Design, synthesis and biological evaluation of new Axl kinase inhibitors containing 1,3,4-oxadiazole acetamide moiety as novel linker

Article abstract of DOI:10.1016/j.ejmech.2019.111867

Using the principle of bioisosteric replacement, we present a structure-based design approach to obtain new Axl kinase inhibitors with significant activity at the kinase and cellular levels. Through a stepwise structure-activity relationships exploration, a series of 6,7-disubstituted quinoline derivatives, which contain 1,3,4-oxadiazol acetamide moiety as novel Linker, were ultimately synthesized with Axl as the primary target. Most of them exhibited moderate to excellent activity, with IC₅₀ values ranging from 0.032 to 1.54 μM against the tested cell lines. Among them, the most promising compound 47e, as an Axl kinase inhibitor (IC₅₀ = 10 nM), shows remarkable cytotoxicity against A549, HT-29, PC-3, MCF-7, H1975 and MDA-MB-231 cell lines. More importantly, 47e also shows a significant inhibitory effect on EGFR-TKI resistant NSCLC cell lines H1975/gefitinib. Meanwhile, this study provides a novel type of linker for Axl kinase inhibitors, namely 1,3,4-oxadiazol acetamide moiety, which is out of the scope of the “5- atoms role ".

Full text of DOI:10.1016/j.ejmech.2019.111867

Journal Pre-proof
Design, synthesis and biological evaluation of new Axl kinase inhibitors containing
1,3,4-oxadiazole acetamide moiety as novel linker
Congjun Xu, Yufei Han, Sicong Xu, Ruxin Wang, Ming Yue, Yu Tian, Xiaofan Li,
Yanfang Zhao, Ping Gong
PII:
S0223-5234(19)31019-0
DOI:
https://doi.org/10.1016/j.ejmech.2019.111867
EJMECH 111867
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 16 July 2019
Revised Date: 31 October 2019
Accepted Date: 7 November 2019
Please cite this article as: C. Xu, Y. Han, S. Xu, R. Wang, M. Yue, Y. Tian, X. Li, Y. Zhao, P. Gong,
Design, synthesis and biological evaluation of new Axl kinase inhibitors containing 1,3,4-oxadiazole
acetamide moiety as novel linker, European Journal of Medicinal Chemistry (2019), doi: https://
doi.org/10.1016/j.ejmech.2019.111867.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Masson SAS.

Design, synthesis and biological evaluation of new Axl kinase inhibitors containing 1,3,4-oxadiazole
acetamide moiety as novel linker
Congjun Xua,b*, Yufei Hana, Sicong Xua, Ruxin Wanga, Ming Yuea, Yu Tiana, Xiaofan Lia, Yanfang Zhaoa ,
Ping Gonga
a
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of
Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province,
PR China
b
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, People’s Republic of
China
Corresponding author. Tel: +86-024-43520216; Fax: +86-024-43520216;
E-mail address: gongpinggp@126.com
Abstract
Using the principle of bioisosteric replacement, we present a structure-based design approach to obtain
new Axl kinase inhibitors with significant activity at the kinase and cellular levels. Through a stepwise
structure-activity relationships exploration, a series of 6,7-disubstituted quinoline derivatives, which
contain 1,3,4-oxadiazol acetamide moiety as novel Linker, were ultimately synthesized with Axl as the
primary target. Most of them exhibited moderate to excellent activity, with IC50 values ranging from 0.032
to 1.54 µM against the tested cell lines. Among them, the most promising compound 47e, as an Axl kinase
inhibitor (IC50 = 10 nM), shows remarkable cytotoxicity against A549, HT-29, PC-3, MCF-7, H1975 and
MDA-MB-231 cell lines. More importantly, 47e also shows a significant inhibitory effect on EGFR-TKI
resistant NSCLC cell lines H1975/gefitinib. Meanwhile, this study provides a novel type of linker for Axl
kinase inhibitors, namely 1,3,4-oxadiazol acetamide moiety, which is out of the scope of the "5- atoms role
".
Keywords: Axl, EGFR, drug resistance, 1,3,4-oxadiazole, Isosteresis
1. Introduction
Lung cancer remains one of the most common malignant cancers worldwide, with approximately 1.8
million new cases diagnosed annually. Among them, non-small cell lung cancer (NSCLC) accounts for
about 85%. NSCLC targeted therapy has now become critically important, and the epidermal growth factor
receptor (EGFR) tyrosine kinase is a particular popular target, but its drug resistance has become a major
challenge in the targeted treatment of NSCLC. The receptor tyrosine kinase Axl is one of most
phosphorylated RTKs in over 50% of non-small cell lung cancer cells (NSCLCs). Accumulating evidence
suggests that Axl is an effective target for the treatment of non-small cell lung cancer and overcoming the
drug resistance of EGFR-TKI[1-3].
Axl belongs to the TAM family as Mer and Tyro-3[4]. Upon activation by its endogenous ligand

growth arrest-specific 6 (Gas6)[5], Axl exhibits a key role in many fundamental cellular processes,
including survival[6], adhesion, proliferation[7], differentiation[8], migration, invasion and angiogenesis
though activating the downstream signaling pathways. Apart from NSCLC, overexpression of Axl has been
observed in a wide range of tumor types, both liquid and solid, such as prostate carcinoma[9], breast
cancer[10], pancreatic cancer[11], leukemia[12], and in most cases high Axl expression correlates with a
poorer patient prognosis.
Moreover, overexpression and/or overactivation of Axl are considered as an important mechanism of
drug-resistance in NSCLC[13]. It has been reported that treatment of resistant cell lines with Axl inhibitors
restored the sensitivity of the cells to some targeted drugs[14]. Thus, Axl becomes a new promising
molecular target for anticancer drug discovery.
In the past decade, several well-characterized receptor tyrosine kinase inhibitors were discovered as Axl
inhibitors with low IC50 values, which were reported as multitarget kinase inhibitors. Cabozantinib[15]
(CometriqTM, 1), a Met/VEGFR2 inhibitor, was approved by FDA in 2012 for the treatment of patients with
progressive metastatic medullary thyroid cancer (MTC). While identified as c-MET and VEGFR2 inhibitor,
Cabozatinib inhibits other kinases such as Axl at the low nanomolar level (IC50 = 7 nM in cell free
assay)[16]. In addition, Liu, L. has reported that Cabozatinib almost inhibited Axl phosphorylation
completely in lapatinib-resistance breast cancer cells at 100 nM and restored sensitivity to lapatinib in
treated cells, suggesting that activation of Axl might be a mechanism of drug resistance [17]. Also as
quinoline derivatives, Foretinib is an extremely potent VEGFR2 inhibitor (IC50 = 0.035 nM, in cell-free
assays) that also inhibits a wide number of kinases, including Met, Kit, Ret, and Axl (IC50= 11 nM, in
cell-free assays) in the low nanomolar range [18]. Other inhibitors such as NPS-1034, LY2801663 and
MGCD265 are also multitarget kinase inhibitors. R428 (BGB324, 3) is recognized as a first selective Axl
inhibitor with an IC50 value of 14.0ꢀnM. However, recent reports suggest that R428 also inhibit other
kinases (e.g. RET, VEGFR2 and Flt3) as potently as Axl[19, 20].
Figure 1. The representative small-molecule Axl inhibitors
Although increasing attention has been focused on the development of Axl kinase inhibitors, improving
the selectivity of Axl inhibitors is still an urgent problem to be solved. Ke Ding’ team developed a series of
6,7-dimethoxyquinazolin derivatives exhibiting considerable selectivity[20, 21]. However, there is a lack of

further investigation on the antitumor activity and overcoming drug resistance of these compounds. Thus,
in this paper, we developed a class of new inhibitors primarily targeting Axl, and explored their antitumor
activity and overcoming EGFR-TKI resistance.
2. Results and discussion
2.1 Design strategy of the new compounds
As shown in Figure 1, significant structural similarities are found in Cabozatinib, Forotinib and other
related multitarget kinase inhibitors such as NPS-1034 (4), LY2801663 (5), MGCD265 (6), 7[20]and 8[21].
These inhibitors include three chemical moieties: the hinge-binding heterocycles at the left side; middle
linker highlighted in red; the terminal para-F phenyl ring.
The SAR studies[22] about these compounds suggested that hinge-binding heterocycles and terminal
phenyl ring (usually 4-fluorophenyl) appear to be critical for kinase activity. Hence, at the beginning of this
study, we introduced five-membered azole heterocycles as bioisosteres into the linker to meet our previous
study “5-atoms role”[23] and got four series of compounds (23a-b, 24a-b, 25a-b and 26a-b in Figure 2
Step A). With the goal of targeting Axl, these compounds were evaluated for their in vitro inhibitory
activity against Axl kinase. The results indicated that they did not show excellent Axl kinase inhibitory
activity, but it can be seen that the cycloamino substituted propoxy substituent at position 7 of quinolines
plays a role in the interaction with the active site of Axl (shown in Table 1). In the molecular docking
experiment, it was found that the cyclic amino group was embedded in the hydrophilic pocket of Axl kinase,
which increased the affinity. (shown in Figure S1 in SI).
Figure 2. The design strategy of target compounds. (Step A): Based on the principle of bioisosteric
replacement, the amide bond is replaced by various five-membered azole heterocycles. (Step B):
CAD-based and SAR-based drug design.
Based on the result above, an assumption was drawn that the replacement of amides with
five-membered heterocycles and the removal of methylene to meet the "5-atoms role" would lead to an
increase in the rigidity of the Linker, which would be detrimental for target compounds into the Axl kinase
binding site. From this assumption, one carbon atom was added at the carbonyl alpha position to increase
molecular flexibility and several alkyl groups were introduced to limit conformations (Figure 2 Step B).
As proof of this concept, two compounds were docked to the binding sites of with AXL (PDB code:

5u6b) to gain an insight into the possible binding modes (shown in Figure 3). The simulation showed a
clear difference in the ligand positioning between the two subtypes. Compared with 23b without
“methylene”, compound 42a containing the “methylene” is shown to interact with multiple residues in the
binding site, such as Arg727, Asn728, Lys619, Met674 and Leu593 and the extension length and flexibility
enhances its affinity and selectivity (Figure 3B). On the other hand, compound 42a with the “methylene”
exhibits a "V" conformation that is more suitable for embedding into the Axl protein to improve affinity.
Namely, the quinoline fragment occupies the intermediate active site, and the cyclic amino substituted
propoxy group is embedded in the hydrophilic pocket A as well as (4-fluorophenyl)-1,3,4-oxadiazol moiety
into the active pocket B. (Figure 3B and Figure S1). The experiments are in good agreement with the
results obtained from the Axl % Inhibition experiment.
Figure 3. Docking studies of AXL (PDB code: 5u6b) and two compounds. (A): Compound 23b without
methylene in the binding site of Axl. (B): Docking poses of compound 42a containing the “methylene” in
the binding site of Axl.
As a result, other three series compounds (41a, 42a-42e and 43a-47e in Figure 2B) were designed and
synthesized, in which, a novel Linker has been developed. Afterwards, a three-carbon tether which
contained different cyclic tertiary amines were introduced at the 7-position of quinolines. After a stepwise
structure-activity relationships (SAR) exploration, a series of 6,7-disubstituted-4-benzyloxyquinoline
derivatives, which contain 1,3,4-oxadiazol acetamide moiety were ultimately synthesized as Axl inhibitors.
1,3,4-oxadiazole is commonly utilized pharmacophore has been subjected to extensive study[24-26]
due to their metabolic profile[27] and pharmacokinetic property[28, 29]. In addition, 1,3,4-oxadiazol
acetamide moiety enhances hydrogen bonding with the Axl protein and affects the conformation of the
compounds so that the compounds can sufficiently occupy the active pocket (Figure 3 and Figure S1).
Hence, 1,3,4-oxadiazol acetamide moiety may be a novel type of linker for Axl kinase inhibitors.

2.2 Chemistry
Compounds 23a-26a and 23b-26b were synthesized according to the routes respectively outlined in
scheme 1. The key intermediates 9 and 10a-e, as shown in Figure 4, were synthesized using a convenient
procedure starting from 1-(3,4-dimethoxyphenyl) ethanone or 1-(4-hydroxy-3-methoxyphenyl)ethanone,
which was illustrated in detail in our previous study[23, 30]. Intermediate 11 was obtained from
commercially available substituted benzoate via hydrazinolysis with 80% hydrazine monohydrate.
Subsequently, condensation with ethyl oxalyl monochloride[31] acnd the intramolecular cyclization[32] in
the presence of POCl3 afforded the ethyl 5-aryl-1,3,4-oxadiazole-2-carboxylate 12. 12 was hydrolyzed and
then reacted with oxalyl chloride to give the key intermediate 5-aryl-1,3,4-oxadiazole-2-carbonyl chloride
13, which underwent a condensation reaction with intermediate 6,7-disubstituted-4-phenoxyquinolines 9
and 10c respectively to give access to the desired target compounds 23a-b. In this way, 24a-b, 25a-b and
26a-b were prepared via cyclization, hydrolysis, acyl chlorination and condensation from 14, 17 and 20
respectively. Substituted benzonitrile reacted with hydroxylamine hydrochloride in EtOH to give
intermediate N-hydroxybenzimidamide 17[33]. 14 was obtained from substituted acetophenone via
substitution, ammonolysis[34]. 20 was obtained from substituted acetophenone after reaction with ethyl
oxalate in the presence of t-BuOK in THF[35].
Scheme 2 depicts the preparation of compounds 41a-47e. Intermediate 17, obtained by conventional
synthesis as described in Scheme 1, reacted with malonate monoethyl ester to afford amide intermediate,
which transformed to oxazole acetate 27. 27 was hydrolyzed and acylated with oxalyl chloride to give the
key intermediate 28, which underwent
a
condensation reaction with intermediate
6,7-disubstituted-4-phenoxyquinolines 10 to yield the desired target compound 41a. The target compounds
42a-42e and 43a-47e were similarly prepared from compounds 14 or 11 respectively.
`
Figure 4. The structure of intermediates 9 and 10a-e

Scheme 1. Reagents and conditions: (i) 80% hydrazine monohydrate, EtOH, reflux; (ii) ethyl oxalyl monochloride,
TEA, DCM, 0 oC to rt; (iii) POCl3, 85 oC; (iv) 1) LiOH, MeOH/THF, H2O; 2) oxalyl chloride, DCM; (v) 9 or 10c, TEA,
DCM; (vi) NBS, DCM; (vii) hexamethylenetetramine, 6N HCl; (viii) NH2OH.HCl, TEA, EtOH; (ix) diethyl oxalate,
t-BuOK, THF; (x) NH2OH.HCl, MeOH, 60 oC.
Scheme 2. Reagents and conditions: (i) monoethyl 2-substituted malonate, EDCI, DCM, 0 °C to rt; (ii) POCl3, 85°C;
(iii) 1) LiOH, MeOH/THF, H2O; 2) oxalyl chloride, DCM; (iv) 10, TEA, DCM, 0 °C to rt.

2.3 In vitro cytotoxicity and structure-activity relationships
Target compounds 23a-26a and 23b-26b were evaluated for their in vitro inhibitory activity against Axl
kinase by Mobility shift assay with ATP concentration at Km at 1.0 µM. The cytotoxicity of the eight
prepared compounds were evaluated in vitro against three cancer cell lines, including, HT-29 (human colon
cancer), A549 (human lung adenocarcinoma) and PC-3 (human prostate cancer cell).
Table 1.
The antiproliferative activities and Axl inhibition of target compounds 23a-26b.
IC50 (µmol/L) ± SD
Axl %
Compd.
R1
Het
Inhibition at 1 µM
A549
HT-29
PC-3
23a
24a
25a
26a
23b
24b
25b
26b
Me
Me
Me
Me
5.14 ± 0.06
52.29±3.62
>100
>100
-2.0±0.4
21.5±0.6
-4.5±0.5
-2.2±0.9
73.2±1.4
80.9±2.9
36.6±2.7
11.0±0.0
5.59±0.03
10.30±0.02
40.37±0.13
2.73±0.05
0.24±0.04
0.87±0.01
3.34±0.06
21.91±0.56
>100
N
39.74±0.75
>100
N
O
29.44±1.01
3.81±0.08
0.72±0.01
1.04±0.02
2.04±0.03
7.89±0.16
1.89±0.04
6.38±0.07
24.56±1.10
N
O
N
Cabozantinibb
Foretinibb
-
-
3.75±0.01
0.21
4.56± 0.08
0.25 ± 0.01
8.25 ± 0.63
0.81± 0.09
-
-
93.8±0.85
ND
aND = not determined;
bUsed as the positive control;
cBold values show the IC50 values of the target compounds lower than the values of the positive control;
This first screening results are listed in Table 1. None of compounds 23a-26a bearing
6,7-dimethoxyquinolin moiety (contained in the structure of Cabozantinib), exhibits inhibitory activity on
Axl at 1µM. Interestingly, their analogues (23b-26b) bearing the cyclic amino propanoxy group (similar to
Foretinib) exhibited a higher inhibitory activity against Axl. Especially, compound 24b with the oxazole as
bioisostere exhibited the highest inhibitory activity with the IC50 values of 0.24 ± 0.04 µM, 1.89 ± 0.04 µM

and 0.72 ± 0.01 µM against A549, HT-29 and PC-3 cell lines respectively and a percent inhibition close to
81% at 1.0 µM, which indicated the cyclic amino propanoxy group seemed to play an important role in the
interaction with the active site of Axl. Compounds 23b and 24b exhibited better Axl kinase inhibitory
activity compared to 25b and 26b, which indicated 1,3,4-oxadiazole and oxazole moiety are more suitable
as isosteres in this study. Interesting, compounds 25b and 26b showed almost no inhibitory activity against
Axl, but exhibited better cytotoxicity against A549 and PC-3 cell lines than Cabozantinib. To explore the
cause of this phenomenon, we tested the inhibition rate of 26b against five other kinases. The result (Table
S1 in SI) indicated that 26b showed good inhibitory activity against FLT3 and KDR at a concentration of
100 nM. Even, 26b had a percent inhibition 87% at 100 nM against c-Met, which suggested 26b may be a
potential c-Met inhibitor.
Meanwhile, the flexibility of the Linker was investigated by evaluating the target compounds 41a-43a.
In this screening whose results were reported in Table 2, further enhanced activity was observed for
compound 42a and 43a with lower IC50 values than the values of the positive control. The results showed
that the activity benefits from the presence of the “methylene”.
Table 2.
The anti-tumor activities and Axl inhibition of target compounds 41a-43a.
IC50 (µmol/L) ± SD
Axl %
Compd.
Het
Inhibition at 1 µM
A549
HT-29
PC-3
N
1.16 ± 0.04
0.109±0.004
0.238 ± 0.006
68.0±1.8
83.1±2.4
88.1±6.0
41a
42a
43a
0.106±0.002
0.33 ± 0.15
O
N
0.105±0.001
0.082±0.004
0.54±0.09
0.28 ± 0.08
Cabozantinib
Foretinib
-
-
3.75±0.01
0.21
4.56± 0.08
8.25 ± 0.63
0.81± 0.09
93.8±0.85
0.25 ± 0.011
ND
aND = not determined;
Based on the preliminary SAR, we decided to focus our screening on some target compounds bearing
cyclic amino propanoxy group at position 7 of quinoline. As shown in Table 3, when the cyclic amino was
morpholinyl group, compound 42b (a percent inhibition only 24% at 100 nM) afforded lower activities in
the anti-Axl activities compared to 42c-42e. The same trend was observed for compounds 43b-43e. In
addition, compounds containing the 1,3,4-oxadiazole moiety (43b-43e) have better activity than
compounds containing an oxazole moiety (42b-42e). The results suggested that the 1,3,4-oxadiazole moiety
was a privileged scafford for anti-Axl activities.
Encouraged by the observations described above, further investigations were performed to study the

cytotoxic activity of different substituents on the position 4 of phenyl ring. As seen from Table 4, among
these compounds (43f-43i), only 43f (containing 4-bromophenyl fragment) exhibited better cytotoxic
activity than Foretinib, but the activity was still weaker than compound 43a, which bear 4-fluorophenyl
moiety. Accordingly, 4-fluorophenyl derivatives were further studied in our work.
Table 3.
The anti-tumor activities and Axl inhibition of target compounds 42b-42e and 43b-43e.
IC50 (µmol/L) ± SD
Axl %
Compd.
R1
Het
Inhibition at 100 nM
A549
HT-29
PC-3
0.596±0.022
13.74±0.75
2.52±0.03
4.17±0.07
1.042±0.021
4.3±0.12
2.41±0.17
24.0±2.7
55.5±3.2
49.0±1.3
37.0±0.28
27.5±3.7
66.0±0.09
61.5±3.5
58.5±1.9
42b
42c
42d
42e
43b
43c
43d
43e
0.254±0.013
0.178±0.005
1.042±0.006
0.103±0.007
0.071±0.014
0.091±0.011
0.813±0.004
0.57±0.06
0.34±0.03
0.53±0.03
0.68±0.07
0.41±0.03
0.21±0.02
0.40±0.01
3.48±0.07
2.37±0.16
0.813±0.041
Cabozantinib
Foretinib
-
-
3.75±0.01
0.21
4.56± 0.08
8.25 ± 0.63
0.81± 0.09
-
-
93.0±0.4
0.25 ± 0.011
ND
aND = not determined;
Our final modification focused on the R3 and R4 group of the methylene at the alpha position of the
carbonyl group. As shown in Table 4, most of them displayed excellent cytotoxicity against four cancer
cells lines (especially in the inhibition of A549 cell line) with potency from single-digit µM to nanomole
range, which were more potent than Foretinib against one or more cell lines. Three compounds (44a, 45a
and 47e) were found to have 1.8-8.4 fold, 1.1-2.9 fold, 1.38-2.0 fold and 2.0-6.5 fold increase in activity
cytotoxic activity than the positive control Foretinib against A549, HT-29, PC-3 and MCF-7 cell lines in
vitro respectively. In order to further summarize the structure-activity relationship, Axl inhibition activity of

those compounds were evaluated. The results showed that most of those compounds exhibit moderate to
excellent anti-Axl activities with Axl % Inhibition at 100 nM > 50%. In addition, there was a positive
correlation between cytotoxicity and Axl kinase inhibitory activity. As for Cyclic amino (R1), compounds
with morpholinyl groups are much weaker in terms of cell and kinase activity, which is consistent with the
above conclusion.
Table 4.
Cytotoxicity of compounds 43f-43i and 44a-47e against A549, HT-29, PC-3 and MCF-7.
IC50(µM)
PC-3
Axl %
Entry
R1
R3
R4
R
Inhibition
at 100 nM
A549
HT-29
MCF-7
a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Cl
H
OMe
F
ND
43f
43h
43g
43i
0.102±0.006
0.63±0.02
0.583±0.01
2.46±0.03
7.81±0.04
7.52±0.04
1.46±0.10
2.54±0.33
1.96±0.01
1.27±0.04
1.00±0.08
0.554±0.03
2.02±0.03
1.54±0.07
0.570±0.016
1.08±0.05
0.648±0.009
2.48±0.11
1.08±0.02
1.03±0.10
0.871±0.002
0.442±0.003
9.33±0.42
1.05±0.07
0.779±0.015
1.03±0.13
1.62±0.07
0.68±0.02
0.36±0.05
4.73±0.03
0.41±0.06
0.53±0.01
1.18±0.02
1.70±0.03
1.08±0.04
1.26±0.04
0.40±0.02
2.53±0.06
0.97±0.03
1.42±0.06
1.47±0.02
1.49±0.02
1.79±0.08
1.90±0.01
1.05±0.07
1.76±0.05
2.18±0.03
12.95±0.13
1.67±0.02
2.34±0.07
0.59±0.04
0.82±0.11
ND
ND
ND
H
0.92±0.06
ND
ND
H
1.56±0.07
ND
ND
44a
44b
44c
Me
Me
Me
Me
Me
Et
Et
0.032±0.001
0.052±0.004
0.075±0.003
0.076±0.002
0.086±0.002
0.119±0.009
0.049±0.007
0.038±0.006
0.078±0.001
0.092±0.099
0.42±0.02
1.00±0
83.2±0.0
47.9±1.2
80.0±0.8
79.3±2.7
69.7±0.3
78.7±0.5
48.9±2.3
76.0±0.2
75.3±1.1
80.1±1.5
69.9±0.0
42.7±0.1
76.3±0.0
70.3±0.2
73.7±1.0
87.9±0.5
42.7±0.7
82.3±0.3
79.3±0.2
93.7±0.2
88.0±0.1
F
1.05±0.04
1.63±0.03
2.70±0.03
1.04±0.02
0.46±0.03
2.69±0.15
2.22±0.32
1.04±0.09
0.41±0.03
0.37±0.08
1.60±0.13
2.48±0.07
ND
F
F
44d
44e
F
45a
45b
45c
F
F
Et
F
Et
F
45d
45e
Et
F
Me Me
Me Me
Me Me
Me Me
Me Me
F
46a
46b
46c
F
0.275±0.0035
0.597±0.0125
0.263±0.03
0.215±0.011
0.120±0.007
1.66±0.03
F
F
46d
46e
F
0.47±0.09
0.74±0.03
>100
F
47a
47b
47c
F
F
2.61±0.22
0.31±0.07
1.01±0.011
2.00±0.06
0.143±0.006
0.150±0.008
0.053±0.008
0.27±0.04
F
47d
47e
F
-
-
-
-
Foretinib

aND = not determined.
To explore the contribution of Axl kinase inhibition to cytotoxicity, we also tested Axl overexpressing
human breast cancer cell line MDA-MB-231[10, 20, 36] and human noncancerous cell line WI-38. The
results indicated 47e had a significant inhibitory effect on the proliferation of MDA-MB-231, which was
much stronger than that on normal cells (Table S2 in SI).
2.4 In vitro enzymatic assays
As shown in Table 5, compounds 44a, 45a and 47e all exhibited excellent Axl enzymatic potency,
suggesting that the inhibition of Axl may be a mechanism for the antitumor effect of these derivatives.
Compounds 45a and 47e showed the potent activity with an IC50 value of 0.036 and 0.010 µM against Axl
respectively, which was comparable to that of the positive control, Foretinib (IC50=0.014 µM), indicating
that these compounds deserve further study with regard to its application in the treatment of cancer.
Table 5.
Inhibitory activities of 44a, 45a, 47e and Foretinib against Axl in vitro.
Compd.
IC50 on Axl (µM)a
44a
0.036
45a
0.077
47e
Foretinib
0.010
0.014
a The values are an average of two separate determinations.
2.5 Enzymatic selectivity assays
Compounds 44a and 47e were screened against other 7 tyrosine kinases to examine their selectivity on
Axl over other kinases (Table 6). Compared with its high potency against Axl (IC50=0.036 and 0.010 µM),
47e exhibited inferior inhibitory effects against c-Met (IC50 = 0.071 µM), VEGFR-2 (IC50 = 0.081 µM) and
c-kit (IC50 = 0.063µM). Compound 47e showed inhibitory potency against Flt-3, PDGFRβ, Mer and Tyro3
lower (>10 fold) than that of Axl. These data suggested that compound 47e seem to be an Axl kinase
inhibitor with some selectivity. To identify other kinase targets of 47e, profiling studies were conducted to
evaluate its selectivity toward Axl (Figure 4). Except for Axl, 47e also shows considerable activity against
the other three kinases (Aurora-B, Flt4 and Ron, % Inhibition at 200 nM > 80%).
Table 6.
Inhibition of tyrosine kinases by compound 44a and 47e.
IC50(µM a
)
Compd.
44a
Axl
c-Met
0.062
VEGFR-2
0.040
c-Kit
Flt-3
>0.2
PDGFRβ
Mer
>0.2
Tyro3
0.190
0.036
0.047
>0.2

0.010
0.071
0.081
0.063
0.103
>0.2
>0.2
>0.2
47e
a The values are an average of two separate determinations.
Figure 4. Compound 47e was profiled against a panel of 30 kinases at 200 nM using Eurofins's
SelectScreen kinase profiling service.
2.6 Study on overcoming drug resistance of EGFR-TKI.
Since Axl inhibitor 47e was obtained after multiple optimizations, the anti-EGFR-TKI resistance activity
was investigated as shown in Table 7. The Axl inhibitor 47e exhibits prominent inhibition against both
H1975 and gefitinib- resistant H1975.
Table 7.
Anti-proliferative activity towards H1975 and H1975/Gefitinib.
IC50(µM)
Entry
H1975
0.099±0.008
6.5±0.14
H1975/Gefitinib
0.107±0.031
78.7±1. 7
47e
Gefitinib
3. Conclusion
In summary, through a stepwise structure-activity relationship analysis, a series of 6,7-disubstituted
quinoline derivatives containing 1,3,4-oxadiazole acetamide moiety were synthesized and evaluated for
their Axl kinase inhibition and cytotoxicity against A549, HT-29, PC-3 and MCF-7 cancer cell lines in vitro.
Most compounds exhibited moderate to excellent activity, with IC50 values ranging from 0.032 to 1.54 µM
against A549, HT-29, PC-3 and MCF-7 respectively. Some selected compounds (44a, 45a and 47e) were
evaluated for the activity against Axl kinase, and compounds 44a and 47e were further evaluated for other
seven tyrosine kinases (c-Met, VEGFR-2, c-Kit, Flt-3, PDGFRβ, Mer and Tyro3) to test the enzyme-based
selectivity. The studies of SARs indicated that the presence of a carbonyl alpha-methylene was of

significant importance to the inhibition potency and selectivity. In a sense, this study provides a novel type
of linker for Axl kinase inhibitors, namely 1,3,4-oxadiazole acetamide moiety, which equipped more
suitable length and flexibility to improve activity. Moreover, the introduction of a three-carbon tether
contained cyclic amino (R1) into the 7-position of quinolines was advantageous to the potency. To our
delight, the most promising compound 47e, as a Axl kinase inhibitor, showed the better cytotoxic activities
than Foretinib with 1.9 fold, 1.57 fold, 1.54 fold and 2.0 fold increases in activity against A549, HT-29,
PC-3 and MCF-7 cell lines in vitro respectively. What's more, compound 47e exhibits prominent inhibition
against both H1975 and gefitinib- resistant NSCLC cell line H1975/ gefitinib.
4. Experimental protocols
4.1 Chemistry
Unless otherwise noted, all materials were obtained from commercial suppliers and used without further
purification. All melting points were obtained on a Büchi Melting Point B-540 apparatus (Büchi
Labortechnik, Flawil, Switzerland) and were uncorrected. The IR spectra were recorded by means of the
KBr pellet technique on a Bruker FTS 135 spectrometer. 1H NMR and 13C NMR spectra were generated on
a Bruker ARX-300 or ARX-600 spectrometers (Bruker Bioscience, Billerica, MA, USA). Column
chromatography was carried out on silica gel (200-300 mesh). Mass spectra (MS) were taken in ESI mode
on Agilent 1100 LC-MS (Agilent, Palo Alto, CA, USA). Elemental analysis was determined on a
Carlo-Erba 1106 Elemental analysis instrument (Carlo Erba, Milan, Italy).
4.2. Preparation of aromatic-substituted heterocyclic carboxylate esters (12, 15, 18 and 21)
4.2.1. The preparation of 4-fluorobenzohydrazide (11)
To a stirred solution of 4-fluoroethylbenzoate (4.5g, 26.7mmol) in EtOH (30mL) was added
.
NH2NH2 H2O (6.67g, 133.5mmol) (80% in H2O) at room temperature and refluxed at 85°C for 10 h. The
reaction was cooled to room temperature, and evaporated in vacuo to afford a crude reside which was
washed with n-hexane (50mL) and then dried to obtain compound. Yield: (4.2g, quantitative yield), white
solid. MS (ESI) m/z (%): 155.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 9.85 (s, 1H), 7.86 (dd, 2H),
7.25 (t, 3H), 4.46 (s, 1H), 3.47 (br s, 1H).
4.2.2. The preparation of ethyl 5-(4-fluorophenyl)-1,3,4-oxadiazole-2-carboxylate (12)
Ethyl oxalyl monochloride (0.64g, 5.25mmol) was added drop-wise to
a
solution of
4-fluorobenzohydrazide (11, 0.78g, 5.0mmol) and triethylamie (1.01g, 10.0mmol) in DCM in an ice bath.
Upon completion of the addition, the reaction mixture was removed from the ice bath and placed in room
temperature for 8h and monitored by thin-layer chromatography (TLC). The mixture was washed with 10%
K2CO3 (150 mLÕ3) followed by brine (150 mLÕ1), and the organic phase was separated, dried, and
evaporated to yield ethyl 2-(2-(4-fluorobenzoyl)hydrazinyl)-2-oxoacetate as yellow solid, Yield: 83%; MS
(ESI)m/z(%): 255.4 [M+Na]+.
Ethyl 2-(2-(4-fluorobenzoyl)hydrazinyl)-2-oxoacetate (2.06g) was added to POCl3 150mL and then

o
heated to 85 C for 3h. The reaction mixture was evaporated and then poured into water, basified with
sodium hydroxide to PH = 7, and extracted with dichloromethane (200 mL Õ 3). The combined extracts
were washed with brine (200 mLÕ2), dried over anhydrous Na2SO4, and concentrated in vacuum to give
the corresponding ethyl 5-(4-fluorophenyl)-1,3,4-oxadiazole-2-carboxylate (12) as white solid; MS (ESI)
1
m/z(%): 237.4 [M+Na]+; H NMR (400 MHz, CDCl3) δ 7.92 (dd, J=8.6, 5.3 Hz, 2H), 7.13 (t, J= 8.5 Hz,
2H), 4.40 (q, J= 7.1 Hz, 2H), 1.40 (t, J= 7.1 Hz, 3H).
4.2.3. The preparation of 2-amino-1-(4-fluorophenyl)ethanone hydrochloride (14)
To a solution of 1-(4-fluorophenyl)ethan-1-one (15.0mmol, 1.0 equiv) in 8 mL of dichloromethane were
added NBS (2.72g, 15.3mmol, 1.02equiv) and p-toluenesulfonic acid (2.85g, 15.0mmol, 1.0 equiv). The
reaction mixture was stirred for 24 h at 50 °C. After that time, the solvent was evaporated under reduced
pressure. A water solution of saturated NaHCO3 (30 mL) was then added, and the solution was extracted
with dichloromethane (3 × 30 mL). The organic layers were combined and dried over Na2SO4. The solvent
was evaporated, and the residue was subjected to column chromatography (silica gel) using
1
hexanes/CH2Cl2 (from 9:1 to 4:1) as eluent to obtain 2-bromo-1-(4-fluorophenyl)ethan-1-one. H NMR
(600 MHz, CDCl3) δ 8.05-8.00 (m, 2H), 7.19-7.13 (m, 2H), 4.41 (s, 2H).
A solution of hexamethylenetetramine (1.42g, 10.1mmol) in CHCl3 was added drop-wise over 30 min to
a solution of 2-bromo-4-fluoroacetophenone (2.0g, 9.2mmol) in dry CHCl3 40 mL at 0 °C. The reaction
mixture was allowed to warm up to room temperature and stirred for 16 h. After completion of the reaction
the solid precipitate was collected by filtration and washed with CHCl3. The solid obtained was suspended
in EtOH 40mL and conc. HCl 4 mL was added. The mixture was heated to 80 °C for 3 h, cooled to room
temperature, and the solid formed was filtered off. The clear filtrate was concentrated.
2-amino-1-(4-fluorophenyl)ethanone hydrochloride (14, 1.5g) as yellow solid. MS (ESI) m/z(%):
154.3[M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.50 (s, 1H), 8.15 (m, 2 H), 7.44 (m, 2 H), 4.65 (m, 2 H).
4.2.4. The preparation of ethyl 5-(4-fluorophenyl)oxazole-2-carboxylate (15)
Ethyl oxalyl monochloride (0.64g, 5.25mmol) was added drop-wise to
a
solution of
2-Amino-1-(4-fluorophenyl)ethanone hydrochloride (14, 0.78g, 5.0mmol) and triethylamie (1.01g,
10.0mmol) in dichloromethane in an ice bath. Upon completion of the addition, the reaction mixture was
removed from the ice bath and placed in room temperature for 8h and monitored by thin-layer
chromatography (TLC). The mixture was washed with 10% K2CO3 (150 mLÕ3) followed by brine (150
mLÕ1), and the organic phase was separated, dried, and evaporated to yield Ethyl
2-((2-(4-fluorophenyl)-2-oxoethyl)amino)-2-oxoacetate as white solid;
Ethyl 2-((2-(4-fluorophenyl)-2-oxoethyl)amino)-2-oxoacetate (2.06g) was added to POCl3 15mL and
then heated to 85oC for 3h. The reaction mixture was evaporated and then poured into water, basified with
sodium hydroxide to PH 7, and extracted with dichloromethane (200 mL Õ 3). The combined extracts were
washed with brine (200 mLÕ2), dried over anhydrous Na2SO4, and concentrated in vacuum to give the
ethyl 5-(4-fluorophenyl)-1,3,4-oxadiazole-2-carboxylate (15) as white solid; MS (ESI) m/z(%):
1
236.3[M+H]+; H NMR (400 MHz, CDCl3) δ7.76 (dd, J=8.7,5.2 Hz, 2H), 7.48 (s,1H), 7.17(t, J=8.6 Hz,
2H), 4.50(q, J=7.1 Hz, 2H),1.46(t, J=7.1 Hz, 3H).

4.2.5. The preparation of 4-fluoro-N-hydroxybenzimidamide (17)
To a solution of 4-fluoro benzonitrile (4.84g, 40mmol) in ethanol (50mL), was added hydroxylamine
hydrochloride (6.5g, 100mmol), followed by addition of triethylamine (5.5g, 52mmol). The reaction mass
was refluxed for 8 h. Excess of solvent was removed under vacuum and the reaction mass was diluted with
water, acidified with dilute HCl and filtered to afford the desired product. MS (ESI) m/z (%): 189.1 [M +
1
H]+; H NMR (DMSO-d6): δ 5.95 (s, 2H), 7.42 (t, J = 8.7 Hz, 1H), 7.69 (m, 1H), 7.83 (dd, 1H), 9.80 (s,
1H).
4.2.6. The preparation of ethyl 3-(4-fluorophenyl)-1,2,4-oxadiazole-5-carboxylate (18)
Ethyl oxalyl monochloride (0.64g, 5.25mmol) was added drop-wise to
a
solution of
4-fluoro-N-hydroxybenzimidamide (17, 0.78g, 5.0mmol) and triethylamie (1.01g, 10.0mmol) in
dichloromethane in an ice bath. Upon completion of the addition, the reaction mixture was removed from
the ice bath and placed in room temperature for 8h and monitored by thin-layer chromatography (TLC).
The mixture was washed with 10% K2CO3 (150 mLÕ3) followed by brine (150 mLÕ1), and the organic
phase was separated, dried, and evaporated to yield Ethyl 2-(2-(4-fluorobenzoyl)hydrazinyl)-2-oxoacetate
as yellow solid. MS (ESI) m/z (%): 255.1 [M + H]+.
Ethyl 2-(2-(4-fluorobenzoyl)hydrazinyl)-2-oxoacetate (2.06g) was added to POCl3 15mL and then
o
heated to 95 C for 3h. The reaction mixture was evaporated and then poured into water, basified with
sodium hydroxide to PH = 7, filtered and obtain the ethyl 5-(4-fluorophenyl)-1,3,4-oxadiazole
-2-carboxylate as yellow solid. MS (ESI) m/z (%): 238.1 [M + H]+; 1H NMR (400 MHz, CDCl3) δ 8.03 (d,
J= 8.4 Hz，2H), 7.66 (d, J= 8.6 Hz，2H), 4.37 (q, J= 7.1 Hz, 2H), 1.42 (t, J= 7.2 Hz, 3H).
4.2.7. The preparation of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate (20)
In a three-necked flask acetophenone (5g, 41.61mmol) and diethyl oxalate (6.76mL, 50mmol) were
dissolved in anhydrous DMF 65mL at 0°C and t-BuOK (2g, 83.25mmol) was slowly added, the mixture
was stirred at 0°C for 15 min and 30 min more at room temperature before heating at 45 °C for 1h.
Reaction was poured into water-acetic acid and product extracted with ethyl acetate. Organic layers were
combined, washed with water and brine, dried over magnesium sulphate, filtered and concentrated to yield
the title compound. MS (ESI) m/z (%): 237.2 [M - H]+
4.2.8. The preparation of ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate (21)
A mixture of 20 (3 g, 11.03 mmol) and NH2-OH.HCl (2.28 g, 33.09 mmol) in MeOH (50 mL) was
heated to reflux overnight. The MeOH was then evaporated and the residue was extracted with ethyl acetate,
dried over Na2SO4. After filtration and concentration in vacuo, the crude residue was purified by column to
1
afford 21; MS (ESI) m/z (%): 236.1[M + H]+; H NMR (400 MHz, CDCl3) δ7.85-7.78 (m, 2H), 7.20(t,
J=8.6 Hz, 2H), 6.89(s, 1H), 4.01(s, 3H).
4.3. General procedure for preparation of aromatic ring-substituted heterocycliccarbonyl chloride (13, 16,
19 and 22)
The corresponding aromatic ring-substituted heterocycliccarbonyl esters (12, 15, 18 and 21, 10mmol)

was dissolved in THF 10mL and methanol 40mL. A solution of lithium hydroxide (0.6g, 30mmol) in water
3mL was slowly added. The reaction mixture was stirred at room temperature for 5 h and monitored by
thin-layer chromatography (TLC). The reaction was extracted with dichloromethane (40 mL Õ 3) and the
aqueous phase was acidified with 1N HCl and the corresponding aromatic ring-substituted
heterocycliccarboxylic acid was isolated as white solid.
Thoroughly dried aromatic ring-substituted heterocyclic carboxylic acid 3.5mmol, DMF 1 drops,
anhydrous dichloromethane was added in a three-neck flask under a N2 atomosphere. Oxalyl chloride
(4.2mmol) was drop-wise added at 0 oC. The reaction mixture was stirred at room temperature for 4h. And
the reaction was then removed in vacuo. The resulting aromatic ring-substituted heterocycliccarbonyl
chloride (13, 16, 19 and 22) was used immediately without further purification.
4.4. General procedure for preparation of target compounds (23a-b, 24a-b, 25a-b and 26a-b)
A mixture of corresponding carbonyl chloride (13, 16, 19 and 22, 1.5eq.) in DCM was added to a
solution of triethylamine (0.2g, 2.0mmol) and 9 or 10c (0.493g, 1.0mmol) in DCM 10 mL. The reaction
mixture was placed at room temperature for 2 h. The solvent was concentrated in vacuum and the residue
was resolved with DCM (100 mL), washed with water (30 mLÕ 3), brine (30 mL), dried over anhydrous
Na2SO4, and concentrated in vacuum. The residue was purified by column chromatography to afford the
target compounds (23a-b, 24a-b, 25a-b and 26a-b).
4.4.1. N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-5-(4-fluorophenyl)-1,3,4-oxadiazole-2-carboxamide
(23a)
Yield: 62%; m.p. 224 - 126oC; MS (ESI) m/z (%): 487.3 [M + H]+; 1H NMR (400 MHz, CDCl3) δ 9.05
(s, 1H), 8.52 (d, J = 5.9 Hz, 1H), 8.22 (dd, J = 8.6, 5.2 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H), 7.86 (s, 1H), 7.61
(s, 1H), 7.32 - 7.25 (m, 4H), 6.64 (d, J = 6.0 Hz, 1H), 4.13 (s, 3H), 4.10 (s, 3H); 13C NMR (101 MHz,
DMSO) δ 165.05, 165.03 (d, J = 251.0 Hz), 160.17, 159.03, 153.07, 151.92, 151.10, 149.86, 149.32,
146.96, 135.45, 130.47 (d, J = 9.5 Hz), 123.14, 121.90, 117.37 (d, J = 22.4 Hz), 115.68, 108.34, 103.85,
99.57, 56.21, 56.19. Anal. calcd. for C26H19FN4O5 (%): C, 64.20; H, 3.94; F, 3.91; N, 11.52; O, 16.44.
Found (%): C, 64.21; H, 3.93; N, 11.51.
4.4.2.
N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-5-(4-fluorophen
yl)-1,3,4-oxadiazole-2-carboxamide (23b)
o
1
Yield: 61%; m.p. 122 - 123 C; MS (ESI) m/z (%): 630.1 [M + H]+; H NMR (600 MHz, DMSO) δ
11.28 (s, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.09 (m, 2H), 7.91 (d, J = 12.7 Hz, 1H), 7.61-7.47（m, 6H）, 6.54 (d,
J = 5.0 Hz, 1H), 4.21 (t, J = 6.1 Hz, 2H), 3.98 (s, 3H), 3.14-2.96(m, 2H), 2.78 – 2.58(m, 2H), 2.07(d, J =
17.0 Hz, 4H), 1.68 (d, J = 12.3 Hz, 2H), 1.48 (s, 1H), 1.25(s, 2H), 0.93 (d, J = 6.4 Hz, 3H). Anal. calcd. for
C34H33F2N5O5 (%): C, 64.86; H, 5.28; F, 6.03; N, 11.12; O, 12.70. Found (%): C, 64.85; H, 5.24; N, 11.15.
4.4.3. N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-5-(4-fluorophenyl)oxazole-2-carboxamide (24a)

Yield: 54%; m.p. 242 - 243 oC; MS (ESI) m/z (%): 486.1 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ
10.94 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.06 (dd, J = 8.6, 5.4 Hz, 2H), 7.97 (d, J = 8.6 Hz, 2H), 7.52 (d, J =
1.8 Hz, 2H), 7.43 (dd, J = 15.9, 7.0 Hz, 3H), 7.31 (d, J = 8.5 Hz, 2H), 6.50 (d, J = 5.3 Hz, 1H), 3.96 (s, 3H),
3.95 (s, 3H).13C NMR (101 MHz, DMSO) δ 170.19, 163.92 (d, J = 249.9 Hz), 160.40, 160.26, 157.64,
153.04, 150.67, 149.82, 149.31, 146.95, 135.97, 128.93 (d, J = 8.9 Hz), 123.46, 122.83, 121.86, 117.02 (d,
J = 22.4 Hz), 115.64, 108.34, 103.71, 100.64, 99.56, 56.19. Anal. calcd. for C27H20FN3O5 (%): C, 66.80; H,
4.15; F, 3.91; N, 8.66; O, 16.48. Found (%): C, 66.76; H, 4.12; N, 8.62.
4.4.4. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-5-(4-fl
uorophenyl)oxazole-2-carboxamide (24b)
o
1
Yield: 57%; m.p. 211 - 213 C; MS (ESI) m/z (%): 629.2 [M + H]+; H NMR (400 MHz, DMSO) δ
11.17 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.11 - 7.99 (m, 3H), 7.79 (d, J = 8.4 Hz, 1H), 7.57 - 7.38 (m, 6H),
6.48 (d, J = 5.2 Hz, 1H), 4.19 (t, J = 6.0 Hz, 2H), 3.96 (s, 3H), 2.92 - 2.78 (m, 2H), 2.47 - 2.37 (m, 2H),
2.04 - 1.81 (m, 5H), 1.65 - 1.52 (m, 2H), 1.40 - 1.26 (m, 2H), 0.89 (d, J = 6.4 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 164.54, 162.54, 159.88, 154.52 (d, J = 250.2 Hz), 154.01 (d, J = 53.0 Hz), 152.69, 152.31, 149.91,
148.73, 146.94, 137.99 (d, J = 12.5 Hz), 135.55 (d, J = 9.6 Hz), 127.18 (d, J = 8.4 Hz), 124.02, 122.93 (d, J
= 3.4 Hz), 122.44, 116.44 (d, J = 22.3 Hz), 116.09 (d, J = 3.4 Hz), 115.47, 109.49 (d, J = 23.2 Hz), 108.81,
102.28, 99.51, 67.52, 56.15, 55.41, 53.94, 33.99, 30.66, 26.28, 21.79. Anal. calcd. for C35H34F2N4O5 (%): C,
66.87; H, 5.45; F, 6.04; N, 8.91; O, 12.72. Found (%): C, 66.84; H, 5.43; N, 8.93.
4.4.5. N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1,2,4-oxadiazole-5-carboxamide
(25a)
Yield: 61%; m.p. 247 - 249oC; MS (ESI) m/z (%): 487.2 [M + H]+; 1H NMR (400 MHz, CDCl3) δ 9.05
(s, 1H), 8.71 (d, J = 5.9 Hz, 1H), 8.17 (dd, J = 8.6, 5.2 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H), 7.86 (s, 1H), 7.61
(s, 1H), 7.42 - 7.35 (m, 4H), 6.64 (d, J = 6.0 Hz, 1H), 4.11 (s, 3H), 4.09 (s, 3H). Anal. calcd. for
C26H19FN4O5 (%): C, 64.20; H, 3.94; F, 3.91; N, 11.52; O, 16.44. Found (%): C, 64.13; H, 3.98; N, 11.51.
4.4.6. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3-(4-fluo
rophenyl)-1,2,4-oxadiazole-5-carboxamide (25b)
o
1
Yield: 61%; m.p. 136 - 137 C; MS (ESI) m/z (%): 630.2 [M + H]+; H NMR (400 MHz, DMSO) δ
11.64 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.19 (dd, J = 8.7, 5.5 Hz, 2H), 8.05 (dd, J = 12.8, 2.3 Hz, 1H), 7.84
(d, J = 9.3 Hz, 1H), 7.60 - 7.37 (m, 6H), 6.52 (d, J = 5.0 Hz, 1H), 4.24 (t, J = 6.4 Hz, 3H), 3.97 (s, 3H),
2.96 (dd, J = 12.2, 5.1 Hz, 2H), 2.15 (s, 2H), 1.80 - 1.67 (m, 3H), 1.60 - 1.44 (m, 2H), 0.93 (d, J = 6.4 Hz,
3H). Anal. calcd. for C34H33F2N5O5 (%): C, 64.86; H, 5.28; F, 6.03; N, 11.12; O, 12.70. Found (%): C, 64.84;
H, 5.23; N, 11.14.
4.4.7. N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-5-(4-fluorophenyl)isoxazole-3-carboxamide (26a)
o
1
Yield: 43%; m.p. 204 – 205 C; MS (ESI) m/z (%): 486.1 [M + H]+; H NMR (400 MHz, DMSO) δ
11.03 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.04 - 7.92 (m, 5H), 7.52 (s, 1H), 7.42 (dd, J = 11.3, 6.3 Hz, 3H),
7.32 (d, J = 8.9 Hz, 2H), 6.50 (d, J = 5.2 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H); 13C NMR (101 MHz, DMSO)
δ 163.08 (d, J = 247.6 Hz), 160.24, 154.42, 153.48, 153.02, 152.66, 150.69, 149.81, 149.30, 146.95, 135.88,

127.65 (d, J = 8.6 Hz), 124.18, 123.80, 123.77, 122.93, 121.81, 116.87 (d, J = 22.3 Hz), 115.64, 108.33,
103.72, 99.55, 56.18, 56.15. Anal. calcd. For C27H20FN3O5 (%): C, 66.80; H, 4.15; F, 3.91; N, 8.66; O,
16.48. Found (%): C, 66.82; H, 4.12; N, 8.63.
4.4.8. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-5-(4-fl
uorophenyl)isoxazole-3-carboxamide (26b)
o
1
Yield: 61%; m.p. 197 – 199 C; MS (ESI) m/z (%): 629.2 [M + H]+; H NMR (400 MHz, DMSO) δ
11.23 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.06 (dd, J = 11.9, 3.3 Hz, 2H), 7.95 (dd, J = 8.8, 5.3 Hz, 2H), 7.83
(d, J = 8.5 Hz, 1H), 7.59 - 7.48 (m, 2H), 7.45 - 7.37 (m, 3H), 6.49 (d, J = 5.2 Hz, 1H), 4.19 (t, J = 6.3 Hz,
2H), 3.96 (s, 3H), 2.88 (s, 2H), 2.51 - 2.37 (m, J = 1.6 Hz, 11H), 2.10 - 1.79 (m, 4H), 1.59 (d, J = 11.5 Hz,
2H), 1.41 - 1.27 (m, 1H), 1.22 - 1.10 (m, J = 11.7 Hz, 2H), 0.89 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz,
DMSO) δ 167.04, 160.78 (d, J = 225.9 Hz), 153.75 (d, J = 244.9 Hz), 154.12, 153.67, 152.89, 152.21,
150.00, 149.39, 146.77, 137.38 (d, J = 9.9 Hz), 137.00 (d, J = 11.9 Hz), 132.50 (d, J = 9.4 Hz), 127.72 (d, J
= 8.2 Hz), 124.39 (d, J = 27.9 Hz), 123.71, 116.91 (d, J = 22.3 Hz), 116.51 (d, J = 294.0 Hz), 115.94 (d, J =
22.5 Hz), 109.90 (d, J = 22.6 Hz), 109.13, 102.67, 99.56, 66.91, 56.29, 54.49, 53.05, 32.73, 29.57, 25.28,
21.76. Anal. calcd. for C35H34F2N4O5 (%): C, 66.87; H, 5.45; F, 6.04; N, 8.91; O, 12.72. Found (%): C,
66.86; H, 5.46; N, 8.95.
4.5.1 The preparation of ethyl 2-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)acetate (27)
Ethyl hydrogen malonate (0.70g, 5.25mmol) was added drop-wise to
a
solution of
4-fluoro-N-hydroxybenzimidamide (17, 0.78g, 5.0mmol), EDCI (1.5eq.) and triethylamine (1.01g,
10.0mmol) in dichloromethane in an ice bath. Upon completion of the addition, the reaction mixture was
removed from the ice bath and placed in room temperature for 8h and monitored by thin-layer
chromatography (TLC). The mixture was washed with 10% K2CO3 (150 mLÕ3) followed by brine (150
mLÕ1), and the organic phase was separated, dried and evaporated to yield ethyl
3-((4-fluorobenzimidamido)oxy)-3-oxopropanoate as yellow solid. MS (ESI) m/z (%): 269.1 [M + H]+.
o
The intermidate was added to POCl3 15mL and then heated to 95 C for 3h. The reaction mixture was
evaporated and then poured into water, basified with sodium hydroxide to PH = 7, filtered and obtain the
ethyl 2-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)acetate as yellow solid. MS (ESI) m/z (%): 251.3 [M +
H]+; 1H NMR (400 MHz, CDCl3) δ 8.06 (dd, J= 3.2, 3.4 Hz 2H), 7.42 (t, J= 8.4 Hz, 2H), 4.36 (s, 2H), 4.17
(q, J= 7.4 Hz 2H), 1.20 (t, J= 7.2 Hz 3H).
4.5.2 The preparation of 2-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)acetyl chloride (28)
The ethyl 2-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)acetate (27, 12.5g, 50mmol) was dissolved in
THF 200mL added methanol and a solution of LiOH (1.8g, 75mmol) in water 15mL. The reaction mixture
was stirred at room temperature for 5 h and monitored by thin-layer chromatography (TLC). The reaction
was extracted with dichloromethane (70 mL Õ 3) and the aqueous phase was acidified with 1N HCl and
the corresponding aromatic ring-substituted heterocyclic carboxylic acid was isolated as white solid.
2-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)acetic acid (7.7g, 35mmol), DMF (2 drops), anhydrous
dichlromethane were added under a N2 atomosphere. Oxalyl chloride (5.28g, 42mmol) was drop-wise
added at 0 oC. The reaction mixture was stirred at room temperature for 4h. The mixture was then removed

in vacuo, and the resulting 5-(4-fluorophenyl)-1,3,4-oxadiazole-2-carbonyl chloride (28) was used
immediately without further purification.
4.5.3 The preparation of N-(3-fluoro-4-((6-methoxy-7- (3-(4-methylpiperidin-1-yl)propoxy)quin-olin-4-yl)
oxy)phenyl)-2-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)acetamide (41a)
Triethylamine (0.2g, 2.0mmol) was added to a solution of 5-(4-fluorophenyl)-1,3,4-oxadiazole-
2-carbonyl chloride 29 and 10 (0.493g, 1.0mmol) in DCM. The reaction mixture was placed at room
temperature for 2 h. The solvent was concentrated in vacuum and the residue was resolved with
dichloromethane (20 mL), washed with water (10 mLÕ 3), brine (30 mL), dried over anhydrous Na2SO4,
and concentrated in vacuum. The residue was purified by column chromatography to afford the target
o
1
compound. Yield: 51%; m.p. 214 - 216 C; MS (ESI) m/z (%): 644.2 [M + H]+; H NMR (600 MHz,
DMSO) δ 11.26 (s, 1H), 8.53 (d, J = 4.1 Hz, 1H), 8.09 (m, 2H), 7.90 (d, J = 12.7 Hz, 1H), 7.59 (s, 1H), 7.48
(m, 5H), 6.54 (d, J = 3.4 Hz, 1H), 4.41 (s, 2H), 4.28 (t, J = 5.2 Hz, 2H), 3.98 (s, 3H), 3.51 (d, J = 11.6 Hz,
2H), 3.21 (s, 3H), 2.94 (dd, J = 21.9, 10.7 Hz, 2H), 2.32 (s, 2H), 1.79 (d, J = 13.4 Hz, 2H), 1.63 (s, 1H),
1.51 (dd, J = 24.2, 11.9 Hz, 2H), 0.93 (d, J = 6.2 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 175.48,
32.7332.7350, 164.52, 164.45 (d, J = 249.3 Hz), 159.93, 153.85 (d, J = 245.7 Hz), 152.12, 150.00, 149.16,
138.13 (d, J = 9.8 Hz), 136.31 (d, J = 11.9 Hz), 130.03 (d, J = 9.0 Hz), 124.68, 123.10, 117.08, 116.86,
115.87 (d, J = 141.7 Hz), 109.04, 108.54 (d, J = 23.0 Hz), 102.66, 99.66, 66.59, 56.35, 54.06, 52.41, 35.48,
31.26, 28.64, 23.72, 21.58; Anal. calcd. for C35H35F2N5O5 (%): C, 65.31; H, 5.48; F, 5.90; N, 10.88; O,
12.43. Found (%): C, 65.25; H, 5.35; N, 10.80.
4.6 General preparation of 42a~42e.
Starting from 2-amino-1-(4-fluorophenyl)ethan-1-one (14), the target compounds were prepared by the
method metioned above.
4.6.1
N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluoro
phenyl)oxazol-2-yl)acetamide (42a)
o
1
Yield: 55%; m.p. 221 - 223 C; MS (ESI) m/z (%): 643.1 [M + H]+; H NMR (400 MHz, DMSO) δ
10.77 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 13.1 Hz, 1H), 7.76 (dd, J = 8.7, 5.4 Hz, 2H), 7.64 (s,
1H), 7.54 (s, 1H), 7.49 - 7.29 (m, 5H), 6.46 (d, J = 4.9 Hz, 1H), 4.22 (t, J = 6.0 Hz, 2H), 4.07 (s, 2H), 3.95
(s, 3H), 3.24 - 2.96 (m, 4H), 2.19 - 1.99 (m, 2H), 1.76 - 1.61 (m, 2H), 1.45 (s, 2H), 1.34 - 1.15 (m, J = 15.6,
8.2 Hz, 3H), 0.91 (d, J = 6.2 Hz, 3H). Anal. calcd. for C36H36F2N4O5 (%): C, 67.28; H, 5.65; F, 5.91; N,
8.72; O, 12.45. Found (%): C, 67.13; H, 5.60; N, 8.73.
4.6.2
N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluorophenyl)oxaz
ol-2-yl)acetamide (42b)
o
1
Yield: 56%; m.p. 157 - 158 C; MS (ESI) m/z (%): 631.2 [M + H]+; H NMR (400 MHz, DMSO) δ
10.77 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 12.7 Hz, 1H), 7.76 (dd, J = 8.7, 5.4 Hz, 1H), 7.64 (s,
1H), 7.53 (s, 1H), 7.46 (d, J = 4.2 Hz, 1H), 7.41 (s, 1H), 7.34 (t, J = 8.9 Hz, 1H), 6.45 (d, J = 5.2 Hz, 1H),

4.21 (t, J = 6.1 Hz, 1H), 4.07 (s, 2H), 3.95 (s, 2H), 3.61 (s, 4H), 2.47 (m, 6H), 2.00 (m, 2H); 13C NMR (101
MHz, DMSO) δ 165.87, 161.97 (d, J = 452.7 Hz), 161.16, 158.68, 154.57 (d, J = 203.2 Hz), 152.29, 150.71,
150.02, 149.33, 146.76, 137.61, 137.44, 136.30, 136.19, 126.63, 126.54, 124.67, 123.06, 119.38, 116.77,
116.56, 116.45, 114.98, 109.05, 108.58, 108.35, 102.51, 99.98, 99.53, 75.08, 66.99, 66.06, 56.28, 55.05,
53.35, 37.09; Anal. calcd. for C34H32F2N4O6 (%): C, 64.75; H, 5.11; F, 6.03; N, 8.88; O, 15.22. Found (%):
C, 64.68; H, 5.10; N, 8.82;.
4.6.3
N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluoro
phenyl)oxazol-2-yl)acetamide (42c)
o
1
Yield: 58%; m.p. 168 - 169 C; MS (ESI) m/z (%): 644.2 [M + H]+; H NMR (400 MHz, DMSO) δ
10.78 (s, 1H), 8.47 (d,J = 5.2 Hz, 1H), 7.87 (d, J = 12.9 Hz, 1H), 7.76 (dd, J = 8.7, 5.4 Hz, 2H), 7.64 (s,
1H), 7.42 (m, 6H), 6.45 (d, J = 5.1 Hz, 1H), 4.19 (t, J = 6.1 Hz, 2H), 4.07 (s, 2H), 3.95 (s, 3H), 2.70 - 2.52
(m, 8H), 2.34 (s, 3H), 2.04 - 1.95(m,2H). Anal. calcd. for C35H35F2N5O5 (%): C, 65.31; H, 5.48; F, 5.90; N,
10.88; O, 12.43.Found(%):C, 65.20; H, 5.45; N, 10.78.
4.6.4 N-(3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-
fluorophenyl)oxazol-2-yl)acetamide (42d)
1
Yield: 53%; m.p. 120 - 121oC; MS (ESI) m/z (%): 615.2 [M + H]+ ; H NMR (400 MHz, DMSO) δ
10.76 (s, 1H), 8.48 (d,J = 5.2 Hz, 1H), 7.87 (dd, J = 12.6, 0.7 Hz, 1H), 7.76 (dd, J = 8.7, 5.4 Hz, 2H), 7.64
(s, 1H), 7.56 (s, 1H), 7.48 - 7.42 (m, 3H), 7.34 (t, J = 8.9 Hz, 2H), 6.47 (d, J = 4.8 Hz, 1H)，4.26 (t, J = 6.0
Hz, 2H), 4.07 (s, 2H), 3.96 (s, 3H), 3.07 (dd, J = 13.9, 6.8 Hz, 5H), 2.25 - 2.13 (m, 2H), 1.98 - 1.86 (m, 4H);
13C NMR (101 MHz, DMSO) δ 165.89, 162.39 (d, J = 246.0 Hz), 159.77, 158.68, 153.88 (d, J = 246.5 Hz),
151.94, 150.71, 149.91, 149.45, 146.68, 138.23 (d, J = 10.1 Hz), 136.23 (d, J = 12.5 Hz), 132.56 (d, J =
10.0 Hz), 126.59 (d, J = 8.5 Hz), 124.65, 123.05, 116.67 (d, J = 22.3 Hz), 116.49, 115.17, 109.28, 108.49 (d,
J = 22.8 Hz), 102.66, 99.63, 66.32, 56.36, 53.89, 52.15, 37.09, 25.66, 23.07; Anal. calcd. For
C34H32F2N4O5(%): C, 66.44; H, 5.25; F, 6.18; N, 9.12; O, 13.01. Found (%): C, 66.34; H, 5.26; N, 9.10.
4.6.5
N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluorophenyl)o
xazol-2-yl)acetamide (42e)
Yield: 52%; m.p. 104 - 106oC; MS (ESI) m/z (%): 629.7 [M + H]+; H NMR (400 MHz, DMSO) δ
1
10.77 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 13.3 Hz, 1H), 7.76 (dd, J = 8.8, 5.4 Hz, 2H), 7.64 (s,
1H), 7.54 (s, 1H), 7.47 (dd, J = 26.5, 22.0 Hz, 3H), 7.34 (t, J = 8.9 Hz, 2H), 6.46 (d, J = 5.0 Hz, 1H), 4.22 (t,
J = 6.1 Hz, 2H), 4.07 (s, 2H), 3.96 (s, 3H), 2.61 (dd, J = 29.0, 16.6 Hz, 6H), 2.11 (s, 2H), 1.62 (s, 4H), 1.46
(s, 2H).Anal. calcd. for C35H34F2N4O5 (%): C, 66.87; H, 5.45; F, 6.04; N, 8.91; O, 12.72. Found (%): C,
66.85; H, 5.40; N, 8.88.
4.7. General preparation of 43a~43i and 44a~47e.
Starting from 4-fluorobenzohydrazide (11), the compounds were prepared by the method mentioned
above.

4.7.1 N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-
fluorophenyl)-1,3,4-oxadiazol-2-yl)acetamide (43a)
1
Yield: 59%; m.p. 123 - 125oC; MS (ESI) m/z (%): 644.2 [M + H]+; H NMR (400 MHz, DMSO) δ
10.89 (s, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.08 (dd, J = 8.8, 5.3 Hz, 2H), 7.86 (d, J = 12.3 Hz, 1H), 7.56 - 7.37
(m, 6H), 6.45 (d, J = 5.1 Hz, 1H), 4.29 (s, 2H), 4.20 (t, J = 6.1 Hz, 2H), 3.95 (s, 3H), 3.12 - 2.94 (m, 2H),
2.77 - 2.57 (m, 2H), 2.07 (d, J = 17.0 Hz, 4H), 1.64 (d, J = 12.3 Hz, 2H), 1.49 - 1.32 (m, 1H), 1.23 (s, 2H),
0.90 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 165.03, 164.58 (d, J = 250.4 Hz), 164.26, 162.35,
159.68, 153.90 (d, J = 246.1 Hz), 152.30, 150.02, 149.32, 146.82, 138.01 (d, J = 9.8 Hz), 136.39 (d, J =
12.2 Hz), 129.66 (d, J = 9.1 Hz), 124.70, 120.44 (d, J = 3.1 Hz), 117.36, 117.13, 115.76 (d, J = 158.1 Hz),
109.11, 108.56 (d, J = 23.2 Hz), 102.53, 99.53, 67.06, 56.28, 54.85, 53.47, 34.23, 28.46, 27.14, 26.11,
22.08; Anal. calcd. For C35H35F2N5O5 (%): C, 65.31; H, 5.48; F, 5.90; N, 10.88; O, 12.43. Found (%): C,
65.25; H, 5.45; N, 10.83.
4.7.2 N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluorophenyl)
-1,3,4-oxadiazol-2-yl)acetamide (43b)
o
1
Yield: 62%; m.p. 181- 183 C; MS (ESI) m/z (%): 632.8 [M + H]+; H NMR (400 MHz, DMSO) δ
10.86 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.11 - 8.05 (m, J = 8.8, 5.4 Hz, 1H), 7.85 (d, J = 13.7 Hz, 1H), 7.55
- 7.38 (m, 6H), 6.45 (d, J = 5.1 Hz, 1H), 4.28 (s, 2H), 4.21 (t, J = 6.1 Hz, 2H), 3.95 (s, 3H), 3.61 (s, 4H),
2.42 (m, 6H), 2.00 (m, 2H); 13C NMR (101 MHz, DMSO) δ 165.03, 164.58 (d, J = 248.9 Hz), 164.28,
162.34, 159.69, 153.89 (d, J = 246.2 Hz), 152.32, 150.03, 149.32, 146.78, 137.98 (d, J = 9.9 Hz), 136.40 (d,
J = 11.8 Hz), 129.67 (d, J = 9.4 Hz), 124.70, 120.42 (d, J = 2.9 Hz), 117.35, 117.13, 115.76 (d, J = 160.1
Hz), 109.05, 108.59 (d, J = 23.6 Hz), 102.53, 99.52, 67.04, 66.15, 56.27, 55.11, 53.46, 34.21, 25.64; Anal.
calcd. For C33H31F2N5O6 (%): C, 62.75; H, 4.95; F, 6.02; N, 11.09; O, 15.20. Found (%): C, 62.73; H, 4.97;
N, 11.05.
4.7.3 N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-
fluorophenyl)-1,3,4-oxadiazol-2-yl)acetamide (43c)
o
1
Yield: 53%; m.p. 122 - 124 C; MS (ESI) m/z (%): 645.2 [M + H]+; H NMR (400 MHz, DMSO) δ
10.85 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.08 (m, 2H), 7.92 - 7.77 (m, 1H), 7.56 - 7.34 (m, 6H), 6.45 (d, J =
5.1 Hz, 1H), 4.28 (s, 2H), 4.19 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.38 (dd, J = 14.0, 7.0 Hz, 3H), 2.40 (m, 8
H), 2.20 (s, 3H), 2.02 - 1.92 (m, 2H); 13C NMR (101 MHz, DMSO) δ 165.03, 164.58 (d, J = 250.3 Hz),
164.28, 162.34, 159.69, 154.00 (d, J = 224.8 Hz), 152.40, 150.04, 149.31, 146.80, 137.83 (d, J = 16.3 Hz),
136.41 (d, J = 12.3 Hz), 129.67 (d, J = 9.1 Hz), 124.71, 120.15 (d, J = 50.2 Hz), 117.36, 117.13, 115.74 (d,
J = 163.6 Hz), 112.16, 108.97, 99.98, 99.50, 67.15, 56.27, 54.70, 54.60, 52.51, 34.21, 26.34, 18.99; Anal.
calcd. For C34H34F2N6O5 (%): C, 63.35; H, 5.32; F, 5.89; N, 13.04; O, 12.41. Found (%): C, 63.33; H, 5.30;
N, 13.02.
4.7.4 N-(3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-
fluorophenyl)-1,3,4-oxadiazol-2-yl)acetamide (43d)
o
1
Yield: 51%; m.p. 131 - 133 C; MS (ESI) m/z (%): 616.7 [M + H]+; H NMR (400 MHz, DMSO) δ
10.86 (s, 1H), 8.47 (d, J = 4.7 Hz, 1H), 8.08 (dd, J = 8.7, 5.4 Hz, 2H), 7.86 (d, J = 13.7 Hz, 1H), 7.56 - 7.36

(m, 6H), 6.45 (d, J = 4.9 Hz, 1H), 4.28 (s, 2H), 4.22 (t, J = 6.2 Hz, 2H), 3.95 (s, 3H), 2.71 (d, J = 33.6 Hz,
6H), 2.08 - 1.98 (m, 2H), 1.76 (s, 4H); 13C NMR (101 MHz, DMSO) δ 165.05, 164.59 (d, J = 250.6 Hz),
164.28, 162.35, 159.72, 152.39 (d, J = 58.4 Hz), 149.95, 149.40, 146.74, 138.37 (d, J = 62.7 Hz), 136.74 (d,
J = 59.2 Hz), 129.67 (d, J = 8.6 Hz), 124.72, 120.43, 117.36, 117.14, 115.84 (d, J = 150.5 Hz), 108.95 (d, J
= 48.2 Hz), 102.46, 99.57, 66.59, 56.33, 53.93, 52.29, 34.21, 26.51, 23.24; Anal. calcd. for C33H31F2N5O5
(%): C, 64.38; H, 5.08; F, 6.17; N, 11.38; O, 12.99. Found (%): C, 64.35; H, 5.04; N, 11.35.
4.7.5 N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-
fluorophenyl)-1,3,4-oxadiazol-2-yl)acetamide (43e)
o
1
Yield: 57%; m.p. 177 - 179 C; MS (ESI) m/z (%): 630.3 [M + H]+; H NMR (400 MHz, DMSO) δ
10.87 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.08 (dd, J = 8.5, 5.4 Hz, 2H), 7.86 (d, J = 13.9 Hz, 1H), 7.56 - 7.36
(m, 6H), 6.45 (d, J = 5.2 Hz, 1H), 4.29 (s, 2H), 4.21 (t, J = 6.2 Hz, 3H), 3.95 (s, 2H), 2.80 - 2.53 (m, 6H),
2.04 (s, 2H), 1.58 (s, 4H), 1.43 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 165.44 (d, J = 80.2 Hz), 164.28,
163.34, 162.35, 159.70, 153.66 (d, J = 291.7 Hz), 149.99, 149.36, 146.76, 138.00 (d, J = 7.4 Hz), 137.46 (d,
J = 11.1 Hz), 129.67 (d, J = 9.2 Hz), 124.72, 120.43, 117.36, 117.13, 115.78 (d, J = 154.6 Hz), 109.13,
108.59 (d, J = 23.1 Hz), 102.56, 99.55, 66.95, 56.29, 54.95, 53.77, 34.22, 25.37, 24.71, 20.11 . Anal. calcd.
For C34H33F2N5O5(%): C, 64.86; H, 5.28; F, 6.03; N, 11.12; O, 12.70. Found (%): C, 64.83; H, 5.25; N,
11.14.
4.7.6 2-(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)-N-(4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)
propoxy)quinolin-4-yl)oxy)phenyl)acetamide (43f)
o
1
Yield: 65%; m.p. 131 - 132 C; MS (ESI) m/z (%): 705.7 [M + H]+; H NMR (600 MHz, DMSO) δ
11.09 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.88 (dd, J = 12.9, 2.0 Hz, 1H), 7.70 (d, J
= 8.6 Hz, 2H), 7.56 (s, 1H), 7.52 - 7.43 (m, 3H), 4.32 (s, 2H), 4.27 (t, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.51 (d,
J = 11.1 Hz, 2H), 3.22 (s, 2H), 2.92 (dd, J = 36.2, 14.3 Hz, 2H), 2.30 (s, 2H), 1.80 (d, J = 13.5 Hz, 2H),
1.62 (s, 1H), 1.48 (dd, J = 24.4, 11.7 Hz, 2H), 0.93 (d, J = 6.2 Hz, 3H); 13C NMR (101 MHz, DMSO) δ
165.03, 162.56, 162.00 (d, J = 452.5 Hz), 153.87 (d, J = 245.9 Hz), 151.98, 149.91, 149.37, 146.66, 138.12
(d, J = 10.0 Hz), 137.23, 136.30 (d, J = 12.2 Hz), 130.17, 128.76, 124.69, 122.61, 116.56, 115.14, 109.30,
108.54 (d, J = 23.1 Hz), 102.61, 99.61, 66.52, 56.32, 54.09, 52.46, 34.21, 31.33, 28.62, 23.78, 21.58; Anal.
calcd. For C35H35BrFN5O5 (%): C, 59.66; H, 5.01; Br, 11.34; F, 2.70; N, 9.94; O, 11.35. Found (%): C,
59.63; H, 5.02; N, 9.95.
4.7.7 2-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-
1-yl)propoxy)quinolin-4-yl)oxy)phenyl)acetamide (43g)
Yield: 64%; m.p. 96 - 98 oC; MS (ESI) m/z (%): 661.0 [M + H]+; 1H NMR (600 MHz, DMSO) δ 10.93
(s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.86 (dd, J = 3.0 Hz, 1H), 7.70 (d, J = 8.6 Hz,
2H), 7.54 (s, 1H), 7.49 - 7.40 (m, 3H), 6.46 (d, J = 5.1 Hz, 1H), 4.30 (s, 2H), 4.23 (t, J = 6.0 Hz, 2H), 3.96
(s, 3H), 3.21 (s, 2H), 3.11 - 2.98 (m, 2H), 2.97 - 2.76 (m, 2H), 2.14 (s, 2H), 1.71 (d, J = 11.0 Hz, 2H), 1.50
(s, 1H), 1.33 (d, J = 31.8 Hz, 2H), 0.92 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 165.00, 162.54,
161.97 (d, J = 458.3 Hz), 153.89 (d, J = 246.5 Hz), 152.15, 149.97, 149.35, 146.78, 138.05 (d, J = 9.8 Hz),
137.23, 136.36 (d, J = 12.2 Hz), 130.15, 128.74, 124.68, 122.61, 116.56, 115.04, 109.20, 108.56 (d, J =

22.7 Hz), 102.55, 99.56, 66.83, 56.28, 54.39, 52.90, 46.04, 34.23, 32.49, 29.41, 25.10, 21.69, 9.21; Anal.
calcd. For C35H35ClFN5O5 (%):C, 63.68; H, 5.34; Cl, 5.37; F, 2.88; N, 10.61; O, 12.12. Found (%): C, 63.65;
H, 5.36; N, 10.56.
4.7.8 N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5
-phenyl-1,3,4-oxadiazol-2-yl)acetamide (43h)
o
1
Yield: 54%; m.p. 210 - 212 C; MS (ESI) m/z (%): 626.9 [M + H]+; H NMR (600 MHz, DMSO) δ
11.33 (s, 1H), 8.63 (s, 1H), 8.02 (d, J = 6.9 Hz, 2H), 7.94 (dd, J = 12.9, 1.7 Hz, 1H), 7.68 - 7.57 (m, 6H),
6.68 (s, 1H), 4.34 (s, 2H), 4.30 (t, J = 5.9 Hz, 2H), 4.00 (s, 3H), 3.48 (d, J = 11.4 Hz, 2H), 3.25 - 3.19 (m,
2H), 2.96 - 2.87 (m, 2H), 2.38 - 2.31 (m, 2H), 1.87 - 1.77 (m, 4H), 1.75 - 1.68 (m, 1H), 0.92 (d, J = 6.4 Hz,
3H); 13C NMR (101 MHz, DMSO-d6) δ 165.20, 164.99, 162.37, 154.15 (d, J = 146.5 Hz), 152.43, 150.68,
146.91, 138.69 (d, J = 9.1 Hz), 135.74 (d, J = 13.1 Hz), 132.50, 129.97, 126.94, 124.59, 123.76, 116.66,
115.33, 108.67 (d, J = 1.0 Hz), 108.44, 102.96, 100.09, 66.95, 56.63, 53.86, 52.52, 34.19, 23.52, 22.83,
21.85; Anal. calcd. For C35H36FN5O5 (%): C, 65.31; H, 5.48; F, 5.90; N, 10.88; O, 12.43. Found (%): C,
65.32; H, 5.45; N, 10.85.
4.7.9 N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5
-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)acetamide (43i)
o
1
Yield: 65%; m.p. 119 - 121 C; MS (ESI) m/z (%): 656.8 [M + H]+; H NMR (600 MHz, DMSO) δ
10.35 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 7.87 (d, J = 13.9 Hz, 2H), 7.94 (dd, J = 12.9, 1.7 Hz, 1H), 7.55-7.48
(m, 6H), 6.45 (d, J = 5.1 Hz, 1H), 4.32 (s, 2H), 4.25 (t, J = 5.9 Hz, 2H), 3.95 (s, 3H), 3.45 (d, J = 11.1 Hz,
2H), 3.16 (s, 2H), 2.88 (m, 2H), 2.23 (s, 2H), 1.78 (d, J = 11.5 Hz, 2H), 1.58 (s, 1H), 1.39 (dd, J = 21.4,
14.7 Hz, 2H), 0.93 (d, J = 5.0 Hz, 3H); Anal. calcd. For C36H38FN5O6 (%): C, 67.19; H, 5.80; F, 3.04; N,
11.19; O, 12.78. Found (%): C, 67.14; H, 5.81; N, 11.15.
4.7.10
N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluoro
phenyl)-1,3,4-oxadiazol-2-yl)propanamide (44a)
Yield: 64%; m.p. 123 - 125 oC; MS (ESI) m/z (%): 658.2 [M + H]+;1H NMR (400 MHz, DMSO) δ 10.86 (s,
1H), 8.47 (d, J = 5.1 Hz, 1H), 8.08 (dd, J = 8.6, 5.4 Hz, 2H), 7.88 (d, J = 11.9 Hz, 1H), 7.56 - 7.36 (m, 6H),
6.45 (d, J = 5.1 Hz, 1H), 4.38 (q, J = 7.1 Hz, 1H), 4.19 (t, J = 6.1 Hz, 2H), 3.95 (s, 3H), 2.95 (d, J = 9.5 Hz,
2H), 2.57 (s, 2H), 2.16 - 1.94 (m, 4H), 1.71 (d, J = 7.1 Hz, 3H), 1.61 (d, J = 12.1 Hz, 2H), 1.36 (s, 1H),
1.21 - 1.09 (m, 2H), 0.89 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 168.64, 165.87, 163.35,
161.53 (d, J = 365.8 Hz), 153.90 (d, J = 245.8 Hz), 152.36, 150.04, 149.30, 146.82, 138.05 (d, J = 10.0 Hz),
136.44 (d, J = 12.1 Hz),129.72 (d, J = 9.0 Hz), 124.70, 120.41, 117.23 (d, J = 22.5 Hz), 116.71, 114.94,
109.02, 108.84, 108.61, 102.50, 99.50, 67.17, 56.26, 54.96, 53.67, 33.91, 30.46, 26.23, 22.12, 15.36. Anal.
calcd. for C36H37F2N5O5 (%): C, 65.74; H, 5.67; F, 5.78; N, 10.65; O, 12.16. Found (%): C, 65.70; H, 5.63;
N, 10.63.
4.7.11
N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluorophenyl)-1,3,

4-oxadiazol-2-yl)propanamide (44b)
o
1
Yield: 63%; m.p. 122 - 124 C; MS (ESI) m/z (%): 646.2 [M + H]+; H NMR (400 MHz, DMSO) δ
10.91 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.08 (dd, J = 8.8, 5.3 Hz, 2H), 7.88 (dd, J = 12.9, 1.8 Hz, 1H), 7.57
- 7.35 (m, 6H), 6.45 (d, J = 5.1 Hz, 1H), 4.40 (t, J = 7.0 Hz, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.96 (s, 3H), 3.64
- 3.59 (m, 3H), 2.55 (m, 2H), 2.46 (s, 4H), 2.07 - 1.94 (m, 2H), 1.71 (d, J = 7.1 Hz, 3H); 13C NMR (101
MHz, DMSO) δ 168.68, 165.87, 163.36, 161.96 (d, J = 445.4 Hz), 153.89 (d, J = 245.9 H) 152.38, 150.03,
149.31, 146.75, 138.02 (d, J = 10.1 Hz), 136.44 (d, J = 12.8 Hz), 129.72 (d, J = 9.0 Hz), 124.70, 120.40,
117.32, 117.21 (d, J = 22.5 Hz), 114.93, 108.93, 108.63, 102.50, 99.48, 67.11, 66.41, 56.26, 55.20, 53.64,
46.16, 25.87, 15.35, 9.06. Anal. calcd. for C34H33F2N5O6(%): C, 63.25; H, 5.15; F, 5.88; N, 10.85; O, 14.87.
Found (%): C, 63.23; H, 5.14; N, 10.84.
4.7.12 N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-
(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)propanamide (44c)
o
1
Yield: 68%; m.p. 120 - 123 C; MS (ESI) m/z (%): 669.0 [M + H]+; H NMR (400 MHz, DMSO) δ
11.00 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.11 - 8.05 (m, 2H), 7.89 (dd, J = 12.9, 2.0 Hz, 1H), 7.55 - 7.38 (m,
6H), 6.45 (d, J = 5.1 Hz, 1H), 4.41 (q, J = 7.1 Hz, 1H), 4.19 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.04 - 2.96 (m,
3H), 2.57 - 2.51 (m, 8H), 2.28 (s, 3H), 2.02 - 1.94 (m, 2H), 1.70 (d, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
DMSO) δ 168.67, 165.89, 163.36, 161.67 (d, J = 443.3 Hz), 153.89 (d, J = 245.9 H), 152.38, 150.04,
149.31, 146.83, 138.11 (d, J = 10.3 Hz), 136.40 (d, J = 12.3 Hz), 129.73 (d, J = 9.0 Hz), 124.70, 120.45,
117.23 (d, J = 22.5 Hz, 3H), 116.71, 114.92, 109.00, 108.82, 108.59, 102.49, 99.50, 67.10, 56.27, 54.52,
52.23, 46.00, 45.19, 26.31, 15.38, 9.26; Anal.calcd. for C36H37F2N5O5(%): C, 63.82; H, 5.51; F, 5.77; N,
12.76; O, 12.14. Found (%): C, 63.84; H, 5.46; N, 12.75.
4.7.13
N-(3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluorophenyl)-
1,3,4-oxadiazol-2-yl)propanamide (44d)
o
1
Yield: 54%; m.p. 144 - 146 C; MS (ESI) m/z (%): 630.2 [M + H]+; H NMR (400 MHz, DMSO) δ
10.99 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.12 - 8.05 (m, 2H), 7.90 (dd, J = 13.0, 1.7 Hz, 1H), 7.58 - 7.39 (m,
6H), 6.46 (d, J = 5.1 Hz, 1H), 4.41 (q, J = 7.0 Hz, 1H), 4.24 (t, J = 6.1 Hz, 2H), 3.96 (s, 3H), 2.99 (d, J =
6.9 Hz, 7H), 2.22 - 2.05 (m, 2H), 1.85 (s, 4H), 1.70 (d, J = 7.1 Hz, 3H); 13C NMR (101 MHz, DMSO) δ
168.68, 165.89, 163.35, 161.92 (d, J = 441.7 Hz),153.89 (d, J = 246.1 Hz), 152.15, 149.96, 149.36, 146.78,
138.13 (d, J = 9.5 Hz), 136.39 (d, J = 11.8 Hz), 129.72 (d, J = 8.8 Hz), 124.70, 120.45, 117.23 (d, J = 22.4
Hz), 116.67, 115.05, 109.16, 108.81, 108.58, 102.56, 99.54, 66.70, 56.31, 53.84, 52.26, 46.01, 26.82, 23.33,
15.39; Anal. calcd. for C34H33F2N5O5 (%): C, 65.06; H, 5.46; F, 3.03; N, 11.16; O, 15.29. Found (%): C,
65.02; H, 5.43; N, 11.12.
4.7.14
N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluorophenyl)-
1,3,4-oxadiazol-2-yl)propanamide (44e)
o
Yield: 52%; m.p. 119 - 120 C; MS (ESI) m/z (%): 644.2 [M + H]+;1H NMR (400 MHz, DMSO) δ
10.91 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.15 - 8.03 (m, 2H), 7.88 (dd, J = 12.7, 1.2 Hz, 1H), 7.57 - 7.32 (m,

6H), 6.45 (d, J = 5.1 Hz, 1H), 4.38 (q, J = 7.0 Hz, 1H), 4.20 (t, J = 6.2 Hz, 2H), 3.95 (s, 3H), 2.90 (dd, J =
16.4, 8.4 Hz, 2H), 2.59 (d, J = 4.1 Hz, 4H), 2.09 - 1.97 (m, 2H), 1.70 (d, J = 7.1 Hz, 3H), 1.61 - 1.51 (m,
4H), 1.42 (d, J = 3.8 Hz, 2H); 13C NMR (101 MHz, DMSO) δ 168.64, 165.88, 163.37, 161.93 (d, J = 444.1
Hz, 1H), 153.90 (d, J = 246.7 Hz, 1H), 152.32, 150.03, 149.33, 146.82, 138.07 (d, J = 9.6 Hz, 0H), 136.43
(d, J = 13.3 Hz, 0H), 129.73 (d, J = 9.0 Hz, 2H), 124.71, 120.42, 117.24 (d, J = 22.3 Hz, 2H), 116.72,
114.96, 109.08, 108.83, 108.61, 102.52, 99.52, 67.09, 56.28, 55.20, 54.11, 46.10, 25.85, 25.32, 23.84, 15.37.
Anal. calcd. for C35H35F2N5O5 (%): C, 65.31; H, 5.48; F, 5.90; N, 10.88; O, 12.43. Found (%): C, 65.25; H,
5.44; N, 10.84.
4.7.15
N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluoro
phenyl)-1,3,4-oxadiazol-2-yl)butanamide (45a)
Yield: 64%; m.p. 127 - 129oC; MS (ESI) m/z (%): 672.4 [M + H]+; H NMR (600 MHz, DMSO) δ
1
10.90 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.08 (dd, J = 8.8, 5.3 Hz, 2H), 7.89 (dd, J = 12.9, 2.0 Hz, 1H), 7.54
(s, 1H), 7.52 - 7.44 (m, 4H), 7.42 (s, 1H), 6.47 (d, J = 5.1 Hz, 1H), 4.22 (t, J = 6.8 Hz, 3H), 3.96 (s, 3H),
3.39 (dd, J = 14.0, 7.0 Hz, 2H), 3.13 (s, 2H), 2.79 (s, 2H), 2.26 - 2.15 (m, 2H), 2.10 (s, 2H), 1.69 (d, J =
11.4 Hz, 2H), 1.47 (s, 1H), 1.25 (d, J = 13.8 Hz, 2H), 1.05 (t, J = 7.4 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H); 13
C
NMR (101 MHz, DMSO) δ 167.67, 165.03, 164.61 (d, J = 250.1 Hz), 164.14, 153.90 (d, J = 245.0 Hz),
152.19, 149.98, 149.36, 146.78, 137.95 (d, J = 9.1 Hz), 136.48 (d, J = 12.5 Hz), 129.74 (d, J = 9.2 Hz),
124.70, 120.43, 117.24 (d, J = 22.5 Hz); 6.75, 115.01, 109.16, 108.87, 108.65, 102.60, 99.54, 66.89, 56.29,
54.55, 53.11, 46.41, 32.89, 29.61, 25.25, 23.47, 21.80, 12.10. Anal. calcd. for C37H39F2N5O5(%): C, 66.16;
H, 5.85; F, 5.66; N, 10.43; O, 11.91. Found (%): C, 66.12; H, 5.83; N, 10.42.
4.7.16
N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluorophenyl)-1,3,
4-oxadiazol-2-yl)butanamide (45b)
Yield: 53%; m.p. 128 - 129oC; MS (ESI) m/z (%): 660.2 [M + H]+;1H NMR (400 MHz, DMSO) δ
10.88 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.07 (m, 2H), 7.89 (d, J = 13.7 Hz, 1H), 7.57 - 7.40 (m, 6H), 6.46 (d,
J = 5.0 Hz, 1H), 4.21 (m, 4H), 3.95 (s, 3H), 3.64 (s, 4H), 3.09 (m, 2H), 2.19 (m, 3H), 2.03 (s, 2H), 1.04 (t, J
= 7.3 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 167.65, 165.02, 164.61 (d, J = 249.9 Hz), 164.14, 153.91 (d,
J = 245.5 Hz), 152.33, 150.03, 149.32, 146.82, 137.93 (d, J = 10.2 Hz), 136.51 (d, J = 12.1 Hz), 129.74 (d,
J = 9.2 Hz), 124.70, 120.41, 117.24 (d, J = 22.3 Hz), 116.74, 114.96, 109.06, 108.89, 108.66, 102.57, 99.50,
67.04, 56.28, 55.13, 53.52, 46.42, 46.15, 23.47, 12.10, 9.08; Anal. calcd. For C35H35F2N5O6 (%): C, 63.72;
H, 5.35; F, 5.76; N, 10.62; O, 14.55. Found (%): C, 63.73; H, 5.33; N, 10.61.
4.7.17
N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluoro
phenyl)-1,3,4-oxadiazol-2-yl)butanamide (45c)
Yield: 54%; m.p.154 - 155oC; MS (ESI) m/z (%): 673.7 [M + H]+;1H NMR (400 MHz, DMSO) δ
10.94 (s, 1H), 8.45 (t, J = 4.9 Hz, 1H), 8.07 (dd, J = 8.8, 5.3 Hz, 2H), 7.89 (dd, J = 12.9, 1.7 Hz, 1H), 7.54 -
7.43 (m, 1H), 7.39 (s, 1H), 6.45 (d, J = 5.2 Hz, 1H), 4.21 - 4.15 (m, J = 10.2, 6.2 Hz, 3H), 3.95 (s, 3H), 2.51

- 2.31 (m, 10H), 2.28 - 2.13 (m, 7H), 1.04 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 167.67,
165.03, 164.60 (d, J = 249.6 Hz), 164.13, 153.90 (d, J = 245.7 Hz), 152.40, 150.05, 149.31, 146.84, 137.95
(d, J = 10.1 Hz), 136.50 (d, J = 12.2 Hz), 129.74 (d, J = 9.3 Hz), 124.70, 120.44, 117.24 (d, J = 22.6 Hz);
116.73, 114.92, 109.00, 108.88, 108.65, 102.01, 99.50, 67.15, 56.27, 54.81, 54.65, 52.64, 46.40, 46.08,
45.62, 26.40, 23.48, 12.09; Anal. calcd. For C36H38F2N6O5(%): C, 64.27; H, 5.69; F, 5.65; N, 12.49; O,
11.89. Found (%): C, 64.23; H, 5.70; N, 12.45.
4.7.18
N-(3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluorophenyl)-
1,3,4-oxadiazol-2-yl)butanamide (45d)
Yield: 55%; m.p. 133 - 134oC; MS (ESI) m/z (%): 643.7 [M + H]+;1H NMR (400 MHz, DMSO) δ
10.91 (s, 1H), 8.46 (t, J = 4.8 Hz, 1H), 8.07 (dd, J = 8.8, 5.4 Hz, 2H), 7.88 (dd, J = 14.2, 12.2 Hz, 1H), 7.56
- 7.36 (m, 6H), 6.46 (d, J = 5.1 Hz, 1H), 4.27 - 4.19 (m, 3H), 3.96 (s, 3H), 2.89 (d, J = 23.0 Hz, 6H), 2.25 -
2.14 (m, 2H), 2.14 - 2.04 (m, 2H), 1.82 (s, 4H), 1.04 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, DMSO) δ
167.67, 165.03, 164.61 (d, J = 251.0 Hz), 164.14, 153.90 (d, J = 247.6 Hz), 152.21, 150.00, 149.37, 146.81,
137.95 (d, J = 8.9 Hz), 136.50 (d, J = 11.6 Hz), 129.74 (d, J = 9.7 Hz), 124.71, 120.45, 117.24 (d, J = 22.3
Hz, 1H), 116.77, 115.02, 109.14, 108.90, 108.69, 102.07, 99.60 (d, J = 12.5 Hz, 1H), 66.80, 56.31, 53.96,
52.41, 46.42, 27.17, 23.47, 23.37, 12.10; Anal. calcd. For C35H35F2N5O5 (%): C, 65.31; H, 5.48; F, 5.90; N,
10.88; O, 12.43. Found (%): C, 65.30; H, 5.45; N, 10.86.
4.7.19
N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluorophenyl)-
1,3,4-oxadiazol-2-yl) butanamide (45e)
Yield: 53%; m.p. 132 - 134oC; MS (ESI) m/z (%): 658.9 [M + H]+;1H NMR (400 MHz, DMSO) δ
10.89 (s, 1H), 8.47 (d, J = 4.8 Hz, 1H), 8.07 (dd, J = 8.4, 5.4 Hz, 2H), 7.89 (d, J = 12.3 Hz, 1H), 7.55 (s,
1H), 7.51 - 7.40 (m, 5H), 6.47 (d, J = 5.1 Hz, 1H), 4.27 - 4.18 (m, 3H), 3.96 (s, 3H), 3.14 - 2.77 (m, 6H),
2.26 - 2.09 (m, 4H), 1.68 (s, 4H), 1.51 (s, 2H), 1.04 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, DMSO) δ
167.65, 165.02, 164.61 (d, J = 250.4 Hz), 164.14, 153.16 (d, J = 247.6 Hz), 152.10, 149.96, 149.39, 146.77,
137.93 (d, J = 8.9 Hz), 136.51 (d, J = 11.6 Hz), 129.74 (d, J = 9.7 Hz), 124.71, 120.44, 117.25 (d, J = 22.3
Hz, 1H), 116.76, 115.07, 109.26, 108.89, 108.67, 102.59, 99.56, 66.73, 56.31, 53.33, 46.42, 46.16, 24.17,
23.46, 12.10, 9.41, 9.21; Anal. calcd. For C36H37F2N5O5 (%): C, 65.74; H, 5.67; F, 5.78; N, 10.65; O, 12.16.
Found (%): C, 65.72; H, 5.65; N, 10.60.
4.7.20N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-
(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-methylpropanamide (46a)
Yield: 70%; m.p. 126 - 128oC; MS (ESI) m/z (%): 672.2 [M + H]+;1H NMR (400 MHz, DMSO) δ
10.02 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.10 (dd, J = 8.8, 5.4 Hz, 2H), 7.88 (dd, J = 13.1, 2.2 Hz, 1H), 7.62
- 7.34 (m,6H), 6.44 (d, J = 5.1 Hz, 1H), 4.18 (t, J = 6.4 Hz, 2H), 3.95 (s, 4H), 3.38 (dd, J = 16.5, 9.5 Hz,
2H), 2.89 (d, J = 11.0 Hz, 2H), 2.47 (s, 2H), 2.05 - 1.89 (m, 4H), 1.92(s, 6H), 1.60 (t, J = 12.5 Hz, 2H), 1.41
- 1.27 (m, 1H), 0.89 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 171.19, 169.01, 164.60 (d, J =
249.8 Hz), 164.08, 159.71, 153.73 (d, J = 245.3 Hz), 152.36, 150.04, 149.31, 146.83, 138.06 (d, J = 9.4 Hz),

136.54 (d, J = 13.2 Hz), 129.76 (d, J = 9.2 Hz), 124.37, 120.54, 117.63, 117.21 (d, J = 22.7 Hz), 114.95,
109.63 (d, J = 23.1 Hz), 109.02, 102.54, 99.50, 67.17, 56.27, 54.97, 53.70, 44.97, 33.97, 30.46, 26.25,
24.25, 22.14; Anal. calcd. For C37H39F2N5O5 (%): C, 66.16; H, 5.85; F, 5.66; N, 10.43; O, 11.91. Found (%):
C, 66.12; H, 5.84; N, 10.41.
4.7.21
N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluorophenyl)-1,3,
4-oxadiazol-2-yl)-2-methylpropanamide (46b)
Yield: 64%; m.p. 134 - 135oC; MS (ESI) m/z (%): 660.2 [M + H]+;1H NMR (400 MHz, DMSO) δ
10.11 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.10 (dd, J = 8.5, 5.4 Hz, 2H), 7.90 (dd, J = 13.1, 1.8 Hz, 1H), 7.64
- 7.36 (m, 6H), 6.43 (t, J = 9.7 Hz, 1H), 4.19 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.64 - 3.53 (m, 4H), 2.95 (q,
J = 7.1 Hz, 2H), 2.47 (t, J = 7.0 Hz, 2H), 2.39 (s, 4H), 2.03 - 1.92 (m, 2H), 1.81 (s, 6H); Anal. calcd. For
C35H35F2N5O6 (%): C, 63.72; H, 5.35; F, 5.76; N, 10.62; O, 14.55. Found (%): C, 63.70; H, 5.34; N, 10.63.
4.7.22
N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluoro
phenyl)-1,3,4-oxadiazol-2-yl)-2-methylpropanamide (46c)
Yield: 55%; m.p. 134 - 135oC; MS (ESI) m/z (%): 673.2 [M + H]+; H NMR (400 MHz, DMSO) δ
1
10.07 (s, 1H), 8.46 (d, J = 5.1 Hz, 1H), 8.10 (dd, J = 8.4, 5.4 Hz, 2H), 7.89 (d, J = 11.5 Hz, 1H), 7.63 - 7.33
(m, 6H), 6.44 (d, J = 5.0 Hz, 1H), 4.18 (t, J = 5.9 Hz, 2H), 3.95 (s, 3H), 3.62 (s, 4H), 2.49 (d, J = 7.6 Hz,
6H), 2.24 (s, 3H), 2.04 - 1.92 (m, 2H), 1.81 (s, 6H). Anal. calcd. for C36H38F2N6O5 (%): C, 64.27; H, 5.69; F,
5.65; N, 12.49; O, 11.89. Found (%): C, 64.23; H, 5.64; N, 12.44.
4.7.23
N-(3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluorophenyl)-
1,3,4-oxadiazol-2-yl)-2-methylpropanamide (46d)
Yield: 65%; m.p. 145 - 146oC; MS (ESI) m/z (%): 644.2 [M + H]+; H NMR (400 MHz, DMSO) δ
1
10.05 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.10 (dd, J = 8.6, 5.4 Hz, 2H), 7.89 (dd, J = 13.1, 2.0 Hz, 1H), 7.61
- 7.35 (m, 6H), 6.45 (d, J = 5.1 Hz, 1H), 4.21 (t, J = 6.2 Hz, 2H), 3.95 (s, 3H), 2.69 (t, J = 6.9 Hz, 2H), 2.59
(s, 4H), 2.09 - 1.96 (m, 2H), 1.81 (s, 6H), 1.73 (s, 4H); 13C NMR (101 MHz, DMSO) δ 171.23, 169.02,
164.59 (d, J = 250.5 Hz), 164.08, 159.73, 153.73 (d, J = 245.6 Hz), 152.33, 150.00, 149.30, 146.78, 138.05
(d, J = 10.0 Hz), 136.52 (d, J = 12.3 Hz), 129.75 (d, J = 9.1 Hz), 124.36, 120.53 (d, J = 3.0 Hz), 117.63,
117.19 (d, J = 22.4 Hz),114.94, 109.64 (d, J = 23.1 Hz), 108.95, 102.52, 99.47, 67.03, 56.26, 54.01, 52.56,
44.99, 27.91, 24.22, 23.47; Anal. calcd. For C35H35F2N5O5 (%): C, 65.31; H, 5.48; F, 5.90; N, 10.88; O,
12.43. Found (%): C, 65.33; H, 5.44; N, 10.83.
4.7.24
N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-2-(5-(4-fluorophenyl)-
1,3,4-oxadiazol-2-yl)-2-methylpropanamide (46e)
Yield: 53%; m.p. 126 - 127oC; MS (ESI) m/z (%): 658.2 [M + H]+; H NMR (400 MHz, DMSO) δ
1
10.02 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.10 (dd, J = 8.8, 5.4 Hz, 2H), 7.88 (dd, J = 13.1, 2.2 Hz, 1H), 7.62

- 7.34 (m, 6H), 6.44 (d, J = 5.1 Hz, 1H), 4.18 (t, J = 6.4 Hz, 2H), 3.95 (s, 2H), 3.38 (dd, J = 16.5, 9.5 Hz,
2H), 2.89 (d, J = 11.0 Hz, 2H), 2.47 (s, 2H), 2.05 - 1.89 (m, 4H), 1.60 (t, J = 12.5 Hz, 2H), 1.41 - 1.27 (m,
1H), 0.89 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 171.22, 169.03, 164.59 (d, J = 250.3 Hz),
164.07, 159.71, 153.73 (d, J = 245.6 Hz), 152.37, 150.03, 149.27, 146.84, 138.09 (d, J = 9.8 Hz, 2H),
136.51 (d, J = 12.3 Hz), 129.74 (d, J = 9.1 Hz), 124.34, 120.57, 117.61, 117.18 (d, J = 22.4 Hz), 114.94,
109.62 (d, J = 23.0 Hz); 109.01, 102.51, 99.48, 67.19, 56.24, 55.38, 54.34, 46.04, 45.01, 26.22, 25.69,
24.23; Anal. calcd. For C36H37F2N5O5 (%): C, 65.74; H, 5.67; F, 5.78; N, 10.65; O, 12.16. Found (%): C,
65.73; H, 5.65; N, 10.63.
4.7.25 N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-1-
(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)cyclopropane-1-carboxamide (47a)
1
Yield: 64%; m.p. 146 - 147oC; MS (ESI) m/z (%): 670.2 [M + H]+; H NMR (400 MHz, DMSO) δ
10.38 (s, 1H), 8.48 (s, 1H), 8.10 (dd, J = 8.7, 5.4 Hz, 2H), 7.86 (dd, J = 13.0, 1.9 Hz, 1H), 7.58 - 7.34 (m,
6H), 6.46 (d, J = 4.9 Hz, 1H), 4.19 (t, J = 6.2 Hz, 2H), 3.95 (s, 3H), 2.93 (d, J = 10.8 Hz, 2H), 2.53 (d, J =
10.1 Hz, 2H), 2.10 - 1.92 (m, 4H), 1.85 - 1.67 (m, 4H), 1.60 (d, J = 11.7 Hz, 2H), 1.35 (s, 1H), 1.29 - 1.11
(m, J = 24.2, 12.1 Hz, 4H), 0.88 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 166.89, 165.69,
164.54 (d, J = 250.4 Hz), 164.00, 159.67, 153.78 (d, J = 245.2 Hz), 152.37, 150.03, 149.28, 146.88,
δ137.93 (d, J = 9.9 Hz), 136.57 (d, J = 12.2 Hz), 129.76 (d, J = 9.0 Hz), 124.42, 120.69, 117.51, 117.14 (d,
J = 22.5 Hz), 114.96, 109.59 (d, J = 22.7 Hz), 109.00, 102.53, 99.48, 67.19, 56.24, 55.02, 53.74, 34.07,
30.58, 26.36, 23.15, 22.17, 17.32; Anal. calcd. for C37H37F2N5O5 (%): C, 65.94; H, 5.38; F, 5.79; N, 10.68;
O, 12.20. Found (%): C, 65.93; H, 5.34; N, 10.64.
4.7.26
N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-1-(5-(4-fluorophenyl)-1,3,
4-oxadiazol-2-yl)cyclopropane-1-carboxamide (47b)
Yield: 64%; m.p. 194 - 196oC; MS (ESI) m/z (%): 658.2 [M + H]+; H NMR (400 MHz, DMSO) δ
1
10.36 (s, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.10 (dd, J = 8.6, 5.4 Hz, 2H), 7.86 (d, J = 11.0 Hz, 1H), 7.58 - 7.36
(m, 6H), 6.45 (d, J = 5.1 Hz, 1H), 4.20 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.59 (t, J = 4.4 Hz, 4H), 2.51 - 2.44
(m, 2H), 2.40 (s, 4H), 2.04 - 1.94 (m, 2H), 1.81 - 1.67 (m, 4H); 13C NMR (101 MHz, DMSO) δ 166.89,
165.69, 164.67 (d, J = 226.9 Hz), 164.01, 159.67, 153.78 (d, J = 245.7 Hz), 152.42, 150.06, 149.31, 146.86,
137.93 (d, J = 9.2 Hz), 136.60 (d, J = 11.2 Hz), 129.78 (d, J = 9.2 Hz), 124.44, 120.73 (d, J = 2.9 Hz),
117.56, 117.16 (d, J = 22.4 Hz), 114.94, 109.60 (d, J = 23.3 Hz), 109.03, 102.54, 99.49, 66.68, 56.26, 55.28,
53.84, 46.09, 26.15, 23.16, 17.28; Anal. calcd. for C35H33F2N5O6 (%): C, 63.92; H, 5.06; F, 5.78; N, 10.65;
O, 14.60. Found (%): C, 63.91; H, 5.04; N, 10.64.
4.7.27
N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-1-(5-(4-fluoro
phenyl)-1,3,4-oxadiazol-2-yl)cyclopropane-1-carboxamide (47c)
1
Yield: 74%; m.p. 130 - 131oC; MS (ESI) m/z (%): 671.2 [M + H]+; H NMR (400 MHz, DMSO) δ
10.39 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.10 (dd, J = 8.8, 5.3 Hz, 2H), 7.87 (dd, J = 13.0, 2.2 Hz, 1H), 7.55
- 7.38 (m, 6H), 6.46 (d, J = 5.1 Hz, 1H), 4.21 (t, J = 6.2 Hz, 2H), 3.95 (s, 3H), 3.37 (dd, J = 12.9, 5.6 Hz,