Design and synthesis of imidazo[4,5-c]pyridine derivatives as promising Aurora kinase A (AURKA) inhibitors

Article abstract of DOI:10.1134/S1070428016120198

Computer simulation at the PM7 level of theory of the structures of imidazo[4,5-c]pyridine derivatives (deaza analogs of purines) and their complexes with Aurora kinase A (AURKA) indicated prospects for their use as potential AURKA inhibitors in the treatment of oncological diseases. A number of new compounds of the selected imidazo[4,5-c]pyridine series, for which the highest inhibitory activity against AURKA was predicted, were synthesized in high yields for further biological testing.

Full text of DOI:10.1134/S1070428016120198

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 12, pp. 1822–1829. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © D.A. Lomov, S.N. Lyashchuk, M.G. Abramyants, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52, No. 12,
pp. 1828–1836.
Design and Synthesis of Imidazo[4,5-c]pyridine Derivatives
as Promising Aurora Kinase A (AURKA) Inhibitors
D. A. Lomov,* S. N. Lyashchuk, and M. G. Abramyants
Litvinenko Institute of Physical Organic Chemistry, ul. Rozy Lyuksemburg 70, Donetsk, 83000 Ukraine
*e-mail: lomov_dmitrii@mail.ru
Received June 28, 2016
Abstract—Computer simulation at the PM7 level of theory of the structures of imidazo[4,5-c]pyridine
derivatives (deaza analogs of purines) and their complexes with Aurora kinase A (AURKA) indicated prospects
for their use as potential AURKA inhibitors in the treatment of oncological diseases. A number of new
compounds of the selected imidazo[4,5-c]pyridine series, for which the highest inhibitory activity against
AURKA was predicted, were synthesized in high yields for further biological testing.
DOI: 10.1134/S1070428016120198
About 6 million new cancer occurrences is regis-
tered worldwide annually, and this situation remains
unchanged over the past two decades. Although cancer
and other malignant oncological diseases constitute 5–
10% of all cases of somatic diseases, they follow next
to cardiovascular disorders with respect to mortality.
hesperadin-induced inhibition of the catalytic activity
of these enzymes has shown [9] that the drug blocks
active site of the enzyme. At present, some leading
pharmaceutical companies perform extensive search
for new Aurora kinase inhibitors with the goal of
creating new-generation anticancer drugs [10]. Cur-
rently known Aurora kinase inhibitors are represented
by various heterocyclic structures; some compounds,
e.g., 2–6, are now under clinical trials [4, 11].
In 1994–1997, three new kinases overexpressed in
cancer have been identified in dividing cells of warm-
blooded by PCR (polymerase chain reaction) [1].
Aurora kinases belong to a small family of serine/
threonine protein kinases, which includes three
enzymes: Aurora kinase A (AURKA), Aurora kinase B
(AURKB), and Aurora kinase C (AURKC) [2–4].
These enzymes are involved in the most important
molecular events in all stages of cell mitosis [5].
Considerable increase of the concentration of AURKA
and AURKB induces nondisjunction, so that some
cells degrade and die, while the others degenerate to
tumor cells with a high probability [6]. It was shown
experimentally that increased concentrations of Aurora
kinases largely determine the development of many
types of stomach, liver, and rectal cancers, some breast
and pancreatic cancers, as well as of leukemia [2].
Thus, detection of increased AURKA and AURKB
contents is an important diagnostic test for carcino-
genic process or precancer state [7].
In recent years, while searching for new kinase
inhibitors, researchers’ attention has been focused on
imidazo[4,5-b]pyridine derivatives [12, 13]. Com-
pounds 5 and 6 showed a pronounced inhibitory effect
against AURKA, and the magnitude of this effect may
change by 1‒2 orders upon insignificant structural
modification of the inhibitor molecule [14, 15]. These
data indicate high selectivity of binding to the enzyme
active site. Analogous studies of imidazo[4,5-c]pyri-
dine derivatives as Aurora kinase inhibitors have not
been reported in the literature. Taking into account that
imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine are
the closest structural analogs, the latter are expected to
exhibit similar biological properties, in particular with
respect to various kinases.
The inhibitory activity of a series of imidazo-
[4,5-c]pyridine derivatives against AURKA was
quantitatively assessed by computational methods (in
silico), followed by directed synthesis of compounds
with the highest predicted activity.
The new drug hesperadin (1) has recently been
introduced into clinical practice; it is capable of
suppressing excess activity of AURKA and AURKB
in tumor tissues [8]. Study of the mechanism of
1822

DESIGN AND SYNTHESIS OF IMIDAZO[4,5-c]PYRIDINE DERIVATIVES
1823
Me
O
HN
N
H
N
O
N
Me
N
N
O
S
NH
N
O
NH
N
N
N
S
Me
H
H
1
2, VX-680
O
N
O
NH
HN
N
OMe
O
NH
N
N
O
N
N
NH
N
H
Me
N
HN
3, PHA-739358
4, AT-9283
Me
O
Me
N
S
N
Me
N
O
N
N
NH
N
N
Me
N
N
N
N
NH
NH
Br
Cl
N
N
5, CCT-137690
6, CCT-129202
In the first step, as subjects for the study we
selected a sample consisting of 24 imidazo[4,5-c]pyri-
dines 7‒30 as potential ligands for AURKA inhibition.
The choice was based on the drug likeness approach
implying that structurally related compounds may
possess similar biological properties. In our case, the
closest analogs of compounds 7‒30 are imidazo-
[4,5-b]pyridine derivatives [12–15].
obtaining more complex analogs through variation and
modification of substituents therein.
An alternative approach to prediction of potential
effect of compounds on cellular processes is provided
by Molinspiration on-line service (version 2004.1)
[17]. This software is based on a huge, continuously
updated database, and it makes it possible not only to
determine whether a compound fits Lipinski’s rules but
also to predict in silico with a high probability some
An empirical approach based on Lipinski’s rules
[16] has found wide application in the design of new
drugs since it allows considerable contraction of the
series of compounds to be studied. According to
Lipinski’s rules, a compound could be a drug if its
molecule contains no more than 5 donor centers
capable of forming hydrogen bonds (OH and NH
groups), no more than 10 hydrogen bond acceptor
centers (N, O), and no more than 15 nonterminal freely
rotating bonds; furthermore, its molecular weight
should be lower than 500, and the octanol–water parti-
tion coefficient logP should be lower than 5. All com-
pounds 7‒30 conform to Lipinski’s rules, and there are
some “reserves” regarding the molecular composition
and properties, which provide the possibility of
O
N
NH
N
R2
X
3N
2
N
4
1N
5N
R1
6
7
7–30
7, 10, 13, 16, 19, 22, 25, 28, X = NH; 8, 11, 14, 17, 20, 23,
26, 29, X = S; 9, 12, 15, 18, 21, 24, 27, 30, X = O; 7–9, 13–
15, 19–21, 25–27, R1 = H; 10–12, 16–18, 22–24, 28–30,
R1 = Me; 7–12, R2 = NMe2; 13–18, R2 = MeO; 19–24,
R2 = Cl; 25–30, R2 = Br.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 12 2016

LOMOV et al.
1824
biological properties of imidazo[4,5-c]pyridine deriva-
tives. The results of the Molinspiration predictions for
compounds 7–30 are given in Table 1.
of molecules 7–30 and their complexes with AURKA.
The calculated parameters given in Table 2 may be
used as descriptors in the assessment of the inhibitory
activity of the ligands against enzymes.
All compounds 7–30 could both activate and inhibit
proteases (IP ‒0.15 to 0.20), modulate and demodulate
ion channels (MIC ‒0.21 to 0.20), and inhibit cellular
enzymes in total (IE 0.02–0.40); however, the prob-
ability of these properties is not high (≤40%). They are
also capable of acting as medium-strength nuclear
receptor activators (NRL ‒0.17 to ‒0.51) and inhibit
transmembrane receptors (GPCR varies over a wide
range from 0.06 to 0.58). The most probable property
is the ability to inhibit kinases (IK 0.23–0.56).
The dipole moments of 7‒30 vary over a wide
range (4.66–12 D) and strongly depend on the substit-
uents in the imidazopyridine fragment. The negative
charge is localized on the nitrogen atom of that frag-
ment, and variation of the substituents exerts an ap-
preciable effect only on the N1 atom: q(N1) ‒0.432 to
‒0.295, q(N2) ‒0.437 to ‒0.366, q(N3) ‒0.550 to
‒0.509 a.u. The positive charge is localized on the
carbon atoms. The absolute electronegativities
EN 4.05–4.81 and the absolute hardnesses η 7.26‒7.81
calculated from the HOMO and LUMO energies [20]
are typical of nitrogen-containing heterocyclic systems
capable of being involved in donor–acceptor interac-
By semiempirical quantum chemical calculations at
the PM7 level of theory [18] using MOPAC2012
version 15.281W [19] we obtained more detailed
information on the structure and electronic properties
Table 1. Some biological activitiesa of compounds 7‒30 predicted by Molinspiration (version 2004.1)
Compound no.
IK
MIC
GPCR
NRL
IP
IE
07
08
09
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
0.53
0.44
0.56
0.39
0.27
0.39
0.49
0.40
0.52
0.35
0.23
0.35
0.52
0.43
0.56
0.37
0.25
0.37
0.50
0.41
0.54
0.35
0.23
0.35
0.06
–0.07–
0.16
0.42
0.17
0.54
0.39
0.13
0.49
0.41
0.15
0.53
0.37
0.10
0.47
0.46
0.19
0.58
0.41
0.14
0.52
0.38
0.11
0.51
0.34
0.06
0.45
–0.25
–0.39
–0.17
–0.26
–0.39
–0.18
–0.28
–0.42
–0.19
–0.29
–0.42
–0.20
–0.29
–0.44
–0.20
–0.30
–0.44
–0.21
–0.37
–0.51
–0.28
–0.37
–0.51
–0.28
0.04
–0.06–
0.14
0.22
0.12
0.39
0.17
0.06
0.32
0.20
0.10
0.38
0.15
0.04
0.31
0.22
0.12
0.40
0.16
0.05
0.33
0.19
0.09
0.37
0.13
0.02
0.30
–0.04–
–0.17–
0.05
–0.03–
–0.13–
0.07
0.02
0.02
–0.10–
0.13
–0.09–
0.12
–0.07–
–0.21–
0.02
–0.05–
–0.15–
0.05
0.08
0.04
–0.05–
0.20
–0.08–
0.14
–0.02–
–0.16–
0.08
–0.04–
–0.15–
0.07
0.03
–0.02–
–0.13–
0.09
–0.10–
0.14
–0.08–
–0.21–
0.02
–0.10–
0.20
0.01
a
IK stands for kinase inhibition; MIC stands for ion channel modulation; GPCR (G protein-coupled receptors) stands for ligand binding to
seven-transmembrane receptors; NRL stands for ligand binding to nuclear receptors; IP stands for protease inhibition; IE stands for
enzyme inhibition. Negative sign of the biological activity indices indicates activation of the respective bioprocess.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 12 2016

DESIGN AND SYNTHESIS OF IMIDAZO[4,5-c]PYRIDINE DERIVATIVES
1825
Table 2. Heats of formation, dipole moments, effective charges on some atoms, and frontier orbital energies of compounds
7–30, calculated by the PM7 method (MOPAC2012)
Effective charges on atoms, a.u.
Energy, eV
Comp.
no.
ΔHf,
kJ/mol
μ, D
N1
C2
N3
C4
N5
C6
HOMO
LUMO
07
08
09
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
339.77
353.27
262.32
357.65
348.10
259.52
165.86
223.52
076.35
145.39
219.72
072.78
302.08
375.39
228.38
321.79
310.34
224.04
356.91
430.14
283.22
352.25
367.43
278.86
06.71
07.24
10.82
09.91
08.08
12.00
06.97
09.22
09.15
07.32
09.84
09.60
04.58
07.42
07.45
06.22
05.89
08.50
04.66
07.42
07.50
05.54
05.70
08.55
–0.422
–0.423
–0.432
–0.316
–0.306
–0.316
–0.427
–0.429
–0.428
–0.310
–0.316
–0.312
–0.419
–0.420
–0.420
–0.305
–0.295
–0.304
–0.418
–0.419
–0.420
–0.303
–0.296
–0.304
0.299
0.313
0.292
0.267
0.298
0.271
0.267
0.272
0.267
0.253
0.264
0.252
0.244
0.246
0.242
0.221
0.255
0.229
0.242
0.244
0.241
0.228
0.256
0.227
–0.406
–0.437
–0.401
–0.384
–0.439
–0.390
–0.376
–0.394
–0.385
–0.383
–0.400
–0.385
–0.369
–0.379
–0.372
–0.366
–0.422
–0.376
–0.369
–0.378
–0.373
–0.372
–0.422
–0.376
0.408
0.409
0.402
0.419
0.410
0.406
0.413
0.403
0.408
0.410
0.398
0.408
0.413
0.406
0.412
0.428
0.414
0.411
0.413
0.407
0.411
0.413
0.414
0.411
–0.517
–0.518
–0.527
–0.546
–0.518
–0.528
–0.531
–0.519
–0.529
–0.524
–0.509
–0.529
–0.524
–0.522
–0.530
–0.550
–0.518
–0.530
–0.521
–0.523
–0.529
–0.524
–0.519
–0.530
0.139
0.143
0.147
0.149
0.138
0.143
0.147
0.151
0.154
0.141
0.141
0.148
0.153
0.157
0.160
0.161
0.145
0.153
0.153
0.158
0.159
0.146
0.145
0.152
–7.91
–8.12
–8.05
–7.90
–8.05
–8.06
–8.22
–8.34
–8.31
–8.24
–8.29
–8.22
–8.44
–8.46
–8.42
–8.14
–8.29
–8.32
–8.43
–8.46
–8.42
–8.33
–8.29
–8.32
–0.36
–0.37
–0.50
–0.21
–0.25
–0.25
–0.67
–0.83
–0.70
–0.57
–0.63
–0.52
–1.08
–1.16
–1.05
–0.88
–0.72
–0.92
–1.09
–1.17
–1.06
–0.93
–0.75
–0.92
tions. According to the X-ray diffraction data for
AURKA complexes with different inhibitors, Aurora
kinase is an enzyme containing 402 amino acid resi-
dues and N- and C-terminal domains.
cules and complex macromolecular assemblies was
applied). The corresponding inhibitor with an IK index
of larger than 0.35 (which rendered it sufficiently
active) was then placed into the active site, and the
structure of the complex was optimized. All enthalpies
of formation (Table 2) were calculated for the op-
timized structures.
The AURKA complexes with potential inhibitors
7–30 were calculated in several steps. In the first step,
the ligand was removed from the active site of the
known AURKA complex with 4-{[2-(4-{[(4-fluoro-
phenyl)carbonyl]amino}-1H-pyrazol-3-yl)-1H-benz-
imidazol-6-yl]methyl}morpholin-4-ium cation [21],
whose structure was determined by X-ray analysis
(RCSB Protein Data Bank ID: 2W1C), using Accelrys
Discovery Studio 3.5 program. The structure of the
protein molecule thus obtained was taken as the initial
approximation and was optimized by PM7 semiem-
pirical quantum chemical calculations (MOPAC2012;
MOZYME module for the calculation of protein mole-
As an example, Fig. 1 shows the calculated struc-
ture of the AURKA complex with compound 11. The
inhibitor molecule binds to the enzyme active site and
is held thereon, thus leading to inactivation of the
kinase in the cell division process. The stability of the
protein–inhibitor complex is determined by the energy
of its formation (exothermic process). Furthermore,
ligand docking induces change of the secondary
protein structure in the regions adjacent to the active
site, which should also favor enzyme deactivation.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 12 2016

LOMOV et al.
1826
Edoc = ΔHfAURKA–L ‒ (ΔHfAURKA + ΔHfL).
(1)
O
N
S
NH
N
The calculated protein–ligand docking energy is
linearly related to the kinase inhibition index IK
determined by Molinspiration 2004.1 (Fig. 2) through
Eq. (2):
NMe2
N
N
N
N
Me
Edoc = (1.31±1.36) – (29.57±2.92)IK;
r2 = 0.871, s0 = 8.32.
(2)
11
Our results indicated that all compounds 7–30 are
capable of binding to the AURKA active site to greater
or lesser extent. This especially applies to those pos-
sessing no methyl group on the nitrogen atom of the
imidazopyridine fragment. Elongation of the alkyl
substituent strongly reduces Edoc in absolute value due
to considerable steric hindrances to approach of the
inhibitor molecule to the active site and holding it
therein.
For further biological testing we synthesized six
imidazo[4,5-c]pyridine derivatives 7, 9, 15, 19, 21, and
27 for which the highest inhibitory activity against
AURKA was predicted. The key intermediate products
for the synthesis of these compounds were 2-chloro-
pyridine-3,4-diamine (31) [22], N-(1H-imidazol-2-yl)-
2-(piperazin-1-yl)acetamide (32), and N-(1,3-oxazol-2-
yl)-2-(piperazin-1-yl)acetamide (33). Acetamides 32
and 33 were synthesized in 72–83% yield by heating
N-imidazolyl- and N-oxazolylchloroacetamides 34 and
35 with piperazine hydrochloride (prepared in situ) in
N-Terminal domain
C-Terminal domain
Fig. 1. Optimized structure of the Aurora kinase A complex
with inhibitor 11 bound to the active site.
Edoc, kcal/mol
24
22
1
26
–10
–12
–14
–16
ethanol (Scheme 1). In the H NMR spectra of 32 and
33, signals of the piperazine fragment appeared as two
singlets as δ 2.70‒2.83 and 3.03‒3.12 ppm.
10
12
20
14
13
2-Chloropyridine-3,4-diamine (31) reacted with
para-substituted benzoic acids 36‒39 in phosphoryl
chloride at 130‒140°C to give 4-chloro-2-phenyl-3H-
imidazo[4,5-c]pyridines 40‒43 in 50–64% yield
(Scheme 2). Compounds 40‒43 displayed in the
1H NMR spectra signals from protons of the pyridine
ring as two doublets at δ 7.57‒7.62 and 7.93‒
8.25 ppm, and protons of the para-substituted benzene
ring resonated at δ 6.83‒7.81 and 8.04‒8.24 ppm.
8
25
15
27
19
21
7
0.35
0.40
0.45
0.50
0.55
IK
Fig. 2. Correlation of the docking energy (Edoc) with the
kinase inhibitory activity (IK) of compounds 7–10, 12–15,
19–22, and 24–27, calculated by Molinspiration program
(version 2004.1).
By reacting 4-chloro-2-phenylimidazo[4,5-c]pyri-
dine derivatives 40‒43 with acetamides 32 and 33 on
heating in ethanol in the presence of triethylamine we
obtained compounds 7, 9, 15, 19, 21, and 27 in 52–
78% yield (Scheme 3). Analogous compounds were
synthesized in [23] under similar conditions. In the
1H NMR spectra of 7, 9, 15, 19, 21, and 27 we
observed doublets at δ 7.58–8.28 and 7.59–7.94 ppm
due to protons in the pyridine ring, doublets at δ 6.81–
The docking energy Edoc for individual compounds
was calculated as the difference in the enthalpy of
formation of the complex ΔHfAURKA–L and the sum of
the enthalpies of formation of unbound AURKA
(ΔHfAURKA) and the corresponding ligand ΔHfL (1):
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 12 2016

DESIGN AND SYNTHESIS OF IMIDAZO[4,5-c]PYRIDINE DERIVATIVES
1827
Scheme 1.
O
O
N
NH
N
X
+
· HCl
NH
N
NH
Cl
HN
X
NH
34, 35
32, 33
32, 34, X = NH; 32, 35, X = O.
Scheme 2.
NH2
NH2
COOH
POCl3
N
+
R
N
N
N
H
R
Cl
Cl
31
36–39
40–43
36, 40, R = Me2N; 37, 41, R = MeO; 38, 42; R = Cl; 39, 43, R = Br.
Scheme 3.
O
N
NH
N
R
O
X
N
N
X
N
N
Et3N
R
NH
N
+
N
N
H
N
N
Me
NH
Cl
32, 33
40–43
7, 9, 15, 19, 21, 27
7, 19, 32, X = NH; 9, 15, 21, 27, 33, X = O; 7, 9, 40, R = Me2N; 15, 41, R = MeO; 19, 21, 42, R = Cl; 27, 43, R = Br.
7.81 and 8.06‒8.26 ppm due to protons of the benzene
ring, and signals of protons in the piperidine and azole
rings.
chloride monohydrate was added, and the mixture was
heated with stirring until it became homogeneous.
A solution of chloroacetamide 34 or 35 in 10 mL of
propan-1-ol was added to the resulting solution of
piperazine hydrochloride, and the mixture was heated
for 2 h at 80‒90°C and cooled. The precipitate of
piperazine dihydrochloride was filtered off and washed
on a filter with 5 mL of propan-1-ol. The filtrate was
evaporated to 1/3 of the initial volume and filtered
while hot. Compounds 32 and 33 crystallized from the
filtrate on cooling.
Thus, computer simulation of deaza analogs of
purine bases, imidazo[4,5-c]pyridine derivatives, and
their complexes with AURKA indicates prospects of
their use as potential inhibitors of this key enzyme for
oncological practice.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
N-(1H-Imidazol-2-yl)-2-(piperazin-1-yl)acet-
1
Avance II 400 spectrometer at 400 MHz using
DMSO-d6 as solvent and tetramethylsilane as internal
standard. The purity of the isolated compounds was
checked by TLC on Silufol UV-254 plates using
methanol–chloroform (1 :10) as eluent; spots were
visualized by treatment with iodine vapor or under
UV light.
amide (32). Yield 83%, mp 107‒109°C. H NMR
spectrum, δ, ppm: 2.83 s (4H, CH2NHCH2), 3.12 s
(4H, CH2NCH2), 3.44 (2H, CH2), 7.12 s (2H, 4-H,
5-H), 11.92 br.s (1H, NH). Found, %: C 51.61;
H 7.25; N 33.41. C9H15N5O. Calculated, %: C 51.66;
H 7.23; N 33.47.
N-(1,3-Oxazol-2-yl)-2-(piperazin-1-yl)acetamide
1
(33). Yield 72%, mp 79‒81°C. H NMR spectrum,
Compounds 32 and 33 (general procedure).
Piperazine hexahydrate, 10 mmol, was dissolved in
10 mL of propan-1-ol, 10 mmol of piperazine dihydro-
δ, ppm: 2.70 s (4H, CH2NHCH2), 3.03 s (4H,
CH2NCH2), 3.32 (2H, CH2), 7.38 d (1H, 4-H, J =
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 12 2016

LOMOV et al.
1828
4.0 Hz), 7.73 d (1H, 5-H, J = 4.0 Hz), 11.92 br.s (1H,
NH). Found, %: C 51.37; H 6.72; N 26.47. C9H14N4O2.
Calculated, %: C 51.42; H 6.71; N 26.65.
2-(4-{2-[(4-Dimethylamino)phenyl]-1H-imidazo-
[4,5-c]pyridin-4-yl}piperazin-1-yl)-N-(1H-imidazol-
2-yl)acetamide (7). Yield 62%, mp 183‒185°C (from
1
EtOH). H NMR spectrum, δ, ppm: 2.85 s (4H,
Compounds 40‒43 (general procedure). A mixture
of 3 mmol of 2-chloropyridine-3,4-diamine 31 and
3 mmol of para-substituted benzoic acid 36‒39 in
4 mL of phosphoryl chloride was heated for 3‒3.5 h at
130‒135°C. Vigorous evolution of hydrogen chloride
was observed. When the reaction was complete, excess
POCl3 was distilled off, the residue was treated with
cold water, and the precipitate was filtered off, dried,
and recrystallized from appropriate solvent.
CH2NCH2), 3.03 s [6H, N(CH3)2], 3.10 s (4H,
CH2NCH2), 3.41 (2H, CH2), 6.81 d (2H, 3′-H, 5′-H,
J = 8.0 Hz), 7.10 s (2H, 4″-H, 5″-H), 7.60 d (1H,
7-H, J = 8.0 Hz), 8.07 d (2H, 2′-H, 6′-H, J = 8.0 Hz),
8.23 d (1H, 6-H, J = 8.0 Hz). Found, %: C 61.98;
H 6.16; N 28.27. C23H27N9O. Calculated, %: C 62.01;
H 6.11; N 28.30.
2-(4-{2-[(4-Dimethylamino)phenyl]-1H-imidazo-
[4,5-c]pyridin-4-yl}piperazin-1-yl)-N-(1,3-oxazol-2-
yl)acetamide (9). Yield 63%, mp 152–154°C (from
4-(4-Chloro-3H-imidazo[4,5-c]pyridin-2-yl)-N,N-
dimethylaniline (40). Yield 64%, mp 245–247°C
1
1
EtOH). H NMR spectrum, δ, ppm: 2.75 s (4H,
(from PrOH). H NMR spectrum, δ, ppm: 3.01 s [6H,
CH2NCH2), 2.99 s [6H, N(CH3)2], 3.05 s (4H,
CH2NCH2), 3.37 (2H, CH2), 6.87 d (2H, 3′-H, 5′-H,
J = 8.0 Hz), 7.37 d (1H, 4″-H, J = 4.0 Hz), 7.63 d (1H,
7-H, J = 8.0 Hz), 7.75 d (1H, 5″-H, J = 4.0 Hz), 8.06 d
(2H, 2′-H, 6′-H, J = 8.0 Hz), 8.28 d (1H, 6-H, J =
8.0 Hz). Found, %: C 61.49; H 5.91; N 25.01.
C23H26N8O2. Calculated, %: C 61.87; H 5.87; N 25.10.
N(CH3)2], 6.83 d (2H, 3′-H, 5′-H, J = 8.0 Hz), 7.62 d
(1H, 7-H, J = 8.0 Hz), 8.04 d (2H, 2′-H, 6′-H, J =
8.0 Hz), 8.25 d (1H, 6-H, J = 8.0 Hz). Found, %:
C 61.60; H 4.82; N 20.51. C14H13ClN4. Calculated %:
C 61.65; H 4.80; N 20.54.
4-Chloro-2-(4-methoxyphenyl)-3H-imidazo-
[4,5-c]pyridine (41). Yield 54%, mp 163‒165°C (from
1
2-{4-[2-(4-Methoxyphenyl)-1H-imidazo[4,5-c]-
pyridin-4-yl]piperazin-1-yl}-N-(1,3-oxazol-2-yl)-
acetamide (15). Yield 78%, mp 193‒195°C (from
H2O). H NMR spectrum, δ, ppm: 3.85 s (3H, OCH3),
7.15 d (2H, 3′-H, 5′-H, J = 8.0 Hz), 7.57 d (1H, 7-H,
J = 8.0 Hz), 8.09 d (1H, 6-H, J = 8.0 Hz), 8.18 d (2H,
2′-H, 6′-H, J = 8.0 Hz). Found, %: C 60.10; H 3.92;
N 16.14. C13H18ClN3O. Calculated, %: C 60.12;
H 3.88; N 16.18.
1
PrOH). H NMR spectrum, δ, ppm: 2.72 s (4H,
CH2NCH2), 3.03 s (4H, CH2NCH2), 3.37 (2H, CH2),
3.85 s (3H, OCH3), 7.14 d (2H, 3′-H, 5′-H, J = 8.0 Hz),
7.37 d (1H, 4″-H, J = 4.0 Hz), 7.59 d (1H, 7-H, J =
8.0 Hz), 7.75 d (1H, 5″-H, J = 4.0 Hz), 8.04 d (1H,
6-H, J = 8.0 Hz), 8.14 d (2H, 2′-H, 6′-H, J = 8.0 Hz).
Found, %: C 60.90; H 5.39; N 21.44. C22H23N7O3.
Calculated, %: C 60.96; H 5.35; N 22.62.
4-Chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-c]-
pyridine (42). Yield 53%, mp 243‒245°C (from
1
PrOH). H NMR spectrum, δ, ppm: 7.57 d (1H, 7-H,
J = 8.0 Hz), 7.68 d (2H, 3′-H, 5′-H, J = 8.0 Hz), 7.93 d
(1H, 6-H, J = 8.0 Hz), 8.24 d (2H, 2′-H, 6′-H, J =
8.0 Hz). Found, %: C 54.53; H 2.69; N 15.87.
C12H7Cl2N3. Calculated, %: C 54.57; H 2.67; N 15.91.
2-{4-[2-(4-Chlorophenyl)-1H-imidazo[4,5-c]-
pyridin-4-yl]piperazin-1-yl}-N-(1H-imidazol-2-yl)-
acetamide (19). Yield 52%, mp 207‒209°C (from
2-(4-Bromophenyl)-4-chloro-3H-imidazo[4,5-c]-
pyridine (43). Yield 50%, mp 268‒270°C (from
1
PrOH). H NMR spectrum, δ, ppm: 2.83 s (4H,
1
CH2NCH2), 3.12 s (4H, CH2NCH2), 3.47 (2H, CH2),
7.16 s (2H, 4″-H, 5″-H), 7.72 d (2H, 3′-H, 5′-H, J =
8.0 Hz), 7.94 d (1H, 6-H, J = 8.0 Hz), 8.26 d (2H,
2′-H, 6′-H, J = 8.0 Hz), 7.58 d (1H, 7-H, J = 8.0 Hz).
Found, %: C 57.65; H 4.87; N 25.58. C21H21ClN8O.
Calculated, %: C 57.73; H 4.84; N 25.65.
PrOH). H NMR spectrum, δ, ppm: 7.60 d (1H, 7-H,
J = 8.0 Hz), 7.81 d (2H, 3′-H, 5′-H, J = 8.0 Hz), 8.13 d
(1H, 6-H, J = 8.0 Hz), 8.15 d (2H, 2′-H, 6′-H, J =
8.0 Hz). Found, %: C 46.68; H 2.31; N 13.58.
C12H7BrClN3. Calculated, %: C 46.71; H 2.29; N 13.62.
Condensation of compounds 40–43 with acet-
amides 32 and 33 (general procedure). A mixture of
0.4 mmol of compound 40–43, 0.4 mmol of acetamide
32 or 33, 0.5 mL of propan-1-ol, and 0.3 mL of
triethylamine was heated for 4‒5 h at 110‒120°C. The
mixture was evaporated to dryness, the residue was
treated with water, and the precipitate was filtered off,
dried, and recrystallized from appropriate solvent.
2-{4-[2-(4-Chlorophenyl)-1H-imidazo[4,5-c]-
pyridin-4-yl]piperazin-1-yl}-N-(1,3-oxazol-2-yl)-
acetamide (21). Yield 52%, mp 173‒175°C (from
1
PrOH). H NMR spectrum, δ, ppm: 2.69 s (4H,
CH2NCH2), 3.03 s (4H, CH2NCH2), 3.35 (2H, CH2),
7.37 d (1H, 4″-H, J = 4.0 Hz), 7.59 d (1H, 7-H, J =
8.0 Hz), 7.68 d (2H, 3′-H, 5′-H, J = 8.0 Hz), 7.71 d
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DESIGN AND SYNTHESIS OF IMIDAZO[4,5-c]PYRIDINE DERIVATIVES
1829
11. Yan, A., Wang, L., Xu, Sh., and Xu, J., Drug Discovery
Today, 2011, vol. 16, p. 261.
(1H, 5″-H, J = 4.0 Hz), 7.95 d (1H, 6-H, J = 8.0 Hz),
8.23 d (2H, 2′-H, 6′-H, J = 8.0 Hz). Found, %:
C 57.56; H 4.62; N 22.37. C21H20ClN7O2. Calculated,
%: C 57.60; H 4.60; N 22.39.
12. Bavetsias, V., Large, J.M., Sun, Ch., Bouloc, N.,
Kosmopoulou, M., Matteucci, M., Wilsher, N.E.,
Martins, V., Reynisson, J., Atrash, B., Faisal, A.,
Urban, F., Valenti, M., de Haven Brandon, A., Box, G.,
Raynaud, F.I., Workman, P., Eccles, S.A., Bayliss, R.,
Blagg, J., Linardopoulos, S., and McDonald, E., J. Med.
Chem., 2010, vol. 53, p. 5213.
2-{4-[2-(4-Bromophenyl)-1H-imidazo[4,5-c]pyri-
din-4-yl]piperazin-1-yl}-N-(1,3-oxazol-2-yl)acet-
amide (27). Yield 78%, mp 212‒214°C (from PrOH).
1H NMR spectrum, δ, ppm: 2.72 s (4H, CH2NCH2),
3.05 s (4H, CH2NCH2), 3.34 (2H, CH2), 7.37 d (1H,
4″-H, J = 4.0 Hz), 7.62 d (1H, 7-H, J = 8.0 Hz), 7.73 d
(1H, 5″-H, J = 4.0 Hz), 7.81 d (2H, 3′-H, 5′-H, J =
8.0 Hz), 8.11 d (2H, 2′-H, 6′-H, J = 8.0 Hz), 8.15 d
(1H, 6-H, J = 8.0 Hz). Found, %: C 52.21; H 4.23;
N 20.29. C21H20BrN7O2. Calculated, %: C 52.29;
H 4.18; N 20.33.
13. Lan, P., Chen Wan-Na, and Chen Wei-Min, Eur. J. Med.
Chem., 2011, vol. 46, p. 77.
14. Bavetsias, V., Crumpler, S., Sun, Ch., Avery, S.,
Atrash, B., Faisal, A., Moore, A.S., Kosmopoulou, M.,
Brown, N., Sheldrake, P.W., Bush, K., Henley, A.,
Box, G., Valenti, M., de Haven Brandon, A.,
Raynaud, F.I., Workman, P., Eccles, S.A., Bayliss, R.,
Linardopoulos, S., and Blagg, J., J. Med. Chem., 2012,
vol. 55, p. 8721.
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