Balancing oral exposure with Cyp3A4 inhibition in benzimidazole-based IGF-IR inhibitors

Article abstract of DOI:10.1016/j.bmcl.2008.05.104

3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1 Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of malonate as methyl anion synthon via S_NAr reaction and double decarboxylation under mild conditions is demonstrated.

Full text of DOI:10.1016/j.bmcl.2008.05.104

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4075–4080
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Balancing oral exposure with Cyp3A4 inhibition in benzimidazole-based
IGF-IR inhibitors
a
a
a
a
Kurt Zimmermann a, , Mark D. Wittman , Mark G. Saulnier , Upender Velaparthi , David R. Langley ,
Xiaopeng Sang a, David Frennesson a, Joan Carboni b, Aixin Li b, Ann Greer b, Marco Gottardis b,
Ricardo M. Attar b, Zheng Yang b, Praveen Balimane b, Lorell N. Discenza b, Dolatrai Vyas a
*
a Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, USA
b Bristol-Myers Squibb Co., Province Lane, Princeton, NJ 08540, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1
Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of
malonate as methyl anion synthon via SNAr reaction and double decarboxylation under mild conditions
is demonstrated.
Received 5 February 2008
Revised 23 May 2008
Accepted 27 May 2008
Available online 21 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
IGF-IR inhibitor
Cyp3A4
Cytochrome 3A4
Oral exposure
Oral bioavailability
Malonate
Methyl anion synthon
SNAr reaction
Decarboxylation
pKa
The Insulin-like Growth Factor-1 (IGF-I) receptor1,2 (IGF-IR) is a
member of the receptor tyrosine kinase family. Signaling through
IGF-IR kinase results in activation of both the RAS/Raf/MAP Kinase
pathway, which is primarily responsible for mitogenesis, the PI-3/
Akt kinase pathway, which has an anti-apoptotic role.1–3 Inhibition
of both of these pathways makes IGF-IR kinase a promising target
for cancer therapy. Epidemiological studies have also highlighted
the importance of IGF-IR signaling in major tumor types by corre-
lating elevated IGF-I levels with increased risk of developing colon,
breast, prostate, and lung tumors.4–8 Recent publications report
pyrrolo-pyrimidines,9 tryphostine analogs,10 picropodophylin,11
and 3-(benzimidazol-2-yl)-pyridine-2-ones3,12–16 to have IGF-IR
inhibitory and anti-tumor activity in animal models.
imidazole chemotype with reduced Cyp inhibition, balanced with
high oral exposure.
Cocrystallization of a number of inhibitors from this class with a
truncated IGF-IR protein containing the kinase domain revealed
that the ‘top left part’ of the molecule (morpholine in 1) is solvent
exposed and therefore offers an opportunity to optimize the phar-
macokinetic properties and reduce Cyp inhibition, without much
influence on kinase potency.12
Replacement of the morpholine of
1 with bioisosteres
(4-hydroxypiperidine 2, alkoxypiperidines 3, 4 and 5, piperidin-
4-one spiroketal 6) resulted in potent IGF-IR kinase inhibitors but
little improvement with respect to Cyp3A4 inhibition (see Table
1). The 4-amino-piperidines ( 7, 8, and 9) stood out with their
5- to 10-fold reduced Cyp3A4 inhibition, compared to 1 (Table 1),
but their oral exposure is extremely low.
Replacing these basic amines with amides or carbamates (10
and 11) resulted in compounds with significantly increased oral
exposure and improved cell potency, higher predicted logD6.5 val-
ues (Table 1), but stronger Cyp3A4 inhibition.
Initial results from our laboratories resulted in the discovery of
morpholino-benzimidazole 1, a potent IGF-IR kinase inhibitor, but
also a strong Cyp3A4 inhibitor (see Table 1).12,13 In this letter, we
report the discovery of several compounds within the same benz-
* Corresponding author. Tel.: +1 203 6777236; fax: +1 203 6777702.
E-mail addresses: Kurt.Zimmermann@bms.com , kzimmermann12@comcast.net
(K. Zimmermann).
Among these early compounds, examples 1–11, we observed a
good correlation between calculated logD (at pH 6.5) and Cyp3A4
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.104

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K. Zimmermann et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4075–4080
Table 1
Kinase inhibition IC50s of compounds 1–25, selected PK data and calculated physical properties
R1
IGF-IRa (nM)
IGF-IR Salb (nM)
Cyp3A4c
0.5
(l
M)
AUCd
51
(l
Mh)
pKa
logDf (6.5)
e
Compound
1
100
110
1.72
N
O
2
3
4
5
6
7
8
9
29
220
150
45
79
155
99
0.4
1
0.5
4.5
1.48
2.12
HO
O
N
N
0.9
1.3
0.7
2.6
3.9
4.5
1.76
O
O
N
55
6.9
18.5
0
1.4
HO
O
N
O
75
121
108
92
1.92
N
O
14
10.26
9.34
ꢀ1.19
ꢀ0.35
0.01
N
HN
33
0.2
0
N
N
27
107
10.27
N
N
HN
O
N
10
11
12
13
14
15
50
69
39
45
49
29
66
39
0.7
0.5
1
7.4
29
1.51
2.08
HN
N
O
O
N
N
O
80
0
7.6
ꢀ0.49
0.76
O
108
83
4.1
3.1
0.5
3.3
6.9
0.5
7.69
7.76
9.27
N
N
N
N
O
O
O
1.67
N
N
86
ꢀ0.78
16
17
18
28
32
12
88
105
145
2.4
0.8
5.6
0
7.66
5.22
ꢀ0.08
1.65
N
N
N
O
0.6
1.4
5.79
5.49
N
N
N
O
1.57
N
N
O
N
O
O
O
19
20
40
193
139
3.0
1.7
2.6
4.5
5.47
5.72
1.51
2.04
N
N
N
O
N
N
N
100
O
O
21
82
77
3.5
11.3
5.67
2.33
N
N
N

K. Zimmermann et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4075–4080
4077
Table 1 (continued)
e
Compound
R1
IGF-IRa (nM)
100
IGF-IR Salb (nM)
115
Cyp3A4c
2.4
(l
M)
AUCd
10.2
(
lM h)
pKa
logDf (6.5)
O
O
22
5.59
5.56
2.36
N
N
N
O
O
23
24
37
9
130
99
1.8
3.9
1.1
1.73
1.33
N
N
N
HO
O
O
N
N
N
N
N
19
6.32
O
N
O
N
N
N
25
16
151
40
1.1
6.78
6.24
1.31
a
IGF-IR kinase IC50
.
b
c
Cellular IC50, measured via thymidine incorporation.
Cyp3A4 inhibition, 7-Benzyloxy-4-trifluoromethylcoumarin was used as probe molecule.
Area under the curve for plasma concentration of compound versus time, interval 0–4 h, after oral administration of 20 mg/kg to mice.
pKa is the predicted pKa value for the amine-nitrogen within R1, calculated for R1-phenyl as a simplified model. pKa values were calculated using ACD/pKa calculator,
d
e
version 8.0, Advanced Chemistry Development, Inc., Toronto ON, Canada, www.acdlabs.com, 2003.
f
LogD(6.5) values were calculated using ACD/LogD Sol Suite, version 7.0, Advanced Chemistry Development, Inc., Toronto ON, Canada, www.acdlabs.com, 2003.
inhibition, with more polar compounds showing less Cyp inhibi-
tion. Oral exposure also followed a good correlation with logD,
more polar compounds having lower oral exposure. Differences
in rate of metabolism cannot explain the higher oral exposure of
more lipophilic compounds, since these displayed comparable or
even higher rates of metabolism in mouse liver microsomes.17 In
an attempt to balance these two contrary trends we focused on
moderating the pKa of the amine-nitrogen of this type of 4-ami-
no-piperidine compounds. b-Electron-withdrawing substituents
are known to reduce the basicity of alkylamines.18 Bis-methoxy-
ethyl amine 12 had good IGF-IR potency, somewhat reduced Cyp
23), and ureas (24 and 25) all have less basic central nitrogens
(pKa ꢁ5.5–6.3) and favorable moderate polarity (logD between
1.5 and 2.5). The carbamates (21, 22, and 23) combine potent
IGF-IR kinase inhibition, acceptable oral exposure, and reduced
Cyp3A4 inhibition.
In conclusion, the current study demonstrates that oral bio-
availability and Cyp3A4 inhibition of 3-(benzimidazol-2-yl)-pyri-
dine-2-one-based IGF-IR kinase inhibitors can be balanced by
careful tuning of the polarity and basicity of the C5 substituent,
although not separated. These compounds are (within the experi-
mental limits) equipotent against IGF-IR and the Insulin Receptor
Kinase (IR).19 Further lead optimization efforts, including work to-
ward compounds with improved selectivity against a wide variety
of kinases, together with in-vivo data, will be subject of future
disclosures.
An ideal synthesis for the series of compounds depicted in Table 1
would build up the core and right side of the molecule first and intro-
duce diversity on the left side late in the synthesis. Attempts to carry
a bromide (R1 = Br in Fig. 1) through the synthesis to introduce var-
ious amines late in the synthesis failed. Buchwald reactions of 4-bro-
mo-2-methyl-6-nitro-aniline with 4-substituted piperidines
required separate optimization for every amine and gave unsatisfac-
tory results, especially on scale-up.12,20 Therefore we turned to the
sequence shown in Scheme 1, three consecutive SNAr reactions on
commercially available 2,4,6-trifluoronitrobenzene 26.
Trifluoronitrobenzene reacts with deprotonated malonate es-
ters to give selectively the mono-ortho-substitution product 27
(ortho:para selectivity ꢁ10:1, <5% bis-substitution). Treatment of
27 with an excess of ammonia in MeOH results in selective
replacement of the other ortho-fluoride to give nitroaniline 28 in
80% yield over two steps. HCl-catalyzed hydrolysis of the bis-
tert-butyl ester and mono-decarboxylation result in formation of
acid 29. The key step of the sequence shown in Scheme 1 is the sec-
ond decarboxylation from 29 to 30. We observed no conversion
under the conditions reported by Toussaint21 (0.1 equiv Cu2O,
50 °C in CH3CN). For our substrate this transformation required
2 equiv Cu2O and 12 h refluxing in CH3CN. Under these more forc-
inhibition (IC50 = 1.0 lM) but no oral exposure. It is known in the
literature that the number of freely rotating bonds correlates inver-
sely with oral bioavailability. Cyclizing (formally) the two meth-
oxy-ethyl chains to a morpholine resulted in compound 13,
which has the same b-oxy-amine substructure as 12 and compara-
ble basicity, but fewer freely rotating bonds. This compound has
good potency (IC50 = 45 nM), reduced Cyp inhibition (Cyp3A4
IC50 = 4.1 lM) and improved oral exposure. Increasing logD by
introduction of methyl substituents on the morpholine (e.g., 14)
only slightly improved oral exposure.
The addition of a methano-bridge over the morpholine results
in a significantly more basic amine 15, similar to the dimethyl
amine 8. This is due to a reduction of the above-mentioned b-oxy-
gen effect because of unfavorable orbital geometry. This increased
basicity (relative to 13) is reflected in a lower calculated logD
(
D
logD6.5 = 1.54) and lower oral exposure (ꢁ6-fold, see Table 1).
For this example Cyp3A4 inhibition does not follow the general
trend. Replacing the morpholino-piperidine substructure with
piperazino-piperidines results in compounds (e.g., 16) with an
additional basic-nitrogen atom, consequently a significantly lower
calculated logD (ꢁ0.0), and (as predicted) low Cyp3A4 inhibition,
and very low oral exposure.
Acylating the piperazine moiety (17 vs 16) not only turns an
amine-nitrogen into a non-basic moiety, but it also reduces,
through an inductive effect, the basicity of the remaining central
amine. Thus, amides (17, 18, 19, and 20), carbamates (21, 22, and

4078
K. Zimmermann et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4075–4080
hydrogenated (Pd/C, 50 psi) to form the highly air-sensitive
O
H
N
R1
NH
ortho-diamines, which were immediately condensed with 4-iodo-
2-methoxy-pyridine-3-carbaldehyde 3322 to give benzimidazoles
34a–f in good yields (Scheme 3).
N
HN
Treatment of benzimidazoles 34a–f with aq HCl in dioxane re-
sults in hydrolysis of the methoxy-pyridine to the corresponding
iodo-pyridone35a–f, withpartialexchangeofI withCl(andcleavage
of the BOC-protecting group in case of 35f). It is noteworthy that the
spiroketal functionality in 35e is not cleaved by these conditions.23
Addition/elimination reaction with an excess of amino alcohol
3612 gives products 3, 4, 5, 6, and 7. The primary amine 37 can be
made directly from 35f, but is contaminated with self-condensation
product. We got better results by BOC-protecting 35f to 35f0, then
performing the SNAr reaction and cleaving BOC again afterward.
Reductive amination of amine 37 with formaldehyde or 2-methoxy-
acetaldehyde24 forms 8 and 12. Acylation of amine 37 with cyclopro-
HO
Cl
Figure 1. General structure of compounds 1–25.
F
F
F
F
F
NH2
NO2
NO2
NO2
O
a
b
F
O
O
O
R
R
R
F
R
O
O
O
28
O
R1
26
27
R= -Bu
N
R2
t
O
H
N
a,b
H
N
NH
NH2
NO2
F
NH2
NO2
6
N
HN
N
R1 R2
HO
d
c
HO
O
29
30
7, 9, 13-16
Cl
Scheme 1. Reagents and conditions: (a) NaH, DMF, bis-tert-butyl-malonate,
0–20 °C; (b) NH3/MeOH, 85 °C, pressure flask, 80%; (c) 1 N HCl, dioxane, 40 °C;
(d) Cu2O, CH3CN, reflux 12 h, 80%.
R1NHR2
CH3NH2
R1NHR2
NH
NH
7
9
ing conditions yields were generally >80%. This result indicates
that this transformation may have broader application than origi-
nally realized and may represent a versatile strategy to introducing
a methyl group onto electron-rich, neutral, and electron-poor aro-
matic rings (Scheme 2).
Fluoro-nitro compound 30 reacts with amines 31a–f to give
compounds 32. Following the same synthetic sequence as de-
scribed in our earlier publication12 the nitroanilines 32 were
O
NH
NH
O
13
15
14
16
O
N
NH
Scheme 3. Reagents and conditions: (a) acetone, aq HCl, 18 h reflux; (b) amine,
ZnCl2, NaCNBH3, MeOH, 20 °C, ꢁ70%.
R'
O
R'
R
R'
R
N
R
O
I
F
NH2
NO2
H
N
NH
31a-f
N
N
O
N
NH2
NO2
I
33
N
g
i
h
30
32a-f
34a-f
R'
R
O
H
N
R'
R
N
NH
8 R,R' = H,(CH3)2N
m
O
X
H
N
j
N
N
NH
HN
+
NH3 Cl-
n
10 R,R' = H,c-C3H5CONH
N
37
HO
HO
o
36
X=Cl, I
35a-f
Cl
11 R,R' = H,CH3OCONH
p
a R,R' = H,CH3O
3 R,R' = H,HO
Cl
b R,R' = H,CH3OCH2CH2O
c R,R' = H,HOCH2CH2O
d R,R' = H,HO
4 R,R' = H,CH3O
12 R,R' = H,(CH3OCH2CH2)2N
5 R,R' = H,CH3OCH2CH2O
6 R,R' = H,HOCH2CH2O
7 R,R' = OCH2CH2O
37 R,R' = H,NH2
e R,R' = OCH2CH2O
f R,R' = H, NH2
f' R,R' = H, NHBOC
k
l
38 R,R' = H,NHBOC
Scheme 2. Reagents and conditions: (g) Huenig’s base, DMSO, 80 °C, 15 h, 80%; (h) H2/Pd/C, 50 psi, 16 h; then 33; air, 20 °C, 63%; (i) aq HCl, dioxane, 3 h, 70 °C; (j) 36, Huenig’s
base, CH3CN, 80 °C 16 h, 50–80%; (k) BOC2O, Huenig’s base, CH2Cl2, 20 °C; (l) CF3COOH, CH2Cl2, 20 °C; (m) aq H2CO, NaCNBH3, HC(OCH3)3, HOAc, 20 °C; (n) c-C3H5COCl,
Huenig’s base, MeOH, 0–20 °C; (o) CH3OCOCl, Huenig’s base, MeOH, 20 °C; (p) aq HCl, acetone, 1,1,2-trimethoxyethane, 5 min 80 °C; then 37, NaCNBH3, HC(OCH3)3, NaOAc,
20 °C.

K. Zimmermann et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4075–4080
4079
Boc
Bo
c
O
N
N
N
N
O
I
O
H
N
O
I
O
X
H
N
H
N
N
a,b
c,d
N
N
N
N
N
NH
N
N
N
34e
39
40
X=Cl , I
17 : R = CH3
18 : R = CH3 OCH2
19 : R = CH3 OCH2 CH2 OCH 2
20 : R =
O
HN
R
N
N
O
O
H
N
H
N
N
N
NH
NH
g
e,f
21: R = CH3O
N
N
36
HN
HN
O
22: R =
23: R =
24: R =
25: R =
O
41
17-25
HO
HO
HO
O
Cl
Cl
O
N
N
N
Scheme 4. Reagents and conditions: (a) acetone, aq HCl, 18 h reflux; (b) N-BOC-piperazine, ZnCl2, NaCNBH3, 20 °C, 80%; (c) aq HCl, dioxane, 1 h, 85 °C; (d) BOC2O, Huenig’s
base, CH2Cl2, 20 °C; (e) 36, Huenig’s base, CH3CN, 80 °C 16 h, 50%, three steps; (f) CF3COOH, CH2Cl2, 20 °C; (g) RCOCl or (RCO)2O, Huenig’s base, MeOH, 0–20 °C, ꢁ80%.
the references cited therein; (c) Yee, D. Br. J. Cancer 2006, 94, 465. and the
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2. (a) Garcia-Echeverria, C. Small-molecule Receptor Tyrosine Kinase Inhibitors in
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of 10 and 11. This order of steps was advantageous to introduce
diversity late in the synthesis. For selective syntheses of any one of
these compounds we got better results by reversing the order of
steps, performing the acylation or reductive amination first, fol-
lowed by the addition/elimination reaction.
Hydrolysis of the ketal 6 to the corresponding ketone can be
achieved using HCl/acetone. This ketone exists as a mixture with
its hydrate or—when isolated from MeOH—methyl-hemiketal.
Reductive amination with methylamine or cyclic secondary amines
yields products 7, 9, and 13-16.
Selective hydrolysis of the spiroketal functionality of 34e (via
transketalization) is accomplished using HCl/acetone. Reductive
amination of this ketone with mono-N-BOC-protected piperazine
leads to 39. Treatment with aq HCl/dioxane hydrolyzes the
methoxypyridine, followed by BOC re-protection to give 40. Addi-
tion of amino alcohol 36,12 followed by deprotection gives 41. Final
acylation with acid chlorides, anhydrides or chloroformates gives
access to products 17–25. To generate hydroxyethyl-carbamate
23 we treated commercially available mono-THP-protected ethyl-
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MeOH. This order of synthetic transformations allowed us to intro-
duce diversity at the last step. For selective syntheses of any one of
these compounds 17–25 a modified synthetic sequence, deprotec-
tion of 39, followed by acylation, then SNAr reaction (steps c then g
then e in Scheme 4) is two steps shorter.
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Acknowledgments
13. (a) Wittman, M. D.; Balasubramanian, N.; Velaparthi, U.; Zimmermann, K.;
Saulnier, M. G.; Liu, P.; Sang, X.; Frennesson, D. B.; Stoffan, K. M.; Tarrant, J. G.;
WO 2002/079192 A1.; (b) Wittman M. D.; Balasubramanian N.; Velaparthi U.;
Zimmermann K.; Saulnier M. G.; Liu P.; Sang X.; Frennesson D. B.; Stoffan K. M.;
Tarrant J. G.; Marinier A.; Roy S.; WO 2004/031401 A2.
14. Velaparthi, U.; Liu, P.; Balasubramanian, B.; Carboni, J.; Attar, R.; Gottardis, M.;
Li, A.; Greer, A.; Zoeckler, M.; Wittman, M. D.; Vyas, D. Bioorg. Med. Chem. Lett.
2007, 17, 3072.
15. Velaparthi, U.; Wittman, M.; Liu, P.; Stoffan, K.; Zimmermann, K.; Sang, X.;
Carboni, J.; Li, A.; Attar, R.; Gottardis, M.; Greer, A.; Chang, C. Y.; Jacobsen, B. L.;
Sack, J. S.; Sun, Y.; Langley, D. R.; Balasubramanian, B.; Vyas, D. Bioorg. Med.
Chem. Lett. 2007, 17, 2317.
The authors thank Prof. Erick Carreira for chemistry suggestions
and the lead profiling and preclinical candidate optimization
departments at Bristol-Myers Squibb for generating the data pre-
sented in Table 1.
References and notes
1. (a) Foulstone, E.; Prince, S.; Zaccheo, O.; Burns, J. L.; Harper, J.; Jacobs, C.;
Church, D.; Hassan, A. B. J. Pathol. 2005, 205, 145. and the references cited
therein; (b) Larsson, O.; Girnita, A.; Girnita, L. Br. J. Cancer 2005, 92, 2097. and

4080
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16. Wittman, M. D.; Balasubramanian, B.; Stoffan, K.; Velaparthi, U.; Liu, P.;
Krishnanathan, S.; Carboni, J.; Li, A.; Greer, A.; Attar, R.; Gottardis, M.; Chang,
C.; Jacobson, B.; Sun, Y.; Hansel, S.; Zoeckler, M.; Vyas, D. Bioorg. Med. Chem.
Lett. 2007, 17, 974.
19. IGF-IR kinase and IR kinase have an overall 84% sequence identity, but
100% identity of the amino acids lining the ATP-binding cleft:
Fevelyukis, S.; Till, J. H.; Hubbard, S. R.; Miller, W. T. Nat. Struct. Biol.
2001, 8, 1058.
17. Compounds 3 and 5 have high rates of metabolism in mouse liver microsomes
(>0.20 nmol/min/mg). Compounds 1, 2, 4, 6, 10, 11, and 13 have moderate rates
(0.10–0.20 nmol/min/mg), Compounds 7, 8, 9, and 14–25 have low rates
(<0.10 nmol/min/mg). We do not have data for 12.
18. For example: pKa for ethylamine = 10.81, 2-methoxyethylamine = 9.89 Data
from CRC Handbook of Chemistry and Physics; Weast, R. C., Astle, M. J., Beyer, W.
H., Eds., 66th ed.; CRC Press: Boca Raton, FL, 1986.
20. Incomplete conversion even with high catalyst loads, difficult
purifications.
21. Toussaint, O.; Capdevielle, P.; Maumy, M. Tetrahedron 1984, 40, 3229.
22. Fang, F. G.; Xie, S.; Lowery, M. W. J. Org. Chem. 1994, 59, 6142.
23. It is possible that the spiroketal re-forms upon evaporation of volatiles out of
the acidic crude reaction mixture.
24. From 1,1,2-trimethoxyethane by heating to 80 °C in aq HCl for 5 min.