Novel imatinib derivatives with altered specificity between Bcr-Abl and FMS, KIT, and PDGF receptors

Article abstract of DOI:10.1002/cmdc.200900394

Imatinib is a clinically important ATP analogue inhibitor that targets the tyrosine kinase domain of the intracellular Abl kinase and the PDGF receptor family. Imatinib has revolutionised the treatment of chronic myeloid leukaemia, which is caused by the oncogene Bcr-Abl and certain solid tumours that harbor oncogenic mutations of the PDGF receptor family. As a leading kinase inhibitor, imatinib also provides an excellent model system to investigate how changes in drug design impact biological activity, which is an important consideration for rational drug design. Herein we report a new series of imatinib derivatives that in general have greater activity against the family of PDGF receptors and poorer activity against Abl, as a result of modifications of the phenyl and N-methylpiperazine rings. These new compounds provide a platform for further drug development against the therapeutically important PDGF receptor family and they also provide insight into the engineering of drugs with altered biological activity.

Full text of DOI:10.1002/cmdc.200900394

MED
DOI: 10.1002/cmdc.200900394
Novel Imatinib Derivatives with Altered Specificity
between Bcr–Abl and FMS, KIT, and PDGF Receptors
Konstantinos Skobridis,*[a] Maria Kinigopoulou,[a] Vassiliki Theodorou,[a] Emilia Giannousi,[a]
Alison Russell,[b] Rakhee Chauhan,[b] Roberta Sala,[b] Nicola Brownlow,[b] Serafim Kiriakidis,[c]
Jan Domin,[d] Andreas G. Tzakos,[a] and Nick J. Dibb[b]
Imatinib is a clinically important ATP analogue inhibitor that
targets the tyrosine kinase domain of the intracellular Abl
kinase and the PDGF receptor family. Imatinib has revolution-
ised the treatment of chronic myeloid leukaemia, which is
caused by the oncogene Bcr–Abl and certain solid tumours
that harbor oncogenic mutations of the PDGF receptor family.
As a leading kinase inhibitor, imatinib also provides an excel-
lent model system to investigate how changes in drug design
impact biological activity, which is an important consideration
for rational drug design. Herein we report a new series of ima-
tinib derivatives that in general have greater activity against
the family of PDGF receptors and poorer activity against Abl,
as a result of modifications of the phenyl and N-methylpipera-
zine rings. These new compounds provide a platform for fur-
ther drug development against the therapeutically important
PDGF receptor family and they also provide insight into the
engineering of drugs with altered biological activity.
Introduction
In 2001, the ATP analogue imatinib (Glivec or STI571) was re-
ported to have striking effects in patients suffering chronic
myeloid leukaemia (CML).[1] Imatinib targets the tyrosine kinase
domain of the oncogenic fusion protein Bcr–Abl that causes
CML and has revolutionised the treatment of this disease. Most
of the members of the platelet-derived growth factor receptor
(PDGFR) family are also sensitive to imatinib.[2] For this reason
imatinib can also be used to treat gastrointestinal stromal tu-
mours (GISTs), which commonly have oncogenic mutations of
the juxtamembrane regions (JMRs) of either of the PDGFR or
the closely related KIT receptor.[3] The other members of the
PDGFR family are the FMS receptor for macrophage colony-
stimulating factor (M-CSF or CSF-1), which is sensitive to imati-
nib and the FLT3 receptor, which is not sensitive.[4]
also effective against most cases of imatinib resistance caused
by point mutations of Abl.[9] The N-methylpiperazine heterocy-
cle may also not be ideal for KIT inhibition, as crystallographic
data show that this ring and the adjoining phenyl ring distort
the positioning of the JMR of the KIT receptor.[7b]
Further studies of imatinib derivatives promise to enhance
our understanding of how changes in drug design affect bio-
logical activity, which is important for rational drug develop-
ment.[9] We report herein the design, synthesis, and biological
evaluation of a new series of phenylaminopyrimidines, struc-
turally related to imatinib, that in general have greater activity
against the PDGFR family and poorer activity against Abl as
the result of alterations to the phenyl and N-methylpiperazine
rings.
In recent years the imatinib success story has stimulated the
discovery of many novel and potent ATP-site-directed inhibi-
tors of protein kinases, and known inhibitors have been im-
proved by using structure-based rational design.[5] However,
our understanding of how changes in drug design impact bio-
logical activity is far from complete.[6] Imatinib, as well as being
an important drug, also provides an excellent model system
with which to analyse drug–target interactions.
[a] Prof. K. Skobridis, M. Kinigopoulou, Prof. V. Theodorou, E. Giannousi,
Dr. A. G. Tzakos
Department of Chemistry
Section of Organic Chemistry and Biochemistry
University of Ioannina, 45110 Ioannina (Greece)
Fax: (+30)26510 08670
E-mail: kskobrid@cc.uoi.gr
Structural studies reveal a remarkable similarity between the
imatinib binding pockets of the distantly related Abl and KIT
kinases.[7] Nevertheless, subtle alterations such as the introduc-
tion of a methyl group onto the pyridine ring of imatinib
(Figure 1, ring A) impairs activity against Abl but not KIT, which
may lead to improvements in the treatment of GISTs.[8]
[b] A. Russell, R. Chauhan, R. Sala, Dr. N. Brownlow, Dr. N. J. Dibb
Imperial College London
Institute for Reproductive and Developmental Biology
Du Cane Road, London W12 0NN (UK)
[c] Dr. S. Kiriakidis
Imperial College London, Faculty of Medicine
Kennedy Institute of Rheumatology Division
65 Aspenlea Road, Hammersmith, London W6 8LH (UK)
The highly polar and basic N-methylpiperazine heterocycle
of imatinib (Figure 1, ring E) has recently been replaced by al-
ternative binding groups to generate AMN107 (nilotinib),
which is a greatly improved inhibitor of Abl, but not KIT, and is
[d] Dr. J. Domin
Imperial College London, Faculty of Medicine, Renal Section
Du Cane Road, London W12 0NN (UK)
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Imatinib Derivatives
strong interactions with residues typically positioned at the
active site of the kinase, especially with positively charged resi-
dues. Moreover, they could decrease the lipophilicity of the in-
hibitors.
All the compounds were prepared according to the classical
methods for the synthesis of pyrimidine ring systems
(Scheme 1).[13] The inhibitors SK1–SK29 reported herein were
1
fully characterised by IR, H NMR, and 13C NMR spectroscopy, as
well as by high-resolution mass spectrometry. These imatinib
derivatives were tested as described below.
Biological activity
Compounds SK1–SK29 were initially screened for possible
nonspecific inhibitory effects by using the haematopoietic cell
line FDC-P1, which is tolerant of imatinib when grown in the
presence of interleukin-3 (IL-3).[4a] In contrast, Figure 2A shows
that compound SK7 at 1 mm substantially inhibits the growth
of FDC-P1 cells in response to IL-3, as do compounds SK9,
SK12, SK13 and SK14. These compounds were therefore con-
sidered to be nonspecifically toxic and were not included in
subsequent analyses. Figure 2B reports the effect of the re-
maining 24 SK compounds and imatinib on the growth of the
K562 cell line, the proliferation of which is known to be driven
by Abl kinase activity.[14] With the exception of SK23, all of the
SK compounds were far less effective inhibitors of the growth
of K562 cells than imatinib, indicating a general loss of Abl
kinase inhibition as a result of the modifications to the imati-
nib parent structure. To confirm that SK23 is still active against
Abl, we tested its effect on the phosphorylation of Crkl, which
is a commonly used test of signalling by Abl in vivo.[15] Crkl is
typically present as a single phosphorylated band in SDS-PAGE
separations of total protein isolates from untreated K562 cells
(Figure 3A, leftmost lane). As expected, imatinib treatment in-
hibited Crkl phosphorylation by Bcr–Abl resulting in the pro-
duction of a second slightly smaller nonphosphorylated Crkl
protein (Figure 3A, lanes 1–4 mm). SK23 was equally effective
as imatinib as an inhibitor of Abl signalling in this assay, where-
as compound SK20 showed no inhibition even at 4 mm.
We next used the haematopoietic cell line FDC-P1 to screen
for the inhibitory effect of our compounds toward growth
stimulation by the FMS receptor for M-CSF (CSF-1). Although
FDC-P1 cells normally require IL-3 to grow, we have previously
established cell lines that can grow without IL-3 following
their expression of oncogenes such as v-fms or v-kit.[16] Fig-
ure 2C shows that 1 mm imatinib substantially inhibits the
growth of the FDv-fms cells, which is in accord with our previ-
ous results.[4a] Compounds SK15, SK17–SK24 and SK26 also
caused evident growth inhibition at a concentration of 1 mm in
this assay.
Figure 1. Design of the SK series of imatinib derivatives: Following removal
of the piperazinyl ring (ring E) of imatinib, modifications (R1–R3) were made
to the pyridine (ring A), phenylamino (ring C), and terminal phenyl (ring D)
moieties as shown; see also Table 1.
Results and Discussion
Design and synthesis
We first screened the three-dimensional architectures that are
available for Abl, FMS, and KIT kinases[7b,10] to identify potential
differences in the imatinib binding pockets. This helped the
design of a series of imatinib derivatives, all of which lack the
N-methylpiperazine group and which also incorporate three
different groups of modifications (Figure 1, Table 1). The R1
group modifications involve repositioning of the nitrogen
atom in the pyridyl moiety (Figure 1, ring A) at the 2-, 3-, or 4-
positions, at the position 4 of the pyrimidine ring (ring B). For
the R2 modifications (Figure 1, ring C) we mainly repositioned
the methyl group in imatinib in order to test for a potentially
more favourable interaction with a hydrophobic pocket adja-
cent to helix C that is isosteric in FMS and c-KIT, but is much
shallower in Abl. Finally, the R3 modifications involve reposi-
tioning of the amide function at the phenyl ring (Figure 1,
ring C) and the incorporation of various groups at the terminal
phenyl ring (Figure 1, ring D), designed in part to explore po-
tentially favourable halogen bond interactions.[11]
Notably, during optimisation of the imatinib structure, it was
established that the introduction only of a “flag-methyl” at the
phenyl ring (Figure 1, ring C) completely abolishes the inhibito-
ry effect of imatinib against protein kinase Ca (PKCa), while
the inhibitory effect against Bcr–Abl is retained or even enhan-
ced.[1d] The dramatic loss of activity against PKCa was ex-
plained by a forced change of the preferred conformation
upon introduction of this “flag-methyl” group. Because the
methyl group in some SK compounds (Table 1), in contrast to
others, is located adjacent to the aminopyrimidine moiety, it is
expected that its steric effect will lead to a conformational
change, as in imatinib.
We previously used specific antibodies against phosphorylat-
ed FMS to show that 1 mm imatinib can substantially inhibit
cellular phosphorylation of the human FMS receptor expressed
in Rat-2 fibroblasts.[4a,17] We used the same assay to screen the
SK compounds and found that only compounds SK17–SK23
are effective inhibitors of cellular phosphorylation of the FMS
receptor at 1 mm (Table 2, Figure 2C). Compounds SK15, SK24,
Interestingly, nitrated compounds were also chosen owing
to their previously reported ability to support cell growth and
efficacy against apoptosis, as well as their antiproliferative
properties against cancer cell lines.[12] Nitro groups can form
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K. Skobridis et al.
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Table 1. Structures of the SK compounds 1–29.
Compd
Scaffold
R1
R2
R3
R4
R5
R6
R7
R8
Formula
SK1
SK2
SK3
SK4
SK5
SK6
SK7
SK8
A
A
A
B
2-pyridyl
2-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
4-pyridyl
4-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
CH3
H
CH3
CH3
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
NO2
CH3
H
H
H
H
NO2
H
CH3
H
H
H
H
H
H
H
H
–
H
H
H
H
H
NO2
NO2
NO2
–
NO2
NO2
NO2
H
NO2
H
NO2
H
H
NO2
H
CF3
NO2
H
NO2
H
NO2
H
CF3
NO2
NO2
H
NO2
H
H
H
H
H
–
H
H
H
OCH3
F
H
NO2
NO2
NO2
–
NO2
NO2
NO2
H
H
NO2
H
H
NO2
H
H
H
H
NO2
H
H
H
H
H
C23H17N7O5
C23H17N7O5
C23H17N7O5
C23H17N7O5
C23H17N7O5
C23H17N7O5
C23H17N7O5
C24H21N5O2
C23H17FN6O3
C23H17FN6O3
C23H17ClN6O3
C23H17CN6O3
C23H17ClN6O3
C23H17ClN6O3
C24H17F3N6O3
C24H17F3N6O3
C23H17FN6O3
C23H17FN6O3
C23H17ClN6O3
C23H17ClN6O3
C23H17ClN6O3
C24H17F3N6O3
C24H17F3N6O3
C24H20N6O3
C24H20N6O3
C24H20N6O3
C23H18N6O3
C23H19N5O
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
CH3
H
SK9
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
SK10
SK11
SK12
SK13
SK14
SK15
SK16
SK17
SK18
SK19
SK20
SK21
SK22
SK23
SK24
SK25
SK26
SK27
SK28
SK29
F
Cl
Cl
Cl
H
CF3
H
H
NO2
H
H
H
H
H
Cl
NO2
NO2
F
H
H
NO2
Cl
NO2
NO2
H
CH3
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
F
Cl
Cl
H
CF3
H
CH3
H
CH3
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
H
H
NO2
H
H
H
H
H
H
H
H
NO2
H
H
C23H18N6O3
and SK26 do not substantially inhibit FMS phosphorylation
and so presumably inhibit the growth of FDv-fms cells (Fig-
ure 2C) for reasons other than FMS inhibition.
Table 2 lists the results of a more detailed analysis of the in-
hibitory effect of compounds SK17–SK23 on the activity of Abl
and the FMS, PDGFb, and KIT receptors. Columns 2–4 list the
IC50 values for the inhibition of cellular receptor phosphoryla-
tion for FMS, PDGFRb, and KIT, as calculated from the type of
examples shown in Figure 3B,C. Compounds SK19, SK20, and
SK23 are markedly better inhibitors of the phosphorylation of
the PDGFR family than imatinib, and compounds SK18 and
SK21 are comparable (Table 2). All compounds, with the excep-
tion of SK23, are much poorer inhibitors of Abl than imatinib
(Table 2, columns 5 and 6), thus demonstrating an overall
marked increase in specificity for the PDGFR family over Abl.
Compounds SK20 and SK23 are also good inhibitors of the
growth of FDv-fms cells (Table 2, column 7, Figure 2C), whereas
compound SK19 has a higher IC50 value than imatinib in this
growth assay despite its considerably lower IC50 values for the
inhibition of receptor phosphorylation. Similar results were
also observed for SK22 relative to imatinib (Table 2). This is
probably a reflection of the different nature of the cellular re-
Scheme 1. Synthesis of inhibitor SK23: a) N,N-dimethylformamide diethyl
acetal, o-xylene, reflux, 4 h (77%); b) HCl(g), cyanamide, room temperature,
2 h (96%); c) iPrOH, Na2CO3, reflux, 24 h (58%); d) H2 (1 atm), Pd/C (10% wt.
cat.), THF, room temperature, 24 h (27%); e) 4-nitro-3-trifluoromethylbenzoyl
chloride, Et3N, THF, room temperature, 24 h (92%).
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Imatinib Derivatives
Figure 3. Cellular phosphorylation inhibitor assays: A) Inhibition of Crkl
phosphorylation by imatinib and SK23. K562 cells were pretreated with the
indicated concentrations of drugs or DMSO only for 3 h, and total proteins
were separated by 10% SDS-PAGE and then western blotted with antibody
against Crkl (Biolabs). B) PDGFRb phosphorylation assay. Rat-2 fibroblasts
were pretreated with the indicated concentrations of imatinib, SK20, or
SK23 for 2 h and then stimulated with PDGF-BB (10 ngmLÀ1) for 5 min, after
which total proteins were separated by 8% SDS-PAGE; subsequent western
blots were first treated with antibody against phosphorylated Tyr751 of the
PDGFR (Biolabs). The blots were then stripped and treated with antibody
against the total PDGFRb population as a loading control. C) KIT receptor
phosphorylation assay. The GM-CSF-dependent human Mo7e leukaemic cell
line was grown in RPMI + 20% FCS + 10 ngmLÀ1 GM-CSF and pretreated
for 2.5 h with the indicated concentrations of imatinib, SK20, and SK23 and
then stimulated with human SCF (10 ngmLÀ1) for 5 min, after which proteins
were analysed by western blotting as described above and treated with anti-
body against phospho-Tyr of the human KIT receptor and then re-probed
with antibody against the total population of KIT receptors as a loading con-
trol.
Figure 2. A) Cell line toxicity assays: FDC-P1 cells were seeded at
1ꢁ104 cellsmLÀ1 in RPMI + 10% foetal calf serum (FCS) in triplicate in 24-
well plates in the presence of IL-3 (10 ngmLÀ1) with either 0.1% DMSO only
(as control), with imatinib (1 mm), or with the SK compounds (1 mm each) at
a final DMSO concentration of 0.1%. Cultures were maintained at 378C
under a humidified atmosphere containing 5% CO2. After 6 days, viable cells
were counted by haemocytometry and Trypan blue exclusion (Invitrogen,
Paisley, UK); error bars indicate standard deviation of the mean. B),C) Kinase
inhibition cellular growth tests: B) K562 cells were seeded at
1ꢁ104 cellsmLÀ1 as described in part A and cultured in RPMI + 10% FCS
with each drug at 0.2 mm. C) FDC-P1 cells that express v-fms were seeded at
1ꢁ104 cellsmLÀ1 in RPMI + 10% FCS without IL-3 in the presence of each
drug at 1 mm. The final DMSO concentration was 0.1% in all cases, which
was also added to the control cells. After 6 days culture, total cell numbers
were counted as described in part A, but are expressed as a percentage of
*
the growth of the control cells. Black dots ( ) indicate compounds that in-
hibit cellular phosphorylation of FMS (see text).
the introduction of the indicated modifications to the adjoin-
ing phenyl group. Consequently, the modifications of rings A,
C, and D of imatinib (Figure 1) that we tested have not gener-
ated anything of interest as yet. The improvement in activity
against the PDGFR family caused by removal of the N-methyl-
piperazinyl ring is consistent with the crystallographic data,
which show that this region of imatinib clashes with the JMR
of KIT and is therefore likely to be detrimental to KIT inhibition
(Figure 4A). However, part of the function of the N-methylpi-
ceptor phosphorylation and growth inhibition assays. Both
assays require that the drugs are able to be taken up by cells
and to compete with endogenous ATP. However, only the
growth assay requires drug stability over a period of many
days.
Table 1 shows that compounds SK17–SK23 are identical to
imatinib except for the lack of an N-methylpiperazinyl ring and
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K. Skobridis et al.
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Table 2. Inhibition of phosphorylation of the FMS, PDGFb, and KIT recep-
tors and Crkl, as well as the growth of the K562 (Bcr–Abl) and FDv-fms
cell lines.
1
2
3
4
5
IC50 [mm][a]
Crkl
6
7
Drug
FMS
PDGFR
KIT
K562
FDv-fms
SK17
SK18
SK19
SK20
SK21
SK22
SK23
Imatinib
0.75
0.5
0.1
0.25
0.5
0.35
0.1
0.75
0.3
ND
ND
ND
0.1
ND
ND
0.05
0.25
ND
ND
ND
>1.0
>1.0
0.5
>1.0
0.5
>1.0
0.1
0.1
0.75
0.75
0.75
0.5
0.75
>1.0
0.15
0.5
0.01
0.025
0.35
0.25
0.1
>4.0
ND
ND
1
1
0.5
0.3
[a] ND: not determined.
perazinyl ring is to improve imatinib solubility and stability,[1d]
and this may explain the relatively good activity of imatinib in
the FDv-fms growth assay relative to some of the SK com-
pounds. This suggests that the N-methylpiperazinyl ring of im-
atinib is probably an advantageous feature for the treatment
of GISTs, because the juxtamembrane deletions of the KIT and
PDGF receptors that commonly occur in this cancer would be
expected to decrease any steric clash with the N-methylpipera-
zinyl ring.[7b]
Modelling
We used the known inactive structures of c-KIT, Abl, and FMS
kinase domains to model the SK drug complexes through flexi-
ble docking calculations (Figure 4B,C). The structure of the
PDGFR kinase domain was modelled by homology modelling,
as crystallographic data are not yet available. We analysed the
inactive rather than the active structures of these kinases be-
cause both imatinib and an imatinib derivative without the N-
methylpiperazine ring were crystallised as type II inhibitors in
complex with inactive Abl[7a,10b] or with inactive KIT.[7b] In addi-
tion, we could independently classify the SK compounds as
type II inhibitors because, like imatinib, they are unable to in-
hibit an oncogenic mutation of FMS that forces the kinase into
its active structure.[4a] All of the resulting models of these com-
plexes could be indirectly validated, as they successfully repro-
duce the hydrogen bonding network that is present in the
common pharmacophore groups of the imatinib–KIT and imati-
nib–Abl complexes[7a,b] (Figure 4B).
Figure 4. Models of SK20 and SK23 bound to c-KIT and Abl: A) Superposi-
tion of c-KIT in complex with imatinib (green, PDB code: 1T46) with the au-
toinhibited form (blue, PDB code: 1T45). The juxtamembrane region (JMR) is
shown in red, and imatinib is represented in space-filling form in yellow. It is
evident that the N-methylpiperazine heterocycle of imatinib is very large
and cannot be fully incorporated in the ATP binding cleft of c-KIT due to
steric clash with the JMR in the autoinhibitory form of c-KIT. B) Model of
SK20 bound to KIT as derived from flexible docking calculations. SK20 is
shown in ball-and-stick representation in blue. Its Cl group is shown in light
green. A yellow dashed line indicates the formation of a potential halogen
bonding interaction between the Cl atom of SK20 and C809 of KIT. The
other dashed lines in white represent hydrogen bonds; these are the same
as those determined for imatinib binding to KIT (PDB code: 1T46). C) Super-
position of the model of the SK23–Abl complex and the X-ray crystal struc-
ture of nilotinib (in red) in complex with Abl (PDB code: 1FUP). The trifluoro-
methyl groups of both analogues are shown in ball-and-stick representation.
Compounds SK19 and SK20 gave the best results in terms
of selectivity, as these have very poor activity against Abl but
markedly enhanced activity against KIT and the PDGFRb rela-
tive to imatinib (Table 2). We suggest that this difference is
partly attributable to halogen bonding between the chlorine
atom of SK19 or SK20 with C809 of KIT and C843 of the
PDGFRb; the equivalent residues are G795 in FMS and A380 in
Abl, just before the start of the activation loop (Figure 4B). The
nitro moiety of SK20 may also form a hydrogen bond with the
cysteine residues of FMS (C774), KIT (C788), and PDGFRb
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Imatinib Derivatives
H2O and dried (P4O10) to yield a first crop of product. A second
crop of product was obtained from the organic phase, which was
separated, washed with H2O and dried (Na2SO4). The solvent was
evaporated under vacuum, and the residue precipitated by the ad-
dition of Et2O or purified by flash chromatography on silica gel.
Specific details are given below for each compound.
(C822), but not the equivalent phenylalanine residue present
in Abl (F359).
Removal of the N-methylpiperazine group of imatinib would
be expected to decrease binding to Abl, as this group is
known to hydrogen bond with Ile360 and His361 of Abl and
to form favourable van der Waals interactions.[1d] Consequently,
the good activity of compound SK23 against Abl was surpris-
ing (Table 2). The reason for this is most probably because the
trifluoromethyl group of SK23 overlaps with the equivalent
group of nilotinib (Figure 4C), and so presumably participates
in the same favourable interactions with a hydrophobic pocket
formed by residues F359, L298, L354, V379, and I293 of Abl.
This hydrophobic pocket is also conserved in the FMS, KIT, and
PDGFb receptors, which may explain the good activity of SK23
against these kinases.
N-[2-methyl-3-(4-pyridin-2-ylpyrimidin-2-ylamino)phenyl]-3,5-di-
nitrobenzamide (SK1): Yellow solid; Yield: 83%; mp: 231–2338C;
1H NMR ([D6]DMSO, 250 MHz): d=2.14 (s, 3H, CH3), 7.18 (d, J=
7.60 Hz, 1H), 7.26 (t, J=7.60 Hz, 1H), 7.45–7.55 (m, 2H), 7.63 (d, J=
5.00 Hz, 1H), 7.96 (dt, J=7.75 and 1.50 Hz, 1H), 8.30 (d, J=7.75 Hz,
1H), 8.52 (d, J=5.00 Hz, 1H), 8.69 (dt, J=5.00 and 1.75 Hz, 1H),
9.00 (t, J=1.75 Hz, 1H), 9.11 (s, 1H), 9.19 (d, J=1.75 Hz, 2H),
10.74 ppm (s, 1H); 13C NMR ([D6]DMSO, 100 MHz): d=13.86,
107.69, 121.40, 123.64, 124.30, 125.73, 125.92, 128.30, 136.40,
137.40, 137.72, 139.18, 148.54, 149.81, 154.03, 159.88, 161.50,
161.75, 163.14 ppm; HRMS (ESI): calcd for C23H17N7O5 [M+H]+ m/z
472.1369, found [M+H]+ m/z 472.1360.
The absence of the N-methylpiperazine group may increase
the off-target activity of the SK compounds against other kin-
ases relative to imatinib. However, the smaller size of the SK
compounds is favourable for further incorporation of modifica-
tions that increase specificity, such as those described herein
and previously.[8]
N-[2-methyl-5-(4-pyridin-2-ylpyrimidin-2-ylamino)phenyl]-3,5-di-
nitrobenzamide (SK2): Yellow solid; Yield: 87%; mp: 254–2558C;
1H NMR ([D6]DMSO, 250 MHz): d=2.20 (s, 3H, CH3), 7.24 (d, J=
9.00 Hz, 1H), 7.53 (ddd, J=7.50, 4.75 and 1.25 Hz, 1H), 7.61 (dd,
J=8.25 and 2.00 Hz, 1H), 7.69 (d, J=5.00 Hz, 1H), 7.95 (td, J=7.75
and 1.75 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 8.46 (dt, J=7.75 and
1.25 Hz, 1H), 8.61 (d, J=5.25 Hz, 1H), 8.71 (ddd, J=5.00, 1.75 and
1.25 Hz, 1H), 9.00 (d, J=2.00 Hz, 1H), 9.20 (d, J=2.25 Hz, 1H), 9.78
(s, 1H), 10.65 ppm (s, 1H); 13C NMR ([D6]DMSO, 100 MHz): d=
17.64, 108.20, 117.45, 117.84, 121.44, 121.58, 126.04, 127.05, 128.28,
130.67, 135.67, 137.40, 137.76, 139.00, 148.57, 149.90, 153.95,
159.86, 160.37, 161.61, 163.00 ppm; HRMS (ESI): calcd for
C23H17N7O5 [M+H]+ m/z 472.1369, found [M+H]+ m/z 472.1362.
Conclusions
Our results show that there is considerable potential to devel-
op imatinib derivatives that are better inhibitors of the thera-
peutically important PDGFR family. The protocols we estab-
lished in this work will also allow us to improve the specificity
of compounds SK20 and SK23 through the testing of further
substitutions. The wealth of structural data available for imati-
nib binding means that modelling can give good insight into
the reasons for the improved activity of compounds such as
SK20. Structural analysis of these compounds will further facili-
tate lead optimisation of imatinib derivatives that are more
potent inhibitors of the PDGFR family than of Abl.
N-[2-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-3,5-di-
nitrobenzamide (SK3): Yellow solid; Yield: 85%; mp: >2578C
1
(dec.); H NMR ([D6]DMSO, 250 MHz): d=2.13 (s, 3H, CH3), 7.18 (dd,
J=8.00 and 1.75 Hz, 1H), 7.26 (t, J=7.75 Hz, 1H), 7.41 (d, J=
5.00 Hz, 1H), 7.46 (dd, J=7.75 and 1.50 Hz, 1H), 7.52 (dd, J=7.75
and 5.00 Hz, 1H), 8.42 (dt, J=7.75 and J=1.75 Hz, 1H), 8.48 (d, J=
5.25 Hz, 1H), 8.68 (dd, J=4.75 and 1.75 Hz, 1H), 9.00 (t, J=2.00 Hz,
1H), 9.12 (brs, 1H), 9.18 (d, J=2.25 Hz, 2H), 9.25 (d, J=2.00 Hz,
1H), 10.69 ppm (brs, 1H); 13C NMR ([D6]DMSO, 100 MHz): d=13.81,
121.42, 123.74, 124.14, 125.71, 128.30, 130.31, 132.51, 134.65,
136.45, 137.43, 139.05, 148.44, 148.53, 151.71, 159.76, 161.63,
161.75, 161.90 ppm; HRMS (ESI): calcd for C23H17N7O5 [M+H]+ m/z
472.1369, found [M+H]+ m/z 472.1362.
Experimental Section
Chemistry
General: Solvents used were puriss. grade, except for THF, which
was purified by fresh distillation over Na/benzophenone. Commer-
cially available reagents were used as received without further pu-
rification. Analytical TLC was performed on commercial Merck silica
gel 60 F254. Flash chromatography was carried out using silica
N-[3-methyl-4-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-3,5-di-
nitrobenzamide (SK4): Yellow solid; Yield: 91%; mp: >2258C
1
(dec.); H NMR ([D6]DMSO, 400 MHz): d=2.26 (s, 3H, CH3), 7.38 (d,
1
J=5.20 Hz, 1H), 7.49–7.55 (m, 2H), 7.63 (d, J=7.60 Hz, 1H), 7.65 (s,
1H), 8.38 (d, J=7.60 Hz, 1H), 8.48 (d, J=5.20 Hz, 1H), 8.67 (dd, J=
4.80 and 1.20 Hz, 1H), 8.95 (s, 1H), 8.98 (brs, 1H), 9.18 (s, 2H), 9.22
(d, J=1,20 Hz, 1H), 10.79 ppm (brs, 1H); 13C NMR ([D6]DMSO,
100 MHz): d=18.35, 107.41, 118.55, 120.93, 122.58, 123.79, 125.49,
127.94, 132.19, 132.78, 134.17, 134.32, 134.92, 137.64, 148.06,
148.12, 151.37, 159.45, 160.93, 161.26, 161.48 ppm; HRMS (ESI):
calcd for C23H17N7O5 [M+H]+ m/z 472.1369, found [M+H]+ m/z
472.1363.
gel 60 (230–400 mesh). H NMR spectra were recorded on a Bruker
AMX (400 and 250 MHz) spectrometer using (CH3)4Si as internal
standard. Chemical shifts (d) are reported in ppm referenced to
(CH3)4Si, and coupling constants (J) are reported in Hz. High-resolu-
tion mass spectra (HRMS) were measured on a Finnigan MAT 8200
spectrometer.
General procedure for coupling of the amines to the corre-
sponding amides (final compounds) SK1–SK29: A solution of the
appropriate benzoyl chloride (0.25 mmol) in THF (10 mL) was
added dropwise to an ice-cold solution of the corresponding
amine (0.2 mmol) and Et3N (0.25 mmol) in THF (20 mL). The mix-
ture was stirred vigorously at 08C for 2 h and at room temperature
for 24 h, then poured into ice and extracted with saturated K2CO3
and CH2Cl2. The precipitated product was filtered off, washed with
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-3,5-di-
nitrobenzamide (SK5): Yellow solid; Yield: 89%; mp: >2908C
1
(dec.); H NMR ([D6]DMSO, 400 MHz): d=2.22 (s, 3H, CH3), 7.25 (d,
J=8.00 Hz, 1H), 7.49 (d, J=5.20 Hz, 1H), 7.54 (dd, J=8.00 and
4.80 Hz, 1H), 7.61 (dd, J=8.00 and 2.00 Hz, 1H), 8.02 (s, 1H), 8.54
ChemMedChem 2010, 5, 130 – 139
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135

K. Skobridis et al.
MED
(d, J=7.60 Hz, 1H), 8.59 (d, J=5.20 Hz, 1H), 8.70 (dd, J=4.80 and
1.20 Hz, 1H), 9.02 (s, 1H), 9.22 (d, J=1.20 Hz, 2H), 9.36 (d, J=
1.60 Hz, 1H), 9.82 (s, 1H), 10.65 ppm (s, 1H, NH); 13C NMR
([D6]DMSO, 100 MHz): d=17.27, 108.06, 117.12, 117.50, 121.09,
123.83, 126.73, 127.99, 130.32, 132.13, 134.44, 135.37, 137.12,
138.60, 148.20, 148.26, 151.49, 159.37, 160.13, 161.32, 161.55 ppm;
HRMS (ESI): calcd for C23H17N7O5 [M+H]+ m/z 472.1369, found
[M+H]+ m/z 472.1364.
J=8.00 Hz, 1H), 8.62 (d, J=4.80 Hz, 1H), 8.64 (m, 1H), 8.74 (d, J=
4.40 Hz, 1H), 9.40 (d, J=1.60 Hz, 1H), 9.78 (s, 1H), 10.14 ppm (s,
1H); 13C NMR ([D6]DMSO, 100 MHz): d=17.70, 108.57, 116.91,
117.70, 118.43, 124.40, 126.18, 126.49, 126.56, 128.65, 130.80,
132.73, 135.03, 135.86, 139.11, 144.46, 144.50, 148.85, 152.06,
160.01, 160.69, 161.21, 162.03 ppm; HRMS (ESI): calcd for
C23H17FN6O3 [M+H]+ m/z 445.1424, found [M+H]+ m/z 445.1419.
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-2-
chloro-3-nitrobenzamide (SK11): Yellow solid; Yield: 83%; mp:
236–2378C (dec.); 1H NMR ([D6]DMSO, 400 MHz): d=2.27 (s, 3H,
CH3), 7.22 (d, J=8.00 Hz, 1H), 7.51–7.57 (m, 3H), 7.75 (t, J=
7.60 Hz, 1H), 7.95 (d, J=7.20 Hz, 1H), 8.15–8.19 (m, 2H), 8.58 (d,
J=7.60 Hz, 1H), 8.61 (d, J=5.20 Hz, 1H), 8.74 (d, J=4.00 Hz, 1H),
9.39 (s, 1H), 9.77 (s, 1H), 10.24 ppm (brs, 1H); 13C NMR ([D6]DMSO,
100 MHz): d=17.95, 108.58, 116.94, 117.73, 122.18, 124.45, 126.15,
126.29, 129.39, 130.83, 132.66, 132.73, 135.06, 135.85, 139.05,
140.15, 148.75, 149.15, 152.08, 160.05, 160.71, 162.01, 164.05 ppm;
HRMS (ESI): calcd for C23H17ClN6O3 [M+H]+ m/z 461.1129, found
[M+H]+ m/z 461.1123.
N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-3,5-di-
nitrobenzamide (SK6): Yellow solid; Yield: 93%; mp: >2758C
1
(dec.); H NMR ([D6]DMSO, 400 MHz] ([D6]DMSO, 400 MHz): d=2.25
(s, 3H, CH3), 7.24 (d, J=8.00 Hz, 1H), 7.44 (d, J=5.20 Hz, 1H), 7.48–
7.56 (m, 2H), 8.12 (s, 1H), 8.49 (d, J=8.40 Hz, 1H), 8.52 (d, J=
5.20 Hz, 1H), 8.68 (d, J=4.00 Hz, 1H), 8.97 (s, 2H), 9.19 (brs, 2H),
9.29 (s, 1H), 10.86 ppm (brs, 1H); 13C NMR ([D6]DMSO, 100 MHz):
d=17.68, 107.58, 117.16, 117.51, 120.69, 123.76, 127.96, 130.14,
132.15, 134.40, 137.29, 137.89, 138.27, 148.04, 148.19, 151.37,
159.45, 161.07, 161.11, 161.61 ppm; HRMS (ESI): calcd for
C23H17N7O5 [M+H]+ m/z 472.1369, found [M+H]+ m/z 472.1366.
N-[2-methyl-5-(4-pyridin-4-ylpyrimidin-2-ylamino)phenyl]-3,5-di-
nitrobenzamide (SK7): Yellow solid; Yield: 87%; mp: 2648C;
1H NMR ([D6]DMSO, 250 MHz): d=2.19 (s, 3H, CH3), 7.17 (d, J=
8.50 Hz, 1H), 7.46 (dd, J=8.00 and 2.25 Hz, 1H), 7.48 (d, J=
5.00 Hz, 2H), 8.00 (d, J=2.25 Hz, 1H), 8.13 (d, J=6.25 Hz, 2H), 8.61
(d, J=5.00 Hz, 1H), 8.72 (d, J=6.00 Hz, 2H), 8.94 (t, J=2.25 Hz,
1H), 9.21 (d, J=2.25 Hz, 1H), 9.72 (s, 1H), 10.66 ppm (brs, 1H, NH);
13C NMR ([D6]DMSO, 100 MHz): d=17.72, 108.34, 116.42, 116.95,
120.48, 121.18, 126.71, 128.03, 130.14, 138.45, 144.03, 148.25,
150.69, 160.03, 160.52, 161.09, 161.47 ppm; HRMS (ESI): calcd for
C23H17N7O5 [M+H]+ m/z 472.1369, found [M+H]+ m/z 472.1362.
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-2-
chloro-4-nitrobenzamide (SK12): Yellow solid; Yield: 86%; mp:
249–2518C (dec.); 1H NMR ([D6]DMSO, 400 MHz): d=2.27 (s, 3H,
CH3), 7.23 (d, J=8.40 Hz, 1H), 7.52–7.59 (m, 3H), 7.94 (d, J=
8.40 Hz, 1H), 8.19 (s, 1H), 8.34 (dd, J=8.40 and 2.40 Hz, 1H), 8.45
(d, J=2.00 Hz, 1H), 8.59 (dt, J=8.00 and 1.75 Hz, 1H), 8.62 (d, J=
5.20 Hz, 1H), 8.75 (dd, J=4.80 and 1.60 Hz, 1H), 9.39 (d, J=
2.00 Hz, 1H), 9.82 (s, 1H), 10.27 ppm (s, 1H); 13C NMR ([D6]DMSO,
100 MHz): d=17.94, 108.61, 117.05, 117.85, 123.10, 124.48, 125.17,
126.46, 130.60, 130.86, 131.64, 132.72, 135.05, 135.63, 139.08,
143.34, 148.76, 148.83, 152.11, 160.06, 160.71, 162.02, 164.22 ppm;
HRMS (ESI): calcd for C23H17ClN6O3 [M+H]+ m/z 461.1129, found
[M+H]+ m/z 461.1123.
N-[2-methyl-3-(4-pyridin-4-ylpyrimidin-2-ylamino)phenyl]-4-me-
thoxybenzamide (SK8): Yellow solid; Yield: 85%; mp: 184–1858C;
1H NMR ([D6]DMSO, 250 MHz): d=2.11 (s, 3H, CH3), 3.84 (s, 3H,
OCH3), 7.06 (d, J=9.00 Hz, 2H), 7.16 (d, J=9.00 Hz, 2H), 7.23 (t, J=
7.50 Hz, 1H), 7.38 (d, J=7.50 Hz, 1H), 7.45 (d, J=5.25 Hz, 1H), 8.00
(d, J=9.00 Hz, 2H), 8.04 (d, J=6.25 Hz, 2H), 8.55 (d, J=5.25 Hz,
1H), 8.74 (d, J=6.00 Hz, 2H), 9.21 (s, 1H), 9.87 ppm (s, 1H, NH);
13C NMR ([D6]DMSO, 100 MHz): d=13.78, 55.74, 108.04, 113.92,
121.15, 123.85, 124.06, 125.44, 126.96, 129.84, 130.48, 137.55,
138.71, 144.18, 150.78, 160.20, 161.63, 161.79, 162.14, 165.10 ppm;
HRMS (ESI): calcd for C24H21N5O2 [M+H]+ m/z 412.1774, found
[M+H]+ m/z 412.1765.
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-2-
chloro-5-nitrobenzamide (SK13): Yellow solid; Yield: 82%; mp:
231–2338C (dec.); 1H NMR ([D6]DMSO, 400 MHz): d=2.27 (s, 3H,
CH3), 7.21 (d, J=8.40 Hz, 1H), 7.49–7.53 (m, 2H), 7.57 (dd, J=8.00
and 4.80 Hz, 1H), 7.91 (d, J=8.80 Hz, 1H), 8.21 (s, 1H), 8.34 (dd, J=
8.80 and 2.00 Hz, 1H), 8.47 (d, J=2.00 Hz, 1H), 8.58–8.63 (m, 2H),
8.74 (dd, J=4.80 and 1.60 Hz, 1H), 9.39 (d, J=2.00 Hz, 1H), 9.79 (s,
1H), 10.29 ppm (brs, 1H); 13C NMR ([D6]DMSO, 100 MHz): d=18.04,
108.50, 117.00, 117.42, 124.35, 124.44, 125.77, 125.87, 126.37,
130.70, 131.83, 132.75, 135.03, 137.63, 138.98, 139.07, 146.71,
148.79, 152.05, 160.00, 160.03, 160.72, 161.99 ppm; HRMS (ESI):
calcd for C23H17ClN6O3 [M+H]+ m/z 461.1129, found [M+H]+ m/z
461.1123.
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-
fluoro-3-nitrobenzamide (SK9): Yellow solid; Yield: 91%; mp: 227–
2298C (dec.); 1H NMR ([D6]DMSO, 400 MHz): d=2.22 (s, 3H, CH3),
7.25 (d, J=8.40 Hz, 1H), 7.51 (d, J=5.20 Hz, 1H), 7.56 (dd, J=7.60
and 4.80 Hz, 1H), 7.62 (dd, J=8.40 and 1.60 Hz, 1H), 7.81 (dd, J=
11.20 and 8.80 Hz, 1H), 8.00 (s, 1H), 8.46 (m, 1H), 8.56 (d, J=
8.00 Hz, 1H), 8.61 (d, J=5.20 Hz, 1H), 8.73 (d, J=4.80 Hz, 1H), 8.82
(dd, J=7.60 and 1.60 Hz, 1H), 9.37 (d, J=1.60 Hz, 1H), 9.79 (s, 1H),
10.29 ppm (s, 1H); 13C NMR ([D6]DMSO, 100 MHz): d=17.84,
108.61, 117.81, 117.86, 119.31, 119.65, 124.43, 126.41, 127.31,
130.79, 131.91, 132.71, 135.03, 136.00, 136.24, 137.36, 139.11,
148.00, 152.08, 159.95, 160.70, 161.09, 162.90 ppm; HRMS (ESI):
calcd for C23H17FN6O3 [M+H]+ m/z 445.1424, found [M+H]+ m/z
445.1419.
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-
chloro-3-nitrobenzamide (SK14): Yellow solid; Yield: 91%; mp:
226–2288C (dec.); 1H NMR ([D6]DMSO, 400 MHz): d=2.21 (s, 3H,
CH3), 7.25 (d, J=8.40 Hz, 1H), 7.52 (d, J=5.20 Hz, 1H), 7.56 (dd, J=
8.00 and 4.80 Hz, 1H), 7.61 (dd, J=8.00 and 2.00 Hz, 1H), 8.00–8.02
(m, 2H), 8.33 (dd, J=8.40 and 2.00 Hz, 1H), 8.56 (dt, J=8.00 and
1.75 Hz, 1H), 8.62 (d, J=5.20 Hz, 1H), 8.70 (d, J=1.20 Hz, 1H), 8.73
(dd, J=4.80 and 1.60 Hz, 1H), 9.38 (d, J=1.60 Hz, 1H), 9.83 (s, 1H),
10.30 ppm (s, 1H); 13C NMR ([D6]DMSO, 100 MHz): d=17.83,
108.61, 117.68, 117.87, 124.43, 125.52, 127.22, 128.64, 130.80,
132.60, 132.70, 133.27, 135.03, 135.14, 136.14, 139.10, 147.98,
148.80, 152.07, 159.96, 160.69, 162.09, 162.97 ppm; HRMS (ESI):
calcd for C23H17ClN6O3 [M+H]+ m/z 461.1129, found [M+H]+ m/z
461.1123.
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-2-
fluoro-5-nitrobenzamide (SK10): Yellow solid; Yield: 87%; mp:
252–2548C (dec.); 1H NMR ([D6]DMSO, 400 MHz): d=2.26 (s, 3H,
CH3), 7.24 (d, J=8.00 Hz, 1H), 7.52 (d, J=5.00 Hz, 1H), 7.53–7.59
(m, 2H), 7.71 (t, J=8.80 Hz, 1H), 8.25 (s, 1H), 8.49 (m, 1H), 8.58 (d,
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-
nitro-2-trifluoromethylbenzamide (SK15): Yellow solid; Yield:
136
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ChemMedChem 2010, 5, 130 – 139

Imatinib Derivatives
1
79%; mp: 269–2718C (dec.); H NMR ([D6]DMSO, 400 MHz): d=2.25
(s, 3H, CH3), 7.24 (d, J=8.40 Hz, 1H), 7.52–7.59 (m, 3H), 8.08 (d, J=
8.40 Hz, 1H), 8.12 (s, 1H), 8.57–8.63 (m, 3H), 8.67 (dd, J=8.40 and
2.00 Hz, 1H), 8.74 (dd, J=4.40 and 1.60 Hz, 1H), 9.38 (d, J=
1.60 Hz, 1H), 9.83 (s, 1H), 10.32 ppm (s, 1H); 13C NMR ([D6]DMSO,
100 MHz): d=17.67, 108.60, 117.13, 117.99, 122.28, 122.45, 124.42,
124.52, 126.46, 128.23, 130.87, 131.31, 132.74, 132.78, 135.02,
135.62, 139.12, 148.37, 148.76, 152.09, 160.03, 160.73, 162.03,
164.70 ppm; HRMS (ESI): calcd for C24H17F3N6O3 [M+H]+ m/z
495.1393, found [M+H]+ m/z 495.1387.
132.71, 134.96, 137.02, 138.57, 139.93, 148.74, 149.10, 151.96,
160.08, 161.56, 162.10, 163.53 ppm; HRMS (ESI): calcd for
C23H17ClN6O3 [M+H]+ m/z 461.1129, found [M+H]+ m/z 461.1123.
N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-2-
chloro-4-nitrobenzamide (SK20): Yellow solid; Yield: 83%; mp:
193–1958C; 1H NMR ([D6]DMSO, 400 MHz): d=2.27 (s, 3H, CH3),
7.27 (d, J=8.40 Hz, 1H), 7.43 (dd, J=8.00 and 2.00 Hz, 1H), 7.48 (d,
J=5.20 Hz, 1H), 7.53 (dd, J=8.00 and 4.80 Hz, 1H), 7.93 (d, J=
8.40 Hz, 1H), 8.09 (d, J=1.60 Hz, 1H), 8.33 (dd, J=8.40 and
2.00 Hz, 1H), 8.46 (d, J=2.00 Hz, 1H), 8.50 (dt, J=8.00 and 2.00 Hz,
1H), 8.56 (d, J=5.20 Hz, 1H), 8.73 (dd, J=4.80 and 1.60 Hz, 1H),
9.04 (s, 1H), 9.31 (d, J=2.00 Hz, 1H), 10.72 ppm (s, 1H); 13C NMR
([D6]DMSO, 100 MHz): d=18.26, 108.23, 116.45, 116.84, 123.07,
124.35, 125.16, 128.63, 130.57, 130.88, 131.70, 132.72, 134.97,
136.95, 138.57, 143.07, 148.74, 148.84, 151.97, 160.09, 161.57,
162.11, 163.70 ppm; HRMS (ESI): calcd for C23H17ClN6O3 [M+H]+ m/
z 461.1129, found [M+H]+ m/z 461.1123.
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-
nitro-3-trifluoromethylbenzamide (SK16): Yellow solid; Yield:
1
88%; mp: 229–2328C (dec.); H NMR ([D6]DMSO, 400 MHz): d=2.23
(s, 3H, CH3), 7.26 (d, J=8.40 Hz, 1H), 7.52 (d, J=5.20 Hz, 1H), 7.56
(dd, J=8.00 and 5.20 Hz, 1H), 7.61 (dd, J=8.40 and 2.00 Hz, 1H),
8.07 (d, J=1.60 Hz, 1H), 8.38 (d, J=8.40 Hz, 1H), 8.54–8.58 (m, 2H),
8.61–8.63 (m, 2H), 8.73 (dd, J=4.80 and 1.60 Hz, 1H), 9.39 (d, J=
2.00 Hz, 1H), 9.84 (s, 1H), 10.45 ppm (s, 1H); 13C NMR ([D6]DMSO,
100 MHz): d=17.83, 108.63, 117.60, 117.96, 124.41, 126.43, 127.18,
127.89, 127.97, 130.86, 132.69, 134.29, 135.04, 136.01, 139.14,
139.18, 148.84, 149.28, 149.37, 152.07, 159.98, 160.69, 162.10,
162.96 ppm; HRMS (ESI): calcd for C24H17F3N6O3 [M+H]+ m/z
495.1393, found [M+H]+ m/z 495.1387.
N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-
chloro-3-nitrobenzamide (SK21): Yellow solid; Yield: 91%; mp:
198–2008C; 1H NMR ([D6]DMSO, 400 MHz): d=2.25 (s, 3H, CH3),
7.26 (d, J=8.40 Hz, 1H), 7.46 (d, J=5.20 Hz, 1H), 7.49 (dd, J=8.40
and 2.00 Hz, 1H), 7.54 (dd, J=8.00 and 4.80 Hz, 1H), 7.99 (d, J=
8.40 Hz, 1H), 8.10 (d, J=2.00 Hz, 1H), 8.28 (dd, J=8.40 and
2.00 Hz, 1H), 8.49 (dt, J=8.00 and 2.00 Hz, 1H), 8.54 (d, J=5.20 Hz,
1H), 8.65 (d, J=2.00 Hz, 1H), 8.71 (dd, J=4.80 and 1.60 Hz, 1H),
9.02 (s, 1H), 9.30 (d, J=2.00 Hz, 1H), 10.53 ppm (s, 1H); 13C NMR
([D6]DMSO, 100 MHz): d=18.25, 108.18, 117.28, 117.72, 124.36,
125.38, 128.50, 128.70, 130.75, 132.48, 132.71, 133.37, 134.97,
135.53, 137.06, 138.48, 147.89, 148.74, 151.95, 160.04, 161.65,
162.16, 162.79 ppm; HRMS (ESI): calcd for C23H17ClN6O3 [M+H]+ m/
z 461.1129, found [M+H]+ m/z 461.1123.
N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-
fluoro-3-nitrobenzamide (SK17): Yellow solid; Yield: 93%; mp:
208–2108C (dec.); 1H NMR ([D6]DMSO, 400 MHz): d=2.25 (s, 3H,
CH3), 7.26 (d, J=8.40 Hz, 1H), 7.46 (d, J=5.20 Hz, 1H), 7.50 (dd, J=
8.40 and 2.00 Hz, 1H), 7.55 (dd, J=8.00 and 4.80 Hz, 1H), 7.79 (dd,
J=11.20 and 8.80 Hz, 1H), 8.10 (d, J=1.60 Hz, 1H), 8.42 (m, 1H),
8.49 (dt, J=8.00 and 2.00 Hz, 1H), 8.53 (d, J=5.20 Hz, 1H), 8.70
(dd, J=4.80 and 1.60 Hz, 1H), 8.77 (dd, J=7.20 and 2.00 Hz, 1H),
9.02 (s, 1H), 9.30 (d, J=2.00 Hz, 1H), 10.53 ppm (s, 1H); 13C NMR
([D6]DMSO, 100 MHz): d=18.25, 108.17, 117.35, 117.80, 119.21,
119.55, 124.36, 126.31, 128.66, 130.74, 132.33, 132.72, 134.98,
136.14, 136.30, 137.13, 138.47, 148.75, 151.97, 160.05, 161.67,
162.17, 162.77 ppm; HRMS (ESI): calcd for C23H17FN6O3 [M+H]+ m/z
445.1424, found [M+H]+ m/z 445.1419.
N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-
nitro-2-trifluoromethylbenzamide (SK22): Yellow solid; Yield:
1
86%; mp: 250–2528C (dec.); H NMR ([D6]DMSO, 250 MHz): d=2.27
(s, 3H, CH3), 7.27 (d, J=8.40 Hz, 1H), 7.40 (dd, J=8.40 and 2.00 Hz,
1H), 7.48 (d, J=5.20 Hz, 1H), 7.54 (dd, J=8.00 and 5.20 Hz, 1H),
8.03 (d, J=2.00 Hz, 1H), 8.07 (d, J=8.40 Hz, 1H), 8.50 (dt, J=8.00
and 2.00 Hz, 1H), 8.55 (d, J=5.20 Hz, 1H), 8.60 (d, J=2.00 Hz, 1H),
8.65 (dd, J=8.40 and 2.40 Hz, 1H), 8.73 (dd, J=5.20 and 1.60 Hz,
1H), 9.03 (s, 1H), 9.30 (d, J=1.60 Hz, 1H), 10.78 ppm (s, 1H);
13C NMR ([D6]DMSO, 100 MHz): d=18.27, 108.23, 116.57, 116.95,
122.24, 122.32, 124.31, 127.46, 128.25, 128.80, 130.90, 131.22,
132.74, 134.96, 136.93, 138.59, 141.96, 148.36, 148.73, 151.97,
160.08, 161.58, 162.11, 164.11 ppm; HRMS (ESI): calcd for
C24H17F3N6O3 [M+H]+ m/z 495.1393, found [M+H]+ m/z 495.1387.
N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-2-
fluoro-5-nitrobenzamide (SK18): Yellow solid; Yield: 84%; mp:
190–1938C; 1H NMR ([D6]DMSO, 400 MHz): d=2.25 (s, 3H, CH3),
7.25 (d, J=8.00 Hz, 1H), 7.43 (d, J=2.00 Hz, 1H), 7.46 (d, J=
5.20 Hz, 1H), 7.54 (dd, J=8.00 and 4.80 Hz, 1H), 7.69 (t, J=9.20 Hz,
1H), 8.07 (d, J=1.60 Hz, 1H), 8.44–8.47 (m, 2H), 8.50–8.57 (m, 2H),
8.71 (d, J=4.80 Hz, 1H), 9.03 (s, 1H), 9.29 (d, J=1.60 Hz, 1H),
10.65 ppm (s, 1H); 13C NMR ([D6]DMSO, 100 MHz): d=18.26,
108.23, 116.62, 117.01, 118.39, 118.79, 124.35, 126.27, 126.36,
126.72, 128.67, 130.87, 132.72, 134.97, 136.95, 138.56, 144.36,
148.76, 151.97, 160.06, 160.91, 161.60, 162.14 ppm; HRMS (ESI):
calcd for C23H17FN6O3 [M+H]+ m/z 445.1424, found [M+H]+ m/z
445.1419.
N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-
nitro-3-trifluoromethylbenzamide (SK23): Yellow solid; Yield:
92%; mp: 218–2198C; 1H NMR ([D6]DMSO, 400 MHz): d=2.29 (s,
3H, CH3), 7.29 (d, J=8.40 Hz, 1H), 7.48 (d, J=5.20 Hz, 1H), 7.52
(dd, J=8.00 and 2.00 Hz, 1H), 7.56 (dd, J=8.00 and 4.80 Hz, 1H),
8.14 (d, J=2.00 Hz, 1H), 8.37 (d, J=8.40 Hz, 1H), 8.51 (dt, J=8.00
and 2.00 Hz, 2H), 8.56 (m, 2H), 8.73 (dd, J=4.80 and 1.60 Hz, 1H),
9.02 (s, 1H), 9.32 (d, J=1.60 Hz, 1H), 10.67 ppm (s, 1H); 13C NMR
([D6]DMSO, 100 MHz): d=18.27, 108.21, 117.31, 117.73, 122.14,
124.35, 126.30, 127.81, 127.89, 128.84, 130.79, 132.69, 134.36,
134.98, 136.97, 138.52, 139.62, 148.76, 149.13, 151.97, 160.05,
161.64, 162.17, 162.82 ppm; HRMS (ESI): calcd for C24H17F3N6O3
[M+H]+ m/z 495.1393, found [M+H]+ m/z 495.1387.
N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-2-
chloro-3-nitrobenzamide (SK19): Yellow solid; Yield: 85%; mp:
223–2258C (dec.); 1H NMR ([D6]DMSO, 400 MHz): d=2.25 (s, 3H,
CH3), 7.24 (d, J=8.40 Hz, 1H), 7.40 (dd, J=8.00 and 2.00 Hz, 1H),
7.46 (d, J=4.80 Hz, 1H), 7.53 (dd, J=8.00 and 4.80 Hz, 1H), 7.73 (t,
J=8.00 Hz, 1H), 7.93 (dd, J=7.60 and 1.60 Hz, 1H), 8.07 (d, J=
2.00 Hz, 1H), 8.16 (dd, J=8.00 and 1.60 Hz, 1H), 8.48 (dt, J=8.00
and 2.00 Hz, 1H), 8.54 (d, J=5.20 Hz, 1H), 8.71 (dd, J=4.80 and
2.00 Hz, 1H), 9.04 (s, 1H), 9.29 (d, J=2.00 Hz, 1H), 10.69 ppm (s,
1H); 13C NMR ([D6]DMSO, 100 MHz): d=18.25, 108.22, 116.37,
116.77, 122.20, 124.34, 126.23, 128.57, 129.40, 130.87, 132,63,
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-2-
methyl-3-nitrobenzamide (SK24): Yellow solid; Yield: 85%; mp:
249–2528C (dec.); 1H NMR ([D6]DMSO, 400 MHz): d=2.26 (s, 3H,
ChemMedChem 2010, 5, 130 – 139
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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137

K. Skobridis et al.
MED
CH3), 2.53 (s, 3H, CH3), 7.23 (d, J=8.40 Hz, 1H), 7.52–7.58 (m, 3H),
7.62 (t, J=8.00 Hz, 1H), 7.85 (d, J=7.60 Hz, 1H), 8.03 (d, J=
7.60 Hz, 1H), 8.17 (s, 1H), 8.58 (dt, J=8.00 and 1.60 Hz, 1H), 8.62
(d, J=5.20 Hz, 1H), 8.75 (dd, J=4.80 and 1.60 Hz, 1H), 9.39 (d, J=
1.60 Hz, 1H), 9.80 (s, 1H), 10.10 ppm (s, 1H); 13C NMR ([D6]DMSO,
100 MHz): d=16.09, 17.97, 108.59, 117.25, 117.68, 124.44, 125.22,
126.52, 127.86, 129.34, 130.79, 131.88, 132.76, 135.01, 136.11,
139.06, 141.05, 148.76, 150.99, 152.10, 160.05, 160.71, 162.02,
166.80 ppm; HRMS (ESI): calcd for C24H20N6O3 [M+H]+ m/z
441.1675, found [M+H]+ m/z 441.1667.
calcd for C23H19N5O [M+H]+ m/z 382.1668, found [M+H]+ m/z
382.1662.
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-ni-
trobenzamide (SK29): Yellow solid; Yield: 90%; mp: 255–2568C
1
(dec.); H NMR ([D6]DMSO, 400 MHz): d=2.23 (s, 3H, CH3), 7.24 (d,
J=8.40 Hz, 1H), 7.52 (d, J=5.20 Hz, 1H), 7.56 (dd, J=8.00 and
4.80 Hz, 1H), 7.62 (dd, J=8.40 and 2.00 Hz, 1H), 8.03 (s, 1H), 8.26
(d, J=8.80 Hz, 2H), 8.41 (d, J=8.80 Hz, 2H), 8.57 (dt, J=8.00 and
1.60 Hz, 1H), 8.62 (d, J=5.20 Hz, 1H), 8.74 (dd, J=4.80 and
1.60 Hz, 1H), 9.38 (d, J=1.60 Hz, 1H), 9.82 (s, 1H), 10.29 ppm (s,
1H); 13C NMR ([D6]DMSO, 100 MHz): d=17.83, 108.61, 117.76,
117.84, 124.22, 124.44, 127.24, 129.72, 130.78, 132.71, 135.03,
136.29, 139.10, 140.85, 148.79, 149.74, 152.12, 159.99, 160.71,
162.08, 164.32 ppm; HRMS (ESI): calcd for C23H18N6O3 [M+H]+ m/z
427.1519, found [M+H]+ m/z 427.1513.
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-4-
methyl-3-nitrobenzamide (SK25): Yellow solid; Yield: 85%; mp:
184–1858C; 1H NMR ([D6]DMSO, 400 MHz): d=2.18 (s, 3H, CH3),
2.60 (s, 3H, CH3), 7.21 (d, J=8.40 Hz, 1H), 7.48 (d, J=5.20 Hz, 1H),
7.52 (dd, J=8.00 and 4.80 Hz, 1H), 7.58 (dd, J=8.40 and 2.40 Hz,
1H), 7.68 (d, J=8.00 Hz, 1H), 7.96 (d, J=1.60 Hz, 1H), 8.23 (dd, J=
8.00 and 1.60 Hz, 1H), 8.52 (dd, J=8.00 and 1.60 Hz, 1H), 8.57 (d,
J=5.20 Hz, 1H), 8.60 (d, J=1.60 Hz, 1H), 8.69 (dd, J=5.20 and
1.60 Hz, 1H), 9.33 (d, J=2.00 Hz, 1H), 9.77 (s, 1H), 10.18 ppm (s,
1H); 13C NMR ([D6]DMSO, 100 MHz): d=17.84, 20.17, 108.59,
117.77, 117.85, 124.19, 124.41, 127.33, 130.74, 132.58, 132.72,
133.72, 134.06, 135.03, 136.37, 136.83, 139.07, 148.78, 149.38,
152.06, 159.95, 160.70, 162.08, 163.67 ppm; HRMS (ESI): calcd for
C24H20N6O3 [M+H]+ m/z 441.1675, found [M+H]+ m/z 441.1667.
Computational methods
The model of the inhibitor-bound structure of the kinase domain
of PDGFR (30 models) was constructed through comparative mod-
elling by the use of MODELER9 v.6[18] based on the solved crystal
structure of the imatinib–c-KIT tyrosine kinase complex (PDB code:
1T46). Of the 30 models, the one with the lowest energy and best
stereochemistry was selected. Docking calculations of the SK li-
gands to c-KIT, FMS, Abl, and PDGFR were carried out using the
provided empirical free energy function and the Lamarckian genet-
ic algorithm (LGA) method[19] as implemented in the AutoDock
program, applying a protocol with an initial population of 50 ran-
domly placed individuals, a maximum number of 1.5ꢁ106 energy
evaluations, a mutation rate of 0.01, a crossover rate of 0.80, and
an elitism value of 1. For the local search, the Solis and Wets algo-
rithm was applied using a maximum of 300 interactions per local
search. Fifty independent docking runs were carried out for each
ligand. Results differing by <1 ꢂ in positional RMSD were clustered
together and represented by the most favourable free energy of
binding.
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-2-
methyl-5-nitrobenzamide (SK26): Yellow solid; Yield: 85%; mp:
184–1858C; 1H NMR ([D6]DMSO, 400 MHz): d=2.24 (s, 3H, CH3),
2.60 (s, 3H, CH3), 7.20 (d, J=8.40 Hz, 1H), 7.49 (d, J=5.20 Hz, 1H),
7.50–7.55 (m, 2H), 7.62 (d, J=8.40 Hz, 1H), 8.11 (s, 1H), 8.25 (dd,
J=8.40 and 2.40 Hz, 1H), 8.31 (d, J=2.40 Hz, 1H), 8.54 (d, J=
8.00 Hz, 1H), 8.58 (d, J=5.20 Hz, 1H), 8.70 (dd, J=4.80 and
1.60 Hz, 1H), 9.35 (d, J=1.60 Hz, 1H), 9.75 (s, 1H), 10.08 ppm (s,
1H); 13C NMR ([D6]DMSO, 100 MHz): d=18.01, 20.21, 108.59,
117.43, 117.75, 122.62, 124.42, 124.70, 126.72, 130.79, 132.63,
132.75, 134.98, 136.10, 138.66, 139.06, 144.43, 145.94, 148.77,
152.07, 160.04, 160.71, 162.02, 166.31 ppm; HRMS (ESI): calcd for
C24H20N6O3 [M+H]+ m/z 441.1675, found [M+H]+ m/z 441.1667.
Acknowledgements
N-[2-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]-3-ni-
trobenzamide (SK27): Yellow solid; Yield: 88%; mp: 1308C;
1H NMR ([D6]DMSO, 400 MHz): d=2.22 (s, 3H, CH3), 7.23 (d, J=
8.40 Hz, 1H), 7.51 (d, J=5.20 Hz, 1H), 7.54–7.61 (m, 2H), 7.86 (t, J=
8.00 Hz, 1H), 8.00 (d, J=1.60 Hz, 1H), 8.45 (dd, J=8.00 and
1.60 Hz, 1H), 8.48 (d, J=7.60 Hz, 1H), 8.57 (dt, J=8.00 and 1.60 Hz,
1H), 8.61 (d, J=4.80 Hz, 1H), 8.73 (dd, J=4.80 and 1.60 Hz, 1H),
8.87 (s, 1H), 9.37 (d, J=2.00 Hz, 1H), 9.79 (s, 1H), 10.37 ppm (s,
1H); 13C NMR ([D6]DMSO, 100 MHz): d=17.27, 108.02, 117.30,
122.45, 123.83, 126.13, 126.78, 130.20, 130.26, 132.16, 134.02,
134.44, 135.76, 135.97, 138.53, 147.85, 148.23, 151.50, 159.37,
160.16, 161.53, 163.24 ppm; HRMS (ESI): calcd for C23H18N6O3
[M+H]+ m/z 427.1519, found [M+H]+ m/z 472.1513.
This work was supported financially by the Research Committee
of Ioannina University, the BBSRC, and the IOG Trust. We thank
Professor A. Giannis (Department of Chemistry, University of Leip-
zig, Germany) for having kindly obtained the ESI HRMS data for
compounds SK1–SK29, the NMR Center of the University of Ioan-
nina, and Mita Vaid for some of the early SK analysis work.
Keywords: drug design
oncogenes · synthesis
· imatinib · kinase inhibitors ·
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([D6]DMSO, 400 MHz): d=2.22 (s, 3H, CH3), 7.23 (d, J=8.40 Hz, 1H),
7.52 (d, J=5.20 Hz, 1H), 7.53–7.63 (m, 5H), 7.99 (d, J=1.60 Hz, 1H),
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148.78, 152.08, 159.96, 169.73, 162.04, 165.76 ppm; HRMS (ESI):
138
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2010, 5, 130 – 139

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Received: September 22, 2009
Revised: October 28, 2009
Published online on November 30, 2009
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