Design and synthesis of novel 4-benzothiazole amino quinazolines Dasatinib derivatives as potential anti-tumor agents

Article abstract of DOI:10.1016/j.ejmech.2013.03.013

Three series of novel 4-benzothiazole amino quinazolines Dasatinib derivatives have been designed and synthesized. The entire target compounds were investigated for their in vitro cytotoxic activity by the MTT-based assay against 6 human cancer cell lines

Full text of DOI:10.1016/j.ejmech.2013.03.013

European Journal of Medicinal Chemistry 63 (2013) 702e712
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design and synthesis of novel 4-benzothiazole amino quinazolines
Dasatinib derivatives as potential anti-tumor agents
,
Jin Cai a, Min Sun a, Xiaoqing Wu b, Junqing Chen a, Peng Wang a, Xi Zong a, Min Ji a
*
a School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao,
Nanjing, Jiangsu 210096, PR China
b Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Three series of novel 4-benzothiazole amino quinazolines Dasatinib derivatives have been designed and
synthesized. The entire target compounds were investigated for their in vitro cytotoxic activity by the
MTT-based assay against 6 human cancer cell lines. Compared with the parental Dasatinib, most of the
new compounds, especially 2, 4, 6-trimethylaniline series (3), demonstrated significant inhibitory ac-
tivities against six cell lines. Furthermore, the target compounds were screened for Src and Abl kinase
inhibitory activity. Among them, 1a, 1f and 3ae3f are more potential dual Src/Abl kinase inhibitors. Thus
they may be promising lead compounds to be developed as an alternative for current Dasatinib therapy
or for Imatinib-resistant patients, potentially via simultaneously blocking multiple RTK signaling
pathways.
Received 5 January 2013
Received in revised form
4 March 2013
Accepted 6 March 2013
Available online 16 March 2013
Keywords:
Dasatinib
Tyrosine kinase
Cytotoxic activity
Cancer cell
quinazolines
CML
Ó 2013 Elsevier Masson SAS. All rights reserved.
1. Introduction
Imatinib resistance [9e11]. To date, at least 50 different point
mutations that encode distinct single amino acid substitutions have
Chronic myeloid leukemia (CML) is a hematopoietic stem cell
cancer that arises following a reciprocal genetic translocation be-
tween chromosomes 9 and 22 [1], resulting in the short Philadel-
phia (Ph) chromosome carrying the Bcr-Abl (Breakpoint cluster
region-Abelson leukemia) oncogene [2e4]. The understanding of
the central role played by Bcr-Abl in the pathogenesis of CML gave
birth to the so-called “targeted therapy” [5]. In 2001, Imatinib
(GleevecÔ, Fig. 1), a potent Bcr-Abl inhibitor, was approved for the
treatment of CML serves as validation of the concept that thera-
peutic agents targeting cancer-specific pathways can offer signifi-
cative improvements over traditional chemotherapeutic agents [6].
Imatinib is now considered as a first-line therapy for the majority of
CML cases due to its high efficacy and relatively mild side effects [7].
However, the initial enthusiasm generated by the high response
rate to this drug has been dampened by the development of
resistance, accounting for 16% in newly diagnosed chronic phase
CML and more than 50% in more advanced stages [8]. Mutations in
the kinase domain of Bcr-Abl are the major mechanism of acquired
been identified in CML patients who are resistant to Imatinib [12].
Despite the fact that the targeted therapy era started as a hunt for
selective kinase inhibitors [13], the aim has recently changed to the
identification of compounds acting on multiple targets in order to
overcome the drug resistance often connected to the activation of
alternative signaling pathways [14,15].
Several studies have provided a rationale for the use of dual Src/
Abl kinase inhibitors to overcome Imatinib resistance [16e18],
overexpression of Src family kinases (SFK) has been implicated in
Bcr-Abl mediated leukemogenesis, particularly the induction of B-
cell acute lymphoblastic leukemia (B-ALL), and also in CML disease
progression [19]. Moreover, inhibition of overexpressed Src was
proven to be very effective in treating a number of tumors such as
colon, breast, pancreas, lung, liver, brain, and bladder cancers [20e
25]. Taken together, since Src shares significant sequence homology
and remarkable structural resemblance with the active form of Abl,
several Src inhibitors showed potent Bcr-Abl inhibitory activity and
were successfully used as second generation antileukemia drugs
[26e28]. An important step forward has been made with the
approval of Dasatinib (SprycelÔ, Fig. 1), a multi-targeted tyrosine
kinase inhibitor, active against 14 of the 15 clinically relevant
Imatinib resistant mutants [29]. Acquired resistance is becoming a
* Corresponding author. Tel.: þ86 25 83272078.
E-mail address: jimin@seu.edu.cn (M. Ji).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.03.013

J. Cai et al. / European Journal of Medicinal Chemistry 63 (2013) 702e712
703
Fig. 1. Chemical structure of Imatinib, Dasatinib, Gefitinib, Erlotinib and Lapatinib.
common issue in targeted therapy of malignant diseases and, as a
consequence, there is a growing interest in developing novel TK
inhibitors able to target Imatinib-resistant form of CML [30,31].
Gefitinib (IressaÔ), Erlotinib (TarcevaÔ) and Lapatinib
(TykerbÔ) (Fig. 1), are three selective EGFR inhibitors approved by
the FDA in 2003, 2004 and 2007 respectively, for locally advanced
or metastatic tumor therapy [32e34]. They possessed the common
pharmacophore: 4-anilino quinazoline moiety. On the basis of our
previous work [35e37], according to structureeactivity relation-
ship (SAR) analysis of the leading compound Dasatinib [38e40], as
well as the basic drug design principals of ring-addition and com-
bination, we have devised and synthesized novel 4-benzothiazole
amino quinazolines derivatives (Fig. 2): (1) replacement of
thiazole ring with benzothiazole; (2) replacement pyrimidine with
quinazoline, methoxy group at position 6 and various secondary
amino-substituted propoxy side chains at position 7 of the quina-
zoline nucleus; and (3) various substituted phenylamines were also
investigated. Our objective was to determine whether these com-
pounds favor greater inhibition of cell proliferation and higher in-
duction of cell death.
2. Chemistry
As summarized in Table 1, up to 18 compounds (1ae1f, 2ae2f
and 3ae3f) were synthesized. The synthetic routes were illustrated
in Schemes 1 and 2.
Synthesis of the key intermediates 10ae10c of the target com-
pounds is shown in Scheme 1. The benzo[d]thiazole ring on com-
pound 5 was assembled via coupling of ethyl 4-aminobenzoate 4
with potassium thiocyanate and copper sulfate in methanol with a
yield of 79%. The amino group of obtained 5 was protected by Boc
Anhydride to give 6, which was hydrolyzed by NaOH in THF
(Tetrahydrofuran) to generate 7 in 91% yield. Compound 7 was
treated with oxalyl chloride and condensed with various
substituted phenylamine to produce 9ae9c. The key intermediates
10ae10c were finally obtained by de-protection of 9ae9c with TFA
(trifluoroacetic acid) in dichloromethane in high yields.
Methyl 4-hydroxy-3-methoxybenzoate 11 as starting material
was alkylated with 1-bromo-3-chloropropane to give 12 in 94%
yield. Nitration of 12 with nitric acid in acetic acid afforded 13,
which was then reduced by powdered iron in acetic acid to give 14
in satisfactory yield (80%). In contrast, catalytic hydrogenation us-
ing Raney/Ni or 5% Pd/C gave incomplete conversions, even after a
long reaction time. Cyclization of 14 with formamidine acetate gave
15 in 95% yield. The next step was nucleophilic displacement of the
chlorine atom with different aliphatic amines to yield the corre-
sponding compounds 16ae16f, which were chloridized with thi-
onyl chloride to give 17ae17f. Aminolysis of 17ae17f was
performed using intermediates 10ae10c to afford the corre-
sponding target compounds 1ae1f, 2ae2f and 3ae3f (Scheme 2).
Fig. 2. A design for Dasatinib derivatives.

704
J. Cai et al. / European Journal of Medicinal Chemistry 63 (2013) 702e712
Table 1
Table 1 (continued)
Structure of compounds 1ae1f, 2ae2f and 3ae3f
Compd R0
R
Mp (ꢀC)
Yields
(%)
3e
3f
2,4,6-tri-Me
2,4,6-tri-Me
151e152 28.6
143e145 31.2
N
O
O
CH3
N
O
.
Compd R0
R
Mp (ꢀC)
Yields
(%)
3. Results and discussion
1a
1b
2-Cl, 6-Me
139e140 28.5
132e134 30.8
N
O
O
O
H3C
3.1. In vitro cytotoxic activity of the target compounds
2-Cl, 6-Me
2-Cl, 6-Me
2-Cl, 6-Me
2-Cl, 6-Me
N
O
All the 18 newly synthesized Dasatinib derivatives (1ae1f, 2ae
2f and 3ae3f) were investigated for their in vitro cytotoxic activity
by the MTT-based assay using Dasatinib as a positive control
against six human cancer cell lines, representing different tumor
types, namely human colon cancer cell lines (HCT-116 and DLD1),
human chronic myeloid leukemia cell line (K562), human acute
monocytic myeloid leukemia cell line (U937) and human lung
cancer cell lines (A549 and NCI-H661). These compounds were
assayed for their anti-proliferative activity indicated by IC50 values,
which were calculated by linear regression analysis of the con-
centrationeresponse curves obtained for each compound.
Table 2 outlines the SAR observed with the different quinazoline
moieties modification at the C2 amine of the benzothiazole nu-
cleus. Almost all the 2, 4, 6-trimethylaniline series (3) compounds
demonstrated potent anti-proliferation effects with IC50 values less
than Dasatinib in 6 cell lines except for 3b and 3e, it is worth
pointing out that the most significant inhibition was achieved for
compound 3f. Compared with series (3), the 2-chloro-6-
methylaniline series (1) compounds displayed lower inhibition
activity in 6 cell lines. While in the 2, 6-dimethylaniline series (2),
most of the compounds demonstrated evident anti-proliferation
effects of leukemia cell lines (K562 and U937), but very poor anti-
proliferation effects of solid tumor cell lines (HCT-116, DLD1,
A549 and NCI-H661).
It is noticeable that compounds 1f and 3f with 2-
methylpiperidine substitution displayed the most strongly cyto-
toxic activity in their respective series, while the piperidine
substituted 1b and 3b showed lower cytotoxic activity. According to
the previous studies of molecular docking and preferred confor-
mation analysis [35,41], we speculated that conformational re-
striction of methyl group in piperidine would help to form
appropriate angle by amino quinazolines ring and benzothiazole
ring, this was more conducive for aniline ring to reside in the active
binding site, meanwhile the nitrogen of 2-methylpiperidine form
hydrogen bond to the hinge region, all of which would help to
improve the anti-proliferation activity. In addition, the morpholine
substituted compounds 1e and 2e almost showed poorest cytotoxic
activity in their respective series, which may be induced by the
electro negativity of the oxygen atoms by our conjecture. Besides
these factors, the structure difference among these compounds in
each series was the basic side chain at position 7 of quinazoline
nucleus, which was reported to affect the pharmacokinetic prop-
erties and solubility of compound in vivo [42,43]. The introduction
of the basic side chains was to increase the volume of distribution at
steady state (Vdss), and thus increased the observed half-life and a
long terminal half-life was desirable in terms of increasing drug
exposure and ultimately efficacy. Moreover, previous SAR studies of
the binding of in the reversible amino quinazolines EGFR inhibitors
1c
1d
1e
128e129 29.7
143e144 28.2
148e149 32.3
N
O
N
O
N
O
O
CH3
1f
2-Cl, 6-Me
144e145 27.7
N
O
2a
2b
2,6-di-Me
2,6-di-Me
137e138 29.5
136e137 31.0
N
H3C
N
O
2c
2d
2e
2,6-di-Me
2,6-di-Me
2,6-di-Me
133e134 32.5
154e155 30.0
147e148 28.4
N
O
N
O
N
O
O
CH3
2f
2,6-di-Me
144e145 32.7
N
O
3a
3b
3c
2,4,6-tri-Me
2,4,6-tri-Me
2,4,6-tri-Me
127e128 26.4
134e135 31.1
131e132 32.6
N
H3C
N
O
N
O
3d
2,4,6-tri-Me
147e148 30.2
N
O

J. Cai et al. / European Journal of Medicinal Chemistry 63 (2013) 702e712
705
Scheme 1. Synthetic route for the preparation of the compounds 10ae10c. Reagents and conditions: (a) KSCN, CuSO4.5H2O, CH3OH, reflux, 6 h, 79%; (b) (Boc)2O, DMAP, THF, rt, 16 h,
86%; (c) NaOH, THF, rt, 12 h, 91%; (d) (COCl)2, cat. DMF, THF, 10 ꢀC, 6 h; (e) substituted phenylamine, Et3N, THF, rt, 2 h, 83e87%; (f) TFA, CH2Cl2, rt, 2 h, 95e97%.
suggested a binding mode whereby 7-position side chains reside in
a large, mostly lipophilic ATP binding pocket toward the solvent
[44], so there was tolerance for substitution at the 7-position with
cationic side chains. As cytotoxicity assay was carried out in vitro,
the inhibitory effect variance among these compounds could be
attributed to the hydrophobicity and permeability changes result-
ing from different basic side chains.
Coincidentally, the benzothiazole derivatives in this article dis-
played the equivalent antiproliferative activity against K562 and
U937 cell lines compared with our previous report about benzo-
thiophene amino quinazolines derivatives [36]. And the SAR of the
basic side chains were similar, 2-methylpiperidine compounds
demonstrated the most strongly cytotoxic activity, while the mor-
pholine compounds showed poor cytotoxic activity.
synthesized compounds, all compounds were preliminarily tested
in a cell-free assay to evaluate their affinity toward Src and Abl
enzymes using Dasatinib as a reference compound. As also shown
in Table 2, almost all the 2,4,6-trimethylaniline series (3) and the 2-
chloro-6-methylaniline series (1) derivatives, with the exception of
1e, have significant dual Src/Abl kinase inhibitory activity. In
addition, the test result of enzyme is consistent with former anti-
proliferative assay. Those compounds such as 1a, 1f and 3ae3f
with stronger cytotoxicity also show better dual Src/Abl kinase
inhibitory potency. Taken the biological data together, we could
preliminarily arrive at the conclusion that part of the target com-
pounds are potential dual Src/Abl kinase inhibitors. Thus they may
be promising lead compounds to be developed as an alternative for
current Dasatinib therapy or for Imatinib-resistant patients,
potentially via simultaneously blocking multiple RTK signaling
pathways. However, we also noticed that all compounds have
decreasing inhibitory potency in both kinases compared to Dasa-
tinib. Therefore, we are currently carrying out more experiments to
access inhibitory activity on other RTKs, hoping to confirm the
exact target(s) and details on the mechanism of action.
3.2. Kinase inhibitory activity
As Gefitinib with quinazoline nucleus is a selective EGFR in-
hibitor, so we firstly determined the EGFR inhibitory activity of
these analogues using an EGFR Kinase Assay Kit. As also shown in
Table 2, the inhibitory potency of the new compounds is much
lower than that of Gefitinib and Erlotinib, which indicates that
these compounds are no longer specific EGFR tyrosine kinase
inhibitors.
Dasatinib, initially designed and synthesized for Src inhibition,
was subsequently found to possess potent Abl inhibitory activity as
well. In order to study the mechanism of action of the new
4. Conclusion
In our study, using Dasatinib as a leading compound, three se-
ries of 18 novel 4-benzothiazole amino quinazolines derivatives
have been designed and synthesized. The entire target compounds
were investigated for their in vitro cytotoxic activity by the MTT-
Scheme 2. Synthetic route for the preparation of the target compounds 1ae1f, 2ae2f and 3ae3f. Reagents and conditions: (a) K2CO3, ClCH2CH2CH2Br, DMF, 2 h, 70 ꢀC, 94%; (b)
HNO3, AcOH, Ac2O, 2 h, 55 ꢀC, 94%; (c) Fe, AcOH, CH3COOC2H5, N2, 6 h, 50 ꢀC, 80%; (d) formamidine acetate, EtOH, 6 h, reflux, 95%; (e) HNR1, KI, DMF, 6 h, 70 ꢀC, 94e97%; (f) SOCl2,
cat. DMF, 1 h, reflux, 77e87%; (g) 10ae10c, NaH, THF, 12 h, rt, 26e51%.

706
J. Cai et al. / European Journal of Medicinal Chemistry 63 (2013) 702e712
Table 2
In vitro cytotoxic activity in different cell lines and enzyme inhibition activity of target compounds 1ae1f, 2ae2f and 3ae3f.
,d
Compd
Cytotoxicity in different cell lines (IC50 mmol/L)a,b
Enzyme inhibition (%)a,c
HCT-116
DLD1
K562
U937
A549
NCI-H661
EGFR
SRC
ABL
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
9.1
11.3
14.7
11.7
60.7
>100
6.7
>100
>100
>100
>100
>100
>100
7.0
24.5
6.8
5.9
5.8
5.7
4.6
NT
NT
8.3
12.5
9.6
9.2
8.6
7.3
9.7
7.9
23.7
28.7
46.8
15.6
10.4
53.6
13.3
17.3
10.5
21.2
9.9
25.4
36.3
37.9
25.4
48.7
45.1
65.8
NT
67.4
83.3
68.2
55.7
34.3
78.9
56.5
43.4
53.6
39.9
28.7
49.0
78.6
69.7
65.3
91.8
80.6
89.2
98.1
NT
56.2
49.9
67.1
78.7
43.7
71.1
54.2
39.0
50.0
34.3
41.7
49.2
68.2
81.6
76.3
82.3
76.5
79.8
96.7
NT
23.4
13.2
63.8
>100
7.2
>100
>100
>100
>100
>100
>100
6.9
16.9
7.5
5.8
5.6
5.6
12.8
10.6
38.6
75.2
6.7
89.7
>100
>100
83.8
>100
75.7
5.4
10.3
5.7
8.9
16.3
5.8
8.2
13.8
11.2
45.5
>100
5.3
72.3
>100
66.5
>100
>100
84.4
7.7
10.0
7.3
9.6
18.4
8.8
7.8
13.3
16.4
6.8
15.8
13.7
28.4
15.7
>100
12.3
5.9
9.3
6.8
4.3
20.0
3.5
19.9
22.6
7.0
11.2
14.7
23.7
18.9
19.2
10.8
5.6
12.2
4.3
4.6
24.2
3.6
12.2
NT
3e
3f
Dasatinib
Gefitinib
Erlotinib
5.3
NT
NT
11.9
NT
NT
NT
NT
NT
NT
98.5
95.7
NT
NT
NT
NT, no test.
a
Values are averages of three independent experiments, SD < 10%.
IC50 is the concentration of compound required to inhibit the cell growth by 50% compared to an untreated control.
Values are averages of two independent experiments, SD < 10%.
Compounds tested at a concentration of 10 mM.
b
c
d
based assay against 6 human cancer cell lines (HCT-116, DLD1,
K562, U937, A549 and NCI-H661). Compared with the parental
Dasatinib, most of the new compounds, especially 2,4,6-
trimethylaniline series (3), demonstrated significant inhibitory ac-
tivities against six cell lines. Furthermore, the target compounds
were screened for Src and Abl kinase inhibitory activity. Among
them, 1a, 1f and 3ae3f are more potential dual Src/Abl kinase in-
hibitors. Thus they may be promising lead compounds to be
developed as an alternative for current Dasatinib therapy or for
Imatinib-resistant patients, potentially via simultaneously blocking
multiple RTK signaling pathways.
room temperature. The precipitate was filtered, washed with water
and dried to get 5 (52.6 g, 79%) as white powder, mp: 242e243 ꢀC
([45], mp, 241e242 ꢀC).
5.1.2. Ethyl 2-(tert-butoxycarbonyl)benzo[d]thiazole-6-carboxylate
(6)
To THF (500 mL) were added compound 5 (22.2 g, 0.1 mol) and
DMAP (1.22 g, 0.01 mol), when all had dissolved, diteutyl dicar-
bonate (26.2 g, 0.12 mol) in THF (150 mL) was added slowly by
dripping at 0 ꢀC. The mixture was stirred at room temperature for
16 h, about 3/4 of the solvent was evaporated under reduced
pressure, the precipitate obtained was filtered, washed with THF
and dried to yield 6 (27.6 g, 86%) as white powder, mp > 300 ꢀC
5. Experimental protocols
[46]. 1H NMR (DMSO-d6, 300 MHz)
OCH2CH3), 1.52 (s, 9H, 3 ꢁ CH3), 4.33 (q, J ¼ 7.1 Hz, 2H, CH2O), 7.74
(d, J ¼ 8.4 Hz, 1H, AreH), 7.97 (d, J ¼ 8.5 Hz, 1H, AreH), 8.58 (s, 1H,
AreH), 12.01 (br, 1H, eNHeBoc).
d
(ppm): 1.34 (t, J ¼ 7.1 Hz, 3H,
5.1. Synthesis
All reagents were purchased from commercial sources and used
without further purification. Melting points were measured on an
RY-1 hot-stage microscope, and the thermometer was uncorrected.
1H NMR and 13C NMR spectra were recorded in CDCl3 on a Bruker-
5.1.3. 2-(tert-Butoxycarbonyl)benzo[d]thiazole-6-carboxylic
acid (7)
ACF 300/500 spectrometer; chemical shifts (
d
) are reported in parts
Compound 6 (25.8 g, 0.08 mol) was added to THF (200 mL) and
2 N NaOH solution (500 mL). The mixture was stirred at room
temperature for 12 h. After THF was evaporated under reduced
pressure, the water layer was cooled to 0 ꢀC, the pH adjusted to 1
with 10% HCl. The precipitate obtained was filtered, washed with
water and dried to yield 7 (21.5 g, 91%) as white solid, mp > 300 ꢀC
[46].
per million (ppm) relative to tetramethylsilane (TMS), used as an
internal standard. Mass spectra (MS) were obtained from Agilent
1100LC/MS Spectrometry Services. IR spectra were run on FI-IR
Spectrometer (PerkineElmer). Elementary analyses were per-
formed on Elementar Vario EL III instrument. All compounds were
routinely checked by TLC with silica gel GF-254 glass plates and
viewed under UV light at 254 nm.
5.1.4. General process for the synthesis of the compounds 9ae9c
Compound 7 (9.6 g, 32 mmol) and DMF (2 mL) were dissolved in
THF (200 mL), to this solution was added slowly oxalyl chloride
(3.2 mL, 38.4 mmol) in THF (50 mL) by dripping at 0 ꢀC. The mixture
was stirred for 6 h at 10 ꢀC. After cooling to 0 ꢀC, to the react so-
lution were added different substituted phenylamine (38.4 mmol)
and triethylamine (7.12 mL, 64 mmol), and the mixture was stirred
for 2 h at room temperature. The precipitate obtained was filtered
and the filtrate was evaporated under reduced pressure to get crude
5.1.1. Ethyl 2-aminobenzo[d]thiazole-6-carboxylate (5)
To methanol (800 mL) were added ethyl 4-aminobenzoate 4
(49.5 g, 0.3 mol), KSCN (291 g, 3 mol) and CuSO4$5H2O (275 g,
1.5 mol). The mixture was heated to reflux by mechanical stir for
6 h. After cooling to room temperature, the precipitate was filtered,
about 2/3 of the filtrate was evaporated under reduced pressure.
Water (600 mL) was added, the precipitate obtained was filtered
and added to 2 N NaOH solution (500 mL), stirred for 10 min at

J. Cai et al. / European Journal of Medicinal Chemistry 63 (2013) 702e712
707
product, which was added to water (200 mL) and stirred for 30 min
at room temperature, the precipitate was filtered, washed with
water and dried to yield the compounds 9ae9c.
5.1.7. Methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate (13)
HNO3 (90 mL, 65e68%) was added dropwise at 0e5 ꢀC to a so-
lution of 12 (120 g, 0.47 mol) in a mixture of CH3COOH (400 mL)
and Ac2O (100 mL). This mixture was stirred at room temperature
for 0.5 h and heated at 55 ꢀC for 2 h, then slowly poured into ice
water (4 L) and extracted with ethyl acetate (4 ꢁ 300 mL). The
combined organic layer was washed with saturated sodium bicar-
bonate (3 ꢁ 200 mL) and brine (2 ꢁ 100 mL) and dried with Na2SO4.
The ethyl acetate was evaporated under reduced pressure to yield a
yellow oil that solidified after standing in a refrigerator for 12 h and
was then recrystallized from ethyl acetate/petroleum ether to
afford the product 13 (133.5 g, 94%) as light yellow crystals, mp:
66e68 ꢀC ([47], mp: 63e64 ꢀC).
Compounds 9ae9c were characterized as follows.
5.1.4.1. tert-Butyl 6-((2-chloro-6-methylphenyl)carbamoyl)benzo[d]
thiazol- 2-yl carbamate (9a). White solid, yield: 84%, mp: 254e
256 ꢀC [46]. 1H NMR (DMSO-d6, 500 MHz)
d (ppm): 1.53 (s, 9H,
3 ꢁ CH3), 2.23 (s, 3H, AreCH3), 7.24e7.30 (m, 2H, AreH), 7.40 (d,
J ¼ 7.7 Hz, 1H, AreH), 7.78 (d, J ¼ 8.5 Hz, 1H, AreH), 8.05 (d,
J ¼ 8.4 Hz, 1H, AreH), 8.58 (s, 1H, AreH), 10.02 (s, 1H, eNHeCOe),
11.95 (br, 1H, eNHeBoc).
5.1.4.2. tert-Butyl 6-((2,6-dimethylphenyl)carbamoyl)benzo[d]thia-
zol-2-ylcarbamate (9b). White solid, yield: 83%, mp: 193e194 ꢀC
5.1.8. Methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate
(14)
[46]. 1H NMR (DMSO-d6, 300 MHz)
d
(ppm): 1.53 (s, 9H, 3 ꢁ CH3),
2.20 (s, 6H, 2 ꢁ AreCH3), 7.13 (s, 3H, AreH), 7.77 (d, J ¼ 8.5 Hz, 1H,
AreH), 8.04 (d, J ¼ 8.5 Hz, 1H, AreH), 8.58 (s, 1H, AreH), 9.78 (s, 1H,
eNHeCOe), 11.96 (br, 1H, eNHeBoc).
Powdered iron (50 g, 0.89 mol) was added to CH3COOH
(500 mL). The resulting suspension was stirred for 15 min at 50 ꢀC
under an atmosphere of N2, and a solution of 13 (90.0 g, 0.30 mol) in
ethyl acetate (300 mL) was added dropwise. The mixture was
stirred for another 6 h at 75 ꢀC. The catalyst was filtered, and the
filtrate was slowly poured into water (4 L) and extracted with ethyl
acetate (4 ꢁ 300 mL). The organic phase was washed with a satu-
rated solution of sodium carbonate (2 ꢁ 200 mL) and brine
(2 ꢁ 100 mL) and then dried with Na2SO4. The solvent was removed
under vacuum and the brown solid residue was recrystallized from
ethyl acetate/petroleum ether to give the product 14 (65.3 g, 80%)
as almost white solid, mp: 97e98 ꢀC ([47], mp: 98e99 ꢀC).
5.1.4.3. tert-Butyl 6-(mesitylcarbamoyl)benzo[d]thiazol-2-
ylcarbamate (9c). White solid, yield: 87%, mp > 300 ꢀC [46]. 1H
NMR (DMSO-d6, 300 MHz)
d
(ppm): 1.53 (s, 9H, 3 ꢁ CH3), 2.12 (s,
6H, 2 ꢁ AreCH3), 2.25 (s, 3H, AreCH3), 7.13 (s, 2H, AreH), 7.77 (d,
J ¼ 8.5 Hz, 1H, AreH), 8.04 (d, J ¼ 8.5 Hz, 1H, AreH), 8.58 (s, 1H, Are
H), 9.66 (s, 1H, eNHeCOe), 11.96 (br, 1H, eNH-Boc).
5.1.5. General process for the synthesis of the compounds 10ae10c
Compounds 9ae9c (23.9 mmol) was dissolved in TFA (30 mL)
and CH2Cl2 (30 mL). The mixture was stirred at room temperature
for 2 h, and the solvent was evaporated under reduced pressure.
Then the pH adjusted to 14 with 1 N NaOH at 0 ꢀC, the precipitate
obtained was filtered, washed with water and dried to yield 10ae
10c as white solid.
5.1.9. 7-(3-Chloropropoxy)-6-methoxyquinazolin-4(3H)-one (15)
A solution of 14 (52 g, 0.19 mol) and formamidine acetate (52 g,
0.40 mol) in ethanol (400 mL) was heated at reflux for 6 h. The
mixture was allowed to stand in the refrigerator overnight. The
precipitate was then collected by filtration, washed with cold
ethanol and dried to give 15 (48.5 g, 95%) as a white powder, mp:
218e219 ꢀC ([47], mp: 259 ꢀC).
Compounds 10ae10c were characterized as follows.
5.1.5.1. 2-Amino-N-(2-chloro-6-methylphenyl)benzo[d]thiazole-6-
carboxamide (10a). White powder, yield: 96%, mp: 211e212 ꢀC
5.1.10. General process for the synthesis of the compounds 16ae16f
Compound 15 (8 g, 29.8 mmol) and KI (0.5 g, 3 mmol) were
added to the solution of HNR1 (200 mmol) in DMF (150 mL). The
solution was stirred at 70 ꢀC for 6 h. The solvent was then removed
under reduced pressure and the residue washed with water, and
then dried to afford 16ae16f.
[38]. 1H NMR (DMSO-d6, 500 MHz)
d (ppm): 2.23 (s, 3H, AreCH3),
7.22e7.30 (m, 2H, AreH), 7.39 (d, J ¼ 7.2 Hz, 1H, AreH), 7.47 (d,
J ¼ 8.4 Hz, 1H, AreH), 7.78 (s, 2H, NH2), 7.96 (d, J ¼ 8.4 Hz, 1H, Are
H), 8.37 (s, 1H, AreH), 9.92 (s, 1H, eNHeCOe).
5.1.5.2. 2-Amino-N-(2,6-dimethylphenyl)benzo[d]thiazole-6-
Compounds 16ae16f were characterized as follows.
carboxamide (10b). White solid, yield: 95%, mp: 240e241 ꢀC [46].
1H NMR (DMSO-d6, 300 MHz)
d
(ppm): 2.19 (s, 6H, 2 ꢁ AreCH3),
5.1.10.1. 6-Methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinazo-
lin-4(3H)-one (16a). White powder, yield: 94%, mp: 195e196 ꢀC
[47].
7.11 (s, 3H, AreH), 7.41 (d, J ¼ 8.4 Hz, 1H, AreH), 7.78 (s, 2H, NH2),
7.90 (d, J ¼ 8.4 Hz, 1H, AreH), 8.31 (s, 1H, AreH), 9.62 (s, 1H, eNHe
COe).
5.1.10.2. 6-Methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4(3H)-
one (16b). White solid, yield: 95%, mp: 217e218 ꢀC ([48], mp: 218e
219 ꢀC).
5.1.5.3. 2-Amino-N-mesitylbenzo[d]thiazole-6-carboxamide
White solid, yield: 97%, mp: 270e271 ꢀC [46]. 1H NMR (DMSO-d6,
300 MHz)
6.91 (s, 2H, AreH), 7.40 (d, J ¼ 8.4 Hz, 1H, AreH), 7.77 (s, 2H, NH2),
7.88 (d, J ¼ 8.4 Hz, 1H, AreH), 8.29 (s, 1H, AreH), 9.53 (s, 1H, eNHe
COe).
(10c).
d
(ppm): 2.13 (s, 6H, 2 ꢁ AreCH3), 2.25 (s, 3H, AreCH3),
5.1.10.3. 7-(3-(Diethylamino)propoxy)-6-methoxyquinazolin-4(3H)-
one (16c). White solid, yield: 97%, mp: 203e204 ꢀC [49].
5.1.10.4. 6-Methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-
5.1.6. Methyl 4-(3-chloropropoxy)-3-methoxybenzoate (12)
4(3H)-one (16d). White solid, yield: 96%, mp: 181e182 ꢀC [50].
A mixture of methyl 4-hydroxy-3-methoxybenzoate (91 g,
0.5 mol), 1-bromo-3-chloropropane (94.5 g, 0.6 mol), and K2CO3
(103.5 g, 0.75 mol) in DMF (300 mL) was heated at 70 ꢀC for 2 h. The
mixture was cooled to room temperature, then poured slowly into
ice water (4 L) while stirring constantly. The precipitate obtained
was filtered, washed with cold water and dried to yield 12 (121 g,
94%) as white powder, mp: 99e100 ꢀC ([47], mp: 98e99 ꢀC).
5.1.10.5. 6-Methoxy-7-(3-morpholinopropoxy)quinazolin-4(3H)-one
(16e). White solid, yield: 97%, mp: 214e215 ꢀC [51]. 1H NMR
(DMSO-d6, 300 MHz) d (ppm): 1.88e1.97 (m, 2H, eCH2eCH2eCH2e
), 2.35e2.51 (m, 6H, 3 ꢁ CH2N), 3.57 (t, J ¼ 4.6 Hz, 4H,
2 ꢁ morpholine-CH2), 3.87 (s, 3H, OCH3), 4.15 (t, J ¼ 6.4 Hz, 2H,
CH2O), 7.12 (s, 1H, AreH), 7.44 (s, 1H, AreH), 7.97 (s, 1H, AreH).

708
J. Cai et al. / European Journal of Medicinal Chemistry 63 (2013) 702e712
5.1.10.6. 6-Methoxy-7-(3-(2-methylpiperidin-1-yl)propoxy)quinazo-
at room temperature, then compound 17ae17f (2 mmol) was
added and stirred for another 12 h at room temperature. CH3COOH
(1 mL) was added to quench the reaction, the solvent was evapo-
rated under reduced pressure and the residue was dissolved in
dichloromethane (100 mL), washed with a saturated solution of
sodium bicarbonate (3 ꢁ 50 mL) and brine (2 ꢁ 50 mL), and dried
with Na2SO4. The solvent was removed under vacuum. The crude
product was purified by column chromatography on silica gel,
eluting with ethyl acetate: triethylamine: methanol (40:2:1) to
afford the final product.
lin-4(3H)-one (16f). White solid, yield: 95%, mp: 201e202 ꢀC [47].
5.1.11. General process for the synthesis of the compounds 17ae17f
Compounds 16ae16f (18.1 mmol) was added to thionyl chloride
(120 mL) with magnetic stirring. DMF (10 mL) was then slowlyadded
dropwise and the mixture was heated to reflux for 1 h. Most of the
excess of thionyl chloride was then removed under reduced pressure
and the residue was dissolved in dichloromethane (200 mL), washed
with a saturated solution of sodium carbonate (3 ꢁ 100 mL) and
water (2 ꢁ 100 mL), and dried with Na2SO4. The dichloromethane
was then removed under reduced pressure to give a powder, which
was recrystalized from ethyl acetate to give the product 17ae17f.
Compounds 17ae17f were characterized as follows.
Compounds 1ae1f, 2ae2f and 3ae3f were characterized as
follows.
5.1.12.1. N-(2-chloro-6-methylphenyl)-2-(6-methoxy-7-(3-(4-
methylpiperidin-1-yl) propoxy)quinazolin-4-ylamino)benzo[d]thia-
zole-6-carboxamide (1a). Light yellow solid, yield: 29%. Mp: 139e
140 ꢀC. IR (KBr, cmꢂ1): 3288.68, 2942.71, 2804.97, 1636.77, 1617.92,
1594.81, 1560.41, 1499.38, 1478.26, 1457.11, 1424.37, 1370.01,
1282.77, 1233.13, 841.28, 757.99; 1H NMR (DMSO-d6, 300 MHz)
5.1.11.1. 4-Chloro-6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)
quinazoline (17a). White solid, yield: 84%, mp: 105e106 ꢀC [52]. 1H
NMR (CDCl3, 300 MHz)
d
(ppm): 0.92 (d, J ¼ 6.2 Hz, 3H, piperidine-
CH3), 1.17e1.38 (m, 3H, piperidine-CH2 and piperidine-CH), 1.60e
1.65 (m, 2H, piperidine-CH2), 1.90e1.98 (m, 2H, eCH2eCH2eCH2e),
2.10e2.14 (m, 2H, CH2N), 2.51e2.55 (m, 2H, CH2N), 2.87e2.91 (m,
2H, CH2N), 4.04 (s, 3H, OCH3), 4.26 (t, J ¼ 6.7 Hz, 2H, CH2O), 7.34 (s,
1H, AreH), 7.37 (s, 1H, AreH), 8.85 (s, 1H, AreH).
d
(ppm): 0.89 (d, J ¼ 6.4 Hz, 3H, piperidine-CH3), 1.12e1.20 (m, 2H,
piperidine-CH2), 1.28e1.35 (m, 1H, piperidine-CH), 1.57 (d,
J ¼ 11.3 Hz, 2H, piperidine-CH2), 1.85e1.93 (m, 2H, eCH2eCH2e
CH2e), 1.95e1.99 (m, 2H, CH2N), 2.22 (s, 3H, AreCH3), 2.42e2.46
(m, 2H, CH2N), 2.84 (d, J ¼ 11.3 Hz, 2H, CH2N), 3.83 (s, 3H, OCH3),
4.29 (t, J ¼ 6.3 Hz, 2H, CH2O), 6.67 (d, J ¼ 8.5 Hz, 1H, AreH), 7.10 (s,
1H, AreH), 7.22e7.30 (m, 2H, AreH), 7.38e7.41 (m, 1H, AreH), 7.53
(s, 1H, AreH), 7.78 (dd, J1 ¼1.5 Hz, J2 ¼ 8.5 Hz, 1H, AreH), 8.18 (s, 1H,
AreH), 8.92 (s, 1H, eNHe), 9.20 (s, 1H, AreH), 9.93 (s, 1H, eNHe
5.1.11.2. 4-Chloro-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazo-
line (17b). Light yellow solid, yield: 82%, mp: 198e199 ꢀC [48]. 1H
NMR (CDCl3, 300 MHz) d (ppm): 1.43e1.46 (m, 2H, piperidine-CH2),
1.54e1.60 (m, 4H, 2 ꢁ piperidine-CH2), 2.06e2.15 (m, 2H, eCH2e
CH2eCH2e), 2.29e2.53 (m, 6H, 3 ꢁ CH2N), 4.04 (s, 3H, OCH3), 4.26
(t, J ¼ 6.6 Hz, 2H, CH2O), 7.34 (s, 1H, AreH), 7.36 (s, 1H, AreH), 8.84
(s, 1H, AreH).
COe); 13C NMR (DMSO-d6, 75 MHz)
d (ppm): 18.19, 21.78, 25.99,
30.35, 33.97, 53.44, 54.49, 56.03, 67.54, 101.95, 107.15, 110.33, 117.48,
121.67, 123.89, 126.16, 126.92, 128.04, 128.94, 132.28, 134.02, 138.60,
142.25, 150.76, 151.04, 153.58, 154.47, 156.13, 157.72, 164.20; ESI-
MS m/z: 631.2 [M þ H]þ, 629.2 [M ꢂ H]ꢂ, 665.2 [M þ Cl]ꢂ; Anal.
calcd for C33H35ClN6O3S (%): C, 62.79; H, 5.59; N, 13.31. Found: C,
62.42; H, 5.72; N, 13.17.
5.1.11.3. 3-(4-Chloro-6-methoxyquinazolin-7-yloxy)-N,
ylpropan-1-amine (17c). Light yellow solid, yield: 77%, mp: 86e
87 ꢀC [49]. 1H NMR (CDCl3, 300 MHz)
(ppm): 1.01e1.06 (m, 6H,
N-dieth-
d
2 ꢁ CH3CH2N), 2.03e2.13 (m, 2H, eCH2eCH2eCH2e), 2.53e2.69
(m, 6H, 3 ꢁ CH2N), 4.04 (s, 3H, OCH3), 4.26 (t, J ¼ 6.5 Hz, 2H, CH2O),
7.33 (s, 1H, AreH), 7.36 (s, 1H, AreH), 8.84 (s, 1H, AreH).
5.1.12.2. N-(2-chloro-6-methylphenyl)-2-(6-methoxy-7-(3-(piper-
idin-1-yl)propoxy) quinazolin-4-ylamino)benzo[d]thiazole-6-
carboxamide (1b). Light yellow solid, yield: 31%. Mp: 132e134 ꢀC.
IR (KBr, cmꢂ1): 3417.42, 2934.63,1658.72,1650.78,1619.88,1594.73,
1574.09, 1500.05, 1479.67, 1453.87, 1424.69, 1370.65, 1328.52,
1283.05, 1233.68, 1206.57, 1143.67, 847.34, 770.42; 1H NMR (DMSO-
5.1.11.4. 4-Chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quina-
zoline (17d). Light yellow solid, yield: 85%, mp: 194e195 ꢀC [53]. 1H
NMR (CDCl3, 300 MHz)
d
(ppm): 2.04 (m, 4H, 2 ꢁ pyrolidine-CH2),
2.40e2.45 (m, 2H, eCH2eCH2eCH2e), 3.02e3.13 (m, 6H,
3 ꢁ CH2N), 4.03 (s, 3H, OCH3), 4.29 (t, J ¼ 6.2 Hz, 2H, CH2O), 7.30 (s,
1H, AreH), 7.36 (s, 1H, AreH), 8.85 (s, 1H, AreH).
d6, 300 MHz) d (ppm): 1.38e1.39 (m, 2H, piperidine-CH2),1.49e1.51
(m, 4H, 2 ꢁ piperidine-CH2), 1.92e2.01 (m, 2H, eCH2eCH2eCH2e),
2.22 (s, 3H, AreCH3), 2.34e2.51 (m, 6H, 3 ꢁ CH2N), 3.83 (s, 3H,
OCH3), 4.29 (t, J ¼ 6.3 Hz, 2H, CH2O), 6.67 (d, J ¼ 8.5 Hz, 1H, AreH),
7.10 (s, 1H, AreH), 7.25e7.33 (m, 2H, AreH), 7.38e7.41 (m, 1H, Are
H), 7.53 (s, 1H, AreH), 7.78 (dd, J1 ¼ 1.5 Hz, J2 ¼ 8.5 Hz, 1H, AreH),
8.18 (s,1H, AreH), 8.92 (s,1H, eNHe), 9.20 (s,1H, AreH), 9.94 (s,1H,
5.1.11.5. 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline
(17e). White solid, yield: 80%, mp: 178e179 ꢀC [54]. 1H NMR
(CDCl3, 300 MHz)
2.49e2.60 (m, 6H,
2 ꢁ morpholine-CH2), 4.04 (s, 3H, OCH3), 4.28 (t, J ¼ 6.5 Hz, 2H,
CH2O), 7.34 (s, 1H, AreH), 7.37 (s, 1H, AreH), 8.85 (s, 1H, AreH).
d
(ppm): 2.10e2.15 (m, 2H, eCH2eCH2eCH2e),
CH2N), 3.72 (t, 4.5 Hz, 4H,
3
ꢁ
J
¼
eNHeCOe); 13C NMR (DMSO-d6, 75 MHz)
d (ppm): 18.19, 24.09,
25.57, 25.88, 54.07, 54.88, 56.04, 67.55, 101.95, 107.16, 110.34, 117.49,
121.67, 123.90, 126.17, 126.93, 128.05, 128.94, 132.29, 134.02, 138.60,
142.26, 150.77, 151.05, 153.59, 154.48, 156.13, 157.73, 164.20; ESI-MS
5.1.11.6. 4-Chloro-6-methoxy-7-(3-(2-methylpiperidin-1-yl)propoxy)
quinazoline (17f). White solid, yield: 87%, mp: 106e107 ꢀC [49]. 1H
m/z: 617.2 [M
32H33ClN6O3S$3/4H2O (%): C, 60.94; H, 5.51; N, 13.33. Found: C,
60.91; H, 5.76; N, 13.36.
þ
H]þ, 615.2 [M
ꢂ
H]ꢂ; Anal. calcd for
NMR (CDCl3, 500 MHz)
d
(ppm): 1.06 (d, J ¼ 6.2 Hz, 3H, piperidine-
C
CH3), 1.27e1.31 (m, 2H, piperidine-CH2), 1.54e1.67 (m, 4H,
2 ꢁ piperidine-CH2), 2.06e2.11 (m, 2H, eCH2eCH2eCH2e), 2.10 (t,
J¼ 10.1 Hz, 1H, CHHN), 2.30e2.31(m,1H, CHN), 2.52(quint, J¼ 10.0 Hz,
1H, CHHN), 2.87e2.93 (m, 2H, CH2N), 4.05 (s, 3H, OCH3), 4.21e4.29 (m,
2H, CH2O), 7.34 (s, 1H, AreH), 7.38 (s, 1H, AreH), 8.85 (s, 1H, AreH).
5.1.12.3. N-(2-chloro-6-methylphenyl)-2-(7-(3-(diethylamino)pro-
poxy)-6-methoxyquinazolin-4-ylamino)benzo[d]thiazole-6-
carboxamide (1c). Light yellow solid, yield: 30%. Mp: 128e129 ꢀC.
IR (KBr, cmꢂ1): 3269.43, 2967.71, 1618.11, 1594.88, 1574.69, 1499.96,
1479.49, 1453.66, 1424.80, 1370.51, 1329.01, 1283.20, 1233.71,
1205.48, 1183.17, 1140.93, 1093.86, 847.05; 1H NMR (DMSO-d6,
5.1.12. General process for the synthesis of the compounds 1ae1f,
2ae2f and 3ae3f
A solution of compounds 10a, 10b or 10c (2 mmol) and NaH
(10 mmol) in anhydrous tetrahydrofuran (50 mL) was stirred for 3 h
300 MHz)
d
(ppm): 0.91e0.98 (m, 6H, 2 ꢁ CH3CH2N), 1.88e1.97 (m,
2H, eCH2eCH2eCH2e), 2.22 (s, 3H, AreCH3), 2.43e2.58 (m, 6H,

J. Cai et al. / European Journal of Medicinal Chemistry 63 (2013) 702e712
709
3 ꢁ CH2N), 3.83 (s, 3H, OCH3), 4.30 (t, J ¼ 6.3 Hz, 2H, CH2O), 6.68 (d,
J ¼ 8.5 Hz, 1H, AreH), 7.10 (s, 1H, AreH), 7.22e7.30 (m, 2H, AreH),
7.38e7.41 (m, 1H, AreH), 7.52 (s, 1H, AreH), 7.78 (dd, J1 ¼ 1.4 Hz,
J2 ¼ 8.5 Hz, 1H, AreH), 8.18 (s, 1H, AreH), 8.92 (s, 1H, eNHe), 9.20
(s, 1H, AreH), 9.94 (s, 1H, eNHeCOe); 13C NMR (DMSO-d6, 75 MHz)
6.67 (d, J ¼ 8.4 Hz, 1H, AreH), 7.10 (s, 1H, AreH), 7.23e7.29 (m, 2H,
AreH), 7.38e7.40 (m, 1H, AreH), 7.53 (s, 1H, AreH), 7.78 (dd,
J1 ¼ 1.5 Hz, J2 ¼ 8.4 Hz, 1H, AreH), 8.18 (s, 1H, AreH), 8.91 (s, 1H, e
NHe), 9.20 (s, 1H, AreH), 9.92 (s, 1H, eNHeCOe); 13C NMR (DMSO-
d6, 125 MHz) d (ppm): 18.14, 18.43, 23.37, 25.18, 25.74, 34.15, 49.42,
d
(ppm): 11.79, 18.19, 26.18, 46.43, 48.38, 56.05, 67.35, 101.93,
51.45, 55.23, 56.03, 67.48, 101.95, 107.12, 110.30, 117.45, 121.62,
123.85, 126.13, 126.87, 127.97, 128.89, 132.26, 134.00, 138.57, 142.22,
150.75, 151.07, 153.54, 154.46, 156.15, 157.69, 164.17; ESI-MS m/z:
631.2 [M þ H]þ, 629.2 [M ꢂ H]ꢂ, 665.2 [M þ Cl]ꢂ; Anal. calcd for
107.08, 110.35, 117.48, 121.66, 123.89, 126.16, 126.93, 128.03, 128.93,
132.28, 134.02, 138.60, 142.26, 150.77, 151.07, 153.58, 154.47, 156.17,
157.73, 164.20; ESI-MS m/z: 605.2 [M þ H]þ, 603.2 [M ꢂ H]ꢂ; Anal.
calcd for C31H33ClN6O3S$3/4H2O (%): C, 60.18; H, 5.62; N, 13.58.
Found: C, 60.30; H, 5.81; N, 13.68.
C
33H35ClN6O3S$3/4H2O (%): C, 61.48; H, 5.71; N, 13.04; Found: C,
61.74; H, 6.12; N, 13.15.
5.1.12.4. N-(2-chloro-6-methylphenyl)-2-(6-methoxy-7-(3-(pyrroli-
din-1-yl)propoxy) quinazolin-4-ylamino)benzo[d]thiazole-6-
carboxamide (1d). Light yellow solid, yield: 28%. Mp: 143e144 ꢀC.
IR (KBr, cmꢂ1): 3257.32, 2958.96, 2798.93,1617.77,1594.60,1576.03,
1499.39, 1479.62, 1453.80, 1424.39, 1370.45, 1329.11, 1283.17,
1233.15, 1205.60, 1139.65, 1098.04, 847.12, 756.87; 1H NMR (DMSO-
5.1.12.7. N-(2, 6-dimethylphenyl)-2-(6-methoxy-7-(3-(4-
methylpiperidin-1-yl)propoxy) quinazolin-4-ylamino)benzo[d]thia-
zole-6-carboxamide (2a). Light yellow solid, yield: 30%. Mp: 137e
138 ꢀC. IR (KBr, cmꢂ1): 3272.95, 2949.47, 1618.12, 1594.76, 1576.87,
1499.36, 1480.24, 1454.43, 1424.26, 1370.03, 1281.76, 1232.57,
1204.66, 1137.90, 767.21; 1H NMR (DMSO-d6, 300 MHz)
d (ppm):
d6, 300 MHz)
d
(ppm): 1.68e1.71 (m, 4H, 2 ꢁ pyrolidine-CH2), 1.95e
0.89 (d, J ¼ 6.4 Hz, 3H, piperidine-CH3), 1.12-1.19 (m, 2H, piperidine-
CH2), 1.31 (br, 1H, piperidine-CH), 1.57 (d, J ¼ 11.1 Hz, 2H, piperi-
dine-CH2), 1.85e1.92 (m, 2H, eCH2eCH2eCH2e), 1.95-1.99 (m, 2H,
CH2N), 2.17 (s, 6H, 2 ꢁ Ar-CH3), 2.42e2.46 (m, 2H, CH2N), 2.84 (d,
J ¼ 11.1 Hz, 2H, CH2N), 3.83 (s, 3H, OCH3), 4.29 (t, J ¼ 6.2 Hz, 2H,
CH2O), 6.66 (d, J ¼ 8.4 Hz, 1H, AreH), 7.10 (s, 1H, AreH), 7.11 (s, 3H,
AreH), 7.53 (s, 1H, AreH), 7.77 (dd, J1 ¼ 1.5 Hz, J2 ¼ 8.5 Hz, 1H, Are
H), 8.18 (s, 1H, AreH), 8.90 (s, 1H, eNHe), 9.20 (s, 1H, AreH), 9.68 (s,
2.04 (m, 2H, eCH2eCH2eCH2e), 2.22 (s, 3H, AreCH3), 2.46e2.51
(m, 4H, 2 ꢁ CH2N), 2.58 (t, J ¼ 7.0 Hz, 2H, CH2N), 3.83 (s, 3H, OCH3),
4.31 (t, J ¼ 6.4 Hz, 2H, CH2O), 6.67 (d, J ¼ 8.4 Hz, 1H, AreH), 7.11 (s,
1H, AreH), 7.22e7.31 (m, 2H, AreH), 7.38-7.41 (m, 1H, AreH), 7.54
(s, 1H, AreH), 7.79 (dd, J1 ¼1.4 Hz, J2 ¼ 8.5 Hz,1H, AreH), 8.18 (s, 1H,
AreH), 8.92 (s, 1H, eNHe), 9.20 (s, 1H, AreH), 9.94 (s, 1H, eNHe
COe); 13C NMR (DMSO-d6, 75 MHz)
d (ppm): 18.19, 23.10, 27.76,
52.00, 53.57, 56.04, 67.46, 101.94, 107.16, 110.33, 117.49, 121.67,
123.90,126.16,126.92,128.03,128.93,132.28,134.02,138.60,142.25,
150.76, 151.03, 153.59, 154.47, 156.12, 157.72, 164.20; ESI-MS m/z:
603.2 [M þ H]þ, 625.2 [M þ Na]þ, 601.2 [M ꢂ H]ꢂ, 637.1 [M þ Cl]ꢂ;
Anal. calcd for C31H31ClN6O3S$3/4H2O (%): C, 60.38; H, 5.31; N,
13.63. Found: C, 60.37; H, 5.57; N, 13.57.
1H, eNHeCOe); 13C NMR (DMSO-d6, 75 MHz)
d (ppm): 18.02,
21.82, 26.00, 30.37, 33.98, 53.47, 54.52, 56.05, 67.56, 101.97, 107.16,
110.35, 117.51, 121.59, 123.84, 126.04, 126.60, 127.68, 128.61, 135.32,
135.58, 142.07, 150.77, 151.04, 153.62, 154.53, 156.13, 157.77, 164.07;
ESI-MS m/z: 611.3 [M þ H]þ, 633.2 [M þ Na]þ, 609.3 [M ꢂ H]ꢂ, 645.2
[M þ Cl]ꢂ; Anal. calcd for C34H38N6O3S$H2O (%): C, 64.94; H, 6.41; N,
13.37. Found: C, 65.16; H, 6.80; N, 13.48.
5.1.12.5. N-(2-chloro-6-methylphenyl)-2-(6-methoxy-7-(3-
morpholinopropoxy) quinazolin-4-ylamino)benzo[d]thiazole-6-
carboxamide (1e). Light yellow solid, yield: 32%. Mp: 148e149 ꢀC.
IR (KBr, cmꢂ1): 3263.35, 2955.87, 2811.74, 1618.19, 1594.46, 1499.41,
1478.99, 1452.43, 1424.49, 1370.19, 1282.90, 1233.23, 1205.42,
5.1.12.8. N-(2,6-dimethylphenyl)-2-(6-methoxy-7-(3-(piperidin-1-yl)
propoxy) quinazolin-4-ylamino)benzo[d]thiazole-6-carboxamide
(2b). Light yellow solid, yield: 31%. Mp: 136e137 ꢀC. IR (KBr,
cmꢂ1): 3269.00, 2933.08, 2852.40, 1618.11, 1594.76, 1575.38,
1499.47, 1480.51, 1454.04, 1424.50, 1370.33, 1327.63, 1282.30,
1232.86, 1205.51, 1141.17, 845.20, 768.33; 1H NMR (DMSO-d6,
1114.88, 848.40, 758.72; 1H NMR (DMSO-d6, 500 MHz)
d (ppm):
1.97e2.02 (m, 2H, eCH2eCH2eCH2e), 2.22 (s, 3H, AreCH3), 2.35e
2.50 (m, 6H, 3 ꢁ CH2N), 3.59 (t, J ¼ 4.5 Hz, 4H, 2 ꢁ morpholine-CH2),
3.83 (s, 3H, OCH3), 4.31 (t, J ¼ 6.2 Hz, 2H, CH2O), 6.68 (d, J ¼ 8.5 Hz,
1H, AreH), 7.11 (s, 1H, AreH), 7.23e7.28 (m, 2H, AreH), 7.38e7.40
(m, 1H, AreH), 7.55 (s, 1H, AreH), 7.78 (dd, J1 ¼ 1.5 Hz, J2 ¼ 8.5 Hz,
1H, AreH), 8.18 (s, 1H, AreH), 8.92 (s, 1H, eNHe), 9.20 (s, 1H, Are
300 MHz)
d (ppm): 1.38e1.40 (m, 2H, piperidine-CH2), 1.50e1.53
(m, 4H, 2 ꢁ piperidine-CH2), 1.96e2.02 (m, 2H, eCH2eCH2eCH2e),
2.17 (s, 6H, 2 ꢁ AreCH3), 2.37e2.47 (m, 6H, 3 ꢁ CH2N), 3.83 (s, 3H,
OCH3), 4.30 (t, J ¼ 6.3 Hz, 2H, CH2O), 6.66 (d, J ¼ 8.5 Hz, 1H, AreH),
7.10 (s, 1H, AreH), 7.11 (s, 3H, AreH), 7.54 (s, 1H, AreH), 7.77 (dd,
J1 ¼ 1.4 Hz, J2 ¼ 8.5 Hz, 1H, AreH), 8.18 (s, 1H, AreH), 8.90 (s, 1H, e
NHe), 9.20 (s, 1H, AreH), 9.68 (s, 1H, eNHeCOe); 13C NMR (DMSO-
H), 9.93 (s, 1H, eNHeCOe); 13C NMR (DMSO-d6, 125 MHz)
d (ppm):
18.14, 25.44, 53.29, 54.57, 56.01, 66.16, 67.39, 101.96, 107.17, 110.30,
117.47, 121.62, 123.85, 126.14, 126.87, 127.98, 128.89, 132.26, 133.99,
138.57, 142.22, 150.73, 151.03, 153.54, 154.46, 156.09, 157.70, 164.18;
ESI-MS m/z: 619.2 [M þ H]þ, 641.2 [M þ Na]þ, 657.2 [M þ K]þ, 617.2
[M ꢂ H]ꢂ, 653.1 [M þ Cl]ꢂ; Anal. calcd for C31H31ClN6O4S$1/2H2O
(%): C, 59.28; H, 5.13; N, 13.38. Found: C, 59.15; H, 5.45; N, 13.35.
d6, 75 MHz) d (ppm): 18.00, 24.01, 25.49, 25.80, 54.03, 54.85, 56.04,
67.53, 101.98, 107.17, 110.32, 117.50, 121.57, 123.81, 126.03, 126.58,
127.66, 128.62, 135.31, 135.57, 142.05, 150.76, 151.04, 153.60, 154.53,
156.12, 157.76, 164.06; ESI-MS m/z: 597.3 [M
þ
H]þ, 619.2
[M þ Na]þ, 595.2 [M ꢂ H]ꢂ, 631.2 [M þ Cl]ꢂ; Anal. calcd for
C33H36N6O3S$3/4H2O (%): C, 64.95; H, 6.19; N, 13.77. Found: C,
5.1.12.6. N-(2-chloro-6-methylphenyl)-2-(6-methoxy-7-(3-(2-
methylpiperidin-1-yl) propoxy)quinazolin-4-ylamino)benzo[d]thia-
zole-6-carboxamide (1f). Light yellow solid, yield: 28%. Mp: 144e
145 ꢀC. IR (KBr, cmꢂ1): 3270.17, 2927.35, 1618.32, 1594.55, 1574.34,
1499.26, 1480.21, 1453.73, 1423.70, 1369.69, 1281.52, 1232.19,
64.79; H, 6.64; N, 13.69.
5.1.12.9. 2-(7-(3-(Diethylamino)propoxy)-6-methoxyquinazolin-4-
ylamino)-N- (2,6-dimethylphenyl)benzo[d]thiazole-6-carboxamide
(2c). Light yellow solid, yield: 33%. Mp: 133e134 ꢀC. IR (KBr,
cmꢂ1): 3268.35, 2966.93, 2818.15, 1618.05, 1594.74, 1575.36,
1499.34, 1480.31, 1424.46, 1370.36, 1328.56, 1282.40, 1232.89,
1204.61, 1140.33, 1093.66, 1036.29, 883.02, 846.70, 767.83, 714.24,
1204.55, 845.20, 755.52; 1H NMR (DMSO-d6, 500 MHz)
d (ppm):
0.99 (d, J ¼ 5.7 Hz, 3H, piperidine-CH3), 1.18e1.23 (m, 2H, piperi-
dine-CH2), 1.42e1.46 (m, 1H, piperidine-CHH), 1.52e1.57 (m, 3H,
piperidine-CHH and piperidine-CH2), 1.92e1.94 (m, 2H, eCH2e
CH2eCH2e), 2.10 (t, J ¼ 9.7 Hz, 1H, CHHN), 2.22 (s, 3H, AreCH3),
2.26e2.27 (m, 1H, CHN), 2.38 (quint, J ¼ 9.7 Hz, 1H, CHHN), 2.80e
2.85 (m, 2H, CH2N), 3.83 (s, 3H, OCH3), 4.29 (t, J ¼ 6.3 Hz, 2H, CH2O),
648.69; 1H NMR (DMSO-d6, 300 MHz)
d (ppm): 0.92e0.98 (m, 6H,
2 ꢁ CH3CH2N), 1.88-1.99 (m, 2H, eCH2eCH2eCH2e), 2.17 (s, 6H,
2 ꢁ AreCH3), 2.44-2.59 (m, 6H, 3 ꢁ CH2N), 3.83 (s, 3H, OCH3), 4.30
(t, J ¼ 6.3 Hz, 2H, CH2O), 6.66 (d, J ¼ 8.5 Hz, 1H, AreH), 7.10 (s, 1H,

710
J. Cai et al. / European Journal of Medicinal Chemistry 63 (2013) 702e712
AreH), 7.11 (s, 3H, AreH), 7.52 (s, 1H, AreH), 7.78 (dd, J1 ¼ 1.7 Hz,
J2 ¼ 8.5 Hz,1H, AreH), 8.17 (s,1H, AreH), 8.90 (s, 1H, eNHe), 9.19 (s,
1H, AreH), 9.68 (s, 1H, eNHeCOe); 13C NMR (DMSO-d6, 75 MHz)
51.44, 55.22, 56.02, 67.47, 101.96, 107.11, 110.27, 117.44, 121.49,
123.75, 125.97, 126.51, 127.59, 128.60, 135.27, 135.52, 142.00, 150.74,
151.05, 153.52, 154.48, 156.13, 157.70, 164.01; ESI-MS m/z: 611.3
[M þ H]þ, 609.3 [M ꢂ H]ꢂ, 645.2 [M þ Cl]ꢂ; Anal. calcd for
d
(ppm): 11.78, 17.99, 26.16, 46.43, 48.38, 56.05, 67.35, 101.96,
107.09, 110.33, 117.49, 121.55, 123.81, 126.02, 126.57, 127.65, 128.60,
135.30, 135.56, 142.05, 150.76, 151.06, 153.58, 154.51, 156.16, 157.75,
164.06; ESI-MS m/z: 585.2 [M þ H]þ, 583.3 [M ꢂ H]ꢂ, 619.2
[M þ Cl]ꢂ; Anal. calcd for C32H36N6O3S$3/4H2O (%): C, 64.25; H,
6.32; N, 14.05. Found: C, 64.40; H, 6.46; N, 13.97.
C34H38N6O3S$3/4H2O (%): C, 65.41; H, 6.38; N, 13.46. Found: C,
65.41; H, 6.42; N, 13.64.
5.1.12.13. N-mesityl-2-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)pr-
opoxy) quinazolin-4-ylamino)benzo[d]thiazole-6-carboxamide (3a).
Light yellow solid, yield: 26%. Mp: 127e128 ꢀC. IR (KBr, cmꢂ1):
3266.65, 2946.86, 2919.54, 1617.76, 1595.37, 1575.74, 1499.56,
1454.19, 1424.25, 1369.46, 1281.93, 1233.01, 1205.71, 1184.13,
5.1.12.10. N-(2,6-dimethylphenyl)-2-(6-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy) quinazolin-4-ylamino)benzo[d]thiazole-6-carboxamide
(2d). Light yellow solid, yield: 30%. Mp: 154e155 ꢀC. IR (KBr,
cmꢂ1): 3260.14, 2955.87, 2795.73, 1617.77, 1594.60, 1576.03,
1499.39, 1479.62, 1453.80, 1424.39, 1370.45, 1283.17, 1233.15,
1205.60, 845.20, 752.31, 569.75; 1H NMR (DMSO-d6, 300 MHz)
848.40, 749.11; 1H NMR (DMSO-d6, 500 MHz)
d (ppm): 0.88 (d,
J ¼ 6.4 Hz, 3H, piperidine-CH3), 1.13e1.18 (m, 2H, piperidine-CH2),
1.31 (br,1H, piperidine-CH),1.57 (d, J ¼ 11.1 Hz, 2H, piperidine-CH2),
1.86e1.90 (m, 2H, eCH2eCH2eCH2e), 1.96e2.00 (m, 2H, CH2N),
2.12 (s, 6H, 2 ꢁ AreCH3), 2.25 (s, 3H, AreCH3), 2.41e2.45 (m, 2H,
CH2N), 2.84 (d, J ¼ 11.1 Hz, 2H, CH2N), 3.82 (s, 3H, OCH3), 4.29 (t,
J ¼ 6.3 Hz, 2H, CH2O), 6.65 (d, J ¼ 8.5 Hz, 1H, AreH), 6.92 (s, 2H, Are
H), 7.10 (s, 1H, AreH), 7.53 (s, 1H, AreH), 7.76 (dd, J1 ¼ 1.5 Hz,
J2 ¼ 8.5 Hz,1H, AreH), 8.16 (s,1H, AreH), 8.89 (s,1H, eNHe), 9.19 (s,
1H, AreH), 9.58 (s, 1H, eNHeCOe); 13C NMR (DMSO-d6, 125 MHz)
d
(ppm): 1.69e1.72 (m, 4H, 2 ꢁ pyrolidine-CH2), 1.96e2.05 (m, 2H,
eCH2eCH2eCH2e), 2.17 (s, 6H, 2 ꢁ AreCH3), 2.50e2.60 (m, 6H,
3 ꢁ CH2N), 3.83 (s, 3H, OCH3), 4.32 (t, J ¼ 6.3 Hz, 2H, CH2O), 6.66 (d,
J ¼ 8.4 Hz, 1H, AreH), 7.11 (s, 4H, AreH), 7.54 (s, 1H, AreH), 7.77 (dd,
J1 ¼ 1.5 Hz, J2 ¼ 8.5 Hz, 1H, AreH), 8.18 (s, 1H, AreH), 8.90 (s, 1H, e
NHe), 9.20 (s, 1H, AreH), 9.68 (s, 1H, eNHeCOe); 13C NMR (DMSO-
d6, 75 MHz)
d
(ppm): 14.04, 17.99, 23.08, 27.67, 51.99, 53.57, 56.04,
d (ppm): 17.85, 20.42, 21.72, 26.09, 30.31, 33.96, 53.39, 54.45, 55.99,
67.53, 101.96, 107.17, 110.32, 117.50, 121.56, 123.81, 126.02, 126.58,
127.65, 128.61, 135.30, 135.56, 142.05, 150.75, 151.02, 153.60, 154.52,
156.10, 157.75, 164.05; ESI-MS m/z: 583.2 [M þ H]þ, 581.2 [M ꢂ H]ꢂ,
617.2 [M þ Cl]ꢂ; Anal. calcd for C32H34N6O3S$H2O (%): C, 63.98; H,
6.04; N, 13.99. Found: C, 64.04; H, 6.12; N, 13.80.
67.52, 101.96, 107.13, 110.24, 117.44, 121.46, 123.71, 125.95, 128.19,
128.69, 132.62, 135.17, 135.45, 141.94, 150.72, 151.02, 153.52, 154.49,
156.10, 157.69, 164.07; ESI-MS m/z: 625.3 [M
þ
H]þ, 647.2
[M þ Na]þ, 623.3 [M ꢂ H]ꢂ, 659.2 [M þ Cl]ꢂ; Anal. calcd for
C35H40N6O3S$3/4H2O (%): C, 65.86; H, 6.55; N, 13.17; Found: C,
65.89; H, 6.81; N, 12.96.
5.1.12.11. N-(2,6-dimethylphenyl)-2-(6-methoxy-7-(3-morpholinopr-
opoxy) quinazolin-4-ylamino)benzo[d]thiazole-6-carboxamide (2e).
Light yellow solid, yield: 28%. Mp: 147e148 ꢀC. IR (KBr, cmꢂ1):
3265.44, 2954.46, 2850.18, 2805.34, 1617.79, 1594.60, 1575.45,
1499.20, 1480.51, 1456.06, 1424.15, 1370.30, 1327.95, 1282.15,
1232.74, 1205.06, 1184.52, 1139.97, 1115.22, 841.99, 745.91; 1H NMR
5.1.12.14. N-mesityl-2-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)qui-
nazolin-4- ylamino)benzo[d]thiazole-6-carboxamide (3b). Light yel-
low solid, yield: 31%. Mp: 134e135 ꢀC. IR (KBr, cmꢂ1): 3261.18,
2932.59, 2852.74, 1616.29, 1566.24, 1499.02, 1453.76, 1423.86,
1369.78, 1311.46, 1266.71, 1232.84, 1205.44, 1139.45, 1094.76,
1035.89, 943.55, 882.79, 847.38, 786.30, 759.16, 710.18, 648.45,
(DMSO-d6, 500 MHz) d (ppm): 1.97e2.02 (m, 2H, eCH2eCH2eCH2e
), 2.17 (s, 6H, 2 ꢁ AreCH3), 2.39e2.51 (m, 6H, 3 ꢁ CH2N), 3.59 (t,
J ¼ 4.6 Hz, 4H, 2 ꢁ morpholine-CH2), 3.83 (s, 3H, OCH3), 4.31 (t,
J ¼ 6.3 Hz, 2H, CH2O), 6.66 (d, J ¼ 8.4 Hz, 1H, AreH), 7.11 (s, 4H, Are
H), 7.54 (s, 1H, AreH), 7.78 (dd, J1 ¼ 1.5 Hz, J2 ¼ 8.5 Hz, 1H, AreH),
8.18 (s,1H, AreH), 8.90 (s,1H, eNHe), 9.20 (s,1H, AreH), 9.67 (s,1H,
563.52; 1H NMR (DMSO-d6, 500 MHz)
d (ppm): 1.38e1.40 (m, 2H,
piperidine-CH2), 1.49e1.53 (m, 4H, 2 ꢁ piperidine-CH2), 1.93e2.00
(m, 2H, eCH2eCH2eCH2e), 2.12 (s, 6H, 2 ꢁ AreCH3), 2.25 (s, 3H, Are
CH3), 2.35e2.49 (m, 6H, 3 ꢁ CH2N), 3.83 (s, 3H, OCH3), 4.29 (t,
J ¼ 6.3 Hz, 2H, CH2O), 6.65 (d, J ¼ 8.4 Hz, 1H, AreH), 6.91 (s, 2H, Are
H), 7.10 (s, 1H, AreH), 7.53 (s, 1H, AreH), 7.76 (dd, J1 ¼ 1.4 Hz,
J2 ¼ 8.5 Hz, 1H, AreH), 8.17 (s, 1H, AreH), 8.89 (s, 1H, eNHe), 9.19 (s,
1H, AreH), 9.58 (s, 1H, eNHeCOe); 13C NMR (DMSO-d6, 75 MHz)
eNHeCOe); 13C NMR (DMSO-d6, 125 MHz)
d (ppm): 17.93, 25.43,
53.29, 54.56, 56.00, 66.15, 67.38,101.97,107.16,110.27,117.46,121.50,
123.76, 125.97, 126.51, 127.60, 128.60, 135.27, 135.52, 142.00, 150.72,
151.01, 153.54, 154.50, 156.08, 157.70, 164.01; ESI-MS m/z: 599.2
[M þ H]þ, 597.2 [M ꢂ H]ꢂ, 633.2 [M þ Cl]ꢂ; Anal. calcd for
d
(ppm): 17.91, 20.48, 24.07, 25.55, 25.86, 54.06, 54.87, 56.03, 67.55,
101.96, 107.16, 110.30, 117.49, 121.54, 123.77, 126.00, 128.26, 128.70,
132.66, 135.21, 135.51, 141.99, 150.78, 151.04, 153.59, 154.52, 156.12,
157.75, 164.11; ESI-MS m/z: 611.3 [M þ H]þ, 609.2 [M ꢂ H]ꢂ, 645.2
[M þ Cl]ꢂ; Anal. calcd for C34H38N6O3S$H2O (%): C, 64.94; H, 6.41; N,
13.37; found: C, 65.06; H, 6.53; N, 13.24.
C
32H34N6O4S$3/4H2O (%): C, 62.78; H, 5.84; N, 13.73. Found: C,
62.89; H, 5.85; N, 13.70.
5.1.12.12. N-(2,6-dimethylphenyl)-2-(6-methoxy-7-(3-(2-methylpip-
eridin-1-yl) propoxy)quinazolin-4-ylamino)benzo[d]thiazole-6-
carboxamide (2f). Light yellow solid, yield: 33%. Mp: 144e145 ꢀC.
IR (KBr, cmꢂ1): 3270.17, 2927.35, 1618.32, 1594.55, 1574.34, 1499.26,
1480.21, 1453.73, 1423.70, 1369.69, 1281.52, 1232.19, 1204.55,
5.1.12.15. 2-(7-(3-(Diethylamino)propoxy)-6-methoxyquinazolin-4-
ylamino)-N-mesitylbenzo[d]thiazole-6-carboxamide (3c). Light yel-
low solid, yield: 33%. Mp: 131e132 ꢀC. IR (KBr, cmꢂ1): 3263.35,
2965.89, 1616.77, 1595.15, 1575.24, 1499.13, 1454.13, 1423.49,
1369.35, 1327.75, 1311.47, 1282.31, 1232.41, 1203.79, 1138.17, 847.56,
838.79, 758.72; 1H NMR (DMSO-d6, 500 MHz)
d (ppm): 0.99 (d,
J ¼ 6.0 Hz, 3H, piperidine-CH3), 1.18e1.26 (m, 2H, piperidine-CH2),
1.42e1.45 (m, 1H, piperidine-CHH), 1.52e1.59 (m, 3H, piperidine-
CHH and piperidine-CH2), 1.92e1.96 (m, 2H, eCH2eCH2eCH2e),
2.10 (t, J ¼ 9.7 Hz, 1H, CHHN), 2.17 (s, 6H, 2 ꢁ AreCH3), 2.27e2.28
(m, 1H, CHN), 2.37 (quint, J ¼ 9.7 Hz, 1H, CHHN), 2.80e2.85 (m, 2H,
CH2N), 3.82 (s, 3H, OCH3), 4.29 (t, J ¼ 6.2 Hz, 2H, CH2O), 6.66 (d,
J ¼ 8.4 Hz, 1H, AreH), 7.10 (s, 4H, AreH), 7.53 (s, 1H, AreH), 7.77 (dd,
J1 ¼ 1.6 Hz, J2 ¼ 8.5 Hz, 1H, AreH), 8.17 (s, 1H, AreH), 8.90 (s, 1H, e
NHe), 9.19 (s, 1H, AreH), 9.67 (s, 1H, eNHeCOe); 13C NMR (DMSO-
758.72; 1H NMR (DMSO-d6, 300 MHz)
d (ppm): 0.93e0.99 (m, 6H,
2 ꢁ CH3CH2N), 1.88e1.99 (m, 2H, eCH2eCH2eCH2e), 2.12 (s, 6H,
2 ꢁ AreCH3), 2.25 (s, 3H, AreCH3), 2.43e2.59 (m, 6H, 3 ꢁ CH2N),
3.83 (s, 3H, OCH3), 4.30 (t, J ¼ 6.3 Hz, 2H, CH2O), 6.66 (d, J ¼ 8.5 Hz,
1H, AreH), 6.93 (s, 2H, AreH), 7.10 (s, 1H, AreH), 7.52 (s, 1H, AreH),
7.77 (dd, J1 ¼ 1.7 Hz, J2 ¼ 8.5 Hz, 1H, AreH), 8.17 (s, 1H, AreH), 8.90
(s, 1H, eNHe), 9.20 (s, 1H, AreH), 9.59 (s, 1H, eNHeCOe); 13C NMR
(DMSO-d6, 75 MHz)
d (ppm): 11.80, 17.91, 20.47, 26.19, 46.43, 48.39,
d6, 125 MHz)
d (ppm): 17.93, 18.44, 23.37, 25.18, 25.73, 34.15, 49.41,
56.03, 67.34, 101.95, 107.07, 110.31, 117.48, 121.52, 123.76, 125.99,

J. Cai et al. / European Journal of Medicinal Chemistry 63 (2013) 702e712
711
128.24, 128.69, 132.66, 135.21, 135.50, 141.99, 150.76, 151.05, 153.57,
5.2. Biological evaluation
154.51, 156.16, 157.75, 164.10; ESI-MS m/z: 599.3 [M þ H]þ, 597.3
[M ꢂ H]ꢂ, 633.2 [M þ Cl]ꢂ; Anal. calcd for C33H38N6O3S$3/4H2O (%):
C, 64.74; H, 6.50; N, 13.73; found: C, 64.92; H, 6.63; N, 13.65.
5.2.1. In vitro cytotoxic activity against 6 human cancer cell lines
All of the target compounds were determined against human
colon cancer cell lines (HCT-116 and DLD1), human chronic myeloid
leukemia cell line (K562), human acute monocytic myeloid leuke-
mia cell line (U937) and human lung cancer cell lines (A549 and
NCI-H661). The cell viability was determined by the MTT-based
assay using cell proliferation reagent WST-8, a reagent solution
prepared as an aqueous solution containing 5 mM WST-8 (Sigma),
0.2 mM 1-methoxyphenazinium salt (Sigma) and 150 mM NaCl
[55]. Briefly, the tumor cell lines in RPMI1640 medium with 10%
fetal bovine serum were plated in 96-well microtiter plates
(5.0 ꢁ 103 cells/well), and allowed to adhere at 37 ꢀC with 5% CO2
for 4 h. The test compound was then added, and the cells were
incubated at 37 ꢀC with 5% CO2 for 72 h later. Subsequently, cell
growth medium was removed, and WST-8 was added to each well
for another incubation of 1.5 h at 37 ꢀC. Absorbance was finally
measured with a plate reader at 450 nm with correction at 650 nm.
The results were expressed as the percentage of absorbance of
treated wells versus that of vehicle control. IC50, the drug concen-
tration causing 50% growth inhibition, was calculated via sigmoid
curve fitting using GraphPad Prism 5.0.
5.1.12.16. N-mesityl-2-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)qui-
nazolin-4- ylamino)benzo[d]thiazole-6-carboxamide (3d). Light yellow
solid, yield: 30%. Mp: 147e148 ꢀC. IR (KBr, cmꢂ1): 3260.63, 2957.78,
2792.53,1617.32,1595.18, 1575,70,1498.99, 1454.15, 1423.52, 1369.80,
1328.01, 1311.59, 1282.23,1232.52,1204.70,1137.28,1093.72,1035.95,
847.73, 758.47; 1H NMR (DMSO-d6, 300 MHz)
d (ppm): 1.68e1.70 (m,
4H, 2 ꢁ pyrolidine-CH2), 1.97e2.04 (m, 2H, eCH2eCH2eCH2e), 2.12
(s, 6H, 2 ꢁ AreCH3), 2.25 (s, 3H, AreCH3), 2.44e2.60 (m, 6H,
3 ꢁ CH2N), 3.83 (s, 3H, OCH3), 4.31 (t, J ¼ 6.3 Hz, 2H, CH2O), 6.65 (d,
J ¼ 8.5 Hz, 1H, AreH), 6.92 (s, 2H, AreH), 7.10 (s, 1H, AreH), 7.53 (s,
1H, AreH), 7.76 (dd, J1 ¼1.5 Hz, J2 ¼ 8.5 Hz,1H, AreH), 8.17 (s,1H, Are
H), 8.90 (s, 1H, eNHe), 9.19 (s,1H, AreH), 9.60 (s,1H, eNHeCOe); 13
C
NMR (DMSO-d6, 75 MHz)
d (ppm): 17.92, 20.48, 23.10, 27.78, 52.01,
53.57, 56.03, 67.46, 101.96, 107.16, 110.30, 117.49, 121.53, 123.77,
126.00, 128.25, 128.70, 132.66, 135.21, 135.51, 141.99, 150.75, 151.02,
153.59, 154.52, 156.12, 157.74, 164.11; ESI-MS m/z: 597.3 [M þ H]þ,
595.3 [M ꢂ H]ꢂ, 631.2 [M þ Cl]ꢂ; Anal. calcd for C33H36N6O3S$H2O
(%): C, 64.47; H, 6.23; N, 13.67; found: C, 64.48; H, 6.20; N, 13.68.
5.1.12.17. N-mesityl-2-(6-methoxy-7-(3-morpholinopropoxy)quina-
zolin-4-ylamino)benzo[d]thiazole-6-carboxamide (3e). Light yellow
solid, yield: 29%. Mp: 151e152 ꢀC. IR (KBr, cmꢂ1): 3256.94, 2959.07,
2853.38,1616.56,1595.05,1575.38,1498.83,1455.15,1423.51,1369.94,
1310.97,1282.06,1232.60,1204.71,1139.14,1115.08, 848.01, 749.11; 1H
5.2.2. In vitro kinase assays
In vitro kinase inhibitory ability was determined using the
HTScan EGFR Kinase Assay Kit (Cell Signaling Technology), Re-
combinant human Src Kinase Assay Kit (Upstate Biotechnology)
and Recombinant human Abl Kinase Assay Kit (Upstate Biotech-
nology), following the manufacturer’s instructions.
NMR (DMSO-d6, 300 MHz) d (ppm): 1.95e2.03 (m, 2H, eCH2eCH2e
CH2e), 2.12 (s, 6H, 2 ꢁ AreCH3), 2.25 (s, 3H, AreCH3), 2.37e2.51 (m,
6H, 3 ꢁ CH2N), 3.59 (t, J ¼ 4.5 Hz, 4H, 2 ꢁ morpholine-CH2), 3.83(s, 3H,
OCH3), 4.31 (t, J ¼ 6.3 Hz, 2H, CH2O), 6.65(d, J ¼ 8.5 Hz,1H, AreH), 6.92
(s, 2H, AreH), 7.10(s, 2H, AreH), 7.54(s,1H, AreH), 7.76(dd, J1 ¼1.6 Hz,
J2 ¼ 8.5 Hz, 1H, AreH), 8.17 (s, 1H, AreH), 8.90 (s, 1H, eNHe), 9.20 (s,
1H, AreH), 9.59 (s, 1H, eNHeCOe); 13C NMR (DMSO-d6, 75 MHz)
Acknowledgments
This work is supported by National Basic Research Program of
China (No. 2011CB933503) and Technology Supporting Program of
Jiangsu province (BE2009639, BE2012657).
d
(ppm): 17.91, 20.48, 25.47, 53.32, 54.60, 56.02, 66.18, 67.40, 101.97,
107.17, 110.30, 117.50, 121.52, 123.76, 125.99, 128.24, 128.69, 132.65,
135.21, 135.50, 141.98, 150.74, 151.01, 153.58, 154.52, 156.09, 157.74,
164.10; ESI-MS m/z: 613.2 [M þ H]þ, 635.2 [M þ Na]þ, 611.2 [M ꢂ H]ꢂ,
647.2 [M þ Cl]ꢂ; Anal. calcd for C33H36N6O4S$1/8H2O (%): C, 64.45; H,
5.94; N, 13.67; found: C, 64.37; H, 5.99; N, 13.48.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2013.03.013.
References
5.1.12.18. N-mesityl-2-(6-methoxy-7-(3-(2-methylpiperidin-1-yl)
propoxy)quinazolin- 4-ylamino)benzo[d]thiazole-6-carboxamide
(3f). Light yellow solid, yield: 31%. Mp: 143e145 ꢀC. IR (KBr,
cmꢂ1): 3256.94, 2927.72, 2843.77, 1617.82, 1595.47, 1576.53,
1498.91, 1423.60, 1369.70, 1327.69, 1311.62, 1281.69, 1232.69,
1204.68, 1183.90, 1138.09, 848.26, 758.72; 1H NMR (DMSO-d6,
[1] A. Quintas-Cardama, J. Cortes, Molecular biology of bcr-abl1-positive chronic
myeloid leukemia, Blood 113 (2009) 1619e1630.
[2] P.C. Nowell, D.A. Hungerford, Minute chromosome in human chronic Granu-
locytic leukemia, Science 132 (1960) 1497, 1497.
[3] J.D. Rowley, Letter: a new consistent chromosomal abnormality in chronic
myelogenous leukaemia identified by quinacrine fluorescence and Giemsa
staining, Nature 243 (1973) 290e293.
[4] J. Groffen, J.R. Stephenson, N. Heisterkamp, A. Deklein, C.R. Bartram,
G. Grosveld, Philadelphia chromosomal breakpoints are clustered within a
limited region, Bcr, on chromosome-22, Cell 36 (1984) 93e99.
[5] F. Palandri, L. Lacobucci, F. Castagnetti, N. Testoni, A. Poerio, M. Amabile,
M. Breccia, T. Intermesoli, F. Luliano, G. Rege-Cambrin, M. Tiribelli, M. Miglino,
F. Pane, G. Saglio, G. Martinelli, G. Rosti, M. Baccarani, CML, front-line treat-
ment of Philadelphia positive chronic myeloid leukemia with imatinib and
interferon-alpha: 5-year outcome, Haematol-Hematol J. 93 (2008) 770e774.
[6] T. Schindler, W. Bornmann, P. Pellicena, W.T. Miller, B. Clarkson, J. Kuriyan,
Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase, Sci-
ence 289 (2000) 1938e1942.
300 MHz)
d
(ppm): 0.99 (d, J ¼ 6.0 Hz, 3H, piperidine-CH3), 1.15e
1.26 (m, 2H, piperidine-CH2), 1.42e1.60 (m, 4H, 2 ꢁ piperidine-
CH2), 1.88e1.97 (m, 2H, eCH2eCH2eCH2e), 2.07e2.12 (m, 7H,
CHHN and 2 ꢁ AreCH3), 2.25e2.27(m, 4H, AreCH3 and CHN), 2.36
(q, J ¼ 9.6 Hz, 1H, CHHN), 2.79e2.88 (m, 2H, CH2N), 3.82 (s, 3H,
OCH3), 4.28 (t, J ¼ 6.2 Hz, 2H, CH2O), 6.65 (d, J ¼ 8.5 Hz, 1H, AreH),
6.92 (s, 2H, AreH), 7.10 (s, 1H, AreH), 7.53 (s, 1H, AreH), 7.76 (dd,
J1 ¼ 1.7 Hz, J2 ¼ 8.5 Hz, 1H, AreH), 8.16 (s, 1H, AreH), 8.90 (s, 1H, e
NHe), 9.19 (s, 1H, AreH), 9.59 (s, 1H, eNHeCOe); 13C NMR (DMSO-
[7] B.J. Druker, C.L. Sawyers, H. Kantarjian, D.J. Resta, S.F. Reese, J.M. Ford,
R. Capdeville, M. Talpaz, Activity of a specific inhibitor of the BCR-ABL tyrosine
kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic
leukemia with the philadelphia chromosome, New Engl. J. Med. 344 (2001)
1038e1042.
[8] B.J. Druker, F. Guilhot, S.G. O’Brien, I. Gathmann, H. Kantarjian, N. Gattermann,
M.W.N. Deininger, R.T. Silver, J.M. Goldman, R.M. Stone, F. Cervantes,
A. Hochhaus, B.L. Powell, J.L. Gabrilove, P. Rousselot, J. Reiffers, J.J. Cornelissen,
T. Hughes, H. Agis, T. Fischer, G. Verhoef, J. Shepherd, G. Saglio, A. Gratwohl,
d6, 75 MHz)
d (ppm): 17.90, 18.52, 20.47, 23.43, 25.15, 25.77, 34.20,
49.44, 51.49, 55.26, 56.04, 67.49, 101.96, 107.12, 110.30, 117.48,
121.51, 123.76, 125.99, 128.24, 128.68, 132.65, 135.20, 135.50, 141.99,
150.76, 151.05, 153.57, 154.51, 156.14, 157.74, 164.10; ESI-MS m/z:
625.3 [M þ H]þ, 623.3 [M ꢂ H]ꢂ, 659.2 [M þ Cl]ꢂ; Anal. calcd for
C
35H40N6O3S$1/8H2O (%): C, 67.04; H, 6.47; N, 13.40; found: C,
67.04; H, 6.60; N, 13.26.

712
J. Cai et al. / European Journal of Medicinal Chemistry 63 (2013) 702e712
J.L. Nielsen, J.P. Radich, B. Simonsson, K. Taylor, M. Baccarani, C. So, L. Letvak,
R.A. Larson, Five-year follow-up of patients receiving imatinib for chronic
myeloid leukemia, New Engl. J. Med. 355 (2006) 2408e2417.
[37] X.Q. Wu, M.D. Li, Y. Qu, W.H. Tang, Y.G. Zheng, J.Q. Lian, M. Ji, L. Xu, Design and
synthesis of novel Gefitinib analogues with improved anti-tumor activity,
Bioorgan Med. Chem. 18 (2010) 3812e3822.
[9] N.P. Shah, C. Tran, F.Y. Lee, P. Chen, D. Norris, C.L. Sawyers, Overriding imatinib
resistance with a novel ABL kinase inhibitor, Science 305 (2004) 399e401.
[10] A. Quintas-Cardama, J. Cortes, Therapeutic options against BCR-ABL1 T315I-
positive chronic myelogenous leukemia, Clin. Cancer Res. 14 (2008) 4392e
4399.
[11] F. Lee, A. Fandi, M. Voi, Overcoming kinase resistance in chronic myeloid
leukemia, Int. J. Biochem. Cell. B 40 (2008) 334e343.
[12] G. Noronha, J.G. Cao, C.P. Chow, E. Dneprovskaia, R.M. Fine, J. Hood, X.S. Kang,
B. Klebansky, D. Lohse, C.C. Mak, A. McPherson, M.S.S. Palanki, V.P. Pathak,
J. Renick, R. Soll, B.Q. Zeng, Inhibitors of ABL and the ABL-T315I mutation,
Curr. Top. Med. Chem. 8 (2008) 905e921.
[13] C. Sawyers, Targeted cancer therapy, Nature 432 (2004) 294e297.
[14] A. Petrelli, S. Giordano, From single- to multi-target drugs in cancer therapy:
when aspecificity becomes an advantage, Curr. Med. Chem. 15 (2008) 422e432.
[15] Z.A. Knight, H. Lin, K.M. Shokat, Targeting the cancer kinome through poly-
pharmacology, Nat. Rev. Cancer 10 (2010) 130e137.
[16] F.X. Mahon, S. Hayette, V. Lagarde, F. Belloc, B. Turcq, F. Nicolini, C. Belanger,
P.W. Manley, C. Leroy, G. Etienne, S. Roche, J.M. Pasquet, Evidence that
resistance to Nilotinib may Be due to BCR-ABL, Pgp, or Src kinase over-
expression, Cancer Res. 68 (2008) 9809e9816.
[17] S. Schenone, F. Manetti, M. Botta, Last findings on dual inhibitors of abl and
SRC tyrosine-kinases, Mini Rev. Med. Chem. 7 (2007) 191e201.
[18] H.M. Kantarjian, F. Giles, A. Quintas-Cardama, J. Cortes, Important therapeutic
targets in chronic myelogenous leukemia, Clin. Cancer Res. 13 (2007) 1089e1097.
[19] Y.G. Hu, Y.H. Liu, S. Pelletier, E. Buchdunger, M. Warmuth, D. Fabbro,
M. Hallek, R.A. Van Etten, S.G. Li, Requirement of Src kinases Lyn, Hck and Fgr
for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid
leukemia, Nat. Genet. 36 (2004) 453e461.
[20] S.I. Park, A.N. Shah, J. Zhang, G.E. Gallick, Regulation of angiogenesis and
vascular permeability by Src family kinases: opportunities for therapeutic
treatment of solid tumors, Expert Opin. Ther. Targets 11 (2007) 1207e1217.
[21] J.M. Summy, G.E. Gallick, Treatment for advanced tumors: Src reclaims center
stage, Clin. Cancer Res. 12 (2006) 1398e1401.
[38] J. Das, R.V. Moquin, J. Lin, C.J. Liu, A.M. Doweyko, H.F. DeFex, Q. Fang, S.H. Pang,
S. Pitt, D.R. Shen, G.L. Schieven, J.C. Barrish, J. Wityak, Discovery of 2-amino-
heteroaryl-benzothiazole-6-anilides as potent p56(lck) inhibitors, Bioorg.
Med. Chem. Lett. 13 (2003) 2587e2590.
[39] C. Ping, D. Norris, J. Das, S.H. Spergel, J. Wityak, L. Leith, R.L. Zhao, B.C. Chen,
S. Pitt, S.H. Pang, R.S. Ding, R. Zhang, H.F. De Fex, A.M. Doweyko,
K.W. McIntyre, D.J. Shuster, K. Behnia, G.L. Schieven, J.C. Barrish, Discovery of
novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally
active Src-family kinase p56(Lck) inhibitors, Bioorg. Med. Chem. Lett. 14
(2004) 6061e6066.
[40] J. Das, P. Chen, D. Norris, R. Padmanabha, J. Lin, R.V. Moquin, Z.Q. Shen,
L.S. Cook, A.M. Doweyko, S. Pitt, S.H. Pang, D.R. Shen, Q. Fang, H.F. de Fex,
K.W. McIntyre, D.J. Shuster, K.M. Gillooly, K. Behnia, G.L. Schieven, J. Wityak,
J.C. Barrish, 2-aminothiazole as a novel kinase inhibitor template. Structuree
activity relationship studies toward the discovery of N-(2-chloro-6-
methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-
pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (Dasatinib, BMS-354825) as
a potent pan-Src kinase inhibitor, J. Med. Chem. 49 (2006) 6819e6832.
[41] Y.G. Zheng, X.Q. Wu, B. Xue, M.D. Li, M. Ji, Design, synthesis, docking and
antitumor activity of Quinazolino [3, 4-a] thieno [3, 2-d] pyrimidin-8-one
derivatives, Chem. Biol. Drug Des. 76 (2010) 285e290.
[42] P. Ballard, R.H. Bradbury, C.S. Harris, L.F.A. Hennequin, M. Hickinson,
J.G. Kettle, J. Kendrew, T. Klinowska, D.J. Ogilvie, S.E. Pearson, E.J. Williams,
I. Wilson, Inhibitors of epidermal growth factor receptor tyrosine kinase:
optimisation of potency and in vivo pharmacokinetics, Bioorg. Med. Chem.
Lett. 16 (2006) 4908e4912.
[43] Y.M. Zhang, S. Cockerill, S.B. Guntrip, D. Rusnak, K. Smith, D. Vanderwall,
E. Wood, K. Lackey, Synthesis and SAR of potent EGFR/erbB2 dual inhibitors,
Bioorg. Med. Chem. Lett. 14 (2004) 111e114.
[44] J.B. Smaill, G.W. Rewcastle, J.A. Loo, K.D. Greis, O.H. Chan, E.L. Reyner, E. Lipka,
H.D.H. Showalter, P.W. Vincent, W.L. Elliott, W.A. Denny, Tyrosine kinase in-
hibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-
(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-
acrylamides bearing additional solubilizing functions, J. Med. Chem. 43
(2000) 1380e1397.
[22] T. Chen, J.A. George, C.C. Taylor, Src tyrosine kinase as a chemotherapeutic
target: is there a clinical case? Anticancer Drugs 17 (2006) 123e131.
[23] R.H. Alvarez, H.M. Kantarjian, J.E. Cortes, The role of Src in solid and hema-
tologic malignancies - development of new-generation Src inhibitors, Cancer
107 (2006) 1918e1929.
[24] A.Y. Tsygankov, S.K. Shore, Src: regulation, role in human carcinogenesis and
pharmacological inhibitors, Curr. Pharm. Des. 10 (2004) 1745e1756.
[25] T.J. Yeatman, A renaissance for SRC, Nat. Rev. Cancer 4 (2004) 470e480.
[26] S. Danhauser-Riedl, M. Warmuth, B.J. Druker, B. Emmerich, M. Hallek, Acti-
vation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells,
Cancer Res. 56 (1996) 3589e3596.
[45] V. Bellavita, L. Santamaria, New derivatives of benzothiazole. I. Synthesis, Boll
Soc. Ital. Biol. Sper. 27 (1951) 296e297.
[46] J. Das, J. Lin, R.V. Moquin, Z.Q. Shen, S.H. Spergel, J. Wityak, A.M. Doweyko,
H.F. DeFex, Q. Fang, S.H. Pang, S. Pitt, D.R. Shen, G.L. Schieven, J.C. Barrish,
Molecular design, synthesis, and structure-activity relationships leading to
the potent and selective P56(lck) inhibitor BMS-243117, Bioorg. Med. Chem.
Lett. 13 (2003) 2145e2149.
[47] S. Nishino, K. Hirotsu, H. Shima, T. Harada, H. Oda, T. Takahashi, S. Suzuki,
Preparation of quinazolin-4-one derivative useful as pharmaceutical and
agrochemical intermediates comprises reacting anthranilic acid derivative
with formic acid derivative in presence of ammonium carboxylate,
WO2003064399-A (2003).
[27] M. Warmuth, R. Damoiseaux, Y. Liu, D. Fabbro, N. Gray, SRC family kinases:
potential targets for the treatment of human cancer and leukemia, Curr.
Pharm. Des. 9 (2003) 2043e2059.
[28] S.G. Li, Src-family kinases in the development and therapy of Philadelphia
chromosome-positive chronic myeloid leukemia and acute lymphoblastic
leukemia, Leuk. Lymphoma. 49 (2008) 19e26.
[48] P. Knesl, D. Roseling, U. Jordis, Improved synthesis of substituted 6,7-
dihydroxy-4-quinazolineamines: tandutinib, erlotinib and gefitinib, Mole-
cules 11 (2006) 286e297.
[29] J.S. Tokarski, J.A. Newitt, C.Y.J. Chang, J.D. Cheng, M. Wittekind, S.E. Kiefer,
K. Kish, F.Y.F. Lee, R. Borzillerri, L.J. Lombardo, D.L. Xie, Y.Q. Zhang, H.E. Klei,
The structure of dasatinib (BMS-354825) bound to activated ABL kinase
domain elucidates its inhibitory activity against imatinib-resistant ABL mu-
tants, Cancer Res. 66 (2006) 5790e5797.
[49] M. Ji, M. Sun, X. Wu, New 2-(4-aminoquinazolinyl)benzo(d)thiazole derivative
used for inhibiting effect on multiplication of tumor cells, preferably for
treating colon cancer, CN101701018-A, 2010.
[50] N.C. Moore, K. Oldham, Use of quinazoline derivatives in the manufacture of a
medicament for the prevention or treatment of T cell mediated diseases or
medical conditions such as autoimmune diseases, WO2003045943-A, 2003.
[51] A. Telliez, M. Desroses, N. Pommery, O. Briand, A. Farce, G. Laconcle,
[30] T. Tauchi, K. Ohyashiki, The second generation of BCR-ABL tyrosine kinase
inhibitors, Int. J. Hematol. 83 (2006) 294e300.
[31] J. Cortes, Overcoming drug resistance in chronic myeloid leukemia, Curr. Opin.
Hematol. 13 (2006) 79e86.
A. Lemoine, P. Depreux, J.P. Henichart, Derivatives of iressa, a specific
epidermal growth factor receptor inhibitor, are powerful apoptosis inducers
in PC3 prostatic cancer cells, ChemMedChem 2 (2007) 318e332.
[52] P. Ple, F.H. Jung, P.P.J.F. Henri, New quinazoline derivatives are platelet-
derived growth factor inhibitors useful to treat cell proliferative disorders
and disease states associated with angiogenesis and/or vascular permeability,
e.g. neoplastic disorder, WO2006040520-A1, 2006.
[53] S. Tasler, O. Muller, T. Wieber, T. Herz, S. Pegoraro, W. Saeb, M. Lang, R. Krauss,
F. Totzke, U. Zirrgiebel, J.E. Ehlert, M.H.G. Kubbutat, C. Schachtele, Substituted
2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization, Bioorgan
Med. Chem. 17 (2009) 6728e6737.
[54] P.A. Ple, T.P. Green, L.F. Hennequin, J. Curwen, M. Fennell, J. Allen, C. Lambert-
van der Brempt, G. Costello, Discovery of a new class of anilinoquinazoline
inhibitors with high affinity and specificity for the tyrosine kinase domain of
c-Src, J. Med. Chem. 47 (2004) 871e887.
[55] M.V. Berridge, P.M. Herst, A.S. Tan, Tetrazolium dyes as tools in cell biology:
new insights into their cellular reduction, Biotechnol. Ann. Rev. 11 (2005)
127e152.
[32] M.H. Cohen, G.A. Williams, R. Sridhara, G. Chen, R. Pazdur, FDA drug approval
summary: Gefitinib (ZD1839) (Iressa (R)) tablets, Oncologist 8 (2003) 303e306.
[33] M.H. Cohen, J.R. Johnson, Y.F. Chen, R. Sridhara, R. Pazdur, FDA drug approval
summary: Erlotinib (Tarceva (R)) tablets, Oncologist 10 (2005) 461e466.
[34] M.G. Kris, R.B. Natale, R.S. Herbst, T.J. Lynch Jr., D. Prager, C.P. Belani,
J.H. Schiller, K. Kelly, H. Spiridonidis, A. Sandler, K.S. Albain, D. Cella,
M.K. Wolf, S.D. Averbuch, J.J. Ochs, A.C. Kay, Efficacy of gefitinib, an inhibitor of
the epidermal growth factor receptor tyrosine kinase, in symptomatic pa-
tients with non-small cell lung cancer: a randomized trial, JAMA 290 (2003)
2149e2158.
[35] M. Sun, Y. Zheng, H. Wei, J. Chen, M. Ji, QSAR studies on 4-anilino-3-
quinolinecarbonitriles as Src kinase inhibitors using robust PCA and both
linear and nonlinear models, J. Enzym. Inhib. Med. Chem. 24 (2009) 1109e1116.
[36] J. Cai, S.N. Zhang, M. Zheng, X.Q. Wu, J.Q. Chen, M. Ji, Design, synthesis, and
in vitro antiproliferative activity of novel Dasatinib derivatives, Bioorg. Med.
Chem. Lett. 22 (2012) 806e810.