Imidazole moiety replacements in the 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor receptor-1 (IGF-1R) to improve cytochrome P450 profile

Article abstract of DOI:10.1016/j.bmcl.2007.03.048

A series of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor receptor-1 (IGF-1R) were examined in which the pendant imidazole moiety was replaced to improve selectivity for IGF-1R inhibition over cytochrome P450 (CYP). Synthesis and SAR of these compounds is presented.

Full text of DOI:10.1016/j.bmcl.2007.03.048

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3072–3076
Imidazole moiety replacements in the 3-(1H-benzo[d]imidazol-
2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor
receptor-1 (IGF-1R) to improve cytochrome P450 profile
Upender Velaparthi,a,* Peiying Liu,a Balu Balasubramanian,a Joan Carboni,c
Ricardo Attar,c Marco Gottardis,c Aixin Li,c Ann Greer,c Mary Zoeckler,b
Mark D. Wittmana and Dolatrai Vyasa
aDepartment of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, CT 06492, USA
bDepartment of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute,
5 Research Parkway, Wallingford, CT 06492, USA
cOncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543, USA
Received 8 February 2007; revised 13 March 2007; accepted 14 March 2007
Available online 19 March 2007
Abstract—A series of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor receptor-1 (IGF-1R)
were examined in which the pendant imidazole moiety was replaced to improve selectivity for IGF-1R inhibition over cytochrome
P450 (CYP). Synthesis and SAR of these compounds is presented.
Ó 2007 Elsevier Ltd. All rights reserved.
Insulin-like growth factor receptor-1 (IGF-1R) plays an
important role in normal cell physiology, and is also
implicated in the establishment and maintenance of
the malignant phenotype.1 IGF-1R is a tyrosine kinase
receptor that is activated by the binding of its ligands,
IGF-I or IGF-II, to the extracellular domain. Ligand
binding causes a conformational change resulting in
autophosphorylation of tyrosine residues in the intracel-
lular kinase domain resulting in activation of both the
mitogenic (Ras/Raf/MAPK) and survival pathways
(PI3K/Akt/mTor).1,2 In addition, recent studies have
shown that IGF-1R regulates cell adhesion and motil-
ity.3 Overexpression of IGF-1R and IGF-I has been
demonstrated in a variety of tumors,4 including glioma,
lung, ovary, breast, carcinomas, sarcomas, and mela-
noma. Therefore, IGF-1R seems to be a very promising
target for cancer therapy.5 As a consequence, the identi-
fication of potent inhibitors of IGF-1R has recently
attracted considerable attention and several classes of
inhibitors have been described.6
We have recently reported the discovery and biological
activity associated with the benzimidazole-pyridone
derivatives stemming from the identification of 1 as a
prototype of a new structural class of IGF-1R kinase
inhibitors.7 Further optimization of 1 by installing basic
amine side chains at the C-4-position of pyridone led to
the identification of 2, 3, and 4 with IC50’s of 390, 530,
and 180 nM, respectively.8 Additionally, compound 4
reduced autophosphorylation of IGF-1R in CD8-
IGF1R mouse xenografts when dosed in vivo. However,
compounds 1–4 exhibited potent cytochrome P450
(CYP) inhibition profiles across 3A4, 2C9, 2C19, 2D6,
and 1A2 isozymes (Table 1). Such potent inhibition of
drug-metabolizing CYP enzymes may cause unfavorable
drug–drug interactions in the clinic.9 Many lead candi-
date molecules in pharmaceutical development fail due
to potent inhibition of one or more CYP enzyme iso-
forms. Consequently, we sought to improve the CYP
inhibition of this chemotype while maintaining or
improving the IGF-1R enzyme potency. By examining
the structural elements within the chemotype 1, it
was reasoned that the pendant imidazole moiety could
be responsible for potent CYP inhibition, as some
Keywords: Insulin-like growth factor-1 receptor; IGF-1R; Tyrosine
kinase; Benzimidazole; Imidazole; CYP450 inhibition; Imidazoline;
Pyridone.
*
Corresponding author. Tel.: +1 203 677 7910; fax: +1 203 677
7702; e-mail: upender.velaparthi@bms.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.03.048

U. Velaparthi et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3072–3076
3073
Table 1. IGF1R and CYP activities11 for compounds 2, 3, and 4
MeO
H
N
Br
NO2
NH2
Br
NH2
NH2
Br
N
b
a
IC50 (lM)
2
3
4
N
IGF-1R
CYP1A2
CYP2C9
0.39
0.53
0.18
I
<0.03
<0.03
0.1
<0.04
<0.04
<0.04
0.56
<0.04
<0.04
<0.04
ND
8
5
6
O
H
N
CYP2C19
CYP2D6
CYP3A4-BFC
Br
NH
5.7
0.08
O
H
0.06
<0.046
Br
N
NH
N
c
d
HN
N
OH
NH
I
imidazole derivatives such as ketoconazole and clotrim-
azole are known to show high affinity for the heme iron
of major drug-metabolizing CYP enzymes Figure 1.9b,10
10
9
R
O
O
H
H
Br
The crystal structure of 1 bound to a truncated IGF-1R
revealed that the pendant imidazole ring is solvent ex-
posed, and is not involved in any favorable hydrogen
bonding interactions with the receptor.7a Therefore, we
explored replacing of the imidazole ring with other
groups in an effort to improve selectivity for IGF-1R
inhibition over cytochrome P450 inhibition.
NH
N
N
f, g
e
N
N
HN
HN
OTr
OH
11
12 R = H
At the outset, we elected to replace the imidazole moi-
ety with both the bromo and cyano groups as these
groups are considered versatile chemical handles for
analog synthesis. Accordingly, the syntheses of bromo
derivative 10 and cyano derivative 24 were accom-
plished as outlined in Schemes 1 and 2. Commercially
available 4-bromo-2-methyl-6-nitro aniline (5) was
reduced to furnish diamine, which was immediately
treated with 2-methoxy-4-iodo-pyridine-3-carboxalde-
hyde12 (7) to afford benzimidazole 8. The methoxy
group in 8 was cleaved, and the resultant iodopyri-
done was heated with (S)-phenyl alaninol to provide
10. Suzuki coupling with aryl boronic acids was rather
sluggish presumably for solubility reasons, and there-
fore the primary hydroxyl was protected as its trityl
ether 11 which underwent Suzuki couplings smoothly
with several aryl boronic acids. Finally, the trityl
group was deprotected with trifluoroacetic acid to
afford biaryls (12, 13, and 14).
13 R =
14 R =
p
-F
p-OMe
Scheme 1. Reagents and conditions: (a) SnCl2Æ2H2O EtOH, reflux,
59%; (b) 2-methoxy-4-iodo pyridine-3-carboxaldehyde (7), MeOH, rt,
50%; (c) 4 N HCl in dioxane, H2O, rt, 100%; (d) phenyl alaninol, Et3N,
DMF, 90 °C, 89%; (e) triphenylmethyl chloride, Et3N, DMAP,
CH2Cl2, 72%; (f) aryl boronic acids, Pd(PPh3)4, K3PO4, THF, reflux,
60–67%; (g) TFA, CH2Cl2, 100%.
Similarly, the cyano derivative 24, which is useful to
synthesize other heterocycles, was synthesized starting
from 3-methyl-4-nitro-benzonitrile (15). The nitro
group was reduced and the resultant aniline 16 was
trifluoroacetylated. The amide 17 was subjected to
nitration by treating with potassium nitrate in sulfuric
acid, and then the trifluoroacetyl group was cleaved.
The nitroaniline 19 was reduced and the resultant phe-
nylene diamine 20 was immediately treated with the
2-methoxy-4-iodo-pyridine-3-carboxaldehyde12 (7) to
furnish the benzimidazole 21. The methoxy group
was cleaved to give the iodo pyridone 22, which was
heated with meta-chloro phenethylamine 23 to afford
24. The nitrile group was hydrolyzed to the corre-
sponding acid 25, which was used to make amides
27–32. Additionally, the cyano compound 24 was also
converted to imidate ester 33 by exposure to anhy-
drous HCl gas in ethanol. Heating 33 with several
1,3 or 1,4 diamines furnished imidazolines (34, 35,
and 36) or tetrahydropyrimidine 37, respectively. The
carbon attached imidazole 39 was built from the imi-
date ester 33 using a two-step procedure.13
N
N
O
O
H
N
H
N
N
NH
N
NH
N
N
N
HN
2
1
N
N
O
O
H
N
H
N
N
NH
N
NH
OH
As outlined in Table 2, biaryls 12–14 represented the
first examples with a reduced cytochrome P450 inhibi-
tion profile in this series of IGF-1R inhibitors. These
results suggest that the pendant imidazole was primar-
ily responsible for potent CYP inhibition as antici-
pated. Interestingly, the bromo compound 10
displayed reduced CYP3A4 inhibition, while still
retaining significant affinity for other CYP isozymes.
N
N
HN
HN
HO
3
4
Cl
Figure 1. Representative benzimidazole IGF-1R inhibitors.

3074
U. Velaparthi et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3072–3076
Table 2. IGF1R and CYP activities11 for imidazole replacements
NC
NC
NC
NC
a
b
c
IC50 (lM)
10
12
13
14
NO2
NO2
NHCOCF3
NH2
IGF-1Ra
CYP1A2
CYP2C9
CYP2C19
CYP2D6b
CYP3A4
1.4
3.1
5.1
3.2
4.0
1.0
ND
6..3
4.0
0.052
0.72
0.32
ND
3.1
0.58
2.3
12.0
11.0
2.2
17
16
15
0.53
ND
3.6
NC
NH2
f
NO2
NH2
NC
NC
e
d
ND
6.8
NH2
NHCOCF3
a IC50 values represent the average of two determinations and standard
deviations ranged from 0.16 to 0.84.
b Overlap with reference, IC50 could not be determined.
19
20
18
O
MeO
H
H
NC
NH
N
N
N
h
g
N
The compound that lacks imidazole, 26, displayed a
fourfold reduction in IGF-1R enzyme potency with an
improved CYP profile. Examination of various func-
tional groups at the imidazole location led to the identi-
fication of amides that retained IGF-1R enzyme potency
while improving the CYP profile. The primary and sec-
ondary amides (27 and 28) displayed equipotency of
180 nM while the tertiary amide (29) was less active
(550 nM). It was found that increasing bulk on the sec-
ondary amide led to a decrease in enzyme potency as
represented by compounds 28 and 30 through 32. The
enhanced IGF-1R potency and acceptable CYP profile
(3.7 lM for 3A4) of secondary amide 28 prompted us
to make the corresponding methyl amidine 38, which
displayed similar IGF-1R potencies of 170 nM with an
improved CYP profile across all isozymes. In order to
fine-tune the potency of amidine containing compounds,
cyclic amidines such as imidazolines were synthesized.
We were delighted to observe a significant improvement
in IGF-1R activity with these imidazolines (34, 35, and
36) and tetrahydropyrimidine 37 with a reduction in
affinity for CYP enzymes. For instance, N-methyl imi-
dazoline 34 displayed an impressive 93 nM IGF-1R
activity and even further reduction in cytochrome
P450 inhibition (>17 lM against all isozymes). Alpha
methyl substitutions on N-methyl imidazoline as repre-
sented by 35 and 36 further enhanced selectivity of
IGF1R versus CYP inhibition with 46 nM for com-
pound 36 while its CYP3A4 affinity was 13 lM.
N
I
I
21
22
O
O
H
N
H
NC
HO2C
NH
NH
N
i
N
N
HN
HN
HO
HO
24
25
Cl
Cl
k
j
22
NH
O
H
N
O
NH
H
N
R1
EtO
NH
N
N
HN
HN
HO
HO
33
Cl
Cl
27-32 R1 = CONR2R3
l
m
N
NH
O
O
H
H
N
NH
N
NH
N
N
H
N
N
HN
HN
HO
HO
The corresponding six-membered tetrahydro pyrimidine
37 also maintains excellent IGF-1R inhibition (68 nM)
with less affinity for CYP enzymes (>8.5 lM). Interest-
ingly, the unsaturated version of imidazoline, the carbon
attached imidazole 39, regained some of its CYP inhibi-
tion. Taken together, these findings demonstrate that
saturated heteroaryls such as imidazolines were optimal
for greater separation of IGF-1R activity versus CYP
inhibition. The reduced CYP inhibition of these imidazo-
lines could be in part due to enhanced basicity. Further
investigation of these imidazolines for selectivity over
other tyrosine kinases, cell-based activities, and optimiza-
tion for desirable ADME properties are ongoing.
Cl
Cl
34
38
Scheme 2. Reagents and conditions: (a) Fe, HOAc, 74%; (b) trifluo-
roacetic anhydride, Et3N, CH2Cl2, 100%; (c) KNO3, concd sulfuric
acid, 52%; (d) 2 M NH3 in MeOH, 95%; (e) SnCl2Æ2H2O, EtOH reflux,
90%; (f) 2-methoxy-4-iodo-pyridine-3-carboxaldehyde (7), I2, MeOH,
46%; (g) 4 N HCl in dioxane, H2O, 100%; (h) 2-amino-1-(3-chloro-
phenyl)-ethanol (23), DMF, Et3N, 80 °C, 94%; (i) 6 N HCl, 80 °C,
54%; (j) DPPA, Et3N, DMF, amines, 40–60%; (k) anhydrous HCl,
EtOH, 90%; (l) N-methyl 1,3-propane diamine, EtOH, reflux, 100%;
(m) NH2Me, heat, 100%.
In summary, the results described herein have demon-
strated that the pendant imidazole was primarily respon-
sible for potent cytochrome P450 inhibition. By
replacing this moiety with other groups such as imidazo-
lines, greater separation of IGF-1R activity versus CYP
inhibition was observed. Future studies will expand on
However, the biaryls (12–14) were found to be less po-
tent against IGF-1R relative to the imidazole contain-
ing compounds (2, 3, and 4). With these promising
initial results in improving the CYP profile our efforts
shifted to cyano compound 24 and derivatives thereof
Table 3.

U. Velaparthi et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3072–3076
Table 3. IGF1R and CYP activities11 for imidazole replacements
3075
O
H
N
R1
NH
N
HN
HO
Cl
Compound
R1
IC50a-IGF1R (lM)
CYP1A2
CYP2C9
CYP2C19
CYP3A4
4
26
27
28
29
30
31
32
Imidazole
H
CONH2
0.18
0.77
0.18
0.18
0.55
0.27
1.3
<0.046
0.38
ND
21.0
15
<0.04
1.5
<0.04
0.26
ND
2.1
<0.046
0.71
ND
2.9
2.8
ND
CONHMe
CONMe2
3.7
2.2
1.7
3.5
CONH-cyclopropyl
CONH-cyclopentyl
CONH-cyclohexyl
N
93
8.1
3.5
10
1.6
11
9.8
0.48
1.3
2.5
59
6.6
34
35
0.093
0.054
53
10
91
67
17
35
N
N
4.7
4.3
N
H
N
36
37
0.046
0.068
11
20
47
5.1
8.5
13
16
15
N
H
N
100
N
H
NH
38
39
0.17
0.14
25
76
3.9
2.0
N
H
N
5.8
7.8
0.36
N
H
a IC50 values represent the average of two determinations. Standard deviations ranged from 0.03 to 0.26.
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these results to identify compounds with superior
ADME properties for further in vivo evaluation.
Acknowledgment
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mixture was in a total volume of 50 ll and contained
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