Structure activity relationships of quinoline-containing c-Met inhibitors

Article abstract of DOI:10.1016/j.ejmech.2007.08.011

A series of quinoline-containing c-Met inhibitors were prepared and studied. Chemistry was developed to introduce a pyridyl moiety onto the 2-aryl ring present in a lead molecule which mitigated the potential for quinone formation relative to the original

Full text of DOI:10.1016/j.ejmech.2007.08.011

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 1321e1329
http://www.elsevier.com/locate/ejmech
Short communication
Structure activity relationships of quinoline-containing
c-Met inhibitors
*
Pei-Pei Kung , Lee Funk, Jerry Meng, Gordon Alton,
Ellen Padrique, Barbara Mroczkowski
Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA
Received 13 May 2007; received in revised form 26 July 2007; accepted 9 August 2007
Available online 11 September 2007
Abstract
A series of quinoline-containing c-Met inhibitors were prepared and studied. Chemistry was developed to introduce a pyridyl moiety onto the
2-aryl ring present in a lead molecule which mitigated the potential for quinone formation relative to the original compound. The study also
assessed the importance of an acylthiourea moiety present in the lead structure for effective binding to the c-Met protein ATP site.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: c-Met; Quinoline
1. Introduction
contain several structural motifs that may be linked to toxicity,
and/or chemical instability (e.g., the masked para-hydroxyani-
line and thiourea moieties) [7,8]. We were intrigued by the re-
ported inhibitory potency of 1 and 2 and sought to synthesize
analogs of this class of compounds that lacked either or both
structural concerns. Below, we detail the results of our efforts.
Initially, compound 3 was synthesized to examine whether
c-Met signaling is implicated in a wide variety of human
malignancies, including colon, gastric, bladder, breast, over-
ian, pancreatic, kidney, liver, lung, and prostate cancers [1,2].
The MET oncogene was isolated from a human osteogenic
sarcoma cell line [3] and analysis of the full-length Met
proto-oncogenic coding sequence revealed structural features
of a membrane spanning receptor tyrosine kinase (TK) [3].
Upon hepatocyte growth factor (HGF) and scattering factor
(SF) binding, c-Met phosphorylation occurs on two tyrosine
residues (Y1234 and Y1235) within the activation loop of the
TK domain which regulates kinase activity [4,5]. Phosphoryla-
tion on two other tyrosine residues near the COOH terminus
(Y1349 and Y1356) forms a multifunctional docking site that
recruits intracellular adaptors leading to downstream signaling
[4,5] and cell proliferation. Therefore, c-Met is an important
target for inhibiting tumor metastasis and angiogenesis.
a
2-amino-4-hydroxypyridine moiety could replace the
masked para-hydroxyaniline present in structures 1 and 2. En-
couragingly, compound 3 displayed similar c-Met inhibitory
properties as compared with the lead molecules (Table 1).
We therefore retained the central 2-amino-4-hydroxypyridine
moiety in our subsequent inhibitor designs in order to mitigate
the risk of metabolically forming a reactive (and potentially
toxic) quinone species [8a,8b].
2. Chemistry
Literature reported c-Met inhibitors 1 and 2 (Table 1)
exhibit very potent c-Met inhibition properties [6] but also
The syntheses of compounds 3 and 7e14 are depicted in
Scheme 1. These compounds could be prepared in moderate
to excellent yields by derivatization of amino-pyridine 6 which
in turn, was prepared in two steps from the known [9a,9b,10]
chloro-quinoline 4 [11]. The synthetic route used to convert 6
* Corresponding author. Tel.: þ1 858 526 4867; fax: þ1 858 526 4447.
E-mail address: peipeikung@pfizer.com (P.-P. Kung).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.08.011

1322
P.-P. Kung et al. / European Journal of Medicinal Chemistry 43 (2008) 1321e1329
Table 1
3. Results and discussion
H
N
H
N
R
O
A key intermediate for our SAR exploration (compound 6,
Table 2) was screened in the c-Met inhibition assay to explore
the importance of the acylthiourea portion of compound 3.
Compound 6 displayed drastically reduced inhibitory potency
compared with 3 and was also significantly weaker than its
acetylated analog (compound 7, Table 2). Introducing a ben-
zylic moiety improved the inhibitory potency 17-fold (com-
pare compound 8 with compound 7) suggesting the presence
of a c-Met hydrophobic binding pocket in the vicinity of the
inhibitor acyl group. A pyridyl moiety was also examined to
replace the phenyl ring present in compound 8 but the new an-
alog (9) lost significant inhibitory potency (Table 2).
S
O
X
H3CO
H3CO
N
Compound no.
R
X
Ki (mM)
1
2
3
F
C
C
N
0.001
0.002
0.003
H
H
In addition to the N-acyl derivatives depicted in Table 2, we
also examined a series of urea-containing c-Met inhibitors
(Table 3). The tertiary urea (compound 16) did not signifi-
cantly inhibit c-Met activity at the highest concentration ex-
amined (30 mM). In contrast, a secondary urea (compound
10) displayed moderate c-Met inhibition properties. This result
suggested the terminal urea NH might act as a hydrogen bond
donor when interacting with the c-Met enzyme. Accordingly,
we examined several other inhibitors which retained this struc-
tural feature in their design (compounds 11, 12, 19, 20,
Table 3). All of these compounds displayed moderately potent
c-Met inhibition activity but were significantly less active than
inhibitors 1e3 (Table 1). We therefore introduced a second
acyl group to our inhibitor design to more closely mimic the
original lead structures. Compounds 22 and 23 improved
c-Met inhibition potency several fold relative to other
urea-containing compounds (e.g., compounds 19 and 20,
Table 3), indicating the importance of the second carbonyl
group to the inhibitor design.
to compound 3 followed a literature procedure with minor
modification [6]. Alternatively, compound 6 was coupled
with various carboxylic acids or acyl chlorides (the former
requiring the inclusion of a carbodiimide activating agent) to
provide inhibitors 7e9. The reaction of compound 6 with var-
ious commercially available isocyanates afforded the urea
derivatives (compounds 10e14).
In contrast, the synthesis of compound 16 from 6 was
achieved through a three-step process including (i) formation
of the isocyanate derivative of 6, (ii) trapping with tert-butyl-1-
piperazine-carboxylate (toform compound 15), and (iii)removal
of the Boc protecting group under acidic conditions (Scheme 2).
The syntheses of compounds 19 and 20 are depicted in
Scheme3. Compound 6 was treatedwithethyl isocyanatoacetate
to give compound 17 which was then hydrolyzed to afford 18.
Derivatization of 18 via HATU-mediated amide formation
then provided compounds 19 and 20. The synthesis of com-
pounds 22 and 23 are depicted in Scheme 4 and involve the
reaction of 6 with chloroacetylisocyanate (to give the intermedi-
ate 21) followed by alkylation of the appropriate amines in the
presence of diisopropylethylamine (50e80% yield in two steps).
Encouraged by these results, we synthesized two additional
acylurea inhibitors which incorporated terminal benzoyl sub-
stituents (compounds 13 and 14, Table 3). Both molecules
NH2
Cl
N
O
N
b
Cl
O
H3CO
H3CO
a
H3CO
H3CO
H3CO
N
H3CO
N
N
N
5
4
6
e
c
d
H
N
H
N
H
N
H
N
R
R
N
S
O
N
O
O
N
O
N
H3CO
H3CO
H3CO
H3CO
H3CO
N
H3CO
3
7-9
10-14
Scheme 1. Reagents and conditions: (a) 2-chloro-5-hydroxypyridine, chlorobenzene, 140 ꢀC, 12 h, 65%; (b) LiN(TMS)2, Pd2(dba)3, 2-(dicyclohexylphosphino)-
biphenyl, 80 ꢀC, 12 h, HCl (aq), 2 h, Na2CO3, 59%; (c) ammonium thiocyanate, phenylacetylchloride, chlorobenzene, 105 ꢀC, 3 h; 70 ꢀC, 3 h, 23%; (d) acyl chlo-
rides, DIEA, CH2Cl2, 23 ꢀC, 12 h, 57% (7); 60% (8) or carboxylic acid, CDI, DIEA, CH2Cl2, 23 ꢀC, 12 h, 34% (9); (e) isocyanates, CH2Cl2, 23 ꢀC, 12 h, 30e95%.

P.-P. Kung et al. / European Journal of Medicinal Chemistry 43 (2008) 1321e1329
1323
NH
N Boc
H
N
H
N
N
N
O
N
O
N
O
N
O
N
a,b
H3CO
H3CO
c
H3CO
H3CO
6
16
15
Scheme 2. Reagents and conditions: (a) triphosgene, CH2Cl2, DIEA, 40 ꢀC; (b) tert-butyl-1-piperazine-carboxylate, CH2Cl2, 23 ꢀC, 12 h, 6% (two steps); (c) HCl,
1,4-dioxane, 23 ꢀC, 12 h, 17%.
exhibited improved c-Met inhibition properties relative to
other compounds described in this work with Ki values
<100 nM. However, the potency of these compounds was at
least 10-fold weaker than that exhibited by compounds 1e3,
indicating the importance of the thiourea moiety and/or the
terminal benzyl substituent present in these molecules for
optimal c-Met recognition.
Table 3
H
N
R
N
O
O
4. Conclusion
H3CO
H3CO
In summary, a variety of 5-[(6,7-dimethoxyquinolin-4-
yl)oxy]pyridin-2-amine derivatives were explored as novel c-
Met inhibitors. The acylthiourea moiety was shown to be
important for the effective binding to the c-Met protein.
N
Compound no.
R
Ki (mM)
>30
16
Table 2
R
N
NH
N
O
H3CO
10
5
N
H3CO
N
H
Compound no.
R
Ki (mM)
6
2% @ 1 mM
NH2
O
11
1
N
7
8
7
H
N
H
19
20
6.4
2.8
0.4
N
N
N
H
O
O
O
O
N
H
9
8
N
N
H
N
H
(continued on next page)

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P.-P. Kung et al. / European Journal of Medicinal Chemistry 43 (2008) 1321e1329
Table 3 (continued)
Compound no.
12
downfield from an internal tetramethylsilane standard.
1
Alternatively, H NMR spectra were referenced to residual
R
Ki (mM)
protic solvent signals as follows: CHCl3 ¼ 7.26 ppm;
DMSO ¼ 2.49 ppm, CH3OH ¼ 3.40 ppm. Peak multiplicities
are designated as follows: s, singlet; d, doublet; dd, doublet of
doublets; t, triplet; q, quartet; br, broad resonance; m, multiplet.
Coupling constants are given in Hertz. Elemental microanalyses
were performed by Atlantic Microlab Inc., Norcross, GA and
gave results for the elements stated within ꢁ0.4% of the theoret-
ical values. Flash column chromatography was performed using
silica gel 60 (Merk Art 9385). Analytical thin layer chromatog-
raphy (TLC) was performed using precoated sheets of Silica 60
1
N
H
22
23
0.5
0.5
O
O
N
N
N
H
F254 (Merk Art 5719). Melting points were determined on a Mel-
Temp apparatus and are uncorrected. All commercial reagents
were used as received from their perspective supplier.
DMF refers to N,N-dimethylformamide. DMSO refers to
dimethylsulfoxide. HMPA refers to hexamethylphosphorous
triamide. Other abbreviations include: CH3OH (methanol),
DCM (dichloromethane), EtOH (ethanol), EtOAc (ethyl ace-
tate), HCl (hydrochloric acid), AcOH (acetic acid), EDC [1-
(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride],
DCC (dicyclohexyl-carbodiimide).
N
H
13
0.08
O
F
N
H
F
14
0.05
O
5.1.1. N-[({5-[(6,7-Dimethoxyquinolin-4-yl)oxy]pyridin-2-
yl}amino)carbonothioyl]-2-phenylacetamide (3)
Ammonium thiocyanate (40 mg, 0.52 mmol) was added to
N
H
a
stirred solution of phenylacetylchloride (0.07 mL,
0.47 mmol) in chlorobenzene (2 mL). The resulting solution
was heated to 105 ꢀC for 3 h. Compound 6 (153.7 mg,
0.52 mmol) was added and the resulting mixture was stirred
at 70 ꢀC for 3 h. Water (50 mL) was added to the reaction mix-
ture to quench the reaction. EtOAc (2 ꢂ 50 mL) was added to
extract the aqueous solution. The combined organic layers
were dried, filtered and evaporated to get a brown yellow oil.
The residue was purified by silica gel chromatography (eluting
with 0 / 5% CH3OH in EtOAc) to give compound 3 as a white
foam (57.5 mg; 0.12 mmol; 23.3% yield); MS (APCI)
5. Experimental section
5.1. Chemistry
General methods: The structures of the compounds of the fol-
lowing examples were confirmed by one or more of the follow-
ing: proton magnetic resonance spectroscopy, liquid
chromatographyemass spectrometry, and elemental microanal-
ysis. Proton magnetic resonance (1H NMR) spectra were deter-
mined using either a Varian UNITY plus 300 or a Brucker 400.
Chemical shifts are reported in parts per million (ppm, d)
1
(M þ H)þ 475. H NMR (400 MHz, CDCl3) d ppm 3.77 (s,
2H) 4.05 (s, 3H) 4.06 (s, 3H) 6.49 (d, J ¼ 5.3 Hz, 1H) 7.27 (s,
1H) 7.33 (m, 2H) 7.40 (m, 3H) 7.51 (s, 1H) 7.57 (dd, J ¼ 9.0,
2.9 Hz, 1H) 8.35 (d, J ¼ 2.8 Hz, 1H) 8.53 (d, J ¼ 5.1 Hz, 1H)
8.61 (s, 1H) 8.88 (d, J ¼ 9.1 Hz, 1H) 12.92 (s, 1H).
O
O
H
N
H
N
H
N
H
N
R1
OR
N
N
O
N
O
R2
O
N
O
N
H3CO
H3CO
b
H3CO
H3CO
a
c
6
17, R= CH2CH3
18, R= H
19,20
Scheme 3. Reagents and conditions: (a) OCNCH2COOC2H5, CH2Cl2, 23 ꢀC, 94%; (b) NaOH, EtOH, 23 ꢀC, 3 h, 94%; (c) amines (cyclopentylamine for 19 and
cyclohexylamine for 20), HATU, DIEA, DMF, 23 ꢀC, 12 h, 27% (19), 18% (20).

P.-P. Kung et al. / European Journal of Medicinal Chemistry 43 (2008) 1321e1329
1325
H
N
H
N
H
N
H
N
R1
Cl
N
O
O
N
O
O
R2
N
O
N
O
H3CO
H3CO
H3CO
H3CO
a
b
6
N
21
22,23
Scheme 4. Reagents and conditions: (a) OCN(CO)CH2Cl, CH2Cl2, 23 ꢀC, 68%; (b) amines (pyrrolidine for 22 and piperidine for 23), DIEA, DMF, 23 ꢀC, 12 h,
50% (22), 81% (23).
Anal. Calcd for C25H22N4O4S$0.2CHCl3$0.75H2O: C,
59.13; H, 4.67; N, 10.94. Found: C, 59.20; H, 4.42; N, 10.76.
5.1.3. N-{5-[(6,7-Dimethoxyquinolin-4-yl)oxy]-
pyridin-2-yl}acetamide (7)
Acetyl chloride (55 mg, 0.66 mmol) and diisopropylethyl-
amine (0.3 mL, 1.65 mmol) were added to a solution of
5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-amine (com-
pound 6, 97 mg, 0.33 mmol) in DCM (10 mL). The mixture
was stirred at room temperature for 16 h. The reaction was
quenched with H2O (10 mL) and EtOAc (2 ꢂ 20 mL). The mix-
turewas then purified by silica gel chromatography (eluting with
100% EtOAc) to afford compound 7 (80 mg, 0.24 mmol, 72%
5.1.2. 5-[(6,7-Dimethoxyquinolin-4-yl)oxy]pyridin-2-amine(6)
5.1.2.1. Synthesis of 4-[(6-chloropyridin-3-yl)oxy]-6,7-dime-
thoxyquinoline (5). 2-Chloro 5-hydroxypyridine (310 mg,
2.3 mmol) and triethylamine (5 mL, 28.7 mmol) were added
sequentially to a stirred solution of 4 (354 mg, 1.58 mmol)
in chlorobenzene (3 mL). The resulting solution was heated
to 140 ꢀC for 12 h. The reaction mixture was quenched with
H2O (100 mL) and EtOAc (2 ꢂ 100 mL) was added to extract
the aqueous solution. The combined organic layers were dried
over Na2SO4 then concentrated under vacuum. The residue
was purified by flash chromatography (eluting with 0 /10%
CH3OH in EtOAc) to give compound 5 as a light brown yel-
low oil (324.2 mg; 1.02 mmol; 64.8% yield); MS (APCI)
1
yield) as a tan solid; MS (m/z) (APCI) [M þ H]þ 340.2. H
NMR (400 MHz, DMSO-d6) d ppm 2.12 (s, 3H) 3.94 (d,
J ¼ 4.0 Hz, 6H) 6.51 (d, J ¼ 5.3 Hz, 1H) 7.41 (s, 1H) 7.53 (s,
1H) 7.77 (dd, J ¼ 9.1, 3.1 Hz, 1H) 8.22 (d, J ¼ 9.1 Hz, 1H)
8.34 (d, J ¼ 2.8 Hz, 1H) 8.48 (d, J ¼ 5.3 Hz, 1H) 10.67 (s, 1H).
Anal. Calcd for C18H17N3O4$0.25HOAc: C, 62.71; H, 5.12;
N, 11.86. Found: C, 62.71; H, 5.27; N, 11.67.
1
(M þ H)þ 317. H NMR (400 MHz, CDCl3) d ppm 4.00 (s,
5.1.4. N-[5-(6,7-Dimethoxy-quinolin-4-yloxy)-
pyridin-2-yl]-2-phenyl-acetamide (8)
3H) 4.01 (s, 3H) 6.45 (d, J ¼ 5.3 Hz, 1H) 7.44 (m, 4H) 8.32
(d, J ¼ 2.5 Hz, 1H) 8.51 (d, J ¼ 5.1 Hz, 1H).
Diisopropylamine (0.4 mL, 2 mmol) and phenylacetyl-
chloride (250 mg, 1.5 mmol) were added to a solution of
5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-amine (com-
pound 6, 150 mg, 0.5 mmol) in 5 mL of DCM. The mixture
was stirred at room temperature for 12 h under inert atmo-
sphere. Water (20 mL) was added to the reaction mixture to
quench the reaction. EtOAc (2 ꢂ 50 mL) was added to extract
the aqueous solution. The combined organic layers were dried
(Na2SO4), filtered and evaporated to get a yellow oil. The res-
idue was purified by silica gel chromatography (eluting with
80 / 90% EtOAc in hexanes) to afford N-[5-(6,7-dimethoxy-
quinolin-4-yloxy)-pyridin-2-yl]-2-phenyl-acetamide (108.4 mg;
0.26 mmol; 52% yield); MS (APCI) (M þ H)þ 416. 1H
NMR (400 MHz, DMSO-d6) d ppm 3.75 (s, 2H) 3.93
(s, 3H) 3.95 (s, 3H) 6.51 (d, J ¼ 5.31 Hz, 1H) 7.21e7.39
(m, 5H) 7.40 (s, 1H) 7.52 (s, 1H) 7.78 (dd, J ¼ 9.1, 2.78 Hz,
1H) 8.21 (d, J ¼ 9.1 Hz, 1H) 8.36 (d, J ¼ 2.8 Hz, 1H) 8.47
(d, J ¼ 5.3 Hz, 1H) 10.93 (s, 1H).
Anal. Calcd for C16H13ClN2O3: C, 60.67; H, 4.14; N, 8.84.
Found: C, 60.25; H, 4.05; N, 8.66.
5.1.2.2. Synthesis of 5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyri-
din-2-amine (6). Lithium hexamethyldisilazide (1.5 mL,
1.5 mmol), tris(dibenzylideneacetone) dipalladium(0) chloro-
form adduct (54 mg, 0.052 mmol), and 2-(dicyclohexylphos-
phino) biphenyl (45 mg, 0.12 mmol) were added sequentially
to a stirred solution of compound 5 (324.4 mg, 1.02 mmol)
in THF (3 mL) under a nitrogen atmosphere. The reaction
mixture was heated at 80 ꢀC for 12 h and then 2 M HCl
(17 mL) was added and the mixture was stirred for an addi-
tional 2 h. The reaction mixture was neutralized with
Na2CO3 and then extracted with THF (2 ꢂ 100 mL). The com-
bined organic layers were dried over Na2SO4 then concen-
trated under vacuum. The residue was purified by silica gel
chromatography (eluting with 10 / 20% CH3OH in EtOAc)
to afford compound 6 as a light brown foam (177.4 mg;
0.60 mmol; 59% yield); MS (APCI) (M þ H)þ 298. 1H
NMR (400 MHz, DMSO-d6) d ppm 3.94 (s, 6H) 6.07 (s,
2H) 6.41 (d, J ¼ 5.1 Hz, 1H) 6.56 (d, J ¼ 9.1 Hz, 1H) 7.34e
7.41 (m, 2H) 7.51 (s, 1H) 8.45 (d, J ¼ 5.3 Hz, 1H).
Anal. Calcd for C24H21N3O4$0.5EtOAc: C, 69.39; H, 5.10;
N, 10.11. Found: C, 68.92; H, 5.13; N, 9.32.
5.1.5. N-{5-[(6,7-Dimethoxyquinolin-4-yl)-
oxy]pyridin-2-yl}-2-pyridin-2-ylacetamide (9)
Diisopropylethylamine (0.2 mL, 1 mmol) and 1,10-carbon-
yldiimidazole (200 mg, 1.2 mmol) were added to a solution
Anal. Calcd for C16H15N3O3$0.3EtOAc: C, 63.81; H, 5.42;
N, 12.98. Found: C, 64.14; H, 5.14; N, 12.71.

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P.-P. Kung et al. / European Journal of Medicinal Chemistry 43 (2008) 1321e1329
of 2-pyridylacetic acid hydrochloride in 2 mL of dichloroeth-
ane. The mixture was stirred at room temperature for
30 min under inert atmosphere. A solution of 5-[(6,7-dime-
then was evaporated to a yellow solid to afford compound
16 (8 mg, 0.02 mmol, 17% yield); MS (m/z) (APCI)
1
[M þ H]þ 410.2. H NMR (400 MHz, MeOD) d ppm 3.01e
thoxyquinolin-4-yl)oxy]pyridin-2-amine
(compound
6,
3.08 (m, 4H) 3.63e3.69 (m, 4H) 4.00 (s, 3H) 4.01 (s, 3H)
6.54 (d, J ¼ 5.3 Hz, 1H) 7.35 (s, 1H) 7.62 (s, 1H) 7.66 (dd,
J ¼ 9.1, 3.0 Hz, 1H) 7.92 (d, J ¼ 9.1 Hz, 1H) 8.22 (d,
J ¼ 2.5 Hz, 1H) 8.43 (d, J ¼ 5.3 Hz, 1H).
150 mg, 0.5 mmol) in 2 mL of dichloroethane was added.
The mixture was heated at 80 ꢀC for 12 h then cooled to ambi-
ent temperature. Water (50 mL) was added to the reaction mix-
ture to quench the reaction. EtOAc (2 ꢂ 50 mL) was added to
extract the aqueous solution. The combined organic layers
were dried (Na2SO4), filtered and evaporated to get a tan oil.
The residue was purified by silica gel chromatography (eluting
with 10% CH3OH in DCM) to afford compound 9 a yellow
solid (70 mg; 0.168 mmol; 33.6% yield); MS (APCI)
5.1.7. N-Cyclohexyl-N0-{5-[(6,7-dimethoxyquinolin-
4-yl)oxy]pyridin-2-yl}urea (10)
Cyclohexyl isocyanate (1 mL, 8 mmol) was added to a solu-
tion of 5-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-2-ylamine
(compound 6, 119 mg, 0.4 mmol) in 4 mL of DCM. The mix-
ture was stirred at room temperature for 12 h.
The reaction mixture was partitioned between DCM
(150 mL) and sat. NaHCO3 solution (50 mL) and brine
(50 mL). The organic layer was dried (Na2SO4) and concen-
trated by vacuum. The residue was purified by silica gel chro-
matography (eluting with 10% CH3OH in DCM) to afford
compound 10 (148 mg, 0.35 mmol, 88% yield) as a yellowish
solid; MS (APCI) (M þ H)þ 423. 1H NMR (400 MHz, CDCl3)
d ppm 1.18e1.45 (m, 3H) 1.58 (s, 2H) 1.71 (s, 2H) 1.85e2.22
(m, 3H) 3.82 (s, 1H) 4.05 (s, 6H) 6.43 (d, J ¼ 5.3 Hz, 1H) 7.04
(d, J ¼ 9.1 Hz, 1H) 7.42e7.50 (m, 2H) 7.54 (s, 1H) 8.12 (d,
J ¼ 2.5 Hz, 1H) 8.50 (d, J ¼ 5.1 Hz, 1H) 8.91 (s, 1H) 8.95e
9.07 (m, 1H).
1
(M þ H)þ 417. H NMR (400 MHz, DMSO-d6) d ppm 4.01
(s, 1H) 4.02 (s, 3H) 4.03 (s, 3H) 4.07 (s, 1H) 6.97 (d,
J ¼ 6.3 Hz, 1H) 7.42e7.50 (m, 1H) 7.53e7.59 (m, 2H) 7.74
(s, 1H) 7.91 (t, J ¼ 9.1, 3.0 Hz, 1H) 7.96 (t, J ¼ 7.2 Hz, 1H)
8.26 (d, J ¼ 9.1 Hz, 1H) 8.48 (d, J ¼ 3.0 Hz, 1H) 8.61 (d,
J ¼ 4.3 Hz, 1H) 8.75e8.84 (m, J ¼ 6.3 Hz, 1H) 11.10 (s, 1H).
Anal. Calcd for C23H20N4O4$2.5CF3COOH$0.5H2O: C,
47.33; H, 3.33; N, 7.89. Found: C, 47.14; H, 3.36; N, 8.07.
5.1.6. N-{5-[(6,7-Dimethoxyquinolin-4-yl)-
oxy]pyridin-2-yl}piperazine-1-carboxamide (16)
5.1.6.1. Synthesis of 4-[5-(6,7-dimethoxy-quinolin-4-yloxy)-
pyridin-2-ylcarbamoyl]-piperazine-1-carboxylic acid tert-butyl
ester (15). DIEA (1 mL, 6 mmol) and triphosgene (200 mg,
0.6 mmol) were added sequentially to a solution of 5-[(6,7-di-
methoxyquinolin-4-yl)oxy]pyridin-2-amine (compound 6,
600 mg, 2 mmol) in 10 mL of DCM under inert atmosphere.
After stirring at room temperature for 12 h and subsequently
heating at 40ꢀC for 6 h, precipitate formed in the reaction mix-
ture. This precipitate was filtered off and the filtrate was con-
centrated to an oil residue. tert-Butyl-1-piperazine-carboxylate
(200 mg, 1.1 mmol) was added to this oil residue (350 mg,
1 mmol) in 10 mL of DCM. The mixture was heated at
room temperature for 12 h then water (50 mL) was added to
the reaction mixture to quench the reaction. EtOAc
(2 ꢂ 50 mL) was added to extract the aqueous solution. The
combined organic layers were dried (Na2SO4), filtered and
evaporated to get a tan oil. The residue was purified by silica
gel chromatography (eluting 80 / 90% EtOAc in hexanes) to
afford compound 15 as a yellow oil (60 mg; 0.12 mmol; 6%
yield); MS (APCI) (M þ H)þ 510. 1H NMR (400 MHz,
CDCl3) d ppm 1.45 (s, 9H) 3.34e3.42 (m, 2H) 3.47e3.53
(m, J ¼ 5.4, 5.4 Hz, 2H) 4.01 (s, 3H) 4.01e4.03 (m, 3H)
6.39 (d, J ¼ 5.3 Hz, 1H) 7.39 (s, 1H) 7.44 (s, 1H) 7.48e7.58
(m, 2H) 8.08e8.17 (m, 2H) 8.46 (d, J ¼ 5.1 Hz, 1H).
Anal. Calcd for C23H26N4O4$0.28hexane: C, 65.69; H,
6.70; N, 12.38. Found: C, 65.63; H, 6.92; N, 12.05.
5.1.8. N-{5-[(6,7-Dimethoxyquinolin-4-yl)amino]pyridin-2-
yl}-N0-(2-phenylethyl)urea (11)
(2-Isocyanatoethyl) benzene (64 mg, 0.437 mmol) was
added to a solution of 5-[(6,7-dimethoxyquinolin-4-yl)oxy]-
pyridin-2-amine (compound 6, 100 mg, 0.34 mmol) in DCM
(2 mL). The mixture was then heated to 75 ꢀC for 16 h and al-
lowed to cool to ambient temperature. The mixture was con-
centrated to dryness and the crude product was purified by
silica gel chromatography (eluting with 10% CH3OH in
DCM) to afford 85 mg of compound 11 as a white solid
(57%); MS (APCI) (M þ H)þ 445. 1H NMR (400 MHz,
DMSO-d6)
d
ppm 2.79 (t, J ¼ 7.1 Hz, 2H) 3.43 (q,
J ¼ 6.8 Hz, 2H) 3.94 (d, J ¼ 2.3 Hz, 6H) 6.47 (d, J ¼ 5.3 Hz,
1H) 7.21 (t, J ¼ 7.1 Hz, 1H) 7.25e7.34 (m, 4H) 7.40 (s, 1H)
7.52 (s, 1H) 7.57 (d, J ¼ 8.8 Hz, 1H) 7.70 (dd, J ¼ 9.1,
2.8 Hz, 1H) 7.88 (s, 1H) 8.14 (d, J ¼ 2.8 Hz, 1H) 8.48 (d,
J ¼ 5.1 Hz, 1H) 9.36 (s, 1H).
Anal. Calcd for C25H24N4O4$0.25H2O: C, 66.88; H, 5.50;
N, 12.48. Found: C, 67.27; H, 5.56; N, 12.01.
5.1.9. 1-[5-(6,7-Dimethoxy-quinolin-4-yloxy)-
5.1.6.2. Synthesis of N-{5-[(6,7-dimethoxyquinolin-4-yl)oxy]-
pyridin-2-yl}piperazine-1-carboxamide (16). Hydrogen chlo-
ride (3 mL, 12 mmol, 4 M in dioxane) was added to
a solution of tert-butyl 4-[({5-[(6,7-dimethoxyquinolin-4-
yl)oxy]pyridin-2-yl}amino)carbonyl]piperazine-1-carboxylate
(compound 15, 60 mg, 0.12 mmol) at room temperature. The
reaction mixture was stirred at room temperature for 12 h
pyridin-2-yl]-3-(2-oxo-2-pyrrolidin-1-yl-ethyl)urea (19)
5.1.9.1. Synthesis of ethyl N-[({5-[(6,7-dimethoxyquinolin-4-
yl)oxy]pyridin-2-yl}amino)carbonyl]glycinate (17). Ethyl iso-
cyanatoacetate (0.12 mL, 1.1 mmol) was added to a reaction
solution of 5-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-2-yl-
amine (297.3 mg, 1 mmol.) in DCM (8 mL). The mixture

P.-P. Kung et al. / European Journal of Medicinal Chemistry 43 (2008) 1321e1329
1327
was stirred at room temperature for 12 h. The reaction mixture
5.1.10.
N-Cyclohexyl-N0-{5-[(6,7-dimethoxyquinolin-4-
was partitioned between DCM (150 mL) and sat. NaHCO3 so-
lution (50 mL). The organic layer was dried (Na2SO4), fil-
tered, and concentrated to an oil residue. The residue was
purified by silica gel chromatography (eluting with eluting
with 10% CH3OH in DCM) to afford compound 17
(400 mg, 94% yield) as a yellowish solid; MS (APCI)
yl)oxy]pyridin-2-yl}urea (20)
Diisopropylethylamine (90 mL, 0.5 mmol) and HATU
(95 mg, 0.25 mmol) were added to a solution of N-[({5-
[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}amino)carbo-
nyl]glycine (compound 18, 100 mg, 0.25 mmol). After stirring
at room temperature for 30 min, cyclohexylamine (22 mg,
0.25 mmol) was added. The resulting mixture was stirred at
room temperature for 12 h. The reaction mixture was parti-
tioned between EtOAc (2 ꢂ 50 mL) and sat. NaHCO3
(20 mL). The organic layer was dried (Na2SO4), filtered, and
then concentrated by vacuum to give a yellow oil. The oil res-
idue was purified by reverse phase chromatography (eluting
with 50% acetonitrile in H2O, containing 0.1% acetic acid)
to afford compound 20 as white solid (20 mg, 18% yield);
1
(M þ H)þ 427. H NMR (400 MHz, CDCl3) d ppm 1.26e
1.33 (m, 3H) 4.07 (d, J ¼ 4.8 Hz, 6H) 4.15e4.21 (m, 2H)
4.23 (d, J ¼ 7.1 Hz, 2H) 6.48 (d, J ¼ 5.6 Hz, 1H) 7.03 (d,
J ¼ 9.1 Hz, 1H) 7.49 (dd, J ¼ 8.8, 2.8 Hz, 1H) 7.55 (s, 1H)
7.61 (s, 1H) 8.17 (d, J ¼ 2.8 Hz, 1H) 8.52 (d, J ¼ 5.6 Hz,
1H) 8.56 (s, 1H) 9.46 (s, 1H).
Anal. Calcd for C21H22N4O6$0.26hexane: C, 59.51; H,
5.70; N, 12.25. Found: C, 59.57; H, 5.47; N, 11.90.
MS (APCI) (M þ H)þ 467. H NMR (400 MHz, DMSO-d6)
1
5.1.9.2. Synthesis of N-[({5-[(6,7-dimethoxyquinolin-4-yl)oxy]-
pyridin-2-yl}amino)carbonyl]glycine (18). Sodium hydroxide
(2 M, 0.9 mL, 1.8 mmol) was added to a solution of ethyl
N-[({5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}amino)
carbonyl]glycinate (compound 17, 390 mg, 0.9 mmol) in
EtOH (20 mL). The resulting mixture was stirred at room tem-
perature for 3 h. The pH of the reaction mixture was adjusted
to 4.0 by adding 4 M HCl and then it was extracted with
EtOAc (2 ꢂ 100 mL). The organic layer was dried (Na2SO4),
filtered, and concentrated by vacuum to afford compound 18
(510 mg, 94% yield) as a yellow solid; MS (APCI)
d ppm 1.35e1.63 (m, 6H) 3.40e3.50 (m, 4H) 3.95 (d,
J ¼ 2.8 Hz, 6H) 4.05 (d, J ¼ 4.6 Hz, 2H) 6.58 (s, 1H) 7.42
(s, 1H) 7.52e7.59 (m, 1H) 7.63e7.70 (m, 1H) 7.70e7.77
(m, 1H) 7.96 (d, J ¼ 11.9 Hz, 1H) 8.18e8.28 (m, 1H) 8.54
(d, J ¼ 5.1 Hz, 1H) 9.59 (s, 1H).
Anal. Calcd for C24H27N5O5$1.42H2O$0.26HOAc: C,
58.12; H, 6.14; N, 13.82. Found: C, 58.01; H, 5.73; N, 13.70.
5.1.11. N-Benzyl-N0-{5-[(6,7-dimethoxyquinolin-
4-yl)oxy]pyridin-2-yl}urea (12)
Isocyanatomethyl benzene (67 mg, 0.51 mmol) was added
to a solution of 5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-
2-amine (compound 6, 100 mg, 0.34 mmol) in DCM (2 mL).
The mixture was then heated to 75 ꢀC for 16 h and allowed
to cool to ambient temperature. The mixture was concentrated
to dryness and the crude product was purified by silica gel
chromatography (eluting with 3% CH3OH in DCM) to afford
compound 12 (137 mg, 95% yield) as a white solid; MS (m/z)
(APCI) [M þ H]þ 431. 1H NMR (400 MHz, DMSO-d6) d ppm
3.94 (d, J ¼ 2.8 Hz, 6H) 4.41 (d, J ¼ 6.1 Hz, 2H) 6.49 (d,
J ¼ 5.3 Hz, 1H) 7.22e7.29 (m, 1H) 7.30e7.37 (m, 4H) 7.40
(s, 1H) 7.52 (s, 1H) 7.62e7.67 (m, 1H) 7.69e7.75 (m, 1H)
8.15e8.25 (m, 2H) 8.47 (d, J ¼ 5.3 Hz, 1H) 9.43 (s, 1H).
Anal. Calcd for C24H22N4O4$0.5H2O: C, 65.59; H, 5.28; N,
12.75. Found: C, 65.43; H, 5.32; N, 12.60.
1
(M þ H)þ 399. H NMR (400 MHz, DMSO-d6) d ppm 3.89
(d, J ¼ 5.8 Hz, 2H) 3.96e4.08 (m, 6H) 6.94 (d, J ¼ 6.3 Hz,
1H) 7.70e7.81 (m, 3H) 7.84 (dd, J ¼ 9.1, 3.0 Hz, 1H) 7.98
(s, 1H) 8.33 (d, J ¼ 2.8 Hz, 1H) 8.77 (d, J ¼ 6.6 Hz, 1H)
9.69 (s, 1H) 12.63 (s, 1H).
5.1.9.3. Synthesis of 1-[5-(6,7-dimethoxy-quinolin-4-yloxy)-
pyridin-2-yl]-3-(2-oxo-2-pyrrolidin-1-yl-ethyl)-urea (19). Dii-
sopropylethylamine (90 mL, 0.5 mmol) and HATU (95 mg,
0.25 mmol) were added to a solution of N-[({5-[(6,7-dime-
thoxyquinolin-4-yl)oxy]pyridin-2-yl}amino)carbonyl]glycine
(compound 18, 100 mg, 0.25 mmol). After stirring at
room temperature for 30 min, cyclopentylamine (20 mg,
0.25 mmol) was added. The resulting mixture was stirred at
room temperature for 12 h. The reaction mixture was parti-
tioned between EtOAc (150 mL) and sat. NaHCO3 (75 mL).
The organic layer was dried (Na2SO4), filtered, and then con-
centrated by vacuum to give a yellow oil. To the oil residue
was added MeOH (5 mL) and a precipitate formed. The pre-
cipitate was collected and washed well with more MeOH.
The solid was dried under vacuum to give compound 19 as
a white solid (30 mg, 27% yield); MS (APCI) (M þ H)þ
5.1.12. N-[({5-[(6,7-Dimethoxyquinolin-4-yl)oxy]pyridin-2-
yl}amino)carbonyl]-2-pyrrolidin-1-ylacetamide (22)
5.1.12.1. Synthesis of 2-chloro-N-[({5-[(6,7-dimethoxyquinolin-
4-yl)oxy]pyridin-2-yl}amino)carbonyl]acetamide (21). Chlor-
oacetylisocyanate (114 mg, 0.95 mmol) was added to a
solution of 5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-amine
(compound 6, 300 mg, 1 mmol) in DCM (5 mL) under inert
atmosphere. After stirring at room temperature for 12 h, a pre-
cipitate formed in the reaction mixture. This precipitate was
collected and washed with DCM to afford compound 21
(270.5 mg, 0.65 mmol, 68.4% yield) as an off white solid;
1
452. H NMR (400 MHz, DMSO-d6) d ppm 1.71e1.83 (m,
2H) 1.84e1.95 (m, 2H) 3.32e3.36 (m, 2H) 3.41 (t,
J ¼ 6.8 Hz, 2H) 3.94 (d, J ¼ 2.3 Hz, 6H) 3.98 (d, J ¼ 4.8 Hz,
2H) 6.48 (d, J ¼ 5.3 Hz, 1H) 7.39 (s, 1H) 7.52 (s, 1H)
7.62e7.67 (m, 1H) 7.66e7.78 (m, 1H) 7.97 (s, 1H) 8.21 (d,
J ¼ 2.8 Hz, 1H) 8.47 (d, J ¼ 5.3 Hz, 1H) 9.56 (s, 1H).
Anal. Calcd for C23H25N5O5$0.36MeOH: C, 60.60; H,
5.76; N, 15.13. Found: C, 60.34; H, 5.61; N, 15.09.
MS (APCI): (M þ H)þ 417. H NMR (400 MHz, DMSO-d6)
1
d ppm 3.93 (s, 3H) 3.94 (s, 3H) 4.43 (s, 2H) 6.54 (d,
J ¼ 5.1 Hz, 1H) 7.41 (s, 1H) 7.52 (s, 1H) 7.84 (dd, J ¼ 9.1,

1328
P.-P. Kung et al. / European Journal of Medicinal Chemistry 43 (2008) 1321e1329
2.8 Hz, 1H) 8.09 (d, J ¼ 9.1 Hz, 1H) 8.37 (d, J ¼ 3.0 Hz, 1H)
8.49 (d, J ¼ 5.1 Hz, 1H).
for 12 h under inert atmosphere. The mixture was evaporated
and the oil residue was purified by silica gel chromatography
(eluting with 1 / 3% CH3OH in EtOAc) to give compound
13 as a white solid (73 mg; 0.15 mmol; 69.4% yield); MS
(APCI) (M þ H)þ 481. 1H NMR (400 MHz, DMSO-d6) d ppm
3.93 (s, 3H) 3.94 (s, 3H) 6.54 (d, J ¼ 5.3 Hz, 1H) 7.41 (s, 1H)
7.53 (s, 1H) 7.59e7.69 (m, 1H) 7.85 (dd, J ¼ 9.0, 2.9 Hz, 1H)
8.10 (d, J ¼ 9.1 Hz, 1H) 8.39 (d, J ¼ 2.8 Hz, 1H) 8.49 (d,
J ¼ 5.3 Hz, 1H) 10.74 (s, 1H) 11.68 (s, 1H).
5.1.12.2. Synthesis of N-[({5-[(6,7-
dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}amino)carbonyl]-
2-pyrrolidin-1-ylacetamide (22)
Pyrrolidine (35 mg, 0.4 mmol) and DIEA (0.2 mL, 1 mmol)
were added sequentially to a solution of 2-chloro-N-[({5-[(6,7-
dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}amino)carbonyl]
acetamide (compound 21, 80 mg, 0.19 mmol) in 3 mL of
DMF. The mixture was heated at 60 ꢀC for 12 h then cooled
to ambient temperature. Water (50 mL) was added to the reac-
tion mixture to quench the reaction. EtOAc (2 ꢂ 50 mL) was
added to extract the aqueous solution. The combined organic
layers were dried (Na2SO4), filtered and evaporated to get
a tan oil. The residue was purified by silica gel chromatogra-
phy (eluting 0 / 5% CH3OH in EtOAc) to afford compound
22 as a white solid (43 mg; 0.09 mmol; 49.5% yield); MS
Anal. Calcd for C24H18F2N4O5$0.25CH2Cl2: C, 58.06; H,
3.72; N, 11.17. Found: C, 58.25; H, 3.82; N, 10.88.
5.1.15. N-[({5-[(6,7-Dimethoxyquinolin-4-yl)-
oxy]pyridin-2-yl}amino)carbonyl]benzamide (14)
Benzoyl isocyanate (0.04 g, 0.25 mmol) was added to a so-
lution of 5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-amine
(compound 6, 40 mg, 0.12 mmol) in DCM (10 mL). The re-
sulting mixture was stirred at room temperature for 12 h under
inert atmosphere. The mixture was evaporated and CH3OH
(5 mL) was added. The precipitate was filtered and washed
with more CH3OH to give compound 14 as a light yellow solid
(39.3 mg; 0.09 mmol; 72% yield); MS (APCI) (M þ H)þ 445.
1H NMR (400 MHz, DMSO-d6) d ppm 4.03 (s, 3H) 4.03 (s,
3H) 6.99 (d, J ¼ 6.3 Hz, 1H) 7.44e7.64 (m, 3H) 7.68 (t,
J ¼ 7.5 Hz, 1H) 7.76 (s, 1H) 7.91e8.03 (m, 1H) 8.04 (d,
J ¼ 7.1 Hz, 2H) 8.26 (d, J ¼ 9.1 Hz, 1H) 8.50 (d, J ¼ 2.8 Hz,
1H) 8.81 (d, J ¼ 6.6 Hz, 1H) 11.32 (s, 1H) 11.46 (s, 1H).
Anal. Calcd for C24H20N4O5$1CH2Cl2$0.75H2O: C, 55.31;
H, 4.36; N, 10.32. Found: C, 55.72; H, 4.60; N, 9.89.
1
(APCI) (M þ H)þ 452. H NMR (400 MHz, MeOD) d ppm
1.82e1.89 (m, 4H) 2.68 (t, J ¼ 5.6 Hz, 4H) 3.39 (s, 2H)
3.97 (s, 3H) 3.98 (s, 3H) 6.53 (d, J ¼ 5.3 Hz, 1H) 7.30 (s,
1H) 7.56 (s, 1H) 7.69 (dd, J ¼ 9.1, 3.0 Hz, 1H) 8.15 (d,
J ¼ 7.3 Hz, 1H) 8.24 (d, J ¼ 2.5 Hz, 1H) 8.40 (d, J ¼ 5.6 Hz,
1H).
Anal. Calcd for C23H25N5O5$0.5H2O: C, 59.99; H, 5.69; N,
15.21. Found: C, 59.76; H, 5.44; N, 15.25.
5.1.13. Compound 15 (PF-3187208, PK7292-086)
5.1.13.1. N-[({5-[(6,7-Dimethoxyquinolin-4-yl)oxy]pyridin-2-
yl}amino)carbonyl]-2-piperidin-1-ylacetamide (23). Piperi-
dine (40 mg, 0.4 mmol) and DIEA (0.2 mL, 1 mmol) were
added sequentially to a solution of 2-chloro-N-[({5-[(6,7-dime-
thoxyquinolin-4-yl)oxy]pyridin-2-yl}amino)carbonyl]acetamide
(compound 21, 80 mg, 0.19 mmol) in DMF (3 mL). The mix-
ture was heated at 60 ꢀC for 12 h then cooled to ambient temper-
ature. Water (50 mL) was added to the reaction mixture to
quench the reaction. EtOAc (2 ꢂ 50 mL) was added to extract
the aqueous solution. The combined organic layers were dried
(Na2SO4), filtered and evaporated to get a tan oil. The residue
was purified by silica gel chromatography (eluting 85 / 90%
EtOAc in hexane) to afford compound 23 as a white solid
(72 mg; 0.16 mmol; 80.7% yield); MS (APCI) (M þ H)þ 466.
1H NMR (400 MHz, MeOD) d ppm 1.43 (d, J ¼ 3.8 Hz, 2H)
1.57e1.65 (m, 4H) 2.44e2.53 (m, 4H) 3.12 (s, 2H) 3.93 (s,
3H) 3.94 (s, 3H) 6.47 (d, J ¼ 5.3 Hz, 1H) 7.22 (s, 1H) 7.47 (s,
1H) 7.63 (dd, J ¼ 9.1, 2.8 Hz, 1H) 8.08 (d, J ¼ 7.3 Hz, 1H)
8.18 (d, J ¼ 2.8 Hz, 1H) 8.35 (d, J ¼ 5.3 Hz, 1H).
5.2. c-Met tyrosine kinase coupled enzymatic
spectrophotometric assay
Human c-Met (Upstate 14-256) was activated by autophos-
phorylation with ATP prior to use in the enzyme assay. The in-
hibition of enzyme activity was determined with a coupled
enzyme system that monitored for the production of ADP
via oxidation of NADH using pyruvate kinase (PK) and lactic
dehydrogenase (LDH). The reaction mix contained 300 mM
ATP, 500 mM Ac-ARDMYDKEYYSVHNK peptide, 20 mM
MgCl2, 1 mM PEP, 300 mM NADH, 2 mM DTT, 15 units/
mL LDH, 15 units/mL PK in 100 mM HEPES, pH 7.5,
37 ꢀC. Compound was added to achieve a final DMSO con-
centration of 2% and the reaction was initiated with c-Met
(25 nM final concentration). The coupling system allowed
for continuous monitoring of the reaction at 340 nm and initial
velocities were calculated by linear regression. Ki values were
determined by fitting to the Morrison tight-binding equation
[12]. Errors for Ki values are less than 10%.
Anal. Calcd for C24H27N5O2$0.5H2O: C, 60.75; H, 5.95; N,
14.76. Found: C, 60.95; H, 5.80; N, 14.80.
References
5.1.14. N-[({5-[(6,7-Dimethoxyquinolin-4-yl)oxy]pyridin-2-
yl}amino)carbonyl]-2,6-difluorobenzamide (13)
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(10 mL). The resulting mixture was stirred at room temperature
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