Design, synthesis and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives as selective c-Met inhibitors

Article abstract of DOI:10.1016/j.bmc.2016.12.002

Two novel series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives bearing 1H-imidazole-4-carboxamido or (E)-3-hydrosulfonylacrylamido motifs (16–31 and 32–42) were designed, synthesized and evaluated for their in vitro cytotoxic activity. Most of the compounds exhibited moderate to excellent potency against tested three cell lines, and fifteen compounds were further examined for their inhibitory activity against c-Met kinase. The most promising compound 16 (c-Met kinase [IC₅₀]?=?1.1?nM) demonstrated high selectivity and remarkable cytotoxicity against HT-29, MKN-45 and A549 cells with IC₅₀values of 0.08, 0.22 and 0.07?μM, which were 3.1-, 1.4- and 2.1-fold more active than Foretinib. The preliminary structure-activity relationships as well as molecular docking disclosed that 1H-imidazole-4-carboxamido as a linker was of great importance for the antitumor activity.

Full text of DOI:10.1016/j.bmc.2016.12.002

Accepted Manuscript
Design, synthesis and biological evaluation of novel 4-(2-fluorophenoxy)qui-
noline derivatives as selective c-Met inhibitors
Xiaoqiang Wang, Nan Jiang, Sijia Zhao, Shuancheng Xi, Jiao Wang, Tongfei
Jing, Wenyu Zhang, Ming Guo, Ping Gong, Xin Zhai
PII:
S0968-0896(16)31175-0
DOI:
http://dx.doi.org/10.1016/j.bmc.2016.12.002
BMC 13428
Reference:
Bioorganic & Medicinal Chemistry
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Received Date:
Accepted Date:
11 November 2016
2 December 2016
Please cite this article as: Wang, X., Jiang, N., Zhao, S., Xi, S., Wang, J., Jing, T., Zhang, W., Guo, M., Gong, P.,
Zhai, X., Design, synthesis and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives as selective
c-Met inhibitors, Bioorganic & Medicinal Chemistry (2016), doi: http://dx.doi.org/10.1016/j.bmc.2016.12.002
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Design, synthesis and biological evaluation of novel 4-(2-fluorophenoxy)quinoline
derivatives as selective c-Met inhibitors
Xiaoqiang Wang#, Nan Jiang#, Sijia Zhao, Shuancheng Xi, Jiao Wang, Tongfei Jing, Wenyu Zhang,
Ming Guo, Ping Gong, Xin Zhai
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical
University, Shenyang 110016, PR China
Abstract
Two novel series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives bearing 1H-
imidazole-4-carboxamido or (E)-3-hydrosulfonylacrylamido motifs (16-31 and 32-42) were
designed, synthesized and evaluated for their in vitro cytotoxic activity. Most of the compounds
exhibited moderate to excellent potency against tested three cell lines, and fifteen compounds
were further examined for their inhibitory activity against c-Met kinase. The most promising
compound 16 (c-Met kinase [IC50] = 1.1 nM) demonstrated high selectivity and remarkable
cytotoxicity against HT-29, MKN-45 and A549 cells with IC50 values of 0.08, 0.22 and 0.07μM,
which were 3.1-, 1.4- and 2.1-fold more active than Foretinib. The preliminary structure-activity
relationships as well as molecular docking disclosed that 1H-imidazole-4-carboxamido as a linker
was of great importance for the antitumor activity.
Keywords: c-Met; antitumor activity; synthesis; molecular docking, 6,7-disubstituted-4-(2-
fluorophenoxy)quinolines
1. Introduction
c-Met, also termed as hepatocyte growth factor receptor (HGFR), is a structurally peculiar
subfamily of receptor tyrosine kinases (RTKs) pertaining to a transmembrane growth factor
receptor [1-2]. Studies reveal that the binding of HGF to c-Met at the extracellular domain induces
several complex signaling pathways，which plays a crucial role during embryo development and
tissue homeostasis [3]. Moreover, aberrant activation of c-Met signal transduction pathways is
validated in a variety of human cancers [4]. Therefore, inhibition of HGF/c-Met signaling pathway
presents great potential in novel cancer therapy [5].
To disrupt the c-Met signaling, several approaches are exploited including anti-HGF
antibodies, anti-c-Met monoclonal antibodies and small molecular inhibitors targeting the kinase
catalytic domain of c-Met [6-8]. Although much lagged behind the other strategies, the
development of small molecular c-Met inhibitors has made significant advances recently [9].
Cabozantinib (1) was approved by U.S. FDA in November 2012 for treatment of patients with
progressive metastatic medullary thyroid cancer [10]. Additional inhibitors have progressed into

Corresponding author.Tel./fax: +86 24 2398 6429.
E-mail address:zhaixin_syphu@126.com(X. Zhai).

clinical or preclinical studies, such as Foretinib (2), Kirin (3), AM7 (4), MG10 (5) and Amgen (6)
(Figure 1) [11-16].
Figure 1. Structures of several 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives
A
report from D′Angelo N.D. et al disclosed that 6,7-disubstituted-4-(2-
fluorophenoxy)quinoline framework (moiety A) and an aryl fragment (moiety B)should be
preserved as the privileged scaffolds in that the quinoline core formed hydrogen bonds and
maintained van der Waals interactions with the backbone of c-Met kinase, and the aryl fragment of
moiety B probably fitted into the hydrophobic pocket [17]. By using of Discovery Studio 3.0, the
spatial distances (SD) of the linkers in Foretinib (2) and AM7 (4) were determined according to
co-crystal structures bound to c-Met kinase as 6.327 Å (PDB code: 3LQ8) and 6.549 Å (PDB code:
2RFN). Accordingly, the distances between 6.3 Å and 6.6 Å probably fitted the moiety B into the
hydrophobic pocket which resulted in an excellent inhibition. Furthermore, we found that the
linkage between moiety A and B had two common features. One was six chemical bonds distance
existing between moiety A and B and in charging of proper SD, which was called as “5 atoms
regulation”; the other was that the linker should contain both hydrogen-bond donor or acceptor
and at least one amide group [18]. Therefore, we were prompted to explore two series of 6,7-
disubstituted-4-(2-fluorophenoxy)quinoline derivatives with satisfactory linkers as promising c-
Met inhibitors.
In light of our previous studies, we found that two building blocks could be used as linkages
on account of the presence of hydrogen bond donors and acceptors. One is 1H-imidazole-4-
carboxamido (C) motif deriving from Temozolomide [19] and the other is (E)-3-
hydrosulfonylacrylamido (D) skeleton, a hybrid linker generated from two fused pharmacophoric
domains of hydrosulfonylethyl from Briciclib Sodium [20] and acrylamido from Chidamide[21]
(Figure2). Importantly, the SD values of motifs C and D were examined approximate 6.389 Å and

6.457 Å (PDB code: 3LQ8), which coincided with the ‘5 atoms regulation’. Therefore, two series
of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives (16-31 and 32-42) were designed by
incorporation of 1H-imidazole-4-carboxamido (C) or (E)-3-hydrosulfonylacrylamido (D)
skeletons as linkages. In addition, the 3-carbon tether at the 7-position of quinoline moiety was
preserved, while the terminal morpholinyl group was replaced by several water-soluble
alicyclic aminyl fragments, and a varieties of substituents were introduced into moiety B. As a
result, two series of compounds were synthesized and the in vitro antitumor activities against three
human cancer cell lines included HT-29, MKN-45 and A549, as well as c-Met kinase was
evaluated, respectively.
Figure 2. Design strategy of 1H-imidazole-4-carboxamido- or (E)-3-hydrosulfonylacrylamido-based quinolones
2. Chemistry
The desired compounds 16-31 were prepared according to the pathway outlined in Scheme 1.
The synthesis of the key intermediates of 4-(2-fluorophenoxy)quinolines 1a-d was achieved in an
eight-step reaction from commercially available 1-(4-hydroxy-3-methoxyphenyl)ethanone which
has been illustrated in detail in our previous study [22-25].An initial formylation of substituted
anilines with formic acid and sodium formate gave rise to the corresponding N-phenylformamides
2a-e,which were further subjected to phosphorus oxychloride and triethylamine in tetrahydrofuran
to afford benzonitriles 3a-e. Intermolecular cyclization of 3a-e with ethyl cyanoacetate in the
presence of copper (I) oxide and 1,10-phenanthroline monohydrate furnished ethyl1H-imidazole-
4-carboxylate 4a-e. The key intermediates 5a-e were obtained via hydrolysis of 4a-e with lithium
hydroxide monohydrate in tetrahydrofuran/water (4:1) at room temperature. Subsequently, the
resultant carboxylic acids 5a-e were converted into the corresponding acyl chlorides on exposure
to thionyl chloride, which underwent a N-acylation reaction with intermediates 1a-d to generate
the target compounds 16-31.

Scheme 1. Reagents and conditions: (a) sodium formate, formic acid, reflux, 12 h; (b) triethylamine,
o
tetrahydrofuran, phosphorus oxychloride/tetrahydrofuran, 0 C, 3 h, r.t., 1 h; (c) ethyl cyanoacetate, copper (I)
oxide, 1,10-phenanthroline monohydrate, tetrahydrofuran, reflux, 10 h; (d) lithium hydroxide monohydrate,
tetrahydrofuran/water, r.t., 20 h; (e) thionyl chloride, reflux, 5 h; potassium carbonate, dichloromethane, r.t., 2 h.
The synthesis of the target compounds 32-42 were depicted in Scheme 2. The intermediates
6a-d was prepared by nucleophilic addition of the triple bond in ethyl propiolate using substituted
thiophenols in tetrahydrofuran at 65oC. The oxidation reaction of 6a-d with hydrogen peroxide in
aceticacid yielded the sulfone 7a-d, which was subsequently hydrolysis with lithium hydroxide
monohydrate in tetrahydrofuran/water (3:2) to generate 8a-d. Finally, the target compounds 32-42
were accomplished as previously described N-acylation reaction shown in Scheme 1.
Scheme 2. Reagents and conditions: (a) ethyl propiolate, tetrahydrofuran,65oC,
1 h; (b)hydrogen
peroxide,aceticacid,90oC, 1 h; (c) lithium hydroxide monohydrate, tetrahydrofuran/water, r.t., 1 h; (d) thionyl
chloride, reflux, 3 h; potassium carbonate, dichloromethane, r.t., 5 h.
1
Structures of all the target compounds were confirmed by H-NMR (400 MHz) and MS
spectra. The target compounds 32-42 could exist in the E or Z isomeric forms due to the carbon-
carbon double bonds formed in addition reaction. For the substituted alkyl (E)-3-(arylsulfonyl)-2-
propiolates, it was reported that the peaks of olefinic protons were observed for the E
configuration (H2: δ = 6.80-7.00 ppm; H3: δ = 7.65-8.00 ppm; J=14.00-15.00 Hz) and Z
configuration (H2: δ = 6.80-7.00 ppm; H3: δ = 7.35-7.50 ppm; J=10.00-11.00 Hz)(Figure 3) [26-

29]. Thus, the difference between the chemical shift and the coupling constants for H3 protons
could be applied to judge on the configuration of the target compounds.
Figure 3. The configurations of Z configuration and E configuration
In order to further confirm the configuration of compounds, compound 32 was selected and
underwent 1H-NMR (600 MHz). The results were listed in Figure 4 and the olefinic protons were
observed as a separate doublets at δ7.69 (J = 14.8 Hz). The values of the chemical shift and the
coupling constants for the olefinic protons indicated that the compound 32 existed exclusively in
the E configuration.
Figure 4. 1H-NMR (600MHz) for the compound 32 in CDCl3
3. Results and discussion
3.1. In vitro cytotoxicity and structure-activity relationships (SARs)
Twenty-seven target compounds (16-42) along with the reference compound Foretinib were
screened in vitro for their cytotoxicity against HT-29 (human colon cancer), MKN-45 (human
gastric cancer) and A549 (human lung adenocarcinoma) cell lines by the MTT assay. The results
expressed as IC50 values were the average of at least three independent experiments and were
outlined in Table 1.
As illustrated in Table 1, most of the target compounds showed preferable cytotoxicity to the
tested three cell lines and five of them (16, 17, 21, 26 and 32) possessed equivalent or even higher
activity compared with Foretinib. The pharmacological data revealed that the replacement of
cyclopropane-1,1-dicarboxamido framework of Foretinib by 1H-imidazole-4-carboxamido or (E)-
3-hydrosulfonylacrylamido moiety maintained the potent antitumor activity significantly, and
compounds 16-31 bearing 1H-imidazole-4-carboxamido moiety exhibited elevated tendency than
compounds 32-42 with the (E)-3-hydrosulfonylacrylamido linkage. Particularly, the most

promising compound 16 demonstrated remarkable biological property against all the tested cell
lines with IC50 values of 0.08, 0.22 and 0.07μM, which were 3.1-, 1.4- and 2.1-fold superior to
Foretinib, respectively. It was noteworthy that most of the compounds displayed more
antiproliferative potency on HT-29and A549 cells, relative poor potency toward MKN-45.
However, compounds 17, 22, 27 and 30 (R2=2-trifluoromethoxy) were as exceptions and
possessed higher selectivity for MKN-45 cell, which could be attributed to the effect of
trifluoromethoxy group.
The preliminary SARs based on IC50 values indicated that variations of the terminal
alicyclic tertiary aminylgroups on the 7-position of the quinoline skeleton would affect the
cytotoxicity. The introduction of N-methyl piperazinyl (16-20, 32-35) was more preferred to the
improvement of antiproliferative potency than other substituents against all the tested cell lines by
3- to 106-times. Based on the pharmacological data above, we could deduce that water-soluble R1
group had a marked influence on antitumor activity with the following rank order generally: N-
methyl piperazinyl > piperidinyl > morpholinyl > 4-methyl piperidinyl.
Further investigations were carried out in detail to study the effect of diversified substituents
on phenyl group (moiety B). For compounds 16-31, the mono-electron-donating groups (mono-
EDGs) contributed positively to the biological activtity, while the mono-electron-withdrawing
groups (mono-EWGs) weaken the cytotoxicity dramatically, as exemplified by 16 (R2=2-methoxyl)
and 17 (R2=2-trifluoromethoxyl) in comparison with 19 (R2=4-chloro) and 20 (R2=2,4-dichloro).
Consistently, compounds 24 and 25 were less potent than compounds 21 and 22. In addition,
compounds 18 containing dimethyl group was found to decrease the antitumor activity slightly
compared with 16 and 17. The result might be explored by the existence of oxygen atom that was
favor of hydrogen-bond interaction between molecules with c-Met kinase residue.
For compounds 32-42 with the (E)-3-hydrosulfonylacrylamido linkage, the proper degree of
electron density and regioselectivity of substituents were beneficial to furnish better biological
property. Introduction of mono-EWGs (32, R′2=2-fluoro) on the phenyl ring led to the
improvement of antitumor activity extremely. However, the replacement of fluorine with mono-
EDGs like methoxyl and methyl resulted in a decreased activity. For instance, compounds 35 and
38 bearing methyl group weaken the antiproliferative potency relative to compounds 34 and 37
containing methoxyl moiety. Besides, substitution on phenyl ring at ortho-position is critical to the
cytotoxicity. A case in point is that ortho-methoxyl group displayed higher antitumor activity than
para-methoxyl group, which was corroborated by data 33 vs. 34 and 36 vs. 37. Hence, fluoro
group at ortho-position of phenyl ring was a preference for enhanced cytotoxic activity.
Table 1. Structures and cytotoxicity of compounds 16-42

IC50 (μmol/L)a±SD
Compd.
R1
R2/R′2
HT-29
MKN-45
A549
0.08±0.02
0.17±0.01
0.47±0.01
1.35±0.02
3.05±0.02
0.10±0.02
0.25±0.03
0.58±0.23
2.78±0.03
4.30±0.02
0.20±0.005
0.43±0.08
1.96±0.14
0.30±0.01
0.69±0.09
2.22±0.07
0.15±0.003
0.27±0.02
1.66±0.1
2.07±0.02
0.66±0.02
1.65±0.01
4.23±0.07
0.60±0.03
1.18±0.01
0.76±0.02
1.96±0.02
0.25±0.01
16
17
N-methyl piperazinyl
N-methyl piperazinyl
N-methyl piperazinyl
N-methyl piperazinyl
N-methyl piperazinyl
piperidinyl
2-OCH3
2-OCF3
2,5-CH3
4-Cl
0.22±0.03
0.12±0.003
0.65±0.02
4.11±0.01
4.84±0.02
0.26±0.05
0.19±0.002
0.83±0.04
5.91±0.01
6.24±0.03
0.32±0.03
0.18±0.02
3.20±0.05
0.60±0.04
0.15±0.01
5.65±0.07
0.28±0.003
0.43±0.01
2.77±0.14
2.51±0.03
0.98±0.06
3.58±0.01
1.69±0.07
0.42±0.01
1.47±0.05
0.84±0.04
2.03±0.02
0.32±0.01
0.07±0.01
0.13±0.03
0.35±0.08
5.20±0.01
3.85±0.01
0.12±0.05
0.27±0.07
0.51±0.09
6.56±0.04
7.49±0.03
0.15±0.07
0.52±0.07
5.48±0.23
0.40±0.12
0.76±0.05
7.42±0.13
0.15±0.05
0.32±0.03
1.87±0.06
1.51±0.03
0.47±0.02
2.22±0.02
2.31±0.02
0.21±0.02
0.77±0.13
0.41±0.01
3.00±0.01
0.15±0.03
18
19
20
2,4-Cl
21
2-OCH3
2-OCF3
2,5-CH3
4-Cl
22
piperidinyl
23
24
25
piperidinyl
piperidinyl
piperidinyl
2,4-Cl
26
morpholinyl
2-OCH3
2-OCF3
2,5-CH3
2-OCH3
2-OCF3
2,5-CH3
2-F
2-OCH3
4-OCH3
4-CH3
2-OCH3
4-OCH3
4-CH3
27
morpholinyl
28
morpholinyl
29
4-methyl piperidinyl
4-methyl piperidinyl
4-methyl piperidinyl
N-methyl piperazinyl
N-methyl piperazinyl
N-methyl piperazinyl
N-methyl piperazinyl
piperidinyl
piperidinyl
piperidinyl
morpholinyl
morpholinyl
30
31
32
33
34
35
36
37
38
39
40
41
2-F
2-OCH3
2-F
4-methyl piperidinyl
4-methyl piperidinyl
41
2-OCH3
Foretinib
aData presented is the mean ± SD value of three independent determinations.
bUsed as positive control.
3.2 In vitro enzymatic assays
Based on the cellular assays, fifteen compounds were determined for c-Met kinase activity
using homogenous time-resolved fluorescence (HTRF) assays and the results were outlined in
Table 2. In parallel with the cellular results, the tested compounds exhibited satisfactory c-Met
enzymatic potency with IC50 values ranging from 1.1 to 58 nM. Among the tested compounds, 16
showed the most potent c-Met inhhibitory with an IC50 value of 1.1nM, which was 1.3-folds
higher than Foretinib (IC50 = 1.43 nM). Moreover compound 17, 22, 27 and 30 showed the weak c-
Met kinase inhibitory activity, which were more potent for MKN-45 cells comparing with 16.
Table 2. Enzymatic inhibition of fifteen compounds and Foretinib against c-Met in vitro.
IC50a on c-Met (nM)
IC50a on c-Met (nM)
Compd.
Compd.
16
17
18
21
22
23
26
27
1.1±0.21
43±0.12
31±0.20
3.9±0.39
53±0.13
29±0.31
20±0.099
21±0.27
29
9.9±0.17
58±0.33
17±0.20
5.6±0.24
22±0.12
18±0.27
35±0.11
1.43±0.18
30
32
33
36
39
40
Foretinibb
Inspired by distinguished potency against c-Met kinase activity, compound 16 was further
screened against other five kinases. The results summarized in Table 3 indicated that compound 16
exhibited excellent selectivity versus VEGFR-2 (IC50 = 589 nM), Flt-3 (IC50 = 400 nM), ALK

(IC50 > 3333nM), EGFR (IC50 = 690 nM) and c-kit (IC50 = 270 nM).
Table 3. Enzymatic inhibition of compound 16 in vitro.
Compd.
IC50 (nM)
ALK
> 3333
VEGFR-2
589
Flt-3
400
EGFR
690
c-kit
270
16
3.4 Binding model analysis
In order to gain the binding model of the title inhibitors with c-Met kinase, we performed
docking analysis using Discovery Studio 3.5 software. The image files were generated by PyMOL
1.5. Using the crystal structure of Foretinib with c-Met (PDB code: 3LQ8), the overall binding
interactions of the optimal compounds 16 and 32 were showed in Figure 5. It could be observed
that the nitrogen atom of the quinoline scaffold in 16 and 32 made one hydrogen bond with
Met1160 residue. The hydrogen atom and nitrogen atom of 1H-imidazole-4-carboxamido motif
binds well to Asp1222 and Lys1110 via two hydrogen bonds. In addition, the oxygen atom on
moiety B of 16 formed a hydrogen bond with Asp1222 which validated the previous speculation.
For compound 32, the oxygen atom and the hydrogen atom of (E)-3-hydrosulfonylacrylamido
moiety generated two hydrogen bonds with Lys1110 and Met1131. The hydrogen bond interaction
between fluoro group on moiety B and Asp1222 residue indicated that the introduction of fluoro
group on moiety B would improve inhibitory activity. Moreover, the potency analogs 16-20 might
be due to extra hydrogen bonding with His1162 through N-methyl piperazinyl, as could be proved
by the binding model of compound 16.
Figure 5. Binding poses of compounds 16 (A) and 32 (B) with the c-Met active site. The compounds 16 and
32were shown in colored sticks (pink: carbon atom, blue: nitrogen atom, red: oxygen atom, gray: hydrogen atom,
green: fluorine atom). The H-bond interaction was shown in yellow dotted lines. (For interpretation of the
references to color in this figure legend, the reader is referred to the web version of this article.)
4. Conclusion
In conclusion, two novel series of 1H-imidazole-4-carboxamido- or (E)-3-
hydrosulfonylacrylamido-based 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives were
synthesized and the configurations of compounds 32-42 were unequivocally confirmed as the E
isomer. Most of compounds exhibited favorable cytotoxicity against HT-29, MKN-45 and A549
cell lines and five of them (16, 17, 21, 26 and 32) displayed comparative or better tendency as
compared with Foretinib. The exploration of preliminary SARs led to the identification of c-Met
inhibitor 16 as a valuable lead molecule, which possessed excellent c-Met kinase inhibition (IC50 = 1.1
nM). The exploration of SARs and molecular docking analysis disclosed that 1H-imidazole-4-

carboxamido as a privileged linkage was of great importance for enhanced potency and the
terminal N-methylpiperazinylpropoxy at 7-position of quinoline core was an optimal group.
Further studies on structural optimization and mechanisms of action of the title compounds are
currently underway, and the results will be reported in the future.
5. Experimental
5.1 Chemistry
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 magnetic
resonance spectroscopy was performed using Bruker ARX-400, 400 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 Chemicals (Qingdao, Shandong, China).
Unless otherwise specified, all materials were obtained from commercially available sources and
were used without further purification.
5.1.1 General procedure for preparation of 3-fluoro-4-(6,7-disubstituted quinolin-4-yloxy)anilines
(1a-d)
The preparation of the key intermediates (1a-d) has been illustrated in detail in our laboratory
previous study [22-25], so the synthesis method would not be listed here.
5.1.1.1. 3-Fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)aniline(1a)
Gray solid; yield: 85.37%; MS (ESI) m/z: 426.3 [M+H]+, 448.2 [M+Na]+.
5.1.1.2. 3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)aniline
(1b)
White solid; yield: 76.53%; MS (ESI) m/z: 440.2 [M+H]+.
5.1.1.3. 3-Fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)aniline (1c)
Light yellow solid; yield: 75.43%; MS (ESI) m/z: 428.2 [M+H]+.
5.1.1.4.3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)aniline
(1d)
White solid; yield: 83.65%; MS (ESI) m/z: 441.3 [M+H]+.
5.1.2. General procedure for preparation of N-phenylformamides (2a-e)
A mixture of sodium formate (8.1 mmol), formic acid (12.5 mL) and various substituted N-
phenylformamides (40.7 mmol) was stirred at reflux for 12 h. The progress of the reaction was
monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under
reduced pressure. The solid was taken up in ethyl acetate to form a solution which was
successively washed with water (2×20 mL) and then evaporated under reduced pressure to obtain
the corresponding amides 2a-e.
5.1.2.1. N-(2-methoxyphenyl)formamide (2a)

Yellow oil; yield: 85.62%; MS (ESI) m/z: 152.3 [M+H]+.
5.1.2.2. N-(2-(trifluoromethoxy)phenyl)formamide (2b)
Yellow oil; yield: 90.56%; MS (ESI) m/z: 206.2 [M+H]+.
5.1.2.3. N-(2,5-dimethylphenyl)formamide(2c)
Yellow oil; yield: 89.34%; MS (ESI) m/z: 150.2 [M+H]+.
5.1.2.4. N-(4-chlorophenyl)formamide (2d)
Yellow oil; yield: 89.07%; MS (ESI) m/z: 156.1 [M+H]+.
5.1.2.5. N-(2,4-dichlorophenyl)formamide (2e)
Yellow oil; yield: 88.51%; MS (ESI) m/z: 190.2 [M+H]+.
5.1.3. General procedure for preparation of benzonitriles (3a-e)
A solution of phosphorus oxychloride (43.0 mmol) in tetrahydrofuran (180 mL) was added
drop wise to a solution of an appropriate N-phenylformamides (33.1 mmol) in tetrahydrofuran (50
mL) at 0°C. Upon the completion of addition, the ice bath has been removed, and the reaction was
stirred at room temperature for 4 h and monitored by thin layer chromatography (TLC). The
resulting solution was stirred at 0°C with the addition of water (250 mL) at 0°C, and then filtered
to afford the corresponding benzonitriles 3a-e.
5.1.3.1. 2-Methoxybenzonitrile (3a)
Light yellow oil; yield: 88.01%; MS (ESI) m/z: 134.1 [M+H]+.
5.1.3.2. 2-(Trifluoromethoxy)benzonitrile (3b)
Light yellow oil; yield: 85.23%; MS (ESI) m/z: 188.2 [M+H]+.
5.1.3.3. 2,5-Dimethylbenzonitrile (3c)
Light yellow oil; yield: 84.56%; MS (ESI) m/z: 132.0 [M+H]+.
5.1.3.4. 4-Chlorobenzonitrile (3d)
Light yellow oil; yield: 88.05%; MS (ESI) m/z: 138.3 [M+H]+.
5.1.3.5. 2,4-Dichlorobenzonitrile (3e)
Light yellow oil; yield: 83.51%; MS (ESI) m/z: 172.0 [M+H]+.
5.1.4. General procedure for preparation of 1-phenyl-1H-imidazole-4-carboxylic acid ethyl ester
(4a-e)
A mixture of copper (I) oxide (3.5 mmol), 1,10-phenanthroline monohydrate(5.1 mmol),
ethyl cyanoacetate (35.4 mmol) and an appropriate benzonitriles (24.8 mmol) in tetrahydrofuran
was stirred at reflux for 3 h. After completion of the reaction, the reaction mixture was evaporated
under reduced pressure. The resultant residue was dissolved in ethyl acetate and filtered. The
filtrate was partially concentrated then cooled. The resultant precipitated was filtered and the filter
cake was washed with cold methanol to give the corresponding 1-phenyl-1H-imidazole-4-
carboxylic acid ethyl esters 4a-e.
5.1.4.1. Ethyl 1-(2-methoxyphenyl)-1H-imidazole-4-carboxylate (4a)
White solid; yield: 22.07%; MS (ESI) m/z:247.3 [M+H]+.
5.1.4.2. Ethyl 1-(2-(trifluoromethoxy)phenyl)-1H-imidazole-4-carboxylate (4b)

White solid; yield: 21.01%; MS (ESI) m/z: 301.1 [M+H]+.
5.1.4.3. Ethyl 1-(2,5-dimethylphenyl)-1H-imidazole-4-carboxylate (4c)
White solid; yield: 20.58%; MS (ESI) m/z: 245.1 [M+H]+.
5. 1.4.4. Ethyl 1-(4-chlorophenyl)-1H-imidazole-4-carboxylate (4d)
White solid; yield: 25.54%; MS (ESI) m/z: 251.2 [M+H]+.
5.1.4.5. Ethyl 1-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (4e)
White solid; yield: 21.03%; MS (ESI) m/z: 285.0 [M+H]+.
5.1.5. General procedure for preparation of 1-phenyl-1H-imidazole-4-carboxylic acid (5a-e)
Lithium hydroxide monohydrate (9.5 mmol) was added to a solution of 1-phenyl-1H-
imidazole-4-carboxylic acid ethyl ester (4.1 mmol) in tetrahydrofuran (8 mL) and water (2 mL).
The mixture was stirred at room temperature for 20 h until the reaction was completed (followed
by TLC). After completion of the reaction, the reaction mixture was concentrated under reduced
pressure. The mixture was poured into water, and then the pH adjusted to pH 3-4 by addition of a
3N aqueous solution of hydrochloric acid and filtered to obtain the corresponding 1-phenyl-1H-
imidazole-4-carboxylic acid 5a-e.
5.1.5.1. 1-(2-Methoxyphenyl)-1H-imidazole-4-carboxylic acid (5a)
White solid; yield: 65.03%; MS (ESI) m/z: 219.1 [M+H]+.
5.1.5.2. 1-(2-(Trifluoromethoxy)phenyl)-1H-imidazole-4-carboxylic acid (5b)
White solid; yield: 65.05%; MS (ESI) m/z: 273.2 [M+H]+.
5.1.5.3. 1-(2,5-Dimethylphenyl)-1H-imidazole-4-carboxylic acid (5c)
White solid; yield: 61.51%; MS (ESI) m/z: 217.0 [M+H]+.
5.1.5.4. 1-(4-Chlorophenyl)-1H-imidazole-4-carboxylic acid (5d)
White solid; yield: 60.07%; MS (ESI) m/z: 223.2 [M+H]+.
5.1.5.5. 1-(2,4-Dichlorophenyl)-1H-imidazole-4-carboxylic acid (5e)
White solid; yield: 61.24%; MS (ESI) m/z: 257.1 [M+H]+.
5.1.6. General procedure for preparation of the target compounds (16-31)
Various substituted 1-phenyl-1H-imidazole-4-carboxylic acid 5a-e (1.3 mmol) were added to
thionyl chloride (10 mL), respectively, and refluxed for 5h. The reaction mixture was evaporated
to afford corresponding 1-phenyl-1H-imidazole-4-carbonyl chloride.
To a mixture of an appropriate aniline 1a-d (1.0mmol), potassium carbonate (4.4mmol) and
dichloromethane (20 mL) in an ice bath, an appropriate carbonyl chloride (1.3mmol) was
dissolved in dried dichloromethane (20 mL) to add drop-wise. Upon the completion of addition,
the stirring was continued at room temperature until the reaction was completed (followed by
TLC).The mixture was washed with water (100 mL), 1% aqueous sodium hydroxide(100 mL),
and then dried and evaporated. The solid was slurred in isopropanol and filtered to yield the target
compounds 16-31.
5.1.6.1.
N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-
yl)oxy)phenyl)-1-(2-methoxyphenyl)-1H-imidazole-4-carboxamide (16)

White solid; yield: 24.2%; m.p.: 220.2-223.2°C, MS (ESI) m/z: 641.3 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.14 (s, 1H), 8.50 (d, J = 2.9 Hz, 1H), 7.96 (s, 2H), 7.77 (s, 1H), 7.59 (s,
1H), 7.51-7.30 (m, 4H), 7.10 (d, J = 7.5 Hz, 2H), 6.45 (d, J = 3.6 Hz, 1H), 4.26 (s, 2H), 4.04 (s,
3H), 3.89 (s,3H), 2.51 (m, 13H), 2.15 (d, J = 5.6 Hz, 2H); Anal. Calcd. for C35H37FN6O5 (%): C,
65.61; H, 5.82; N, 13.12; Found (%): C, 65.63; H, 5.81; N, 13.11.
5.1.6.2.
N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-
yl)oxy)phenyl)-1-(2-(trifluoromethoxy)phenyl)-1H-imidazole-4-carboxamiden (17)
White solid; yield: 25.5%; m.p.: 193.4-194.7°C, MS (ESI) m/z: 695.2 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.13 (s, 1H), 8.50 (d, J = 5.1 Hz, 1H), 7.99-7.91 (m, 2H), 7.74 (d, J = 0.5
Hz, 1H),7.58 (s,1H), 7.52 (m, 4H), 7.42 (d, J = 9.5 Hz, 2H), 6.44 (d, J = 5.1 Hz, 1H), 4.26 (t, J =
6.5 Hz, 2H), 4.04 (s, 3H), 2.77-2.50 (m, 10H), 2.38 (s, 3H), 2.18-2.10 (m, 2H); Anal. Calcd. for
C35H34F4N6O5 (%): C, 60.51; H, 4.93; N, 12.10; Found (%): C, 60.53; H, 4.91; N, 12.11.
5.1.6.3.1-(2,5-Dimethylphenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)
quinolin-4-yl)oxy)phenyl)-1H-imidazole-4-carboxamide (18)
White solid; yield: 24.5%; m.p.: 213.5-214.7°C, MS (ESI) m/z: 639.2 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.17 (s, 1H), 8.49 (s, 1H), 7.96 (d, J = 11.7 Hz, 1H), 7.68 (s, 1H), 7.58 (s,
1H), 7.44 (d, J = 14.2 Hz, 3H), 7.31 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 6.4 Hz, 2H), 6.44 (s, 1H), 4.26
(s, 2H), 4.04 (s, 3H), 2.54 (m, 10H), 2.31 (s, 3H), 2.13 (s, 2H), 2.07 (s, 6H); Anal. Calcd. for
C36H39FN6O4 (%): C, 67.69; H, 6.15; N, 13.16; Found (%): C, 67.70; H, 6.13; N, 13.15.
5.1.6.4.
1-(2-Chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-1H-imidazole-4-carboxamide(19)
White solid; yield: 23.0%; m.p.: 206.0-207.1°C, MS (ESI) m/z: 645.5 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.09 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.02-7.92 (m,2H), 7.81 (s, 1H), 7.58
(s, 1H), 7.52 (d, J = 8.6 Hz, 2H), 7.45-7.36 (m, 4H), 4.26 (t, J = 6.6 Hz, 2H), 4.04 (s, 3H), 2.91-
2.36 (m, 10H), 2.32 (s, 3H), 2.14 (dt, J = 13.7, 6.7 Hz, 2H); Anal. Calcd. for C34H34ClFN6O4 (%):
C, 63.30; H, 5.31; N, 13.03; Found (%): C, 63.33; H, 5.30; N, 13.01.
5.1.6.5.1-(2, 4-Dichlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)
quinolin-4-yl)oxy)phenyl)-1H-imidazole-4-carboxamide (20)
White solid; yield: 20.3%; m.p.: 199.4-201.5°C, MS (ESI) m/z: 679.1 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.13 (s, 1H), 8.49 (s, 1H), 7.95 (d, J = 12.0 Hz, 1H), 7.87 (s, 1H), 7.72-7.53
(m, 3H), 7.43 (s, 3H), 7.35 (d, J = 7.9 Hz, 1H), 6.44 (s, 1H), 4.26 (s, 2H), 4.04 (s, 3H), 2.61 (s,
10H), 2.37 (s, 3H), 2.14 (s, 2H); Anal. Calcd. for C34H33Cl2FN6O4 (%): C, 60.09; H, 4.89; N,
12.47; Found (%): C, 60.11; H, 4.87; N, 12.46.
5.1.6.6. N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-1-(2-
methoxyphenyl)-1H-imidazole-4-carboxamide (21)
White solid; yield: 22.4%; m.p.: 223.8-224.6°C, MS (ESI) m/z: 626.2 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.13 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 7.98-7.94 (m, 2H), 7.76 (d, J = 1.1
Hz, 1H), 7.58 (s, 1H), 7.42 (d, J = 5.7 Hz, 3H), 7.33 (dd, J = 7.7, 1.2 Hz, 1H), 7.11 (s, 1H), 7.09 (s,

1H), 6.44 (d, J = 5.2 Hz, 1H), 4.25 (t, J = 6.5 Hz, 2H), 4.04 (s, 3H), 3.89 (s,3H), 2.63 (s, 6H), 2.23
(s, 2H), 1.70 (s, 4H), 1.49 (s, 2H); Anal. Calcd. for C35H36FN5O5 (%): C, 67.19; H, 5.80; N, 11.19;
Found (%): C, 67.21; H, 5.81; N, 11.17.
5.1.6.7. N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-1-(2-
(trifluoromethoxy)phenyl)-1H-imidazole-4-carboxamide (22)
White solid; yield: 25.1%; m.p.: 197.5-198.2°C, MS (ESI) m/z: 680.1 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.13 (s, 1H), 8.50 (d, J = 3.8 Hz, 1H), 8.01-7.89 (m, 2H), 7.74 (s,1H), 7.61-
7.46 (m, 5H), 7.42 (d, J = 8.7 Hz, 2H), 6.44 (d, J = 4.7 Hz, 1H), 4.26 (t, J = 6.1 Hz, 2H), 4.04 (s,
3H), 2.76 (s, 6H), 2.31 (s, 2H), 1.78 (s, 4H), 1.53 (s, 2H); Anal. Calcd. for C35H34F4N5O5 (%): C,
61.85; H, 4.89; N, 10.30; Found (%): C, 61.86; H, 4.87; N, 10.32.
5.1.6.8.
1-(2,5-Dimethylphenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-1H-imidazole-4-carboxamide (23)
White solid; yield: 25.5%; m.p.: 215.6-216.3°C, MS (ESI) m/z: 624.4 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.17 (s, 1H), 8.50 (s, 1H), 7.96 (d, J = 11.8 Hz, 1H), 7.69 (s, 1H), 7.59 (d, J
= 1.4 Hz, 1H), 7.49-7.38 (m, 3H), 7.32 (t, J = 7.1 Hz, 1H), 7.21 (d, J = 6.6 Hz, 2H), 6.45 (s, 1H),
4.26 (s, 2H), 4.04 (s, 3H), 2.63 (s, 6H), 2.23 (s, 2H), 2.08 (s, 6H), 1.69 (s, 4H), 1.49 (s, 2H); Anal.
Calcd. for C36H38FN5O4 (%): C, 69.32; H, 6.14; N, 11.23; Found (%): C, 69.34; H, 6.12; N, 11.24.
5.1.6.9. 1-(4-Chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-
yl)oxy)phenyl)-1H-imidazole-4-carboxamide (24)
White solid; yield: 23.0%; m.p.: 209.0-210.1°C, MS (ESI) m/z: 630.1 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.09 (s, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.02-7.91 (m, 2H), 7.81 (s, 1H), 7.58
(s, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.40 (t, J = 6.8 Hz, 4H), 6.43 (d, J = 5.2 Hz, 1H), 4.26 (t, J = 6.4
Hz, 2H), 4.04 (s, 3H), 2.62 (s, 6H), 2.23 (s, 2H), 1.69 (s, 4H), 1.49 (s, 2H); Anal. Calcd. for
C34H33ClFN5O4 (%): C, 64.81; H, 5.28; N, 11.11; Found (%): C, 64.82; H, 5.29; N, 11.10.
5.1.6.10.
1-(2,4-Dichlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-1H-imidazole-4-carboxamide (25)
White solid; yield: 22.0%; m.p.: 200.7-201.4°C, MS (ESI) m/z: 664.2 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.11 (s, 1H), 8.49 (t, J = 4.5 Hz, 1H), 7.95 (d, J = 13.4 Hz, 1H), 7.86 (d, J =
1.5 Hz, 1H), 7.65 (dd, J = 16.6, 1.2 Hz, 2H), 7.58 (d, J = 2.4 Hz, 1H), 7.42 (s, 3H), 7.38-7.32 (m,
1H), 6.44 (s, 1H), 4.26 (d, J = 3.9 Hz, 2H), 4.04 (s, 3H), 2.63 (s, 6H), 2.23 (s, 2H), 1.69 (s, 4H),
1.49 (s, 2H); Anal. Calcd. for C34H32Cl2FN5O4 (%): C, 61.45; H, 4.85; N, 10.54; Found (%): C,
61.47; H, 4.84; N, 10.55.
5.1.6.11.
N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-1-(2-
methoxyphenyl)-1H-imidazole-4-carboxamide (26)
White solid; yield: 25.3%; m.p.: 228.3-229.0°C, MS (ESI) m/z: 628.2 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.14 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.00-7.91 (m, 2H), 7.76 (s, 1H), 7.59
(s, 1H), 7.43 (t, J = 7.8 Hz, 3H), 7.33 (d, J = 7.5 Hz, 1H), 7.09 (t, J = 7.9 Hz, 2H), 6.44 (d, J = 5.2
Hz, 1H), 4.27 (t, J = 6.6 Hz, 2H), 4.04 (s, 3H), 3.88 (s,3H), 3.73 (t, J = 4.4 Hz, 4H), 2.58 (t, J =

7.1 Hz, 2H), 2.49 (s, 4H), 2.18-2.09 (m, 2H); Anal. Calcd. for C34H34FN5O6 (%): C, 65.06; H, 5.46;
N, 11.16; Found (%): C, 65.08; H, 5.45; N, 11.17.
5.1.6.12. N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-1-(2-
(trifluoromethoxy)phenyl)-1H-imidazole-4-carboxamide (27)
White solid; yield: 27.0%; m.p.: 201.4-202.8°C, MS (ESI) m/z: 682.3 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.14 (s, 1H), 8.48 (d, J = 4.7 Hz, 1H), 8.06-7.82 (m, 2H), 7.72 (s,1H),7.57
(s,1H), 7.56-7.44 (m, 4H), 7.41 (d, J = 10.9 Hz, 2H), 6.43 (d, J = 4.8 Hz, 1H), 4.26 (t, J = 6.3 Hz,
2H), 4.03 (s, 3H), 3.71 (s, 4H), 2.57 (t, J = 6.9 Hz, 2H), 2.48 (s, 4H), 2.19-2.05 (m, 2H); Anal.
Calcd. for C34H31F4N5O6 (%): C, 59.91; H, 4.58; N, 10.27; Found (%): C, 59.92; H, 4.57; N, 10.28.
5.1.6.13. 1-(2,5-Dimethylphenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-
4-yl)oxy)phenyl)-1H-imidazole-4-carboxamide (28)
White solid; yield: 27.6%; m.p.: 216.3-217.0°C, MS (ESI) m/z: 626.2 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.17 (s, 1H), 8.50 (d, J = 4.3 Hz, 1H), 7.96 (d, J = 12.2 Hz, 1H), 7.68 (s,
1H), 7.59 (s, 1H), 7.44 (t, J = 9.3 Hz, 3H), 7.32 (t, J = 7.2 Hz, 1H), 7.21 (d, J = 6.9 Hz, 2H), 6.45
(s, 1H), 4.28 (s, 2H), 4.05 (s, 3H), 3.73 (s, 4H), 2.59 (s, 2H), 2.50 (s, 4H), 2.14 (s, 2H), 2.08 (s,
6H); Anal. Calcd. for C35H36FN5O6 (%): C, 67.19; H, 5.80; N, 11.19; Found (%): C, 67.21; H,
5.81; N, 11.17.
5.1.6.14.
N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-
yl)oxy)phenyl)-1-(2-methoxyphenyl)-1H-imidazole-4-carboxamide (29)
White solid; yield: 25.1%; m.p.: 234.7-236.4°C, MS (ESI) m/z: 640.5 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.14 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.99-7.93 (m, 2H), 7.76 (d, J = 0.7
Hz, 1H), 7.58 (s, 1H), 7.44 (dd, J = 12.8, 4.6 Hz, 3H), 7.33 (dd, J = 7.6, 1.1 Hz, 1H), 7.09 (t, J =
7.8 Hz, 2H), 6.44 (d, J = 5.0 Hz, 1H), 4.25 (t, J = 6.4 Hz, 2H), 4.04 (s, 3H), 3.89 (s,3H), 2.73 (s,
2H), 2.21 (s, 4H), 1.69 (d, J = 9.1 Hz, 2H), 1.44 (s, 3H), 0.96 (s, 3H);Anal. Calcd. for
C36H38FN5O5 (%): C, 67.59; H, 5.99; N, 10.95; Found (%):C, 67.61; H, 5.98; N, 10.94.
5.1.6.15.
N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-
yl)oxy)phenyl)-1-(2-(trifluoromethoxy)phenyl)-1H-imidazole-4-carboxamide (30)
Light yellow solid; yield: 23.1%; m.p.: 221.0-222.6°C, MS (ESI) m/z: 694.2 [M+H]+.1H-
NMR (400 MHz, CDCl3) δ(ppm): 9.13 (s, 1H), 8.50 (s,1H), 8.04-7.85 (m, 2H), 7.73 (s,1H), 7.53
(m, 5H), 7.41 (d, J = 8.8 Hz, 2H), 6.45 (s, 1H), 4.25 (s, 2H), 4.03 (s, 3H), 3.24 (s, 2H), 2.94 (s,
2H), 2.37 (s, 4H), 1.82-1.47 (m, 5H), 0.99 (d, J = 4.7 Hz, 3H);Anal. Calcd. for C36H35F4N5O5 (%):
C, 62.33; H, 5.09; N, 10.10; Found (%): C, 62.35; H, 5.07; N, 10.11.
5.1.6.16.1-(2,5-Dimethylphenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)prop-
oxy)quinolin-4-yl)oxy)phenyl)-1H-imidazole-4-carboxamide (31)
White solid; yield: 23.5%; m.p.: 220.5-221.1°C, MS (ESI) m/z: 638.3 [M+H]+.1H-NMR (400
MHz, CDCl3) δ(ppm): 9.17 (s, 1H), 8.49 (s, 1H), 7.96 (d, J = 11.8 Hz, 1H), 7.68 (s, 1H), 7.58
(s,1H), 7.44 (m, 3H), 7.32 (t, J = 7.0 Hz, 1H), 7.20 (d, J = 6.3 Hz, 2H), 6.44 (s, 1H), 4.26 (s, 2H),
4.04 (s, 3H), 3.04 (s, 2H), 2.69 (s, 2H), 2.23 (s, 2H), 2.08 (s, 8H), 1.67 (d, J = 5.5 Hz, 2H), 1.40 (s,

3H), 0.95 (s, 3H); Anal. Calcd. for C37H40FN5O4 (%): C, 69.68; H, 6.32; N, 10.98; Found (%): C,
69.69; H, 6.31; N, 10.97.
5.1.7. General procedure for preparation of (E)-3-(phenylthio)acrylate ethyl (6a-d)
Various substituted benzenethiol (21.4 mmol) were dissolved in tetrahydrofuran (20 mL)
after which ethyl propiolate (23.6 mmol) were added and the mixture was stirred at 65°C for 1 h.
After completion of the reaction, the resulting solution was evaporated under reduced pressure and
gave corresponding (E)-3-(phenylthio)acrylate ethyl 6a-d.
5.1.7.1. Ethyl (E)-3-((2-fluorophenyl)thio)acrylate (6a)
Yellow oil; yield: 78.06%; MS (ESI) m/z: 227.0 [M+H]+.
5.1.7.2. Ethyl (E)-3-((2-methoxyphenyl)thio)acrylate (6b)
Yellow oil; yield: 78.93%; MS (ESI) m/z: 239.2 [M+H]+.
5.1.7.3. Ethyl (E)-3-((4-methoxyphenyl)thio)acrylate (6c)
Yellow oil; yield: 75.02%; MS (ESI) m/z: 239.0 [M+H]+.
5.1.7.4. Ethyl (E)-3-(p-tolylthio)acrylate (6d)
Yellow oil; yield: 75.67%; MS (ESI) m/z: 223.1 [M+H]+.
5.1.8. General procedure for preparation of (E)-3-(phenylsulfonyl)acrylate ethyl (7a-d)
Hydrogen peroxide (62.8 mmol) was added to a solution of (E)-3-(phenylthio)acrylate ethyl
(12.6 mmol) in aceticacid (60 mL) and the mixture heated at 90°C with stirring for 1 h(monitored
by TLC). The resulting solution was evaporated under reduced pressure and obtained
corresponding (E)-3-(phenylsulfonyl)acrylate ethyl 7a-d.
5.1.8.1. Ethyl (E)-3-((2-fluorophenyl)sulfonyl)acrylate (7a)
Yellow oil; yield: 86.23%; MS (ESI) m/z: 259.1 [M+H]+.
5.1.8.2. Ethyl (E)-3-((2-methoxyphenyl)sulfonyl)acrylate (7b)
Yellow oil; yield: 89.14%; MS (ESI) m/z: 271.0 [M+H]+.
5.1.8.3. Ethyl (E)-3-((4-methoxyphenyl)sulfonyl)acrylate (7c)
Yellow oil; yield: 85.57%; MS (ESI) m/z: 271.2 [M+H]+.
5.1.8.4. Ethyl (E)-3-tosylacrylate (7d)
Yellow oil; yield: 91.51%; MS (ESI) m/z: 255.1 [M+H]+.
5.1.9. General procedure for preparation of (E)-3-(phenylsulfonyl)acrylic acid (8a-d)
Lithium hydroxide monohydrate (16.4 mmol) was added to a mixed solution of 1-phenyl-1H-
imidazole-4-carboxylic acid ethyl ester (7.1 mmol) in tetrahydrofuran (15 mL) and water (10 mL).
The mixture was stirred at room temperature until the reaction was completed (followed by TLC).
When the reaction was deemed complete, the reaction mixture was concentrated under reduced
pressure. The mixture was poured into water, then the pH adjusted to pH 3-4 by addition of a 3N
aqueous solution of hydrochloric acid and filtered to obtain the corresponding(E)-3-
(phenylsulfonyl)acrylic acid 8a-d.
5.1.9.1. (E)-3-((2-fluorophenyl)sulfonyl)acrylic acid (8a)
Yellow solid; yield: 79.52%; MS (ESI) m/z: 231.3 [M+H]+.

5.1.9.2. (E)-3-((2-methoxyphenyl)sulfonyl)acrylic acid (8b)
Yellow solid; yield: 78.07%; MS (ESI) m/z: 243.1 [M+H]+.
5.1.9.3. (E)-3-((4-methoxyphenyl)sulfonyl)acrylic acid (8c)
Yellow solid; yield: 75.21%; MS (ESI) m/z: 243.2 [M+H]+.
5.1.9.4. (E)-3-tosylacrylic acid (8d)
Yellow solid; yield: 80.14%; MS (ESI) m/z: 227.0 [M+H]+.
5.1.10. General procedure for preparation of the target compounds (32-42)
Thionyl chloride (76 mL) were added to various substituted (E)-3-(phenylsulfonyl)acrylic
acid 8a-d(1.5 mmol), respectively, and refluxed for 3 h. The reaction mixture was evaporated to
afford corresponding(E)-3-(phenylthio)acryloyl chloride.
To a mixture of an appropriate aniline 1a-d (1.0 mmol), potassium carbonate (3.0 mmol) and
dichloromethane (20 mL) in an ice bath, an appropriate carbonyl chloride (1.3 mmol) was
dissolved in dried dichloromethane (20 mL) to add drop-wise. Upon the completion of addition,
the stirring was continued at room temperature until the reaction was completed (followed by
TLC). The mixture was evaporated under reduced pressure, and then extracted with ethyl
acetate( 3×20 mL). The organic extracts were combined and washed with potassium carbonate
(5%, 2×15 mL), brine (2×15 mL). Evaporation of the solvent yielded the target compounds 32-42.
5.1.10.1.
(E)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-
yl)oxy)phenyl)-3-((2-fluorophenyl)sulfonyl)acrylamide (32)
Yellow solid; yield: 22.0%; m.p.: 109.7-110.7°C, MS (ESI) m/z: 653.2 [M+H]+.1H-NMR
(400 MHz, CDCl3) δ(ppm): 8.47 (d, J = 5.3 Hz, 1H), 8.01-7.92 (m, 1H), 7.77 (dd, J = 11.8, 2.4 Hz,
1H), 7.72-7.65 (m, 1H), 7.59-7.54 (m, 1H), 7.46 (s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 9.1
Hz, 2H), 7.26-7.21 (m, 1H), 6.39 (d, J = 4.9 Hz, 1H), 4.28 (t, J = 6.3 Hz, 2H), 4.04 (s, 3H), 3.25-
2.69 (m, 10H), 2.64 (s, 3H), 2.21-2.09 (m, 2H); Anal. Calcd.for C33H34F2N4O6S (%): C, 60.73; H,
5.25; N, 8.58; Found (%): C, 60.75; H, 5.24; N, 8.59.
5.1.10.2.
(E)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-
yl)oxy)phenyl)-3-((2-methoxyphenyl)sulfonyl)acrylamide (33)
Yellow solid; yield: 27.1%; m.p.: 110.3-111.5°C, MS (ESI) m/z: 665.2 [M+H] +. 1H-NMR
(400 MHz, CDCl3) δ(ppm): 8.44 (d, J = 5.3 Hz, 1H), 8.09-7.84 (m, 2H), 7.74-7.53 (m, 4H), 7.48
(s, 1H), 7.22-7.07 (m, 2H), 7.03 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 5.1 Hz, 1H), 4.28 (t, J = 5.9 Hz,
2H), 4.01 (d, J = 6.3 Hz, 3H), 3.77-3.62 (m, 3H), 2.86 (m, 13H), 2.22-2.11 (m, 2H); Anal. Calcd.
for C34H37FN4O7S (%): C, 61.43; H, 5.61; N, 8.43; Found (%): C, 61.45; H, 5.62; N, 8.41.
5.1.10.3.
(E)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-
yl)oxy)phenyl)-3-((4-methoxyphenyl)sulfonyl)acrylamide (34)
Yellow solid; yield: 27.0%; m.p.: 112.6-113.5°C, MS (ESI) m/z: 665.3 [M+H]+.1H-NMR
(400 MHz, CDCl3) δ(ppm): 8.43 (d, J = 5.3 Hz, 1H), 7.91 (dd, J = 12.1, 2.3 Hz, 1H), 7.87-7.77
(m, 2H), 7.62-7.47 (m, 3H), 7.43 (d, J = 13.9 Hz, 2H), 7.16 (t, J = 8.7 Hz, 1H), 7.01 (d, J = 9.0 Hz,
2H), 6.37 (d, J = 5.0 Hz, 1H), 4.25 (t, J = 6.2 Hz, 2H), 4.00 (s, 3H), 3.91-3.84 (m, 3H), 2.86 (m,

10H), 2.54 (s, 3H), 2.22-2.08 (m, 2H); Anal. Calcd. for C34H37FN4O7S (%): C, 61.43; H, 5.61; N,
8.43; Found (%): C, 61.44; H, 5.60; N, 8.44.
5.1.10.4.
(E)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-
yl)oxy)phenyl)-3-tosylacrylamide (35)
Yellow solid; yield: 28.0%; m.p.: 108.1-109.0°C, MS (ESI) m/z: 649.4 [M+H]+.1H-NMR
(400 MHz, CDCl3) δ(ppm): 8.42 (d, J = 5.3 Hz, 1H), 7.93 (dd, J = 12.1, 2.3 Hz, 1H), 7.77 (d, J =
8.3 Hz, 2H), 7.62-7.48 (m, 3H), 7.46-7.38 (m, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.16 (t, J = 8.7 Hz,
1H),6.36 (d, J = 5.3 Hz, 1H), 4.25 (t, J = 6.3 Hz, 2H), 4.00 (s, 3H), 3.10-2.69 (m, 10H), 2.65 (s,
3H), 2.43 (s, 3H), 2.21-2.09 (m, 2H); Anal. Calcd. for C34H37FN4O6S (%): C, 62.95; H, 5.75; N,
8.64; Found (%): C, 62.97; H, 5.73; N, 8.65.
5.1.10.5. (E)-N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-
3-((2-methoxyphenyl)sulfonyl)acrylamide (36)
Yellow solid; yield: 23.0%; m.p.: 111.7-112.3°C, MS (ESI) m/z: 650.2 [M+H]+.1H-NMR
(400 MHz, CDCl3) δ(ppm): 8.45 (d, J = 5.2 Hz, 1H), 8.07-7.82 (m, 2H), 7.71-7.54 (m, 4H), 7.46
(s, 1H), 7.20-7.06 (m, 2H), 7.01 (d, J = 8.3 Hz, 1H), 6.38 (d, J = 5.0 Hz, 1H), 4.26 (t, J = 6.0 Hz,
2H), 4.03 (d, J = 6.2 Hz, 3H), 3.78-3.60 (m, 3H), 2.65 (s, 6H), 2.20-2.11 (m, 2H), 1.68 (s, 4H),
1.44 (s, 2H); Anal. Calcd. for C34H36FN3O7S (%): C, 62.85; H, 5.59; N, 6.47; Found (%): C, 62.87;
H, 5.58; N, 6.46.
5.1.10.6. (E)-N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-
3-((4-methoxyphenyl)sulfonyl)acrylamide (37)
Yellow solid; yield: 24.1%; m.p.: 115.2-116.0°C, MS (ESI) m/z: 650.1 [M+H]+.1H-NMR
(400 MHz, CDCl3) δ(ppm): 8.44 (d, J = 5.3 Hz, 1H), 7.92 (dd, J = 12.0, 2.4 Hz, 1H), 7.85-7.73
(m, 2H), 7.65-7.48 (m, 3H), 7.45 (d, J = 13.7 Hz, 2H), 7.03 (d, J = 8.9 Hz, 2H), 6.39 (d, J = 5.1 Hz,
1H), 4.28 (t, J = 6.3 Hz, 2H), 4.01 (s, 3H), 3.90-3.85 (m, 3H), 2.63 (s, 6H), 2.22-2.08 (m, 2H),
1.69(s, 4H), 1.49 (s, 2H);Anal. Calcd. for C34H36FN3O7S (%): C, 62.85; H, 5.59; N, 6.47; Found
(%): C, 62.86; H, 5.58; N, 6.48.
5.1.10.7. (E)-N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-
3-tosylacrylamide (38)
Yellow solid; yield: 23.7%; m.p.: 110.3-111.2°C, MS (ESI) m/z: 634.1 [M+H]+.1H-NMR
(400 MHz, CDCl3) δ(ppm): 8.43 (d, J = 5.3 Hz, 1H), 7.93 (dd, J = 12.1, 2.3 Hz, 1H), 7.78 (d, J =
8.2 Hz, 2H), 7.62-7.47 (m, 3H), 7.43-7.38 (m, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.37 (d, J = 5.1 Hz,
1H), 4.25 (t, J = 6.2 Hz, 2H), 4.01 (s, 3H),2.65 (s, 3H), 2.41 (s, 3H), 2.22-2.08 (m, 2H), 1.67 (s,
4H), 1.46 (s, 2H); Anal. Calcd. for C34H36FN3O6S (%): C, 64.44; H, 5.73; N, 6.63; Found (%): C,
64.46; H, 5.72; N, 6.65.
5.1.10.8. (E)-N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-3-
((2-fluorophenyl)sulfonyl)acrylamide (39)
Yellow solid; yield: 22.1%; m.p.: 115.1-115.5°C, MS (ESI) m/z: 640.1 [M+H]+.1H-NMR
(400 MHz, CDCl3) δ(ppm): 8.48 (d, J = 5.4 Hz, 1H), 8.01-7.92 (m, 1H), 7.77 (dd, J = 11.8, 2.3 Hz,

1H), 7.73-7.64 (m, 1H), 7.57 (s, 1H), 7.50 (s, 1H), 7.36 (td, J = 7.8, 0.9 Hz, 1H), 7.30 (dd, J = 8.6,
2.6 Hz, 2H), 7.26-7.20 (m, 1H), 6.41 (d, J = 4.9 Hz, 1H), 4.29 (t, J = 6.3 Hz, 2H), 4.04 (s, 3H),
3.88-3.84 (m, 4H), 2.87-2.78 (m, 2H), 2.73 (s, 4H), 2.28 (dt, J = 13.1, 6.5 Hz, 2H); Anal. Calcd.
for C32H31F2N3O7S (%): C, 60.09; H, 4.89; N, 6.57; Found (%):C, 60.11; H, 4.87; N, 6.58.
5.1.10.9. (E)-N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-3-
((2-methoxyphenyl)sulfonyl)acrylamide (40)
Yellow solid; yield: 24.5%; m.p.: 112.6-113.1°C, MS (ESI) m/z: 652.5 [M+H]+.1H-NMR
(400 MHz, CDCl3) δ(ppm): 8.46 (d, J = 5.2 Hz, 1H), 7.97 (dd, J = 13.0, 2.3 Hz, 1H), 7.75 (d, J =
9.7 Hz, 1H), 7.63-7.32 (m, 5H), 7.22 (d, J = 8.2 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.44 (d, J = 5.2
Hz, 1H), 4.17 (t, J = 6.3 Hz, 2H), 3.93 (s, 3H), 3.79 (s, 3H), 3.51 (s, 4H), 2.92 (d, J = 10.9 Hz, 2H),
2.54 (t, J = 6.4 Hz, 2H), 2.50-2.47 (m, 2H), 2.00 (dd, J = 13.1, 6.3 Hz, 2H); Anal. Calcd. for
C33H34FN3O8S (%): C, 60.82; H, 5.26; N, 6.45; Found (%): C, 60.84; H, 5.25; N, 6.44.
5.1.10.10.
(E)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-
yl)oxy)phenyl)-3-((2-fluorophenyl)sulfonyl)acrylamide (41)
Yellow solid; yield: 25.1%; m.p.: 115.8-116.6°C, MS (ESI) m/z: 652.2 [M+H]+.1H-NMR
(400 MHz, CDCl3) δ(ppm): 8.48 (d, J = 5.6 Hz, 1H), 8.00-7.93 (m, 1H), 7.82 (dd, J = 11.9, 2.4 Hz,
1H), 7.72-7.65 (m, 1H), 7.62 (s, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.40-7.33 (m, 2H), 7.30 (s, 1H),
7.24 (t, J = 6.8 Hz, 1H), 6.48 (d, J = 5.4 Hz, 1H), 4.32 (t, J = 5.6 Hz, 2H), 4.03 (s, 3H), 3.33-3.26
(m, 2H), 2.77 (s, 2H), 2.60 (dt, J = 11.3, 5.2 Hz, 2H), 2.00 (s, 2H), 1.87 (s, 2H), 1.66 (s, 1H), 1.25
(s, 2H), 1.09 (t, J = 7.0 Hz, 3H); Anal. Calcd. for C34H35F2N3O6S (%): C, 62.66; H, 5.41; N, 6.45;
Found (%): C, 62.68; H, 5.42; N, 6.44.
5.1.10.11.
(E)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-
yl)oxy)phenyl)-3-((2-methoxyphenyl)sulfonyl)acrylamide (42)
Yellow solid; yield: 24.5%; m.p.: 114.7-116.2°C, MS (ESI) m/z: 664.4 [M+H]+.1H-NMR
(400 MHz, CDCl3) δ(ppm): 8.82 (s, 1H), 8.52 (d, J = 5.3 Hz, 1H), 7.94-7.79 (m, 3H), 7.59 (s, 1H),
7.43 (d, J = 5.8 Hz, 2H), 7.35-7.26 (m, 2H), 7.01 (d, J = 9.2 Hz, 2H), 6.45 (d, J = 5.2 Hz, 2H),
4.28 (t, J = 6.3 Hz, 2H), 4.05 (s, 3H), 3.75 (s, 3H), 2.79 (d, J = 42.5 Hz, 6H), 2.33 (dd, J = 13.3,
6.2 Hz, 2H), 1.81 (s, 3H), 1.56 (s, 2H), 1.27 (s, 3H); Anal. Calcd. for C35H38FN3O7S (%): C, 63.33;
H, 5.77; N, 6.33; Found (%): C, 63.34; H, 5.75; N, 6.34.
5.2 Pharmacology
5.2.1. MTT assay in vitro
The cytotoxic activity of compounds (16-31and 32-42) was evaluated with HT-29, MKN-45
and A549 cells by the MTT assay in vitro, with Foretinib as references. The cancer cells were
cultured in minimum essential medium (MEM) supplemented with 10% fetal bovine serum (FBS).
Approximately 4×103 cells, suspended 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 test compounds were added to the culture
medium at the indicated final concentrations and the cell cultures were continued for 72 h. Fresh
MTT was added to each well at a final concentration of5.0μg/mL and incubated with cells at

37 °C for 4 h. The formazan crystals were dissolved in 100.0 μL DMSO per each well, and the
absorbency at 492 nm (for the absorbance of MTT formazan) and 630 nm (for the reference
wavelength) was measured with the ELISA reader. All of the compounds were tested three times
in each of the cell lines. The results expressed as IC50 (inhibitory concentration of 50%) were the
mean ± SD and were calculated by using the Bacus Laboratories Incorporated Slide Scanner (Bliss)
software.
5.2.2. c-Met Kinase assays
The c-Met kinase activity was determined using homogenous time-resolved fluorescence
(HTRF) assays following the manufacture’s instruction, with Foretinib as positive control. Briefly,
20.0 mg/mL poly (Glu, Tyr) 4:1 (Sigma) was precoated as a substrate in 384-well plates.
Then50.0 mL of 10.0 mM ATP (Invitrogen) solution diluted in kinase reaction buffer (50.0 mM
HEPES, pH 7.0, 1.0 M DTT, 1.0 M MgCl2, 1.0 M MnCl2, 0.1% NaN3) was added to each well.
Various concentrations of compounds diluted in 10.0 mL of 1% DMSO v/v were used as the
negative control. The kinase reaction was initiated by the addition of purified tyrosine kinase
proteins duluted in 39.0 mL of kinase reaction buffer solution. Reactions were incubated for 30
min at 25°C and stopped by the addition of 5.0 mL Streptavidin-XL665 and 5.0 mL Tk Antibody
Cryptate working solution to all of wells. The plate was read using Envision (PerkinElmer) at 320
nm and 615 nm. The inhibition rate (%) was calculated using the following equation: % inhibition
= 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 observed
enzyme activity in the presence of substrates, cofactors and in the absence of enzyme). IC50 values
were calculated from the inhibition curves.
Acknowledgments
The work was supported by National Natural Science Foundation of China (81573295),
Program
for
Liaoning
Excellent
Talents
in
University
(LR2014030),
Project of Education Department of Liaoning (L2013382) and Development Project of Ministry of
Education Innovation Team (IRT1073).
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Graphical abstract
IC50 (nM)
A549
Compd.
HT-29
MKN-45
c-Met
16
80
220
70
1.1

Highlights
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Twenty-seven novel 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives were
designed and synthesized.
1H-imidazole-4-carboxamido and (E)-3-hydrosulfonylacrylamido motifs as linkers were
designed to identify the ‘five atoms regulation’.
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The configurations of compounds 32-42 were unequivocally confirmed as the E isomer.
The compound 16 demonstrated remarkably better biological property against all the
tested cell lines than Foretinib.
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The most promising compound 16 exhibited remarkable c-Met kinase inhibition (IC50 =
1.1 nM) and high selectivity.
Molecular docking analysis was supplied to guide and explain the observed SARs as
well.