Novel 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase

Article abstract of DOI:10.1016/j.bmcl.2006.11.041

A novel class of 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase is described. This report discusses the SAR of 4-(2-hydroxy-2-phenylethylamino)-substituted pyridones with improved IGF-1R potency.

Full text of DOI:10.1016/j.bmcl.2006.11.041

Bioorganic & Medicinal Chemistry Letters 17 (2007) 974–977
Novel 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors
of insulin-like growth factor I (IGF-1R) kinase
Mark D. Wittman,a,* Balu Balasubramanian,a Karen Stoffan,a Upender Velaparthi,a
Pieying Liu,a Subramaniam Krishnanathan,b Joan Carboni,c Aixin Li,c Ann Greer,c
Ricardo Attar,c Marco Gottardis,c Chiehying Chang,d Bruce Jacobson,d Yax Sun,e
Steven Hansel,f Mary Zoecklerf and Dolatrai M. Vyasa
aDepartment of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5100, Wallingford,
CT 06492-7660, USA
bDepartment of Chemical Synthesis, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5100, Wallingford,
CT 06492-7660, USA
cDepartment of Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000,
Princeton, NJ 08543-4000, USA
dDepartment of Macromolecular Structure, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000,
Princeton, NJ 08543-4000, USA
eDepartment of Computer Aided Drug Design, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5100,
Wallingford, CT 06492-7660, USA
fDepartment of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute,
PO Box 5100, Wallingford, CT 06492-7660, USA
Received 23 October 2006; revised 9 November 2006; accepted 13 November 2006
Available online 17 November 2006
Abstract—A novel class of 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase is
described. This report discusses the SAR of 4-(2-hydroxy-2-phenylethylamino)-substituted pyridones with improved IGF-1R
potency.
Ó 2006 Elsevier Ltd. All rights reserved.
Considerable attention has been focused on understand-
ing the role of insulin-like growth factor I receptor
(IGF-1R) signaling in stimulating mitogenesis, transfor-
mation to the oncogenic phenotype, and the anti-apop-
totic effects observed in malignant cells.1 Binding of the
ligands IGF-I and/or IGF-II to the extracellular domain
of the receptor leads to receptor autophosphorylation
and activation of the intrinsic kinase activity present in
the cytoplasmic domain of the receptor. Activation
of the kinase activity results in the phosphorylation of
the downstream signaling molecules IRS-1 and IRS-2
which in turn activates the mitogenic RAS/Raf/MAPK
and PI-3/Akt survival signaling cascades.2,3 The current
level of interest in finding kinase inhibitors of IGF-1R
stems from the expectation that such inhibitors would
block signaling through both the mitogenic an anti-ap-
optotic pathways. From a clinical perspective, epidemi-
ological studies have correlated elevated IGF-I levels
with an increased risk of developing colon, breast, pros-
tate, and lung tumors.4–8A significant challenge in devel-
oping ATP-competitive inhibitors of IGF-1R kinase is
building in selectivity over the related insulin receptor
(IR) due to the high sequence homology (84%) between
these two receptors and the fact that the residues which
contact ATP are identical.9 Not surprisingly, no kinase
selectivity over IR was observed for the inhibitors within
the 1H-(benzimidazol-2-yl)-1H-pyridin-2-one series.
This paper describes SAR that contributed to the iden-
tification of BMS-536924, an inhibitor of IGF-1R ki-
nase with broad-spectrum in vivo activity.10
Keywords: Insulin-like growth factor; IGF-1R; Inhibitor; Kinase; ATP
competitive; Benzimidazole; 4-Aminopyridone; Substituted 2-hydroxy-
2-phenyl-aminoethanol.
*
Corresponding author. Tel.: +1 203 677 6318; fax: +1 203 677
7702; e-mail: mark.wittman@bms.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.11.041

M. D. Wittman et al. / Bioorg. Med. Chem. Lett. 17 (2007) 974–977
975
Results and discussion: In the course of exploring the
SAR of the initial lead (1), we identified the chromen-
4-one (2) as a sub-micromolar inhibitor of IGF-1R.
Crystallization of this inhibitor with the kinase domain
of IGF-1R revealed potential new interactions to ex-
plore via the 4-position of the pyridone ring. Figure 1
shows the overlay of the crystal structures of (1) and
(2), each bound to IGF-1R (the structure of IGF-1R
has been removed for clarity). The key features of the
binding of (2) with IGF-1R are the hydrogen bond do-
nor/acceptor diad across the top of the molecule with
extension of the benzyl piperidine into the unfilled re-
gion corresponding to the 4-position of pyridine (1).
This observation prompted an exploration of the effect
of substituents at the 4-position of the pyridone ring.
Using chemistry originally described by Curran11a and
Fang11b in the course of their campothecin work, the
4-iodopyridone (7) was prepared according to Scheme
1. Starting from the commercially available 5-fluoro-2-
nitro-toluene (3), SNAr addition of imidazole followed
by catalytic reduction provided aniline (4). Acylation
and ortho-nitration provided (5). De-acetylation fol-
lowed by reduction of the nitro group provided the req-
uisite diamine for condensation with the known
iodopyridine aldehyde to provide benzimidazole (6). It
is interesting to note that the benzimidazole formation
occurs without the need for additional oxidant. Addi-
tion of oxidants such as iodine did not improve the yield
of the benzimidazole. Cleavage of the methoxy group
under acidic conditions provided the 4-iodopyridone
(7). Addition of excess amine to pyridone (7) provided
analogs (8–33).
Scheme 1. Reagents and conditions: (a) KOH, DMSO, imidazole
(95%); (b) Pd–C, EtOH, cyclohexene, reflux (quant); (c) TFAA,
pyridine, DMAP; H2SO4/HNO3 (50:50) (70%); (d) EtOH, KOH (72%);
(e) Pd–C, EtOH, HOAc, H2 then 4-iodo-3-formyl-2-methoxy-pyridine,
MeOH (61%) open to air; (f) 1 N HCl 70 °C (63%); (g) amine, DMF,
80 °C.
The racemic amino alcohols used in this study were pre-
pared according to Scheme 2. Optimally, the aldehyde
was condensed with nitromethane12 and the resulting
nitroaldol adduct trapped as the TES ether (34). Reduc-
tion of the nitro group followed by cleavage of the TES
Scheme 2. Reagents and conditions: (a) CH3NO2, EtOH, 2% HOAc,
10% NaOH; TESCl, imidazole, CH2Cl2; (b) Raney nickel, H2,
methanol; Bu4NF, THF; (c) S-CBS methyl oxazaborolidine
(0.02 equiv); BH3ÆTHF, THF; (d) 7 M NH3 in methanol (recrystallized
from EtOAc/ethanol).
a
Table 1. SAR of 4-aminopyridone analogs
a
Compound
R
IGF-1R IC50 (lM)
1
8
H
3.50
3.00
3.05
NHCH2CH2OH
NHCH2CH2–Ph
b
9
10
(R/S) NHCH2CH(OH)–Ph 0.72
a IC50 values were determined using 125 ng of baculovirus-expressed
enzyme, 2.5 lg of poly(Glu/Tyr), 25 lM of ATP, and 0.1 lCi of
[c-33P]ATP.
ether afforded the desired amino alcohol (35). The (R)
and (S) enantiomers were prepared using a sequence in
which the a-chloromethyl ketone (36)13 was reduced
with Corey’s CBS oxazaborolidine catalyst.14 Reduc-
tions to the chlorohydrin typically proceeded in high
yield and >95% ee. Treatment of the chlorohydrin (37)
with excess 7 M NH3 in methanol provided the hydro-
chloride salt (38) directly which could be recrystallized
to high enantiomeric purity (>99% ee).15a
Figure 1.

976
M. D. Wittman et al. / Bioorg. Med. Chem. Lett. 17 (2007) 974–977
The addition of amines to the 4-iodopyridone via an
addition/elimination sequence provided a straightfor-
ward means to explore a wide range of chemical diversi-
ty at this position. The addition of secondary amines
and anilines provided compounds devoid of IGF-1R
activity. In contrast, the addition of primary amines
did provide compounds with IGF-1R inhibitory activi-
ty. A key breakthrough was realized when the ethanol
amine (8) and phenyl ethylamine (9) elements were com-
bined in the 2-hydroxy-2-phenylethylamine (10). Each
of these elements alone did not provide a significant
improvement in potency over R = H (1) but together
provided sub-micromolar IGF-1R inhibitory activity
(Table 1).
(16) may be the result of a hydrogen-bond in the active
site. This would be consistent with the observed loss in
potency of the methoxy derivative (21). The combina-
tion of a 3-halogen with a 4-substituent also provided
an improvement in IGF-1R potency. Optimal substitu-
ents were the 4-fluoro group (27) and the 4-methoxy
group (28). Increasing the size of the 4-methoxy group
to an n-propoxy (29) resulted in a significant loss of
activity. Methylation of the secondary hydroxyl group
(30 vs 14) resulted in a loss of potency as did steric
shielding of the hydroxyl group with the addition of a
benzylic methyl group (31 vs 15).
Compounds with in vitro kinase potency were tested for
their effect on cellular proliferation in the engineered cell
line IGF-1R Sal.16 This cell line overexpresses a consti-
tutively activated IGF-1R receptor and is particularly
sensitive to IGF-1R inhibitors. Halogen or alkyl substi-
tution gave compounds (13, 14, 19, 28) with the most
potent cell-based effects, with 3-substituted derivatives
being preferred (13, 14, 19). Compounds with polar sub-
stituents tended to show a decrease in cell potency (17,
18). The optimal cell activity was observed with the
With the identification of 2-hydroxy-2-phenylethyl-
amine (10), a focused exploration of the SAR of the aryl
ring was initiated. Scanning the various positions on the
aromatic group revealed that meta-substitution was
optimal. Introduction of methyl, electron-donating,
and electron-withdrawing meta-substituents indicated
that halogen or hydroxyl substitution was preferred
(13–16). The potency observed for the hydroxyl analog
Table 2. SAR of phenylethylamine analogs 8–33
a
b
Compound
R
Z
IGF-1R IC50 (lM)
IGF-1R Sal IC50 (lM)
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
2-Cl
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OH(R/S)
OMe(R/S)
Me, OH(R/S)
OH(S)
0.80
1.59
0.52
0.18
0.14
0.19
0.24
0.30
0.34
0.53
0.71
1.20
0.35
0.52
0.25
0.47
0.16
0.15
>25
3.63
0.79
0.14
0.83
2-NHSO2CH3
3-F
3-Cl
0.47
0.37
3-Br
3-OH
3-CN
1.64
3.63
0.42
0.78
0.78
3-NHSO2CH3
3-CH3
3-CF3
3-OCH3
4-NHSO2CH3
4-CH3
0.75
0.61
4-OCH3
3,5-Cl
3,4-Cl
1.27
0.76
0.54
3-Cl–4-F
3-Cl–4-OMe
3-Cl–4-O-n-Pr
3-Cl
3-Br
3-Cl
1.79
0.19
0.44
3-Cl
OH(R)
a IC50 values represent the average of two determinations using 125 ng of baculovirus-expressed enzyme, 2.5 lg of poly(Glu/Tyr), 25 lM of ATP, and
0.1 lCi of [c-33P]ATP. Standard deviations ranged from 0.01 to 0.17.
b The effect on cell proliferation was measured in the engineered cell line IGF-1R Sal16 and was determined using thymidine incorporation.

M. D. Wittman et al. / Bioorg. Med. Chem. Lett. 17 (2007) 974–977
977
4. Ma, J.; Pollak, M. N.; Giovannucci, E.; Chan, J. M.; Tao,
Y.; Hennekens, C. H.; Stampfer, M. J. J. Natl. Cancer
Inst. 1999, 91, 620.
5. (a) Hankinson, S. E.; Willett, W. C.; Colditz, G. A.;
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Table 3. Oral exposure
Compound
R
Z
AUC 0–4 h lM ha
14
15
32
33
3-Cl
3-Br
3-Cl
3-Cl
OH(R/S)
OH(R/S)
OH(S)
43
5
124
25
OH(R)
a AUC was determined after dosing three mice 20 mpk of compound in
80:20 PEG400 water solution. Time points were taken at 1 and 4 h.
AUC are in lM h for 0–4 h.
6. Chan, J. M.; Stampfer, M. J.; Giovannucci, E.; Gann, P.
H.; Ma, J.; Wilkinson, P.; Hennekens, C. H.; Pollak, M.
Science 1998, 279, 563.
3-Cl derivative (14). The enantiomers of this derivative
were resolved chromatographically. The (S) enantiomer
(32) was more potent than the corresponding (R) enan-
tiomer (33) in both the in vitro kinase assay and against
the IGF-1R Sal cell line (Table 2).
7. Wolk, A.; Mantzoros, C. S.; Andersson, S. O.;
Bergstrom, R.; Signorello, L. B.; Lagiou, P.; Adami,
H. O.; Trichopoulos, D. J. Natl. Cancer Inst. 1998,
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9. Favelyukis, S.; Till, J. H.; Hubbard, S. R.; Miller, W. T.
Nat. Struct. Biol. 2001, 8, 1058.
Evaluation of the oral exposure of compounds (14) and
(15) revealed that the 3-chloro (14) had significantly better
exposure than the more potent 3-bromo derivative (15).
The (S) enantiomer (32) maintained the good exposure
observed with the racemate, while the less active (R) enan-
tiomer (33) had significantly lower exposure. While the
potency and oral exposure of compound 32 were very
promising, this compound was not active in the IGF-Sal
in vivo tumor model16 most likely due to high protein
binding (>99%). Further improvements in cellular poten-
cy did lead to compounds with in vivo activity10 (Table 3).
10. Wittman, M.; Carboni, J.; Attar, R.; Balasubramanian,
B.; Balimane, P.; Brassil, P.; Beaulieu, F.; Chang, C.;
Clarke, W.; Dell, J.; Eummer, J.; Frennesson, D.;
Gottardis, M.; Greer, A.; Hansel, S.; Hurlburt, W.;
Jacobson, B.; Krishnananthan, S.; Lee, F. Y.; Li, A.;
Lin, T.-A.; Liu, P.; Ouellet, C.; Sang, X.; Saulnier, M. G.;
Stoffan, K.; Sun, Y.; Velaparthi, U.; Wong, H.; Yang, Z.;
Zimmermann, K.; Zoeckler, M.; Vyas, D. J. Med. Chem.
2005, 48, 5639.
11. (a) Gabarda, A. E.; Du, W.; Isarno, T.; Tangirala, R. S.;
Raghuram, S.; Curran, D. P. Tetrahedron 2002, 58, 6329;
(b) Fang, F. G.; Xie, S.; Lowery, M. W. J. Org. Chem.
1994, 59, 6142.
12. Szczepankiewicz, B. G.; Liu, G.; Jae, H-S.; Tasker, A. S.;
Gunawardana, I. W.; von Geldern, T. W.; Gwaltney, S.
L., II; Wu-Wong, J. R.; Gehrke, L.; Chiou, W. J.; Credo,
R. B.; Alder, J. D.; Nukkala, M. A.; Zielinski, N. A.;
Jarvis, K.; Mollison, K. W.; Frost, D. J.; Bauch, J. L.;
Hui, Y. H.; Claiborne, A. K.; Li, Q.; Rosenberg, S. H.
J. Med. Chem. 2001, 44, 4416.
In summary, the initial screening lead (1) has been opti-
mized for IGF-1R potency, cell potency, and oral expo-
sure via substitution of the 4-position of the pyridone
ring to provide (S)-2-hydroxy-2-(3-Cl-phenyl)-ethyla-
mine analog (32). Future communications will focus
on the replacement of the imidazole ring to reduce pro-
tein binding and optimize ADME and drug safety
parameters.
13. Devocelle, M.; Mortreux, A.; Agbossou, F.; Dormoy, J.-
R. Tetrahedron Lett. 1999, 40, 4551, A modified procedure
was used in which methanol was added to greatly enhance
the yield of the desired a-chloroketone.
Acknowledgment
14. Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem.
1988, 53, 2861.
The authors thank David R. Langley for assistance in
preparing Figure 1.
15. (a) Enantiomeric excess was determined by protecting the
amine as the Boc derivative and analyzed using a chiralcel
OJ column (95% hexane/ethanol); (b) Saulnier, M. G.;
Zimmermann, K.; Struzynski, C. P.; Sang, X.; Velaparthi,
U.; Wittman, M.; Frennesson, D. B. Tetrahedron Lett.
2004, 45, 397.
16. Carboni, J. M.; Lee, A. V.; Hadsell, D. L.; Rowley, B. R.;
Lee, F. Y.; Bol, D. K.; Camuso, A. E.; Gottardis, M.;
Greer, A. F.; Ho, C. P.; Hurlburt, W.; Li, A.; Saulnier, M.;
Velaparthi, U.; Wang, C.; Wen, M.-L.; Westhouse, R. A.;
Wittman, M.; Zimmermann, K.; Rupnow, B. A.; Wong,
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