-3-
carboxylic acid (13j)
Mp 258–259 °C; MS m/z (ESI): 307.0 [M+Na]+, 323.0 [M+k]+.
To a mixture of substituted phenyl amine (0.06 mol) and 20%
HCl (50 mL), NaNO2 (0.123 mol) in H2O (200 mL) was added
drop-wise at 0 °C. After the completion of addition, the reaction
mixture was stirred at this temperature for 30 min, and then it is
7.11.11. 1-(4-Bromophenyl)-4-oxo-1,4-dihydrocinnoline-3-
carboxylic acid (13k)
Mp 291–292 °C; MS m/z (ESI): 346.1 [M+H]+, 368.1 [M+Na]+.

S. Li et al. / Bioorg. Med. Chem. 21 (2013) 2843–2855
2851
7.11.12. 1-p-Tolyl-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid
(13l)
Mp 252–253 °C; MS m/z (ESI): 303.1 [M+Na]+.
7.12.1. 1-(2-Chlorophenyl)-N-(3-fluoro-4-(6-methoxy-7-(3-
(piperidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxamide (17)
Yield: 63%; mp 167–169 °C; 1H NMR (300 MHz, DMSO-d6) d
11.84 (s, 1H), 8.85 (d, J = 6.5 Hz, 1H), 8.39 (d, J = 8.1 Hz, 1H), 8.12
(m, 1H), 7.91 (m, J = 7.5, 3H), 7.79 (m, J = 4.8, 3H), 7.73 (m,
J = 10.2 Hz, 3H), 7.65 (m, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.04 (d,
J = 6.5 Hz, 1H), 4.36 (3, 2H), 4.06 (s, 3H), 3.61 (s, 6H), 3.23 (s, 2H),
2.38 (s, 2H), 1.82 (s, 4H); MS m/z (ESI): 708.4 [M+H]+; Anal. Calcd
for C39H35ClFN5O5 (%): C, 66.14; H, 4.98; N, 9.89. Found (%): C,
66.21; H, 5.05; N, 9.95.
7.11.13. 1-(2,4-Dichlorophenyl)-4-oxo-1,4-dihydrocinnoline-3-
carboxylic acid (13m)
Mp >300 °C; MS m/z (ESI): 368.4 [M+Cl]+.
7.11.14. 1-(2,6-Dichlorophenyl)-4-oxo-1,4-dihydrocinnoline-3-
carboxylic acid (13n)
Mp 290–291 °C; MS m/z (ESI): 336.7 [M+H]+, 356.9 [M+Na]+.
7.12.2. N-(3-Fluoro-4-(6-methoxy-7-(3-(piperidin-1-
yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1-(2-
(trifluoromethyl)phenyl)-1,4-dihydrocinnoline-3-carboxamide
(18)
7.11.15. 1-(3,4-Difluorophenyl)-4-oxo-1,4-dihydrocinnoline-3-
carboxylic acid (13o)
Mp 281–283 °C; MS m/z (ESI): 325.0 [M+Na]+.
Yield: 58.9%; mp 156–158 °C; IR (KBr) cmꢀ1: 3412.0, 2935.2,
1692.1, 1595.5, 1479.4, 1317.3, 1211.4, 853.7, 765.2; 1H NMR
(300 MHz, DMSO-d6) d 12.29 (s, 1H), 8.52 (d, J = 8.6 Hz, 2H), 8.05
(d, J = 11.9 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.82 (m, J = 16.0 Hz,
2H), 7.73 (d, J = 7.6 Hz, 1H), 7.63 (m, J = 13.3 Hz, 3H), 7.52 (d,
J = 8.8 Hz, 1H), 7.41 (s, 1H), 7.26 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H),
6.46 (d, J = 4.7 Hz, 1H), 4.27 (s, 2H), 4.03 (s, 3H), 3.02 (m, 6H),
2.39 (s, 2H), 1.88 (s, 4H), 1.58 (s, 2H); 13C NMR (CDCl3) d 170.91,
160.07, 159.51, 155.12, 153.47, 151.78, 149.63, 148.77, 146.56,
142.36, 138.49, 137.02, 136.80, 134.76, 133.90, 131.25, 130.05,
128.26, 127.33, 125.60, 123.65, 123.43, 121.62, 117.46, 116.62,
115.67, 109.97, 109.81, 108.83, 102.36, 99.71, 66.55, 56.05, 55.34,
53.81 (2C), 24.64, 23.89 (2C), 22.91; MS m/z (ESI): 742.5 [M+H]+;
Anal. Calcd for C40H35F4N5O5 (%): C, 64.77; H, 4.76; N, 9.44. Found
(%): C, 64.80; H, 4.78; N, 9.48.
7.11.16. 1-(2,4-Dimethylphenyl)-4-oxo-1,4-dihydrocinnoline-3-
carboxylic acid (13p)
Mp 259–261 °C; MS m/z (ESI): 295.2 [M+H]+, 317.2 [M+Na]+.
7.11.17. 1-(2,5-Dimethylphenyl)-4-oxo-1,4-dihydrocinnoline-3-
carboxylic acid (13q)
Mp 263–264 °C; MS m/z (ESI): 317.0 [M+Na]+.
7.11.18. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxylic acid (13r)
Mp >300 °C; IR (KBr) cmꢀ1: 3142.9, 1640.8, 1605.0, 1478.3,
1323.4, 1124.1, 774.7; 1H NMR (300 MHz, DMSO-d6) d 8.15 (d,
J = 7.8 Hz, 1H), 8.10 (s, 1H), 7.98 (m, 2H), 7.68 (t, J = 7.6 Hz, 1H),
7.43 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H); MS m/z (ESI):
369.1 [M+H]+, 391.1[M+Na]+.
7.12.3. N-(3-Fluoro-4-(6-methoxy-7-(3-(piperidin-1-
yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1-(3-
fluorophenyl)-1,4-dihydrocinnoline-3-carboxamide (19)
Yield: 59.5%; mp 146–148 °C; 1H NMR (300 MHz, DMSO-d6) d
11.89 (s, 1H), 8.52 (d, J = 5.0 Hz, 1H), 8.40 (d, J = 7.9 Hz, 1H), 8.08
(d, J = 11.9 Hz, 1H), 7.92 (t, J = 7.5 Hz, 1H), 7.75 (m, J = 19.7 Hz,
3H), 7.66 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 9.3 Hz, 2H), 7.52 (d,
J = 9.0 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J = 8.7 Hz, 1H), 6.54 (d,
J = 5.0 Hz, 1H), 4.28 (s, 2H), 4.00 (s, 3H), 3.09 (s, 6H), 2.28 (s, 2H),
1.78 (s, 4H), 1.56 (s, 2H); MS m/z (ESI): 692.1 [M+H]+; Anal. Calcd
for C39H35F2N5O5 (%): C, 67.72; H, 5.10; N, 10.12. Found (%): C,
67.69; H, 5.13; N, 10.20.
7.11.19. 1-(2-Chloro-5-(trifluoromethyl)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxylic acid (13s)
Mp >300 °C; MS m/z (ESI): 369.7 [M+H]+.
7.11.20. 1-(2-Bromo-4-fluorophenyl)-4-oxo-1,4-dihydro-
cinnoline-3-carboxylic acid (13t)
Mp 296–297 °C; MS m/z (ESI): 365.2 [M+H]+.
7.11.21. 1-(2-Chlorophenyl)-7-fluoro-4-oxo-1,4-dihydro-
cinnoline-3-carboxylic acid (14a)
7.12.4. N-(3-Fluoro-4-(6-methoxy-7-(3-(piperidin-1-
yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1-(3-
Mp 284–285 °C; MS m/z (ESI): 319.7 [M+H]+, 341.6 [M+Na]+.
(trifluoromethyl)phenyl)-1,4-dihydrocinnoline-3-carboxamide
(20)
7.11.22. 7-Fluoro-1-(2-fluorophenyl)-4-oxo-1,4-dihydro-
cinnoline-3-carboxylic acid (14b)
Yield: 62.1%; mp 171–173 °C; 1H NMR (300 MHz, DMSO-d6) d
11.86 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.38 (d, J = 7.9 Hz, 1H), 8.24
(s, 1H), 8.08 (d, J = 8.2 Hz, 2H), 8.01 (m, 1H), 7.94 (m, 1H), 7.88
(d, J = 8.6 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.63 (d, J = 9.2 Hz, 1H),
7.56 (s, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.44 (s, 1H), 7.33 (d,
J = 8.6 Hz, 1H), 6.51 (d, J = 5.2 Hz, 1H), 4.25 (t, J = 6.1 Hz,2H), 3.97
(s, 3H), 3.03 (s, J = 24.1 Hz, 6H), 2.22 (s, 2H), 1.72 (d, J = 5.0 Hz,
4H), 1.52 (s, 2H); MS m/z (ESI): 742.1 [M+H]+; Anal. Calcd for
Mp 258–259 °C; MS m/z (ESI): 303.1 [M+H]+.
7.12. General procedure for preparation of compounds (17–49)
A mixture of an appropriate acid (13a–t or 14a, or 14b)
(0.58 mmol), toluene (5 mL), and SOCl2 (10 mL) was heated to
80 °C for 5 h. Upon cooling to room temperature, the solvent was
evaporated in vacuum and the residue was dissolved in dried
CH2Cl2 (10 mL) to add drop-wise to a mixture of an appropriate
aniline (8a–d) (0.48 mmol), Et3N (0.58 mol) and CH2Cl2 (10 mL)
in an ice bath, which was removed to room temperature for 10 h
and monitored by TLC. The mixture was washed with 10% K2CO3
(20 mL ꢁ 3), brine (20 mL ꢁ 3) in sequence, and the organic phase
was separated, dried, and evaporated. The crude product was puri-
fied by chromatography on silica gel using CH2Cl2/MeOH (40:1) to
afford white solids 17–49.
C40H35F4N5O5 (%): C, 64.75; H, 4.76; N, 9.43. Found (%): C, 64.77;
H, 4.75; N, 9.46.
7.12.5. 1-(4-Chlorophenyl)-N-(3-fluoro-4-(6-methoxy-7-(3-
(piperidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxamide (21)
Yield: 63.8%; mp 162–164 °C; 1H NMR (300 MHz, DMSO-d6) d
11.85 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.37 (d, J = 7.5 Hz, 1H), 8.04
(d, J = 11.5 Hz, 1H), 7.87 (t, J = 7.4 Hz, 1H), 7.78 (s, 3H), 7.70 (d,

2852
S. Li et al. / Bioorg. Med. Chem. 21 (2013) 2843–2855
J = 7.6 Hz, 1H), 7.63 (dd, J = 14.0, 6.3 Hz, 2H), 7.55 (s, 1H), 7.49 (t,
J = 8.9 Hz, 1H), 7.42 (s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 6.50 (d,
J = 5.0 Hz, 1H), 4.23 (s, 2H), 3.95 (s, 3H), 2.89 (s, 6H), 2.15 (s, 2H),
1.67 (s, 4H), 1.48 (s, 2H); MS m/z (ESI): 708.1 [M+H]+; Anal. Calcd
for C39H35ClFN5O5 (%): C, 66.14; H, 4.98; N, 9.89. Found (%): C,
66.21; H, 4.95; N, 9.87.
J = 5.9 Hz, 3H). MS m/z (ESI): 706.2 [M+H]+, 728.2 [M+Na]+; Anal.
Calcd for C41H40F2N5O5 (%): C, 68.07; H, 5.28; N, 9.92. Found (%):
C, 68.25; H, 5.29; N, 9.95.
7.12.11. 1-(2-Bromophenyl)-N-(3-fluoro-4-(6-methoxy-7-(3-(4-
methylpiperidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-
1,4-dihydrocinnoline-3-carboxamide (27)
7.12.6. 1-(4-Bromophenyl)-N-(3-fluoro-4-(6-methoxy-7-(3-
(piperidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxamide (22)
Yield: 60.2%; mp 184–186 °C; 1H NMR (300 MHz, DMSO-d6) d
11.79 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.40 (d, J = 7.5 Hz, 1H), 8.05
(dd, J = 15.2, 4.6 Hz, 2H), 7.91 (t, J = 6.9 Hz, 2H), 7.77 (t, J = 7.2 Hz,
1H), 7.71 (m, J = 15.6, 7.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.55 (s,
1H), 7.51 (t, J = 8.9 Hz, 1H), 7.41 (s, 1H), 7.07 (d, J = 8.7 Hz, 1H),
6.51 (d, J = 5.0 Hz, 1H), 4.21 (t, J = 6.1 Hz, 2H), 3.96 (s, 3H), 3.02
(s, 2H), 2.66 (s, 2H), 2.05 (s, 2H), 1.64 (d, J = 11.8 Hz, 2H), 1.41 (s,
1H), 1.23 (s, 4H), 0.90 (d, J = 6.5 Hz, 3H); MS m/z (ESI): 768.3
[M+H]+; Anal. Calcd for C40H37BrFN5O5 (%): C, 62.66; H, 4.86; N,
9.13. Found (%): C, 62.60; H, 4.84; N, 9.10.
Yield: 52.6%; mp 175–177 °C; 1H NMR (300 MHz, DMSO-d6) d
11.88 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.07
(d, J = 11.9 Hz, 1H), 7.93 (d, J = 13.8 Hz, 3H), 7.75 (d, J = 8.3 Hz,
3H), 7.65 (d, J = 9.3 Hz, 1H), 7.60 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H),
7.47 (s, 1H), 7.40 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 4.6 Hz, 1H), 4.28
(s, 2H), 4.00 (s, 3H), 3.09 (s, 6H), 2.27 (s, 2H), 1.77 (s, 4H), 1.55
(s, 2H); MS m/z (ESI): 752.4 [M+H]+; Anal. Calcd for C39H35BrFN5O5
(%): C, 62.24; H, 4.69; N, 9.31. Found (%): C, 62.17; H, 4.69; N, 9.38.
7.12.12. N-(3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1-(3-
(trifluoromethyl)phenyl)-1,4-dihydrocinnoline-3- carboxamide
(28)
7.12.7. 1-(2,4-Dichlorophenyl)-N-(3-fluoro-4-(6-methoxy-7-(3-
(piperidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxamide (23)
Yield: 62.1%; mp 185–189 °C; 1H NMR (300 MHz, DMSO-d6) d
11.72 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.12
(s, 1H), 8.04 (d, J = 13.1 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.87 (m,
2H), 7.71 (t, J = 7.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.52 (dd,
J = 17.0, 8.2 Hz, 2H), 7.42 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 6.51 (d,
J = 4.7 Hz, 1H), 4.22 (s, 2H), 3.97 (s, 3H), 2.68 (s, 6H), 2.09 (s, 2H),
1.61 (s, 4H), 1.45 (s, 2H); MS m/z (ESI): 742.4 [M+H]+; Anal. Calcd
for C39H34Cl2FN5O5 (%): C, 63.08; H, 4.61; N, 9.43. Found (%): C,
63.15; H, 4.59; N, 9.45.
Yield: 59.8%; mp 182–184 °C; 1H NMR (300 MHz, DMSO-d6) d
11.85 (s, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.39 (d, J = 7.9 Hz, 1H), 8.24
(s, 1H), 8.10 (m, 2H), 7.94 (m, 3H), 7.71 (t, J = 7.5 Hz, 1H), 7.63 (d,
J = 9.2 Hz, 1H), 7.56 (s, 1H), 7.50 (t, J = 9.0 Hz, 1H), 7.43 (s, 1H),
7.33 (d, J = 8.7 Hz, 1H), 6.51 (d, J = 4.7 Hz, 1H), 4.24 (s, 2H), 3.97
(s, 3H), 3.18 (m, 2H), 2.95 (s, 2H), 2.51 (s, 2H), 2.18 (s, 2H), 1.72
(d, J = 12.5 Hz, 2H), 1.53 (s, 1H), 1.37 (d, J = 12.6 Hz, 2H), 0.92 (d,
J = 6.0 Hz, 3H); MS m/z (ESI): 756.2 [M+H]+; Anal. Calcd for
C41H37F4N5O5 (%): C, 65.16; H, 4.93; N, 9.27. Found (%): C, 65.24;
H, 4.93; N, 9.26.
7.12.8. 1-(2,6-Dichlorophenyl)-N-(3-fluoro-4-(6-methoxy-7-(3-
(piperidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxamide (24)
7.12.13. N-(3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yloxy-)phenyl)-4-oxo-1-(4-
Yield: 66.5%; mp 179–182 °C; 1H NMR (300 MHz, DMSO-d6) d
11.61 (s, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.06
(d, J = 14.3 Hz, 1H), 7.96 (m, 3H), 7.85 (d, J = 7.2 Hz, 1H), 7.77 (dd,
J = 15.5, 7.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.53 (t,
J = 8.9 Hz, 1H), 7.46 (s, 1H), 7.17 (d, J = 8.6 Hz, 1H), 6.54 (d,
J = 5.1 Hz, 1H), 4.25 (d, J = 5.8 Hz, 2H), 3.99 (s, 3H), 2.87 (s, 6H),
2.18 (s, 2H), 1.69 (s, 4H), 1.50 (s, 2H); MS m/z (ESI): 742.7
[M+H]+; Anal. Calcd for C39H34Cl2FN5O5 (%): C, 63.07; H, 4.61; N,
9.43. Found (%): C, 63.18; H, 4.65; N, 9.36.
fluorophenyl)-1,4-dihydrocinnoline-3-carboxamide (29)
Yield: 65%; mp 145–147 °C; 1H NMR (300 MHz, DMSO-d6) d
11.93 (s, 1H), 8.51 (d, J = 4.7 Hz, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.07
(d, J = 12.5 Hz, 1H), 7.91 (m, 1H), 7.85 (s, 2H), 7.72 (t, J = 7.3 Hz,
1H), 7.65 (d, J = 8.4 Hz, 1H), 7.59 (m, 3H), 7.53 (t, J = 8.8 Hz, 1H),
7.45 (s, 1H), 7.34 (d, J = 8.6 Hz, 1H), 6.53 (d, J = 4.6 Hz, 1H), 4.26
(s, 2H), 3.99 (s, 3H), 3.31 (s, 4H), 2.67 (s, 2H), 2.23 (s, 2H), 1.75
(d, J = 12.3 Hz, 2H), 1.57 (s, 1H), 1.43 (d, J = 11.5 Hz, 2H), 0.95 (d,
J = 6.0 Hz, 3H); MS m/z (ESI): 706.8 [M+H]+; Anal. Calcd for
C40H37F2N5O5 (%): C, 68.07; H, 5.25; N, 9.91 Found (%): C, 68.21;
7.12.9. 1-(2,4-Dimethylphenyl)-N-(3-fluoro-4-(6-methoxy-7-(3-
(piperidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxamide (25)
H, 5.30; N, 9.88.
7.12.14. N-(3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1-p-tolyl-1,4-
dihydrocinnoline-3-carboxamide (30)
Yield: 74.5%; mp 153–155 °C; 1H NMR (300 MHz, DMSO-d6) d
11.90 (s, 1H), 8.49 (s, 1H), 8.40 (d, J = 6.6 Hz, 1H), 8.05 (d,
J = 12.8 Hz, 1H), 7.88 (s, 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.48 (d,
J = 8.4 Hz, 3H), 7.38 (d, J = 14.6 Hz, 3H), 7.08 (d, J = 8.5 Hz, 1H),
6.51 (s, 1H), 4.19 (s, 2H), 3.96 (s, 3H), 2.41 (d, J = 19.0 Hz, 9H),
1.99 (s, 5H), 1.46 (m, 6H); MS m/z (ESI): 702.5 [M+H]+; Anal. Calcd
for C41H40FN5O5 (%): C, 70.17; H, 5.75; N, 9.98. Found (%): C, 69.86;
H, 5.74; N, 10.01.
Yield: 67.6%; mp 143–145 °C; 1H NMR (300 MHz, DMSO-d6) d
11.92 (s, 1H), 8.50 (d, J = 5.1 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.06
(d, J = 12.7 Hz, 1H), 7.88 (t, J = 7.8 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H),
7.61 (d, J = 13.9 Hz, 3H), 7.57 (s, 1H), 7.51 (d, J = 13.3 Hz, 3H),
7.45 (s, 1H), 7.32 (d, J = 8.7 Hz, 1H), 6.52 (d, J = 5.1 Hz, 1H), 4.27
(s, 2H), 3.97 (s, 3H), 3.49 (s, 2H), 3.20 (s, 2H), 2.92 (s, 2H), 2.48
(s, 3H), 2.30 (s, 2H), 1.79 (d, J = 11.4 Hz, 2H), 1.62 (s, 1H), 1.49 (s,
2H), 0.93 (s, 3H); MS m/z (ESI): 702.3 [M+H]+; Anal. Calcd for
7.12.10. N-(3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1-(2-
C41H40FN5O5 (%): C, 70.16; H, 5.70; N, 9.98 Found (%): C, 70.01;
fluorophenyl)-1,4-dihydrocinnoline-3-carboxamide (26)
Yield: 64.5%; mp 173–175 °C; 1H NMR (300 MHz, DMSO-d6) d
11.71 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.04
(d, J = 13.0 Hz, 1H), 7.90 (d, J = 15.5, 2H), 7.78 (s, 1H), 7.61 (m,
6H), 7.43 (s, 1H), 7.24 (d, J = 8.5 Hz, 1H), 6.51 (d, J = 5.0 Hz, 1H),
4.24 (s, 2H), 3.97 (s, 3H), 3.45 (s, 2H), 2.93 (s, 2H), 2.51 (s, 2H),
2.19 (s, 2H), 1.72 (d, J = 11.6 Hz, 2H), 1.43 (m, 3H), 0.92 (d,
H, 5.71; N, 9.99.
7.12.15. 1-(2,6-Dichlorophenyl)-N-(3-fluoro-4-(6-methoxy-7-(3-
(4-methylpiperi-din-1-yl)propoxy)quinolin-4-yloxy)phenyl)-4-
oxo-1,4-dihydrocinnoline-3-carboxamide (31)
Yield: 68.3%; mp 162–164 °C; 1H NMR (300 MHz, DMSO-d6) d
11.55 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.01

S. Li et al. / Bioorg. Med. Chem. 21 (2013) 2843–2855
2853
(dd, J = 12.9, 2.0 Hz, 1H), 7.92 (m, 3H), 7.80 (d, J = 9.2 Hz, 1H), 7.72
(t, J = 7.7 Hz, 1H), 7.61 (d, J = 9.5 Hz, 1H), 7.53 (d, J = 4.4 Hz, 1H),
7.48 (d, J = 9.0 Hz, 1H), 7.39 (s, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.49
(d, J = 5.2 Hz, 1H), 4.18 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 2.89 (d,
J = 10.3 Hz, 2H), 2.71 (s, 4H), 1.58 (d, J = 12.0 Hz, 2H), 1.22 (m,
5H), 0.88 (d, J = 6.4 Hz, 3H); MS m/z (ESI): 756.1 [M+H]+; Anal.
Calcd for C40H37Cl2FN5O5 (%): C, 63.49; H, 4.80; N, 9.26. Found
(%): C, 63.61; H, 4.81; N, 9.30.
7.12.20. 1-(2,6-Dichlorophenyl)-N-(3-fluoro-4-(6-methoxy-7-(3-
(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxamide (36)
Yield: 62.1%; mp 173–175 °C; 1H NMR (300 MHz, DMSO-d6) d
11.58 (s, 1H), 8.51 (d, J = 5.0 Hz, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.03
(d, J = 12.8 Hz, 1H), 7.94 (m, 3H), 7.82 (m, 1H), 7.74 (t, J = 7.5 Hz,
1H), 7.63 (d, J = 9.1 Hz, 1H), 7.58 (s, 1H), 7.53 (d, J = 8.9 Hz, 1H),
7.47 (d, J = 6.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 5.0 Hz,
1H), 4.29 (s, 2H), 3.98 (s, 3H), 3.59 (s, 2H), 3.05 (m, 4H), 2.28 (s,
2H), 1.98 (s, 4H); MS m/z (ESI): 728.0 [M+H]+; Anal. Calcd for
7.12.16. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-
(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-
yloxy)phenyl)-4-oxo-1,4-dihydro-cinnoline-3-carboxamide (32)
Yield: 68.3%; mp 193–195 °C; 1H NMR (300 MHz, DMSO-d6) d
11.80 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.35 (d, J = 6.2 Hz, 2H), 8.10
(q, J = 8.8 Hz, 2H), 8.00 (d, J = 13.2 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H),
7.68 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.51 (m, 2H), 7.43
(m, 2H), 6.49 (d, J = 5.1 Hz, 1H), 4.21 (s, 2H), 3.95 (s, 3H), 3.10 (s,
2H), 2.76 (s, 2H), 2.34 (s, 2H), 2.09 (s, 2H), 1.66 (d, J = 11.1 Hz,
2H), 1.44 (s, 1H), 1.25 (m, 2H), 0.90 (d, J = 6.2 Hz, 3H); MS m/z
(ESI): 790.2 [M+H]+; Anal. Calcd for C41H39F2N5O5 (%): C, 68.42;
H, 5.46; N, 9.73. Found (%): C, 68.59; H, 5.44; N, 9.68.
C38H32Cl2FN5O5 (%): C, 62.64; H, 4.43; N, 9.61. Found (%): C,
62.56; H, 4.45; N, 9.65.
7.12.21. 1-(2-Chloro-5-(trifluoromethyl)phenyl)-N-(3-fluoro-4-
(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy)p-
henyl)-4-oxo-1,4-dihydrocinnoline-3-carboxamide (37)
Yield: 57.1%; mp 191–193 °C; 1H NMR (300 MHz, DMSO-d6) d
11.70 (s, 1H), 8.50 (d, J = 5.8 Hz, 2H), 8.39 (d, J = 8.0 Hz, 1H), 8.16
(s, 2H), 8.03 (d, J = 12.5 Hz, 1H), 7.91 (t, J = 8.0 Hz, 1H), 7.72 (t,
J = 7.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.49 (m, 2H),
7.19 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 5.3 Hz, 1H), 4.28 (s, 2H), 3.97
(s, 3H), 3.24 (s, 6H), 2.24 (s, 2H), 1.94 (s, 4H); MS m/z (ESI):
762.1 [M+H]+; Anal. Calcd for C39H32ClF4N5O5 (%): C, 61.46; H,
4.23; N, 9.19. Found (%): C, 61.60; H, 4.23; N, 9.16.
7.12.17. N-(3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1-(2-
7.12.22. 1-(2,5-Dimethylphenyl)-N-(3-fluoro-4-(6-methoxy-7-
(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy)p-henyl)-4-oxo-
1,4-dihydrocinnoline-3-carboxamide (38)
(trifluoromethyl)phenyl)-1,4-dihydrocinnoline-3-carboxamide
(33)
Yield: 66.3%; mp 163–165 °C; IR (KBr) cmꢀ1: 3421.3, 3046.1,
2959.4, 2796.4, 1695.7, 1597.1, 1478.6, 1317.6, 1210.6, 855.4,
763.7; 1H NMR (300 MHz, DMSO-d6) d 11.84 (s, 1H), 8.85 (d,
J = 6.5 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.20 (m, 3H), 8.04 (m, 2H),
7.94 (m, 2H), 7.80 (s, 1H), 7.77 (m, 3H), 7.06 (dd, J = 10.4, 7.8 Hz,
2H), 4.38 (t, J = 5.6 Hz, 2H), 4.05 (d, J = 12.1 Hz, 3H), 3.66–3.52
(m, 4H), 3.06 (s, 2H), 2.36 (s, 2H), 1.99 (m, 4H); 13C NMR (CDCl3)
d 170.94, 160.03, 159.47, 155.17, 153.52, 152.03, 149.73, 148.81,
146.79, 142.37, 138.52, 137.21, 136.88, 134.72, 133.86, 131.22,
130.04, 128.28, 127.29, 125.99, 125.62, 123.65, 123.43, 117.44,
116.61, 115.52, 109.99, 109.83, 108.83, 102.28, 99.55, 67.06,
56.10, 54.07 (2C), 52.97, 27.73, 23.44 (2C); MS m/z (ESI): 728.7
[M+H]+; Anal. Calcd for C39H33F4N5O5 (%): C, 64.37; H, 4.57; N,
9.62. Found (%): C, 64.52; H, 4.59; N, 9.59.
Yield: 76.0%; mp 144–146 °C; 1H NMR (300 MHz, DMSO-d6) d
11.91 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.05
(d, J = 12.8 Hz, 1H), 7.89 (t, J = 7.9 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H),
7.62 (d, J = 8.9 Hz, 1H), 7.56 (s, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.44
(m, 4H), 7.09 (d, J = 8.5 Hz, 1H), 6.51 (d, J = 5.0 Hz, 1H), 4.26 (t,
J = 6.1 Hz, 2H), 3.97 (s, 3H), 3.05 (m, 6H), 2.40 (s, 3H), 2.17 (d,
J = 6.5 Hz, 2H), 1.98 (s, 3H), 1.89 (d, J = 11.2 Hz, 4H); MS m/z
(ESI): 688.2 [M+H]+, 710.3 [M+Na]+; Anal. Calcd for C40H38FN5O5
(%): C, 69.85; H, 5.57; N, 10.18. Found (%): C, 70.03; H, 5.56; N,
10.32.
7.12.23. 1-(2-Bromo-4-fluorophenyl)-N-(3-fluoro-4-(6-
methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy)p-
henyl)-4-oxo-1,4-dihydrocinnoline-3-carboxamide (39)
Yield: 60.1%; mp 173–175 °C; 1H NMR (300 MHz, DMSO-d6) d
11.80 (s, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.05
(m, 3H), 7.93 (m, 1H), 7.71 (m, 3H), 7.55 (d, J = 9.6 Hz, 2H), 7.47
(s, 1H), 7.16 (d, J = 8.6 Hz, 1H), 6.54 (d, J = 4.5 Hz, 1H), 4.28 (s,
2H), 4.00 (s, 3H), 3.03 (m, 6H), 2.24 (s, 2H), 1.75 (s, 4H), 1.54 (s,
2H); MS m/z (ESI): 758.6 [M+H]+; Anal. Calcd for C40H38BrFN5O5
(%): C, 60.31; H, 4.26; N, 9.24. Found (%): C, 60.33; H, 4.27; N, 9.41.
7.12.18. N-(3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)
propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1-(3-
(trifluoromethyl)phenyl)-1,4-dihydrocinnoline-3-carboxamide
(34)
Yield: 59.8%; mp 176–179 °C; 1H NMR (300 MHz, DMSO-d6) d
11.86 (s, 1H), 8.51 (d, J = 4.3 Hz,1H), 8.40 (d, J = 8.1 Hz, 1H), 8.24
(s, 1H), 7.99 (m, 5H), 7.73 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 9.2 Hz,
1H), 7.58 (s, 1H), 7.50 (d, J = 18.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 1H),
6.53 (d, J = 4.8 Hz, 1H), 4.28 (s, 2H), 3.98 (s, 3H), 3.14 (m, 6H),
2.24 (s, 2H), 1.93 (s, 4H). MS m/z (ESI): 728.7 [M+H]+; Anal. Calcd
for C39H33F4N5O5 (%): C, 64.37; H, 4.57; N, 9.62. Found (%): C,
64.39; H, 4.54; N, 9.70.
7.12.24. N-(3-Fluoro-4-(6-methoxy-7-(3-
morpholinopropoxy)quinolin-4-yloxy)phenyl)-4-oxo-1-phenyl-
1,4-dihydrocinnoline-3-carboxamide (40)
Yield: 61%; mp 148–150 °C; 1H NMR (300 MHz, DMSO-d6) d
11.91 (s, 1H), 8.48 (d, J = 5.0 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.05
(d, J = 13.0 Hz, 1H), 7.88 (m, 1H), 7.73 (s, 6H), 7.62 (d, J = 8.8 Hz,
1H), 7.51 (m, 2H), 7.41 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.50 (d,
J = 4.9 Hz, 1H), 4.21 (t, 2H), 3.96 (s, 3H), 3.61 (s, 4H), 2.47 (m,
J = 15.5 Hz, 6H), 2.00 (m, 2H); MS m/z (ESI): 676.1 [M+H]+; Anal.
Calcd for C38H34FN5O6 (%): C, 67.55; H, 5.07; N, 10.36. Found (%):
C, 67.82; H, 5.10; N, 10.31.
7.12.19. 1-(3,4-Difluorophenyl)-N-(3-fluoro-4-(6-methoxy-7-(3-
(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxamide (35)
Yield: 70.3%; mp 147–150 °C; 1H NMR (300 MHz, DMSO-d6) d
11.87 (s, 1H), 8.53 (d, J = 4.6 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.07
(d, J = 12.3 Hz, 2H), 7.87 (m, 2H), 7.70 (d, J = 16.5 Hz, 3H), 7.60 (s,
1H), 7.55 (d, J = 8.9 Hz, 1H), 7.46 (d, J = 16.4 Hz, 2H), 6.55 (d,
J = 4.7 Hz, 1H), 4.31 (s, 2H), 4.00 (s, 3H), 3.29 (s, 6H), 2.28 (s, 2H),
1.97 (s, 4H); MS m/z (ESI): 696.1 [M+H]+; Anal. Calcd for
7.12.25. 1-(2-Chlorophenyl)-N-(3-fluoro-4-(6-methoxy-7-(3-
morpholinopropoxy) quinolin-4-yloxy)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxamide (41)
Yield: 62.3%; mp 142–144 °C; IR (KBr) cmꢀ1: 3432.7, 2957.9,
1700.1, 1595.8, 1555.3, 1478.8, 1209.7, 857.5, 760.6; 1H NMR
C38H32F3N5O5 (%): C, 65.60; H, 4.64; N, 10.06. Found (%): C,
65.71; H, 4.66; N, 10.21.

2854
S. Li et al. / Bioorg. Med. Chem. 21 (2013) 2843–2855
(300 MHz, DMSO-d6) d 11.75 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.41 (d,
J = 8.0 Hz, 1H), 8.05 (dd, J = 12.8, 2.3 Hz, 1H), 7.91 (m, 3H), 7.76 (m,
3H), 7.63 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 5.0 Hz, 1H), 7.50 (d,
J = 8.9 Hz, 1H), 7.42 (s, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.51 (d,
J = 5.2 Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 3.97 (s, 3H), 3.62 (s, 4H),
2.48 (m, J = 15.4 Hz, 6H), 2.02 (m, J = 6.4 Hz, 2H); MS m/z (ESI):
710.7 [M+H]+; Anal. Calcd for C38H33ClFN5O6 (%): C, 64.27; H,
4.68; N, 9.86. Found (%): C, 63.96; H, 4.67; N, 9.91.
[M+H]+, 726.3 [M+Na]+; Anal. Calcd for C40H38FN5O6 (%): C,
68.26; H, 5.44; N, 9.94. Found (%): C, 68.82; H, 5.48; N, 10.00.
7.12.30. 7-Fluoro-N-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-
yl)propoxy)quinolin-4-yloxy)phenyl)-1-(2-fluorophenyl)-4-
oxo-1,4-dihydrocinnoline-3-carboxamide (46)
Yield: 60.6%; mp 143–145 °C; 1H NMR (300 MHz, DMSO-d6) d
11.56 (d, J = 10.8 Hz, 1H), 8.41 (m, 3H), 8.01 (d, J = 12.6 Hz, 1H),
7.87 (t, J = 7.5 Hz, 1H), 7.78 (s, 1H), 7.57 (m, 6H), 7.43 (s, 1H),
7.02 (d, J = 9.9 Hz, 1H), 6.50 (d, J = 4.9 Hz, 1H), 4.22 (d, J = 5.8 Hz,
2H), 3.96 (s, 3H), 2.82 (s, 6H), 2.15 (s, 2H), 1.67 (s, 4H), 1.48 (s,
2H). MS m/z (ESI): 710.2 [M+H]+; Anal. Calcd for C39H34F3N5O5
(%): C, 66.00; H, 4.83; N, 9.87. Found (%): C, 66.59; H, 4.85; N, 10.01.
7.12.26. N-(3-Fluoro-4-(6-methoxy-7-(3-
morpholinopropoxy)quinolin-4-yloxy)phenyl)-4-oxo-1-(2-
(trifluoromethyl)phenyl)-1,4-dihydrocinnoline-3-carboxamide
(42)
Yield: 66.9%; mp 151–153 °C; IR (KBr) cmꢀ1: 3426.8, 2960.8,
1692.3, 1595.6, 1479.2, 1317.7, 1211.4, 855.3, 765.3; 1H NMR
(300 MHz, DMSO-d6) d 11.73 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.39
(d, J = 7.5 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.06 (m, 2H), 7.99 (t,
J = 7.9 Hz, 2H), 7.88 (m, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.62 (d,
J = 8.7 Hz, 1H), 7.55 (s, 1H), 7.51 (t, J = 8.9 Hz, 1H), 7.41 (s, 1H),
7.08 (d, J = 8.7 Hz, 1H), 6.50 (d, J = 5.1 Hz, 1H), 4.21 (t, J = 6.4 Hz,
2H), 3.96 (s, 3H), 3.59 (t, J = 4.3 Hz, 4H), 2.48 (t, J = 7.1 Hz, 2H),
2.40 (s, 4H), 1.99 (m, 2H); 13C NMR (DMSO-d6) d: 169.82, 160.28,
159.65, 154.78, 153.15, 152.40, 150.04, 149.28, 146.85, 142.56,
139.49, 138.63, 137.52, 136.71, 135.70, 135.41, 132.22, 131.00,
128.70, 127.65, 126.64, 125.51, 125.26, 124.74, 124.20, 118.17,
117.19, 114.93, 108.98, 102.55, 99.48, 67.13, 66.67 (2C), 56.23,
55.26, 53.83 (2C), 26.14; MS m/z (ESI): 744.6 [M+H]+; Anal. Calcd
for C39H33F4N5O6 (%): C, 62.96; H, 4.47; N, 9.40. Found (%): C,
63.16; H, 4.47; N, 9.42.
7.12.31. 1-(2-Chlorophenyl)-7-fluoro-N-(3-fluoro-4-(6-
methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-
yloxy)phenyl)-4-oxo-1,4-dihydrocinnoline-3-carboxamide (47)
Yield: 61.9%; mp 174–176 °C; 1H NMR (300 MHz, DMSO-d6) d
11.90 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.32 (d, J = 9.2 Hz, 1H), 8.03
(d, J = 12.4 Hz, 1H), 7.89 (s,2H), 7.75 (m, 2H), 7.61 (s, 1H), 7.56 (s,
1H), 7.51 (d, J = 9.0 Hz, 1H), 7.44 (s, 1H), 7.33 (d, J = 9.7 Hz, 1H),
6.51 (d, J = 5.0 Hz, 1H), 6.21 (s, 1H), 4.26 (s, 2H), 3.97 (s, 3H), 3.06
(s, 6H), 2.25 (s, 2H), 1.76 (s, 4H), 1.54 (s, 2H); MS m/z (ESI):
726.1 [M+H]+; Anal. Calcd for C39H34ClF2N5O5 (%): C, 64.48; H,
4.73; N, 9.60. Found (%): C, 64.83; H, 4.72; N, 9.55.
7.12.32. 7-Fluoro-N-(3-fluoro-4-(6-methoxy-7-(3-
morpholinopropoxy)quinolin-4-yloxy)phenyl)-1-(2-
fluorophenyl)-4-oxo-1,4-dihydrocinnoline-3-carboxamide (48)
Yield: 67.5%; mp 138–139 °C; 1H NMR (300 MHz, DMSO-d6) d
11.52 (d, J = 11.6 Hz, 1H), 8.48 (m, 1H), 8.39 (m, 1H), 8.01 (d,
J = 12.6 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.78 (m, 1H), 7.57 (m,
6H), 7.44 (s, 1H), 7.02 (d, J = 10.0 Hz, 1H), 6.51 (d, J = 5.1 Hz, 1H),
4.24 (t, J = 5.8 Hz, 2H), 3.96 (s, 3H), 3.73 (s, 4H), 2.85 (s, 6H), 2.13
(s, 2H); MS m/z (ESI): 712.7 [M+H]+; Anal. Calcd for C38H32F3N5O6
(%): C, 64.13; H, 4.53; N, 9.84. Found (%): C, 63.95; H, 4.52; N, 10.02.
7.12.27. N-(3-Fluoro-4-(6-methoxy-7-(3-
morpholinopropoxy)quinolin-4-yloxy)phenyl)-4-oxo-1-(2-
(trifluoromethoxy)phenyl)-1,4-dihydrocinnoline-3-
carboxamide (43)
Yield: 62.3%; mp 159–161 °C; 1H NMR (300 MHz, DMSO-d6) d
11.69 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.04
(m, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.90 (m, 2H), 7.82 (d, J = 8.3 Hz,
1H), 7.78 (t, J = 7.7 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.62 (d,
J = 8.6 Hz, 1H), 7.56 (s, 1H), 7.51 (t, J = 8.9 Hz, 1H), 7.42 (s, 1H),
7.17 (d, J = 8.7 Hz, 1H), 6.51 (d, J = 5.1 Hz, 1H), 4.23 (t, J = 6.1 Hz,
2H), 3.96 (s, 3H), 3.66 (s, 4H), 3.07 (m, 4H), 2.62 (s, 2H), 2.51 (s,
3H), 2.06 (s, 2H); MS m/z (ESI): 760.8 [M+H]+; Anal. Calcd for
C39H33F4N5O7 (%): C, 61.66; H, 4.38; N, 9.22. Found (%): C, 61.75;
H, 4.40; N, 9.27.
7.12.33. 1-(2-Chlorophenyl)-7-fluoro-N-(3-fluoro-4-(6-
methoxy-7-(3-(4-methyl piperidin-1-yl)propoxy)quinolin-4-
yloxy)phenyl)-4-oxo-1,4-dihydrocinnoline-3-carboxamide (49)
Yield: 62.3%; mp 152–154 °C; 1H NMR (300 MHz, DMSO-d6) d
11.55 (d, J = 22.2 Hz, 1H), 8.46 (d, J = 15.6 Hz, 2H), 8.01 (d,
J = 12.2 Hz, 1H), 7.87 (s, 1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.58 (m,
4H), 7.50 (s, 1H), 7.42 (s, 1H), 7.02 (d, J = 9.4 Hz, 1H), 6.50 (s, 1H),
4.25 (s, 2H), 3.99 (s, 3H), 3.20 (s, 4H), 2.87 (s, 2H), 2.16 (s, 2H),
1.72 (d, J = 10.4 Hz, 2H), 1.52 (s, 1H), 1.35 (s, 2H), 0.94 (d,
J = 6.3 Hz, 3H); MS m/z (ESI): 741.1 [M+H]+. Anal. Calcd for
7.12.28. N-(3-Fluoro-4-(6-methoxy-7-(3-
morpholinopropoxy)quinolin-4-yloxy)phenyl)-4-oxo-1-p-tolyl-
1,4-dihydrocinnoline-3-carboxamide (44)
C41H36ClF2N4O5 (%): C, 66.62; H, 5.05; N, 7.58. Found (%): C,
Yield: 67.6%; mp 138–140 °C; 1H NMR (300 MHz, DMSO-d6) d
11.94 (s, 1H), 8.50 (s, 1H), 8.38 (s, 1H), 8.07 (d, J = 12.5 Hz, 1H),
7.89 (s, 1H), 7.63 (t, J = 24.0 Hz, 8H), 7.43 (s, 1H), 7.35 (s, 1H),
6.52 (s, 1H), 4.24 (s, 2H), 3.98 (s, 3H), 3.66 (s, 4H), 2.53 (s, 9H),
2.05 (s, 2H); MS m/z (ESI): 690.6 [M+H]+, 712.6 [M+Na]+; Anal.
Calcd for C39H36FN5O6 (%): C, 67.91; H, 5.26; N, 10.15. Found (%):
C, 67.57; H, 5.28; N, 10.21.
67.01; H, 5.06; N, 7.58.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2013.04.013.
7.12.29. 1-(2,5-Dimethylphenyl)-N-(3-fluoro-4-(6-methoxy-7-
(3-morpholinopro-poxy)quinolin-4-yloxy)phenyl)-4-oxo-1,4-
dihydrocinnoline-3-carboxamide (45)
References and notes
1. Longati, P.; Comoglio, P. M.; Bardelli, A. Curr. Drug Targets 2001, 2, 41.
2. Maulik, G.; Shrikhande, A.; Kijima, T.; Ma, P. C.; Morrison, P. T.; Salgi, R. Cytokine
Growth Factor Rev. 2002, 13, 41.
3. Haddad, R.; Lipson, K. E.; Webb, C. P. Anticancer Res. 2001, 21, 4243.
4. Matsumoto, K.; Date, K.; Shimura, H.; Nakamura, T. Jpn. J. Cancer Res. 1996, 87,
702.
5. Birchmeier, C.; Birchmeier, W.; Gherardi, E.; Vande Woude, G. F. Nat. Rev. Mol.
Cell Biol. 2003, 4, 915.
6. Corso, S.; Comoglio, P. M.; Giordano, S. Trends Mol. Med. 2005, 11, 284.
7. Jeffers, M.; Rong, S.; Vande Woude, G. F. Mol. Cell. Biol. 1996, 16, 1115.
Yield: 77.5%; mp 134–136 °C; 1H NMR (300 MHz, DMSO-d6) d
11.91 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.40 (d, J = 7.9 Hz, 1H), 8.05
(dd, J = 12.8, 2.0 Hz, 1H), 7.89 (t, J = 7.8 Hz, 1H), 7.70 (t, J = 7.5 Hz,
1H), 7.61 (d, J = 8.6 Hz, 1H), 7.55 (s, 1H), 7.50 (t, J = 8.9 Hz, 1H),
7.47 (d, J = 7.8 Hz, 1H), 7.43 (m, 3H), 7.09 (d, J = 8.7 Hz, 1H), 6.50
(d, J = 5.1 Hz, 1H), 4.22 (t, J = 6.2 Hz, 2H), 3.96 (s, 3H), 3.63 (s,
4H), 2.54 (m, 6H), 2.40 (s, 3H), 1.99 (m, 5H); MS m/z (ESI): 704.2

S. Li et al. / Bioorg. Med. Chem. 21 (2013) 2843–2855
2855
8. Dussault, I.; Kaplan-Lefko, P.; Jun, T.; Coxon, A.; Burgess, T. L. Drugs Future 2006,
31, 819.
9. Ma, P. C.; Maulik, G.; Christensen, J.; Salgia, R. Cancer Metastasis Rev. 2003, 22,
309.
10. D’Angelo, D. N.; Bellon, F. S.; Booker, K. S.; Cheng, Y.; Coxon, A.; Dominguez, C.;
Fellows, I.; Hoffman, D.; Hungate, R.; Kaplan-Lefko, P.; Lee, P. M.; Li, C.; Liu, L.;
Rainbeau, E.; Reider, J. P.; Rex, K.; Siegmund, A.; Sun, Y.; Tasker, S. A.; Xi, N.; Xu,
S.; Yang, Y.; Zhang, Y.; Burgess, L. T.; Dussault, I.; Kim, T. S. J. Med. Chem. 2008,
51, 5766.
30. Kollmannsberger, C. K.; Hurwitz, H.; Vlahovic, G.; Maroun, C.; Dumouchel, J.;
Reid, G.; Martell, R.; Shapiro, G. The ASCO Annual Meeting, 2009, Abstract,
e14525.
31. Schroeder, G. M.; An, Y. M.; Cai, Z. W.; Chen, X. T.; Clark, C.; Cornelius, L. A. M.;
Dai, J.; Gullo-Brown, J.; Gupta, A.; Henley, B.; Hunt, J. T.; Jeyaseelan, R.; Kamath,
A.; Kim, K.; Lippy, J.; Lombardo, L. J.; Manne, V.; Oppenheimer, S.; Sack, J. S.;
Schmidt, R. J.; Shen, G. X.; Stefanski, K.; Tokarski, J. S.; Trainor, G. L.; Wautlet, B.
S.; Wei, D.; Williams, D. K.; Zhang, Y. R.; Zhang, Y. P.; Fargnoli, J.; Borzilleri, R.
M. J. Med. Chem. 2009, 52, 1251.
11. Cao, B.; Su, Y.; Oskarsson, M.; Zhao, P.; Kort, E. J.; Fisher, R. J.; Wang, L. M.;
Woude, G. F. V. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 7443.
12. Burgess, T.; Coxon, A.; Meyer, S.; Sun, J.; Rex, K.; Tsuruda, T.; Chen, Q.; Ho, S. Y.;
Li, L.; Kaufman, S.; McDorman, K.; Cattley, R. C.; Sun, J.; Elliot, G.; Zhang, K.;
Feng, X.; Jia, X. C.; Green, L.; Radinsky, R.; Kendall, R. Cancer Res. 2006, 66,
1721.
13. Kim, K. J.; Wang, L.; Su, Y. C.; Gillespie, G. Y.; Salhotra, A.; Lal, B.; Laterra, J. Clin.
Cancer Res. 2006, 12, 1292.
14. Martens, T.; Schmidt, N. O.; Eckerich, C.; Fillbrandt, R.; Merchant, M.; Schwall,
R.; Westphal, M.; Lamszus, K. Clin. Cancer Res. 2006, 12, 6144.
15. Date, K.; Matsumoto, K.; Shimura, H.; Tanaka, M.; Nakamura, T. FEBS Lett. 1997,
420, 1.
32. Mannion, M.; Raeppel, S.; Claridge, S.; Zhou, N.; Saavedra, O.; Isakovic, L.; Zhan,
L.; Gaudette, F.; Raeppel, F.; Déziel, R.; Beaulieu, N.; Nguyen, H.; Chute, I.;
Beaulieu, C.; Dupont, I.; Robert, M. F.; Lefebvre, S.; Dubay, M.; Rahil, J.; Wang, J.;
Ste-Croix, H.; Macleod, A. R.; Beaterman, J. M.; Vaisburg, A. Bioorg. Med. Chem.
Lett. 2009, 19, 6552.
33. Bellon, S. F.; Kaplan-Lefko, P.; Yang, Y. J.; Zhang, Y. H.; Moriguchi, J.; Rex, K.;
Johnson, C. W.; Rose, P. E.; Long, A. M.; O’Connor, A. B.; Gu, Y.; Coxon, A.; Kim, T.
S.; Tasker, A.; Burgess, T. L.; Dussault, I. J. Biol. Chem. 2008, 283, 2675.
34. Graybill, T. L.; Dolle, R. E.; Osifo, I. K.; Schmidt, S. J.; Gregory, J. S.; Harris, A. L.;
Miller, M. S. Bioorg. Med. Chem. Lett. 1995, 5, 387.
35. Muthuppla, N. M.; Margal, S.; Sukeerthi, K.; Khairatkar, J. N.; Karnik, P.
WO2009053799-A1.
16. Tomioka, D.; Maehara, N.; Kuba, K.; Mizumoto, K.; Tanaka, M.; Matsumoto, K.;
Nakamura, T. Cancer Res. 2001, 61, 7518.
36. Balasubramanian, G.; Rajagopal, S.; Rathinasamy, S.; Kilambi, N.; Rajendran, P.;
Narayanan, S. WO2010073078-A2.
17. Brochmann, M. A.; Papadimitriou, A.; Brandt, M.; Fillbrandt, R.; Westphal, M.;
Lamszus, K. Clin. Cancer Res. 2003, 9, 4578.
18. Michieli, P.; Mazzone, M.; Basilico, C.; Cavassa, S.; Sottile, A.; Naldini, L.;
Comoglio, P. M. Cancer Res. 2004, 6, 61.
19. Kong-Beltran, M.; Stamos, J.; Wickramasinghe, D. Cancer Cell 2004, 6, 75.
20. Abounader, R.; Ranganathan, S.; Lal, B.; Fielding, K.; Book, A.; Diez, H.; Burger,
P.; Laterra, J. J. Natl. Cancer Inst. 1999, 91, 1548.
37. Wilcox, M.; Viola, R. W.; Johnson, K. W.; Billington, A. P.; Carpenter, B. K.;
McCray, J. A.; Guzikowski, A. P.; Hess, G. P. J. Org. Chem. 1990, 55, 1585.
38. Tois, J.; Vahermo, M.; Koskinen, A. Tetrahedron Lett. 2005, 46, 735.
39. Zhang, D. Y.; Ai, J.; Liang, Z. J.; Li, C. P.; Peng, X.; Ji, Y. C.; Jiang, H. L.; Geng, M. Y.;
Luo, C.; Liu, H. Bioorg. Med. Chem. 2012, 20, 5169.
40. Norman, M. H.; Liu, L.; Lee, M.; Xi, N.; Fellows, I.; D’Angelo, N. D.; Dominguez,
C.; Rex, K.; Bellon, S. F.; Kim, T. S.; Dussault, I. J. Med. Chem. 2012, 55, 1858.
41. Hogenkamp, D. J.; Johnstone, T. B. C.; Huang, J. C.; Li, W. Y.; Tran, M.;
Whittemore, E. R.; Bagnera, R. E.; Gee, K. W. J. Med. Chem. 2007, 50, 3369.
42. Ames, D. E.; Leung, O. T.; Singh, A. G. Synthesis 1983, 1, 52.
43. Muthupplaniappan, M.; Margal, S.; Sukeerthi, K.; Khair, N.; Karnik, P. A.;
Glenmark, P.; Switz, S. A. WO2009053799-A1.
44. Liu, L. B.; Siegmund, A.; Xi, N.; Kaplan-Lefko, P.; Rex, K.; Chen, A.; Lin, J.;
Moriguchi, J.; Berry, L.; Huang, L. Y.; Teffera, Y.; Yang, Y. J.; Zhang, Y. H.; Bellon,
S. F.; Lee, M.; Shimanovich, R.; Bak, A.; Dominguez, C.; Norman, M. H.;
Harmange, J. C.; Dussault, I.; Kim, T. S. J. Med. Chem. 2008, 51, 3688.
45. Peach, M. L.; Tan, N.; Tan, N.; Choyke, S. J.; Giubellino, A.; Athauda, G.; Burke, T.
R.; Nicklaus, M. C.; Bottaro, D. P. J. Med. Chem. 2009, 52, 943.
46. Zhang, Z.; Lee, J. C.; Olivas, V.; Au, V.; LaFramboise, T.; Abdel-Rahman, M.;
Wang, X.; Levine, A. D.; Rho, J. K.; Choi, Y. J.; Choi, C. M.; Kim, S. W.; Jang, S. J.;
Park, Y. S.; Kim, W. S.; Lee, D. H.; Lee, J. S.; Miller, V. A.; Arcila, M.; Ladanyi, M.;
Moonsamy, P.; Sawyers, C.; Boggon, T. J.; Ma, P. C.; Costa, C.; Taron, M.; Rosell,
R.; Halmos, B.; Bivona, T. G. Nat. Genet. 2012, 44, 852.
21. Porter, J. Expert Opin. Ther. Pat. 2010, 20, 159.
22. Mannion, M.; Raeppel, S.; Claridge, S.; Claridge, S.; Zhou, N.; Saavedra, O.;
Isakovic, L.; Zhan, L.; Gaudette, F.; Raeppel, F.; Déziel, R.; Beaulieu, N.; Nguyen,
H.; Chute, I.; Beaulieu, C.; Dupont, I.; Robert, M. F.; Lefebvre, S.; Dubay, M.;
Rahil, J.; Wang, J.; Ste-Croix, H.; Macleod, A. R.; Besterman, M. J.; Vaisburg, A.
Bioorg. Med. Chem. Lett. 2009, 19, 6552.
23. Nakagawa, T.; Tohyama, O.; Yamaguchi, A.; Matsushima, T.; Takahashi, K.;
Funasaka, S.; Shirotori, S.; Asada, M.; Obaishi, H. Cancer Sci. 2010, 101, 210.
24. Saavedra, O.; Claridge, S.; Zhan, L.; Raeppel, F.; Granger, M. C.; Raeppel, S.;
Mannion, M.; Gaudette, F.; Zhou, N.; Isakovic, L.; Bernstein, N.; Déziel, R.;
Nguyen, H.; Normand, B.; Beaulieu, C.; Dupont, I.; Wang, J.; Macleod, R. A.;
Besterman, M. J.; Vaisburg, A. Bioorg. Med. Chem. Lett. 2009, 19, 6836.
25. Cai, Z. W.; Wei, D.; Schroeder, M. G.; Cornelius, A. M. L.; Kim, K.; Chen, X. T.;
Schmidt, J. R.; Williams, K. D.; Tokarski, S. J.; An, Y.; Sack, S. J.; Manne, V.;
Kamath, A.; Zhang, Y.; Marathe, P.; Hunt, T. J.; Lombardo, J. L.; Fargnoli, J.;
Borzilleri, M. R. Bioorg. Med. Chem. Lett. 2008, 18, 3224.
26. Caballero, J.; Quiliano, M.; Alzate-Morales, H. J.; Zimic, M.; Deharo, E. J. Comput.
Aided Mol. Des. 2011, 25, 349.
47. Tiedt, R.; Degenkolbe, E.; Furet, P.; Appleton, B. A.; Wagner, S.; Schoepfer, J.;
Buck, E.; Ruddy, D. A.; Monahan, J. E.; Jones, M. D.; Blank, J.; Haasen, D.;
Drueckes, P.; Wartmann, M.; McCarthy, C.; Sellers, W. R.; Hofmann, F. Cancer
Res. 2011, 71, 5255.
48. Takayuki, N.; Osamu, T.; Atsumi, Y.; Tomohiro, M.; Keiko, T.; Setsuo, F.; Shuji,
S.; Makoto, A.; Hiroshi, O. Cancer Sci. 2010, 101, 210.
27. Sun, Q.; Ng, C.; Guy, R. G.; Sivaraman, J. FEBS Lett. 2011, 585, 281.
28. Underiner, L. T.; Herbertz, T.; Miknyoczki, J. S. Anticancer Agent Med. 2010, 10, 7.
29. Yakes, F. M.; Chen, J.; Tan, J.; Yamaguchi, K.; Shi, Y. C.; Yu, P. W.; Qian, F.; Chu,
F.; Bentzien, F.; Cancilla, B.; Orf, J.; You, A.; Laird, A. D.; Engst, S.; Lee, L.; Lesch,
J.; Chou, Y. C.; Joly, A. H. Mol. Cancer Ther. 2011, 10, 2298.
49. Ted, L. U.; Torsten, H.; Sheila, J. M. Anticancer Agent Med. 2010, 10, 7.