Discovery of novel type II c-Met inhibitors based on BMS-777607

Article abstract of DOI:10.1016/j.ejmech.2014.04.056

Twenty-two new analogs based on the structure of BMS-777607 were designed, synthesized, and evaluated to determine their biological activities. Compounds bearing a cyclic sulfonamide or α-chloropiperidone scaffold exhibited good activity, which may provid

Full text of DOI:10.1016/j.ejmech.2014.04.056

European Journal of Medicinal Chemistry 80 (2014) 254e266
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Discovery of novel type II c-Met inhibitors based on BMS-777607
,
,
,
*
Wei Zhang a 1, Jing Ai b 1, Dakuo Shi c, Xia Peng b, Yinchun Ji b, Jian Liu a, Meiyu Geng b
,
,
Yingxia Li a
*
a School of Pharmacy, Fudan University, Shanghai 201203, China
b Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
Shanghai 201203, China
c School of Pharmacy, Ocean University of China, Qingdao 266003, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Twenty-two new analogs based on the structure of BMS-777607 were designed, synthesized, and
evaluated to determine their biological activities. Compounds bearing a cyclic sulfonamide or -chlor-
Received 29 September 2013
Received in revised form
17 April 2014
Accepted 19 April 2014
Available online 21 April 2014
a
opiperidone scaffold exhibited good activity, which may provide a new basis for further structural
optimization. Quinoline-containing analogs exhibited better results than did their counterparts with an
aminopyrimidine, aminopyridine, or pyrrolopyridine unit. Two analogs, 22d and 22e, stood out as the
most potent c-Met inhibitors with IC50s of 0.9 and 1.7 nM, respectively. These two compounds were more
potent than BMS-777607 in enzymatic inhibition and cell proliferation studies.
Keywords:
c-Met
Ó 2014 Elsevier Masson SAS. All rights reserved.
Synthesis
Kinase inhibitor
1. Introduction
conformation are defined as type II inhibitors. This type of com-
pounds binds to the same area occupied by the type I inhibitors but
c-Met is a prototype member of a subfamily of heterodimeric
receptor tyrosine kinases (RTKs). The c-Met pathway is frequently
deregulated in a wide variety of human cancers and plays critical
roles in cancer formation, progression, and dissemination, as well
as the resistance to approved therapies [1e4]. Therefore, the inhi-
bition of increased c-Met signaling may have a significant impact
on the treatment of human cancers in which the c-Met pathway is
aberrantly activated. In fact, recent clinical trials of c-Met pathway-
targeted agents have yielded convincing evidence to support the
potential utility of this class of agents in the treatment of various
human cancers [5e7]. To date, the development of small molecular
c-Met kinase inhibitors has made remarkable progress, resulting in
more than ten candidates reaching clinical trials [8]. These known
small molecular inhibitors have been categorized into two types
based on their binding mode in the DFG motif (aspartate-phenyl-
alanine-glycine) of the c-Met activation loop. Type I inhibitors bind
the DFG-in conformation with a U-shaped geometry and are
defined as ATP-competitive inhibitors of the activated kinase. In
contrast to type I inhibitors, those that bind the inactivated DFG-out
also exploits hydrogen bonding and hydrophobic interactions with
the allosteric site [9,10].
As disclosed recently, certain mutations near the active site of c-
Met may cause resistance of type I inhibitors. In contrast, type II
inhibitors are postulated to be more effective against these muta-
tions because their binding interactions extend beyond the
entrance to c-Met’s active site [11e13]. Initiated by Kirin Brewery
Company in 2003 [14], numerous type II inhibitors with different
structures have been reported in the past ten years, and some of
these are currently in clinical trials or pre-clinical development
(Fig. 1) [9]. A good example of these type II inhibitors is BMS-
777067, which inhibits the kinase activity of c-Met
(IC50 ¼ 3.9 nM), as well as that of Axl (IC50 ¼ 1.1 nM), Ron
(IC50 ¼ 1.8 nM), and Tyro3 (IC50 ¼ 4.3 nM) [15]. This compound is
now in phase 2 trial because of its excellent in vivo efficacy and
favorable pharmacokinetic and preclinical safety profiles.
As displayed in Fig 1, most of the type II inhibitors may be
disconnected into four units according to their structures and sub-
unit functions. Moiety A is a phenyl ring or para-substituted
(usually fluorine) phenyl ring. As disclosed by the crystal structure
of the c-Met kinase domain in complex with BMS-777607 [15],
this aromatic ring occupies a deep hydrophobic pocket defined by
three residues (F1134, L1195, and F1200). The main chain of
moiety B is usually constituted by five atoms (i.e., six chemical
* Corresponding authors.
E-mail addresses: mygeng@simm.ac.cn (M. Geng), liyx417@fudan.edu.cn (Y. Li).
These authors contributed equally to this work.
1
http://dx.doi.org/10.1016/j.ejmech.2014.04.056
0223-5234/Ó 2014 Elsevier Masson SAS. All rights reserved.

W. Zhang et al. / European Journal of Medicinal Chemistry 80 (2014) 254e266
255
Fig. 1. Some representative type II c-Met inhibitors and their structural characteristics.
bonds, as summarized recently by Gong et al. [16,17]), bearing at
least one amide bond, with or without a ring on the side chain. In
the compound BMS-777607, the carbonyl group in this moiety
forms a hydrogen bond with residue D1222. The structure of
key intermediates 6aef. Finally, a Hoffman rearrangement resulted
in 7aef at high yields.
For the preparation of isomeric sulfamoyl acetamides (11aec)
and isomeric six-membered sulfamoyl acetamides (11def) deri-
vates, chloroacetyl chloride was first coupled with substituted an-
ilines (2aec) to give compounds 8aec, which were then
converted to sulfochlorides 9aec in the presence of sodium sulfite
followed by phosphorous pentachloride. The coupling of amine 5
with sulfochlorides 9aec produced sulfamoyl acetamide analogs
10aec, respectively. The treatment of 10aec with 1,3-
bromocholoropropane in the presence of potassium carbonate
provided the cyclic sulfamoyl acetamide analogs 10def. Finally, a
Hoffman rearrangement delivered aminopyridines 11aef from the
amide precursors 10aef, and these reactions were mediated by
PhI(OAc)2 (Scheme 2).
moiety C is comparatively conserved, bearing a phenyl ring
p-
stacked with residue F1223 of the DFG motif. In contrast, the
structure of moiety D is alterable, and fused pyridine derivates
(substituted quinoline, pyrrolopyridine, and thienopyridine) and a
simple substituted pyridine are tolerant. The role of the pyridine
nitrogen is an anchor to the hinge region through its interaction
with M1160 [15].
Based on the unique structure of BMS-777607, we designed and
prepared two series of new analogs in this study (Fig. 2). In series 1,
moieties D and C in the parent compound were fixed, whereas the
pyridone fragment in moiety B was replaced with sulfonamide
(cyclic or linear) or substituted piperidone. In addition, several
minor modifications were performed on the phenyl ring of moiety
A. In the second series, moieties A and C were fixed, and moiety D
was replaced with other aromatic rings. Moiety B also underwent
several modifications in this series.
The synthesis of piperidone analogs is displayed in Scheme 3.
The coupling of 2-piperidone acid 16a with amine 5 smoothly
produced the corresponding 2-piperidone analog 17a. The treat-
ment of 17a with PhI(OAc)2 gave the desired aminopyridine 18a. In
contrast, the coupling of
amine 5 in the presence of EDC$HCl (2.5 eq) and DMAP afforded the
halo-exchanged -chloro product 17b. A similar procedure as that
a-bromo-2-piperidone acid 16b with
2. Chemistry
a
described above gave the final product 18b.
Substituted N-phenyl sulfamoyl acetamides 7aef were prepared
according to the sequence outlined in Scheme 1. Commercially
available ethyl 2-(chlorosulfonyl)acetate 1 and substituted anilines
2aec were coupled in the presence of triethylamine to yield the
corresponding linear sulfonamides 3aec, respectively. The six-
membered cyclic sulfamoyl acetamide esters 3def were obtained
through the treatment of 3aec with 1-bromo-3-chloropropane.
The hydrolysis of 3aef gave 4aef, and the coupling of these com-
pounds with amine 5 [15] under standard conditions yielded the
For the preparation of the series 2 compounds, two building
blocks (19, 20) were prepared through known procedures
[15,18,19]. Carboxylic acid 19a was activated with SOCl2 and then
coupled with aromatic amine 20a. The removal of the protecting
group resulted in the desired analog 21a at good yield. Compounds
21b and 21c were obtained using similar procedure without the
deprotection step. For compounds 22aee, the substitution on the
pyridone motif was transformed after the coupling of the building
blocks 19b and 20aec (Scheme 4).

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W. Zhang et al. / European Journal of Medicinal Chemistry 80 (2014) 254e266
Fig. 2. Design of two series of novel c-Met inhibitors.
3. Biology
incubation for 60 min at 37 ꢀC, the plate was washed three times
with phosphate-buffered saline (PBS) containing 0.1% Tween 20 (T-
PBS). Anti-phosphotyrosine (PY99) antibody (100 L; 1:500, diluted
in 5 mg/mL BSAT-PBS) was then added. After a 30-min incubation at
37 ꢀC, the plate was washed three times, and 100
L of horseradish
3.1. c-Met kinase assay
m
The effects of the indicated compound on the activities of c-Met
kinases were determined using enzyme-linked immunosorbent
assays (ELISAs) with purified recombinant proteins. Briefly, 96-well
m
peroxidase-conjugated goat anti-mouse IgG (1:2000, diluted in
5 mg/mL BSA T-PBS) was added. The plate was then incubated at
plates were pre-coated with 20
m
g/mL poly (Glu,Tyr)4:1 (Sigma) as
37 ꢀC for 30 min and washed three times. A 100-
mL aliquot of a so-
the substrate. A 50- L aliquot of 10
kinase reaction buffer (50 mmol/L HEPES [pH 7.4], 50 mmol/L MgCl2,
0.5 mmol/L MnCl2, 0.2 mmol/L Na3VO4, and 1 mmol/L DTT) was
m
m
mol/L ATP solution diluted in
lution containing 0.03% H2O2 and 2 mg/mL o-phenylenediamine in
0.1 mol/L citrate buffer (pH 5.5) was added. The reaction was
terminated by the addition of 50 mL of 2 mol/L H2SO4 when the color
added to each well, and 1
m
L of various concentrations of Yhhu3813
changed, and the plate was analyzed using a multi-well spectro-
photometer (SpectraMAX 190, Molecular Devices) at 490 nm. The
inhibition rate (%) was calculated using the following equation:
[1 ꢁ (A490/A490 control)] ꢂ 100%. The IC50 values were calculated
from the inhibition curves obtained from two separate experiments.
diluted in 1% DMSO (v/v) (Sigma) were then added to each reaction
well. DMSO (1%, v/v) was used as the negative control. The kinase
reaction was initiated by the addition of purified c-Met tyrosine
kinase proteins diluted in 49
mL of kinase reaction buffer. After
Scheme 1. Reagents and conditions: a) Et3N, toluene; b) 1-bromo-3-chloropropane, K2CO3, DMF; c) NaOH, EtOH; d) EDC$HCl, DMAP; e) PhI(OAc)2.

W. Zhang et al. / European Journal of Medicinal Chemistry 80 (2014) 254e266
257
Scheme 2. Reagents and conditions: a) Et3N, CH2Cl2; b) Na2SO3, EtOH, H2O; c)PCl5; d) DIPEA, THF; e) 1-bromo-3-chloropropane, K2CO3, DMF; f) PhI(OAc)2.
3.2. Western blot analysis
good inhibition of the c-Met enzyme. The compounds (7aec)
bearing a linear sulfonamide motif in the right site of moiety B
(near moiety A) showed IC50s ranging from 290 to 500 nM, whereas
the presence of sulfonamide in a six-member ring (7de7f) resulted
in a 1.7e5.3-fold enhancement of the activity (7d vs. 7a, 7e vs. 7b,
and 7f vs. 7c). The replacement of the amide bond near moiety C
with linear sulfonamide (11aec) slightly decreased the enzyme
inhibition. However, the presence of cyclic sulfonamide at this
position (11def) caused a loss of activity. The analog bearing
saturated pyridone (i.e., piperidone) (18a) showed weaker activity
compared to that bearing cyclic sulfonamide (7def). However, the
MKN45 cells were treated with an increasing dose of the
indicated compound for 2 h at 37 ꢀC and then lysed in 1ꢂ SDS
sample buffer. The cell lysates were subsequently resolved by 10%
SDS-PAGE and transferred to nitrocellulose membranes. The
membranes were probed with the appropriate primary antibodies
and then with horseradish peroxidase-conjugated anti-rabbit or
anti-mouse IgG. The immunoreactive proteins were detected using
an enhanced chemiluminescence detection reagent (Thermo
Fisher).
substitution of the
a-position of piperidone with chlorine (18b)
resulted in a 5-fold enhancement in the activity (18b vs. 18a). The
investigation of different groups (H, Me, or F) at the para-site of the
phenyl ring in moiety A indicated that para-fluoride gave slightly
better results (7c, 7f, and 11c). Although all of the compounds (7ae
f, 11aef, and 18aeb) belonging to series 1 that did not contain a
pyridone moiety showed weaker activities compared to the posi-
tive control BMS-777607, the novel designed cyclic sulfonamide
3.3. Cell proliferation assay
Cells were seeded in 96-well tissue culture plates. The following
day, the cells were exposed to various concentrations of the com-
pounds and further cultured for 72 h. The cell proliferation was
then determined using the sulforhodamine B (SRB, Sigma) or the
thiazolyl blue tetrazolium bromide (MTT, Sigma) assay. The IC50
values were calculated through fitting of the concentratione
response curve using the four-parameter method.
(7f) and a-chloropiperidone (18b) scaffolds lead to the develop-
ment other new analogs with improved activity.
Most of the compounds belonging to series 2 (21aec, 22aee)
exhibited good to excellent inhibition against c-Met kinase. Of
these, three compounds (22cee) showed better activity than the
positive control. If moiety B was fixed as un-substituted pyridone
(21aec), the analogs bearing pyrimidine (21a) or pyrrolopyridine
4. Results and discussion
As illustrated in Table 1, most of the designed compounds
belonging to series 1 (7aef, 11aef, 18aeb) showed moderate to
Scheme 3. Reagents and conditions: a) CuI, K3PO4, DMF, 90%; b) tBuLi, isobutyl chloroformate, 82%; c) LiOH, 87%; d) Br2, Et2O, 92%; e) EDC$HCl, DMAP, 76% for 17a, 68% for 17b; f)
PhI(OAc)2, 72% for 18a, 76% for 18b.

258
W. Zhang et al. / European Journal of Medicinal Chemistry 80 (2014) 254e266
Scheme 4. Reagents and conditions: a) SOCl2, DIPEA, THF; b) TFA; c) NaH, EtOH/THF; d) NaH, MeOH/THF.
(21b) showed better results (IC50 ¼ 20e39 nM) than their coun-
terpart containing a quinoline scaffold (21c). However, the weak
activity of 21c may be caused by its poor solubility. A compound
bearing the same scaffold (22d) displayed much better activity than
its counterparts (22a, 22b), i.e., its activity was as low as 0.9 nM,
which is 4-fold stronger than that of BMS-777607. In general,
quinoline moiety-containing compounds gave better results (22d
vs. 22a, 22b, and BMS-777607). The investigation of compounds
with a quinoline unit in moiety D revealed that the substitution of
pyridone in moiety B with iodide (22c) or methoxylation (22e) at
the 4-position gave good results.
roles in c-Met functioning, were also significantly inhibited as a
result of 22d treatment (Fig. 4). These data support the finding that
22d inhibits c-Met signaling and, in turn, suppresses c-Met-
dependent cell proliferation.
5. Conclusion
In summary, two series of analogs based on BMS-777607 were
designed, synthesized, and evaluated to determine their effect on
c-Met inhibition. Modifications at moiety B revealed that the novel
designed cyclic sulfonamide and a-chloropiperidone scaffolds may
We then evaluated the inhibitory effect of increasing concen-
trations (0.1, 1, and 10 mM) of the promising compounds on prolif-
eration of BaF3/TPR-Met cells, which stably express a constitutively
active c-Met due to a chromosomal rearrangement. As shown in
Fig. 3, five compounds (21b, 22b, 22c, 22d, and 22e) displayed
significant inhibitory activity against cell proliferation (>80%) at a
provide a new basis for further optimization. The quinoline
moiety-containing analogs gave better result than their counter-
parts bearing aminopyrimidine, aminopyridine, or pyrrolopyr-
idine. Two analogs, namely compounds 22d and 22e, stood out as
the most potent c-Met inhibitors with IC50s of 0.9 and 1.7 nM,
respectively. These two compounds exhibited approximately 5ꢁ9-
fold higher potency than did BMS-777607 with respect to the
inhibition of cell proliferation. Further studies on the structural
optimization of these derivatives are currently underway in our
laboratory.
concentration of 10
showed strong activity at a concentration of 1
compounds 22d and 22e continued to show significant inhibitory
effects even at a concentration of 0.1 M, which indicates that these
mM, and three compounds (22c, 22d, and 22e)
mM. In addition,
m
two compounds are more potent than BMS-777607. The IC50 values
of 22d and 22e with respect to the cell proliferation of the c-Met-
constitutively activated MKN45 and BaF3/TPR-Met cells are shown
in Table 2. Indeed, these two compounds showed approximately
5ꢁ9-fold higher potency than BMS-777607.
6. Experimental protocols
6.1. Chemistry
Based on the data above, 22d and 22e were proven to be potent
c-Met inhibitors through both c-Met enzymatic and cell prolifera-
tion assays. To further determine whether the c-Met kinase inhi-
bition of these two compounds in a cell-free system can be
recapitulated in vitro, the cellular c-Met-targeting signal pathway of
22d in c-Met constitutively activated MKN45 cancer cells was
investigated. The results showed that 22d inhibited c-Met phos-
phorylation in MKN45 cells in a dose-dependent manner, with
All chemical reagents were used as supplied unless indicated.
Solvents used in organic reactions were distilled under an inert
atmosphere. Unless otherwise noted, all reactions were carried out
at room temperature and were performed under a positive pres-
sure of argon. Flash column chromatography was performed on
silica gel (200e300 mesh, Qingdao, China). Analytical thin layer
chromatography (TLC) was performed on glass plates pre-coated
with a 0.25 mm thickness of silica gel. 1H NMR and 13C NMR
spectra were taken on a Jeol JNM-ECP 600 or a Bruker Avance III
400 spectrometer at rt. Chemical shifts of the 1H NMR spectra are
complete abolishment at 0.1
mM (Fig. 4). In addition, Erk1/2 and
AKT, the key downstream molecules of c-Met that play important

W. Zhang et al. / European Journal of Medicinal Chemistry 80 (2014) 254e266
Table 1 (continued )
259
Table 1
c-Met enzymatic activity of the designed compounds.
Cmpd
Moiety D
Moiety B
R1 c-Met IC50 (nM)
11d
H
Not detected
11e
11f
18a
18b
21a
CH3 Not detected
Cmpd
Moiety D
Moiety B
R1 c-Met IC50 (nM)
7a
H
290.5 ꢃ 18.6
F
F
F
F
Not detected
427.0 ꢃ 6.1
81.0 ꢃ 7.6
39.0 ꢃ 0.2
7b
CH3 494.7 ꢃ 145.4
7c
F
373.2 ꢃ 28.5
168.7 ꢃ 26.4
7d
H
7e
CH3 165.5 ꢃ 30.1
21b
21c
F
F
20.0 ꢃ 1.0
7f
F
70.2 ꢃ 3.1
29.7% @ 10 mM
11a
11b
11c
H
100.8 ꢃ 15.7
22a
22b
F
F
26.9 ꢃ 3.9
49.6 ꢃ 3.0
CH3 1044 ꢃ 108.9
F
432.9 ꢃ 27.0
22c
F
0.7 ꢃ 0.1
(continued on next page)

260
W. Zhang et al. / European Journal of Medicinal Chemistry 80 (2014) 254e266
6.2.3. Ethyl 2-(N-40-fulorophenylsulfamoyl)acetate (3c)
Yellow solid; yield 65%; 1H NMR (CDCl3, 600 MHz)
Table 1 (continued )
d
7.33e7.31
Cmpd
Moiety D
Moiety B
R1 c-Met IC50 (nM)
(m, 2H, ArH), 7.09 (s, 1H, NH), 7.07e7.04 (m, 2H, ArH), 4.26 (q,
2H, CH2O), 3.91 (s, 2H, COCH2SO2), 1.31 (t, 3H, J ¼ 7.2 Hz,
OCH2CH3).
22d
F
F
F
0.9 ꢃ 0.1
1.7 ꢃ 0.4
6.3. General methods for preparation of cyclic sulfonamide 3def
A solution of 1-bromo-3-chloropropane (600
mL, 930 mg,
22e
6 mmol) in DMF (60 mL) was added during 1.5 h to a mixture of
sulfonamide 3aec (5 mmol) and potassium carbonate (2.07 g,
15 mmol) in DMF (60 mL) at 60 ꢀC. This reaction mixture was
stirred until the end of the reaction (checked by TLC). The reac-
tion mixture was then diluted with water (150 mL), acidified with
conc. HCl to pH ¼ 1, and extracted with dichloromethane
(3 ꢂ 50 mL). The organic phase was washed with 2% HCl
(3 ꢂ 10 mL), dried over sodium sulfate, and evaporated to dry-
ness. The product was recrystallized from a mixture of diethyl
ether and hexane.
BMS-777607
3.7 ꢃ 1.3
3.9 ꢃ 0.5 (lit.)
The IC50 values are shown as the means ꢃ SD (nM) from two separate experiments.
expressed in ppm relative to the solvent residual signal 7.26 in
¼ 0.00). Chemical shifts of the 13
C
6.3.1. Ethyl 2-phenyl-1,2-thiazinane-1,1-dioxide-6-carboxylate (3d)
CDCl3 or to tetramethylsilane (
d
Yellow solid; yield: 75%; 1H NMR (600 MHz, CDCl3)
d 7.41e7.30
NMR spectra are expressed in ppm relative to the solvent signal
(m, 4H, ArH), 7.30e7.24 (m, 1H, ArH), 4.35e4.19 (m, 2H, CH2O), 4.04
(dd, 1H, J ¼ 9.9, 4.1 Hz, CH), 4.02e3.92 (m, 1H, CHH), 3.77e3.67 (m,
1H, CHH), 2.65e2.54 (m, 1H, CHH), 2.54e2.46 (m, 1H, CHH), 2.15e
2.06 (m, 1H, CHH), 1.98e1.88 (m, 1H, CHH), 1.29 (t, 3H, J ¼ 7.1 Hz,
CH2CH3).
77.00 in CDCl3 or to tetramethylsilane (
noted. Electrospray (ESI) mass spectra were recorded on a Global Q-
TOF mass spectrometer.
d
¼ 0.00) unless otherwise
6.2. General methods for preparation of linear sulfonamide 3aec
Sulfonyl chloride 1 (33 mmol) in THF (10 mL) was added drop-
wise to a solution of aromatic amine 2 (33 mmol) and triethylamine
(4.4 mL, 35 mmol) in 100 mL THF at 0 ꢀC. Upon completion of the
addition, the reaction mixture was stirred at room temperature for
1 h before concentrated in vacuo. The residue was dissolved in
EtOAc (100 mL), washed with saturated brine (3 ꢂ 20 mL), dried
over Na2SO4, and concentrated in vacuo. The crude product was
purified by flash chromatography on silica gel to give compounds
3aec.
6.3.2. Ethyl 2-(p-tolyl)-1,2-thiazinane-1,1-dioxide-6-carboxylate
(3e)
Yellow solid; yield 74%; 1H NMR (600 MHz, CDCl3)
d 7.24e7.18
(m, 2H, ArH), 7.17e7.13 (m, 2H, ArH), 4.41e4.17 (m, 2H, CH2O), 4.03
(dd, 1H, J ¼ 10.1, 4.1 Hz, COCHSO2), 3.99e3.87 (m, 1H, CHH), 3.75e
3.59 (m,1H, CHH), 2.67e2.53 (m,1H, CHH), 2.53e2.40 (m,1H, CHH),
2.33 (s, 3H, CH3), 2.16e2.01 (m, 1H, CHH), 2.00e1.86 (m, 1H, CHH),
1.29 (t, 3H, J ¼ 7.1 Hz, CH2CH3).
6.3.3. Ethyl 2-(4-fluorophenyl)-1,2-thiazinane-1,1-dioxide-6-
carboxylate (3f)
6.2.1. Ethyl 2-(N-phenylsulfamoyl)acetate (3a)
Yellow oil; yield 65%; 1H NMR (CDCl3, 600 MHz)
d 7.31e7.38 (m,
Yellow solid; yield 77%; 1H NMR (600 MHz, CDCl3)
d 7.35e7.27
4H, ArH), 7.25e7.22 (m, 1H, ArH), 7.13 (s, 1H, NH), 4.26 (q, 2H,
CH2O), 3.94 (s, 2H, COCH2SO2), 1.30 (t, 3H, J ¼ 7.1 Hz, OCH2CH3).
(m, 2H, ArH), 7.08e6.99 (m, 2H, ArH), 4.35e4.17 (m, 2H, CH2O), 4.04
(dd, 1H, J ¼ 9.5, 4.2 Hz, COCHSO2), 3.94e3.86 (m, 1H, CHH), 3.71e
3.62 (m, 1H, CHH), 2.62e2.54 (m,1H, CHH), 2.54e2.47 (m, 1H, CHH),
2.20e2.04 (m, 1H, CHH), 1.98e1.83 (m, 1H, CHH).
6.2.2. Ethyl 2-(N-p-tolylsulfamoyl)acetate (3b)
Yellow solid; yield 72%; 1H NMR (CDCl3, 600 MHz)
d 7.21e7.20
(m, 2H, ArH), 7.16 (d, 2H, J ¼ 8.4 Hz, ArH), 6.96 (s, 1H, NH), 4.26 (q,
2H, CH2O), 3.91 (s, 2H, COCH2SO2), 2.33 (s, 3H, CH3), 1.31 (t, 3H,
J ¼ 7.1 Hz, OCH2CH3).
6.4. General methods for preparation of amide 6aef
Ethyl ester 3 (3 mmol) was treated with KOH (672 mg, 12 mmol)
in a mixed solvent of methanol (5 mL) and water (5 mL) for 3 h.
After most of the solvent was evaporated, the solution was acidified
to pH 1 with 1 M HCl and extracted with EtOAc (3 ꢂ 20 mL). The
organic extracts were combined and washed with brine (2 ꢂ 5 mL).
Evaporation of the solvent gave the corresponding acid, which was
used directly in the next step.
EDC$HCl (1.2 g, 6.25 mmol) was added to a suspension of the
carboxylic acid and the amine [15] (5, 705 mg, 2.5 mmol) in THF
(25 mL) at 0 ꢀC followed by DMAP (30 mg, 0.25 mmol). The reaction
mixture was warmed to room temperature and stirred overnight.
After diluted with EtOAc (150 mL), the whole mixture was washed
with 1 M HCl (3 ꢂ 10 mL), 5% NaHCO3 (3 ꢂ 10 mL), and brine
(3 ꢂ 10 mL), dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography to give corre-
sponding amides 6aef.
Fig. 3. Effect of the promising compounds on BF3/TPR-Met cell proliferation.

W. Zhang et al. / European Journal of Medicinal Chemistry 80 (2014) 254e266
261
Table 2
6.91 (d, 1H, J ¼ 5.5 Hz, ArH), 4.30 (dd,1H, J ¼ 10.9, 3.7 Hz, COCHSO2),
4.06e3.94 (m, 1H, CHH), 3.82e3.71 (m, 1H, CHH), 2.77e2.62 (m, 1H,
CHH), 2.54e2.42 (m, 1H, CHH), 2.17e2.05 (m, 2H, CH2); 13C NMR
Effects of 22d and 22e on cell proliferation (nM).
Cmpd
BaF3/TPR-Met
MKN45
(150 MHz, Acetone-d6)
d 162.9, 162.0, 153.7, 152.6, 148.9, 142.3,
142.2, 129.9, 129.8,127.9, 127.8, 127.7, 127.6, 124.5, 117.2, 112.2, 100.8,
66.0, 61.3, 60.5, 54.1, 36.2, 28.1, 24.0, 23.8, 14.4.
22d
22e
BMS777607
19.5 ꢃ 8.8
36.3 ꢃ 1.2
188.4 ꢃ 9.3
39.7 ꢃ 9.1
57.7 ꢃ 6.6
285.8 ꢃ 22.7
6.4.5. N-(4-((2-carbamoyl-3-chloropyridin-4-yl)oxy)-3-
fluorophenyl)-2-(p-tolyl)-1,2-thiazinane-6-carboxamide 1,1-dioxide
(6e)
The IC50 values are shown as the means ꢃ SD (nM) from two separate experiments.
White solid; yield 55%; 1H NMR (600 MHz, Acetone-d6)
d 9.73 (s,
1H, NH), 8.33 (d, 1H, J ¼ 5.6 Hz, ArH), 7.94 (dt, 2H, J ¼ 8.4, 0.9 Hz,
ArH), 7.72 (dt, 2H, J ¼ 8.4, 1.0 Hz, ArH), 7.55 (ddd, 1H, J ¼ 8.2, 6.9,
0.9 Hz, ArH), 7.51e7.47 (m, 1H, ArH), 7.43 (ddd, 1H, J ¼ 8.4, 6.9,
1.0 Hz, ArH), 7.37 (t, 1H, J ¼ 8.8 Hz, ArH), 7.30e7.26 (m, 2H, ArH),
7.24e7.18 (m, 2H, ArH), 6.99 (s, 1H, NH), 6.91 (dd, 1H, J ¼ 5.5, 1.1 Hz,
ArH), 4.28 (dd, 1H, J ¼ 10.9, 3.7 Hz, COCHSO2), 4.03e3.95 (m, 1H,
CHH), 3.70 (m,1H, CHH), 2.73e2.62 (m,1H, CHH), 2.53e2.44 (m,1H,
CHH), 2.33 (s, 3H, CH3), 2.12e2.06 (m, 2H, CH2); 13C NMR (150 MHz,
Acetone-d6)
d 163.0, 162.9, 155.3, 153.7, 152.6, 148.9, 138.2, 137.1,
129.9, 124.5, 117.0, 116.5, 112.2, 65.9, 65.9, 54.3, 36.1, 28.2, 23.7, 14.4.
Fig. 4. 22d suppresses c-Met phosphorylation and downstreams signaling in
MKN45 cells.
6.4.6. N-(4-((2-carbamoyl-3-chloropyridin-4-yl)oxy)-3-
fluorophenyl)-2-(4-fluorophenyl)-1,2-thiazinane-6-carboxamide
1,1-dioxide (6f)
White solid; yield 49%; 1H NMR (600 MHz, Acetone-d6)
d 9.73 (s,
6.4.1. 3-Chloro-4-(2-fluoro-4-(2-(N-phenylsulfamoyl)acetamido)
phenoxy)picolinamide (6a)
1H, NH), 8.34 (d,1H, J ¼ 5.5 Hz, ArH), 7.98e7.89 (m,1H, ArH), 7.65 (s,
1H, ArH), 7.53e7.47 (m,1H, ArH), 7.47e7.43 (m, 2H, ArH), 7.37 (t,1H,
J ¼ 8.9 Hz, ArH), 7.22e7.15 (m, 2H, ArH), 6.94 (s, 1H, NH), 6.91 (dd,
1H, J ¼ 5.5, 1.1 Hz, ArH), 4.32 (dd, 1H, J ¼ 10.6, 3.7 Hz, COCHSO2),
4.02e3.96 (m, 1H, CHH), 3.77e3.72 (m, 1H, CHH), 2.73e2.61 (m, 1H,
CHH), 2.54e2.43 (m, 1H, CHH), 2.17e2.07 (m, 2H, CH2); 13C NMR
Gray solid; yield 55%; 1H NMR (DMSO-d6, 600 MHz)
d 10.74 (s,
1H, NH), 10.13 (s, 1H, NH), 8.34 (d, 1H, J ¼ 5.5 Hz, ArH), 8.08 (s, 1H,
NH), 7.82 (dd, 1H, J ¼ 12.8, 2.3 Hz, ArH), 7.78 (s, 1H, NH), 7.45e7.34
(m, 4H, ArH), 7.30 (s, 1H, NH), 7.29 (d, 1H, J ¼ 7.4 Hz, ArH), 7.15e7.12
(m, 1H, ArH), 6.83 (d, 1H, J ¼ 5.0 Hz), 4.18 (s, 1H, COCH2SO2); 13C
(150 MHz, Acetone-d6) d 162.2, 161.2, 151.8, 148.1, 138.8, 137.0, 129.6,
129.5, 127.0, 126.8, 123.7, 116.3, 111.4, 65.1, 59.7, 53.4, 27.4, 23.1, 20.1.
NMR (DMSO-d6, 150 MHz)
d 167.1, 162.9, 161.0, 160.5, 154.8, 152.7,
149.4, 138.2, 135.9, 129.8, 124.8. 124.4, 121.2, 119.7, 116.9, 116.7, 111.3,
108.8, 58.0.
6.5. General methods for preparation of compounds 7aef
6.4.2. 3-Chloro-4-(2-fluoro-4-(2-(N-(p-tolyl)sulfamoyl)acetamido)
phenoxy)picolinamide (6b)
To amide 6 (0.2 mmol) in ethyl acetate (2 mL), acetonitrile
(2 mL), and water (1 mL) at 0 ꢀC was added iodobenzene diacetate
(82 mg, 0.26 mmol). After stirring at room temperature for 2 h,
saturated NaHCO3 (3 mL) was added, followed by 30 mL of ethyl
acetate. The mixture was filtered, and the filtrate was washed with
brine (3 ꢂ 5 mL), dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel to give
compounds 7aef.
White solid; yield 57%; 1H NMR (DMSO-d6, 600 MHz)
d 10.71 (s,
1H, NH), 9.95 (s, 1H, NH), 8.33 (d, 1H, J ¼ 6.1 Hz, ArH), 8.07 (s, 1H,
NH), 7.83 (dd, 1H, J ¼ 12.8, 1.9 Hz, ArH), 7.78 (s, 1H, NH), 7.44 (t-like,
1H, J ¼ 9.0, 8.7 Hz, ArH), 7.38 (d, 1H, J ¼ 8.7 Hz, ArH), 7.17 (m, 4H,
ArH), 6.83 (d, 1H, J ¼ 5.0 Hz), 4.11 (s, 1H, COCH2SO2), 2.26 (s, 1H,
CH3); 13C NMR (DMSO-d6, 150 MHz)
d 167.1, 161.1, 160.5, 154.8,
154.3, 152.7, 149.4, 138.4, 135.9, 135.5, 134.3, 130.1, 124.4, 121.9,
116.9, 116.7, 111.3, 108.8, 57.7, 20.9.
6.5.1. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-
2-(N-phenylsulfamoyl)acetamide (7a)
White solid; yield 67%; 1H NMR (600 MHz, Methanol-d4)
d 7.73
6.4.3. 3-Chloro-4-(2-fluoro-4-(2-(N-(4-fluorophenyl)sulfamoyl)
acetamido)phenoxy)picolinamide (6c)
(dd,1H, J ¼ 12.6, 2.5 Hz, ArH), 7.69 (d,1H, J ¼ 5.9 Hz, ArH), 7.39e7.23
White solid; yield 48%; 1H NMR (DMSO-d6, 600 MHz)
d 10.73 (s,
(m, 5H, ArH), 7.22e7.07 (m, 2H, ArH), 5.96 (dd, 1H, J ¼ 5.9, 0.9 Hz,
ArH); 13C NMR (150 MHz, Methanol-d4)
d 162.5, 162.1, 156.0, 154.4,
1H, NH), 10.11 (s, 1H, NH), 8.33 (d, 1H, J ¼ 5.5 Hz, ArH), 8.08 (s, 1H,
NH), 7.83 (dd, 1H, J ¼ 12.8, 1.9 Hz, ArH), 7.78 (s, 1H, NH), 7.45e7.36
(m, 2H, ArH), 7.33e7.31 (m, 2H, ArH), 7.23e7.19 (m, 2H, ArH), 6.83
(d, 1H, J ¼ 5.5 Hz), 4.13 (s, 1H, COCH2SO2); 13C NMR (DMSO-d6,
147.6, 147.5, 138.5, 138.4, 130.3, 126.2, 124.4, 122.9, 117.4, 110.2, 110.1,
102.1; MS (ESI pos ion) m/z: calcd for C19H16ClFN4O4S, 450.1; found,
450.9 (MþH).
150 MHz) d 167.1, 161.1, 160.5, 159.1, 154.8, 149.4, 138.3, 135.9, 134.3,
124.4, 116.9, 116.7, 116.5, 116.4, 111.3, 108.8, 57.8.
6.5.2. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-
2-(N-(p-tolyl)sulfamoyl)acetamide (7b)
6.4.4. N-(4-((2-carbamoyl-3-chloropyridin-4-yl)oxy)-3-
fluorophenyl)-2-phenyl-1,2-thiazinane-6-carboxamide 1,1-dioxide
(6d)
White solid; yield 71%; 1H NMR (600 MHz, Acetone-d6)
d 9.84 (s,
1H, NH), 8.76 (s, 1H, NH), 7.85 (d, 1H, J ¼ 12.8 Hz, ArH), 7.80 (d, 1H,
J ¼ 5.8 Hz, ArH), 7.39 (d, 2H, J ¼ 8.8 Hz, ArH), 7.34 (d, 2H, J ¼ 8.23 Hz,
ArH), 7.29 (t, 1H, J ¼ 8.8 Hz, ArH), 7.19 (d, 3H, J ¼ 8.0 Hz, ArH), 6.03
(d, 1H, J ¼ 5.5 Hz, ArH), 5.88 (s, 1H, NH), 5.87 (s, 1H, NH), 4.12 (s, 2H,
COCH2SO2), 2.31 (s, 3H, CH3); 13C NMR (150 MHz, Acetone-d6)
White solid; yield 43%; 1H NMR (600 MHz, Acetone-d6)
d 9.73 (s,
1H, NH), 8.34 (d, J ¼ 5.5 Hz, 1H, NH), 7.94 (dt, 1H, J ¼ 8.5, 1.0 Hz,
ArH), 7.72 (dt, 1H, J ¼ 8.3, 1.0 Hz, ArH), 7.58e7.53 (m, 1H, ArH), 7.49
(dt, 1H, J ¼ 8.9, 1.7 Hz, ArH), 7.47e7.36 (m, 5H, ArH), 6.99 (s, 1H, NH),
d
161.7, 161.1, 158.4, 155.5, 153.8, 148.1, 135.9, 135.8, 130.6, 124.3,

262
W. Zhang et al. / European Journal of Medicinal Chemistry 80 (2014) 254e266
123.4, 116.8, 116.7, 109.4, 109.3, 101.8, 57.3, 20.8; MS (ESI pos ion) m/
z: calcd for C20H18ClFN4O4S, 464.1; found, 465.1 (MþH).
in vacuo. The crude product was purified by recrystallization from
ethyl acetate and hexane.
6.6.1. 2-Chloro-N-phenylacetamide (8a)
6.5.3. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-
2-(N-(4-fluorophenyl)sulfamoyl)acetamide (7c)
Gray solid; yield 89%; 1H NMR (600 MHz, CDCl3)
d 8.30e8.22 (m,
White solid; yield 73%; 1H NMR (600 MHz, Methanol-d4)
d 7.75
1H, ArH), 7.57e7.50 (m, 2H, ArH), 7.36 (dd, 2H, J ¼ 8.5, 7.4 Hz, ArH),
7.21e7.14 (m, 1H, ArH), 4.18 (s, 2H, CH2).
(dd, 1H, J ¼ 12.6, 2.5 Hz, ArH), 7.69 (d, 1H, J ¼ 5.9 Hz, ArH), 7.41e7.34
(m, 2H, ArH), 7.31e7.24 (m, 1H, ArH), 7.18 (t, 1H, J ¼ 8.8 Hz, ArH),
7.09e7.02 (m, 2H, ArH), 5.96 (dd, 1H, J ¼ 5.9, 1.0 Hz, ArH); 13C NMR
6.6.2. 2-Chloro-N-(p-tolyl)acetamide (8b)
Gray solid; yield 93%; 1H NMR (600 MHz, CDCl3)
d 8.22 (s, 1H,
(150 MHz, Methanol-d4)
d 162.7, 162.5, 158.7, 156.0, 154.4, 147.4,
NH), 7.43e7.40 (m, 1H, ArH), 7.17e7.14 (m, 1H, ArH), 4.17 (s, 1H,
CH2), 2.33 (s, 3H, CH3).
138.5, 134.7, 125.9, 125.8, 124.5, 117.4, 116.9, 116.8, 110.2, 102.1; MS
(ESI pos ion) m/z: calcd for C19H15ClF2N4O4S, 468.0; found, 469.0
(MþH).
6.6.3. 2-Chloro-N-(4-fluorophenyl)acetamide (8c)
Gray solid; yield 95%; 1H NMR (600 MHz, CDCl3)
d 8.23 (s, 1H,
6.5.4. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-
2-phenyl-1,2-thiazinane-6-carboxamide 1,1-dioxide (7d)
NH), 7.53e7.49 (m, 2H, ArH), 7.07e7.03 (m, 2H, ArH), 4.19 (s, 1H,
CH2).
White solid; yield 72%; 1H NMR (600 MHz, CDCl3)
d 9.09 (s, 1H,
NH), 7.87e7.54 (m, 2H, ArH), 7.33e7.22 (m, 5H, ArH), 7.20 (s, 1H,
NH), 7.16e7.11 (m, 1H, ArH), 7.03 (t, 1H, J ¼ 8.6 Hz, ArH), 5.94 (dd,
1H, J ¼ 6.0, 1.0 Hz, ArH), 5.48 (s, 2H, NH2), 4.09 (dd, 1H, J ¼ 9.8,
4.0 Hz, COCHSO2), 3.96e3.85 (m,1H, CHH), 3.75e3.65 (m, 1H, CHH),
2.70e2.59 (m, 1H, CHH), 2.59e2.50 (m, 1H, CHH), 2.12e2.01 (m, 1H,
6.7. General methods for preparation of amide 10aec
Sulfonyl chloride 9 (0.6 mmol) was diluted with dry THF (2 mL)
and added to a solution of amine 5 (141 mg, 0.5 mmol) and DIPEA
(174 mL, 1 mmol) in dry THF (10 mL). The mixture was stirred for
another 1 h before concentrated in vacuo. The residue was re-
dissolved in ethyl acetate (50 mL) and washed with brine
(3 ꢂ 10 mL). After dried over Na2SO4 and concentrated in vacuo, the
residue was purified by column chromatography to give corre-
sponding amide 10aec.
CHH), 2.00e1.86 (m, 1H, CHH); 13C NMR (150 MHz, CDCl3)
d 162.0,
161.7,155.1,154.6,153.0,142.0,129.5,128.0,127.3,123.3,116.5,116.4,
109.8, 109.6, 103.2, 101.8, 64.7, 53.8, 27.4, 23.4; MS (ESI pos ion) m/z:
calcd for C22H20ClFN4O4S, 490.1; found, 490.9 (MþH).
6.5.5. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-
2-(p-tolyl)-1,2-thiazinane-6-carboxamide 1,1-dioxide (7e)
6.7.1. 3-Chloro-4-(2-fluoro-4-(2-oxo-2-(phenylamino)
ethylsulfonamido)phenoxy)picolinamide (10a)
White solid; yield 67%; 1H NMR (600 MHz, CDCl3)
d 9.14 (s, 1H,
NH), 7.72 (d, 1H, J ¼ 6.3 Hz, ArH), 7.70 (dd, 2H, J ¼ 12.0, 2.5 Hz, ArH),
7.24e7.19 (m, 4H, ArH), 7.17 (d, 2H, J ¼ 8.3 Hz, ArH), 7.09 (t, 1H,
J ¼ 8.6 Hz, ArH), 6.01 (dd, 1H, J ¼ 6.3, 1.0 Hz, ArH), 5.54 (s, 2H, NH2),
4.16e4.10 (m, 1H, COCHSO2), 3.97e3.88 (m, 1H, CHH), 3.78e3.67
(m,1H, CHH), 2.75e2.65 (m,1H, CHH), 2.65e2.55 (m,1H, CHH), 2.33
(s, 3H, CH3), 2.13e2.06 (m, 1H, CHH), 2.03e1.94 (m, 1H, CHH); 13C
Yellow solid; yield 65%; 1H NMR (600 MHz, DMSO-d6)
d 10.49 (s,
1H, NH), 10.36 (s, 1H, NH), 8.34 (d, 1H, J ¼ 5.6 Hz, ArH), 8.06 (d, 1H,
J ¼ 2.3 Hz, ArH), 7.76 (s, 1H, NH), 7.58e7.54 (m, 2H, ArH), 7.42 (t, 1H,
J ¼ 9.0 Hz, ArH), 7.36e7.29 (m, 3H, ArH), 7.19 (dd, 1H, J ¼ 8.5, 2.5 Hz,
ArH), 7.10 (t,1H, J ¼ 7.3 Hz, ArH), 6.79 (d,1H, J ¼ 5.6 Hz, ArH), 4.30 (s,
2H, CH2); 13C NMR (150 MHz, DMSO-d6)
d 167.6, 166.5, 160.0, 159.8,
NMR (150 MHz, CDCl3) d 161.6, 161.3, 155.8, 154.8, 153.1, 144.1, 138.3,
154.2,154.0,152.4,148.7,138.3,137.3,128.9,124.0, 119.2,117.2, 116.4,
110.6, 109.1, 109.0, 57.7.
137.6, 137.1, 136.5, 130.1, 127.1, 123.3, 116.5, 116.4, 112.7, 109.8, 109.7,
102.9, 101.9, 64.5, 53.8, 27.3, 23.4, 21.1; MS (ESI pos ion) m/z: calcd
for C23H22ClFN4O4S, 504.1; found, 504.9 (MþH).
6.7.2. 3-Chloro-4-(2-fluoro-4-(2-oxo-2-(p-tolylamino)
ethylsulfonamido)phenoxy)picolinamide (10b)
Yellow solid; yield 59%; 1H NMR (600 MHz, DMSO-d6)
d 10.47 (s,
6.5.6. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-
2-(4-fluorophenyl)-1,2-thiazinane-6-carboxamide 1,1-dioxide (7f)
1H, NH), 10.28 (s, 1H, NH), 8.33 (d, J ¼ 5.6 Hz, 1H, ArH), 8.07 (s, 1H,
NH), 7.76 (s, 1H, NH), 7.47e7.39 (m, 3H, ArH), 7.32 (dd, 1H, J ¼ 12.2,
2.5 Hz, ArH), 7.21e7.16 (m, 1H, ArH), 7.13 (d, J ¼ 8.3 Hz, 2H, ArH),
6.79 (d, 1H, J ¼ 5.6 Hz, ArH), 4.27 (s, 2H, SO2CH2CO), 2.25 (s, 3H,
White solid; yield 77%; 1H NMR (600 MHz, CDCl3)
d 9.12 (s, 1H,
NH), 7.73 (d, 1H, J ¼ 6.0 Hz, ArH), 7.70 (dd, 1H, J ¼ 11.9, 2.5 Hz, ArH),
7.34e7.29 (m, 2H, ArH), 7.21e7.17 (m, 1H, ArH), 7.09 (t, 1H,
J ¼ 8.6 Hz, ArH), 7.07e7.03 (m, 2H, ArH), 6.00 (dd, 1H, J ¼ 6.0, 1.0 Hz,
ArH), 5.41 (s, 2H, NH2), 4.15 (dd,1H, J ¼ 9.6, 4.0 Hz, COCHSO2), 3.94e
3.86 (m,1H, CHH), 3.74e3.68 (m,1H, CHH), 2.75e2.65 (m, 1H, CHH),
2.65e2.56 (m, 1H, CHH), 2.20e2.08 (m, 1H, CHH), 2.02e1.90 (m, 1H,
CH3); 13C NMR (150 MHz, DMSO-d6)
d 166.6, 159.9, 159.6, 154.2,
154.0, 152.4, 149.4, 148.7, 137.3, 135.9, 133.1, 129.3, 124.0, 120.4,
119.3, 117.2, 116.4, 110.7, 109.1, 109.0, 105.9, 57.6, 20.5.
CHH); 13C NMR (150 MHz, CDCl3)
d 162.8, 161.3, 161.2, 161.0, 156.0,
6.7.3. 3-Chloro-4-(2-fluoro-4-(2-((4-fluorophenyl)amino)-2-
oxoethylsulfonamido)phenoxy)picolinamide (10c)
154.8, 153.1, 144.8, 136.3, 135.9, 129.2, 123.3, 116.4, 116.3, 116.2, 116.1,
109.6, 102.8, 101.9, 64.5, 60.5, 53.9, 27.3, 23.3, 14.2; MS (ESI pos ion)
m/z: calcd for C23H22ClF2N4O4S, 508.1; found, 508.9 (MþH).
Yellow solid; yield 61%; 1H NMR (600 MHz, DMSO-d6)
d 10.50 (s,
1H, NH), 10.44 (s, 1H, NH), 8.34 (d, 1H, J ¼ 5.6 Hz, ArH), 8.06 (s, 1H,
NH), 7.78e7.74 (m, 1H, ArH), 7.61e7.56 (m, 2H, ArH), 7.42 (t, 1H,
J ¼ 9.0 Hz, ArH), 7.31 (dd,1H, J ¼ 12.2, 2.5 Hz, ArH), 7.21e7.15 (m, 3H,
ArH), 6.79 (d, 1H, J ¼ 5.5 Hz, ArH), 4.28 (s, 2H, SO2CH2CO); 13C NMR
6.6. General methods for preparation of compounds 8aec
Triethylamine (14 mL) was added to a solution of the aromatic
amine (2, 50 mmol) in dry DCM (100 mL) at 0 ꢀC. The mixture was
stirred at room temperature for another 5 h after the addition of 2-
chloroacetyl chloride (5.65 mL) at 0 ꢀC. Ethyl acetate (150 mL) was
added; the whole organic layer was washed with 1 M HCl
(3 ꢂ 30 mL), saturated NaHCO3 (2 ꢂ 20 mL), and brine (2 ꢂ 20 mL).
The organic solvent was dried over Na2SO4 and then concentrated
(150 MHz, DMSO-d6) d 166.5, 166.4, 159.9, 159.8, 159.2, 157.6, 157.3,
154.2, 154.0, 152.4, 148.7, 135.7, 134.7, 124.0, 121.3, 121.1, 117.2, 116.4,
115.6, 115.4, 110.6, 109.1, 108.9, 57.6.
6.8. General methods for preparation of cyclic sulfonamide 10def
Similar to the preparation method of 3def.

W. Zhang et al. / European Journal of Medicinal Chemistry 80 (2014) 254e266
263
6.8.1. 2-(4-((2-Carbamoyl-3-chloropyridin-4-yl)oxy)-3-
fluorophenyl)-N-phenyl-1,2-thiazinane-6-carboxamide 1,1-dioxide
(10d)
J ¼ 8.6, 2.0 Hz, ArH), 7.44 (dd, 1H, J ¼ 12.1, 2.5 Hz, ArH), 7.36e7.32
(m,1H, ArH), 7.30 (t,1H, J ¼ 8.6 Hz, ArH), 7.14 (d, 2H, J ¼ 8.3 Hz, ArH),
6.02 (dd, 1H, J ¼ 5.7, 1.0 Hz, ArH), 5.87 (s, 2H, NH2), 4.23 (s, 2H,
SO2CH2CO), 2.28 (s, 3H, CH3); 13C NMR (150 MHz, Acetone-d6)
From 10a; white solid; yield 52%; 1H NMR (600 MHz, Acetone-
d6)
d
9.39 (s, 1H, NH), 8.38 (d, 1H, J ¼ 5.3 Hz, ArH), 7.69e7.65 (m, 2H,
d 160.9, 160.8, 158.3, 155.6, 154.0, 148.0, 147.7, 138.9, 138.8, 137.4,
ArH), 7.48 (dd, 1H, J ¼ 11.8, 2.5 Hz, ArH), 7.44 (t, 1H, J ¼ 8.8 Hz, ArH),
7.40e7.37 (m, 1H, ArH), 7.35e7.31 (m, 2H, ArH), 7.13e7.09 (m, 1H,
ArH), 6.95 (s,1H, NH), 6.89 (dd,1H, J ¼ 5.4,1.1 Hz, ArH), 4.39 (dd,1H,
J ¼ 10.3, 3.9 Hz, CH), 4.09e4.02 (m, 1H, CHH), 3.92e3.86 (m, 1H,
CHH), 2.73e2.62 (m, 1H, CHH), 2.54e2.46 (m, 1H, CHH), 2.23e2.13
(m, 1H, CHH), 2.13e2.07 (m, 1H, CHH); 13C NMR (150 MHz, Acetone-
137.3, 136.8, 134.5, 130.0, 124.5, 120.3, 120.2, 119.1, 111.4, 111.3, 101.8,
57.6, 20.8; MS (ESI pos ion) m/z: calcd for C20H18ClFN4O4S, 464.1;
found, 465.1 (MþH).
6.9.3. 2-(N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-
fluorophenyl)sulfamoyl)-N-(4-fluorophenyl)acetamide (11c)
From 10c; white solid; yield 68%; 1H NMR (600 MHz, Acetone-
d6) d 162.2, 161.6, 154.9, 153.3, 152.7, 148.9, 140.9, 139.9, 139.4, 129.6,
125.0, 124.7, 124.5, 123.8, 120.4, 120.3, 116.8, 116.6, 112.6, 66.0, 54.1,
28.3, 23.4.
d6)
d
9.62 (s, 1H, NH), 9.04 (s, 1H, NH), 7.79 (d, 1H, J ¼ 5.5 Hz, ArH),
7.68e7.62 (m, 2H, ArH), 7.44 (dd, 1H, J ¼ 12.0, 2.4 Hz, ArH), 7.36e
7.29 (m, 2H, ArH), 7.14e7.08 (m, 2H, ArH), 6.02 (dd, 1H, J ¼ 5.6,
0.9 Hz, ArH), 5.85 (s, 2H, NH2), 4.24 (s, 2H, CH2); 13C NMR (150 MHz,
6.8.2. 2-(4-((2-Carbamoyl-3-chloropyridin-4-yl)oxy)-3-
fluorophenyl)-N-(p-tolyl)-1,2-thiazinane-6-carboxamide 1,1-
dioxide (10e)
Acetone-d6)
d 160.9, 160.8, 158.2, 155.5, 153.9, 147.9, 147.7, 138.8,
138.7, 137.3, 137.2, 135.5, 124.4, 122.2, 122.1, 122.0, 119.0, 118.9, 116.1,
115.9, 111.3, 111.1, 102.1, 101.7, 57.6; MS (ESI pos ion) m/z: calcd for
From 10b; white solid; yield 59%; 1H NMR (600 MHz, Acetone-
d6)
d
9.29 (s, 1H, NH), 8.37 (d, 1H, J ¼ 5.4 Hz, ArH), 7.65 (s, 1H, NH),
C
19H15ClF2N4O4S, 468.0; found, 469.0 (MþH).
7.55e7.52 (m, 2H, ArH), 7.47 (dd, 1H, J ¼ 11.8, 2.6 Hz, ArH), 7.43 (t,
1H, J ¼ 8.8 Hz, ArH), 7.39e7.36 (m, 1H, ArH), 7.16e7.12 (m, 2H, ArH),
6.96 (s, 1H, NH), 6.89 (dd, 1H, J ¼ 5.5, 1.1 Hz, ArH), 4.36 (dd, 1H,
J ¼ 10.2, 3.8 Hz, CH), 4.08e4.00 (m, 1H, CHH), 3.92e3.85 (m, 1H,
CHH), 2.72e2.63 (m, 1H, CHH), 2.52e2.46 (m, 1H, CHH), 2.28 (s, 3H,
CH3), 2.20e2.13 (m, 1H, CHH), 2.12e2.06 (m, 1H, CHH); 13C NMR
(150 MHz, Acetone-d6)
139.2, 136.1, 133.6, 129.2, 123.8, 123.1, 119.7, 119.6, 115.9, 111.8, 104.3,
100.0, 65.2, 53.3, 27.5, 22.6, 20.0.
6.9.4. 2-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-
N-phenyl-1,2-thiazinane-6-carboxamide 1,1-dioxide (11d)
From 10d; white solid; yield 66%; 1H NMR (600 MHz, CDCl3)
d
8.79 (s, 1H, NH), 7.75 (d, 1H, J ¼ 6.0 Hz, ArH), 7.55e7.47 (m, 2H,
ArH), 7.31 (t, 2H, J ¼ 7.9 Hz, ArH), 7.25 (dd, 1H, J ¼ 11.6 Hz, ArH),
7.20e7.10 (m, 3H, ArH), 6.01 (d, 1H, J ¼ 5.9 Hz, ArH), 5.47 (s, 2H,
NH2), 4.15 (dd, 1H, J ¼ 9.2, 4.0 Hz, CH), 3.97e3.86 (m, 1H, CHH),
3.85e3.71 (m, 1H, CHH), 2.76e2.67 (m, 1H, CHH), 2.67e2.58 (m, 1H,
CHH), 2.23e2.13 (m, 1H, CHH), 2.02e1.91 (m, 1H, CHH); 13C NMR
d 161.2, 160.8, 152.5, 152.0, 148.2, 140.2,
6.8.3. 2-(4-((2-Carbamoyl-3-chloropyridin-4-yl)oxy)-3-
fluorophenyl)-N-(4-fluorophenyl)-1,2-thiazinane-6-carboxamide
1,1-dioxide (10f)
(150 MHz, CDCl3) d 160.7, 160.5, 156.3, 154.5, 152.9, 145.1, 140.5,
138.4,138.3,137.2,129.1,125.2,123.6,123.5,123.1,120.3,116.6,116.5,
103.3, 102.3, 100.0, 64.7, 53.7, 29.8, 27.4, 23.2, 22.8; MS (ESI pos ion)
m/z: calcd for C22H20ClFN4O4S, 490.1; found, 490.9 (MþH).
From 10c; white solid; yield 54%; 1H NMR (600 MHz, DMSO-d6)
d
10.40 (s, 1H, NH), 8.39 (d, 1H, J ¼ 5.5 Hz, ArH), 8.06e8.04 (m, 1H,
ArH), 7.95 (s, 1H, NH), 7.76 (s, 1H, NH), 7.64e7.60 (m, 2H, ArH), 7.56
(dd, 1H, J ¼ 11.8, 2.6 Hz, ArH), 7.47 (t, 1H, J ¼ 9.0 Hz, ArH), 7.35 (ddd,
1H, J ¼ 8.8, 2.6, 1.2 Hz, ArH), 7.26e7.15 (m, 2H, ArH), 6.87 (dd, 1H,
J ¼ 5.5, 0.9 Hz, ArH), 4.33 (dd,1H, J ¼ 10.7, 3.8 Hz, CH), 3.99e3.91 (m,
1H, CHH), 3.83e3.76 (m, 1H, CHH), 2.55e2.47 (m, 1H, CHH), 2.40e
2.33 (m, 1H, CHH), 2.01e1.93 (m, 2H, CHH); 13C NMR (150 MHz,
6.9.5. 2-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-
N-(p-tolyl)-1,2-thiazinane-6-carboxamide 1,1-dioxide (11e)
From 10e; white solid; yield 58%; 1H NMR (600 MHz, Acetone-
d6)
d
9.28 (s, 1H, NH), 7.82 (d, 1H, J ¼ 5.6 Hz, ArH), 7.58e7.48 (m, 2H,
ArH), 7.45e7.37 (m, 1H, ArH), 7.32 (d, 2H, J ¼ 5.6 Hz, ArH), 7.13 (d,
2H, J ¼ 8.2 Hz, ArH), 6.04 (d, 2H, J ¼ 5.8 Hz, ArH), 5.91 (d, 1H,
J ¼ 8.7 Hz, ArH), 4.34 (dd, 1H, J ¼ 10.3, 3.8 Hz, CH), 4.10e3.97 (m, 1H,
CHH), 3.92e3.80 (m, 1H, CHH), 2.72e2.60 (m, 1H, CHH), 2.53e2.43
(m, 1H, CHH), 2.28 (s, 3H, CH3), 2.18e2.12 (m, 1H, CHH), 2.12e2.06
(m, 1H, CHH); MS (ESI pos ion) m/z: calcd for C23H22ClFN4O4S,
504.1; found, 504.9 (MþH).
DMSO-d6) d 167.0, 162.8, 161.9, 160.1, 159.7, 158.1, 154.0, 152.4, 149.4,
140.1, 139.0, 135.3, 124.3, 123.6, 121.8, 121.7, 117.3, 116.2, 116.1, 115.9,
111.7, 65.3, 56.3, 53.6, 36.3, 31.3, 30.1, 27.8, 22.6.
6.9. General method for preparation of 11aef
Similar to the preparation of 7aef.
6.9.6. 2-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-
N-(4-fluorophenyl)-1,2-thiazinane-6-carboxamide 1,1-dioxide (11f)
From 10f; white solid; yield 68%; 1H NMR (600 MHz, Acetone-
6.9.1. 2-(N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-
fluorophenyl)sulfamoyl)-N-phenylacetamide (11a)
d6)
d
9.46 (s, 1H, NH), 7.82 (d, 1H, J ¼ 5.7 Hz, ArH), 7.71e7.66 (m, 2H,
From 10a; white solid; yield 72%; 1H NMR (600 MHz, Acetone-
ArH), 7.45e7.40 (m, 1H, ArH), 7.34e7.29 (m, 2H, ArH), 7.13e7.08 (m,
2H, ArH), 6.04 (dd, 1H, J ¼ 5.7, 0.9 Hz, ArH), 5.90 (s, 2H, NH2), 4.35
(dd,1H, J ¼ 10.4, 3.8 Hz, CH), 4.07e4.00 (m, 1H, CHH), 3.88e3.83 (m,
1H, CHH), 2.71e2.63 (m, 1H, CHH), 2.53e2.45 (m, 1H, CHH), 2.19e
2.12 (m, 1H, CHH), 2.08e2.06 (m, 1H, CHH); 13C NMR (150 MHz,
d6)
d
9.58 (s, 1H, NH), 9.19 (s, 1H, NH), 7.79 (d, J ¼ 5.7 Hz, 1H, ArH),
7.64e7.60 (m, 2H, ArH), 7.45 (dd, 1H, J ¼ 12.0, 2.5 Hz, ArH), 7.37e
7.29 (m, 4H, ArH), 7.12 (tt, 1H, J ¼ 7.4, 1.1 Hz, ArH), 6.02 (dd, 1H,
J ¼ 5.8, 1.0 Hz, ArH), 5.86 (s, 2H, NH2), 4.25 (s, 2H, SO2CH2CO); 13C
NMR (150 MHz, Acetone-d6)
d
161.0, 160.9, 158.4, 155.7, 154.0, 148.3,
Acetone-d6) d 162.2, 160.8, 158.5, 155.1, 148.2, 140.9, 140.8, 140.3,
148.1, 139.3, 139.0, 138.9, 137.5, 137.3, 129.7, 125.1, 124.5, 120.3,119.2,
140.2, 135.7, 124.4, 123.5,122.4, 122.3, 122.2, 116.7, 116.5, 116.2, 116.1,
119.1, 111.5, 111.3, 101.9, 57.8; MS (ESI pos ion) m/z: calcd for
102.3, 100.8, 66.0, 54.2, 28.3, 23.5; MS (ESI pos ion) m/z: calcd for
C
19H16ClFN4O4S, 450.1; found, 450.9 (MþH).
C23H22ClFN4O4S, 504.1; found, 504.9 (MþH).
6.9.2. 2-(N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-
fluorophenyl)sulfamoyl)-N-(p-tolyl)acetamide (11b)
6.10. Preparation of 1-(4-fluorophenyl)piperidin-2-one (14)
From 10b; white solid; yield 62%; 1H NMR (600 MHz, Acetone-
1-Fluoro-4-iodobenzene (2.22 g, 10 mmol) and piperidin-2-one
(1.2 g, 12 mmol) were added to 30 mL of dry DMF, followed by the
d6)
d
9.54 (s, 1H, NH), 7.78 (d, 1H, J ¼ 5.7 Hz, ArH), 7.50 (dd, 2H,

264
W. Zhang et al. / European Journal of Medicinal Chemistry 80 (2014) 254e266
addition of K3PO4 (6.36 g, 30 mmol) and CuI (190 mg, 0.1 mmol).
The mixture solution was heated to 100 ꢀC for 12 h, before filtered
through celite. After washed with ethyl acetate (3 ꢂ 10 mL), the
combined organic phase was concentrated and the residue was
purified by column go give 1.73 g (90%) of compound 14 as yellow
6.14.1. 3-Chloro-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-
oxopiperidine-3-carboxamido)phenoxy)picolinamide (17a)
From 16a; white solid; yield 76%; 1H NMR (600 MHz, DMSO-d6)
d
10.56 (s, 1H, NH), 8.33 (d,1H, J ¼ 5.5 Hz, ArH), 8.07 (s, 1H, NH), 7.91
(dd, 1H, J ¼ 12.9, 2.4 Hz, ArH), 7.77 (s, 1H, NH), 7.44 (dd, 1H, J ¼ 8.9,
2.4 Hz, ArH), 7.41 (t, 1H, J ¼ 8.8 Hz, ArH), 7.36e7.32 (m, 2H, ArH),
7.26e7.20 (m, 2H, ArH), 6.84 (dd, 1H, J ¼ 5.5, 1.1 Hz, ArH), 3.76e3.68
(m, 1H, CH), 3.65e3.57 (m, 2H, CH2), 2.21e2.13 (m, 2H, CH2), 2.12e
2.04 (m, 1H, CHH), 1.96e1.87 (m, 1H, CHH); 13C NMR (150 MHz,
solid. 1H NMR (600 MHz, CDCl3)
d
7.20 (dd, 2H, J ¼ 8.5, 5.0 Hz, ArH),
7.06 (t, 2H, J ¼ 8.4 Hz, ArH), 3.60 (t, 2H, J ¼ 5.4 Hz, NCH2), 2.54 (t, 2H,
J ¼ 6.2 Hz, COCH2), 2.01e1.84 (m, 4H, CH2CH2); 13C NMR (150 MHz,
CDCl3)
21.5.
d 170.2, 161.9, 160.2, 139.3, 128.0, 127.9, 115.9, 51.9, 32.8, 23.5,
DMSO-d6)
d 169.3, 166.5, 160.9, 160.0, 159.3, 154.2, 153.8, 152.2,
148.7, 139.4, 138.5, 138.4, 134.8, 134.7, 128.3, 128.2, 123.7, 116.3,
115.9,115.6,115.4,110.6,107.9,107.8, 54.9, 51.2, 50.5, 48.6, 24.8, 21.2;
MS (ESI pos ion) m/z: calcd for C24H19ClF2N4O4, 500.1; found, 501.1
(MþH).
6.11. Preparation of isobutyl 1-(4-fluorophenyl)-2-oxopiperidine-3-
carboxylate (15)
Piperidone (14, 386 mg, 2 mmol) was dissolved in 20 mL of dry
THF and cooled to ꢁ78 ꢀC. After the addition of tBuLi (1.4 mL, 1.6 M
6.14.2. 3-Chloro-4-(4-(3-chloro-1-(4-fluorophenyl)-2-
oxopiperidine-3-carboxamido)-2-fluorophenoxy)picolinamide
(17b)
in THF, 2.2 mmol) and stirred at this temperature for 4 h, 400 mL
(2 mmol) of isobutyl chlorofomate was added. 10 min later, the
reaction was quenched by 2 mL of saturated NH4Cl. The mixture
was diluted with water (20 mL) and extracted with EtOAc
(3 ꢂ 20 mL). The combined organic layer was washed with brine,
dried over Na2SO4, and concentrated in vacuo. The residue was
purified by column to give compound 15 (480 mg, 82%) as yellow
From 16b; white solid; yield 68%; 1H NMR (600 MHz, CDCl3)
d
10.11 (s, 1H, NH), 8.24 (d, 1H, J ¼ 5.5 Hz, ArH), 7.80 (dd, 1H, J ¼ 11.9,
2.5 Hz, ArH), 7.54 (d, 1H, J ¼ 3.9 Hz, ArH), 7.33e7.22 (m, 3H, ArH),
7.18e7.11 (m, 3H, NH), 6.68 (dd, 1H, J ¼ 5.5, 1.1 Hz, ArH), 6.15 (d, 1H,
J ¼ 3.4 Hz, ArH), 3.85e3.78 (m, 1H, CHH), 3.73e3.68 (m, 1H, CHH),
2.96e2.87 (m, 1H, CHH), 2.65e2.56 (m, 1H, CHH), 2.45e2.34 (m, 1H,
wax. 1H NMR (600 MHz, CDCl3)
d 7.25e7.20 (m, 2H, ArH), 7.09e7.03
CHH), 2.17e2.07 (m, 1H, CHH); 13C NMR (150 MHz, CDCl3)
d 166.8,
(m, 2H, ArH), 3.99 (dd, 1H, J ¼ 10.6, 6.7 Hz, CH), 3.83 (d, 1H,
J ¼ 6.7 Hz, CHH), 3.70e3.61 (m, 1H, CHH), 3.58 (t,1H, J ¼ 6.9 Hz, CH),
2.32e2.24 (m, 1H, CHH), 2.23e2.16 (m, 1H, CHH), 2.12e2.04 (m, 1H,
CHH), 2.02e1.87 (m, 2H, CH, CHH), 0.94 (d, 6H, J ¼ 6.6 Hz, CH3 ꢂ 2);
166.0, 164.9, 162.6, 161.8, 160.9, 154.7, 153.0, 148.3, 147.0, 137.9,
136.9, 136.8, 136.7, 127.9, 127.8, 123.4, 121.2, 116.7, 116.6, 116.5, 111.7,
109.8, 109.6, 64.4, 52.6, 33.8, 19.4; MS (ESI pos ion) m/z: calcd for
C24H18Cl2F2N4O4, 534.1; found, 535.1 (MþH), 537.1 (MþHþ2).
13C NMR (150 MHz, CDCl3)
d 171.0, 166.3, 162.1, 160.4, 138.8, 127.9,
127.9, 116.2, 116.0, 100.0, 71.5, 51.6, 49.6, 27.8, 25.3, 21.4, 19.1.
6.15. Preparation of 18a and 18b
6.12. Preparation of 1-(4-fluorophenyl)-2-oxopiperidine-3-
carboxylic acid (16a)
The procedure is very similar to the preparation of 11.
6.15.1. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-
1-(4-fluorophenyl)-2-oxopiperidine-3-carboxamide (18a)
To a solution of 15 (217 mg, 0.74 mmol) in THF/MeOH/H2O (1/1/
1, 3 mL in total) at 0 ꢀC was added LiOH monohydrate (94 mg,
2.2 mmol). The reaction mixture was warmed to room temperature
and stirred for 5 h. The solution was acidified to pH 1 with 1 M HCl
and extracted with EtOAc (3 ꢂ 20 mL). The organic extracts were
combined and washed with brine (2 ꢂ 5 mL). Evaporation of the
solvent gave the corresponding acid 16a (152 mg, 87%) as white
From 17a; white solid; yield 72%; 1H NMR (600 MHz, CDCl3)
d
10.00 (s, 1H, NH), 7.71 (dd, 1H, J ¼ 12.6, 2.5 Hz, ArH), 7.24e7.18 (m,
3H, ArH), 7.17e7.10 (m, 3H, ArH), 7.02 (dt, 1H, J ¼ 9.0, 1.8 Hz, ArH),
6.62 (t, 1H, J ¼ 8.9 Hz, ArH), 5.01 (s, 2H, NH2), 3.65 (dq, 2H, J ¼ 7.2,
4.3, 3.4 Hz, NCH2), 3.54 (t, J ¼ 6.3 Hz, 1H, CH), 2.59e2.49 (m, 1H,
CHH), 2.21e2.15 (m, 1H, CHH), 2.10e2.05 (m, 1H, CHH), 2.04e1.98
(m, 1H, CHH); 13C NMR (150 MHz, CDCl3) 169.4, 165.7, 162.5, 160.9,
155.6, 154.7, 151.1, 146.5, 139.9, 138.5, 134.5, 134.4, 128.3, 128.2,
123.3, 116.9, 116.8, 116.7, 116.6, 116.5, 115.3, 115.2, 109.4, 109.2, 108.9,
52.8, 47.6, 47.5, 29.8, 22.9, 21.8; MS (ESI pos ion) m/z: calcd for
solid. 1H NMR (600 MHz, DMSO-d6)
d 12.61 (s, 1H, OH), 7.33e7.28
(m, 1H, ArH), 7.25e7.19 (m, 1H, ArH), 3.69e3.55 (m, 2H, NCH2), 3.43
(dd, 1H, J ¼ 8.2, 6.5 Hz, CH), 2.16e2.10 (m, 1H, CHH), 2.08e2.02 (m,
1H, CHH), 1.98e1.91 (m, 1H, CHH), 1.91e1.83 (m, 1H, CHH).
C23H19ClF2N4O3, 472.1; found, 473.1 (MþH).
6.13. Preparation of 3-bromo-1-(4-fluorophenyl)-2-oxopiperidine-
3-carboxylic acid (16b)
6.15.2. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-
3-chloro-1-(4-fluorophenyl)-2-oxopiperidine-3-carboxamide (18b)
From 17b; white solid; yield 76%; 1H NMR (600 MHz, CDCl3)
To a solution of acid 16a (220 mg, 0.93 mmol) in Et2O (5 mL) was
d
10.02 (s,1H, NH), 7.77 (d,1H, J ¼ 5.8 Hz, ArH), 7.74 (dd, 1H, J ¼ 12.0,
added liquid Br2 (48 m
L, 0.93 mmol) at 0 ꢀC. The reaction mixture
2.5 Hz, ArH), 7.26e7.23 (m, 2H, ArH), 7.23e7.20 (m, 1H, ArH), 7.16e
7.11 (m, 3H, ArH), 5.99 (dd,1H, J ¼ 5.8,1.0 Hz, ArH), 5.04 (s, 2H, NH2),
3.84e3.74 (m, 1H, CHH), 3.74e3.66 (m, 1H, CHH), 2.94e2.82 (m, 1H,
CHH), 2.63e2.57 (m, 1H, CHH), 2.43e2.34 (m, 1H, CHH), 2.14e2.09
was stirred for 2 h, before concentrated in vacuo. The residue was
purified by column, giving compound 16b (265 mg, 91%) as white
solid. 1H NMR (600 MHz, Acetone-d6)
d 13.03 (s, 1H, OH), 7.44e7.40
(m, 2H, ArH), 7.25e7.20 (m, 2H, ArH), 4.04 (td, 1H, J ¼ 12.1, 4.6 Hz,
NCHH), 3.82 (ddt, 1H, J ¼ 13.0, 6.3, 2.4 Hz, NCHH), 2.77e2.69 (m, 1H,
CHH), 2.62e2.56 (m, 1H, CHH), 2.53e2.43 (m, 1H, CHH), 2.19e2.12
(m, 1H, CHH); 13C NMR (150 MHz, CDCl3)
d 166.9, 164.8, 162.6, 161.0,
160.5, 156.6, 155.0, 153.3, 148.6, 147.8, 146.7, 137.9, 136.2, 127.8,
123.4, 116.7, 116.6, 116.2, 109.6, 109.4, 102.6, 102.1, 91.8, 64.2, 52.7,
33.8, 19.5; MS (ESI pos ion) m/z: calcd for C23H18Cl2F2N4O3, 506.1;
found, 507.1 (MþH), 509.1 (MþHþ2).
(m, 1H, CHH); 13C NMR (150 MHz, Acetone-d6)
d 166.4, 162.5, 160.9,
140.6, 140.4, 129.0, 128.9, 116.2, 52.1, 32.3, 20.4.
6.14. Preparation of 17a and 17b
6.16. Preparation of fragments 19aeb and 20aec
The procedure is very similar to the preparation of 6.
Following the known procedure [15,18,19].

W. Zhang et al. / European Journal of Medicinal Chemistry 80 (2014) 254e266
265
6.17. Preparation of N-(4-((2-aminopyrimidin-4-yl)oxy)-3-
fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-
carboxamide (21a)
6.18.3. N-(3-fluoro-4-((2-((4-methoxybenzyl)amino)pyrimidin-4-
yl)oxy)phenyl)-1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-
dihydropyridine-3-carboxamide (23)
From 19b and 20a; yellow solid; yield 56%. Used directly for the
To the suspension of carboxylic acid 19a (27 mg, 0.11 mmol)
in dry toluene (5 mL) was added sulfuryl dichloride (0.5 mL). The
mixture was stirred for 3 h before concentrated in vacuo. The
residue was redissolved in 5 mL of dry toluene and concentrated
again. The resulting yellow solid was then dissolved in 5 mL of
dry THF and the solution was cooled to 0 ꢀC. Compound 20a
next step without further structure characterization.
6.18.4. N-(4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-3-
fluorophenyl)-1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-
dihydropyridine-3-carboxamide (25)
From 19b and 29b; white solid; yield 46%; Used directly for the
next step without further structure characterization.
(30 mg, 0.1 mmol) and DIPEA (50.6 mL, 0.29 mmol) was added to
the mixture, respectively. After stirred at 0 ꢀC for 15 min and at
room temperature for 1 h, the reaction mixture was diluted with
water (10 mL) and then extracted with EtOAc (3 ꢂ 20 mL). The
combined organic layer was dried over Na2SO4 and concentrated
in vacuo, giving a yellow solid (38 mg, 67%), which was directly
dissolved in TFA (1 mL). The reaction mixture was heated to
reflux for 6 h before concentrated in vacuo. The residue was
purified by column, giving compound 21a (24 mg, 77%) as pale
6.18.5. N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-
(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamide
(22c)
From 19b and 20c; white solid; yield 76%; 1H NMR (600 MHz,
CDCl3)
d
11.61 (s, 1H, NH), 8.43 (d, 1H, J ¼ 5.5 Hz, ArH), 7.89 (dd, 1H,
J ¼ 12.1, 2.6 Hz, ArH), 7.57e7.44 (m, 2H, ArH), 7.39e6.97 (m, 8H,
ArH), 6.40 (d, 1H, J ¼ 5.5 Hz, ArH), 3.99 (s, 3H, OCH3), 3.98 (s, 3H,
yellow solid. 1H NMR (600 MHz, Acetone-d6)
d 8.70e8.60 (m, 1H,
OCH3); 13C NMR (150 MHz, CDCl3)
d 162.1, 161.3, 160.5, 157.3, 156.3,
ArH), 8.35 (d, 1H, J ¼ 7.0 Hz, ArH), 8.10 (dd, 1H, J ¼ 12.7, 2.3 Hz,
ArH), 8.06 (dd, 1H, J ¼ 6.6, 2.2 Hz, ArH), 7.67e7.63 (m, 2H, ArH),
7.48e7.45 (m, 1H, ArH), 7.42e7.38 (m, 2H, ArH), 7.36 (t, 1H,
155.1, 154.0, 153.4, 150.3, 137.8, 135.4, 134.9, 133.0, 128.4, 128.3,
128.2, 125.3, 123.6, 121.9, 120.4, 120.0, 117.1, 117.0, 116.8, 116.5, 115.7,
100.0, 99.7, 56.6, 56.4; MS (ESI pos ion) m/z: calcd for
J ¼ 8.6 Hz, ArH); 13C NMR (150 MHz, Acetone-d6)
d 172.2, 163.2,
C29H20F2IN3O5, 655.0; found, 655.8 (MþH).
162.6, 159.3, 155.4, 153.8, 150.2, 150.1, 146.0, 144.6, 139.1, 135.1,
130.2, 130.0, 121.8, 117.1, 116.9, 108.9, 107.8, 107.7, 99.2, 99.1; MS
(ESI pos ion) m/z: calcd for C22H15F2N5O3, 435.1; found, 436.0
(MþH).
6.19. 4-Ethoxy-N-(3-fluoro-4-((2-((4-methoxybenzyl)amino)
pyrimidin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-
dihydropyridine-3-carboxamide (24)
Sodium hydride (7 mg, 0.16 mmol, 60% dispersion in mineral oil)
was added slowly to a solution of ethanol (1 mL) and THF (1 mL)
under argon and the resulting mixture was stirred at rt for 5 min.
After re-cooled to 0 ꢀC, compound 23 (76 mg, 0.11 mmol) was
added to the mixture. The resulting solution was kept stirring at
6.18. General procedure for the preparation of 21b, 21c, 23, 25 and
22c
Similar to the preparation of 21a, but omitting the second step
(treatment with TFA).
0
ꢀC for 10 min, and then warmed to rt and stirred for 1 h. The
reaction mixture was concentrated in vacuo. The resulting crude
solid was suspended in ethyl acetate, washed with saturated
aqueous sodium bicarbonate solution, and water. The organic layer
was dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column to give the compound 24 (48 mg, 72%) as white
6.18.1. N-(4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-3-
fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-
carboxamide (21b)
From 19a and 20b; white solid; yield 34%; 1H NMR (600 MHz,
solid. 1H NMR (600 MHz, CDCl3)
d 8.09 (s, 1H, NH), 7.86 (d, 1H,
DMSO-d6)
d 11.83 (s, 1H, NH), 11.62 (s, 1H, NH), 8.14 (dd, 1H,
J ¼ 12.3 Hz, ArH), 7.48 (dd, 1H, J ¼ 7.9, 2.0 Hz, ArH), 7.33 (ddt, 2H,
J ¼ 6.5, 4.4, 2.0 Hz, ArH), 7.28e7.18 (m, 4H, ArH), 7.16e6.98 (m, 2H,
ArH), 6.79 (d, 2H, J ¼ 7.9 Hz, ArH), 6.33 (dd, 1H, J ¼ 7.9, 2.0 Hz, ArH),
6.13 (dd, 1H, J ¼ 5.7, 1.9 Hz, ArH), 5.52 (dd, 1H, J ¼ 4.5, 2.2 Hz, ArH),
4.32 (q, 2H, J ¼ 7.1 Hz, OCH2), 4.28 (s, 1H, NH), 4.03e4.01 (m, 1H,
NCHH), 3.87e3.77 (m, 1H, NCHH), 3.76 (s, 3H, OCH3), 1.55 (t, 3H,
J ¼ 7.2, 2.3 Hz, ArH), 7.84 (s, 1H, ArH), 7.66 (dd, 1H, J ¼ 6.5,
2.3 Hz, ArH), 7.51 (dd, 1H, J ¼ 12.6, 2.5 Hz, ArH), 7.18e7.13 (m,
2H, ArH), 7.05 (t, 1H, J ¼ 3.0 Hz, ArH), 7.01e6.92 (m, 4H, ArH),
6.27 (t, 1H, J ¼ 6.9 Hz, ArH), 6.14 (dd, 1H, J ¼ 3.6, 1.7 Hz, ArH);
13C NMR (150 MHz, DMSO-d6)
d 163.2, 162.1, 161.6, 161.4, 155.1,
154.1, 153.5, 150.5, 145.5, 144.6, 137.4, 137.3, 136.8, 135.8, 135.7,
129.9, 129.8, 126.1, 125.2, 120.7, 116.7, 116.6, 116.5, 107.5, 104.6,
100.0, 98.4; MS (ESI pos ion) m/z: calcd for C24H15F2N5O3, 459.1;
found, 460.0 (MþH), 482.1 (MþNa).
J ¼ 7.0 Hz, CH3); 13C NMR (150 MHz, CDCl3)
d 170.9, 163.7, 163.5,
162.2, 161.9, 161.7, 158.8, 153.4, 140.5, 128.9, 128.7, 123.7, 116.9, 116.7,
113.9, 109.1, 106.6, 103.4, 100.0, 98.5, 97.4, 66.4, 55.4, 33.3, 14.8; MS
(ESI pos ion) m/z: calcd for C32H27F2N5O5, 599.2; found, 600.1
(MþH).
6.18.2. N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-
(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (21c)
From 19a and 20c; white solid; yield 78%; 1H NMR (600 MHz,
6.20. Preparation of N-(4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-
3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-
dihydropyridine-3-carboxamide (22b)
DMSO-d6)
d
11.98 (s, 1H, NH), 8.52 (d, 1H, J ¼ 5.4 Hz, ArH), 8.50 (d,
1H, J ¼ 3.0 Hz, ArH), 8.47 (d, 1H, J ¼ 3.0 Hz, ArH), 8.05 (dd, 1H,
J ¼ 12.7, 2.5 Hz, ArH), 7.66e7.61 (m, 2H, ArH), 7.58e7.54 (m, 2H,
ArH), 7.50e7.41 (m, 4H, ArH), 3.96 (s, 3H, OCH3), 3.95 (s, 3H, OCH3);
Similar to the preparation of 24 but using 25 as starting material.
White solid; yield 46%; 1H NMR (600 MHz, DMSO-d6)
d 12.31 (s, 1H,
13C NMR (150 MHz, DMSO-d6)
d
162.9, 160.5, 159.8, 154.3, 153.0,
NH), 10.56 (s, 1H, NH), 8.30 (s, 1H, ArH), 7.97e7.79 (m, 2H, ArH),
7.63e7.27 (m, 7H, ArH), 6.60 (d, 1H, J ¼ 3.5 Hz, ArH), 6.53 (d, 1H,
J ¼ 7.9 Hz, ArH), 4.26 (q, 2H, J ¼ 6.9 Hz, OCH2CH3), 1.31 (t, 3H,
149.7, 148.2, 144.2, 142.0, 136.2, 135.6, 129.6, 129.4, 128.2, 128.0,
125.5,124.3,121.0,116.2,116.0,114.6,112.2,108.9,108.7,106.9,102.3,
99.0, 55.8; MS (ESI pos ion) m/z: calcd for C29H21F2N3O5, 529.1;
found, 530.0 (MþH).
J ¼ 7.0 Hz, OCH2CH3); 13C NMR (150 MHz, DMSO-d6)
d 165.0, 162.9,
161.5, 161.1, 160.5, 153.9, 150.5, 141.3, 136.9, 129.7, 129.6, 125.0, 116.5,

266
W. Zhang et al. / European Journal of Medicinal Chemistry 80 (2014) 254e266
116.3, 111.9, 104.5, 98.3, 96.5, 65.6, 31.2, 15.2; MS (ESI pos ion) m/z:
calcd for C26H19F2N5O4, 503.1; found, 503.9 (MþH), 526.1 (MþNa).
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.04.056.
6.21. Preparation of N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-
fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-
dihydropyridine-3-carboxamide (22d)
References
Similar to the preparation of 24 but using 22c as starting ma-
terial. White solid; yield 71%; 1H NMR (400 MHz, CDCl3)
d 11.66 (s,
[1] P.M. Comoglio, S. Giordano, L. Trusolino, Drug development of MET inhibitors:
targeting oncogene addiction and expedience, Nature Reviews. Drug Discov-
ery 7 (2008) 504e516.
[2] E. Gherardi, W. Birchmeier, C. Birchmeier, G.F. Vande Woude, Targeting MET
in cancer: rationale and progress, Nature Reviews Cancer 12 (2012) 89e103.
[3] R. Straussman, T. Morikawa, K. Shee, M. Barzily-Rokni, Z.R. Qian, J. Du,
A. Davis, M.M. Mongare, J. Gould, D.T. Frederick, Z.A. Cooper, P.B. Chapman,
D.B. Solit, A. Ribas, R.S. Lo, K.T. Flaherty, S. Ogino, J.A. Wargo, T.R. Golub,
Tumour micro-environment elicits innate resistance to RAF inhibitors through
HGF secretion, Nature 487 (2012) 500e504.
[4] J.A. Engelman, K. Zejnullahu, T. Mitsudomi, Y. Song, C. Hyland, J.O. Park,
N. Lindeman, C.M. Gale, X. Zhao, J. Christensen, T. Kosaka, A.J. Holmes,
A.M. Rogers, F. Cappuzzo, T. Mok, C. Lee, B.E. Johnson, L.C. Cantley, P.A. Janne,
MET amplification leads to Gefitinib resistance in lung cancer by activating
ERBB3 signaling, Science 316 (2007) 1039e1043.
[5] G.R. Blumenschein Jr., G.B. Mills, A.M. Gonzalez-Angulo, Targeting the hepa-
tocyte growth factor-cMET axis in cancer therapy, Journal of Clinical Oncology
30 (2012) 3287e3296.
[6] D.R. Feldman, L.H. Einhorn, D.I. Quinn, Y. Loriot, J.K. Joffe, D.J. Vaughn,
A. Fléchon, J. Hajdenberg, A.B. Halim, H. Zahir, R.J. Motzer, A phase 2 multi-
center study of tivantinib (ARQ 197) monotherapy in patients with relapsed or
refractory germ cell tumors, Investigational New Drugs 31 (2013) 1016e1022.
[7] M.H. Wang, S.S. Padhye, S. Guin, Q. Ma, Y.Q. Zhou, Potential therapeutics
specific to c-MET/RON receptor tyrosine kinases for molecular targeting in
cancer therapy, Acta Pharmacologica Sinica 31 (2010) 1181e1188.
[8] https://integrity.thomson-pharma.com/integrity/xmlxsl.
[9] T.L. Underiner, T. Herbertz, S.J. Miknyoczki, Discovery of small molecule c-Met
inhibitors: evolution and profiles of clinical candidates, Anti-Cancer Agents in
Medicinal Chemistry 10 (2010) 7e27.
[10] F. Zuccotto, E. Ardini, E. Casale, M. Angiolini, Through the “gatekeeper door”:
exploiting the active kinase conformation, Journal of Medicinal Chemistry 53
(2010) 2681e2694.
1H, NH), 8.48 (d, 1H, J ¼ 5.3 Hz, ArH), 7.97 (dd, 1H, J ¼ 12.6, 2.4 Hz,
ArH), 7.59 (s, 1H, ArH), 7.53 (d, 1H, J ¼ 7.8 Hz, ArH), 7.42 (s, 1H, ArH),
7.39e7.33 (m, 3H, ArH), 7.26e7.22 (m, 2H, ArH), 7.16 (t, 1H,
J ¼ 8.7 Hz, ArH), 6.42 (dd, 1H, J ¼ 5.2, 0.8 Hz, ArH), 6.38 (d, 1H,
J ¼ 7.9 Hz, ArH), 4.37 (q, 2H, J ¼ 7.0 Hz, OCH2CH3), 4.06 (s, 3H, OCH3),
4.05 (s, 3H, OCH3), 1.59 (t, 3H, J ¼ 7.0 Hz, OCH2CH3); 13C NMR
(100 MHz, CDCl3)
d 171.0, 164.0, 163.8, 162.1, 160.4, 155.7, 152.9,
149.6,149.0,146.9,140.6,137.8,137.7,136.0,128.8,128.7,123.5,117.0,
116.8, 116.6, 115.7, 107.9, 106.5, 102.4, 99.7, 97.5, 66.5, 56.3, 14.8; MS
(ESI pos ion) m/z: calcd for C31H25F2N3O6, 573.2; found, 574.1
(MþH).
6.22. Preparation of N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-
fluorophenyl)-1-(4-fluorophenyl)-4-methoxy-2-oxo-1,2-
dihydropyridine-3-carboxamide (22e)
Similar to the preparation of 24 but using 22c as starting ma-
terial; ethanol was replaced with methanol. White solid; yield 71%;
1H NMR (400 MHz, CDCl3)
d
11.75 (s, 1H, NH), 8.49 (d, 1H, J ¼ 5.3 Hz,
ArH), 8.40 (dd, 1H, J ¼ 12.6, 2.4 Hz, ArH), 7.59 (s, 1H, ArH), 7.57 (d,
1H, J ¼ 7.8 Hz, ArH), 7.42 (s, 1H, ArH), 7.39e7.33 (m, 3H, ArH), 7.29e
7.27 (m, 1H, ArH), 7.26e7.23 (m, 1H, ArH), 7.16 (t, 1H, J ¼ 8.7 Hz,
ArH), 6.44e6.41 (m, 2H, ArH), 4.13 (s, 3H, OCH3), 4.06 (s, 3H, OCH3),
4.05 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3)
d 171.8, 163.7, 162.1,
[11] S. Berthou, D.M. Aebersold, L.S. Schmidt, D. Stroka, C. Heigl, B. Streit, D. Stalder,
G. Gruber, C. Liang, A.R. Howlett, D. Candinas, R.H. Greiner, K.E. Lipson,
Y. Zimmer, The Met kinase inhibitor SU11274 exhibits a selective inhibition
pattern toward different receptor mutated variants, Oncogene 23 (2004)
5387e5393.
160.4,155.7,153.2,152.9,149.6,149.1,146.9,140.9,137.8,137.7,136.5,
135.9, 128.8, 128.7, 123.5, 117.1, 116.8, 116.5, 115.7, 107.9, 106.3, 102.4,
99.6, 96.8, 57.5, 56.31, 56.26; MS (ESI pos ion) m/z: calcd for
[12] S.G. Buchanan, J. Hendle, P.S. Lee, C.R. Smith, P.-Y. Bounaud, K.A. Jessen,
C.M. Tang, N.H. Huser, J.D. Felce, K.J. Froning, M.C. Peterman, B.E. Aubol,
S.F. Gessert, J.M. Sauder, K.D. Schwinn, M. Russell, I.A. Rooney, J. Adams,
B.C. Leon, T.H. Do, J.M. Blaney, P.A. Sprengeler, D.A. Thompson, L. Smyth,
L.A. Pelletier, S. Atwell, K. Holme, S.R. Wasserman, S. Emtage, S.K. Burley,
S.H. Reich, SGX523 is an exquisitely selective, ATP-competitive inhibitor of the
MET receptor tyrosine kinase with antitumor activity in vivo, Molecular
Cancer Therapeutics 8 (2009) 3181e3190.
C
30H23F2N3O6, 559.2; found, 559.8 (MþH).
6.23. Preparation of N-(4-((2-aminopyrimidin-4-yl)oxy)-3-
fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-
dihydropyridine-3-carboxamide (22a)
[13] M.H. Norman, L. Liu, M. Lee, N. Xi, I. Fellows, N.D. D’Angelo, C. Dominguez,
K. Rex, S.F. Bellon, T.-S. Kim, I. Dussault, Structure-based design of novel class
II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives, Journal
of Medicinal Chemistry 55 (2012) 1858e1867.
[14] Y. Fujiwara, T. Senga, T. Nishitoba, T. Osawa, A. Miwa, K. Nakamura,
WO03000660.
[15] G.M. Schroeder, Y. An, Z.W. Cai, X.T. Chen, C. Clark, L.A. Cornelius, J. Dai,
J. Gullo-Brown, A. Gupta, B. Henley, J.T. Hunt, R. Jeyaseelan, A. Kamath, K. Kim,
J. Lippy, L.J. Lombardo, V. Manne, S. Oppenheimer, J.S. Sack, R.J. Schmidt,
G. Shen, K. Stefanski, J.S. Tokarski, G.L. Trainor, B.S. Wautlet, D. Wei,
D.K. Williams, Y. Zhang, J. Fargnoli, R.M. Borzilleri, Discovery of N-(4-(2-
amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-
Compound 24 (40 mg, 0.07 mmol) was dissolved in TFA and
heated to reflux for 6 h. The solvent was removed before the residue
was purified by column, giving title compound (23 mg, 77%) as pale
yellow solid. 1H NMR (600 MHz, DMSO-d6)
d
10.57 (s, 1H, NH), 8.26
(d,1H, J ¼ 6.3 Hz, ArH), 7.87e7.80 (m, 4H, ArH þ NH2), 7.47e7.43 (m,
2H, ArH), 7.40 (dd, 1H, J ¼ 8.9, 2.4 Hz, ArH), 7.39e7.31 (m, 3H, ArH),
4.25 (q, 2H, J ¼ 7.0 Hz, OCH2), 1.29 (t, 3H, J ¼ 7.0 Hz, CH3); 13C NMR
(150 MHz, DMSO-d6)
d 170.2, 164.5, 162.7, 160.7, 160.0, 154.1, 152.5,
140.9, 138.7, 138.6, 136.4, 129.2, 129.1, 124.2, 116.0, 115.9, 115.4, 111.5,
97.1, 96.1, 65.1, 14.7; MS (ESI pos ion) m/z: calcd for C24H19F2N5O4,
479.1; found, 480.1 (MþH).
fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607),
a
selective and orally efficacious inhibitor of the Met kinase superfamily, Journal
of Medicinal Chemistry 52 (2009) 1251e1254.
[16] S. Li, Q. Huang, Y. Liu, X. Zhang, S. Liu, C. He, P. Gong, Design, synthesis and
antitumour activity of bisquinoline derivatives connected by 4-oxy-3-
fluoroaniline moiety, European Journal of Medicinal Chemistry 64 (2013)
62e73.
[17] S. Li, Y. Zhao, K. Wang, Y. Gao, J. Han, B. Cui, P. Gong, Discovery of novel 4-(2-
fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-
Acknowledgments
This work was supported by grants of the National Program on
Key Basic Research Project of China (No. 2012CB910704), the Nat-
ural Science Foundation of China for Innovation Research Group
(No. 81021062), the National Natural Science Foundation (Nos.
81102461, 91229205), and the National S&T Major Projects
(2012ZX09301001-007).
carboxamide moiety as c-Met kinase inhibitors, Bioorganic
& Medicinal
Chemistry 21 (2013) 2843e2855.
[18] R.A. Borzilleri, L.A.M. Cornelius, R.J. Schmidt, G.M. Schroeder, K.S. Kim,
WO2005117867.
[19] A. Nagle, N.S. Gray, WO2007053343.