2-Aminoxazole and 2-Aminothiazole Dasatinib Derivatives as Potent Inhibitors of Chronic Myeloid Leukemia K562 Cells

Article abstract of DOI:10.1002/ardp.201600010

Dasatinib is an important drug against chronic myeloid leukemia (CML). In this paper, we describe the preparation and anti-CML activity of 2-aminoxazole and 2-aminothiazole dasatinib derivatives. Biological activity was measured by the inhibition of proliferation of human CML K562 cells. The 2-aminoxazole derivatives had similar activities as the 2-aminothiazole derivatives. All newly synthesized compounds demonstrated more potent antiproliferative activity than imatinib. A few compounds (8b, 8c, 9b) showed nanomolar inhibitory activity, similar to that of dasatinib.

Full text of DOI:10.1002/ardp.201600010

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Arch. Pharm. Chem. Life Sci. 2016, 349, 1–9
Archiv der Pharmazie
Full Paper
2-Aminoxazole and 2-Aminothiazole Dasatinib Derivatives as
Potent Inhibitors of Chronic Myeloid Leukemia K562 Cells
Xing-Xing Chaiꢀ, Zhi-Ping Caiꢀ, Mian-Tian Yang, Ying Zhou, Ying-Jun Fu, and Yuan-Zhen Xiong
Medical School of Nanchang University, Nanchang, China
Dasatinib is an important drug against chronic myeloid leukemia (CML). In this paper, we describe
the preparation and anti-CML activity of 2-aminoxazole and 2-aminothiazole dasatinib derivatives.
Biological activity was measured by the inhibition of proliferation of human CML K562 cells. The
2-aminoxazole derivatives had similar activities as the 2-aminothiazole derivatives. All newly
synthesized compounds demonstrated more potent antiproliferative activity than imatinib. A few
compounds (8b, 8c, 9b) showed nanomolar inhibitory activity, similar to that of dasatinib.
Keywords: 2-Aminoxazole series / 2-Aminothiazole series / CML inhibitor / Dasatinib derivatives
Received: January 13, 2016; Revised: March 25, 2016; Accepted: April 11, 2016
DOI 10.1002/ardp.201600010
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
on simplified structure of dasatinib, synthesized and evalu-
ated the biological activity of 2-aminoxazole-5-carbamides
Introduction
Chronic myeloid leukemia (CML) is a myeloproliferative
disorder that is caused by hematopoietic stem cells
and 2-aminothiazole-5-carbamides, in which acetyl and
phenyl acetyl substitutions (R3 in 2 in Fig. 1) were adopted
as alternate scaffolds instead of pyrimidin-4-ylamino moiety
at the 2 position of thiazole or oxazole ring, and published
our initial results (2 in Fig. 1) [10–12]. We observed that 2- or
4-substitution of the phenylamide is a good alternative to the
2,6-disubstitution, and aminoxazole is a good replacement of
the aminothiazole core, which have led us to identify a novel
oxazole lead as a CML inhibitor. However, improvement in the
cellular activity profile was not observed compared with lead
compound dasatinib. From these results, we would like to
know whether the oxazole compounds connected to the
pyrimidine ring can improve their anticancer activity, thus
minor modification were made by replacement of the
thiazole core with oxazole skeleton, and holding dasatinib
entire aromatic ring structure. We also combined 2- or
4-substitution of the phenylamine with the aminopyrimidine
moiety in this design. Thus, series of aminoxazole derivatives
structurally related with 2- or 4-substitution of the phenyl-
amide and pyrimidine ring were generated (9a–h in Fig. 1 and
Table 1). In order to compare the electrotopological effect
on the biological activity, corresponding aminothiazole
a
chromosomal aberration, the Philadelphia (Ph) chromosome,
formed by the chromosomal translocation t(9;22)(q34;q11).
The resulting chimeric protein from the chromosomal
aberration is a constitutively active Abl tyrosine kinase (Bcr-
Abl). Expression of Bcr-Abl is considered to be sufficient for
CML formation [1, 2]. The central role of Bcr-Abl in the
pathophysiology of CML led to the development of related
inhibitors. Dasatinib (1 in Fig. 1), a Bcr-Abl inhibitor that
targets most of imatinib-resistant Bcr-Abl mutations, is an
improvement upon the first generation inhibitor imatinib,
because it is more potent and inhibits a few other kinases,
including Src and Btk family members, which are considered
as good cancer targets [3–7]. It is approved for the treatment
of all phases of CML and Ph chromosome-positive acute
lymphoblastic leukemia (ALL) resistant or intolerant to prior
imatinib treatment and first-line treatment for CML in chronic
phase [3, 5, 8, 9]. We have tried to make modification based
Correspondence: Prof. Yuan-Zhen Xiong, the College of Phar-
macy, Nanchang University, Nanchang 330006, China.
E-mail: xyz16262@163.com
Fax: þ86 791 86361839
ꢀThese two authors contributed equally to this work.
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compounds 8a–h (3 in Fig. 1 and Table 1) were also prepared,
and the antiproliferation assay of the novel compounds were
evaluated by using human chronic myeloid leukemia K562 cell
line. This cell line was also used by others for the optimization
of dasatinib derivatives [3, 6, 8]. Herein, we report the
identification of
a series of 2-aminoxazole series and
2-aminothiazole series dasatinib derivatives as CML inhibitor
through rational drug design. The structures of all novel
compounds were confirmed by IR, 1H NMR, 13C NMR spectra,
and elemental analysis.
Results and discussion
Chemistry
The 2-amino-heterocyclic thiazole and oxazole anilide ana-
logs (8a–h, 9a–h) are summarized in Table 1, 16 compounds
were synthesized as illustrated in Scheme 1. What made this
approach more feasible for the synthesis of diverse enone
analogs is that a great variety of amines are used commer-
cially. The known intermediates 4a–d and 5a–d were prepared
according to our previous paper [12]. Reaction of 4a–d and
5a–d with 4,6-dichloro-2-methyl-pyrimidine or 4,6-dichloro-
pyrimidine in the presence of sodium tert-butoxide (NaOBu-t)
in tetrahydrofuran (THF) to afford 6a–h and 7a–h, further
homologation of 6a–h or 7a–h by treatment with 1-(2-
hydroxyethyl)piperazine in N,N-dimethylformamide (DMF)
afforded targets 8a–h and 9a–h, respectively.
Figure 1. Chemical structures of dasatinib (1) and its derivatives.
Anti-CML activity
All newly synthesized compounds were evaluated on K562
cells in vitro for anti-CML activity, in comparison with the
Table 1. The inhibitory activity against K562 cells of novel compounds.
Code
R1
R2
X
R3
IC50 (mM)
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
9d
9e
9f
9g
9h
H
H
CH3
H
H
H
CH3
H
H
H
CH3
H
H
H
CH3
H
H
CH3
H
OCH3
H
CH3
H
OCH3
H
CH3
H
OCH3
S
S
S
S
S
S
S
S
O
O
O
O
O
O
O
O
CH3
CH3
CH3
CH3
H
H
H
0.0122 ꢁ 0.0003
0.0059 ꢁ 0.0016
0.0050 ꢁ 0.0005
0.0280 ꢁ 0.0028
0.0120 ꢁ 0.0015
0.0201 ꢁ 0.0023
0.0096 ꢁ 0.0017
0.0456 ꢁ 0.0013
0.0085 ꢁ 0.0007
0.0038 ꢁ 0.0013
0.0379 ꢁ 0.0018
0.0379 ꢁ 0.0018
0.0119 ꢁ 0.0006
0.0228 ꢁ 0.0006
0.0397 ꢁ 0.0023
0.0183 ꢁ 0.0011
0.0060 ꢁ 0.0002
0.3120 ꢁ 0.0021
H
CH3
CH3
CH3
CH3
H
H
H
H
CH3
H
OCH3
H
Dasatinib
Imatinib
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Scheme 1. Synthesis of the target compounds.
Reagents and conditions: (a) 0–5°C, 2 h; then
10°C, 0.5 h; (b) THF, Py, 0°C for 1 h, then r.t., 2 h;
(c) 1,4-dioxane and H2O, 0–10°C, NBS, for 1 h,
then urea/thiourea, 70°C, 2 h; (d) sodium tert-
butoxideinTHF, ꢂ15–0°C;(e) 1-(2-hydroxyethyl)-
piperazine, 1,4-dioxane, reflux; (f) HCl, Et2O,
MeOH.
marketed drugs, dasatinib and imatinib, which were used as
references, and the assays are summarized in Table 1. They
therapy or for imatinib-resistant patients. Our next effort
will focus on developing the structure–activity relationship
with respect to the substitution pattern on the pyrimidine
ring. In both series of compounds, conservative substitution
of a methyl group on the pyrimidine ring, introduction of
a methyl at the 4-position of the phenyl leads to a dramatic
increase in biochemical potency. To evaluate electron-
endowed effect on the potency, compounds 8d,h and 9d,h
had been synthesized; unfortunately, the compounds were
substantially less effective versus the remainder of the panel.
In summary, we have discovered equal potent dasatinib
analogs and identified a novel oxazole lead as a CML
inhibitor, and aminoxazole is a good replacement for the
aminothiazole core in the structure of dasatinib. We also
confirmed that 2- or 4-substitution of the phenylamide is as
good as 2,6-disubstitution, retaining the pyrimidin-4-ylamino
could enhance their anticancer activity; these results provide a
guide for further rational design of new inhibitors of this class
of compounds for the treatment of CML.
were expressed as IC50, a concentration at which the
compounds inhibit the cell proliferation for 50%. All the
compounds we made showed higher inhibitory activity
against K562 cells in comparison with imatinib.
Consistent with our previous results [12], the 2-aminoxazole
analogs 9a–h had excellent activity versus the K562 cellular
profile, similar to their counterparts thiazole-based analogs
8a–h; which is an indicator that electrotopological effect of
the oxazole and thiazole makes no significant difference on
the whole set of the interactions.
Five of the prepared products showed significant inhibi-
tion effect on K562 leukemia cells at nanomolar concentra-
tion (for compound 8b: IC50 ¼ 5.9 nM; for compound 8c:
IC50 ¼ 5 nM; for compound 8g: IC50 ¼ 9.6 nM; for compound
9a: IC50 ¼ 8.5 nM; for compound 9b: IC50 ¼ 3.8 nM), which
were about 7- to 70-fold more active than imatinib (IC50
¼ 312 nM). Three compounds 8b, 8c, and 9b exhibited
excellent potency versus the K562 cell line, which were
more effective than the parent compound dasatinib (IC50
¼ 6.0 nM) against the tumor line. The oxazole-based analog
9b (IC50 ¼ 3.8 nM) proved to be the most potent compound
versus the K562 cell line, which was about 70-fold more
potent than imatinib. This may be promising lead compound
to be developed as an alternative for current dasatinib
Experimental
Chemistry
All chemicals and solvents were reagent grade and purified
by standard methods prior to use. Mp: WRS-1 digital mp
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apparatus, uncorrected. NMR spectra: Bruker ACF-600 Q
apparatus at 600 MHz for 1H NMR and 13C NMR (internal
standard, TMS), chemical shifts were expressed in ppm
downfield. Mass spectrometry: Agilent MS/5975 mass spec-
trometer. Elemental analysis: Carlo Erba 1106 instrument, the
results of elemental analysis for C, H, N, and S were within
0.4% of the theoretical values. IR spectra (KBr): JASCO FT/IR-
8400 instrument. Mp: Capillary tube; uncorrected. All the
reactions were monitored by TLC on pre-coated silica gel G
plates at 254 nm under a UV lamp. The (E)-3-ethoxy-N-
arylpropenamides, 2-amino-N-arylthiazole-5-carboxamides
(4a–d), and 2-amino-N-aryloxazole-5-carboxamides (5a–d)
were synthesized according to our previously published
method [11, 12].
N-(2-Methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)-
amino]-5-thiazolecarboxamide 6c
Yield 73.7%, light-yellow solid, mp 293–295°C. IR (KBr):
Vꢀ¼ 3276, 3143.7, 2947.5, 2945.2, 2856.1, 1625.9, 1573.7,
1535.2, 1508.2, 1473.5, 1448.4 cmꢂ1
;
1H NMR (600 MHz,
DMSO-d6): d ¼ 12.14 (s, 1H, –NH–CO–), 9.75 (s, 1H, –NH),
8.20 (s, 1H, thiazole), 7.50 (m, J ¼ 8.00, 1H, Ar–H), 7.40 (dd,
J ¼ 8.32 Hz, 2H, Ar–H), 7.29 (d, J ¼ 8.27 Hz, 1H, Ar–H), 6.90 (s,
1H, pyrimidine), 2.42 (s, 3H, pyrimidine–CH3), 2.24 (s, 3H,
Ar–CH3) ppm; 13C NMR (125 MHz, DMSO-d6): d ¼ 18.32, 21.74
(–CH3), 125.65, 126.21, 126.66, 130.80, 130.94, 138.50 (Ar),
–
127.27, 141.35, 157.13 (thiazole), 160.34 (C O, carboxamide),
–
86.00, 158.21, 162.62, 163.75 (pyrimidine) ppm; MS (70 eV):
m/z ¼ 360.8 ([MþH]þ, C16H15N5OSClþ).
The InChI codes of the new compounds are provided in the
Supporting Information.
N-(4-Methoxyphenyl)-2-[(6-chloro-2-methyl-4-
pyrimidinyl)amino]-5-thiazolecarboxamide 6d
General method for the synthesis of compounds 6a–h
To a stirring of 2-amino-N-phenyl-5-thiazolecarboxamide
(10 mmol) and 4,6-dichloro-2- methylpyrimidine or 4,6-
dichloropyrimidine (12 mmol) in anhydrous THF (40 mL) was
added a 20 wt% solution of sodium tert-butoxide in anhy-
drous THF (30 mmol, 2.88 g) slowly, while keeping the
temperature at ꢂ15°C. The mixture was stirred for another
2.5 h, the pH of the resultant was adjusted to 6–7 by
hydrochloric acid (2 mol/L) and then concentrated in vacuo;
the crude product was recrystallized from ethanol, affording
the counterparts 6a–h.
Yield 84.3%, light-yellow solid, mp 255–257°C. IR (KBr):
Vꢀ¼ 3254, 3145.7, 2965.7, 2945.2, 2856.1, 1632.9, 1577.7,
1535.2, 1507.5, 1473.5, 1448.4 cmꢂ1
;
1H NMR (600 MHz,
DMSO-d6): d ¼ 12.05 (s, 1H, –NH–CO–), 9.95 (s, 1H, –NH),
8.18 (s, 1H, thiazole), 7.58 (m, J ¼ 8.88, 2H, Ar–H), 6.92 (m,
J ¼ 8.89 Hz, 2H, Ar–H), 6.88 (s, 1H, pyrimidine), 3.74 (s, 3H,
–OCH3), 2.42 (s, 3H, pyrimidine–CH3) ppm; 13C NMR (125 MHz,
DMSO-d6): d ¼ 21.74 (–CH3), 55.70 (–OCH3), 114.33 (2), 122.34
(2), 123.98, 132.42 (Ar), 127.36, 140.96, 157.14 (thiazole),
–
160.00 (C O, carboxamide), 85.84, 156.00, 162.52, 163.82
–
(pyrimidine) ppm; MS (70 eV): m/z ¼ 376.8 ([MþH]þ,
C
16H15N5O2SClþ).
N-Phenyl-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-
thiazolecarboxamide 6a
Yield 81.6%, light-yellow solid, mp 254–256°C. IR (KBr):
N-Phenyl-2-[(6-chloro-4-pyrimidinyl)amino]-5-
thiazolecarboxamide 6e
Vꢀ¼ 3276, 3145.7, 2935.2, 2846.1, 1625.9, 1577.7, 1535.2,
Yield 81.5%, light-yellow solid, mp 271–273°C. IR (KBr):
1473.5, 1448.4 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 12.04
Vꢀ¼ 3276, 3145.7, 2846.1, 1625.9, 1577.7, 1535.2, 1448.4 cmꢂ1
;
(s, 1H, –NH–CO–), 10.05 (s, 1H, –NH), 8.32 (s, 1H, thiazole), 7.70
(d, J ¼ 7.60, 2H, Ar–H), 7.32 (t, J ¼ 7.55 Hz, 2H, Ar–H), 7.08 (t,
J ¼ 7.35, 1H, Ar–H), 6.88 (s, 1H, pyrimidine), 2.42 (s, 3H,
1H NMR (600 MHz, DMSO-d6): d ¼ 12.02 (s, 1H, –NH–CO–), 10.05
–
–
–
(s, 1H, –NH), 8.34 (s, 1H, thiazole), 7.98 (s, 1H, –N CH–N ), 7.70
–
(d, J ¼ 7.60, 2H, Ar–H), 7.32 (t, J ¼ 7.55 Hz, 2H, Ar–H), 7.08 (t,
J ¼ 7.35, 1H, Ar–H), 6.83 (s, 1H, pyrimidine) ppm; 13C NMR
(125 MHz, DMSO-d6): d ¼ 120.65 (2), 129.16 (2), 123.9, 139.42
pyrimidine–CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d
¼ 21.74 (–CH3); 120.65 (2), 129.16 (2), 123.9, 139.42 (Ar);
–
–
127.00, 141.35, 157.13 (thiazole); 160.34 (C O, carboxamide);
(Ar), 127.00, 141.35, 157.13 (thiazole), 160.34 (C O, carbox-
–
–
86.00, 158.21, 162.62, 163.75 (pyrimidine) ppm; MS (70 eV):
amide), 86.00, 157.63, 162.62, 163.75 (pyrimidine) ppm; MS
m/z ¼ 346.8 ([MþH]þ, C15H13N5OSClþ).
(70 eV): m/z¼ 332.8 ([MþH]þ, C14H11N5OSClþ).
N-(4-Methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)-
amino]-5-thiazolecarboxamide 6b
N-(4-Methylphenyl)-2-[(6-chloro-4-pyrimidinyl)amino]-5-
thiazolecarboxamide 6f
Yield 85.2%, light-yellow solid, mp 271–273°C. IR (KBr):
Vꢀ¼ 3261.4, 3132.7, 2954.2, 2934.7, 2821.3, 1627.8, 1587.4,
1523.7, 1508, 1477.4, 1442.7 cmꢂ1; 1H NMR (600 MHz, DMSO-
d6): d ¼ 12.04 (s, 1H, –NH–CO–), 9.99 (s, 1H, –NH), 8.22 (s, 1H,
thiazole), 7.56 (m, J ¼ 8.00, 2H, Ar–H), 7.15 (m, J ¼ 8.27 Hz, 2H,
Ar–H), 6.90 (s, 1H, pyrimidine), 2.42 (s, 3H, pyrimidine–CH3),
2.37 (s, 3H, Ar–CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d ¼ 20.98, 21.74 (–CH3), 120.75 (2), 129.62 (2), 133.22, 136.42
Yield 83.8%, light-yellow solid, mp 281–283°C. IR (KBr):
Vꢀ¼ 3261.4, 3132.7, 2934.7, 2821.3, 1627.8, 1587.4, 1523.7,
1477.4, 1442.7 cmꢂ1
(s, 1H, –NH–CO–), 10.09 (s, 1H, –NH), 8.32 (s, 1H, thiazole), 8.09
;
1H NMR (600 MHz, DMSO-d6): d ¼ 12.04
–
–
(s, 1H, –N CH–N ), 7.56 (m, J ¼ 8.00, 2H, Ar–H), 7.15 (m,
–
–
J ¼ 8.27 Hz, 2H, Ar–H), 6.94 (s, 1H, pyrimidine), 2.37 (s, 3H,
Ar–CH3) ppm; 13C NMR (125 MHz, DMSO-d6): d ¼ 20.98 (–CH3),
120.75 (2), 129.62 (2), 133.22, 136.42 (Ar), 127.74, 141.35,
–
–
(Ar), 127.74, 41.35, 157.13 (thiazole), 160.34 (C O, carbox-
157.13 (thiazole), 160.34 (C O, carboxamide), 86.00, 157.21,
–
–
amide), 86.00, 158.21, 162.62, 163.75 (pyrimidine) ppm; MS
162.62, 163.75 (pyrimidine) ppm; MS (70 eV): m/z ¼ 346.8
(70 eV): m/z ¼ 360.8 ([MþH]þ, C16H15N5OSClþ).
([MþH]þ, C15H13N5OSClþ).
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N-(2-Methylphenyl)-2-[(6-chloro-4-pyrimidinyl)amino]-5-
thiazolecarboxamide 6g
Yield 75.2%, light-yellow solid, mp 284–286°C. IR (KBr):
N-(4-Methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-
piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-
thiazolecarboxamide 8b
Vꢀ¼ 3276, 3143.7, 2945.2, 2856.1, 1625.9, 1573.7, 1535.2,
Yield 78.4%, white solid, mp 221–223°C. IR (KBr): Vꢀ¼ 3372,
1473.5, 1448.4 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 12.20
3261.4, 3132.7, 2954.2, 2934.7, 2821.3, 1627.8, 1587.4,
(s, 1H, –NH–CO–), 10.05 (s, 1H, –NH), 8.30 (s, 1H, thiazole), 7.96
1523.7, 1508, 1477.4, 1442.7 cmꢂ1 1H NMR (600 MHz,
;
–
–
(s, 1H, –N CH–N ), 7.50 (m, J ¼ 8.00, 1H, Ar–H), 7.40 (dd,
DMSO-d6): d ¼ 11.46 (s, 1H, –NH–CO–), 9.99 (s, 1H, –NH),
8.22 (s, 1H, thiazole), 7.56 (dd, J ¼ 8.00, 2H, Ar–H), 7.15 (d,
J ¼ 8.27 Hz, 2H, Ar–H), 6.04 (s, 1H, pyrimidine), 4.47 (s, 1H,
–OH), 3.54 (t, J ¼ 6.05, 2H, CH2–OH), 3.51 (m, 4H, pyrimidi-
ne–N–CH2), 2.42–2.48 (m, 6H, CH2–N–CH2), 2.42 (s, 3H,
pyrimidine–CH3), 2.37 (s, 3H, Ar–CH3) ppm; 13C NMR
(125 MHz, DMSO-d6): d ¼ 20.98, 21.74 (–CH3), 44.46 (2),
53.26 (2) (piperazidine), 59.00, 60.61 (–CH2–CH2–OH), 120.75
(2), 129.62 (2), 133.22, 136.42 (Ar), 127.74, 141.35, 157.13
–
–
J ¼ 8.32 Hz, 2H, Ar–H), 7.29 (d, J ¼ 8.27 Hz, 1H, Ar–H), 6.94
(s, 1H, pyrimidine), 2.42 (s, 3H, pyrimidine–CH3), 2.24 (s, 3H,
Ar–CH3) ppm; 13C NMR (125 MHz, DMSO-d6): d ¼ 18.32
(–CH3), 125.65, 126.21, 126.66, 130.80, 130.94, 138.50 (Ar),
–
–
127.27, 141.35, 157.13 (thiazole), 160.34 (C O, carboxamide),
86.00, 157.40, 162.62, 163.75 (pyrimidine) ppm; MS (70 eV):
m/z ¼ 346.8 ([MþH]þ, C15H13N5OSClþ).
–
N-(4-Methoxyphenyl)-2-[(6-chloro-4-pyrimidinyl)amino]-
5-thiazolecarboxamide 6h
Yield 84.6%, light-yellow solid, mp 279–281°C. IR (KBr):
Vꢀ¼ 3254, 3145.7, 2921.2, 2856.1, 1632.9, 1577.7, 1535.2,
1473.5, 1448.4 cmꢂ1; 1H NMR (600MHz, DMSO-d6): d ¼ 12.04 (s,
1H, –NH–CO–), 10.05 (s, 1H, –NH), 8.32 (s, 1H, thiazole), 7.90 (s,
(thiazole), 160.34 (C O, carboxamide), 86.00, 158.21, 162.62,
–
163.75 (pyrimidine) ppm; MS (70 eV): m/z ¼ 454.5 ([MþH]þ,
C
22H28N7O2Sþ).
N-(2-Methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-
piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-
thiazolecarboxamide 8c
–
–
1H,–N CH–N ),7.58(m,J ¼ 8.88,2H,Ar–H),6.92(m,J ¼ 8.89Hz,
–
–
2H, Ar–H), 6.86 (s, 1H, pyrimidine), 3.74 (s, 3H, –OCH3), 13C NMR
(125 MHz, DMSO-d6): d ¼ 114.33 (2), 122.34 (2), 123.98, 132.42
Yield 77.9%, white solid, mp 254–256°C. IR (KBr): Vꢀ¼ 3381.3,
3276, 3143.7, 2947.5, 2945.2, 2856.1, 1625.9, 1573.7, 1535.2,
–
–
(Ar), 127.36, 140.96, 157.14 (thiazole), 160.00 (C O, carbox-
1508.2, 1473.5, 1448.4 cmꢂ1 1H NMR (600 MHz, DMSO-d6):
;
amide), 85.84, 156.00, 162.52, 163.82 (pyrimidine) ppm; MS
d ¼ 11.46 (s, 1H, –NH–CO–), 9.75 (s, 1H, –NH), 8.20 (s, 1H,
thiazole), 7.50 (m, J ¼ 8.00, 1H, Ar–H), 7.40 (dd, J ¼ 8.32 Hz, 2H,
Ar–H), 7.29 (d, J ¼ 8.27 Hz, 1H, Ar–H), 6.04 (s, 1H, pyrimidine),
4.45 (s, 1H, –OH), 3.54 (t, J ¼ 6.05, 2H, CH2–OH), 3.51 (m, 4H,
pyrimidine–N–CH2), 2.42–2.48 (m, 6H, CH2–N–CH2), 2.42 (s, 3H,
pyrimidine–CH3), 2.24 (s, 3H, Ar–CH3) ppm; 13C NMR (125 MHz,
DMSO-d6): d ¼ 18.32, 21.74 (–CH3), 44.47 (2), 53.28 (2)
(piperazidine), 59.04, 60.70 (–CH2–CH2–OH), 125.65, 126.21,
126.66, 130.80, 130.94, 138.50 (Ar), 127.27, 141.35, 157.13
(70 eV): m/z¼ 362.8 ([MþH]þ, C15H13N5O2SClþ).
General method for the synthesis of compounds 8a–h
To a stirring solution of 6a–h (10 mmol) and hydroxyethyl
piperazine (30 mmol, 3.9 g) in DMF (30 mL) was added
triethylamine (2.8 mL, 20 mmol). The slurry was heated at
80°C for 4 h, then cooled to room temperature. The solid was
collected by vacuum filtration. The product was dissolved in
hot 80% EtOH–H2O (80 mL), and the solution was clarified by
filtration. The hot solution was slowly diluted with water
(40 mL) and cooled slowly to room temperature. The solid was
collected by vacuum filtration and recrystallized from ethanol
to afford 8a–h.
–
(thiazole), 160.34 (C O, carboxamide), 86.00, 158.21, 162.62,
–
163.75 (pyrimidine) ppm; MS (70 eV): m/z ¼ 454.5 ([MþH]þ,
C
22H28N7O2Sþ).
N-(4-Methoxyphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-
piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-
thiazolecarboxamide 8d
N-Phenyl-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-
methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide 8a
Yield 79.6%, white solid, mp 210–212°C. IR (KBr): Vꢀ¼ 3392,
3276, 3145.7, 2935.2, 2846.1, 1625.9, 1577.7, 1535.2, 1473.5,
Yield 74.5%, white solid, mp 270–272°C. IR (KBr): Vꢀ¼ 3386,
3254, 3145.7, 2965.7, 2945.2, 2856.1, 1632.9, 1577.7, 1535.2,
1507.5, 1473.5, 1448.4 cmꢂ1 1H NMR (600 MHz, DMSO-d6):
;
1448.4 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 11.52 (s,
d ¼ 11.46 (s, 1H, –NH–CO–), 9.95 (s, 1H, –NH), 8.18 (s, 1H,
thiazole), 7.58 (m, J ¼ 8.88, 2H, Ar–H), 6.92 (m, J ¼ 8.89 Hz,
2H, Ar–H), 6.22 (s, 1H, pyrimidine), 4.47 (s, 1H, –OH), 3.74 (s,
3H, –OCH3), 3.54 (t, J ¼ 6.05, 2H, CH2–OH), 3.51 (m, 4H,
pyrimidine–N–CH2), 2.42–2.48 (m, 6H, CH2–N–CH2), 2.42 (s,
3H, pyrimidine–CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d ¼ 21.74 (–CH3), 44.15 (2), 53.18 (2) (piperazidine), 55.70
(–OCH3), 59.08, 60.70 (–CH2–CH2–OH), 114.33 (2), 122.34 (2),
123.98, 132.42 (Ar), 127.36, 140.96, 157.14 (thiazole),
1H, –NH–CO–), 10.05 (s, 1H, –NH), 8.24 (s, 1H, thiazole), 7.70
(d, J ¼ 7.60, 2H, Ar–H), 7.32 (t, J ¼ 7.55 Hz, 2H, Ar–H), 7.08
(t, J ¼ 7.35, 1H, Ar–H), 6.22 (s, 1H, pyrimidine), 4.43 (s,
1H, –OH), 3.54 (t, J ¼ 6.05, 2H, CH2–OH), 3.51 (t, 4H,
pyrimidine–N–CH2), 2.48–2.50 (m, 6H, CH2–N–CH2), 2.42
(s, 3H, pyrimidine–CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d ¼ 21.74 (–CH3), 44.47 (2), 53.28 (2) (piperazidine), 59.04,
60.70 (–CH2–CH2–OH), 120.65 (2), 129.16 (2), 123.9, 139.42
–
–
(Ar), 127.00, 141.35, 157.13 (thiazole), 160.34 (C O, carbox-
160.00 (C O, carboxamide), 85.84, 156.00, 162.52, 163.82
–
–
amide), 86.00, 158.21, 162.62, 163.75 (pyrimidine) ppm; MS
(pyrimidine) ppm; MS (70 eV): m/z ¼ 470.5 ([MþH]þ,
(70 eV): m/z ¼ 440.5 ([MþH]þ, C21H26N7O2Sþ).
C
22H28N7O3Sþ).
ß 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

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Arch. Pharm. Chem. Life Sci. 2016, 349, 1–9
X.-X. Chai et al.
Archiv der Pharmazie
N-Phenyl-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-4-
pyrimidinyl]amino]-5-thiazolecarboxamide 8e
Ar–H), 6.22 (s, 1H, pyrimidine), 4.47 (s, 1H, –OH), 3.74 (s, 3H,
–OCH3), 3.54 (t, J ¼ 6.05, 2H, CH2–OH), 3.51 (m, 4H, pyrimidi-
ne–N–CH2), 2.42–2.48 (m, 6H, CH2–N–CH2) ppm; 13C NMR
(125 MHz, DMSO-d6): d ¼ 55.70 (–OCH3), 44.15 (2), 53.18 (2)
(piperazidine), 59.08, 60.70 (–CH2–CH2–OH), 114.33 (2), 122.34
(2), 123.98, 132.42 (Ar), 127.36, 140.96, 157.14(thiazole), 160.00
Yield76.8%,whitesolid,mp268–270°C.IR(KBr):Vꢀ¼ 3392,3276,
3145.7, 2846.1, 1625.9, 1577.7, 1535.2, 1448.4 cmꢂ1 1H NMR
;
(600 MHz, DMSO-d6): d¼ 11.52 (s, 1H, –NH–CO–), 10.05 (s, 1H,
–
–
–
–NH), 8.24 (s, 1H, thiazole), 7.98 (s, 1H, –N CH–N ), 7.70 (d,
–
–
J ¼ 7.60, 2H, Ar–H), 7.32 (t, J ¼ 7.55 Hz, 2H, Ar–H), 7.08
(t, J ¼ 7.35, 1H, Ar–H), 6.22 (s, 1H, pyrimidine), 4.43 (s, 1H,
–OH), 3.54 (t, J ¼ 6.05, 2H, CH2–OH), 3.51 (t, 4H, pyrimidi-
ne–N–CH2), 2.48–2.50 (m, 6H, CH2–N–CH2) ppm; 13C NMR
(125 MHz, DMSO-d6): d¼ 44.47 (2), 53.28 (2) (piperazidine),
59.04, 60.70 (–CH2–CH2–OH), 120.65 (2), 129.16 (2), 123.9, 139.42
(C O, carboxamide), 85.84, 156.00, 162.52, 163.82 (pyrimidine)
–
ppm; MS (70 eV): m/z¼ 456.5 ([MþH]þ, C21H26N7O3Sþ).
General method for the synthesis of compounds 7a–h
To a stirring solution of 2-amino-N-phenyl-5-oxazolecarbox-
amide (10 mmol) and 4,6-dichloro-2-methylpyrimidine or 4,6-
dichloropyrimidine (12 mmol) in anhydrous THF (20 mL) was
added a 20% wt solution of sodium tert-butoxide in anhy-
drous THF (30 mmol, 2.88 g) slowly with cooling to keep the
temperature at 0°C and stirred for 6 h, the pH of the resultant
was adjusted to 6–7 by hydrochloric acid (2 mol/L). Evapora-
tion of the solvent in reduced pressure gave the crude
product. Thereafter, products were further subjected to silica
gel column by eluting stepwise with petroleum ether–acetone
(20:1–4:1, v/v) to obtain the pure product, which was
crystallized from ethanol, affording 7a–h.
–
(Ar), 127.00, 141.35, 157.13 (thiazole), 160.34 (C O, carbox-
–
amide), 86.00, 157.63, 162.62, 163.75 (pyrimidine) ppm; MS
(70 eV): m/z ¼ 426.5 ([MþH]þ, C20H24N7O2Sþ).
N-(4-Methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-
4-pyrimidinyl]amino]-5-thiazolecarboxamide 8f
Yield 77.2%, white solid, mp 235–237°C. IR (KBr): Vꢀ¼ 3372,
3261.4, 3132.7, 2934.7, 2821.3, 1627.8, 1587.4, 1523.7, 1477.4,
1442.7 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 11.46 (s, 1H,
–NH–CO–), 9.99 (s, 1H, –NH), 8.22 (s, 1H, thiazole), 7.99 (s, 1H,
–
–
–N CH–N ),7.56(m,J ¼ 8.00,2H,Ar–H),7.15(m,J ¼ 8.27 Hz,2H,
–
–
Ar–H), 6.04 (s, 1H, pyrimidine), 4.47 (s, 1H, –OH), 3.54 (t, J ¼ 6.05,
2H, CH2–OH), 3.51(m, 4H, pyrimidine–N–CH2), 2.42–2.48(m, 6H,
CH2–N–CH2), 2.37 (s, 3H, Ar–CH3) ppm; 13C NMR (125 MHz,
DMSO-d6): d ¼ 20.98 (–CH3), 44.46 (2), 53.26 (2) (piperazidine),
59.00, 60.61 (–CH2–CH2–OH), 120.75 (2), 129.62 (2), 133.22,
N-Phenyl-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-
oxazolecarboxamide 7a
Yield 32.4%, light-yellow solid, mp 275–277°C. IR (KBr):
Vꢀ¼ 3276, 3145.7, 2935.2, 2846.1, 1625.9, 1577.7, 1535.2,
1473.5, 1448.4 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 12.04
–
136.42 (Ar), 127.74, 141.35, 157.13 (thiazole), 160.34 (C O,
(s, 1H, –NH–CO–), 10.24 (s, 1H, –NH), 8.26 (s, 1H, oxazole), 7.93
(s, 1H, pyrimidine), 7.66 (d, J ¼ 7.60, 2H, Ar–H), 7.34 (t,
J ¼ 7.55 Hz, 2H, Ar–H), 7.11 (t, J ¼ 7.35, 1H, Ar–H), 6.88 (s, 1H,
pyrimidine), 2.42 (s, 3H, pyrimidine–CH3) ppm; 13C NMR
(125 MHz, DMSO-d6): d ¼ 20.98 (–CH3), 120.75 (2), 129.63 (2),
133.22, 136.42 (Ar), 131.74, 133.23, 157.84 (oxazole), 160.34
–
carboxamide), 86.00, 157.21, 162.62, 163.75 (pyrimidine) ppm;
MS (70eV): m/z ¼ 440.5 ([MþH]þ, C21H26N7O2Sþ).
N-(2-Methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-
4-pyrimidinyl]amino]-5-thiazolecarboxamide 8g
–
Yield 77.7%, white solid, mp 243–245°C. IR (KBr): Vꢀ¼ 3381.3,
(C O, carboxamide), 84.33, 155.57, 163.42, 163.58 (pyrimi-
–
3276, 3143.7, 2945.2, 2856.1, 1625.9, 1573.7, 1535.2, 1473.5,
dine) ppm; MS (70 eV): m/z ¼ 330.7 ([MþH]þ, C15H13N5O2Clþ).
1448.4 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 11.46 (s, 1H,
–NH–CO–), 9.75 (s, 1H, –NH), 8.20 (s, 1H, thiazole), 7.96 (s, 1H,
N-(4-Methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)-
amino]-5-oxazolecarboxamide 7b
–
–
–
–
–N CH–N ), 7.50 (m, J ¼ 8.00, 1H, Ar–H), 7.40 (dd, J ¼ 8.32Hz,
2H,Ar–H),7.29(d,J ¼ 8.27Hz,1H,Ar–H),6.04(s,1H,pyrimidine),
4.45 (s, 1H, –OH), 3.54 (t, J ¼ 6.05, 2H, CH2–OH), 3.51 (m, 4H,
pyrimidine–N–CH2), 2.42–2.48 (m, 6H, CH2–N–CH2), 2.42 (s, 3H,
pyrimidine–CH3), 2.24 (s, 3H, Ar–CH3) ppm; 13C NMR (125 MHz,
DMSO-d6): d ¼ 18.32 (–CH3), 44.47 (2), 53.28 (2) (piperazidine),
59.04, 60.70 (–CH2–CH2–OH), 125.65, 126.21, 126.66, 130.80,
130.94, 138.50 (Ar), 127.27, 141.35, 157.13 (thiazole), 160.34
Yield 35.7%, light-yellow solid, mp 288–290°C. IR (KBr):
Vꢀ¼ 3261.4, 3132.7, 2954.2, 2934.7, 2821.3, 1627.8, 1587.4,
1523.7, 1508, 1477.4, 1442.7 cmꢂ1; 1H NMR (600 MHz, DMSO-
d6): d ¼ 12.04 (s, 1H, –NH–CO–), 10.24 (s, 1H, –NH), 8.25 (s, 1H,
oxazole), 7.56 (m, J ¼ 8.00, 2H, Ar–H), 7.15 (m, J ¼ 8.27 Hz, 2H,
Ar–H), 6.88 (s, 1H, pyrimidine), 2.42 (s, 3H, pyrimidine–CH3),
2.37 (s, 3H, Ar–CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d ¼ 20.34, 20.98 (–CH3), 120.75 (2), 129.62 (2), 133.22, 136.42
–
(C O, carboxamide), 86.00, 157.40, 162.62, 163.75 (pyrimidine)
–
ppm; MS (70 eV): m/z¼ 440.5 ([MþH]þ, C21H26N7O2Sþ).
(Ar), 131.74, 133.23, 157.84 (oxazole), 160.34 (C O, carbox-
–
–
amide), 84.33, 155.57, 163.42, 163.58 (pyrimidine) ppm; MS
N-(4-Methoxyphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-
(70 eV): m/z ¼ 344.8 ([MþH]þ, C16H15N5O2Clþ).
piperazinyl]-4-pyrimidinyl]amino]-5-thiazolecarboxamide 8h
Yield 78.6%, white solid, mp 276–278°C. IR (KBr): Vꢀ¼ 3386,
3254, 3145.7, 2921.2, 2856.1, 1632.9, 1577.7, 1535.2, 1473.5,
N-(2-Methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)-
amino]-5-oxazolecarboxamide 7c
Yield 31.3%, light-yellow solid, mp 279–281°C. IR (KBr):
1448.4 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 11.46 (s, 1H,
–NH–CO–), 9.95 (s, 1H, –NH), 8.18 (s, 1H, thiazole), 7.90 (s, 1H,
Vꢀ¼ 3276, 3143.7, 2947.5, 2945.2, 2856.1, 1625.9, 1573.7,
–N CH–N ),7.58(m,J ¼ 8.88,2H,Ar–H),6.92(m,J ¼ 8.89 Hz,2H,
;
1535.2, 1508.2, 1473.5, 1448.4 cmꢂ1 1H NMR (600 MHz,
–
–
–
–
ß 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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6

RCHH HARM
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Arch. Pharm. Chem. Life Sci. 2016, 349, 1–9
2-Aminoxazole and 2-Aminothiazole Dasatinib Derivatives
Archiv der Pharmazie
–
–
–
DMSO-d6):d ¼ 12.04(s, 1H, –NH–CO–), 10.15 (s, 1H, –NH), 8.35(s,
1H, oxazole), 7.56 (m, J ¼ 8.00, 1H, Ar–H), 7.24 (dd, J ¼ 8.32Hz,
1H, Ar–H), 7.18 (d, J ¼ 8.27 Hz, 1H, Ar–H), 7.11 (m, J ¼ 8.00, 1H,
Ar–H), 6.88(s, 1H,pyrimidine), 2.42(s, 3H, pyrimidine–CH3),2.24
(s, 3H, Ar–CH3) ppm; 13C NMR (125MHz, DMSO-d6): d ¼ 18.32,
20.98(–CH3), 125.65,126.21, 126.66, 130.80,130.94, 138.50 (Ar),
(s, 1H, –N CH–N ), 7.50 (m, J ¼ 8.00, 1H, Ar–H), 7.40 (dd,
–
J ¼ 8.32 Hz, 2H, Ar–H), 7.29 (d, J ¼ 8.27 Hz, 1H, Ar–H), 6.82 (s,
1H, pyrimidine), 2.24 (s, 3H, Ar–CH3) ppm; 13C NMR (125 MHz,
DMSO-d6): d ¼ 18.32 (–CH3), 125.65, 126.21, 126.66, 130.80,
130.94, 138.50 (Ar), 131.74, 133.23, 157.84 (oxazole), 160.34
–
–
(C O, carboxamide), 84.33, 155.57, 163.42, 163.58 (pyrimi-
–
131.74, 133.23, 157.84 (oxazole), 160.34 (C O, carboxamide),
dine) ppm; MS (70 eV): m/z ¼ 330.7 ([MþH]þ, C15H13N5O2Clþ).
–
84.33, 155.57, 163.42, 163.58 (pyrimidine) ppm; MS (70 eV):
m/z¼ 344.8 ([MþH]þ, C16H15N5O2Clþ).
N-(4-Methoxyphenyl)-2-[(6-chloro-4-pyrimidineyl)amino]-
5-oxazolecarboxamide 7h
N-(4-Methoxyphenyl)-2-[(6-chloro-2-methyl-4-
Yield 39.2%, light-yellow solid, mp 294–296°C. IR (KBr):
pyrimidinyl)amino]-5-oxazolecarboxamide 7d
Vꢀ¼ 3254.7, 3145.7, 2921.2, 2856.1, 1632.9, 1577.7, 1535.2,
Yield 37.7%, light-yellow solid, mp 277–279°C. IR (KBr):
Vꢀ¼ 3254.6, 3145.7, 2965.7, 2921.2, 2856.1, 1632.9, 1577.7,
1535.2, 1507.5, 1473.5, 1442.6 cmꢂ1; 1H NMR (600MHz,
DMSO-d6):d ¼ 12.04(s, 1H, –NH–CO–), 10.05 (s, 1H, –NH), 8.28(s,
1H, oxazole), 7.58 (m, J ¼ 8.88, 2H, Ar–H), 6.92 (m, J ¼ 8.89Hz,
2H, Ar–H), 6.04 (s, 1H, pyrimidine), 3.74 (s, 3H, –OCH3), 2.42 (s,
3H, pyrimidine–CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d ¼ 20.98 (–CH3), 55.72 (–OCH3), 114.33 (2), 122.34 (2), 123.98,
1473.5, 1445.7 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 12.04
(s, 1H, –NH–CO–), 10.05 (s, 1H, –NH), 8.18 (s, 1H, oxazole), 7.92
–
–
(s, 1H, –N CH–N ), 7.58 (m, J ¼ 8.88, 2H, Ar–H), 6.92 (m,
–
–
J ¼ 8.89 Hz, 2H, Ar–H), 6.86 (s, 1H, pyrimidine) 3.74 (s, 3H,
–OCH3) ppm; 13C NMR (125 MHz, DMSO-d6): d ¼ 55.74
(–OCH3), 114.33 (2), 122.34 (2), 123.98, 132.42 (Ar), 131.74,
–
133.23, 157.84 (oxazole), 160.34 (C O, carboxamide), 84.33,
–
155.57, 163.42, 163.58 (pyrimidine) ppm; MS (70 eV):
m/z ¼ 346.7 ([MþH]þ, C15H13N5O3Clþ).
–
–
132.42 (Ar), 131.74, 133.23, 157.84 (oxazole), 160.34 (C O,
carboxamide), 84.33, 155.57, 163.42, 163.58 (pyrimidine) ppm;
MS (70eV): m/z ¼ 360.8 ([MþH]þ, C16H15N5O3Clþ).
General method for the synthesis of compounds 9a–h
To a stirring solution of 7a–h (3 mmol) and hydroxyethyl
piperazine (9 mmol, 1.17 g) in DMF (30 mL) was added
triethylamine (6 mmol, 0.6 mL). The slurry was heated at
80°C for 4 h, and then cooled to room temperature. The solid
was collected by vacuum filtration. The product was dissolved
in hot 80% EtOH–H2O (40 mL), and the solution was clarified
by filtration. The hot solution was slowly diluted with water
(15 mL) and cooled slowly to room temperature. The solid was
collected by vacuum filtration and dried, which was recrystal-
lized from ethanol, affording 9a–h.
N-Phenyl-2-[(6-chloro-4-pyrimidinyl)amino]-5-
oxazolecarboxamide 7e
Yield 34.7%, light-yellow solid, mp 258–260°C. IR (KBr):
Vꢀ¼ 3266.9, 3145.7, 2846.1, 1625.9, 1577.7, 1535.2,
1448.4 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 12.04 (s, 1H,
–NH–CO–), 10.05 (s, 1H, –NH), 8.24 (s, 1H, oxazole), 7.99 (s, 1H,
–
–
–N CH–N ), 7.70 (d, J ¼ 7.60, 2H, Ar–H), 7.32 (t, J ¼ 7.55 Hz,
–
–
2H, Ar–H), 7.08 (t, J ¼ 7.35, 1H, Ar–H), 6.87 (s, 1H, pyrimidine)
ppm; 13C NMR (125 MHz, DMSO-d6): d ¼ 120.65 (2), 129.16 (2),
123.9, 139.42 (Ar), 131.74, 133.23, 157.84 (oxazole), 160.34
–
(C O, carboxamide), 84.33, 155.57, 163.42, 163.58 (pyrimi-
N-Phenyl-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-
methyl-4-pyrimidinyl]amino]-5-oxazolecarboxamide 9a
Yield 79.4%, white solid, mp 206–208°C. IR (KBr): Vꢀ¼ 3392,
3276, 3145.7, 2935.2, 2846.1, 1625.9, 1577.7, 1535.2, 1473.5,
–
dine) ppm; MS (70 eV): m/z ¼ 316.7 ([MþH]þ, C14H11N5O2Clþ).
N-(4-Methylphenyl)-2-[(6-chloro-4-pyrimidinyl)amino]-5-
oxazolecarboxamide 7f
Yield 41.9%, light-yellow solid, mp 293–295°C. IR (KBr):
Vꢀ¼ 3261.4, 3132.7, 2934.7, 2821.3, 1627.8, 1587.4, 1523.7,
1477.4, 1442.7 cmꢂ1; 1H NMR (600 MHz, DMSO-d6): d¼ 12.06 (s,
1H, –NH–CO–), 10.09 (s, 1H, –NH), 8.22 (s, 1H, oxazole), 7.84 (s, 1H,
1448.4 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 11.34 (s, 1H,
–NH–CO–), 10.24 (s, 1H, –NH), 8.26 (s, 1H, oxazole), 7.93 (s, 1H,
pyrimidine), 7.66 (d, J ¼ 7.60, 2H, Ar–H), 7.34 (t, J ¼ 7.55 Hz, 2H,
Ar–H), 7.11 (t, J ¼ 7.35, 1H, Ar–H), 6.22 (s, 1H, pyrimidine), 4.43
(s, 1H, –OH), 3.54 (t, J ¼ 6.05, 2H, CH2–OH), 3.51 (t, 4H,
pyrimidine–N–CH2), 2.48–2.50 (m, 6H, CH2–N–CH2), 2.42 (s, 3H,
–
–
–
–N CH–N ), 7.56 (m, J¼ 8.00, 2H, Ar–H), 7.15 (m, J ¼ 8.27 Hz, 2H,
–
Ar–H), 6.88 (s, 1H, pyrimidine), 2.37 (s, 3H, Ar–CH3) ppm; 13C NMR
(125 MHz, DMSO-d6): d¼ 20.98 (–CH3), 120.75 (2), 129.62 (2),
133.22, 136.42 (Ar), 131.74, 133.23, 157.84 (oxazole), 160.34
pyrimidine–CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d
¼ 20.98 (–CH3), 44.19 (2), 53.30 (2) (piperazidine), 59.02,
60.70 (–CH2–CH2–OH), 120.75 (2), 129.63 (2), 133.22, 136.42
–
–
(C O, carboxamide), 84.33, 155.57, 163.42, 163.58 (pyrimidine)
(Ar), 131.74, 133.23, 157.84 (oxazole), 160.34 (C O, carbox-
–
–
ppm; MS (70 eV): m/z ¼ 330.7 ([MþH]þ, C15H13N5O2Clþ).
amide), 84.33, 155.57, 163.42, 163.58 (pyrimidine) ppm; MS
(70 eV): m/z ¼ 424.5 ([MþH]þ, C21H26N7O3þ).
N-(2-Methylphenyl)-2-[(6-chloro-4-pyrimidinyl)amino]-5-
oxazolecarboxamide 7g
Yield 30.5%, light-yellow solid, mp 296–298°C. IR (KBr):
N-(4-Methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-
piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-
oxazolecarboxamide 9b
Vꢀ¼ 3276.0, 3143.7, 2945.2, 2856.1, 1625.9, 1573.7, 1535.2,
1473.5, 1448.4 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 12.04
Yield 78.8%, white solid, mp 212–214°C. IR (KBr): Vꢀ¼ 3372,
(s, 1H, –NH–CO–), 10.05 (s, 1H, –NH), 8.20 (s, 1H, oxazole), 7.95
3261.4, 3132.7, 2954.2, 2934.7, 2821.3, 1627.8, 1587.4, 1523.7,
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Arch. Pharm. Chem. Life Sci. 2016, 349, 1–9
X.-X. Chai et al.
Archiv der Pharmazie
1508, 1477.4, 1442.7 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6):
(d, J ¼ 7.60, 2H, Ar–H), 7.32 (t, J ¼ 7.55 Hz, 2H, Ar–H), 7.08 (t,
J ¼ 7.35, 1H, Ar–H), 6.17 (s, 1H, pyrimidine), 4.43 (s, 1H, –OH),
3.54 (t, J ¼ 6.05, 2H, CH2–OH), 3.51 (t, 4H, pyrimidine–N–CH2),
2.48–2.50 (m, 6H, CH2–N–CH2) ppm; 13C NMR (125 MHz,
DMSO-d6): d ¼ 44.19 (2), 53.30 (2) (piperazidine), 59.02, 60.70
(–CH2–CH2–OH), 120.65 (2), 129.16 (2), 123.9, 139.42 (Ar),
d ¼ 11.46 (s, 1H, –NH–CO–), 9.99 (s, 1H, –NH), 8.25 (s, 1H,
oxazole), 7.56 (m, J ¼ 8.00, 2H, Ar–H), 7.15 (m, J ¼ 8.27 Hz, 2H,
Ar–H), 6.04 (s, 1H, pyrimidine), 4.47 (s, 1H, –OH), 3.54 (t,
J ¼ 6.05, 2H, CH2–OH), 3.51 (m, 4H, pyrimidine–N–CH2), 2.42–
2.48 (m, 6H, CH2–N–CH2), 2.42 (s, 3H, pyrimidine–CH3), 2.37 (s,
3H, Ar–CH3) ppm; 13C NMR (125 MHz, DMSO-d6): d ¼ 20.34,
20.98 (–CH3), 44.19 (2), 53.30 (2) (piperazidine), 59.02, 60.70
(–CH2–CH2–OH), 120.75 (2), 129.62 (2), 133.22, 136.42 (Ar),
–
131.74, 133.23, 157.84 (oxazole), 160.34 (C O, carboxamide),
–
84.33, 155.57, 163.42, 163.58 (pyrimidine) ppm; MS (70 eV):
m/z¼ 410.5 ([MþH]þ, C20H24N7O3þ).
–
–
131.74, 133.23, 157.84 (oxazole), 160.34 (C O, carboxamide),
84.33, 155.57, 163.42, 163.58 (pyrimidine) ppm; MS (70 eV):
N-(4-Methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-
piperazinyl]-4-pyrimidinyl]amino]-5-oxazolecarboxamide
9f
m/z ¼ 438.5 ([MþH]þ, C22H28N7O3þ).
N-(2-Methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-
piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-
oxazolecarboxamide 9c
Yield 77.5%, white solid, mp 246–248°C. IR (KBr): Vꢀ¼ 3372.4,
3261.4, 3132.7, 2934.7, 2821.3, 1627.8, 1587.4, 1523.7, 1477.4,
1442.7 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 11.46 (s, 1H,
–
–
Yield 78.7%, white solid, mp 242–244°C. IR (KBr): Vꢀ¼ 3381.3,
–NH–CO–),9.99(s,1H,–NH),8.22(s,1H,oxazole),7.85(s,1H,–N
–
3276, 3143.7, 2947.5, 2945.2, 2856.1, 1625.9, 1573.7, 1535.2,
CH–N ), 7.56 (m, J ¼ 8.00, 2H, Ar–H), 7.15 (m, J ¼ 8.27 Hz, 2H,
–
1508.2, 1473.5, 1448.4 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6):
Ar–H), 6.21 (s, 1H, pyrimidine), 4.47 (s, 1H, –OH), 3.54 (t, J ¼ 6.05,
2H, CH2–OH), 3.51(m, 4H, pyrimidine–N–CH2), 2.42–2.48(m, 6H,
CH2–N–CH2), 2.37 (s, 3H, Ar–CH3) ppm; 13C NMR (125 MHz,
DMSO-d6): d ¼ 20.98 (–CH3), 44.19 (2), 53.30 (2) (piperazidine),
59.02, 60.70 (–CH2–CH2–OH), 120.75 (2), 129.62 (2), 133.22,
d ¼ 11.46 (s, 1H, –NH–CO–), 9.75 (s, 1H, –NH), 8.25 (s, 1H,
oxazole), 7.56 (m, J ¼ 8.00, 1H, Ar–H), 7.24 (dd, J ¼ 8.32 Hz, 1H,
Ar–H), 7.18 (d, J ¼ 8.27 Hz, 1H, Ar–H), 7.11 (m, J ¼ 8.00, 1H,
Ar–H), 6.05 (s, 1H, pyrimidine), 4.45 (s, 1H, –OH), 3.54 (t,
J ¼ 6.05, 2H, CH2–OH), 3.51 (m, 4H, pyrimidine–N–CH2), 2.42–
2.48 (m, 6H, CH2–N–CH2), 2.42 (s, 3H, pyrimidine–CH3), 2.24 (s,
3H, Ar–CH3) ppm; 13C NMR (125 MHz, DMSO-d6): d ¼ 18.32,
20.98 (–CH3), 44.19 (2), 53.30 (2) (piperazidine), 59.02, 60.70
(–CH2–CH2–OH), 125.65, 126.21, 126.66, 130.80, 130.94, 138.50
–
136.42 (Ar), 131.74, 133.23, 157.84 (oxazole), 160.34 (C O,
–
carboxamide), 84.33, 155.57, 163.42, 163.58 (pyrimidine) ppm;
MS (70eV): m/z ¼ 424.5 ([MþH]þ, C21H26N7O3þ).
N-(2-Methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-
piperazinyl]-4-pyrimidinyl]amino]-5-oxazolecarboxamide
9g
–
(Ar), 131.74, 133.23, 157.84 (oxazole), 160.34 (C O, carbox-
–
amide), 84.33, 155.57, 163.42, 163.58 (pyrimidine) ppm; MS
(70 eV): m/z ¼ 438.5 ([MþH]þ, C22H28N7O3þ).
Yield 76.8%, white solid, mp 235–237°C. IR (KBr): Vꢀ¼ 3381.3,
3276.0, 3143.7, 2945.2, 2856.1, 1625.9, 1573.7, 1535.2, 1473.5,
N-(4-Methoxyphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-
piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-
oxazolecarboxamide 9d
1448.4 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 11.46 (s, 1H,
–NH–CO–), 9.75 (s, 1H, –NH), 8.20 (s, 1H, oxazole), 7.95 (s, 1H,
–
–
–N CH–N ), 7.50 (m, J ¼ 8.00, 1H, Ar–H), 7.40 (dd, J ¼ 8.32 Hz,
–
–
Yield 78.7%, white solid, mp 198–200°C. IR (KBr): Vꢀ¼ 3386.5,
2H, Ar–H), 7.29 (d, J ¼ 8.27 Hz, 1H, Ar–H), 6.12 (s, 1H,
pyrimidine), 4.45 (s, 1H, –OH), 3.54 (t, J ¼ 6.05, 2H, CH2–OH),
3.51 (m, 4H, pyrimidine–N–CH2), 2.42–2.48 (m, 6H,
CH2–N–CH2), 2.24 (s, 3H, Ar–CH3) ppm; 13C NMR (125 MHz,
DMSO-d6): d ¼ 18.32 (–CH3), 44.19 (2), 53.30 (2) (piperazidine),
59.02, 60.70 (–CH2–CH2–OH), 125.65, 126.21, 126.66, 130.80,
130.94, 138.50 (Ar), 131.74, 133.23, 157.84 (oxazole), 160.34
3254.6, 3145.7, 2965.7, 2921.2, 2856.1, 1632.9, 1577.7, 1535.2,
1507.5, 1473.5, 1442.6 cmꢂ1 1H NMR (600 MHz, DMSO-d6):
;
d ¼ 11.46 (s, 1H, –NH–CO–), 9.95 (s, 1H, –NH), 8.18 (s, 1H,
oxazole), 7.58 (m, J ¼ 8.88, 2H, Ar–H), 6.92 (m, J ¼ 8.89 Hz, 2H,
Ar–H), 6.04 (s, 1H, pyrimidine), 4.47 (s, 1H, –OH), 3.74 (s, 3H,
–OCH3), 3.54 (t, J ¼ 6.05, 2H, CH2–OH), 3.51 (m, 4H, pyrimi-
dine–N–CH2), 2.42–2.48 (m, 6H, CH2–N–CH2), 2.42 (s, 3H,
–
(C O, carboxamide), 84.33, 155.57, 163.42, 163.58 (pyrimi-
–
pyrimidine–CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d
dine) ppm; MS (70 eV): m/z ¼ 424.5 ([MþH]þ, C21H26N7O3þ).
¼ 20.98 (–CH3), 44.19 (2), 53.30 (2) (piperazidine), 55.72
(–OCH3), 59.02, 60.70 (–CH2–CH2–OH), 114.33 (2), 122.34 (2),
123.98, 132.42 (Ar), 131.74, 133.23, 157.84 (oxazole), 160.34
N-(4-Methoxyphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-
piperazinyl]-4-pyrimidinyl]amino]-5-oxazolecarboxamide
9h
–
(C O, carboxamide), 84.33, 155.57, 163.42, 163.58 (pyrimi-
–
dine) ppm; MS (70 eV): m/z ¼ 454.5 ([MþH]þ, C22H28N7O4þ).
Yield 74.6%, white solid, mp 192–194°C. IR (KBr): Vꢀ¼ 3386.3,
3254.7, 3145.7, 2921.2, 2856.1, 1632.9, 1577.7, 1535.2, 1473.5,
N-Phenyl-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-4-
pyrimidinyl]amino]-5-oxazolecarboxamide 9e
1445.7 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6): d ¼ 11.46 (s, 1H,
–NH–CO–), 9.95 (s, 1H, –NH), 8.18 (s, 1H, oxazole), 7.92 (s, 1H,
–
–
Yield 76.3%, white solid, mp 194–196°C. IR (KBr): Vꢀ¼ 3392.6,
–N CH–N ), 7.58 (m, J ¼ 8.88, 2H, Ar–H), 6.92 (m, J ¼ 8.89 Hz,
–
–
3266.9, 3145.7, 2846.1, 1625.9, 1577.7, 1535.2, 1448.4 cmꢂ1
;
2H, Ar–H), 6.12 (s, 1H, pyrimidine), 4.47 (s, 1H, –OH), 3.74 (s,
3H, –OCH3), 3.54 (t, J ¼ 6.05, 2H, CH2–OH), 3.51 (m, 4H,
pyrimidine–N–CH2), 2.42–2.48 (m, 6H, CH2–N–CH2) ppm;
1H NMR (600 MHz, DMSO-d6): d ¼ 11.52 (s, 1H, –NH–CO–), 10.05
–
–
–
(s, 1H, –NH), 8.24 (s, 1H, oxazole), 7.99 (s, 1H, –N CH–N ), 7.70
–
ß 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2016, 349, 1–9
2-Aminoxazole and 2-Aminothiazole Dasatinib Derivatives
Archiv der Pharmazie
13C NMR (125 MHz, DMSO-d6): d ¼ 44.19 (2), 53.30 (2)
(piperazidine), 55.74 (–OCH3), 59.02, 60.70 (–CH2–CH2–OH),
114.33 (2), 122.34 (2), 123.98, 132.42 (Ar), 131.74, 133.23,
[2] M. Brehme, O. Hantschel, J. Colinge, Proc. Natl. Acad.
Sci. U. S. A. 2009, 106(18), 7414–7419.
ꢁ
[3] K. Futosi, T. Nemeth, R. Pick, Blood 2012, 119(21),
–
157.84 (oxazole), 160.34 (C O, carboxamide), 84.33, 155.57,
4981–4991.
–
163.42, 163.58 (pyrimidine) ppm; MS (70 eV): m/z ¼ 440.5
[4] F. Franco, G. M. Xerardo, M. Melvin, E. Jose, Synthesis
2001, 2, 239–242.
([MþH]þ, C21H26N7O4þ).
[5] J. Das, P. Chen, D. Norris, R. Padmanabha, J. Lin,
R. V. Moquin, Z. Shen, L. S. Cook, A. M. Doweyko, S,
Pitt, S. 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, J. Med. Chem.
2006, 49, 6819–6832.
[6] L. J. Lombardo, F. Y. Lee, P. Chen, D. Norris, J. C. Barrish,
K. Behnia, S. Castaneda, J. Das, A. M. Doweyko,
C. Fairchild, J. T. Hunt, I. Inigo, K. Johnston,
A. Kamath, D. Kann, H. Klei, P. Marathe, S. Pang,
R. Peterson, S. Pitt, G. L. Schieven, R. J. Schmidt,
J. Tokarski, M. L. Wen, J. Wityak, R. M. Borzilleri,
J. Med. Chem. 2004, 47, 6658–6661.
Biological activity
The human erythroleukemia K562 cell line maintained in
suspension culture in Iscove’s medium supplemented with
10% iron-supplemented calf serum, 100 IU/cm3 penicillin, and
0.1 mg/cm3 streptomycin was added at 37°C in a 7% CO2
incubator. Cells were seeded in triplicate in 96-well plates at a
density of 104 cells per well. Various concentrations of drugs
(10ꢂ2–10ꢂ3 mM) were dissolved in dimethyl sulfoxide (DMSO),
the concentration of DMSO did not exceed 0.5% to avoid the
effect of DMSO on K562 cells. The cell proliferation assay was
determined by the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-
tetrazolium bromide (MTT) colorimetric method after 2 days
of incubation [7].
[7] N. R. Murray, G. P. Baumgardner, D. J. Burns, A. P. Fields,
J. Biol. Chem. 1993, 268, 15847–15853.
This work is supported by National Basic Research Program of
China (no. 81260470) and Technology Supporting Program of
Jiangxi province (BE2009639).
[8] D. S. Prasanna, C. V. Kavitha, K. Vinaya, S. R. Ranganatha,
S. C. Raghavan, K. S. Rangappa, Eur. J. Med. Chem. 2010,
45, 5331–5336.
[9] M. Preyer, P. Vigneri, J. Y. Wang, PloS ONE 2011, 6(2),
17020.
The authors have declared no conflict of interest.
[10] Y. Z. Xiong, P. Y. Chen, J. Mol. Model. 2008, 14,
1083–1086.
[11] Y. Z. Xiong, X. B. He, Y. Z. Xiong, X. X. Chai, C.A. Patent
104163818A, 2014.
References
[1] A. Hochhaus, H. Kantarjian, J. Cancer Res. Clin. Oncol.
2013, 139(12), 1971–1984.
[12] Y. Zhou, X. B. He, Y. Z. Xiong, X. X. Chai, H. P. Chen,
Monatsh. Chem. 2015, 146, 997–1003.
ß 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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