Novel morpholin-3-one fused quinazoline derivatives as EGFR tyrosine kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.02.009

A series of novel morpholin-3-one-fused quinazoline derivatives were designed, synthesized and evaluated as EGFR tyrosine kinase inhibitors. Nineteen compounds showed significant inhibitory activities against EGFR^wtkinase (IC₅₀?wt(IC₅₀?=?53.1?nM). Compound a7 and a8 showed excellent inhibitory activities against mutant EGFR^T790M/L858Rand strong antiproliferative activity against H358 and A549 cell lines. Finally, molecular docking studies were performed to predict the possible binding mode of the target compounds. It is believed that this work would be very useful for designing a new series of tyrosine kinase inhibitors targeting EGFR.

Full text of DOI:10.1016/j.bmcl.2016.02.009

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel morpholin-3-one fused quinazoline derivatives as EGFR
tyrosine kinase inhibitors
Xuemei Qin , Yongjuan Lv , Peng Liu , Zhipeng Li , Liming Hu , Chengchu Zeng , Leifu Yang c
a
a
b
a
a,
⇑
a
a
College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China
Guangzhou Institute of Biomedicine and Health, Chinese Academy of Science, Guangzhou 510530, China
Beijing Dalitai Pharmaceutical Technology Co. Ltd, Beijing 100176, China
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel morpholin-3-one-fused quinazoline derivatives were designed, synthesized and evalu-
Received 10 December 2015
Revised 1 February 2016
Accepted 4 February 2016
Available online xxxx
ated as EGFR tyrosine kinase inhibitors. Nineteen compounds showed significant inhibitory activities
wt
against EGFR kinase (IC50 < 1 lM). Compound a8 demonstrated the most potent inhibitory activity
wt
toward EGFR (IC50 = 53.1 nM). Compound a7 and a8 showed excellent inhibitory activities against
T790M/L858R
mutant EGFR
and strong antiproliferative activity against H358 and A549 cell lines. Finally,
molecular docking studies were performed to predict the possible binding mode of the target
compounds. It is believed that this work would be very useful for designing a new series of tyrosine
kinase inhibitors targeting EGFR.
Keywords:
EGFR inhibitors
NSCLC
Quinazoline
Molecular docking
Anti-cancer
Ó 2016 Published by Elsevier Ltd.
The epidermal growth factor receptor (EGFR) tyrosine kinase is
a key mediator in cellular signalling transduction pathways and is
closely related to cell proliferation, survival, adhesion, migration,
active site, were developed.15–17 Afatinib was the first approved
irreversible EGFR inhibitor by the US FDA for the treatment of
late-stage NSCLC patients with actively mutated EGFR.18 However,
1
,2
and differentiation.
Deregulation of EGFR signalling has been
these irreversible EGFR inhibitors lacked significant selectivity
T790M
observed in many human cancers, including colorectal, head and
neck, lung, breast, ovarian, and bladder cancers.3 Thus, EGFR and
its family members have emerged as attractive targets for anti-
cancer therapy, especially for the treatment of non-small-cell lung
between EGFR T790M (EGFR
) mutants and the wild-type
kinase that leads to dose-limiting toxicities in these patients,
including skin rash and diarrhea that can result in severe dehydra-
1
4,19
tion and kidney failure.
Recently, third-generation covalent
4
,5
cancer (NSCLC). Several EGFR inhibitors, such as gefitinib and
erlotinib (Fig. 1) belonging to a class of 4-anilinoquinazolines have
made significant progress in the treatment of NSCLC patients har-
inhibitors including AZD9291 and CO-1686 have been generated
T790M
that demonstrate selectivity for EGFR
mutants over wild-type
EGFR (EGFRwt), and early phase I data indicated promising effi-
6
–8
20–22
boring somatic EGFR mutations L858R and delE746_A750.
How-
cacy.
Although, the number of potent EGFR inhibitors is con-
ever, the undeniable success of EGFR tyrosine kinase inhibitors are
limited by the up-regulation of bypass signalling pathways and
acquired point mutations.9 After treatment 10–16 months with
these inhibitors in western countries, approximately 50% of the
NSCLC patients gain an additional gate keeper mutation
stantly expanding, discovery of inhibitors with novel scaffolds
remains a focus nowadays. Herein, we would like to report the
design, synthesis and biological evaluation of morpholin-3-one
fused quinazoline derivatives as new EGFR inhibitors.
,10
8
,23
The co-crystal structures of gefitinib or erlotinib
with EGFR
1
1,12
(
T790M).
The secondary T790M mutation decreases sensitivity
have provided valuable structural information for helping the
rational design of potent EGFR inhibitors. Binding mode analysis
of gefitinib suggests several key interactions with the ATP binding
pocket of EGFR, including the critical H-bond of quinazoline moiety
with the hinge region, the hydrophobic pocket filled up by the 3-
chloro-4-fluoro aniline substituent and the solvent region occupa-
tion of 6-morpholinopropoxy group. Solvent region generally
accommodate a variety of polar functional groups with little affec-
to gefitinib or erlotinib and increases the binding affinity for
1
3,14
ATP.
In order to overcome the T790M mutation related resistance,
several irreversible EGFR second-generation covalent inhibitors
(Fig. 1), which form a covalent bond with Cys797 within the EGFR
2
4
⇑
Corresponding author. Tel./fax: +86 10 6739 6211.
E-mail address: huliming@bjut.edu.cn (L. Hu).
tion on the efficacy. The success of icotinib (Fig. 1), which mimics
erlotinib with a crown ether fused quinazoline, is a good example of
http://dx.doi.org/10.1016/j.bmcl.2016.02.009
960-894X/Ó 2016 Published by Elsevier Ltd.
0
Please cite this article in press as: Qin, X.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.02.009

2
X. Qin et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Reversible EGFR inhibitors
O
F
HN
Cl
HN
HN
N
O
O
O
O
O
O
O
N
O
O
N
N
O
N
N
N
Gefitinib
Erlotinib
Icotinib
Irreversible EGFR inhibitors
F
F
F
O
O
N
HN
N
Cl
HN
Cl
HN
N
Cl
H
HN
O
N
HN
N
N
N
N
O
O
O
N
N
O
O
Canertinib
Afatinib
Figure 1. Chemical structures of EGFR-TKIs.
Dacomitinib
this strategy.25,26 Accordingly, we have designed and synthesized a
series of novel morpholin-3-one fused quinazoline derivatives
through intramolecular cyclization as new EGFR inhibitors (Fig. 2).
The synthetic route of compounds a1–a15 is illustrated in
Scheme 1. Commercially available 4-hydroxy-3-nitrobenzoic acid
(a1–a15), the inhibitory activities against EGFRwt ranged from
53.1 nM to 829.2 nM except a5 and a14 in which IC50 > 1000 nM.
1
2
When R was halogen (F, Cl or Br) and R was hydrogen (a1, a2,
a3), compounds substituted by Cl or Br (a2, IC50 = 63.1 nM; a3,
IC50 = 89.6 nM) displayed 2-fold increase in potency than substi-
tuted by F (a1, IC50 = 245.1 nM). While R was hydrogen and R2
was halogen atom (a9, a10, a11), the results of inhibition against
EGFR was unsatisfactory. This may be that meta-position com-
pounds (a1, a2, a3) could form a stronger interaction with EGFR
1
1
was esterified with methanol using concentrated sulfuric acid
27
as a catalyst to give compound 2. Alkylation of methyl 4-
hydroxy-3-nitrobenzoate 2 with ethyl bromoacetate and reduction
of the nitro group with Fe/acetic acid followed by in situ cyclization
yielded intermediate 4. Subsequent nitration and alkylation pro-
vided 6. Then reduction the nitro group of 6 using Fe/acetic acid
gave 7, which was subjected to cyclization to generate intermedi-
ate 8. Following, 8 was chloridized by phosphorus oxychloride to
generate intermediate 9. Finally, condensation of 9 with substi-
tuted anilines afforded 4-anilinoquinazoline derivatives a1–a15.
Synthesis of compounds b1–b6 is shown in Scheme 2. Interme-
diate 5, which could be synthesized according to Scheme 1, was
reacted with 1-bromo-3-chloropropane and piperidine in sequence
to achieve 11. The target compounds were synthesized in good
yields by the next four step reactions according to Scheme 1.
To evaluate the EGFR inhibitory potency of the new compounds,
Kinase-Glo luminescent assay is used to test their ability to block
EGFR tyrosine kinase. Compounds were initially texted at final con-
centrations of 1000, 200, 40, 8, 1.6, 0.32, and 0.06 nM and per-
formed in duplicate at each concentration with gefitinib as
positive control. Compound inhibition curve was fitted using
Graphpad Prism 5.0 software based on the inhibition rate of all
compounds at different concentrations. The testing results are
summarized in Table 1. Almost all the compounds displayed signif-
1
kinase than para-position compounds (a9, a10, a11). When R
2
was Cl and R was F, compound a8 displayed the most inhibitory
wt
1
2
activity toward EGFR (IC50 = 53.1 nM). When R or R was meth-
oxy or trifluoromethyl group, compounds (a5, a6, a14,) displayed
weaker potency against EGFR kinase. One explanation might be
1
that a larger volume of R group could not effectively fill up well
1
the hydrophobic pocket of EGFR kinase. In summary, when R
2
was Cl or Br, and R was H or F, compounds (a2, a3, a8) displayed
wt
excellent inhibitory activities against EGFR
(IC50 < 89.6 nM).
Among them, compound a8 displayed the most inhibitory activity
wt
toward EGFR (IC50 = 53.1 nM).
To find a more potent EGFR inhibitor, R was substituted by 3-
(piperidin-1-yl)propyl in the subsequent synthesis (b1–b6).
Among them, b3 was the most active compound against EGFR
1
(IC50 = 99 nM). Compounds b2, b3, b6 (R = Cl or Br) showed much
1
more potency than b1 (R = F). This was the same phenomena as
1
the former discussion (a1–a3, R = halogen). The reason may be
that small fluorine atom could be too small to fill up well the
hydrophobic pocket of EGFR kinase pocket. However, when R1
was a relatively larger volume group methyl or ethynyl, com-
pounds (b4, b5) did not showed good inhibitory activities towards
icant EGFR inhibitory activities (IC50 < 1 lM). Among them, com-
wt
1
pound a8 showed the most potent inhibitory activity against
EGFR . As a whole, R was Cl or Br would be beneficial for improv-
wt
wt
EGFR kinase (IC50 = 53.1 nM). When R was 3-morpholinopropyl
ing the inhibitory activities against EGFR .
O
N
F
R
O
R2
R1
HN
N
Cl
HN
N
O
O
Design
N
O
N
N
Cycliczation
Gefitinib
Figure 2. Design strategy and modification of novel EGFR inhibitors.
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X. Qin et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
O
O
O
O
H
N
O N
O N
O
2
N
O
2
2
OH
a
O
b
O
c
O
O
O
HO
HO
O
O
1
2
3
4
O
O
N
N
O
H
O
N
g
d
O
O
f
e
O
O
N
O
O
N
O
NO
O
NO
2
O
2
O
NH2
5
6
7
O
O
O
N
O
N
O
R2
R1
N
O
N
Cl
N
i
HN
N
h
N
N
O
O
N
NH
N
N
O
O
8
9
a1-a15
SO , reflux; (b) ethyl bromoacetate, K
Scheme 1. Synthetic route of the target compounds a1–a15. Reagents and conditions: (a) CH
3
OH, conc. H
2
4
2
CO
3
, DMF, 70 °C; (c) Fe, HAc,
7
0 °C; (d) HAc/HNO
3
; (e) 4-(3-chloropropyl)morpholine, K
2
CO
3 2 3
, KI, DMF, 80 °C; (f) Fe, HAc, EtOH/H O; (g) formamidine acetate, EtOH, reflux; (h) POCl , 120 °C; (i) anilines,
isopropanol, reflux.
Cl
N
O
N
O
O
O
O
H
N
O
O
N
O
O
N
O
N
O
O
a
O
b
O
c
O
O
NO2
NO2
NO2
NH2
5
10
11
12
N
O
N
O
N
R2
O
N
Cl
N
HN
N
R
1
d
e
f
N
N
O
O
N
O
NH
N
N
O
1
3
14
b1-b6
Scheme 2. Synthetic route of the target compounds b1–b6. Reagents and conditions: (a) 1-bromo-3-chloropropane, Cs
c) Fe, HAc, EtOH/H O; (d) formamidine acetate, EtOH, reflux; (e) POCl , 120 °C; (f) anilines, isopropanol, reflux.
2 3 2 3
CO , acetonitrile, rt; (b) piperidine, K CO , KI, DMF, rt;
(
2
3
By comparing a1&b1, a2&b2, a3&b3, a4&b4, a7&b5 and a8&b6,
In the T790M/L858R mutant EGFR kinase assays (Table 2), com-
pound a8 (IC50 = 0.88 M) was about 2-fold more potent than a7
(IC50 = 0.336 M). The two compounds showed significant inhibi-
it is easy to find that compounds with R being 3-morpholinopropyl
l
wt
show much more inhibitory efficiency against EGFR than com-
l
7
90M/L858R
pounds with R being 3-(piperidin-1-yl)propyl do. This indicates
that the increased hydrophily of 6-position substituent of quinazo-
line may be beneficial for enhancing the inhibitory activity against
EGFR.
tory activities against EGFRT
compared to the standards
erlotinib and gefitinib.
To experiment the antiproliferative activity of a7 and a8, both
compounds were tested on H358 (human NSCLC cell line) and
A549 (a human lung adenocarcinoma cell line). As showed in
Table 2, a7 and a8 strongly suppressed the proliferation of H358
and A549 cells compared to gefitinib and erlotinib.
To gain more understanding of the structure-activity relation-
ships observed for EGFR kinase, molecular docking of the a8 into
ATP binding site of EGFR kinase was performed on the binding
model based on the EGFR/gefitinib complex crystal structure
(2ITY.pdb). Docking mode appeared superimposition of the a8 with
the control ligand gefitinib in a similar binding mode. The
Among all the compounds, a7 and a8 were picked up for further
biological evaluation. One reason was their good inhibitory activi-
ties against wipe-type EGFR. The other reason was that 4-position
substituent of quinazoline was 3-chloro-4-fluro or 3-ethynyl ani-
line, which was found in many marketed drugs as an important
group and were studied widely in different areas. The third reason
was that target compounds showed much more inhibitory effi-
wt
ciency to EGFR when R was 3-morpholino-propyl than when R
was 3-(piperidin-1-yl)propyl.
Please cite this article in press as: Qin, X.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.02.009

4
X. Qin et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 1
In vitro enzymatic inhibitory activities of compounds a1–a15 and b1–b6 against
wt
EGFR
O
N
O
R2
R1
R2
R1
N
O
HN
N
HN
N
N
O
N
O
N
N
a
b
Compound
R1
R2
EGFRwt IC50 (nM)
Figure 3. Docking modes of compound a8 (gray) overlaid with the binding
conformation of gefitinib (yellow) into the EGFR kinase domain.
a1
a2
F
Cl
H
H
245.1
63.1
a3
Br
H
89.6
a4
a5
a6
a7
a8
a9
a10
a11
a12
a13
a14
a15
b1
b2
b3
b4
b5
Me
MeO–
H
H
H
H
F
F
Cl
Br
Me
H
MeO–
Me
H
H
H
H
H
186.9
>1000
829.2
139.0
53.1
434.1
353.7
823.9
594.5
518.6
>1000
162.7
460.0
115.9
99.0
strong antiproliferative activity against H358 and A549 cell line
compared to gefitinib and erlotinib. Docking modes of compound
a8 overlaid well with the binding conformation of gefitinib in the
EGFR kinase domain. It is believed that this work would have
important implications for the design of new tyrosine kinase inhi-
bitors targeting EGFR.
–CF
3
Ethynyl
Cl
H
H
H
H
H
MeO–
Cl
F
Cl
Br
Me
Ethynyl
Cl
Acknowledgments
The authors would like to acknowledge financial support from
the National Science Foundation of China (21272020), the Project
of Construction of Innovative Teams and Teacher Career Develop-
ment for Universities and Colleges under Beijing Municipality
456.2
211.4
137.9
11.8
(
IDHT20140504), Beijing Key Laboratory for Green Catalysis and
b6
Gefitinib
F
Separation.
Supplementary data
morpholin-3-one fused scaffold was located well in the ATP pocket.
One conventional hydrogen bond was observed between the nitro-
gen of the quinazoline ring and the hydrogen of Met793 amide and
another water mediated hydrogen bond was observed between
oxygen on the quinazoline ring and the amide nitrogen of
Thr791. This may be the reason that a8 showed wonderful inhibi-
tory activity against EGFR kinase. And we can observe from Figure 3
the morphin-3-one group of a8 is shifted away from the morphine
of gefitinib. However, it is believed that the charge-charge interac-
tion between basic nitrogen in morpholin-3-one group of gefitinib
and Asp800 is very important for gefitinib binding into EGFR active
site. This may be the reason why a8 is less potent activities to EGFR
kinase than gefitinib in its inhibitory activity against EGFR kinase.
Therefore, one way to improve the inhibitory activities for these
kind compounds could be to link the amine group with different
linkers.
Supplementary data (supplementary material that may be help-
ful in the review process should be prepared and provided as a sep-
arate electronic file) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.02.
009.
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