Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors

Article abstract of DOI:10.1016/j.ejmech.2015.08.026

We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies.

Full text of DOI:10.1016/j.ejmech.2015.08.026

European Journal of Medicinal Chemistry 102 (2015) 445e463
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Research paper
Structure-activity study of quinazoline derivatives leading to the
discovery of potent EGFR-T790M inhibitors
Long Zhang, Yingying Yang, Haojie Zhou, Qingmei Zheng, Yuhao Li, Shansong Zheng,
Shuyong Zhao, Dong Chen, Chuanwen Fan*
Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong
Province, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned
as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As
compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells
(EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmaco-
kinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at
a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f
are promising candidates for further studies.
Received 22 November 2014
Received in revised form
8 August 2015
Accepted 11 August 2015
Available online 17 August 2015
Keywords:
Quinazoline derivatives
H1975
© 2015 Elsevier Masson SAS. All rights reserved.
EGFR-T790M
HCC827
A-431
1. Introduction
mutation [7e10]. Two kinds of compounds may be used to solve the
above problem. The first class of compounds has less activity
EGFR inhibitors, such as gefitinib and erlotinib, are effective
clinical treatments for NSCLC patients whose tumors harbor acti-
vating mutations in EGFR [1e3]. However, all patients will ulti-
mately manifest disease progression due to acquired resistance
which in part is explained by a second-site T790M mutation in
EGFR kinase domain. Although the second-generation irreversible
EGFR inhibitors including dacomitinib [4], neratinib [5] and afatinib
[6] have demonstrated activity in preclinical studies against T790M
mutations, clinical trial data did not demonstrate distinctly
improved efficacy. This was partially attributed to the dosage lim-
itation imposed by the toxicity, which led to insufficient exposure
level in plasma and remarkably decreased efficacy when used in
patients with advanced lung tumor harboring the T790M acquired
against EGFR-wt but keeping the high efficacy against EGFR-
T790M. The third-generation irreversible EGFR inhibitors, such as
AZD-9291 [11,12] and CO-1686 [13], are characterized by potently
inhibiting EGFR phosphorylation in EGFRmþ/T790M, whilst
demonstrating much less activity against EGFR-wt. Avoiding the
toxicity induced by the inhibition of EGFR-wt, AZD-9291 and CO-
1686 are currently in human phase 2 clinical trials. The second
class of compounds has comparable efficacy against EGFR-wt, but
with greatly increased efficacy against EGFR-T790M in comparison
with afatinib. Without needing the high dosage, these compounds
can achieve safe and effective inhibiting concentration in vivo
against EGFR-T790M resistance tumor. The designing of the second
type of compounds has been proved to be quite challenging, and
few reports exists.
Despite the rapid advances in EGFR oncology therapeutics over
the past decade, substantial room for improvement remains. Most
cancer patients do not respond to EGFR inhibitors therapy, which
implied intrinsic resistance (e.g., over-expressing EGFR-wt or
‘oncogenic shift’) [14,15]. Although many papers or patents have
been presented for quinazoline-based EGFR inhibitors [16e19], and
afatinib has been discovered, it is still in high demand to develop
safer and more effective irreversible EGFR inhibitors. As part of our
Abbreviations: EGFR, Epidermal growth factor receptor; NSCLC, Non-small cell
lung cancer; SAR, Structure-activity relationship; DMF, Dimethylformamide; TLC,
Thin layer chromatography; THF, Tetrahydrofuran; NMP, N-methyl-2-pyrrolidone;
Rf, Retention factor; DMSO, Dimethyl sulphoxide; RPMI, Roswell Park Memorial
Institute; GI50, The concentration that causes 50% growth inhibition; PO, Oral
administration; QD, One a day (from the Latin quaque die).
* Corresponding author.
E-mail address: chuanwen.fan@qilu-pharma.com (C. Fan).
http://dx.doi.org/10.1016/j.ejmech.2015.08.026
0223-5234/© 2015 Elsevier Masson SAS. All rights reserved.

446
L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
ongoing research program in designing new irreversible inhibitors
that overcome EGFR-over-expressing or EGFR-T790M resistance, a
series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives
were synthesized. We discovered that compounds with a primary
amine-substituted center at the end of the Michael acceptor caused
a significant improvement in cellular potency against T790M in
comparison with afatinib. These efforts resulted in the identifica-
tion of the novel quinazoline-based compounds 7q and 8f with
greatly increased efficacy against H1975 (EGFR-T790M) tumors at a
non-toxic dose in comparison with afatinib.
Considering that the terminal dialkylamino group of the croto-
namide Michael acceptor affected the compound's physico-
chemical properties, water-solubility as well as the activity in
both kinase and cell proliferation assays [20], further optimizing
the Michael acceptor side chains were done. Tables 2 and 3 show
compounds where the terminal alkylamino group of the crotona-
mide Michael acceptor was varied. It was evident that N-piper-
idinyl, cyclopropanamine, N-methylcyclopropanamine and
propan-2-amine groups were very well tolerated, and for most of
these analogs, the kinase and cellular activities were minimally
affected by the choice of these alkylamino groups. One exception
was the dicyclopropylamine group that greatly reduced potency of
compounds 7ke7n, which implied that incorporation of some
steric bulk at the end of the Michael acceptor might be unfavorable
and hinder the intramolecular base catalysis of the Michael addi-
tion to form a covalent adduct. Compound 7g, where the Michael
acceptor was terminated with a 3, 3-difluoroazetidine group,
showed reduced activity in the kinase assay, and this loss of activity
was likely attributed to the reduced basicity [21]. However, the
diminished activity of piperidin-4-one-N-substituted analog 7c or
thiomorpholine-1-oxide-N-substituted analogs 7he7j may be due
to the acyl group which interrupted the intramolecular base-
catalyzed Michael addition. As expected, when the Michael
acceptor side chains containing piperidinyl, cyclopropanamine, N-
methylcyclopropanamine or propan-2-amine group were intro-
duced into 4-(3-ethynylaniline)-substituted quinazoline analogs,
compounds 8ae8i also showed high in vitro efficacy. There was no
major difference in activities between the 3-chloro-4-fluoroaniline-
substituted derivatives and the 3-ethynylaniline -substituted de-
rivatives (Tables 2 and 3).
In addition, H1975 cell growth inhibition assay was used to
demonstrate the superior cell-based efficacy of those analogs
against the resistant EGFR mutants (EGFR-T790M). The primary
amine-substituted analogs 7oe7q showed the highest potency and
were at least 5-fold more effective than afatinib in abolishing sur-
vival of H1975 cells (Table 2). Similar results were also observed in
the 3-ethynylaniline-substituted derivatives 8fe8i (Table 3).
After the promising in vitro results were observed, further in vivo
antitumor activities of the primary amine-substituted analogs
7oe7q, 7r, 7u and 8ee8i were evaluated first using a H1975
xenograft model (Supplementary information). Because the afati-
nib free base was difficult to dissolve at a high dose, and resulted in
uneven dispersion, afatinib dimaleate was prepared for in vivo
evaluation. Except for 7u and 8i, reductions of tumor size were
observed versus controls in H1975 xenograft (Fig. 1). Intriguingly,
although with high potency in vitro, compound 7u or 8i at 50 mg/
kg/day dose level didn't show any activities in H1975 xenograft.
2. Results and discussion
The aniline-substituted quinazoline motif (Intermediate 4) was
prepared in the following way: 7-fluoro-6-nitro-3H-quinazolin-4-
one was firstly treated with thionyl chloride, and then reacted
with an aromatic amine to give the intermediate 2, which was
further reacted with an alcohol of formula R3OH in the presence of
NaH to provide the intermediate 3. Reduction of 3 gave the aniline-
substituted quinazoline motif 4. The Michael acceptor at the 6-
position was constructed by reacting intermediate 4 with acryloyl
chloride or (E)-4-bromobut-2-enoyl chloride which further reacted
with various secondary amines or primary amines (Scheme 1).
The optimization of aromatic amine groups at the 4-position
was firstly investigated, and the results are shown in Table 1.
These data indicated that 3-chloro-4-fluoroaniline, 3-
ethynylaniline, 4-(pyridin-2-ylmethoxy)aniline or 3-chloro-4-
(pyridin-2-ylmethoxy)aniline group gratifyingly afforded a number
of analogs (e.g., 5b, 5n, 6b) with high activities against EGFR. 3-
Chloro-4-(3-fluorobenzyloxy)aniline, 4-chloro-3-(trifluoromethyl)
aniline, 5-amino-2-fluorobenzonitrile and N-(4-amino-2-(tri-
fluoromethyl)phenyl)acrylamide were not ideal pharmacophore
groups, and compounds containing those groups (e.g., 6a, 6e, 6p)
couldn't effectively inhibit EGFR kinase. The presence of linear
chain or heterocyclic groups at the 7-position of the quinazoline
scaffold was well tolerated and often had little effect on its' in vitro
activities. The introduction of a dimethylamine group at the end of
the Michael acceptor led to a modest increase in potency, most
compounds of series 6 in Table 1 were more active in comparison
with the corresponding compounds of series 5. Although with
excellent in vitro activities, compounds containing the 4-(pyridin-
2-ylmethoxy)aniline or 3-chloro-4-(pyridin-2-ylmethoxy)aniline
group (e.g., 6g, 6m and 6n) exhibited weak activities against A431
(human epidermoid carcinoma) xenografts in nude mice, which
might be attributed to their large molecular weight and low
permeability. Hence, the ideal groups at the 4-position of the qui-
nazoline were 3-chloro-4-fluoroaniline and 3-ethynylaniline.
Scheme 1. Synthesis of 6, 7-disubstituted-4-anilino quinazoline derivatives (series 5e8). Reaction and conditions: (a) thionyl chloride, DMF, reflux; (b) CH3CN, reflux; (c) NaH,
anhydrous THF, 0 ꢀC to rt; (d) Fe, NH4Cl, ethanol/water, 60 ꢀC; (e) CH3CN, NMP, ꢁ5 ꢀC; (f) anhydrous THF, triethylamine, 0 ꢀC; (g) K2CO3, KI, DMF, 40 ꢀC.

L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
447
Table 1
EGFR kinase inhibition (IC50) by 6, 7-disubstituted-4-anilino quinazoline derivatives 5 and 6.
R2
R2
HN
N
R1
HN
N
R1
H
N
N
H
N
N
N
O
O
O
R3
O
R3
5
6
Comp.
R3O-
EGFR (IC50, nM)
102.2
Comp.
R3O-
EGFR (IC50, nM)
R2
R2
R1
R1
5a
6a
>1000
F
F
O
O
O
O
O
O
O
Cl
Cl
O
O
5b
1.8
6b
1.2
O
5c
>1000
6c
573.6
102.3
F3
C
F3C
O
O
O
O
Cl
Cl
O
O
O
O
5d
115.1
6d
CF3
CF3
H
N
H
N
N
O
O
5e
5f
195.8
560.4
6e
6f
>1000
F
F
O
O
O
O
O
O
N
N
F
91.0
5.4
F
O
Cl
O
O
O
5g
F
72.2
6g
Cl
N
O
O
O
O
O
O
O
5h
5i
134.9
100.1
32.2
6h
6i
10.0
1.2
Cl
N
N
O
O
O
O
O
O
O
O
O
O
Cl
N
O
F
O
5j
6j
3.0
Br
F
O
O
5k
5l
104.7
6k
6l
510.2
133.9
F3
C
F
O
O
O
Cl
Cl
O
O
>1000
F
CF3
O
O
O
H
N
O
O
O
5m
5n
167.3
5.8
6m
6n
8.1
9.0
F
Cl
N
N
O
O
O
O
N
O
O
O
Cl
O
F
O
O
(continued on next page)

448
L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
Table 1 (continued )
Comp.
R3O-
EGFR (IC50, nM)
Comp.
R3O-
EGFR (IC50, nM)
R2
R2
R1
R1
5o
121.1
6o
1.2
Br
F
O
O
O
O
6p
6q
6r
>1000
147.4
6.0
F3
C
O
Cl
F
O
O
N
O
O
O
6s
8.1
O
N
Even at a dose of 100 mg/kg/day from day 7, 8i still couldn't achieve
effective inhibition (Fig.1a). Further PK study indicated that the low
in vivo activities of 7u and 8i might be attributed to their low oral
bioavailability and fast clearance (Table 4). Afatinib dimaleate at
20 mg/kg/day were tolerated, but couldn't effectively inhibit the
growth of H1975 tumor (TGI < 50%) (Fig. 1a), and when 30 mg/kg/
day dose was given, high potency as well as severe toxicity were
observed and mice began to die from day 10 (Fig. 1c). Compounds
7o, 7p, 8e and 8h exhibited better in vivo activities, but also higher
toxicity in comparison with afatinib dimaleate. In case of 7o and 7p,
severe weight-loss was observed, the experimental athymic mice
became weak or lethargic, further developed eye diseases and
exfoliative skin disorder, and nine days later, more than half of the
mice had died. These two groups' animals were sacrificed. A similar
observation was noted in mice treated with 8e and 8h, and more
than half of the mice had died at day 7. For observation, we sacri-
ficed the mice of 8e group and kept 8h. The rest of the mice in the
8h group were gradually recovering after stopping the adminis-
tration of compound 8h at day 7 (Fig. 1d). Compound 7q, 8f and 8g
exhibited improved safety profiles in comparison with afatinib
dimaleate, and the animals treated with these compounds
appeared healthy and active throughout the study duration.
Although no significant effect on the body weight of the mice in 8g
group was noticed, a slightly skin toxicity was observed. While
providing higher in vivo activities (vs afatinib), 7q and 8f were well
tolerated, and no overt toxicity (e.g., eye diseases and exfoliative
skin disorder) or weight-loss was observed in mice. These data
indicated the (S)-tetrahydrofuran-3-ol substitution at the 7-
position improved the safety profiles in comparison with alkyl
groups. Hence 7q and 8f were selected for further in vivo studies.
Compounds 7q and 8f showed high selectivity for HCC827
xenograft (EGFR-delE746-A750 represents EGFRmþ) over A431
xenograft (EGFR-wt) (Fig. 2). In A431 xenograft, 7q and 8f couldn't
achieve effective inhibition at 5 mg/kg/day dose level (Fig. 2a).
However, in HCC827 xenograft, 7q and 8f at 5 mg/kg/day dose level
significantly inhibited the growth of tumor, and tumor regressions
were observed in all mice after being treated with 7q and 8f (Fig. 2c
and table in Supplementary information). Afatinib dimaleate at
5 mg/kg/day dose level effectively inhibited the growth of A431
tumor and HCC827 tumor (Fig. 2a and c). As compared with afatinib
dimaleate (5 mg/kg/day dose), 7q was more active and 8f was as
active against HCC827 xenograft at 5 mg/kg/day dose level. Both
compounds when administrated at a dose of 10 mg/kg/day
exhibited higher potency against A431 xenograft (Fig. 2a and 2c).
Besides, no overt toxicity (e.g., eye diseases and exfoliative skin
disorder) or weight-loss was observed in all mice at those dose
levels (Fig. 2b and 2d). Because patients with advanced lung tumor
harboring the T790M acquired mutation usually have a high EGFR-
wt/EGFRmþ expression ratio, 7q and 8f might have special ad-
vantages, and more patients would be benefit from them.
The cyclopropylamine moiety has been widely used in the
structures of fluoroquinolone antimicrobials (e.g., moxifloxacin
[22], gemifloxacin [23], ciprofloxacin [24], sitafloxacin [25] and
trovafloxacin
[26]).
Except
for
trovafloxacin,
these
cyclopropylamine-containing drugs were tolerated, and no sever
hepatotoxicity was observed [22e27]. The cyclopropylamine group
of trovafloxacin is considered to be the most suspected substruc-
ture responsible for its hepatotoxicity [28]. The unique chemistry of
cyclopropylamine moiety was illustrated by their tendency to
produce a nitrogen radical cation when oxidized by P450 enzymes,
which followed by rapid ring opening to form a highly reactive
carbon-centered radical [28,29]. In the present investigation, the
cyclopropylamine group was introduced into the structures of
anticancer compounds, and 7q and 8f were discovered. Although
7q and 8f at present dose level were well tolerated, and no overt
toxicity was observed, more studies (e.g., metabolite identification
and toxicity) should be done to investigate whether the sever
hepatotoxicity would be observed at higher dose level as well as the
potential metabolic reactive intermediates and the metabolism.
Because of the existence of a, ß-unsaturated Michael acceptor, the
toxicological mechanism of compounds 7q and 8f will be expected
to be very complex.
3. Conclusions
In summary, we have described the SARs of a series of 6, 7-
disubstituted-4-anilino quinazoline derivatives and confirmed
that the ideal groups at the 4-position of the quinazoline are 3-

L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
449
Table 2
EGFR inhibition (IC50) and H1975 cancer cell proliferation inhibition (GI50) by 7ae7u.
Comp.
R2
R3O-
EGFR (IC50, nM)
1.0
H1975 (GI50, nM)
Afatinib
107.1
O
O
Dacomitinib
eOCH3
1.8
5.3
123.3
168.0
7a
O
O
7b
7c
eOCH2CH2OCH3
2.1
92.3
ND
520.2
O
O
7d
7e
7f
eOCH3
26.9
8.9
32.2
87.1
160.2
ND
eOCH2CH2OCH3
eOCH2CH3
5.5
7g
>1000
O
O
7h
7i
eOCH3
>1000
ND
ND
109.4
O
O
7j
eOCH2CH2OCH3
356.6
ND
ND
7k
eOCH3
>1000
7l
>1000
ND
O
O
7m
7n
7o
eOCH2CH2OCH3
>1000
>1000
0.9
ND
eOCH2CH3
ND
eOCH2CH3
eOCH3
11.6
7p
7q
2.1
6.5
11.2
10.2
O
O
(continued on next page)

450
L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
Table 2 (continued )
Comp.
R2
R3O-
EGFR (IC50, nM)
H1975 (GI50, nM)
34.6
7r
eOCHF2
9.6
7s
7t
eOCH2CF3
eOCH3
6.9
20.3
98.7
22.4
141.0
7.0
7u
O
O
chloro-4-fluoroaniline and 3-ethynylaniline for EGFR inhibition.
Most importantly, we found that a primary amine-substituted
center at the end of the Michael acceptor resulted in a significant
improvement in T790M cellular potency relative to afatinib. These
findings led to the discovery of some promising compounds (e.g.,
7oe7q, 8fe8i) which manifested higher activities against H1975
cells (EGFR-T790M) and kept certain potency against A431 cells
(EGFR-wt) in comparison with afatinib. Further studies showed
that the optimized compounds 7q and 8f demonstrated good
pharmacokinetic profiles, oral bioavailability as well as excellent
in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic
dose.
mixture was warmed to room temperature and stirred for 0.5 h.
Then, the mixture was cooled to 0 ꢀC, the suspension of N-(3-
chloro-4-(3-fluorobenzyloxy)phenyl)-7-fluoro-6-nitroquinazolin-
4-amine (4.4 g,10 mmol) in anhydrous THF (50 ml) were added into
dropwise. The mixture was warmed to room temperature and
reacted for 2 h. Once the reaction was completed as indicated by
TLC, the mixture was concentrated under vacuum at 30 ꢀC to
remove THF, and diluted with ice water (400 ml). The precipitate
was collected by filtration, washed with water and dried to pro-
vided
N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-7-(2-
methoxyethoxy)-6-nitroquinazolin-4-amine 3.5 g (7 mmol, 71%).
To a suspension of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-
7-(2-methoxyethoxy)-6-nitroquinazolin-4-amine (2.5 g, 5 mmol)
in alcohol (25 ml) and water (25 ml), were added Fe powder (1.1 g,
4. Experimental protocols
4.1. Chemistry
Table 3
The reagents were all analytically grade. Yields refer to purified
products and are not optimized. 1H NMR and 13C NMR spectra were
recorded on a on a Varian-600 or Bruck-400 spectrometer in
DMSO-d6 with TMS as the internal reference. The values of chem-
ical shifts are expressed in ppm. MS spectra were determined using
either an Agilent 1100 LC/MSD or a Thermo Fisher Scientific
LCQFleet LC/MSn, and the signals were given in m/z. The elemental
carbon, hydrogen, and nitrogen content were measured using a
ThermoFisher FLASH 2000 Organic Elemental Analyzer. The exact
amount of residue solvent in products was determined by Agilent
7890A using external standard calibration.
EGFR inhibition (IC50) and H1975 cancer cell proliferation inhibition (GI50) by 8ae8i.
Comp.
R2
R3O-
EGFR (IC50, nM)
5.3
H1975 (GI50, nM)
40.1
8a
O
In a similar manner to that described in paper, the following
compounds of formula 5 were prepared.
O
8b
8c
8d
eOCH3
2.7
6.1
3.3
48.9
30.4
70.5
4.1.1. N-(4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-7-(2-
methoxyethoxy)quinazolin-6-yl)acrylamide (5a)
eOCH2CH3
eOCH3
To a suspension of 7-fluoro-6-nitroquinazolin-4-ol (41.8 g,
0.2 mol) in thionyl chloride (350 ml) was added DMF (5 ml)
dropwise under stirring at room temperature, and then the mixture
was raised to reflux for 4 h until to be a clear solution. After
removing thionyl chloride under vacuum, the residue was diluted
with CH2Cl2 and concentrated to provide 4-chloro-7-fluoro-6-
nitroquinazoline 49 g (216 mmol, 108%).
8e
8f
eOCH2CH3
2.4
5.6
41.0
16.1
O
To a solution of 4-chloro-7-fluoro-6-nitroquinazoline (4.58 g,
20 mmol) in acetonitrile (500 ml) was added 3-chloro-4-(3-
fluorobenzyloxy)aniline (4.77 g, 19 mmol), and then the mixture
was raised to reflux. Once the reaction was completed as indicated
by TLC, The precipitate was collected by filtration, and washed with
acetonitrile to give N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-7-
fluoro-6-nitroquinazolin-4-amine 7.5 g (16.9 mmol, 85%).
To a suspension of NaH (800 mg) in anhydrous THF (240 ml)
were added the solution of 2-methoxyethanol (1.5 g, 20 mmol) in
anhydrous THF (10 ml) dropwise at 0 ꢀC. After the addition, the
O
8g
8h
8i
eOCH3
7.9
4.2
6.4
18.9
16.5
19.8
eOCH2CH3
O
O

L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
451
Fig. 1. Antitumor activities of 7oe7u and 8ee8i in H1975 xenograft model. (a) and (c) Relative tumor volumes vs time; (b) and (d) Body weight change vs time.
Table 4
Pharmacokinetic study of 7q, 7u, 8f and 8i in rats (IV, 1.00 mg/kg, n ¼ 3).
fluorobenzyloxy)phenyl)-7-(2-methoxyethoxy)quinazoline-4,6-
diamine 2.1 g (4.5 mmol, 90%).
N4-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-7-(2-
Parameters
7u
8i
7q
8f
Afatinib
methoxyethoxy)quinazoline-4,6-diamine (0.94 g, 2 mmol) was
dissolved in acetonitrile (50 ml) and NMP (3 ml) and stirred
at ꢁ5 ꢀC, to which a solution of acryloyl chloride (0.5 ml) in
acetonitrile (3 ml) was added dropwise. Once the reaction was
completed as indicated by TLC, water (2 ml) was added, and the
mixture was concentrated under vacuum at 35 ꢀC. The residue was
diluted with 10% sodium bicarbonate solution (160 ml), and the
precipitate was collected by filtration, washed with 10% sodium
bicarbonate solution, and dried to give a crude product, which was
purified by column chromatograph on silica gel (Solvent system:
ethyl acetate/methanol, gradient elution (volume-to-volume ra-
tios) from 50:1 to 20:1; Rf ¼ 0.31 at 20:1 solvent system) to obtain
the title compound 489 mg (0.94 mmol, 47%).
AUC0e24 (ng h/ml)a
AUC0e∞ (ng h/ml)b
MRT (h)c
166.3
196.7
8.8
9.9
5.4
92.6
105.3
2.6
1.5
10.2
7.4
659.6
662.4
3.88
3.15
1.54
3.82
471.4
480.2
1.7
2.3
3.0
276.8
324.5
10.57
9.6
3.25
10.77
62.3%
T1/2 (h)d
CL(L/h/kg)e
Vd(L/kg)f
6.5
<5%
2.2
37.9%
Fg
<5%
83.47%
a
AUC0e24 (ng h/ml), Area under the plasma concentration-time curve (0e24 h).
AUC0e∞ (ng h/ml), Area under the plasma concentration-time curve (0e∞ h).
MRT, Mean retention time.
T1/2, Elimination half life.
Vd, Apparent volume of distribution.
CL, Clearance.
b
c
d
e
f
g
F, Bioavailability.
1H NMR (600 MHz, DMSO-d6, dppm): 9.69 (s, 1H), 9.62 (s, 1H),
8.87 (s, 1H), 8.49 (s, 1H), 7.98 (d, 1H, J ¼ 2.4 Hz, arylamine-2-]CH),
7.69e7.71 (dd, 1H, J ¼ 8.4 Hz, J ¼ 2.4 Hz, arylamine-6-]CH),
7.45e7.49 (dd, 1H, J ¼ 7.8 Hz, J ¼ 7.2 Hz, 3-fluorobenzyloxy-5-]CH),
7.33e7.34 (m, 2H, 3-fluorobenzyloxy-2,6-]CH), 7.31 (s,1H), 7.24 (d,
1H, J ¼ 8.4 Hz, arylamine-5-]CH), 7.17e7.20 (dd, 1H, 3JF-H ¼ 8.4 Hz,
19.6 mmol) and NH4Cl (1.1 g, 20.6 mmol) respectively, and then the
temperature was raised to 60 ꢀC and the mixture was stirred for 6 h.
Once the reaction was completed, the mixture was diluted with
water (50 ml), and extracted with CH2Cl2 (3 ꢂ 100 ml). The com-
bined organic phase was washed with water, dried over anhydrous
Na2SO4, and concentrated to provide N4-(3-chloro-4-(3-
J
¼
7.8 Hz, 3-fluorobenzyloxy-4-]CH), 6.70e6.74 (dd, 1H,

452
L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
Fig. 2. Antitumor activities of 7q and 8f in A431 and HCC827 xenograft models. (a) and (c) Relative tumor volumes vs time; (b) and (d) Body weight change vs time.
J ¼ 17.4 Hz, J ¼ 10.2 Hz, eCH]CH2), 6.32 (d, 1H, J ¼ 17.4 Hz, eCH]
CH2), 5.82 (d, 1H, J ¼ 10.2 Hz, eCH]CH2), 5.25 (s, 2H, 3-
4.1.3. N-(4-(4-Chloro-3-(trifluoromethyl)phenylamino)-7-(2-
methoxyethoxy)quinazolin-6-yl)acrylamide (5c)
The title compound was prepared in a manner similar to that
described for 5a yielding 152 mg (0.33 mmol, 60%).
fluorobenzyloxy-CH2Oe), 4.36e4.37 (ap. t., 2H,
J
¼
4.8 Hz,
J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.79e3.81 (ap. t., 2H, J ¼ 4.8 Hz,
J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.35 (s, 3H, CH3Oe). ESI-MS (m/z):
[MꢁH]ꢁ 521.3, [MþH]þ 523.2.
1H-NMR (600 MHz, DMSO-d6, dppm): 10.0 (s, 1H), 9.69 (s, 1H),
8.95 (s, 1H), 8.59 (s, 1H), 8.42 (d, 1H, J ¼ 2.4 Hz, arylamine-2-]CH),
8.29e8.31 (dd, 1H, J ¼ 8.4 Hz, J ¼ 2.4 Hz, arylamine-6-]CH), 7.73 (d,
1H, J ¼ 8.4 Hz, arylamine-5-]CH), 7.37 (s, 1H), 6.75e6.78 (dd, 1H,
J ¼ 16.8 Hz, J ¼ 10.8 Hz, eCH]CH2), 6.32e35 (dd, 1H, J ¼ 16.8 Hz,
J ¼ 1.8 Hz, eCH]CH2), 5.83e5.85 (ap. t., 1H, J ¼ 10.8 Hz, J ¼ 1.8 Hz,
eCH]CH2), 4.39e4.40 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz,
CH3OCH2CH2Oe), 3.80e3.82 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz,
CH3OCH2CH2Oe), 3.35 (s, 3H, CH3Oe). ESI-MS (m/z): [MþH]þ
467.3.
4.1.2. N-(4-(3-Ethynylphenylamino)-7-(2-methoxyethoxy)
quinazolin-6-yl)acrylamide (5b)
The title compound was prepared in a manner similar to that
described for 5a yielding 136 mg (0.35 mmol, 72%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.76 (s, 1H), 9.64 (s, 1H),
8.91 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.87e7.89 (dd, 1H, J ¼ 8.4 Hz,
J ¼ 1.2 Hz, arylamine-6-]CH), 7.37e7.40 (ap. t., 1H, J ¼ 8.4 Hz,
J ¼ 7.8 Hz, arylamine-5-]CH), 7.33 (s, 1H), 7.20 (d, 1H, J ¼ 7.8 Hz,
arylamine-4-]CH), 6.70e6.75 (dd, 1H, J ¼ 16.8 Hz, J ¼ 9.6 Hz,
eCH]CH2), 6.31e6.34 (dd, 1H, J ¼ 16.8 Hz, J ¼ 1.8 Hz, eCH]CH2),
5.82e5.83 (dd, 1H, J ¼ 9.6 Hz, J ¼ 1.8 Hz, eCH]CH2), 4.37e4.38 (ap.
t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe), 4.19 (s, 1H, alkyne-H),
3.80e3.81 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.36 (s,
3H, CH3Oe). ESI-MS (m/z): [MþH]þ 389.2.
4.1.4. N-(4-(4-Acrylamido-3-(trifluoromethyl)phenylamino)-7-(2-
methoxyethoxy)quinazolin-6-yl)acrylamide (5d)
The title compound was prepared in a manner similar to that
described for 5a yielding 174 mg (0.35 mmol, 69%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.97 (s, 1H), 9.74 (s, 1H),
9.67 (s, 1H), 8.94 (s, 1H), 8.56 (s, 1H), 8.25 (s, 1H), 8.22 (d, 1H,

L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
453
J ¼ 8.4 Hz, arylamine-5-]CH), 7.51 (d, 1H, J ¼ 8.4 Hz, arylamine-6-
]CH), 7.35 (s,1H), 6.73e6.75 (dd,1H, J ¼ 17.4 Hz, J ¼ 10.2 Hz, eCH]
CH2), 6.52e6.54 (dd,1H, J ¼ 17.4 Hz, J ¼ 10.2 Hz, eCH]CH2), 6.34 (d,
1H, J ¼ 17.4 Hz, eCH]CH2), 6.25 (d,1H, J ¼ 17.4 Hz, eCH]CH2), 5.83
(d, 1H, J ¼ 10.2 Hz, eCH]CH2), 5.78 (d, 1H, J ¼ 10.2 Hz, eCH]CH2),
4.39e4.40 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe),
3.80e3.82 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.35 (s,
3H, CH3Oe). ESI-MS (m/z): [MþH]þ 502.4, [MꢁH]ꢁ 500.3.
1H NMR (600 MHz, DMSO-d6, dppm): 9.71 (s, 1H), 9.55 (s, 1H),
8.91 (s, 1H), 8.60 (d, 1H, J ¼ 3.6 Hz, pyridin-6-]CH), 8.49 (s, 1H),
7.99 (s, 1H), 7.88e7.90 (ap. t., 1H, J ¼ 7.8 Hz, J ¼ 7.2 Hz, pyridin-4-]
CH), 7.69 (d, 1H, J ¼ 8.4 Hz, arylamine-6-]CH), 7.59 (d, 1H,
J ¼ 7.8 Hz, pyridin-3-]CH), 7.36e7.38 (ap. t., 1H, J ¼ 6.6 Hz,
J ¼ 5.4 Hz, pyridin-5-]CH), 7.25 (d, 1H, J ¼ 8.4 Hz, arylamine-5-]
CH), 7.23 (s, 1H), 6.72e6.77 (dd, 1H, J ¼ 17.4 Hz, J ¼ 10.2 Hz, eCH]
CH2), 6.33 (d, 1H, J ¼ 16.2 Hz, eCH]CH2), 5.83 (d, 1H, J ¼ 10.2 Hz,
eCH]CH2), 5.29 (broad s, 3H, pyridin-2-yl-CH2Oe and tetrahy-
drofuran-3-CH), 3.98e4.02 (m, 2H, tetrahydrofuran-2-CH2),
3.91e3.95 (m, 1H, tetrahydrofuran-5-CH2), 3.77e3.80 (m, 1H,
tetrahydrofuran-5-CH2), 2.32e2.38 (m,1H, tetrahydrofuran-4-CH2),
2.13e2.15 (m, 1H, tetrahydrofuran-4-CH2). ESI-MS (m/z): [MþH]þ
518.4.
4.1.5. N-(4-(3-Cyano-4-fluorophenylamino)-7-(2-methoxyethoxy)
quinazolin-6-yl)acrylamide (5e)
The title compound was prepared in a manner similar to that
described for 5a yielding 102 mg (0.25 mmol, 59%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.96 (s, 1H), 9.65 (s, 1H),
8.92 (s, 1H), 8.56 (s, 1H), 8.38e8.39 (dd,1H, 4JF-H ¼ 5.4 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 8.14e8.17 (m, 1H, arylamine-6-]CH), 7.56 (t,
1H, J ¼ 9.0 Hz, arylamine-5-]CH), 7.34 (s, 1H), 6.72e6.76 (dd, 1H,
J ¼ 17.4 Hz, J ¼ 10.8 Hz, eCH]CH2), 6.31e6.34 (dd, 1H, J ¼ 17.4 Hz,
J ¼ 1.8 Hz, eCH]CH2), 5.82e5.84 (dd, 1H, J ¼ 10.8 Hz, J ¼ 1.8 Hz,
eCH]CH2), 4.38e4.39 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz,
CH3OCH2CH2Oe), 3.80e3.81 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz,
CH3OCH2CH2Oe), 3.33 (s, 3H, CH3Oe). ESI-MS (m/z): [MþH]þ
408.2.
4.1.9. (S)-N-(4-(4-(Pyridin-2-ylmethoxy)phenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)acrylamide (5i)
The title compound was prepared in a manner similar to that
described for 5a giving 174 mg (0.36 mmol, 46%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.63 (s, 1H), 9.53 (s, 1H),
8.89 (s, 1H), 8.59 (d, J ¼ 4.8 Hz, 1H, pyridin-6-]CH), 8.41 (d, 1H),
7.84e7.87 (m, 1H, pyridin-4-]CH), 7.64 (d, 2H, J ¼ 9.0 Hz, aryl-
amine-2,6-]CH), 7.55 (d, 1H, J ¼ 8.4 Hz, pyridin-3-]CH), 7.35e7.38
(m, 1H, pyridin-5-]CH), 7.20 (s, 1H), 7.04 (d, 2H, J ¼ 9.0 Hz, aryl-
amine-3,5-]CH), 6.71e6.74 (dd, 1H, J ¼ 16.8 Hz, J ¼ 10.2 Hz, eCH]
CH2), 6.30e6.33 (dd, 1H, J ¼ 16.8 Hz, J ¼ 1.2 Hz, eCH]CH2),
5.81e5.83 (ap. t., 1H, J ¼ 10.2 Hz, J ¼ 1.2 Hz, eCH]CH2), 5.28 (broad
s, 1H, tetrahydrofuran-3-CH), 5.19 (s, 2H, pyridin-2-yl-CH2Oe),
3.97e4.02 (m, 2H, tetrahydrofuran-2-CH2), 3.91e3.95 (m, 1H,
tetrahydrofuran-5-CH2), 3.76e3.80 (m,1H, tetrahydrofuran-5-CH2),
2.31e2.36 (m, 1H, tetrahydrofuran-4-CH2), 2.11e2.15 (m, 1H,
tetrahydrofuran-4-CH2). ESI-MS (m/z): [MþH]þ 484.4.
4.1.6. (S)-N-(4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)acrylamide (5f)
The title compound was prepared in a manner similar to that
described for 5a yielding 198 mg (0.37 mmol, 37%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.70 (s, 1H), 9.45 (s, 1H),
8.90 (s, 1H), 8.49 (s, 1H), 7.97 (d, 1H, J ¼ 2.4 Hz, arylamine-2-]CH),
7.68e7.70 (dd, 1H, J ¼ 8.4 Hz, J ¼ 2.4 Hz, arylamine-6-]CH),
7.45e7.49 (m, 1H, 3-fluorobenzyloxy-5-]CH), 7.31e7.34 (ap. t., 2H,
JF-H ¼ 11.4 Hz, J ¼ 7.8 Hz, 3-fluorobenzyloxy-2,6-]CH), 7.25 (d, 1H,
J ¼ 8.4 Hz, arylamine-5-]CH), 7.23 (s, 1H), 7.17e7.20 (m, 1H, 3-
4.1.10. (S)-N-(4-(3-Ethynylphenylamino)-7-(tetrahydrofuran-3-
yloxy)quinazolin-6-yl)acrylamide (5j)
The title compound was prepared in a manner similar to that
described for 5a giving 168 mg (0.41 mmol, 42%).
fluorobenzyloxy-4-]CH), 6.74e6.76 (dd, 1H,
J
¼
17.4 Hz,
J ¼ 10.2 Hz, eCH]CH2), 6.31e6.34 (dd, 1H, J ¼ 17.4 Hz, J ¼ 2.4 Hz,
eCH]CH2), 5.83 (d, 1H, J ¼ 10.2 Hz, eCH]CH2), 5.29 (broad s, 1H,
tetrahydrofuran-3-CH), 5.25 (s, 2H, 3-fluorobenzyloxy-CH2Oe),
3.97e4.02 (m, 2H, tetrahydrofuran-2-CH2), 3.91e3.95 (m, 1H,
tetrahydrofuran-5-CH2), 3.77e3.80 (m,1H, tetrahydrofuran-5-CH2),
2.32e2.38 (m, 1H, tetrahydrofuran-4-CH2), 2.12e2.16 (m, 1H,
tetrahydrofuran-4-CH2). ESI-MS (m/z): [MþH]þ 535.4.
1H NMR (600 MHz, DMSO-d6, dppm): 9.78 (s, 1H), 9.56 (s, 1H),
8.95 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.87 (d, 1H, J ¼ 7.8 Hz, aryl-
amine-6-]CH), 7.37e7.40 (ap. t., 1H, J ¼ 8.4 Hz, J ¼ 7.8 Hz, aryl-
amine-5-]CH), 7.25 (s, 1H), 7.20 (d, 1H, J ¼ 8.4 Hz, arylamine-4-]
CH), 6.72e6.77 (dd, 1H, J ¼ 16.8 Hz, J ¼ 12.0 Hz, eCH]CH2),
6.31e6.34 (dd, 1H, J ¼ 16.8 Hz, J ¼ 1.8 Hz, eCH]CH2), 5.82e5.84
(dd, 1H, J ¼ 12.0 Hz, J ¼ 1.8 Hz, eCH]CH2), 5.30 (broad s, 1H,
tetrahydrofuran-3-CH), 4.20 (s, 1H, alkyne-H), 3.97e4.02 (m, 2H,
tetrahydrofuran-2-CH2), 3.91e3.94 (m, 1H, tetrahydrofuran-5-CH2),
3.78e3.80 (m, 1H, tetrahydrofuran-5-CH2), 2.33e2.36 (m, 1H,
tetrahydrofuran-4-CH2), 2.12e2.16 (m, 1H, tetrahydrofuran-4-CH2).
ESI-MS (m/z): [MþH]þ 401.3.
4.1.7. (S)-N-(4-(4-(3-Fluorobenzyloxy)phenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)acrylamide (5g)
The title compound was prepared in a manner similar to that
described for 5a yielding 200 mg (0.40 mmol, 50%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.62 (s, 1H), 9.53 (s, 1H),
8.89 (s, 1H), 8.42 (s, 1H), 7.65 (d, 2H, J ¼ 8.4 Hz, arylamine-2,6-]
CH), 7.44e7.47 (m,1H, 3-fluorobenzyloxy-5-]CH), 7.29e7.32 (ap. t.,
2H, 3JF-H ¼ 9.6 Hz, J ¼ 7.8 Hz, 3-fluorobenzyloxy-2,6-]CH), 7.20 (s,
1H), 7.17e7.18 (m, 1H, 3-fluorobenzyloxy-4-]CH), 7.03 (d, 2H,
J ¼ 8.4 Hz, arylamine-3,5-]CH), 6.71e6.75 (dd, 1H, J ¼ 17.4 Hz,
J ¼ 10.2 Hz, eCH]CH2), 6.31 (d, 1H, J ¼ 17.4 Hz, eCH]CH2), 5.82 (d,
1H, J ¼ 10.2 Hz, eCH]CH2), 5.28 (broad s, 1H, tetrahydrofuran-3-
CH), 5.15 (s, 2H, 3-fluorobenzyloxy-CH2Oe), 3.97e4.02 (m, 2H,
tetrahydrofuran-2-CH2), 3.91e3.95 (m, 1H, tetrahydrofuran-5-CH2),
3.76e3.80 (m, 1H, tetrahydrofuran-5-CH2), 2.31e2.36 (m, 1H,
tetrahydrofuran-4-CH2), 2.12e2.15 (m, 1H, tetrahydrofuran-4-CH2).
ESI-MS (m/z): [MþH]þ 501.3.
4.1.11. (S)-N-(4-(4-Chloro-3-(trifluoromethyl)phenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)acrylamide (5k)
The title compound was prepared in a manner similar to that
described for 5a giving 167 mg (0. 35 mmol, 49%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.58 (s, 1H), 8.99 (s, 1H),
8.59 (s, 1H), 8.41 (d, 1H, J ¼ 2.4 Hz, arylamine-2-]CH), 8.28e8.30
(dd, 1H, J ¼ 8.4 Hz, J ¼ 2.4 Hz, arylamine-6-]CH), 7.73 (d, 1H,
J ¼ 8.4 Hz, arylamine-5-]CH), 7.28 (s, 1H), 6.74e6.79 (dd, 1H,
J ¼ 16.8 Hz, J ¼ 12.0 Hz, eCH]CH2), 6.32e6.35 (ap. t., 1H,
J ¼ 16.8 Hz, J ¼ 1.8 Hz, eCH]CH2), 5.84 (d, 1H, J ¼ 11.4 Hz, eCH]
CH2), 5.31 (broad s, 1H, tetrahydrofuran-3-CH), 3.97e4.03 (m, 2H,
tetrahydrofuran-2-CH2), 3.92e3.95 (m,1H, tetrahydrofuran-5-CH2),
3.77e3.81 (m, 1H, tetrahydrofuran-5-CH2), 2.33e2.39 (m, 1H,
tetrahydrofuran-4-CH2), 2.14e2.18 (m, 1H, tetrahydrofuran-4-CH2).
ESI-MS (m/z): [MþH]þ 479.2.
4.1.8. (S)-N-(4-(3-Chloro-4-(pyridin-2-ylmethoxy)phenylamino)-
7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)acrylamide (5h)
The title compound was prepared in a manner similar to that
described for 5a yielding 238 mg (0.46 mmol, 46%).

454
L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
4.1.12. (S)-N-(4-(4-Acrylamido-3-(trifluoromethyl)phenylamino)-
7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)acrylamide (5l)
The title compound was prepared in a manner similar to that
described for 5a giving 159 mg (0.31 mmol, 62%).
4.1.16. (E)-N-(4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-7-
(2-methoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-
enamide (6a)
To a solution of N4-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-7-
(2-methoxyethoxy)quinazoline-4,6-diamine (0.94 g, 2 mmol) in
anhydrous THF (10 ml) and triethylamine (0.4 ml) was added a
solution of 4-bromo-but-2-enoyl chloride (0.46 g, 2.5 mmol) in
anhydrous THF (5 ml) dropwise at 0 ꢀC, and the mixture was stirred
for 1 h. Once the reaction was completed as indicated by TLC, water
(0.5 ml) was added into the mixture. After the solvent was removed
under vacuum at 35 ꢀC, the residue was diluted with water (20 ml),
and extracted with CH2Cl2 (3 ꢂ 30 ml). The combined organic phase
was washed with brine, dried over anhydrous Na2SO4, concen-
trated and purified by column chromatograph to provide (E)-4-
bromo-N-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-7-(2-
1H NMR (600 MHz, DMSO-d6, dppm): 9.97 (s, 1H), 9.74 (s, 1H),
9.58 (s, 1H), 8.98 (s, 1H), 8.56 (s, 1H), 8.25 (s, 1H), 8.21 (d, 1H,
J ¼ 8.4 Hz, arylamine-6-]CH), 7.50 (d, 1H, J ¼ 8.4 Hz, arylamine-5-
]CH), 7.27 (s,1H), 6.74e6.78 (dd,1H, J ¼ 16.8 Hz, J ¼ 10.2 Hz, eCH]
CH2), 6.51e6.56 (dd, 1H, J ¼ 16.8 Hz, J ¼ 10.8 Hz, eCH]CH2),
6.32e6.35 (dd, 1H, J ¼ 16.8 Hz, J ¼ 1.8 Hz, eCH]CH2), 6.24e6.27
(dd, 1H, J ¼ 16.8 Hz, J ¼ 1.8 Hz, eCH]CH2), 5.84 (d, 1H, J ¼ 10.2 Hz,
eCH]CH2), 5.78 (d, 1H, J ¼ 10.8 Hz, eCH]CH2), 5.31 (broad s, 1H,
tetrahydrofuran-3-CH), 3.99e4.03 (m, 2H, tetrahydrofuran-CH2),
3.92e3.96 (m, 1H, tetrahydrofuran-5-CH2), 3.77e3.81 (m, 1H,
tetrahydrofuran-5-CH2), 2.33e2.39 (m,1H, tetrahydrofuran-4-CH2),
2.14e2.18 (m, 1H, tetrahydrofuran-4-CH2). ESI-MS (m/z): [MþH]þ
514.3, [MꢁH]ꢁ 512.3.
methoxyethoxy)quinazolin-6-yl)but-2-enamide
(0.98 mmol, 49%).
497
mg
To
a
solution
of
(E)-4-bromo-N-(4-(3-chloro-4-(3-
4.1.13. (S)-N-(4-(3-Cyano-4-fluorophenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)acrylamide (5m)
The title compound was prepared in a manner similar to that
described for 5a giving 168 mg (0.40 mmol, 35%).
fluorobenzyloxy)phenylamino)-7-(2-methoxyethoxy)quinazolin-
6-yl)but-2-enamide (470 mg, 0.93 mmol) in DMF (5 ml) were
added dimethylamine hydrochloride (300 mg, 3.68 mmol), potas-
sium carbonate (300 mg, 2.17 mmol) and potassium iodide
ꢀ
1H NMR (600 MHz, DMSO-d6, dppm): 9.97 (s, 1H), 9.57 (s, 1H),
8.96 (s, 1H), 8.56 (s, 1H), 8.37e8.39 (dd,1H, 4JF-H ¼ 5.4 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 8.14e8.17 (m, 1H, arylamine-6]CH), 7.54e7.57
(ap. t., 1H, 3JF-H ¼ 9.6 Hz, J ¼ 9.0 Hz, arylamine-5-]CH), 7.27 (s, 1H),
6.74e6.79 (dd, 1H, J ¼ 16.8 Hz, J ¼ 10.2 Hz, eCH]CH2), 6.32e6.35
(dd, 1H, J ¼ 16.8 Hz, J ¼ 1.8 Hz, eCH]CH2), 5.83e5.85 (dd, 1H,
J ¼ 10.2 Hz, J ¼ 1.8 Hz, eCH]CH2), 5.31 (broad s, 1H, tetrahydro-
furan-3-CH), 3.99e4.04 (m, 2H, tetrahydrofuran-2-CH2), 3.92e3.96
(m, 1H, tetrahydrofuran-5-CH2), 3.77e3.81 (m, 1H, tetrahydro-
furan-5-CH2), 2.33e2.39 (m, 1H, tetrahydrofuran-4-CH2), 2.13e2.17
(m, 1H, tetrahydrofuran-4-CH2). ESI-MS (m/z): [MþH]þ 420.3.
(270 mg, 1.63 mmol) at 0 ꢀC. The mixture was raised to 40 C and
stirred for 3 h under N2 atmosphere. Once the reaction was
completed as indicated by TLC, the mixture was diluted with water
(60 ml) and extracted with CH2Cl2 (3 ꢂ 30 ml). The combined ex-
tracts were dried over anhydrous Na2SO4, concentrated and puri-
fied by column chromatograph on silica gel (Solvent system: ethyl
acetate/methanol from 20:1 to 5:1 and 0.5% triethylamine (volume-
to-volume ratios), gradient elution; Rf ¼ 0.15 at 5:1 solvent system
and 0.5% triethylamine) to obtain the title compound 108 mg
(0.19 mmol, 24%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.68 (s, 1H), 9.52 (s, 1H),
8.88 (s, 1H), 8.48 (s, 1H), 7.97 (d, 1H, J ¼ 2.4 Hz, arylamine-2-]CH),
7.69e7.71 (dd, 1H, J ¼ 9.0 Hz, J ¼ 2.4 Hz, arylamine-6-]CH),
7.46e7.49 (m, 1H, 3-fluorobenzyloxy-5-]CH), 7.31e7.34 (m, 2H, 3-
fluorobenzyloxy-2,6-]CH), 7.29 (s, 1H), 7.24 (d, 1H, J ¼ 9.0 Hz,
arylamine-5-]CH), 7.17e7.20 (m, 1H, 3-fluorobenzyloxy-4-]CH),
6.78e6.82 (m, 1H, eCH]CHeCH2e), 6.56 (d, 1H, J ¼ 15.0 Hz, eCH]
CHeCH2e), 5.25 (s, 2H, 3-fluorobenzyloxy-CH2Oe), 4.35e4.36 (ap.
t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.79e3.81 (ap. t., 2H,
J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.35 (s, 3H, CH3Oe), 3.10 (d,
2H, J ¼ 5.4 Hz, -eCH2eN(CH3)2), 2.19 (s, 6H, eN(CH3)2). ESI-MS(m/
z): [MþH]þ 580.5.
4.1.14. (S)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)acrylamide (5n)
The title compound was prepared in a manner similar to that
described for 5a giving 184 mg (0.43 mmol, 55%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.83 (s, 1H), 9.56 (s, 1H),
8.95 (s, 1H), 8.54 (d, 1H), 8.13e8.15 (dd, 1H, 4JF-H ¼ 6.6 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.79e7.82 (m, 1H, arylamine-6-]CH),
3
7.41e7.44 (ap. t., JF-H ¼ 9.6 Hz, 1H, J ¼ 8.4 Hz, arylamine-5-]CH),
7.26 (s, 1H), 6.73e6.78 (dd, 1H, J ¼ 16.8 Hz, J ¼ 10.2 Hz, eCH]CH2),
6.32e6.35 (dd, 1H, J ¼ 16.8 Hz, J ¼ 1.8 Hz, eCH]CH2), 5.83e5.85
(dd, 1H, J ¼ 10.2 Hz, J ¼ 1.8 Hz, eCH]CH2), 5.31 (broad s, 1H,
tetrahydrofuran-3-CH), 3.99e4.03 (m, 2H, tetrahydrofuran-2-CH2),
3.92e3.96 (m, 1H, tetrahydrofuran-5-CH2), 3.77e3.81 (m, 1H,
tetrahydrofuran-5-CH2), 2.32e2.38 (m,1H, tetrahydrofuran-4-CH2),
2.13e2.17 (m, 1H, tetrahydrofuran-4-CH2). ESI-MS (m/z): [MþH]þ
429.3.
4.1.17. (E)-4-(Dimethylamino)-N-(4-(3-ethynylphenylamino)-7-(2-
methoxyethoxy)quinazolin-6-yl)but-2-enamide (6b)
The title compound was prepared in a manner similar to that
described for 6a giving 276 mg (0.62 mmol, 15%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.75 (s, 1H), 9.54 (s, 1H),
8.92 (s, 1H), 8.53 (s, 1H), 8.00 (s, 1H), 7.80 (d, 1H, J ¼ 7.8 Hz, aryl-
amine-6-]CH), 7.37e7.40 (ap. t., 1H, J ¼ 7.8 Hz, J ¼ 7.2 Hz, aryl-
amine-5-]CH), 7.30 (s, 1H), 7.20 (d, 1H, J ¼ 7.2 Hz, arylamine-4-]
CH), 6.78e6.83 (m, 1H, eCH]CHeCH2e), 6.57 (d, 1H, J ¼ 15.0 Hz,
-eCH]CHeCH2-), 4.36e4.37 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz,
CH3OCH2CH2Oe), 4.20 (s, 1H, alkyne-H), 3.80e3.81 (ap. t., 2H,
J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2O-), 3.35 (s, 3H, CH3Oe), 3.09 (d,
2H, J ¼ 6.0 Hz, eCH2eN(CH3)2), 2.19 (s, 6H, eN(CH3)2). ESI-MS(m/z):
[MþH]þ 446.4.
4.1.15. (S)-N-(4-(4-Bromo-2-fluorophenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)acrylamide (5o)
The title compound was prepared in a manner similar to that
described for 5a giving 280 mg (0.59 mmol, 49%).
1H NMR (600 MHz, DMSO-d6, dp3pm): 9.78 (s, 1H), 9.53 (s, 1H),
8.95 (s, 1H), 8.40 (s, H), 7.64 (d, 1H, JF-H ¼ 9.6 Hz, arylamine-3-]
CH), 7.44e7.50 (m, 2H, arylamine-5,6-]CH), 7.25 (s, 1H), 6.74e6.79
(dd, 1H, J ¼ 17.4 Hz, J ¼ 10.2 Hz, eCH]CH2), 6.32 (d, 1H, J ¼ 17.4 Hz,
eCH]CH2), 5.83 (d, 1H, J ¼ 10.2 Hz, eCH]CH2), 5.30 (broad s, 1H,
tetrahydrofuran-3-CH-), 4.00e4.04 (m, 2H, tetrahydrofuran-5-
CH2), 3.92e3.96 (m, 1H, tetrahydrofuran-5-CH2), 3.77e3.80 (m,
1H, tetrahydrofuran-5-CH2), 2.32e2.37 (m, 1H, tetrahydrofuran-4-
CH2), 2.14e2.18 (m, 1H, tetrahydrofuran-4-CH2). ESI-MS (m/z):
[MþH]þ 475.1.
4.1.18. (E)-N-(4-(4-Chloro-3-(trifluoromethyl)phenylamino)-7-(2-
methoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide
(6c)
The title compound was prepared in a manner similar to that
described for 6a giving 283 mg (0.54 mmol, 21%).

L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
455
1H NMR (600 MHz, DMSO-d6, dppm): 10.00 (s, 1H), 9.56 (s, 1H),
8.96 (s, 1H), 8.58 (s, 1H), 8.40 (d, 1H, J ¼ 2.4 Hz, arylamine-2-]CH),
8.28e8.30 (dd,1H, J ¼ 8.4 Hz, J ¼ 2.4 Hz, arylamine-6-]CH), 7.72 (d,
1H, J ¼ 8.4 Hz, arylamine-5-]CH), 7.35 (s, 1H), 6.79e6.84 (m, 1H,
eCH]CHeCH2e), 6.58 (d, 1H, J ¼ 15.6 Hz, eCH]CHeCH2e),
4.37e4.39 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe),
3.80e3.82 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.35 (s,
3H, CH3Oe), 3.09 (d, 2H, J ¼ 6.0 Hz, eCH2eN(CH3)2), 2.19 (s, 6H,
eN(CH3)2). ESI-MS(m/z): [MþH]þ524.40.
1H NMR (600 MHz, DMSO-d6, dppm): 9.69 (s, 1H), 9.54 (s, 1H),
8.88 (s, 1H), 8.60 (d, 1H, J ¼ 4.2 Hz, pyridin-6-]CH), 8.48 (s, 1H),
7.98 (d, 1H, J ¼ 2.4 Hz, arylamine-2-]CH), 7.88e7.90 (m, 1H, pyr-
idin-4-]CH), 7.68e7.70 (dd, 1H, J ¼ 8.4 Hz, J ¼ 2.4 Hz, arylamine-6-
]CH), 7.59 (d, 1H, J ¼ 7.8 Hz, pyridin-3-]CH), 7.37 (t,1H, pyridin-5-
]CH), 7.29 (s, 1H), 7.25 (d, 1H, J ¼ 8.4 Hz, arylamine-5-]CH),
6.78e6.81 (m, 1H, eCH]CHeCH2e), 6.57 (d, 1H, J ¼ 15.6 Hz, eCH]
CHeCH2e), 5.29 (s, 2H, pyridin-2-yl-CH2O-), 4.35e4.36 (ap. t., 2H,
J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.79e3.81 (ap. t., 2H,
J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.35 (s, 3H, CH3Oe), 3.14
(broad s, 2H, eCH2eN(CH3)2), 2.22 (s, 6H, eN(CH3)2). ESI-MS (m/z):
[MþH]þ563.5.
4.1.19. (E)-4-(Dimethylamino)-N-(4-(4-((E)-4-(dimethylamino)
but-2-enamido)-3-(trifluoromethyl)phenylamino)-7-(2-
methoxyethoxy)quinazolin-6-yl)but-2-enamide (6d)
The title compound was prepared in a manner similar to that
described for 6a giving 277 mg (0.45 mmol, 12%).
4.1.23. (E)-4-(Dimethylamino)-N-(7-(2-methoxyethoxy)-4-(4-
(pyridin-2-ylmethoxy)phenylamino)quinazolin-6-yl)but-2-enamide
(6h)
The title compound was prepared in a manner similar to that
described for 6a giving 185 mg (0.35 mmol, 35%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.95 (s, 1H), 9.64 (s, 1H),
9.56 (s, 1H), 8.95 (s, 1H), 8.55 (s, 1H), 8.23 (s, 1H), 8.20 (d, 1H,
J ¼ 7.8 Hz, arylamine-5-]CH), 7.50 (d, 1H, J ¼ 7.8 Hz, arylamine-6-
]CH), 7.34 (s, 1H), 6.79e6.84 (m, 1H, eCH]CHeCH2e), 6.70e6.75
(m, 1H, eCH]CHeCH2e), 6.58 (d, 1H, J ¼ 15.0 Hz, eCH]
CHeCH2e), 6.36 (d, 1H, J ¼ 15.0 Hz, eCH]CHeCH2e), 4.37e4.38
(ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.81e3.82 (ap. t.,
2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.35 (s, 3H, CH3Oe),
3.09 (d, 2H, J ¼ 5.4 Hz, eCH2eN(CH3)2), 3.06 (d, 2H, J ¼ 5.4 Hz,
eCH2eN(CH3)2), 2.19 (s, 6H, eN(CH3)2), 2.18 (s, 6H, eN(CH3)2). ESI-
MS(m/z): [MþH]þ 616.5, [MꢁH]ꢁ 614.4.
1H NMR (600 MHz, DMSO-d6, dppm): 8.86 (s, 1H), 8.59 (d, 1H
J ¼ 4.8 Hz, pyridin-6-]CH), 8.41 (s, 1H), 7.84e7.87 (m, 1H, pyridin-
4-]CH), 7.65 (d, 2H, J ¼ 9.0 Hz, arylamine-2,6-]CH), 7.54 (d, 1H,
J ¼ 8.4 Hz, pyridin-3-]CH), 7.35e7.37 (m, 1H, pyridin-5-]CH), 7.27
(s, 1H), 7.04 (d, 2H, J ¼ 9.0 Hz, arylamine-3,5-]CH), 6.77e6.81 (m,
1H, eCH]CHeCH2e), 6.55 (d, 1H, J ¼ 15.0 Hz, eCH]CHeCH2e),
4.34e4.35 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe),
3.79e3.80 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.35 (s,
3H, CH3OCH2CH2Oe), 3.10 (d, 2H, J ¼ 5.4 Hz, eCH2eN(CH3)2), 2.19
(s, 6H, eN(CH3)2). ESI-MS (m/z): [MþH]þ 529.5.
4.1.20. (E)-N-(4-(3-Cyano-4-fluorophenylamino)-7-(2-
methoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide
(6e)
The title compound was prepared in a manner similar to that
described for 6a giving 172 mg (0.37 mmol, 17%).
4.1.24. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(2-
methoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide
(6i)
1H NMR (600 MHz, DMSO-d6, dppm): 9.95 (s, 1H), 9.55 (s, 1H),
8.93 (s, 1H), 8.55 (s, 1H), 8.37e8.38 (m, 1H, 4JF-H ¼ 5.4 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 8.14e8.16 (m, 1H, arylamine-6-]CH), 7.55 (t,
1H, J ¼ 9.0 Hz, arylamine-5-]CH), 7.34 (s, 1H), 6.78e6.83 (m, 1H,
eCH]CHeCH2e), 6.58 (d, 1H, J ¼ 15.6 Hz, eCH]CHeCH2e),
4.37e4.38 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe),
3.80e3.82 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.33 (s,
3H, CH3Oe), 3.09 (d, 2H, J ¼ 6.0 Hz, eCH2eN(CH3)2), 2.19 (s, 6H,
eN(CH3)2). ESI-MS (m/z): [MþH]þ 465.4.
The title compound was prepared in a manner similar to that
described for 6a giving 142 mg (0.30 mmol, 55%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.75 (s, 1H), 9.53 (s, 1H),
8.93 (s, 1H), 8.53 (s, 1H), 8.13e8.15 (dd, 1H, 4JF-H ¼ 6.6 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.80e7.82 (m, 1H, arylamine-6-]CH),
3
7.41e7.44 (ap. t., 1H, JF-H ¼ 9.6 Hz, J ¼ 8.4 Hz, arylamine-5-]CH),
7.26 (s, 1H), 6.80 (m, 1H, eCH]CHeCH2e), 6.57 (d, 1H, J ¼ 15.0 Hz,
eCH]CHeCH2e), 4.35e4.37 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz,
CH3OCH2CH2Oe), 3.80e3.82 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz,
CH3OCH2CH2Oe), 3.35 (s, 3H, CH3Oe), 3.09 (d, 2H, J ¼ 5.4 Hz,
eCH2eN(CH3)2), 2.19 (s, 6H, eN(CH3)2). ESI-MS (m/z): [MþH]þ
474.3.
4.1.21. (E)-4-(Dimethylamino)-N-(4-(4-(3-fluorobenzyloxy)
phenylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)but-2-enamide
(6f)
The title compound was prepared in a manner similar to that
described for 6a giving 190 mg (0.35 mmol, 20%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.62 (s, 2H), 8.85 (s, 1H),
8.42 (s, 1H), 7.65 (d, 2H, J ¼ 8.4 Hz, arylamine-2,6-]CH), 7.44e7.47
4.1.25. (E)-N-(4-(4-Bromo-2-fluorophenylamino)-7-(2-
methoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide
(6j)
The title compound was prepared in a manner similar to that
described for 6a giving 129 mg (0.25 mmol, 49%).
3
(m, 1H, 3-fluorobenzyloxy-5-]CH), 7.29e7.32 (ap. t., 2H, JF-
¼ 9.6 Hz, J ¼ 7.8 Hz, 3-fluorobenzyloxy-2,6-]CH), 7.27 (s, 1H),
1H NMR (600 MHz, DMSO-d6, dppm): 9.75 (s, 1H), 9.51 (s, 1H),
8.92 (s, 1H), 8.39 (s, 1H), 7.63e7.65 (m, 1H, arylamine-3-]CH),
7.44e7.50 (m, 2H, arylamine-5,6-]CH), 7.31 (s, 1H), 6.78e6.82 (m,
1H, eCH]CHeCH2e), 6.59 (d, 1H, J ¼ 15.0 Hz, eCH]CHeCH2e),
4.36e4.38 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe),
3.80e3.82 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz, CH3OCH2CH2Oe), 3.35 (s,
3H, CH3Oe), 3.09 (d, 2H, J ¼ 5.4 Hz, eCH2eN(CH3)2), 2.19 (s, 6H,
eN(CH3)2). ESI-MS (m/z): [MþH]þ 518.2.
H
7.15e7.18 (m,1H, 3-fluorobenzyloxy-4-]CH), 7.03 (d, 2H, J ¼ 8.4 Hz,
arylamine-3,5-]CH), 6.77e6.82 (m, 1H, eCH]CHeCH2e), 6.54 (d,
1H, J ¼ 15.0 Hz, eCH]CHeCH2e), 5.15 (s, 2H, 3-fluorobenzyloxy-
CH2Oe), 4.34e4.37 (ap. t., 2H,
J
¼
4.8 Hz,
J
¼
4.2 Hz,
CH3OCH2CH2Oe), 3.80e3.81 (ap. t., 2H, J ¼ 4.8 Hz, J ¼ 4.2 Hz,
CH3OCH2CH2Oe), 3.34 (s, 3H, CH3Oe), 3.09 (d, 2H, J ¼ 5.4 Hz,
eCH2eN(CH3)2), 2.19 (s, 6H, eN(CH3)2). ESI-MS (m/z): [MþH]þ
546.5, [MꢁH]ꢁ 544.4.
4.1.26. (S,E)-N-(4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-
7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(dimethylamino)
but-2-enamide (6k)
The title compound was prepared in a manner similar to that
described for 6a giving 248 mg (0.42 mmol, 28%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.70 (s, 1H), 9.45 (s, 1H),
4.1.22. (E)-N-(4-(3-Chloro-4-(pyridin-2-ylmethoxy)phenylamino)-
7-(2-methoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-
enamide (6g)
The title compound was prepared in a manner similar to that
described for 6a giving 219 mg (0.39 mmol, 38%).

456
L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
8.93 (s, 1H), 8.55 (s, 1H), 7.97 (d, 1H, J ¼ 2.4 Hz, arylamine-2-]CH),
eCH]CHeCH2e), 5.27 (broad s, 1H, tetrahydrofuran-3-CH), 5.19 (s,
2H, pyridin-2-yl-CH2Oe), 3.99 (broad s, 2H, tetrahydrofuran-2-
CH2), 3.91e3.95 (m, 1H, tetrahydrofuran-5-CH2), 3.77e3.79 (m,
1H, tetrahydrofuran-5-CH2), 3.10 (d, 2H, J ¼ 3.0 Hz, eCH2eN(CH3)2),
2.31e2.36 (m, 1H, tetrahydrofuran-4-CH2), 2.20 (s, 6H, eN(CH3)2),
2.13e2.16 (m, 1H, tetrahydrofuran-4-CH2). ESI-MS (m/z): [MþH]þ
541.4.
7.70 (d, 1H, J ¼ 7.2 Hz, arylamine-6-]CH), 7.45e7.49 (m, 1H, 3-
3
fluorobenzyloxy-5-]CH), 7.31e7.34 (m, 2H, JF-H
¼
11.4 Hz,
J ¼ 7.8 Hz, 3-fluorobenzyloxy-2,6-]CH), 7.24 (d, 1H, J ¼ 7.2 Hz,
arylamine-5-]CH), 7.21 (s, 1H), 7.17e7.20 (m, 1H, 3-
fluorobenzyloxy-5-]CH), 6.78e6.83 (m, 1H, eCH]CHeCH2e),
6.60 (d, 1H, J ¼ 15.0 Hz, eCH]CHeCH2e), 5.29 (broad s, 1H,
tetrahydrofuran-3-CH), 5.25 (s, 2H, 3-fluorobenzyloxy-CH2Oe),
4.00 (d, 2H, J ¼ 2.4 Hz, tetrahydrofuran-2-CH2), 3.91e3.95 (m, 1H,
tetrahydrofuran-5-CH2), 3.78e3.80 (m,1H, tetrahydrofuran-5-CH2),
3.09 (d, 2H, J ¼ 5.4 Hz, eCH2eN(CH3)2), 2.32e2.37 (m, 1H, tetra-
hydrofuran-4-CH2), 2.19 (s, 6H, eN(CH3)2), 2.14e2.17 (m, 1H,
tetrahydrofuran-4-CH2). ESI-MS (m/z): [MþH]þ 592.5.
4.1.30. (S,E)-4-(Dimethylamino)-N-(4-(3-ethynylphenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)but-2-enamide (6o)
The title compound was prepared in a manner similar to that
described for 6a giving 210 mg (0.46 mmol, 39%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.75 (s, 1H), 9.45 (s, 1H),
8.97 (s, 1H), 8.53 (s, 1H), 8.00 (s, 1H), 7.87 (d, 1H, J ¼ 7.8 Hz, aryl-
amine-6-]CH), 7.37e7.40 (ap. t., 1H, J ¼ 7.8 Hz, J ¼ 7.2 Hz, aryl-
amine-5-]CH), 7.24 (s, 1H), 7.20 (d, 1H, J ¼ 7.2 Hz, arylamine-4-]
CH), 6.79e6.83 (m, 1H, eCH]CHeCH2e), 6.60 (d, 1H, J ¼ 15.6 Hz,
eCH]CHeCH2-e), 5.30 (s, 1H, tetrahydrofuran-3-CH), 4.20 (s, 1H,
4.1.27. (S,E)-4-(Dimethylamino)-N-(4-(4-(3-fluorobenzyloxy)
phenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)but-2-
enamide (6l)
The title compound was prepared in a manner similar to that
described for 6a giving 173 mg (0.31 mmol, 41%).
alkyne-H), 4.00 (d, 2H,
J
¼
3.0 Hz, tetrahydrofuran-2-CH2),
1H NMR (600 MHz, DMSO-d6, dppm): 9.63 (d, 1H), 9.44 (s, 1H),
8.89 (d, 1H), 8.42 (s, 1H), 7.65 (d, 2H, J ¼ 8.4 Hz, arylamine-2,6-]
CH), 7.43e7.46 (m, 1H, 3-fluorobenzyloxy-5-]CH), 7.29e7.32 (m,
3.91e3.95 (m, 1H, tetrahydrofuran-5-CH2), 3.78e3.81 (m, 1H,
tetrahydrofuran-5-CH2), 3.09 (d, 2H, J ¼ 3.0 Hz, eCH2eN(CH3)2),
2.33e2.36 (m, 1H, tetrahydrofuran-4-CH2), 2.19 (s, 6H, eN(CH3)2),
2.13e2.17 (m, 1H, tetrahydrofuran-4-CH2). ESI-MS (m/z): [MþH]þ
458.4.
3
2H, JF-H ¼ 9.6 Hz, J ¼ 7.8 Hz, 3-fluorobenzyloxy-2,6-]CH),
7.16e7.21 (m, 1H, 3-fluorobenzyloxy-4-]CH), 7.03 (d, 2H,
J
¼
8.4 Hz, arylamine-3,5-]CH), 6.77e6.81 (m, 1H, eCH]
CHeCH2e), 6.59 (d, 1H, J ¼ 15.0 Hz, eCH]CHeCH2e), 5.27 (broad s,
1H, tetrahydrofuran-3-CH), 5.15 (s, 2H, 3-fluorobenzyloxy-CH2Oe),
3.99 (broad s, 2H, tetrahydrofuran-2-CH2), 3.92e3.97 (m, 1H,
tetrahydrofuran-5-CH2), 3.77e3.79 (m, 1H, tetrahydrofuran-5-CH2),
3.10 (d, 2H, J ¼ 5.4 Hz, eCH2eN(CH3)2), 2.32e2.35 (m, 1H, tetra-
hydrofuran-4-CH2), 2.19 (s, 6H, eN(CH3)2), 2.12e2.16 (m, 1H,
tetrahydrofuran-4-CH2). ESI-MS (m/z): [MþH]þ 558.5.
4.1.31. (S,E)-4-(Dimethylamino)-N-(4-(4-chloro-3-
(trifluoromethyl)phenylamino) -7-(tetrahydrofuran-3-yloxy)
quinazolin-6-yl)but-2-enamide (6p)
The title compound was prepared in a manner similar to that
described for 6a giving 214 mg (0.40 mmol, 33%).
1H NMR (600 MHz, DMSO-d6, dppm): 10.0 (s, 1H), 9.48 (s, 1H),
9.01 (s, 1H), 8.58 (s, 1H), 8.40 (d, 1H, J ¼ 2.4 Hz, arylamine-2-]CH),
8.28e8.30 (dd,1H, J ¼ 8.4 Hz, J ¼ 2.4 Hz, arylamine-6-]CH), 7.72 (d,
1H, J ¼ 8.4 Hz, arylamine-5-]CH), 7.27 (s, 1H), 6.80e6.85 (m, 1H,
eCH]CHeCH2e), 6.61 (d, 1H, J ¼ 15.6 Hz, eCH]CHeCH2e), 5.31
(broad s, 1H, tetrahydrofuran-3-CH), 4.00 (broad s, 2H, tetrahy-
drofuran-2-CH2), 3.92e3.96 (m, 1H, tetrahydrofuran-5-CH2),
3.77e3.81 (m,1H, tetrahydrofuran-5-CH2), 3.09 (d, 2H, J ¼ 3.0 Hz,
eCH2-eN(CH3)2), 2.34e2.37 (m, 1H, tetrahydrofuran-4-CH2), 2.19
(s, 6H, eN(CH3)2), 2.13e2.17 (m, 1H, tetrahydrofuran-4-CH2). ESI-
MS (m/z): [MþH]þ 536.4.
4.1.28. (S,E)-N-(4-(3-Chloro-4-(pyridin-2-ylmethoxy)
phenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-
(dimethylamino)but-2-enamide (6m)
The title compound was prepared in a manner similar to that
described for 6a giving 195 mg (0.34 mmol, 38%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.69 (s, 1H), 9.44 (s, 1H),
8.93 (s, 1H), 8.60 (d, 1H, J ¼ 4.8 Hz, pyridin-6-]CH), 8.48 (s, 1H),
7.98 (d, 1H, J ¼ 2.4 Hz, arylamine-2-]CH), 7.87e7.90 (m, 1H, pyr-
idin-4-]CH), 7.68e7.70 (dd, 1H, J ¼ 8.4 Hz, J ¼ 2.4 Hz, arylamine-6-
]CH), 7.59 (d, 1H, J ¼ 7.8 Hz, pyridin-3-]CH), 7.36e7.38 (m, 1H,
pyridin-5-]CH), 7.24 (d, 1H, J ¼ 8.4 Hz, arylamine-5-]CH), 7.19 (s,
1H), 6.78e6.83 (m, 1H, eCH]CHeCH2e), 6.59 (d, 1H, J ¼ 15.0 Hz,
eCH]CHeCH2e), 5.29 (s, 3H, pyridin-2-yl-CH2Oe and tetrahy-
drofuran-3-CH), 4.00 (d, 2H, J ¼ 2.4 Hz, tetrahydrofuran-2-CH2),
3.91e3.95 (m, 1H, tetrahydrofuran-5-CH2), 3.77e3.80 (m, 1H,
tetrahydrofuran-5-CH2), 3.09 (d, 2H, J ¼ 5.4 Hz, -CH2-N(CH3)2),
2.31e2.37 (m, 1H, tetrahydrofuran-4-CH2), 2.20 (s, 6H, eN(CH3)2),
2.14e2.16 (m, 1H, tetrahydrofuran-4-CH2). ESI-MS (m/z): [MþH]þ
575.4.
4.1.32. (S,E)-N-(4-(3-Cyano-4-fluorophenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(dimethylamino)but-
2-enamide (6q)
The title compound was prepared in a manner similar to that
described for 6a giving 261 mg (0.55 mmol, 25%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.96 (s, 1H), 9.46 (s, 1H),
8.98 (s, 1H), 8.55 (s, 1H), 8.38 (d, 1H, J ¼ 2.4 Hz, arylamine-2-]CH),
4
8.15e8.16 (ap. t., 1H, JF-H ¼ 4.2 Hz, J ¼ 3.6 Hz, arylamine-6-]CH),
7.55 (t, 1H, J ¼ 9.0 Hz, arylamine-5-]CH), 7.26 (s, 1H), 6.79e6.84
(m, 1H, eCH]CHeCH2e), 6.61 (d, 1H, J ¼ 15.6 Hz, eCH]
CHeCH2e), 5.31 (broad s, 1H, tetrahydrofuran-3-CH), 4.00 (d, 2H,
J ¼ 2.4 Hz, tetrahydrofuran-2-CH2), 3.92e3.96 (m, 1H, tetrahydro-
furan-5-CH2), 3.77e3.81 (m, 1H, tetrahydrofuran-5-CH2), 3.10 (d,
2H, J ¼ 3.0 Hz, eCH2eN(CH3)2), 2.31e2.38 (m, 1H, tetrahydrofuran-
4-CH2), 2.19 (s, 6H, -N(CH3)2), 2.15e2.17 (m, 1H, tetrahydrofuran-4-
CH2). ESI-MS (m/z): [MþH]þ 477.4, [MꢁH]ꢁ 475.3.
4.1.29. (S,E)-4-(Dimethylamino)-N-(4-(4-(pyridin-2-ylmethoxy)
phenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)but-2-
enamide (6n)
The title compound was prepared in a manner similar to that
described for 6a giving 189 mg (0.35 mmol, 45%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.65 (d, 1H, J ¼ 18.6 Hz),
9.48 (s, 1H), 8.90 (s, 1H), 8.59 (d, 1H, J ¼ 4.2 Hz, 1H, pyridin-6-]CH),
8.41 (s, 1H), 7.85 (t, 1H, J ¼ 7.8 Hz, pyridin-4-]CH), 7.65 (d, 2H,
J ¼ 8.4 Hz, arylamine-2,6-]CH), 7.55 (d, 1H, J ¼ 7.8 Hz, pyridin-3-]
CH), 7.35e7.37 (ap. t., 1H, J ¼ 7.2 Hz, J ¼ 4.8 Hz, pyridin-5-]CH), 7.19
(s, 1H), 7.04 (d, 2H, J ¼ 8.4 Hz, arylamine-3,5-]CH), 6.77e6.82 (m,
1H, eCH]CHeCH2e), 6.56e6.61 (ap. t., 1H, J ¼ 15.0 Hz, J ¼ 8.4 Hz,
4.1.33. (E)-4-(Dimethylamino)-N-(4-(3-ethynylphenylamino)-7-
(tetrahydro-2H-pyran-4-yloxy)quinazolin-6-yl)but-2-enamide (6r)
The title compound was prepared in a manner similar to that
described for 6a giving 151 mg (0.32 mmol, 32%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.78 (s, 1H), 8.93 (s, 1H),
8.60 (s, 1H), 7.97 (s, 1H), 7.85 (d, 1H, J ¼ 7.8 Hz, arylamine-6-]CH),

L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
457
2
2
7.41 (s, 1H), 7.41 (t, 1H, J ¼ 7.8 Hz, arylamine-5-]CH), 7.24 (d, 1H,
J ¼ 7.8 Hz, arylamine-4-]CH), 6.76e6.83 (m, 2H, eCH]CHeCH2e),
4.94e4.97 (m, 1H, tetrahydro-2H-pyran-4-CH), 4.22 (s, 1H, alkyne-
H), 3.99 (d, 2H, J ¼ 5.4 Hz, eCH2eN(CH3)2), 3.89e3.92 (m, 2H, tet-
rahydro-2H-pyran-2-CH2), 3.54e3.58 (m, 2H, tetrahydro-2H-py-
ran-2-CH2), 2.83 (s, 6H, eN(CH3)2), 2.06e2.09 (m, 2H, tetrahydro-
2H-pyran-3-CH2), 1.73e1.78 (m, 2H, tetrahydro-2H-pyran-3-CH2).
ESI-MS (m/z): [MþH]þ 472.3.
122.9, 122.8, 119.1 (d, JF-C ¼ 15 Hz), 116.9 (d, JF-C ¼ 22 Hz), 109.4,
108.2, 70.5, 68.9, 59.8, 58.8, 54.6, 26.0, 24.4. ESI-MS (m/z): [MþH]þ
514.2.
4.1.37. (S,E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(4-oxopiperidin-1-yl)
but-2-enamide (7c)
The title compound was prepared in a manner similar to that
described for 6a giving 232 mg (0.43 mmol, 43%).
4.1.34. (E)-4-(Dimethylamino)-N-(4-(3-ethynylphenylamino)-7-(1-
methylpiperidin-4-yloxy)quinazolin-6-yl)but-2-enamide (6s)
The title compound was prepared in a manner similar to that
described for 6a giving 223 mg (0.46 mmol, 30%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.82 (s, 1H), 9.49 (s, 1H),
8.95 (s, 1H), 8.54 (s, H), 8.12e8.14 (dd, 1H, 4JF-H ¼ 6.0 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.79e7.81 (m, 1H, arylamine-6-]CH), 7.43 (t,
1H, J ¼ 9.0 Hz, arylamine-5-]CH), 7.25 (s, 1H), 6.83e6.89 (m, 1H,
eCH2eCH]CH-e), 6.61e6.63 (m, 1H, eCH2eCHeCHe), 5.30 (d, 1H,
J ¼ 3.0 Hz, tetrahydrofuran-3-CH), 4.00e4.02 (m, 2H, tetrahydro-
furan-2-CH2), 3.92e3.95 (m, 1H, tetrahydrofuran-5-CH2),
3.78e3.80 (m, 1H, tetrahydrofuran-5-CH2), 3.09e3.10 (m, 2H,
eCH2eCH]CHe), 2.72e2.76 (m, 4H, 2 ꢂ 4-oxopiperidin-3-CH2),
2.35e2.39 (m, 5H, one hydrogen of tetrahydrofuran-4-CH2 and
2 ꢂ 4-oxopiperidin-2-CH2), 2.14e2.16 (m, 1H, tetrahydrofuran-4-
CH2). ESI-MS (m/z): [MþH]þ 540.3.
1H NMR (600 MHz, DMSO-d6, dppm): 9.73 (s, 1H), 9.44 (s, 1H),
8.89 (s, 1H), 8.52 (s, 1H), 8.01 (s, 1H), 7.88e7.89 (dd, 1H, J ¼ 7.8 Hz,
J ¼ 1.2 Hz, arylamine-6-]CH), 7.38 (t,1H, J ¼ 7.8 Hz, arylamine-5-]
CH), 7.32 (s, 1H), 7.19 (d, 1H, J ¼ 7.2 Hz, arylamine-4-]CH),
6.78e6.83 (m, 1H, eCH]CHeCH2e), 6.56 (d, 1H, J ¼ 15.6 Hz, eCH]
CHeCH2e), 4.71e4.72 (m, 1H, 1-methylpiperidin-4-CH-), 4.20 (s,
1H, alkyne-H), 3.09 (d, 2H, J ¼ 5.4 Hz, eCH2eN(CH3)2), 2.62e2.65
(m, 2H, 1-methylpiperidin-2-CH2), 2.23e2.26 (m, 2H, 1-
methylpiperidin-2-CH2), 2.19 (broad s, 9H, -N(CH3)2 and 1-
methylpiperidin-1-CH3), 1.92e2.01 (m, 2H, 1-methylpiperidin-3-
CH2), 1.79e1.85 (m, 2H, 1-methylpiperidin-3-CH2). ESI-MS (m/z):
[MþH]þ 485.3.
4.1.38. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
methoxyquinazolin-6-yl)-4-(cyclopropyl(methyl)amino)but-2-
enamide (7d)
The title compound was prepared in a manner similar to that
described for 6a giving 273 mg (0.6 mmol, 40%).
4.1.35. (S,E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(piperidin-1-yl)but-2-
enamide (7a)
1H NMR (600 MHz, DMSO-d6, dppm): 9.83 (s, 1H), 9.70 (s, 1H),
8.94 (s, 1H), 8.54 (s, H), 8.12e8.14 (dd, 1H, 4JF-H ¼ 6.6 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.79e7.81 (m, 1H, arylamine-6-]CH),
The title compound was prepared in a manner similar to that
described for 6a giving 457 mg (0.87 mmol, 47%).
3
7.41e7.44 (ap. t., 1H, JF-H ¼ 9.6 Hz, J ¼ 8.4 Hz, arylamine-5-]CH),
1H NMR (600 MHz, DMSO-d6, dppm): 9.82 (s, 1H), 9.47 (s, 1H),
8.95 (s, 1H), 8.53 (s, H), 8.12e8.14 (dd, 1H, 4JF-H ¼ 6.6 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.79e7.82 (m, 1H, arylamine-6-]CH),
7.29 (s, 1H), 6.81e6.86 (m, 1H, eCH2eCH]CHe), 6.57e6.59 (m, 1H,
eCH2eCH]CHe), 4.02 (s, 3H, CH3O), 3.34e3.35 (m, 2H,
eCH2eCH]CHe), 2.29 (s, 3H, NeCH3), 1.77e1.82 (m, 1H, cyclo-
propyl-1-CH), 0.36e0.47 (m, 4H, 2 ꢂ cyclopropyl-2-CH2). ESI-MS
(m/z): [MþH]þ 456.2.
3
7.41e7.44 (ap. t., 1H, JF-H ¼ 9.6 Hz, J ¼ 8.4 Hz, arylamine-5-]CH),
7.24 (s, 1H), 6.79e6.84 (m, 1H, eCH2eCH]CH-), 6.58 (d, 1H,
J ¼ 15.0 Hz, eCH2eCH]CHe), 5.30 (s, 1H, tetrahydrofuran-3-CH),
4.01e4.05 (m, 2H, tetrahydrofuran-2-CH2), 3.92e3.95 (m, 1H,
tetrahydrofuran-5-CH2), 3.77e3.80 (m,1H, tetrahydrofuran-5-CH2),
3.13 (broad s, 2H, eCH2eCH]CHe), 2.32e2.38 (m, 5H, one
hydrogen of tetrahydrofuran-4-CH2 and 2 ꢂ piperidin-2-CH2),
2.14e2.16 (m, 1H, tetrahydrofuran-4-CH2), 1.54 (broad s, 4H,
2 ꢂ piperidin-3-CH2), 1.39e1.44 (m, 2H, piperidin-4-CH2). 13C NMR
4.1.39. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(2-
methoxyethoxy)quinazolin-6-yl)-4-(cyclopropyl(methyl)amino)
but-2-enamide (7e)
The title compound was prepared in a manner similar to that
described for 6a giving 524 mg (1.05 mmol, 38%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.82 (s, 1H), 9.52 (s, 1H),
8.91 (s, 1H), 8.53 (s, H), 8.13e8.14 (dd, 1H, 4JF-H ¼ 6.6 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.79e7.82 (m, 1H, arylamine-6-]CH), 7.43 (t,
1H, J ¼ 8.4 Hz, arylamine-5-]CH), 7.32 (s, 1H), 6.82e6.87 (m, 1H,
eCH2eCH]CHe), 6.54 (d, 1H, J ¼ 15.6 Hz, eCH2eCH]CHe),
4.36e4.38 (m, 2H, CH3OCH2CH2Oe), 3.80e3.81 (m, 2H,
CH3OCH2CH2Oe), 3.35 (s, 3H, CH3Oe), 3.17e3.18 (m, 2H,
eCH2eCH]CHe), 2.29 (s, 3H, NeCH3), 1.75e1.76 (m, 1H, cyclo-
propyl-1-CH), 0.36e0.47 (m, 4H, 2 ꢂ cyclopropyl-2-CH2). 13C NMR
(150 MHz, DMSO-d6, dppm): 164.0, 157.2, 155.0, 154.3, 153.6 (d, 1JF-
1
(100 MHz, DMSO-d6, dppm): 164.0, 157.2, 154.3, 153.6 (d, JF-
¼ 242 Hz), 153.7, 149.2, 142.0, 137.3 (d, 3JF-C ¼ 3 Hz), 128.0, 126.7,
C
2
2
124.0, 122.9, 122.8, 119.2 (d, JF-C ¼ 18 Hz), 116.9 (d, JF-C ¼ 21 Hz),
109.4, 108.5, 79.3, 72.5, 67.1, 59.6, 54.5, 32.9, 25.8, 24.2. ESI-MS (m/
z): [MþH]þ 526.2.
4.1.36. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(2-
methoxyethoxy)quinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide
(7b)
The title compound was prepared in a manner similar to that
described for 6a giving 385 mg (0.75 mmol, 50%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.81 (s, 1H), 9.54 (s, 1H),
8.89 (s, 1H), 8.53 (s, H), 8.13e8.14 (dd, 1H, 4JF-H ¼ 6.0 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.80e7.81 (m, 1H, arylamine-6-]CH),
¼ 242 Hz), 149.3, 142.3, 137.2 (d, 3JF-C ¼ 3.5 Hz), 127.7, 126.2, 123.9,
C
2
2
122.8, 122.7, 119.1 (d, JF-C ¼ 18 Hz), 116.9 (d, JF-C ¼ 22 Hz), 116.5,
109.4, 108.0, 70.4, 68.8, 58.7, 58.5, 42.6, 38.7, 7.2. ESI-MS (m/z):
[MþH]þ 500.2.
3
7.41e7.44 (ap. t., 1H, JF-H ¼ 9.6 Hz, J ¼ 8.4 Hz, arylamine-5-]CH),
4.1.40. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
ethoxyquinazolin-6-yl)-4-(cyclopropyl(methyl)amino)but-2-
enamide (7f)
The title compound was prepared in a manner similar to that
described for 6a giving 423 mg (0.90 mmol, 45%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.80 (s, 1H), 9.52 (s, 1H),
8.93 (s, 1H), 8.52 (s, H), 8.12e8.14 (dd, 1H, 4JF-H ¼ 6.6 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.78e7.81 (m, 1H, arylamine-6-]CH),
7.32 (s, 1H), 6.78e6.83 (m, 1H, eCH2eCH]CHe), 6.54 (d, 1H,
J ¼ 15.6 Hz, eCH2eCH]CHe), 4.37 (broad s, 2H, CH3OCH2CH2Oe),
3.80 (broad s, 2H, CH3OCH2CH2Oe), 3.35 (s, 3H, CH3Oe), 3.13 (broad
s, 2H, eCH2eCH]CHe), 2.37 (broad s, 4H, 2 ꢂ piperidin-2-CH2),
1.53 (broad s, 4H, 2 ꢂ piperidin-3-CH2), 1.39 (broad s, 2H, piperidin-
4-CH2). 13C NMR (100 MHz, DMSO-d6, dppm): 164.1, 157.2, 155.2,
154.3,153.6 (d, 1JF-C ¼ 241 Hz),149.4,142.5,137.3,127.8,126.3,124.0,

458
L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
3
7.41e7.44 (ap. t., 1H, JF-H ¼ 9.6 Hz, J ¼ 9.0 Hz, arylamine-5-]CH),
7.27 (s, 1H), 6.82e6.86 (m, 1H, eCH2eCH]CHe), 6.55 (d, 1H,
J ¼ 16.2 Hz, eCH2eCH]CHe), 4.29e4.31 (m, 2H, CH3CH2Oe),
3.32e3.34 (m, 2H, eCH2eCH]CHe), 2.28 (s, 3H, NeCH3), 1.75e1.76
(m, 1H, cyclopropyl-1-CH), 1.45e1.47 (m, 3H, CH3CH2O-), 0.36e0.47
(m, 4H, 2 ꢂ cyclopropyl-2-CH2). 13C NMR (150 MHz, DMSO-d6,
4.1.44. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(2-
methoxyethoxy)quinazolin-6-yl)-4-(thiomorpholine-1-oxide-4-y)
but-2-enamide (7j)
The title compound was prepared in a manner similar to that
described for 6a giving 384 mg (0.70 mmol, 46%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.82 (s, 1H), 9.58 (s, 1H),
1
4
dppm): 164.0, 157.2, 154.9, 154.3, 153.6 (d, JF-C ¼ 241 Hz), 149.4,
8.90 (s, 1H), 8.54 (s, H), 8.13 (d, 1H, JF-H ¼ 5.4 Hz, arylamine-2-]
142.3,137.3 (d, 3JF-C ¼ 3 Hz),127.8,126.2,124.0,122.9,122.8,119.1 (d,
2JF-C ¼ 18 Hz), 116.9 (d, 2JF-C ¼ 22 Hz), 116.3, 109.2, 107.6, 65.0, 58.6,
42.7, 38.7, 14.7, 7.2. ESI-MS (m/z): [MþH]þ 470.3.
CH), 7.79e7.81 (m, 1H, arylamine-6-]CH), 7.42 (t, 1H, J ¼ 9.0 Hz,
arylamine-5-]CH), 7.33 (s, 1H), 6.79e6.83 (m, 1H, eCH2eCH]
CHe), 6.60 (d, 1H, J ¼ 15.6 Hz, eCH2eCH]CHe), 4.37 (broad s, 2H,
CH3OCH2CH2O-), 3.80 (broad s, 2H, CH3OCH2CH2Oe), 3.35 (s, 3H,
CH3O-), 3.27e3.30 (m, 2H, eCH2eCH]CHe), 2.90e2.93 (m, 4H,
2 ꢂ thiomorpholine-1-oxide-3-CH2), 2.77e2.81 (m, 2H, thio-
morpholine-1-oxide-2-CH2), 2.65e2.70 (m, 2H, thiomorpholine-1-
oxide-2-CH2). 13C NMR (150 MHz, DMSO-d6, dppm): 163.8, 157.2,
155.2, 154.3, 153.6 (d, 1JF-C ¼ 242 Hz), 149.1, 137.2, 127.6, 124.0, 122.9,
4.1.41. (S,E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(3,3-difluoroazetidin-
1-yl)but-2-enamide (7g)
The title compound was prepared in a manner similar to that
described for 6a giving 192 mg (0.36 mmol, 31%).
2
2
1H NMR (600 MHz, DMSO-d6, dppm): 9.90 (s, 1H), 9.59 (s, 1H),
8.93 (s, 1H), 8.53 (s, H), 8.12e8.14 (dd, 1H, 4JF-H ¼ 6.0 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.78e7.80 (m, 1H, arylamine-6-]CH), 7.42 (t,
1H, J ¼ 9.0 Hz, arylamine-5-]CH), 7.33 (s, 1H), 6.82e6.87 (m, 1H,
eCH2eCH]CHe), 6.55 (d, 1H, J ¼ 15.0 Hz, eCH2eCH]CHe),
4.47e4.50 (m, 1H, tetrahydrofuran-3-CH), 4.00e4.02 (m, 2H,
tetrahydrofuran-2-CH2), 3.91e3.95 (m, 1H, tetrahydrofuran-5-CH2),
3.78e3.80 (m, 2H, tetrahydrofuran-5-CH2), 3.50e3.53 (m, 4H,
2 ꢂ 3,3-difluoroazetidin-2-CH2), 3.43e3.44 (m, 2H, eCH2eCH]
CHe), 2.42e2.44 (m, 1H, tetrahydrofuran-4-CH2), 2.15e2.17 (m, 1H,
tetrahydrofuran-4-CH2). ESI-MS (m/z): [MþH]þ 534.2.
119.1 (d, JF-C ¼ 18 Hz), 116.9 (d, JF-C ¼ 21 Hz), 109.3, 107.9, 70.4,
68.9, 58.8, 58.4, 45.7, 44.0. ESI-MS (m/z): [MþH]þ 548.2. Anal.
Calc'd for C25H27ClFN5O4S-1.1H2O: C, 52.88; H, 5.18; N, 12.33.
Found; C, 52.91; H, 5.26; N, 12.29.
4.1.45. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
methoxyquinazolin-6-yl)-4-(dicyclopropylamino)but-2-enamide
(7k)
The title compound was prepared in a manner similar to that
described for 6a giving 151 mg (0.26 mmol, 28%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.82 (s, 1H), 9.67 (s, 1H),
4
8.95 (s, 1H), 8.54 (s, H), 8.13 (d, 1H, JF-H ¼ 4.8 Hz, arylamine-2-]
CH), 7.79e7.81 (m, 1H, arylamine-6-]CH), 7.41e7.44 (ap. t., 1H, 3JF-
4.1.42. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
methoxyquinazolin-6-yl)-4-(thiomorpholine-1-oxide-4-yl)but-2-
enamide (7h)
The title compound was prepared in a manner similar to that
described for 6a giving 136 mg (0.27 mmol, 32%).
¼ 9.6 Hz, J ¼ 9.0 Hz, arylamine-5-]CH), 7.29 (s,1H), 6.96e7.01 (m,
H
1H, eCH2eCH]CHe), 6.58 (d, 1H, J ¼ 15.0 Hz, eCH2eCH]CHe),
4.01 (s, 3H, CH3Oe), 3.45 (d, 2H, J ¼ 6.6 Hz, eCH2eCH]CHe), 2.00
(broad s, 2H, 2 ꢂ dicyclopropylamino-1-CH), 0.43e0.44 (m, 4H,
2
ꢂ
dicyclopropylamino-2-CH2),
0.34e0.36
(m,
4H,
1H NMR (600 MHz, DMSO-d6, dppm): 9.87 (s, 1H), 9.77 (s, 1H),
8.94 (s, 1H), 8.56 (s, H), 8.12e8.14 (dd, 1H, 4JF-H ¼ 6.0 Hz, J ¼ 3.0 Hz,
arylamine-2-]CH), 7.78e7.80 (m, 1H, arylamine-6-]CH),
7.42e7.45 (m, 1H, 3JF-H ¼ 9.6 Hz, J ¼ 9.0 Hz, arylamine-5-]CH), 7.30
(s, 1H), 6.81e6.83 (m, 1H, eCH2eCH]CHe), 6.65 (d, 1H, J ¼ 15.0 Hz,
eCH2eCH]CHe), 4.02 (s, 3H, CH3Oe), 3.26e3.27 (m, 2H,
eCH2eCH]CHe), 2.88e2.93 (m, 4H, 2 ꢂ thiomorpholine-1-oxide-
3-CH2), 2.76e2.80 (m, 2H, thiomorpholine-1-oxide-2-CH2),
2.66e2.69 (m, 2H, thiomorpholine-1-oxide-2-CH2). ESI-MS (m/z):
[MþH]þ 504.1.
2 ꢂ dicyclopropylamino-2-CH2). 13C NMR (100 MHz, DMSO-d6,
dppm): 164.1,157.3,155.7,154.3,153.6 (d, 1JF-C ¼ 242 Hz),149.4,142.3,
137.3 (d, 3JF-C ¼ 2 Hz), 127.8, 126.3, 124.0, 122.9, 122.8, 119.1 (d, 2JF-
¼ 18 Hz), 116.9 (d, 2JF-C ¼ 22 Hz), 116.1109.4, 107.1, 57.5, 56.7, 36.6,
C
6.3. ESI-MS (m/z): [MþH]þ 582.4. Anal. Calc'd for C25H25ClFN5O2-
1.5H2O: C, 58.99; H, 5.54; N,13.76. Found; C, 58.97; H, 5.60; N,13.75.
4.1.46. (S,E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(dicyclopropylamino)
but-2-enamide (7l)
The title compound was prepared in a manner similar to that
described for 6a giving 349 mg (0.65 mmol, 28%).
4.1.43. (S,E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(thiomorpholine-1-
oxide-4-y)but-2-enamide (7i)
1H-NMR (600 MHz, DMSO-d6, dppm): 9.83 (s, 1H), 9.42 (s, 1H),
8.97 (s, 1H), 8.53 (s, H), 8.12e8.14 (dd, 1H, 4JF-H ¼ 6.6 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.79e7.81 (m, 1H, arylamine-6-]CH), 7.43 (t,
1H, J ¼ 9.0 Hz, arylamine-5-]CH), 7.24 (s, 1H), 6.98e7.03 (m, 1H,
eCH2eCH]CHe), 6.58 (d, 1H, J ¼ 15.0 Hz, eCH2eCH]CHe), 5.30
(d, 1H, J ¼ 3.0 Hz, tetrahydrofuran-3-CH), 4.01 (d, 2H, J ¼ 3.0 Hz,
tetrahydrofuran-2-CH2), 3.92e3.95 (m,1H, tetrahydrofuran-5-CH2),
3.77e3.81 (m, 1H, tetrahydrofuran-5-CH2), 3.47 (d, 2H, J ¼ 6.6 Hz,
eCH2-CH]CHe), 2.33e2.36 (m, 1H, tetrahydrofuran-4-CH2),
2.14e2.18 (m, 1H, tetrahydrofuran-4-CH2), 1.98e2.02 (m, 2H,
The title compound was prepared in a manner similar to that
described for 6a giving 168 mg (0.30 mmol, 49%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.82 (s, 1H), 9.50 (s, 1H),
8.95 (s, 1H), 8.54 (s, H), 8.13e8.14 (dd, 1H, 4JF-H ¼ 7.2 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.79e7.82 (m, 1H, arylamine-6-]CH),
3
7.41e7.44 (ap. t., 1H, JF-H ¼ 9.6 Hz, J ¼ 9.0 Hz, arylamine-5-]CH),
7.25 (s, 1H), 6.79e6.84 (m, 1H, eCH2eCH]CHe), 6.61 (d, 1H,
J ¼ 15.0 Hz, eCH2eCH]CHe), 5.30 (d, 1H, J ¼ 2.4 Hz, tetrahydro-
furan-3-CH), 4.00 (d, 2H, J ¼ 3.0 Hz, tetrahydrofuran-2-CH2),
3.92e3.96 (m, 1H, tetrahydrofuran-5-CH2), 3.77e3.80 (m, 1H,
tetrahydrofuran-5-CH2), 3.26e3.27 (m, 2H, eCH2eCH]CHe),
2.88e2.94 (m, 4H, 2 ꢂ thiomorpholine-1-oxide-3-CH2), 2.76e2.79
(m, 2H, thiomorpholine-1-oxide-2-CH2), 2.66e2.69 (m, 2H, thio-
morpholine-1-oxide-2-CH2), 2.34e2.37 (m, 1H, tetrahydrofuran-3-
yloxy-4-CH2), 2.14e2.17 (m, 1H, tetrahydrofuran-4-CH2). ESI-MS
(m/z): [MþH]þ 560.3. Anal. Calc'd for C26H27ClFN5O4S-1.5H2O: C,
53.19; H, 5.15; N, 11.93. Found; C, 53.26; H, 5.24; N, 11.75.
2
2
ꢂ
dicyclopropylamino-1-CH),
dicyclopropylamino-2-CH2),
0.42e0.48
0.34e0.37
(m,
(m,
4H,
4H,
ꢂ
2 ꢂ dicyclopropylamino-2-CH2). 13C NMR (100 MHz, DMSO-d6,
1
dppm): 164.0, 157.3, 154.3, 153.7, 153.6 (d, JF-C ¼ 242 Hz), 149.2,
142.4,137.3 (d, 3JF-C ¼ 3 Hz), 128.1, 126.3, 124.0, 122.9, 122.8,119.1 (d,
2JF-C ¼ 18 Hz), 116.9 (d, 2JF-C ¼ 22 Hz), 116.5109.4, 108.5, 79.3, 72.5,
67.1, 57.6, 36.6, 32.9, 6.3. ESI-MS (m/z): [MþH]þ 538.3. Anal. Calc'd
for C28H29ClFN5O3-0.8H2O: C, 60.88; H, 5.58; N, 12.68. Found; C,
60.91; H, 5.66; N, 12.60.

L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
459
4.1.47. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(2-
methoxyethoxy)quinazolin-6-yl)-4-(dicyclopropylamino)but-2-
enamide (7m)
The title compound was prepared in a manner similar to that
described for 6a giving 268 mg (0.51 mmol, 32%).
described for 6a giving 2.426 g (5.5 mmol, 19%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.82 (s, 1H), 9.64 (s, 1H),
8.93 (s, 1H), 8.53 (s, H), 8.12e8.14 (dd, 1H, 4JF-H ¼ 7.2 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.79e7.82 (m, 1H, arylamine-6-]CH), 7.42 (t,
1H, J ¼ 9.0 Hz, arylamine-5-]CH), 7.29 (s, 1H), 6.86e6.90 (m, 1H,
eCH2eCH]CHe), 6.55 (d, 1H, J ¼ 15.6 Hz, eCH2eCH]CHe), 4.14
(s, 3H, CH3O-), 3.43 (d, 2H, J ¼ 4.8 Hz, eCH2eCH]CHe), 2.16e2.18
(m, 1H, cyclopropylamino-1-CH), 0.40e0.43 (m, 2H, cyclo-
propylamino-2-CH2), 0.29e0.30 (m, 2H, cyclopropylamino-2-CH2).
13C NMR (100 MHz, DMSO-d6, dppm): 164.4, 157.2, 155.7, 154.2, 153.6
1H NMR (600 MHz, DMSO-d6, dppm): 9.82 (s, 1H), 9.51 (s, 1H),
8.93 (s, 1H), 8.53 (s, H), 8.12e8.14 (dd, 1H, 4JF-H ¼ 7.2 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.79e7.82 (m, 1H, arylamine-6-]CH), 7.42 (t,
1H, J ¼ 9.0 Hz, arylamine-5-]CH), 7.32 (s, 1H), 6.97e7.02 (m, 1H,
eCH2eCH]CHe), 6.55 (d, 1H, J ¼ 15.6 Hz, eCH2eCH]CHe),
4.36e4.38 (m, 2H, CH3OCH2CH2Oe), 3.80e3.81 (m, 2H,
CH3OCH2CH2Oe), 3.47 (d, 2H, J ¼ 6.6 Hz, eCH2eCH]CHe), 3.35 (s,
3H, CH3Oe), 1.99e2.02 (m, 2H, 2 ꢂ dicyclopropylamino-1-CH),
0.40e0.45 (m, 4H, 2 ꢂ dicyclopropylamino-2-CH2), 0.35e0.39 (m,
4H, 2 ꢂ dicyclopropylamino-2-CH2). 13C NMR (100 MHz, DMSO-d6,
dppm): 164.1,157.3,155.0,154.3,153.6 (d, 1JF-C ¼ 241 Hz),149.3,142.3,
1
(d, JF-C ¼ 241 Hz), 149.3, 144.6, 137.3, 127.8, 124.5, 124.0, 122.9,
2
2
122.8, 119.1 (d, JF-C ¼ 18 Hz), 116.8 (d, JF-C ¼ 21 Hz), 116.1, 109.4,
107.1, 56.7, 50.2, 30.5, 6.6. ESI-MS (m/z): [MþH]þ 442.1. Anal. Calc'd
for C22H21ClFN5O2-0.3CH3CH2OOCCH3-0.5H2O: C, 58.38; H, 5.15; N,
14.67. Found; C, 58.50; H, 5.17; N, 14.61.
3
137.3 (d, 1C, JF-C ¼ 3 Hz), 127.8, 126.3, 124.0, 122.9, 122.8, 119.1 (d,
4.1.51. (S,E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(cyclopropylamino)
but-2-enamide (7q)
2JF-C ¼ 19 Hz), 116.8 (d, 2JF-C ¼ 21 Hz), 116.5, 109.5, 108.1, 70.5, 68.9,
58.8, 57.5, 36.6, 6.3. ESI-MS (m/z): [MþH]þ 526.2. Anal. Calc'd for
C
27H29ClFN5O3-0.3CH3CH2OOCCH3-0.5H2O: C, 60.33; H, 5.82; N,
The title compound was prepared in a manner similar to that
described for 6a giving 2.287 g (4.6 mmol, 23%).
12.47. Found; C, 60.34; H, 5.90; N, 12.41.
1H NMR (600 MHz, DMSO-d6, dppm): 9.83 (s, 1H), 9.41 (s, 1H),
8.95 (s, 1H), 8.53 (s, H), 8.12e8.14 (dd, 1H, 4JF-H ¼ 7.2 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.79e7.82 (m, 1H, arylamine-6-]CH),
4.1.48. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
ethoxyquinazolin-6-yl)-4-(dicyclopropylamino)but-2-enamide (7n)
The title compound was prepared in a manner similar to that
described for 6a giving 198 mg (0.4 mmol, 40%).
3
7.41e7.44 (ap. t., 1H, J ¼ 9.0 Hz, JF-H ¼ 9.6 Hz, arylamine-5-]CH),
7.24 (s, 1H), 6.88e6.92 (m, 1H, eCH2eCH]CHe), 6.55 (d, 1H,
J ¼ 15.6 Hz, eCH2eCH]CHe), 5.30 (d, 1H, J ¼ 3.6 Hz, tetrahydro-
furan-3-CH), 4.00 (d, 2H, J ¼ 2.4 Hz, tetrahydrofuran-2-CH2),
3.91e3.95 (m, 1H, tetrahydrofuran-5-CH2), 3.77e3.81 (m, 1H,
tetrahydrofuran-5-CH2), 3.43 (d, 2H, J ¼ 4.8 Hz, eCH2eCH]CHe),
2.33e2.36 (m, 1H, tetrahydrofuran-4-CH2), 2.13e2.17 (m, 2H,
tetrahydrofuran-4-CH2 and cyclopropylamino-1-CH), 0.39e0.42
(m, 2H, cyclopropylamino-2-CH2), 0.27e0.29 (m, 2H, cyclo-
propylamino-2-CH2). 13C NMR (100 MHz, DMSO-d6, dppm): 164.3,
1H NMR (600 MHz, DMSO-d6, dppm): 9.81 (s, 1H), 9.50 (s, 1H),
8.94 (s, 1H), 8.52 (s, H), 8.12e8.13 (dd, 1H, 4JF-H ¼ 6.6 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.79e7.81 (m, 1H, arylamine-6-]CH), 7.42 (t,
1H, J ¼ 9.0 Hz, arylamine-5-]CH), 7.26 (s, 1H), 6.97e7.02 (m, 1H,
eCH2eCH]CHe), 6.57 (d, 1H, J ¼ 15.0 Hz, eCH2eCH]CHe),
4.28e4.31 (m, 2H, CH3CH2Oe), 3.47 (d, 2H, J ¼ 6.6 Hz, eCH2eCH]
CHe), 1.98e2.01 (m, 2H, 2 ꢂ dicyclopropylamino-1-CH), 1.45e1.47
(m, 3H, CH3CH2Oe), 0.43e0.45 (m, 4H, 2 ꢂ dicyclopropylamino-2-
CH2), 0.35e0.36 (m, 4H, 2 ꢂ dicyclopropylamino-2-CH2). 13C NMR
(100 MHz, DMSO-d6, dppm): 164.0, 157.2, 154.9, 154.2, 153.6 (d, 1JF-
157.2, 154.3, 153.6 (d, 1JF-C ¼ 242 Hz), 153.6, 149.1, 144.7, 137.3 (d, 3JF-
2
¼ 3 Hz), 128.1, 124.4, 124.0, 122.9, 122.8, 119.1 (d, JF-C ¼ 18 Hz),
C
¼ 241 Hz), 149.4, 142.3, 137.3 (d, 3JF-C ¼ 3 Hz), 127.8, 126.3, 124.0,
116.8 (d, 2JF-C ¼ 22 Hz), 116.4, 109.4, 108.4, 79.2, 72.5, 67.1, 50.3, 32.9,
C
122.9, 122.8, 119.1 (d, 2JF-C ¼ 18 Hz), 116.8 (d, 2JF-C ¼ 21 Hz), 116.20,
109.3, 107.6, 65.0, 57.6, 36.6, 14.7, 6.3. ESI-MS (m/z): [MþH]þ 496.1.
Anal. Calc'd for C26H27ClFN5O2: C, 62.96; H, 5.49; N, 14.12. Found; C,
62.94; H, 5.50; N, 14.12.
30.6, 6.6. ESI-MS (m/z): [MþH]þ 498.1. Anal. Calc'd for
C
25H25ClFN5O3-1.1H2O: C, 57.99; H, 5.30; N, 13.53. Found; C, 58.01;
H, 5.40; N, 13.49.
4.1.52. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
4.1.49. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
(difluoromethoxy)quinazolin-6-yl)-4-(cyclopropylamino)but-2-
enamide (7r)
ethoxyquinazolin-6-yl)-4-(cyclopropylamino)but-2-enamide (7o)
The title compound was prepared in a manner similar to that
described for 6a giving 1.912 g (4.2 mmol, 21%).
To a suspension of p-toluenesulfonic acid (13 g, 76 mmol) in
DMSO (120 ml) was added NaH (7.4 g) under stirred at 0 ꢀC. After
the addition, the mixture was warmed to room temperature and
stirred for 0.5 h. Then, N-(3-chloro-4-fluorophenyl)-7-fluoro-6-
nitroquinazolin-4-amine (prepared in a manner similar to that
described in 5a) (20 g, 60 mmol) was added into, and the mixture
was raised to 90 ꢀC and stirred for 3 h. Once the reaction was
completed as indicated by TLC, the mixture was diluted with water
(800 ml). After adjusting the pH to 3e4 with 4 N hydrochloric acid
solution, the precipitate was collected by filtration, washed with
water and dried under vacuum to provide 4-((3-chloro-4-
fluorophenyl)amino)-6-nitroquinazolin-7-ol 18.8 g (56.3 mmol,
94.6%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.80 (s, 1H), 9.47 (s, 1H),
8.92 (s, 1H), 8.52 (s, H), 8.12e8.14 (dd, 1H, 4JF-H ¼ 6.6 Hz, J ¼ 1.8 Hz,
arylamine-2-]CH), 7.80e7.81 (m, 1H, arylamine-6-]CH), 7.42 (t,
1H, J ¼ 9.0 Hz, arylamine-5-]CH), 7.26 (s, 1H), 6.87e6.91 (m, 1H,
eCH2eCH]CHe), 6.55 (d, 1H, J ¼ 15.6 Hz, -eCH2eCH]CHe),
4.27e4.31 (m, 2H, CH3CH2Oe), 3.42 (d, 2H, J ¼ 4.8 Hz, eCH2eCH]
CHe), 2.12e2.14 (m, 1H, cyclopropylamino-1-CH), 1.45e1.47 (m, 3H,
CH3CH2O-), 0.39e0.40 (m, 2H, cyclopropylamino-2-CH2),
0.26e0.28 (m, 2H, cyclopropylamino-2-CH2). 13C NMR (100 MHz,
DMSO-d6, dppm): 164.3, 157.2, 154.9, 154.2, 153.6 (d, 1JF-C ¼ 241 Hz),
2
149.3, 144.5, 137.4, 127.9, 124.5, 123.9, 122.8, 122.76, 119.1 (d, JF-
¼ 19 Hz),116.8 (d, 2JF-C ¼ 21 Hz),116.2,109.2,107.6, 65.0, 50.2, 30.6,
The
mixture
of
4-((3-chloro-4-fluorophenyl)amino)-6-
C
14.7, 6.5. ESI-MS (m/z): [MþH]þ 456.2. Anal. Calc'd for
nitroquinazolin-7-ol (6.68 g, 20 mmol), sodium chlorodi-
fluoroacetate (4.6 g, 30 mmol) and Cs2CO3 (16.3 g, 50 mmol) in
DMSO (200 ml) and water (50 ml) was raised to 110 ꢀC and stirred
for 48 h under N2 atmosphere. Once the reaction was completed as
indicated by TLC, the mixture was diluted with water (1 L). After
adjusting the pH to 7 with 4 N hydrochloric acid solution, the
precipitate was collected by filtration, washed with water and dried
C
23H23ClFN5O2-0.1CH3CH2OOCCH3-1.0H2O: C, 58.22; H, 5.39; N,
14.51. Found; C, 58.31; H, 5.45; N, 14.44.
4.1.50. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
methoxyquinazolin-6-yl)-4-(cyclopropylamino)but-2-enamide (7p)
The title compound was prepared in a manner similar to that

460
L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
under vacuum to provide N-(3-chloro-4-fluorophenyl)-7-(difluor-
omethoxy)-6-nitroquinazolin-4-amine 2.15 g (5.6 mmol, 28%).
(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(difluoromethoxy)
quinazolin-6-yl)-4-(cyclopropylamino)but-2-enamide (7r) was
prepared in a manner similar to that described for 6a giving 115 mg
(0.24 mmol, 24%).
4.1.55. (S,E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(isopropylamino)but-
2-enamide (7u)
The title compound was prepared in a manner similar to that
described for 6a giving 1.447 g (2.9 mmol, 30%).
1H NMR (400 MHz, DMSO-d6, dppm): 9.80 (s, 1H), 9.42 (s, 1H),
8.92 (s, 1H), 8.52 (s, 1H), 8.10e8.13 (dd, 1H, 4JF-H ¼ 6.8 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.77e7.81 (m, 1H, arylamine-6-]CH), 7.42 (t,
1H, J ¼ 9.2 Hz, arylamine-5-]CH), 7.23 (s, 1H), 6.85e6.90 (m, 1H,
eCH2eCH]CHe), 6.56 (d, 1H, J ¼ 15.2 Hz, eCH2eCH]CHe), 5.28
(d, 1H, J ¼ 3.2 Hz, tetrahydrofuran-3-CH), 3.98e3.99 (m, 2H,
tetrahydrofuran-2-CH2), 3.89e3.95 (m,1H, tetrahydrofuran-5-CH2),
3.75e3.80 (m, 1H, tetrahydrofuran-5-CH2), 3.39 (d, 2H, J ¼ 4.4 Hz,
eCH2eCH]CHe), 2.76e2.80 (m, 1H, isopropylamino-CH),
2.31e2.34 (m, 1H, tetrahydrofuran-4-CH2), 2.12e2.15 (m, 1H,
tetrahydrofuran-4-CH2), 1.01 (d, 6H, J ¼ 6.0 Hz, 2 ꢂ isopropylamino-
CH3). 13C NMR (150 MHz, DMSO-d6, dppm): 164.3, 157.2, 154.3, 153.6
(d, 1JF-C ¼ 241 Hz), 149.1, 144.5, 137.2, 128.0, 124.5, 123.9, 122.8, 119.1
1H NMR (600 MHz, DMSO-d6, dppm): 10.0 (s, 1H), 9.89 (s, 1H),
8.94 (s, 1H), 8.61 (s, 1H), 8.14e8.16 (dd, 1H, 4JF-H ¼ 6.6 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.80e7.83 (m, 1H, arylamine-6-]CH), 7.56 (s,
1H), 7.43e7.47 (ap. t., 1H, 3JF-H ¼ 9.6 Hz, J ¼ 9.0 Hz, arylamine-5-]
CH), 6.90e6.93 (m, 1H, eCH2eCH]CHe), 6.51 (d, 1H, J ¼ 15.0 Hz,
eCH2eCH]CHe), 3.42 (d, 2H, J ¼ 4.8 Hz, eCH2eCH]CHe),
2.12e2.14 (m, 1H, cyclopropylamino-1-CH), 0.38e0.40 (m, 2H,
cyclopropylamino-2-CH2), 0.26e0.28 (m, 2H, cyclopropylamino-2-
CH2). ESI-MS (m/z): [MþH]þ 478.2. 13C NMR (100 MHz, DMSO-d6,
1
dppm): 164.6, 157.4, 155.0, 153.6 (d, JF-C ¼ 241 Hz), 152.7, 148.5,
145.0, 136.9, 128.1, 124.4, 123.9,123.2, 123.15, 119.3 (d, 2JF-C ¼ 18 Hz),
117.1, 116.7 (d, 2JF-C ¼ 29 Hz), 114.0, 112.2, 50.2, 30.6, 6.6. Anal. Calc'd
for C22H19ClF3N5O2-0.3CH3CH2OOCCH3-0.3H2O: C, 54.67; H, 4.35;
N, 13.74. Found; C, 54.67; H, 4.40; N, 13.72.
2
(d, JF-C ¼ 18 Hz), 116.9, 116.8, 116.5, 109.3, 108.4, 79.2, 72.4, 67.0,
48.3, 47.8, 32.8, 22.9. ESI-MS (m/z): [MþH]þ 500.1. Anal. Calc'd for
C25H27ClFN5O3-0.8H2O: C, 58.37; H, 5.60; N, 13.62. Found; C, 58.35;
H, 5.67; N, 13.61.
4.1.53. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(2,2,2-
trifluoroethoxy)quinazolin-6-yl)-4-(cyclopropylamino)but-2-
enamide (7s)
The title compound was prepared in a manner similar to that
described for 6a giving 1.884 g (3.7 mmol, 22%).
4.1.56. (S,E)-N-(4-(3-Ethynylphenylamino)-7-(tetrahydrofuran-3-
yloxy)quinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide (8a)
The title compound was prepared in a manner similar to that
described for 6a giving 547 mg (1.1 mmol, 42%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.74 (s, 1H), 9.45 (s, 1H),
8.95 (s, 1H), 8.53 (s, 1H), 8.00 (s, 1H), 7.87 (d, 1H, J ¼ 8.4 Hz, aryl-
amine-6-]CH), 7.38 (t, 1H, J ¼ 7.8 Hz, arylamine-5-]CH), 7.24 (s,
1H), 7.20 (d, 1H, J ¼ 7.8 Hz, arylamine-4–]CH), 6.79e6.83 (m, 1H,
eCH2eCH]CHe), 6.57 (d, 1H, J ¼ 15.6 Hz, eCH2eCH]CHe), 5.30
(d, 1H, J ¼ 1.8 Hz, tetrahydrofuran-3-CH), 4.19 (s, 1H, alkyne-H),
3.99e4.01 (m, 2H, tetrahydrofuran-2-CH2), 3.91e3.95 (m, 1H,
tetrahydrofuran-5-CH2), 3.77e3.80 (m, 1H, tetrahydrofuran-5-CH2),
3.12 (broad s, 2H, eCH2eCH]CHe), 2.32e2.38 (m, 5H, one
hydrogen of tetrahydrofuran-4-CH2 and 2 ꢂ piperidin-2-CH2),
2.13e2.16 (m,1H, tetrahydrofuran-4-CH2), 1.53 (broad s, 4H,
2 ꢂ piperidin-3-CH2), 1.40 (broad s, 2H, piperidin-4-CH2). 13C NMR
(100 MHz, DMSO-d6, dppm): 164.0, 157.4, 154.4, 153.7, 149.3, 142.4,
140.3, 129.2, 127.9, 126.8, 125.3, 123.1, 123.0, 122.1, 116.9, 109.5,
108.5, 84.1, 80.9, 79.2, 72.5, 67.1, 59.7, 54.5, 32.9, 26.0, 24.3, 14.5. ESI-
MS (m/z): [MþH]þ 498.4. Anal. Calc'd for C29H31N5O3-
0.2CH3CH2OOCCH3-1.5H2O: C, 66.01; H, 6.62; N, 12.92. Found; C,
66.05; H, 6.70; N, 12.90.
1H NMR (400 MHz, DMSO-d6, dppm): 9.86 (s, 1H), 9.58 (s, 1H),
8.81 (s, 1H), 8.56 (s, 1H), 8.12e8.15 (dd, 1H, 4JF-H ¼ 6.8 Hz, J ¼ 2.8 Hz,
arylamine-2-]CH), 7.78e7.82 (m, 1H, arylamine-6-]CH), 7.48 (s,
1H), 7.42 (t, 1H, J ¼ 9.2 Hz, arylamine-5-]CH), 6.84e6.91 (m, 1H,
eCH2eCH]CHe), 6.45 (d, 1H, J ¼ 15.6 Hz, eCH2eCH]CHe),
5.00e5.07 (m, 2H, CF3CH2O-), 3.38 (d, 2H, J ¼ 4.4 Hz, eCH2eCH]
CHe), 2.08e2.13 (m, 1H, cyclopropylamino-1-CH), 0.35e0.39 (m,
2H, cyclopropylamino-2-CH2), 0.23e0.26 (m, 2H, cyclo-
propylamino-2-CH2). 13C NMR (150 MHz, DMSO-d6, dppm): 164.5,
157.2, 154.7, 154.1, 153.7 (d, 1JF-C ¼ 242 Hz), 149.3, 144.7, 137.1 (d, 3JF-
¼ 2 Hz), 121.3e127.3 (q, CF3CH2O-), 124.1, 122.923, 122.877, 119.2
C
2
(d, JF-C ¼ 17 Hz), 118.8, 117.0, 116.9, 110.2, 109.2, 65.8e65.4 (q,
CF3CH2O-), 50.2, 30.5, 6.5. ESI-MS (m/z): [MþH]þ 510.2. Anal. Calc'd
for C23H20ClF4N5O2-0.1CH3CH2OOCCH3: C, 54.18; H, 4.04; N, 13.50.
Found; C, 54.20; H, 4.14; N, 13.45.
4.1.54. (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-
methoxyquinazolin-6-yl)-4-(3, 3-difluorocyclobutylamino)but-2-
enamide (7t)
4.1.57. (E)-N-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-
yl)-4-(piperidin-1-yl)but-2-enamide (8b)
The title compound was prepared in a manner similar to that
described for 6a giving 2.113 g (4.3 mmol, 20%).
The title compound was prepared in a manner similar to that
described for 6a giving 119 mg (0.27 mmol, 40%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.81 (s, 1H), 9.65 (s, 1H),
8.92 (s, 1H), 8.34 (s, 1H), 8.12e8.14 (dd, 1H, 4JF-H ¼ 7.2 Hz, J ¼ 2.4 Hz,
arylamine-2-]CH), 7.79e7.81 (m, 1H, arylamine-6-]CH), 7.43 (t,
1H, J ¼ 9.0 Hz, arylamine-5-]CH), 7.29 (s, 1H), 6.82e6.87 (m, 1H,
eCH2eCH]CHe), 6.56 (d, 1H, J ¼ 15.0 Hz, eCH2eCH]CHe), 4.04
(s, 3H, CH3Oe), 3.30 (d, 2H, J ¼ 4.2 Hz, eCH2eCH]CHe), 2.73e2.76
(m, 2H, 3,3-difluorocyclobutylamino-2-CH2), 2.33e2.36 (m, 2H,
3,3-difluorocyclobutylamino-2-CH2). 13C NMR (100 MHz, DMSO-d6,
1H NMR (600 MHz, DMSO-d6, dppm): 9.76 (s, 1H), 9.71 (s, 1H),
8.94 (s, 1H), 8.55 (s, 1H), 8.02 (s, 1H), 7.88 (d, 1H, J ¼ 8.4 Hz, aryl-
amine-6-]CH), 7.38 (t, 1H, J ¼ 7.8 Hz, arylamine-5-]CH), 7.29 (s,
1H), 7.20 (d, 1H, J ¼ 7.8 Hz, arylamine-4-]CH), 6.79e6.83 (m, 1H,
eCH2eCH]CHe), 6.59 (d, 1H, J ¼ 15.0 Hz, eCH2eCH]CHe), 4.20
(s,1H, alkyne-H), 4.02 (s, 3H, CH3Oe), 3.14 (broad s, 2H, eCH2eCH]
CHe), 2.40 (broad s, 4H, 2 ꢂ piperidin-2-CH2), 1.54 (broad s, 4H,
2 ꢂ piperidin-3-CH2), 1.40 (broad s, 2H, piperidin-4-CH2). ESI-MS
(m/z): [MþH]þ 442.3. Anal. Calc'd for C26H27N5O2: C, 70.73; H,
6.16; N, 15.86. Found; C, 70.71; H, 6.21; N, 15.85.
1
dppm): 164.3, 157.3, 155.8, 154.3, 153.6 (d, JF-C ¼ 241 Hz), 149.4,
143.9, 137.3 (d, 3JF-C ¼ 3 Hz), 127.8, 124.7124.0, 117.4e123.3 (q, 3,3-
difluorocyclobutylamino-3-CF2), 119.1 (d, 2JF-C ¼ 18 Hz), 117.0, 116.8,
116.2, 109.4, 107.1, 56.7, 48.0, 42.4e42.9 (t, 2C, 3,3-
difluorocyclobutylamino-2-CH2). ESI-MS (m/z): [MþH]þ 492.4.
4.1.58. (E)-N-(7-Ethoxy-4-(3-ethynylphenylamino)quinazolin-6-
yl)-4-(piperidin-1-yl)but-2-enamide (8c)
The title compound was prepared in a manner similar to that
described for 6a giving 291 mg (0.64 mmol, 41%).
Anal. Calc'd for
C23H21ClF3N5O2-0.1CH3CH2OOCCH3-0.5H2O: C,
55.14; H, 4.51; N, 13.74. Found; C, 55.15; H, 4.55; N, 13.72.

L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
461
1H NMR (600 MHz, DMSO-d6, dppm): 9.74 (s, 1H), 9.54 (s, 1H),
4.1.62. (E)-4-(Cyclopropylamino)-N-(4-(3-ethynylphenylamino)-7-
8.93 (s, 1H), 8.53 (s, 1H), 8.00 (s, 1H), 7.88 (d, 1H, J ¼ 8.4 Hz, aryl-
amine-6-]CH), 7.39 (t, 1H, J ¼ 7.8 Hz, arylamine-5-]CH), 7.27 (s,
1H), 7.20 (d, 1H, J ¼ 7.8 Hz, arylamine-4-]CH), 6.79e6.83 (m, 1H,
eCH2eCH]CHe), 6.56 (d, 1H, J ¼ 15.0 Hz, eCH2eCH]CHe),
4.28e4.31 (m, 2H, CH3CH2Oe), 4.20 (s, 1H, alkyne-H), 3.12 (broad s,
2H, eCH2eCH]CHe), 2.37 (broad s, 4H, 2 ꢂ piperidin-2-CH2), 1.54
(broad s, 4H, 2 ꢂ piperidin-3-CH2), 1.46 (t, 3H, J ¼ 6.6 Hz, CH3CH2O-
), 1.40 (broad s, 2H, piperidin-4-CH2). 13C NMR (100 MHz, DMSO-d6,
dppm): 164.0, 157.3, 155.0, 154.4, 149.5, 142.4, 140.3, 129.3, 127.6,
126.8, 126.4, 125.3, 123.1, 122.1, 116.7, 109.4, 107.6, 84.1, 80.9, 64.9,
59.8, 54.5, 26.0, 24.3, 14.5. ESI-MS (m/z): [MþH]þ 456.4.
methoxyquinazolin-6-yl)but-2-enamide (8g)
The title compound was prepared in a manner similar to that
described for 6a giving 1.859 g (4.5 mmol, 20%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.75 (s,1H), 9.62 (s, 1H), 8.94
(s,1H), 8.53 (s,1H), 8.01 (s,1H), 7.87 (d,1H, J ¼ 8.4 Hz, arylamine-6-]
CH), 7.38 (t,1H, J ¼ 7.8 Hz, arylamine-5-]CH), 7.28 (s,1H), 7.20 (d,1H,
J ¼ 7.8 Hz, arylamine-4-]CH), 6.86e6.90 (m, 1H, eCH2eCH]CHe),
6.53 (d,1H, J ¼ 15.0 Hz, eCH2eCH]CHe), 4.19 (s,1H, alkyne-H), 3.98
(s, 3H, CH3Oe), 3.39 (d, 2H, J ¼ 4.2 Hz, eCH2eCH]CHe), 2.53 (s, 1H),
2.12e2.13 (m, 1H, cyclopropylamino-1-CH), 0.38e0.39 (m, 2H,
cyclopropylamino-2-CH2), 0.26 (broad s, 2H, cyclopropylamino-2-
CH2). 13C NMR (100 MHz, DMSO-d6, dppm): 164.4, 157.4, 155.8,
154.4, 149.4, 144.5, 140.3, 129.2, 127.8, 126.8, 125.3, 124.5, 123.2, 122.1,
116.4, 109.5, 107.1, 84.1, 80.8, 56.7, 50.2, 30.5, 6.6. ESI-MS (m/z):
[MþH]þ 414.2. Anal. Calc'd for C24H23N5O2-1.0H2O: C, 66.81; H, 5.84;
N, 16.23. Found; C, 68.82; H, 5.87; N, 16.22.
4.1.59. (E)-4-(Cyclopropyl(methyl)amino)-N-(4-(3-
ethynylphenylamino)-7-methoxyquinazolin-6-yl)but-2-enamide
(8d)
The title compound was prepared in a manner similar to that
described for 6a giving 154 mg (0.36 mmol, 36%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.76 (s, 1H), 9.68 (s, 1H),
8.95 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.88 (d, 1H, J ¼ 8.4 Hz, aryl-
amine-6-]CH), 7.39 (t, 1H, J ¼ 7.8 Hz, arylamine-5-]CH), 7.29 (s,
1H), 7.20 (d, 1H, J ¼ 7.8 Hz, arylamine-4-]CH), 6.81e6.86 (m, 1H,
eCH2eCH]CHe), 6.56 (d, 1H, J ¼ 15.6 Hz, eCH2eCH]CHe), 4.20
(s, 1H, alkyne-H), 4.02 (s, 3H, CH3O-), 3.32 (d, 2H, J ¼ 6.0 Hz,
eCH2eCH]CHe), 2.28 (s, 3H, NeCH3), 1.74e1.76 (m, 1H, cyclo-
propyl-1-CH), 0.45e0.46 (m, 2H, cyclopropyl-2-CH2), 0.35e0.36 (m,
2H, cyclopropyl-2-CH2). ESI-MS (m/z): [MþH]þ 428.3.
4.1.63. (E)-4-(Cyclopropylamino)-N-(7-ethoxy-4-(3-
ethynylphenylamino)quinazolin-6-yl)but-2-enamide (8h)
The title compound was prepared in a manner similar to that
described for 6a giving 2.051 g (0.48 mmol, 24%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.75 (s, 1H), 9.46 (s, 1H),
8.94 (s, 1H), 8.53 (s, 1H), 8.01 (s, 1H), 7.88 (d, 1H, J ¼ 8.4 Hz, aryl-
amine-6-]CH), 7.37e7.40 (ap. t., 1H, J ¼ 8.4 Hz, J ¼ 7.8 Hz, aryl-
amine-5-]CH), 7.26 (s, 1H), 7.20 (d, 1H, J ¼ 7.8 Hz, arylamine-4-]
CH), 6.87e6.92 (m, 1H, eCH2eCH]CHe), 6.54 (d, 1H, J ¼ 15.0 Hz,
eCH2eCH]CHe), 4.28e4.31 (m, 2H, CH3CH2O-), 4.20 (s, 1H,
alkyne-H), 3.42 (d, 2H, J ¼ 4.2 Hz, eCH2eCH]CHe), 2.12e2.15 (m,
1H, cyclopropylamino-1-CH), 1.47 (ap. t., 3H, J ¼ 7.2 Hz, J ¼ 6.6 Hz,
CH3CH2O-), 0.38e0.42 (m, 2H, cyclopropylamino-2-CH2),
0.27e0.28 (m, 2H, cyclopropylamino-2-CH2). 13C NMR (100 MHz,
DMSO-d6, dppm): 164.3, 157.4, 154.9, 154.3, 149.4, 144.3, 140.3, 129.2,
127.8, 126.8, 125.3, 124.6, 123.1, 122.1, 116.4, 109.4, 107.5, 84.1, 80.8,
64.9, 50.2, 30.5, 14.7, 6.5. ESI-MS (m/z): [MþH]þ 428.3. Anal. Calc'd
for C25H25N5O2-0.06CH3CH2OOCCH3-0.5H2O: C, 68.62; H, 6.04; N,
15.85. Found; C, 68.68; H, 6.15; N, 15.79.
4.1.60. (E)-4-(Cyclopropyl(methyl)amino)-N-(7-ethoxy-4-(3-
ethynylphenylamino)quinazolin-6-yl)but-2-enamide (8e)
The title compound was prepared in a manner similar to that
described for 6a giving 1.765 g (4.0 mmol, 40%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.75 (s, 1H), 9.54 (s, 1H),
8.94 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.88 (d, 1H, J ¼ 8.4 Hz, aryl-
amine-6-]CH), 7.39 (t, 1H, J ¼ 7.8 Hz, arylamine-5-]CH), 7.29 (s,
1H), 7.20 (d, 1H, J ¼ 7.8 Hz, arylamine-4-]CH), 6.82e6.86 (m, 1H,
eCH2eCH]CHe), 6.54e6.57 (m, 1H, J ¼ 15.6 Hz, eCH2eCH]CHe),
4.27e4.31 (m, 2H, CH3CH2Oe), 4.20 (s, 1H, alkyne-H), 3.32e3.33 (m,
2H, eCH2eCH]CHe), 2.28 (s, 3H, NeCH3), 1.74e1.75 (m, 1H,
4.1.64. (S,E)-N-(4-(3-Ethynylphenylamino)-7-(tetrahydrofuran-3-
yloxy)quinazolin-6-yl)-4-(isopropylamino)but-2-enamide (8i)
The title compound was prepared in a manner similar to that
described for 6a giving 1.32 g (2.8 mmol, 22%).
cyclopropyl-1-CH), 1.44e1.47 (t, 3H,
J
¼
7.2 Hz, CH3CH2O-),
0.45e0.47 (m, 2H, cyclopropyl-2-CH2), 0.35e0.36 (m, 2H, cyclo-
propyl-2-CH2). ESI-MS (m/z): [MþH]þ 442.3.
1H NMR (400 MHz, DMSO-d6, dppm): 9.74 (s, 1H), 9.41 (s, 1H),
8.93 (s, 1H), 8.51 (s, 1H), 7.99 (s, 1H), 7.85e7.87 (ap. t., 1H, J ¼ 8.4 Hz,
J ¼ 1.2 Hz, arylamine-6-]CH), 7.37 (t,1H, J ¼ 8.0 Hz, arylamine-5-]
CH), 7.22 (s, 1H), 7.18 (d, 1H, J ¼ 7.6 Hz, arylamine-4-]CH),
6.85e6.90 (m, 1H, -eCH2eCH]CHe), 6.55 (d, 1H, J ¼ 15.6 Hz,
eCH2eCH]CHe), 5.28 (d, 1H, J ¼ 3.2 Hz, tetrahydrofuran-3-CH),
4.18 (s, 1H), 3.99-3.40 (m, 2H, tetrahydrofuran-2-CH2), 3.91e3.93
(m, 1H, tetrahydrofuran-5-CH2), 3.76e3.80 (m, 1H, tetrahydro-
furan-5-CH2), 3.36e3.39 (m, 2H, eCH2eCH]CHe), 2.74e2.78 (m,
1H, isopropylamino-CH), 2.30e2.34 (m, 1H, tetrahydrofuran-4-
CH2), 2.13e2.15 (m, 1H, tetrahydrofuran-4-CH2), 1.01 (d, 6H,
J ¼ 6.4 Hz, 2 ꢂ isopropylamino-CH3).13C NMR (100 MHz, DMSO-d6,
dppm): 164.3, 157.1, 154.4, 149.2, 140.2, 129.2, 127.9, 126.8, 125.3,
123.1, 122.1, 109.5, 108.4, 84.0, 80.9, 79.1, 72.5, 67.0, 48.3, 47.8, 32.8,
23.0. ESI-MS (m/z): [MþH]þ 472.3. Anal. Calc'd for C27H29N5O3: C,
68.77; H, 6.20; N, 14.85. Found; C, 68.78; H, 6.25; N, 14.82.
4.1.61. (S,E)-4-(Cyclopropylamino)-N-(4-(3-ethynylphenylamino)-
7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)but-2-enamide (8f)
The title compound was prepared in a manner similar to that
described for 6a giving 1.783 g (3.8 mmol, 19%).
1H NMR (600 MHz, DMSO-d6, dppm): 9.77 (s, 1H), 9.41 (s, 1H),
8.96 (s, 1H), 8.53 (s, 1H), 8.01 (s, 1H), 7.87 (d, 1H, J ¼ 8.4 Hz, aryl-
amine-6-]CH), 7.38 (t, 1H, J ¼ 7.8 Hz, arylamine-5-]CH), 7.23 (s,
1H), 7.20 (d, 1H, J ¼ 7.8 Hz, arylamine-4-]CH), 6.88e6.92 (m, 1H,
-eCH2eCH]CHe), 6.54 (d, 1H, J ¼ 15.6 Hz, eCH2eCH]CHe), 5.29
(d,1H, J ¼ 3.6 Hz, tetrahydrofuran-3-CH), 4.19 (s,1H, alkyne-H), 4.01
(d, 2H, J ¼ 2.4 Hz, tetrahydrofuran-2-CH2), 3.91e3.95 (m, 1H,
tetrahydrofuran-5-CH2), 3.78e3.80 (m,1H, tetrahydrofuran-5-CH2),
3.42 (d, 2H, J ¼ 4.8 Hz, eCH2eCH]CHe), 2.31e2.36 (m, 1H, tetra-
hydrofuran-4-CH2), 2.11e2.17 (m, 2H, tetrahydrofuran-4-CH2 and
cyclopropylamino-1-CH), 0.38e0.41 (m, 2H, cyclopropylamino-2-
CH2), 0.27e0.28 (m, 2H, cyclopropylamino-2-CH2). 13C NMR
(100 MHz, DMSO-d6, dppm): 164.3, 157.4, 154.4, 153.7, 149.2, 144.7,
140.3, 129.2, 128.0, 126.8, 125.4, 124.4, 123.2, 122.1, 116.6, 109.6,
108.4, 84.1, 80.8, 79.2, 72.5, 67.1, 65.4, 50.3, 32.9, 30.6, 6.6. ESI-MS
(m/z): [MþH]þ 470.2. Anal. Calc'd for C27H27N5O3-0.8H2O: C,
68.28; H, 5.86; N, 14.75. Found; C, 68.30; H, 5.87; N, 14.74.
4.2. Biological evaluation
4.2.1. EGFR tyrosine kinase enzyme inhibition assay
EGFR tyrosine kinase activity was determined by an enzyme-
linked-immuno-sorbent assay (ELISA) as described in our previ-
ous report [30].

462
L. Zhang et al. / European Journal of Medicinal Chemistry 102 (2015) 445e463
4.2.2. Cancer cell proliferation inhibition assay
References
NCI-H1975 cells were purchased from the American Type Cul-
ture Collection (ATCC, Manassas/VA), and were cultured in RPMI
medium containing 1 mM sodium pyruvate. The RPMI medium was
supplemented with 1% penicillinestreptomycin and 10% fetal
bovine serum (FBS). Cells were incubated in a humidified atmo-
sphere under 5% CO2 at 37 ꢀC. Cell growth inhibition assays and GI50
determinations were performed as previously described [4].
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for chemotherapy-naive patients with advanced non-small-cell lung cancer
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in circulating lung-cancer cells, N. Engl. J. Med. 359 (2008) 366e377.
[3] L.V. Sequist, R.G. Martins, D. Spigel, et al., First-line gefitinib in patients with
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[4] J.A. Engelman, K. Zejnullahu, C.M. Gale, et al., PF00299804, an irreversible pan-
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tations that are resistant to gefitinib, Cancer Res. 67 (2007) 11924e11932.
[5] E.L. Kwak, R. Sordella, D.W. Bell, et al., Irreversible inhibitors of the EGF re-
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[6] D. Li, L. Ambrogio, T. Shimamura, et al., BIBW2992, an irreversible EGFR/HER2
inhibitor highly effective in preclinical lung cancer models, Oncogene 27
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4.2.3. In vivo efficacy study
Pathogen-free, 6-8 week-old, female BALB/c nude mice (Vital
River Laboratory Animal Technology Co. Ltd) were maintained
under clean-room conditions in sterile filter-top cages with Aspen
Chip bedding. A431, HCC-827 or NCI-H1975 xenograft model was
established by inoculated 2 ꢂ 106 cancer cells subcutaneous in the
right flanks of athymic mice. When the tumor reached a volume of
100e300 mm3, the mice were randomly assigned into control and
treatment groups (n ¼ 6 per group). Control groups were given
vehicle alone, and treatment groups received different drugs.
Health conditions of mice were observed daily. The size of tumor
and body weight was measured on the indicated days during the
treatment.
Tumor
volume
(V)
was
calculated
as
V ¼ (length ꢂ width2)/2. The individual relative tumor volume
(RTV) was calculated as follows: RTV ¼ Vt/V0, where Vt represented
the tumor size measured on the indicated days and V0 represented
the predosing tumor size (in case where tumor regression occurred,
RTV < 1). The body weight change (%) was calculated as follows:
body weight change (%) ¼ (Wt/W0 ꢁ 1) ꢂ 100, where Wt repre-
sented the body weight measured on the indicated days and W0
represented the predosing body weight. Results are presented as
mean for each group. Error bars represent the standard error of the
mean (SEM). Therapeutic effect of each compound was expressed
in terms of Tumor Growth Inhibition (TGI) and the calculation
formula was: TGI ¼ (1 ꢁ T/C) ꢂ 100%, where T was mean RTV of the
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4.3. Pharmacokinetics (PK) analysis
PK studies were conducted in rats, and compound 7q, 7u, 8f, 8i or
afatinib was formulated as a clear solution of 1 mg/ml in 5%DMSO/
30%PEG400/65%H2O, respectively. By use of the same formulation of
each compound, male SpragueeDawley rats were administered
intravenously via the tail vein at a single 1 mg/kg dose (n ¼ 3) or
orally via gavage at a single 5 mg/kg dose (n ¼ 3). Serial blood
samples were collected from each rat over a 24 h period after dosing.
Plasma samples were analyzed for the corresponding compound
concentrations by LC/MS/MS (Column: Angilent Zorbax Rx-C18
150 ꢂ 2.1 mm; Mobil phase: 10 mM ammonium formate-0.1% for-
mic acid water/methanol ¼ 10/90; Ionization: electrospray positive
ion mode; Data acquisition: Analyst®, Version 1.5). Pharmacokinetic
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This work was supported by the Project of Innovative Antineo-
plastic Drug Incubation Base Construction from the Ministry of
Science and Technology of the PR China (2011ZX09401-015).
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