Synthesis, activity and docking studies of phenylpyrimidine–carboxamide Sorafenib derivatives

Article abstract of DOI:10.1016/j.bmc.2016.09.021

Two series of Sorafenib derivatives bearing phenylpyrimidine–carboxamide moiety (16a–g and 17a–p) were designed, synthesized and evaluated for the IC₅₀values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC₅₀values of 6.35 ± 0.43 μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC₅₀values of 3.39 ± 0.37 μM. Structure–activity relationships (SARs) and docking studies indicated that the second series (17a–p) showed more active than the first series (16a–g). What's more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity.

Full text of DOI:10.1016/j.bmc.2016.09.021

Bioorganic & Medicinal Chemistry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis, activity and docking studies of phenylpyrimidine–
carboxamide Sorafenib derivatives
Wenhui Wang a,y, Chunjiang Wu a,y, Jianqiang Wang b, Rong Luo c, Caolin Wang a, Xiaobo Liu a, Jiqing Li a,
Wufu Zhu a, , Pengwu Zheng a,
⇑
⇑
a School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China
b Fushun Center for Drug Control, Fushun 113000, China
c Jiangxi Province Institute of Materia Medica, Nanchang 330000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two series of Sorafenib derivatives bearing phenylpyrimidine–carboxamide moiety (16a–g and 17a–p)
were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549,
MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against
VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity
against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line,
Received 24 July 2016
Revised 7 September 2016
Accepted 9 September 2016
Available online xxxx
with the IC50 values of 6.35 0.43
against A549 cell line, with the IC50 values of 3.39 0.37
and docking studies indicated that the second series (17a–p) showed more active than the first series
(16a–g). What’s more, the introduction of fluoro atom to the phenoxy part played no significant impact
on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity.
Ó 2016 Elsevier Ltd. All rights reserved.
l
M. Meanwhile, compound 17n revealed more active than Sorafenib
M. Structure–activity relationships (SARs)
Keywords:
Phenylpyrimidine
Sorafenib
Synthesis
Docking
l
VEGFR2/KDR
Antitumor activity
1. Introduction
bearing phenylpyrimidine–carboxamide scaffold as potential
antitumor agents.14,15 Most of them exhibited excellent antitumor
VEGFR2 is the major VEGF receptor, which can promote
endothelial cell division, proliferation and induce tumor angiogen-
esis and metastasis. VEGF family and its receptors are one of the
strongest positive regulatory factor in the process of tumor angio-
genesis. They have become the main target in anti-angiogenesis on
account of their overexpression in tumor angiogenesis.
In recent years, many VEGFR2/KDR inhibitors were reported,
such as Lenvatinib (E7080),1,2 Tivozanib(AV-951),3 Sorafenib4,5and
Regorafenib(BAY 73-4506)6 (the structures of them are shown in
Fig. 1). Sorafenib, a diaryl urea multiple-targeted antitumor agent,
was approved by FDA for the treatment of advanced hepatocellular
carcinoma (HCC) in 2005.7–9 Based on its broad-spectrum
antitumor activity, multi-antitumor mechanism and satisfactory
druggability, Sorafenib and its derivates have been researched
extensively.7,10–13
activity. Meanwhile, the structure–activity relationships (SARs)
showed that the phenylpyrimidine–carboxamide scaffold is benefit
to the activity. Inspired by these compounds, we replaced bis-aryl
urea moiety of Sorafenib with phenylpyrimidine–carboxamide
scaffold in this paper. In addition, fluoro atom was introduced to
the phenoxy group according to Regorafenib. As a result, two series
of Sorafenib derivatives bearing phenylpyrimidine–carboxamide
scaffold were designed and synthesized. The structures of the
target compounds were shown in Figure 1.
Herein we disclosed the synthesis and antitumor activity
against A549 (human lung cancer), PC-3 (human prostatic cancer)
and MCF-7(human breast cancer) cancer cell lines, and VEGFR2/
KDR kinase of Sorafenib derivatives bearing phenylpyrimidine–
carboxamide unit. Moreover, docking studies were presented in
this paper as well.
In our previous study, we reported two series of quinoline-
based derivatives and 1H-pyrrolo[2,3-b]pyridine derivatives
2. Chemistry
The preparation of target compounds 16a–g and 17a–p is
described in Scheme 1.
⇑
Corresponding authors. Tel./fax: +86 791 8380 2393.
E-mail addresses: zhuwf@jxstnu.edu.cn, zhuwufu-1122@163.com (W. Zhu),
Compounds 2, 3 and 4 were synthesized according to the
zhengpw@126.com (P. Zheng).
reported procedures.16
y
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.bmc.2016.09.021
0968-0896/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wang, W.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.09.021

2
W. Wang et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
O
NH2
R
O
H
N
H
N
CF3
Cl
O
N
Cl
O
O
O
O
N
N
O
HN
O
NH
O
N
N
O
H
N
NH
O
H
Cl
Sorafenib, R=H
Regorafenib, R=F
Lenvatinib (E7080)
Tivozanib (AV-951)
N
Y
N
Z
N
H
N
H
N
H
N
X
O
(F)H
O
(F)H
F
X
Y
R
R
R
O
O
O
O
O
O
H
N
16a-g:X=N,Y=CH
17a-p:X=CH,Y=N
R
N
N
N
N
H
O
Target compounds
Compounds in our previous study
Figure 1. Structures of small-molecule VEGFR2/KDR inhibitors and target compounds.
Cl
Cl
O
O
c
a
b
N
H
H
N
N
N
N
1
COOH
N
2
COCl
N
NH2
NH2
3
4
6
O
d
O
O
O
O
F
N
H
N
H
e
N
F
NO2
5
O
N
OH
N
O
NH2
N
N
i
h
R
R
O
O
N
N
10a-e
11a-e
g
f
N
R
R
R
N
N
N
N
7a-h
8a-h
9a-h
NH2
OH
i
R
R
j
O
O
O
13a-h
12a-h
X
O
Cl
N
O
O
N
N
H
R
k
k
l
N
N
N
11a-e
13a-h
N
4
6
or
R
H
14a-e
16a-e:X=H
16f-g:X=F
N
N
X
O
O
Cl
l
or
N
O
R
R
H
O
4
6
N
15a-h
N
H
N
N
17a-h:X=H
17i-p:X=F
Scheme 1. Synthetic route of target compounds. Reagents and conditions: (a) SOCl2, NaBr, chlorobenzene, 85 °C, 20 h; (b) 30% MeNH2, toluene, 10–20 °C, 6 h;
(c) 4-aminophenol, t-BuOK, NaI, DMF, 6 h; (d) 4-amino-2-fluorophenol, chlorobenzene, reflux, 30 h; (e) EtOH, FeCl3ꢀ6H2O, N2H4ꢀH2O, reflux, 8 h; (f) DMF-DMA, 80 °C, 8–12 h;
(g) formamidine acetate, EtONa, EtOH, 70 °C, 1 h, reflux, 15–20 h; (h) acetamide, 98%H2SO4, FeSO4ꢀ7H2O, 30%H2O2, 0–10 °C, 1 h, 10–15 °C, 30 min; (i) 20%H2SO4, 100 °C,
5–10 h; (j) acetamide, 98%H2SO4, FeSO4ꢀ7H2O, tert-Butyl hydroperoxide, 0–10 °C, 1 h, 10–15 °C, 30 min; (k) (COCl)2, DMF, CH2Cl2, rt, 0.5 h; (l) DIPEA, CH2Cl2, rt, 0.5 h.
The mixtures of 4-chloro-N-methylpicolinamide
3
and
were then substituted with amides 4 or 6 promoted by DIPEA
in dichloromethane to yield the target compounds 16a–g and
17a–p, respectively.
2-fluoro-4-nitrophenol was refluxed in chlorobenzene to get com-
pound 4-(2-fluoro-4-nitrophenoxy)-N-methylpicolinamide 5. Then
compound 5 was reduced to the key intermediate 4-(4-amino-2-
fluorophenoxy)-N-methylpicolinamide 6.
The preparation of the key intermediates 11a–e has been illus-
trated in detail in our previous work.14 Meanwhile, the synthesis
method of 13a–h was illustrated in Sakamoto’s work.17 11a–e
and 13a–h were chlorinated with oxalyl chloride to obtain
phenylpyrimidine–carbonyl chloride 14a–e and 15a–h, which
3. Results and discussion
3.1. Biological evaluation
Taking Sorafenib as reference compound, the target compounds
(16a–g and 17a–p) were evaluated for the cytotoxicity against
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W. Wang et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
3
Table 3
three cancer cell lines A549, PC-3 and MCF-7 by 3-(4,5-dimethylth-
Activity against VEGFR2/KDR kinase of compound 17n and 17f
iazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) cell prolifera-
tion assay. In addition, two selected compounds (17n and 17f)
were further evaluated for VEGFR2/KDR kinase inhibitory
activity. The results expressed as IC50 values were summarized in
Tables 1–3, Figure 2 and the values are the average of at least
two independent experiments.
As shown in Tables 1 and 2, more than half of the target com-
pounds showed moderate cytotoxicity activity against the different
cancer cells.
a
Compd no
IC50 (lM)
VEGFR2/KDR
17f
17n
3.6 0.38
1.2 0.11
0.17 0.09
0.072 0.002
Sorafenibb
Staurosporineb
a
The values are an average of two separate determinations.
Used as positive controls.
b
The activity results of the first series 16a–g are shown in Table 1.
The results showed that the activity of 16a–g against PC-3 is supe-
rior to it against A549 and MCF-7. What’s more, the introduction of
fluoro atoms to the phenoxy part was adverse for the activity by
comparing 16b and 16f or 16d and 16g. Compared with 16a, the
presence of electron-donating (–CH3, –OCH3) on aryl group played
no significant impact on the activity, such as compounds 16b and
Table 1
Structures and cytotoxicity of compounds 16a–g
N
N
H
N
X
N
H
N
O
R
O
O
16a-g X=H or F
a
Compd
X
R
IC50
(lM)
A549
MCF-7
PC-3
16a
16b
16c
16d
16e
16f
–H
–H
–H
–H
–H
–F
–H
4-OCH3
3-Cl
4-CH3
4-NO2
4-OCH3
4-CH3
—
26.20 1.05
11.10 0.87
>100
28.44 1.09
>100
16.62 0.88
33.21 1.03
6.53 0.44
39.12 1.17
35.17 1.04
>100
44.25 1.21
>100
>100
69.20 1.21
4.21 0.31
7.31 0.58
14.18 0.99
20.80 0.86
13.06 0.94
>100
24.27 1.01
28.39 0.94
3.03 0.28
16g
–F
—
Sorafenibb
a
The values are an average of two separate determinations.
Used as a positive controls.
b
Table 2
Structures and cytotoxicity of compounds 17a–p
N
N
H
N
X
O
N
H
N
R
O
O
17a-p X=H or F
a
Compd
X
R
IC50
(
lM)
A549
MCF-7
PC-3
17a
17b
17c
17d
17e
17f
17g
17h
17i
17j
17k
17l
17m
17n
17o
17p
Sorafenibb
–H
–H
–H
–H
–H
–H
–H
–H
–F
–F
–F
–F
–F
–F
–F
–F
—
–H
4-OCH3
4-Cl
27.13 1.03
13.53 0.81
>100
>100
>100
13.26 0.65
>100
>100
23.22 0.96
34.47 0.92
>100
18.23 0.92
29.23 0.95
>100
44.23 1.34
38.80 1.24
>100
>100
>100
29.28 0.89
>100
>100
44.34 1.25
56.23 1.27
>100
4-F
>100
4-CH3
4-C2H5
4-CF3
4-Br
–H
4-OCH3
4-Cl
34.62 1.07
6.35 0.43
>100
>100
32.39 1.01
46.22 1.04
>100
4-F
>100
>100
>100
4-CH3
4-C2H5
4-CF3
4-Br
13.22 0.88
3.39 0.37
>100
>100
6.53 0.44
19.20 0.99
7.63 0.45
>100
>100
4.21 0.31
40.24 1.05
15.60 0.69
>100
>100
3.03 0.38
—
a
The values are an average of two separate determinations.
Used as a positive controls.
b
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W. Wang et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
Figure 2. Relationship between activity and concentration of selected compound 17f and 17n against three cancer cell lines.
16d. However, the presence of electron withdrawing group
(–Cl, –NO2) decreased or vanished the activity against all the three
cancer lines of the target compounds, such as 16c and 16e.
As shown in Table 2, the activity of the second series 17a–p
against A549 and MCF-7 was better than it against PC-3. And the
introduction of fluoro atoms to the phenoxy part displayed no sig-
nificant impact on the activity, such as compounds 17i, 17j, 17m
and 17n. In addition, the introduction of electron-donating such
as –CH3, –C2H5 and -OCH3 might be appropriate to increase the
activity. Among them, compounds 17f and 17n substituted with
ethyl at C-4 position of aryl group displayed better activity against
MCF-7 and A549 cell lines, respectively. Especially, 17n showed
better activity than positive control Sorafenib against A549 cell
lines. In contrast, the introduction of electron withdrawing group
(–F, –Cl, –Br, –NO2, –CF3) vanished the activity of the target com-
pounds, such as compounds 16c, 16e, 17c–d, 17g–h, 17k–l and
17o–p.
and –OCH3 played no significant impact or slight impact on the
activity. And For the representative compounds 17f and 17n, the
phenomenon of dose-dependent was observable in Figure 2.
The inhibitory activity against VEGFR2/KDR kinase of two
selected compounds was further evaluated. Compounds 17f and
17n revealed moderate activity against VEGFR2/KDR kinase with
the IC50 values of 3.6
In summary, the results suggested that the introduction of
phenylpyrimidine–carboxamide scaffold bearing electron-
lM and 1.2 lM, respectively.
donating on aryl group could increase the activity appropriately.
Meanwhile, the position connecting between amide and
phenylpyrimidine impacted the activity slightly. Therefore, the
two series of compounds as VEGFR2/KDR inhibitors are worth
studying deeply.
3.2. Molecular docking study
By comparison, the second series (17a–p) showed better activ-
ity than the first series (16a–g) against MCF-7 cell lines. However,
the result was opposite against PC-3 cell lines. The difference
might be resulted from the different positions of the N atom lead-
ing to selectivity of these compounds. In general, the introduction
of fluoro atoms to the phenoxy part was adverse for the activity.
What’s more, the substitutions of aryl group could affect the
cytotoxicity of target compounds simultaneously. Furthermore,
the presence of electron withdrawing group (–F, –Cl, –Br, –NO2,
–CF3) decreased or vanished the activity of the target compounds.
In contrast, the presence of electron-donating such as –CH3, –C2H5
To explore the binding modes of target compounds with the
active site of VEGFR2/KDR, molecular docking simulation studies
were carried out by using SURFLEX-DOCK module of SYBYL pack-
age version. Based on the in vitro inhibition results, we selected
compound 17n, our best VEGFR2/KDR inhibitor in this study, as
the ligand example, and the structure of VEGFR2/KDR was selected
as the docking model (PDB ID code: 4ASD13).
The binding modes of compound 17n and lead compound
Sorafenib were shown in Figure 3. As depicted in Figure 3,
compound 17n and lead compound can mostly overlap in the bind-
ing model and pyridine part, amide moiety formed four hydrogen
Figure 3. Binding poses of compound 17n with VEGFR2. The binding modes of Sorafenib and 17n were denoted by green and purple, respectively. H-bonding interactions
between the 17n, Sorafenib and VEGFR2 were denoted by dashed lines in yellow.
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W. Wang et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
5
bonds with residues CYS919, ASP1046 and GLU885, respectively.
added drop-wise to
a
solution of phenylpyrimidine chloride
Analysis of compound 17n’s binding mode in the active binding
site demonstrated that the docking mode of the 17n is similar to
the lead compound with the same H-bond between pyridine part,
amide moiety and CYS919, ASP1046, GLU885. The binding modes
showed that 4-ehylpheyl of compound 17n could be inserted into
the protein cavity contrary to 4-chloro-3-trifluoromethylphenyl of
Sorafenib to form relatively weak hydrophobic interactions. The
above-mentioned results of SARs analysis and molecular docking
study may allow the rational design of potential VEGFR2/KDR
inhibitors.
(0.8 mmol, 14a–e and 15a–h) in dichloromethane (10 mL) in an
ice bath. Upon completion of the addition, the reaction mixture
was removed from the ice bath and placed in room temperature
for 30 min and monitored by thin-layer chromatography (TLC).
The mixture was washed with 10% K2CO3 (50 mL ꢁ 3) followed
by brine (50 mL ꢁ 1), and the organic phase was separated, dried,
and evaporated to yield 16a–g and 17–p,which was recrystallized
by isopropanol.
5.4.1. N-(4-(2-(Methylcarbamoyl)pyridin-4-yloxy)phenyl)-4-
phenylpyrimidine-2-carboxamide (16a)
Yield:50.4%; ESI-MS [M+H]+ m/z: 426.2; mp 190.9–191.7 °C; 1
H
4. Conclusions
NMR (400 MHz, CDCl3) d 10.08 (s, 1H), 9.78 (s, 1H), 9.29 (s, 1H),
8.60 (s, 1H), 8.48 (d, J = 6.0 Hz, 1H), 8.19 (d, J = 6.4 Hz, 2H), 8.02
(s, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.53 (s, 3H), 7.33 (s, 1H), 7.16 (d,
J = 8.0 Hz, 2H), 3.01 (s, 3H). 13C NMR (101 MHz, DMSO) d 167.03,
165.73, 162.14, 158.65, 158.35, 150.07, 142.66, 136.45, 136.03,
132.27, 129.73, 127.85, 123.11, 121.74, 119.27, 114.79, 114.62,
110.02, 102.00, 26.57.
In summary, we designed and synthesized two series of Sorafe-
nib derivatives bearing phenylpyrimidine–carboxamide scaffold.
All of the target compounds were evaluated for the IC50 values
against three cancer cell lines and two selected compounds were
further evaluated for the activity against VEGFR2/KDR kinase. More
than half of the target compounds showed moderate to excellent
activity compared with positive control Sorafenib against three
cancer cell lines. Compound 17f showed equal activity to Sorafenib
5.4.2. 4-(4-Methoxyphenyl)-N-(4-(2-(methylcarbamoyl)pyridin-
4-yloxy)phenyl)pyrimidine-2-carboxamide (16b)
against MCF-7 cell line, with the IC50 values of 6.35 0.43
compound 17n revealed more active than Sorafenib against A549
cell line, with the IC50 values of 3.39 0.37 M. Structure–activity
lM, and
Yield: 52.3%; ESI-MS [M+K]+ m/z: 494.2; mp 92.2–93.8 °C; 1H
NMR (400 MHz, DMSO) d 11.05 (s, 1H), 9.39 (s, 1H), 8.80 (s, 1H),
8.54 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.32 (d, J = 8.6 Hz, 2H), 8.08
(d, J = 8.8 Hz, 2H), 7.41 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.7 Hz, 2H),
7.20–7.16 (m, 1H), 7.14 (d, J = 8.6 Hz, 2H), 3.87 (s, 3H), 2.79 (s,
3H). 13C NMR (101 MHz, CDCl3) d 166.11, 165.20, 164.20, 162.74,
162.08, 158.40, 157.85, 152.93, 150.82, 149.88, 136.19, 129.51
(2C), 128.20, 122.94 (2C), 121.63 (2C), 115.02 (2C), 114.53,
113.47, 109.36, 55.86, 26.39.
l
relationships (SARs) and docking studies indicated that the second
series (17a–p) showed more active than the first series (16a–g).
What’s more, the introduction of fluoro atom to the phenoxy part
played no significant impact on activity. In addition, the presence
of electron-donating on aryl group is benefit for the activity. Fur-
ther study will be carried out to identify the exact action mecha-
nism in near future.
5. Experimental
5.1. Chemistry
5.4.3. 4-(3-Chlorophenyl)-N-(4-(2-(methylcarbamoyl)pyridin-4-
yloxy)phenyl)pyrimidine-2-carboxamide (16c)
Yield: 40.1%; ESI-MS [M+H]+ m/z: 460.2; mp 172.3–173.5 °C; 1H
NMR (400 MHz, DMSO) d 11.05 (s, 1H), 9.45 (s, 1H), 8.75 (d,
J = 4.4 Hz, 1H), 8.64 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.33 (s, 1H),
8.27 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 7.8 Hz,
1H), 7.59 (t, J = 7.8 Hz, 1H), 7.37 (s, 1H), 7.24 (d, J = 8.7 Hz, 2H),
7.14 (d, J = 5.2 Hz, 1H), 2.74 (s, 3H). 13C NMR (101 MHz, DMSO) d
166.18, 164.24, 161.90, 158.65, 158.60, 152.96, 150.89, 150.00,
138.11, 136.24, 134.65, 131.93, 131.56, 127.48, 126.55, 123.05
(2C), 121.73 (2C), 115.08, 114.62, 109.42, 109.33, 26.48.
All melting points were obtained on a Büchi Melting Point B-
540 apparatus (Büchi Labortechnik, Flawil, Switzerland) and were
uncorrected. NMR spectra were performed using Bruker 400 MHz
spectrometers (Bruker Bioscience, Billerica, MA, USA) with TMS
as an internal standard. Mass spectra (MS) were taken in ESI mode
on Agilent 1100 LCMS (Agilent, Palo Alto, CA, USA). TLC analysis
was carried out on silica gel plates GF254 (Qindao Haiyang Chem-
ical, China). All the materials were obtained from commercial sup-
pliers and used without purification, unless otherwise specied.
Yields were not optimized.
5.4.4. N-(4-(2-(Methylcarbamoyl)pyridin-4-yloxy)phenyl)-4-p-
tolylpyrimidine-2-carboxamide (16d)
Yield: 61.3%; ESI-MS [M+H]+ m/z: 440.2; mp 196.1–197.8 °C; 1H
NMR (400 MHz, DMSO) d 11.09 (s, 1H), 9.44 (s, 1H), 8.89 (s, 1H),
8.65–8.51 (m, 2H), 8.25 (d, J = 7.4 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H),
7.49 (s, 1H), 7.42 (d, J = 7.7 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.23
(s, 1H), 2.80 (s, 3H), 2.42 (s, 3H). 13C NMR (101 MHz, DMSO) d
167.58, 165.63, 162.80, 162.13, 158.55, 158.09, 150.92, 149.42,
142.38, 136.59, 133.21, 130.30 (2C), 127.75 (2C), 123.07 (2C),
121.70 (2C), 114.83, 114.13, 110.50, 101.99, 26.63, 21.52.
5.2. General procedure for preparation of compounds 2, 3, 4, 5
and 6
Compounds 2, 3, 4, 5 and 6 were synthesized according to the
reported procedures by our research group.16
5.3. General procedure for the preparation of compounds 11a–e,
13a–h, 14a–e and 15a–h
5.4.5. N-(4-(2-(Methylcarbamoyl)pyridin-4-yloxy)phenyl)-4-(4-
nitrophenyl)pyrimidine-2-carboxamide (16e)
Compounds 11a–e, 13a–h, 14a–e and 15a–h were synthesized
according to the reported procedures by our research group.14,17
Yield: 46.7%; ESI-MS [M+Na]+ m/z: 493.1; mp 285.6–286.3 °C;
1H NMR (400 MHz, DMSO) d 11.15 (s, 1H), 9.58 (s, 1H), 8.80 (d,
J = 4.2 Hz, 1H), 8.77 (s, 1H), 8.61 (d, J = 8.6 Hz, 2H), 8.53 (d,
J = 5.5 Hz, 1H), 8.43 (d, J = 8.5 Hz, 2H), 8.10 (d, J = 8.7 Hz, 2H),
7.42 (s, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 3.2 Hz, 1H), 2.80
(s, 3H).
5.4. General procedure for the preparation of compounds 16a–g
and 17a–p
A solution of an appropriate aniline 4 or 6 (0.4 mmol) and diiso-
propylethylamine (0.49 mmol) in dichloromethane (10 mL) was
Please cite this article in press as: Wang, W.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.09.021

6
W. Wang et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
5.4.6. N-(3-Fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)
phenyl)-4-(4-methoxyphenyl)pyrimidine-2-carboxamide (16f)
Yield: 64.2%; ESI-MS [M+K]+ m/z: 512.1; mp 207.8–208.4 °C; 1H
NMR (400 MHz, DMSO) d 11.24 (s, 1H), 9.39 (s, 1H), 8.83 (s, 1H),
8.55 (d, J = 4.8 Hz, 2H), 8.32 (d, J = 8.3 Hz, 2H), 8.16 (d, J = 13.0 Hz,
1H), 7.93 (d, J = 8.7 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.41 (s, 1H),
7.24 (s, 1H), 7.13 (d, J = 8.3 Hz, 2H), 3.86 (s, 3H), 2.79 (s, 3H). 13C
NMR (101 MHz, DMSO) d 165.54, 165.27, 164.08, 162.77, 162.39,
158.40, 157.48, 154.85, 153.10, 150.96, 137.71, 129.51 (2C),
128.14, 124.18, 118.02, 115.01 (2C), 113.79, 113.54, 109.98,
109.74, 108.52, 55.85, 26.40.
2H), 7.22–7.16 (m, 1H), 2.78 (s, 3H). 13C NMR (101 MHz, CDCl3) d
166.19, 165.50, 164.43, 160.49, 157.75, 157.14, 149.68, 134.69,
132.01, 129.69 (2C), 129.60 (2C), 121.70 (2C), 121.55 (2C),
116.38, 116.16, 114.08, 113.64, 110.20, 101.93, 26.06.
5.4.12. N-(4-(2-(Methylcarbamoyl)pyridin-4-yloxy)phenyl)-6-p-
tolylpyrimidine-4-carboxamide (17e)
Yield: 43.4%; ESI-MS [M+K]+ m/z: 478.2; mp 186.4–188.1 °C; 1H
NMR (400 MHz, DMSO) d 11.05 (s, 1H), 9.42 (s, 1H), 8.79 (d,
J = 4.4 Hz, 1H), 8.57 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.23 (d,
J = 8.1 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 7.44–7.38 (m, 3H), 7.27 (d,
J = 8.8 Hz, 2H), 7.18 (dd, J = 5.5, 2.5 Hz, 1H), 2.79 (s, 3H), 2.41 (s,
3H). 13C NMR (101 MHz, DMSO) d 166.11, 165.52, 164.20, 162.04,
158.49, 158.12, 152.79, 150.83, 149.79, 142.36, 136.19, 133.18,
130.24 (2C), 127.69 (2C), 122.97 (2C), 121.65 (2C), 114.54,
114.05, 109.36, 26.39, 21.42.
5.4.7. N-(3-Fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)
phenyl)-4-p-tolylpyrimidine-2-carboxamide (16g)
Yield: 48.8%; ESI-MS [M+K]+ m/z: 496.2; mp 144.7–146.2 °C; 1H
NMR (400 MHz, DMSO) d 11.23 (s, 1H), 9.44 (s, 1H), 8.79 (s, 1H),
8.58 (s, 1H), 8.55 (d, J = 5.3 Hz, 1H), 8.24 (d, J = 7.5 Hz, 2H), 8.16
(d, J = 13.0 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H),
7.41 (s, 3H), 7.23 (s, 1H), 2.80 (s, 3H), 2.42 (s, 3H). 13C NMR
5.4.13. 6-(4-Ethylphenyl)-N-(4-(2-(methylcarbamoyl)pyridin-4-
yloxy)phenyl)pyrimidine-4-carboxamide (17f)
(101 MHz, DMSO)
d
165.64, 164.16, 162.46, 158.56, 157.92,
Yield: 42.1%; ESI-MS [M+K]+ m/z: 492.2; mp 144.2–145.1 °C; 1H
NMR (400 MHz, DMSO) d 11.00 (s, 1H), 9.37 (s, 1H), 8.72 (d,
J = 4.4 Hz, 1H), 8.52 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.19 (d,
J = 7.8 Hz, 2H), 8.02 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H),
7.35 (s, 1H), 7.22 (d, J = 8.7 Hz, 2H), 7.14–7.09 (m, 1H), 2.73 (s,
3H), 2.65 (dd, J = 14.9, 7.4 Hz, 2H), 1.22–1.16 (m, 3H). 13C NMR
157.86, 154.90, 153.15, 151.04, 142.44, 137.96, 133.19, 130.29
(2C), 127.75 (2C), 124.24, 118.15, 114.19, 113.87, 110.08, 109.84,
108.59, 26.49, 21.49.
5.4.8. N-(4-(2-(Methylcarbamoyl)pyridin-4-yloxy)phenyl)-6-
phenylpyrimidine-4-carboxamide (17a)
(101 MHz, DMSO)
d 166.11, 165.59, 164.25, 162.10, 158.55,
Yield: 87.4%; ESI-MS [M+K]+ m/z: 464.1; mp 181.2–182.7 °C; 1H
NMR (400 MHz, DMSO) d 11.07 (s, 1H), 9.47 (s, 1H), 8.79 (d,
J = 4.7 Hz, 1H), 8.61 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.33 (d,
J = 5.8 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 6.3 Hz, 3H),
7.41 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.17 (dd, J = 5.4,
2.4 Hz, 1H), 2.79 (s, 3H). 13C NMR (101 MHz, CDCl3) d 166.64,
166.25, 164.34, 160.59, 157.74, 156.67, 152.28, 150.34, 150.32,
149.58, 135.82, 134.77, 131.73, 129.12 (2C), 127.44 (2C), 121.69
(2C), 121.52 (2C), 114.04, 110.28, 26.08.
158.07, 152.87, 150.82, 148.36, 136.15, 133.44, 128.92 (2C),
127.80 (2C), 127.43, 122.90 (2C), 121.39 (2C), 114.54, 114.09,
109.37, 28.47, 26.29, 15.56.
5.4.14. N-(4-(2-(Methylcarbamoyl)pyridin-4-yloxy)phenyl)-6-
(4-(trifluoromethyl)phenyl)pyrimidine-4-Carboxamide (17g)
Yield: 66.3%; ESI-MS [M+K]+ m/z: 532.1; mp 233.0–234.7 °C; 1H
NMR (400 MHz, DMSO) d 11.12 (s, 1H), 9.54 (s, 1H), 8.79 (d,
J = 4.7 Hz, 1H), 8.72 (s, 1H), 8.58–8.51 (m, 3H), 8.09 (d, J = 8.8 Hz,
2H), 7.97 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 2.1 Hz, 1H), 7.29 (d,
J = 8.8 Hz, 2H), 7.18 (dd, J = 5.4, 2.4 Hz, 1H), 2.79 (s, 3H). 13C NMR
5.4.9. 6-(4-Methoxyphenyl)-N-(4-(2-(methylcarbamoyl)pyridin-
4-yloxy)phenyl)pyrimidine-4-carboxamide (17b)
(101 MHz, CDCl3)
d 167.10, 165.13, 163.26, 160.30, 157.91,
Yield: 60.4%; ESI-MS [M+K]+ m/z: 494.2; mp 101.7–102.5 °C; 1H
NMR (400 MHz, DMSO) d 11.04 (s, 1H), 9.39 (s, 1H), 8.79 (d,
J = 4.6 Hz, 1H), 8.55 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.32 (d,
J = 8.7 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 2.2 Hz, 1H),
7.28 (d, J = 8.8 Hz, 2H), 7.18 (dd, J = 5.5, 2.5 Hz, 1H), 7.14 (d,
J = 8.7 Hz, 2H), 3.87 (s, 3H), 2.79 (s, 3H). 13C NMR (101 MHz, DMSO)
d 166.10, 165.18, 164.20, 162.72, 162.06, 158.38, 157.82, 152.92,
150.80, 136.19, 129.49 (2C), 128.18, 126.82, 122.92 (2C), 121.62
(2C), 114.99 (2C), 114.50, 113.46, 109.35, 55.84, 26.39.
157.12, 151.39, 150.08, 148.45, 139.07, 134.93, 127.82 (2C),
126.09, 126.05 (2C), 125.06, 121.82 (2C), 121.53 (2C), 114.38,
114.24, 110.93, 26.26.
5.4.15. 6-(4-Bromophenyl)-N-(4-(2-(methylcarbamoyl)pyridin-
4-yloxy)phenyl)pyrimidine-4-carboxamide (17h)
Yield: 60.5%; ESI-MS [M+K]+ m/z: 542.1; mp 241.5–242.6 °C; 1H
NMR (400 MHz, DMSO) d 11.04 (s, 1H), 9.39 (s, 1H), 8.79 (d,
J = 4.6 Hz, 1H), 8.55 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.32 (d,
J = 8.7 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 2.2 Hz, 1H),
7.28 (d, J = 8.8 Hz, 2H), 7.18 (dd, J = 5.5, 2.5 Hz, 1H), 7.14 (d,
J = 8.7 Hz, 2H), 3.87 (s, 3H), 2.79 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 165.53, 162.94, 160.46, 157.81, 156.82, 149.95, 149.92, 148.11,
135.07, 134.65, 132.46, 132.41 (2C), 128.90 (2C), 126.72, 121.81
(2C), 121.52 (2C), 114.24, 113.74, 111.17, 26.33.
5.4.10. 6-(4-Chlorophenyl)-N-(4-(2-(methylcarbamoyl)pyridin-
4-yloxy)phenyl)pyrimidine-4-carboxamide (17c)
Yield: 47.9%; ESI-MS [M+K]+ m/z: 498.1; mp 233.4–235.4 °C; 1H
NMR (400 MHz, DMSO) d 11.08 (s, 1H), 9.47 (s, 1H), 8.79 (d,
J = 4.7 Hz, 1H), 8.63 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.36 (d,
J = 8.5 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H),
7.41 (d, J = 2.2 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.18 (dd, J = 5.4,
2.4 Hz, 1H), 2.79 (s, 3H). 13C NMR (101 MHz, CDCl3) d 167.21,
165.42, 163.14, 160.46, 157.80, 156.80, 151.33, 149.97, 148.34,
138.19, 135.03, 134.21, 129.41 (2C), 128.71 (2C), 121.80 (2C),
121.51 (2C), 114.22, 113.74, 111.03, 26.30.
5.4.16. N-(3-Fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)
phenyl)-6-phenylpyrimidine-4-carboxamide (17i)
Yield: 75.3%; ESI-MS [M+H]+ m/z: 444.1; mp 202.2–203.3 °C;
1H NMR (400 MHz, DMSO) d 11.29 (s, 1H), 9.48 (s, 1H), 8.82
(d, J = 4.4 Hz, 1H), 8.63 (s, 1H), 8.55 (d, J = 5.6 Hz, 1H), 8.33 (d,
J = 6.7 Hz, 2H), 8.17 (d, J = 12.6 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H),
7.61 (d, J = 5.7 Hz, 3H), 7.49 (t, J = 9.0 Hz, 1H), 7.41 (d,
J = 2.2 Hz, 1H), 7.24 (s, 1H), 2.79 (s, 3H). 13C NMR (101 MHz,
5.4.11. 6-(4-Fluorophenyl)-N-(4-(2-(methylcarbamoyl)pyridin-
4-yloxy)phenyl)pyrimidine-4-carboxamide (17d)
Yield: 40.8%; ESI-MS [M+K]+ m/z: 482.1; mp 181.6–183.2 °C; 1H
NMR (400 MHz, DMSO) d 11.08 (s, 1H), 9.46 (s, 1H), 8.78 (d,
J = 4.1 Hz, 1H), 8.62 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.46–8.39 (m,
2H), 8.08 (d, J = 8.7 Hz, 2H), 7.48–7.38 (m, 3H), 7.28 (d, J = 8.7 Hz,
DMSO) d 165.67, 165.55, 164.07, 162.35, 158.55, 158.03,
154.84, 153.08, 150.97, 137.80, 135.88, 132.19, 129.61 (2C),
127.75 (2C), 124.20, 118.11, 114.57, 113.81, 110.03, 109.81,
108.48, 26.41.
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W. Wang et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
7
5.4.17. N-(3-Fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)
phenyl)-6-(4-methoxyphenyl)pyrimidine-4-carboxamide (17j)
Yield: 60.4%; ESI-MS [M+K]+ m/z: 512.1; mp 197.4–198.5 °C; 1H
NMR (400 MHz, DMSO) d 11.23 (s, 1H), 9.39 (s, 1H), 8.82 (s, 1H),
8.55 (d, J = 4.6 Hz, 2H), 8.32 (d, J = 8.5 Hz, 2H), 8.16 (d, J = 13.1 Hz,
1H), 7.93 (d, J = 9.0 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.41 (s, 1H),
7.23 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H), 2.79 (s, 3H). 13C
NMR (101 MHz, DMSO) d 165.62, 165.30, 164.16, 162.80, 162.41,
158.44, 157.50, 154.91, 153.17, 152.48, 151.01, 129.56, 128.16
(2C), 124.22, 118.03, 115.03 (2C), 113.84, 113.57, 110.01, 109.76,
108.56, 55.89, 26.48.
J = 4.4 Hz, 1H), 8.72 (s, 1H), 8.58–8.52 (m, 3H), 8.16 (d,
J = 12.9 Hz, 1H), 7.99–7.91 (m, 3H), 7.49 (t, J = 9.0 Hz, 1H), 7.41
(d, J = 2.2 Hz, 1H), 7.26–7.22 (m, 1H), 2.79 (s, 3H). 13C NMR
(101 MHz, CDCl3)
d 166.23, 165.26, 163.61, 160.42, 157.94,
156.80, 153.04, 151.89, 149.29, 148.91, 139.02, 136.06, 135.99,
127.84 (2C), 126.10, 126.08 (2C), 123.71, 116.26, 114.40, 113.60,
109.70, 109.41, 26.18.
5.4.23. 6-(4-Bromophenyl)-N-(3-fluoro-4-(2-(methylcarbamoyl)
pyridin-4-yloxy)phenyl)pyrimidine-4-carboxamide (17p)
Yield: 60.2%; ESI-MS [M+K]+ m/z: 560.1; mp 255.9–257.5 °C; 1H
NMR (400 MHz, DMSO) d 11.28 (s, 1H), 9.48 (s, 1H), 8.82 (d,
J = 4.3 Hz, 1H), 8.64 (s, 1H), 8.55 (d, J = 5.6 Hz, 1H), 8.29 (d,
J = 8.4 Hz, 2H), 8.16 (d, J = 12.9 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H),
7.80 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 9.0 Hz, 1H), 7.41 (d, J = 2.2 Hz,
1H), 7.26–7.22 (m, 1H), 2.79 (s, 3H).
5.4.18. 6-(4-Chlorophenyl)-N-(3-fluoro-4-(2-(methylcarbamoyl)
pyridin-4-yloxy)phenyl)pyrimidine-4-carboxamide (17k)
Yield: 48.2%; ESI-MS [M+H]+ m/z: 478.1; mp 246.9–248.3 °C; 1H
NMR (400 MHz, DMSO) d 11.29 (s, 1H), 9.49 (s, 1H), 8.82 (s, 1H),
8.65 (s, 1H), 8.55 (d, J = 5.6 Hz, 1H), 8.37 (d, J = 8.1 Hz, 2H), 8.16
(d, J = 12.9 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H),
7.50 (t, J = 9.0 Hz, 1H), 7.41 (s, 1H), 7.23 (d, J = 5.5 Hz, 1H), 2.79
(s, 3H). 13C NMR (101 MHz, CDCl3) d 166.69, 165.62, 163.20,
160.67, 157.88, 156.55, 155.51, 153.03, 151.62, 148.49, 138.35,
134.23, 129.49 (2C), 128.79 (2C), 123.68, 116.34, 113.82, 113.70,
110.19, 109.71, 109.47, 26.29.
5.5. VEGFR2/KDR kinases assay
The inhibitory activity against VEGFR2/KDR Kinases Assay at
10 lM level in vitro or IC50 is evaluated through the mobility shift
assay or Lanthascreen assay together with reference compounds
Sorafenib and Staurosporine according to the reported
procedures.16,18
5.4.19. N-(3-Fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)
phenyl)-6-(4-fluorophenyl)pyrimidine-4-carboxamide (17l)
Yield: 45.5%; ESI-MS [M+K]+ m/z: 500.1; mp 202.8–203.5 °C; 1H
NMR (400 MHz, DMSO) d 11.29 (s, 1H), 9.47 (s, 1H), 8.83 (s, 1H),
8.63 (s, 1H), 8.55 (d, J = 4.9 Hz, 1H), 8.42 (s, 2H), 8.17 (d,
J = 12.5 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.49 (t, J = 10.9 Hz, 1H),
7.46–7.39 (m, 3H), 7.24 (s, 1H), 2.79 (s, 3H). 13C NMR (101 MHz,
CDCl3) d 167.02, 166.52, 165.68, 164.00, 162.78, 160.76, 157.86,
156.39, 148.23, 131.95, 129.78 (2C), 129.70, 129.23, 123.82,
116.46 (2C), 116.24, 115.09, 113.90, 113.71, 110.63, 109.75,
109.51, 26.47.
5.6. Cytotoxicity assay in vitro
The cytotoxic activities of compounds (16a–g and 17a–p) were
evaluated by A549, PC-3 and MCF-7 cell lines by the standard MTT
assay in vitro, with VEGFR2 inhibitors Sorafenib as positive control
according to the reported procedures.15,16
5.7. Docking studies
Docking studies were carried out according to the reported
procedures.16,19
5.4.20. N-(3-Fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)
phenyl)-6-p-tolylpyrimidine-4-carboxamide (17m)
Acknowledgments
Yield: 43.8%; ESI-MS [M+K]+ m/z: 496.2; mp 199.6–200.4 °C; 1H
NMR (400 MHz, DMSO) d 11.29 (s, 1H), 9.44 (s, 1H), 8.84 (d,
J = 4.7 Hz, 1H), 8.59 (s, 1H), 8.55 (d, J = 5.6 Hz, 1H), 8.24 (d,
J = 7.9 Hz, 2H), 8.17 (d, J = 13.0 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H),
7.50 (t, J = 9.0 Hz, 1H), 7.41 (d, J = 7.7 Hz, 3H), 7.24 (d, J = 3.2 Hz,
1H), 2.78 (s, 3H), 2.41 (s, 3H). 13C NMR (101 MHz, CDCl3) d
166.12, 165.55, 164.19, 162.05, 158.48, 158.17, 152.93, 152.90,
150.82, 149.86, 142.34, 136.29, 133.18, 130.23 (2C), 127.68 (2C),
122.98 (2C), 121.64, 114.53, 114.05, 109.35, 26.39, 21.42.
We gratefully acknowledge the generous support provided by
The National Natural Science Funds (No. 81460527), Science and
Technology Project Founded by the Education Department of
Jiangxi Province (No. GJJ150796), Top-notch talent project of
Jiangxi
Science
&
Technology
Normal
University
(2015QNBJRC001), College Students’ Science and Technology Inno-
vation Project of Jiangxi Province (YC2015-X28).
References and notes
5.4.21. 6-(4-Ethylphenyl)-N-(3-fluoro-4-(2-(methylcarbamoyl)
pyridin-4-yloxy)phenyl)pyrimidine-4-carboxamide (17n)
Yield: 42.3%; ESI-MS [M+K]+ m/z: 482.2; mp 154.6–155.4 °C; 1H
NMR (400 MHz, DMSO) d 11.26 (s, 1H), 9.45 (s, 1H), 8.81 (s, 1H),
8.59 (s, 1H), 8.55 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 7.8 Hz, 2H), 8.17
(d, J = 13.0 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 9.8 Hz, 1H),
7.45 (d, J = 8.0 Hz, 2H), 7.42 (s, 1H), 7.24 (s, 1H), 2.79 (s, 3H), 2.71
(dd, J = 14.9, 7.4 Hz, 2H), 1.28–1.23 (m, 3H). 13C NMR (101 MHz,
DMSO) d 165.66, 165.54, 164.06, 162.37, 158.49, 157.73, 153.02,
152.40, 150.97, 148.49, 137.62, 129.03 (2C), 127.79 (2C), 127.58,
124.21, 118.02, 114.15, 113.84, 109.99, 109.75, 108.50, 28.46,
26.41, 15.54.
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