Inhibition of PDGFR tyrosine kinase activity by a series of novel N-(3-(4-(pyridin-3-yl)-1H-imidazol-2-ylamino)phenyl)amides - A SAR study on the bioisosterism of pyrimidine and imidazole

Article abstract of DOI:10.1016/j.ejmech.2007.09.021

A series of N-(3-(4-(pyridin-3-yl)-1H-imidazol-2-ylamino)phenyl)amides were synthesized and tested for inhibition of PDGFR and FLT3 autophosphorylation. The novel N-(3-(4-(pyridin-3-yl)-1H-imidazol-2-ylamino)phenyl)amides, obtained by replacement of the pyrimidine system in Imatinib (1) with an imidazole ring, exhibit potent inhibitory activity on PDGFR, similar to the parent compound (IC₅₀ (9e) = 0.2 μM; IC₅₀ Imatinib (1) = 0.3 μM). Selectivity hereby seems to be conserved, as shown by the lack of activity on FLT3, a closely related class III receptor tyrosine kinase, which is not affected by the parent compound Imatinib.

Full text of DOI:10.1016/j.ejmech.2007.09.021

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European Journal of Medicinal Chemistry 43 (2008) 1444e1453
http://www.elsevier.com/locate/ejmech
Original article
Inhibition of PDGFR tyrosine kinase activity by a series of
novel N-(3-(4-(pyridin-3-yl)-1H-imidazol-2-ylamino)phenyl)
amides e A SAR study on the bioisosterism
of pyrimidine and imidazole
a
a
a
Siavosh Mahboobi a, , Andreas Sellmer , Asma Eswayah , Sigurd Elz ,
*
Andrea Uecker b, Frank-D. Bohmer b
¨
a Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, D-93040 Regensburg, Germany
b Institute of Molecular Cell Biology, Jena University Hospital, D-07747 Jena, Germany
Received 19 June 2007; received in revised form 12 September 2007; accepted 13 September 2007
Available online 2 October 2007
This paper is dedicated to Professor Wolfgang Wiegrebe on the occasion of his 75th birthday.
Abstract
A series of N-(3-(4-(pyridin-3-yl)-1H-imidazol-2-ylamino)phenyl)amides were synthesized and tested for inhibition of PDGFR and FLT3
autophosphorylation. The novel N-(3-(4-(pyridin-3-yl)-1H-imidazol-2-ylamino)phenyl)amides, obtained by replacement of the pyrimidine sys-
tem in Imatinib (1) with an imidazole ring, exhibit potent inhibitory activity on PDGFR, similar to the parent compound (IC50 (9e) ¼ 0.2 mM;
IC50 Imatinib (1) ¼ 0.3 mM). Selectivity hereby seems to be conserved, as shown by the lack of activity on FLT3, a closely related class III
receptor tyrosine kinase, which is not affected by the parent compound Imatinib.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: 1H-Imidazol-2-ylamine; Pyrimidine; Receptor tyrosine kinase; PDGFR; Bioisosterism
1. Introduction
for the colony stimulating factor 1 (CSF1R), and FLT3.
PDGF receptors are expressed on several cell types, including
fibroblasts, vascular smooth muscle cells, and pericytes, and
are involved in wound healing and regulation of homeostasis
of the connective tissue compartment [4]. A very well known
and highly selective tyrosine kinase inhibitor is STI571 (Ima-
tinib, 1) (Fig. 1). Imatinib is active towards both isoforms of
PDGFR [5,6] Moreover, Imatinib is highly active towards
ABL/BCR-ABL [7] and c-KIT, and, based on this capacity,
is successfully used in the therapy of chronic myeloid leuke-
mia (CML), and gastrointestinal stroma tumors [8e10].
The pharmacophore for this compound, described in early
reports from Zimmermann et al. [5], comprises the following
features: (i) a N-phenylpyrimidin-2-amine (b-ring system)
substituted in position 4 with a 3-pyridyl-substituent (a-ring
system; part A). (ii) The phenylamino substituent is moreover
Selective inhibition of protein kinases appears as an effec-
tive therapeutic approach for the treatment of certain types of
human cancer [1]. Platelet-derived growth factor receptors
(PDGFRs) have been implicated in a number of pathologies,
especially in various cancers, and are therefore considered as
promising drug targets (for review see Refs. [2,3]. The two
types of PDGF receptors, PDGFRa and b, are members of
the class III receptor tyrosine kinase (RTK) family, which
also includes the receptors for the stem cell factor (c-KIT),
* Corresponding author. Tel.: þ49 (0)941 943 4824; fax: þ49 (0)941 943
1737.
E-mail address: siavosh.mahboobi@chemie.uni-regensburg.de (S. Mahboobi).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.09.021

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 1444e1453
1445
"Flag-Methyl"
CH3
H
N
R1
c
H
N
3
N
b
N
b
A
Isosteric Modification
c
N
NH
6
4
HN
O
N
O
HN
a
a
R2
N
X
Y
B
d
general structure (2)
R1 = H, CH3, C2H5
R2 = CH3, Aryl
X, Y= CH, N
Imatinib (1)
N
Fig. 1. Structure of ImatinibÒ (1) (left) and general structure (2) of the isosterically modified imidazolyl analogs investigated (right). The pharmacophore of
ImatinibÒ responsible for PDGFR inhibitory activity is shown in bold. Without substitution of the Flag-Methyl group, compounds of the phenylaminopyrimidine
class have also been shown to be potent inhibitors of PKC-subtypes a,d and c-SRC.
modified as shown in Fig. 1 by substitution with methyl (or
chlorine) in position 3 of the c-ring system and by substitution
with a benzamide substructure in position 6. Hereby, the so
called ‘‘Flag-Methyl’’ group has been shown to be responsible
for enhancement of PDGFR inhibitor activity as well as selec-
tivity. (iii) The benzamide substituent preferably bears a lipo-
philic substructure in para position (substructure part B).
However, to what extent are the described structural re-
quirements essential for full inhibitory activity? To answer
this question, we investigated several derivatives replacing
the pyrimidine ring system by an imidazolyl system, a strategy
that has obviously also been pursued by Ciufolini et al. in
a similar manner, who recently patented aminoaryl substituted,
five-membered heterocyclic compounds for the treatment of
diseases and described their inhibitory activity towards wild
type and mutated c-KIT [11].
to the desired N-(2-methyl-5-nitrophenyl)-4-phenyl-1H-imida-
zol-2-amine (5a), respectively, to the N-(3-nitrophenyl)-4-(pyr-
idinyl)-1H-imidazol-2-amines 5be5e. Catalytic reduction with
ammonium formate on PdC in methanolic solution led to 6-
methyl-N1-(4-phenyl-1H-imidazol-2-yl)benzene-1,3-diamine
(6a) and N1-(4-(pyridinyl)-1H-imidazol-2-yl)benzene-1,3-
diamines 6be6e, which were transformed to the corresponding
amides 8ae12 (Scheme 1) by reaction with carboxylic acid
chlorides (7ae7l). In case of 9i, the arylamide was additionally
modified by reduction of the nitro group, affording the corre-
sponding amino derivative 9m.
3. Results and discussion
The five-membered ring system of imidazole exhibits an
additional hydrogen bridge donor, and lacks one hydrogen
bridge acceptor in comparison to pyrimidine. An exchange
of donor and acceptor hereby is easily possible by tautomer-
ism [16]. The heterocyclic imidazolyl analog moreover ex-
hibits a modified molecular geometry, caused by the
changed binding angles. Therefore, as already mentioned
above, the 3-pyridyl ring was replaced by benzene and by
a 4-pyridyl substituent, with respect to the modified geometri-
cal structure resulting from the exchange of a six-membered
ring system by a five-membered ring system, in addition. A
summary of the biological data for inhibition of PDGFR by
2-arylaminoimidazolyl compounds modifying the pyridine
and amide substituent is compiled in Table 1. To determine
if the selectivity of the compounds was retained, activity on
FLT3, a closely related member of the class III receptor tyro-
sine kinase (RTK) family, which is not affected by the parent
compound Imatinib [17,18], was tested additionally.
2. Chemistry
The first stage of our study comprised the synthesis of the
imidazolyl isostere of the ImatinibÒ pharmacophore and a se-
ries of derivatives, where the 3-pyridyl ring was replaced by
benzene and, with respect to the modified geometrical structure
resulting from the exchange of a six-membered ring system by
a five-membered ring system, by a 4-pyridyl substituent.
Chemical modification was then performed by replacing the
benzamide substructure in position 3 or modifying this substit-
uent. Finally, also the influence of the ‘‘Flag-Methyl’’ group
was investigated. The synthetic route (Scheme 1), which was
simultaneously developed for the synthesis of the structurally
closely related N-(3-(4-(pyridin-4-yl)-1H-imidazol-2-ylami-
no)phenyl)amides in a similar manner by Ciufolini et al.
[11], is described in the following: ring closure of 2-bromo-
1-phenylethanone (3a) or 2-bromo-1-(pyridinyl)ethanone
hydrobromides 3b [12] and 3c [13] with suitably substituted
1-(3-nitrophenyl)guanidine nitrates 4a [14], 4b [15] or 4c led
As shown in Table 1, exchange of the pyrimidine to an im-
idazole system is well tolerated. In case of 9a, even an en-
hancement in activity compared to the pyrimidine compound
(13) can be observed (5.9 mM vs. 50 mM). As in the parent

1446
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 1444e1453
R1
R1
N
H
O
PdC (10%)
EtOH , NaOH
N
H
Br
N
+
Δ
NO2 NEt3,
x HNO3
MeOH, NH4 HCO2
NH
NO2
Y
H2N
NH
X
Y
X
Y = CH
4a: R1 = H
Y = CH
Y = N
Y = CH
X = N
3a: X = CH
3b: X = N
4b: R1 = CH3
4c: R1 = C2H5
X = CH
X = CH
5a: R1 = CH3
5e: R1 = CH3
5b: R1 = H
Y = N
5c: R1 = CH3
5d: R1= C2H5
3c: X = CH
R1
R1
H
H
N
H
N
PdC, NH4HCO2
N
Pyridine, NaH
N
Δ
MeOH,
N
N
NH2
NH
NH
NH
NH
R2
NH
O
O
7a-l
O
Y
X
Y
R2
Cl
N
X
Y = CH
Y = CH
X = CH
X = N
9m
8a, 8b, 8k
9a-9l
6a: R1 = CH3
6b: R1 = H
6c: R1 = CH3
NH2
10c-10d, 10l
11b-11e
6d: R1 = C2H5
Y = N
12b, 12l
X = CH
6e: R1 = CH3
Y = CH, X = N
Y = CH, X = CH
Y = CH, X = N
1
7a: R2 = CH3
R = H
1
1
R = CH3
R = CH3
7b: R2 = Ph
10c: R2 = 2-CH3-Ph
10d: R2 = 3-CH3-Ph
10e: R2 = 4-CH3-Ph
8a: R2 = CH3
8b: R2 = Ph
9a: R2 = CH3
7c: R2 = 2-CH3-Ph
7d: R2 = 3-CH3-Ph
7e: R2 = 4-CH3-Ph
9b: R2 = Ph
9c: R2 = 2-CH3-Ph
9d: R2 = 3-CH3-Ph
9e: R2 = 4-CH3-Ph
10l: R2 =
8l: R2=
N
N
N
N
7f: R2 = 4-n-Decyl-Ph
7g: R2 = 4-OCH3-Ph
7h: R2 = 3,4,5-OCH3-Ph
7i: R2 = 4-NO2-Ph
7j: R2 = 4-Cl-Ph
9f: R2 = 4-n-Decyl-Ph
9g: R2 = 4-OCH3-Ph
9h: R2 = 3,4,5-OCH3-Ph
9i: R2 = 4-NO2-Ph
9j: R2 = 4-Cl-Ph
Y = CH, X = N
1
R = C2H5
7k: R2 = 4-Pyridyl
11b: R2 = Ph
9k: R2 = 4-Pyridyl
11c: R2 = 2-CH3-Ph
11d: R2 = 3-CH3-Ph
11e: R2 = 4-CH3-Ph
7l: R2 =
N
N
9l : R2
=
N
N
9m: R2 = 4-NH2-Ph
Y = N, X = CH
1
R = CH3
12b: R2 = Ph
12l: R2 =
N
N
Scheme 1. Synthesis of target compounds.
compound, the 3-pyridyl-substituted derivatives (9a, 9b) ex-
hibit most potent inhibitory activity, decreasing by replace-
ment of the 3-pyridyl substituent by phenyl (8b), and even
more significant by replacement by 4-pyridyl (12b).
For the 3-pyridyl compounds exhibiting most potent inhib-
itory activity, we studied the influence of the substitution
patterns of the benzamide substituent in this system in the fol-
lowing. The investigated compounds are compiled in Table 2.
Again, none of these compounds affected FLT3 up to concen-
trations of 10 mg/mL.
In case of the pyrimidine series, substitution by a lipophilic
substituent in para position of the benzamide substructure led
to significant increase of potency [5]. In case of the imidazolyl
compounds, however, para-substitution in the benzene ring by
methyl (9e) or chlorine (9j) is tolerated, but affects activity
only slightly, showing best inhibitory activity for the 4-methyl
derivative 9e. Introduction of more voluminous substituents, as
demonstrated by the C10-chain of 9f reduces activity as much
The amide substructure is essential for activity. All investi-
gated compounds lacking this structural feature (compounds
5ae5e and 6ae6e, Scheme 1) neither inhibited PDGFR nor
FLT3 up to concentrations of 10 mg/mL (data not shown).
As reported for the pyrimidine series [5], the benzamides 8b
and 9b are superior to their corresponding acetamides 8a
and 9a. In contrast to the pyrimidine series, introduction of
the 1-methyl-4-benzylpiperazine in the imidazolyl series is
detrimental (9l vs. 9b). None of the investigated compounds
affected FLT3 up to concentrations of 10 mg/mL.

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 1444e1453
1447
Table 1
Inhibition of PDGFR by 2-arylaminoimidazolyl compounds
H3C
H3C
O
O
H
N
H
N
N
H
R2
N
H
R2
N
N
NH
N
R1
R1
R1
R2
Nr.
IC50 PDGFR [mM]
Nr.
IC50 PDGFR [mM]
Ph
3-Pyridyl
Ph
CH3
CH3
Ph
8a
9a
>30
5.9 mM
7.1
13
14
50 [5]
a
8b
9b
12b
3-Pyridyl
4-Pyridyl
Ph
Ph
0.3
>10
0.1e0.3 [5]
a
N
N
a
Ph
8l
>10
>10
>10
N
N
N
3-Pyridyl
9l
Imatinib (1)
0.3b
N
4-Pyridyl
12l
a
No data from literature.
Values for Imatinib as a reference compound in the used swiss 3T3 cell model.
b
as introduction of methoxy groups (9g, 9h) or introduction of
nitro (9i) or amino groups does (9m). The 4-pyridyl-substitu-
ent (9k) instead of a benzene system (9b) is tolerated much
better.
In the following, the effect of the ‘‘Flag-Methyl’’ in the
imidazolyl system was investigated, replacing this group by
hydrogen or an ethyl substituent. With respect to the changed
geometrical structure, chemical modification was also per-
formed including different substitution patterns in the benza-
mide system (Table 3).
and 10, being substituted in para position by a methyl group.
Comparing the data of 9ce9e and 10ce10e, no significant ef-
fect by introduction of the ‘‘Flag-Methyl’’ group can be ob-
served, also 9e exhibits similar activity as 10e. In contrast,
for the series 11be11e inhibitory activity is highest for the
meta-substituted compound 11d, exhibiting an IC50 value of
0.3 mM. Also in case of 10l, as already seen for the series of
compounds 9, introduction of the 1-methylene-4-methylpipera-
zine-substructure is detrimental for activity.
As demonstrated by the data shown in Table 3, highest in-
hibitory activity is observed within the series of compounds 9
4. Conclusions
The novel N-(3-(4-(pyridin-3-yl)-1H-imidazol-2-ylamino)-
phenyl)amides, obtained by replacement of the pyrimidine
system in Imatinib (1) by an imidazole ring, exhibit potent in-
hibitory activity on PDGFR, similar to the parent compound
(IC50 (9e) ¼ 0.2 mM; IC50 Imatinib (1) ¼ 0.3 mM). Selectivity
hereby seems to be conserved, as shown by the lack of activity
on FLT3, a closely related receptor tyrosine kinase, which is
not affected by the parent compound Imatinib.
Table 2
Inhibition of PDGFR by 2-arylaminoimidazolyl compounds by modification
of the amide substituent
H3C
O
H
N
N
H
R
N
NH
As in the parent pyrimidine series, the amide substructure is
essential for activity as well as substitution of the b-ring by
a 3-pyridyl substituent. Also, as observed for the parent com-
pounds, benzamides in general are superior to acetamides, but
in contrast to the pyrimidine series, introduction of a methyl
group in position 3 of the c-ring system (Fig. 1) affects activity
only slightly.
N
Nr.
IC50 PDGFR [mM]
4-Ph
9b
9e
9f
0.3
0.2
4-CH3-Ph
4-n-Decyl-Ph
4-OCH3-Ph
3,4,5-OCH3-Ph
4-NO2-Ph
4-Chlor-Ph
4-Pyridyl
4-NH2
>10
>30
>10
>30
0.4
9g
9h
9i
5. Experimental part
9j
9k
9m
1.8
>30
Inhibition of PDGF receptors and of FLT3 were assessed in
Swiss 3T3 fibroblasts or in EOL-1 cells, respectively, exactly

1448
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 1444e1453
Table 3
Inhibition of PDGFR by 2-arylaminoimidazolyl compounds e modification of the c-ring system and the benzamide substituent
CH3
H
H3C
O
O
O
H
N
H
N
N
N
H
H
N
N
H
R
N
N
H
R
NH
R
NH
N
NH
N
N
N
R1
Nr.
IC50 PDGFR [mM]
Nr.
IC50 PDGFR [mM]
Nr.
IC50 PDGFR [mM]
H
9b
9c
9d
9e
9l
0.3
0.6
11b
11c
11d
11e
4.7
1.6
0.3
6.5
2-CH3
3-CH3
4-CH3
10c
10d
10e
10l
0.6
0.3
0.2
6.5
2.2
0.2
>10
N
N
as previously described [19]. All IC50 values were derived
from duplicate or triplicate determinations, and were deter-
mined from a concentration curve comprising six concentra-
tions using the program SigmaPlot (Systat Software Inc.) as
described earlier [20]. The standard errors of the mean
(SEM) are always in the range of ꢀ50%.
(SiO2; CH2Cl2/MeOH 10:1; vol./vol.) and crystallisation
from ethyl acetate.
6.2.1. N-(2-Methyl-5-nitrophenyl)-4-phenyl-1H-imidazol-2-
amine (5a)
Yield: 3.84 g (55%), yellow crystals, mp: 186.8e187.1 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3405, 1652. 1H NMR (DMSO-d6):
d (ppm) ¼ 2.26 (s, 3H), 5.61 (s, 2H, exchangeable), 7.11e
7.19 (m, 1H, aromat.), 7.27e7.37 (m, 3H, aromat.), 7.66e
7.75 (m, 3H, aromat.), 8.14 (d, 1H, J ¼ 2.3 Hz, aromat.),
8.26 (dd, 1H, J ¼ 2.3 Hz, J ¼ 8.5 Hz,). EI-MS (70 eV) m/z
6. Chemical procedures
6.1. General
ꢄ
(%): 294 (100) [M]þ , 264 (5), 248 (6). Anal.
NMR spectra were recorded with a Bruker Avance
300 MHz spectrometer at 300 K, using TMS as an internal
standard. IR spectra (KBr or pure solid) were measured with
a Bruker Tensor 27 spectrometer. Melting points were deter-
(C16H14N4O2$1/4H2O): C 64.31 H 4.89 N 18.75 Found: C
64.46 H 4.78 N 18.91.
6.2.2. N-(3-Nitrophenyl)-4-(pyridin-3-yl)-
1H-imidazol-2-amine (5b)
mined with a Buchi B-545. MS spectra were measured with
¨
a Finnigan MAT 95 (EI, 70 eV), or with a Finnigan Thermo
Quest TSQ 7000 (ESI) (DCM/MeOH þ 10 mmol/l NH4Ac).
All reactions were carried out under nitrogen atmosphere. El-
emental analyses were performed by the Analytical Labora-
tory of the University of Regensburg.
Yield: 9.19 g, 32.70 mmol (66%) of yellow crystals, mp:
191.8e192.0 ꢁC. IR (KBr): n (cmꢃ1) ¼ 3406, 3099, 1600,
1526. 1H NMR (DMSO-d6): d (ppm) ¼ 6.00 (s, br., 2H),
7.37 (dd, 1H, J ¼ 7.8 Hz, J ¼ 4.9 Hz), 7.73 (s, 1H), 7.83 (t,
1H, J ¼ 8.2 Hz), 8.06e8.00 (m, 2H), 8.23 (ddd, 1H,
J ¼ 8.2 Hz, J ¼ 2.2 Hz, J ¼ 0.8 Hz), 8.39e8.37 (m, 2 H),
8.95 (d, 1H, J ¼ 1.7 Hz). CI-MS (NH3) m/z (%): 252 (100),
282 (25) [M ꢃ Hþ]ꢃ. Anal. (C14H11N5O2$1/2H2O): C, H, N.
6.2. Preparation of 4a-4c e general procedure A
To a stirred suspension of the respective guanidinium ni-
trate 4a [14], 4b [15] or 4c (23.4 mmol) in ethanol
(300 mL), powdered KOH (23.4 mmol, 1.31 g) was added
and the mixture heated to 80 ꢁC, liberating the free base of
guanidine in situ. A mixture of the respective 2-bromo-1-
arylethanone (3ae3c) (23.4 mmol) and triethylamine
(23.4 mmol) in 150 mL of ethanol was added within half an
hour and the mixture stirred at 80 ꢁC for 12 h. The solvent
was removed under reduced pressure, diluted aqueous ammo-
nia solution was added (100 mL) and the residue extracted
with ethyl acetate (3 ꢂ 250 mL). The combined organic layers
were dried (Na2SO4), the solvent removed under reduced pres-
sure, and the product purified by column chromatography
6.2.3. N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl)-
1H-imidazol-2-amine (5c)
Yield: 3.45 g (50%), yellow crystals, mp: 153.0e154.0 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3432, 3084, 1629, 1522. 1H NMR
(DMSO-d6): d (ppm) ¼ 2.27 (s, 3H), 5.74 (s, 2H, exchange-
able), 7.34 (dd, 1H, J ¼ 7.7 Hz, J ¼ 4.7 Hz, aromat.), 7.45 (s,
1H, aromat.), 7.73 (d, 1H, J ¼ 8.5 Hz aromat.), 8.00 (d, 1H,
J ¼ 7.7 Hz, aromat.), 8.16 (d, 1H, J ¼ 2.5 Hz, aromat.), 8.27
(dd, 1H, J ¼ 8.5 Hz, J ¼ 2.5 Hz, aromat.), 8.36 (dd, 1H,
J ¼ 4.7 Hz, J ¼ 1.6 Hz, aromat.), 8.91 (d, 1H, J ¼ 1.6 Hz, aro-
ꢄ
mat.). EI-MS (70 eV) m/z (%): 295 (100) [M]þ , 265 (5), 249
(6). Anal. (C15H13N5O2): C, H, N.

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 1444e1453
1449
6.2.4. N-(2-Ethyl-5-nitrophenyl)-4-(pyridin-3-yl)-
1H-imidazol-2-amine (5d)
d (ppm) ¼ 5.39 (s, 2H), 5.55 (s, 2H), 6.57 (dd, 2H, J ¼ 1.1 Hz,
J ¼ 7.9 Hz, aromat.), 6.65 (t, 1H, J ¼ 2.0 Hz, aromat.), 7.14 (t,
1H, J ¼ 7.9 Hz, aromat.), 7.32 (dd, 1H, J ¼ 4.7 Hz, J ¼ 7.9 Hz,
aromat.), 7.45 (s, 1H, aromat.), 8.00 (td, 1H, J ¼ 1.9 Hz,
J ¼ 7.9 Hz, aromat.), 8.33 (dd, 1H, J ¼ 1.6 Hz, J ¼ 4.7 Hz, ar-
omat.), 8.91 (d, 1H, J ¼ 1.6 Hz, aromat.). CI-MS (NH3) m/z
(%): 252 (100) [M þ Hþ]þ. Anal. (C14H13N5$1/4H2O): C,
H, N.
Yield: 2.93 g, 9.47 mmol (41%) of yellow crystals, mp:
166.9e167.0 ꢁC. IR (KBr): n (cmꢃ1) ¼ 3301, 3129, 1635,
1521. 1H NMR (DMSO-d6):
d
(ppm) ¼ 1.12 (t, 3H,
J ¼ 7.5 Hz), 2.59 (q, 2H, J ¼ 7.5 Hz), 5.71 (s, 2H), 7.34 (dd,
1H, J ¼ 7.9 Hz, J ¼ 4.7 Hz, aromat.), 7.45 (s, 1H, aromat.),
7.75 (d, 1H, J ¼ 8.8 Hz, aromat.), 8.00 (td, 1H, J ¼ 8.1 Hz,
J ¼ 2.0 Hz, aromat.), 8.14 (d, 1H, J ¼ 2.5 Hz, aromat.),
8.30e8.37 (m, 2H, aromat.), 8.91 (d, 1H, J ¼ 1.4 Hz, aromat.).
CI-MS (NH3) m/z (%): 310 (27) [M þ Hþ]þ, 280 (100). Anal.
(C16H15N5O2$1/4H2O): C, H, N.
6.3.3. 6-Methyl-N1-(4-(pyridin-3-yl)-1H-imidazol-
2-yl)benzene-1,3-diamine (6c)
Yield: 1.06 g (80%), colorless crystals, mp: 121.9e
1
122.4 ꢁC. IR (KBr): n (cmꢃ1) ¼ 3340, 3217, 1619. H NMR
6.2.5. N-(2-Methyl-5-nitrophenyl)-4-(pyridin-4-yl)-
1H-imidazol-2-amine (5e) [11]
(DMSO-d6): d (ppm) ¼ 1.94 (s, 3H), 5.17 (s, br., 2H, ex-
changeable), 5.32 (s, 2H, exchangeable), 6.49 (d, 1H,
J ¼ 2.4 Hz, aromat.), 6.59 (dd, 1H, J ¼ 8.2 Hz, J ¼ 2.4 Hz, ar-
omat.), 7.02 (d, 1H, J ¼ 8.2 Hz, aromat.), 7.30 (s, 1H, aro-
mat.), 7.31 (ddd, 1H, J ¼ 7.9 Hz, J ¼ 4.8 Hz, J ¼ 0.9 Hz,
aromat.), 7.98 (ddd, 1H, J ¼ 7.9 Hz, J ¼ 1.7 Hz, J ¼ 2.2 Hz,
aromat.), 8.32 (dd, 1H, J ¼ 4.8 Hz, J ¼ 1.7 Hz, aromat.),
8.90 (d, 1H, J ¼ 2.2 Hz, J ¼ 0.9 Hz, aromat.). CI-MS (NH3)
m/z (%): 266 (100) [M þ Hþ]þ. Anal. (C15H15N5$H2O): C,
H, N.
Yield: 1.82 g (21%), yellow crystals, mp: 156.9e157.2 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3252, 3107, 1665, 1599. 1H NMR
(DMSO-d6): d (ppm) ¼ 2.26 (s, 3H), 5.78 (s, 2H, exchange-
able), 7.60 (AA0, 2H, aromat.), 7.62 (s, 1H, aromat.), 7.74
(d, 1H, J ¼ 8.5 Hz aromat.), 8.18 (d, 1H, J ¼ 2.5 Hz aromat.),
8.28 (dd, 1H, J ¼ 8.5 Hz, J ¼ 2.5 Hz, aromat.), 8.46 (XX0, 2H,
aromat.). Anal. (C15H13N5O2): C, H, N.
6.3. Preparation of compounds 6ae6e by catalytic
reduction of the nitro group e general procedure B
6.3.4. 4-Ethyl-N-(4-pyridin-3-yl-1H-imidazol-2-yl)-
benzene-1,3-diamine (6d)
To a stirred solution of the respective nitro precursor 5ae5e
(5.00 mmol) and NH4HCOO (50.0 mmol) in methanol
(100 mL), Pd on charcoal (10%, 0.5 g) was added and the mix-
ture heated to 60 ꢁC for 15e30 min until an excessive gas de-
velopment occurred. The hot solution was filtered over a pad
of Na2SO4 to remove the catalyst, and the solvent was distilled
off under reduced pressure. In case of 6be6e, the remaining
solid was dissolved in CH2Cl2, extracted with diluted aqueous
ammonia, the organic layer dried (Na2SO4), the solvent re-
moved, and the product purified by column chromatography
(SiO2; CH2Cl2/MeOH, 10:1). In case of 6a, the crude solid
was directly subjected to column chromatography (SiO2;
CH2Cl2/MeOH, 10:1).
Yield: 1.31 g (61%), yellow crystals, mp: 162.6e162.8 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3346, 3127, 1601. 1H NMR (DMSO-d6):
d (ppm) ¼ 0.99 (t, 3H, J ¼ 7.5 Hz), 2.28 (q, v br., 2H,
J ¼ 8.6 Hz), 5.19 (s, br., 2H), 5.28 (s, br., 2H), 6.45 (d, 1H,
J ¼ 2.2 Hz, aromat.), 6.63 (dd, 1H, J ¼ 8.2 Hz, J ¼ 2.2 Hz, ar-
omat.), 7.05 (d, 1H, J ¼ 8.23 Hz, aromat.), 7.30 (m, 2H, aro-
mat.), 7.98 (td, 1H, J ¼ 8.1 Hz, J ¼ 2.0 Hz, aromat.), 8.31
(dd, 1H, J ¼ 4.7 Hz, J ¼ 1.6 Hz, aromat.), 8.89 (d, 1H,
J ¼ 1.4 Hz, aromat.). CI-MS (NH3) m/z (%): 280 (100)
[M þ Hþ]þ. Anal. (C16H17N5$1/4H2O): C, H, N.
6.3.5. 6-Methyl-N1-(4-(pyridin-4-yl)-1H-imidazol-
2-yl)benzene-1,3-diamine (6e) [11]
Yield: 1.29 g (97%), colorless solid.
6.3.1. 6-Methyl-N1-(4-phenyl-1H-imidazol-
2-yl)benzene-1,3-diamine formate (6a)
6.4. Preparation of amides 8a, 8b, 8k, 9ae9l, 10c, 10d,
10l, 11be11e, 12b and 12l e general procedure C
Yield: 1.08 g (82%), colorless solid, mp: 156.6e160.0 ꢁC.
1
IR (KBr): n (cmꢃ1) ¼ 3459, 3197, 1670. H NMR (DMSO-
d6): d (ppm) ¼ 1.94 (s, 3H), 5.30 (s, vbr., 2H, exchangeable),
5.46 (s, 3H, exchangeable), 6.49 (d, 1H, J ¼ 2.4 Hz, aromat.),
6.59 (dd, 1H, J ¼ 8.2 Hz, J ¼ 2.4 Hz, aromat.), 7.02 (d, 1H,
J ¼ 8.2 Hz, aromat.), 7.15e7.16 (m, 1H, aromat.), 7.17 (s,
1H, aromat.), 7.28e7.32 (m, 2H, aromat.), 7.66e7.69 (m,
2H, aromat.), 8.18 (s, 1H). EI-MS (70 eV) m/z (%): 264
The amidations of the arylamines 6ae6e were performed
with the respective free base. In case of 6a, this was obtained
by subjecting the formamidinium salt to the following proce-
dure: the salt was dissolved in CH2Cl2, the organic layer ex-
tracted with diluted aqueous ammonia, the organic layer
dried (Na2SO4), and the solvent removed.
Amidation procedure of the arylamines: to a stirred solution
of the respective arylamine (1.0 mmol) in pyridine (20.0 mL),
the respective carboxylic acid chloride (7ae7j), 4-(pyridin-4-
yl)benzoyl chloride hydrochloride (7k) or 40-((4-methylpipera-
zin-1-yl)methyl)biphenyl-4-carbonyl chloride dihydrochloride
(7l) (1.1 mmol) was added, and the mixture stirred at room
temperature for 1e2 h. NaH (1.1 mmol) was added and the
ꢄ
(100) [M]þ , 221 (13), 161 (26), 146 (28), 132 (17). Anal.
(C16H16N4$HCOOH): C, H, N.
6.3.2. N-(4-Pyridin-3-yl-1H-imidazol-2-yl)-
benzene-1,3-diamine (6b)
Yield: 1.46 g (81%), yellow crystals, mp: 129.5e129.6 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3386, 3091, 1601. 1H NMR (DMSO-d6):

1450
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 1444e1453
mixture stirred for additional 12 h. If carbonic acid chloride
hydrochlorides were used for amidation, additional 1.1 equiv
of NaH were added for each hydrochloride equivalent. The sol-
vent was removed under reduced pressure, the residue treated
with diluted aqueous ammonia (30 mL), extracted with
CH2Cl2 (3 ꢂ 50 mL), the organic layer dried (Na2SO4) and
the solvent removed.
Purification was performed by column chromatography (7l,
8l, 9l, 10l and 12l: SiO2; CH2Cl2/MeOH/NH3 conc. 3:1:0.01;
all other compounds: CH2Cl2/MeOH/NH3 conc. 10:1:0.01),
yielding the desired amides as colorless solids.
1H, J ¼ 2.0 Hz, J ¼ 8.0 Hz, aromat.), 8.34 (dd, 1H,
J ¼ 1.6 Hz, J ¼ 8.4 Hz, aromat.), 8.91 (d, 1H, J ¼ 1.7 Hz, aro-
ꢄ
mat.), 10.07 (s, 1H). EI-MS (70 eV) m/z (%): 307 (100) [M]þ ,
160 (44). Anal. (C17H17N5O$2/3H2O): C, H, N.
6.4.5. N-(4-Methyl-3-(4-(pyridin-3-yl)-1H-imidazol-
2-ylamino)phenyl)benzamide (9b)
Yield: 0.22 g (42%), mp: 240.2e240.9 ꢁC. IR (KBr): n
1
(cmꢃ1) ¼ 3435, 2924, 2854, 1668, 1604. H NMR (DMSO-
d6): d (ppm) ¼ 2.12 (s, 3H), 5.53 (s, 2H), 7.33 (dd, 1H,
J ¼ 4.8 Hz, J ¼ 7.3 Hz, aromat.), 7.38 (d, 2H, J ¼ 5.0 Hz, aro-
mat.), 7.51e7.63 (m, 3H), 7.82 (dd, 2H, J ¼ 2.0 Hz,
J ¼ 7.0 Hz, aromat.), 7.95 (dd, 2H, J ¼ 1.5 Hz, J ¼ 8.1 Hz, ar-
omat.), 8.01 (td, 1H, J ¼ 2.0 Hz, J ¼ 8.0 Hz, aromat.), 8.34
(dd, 1H, J ¼ 1.6 Hz, J ¼ 4.7 Hz, aromat.), 8.92 (d, 1H,
J ¼ 1.7 Hz, aromat.), 10.39 (s, 1H). PI-EIMS (70 eV) m/z
6.4.1. N-(4-Methyl-3-(4-phenyl-1H-imidazol-
2-ylamino)phenyl)acetamide (8a)
Yield: 0.14 g (24%), mp: 191.6e192.9 ꢁC. IR (KBr): n
(cmꢃ1) ¼ 3311, 1681, 1604. 1H NMR (DMSO-d6):
d (ppm) ¼ 2.06 (d, 6H, J ¼ 6.6 Hz), 5.37 (s, 2H), 7.13 (t,
1H, J ¼ 7.3 Hz, aromat.), 7.19 (s, 1H, aromat.), 7.30 (t, 3H,
J ¼ 7.5 Hz, aromat.), 7.54 (dd, 1H, J ¼ 2.0 Hz, J ¼ 8.2 Hz, ar-
omat.), 7.60 (d, 1H, J ¼ 2.0 Hz, aromat.), 7.68 (d, 2H,
J ¼ 7.1 Hz, aromat.), 10.08 (s, 1H). PI-EIMS (70 eV) m/z
ꢄ
(%): 369 (100) [M]þ , 105 (56), 77 (30), 160 (15). Anal.
(C22H19N5O$H2O): C, H, N.
6.4.6. 2-Methyl-N-(4-methyl-3-(4-(pyridin-3-yl)-
1H-imidazol-2-ylamino)phenyl)benzamide (9c)
ꢄ
(%): 306 (100) [M]þ , 160 (39). Anal. (C18H18N4O$1/
Yield: 0.45 g (59%), white crystals, mp: 117.6e118.2 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3432, 2924, 1669, 1616. 1H NMR
(DMSO-d6): d (ppm) ¼ 2.10 (s, 3H), 2.38 (s, 3H), 5.53 (s,
2H), 7.25e7.47 (m, 7H, aromat.), 7.76 (ddd, 2H, J ¼ 8.1 Hz,
J ¼ 8.1 Hz, aromat.), 8.01 (td, 1H, J ¼ 7.7 Hz, J ¼ 1.6 Hz, ar-
omat.), 8.34 (dd, 1H, J ¼ 4.7 Hz, J ¼ 1.4 Hz, aromat.), 8.92 (d,
1H, J ¼ 1.6 Hz, aromat.), 10.47 (s, 1H). CI-MS (NH3) m/z (%):
384 (100) [M þ Hþ]þ. Anal. (C23H21N5O$1/2H2O): C, H, N.
3H2O): C, H, N.
6.4.2. N-(4-Methyl-3-(4-phenyl-1H-imidazol-
2-ylamino)phenyl)benzamide (8b)
Yield: 0.27 g (39%), mp: 191.4e193.0 ꢁC. IR (KBr): n
(cmꢃ1) ¼ 3380, 2922, 1650, 1615. 1H NMR (DMSO-d6):
d (ppm) ¼ 2.12 (s, 3H), 5.40 (s, 2H), 7.14 (t, 1H, J ¼ 7.3 Hz,
aromat.), 7.23 (s, 1H), 7.31 (t, 2H, J ¼ 7.7 Hz, aromat.), 7.38
(d, 1H, J ¼ 9.0 Hz, aromat.), 7.50e7.69 (m, 3H, aromat.),
7.70 (d, 2H, J ¼ 7.2 Hz, aromat.), 7.82 (dd, 2H, J ¼ 2.2 Hz,
J ¼ 4.2 Hz, aromat.), 7.95 (d, 2H, J ¼ 6.7 Hz, aromat.),
6.4.7. 3-Methyl-N-(4-methyl-3-(4-(pyridin-3-yl)-
1H-imidazol-2-ylamino)phenyl)benzamide (9d)
Yield: 0.13 g (17%), white crystals, mp: 151.9e153.2 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3322, 2921, 1663, 1599. 1H NMR
(DMSO-d6): d (ppm) ¼ 2.12 (s, 3H), 2.40 (s, 3H), 5.53 (s,
2H), 7.26e7.47 (m, 5H, aromat.), 7.71e7.86 (m, 4H, aromat.),
8.01 (td, 1H, J ¼ 7.0 Hz, J ¼ 1.4 Hz, aromat.), 8.34 (dd, 1H,
J ¼ 4.7 Hz, J ¼ 1.4 Hz, aromat.), 8.92 (d, 1H, J ¼ 2.0 Hz, aro-
mat.), 10.34 (s, 1H). CI-MS (NH3) m/z (%): 384 (100)
[M þ Hþ]þ. Anal. (C23H21N5O$1/3H2O): C, H, N.
ꢄ
10.39 (s, 1H). PI-EIMS (70 eV) m/z (%): 368 (100) [M]þ .
Anal. (C23H20N4O$1/2H2O): C, H, N.
6.4.3. N-(4-Methyl-3-(4-phenyl-1H-imidazol-2-
ylamino)phenyl)-4-((4-methylpiperazin-1-yl)
methyl)benzamide (8l)
Yield: 0.13 g (28%), mp: 126.0e131.0 ꢁC. IR (KBr): n
(cmꢃ1) ¼ 3325, 2950, 2805, 1659. 1H NMR (DMSO-d6):
d (ppm) ¼ 2.11 (s, 3H), 2.18 (s, 3H), 2.39 (s, br., 8H), 3.54 (s,
2H), 5.37 (s, 2H, exchangeable), 7.13e7.19 (m, 1H, aromat.),
7.22 (s, 1H, aromat.), 7.29e7.35 (m, 2H, aromat.), 7.38e7.40
(m, 1H, aromat.), 7.44e7.47 (AA0, 2H, aromat.), 7.68e7.72
(m, 2H, aromat.), 7.78e7.82 (m, 2H, aromat.), 7.89e7.92
(BB0, 2H, aromat.), 10.33 (s, 1H, exchangeable). ESI-MS
(CH2Cl2, MeOH, 10 mmol Lꢃ1 NH4Ac) m/z (%): 481 (100)
[M þ Hþ]þ. Anal. (C29H32N6O$3H2O): C, H, N.
6.4.8. 4-Methyl-N-(4-methyl-3-(4-(pyridin-3-yl)-
1H-imidazol-2-ylamino)phenyl)benzamide (9e)
Yield: 0.68 g (94%), mp: 202.6e202.7 ꢁC. IR (KBr): n
1
(cmꢃ1) ¼ 1653, 1610. H NMR (DMSO-d6): d (ppm) ¼ 2.11
(s, 3H), 2.93 (s, 3H), 5.51 (s, 2H), 7.30e7.40 (m, 5H, aromat.),
7.80e7.90 (m, 4H, aromat.), 8.01 (td, 1H, J ¼ 1.8 Hz,
J ¼ 8.0 Hz, aromat.), 8.34 (dd, 1H, J ¼ 1.6 Hz, J ¼ 4.7 Hz, ar-
omat.), 8.92 (d, 1H, J ¼ 1.6 Hz, aromat.), 10.30 (s, 1H). EI-MS
(70 eV) m/z (%): 119 (100), 383 (71) [M]þ, 91 (42), 160 (13).
Anal. (C23H21N5O): C, H, N.
6.4.4. N-(4-Methyl-3-(4-(pyridin-3-yl)-1H-imidazol-
2-ylamino)phenyl)acetamide (9a)
Yield: 0.18 g (35%), mp: 140.9e146.2 ꢁC. IR (KBr): n
(cmꢃ1) ¼ 3305, 2365, 1671, 1601. 1H NMR (DMSO-d6):
d (ppm) ¼ 2.06 (d, 6H, J ¼ 6.8 Hz), 5.48 (s, 2H), 7.54 (dd,
1H, J ¼ 2.1 Hz, J ¼ 8.4 Hz, aromat.), 7.62 (d, 1H,
J ¼ 2.1 Hz, aromat.), 7.30e7.37 (m, 3H, aromat.), 7.99 (td,
6.4.9. 4-Decyl-N-(4-methyl-3-(4-(pyridin-3-yl)-
1H-imidazol-2-ylamino)phenyl)benzamide (9f)
Yield: 0.68 g (71%), mp: 109.3e109.8 ꢁC. IR (KBr): n
1
(cmꢃ1) ¼ 3442, 2925, 2854, 1671, 1611. H NMR (DMSO-
d6): d (ppm) ¼ 0.85 (t, 3H, J ¼ 6.7 Hz), 1.24 (s, br., 14H),

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 1444e1453
1451
1.59 (s, 2H), 2.11 (s, 3H), 2.65 (t, 2H, J ¼ 7.5 Hz), 5.50 (s,
6.4.14. N-(4-Methyl-3-(4-(pyridin-3-yl)-1H-imidazol-
2-ylamino)phenyl)isonicotinamide (9k)
Crystallisation from ethyl acetate. Yield: 0.39 g (56%), mp:
2H), 7.30e7.42 (m, 5H, aromat.), 7.79e7.91 (m, 4H, aromat.),
8.01 (d, 1H, J ¼ 7.9 Hz), 8.34 (dd, 1H, J ¼ 1.3 Hz, J ¼ 4.6 Hz,
aromat.), 8.92 (d, 1H, J ¼ 1.7 Hz, aromat.), 10.41 (s, 1H). EI-
1
261.5e262.9 ꢁC. IR (KBr): n (cmꢃ1) ¼ 3404, 1666, 1603. H
ꢄ
MS (70 eV) m/z (%): 509 (100) [M]þ 245 (58). Anal.
NMR (DMSO-d6): d (ppm) ¼ 2.13 (s, 3H), 5.53 (s, 2H),
7.33 (dd, 1H, J ¼ 5.0 Hz, J ¼ 7.5 Hz, aromat.), 7.39e7.44
(m, 2H), 7.79e7.89 (m, 4H, aromat.), 8.01 (td, 1H,
J ¼ 2.0 Hz, J ¼ 8.0 Hz, aromat.), 8.34 (dd, 1H, J ¼ 1.6 Hz,
J ¼ 4.7 Hz, aromat.), 8.80 (dd, 2H, J ¼ 1.6 Hz, J ¼ 4.4 Hz, ar-
omat.), 8.92 (d, 1H, J ¼ 1.6 Hz, aromat.), 10.64 (s, 1H). PI-
(C32H39N5O$1/4C4H8O2): C, H, N.
6.4.10. 4-Methoxy-N-(4-methyl-3-(4-(pyridin-3-yl)-
1H-imidazol-2-ylamino)phenyl)benzamide (9g)
Crystallisation from diethyl ether. Yield: 0.48 g (28%), mp:
196.1e198.8 ꢁC. IR (KBr): n (cmꢃ1) ¼ 3433, 2838, 1659,
ꢄ
EIMS (70 eV) m/z (%): 370 (100) [M]þ , 78 (16), 106 (14).
1
1605. H NMR (DMSO-d6): d (ppm) ¼ 2.11 (s, 3H), 3.84 (s,
Anal. (C21H18N6O$1/4C4H8O2): C, H, N.
3H), 5.50 (s, 2H), 7.07 (d, 2H, J ¼ 9.0 Hz, aromat.), 7.30e
7.40 (m, 3H), 7.82 (dd, 2H, J ¼ 2.1 Hz, J ¼ 6.0 Hz, aromat.),
7.93e8.03 (m, 3H), 8.34 (dd, 1H, J ¼ 1.6 Hz, J ¼ 4.7 Hz,
aromat.), 8.92 (d, 1H, J ¼ 1.7 Hz, aromat.), 10.23 (s, 1H).
6.4.15. N-(4-Methyl-3-(4-(pyridin-3-yl)-1H-imidazol-
2-ylamino)phenyl)-4-((4-methylpiperazin-1-
yl)methyl)benzamide (9l)
ꢄ
PI-EIMS (70 eV) m/z (%): 399 (100) [M]þ , 135 (95). Anal.
(C23H21N5O2$1/4 C4H10O): C, H, N.
Yield: 0.18 g (38%), mp: 230.1e232.0 ꢁC. IR (KBr): n
(cmꢃ1) ¼ 2945, 2809, 1639. 1H NMR (DMSO-d6):
d (ppm) ¼ 2.11 (s, 3H), 2.15 (s, 3H), 2.35 (s, br., 8H), 3.53
(s, 2H), 5.50 (s, 2H, exchangeable), 7.31e7.40 (m, 2H, aromat.),
7.39 (s, 1H, aromat.), 7.44e7.46 (AA0, 2H, aromat.), 7.80e7.83
(m, 2H, aromat.), 7.89e7.92 (BB0, 2H, aromat.), 7.99e8.03
(m, 1H, aromat.), 8.33e8.35 (m, 1H, aromat.), 8.92e8.93 (m,
1H, aromat.), 10.36 (s, 1H, exchangeable). EI-MS (70 eV)
6.4.11. 3,4,5-Trimethoxy-N-(4-methyl-3-
(4-(pyridin-3-yl)e1H-imidazol-2-ylamino)
phenyl)benzamide (9h)
Yield: 0.24 g (28%), mp: 221.7e222.8 ꢁC. IR (KBr): n
(cmꢃ1) ¼ 3451, 1653, 1616. 1H NMR (DMSO-d6):
d (ppm) ¼ 2.12 (s, 3H), 3.73 (s, 3H), 3.87 (s, 6H), 5.51 (s,
2H), 7.28 (s, 2H, aromat.), 7.33 (dd, 1H, J ¼ 4.5 Hz,
J ¼ 8.2 Hz, aromat.), 7.41 (d, 2H, J ¼ 7.3 Hz, aromat.), 7.76
(d, 1H, J ¼ 2.1 Hz, aromat.), 7.84 (dd, 1H, J ¼ 2.1 Hz,
J ¼ 8.3 Hz, aromat.), 8.01 (td, 1H, J ¼ 2.0 Hz, J ¼ 8.0 Hz, ar-
omat.), 8.34 (dd, 1H, J ¼ 1.6 Hz, J ¼ 4.8 Hz, aromat.), 8.92 (d,
1H, J ¼ 1.6 Hz, aromat.), 10.23 (s, 1H). EI-MS (70 eV) m/z
ꢄ
m/z (%): 481 (17) [M]þ , 466 (10), 425 (21), 411 (94), 383
(100), 118 (79), 99 (52), 90 (78). Anal. (C28H31N7O$2H2O):
C, H, N.
6.4.16. 4-Amino-N-(4-methyl-3-(4-(pyridin-3-yl)-
1H-imidazol-2-ylamino)phenyl)benzamide (9m)
ꢄ
(%): 195 (100), 459 (50) [M]þ . Anal. (C25H25N5O4$1/
4H2O): C, H, N.
Preparation was performed from 9i by catalytic reduction
of the nitro group according to general procedure B as de-
scribed for 6be6e: crystallisation from ethyl acetate. Yield:
6.4.12. N-(4-Methyl-3-(4-(pyridin-3-yl)-1H-imidazol-
2-ylamino)phenyl)-4-nitrobenzamide (9i)
0.16 g (41%), mp: 161.9e167.9 ꢁC. IR (KBr):
n
Yield: 0.74 g (95%), yellow crystals, mp: 191.6e195.7 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3383, 2923, 2795, 1664, 1600. 1H NMR
(DMSO-d6): d (ppm) ¼ 2.13 (s, 3H), 5.53 (s, 2H), 7.33 (dd,
1H, J ¼ 4.8 Hz, J ¼ 8.0 Hz, aromat.), 7.39e7.45 (m, 2H),
7.82 (dd, 2H, J ¼ 2.1 Hz, J ¼ 6.4 Hz, aromat.), 8.01 (td, 1H,
J ¼ 2.0 Hz, J ¼ 8.0 Hz, aromat.), 8.19 (d, 2H, J ¼ 8.8 Hz, aro-
mat.), 8.33e8.42 (m, 3H), 8.92 (d, 1H, J ¼ 1.6 Hz, aromat.),
(cmꢃ1) ¼ 3442, 1658, 1603. 1H NMR (DMSO-d6):
d (ppm) ¼ 2.10 (s, 3H), 5.51 (s, 2H), 5.79 (s, 2H), 6.60 (d,
2H, J ¼ 8.6 Hz, aromat.), 7.30e7.40 (m, 3H), 7.71 (d, 2H,
J ¼ 8.8 Hz, aromat.), 7.80 (d, 2H, J ¼ 7.41 Hz, aromat.),
8.01 (td, 1H, J ¼ 1.8 Hz, J ¼ 8.0 Hz, aromat.), 8.34 (dd, 1H,
J ¼ 1.5 Hz, J ¼ 4.7 Hz, aromat.), 8.92 (d, 1H, J ¼ 1.6 Hz, aro-
mat.), 9.91 (s, 1H). PI-EIMS (70 eV) m/z (%): 120 (100), 384
ꢄ
ꢄ
10.71 (s, 1H). PI-EIMS (70 eV) m/z (%): 414 (100) [M]þ .
(87) [M]þ . Anal. (C22H20N6O$1/3C4H8O2): C, H, N.
Anal. (C22H18N6O3$H2O): C, H, N.
6.4.13. 4-Chloro-N-(4-methyl-3-(4-(pyridin-3-yl)-
1H-imidazol-2-ylamino)phenyl)benzamide (9j)
Crystallisation from ethyl acetate. Yield: 0.39 g (51%), mp:
6.4.17. 2-Methyl-N-(3-(4-(pyridin-3-yl)-1H-imidazol-
2-ylamino)phenyl)benzamide (10c)
Yield: 0.33 g (45%), white crystals, mp: 116.1e116.3 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3425, 3061, 1665, 1601. 1H NMR
(DMSO-d6): d (ppm) ¼ 2.40 (s, 3H), 5.72 (s, 2H), 7.23e7.55
(m, 8H, aromat.), 7.76 (d, 1H, J ¼ 7.4 Hz, aromat.), 7.95 (s,
v br., 1H, aromat.), 8.02 (td, 1H, J ¼ 8.1 Hz, J ¼ 2.0 Hz, aro-
mat.), 8.35 (dd, 1H, J ¼ 4.8 Hz, J ¼ 1.5 Hz, aromat.), 8.93
(d, 1H, J ¼ 1.6 Hz, aromat.), 10.53 (s, 1H). CI-MS (NH3) m/
z (%): 370 (100) [M þ Hþ]þ. Anal. (C22H19N5O$3/4H2O):
C, H, N.
1
241.8e243.5 ꢁC. IR (KBr): n (cmꢃ1) ¼ 3424, 1649, 1602. H
NMR (DMSO-d6): d (ppm) ¼ 2.12 (s, 3H), 5.55 (s, 2H), 7.33
(dd, 1H, J ¼ 4.9 Hz, J ¼ 7.8 Hz, aromat.), 7.40 (t, 2H,
J ¼ 4.5 Hz, aromat.), 7.63 (d, 2H, J ¼ 8.6 Hz, aromat.), 7.81 (d,
2H, J ¼ 6.6 Hz, aromat.), 7.96e8.03 (m, 3H), 8.34 (dd, 1H
J ¼ 1.5 Hz, J ¼ 4.7 Hz, aromat.), 8.92 (d, 1H, J ¼ 1.7 Hz, aro-
mat.), 10.46 (s, 1H). EI-MS (70 eV) m/z (%): 139 (100), 403
ꢄ
(96)[M]þ , 111 (45). Anal. (C22H18ClN5O$1/4C4H8O2):C, H, N.

1452
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 1444e1453
6.4.18. 3-Methyl-N-(3-(4-(pyridin-3-yl)-1H-imidazol-
2-ylamino)phenyl)benzamide (10d)
6.4.22. N-(4-Ethyl-3-(4-(pyridin-3-yl)-1H-imidazol-
2-ylamino)phenyl)-2-methylbenzamide (11c)
Yield: 0.16 g (22%), white crystals, mp: 120.3e120.6 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3422, 3065, 1652, 1603. 1H NMR
(DMSO-d6): d (ppm) ¼ 2.41 (s, 3H), 5.74 (s, 2H), 7.23 (dd,
1H, J ¼ 7.7 Hz, J ¼ 1.6 Hz, aromat.), 7.35 (dd, 1H,
J ¼ 7.9 Hz, J ¼ 4.9 Hz, aromat.), 7.42e7.57 (m, 4H, aromat.),
7.75e7.86 (m, 3H, aromat.), 8.00 (ttt, 2H, J ¼ 9.1 Hz,
J ¼ 1.7 Hz, aromat.), 8.36 (dd, 1H, J ¼ 4.7 Hz, J ¼ 1.6 Hz, ar-
omat.), 8.94 (d, 1H, J ¼ 1.9 Hz, aromat.), 10.42 (s, 1H). CI-
MS (NH3) m/z (%): 370 (100) [M þ Hþ]þ. Anal.
(C22H19N5O$H2O): C, H, N.
Yield: 0.49 g (62%), white crystals, mp: 120.3e122.3 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3440, 2968, 1659, 1616. 1H NMR
(DMSO-d6): d (ppm) ¼ 1.07 (t, 3H, J ¼ 7.5 Hz), 2.39 (s,
3H), 2.44 (q, 2H, J ¼ 5.0 Hz), 5.49 (s, 2H), 7.28e7.47 (m,
7H, aromat.), 7.75e7.81 (m, 2H, aromat.), 8.00 (td, 1H,
J ¼ 8.0 Hz, J ¼ 2.0 Hz, aromat.), 8.34 (dd, 1H, J ¼ 4.7 Hz,
J ¼ 1.6 Hz, aromat.), 8.92 (d, 1H, J ¼ 1.6 Hz), 10.47 (s, 1H).
CI-MS (NH3) m/z (%): 398 (100) [M þ Hþ]þ. Anal.
(C24H23N5O$2/3H2O): C, H, N.
6.4.23. N-(4-Ethyl-3-(4-(pyridin-3-yl)-1H-imidazol-
2-ylamino)phenyl)-3-methylbenzamide (11d)
6.4.19. 4-Methyl-N-(3-(4-(pyridin-3-yl)-
1H-imidazol-2-ylamino)phenyl)benzamide (10e)
Yield: 0.47 g (59%), white crystals, mp: 161.7e163.2 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3436, 2965, 1667, 1600. 1H NMR
(DMSO-d6): d (ppm) ¼ 1.08 (t, 3H, J ¼ 7.5 Hz), 2.40 (s,
3H), 2.45 (q, br., 2H, J ¼ 7.1 Hz), 5.48 (s, 2H), 7.30e7.37
(m, 1H, aromat.), 7.39e7.44 (m, 4H, J ¼ 8.5 Hz, aromat.),
7.72e7.81 (m, 3H, aromat.), 7.88 (dd, 1H, J ¼ 8.5 Hz,
J ¼ 2.2 Hz, aromat.), 8.00 (td, 1H, J ¼ 8.1 Hz, J ¼ 2.0 Hz, ar-
omat.), 8.34 (dd, 1H, J ¼ 4.7 Hz, J ¼ 1.7 Hz, aromat.), 8.92 (d,
1H, J ¼ 1.6 Hz, aromat.), 10.35 (s, 1H). CI-MS (NH3) m/z (%):
398 (100) [M þ Hþ]þ. Anal. (C24H23N5O$1/3H2O): C, H, N.
Yield: 0.17 g (23%), white crystals, mp: 218.8e219.0 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3440, 3126, 1665, 1598. 1H NMR
(DMSO-d6): d (ppm) ¼ 2.39 (s, 3H), 5.74 (s, 2H), 7.23 (dd,
1H, J ¼ 8.0 Hz, J ¼ 1.4 Hz, aromat.), 7.32e7.38 (m, 3H, aro-
mat.), 7.48e7.57 (m, 2H, aromat.), 7.82e7.93 (m, 3H, aro-
mat.), 8.01 (ttt, 2H, J ¼ 7.7 Hz, J ¼ 2.0 Hz, aromat.), 8.35
(dd, 1H, J ¼ 4.7 Hz, J ¼ 1.6 Hz, aromat.), 8.94 (d, 1H,
J ¼ 2.0 Hz, aromat.), 10.37 (s, 1H). CI-MS (NH3) m/z (%):
370 (100) [M þ Hþ]þ. Anal. (C22H19N5O): C, H, N.
6.4.24. N-(4-Ethyl-3-(4-(pyridin-3-yl)-1H-imidazol-
2-ylamino)phenyl)-4-methylbenzamide (11e)
6.4.20. 4-((4-Methylpiperazin-1-yl)methyl)-N-
(3-(4-(pyridin-3-yl)-1H-imidazol-2-ylamino)
phenyl)benzamide (10l)
Yield: 0.41 g (51%), white crystals, mp: 150.4e150.6 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3436, 2965, 1669, 1611. 1H NMR
(DMSO-d6): d (ppm) ¼ 1.08 (t, 3H, J ¼ 7.5 Hz), 2.39 (s,
3H), 2.44 (q, br., 2H, J ¼ 6.9 Hz), 5.47 (s, 2H), 7.30e7.37
(m, 3H, aromat.), 7.41 (d, 2H, J ¼ 8.9 Hz, aromat.), 7.80 (d,
1H, J ¼ 2.2 Hz, aromat.), 7.89 (d, 3H, J ¼ 8.2 Hz, aromat.),
8.00 (td, 1H, J ¼ 8.0 Hz, J ¼ 2.0 Hz, aromat.), 8.34 (dd, 1H,
J ¼ 4.8 Hz, J ¼ 1.5 Hz, aromat.), 8.92 (d, 1H, J ¼ 1.9 Hz, aro-
mat.), 10.31 (s, 1H). CI-MS (NH3) m/z (%): 398 (100)
[M þ Hþ]þ. Anal. (C24H23N5O): C, H, N.
Yield: 0.43 g (58%), white crystals, mp: 150.9e151.2 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3324, 2941, 1651, 1603. 1H NMR
(DMSO-d6): d (ppm) ¼ 2.15 (s, 3H), 2.37 (s, v br., 8H), 3.54
(s, 2H), 5.73 (s, 2H), 7.23 (dd, 1H, J ¼ 8.0 Hz, J ¼ 1.4 Hz, ar-
omat.), 7.34 (ddd, 1H, J ¼ 8.1 Hz, J ¼ 6.0 Hz, aromat.), 7.44e
7.56 (m, 4H), 7.84 (dd, 1H, J ¼ 8.2 Hz, J ¼ 1.1 Hz, aromat.),
7.93 (d, 2H, J ¼ 8.5 Hz, aromat.), 8.01 (ttt, 2H, J ¼ 8.2 Hz,
J ¼ 2.0 Hz, aromat.), 8.36 (dd, 1H, J ¼ 4.7 Hz, J ¼ 1.6 Hz, ar-
omat.), 8.94 (d, 1H, J ¼ 1.4 Hz, aromat.), 10.42 (s, 1H). CI-
MS (NH3) m/z (%): 468 (100) [M þ Hþ]þ. Anal.
(C27H29N7O$H2O):C, H, N.
6.4.25. N-(4-Methyl-3-(4-(pyridin-4-yl)-1H-imidazol-
2-ylamino)phenyl)benzamide (12b)
Yield: 0.36 g (65%), yellow crystals, mp: 248.9e251.1 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3423, 1640, 1604. 1H NMR (DMSO-d6):
d (ppm) ¼ 2.11 (s, 3H), 5.56 (s, 2H), 7.40 (d, 1H, J ¼ 9.1 Hz,
aromat.), 7.51e7.68 (m, 6H, aromat.), 7.81e7.86 (m, 2H, ar-
omat.), 7.95 (dd, 2H, J ¼ 1.4 Hz, J ¼ 8.1 Hz, aromat.), 8.45
(dd, 2H, J ¼ 1.5 Hz, J ¼ 4.6 Hz, aromat.), 10.39 (s, 1H). PI-
6.4.21. N-(4-Ethyl-3-(4-(pyridin-3-yl)-1H-imidazol-
2-ylamino)phenyl)benzamide (11b)
Yield: 0.48 g (63%), white crystals, mp: 165.8e166.4 ꢁC.
IR (KBr): n (cmꢃ1) ¼ 3436, 2966, 1667, 1604. 1H NMR
(DMSO-d6): d (ppm) ¼ 1.08 (t, 3H, J ¼ 7.5 Hz), 2.44 (q, br.,
2H, J ¼ 7.4 Hz), 5.49 (s, 2H), 7.33 (dd, 1H, J ¼ 8.0 Hz,
J ¼ 4.7 Hz, aromat.), 7.42 (d, 2H, J ¼ 10.4 Hz, aromat.),
7.51e7.63 (m, 3H, aromat.), 7.81 (d, 1H, J ¼ 2.0 Hz), 7.88
(dd, 1H, J ¼ 8.5 Hz, J ¼ 2.2 Hz, aromat.), 7.96 (dd, 2H,
J ¼ 8.1 Hz, J ¼ 1.5 Hz, aromat.), 8.01 (td, 1H, J ¼ 7.6 Hz,
J ¼ 2.0 Hz, aromat.), 8.34 (dd, 1H, J ¼ 4.8 Hz, J ¼ 1.5 Hz, ar-
omat.), 8.92 (d, 1H, J ¼ 1.6 Hz, aromat.), 10.41 (s, 1H). CI-
MS (NH3) m/z (%): 384 (100) [M þ Hþ]þ. Anal.
(C23H21N5O$2/5H2O): C, H, N.
ꢄ
EIMS (70 eV) m/z (%): 369 (100) [M]þ , 105 (78), 77 (51).
Anal. (C22H19N5O$1/2H2O): C, H, N.
6.4.26. N-(4-Methyl-3-(4-(pyridin-4-yl)-1H-imidazol-
2-ylamino)phenyl)-4-((4-methylpiperazin-1-
yl)methyl)benzamide (12l)
Yield: 0.22 g (47%), mp: 256.6e256.7 ꢁC. IR (KBr): n
(cmꢃ1) ¼ 3402, 2941, 2800, 1647. 1H NMR (DMSO-d6):
d (ppm) ¼ 2.10 (s, 3H), 2.16 (s, 3H), 2.35 (s, br., 8H), 3.53
(s, 2H), 5.55 (s, 2H, exchangeable), 7.37e7.40 (m, 1H, aro-
mat.), 7.43e7.46 (m, 2H, aromat.), 7.55 (s, 1H, aromat.),

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 1444e1453
1453
7.60e7.62 (AA0, 2H, aromat.), 7.80e7.84 (m, 2H, aromat.),
7.89e7.91 (BB0, 2H, aromat.), 8.44e8.46 (BB0, 2H, aromat.),
10.35 (s, 1H, exchangeable). EI-MS (70 eV) m/z (%): 481 (31)
[9] R. Capdeville, E. Buchdunger, J. Zimmermann, A. Matter, Nat. Rev.
Drug Discov. 1 (2002) 493e502.
[10] M. Deininger, E. Buchdunger, B.J. Druker, Blood 105 (2005) 2640e
2653.
ꢄ
[M]þ , 466 (18), 425 (27), 411 (88), 383 (100), 118 (23), 99
[11] M. Ciufolini, A. Benjahad, B. Giethlen, A. Moussy, C. Wermuth, PCT
Int. Appl., WO 2006/064375 A2, 2006.
(20), 90 (18). Anal. (C28H31N7O$1/2H2O): C, H, N.
[12] A. Dornow, H. Machens, K. Bruncken, Chem. Ber. 84 (1951)
147e150.
[13] E. Vanotti, R. D’Alessio, M. Tibolla, M. Varasi, A. Montagnoli, C. San-
tocanale, K. Martina, M. Menichincheri, PCT Int. Appl., WO
2005013986 A1, 2005.
Appendix. Supplementary data
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.ejmech.
2007.09.021.
[14] S. Wang, G. Wood, C. Meades, G. Griffiths, C. Midgley, I. McNae,
C. McInnes, S. Anderson, W. Jackson, M. Mezna, R. Yuill,
M. Walkinshaw, P.M. Fischer, Bioorg. Med. Chem. Lett. 14 (2004)
4237e4240.
[15] Z. Szakacs, S. Beni, Z. Varga, L. Oerfi, G. Keri, B. Noszla, J. Med.
Chem. 48 (2005) 249e255.
References
[16] S. Mahboobi, A. Sellmer, T. Burgemeister, A. Lyssenko, D. Schollmeyer,
Monatsh. Chem. 135 (2004) 333e342.
[17] M. Sattler, S. Verma, C.H. Byrne, G. Shrikhande, T. Winkler,
P.A. Algate, L.R. Rohrschneider, J.D. Griffin, Mol. Cell. Biol. 19
(1999) 7473e7480.
[1] J. Dancey, E.A. Sausville, Nat. Rev. Drug Discov. 2 (2003) 296e313.
[2] K. Pietras, T. Sjoblom, K. Rubin, C.H. Heldin, A. Ostman, Cancer Cell 3
(2003) 439e443.
[3] A. Ostman, C.H. Heldin, Adv. Cancer Res. 97 (2007) 247e274.
[4] C.H. Heldin, A. Ostman, L. Ronnstrand, Biochim. Biophys. Acta 1378
(1998) 79e113.
[18] F.D. Bo¨hmer, L. Karagyozov, A. Uecker, H. Serve, A. Botzki,
S. Mahboobi, S. Dove, J. Biol. Chem. 278 (2003) 5148e5155.
´
[19] S. Mahboobi, A. Uecker, A. Sellmer, C. Cenac, H. Hocher, H. Pongratz,
¨
[5] J. Zimmermann, E. Buchdunger, H. Mett, T. Meyer, N.B. Lydon,
B. Nicholas, P. Traxler, Bioorg. Med. Chem. Lett. 6 (1996) 1221e1226.
[6] E. Buchdunger, C.L. Cioffi, N. Law, D. Stover, S. Ohno-Jones,
B.J. Druker, N.B. Lydon, J. Pharmacol. Exp. Ther. 295 (2000) 139e145.
[7] J. Zimmermann, E. Buchdunger, H. Mett, T. Meyer, N.B. Lydon, Bioorg.
Med. Chem. Lett. 7 (1997) 187e192.
E. Eichhorn, H. Hufsky, A. Trumpler, M. Sicker, F. Heidel, T. Fischer,
¨
C. Stocking, S. Elz, F.-D. Bo¨hmer, S. Dove, J. Med. Chem. 49 (2006)
3101e3115.
[20] S. Mahboobi, S. Teller, H. Pongratz, H. Hufsky, A. Sellmer, A. Botzki,
A. Uecker, T. Beckers, S. Baasner, C. Schachtele, F. Ueberall,
M.U. Kassack, S. Dove, F.-D. Bohmer, J. Med. Chem. 45 (2002)
¨
1002e1018.
[8] E. Buchdunger, T. O’Reilly, J. Wood, Eur. J. Cancer 38 (Suppl. 5) (2002)
28e36.