Design and synthesis of novel substituted naphthyridines as potential c-Met kinase inhibitors based on MK-2461

Article abstract of DOI:10.1016/j.bmcl.2015.05.082

Abstract Two series of novel 1,5-naphthyridine and 1,6-naphthyridine derivatives were designed and synthesized based on the c-Met kinase inhibitor MK-2461 under the guidance of scaffold hopping strategy. All were tested on c-Met kinase and in vitro anti-tumor activities against Hela and A549 cell lines. The results indicated that 1,6-naphthyridine was a more promising c-Met inhibitory structure core compared with 1,5-naphthyridine. Among them, 26b and 26c showed the best enzymic and cytotoxic activities. The western blot experiments implied that the cytotoxic activity of 26c might be partially through suppressing the phosphorylation of c-Met kinase.

Full text of DOI:10.1016/j.bmcl.2015.05.082

Bioorganic & Medicinal Chemistry Letters 25 (2015) 3251–3255
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of novel substituted naphthyridines
as potential c-Met kinase inhibitors based on MK-2461
a,
Jing-Fang Wu a, Ming-Ming Liu a, Shao-Xu Huang b, , Yang Wang
⇑
⇑
a Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two series of novel 1,5-naphthyridine and 1,6-naphthyridine derivatives were designed and synthesized
based on the c-Met kinase inhibitor MK-2461 under the guidance of scaffold hopping strategy. All were
tested on c-Met kinase and in vitro anti-tumor activities against Hela and A549 cell lines. The results
indicated that 1,6-naphthyridine was a more promising c-Met inhibitory structure core compared with
1,5-naphthyridine. Among them, 26b and 26c showed the best enzymic and cytotoxic activities.
The western blot experiments implied that the cytotoxic activity of 26c might be partially through
suppressing the phosphorylation of c-Met kinase.
Received 3 May 2015
Revised 22 May 2015
Accepted 25 May 2015
Available online 31 May 2015
Keywords:
c-Met kinase inhibitors
MK-2461
Ó 2015 Elsevier Ltd. All rights reserved.
1,5-Naphthyridine derivatives
1,6-Naphthyridine derivatives
Cytotoxic activity
c-Met is confirmed as the only high affinity receptor tyrosine
kinase (RTK) that binds with the hepatocyte growth factor
(HGF).1 c-Met/HGF widely exists in the development of mam-
malian cells, but its expression level is very low in normal tissues.2
Tumor biopsies reveal that c-Met overexpresses and HGF widely
exists in solid cancer.3 Binding of HGF to c-Met results in the
autophosphorylation of Tyr1234/1235 in activation loop, which
activates the downstream pathways involving promoting cell
growth, inhibiting cell apoptosis, changing cytoskeleton function
and increasing the metastasis.4,5 A number of small-molecule c-
Met inhibitors have been reported and marketed (Fig. 1).6–11
Among them, MK-2461 was developed by Merck and identified
as an ATP-competitive c-Met inhibitor. It is efficacious in preclini-
cal animal models of tumor suppression and its phase I/II study in
patients with advanced solid tumors has also been completed
recently.8 As the fused tricyclic core of MK-2461 is unfavourable
to its water solubility and pharmacokinetic profile, two series of
1,5-naphthyridine and 1,6-naphthyridine (Fig. 2) in which the hep-
tatomic ring is omitted compared with MK-2461, have been
designed under the guidance of scaffold hopping strategy in medic-
inal chemistry. Based on the structure–activity relationship (SAR)
studies of MK-2461, the nitrogen of its ring A forms a key hydrogen
bond with NH of Met1160 main chain in the hinge, so ring A is
preserved in the target scaffolds. The scaffolds still remain pla-
narity, meanwhile N atom at 5- or 6-position of ring B could sim-
ulate the hydrogen bond between the atom O of carbonyl and
water in the original heptatomic ring of MK-2461. The SAR studies
of MK-2461 revealed that substitution of phenyl group at 3-posi-
tion with 1-methyl-4-pyrazolyl slightly increases the inhibitory
activity of enzyme but greatly improves the cytotoxic activity,8
so the pyrazolyl groups are reserved as designed. The studies on
the SAR of these naphthyridines might identify the simplified phar-
macophore and provide useful information for this class of potent
c-Met inhibitor. Herein we report the synthesis of these substi-
tuted naphthyridines and their preliminary c-Met inhibitory
results as well as the antiproliferative activities in cancer cells.
The synthesis of scaffold 1 was accomplished by a seven-step
sequence, as illustrated in Scheme 1. In the Skraup reaction to pre-
pare 1,5-naphthyridine 4, m-NO2PhSO3Na was used as an oxi-
dant,12 which displayed
a higher yield (45%) and a better
reproducibility than I2.13 After bromination and oxidation,14 com-
pound 6 was obtained in a relatively low yield of 37% for 2 steps,
which was attributed to the low regioselectivities of these reac-
tions. Then compound 7 was obtained in 62% yield by the reaction
of 6 with TsCl under the condition of K2CO3. Compound 9 was pre-
pared in 83% yield by Suzuki reaction of 7 and 8 under the catalysis
of Pd(PPh3)4 with Cs2CO3 as the alkali. K2CO3 and CsF were also
examined under the same condition but showed extremely poor
conversions. Compound 9 could be converted to 10 by refluxing
in POCl3 in 68% yield. In the workup procedure, the pH of the
⇑
Corresponding authors.
E-mail addresses: hsx@sioc.ac.cn (S.-X. Huang), wangyang@shmu.edu.cn
(Y. Wang).
http://dx.doi.org/10.1016/j.bmcl.2015.05.082
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

3252
J.-F. Wu et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3251–3255
H
N
position. However, after regioselective replacement of Cl to a more
active I,18 the transformation of 14 to 15 exhibited a much higher
yield of 93% (from 13 to 15, 70% yield in 2 steps). After addition of
the triple bond, the aldehyde acetal 16 was obtained in 68% yield.
Compound 17 was produced by oxidation of the cyano group, fol-
lowed by cyclization to get compound 18 in 52% yield for 2 steps.19
Afterwards, the preparation of 2 from 18 was the same as that of 1
from 7. Thus, the synthesis of novel scaffold 2 was achieved in 2.9%
overall yield via 11 steps synthetic route.
With scaffolds 1 and 2 in hand, we subsequently proceeded to
the functionalization of their amino groups using MK-2461 as a
reference. Three series of 1,5-naphthyridine derivatives 21–23
and 1,6-naphthyridine derivatives 25–27, including acylated, alky-
lated and sulfonylated derivatives, were designed and synthesized
according to the theory of bioisosterism (Scheme 3). The acylation
of the scaffolds 1 and 2 with various acyl chlorides containing
alkyl, cycloalkyl, phenyl and heterocyclic groups afforded the tar-
get compounds 21 and 25. Unexpectedly, only di-acylated products
24a–e were attained from 1,6-naphthyridine scaffold 2, so alcohol-
ysis of 24a–e was subsequently carried out to get mono-acylated
products 25a–e. Compounds 21 and 25 were refluxed in THF with
reductant LiAlH4 for about 3 h to achieve the alkylated derivatives
22 and 26, respectively. It is worth mentioning that the sulfonyla-
tion of 1 and 2 did not occur by heating at 120 °C, as sulfochlorides
were less active than acylchlorides. The reaction proceeded effi-
ciently under the condition of microwave at 120 °C for 1h to give
23 and 27 in good yields.
O
O
NH2
N
Cl
H
H
F
HN
O
N
N
N
N
H
Cl
Crizotinib
Tivantinib
O
H
N
N
F
N
O
N
N
S
O
H
O
N
O
O
O
O
F
O
Cl
N
H2N
N
BMS-777607
MK-2461
Figure 1. Representatives of c-Met inhibitors.
N
N
N
S
O
H
N
O
3
O
O
O
A
N
MK-2461
N
N
R
N
5
HN
B
H
N
3
N
B
N
3
N 6
R
A
N
A
N
The preliminary c-Met inhibitory activity of these target com-
pounds and their antiproliferative activities in cancer cells were
evaluated and listed in Table 1. The compounds were tested at a
Figure 2. Design of 1,5-naphthyridine and 1,6-naphthyridine scaffolds.
single concentration of 10 lM and defined as effective which inhi-
bit over half of the c-Met kinase at that concentration. Most of the
1,6-naphthyridine derivatives (2, 25a–c, 26a–c, 27h and 27j) were
effective, while a minority of the 1,5-naphthyridine derivatives (1,
21b and 22a–d) were active. Therefore it can be inferred that the
alkylamino side chain at the 5-position was beneficial to the inhi-
bition of c-Met kinase.
The compounds were further tested on the Hela and A549 cell
lines (Table 1). Hela is a cervical cancer cell line and A549 is a lung
cancer cell line, both of which could express high level of c-Met.
1,6-Naphthyridine derivatives performed better than 1,5-naph-
thyridine derivatives on both enzymic and cytotoxic activities,
indicating that 1,6-naphthyridine skeleton could be a potential c-
Met inhibitory structure core. Among 1,5-naphthyridine deriva-
tives, only 21d had cytotoxic activities in Hela and A549 cell lines,
however 21d could merely inhibit around 30% of the c-Met kinase,
indicating that it might follow a different mechanism of action.
Among 1,6-naphthyridine derivatives, 26b, 26c and 27h showed
reaction mixture should be neutralized carefully around 7.0 with
aqueous NaOH, in case product 10 hydrolyzed to 9. The mixture
of compound 10 and 25% aqueous ammonia was stirred at 120 °C
using
a microwave reaction device, but few product was
obtained.15 Finally, the azidation of 10 with NaN3 followed by
16
reduction with SnCl2 gave 1,5-naphthyridine scaffold 1 in 63%
yield for 2 steps. So far, the synthesis of compound 1 was accom-
plished via 7 steps synthetic route with commercial available 3-
aminopyridine and glycerol as starting materials in 3.3% overall
yield.
As shown in Scheme 2, the preparation of scaffold 2 followed a
different synthetic route with
1
using 1,1,3,3-tetram-
ethoxypropane and 2-cyanoacetamide as starting materials. The
compounds 11–13 were synthesized according to the literature
procedures17 in a yield of 26% for 3 steps. The conversion of 13
to 15 was firstly tried by Sonogashira reaction directly, but
achieved a yield as low as 50% since the 5-Br was a competitive
cytotoxic activities with IC50 in the range of 5–10 lM. It was noting
N
NH2
N
N
m-NO2PhSO3Na, glycerol
H2SO4, H2O, 150oC
Br2, NaOAc
AcOH, 85oC
m-CPBA
Br
N
O
DCM
N
N
Br
N
3
4
5 (55%)
6 (67%)
(45%)
N
N
N
8, Pd(PPh3)4, Cs2CO3
TsCl, K2CO3
DCM, H2O
POCl3
reflux
N
H
O
N
Cl
Br
N
H
O
DMF, 100oC
N
N
N
N
7
9
10
(68%)
(62%)
(83%)
N
1) NaN3, DMF, 120oC
2) SnCl2, HCl, MeOH, 60oC
O
B
N
NH2
O
N
N
N
N
1 (63%)
8
Scheme 1. Synthesis of 1,5-naphthyridine scaffold 1.

J.-F. Wu et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3251–3255
3253
H
N
H
N
N
Cl
O
O
O
HCl, Et3N
Br2, NaOAc
AcOH
PCl5, POCl3
100oC
O
O
+
CN
H2N
N
O
O
Br
CN
CN
Br
CN
11 (41%)
12 (75%)
13 (84%)
TMS
O
N
O
I
TMS
, PdCl2(PPh3)2, CuI
NaI, TMSCl
CH3CN, 80oC
NaOMe, MeOH
reflux
N
Et3N, toluene
Br
CN
Br
CN
Br
CN
16
(68%)
14
15
(75%)
(93%)
O
N
O
N
N
TsOH.H2O, toluene
reflux
Na2CO3, H2O2
acetone
8, Cs2CO3, Pd(PPh3)4
NH
NH
DMF, 100oC
Br
N
NH2
O
O
Br
N
O
17 (93%)
18 (56%)
19 (80%)
N
N
POCl3
N
1) NaN3, DMF, 120oC
2) SnCl2, HCl, MeOH, 60oC
N
N
NH2
N
N
Cl
N
20 (69%)
2 (82%)
Scheme 2. Synthesis of 1,6-naphthyridine scaffold 2.
N
N
NH2
R
N
N
rt
1
S
,
e
O
2
n
i
C
d
m
ri
l
,
p
i
y
c
p
r
o
w
y
,
l
r
i
d
C
a
i
n
v
e
e
CO
,
R
1
2
0
°
C
N
N
N
O
O
O
R
LiAlH4
THF, reflux
S
N
N
H
R
N
N
R
N
N
N
N
N
N
H
H
N
N
21a e
22a d
23f i
-
-
-
a
b
c
d
e
a
b
c
d
f
g
h
i
97% ( ), 93% ( ), 91% ( ), 89% ( ), 85% ( )
28% ( ), 63% ( ), 38% ( ), 28% (
)
36% ( ), 48% ( ), 42% ( ), 42% ( )
R = methyl (a)
N
b
cyclopropyl (
)
N
4-fluorophenyl (c)
4-methoxyphenyl (
3-pyridinyl (e)
N
R
RCOCl, pyridine, rt
d
)
N
N
N
N
O
N
O
N
f
4-trifluoromethylphenyl ( )
NH2
g
4-methylphenyl (
)
2
R
2-thienyl (h)
R
S
24a e
-
O
i
2,4-dichlorophenyl ( )
2
C
m
l
,
i
c
p
2,6-dichlorophenyl (j)
r
y
o
r
w
i
d
a
NaOH 1,4-dioxane/methanol, rt
N
i
n
e
v
e
,
1
2
0
°
C
N
N
N
N
R
N
O
S
LiAlH4
N
N
N
N
N
THF, reflux
HN
25a-e
O
HN
HN
N
O
R
R
26a-d
27f-h, j
a
b
c
d
e
a
b
c
d
)
f g h j
94% ( ), 83% ( ), 42% ( ), 52% ( )
88% ( ), 92% ( ), 81% ( ), 88% ( ), 82% ( ) 30% ( ), 54% ( ), 43% ( ), 31% (
Scheme 3. Synthesis of 1,5-naphthyridine derivatives (21–23) and 1,6-naphthyridine derivatives (25–27).
that amide as the connection of side chain at 5-position in 25a–e
totally lost the cytotoxic activities. Consistent with the results of
c-Met inhibitory activities, the series of 26 displayed stronger cyto-
toxicity than the series of 25 and 27. A possible explanation was
that 26b and 26c had flexible alkylamino side chains which were
more suitable for their induced fit interaction with the hydropho-
bic region of c-Met kinase. Moreover, the target molecules with
rigid connecting side chains showed poor water and lipid solubil-
ity. Therefore, 26b and 26c were regarded as the most promising
candidates as potential c-Met inhibitors among these target
molecules.
Western blot analysis. Hela cells were treated with 26c at different
concentrations (1.25–20 M) or DMSO as negative control for 24 h.
l
Then, the cells were harvested, lysed and subjected to Western blot
analysis with the antibodies of phospho-Met (Tyr1234/1235) and
Met, in which the level of actin served as loading control. Indeed,
as shown in Figure 3, the phosphorylation of c-Met was suppressed
by 26c in a concentration dependent way, whereas the Met expres-
sion level was not obviously influenced. These results implied that
the cytotoxic activity of 26c might be, at least partially, through
repressing c-Met kinase activation.
Based on the X-ray co-crystal structure of MK-2461 analog
bound to the c-Met kinase domain (PDB: 3R7O8), we established
the binding mode of new scaffold inhibitor 26c by Schrodinger
Further, compound 26c was selected to determine the
inhibitory effect on phosphorylation of c-Met kinase using

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J.-F. Wu et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3251–3255
Table 1
backbone NH of Met1160. In this orientation, the pyrazole moiety
extends along the hinge and faces to the solvent accessible region.
The H atom of amino group at 5-positon is involved in a water-me-
diated hydrogen bond to the carboxyl oxygen of side-chain
Asp1164, and the p-fluorophenyl tail falls into the hydrophobic
pocket. All these interactions contribute to the tight binding and
greatly enhance the inhibitory potency of 26c. Compared with
MK-2461, 26c lacks a side chain hydrogen bonding interaction
with the c-Met, so further structural modifications will be focused
on the substituents with hydrogen-bonding donor/acceptor.
In conclusion, two series of novel 1,5-naphthyridine and 1,6-
naphthyridine derivatives were designed and synthesized based
on c-Met kinase inhibitor MK-2461, and the preliminary inhibitory
activities on c-Met and the antiproliferative activities in cancer
cells were evaluated. Among 28 derivatives, 26b and 26c were
identified as the promising c-Met kinase inhibitor candidates with
obvious cytotoxic activities against Hela and A549 cell lines.
Additionally, Western blotting results showed that phosphoryla-
tion levels of c-Met at Tyr1234/1235 were dose-dependently
decreased by 26c in Hela cells. The SAR outlined in the current
study will definitely facilitate the further structural modification
of these naphthyridine derivatives as potential anti-cancer agents
by targeting c-Met kinase.
The inhibitory activities of 1,5-naphthyridine and 1,6-naphthyridine derivatives on c-
Met kinase, Hela and A549 cell lines
Compd
c-Met
(%)
Hela
IC50
A549
IC50
Compd
c-Met
(%)
Hela
IC50
A549
IC50
(lM)
(10
lM)
(lM)
(l
M)
(10
lM)
(lM)
1
57.1
47.8
74.6
17.6
30.4
45.5
61.1
64.0
61.4
58.6
47.4
39.3
44.2
36.2
>50
>50
>50
>50
4.9
>50
>50
>50
46.6
>50
>50
>50
38.4
>50
—
>50
>50
>50
>50
6.4
>50
>50
>50
>50
>50
>50
45.5
39.5
>50
—
2
73.7
55.4
60.1
55.0
49.8
48.7
59.2
61.4
73.5
38.1
18.6
29.3
57.0
64.4
—
40.8
>50
>50
>50
>50
>50
>50
7.4
33.4
>50
>50
>50
>50
>50
40.7
8.9
21a
21b
21c
21d
21e
22a
22b
22c
22d
23f
23g
23h
23i
25a
25b
25c
25d
25e
26a
26b
26c
26d
27f
9.2
5.2
42.2
>50
>50
17.4
>50
3.3
>50
>50
>50
9.4
>50
20.4
27g
27h
27j
Crizotinib 100%
@50 nM
Cisplatin
Acknowledgements
Financial supports from the National Natural Science
Foundation of China (No. 21472025, 81071839) and Shanghai
Natural Science Foundation (No. 13ZR1464900) are gratefully
acknowledged. We sincerely thank Prof. Meiyu Geng and Jing Ai
and their research group, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, for their generous assistance in the
evaluation with the c-Met kinase inhibition.
Figure 3. Effects of 26c on the phosphorylation of c-Met kinase and its expression
level in Hela cells.
Supplementary data
10.1. As shown in Figure 4, the 1,6-naphthyridine derivative 26c
binds to the ATP binding pocket of the activated (phosphorylated)
c-Met kinase domain in a ‘U-shape’ conformation. In particular, the
N atom of A ring forms a key hydrogen bond with the hinge
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.05.
082.
Figure 4. Proposed binding mode of 26c in the ATP binding pocket of the c-Met kinase domain.

J.-F. Wu et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3251–3255
3255
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