Discovery of 1,6-naphthyridinone-based MET kinase inhibitor bearing quinoline moiety as promising antitumor drug candidate

Article abstract of DOI:10.1016/j.ejmech.2020.112174

A series of 1,6-naphthyridinone-based MET kinase inhibitors bearing quinoline moiety in block A were designed and synthesized based on the structures of Cabozantinib and our reported compound IV. Extensive SAR and DMPK studies led to the identification of 20j, a potent and orally bioavailable MET kinase inhibitor with favorable kinase selectivity. More importantly, 20j exhibited statistically significant tumor growth inhibition (Tumor growth inhibition/TGI of 131%, 4/6 partial regression/PR) in the U-87 MG xeograft model, which is superior to that of Cabozantinib (TGI of 97%, 2/6 PR), and significantly better than that of compound IV (TGI of 15%, 0/6 PR) at the same dose (12.5 mg/kg). Combined with favorable in vitro potency, kinase selectivity, pharmacokinetic profile and in vivo efficacy, the promising antitumor drug candidate 20j has subsequently advanced into preclinical research.

Full text of DOI:10.1016/j.ejmech.2020.112174

Journal Pre-proof
Discovery of 1,6-naphthyridinone-based MET kinase inhibitor bearing quinoline
moiety as promising antitumor drug candidate
Tao Chen, Lin-Sheng Zhuo, Peng-Fei Liu, Wei-Rong Fang, Yun-Man Li, Wei Huang
PII:
S0223-5234(20)30141-0
DOI:
https://doi.org/10.1016/j.ejmech.2020.112174
EJMECH 112174
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 25 November 2019
Revised Date: 14 February 2020
Accepted Date: 19 February 2020
Please cite this article as: T. Chen, L.-S. Zhuo, P.-F. Liu, W.-R. Fang, Y.-M. Li, W. Huang, Discovery
of 1,6-naphthyridinone-based MET kinase inhibitor bearing quinoline moiety as promising antitumor
drug candidate, European Journal of Medicinal Chemistry (2020), doi: https://doi.org/10.1016/
j.ejmech.2020.112174.
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.
© 2020 Published by Elsevier Masson SAS.

Graphical Abstract
Discovery of 1,6-Naphthyridinone-Based MET Kinase
Inhibitor Bearing Quinoline Moiety as Promising Antitumor
Drug Candidate
Tao Chen1,†, Lin-Sheng Zhuo2,†, Peng-Fei Liu2, Wei-Rong Fang1, Yun-Man Li1,*, and
Wei Huang2,*

1
2
3
4
Discovery of 1,6-Naphthyridinone-Based MET Kinase Inhibitor
Bearing Quinoline Moiety as Promising Antitumor Drug
Candidate
5
6
7
Tao Chen1,†, Lin-Sheng Zhuo2,†, Peng-Fei Liu2, Wei-Rong Fang1, Yun-Man Li1,*, and Wei
Huang2,*
8
9
1 State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy,
China Pharmaceutical University, Nanjing, P.R. China
10
11
12
2 Nanjing Natinefy Pharmatech. Co., Ltd., Nanjing, P.R. China
13
14
15
16
* Corresponding authors. E-mail address: weihuangwuhan@126.com (W. Huang),
yunmanlicpu@163.com (Y. Li).
† T.C. and L.Z. contributed equally to this work.
17
18
ABSTRACT: A series of 1,6-naphthyridinone-based MET kinase inhibitors bearing
quinoline moiety in block A were designed and synthesized based on the structures of
Cabozantinib and our reported compound IV. Extensive SAR and DMPK studies led to the
identification of 20j, a potent and orally bioavailable MET kinase inhibitor with favorable
kinase selectivity. More importantly, 20j exhibited statistically significant tumor growth
inhibition (Tumor growth inhibition/TGI of 131%, 4/6 partial regression/PR) in the U-87 MG
xeograft model, which is superior to that of Cabozantinib (TGI of 97%, 2/6 PR), and
significantly better than that of compound IV (TGI of 15%, 0/6 PR) at the same dose (12.5
mg/kg). Combined with favorable in vitro potency, kinase selectivity, pharmacokinetic
profile and in vivo efficacy, the promising antitumor drug candidate 20j has subsequently
advanced into preclinical research.
19
20
21
22
23
24
25
26
27
28
29
30
31
KEYWORDS: 1,6-Naphthyridone, Quinoline, MET kinase inhibitor, Antitumor efficacy
1

1
2
3
4
5
6
7
8
9
1. Introduction
The MET receptor tyrosine kinase (RTK) is activated by its natural ligand, hepatocyte
growth factor/scatter factor (HGF/SF) [1]. In a variety of human cancers, abnormalities in
MET signaling (MET genomic amplification, MET overexpression, or MET mutations) have
been reported to correlate with poor clinical outcomes [2]. Consequently, MET kinase has
been considered as an attractive target for molecular targeted therapy in cancers [3,4].
Cabozantinib (I), the first small molecule MET inhibitor, was approved by FDA for the
treatment of patients with progressive metastatic medullary thyroid cancer, advanced kidney
cancer and liver cancer [5].
10
11
Figure 1. Reported block A of clinical candidates based on Cabozantinib (I)
12
13
14
15
16
17
18
19
20
21
As shown in Figure 1, the molecular structure of Cabozantinib (I) was divided to block A,
B, C and D. Recently, many derivatives of Cabozantinib (I) were reported. The main
modification of these different series of derivatives was focused on the block C and block A.
As the block A is directed towards the solvation region outside the binding pocket，the
bioisosterism strategy of block A resulted in the discovery of many new MET inhibitors.
More than a dozen drug candidates bearing diversified block A, such as quinoline moiety
(TAS-115 [6], Foretinib [7], RXDX-106 [8], AMG-458 [9], Ningetinib [10]), pyridine moiety
(BMS-777607 [11], Golvatinib [12], Altiratinib [13], BMS-794833 [14]), quinazoline moiety
(BPI-9016 [15]), thieno[3,2-b]pyridine moiety (Glesatinib [16], Sitravatinib [17]), and
indazole moiety (Merestinib [18]), have been advanced into clinical trials. Among them,
2

1
2
quinoline and pyridine moiety are the most common, indicating that they are the privileged
scaffolds with favorable drug-likeness.
3
4
5
Figure 2. Design of 1,6-naphthyridinone derivatives bearing quinoline moiety in block A as new MET
inhibitors
6
7
In our previous report, a novel 2,7-naphthyridone-based MET kinase inhibitor III [19]
bearing the same block A (2-amino-3-chloropyridin-4-yl group) with II (BMS-777607) was
discovered based on the scaffold hopping strategy a (cyclization & bioisosterism) of block C.
A new 1,6-naphthyridone-based MET kinase inhibitor IV bearing pyridine moiety in block A
was further designed via the scaffold hopping strategy b [20]. Unfortunately, compound IV
displayed unfavorable PK properties (AUC0-∞ = 2.2 µg·h/m, T1/2 = 1.0 h, CL = 5.0 L/h/kg
after oral dose of 10 mg/kg) and poor in vivo antitumor efficacy (Tumor growth
inhibition/TGI of 15% at 12.5 mg/kg Q.D.). Herein, we proposed a bioisosterism strategy c
that replace pyridine moiety with quinoline moiety in block A of the molecule (Figure 2).
Furthermore, the extensive structure-activity relationship (SAR) studies of the block A, C and
D were carried out to optimize the drug-likeness.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
2. Chemistry
On the basis of our previous experience in the synthesis of compound IV [20], the
assembly of chlorinated 1,6-naphthyridone (block C-D) with aromatic amine (block A-B) was
designed to generate target molecule V. Diverse quinoline-based aromatic amine could be
obtained by the modified reported methods [21-24].
3

1
2
Scheme 1. Reaction conditions and reagents: (i) BnBr, K2CO3, DMF, R.T.~40°C, overnight; (ii) Fe,
NH4Cl, EtOH/H2O=3/1, reflux, 1h; (iii)Triethyl orthoformate, Meldrum's acid, dry EtOH, reflux, 1h; (iv)
1,2-dichlorobenzene, 180°C, 5h; (v) POCl3, toluene, reflux, 1.5h; (vi) 2-fluoro-4-nitrophenol, toluene,
DIPEA, reflux, 72h; (vii) HBr (aq 40%), CH3COOH, 80°C, 5h; (viii) R5X, K2CO3, dry DMF, 70°C.
3
4
5
6
7
The synthesis of aromatic amine 10 bearing 6-methoxy-7-alkoxy-quinoline unit was
shown in Scheme 1. Firstly, the key intermediate 7-(benzyloxy)-4-chloro-6-methoxyquinoline
6 was produced by five steps reaction (protection-reduction-condensation-cyclization-
chlorination) of 1. Then the framework of block A-B (7) was constructed by a convenient
nucleophilic substitution reaction of 6 and 2-fluoro-4-nitrophenol. The desired aromatic
amine 10 was ultimately produced by a deprotection-substitution-reduction reaction of 7.
8
9
10
11
12
13
14
15
Scheme 2. Reaction conditions and reagents: (i) DIPEA, toluene, reflux, 24 to 50h; (ii) BBr3, dry DCM,
TEBA, 20h; (iii) R5X, K2CO3, dry DMF, 70°C, 7h; (iv) Fe, NH4Cl, reflux, EtOH/H2O=3/1, 1h.
4

1
2
3
4
5
6
The synthesis of other aromatic amine bearing 7-methoxy (15), 7-hydroxy (16) and
7-alkoxy (17) substituted quinoline unit was shown in Scheme 2. The framework of block
A-B (12) was conveniently constructed from the commercially available
4-chloro-7-methoxyquinoline 11 and 2-fluoro-4-nitrophenol. The deprotection and
substitution can afford nitro-substituted block A-B 13 and 14. The desired aromatic amines
15-17 can be obtained smoothly by subsequent reduction reaction of 12-14.
H
R3
N
NH2
F
H
N
N
R3
O
+
NH
O
R4
F
i)
N
R2
R1
Cl
O
R4
O
N
R2
R1
19a-p (R2 = OMe)
20a-l (R2 = H)
18a,b (R3 = H)
18c (R3 = Me)
10, 15-17
N
7
8
Scheme 3. Reaction conditions and reagents: (i) PTSA, propan-2-ol, 90°C.
9
10
11
12
The chlorinated 1,6-naphthyridine 18a-c were smoothly obtained using a modified
method from a previous report [20]. With the desired quinoline-based aromatic amine 10,
15-17 and chlorinated 1,6-naphthyridine 18 in hand, target compounds 19 and 20 were
conveniently synthesized through an acid-catalyzed nucleophilic substitution reaction.
13
14
3. Results and discussion
Firstly, the 6-R2 group of quinoline moiety in block A was fixed in methoxy group and the
15
16
17
18
19
20
21
22
23
24
25
26
27
28
SAR study of 7-R1 group was performed (Table 1). Compound 19a bearing the same block A
(6,7-dimethoxyquinolin-4-yl) with I (Cabozantinib) only displayed moderate MET inhibitory
activity (IC50 of 76.6 nM). The replacement of the methyl group of OMe with iso-butyl group
resulted in a 3.9-fold improvement of MET potency (IC50 of 19.7 nM, 2.3-fold lower potency
compared with I). Interestingly, compound 19c and 19d which replaced the methyl with
hydroxyethyl and methoxyethyl group displayed comparable MET inhibitory activity (IC50 of
5.7 and 8.3 nM) to that of I (Cabozantinib). Compounds 19c and 19d were screened in
preliminary rat microsomal metabolic stability and showed moderate half-life (T1/2 = 88.9 and
63.4 min). To further improve the drug-likeness, mono-methyl or di-methyl group was
introduced into the hydroxyethyl or methoxyethyl group, the resulted compounds 19e-g
exhibited good inhibitory activity (IC50 of 12.1 to 19.4 nM). More importantly, compound 19f
displayed a longer half-life (T1/2 of 310.2 min). After the alicyclic amines (morpholine,
pyrrolidine, piperidine) were introduced in 7-R1 group, compounds 19h-k all showed
comparable inhibitory activity (IC50 of 10.1 to 17.8 nM) to that of hydroxyethyl and
5

1
2
3
methoxyethyl substituted compounds. When the R4 group in block D was replaced from F to
H, the resulted compounds 19l-p all displayed good MET inhibitory activity (IC50 of 7.7 to
20.1 nM).
4
Table 1. Activity of 19a-p against METa and microsomal metabolic stability (rat)
5
Metabolic
MET, IC50
R1
stability
Compd
R4
(nM)
(T1/2, min)
OMe
19a
19b
F
F
76.6
19.7
5.7
-
F
19c
19d
19e
19f
88.9
F
F
8.3
63.4
15.6
19.4
12.1
18.1
17.8
13.2
10.1
7.7
-
F
F
310.2
19g
19h
19i
-
-
-
-
-
-
-
-
-
-
-
-
-
F
F
19j
F
19k
19l
F
H
H
H
H
H
19m
19n
19o
19p
20.1
10.5
10.1
9.4
I (Cabozantinib)
III [19]
8.4
9.9
IV [20]
9.8
6
7
a In vitro kinase assay were performed with the indicated purified recombinant MET kinase domain
(nM).
8
9
Moreover, the 6-methoxy group of quinoline moiety in block A was moved to further
investigate the SAR and drug-likeness (Table 2). Similar with the SAR of compounds 19a-p,
the hydroxyethyl, methoxyethyl and alicyclic amines derivatives 20c-h and 20j-k all displayed
10
6

1
2
excellent MET inhibitory activity (IC50 of 5.7 to 13.3 nM). Interestingly, compound 20i with
7-hydrxoy group showed comparable inhibitory activity (IC50 of 5.0 nM) to that of I
(Cabozantinib). The introduction of methyl group into the 2-position of 1,6-naphthyridinone
resulted in a slight loss of activity (20l, IC50 of 40.3 nM, 5.4-fold lower potency compared
with 20j). The structure–pharmacokinetic relationship (SPR) of compounds 20 were studied
based on the screen of rat microsomal metabolic stability. The morpholine substituted
compounds 20h and 20k exhibited high clearance rates in rat microsomes (T1/2 < 20 min),
while alkoxy derivatives displayed moderate to low clearance rates (T1/2 > 50 min). More
importantly, compounds 20f and 20j showed longer half-life (T1/2 = 248.4 and 322.3 min),
which proposed the side chain of 7-hydroxyethoxy group was a key metabolic site.
3
4
5
6
7
8
9
10
11
12
Table 2. Activity of 20a-l against METa and microsomal metabolic stability (rat)
H
R3
N
N
NH
O
R4
F
O
20a-l
R1
N
Metabolic
stability
(T1/2, min)
-
MET, IC50
(nM)
R1
Compd
R3
R4
OMe
H
H
F
F
41.4
27.8
20a
20b
20c
20d
20e
20f
90.1
90.6
103.8
85.4
248.4
86.8
6.6
H
H
H
H
H
H
H
H
H
F
F
6.8
8.4
F
13.3
7.6
F
F
13.1
10.9
5.0
20g
20h
20i
F
OH
F
53.6
322.3
17.8
-
H
H
H
7.4
20j
20k
20l
5.7
Me
40.3
13
14
a In vitro kinase assay were performed with the indicated purified recombinant MET kinase domain
(nM).
15
16
17
18
19
Molecular docking experiments were further performed to determine the SAR of block C.
As shown in Figure 3A, compound 20j was located deep in the MET pocket, and since three
key H-bond interactions were observed in the binding mode: one was established between the
carbonyl group in block C and residue Asp1222, another formed between the N-methyl group
in block C and Glu1127, the third formed between N atom in block A and Met1160, 20j
7

1
2
3
4
5
displayed comparable MET enzymatic activity to that of I. As shown in Figure 3B-C, the
introduction of a C(3) methyl group in block C of 20j resulted in a rotation of residue
Glu1127, which led to a disappearance of the H-bond interaction between N-methyl group in
block C of 20l and the residue Glu1127. As a result, 20j showed 5.4-fold higher potency
compared with 20l.
6
7
8
9
Figure 3. (A)The proposed binding mode of 20j with MET; (B) The proposed binding mode of 20l with
MET; (C) The binding mode overlay of 20j (yellow) and 20l (gray) with MET. Each dashed red line
represents hydrogen bonds between residues with 20j and 20l.
10
11
12
13
14
15
16
The inhibitory activity of compound 20j against a panel of forty eight other kinases was
also assayed (Figure 4). In contrast to its high potency against MET (IC50 of 7.4 nM), 20j
only exhibited high inhibitory effects against AXL, Flt4, KDR, Mer, TEK and TYRO3
(inhibitory rate > 80% in 1 µM). The IC50 of 20j agsinst these six kinases was shown in Table
3. These kinase profiling data suggested that compound 20j is a more selective kinase
inhibitor than I (cabozantnib) [25]. More importantly, it provided a novel scaffold for further
kinase selectivity enhancement.
17
18
Figure 4. Preliminary results of kinase profile of 20j (Inhibitory rate in 1µM)
Table 3. Activity of 20j against AXL, Flt4, KDR, Mer, TEK and TYRO3
19
20
N.O.
Kinase
AXL
Flt4
IC50, nM
32.3
1
2
116
8

3
4
5
6
KDR
Mer
198
16.5
19.0
91.6
TEK
TYRO3
1
2
3
4
5
6
7
8
Antiproliferative activities of the selected compounds (good MET inhibitory activity
and favorable microsomal metabolic stability) against U-87 MG (human glioblastoma),
NIH-H460 (human lung cancer), HT-29 (human colorectal cancer), MKN-45 (human
gastric cancer) cell lines were also evaluated in vitro using compound I (Cabozantinib) as a
positive control. As shown in Table 4, most of the selected compounds except 20g
displayed good and broad-spectrum antiproliferative activity (IC50 of 1.4-8.5 µM) against
the tested cancer cell lines, which is comparable to that of compound I (Cabozantinib, IC50
of 3.2-5.8 µM) .
9
Table 4. Antiproliferative activity of selected compounds against U-87 MG, NIH-H460, HT-29 and
10
MKN-45 cell lines.
IC50 (
µM)
Compds.
U-87MG
4.1
NIH-H460
HT-29
2.9
4.6
2.1
5.5
6.5
3.9
3.4
4.8
5.9
4.2
5.3
MKN-45
1.6
19c
19d
19f
20c
20d
20e
20f
20g
20i
20j
I
2.0
3.0
1.7
3.5
4.3
3.4
3.2
4.4
4.3
3.6
3.6
5.2
3.1
2.6
1.4
4.9
4.7
5.1
5.6
8.5
3.1
4.7
2.7
16.4
7.2
5.5
5.0
4.5
2.9
5.8
3.2
11
12
13
14
15
16
17
The PK properties of potent lead compound 20j was further evaluated in rats. As
summarized in Table 5, the chemical structure of block A (quinoline or pyridine-based) had
a significant influence on the PK properties after oral administration in rats. Compound 20j
displayed favorable overall PK profiles, with maximal plasma concentration (Cmax = 1.5
µg/mL, 5-fold higher to that of IV), plasma exposure (AUC0-∞ = 10.7 µg·h/mL, 9.7-fold
higher to that of IV), half-life (T1/2 = 4.9 h, 4.9-fold longer to that of IV), total clearance CL
(0.5 L/h/kg; 10-fold lower to that of IV), and oral bioavailability (F = 32%, 2.7-fold higher
9

1
2
to that of IV) after oral dose of 5 mg/kg (10 mg/kg for IV).
Table 5. In vivo PK profiles of compound 20j in rata,b
AUC0-∞
(µg* h
/mL)
10.7
6.6
Dose
Cmax
Tmax
T1/2
CL
Vz
F
Compd. route
(mg/kg) (µg/mL)
(L/h/kg) (L/kg)
(%)
p.o.
5
1
1.5
0.5
4.0
-
4.9
4.0
1.0
0.5
0.5
0.2
5.0
0.6
3.3
0.9
32
-
20j
i.v.
p.o.
IV [20]
10
2.5
0.6
2.7
-
2.2
7.5
12
-
i.v.
16.4
4.5
10.4
a
3
4
5
Vehicle: 70% PEG400-30% water. Cmax, maximum concentration; Tmax, time of maximum concentration;
T1/2, half-lif; AUC0-∞, area under the plasma concentration time curve; CL, clearance; VZ, volume of
distribution; F, oral bioavailability. b Data reported as the average of three animals.
6
7
As a representative MET-positive tumor cell line, U-87 MG human glioblastoma
xenograft model [9] was selected to evaluated the in vivo antitumor efficacy of compound
20j (Table 6 & Figure 5). When administered orally Q.D., compound 20j induced
dose-dependent tumor growth inhibition. The minimum effective dose (MED, 50% inhibition
of tumor growth) of 20j was about 3 mg/kg. And, more importantly, 20j displayed an
excellent in vivo efficacy (TGI of 131%, 4/6 PR) superior to that of compound I
(Cabozantinib, TGI of 97%, 2/6 PR), whereas compound III and IV only showed moderate
or weak efficacy (TGI of 53% or 15%) at the same dose (12.5 mg/kg). All tested animals
displayed tumor regressions at higher dose (37.5 mg/kg) of 20j (TGI of 172%, 6/6 PR).
Table 6. In vivo tumor growth inhibition activity in U-87 MG xenograft model
8
9
10
11
12
13
14
15
Model
Compd.
Dose a (mg/kg) TGI (%)b
PRc
6/6
4/6
0/6
0/6
3/6
0/6
0/6
37.5
12.5
6
172**
131**
57
20j
U-87 MG
3
47
I (Cabozantinib)
III [19]
12.5
12.5
12.5
97**
53
IV [20]
15
16
17
18
a1Q.D.×21/70% PEG-400/H2O/p.o.; bTGI, Tumor growth inhibition value; **: P<0.01; cPR, partial
regression.
10

1
2
3
4
5
6
Figure 5. Antitumor efficacy of compound 20j in the U-87 MG xenograft model. Tumor-bearing nude
mice were randomly divided into groups when the tumor volume reached 100-200 mm3 and given
corresponding compounds p.o. at the indicated dose levels or vehicle alone over the designated treatment
schedule. Data are presented as the mean (+ SEM; n = 6 mice per group).
7
8
4. Conclusions
In the present work, we described the design, synthesis, and biological evaluation of a
9
10
11
12
13
14
15
16
17
18
series of 1,6-naphthyridinone-based class II MET kinase inhibitors bearing quinoline moiety
in block A based on the structures of Cabozantinib and our reported compound IV with
pyridine moiety in block A. Extensive SAR and DMPK studies led to the identification of 20j,
a potent and orally bioavailable MET kinase inhibitor with favorable kinase selectivity. More
importantly, 20j exhibited statistically significant tumor growth inhibition (TGI of 131%, 4/6
PR) in the U-87 MG xenograft model, which is superior to that of Cabozantinib (TGI of 97%,
2/6 PR), and significantly better than that of compound IV (TGI of 15%, 0/6 PR ) at the same
dose (12.5 mg/kg). Combined with favorable in vitro potency, kinase selectivity,
pharmacokinetic profile and in vivo efficacy, the promising antitumor drug candidate 20j has
subsequently advanced into preclinical research.
19
20
21
22
23
24
5. Experimental
5.1. General methods
Unless otherwise noted, all chemical reagents were commercially available and treated
with standard methods. Silica gel column chromatography (CC). silica gel (200-400 Mesh;
Qingdao Makall Group Co., Ltd; Qingdao; China). Solvents were dried in a routine way
and redistilled. Melting points of compounds were measured on a Melt-Temp II apparatus
11

1
1
2
and uncorrected. H NMR spectra (400 MHz ) and 13C NMR (100 MHz) spectra were
recorded on a Bruker BioSpin AG (Ultrashield Plus AV 400) spectrometer as
deuterochloroform (CDCl3) or dimethyl sulfoxide-d6 (DMSO-d6) solutions using
tetramethylsilane (TMS) as an internal standard (δ = 0) unless noted otherwise. MS spectra
were obtained on an Agilent technologies 6120 quadrupole LC/MS (ESI). High-resolution
mass spectra (HR-MS) were obtained on an Agilent 6224 TOF LC/MS (USA). All
reactions were monitored using thin-layer chromatography (TLC) on silica gel plates.
Yields were of purified compounds and were not optimized.
3
4
5
6
7
8
9
5.2. General procedures for the synthesis of intermediates
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
The intermediates 2-18 were prepared according to reported methods [21-24]
5.2.1 2-(benzyloxy)-1-methoxy-4-nitrobenzene (2)
A mixture of 2-methoxy-5-nitrophenol 1 (20 g, 118 mmol), benzyl bromide (177 mmol)
and K2CO3 (355 mmol) in DMF (200 mL) was stirred at 90°C for 5 hours. The reaction was
cooled to room temperature and poured into a mixture of ice and water (1000 mL). The solid
was collected by filtration, washed with water and dried in vacuo to give the title compound.
1
2 as a white solid (28.8 g, 94%). m.p.: 93-94 °C (91-92°C, ref 26); H NMR (400 MHz,
DMSO-d6) δ 7.91 (dd, J = 8.8, 2.6 Hz, 1H, Ar-H), 7.83 (d, J = 2.6 Hz, 1H, Ar-H), 7.45 (d, J
= 7.2 Hz, 2H, Ar-H), 7.40 (t, J = 7.2 Hz, 2H, Ar-H), 7.35 (d, J = 7.0 Hz, 1H, Ar-H), 7.18 (d, J
= 9.0 Hz, 1H, Ar-H), 5.21 (s, 2H, PhCH2-), 3.91 (s, 3H, -OCH3). MS (ESI) m/z: 260.1
[M+H]+.
5.2.2 3-(benzyloxy)-4-methoxyaniline (3)
A mixture of iron powder (755 mmol), ammonium chloride (324 mmol),
2-(benzyloxy)-1-methoxy-4-nitrobenzene 2 (28 g, 108 mmol), ethanol (150 ml) and water
(50 ml) was refluxed for 3 hours. The mixture was filtered through celite and washed with
EtOAc. The organic layer was washed with water and Sat. NaCl, dried over Na2SO4, and
concentrated to afford the title compound 3 as a pale-yellow solid (22.2 g, 90%). m.p.:
1
97-99 °C (100-101 °C, ref 26); H NMR (600 MHz, CDCl3) δ 7.42 (d, J = 6.0 Hz, 2H,
Ar-H), 7.35 (t, J = 6.9 Hz, 2H, Ar-H), 7.30 (d, J = 6.6 Hz, 1H, Ar-H), 6.73 (d, J = 7.8 Hz,
1H, Ar-H), 6.32 (s, 1H, Ar-H), 6.25 (d, J = 7.2 Hz, 1H, Ar-H), 5.10 (s, 2H, PhCH2-), 3.81 (s,
3H, -OCH3), 3.37 (s, 2H, -NH2). MS (ESI) m/z: 230.1 [M+H]+.
12

1
2
5.2.3
5-{[(3-(benzyloxy)-4-methoxyphenyl)amino]methylene}-2,2-dimethyl-1,3-dioxane-4,6-
dione (4)
3
4
To a stirred solution of 3-(benzyloxy)-4-methoxyaniline 3 (22 g, 96 mmol),
2,2-dimethyl-1,3-dioxane-4,6-dione (115.2 mmol) in absolute ethanol (55 mL) was added
drop-wise triethyl orthoformate (115.2 mmol). Upon the completion of addition, the
reaction mixture was heated at 80 °C for 1 h. The mixture was cooled and poured into
ice-water. The mixture was filtrated and washed with water, and then dried to give the title
5
6
7
8
1
9
compound 4 as a pale-green solid (33.8 g, 92%). m.p.: 84-85 °C; H NMR (600 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
CDCl3) δ 11.16 (d, J = 13.8 Hz, 1H, NH), 8.48 (d, J = 14.4 Hz, 1H, Ar-H), 7.46 (d, J = 7.2
Hz, 2H, Ar-H), 7.40 (t, J = 7.2 Hz, 2H, Ar-H), 7.34 (t, J = 6.9 Hz, 1H, Ar-H), 6.91 (d, J =
8.4 Hz, 1H, Ar-H), 6.81 (d, J = 9.0 Hz, 1H, Ar-H), 6.79 (s, 1H, -CH=C-), 5.17 (s, 2H,
PhCH2-), 3.91 (s, 3H, -OCH3), 1.75 [s, 6H, -(CH3)2]. MS (ESI) m/z: 384.1 [M+H]+.
5.2.4 7-(benzyloxy)-6-methoxyquinolin-4-ol (5)
A mixture of 5-(((3-(benzyloxy)-4-methoxyphenyl)amino)methylene)-2,2-dimethyl-
1,3-dioxane-4,6-dione 4 (33 g, 86 mmol) in 1,2-dichlorobenzene (200 mL) was stirred at
180°C for 7 hours, subsequently the mixture was cooled to room temperature and was
stirred at 0°C for 3 hours. The mixture was filtrated and washed with cooled
1,2-dichlorobenzene and diethyl ether, and then dried to give the title compound 5 as a
1
pale-yellow solid (13.1 g, 54%). m.p.: 238-239 °C; H NMR (600 MHz, DMSO-d6) δ
11.57 (s, 1H, -OH), 7.77 (s, 1H, , Ar-H), 7.54 – 7.45 (m, 3H, Ar-H), 7.45 – 7.35 (m, 3H,
Ar-H), 7.06 (s, 1H, Ar-H), 5.95 (d, J = 6.6 Hz, 1H, Ar-H), 5.19 (s, 2H, PhCH2-), 3.84 (s, 3H,
-OCH3). MS (ESI) m/z: 282.2 [M+H]+.
5.2.5 7-(benzyloxy)-4-chloro-6-methoxyquinoline (6)
A solution of 7-(benzyloxy)-6-methoxyquinolin-4-ol 5 (13 g, 46 mmol) and DMF (2d)
in POCl3 (50 mL) was heated at 100 °C for 1 hour. The mixture was evaporated under
reduced pressure and the residue was added to ice water, and then extracted with DCM.
The organic layer was separated, washed with brine, dried over anhydrous Na2SO4. The
residue was purified by chromatography (PE/EA = 30:1) to yield the title compound 6 as a
1
yellow solid (12.4 g, 90%). m.p.: 132-133 °C (135-136 °C, ref 27); H NMR (600 MHz,
13

1
2
DMSO-d6) δ 8.61 (d, J = 4.2 Hz, 1H, Ar-H), 7.57 (s, 2H, Ar-H), 7.52 (d, J = 7.2 Hz, 2H,
Ar-H), 7.43 (t, J = 7.2 Hz, 2H, Ar-H), 7.45 – 7.35 (m, 2H, Ar-H), 5.32 (s, 2H, PhCH2-),
3.98 (s, 3H, -OCH3). MS (ESI) m/z: 300.1 [M+H]+.
3
4
5.2.6 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline (7)
5
A solution of 7-(benzyloxy)-4-chloro-6-methoxyquinoline 6 (12 g, 40 mmol),
2-fluoro-4-nitrophenol (60 mmol) and DIPEA (120 mmol) in toluene (150 mL) was
refluxed for 8 hour, then cooled to room temperature. The reaction mixture was
concentrated under reduced pressure, and purified by chromatography (PE/EA = 30:1) to
yield the title compound 7 as a yellow solid (13.4 g, 80%). m.p.: 169-170 °C (170-171 °C,
ref 24); 1H NMR (600 MHz, CDCl3) δ 8.56 (d, J = 5.1 Hz, 1H, Ar-H), 8.19 (dd, J = 9.6, 2.4
Hz, 1H, Ar-H), 8.15– 8.10 (m , 1H, Ar-H), 7.52 (d, J = 7.2 Hz, 2H, Ar-H), 7.50 (s, 1H,
Ar-H), 7.46 (s, 1H, Ar-H), 7.40 (t, J = 7.5 Hz, 2H, Ar-H), 7.34 (t, J = 8.4 Hz, 2H, Ar-H),
6.54 (d, J = 5.1 Hz, 1H, Ar-H), 5.34 (s, 2H, PhCH2-), 4.04 (s, 3H, -OCH3). MS (ESI) m/z:
421.1 [M+H]+.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
5.2.7 4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-ol (8)
A solution of 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline 7 (13 g,
31 mmol) and TFA (310 mmol) in DCM (150 mL) was stirred at room temperature for 30
min. The reaction mixture was quenched with a saturated aqueous NaHCO3 solution. The
resulting suspension was filtered and the solid dried to afford the title compound 8 as a
1
yellow solid (9.2 g, 90%). m.p.: 216-217 °C (219-220 °C, ref 24); H NMR (400 MHz,
DMSO-d6) δ 11.79 (s, 1H, OH), 8.85 (d, J = 6.4 Hz, 1H, Ar-H), 8.56 (dd, J = 10.0, 2.6 Hz,
1H, Ar-H), 8.31 (dd, J = 9.6, 1.8 Hz, 1H, Ar-H), 7.89 (t, J = 8.4 Hz, 1H, Ar-H), 7.73 (s, 1H,
Ar-H), 7.53 (s, 1H, Ar-H), 7.13 (d, J = 6.6 Hz, 1H, Ar-H), 4.03 (s, 3H, -OCH3). MS (ESI)
m/z: 331.1 [M+H]+.
5.2.8 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-(substituted alkoxy)quinoline (9)
A solution of 4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-ol 8 (500 mg, 1.5
mmol) and K2CO3 (4.5 mmol) in CH3CN (25 mL) was stirred at room temperature for 30
min. various alkyl halides (2.3 mmol) was added to the reaction mixture and subsequently
refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, and
purified by chromatography (PE/EA = 10:1) to yield the title compound 9.
14

1
2
4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (9a): yield: 80%; m.p.:
1
152-153 °C (150-151 °C, ref 24); H NMR (600 MHz, DMSO-d6) δ 8.58 (d, J = 5.2 Hz,
3
1H, Ar-H), 8.47 (dd, J = 10.3, 1.9 Hz, 1H, Ar-H), 8.21 (d, J = 8.9 Hz, 1H, Ar-H), 7.63 (t, J
= 8.5 Hz, 1H, Ar-H), 7.46 (s, 2H, Ar-H), 6.79 (d, J = 5.1 Hz, 1H, Ar-H), 3.97 (s, 3H,
-OCH3), 3.93 (s, 3H, -OCH3).
4
5
6
4-(2-fluoro-4-nitrophenoxy)-7-isobutoxy-6-methoxyquinoline (9b): yield: 83%; m.p.:
145-146 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 5.2 Hz, 1H, Ar-H), 8.42 (dd, J
= 10.4, 2.4 Hz, 1H, Ar-H), 8.16 (d, J = 7.6 Hz, 1H, Ar-H), 7.58 (t, J = 8.4 Hz, 1H, Ar-H),
7.42 (s, 1H, Ar-H), 7.40 (s, 1H, Ar-H), 6.75 (d, J = 5.2 Hz, 1H, Ar-H), 3.94 (d, J = 6.8 Hz,
2H, -CH2-), 3.92 (s, 3H, -OCH3), 2.18 – 2.07 (m, 1H, -CH-), 1.04 [d, J = 6.8 Hz, 6H,
-(CH3)2].
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)ethan-1-ol (9c): yield:
75%; m.p.: 144-145 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 5.2 Hz, 1H, Ar-H),
8.43 (dd, J = 10.4, 2.6 Hz, 1H, Ar-H), 8.17 (d, J = 8.8 Hz, 1H, Ar-H), 7.59 (t, J = 8.4 Hz,
1H, Ar-H), 7.43 (s, 2H, Ar-H), 6.75 (d, J = 5.2 Hz, 1H, Ar-H), 4.94 (t, J = 5.2 Hz, 1H, OH),
4.20 – 4.15 (m, 2H, -CH2-),3.92 (s, 3H, -OCH3), 3.84 – 3.80 (m, 2H, -CH2-).
4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-(2-methoxyethoxy)quinoline (9d): yield:
86%; m.p.: 154-155 °C; 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 5.2 Hz, 1H, Ar-H), 8.16
(dd, J = 9.6, 2.6 Hz, 1H, Ar-H), 8.11 (dd, J = 8.8, 1.2 Hz, 1H, Ar-H), 7.44 (s, 1H, Ar-H),
7.41 (s, 1H, Ar-H), 7.3 (t, J = 8.8 Hz, 1H, Ar-H), 6.53 (d, J = 4.8 Hz, 1H, Ar-H), 4.43 (t, J =
4.8 Hz, 2H, -CH2-), 4.00 (s, 3H, -OCH3), 3.90 (t, J = 4.8 Hz, 2H, -CH2-), 3.48 (s, 3H,
-OCH3).
1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)propan-2-ol (9e): yield:
85%; m.p.: 158-159 °C; 1H NMR (600 MHz, CDCl3) δ 8.58 (d, J = 4.9 Hz, 1H, Ar-H), 8.20
(d, J = 9.5 Hz, 1H, Ar-H), 8.15 (d, J = 8.7 Hz, 1H, Ar-H), 7.48 (s, 1H, Ar-H), 7.46 (s, 1H,
Ar-H), 7.36 (t, J = 8.2 Hz, 1H, Ar-H), 7.27 (s, 1H, Ar-H), 6.56 (d, J = 4.9 Hz, 1H, Ar-H),
4.93 (s, 1H, -OH), 4.10 – 3.98 (m, 3H), 3.94 (s, 3H, -OCH3), 1.21 (d, J = 6.0 Hz, 3H,
-CH3).
1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)-2-methylpropan-2-ol
(9f): yield: 88%; m.p.: 154-155 °C; 1H NMR (600 MHz, DMSO-d6) δ 8.57 (d, J = 5.2 Hz,
15

1
2
1H, Ar-H), 8.46 (dd, J = 10.4, 2.7 Hz, 1H, Ar-H), 8.20 (dd, J = 8.5, 2.3 Hz, 1H, Ar-H), 7.62
(t, J = 8.5 Hz, 1H, Ar-H), 7.46 (s, 1H, Ar-H), 7.44 (s, 1H, Ar-H), 6.78 (d, J = 5.1 Hz, 1H,
Ar-H), 4.71 (s, 1H, -OH), 3.94 (s, 3H, -OCH3), 3.92 (s, 2H, -CH2-), 1.27 [s, 6H, -(CH3)2].
4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-(2-methoxy-2-methylpropoxy)quinoline (9g):
yield: 83%; m.p.: 141-142 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 5.1 Hz, 1H,
Ar-H), 8.42 (dd, J = 10.4, 2.7 Hz, 1H, Ar-H), 8.17 (d, J = 8.9 Hz, 1H, Ar-H), 7.58 (t, J = 8.5
Hz, 1H, Ar-H), 7.45 (s, 1H, Ar-H), 7.43 (s, 1H, Ar-H), 6.75 (d, J = 5.1 Hz, 1H, Ar-H), 4.03
(s, 2H, -CH2-), 3.92 (s, 3H, -OCH3), 3.19 (s, 3H, -OCH3), 1.27 [s, 6H, -(CH3)2].
4-(2-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)ethyl)morpholine (9h)
[24]: yield: 81%; m.p.: 153-154 °C; 1H NMR (600 MHz, DMSO-d6) δ 8.57 (d, J = 5.1 Hz,
1H, Ar-H), 8.47 (dd, J = 10.2, 2.1 Hz, 1H, Ar-H), 8.21 (d, J = 8.7 Hz, 1H, Ar-H), 7.62 (t, J
= 8.4 Hz, 1H, Ar-H), 7.49 (s, 1H, Ar-H), 7.46 (s, 1H, Ar-H), 6.78 (d, J = 5.1 Hz, 1H, Ar-H),
4.29 (t, J = 5.4 Hz, 2H, -CH2-), 3.93 (s, 3H, -OCH3), 3.64 – 3.56 (m, 4H, -CH2-), 2.80 (t, J
= 5.4 Hz, 2H, -CH2-), 2.56 – 2.52 (m, 4H, -CH2-).
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
4-(3-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)propyl)morpholine (9i)
[24]: yield: 77%; m.p.: 135-136°C (137-139 °C, ref 24); 1H NMR (600 MHz, DMSO-d6) δ
8.57 (d, J = 5.1 Hz, 1H, Ar-H), 8.47 (dd, J = 10.2, 2.4 Hz, 1H, Ar-H), 8.20 (d, J = 9.0 Hz,
1H, Ar-H), 7.62 (t, J = 8.4 Hz, 1H, Ar-H), 7.45 (d, J = 3.0 Hz, 2H, Ar-H), 6.78 (d, J = 5.1
Hz, 1H, Ar-H), 4.21 (t, J = 6.6 Hz, 2H, -CH2-), 3.93 (s, 3H, -OCH3), 3.59 (t, J = 3.9 Hz, 4H,
-CH2-), 2.47 (t, J = 6.9 Hz, 2H, -CH2-), 2.43 – 2.36 (m, 4H, -CH2-), 2.01 – 1.96 (m, 2H,
-CH2-).
4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (9j)
[28]: yield: 82%; m.p.: 142-143 °C (140-141 °C, ref 29); 1H NMR (600 MHz, DMSO-d6
)
δ 8.57 (d, J = 4.8 Hz, 1H, Ar-H), 8.46 (dd, J = 10.2, 1.8 Hz, 1H, Ar-H), 8.20 (d, J = 9.0 Hz,
1H, Ar-H), 7.62 (t, J = 8.7 Hz, 1H, Ar-H), 7.46 (s, 1H, Ar-H), 7.44 (s, 1H, Ar-H), 6.78 (d, J
= 4.8 Hz, 1H, Ar-H), 4.22 (t, J = 6.0 Hz, 2H, -CH2-), 3.93 (s, 3H, -OCH3), 2.62 (t, J = 6.0
Hz, 2H, -CH2-), 2.54 – 2.47 (m, 4H, -CH2-), 2.03 – 1.98 (m, 2H, -CH2-), 1.74 – 1.68 (m,
4H, -CH2-).
4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinolin
e (9k) [30]: yield: 88%; m.p.: 156-157 °C; 1H NMR (600 MHz, CDCl3) δ 8.57 (d, J = 3.9
16

1
2
Hz, 1H, Ar-H), 8.19 (d, J = 9.0 Hz, 1H, Ar-H), 8.14 (d, J = 8.4 Hz, 1H, Ar-H), 7.44 (s, 1H,
Ar-H), 7.42 (s, 1H, Ar-H), 7.35 (t, J = 7.8 Hz, 1H, Ar-H), 6.56 (d, J = 3.6 Hz, 1H, Ar-H),
4.09 (d, J = 5.4 Hz, 2H, -CH2-), 4.01 (s, 3H, -OCH3), 3.22 (d, J = 9.6 Hz, 2H, -CH2-), 2.53
(s, 3H, -NCH3), 2.44 – 2.32 (m, 2H, -CH2-), 2.20 – 2.10 (m, 1H, -CH-), 2.06 (d, J = 12.3
Hz, 2H, -CH2-), 1.81 – 1.69 (m, 2H, -CH2-).
3
4
5
6
5.2.9 3-fluoro-4-{[6-methoxy-7-(substituted alkoxy)quinolin-4-yl]oxy}aniline (10)
Prepared according to the procedure for the preparation of 3, from 9, to yield the title
compound 10.
7
8
9
4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (10a): yield: 88%; m.p.:
191-192 °C (191-193 °C, ref 24); 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 4.4 Hz, 1H,
Ar-H), 7.53 (s, 1H, Ar-H), 7.41 (s, 1H, Ar-H), 7.11 (t, J = 9.0 Hz, 1H, Ar-H), 6.58 (dd, J =
13.2, 2.6 Hz, 1H, Ar-H), 6.50 (d, J = 8.5 Hz, 1H, Ar-H), 6.42 (d, J = 5.2 Hz, 1H, Ar-H),
5.55 (s, 2H, -NH2), 3.97 (ovl, s, 6H, -OCH3).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
3-fluoro-4-((7-isobutoxy-6-methoxyquinolin-4-yl)oxy)aniline (10b): yield: 87%; m.p.:
182-183 °C 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 5.2 Hz, 1H, Ar-H), 7.48 (s, 1H,
Ar-H), 7.33 (s, 1H, Ar-H), 7.04 (t, J = 9.0 Hz, 1H, Ar-H), 6.53 (dd, J = 13.2, 2.4 Hz, 1H,
Ar-H), 6.44 (dd, J = 8.6, 2.4 Hz, 1H, Ar-H), 6.36 (d, J = 5.2 Hz, 1H, Ar-H), 5.46 (s, 2H,
-NH2), 3.94 (s, 3H, -OCH3), 3.91 (d, J = 6.6 Hz, 2H, -CH2-), 2.18 – 2.06 (m, 1H, -CH-),
1.03 [d, J = 6.6 Hz, 6H, -(CH3)2].
2-((4-(4-amino-2-fluorophenoxy)-6-methoxyquinolin-7-yl)oxy)ethan-1-ol (10c): yield:
90%; m.p.: 197-198 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 5.2 Hz, 1H, Ar-H),
7.49 (s, 1H, Ar-H), 7.36 (s, 1H, Ar-H), 7.05 (t, J = 9.0 Hz, 1H, Ar-H), 6.53 (dd, J = 13.2,
2.4 Hz, 1H, Ar-H), 6.45 (dd, J = 8.6, 2.4 Hz, 1H, Ar-H), 6.37 (d, J = 5.2 Hz, 1H, Ar-H),
5.46 (s, 2H, -NH2), 4.93 (t, J = 5.2 Hz, 1H, OH), 4.15 (t, J =5.0 Hz, 2H, -CH2-), 3.94 (s, 3H,
-OCH3), 2.84 – 3.77 (m, 2H, -CH2-).
3-fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl)oxy)aniline (10d): yield:
89%; m.p.: 185-186 °C; 1H NMR (600 MHz, CDCl3) δ 8.47 (d, J = 4.5 Hz, 1H, Ar-H), 7.58
(s, 1H, Ar-H), 7.43 (s, 1H, Ar-H), 7.03 (t, J = 8.4 Hz, 1H, Ar-H), 6.56 (d, J = 12.0 Hz, 1H,
Ar-H), 6.50 (d, J = 7.8 Hz, 1H, Ar-H), 6.41 (d, J = 4.2 Hz, 1H, Ar-H), 4.36 – 4.32 (m, 2H,
-CH2-), 4.03 (s, 3H, -OCH3), 3.93 – 3.88 (m, 2H, -CH2-), 3.84 (s, 2H, -NH2), 3.49 (s, 3H,
17

1
2
-OCH3).
1-((4-(4-amino-2-fluorophenoxy)-6-methoxyquinolin-7-yl)oxy)propan-2-ol (10e): yield:
3
94%; m.p.: 192-193 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 5.2 Hz, 1H, Ar-H),
7.49 (s, 1H, Ar-H), 7.34 (s, 1H, Ar-H), 7.05 (t, J = 8.9 Hz, 1H, Ar-H), 6.53 (d, J = 13.2 Hz,
1H, Ar-H), 6.45 (d, J = 8.6 Hz, 1H, Ar-H), 6.37 (d, J = 4.8 Hz, 1H, Ar-H), 5.47 (s, 2H,
-NH2), 4.93 (s, 1H, -OH), 4.10 – 3.98 (m, 3H), 3.94 (s, 3H, -OCH3), 1.21 (d, J = 5.9 Hz, 3H,
-CH3).
4
5
6
7
8
1-((4-(4-amino-2-fluorophenoxy)-6-methoxyquinolin-7-yl)oxy)-2-methylpropan-2-ol
(10f): yield: 89%; m.p.: 188-189 °C; 1H NMR (600 MHz, DMSO-d6) δ 8.45 (d, J = 5.0 Hz,
1H, Ar-H), 7.52 (s, 1H, Ar-H), 7.36 (s, 1H, Ar-H), 7.09 (d, J = 8.9 Hz, 1H, Ar-H), 6.56 (d, J
= 13.1 Hz, 1H, Ar-H), 6.47 (d, J = 8.3 Hz, 1H, Ar-H), 6.39 (d, J = 4.9 Hz, 1H, Ar-H), 5.51
(s, 2H, -NH2), 4.71 (s, 1H, -OH), 3.96 (s, 3H, -OCH3), 3.89 (s, 2H, -CH2-), 1.27 [s, 6H,
-(CH3)2].
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
3-fluoro-4-((6-methoxy-7-(2-methoxy-2-methylpropoxy)quinolin-4-yl)oxy)aniline
(10g): yield: 90%; m.p.: 184-185 °C 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 5.1 Hz, 1H,
Ar-H), 7.49 (s, 1H, Ar-H), 7.38 (s, 1H, Ar-H), 7.05 (t, J = 8.9 Hz, 1H, Ar-H), 6.53 (dd, J =
13.2, 2.3 Hz, 1H, Ar-H), 6.45 (dd, J = 8.3, 1.6 Hz, 1H, Ar-H), 6.37 (d, J = 5.2 Hz, 1H,
Ar-H), 5.46 (s, 2H, -NH2), 4.01 (s, 2H, -CH2-), 3.94 (s, 3H, -OCH3), 3.20 (s, 3H, -OCH3),
1.27 [s, 6H, -(CH3)2].
3-fluoro-4-((6-methoxy-7-(2-morpholinoethoxy)quinolin-4-yl)oxy)aniline (10h) [24]:
yield: 91%; m.p.: 179-180 °C (180-181 °C, ref 24); 1H NMR (400 MHz, DMSO-d6) δ 8.42
(d, J = 5.2 Hz, 1H, Ar-H), 7.48 (s, 1H, Ar-H), 7.39 (s, 1H, Ar-H), 7.05 (t, J = 9.0 Hz, 1H,
Ar-H), 6.53 (dd, J = 13.2, 2.4 Hz, 1H, Ar-H), 6.44 (dd, J = 8.6, 2.4 Hz, 1H, Ar-H), 6.37 (d,
J = 5.2 Hz, 1H, Ar-H), 5.48 (s, 2H, -NH2), 4.25 (t, J = 5.6 Hz, 2H, -CH2-), 3.93 (s, 3H,
-OCH3), 3.64 – 3.52 (m, 4H, -CH2-), 2.78 (t, J = 5.6 Hz, 2H, -CH2-), 2.55 – 2.51 (m, 4H,
-CH2-).
3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)aniline (10i) [24]:
yield: 91%; m.p.: 120-121 °C (119-121 °C, ref 24); 1H NMR (400 MHz, DMSO-d6) δ 8.41
(d, J = 5.2 Hz, 1H, Ar-H), 7.48 (s, 1H, Ar-H), 7.35 (s, 1H, Ar-H), 7.03 (d, J = 8.8 Hz, 1H,
Ar-H), 6.53 (dd, J = 13.2, 2.4 Hz, 1H, Ar-H), 6.44 (dd, J = 8.4, 1.6 Hz, 1H, Ar-H), 6.36 (d,
18

1
2
J = 4.8 Hz, 1H, Ar-H), 5.48 (s, 2H, -NH2), 4.17 (t, J = 6.2 Hz, 2H, -CH2-), 3.93 (s, 3H,
-OCH3), 3.62 – 3.51 (m, 2H, -CH2-), 2.48 – 2.43 (m, 2H, -CH2-), 2.41 – 2.35 (m, 4H,
-CH2-), 2.02 – 1.92 (m, 2H, -CH2-).
3
4
3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)aniline (10j)
[28]: yield: 89%; m.p.: 165-166 °C; 1H NMR (600 MHz, DMSO-d6) δ 8.45 (d, J = 4.5 Hz,
1H, Ar-H), 7.52 (s, 1H, Ar-H), 7.39 (s, 1H, Ar-H), 7.07 (t, J = 9.0 Hz, 1H, Ar-H), 6.55 (d, J
= 12.9 Hz, 1H, Ar-H), 6.47 (d, J = 8.4 Hz, 1H, Ar-H), 6.39 (d, J = 4.5 Hz, 1H, Ar-H), 5.52
(s, 2H, -NH2), 4.29-4.16 (m, 2H, -CH2-), 3.95 (s, 3H, -OCH3), 3.00 – 2.80 (m, 6H, -CH2-),
2.15 – 2.07 (m, 2H, -CH2-), 1.82 (s, 4H, -CH2-).
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
3-fluoro-4-((6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinolin-4-yl)oxy)aniline
1
(10k) [30]: yield: 93%; m.p.: 178-179 °C; H NMR (600 MHz, CD3OD) δ 8.48 (s, 1H,
Ar-H), 7.68 (s, 1H, Ar-H), 7.39 (s, 1H, Ar-H), 7.07 (t, J = 9.0 Hz, 1H, Ar-H), 6.67 – 6.54
(m, 3H, Ar-H), 4.14 (s, 2H, -NH2), 4.02 (s, 3H, -OCH3), 3.66 – 3.54 (m, 2H, -CH2-), 3.20 –
3.08 (m, 2H, -CH2-), 2.91 (s, 3H, -NCH3), 2.35 – 2.25 (m, 1H, -CH-), 2.21 (d, J = 13.8 Hz,
2H, -CH2-), 1.90 – 1.76 (m, 2H, -CH2-).
5.2.10 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline (12)[9]
Prepared according to the procedure for the preparation of 7, from
4-chloro-7-methoxyquinoline 11 (10 g, 52 mmol), to yield the title compound 12 as a
yellow solid (13.5 g, 83%). m.p.: 142-143 °C; 1H NMR (600 MHz, DMSO-d6) δ 8.70 (d, J
= 5.1 Hz, 1H, Ar-H), 8.46 (dd, J = 10.2, 2.4 Hz, 1H, Ar-H), 8.19 (dd, J = 9.0, 2.1 Hz, 1H,
Ar-H), 8.14 (d, J = 9.0 Hz, 1H, Ar-H), 7.63 (t, J = 8.4 Hz, 1H, Ar-H), 7.46 (d, J = 2.4 Hz,
1H, Ar-H), 7.32 (dd, J = 9.0, 2.4 Hz, 1H, Ar-H), 6.77 (d, J = 5.1 Hz, 1H, Ar-H), 3.93 (s, 3H,
-OCH3); MS (ESI) m/z: 315.1 [M+H]+.
5.2.11 4-(2-fluoro-4-nitrophenoxy)quinolin-7-ol (13) [24]
To a solution of 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline 12 (8 g, 25.4 mmol)
in DCM (80 mL) was added drop-wise a solution of boron tribromide (76.4 mmol) in DCM
(30 mL) at -50°C and subsequently stirred for 1 hour. And then the mixture was warmed to
room temperature and stirred overnight. The reaction mixture was poured into ice-water
slowly and alkalized to pH 12 with saturated sodium hydroxide solution cautiously. After
the organic layer was separated, the aqueous phase was acidated to pH 6 with 1N HCl with
19

1
2
solid precipitated. The resulting suspension was filtered the solid dried to afford the title
1
compound 13 as a yellow solid (4.6 g, 60%); m.p.: 248-250 °C (250-252 °C, ref 24); H
3
NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H, -OH), 9.00 (d, J = 6.4 Hz, 1H, Ar-H), 8.56
(dd, J = 10.0, 1.6 Hz, 1H, Ar-H), 8.43 (d, J = 9.6 Hz, 1H, Ar-H), 8.31 (d, J = 8.8 Hz, 1H,
Ar-H), 7.91 (t, J = 8.4 Hz, 1H, Ar-H), 7.61 – 7.38 (m, 2H, Ar-H), 7.10 (d, J = 6.4 Hz, 1H,
Ar-H); MS (ESI) m/z: 301.3 [M+H]+.
4
5
6
7
5.2.12 4-(2-fluoro-4-nitrophenoxy)-7-(substituted alkoxy)quinoline (14)
8
Prepared according to the procedure for the preparation of 9, from
4-(2-fluoro-4-nitrophenoxy)quinolin-7-ol 13, to yield the title compound 14.
4-(2-fluoro-4-nitrophenoxy)-7-isobutoxyquinoline (14a): yield 84%; m.p.: 133-134 °C;
1H NMR (600 MHz, DMSO-d6) δ 8.71 (d, J = 5.1 Hz, 1H, Ar-H), 8.47 (d, J = 10.3 Hz, 1H,
Ar-H), 8.20 (d, J = 9.0 Hz, 1H, Ar-H), 8.15 (d, J = 9.0 Hz, 1H, Ar-H), 7.64 (t, J = 8.4 Hz,
1H, Ar-H), 7.45 (s, 1H, Ar-H), 7.34 (d, J = 9.0 Hz, 1H, Ar-H), 6.79 (d, J = 5.1 Hz, 1H,
Ar-H), 3.96 (d, J = 6.3 Hz, 2H, -CH2-), 2.15 – 2.07 (m, 1H, -CH-), 1.04 [d, J = 6.6 Hz, 6H,
-(CH3)2].
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2-((4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl)oxy)ethan-1-ol (14b): yield 83%; m.p.:
143-144 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 4.8 Hz, 1H, Ar-H), 8.43 (dd, J
= 10.4, 2.6 Hz, 1H, Ar-H), 8.17 (d, J = 9.0 Hz, 1H, Ar-H), 8.13 (d, J = 9.0 Hz, 1H, Ar-H),
7.61 (t, J = 8.4 Hz, 1H, Ar-H), 7.44 (s, 1H, Ar-H), 7.32 (dd, J = 9.0, 2.2 Hz, 1H, Ar-H),
6.76 (d, J = 5.2 Hz, 1H, Ar-H), 4.94 (t, J = 5.4 Hz, 1H, -OH), 4.18 (t, J = 4.8 Hz, 2H,
-CH2-), 3.80 (q, J = 4.8 Hz, 2H, -CH2-).
4-(2-fluoro-4-nitrophenoxy)-7-(2-methoxyethoxy)quinoline (14c): yield 79%; m.p.:
132-133 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 5.0 Hz, 1H, Ar-H), 8.47 – 8.38
(m, 1H, Ar-H), 8.17 (d, J = 9.0 Hz, 1H, Ar-H), 8.13 (d, J = 9.2 Hz, 1H, Ar-H), 7.62 (t, J =
8.4 Hz, 1H, Ar-H), 7.46 (s, 1H, Ar-H), 7.33 (d, J = 9.0 Hz, 1H, Ar-H), 6.77 (d, J = 4.8 Hz,
1H, Ar-H), 4.37 – 4.20 (m, 2H, -CH2-), 3.82 – 3.68 (m, 2H, -CH2-), 3.35 (s, 3H, -OCH3).
1-((4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl)oxy)propan-2-ol (14d): yield 77%; m.p.:
140-141 °C; 1H NMR (600 MHz, CDCl3) δ 8.58 (d, J = 4.9 Hz, 1H, Ar-H), 8.20 (d, J = 9.5
Hz, 1H, Ar-H), 8.15 (d, J = 8.7 Hz, 1H, Ar-H), 7.48 (s, 1H, Ar-H), 7.46 (s, 1H, Ar-H), 7.36
(t, J = 8.2 Hz, 1H, Ar-H), 7.27 (s, 1H, Ar-H), 6.56 (d, J = 4.9 Hz, 1H, Ar-H), 4.93 (s, 1H,
20

1
2
-OH), 4.10 – 3.98 (m, 3H), 1.21 (d, J = 6.0 Hz, 3H, -CH3)
1-((4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl)oxy)-2-methylpropan-2-ol (14e) [22]:
1
3
yield 84%; m.p.: 135-136 °C; H NMR (600 MHz, DMSO-d6) δ 8.72 (d, J = 5.0 Hz, 1H,
4
Ar-H), 8.48 (d, J = 10.1 Hz, 1H, Ar-H), 8.20 (d, J = 9.1 Hz, 1H, Ar-H), 8.16 (d, J = 9.1 Hz,
1H, Ar-H), 7.64 (t, J = 8.6 Hz, 1H, Ar-H), 7.44 (s, 1H, Ar-H), 7.36 (d, J = 9.1 Hz, 1H,
Ar-H), 6.80 (d, J = 4.9 Hz, 1H, Ar-H), 4.76 (s, 1H, -OH), 3.93 (s, 2H, -CH2-), 1.27 [s, 6H,
-(CH3)2].
5
6
7
8
4-(2-fluoro-4-nitrophenoxy)-7-(2-methoxy-2-methylpropoxy)quinoline (14f): yield
1
9
88%; m.p.: 116-117 °C; H NMR (600 MHz, DMSO-d6) δ 8.72 (d, J = 5.2 Hz, 1H, Ar-H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
8.47 (d, J = 10.5 Hz, 1H, Ar-H), 8.20 (d, J = 9.4 Hz, 1H, Ar-H), 8.15 (dd, J = 8.9, 0.5 Hz,
1H, Ar-H), 7.64 (t, J = 8.4 Hz, 1H, Ar-H), 7.49 (s, 1H, Ar-H), 7.37 (d, J = 9.1 Hz, 1H,
Ar-H), 6.80 (d, J = 5.2 Hz, 1H, Ar-H), 4.06 (s, 2H, -CH2-), 3.20 (s, 3H, -OCH3), 1.27 [s, 6H,
-(CH3)2].
4-(2-((4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl)oxy)ethyl)morpholine (14g): yield
90%; m.p.: 138-139 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 5.2 Hz, 1H, Ar-H),
8.43 (dd, J = 10.4, 2.8 Hz, 1H, Ar-H), 8.17 (d, J = 9.0 Hz, 1H, Ar-H), 8.11 (d, J = 9.0 Hz,
1H, Ar-H), 7.60 (t, J = 8.4 Hz, 1H, Ar-H), 7.47 (d, J = 2.4 Hz, 1H, Ar-H), 7.31 (dd, J = 9.0,
2.4 Hz, 1H, Ar-H), 6.77 (d, J = 5.2 Hz, 1H, Ar-H), 4.28 (t, J = 5.6 Hz, 2H, -CH2-), 3.64 –
3.52 (m, 4H, -CH2-), 2.78 (t, J = 5.6 Hz, 2H, -CH2-), 2.57 – 2..44 (m, 4H, -CH2-).
4-(3-((4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl)oxy)propyl)morpholine (14h): yield
84%; m.p.: 111-112 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 4.8 Hz, 1H, Ar-H),
8.20 – 8.02 (m, 3H, Ar-H), 7.43 (s, 1H, Ar-H), 7.31 (t, J = 8.2 Hz, 1H, Ar-H), 7.28 – 7.21
(m, 1H, Ar-H), 6.51 (d, J = 4.8 Hz, 1H, Ar-H), 4.20 (t, J = 6.0 Hz, 2H, -CH2-), 3.83 – 3.64
(m, 4H, -CH2-), 2.64 – 2.55 (m, 2H, -CH2-), 2.49 – 2.35 (m, 4H, -CH2-), 2.13 – 2.01 (m, 2H,
-CH2-).
5.2.13 3-fluoro-4-[(7-methoxyquinolin-4-yl)oxy]aniline (15) [9]
Prepared according to the procedure for the preparation of 3, from
4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline 12 (300 mg, 0.95 mmol), to yield the title
1
compound 15 as s yellow solid (234 mg, 86%); m.p.: 188-189 °C; H NMR (600 MHz,
DMSO-d6) δ 8.60 (d, J = 5.1 Hz, 1H, Ar-H), 8.21 (d, J = 9.0 Hz, 1H, Ar-H), 7.40 (d, J =
21

1
2
1.8 Hz, 1H, Ar-H), 7.28 (dd, J = 9.0, 1.8 Hz, 1H, Ar-H), 7.09 (t, J = 9.0 Hz, 1H, Ar-H), 6.56
(dd, J = 13.2, 1.8 Hz, 1H, Ar-H), 6.48 (d, J = 8.4 Hz, 1H, Ar-H), 6.41 (d, J = 5.1 Hz, 1H,
Ar-H), 5.52 (s, 2H, -NH2), 3.94 (s, 3H, -OCH3); MS (ESI) m/z: 285.1 [M+H]+.
5.2.14 4-(4-amino-2-fluorophenoxy)quinolin-7-ol (16) [24]
3
4
5
Prepared according to the procedure for the preparation of 3, from
4-(2-fluoro-4-nitrophenoxy)quinolin-7-ol 13 (300 mg, 1 mmol), to yield the title compound
16 as s yellow solid (237 mg, 88%); m.p.: 267-268 °C; 1H NMR (600 MHz, DMSO-d6) δ
10.25 (s, 1H, -OH), 8.49 (d, J = 5.1 Hz, 1H, Ar-H), 8.14 (d, J = 9.0 Hz, 1H, Ar-H), 7.22 (s,
1H, Ar-H), 7.16 (dd, J = 9.0, 1.8 Hz, 1H, Ar-H), 7.05 (t, J = 9.0 Hz, 1H, Ar-H), 6.53 (d, J =
13.2 Hz, 1H, Ar-H), 6.44 (d, J = 7.2 Hz, 1H, Ar-H), 6.29 (d, J = 5.1 Hz, 1H, Ar-H), 5.50 (s,
2H, -NH2); MS (ESI) m/z: 271.1 [M+H]+.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
5.2.15 3-fluoro-4-((7-(substituted alkoxy)quinolin-4-yl)oxy)aniline (17)
Prepared according to the procedure for the preparation of 3, from 14, to yield the title
compound 17.
3-fluoro-4-((7-isobutoxyquinolin-4-yl)oxy)aniline (17a): yield 88%; m.p.: 168-169 °C;
1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 5.2 Hz, 1H, Ar-H), 8.17 (d, J = 9.2 Hz, 1H,
Ar-H), 7.34 (s, 1H, Ar-H), 7.25 (dd, J = 9.2, 2.4 Hz, 1H, Ar-H), 7.05 (t, J = 9.0 Hz, 1H,
Ar-H), 6.53 (dd, J = 13.2, 2.4 Hz, 1H, Ar-H), 6.44 (dd, J = 8.8, 2.0 Hz, 1H, Ar-H), 6.37 (d,
J = 5.2 Hz, 1H, Ar-H), 5.50 (s, 2H, -NH2), 3.92 (d, J = 6.4 Hz, 2H, -CH2-), 2.18 – 2.04 (m,
1H, -CH-), 1.03 [d, J = 6.6 Hz, 6H, -(CH3)2].
2-((4-(4-amino-2-fluorophenoxy)quinolin-7-yl)oxy)ethan-1-ol (17b) [22]: yield 89%;
m.p.: 175-176 °C;1H NMR (600 MHz, DMSO-d6) δ 8.60 (d, J = 4.8 Hz, 1H, Ar-H), 8.22
(d, J = 9.0 Hz, 1H, Ar-H), 7.40 (s, 1H, Ar-H), 7.30 (d, J = 8.4 Hz, 1H, Ar-H), 7.09 (t, J =
9.0 Hz, 1H, Ar-H), 6.57 (d, J = 13.2 Hz, 1H, Ar-H), 6.48 (d, J = 8.4 Hz, 1H, Ar-H), 6.42 (d,
J = 4.8 Hz, 1H, Ar-H), 5.63 (s, 2H, -NH2), 4.99 (s, 1H, -OH), 4.18 (s, 2H, -CH2-), 3.81 (s,
2H, -CH2-).
3-fluoro-4-((7-(2-methoxyethoxy)quinolin-4-yl)oxy)aniline (17c): yield 84%; m.p.:
159-160 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 5.0 Hz, 1H, Ar-H), 8.18 (d, J =
9.2 Hz, 1H, Ar-H), 7.38 (s, 1H, Ar-H), 7.26 (dd, J = 9.0, 2.0 Hz, 1H, Ar-H), 7.05 (t, J = 9.0
Hz, 1H, Ar-H), 6.54 (dd, J = 13.2, 1.6 Hz, 1H, Ar-H), 6.45 (d, J = 8.4 Hz, 1H, Ar-H), 6.38
22

1
2
(d, J = 5.0 Hz, 1H, Ar-H), 5.48 (s, 2H, -NH2), 4.30 – 4.21 (m, 2H, -CH2-), 3.77 – 3.69 (m,
2H, -CH2-), 3.34 (s, 3H, -OCH3).
3
1-((4-(4-amino-2-fluorophenoxy)quinolin-7-yl)oxy)propan-2-ol (17d): yield 83%; m.p.:
168-169 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 5.2 Hz, 1H, Ar-H), 7.49 (s, 1H,
Ar-H), 7.34 (s, 1H, Ar-H), 7.05 (t, J = 8.9 Hz, 1H, Ar-H), 6.53 (d, J = 13.2 Hz, 1H, Ar-H),
6.45 (d, J = 8.6 Hz, 1H, Ar-H), 6.37 (d, J = 4.8 Hz, 1H, Ar-H), 5.47 (s, 2H, -NH2), 4.93 (s,
1H, -OH), 4.10 – 3.98 (m, 3H), 1.21 (d, J = 6.0 Hz, 3H, -CH3).
4
5
6
7
8
1-((4-(4-amino-2-fluorophenoxy)quinolin-7-yl)oxy)-2-methylpropan-2-ol (17e) [22]:
1
9
yield 87%; m.p.: 171-172 °C; H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.0 Hz, 1H,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Ar-H), 8.18 (d, J = 8.8 Hz, 1H, Ar-H), 7.34 (s, 1H, Ar-H), 7.28 (d, J = 9.0 Hz, 1H, Ar-H),
7.06 (t, J = 8.8 Hz, 1H, Ar-H), 6.53 (d, J = 12.9 Hz, 1H, Ar-H), 6.45 (d, J = 8.6 Hz, 1H,
Ar-H), 6.38 (d, J = 4.7 Hz, 1H, Ar-H), 5.51 (br, s, 2H, -NH2), 4.72 (s, 1H, -OH), 3.89 (s, 2H,
-CH2-), 1.26 [s, 6H, -(CH3)2].
3-fluoro-4-((7-(2-methoxy-2-methylpropoxy)quinolin-4-yl)oxy)aniline (17f): yield 83%;
m.p.: 167-168 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 5.2 Hz, 1H, Ar-H), 8.18 (d,
J = 9.1 Hz, 1H, Ar-H), 7.39 (s, 1H, Ar-H), 7.28 (d, J = 9.1 Hz, 1H, Ar-H), 7.06 (t, J = 9.0
Hz, 1H, Ar-H), 6.54 (d, J = 13.1 Hz, 1H, Ar-H), 6.45 (d, J = 8.4 Hz, 1H, Ar-H), 6.38 (d, J =
5.1 Hz, 1H, Ar-H), 5.49 (br, s, 2H, -NH2), 4.02 (s, 2H, -CH2-), 3.19 (s, 3H, -OCH3), 1.27 [s,
6H, -(CH3)2].
3-fluoro-4-((7-(2-morpholinoethoxy)quinolin-4-yl)oxy)aniline (17g): yield 89%; m.p.:
164-165 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 5.2 Hz, 1H, Ar-H), 8.17 (d, J =
9.0 Hz, 1H, Ar-H), 7.38 (s, 1H, Ar-H), 7.25 (dd, J = 9.0, 2.2 Hz, 1H, Ar-H), 7.05 (t, J = 9.0
Hz, 1H, Ar-H), 6.53 (dd, J = 13.2, 2.2 Hz, 1H, Ar-H), 6.44 (d, J = 8.4 Hz, 1H, Ar-H), 6.38
(d, J = 5.2 Hz, 1H, Ar-H), 5.47 (s, 2H, -NH2), 4.26 (t, J = 5.6 Hz, 2H, -CH2-), 3.64 – 3.52
(m, 4H, -CH2-), 2.77 (t, J = 5.6 Hz, 2H, -CH2-), 2.56 – 2..43 (m, 4H, -CH2-).
3-fluoro-4-((7-(3-morpholinopropoxy)quinolin-4-yl)oxy)aniline (17h) [31]: yield 85%;
m.p.: 118-119 °C; 1H NMR (600 MHz, DMSO-d6) δ 8.56 (d, J = 5.4 Hz, 1H, Ar-H), 8.18
(d, J = 9.0 Hz, 1H, Ar-H), 7.36 (s, 1H, Ar-H), 7.24 (dd, J = 9.0, 2.4 Hz, 1H, Ar-H), 7.06 (t,
J = 9.0 Hz, 1H, Ar-H), 6.53 (dd, J = 13.2, 2.4 Hz, 1H, Ar-H), 6.45 (d, J = 8.4 Hz, 1H, Ar-H),
6.37 (d, J = 4.8 Hz, 1H, Ar-H), 5.50 (s, 2H, -NH2), 4.17 (t, J = 6.0 Hz, 2H, -CH2-), 3.66 –
23

1
2
3.50 (m, 4H, -CH2-), 4.45 (t, J = 6.0 Hz, 2H, -CH2-), 2.41 – 2.32 (m, 4H, -CH2-), 2.00 –
1.87 (m, 2H, -CH2-).
3
5.3. General procedures for the synthesis of targets 19a-19p and 20a-l.
General Procedure A:
4
5
To the solution of aromatic amine (0.7 mmol) and the corresponding chlorinated
1,6-naphthyridine (0.7 mmol) in isopropanol (10 mL), HCl (20 mmol%) was added
drop-wise, and then heated to 90 °C under nitrogen for 2 h. The mixture was filtered, and
the solid was dissolved in ethyl acetate. The solution was stired with K2CO3 (1 mmol) at r.t.
for 1h and filtered. The filtrate was concentrated in vacuum and purified by flash
chromatography (CH2Cl2/MeOH = 20:1) to yield the corresponding targets.
General Procedure B:
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
A solution of aromatic amine (0.7 mmol), the corresponding chlorinated
1,6-naphthyridine (0.7 mmol) and PTSA (0.5 mmol) in isopropanol (10 mL) was heated to
90 °C under nitrogen for 2 h. The mixture was filtered, and the solid was washed with
ice-cold ethanol to yield the corresponding targets.
5.3.1 5-{[4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl]amino}-3-(4-fluorophenyl)-
1,6-naphthyridin-4(1H)-one (19a)
Prepared according to general procedure A. Yellow solid; yield: 85%; m.p.:
279-281 °C; 1H NMR (600 MHz, DMSO-d6) δ13.22 (s, 1H, -NH), 12.50 (s, 1H, -NH), 8.52
– 8.47 (m, 1H, Ar-H), 8.46 – 8.39 (m, 1H, Ar-H), 8.25 – 8.16 (m, 2H, Ar-H), 7.77 – 7.70 (m,
2H, Ar-H), 7.59 – 7.49 (m, 2H, Ar-H), 7.46 – 7.37 (m, 2H, Ar-H), 7.27 (t, J = 8.4 Hz, 2H,
Ar-H), 6.88 (d, J = 5.2 Hz, 1H, Ar-H), 6.53 – 6.45 (m, 1H, Ar-H), 3.96 (s, 6H, -OCH3). 13C
NMR (100 MHz, DMSO-d6) δ 177.49 (C=O), 155.46 (d, J = 196.4 Hz, 3-F-Ph), 148.99,
146.78, 139.09, 131.32, 130.16, 123.66, 115.27, 107.55, 104.60, 99.02, 56.75 (-OCH3), 56.51
(-OCH3)(Remark: some chemical shifts do not appear in the spectra due to the use of
insufficient quantities of the substance); HRMS(ESI): calcd for C31H23F2N4O4 [M+H]+
553.1681, Found 553.1679.
5.3.2 5-{[3-fluoro-4-((7-isobutoxy-6-methoxyquinolin-4-yl)oxy)phenyl]amino}-3-(4-fluoro-
phenyl)-1,6-naphthyridin-4(1H)-one 4-methylbenzenesulfonate (19b)
Prepared according to general procedure B. White solid; yield: 87%; m.p.: 234-236 °C;
24

1
2
1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H, -NH), 12.93 (s, 1H, -NH), 8.83 (d, J = 6.4
Hz, 1H, Ar-H), 8.33 – 8.19 (m, 2H, Ar-H), 8.12 – 8.03 (m, 1H, Ar-H), 7.77 – 7.68 (m, 3H,
Ar-H), 7.67 – 7.55 (m, 3H, Ar-H), 7.48 – 7.42 (m, 2H, Ar-H), 7.29 – 7.21 (m, 2H, Ar-H),
7.19 – 7.04 (m, 3H, Ar-H), 7.02 – 6.94 (m, 1H, Ar-H), 4.05 (s, 3H, -OCH3), 4.02 – 3.99 (m,
2H, -OCH2-), 2.27 (s, 3H, -CH3), 2.22 – 2.14 (m, 1H, -CH-), 1.05 [d, J = 6.8 Hz, 6H,
-(CH3)2]. 13C NMR (150 MHz, DMSO-d6) δ 176.79 (C=O), 164.57, 162.51 (d, J = 246.7 Hz,
4-F-Ph), 155.62 (d, J = 226.1 Hz, 3-F-Ph), 154.39, 154.12, 152.74, 151.50, 147.11, 144.93,
143.02, 138.88, 138.20, 137.09, 130.92 (d, J = 8.3 Hz),130.13, 128.29, 125.52, 124.85,
124.22, 115.05 (d, J = 22.8 Hz), 114.86, 106.62, 104.02, 103.30, 100.29, 100.11, 75.24,
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
56.61, 27.46, 20.84 (-CH3Ph), 18.99 [-(CH3)2]; HRMS(ESI): calcd for C34H29F2N4O4
[M+H]+ 595.2151, Found 595.2159.
5.3.3 5-{[3-fluoro-4-((7-(2-hydroxyethoxy)-6-methoxyquinolin-4-yl)oxy)phenyl]amino}-3-
(4-fluorophenyl)-1,6-naphthyridin-4(1H)-one 4-methylbenzenesulfonate (19c)
Prepared according to general procedure B. White solid; yield: 81%; m.p.: 241-243 °C;
1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H, -NH), 12.92 (s, 1H, -NH), 8.84 (d, J = 6.4
Hz, 1H, Ar-H), 8.33 – 8.22 (m, 2H, Ar-H), 8.09 (d, J = 6.2 Hz, 1H, Ar-H), 7.76 (s, 1H,
Ar-H), 7.73 (d, J = 5.6 Hz, 1H, Ar-H), 7.71 (d, J = 5.6 Hz, 1H, Ar-H), 7.69 (s, 1H, Ar-H),
7.62 – 7.55 (m, 2H, Ar-H), 7.46 (d, J = 8.0 Hz, 2H, Ar-H), 7.26 (t, J = 8.8 Hz, 2H, Ar-H),
7.15 (d, J = 6.4 Hz, 1H, Ar-H), 7.09 (d, J = 8.0 Hz, 2H, Ar-H), 6.99 (d, J = 6.2 Hz, 1H,
Ar-H), 4.29 – 4.22 (m, 2H, HOCH2-),4.05 (s, 3H, -OCH3), 3.89 – 3.83 (m, 2H, -OCH2-),
2.28 (s, 3H, -CH3); 13C NMR (150 MHz, DMSO-d6
) δ 176.80 (C=O), 164.56, 162.48 (d,
J = 243.2 Hz, 4-F-Ph), 154.36, 154.13 (d, J = 233.7 Hz, 3-F-Ph), 152.73, 151.43, 147.09,
144.99, 142.95, 138.80, 138.15, 137.05, 130.90 (d, J = 8.0 Hz), 130.15, 128.26, 125.51,
124.79, 124.17, 115.02 (d, J = 20.7 Hz), 106.62, 103.99, 103.35, 100.33, 100.13, 71.35,
59.06, 56.49 , 20.82
Found 583.1792.
(-CH3Ph)
; HRMS(ESI): calcd for C32H25F2N4O5 [M+H]+ 583.1787,
5.3.4 5-{[3-fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl)oxy)phenyl]amino}-3-
(4-fluorophenyl)-1,6-naphthyridin-4(1H)-one 4-methylbenzenesulfonate (19d)
Prepared according to general procedure B. White solid; yield: 80%; m.p.: 235-236 °C;
1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H, -NH), 12.86 (s, 1H, -NH), 8.84 (d, J = 6.8
25

1
2
Hz, 1H, Ar-H), 8.39 – 8.27 (m, 1H, Ar-H), 8.25 (d, J = 5.6 Hz, 1H, Ar-H), 8.10 (d, J = 6.4
Hz, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.75 – 7.51 (m, 5H, Ar-H), 7.45 (d, J = 7.8 Hz, 2H,
Ar-H), 7.31 – 7.20 (m, 2H, Ar-H), 7.18 – 7.12 (m, 1H, Ar-H), 7.09 (d, J = 7.8 Hz, 2H,
Ar-H), 7.01 – 6.90 (m, 1H, Ar-H), 4.36 (t, J = 4.4 Hz, 2H, -OCH2-), 4.04 (s, 3H, -OCH3),
3.80 (t, J = 4.4 Hz, 2H, -OCH2-), 3.35 (s, 3H, -OCH3), 2.28 (s, 3H, -CH3). 13C NMR (150
3
4
5
6
MHz, DMSO-d6) δ 176.84 (C=O), 164.62, 162.49 (d, J = 243.4 Hz, 4-F-Ph), 155.45
7
(d, J = 234.2 Hz, 3-F-Ph), 154.36, 152.71, 151.39, 147.05, 145.09, 143.06, 138.83,
138.12, 137.00, 130.92 (d, J = 7.4 Hz), 130.22, 128.26, 125.53, 124.73, 124.11,
115.02 (d, J = 20.1 Hz), 106.67, 103.99, 103.37, 100.43 (d, J = 32.1 Hz), 69.77, 68.81,
58.36, 56.55, 20.83 (-CH3Ph); HRMS(ESI): calcd for C33H27F2N4O5[M+H]+ 597.1944,
Found 597.1940.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
5.3.5 5-{[3-fluoro-4-((7-(2-hydroxypropoxy)-6-methoxyquinolin-4-yl)oxy)phenyl]amino}-3-
(4-fluorophenyl)-1,6-naphthyridin-4(1H)-one 4-methylbenzenesulfonate (19e)
Prepared according to general procedure B. White solid; yield: 80%; m.p.: 236-237 °C;
1H NMR (400 MHz, DMSO-d6): δ13.22 (s, 1H, -NH), 12.47 (s, 1H, -NH), 8.67 (d, J = 6.8
Hz, 1H, Ar-H), 8.44 (d, J = 13.6 Hz, 1H, Ar-H), 8.23 – 8.10 (m, 2H, Ar-H), 7.79 – 7.62 (m,
3H, Ar-H), 7.61 – 7.36 (m, 5H, Ar-H), 7.31 – 7.17 (m, 2H, Ar-H), 7.16 – 7.02 (m, 3H,
Ar-H), 6.92 – 6.84 (m, 1H, Ar-H), 6.82 – 6.75 (m, 1H, Ar-H), 5.10 (m, 1H), 4.13 – 3.96 (m,
13
5H), 2.28 (s, 3H, -CH3), 1.22 (d, J = 6.0 Hz, 3H, -CH3)； C NMR (150 MHz, DMSO-d6) δ
177.01 (C=O), 162.61, 162.21 (d, J = 243.6 Hz, 4-F-Ph), 155.52, 154.06 (d, J = 244.1 Hz,
3-F-Ph), 150.61, 148.31, 146.01, 145.57, 145.22, 140.93, 139.91, 138.38, 138.01, 133.37,
131.06, 130.80 (d, J = 7.4 Hz), 128.20, 125.55, 123.79, 122.78, 116.38, 114.83 (d, J = 19.1
Hz), 108.00, 106.95, 103.87, 103.44, 102.47, 99.72, 74.23, 64.27, 56.19, 20.82
(-CH3Ph),
20.24 -CH3). HRMS(ESI): calcd for C33H27F2N4O5[M+H]+ 597.1944, Found 597.1926.
(
5.3.6 5-{[3-fluoro-4-((7-(2-hydroxy-2-methylpropoxy)-6-methoxyquinolin-4-yl)oxy)phenyl]-
amino}-3-(4-fluorophenyl)-1,6-naphthyridin-4(1H)-one 4-methylbenzenesulfonate (19f)
Prepared according to general procedure B. White solid; yield: 84%; m.p.: 232-233 °C;
1H NMR (600 MHz, DMSO-d6): δ 13.40 (s, 1H, -NH), 12.97 (s, 1H, -NH), 8.89 (d, J = 6.8
Hz, 1H, Ar-H), 8.36 – 8.24 (m, 2H, Ar-H), 8.17 – 8.06 (m, 1H, Ar-H), 7.79 (s, 1H, Ar-H),
7.77 – 7.57 (m, 5H, Ar-H), 7.48 (d, J = 7.8 Hz, 2H, Ar-H), 7.29 (t, J = 8.4 Hz, 2H, Ar-H),
26

1
2
7.21 – 7.15 (m, 1H, Ar-H), 7.12 (d, J = 7.8 Hz, 2H, Ar-H), 7.04 – 6.98 (m, 1H, Ar-H), 4.07
(s, 3H, -CH3), 3.99 (s, 2H, -CH2-), 2.28 (s, 3H, -CH3), 1.29 [s, 6H, -(CH3)2]. 13C NMR (150
MHz, DMSO-d6) δ 177.09 (C=O), 164.87, 162.75 (d, J = 243.9 Hz, 4-F-Ph), 156.07, 154.63
(d, J = 244.7 Hz, 3-F-Ph), 151.85, 147.35, 145.33, 143.30, 139.12, 138.37, 137.35, 131.15,
130.47 (d, J = 7.4 Hz), 128.52, 125.79, 125.02, 124.42, 115.22, 114.36 (d, J = 21.1 Hz),
106.93 , 104.27 , 103.58 , 100.77 , 100.46 , 77.48 , 68.88, 56.96, 26.90 [-(CH3)2], 21.10
3
4
5
6
7
(
-CH3Ph
)
. HRMS(ESI): calcd for C34H28F2N4O5 [M+H]+611.2100, Found 611.2106.
8
5.3.7
9
5-{[3-fluoro-4-((6-methoxy-7-(2-methoxy-2-methylpropoxy)quinolin-4-yl)oxy)phenyl]-
amino}-3-(4-fluorophenyl)-1,6-naphthyridin-4(1H)-one 4-methylbenzenesulfonate (19g)
Prepared according to general procedure B. White solid; yield: 86%; m.p.: 241-242 °C;
1H NMR (400 MHz, DMSO-d6): δ 13.34 (s, 1H, -NH), 12.86 (s, 1H, -NH), 8.84 (d, J = 6.8
Hz, 1H, Ar-H), 8.32 – 8.21 (m, 2H, Ar-H), 8.08 (d, J = 6.4 Hz, 1H, Ar-H), 7.76 (s, 1H,
Ar-H), 7.72 (d, J = 5.6 Hz, 1H, Ar-H), 7.70 (d, J = 5.6 Hz, 1H, Ar-H), 7.67 (s, 1H, Ar-H),
7.65 – 7.55 (m, 2H, Ar-H), 7.46 (d, J = 8.0 Hz, 2H, Ar-H), 7.26 (t, J = 8.4 Hz, 1H, Ar-H),
7.13 (d, J = 6.8 Hz, 1H, Ar-H), 7.09 (d, J = 8.0 Hz, 2H, Ar-H), 6.97 (d, J = 6.4 Hz, 1H,
Ar-H), 4.11 (s, 2H, -OCH2-), 4.06 (s, 3H, -OCH3), 3.20 (s, 3H, -OCH3), 2.27 (s, 3H, -CH3),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
13
1.30 [s, 6H, -(CH3)2]； C NMR (150 MHz, DMSO-d6) δ 176.79 (C=O), 164.59, 162.47 (d,
J = 243.2 Hz, 4-F-Ph), 155.58 (d, J = 213.6 Hz, 3-F-Ph), 154.34, 152.70, 151.54, 147.07,
144.99, 143.11, 138.85, 138.12, 137.00, 130.89 (d, J = 7.7 Hz), 130.15, 128.24, 125.50,
124.76, 124.17, 114.86 (d, J = 20.6 Hz), 106.62, 103.99, 103.33, 100.60, 100.20, 74.44,
73.70, 56.70, 49.36, 21.94 [-(CH3)2], 20.80
C35H31F2N4O5 [M+H]+625.2257, Found 625.2260.
(-CH3Ph) ； HRMS(ESI): Calcd for
5.3.8 5-{[3-fluoro-4-((6-methoxy-7-(2-morpholinoethoxy)quinolin-4-yl)oxy)phenyl]amino}-
3-(4-fluorophenyl)-1,6-naphthyridin-4(1H)-one 4-methylbenzenesulfonate (19h)
Prepared according to general procedure B. White solid; yield: 86%; m.p.: 241-242 °C;
1H NMR (600 MHz, DMSO-d6) δ 13.32 (s, 1H, -NH), 12.66 (s, 1H, -NH), 11.04 (s, 1H,
-SO2OH), 8.91 – 8.80 (m, 1H, Ar-H), 8.45 (d, J = 12.2 Hz, 1H, Ar-H), 8.26 – 8.09 (m, 2H,
Ar-H), 7.81 (s, 1H, Ar-H), 7.76 – 7.71 (m, 3H, Ar-H), 7.64 – 7.60 (m, 1H, Ar-H), 7.58 –
7.53 (m, 1H, Ar-H), 7.48 (d, J = 6.8 Hz, 2H, Ar-H), 7.30 – 7.24 (m, 2H, Ar-H), 7.10 (d, J =
27

1
2
6.8 Hz, 2H, Ar-H), 7.05 (s, 1H, Ar-H), 6.95 (s, 1H, Ar-H), 4.76 – 4.70 (m, 2H), 4.07 (s, 3H,
-OCH3), 4.03 – 3.99 (m, 2H), 3.86 – 3.79 (m, 2H), 3.76 – 3.72 (m, 2H), 3.62 – 3.55 (m,
3
2H), 3.35 – 3.26 (m, 2H), 2.28 (s, 3H, -CH3); 13C NMR (150 MHz, DMSO-d6
) δ 177.00
4
(C=O), 164.66, 161.49 (d, J = 242.1 Hz, 4-F-Ph), 154.43 (d, J = 214.7 Hz, 3-F-Ph)
,
5
154.15, 153.97, 152.34, 151.15, 146.27, 145.14, 143.77, 138.55, 138.05, 137.19,
130.61 (d, J = 6.5 Hz), 128.23, 125.51, 123.97, 123.12, 115.41, 114.83 (d, J = 20.9
Hz), 106.92, 103.70, 103.23, 101.60, 100.50, 64.39, 63.33, 56.76, 54.72, 52.18,
20.82 (-CH3Ph); HRMS(ESI): calcd for C36H32F2N5O5[M+H]+ 652.2366, Found 652.2358.
5.3.9
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
5-{[3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl]amino}
-3-(4-fluorophenyl)-1,6-naphthyridin-4(1H)-one 4-methylbenzenesulfonate (19i)
Prepared according to general procedure B. Pale-yellow solid; yield: 70%; m.p.:
1
238-240 °C; H NMR (600 MHz, DMSO-d6) δ 13.33 (s, 1H, -NH), 12.68 (s, 1H, -NH),
10.51 (s, 1H, -SO2OH), 8.86 (d, J = 6.4 Hz, 1H, Ar-H), 8.45 (d, J = 13.2 Hz, 1H, Ar-H),
8.26 – 8.14 (m, 2H, Ar-H), 7.80 (s, 1H, Ar-H), 7.77 – 7.65 (m, 3H, Ar-H), 7.66 – 7.53 (m,
2H, Ar-H), 7.49 (d, J = 7.2 Hz, 2H, Ar-H), 7.32 – 7.22 (m, 2H, Ar-H), 7.11 (d, J = 7.2 Hz,
2H, Ar-H), 7.07 (d, J = 6.4 Hz, 1H, Ar-H), 6.96 (d, J = 6.0 Hz, 1H, Ar-H), 4.43 – 4.29 (m,
2H,-CH2-), 4.06 (s, 3H, -OCH3), 4.04 – 3.95 (m, 2H, -CH2-), 3.79 (t, J = 12.4 Hz, 2H,
-CH2-), 3.57 – 3.49 (m, 2H, -CH2-), 3.38 – 3.27 (m, 2H, -CH2-), 3.19 – 3.07 (m, 2H, -CH2-),
2.41 – 2.32 (m, 2H, -CH2-), 2.28 (s, 3H, -CH3); 13C NMR (150 MHz, DMSO-d6
) δ
176.96 (C=O), 164.74, 161.52 (d, J = 242.7 Hz, 4-F-Ph), 154.56 (d, J = 214.3 Hz, 3-F-Ph),
152.41, 151.27, 146.41, 145.05, 143.32, 138.13, 137.07, 130.83 (d, J = 7.8 Hz), 128.33,
128.20, 125.52 (d, J = 11.0 Hz), 124.43, 123.31, 115.08, 114.87, 114.72, 106.87, 103.67,
103.06, 100.76, 100.30, 66.99, 63.35, 56.62, 53.60, 51.29, 22.76, 20.83
HRMS(ESI): Calcd for C37H34F2N5O5 [M+H]+ 666.2522, Found 666.2507.
(-CH3Ph);
5.3.10 5-{[3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl]-
amino}-3-(4-fluorophenyl)-1,6-naphthyridin-4(1H)-one 4-methylbenzenesulfonate (19j)
Prepared according to general procedure B. Pale-yellow solid; yield: 70%; m.p.:
1
177-178 °C; H NMR (600 MHz, DMSO-d6) δ 13.37 (s, 1H, -NH), 12.88 (s, 1H, -NH),
10.50 (s, 1H, -SO2OH), 8.87 (d, J = 6.6 Hz, 1H, Ar-H), 8.32 (dd, J = 18.0, 8.4 Hz, 1H,
28