Design and Synthesis of Novel 4-Phenoxyquinolines Bearing 3-Hydrosulfonylacrylamido or 1H-Imidazole-4-carboxamido Scaffolds as c-Met Kinase Inhibitors

Article abstract of DOI:10.1002/ardp.201600307

A series of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing (E)-3-hydrosulfonylacrylamido or 1H-imidazole-4-carboxamido moieties were designed, synthesized and evaluated for their cytotoxicity against A549, MKN-45, and HT-29 cancer cell lines in vitro. All the target compounds showed moderate to significant cytotoxic activity against the tested cells with IC₅₀ values ranging from 0.13 to 2.65 μM. Five of them were further examined for their inhibitory activity against c-Met kinase, which identified compound 30 as a promising agent (c-Met IC₅₀ = 1.52 nM) with IC₅₀ values of 0.24, 0.45, and 0.13 μM against HT-29, MKN-45, and A549 cells, respectively.

Full text of DOI:10.1002/ardp.201600307

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Full Paper
Design and Synthesis of Novel 4-Phenoxyquinolines Bearing
3-Hydrosulfonylacrylamido or 1H-Imidazole-4-carboxamido
Scaffolds as c-Met Kinase Inhibitors
Jiao Wang1, Lijun Xie2, Yu Wang1, Xiaoqiang Wang1, Shuancheng Xi1, Tianfang Zeng1, Ping Gong1,
and Xin Zhai1
1
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang
Pharmaceutical University, Shenyang, P. R. China
Fujian Institute of Microbiology, Changshang District, Fuzhou, P. R. China
2
A series of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing (E)-3-hydrosulfonylacry-
lamido or 1H-imidazole-4-carboxamido moieties were designed, synthesized and evaluated for their
cytotoxicity against A549, MKN-45, and HT-29 cancer cell lines in vitro. All the target compounds
showed moderate to significant cytotoxic activity against the tested cells with IC50 values ranging
from 0.13 to 2.65 mM. Five of them were further examined for their inhibitory activity against c-
Met kinase, which identified compound 30 as a promising agent (c-Met IC50 ¼ 1.52 nM) with IC50
values of 0.24, 0.45, and 0.13 mM against HT-29, MKN-45, and A549 cells, respectively.
Keywords: Antitumor activity / c-Met inhibitors / QSAR / Synthesis
Received: October 26, 2016; Revised: December 22, 2016; Accepted: January 4, 2017
DOI 10.1002/ardp.201600307
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
discovered, such as foretinib (1), cabozantinib (2), AM7 (3),
MG10 (4), Amgen (5), etc. (1–5 in Fig. 1) [8–11].
Introduction
c-Met, a receptor tyrosine kinase, is normally activated by
binding its natural ligand hepatocyte growth factor (HGF)
which induces several complex signaling pathways and results
in cell proliferation, motility, migration, and survival [1–3].
Thus, the aberrant activation of HGF/c-Met signaling can lead
to a variety of malignancies [4].
Recently, c-Met as a potential target has drawn consider-
able attention for cancer treatment [5–7], prompting a
number of c-Met inhibitors with diverse molecular scaffolds.
Among them, novel 6,7-disubstituted-4-phenoxyquinoline
derivatives with remarkable antitumor activity have been
The c-Met inhibitors undergoing clinical trials or
launched suggested that quinoline pharmacophores were
essential for furnishing hydrogen bonds with the backbone
of c-Met kinase, and the aryl fragment (moiety B) probably
generated hydrophobic binds. Importantly, there should be
two structural characteristics on the linkage (moiety C)
between moiety A and B, one is 5-atoms regulation and the
other is possessing hydrogen-bond donors or acceptors
simultaneously [12–14]. In our previous studies, a variety of
pharmacodynamics skeletons were introduced as the linker,
which resulted in various derivatives 6–10 (Fig. 2) with
excellent c-Met inhibition potency [12–18].
As an extension of our work on the discovery of novel
potent c-Met inhibitors based on the 5-atom regulation,
two
kinds
of
new
frameworks,
namely
(E)-3-
Correspondence: Dr. Xin Zhai, Key Laboratory of Structure-Based
Drug Design and Discovery, Ministry of Education, Shenyang
Pharmaceutical University, 103 Wenhua Road, Shenhe District,
110016 Shenyang, Liaoning, P. R. China.
E-mail: leixinjia@126.com
Fax: þ86 24 2398-6429
hydrosulfonylacrylamido and 1H-imidazole-4-carboxamido
scaffolds (Fig. 3) [19–21], were introduced into moiety C.
Based on the above design, we reserved the 3-carbon tether
at the 7-position of quinoline skeleton, further replaced the
morpholinyl group (moiety A) by other alicyclic tertiary
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Figure 1. Representative c-Met inhibitors based on 6,7-disubstituted-4-phenoxyquinoline scaffolds.
amino groups to optimal cellular potency via improving
water solubility. Furthermore, various substituents were
Results and discussion
Chemistry
introduced into the phenyl ring (moiety B) with the purpose
of enriching the structural diversity. Therefore, a series of
novel 6,7-disubstituted-4-phenoxyquinoline derivatives pos-
sessing (E)-3-hydrosulfonylacrylamido or 1H-imidazole-4-
carboxamido motifs as c-Met kinase inhibitors were designed
and synthesized. In the current study, all target compounds
were evaluated for their cytotoxicity against A549, MKN-45,
and HT-29 cancer cell lines in vitro. Additionally, enzymatic
assays of five active compounds are also presented in this
study.
Scheme 1 depicts the preparation of compounds 20–29. The
key intermediates of 4-(2-fluorophenoxy)quinolones 12a–e
were synthesized through an eight-step reaction starting
from commercially available 1-(4-hydroxy-3-methoxyphenyl)-
ethanone which has been illustrated in detail in our previous
study [12–18].
Various substituted anilines were refluxed with sodium
format in formic acid for 12 h to afford N-phenylformamides
13a–d, which were converted to benzonitriles 14a–d on
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Figure 2. Representative c-Met inhibitors in our previous studies.
exposure to phosphorus oxychloride in the presence of
triethylamine in tetrahydrofuran at room temperature.
Treatment of 14a–d with 4-methoxy-3-oxobutanenitrile
under the catalysis of 1,10-phenanthroline monohydrate
and cuprous oxide in tetrahydrofuran furnished 15a–d, which
were then reacted with lithium hydroxide monohydrate in
tetrahydrofuran/water (4:1) at room temperature to give the
key intermediates 16a–d. Finally, 16a–d were chlorinated by
thionyl chloride and subsequently condensed with 12a–e in
the existence of potassium carbonate in dichloromethane to
generate the target compounds 20–29.
The synthesis of target compounds 30–40 is described in
Scheme 2. Sulfur-alkylation of commercially available various
benzenethiols with ethyl propiolate provided intermediates
17a–d, which were oxidized by hydrogen peroxide to afford
18a–d. Subsequently, 18a–d were subjected to hydrolyzation
by lithium hydroxide monohydrate in tetrahydrofuran/water
(5:1) to obtain the key intermediates 19a–d. The synthesis of
Figure 3. General structures of target compounds 20–40.
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Scheme 1. Reagents and conditions: (i) HCOONa, HCOOH, reflux, 12 h; (ii) POCl3, Et3N, THF, 0°C, 30 min, r.t., 1 h; (iii) Cu2O, THF,
4-methoxy-3-oxobutanenitrile, 1,10-phenanthroline, reflux, 3 h; (iv) lithium hydroxide, THF/ H2O, r.t., 20 h; (v) SOCl2, K2CO3, r.t., 5 h.
Biological assays
compounds 30–40 was progressed as previously described
reactions from 19a–d and 12a–d in Scheme 1.
In vitro cytotoxicity and structure–activity relationships
(SAR)
The existing carbon–carbon double bonds in compounds
30–40 could lead to E or Z isomeric forming. According to the
reported motif of 3-(arylsulfonyl)-2-propiolates, the coupling
constants of olefinic protons were observed for the E
configuration (3J > 12.00 Hz) and Z configuration (3J < 11.00
Hz) (Fig. 4) [22, 23]. The coupling constants of compound 33
were furtherly identified using 1H NMR (400 MHz) and the
resulting coupling values of 12.0 Hz verified that its configu-
ration is exclusive E isomer.
All the target compounds (20–40) were screened for their
in vitro cytotoxic activity against three human cancer cell lines
containing human colon cancer cell line (HT-29), human lung
adenocarcinoma cell line (A549), and human gastric cancer
cell line (MKN-45) with the positive control foretinib by MTT
assay. The results were conveyed as IC50 values which were the
average of at least three independent experiments, and are
summarized in Table 1.
Scheme 2. Reagents and conditions: (i) Ethyl propionate, THF, 65°C, 1 h; (ii) H2O2, HOAc, 90°C, 1 h; (iii) lithium hydroxide, THF/ H2O,
r.t., 1 h.
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Figure 4. The configurations of (E)- or (Z)-3-
(arylsulfonyl)-2-propiolate isomers.
As illustrated in Table 1, most of compounds showed
moderate to excellent cytotoxic activity against tested
cancer cells with IC50 ranging from 0.13 to 2.65 mM,
which demonstrated that the introduction of (E)-3-
hydrosulfonylacrylamido or 1H-imidazole-4-carboxamido
moieties as the linker maintained antitumor potency. Among
them, compound 30 exhibited the most promising cytotoxicity
with the IC50 values of 0.24, 0.45, and 0.13 mM against HT-29,
MKN-45, and A549 cells as comparable to foretinib (0.25, 0.32,
0.15 mM). It was noticeable that the majority of compounds
were more effective against A549 than other two cell lines
which reflected good selectivity for lung adenocarcinoma.
The data in Table 1 disclosed that a tether linkage of
(E)-3-hydrosulfonylacrylamido motif was superior to the cyclic
linker of 1H-imidazole-4-carboxamido moiety. Preliminary
SAR study focused on 6,7-disubstituted-4-phenoxyquinoline
derivatives bearing 1H-imidazole-4-carboxamido moiety (20–
29) and indicated that the introduction of various tertiary
amines groups at R1 group had a moderate influence on
activity. For example, compounds 20 or 21 with pyrrolidinyl or
4-methyl piperidinyl groups were better than the morpholinyl
derivatives 22 in the antiproliferative activities, and the same
trend was observed for compounds 24–26.
compounds with 4-methoxy (34, IC50 ¼ 0.63 mM against A549)
or 2,4-dimethyl (37, IC50 ¼ 1.00 mM against A549) brought
about 1.2-fold less in activity in contrast with the compound
31 (IC50 ¼ 0.58 mM against A549) than with no substituent on
the phenyl ring.
In vitro enzymatic assays
Based on the cellular assays, five compounds (20, 21, 30, 31,
and 33) were selected for further in vitro c-Met inhibitory
studies. In parallel with the cellular results, all of the tested
compounds displayed good to significant potency against
c-Met with values ranging from 1.52 to 30.15 nM. As shown in
Table 2, the most potent compound 30 exhibited prominent
potency against c-Met kinase with an IC50 value of 1.52 nM,
which was similar to the positive control foretinib
(IC50 ¼ 1.48 nM).
For examining the selectivity of the most potent
compound 30 on c-Met over other kinases, it was sifted
against five other tyrosine kinases (Table 3). The data
showed that 30 expressed little inhibitory effects against
c-Kit, Flt-3, PDGFRa, and VEGFR-2 kinase with the potency
58.6- to 352.1-fold lower than that against c-Met. Likewise,
30 showed barely inhibited kinase activity against EGFR
kinase (IC50 > 3 mM). The pharmacological data in Tables 2
and 3 indicated that 6,7-disubstituted-4-phenoxyquinoline
derivatives possessing (E)-3-hydrosulfonylacrylamido moi-
ety are novel selectivity c-Met inhibitors, which deserves
further study with respect to its application in the
treatment of cancer.
In addition, further analysis clearly revealed that different
biological properties were observed when diverse R2 groups
were introduced into the phenyl ring (moiety B). The
introduction of mono-electron-withdrawing groups (20,
0
R2 ¼ 4-chloride, IC50 ¼ 0.25 mM against A549) exhibited
improved cytotoxic activity compared to double-EWGs (24,
0
R2 ¼ 2,4-dichloro, IC50 ¼ 0.44 mM against A549) by 1.45-fold.
Binding model analysis
Moreover, the incorporation of different double-EWGs
made0a negative contribution to potency, such as compound
26 (R2 ¼ 2,4-dichloro, IC50 ¼ 1.13 mM against A549) was more
To further elucidate the binding mode of compounds, the
docking simulation was conducted using Discovery Studio
3.0 software. The co-crystal structure of foretinib (GSK
1363089) with c-Met was selected as the docking model
(PDB ID code: 3LQ8). The binding model was exemplified by
the interaction of compounds 20 and 30 with c-Met. As
shown in Fig. 5, the oxygen atom of 1H-imidazole-4-
carboxamido moiety and the nitrogen atom of the
quinoline ring in 20 formed two hydrogen binds with
protein residues Lys1110 and Met1160. It can be observed
that compound 30 bound well to c-Met domain via four
hydrogen bonds. The nitrogen atom of 2-position and
oxygen atom at 6-position of quinoline interacted with
0
active than 29 (R2 ¼ 2,4-1,2-difluoro, IC50 ¼ 1.43 mM against
A549).
To further verify the optimized structural skeleton and
explore the SAR, our attention was converted to compounds
30–40 with (E)-3-hydrosulfonylacrylamido linkage. It can be
noted that compound 35 with N-methylpiperazinyl at R1
group afforded the improved antitumor potency than the
derivatives 36–38 with morpholinyl, 4-methylpiperidinyl, or
piperidinyl groups, respectively. The introduction of electron-
donating groups (EDGS) into the phenyl ring (B moiety)
resulted in a decrease in antitumor activity. For instance,
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Table 1. Structures and cytotoxicities of compounds 20–40 against HT-29, MKN-45, A549 cell lines in vitro.
IC50 (mmol/L) ꢀ SD
0
Compd.
R1
R2/R2
HT29
MKN45
A549
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
Pyrrolidinyl
4-Methylpiperidinyl
Morpholinyl
Pyrrolidinyl
Pyrrolidinyl
4-Methylpiperidinyl
Morpholinyl
4-Methylpiperazinyl
Piperidinyl
4-Cl
4-Cl
4-Cl
2-OCH3
2,4-Cl
2,4-Cl
2,4-Cl
2,4-F
2,4-F
2,4-F
H
H
0.29 ꢀ 0.01
0.33 ꢀ 0.04
0.78 ꢀ 0.004
0.45 ꢀ 0.01
0.54 ꢀ 0.22
0.90 ꢀ 0.002
1.63 ꢀ 0.01
1.34 ꢀ 0.30
1.50 ꢀ 0.05
1.67 ꢀ 0.16
0.24 ꢀ 0.01
0.63 ꢀ 0.002
0.60 ꢀ 0.08
0.35 ꢀ 0.13
0.93 ꢀ 0.01
0.92 ꢀ 0.11
1.12 ꢀ 0.07
1.30 ꢀ 0.004
1.57 ꢀ 0.16
0.84 ꢀ 0.08
0.88 ꢀ 0.04
0.25 ꢀ 0.01
0.33 ꢀ 0.03
0.38 ꢀ 0.02
0.87 ꢀ 0.02
0.37 ꢀ 0.11
0.48 ꢀ 0.03
0.98 ꢀ 0.04
1.35 ꢀ 0.02
1.43 ꢀ 0.01
2.41 ꢀ 0.03
1.49 ꢀ 0.03
0.45 ꢀ 0.01
0.65 ꢀ 0.02
0.83 ꢀ 0.02
0.41 ꢀ 0.03
1.18 ꢀ 0.12
0.89 ꢀ 0.04
0.92 ꢀ 0.02
0.85 ꢀ 0.01
2.65 ꢀ 0.03
0.60 ꢀ 0.01
0.93 ꢀ 0.01
0.32 ꢀ 0.03
0.25 ꢀ 0.08
0.32 ꢀ 0.01
0.50 ꢀ 0.05
0.35 ꢀ 0.03
0.44 ꢀ 0.11
0.71 ꢀ 0.05
1.13 ꢀ 0.17
1.28 ꢀ 0.02
1.42 ꢀ 0.12
1.43 ꢀ 0.09
0.13 ꢀ 0.11
0.58 ꢀ 0.10
0.60 ꢀ 0.03
0.34 ꢀ 0.03
0.63 ꢀ 0.17
0.62 ꢀ 0.11
0.78 ꢀ 0.13
1.00 ꢀ 0.05
1.30 ꢀ 0.07
0.70 ꢀ 0.05
0.85 ꢀ 0.02
0.15 ꢀ 0.01
Morpholinyl
4-Methylpiperazinyl
4-Methylpiperidinyl
Piperidinyl
H
Morpholinyl
4-OCH3
4-OCH3
2,4-CH3
2,4-CH3
2,4-CH3
2,4-CH3
4-CH3
4-CH3
4-Methylpiperidinyl
4-Methylpiperazinyl
Morpholinyl
36
37
38
39
40
Foretinib
4-Methylpiperidinyl
Piperidinyl
Morpholinyl
4-Methylpiperidinyl
Met1160 and Asp1164 via two hydrogen bonds, and the
(E)-3-hydrosulfonylacrylamido moiety formed two hydro-
gen-bonding with Met1131 and Asp1222, respectively.
Hence, 30 contained more hydrogen bonds as compared
with 20, suggesting that the much stronger binding force
with c-Met could be the reason for that (E)-3-hydro-
sulfonylacrylamido-based derivatives (30–40) were superior
to the cyclic linker of 1H-imidazole-4-carboxamido-based
derivatives (20–29).
Conclusion
In summary, 21 novel 6,7-disubstituted-4-phenoxyquinoline
derivatives conjugated with 1H-imidazole-4-carboxamido or
Table 2. c-Met kinase activity of selected compounds 20,
21, 30, 31, 33, and foretinib in vitro.
Table 3. Inhibition of tyrosine kinases by compound 30.
Compd.
IC50 on c-Met (nM)
Kinase
Enzyme IC50 (nM)
20
21
30
31
33
Foretinib
10.79
30.15
1.52
18.65
14.55
1.48
c-Kit
Flt-3
PDGFRa
VEGFR-2
EGFR
89.0
124.5
535.2
1323
>3000
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Figure 5. The proposed binding model of compounds 20 or 30 with c-Met. The protein is displayed by secondary structure.
Compounds 20 and 30 are shown in colored sticks (pink: carbon atom, blue: nitrogen atom, red: oxygen atom, white: hydrogen
atom). The hydrogen-bond is shown in yellow-dotted lines.
(E)-3-hydrosulfonylacrylamido moieties as c-Met inhibitors
were designed, synthesized and evaluated for their biological
activity. The screening of cytotoxicity and enzyme activities
led to the identification of a most promising compound 30
(c-Met IC50 ¼ 1.52 nM) with IC50 values of 0.24, 0.45, 0.13 mM
against HT-29, MKN-45, and A549 cells, representing a
promising lead for further optimization. The initial SARs
analysis disclosed that the (E)-3-hydrosulfonylacrylamido
scaffolds as the preferred linkage was benefit to the
improvement of antitumor activity, and the introduction of
N-methylpiperazinyl at R1 group is indispensable for good
cytotoxicity. Meanwhile, differences in various substituents
on phenyl ring (B moiety) would result in lower or complete
loss of antitumor potency. Further studies on structural
optimization and the mechanisms of action are still underway
and will be reported in the future.
Some NMR spectra as well as the InChI codes of the
investigated compounds together with some biological
activity data are provided as Supporting Information.
Preparation of 3-fluoro-4-(6,7-disubstituted quinolin-4-
yloxy)anilines 12a–e
The preparation of the key intermediates (12a–e) has been
illustrated in detail in our laboratory previous study, so the
synthesis method would not be listed here.
3-Fluoro-4-(6-methoxy-7-(3-(piperdine-1-yl)propoxy)-
quinolin-4-yloxy)aniline (12a)
Gray solid; yield: 85.5%; m.p.: 196–197°C; MS (ESI) m/z: 426.3
[MþH]þ.
3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperdine-1-yl)-
propoxy)quinolin-4-yl-oxy)aniline (12b)
White solid; yield: 77.4%; m.p.: 193–194°C; MS (ESI) m/z: 440.3
[MþH]þ.
Experimental
Chemistry
General
3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperazine-1-yl)-
propoxy)quinolin-4-yl-oxy)aniline (12c)
€
All melting points were obtained on a Buchi Melting Point
White solid; yield: 77%; m.p.: 201–202°C; MS (ESI) m/z: 441.4
B-540 apparatus (Buchi Labortechnik, Flawil, Switzerland).
[MþH]þ, 463.3 [MþNa]þ.
€
Mass spectra (MS) were taken in ESI mode on Agilent 1100
LC-MS (Agilent, Palo Alto, CA). 1H NMR was recorded on
Bruker ARX-400, 400 MHz (Bruker Bioscience, Billerica, MA)
with TMS as an internal standard. All materials were obtained
from commercial suppliers and were used without further
purification. Reaction times and purity of the products were
monitored by TLC on FLUKA silica gel aluminum cards (0.2 mm
thickness) with fluorescent indicator 254 nm. Column chro-
matography was run on silica gel (200–300 mesh) from
Qingdao Ocean Chemicals (Qingdao, Shandong, China).
3-Fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)quinolin-
4-yloxy)aniline (12d)
White solid; yield: 81.8%; m.p.: 217–218°C; MS (ESI) m/z: 428.2
[MþH]þ, 450.1 [MþNa]þ.
3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-
quinolin-4-yloxy)aniline (12e)
Light yellow solid; yield: 72.3%; m.p.: 208–209°C; MS (ESI) m/z:
412.5 [MþH]þ.
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General procedure for the preparation of the
intermediates of N-phenylformamide (13a–d)
Commercially available substituted aniline (40.7 mmol) and
sodium formate were added portionwise to a solution of
formic acid (12.5 mL). The above mixture was stirred at room
temperature for 12 h. The reaction mixture was evaporated,
dissolved in ethyl acetate (50 mL), washed by water (20 mL),
and then was evaporated to afford light yellow solids
(13a–d).
Ethyl 1-(2,4-difluorophenyl)-1H-imidazole-4-carboxylate
(15a)
Light yellow solid; yield: 63.2%; MS (ESI) m/z: 253.1 [MþH]þ.
Ethyl 1-(4-chlorophenyl)-1H-imidazole-4-carboxylate (15b)
Light yellow solid; yield: 53.8%; MS (ESI) m/z: 252.0 [MþH]þ.
Ethyl 1-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate
(15c)
Light yellow solid; yield: 66.4%; MS (ESI) m/z: 285.0 [MþH]þ.
N-(2,4-Difluorophenyl)formamide (13a)
Light yellow solid; yield: 83%; MS (ESI) m/z: 158.0 [MþH]þ.
Ethyl 1-(2-methoxyphenyl)-1H-imidazole-4-carboxylate
(15d)
N-(4-Chlorophenyl)formamide (13b)
Light yellow solid; yield: 81.5%; MS (ESI) m/z: 157.0
[MþH]þ.
Light yellow solid; yield: 87.4%; MS (ESI) m/z: 247.1 [MþH]þ.
General procedure for the preparation of 1-phenyl-1H-
imidazole-4-carboxylic acids (16a–d)
N-(2,4-Dichlorophenyl)formamide (13c)
To a solution of an appropriate intermediate 15a–d
Yellow solid; yield: 78.9%; MS (ESI) m/z: 191.1 [MþH]þ.
(4.1 mmol) dissolved in THF/H2O (10 mL, 4:1) was added 2 eq
of lithium hydroxide monohydrate, and the resulting
suspension was stirred for 20 h at room temperature. Then,
most of the solvent was evaporated, and the residue was
poured into water (5 mL) and the resulting solution was
extracted with ethyl acetate two times (20 mL ꢁ 2). The
aqueous layer was acidified by addition of 6 N hydrogen
chloride solutions until pH 3. The solid which precipitated was
collected by filtration to afford substituted acids (16a–d).
N-(2-Methoxyphenyl)formamide (13d)
Yellow solid; yield: 85.0%; MS (ESI) m/z: 152.1 [MþH]þ.
General procedure for the preparation of benzonitriles
(14a–d)
A mixture of appropriate substituted benzonitrile 13a–d
(33.1 mmol) and triethylamine (128.7 mmol) in THF was
cooled to 0°C. A solution of POCl3 (41.4 mmol) in THF (20 mL)
was slowly added thereto for 30 min. The reaction mixture
was stirred at room temperature for 1 h. The reaction
mixture was cooled to 0°C, was added to water (250 mL),
filtered, and dried under vacuum to afford the title
compounds 14a–d.
1-(2,4-Difluorophenyl)-1H-imidazole-4-carboxylic acid
(16a)
White solid; yield: 73.2%; m.p.: 144.4–146.0°C; MS (ESI) m/z:
225.0 [MþH]þ.
1-(4-Chlorophenyl)-1H-imidazole-4-carboxylic acid (16b)
White solid; yield: 80.2%; m.p.: 154.4–156.0°C; MS (ESI) m/z:
223.0 [MþH]þ.
2,4-Difluorobenzonitrile (14a)
Yellow solid; yield: 85.6%; MS (ESI) m/z: 140.0 [MþH]þ.
4-Chlorobenzonitrile (14b)
1-(2,4-Dichlorophenyl)-1H-imidazole-4-carboxylic acid
(16c)
Yellow solid; yield: 88.2%; MS (ESI) m/z: 139.0 [MþH]þ.
White solid; yield: 78.0%; m.p.: 160.0–162.8°C; MS (ESI) m/z:
2,4-Dichlorobenzonitrile (14c)
257.0 [MþH]þ.
Yellow solid; yield: 86.2%; MS (ESI) m/z: 173.0 [MþH]þ.
1-(2-Methoxyphenyl)-1H-imidazole-4-carboxylic acid (16d)
White solid; yield: 86.2%; m.p.: 161.0–163.0°C; MS (ESI) m/z:
219.1 [MþH]þ.
2-Methoxybenzonitrile (14d)
Yellow solid; yield: 87.4%; MS (ESI) m/z: 134.1 [MþH]þ.
General procedure for the preparation of ethyl 1-phenyl-
1H-imidazole-4-carboxylates (15a–d)
General procedure for the preparation of ethyl (E)-3-
(phenylthio)acrylates (17a–d)
A mixture of appropriate 14a–d (24.8 mmol), 4-methoxy-3-
oxobutanenitrile (35.4 mmol), cuprous oxide (3.5 mmol), and
1,10-phenanthroline (5.1 mmol) in THF (50 mL) was refluxed
for 3 h. The reaction mixture was concentrated under reduced
pressure, dissolved into ethyl acetate (50 mL), filtered,
evaporated the most solution, and then was cooled to
separate out solid. The solid was washed with cool methanol
to afford 15a–d.
A mixture of commercially available substituted benzenethiol
(21.4 mmol), ethyl propionate (23.6 mmol), and THF (5 mL)
was heated at 65°C for 1 h. Upon cooling to room tempera-
ture, the solvent was evaporated in vacuum to afford
compounds (17a–d).
Ethyl (E)-3-(phenylthio)acrylate (17a)
White solid; yield: 71.2%; MS (ESI) m/z: 209.1 [MþH]þ.
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Ethyl (E)-3-((2,4-dimethylphenyl)thio)acrylate (17b)
White solid; yield: 83.2%; MS (ESI) m/z: 237.1 [MþH]þ.
(E)-3-((2-Methoxyphenyl)sulfonyl)acrylic acid (19d)
Yellow solid; yield: 76.2%; m.p.: 97.0–99.4°C; MS (ESI) m/z:
243.0 [MþH]þ.
Ethyl (E)-3-(p-tolylthio)acrylate (17c)
White solid; yield: 69.7%; MS (ESI) m/z: 223.1 [MþH]þ.
General procedure for the preparation of the target
compounds 20–29
Ethyl (E)-3-((4-methoxyphenyl)thio)acrylate (17d)
A mixture of the corresponding acid (16a–d) (1.0 mmol),
toluene (10 mL), and SOCl2 (10 mL) was heated at 85°C for 5 h.
Upon cooling to room temperature, the solvent was
evaporated in vacuum. The residue was dissolved in dried
dichloromethane (20 mL) and dropwise added to a mixture
of the corresponding aniline (12a–e) (1.3 mmol), K2CO3
(4.4 mmol) and dichloromethane (20 mL) in an ice bath for
30 min, which was then removed to raise the temperature to
room temperature and stirred for 2 h. The resulting mixture
was sequentially washed with water (100 mL) and 1% K2CO3
(100 mL), and the organic phase was separated, dried, and
evaporated. The crude product obtained was purified by silica
gel chromatography using a mixture of CH2Cl2/MeOH (25:1) to
afford 20–29 as white solids.
White solid; yield: 86.2%; MS (ESI) m/z (%): 239.1 [MþH]þ.
General procedure for the preparation of ethyl (E)-3-
(phenylsulfonyl)acrylates (18a–d)
To a solution of 17a–d (12.6 mmol) in acetic acid (60 mL), 30%
hydrogen peroxide (208.8 mmol) was added dropwise while
maintaining the temperature below 50°C. After the addition
was completed, the mixture was heated to 90°C for 1 h. After
cooling, the reaction mixture was evaporated to give
compounds 18a–d.
Ethyl (E)-3-(phenylsulfonyl)acrylate (18a)
Light yellow solid; yield: 83.2%; MS (ESI) m/z: 241.0 [MþH]þ.
Ethyl (E)-3-((2,4-dimethylphenyl)sulfonyl)acrylate (18b)
Light yellow solid; yield: 85.2%; MS (ESI) m/z: 269.1
[MþH]þ.
1-(4-Chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-1H-
imidazole-4-carboxamide (20)
Yield: 79.7%; m.p.: 157.9–160.0°C; MS (ESI) m/z: 616.2 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 9.10 (s, 1H), 8.49 (d,
J ¼ 5.2 Hz, 1H), 8.00 (s, 1H), 7.95 (dd, J ¼ 1.2 Hz, 1H), 7.82 (s, 1H),
7.58 (s, 1H), 7.53 (d, J ¼ 8.5 Hz, 2H), 7.43 (s, 1H), 7.40 (d,
J ¼ 8.9 Hz, 1H), 7.41 (s, 1H), 7.26 (s, 1H), 6.44 (d, J ¼ 5.1 Hz, 1H),
4.27 (t, J ¼ 6.2 Hz, 2H), 4.04 (s, 3H), 2.94 (m, 4H), 2.81 (m, 2H),
2.32 (s, 2H), 1.94 (s, 4H). Anal. calcd. for C33H31ClFN5O4 (%): C,
64.34; H, 5.07; N, 11.37. Found (%): C, 64.32; H, 5.02; N, 11.34.
Ethyl (E)-3-tosylacrylate (18c)
Light yellow solid; yield: 80.2%; MS (ESI) m/z: 255.1 [MþH]þ.
Ethyl (E)-3-((2-methoxyphenyl)sulfonyl)acrylate (18d)
Light yellow solid; yield: 73.2%; MS (ESI) m/z: 271.1
[MþH]þ.
General procedure for the preparation of (E)-3-
(phenylsulfonyl)acrylic acids (19a–d)
1-(4-Chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-
methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-
1H-imidazole-4-carboxamide (21)
To a solution of an appropriate intermediate 18a–d
(7.1 mmol) dissolved in THF/H2O (25 mL, 3:2) was added 2
eq of lithium hydroxide monohydrate, and the resulting
suspension was stirred for 1 h at room temperature.
Then, most of the solvent was evaporated, and the
residue was poured into water (5 mL). The aqueous layer
was acidified by addition of 6 N hydrochloric acid
solutions until pH 3, and then separated out from
hydraulic. The mixture was filtered to collected substi-
tuted acids (19a–d).
Yield: 80.7%; m.p.: 167.9–169.0°C; MS (ESI) m/z: 644.2 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 9.09 (s, 1H), 8.49 (d,
J ¼ 5.2 Hz, 1H), 8.00 (d, J ¼ 1.2 Hz, 1H), 7.95 (dd, J ¼ 12.1, 2.4 Hz,
1H), 7.81 (d, J ¼ 1.2 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J ¼ 8.7 Hz, 2H),
7.40 (t, J ¼ 6.3 Hz, 4H), 7.27 (s, 1H), 6.43 (d, J ¼ 5.2 Hz, 1H), 4.25
(t, J ¼ 6.5 Hz, 2H), 4.04 (s, 3H), 3.02 (s, 2H), 2.66 (s, 1H), 2.14 (m,
4H), 1.66 (d, J ¼ 10.1 Hz, 2H), 1.39 (m, 4H), 0.95 (s, 3H). Anal.
calcd. for C35H35ClFN5O4 (%): C, 65.26; H, 5.48; N, 10.87. Found
(%): C, 65.23; H, 5.42; N, 10.86.
(E)-3-(Phenylsulfonyl)acrylic acid (19a)
Yellow solid; yield: 73.2%; m.p.: 117.0–119.4°C; MS (ESI) m/z:
213.0 [MþH]þ.
1-(4-Chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-1H-
imidazole-4-carboxamide (22)
(E)-3-((2,4-Dimethylphenyl)sulfonyl)acrylic acid (19b)
Yellow solid; yield: 74.0%; m.p.: 118.0–119.4°C; MS (ESI) m/z:
241.0 [MþH]þ.
Yield: 83.7%; m.p.: 157.9–159.0°C; MS (ESI) m/z: 632.2 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 9.09 (s, 1H), 8.49 (d,
J ¼ 5.3 Hz, 1H), 8.00 (d, J ¼ 1.1 Hz, 1H), 7.95 (dd, J ¼ 2.3, 1.7 Hz,
1H), 7.81 (d, J ¼ 1.0 Hz, 1H), 7.59 (s, 1H), 7.53 (d, J ¼ 8.7 Hz, 2H),
7.44 (s, 1H), 7.40 (d, J ¼ 8.7 Hz, 2H), 7.24 (s, 1H), 6.44 (d,
J ¼ 5.2 Hz, 1H), 4.28 (t, J ¼ 6.6 Hz, 2H), 4.05 (s, 3H), 3.79–3.67
(m, 4H), 2.59 (t, J ¼ 6.8 Hz, 4H), 2.47 (m, 2H), 2.18–2.11 (m,
(E)-3-Tosylacrylic acid (19c)
Yellow solid; yield: 83.2%; m.p.: 100.2–102.4°C; MS (ESI) m/z:
227.0 [MþH]þ.
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J ¼ 6.8 Hz, 2H). Anal. calcd. for C33H31ClFN5O5 (%): C, 62.71; H,
1-(2,4-Difluorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-
methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-
1H-imidazole-4-carboxamide (27)
4.94; N, 11.08. Found (%): C, 62.70; H, 4.93; N, 11.09.
N-(3-Fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-
quinolin-4-yl)oxy)phenyl)-1-(2-(trifluoromethoxy)phenyl)-
1H-imidazole-4-carboxamide (23)
Yield: 82.1%; m.p.: 116.0–118.2°C; MS (ESI) m/z: 647.3 [MþH]þ;
1H NMR (400 MHz, Acetic) d (ppm) 9.86 (s, 1H), 8.85 (d,
J ¼ 6.6 Hz, 1H), 8.58 (s, 1H), 8.34 (s, 1H), 8.16 (dd, J ¼ 12.6,
2.1 Hz, 1H), 7.94 (s, 1H), 7.90 (d, J ¼ 8.8 Hz, 1H), 7.80 (s, 1H),
7.51 (t, J ¼ 8.8 Hz, 1H), 7.34 (d, J ¼ 5.5 Hz, 2H), 7.05 (t, J ¼ 9.0 Hz,
1H), 6.97 (d, J ¼ 6.4 Hz, 1H), 4.45 (t, J ¼ 4.5 Hz, 2H), 3.92 (s, 3H),
2.48 (d, J ¼ 11.6 Hz, 2H), 2.29 (t, J ¼ 7.1 Hz 8H), 2.14 (s, 3H), 1.83
(d, J ¼ 11.6 Hz, 2H). Anal. calcd. for C34H33F3N6O4 (%): C, 63.15;
H, 5.14; N, 13.00. Found (%): C, 63.14; H, 5.15; N, 13.01.
Yield: 80.1%; m.p.: 157.9–160.0°C; MS (ESI) m/z: 666.2 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 9.14 (s, 1H), 8.51 (s, 1H), 7.96
(d, J ¼ 13.0 Hz, 1H), 7.92 (s, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.54
(m, 1H), 7.52 (s, 1H), 7.49 (d, J ¼ 3.2 Hz, 2H), 7.42 (d, J ¼ 8.4 Hz,
2H), 7.23 (s, 1H), 6.46 (s, 1H), 4.27 (s, 2H), 4.03 (s, 3H), 3.32 (s,
6H), 2.54 (s, 2H), 2.15 (s, 4H). Anal. calcd. for C34H31F4N5O5 (%):
C, 61.35; H, 4.69; N, 10.52. Found (%): C, 61.33; H, 4.71; N,
10.54.
1-(2,4-Difluorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-1H-
imidazole-4-carboxamide (28)
1-(2,4-Dichlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-1H-
imidazole-4-carboxamide (24)
Yield: 77.8%; m.p.: 145.9–147.6°C; MS (ESI) m/z: 632.2 [MþH]þ;
1H NMR (400 MHz, Acetic) d (ppm) 8.85 (d, J ¼ 6.6 Hz, 1H), 8.59
(s, 1H), 8.34 (s, 1H), 8.15 (dd, J ¼ 12.6, 2.1 Hz, 1H), 7.94 (s, 1H),
7.88 (d, J ¼ 8.8 Hz, 1H), 7.84 (s, 1H), 7.51 (t, J ¼ 8.8 Hz, 1H), 7.38
(d, J ¼ 5.5 Hz, 2H), 7.08 (t, J ¼ 9.0 Hz, 1H), 6.99 (d, J ¼ 6.4 Hz,
1H), 4.45 (t, J ¼ 4.5 Hz, 2H), 4.12 (s, 3H), 3.79 (d, J ¼ 11.6 Hz, 2H),
3.45 (t, J ¼ 7.3 Hz, 2H), 2.98 (t, J ¼ 11.2 Hz, 2H), 2.50 (s, 2H), 1.95
(s, 6H). Anal. calcd. For C34H32F3N5O4 (%): C, 64.65; H, 5.11; N,
11.09. Found (%): C, 64.65; H, 5.13; N, 11.08.
Yield: 79.7%; m.p.: 157.9–160.0°C; MS (ESI) m/z: 650.2
[MþH]þ; 1H NMR (400 MHz, CDCl3) d (ppm) 9.05 (s, 1H), 8.44
(d, J ¼ 8.0 Hz, 1H), 7.89 (d, J ¼ 16.0 Hz, 1H), 7.80 (s, 1H), 7.61
(s, 1H), 7.57 (d, J ¼ 1.76 Hz, 1H), 7.53 (s, 1H), 7.37 (d,
J ¼ 4.0 Hz, 1H), 7.34 (s, 1H), 7.29 (d, J ¼ 8.4 Hz, 1H), 7.16 (s,
1H), 7.08 (t, J ¼ 9.0 Hz, 1H), 6.39 (d, J ¼ 5.1 Hz, 1H), 4.20 (t,
J ¼ 5.7 Hz, 2H), 3.97 (s, 3H), 3.12 (s, 2H), 2.37 (s, 2H), 2.01 (s,
4H), 1.61 (s, 4H). Anal. calcd. for C33H30Cl2FN5O4 (%): C,
60.93; H, 4.65; N, 10.77. Found (%): C, 60.91; H, 4.67; N,
10.73.
1-(2,4-Difluorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-1H-
imidazole-4-carboxamide (29)
1-(2,4-Dichlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-
methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-
1H-imidazole-4-carboxamide (25)
Yield: 81.7%; m.p.: 146.2–148.7°C; MS (ESI) m/z: 634.2 [MþH]þ;
1H NMR (400 MHz, Acetic) d (ppm) 8.85 (d, J ¼ 6.6 Hz, 1H), 8.59
(s, 1H), 8.34 (s, 1H), 8.15 (dd, J ¼ 12.6, 2.1 Hz, 1H), 7.94 (s, 1H),
7.88 (d, J ¼ 8.8 Hz, 1H), 7.84 (s, 1H), 7.51 (t, J ¼ 8.8 Hz, 1H), 7.38
(d, J ¼ 5.5 Hz, 2H), 7.08 (t, J ¼ 9.0 Hz, 1H), 6.99 (d, J ¼ 6.4 Hz,
1H), 4.27 (s, 2H), 4.04 (s, 3H), 3.73 (s, 4H), 2.54 (d, J ¼ 35.1 Hz,
6H), 2.14 (s, 2H). Anal. calcd. for C33H30F3N5O5 (%): C, 62.55; H,
4.77; N, 11.05. Found (%): C, 62.52; H, 4.80; N, 11.03.
Yield: 80.1%; m.p.: 145.9–147.6°C; MS (ESI) m/z: 678.2 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 9.11 (s, 1H), 8.49 (d,
J ¼ 5.2 Hz, 1H), 7.95 (dd, J ¼ 12.1, 2.0 Hz, 1H), 7.86 (s, 1H), 7.67
(s, 1H), 7.63 (d, J ¼ 2.0 Hz, 1H), 7.58 (s, 1H), 7.44 (d, J ¼ 2.1 Hz,
1H), 7.42 (d, J ¼ 2.0 Hz, 1H), 7.40 (m, 1H), 7.35 (d, J ¼ 8.5 Hz,
1H), 7.24 (s, 1H), 6.43 (d, J ¼ 5.2 Hz, 1H), 4.25 (t, J ¼ 6.4 Hz, 2H),
4.03 (s, 3H), 3.05 (s, 2H), 2.70 (s, 1H), 2.17 (m, 4H), 1.67 (d,
J ¼ 10.4 Hz, 2H), 1.40 (s, 4H), 0.94 (d, J ¼ 4.9 Hz, 3H). Anal. calcd.
for C35H34Cl2FN5O4 (%): C, 61.95; H, 5.05; N, 10.32. Found (%):
C, 61.93; H, 5.07; N, 10.30.
General procedure for the preparation of the target
compounds 30–40
The compounds 19a–d (1.5 mmol) were each dissolved in dried
dichloromethane (15 mL), and refluxed with SOCl2 (15 mL) for
3 h. Upon cooling to room temperature, the solvent was
evaporated in vacuum. The residue was dissolved in dried
dichloromethane (10 mL) and dropwise added to a mixture of
the corresponding aniline (12a–d) (1 mmol), K2CO3 (2.1 mmol)
and CH2Cl2 (15 mL) in an ice bath for 30 min, which was then
removed to raise the temperature to room temperature and
stirred for 5 h. The resulting mixture was evaporated and
extracted with ethyl acetate (3 ꢁ 75 mL). The organic phase
was sequentially washed with 5% K2CO3 (2 ꢁ 15 mL) and
saturated sodium chloride solution (2 ꢁ 15 mL), and the
organic phase was separated, dried, and evaporated. The
crude product obtained was purified by silica gel chromatog-
raphy using a mixture of CH2Cl2/MeOH (25:1) to afford 30–40.
1-(2,4-Dichlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-1H-
imidazole-4-carboxamide (26)
Yield: 80.1%; m.p.: 110.0–110.2°C; MS (ESI) m/z: 666.2
[MþH]þ; 1H NMR (400 MHz, CDCl3) d (ppm) 9.12 (s, 1H),
8.49 (s, 1H), 7.95 (d, J ¼ 11.7 Hz, 1H), 7.86 (s, 1H), 7.67 (s, 1H),
7.63 (d, J ¼ 2.0 Hz, 1H), 7.58 (s, 1H), 7.44 (d, J ¼ 2.1 Hz, 1H),
7.42 (d, J ¼ 2.0 Hz, 1H), 7.40 (m, 1H), 7.35 (d, J ¼ 8.5 Hz, 1H),
7.24 (s, 1H), 6.44 (s, 1H), 4.27 (s, 2H), 4.04 (s, 3H), 3.73 (s, 4H),
2.59 (s, 2H), 2.50 (s, 4H), 2.14 (s, 2H). Anal. calcd. for
C
33H30Cl2FN5O5 (%): C, 59.47; H, 4.54; N, 10.51. Found (%): C,
59.49; H, 4.52; N, 10.51.
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(E)-N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-(phenylsulfonyl)
acrylamide (30)
(E)-N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-((4-
methoxyphenyl)sulfonyl)acrylamide (34)
Yield: 83.4%; m.p.: 114.2–116.0°C; MS (ESI) m/z: 635.2 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 10.22 (s, 1H), 8.43 (d,
J ¼ 8.0 Hz, 1H), 7.92 (m, J ¼ 12.0, 1.4 Hz, 4H), 7.66 (t, J ¼ 8.0 Hz,
1H), 7.58 (d, J ¼ 4.0 Hz, 2H), 7.56 (s, 1H), 7.50 (s, 1H), 7.46 (s,
1H), 7.42 (d, J ¼ 12.0 Hz, 1H), 7.16 (t, J ¼ 8.0 Hz, 1H), 6.36 (d,
J ¼ 4.0 Hz, 1H), 4.25 (t, J ¼ 6.4 Hz, 2H), 4.02 (s, 3H), 3.67
(d, J ¼ 4.0 Hz, 2H), 2.89 (s, 3H), 2.70 (m, J ¼ 7.0 Hz, 8H), 2.14 (t,
J ¼ 7.0 Hz, 2H). Anal. calcd. for C33H35FN4O6S (%): C, 62.45; H,
5.56; N, 8.83. Found (%): C, 62.43; H, 5.58; N, 8.85.
Yield: 7.9%; m.p.: 129.0–131.1°C; MS (ESI) m/z: 664.2 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 9.12 (s, 1H), 8.58 (d,
J ¼ 4.0 Hz, 1H), 7.96 (d, J ¼ 8.0 Hz, 2H), 7.64 (d, J ¼ 12.0 Hz, 1H),
7.52 (s, 1H), 7.49 (d, J ¼ 12.0 Hz, 1H), 7.39 (s, 1H), 7.32 (d,
J ¼ 8.0 Hz, 1H), 7.26 (s, 1H), 7.10 (d, J ¼ 8.0 Hz, 1H), 6.94
(d, J ¼ 8.0 Hz, 2H), 4.27 (t, J ¼ 8.0 Hz, 2H), 3.98 (s, 3H), 2.53 (t,
J ¼ 8.0 Hz, 2H), 2.46 (t, J ¼ 8.0 Hz, 4H), 2.39 (s, 3H), 2.07 (m,
J ¼ 8.0 Hz, 2H), 1.60 (m, J ¼ 8.0 Hz, 1H), 1.40 (m, J ¼ 8.0 Hz, 4H),
0.90 (s, 3H). Anal. calcd. for C35H38FN3O7S (%): C, 63.33; H,
5.77; N, 6.33. Found (%): C, 63.35; H, 5.75; N, 6.35.
(E)-N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-(phenylsulfonyl)-
acrylamide (31)
(E)-3-((2,4-Dimethylphenyl)sulfonyl)-N-(3-fluoro-4-((6-
methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-
4-yl)oxy)phenyl)acrylamide (35)
Yield: 62.4%; m.p.: 157.2–159.0°C; MS (ESI) m/z: 634.2
[MþH]þ; 1H NMR (400 MHz, CDCl3) d (ppm) 9.10 (s, 1H),
8.43 (d, J ¼ 4.0 Hz, 1H), 7.90 (d, J ¼ 8.0 Hz, 2H), 7.83 (d,
J ¼ 12.0 Hz, 1H), 7.71 (d, J ¼ 8.0 Hz, 1H), 7.61 (dd, J ¼ 8.0 Hz,
2H), 7.56 (s, 1H), 7.49 (d, J ¼ 12.0 Hz, 1H), 7.43 (s, 1H), 7.32
(d, J ¼ 8.0 Hz, 1H), 7.28 (s, 1H), 7.21 (d, J ¼ 8.0 Hz, 1H), 4.07 (t,
J ¼ 8.0 Hz, 2H), 3.92 (s, 3H), 2.57 (t, J ¼ 8.0 Hz, 2H), 2.53 (s, 3H),
2.05 (m, J ¼ 8.0 Hz, 2H), 2.40 (t, J ¼ 8.0 Hz, 4H), 1.62 (m,
J ¼ 8.0 Hz, 1H), 1.33 (m, J ¼ 8.0 Hz, 4H), 0.86 (s, 3H). Anal.
calcd. for C34H36FN3O6S (%): C, 64.44; H, 5.73; N, 6.63. Found
(%): C, 64.46; H, 5.71; N, 6.59.
Yield: 84.4%; m.p.: 104.2–106.0°C; MS (ESI) m/z: 663.3 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 9.09 (s, 1H), 8.32 (d,
J ¼ 4.0 Hz, 1H), 7.91 (d, J ¼ 12.0 Hz, 1H), 7.68 (d, J ¼ 8.0 Hz, 1H),
7.52 (s, 1H), 7.48 (d, J ¼ 12.0 Hz, 1H), 7.42 (s, 1H), 7.37 (s, 1H),
7.34 (d, J ¼ 8.0 Hz, 1H), 7.32 (d, J ¼ 8.0 Hz, 1H), 7.28 (s, 1H), 7.21
(d, J ¼ 8.0 Hz, 1H), 6.48 (s, 1H), 4.27 (t, J ¼ 8.0 Hz, 2H), 4.04 (s,
3H), 2.64 (s, 3H), 2.59 (t, J ¼ 8.0 Hz, 2H), 2.36 (s, 3H), 2.30 (t,
J ¼ 8.0 Hz, 8H), 2.14 (s, 3H), 2.07 (m, J ¼ 8.0 Hz, 2H). Anal. calcd.
for C35H39FN4O6S (%): C, 63.43; H, 5.93; N, 8.45. Found (%): C,
63.40; H, 5.96; N, 8.47.
(E)-N-(3-Fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)-
propoxy)quinolin-4-yl)oxy)phenyl)-3-(phenylsulfonyl)-
acrylamide (32)
(E)-3-((2,4-Dimethylphenyl)sulfonyl)-N-(3-fluoro-4-((6-
methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)-
phenyl)acrylamide (36)
Yield: 87.0%; m.p.: 219.0–220.0°C; MS (ESI) m/z: 620.2 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 9.03 (s, 1H), 8.48 (d,
J ¼ 4.0 Hz, 1H), 7.89 (d, J ¼ 8.0 Hz, 2H), 7.76 (d, J ¼ 12.0 Hz, 1H),
7.67 (d, J ¼ 8.0 Hz, 1H), 7.60 (dd, J ¼ 8.0 Hz, 2H), 7.56 (s, 1H),
7.49 (d, J ¼ 12.0 Hz, 1H), 7.36 (s, 1H), 7.32 (d, J ¼ 8.0 Hz, 1H),
7.20 (s, 1H), 7.12 (d, J ¼ 8.0 Hz, 1H), 4.45 (t, J ¼ 4.5 Hz, 2H), 4.12
(s, 3H), 3.79 (d, J ¼ 11.6 Hz, 2H), 3.45 (t, J ¼ 7.3 Hz, 2H), 2.98 (t,
J ¼ 11.2 Hz, 2H), 2.50 (s, 2H), 1.95 (s, 6H). Anal. calcd. for
Yield: 82.3%; m.p.: 106.0–108.2°C; MS (ESI) m/z: 650.2 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 8.98 (s, 1H), 8.62 (d,
J ¼ 4.0 Hz, 1H), 7.80 (d, J ¼ 12.0 Hz, 1H), 7.70 (d, J ¼ 8.0 Hz, 1H),
7.56 (s, 1H), 7.49 (d, J ¼ 12.0 Hz, 1H), 7.42 (s, 1H), 7.43 (s, 1H),
7.34 (d, J ¼ 8.0 Hz, 1H), 7.32 (d, J ¼ 8.0 Hz, 1H), 7.28 (s, 1H), 7.21
(d, J ¼ 8.0 Hz, 1H), 4.27 (t, J ¼ 8.0 Hz, 2H), 4.04 (s, 3H), 3.74 (s,
4H), 2.64 (s, 3H), 2.59 (t, J ¼ 8.0 Hz, 2H), 2.50 (s, 4H), 2.31 (s, 3H),
2.07 (m, J ¼ 8.0 Hz, 2H). Anal. calcd. for C34H36FN3O7S (%): C,
62.85; H, 5.59; N, 6.47. Found (%): C, 62.87; H, 5.61; N, 6.49.
C
33H34FN3O6S (%): C, 63.96; H, 5.53; N, 6.78. Found (%): C,
63.94; H, 5.55; N, 6.78.
(E)-3-((2,4-Dimethylphenyl)sulfonyl)-N-(3-fluoro-4-((6-
methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-
4-yl)oxy)phenyl)acrylamide (37)
(E)-N-(3-Fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)-
quinolin-4-yl)oxy)phenyl)-3-((4-methoxyphenyl)sulfonyl)-
acrylamide (33)
Yield: 78.8%; m.p.: 111.0–113.2°C; MS (ESI) m/z: 662.3 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 9.11 (s, 1H), 8.45 (d,
J ¼ 4.0 Hz, 1H), 7.83 (d, J ¼ 12.0 Hz, 1H), 7.70 (d, J ¼ 8.0 Hz, 1H),
7.56 (s, 1H), 7.49 (d, J ¼ 12.0 Hz, 1H), 7.42 (s, 1H), 7.43 (s, 1H),
7.34 (d, J ¼ 8.0 Hz, 1H), 7.32 (d, J ¼ 8.0 Hz, 1H), 7.28 (s, 1H), 7.21
(d, J ¼ 8.0 Hz, 1H), 4.27 (t, J ¼ 8.0 Hz, 2H), 4.04 (s, 3H), 4.04 (s,
3H), 2.59 (t, J ¼ 8.0 Hz, 2H), 2.43 (s, 3H), 2.07 (m, J ¼ 8.0 Hz, 2H),
2.46 (t, J ¼ 8.0 Hz, 4H), 1.60 (m, J ¼ 8.0 Hz, 1H), 1.48 (m,
J ¼ 8.0 Hz, 4H), 0.86 (s, 3H). Anal. calcd. for C36H40FN3O6S (%):
C, 65.34; H, 6.09; N, 6.35. Found (%): C, 65.30; H, 6.13; N, 6.33.
Yield: 82.1%; m.p.: 112.0–113.2°C; MS (ESI) m/z: 652.2 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 9.13 (s, 1H), 8.45 (d,
J ¼ 4.0 Hz, 1H), 7.88 (d, J ¼ 8.0 Hz, 2H), 7.83 (d, J ¼ 12.0 Hz, 1H),
7.56 (s, 1H), 7.49 (d, J ¼ 12.0 Hz, 1H), 7.43 (s, 1H), 7.32 (d,
J ¼ 8.0 Hz, 1H), 7.28 (s, 1H), 7.21 (d, J ¼ 8.0 Hz, 1H), 7.06 (d,
J ¼ 8.0 Hz, 2H), 4.27 (t, J ¼ 8.0 Hz, 2H), 4.04 (s, 3H), 3.91 (s, 3H),
3.74 (s, 4H), 2.59 (t, J ¼ 8.0 Hz, 2H), 2.50 (s, 4H), 2.07 (m,
J ¼ 8.0 Hz, 2H). Anal. calcd. for C33H34FN3O8S (%): C, 60.82; H,
5.26; N, 6.45. Found (%): C, 60.80; H, 5.28; N, 6.47.
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(E)-3-((2,4-Dimethylphenyl)sulfonyl)-N-(3-fluoro-4-((6-
methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)-
phenyl)acrylamide (38)
All compounds were tested three times in each of the cell lines.
The results expressed as IC50 (inhibitory concentration 50%)
were the averages of three determinations and calculated by
using the Bacus Laboratories Incorporated Slide Scanner (Bliss)
software.
Yield: 65.0%; m.p.: 154.0–156.2°C; MS (ESI) m/z: 648.2 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 9.14 (s, 1H), 8.45 (d,
J ¼ 4.0 Hz, 1H), 7.83 (d, J ¼ 12.0 Hz, 1H), 7.70 (d, J ¼ 8.0 Hz, 1H),
7.56 (s, 1H), 7.49 (d, J ¼ 12.0 Hz, 1H), 7.42 (s, 1H), 7.43 (s, 1H),
7.34 (d, J ¼ 8.0 Hz, 1H), 7.32 (d, J ¼ 8.0 Hz, 1H), 7.28 (s, 1H), 7.21
(d, J ¼ 8.0 Hz, 1H), 4.45 (t, J ¼ 4.5 Hz, 2H), 4.12 (s, 3H), 3.79 (d,
J ¼ 11.6 Hz, 2H), 3.45 (t, J ¼ 7.3 Hz, 2H), 2.98 (t, J ¼ 11.2 Hz, 2H),
2.50 (s, 2H), 1.95 (s, 6H). Anal. calcd. for C35H38FN3O6S (%): C,
64.90; H, 5.91; N, 6.49. Found (%): C, 64.93; H, 5.88; N, 6.47.
c-Met kinase assay
The c-Met kinase activity was evaluated using homogeneous
time-resolved fluorescence (HTRF) assays as previously
reported protocol [24, 25]. Briefly, 20 mg/mL poly(Glu, Tyr)
4:1 (Sigma) was preloaded as a substrate in 384-well plates.
Then 50 mL of 10 mM ATP (Invitrogen) 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 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 diluted in 39 mL of kinase reaction buffer
solution. The incubation time for the reactions was 30 min at
25°C and the reactions were stopped by the addition of 5 mL of
Streptavidin-XL665 and 5 mL Tk Antibody Cryptate working
solution to all of wells. The plate was read using Envision
(Perkin Elmer) at 320 and 615 nm. The inhibition rate (%) was
calculated using the following equation: % inhibition ¼ 100
ꢂ [(Activity of enzyme with tested compounds ꢂ Min)/(Max
ꢂ 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.
(E)-N-(3-Fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)-
quinolin-4-yl)oxy)phenyl)-3-tosylacrylamide (39)
Yield: 83.4%; m.p.: 116.2–118.0°C; MS (ESI) m/z: 636.2 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 9.65 (s, 1H), 8.45 (d,
J ¼ 4.0 Hz, 1H), 7.88 (dd, J ¼ 2.2 Hz, 1H), 7.80 (d, J ¼ 8.0 Hz, 2H),
7.55 (s, 1H), 7.45 (s, 1H), 7.44 (s, 1H), 7.40 (s, 1H), 7.37 (d,
J ¼ 8.0 Hz, 2H), 7.16 (t, J ¼ 12.0 Hz, 1H), 6.38 (d, J ¼ 4.0 Hz, 1H),
4.29 (t, J ¼ 8.0 Hz, 2H), 4.01 (s, 3H), 3.82 (m, J ¼ 4.0 Hz, 4H), 2.76
(m, J ¼ 8.0 Hz, 2H), 2.68 (d, J ¼ 2.8 Hz, 4H), 2.45 (s, 3H), 2.22 (m,
J ¼ 8.0 Hz, 2H). Anal. calcd. for C33H34FN3O7S (%): C, 62.35; H,
5.39; N, 6.61. Found (%): C, 62.30; H, 5.44; N, 6.63.
(E)-N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-tosylacrylamide
(40)
Yield: 75.9%; m.p.: 120.1–123.5°C; MS (ESI) m/z: 648.2 [MþH]þ;
1H NMR (400 MHz, CDCl3) d (ppm) 10.81 (s, 1H), 8.35 (d,
J ¼ 4.0 Hz, 1H), 7.91 (dd, J ¼ 4.0 Hz, 1H), 7.76 (d, J ¼ 8.0 Hz, 2H),
7.68 (d, J ¼ 16.0 Hz, 1H), 7.52 (s, 1H), 7.51 (s, 1H), 7.44 (s, 1H),
7.41 (d, J ¼ 12.0 Hz, 1H), 7.31 (d, J ¼ 8.0 Hz, 2H), 7.08 (t,
J ¼ 8.0 Hz, 1H), 6.33 (d, J ¼ 8.0 Hz, 1H), 4.34 (d, J ¼ 4.0 Hz, 2H),
3.96 (s, 3H), 3.76 (d, J ¼ 12.0 Hz, 2H), 3.39 (m, J ¼ 8.0, 4.0 Hz,
2H), 2.56 (s, 3H), 2.39 (d, J ¼ 12.0 Hz, 2H), 1.92 (s, 4H), 1.25 (s,
1H), 1.05 (d, J ¼ 8.0 Hz, 3H). Anal. calcd. for C35H38FN3O6S (%):
C, 64.90; H, 5.91; N, 6.49. Found (%): C, 64.93; H, 5.88; N, 6.52.
This work was supported by National Natural Science
Foundation of China (81573295), Program for Liaoning
Excellent Talents in University (LR2014030), and Development
Project of Ministry of Education Innovation Team (IRT1073).
The authors have declared no conflicts of interest.
Pharmacology
MTT assay in vitro
References
The anti-proliferative activities of compounds 20–40 were
evaluated against HT-29, A549, and MKN-45 cell lines using the
standard MTT assay in vitro, with foretinib as the positive
control.Thecancercelllineswereculturedinminimumessential
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 tested compounds at the indicated
finalconcentrationswereaddedtotheculturemediumandthe
cell cultures were continued for 72 h. Fresh MTT was added to
each well at a terminal concentration of 5 mg/mL, and
incubated with cells at 37°C for 4 h. The formazan crystals
were dissolved in 100mL DMSO each well, and the absorbency
at 492nm (for absorbance of MTT formazan) and 630 nm (for
the reference wavelength)was measured with an ELISAreader.
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