Design, Synthesis, and Evaluation of the Kinase Inhibition Potential of Pyridylpyrimidinylaminophenyl Derivatives

Article abstract of DOI:10.1002/ardp.201600390

In view of potent kinase inhibitors for the treatment of myriad human disorders, we synthesized some structurally variant amide/cyclic amide derivatives based on pyridylpyrimidinylaminophenyl amine, the key pharmacophore of the kinase inhibitor drug molecule, imatinib, and evaluated their kinase inhibition potency. Among the various synthesized amides, compound 20, a cyclic amide/pyridin-2(1H)-one derivative, exhibited an IC₅₀ value comparable to that of the drug imatinib against c-Src kinase, and another compound (14) containing a 2-((4-methyl-2-oxo-2H-chromen-6-yl)oxy)acetamide demonstrated an IC₅₀ value of 8.39 μM. Furthermore, the constitution of the cyclic amide derivative was confirmed by the single-crystal X-ray diffraction technique. These results may serve as a gateway for developing novel next-generation kinase inhibitors.

Full text of DOI:10.1002/ardp.201600390

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Arch. Pharm. Chem. Life Sci. 2017, 350, e1600390
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Full Paper
Design, Synthesis, and Evaluation of the Kinase Inhibition Potential
of Pyridylpyrimidinylaminophenyl Derivatives
1
1
1,2
3
3
Priyanka Manchanda , Badri Parshad , Amit Kumar , Rakesh K. Tiwari , Amir N. Shirazi ,
3
1
Keykavous Parang , and Sunil K. Sharma
1
Department of Chemistry, University of Delhi, Delhi, India
Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard (Hamdard University),
New Delhi, India
Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman
University School of Pharmacy, Irvine, CA, USA
2
3
In view of potent kinase inhibitors for the treatment of myriad human disorders, we synthesized some
structurally variant amide/cyclic amide derivatives based on pyridylpyrimidinylaminophenyl amine, the
key pharmacophore of the kinase inhibitor drug molecule, imatinib, and evaluated their kinase
inhibition potency. Among the various synthesized amides, compound 20, a cyclic amide/pyridin-2(1H)-
one derivative, exhibited an IC50 value comparable to that of the drug imatinib against c-Src kinase, and
another compound (14) containing a 2-((4-methyl-2-oxo-2H-chromen-6-yl)oxy)acetamide demonstrated
an IC50 value of 8.39 mM. Furthermore, the constitution of the cyclic amide derivative was confirmed by
the single-crystal X-ray diffraction technique. These results may serve as a gateway for developing novel
next-generation kinase inhibitors.
Keywords: Amide derivatives / Imatinib / Kinase inhibitors / Pyridin-2(1H)-one /
Pyridylpyrimidinylaminophenyl
Received: December 23, 2016; Revised: February 25, 2017; Accepted: February 27, 2017
DOI 10.1002/ardp.201600390
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
Introduction
process [3, 4]. c-Src kinase is recognized to play a critical role
in the genesis and progression of myriad human disorders,
including cancers of the breast, colon, prostate, lung, ovary,
and in myeloproliferative disorders by inducing STATs (signal
transducer and activator of transcription) [5, 6]. Consequently,
there are bestowed interest both in academia and industry in
the development of novel and potent kinase inhibitors for
therapeutic interventions in the treatment of cancer. The
most popular approaches for cancer treatment since 1980’s
includes the use of cytotoxic agents like antimetabolic and
microtubule-destabilizing drugs [7], and targeting selective
signal elements for cancer cells [8]. However, the latter
approach is grounded upon the development of protein
kinase inhibitors that act by intruding the signaling network
Protein kinases are key regulators that mediate signal
transduction pathways, and regulate various cellular activities
like proliferation, survival, apoptosis, metabolism, transcrip-
tion, differentiation, by catalyzing the transfer of the
g-phosphate group of ATP onto a substrate [1]. Deregulation
of kinase activity has emerged as a major mechanism by which
cells develop pathophysiological conditions regarding cell
growth and fate leading to mortal diseases such as cancer [2].
The Abl and c-Src kinases belong to the family of non-receptor
tyrosine kinases that are involved in the tumorigenesis
Correspondence: Dr. Sunil K. Sharma, Department of Chemistry,
University of Delhi, Delhi 110 007, India.
E-mail: sk.sharma90@gmail.com; sksharma@chemistry.du.ac.in
Fax: þ91-11-2766 6605
Priyanka Manchanda and Badri Parshad contributed equally to
this work.
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of cancer cells. Naturally occurring bioactive alkaloid like
staurosporine, a prototype ATP-competitive protein kinase
inhibitor with strong binding affinity, has been explored for
its anticancer potency but has not made it to therapeutic
usage due to its limited selectivity and lack of specificity [9].
However, it is commonly used as a positive control in kinase
assays. The early success in the field of targeted therapy of
cancer was achieved in 2001 by the efficacious use of Gleevec
(
imatinib, 1a), the foremost FDA-approved tyrosine kinase
inhibiting drug for treatment of chronic myeloid leukemia
CML) [10–12]. The discovery of imatinib (1a), a type II kinase
Figure 1. FDA approved tyrosine kinase inhibitors containing
(
the boxed pyridylpyrimidinylaminophenyl (PPAP) scaffold.
inhibitor, is a pathbreaking discovery in selective cancer
therapy as it works by inhibiting a constitutively active fusion
protein, Bcr-Abl (present exclusively in >90% of CML cancer
cells), from phosphorylating successive proteins thereby
suppressing the signaling cascade essential for cancer
development, thus leading to cell death by apoptosis [13].
The FDA approved imatinib has been rationally developed
acid, hippuric acid, piperic acid, 2-oxoquinolinacetic acid,
3-oxobenzooxazinacetic acid [37], and trimethoxyphenyl
acrylic acid [38], with PPAP moiety to form the amide/cyclic
amide derivatives.
from
a 2-phenylaminopyrimidine (PAP) scaffold found
through high-throughput screening against the Bcr-Abl
fusion protein, the lead structure responsible for kinase
inhibition [14]. The structure was further modified for
improved binding efficacy and selectivity by introduction of
the pyridine moiety at C-4 position of pyrimidine leading to
enhancement of protein kinase C inhibition, and the phenyl
amide part for conferring high tyrosine kinase and Bcr-Abl
kinase inhibition. Additional gain in selectivity toward Bcr-Abl
was achieved by restricting the conformation by attachment
of methyl at the C-6 position of phenyl ring [14, 15]. The
crystal structure of the kinase domain of c-Abl with imatinib
has shown the pyridylpyrimidinylaminophenyl (PPAP) part to
interact with the ATP binding region in the Bcr-Abl fusion
enzyme, thereby inhibiting its activity [16].
As a part of our enduring research program in the design
and synthesis of biologically potent diversity of heterocycles
we have identified few compounds that possess significant
antiproliferative and kinase inhibition activity [17–23]. This
study motivated us to assemble newer and more widely
effective kinase inhibitors. Our synthetic approach is based
on the concept of molecular hybridization, an effective tool
for the cogent design of novel molecular constructs by
covalently conjugating two or more active pharmaco-
phores [24]. Such constructs are known to exhibit improved
pharmacokinetic-dynamic properties, potency to act on
more than one target with reduced side effects and efficacy
in case of drug resistant cases [25]. Success of molecular
hybridization in medicinal chemistry has been exemplified in
Results and discussion
Chemistry
The pharmacophore 6-methyl-N-(4-(pyridin-3-yl)pyrimidin-2-
yl)benzene-1,3-diamine (8), was synthesized by using a route
that partially follows the reported preparation of imatinib
(Scheme 1) [29]. The reaction of 3-acetylpyridine 2 with an
excess of dimethylformamide dimethyl acetal (DMF DMA) in
xylene gave the enaminone 3. It was reacted further with
guanidine hydrochloride and sodium hydroxide in n-butanol
leading to the formation of the pyrimidine ring shown in
compound 4. o-Bromo-p-nitrotoluene 6 was synthesized from
p-nitrotoluene 5 and was then coupled with 4 by Ullman type
coupling using copper iodide (CuI), N,N-dimethylethylenedi-
amine (DMEDA), potassium iodide (KI), and potassium carbon-
2 3
ate (K CO ) in dry dioxane at 100°C for 24 h leading to
formation of pyrimidine nitro derivative 7. Reduction of the
nitro group of compound 7 to an amine has been previously
reported by different hydrogenation strategies [39]. We
adopted a very convenient methodology for this reduction
reaction by employing ammonium formate with 10% Pd/C in
anhydrous methanol [40]. The in situ generated hydrogen
reduces nitro compound 7 to corresponding amine 8 in short
reaction time of 3–4 h with 80% isolated yield.
Amides (9–16) were synthesized by using N-(3-dimethyl-
aminopropyl)-N’-ethylcarbonate (EDC.HCl) as the coupling
agent and hydroxybenzotriazole (HOBt) as an additive for the
reaction between amine 8 and different acids in DMF in the
presence of base triethylamine (TEA)/N,N-diisopropyl-
ethylamine (DIPEA) (Scheme 1). 1-[Bis(dimethylamino)methy-
lene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluoro-
phosphate (HATU) was employed as a coupling agent for the
synthesis of amide 17 (Scheme 1). Amine 8 was also coupled
with 4-bromomethylbenzoic acid to obtain the corresponding
pyrimidine amide derivative, which was sequentially
treated with 1-methylpiperazine to form imatinib (1a)
(Scheme 1) [41].
the development of
a tyrosine kinase inhibitor drug
“
nilotinib” (1b) (Fig. 1), a hybrid/variant of imatinib having
the active pharmacophore PPAP (Fig. 1) [26] conserved in its
structure; the drug is efficacious in imatinib resistant
cases [27]. On the basis of above and considering the
literature reports discussing Abl-imatinib structural inter-
actions [16, 26–32], we decided to conjugate the scaffolds
based on 2-pyridone [21, 33, 34], benzopyran-2-one [35],
benzopyran-4-one [22, 36], indole acetic acid, iso-nicotinic
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Scheme 1. Synthesis of amide derivatives of 6-methyl-N-(4-(pyridin-4-yl)pyrimidin-2-yl)benzene-1,3-diamine. Reagents and
conditions: i. DMF DMA, xylene, reflux; ii. guanidine hydrochloride, NaOH, n-butanol; iii. N-bromosuccinimide, H SO /H O (1:1);
2
4
2
iv. CuI, KI, DMEDA, dry dioxane; v. ammonium formate, 10% Pd/C, dry methanol; vi. EDC.HCl, HOBt, DIPEA, DMF, 30°C, 24 h (for
compound 17 vi. HATU, DIPEA, DMF, 30°C, 24 h); vii. 4-bromomethylbenzoic acid, EDC.HCl, HOBt, DIPEA, DMF, 30°C, 24 h;
viii. 1-methylpiperazine, dioxane, 30°C, 1 h.
Cyclic amides 20/21 (2-pyridone derivatives) were synthe-
sized by coupling diamine with (E)-3-(4-oxo-4H-
value ruled out the formation of simple acyclic amide and
rather suggested the presence of 2-pyridone 21 formed by
the Michael addition of the aromatic amine via nucleo-
philic nitrogen on the O-acylisourea intermediate of the
acrylic acid followed by subsequent ring opening and
closure [42]. The structure was further confirmed by single
crystal X-ray diffraction (SCXRD) analysis. Compound 21
crystalizes in monoclinic P21 space group with two ligand
units present in the asymmetric unit (Fig. 2 and Supporting
Information Tables S2–S4). The characteristic carbonyl
peak for the benzoyl moiety in compound 20 was also
observed in a similar range, that is, at d 191.7 ppm, thus
confirming the structure of compound 20 to be similar to
that of 21 as shown in Scheme 2.
8
chromen-3-yl)acrylic acid and (E)-3-(7-fluoro-4-oxo-4H-
chromen-3-yl)acrylic acid, respectively, in the presence
of EDC.HCl and HOBt (Scheme 2). Both compounds were
characterized on the basis of their spectral data. The
1
3
proton noise decoupled C NMR spectra for 5-(4-fluoro-2-
hydroxybenzoyl)-1-(4-methyl-3-((4-(pyridin-3-yl)pyrimidi
n-2-yl)amino)phen-yl)pyridin-2(1H)-one (21) showed
a
characteristic carbonyl peak at d 193 ppm, this deshielded
The methodology for the synthesis of (E)-3-(4-oxo-4H-
chromen-3-yl)acrylic acid, (E)-3-(3,4,5-trimethoxyphenyl)-
acrylic acid, 2-((4-methyl-2-oxo-2H-chromen-6-yl)oxy)acetic
acid, 2-(6-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetic
acid, 2-(3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetic acid
w
and methoxypolyethylene glycol acid (M : 350) is described
in the Supporting Information (Schemes S1–S5). Other
acids, such as indole acetic acid, hippuric acid, piperic acid,
isonicotinic acid were procured from Sigma–Aldrich. All the
amides (9–17, 20–21) were obtained in moderate to good
yields.
Scheme 2. Synthesis of cyclic amide analogue of imatinib.
Reagents and conditions: i. EDC.HCl, HOBt, DIPEA, DMF,
3
0°C, 24 h.
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Imatinib (1a) showed IC50 values of 0.27, >50, 35.1, and
0
.26 mM against Abl1, EGFR, c-Src, and Lck, respectively.
Staurosporine exhibited IC50 values of 31.3, 79.5, 3.0, and
.4 nM against Abl1, EGFR, c-Src, and Lck, respectively. The
1
cyclic amide derivative 20 exhibited higher c-Src inhibition as
compared to imatinib. It showed Abl1, c-Src, and Lck kinase
inhibition with IC50 values of 2.7, 2.8, and 9.9 mM, respectively,
while it did not show high inhibitory activity against EGFR.
Compound 14 containing a 2-((4-methyl-2-oxo-2H-chromen-
6
-yl)oxy)acetamide moiety exhibited less kinase inhibition. It
demonstrated IC50 values of 8.4, 99.7, and 14.4 mM against
Abl1, EGFR, and Lck, respectively, while no significant
inhibitory activity was observed against c-Src. Compound 14
showed higher selectivity against Lck when compared with
imatinib. The data suggest it is possible to generate selectivity
with appropriate substitution on PPAP scaffold (Table 2).
Figure 2. Molecular structure of compound 21 (CCDC Number
1
483452).
Biology
Cell viability assay
Kinase inhibitory activity evaluation
The activity of the compounds was examined on the cell
viability of human leukemia cell line CCRF-CEM for 72 h at a
concentration of 50 mM (Fig. 3). Compounds 1a, 10, 12, and 20
exhibited modest antiproliferative activity.
The kinase inhibition potential of all the synthesized
pyridylpyrimidinylaminophenyl derivatives was screened
against Abl1 and c-Src kinase. Compounds were tested in
single dose duplicate mode at a concentration of 50 mM
Among all the compounds, compound 20 reduced the cell
viability of human leukemia cell line (CCRF-CEM) by 56.2%.
Compounds 13 and 14 were not active against c-Src; also these
compounds did not show any significant anticancer activity.
There was no clear correlation between kinase inhibitory
activity and anticancer assay possibly due to differences in
cellular uptake and solubility of the compounds. Optimized
compounds such as compound 20 that demonstrated both
tyrosine kinase inhibition and anticancer activity could
generate analogs with higher efficacy profile at the site of
action.
(
Table 1). Reactions were carried out in the presence of 10 mM
ATP. Control compound, staurosporine, was tested in 10-dose
IC50 mode with fourfold serial dilution starting at 20 mM and
showed IC50 values of 25.2 and 1.61 nM against Abl1 and c-Src,
respectively. A number of compounds showed more than 50%
inhibition against Abl1 and c-Src. Among all the compounds
screened, compound 20 showed maximum enzyme inhibition
activity against both Abl1 and c-Src kinases. Compounds 13
and 14 did not show any inhibitory activity against c-Src
kinase.
Although imatinib is marketed as a drug in the form of its
mesylate salt, we have synthesized it in non-salt form for a
better in vitro comparison with the synthesized compounds.
Conclusions
A series of structurally varied novel PPAP amide derivatives
were designed, synthesized, and evaluated for their enzyme
inhibition activity against tyrosine kinases. The structures of
Table 1. Percentage of inhibition by compounds against
Abl1 and c-Src.
Normalized % inhibition
Compound
Abl1
c-Src
Table 2. IC50 values for compounds 14 and 20 against
Abl1, EGFR, c-Src, and Lck.
1
9
1
1
1
1
1
1
1
1
2
a
100.29
85.29
43.14
46.56
86.06
63.17
78.36
43.41
82.11
88.09
90.98
70.68
74.54
11.44
15.05
66.34
NA
NA
9.35
1.09
42.31
92.81
a)
IC50 (mM)
0
1
2
3
4
5
6
7
0
Compound
Abl1
EGFR
c-Src
Lck
b
14
20
8.39
2.67
0.27
99.70
NA
>50
NA
14.40
9.96
0.26
2.79
35.10
0.0029
Imatinib (1a)
Staurosporine
0.031
0.079
0.0014
a)
b)
All data were calculated based on triplicate assays;
No
significant inhibitory activity was observed at tested
concentration (data could not be fit to an IC50 curve).
All the experiments were performed in triplicate (ꢀ SD).
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The NMR and HRMS spectra (Figs. S1–S11) and InChI codes
along with biological activity details (Table S1) of the
investigated compounds are provided as Supporting
Information.
N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl)pyrimidin-2-
amine (7)
An oven dried round bottom flask was charged with
compound 4 (1 mmol), CuI (0.25 mmol), KI (2.0 mmol), K
2.0 mmol), and anhydrous dioxane under N atmosphere.
o-Bromo-p-nitrotoluene (1.0 mmol) synthesized from
p-nitrotoluene 5 following the literature report [43], and
DMEDA (0.25 mmol) were added to the reaction flask, the
reaction mixture was refluxed at 120°C for 15 h, then cooled
to room temperature. Concentrated ammonia (4 mL) and
brine (20 mL) were added to the reaction mixture and the
solution was filtered over Celite, extracted with ethyl acetate.
2 3
CO
(
2
6
Figure 3. Normalized viability of CCRF-CEM cells determined
after 72 h treatment of compounds at 50 mM concentration. The
untreated DMSO control was set to 100% viability. Doxorubicin
(
Dox) was applied at a concentration of (10 mM) and served as a
positive toxic control. All the experiments were performed in
triplicate (ꢀSD).
2 4
The organic layer was dried over anhydrous Na SO and
1
all the compounds were well established by FT-IR, H NMR,
concentrated in vacuum. The crude product was purified by
column chromatography on silica gel to give the desired
product as a pale-yellow solid in 55% yield, m.p.: 198–
201°C (lit.: 194–199°C) [29].
13
C NMR, and HRMS. In addition, the structure of a cyclic
amide was established on the basis of SCXRD data. Among the
0 novel amides synthesized, compound 20, a cyclic amide/
1
pyridin-2(1H)-one derivative exhibited an IC50 value better
than the drug imatinib against c-Src kinase, and compound 14
containing a 2-((4-methyl-2-oxo-2H-chromen-6-yl)oxy)acet-
amide demonstrated an IC50 value of 8.39 mM against Abl1
kinase. To the best of our knowledge this is the first report of
synthesis of cyclic amide (2-pyridone) derivative of PPAP and
its screening of kinase inhibition. The kinase inhibitory study
reflected the potency and selectivity of synthesized molecular
hybrids, which can serve as leads for further exploration and
development of kinase inhibitors.
6-Methyl-N-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-
diamine (8)
An oven dried round bottom flask was charged with N-(2-
methyl-5-nitrophenyl)-4-(pyridin-3-yl)pyrimidin-2-amine (7)
2
(3.2 mmol, 1 g) under N atmosphere, anhydrous methanol
(50 mL) was then added and the reaction mixture was stirred
for 10 min. Ammonium formate (55.3 mmol) and Pd/C
(100 mg) were added sequentially to the reaction mixture
under inert atmosphere. The reaction mixture was allowed to
stir for 4 h at 30°C. Completion of the reaction was confirmed
by the disappearance of the starting material using TLC. The
reaction mixture was filtered, the filtrate was concentrated,
and the residue was taken up in chloroform and the organic
layer was washed with water. The organic layer was collected
Experimental
Chemistry
General
2 4
and dried over anhydrous Na SO and the solvent was
All commercially available compounds were used as received
without further purification. All the solvents were distilled
and some even dried prior to their use. Reactions were
monitored by pre-coated TLC plates (Merck silica gel 60F254);
the spots were visualized either by UV light, or by spraying
with Ninhydrin stain solution. Silica gel (100–200 mesh) was
used for column chromatography. All of the chemicals and
reagents were procured from Spectrochem Pvt. Ltd., India and
Sigma–Aldrich, USA. Melting points (m.p.) were measured on
a B u€ chi M-560 equipment and are uncorrected. Infrared
removed under reduced pressure. The crude product was
then subjected to column chromatography over silica gel. The
pure diamine (8) was eluted in 1.5–2.5% methanol/chloro-
form as
a yellow solid in 80% isolated yield. m.p.:
142–144°C (lit.: 140–143°C) [29].
General procedure for the synthesis of amide derivatives
(9–17, 20, 21)
To the solution of an acid (2.7 mmol) in 10mL DMF, EDC.HCl
(2.1 mmol) and HOBt (2.1 mmol) were added sequentially at
0°C. After 30min, the amine 8 (1.8 mmol) was added, followed
by the addition of TEA (5.4 mmol) at 25–30°C. The reaction
mixture was allowed to stir for 24 h. The completion of reaction
was monitored by the disappearance of the amine on the TLC.
Thereaction mixture was concentrated under reducedpressure
to remove DMF. The residue was taken up in chloroform and
washed with cold water. The organic layer was washed with
saturated sodium bicarbonate solution, subsequently with 3%
spectra were recorded on a PerkinElmer SPECTRUM BX FTIR
1
and SPECTRUM XIFT IR spectrophotometer. The H and
1
3
C NMR spectra were recorded on a Jeol-400 (400 MHz,
00.5 MHz) NMR spectrometer using tetramethylsilane (TMS)
1
as an internal standard. The chemical shift values are on a d
scale and the coupling constant values (J) are in Hertz. The
HRMS data were recorded on Agilent 6210 ESI-TOF, Agilent
Technologies, Santa Clara, CA, USA.
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1
HCl solution and then with brine. The organic layer was dried
6
1424, 1408; H NMR (400 MHz, DMSO-d , d): 10.46 (s, 1H), 9.27
over anhydrous Na
2
SO
4
and the solvent was removed under
(d, 1H, J ¼ 1.53 Hz), 8.99 (s, 1H), 8.78 (d, 2H, J ¼ 5.34 Hz), 8.68
(d, 1H, J ¼ 4.58 Hz), 8.51 (d, 1H, J ¼ 5.34 Hz), 8.49–8.45 (m, 1H),
8.10 (s, 1H), 7.86 (d, 2H, J ¼ 4.58 Hz), 7.53–7.47 (m, 2H), 7.43
(d, 1H, J ¼ 4.58 Hz), 7.23 (d, 1H, J ¼ 8.39 Hz), 2.23 (s, 3H);
reduced pressure. The crude product was purified with column
chromatographyusingagradientofmethanol/chloroformover
silica gel.
1
3
6
C NMR (100.5 MHz, DMSO-d , d): 163.8, 161.6, 161.1, 159.5,
2
-(1H-Indol-3-yl)-N-(4-methyl-3-((4-(pyridin-3-yl)-
151.4, 150.2, 148.2, 142.0, 137.9, 136.6, 134.4, 132.2, 130.2,
pyrimidin-2-yl)amino)phenyl)acetamide (9)
Compound 9 was obtained as a brown solid in 89% yield; m.p.:
128.1, 123.8, 121.6, 117.1, 116.7, 107.6, 17.7; HRMS, m/z:
þ
calculated for C22
H
18 6
N O [MþH] 383.1615, found 383.1619.
ꢁ
1
2
1
1
01–203°C; IR (KBr, cm ): 3404, 3105, 1637, 1596, 1581, 1521,
1
480, 1437, 1401; H NMR (400 MHz, DMSO-d
6
, d): 10.90 (s, 1H),
(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-((4-
(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)penta-2,4-
dienamide (13)
0.04 (s, 1H), 9.25 (d, 1H, J ¼ 1.53 Hz), 8.91 (s, 1H), 8.66 (d, 1H,
J ¼ 4.58Hz), 8.48 (d, 1H, J ¼ 5.3 Hz), 8.44–8.41 (m, 1H), 7.93
(
s, 1H), 7.61 (d, 1H, J ¼ 7.63Hz), 7.42–7.38 (m, 2H), 7.35 (d, 1H,
Compound 13 was obtained as an off-white solid in 82%
ꢁ
1
J ¼ 8.39Hz), 7.32–7.29 (m, 1H), 7.26 (s, 1H), 7.13 (d, 1H,
J ¼ 8.39Hz), 7.08–7.04 (m, 1H), 6.98–6.95 (m, 1H), 3.72 (s, 2H),
yield; m.p.: 245–247°C; IR (KBr, cm ): 3448, 3256, 1648, 1615,
1
6
1582, 1533, 1451; H NMR (400 MHz, DMSO-d , d): 10.06 (s,
13
2
1
1
1
.18 (s, 3H); C NMR (100.5 MHz, DMSO-d
6
, d): 169.5, 161.5,
1H), 9.25 (d, 1H, J ¼ 1.53 Hz), 8.95 (s, 1H), 8.67 (d, 1H,
J ¼ 4.58 Hz), 8.49 (d, 1H, J ¼ 5.34 Hz), 8.44–8.46 (m, 1H), 7.95
(s, 1H), 7.53–7.50 (dd, 1H, J ¼ 8.39 Hz and 4.58 Hz), 7.42–7.37
(m, 2H), 7.32–7.25 (m, 2H), 7.15 (d, 1H, J ¼ 8.39 Hz), 7.01–6.90
(m, 4H), 6.28 (d, 1H, J ¼ 15.26 Hz), 6.04 (s, 2H), 2.10 (s, 3H);
61.1, 159.5, 151.3, 148.1, 137.8, 137.4, 136.1, 134.4, 132.2,
30.1, 127.2, 126.8, 123.9, 123.8, 121.0, 118.7, 118.4, 115.8,
15.4, 111.4, 108.7, 107.5, 39.0, 17.6; HRMS, m/z: calculated for
C
H N
26 22 6
O [MþH]þ 435.1928, found 435.1933.
1
3
6
C NMR (100.5 MHz, DMSO-d , d): 163.6, 161.6, 161.1, 159.4,
2
-(6-Methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)-N-(4-
151.4, 148.2, 147.9, 147.8, 140.7, 138.8, 137.8, 137.4, 134.4,
132.2, 130.8, 130.2, 127.1, 125.1, 124.5, 123.8, 122.9, 115.9,
methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-
acetamide (10)
Compound 10 was obtained as an off-white solid in 78% yield;
115.5, 108.4, 107.5, 105.7, 101.3, 17.6; HRMS, m/z: calculated
þ
for C28H N
23 5
O
3
[MþH] 478.1874, found 478.1883.
ꢁ
1
m.p.: 209–211°C; IR (KBr, cm ): 3435, 3268, 3052, 2959, 1677,
1
1
(
663, 1582, 1528, 1423; H NMR (400 MHz, DMSO-d
s, 1H), 9.17 (d, 1H, J ¼ 1.53 Hz), 8.86 (s, 1H), 8.61 (d, 1H,
J ¼ 4.58 Hz), 8.44 (d, 1H, J ¼ 4.88 Hz), 8.40–8.38 (m, 1H), 7.91 (s,
H), 7.37–7.31 (m, 3H), 7.21–7.16 (m, 3H), 7.11 (d, 1H,
J ¼ 8.54 Hz), 6.52 (s, 1H), 5.05 (s, 2H), 3.77 (s, 3H), 2.40
6
, d): 10.30
2-((4-Methyl-2-oxo-2H-chromen-6-yl)oxy)-N-(4-methyl-3-
((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acetamide
(14)
1
Compound 14 was obtained as light yellow solid in 56%
ꢁ
1
yield; m.p.: 237–239°C; IR (KBr, cm ): 3347, 2362, 1707, 1683,
1
3
1
(
s, 3H), 2.15 (s, 3H); C NMR (100.5 MHz, DMSO-d
6
, d): 165.6,
1576, 1533, 1415, 1247, 1171, 1058, 933, 872; H NMR
1
1
1
61.5, 161.0, 160.5, 159.4, 154.1, 151.2, 148.0, 146.7, 137.9,
36.8, 134.5, 133.9, 132.1, 130.2, 126.8, 123.7, 121.4, 120.4,
(400 MHz, DMSO-d
6
, d): 10.07 (s, 1H), 9.24 (d,1H, J ¼ 0.76 Hz),
8.96 (s, 1H), 8.67 (d, 1H, J ¼ 4.58 Hz), 8.50 (d, 1H, J ¼ 3.81 Hz),
8.45–8.43 (m, 1H), 7.94 (s, 1H), 7.49–7.46 (m, 1H), 7.42 (d, 1H,
J ¼ 5.34 Hz), 7.39–7.31 (m, 4H), 7.18 (d, 1H, J ¼ 7.63 Hz), 6.40
18.5, 116.2, 115.5, 115.1, 107.9, 107.5, 55.5, 44.9, 18.6, 17.6;
þ
HRMS, m/z: calculated for C29
found 507.2138.
H N
26 6
O
3
[MþH] 507.2139,
13
(s, 1H), 4.80 (s, 2H), 2.40 (s, 3H), 2.20 (s, 3H); C NMR
(
6
100.5 MHz, DMSO-d , d): 166.0, 161.5, 161.0, 159.8, 159.4,
N-(4-Methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-
phenyl)methoxypolyethyleneglycol amide (11)
154.1, 152.8, 151.3, 148.1, 147.5, 137.9, 136.2, 134.4, 132.1,
130.2, 127.7, 123.7, 120.1, 119.6, 117.5, 116.5, 116.1, 114.8,
Compound 11 was obtained as a colorless semi solid in 77% yield;
109.6, 107.5, 67.7, 18.1, 17.6; HRMS, m/z: calculated for
ꢁ1
1
þ
IR (KBr, cm ): 3311, 2874, 1677, 1577, 1528, 1447; H NMR
400 MHz, CDCl , d): 9.26 (s, 1H), 8.86 (s, 1H), 8.70 (d, 1H,
C
H N
28 23 5
O
4
[MþH] 494.1823, found 494.1828.
(
3
J¼ 3.81 Hz), 8.51–8.45 (m, 3H), 7.44–7.41 (dd, 1H, J¼ 7.63 Hz and
N-(2-((4-Methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-
phenyl)amino)-2-oxoethyl)benzamide (15)
5
.34 Hz), 7.25–7.23 (m, 1H), 7.18–7.16 (m, 1H), 4.13 (s, 2H),
13
3
,79–3.50 (m, 26H), 3.38–3.33 (m, 3H), 2.32 (s, 3H); C NMR
, d): 167.7, 162.2, 160.3, 158.8, 151.0, 148.2,
Compound 15 was obtained as light yellow solid in 72%
ꢁ
1
(100.5 MHz, CDCl
3
yield; m.p.: 150–152°C; IR (KBr, cm ): 3434, 3270, 2927, 2362,
1
1
7
37.3, 135.7, 134.6, 132.3, 130.3, 124.6, 123.4, 115.2, 113.4, 107.8,
1.5, 70.8, 70.2, 70.1, 70.0, 69.8, 58.7, 17.4.
1674, 1647, 1584, 1557, 1531, 1457; H NMR (400 MHz, DMSO-
6
d , d): 9.99 (s, 1H), 9.23 (s, 1H), 8.90 (s, 1H), 8.81 (t, 1H,
J ¼ 6.10 Hz), 8.64 (d, 1H, J ¼ 3.66 Hz), 8.49 (d, 1H, J ¼ 4.88 Hz),
8.46–8.44 (m,1H), 7.92–7.88 (m, 3H), 7.53–7.45 (m, 4H), 7.40 (d,
1H), 7.30–7.28 (dd, 1H, J ¼ 7.93 Hz and 1.83 Hz), 7.15 (d, 1H,
N-(4-Methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-
phenyl)isonicotinamide (12)
1
3
Compound 12 was obtained as an off-white solid in 90%
J ¼ 7.93 Hz), 4.05 (d, 2H, J ¼ 5.49 Hz), 2.18 (s, 3H); C NMR
ꢁ
1
yield; m.p.: 199–201°C; IR (KBr, cm ): 3231, 3103, 3043, 2371,
345, 1675, 1654, 1647, 1589, 1560, 1533, 1499, 1483, 1446,
6
(100.5 MHz, DMSO-d , d): 167.5, 166.6, 161.5, 161.0, 159.4,
2
151.2, 148.0, 137.8, 136.9, 134.4, 133.9, 132.1, 131.3, 130.1,
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1
28.2, 127.3, 126.8, 123.8, 115.8, 115.4, 107.5, 43.2, 17.5;
J ¼ 5.34 Hz), 8.47–8.46 (m, 1H), 8.38–8.36 (m, 1H), 8.05–8.04
(m, 1H), 7.87–7.84 (m, 1H), 7.65–7.61 (m, 1H), 7.44–7.41 (m,
1H), 7.36 (d, 1H, J ¼ 8.39 Hz), 7.23–7.22 (m, 1H), 7.14 (s, 1H),
þ
HRMS, m/z: calculated for C25
found 439.1878.
H N
22 6
O
2
[MþH] 439.1877,
7
.03–7.01 (m, 1H), 6.75–6.70 (m, 2H), 6.63–6.58 (m, 1H), 2.42 (s,
1
3
N-(4-Methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-
phenyl)-2-(3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)-
acetamide (16)
3H); C NMR (100.5 MHz, DMSO-d
J
6
, d): 193.7, 166.9 (d,
1
3
CF ¼ 256.87 Hz), 163.9 (d, JCF ¼ 14.30 Hz), 162.3, 161.9, 160.0,
4
159.1, 151.2, 148.2, 143.8, 138.9, 138.3 (d,
JCF ¼ 5.75 Hz),
3
Compound 16 was obtained as white solid in 74% yield; m.p.:
134.6, 133.6 (d,
JCF ¼ 11.5 Hz), 132.3, 131.2, 128.4, 123.7,
ꢁ
1
2
2
1
61–263°C, IR (KBr, cm ): 3449, 3274, 2360, 1683, 1670, 1552,
120.8, 120.5, 118.6, 117.2, 116.7, 108.6, 107.1 (d, JCF ¼ 23.00
1
2
532, 1402; H NMR (400 MHz, DMSO-d
6
, d): 10.26 (s, 1H), 9.22
Hz), 105.1 (d, JCF ¼ 23.96 Hz), 17.8; HRMS, m/z: calculated for
þ
(
1
7
d, 1H, J ¼ 1.83 Hz), 8.91 (s, 1H), 8.66 (d, 1H, J ¼ 3.05Hz), 8.48 (d,
C
28
H
20FN
5
O
3
[MþH] 494.1623, found 494.1614.
H,J ¼ 4.88Hz),8.45–8.43(m,1H),7.94(s,1H),7.43–7.40(m,2H),
.25–7.20 (dd, 1H, J ¼ 7.93Hz and 1.83 Hz), 7.15 (d, 1H,
N-(4-Methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-
phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide
(1a)
J ¼ 8.54Hz), 7.05–6.99 (m, 4H), 4.72 (s, 2H), 4.69 (s, 2H), 2.18
13
(
s, 3H); C NMR (100.5 MHz, DMSO-d
6
, d): 165.0, 164.5, 161.5,
1
1
1
61.0, 159.4, 151.3, 148.1, 144.5, 137.9, 136.6, 134.5, 132.2,
30.2, 129.1, 127.0, 123.7, 123.5, 122.7, 116.5, 115.6, 115.4,
Compound 1a was obtained as off-white solid in 62%
yield, m.p.: 201–204°C (lit.: 206–209°C); HRMS, m/z: calculated
þ
15.3, 107.6, 66.9, 44.1, 17.6; HRMS, m/z: calculated for
for C29H N
31 7
O [MþH] 494.2663, found 494.2668.
þ
C
H N O
26 22 6 3
[MþH] 467.1826, found 467.1839.
Biology
Kinase inhibitory activity assay
(
E)-N-(4-Methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-
phenyl)-3-(3,4,5-trimethoxyphenyl)acrylamide (17)
All the compounds were first screened in duplicate at 50mM for
Abl1 and c-Src kinase. Two potent compounds that showed
enzyme inhibition more than 60% were selected to test against
four kinases, in duplicate. Compounds were tested in a 10-dose
IC50 mode with threefold serial dilution starting at 50 mM.
Control compound, staurosporine, was tested in a 10-dose IC50
with fourfold serial dilution starting at 20 mM. All kinase
reactions were performed in the presence of 10mM ATP. The
compoundswerepre-incubatedwiththeenzymeandsubstrate
mixture about 20 min, and then P-ATP(specific activity 10mCi/
mL)wasaddedtostartthereaction.Thereactionwascarriedout
for 2 h at room temperature. Curve fits were performed when
the activities at the highest concentration of compounds were
less than 65%. The detailed procedure is given in Supporting
Information Table S1.
Compound 17 was obtained as off-white solid in 80%
ꢁ
1
yield; m.p.: 246–248°C. IR (KBr, cm ): 3347, 3270, 2926,
1
1
1
1
(
(
(
6
659; H NMR (400 MHz, DMSO-d , d): 10.16 (s, 1H), 9.27 (d,
H, J ¼ 1.53 Hz), 9.00 (s, 1H), 8.68 (d, 1H, J ¼ 4.58 Hz), 8.51 (d,
H, J ¼ 5.34 Hz), 8.46 (d, 1H, J ¼ 8.39 Hz), 7.98 (s, 1H), 7.54–7.50
m, 2H), 7.42 (d, 2H, J ¼ 5.34 Hz), 7.18 (d, 1H, J ¼ 8.39 Hz), 6.96
s, 2H), 6.78 (d, 1H, J ¼ 15.26 Hz), 3.83 (s, 6H), 3.69 (s, 3H), 2.20
13
6
s, 3H); C NMR (100.5 MHz, DMSO-d , d): 163.4, 161.7, 160.9,
3
3
1
1
1
59.3, 153.1, 151.3, 148.1, 140.0, 138.8, 137.9, 137.3, 134.4,
32.1, 130.3, 130.2, 127.3, 123.8, 121.7, 115.9, 115.5, 107.5,
27 5 4
05.0, 60.1, 55.8, 17.7; HRMS; m/z: calculated for C28H N O
[
MþH]þ 498.2136 found 498.2130.
5
-(2-Hydroxybenzoyl)-1-(4-methyl-3-((4-(pyridin-3-yl)-
pyrimidin-2-yl)amino)phenyl)pyridin-2(1H)-one (20)
Compound 20 was obtained as yellow solid in 60% yield; m.p.:
Cell culture and cell viability assay
Cell culture: Human leukemia cell line CCRF-CEM (ATCC no.
ꢁ
1
1
1
9
8
7
24–126°C; IR (KBr, cm ): 3270, 3053, 2925, 1671, 1582, 1445,
289; H NMR (400 MHz, DMSO-d , d): 10.32 (s, 1H), 9.24 (s, 1H),
6
.08 (s, 1H), 8.69 (d, 1H, J ¼ 4.58Hz), 8.50 (d, 1H, J ¼ 5.50Hz),
.47–8.43 (m, 1H), 7.92–7.88 (m, 2H), 7.78–7.77 (m, 1H), 7.52–
.47 (m, 2H), 7.37–7.33 (m, 3H), 7.12–7.10 (dd, 1H, J ¼ 9.16 Hz
1
CCL-119) purchased from American Type Culture Collection
2
Organization. 75 cm cell culture flasks were used to grow
cells using RPMI-16 medium. The medium was supplemented
with growth protein (10% fetal bovine serum), and antibiotics
(1% penicillin/streptomycin mixture, 10000 units of penicillin
and 10 mg of streptomycin in 0.9% NaCl). The environment
and 1.53Hz), 6.93–6.87 (m, 2H), 6.61 (d, 1H, J ¼ 9.16Hz), 2.31 (s,
13
3
1
1
1
6
H); C NMR (100.5 MHz, DMSO-d , d): 191.3, 161.4, 161.1,
60.6, 159.5, 155.5, 151.4, 148.0, 145.7, 138.7, 138.4, 138.0,
34.5, 132.7, 132.2, 132.0, 130.8, 129.9, 124.8, 123.9, 122.2,
21.8, 119.7, 119.3, 116.9, 116.5, 108.0, 17.8; HRMS; m/z:
2
was adjusted at CO (5%), air (95%) at 37°C.
Cell viability assay: In order to measure the cell viability,
CellTiter 96 aqueous one solution (Promega, USA) was
employed. In brief, when cells reached 75–80% degree of
confluency, 50000 cells/well were seeded in each well in
96-well microplate in 100 mL of RPMI-16 medium. This process
was followed by adding the compounds (50 mM) into each
well in triplicate in 96-well plate. As a positive control in this
assay, doxorubicin (Dox, 10 mM) was employed in terms of cell-
viability. After incubation period is over (72 h), a volume of
þ
calculated for C28
H N O
21 5 3
[MþH] 476.1717, found 476.1719.
5
3
-(4-Fluoro-2-hydroxybenzoyl)-1-(4-methyl-3-((4-(pyridin-
-yl)pyrimidin-2-yl)amino)phenyl)pyridin-2(1H)-one (21)
Compound 21 was obtained as off-white solid in 76%
ꢁ
1
yield; m.p.: 169–171°C; IR (CHCl
1
1
3
solution, cm ): 3005,
672, 1583, 1440, 1256; H NMR (400 MHz, DMSO-d , d):
2.03 (s, 1H), 9.23 (s, 1H), 8.69–8.68 (m, 1H), 8.52 (d, 1H,
1
6
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P. Manchanda et al.
ARC HH PHARM
Archiv der Pharmazie
2
0 mL of CellTiter 96 aqueous solution was added into each
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well. The plates were transferred into the incubator for 1 h
under humidified atmosphere at 37°C. After the incubation
time was over, microplate was employed to measure the
formazan absorbance at 490 nm. The wells containing cells
with no treatment were used as negative control. The results
of the assay were calculated as a percentage of the negative
control.
Crystallography
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A single crystal structure of compound 21 was collected on the
Oxford Diffraction Xcalibur CCD diffractometer with the
graphite monochromatic MoKa radiation (graphite crystal
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(
chloroform) within the voids was removed using the SQUEEZE
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F. For eꢀ , P. Coopman, B. W. Vanhoecke, T. Boterberg,
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The financial support from University of Delhi and Depart-
ment of Science and Technology (DST), Government of India
for DU-DST Purse Grant, and Chapman University School of
Pharmacy is gratefully acknowledged. The authors P.M. and
B.P. are thankful to SERB-DST and CSIR (Council of Scientific
and Industrial Research), respectively, for providing Junior
and Senior Research Fellowships. A.K. is thankful to University
Grants Commission (UGC) for providing Dr. DS Kothari Post-
Doctoral Fellowship. Also, we thank Dr. Himanshu Aggarwal,
Department of Chemistry and Polymer Science, University of
Stellenbosch, South Africa for assisting in solving and
analyzing the crystal data.
[19] K. Chand, A. N. Shirazi, P. Yadav, R. K. Tiwari, M. Kumari,
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The authors have declared no conflict of interest.
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www.archpharm.com
(8 of 9) e1600390

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Pyridylpyrimidinylaminophenyl Amides as Kinase Inhibitors
ARC HH PHARM
Archiv der Pharmazie
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