Design, synthesis and biological evaluation of novel 6,7-disubstituted-4- phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties as c-Met kinase inhibitors

Article abstract of DOI:10.1016/j.bmc.2014.05.013

A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against H460, MKN-45, HT-29 and MDA-MB-231 cancer cell lines in vitro. Most compounds displayed good to excellent potency against four tested cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially fluoro groups at 4-position on the phenyl ring (moiety B) were more effective than those with nitro groups or methoxy groups. In this study, a promising compound 33 (c-Met IC₅₀ = 1.63 nM) was identified, which showed the most potent antitumor activities with IC₅₀ values of 0.055 μM, 0.071 μM, 0.13 μM, and 0.43 μM against H460, MKN-45, HT-29 and MDA-MB-231 cell lines, respectively.

Full text of DOI:10.1016/j.bmc.2014.05.013

Bioorganic & Medicinal Chemistry 22 (2014) 3642–3653
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis and biological evaluation of novel
6,7-disubstituted-4-phenoxyquinoline derivatives bearing
4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties as c-Met
kinase inhibitors
⇑
Zijian Liu, Rui Wang, Ruiming Guo, Jinxing Hu, Ruijuan Li, Yanfang Zhao, Ping Gong
Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016,
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 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-
carboxamide moieties were designed, synthesized and evaluated for their c-Met kinase inhibition and
cytotoxicity against H460, MKN-45, HT-29 and MDA-MB-231 cancer cell lines in vitro. Most compounds
displayed good to excellent potency against four tested cancer cell lines as compared with foretinib. The
SAR analyses indicated that compounds with halogen groups, especially fluoro groups at 4-position on
the phenyl ring (moiety B) were more effective than those with nitro groups or methoxy groups. In this
study, a promising compound 33 (c-Met IC50 = 1.63 nM) was identified, which showed the most potent
Received 22 April 2014
Revised 9 May 2014
Accepted 9 May 2014
Available online 17 May 2014
Keywords:
c-Met
Antitumor activity
4-Phenoxyquinoline derivatives
2-Phenylphthalazin-1(2H)-one
antitumor activities with IC50 values of 0.055
l
M, 0.071
lM, 0.13
lM, and 0.43 lM against H460,
MKN-45, HT-29 and MDA-MB-231 cell lines, respectively.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
foretinib (1, Phase II), cabozantinib (2, Phase III), as well as several
newly developed compounds bearing 6,7-disubstituted-4-phen-
oxyquinoline frameworks, such as AM7 (3, Preclinical), MG10 (4,
Preclinical) and Amgen (5, Preclinical) et al., as the primary phar-
macophoric scaffolds (Fig. 1).20–24
The receptor tyrosine kinase, c-Met, and its natural ligand,
hepatocyte growth factor (HGF), are involved in cell proliferation,
migration and invasion, and are essential for normal embryonic
development.1 Binding of active HGF ligand to the c-Met extracel-
lular domain causes receptor polymerization and phosphorylation
of tyrosine residues in the intracellular c-Met domains.2,3 Aberrant
HGF/c-Met signaling has been identified in a wide range of human
malignancies, including bladder, breast, cervical, colorectal, endo-
metrial, gastric, kidney, liver, lung, pancreatic, prostate, and
thyroid cancers.4–10 Therefore, c-Met has gained considerable
attention as a potential target for cancer treatment.
In recent years, research has highlighted c-Met as an attractive
cancer drug target, triggering a number of approaches to disrupt
HGF/c-Met signaling. Both small-molecule c-Met kinase inhibitors
and antibodies targeting c-Met or HGF have exhibited antitumor
activities in preclinical models.11–19 Recently, significant progress
has been made on the development of c-Met inhibitors resulting
in more than ten candidates have been in clinical trials, including
The structure–activity relationships (SARs) of 6,7-disubstituted-
4-phenoxyquinoline based inhibitors suggested that quinoline
pharmacophores were responsible for forming hydrogen bonds
with the backbone of c-Met kinase, and an aryl fragment (moiety
B) probably extended into the hydrophobic pocket.25–27 Appar-
ently, there are two structural characteristics in the linkers
between moiety A and moiety B. One is ‘5 atoms regulation’, which
means the distance of six chemical bonds exists between moiety A
and moiety B; the other is the linker containing both hydrogen-
bond donor or acceptor and at least one amide group. In view of
above-mentioned results, our research group have introduced dif-
ferent biologically active fragments, such as pyridine, pyrimidine,
semicarbazone, quinoline, 1,4-dihydrocinnoline and pyrimidine-
2,4,6-trione into the 5-atom linker and the resulting derivatives
6–10 (Fig. 2) showed excellent potency.28–34
As an extension of our work on the development of novel potent
c-Met inhibitors, we noticed that compounds 11–13 (Fig. 3), which
contain a 2-phenylphthalazin-1(2H)-one (PHTZ) framework, dis-
played a multitude of biological activities, including antitumor,
⇑
Corresponding author. Tel./fax: +86 24 23986429.
E-mail address: gongpinggp@126.com (P. Gong).
http://dx.doi.org/10.1016/j.bmc.2014.05.013
0968-0896/Ó 2014 Elsevier Ltd. All rights reserved.

Z. Liu et al. / Bioorg. Med. Chem. 22 (2014) 3642–3653
3643
Figure 1. The representative small-molecule c-Met inhibitors based on the 6,7-disubstituted-4-phenoxyquinoline scaffold.
Figure 2. Representative compounds in our previous work on small-molecule c-Met kinase inhibitors.
Figure 3. Structures of several PHTZ derivatives and 5-atom linker.
anti-autoimmune and anti-inflammatory activities.35–37 Recently,
some PHTZ derivatives have been reported as the core skeleton
for the design of potent and selective human A3 adenosine receptor
(hA3 AR) antagonists, especially the 2,5-dimethoxyphenylphthala-
zin-1(2H)-one 12 being the most potent and selective hA3 AR
antagonist (Ki = 0.776 nM; hA1/hA3 and hA2A/hA3 >12,000).38 Con-
sidering its strong potency and basing on the ‘5 atoms regulation’,
we introduced PHTZ as a part of the 5-atom linker to the 6,7-disub-
stituted-4-phenoxyquinoline moiety via an amide bond, which
was called 4-oxo-3,4-dihydrophthalazine-1-carboxamide moiety
(Fig. 3).
According to our previous studies, 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 pip-
erazinyl groups, to observe the effects of the different cyclic ter-
tiary amino groups on activity. Furthermore, various substituents
were introduced at the phenyl ring (moiety B) with the aim to

3644
Z. Liu et al. / Bioorg. Med. Chem. 22 (2014) 3642–3653
explore the effect of substituents on biological activity. Accord-
ingly, we designed a novel series of 6,7-disubstituted-4-phenoxy-
quinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-
carboxamide moieties as c-Met kinase inhibitors (Fig. 4).
In the current study, all target compounds were evaluated for
their antiproliferative activity in vitro against four cancer cell lines:
H460 (human lung cancer), MKN-45 (human gastric cancer), HT-29
(human colon cancer) and MDA-MB-231 (human breast cancer).
Additionally, to determine c-Met kinase inhibition and selectivity,
the enzymatic assays of several potent compounds were evaluated,
and most of them showed promising inhibition. Furthermore, a
docking analysis was also performed to elucidate the binding mode
of the target compound 33 with c-Met kinase.
hydrazines to achieve PHTZ derivatives 23a–h,40 which were
refluxed in SOCl2 for 6 h to provide acyl chlorides 24a–h. Finally,
compounds 25–59 were successfully obtained via the reaction of
the amides 21a–e with 24a–h in the presence of triethylamine in
dichloromethane at room temperature overnight.
3. Biology
3.1. Cytotoxic activities against tumor cells assay
The antiproliferative activities of compounds 25–59 were evalu-
ated against H460, MKN-45, HT-29 and MDA-MB-231 cell lines by
the standard MTT assay in vitro, with foretinib as the positive con-
trol.41,42 The cancer cell lines were cultured in minimum essential
medium (MEM) supplement with 10% fetal bovine serum (FBS).
Approximate 4 Â 103 cells, suspended in MEM medium, were pla-
ted into each well of a 96-well plate and incubated in 5% CO2 at
37 °C for 24 h. The tested compounds at the indicated final concen-
trations were added to the culture medium and incubated for 72 h.
Fresh MTT was added to each well at the terminal concentration of
2. Chemistry
The synthesis of the key intermediates of 4-(2-fluorophen-
oxy)quinolines 21a–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
study28–34 (see also Supplementary information).
5
lg/mL, and incubated with cells at 37 °C for 4 h. The formazan
Target compounds 25–59 were prepared as outlined in
Scheme 2. The side chains 24a–h were synthesized from naphtha-
lene, which was dissolved in 0.5 N NaOH and refluxed with KMnO4
aq. for 2 h to afford 2-(carboxycarbonyl)benzoic acid 22.39
Subsequently, 22 was reacted with various substituted phenyl
crystals in each well were dissolved in 100 L DMSO, and the absor-
l
bency at 492 nm (for absorbance of MTT formazan) and 630 nm (for
the reference wavelength) was measured with an ELISA reader. All
of the compounds were tested three times in each of the cell lines.
The results, expressed as IC50 (inhibitory concentration 50%), were
Figure 4. Design strategy for the 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties.
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.

Z. Liu et al. / Bioorg. Med. Chem. 22 (2014) 3642–3653
3645
Scheme 2. Reagents and conditions: (i) 0.5 mol/L NaOH aq, KMnO4, H2O, reflux, 2 h; (ii) substituted phenyl hydrazine, EtOH, rt, 15 h; (iii) SOCl2, reflux, 6 h; (iv) appropriate
aniline, carbonyl chloride, Et3N, DCM, rt, overnight.
the averages of three determinations and calculated by the Bacus
Laboratories Incorporated Slide Scanner (Bliss) software.
Preliminary structure–activity relationships (SARs) indicated
that the introduction of different water-soluble R1 groups only
slightly altered cytotoxicity, suggesting that the R1 group contrib-
uted little to their potency. For example, compounds 41 (R1 = 4-
Methyl Piperazinyl, R2 = 4-F), 48 (R1 = Piperidinyl, R2 = 4-F) and
54 (R1 = 4-Methyl Piperidinyl, R2 = 4-F) exhibited comparable cyto-
toxic activities against the different cancer cells. However, different
biological properties were observed when various R2 groups were
introduced to the phenyl ring (moiety B). Compound 32 (R1 = Pyr-
rolidinyl, R2 = H), with no substituent on the phenyl ring, showed
promising cytotoxicity against H460 and MKN-45 cell lines with
3.2. HTRF kinase assay
The c-Met kinase assays of tested compounds were performed
by homogeneous time-resolved fluorescence (HTRF) assay as previ-
ously reported protocol.43,44 To examine the selectivity of the most
promising compound 33 on c-Met over other tyrosine kinases, it
was screened against c-Kit, Flt-3, PDGFR
Briefly, 20 g/mL poly (Glu, Tyr) 4:1 (Sigma) was preloaded as a
substrate in 384-well plates. Then 50 L of 10 mM ATP (Invitrogen)
a, VEGFR-2 and EGFR.
l
l
IC50 values of 0.48 lM and 0.53 lM, respectively. The introduction
solution diluted in kinase reaction buffer (50 mM HEPES, Ph 7.0,
1 mM DTT, 1 mM MgCl2, 1 mM MnCl2, 0.1% NaN3) was added to
each well. Various concentrations of compounds were diluted in
of halogen groups, especially fluoro groups, 33–37 (R2 = 4-F, 3-F, 2-
F, 4-Br, 2-Br, respectively) led to an obvious improvement in anti-
tumor activity than compound 32, which could be further con-
firmed by compounds 40 and 41–44. However, the introduction
10
control. The kinase reaction was initiated by the addition of purified
tyrosine kinase proteins diluted in 39 L of kinase reaction buffer
solution. Reactions were incubated for 30 min at 25 °C and stopped
by the addition of 5 L Streptavidin-XL665 and 5 L Tk Antibody
lL of 1% DMSO (v/v), with blank DMSO solution as the negative
of nitro groups (38, IC50 = 1.24
lM against H460) or methoxy
l
groups (39, R2 = 4-OCH3, IC50 = 1.65
l
M against H460) caused the
potency to be lowered by 2.6- and 3.4-fold, respectively. This could
demonstrate that halogen groups had a positive effect on antitu-
mor activity, but nitro groups and methoxy groups showed nega-
tive results.
Further analysis revealed that the position of R2 group was clo-
sely related to antitumor activity as well. Compounds with 4-
l
l
Cryptate working solution to all of wells. The plate was read by
Envision (Perkinelmer) at 320 nm and 615 nm. IC50 values were cal-
culated from the inhibition curves.
substituted phenyl group (33, R2 = 4-F, IC50 = 0.055
R2 = 4-Br, IC50 = 0.18 M against H460) displayed higher potency
than those with 2-substituted phenyl group (35, R2 = 2-F,
IC50 = 0.23 M and 37, R2 = 2-Br, IC50 = 0.32 M against H460) or
3-substituted phenyl group (34, R2 = 3-F, IC50 = 0.19 M). Among
lM and 36,
4. Results and discussion
l
4.1. In vitro cytotoxic activities and structure activity
relationships
l
l
l
them, 4-fluoro group on phenyl ring (moiety B) was the most
favorable substituent for activity.
The cytotoxic activities of the target compounds 25–59 were
evaluated in H460 (human lung cancer), MKN-45 (human gastric
cancer), HT-29 (human colon cancer), and MDA-MB-231 (human
breast cancer) cell lines using the MTT assay. Foretinib was used
as the positive control. The results were expressed as half-maximal
inhibitory concentration (IC50) values and were presented in
Table 1, as mean values of experiments performed in triplicate.
As illustrated in Table 1, all the target compounds showed mod-
erate to excellent cytotoxic activities against the different cancer
4.2. In vitro enzymatic assays
As shown in Table 2, the six tested compounds all exhibited
excellent c-Met enzymatic potency, suggesting that the inhibition
of c-Met is a candidate underlying mechanism for the antitumor
effect. Compound 33 showed the most potent activity with an
IC50 value of 1.63 nM, which was comparable to that of the positive
control, foretinib (IC50 = 1.56 nM). Thus, compound 33 is worth fur-
ther studying as new potential anticancer agent for the treatment
of human cancers.
cells with potencies in the single-digit lM range, which suggested
that the replacement of the cyclopropane-1,1-dicarboxamide
framework of foretinib with the 4-oxo-3,4-dihydrophthalazine-1-
carboxamide moiety maintained the potent cytotoxicity. The IC50
values of the most promising compound 33 were 0.055
lM,
4.3. Enzymatic selectivity assays
0.071 M, 0.13 M, and 0.43 M against H460, MKN-45, HT-29
l
l
l
and MDA-MB-231 cell lines, respectively. More importantly, most
of the compounds were more potent against H460 and MKN-45
cell lines than HT-29 and MDA-MB-231 cell lines. These results
revealed that this series of compounds possessed selectivity for
H460 and MKN-45 cancer cell lines, and had the makings of good
drugs for lung and gastric cancer.
To examine the selectivity of compound 33 on c-Met over other
kinases, it was screened against 5 other tyrosine kinases (Table 3).
Compared with its high potency against c-Met (IC50 = 1.63 nM), 33
also exhibited inhibitory effects against c-Kit, Flt-3, PDGFR
a and
VEGFR-2, although the potency was 1.3- to 43.2-fold lower than

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Z. Liu et al. / Bioorg. Med. Chem. 22 (2014) 3642–3653
Table 1
Structures and cytotoxicities of compounds 25–59 against H460, MKN-45, HT-29 and MDA-MB-231 cancer cell lines in vitro
a
Compd.
R1
R2
IC50
(lmol/L) SD
H460
MKN-45
HT-29
MDA-MB-231
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
foretinibb
Morpholinyl
Morpholinyl
Morpholinyl
Morpholinyl
Morpholinyl
Morpholinyl
Morpholinyl
Pyrrolidinyl
Pyrrolidinyl
Pyrrolidinyl
Pyrrolidinyl
Pyrrolidinyl
Pyrrolidinyl
Pyrrolidinyl
Pyrrolidinyl
4-Methyl piperazinyl
4-Methyl piperazinyl
4-Methyl piperazinyl
4-Methyl piperazinyl
4-Methyl piperazinyl
4-Methyl piperazinyl
4-Methyl piperazinyl
Piperidinyl
Piperidinyl
Piperidinyl
Piperidinyl
Piperidinyl
H
4-F
2-F
4-Br
2-Br
4-NO2
4-OCH3
H
4-F
3-F
2-F
4-Br
2-Br
4-NO2
4-OCH3
H
0.58 0.038
0.10 0.012
0.19 0.024
0.29 0.025
0.37 0.037
1.89 0.14
1.24 0.095
0.48 0.026
0.055 0.010
0.19 0.013
0.23 0.040
0.18 0.015
0.32 0.041
1.24 0.23
1.65 0.37
0.45 0.074
0.091 0.011
0.23 0.030
0.25 0.015
0.29 0.014
0.98 0.12
1.11 0.20
0.65 0.10
0.12 0.017
0.16 0.020
0.41 0.031
1.3 0.26
0.43 0.031
0.09 0.010
0.15 0.016
0.34 0.038
0.45 0.025
1.94 0.20
1.62 0.13
0.53 0.053
0.071 0.011
0.16 0.010
0.14 0.012
0.23 0.012
0.41 0.050
1.62 0.22
1.32 0.13
0.62 0.10
0.15 0.013
0.21 0.015
0.35 0.020
0.40 0.031
1.32 0.29
1.32 0.40
0.59 0.074
0.18 0.015
0.35 0.018
0.50 0.031
1.14 0.24
0.95 0.12
0.58 0.073
0.13 0.015
0.22 0.019
0.26 0.024
0.33 0.040
0.51 0.036
1.15 0.13
0.032 0.005
1.38 0.14
0.26 0.027
0.47 0.033
0.71 0.035
0.68 0.041
2.52 0.22
3.36 0.23
0.98 0.055
0.13 0.016
0.46 0.063
0.40 0.060
0.67 0.058
0.85 0.047
1.76 0.22
2.36 0.20
1.14 0.33
0.32 0.019
0.48 0.022
0.85 0.058
1.19 0.29
2.56 0.30
3.70 0.60
1.31 0.25
0.29 0.021
0.63 0.026
0.77 0.032
2.17 0.35
1.45 0.21
1.04 0.18
0.33 0.049
0.50 0.035
0.51 0.062
0.92 0.10
0.95 0.14
2.45 0.38
0.19 0.01
1.23 0.26
0.67 0.072
0.70 0.040
0.96 0.10
1.56 0.12
3.48 0.21
3.98 0.24
1.13 0.18
0.43 0.050
0.88 0.12
0.95 0.055
1.16 0.19
1.02 0.27
2.98 0.33
3.45 0.39
1.58 0.18
0.46 0.016
1.05 0.11
1.37 0.15
1.68 0.20
3.49 0.26
3.98 0.34
1.88 0.27
0.55 0.014
0.91 0.026
1.13 0.15
2.62 0.39
2.01 0.41
1.48 0.29
0.66 0.040
0.86 0.071
0.67 0.039
1.16 0.19
1.24 0.25
4.01 0.50
0.54 0.062
4-F
2-F
4-Br
2-Br
4-NO2
4-OCH3
H
4-F
2-F
4-Br
4-NO2
4-OCH3
H
4-F
3-F
2-F
4-Br
2-Br
4-NO2
Piperidinyl
0.84 0.095
0.55 0.038
0.11 0.011
0.19 0.024
0.20 0.017
0.35 0.022
0.39 0.045
1.34 0.29
0.21 0.03
4-Methyl piperidinyl
4-Methyl piperidinyl
4-Methyl piperidinyl
4-Methyl piperidinyl
4-Methyl piperidinyl
4-Methyl piperidinyl
4-Methyl piperidinyl
a
Data presented is the mean SD value of three independent determinations.
Used as positive control.
b
Table 2
5. Binding model analysis
c-Met kinase activity of selected compounds 32, 33, 34, 35, 41, 48 and foretinib
in vitro
To further elucidate the binding mode of compounds, a docking
analysis was performed. In our study, the co-crystal structure of
foretinib (GSK1363089) with c-Met kinase was selected as the
docking model (PDB ID: 3LQ8). The docking simulation was con-
ducted with Glide XP (Schrödinger 2014), since Glide uses a hierar-
chical series of filters to search for possible locations of the ligand in
the active-site region of the receptor. The shape and properties of
the receptor were 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 by Accelrys DS visual-
izer 4.0 system. The binding model was exemplified by the interac-
tion of compound 33 with c-Met. As shown in Figure 5, the nitrogen
atom of pyrrolidine, the oxygen and fluorine atoms of 4-phenoxy-
quinoline in compound 33 formed three H-bond interactions with
residue ASP1222. In the meantime, one Pi–Pi interaction between
the phenyl ring (moiety B) and PHE1223, and one Pi–Sigma interac-
tion between 3,4-dihydrophthalazine with ILE1084 had been
formed. Both Pi–Pi and Pi–Sigma interactions played an important
role in stabilizing the conformation of ligand–protein complex.
a
Compd.
IC50 on c-Met (nM)
32
33
34
35
13.57 1.23
1.63 0.12
4.31 0.15
3.98 0.35
1.98 0.18
2.03 0.22
1.56 0.17
41
48
foretinibb
a
Data presented is the mean SD value of three independent determinations.
Used as positive control.
b
Table 3
Inhibition of tyrosine kinases by compound 33
Kinase
Enzyme IC50 (nM)
c-kit
Flt-3
PDGFR
VEGFR-2
EGFR
2.17
3.49
15.73
70.41
>10,000
a
6. Conclusions
that against c-Met. Moreover, this compound showed little or no
kinase inhibition activity against EGFR kinase (IC50 >10 M). These
data suggested that compound 33 is a promising selective multi-
In summary, a series of 6,7-disubstituted-4-phenoxyquinoline
derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide
moieties were designed, synthesized and evaluated for their biological
l
target kinase inhibitor.

Z. Liu et al. / Bioorg. Med. Chem. 22 (2014) 3642–3653
3647
mixture was quenched by addition of 100 mL of ethanol, allowed
to cool at room temperature and filtered. The resulting filtrate
was acidified with 30% HCl and extracted with ethyl acetate
(3 Â 75 mL). The combined organic layer was dried over anhydrous
Na2SO4, and concentrated under vacuum to afford 2-(carboxycar-
bonyl)benzoic acid 22 8.5 g. White solid; yeild: 35%; mp: 142–
144 °C; 1H NMR (400 MHz, CDCl3) d 7.95 (dd, J = 7.6, 0.8 Hz, 1H),
7.77 (dd, J = 7.5, 1.1 Hz,1H), 7.68 (dd, J = 7.5, 1.0 Hz, 1H), 7.58 (dd,
J = 7.6, 0.8 Hz, 1H); MS (ESI) m/z (%): 192.0 [MÀH]+.
7.2. General procedure for preparation of 4-oxo-3-substituted
phenyl-3,4-dihydrophthalazine-1-carboxylic acid (23a–h)
To a solution of 22 (13 g, 0.067 mol) in water (100 mL), an
appropriate phenyl hydrazine (0.067 mol) in ethanol (200 mL)
was added. After stirring at room temperature for 15 h, the resul-
tant precipitate was filtered, washed with dichloromethane and
dried under vacuum to afford the title compounds 23a–h.
Figure 5. The c-Met active site in complex with compound 33 and its hydrophobic
surface (brown: highly hydrophobic, blue: highly hydrophilic). The protein was
displayed by secondary structure. Compound 33 was shown in colored sticks (cyan:
carbon atom, blue: nitrogen atom, red: oxygen atom, white: hydrogen atom). The
H-bond interaction was shown in green dotted lines, Pi–Pi interaction was shown in
pink dotted lines, and Pi–Sigma interaction was shown in purple dotted lines.
7.2.1. 4-Oxo-3-phenyl-3,4-dihydrophthalazine-1-carboxylic
acid (23a)
White solid; yield: 85%; mp: 217–218 °C; MS (ESI) m/z (%):
267.1 [M+H]+; 1H NMR (400 MHz, DMSO) d 9.13 (d, J = 8.2 Hz,
1H), 8.48 (dd, J = 7.8, 0.8 Hz, 1H), 7.90 (dd, J = 7.6, 1.4 Hz, 1H),
7.83 (dd, J = 8.1, 1.1 Hz, 1H), 7.56–7.54 (m, 2H), 7.51–7.47 (m,
2H), 7.42–7.39 (m, 1H).
activity. The preliminary investigation showed that most compounds
displayed good to excellent potency against four tested cancer cell
lines as compared with foretinib. In particular, the most promising
compound 33 (c-Met IC50 = 1.63 nM, a multi-target tyrosine kinase
inhibitor) showed the most potent antitumor activities with IC50 val-
7.2.2. 3-(4-Fluorophenyl)-4-oxo-3,4-dihydrophthalazine-1-
carboxylic acid (23b)
ues of 0.055 lM, 0.071 lM, 0.13 lM, and 0.43 lM against H460,
MKN-45, HT-29 and MDA-MB-231 cell lines, respectively. The SAR
analyses indicated that the replacement of the cyclopropane-1,1-
dicarboxamideframeworkof foretinibwith the 4-oxo-3,4-dihydroph-
thalazine-1-carboxamide moiety maintained the potent cytotoxicity.
Moreover, compounds with halogen groups, especially fluoro groups
at 4-position on the phenyl ring (moiety B) were more active than
those with nitro groups or methoxy groups. Further studies on SARs
and mechanism of action of these compounds are in progress, and
their results will be reported in the future.
White solid; yield: 77%; mp: 215–217 °C; MS (ESI) m/z (%):
285.1 [M+H]+; 1H NMR (400 MHz, DMSO) d 8.58 (d, J = 8.2 Hz,
1H), 8.38 (dd, J = 7.9, 0.8 Hz, 1H), 8.04 (dd, J = 7.4, 1.4 Hz, 1H),
7.96 (dd, J = 8.2, 1.2 Hz, 1H), 7.71–7.68 (m, 2H), 7.41–7.37 (m, 2H).
7.2.3. 3-(3-Fluorophenyl)-4-oxo-3,4-dihydrophthalazine-1-
carboxylic acid (23c)
Yellow solid; yield: 75%; mp: 205–207 °C; MS (ESI) m/z (%):
285.5 [M+H]+. 1H NMR (400 MHz, DMSO) d 8.55 (d, J = 8.5 Hz,
1H), 8.38 (d, J = 8.0 Hz, 1H), 8.10–8.06 (m, 2H) 8.05–8.01 (m, 2H),
7.76–7.72 (m, 1H), 7.33–7.30 (m, 1H).
7. Experimental
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 recorded
by means of the KBr pellet technique on a Bruker FTS 135 spec-
trometer. Elemental analysis was determined on a Carlo-Erba
1106 Elemental analysis instrument (Carlo Erba, Milan, Italy).
7.2.4. 3-(2-Fluorophenyl)-4-oxo-3,4-dihydrophthalazine-1-
carboxylic acid (23d)
Yellow solid; yield: 79%; mp: 214–217 °C; MS (ESI) m/z (%):
285.2 [M+H]+. 1H NMR (400 MHz, DMSO) d 8.56 (d, J = 8.1 Hz,
1H), 8.37 (d, J = 8.5 Hz, 1H), 8.12–8.02 (m, 3H), 7.52–7.50 (m,
2H), 7.31–7.28 (m, 1H).
7.2.5. 3-(4-Bromophenyl)-4-oxo-3,4-dihydrophthalazine-1-
carboxylic acid (23e)
Yellow solid; yield: 82%; mp: 202–205 °C; MS (ESI) m/z
(%):345.0 [M+H]+; 1H NMR (400 MHz, DMSO) d 8.58 (d, J = 8.4 Hz,
1H), 8.39 (dd, J = 8.8, 0.9 Hz, 1H), 8.04 (dd, J = 7.3, 1.4 Hz, 1H),
7.96 (dd, J = 8.0, 1.2 Hz, 1H), 7.72–7.69 (m, 2H), 7.74–7.61 (m, 2H).
7.2.6. 3-(2-Bromophenyl)-4-oxo-3,4-dihydrophthalazine-1-
carboxylic acid (23f)
Yellow solid; yield: 81%; mp: 206–209 °C; MS (ESI) m/z
(%):345.3 [M+H]+. 1H NMR (400 MHz, DMSO) d 8.59 (d, J = 8.0 Hz,
1H), 8.38 (d, J = 7.2 Hz, 1H), 8.15–8.09 (m, 2H) 8.08–8.03 (m, 2H),
7.70–7.66 (m, 1H), 7.51–7.47 (m, 1H).
7.1. 2-(Carboxycarbonyl)benzoic acid (22)
Naphthalene (16 g, 0.125 mol) was dissolved in 0.5 N NaOH
(250 mL) under reflux to which 750 mL of boiling aqueous potas-
sium permanganate (106 g, 0.67 mol) was added dropwise during
an interval of 1.5 h under stirring. The reaction was continued to
reflux for another 30 min to complete the oxidation. The reaction
7.2.7. 3-(4-Nitrophenyl)-4-oxo-3,4-dihydrophthalazine-1-
carboxylic acid (23g)
Yellow solid; yield: 81%; mp: 217–219 °C; MS (ESI) m/z
(%):312.6 [M+H]+. 1H NMR (400 MHz, DMSO) d 8.74–8.70 (m,

3648
Z. Liu et al. / Bioorg. Med. Chem. 22 (2014) 3642–3653
2H), 8.65–8.63 (m, 2H), 8.52 (d, J = 8.6 Hz, 1H), 8.41 (dd, J = 8.6,
1.0 Hz, 1H), 8.13 (dd, J = 7.5, 1.1 Hz, 1H), 7.98 (dd, J = 8.2, 1.2 Hz,
1H).
d162.73, 162.33, 160.43, 159.69, 158.69, 152.67, 152.43, 150.07,
149.31, 146.87, 140.20, 137.97, 137.67, 136.82, 134.78, 133.26,
128.88, 128.79, 128.41, 127.37, 126.87 (s, 1H), 124.68, 117.64,
116.02, 115.79, 114.92, 109.58, 109.01, 102.54, 99.48, 67.16,
66.70 (2C), 56.27, 55.29, 53.86 (2C), 26.17. Anal. Calcd for C38H33F2-
N5O6: C, 65.79; H, 4.79; N, 10.10. Found: C, 65.81; H, 4.75; N, 10.08.
7.2.8. 3-(4-Methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-1-
carboxylic acid (23h)
White solid; yield: 87%; mp: 219–220 °C; MS (ESI) m/z (%):
297.2 [M+H]+; 1H NMR (400 MHz, DMSO) d 8.57 (d, J = 8.0 Hz,
1H), 8.37 (dd, J = 7.8 and 0.7 Hz, 1H), 8.05–8.02 (m, 1H), 7.94 (dd,
J = 8.0, 1.0 Hz, 1H), 7.56–7.52 (m, 2H), 7.10–7.06 (m, 2H), 3.83 (s,
3H).
7.4.3. N-(3-Fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yl)oxy)phenyl)-3-(2-fluorophenyl)-4-oxo-3,4-
dihydrophthalazine-1-carboxamide (27)
Yellow solid; yield: 58%; mp: 158–160 °C; MS (ESI) m/z (%):
694.3 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.28 (d, J = 8.1 Hz,
1H), 9.17 (s, 1H), 8.56 (d, J = 7.8 Hz, 1H), 8.48 (dd, J = 9.1, 5.3 Hz,
1H), 8.02–7.96 (m, 1H), 7.94–7.91 (m, 1H), 7.89 (t, J = 3.9 Hz, 1H),
7.58 (d, J = 2.2 Hz, 1H), 7.57 (s, 1H), 7.56–7.49 (m, 1H), 7.48–7.27
(m, 4H), 7.09–6.95 (m, 1H), 6.60–6.45 (m, 1H), 6.41 (t, J = 4.6 Hz,
1H), 4.32–4.23 (m, 2H), 4.04 (s, 3H), 3.73 (t, J = 4.5 Hz, 4H), 2.59
(t, J = 7.1 Hz, 2H), 2.50 (s, 4H), 2.14 (p, J = 6.8 Hz, 2H); 13C NMR
7.3. General procedure for preparation of 4-oxo-3-substituted
phenyl-3,4-dihydrophthalazine-1-carbonyl chloride (24a–h)
An appropriate 4-oxo-3-substituted phenyl-3,4-dihydrophthal-
azine-1-carboxylic acid 23a–h (0.01 mol) was added to thionyl
chloride (15 mL), and refluxed for 5–7 h. The reaction mixture
was evaporated to yield corresponding 4-oxo-3-phenyl-3,4-
dihydrophthalazine-1-carbonyl chloride 24a–h.
(400 MHz, CDCl3)
d 160.90, 159.99, 158.86, 152.31, 149.90,
148.71, 146.89, 137.67, 136.75, 135.89, 134.40, 132.61, 131.00,
128.79, 128.24, 127.82, 127.56, 124.78, 123.88, 117.01, 116.81,
116.45, 115.44, 109.83, 109.60, 108.75, 102.20, 101.92, 99.51,
67.25, 66.99 (2C), 56.17, 55.40, 53.71 (2C), 25.97. Anal. Calcd for
7.4. General procedure for preparation of the target compounds
(25–59)
C38H33F2N5O6: C, 65.79; H, 4.79; N, 10.10. Found: C, 65.77; H,
To a mixture of an appropriate aniline 21a–e (0.48 mmol), tri-
ethylamine (0.58 mmol) and dichloromethane (10 mL) in an ice
bath, an appropriate carbonyl chloride 24a–h (0.52 mol) was dis-
solved in dried dichloromethane (10 mL) to add drop-wise. Upon
the completion of addition, the reaction mixture was removed to
room temperature for 10 h and monitored by TLC. The mixture
was washed with 10% K2CO3 (20 mL Â 3), brine (20 mL Â 3) in
sequence, and the organic phase was separated, dried, and evapo-
rated. The crude product was purified by chromatography on silica
gel using CH2Cl2/MeOH/Et3N (40:1:1) to afford the target com-
pounds 25–59.
4.80; N, 10.07.
7.4.4. 3-(4-Bromophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-4-oxo-3,4-
dihydrophthalazine-1-carboxamide (28)
Yellow solid; yield: 64%; mp: 154–157 °C; MS (ESI) m/z (%):
754.6 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.26 (d, J = 8.0 Hz,
1H), 9.18 (s, 1H), 8.59–8.52 (m, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.01–
7.87 (m, 3H), 7.72–7.66 (m, 2H), 7.58 (dd, J = 5.9, 2.9 Hz, 3H),
7.45 (s, 1H), 7.40 (d, J = 10.0 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 6.42
(d, J = 5.3 Hz, 1H), 4.28 (t, J = 6.6 Hz, 2H), 4.05 (s, 3H), 3.75 (t,
J = 4.4 Hz, 4H), 2.62 (t, J = 7.0 Hz, 2H), 2.53 (s, 4H), 2.22–2.11 (m,
2H); 13C NMR (400 MHz, CDCl3) d 160.98, 160.05, 158.93, 155.72,
153.23, 152.35, 149.92, 148.53, 146.71, 140.05, 137.64, 136.81,
136.00, 134.36, 132.60, 132.13 (2C), 128.38, 127.85–127.45 (2C),
127.30 (2C), 123.90, 122.23, 116.42, 115.45, 109.70, 108.59,
102.18, 99.53, 67.19, 66.85 (2C), 56.16, 55.38, 53.63 (2C), 25.87.
Anal. Calcd for C38H33BrFN5O6: C, 60.48; H, 4.41; N, 9.28. Found:
C, 60.51; H, 4.43; N, 9.30.
7.4.1. N-(3-Fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yl)oxy)phenyl)-4-oxo-3-phenyl-3,4-dihydrophthal-
azine-1-carboxamide (25)
Yellow solid; yield: 62%; mp: 157–159 °C; MS (ESI) m/z (%):
676.5 [M+H]+; 1H NMR (400 MHz, DMSO) d 11.24 (s, 1H), 8.64 (d,
J = 5.5 Hz, 1H), 8.44 (d, J = 7.8 Hz, 2H), 8.16–7.97 (m, 3H), 7.84 (d,
J = 7.7 Hz, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H), 7.59 (d,
J = 7.8 Hz, 2H), 7.56 (s, 1H), 7.48 (t, J = 7.3 Hz, 1H), 6.70 (d,
J = 5.3 Hz, 1H), 4.32 (s, 2H), 4.01 (s, 3H), 3.94 (d, J = 24.8 Hz, 4H),
3.50 (s, 2H), 3.13 (s, 2H), 2.51 (s, 2H), 2.37 (s, 2H); 13C NMR
7.4.5. 3-(2-Bromophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-4-oxo-3,4-
dihydrophthalazine-1-carboxamide (29)
(400 MHz, DMSO)
d 162.47, 161.58, 158.64, 154.90, 153.24,
152.46, 150.58, 147.27, 141.72, 140.24, 138.31, 138.21, 136.38,
136.26, 134.74, 133.22, 129.08 (2C), 128.44, 127.41, 127.29,
126.75, 126.69 (2C), 124.60, 117.74, 115.30, 109.71, 109.48,
102.93, 99.99, 66.85, 63.68 (2C), 56.59, 54.00, 51.57 (2C), 23.26.
Anal. Calcd for C38H34FN5O6: C, 67.55; H, 5.07; N, 10.36. Found:
C, 67.52; H, 5.10; N, 10.33.
Yellow solid; yield: 56%; mp: 149–152 °C; MS (ESI) m/z (%):
754.5 [M+H]+; IR (KBr) cmÀ1: 3384.3, 3066.0, 2927.2, 2851.5,
2811.6, 1725.7, 1682.3, 1620.7, 1598.6, 1578.7, 1508.0, 1478.6,
1430.6, 1384.0, 1348.4,1305.4, 1249.6, 1210.3, 1172.5, 1142.7,
1115.5, 1045.4, 1020.9, 971.8, 891.8, 853.0, 790.3, 750.2, 728.5,
686.3, 658.7, 618.7, 474.4; 1H NMR (400 MHz, CDCl3) d 9.30 (d,
J = 8.2 Hz, 1H), 9.21 (s, 1H), 8.56 (d, J = 7.3 Hz, 1H), 8.48 (d,
J = 5.2 Hz, 1H), 7.98 (dd, J = 14.0, 6.7 Hz, 1H), 7.95–7.85 (m, 1H),
7.81 (d, J = 8.0 Hz, 1H), 7.61–7.48 (m, 3H), 7.48–7.36 (m, 3H),
7.25 (d, J = 8.7 Hz, 1H), 6.40 (d, J = 5.2 Hz, 1H), 4.28 (dd, J = 12.5,
6.0 Hz, 2H), 4.09–4.02 (m, 3H), 3.77–3.70 (m, 4H), 2.59 (dd,
J = 14.0, 7.0 Hz, 2H), 2.49 (s, 4H), 2.13 (dd, J = 13.6, 6.8 Hz, 2H);
13C NMR (400 MHz, CDCl3) d 160.95, 159.96, 158.86, 152.28,
149.87, 148.75, 146.94, 140.05, 137.62, 136.39, 135.93, 134.42,
133.85, 132.54, 130.89, 129.46, 128.55, 128.42, 127.96, 127.82,
127.59, 123.86, 121.67, 116.44, 115.42, 109.80, 109.57, 108.79,
102.17, 99.50, 67.25, 67.03 (2C), 56.16, 55.39, 53.73 (2C), 26.01.
7.4.2. N-(3-Fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-4-oxo-3,4-
dihydrophthalazine-1-carboxamide (26)
Yellow solid; yield: 65%; mp: 154–156 °C; MS (ESI) m/z (%):
694.3 [M+H]+; 1H NMR (400 MHz, DMSO) d 11.04 (s, 1H), 8.53–
8.40 (m, 3H), 8.11–7.97 (m, 3H), 7.86 (dd, J = 8.9, 5.0 Hz, 2H),
7.70 (d, J = 8.7 Hz, 1H), 7.59–7.48 (m, 2H), 7.47–7.36 (m, 3H),
6.48 (d, J = 5.1 Hz, 1H), 4.20 (t, J = 6.4 Hz, 2H), 3.95 (d, J = 7.5 Hz,
3H), 3.59 (t, J = 4.4 Hz, 4H), 2.47 (t, J = 7.1 Hz, 2H), 2.39 (s, 4H),
1.99 (dd, J = 13.4, 6.6 Hz, 2H); 13C NMR (400 MHz, DMSO)

Z. Liu et al. / Bioorg. Med. Chem. 22 (2014) 3642–3653
3649
Anal. Calcd for C38H33BrFN5O6: C, 60.48; H, 4.41; N, 9.28. Found: C,
60.50; H, 4.39; N, 9.25.
162.84, 162.41, 160.40, 159.71, 158.66, 155.07, 152.44, 150.05,
149.31, 146.88, 140.37, 137.96, 136.77, 134.73, 133.18, 128.94
(2C), 128.62, 128.38, 127.33, 126.77, 124.61, 117.64, 115.94,
115.71, 114.90, 109.54, 108.96, 102.49, 99.48, 67.21, 56.27, 54.11
(2C), 52.70, 28.52, 23.60 (2C). Anal. Calcd for C38H33F2N5O5: C,
67.35; H, 4.91; N, 10.33. Found: C, 67.33; H, 4.93; N, 10.35.
7.4.6. N-(3-Fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yl)oxy)phenyl)-3-(4-nitrophenyl)-4-oxo-3,4-
dihydrophthalazine-1-carboxamide (30)
Yellow solid; yield: 58%; mp: 151–154 °C; MS (ESI) m/z (%):
721.3 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.29 (s, 1H), 9.21 (d,
J = 8.0 Hz, 1H), 8.59 (d, J = 7.1 Hz, 1H), 8.51 (d, J = 5.3 Hz, 1H),
8.42 (d, J = 9.1 Hz, 2H), 8.05–7.98 (m, 4H), 7.94 (t, J = 7.6 Hz, 1H),
7.60 (s, 1H), 7.54 (d, J = 6.9 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.31
(dd, J = 16.0, 7.4 Hz, 1H), 6.49 (d, J = 5.4 Hz, 1H), 4.31 (dd, J = 10.7,
6.3 Hz, 2H), 4.06 (s, 3H), 3.91 (s, 4H), 3.12 (q, J = 7.3 Hz, 2H), 2.86
(d, J = 30.3 Hz, 4H), 2.33 (s, 2H). Anal. Calcd for C38H33FN6O8: C,
63.33; H, 4.62; N, 11.66. Found: C, 63.35; H, 4.59; N, 11.63.
7.4.10. N-(3-Fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-3-(3-fluorophenyl) -4-oxo-
3,4-dihydrophthalazine-1-carboxamide (34)
Yellow solid; yield: 67%; mp: 157–160 °C; MS (ESI) m/z (%):
678.3 [M+H]+; 1H NMR (400 MHz, DMSO) d 11.26 (s, 1H), 8.65 (d,
J = 5.8 Hz, 1H), 8.45 (d, J = 8.0 Hz, 2H), 8.17–7.98 (m, 3H), 7.86–
7.77 (m, 2H), 7.74 (d, J = 8.1 Hz, 1H), 7.67 (s, 1H), 7.65–7.54 (m,
3H), 7.33 (td, J = 8.4, 2.0 Hz, 1H), 6.72 (d, J = 5.6 Hz, 1H), 4.32 (s,
2H), 4.01 (s, 3H), 3.59 (d, J = 5.0 Hz, 2H), 3.36–3.31 (m, 3H), 3.06
(dd, J = 7.2, 4.7 Hz, 2H), 2.38–2.25 (m, 2H), 2.02 (s, 2H), 1.92 (dd,
J = 13.1, 8.1 Hz, 2H). Anal. Calcd for C38H33F2N5O5: C, 67.35; H,
4.91; N, 10.33. Found: C, 67.37; H, 4.90; N, 10.31.
7.4.7. N-(3-Fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)
quinolin-4-yl)oxy)phenyl)-3-(4-methoxyphenyl)-4-oxo-3,4-
dihydrophthalazine-1-carboxamide (31)
Yellow solid; yield: 68%; mp: 153–156 °C; MS (ESI) m/z (%):
706.4 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.31–9.18 (m, 2H),
8.54 (d, J = 7.9 Hz, 1H), 8.49 (d, J = 5.3 Hz, 1H), 7.99–7.84 (m, 3H),
7.66 (dd, J = 14.3, 4.8 Hz, 1H), 7.60–7.51 (m, 2H), 7.45–7.38 (m,
2H), 7.29 (dd, J = 8.1, 4.7 Hz, 1H), 7.03 (t, J = 10.4 Hz, 1H), 6.42 (d,
J = 5.3 Hz, 1H), 4.31–4.22 (m, 2H), 4.05 (s, 3H), 3.91 (t, J = 22.7 Hz,
3H), 3.78–3.67 (m, 4H), 2.58 (t, J = 7.1 Hz, 2H), 2.49 (s, 4H), 2.20–
2.08 (m, 2H); 13C NMR (400 MHz, CDCl3) d 161.17, 160.98,
159.97, 159.50, 159.30, 159.26, 152.30, 149.88, 148.74, 146.94,
135.85, 134.31, 134.13, 132.47, 128.46, 127.85, 127.66, 127.56,
127.07, 126.43, 125.32, 123.91, 116.29, 115.43, 114.25, 111.69,
109.50, 108.78, 102.19, 99.50, 67.26, 67.04 (2C), 56.48, 56.17,
55.40, 53.73 (2C), 26.01. Anal. Calcd for C39H36FN5O7: C, 66.37; H,
5.14; N, 9.92. Found: C, 66.36; H, 5.12; N, 9.94.
7.4.11. N-(3-Fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-3-(2-fluorophenyl) -4-oxo-
3,4-dihydrophthalazine-1-carboxamide (35)
Yellow solid; yield: 54%; mp: 166–168 °C; MS (ESI) m/z (%):
678.5 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.26 (d, J = 8.1 Hz,
1H), 9.22 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.48 (d, J = 5.3 Hz, 1H),
8.01–7.95 (m, 1H), 7.90 (dt, J = 11.2, 5.2 Hz, 2H), 7.59–7.47 (m,
3H), 7.40 (d, J = 10.5 Hz, 2H), 7.37–7.28 (m, 2H), 7.25 (d,
J = 8.7 Hz, 1H), 6.40 (d, J = 5.2 Hz, 1H), 4.26 (t, J = 6.6 Hz, 2H), 4.04
(s, 3H), 2.74 (t, J = 7.4 Hz, 2H), 2.62 (s, 4H), 2.24–2.15 (m, 2H),
1.84 (d, J = 13.9 Hz, 4H); 13C NMR (400 MHz, CDCl3) d 160.92,
159.94, 158.71, 156.07, 155.74, 152.27, 149.89, 148.72, 146.94,
137.68, 136.82, 135.90, 134.39, 132.59, 130.97, 128.91, 128.78,
128.21, 127.81, 127.54, 124.76, 123.87, 116.87, 116.43, 115.44,
109.82, 109.59, 108.82, 102.18, 99.50, 67.39, 56.16, 54.22 (2C),
53.01, 28.21, 23.50 (2C). Anal. Calcd for C38H33F2N5O5: C, 67.35;
H, 4.91; N, 10.33. Found: C, 67.38; H, 4.92; N, 10.29.
7.4.8. N-(3-Fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-4-oxo-3-phenyl-3,4-
dihydrophthalazine-1-carboxamide (32)
Yellow solid; yield: 68%; mp: 163–166 °C; MS (ESI) m/z (%):
660.2 [M+H]+; 1H NMR (400 MHz, DMSO) d 11.18 (s, 1H), 8.67 (d,
J = 5.8 Hz, 1H), 8.45 (d, J = 7.8 Hz, 2H), 8.14–7.98 (m, 3H), 7.82 (d,
J = 7.7 Hz, 2H), 7.77 (d, J = 9.3 Hz, 1H), 7.68 (s, 1H), 7.58 (dd,
J = 13.3, 7.3 Hz, 4H), 7.48 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 5.3 Hz,
1H), 4.33 (t, J = 6.0 Hz, 2H), 4.02 (s, 3H), 3.60 (d, J = 5.0 Hz, 2H),
3.33 (dd, J = 14.1, 6.4 Hz, 2H), 3.11–2.98 (m, 2H), 2.37–2.24 (m,
2H), 2.03 (s, 2H), 1.97–1.83 (m, 2H); 13C NMR (400 MHz, CDCl3) d
167.24, 166.84, 163.39, 159.59, 158.35, 157.15, 155.52, 151.38,
146.48, 144.98, 143.14, 140.94, 139.41, 137.94, 133.88, 133.82
(2C), 133.18, 132.14, 132.03, 131.48, 131.45 (2C), 129.31, 122.51,
120.08, 114.35, 110.28, 107.75, 104.86, 71.55, 61.42, 58.10 (2C),
56.38, 30.18, 27.98 (2C). Anal. Calcd for C38H34FN5O5: C, 69.18; H,
5.19; N, 10.62. Found: C, 69.15; H, 5.18; N, 10.64.
7.4.12. 3-(4-Bromophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl) -4-oxo-3,4-
dihydrophthalazine-1-carboxamide (36)
Yellow solid; yield: 57%; mp: 168–170 °C; MS (ESI) m/z (%):
638.2 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.27 (s, 1H), 9.23 (d,
J = 8.1 Hz, 1H), 8.57–8.51 (m, 1H), 8.48 (d, J = 5.3 Hz, 1H), 7.93
(dtd, J = 15.2, 8.2, 1.1 Hz, 3H), 7.66 (d, J = 8.8 Hz, 2H), 7.56 (dd,
J = 6.7, 2.1 Hz, 3H), 7.41 (d, J = 4.9 Hz, 2H), 7.29 (d, J = 9.1 Hz, 1H),
6.41 (d, J = 5.2 Hz, 1H), 4.30–4.22 (m, 2H), 4.04 (s, 3H), 2.90–2.81
(m, 2H), 2.76 (s, 4H), 2.31–2.21 (m, 2H), 1.89 (s, 4H); 13C NMR
(400 MHz, CDCl3)
d 160.94, 159.93, 158.98, 155.75, 153.27,
152.13, 149.84, 148.74, 146.87, 140.07, 137.70, 136.70, 135.90,
134.39, 132.63, 132.19, 128.41, 127.76 (2C), 127.35 (2C), 123.93,
122.30, 116.39, 115.51, 109.69, 108.88, 102.22, 99.55, 67.07,
56.15, 54.11 (2C), 53.01, 45.90, 27.68, 23.48 (2C). Anal. Calcd for
7.4.9. N-(3-Fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-4-oxo-
3,4-dihydrophthalazine-1-carboxamide (33)
C38H33BrFN5O5: C, 61.79; H, 4.50; N, 9.48. Found: C, 61.77; H,
4.55; N, 9.50.
Yellow solid; yield: 62%; mp: 160–163 °C; MS (ESI) m/z (%):
678.3 [M+H]+; IR (KBr) cmÀ1: 3377.7, 3075.1, 2956.2, 2877.0,
2794.1, 1677.1, 1620.7, 1604.5, 1579.9, 1508.0, 1430.6, 1384.5,
1349.6, 1329.9, 1305.8, 1250.4, 1210.9, 1172.4, 1139.5, 1077.6,
1020.8, 971.5, 852.8, 836.2, 789.4, 726.0, 685.9, 617.6, 590.7,
544.9, 525.7; 1H NMR (400 MHz, DMSO) d 11.37 (s, 1H), 8.49 (d,
J = 5.2 Hz, 1H), 8.42 (d, J = 8.1 Hz, 2H), 8.15–7.96 (m, 3H), 7.92
(dd, J = 8.7, 5.0 Hz, 2H), 7.82–7.74 (m, 1H), 7.52 (dd, J = 16.6,
7.5 Hz, 2H), 7.40 (t, J = 8.8 Hz, 3H), 6.48 (d, J = 5.1 Hz, 1H), 4.21 (t,
J = 6.3 Hz, 2H), 3.97 (s, 3H), 2.57 (t, J = 7.1 Hz, 2H), 2.46 (s, 4H),
2.05–1.93 (m, 2H), 1.69 (s, 4H); 13C NMR (400 MHz, DMSO) d
7.4.13. 3-(2-Bromophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl) -4-oxo-3,4-
dihydrophthalazine-1-carboxamide (37)
Yellow solid; yield: 51%; mp: 162–164 °C; MS (ESI) m/z (%):
638.2 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.31 (d, J = 8.1 Hz,
1H), 9.23 (s, 1H), 8.57 (d, J = 6.5 Hz, 1H), 8.48 (t, J = 9.3 Hz, 1H),
8.04–7.97 (m, 1H), 7.96–7.86 (m, 2H), 7.82 (d, J = 7.6 Hz, 1H),
7.62–7.49 (m, 3H), 7.49–7.38 (m, 3H), 7.26 (d, J = 8.7 Hz, 1H),
6.41 (d, J = 5.1 Hz, 1H), 4.34–4.23 (m, 2H), 4.05 (s, 3H), 2.71 (t,
J = 7.0 Hz, 2H), 2.58 (s, 4H), 2.18 (dd, J = 14.1, 7.0 Hz, 2H), 1.82 (s,

3650
Z. Liu et al. / Bioorg. Med. Chem. 22 (2014) 3642–3653
4H). Anal. Calcd for C38H33BrFN5O5: C, 61.79; H, 4.50; N, 9.48.
Found: C, 61.73; H, 4.53; N, 9.53.
7.4.18. N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-(2-fluorophenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (42)
7.4.14. N-(3-Fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-nitrophenyl)-4-oxo-
3,4-dihydrophthalazine-1-carboxamide (38)
Yellow solid; yield: 65%; mp: 141–143 °C; MS (ESI) m/z (%):
707.3 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.28 (d, J = 8.1 Hz,
1H), 9.17 (s, 1H), 8.55 (dd, J = 8.3, 7.4 Hz, 1H), 8.48 (d, J = 5.3 Hz,
1H), 8.03–7.95 (m, 1H), 7.91 (dt, J = 14.3, 5.0 Hz, 2H), 7.61–7.49
(m, 3H), 7.44–7.28 (m, 4H), 7.25 (d, J = 8.7 Hz, 1H), 6.41 (d,
J = 5.3 Hz, 1H), 4.32–4.20 (m, 2H), 4.10–3.99 (m, 3H), 2.75–2.50
(m, 8H), 2.60 (d, J = 7.3 Hz, 2H), 2.35 (s, 3H), 2.19–2.09 (m, 2H);
13C NMR (400 MHz, CDCl3) d 160.90, 159.96, 158.85, 158.61,
156.09, 155.75, 153.26, 152.30, 149.89, 148.73, 146.93, 137.68,
136.76, 135.88, 134.40, 132.61, 130.99, 128.79, 128.23, 127.82,
127.56, 124.78, 123.89, 116.91, 116.44, 115.43, 109.71 108.78,
102.19, 99.50, 67.29, 56.17, 54.94 (2C), 54.82, 52.76 (2C), 45.75,
26.28. Anal. Calcd for C39H36F2N6O5: C, 66.28; H, 5.13; N, 11.89.
Found: C, 66.26; H, 5.13; N, 11.91.
Yellow solid; yield: 56%; mp: 171–174 °C; MS (ESI) m/z (%):
705.2 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.24 (d, J = 8.1 Hz,
1H), 9.14 (s, 1H), 8.59 (d, J = 7.8 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H),
8.43 (d, J = 9.0 Hz, 2H), 8.04–7.90 (m, 5H), 7.58 (s, 1H), 7.41 (d,
J = 9.4 Hz, 2H), 7.30 (t, J = 8.3 Hz, 1H), 6.43 (d, J = 5.2 Hz, 1H), 4.28
(dd, J = 13.8, 8.1 Hz, 2H), 4.04 (s, 3H), 3.18 (s, 4H), 3.08 (dd,
J = 14.6, 7.2 Hz, 2H), 2.44 (s, 2H), 2.05 (d, J = 15.0 Hz, 4H). Anal.
Calcd for C38H33FN6O7: C, 64.77; H, 4.72; N, 11.93. Found: C,
64.73; H, 4.75; N, 11.96.
7.4.15. N-(3-Fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-methoxy phenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (39)
7.4.19. 3-(4-Bromophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-
methylpiperazin-1-yl)propoxy)quinolin-4-yl) oxy)phenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (43)
Yellow solid; yield: 59%; mp: 163–164 °C; MS (ESI) m/z (%):
705.2 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.31–9.17 (m, 2H),
8.54 (d, J = 7.9 Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.01–7.84 (m, 3H),
7.71–7.65 (m, 1H), 7.60–7.51 (m, 2H), 7.41 (d, J = 11.5 Hz, 2H),
7.29 (dd, J = 8.2, 4.7 Hz, 1H), 7.25 (d, J = 3.3 Hz, 1H), 7.06 (dd,
J = 9.0, 3.0 Hz, 1H), 6.42 (d, J = 5.2 Hz, 1H), 4.31–4.23 (m, 2H),
4.03 (d, J = 8.5 Hz, 3H), 3.94 (d, J = 37.8 Hz, 3H), 3.04 (s, 2H), 3.00
(d, J = 16.6 Hz, 4H), 2.42–2.28 (m, 2H), 1.99 (s, 4H). Anal. Calcd
for C39H36FN5O6: C, 67.91; H, 5.26; N, 10.15. Found: C, 67.93; H,
5.25; N, 10.14.
Yellow solid; yield: 58%; mp: 143–145 °C; MS (ESI) m/z (%):
767.2 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.32 (s, 1H), 9.22 (d,
J = 8.0 Hz, 1H), 8.53 (dd, J = 7.9, 0.8 Hz, 1H), 8.48 (d, J = 5.3 Hz,
1H), 8.00–7.91 (m, 2H), 7.91–7.84 (m, 1H), 7.68–7.60 (m, 2H),
7.60–7.53 (m, 3H), 7.46–7.39 (m, 2H), 7.29 (d, J = 7.2 Hz, 1H),
6.41 (d, J = 5.2 Hz, 1H), 4.25 (t, J = 6.7 Hz, 2H), 4.04 (s, 3H), 2.61
(d, J = 7.1 Hz, 2H), 2.59 (dd, J = 19.2, 11.9 Hz, 8H), 2.33 (s, 3H),
2.19–2.09 (m, 2H); 13C NMR (400 MHz, CDCl3) d 160.96, 159.93,
158.94, 155.73, 153.25, 152.31, 149.88, 148.67, 146.90, 140.04,
137.68, 136.78, 135.93, 134.37, 132.61, 132.14 (2C), 128.38,
127.72–127.45 (2C), 127.31 (2C), 123.92, 122.25, 116.40, 115.40,
109.68, 108.72, 102.15, 99.47, 67.31, 56.16, 55.01 (2C), 54.85,
52.91 (2C), 45.78, 26.29. Anal. Calcd for C39H36BrFN6O5: C, 61.02;
H, 4.73; N, 10.95. Found: C, 61.04; H, 4.74; N, 10.92.
7.4.16. N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-4-oxo-3-phenyl-3,4-
dihydrophthalazine-1-carboxamide (40)
Yellow solid; yield: 69%; mp: 137–140 °C; MS (ESI) m/z (%):
689.3 [M+H]+; IR (KBr) cmÀ1: 3418.3, 2345.9, 1639.7, 1532.9,
1506.3, 1437.8, 1384.0, 1099.6, 791.8, 710.5, 688.7, 617.4, 466.3;
1H NMR (400 MHz, DMSO) d 11.18 (s, 1H), 8.48 (d, J = 5.2 Hz,
1H), 8.44 (d, J = 8.2 Hz, 2H), 8.12–7.97 (m, 3H), 7.81 (d, J = 7.7 Hz,
2H), 7.73 (d, J = 8.8 Hz, 1H), 7.62–7.53 (m, 3H), 7.48 (dd, J = 15.2,
8.1 Hz, 2H), 7.40 (s, 1H), 6.48 (d, J = 5.1 Hz, 1H), 4.19 (t,
J = 6.2 Hz, 2H), 3.96 (s, 3H), 2.46 (t, J = 7.1 Hz, 2H), 2.43 (dd,
J = 32.0, 24.9 Hz, 8H), 2.15 (s, 3H), 2.02–1.92 (m, 2H). 13C NMR
7.4.20. 3-(2-Bromophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl) -4-oxo-3,4-
dihydrophthalazine-1-carboxamide (44)
Yellow solid; yield: 55%; mp: 139–142 °C; MS (ESI) m/z (%):
767.2 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.32 (d, J = 8.1 Hz,
1H), 9.19 (s, 1H), 8.58 (d, J = 7.0 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H),
8.00 (t, J = 7.6 Hz, 1H), 7.92 (t, J = 7.8 Hz, 2H), 7.83 (d, J = 8.1 Hz,
1H), 7.62–7.52 (m, 3H), 7.52–7.38 (m, 3H), 7.30 (d, J = 12.0 Hz,
1H), 6.42 (d, J = 5.2 Hz, 1H), 4.27 (t, J = 6.3 Hz, 2H), 4.11–4.00 (m,
3H), 2.63 (d, J = 6.6 Hz, 2H), 2.74–2.44 (m, 8H), 2.37 (s, 3H), 2.21–
2.08 (m, 2H). Anal. Calcd for C39H36BrFN6O5: C, 61.02; H, 4.73; N,
10.95. Found: C, 61.03; H, 4.74; N, 10.93.
(400 MHz, DMSO)
d 162.45, 159.70, 158.64, 155.10, 152.66,
152.44, 150.07, 149.31, 146.87, 141.72, 140.39, 137.88, 136.80,
134.73, 133.20, 129.09 (2C), 128.44, 127.40, 127.32, 126.81,
126.65 (2C), 124.63, 117.68, 114.92, 109.57, 108.98, 102.52,
99.49, 67.21, 56.27, 55.27 (2C), 54.83, 53.23 (2C), 46.24, 26.53.
Anal. Calcd for C39H37FN6O5: C, 68.01; H, 5.41; N, 12.20. Found:
C, 67.98; H, 5.44; N, 12.22.
7.4.21. N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-nitro phenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (45)
7.4.17. N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (41)
Yellow solid; yield: 64%; mp: 136–138 °C; MS (ESI) m/z (%):
707.5 [M+H]+; 1H NMR (400 MHz, DMSO) d 11.27 (s, 1H), 8.63
(d, J = 44.5 Hz, 1H), 8.41 (t, J = 12.5 Hz, 2H), 8.24–7.97 (m, 3H),
7.87 (d, J = 28.6 Hz, 2H), 7.79 (s, 1H), 7.74–7.52 (m, 3H), 7.40
(s, 2H), 6.77 (s, 1H), 4.30 (s, 2H), 4.02 (s, 3H), 3.41 (s, 8H),
3.09 (s, 2H), 2.77 (s, 3H), 2.25 (s, 2H); 13C NMR (400 MHz,
Yellow solid; yield: 58%; mp: 146–148 °C; MS (ESI) m/z (%): 734.1
[M+H]+; 1H NMR (400 MHz, CDCl3) d 9.24 (s, 1H), 9.21 (d, J = 8.1 Hz,
1H), 8.58 (d, J = 7.3 Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.43 (t, J = 9.6 Hz,
2H), 8.06–7.89 (m, 4H), 7.58 (s, 1H), 7.47 (dd, J = 20.6, 14.2 Hz, 2H),
7.35–7.27 (m, 2H), 6.45 (t, J = 5.7 Hz, 1H), 4.28 (t, J = 6.2 Hz, 2H),
4.05 (s, 3H), 3.11 (q, J = 7.0 Hz, 2H), 2.87 (dd, J = 45.6, 38.7 Hz, 8H),
2.68 (s, 3H), 2.15 (d, J = 6.1 Hz, 2H). Anal. Calcd for C39H36FN7O7: C,
63.84; H, 4.95; N, 13.36. Found: C, 63.82; H, 4.96; N, 13.37.
DMSO)
d 162.85, 162.44, 160.41, 158.74, 154.80, 153.91,
152.35, 150.90, 146.20, 140.18, 138.46, 138.02, 136.09, 134.68,
133.20, 132.79, 128.94 (2C), 128.37, 127.33, 126.82, 124.53,
117.76, 116.01, 115.79 (2C), 115.31, 109.60, 103.01, 100.14,
67.08, 56.70, 53.36, 50.77 (2C), 48.86 (2C), 42.33, 24.52. Anal.
Calcd for C39H36F2N6O5: C, 66.28; H, 5.13; N, 11.89. Found: C,
66.25; H, 5.14; N, 11.91.
7.4.22. N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-methoxyphenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (46)
Yellow solid; yield: 62%; mp: 147–148 °C; MS (ESI) m/z (%):
719.5 [M+H]+; IR (KBr) cmÀ1: 3380.0, 3071.5, 2934.6, 2794.2,

Z. Liu et al. / Bioorg. Med. Chem. 22 (2014) 3642–3653
3651
1676.5, 1620.6, 1605.7, 1579.5, 1509.2, 1479.3, 1430.3, 1384.1,
1348.8, 1304.8, 1251.0, 1211.0, 1168.4, 1139.5, 1021.3, 853.7,
832.5, 728.7, 686.3, 618.1, 555.7; 1H NMR (400 MHz, CDCl3) d
9.42–9.30 (m, 1H), 9.30–9.14 (m, 1H), 8.52 (dd, J = 7.9, 1.6 Hz,
1H), 8.48 (d, J = 5.2 Hz, 1H), 8.02–7.91 (m, 2H), 7.91–7.82 (m,
1H), 7.68–7.63 (m, 1H), 7.60–7.54 (m, 2H), 7.54 (s, 1H), 7.47–
7.39 (m, 2H), 7.31–7.28 (m, 1H), 7.06–6.98 (m, 1H), 6.42 (d,
J = 5.2 Hz, 1H), 4.25 (t, J = 6.6 Hz, 2H), 4.04 (s, 3H), 3.99–3.84 (m,
3H), 2.62 (s, 2H), 2.71–2.48 (m, 8H), 2.37 (s, 3H), 2.18–2.10 (m,
2H); 13C NMR (400 MHz, CDCl3) d 161.12, 159.97, 158.99, 155.72,
154.97, 153.23, 152.28, 149.87, 148.69, 146.88, 135.96, 134.09,
132.43, 128.16, 127.74, 127.55 (2C), 127.02, 126.36, 125.27,
123.88, 122.65, 116.40, 115.42, 114.19, 111.62, 109.36, 108.71,
102.18, 99.50, 67.24, 56.15, 55.60, 54.90 (2C), 54.78, 52.67 (2C),
45.69, 26.26. Anal. Calcd for C40H39FN6O6: C, 66.84; H, 5.47; N,
11.69. Found: C, 66.85; H, 5.46; N, 11.67.
J = 15.4, 6.6 Hz, 2H), 7.37–7.29 (m, 2H), 7.25 (s, 1H), 6.42 (d,
J = 5.2 Hz, 1H), 4.26 (t, J = 6.7 Hz, 2H), 4.05 (s, 3H), 2.54 (t,
J = 7.3 Hz, 2H), 2.43 (s, 4H), 2.20–2.11 (m, 2H), 1.60 (dd, J = 10.8,
5.3 Hz, 4H), 1.45 (s, 2H); 13C NMR (400 MHz, CDCl3) d 160.89,
159.94, 158.86, 158.62, 156.10, 155.76, 153.27, 152.38, 149.93,
148.71, 146.99, 137.72, 136.75, 135.84, 134.41, 132.61, 131.00,
128.79, 128.24, 127.84, 127.56, 124.78, 123.89, 116.91, 116.43,
115.39, 109.71, 108.79, 102.16, 99.45, 67.69, 56.17, 55.81, 54.63
(2C), 26.42, 26.05 (2C), 24.48. Anal. Calcd for C39H35F2N5O5: C,
67.72; H, 5.10; N, 10.12. Found: C, 67.74; H, 5.11; N, 10.09.
7.4.26. 3-(4-Bromophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-
(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl) -4-oxo-3,4-
dihydrophthalazine-1-carboxamide (50)
Yellow solid; yield: 56%; mp: 178–180 °C; MS (ESI) m/z (%):
752.5 [M+H]+; IR (KBr) cmÀ1: 3379.4, 2931.8, 2851.1, 1677.0,
1620.4, 1597.5, 1578.5, 1508.2, 1479.3, 1430.2, 1384.1, 1348.7,
1326.0, 1305.7, 1249.8, 1210.6, 1171.4, 1138.9, 1078.6, 1011.5,
852.2, 828.4, 788.8, 751.6, 686.4, 616.3, 513.9; 1H NMR
(400 MHz, CDCl3) d 9.28 (s, 1H), 9.24 (d, J = 8.1 Hz, 1H), 8.59–8.52
(m, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.01–7.86 (m, 3H), 7.70–7.64 (m,
2H), 7.58 (dt, J = 6.7, 2.3 Hz, 3H), 7.42 (d, J = 7.2 Hz, 2H), 7.29 (d,
J = 9.5 Hz, 1H), 6.42 (d, J = 5.2 Hz, 1H), 4.25 (t, J = 6.4 Hz, 2H), 4.04
(s, 3H), 2.72 (s, 2H), 2.62 (s, 4H), 2.32–2.18 (m, 2H), 1.72 (s, 4H),
1.51 (s, 2H); 13C NMR (400 MHz, CDCl3) d 161.05, 159.94, 158.91,
155.69, 153.21, 152.17, 149.84, 148.65, 146.81, 140.03, 137.62,
137.02, 136.07, 134.32, 132.56, 132.06 (2C), 128.34, 127.57,
127.47, 127.28 (2C), 123.88, 122.15, 116.46, 115.49, 109.70,
108.78, 102.20, 99.55, 67.21, 56.12, 55.59, 54.27 (2C), 25.68,
25.15 (2C), 23.86. Anal. Calcd for C39H35BrFN5O5: C, 62.24; H,
4.69; N, 9.31. Found: C, 62.22; H, 4.70; N, 9.33.
7.4.23. N-(3-Fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-4-oxo-3-phenyl-3,4-
dihydrophthalazine-1-carboxamide (47)
Yellow solid; yield: 61%; mp: 183–185 °C; MS (ESI) m/z (%):
674.1 [M+H]+; IR (KBr) cmÀ1: 3384.5, 3060.4, 2941.1, 2638.0,
2537.1, 1671.7, 1597.0, 1507.4, 1478.7, 1431.2, 1384.6, 1350.3,
1329.9, 1306.0, 1282.6, 1252.5, 1210.5, 1173.0, 1140.0, 1113.0,
1078.6, 1020.4, 971.8, 938.5, 852.8, 756.3, 687.6, 568.6; 1H NMR
(400 MHz, DMSO)
d 11.21 (s, 1H), 10.51 (s, 1H), 8.61 (d,
J = 5.1 Hz, 1H), 8.44 (d, J = 6.9 Hz, 2H), 8.18–7.95 (m, 3H), 7.83 (d,
J = 7.5 Hz, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.56 (d,
J = 8.2 Hz, 3H), 7.48 (d, J = 7.1 Hz, 1H), 6.67 (d, J = 4.0 Hz, 1H),
4.30 (s, 2H), 4.00 (s, 3H), 3.49 (d, J = 10.6 Hz, 2H), 2.92 (s, 2H),
2.50 (s, 2H), 2.34 (s, 2H), 1.81 (s, 4H), 1.76–1.31 (m, 2H); 13C
NMR (400 MHz, DMSO) d 162.47, 161.88–160.56 (m, 1H), 158.64,
155.05–154.78 (m, 0H), 153.29–152.82 (m, 1H), 152.60–152.36
(m, 0H), 150.51, 147.72–147.27 (m, 1H), 141.71, 140.25, 138.48–
137.97 (m, 1H), 136.52–136.07 (m, 1H), 134.76, 133.23, 129.17,
129.09 (s, 2H), 128.44, 127.41, 127.29, 126.68 (s, 3H), 124.62,
117.71, 115.27, 109.95–109.58 (m, 0H), 109.58–109.20 (m, 0H),
102.90, 99.95, 66.84, 56.57, 53.89, 52.52 (s, 2H), 23.54, 22.85 (s,
3H), 21.85. Anal. Calcd for C39H36FN5O5: C, 69.53; H, 5.39; N,
10.39. Found: C, 69.50; H, 5.40; N, 10.40.
7.4.27. N-(3-Fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-nitrophenyl)-4-oxo-
3,4-dihydrophthalazine-1-carboxamide (51)
Yellow solid; yield: 51%; mp: 187–190 °C; MS (ESI) m/z (%):
718.4 [M+H]+; IR (KBr) cmÀ1: 3418.4, 2935.3, 1679.9, 1621.1,
1596.0, 1509.7, 1432.2, 1384.4, 1349.2, 1323.8, 1307.1, 1252.3,
1211.4, 1172.6, 1139.5, 1114.8, 1022.0, 972.4, 941.0, 845.4, 750.7,
686.7, 617.9; 1H NMR (400 MHz, CDCl3) d 9.34 (s, 1H), 9.20 (d,
J = 8.1 Hz, 1H), 8.58 (d, J = 7.2 Hz, 1H), 8.49 (d, J = 4.6 Hz, 1H),
8.39 (t, J = 10.4 Hz, 2H), 8.05–7.97 (m, 4H), 7.94 (dd, J = 11.2,
4.0 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.38 (s, 1H), 7.31
(t, J = 7.1 Hz, 1H), 6.43 (d, J = 5.1 Hz, 1H), 4.26 (t, J = 5.6 Hz, 2H),
4.03 (s, 3H), 3.42–2.82 (m, 6H), 2.53 (d, J = 4.6 Hz, 2H), 2.03 (s,
4H), 1.69 (s, 2H); 13C NMR (400 MHz, CDCl3) d 160.77, 160.02,
158.92, 155.72, 153.24, 151.66, 149.71, 148.74, 146.64, 146.03,
137.99, 137.72, 135.96, 134.75, 133.01, 128.36, 127.82, 127.46,
126.31 (2C), 124.37 (2C), 123.97, 116.54, 115.84, 109.84, 109.05,
102.41, 99.76, 66.12, 56.09, 55.30, 53.58 (2C), 23.85, 22.93 (2C),
22.32. Anal. Calcd for C39H35FN6O7: C, 65.17; H, 4.91; N, 11.69.
Found: C, 65.19; H, 4.90; N, 11.67.
7.4.24. N-(3-Fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-4-oxo-
3,4-dihydrophthalazine-1-carboxamide (48)
Yellow solid; yield: 59%; mp: 187–190 °C; MS (ESI) m/z (%):
692.3 [M+H]+; 1H NMR (400 MHz, DMSO) d 10.47 (s, 1H), 8.71 (d,
J = 5.4 Hz, 1H), 8.44 (d, J = 7.8 Hz, 2H), 8.17–7.97 (m, 3H), 7.91
(dd, J = 19.2, 11.2 Hz, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.69 (d,
J = 16.4 Hz, 2H), 7.61 (t, J = 8.8 Hz, 1H), 7.41 (t, J = 8.5 Hz, 2H),
6.81 (d, J = 4.9 Hz, 1H), 4.32 (s, 2H), 4.03 (s, 3H), 3.49 (d,
J = 11.1 Hz, 2H), 3.22 (s, 2H), 2.92 (s, 2H), 2.36 (s, 2H), 1.82 (s,
4H), 1.76–1.33 (m, 2H); 13C NMR (400 MHz, DMSO) d 164.83,
162.46, 160.42, 158.74, 154.77, 154.00, 152.32, 150.98, 145.86,
140.19, 138.56, 138.06, 136.00, 134.68, 133.19, 132.79, 128.95
(2C), 128.37, 127.34, 126.73, 124.52, 117.79, 115.90, 116.01 (2C),
115.38, 109.60, 103.09, 100.23, 67.11, 56.75, 53.79, 52.49 (2C),
23.46, 22.79 (2C), 21.88. Anal. Calcd for C39H35F2N5O5: C, 67.72;
H, 5.10; N, 10.12. Found: C, 67.75; H, 5.12; N, 10.09.
7.4.28. N-(3-Fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-methoxy phenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (52)
Yellow solid; yield: 54%; mp: 183–185 °C; MS (ESI) m/z (%):
703.3 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.25 (dt, J = 22.0,
11.7 Hz, 2H), 8.56 (d, J = 7.8 Hz, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.03–
7.84 (m, 3H), 7.74–7.66 (m, 1H), 7.57 (dt, J = 8.8, 3.1 Hz, 2H), 7.44
(s, 1H), 7.41 (d, J = 6.8 Hz, 1H), 7.33–7.25 (m, 2H), 7.07 (dd,
J = 9.0, 2.6 Hz, 1H), 6.43 (d, J = 5.3 Hz, 1H), 4.26 (t, J = 6.7 Hz, 2H),
4.06 (s, 3H), 4.03–3.86 (m, 3H), 2.57 (t, J = 7.1 Hz, 2H), 2.46 (s,
4H), 2.25–2.10 (m, 2H), 1.68–1.55 (m, 4H), 1.46 (s, 2H). Anal. Calcd
for C40H38FN5O6: C, 68.27; H, 5.44; N, 9.95. Found: C, 68.24; H,
5.46; N, 9.97.
7.4.25. N-(3-Fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)-3-(2-fluorophenyl)-4-oxo-
3,4-dihydrophthalazine-1-carboxamide (49)
Yellow solid; yield: 63%; mp: 181–183 °C; MS (ESI) m/z (%):
692.3 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.29 (d, J = 8.2 Hz,
1H), 9.18 (s, 1H), 8.56 (t, J = 8.5 Hz, 1H), 8.53–8.44 (m, 1H), 7.99
(t, J = 7.8 Hz, 1H), 7.96–7.87 (m, 2H), 7.62–7.49 (m, 3H), 7.41 (dd,

3652
Z. Liu et al. / Bioorg. Med. Chem. 22 (2014) 3642–3653
7.4.29. N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-4-oxo-3-phenyl-3,4-
dihydrophthalazine-1-carboxamide (53)
(m, 3H), 7.47–7.38 (m, 2H), 7.35 (dd, J = 8.7, 3.6 Hz, 1H), 7.33–
7.25 (m, 2H), 6.41 (t, J = 5.5 Hz, 1H), 4.32–4.21 (m, 2H), 4.05 (s,
3H), 2.98 (d, J = 10.6 Hz, 2H), 2.63 (s, 2H), 2.20 (s, 2H), 2.05 (s,
2H), 1.67 (d, J = 11.2 Hz, 2H), 1.38 (s, 1H), 1.37–1.16 (m, 2H), 0.97
(dd, J = 13.3, 6.6 Hz, 3H); 13C NMR (400 MHz, CDCl3) d 160.89,
159.94, 158.86, 156.11, 153.56–153.11, 152.28, 149.90, 148.75,
146.96, 137.66, 136.74, 135.90, 134.40, 132.61, 131.00, 128.80,
128.24, 127.84, 127.56, 124.78, 123.89, 117.02, 116.82, 116.40,
115.45, 109.82, 109.59, 108.86, 102.20, 99.50, 67.49, 56.16, 55.40,
53.93 (2C), 33.97 (2C), 30.66, 26.25, 21.79. Anal. Calcd for C40H37F2-
N5O5: C, 68.07; H, 5.28; N, 9.92. Found: C, 68.05; H, 5.27; N, 9.95.
Yellow solid; yield: 57%; mp: 173–175 °C; MS (ESI) m/z (%):
688.6 [M+H]+; IR (KBr) cmÀ1: 3426.8, 3065.2, 2951.3, 2617.4,
2507.5, 1668.5, 1597.4, 1507.0, 1478.3, 1456.9, 1432.3, 1350.1,
1332.1, 1282.8, 1218.4, 1174.1, 1140.7, 1019.7, 857.1, 756.1,
688.7, 631.9, 573.1; 1H NMR (400 MHz, DMSO) d 11.20 (s, 1H),
8.65 (d, J = 5.4 Hz, 1H), 8.18–7.90 (m, 4H), 7.82 (d, J = 7.6 Hz, 2H),
7.77 (d, J = 8.8 Hz, 1H), 7.71–7.62 (m, 2H), 7.58 (dd, J = 12.8,
8.5 Hz, 4H), 7.47 (t, J = 7.1 Hz, 1H), 6.73 (d, J = 4.7 Hz, 1H), 4.30 (s,
2H), 4.01 (s, 3H), 3.51 (d, J = 10.9 Hz, 2H), 3.22 (s, 2H), 2.93 (d,
J = 11.2 Hz, 2H), 2.35 (s, 2H), 1.90–1.71 (m, 2H), 1.62 (s, 1H),
1.59–1.40 (m, 2H), 0.97 (dd, J = 33.6, 5.7 Hz, 3H); 13C NMR
7.4.33. 3-(4-Bromophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-
methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy) phenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (57)
(400 MHz, DMSO)
d 164.91, 162.48, 161.87, 158.69, 154.85,
153.43, 152.41, 150.67, 146.82, 141.80, 140.21, 138.36, 137.30,
136.22, 134.64, 132.95, 129.15, 129.06 (2C), 128.42, 127.23,
126.70 (2C), 124.54, 117.74, 115.31, 109.59, 105.88, 102.95,
100.05, 66.96, 56.63, 53.91, 52.35 (2C), 31.15 (2C), 28.67, 23.58,
21.58. Anal. Calcd for C40H38FN5O5: C, 69.85; H, 5.57; N, 10.18.
Found: C, 69.88; H, 5.55; N, 10.16.
Yellow solid; yield: 55%; mp: 169–172 °C; MS (ESI) m/z (%):
766.2 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.33 (s, 1H), 9.22 (d,
J = 8.1 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.48 (d, J = 5.3 Hz, 1H),
8.02–7.93 (m, 2H), 7.88 (dd, J = 11.1, 4.1 Hz, 1H), 7.71–7.62 (m,
2H), 7.62–7.52 (m, 3H), 7.47–7.38 (m, 2H), 7.29 (d, J = 8.0 Hz,
1H), 6.41 (d, J = 5.2 Hz, 1H), 4.24 (t, J = 6.3 Hz, 2H), 4.04 (s, 3H),
2.80 (s, 2H), 2.27 (d, J = 6.4 Hz, 4H), 1.71 (d, J = 9.1 Hz, 2H), 1.44
(d, J = 32.5 Hz, 3H), 1.38–1.29 (m, 2H), 0.97 (d, J = 4.6 Hz, 3H); 13C
NMR (400 MHz, CDCl3) d 160.99, 159.95, 158.96, 155.72, 153.24,
152.09, 149.82, 148.71, 146.81, 140.07, 137.65, 136.83, 135.97,
134.36, 132.61, 132.15 (2C), 128.39, 127.76 (2C), 127.35 (2C),
123.90, 122.25, 116.42, 115.53, 109.70, 108.86, 102.22, 99.56,
67.09, 56.12, 55.19, 53.58 (2C), 32.98 (2C), 30.24, 25.54, 21.50.
Anal. Calcd for C40H37BrFN5O5: C, 62.67; H, 4.86; N, 9.13. Found:
C, 62.64; H, 4.88; N, 9.12.
7.4.30. N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (54)
Yellow solid; yield: 62%; mp: 171–174 °C; MS (ESI) m/z (%):
706.3 [M+H]+; IR (KBr) cmÀ1: 3383.9, 3080.3, 3010.5, 2953.3,
2922.3, 2776.8, 1671.4, 1622.6, 1605.9, 1583.3, 1509.3, 1429.5,
1385.4, 1349.7, 1329.6, 1305.1, 1291.3, 1255.3, 1174.7, 1138.8,
1051.2, 1021.1, 974.9, 933.0, 851.6, 838.3, 726.1, 683.5, 617.9,
593.4, 526.3; 1H NMR (400 MHz, DMSO) d 11.37 (s, 1H), 8.48 (d,
J = 5.2 Hz, 1H), 8.14–7.95 (m, 3H), 7.94–7.88 (m, 2H), 7.88–7.72
(m, 2H), 7.51 (dd, J = 17.0, 8.0 Hz, 2H), 7.43–7.35 (m, 3H), 7.31
(dd, J = 12.2, 5.5 Hz, 1H), 6.47 (d, J = 4.9 Hz, 1H), 4.18 (t, J = 6.4 Hz,
2H), 3.96 (s, 3H), 2.84 (d, J = 11.2 Hz, 2H), 2.43 (t, J = 7.1 Hz, 2H),
2.02–1.91 (m, 2H), 1.86 (t, J = 11.4 Hz, 2H), 1.56 (d, J = 11.5 Hz,
2H), 1.38–1.25 (m, 1H), 1.13 (qd, J = 12.2, 3.5 Hz, 2H), 0.86 (t,
J = 11.6 Hz, 3H); 13C NMR (400 MHz, DMSO) d 166.71, 163.08,
162.39, 160.40, 159.70, 158.65, 152.54, 150.06, 149.29, 146.87,
140.31, 138.00, 137.83, 136.78, 134.72, 133.18, 128.92, 128.61,
128.36, 127.31, 124.61, 117.63, 115.94, 115.71, 115.53, 114.90,
109.41, 108.96, 99.47, 67.28, 56.26, 55.19, 53.98 (2C), 34.50 (2C),
30.90, 26.71, 22.32. Anal. Calcd for C40H37F2N5O5: C, 68.07; H,
5.28; N, 9.92. Found: C, 68.04; H, 5.29; N, 9.90.
7.4.34. 3-(2-Bromophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-
methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy) phenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (58)
Yellow solid; yield: 57%; mp: 170–172 °C; MS (ESI) m/z (%):
766.2 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.31 (d, J = 8.2 Hz,
1H), 9.22 (s, 1H), 8.57 (d, J = 7.9 Hz, 1H), 8.48 (t, J = 6.6 Hz, 1H),
8.05–7.96 (m, 1H), 7.96–7.86 (m, 2H), 7.82 (d, J = 7.8 Hz, 1H),
7.60–7.53 (m, 3H), 7.46–7.39 (m, 3H), 7.25 (d, J = 8.7 Hz, 1H),
6.41 (d, J = 5.2 Hz, 1H), 4.25 (t, J = 6.5 Hz, 2H), 4.04 (s, 3H), 2.96
(d, J = 8.6 Hz, 2H), 2.59 (s, 2H), 2.15 (dd, J = 13.8, 6.8 Hz, 2H), 1.99
(s, 2H), 1.64 (d, J = 12.0 Hz, 2H), 1.40 (d, J = 31.8 Hz, 1H), 1.28 (d,
J = 10.2 Hz, 2H), 0.94 (d, J = 6.2 Hz, 3H). Anal. Calcd for C40H37-
BrFN5O5: C, 62.67; H, 4.86; N, 9.13. Found: C, 62.65; H, 4.87; N,
9.12.
7.4.31. N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-(3-fluorophenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (55)
7.4.35. N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-nitro phenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (59)
Yellow solid; yield: 66%; mp: 165–168 °C; MS (ESI) m/z (%):
706.2 [M+H]+; 1H NMR (400 MHz, DMSO) d 11.41 (s, 1H), 8.84 (s,
1H), 8.43 (d, J = 3.7 Hz, 2H), 8.17 (d, J = 12.6 Hz, 1H), 8.03 (dd,
J = 17.5, 7.0 Hz, 2H), 7.94–7.80 (m, 3H), 7.78 (s, 1H), 7.75 (d,
J = 7.7 Hz, 1H), 7.65 (dd, J = 15.3, 7.0 Hz, 1H), 7.60 (d, J = 6.8 Hz,
1H), 7.33 (d, J = 7.5 Hz, 1H), 7.00 (s, 1H), 4.34 (s, 2H), 4.06 (s, 3H),
3.50 (d, J = 9.4 Hz, 2H), 3.22 (s, 2H), 2.93 (d, J = 9.0 Hz, 2H), 2.39
(s, 2H), 1.78 (d, J = 11.9 Hz, 2H), 1.58 (d, J = 12.1 Hz, 2H), 1.54 (s,
1H), 0.92 (d, J = 4.2 Hz, 3H). Anal. Calcd for C40H37F2N5O5: C,
68.07; H, 5.28; N, 9.92. Found: C, 68.05; H, 5.29; N, 9.90.
Yellow solid; yield: 54%; mp: 175–177 °C; MS (ESI) m/z (%):
733.4 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.24 (d, J = 5.2 Hz,
1H), 9.23 (s, 1H), 8.59 (d, J = 7.5 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H),
8.43 (d, J = 9.0 Hz, 2H), 8.06–7.91 (m, 5H), 7.58 (s, 1H), 7.44 (d,
J = 8.7 Hz, 1H), 7.40 (s, 1H), 7.32 (d, J = 8.6 Hz, 1H), 6.43 (d,
J = 5.1 Hz, 1H), 4.26 (t, J = 5.9 Hz, 2H), 4.04 (s, 3H), 3.10–2.92 (m,
2H), 2.43 (s, 2H), 2.40 (s, 2H), 1.78 (s, 2H), 1.58 (s, 2H), 1.51–1.38
(m, 1H), 1.23 (dd, J = 15.8, 8.7 Hz, 2H), 1.02 (d, J = 6.0 Hz, 3H). Anal.
Calcd for C40H37FN6O7: C, 65.56; H, 5.09; N, 11.47. Found: C, 65.54;
H, 5.10; N, 11.49.
7.4.32. N-(3-Fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-
yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-(2-fluorophenyl)-4-
oxo-3,4-dihydrophthalazine-1-carboxamide (56)
Acknowledgments
Yellow solid; yield: 59%; mp: 174–176 °C; MS (ESI) m/z (%):
706.3 [M+H]+; 1H NMR (400 MHz, CDCl3) d 9.29 (d, J = 8.0 Hz,
1H), 9.17 (s, 1H), 8.57 (d, J = 7.1 Hz, 1H), 8.49 (dd, J = 9.3, 5.2 Hz,
1H), 8.05–7.96 (m, 1H), 7.92 (dt, J = 14.2, 4.9 Hz, 2H), 7.66–7.50
The work was supported by Program for Innovative Research
Team of the Ministry of Education of the People’s Republic of China
and Program for Liaoning Innovative Research Team in University
(IRT1073).

Z. Liu et al. / Bioorg. Med. Chem. 22 (2014) 3642–3653
3653
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Bellon, S. F.; Whittington, D. A.; Harmange, J. C.; Dominguez, C.; Kim, T. S.;
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2014.05.013.
References and notes
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