Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives as Potential Angiogenesis Inhibitors

Article abstract of DOI:10.1002/cbdv.201900232

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays an important role in both vasculogenesis and angiogenesis. Inhibition of VEGFR-2 has been demonstrated as a key method against tumor-associated angiogenesis. Thiazolopyrimidine is an important analog of the purine ring, and we choose the thiazolopyrimidine scaffold as the mother nucleus. Two series of thiazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activity. In HUVEC inhibition assay, compounds 3l (=1-(5-{[2-(4-chlorophenyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}pyridin-2-yl)-3-(3,4-dimethylphenyl)urea) and 3m (=1-(5-{[2-(4-chlorophenyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}pyridin-2-yl)-3-(4-methoxyphenyl)urea) exhibited the most potent inhibitory effect (IC₅₀=1.65 and 3.52 μm, respectively). Compound 3l also showed the best potency against VEGFR-2 at 50 μm (98.5 %). These results suggest that further investigation of compound 3l might provide potential angiogenesis inhibitors.

Full text of DOI:10.1002/cbdv.201900232

Title: Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine
Derivatives as Angiogenesis Inhibitors
Authors: Li-Ping Sun, Wen-jun Xue, Ya-hui Deng, Zhong-hui Yan, Ji-
ping Liu, Yu Liu, and Jian-yao Du
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Biodiversity 10.1002/cbdv.201900232
Link to VoR: http://dx.doi.org/10.1002/cbdv.201900232

10.1002/cbdv.201900232
Chemistry & Biodiversity
Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives as
Angiogenesis Inhibitors
Wen-jun Xue1, #, Jian-yao Du1, #, Ya-hui Deng1, 3, #, Zhong-hui Yan1, Ji-ping Liu2, Yu Liu2, *
Li-ping Sun1, **
,
1Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China
Pharmaceutical University, Nanjing, P. R. China
2School of Life Science and Technology, China Pharmaceutical University, Nanjing, P. R. China
3Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and
Technology, Wuhan, P. R. China
# These authors contributed equally to this work
*Author for correspondence: liuyu@cpu.edu.cn
**Author for correspondence: chslp@cpu.edu.cn
Abstract: Vascular endothelial growth factor receptor-2 (VEGFR-2) plays an important role in
both vasculogenesis and angiogenesis. Inhibition of VEGFR-2 has been demonstrated as a key
method against tumor-associated angiogenesis. Thiazolopyrimidine is an important analogue of
the purine ring and we choose the thiazolopyrimidine scaffold as the mother nucleus. Two series of
thiazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for their anti-proliferative
activity. In HUVEC inhibition assay, compound 3l and 3m exhibited the most potent inhibitory
effect (IC50 = 1.65 and 3.52 μM respectively). Compound 3l also showed the best potency against
VEGFR-2 at 50 μM (98.5%). These results suggest that further investigation of compound 3l
might provide potential angiogenesis inhibitors.
Keywords: Thiazolopyrimidine, VEGFR-2, Angiogenesis
Introduction
Angiogenesis, the generation and growth of new blood vessels from pre-existing vessels, is a
vital process in both normal embryonic and adult development[1]. Aberrant regulation of
angiogenesis observed in many diseases including cancer, psoriasis, rheumatoid arthritis,
inflammation, and retinal complications[2, 3]. As described by Judah Folkman, tumor growth and
progression depend on angiogenesis[4]. Based on this theory, selective inhibition of tumor
angiogenesis has been introduced as a potential and attractive therapeutic strategy. Angiogenesis is
controlled by many pro-angiogenic and anti-angiogenic factors. Among these factors, VEGF is a
certain well-known pro-angiogenic factor in the direct regulation of tumor angiogenesis[5]. The
binding of VEGF to VEGFR promotes endothelial cell survival, proliferation, and migration.
The overexpression of VEGFR-2 is implicated in the angiogenesis of solid tumors[6].
Some VEGFR-2 inhibitors have been approved by FDA for the treatment of tumor, namely
Sorafenib, Sunitinib, Axitinib, Nintedanib, Pazopanib, Vandetanib, Regorafenib, Apatinib,
Lenvatinib (Figure 1)[7, 8]. Various scaffolds are involved in these inhibitors including
anthracenes[9], indazoles[10], quinazolines[11], pyrimidines[12] and pyridines[13]. We have previously
disclosed the oxazolopyrimidine derivatives as potent VEGFR-2 inhibitors[14, 15]. The scaffold of
thiazolopyrimidines can be considered as an important analogue of the purine ring. It can also be
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900232
Chemistry & Biodiversity
regarded as an isostere of quinazoline. Compounds with the thiazolo[5,4-d]pyrimidine scaffold
have been reported to exhibit antibacterial, anti-tumor and other pharmacological activity[16-19]. We
envisioned the replacement of oxazolopyrimidine with thiazolopyrimidine to provide the novel
series of compounds. Bis-aryl urea is a frequent structure in tyrosine kinase inhibitors, such as
sorafenib, regorafenib and lenvatinib (Figure 1). With the aim to enhance the affinity of the
compounds with VEGFR-2, we introduced urea moiety to the mother nucleus. We have previously
disclosed two series of thiazolo[5,4-d]pyrimidine compounds[20]. Two other series of
thiazolopyrimidine-urea derivatives were designed based on our previous work. In this paper, we
disclose the synthesis and characterization of the two series compounds as potent angiogenesis
inhibitors.
Figure 1. VEGFR-2 inhibitors of various scaffolds.
Results and discussion
Chemistry
To achieve a SARs exploration, two efficient synthetic routes adopted to obtain the different
derivatives (3a-3o, 10a-10f) were outlined in Scheme 1 and Scheme 2.
The synthesis of 3a-3o was illustrated in Scheme 1. The starting material 1a and 1b was
synthesized according to the previously reported route[20]. The urea moiety 6a-6i was synthesized
from 5-nitropyridin-2-amine and aromatic amines in the presence of triphosgene. Then compound
6a-6i was reduced to corresponding amine 2a-2i in the condition of hydrogen[21]. Reaction of
compound 1a, 1b and 2a-2i in isopropanol afforded the compounds of series I in good yields.
The synthesis of 10a-10f was shown in Scheme 2. The starting material 7 was obtained
according to the synthetic route we reported previously[20, 22]. Compound 7 reacted with sodium
sulfide and then cyclized to give the mother nucleus 9. The target compounds were prepared in the
same way as series I.
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900232
Chemistry & Biodiversity
Scheme 1. Synthesis of compounds 3a-3o. Reagents and conditions: A) a) Isopropanol, HCl, 85°C .
B) b) Triphosgene, Et3N, toluene, 110°C; (c) H2/Pd, MeOH or ethyl acetate, r.t.
Scheme 2. Synthesis of compounds 10a-10f. Reagents and conditions: (a) Na2S.9H2O, DMSO,
85°C; (b) HC(OEt)3, 110°C; (c) Isopropanol, HCl, 85°C .
Anti-proliferation assay
All the synthesized compounds were included in the VEGF-induced HUVEC proliferation
assay (shown in Table 1). In the VEGF-HUVEC anti-proliferation assay, VEGF can induce
phosphorylation of VEGFR and new blood vessels will be generated, leading to rapid proliferation
of endothelial cells. The results of the HUVEC anti-proliferation assay can indicate the
anti-angiogenic activity of the compounds.
Based on the anti-proliferative activity of the series I compounds, it can be found that the
substituents of the two benzene rings had great effect on the anti-proliferative activity. According
to the result of the compound 3b-3f, it showed that the electron donating groups of the B ring
maybe not favorable for binding when the R1 was hydrogen atom. Interestingly, compound 3g
maintained the anti-proliferative activity with IC50 value of 11.25μM. On the contrary, when the
R1 of the A ring was replaced by a chlorine group, electron withdrawing groups of the B ring were
not favorable for binding. This conclusion can be seen when we compared the compounds 3i, 3j
with 3l, 3m. When the R2 group was the same, the substituents of the A ring also had different
effect on the anti-proliferative activity. Compared the compound 3b, 3c with 3i, 3j, the activity of
3i and 3j was slightly decreased when the hydrogen atom of the A ring was replaced by a chlorine
group. Compound 3b showed moderate activity with IC50 value of 7.59 μM. However, when R2
was an electron donating group, the activity of the compound 3k, 3l, 3m was improved compared
with compound 3e, 3f, 3g respectively. A 3, 4-dimethyl group (compound 3l) resulted in the best
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900232
Chemistry & Biodiversity
anti-proliferative activity with IC50 value of 1.65 μM. 4-methoxy substitution on the B ring
(compound 3m) also achieved good activity with IC50 value of 3.51 μM.
In order to enhance the activity by improving the solubility, we introduced a flexible side
chain on the B ring. The activity of the compound 3n was better than compound 3a and 3c-3f.
When the hydrogen atom of the A ring was replaced by a chlorine group, the activity of compound
3o was not satisfactory compared with 3l and 3m. Above all, in series I compounds, compound 3l
and 3m showed the good anti-proliferative activity with IC50 value of 1.65 μM and 3.51 μM
respectively.
The 2-position benzene ring was removed and six series II compounds were synthesized. We
envisioned that series II compounds (compound 10a-10f) can improve the solubility by reducing
the molecular weight. Then they may enhance the affinity with VEGFR-2. However, the results of
anti-proliferative test were unsatisfactory. Compound 10a in which R2 is a hydrogen atom
maintained activity. The other compounds (compounds 10c-10e) showed decreased
anti-proliferative activity comparing with series I compounds. The results indicate that the phenyl
ring on the thiazolopyrimidine ring may be essential for the activity and it may be more favorable
for hydrophobic interaction with kinase.
Table 1. Inhibition activity of thiazolopyrimidine-urea derivatives on HUVEC proliferation
Entry
Compound No.
Series
R1
H
R2
H
IC50/μM
87.3
1
2
3a
3b
3c
3d
3e
3f
I
I
I
I
I
I
I
I
I
I
I
I
I
H
4-F
7.59
3
H
4-Cl
87.37
68.01
145.8
116.9
11.25
23.67
16.55
217.6
61.53
1.65
4
H
4-Br
5
H
4-CH3
3,4-diCH3
4-OCH3
H
6
H
7
3g
3h
3i
H
8
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
9
4-F
10
11
12
13
14
3j
4-Cl
3k
3l
4-CH3
3,4-diCH3
4-OCH3
3m
3.51
3n
3o
I
I
H
14.9
15
4-Cl
106.2
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900232
Chemistry & Biodiversity
16
17
18
19
20
21
22
23
10a
10b
II
II
II
II
II
II
\
\
\
\
\
\
\
\
\
H
4-CH3
2-F
11.2
N.D[a]
188.8
115.5
118.3
N.D
10c
10d
4-Cl
4-F
10e
10f
4-OCH3
\
Sorafenib
Sunitinib
15.99
2.58
\
\
[a]: Not determined.
VEGFR-2 enzyme assay
According to the result of VEGF-induced HUVEC proliferation assay, eleven series I
compounds were selected for VEGFR2 kinase inhibitory assay. Six compounds (compound 3a, 3c,
3e, 3f, 3g, 3i, 3k and 3l) showed good inhibitory potencies with inhibition rate over 50% at 50 μM.
Even though compound 3e and 3f showed good inhibitory potencies (74.6% and 82.6%
respectively), the results of their cellular assay were unsatisfactory and some unknown mechanism
may be involved in it. Compound 3b showed moderate activity with IC50 value of 7.59 μM, the
inhibition rate of it was 45.7%. The result suggested that compound 3b could inhibit the
proliferation of HUVEC and it may act on HUVEC through another mechanism of action.
Compound 3l exhibited the best potency against VEGFR-2 at 50 μM (98.5%) and the result is
consistent with its VEGF-HUVEC anti-proliferation assay. The information of SAR provided us a
guideline in further evaluation of the compounds.
Table 2. Inhibition activity of thiazolopyrimidine-urea derivatives on VEGFR-2 (percentage
inhibition at 50 μM)
%inhibition on VEGFR-2
SD
2.0
4.3
2.8
3.8
1.0
11.1
3.8
0.6
4.3
0.4
0.4
0.4
Compound
R1
H
R2
H
3a
51.2
45.7
57.9
74.6
82.6
69.4
44.9
50.2
46.3
64.3
98.5
99.0
3b
H
4-F
3c
H
4-Cl
3e
H
4-CH3
3,4-diCH3
4-OCH3
H
3f
H
3g
H
3h
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
\
3i
4-F
3j
3k
4-Cl
4-CH3
3,4-diCH3
\
3l
Sorafenib
Conclusion
Angiogenesis plays a major role in the development of pathological diseases and it has been
recognized as a hallmark in the field of tumors. Herein, two series of thiazolopyrimidine-urea
derivatives were synthesized and evaluated for their anti-proliferative activity. Compared with
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900232
Chemistry & Biodiversity
previously published thiazolopyrimidine derivatives[20], the VEGFR-2 inhibition activity of the
new compounds was improved by replacing one benzene ring in the urea moiety with a 2-pyridine
ring. Overall, the activity of all the thiazolo[5,4-d]pyrimidine derivatives was decreased after the
replacement of the oxazolopyrimidine scaffold[14,15]. In this paper, compound 3l and 3m exhibited
the most potent inhibitory effect on HUVEC proliferation (IC50 = 1.65 and 3.52 μM respectively).
Overall, the anti-proliferative activity of series II compounds was lower than series I compounds
and this indicated that the phenyl ring on the thiazole pyrimidine ring may be essential for the
activity. In VEGFR-2 kinase inhibitory assay, compound 3l also showed the best potency against
VEGFR-2 at 50 μM (98.5%). Hence, these results showed that the thiazolopyrimidine-urea
derivatives can be used for design of novel promising angiogenesis agents.
Experimental Section
Chemical part
All reactions were monitored by HPLC or by thin-layer chromatography (TLC) in silica gel
(purchased from Qingdao Haiyang chemical plant). All products visualized by using ultraviolet
lamp (254 and 365 nm). Melting points (uncorrected) were determined on a XT-4 apparatus.
Infrared spectra were recorded on Nicolet Impact 410 spectrophotometer. 1H nuclear magnetic
resonance (NMR) spectra were determined in CDCl3 or DMSO-d6 as the solvent with TMS as the
internal reference by using a Brucker AMX 300 MHz spectrometer. Mass spectra were obtained
on SHIMADZU GCMS-QP2010 system.
1-(5-nitropyridin-2-yl)-3-phenylurea(6a)
A mixture of triphosgene（256 mg, 0.86 mmol）, aniline (223 mg, 2.4 mmol） and Et3N（485 mg,
4 mmol）in toluene (3 mL) was stirred at 0 °C for 30min. 5-nitropyridin-2-amine (278 mg, 2 mmol)
was added to the system and the mixture was stirred at 115°C for 12h. After the mixture was
cooled, it was filtered and the residue was washed with ethyl acetate and methanol. It was dried
under vacuum to give the title compound as a yellow solid (370 mg, 72%). ESI-MS: m/z
281.1[M+Na]+.
1-(5-aminopyridin-2-yl)-3-phenylurea(2a)
A solution of 1-(5-nitropyridin-2-yl)-3-phenylurea (2.8 g, 20 mmol) in ethyl acetate (25 mL) was
hydrogenated in the presence of 10% Pd/C. The reaction mixture was filtered through Celite and
dried under vacuum to give 1-(5-aminopyridin-2-yl)-3-phenylurea as a pink solid (320 mg, 98%).
1H-NMR (300 MHz, DMSO-d6 ): δ ppm 4.93 (s, 2H), 6.93-7.01 (m, 2H), 7.18 (d, J = 8.7 Hz, 1H),
7.23-7.28 (m, 2H), 7.45-7.49 (m, 2H), 7.63 (d, J = 2.5 Hz, 1H), 8.89 (s, 1H), 10.27 (s, 1H).
ESI-MS: m/z 229.1[M+H]+. When the same procedure for preparing compound 2b-2i was used,
the different substituted diaryl ureas were obtained.
5-amino-6-chloro-2-methylpyrimidine-4-thiol (8)
Sodium sulfide hydrate (1.01 g, 4.2 mmol) was added to the solution of
4,6-dichloro-2-methylpyrimidine-5-amine (497 mg, 2.8 mmol) in dimethyl sulfoxide. The mixture
was stirred at 25 °C for 30min and then heated to 85 °C for 2h. The mixture was added to an
appropriate amount of water. The pH was adjusted to 5-6 by using concentrated hydrochloric acid.
It was extracted with ethyl acetate and was purified by flash chromatography on silica gel
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900232
Chemistry & Biodiversity
1
(petroleum ether / ethyl acetate 4:1) to yield the title compound (262 mg, 53%). H-NMR (300
MHz, DMSO-d6 ): δ 2.30 (s, 3H), 5.54 (s, 2H), 14.12 (s, 1H).
7-chloro-5-methylthiazolo[5,4-d]pyrimidine (9)
A mixture of 5-amino-6-chloro-2-methylpyrimidine-4-thiol (258 mg, 1.47 mmol) and triethyl
orthoformate was stirred at 110 °C for 1 hour. The reaction mixture was dried under vacuum. It
was purified by flash chromatography on silica gel (ethyl acetate / petroleum ether 1:8) to yield
the title compound as a white solid (246 mg, 90.1%).
General procedure for 3a-3o and 10a-10f
Compound 1a, 1b or 9 (0.35 mmol) and aniline 2a-2i (0.35 mmol) were added in to a round
bottom bottle. Then 2mL of isopropanol and a drop of hydrochloric acid were added. The mixture
was refluxed overnight at 82°C. It was then cooled and filtered. The residue was washed with
methanol and ethyl acetate, recrystallized in methanol to give the title compound
1-(5-((5-methyl-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)-3-phenylurea (3a)
Yield: 59%. m.p 238～239°C. IR（KBr）： 3133.1, 1706.2, 1655.4, 1583.9, 1560.5, 1528.8, 1498.6,
1470.5, 1445.5, 1402.9, 1319.9, 1288.7, 1251.8, 1215.1, 1191.8, 1151.4, 1061.6, 1027.9, 906.9,
1
835.5, 757.1, 689.0, 632.1 cm-1； H-NMR (300 MHz, DMSO-d6 ): δ 2.57 (s, 3H), 7.03 (t, J = 7.4
Hz, 1H), 7.29-7.35 (m, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.57-7.62 (m, 4H), 8.09-8.12 (m, 2H), 8.44
(dd, J = 9.0 Hz, J = 2.2 Hz, 1H), 9.02 (d, J = 2.1 Hz, 1H), 10.19 (s, 1H), 10.29 (s, 1H), 10.37 (s,
1H). ESI-MS: m/z 454.2[M+H]+. HR-MS (ESI): m/z calcd for (C24H19N7OS+H)+: 454.1450;
found: 454.1443.
1-(4-fluorophenyl)-3-(5-((5-methyl-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl
)urea (3b)
Yield: 86.5%. m.p 243～244°C. IR（KBr）： 3132.4, 1715.8, 1654.7, 1623.4, 1567.5, 1527.5,
1509.0, 1470.6, 1401.5, 1318.3, 1282.8, 1206.3, 1185.8, 1156.2, 1059.7, 1037.7, 906.6, 830.7,
1
765.3, 740.3, 694.6, 551.0 cm-1； H-NMR (300 MHz, DMSO-d6 ): δ 2.59 (s, 3H), 7.13-7.20 (m,
2H), 7.49-7.56 (m, 2H), 7.58-7.63 (m, 4H), 8.11-8.15 (m, 2H), 8.46 (dd, J = 9.3 Hz, J = 2.4 Hz,
1H), 9.03 (d, J = 2.2 Hz, 1H), 10.29 (s, 1H), 10.35 (s, 1H), 10.40 (s, 1H). ESI-MS: m/z
470.2[M-H]-. HR-MS (ESI): m/z calcd for (C24H18FN7OS+H)+: 472.1356; found: 472.1353.
1-(4-chlorophenyl)-3-(5-((5-methyl-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-y
l)urea (3c)
Yield: 52%. m.p 252～253°C. IR（KBr）： 3126.9, 1591.4, 1527.4, 1491.8, 1400.8, 1124.9, 987.4,
1
907.2, 831.1, 735.4, 685.3, 551.9, 423.2 cm-1； H-NMR (300 MHz, DMSO-d6 ): δ 2.57 (s, 3H),
7.36 (d, J = 8.8 Hz, 2H), 7.52-7.62 (m, 6H), 8.09-8.12 (m, 2H), 8.44 (dd, J = 9.0 Hz, J = 2.6 Hz,
1H), 9.01 (d, J = 2.2 Hz, 1H), 10.34 (s, 1H), 10.37 (s, 1H), 10.41 (s, 1H). ESI-MS: m/z
486.1[M-H]-. HR-MS (ESI): m/z calcd for (C24H18ClN7OS+H)+: 488.1060; found: 488.1053.
1-(4-bromophenyl)-3-(5-((5-methyl-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-y
l)urea (3d)
Yield: 36%. m.p 245～246°C. IR（KBr）： 3125.8, 1709.7, 1593.0, 1526.4, 1489.4, 1400.8, 1320.7,
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900232
Chemistry & Biodiversity
1242.1, 1188.1, 1135.9, 1073.5, 1001.7, 904.3, 833.1, 760.9, 738.4, 688.3, 630.1, 553.7 cm-1；
1H-NMR (300 MHz, DMSO-d6 ): δ 2.59 (s, 3H), 7.05 (t, J = 7.4 Hz, 1H), 7.31-7.43 (m, 2H), 7.51
(s, 2H), 7.59-7.65 (m, 4H), 8.12-8.14 (m, 2H), 8.45-8.50 (m, 1H), 8.99-9.05 (m, 1H), 10.23 (s, 1H),
10.35 (s, 1H), 10.42 (s, 1H). ESI-MS: m/z 452.1[M-H]-. HR-MS (ESI): m/z calcd for
(C24H18BrN7OS+H)+: 532.0555; found: 532.0539.
1-(5-((5-methyl-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)-3-(p-tolyl) urea
(3e)
Yield: 57%. m.p 242～243°C. IR（KBr）： 3128.3, 1605.4, 1541.6, 1513.9, 1490.6, 1400.8, 1243.2,
1
1123.6, 903.7, 833.7, 810.6, 737.9, 689.8, 556.8 cm-1； H-NMR (300 MHz, DMSO-d6 ): δ 2.26
(s, 3H), 2.59 (s, 3H), 7.14 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 7.60 (s, 4H), 8.13 (s, 2H),
8.49 (d, J = 8.7 Hz, 1H), 9.07 (s, 1H), 10.13 (s, 1H), 10.36 (s, 1H), 10.56 (s, 1H). ESI-MS: m/z
466.1[M-H]-. HR-MS (ESI): m/z calcd for (C25H21N7OS+H)+: 468.1607; found: 468.1607.
1-(3,4-dimethylphenyl)-3-(5-((5-methyl-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)amino)
pyridin-2-yl)urea (3f)
Yield: 36%. m.p 244～246°C. IR（KBr）： 3128.2, 1697.9, 1655.4, 1590.8, 1534.8, 1504.5, 1401.0,
1
1198.2, 1122.3, 1000.6, 906.5, 830.4, 763.4, 734.0, 692.1, 519.4 cm-1； H-NMR (300 MHz,
DMSO-d6 ): δ 2.19 (s, 3H), 2.21 (s, 3H), 2.58 (s, 3H), 7.04-7.08 (m, 2H), 7.21-7.29 (m, 2H),
7.56-7.64 (m, 3H), 8.14 (s, 2H), 8.44 (d, J = 9.1 Hz, 1H), 9.01 (s, 1H), 9.85 (s, 1H), 10.06 (s, 1H),
10.28 (s, 1H). ESI-MS: m/z 480.2[M-H]-. HR-MS (ESI): m/z calcd for (C26H23N7OS+H)+:
482.1763; found: 482.1761.
1-(4-methoxyphenyl)-3-(5-((5-methyl-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2
-yl)urea (3g)
Yield: 59%. m.p 246～247°C. IR（KBr）： 3125.9, 1706.5, 1609.1, 1578.4, 1560.5, 1527.4, 1511.5,
1400.6, 1290.0, 1240.9, 1213.2, 1188.6, 1150.2, 1028.4, 907.4, 832.4, 735.8, 688.2, 556.9 cm-1；
1H-NMR (300 MHz, DMSO-d6 ): δ 2.60 (s, 3H), 3.73 (s, 3H), 6.92 (d, J = 8.4 Hz, 2H), 7.43 (d, J
= 8.8 Hz, 2H), 7.57-7.60 (m, 4H), 8.14 (s, 2H), 8.47-8.52 (m, 1H), 9.07 (s, 1H), 10.03 (s, 1H),
10.36 (s, 1H), 10.46 (s, 1H). ESI-MS: m/z 482.2[M-H]-. HR-MS (ESI): m/z calcd for
(C25H21N7O2S+H)+: 484.1556; found: 484.1552.
1-(5-((2-(4-chlorophenyl)-5-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)-3-phen
ylurea (3h)
Yield: 65.5%. m.p 265～267°C. IR（KBr）： 3131.5, 1707.2, 1655.2, 1601.9, 1560.9, 1541.1,
1498.7, 1400.7, 1242.9, 1185.4, 1134.5, 1087.5, 903.3, 825.5, 750.6, 737.8, 554.9 cm-1； 1H-NMR
(300 MHz, DMSO-d6 ): δ 2.58 (s, 3H), 7.05 (t, J = 7.3 Hz, 1H), 7.31-7.36 (m, 2H), 7.54 (d, J = 7.7
Hz, 2H), 7.61-7.68 (m, 3H), 8.13 (d, J = 8.6 Hz, 2H), 8.44 (dd, J = 9.0 Hz, J = 2.2 Hz, 1H), 9.02
(d, J = 2.2 Hz, 1H), 10.20 (s, 1H), 10.29 (s, 1H), 10.32 (s, 1H). ESI-MS: m/z 486.1[M-H]-.
HR-MS (ESI): m/z calcd for (C24H18ClN7OS+H)+: 488.1060; found: 488.1056.
1-(5-((2-(4-chlorophenyl)-5-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)-3-(4-flu
orophenyl)urea (3i)
Yield: 55.4%. m.p 270～272°C. IR（KBr）： 3127.2, 1708.3, 1603.1, 1577.2, 1541.5, 1508.9,
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900232
Chemistry & Biodiversity
1465.4, 1400.9, 1246.2, 1213.4, 1187.6, 1136.2, 1033.7, 1010.4, 903.6, 735.8, 552.9, 520.8 cm-1；
1H-NMR (300 MHz, DMSO-d6): δ 2.57 (s, 3H), 7.14-7.20 (m, 3H), 7.51-7.56 (m, 2H), 7.63-7.73
(m, 3H), 8.12 (d, J = 8.3 Hz, 2H), 8.96 (s, 1H), 10.12 (s, 1H), 10.25 (s, 1H), 10.27 (s, 1H).
ESI-MS: m/z 504.1[M-H]-. HR-MS (ESI): m/z calcd for (C24H17ClFN7OS+H)+: 506.0966; found:
506.0968.
1-(4-chlorophenyl)-3-(5-((2-(4-chlorophenyl)-5-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)p
yridin-2-yl)urea (3j)
Yield: 60%. m.p 295～297°C. IR（KBr）： 3124.7, 1706.0, 1655.1, 1602.8, 1560.4, 1541.1, 1491.9,
1400.7, 1270.7, 1241.7, 1186.5, 1088.9, 1010.9, 903.5, 824.7, 737.7, 627.8, 558.3 cm-1；1H-NMR
(300 MHz, DMSO-d6 ): δ 2.57 (s, 3H), 7.37 (d, J = 8.8 Hz, 2H), 7.56-7.65 (m, 3H), 7.68 (d, J =
8.6 Hz, 2H), 8.13-8.16 (m, 2H), 8.34 (dd, J = 9.3 Hz, J = 2.6 Hz, 1H), 8.91 (d, J = 2.1 Hz, 1H),
9.85 (s, 1H), 10.19 (s, 1H), 10.34 (s, 1H). ESI-MS: m/z 522.1[M+H]+. HR-MS (ESI): m/z calcd
for (C24H17Cl2N7OS+H)+: 522.0671; found: 522.0657.
1-(5-((2-(4-chlorophenyl)-5-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)-3-(p-tol
yl)urea (3k)
Yield: 30%. m.p 255～256°C. IR（KBr）： 3126.5, 1686.4, 1609.9, 1544.3, 1490.9, 1465.9, 1400.8,
1319.9, 1297.9, 1268.5, 1244.4, 1122.9, 1091.3, 1007.6, 923.9, 833.0, 735.5, 554.2, 428.2 cm-1；
1H-NMR (300 MHz, DMSO-d6 ): δ 2.26 (s, 3H), 2.55 (s, 3H), 7.12 (d, J = 8.2 Hz, 2H), 7.41 (d, J
= 8.3 Hz, 2H), 7.65-7.73 (m, 3H), 8.12 (d, J = 8.6 Hz, 2H), 8.21 (d, J = 8.6 Hz, 1H), 8.83 (s, 1H),
9.53 (s, 1H), 10.08 (s, 1H), 10.11 (s, 1H). ESI-MS: m/z 500.1[M-H]-. HR-MS (ESI): m/z calcd for
(C25H20ClN7OS+H)+: 502.1217; found: 502.1209.
1-(5-((2-(4-chlorophenyl)-5-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)-3-(3,4-d
imethylphenyl)urea (3l)
Yield: 60.6%. m.p 291～292°C. IR（KBr）： 3124.6, 1693.7, 1659.2, 1593.1, 1529.8, 1505.5,
1469.4, 1401.1, 1286.2, 1223.6, 1185.4, 1123.5, 1084.3, 1063.5, 1009.6, 906.4, 834.1, 631.2,
1
555.0, 450.8, 413.2 cm-1； H-NMR (300 MHz, DMSO-d6 ): δ 2.17 (s, 3H), 2.20 (s, 3H), 2.58 (s,
3H), 7.07 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.28 (s,1H), 7.56 (d, J = 9.2 Hz, 1H), 7.65
(d, J = 8.6 Hz, 2H), 8.11 (d, J = 8.6 Hz, 2H), 8.46 (dd, J = 9.2 Hz, J = 2.3 Hz, 1H), 9.05 (d, J = 2.0
Hz, 1H), 10.03 (s, 1H), 10.28 (s, 1H), 10.47 (s, 1H). ESI-MS: m/z 516.2[M+H]+. HR-MS (ESI):
m/z calcd for (C26H22ClN7OS+H)+: 516.1373; found: 516.1379.
1-(5-((2-(4-chlorophenyl)-5-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)-3-(4-me
thoxyphenyl)urea (3m)
Yield: 57.5%. m.p 263～264°C. IR（KBr）： 3131.03, 1704.7, 1655.3, 1602.6, 1567.5, 1541.5,
1511.3, 1465.3, 1400.8, 1246.6, 1175.8, 1087.7, 1029.2, 903.3, 823.5, 735.9, 670.2, 627.9, 553.4
1
cm-1； H-NMR (300 MHz, DMSO-d6 ): δ 2.56 (s, 3H), 3.72 (s, 3H), 6.90 (d, J = 8.9 Hz, 2H),
7.42 (d, J = 8.9 Hz, 2H), 7.56 (d, J = 9.1 Hz, 1H), 7.67 (d, J = 8.5 Hz, 2H), 8.13 (d, J = 8.5 Hz,
2H), 8.37 (d, J = 9.1 Hz, 1H), 8.92 (s, 1H), 9.96 (s, 1H), 10.01 (s, 1H), 10.22 (s, 1H). ESI-MS: m/z
540.5[M+Na]+. HR-MS (ESI): m/z calcd for (C25H20ClN7OS+H)+: 518.1166; found: 518.1174.
1-(5-((5-methyl-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)-3-(4-(3-morpholi
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900232
Chemistry & Biodiversity
nopropoxy)phenyl)urea (3n)
Yield: 62.8%. m.p 265～267°C. IR（KBr）： 3124.5, 2432.0, 1709.9, 1649.7, 1605.0, 1576.8,
1556.1, 1526.3, 1509.0, 1469.5, 1400.9, 1316.4, 1266.5, 1241.5, 1207.9, 1175.1, 1109.4, 1032.7,
1
1011.6, 907.2, 835.1, 761.5, 742.7, 687.9, 617.3, 526.3 cm-1； H-NMR (300 MHz, DMSO-d6 ): δ
1.94-2.05 (m, 2H), 2.41 (t, J = 4.5 Hz, 4H), 2.50 (t, J = 7.3 Hz, 2H), 2.57 (s, 3H), 3.73 (t, J = 4.5
Hz, 4H), 4.14 (t, J = 6.6 Hz, 2H), 7.03-7.11 (m, 2H), 7.24-7.29 (m, 3H), 7.35-7.40 (m,4H), 7.58
(dd, J = 8.9 Hz, J = 3.2 Hz, 2H), 7.93 (s, 2H), 9.02 (s, 1H), 9.35 (s, 1H), 10.09 (s, 1H). ESI-MS:
m/z 597.3[M+H]+. HR-MS (ESI): m/z calcd for (C31H32N8O3S+H)+: 597.2396; found: 597.2396.
1-(5-((2-(4-chlorophenyl)-5-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)-3-(4-(3-
morpholinopropoxy)phenyl)urea (3o)
Yield: 36.9%. m.p 221～222°C. IR（KBr）： 3128.8, 1624.7, 1561.0, 1510.6, 1400.5, 1202.5,
1109.7, 987.3, 908.8, 830.6, 733.1, 522.7 cm-1； 1H-NMR (300 MHz, DMSO-d6 ): δ 1.98-2.10 (m,
2H), 2.43 (t, J = 4.5 Hz, 4H), 2.51 (t, J = 7.3 Hz, 2H), 2.59 (s, 3H), 3.69 (t, J = 4.6 Hz, 4H), 4.09 (t,
J = 6.5 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 7.39 (t, J = 9.7 Hz, 2H), 7.65 (t,
J = 8.7 Hz, 2H), 7.73 (t, J = 8.7 Hz, 2H), 8.15 (t, J = 6.9 Hz, 2H), 8.81 (s, 1H), 9.10 (s, 1H), 10.32
(s, 1H). ESI-MS: m/z 631.2[M+H]+. HR-MS (ESI): m/z calcd for (C31H31ClN8O3S+H)+: 631.2007;
found: 631.2001.
1-(5-((5-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)-3-phenylurea (10a)
Yield: 51.3%. m.p 215～216°C. IR（KBr）： 3131.4, 1600.7, 1534.6, 1491.2, 1400.6, 1125.9,
1
555.2 cm-1； H-NMR (300 MHz, DMSO-d6 ): δ 2.52 (s, 3H), 6.99 (t, J = 7.4 Hz, 1H), 7.26-7.32
(m, 2H), 7.50-7.58 (m, 3H), 8.25 (dd, J = 9.0 Hz, J = 2.6 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H), 9.28
(s,1H), 9.34 (s, 1H), 10.18 (s, 1H), 10.21 (s, 1H). ESI-MS: m/z 376.1[M-H]-. HR-MS (ESI): m/z
calcd for (C18H15N7OS+H)+: 378.1137; found: 378.1134.
1-(5-((5-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)-3-(p-tolyl)urea (10b)
Yield: 67.9%. m.p 232～234°C. IR（KBr）： 3127.1, 1655.2, 1583.9, 1529.0, 1491.2, 1400.8,
1187.4, 1124.4, 552.9 cm-1；1H-NMR (300 MHz, DMSO-d6 ): δ 2.24 (s, 3H), 2.59 (s, 3H), 7.12 (d,
J = 8.2 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 9.2 Hz, 1H), 8.46 (dd, J = 9.2 Hz, J = 2.4 Hz,
1H), 9.08 (d, J = 2.0 Hz, 1H), 9.36 (s, 1H), 10.12 (s, 1H), 10.63 (s, 1H), 10.74 (s, 1H). ESI-MS:
m/z 392.2[M+H]+. HR-MS (ESI): m/z calcd for (C19H17N7OS+H)+: 392.1294; found: 392.1290.
1-(2-fluorophenyl)-3-(5-((5-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)urea
(10c)
Yield: 50.5%. m.p 215～216°C. IR（KBr）： 3126.9, 1686.2, 1623.2, 1545.6, 1492.4, 1400.6,
1
1254.9, 1126.2, 555.3 cm-1； H-NMR (300 MHz, DMSO-d6 ): δ 2.59 (s, 3H), 7.03-7.09 (m, 1H),
7.14-7.19 (m, 1H), 7.23-7.29 (m, 1H), 7.53 (d, J = 9.2 Hz, 1H), 8.11-8.16 (m, 1H), 8.39 (dd, J =
8.9 Hz, J = 2.1 Hz, 1H), 8.94 (s, 1H), 9.36 (s, 1H), 10.32 (s, 1H), 10.54 (s, 1H), 10.74 (s, 1H).
ESI-MS: m/z 396.1[M+H]+. HR-MS (ESI): m/z calcd for (C18H14FN7OS+H)+: 396.1043; found:
396.1039.
1-(4-chlorophenyl)-3-(5-((5-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)urea
(10d)
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900232
Chemistry & Biodiversity
Yield: 61.3%. m.p 268～270°C. IR（KBr）： 3125.4, 1580.4, 1550.8, 1525.8, 1492.4, 1401.2,
1
1280.1, 1244.8, 1188.8, 1122.6, 1091.0, 834.9, 555.4 cm-1； H-NMR (300 MHz, DMSO-d6 ): δ
2.58 (s, 3H), 7.7.35 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 9.1 Hz, 1H), 8.38 (dd,
J = 9.1 Hz, J = 2.4 Hz, 1H), 8.96 (d, J = 2.2 Hz, 1H), 9.34 (s, 1H), 10.15 (s, 1H), 10.36 (s, 1H),
10.61 (s, 1H). ESI-MS: m/z 410.1[M-H]-. HR-MS (ESI): m/z calcd for (C18H14ClN7OS+H)+:
412.0747; found: 412.0747.
1-(4-fluorophenyl)-3-(5-((5-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)urea
(10e)
Yield: 20.5%. m.p 235～236°C. IR（KBr）： 3125.0, 1697.2, 1662.6, 1597.6, 1581.5, 1560.5,
1532.6, 1502.9, 1401.1, 1285.4, 1247.5, 1214.2, 1182.9, 1124.8, 928.9, 842.2, 550.3, 522.2, 488.5
1
cm-1； H-NMR (300 MHz, DMSO-d6 ): δ 2.59 (s, 3H), 7.13-7.19 (m, 2H), 7.49-7.54 (m, 2H),
7.58 (d, J = 9.0 Hz, 1H), 8.45 (d, J = 7.3 Hz, 1H), 9.06 (s, 1H), 9.35 (s, 1H). ESI-MS: m/z
396.2[M+H]+. HR-MS (ESI): m/z calcd for (C18H14FN7OS+H)+: 396.1043; found: 396.1043.
1-(4-methoxyphenyl)-3-(5-((5-methylthiazolo[5,4-d]pyrimidin-7-yl)amino)pyridin-2-yl)urea
(10f)
Yield: 13.3%. m.p 238～240°C. IR（KBr）： 3124.7, 1717.7, 1610.5, 1570.8, 1547.5, 1512.1,
1
1496.9, 1400.7, 1325.7, 1235.4, 1122.4, 818.2, 795.4, 625.1, 534.2 cm-1； H-NMR (300 MHz,
DMSO-d6 ): δ 2.52 (s, 3H), 3.71 (s, 3H), 6.87 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.51 (d,
J = 8.9 Hz, 1H), 8.23 (dd, J = 9.0 Hz, J = 2.2 Hz, 1H), 8.76 (d, J = 1.9 Hz, 1H), 9.29 (s, 2H),
10.06 (s, 1H), 10.20 (s, 1H). ESI-MS: m/z 408.1[M+H]+. HR-MS (ESI): m/z calcd for
(C19H17N7O2S+H)+: 408.1243; found: 408.1245.
Biological evaluation part
Materials: VEGFR-2 was purchased from Invitrogen. ATP, MgCl2, MnCl2, DTT were purchased
from Sigma. 96-well plate was purchased from Thermo. 384-well plate was purchased from
Corning. HTRF KinEASE-TK was purchased from Cisbio. FBS was purchased from Gibco. MTT
was purchased from Aladdin.
VEGFR-2 Kinase Assay
A Caliper motility shift assay was used to measure the potency of target compounds against
VEGFR-2. Compounds were serially diluted in 96-well plates to obtain different concentrations of
compounds ranging from 50 μM to 2.5 nM. Add 100μl of 100% DMSO to two empty wells for no
compound control and no enzyme control in the same 96-well plate. Add 90μl of 1x Kinase base
buffer to a new 96-well plate with 10μl of compound. Transfer 5μl of each well from the 96-well
plate to a 384-well plate in duplicates. Transfer 10μl of 2.5x enzyme solution to each well of the
384-well plate. After incubating at room temperature for 10 min, 10μl of 2.5x peptide
solution(prepared by adding FAM-labeled peptide and ATP into the 1.25 kinase base buffer) was
added to each well of the 384-well plate. Incubate at 28°C for specified period of time. Add 25μl
of stop buffer to stop reaction.
Collect conversion data on Beckman Coulter program. Convert conversion values to
inhibition values according to percent inhibition ¼ (max-conversion)/(max-min)*100, in which
“max” stands for DMSO control; “min” stands for no enzyme activity control.
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900232
Chemistry & Biodiversity
Anti-proliferation Assay
HUVECs were added onto 96-well microculture plates at a cell volume of 4000 cells/well.
Then, they were incubated in the presence of 5% CO2 for 24h at 37°C . The compounds were
diluted to the corresponding concentration using 5% FBS and appropriate amount of VEGF. After
the cells were completely adhered, different concentrations of the test compounds were added onto
96-well microculture plates. Cells were continued to incubate for 72 h at 5% CO2, 37°C. Then
20μL MTT (0.5%) was added to the cells and incubated at 37°C for further 4 h. After removing
the medium, 100μL DMSO were added to each well and the optical density (OD) was measured at
490 nm. Average IC50 values were determined by MTT tetrazolium dye assay. Each experiment
was performed three times.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (NO. 20872181,
NO. 21172265), Innovation Program for the Postgraduates in Jiangsu Province (NO. 02705116)
and Jiangsu Provincial Natural Science Funding (NO. BK20181333).
Conflict of Interest: We declare that we have no conflicts of interest.
Author Contribution Statement
Wen-jun Xue, Ya-hui Deng designed and synthesized these compounds. Jian-yao Du, Zhong-hui
Yan, Ji-ping Liu performed the VEGFR-2 Kinase Assay and anti-proliferation Assay. Yu Liu and
Li-ping Sun conceived and designed the experiments.
Reference
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
M. de Palma, D. Biziato, T. V. Petrova, ‘Microenvironmental regulation of tumour
angiogenesis’, Nat. Rev. Cancer 2017, 17, 457-474.
Y. Zhao, A. A. Adjei, ‘Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular
Endothelial Growth Factor’, Oncologist 2015, 20, 660-673.
M. Potente, H. Gerhardt, P. Carmeliet, ‘Basic and therapeutic aspects of angiogenesis’, Cell
2011, 146, 873-887.
J. Folkman, ‘Tumor angiogenesis: therapeutic implications’, N. Engl. J. Med. 1971, 285,
1182-1186.
S. Qin, A. Li, M. Yi, S. Yu, M. Zhang, K. Wu, ‘Recent advances on anti-angiogenesis receptor
tyrosine kinase inhibitors in cancer therapy’, J. Hematol. Oncol. 2019, 12, 27.
J. Zhang, L. Zhang, Y. Wang, G. Zhao, ‘Development of anti-angiogenic tyrosine kinases
inhibitors: molecular structures and binding modes’, Cancer Chem. Pharm. 2016, 77, 905-926.
C. Ding, C. Zhang, M. Zhang, Y. Z. Chen, C. Tan, Y. Tan, Y. Jiang, ‘Multitarget inhibitors derived
from crosstalk mechanism involving VEGFR2’, Future Med. Chem. 2014, 6, 1771-1789.
L. Huang, Z. Huang, Z. Bai, R. Xie, L. Sun, K. Lin, ‘Development and strategies of VEGFR-2/KDR
inhibitors’, Future Med. Chem. 2012, 4, 1839-1852.
C. Porta, M. E. Gore, B. I. Rini, B. Escudier, S. Hariharan, L. P. Charles, L. Yang, L. DeAnnuntis, R.
J. Motzer, ‘Long-term Safety of Sunitinib in Metastatic Renal Cell Carcinoma’, Eur. Urol. 2016,
69, 345-351.
[10]
T. Pemovska, E. Johnson, M. Kontro, G. A. Repasky, J. Chen, P. Wells, C. N. Cronin, M. McTigue,
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900232
Chemistry & Biodiversity
O. Kallioniemi, K. Porkka, B. W. Murray, K. Wennerberg, ‘Axitinib effectively inhibits
BCR-ABL1(T315I) with a distinct binding conformation’, Nature 2015, 519, 102-105.
A. Morabito, M. C. Piccirillo, F. Falasconi, G. De Feo, A. Del Giudice, J. Bryce, M. Di Maio, E. De
Maio, N. Normanno, F. Perrone, ‘Vandetanib (ZD6474), a dual inhibitor of vascular
endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR)
tyrosine kinases: current status and future directions’, Oncologist 2009, 14, 378-390.
Z. Szucs, C. Messiou, H. H. Wong, H. Hatcher, A. Miah, S. Zaidi, W. T. van der Graaf, I. Judson, R.
L. Jones, C. Benson, ‘Pazopanib, a promising option for the treatment of aggressive
fibromatosis’, Anticancer Drugs 2017, 28, 421-426.
[11]
[12]
[13]
Y. J. Mi, Y. J. Liang, H. B. Huang, H. Y. Zhao, C. P. Wu, F. Wang, L. Y. Tao, C. Z. Zhang, C. L. Dai, A.
K. Tiwari, X. X. Ma, K. K. To, S. V. Ambudkar, Z. S. Chen, L. W. Fu, ‘Apatinib (YN968D1) reverses
multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette
transporters’, Cancer Res. 2010, 70, 7981-7991.
[14]
[15]
[16]
[17]
Y. H. Deng, D. Xu, Y. X. Su, Y. J. Cheng, Y. L. Yang, X. Y. Wang, J. Zhang, Q. D. You, L. P. Sun,
‘Synthesis and biological evaluation of novel oxazolo*5,4-d]pyrimidines as potent VEGFR-2
inhibitors’, Chem. Biodiversity 2015, 12, 528-537.
Y. H. Deng, J. P. Liu, Y. J. Cheng, Y. Liu, L. P. Sun, ‘Diarylureas and Diarylamides with
Oxazolo[5,4-d+pyrimidine Scaffold as Angiogenesis Inhibitors’, Chem. Biodiversity 2016, 13,
1230-1239.
A. Baxter, A. Cooper, E. Kinchin, K. Moakes, J. Unitt, A. Wallace, ‘Hit-to-Lead studies: the
discovery of potent, orally bioavailable thiazolopyrimidine CXCR2 receptor antagonists’,
Bioorg. Med. Chem. Lett. 2006, 16, 960-963.
J. G. Geist, S. Lauw, V. Illarionova, B. Illarionov, M. Fischer, T. Grawert, F. Rohdich, W.
Eisenreich, J. Kaiser, M. Groll, C. Scheurer, S. Wittlin, J. L. Alonso-Gomez, W. B. Schweizer, A.
Bacher,
F.
Diederich,
‘Thiazolopyrimidine
inhibitors
of
2-methylerythritol
2,4-cyclodiphosphate synthase (IspF) from Mycobacterium tuberculosis and Plasmodium
falciparum’, Chem. Med. Chem. 2010, 5, 1092-1101.
[18]
[19]
[20]
[21]
[22]
A. E. G. Hammam, M. A. Sharaf, N. A. Abd El-Hafez, ‘Synthesis and anti-cancer activity of
pyridine and thiazolopyrimidine derivatives using 1-ethylpiperidone as a synthon’, Indian J.
Chem. B. 2001, 40, 213-221.
S. F. Mohamed, E. M. Flefel, A. E. E. Amr, D. N. A. El-Shafy, ‘Anti-HSV-1 activity and mechanism
of action of some new synthesized substituted pyrimidine, thiopyrimidine and
thiazolopyrimidine derivatives’, Eur. J. Med. Chem. 2010, 45, 1494-1501.
W. J. Xue, Y. H. Deng, Z. H. Yan, J. P. Liu, Y. Liu, L. P. Sun, ‘Phenyl and Diarylureas with Thiazolo
[5,4-d]pyrimidine Scaffold as Angiogenesis Inhibitors: Design, Synthesis and Biological
Evaluation', Chem. Biodiversity 2019, e1800493.
Y. H. Deng, Z. H. Yan, J. P. Liu, Y. Liu, L. P. Sun, ‘Pyrimidinylacetamide-based 2-pyridylureas as
Angiogenesis Inhibitors: Design, Synthesis and Biological Evaluation’, Arch. Med. Res. 2017, 48,
333-342.
D. Xu, L. P. Sun, Q. D. You, ‘Facile synthesis of 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidines
via copper-catalyzed intramolecular C-O bond formation’, Tetrahedron 2012, 68, 4248-4251
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900232
Chemistry & Biodiversity
Graphical abstract:
This article is protected by copyright. All rights reserved.