Discovery of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety as c-Met kinase inhibitors

Article abstract of DOI:10.1016/j.bmc.2014.01.014

A series of novel quinoline derivatives bearing 5-(aminomethylene) pyrimidine-2,4,6-trione moiety were designed, synthesized, and evaluated for their c-Met kinase inhibitory activities and antiproliferative activities against 5 cancer cell lines (HT-29, H460, MKN-45, A549, and U87MG) in vitro. Most compounds showed moderate to excellent potency, with the most promising analogue 45 (c-Met half-maximal inhibitory concentration [IC₅₀] = 1.15 nM) showing high selectivity versus 5 other tyrosine kinases, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR. Structure-activity relationship studies indicated that electron-donating groups on the phenyl ring at the 3-position of pyrimidine-2,4,6-trione were required to increase the electron density on the 5-(aminomethylene)pyrimidine-2,4,6-trione moiety.

Full text of DOI:10.1016/j.bmc.2014.01.014

Bioorganic & Medicinal Chemistry 22 (2014) 1236–1249
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Discovery of novel 6,7-disubstituted-4-phenoxyquinoline derivatives
bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety as c-Met
kinase inhibitors
Qidong Tang a, Guogang Zhang b, Xinming Du a, Wufu Zhu c, Ruijuan Li a, Huafang Lin a, Pengcheng Li a,
Maosheng Cheng a, Ping Gong a, Yanfang Zhao a,
⇑
a Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University,
103 Wenhua Road, Shenhe District, Shenyang 110016, PR China
b State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, College of Chemical & Pharmaceutical Engineering,
Hebei University of Science & Technology, Shijiazhuang 050018, PR China
c School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi 330013, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel quinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety were
designed, synthesized, and evaluated for their c-Met kinase inhibitory activities and antiproliferative
activities against 5 cancer cell lines (HT-29, H460, MKN-45, A549, and U87MG) in vitro. Most compounds
showed moderate to excellent potency, with the most promising analogue 45 (c-Met half-maximal inhib-
itory concentration [IC50] = 1.15 nM) showing high selectivity versus 5 other tyrosine kinases, VEGFR-2,
Flt-3, PDGFR-b, c-Kit, and EGFR. Structure–activity relationship studies indicated that electron-donating
groups on the phenyl ring at the 3-position of pyrimidine-2,4,6-trione were required to increase the elec-
tron density on the 5-(aminomethylene)pyrimidine-2,4,6-trione moiety.
Received 15 December 2013
Revised 10 January 2014
Accepted 10 January 2014
Available online 22 January 2014
Keywords:
c-Met
Receptor tyrosine kinase
Anti-tumor
Ó 2014 Elsevier Ltd. All rights reserved.
Quinoline derivatives
Pyrimidine-2,4,6-trione
1. Introduction
activities in clinical/preclinical models.16–28 Recently, significant
progress has been made in the development of small-molecule
c-Met, known as a hepatocyte growth factor receptor (HGFR),
belongs to a subfamily of receptor tyrosine kinases (RTKs) that
c-Met inhibitors, resulting in the marketing of cabozantinib
(3, Fig. 1) and more than 10 candidates currently under clinical
trials.29–31 Many structure types of these derivatives were in-
cluded, such as thieno[2,3-b]pyridine, 2-amino-3-chloropyridine,
and 6,7-disubstitutedquinoline series (1, 2, and 3–6, respectively,
Fig. 1).32–38 However, the main modification of these different
series of derivatives was focused on the 5-atom linker between
moiety A and moiety B, which was characterized by the illustrated
‘5 atoms regulation’ and ‘hydrogen-bond donor or acceptor’.41,42 In
our previous study, we introduced pyridine, semicarbazone, quin-
oline, and 1,4-dihydrocinnoline fragments into the 5-atom linker
based on the ‘5 atoms regulation’/’hydrogen-bond donor or accep-
tor’, and the resulting derivatives 7–10 (Fig. 2) showed excellent
potency.39–42 These compounds all contained an amide group in
the linker.
are composed of an extracellular
a chain and a membrane-span-
ning b chain connected through a disulfide bond.1–3 In normal
physiology, the HGF/Met pathway regulates several cellular
responses including cell proliferation, invasion, motility, survival,
and morphogenesis.4,5 c-Met has been shown to be frequently
amplified or overexpressed in various cancers, including brain,
colorectal, gastric, lung, head, neck, and stomach cancers;6–8 and
circulating HGF levels are elevated in most cancers.9,10 Both
amplifications/overexpression are associated with poor clinical
outcomes,11–15 underscoring the importance of increased c-Met
signaling in these cancer types. Therefore, c-Met shows high
potential as a therapeutic target for human cancer.
In recent years, research has highlighted c-Met as an attractive
cancer drug target, triggering a number of approaches to disrupt
HGF/Met signaling. Both small-molecule c-Met kinase inhibitors
and antibodies targeting c-Met or HGF have exhibited antitumor
Pyrimidine-2,4,6-trione (PYT) is widely used as a building
block in the design of anticancer agents because of its ability to
form hydrogen-bonding interactions with drug targets (11–14,
Fig. 3).43–46 To make further study, we replaced the amide group
in the 5-atom linker with an aminomethylene group, and intro-
duced PYT to form the C1 fragment (Fig. 4) based on the ‘5 atoms
⇑
Corresponding author. Tel./fax: +86 24 23989907.
E-mail address: yanfangzhao@126.com (Y. Zhao).
0968-0896/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2014.01.014

Q. Tang et al. / Bioorg. Med. Chem. 22 (2014) 1236–1249
1237
Figure 1. The representative small-molecule c-Met kinase inhibitors.
Figure 2. Our previous work on small-molecule c-Met kinase inhibitors.
Figure 3. Anticancer agents bearing pyrimidine-2,4,6-trione fragments.
Figure 4. Design strategy for the quinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety.

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Q. Tang et al. / Bioorg. Med. Chem. 22 (2014) 1236–1249
Scheme 1. Reagents and conditions: (i) Br(CH2)3Cl, acetone, 0 °C, 30 min, rt, 12 h; (ii) 98% HNO3, CH2Cl2, 0 °C, 4 h; (iii) DMF-DMA, toluene, 110 °C, 10 h; (iv) Fe powder, AcOH,
rt, 30 min, 80 °C, 2 h; (v) secondary amines, CH3CN, 85 °C, 10 h; (vi) POCl3, 85 °C, 6 h; (vii) 2-fluoro-4-nitrophenol, PhCl, 140 °C, 30 h; (viii) Fe powder, NH4Cl (cat.), EtOH/H2O,
reflux, 5 h.
Scheme 2. Reagents and conditions: (i) NaOCN, AcOH/H2O, 40 °C, 2–4 h; (ii) dimethyl malonate, EtONa, EtOH, reflux, 8–12 h; (iii) DMF-DMA, 50 °C, 6–10 h; (iv) appropriate
aniline, AcOH, 80 °C, 20–30 h.
regulation’. In this study, a 5-(aminomethylene)pyrimidine-2,4,6-
trione moiety was used as the 5-atom linker.
solids.47 Acylation of the 1-substitutedphenylureas 25a–h with di-
methyl malonate in the presence of sodium ethylate (NaOC2H5) in
refluxing ethanol (EtOH) yielded 1-substitutedphenylpyrimidine-
2,4,6-triones 26a–h.48 Subsequent aminomethylenation using mod-
ified Vilsmeier–Haack reagent N,N-dimethyl formamide dimethyl
acetal (DMF-DMA) at 50 °C afforded intermediates 27a–h as yellow
solids.49 Reaction of amides 23a–e with 27a–h promoted by hot
AcOH yielded the target compounds 28–67.
The chemical structures of the target compounds were deter-
mined by mass spectrometry (MS), 1H nuclear magnetic resonance
(NMR), 13C NMR, and infrared (IR) spectra. All target compounds
were found to exist in the E and Z isomeric forms with carbon–car-
bon double bonds. In our study, a single isomeric form was not
obtained because the silica gel column chromatography could not
separate the E and Z isomeric forms due to their similar polarity.
For the representative compound 53, 2 groups of peaks were ob-
According to our previous study, the 3-carbon tether at the 7
position of quinoline was reserved, while the morpholinyl group
was replaced by four other water-soluble substituents, including
piperidinyl, 4-methyl piperidinyl, pyrrolidinyl, and 4-methyl
piperazinyl groups, to observe the effects of the different cyclic
tertiary amino groups on activity of the new compounds. Further-
more, various substituents were introduced at the phenyl ring
(moiety B) to investigate their effects on activity. Accordingly, we
designed a novel series of 6,7-disubstituted-4-phenoxyquinoline
derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione
moiety.
The target compounds synthesized were evaluated for their
c-Met kinase activities and antiproliferative activities against 5
cancer cell lines included the HT-29 (human colon cancer), H460
(human lung cancer), A549 (human lung adenocarcinoma), MKN-
45 (human gastric cancer), and U87MG (human glioblastoma).
served for the
E isomeric form (H1: d, J = 13.4 Hz, 0.57H,
d = 11.86 ppm; H2: s, 0.57H, d = 11.26 ppm; H3: d, J = 13.4 Hz,
0
0.58H, d = 8.64 ppm) and Z isomeric form (H1 : d, J = 12.6 Hz,
0
0
0.42H, d = 12.01 ppm; H2 : s, 0.42H, d = 11.41 ppm; H3 : d,
J = 12.6 Hz, 0.42H, d = 8.57 ppm) in 1H NMR as shown in Figure 5.
H4 (d, J = 5.2 Hz, 1H) at the 2-position of the quinoline ring showed
thesamechemicalshiftat d = 8.47 ppmintheE andZisomericforms.
2. Chemistry
The synthesis of the key intermediates of 6,7-disubstituted-
4-phenoxyquinolines 23a–e was achieved in 8 steps from
commercially available 1-(4-hydroxy-3-methoxyphenyl)ethanone
as shown in Scheme 1, which has been illustrated in detail in our
previous study.41,42
3. Biology
The target compounds 28–67 were prepared as illustrated in
Scheme 2. Condensation of commercially available substituted phe-
nylamines 24a–h with sodium cyanate (NaOCN) in AcOH/H2O (1:1
v/v) at 40 °C resulted in high yield of intermediates 25a–h as white
3.1. HTRF kinase assay
The c-Met kinase assays of all compounds were performed by
homogeneous time-resolved fluorescence (HTRF) assay as

Q. Tang et al. / Bioorg. Med. Chem. 22 (2014) 1236–1249
1239
Figure 5. 1H NMR (600 MHz) for compound 53 in DMSO-d6.
Table 1
c-Met kinase activities of the target compounds 28–67
0.1% NaN3) was added to each well. Various concentrations of
compounds diluted in 10 L 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 L of kinase reac-
tion buffer solution. The incubation time for the reactions was
30 min at 25 °C, and the reactions were stopped by the addition
l
Compd
R1
R2
c-Met IC50 (nM)
28
29
H
4-CH3
4.31 0.15
2.58 0.18
l
N
30
31
32
33
34
35
2,6-(CH3)2
4-F
2,4-(F)2
3-Cl-4-F
2-CF3
2,5-(OCH3)2-4-Cl
3.72 0.31
3.64 0.45
9.27 1.42
3.15 0.19
18.54 1.62
27.91 2.43
of 5 lL of Streptavidin-XL665 and 5 lL Tk Antibody Cryptate work-
ing solution to all of wells. The plates were 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 inhi-
bition curves.
36
37
H
4-CH3
2,6-(CH3)2
4-F
2,4-(F)2
3-Cl-4-F
2-CF3
2,5-(OCH3)2-4-Cl
3.84 0.23
1.64 0.16a
N
N
N
N
38
39
40
41
42
43
2.83 0.42
3.09 0.53
15.96 2.39
4.82 0.56
18.25 1.25
19.15 1.43
44
45
H
4-CH3
2,6-(CH3)2
4-F
2,4-(F)2
3-Cl-4-F
2-CF3
2,5-(OCH3)2-4-Cl
3.36 0.45
1.15 0.16
3.2. Cytotoxic activities against tumor cells assay
46
47
48
49
50
51
2.35 0.14
2.68 0.48
12.39 1.51
2.38 0.38
7.51 0.76
16.8 2.15
The cytotoxic activities of compounds 28–67 were evaluated
against the HT-29, H460, MKN-45, A549, and U87MG cell lines
using the standard MTT assay in vitro, with foretinib used as the
positive control.52,53 The cancer cell lines were cultured in
minimum essential medium (MEM) supplemented with 10%
fetal bovine serum (FBS). Approximate 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 compounds tested
at the indicated final concentrations were added to the culture
medium and the cell cultures were continued for 72 h. Fresh
52
53
H
4-CH3
2,6-(CH3)2
4-F
2,4-(F)2
3-Cl-4-F
2-CF3
2,5-(OCH3)2-4-Cl
4.57 0.27
2.16 0.63
O
N
54
55
56
57
58
59
3.03 0.16
3.58 0.35
12.36 1.25
5.14 0.48
21.24 2.18
32.82 2.25
60
61
H
4-CH3
3.29 0.24
2.68 0.62
MTT was added to each well at a terminal concentration of 5 lg/
mL, and incubated with cells at 37 °C for 4 h. The formazan crystals
were dissolved in 100 mL DMSO of each well, and the absorbency
at 492 nm (for absorbance of MTT formazan) and 630 nm (for the
reference wavelength) was measured with an ELISA reader. All of
the compounds were tested in triplicate in each cell line. The re-
sults expressed as IC50 (inhibitory concentration 50%) were the
averages of three determinations and calculated by using the Bacus
Laboratories Incorporated Slide Scanner (Bliss) software.
62
63
64
65
2,6-(CH3)2
4-F
2,4-(F)2
3-Cl-4-F
2-CF3
2,5-(OCH3)2-4-Cl
3.26 0.28
3.15 0.35
8.35 1.06
3.15 0.23
8.14 2.38
24.72 3.35
1.86 0.11
66
67
Foretinibb
a
Bold values show the IC50 values of the target compounds lower than the value
of the positive control.
b
Used as the positive control.
4. Results and discussion
previously reported protocol.50,51 In order to examine the selectiv-
ity of the most promising compound 45 on c-Met over other
tyrosine kinases, it was screened against VEGFR-2, Flt-3, PDGFR-
4.1. In vitro enzymatic assays
b, c-Kit, and EGFR. Briefly, 20
was preloaded as a substrate in 384-well plates. Then 50
10 mM ATP (Invitrogen) solution diluted in kinase reaction buffer
l
g/mL poly (Glu, Tyr) 4:1 (Sigma)
L of
The c-Met enzymatic assays of all synthesized compounds were
evaluated using homogeneous time-resolved fluorescence (HTRF)
assay. Foretinib was used as a positive control, with the results
l
(50 mM HEPES, pH 7.0, 1 M DTT, 1 M MgCl2, 1 M MnCl2, and
expressed as the half-maximal inhibitory concentration (IC50
)

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Q. Tang et al. / Bioorg. Med. Chem. 22 (2014) 1236–1249
values presented in Table 1; the mean values of experiments
performed in triplicate are shown.
increased the c-Met inhibitory efficacy, while incorporation of
the mono-EDGs showed higher preference. For example,
a
As illustrated in Table 1, these novel 6,7-disubstituted-4-phen-
oxyquinoline derivatives bearing 5-(aminomethylene)pyrimidine-
2,4,6-trione moiety were found to be active against c-Met kinase
with IC50 values ranging from 1.15–32.82 nM; 2 of them (45,
IC50 = 1.15 nM; 37, IC50 = 1.64 nM) showed higher potency than
foretinib (IC50 = 1.86 nM), indicating that replacement of the
cyclopropane-1,1-dicarboxamide fragment in foretinib with the
5-(aminomethylene)pyrimidine-2,4,6-trione moiety maintained
the c-Met inhibitory efficacy.
According to the data shown in Table 1, enzymatic assays data
showed no preference for activity when the R1 group was intro-
duced to other different cyclic tertiary amino groups, indicating
that the R1 group contributed little to c-Met inhibitory efficacy.
For example, the IC50 value of compound 44 was 3.36 nM, which
was comparable to the values of 28, 36, 52, and 60, which were
4.31, 3.84, 4.57, and 3.29 nM, respectively.
compound 44, with no substituent on the phenyl ring, showed a
c-Met IC50 value 3.36 nM. Introduction of mono-EDGs to R2 (45,
R2 = 4-CH3, IC50 = 1.15 nM, increased 2.9-fold) increased the inhib-
itory efficacy to a greater extent than that of mono-EWGs (47,
R2 = 4-F, IC50 = 2.68 nM, increased 1.3-fold). This was further con-
firmed by introduction of these 2 types of groups in compounds
29/31, 53/55, and 61/63. However, incorporation of double
electron-donating groups (double-EDGs) and double electron-
withdrawing groups (double-EWGs) showed opposite trend in
potency of the compounds. Incorporation of double-EDGs
increased the c-Met inhibitory efficacy; in contrast, the double-
EWGs clearly decreased the potency, such as 46 (R2 = 2,6-(CH3)2,
IC50 = 2.35 nM) and 48 (R2 = 2,4-(F)2, IC50 = 12.39 nM). Similarly
to our previous study, regulating electron density on the 5-atom
linker to a proper degree was a key factor in improving inhibitory
activity.39 The pyrimidine-2,4,6-trione ring, which is part of the
5-atom linker, has lower electron density because of the electronic
withdrawing effect of the 3 carbonyl groups. Therefore, EDGs (such
as methyl) were required to increase the lower electron density on
the 5-(aminomethylene)pyrimidine-2,4,6-trione moiety.
Further studies were performed to examine the effect of differ-
ent substituents on the phenyl ring (moiety B) on potency. Both the
mono-electron-donating groups (mono-EDGs) and mono-electron-
withdrawing groups (mono-EWGs) introduced to the phenyl ring
Table 2
Cytotoxic activities of the target compounds 28–67 against the HT-29, H460, MKN-45, A549, and U87MG cancer cell lines in vitro
Compd
R1
R2
IC50 (lM) SD
HT-29
H460
MKN-45
A549
U87MG
28
29
H
4-CH3
2,6-(CH3)2
4-F
2,4-(F)2
3-Cl-4-F
2-CF3
2,5-(OCH3)2-4-Cl
0.16 0.058
0.12 0.027
0.22 0.074
0.10 0.040
0.28 0.063
0.19 0.058
0.49 0.012
0.48 0.020
3.9 0.15
0.04 0.0060
0.10 0.032
1.97 0.21
0.51 0.040
0.38 0.035
1.3 0.10
1.5 0.37
1.2 0.21
ND
ND
1.0 0.28
ND
a
N
N
N
N
N
30
31
32
33
34
35
0.20 0.12
0.14 0.021
0.42 0.018
0.20 0.052
1.3 0.36
0.16 0.051
0.16 0.030
1.1 0.14
0.08 0.0062
0.93 0.043
1.2 0.37
0.31 0.024
NDb
ND
0.18 0.051
ND
ND
2.6 0.32
ND
36
37
H
4-CH3
2,6-(CH3)2
4-F
2,4-(F)2
3-Cl-4-F
2-CF3
2,5-(OCH3)2-4-Cl
0.28 0.070
0.14 0.080
0.17 0.075
0.059 0.0046
0.046 0.0050
0.056 0.0080
0.39 0.022
0.99 0.024
ND
0.35 0.036
ND
ND
1.42 0.43
0.92 0.072
ND
3.2 0.37
ND
ND
ND
3.4 0.18
38
39
40
41
42
43
0.12 0.052
0.22 0.090
5.1 0.27
0.15 0.053
0.60 0.035
0.63 0.015
0.15 0.042
0.11 0.0070
0.26 0.026
0.087 0.0056
0.38 0.030
0.57 0.035
0.13 0.025
0.12 0.082
0.46 0.031
0.065 0.0054
0.31 0.032
0.46 0.015
ND
0.64 0.014
44
45
H
4-CH3
2,6-(CH3)2
4-F
2,4-(F)2
3-Cl-4-F
2-CF3
2,5-(OCH3)2-4-Cl
0.20 0.021
0.13 0.060
0.29 0.022
0.051 0.0080
0.21 0.030
0.057 0.0040
0.90 0.014
1.2 0.26
2.8 0.37
0.072 0.0090
1.4 0.20
0.35 0.061
ND
ND
0.64 0.045
1.24 0.16
ND
ND
0.68 0.030
ND
2.8 0.35
0.072 0.0060
0.23 0.057
ND
ND
0.19 0.015
ND
46
47
48
49
50
51
0.12 0.071
0.49 0.060
0.71 0.026
0.19 0.043
0.37 0.011
9.4 0.41
0.16 0.030
0.62 0.015
0.24 0.060
0.054 0.0045
0.36 0.031
0.71 0.040
0.38 0.025
52
53
H
4-CH3
2,6-(CH3)2
4-F
2,4-(F)2
3-Cl-4-F
2-CF3
2,5-(OCH3)2-4-Cl
0.35 0.016
0.18 0.030
0.26 0.063
0.061 0.0050
0.31 0.052
0.21 0.040
0.93 0.064
0.11 0.030
2.2 0.14
ND
ND
0.27 0.053
ND
ND
4.8 0.26
8.5 0.50
7.1 0.43
ND
ND
0.58 0.080
ND
O
N
54
55
56
57
58
59
0.14 0.025
0.24 0.074
0.56 0.060
0.28 0.026
3.7 0.53
0.085 0.0041
0.12 0.032
0.85 0.026
0.12 0.014
2.3 0.64
5.5 0.16
0.74 0.063
0.78 0.080
0.11 0.031
18.4 1.5
1.3 0.13
0.54 0.063
2.4 0.35
ND
60
61
H
4-CH3
0.19 0.034
0.49 0.090
0.29 0.052
0.070 0.0053
0.52 0.080
0.16 0.037
ND
0.43 0.024
ND
3.2 0.31
62
63
64
65
2,6-(CH3)2
4-F
2,4-(F)2
3-Cl-4-F
2-CF3
0.26 0.060
0.31 0.048
1.5 0.17
0.15 0.013
7.3 0.46
0.17 0.010
0.12 0.041
1.17 0.13
0.076 0.0032
4.2 0.14
0.45 0.026
0.12 0.010
0.51 0.032
0.066 0.0040
3.5 0.21
ND
ND
0.51 0.060
0.38 0.034
0.31 0.042
ND
1.6 0.32
0.75 0.066
ND
66
67
2,5-(OCH3)2-4-Cl
7.7 0.12
0.16 0.015
1.8 0.24
0.19 0.036
0.48 0.030
0.032 0.0052
ND
0.13 0.010
ND
1.1 0.12
Foretinibc
a
b
c
Bold values show the IC50 values of the target compounds lower than the values of the positive control.
ND: Not determined.
Used as the positive control.

Q. Tang et al. / Bioorg. Med. Chem. 22 (2014) 1236–1249
1241
Table 3
promising compound, 45, were 0.13, 0.051, 0.072, and 0.64 lM
Inhibition of tyrosine kinases by compound 45
against the HT29, H460, A549, and U87MG cell lines, respectively,
indicating that this compound was 1.2-, 3.7-, 1.8-, and 1.7-times
more active than foretinib (IC50 values: 0.16, 0.19, 0.13, and
Kinase
Enzyme IC50 (nM)
VEGFR-2
Flt-3
PDGFR-b
c-Kit
384.1
496.3
530.6
652.5
1.1 lM, respectively). Examination of the structure–activity rela-
tionships (SARs) indicated that these analogs had similar SARs as
summarized in the c-Met kinase level: (a) different cyclic tertiary
amino groups (R1 group) contributed only minimally to the
potency of the target compounds; (b) the pyrimidine-2,4,6-trione
ring, which was a part of the 5-atom linker, required EDGs (such
as methyl) to increase the electron density; (c) the number, size,
and electronic property of substituents (R2 group) on the phenyl
ring (moiety B) were key factors in improving the potency.
EGFR
>100,000
A preference was observed for the number of substituents
on the phenyl ring (moiety B), with following rank order:
1 > 2 > 0 > 3, including 29 (R2 = 4-CH3, IC50 = 2.58 nM), 30 (R2 =
2,6-(CH3)2, IC50 = 3.72 nM), 28 (R2 = H, IC50 = 4.31 nM), and 35
(R2 = 2,5-(OCH3)2-4-Cl, IC50 = 27.91 nM). Moreover, potency
decreased with the incorporation of bulky groups on the phenyl
ring, such as a trifluoromethyl group (34, 42, 50, 58, and 66).
4.3. Enzymatic selectivity assays
To examine the selectivity of compound 45 on c-Met over
other kinases, this compound was screened against 5 other tyro-
sine kinases. As shown in Table 3, compound 45 exhibited excel-
lent selectivity versus VEGFR-2 (IC50 = 384.1 nM, 334-fold), Flt-3
(IC50 = 496.3 nM, 432-fold), PDGFR-b (IC50 = 530.6 nM, 461-fold),
and c-Kit (IC50 = 652.5 nM, 567-fold), with no inhibition activity
4.2. In vitro cytotoxic activities
Using foretinib as the positive control, the cytotoxic activities of
all target compounds 28–67 have been evaluated against the
HT-29, H460, and MKN-45 cell lines using the MTT assay. Some
potent compounds were further evaluated against the A549 and
U87MG cell lines. The results expressed as IC50 values are shown
in Table 2 as the mean values of triplicate experiments.
against EGFR (IC50 > 100 lM). These data suggest that compound
45 may be a selective single target c-Met kinase inhibitor.
5. Binding model analysis
All target compounds showed moderate to excellent cytotoxic
activity against different cancer cells with potencies in the
To further elucidate the binding mode of compounds, docking
analysis was performed. In our study, the co-crystal structure of
foretinib (GSK1363089) with c-Met kinase was selected as the
single-digit
lM range, and 19 of them were more potent than
foretinib against one or more cell lines. The IC50 values of the most
Figure 6. Binding poses of compound Z-45 (A) and E-45 (B) with c-Met. The proteins were displayed by silver ribbon. Compound Z-45 and E-45 were displayed by pink and
cyan sticks, respectively. H-bonding interactions between the 45 and c-Met were indicated with dashed lines in green. Pi–Pi and Pi–Sigma interactions were shown with
orange–yellow lines.

1242
Q. Tang et al. / Bioorg. Med. Chem. 22 (2014) 1236–1249
docking model (PDB ID: 3LQ8). The docking simulation was
conducted using Glide XP (Schrödinger2013), since Glide uses a
hierarchical series of filters to search for possible locations of the
ligand in the active-site region of the receptor. The shape and prop-
erties of the receptor are represented on a grid by several different
sets of fields that provide progressively more accurate scoring of
the ligand poses. The image files were generated using Accelrys
DS visualizer 3.0 system. The binding model was exemplified by
the interaction of compound 45 with c-Met. As shown in Figure 6,
the protonated nitrogen atom of pyrrolidine and the nitrogen atom
of the quinoline ring in 45 formed hydrogen-bonding interactions
with LYS1161 and MET1160, respectively. The Pi-Pi interactions
had been formed between the quinoline ring and TYR1159. In addi-
tion, two oxygen atoms of PYT in Z-45 formed two hydrogen bonds
with ASP1222 and LYS1110. While, the Pi-Sigma interaction was
forged between the phenyl ring (moiety B) in E-45 and GLU1127.
7.1.1. 3-Fluoro-4-(6-methoxy-7-(3-(piperdin-1-
yl)propoxy)quinolin-4-yloxy)aniline (23a)
Gray solid; yield: 86%; mp 196–197 °C; IR (KBr) cmꢀ1: 3482.2,
3387.0, 2946.5, 2835.1, 2788.1, 1621.1, 1587.8, 1512.8, 1483.4,
1252.9, 1215.4, 853.5; 1H NMR (300 MHz, CDCl3) d 8.46 (d,
J = 5.3 Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 7.03 (t, J = 8.7 Hz, 1H),
6.56 (dd, J = 11.8, 2.6 Hz, 1H), 6.50 (m, 1H), 6.39 (dd, J = 5.3,
1.1 Hz, 1H), 4.24 (t, J = 6.8 Hz, 2H), 4.04 (d, J = 3.8 Hz, 3H), 3.81 (s,
2H), 2.54 (m, 2H), 2.43 (s, 4H), 2.14 (m, 2H), 1.60 (m, 4H), 1.45
(d, J = 5.2 Hz, 2H); MS m/z (ESI): 426.4 [M+H]+, 448.4 [M+Na]+.
7.1.2. 3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperdin-1-
yl)propoxy)quinolin-4-yl-oxy)aniline (23b)
White solid; yield: 77%; mp 193–194 °C; 1H NMR (300 MHz,
CDCl3) d 8.46 (d, J = 5.3 Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 7.03
(t, J = 8.7 Hz, 1H), 6.56 (dd, J = 11.8, 2.6 Hz, 1H), 6.50 (dd, J = 9.0,
2.9 Hz, 1H), 6.39 (dd, J = 5.3, 0.8 Hz, 1H), 4.25 (t, J = 6.7 Hz, 2H),
4.03 (s, 3H), 3.82 (s, 2H), 2.94 (d, J = 11.5 Hz, 2H), 2.57
(m, 2H), 2.15 (m, 2H), 1.98 (t, J = 10.9 Hz, 2H), 1.63 (d, J = 10.4 Hz,
2H), 1.28 (m, 3H), 0.93 (d, J = 6.0 Hz, 3H); MS m/z (ESI): 440.3
[M+H]+.
6. Conclusions
In summary, we designed and synthesized 40 quinoline deriva-
tives bearing a 5-(aminomethylene)pyrimidine-2,4,6-trione scaf-
fold. c-Met kinase and 5 human cancer cell lines (HT-29, H460,
MKN-45, A549, and U87MG) were used to evaluate the potency
of the synthesized compounds. Compared with foretinib, 2 of the
derivatives showed higher c-Met kinase inhibitory activity, and
19 were more potent against one or more cell lines. The most
promising compound, 45, showed excellent inhibition on c-Met
kinase (IC50 = 1.15 nM) compared to the 5 other tyrosine kinases
screened in this report; its cytotoxic activity against the HT-29,
H460, A549, and U87MG cell lines (IC50 values: 0.13, 0.051,
7.1.3. 3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy)quinolin-4-yloxy)aniline (23c)
Light yellow solid; yield: 72%; mp 208–209 °C; 1H NMR
(300 MHz, DMSO-d6) d 8.49 (d, J = 5.2 Hz, 1H), 7.55 (s, 1H), 7.44
(s, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.57 (d, J = 14.1 Hz, 1H), 6.46 (m,
J = 12.8, 7.1 Hz, 2H), 4.28 (t, J = 5.7 Hz, 2H), 3.96 (s, 3H), 3.59 (s,
2H), 3.04 (m, 9H), 2.28 (m, 2H), 1.96 (d, J = 28.0 Hz, 4H); MS m/z
(ESI): 412.2 [M+H]+.
0.072, and 0.64 lM, respectively) were 1.2-, 3.7-, 1.8-, and 1.7-
times more active than that of foretinib, respectively. Analysis of
SARs indicated that EDGs on the phenyl ring (moiety B) were
required to increase the electron density on the 5-(aminomethyl-
ene)pyrimidine-2,4,6-trione moiety. In addition, the hydrophobic
pocket of c-Met was probably not sufficiently large to accommo-
date moiety B with bulky groups. Therefore, a methyl group was
the most favorable substituent on the phenyl ring. Further studies
on SARs and the mechanism of action of these compounds are
underway in our laboratory.
7.1.4. 3-Fluoro-4-(6-methoxy-7-(3-
morpholinopropoxy)quinolin-4-yloxy)aniline (23d)
White solid; yield: 82%; mp 217–218 °C; 1H NMR (300 MHz,
CDCl3) d 8.47 (d, J = 5.2 Hz, 1H), 7.58 (s, 1H), 7.44 (s, 1H), 7.04 (t,
J = 8.7 Hz, 1H), 6.57 (dd, J = 11.9, 2.6 Hz, 1H), 6.50 (m, 1H), 6.41
(d, J = 5.3 Hz, 1H), 4.27 (t, J = 6.6 Hz, 2H), 4.04 (s, 3H), 3.82 (s,
2H), 3.74 (m, 4H), 2.60 (t, J = 7.1 Hz, 2H), 2.51 (d, J = 4.2 Hz, 4H),
2.13 (m, 2H); MS m/z (ESI): 428.3 [M+H]+.
7.1.5. 3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yl-oxy)aniline (23e)
7. Experimental
White solid; yield: 77%; mp 193–194 °C; 1H NMR (300 MHz,
CDCl3) d 8.46 (d, J = 5.3 Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 7.03 (t,
J = 8.7 Hz, 1H), 6.56 (dd, J = 11.8, 2.6 Hz, 1H), 6.50 (dd, J = 9.0,
2.9 Hz, 1H), 6.39 (dd, J = 5.3, 0.8 Hz, 1H), 4.25 (t, J = 6.7 Hz, 2H),
4.03 (s, 3H), 3.82 (s, 2H), 2.94 (d, J = 11.5 Hz, 2H), 2.57 (m, 2H),
2.15 (m, 2H), 1.98 (t, J = 10.9 Hz, 2H), 1.63 (d, J = 10.4 Hz, 2H),
1.28 (m, 3H), 0.93 (d, J = 6.0 Hz, 3H); MS m/z (ESI): 441.4 [M+H]+.
Unless otherwise noted, all materials were obtained from com-
mercial suppliers and were used without further purification.
Reactions’ time 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 chromatography was run
on silica gel (200–300 mesh) from Qingdao Ocean Chemicals
(Qingdao, Shandong, China). 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). 1H NMR and 13C NMR spectra were recorded on Bruker
ARX-300, 300 MHz; Bruker ARX-400, 400 MHz; or Bruker
ARX-600, 600 MHz spectrometers (Bruker Bioscience, Billerica,
MA, USA) with TMS as an internal standard. The IR spectra were re-
corded by means of the KBr pellet technique on a Bruker FTS 135
spectrometer. Elemental analysis was determined on a Carlo-Erba
1106 Elemental analysis instrument (Carlo Erba, Milan, Italy).
7.2. General procedure for preparation of 1-
substitutedphenylureas (25a–25h)
To the mixture of an appropriately substituted phenylamine
(0.43 mol), glacial acetic acid (120 mL) and H2O (120 mL), and
sodium cyanate (0.86 mol) was added slowly at room temperature.
Upon the completion of addition, the reaction mixture was stirred
at 40 °C for 2–4 h and monitored by thin-layer chromatography
(TLC). The reaction mixture was poured into water (500 mL) and
stirred for 0.5 h; the precipitated was collected by filtration and
dried to give the corresponding substituted phenylureas 25a–25h
as white solids.
7.1. General procedure for preparation of 3-fluoro-4-(6,7-
disubstituted quinolin-4-yloxy)anilines (23a–23e)
The preparation of the key intermidiates 23a–23e has been
illustrated in detail in our previous work,41,42 and so the synthesis
method would not be listed here.
7.2.1. 1-Phenylurea (25a)
Yield: 82%; mp 257–258 °C; IR (KBr) cmꢀ1: 3429.8, 3414.2,
2919.2, 2850.5, 1655.8, 1614.3, 1592.4, 1554.3, 1449.2, 1127.6,

Q. Tang et al. / Bioorg. Med. Chem. 22 (2014) 1236–1249
1243
696.9, 620.2, 588.5; 1H NMR (400 MHz, DMSO-d6) d 8.51 (s, 1H),
7.40 (d, J = 7.9 Hz, 2H), 7.21 (t, J = 7.8 Hz, 2H), 6.89 (t, J = 7.3 Hz,
1H), 5.86 (s, 2H); MS m/z (ESI): 159.1 [M+Na]+.
7.3.3. 1-(2,6-Dimethylphenyl)pyrimidine-2,4,6-trione (26c)
Yield: 73%; mp 214–217 °C; 1H NMR (400 MHz, DMSO-d6) d
11.62 (s, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.13 (d, J = 7.4 Hz, 2H), 3.90
(s, 2H), 2.06 (s, 6H); MS m/z (ESI): 233.4 [M+H]+.
7.2.2. 1-p-Tolylurea (25b)
Yield: 85%; mp 242–243 °C; 1H NMR (400 MHz, DMSO-d6) d
8.39 (s, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 8.1 Hz, 2H), 5.78
(s, 2H), 2.21 (s, 3H); MS m/z (ESI): 151.2 [M+H]+, 173.4 [M+Na]+.
7.3.4. 1-(4-Fluorophenyl)pyrimidine-2,4,6-trione (26d)
Yield: 76%; mp 221–222 °C; IR (KBr) cmꢀ1: 3439.0, 3204.0,
3151.5, 3084.9, 2885.7, 1730.5, 1689.2, 1511.2, 1430.3, 1345.2,
1244.7, 1209.2, 843.3, 722.0, 539.2, 500.3; 1H NMR (400 MHz,
DMSO-d6) d 11.54 (s, 1H), 7.29 (d, J = 6.8 Hz, 4H), 3.74 (s, 2H); MS
m/z (ESI): 223.5 [M+H]+.
7.2.3. 1-(2,6-Dimethylphenyl)urea (25c)
Yield: 82%; mp 229–230 °C; 1H NMR (400 MHz, DMSO-d6) d
7.53 (s, 1H), 7.03–6.95 (m, 3H), 5.70 (s, 2H), 2.17 (s, 6H); MS m/z
(ESI): 165.4 [M+H]+.
7.3.5. 1-(2,4-Difluorophenyl)pyrimidine-2,4,6-trione (26e)
Yield: 70%; mp 228–229 °C; 1H NMR (400 MHz, DMSO-d6) d
11.64 (s, 1H), 7.45 (s, 2H), 7.16 (s, 1H), 3.75 (s, 2H); MS m/z
(ESI): 241.6 [M+H]+, 263.2 [M+Na]+.
7.2.4. 1-(4-Fluorophenyl)urea (25d)
Yield: 86%; mp 245–246 °C; 1H NMR (400 MHz, DMSO-d6) d
8.56 (s, 1H), 7.48–7.31 (m, 2H), 7.04 (t, J = 8.9 Hz, 2H), 5.84 (s,
2H).MS m/z (ESI): 151.2 [M+H]+.
7.3.6. 1-(3-Chloro-4-fluorophenyl)pyrimidine-2,4,6-trione (26f)
Yield: 74%; mp 224–225 °C; 1H NMR (400 MHz, DMSO-d6) d
11.61 (s, 1H), 7.69–7.41 (m, 2H), 7.30 (ddd, J = 8.7, 4.3, 2.5 Hz,
1H), 3.73 (s, 2H); MS m/z (ESI): 256.9 [MꢀH]ꢀ.
7.2.5. 1-(2,4-Difluorophenyl)urea (25e)
Yield: 85%; mp 243–244 °C; 1H NMR (400 MHz, DMSO-d6) d
8.76 (s, 1H), 7.74–7.52 (m, 1H), 7.32–7.18 (m, 1H), 7.08–6.92 (m,
1H), 5.97 (s, 2H); MS m/z (ESI): 173.1 [M+H]+, 367.2 [2M+Na]+.
7.3.7. 1-(2-(Trifluoromethyl)phenyl)pyrimidine-2,4,6-trione
(26g)
7.2.6. 1-(3-Chloro-4-fluorophenyl)urea (25f)
Yield: 81%; mp 235–236 °C; 1H NMR (400 MHz, DMSO-d6) d
8.84 (s, 1H), 7.78 (dd, J = 6.9, 2.4 Hz, 1H), 7.30–7.16 (m, 2H), 6.00
(s, 2H); MS m/z (ESI): 189.6 [M+H]+.
Yield: 72%; mp 223–224 °C; 1H NMR (400 MHz, DMSO-d6) d
11.72 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.68
(t, J = 7.5 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 4.08 (d, J = 21.1 Hz, 1H),
3.67 (d, J = 21.1 Hz, 1H); MS m/z (ESI): 297.3 [M+Na]+.
7.2.7. 1-(2-(Trifluoromethyl)phenyl)urea (25g)
Yield: 83%; mp 234–236 °C; IR (KBr) cmꢀ1: 3437.5, 3340.3,
2919.1, 2850.5, 1656.2, 1617.8, 1590.2, 1522.1, 1321.0, 1109.1,
761.1, 649.7, 597.6; 1H NMR (400 MHz, DMSO-d6) d 7.94 (d,
J = 8.2 Hz, 1H), 7.81 (s, 1H), 7.63–7.49 (m, 2H), 7.18 (t, J = 7.6 Hz,
1H), 6.39 (s, 2H); MS m/z (ESI): 205.3 [M+H]+.
7.3.8. 1-(4-Chloro-2,5-dimethoxyphenyl)pyrimidine-2,4,6-
trione (26h)
Yield: 73%; mp 214–215 °C; 1H NMR (400 MHz, DMSO-d6) d
11.53 (s, 1H), 7.16 (s, 1H), 7.02 (s, 1H), 3.72 (s, 3H), 3.64 (s, 3H),
3.72 (s, 2H); MS m/z (ESI): 299.5 [M+H]+.
7.2.8. 1-(4-Chloro-2,5-dimethoxyphenyl)urea (25h)
Yield: 84%; mp 213–214 °C; 1H NMR (400 MHz, DMSO-d6) d
7.91 (s, 1H), 7.58 (s, 1H), 7.06 (s, 1H), 6.19 (s, 2H), 3.70 (s, 3H),
3.62 (s, 3H); MS m/z (ESI): 231.4 [M+H]+.
7.4. General procedure for preparation of 5-
((dimethylamino)methylene)-1-substitutedphenylpyrimidine-
2,4,6-triones (27a–27h)
7.3. General procedure for preparation of 1-
substitutedphenylpyrimidine-2,4,6-triones (26a–26h)
A mixture of an appropriately 1-substituted phenylpyrimidine-
2,4,6-trione (0.05 mol) and DMF-DMA (66 mL, 0.5 mol) was heated
at 50 °C for 6–10 h and monitored by TLC. Upon cooling the
reaction mixture to room temperature, the precipitate was
collected by filtration, washed with Et2O (40 mL), and dried to give
the corresponding 5-((dimethylamino)methylene)-1-substituted-
phenylpyrimidine-2,4,6-triones as yellow solids.
Sodium (7.4 g, 0.32 mol) was added into anhydrous EtOH
(300 mL) in batches in an ice bath. After disappearance of the solid
sodium in anhydrous EtOH, an appropriate substituted phenylurea
(0.16 mol) and dimethyl malonate (20.2 g, 0.19 mol) was added
slowly at room temperature and stirred for 0.5 h. The reaction mix-
ture then was stirred at reflux for 8–12 h and monitored by TLC.
The solvent was concentrated in a vacuum and the residue was re-
solved with water (400 mL), acidified with hydrochloric acid to pH
2, and stirred for 0.5 h. The precipitated was collected by filtration
and dried to give the corresponding 4-substitutedphenylpyrimi-
dine-2,4,6-triones at moderate yield.
7.4.1. (E)-5-((Dimethylamino)methylene)-1-phenylpyrimidine-
2,4,6-trione (27a)
Yield: 71%; mp 292–293 °C; 1H NMR (400 MHz, DMSO-d6) d
8.12 (s, 1H), 7.32–7.11 (m, 5H), 3.43 (s, 3H), 3.24 (s, 3H); MS m/z
(ESI): 282.4 [M+Na]+.
7.4.2. (E)-5-((Dimethylamino)methylene)-1-p-tolylpyrimidine-
2,4,6-trione (27b)
7.3.1. 1-Phenylpyrimidine-2,4,6-trione (26a)
Yield: 76%; mp 247–248 °C; 1H NMR (400 MHz, DMSO-d6) d
11.58 (s, 1H), 7.43–7.26 (m, 5H), 3.73 (s, 2H); MS m/z (ESI):
205.2 [M+H]+.
Yield: 69%; mp 287–288 °C; 1H NMR (400 MHz, DMSO-d6) d
8.12 (s, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 3.43
(s, 3H), 3.24 (s, 3H), 2.34 (s, 3H); MS m/z (ESI): 274.1 [M+H]+.
7.3.2. 1-p-Tolylpyrimidine-2,4,6-trione (26b)
Yield: 71%; mp 235–237 °C; IR (KBr) cmꢀ1: 3437.2, 3204.5,
3153.9, 3086.6, 2882.9, 1730.4, 1686.0, 1515.5, 1428.8, 1342.4,
1209.3, 822.1, 718.8, 627.5, 483.2; 1H NMR (400 MHz, DMSO-d6)
d 11.47 (s, 1H), 7.25 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H),
3.72 (s, 2H), 2.35 (s, 3H); MS m/z (ESI): 217.1 [MꢀH]ꢀ.
7.4.3. (E)-5-((Dimethylamino)methylene)-1-(2,6-
dimethylphenyl)pyrimidine-2,4,6-trione (27c)
Yield: 73%; mp 275–276 °C; 1H NMR (400 MHz, DMSO-d6) d
8.12 (s, 1H), 7.21–7.06 (m, 3H), 3.43 (s, 3H), 3.24 (s, 3H); MS m/z
(ESI): 288.3 [M+H]+, 310.6 [M+Na]+.

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Q. Tang et al. / Bioorg. Med. Chem. 22 (2014) 1236–1249
7.4.4. (E)-5-((Dimethylamino)methylene)-1-(4-
J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.13 (d,
fluorophenyl)pyrimidine-2,4,6-trione (27d)
J = 7.8 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 8.2 Hz, 1H),
6.42 (d, J = 4.9 Hz, 1H), 4.14 (t, J = 6.3 Hz, 2H), 3.90 (s, 3H), 2.38
(t, J = 7.1 Hz, 2H), 2.31 (br, 4H), 2.28 (s, 3H), 1.98–1.84 (m, 2H),
1.52–1.41 (m, 4H), 1.39–1.28 (m, 2H); MS m/z (ESI): 654.3
[M+H]+, 676.4 [M+Na]+; Anal. Calcd for C36H36FN5O6: C, 66.14; H,
5.55; N, 10.71. Found: C, 66.18; H, 5.59; N, 10.81.
Yield: 71%; mp 283–284 °C; IR (KBr) cmꢀ1: 3434.8, 3178.6,
3060.0, 2919.9, 2849.9, 1721.8, 1676.4, 1644.7, 1518.3, 1432.0,
1384.3, 1285.9, 1144.2, 777.7, 650.1, 617.0, 541.2; 1H NMR
(400 MHz, DMSO-d6) d 10.55 (br, 1H), 8.12 (s, 1H), 7.38–7.19 (m,
4H), 3.43 (s, 3H), 3.24 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H); MS m/z
(ESI): 277.3, 278.3 [M+H]+.
7.5.3. 5-((3-Fluoro-4-(6-methoxy-7-(3-(piperidin-1-
7.4.5. (E)-5-((Dimethylamino)methylene)-1-(2,4-
difluorophenyl)pyrimidine-2,4,6-trione (27e)
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(2,6-
dimethylphenyl)pyrimidine-2,4,6-trione (30)
Yield: 72%; mp 278–279 °C; 1H NMR (400 MHz, DMSO-d6) d
10.51 (br, 1H), 8.12 (s, 1H), 7.47 (s, 2H), 7.13 (s, 1H), 3.43 (s, 3H),
3.24 (s, 3H); MS m/z (ESI): 296.5 [M+H]+.
Yield: 55%; mp 236–237 °C; 1H NMR (300 MHz, DMSO-d6) d
11.88 (br, 1H), 11.36 (br, 1H), 8.62 (br, 1H), 8.44 (d, J = 5.4 Hz,
1H), 7.88 (d, J = 12.5 Hz, 1H), 7.50 (s, 1H), 7.48 (s, 1H), 7.38 (s,
1H), 7.21–7.03 (m, 4H), 6.44 (d, J = 5.2 Hz, 1H), 4.18 (t, J = 6.4 Hz,
2H), 3.90 (s, 3H), 2.87–2.58 (m, 6H), 2.02 (s, 6H), 1.69–1.52 (m,
4H), 1.48–1.34 (m, 2H); 13C NMR (150 MHz, DMSO-d6) d 165.42,
164.56, 162.33, 159.43, 155.30, 153.66, 152.40, 150.14, 150.07,
149.29, 146.89, 138.77, 138.03, 136.44, 133.43, 128.77, 128.47
(2C), 125.16, 116.69, 114.95, 109.20, 108.99, 102.75, 99.43, 93.35,
67.17, 56.24, 55.37, 54.33 (2C), 26.25, 25.67 (2C), 24.19, 17.75
(2C); MS m/z (ESI): 668.1 [M+H]+; Anal. Calcd for C37H38FN5O6: C,
66.55; H, 5.74; N, 10.49. Found: C, 66.57; H, 5.69; N, 10.51.
7.4.6. (E)-5-((Dimethylamino)methylene)-1-(3-chloro-4-
fluorophenyl)pyrimidine-2,4,6-trione (27f)
Yield: 68%; mp 268–269 °C; IR (KBr) cmꢀ1: 3436.3, 3198.8,
3066.5, 2920.0, 2850.5, 1724.3, 1679.8, 1626.9, 1501.0, 1438.1,
1384.5, 1264.1, 1143.7, 776.5, 529.1; 1H NMR (400 MHz, DMSO-
d6) d 8.12 (s, 1H), 7.58 (dd, J = 6.8, 2.4 Hz, 1H), 7.47 (t, J = 9.0 Hz,
1H), 7.29 (ddd, J = 8.7, 4.4, 2.5 Hz, 1H), 3.44 (s, 3H), 3.24 (s, 3H);
MS m/z (ESI): 332.3, 334.0 [M+Na]+, 644.9, 646.0 [2M+Na]+.
7.4.7. (E)-5-((Dimethylamino)methylene)-1-(2-
7.5.4. 5-((3-Fluoro-4-(6-methoxy-7-(3-(piperidin-1-
(trifluoromethyl)phenyl)pyrimidine-2,4,6-trione (27g)
Yield: 70%; mp 270–271 °C; 1H NMR (400 MHz, DMSO-d6) d
8.12 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.67
(t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 3.43 (s, 3H), 3.24 (s,
3H); MS m/z (ESI): 328.5 [M+H]+.
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(4-
fluorophenyl)pyrimidine-2,4,6-trione (31)
Yield: 49%; mp 273–274 °C; IR (KBr) cmꢀ1: 3437.3, 3074.4,
2923.2, 2851.0, 1729.5, 1683.8, 1635.6, 1614.6, 1588.1, 1512.3,
1466.2, 1432.6, 1384.4, 1350.1, 1308.2, 1211.7, 1156.0, 1127.3,
1.17.9, 842.4, 780.8, 618.5, 531.6, 518.1, 428.4; 1H NMR
(300 MHz, DMSO-d6) d 11.81 (br, 1H), 11.30 (br, 1H), 8.58 (br,
1H), 8.44 (d, J = 4.8 Hz, 1H), 7.87 (d, J = 12.1 Hz, 1H), 7.48 (s, 3H),
7.36 (s, 3H), 7.27 (d, J = 7.9 Hz, 2H), 6.44 (d, J = 4.2 Hz, 1H), 4.15
(t, J = 6.6 Hz, 2H), 3.90 (s, 3H), 2.62–2.35 (m, 6H, superposed with
DMSO), 2.02–1.88 (m, 2H), 1.58–1.43 (m, 4H), 1.41–1.27 (m, 2H);
MS m/z (ESI): 658.6 [M+H]+; Anal. Calcd for C35H32F2N5O6: C,
63.92; H, 5.06; N, 10.65. Found: C, 64.02; H, 5.01; N, 10.69.
7.4.8. (E)-5-((Dimethylamino)methylene)-1-(4-chloro-2,5-
dimethoxyphenyl)pyrimidine-2,4,6-trione (27h)
Yield: 71%; mp 264–265 °C; 1H NMR (400 MHz, DMSO-d6) d
8.12 (s, 1H), 7.15 (s, 1H), 7.01 (s, 1H), 3.71 (s, 3H), 3.63 (s, 3H),
3.43 (s, 3H), 3.24 (s, 3H); MS m/z (ESI): 354.4 [M+H]+.
7.5. General procedure for preparation of the target compounds
(28–67)
7.5.5. 5-((3-Fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)
quinolin-4-yloxy)phenylamino)methylene)-1-(2,4-
difluorophenyl)pyrimidine-2,4,6-trione (32)
A mixture of an appropriately 5-((dimethylamino)methylene)-
1-substitutedphenylpyrimidine-2,4,6-trione and glacial acetic acid
was heated at 80 °C for 20–30 h and monitored by TLC. The solvent
was concentrated in a vacuum and the residue was resolved with
dichloromethane (300 mL), washed with 5% Na2CO3 (80 mL ꢁ 5),
brine (80 mL), dried over anhydrous Na2SO4, and concentrated in
a vacuum. The crude product was purified by chromatography on
silica gel using MeOH/CH2Cl2 to afford the white solids 28–67.
Yield: 48%; mp 263–264 °C; 1H NMR (300 MHz, DMSO-d6) d
8.55 (br, 1H), 8.44 (d, J = 5.8 Hz, 1H), 7.68 (s, 1H), 7.56–7.31 (m,
6H), 7.17 (d, J = 7.8 Hz, 1H), 6.42 (d, J = 5.4 Hz, 1H), 4.14 (t,
J = 6.6 Hz, 2H), 3.90 (s, 3H), 2.38 (t, J = 7.2 Hz, 2H), 2.31 (br, 4H),
1.97–1.85 (m, 2H), 1.52–1.41 (m, 4H), 1.39–1.30 (m, 2H); MS m/z
(ESI): 676.4 [M+H]+, 698.6 [M+Na]+; Anal. Calcd for C35H32F3N5O6:
C, 62.22; H, 4.77; N, 10.37. Found: C, 62.28; H, 4.72; N, 10.15.
7.5.1. 5-((3-Fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)
quinolin-4-yloxy)phenylamino)methylene)-1-
phenylpyrimidine-2,4,6-trione (28)
7.5.6. 5-((3-Fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)
quinolin-4-yloxy)phenylamino)methylene)-1-(3-chloro-4-
fluorophenyl)pyrimidine-2,4,6-trione (33)
Yield: 52%; mp 248–249 °C; 1H NMR (300 MHz, DMSO-d6) d
8.54 (br, 1H), 8.44 (d, J = 5.0 Hz, 1H), 7.63 (d, J = 12.4 Hz, 1H),
7.48 (s, 1H), 7.44–7.29 (m, 5H), 7.23 (d, J = 7.0 Hz, 2H), 7.11 (d,
J = 7.8 Hz, 1H), 6.43 (d, J = 5.2 Hz, 1H), 4.14 (t, J = 6.4 Hz, 2H), 3.90
(s, 3H), 2.38 (t, J = 7.0 Hz, 2H), 2.31 (br, 4H), 1.99–1.83 (m, 2H),
1.52–1.41 (m, 4H), 1.39–1.28 (m, 2H); MS m/z (ESI): 640.2
[M+H]+; Anal. Calcd for C35H34FN5O6: C, 65.72; H, 5.36; N, 10.95.
Found: C, 65.56; H, 5.38; N, 10.96.
Yield: 46%; mp 252–253 °C; 1H NMR (300 MHz, DMSO-d6) d
8.51 (br, 1H), 8.43 (d, J = 5.0 Hz, 1H), 7.57 (d, J = 6.8 Hz, 2H),
7.49–7.24 (m, 6H), 6.41 (d, J = 5.2 Hz, 1H)), 4.14 (t, J = 6.7 Hz, 2H),
3.90 (s, 3H), 2.39 (t, J = 6.4 Hz, 2H), 2.30 (br, 4H), 1.98–1.82 (m,
2H), 1.52–1.39 (m, 4H), 1.38–1.26 (m, 2H); MS m/z (ESI): 692.6
[M+H]+, 714.3 [M+Na]+; Anal. Calcd for C35H32ClF2N5O6: C, 60.74;
H, 4.66; N, 10.12. Found: C, 61.02; H, 4.69; N, 10.15.
7.5.2. 5-((3-Fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)
quinolin-4-yloxy)phenylamino)methylene)-1-p-
7.5.7. 5-((3-Fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)
quinolin-4-yloxy)phenylamino)methylene)-1-(2-
tolylpyrimidine-2,4,6-trione (29)
(trifluoromethyl)phenyl)pyrimidine-2,4,6-trione (34)
Yield: 49%; mp 247–248 °C; 1H NMR (300 MHz, DMSO-d6) d
8.51 (br, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.49 (s, 1H), 7.47–7.36 (m,
Yield: 54%; mp 264–265 °C; 1H NMR (300 MHz, DMSO-d6) d
8.49 (br, 1H), 8.43 (d, J = 5.3 Hz, 1H), 7.48 (s, 1H), 7.40 (d,

Q. Tang et al. / Bioorg. Med. Chem. 22 (2014) 1236–1249
1245
5H), 7.35 (s, 1H), 7.24 (s, 1H), 6.42 (d, J = 5.6 Hz, 1H), 4.15 (t,
J = 6.5 Hz, 2H), 3.91 (s, 3H), 2.38 (t, J = 7.1 Hz, 2H), 2.31 (br, 4H),
1.97–1.86 (m, 2H), 1.51–1.40 (m, 4H), 1.39–1.28 (m, 2H); 13C
NMR (150 MHz, DMSO-d6) d 165.43, 164.51, 160.60, 159.60,
152.35, 151.17, 150.56, 150.05, 149.28, 146.77, 145.76, 132.66,
130.69, 129.87, 127.88, 124.72, 121.07, 117.09, 114.89, 110.57,
108.93, 108.87, 106.11, 101.95, 99.44, 95.45, 67.28, 56.23, 55.57,
54.59 (2C), 26.57, 26.08 (2C), 24.62; MS m/z (ESI): 730.6
[M+Na]+; Anal. Calcd for C36H33F4N5O6: C, 61.10; H, 4.70; N, 9.90.
Found: C, 61.14; H, 4.87; N, 10.03.
109.21, 108.99, 102.75, 99.42, 93.35, 67.18, 56.23, 55.19, 53.78
(2C), 34.17 (2C), 30.65, 25.86, 22.17, 11.76 (2C); MS m/z (ESI):
682.4 [M+H]+; Anal. Calcd for C38H40FN5O6: C, 66.95; H, 5.91; N,
10.27. Found: C, 67.08; H, 5.92; N, 10.21.
7.5.12. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(4-
fluorophenyl)pyrimidine-2,4,6-trione (39)
Yield: 47%; mp 247–248 °C; 1H NMR (300 MHz, DMSO-d6) d
8.59 (br, 1H), 8.44 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 12.1 Hz, 1H),
7.49 (s, 1H), 7.47 (s, 1H), 7.38–7.32 (m, 2H), 7.30–7.18 (m, 4H),
6.45 (d, J = 5.1 Hz, 1H), 6.45 (d, J = 5.1 Hz, 1H), 4.14 (t, J = 6.3 Hz,
2H), 3.90 (s, 3H), 2.86 (d, J = 8.8 Hz, 2H), 2.48–2.43 (m, 2H, super-
posed with DMSO), 2.01–1.83 (m, 4H), 1.55 (d, J = 13.4 Hz, 2H),
1.30 (br, 1H), 1.09 (d, J = 13.7, 2H), 0.84 (d, J = 6.4 Hz, 3H); MS m/
z (ESI): 672.7 [M+H]+; Anal. Calcd for C36H35F2N5O6: C, 64.37; H,
5.25; N, 10.43. Found: C, 64.41; H, 5.22; N, 10.31.
7.5.8. 5-((3-Fluoro-4-(6-methoxy-7-(3-(piperidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(4-
chloro-2,5-dimethoxyphenyl)pyrimidine-2,4,6-trione (35)
Yield: 50%; mp 212–213 °C; 1H NMR (300 MHz, DMSO-d6) d
8.44 (br, 1H), 8.42 (d, J = 5.4 Hz, 1H), 7.49 (s, 1H), 7.35 (s, 1H),
7.17 (s, 1H), 7.13 (s, 1H), 7.06–6.98 (m, 2H), 6.95 (s, 1H), 6.40 (d,
J = 5.3 Hz, 1H), 4.14 (s, 2H), 3.90 (d, J = 3.1 Hz, 3H), 3.71 (s, 3H),
3.63 (s, 3H), 2.38 (t, J = 7.1 Hz, 3H), 2.30 (br, 4H), 1.95–1.86 (m,
2H), 1.52–1.41 (m, 4H), 1.38–1.27 (m, 2H); MS m/z (ESI): 734.5
[M+H]+; Anal. Calcd for C37H37ClFN5O8: C, 60.53; H, 5.08; N, 9.54.
Found: C, 60.61; H, 5.09; N, 9.94.
7.5.13. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(2,4-
difluorophenyl)pyrimidine-2,4,6-trione (40)
Yield: 51%; mp 236–237 °C; 1H NMR (300 MHz, DMSO-d6) d
11.79 (br, 1H), 11.37 (br, 1H), 8.62 (br, 1H), 8.47 (d, J = 5.2 Hz,
1H), 7.89 (d, J = 12.6 Hz, 1H), 7.59–7.47 (m, 5H), 7.39 (s, 1H), 7.24
(br, 1H), 6.47 (d, J = 5.1 Hz, 1H), 4.17 (t, J = 6.3 Hz, 2H), 3.93 (s,
3H), 2.95–2.83 (m, 2H), 2.52–2.45 (m, 2H, superposed with DMSO),
2.06–1.88 (m, 4H), 1.58 (d, J = 12.3 Hz, 2H), 1.33 (br, 1H), 1.15 (d,
J = 12.5, 2H), 0.87 (d, J = 6.5 Hz, 3H); MS m/z (ESI): 690.3 [M+H]+,
712.5 [M+Na]+; Anal. Calcd for C36H34F3N5O6: C, 62.69; H, 4.97;
N, 10.15. Found: C, 62.75; H, 5.01; N, 10.06.
7.5.9. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-
phenylpyrimidine-2,4,6-trione (36)
Yield: 54%; mp 251–252 °C; 1H NMR (300 MHz, DMSO-d6) d
8.54 (br, 1H), 8.44 (d, J = 5.4 Hz, 1H), 7.81 (d, J = 12.2 Hz, 1H),
7.48 (s, 1H), 7.45–7.27 (m, 5H), 7.21 (d, J = 7.1 Hz, 2H), 7.09 (d,
J = 7.7 Hz, 1H), 6.43 (d, J = 5.4 Hz, 1H), 4.16 (t, J = 6.4 Hz, 2H), 3.90
(s, 3H), 2.83 (d, J = 10.9 Hz, 2H), 2.41 (t, J = 7.1 Hz, 2H), 1.95–1.89
(m, 2H), 1.84 (t, J = 11.2 Hz, 2H), 1.55 (d, J = 13.7 Hz, 2H), 1.19 (br,
1H), 1.13 (d, J = 12.7, Hz, 2H), 0.85 (d, J = 6.4 Hz, 3H); MS m/z (ESI):
654.3 [M+H]+; Anal. Calcd for C36H36FN5O6: C, 66.14; H, 5.55; N,
10.71. Found: C, 66.08; H, 5.49; N, 10.81.
7.5.14. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(3-
chloro-4-fluorophenyl)pyrimidine-2,4,6-trione (41)
Yield: 48%; mp 225–226 °C; 1H NMR (300 MHz, DMSO-d6) d
8.53 (br, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.61 (dd, J = 6.9, 2.3 Hz, 1H),
7.54–7.25 (m, 7H), 6.43 (d, J = 5.2 Hz, 1H), 4.13 (t, J = 6.2 Hz, 2H),
3.90 (s, 3H), 2.80 (d, J = 11.6 Hz, 2H), 2.39 (t, J = 7.0 Hz, 2H),
1.99–1.87 (m, 2H), 1.82 (t, J = 11.6 Hz, 2H), 1.52 (d, J = 13.2 Hz,
2H), 1.18 (br, 1H), 1.10 (dd, J = 12.2, 9.0 Hz, 2H), 0.84 (d,
J = 6.4 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) d 165.07, 163.87,
162.76, 160.62, 159.47, 155.91, 153.63, 152.27, 150.92, 149.85,
149.33, 146.70, 132.39, 131.09, 129.76, 124.55, 119.50, 116.90,
114.96, 110.63, 109.02, 108.97, 102.06, 99.64, 95.91, 93.88, 67.22,
56.23, 55.07, 53.80 (2C), 34.20 (2C), 30.68, 26.47, 22.20; MS m/z
(ESI): 706.4 [M+H]+; Anal. Calcd for C36H34ClF2N5O6: C, 61.23; H,
4.85; N, 9.92. Found: C, 61.51; H, 4.92; N, 9.99.
7.5.10. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-p-
tolylpyrimidine-2,4,6-trione (37)
Yield: 55%; mp 238–239 °C; IR (KBr) cmꢀ1: 3435.6, 3208.2,
3068.4, 2923.4, 2850.0, 1727.8, 1681.5, 1621.7, 1512.2, 1475.8,
1431.3, 1384.1, 1349.3, 1306.7, 1272.5, 1211.4, 1170.4, 1018.6,
852.3, 778.9, 618.7, 526.9, 429.0; 1H NMR (300 MHz, DMSO-d6) d
8.61 (br, 1H), 8.45 (d, J = 5.4 Hz, 1H), 7.49 (s, 1H), 7.42–7.29 (m,
2H), 7.18 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.04 (d,
J = 8.1 Hz, 2H), 6.96 (d, J = 8.1 Hz, 1H), 6.43 (d, J = 5.2 Hz, 1H),
4.16 (t, J = 6.7 Hz, 2H), 3.90 (s, 3H), 2.82 (d, J = 11.2 Hz, 2H), 2.48–
2.39 (m, 2H, superposed with DMSO), 2.28 (s, 3H), 1.98–1.86 (m,
2H), 1.82 (t, J = 11.6 Hz, 2H), 1.54 (d, J = 12.7 Hz, 2H), 1.25 (br,
1H), 1.10 (d, J = 12.7 Hz, 2H), 0.84 (d, J = 6.4 Hz, 3H); MS m/z
(ESI): 668.1 [M+H]+; Anal. Calcd for C37H38FN5O6: C, 66.55; H,
5.74; N, 10.49. Found: C, 66.62; H, 5.83; N, 10.45.
7.5.15. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(2-
(trifluoromethyl)phenyl)pyrimidine-2,4,6-trione (42)
Yield: 44%; mp 234–235 °C; 1H NMR (300 MHz, DMSO-d6) d
8.45 (br, 1H), 8.43 (d, J = 5.1 Hz, 1H), 7.49 (s, 1H), 7.46–7.30 (m,
7H), 7.05 (d, J = 7.2 Hz, 1H), 6.40 (d, J = 5.1 Hz, 1H), 4.15 (t,
J = 6.4 Hz, 2H), 3.90 (s, 3H), 2.80 (d, J = 10.9 Hz, 2H), 2.39 (t,
J = 7.0 Hz, 2H), 1.94–1.88 (m, 2H), 1.83 (t, J = 11.0 Hz, 2H), 1.53
(d, J = 14.1 Hz, 2H), 1.19 (br, 1H), 1.11 (dd, J = 12.9, 9.1 Hz, 2H),
0.84 (d, J = 6.3 Hz, 3H); MS m/z (ESI): 722.8 [M+H]+, 744.3
[M+Na]+; Anal. Calcd for C37H35F4N5O6: C, 61.58; H, 4.89; N, 9.70.
Found: C, 61.62; H, 4.92; N, 9.91.
7.5.11. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(2,6-
dimethylphenyl)pyrimidine-2,4,6-trione (38)
Yield: 46%; mp 234–235 °C; 1H NMR (300 MHz, DMSO-d6) d
8.60 (br, 1H), 8.48 (d, J = 5.5 Hz, 1H), 7.70 (d, J = 12.4 Hz, 1H),
7.52 (s, 1H), 7.50–7.42 (m, 1H), 7.39 (s, 1H), 7.27–7.05 (m, 4H),
6.46 (d, J = 5.0 Hz, 1H), 4.18 (t, J = 6.4 Hz, 2H), 3.94 (s, 3H), 2.84
(d, J = 10.7 Hz, 2H), 2.43 (t, J = 6.9 Hz, 2H), 2.05 (s, 6H), 1.98–1.90
(m, 2H), 1.85 (t, J = 5.8 Hz, 2H), 1.56 (d, J = 12.6 Hz, 2H), 1.23 (br,
1H), 1.13 (d, J = 12.9 Hz, 2H), 0.88 (d, J = 6.4 Hz, 3H); 13C NMR
(150 MHz, DMSO-d6) d 165.41, 164.56, 162.97, 159.43, 155.30,
153.68, 152.41, 150.14, 150.07, 149.29, 146.88, 138.76, 138.04,
136.43, 133.56, 128.78, 128.47 (2C), 125.16, 116.68, 114.95,
7.5.16. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(4-
chloro-2,5-dimethoxyphenyl)pyrimidine-2,4,6-trione (43)
Yield: 48%; mp 213–214 °C; 1H NMR (300 MHz, DMSO-d6) d
8.45 (br, 1H), 8.38 (d, J = 5.3 Hz, 1H), 7.49 (s, 1H), 7.34 (s, 1H),

1246
Q. Tang et al. / Bioorg. Med. Chem. 22 (2014) 1236–1249
7.32–7.27 (m, 1H), 7.15 (s, 1H), 7.14 (s, 1H), 6.95 (s, 1H), 6.89–6.86
(m, 1H), 6.40 (d, J = 5.2 Hz, 1H), 4.13 (t, J = 6.7 Hz, 2H), 3.91 (s, 3H),
3.71 (s, 3H), 3.63 (s, 3H), 2.79 (d, J = 11.2 Hz, 2H), 2.39 (t, J = 7.1 Hz,
2H), 1.98–1.86 (m, 2H), 1.83 (t, J = 11.4 Hz, 2H), 1.53 (d, J = 13.4 Hz,
2H), 1.28 (br, 1H), 1.12 (d, J = 12.1 Hz, 2H), 0.84 (d, J = 6.4 Hz, 3H);
MS m/z (ESI): 748.6 [M+H]+; Anal. Calcd for C38H39ClFN5O8: C,
61.00; H, 5.25; N, 9.36. Found: C, 61.46; H, 5.32; N, 9.84.
Anal. Calcd for C34H31F2N5O6: C, 63.45; H, 4.85; N, 10.88. Found:
C, 63.46; H, 4.89; N, 10.79.
7.5.21. 5-((3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(2,4-
difluorophenyl)pyrimidine-2,4,6-trione (48)
Yield: 47%; mp 242–243 °C; 1H NMR (300 MHz, DMSO-d6) d
11.43 (br, 2H), 8.59 (br, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.88 (d,
J = 13.0 Hz, 1H), 7.52 (dd, J = 18.3, 7.6 Hz, 5H), 7.37 (s, 1H), 7.22
(d, J = 7.1 Hz, 1H), 6.45 (d, J = 4.9 Hz, 1H), 4.18 (t, J = 6.0 Hz, 2H),
3.90 (s, 3H), 2.73 (br, 2H), 2.65 (br, 4H), 2.06–1.93 (m, 2H), 1.72
(s, 4H); MS m/z (ESI): 662.7 [M+H]+, 684.5 [M+Na]+; Anal. Calcd
for C34H30F3N5O6: C, 61.72; H, 4.57; N, 10.59. Found: C, 62.24; H,
4.62; N, 10.87.
7.5.17. 5-((3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-
phenylpyrimidine-2,4,6-trione (44)
Yield: 51%; mp 236–237 °C; 1H NMR (300 MHz, DMSO-d6) d
11.86 (br, 1H), 11.24 (br, 1H), 8.58 (br, 1H), 8.44 (d, J = 5.2 Hz,
1H), 7.84 (d, J = 12.7 Hz, 1H), 7.49–7.34 (m, 7H), 7.27 (d,
J = 7.1 Hz, 1H), 6.44 (d, J = 4.8 Hz, 1H), 4.17 (s, 2H), 3.90 (s, 3H),
2.74–2.50 (m, 6H), 2.06–1.93 (m, 2H), 1.70 (s, 4H); MS m/z (ESI):
648.3 [M+Na]+; Anal. Calcd for C34H32FN5O6: C, 65.27; H, 5.16; N,
11.19. Found: C, 65.23; H, 5.15; N, 11.26.
7.5.22. 5-((3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(3-
chloro-4-fluorophenyl)pyrimidine-2,4,6-trione (49)
Yield: 45%; mp 215–216 °C; IR (KBr) cmꢀ1: 3440.3, 3062.4,
2920.1, 2850.8, 1728.5, 1682.4, 1641.4, 1590.8, 1501.6, 1464.0,
1432.9, 1384.3, 1350.6, 1307.0, 1258.7, 1212.3, 1170.9, 1130.0,
1018.7, 848.6, 779.2, 618.6, 530.3, 430.0; 1H NMR (300 MHz,
DMSO-d6) d 11.43 (br, 2H), 8.59 (br, 1H), 8.44 (d, J = 5.3 Hz, 1H),
7.88 (d, J = 12.7 Hz, 1H), 7.67 (d, J = 5.4 Hz, 1H), 7.52–7.32
(m, 6H), 6.45 (d, J = 5.1 Hz, 1H), 4.17 (t, J = 6.0 Hz, 2H), 3.90
(s, 3H), 2.73 (s, 2H), 2.65 (s, 4H), 2.09–1.95 (m, 2H), 1.72
(s, 4H); MS m/z (ESI): 678.2 [M+H]+; Anal. Calcd for C34H30ClF2N5
O6: C, 60.22; H, 4.46; N, 10.33. Found: C, 61.83; H, 4.58; N,
10.84.
7.5.18. 5-((3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-p-
tolylpyrimidine-2,4,6-trione (45)
Yield: 50%; mp 225–226 °C; IR (KBr) cmꢀ1: 3435.7, 3207.8,
3069.4, 2922.9, 2850.6, 1728.0, 1682.3, 1621.8, 1511.9, 1475.9,
1431.2, 1384.7, 1349.3, 1306.7, 1211.4, 1171.8, 1138.6, 1019.9,
851.4, 779.0, 618.7, 526.9, 429.4; 1H NMR (600 MHz, DMSO-d6) d
11.84 (br, 1H), 11.30 (br, 1H), 8.61 (br, 1H), 8.47 (d, J = 5.2 Hz,
1H), 7.90 (d, J = 11.2 Hz, 1H), 7.56–7.47 (m, 3H), 7.38 (s, 1H), 7.25
(d, J = 8.0 Hz, 2H), 7.16 (s, 2H), 6.47 (d, J = 5.1 Hz, 1H), 4.19 (t,
J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.62 (br, 2H), 2.51 (br, 4H, superposed
with DMSO), 2.34 (s, 3H), 2.01–1.97 (m, 2H), 1.70 (s, 4H); 13C NMR
(150 MHz, DMSO-d6) d 165.11, 162.95, 162.36, 159.45, 155.35,
153.70, 152.40, 151.12, 150.05, 149.28, 146.88, 138.62, 138.08,
137.94, 129.66 (2C), 129.48 (2C), 125.20, 116.47, 114.93, 108.94,
108.81, 102.74, 99.41, 94.02, 67.09, 56.23, 54.06 (2C), 52.61,
28.17, 23.53 (2C), 21.20; MS m/z (ESI): 640.2 [M+H]+; Anal. Calcd
for C35H34FN5O6: C, 65.72; H, 5.36; N, 10.95. Found: C, 65.59; H,
5.34; N, 10.97.
7.5.23. 5-((3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(2-
(trifluoromethyl)phenyl)pyrimidine-2,4,6-trione (50)
Yield: 48%; mp 225–226 °C; 1H NMR (300 MHz, DMSO-d6) d
8.45 (br, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.49 (s, 1H), 7.47–7.23 (m,
9H), 7.06 (d, J = 7.9 Hz, 1H), 6.41 (d, J = 5.3 Hz, 1H), 4.16 (t,
J = 6.5 Hz, 2H), 3.91 (s, 3H), 2.53 (t, J = 7.1 Hz, 2H), 2.42 (br, 4H),
2.00–1.88 (m, 2H), 1.65 (s, 4H); MS m/z (ESI): 694.4 [M+H]+; Anal.
Calcd for C35H31F4N5O6: C, 60.60; H, 4.50; N, 10.10. Found: C,
61.02; H, 4.58; N, 10.16.
7.5.19. 5-((3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(2,6-
dimethylphenyl)pyrimidine-2,4,6-trione (46)
7.5.24. 5-((3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(4-
chloro-2,5-dimethoxyphenyl)pyrimidine-2,4,6-trione (51)
Yield: 49%; mp 203–204 °C; 1H NMR (300 MHz, DMSO-d6) d
8.44 (br, 1H), 8.42 (d, J = 5.4 Hz, 1H), 7.49 (s, 1H), 7.34 (s, 1H),
7.17 (s, 1H), 7.13 (s, 1H), 7.01 (s, 2H), 6.94 (s, 1H), 6.40 (d,
J = 5.3 Hz, 1H), 4.17 (t, J = 6.1 Hz, 2H), 3.91 (s, 3H), 3.73 (s, 3H),
3.65 (s, 3H), 2.52 (t, J = 7.1 Hz, 3H), 2.41 (br, 4H), 1.98–1.89 (m,
2H), 1.68–1.60 (m, 4H); MS m/z (ESI): 742.2 [M+Na]+; Anal. Calcd
for C36H35ClFN5O8: C, 60.04; H, 4.90; N, 9.72. Found: C, 60.16; H,
5.01; N, 9.78.
Yield: 52%; mp 214–215 °C; 1H NMR (300 MHz, DMSO-d6) d
11.83 (br, 1H), 11.40 (br, 1H), 8.62 (br 1H), 8.45 (d, J = 5.2 Hz,
1H), 7.87 (d, J = 13.1 Hz, 1H), 7.50 (s, 1H), 7.48 (s, 1H), 7.38 (s,
1H), 7.23–7.04 (m, 4H), 6.45 (d, J = 5.3 Hz, 1H), 4.21 (t, J = 6.1 Hz,
2H), 3.91 (s, 3H), 2.98 (br, 6H), 2.19–2.08 (m, 2H), 2.02 (s, 6H),
1.82 (s, 4H); 13C NMR (150 MHz, DMSO-d6) d 165.42, 164.56,
162.97, 159.43, 155.30, 153.69, 152.40, 150.14, 150.07, 149.29,
146.88, 138.75, 138.04, 136.43, 133.43, 128.78, 128.47 (2C),
125.16, 116.68, 114.95, 109.21, 108.98, 102.75, 99.43, 93.35,
67.15, 56.27, 54.07 (2C), 52.72, 26.26, 23.56 (2C), 17.74 (2C); MS
m/z (ESI): 654.8 [M+H]+; Anal. Calcd for C36H36FN5O6: C, 66.14;
H, 5.55; N, 10.71. Found: C, 66.09; H, 5.52; N, 10.86.
7.5.25. 5-((3-Fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yloxy)phenylamino)methylene)-1-phenylpyrimidine-
2,4,6-trione (52)
7.5.20. 5-((3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(4-
fluorophenyl)pyrimidine-2,4,6-trione (47)
Yield: 49%; mp 231–232 °C; 1H NMR (300 MHz, DMSO-d6) d
8.45 (br, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.48 (s, 1H), 7.44–7.25 (m,
6H), 7.17 (d, J = 7.0 Hz, 2H), 7.08 (d, J = 6.4 Hz, 1H), 6.41 (d,
J = 5.1 Hz, 1H), 4.15 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.54 (s, 4H),
2.47–2.38 (m, 2H, superposed with DMSO), 2.34 (br, 4H),
2.03–1.88 (m, 2H); MS m/z (ESI): 642.7 [M+H]+, 664.4 [M+Na]+;
Anal. Calcd for C34H32FN5O7 C, 63.64; H, 5.03; N, 10.91. Found: C,
63.68; H, 5.11; N, 10.98.
Yield: 49%; mp 231–232 °C; 1H NMR (300 MHz, DMSO-d6) d
8.61 (br, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.89 (d, J = 12.8 Hz, 1H),
7.50 (d, J = 5.9 Hz, 2H), 7.39 (s, 1H), 7.36 (s, 1H), 7.29 (t,
J = 8.7 Hz, 2H), 7.23 (dd, J = 6.8, 4.5 Hz, 2H), 6.48 (d, J = 5.1 Hz,
1H), 4.20 (t, J = 6.1 Hz, 2H), 3.93 (s, 3H), 2.69 (br, 2H), 2.60 (br,
4H), 2.09–1.98 (m, 2H), 1.72 (s, 4H); MS m/z (ESI): 644.1 [M+H]+;

Q. Tang et al. / Bioorg. Med. Chem. 22 (2014) 1236–1249
1247
7.5.26. 5-((3-Fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yloxy)phenylamino)methylene)-1-p-tolylpyrimidine-
2,4,6-trione (53)
2.04–1.85 (m, 2H); MS m/z (ESI): 678.7 [M+H]+; Anal. Calcd for C34-
H30F3N5O7: C, 60.26; H, 4.46; N, 10.34. Found: C, 60.41; H, 4.50; N,
10.42.
Yield: 52%; mp 258–259 °C; IR (KBr) cmꢀ1: 3441.6, 3061.2,
2921.4, 2851.5, 1724.8, 1679.3, 1658.5, 1587.0, 1510.7, 1477.1,
1433.1, 1384.4, 1351.4, 1307.8, 1212.9, 1174.1, 1118.7, 1009.5,
850.5, 779.2, 619.1, 524.8, 514.6, 429.2; 1H NMR (600 MHz,
DMSO-d6) d 12.01 (d, J = 12.6 Hz, 0.42H), 11.86 (d, J = 13.4 Hz,
0.57H), 11.41 (s, 0.42H), 11.26 (s, 0.57H), 8.64 (d, J = 13.4 Hz, 1H),
8.57 (d, J = 12.6 Hz, 0.42H), 8.47 (d, J = 5.2 Hz, 1H), 7.90 (d,
J = 11.9 Hz, 1H), 7.51 (br, 2H), 7.50 (s, 1H), 7.39 (s, 1H), 7.25 (t,
J = 8.9 Hz, 2H), 7.18 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H),
6.47 (d, J = 5.4 Hz, 1H), 4.18 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 3.57
(s, 4H), 2.45 (t, J = 7.0 Hz, 2H), 2.37 (br, 4H), 2.34 (s, 3H),
2.00–1.93 (m, 2H); 13C NMR (150 MHz, DMSO-d6) d 165.03,
162.96, 162.52, 159.09, 154.99, 153.34, 152.65, 152.08, 150.75,
149.72, 148.90, 146.54, 138.29, 137.67, 129.30 (2C), 129.14 (2C),
124.83, 116.03, 114.58, 108.61 (2C), 102.38, 99.08, 93.67, 66.78,
66.32 (2C), 55.86, 54.92, 53.48 (2C), 25.78, 20.84; MS m/z (ESI):
656.1 [M+H]+, 678.2 [M+Na]+; Anal. Calcd for C35H34FN5O7: C,
64.11; H, 5.23; N, 10.68. Found: C, 64.15; H, 5.31; N, 10.72.
7.5.30. 5-((3-Fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yloxy)phenylamino)methylene)-1-(3-chloro-4-
fluorophenyl)pyrimidine-2,4,6-trione (57)
Yield: 47%; mp 208–209 °C; 1H NMR (300 MHz, DMSO-d6) d
8.59 (br, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 13.0 Hz, 1H),
7.73–7.39 (m, 6H), 7.36 (s, 1H), 6.45 (d, J = 4.7 Hz, 1H), 4.16 (t,
J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.55 (s, 4H), 2.48–2.41 (m, 2H, super-
posed with DMSO), 2.36 (s, 4H), 2.03–1.84 (m, 2H); MS m/z (ESI):
694.2 [M+H]+; Anal. Calcd for C34H30ClF2N5O7: C, 58.84; H, 4.36;
N, 10.09. Found: C, 58.92; H, 4.39; N, 10.11.
7.5.31. 5-((3-Fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yloxy)phenylamino) methylene)-1-(2-
(trifluoromethyl)phenyl)pyrimidine-2,4,6-trione (58)
Yield: 48%; mp 247–248 °C; 1H NMR (300 MHz, DMSO-d6) d
11.60 (br, 2H), 8.60 (br, 1H), 8.44 (d, J = 5.3 Hz, 1H), 7.83 (d,
J = 12.0 Hz, 1H), 7.56–7.43 (m, 7H), 7.36 (s, 1H), 6.44 (d,
J = 5.4 Hz, 1H), 4.14 (t, J = 6.5 Hz, 2H), 3.90 (s, 3H), 3.54 (s, 4H),
2.47–2.38 (m, 2H, superposed with DMSO), 2.34 (br, 4H),
2.01–1.83 (m, 2H); 13C NMR (150 MHz, DMSO-d6) d 164.80,
163.64, 160.62, 159.46, 155.71, 153.54, 152.48, 150.29, 150.13,
149.25, 146.94, 145.61, 138.78, 132.56, 130.94, 128.11, 125.05,
121.37, 119.15, 116.77, 115.00, 109.23, 109.02, 102.78, 99.49,
93.14, 67.17, 66.69 (2C), 56.21, 55.27, 53.84 (2C), 26.16; MS m/z
(ESI): 710.6 [M+H]+, 734.8 [M+Na]+; Anal. Calcd for C35H31F4N5O7:
C, 69.24; H, 4.40; N, 9.87. Found: C, 69.31; H, 4.38; N, 9.96.
7.5.27. 5-((3-Fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yloxy)phenylamino)methylene)-1-(2,6-
dimethylphenyl)pyrimidine-2,4,6-trione (54)
Yield: 51%; mp 262–263 °C; 1H NMR (600 MHz, DMSO-d6) d
12.06 (d, J = 13.7 Hz, 0.43H), 11.91 (d, J = 14.1 Hz, 0.57H), 11.55
(s, 0.43H), 11.41 (s, 0.57H), 8.69 (d, J = 14.1 Hz, 0.57H), 8.61 (d,
J = 13.7 Hz, 0.43H), 8.48 (d, J = 5.4 Hz, 1H), 7.92 (t, J = 9.7 Hz, 1H),
7.58–7.45 (m, 3H), 7.40 (s, 1H), 7.26–7.12 (m, 3H), 6.47 (dd,
J = 11.8, 5.1 Hz, 1H), 4.19 (t, J = 6.6 Hz, 2H), 3.93 (s, 3H), 3.58 (br,
4H), 2.45 (br, 2H), 2.37 (br, 4H), 2.06 (s, 3H), 2.04 (s, 3H), 1.97
(br, 2H); 13C NMR (150 MHz, DMSO-d6) d 165.39, 164.56, 162.97,
159.43, 155.30, 153.71, 152.41, 150.14, 150.06, 149.29, 146.88,
138.74, 138.04, 136.43, 133.43, 128.78, 128.47 (2C), 125.16,
116.60, 114.94, 109.22, 108.98, 102.75, 99.42, 93.35, 67.09, 66.64
(2C), 56.24, 55.23, 53.82 (2C), 25.98, 17.76, 17.68; MS m/z (ESI):
670.6 [M+H]+; Anal. Calcd for C36H36FN5O7: C, 64.56; H, 5.42; N,
10.46. Found: C, 64.52; H, 5.39; N, 10.56.
7.5.32. 5-((3-Fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yloxy)phenylamino)methylene)-1-(4-chloro-2,5-
dimethoxyphenyl)pyrimidine-2,4,6-trione (59)
Yield: 44%; mp 208–209 °C; 1H NMR (300 MHz, DMSO-d6)
d
8.53 (br, 1H), 8.43 (d, J = 5.4 Hz, 1H), 7.48 (s, 1H), 7.35 (s, 1H),
7.32 (s, 1H), 7.18 (s, 1H), 7.14 (s, 1H), 7.03 (s, 1H), 6.98 (s, 1H),
6.43 (d, J = 5.4 Hz, 1H), 4.15 (t, J = 6.7 Hz, 2H), 3.90 (s, 3H), 3.71
(s, 3H), 3.63 (s, 3H), 3.55 (s, 4H), 2.50–2.42 (m, 2H, superposed with
DMSO), 2.37 (s, 4H), 2.04–1.85 (m, 2H); MS m/z (ESI): 736.3
[M+H]+; Anal. Calcd for C36H35ClFN5O9: C, 58.74; H, 4.79; N, 9.51.
Found: C, 58.68; H, 4.82; N, 9.57.
7.5.28. 5-((3-Fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yloxy)phenylamino)methylene)-1-(4-fluorophenyl)
pyrimidine-2,4,6-trione (55)
Yield: 48%; mp 267–268 °C; 1H NMR (300 MHz, DMSO-d6) d
8.60 (br, 1H), 8.44 (d, J = 5.0 Hz, 1H), 7.87 (d, J = 11.7 Hz, 1H),
7.48 (s, 1H), 7.47 (s, 1H), 7.37 (s, 1H), 7.32–7.17 (m, 5H), 6.45
(d, J = 5.0 Hz, 1H), 4.16 (t, J = 6.3 Hz, 2H), 3.90 (s, 3H), 3.59–3.49
(m, 4H), 2.49–2.41 (m, 2H, superposed with DMSO), 2.36
(s, 4H), 2.02–1.83 (m, 2H); 13C NMR (150 MHz, DMSO-d6) d
165.36, 162.94, 162.09, 161.09, 159.45, 155.33, 153.69, 152.42,
151.08, 150.07, 149.27, 146.87, 138.67, 138.01, 131.90 (2c),
125.19, 116.08, 115.90, 115.72, 114.94, 108.95, 108.81,
102.75, 99.43, 94.01, 89.56, 67.12, 66.57 (2C), 56.22, 55.24,
53.76 (2C), 26.03; MS m/z (ESI): 660.5 [M+H]+; Anal. Calcd for
7.5.33. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-
phenylpyrimidine-2,4,6-trione (60)
Yield: 50%; mp 226–227 °C; 1H NMR (300 MHz, DMSO-d6) d
8.56 (br, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 12.2 Hz, 1H),
7.48 (s, 1H), 7.43–7.24 (m, 5H), 7.25 (d, J = 7.1 Hz, 2H), 7.07 (d,
J = 7.7 Hz, 1H), 6.43 (d, J = 5.4 Hz, 1H), 4.14 (t, J = 6.4 Hz, 2H), 3.90
(s, 3H), 2.53–2.31 (m, 10H, superposed with DMSO), 2.14 (s, 3H),
1.98–1.89 (m, 2H); MS m/z (ESI): 655.8 [M+H]+; Anal. Calcd for
C35H35FN6O6: C, 64.21; H, 5.39; N, 12.84. Found: C, 64.18; H,
5.41; N, 12.78.
C34H31F2N5O7: C, 61.91; H, 4.74; N, 10.62. Found: C, 62.01; H,
4.68; N, 10.53.
7.5.34. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-p-
tolylpyrimidine-2,4,6-trione (61)
7.5.29. 5-((3-Fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yloxy)phenylamino)methylene)-1-(2,4-
difluorophenyl)pyrimidine-2,4,6-trione (56)
Yield: 56%; mp 243–244 °C; IR (KBr) cmꢀ1: 3435.2, 3208.7,
2921.1, 2850.0, 2797.8, 1727.5, 1679.6, 1621.9, 1513.3, 1476.3,
1431.6, 1385.0, 1349.4, 1306.4, 1273.4, 1211.6, 1169.5, 1013.9,
853.1, 778.8, 618.6, 527.0, 428.8; 1H NMR (300 MHz, DMSO-d6) d
8.43 (br, 1H), 8.41 (d, J = 5.3 Hz, 1H), 7.49 (s, 1H), 7.34 (s, 1H),
7.30 (d, J = 8.8 Hz, 1H), 7.22–7.11 (m, 3H), 7.01 (d, J = 8.2 Hz, 2H),
6.96 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 5.1 Hz, 1H), 4.15 (t, J = 6.0 Hz,
2H), 3.90 (s, 3H), 2.42–2.19 (m, 13H), 2.10 (s, 3H), 1.95–1.87 (m,
Yield: 50%; mp 235–236 °C; 1H NMR (300 MHz, DMSO-d6) d
12.00 (br, 0.40H), 11.77 (br, 0.59H), 11.48 (s, 0.43H), 11.32 (s,
0.57H), 8.59 (br, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.89 (d, J = 13.0 Hz,
1H), 7.61–7.42 (m, 5H), 7.37 (s, 1H), 7.27–7.14 (m, 1H), 6.45 (d,
J = 4.9 Hz, 1H), 4.16 (t, J = 6.1 Hz, 2H), 3.90 (s, 3H), 3.55 (s, 4H),
2.50–2.42 (m, 2H, superposed with DMSO), 2.37 (s, 4H),

1248
Q. Tang et al. / Bioorg. Med. Chem. 22 (2014) 1236–1249
2H); 13C NMR (150 MHz, DMSO-d6) d 165.16, 162.92, 162.37,
159.56, 155.35, 153.82, 152.48, 151.29, 150.11, 149.27, 146.91,
137.73, 129.81, 129.59 (2C), 129.54 (2C), 129.36, 124.93, 116.75,
114.98, 109.18, 109.01, 102.70, 101.99, 99.51, 67.23, 56.24, 55.25
(2H), 54.82, 53.20 (2H), 46.20, 26.53, 21.15; MS m/z (ESI): 669.4
[M+H]+; Anal. Calcd for C36H37FN6O6: C, 64.66; H, 5.58; N, 12.57.
Found: C, 64.53; H, 5.46; N, 12.59.
7.5.40. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(4-
chloro-2,5-dimethoxyphenyl)pyrimidine-2,4,6-trione (67)
Yield: 45%; mp 225–226 °C; 1H NMR (300 MHz, DMSO-d6) d 8.53
(br, 1H), 8.44 (d, J = 5.3 Hz, 1H), 7.48 (s, 1H), 7.44–7.39 (m, 1H), 7.35
(s, 1H), 7.21 (s, 1H), 7.12 (s, 2H), 6.94–6.91 (m, 1H), 6.42 (d, J = 5.4 Hz,
1H), 4.14 (t, J = 6.7 Hz, 2H), 3.90 (s, 3H), 3.73 (s, 3H), 3.67 (s, 3H),
2.43–2.19 (m, 10H), 2.10 (s, 3H), 1.97–1.86 (m, 2H); MS m/z (ESI):
749.3 [M+H]+; Anal. Calcd for C37H38ClFN6O8: C, 59.32; H, 5.11; N,
11.22. Found: C, 59.39; H, 5.25; N, 11.24.
7.5.35. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(2,6-
dimethylphenyl)pyrimidine-2,4,6-trione (62)
Yield: 55%; mp 251–252 °C; 1H NMR (300 MHz, DMSO-d6) d
8.62 (br, 1H), 8.45 (d, J = 5.4 Hz, 1H), 7.88 (d, J = 12.4 Hz, 1H),
7.51 (s, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.22–7.02 (m, 4H), 6.44 (d,
J = 5.2 Hz, 1H), 4.18 (t, J = 6.2 Hz, 2H), 3.90 (s, 3H), 2.51–2.29 (m,
10H, superposed with DMSO), 2.15 (s, 3H), 2.06 (s, 6H), 2.01–
1.91 (m, 2H); 13C NMR (150 MHz, DMSO-d6) d 165.42, 164.56,
162.97, 159.43, 155.30, 153.68, 152.41, 150.14, 150.07, 149.29,
146.89, 138.75, 138.03, 136.44, 133.43, 128.77, 128.47 (2C),
125.16, 116.68, 114.95, 109.21, 108.99, 102.75, 99.43, 93.35,
67.40, 56.20, 55.21 (2C), 54.79, 53.16 (2C), 46.15, 26.42, 17.74
(2C); MS m/z (ESI): 707.3 [M+Na]+; Anal. Calcd for C35H39FN6O6:
C, 65.09; H, 5.76; N, 12.31. Found: C, 65.12; H, 5.65; N, 12.27.
Acknowledgments
This work was supported by National Natural Science
Foundation of China (NSFC No. 81102470) and Liaoning Science
and Technology Program (No. 2011412004-3).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2014.01.014.
References and notes
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7.5.36. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(4-
fluorophenyl)pyrimidine-2,4,6-trione (63)
Yield: 50%; mp 262–263 °C; 1H NMR (300 MHz, DMSO-d6) d
11.76 (br, 1H), 11.24 (br, 1H), 8.58 (br, 1H), 8.47 (d, J = 5.0 Hz,
1H), 7.86 (d, J = 12.0 Hz, 1H), 7.52–7.41 (m, 4H), 7.35–7.21 (m,
4H), 6.46 (d, J = 5.0 Hz, 1H), 4.17 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H),
2.96–2.48 (m, 13H, superposed with DMSO), 2.07–1.89 (m, 2H);
MS m/z (ESI): 673.5 [M+H]+; Anal. Calcd for C35H34F2N6O6: C,
62.49; H, 5.09; N, 12.49. Found: C, 62.56; H, 5.13; N, 12.53.
7.5.37. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(2,4-
difluorophenyl)pyrimidine-2,4,6-trione (64)
Yield: 51%; mp 271–272 °C; 1H NMR (300 MHz, DMSO-d6) d 8.55
(br, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.54–7.41 (m, 5H), 7.38 (s, 1H), 7.18
(s, 1H), 7.05 (s, 1H), 6.45 (d, J = 5.3 Hz, 1H), 4.17 (t, J = 6.5 Hz, 2H),
3.93 (s, 3H), 2.47–2.20 (m, 10H), 2.13 (s, 3H), 1.97–1.92 (m, 2H);
MS m/z (ESI): 691.6 [M+H]+; Anal. Calcd for C35H33F3N6O6: C,
60.86; H, 4.28; N, 12.17. Found: C, 60.98; H, 4.35; N, 12.05.
7.5.38. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(3-
chloro-4-fluorophenyl)pyrimidine-2,4,6-trione (65)
Yield: 46%; mp 241–242 °C; 1H NMR (300 MHz, DMSO-d6) d
8.61 (br, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 12.1 Hz, 1H),
7.68 (br, 1H), 7.58–7.42 (m, 5H), 7.38 (s, 1H), 6.47 (d, J = 5.1 Hz,
1H), 4.17 (t, J = 6.3 Hz, 2H), 3.92 (s, 3H), 2.55–2.30 (m, 10H, super-
posed with DMSO), 2.19 (s, 3H), 1.99–1.91 (m, 2H); MS m/z (ESI):
707.3 [M+H]+, 729.6 [M+Na]+; Anal. Calcd for C35H33ClF2N6O6: C,
59.45; H, 4.76; N, 11.88. Found: C, 60.02; H, 4.82; N, 11.54.
7.5.39. 5-((3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yloxy)phenylamino)methylene)-1-(2-
(trifluoromethyl)phenyl)pyrimidine-2,4,6-trione (66)
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d 8.47 (br, 1H), 8.43 (d, J = 5.3 Hz, 1H), 7.50–7.33 (m, 8H),
7.12–6.98 (m, 1H), 6.41 (d, J = 6.7 Hz, 1H), 4.13 (t, J = 6.2 Hz, 2H),
3.90 (s, 3H), 2.44–2.18 (m, 10H), 2.10 (s, 3H), 1.96–1.85 (m, 2H);
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